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The Pennsylvania State University
The Graduate School
Eberly College of Science
TOTAL SYNTHESIS OF THE TETRACYCLIC ANTIMALARIAL
MYRIONEURON ALKALOID (±)-MYRIONEURINOL
A Dissertation in
Chemistry
by
Anthony J. Nocket
© 2015 Anthony J. Nocket
Submitted in Partial Fulfillment
of the Requirements
for the Degree of
Doctor of Philosophy
August 2015
ii
The dissertation of Anthony J. Nocket was reviewed and approved* by the following:
Steven M. Weinreb
Russell and Mildred Marker Professor of
Natural Products Chemistry
Dissertation Advisor
Chair of Committee
Kenneth E. Feldman
Professor of Chemistry
Alexander Radosevich
Assistant Professor of Chemistry
Edward G. Dudley
Associate Professor of Food Science
Tom Mallouk
Evan Pugh Professor of Chemistry, Physics, Biochemistry, and Molecular Biology
Head of the Department of Chemistry
*Signatures are on file in the Graduate School
iii
ABSTRACT
The first total synthesis of the tetracyclic antimalarial alkaloid myrioneurinol (19) in
racemic form has been completed in twenty-seven steps and in 1.8% overall yield from
commercially available materials. The spiranic A/D-ring subunit of the metabolite with the
attendant C5,6-stereocenters was constructed via a highly diastereoselective intramolecular
Michael addition (IMA) of N-Cbz lactam/(E)-α,β-unsaturated ester cyclization precursor 61 to
afford spirocycle 62. After a series of failed attempts to alkylate various ester enolate and
pyrrolidinoenamine derivatives of 62 at C7, an umpolung strategy involving the conjugate addition
of a malonate enolate to the nitrosoalkene intermediate 124, derived from α-chloro-O-
silylaldoxime 122, provided oxime geometric isomers 123a/b. Both of these isomers possessed
the correct C7-stereochemistry for the natural product. Several methods were then explored to
accomplish the pivotal C9,10 carbon-carbon bond formation to construct the B-ring within the cis-
decahydroquinoline (DHQ) scaffold of the alkaloid. These approaches included the unsuccessful
nitrile α-anion/imidate cyclization of precursor 133 and the olefin/lactam Rainier metathesis of N-
sulfonyllactam precursors 156 and 160 to provide tricyclic enesulfonamides 157 and 161,
respectively. Although the latter ring-closing metathesis method was successful, we were unable
to functionalize tricycles 157 and 161 at C9 in order to complete the total synthesis. We were
pleased to discover that an intramolecular allyl silane/N-sulfonyliminium ion variant of the Sakurai
reaction could be utilized to construct the B-ring of the cis-DHQ system, resulting in a single
diastereomer of tricycle 191 with the desired C9,10 relative configuration, which we were able to
elaborate to (±)-myrioneurinol.
iv
TABLE OF CONTENTS
LIST OF FIGURES vii
ACKNOWLEDGEMENTS viii
CHAPTER 1. INTRODUCTION AND BACKGROUND
1.1. Myrioneuron and Nitraria Alkaloids: Typical Structures and a Unified
Biosynthetic Pathway 1
1.2. A Novel Tetracyclic Myrioneuron Alkaloid: (+)-Myrioneurinol 5
1.3. Previous Synthetic Studies toward the Myrioneuron Alkaloids 9
1.4. First Generation Retrosynthesis of (±)-Myrioneurinol 12
1.5. Background on Diastereoselective Intramolecular Michael Additions
(IMAs) and Related Reactions 13
1.6. Preliminary Studies on the IMA Spirocyclization toward Myrioneurinol 17
CHAPTER 2. IMA STRATEGY TO CONSTRUCT A/D-RING SUBUNIT
2.1. ‘Soft’ Enolization Inspired by Evans, et al. 19
2.2. First Generation Route to N-Cbz Lactam Cyclization Precursor 20
2.3. Attempted ‘Soft’ IMA of Lactam Enoate 61 21
2.4. Determination of the Relative C5,6-Configuration of Spirocycle 62 23
2.5. Second Generation Route to Cyclization Precursor 61 25
2.6. Optimization Studies on the Pivotal IMA Spirocyclization 26
2.7. Exploration of Some Homologous IMA Spirocyclizations 28
2.7.1. Studies with Five-Membered Lactam Analog 74 29
2.7.2. Studies with Seven-Membered Lactam Analog 81 30
2.7.3. Rationalization for Failure of Enoates 74 and 81 to Spirocyclize 31
2.7.4. Modification of the Ester Tether Length 31
2.7.5. Studies with Homologues Pre-Functionalized at C7 33
v
2.8. Attempted Asymmetric IMA Spirocyclization 35
2.8.1. Studies with (-)-Menthyl Carbamate Cyclization Precursor 103 35
2.8.2. Studies with (+)-TCC Ester Cyclization Precursor 107 36
CHAPTER 3: HOMOLOGATION OF A/D-RING SUBUNIT AT C7
3.1. Attempts to Homologate via Formation of C7 Ester Enolates 39
3.2. Attempts to Homologate at C7 via Enamine Chemistry 41
3.2.1. Studies with N-H Lactam (E)-Pyrrolidinoenamine 112 41
3.2.2. Studies with N-Bn Lactam (E)-Pyrrolidinoenamine 116 43
3.3 C7-Homologation via Nitrosoalkene Umpolung Conjugate Addition 44
3.3.1. Background on Nitrosoalkene Conjugate Additions 44
3.3.2. Nitrosoalkene Michael Addition of α-Chloro-O-Silylaldoxime 122 46
3.3.3. Rationalization of Observed C7-Diastereoselectivity 49
CHAPTER 4: B-RING CLOSURE STRATEGIES
4.1. Imidate/Nitrile α-Anion Cyclization Strategy 50
4.1.1. Preparation of Cyclization Precursor 50
4.1.2. Imidate/Nitrile α-Anion Cyclization Studies 52
4.2. Rainier Metathesis Strategy 54
4.2.1. Background on the Rainier Metathesis Reaction 54
4.2.2. Second Generation Retrosynthesis 55
4.2.3. Preparation of N-Tosyllactam/Terminal Olefin Cyclization Precursor 56
4.2.3.1. Lactam Nitrile System 56
4.2.3.2. Methoxymethyl (MOM) Ether System 57
4.2.3.3. Rainier Metathesis of N-Tosyllactam 156 59
4.2.3.4. Attempted Elaboration of N-Ts Enesulfonamide 157 60
4.2.4. N-SES-Lactam System 62
4.3. Allyl Silane/N-Sulfonyliminium Aza-Sakurai Strategy 63
4.3.1. Background: Weinreb Synthesis of the Sarain A Core Structure 63
vi
4.3.2. Third Generation Myrioneurinol Retrosynthesis 66
4.3.3. Preparation of Cyclization Precursor 67
4.3.3.1. Attempted Allyl Silane Formation via Fleming Cuprate
Methodology in Nitrile System 67
4.3.3.2. Attempted Allyl Silane Formation in Methoxymethyl
(MOM) Ether-Protected System 68
4.3.3.3. Seyferth-Wittig Homologation of Aldehyde 182 70
4.3.4. Aza-Sakurai Reaction of N-Tosyllactam/Allyl Silane 189 72
4.3.5. Confirmation of the C9,10 Stereochemistry of Tricycle 191 74
CHAPTER 5: COMPLETION OF THE MYRIONEURINOL SYNTHESIS
5.1. Attempted Elaboration of N-Ts Tricyle 191 76
5.2. Alternative Protecting Groups for the Lactam Nitrogen 78
5.2.1. N-SES-Lactam System 78
5.2.2. N-Nosyllactam System 79
5.2.3. Acid-Labile Sulfonamides 80
5.2.4. Attempted Cyclization of N-Cbz Lactam 82
5.3. N-Tosyllactam System Revisted 82
5.4. Endgame: Closure of the 1,3-Oxazine C-Ring 84
5.5. Concluding Remarks 85
CHAPTER 6: EXPERIMENTAL SECTION 89
REFERENCES 163
vii
LIST OF FIGURES
Figure 1. Structures of Some Representative Myrioneuron Alkaloids 2
Figure 2. Structures of Some Representative Spiranic Nitraria Alkaloids 3
Figure 3. Structure and Conformation of (+)-Myrioneurinol (19) 5
Figure 4. Two-Dimensional NMR Analysis of (+)-Myrioneurinol (19) 6
Figure 5. NOESY Correlations for Tricycle 191 75
viii
ACKNOWLEDGEMENTS
Over the past five and a half years, I have had the great pleasure of pursuing my fascination
with organic chemistry under the guidance of my advisor, Professor Steven M. Weinreb. I credit
my growth as a scientist both to the challenging nature of natural product synthesis itself, and to
the degree of independence and freedom of thought I have gained while working in his laboratory.
Furthermore, I would like to acknowledge the insightful discussions, assistance, and training I
have received from other members of the Weinreb laboratory, both past and present. My most
heartfelt thanks must also be extended to the many wonderful friends I have made during my time
here at Penn State, to whom I owe a great deal of my sanity. Finally, I would be remiss if I did not
acknowledge the unwavering support of my beloved family, to whom I dedicate this dissertation.
Without their constant words of encouragement in the face of the uncertainties and unavoidable
setbacks of research, none of my accomplishments would have been possible.
1
CHAPTER 1: INTRODUCTION AND BACKGROUND
1.1. Myrioneuron and Nitraria Alkaloids: Typical Structures and a Unified Biosynthetic
Pathway
The higher plant genus Myrioneuron (family Rubiaceae) includes approximately fifteen
species distributed across southeast Asia. In recent years, M. nutans, a diminutive tree endemic to
the forests of North Vietnam, has yielded a number of unusual secondary metabolites isolated from
its aerial structures.1 These so-called ‘Myrioneuron alkaloids’ typically contain an array of chair
six-membered rings including a cis-decahydroquinoline (cis-DHQ) moiety tightly fused to various
carbocyclic or heterocyclic structural elements such as 1,3-oxazine and/or 1,3-diazine subunits.
These natural products range in complexity from the simple tricyclic compounds (+)-myrioxazines
A (Figure 1, 1) and B (2)2 to tetracycles such as (-)-schoberine (3) and (+)-myrionamide (4),3
pentacycles such as (+)-myriberine A (5),4 the hexacyclic compound (+)-myrobotinol (6),5 to the
most complex metabolite isolated to date, the dimeric decacycle (+)-myrifabine (7).6 Myrioneuron
alkaloids exhibit a variety of differing types of biological activity. For example, (+)-myriberine A
(5) was reported to effectively inhibit the hepatitis C virus. Moreover, some alkaloids, including
an ester derivative of (+)-myrobotinol (6) as well as (+)-myrifabine (7), have shown promising
cytotoxicity against KB cell lines.
2
N
N
H H
H
HO
H
(+)-myriberine A (5)
R = H2, (-)-schoberine (3)
R = O, (+)-myrionamide (4)
(+)-myrioxazine A (1) (+)-myrioxazine B (2)
Figure 1. Structures of Some Representative Myrioneuron Alkaloids.
N
O
HO
N
(+)-myrobotinol (6)
N
O
H
H
H
N
O
H
H
H
N
N
H
H
H
O
OH
HH
H HH
N
N
H
H
H
R
H
N
H
H
O
H
H
NO
H
H
NN
NN
NH
H
H
H
(+)-myrifabine (7)
Bodo, et al. have suggested that these metabolites all share a common biosynthetic pathway
from L-lysine, despite their structural diversity.1 Even more intriguing is the proposed intersection
of Myrioneuron alkaloid biosynthesis with that of the alkaloids of the somewhat distantly related
higher plant genus Nitraria (family Nitrariaceae) via a common intermediate (vide infra).
The Nitraria species comprise a series of compact shrub-like plants distributed across arid
regions of the Old World that have yielded a wealth of alkaloid natural products with varying types
of biological activity. Representative examples of these metabolites range in complexity from the
simple bicyclic compounds (+)-nitramine (Figure 2, 8)7 and (-)-isonitramine (9),8 to the tricyclic
compound (-)-sibirinine (10),9 and the unusual hexacycle nitraramine (11).10 A common structural
3
feature within these and other Nitraria alkaloids is the presence of a distinctive spirocyclic ring
system.
HN
OH
HN
OH
O N
N H
(+)-nitramine (8) (-)-isonitramine (9)
ONMe
O
(-)-sibirinine (10) nitraramine (11)
Figure 2. Structures of Some Representative Spiranic Nitraria Alkaloids.
NH
N
O
H
The proposed biosynthetic pathway1 for the alkaloids of both the Myrioneuron and Nitraria
genera commences with the decarboxylation of L-lysine (12) to provide cadaverine (13), which is
then oxidatively deaminated to furnish 5-aminopentanal (14) (Scheme 1). Cyclization of 14
provides imine/enamine pair 15a/b, which undergoes further Mannich-aldol and retro-Michael
type transformations via tetrahydroanabasine (16), followed by a second oxidative deamination to
furnish vinylogous imino-aldehyde intermediate 17. It is interesting to note that 16 is also
implicated as a key intermediate in the biosynthesis of the alkaloids of the genus Lupinus (family
Fabaceae).
4
O
O
NH3
NH3
NH3
NH3
oxidativedeamination NH3
O
-H2O
-CO2
HN
N
Mannich-aldol type
HN
HN
H
L-lysine (12) cadaverine (13) 5-aminopentanal (14)
15a
15btetrahydroanabasine (16)
retro-Michael
N
H2N
oxidativedeamination
N
O
17
N[H-]
O
H
HN
O
Mannich spirocyclization
18a 18b
quinolinicMyrioneuron
alkaloids
spiranicNitraria
alkaloids
key imine/enamine tautomeric pair
Scheme 1. A Unified Biosynthetic Pathway to the Myrioneuron and Nitraria Alkaloids from L-lysine (12)
At this juncture, upon partial reduction of the α,β-unsaturated imine moiety in 17 to form
tautomeric pair 18a/b, the biosynthetic pathways within the two genera appear to bifurcate.
Whereas the cis-DHQ system within the Myrioneuron alkaloid scaffold is thought to emerge via
Mannich cyclization of imino-aldehyde tautomer 18a, the simple spiranic Nitraria alkaloids such
as 8 and 9 can arise via spirocyclization of the enamine form 18b. The biosynthetic routes to the
5
more complex members of both the spiranic Nitraria and quinolinic Myrioneuron alkaloid classes
are postulated to involve the incorporation of additional piperidine subunits derived from L-lysine.
1.2. A Novel Tetracyclic Myrioneuron Alkaloid: (+)-Myrioneurinol.
Evidence in favor of the above putative unified metabolic pathway for Myrioneuron and
Nitraria alkaloid biosynthesis had already come in the form of the isolation of (-)-schoberine (3)
from members of both genera.1 However, the isolation of (+)-myrioneurinol (19) from the alkaline
leaf extracts of M. nutans by Bodo, et al. in 2007 provided yet another vital piece of the
biosynthesis puzzle (vide infra).11 This tightly fused tetracycle contains structural elements
emblematic of the Myrioneurion alkaloids including cis-DHQ and 1,3-oxazine ring systems.
However, since 19 also contains an unprecedented C5-spirocyclic quaternary center, this
metabolite has been hailed as somewhat of a ‘missing link’ between the biosynthetic pathways of
both genera.1 As with some other Myrioneuron alkaloids, (+)-myrioneurinol showed weak
inhibitory activity against KB cells, as well as moderate antimalarial activity against Plasmodium
falciparum.
N
O
H H
H
OH
N
OHHH
A
B
C
D5
6
H
7
109
Figure 3. Structure and Conformation of (+)-Myrioneurinol (19).
HO
11
18
6
Using flash column chromatographic purification, the free base of (+)-myrioneurinol was
isolated by Bodo and coworkers as a colorless microcrystalline solid that provided an ESI-MS
protonated molecular ion value of m+/z 266.2149, consistent with the formula C16H28NO2. An
absorption consistent with a hydroxylic O-H stretching vibration (3400 cm-1) was observed in the
infrared spectrum of the compound. The 1D 1H and 13C NMR (APT) spectra revealed the presence
of a quaternary center, four methines, and 11 methylene units within the molecule. Detailed 2D
NMR analysis was utilized to establish the connectivity and relative stereochemistry of the
metabolite, as outlined below.
N
O
OH
2
3
4
5
14
15
16
1718
7
89
10
6
1113
N
O
OH
HH
H H
H
H
H
H
H
H
H
H
H
H
H
H
H H
H
H
2
3 4 5
14
15 16
17
13
11
10
9
7
8
18
6
Figure 4. Two-Dimensional NMR analysis of (+)-Myrioneurinol (19):
(left) 1H-1H COSY ( ) and 1H-13C HMBC (H C) Correlations;
(right) NOESY Correlations (H H).
The 1H-1H COSY and 1H-13C HMBC 2D NMR spectra of 19 were essential in establishing
the basic connectivity of the tetracyclic ring system of the metabolite (Figure 4). The relative
configuration of the five contiguous stereocenters of the alkaloid were then deduced from NOE
experiments. The C9/C10 trans-configuration of the cis-DHQ (A/B) ring system was substantiated
7
by the large reciprocal 1H-1H vicinal coupling constant values between both H-10 and H-9, H-11ax
and H-9, as well as H-8ax and H-9 obtained from the NOE experiments. Likewise the C6/C7 trans-
stereochemical relationship of the A/B-ring subunit was established from similar large reciprocal
J-values between H-6 and both H-7 and H-17ax. Furthermore, strong correlations were observed
in the NOESY spectrum between H-10 and H-14ax, H-13ax, H-8ax, and H-6 as well as between H-
6 and H-14ax, H-8ax, and H-16ax which indicated a syn-facial disposition for H-10 and H-6. The
results of the 2D NMR experiments led to assignment of an all-chair fused tetracyclic scaffold that
shares a common A/B/C-ring core with the tricyclic alkaloid myrioxazine A (1), which had
previously been isolated from M. nutans (Cf. Figure 1).
The absolute configuration of (+)-19 was established as 5R,6R,7S,9R,10S utilizing a
modified Mosher method involving derivatization of the C7-hydroxymethyl group of the natural
product with (R)- and (S)-9-anthrylmethoxyacetic acid (9-AMAA) and subsequent detailed 1H
NMR analysis.
A plausible biosynthetic pathway to (+)-myrioneurinol from L-lysine has been proposed
by Bodo and coworkers that shares many similarities with that of other Myrioneuron alkaloids, but
also contains some intriguing differences.1,11 In this proposed biogenetic route (Scheme 2),
nucleophilic attack of the enamine moiety in Δ2-piperidine 15a on unsaturated imine 17 (Cf.
Scheme 1) results in formation of enamine aldehyde 20. Stereoselective spirocyclization of 20
establishes the C5-quaternary center within the A/D-ring subunit (21) of the alkaloid. Subsequent
deoxygenation, imine hydrolysis, and oxidative deamination provide the spirocyclic imino-
dialdehyde 22, which can undergo a Mannich-type cyclization in accordance with the biosyntheses
of the other Myrioneuron alkaloids (Cf. Scheme 1) to establish the cis-DHQ A/B/D-ring system
23. Global reduction of the aldehyde moieties in 23 followed by incorporation of formaldehyde
8
into the 1,3-oxazine C-ring then provides the tetracyclic scaffold of the alkaloid 19. Particularly
noteworthy is the proposed intermediacy of bis-iminoalcohol 21, which has also been implicated
in the biosynthetic pathway to the nitraramine (11) metabolite from the genus Nitraria.
N
O
NH
N
HO
N
NH
O
N
Michael-type
spiro-cyclization
deoxygenation
N
N
ringinversion
NH
N
O
1) hydrolysis
2) oxidativedeamination
N
O
ON
HO
O
cyclization
NH2
H
O
O
H
H[H]
H2CO
15a
17
20 21
23
22
Scheme 2. Proposed Biosynthetic Pathway to Myrioneurionol (19)
Complex spiranic Nitraria alkaloids
1)
2) cyclization
H
N
H
OH
H
H
O
myrioneurinol (19)
H
A
D
nitraramine (11)
A
D
B A B
D
C
9
1.3. Previous Synthetic Studies toward the Myrioneuron Alkaloids.
In spite of their unusual structures and intriguing biological activities, few syntheses of the
alkaloids of the genus Myrioneuron have previously been reported. Perhaps due to the relative
infancy of the field, especially when compared with the substantial body of work directed toward
the Nitraria alkaloids, to date only the simplest members of the class have succumbed to total
synthesis.
Bodo and coworkers reported the first asymmetric total syntheses of the simple tricyclic
alkaloids (+)-myrioxazine A (1) and B (2) (Scheme 3).2 Employing a pivotal (S)-camphanyl-ester
based resolution of easily prepared (±)-8-hydroxymethyl tetrahydroquinoline (24), this group was
able to prepare the two natural products via catalytic hydrogenation of the corresponding
enantiopure tetrahydroquinolines 25a/b, followed by treatment of the resulting enantiopure DHQs
26a and 26b with formaldehyde to construct the 1,3-oxazine rings of the myrioxazines.
10
N
(CH2O)n90 oC
N
OH
Me Me
Me
COCl
37%
CH2Cl2, Py
91%
(±)-24
N
OH
N
OH
+
24a 24b
1)
2) NaOH, H2O
60 oC
97%
H H
Scheme 3. Bodo Synthesis of (+)-Myrioxazines A and B
N
OH24a
N
OH24b
H2/PtO2
AcOH
82%
H2/PtO2
AcOH
82%
NH
OH25a
H
H
HH
NH
OH
H
H
H
+
H2CO
H2O
95%N
H
H
H
O
NH
OH25b
H
H
H
NH
OH
H
H
+
H2CO
H2O
95%N
H
H
H
O
H
(+)-myrioxazine A (1)
(+)-myrioxazine B (2)
H
Bodo, et al. have also prepared the simple tricyclic alkaloid (-)-myrionine (26) via
derivatization of cis-DHQ intermediate 25a obtained from the aforementioned myrioxazine A total
synthesis (Scheme 4).12 The same group then elaborated 26 to both the amidinium alkaloid (-)-
myrionidine (27) as well as the closely related 1,3-diazine alkaloid (-)-schoberine (3) using
straightforward chemistry.13
11
NH
OH
H
H
H
BnBr, NaHCO3
CH2Cl2, H2O, 93%
1)
2) MsCl, CH2Cl2, -5 oC
3) 2-piperidone, KH
DMF, -5 oC to rt
75% (2 steps)
NH
N
H
H
H
O
4) H2/Pd/C, HOAc, 90%
POCl3, PhMe
reflux;
then NaOH,
H2O, MeOH
97% N
H
H
H
N
LiAlH4
THF
0 oC to rt
87%N
H
H
H
N
25a
Scheme 4. Bodo Syntheses of (-)-Myrionine (26), (-)-Myrionidine (27), and (-)-Schoberine (3) from cis-DHQ 25a
(-)-myrionine (26)
(-)-myrionidine (27) (-)-schoberine (3)
More recently, Burrell and coworkers reported a racemic synthesis of the simple tricyclic
Myrioneuron alkaloid myrioxazine A (1) that utilized a pivotal tandem condensation, cyclization,
and dipolar cycloaddition sequence via nitrone intermediate 28 to access the tricyclic cis-DHQ
system 29 (Scheme 5a).14 Tricycle 29 was then elaborated to the natural product in excellent yield
following reductive cleavage of the nitrogen-oxygen bond and cyclization of the resulting 3-
aminoalcohol with formaldehyde. Shortly thereafter, the same group employed similar
methodology to construct a model compound 30 containing the A/B/C-ring subunit of
myrioneurinol (Scheme 5b).15
12
CHO
Cl
NH2OH ClDIEA, 110 oC
77%N
O
H H
H
1) Zn, HOAc
H2O, 70 oC, 98%
2) (CH2O)n, p-TsOH
CHCl3, 70 oC, 95%
NH H
H
O
Scheme 5. Myrioneuron Alkaloid Synthetic Work by Burrell, et al.
29
NH
H
O
30
(±)-myrioxazine A (1)
B C
A
NO [3+2]
a) Synthesis of Racemic Myrioxazine A (1)
b) Synthesis of Abbreviated Myrioneurinol Compound 30
CHO
Cl
28
1.4. First Generation Retrosynthesis of (±)-Myrioneurinol
Our interest in performing the first total synthesis of 19 was motivated by the challenging
fused tetracyclic structure and reported biological activity of the metabolite (vide supra) as well as
the relative dearth of synthetic work that had hitherto been conducted in this area. Our initial
retrosynthetic plan was predicated upon the preparation of advanced tricyclic intermediate 31,
which contains the A/B/D-ring subunit and five contiguous stereogenic centers of the alkaloid. We
anticipated that hydrolysis and/or reduction of the R-groups in tricycle 32 would eventually
provide the requisite C7- and C9- hydroxymethyl functionalities, with the latter being incorporated
into the 1,3-oxazine C-ring of the metabolite. We further envisioned that stereoselective reduction
of either an enecarbamate or cyanoenamine moiety within 32 would establish the requisite C9,10-
13
relative configuration. The B-ring of tricycle 32 would be installed via the cyclization of imidate
precursor 33,16 itself prepared via the intermolecular Michael addition of the C7-enolate of bicyclic
ester 34 to an appropriate acceptor. We envisaged that spirocycle 34 could arise via a pivotal
intramolecular Michael addition (IMA) of a valerolactam-derived α,β-unsaturated ester cyclization
precursor such as 36.17 According to literature precedent (vide infra), we postulated that the use of
a chelating metal in this spirocyclization would provide diastereocontrol over the C5,6-
configuration of 34 via a rigid intermediate such as 35.
N
RH
X
NP
CO2R1H
OD
A
5
6
NP
O
O
OR
MN P
CO2R
O
Scheme 6. First Generation Retrosynthetic Analysis for Myrioneurinol (19)
N
R
RH
H
B
7
7
34 35 36
3332
D
A
RN
OHHH
A
B
C
D
HO
19
R = CO2R1, CN
910
7
9
R
N
OHHH
HHO
H
D B
A
31
CH2O [H-]
1.5. Background on Diastereoselective Intramolecular Michael Additions (IMAs) and
Related Reactions
Over the past several decades, intramolecular Michael additions (IMAs) have been utilized
as important carbon-carbon bond forming operations and in a number of total syntheses.17 In our
first generation retrosynthesis of 19, we envisaged that the C5,6-connection in spirocyclic ester
14
intermediate 34 could arise via a diastereoselective IMA that utilizes a chelating metal ion (Cf.
Scheme 6). Existing literature precedent for this pivotal transformation included some examples
of stereoselective IMAs, as well as related spirocyclizations in approaches to total syntheses of a
few of the Nitraria alkaloids.
For example, Fukumoto, Kametani, et al. have reported that the lithium
hexamethyldisilazide (LiHMDS)-induced double IMA of bis-α,β-unsaturated dicarbonyl substrate
37 (Scheme 7a) furnished a single diastereomeric tricyclic ketoester 39, presumably via a lithium
metal-chelated intermediate such as 38.18 Support for this mechanistic hypothesis came via the
addition of the strongly coordinating co-solvent HMPA to the reaction mixture to solvate the Li+
cation, thereby interrupting the chelating effect, which dramatically lowered the yield of 39.
Furthermore, d’Angelo and Ferroud utilized a thermal cyclization of an imine 40 to prepare
spirocyclic ketoester 41 as a single diastereomer and enantiomer, a system closely related to the
desired intermediate 34 for our myrioneurinol synthesis (Scheme 7b).19 The authors rationalized
the syn-C1,2-diastereoselectivity observed for this transformation by invoking a preferred aza-ene-
like transition state conformation 42 which places the C1,11 and C2,12 components in a synclinal
gauche disposition.
15
OO
OEt
LiEtO2C
H O
O
EtO2CLiHMDS
THF-78 °C-rt
30-60%
a) Fukumoto/Kametani Work
Scheme 7. Relevant Intramolecular Michael Cyclizations.
37 38 39
CO2MeH
O
b) d'Angelo's Work
CO2Me
NPh
HMe
1) DMF120 °C
2) HOAcH2O85%
40 41R
1
2
11
12
NH
PhMe
HO
MeO
aza-ene-like TS (42)
1
212
11
single diastereomer and enantiomer
Koomen and coworkers have utilized two biomimetically-inspired chelation-controlled
spirocyclization reactions to construct alkaloids of the genus Nitraria. In their total synthesis of
the simple spiranic alkaloid (±)-nitramine (8), a pivotal syn-diastereoselective thiophenolate-
induced intramolecular aldol type addition of N-Bn glutarimide/aldehyde 43 was employed that is
believed to proceed through an aluminum-chelated enolate intermediate 44 to afford spirocycle 45
in good yield (Scheme 8a).20
The same group reported a similar thiophenolate-induced Michael addition of bis-
glutarimide substrate 46 en route to an attempted biomimetic total synthesis of the complex
Nitraria alkaloid nitraramine (11) (Scheme 8b). Although the chelating aluminum metal was
16
effective in establishing the desired syn-C6,7-relative configuration, the C6,11 configuration of 47
was unsuitable for elaboration to the natural product.21
O
BnNO O
BnNO O
SPh
O
Al
Me
MePhS-AlMe2
THF, rt
82%
BnNO O
SPh
OH
43 44
45
BnNO O
46
BnNO O
6
7
PhS-AlMe2
THF, rt
81%
BnNO O
PhS
NBnH
O
O
67
11
12
dr C11,12 = 3:2
47
Scheme 8. Chelation Controlled Diastereoselective Spirocyclizations of Koomen, et al.
a) Racemic Total Synthesis of Nitramine (8)
b) Studies Toward Nitraramine (11)
HN
OH
O N
N H
(±)-nitramine (8)
(±)-nitraramine (11)
17
1.6. Preliminary Studies on the IMA Spirocyclization toward Myrioneurinol
Former Weinreb group member Yiqing Feng began our exploratory studies toward
effecting the desired diastereoselective IMA for the (±)-myrioneurinol total synthesis.22a He
initially decided to attempt the IMA of an N-benzyllactam substrate (Cf. Scheme 6, 36 P = Bn),
and thus the appropriate cyclization precursor was prepared from commercially available N-
benzyl-2-piperidone (48) (Scheme 9). To this end, lactam 48 was C-monoalkylated with known
iodoacetal 4923 to afford lactam acetal 50 in moderate yield. Hydrolysis of the dioxolane in 50
unmasked the aldehyde functionality, giving 51, which was subjected to Wadsworth-Emmons-
Horner olefination to provide the desired (E)-α,β-unsaturated ester 52 in excellent yield.
N O N O
O
N O
CHOBn Bn BnO
NBn
CO2Me
O
NBn
CO2MeH
O
53
5
6
Scheme 9. Preparation and Cyclization of N-Benzyllactam Enoate 52 by Feng.
O
O(CH2)3CH2I
LDA, THF, -78 °C
48 4951
52
49%
HCl, THFrt, 100%
(EtO)2POCH2CO2MeLiCl, DBU, MeCN, rt
90%
LDA, THF-78 °C-rt
~20%
50
NBn
CO2MeH
O5
6
HH
H
H
H
14
16
3
Key NOESY Correlationsfor 53 (H H).
H
H15
A variety of experimental conditions were then screened in order to effect the desired
spirocyclization of enoate 52. Feng ultimately discovered that treatment of the cyclization
18
precursor with lithium diisopropylamide (LDA) at -78 ºC followed by slow warming to room
temperature overnight furnished a single spirocyclic product 53. The C5,6 relative configuration
of 53 was found to be correct for myrioneuriniol via strong 1H-1H NOESY correlations for H6
with H14ax and H16ax, as well as H3ax with H14eq and H15ax.
Although encouraged that our IMA strategy might indeed be viable, we were disappointed
to discover that the maximum attainable yield of 53 in this transformation was ca. 20%, with
decomposition products and recovered starting material accounting for the remainder of the mass
balance. Attempts to effect the IMA of 52 with a variety of alternative non-nucleophilic bases
including KHMDS, NaH, or KOt-Bu were unsuccessful. Thus, given Feng’s inability to perform
the lithium amide base-induced spirocyclization of N-benzyllactam enoate 52 in a synthetically
useful yield, we began investigating alternative strategies to carry out this pivotal transformation.
19
CHAPTER 2: IMA STRATEGY TO CONSTRUCT A/D-RING SUBUNIT
2.1. ‘Soft’ Enolization Inspired by Evans, et al.
Although Feng had demonstrated the feasibility of effecting the desired spirocyclization of
N-benzyllactam enoate 52, the low yields obtained from this pivotal IMA forced us to modify our
approach. A survey of the chemical literature revealed that Evans and coworkers had reported the
IMA of N-acyloxazolidinone 54 to afford the corresponding diastereomeric cyclopentane
derivatives 55a/b using titanium trichloroisopropoxide and triethylamine (Scheme 10).24
ON
O
Bn
O
CO2Me
Ti(Oi-Pr)Cl3, Et3N
CH2Cl2, -78 oCO
N
O
Bn
O
H CO2Me
dr = 93 : 7
88%
Scheme 10. Intramolecular Michael Addition of N-acyloxazolidinones by Evans, et al.
54
ON
O
Bn
O
H CO2Me+
55a 55b
In the presence of the Lewis acidic metal cation Ti4+, the rather weak tertiary amine base
is sufficient to effect the enolization of imide 54. This strategy, referred to as “soft” enolization,
represents a milder method for the generation of metal enolates when compared to so-called “hard”
enolization via the deprotonation of a carbonyl species with a strong amide base.25
20
Since Feng had hypothesized that competitive γ-deprotonation of the enoate and Michael-
type addition of the lithium amide base were possibly complicating the IMA of benzyllactam 52,
we hoped that the Evans conditions might improve the chemoselectivity for the enolization of an
appropriate cyclization precursor. For this approach, the benzyloxycarbonyl (Cbz) protecting
group was selected for the lactam nitrogen in order to approximate the electron withdrawing
character of the oxazolidinone auxiliary in 54.
2.2. First Generation Route to N-Cbz Lactam Cyclization Precursor
Because Feng had been unsuccessful in directly alkylating N-Cbz valerolactam 56 with
iodoacetal 49 (Scheme 11a), it was decided to reverse the order of the alkylation and protective
operations.26 To this end, valerolactam (57) was treated with two equivalents of n-butyllithium to
generate the dianion, which was C-monoalkylated with iodide 49 in modest yield (Scheme 11b).27
The N-H lactam acetal 58 was then protected as the N-Cbz derivative 59 via treatment with benzyl
chloroformate in acceptable yield, followed by hydrolysis of the dioxolane with aqueous HCl in
THF to cleanly afford aldehyde 60. Wadsworth-Emmons-Horner olefination of 60 then provided
the desired (E)-α,β-unsaturated ester cyclization precursor 61 in good yield.
21
N O N O
OCbz Cbz
O
O
O(CH2)3CH2I
LDA, THF, -78 °C
4956
N O
OH
O
N O
H
n-BuLi (2 equiv.)
O
O(CH2)3CH2I
49
n-BuLiTHF, 0 °C THF, -78 °C
CbzCl N O
OCbz
O
N O
CHOCbz
HCl, THF
60
N Cbz
CO2Me
O
61
57 58 59
a) Attempted Preparation by Feng
b) First Generation Route to Cyclization Precursor 61
24%
65%
82%
rt, 100%
(EtO)2POCH2CO2Me
LiCl, DBU, MeCN, rt
Scheme 11. Preparation of N-Cbz Lactam Cyclization Precursor
2.3. Attempted ‘Soft’ IMA of Lactam Enoate 61.
At this stage, the spirocyclization of N-Cbz lactam enoate 61 was explored using conditions
inspired by the Evans procedure. Thus, substrate 61 was first treated with titanium (IV) chloride
and triethylamine at -78 ºC and the mixture was allowed to stir for one hour before an aqueous
quench (Scheme 12, entry 1). NMR analysis of the reaction mixture revealed only the presence of
unreacted starting material. In a second trial, the addition was performed at -78 ºC and the mixture
allowed to warm to room temperature over several hours (entry 2). Proton NMR analysis of the
22
major product upon chromatographic purification suggested that some of the desired
spirocyclization of 61 had taken place.28 We were somewhat disappointed, however, to discover
that the yield of bicycle 62 from this run was only ca. 15%. A third reaction was allowed to stir
for a longer time period (entry 3), but provided only a very polar spot on the TLC, later identified
as spirocyclic N-H lactam/ester 63, which could not be separated from the complex mixture. We
hypothesized that titanium (IV)-induced deacylation of spirocycle 62 was occurring as a result of
the prolonged reaction times, and thought that perhaps carrying the transformation out at a slightly
higher temperature might ameliorate this problem. To our delight, treatment of 61 with titanium
(IV) chloride and triethylamine at 0 ºC, followed by gradual warming to room temperature over
one hour provided spirocycle 62 in a synthetically useful (but unoptimized) 60% yield (entry 4).
It is worthy of note that exposure of the Feng’s N-benzyllactam substrate 52 to these “soft” IMA
conditions led only to the recovery of unreacted starting material (entry 5), thus demonstrating the
need to employ the electron withdrawing carbamate protecting group on the lactam nitrogen.
23
NP
CO2Me
O
N P
CO2Me
O
H
entry temp. (oC) result (% yield)
Et3N, CH2Cl2
conditions
1 -78 NR
2 -78 to rt 62 (15) + 63*
time (h)
1
4
3 -78 to rt 62 (trace) + 63*20
TiCl4
4 0 to rt 62 (60) + 63*1
61
61
61
61
5 52 0 to rt 20 NR
NR = no reaction*yield not determined due to purification difficulty
Scheme 12. Development of Pivotal IMA Spirocyclization
substrate
62 P = Cbz
63 P = H
61 P = Cbz
52 P = Bn
2.4. Determination of the Relative C5,6-Configuration of Spirocycle 62.
Before proceeding with any optimization studies on this novel titanium-induced IMA of
61, we decided to verify that the C5,6-relative stereochemistry of spirocyclic lactam ester 62 was
indeed correct for elaboration to myrioneurinol. To this end, the benzyloxycarbonyl group on the
lactam nitrogen in 62 was cleaved hydrogenolytically to afford N-H lactam 63 in nearly
quantitative yield (Scheme 13). Chemoselective reduction of the ester carbonyl in lactam 63 with
lithium aluminum hydride at 0 ºC provided alcohol 64 as a white crystalline solid. Recrystallization
of 64 from a mixture of diethyl ether and methanol provided clear prisms that were of suitable
quality for single crystal X-ray diffraction analysis which confirmed the structure to be as shown
(ORTEP in Scheme 13). Furthermore, installation of an N-benzyl protecting group on 63 using
24
silver (I) oxide and neat benzyl bromide provided benzyllactam 53 which was found to be identical
spectroscopically to the spirocycle prepared by Feng from 52 (Cf. Scheme 9).
H2, EtOAc
N H
CO2MeH
O
N H
H
O
HO
63 64 (X-ray)
Scheme 13. Confirmation of the C5,6 Stereochemistry of Spirocycle 62
82%
73%
98%
NBn
CO2MeH
O
10% Pd-C
N Cbz
CO2MeH
O
62
LiAlH4
Et2O
0 °C
BnBrAg2O, TBAI
CaSO4, rt
5
6
5
6
53
We attribute the observed high degree of C5,6 diastereoselectivity in the IMA of 61 to the
formation of a rigid titanium chelate such as 65 during the course of the spirocyclization (Scheme
14). The superior yields of spirocycle 62 from this method likely arise from the higher degree of
chemoselectivity for soft enolization/cyclization that proceeds without the undesired side reactions
observed in Feng’s N-benzyllactam system.
25
N Cbz
CO2MeH
O
N Cbz
CO2Me
O
0 °C-rt
NCbzO
O
OMe
Ti Cl
ClCl
61 65 62
Scheme 14. Rationalization of the Observed C5,6-Diastereoselectivity
5
6TiCl4Et3N
CH2Cl2
2.5. Second Generation Route to Cyclization Precursor 61.
Poor individual reaction yields and scalability issues in the first generation route to (E)-
α,β-unsaturated ester cyclization precursor 61 (Cf. Scheme 11b) prompted us to develop an
improved preparation of this compound prior to proceeding further with optimization studies on
the pivotal IMA. The issues within the existing sequence appeared to derive from incompatibility
between dioxolane 49 and the alkyllithium or lithium amide bases employed to effect the
enolization of the lactam 57.
A suitable solution to these problems was envisioned that installed the requisite aldehyde
functionality via ozonolytic cleavage of a terminal alkene rather than the unmasking of dioxolane
59. Towards this end, the dianion of valerolactam (57) was treated with commercially available 6-
bromo-1-hexene and the resulting N-H lactam olefin 66 was treated with benzyl chloroformate to
furnish the N-Cbz derivative 67 in good overall yield (Scheme 15).27 Ozonolytic cleavage of the
alkene 67, followed by reductive workup with triphenylphosphine, furnished aldehyde 60 in
excellent yield. As had been shown previously (Cf. Scheme 11b), Wadsworth-Emmons-Horner
olefination of 60 provided the (E)-α,β-unsaturated ester cyclization precursor 61 in good yield. We
26
were pleased to discover that this synthesis of 61 could be carried out on a multi-decagram scale
with no significant attenuation of the individual reaction yields.
NH
O
n-BuLi (2 equiv.)
Br
NH
O NCbz
O89%
(2 steps)
NCbz
O
CHO
-78 °C-rt LiCl, DBU, MeCN, rt
82%90%
57 66 67
60
Scheme 15. Second Generation Route to N-Cbz Lactam Cyclization Precursor 61
N Cbz
CO2Me
O
61
THF, 0 °CTHF, -78 °C
n-BuLi
CbzCl
O3, CH2Cl2-78 °C; PPh3 (EtO)2POCH2CO2Me
2.6. Optimization Studies on the Pivotal IMA Spirocyclization
With a reliable route to (E)-α,β-unsaturated ester cyclization precursor now established, we
next turned our attention toward the optimization of the IMA of 61 by screening different Lewis
acids and amine bases (Scheme 16). Titanium (IV) chloride was found to be the best Lewis acid
for the soft enolization of lactam 61. Performing the reaction with triethylamine as the base in the
presence of titanium (IV) isopropoxide (entry 1), boron trifluoride diethyl etherate (entry 2), or
trimethylaluminum (entry 3) resulted only in the recovery of unreacted 61 or deacylated (E)-α,β-
unsaturated ester cyclization precursor 68. Titanium (IV) trichloroisopropoxide, the Lewis acid
employed by Evans and coworkers in the IMA of imide 54 (Cf. Scheme 10),24 provided some of
the desired spirocycle 62 along with a significant amount of an inseparable impurity 69 that
27
appeared to result from transesterification of the nascent spirocycle by the isopropoxide (entry 4).
The use of Hünig’s base (DIEA) in place of triethylamine resulted only in the recovery of
deacylated precursor 68 or unreacted starting material (entries 5-6).
With titanium (IV) chloride and triethylamine established as the optimal reagent
combination for the spirocyclization of 61, the molar equivalents of each component were next
screened. It was determined that, two equivalents of TiCl4 were necessary to ensure complete
conversion of precursor 61 to spirocycle 62 (entry 7-8). We were pleased to discover that
performing the transformation at 0 ºC with two equivalents of both triethylamine and TiCl4
afforded the desired spirocycle in 86% isolated yield (entry 9). Employing additional equivalents
of TiCl4 and Et3N resulted only in greater difficulty in performing the aqueous workup and
purification of the reaction mixture without any noticeable improvement in the yield (entry 10).
Thus, with a set of optimized conditions in hand, we next decided to explore the substrate scope
of this novel spirocyclization method before proceeding further with the myrioneurinol total
synthesis.
28
NCbz
CO2Me
O
NCbz
CO2Me
O
H
entry result (% yield)
N
CO2Me
O
H
NH
CO2Me
O
H
base, CH2Cl2
0 °C to rt
1
2
time (h)
3
Lewis Acid
4
5
NR = no reaction; SM = starting material*yield not determined due to purification difficulty
68
63
Scheme 16. Optimization of Pivotal IMA Spirocyclization of 61
61 62
Lewis acid (equiv.) base (equiv.)
Et3N (1)
Et3N (1)
Et3N (1)
Et3N (1)
Ti(Oi-Pr)4 (1)
BF3 OEt2 (1)
Me3Al (1)
Ti(Oi-Pr)3Cl (1)
TiCl4 (1) DIEA (1)
6 DIEA (1)Ti(Oi-Pr)4 (1)
1.5
1.5
1.5
7
9
TiCl4 (1) Et3N (1)
TiCl4 (2) Et3N (2)
10 TiCl4 (3) Et3N (3)
1
1
1
1.5
1
1
N H
CO2i-Pr
O
H
69
68*
NR
NR
62 + 69*
68*
NR
62 (20%) + SM
62 (86%) + 63*
62 (51%) + 63*
8 TiCl4 (2) Et3N (1) 1 62 (60%) + SM
2.7 Exploration of Some Homologous IMA Spirocyclizations
Since we had demonstrated that titanium (IV) chloride/triethylamine-induced IMA of (E)-
α,β-unsaturated ester 61 provided a single diastereomer of spirocycle 62 in high yield (vide supra),
we sought to explore the scope of this interesting stereoselective transformation. To this end,
several cyclization precursors containing varying lactam ring sizes and unsaturated ester tether
lengths were prepared via appropriate modifications of the route used to synthesize 61.
29
2.7.1. Studies with Five-Membered Lactam Analog 74.
To begin these studies, the dianion of 2-pyrrolidinone (70) was treated with 6-bromo-1-
hexene and the crude product 71 was protected as the N-Cbz derivative 72 in modest yield (Scheme
17). Ozonolysis of terminal olefin 72 followed by Wadsworth-Emmons-Horner olefination of
aldehyde 73 provided cyclization precursor 74 which was subjected to the optimized IMA
conditions. However, we were disappointed to recover only the deacylated (E)-α,β-unsaturated
ester 76, rather than the desired spirocycle 75 after allowing the reaction mixture to stir overnight
at room temperature.
70 71 72
73
Scheme 17. Studies upon the IMA of 2-Pyrrolidinone Analog 74
N Cbz
CO2Me
O
74
NH
O
NH
ONCbz
O
NCbz
OCHO
NCbz
CO2Me
O
H
75
TiCl4Et3N
CH2Cl20 °C-rt
18% (2 steps)
79% 56%
n-BuLi (2 equiv.)
Br
THF, 0 °C
THF, -78 °Cn-BuLi
CbzCl
-78 °C-rt
O3, CH2Cl2-78 °C; PPh3
LiCl, DBU, MeCN, rt
(EtO)2POCH2CO2Me
NH
CO2Me
O
76
30
2.7.2. Studies with Seven-Membered Lactam Homologue 81.
Similarly, the dianion of caprolactam (77) was alkylated with 6-bromo-1-hexene and the
product 78 was protected as the N-Cbz derivative 79. Ozonolysis of 79, followed by Wadsworth-
Emmons-Horner olefination of the resulting aldehyde 80, furnished (E)-α,β-unsaturated ester
cyclization precursor 81. Exposure of this compound to the optimized IMA conditions once again
led only to the recovery of deacylated (E)-α,β-unsaturated ester 83 rather than the desired
spirocycle 82 .
NH
O
n-BuLiTHF, -78 °C
CbzCl
NCbz
O
NH
O
NCbz
OCHO N
Cbz
CO2Me
O
TiCl4Et3N
CH2Cl20 °C-rt
N Cbz
CO2Me
O
H
Scheme 18. Studies on the IMA of Caprolactam Analog 81
77 78 79
80
82
72%58%
27% (2 steps)
n-BuLi (2 equiv.)
Br
THF, 0 °C
-78 °C-rt
O3, CH2Cl2
-78 °C; PPh3 (EtO)2POCH2CO2Me
LiCl, DBU, MeCN, rt
81
N H
CO2Me
O
83
31
2.7.3. Rationalization for Failure of Enoates 74 and 81 to Spirocyclize
We hypothesize that substrates 74 and 81 may be reluctant to undergo the desired
spirocyclization reactions due to their inability to assume the requisite rigid chelated transition
state conformations 84 and 85, respectively, for the IMA. In the 2-pyrrolidinone system (74), it is
conceivable that the five-membered cyclic enolate is unable to achieve the necessary
stereoelectronic alignment with the Michael acceptor due to geometric restrictions imposed by the
smaller ring size. For caprolactam homologue 81, the seven-membered ring may, in fact, be too
conformationally labile, raising the energy of IMA transition state 85 to a prohibitive level and
instead favoring the deacylation pathway to afford N-H lactam 83.
N Cbz
O
O
OMe
Ti Cl
ClCl
84
NCbz
O
O
OMe
Ti Cl
ClCl
85
Scheme 19. Hypothetical Chelated Transition States for Homologous Spirocyclizations
2.7.4. Modification of the Ester Tether Length
In light of our failure to effect the spirocyclization of substrates containing five- and seven-
membered lactam rings with six-carbon (E)-α,β-unsaturated ester side chains, we next turned our
attention toward modification of the tether of the cyclization precursor. Towards this end, the
dianion of valerolactam (57) was C-monoalkylated with commercially available 5-bromo-1-
pentene and the resulting N-H lactam 86 was protected as the N-Cbz derivative 87 in good yield
32
(Scheme 20). Ozonolysis of 87 followed by reductive workup with triphenylphosphine provided
the aldehyde 88 which was then elaborated to (E)-α,β-unsaturated ester 89 in moderate yield. We
were again disappointed to discover that subjection of 89 to the optimized spirocyclization
conditions resulted only in the recovery of the deacylated compound 92 rather than the desired
spirocycle 91. Although Evans and coworkers had demonstrated that their IMA of N-
acyloxazolidinone 54 (Cf. Scheme 10) resulted in cyclopentane formation,24 it seems reasonable
to hypothesize that conformational restrictions imposed by the spiranic nature of chelated
transition state 90 disfavor the desired IMA pathway.
NH
O NH
O NCbz
O
NCbz
O CHO
57 86 87
88
TiCl4Et3N
CH2Cl20 °C-rt
N CbzO
91
68% (2 steps)
64% 67%
Scheme 20. Modification of Ester Tether Length
n-BuLi (2 equiv.)
Br
THF, 0 °CTHF, -78 °C
n-BuLi
CbzCl
-78 °C-rt
O3, CH2Cl2
-78 °C; PPh3
LiCl, DBU, MeCN, rt
(EtO)2POCH2CO2Me
N Cbz
CO2MeO
NCbz
O
O
OMe
Ti Cl
ClCl
90
CO2MeH
89
N H
CO2MeO
92
33
2.7.5. Studies with Homologues Pre-Functionalized at C7
Since our retrosynthetic strategy toward myrioneurinol was predicated upon the eventual
installation of functionality at C7 (Cf. Scheme 6) we decided to prepare a series of cyclization
precursors that were pre-functionalized at that position. Thus, aldehyde 60 was subjected to
Wadsworth-Emmons-Horner olefination with both an α-methylphosphonoester and α-
allylphosphonoester to afford the corresponding cyclization precursors 93 and 94, respectively,
both as inseparable mixtures of E/Z-olefin geometric isomers in acceptable (but unoptimized)
yields (Scheme 21). However, upon exposure to the optimized IMA conditions for precursor 61,
neither 93 nor 94 underwent any spirocyclization even after being stirred overnight at room
temperature. Instead, in each case only the corresponding deacylated α,β-unsaturated esters 95
were isolated from the reaction mixture.
NCbz
O
CHO
KHMDS, THF, -78 °C
60
NCbz
CO2R2
OR1
7
~2.5:1
TiCl4Et3N
CH2Cl20 °C-rt
NCbz
CO2R2
OR1
H
NH
CO2R2
OR1
P
O
EtOEtO
CO2R2
R1
93 Me 29
94 ~4.2:1allyl 47
yield (%) E/Z*
7
*E/Z mixture subjected to IMA.
95
R = Me, allyl
Scheme 21. Preparation and Attempted IMA of C7-Prefunctionalized Cyclization Precursors
R1
Et
Me
R2
34
Likewise, (E)-α,β-unsaturated δ-valerolactone cyclization precursor 97 was synthesized
via Wadsworth-Emmons-Horner olefination of aldehyde 60 with easily-prepared δ-
phosphonolactone 96 (Scheme 22, yield unoptimized). This substrate also failed to undergo the
desired spirocyclization reaction, instead providing the N-deacylated compound 98 after being
stirred overnight at room temperature.
NCbz
O
O
O
7
NCbz
O
CHO
KHMDS, 18-crown-6
60
TiCl4Et3N
CH2Cl20 °C-rt
O
O
P
O
OEtOEt
19% (E)-isomerN
Cbz
O
O
OH
97
98N
H
O
O
O
Scheme 22. Preparation and Attempted IMA of Phosphonolactone 97
7
96
THF, -78 °C
We hypothesize that C7-prefunctionalized substrates 93, 94, and 97 may have failed to
spirocyclize due to excessive steric strain in the chelated transition states leading to the desired
IMA. We next briefly explored the spirocyclization of enedioate 99, which was easily prepared
via Knoevenagel reaction of aldehyde 60 with diethyl malonate. Unfortunately, 99 failed to cyclize
when subjected to the optimized experimental conditions, providing only the deacylated lactam
100 after stirring overnight at room temperature.
35
NCbz
O
60CHO
CO2EtEtO2C
piperidine, HOAc
PhH, 80 °C
91%
TiCl4Et3N
CH2Cl20 °C-rt
NCbz
CO2Et
OCO2Et
99
NCbz
CO2Et
OCO2Et
H
Scheme 23. Synthesis and Attempted Spirocyclization of Enedioate 99
NH
CO2Et
OCO2Et
100
2.8. Attempted Asymmetric IMA Spirocyclization
2.8.1. Studies with (-)-Menthyl Carbamate Cyclization Precursor 103
We next briefly examined the feasibility of preparing the appropriate aza-
spiro[5.5]undecane scaffold for myrioneurinol in enantioenriched form via the incorporation of a
chiral auxiliary into the cyclization precursor for the IMA. Thus, the nitrogen of lactam olefin 66
(Cf. Scheme 15) was converted to the (-)-menthyl carbamate 101 (Scheme 24). Ozonolysis of 101
with a reductive workup furnished aldehyde 102, which was subjected to Wadsworth-Emmons-
Horner olefination to afford (E)-α,β-unsaturated ester precursor 103 in good yield. Unfortunately,
exposure of the cyclization precursor 103 to the optimized IMA conditions led to the formation of
a ca. 1:1 diastereomeric mixture of spirocycles 104a/b as determined by HPLC and NMR
experiments.
36
N
CO2Me
O
O
O
Me Me
Me
NH
O
n-BuLiTHF, -78 °C
67%
66
Me
O Me
Me
101
70%
100%
TiCl4Et3N
CH2Cl20 °C-rt
N
CO2Me
O
O
O
Me Me
Me
H
66%
dr ~ 1:1
102
103
104a
O
Cl
Scheme 24. Preparation and IMA of (-)-Menthyl Carbamate Cyclization Precursor 103.
N O
O O
Me
Me
Me
N O
CHOO O
Me
Me
Me
-78°C-rt
O3, CH2Cl2-78 °C; PPh3
LiCl, DBU, MeCN, rt
(EtO)2POCH2CO2Me
N
MeO2C
O
O
O
MeMe
Me
H
104b
+
2.8.2. Studies with (+)-TCC Ester Cyclization Precursor 107
Given our failure to effect any measurable asymmetric induction in the spirocyclization of
103, an alternative substrate bearing a chiral (+)-trans-2-(α-cumyl)cyclohexyl ((+)-TCC) ester
auxiliary was next prepared.29 To this end, commercial (+)-TCC alcohol (105) was first converted
to phosphonoester 106 via acylation with diethylphosphonoacetyl chloride.30 Wadsworth-
37
Emmons-Horner olefination of aldehyde 60 with (+)-TCC phosphonoester 106 furnished the (E)-
α,β-unsaturated ester cyclization precursor 107. However, exposure of 107 to the optimized IMA
conditions led to the recovery of deacylated product 109, rather than the desired spirocycle 108.
We hypothesize that precursor 107 may have failed to spirocyclize due to the steric bulk of the
(+)-TCC auxiliary.
NCbz
O
O
OMe
Ph
Me
P
O
EtOEtO
CO2Cl
OH Me
Me
Ph CH2Cl, 0o C
Et3NP
O
EtOEtO
O
O Me
Me
Ph47%
106
KHMDS, THF
-78 oC
106
32%
TiCl4Et3N
CH2Cl20 °C-rt
NCbz
O
O
OMe
Ph
Me
H
108
Scheme 25. Studies with (+)-TCC Ester 107
NCbz
O
CHO60
105
107
NH
O
O
OMe
Ph
Me
109
38
Although we were disappointed to discover that our novel titanium (IV) induced IMA was
(1) not general outside of the azaspiro[5.5]undecane scaffold, (2) was incompatible with precursors
bearing a C7-substituent (myrioneurinol numbering) and (3) was not amenable to auxiliary-based
enantioenrichment, the transformation nevertheless permitted us to continue our synthetic studies
toward racemic myrioneurinol.
39
CHAPTER 3: HOMOLOGATION OF A/D-RING SUBUNIT AT C7
3.1. Attempts to Homologate via Formation of C7 Ester Enolates
Since we were unable to incorporate a C7-substituent into the pivotal spirocyclization
reaction (vide supra), it was decided instead to investigate various post-Michael methods to
homologate spirocycle 62 at C7. We had initially hoped that metalation of spirocyclic N-Cbz
lactam/ester 62 would furnish a C7-ester enolate that could react with an appropriate electrophile
to accomplish the desired C7,8 bond formation leading eventually to a 1,5-dicarbonyl imidate
cyclization precursor like 33 (Cf. Scheme 6).
However, the benzyloxycarbonyl (Cbz) protecting group on the lactam nitrogen of ester 62
proved to be labile to treatment with LDA or LiHMDS, leading either to decomposition or to the
recovery of N-H lactam 63 along with significant amounts of benzyl alcohol (Scheme 26, entries
1-4). The reactivities of spirocyclic N-H lactam ester 63 (entry 5) and N-Bn lactam ester 53 upon
treatment with the non-nucleophilic bases LDA, LiHMDS, and KH (entries 6-10) followed by the
addition of an electrophile were next evaluated. However, neither substrate underwent any
detectable C7-functionalization with methyl acrylate, allyl iodide, or even methyl iodide.
Moreover, treatment of 53 with base, followed by a D2O quench, failed to provide any evidence
of deuterium incorporation at C7, even with the addition of HMPA or 18-crown-6 to the mixture
(entries 11-12).
40
N
CO2MeH
O
P
1. base, conditions
2. electrophile (E) N
CO2MeH
O
P
E
entry P = base conditions electrophile result
1 Cbz LDA THF, -78 °C CO2Me 63
2 Cbz LDA THF, -78 °C to rt
4 Cbz LDA THF, -78 °CI
6 LDA THF, -78 °C to rtH CO2Me D
3 Cbz LiHMDS THF, -78 °C to rt CO2Me D
DCO2Me
7 LDA THF, -78 °C to rtBn CO2Me NR
11 LDA THF, HMPA, -78 °C to rtBn NRD2O
12 KHMDS THF, 18-crown-6, -78 °C to rtBn NRD2O
5 Cbz - HOAc, rt Br2 NR
Scheme 26. Attempts to Functionalize Spirocyclic Esters at C7
9 THF, 0 °C to rtBn NRKH I
NR = no reaction;D = decomposition
7
8 LiHMDS THF, -78 °C to rtBn CO2Me NR
10 LDA THF, HMPA, -78 °C to rtBn NRMeI
63
The methyl imidate 110, easily prepared via treatment of N-H lactam 63 with methyl
trifluoromethanesulfonate in quantitative yield, was similarly resistant to attempts at C7-
functionalization with a variety of non-nucleophilic bases and electrophiles including methyl
acrylate, allyl iodide, TMSCl, methyl iodide and D2O (Scheme 27).
41
N
CO2MeH
OMe
Scheme 27. Preparation and Attempted C7-Functionalization of Imidate 110
63
MeOTfCH2Cl2
rt
110
~100%
base, E
N
CO2MeH
O
H N
CO2MeH
OMe
E
3.2. Attempts to Homologate at C7 via Enamine Chemistry
3.2.1. Studies with N-H Lactam (E)-Pyrrolidinoenamine 112.
The failed exchange experiments with D2O, in particular, provided strong evidence that
spirocycles 53, 62, 63, and 110 do not undergo the desired ester enolization upon treatment with
base. In view of these inexplicable results, we turned to the possibility of accomplishing the desired
C7-functionalization via an enamine alkylation.
Towards this end, N-H lactam ester 63 was chemoselectively reduced with
diisobutylaluminum hydride (DIBAL-H) at -78 ºC to afford aldehyde 111 in moderate yield
(Scheme 28). Whereas the conversion of aldehydes to enamines often employs harsh conditions
and provides low product yields, the mild procedure developed by Bélanger and coworkers can
mitigate these issues.31 Accordingly, treatment of aldehyde 111 with pyrrolidine and molecular
sieves in chloroform at 0 ºC provided (E)-pyrrolidinoenamine 112 as a white crystalline solid. We
were rather surprised to discover that enamine 112 was remarkably stable, even allowing for
recrystallization from diethyl ether, which provided material suitable for single crystal X-ray
diffraction analysis (ORTEP in Scheme 28).
42
N H
CHOH
O
65%
NH
H
O
N
112 (X-ray)
R
R = CO2Me,
DIBAL-H
111
pyrrolidine
100%
Scheme 28. Synthesis and Attempted C7-Functionalization of (E)-Pyrrolidinoenamine 112
NH
CO2MeH
O
63
N H
CHOH
O
R
then H3O+
CH2Cl2
-78 °C
CHCl3, 0 °C
4Å MS
CHO, CN,
CH2Br
7
113
Since Michael-type addition of enamine 112 to an α,β-unsaturated carbonyl species (Stork
enamine chemistry)32 appeared the most direct route to the appropriate 1,5-dicarbonyl cyclization
precursor needed to probe the pivotal B-ring closure (Cf. Scheme 6), a number of conditions to
perform this transformation were screened. However, we were disappointed to discover that
heating enamine 112 in the presence of excess methyl acrylate, acrylonitrile, or acrolein at reflux
in a sealed tube overnight, followed by an aqueous acidic quench led only to the recovery of
aldehyde 111. Even performing the reaction in neat methyl acrylate at 180 ºC under microwave
43
irradiation, gave no evidence of the desired C7-adduct 113. Likewise, (E)-pyrrolidinoenamine 112
failed to undergo alkylation with allyl bromide even at elevated temperatures.
3.2.2. Studies with N-Bn Lactam (E)-Pyrrolidinoenamine 116.
Reasoning that perhaps better results might be obtained using the enamine derived from
the N-benzyllactam series, spirocyclic ester 53 was first converted to N-methoxy-N-methylamide
114 in high yield using a combination of N,O-dimethylhydroxylamine hydrochloride and
dimethylaluminum chloride (Scheme 29).33 Chemoselective reduction of amide 114 with lithium
aluminum hydride at -40 ºC then furnished aldehyde 115 in excellent yield.34 Conversion of 115
to (E)-pyrrolidinoenamine 116 using the Bélanger protocol was accomplished in quantitative
yield.31 However, enamine 116 was again resistant to reaction with various Michael acceptors as
well as allyl bromide even under forcing conditions.
NBn
H
O
115
N Bn
H
O
N
116
pyrrolidine
NBn
CHOH
O
114
91%
53
100%
Me(OMe)NH2Cl
N
OMe
OMe
-40 °C
Scheme 29. Synthesis and Attempted C7-Functionalization of (E)-Pyrrolidinoenamine 116.
R
NBn
H
O
CO2Me
then H3O+
NBn
CHOH
O
R
Me2AlCl, CH2Cl20 °C-rt
90%
LiAlH4, THF
CHCl3, 0 °C
4Å MS
R = CO2Me,
CHO, CN,
CH2Br
7
44
With our options for C7-homologation dwindling, we next explored the halogenation of N-
benzyl (E)-pyrrolidinoenamine 116. Gratifyingly, it was discovered that treatment of 116 with one
equivalent of N-chlorosuccinimide,35 followed by hydrolysis with aqueous acetic acid, provided
α-chloroaldehyde 117 as a 2.2:1 mixture of C7-diastereomers (Scheme 30). We hoped, at this
stage, that elaboration of this α-chloroaldehyde 117 to the B-ring cyclization precursor might be
feasible using nitrosoalkene “umpolung” conjugate addition methodology developed recently in
our laboratory (vide infra).
N Bn
H
O
N
116
NBn
CHOH
O
Cl1) NCS, 65 °C
2) HOAc, H2O
117 (dr = 2.2:1)
Scheme 30. Chlorination of (E)-Pyrrolidinoenamine 116 at C7
Et2O, CHCl3
82%
3.3 C7-Homologation via Nitrosoalkene Umpolung Conjugate Addition
3.3.1. Background on Nitrosoalkene Conjugate Additions
Although nitrosoalkenes 120 (Scheme 31) had first been hypothesized as reactive
intermediates as early as in the late nineteenth century, spectroscopic evidence for their existence
did not come until the 1960’s.36 These transient species, occasionally accompanied by a fleeting
blue color in a reaction mixture, readily participate in a number of transformations including
thermal [4+2] cycloadditions as well as in conjugate additions, in which they can function as
electrophilic “enolonium” ion equivalents.
45
Often high yielding and reproducible, conjugate additions to nitrosoalkenes provide a
reliable route to 1,4-dicarbonyl synthons (as exemplified by 121) that can be difficult to prepare
using alternative methods. In recent years, our laboratory has studied both the inter- and
intramolecular Michael-type additions of various nucleophiles, primarily 1,3-dicarbonyl species,
to nitrosoalkenes generated in situ from α-chloroaldoximes and ketoximes.37
Although a number of procedures for the generation of nitrosoalkenes have been reported,
the Weinreb laboratory conjugate addition methodologies have relied upon either the ‘classical’
base promoted 1,4-hydrogen chloride elimination of free α-chlorooximes 118 (Method A) or the
fluoride promoted 1,4-elimination of α-halo-O-silyloximes 119 developed by Denmark and
coworkers (Method B).38 In the former method, nitrosoalkene formation typically occurs
concurrently with the addition of the anionic donor, or in the case of intramolecular reactions,
addition of a strong base to generate the nucleophilic species. Thus, the ‘classical’ method can
become problematic when expensive nucleophiles are utilized since two or more equivalents of
the anionic species are required with one serving sacrificially to generate the nitrosoalkene
intermediate. Likewise, intramolecular Michael addition (IMA) reactions can be difficult to
achieve using the classical method, since the cyclization precursors typically undergo both
deprotonation and nitrosoalkene formation upon addition of the base. In these instances, the
Denmark protocol can offer the synthetic chemist a great deal more flexibility, since nitrosoalkene
formation occurs chemoselectively at a specific point in the reaction only after the addition of a
fluoride source such as tetra-n-butylammonium fluoride (TBAF) or cesium fluoride. Thus,
nitrosoalkene formation and deprotonation (or addition) of the anionic nucleophile precursor can
occur independently of one another.
46
NOH
F- source
base
118
Method A
Method B
Scheme 31. Conjugate Additions of Nitrosoalkene Intermediates
EWG EWG
EWG = R1CO, R1CO2,
CN, RSO2, etc.
Cl
NOSiR3
119
Cl
NO
120
NOH
121
EWG
EWG
O
enolonium ionequivalent
3.3.2. Nitrosoalkene Michael Addition of α-Chloro-O-Silylaldoxime 122.
In light of our failure to accomplish the desired C7-homologation en route to myrioneurinol
via traditional enolate or enamine chemistry, we hoped that a nitrosoalkene ‘umpolung’ conjugate
addition of an appropriate soft nucleophile to an oxime derived from α-chloroaldehyde 117 would
provide a solution to this hitherto intractable problem. Towards this end, α-chloroaldehyde C7-
diastereomeric mixture 117 was converted to O-TBS-α-chlorooximes 122 in good yield (Scheme
32). Although the C7-configuration of chlorooxime 122 is of no consequence to the proposed
nitrosoalkene Michael addition, the O-silyloxime diastereomers were nevertheless separable on a
column of silica gel, and could therefore be characterized individually.
47
NBn
H
O
N
OTBS
ClTBSONH2
PPTSCH2Cl2, rt
85%
122
N Bn
CHOH
O
Cl
117
Scheme 32. Conversion of Aldehyde 117 to O-Silyloxime 122
dr ~ 2.2:1
At this stage, we were prepared to investigate the proposed Michael addition to a
nitrosoalkene intermediate generated from O-TBS-α-chlorooxime 122 via the Denmark protocol.
The lithium enolate of dimethyl malonate was selected as the nucleophile since this 1,3-dicarbonyl
derivative was not particularly sterically demanding and would also permit elaboration of the
resulting adduct to the desired B-ring cyclization precursor 33 (Cf. Scheme 6) via decarboxylation
and one carbon homologation (vide infra). Since very little is known about the reactive
conformation of nitrosoalkene intermediates, we could not easily predict the stereochemical
outcome of the addition. We anticipated, however, that a mixture of C7-diastereomers would
probably result and hoped that the compound with the correct configuration for elaboration to the
natural product would comprise a substantial amount of the product mixture.
In accordance with the experimental protocols which had been developed in our laboratory,
O-TBS-α-chlorooxime 122 was added dropwise to a solution of the pre-generated malonate
lithium enolate at -78 ºC, followed by slow addition of a solution of TBAF in THF at that
temperature and immediate warming to 0 ºC, which provided a ca. 5:1 mixture of two products
(ratio determined by proton NMR) which were difficult to separate completely using either a
column of silica gel or preparative TLC (Scheme 33). Mass spectrometric analysis of the mixture
revealed that both compounds possessed the correct molecular weight. The compounds were
initially and incorrectly assigned to be a mixture of C7-diastereomers (vide infra).
48
Despite both compounds having different Rf values on the TLC, complete purification of a
sufficient quantity of the minor product for detailed NMR analysis could not be done. A moderate
degree of resolution was achieved via iterative flash column chromatographic separation of
fractions collected from the extreme ends of product elution from the previous column, resulting
in partial crystallizations of both the major and minor components. Recrystallization of the crude
solids from diethyl ether provided clear prisms of the pure major and minor products that proved
to be of sufficient quality for single crystal X-ray diffraction analysis. We were quite pleased to
discover that both compounds possessed the correct C7-configuration needed for elaboration to
myrioneurinol and were simply (E)- and (Z)-oxime geometric isomers 123a and 123b, respectively
(ORTEP renderings shown in Scheme 33).
CO2Me
CO2Me
then TBAF NCO2Me
NH
CO2Me
O
OH
Bn
123a E-oxime (X-ray)123b Z-oxime (X-ray) ~5:1 E/Z
H
7
6
5
(E)-oxime 123a (Z)-oxime 123b
N Bn
H
O
N
OTBS
Cl
122
Scheme 33. Diastereoselective Nitrosoalkene Michael Addition
LiHMDS, THF
-78 oC
-78 oC to 0 oC
93%
5 56
67
7
49
3.3.3. Rationalization of Observed C7-Diastereoselectivity
Because of their transient nature, little is known about the geometry and stereoelectronic
disposition of nitrosoalkene intermediates. Our laboratory has conducted detailed studies on the
Michael-type addition of malonate nucleophiles to nitrosoalkenes derived from acyclic γ-chiral α-
chloroaldoximes that provided stereochemical outcomes that could be rationalized via a modified
Felkin-Anh model.37d In these studies, the nitrosoalkenes were assumed to adopt the more stable
(E)-configuration and were postulated to be stereoelectronically comparable to (E)-α,β-
unsaturated ester species. Although the complexity of spirocyclic scaffold in the oxime 122
precluded our ability to apply these findings to the myrioneurinol system directly, we nevertheless
developed a working model to rationalize the stereochemical outcome of the Michael addition that
involves attack of the malonate anion onto the least hindered face of hypothetical (E)-nitrosoalkene
conformer 124 (Scheme 34). We are unable, however, to provide a rationalization as to why 124
is the reactive conformation.
CO2Me
CO2Me
NBn
HO
N
O
NO
Bn
H H
NOH
124
Scheme 34. Conformational Rationalization for Observed C7 Diastereoselectivity
NCO2Me
NH
CO2Me
O
OH
Bn
123a/b
H
7
6
7C6,7
bond rotation
50
CHAPTER 4: B-RING CLOSURE STRATEGIES
4.1. Imidate/Nitrile α-Anion Cyclization Strategy
4.1.1. Preparation of Cyclization Precursor
With intermediates 123a/b containing the C5, C6, and C7-stereocenters in hand, we turned
our attention next toward the construction of the B-ring of the cis-DHQ system of myrioneurinol.
Since our first generation retrosynthesis of the alkaloid was predicated upon the cyclization of an
intermediate such as imidate (Cf. Scheme 6) we needed to perform a series of functional group
manipulations as well as a one-carbon homologation of 1,4-dicarbonyl surrogate 123a/b.
Thus, E/Z-oxime mixture 123a/b was first dehydrated to afford nitrile malonate 125 in
excellent yield (Scheme 35).39 Various reductive and oxidative oxime cleavage methods to afford
the corresponding aldehyde from aldoximes 123a/b were also screened at this time. However these
experiments ultimately resulted either in the formation of nitrile 125 or decomposition. We
reasoned that a late-stage nitrile hydrolysis and reduction of the derived acid moiety could be
employed to install the requisite C8-hydroxymethyl functionality, and therefore we decided to
proceed with the nitrile substrate.
Krapcho decarboxylation of malonate 125 with lithium chloride in refluxing DMSO/water
then furnished nitrile ester 126 in good yield.40 Nitrile ester 126 was then chemoselectively reduced
in good yield using lithium borohydride to afford alcohol 127, which was cleanly converted to the
corresponding mesylate 128. Heating of mesylate 128 with tetraethylammonium cyanide provided
N-benzyllactam dinitrile 129. Since the N-H lactam 130 was required for methyl imidate
formation, the removal of the protecting group on nitrogen was attempted at this stage. However,
dissolving metal reduction of N-benzyllactam 129 using sodium in liquid ammonia at -78 ºC
51
resulted in decomposition of the starting material, perhaps due to reduction of one or both of the
nitrile moieties under these conditions.
DCC, CuSO4Et3N, pyr, rt
CH2Cl2N
CO2Me
CNH
CO2Me
O
BnH
LiClDMSOH2O
155 oC73%
N
CNH
CO2Me
O
BnH
LiBH4THF, rt
93%N
CNH
O
BnH OR
Na/NH3Et2O
-78 oC
127 R = H
128 R = Ms
MsCl, Et3NCH2Cl2, rt, 64%
Et4NCN
4Å• MSMeCN
60 oC100%
96%
125 126
NCO2Me
NH
CO2Me
O
OH
BnH
7
123a/b
N
CNH
O
BnH CN
129
N
CNH
O
HH CN
130
Scheme 35. Attempted Elaboration of Oximes 123a/b to Dinitrile 130
Gratifyingly, N-benzyllactam alcohol 127 could be deprotected using a dissolving metal
reduction to afford the N-H lactam alcohol 131 in excellent yield (Scheme 36). Alcohol 131 was
then cleanly converted to the mesylate 132 and homologated to the dinitrile 130 in excellent yield.
Treatment of N-H lactam 130 with methyl trifluoromethanesulfonate furnished the desired methyl
imidate 133 in good yield.
52
N
CNH
O
BnH OH
Na/NH3Et2O
-78 oC
87%N
CNH
O
HH OR
131 R = H
132 R = Ms
MsCl, Et3NCH2Cl2, rt, 99%
Et4NCN
4Å MSMeCN
60 oC99%
N
CNH
O
HH CN N
CNH
OMe
CN75%
MeOTfCH2Cl2
rt
127
130 133
Scheme 36. Successful Elaboration of Alcohol Lactam 127 to Imidate 133
4.1.2. Imidate/Nitrile α-Anion Cyclization Studies
We were now prepared to explore the proposed C9,10 bond formation via intramolecular
cyclization of imidate dinitrile 133. Although no examples of such a nitrile α-anion/imidate
cyclization could be found in the literature, we had hoped that treatment of the cyclization
precursor with a strong non-nucleophilic base would induce the desired reaction pathway, resulting
in tricyclic cyanoenamine 134 (Scheme 37). To this end, dinitrile 133 was treated with freshly-
prepared LDA in THF at -78 ºC and the reaction mixture was slowly warmed to room temperature
and stirred overnight. After an aqueous workup, NMR analysis of the crude mixture revealed the
presence of only starting material (entry 1). Reasoning that perhaps the cyclization would benefit
from being performed at a higher temperature, trials in which the LDA was added at 0 ºC and at
room temperature were next performed (entries 2-3). However, in both cases, varying degrees of
decomposition were observed, along with the recovery of a small amount of unreacted starting
material. In neither case was any amount of tricycle 134 detected spectroscopically. The amide
53
base KHMDS was also screened (entry 4) but similarly afforded none of the desired cyclized
product 134. Thus, in view of these failures, the nitrile anion/imidate B-ring closure strategy was
abandoned in favor of alternative annulation methods.
N
CNH
OMe
CN
133
N
CN
CNH
H
134
base
conditions
entry base conditions result
1
2
3
4
LDA THF, -78 oC to rt NR
LDA THF, 0 oC to rt SM + D
LDA THF, rt SM (trace) + D
KHMDS THF, 0 oC to rt NR
Scheme 37. Attempted B-ring Closure via Nitrile Anion/Imidate Cyclization
NR = no reaction;SM = starting material;D = decomposition
54
4.2. Rainier Metathesis Strategy
4.2.1. Background on the Rainier Metathesis Reaction
The Rainier laboratory has developed a series of olefin/carbonyl metathesis reactions to
construct electron rich heteroatom substituted olefins.41 These useful transformations provide
access to synthetically important enol ether and enamide intermediates via the insertion of what
are hypothesized to be titanium ethylidenes generated in situ into ester and amide carbonyl groups,
respectively. Recently, Rainier and coworkers have reported the ring closing metathesis of
substrates containing N-tosyllactam and terminal olefin moieties such as 135 to provide the
corresponding bicyclic enesulfonamides 136 (Scheme 38).41d The methodology was tolerant of a
variety of lactam ring sizes and olefin tether lengths and provided the enesulfonamide products in
moderate to excellent yields, along with minor amounts of the acyclic products 137 resulting from
the carbonyl insertion and olefin metathesis of the titanium ethylidene derived from 1,1-
dibromoethane.
135
TiCl4, Zno, PbCl2Br2HCCH3
TMEDA, THFCH2Cl2
NTs
O
n
NTs
O[Ti]
n NTs
n
136
Scheme 38. Intramolecular Olefinic-Lactam Rainier Metathesis Reaction.
mm
m
entry m n yield*
1
2
3
4
5
1
+
NTs
nm
137
Me
Me
2 82
136:137
>95:5
2 2 75 87:13
3 2 78 90:10
3 1 70 >95:5
3 3 82 >95:5
*combined yield of 136 and 137
55
4.2.2. Second Generation Retrosynthesis
We recognized that such an olefinic-lactam metathesis reaction could potentially be
utilized to construct the B-ring of myrioneurinol, accomplishing the pivotal C9,10 bond formation.
Our modified retrosynthetic strategy was thus predicated upon the elaboration of nitrile/ester 126
to N-tosyllactam/olefin cyclization precursor 138 (Scheme 39). We hoped that metathesis of 138
would afford tricyclic enesulfonamide intermediate 139 which contains the A/B/D-ring subunit of
myrioneurinol. We expected that cleavage of the sulfonyl group from nitrogen would induce
tautomerization of enesulfonamide 139 to endocyclic imine 140. Since, the α-alkylation of imines
via 1-azaallyl anion formation is well documented,42 we hoped that metallation of 140 followed
by treatment with an appropriate electrophile would accomplish the necessary C9,11 bond
formation necessary for the eventual installation of the 1,3-oxazine C-ring. Examination of
molecular models of 1-azaallyl anion 141 suggested that the approach of the electrophile would
favor a trajectory leading to an equatorial disposition of the C11-substituent. We further theorized
that reduction of imine 142 should occur from the less-hindered convex face, thus establishing the
proper C10-stereochemistry for elaboration of piperidine 143 to myrioneurinol.
56
N
CNH
O
TsH
N
CNH
O
BnH
CO2Me
126 138
N
CNH
Ts
9
139
Scheme 39. Rainier Metathesis Strategy for Myrioneurinol B-Ring Closure.
Rainier metathesis
10
N
CNH
H
X OR
deprotect
140
base
N
CNH
H
141
N
CNH
H OR
[H-]
N
CNH
H OR
H
9
H H
910
142 143
11 11
H
[H-]
4.2.3. Preparation of N-Tosyllactam/Terminal Olefin Cyclization Precursor
4.2.3.1. Lactam Nitrile System
In order to prepare the requisite cyclization precursor for the pivotal Rainier metathesis
reaction, nitrile ester 126 was first converted to N-methoxy-N-methylamide 144 in moderate yield
using a combination of N,O-dimethylhydroxylamine hydrochloride and dimethylaluminum
chloride (Scheme 40).33 Chemoselective reduction of amide 144 with lithium aluminum hydride
at -40 ºC furnished aldehyde 145 in excellent yield.34 We were surprised to discover that Wittig
olefination of 145 with methylenetriphenylphosphorane resulted only in ca. 5% yield of the desired
terminal olefin 147. Various alternative methylenation strategies for 145 were explored including
57
Peterson olefination and treatment with the Tebbe-Petasis reagent. Eventually, Julia-Kocienski
olefination of aldehyde 145 with easily prepared phenyltetrazoylmethyl sulfone 146 was found to
provide olefin 147 in a more acceptable (and unoptimized) 32% yield.43 However, we were
disappointed to discover that during the removal of the benzyl protecting group from the lactam
nitrogen of 147 via dissolving metal reduction with sodium in liquid ammonia at -78 ºC,
concomitant loss of the nitrile functionality resulted leading to olefin 148.44
N
CNH
O
BnH
CO2Me
126
Me2AlClCH2Cl2
0 °C-rt, 73%
Me(OMe)NH2Cl
N
CNH
O
BnH
144
O
N
Me
OMeLiAlH4
THF, -40 oC
93%
N
CNH
O
BnH
CHO
145
N NN
N
PhMeO2S
146
LiHMDS, THF/HMPArt, 32%
N
CNH
O
BnH
147
Na/NH3
Et2O -78 oC
N
HO
H
148
Scheme 40. Attemped Elaboration of Nitrile Ester 126 to Rainier Metathesis Cyclization Precursor 138.
4.2.3.2. Methoxymethyl (MOM) Ether System
The low yields observed for the olefination in the nitrile series and our failure to
successfully cleave the benzyl protecting group from 147 forced us to revisit the oxime cleavage
of Michael adducts 123a/b. We were pleased to discover that a reductive deoximation method
recently developed in our laboratory employing titanium (IV) chloride and zinc metal dust at 0 ºC
58
cleanly converted the aldoxime E/Z-mixture 123a/b to aldehyde 149 in moderate yield (Scheme
41).45 Subsequent reduction of aldehyde 149 with one equivalent of sodium borohydride at 0 ºC
led to the isolation of α-carbomethoxylactone 150, which results from translactonization by the
intermediate C7-hydroxymethyl group resulting from reduction of the aldehyde. Krapcho
decarboxylation of 150 using lithium chloride in refluxing DMSO/water then furnished γ-lactone
151 in excellent yield.40
NCO2Me
CHOH
CO2Me
O
BnH
TiCl4, Zno
THF, 0 oC
63%
N
CO2Me
HO
Bn
O
O
HN
HO
Bn
OO
H
NaBH4MeOH 0 oC
81%
LiClDMSO/H2O155-160 oC
90%
Scheme 41. Elaboration of Oximes 123a/b to Lactone 151
150 151
NCO2Me
NH
CO2Me
O
OH
BnH
123a/b 149
Chemoselective reduction of γ-lactone 151 with DIBAL-H provided a ca. 3:1
diastereomeric mixture of γ-lactols 152 in good yield (Scheme 42). Wittig olefination of lactol
mixture 152 with excess methylenetriphenylphosphorane furnished the desired terminal olefin 153
in a yield much improved over that observed for the methylenation in the nitrile series (Cf. Scheme
40). The C7-hydroxymethyl group in 153 was then protected as the methoxymethyl (MOM) ether
154 in excellent yield. Dissolving metal reduction of N-benzyllactam 154 with sodium metal and
59
liquid ammonia at -78 ºC cleanly furnished N-H lactam olefin 155, which was treated with
LiHMDS followed by p-toluenesulfonyl chloride to furnish N-tosyllactam 156 in excellent yield.
DIBAL-HTHF
-78 oC
83%N
HO
Bn
O
H
OHPh3PMeBr
n-BuLi, THF 0 oC
68%
N
HO
Bn
OH
H
MOMClDIEA 0 oC
CH2Cl2
92% N
HO
Bn
OMOM
H
Na/NH3Et2O
-78 oC
92%
N
HO
H
OMOM
H
152
153 154
155
N
HO
Bn
OO
H
151
TsCl LiHMDS
THF, 0 oC
N
HO
Ts
OMOM
H88%
156
Scheme 42. Elaboration of Lactone 151 to Rainier Metathesis Cyclization Precursor 156
dr ~3:1
4.2.3.3. Rainier Metathesis of N-Tosyllactam 156.
With the requisite N-sulfonyllactam terminal olefin Rainier metathesis cyclization
precursor 156 in hand, we began to explore the conditions required to effect this pivotal
transformation. Gratifyingly, subjection of 156 to the metathesis conditions outlined by Rainier
provided the desired tricyclic ensulfonamide 157 in ca. 30% unoptimized yield (Scheme 43, entry
1).41d Since a small amount of the undesired acyclic enesulfonamide side product 158 resulting
from the insertion of the reduced titanium ethylidene formed from 1,1-dibromoethane was also
60
detected, we reasoned that increasing the concentration of cyclization precursor 156 might
ameliorate this problematic side reaction. Indeed, tripling the concentration of lactam olefin 156
improved the yield of tricycle 157 to a more synthetically useful 55%, with none of the acyclic
side product 158 detected by TLC or NMR analysis of the crude mixture (entry 2).
N
HO
Ts
OMOM
H
156
N
H
Ts
TiCl4, Zno, PbCl2Br2HCCH3
TMEDA, THF
CH2Cl2,
157
OMOM
55 oC
N
H
Ts
OMOM
H
158
Me
Me
entry concentration (M) result
1
2
0.003
0.009
157 (30%) + 158*
157 (55%)
Scheme 43. Preliminary Studies on Rainier Metathesis Reaction of 156
+
*yield not determined due to complex mixture
4.2.3.4. Attempted Elaboration of N-Ts Enesulfonamide 157.
Rather than trying to optimize the Rainier metathesis of lactam olefin 156 at this stage, we
instead decided to attempt to further elaborate tricycle 157. Since cleavage of the tosyl protecting
group from nitrogen was necessary for the tautomerization of enesulfonamide 157 to the
endocyclic imine 159, various conditions were explored to deprotect the tricyclic substrate
(Scheme 44). Unfortunately, enesulfonamide 157 was resistant to a variety of standard tosyl group
cleavage methods including treatment with lithium or sodium naphthalenide (entries 1-2) and
61
dissolving metal reduction in liquid ammonia at -78 ºC (entries 3-4). In each case, extensive
decomposition of the starting material was observed.
We hypothesized that these strongly reducing conditions might be incompatible with the
enesulfonamide moiety and thus also investigated several milder detosylation protocols.
Unfortunately, a mild aqueous samarium diiodide-mediated procedure,46a sonication of 157 with
magnesium turnings in anhydrous methanol,46b and treatment of 157 with potassium
diphenylphosphide46c were all unsuccessful in furnishing any endocyclic imine 159.
N
H
Ts
157
OMOM
conditions
N
H
159
OMOM
entry conditions result
1 Nao, naphthalene, THF, -78 oC D
2 Lio, naphthalene, THF, -78 oC D
3 Nao, NH3, Et2O, -78 oC D
4 Lio, NH3, Et2O, -78 oC D
5 SmI2, H2O, 0 oC NR
6 Mgo, MeOH, sonication D
7 KPPh2, THF, -78 oC D*
*small amount of unidentified side product
Scheme 44. Attempted Desulfonylation of Enesulfonamide 157
62
4.2.4. N-SES-Lactam System
Since we were unable to cleave the tosyl group from the enesulfonamide nitrogen in
tricycle 157, an alternative cyclization precursor for the pivotal Rainier metathesis reaction
containing a more labile 2-trimethylsilylethylsulfonyl (SES) protecting group for the lactam
nitrogen was prepared.47 Thus, treatment of N-H lactam olefin 155 with SES chloride48 cleanly
furnished the N-SES lactam olefin 160 in good yield. We were pleased to discover that subjection
of 160 to our optimized metathesis reaction conditions for tosyllactam 157 provided the desired
tricyclic N-SES enesulfonamide 161 in excellent 83% yield. Unfortunately, enesulfonamide 161
could not be desulfonylated using any of the existing fluoride-mediated protocols including
treatment with CsF,47a TBAF,47b TAS-F,47c and HF-pyridine complex.
N
HO
H
OMOM
H
155
SESCl LiHMDSTHF, 0 oC
N
HO
SES
OMOM
H78%
160
N
H
SES
TiCl4, Zno, PbCl2Br2HCCH3
TMEDA, THF
CH2Cl2, 55 oC
161
OMOM
83% N
OMOMH
159
H9
Scheme 45. Rainier Metathesis of N-SES Lactam Olefin 160
We also briefly examined the possibility of utilizing the weakly nucleophilic character of
enesulfonamides 157 and 161 to effect C9-functionalization.49 However, both compounds were
63
resistant to halogenation with elemental bromine and N-chlorosuccinimide,50a hydroboration,
acylation with various acyl halides,50b Vilsmier-Haack formylation,50c and Simmons-Smith
cyclopropanation.50d In each case, either decomposition or recovery of the starting material was
observed.
Although we had demonstrated that the pivotal Rainier metathesis of N-sulfonyllactam
olefins 156 and 160 could accomplish the desired B-ring formation, our failure to elaborate the
tricyclic products 157 and 161 forced us to abandon this route to myrioneurinol.
4.3. Allyl Silane/N-Sulfonyliminium Aza-Sakurai Strategy
4.3.1. Background: Weinreb Synthesis of the Sarain A Core Structure
Some time ago, the Weinreb laboratory had successfully employed an intramolecular
variant of the Sakurai reaction in a pivotal stereoselective carbon-carbon bond formation step in
the synthesis of the core structure 170 of the unusual marine alkaloid sarain A (171) (Scheme 46).51
In order to prepare the requisite cyclization precursor 167, Weinreb and coworkers had first treated
N-benzyllactam aldehyde 162 with vinylmagnesium bromide to furnish a diastereomeric mixture
of allylic alcohols 163. Alcohols 163 were then acylated with acetic anhydride to furnish allyl
acetates 164, in order to improve the nucleofugicity of the hydroxyl group. The acetate
diastereomeric mixture 164 was next treated with a trimethylsilylcuprate reagent generated in situ,
according to the method of Fleming and coworkers,52 which provided allyl silane 165 as an
inconsequential mixture of (E)- and (Z)-olefin geometric isomers. It should be noted that Weinreb
and coworkers determined that only the N-sulfonyllactam 167, as opposed to the N-benzyl
protected substrate 165, could be partially reduced with diisobutylaluminum hydride (DIBAL-H)
64
to afford a diastereomeric mixture of hemiaminals 168. Thus, the N-benzyl protecting group on
lactam 165 was removed via dissolving metal reduction with sodium and liquid ammonia at -78
ºC to afford N-H lactam 166, which was in turn protected as the N-tosyl derivative 167. Upon
reduction of 167 with DIBAL-H, it was discovered that treatment of the resulting mixture of
hemiaminals 168 with the Lewis acid iron (III) chloride effected the desired stereoselective six-
membered ring closure adjacent to the nitrogen. Weinreb and coworkers hypothesized that this
interesting cyclization likely involved the highly electrophilic N-sulfonyliminium ion intermediate
169 which is attacked by the π-system of the pendant allyl silane moiety that occupies a quasi-
equatorial position in the chair-like conformation shown, resulting in the observed stereochemistry
for tricycle 170.
65
RN
O
NH
H
Bn
SiMe3
165 R = Bn (50%)
H
BnN
O
NH
H
Bn
CHO
162
H
MgBr
THF, 0 oC to rt BnN
O
NH
H
Bn
163 R = H
HOR
164 R = Ac
Ac2O, Et3N
DMAP, CH2Cl235% (2 steps)
(TMS)2(CN)Li2Cu
THF: HMPA, -25 oC
50%
DIBAL-H
CH2Cl2-78 oC to rt
93%
TsN NH
H
Bn
SiMe3
H
OH
168
FeCl3, CH2Cl2
-78 oC to rt
N
H
NBn
H
Ts
SiMe3
H61%
N
H
NBn
H
TsH
H
169 170
N
H
NH
sarain A (171)
O
HO H
HHO
166 R = H
167 R = Ts
Nao, NH3
THF, -78 oC(95%)
(71%)
TsCl, LiHMDSTHF, 0 oC
Scheme 46. Pivotal Aza-Sakurai Cyclization in Weinreb Route to Sarain A Core
We recognized the fundamental similarity of this transformation with the desired C9,10
bond formation to construct the cis-DHQ in the myrioneurinol system and thus sought to explore
this B-ring closure strategy further (vide infra).
66
4.3.2. Third Generation Myrioneurinol Retrosynthesis
Due to the failure of our studies on the Rainier metathesis strategy for B-ring closure, we
explored the possibility of accomplishing the pivotal C9,10 bond formation in the myrioneurinol
total synthesis using a related allyl silane/N-sulfonyliminium aza-Sakurai reaction. This strategy
was predicated upon our ability to elaborate nitrosoalkene Michael adducts 123a/b to the
appropriate aza-Sakurai cyclization precursor (Scheme 47). Partial reduction of the N-
sulfonyllactam carbonyl in 172 with DIBAL-H would furnish a mixture of hemiaminal
diastereomers 173, which upon treatment with an appropriate Lewis acid would dehydrate to
afford N-sulfonyliminium intermediate 174. We anticipated that 174 would cyclize via the
conformation shown where the incipient B-ring would be chair-like and the allyl silane moiety
would occupy a quasi-equatorial position leading to tricycle 175 which contains the desired C9,10
relative configuration for elaboration to the natural product.
NCO2Me
NH
CO2Me
O
OH
BnH
123a/b 172
N
RH
Ts
SiMe3
O
174
N
RH
Ts
SiMe3
DIBAL-H
173
N
RH
Ts
SiMe3
OH
Lewis Acid
N
RHH
Ts
175
H910
Scheme 47. Aza-Sakurai Approach to Forming the Myrioneurinol B-Ring
R = CN, CH2OMOM
67
4.3.3. Preparation of Cyclization Precursor
4.3.3.1. Attempted Allyl Silane Formation via Fleming Cuprate Methodology in Nitrile
System
At the outset of our studies on the intramolecular aza-Sakurai reaction, the successful
oxime cleavage method for converting 123a/b into aldehyde 149 (Cf. Scheme 41) had not yet been
discovered. Therefore, the preliminary investigative work toward allyl silane/sulfonyllactam
cyclization precursor 172 was performed from nitrile aldehyde 145 (Cf. Scheme 40). Towards this
end, aldehyde 145 was first treated with vinylmagnesium bromide to furnish allyl alcohols 176 in
moderate yield (Scheme 48). Acylation of 176 with acetic anhydride then furnished the desired
acetate mixture 177 in good yield. Disappointingly, acetates 177 did not undergo the desired
conversion to the allyl silane 179 when subjected to the Fleming silylcuprate methodology.52a A
related trimethylsilylcuprate addition to the corresponding allylic mesylates 178, prepared from
alcohol 176 in good yield, was similarly unsuccessful in generating any of the desired allyl silane
179.52b
68
N
CNH
O
BnH
CHO
145
MgBr
THF, rt
N
CNH
O
BnH
176 R = H
OR
177 R = Ac
Ac2O, Et3N
DMAP, CH2Cl273% (2 steps)
Scheme 48. Attempted Fleming Silylcuprate Additions to Derivatives of Aldehyde 145
(TMS)2(CN)Li2Cu
THF, HMPA, -25 oC
N
CNH
O
BnH
SiMe3
and
176 R = H
178 R = Ms
MsCl, Et3N
CH2Cl2, 0 oC
177 or 178
76% (2 steps)
179
dr ~ 4:1
4.3.3.2. Attempted Allyl Silane Formation in Methoxymethyl (MOM) Ether-Protected
System
Having developed the sequence to convert nitrosoalkene Michael adducts 123a/b to γ-
lactone 151 (Cf. Scheme 41), we decided to explore the elaboration of this compound to the
requisite precursor for the aza-Sakurai reaction. Towards this end, lactone 151 was first ring
opened to N-methoxy-N-methylamide 180 using N,O-dimethylhydroxylamine hydrochloride and
dimethylaluminum chloride in good yield (Scheme 49).33 Since immediate protection of the C7-
hydroxymethyl group of 180 was necessary to prevent reversion to γ-lactone 151, the alcohol was
converted to the methoxymethyl (MOM) ether 181 in good yield. At this stage, chemoselective
69
reduction of the N-methoxy-N-methylamide moiety in 181 with lithium aluminum hydride at -40
ºC furnished aldehyde 182.34
180 R = H (86%)
181 R = MOM (80%)
N
HO
Bn
OR
H
O
NOMeMe
MOMClDIEA
THF, 0 °C
Me2AlClCH2Cl20 °C-rt
Me(OMe)NH2Cl
N
HO
Bn
OO
H
151
Scheme 49. Elaboration of Lactone 151 to Aldehyde 182
N
H
CHO
O
Bn
OMOM
H
182
LiAlH4THF, -40 °C
Addition of vinylmagnesium bromide to aldehyde 182 provided a mixture of allyl alcohol
diastereomers 183 in good yield (Scheme 50). Alcohols 183 were then converted to the
corresponding acetates 184 in excellent yield via acylation with acetic anhydride. We were again
disappointed to discover that acetates 184 failed to undergo the Fleming trimethylsilylcuprate
addition to afford allyl silane 187.52a Moreover, attempts to prepare the corresponding mesylate
185 from alcohols 183 resulted instead in the isolation of vinylic furan 186 which presumably
arises via in situ methoxymethyl group cleavage followed by intramolecular displacement of the
mesylate.
70
N
H
CHO
O
Bn
OMOM
H
182
MgBr
THF, rt
N
HO
Bn
OMOM
H
183 R = H
OR
184 R = Ac
Ac2O, Et3N
DMAP, CH2Cl2, 0 oC
N
HO
BnH
186
O
184
(TMS)2(CN)Li2Cu
THF, HMPA, -25 oC
N
HO
BnH
SiMe3
OMOM
187
Scheme 50. Attempted Elaboration and Fleming Silylcuprate Addition in MOM Ether Series.
(91%)
183 R = H
185 R = Ms
MsCl, Et3NNaHCO3, CH2Cl2, 0 oC
58%
dr ~ 10:1
4.3.3.3. Seyferth-Wittig Homologation of Aldehyde 182
Since acetate mixture 184 was unreactive toward the Fleming silylcuprate addition
protocol, the search for an alternative allyl silane formation method became necessary.
Examination of the synthetic work on the sarain A core revealed that attempted homologation of
aldehyde 162 (Cf. Scheme 46) with the Seyferth-Wittig reagent using 2-
trimethylsilylethyltriphenylphosphonium iodide (SETPPI),53 had been attempted but was
unsuccessful in generating allyl silane 165.
71
Nevertheless, we reasoned that perhaps this method might work for the desired
homologation of aldehyde 182 in the myrioneurinol route. We were pleased to discover that
treatment of 182 with five equivalents of the Seyferth-Wittig reagent, generated via treatment of
SETPPI with phenyllithium at a room temperature, led to formation of allyl silane 187 as an
inconsequential ca. 2.5:1 Z/E mixture of olefin geometric isomers (Scheme 51). With allyl silanes
187 finally in hand, the benzyl protecting group on the lactam nitrogen was removed in good yield
using dissolving metal reduction with sodium in liquid ammonia at -78 ºC to afford the rather
unstable N-H lactam 188. Immediate sulfonylation of 188 via treatment with LiHMDS followed
by p-toluenesulfonyl chloride afforded the requisite N-tosyllactam allyl silane cyclization
precursor 189 for the proposed intramolecular aza-Sakurai reaction in high yield.
188 R = H (79%)
189 R = Ts (87%)
187
Me3SiPPh3 I
PhLi, THF, rt
74% (2 steps)
Na/NH3Et2O
-78 °C
LiHMDSTsCl, THF
DMAP
N
OMOMH
Bn
SiMe3
O
N
OMOMH
R
SiMe3
O
N
H
CHO
O
Bn
OMOM
H
182
Scheme 51. Seyferth-Wittig Homologation of Aldehyde 182
72
4.3.4. Aza-Sakurai Reaction of N-Tosyllactam/Allyl Silane 189.
The pivotal intramolecular allyl silane/N-sulfonyliminium aza-Sakurai reaction of 189 was
next addressed. In the sarain A work, partial reduction of sulfonyllactam 167 with DIBAL-H was
utilized to afford the chromatographically-isolable hemiaminals 168 as a diastereomeric mixture
(Cf. Scheme 46).51a Accordingly, we were pleased to discover that treatment of 189 with fifteen
equivalents of DIBAL-H at -78 ºC resulted in complete consumption of the starting material and
the emergence of two new spots on the reaction TLC, as well as the correct molecular ion peak for
hemiaminal 190 upon mass spectrometric analysis (Scheme 52). However, the yields of 190 upon
aqueous workup and flash column chromatographic purification on silica gel were very low (<5%).
Moreover, treatment of the presumed purified hemiaminal mixture 190 with anhydrous iron (III)
chloride at -78 ºC, followed by gradual warming to room temperature, conditions which had been
successful in the sarain A route, led only to decomposition of the starting material.
190
DIBAL-H
N
OMOMH
Ts
SiMe3
OH
-78 oC
189
N
OMOMH
Ts
SiMe3
O
<5%
FeCl3CH2Cl2
-78 oC to rt
191
N
OMOMH
Ts
H
H
Scheme 52. Attemped Aza-Sakurai Cyclization of Allyl Silane 189Using Conditions from Sarain A Work
73
Since the isolation of the hemiaminals 190 appeared to be problematic, it was decided to
attempt to perform the partial reduction and the cyclization in one synthetic operation. To our
delight, treatment of 189 with fifteen equivalents DIBAL-H at -78 ºC, followed by addition of
anhydrous iron (III) chloride and gradual warming to 0 ºC over two hours and an aqueous workup,
provided proton NMR evidence for the formation of a single diastereomeric compound possessing
the correct molecular weight (as determined by LRMS) for tricyclic olefin 191 (Scheme 53, entry
1). The reaction appeared to be approximately 40% complete, with hemiaminals 190 comprising
the remainder of the mixture. Encouraged by this result, in an attempt to drive the reaction to
completion, another trial was performed in which the reaction mixture was allowed to warm to
room temperature (entry 2). However, we were disappointed to observe extensive decomposition
under these conditions via TLC and NMR analysis. The optimal reaction temperature range for
the aza-Sakurai cyclization of 189 was eventually discovered to be -78 to ca. 5 ºC (entry 3).
Careful monitoring of the temperature was essential to the reproducibility of the procedure, as was
immediate aqueous quenching of the mixture when the temperature had reached 5 ºC. In this
manner, tricyclic olefin 191 could be consistently isolated in yields greater than 70% even on a
several hundred milligram scale.
74
189
N
OMOMH
Ts
SiMe3
ODIBAL-H
-78 oCCH2Cl2
then FeCl3
191
N
OMOMH
Ts
H
H
+
190
N
OMOMH
Ts
SiMe3
OH
entry temperature result (% yield)
1 -78 oC to 0 oC 190 (~30) + 191 (~20)
2 -78 oC to rt D
3 -78 oC to 5 oC 191 (78%)
Scheme 53. Optimization of the 'One Pot' Aza-Sakurai Cyclization of 189
temperature
D = decomposition
4.3.5. Confirmation of the C9,10 Stereochemistry of Tricycle 191
A single diastereomer of tricyclic olefin 191 was produced in the aza-Sakurai cyclization
which was determined to possess the correct C9,10 relative configuration for elaboration to
myrioneurinol. Two-dimensional NMR study of tricycle 191 revealed strong 1H-1H NOESY
correlations between H10 with H6, H16ax, H14ax, and H8ax suggesting a syn-facial disposition for
these hydrogens (Figure 5). Moreover, a strong NOESY correlation between H9 with H7, H4ax
and H2ax provided strong evidence that these signals were disposed to the same face. Since no such
correlation was observed between H9 and H10, and the aforementioned correlations were
consistent with those in the NOESY spectrum of natural myrioneurinol,54 we were confident that
tricycle 191 contained the five contiguous stereocenters in the correct relative configuration for
the alkaloid.
75
NOMOM
H
H
H
2
3 4 5
14
15 16
17
10
9
7
8
18
6
Ts
H
H
H
HH
H
Figure 5. NOESY Correlations for Tricycle 191 (H H)
H
H
H
H
H
76
CHAPTER 5: COMPLETION OF THE MYRIONEURINOL SYNTHESIS
5.1. Attempted Elaboration of N-Ts Tricyle 191
With the advanced tricyclic intermediate 191 containing all five contiguous stereocenters
and the A/B/D-rings of the alkaloid secured, the installation of the 1,3-oxazine C-ring was next
addressed in order to complete the total synthesis of the alkaloid. Thus, the vinyl group in tricycle
191 was cleaved ozonolytically using a two step reductive workup first involving treatment of the
ozonide with triphenylphosphine overnight, followed by reduction of the crude intermediate
aldehyde with sodium borohydride to furnish alcohol 192 in excellent yield (Scheme 54). At this
stage, removal of the N-tosyl group from alcohol 192 to afford free piperidine 193 was attempted
using a variety of methods. Strongly reducing conditions including treatment with either sodium
or lithium naphthalenide (entries 1-2), dissolving metal reduction with either sodium or lithium
metal in liquid ammonia at -78 ºC (entries 3-4), and treatment with freshly-prepared sodium
amalgam (entry 5) each led to extensive decomposition of the starting material. Milder
desulfonylation methods such as the sonication of 192 with magnesium turnings in anhydrous
methanol46b (entry 6) and treatment with aqueous samarium diiodide46a (entry 7) were likewise
unsuccessful.
77
N
OMOMHH
Ts
OH
1) O3, CH2Cl2-78 °C; PPh3
2) NaBH4MeOH, 0 °C
N
OMOMHH
Ts
191
H H
19292%
Scheme 54. Ozonolytic Cleavage with Reductive Workup of Olefin 191 and Attemped Desulfonylation of 192
conditions
N
OMOMHH
H
OHH
193
entry conditions result
1 Nao, naphthalene, THF, -78 oC D
2 Lio, naphthalene, THF, -78 oC D
3 Nao, NH3, Et2O, -78 oC D
4 Lio, NH3, Et2O, -78 oC D
5 Na-Hg, MeOH, rt D
6 Mgo, MeOH, sonication, rt D
7 SmI2, THF, pyrrolidine, H2O, rt NR
8 Red-Al, PhMe, reflux D
D = decomposition;NR = no reaction
Heating alcohol MOM ether 192 at 50 ºC in 6 N aqueous HCl in THF cleanly removed the
methoxymethyl protecting group, providing diol 194 in quantitative yield (Scheme 55). However,
diol 194 proved equally resistant to desulfonylation utilizing a number of the aforementioned
methods, with decomposition being observed in the majority of cases.
N
OMOMHH
Ts
OH
H
192
6 N HClTHF/H2O
50 oC
100%N
OHHH
Ts
OH
H
194
N
OHHH
H
OHH
195
Scheme 55. Removal of the Methoxymethyl Protecting Group from sulfonamide 192 and Attempted N-Ts Cleavage
N-Tscleavage
78
5.2. Alternative Protecting Groups for the Lactam Nitrogen
5.2.1. N-SES-Lactam System
Since the inability to remove the sulfonyl protecting group from the nitrogen of tricycles
192 and 194 presented a serious obstacle to the completion of the total synthesis of myrioneurinol,
it was decided to evaluate the feasibility of performing the aza-Sakurai reaction on N-
sulfonyllactam substrates bearing more easily cleaved protecting groups. Towards this end, the N-
SES lactam allyl silane precursor 196 was prepared from N-H lactam 188 in moderate yield
(Scheme 56a).47,48 Subjection of 196 to the optimized conditions for the cyclization of N-Ts lactam
189 provided a small amount of the desired N-SES tricyclic olefin 197 along with what appeared
to be hemiaminals 198. Attempted desulfonylation of tricycle 197 utilizing the fluoride sources
CsF or TBAF at elevated temperatures led only to decomposition or recovery of the starting
material (Scheme 56b).
79
DIBAL-H
-78 oCCH2Cl2
then FeCl3
197
N
OMOMHH
+
198
N
OMOMH
SES
SiMe3
OH
Scheme 56. Studies on Aza-Sakurai Cyclization of N-SES Series
warm to ~5 oCSES
196
N
OMOMH
SES
SiMe3
O
188
N
OMOMH
H
SiMe3
O
LiHMDS, SES-Cl
THF, 0 oC to rt
73%
27% 41%
197
conditions
N
OMOMHH
H
entry conditions result
1 CsF, DMF, rt to 95 oC D
2 TBAF, THF, reflux NR
a) Preparation and Cyclization of N-SES Lactam/Allyl Silane 196
b) Attempted Desulfonylation of Tricycle 197
5.2.2 N-Nosyllactam System
Cyclization precursor 199 containing the 4’-nitrobenzenesulfonyl (nosyl) protecting group
on nitrogen was prepared from N-H lactam 188 in good yield (Scheme 57). However, attempted
partial reduction/cyclization of 199 using both the optimized method developed for N-tosyllactam
80
189 as well as a related Sc(OTf)3-mediated protocol55 resulted in the formation of a complex
mixture of products, none of which was consistent with the desired tricyclic olefin 200.
199
N
OMOMH
Ns
SiMe3
O
188
N
OMOMH
H
SiMe3
OLiHMDS, NsCl
THF, 0 oC to rt
80%
conditions
200
N
OMOMHH
Ns
entry conditions result
1 DIBAL-H, CH2Cl2, -78 oC, then FeCl3 warm to ~5oC D
2 DIBAL-H, CH2Cl2, -78 oC, aqueous quench then FeCl3,
CH2Cl2, -78 oC to 0 oCD
3 DIBAL-H,CH2Cl2, -78 oC, aqueous quench then Sc(OTf)3,
CH2Cl2, -78 oC to rt
unidentified SP
Scheme 57. Synthesis and Attempted Cyclization of N-Ns Substrate 199
D = decomposition; SP = side product
5.2.3. Acid-Labile Sulfonamides
The t-butylsulfonyl (Bus) protecting group is orthogonal to the majority of other sulfonyl
groups for nitrogen, requiring strong acid for cleavage rather than reductive conditions.56 Thus,
the preparation of a cyclization precursor 201 containing an N-Bus lactam was also attempted
(Scheme 58a). However, the two-step process for N-Bus group installation involving treatment of
81
the N-H lactam 188 with t-butylsulfinyl chloride followed by chemoselective oxidation of the
resulting sulfinamide to the sulfonamide appeared to be incompatible with the rather delicate allyl
silane moiety in 188.
A cyclization precursor 202 containing another acid-labile sulfonyl protecting group,
2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl (pbf),57 was prepared successfully from N-H
lactam 188 in moderate yield. However, perhaps due to steric reasons, N-pbf lactam 202 failed to
cyclize to tricycle 203 in the desired manner leading instead to a complex mixture of products.
188
N
OMOMH
H
SiMe3
O 1) t-BuSOCl
LiHMDS, THF, 0 oC
2) mCPBA, CH2Cl2, 0 oC
201
N
OMOMH
Bus
SiMe3
O
Scheme 58. Attempted aza-Sakurai Cyclizations with Acid Labile Sulfonamides
188
N
OMOMH
H
SiMe3
OpbfCl, LiHMDS
THF, DMAP
0 oC to rt
202
N
OMOMH
pbf
SiMe3
O
63%
Me
O Me
Me
Me
Me
ClO2S
pbfCl
DIBAL-H
-78 oCCH2Cl2
then FeCl3warm to ~5 oC 203
N
OMOMHH
pbf
A) Attempted N-Bus Protection of 188
B) N-pbf Protection and Attempted Cyclization of 202
= BusS
O
O
82
5.2.4. Attempted Cyclization of N-Cbz Lactam
We also briefly examined the possibility of performing an allyl silane/N-acyliminium aza-
Sakurai reaction58 of N-Cbz lactam cyclization precursor 204 which was prepared via treatment of
N-H lactam 188 with benzyl chloroformate in acceptable yield (Scheme 59). However, treatment
of N-acyllactam 204 with DIBAL-H did not provide any evidence of partial reduction of the lactam
carbonyl at -78 ºC. After gradual warming to room temperature followed by an aqueous quench,
evidence of the N-H lactam 188 and benzyl alcohol was observed in the NMR of the crude mixture,
suggesting that deacylation of N-Cbz lactam 204 was the primary mode of reactivity.
188
N
OMOMH
H
SiMe3
O n-BuLi, CbzCl
THF, -78 oC to rt
N
OMOMH
Cbz
SiMe3
O
204
58%
DIBAL-H
-78 oCCH2Cl2
then FeCl3warm to ~5 oC 205
N
OMOMHH
Cbz
Scheme 59. Attempted N-Acyliminium Aza-Sakurai Reaction of 204
5.3. N-Tosyllactam System Revisted
Since the intramolecular aza-Sakurai cyclization of sulfonamide 189 was by far the highest
yielding and most reproducible (vide supra), we decided to revisit the desulfonylation of the N-
tosyl series. The protection of the C7-hydroxymethyl group as a methoxymethyl (MOM) ether had
83
been necessary throughout the entire sequence to prevent undesired side reactions from occurring.
We therefore wondered whether the free C9-hydroxymethyl was somehow interfering with the
desulfonylation of tricycles 192 and 194.
To verify this hypothesis, tricyclic alcohol 192 was protected as the bis-methoxymethyl
ether 206 in good yield (Scheme 60). The cleavage of the N-tosyl group from 206 was first
attempted using magnesium metal turnings in anhydrous methanol under sonication46b (entry 1)
providing what appeared to be a trace amount of the desired product 207 upon mass spectrometric
analysis of the crude mixture. However, we were unable to drive this rather sluggish reaction to
completion without decomposing the posited N-H piperidine 207 (entry 2). We reasoned that
perhaps subjecting bis-MOM ether 206 to more strongly reducing conditions for a very brief period
of time might be more successful in cleaving the sulfonamide. To our delight, subjection of 206 to
dissolving metal reduction with lithium metal in liquid ammonia at -78 ºC for just one minute
followed by an immediate quench at that temperature with solid ammonium chloride cleanly
furnished free piperidine 207 in good yield (entry 3).
84
N
OMOMHH
Ts
OH
H
192
MOMClDIPEA
THF, 0 °C
80% N
OMOMHH
Ts
OMOM
H
206
7 7
9 9
conditions
N
OMOMHH
H
OMOMH
207
7
9
entry
1
conditions result
Mgo, MeOH, rt, 1h SM + 207 (trace)
2 Mgo, MeOH, 40 oC, 4h SM + 207 (trace) + D
3 Lio, NH3, Et2O, -78 oC, 1 min 207 (81%)
Scheme 60. MOM-Protection of Alcohol 192 and Desulfonylation of 206
5.4. Endgame: Closure of the 1,3-Oxazine C-Ring
With free piperidine 207 finally in hand, the final tasks remaining in the total synthesis of
myrioneurinol were the cleavage of the two methoxymethyl (MOM) ethers and formation of the
1,3-oxazine C-ring. We recognized that it might be feasible to directly utilize the MOM-protected
C9-hydroxymethyl group to install the C-ring, since the methylene of the protecting group could
serve as a formaldehyde surrogate for C13 of the alkaloid.
It was discovered that stirring N-H piperidine 207 with 6 N aqueous HCl in THF at room
temperature provided a mixture of compounds that were identified via mass spectrometry as
unreacted starting material, MOM-protected myrioneurinol 208, along with a trace amount of the
natural product itself (Scheme 61, entry 1). To our delight, simply warming the reaction mixture
85
to 50 ºC accomplished the desired 1,3-oxazine ring formation with concomitant deprotection of
the C7-hydroxymethyl group providing the racemic alkaloid 19 in good yield (entry 2). This
synthetic material had proton and carbon NMR spectra (including 2D spectra) identical to those of
the natural material isolated by Bodo and coworkers.54
N
OMOMHH
H
OMOM
207
6 N HClTHF/H2O
(±)-19 R = H
N
ORHH
HOH
Scheme 61. Completion of the Myrioneurinol Total Synthesis
conditions
208 R = MOM
entry conditions result
1 rt, 1 h 208 + (±)-19 (trace)
2 50 oC, 1 h (±)-19 (75%)
5.5. Concluding Remarks
In summary, we have completed the first total synthesis of the tetracyclic antimalarial
alkaloid (±)-myrioneurinol in twenty-seven steps starting from commercial materials and in 1.8%
overall yield (Scheme 62).23 Three highly diastereoselective reactions were utilized as pivotal steps
including: (1) an IMA of an N-Cbz lactam/(E)-α,β-unsaturated ester to construct the spirocyclic
A/D-ring subunit with the correct C5,6 relative configuration for the alkaloid (2) a malonate
enolate umpolung conjugate addition to a transient nitrosoalkene intermediate derived from an α-
chloro-O-silyloxime to install the requisite functionality at C7 and (3) an allyl silane/N-
86
sulfonyliminium aza-Sakurai reaction of a sulfonyllactam to install the B-ring and attendant C9,10
stereocenters within the cis-DHQ scaffold.
The hypothesized position of myrioneurinol at the nexus of the biosynthetic pathways of
the Myrioneuron and Nitraria alkaloids, as well as its challenging structure containing five
contiguous stereocenters (including the C5-spiranic carbon), motivated us to design and carry out
a total synthesis of this metabolite. It is our hope that the chemistry developed and utilized herein
will stimulate further research in the somewhat underexplored field of Myrioneuron alkaloid
synthesis and might benefit organic synthesis in general. In particular, the nitrosoalkene umpolung
solution to the intractable C7-functionalization problem has the potential to find broader
application to other systems that are likewise unreactive toward classical enolate chemistry. We
anticipate that this total synthesis, which showcases the utility of nitrosoalkene conjugate addition
chemistry, along with other work both past and ongoing in the Weinreb laboratory, will allow this
useful methodology to play a prominent role in modern organic synthesis.
87
NH
O
n-BuLi (2 equiv.)
Br
NH
O NCbz
O89%
(2 steps)NCbz
O
CHO
-78 °C-rt
LiCl, DBU, MeCN, rt
82%
90%
Scheme 62. Overall Final Synthetic Route to (±)-Myrioneurinol
NCbz
CO2Me
O
THF, 0 °CTHF, -78 °C
n-BuLi
CbzCl
O3, CH2Cl2-78 °C; PPh3
(EtO)2POCH2CO2Me
H2, EtOAc
NR
CO2MeH
O
R = Cbz
10% Pd-C
TiCl4, Et3N
CH2Cl20 °C-rt
(86%)
R = H (98%)
R = Bn (73%)
BnBr, Ag2O, TBAICaSO4, rt
NBn
H
O
NBn
CHOH
O91%
Me(OMe)NH2Cl
N
O
Me
OMe
-40 °CMe2AlCl, CH2Cl2
0 °C-rt
90%N
Bn
H
O
N
pyrrolidine
100%
CHCl3, 0 °C
4Å MS
LiAlH4
THF
NBn
CHOH
O
Cl1) NCS, 65 °C
2) HOAc, H2O
dr = 2.2:1
Et2O, CHCl3
82%N
Bn
H
O
N
OTBS
ClTBSONH2
PPTSCH2Cl2, rt
85%
CO2Me
CO2Me
then TBAF
LiHMDS, THF
-78 oC
-78 oC to 0 oC
93%
NCO2Me
NH
CO2Me
O
OH
Bn
~5:1 E/Z
HN
CO2Me
CHOH
CO2Me
O
BnH
TiCl4, Zno
THF, 0 oC
63%
NaBH4MeOH 0 oC
81% N
CO2Me
HO
Bn
O
O
H
dr ~ 2.2:1
88
N
HO
Bn
OO
H
LiClDMSO/H2O155-160 oC
90%
R = H (86%)
R = MOM (80%)
N
HO
Bn
OR
H
O
NOMeMe
MOMClDIEA
THF, 0 °C
Me2AlClCH2Cl20 °C-rt
Me(OMe)NH2Cl
N
H
CHO
O
Bn
OMOM
H
-40 °C
LiAlH4
THF Me3SiPPh3 I
PhLi, THF, rt
74% (2 steps)N
OMOMH
Bn
SiMe3
O
R = H (79%)
R = Ts (87%)
Na/NH3Et2O
-78 °C
LiHMDSTsCl, THF
DMAP
N
OMOMH
R
SiMe3
O DIBAL-H
-78 oCCH2Cl2
then FeCl3N
OMOMH
Ts
H
H
warm to 5 oC
78%
N
OMOMHH
Ts
OR
1) O3, CH2Cl2-78 °C; PPh3
2) NaBH4MeOH, 0 °C
H
R = H (92%, 2 steps)
R = MOM (80%)
MOMClDIPEA
THF, 0 °C
N
OMOMHH
H
OMOM
Li/NH3Et2O
-78 °C
81%
6 N HClTHF/H2O
50 °C
75% N
OHHH
HOH
(±)-myrioneurinol
89
CHAPTER 6. EXPERIMENTAL SECTION
General Methods. All non-aqueous reactions were carried out in oven- or flame-dried
glassware under an atmosphere of argon. All reagents were purchased from commercial vendors
and used as recieved, unless otherwise specified. Anhydrous tetrahydrofuran (THF),
dichloromethane (CH2Cl2), diethyl ether (Et2O), and acetonitrile (MeCN) were obtained from a
solvent purification system. Reactions were stirred magnetically and monitored by thin layer
chromatography (TLC) with 250 μm EMD 60 F254 precoated silica gel plates. Flash
chromatographic separations were performed using silica gel (240-400 mesh). Proton and carbon-
13 NMR chemical shifts are reported relative to chloroform for 1H and 13C NMR (δ 7.24 and 77.0,
respectively). High resolution mass spectra were recorded on a time-of-flight (TOF) mass
spectrometer.
N O
OBn
O50
3-(4-(1,3-Dioxolan-2-yl)butyl)-1-benzylpiperidin-2-one (50). n-Butyllithium (2.5 M in
hexanes, 1.25 mL, 3.12 mmol) was added to diisopropylamine (0.42 mL, 2.92 mmol) at 0 ºC and
the resulting light yellow gel was diluted with anhydrous THF (0.1 mL) and stirred for 45 min at
that temperature. This solution of LDA was added dropwise at -78 ºC to a stirred solution of 1-
benzylpiperidin-2-one (48, 509 mg, 2.7 mmol) in dry THF (5 mL). The mixture was warmed to 0
ºC and stirred for 1 h. Neat 2-(4-iodobutyl)-1,3-dioxolane (49, 2.07 g, 8.1 mmol) was added
90
dropwise, the mixture was warmed to rt and stirred overnight. The mixture was diluted with
saturated NH4Cl (aq) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were
washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The crude product
was purified by flash chromatography on silica gel (gradient 20% to 50% EtOAc/hexanes) to
afford lactam 50 (416 mg, 49%) as a clear colorless gum: 1H NMR (400 MHz, CDCl3) δ 7.15-7.26
(m, 5H), 4.78 (t, J = 4.6 Hz, 1H), 4.57 (d, J = 10.4 Hz, 1H), 4.51 (d, J = 10.4 Hz, 1H), 3.89-3.91
(m, 2H), 3.76-3.77 (m, 2H), 3.11 (t, J = 5.9 Hz, 2H), 2.28-2.29 (m, 1H), 1.89-1.93 (m, 2H), 1.19-
1.62 (m, 10H); 13C NMR (75 MHz, CDCl3) δ 173.1, 137.9, 128.9, 128.3, 127.6, 104.9, 65.2, 50.7,
47.8, 41.9, 34.2, 32.4, 27.5, 26.9, 24.5, 22.0; HRMS-ES+ (C19H28NO3) calcd 318.2069 (MH+),
found 318.2054.
N O
CHOBn51
5-(1-Benzyl-2-oxopiperidin-3-yl)pentanal (51). To a solution of lactam 50 (416 mg, 1.3
mmol) in THF (5 mL) was added 1 N HCl (aq) (5 mL) and the mixture was stirred at rt for 6 h.
Saturated NaHCO3 (aq) was added and the mixture was extracted with CH2Cl2 (3 x 50 mL). The
combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated
in vacuo to afford aldehyde 51 (355 mg, 100%) as a clear colorless gum that was used in the
subsequent step without further purification: 1H NMR (400 MHz, CDCl3) δ 9.77 (s, 1H), 7.22-7.33
(m, 5H), 4.62 (d, J = 14.6 Hz, 1H), 4.53 (d, J = 14.6 Hz, 1H), 3.19 (dd, J = 7.3, 4.9 Hz, 2H), 2.45
(t, J = 1.7 Hz, 2H), 2.33-2.34 (m, 1H), 1.89-2.04 (m, 2H), 1.81-1.89 (m, 1H), 1.66-1.70 (m, 3H),
91
1.42-1.56 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 202.7, 172.5, 137.5, 128.5, 128.0, 127.3, 50.3,
47.4, 43.7, 41.4, 31.7, 26.6, 26.5, 22.1, 21.7; IR (neat) 1724, 1605 cm-1; HRMS-ES+ (C17H24NO2)
calcd 274.1807 (MH+), found 274.1803.
N Bn
CO2Me
O
52
Methyl 7-(1-Benzyl-2-oxopiperidin-3-yl)hept-2-enoate (52). To a stirred suspension of
anhydrous lithium chloride (81 mg, 1.9 mmol) in dry MeCN (15 mL) at rt was added methyl
diethylphosphonoacetate (0.34 mL, 1.9 mmol) and DBU (0.24 mL, 1.8 mmol). A solution of
aldehyde 51 (440 mg, 1.61 mmol) in dry MeCN (5 mL) was added dropwise over 5 min. The
resulting cloudy suspension was stirred for 24 h at rt, then diluted with saturated NH4Cl (aq). The
reaction mixture was extracted with EtOAc (3 x 50 mL) and the combined organics were washed
with brine, dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash
column chromatography on silica gel (25% EtOAc/hexanes) to afford (E)-α,β-unsaturated ester 52
(477 mg, 90%) as a clear colorless gum: 1H NMR (400 MHz, CDCl3) δ 7.15-7.26 (m, 5H), 6.89-
6.96 (m, 1H), 5.75 (d, J = 15.7 Hz, 1H), 4.55 (d, J = 14.6 Hz, 1H), 4.47 (d, J = 14.6 Hz, 1H), 3.66
(s, 3H), 3.11-3.14 (m, 2H), 2.27-2.29 (m, 1H), 2.16 (q, J = 6.9 Hz, 2H), 1.20-1.76 (m, 10H); 13C
NMR (75 MHz, CDCl3) δ 172.9, 167.5, 149.9, 137.9, 128.9, 128.3, 127.6, 121.3, 51.7, 50.7, 47.7,
41.9, 32.5, 32.1, 28.4, 27.2, 26.8, 22.1; HRMS-ES+ (C20H28NO3) calcd 330.2069 (MH+), found
330.2070.
92
N Bn
CO2MeH
O
53
Methyl 2-Benzyl-1-oxo-2-azaspiro[5.5]undecan-7-yl)acetate (53). Method A. To a
stirred solution of (E)-α,β-unsaturated ester 52 (215 mg, 0.65 mmol) in anhydrous THF (7 mL)
was added dropwise freshly prepared LDA (1.7 M in THF, 0.45 mL, 0.78 mmol) at -78 ºC. The
resulting bright yellow reaction mixture was slowly warmed to rt over 24 h then diluted with
saturated NH4Cl (aq). The mixture was extracted with EtOAc (3 x 25 mL) and the combined organic
layers were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The crude
product was purified by flash column chromatography (gradient 10% to 30% EtOAc/hexanes) to
afford spirocycle 53 (41 mg, 19%) as a light yellow gum: 1H NMR (400 MHz, CDCl3) δ 7.15-7.25
(m, 5H), 4.66 (d, J = 14.5 Hz, 1H), 4.36 (d, J = 14.5 Hz, 1H), 3.59 (s, 3H), 3.08-3.12 (m, 2H), 2.69
(t, J = 10.7 Hz, 1H), 2.12 (dd, J = 14.4, 3.2 Hz, 1H), 1.96 (dd, J = 14.5, 10.6 Hz, 1H), 1.05-1.75
(m, 12H); 13C NMR (100 MHz, CDCl3) δ 175.3, 173.6, 138.1, 128.9, 128.4, 127.6, 52.0, 51.1,
47.5, 46.2, 39.9, 37.8, 34.9, 27.2, 26.0. 23.4, 20.9, 19.7; IR (neat) 1733, 1675, 1172 cm-1; HRMS-
ES+ (C20H28NO3) calcd 330.2069 (MH+), found 330.2065.
Method B. To a stirred solution of the N-H lactam 63 (11.68 g, 48.7 mmol) in benzyl
bromide (120 mL) was added silver (I) oxide (32.91 g, 146 mmol), tetra-n-butylammonium iodide
(18.25 g, 48.7 mmol) and anhydrous calcium sulfate (33.90 g, 244 mmol). The reaction flask was
covered with aluminum foil and the mixture was stirred at rt for 44 h. The mixture was filtered
through a Celite pad, which was washed with Et2O, and the total filtrate was concentrated in vacuo.
93
The residue was purified by flash column chromatography on silica gel (gradient 100% hexanes
to 30% EtOAc/hexanes) to afford the N-Bn lactam ester 53 as a greenish gum (11.59 g, 73%). This
material had spectroscopic data identical to that prepared by Method A.
N O
OH
O58
3-(4-[1,3]Dioxolan-2-yl-butyl)-piperidin-2-one (58). To a stirred solution of
valerolactam (57, 250 mg, 2.52 mmol) in THF (10 mL) at -78 ºC was added dropwise n-
butyllithium (2.5 M in hexanes, 2.1 mL, 5.25 mmol) and the mixture was warmed to 0 ºC for 1 h.
Iodoacetal 49 (955 mg, 3.73 mmol) was added dropwise and the reaction mixture was stirred at 0
ºC for 3 h then diluted with saturated aqueous NH4Cl. The mixture was extracted with CH2Cl2 (3
x 50 mL) and the combined organic layers were washed with brine, dried over anhydrous Na2SO4
and concentrated in vacuo. The crude product was purified via flash column chromatography on
silica gel (gradient 25% to 100% EtOAc/hexanes) to afford lactam acetal 58 (135 mg, 24%) as a
yellowish solid: 1H NMR (300 MHz, CDCl3) δ 6.33 (br s, 1H), 4.85 (t, J = 4.7 Hz, 1H), 3.84-3.97
(m, 4H), 3.27-3.30 (m, 2H), 2.11-2.24 (m, 1H), 1.41-1.91 (m, 12H); 13C NMR (75 MHz, CDCl3)
δ 175.5, 105.0, 104.9, 65.2, 42.8, 41.3, 34.2, 31.9, 27.4, 26.5, 24.5, 21.8.
94
N O
OCbz
O59
3-(4-[1,3]Dioxolan-2-yl-butyl)-2-oxopiperidine-1-carboxylic Acid Benzyl Ester (59).
To a stirred solution of lactam acetal 58 (135 mg, 0.59 mmol) in THF (2 mL) at -78 ºC was added
n-butyllithium (2.5 M in hexanes, 0.283 mL, 0.71 mmol) and the mixture was stirred at that
temperature for 1 h. Benzyl chloroformate (0.168 mL, 1.18 mmol) was added dropwise and the
mixture was stirred for 1 h at -78 ºC, then warmed to 0 ºC for 1 h. Saturated aqueous NH4Cl was
added and the mixture was extracted with EtOAc (3 x 25 mL), the combined organic layers were
washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The crude material
was purified via flash column chromatography on silica gel (25% EtOAc/hexanes) to afford N-
Cbz lactam acetal 59 (140 mg, 65%) as a clear oil: (300 MHz, CDCl3) δ 7.29-7.43 (m, 5H), 5.26
(s, 2H), 4.83 (t, J = 4.8 Hz, 1H), 3.78-3.93 (m, 4H), 3.55-3.61 (m, 1H), 2.21-2.37 (m, 1H), 1.40-
1.87 (m, 13H); 13C NMR (75 MHz, CDCl3) δ 174.6, 154.7, 136.0, 128.9, 128.5, 128.3, 104.9, 68.8,
65.3, 46.4, 44.1, 34.2, 31.4, 27.3, 26.3, 24.4, 22.0.
N O
CHOCbz60
Benzyl 2-Oxo-3-(5-oxopentyl)piperidine-1-carboxylate (60) Method A. A solution of
N-Cbz lactam acetal 59 (140 mg, 0.39 mmol) in THF (5 mL) and 1 N HCl(aq) (5 mL) was stirred
for 4 h at rt. The mixture was extracted with EtOAc (2 x 25 mL) and the combined organic layers
95
were washed with 1 M NaHCO3(aq), brine, dried over anhydrous MgSO4, then concentrated in
vacuo to afford aldehyde 60 (124 mg, 100%) as a clear gum that was used in the subsequent step
without further purification. This material had spectroscopic data identical to that prepared by
Method B.
Method B A solution of N-Cbz lactam 67 (17.37 g, 55.1 mmol) in dry CH2Cl2 (500 mL)
was cooled to -78 °C and ozone was bubbled through the reaction mixture for 1 h until a light blue
coloration was achieved. The mixture was then purged with argon for 5 min followed by the
portionwise addition of triphenylphosphine (17.36 g, 66.2 mmol). The reaction mixture was
warmed to rt over 6 h and then concentrated in vacuo to afford a yellowish oil. This material was
purified by flash column chromatography on silica gel (gradient 25% to 40% EtOAc/hexanes) to
afford aldehyde 60 (15.86 g, 90%) as a clear colorless oil: 1H NMR (300 MHz, CDCl3) δ 9.70-
9.75 (m, 1H), 7.31-7.45 (m, 5H), 5.27 (s, 2H), 3.69-3.82 (m, 1H), 3.47-3.67 (m, 1H), 2.42-2.47
(m, 3H), 1.62-1.88 (m, 5H), 1.23-1.49 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 203.0, 174.5, 154.6,
135.9, 129.0, 128.6, 128.5, 68.8, 46.4, 44.0, 31.2, 26.9, 26.3, 22.4, 21.9, 21.4; HRMS-ES+
(C18H24NO4) calcd 318.1705 (MH+), found 318.1696.
N Cbz
CO2Me
O
61
(E)-Benzyl 3-(Hex-5-en-1-yl)-2-oxopiperidine-1-carboxylate (61). Anhydrous LiCl
(2.63 g, 62.0 mmol) was flame-dried under a stream of argon and then suspended in dry MeCN
(420 mL) to which was added methyl diethylphosphonoacetate (11.0 mL, 62.2 mmol) and DBU
96
(7.9 mL, 56.9 mmol) at rt. A solution of aldehyde 60 (16.43 g, 51.8 mmol) in dry MeCN (150 mL)
was added dropwise over 1 h and the resulting cloudy white reaction mixture was stirred for 48 h
at rt. Saturated NH4Cl (aq) was added, the organic layer was separated, and the aqueous layer was
extracted with EtOAc (3 x 250 mL). The combined organic extracts were washed with brine, dried
over anhydrous MgSO4, and concentrated in vacuo to afford a brownish oil. This crude material
was purified by flash column chromatography on silica gel (20% EtOAc/hexanes) to provide (E)-
α,β-unsaturated ester 61 (15.83 g, 82%) as a clear colorless oil: 1H NMR (300 MHz, CDCl3) δ
7.29-7.72 (m, 5H), 6.97 (dt, J = 15.6, 7.0 Hz, 1H), 5.83 (d, J = 15.6 Hz, 1H), 5.29 (s, 2H), 3.80-
3.89 (m, 1H), 3.65-3.75 (m, 4H), 2.36-2.48 (m, 1H), 2.21 (q, J = 7.2 Hz, 2H), 1.81-1.95 (m, 4H),
1.28-1.52 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 174.6, 167.5, 154.7, 149.8, 135.9, 129.0, 128.7,
128.4, 121.5, 68.8, 51.8, 46.4, 44.2, 32.4, 31.3, 28.4, 27.0, 26.4, 22.0; HRMS-ES+ (C21H28NO5)
calcd 374.1967 (MH+), found 374.1958.
N Cbz
CO2MeH
O
62
Benzyl 7-(2-Methoxy-2-oxoethyl)-1-oxo-2-azaspiro[5.5]undecane-2-carboxylate (62).
TiCl4 (10.1 mL, 91.4 mmol) and dry Et3N (12.7 mL, 91.4 mmol) were dissolved in dry CH2Cl2
(275 mL) at 0 °C and the resulting deep maroon solution was stirred for 15 min. A solution of (E)-
α,β-unsaturated ester 61 (16.95 g, 45.5 mmol) in dry CH2Cl2 (120 mL) was added dropwise over
10 min and the reaction mixture was subsequently stirred at rt for 1 h. Saturated NaHCO3 (aq) was
carefully added at 0 °C, the mixture was stirred for 30 min and then extracted with CH2Cl2 (4 x
97
250 mL). The combined organic layers were dried over anhydrous MgSO4 and concentrated in
vacuo to afford a yellow oil that was purified by flash chromatography on silica gel (gradient 20%
to 35% EtOAc/hexanes) to give spirocyclic ester 62 (14.58 g, 86%) as a light yellow gum: 1H
NMR (300 MHz, CDCl3) δ 7.28-7.41 (m, 5H), 5.23 (s, 2H), 3.66-3.79 (m, 1H), 3.55-3.62 (m, 4H),
2.65 (t, J = 9.6 Hz, 1H), 2.22 (dd, J = 12.4, 2.9 Hz, 1H), 2.02 (dd, J = 18.9, 7.7 Hz, 1H), 1.56-1.86
(m, 9H), 1.19-1.26 (m, 2H), 1.09 (q, J = 9.6 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 177.4, 173.2,
155.0, 136.0, 128.9, 128.4, 128.3, 68.7, 51.9, 49.4, 47.5, 39.8, 37.4, 35.6, 27.3, 25.8, 24.2, 20.9,
20.2; HRMS-ES+ (C21H28NO5) calcd 374.1967 (MH+), found 374.1968.
N H
CO2MeH
O
63
Methyl 2-(1-Oxo-2-azaspiro[5.5]undecan-7-yl)acetate (63). To a stirred solution of
spirocyclic ester 62 (14.57 g, 39.1 mmol) in EtOAc (150 mL) was added 10% palladium on carbon
(20% w/w, 2.91 g). The reaction flask was purged and filled with hydrogen gas at 1 atm (supplied
via two balloons). The resulting suspension was stirred for 36 h at rt, then filtered through a pad
of Celite, which was washed with EtOAc. The filtrate was concentrated in vacuo to afford the
N-H lactam 63 (9.21 g, 98%) as a slightly yellowish gum which was used in the next step without
further purification: 1H NMR (300 MHz, CDCl3) δ 6.56 (br s, 1H), 3.26 (s, 3H), 3.23-3.25 (m,
2H), 2.62 (t, J = 10.7 Hz, 1H), 2.23 (dd, J = 14.5, 3.2 Hz, 1H), 2.05 (dd, J = 14.6, 10.7 Hz, 1H),
1.25-1.87 (m, 11H), 1.06 (q, J = 13.1 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 177.7, 173.5, 51.9,
98
45.7, 42.5, 39.4, 37.7, 34.6, 26.8, 25.9, 23.2, 20.7, 19.7; HRMS-ES+ (C13H22NO3) calcd 240.1600
(MH+), found 240.1579.
NH
H
O
HO
64
7-(2-Hydroxyethyl)-2-azaspiro[5.5]undecan-1-one (64). To a stirred suspension of
LiAlH4 (20 mg, 0.40 mmol) in anhydrous THF (1 mL) at 0 °C was added dropwise N-H lactam 63
(25 mg, 0.10 mmol) as a solution in THF (1 mL) over 5 min. The reaction mixture was stirred for
4 h at 0 °C, then carefully quenched with MeOH. The mixture was diluted with 1 N HCl (aq) and
extracted with CHCl3 (3 x 25 mL). The combined organic layers were washed with brine, dried
over anhydrous MgSO4, and concentrated in vacuo to provide alcohol 64 as a white crystalline
solid. The crude alcohol 64 was recrystallized from a minimal amount of refluxing Et2O/MeOH to
afford clear prisms that were suitable for X-ray analysis (17 mg, 82%): 1H NMR (300 MHz,
CDCl3) δ 6.24 (br s, 1H), 3.57 (t, J = 5.9 Hz, 2H), 3.22-3.31 (m, 2H), 2.80 (br s, 1H), 2.18-2.29
(m, 1H), 1.07-1.98 (m, 14H); 13C NMR (75 MHz, CDCl3) δ 179.7, 61.0, 42.6, 38.4, 36.7, 34.6,
30.1, 28.0, 26.3, 22.6, 20.8, 19.3; IR (neat) 3290, 1636, 1049 cm-1; HRMS-ES+ (C12H22NO2) calcd
212.1651 (MH+), found 212.1670.
99
NCbz
O
67
Benzyl 3-(Hex-5-en-1-yl)-2-oxopiperidine-1-carboxylate (67). To a stirred solution of
valerolactam (57, 6.12 g, 61.7 mmol) in dry THF (250 mL) was added n-butyllithium (2.5 M in
hexanes, 52 mL, 129.6 mmol) at 0 °C. The resulting yellowish-orange solution was stirred at 0 °C
for 1 h and then 6-bromohex-1-ene (10.00 g, 61.7 mmol) was added rapidly in one portion. The
reaction mixture was stirred for 1 h and was gradually warmed to rt. Brine was added and the
organic layer was separated. The aqueous layer was extracted with dichloromethane (2 x 250 mL).
The combined organic layers were dried over anhydrous MgSO4 and concentrated in vacuo to
provide lactam 66 as a yellowish solid.
The crude lactam 66 was dissolved in dry THF (250 mL), n-butyllithium (2.5 M in hexanes,
27.2 mL, 67.9 mmol) was added at -78 °C and the reaction mixture was stirred for 30 min. Benzyl
chloroformate (13.3 mL, 92.6 mmol) was added dropwise and the resulting bright yellow solution
was slowly warmed to rt over 1 h. Saturated NH4Cl (aq) was added and the mixture was extracted
with ethyl acetate (3 x 250 mL). The organic phase was washed with brine and dried over
anhydrous MgSO4. The solution was concentrated in vacuo to afford a viscous yellowish oil that
was purified by flash column chromatography on silica gel (15% EtOAc/hexanes) to yield N-Cbz
lactam 67 (17.37 g, 89%) as a clear colorless oil: 1H NMR (300 MHz, CDCl3) δ 7.29-7.48 (m,
5H), 5.76-5.89 (m, 1H), 5.30 (s, 2H), 4.94-5.05 (m, 2H), 3.81-3.89 (m, 1H), 3.67-3.75 (m, 1H),
2.41-2.45 (m, 1H), 1.72-2.12 (m, 6H), 1.28-1.59 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 174.8,
154.8, 139.2, 136.0, 129.0, 128.6, 128.4, 114.9, 68.9, 46.5, 44.3, 34.1, 31.4, 29.3, 26.9, 26.2, 21.8;
HRMS-ES+ (C19H26NO3) calcd 316.1913 (MH+), found 316.1909.
100
72
NCbz
O
3-Hex-5-enyl-2-oxopyrrolidine-1-carboxylic Acid Benzyl Ester (72). To a stirred
solution of 2-pyrrolidinone (70, 500 mg, 5.9 mmol) in THF (10 mL) at 0 ºC was added n-
butyllithium (2.5 M in THF, 4.9 mL, 12.4 mmol) and the mixture was stirred for 1 h. To the
resulting orange-red solution was added 6-bromo-1-hexene (952 mg, 5.9 mmol) in one portion and
the mixture was stirred for 1 h at 0 ºC. Brine was added and the mixture was extracted with CH2Cl2
(3 x 50 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo to
afford lactam 71 as a yellowish gum.
To a solution of crude lactam 71 in THF (10 mL) was added n-butyllithium (2.5 M in
hexanes, 2.61 mL, 6.5 mmol) at -78 ºC and the mixture was stirred for 1 h at that temperature.
Benzyl chloroformate (1.52 mL, 10.6 mmol) was added dropwise and the mixture was stirred at -
78 ºC for 1 h, then warmed to rt. Saturated NH4Cl (aq) was added and the mixture was extracted
with EtOAc (3 x 25 mL). The combined organic layers were washed with brine, dried over
anhydrous MgSO4, and concentrated in vacuo. The crude material was purified via flash column
chromatography on silica gel (gradient 10% to 20% EtOAc/hexanes) to afford N-Cbz lactam 72 as
a clear gum (318 mg, 18%): 1H NMR (300 MHz, CDCl3) δ 7.19-7.33 (m, 5H), 5.55-5.76 (m, 1H),
5.12 (s, 2H), 4.85-5.01 (m, 2H), 4.01 (m, 2H), 1.29-2.12 (m, 11H); 13C NMR (75 MHz, CDCl3) δ
175.4, 155.3, 140.6, 128.7, 127.3, 114.2, 69.5, 48.2, 33.5, 33.2, 30.2, 29.6, 27.2, 25.4, 20.4, 19.4.
101
73
NCbz
OCHO
2-Oxo-3-(5-oxopentyl)-pyrrolidine-1-carboxylic Acid Benzyl Ester (73). A solution of
N-Cbz lactam 72 (318 mg, 1.1 mmol) in dry CH2Cl2 (10 mL) was cooled to -78 °C and ozone was
bubbled through the reaction mixture for 5 min until a light blue coloration was achieved. The
mixture was then purged with argon for 5 min followed by the portionwise addition of
triphenylphosphine (278 mg, 1.2 mmol). The reaction mixture was warmed to rt over 4 h and then
concentrated in vacuo to afford a yellowish oil. This material was purified by flash column
chromatography on silica gel (gradient 20% to 35% EtOAc/hexanes) to afford aldehyde 73 (254
mg, 79%) as a clear colorless oil: 1H NMR (300 MHz, CDCl3) δ 9.63-9.69 (m, 1H), 7.25-7.43 (m,
5H), 5.21 (s, 2H), 3.91-3.95 (m, 2H), 2.49-2.58 (m, 2H), 1.29-2.22 (m, 9H); 13C NMR (75 MHz,
CDCl3) δ 200.3, 176.5, 155.6, 140.9, 129.0, 128.6, 127.5, 68.5, 48.4, 44.0, 33.2, 27.9, 26.3, 22.4,
21.4.
N Cbz
CO2Me
O
74
3-(6-Methoxycarbonyl-hex-5-enyl)-2-oxopyrrolidine-1-carboxylic Acid Benzyl Ester
(74). Anhydrous LiCl (90 mg, 2.1 mmol) was flame-dried under a stream of argon and then
suspended in dry MeCN (10 mL) to which was added methyl diethylphosphonoacetate (0.22 mL,
1.3 mmol) and DBU (0.16 mL, 1.2 mmol) at rt. A solution of aldehyde 73 (254 mg, 1.06 mmol)
102
in dry MeCN (5 mL) was added dropwise over 5 min and the resulting cloudy white reaction
mixture was stirred for 48 h at rt. Saturated NH4Cl (aq) was added, the organic layer was separated,
and the aqueous layer was extracted with EtOAc (3 x 25 mL). The combined organic extracts were
washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo to afford a brownish
oil. This crude material was purified by flash column chromatography on silica gel (20%
EtOAc/hexanes) to provide (E)-α,β-unsaturated ester 74 (213 mg, 56%) as a clear colorless oil: 1H
NMR (300 MHz, CDCl3) δ 7.31-7.69 (m, 5H), 6.87 (dt, J = 15.4, 7.2 Hz, 1H), 5.76 (d, J = 15.3
Hz, 1H), 5.21 (s, 2H), 3.90-3.99 (m, 2H), 1.25-2.30 (m, 14H); 13C NMR (75 MHz, CDCl3) δ 176.6,
165.0, 155.7, 146.8, 136.0, 129.1, 128.7, 128.3, 122.5, 69.8, 50.8, 48.4, 44.3, 32.1, 31.7, 28.2, 27.1,
22.0.
NCbz
O
79
3-Hex-5-enyl-2-oxoazepane-1-carboxylic Acid Benzyl Ester (79). To a stirred solution
of caprolactam (77, 1.00 g, 8.8 mmol) in THF (40 mL) at 0 ºC was added n-butyllithium (2.5 M
in THF, 7.40 mL, 18.5 mmol) and the mixture was stirred for 1 h. To the resulting yellowish
solution was added 6-bromo-1-hexene (1.28 mL, 9.3 mmol) in one portion and the mixture was
stirred for 1 h at 0 ºC. Brine was added and the mixture was extracted with CH2Cl2 (3 x 50 mL).
The combined organic layers were dried over MgSO4 and concentrated in vacuo to afford lactam
78 as a yellowish gum.
103
To a solution of the crude lactam 78 in THF (40 mL) was added n-butyllithium (2.5 M in
hexanes, 3.91 mL, 9.7 mmol) at -78 ºC and the mixture was stirred for 30 min at that temperature.
Benzyl chloroformate (2.21 mL, 15.5 mmol) was added dropwise and the mixture was stirred at -
78 ºC for 20 min, then warmed to rt for 2 h. Saturated NH4Cl (aq) was added and the mixture was
extracted with EtOAc (3 x 25 mL). The combined organic layers were washed with brine, dried
over anhydrous MgSO4, and concentrated in vacuo. The crude material was purified via flash
column chromatography on silica gel (10% EtOAc/hexanes) to afford N-Cbz lactam 79 as a clear
gum (790 mg, 27%): 1H NMR (300 MHz, CDCl3) δ 7.19-7.37 (m, 5H), 5.66-5.79 (m, 1H), 5.19
(s, 2H), 4.84-4.96 (m, 2H), 3.30 (dd, J = 14.9, 10.5 Hz, 1H), 2.52-2.57 (m, 1H), 1.98 (q, J = 6.6
Hz, 2H), 1.15-1.85 (m, 13H); 13C NMR (75 MHz, CDCl3) δ 177.2, 154.9, 139.1, 136.1, 128.8,
128.4, 128.1, 114.8, 68.7, 46.6, 45.7, 34.1, 32.9, 31.1, 29.4, 28.5, 28.4, 27.3.
NCbz
OCHO
80
2-Oxo-3-(5-oxopentyl)-azepane-1-carboxylic Acid Benzyl Ester (80). A solution of N-
Cbz lactam 79 (790 mg, 2.40 mmol) in dry CH2Cl2 (35 mL) was cooled to -78 °C and ozone was
bubbled through the reaction mixture for 25 min until a light blue coloration was achieved. The
mixture was then purged with argon for 5 min followed by the portionwise addition of
triphenylphosphine (755 mg, 2.88 mmol). The reaction mixture was warmed to rt over 4 h and
then concentrated in vacuo to afford a yellowish oil. This material was purified by flash column
chromatography on silica gel (gradient 20% to 35% EtOAc/hexanes) to afford aldehyde 80 (470
104
mg, 58%) as a clear colorless oil: 1H NMR (300 MHz, CDCl3) δ 9.60 (s, 1H), 7.16-7.34 (m, 5H),
5.16 (s, 2H), 4.21 (dd, J = 15.1, 3.8 Hz, 1H), 3.31 (dd, J = 15.2, 10.6 Hz, 1H), 2.52-2.57 (m, 1H),
2.30 (t, J = 7.2 Hz, 2H), 1.11-1.87 (m, 11H); 13C NMR (75 MHz, CDCl3) δ 202.9, 177.1, 154.9,
136.1, 128.8, 128.2, 128.1, 68.7, 46.4, 45.7, 44.0. 32.9, 31.1, 28.5, 28.3, 27.3, 22.5.
N Cbz
CO2Me
O
81
3-(6-Methoxycarbonylhex-5-enyl)-2-oxoazepane-1-carboxylic Acid Benzyl Ester (81).
Anhydrous LiCl (75 mg, 1.77 mmol) was flame-dried under a stream of argon and then suspended
in dry MeCN (10 mL) to which was added methyl diethylphosphonoacetate (0.29 mL, 1.67 mmol)
and DBU (0.22 mL, 1.54 mmol) at rt. A solution of aldehyde 80 (470 mg, 1.40 mmol) in dry MeCN
(4 mL) was added dropwise over 5 min and the resulting cloudy white reaction mixture was stirred
for 22 h at rt. Saturated NH4Cl (aq) was added, the organic layer was separated, and the aqueous
layer was extracted with EtOAc (3 x 25 mL). The combined organic extracts were washed with
brine, dried over anhydrous MgSO4, and concentrated in vacuo to afford a brownish oil. This crude
material was purified by flash column chromatography on silica gel (gradient 10% to 20%
EtOAc/hexanes) to provide (E)-α,β-unsaturated ester 81 (390 mg, 72%) as a clear colorless gum:
1H NMR (300 MHz, CDCl3) δ 7.19-7.40 (m, 5H), 6.90 (dt, J = 15.7, 7.0 Hz, 1H), 5.76 (dt, J =
15.6, 1.4 Hz, 1H), 5.22 (s, 2H), 4.28 (dd, J = 15.1, 3.9 Hz, 1H), 3.65 (s, 3H), 3.36 (dd, J = 14.8,
10.2 Hz, 1H), 2.55-2.59 (m, 1H), 2.15 (q, J = 6.8 Hz, 2H), 1.20-1.86 (m, 12H); 13C NMR (75 MHz,
105
CDCl3) δ 177.2, 167.4, 154.9, 149.8, 136.0, 128.9, 128.5, 128.2, 121.3, 51.7, 46.6, 45.8, 32.9, 32.4,
31.1, 28.6, 28.5, 28.3, 27.4.
NCbz
O
87
2-Oxo-3-pent-4-enylpiperidine-1-carboxylic Acid Benzyl Ester (87). To a stirred
solution of valerolactam (57, 1.00 g, 10.1 mmol) in dry THF (50 mL) was added n-butyllithium
(2.5 M in hexanes, 8.9 mL, 22.2 mmol) at 0 °C. The resulting yellowish-orange solution was stirred
at 0 °C for 1 h and then 5-bromopent-1-ene (1.65 g, 11.1 mmol) was added rapidly in one portion.
The reaction mixture was stirred for 1 h and was gradually warmed to rt. Brine was added and the
organic layer was separated. The aqueous layer was extracted with dichloromethane (2 x 50 mL).
The combined organic layers were dried over anhydrous MgSO4 and concentrated in vacuo to
provide lactam 86 as a yellowish solid.
The crude lactam 86 was dissolved in dry THF (25 mL), n-butyllithium (2.5 M in hexanes,
4.4 mL, 11.1 mmol) was added at -78 °C and the reaction mixture was stirred for 30 min. Benzyl
chloroformate (2.1 mL, 15.2 mmol) was added dropwise and the resulting bright yellow solution
was slowly warmed to rt over 1 h. Saturated NH4Cl (aq) was added and the mixture was extracted
with ethyl acetate (3 x 50 mL). The organic phase was washed with brine and dried over anhydrous
MgSO4. The solution was concentrated in vacuo to afford a viscous yellowish oil that was purified
by flash column chromatography on silica gel (15% EtOAc/hexanes) to yield N-Cbz lactam 87
(2.07 g, 68%) as a clear oil: 1H NMR (300 MHz, CDCl3) δ 7.33-7.48 (m, 5H), 5.76-5.90 (m, 1H),
106
5.30 (s, 2H), 4.95-5.06 (m, 2H), 3.80-3.89 (m, 1H), 3.66-3.75 (m, 1H), 2.39-2.49 (m, 1H), 1.75-
2.13 (m, 7H), 1.45-1.57 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 174.7, 154.7, 138.9, 135.9, 128.9,
128.5, 128.3, 115.1, 68.8, 46.5, 44.2, 34.2, 31.1, 26.7, 26.3, 22.0.
NCbz
O CHO
88
2-Oxo-3-(4-oxobutyl)-piperidine-1-carboxylic acid Benzyl Ester (88). A solution of N-
Cbz lactam 87 (2.07 g, 6.8 mmol) in dry CH2Cl2 (75 mL) was cooled to -78 °C and ozone was
bubbled through the reaction mixture for 20 min until a light blue coloration was achieved. The
mixture was then purged with argon for 5 min followed by the portionwise addition of
triphenylphosphine (2.14 mg, 8.16 mmol). The reaction mixture was warmed to rt over 2 h and
then concentrated in vacuo to afford a yellowish oil. This material was purified by flash column
chromatography on silica gel (gradient 25% to 35% EtOAc/hexanes) to afford aldehyde 88 (1.31
g, 64%) as a clear colorless oil: 1H NMR (300 MHz, CDCl3) δ 9.75 (s, 1H), 7.30-7.44 (m, 5H),
5.26 (s, 2H), 3.78-3.87 (m, 1H), 3.63-3.71 (m, 1H), 2.37-2.55 (m, 3H), 1.41-2.08 (m, 8H); 13C
NMR (75 MHz, CDCl3) δ 202.7, 174.3, 154.5, 135.9, 128.9, 128.5, 128.4, 68.8, 46.4, 44.2, 44.1,
30.9, 26.3, 22.0, 20.0.
107
N Cbz
CO2MeO
89
3-(5-Methoxycarbonylpent-4-enyl)-2-oxopiperidine-1-carboxylic Acid Benzyl Ester
(89). Anhydrous LiCl (90 mg, 2.1 mmol) was flame-dried under a stream of argon and then
suspended in dry MeCN (12 mL) to which was added methyl diethylphosphonoacetate (0.35 mL,
1.9 mmol) and DBU (0.25 mL, 1.8 mmol) at rt. A solution of aldehyde 88 (500 mg, 1.7 mmol) in
dry MeCN (4 mL) was added dropwise over 5 min and the resulting cloudy white reaction mixture
was stirred for 24 h at rt. Saturated NH4Cl (aq) was added, the organic layer was separated, and the
aqueous layer was extracted with EtOAc (3 x 25 mL). The combined organic extracts were washed
with brine, dried over anhydrous MgSO4, and concentrated in vacuo to afford a brownish oil. This
crude material was purified by flash column chromatography on silica gel (20% EtOAc/hexanes)
to provide (E)-α,β-unsaturated ester 89 (395 mg, 67%) as a clear colorless gum: 1H NMR (300
MHz, CDCl3) δ 7.27-7.41 (m, 5H), 6.94 (dt, J =15.7, 7.0 Hz, 1H), 5.80 (dt, J = 15.6, 1.5 Hz, 1H),
5.23 (s, 2H), 3.75-3.83 (m, 1H), 3.67 (s, 3H), 3.55-3.66 (m, 1H), 2.34-2.45 (m, 1H), 2.17 (q, J =
5.2 Hz, 2H), 1.42-1.99 (m, 8H); 13C NMR (75 MHz, CDCl3) δ 174.3, 167.4, 154.5, 149.3, 135.9,
128.9, 128.4, 128.2, 121.6, 68.7, 51.7, 46.3, 44.0, 35.3, 31.0, 26.4, 25.9, 21.9.
108
NCbz
CO2Et
OMe
93
3-(6-Ethoxycarbonylhept-5-enyl)-2-oxopiperidine-1-carboxylic Acid Benzyl Ester
(93). To a stirred solution of triethyl 2-phosphonopropionate (0.41 mL, 1.9 mmol) in THF (10 mL)
at -78 ºC was added solid KHMDS (347 mg, 1.7 mmol) in one portion. The mixture was stirred
for 30 min at -78 ºC, then aldehyde 60 (500 mg, 1.6 mmol) in THF (5 mL) was added dropwise.
The mixture was warmed to rt over 3 h, diluted with saturated NH4Cl (aq), and extracted with ethyl
acetate (3 x 25 mL). The combined organic layers were washed with brine, dried over anhydrous
MgSO4 and concentrated in vacuo. The crude product was purified via flash column
chromatography on silica gel (20% EtOAc/hexanes) to afford enoate 93 (177 mg, 29%) as a ~2.5:1
inseparable mixture of (E)- and (Z)-olefin geometric isomers: 1H NMR (300 MHz, CDCl3) δ 7.24-
7.39 (m, 5H), 6.69 (t, J = 7.4 Hz, 1H), 5.86 (t, J = 7.2 Hz, 1H), 5.21 (s, 2H), 4.11 (q, J = 7.3 Hz,
2H), 3.62-3.84 (m, 2H), 2.27-2.45 (m, 2H), 2.12 (q, J = 7.0 Hz, 2H), 1.71-1.98 (m, 5H), 1.25-1.44
(m, 6H), 1.21 (t, J = 6.5 Hz, 3H).
NCbz
CO2Me
O
94
3-(6-Methoxycarbonylnona-5,8-dienyl)-2-oxopiperidine-1-carboxylic Acid Benzyl
Ester (94). To a stirred solution of 2-(diethoxyphosphoryl)-pent-4-enoic acid methyl ester (90 mg,
0.38 mmol) in THF (2 mL) at -78 ºC was added in one portion solid KHMDS (78 mg, 0.40 mmol).
109
The mixture was stirred for 30 min at -78 ºC, then aldehyde 60 (131 mg, 0.41 mmol) as a solution
in THF (1 mL) was added dropwise. The mixture was warmed to rt and stirred overnight then
saturated NH4Cl (aq) was added. The mixture was extracted with EtOAc (3 x 20 mL), the combined
organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo.
The crude material was purified via flash column chromatography on silica gel (10%
EtOAc/hexanes) to afford enoate 94 (81 mg, 47%) as a ~4.2:1 inseparable mixture of (E)- and (Z)-
olefin geometric isomers: 1H NMR (360 MHz, CDCl3) 7.30-7.47 (m, 5H), 6.85 (t, J = 7.5 Hz, 1H),
5.93 (t, J = 7.2 Hz, 1H), 5.75-5.87 (m, 1H), 5.29 (s, 2H), 4.97-5.04 (m, 2H), 3.81-3.86 (m, 1H),
3.68-3.75 (m, 4H), 3.08 (d, J = 5.9 Hz, 2H), 3.01 (d, J = 5.8 Hz, 2H), 2.40-2.44 (m, 1H), 2.21 (d,
J = 7.2 Hz, 2H), 1.79-2.06 (m, 9H), 1.37-1.65 (m, 9H); 13C NMR (90 MHz, CDCl3) 174.2, 168.1,
154.3, 143.9, 143.2, 135.5, 135.4, 130.0. 129.7, 128.6, 128.5, 128.2, 128.1, 128.0, 128.0, 116.1,
115.0, 68.4, 64.4, 51.7, 51.3, 46.0, 43.8, 42.0, 38.3, 31.6, 30.9, 30.8, 30.6, 29.5, 29.4, 28.7, 28.4,
26.9, 26.7, 26.0, 25.9, 22.7, 21.6, 19.1, 14.1, 13.7.
NCbz
O
O
O
97
2-Oxo-3-[5-(2-oxo-dihydropyran-3-ylidene)-pentyl]-piperidine-1-carboxylic Acid
Benzyl Ester (97) A stirred solution of phosphonolactone 96 (188 mg, 0.80 mmol) and 18-crown-
6 (1.05 g, 3.9 mmol) in THF (18 mL) was cooled to -78 ºC and KHMDS (1 M in THF, 0.86 mL,
0.86 mmol) was added dropwise. The mixture was stirred for 30 min at -78 ºC, then aldehyde 60
(241 mg, 0.76 mmol) was added dropwise as a solution in THF (5 mL). The reaction mixture was
110
allowed to slowly warm to rt over 3 h, then saturated NH4Cl (aq) was added. The mixture was
extracted with Et2O (3 x 25 mL) and the combined organic layers were washed with water then
brine, dried over anhydrous MgSO4, and concentrated in vacuo. The crude product (which
contained a ~3:2 mixture of (Z)- and (E)-olefin geometric isomers) was purified via flash column
chromatography on silica gel (gradient 25% to 35% EtOAc/hexanes) to furnish the desired (E)-
olefin 97 (57 mg, 19%) as a clear colorless gum: 1H NMR (300 MHz, CDCl3) δ 7.33-7.45 (m, 5H),
7.05 (tt, J = 5.1, 2.2 Hz, 1H), 5.29 (s, 2H), 4.32 (dd, J = 5.2, 5.1 Hz, 2H), 3.81-3.89 (m, 1H), 3.60-
3.74 (m, 1H), 2.53 (t, J = 5.7 Hz, 2H), 2.38-2.44 (m, 1H), 2.18 (q, J = 7.1 Hz, 2H), 1.78-2.08 (m,
6H), 1.39-1.58 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 174.6, 167.1, 154.6, 146.7, 135.9, 129.1,
128.7, 128.5, 126.0, 69.0, 68.9, 46.4, 44.2, 31.3, 28.5, 27.2, 26.4, 24.1, 23.1, 22.0.
NCbz
CO2Et
OCO2Et
99
2-[5-(1-Benzyloxycarbonyl-2-oxopiperidin-3-yl)-pentylidene]-malonic Acid Diethyl
Ester (99). To a solution of aldehyde 60 (250 mg, 0.79 mmol) in dry PhH (10 mL) was added
diethyl malonate (0.14 mL, 0.95 mmol), piperidine (0.015 mL, 0.15 mmol) and HOAc (2 drops,
cat). The mixture was heated at reflux for 3 h, then cooled to rt and extracted with EtOAc (2 x 50
mL). The combined organic layer was washed with 1 M HCl (aq), brine, dried over anhydrous
MgSO4, and concentrated in vacuo. The crude product was purified via flash column
chromatography on silica gel (10% EtOAc/hexanes) to afford enedioate 99 (330 mg, 91%) as a
clear colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.30-7.43 (m, 5H), 6.96 (t, J = 7.9 Hz, 1H), 5.26
111
(s, 2H), 4.28 (q, J = 7.1 Hz, 2H), 4.20 (q, J = 7.1 Hz, 2H), 3.82 (ddd, J = 12.8, 7.5, 5.0 Hz, 1H),
3.67 (ddd, J = 12.4, 7.0, 5.3 Hz, 1H), 2.38-2.45 (m, 1H), 2.30 (q, J = 7.4 Hz, 2H), 2.00 (sex, J =
6.3 Hz, 1H), 1.79-1.91 (m, 3H), 1.33-1.54 (m, 6H), 1.31 (t, J = 7.2 Hz, 3H), 1.28 (t, J = 7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 174.5, 168.8, 165.9, 164.3, 154.6, 149.4, 135.9, 129.2, 128.9,
128.6, 128.4, 68.8, 61.6, 46.3, 44.1, 31.2, 29.9, 28.7, 27.1, 26.4, 22.0, 14.5.
101
N O
O O
Me
Me
Me
3-Hex-5-enyl-2-oxopiperidine-1-carboxylic Acid 2-Isopropyl-5-methylcyclohexyl
Ester (101). To a stirred solution of N-H lactam 66 (1.83 g, 10.1 mmol) in THF (25 mL) at -78 ºC
was added dropwise n-butyllithium (2.5 M in hexanes, 4.40 mL, 11.1 mmol) and the reaction
mixture was stirred for 30 min at that temperature. (-)-Menthyl chloroformate (3.21 mL, 15.2
mmol) was added dropwise and the mixture was warmed to rt over 1 h. Saturated NH4Cl (aq) was
added and the mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were
washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The crude material
was purified via flash column chromatography on silica gel (gradient 5% to 7.5% EtOAc/hexanes)
to afford (-)-menthyl carbamate 101 (2.47 g, 67%) as a clear colorless oil: 1H NMR (300 MHz,
CDCl3) δ 5.74-5.82 (m, 1H), 4.98 (dp, J = 13.2, 1.1 Hz, 1H), 4.91 (dp, J = 8.6, 1.0 Hz, 1H), 4.71
(tt, J = 10.5, 2.4 Hz, 1H), 3.73-3.79 (m, 1H), 3.61-3.67 (m, 1H), 2.34-2.43 (m, 1H), 1.66-2.12 (m,
9H), 1.01-1.54 (m, 12H), 0.90 (d, J = 4.7 Hz, 6H), 0.78 (d, J = 5.2 Hz, 3H); 174.6, 154.6, 154.5,
112
139.2, 114.8, 77.7, 47.2, 46.32, 46.28, 44.22, 44.19, 41.14, 41.10, 34.6, 34.0, 31.9, 31.3, 31.31,
31.26, 29.2, 26.84, 26.81, 26.45, 26.36, 26.33, 26.29, 23.60, 23.58, 22.4, 22.1, 22.0, 21.3. 21.2,
16.5.
102
N O
CHOO O
Me
Me
Me
2-Oxo-3-(5-oxopentyl)-piperidine-1-carboxylic Acid 2-Isopropyl-5-methylcyclohexyl
Ester (102). A solution of (-)-menthyl carbamate 101 (1.0 g, 2.8 mmol) in dry CH2Cl2 (25 mL)
was cooled to -78 °C and ozone was bubbled through the reaction mixture for 10 min until a light
blue coloration was achieved. The mixture was then purged with argon for 5 min followed by the
portionwise addition of triphenylphosphine (866 mg, 3.3 mmol). The reaction mixture was warmed
to rt over 2 h and then concentrated in vacuo to afford a yellowish oil. This material was purified
by flash column chromatography on silica gel (gradient 10% to 15% EtOAc/hexanes) to afford
aldehyde 102 (979 mg, 100%) as a clear colorless oil: 1H NMR (300 MHz, CDCl3) δ 9.78 (t, J =
1.7 Hz, 1H), 4.74 (tdd, J = 10.8, 4.4, 2.0 Hz, 1H), 3.75-3.84 (m, 1H), 3.64-3.69 (m, 1H), 2.47 (td,
J = 7.2, 1.7 Hz, 2H), 2.35-2.44 (m, 1H), 2.12 (br d, J = 12.1 Hz, 1H), 1.39-2.06 (m, 17H), 0.98-
1.16 (m, 2H), 0.92 (d, J = 5.7 Hz, 6H), 0.79 (d, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
203.0, 174.5, 154.4, 77.8, 47.3, 46.3, 46.3, 44.1, 44.04, 44.01, 41.2, 41.1, 34.6, 31.9, 31.21, 31.16,
26.97, 26.94, 26.5, 26.42, 26.38, 23.65, 23.62, 22.43, 22.40, 22.37, 22.2, 22.1, 21.29, 21.26, 16.60,
16.56.
113
N
CO2Me
O
O
O
Me Me
Me103
3-(6-Methoxycarbonylhex-5-enyl)-2-oxopiperidine-1-carboxylic Acid 2-Isopropyl-5-
methylcyclohexyl Ester (103). Anhydrous LiCl (160 mg, 3.7 mmol) was flame-dried under a
stream of argon and then suspended in dry MeCN (15 mL) to which was added methyl
diethylphosphonoacetate (0.58 mL, 3.3 mmol) and DBU (0.42 mL, 3.0 mmol) at rt. A solution of
aldehyde 102 (979 mg, 2.75 mmol) in dry MeCN (9 mL) was added dropwise over 5 min and the
resulting cloudy white reaction mixture was stirred for 24 h at rt. Saturated NH4Cl (aq) was added,
the organic layer was separated, and the aqueous layer was extracted with EtOAc (3 x 50 mL). The
combined organic extracts were washed with brine, dried over anhydrous MgSO4, and
concentrated in vacuo to afford a brownish oil. This crude material was purified by flash column
chromatography on silica gel (10% EtOAc/hexanes) to provide (E)-α,β-unsaturated ester 103 (814
mg, 70%) as a clear colorless oil: 1H NMR (300 MHz, CDCl3) δ 6.84 (dt, J = 15.6, 7.0 Hz, 1H),
5.71 (dt, J = 15.7, 1.5 Hz, 1H), 4.61 (tdd, J = 10.9, 4.3, 2.0 Hz, 1H), 3.52-3.72 (m, 2H), 3.61 (s,
3H), 2.20-2.32 (m, 1H), 2.11 (q, J = 6.5 Hz, 2H), 1.51-2.06 (m, 10H), 1.20- 1.47 (m, 9H), 0.84-
0.98 (m, 2H), 0.82 (d, J = 6.8 Hz, 6H), 0.67 (d, J = 7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
174.3, 167.2, 154.4, 154.3, 149.6, 121.3, 77.6, 51.6, 47.2, 46.2, 46.1, 44.1, 44.0, 41.1, 41.0, 34.5,
32.3, 31.7, 31.13, 31.07, 28.4, 26.9, 26.8, 26.5, 26.3, 26.2, 23.6, 23.5, 22.3, 22.1, 22.0, 21.13,
21.10, 16.5, 16.4.
114
N
CO2Me
O
O
O
Me Me
Me
H
104a
N
MeO2C
O
O
O
MeMe
Me
H
104b
7-Methoxycarbonylmethyl-1-oxo-2-azaspiro[5.5]undecane-2-carboxylic Acid 2-
Isopropyl-5-methylcyclohexyl Ester (104a/b). TiCl4 (0.153 mL, 1.35 mmol) and dry Et3N (0.190
mL, 1.35 mmol) were dissolved in dry CH2Cl2 (6 mL) at 0 °C and the resulting deep maroon
solution was stirred for 5 min. A solution of (E)-α,β-unsaturated ester 103 (284 mg, 0.68 mmol)
in dry CH2Cl2 (5 mL) was added dropwise and the reaction mixture was slowly warmed to rt over
3 h. Saturated NaHCO3 (aq) was carefully added, the mixture was stirred for 30 min and then
extracted with CH2Cl2 (3 x 20 mL). The combined organic layers were dried over anhydrous
MgSO4 and concentrated in vacuo to afford a reddish oil that was purified by flash chromatography
on silica gel (10% EtOAc/hexanes) to give spirocyclic ester 104a/b (165 mg, 66%) as a light
yellow gum in a 1:1 diastereomeric mixture: 1H NMR (300 MHz, CDCl3) δ 4.71 (td, J = 10.8, 4.4
Hz, 1H), 3.72-3.78 (m, 1H), 3.64 (s, 3H), 3.52-3.62 (m, 1H), 2.59-2.71 (m, 1H), 2.25-2.30 (m,
1H), 1.07-2.09 (m, 30H), 0.89-0.93 (m, 11H), 0.79 (d, J = 5.2, 3H), 0.77 (d, J = 5.2 Hz, 3H); 13C
NMR (75 MHz, CDCl3) δ 177.5, 177.4, 173.3, 173.2, 154.9, 154.7, 77.9, 77.8, 53.8, 51.9, 49.4,
49.3, 47.3, 47.2, 41.1, 40.3, 39.8, 37.4, 37.3, 35.6, 35.2, 35.1, 34.6, 32.0, 31.8, 27.4, 26.7, 26.4,
25.8, 24.4, 24.1, 23.9, 23.6, 23.1, 22.4, 21.3, 21.1, 21.05, 20.99, 20.4, 20.3, 16.9, 16.5, 14.5.
115
P
O
EtOEtO
O
O Me
Me
Ph
106
(Diethoxyphosphoryl)-acetic Acid 2-(1-Methyl-1-phenylethyl)-cyclohexyl Ester (106).
To a stirred solution of diethoxyphosphorylacetyl chloride (265 mg, 1.2 mmol) in dry CH2Cl2 (4
mL) at 0 ºC was added dropwise (+)-TCC alcohol (105, 250 mg, 1.2 mmol) as a solution in dry
CH2Cl2 (2 mL) followed by Et3N (0.16 mL, 1.2 mmol). The mixture was warmed to rt and stirred
overnight, then saturated NH4Cl (aq) was added. The mixture was extracted with Et2O (3 x 25 mL)
and the combined organic layers were washed with brine and dried over anhydrous MgSO4 then
concentrated in vacuo. The crude product was purified via flash column chromatography on silica
gel (50% EtOAc/hexanes) to afford (+)-TCC phosphonoester 106 (213 mg, 47%) as a clear gum:
1H NMR (300 MHz, CDCl3) δ 7.22-7.29 (m, 4H), 7.07-7.13 (m, 1H), 4.78 (td, J = 10.3, 4.6 Hz,
1H), 3.91- 4.12 (m, 4H), 2.34 (dd, J = 21.3, 14.4 Hz, 1H), 1.99-2.11 (m, 2H), 1.79-1.92 (m, 2H),
1.66-1.70 (m, 2H), 1.02-1.29 (m, 16H); 13C NMR (75 MHz, CDCl3) δ 165.5, 165.4, 152.2, 128.3,
125.7, 125.4, 75.8, 62.8, 62.7, 51.1, 39.9, 35.1, 33.4, 29.6, 27.1, 26.3, 24.9, 23.6, 16.7, 16.6.
NCbz
O
O
OMe
Ph
Me
107
3-{6-[2-(1-Methyl-1-phenylethyl)-cyclohexyloxycarbonyl]-hex-5-enyl}-2-
oxopiperidine-1-carboxylic Acid Benzyl Ester (107). To a stirred solution of (+)-TCC
phosphonoester 106 (50 mg, 0.13 mmol) in dry THF (2 mL) at -78 ºC was added in one portion
116
solid KHMDS (27 mg, 0.13 mmol) and the mixture was stirred at that temperature for 30 min. A
solution of aldehyde 60 (40 mg, 0.13 mmol) in dry THF (0.5 mL) was added dropwise and the
mixture was allowed to warm to rt overnight. Saturated NH4Cl (aq) was added and the mixture was
extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried
over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified via flash
column chromatography on silica gel (15% EtOAc/hexanes) to afford (E)-α,β-unsaturated ester
107 (23 mg, 32%) as a clear gum: 1H NMR (300 MHz, CDCl3) δ 7.12-7.47 (m, 10H), 6.50 (dt, J
= 11.7, 5.3 Hz, 1H), 5.25 (s, 2H), 4.79-4.85 (m, 1H), 3.65-3.89 (m, 2H), 2.22-2.45 (m, 1H), 1.09-
2.10 (m, 28H).
N
CO2MeH
OMe
110
(1-Methoxy-2-azaspiro[5.5]undec-1-en-7-yl)-acetic Acid Methyl Ester (110). To a
solution of N-H lactam 63 (90 mg, 0.38 mmol) in dry CH2Cl2 (2 mL) was added freshly distilled
methyl trifluoromethanesulfonate (0.054 mL, 0.47 mmol) and the mixture was stirred for 8 h at rt.
Saturated Na2CO3 (aq) was added and the mixture was extracted with CH2Cl2 (3 x 25 mL). The
combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo to
furnish imidate 110 (96 mg, 100%) as a light brownish gum which was used without further
purification: 1H NMR (400 MHz, CDCl3) δ 3.66 (s, 3H), 3.45-3.60 (m, 4H), 3.25-3.33 (m, 1H),
2.46-2.57 (m, 1H), 2.05-2.12 (m, 2H), 1.31-1.75 (m, 12H); 13C NMR (75 MHz, CDCl3) δ 173.9,
167.0, 52.7, 51.9, 47.4, 42.6, 39.3, 37.4, 34.2, 26.8, 26.2, 23.9, 20.8, 20.4; HRMS-ES (m/z): [M +
117
H]+ calcd for C14H23NO3, 254.3413; found, 254.3419.
N H
CHOH
O
111
2-(1-Oxo-2-azaspiro[5.5]undecan-7-yl)acetaldehyde (111). To a stirred solution of N-H
lactam 63 (355 mg, 1.48 mmol) in dry CH2Cl2 (35 mL) at -78 °C was added dropwise DIBAL-H
(1.5 M in PhMe, 2.96 mmol, 2.0 mL) over 5 min. The reaction mixture was stirred for 2 h at -78
°C, carefully quenched with MeOH, then warmed to rt. An equal volume of saturated aqueous
potassium sodium tartrate solution was added and the mixture was stirred at rt for 1 h. The mixture
was separated and the aqueous layer extracted with CH2Cl2 (2 x 50 mL). The combined organic
layers were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The crude
product was purified by flash column chromatography on silica gel (20% CH2Cl2/Et2O + 1%
MeOH) to furnish the aldehyde 111 as a clear gum (208 mg, 67%): 1H NMR (300 MHz, CDCl3)
δ 9.63-9.67 (m, 1H), 6.37 (br s, 1H), 3.25-3.48 (m, 2H), 2.72-2.80 (m, 1H), 2.31 (ddd, J = 17.1,
3.5, 1.6 Hz, 1H), 1.91 (ddd, J = 15.0, 9.1, 3.7 Hz, 1H), 1.67-1.98 (m, 6H), 1.04-1.66 (m, 6H); 13C
NMR (75 MHz, CDCl3) δ 203.0, 177.7, 47.3, 45.8, 42.5, 37.1, 34.5, 27.4, 26.1, 23.3, 20.6, 19.6;
IR (neat) 1720, 1645 cm-1; HRMS-ES+ (C12H20NO2) calcd 210.1494 (MH+), found 210.1495.
118
N H
H
O
N
112
7-(E)-2-(Pyrrolidin-1-yl)vinyl)-2-azaspiro[5.5]undecan-1-one (112). To a stirred
solution of aldehyde 111 (50 mg, 0.24 mmol) in CHCl3 (1 mL) at 0 °C was added 4Å molecular
sieves (300 mg) and pyrrolidine (0.29 mmol, 0.024 mL). The reaction mixture was stirred for 1.5
h at 0 °C, then filtered through a Celite pad and concentrated in vacuo to give pyrrolidinoenamine
112 as a white solid that was used without further purification (63 mg, 100%). A small sample (ca.
5 mg) of enamine 112 was recrystallized from Et2O to afford clear prisms that were suitable for
X-ray analysis: 1H NMR (300 MHz, CDCl3) δ 6.08-6.19 (m, 2H), 3.95 (dd, J = 13.8, 7.6 Hz, 1H),
2.85-3.25 (m, 6H), 2.62-2.73 (m, 1H), 1.11-2.05 (m, 16H); 13C NMR (75 MHz, CDCl3) δ 178.6,
136.9, 100.2, 49.6, 47.4, 43.8, 42.7, 34.3, 28.1, 26.3, 25.2, 23.5, 20.8, 20.4; HRMS-ES+
(C16H27N2O) calcd 263.2123 (MH+), found 263.2131.
NBn
H
O
114
N
OMe
OMe
2-(2-Benzyl-1-oxo-2-azaspiro[5.5]undecan-7-yl)-N-methoxy-N-methylacetamide
(114). To a stirred suspension of N,O-dimethylhydroxylamine hydrochloride (10.16 g, 105.7
mmol) in dry CH2Cl2 (300 mL) at 0 °C was added dropwise dimethylaluminum chloride (1 M in
hexane, 105.7 mL, 105.7 mmol). The reaction mixture was warmed to rt and stirred for 2 h. A
solution of N-Bn lactam 53 (11.59 g, 35.2 mmol) in dry CH2Cl2 (60 mL) was added and the mixture
119
was stirred for 24 h at rt. An equal volume of saturated aqeuous potassium sodium tartrate solution
was added and the resulting biphasic mixture was stirred for 2 h at rt. The aqueous layer extracted
with CH2Cl2 (3 x 250 mL). The combined organic layers were washed with brine, dried over
anhydrous MgSO4, and concentrated in vacuo to afford a brownish oil. This material was purified
via flash column chromatography on silica gel (50% EtOAc/hexanes) to afford N-methoxy-N-
methylamide 114 (11.34 g, 90%) as a light yellow gum: 1H NMR (300 MHz, CDCl3) δ 7.21-7.31
(m, 5H), 4.68 (d, J = 14.6 Hz, 1H), 4.46 (d, J = 14.6 Hz, 1H), 3.65 (s, 3H), 3.16-3.27 (m, 5H), 2.75
(br s, 1H), 2.27 (m, 1H), 2.12 (m, 1H), 1.10-1.94 (m, 12H); 13C NMR (75 MHz, CDCl3) δ 175.4,
138.2, 128.9, 128.3, 127.6, 61.6, 51.1, 47.7, 46.3, 39.6, 35.6, 35.1, 32.6, 27.2, 26.1, 23.5, 20.9,
19.7; HRMS-ES+ (C21H31N2O3) calcd 359.2335 (MH+), found 359.2335.
115
NBn
CHOH
O
2-(2-Benzyl-1-oxo-2-azaspiro[5.5]undecan-7-yl)acetaldehyde (115). To a stirred
solution of N-methoxy-N-methylamide 114 (11.34 g, 31.7 mmol) in dry THF (300 mL) at -40 °C
was added lithium aluminum hydride (4.79 g, 126.6 mmol) in portions over 5 min. The resulting
dark grey suspension was stirred for 1 h at -40 °C, then carefully diluted with methanol followed
by 1 N NaOH (aq). The mixture was warmed to rt and additional 1 N NaOH (aq) solution was added.
The mixture was extracted with EtOAc (4 x 200 mL). The combined organic layers were washed
with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The crude material was
purified via flash column chromatography on silica gel (gradient 25% to 35% EtOAc/hexanes) to
120
afford aldehyde 115 (8.62 g, 91%) as a waxy yellowish solid: 1H NMR (300 MHz, CDCl3) 9.61
(dd, J = 3.7, 1.6 Hz, 1H), 7.17-7.34 (m, 5H), 4.67 (d, J = 14.5 Hz, 1H), 4.37 (d, J = 14.5 Hz, 1H),
3.05-3.21 (m, 2H), 2.78-2.86 (m, 1H), 2.15 (ddd, J = 14.4, 3.6, 1.5 Hz, 1H), 2.04 (ddd, J = 14.5,
10.3, 3.8 Hz, 1H), 1.65-2.00 (m, 7H), 1.34-1.64 (m, 6H), 1.17 (qd, J = 12.5, 4.2 Hz, 1H); 13C NMR
(75 MHz, CDCl3) 203.3, 175.3, 137.9, 129.1, 128.4, 127.8, 51.2, 47.6, 47.4, 46.2, 37.7, 34.8,
27.7, 26.1, 23.5, 20.8, 19.6; HRMS-ES+ (C19H26NO2) calcd 300.1964 (MH+), found 300.1956.
N Bn
CHOH
O
Cl
117
2-(2-Benzyl-1-oxo-2-azaspiro[5.5]undecan-7-yl)-2-chloroacetaldehyde (117). To a
stirred solution of aldehyde 115 (8.62 g, 28.8 mmol) in dry CHCl3 (175 mL) at 0 °C were added
powdered 4Å molecular sieves (38.2 g) and pyrrolidine (2.82 mL, 34.5 mmol). The reaction
mixture was stirred for 1.5 h at 0 °C, then filtered through a pad of Celite, which was washed with
dry Et2O (1 x 50 mL) and dry CH2Cl2 (2 x 50 mL) to afford a solution of (E)-pyrrolidinoenamine
116: 1H NMR (obtained on a sample of crude material after concentration in vacuo) (300 MHz,
CDCl3) δ 7.23-7.36 (m, 5H), 6.20 (d, J = 13.7 Hz, 1H), 5.13 (d, J =14.7 Hz, 1H), 4.12 (d, J = 14.7
Hz, 1H), 3.96 (dd, J = 13.6, 7.8 Hz, 1H), 3.02-3.23 (m, 2H), 2.92-3.01 (m, 4H), 2.80-2.88 (m, 1H),
1.14-1.93 (m, 16H); 13C NMR (75 MHz, CDCl3) δ 176.2, 138.2, 136.9, 128.8, 128.4, 127.4, 100.2,
51.3, 49.4, 47.9, 44.6, 34.5, 28.6, 26.5, 25.3, 23.9, 21.1, 20.4.
121
To the above stirred CHCl3/Et2O solution of enamine 116 (10.14 g, 28.8 mmol) was added
N-chlorosuccinimide (3.81 g, 28.5 mmol) in one portion. The reaction mixture was heated at reflux
for 30 min and then stirred at rt for 5 h. Aqueous acetic acid (10% v/v) was added and the resulting
biphasic mixture was stirred for 30 min. The aqueous layer was extracted with EtOAc (2 x 50 mL)
and the combined organic layers were washed with 1 N HCl (aq), saturated NaHCO3 (aq), and brine,
dried over anhydrous MgSO4 and then concentrated in vacuo. The resulting brownish oil was
purified by flash column chromatography on silica gel (gradient 7.5% to 15% EtOAc/hexanes) to
afford α-chloroaldehyde 117 (7.84 g, 82%) as an inseparable ~2.2:1 mixture of C7-diastereomers:
1H NMR (300 MHz, CDCl3) δ 9.37 (d, J = 4.8 Hz, 1H), 9.30 (d, J = 3.6 Hz, 1H), 7.21-7.35 (m,
5H), 5.05 (d, J = 14.7 Hz, 1H), 4.93 (d, J = 14.5 Hz, 1H), 4.72 (s, 1H), 4.22 (d, J = 14.5 Hz, 1H),
3.98-4.04 (m, 2H), 3.87 (dd, J = 8.4, 4.8 Hz, 1H), 2.98-3.31 (m, 4H), 1.22-2.04 (m, 9H); 13C NMR
(75 MHz, CDCl3) δ 194.4, 193.9, 175.3, 175.2, 137.7, 137.7, 129.0, 128.9, 128.7, 128.4, 127.4,
127.3, 68.3, 66.3, 65.8, 65.7, 51.4, 51.0, 47.4, 47.1, 46.3, 45.3, 43.9, 43.6, 35.5, 35.4, 25.9, 25.8,
25.1, 24.1, 23.5, 23.1, 20.7, 20.6, 19.6, 19.2, 15.7; HRMS-ES+ (C19H25NO2Cl) calcd 334.1574
(MH+), found 334.1574.
NBn
H
O
N
OTBS
Cl
122
(E)-2-(2-Benzyl-1-oxo-2-azaspiro[5.5]undecan-7-yl)-2-chloroacetaldehyde O-(tert-
Butyldimethylsilyl)oxime (122). To a stirred solution of α-chloroaldehyde 117 (~2.2:1 C7-
diastereomeric mixture, 7.84 g, 23.54 mmol) in dry CH2Cl2 (110 mL) was added O-TBS-
122
hydroxylamine (6.85 g, 47.08 mmol), powdered 4Å molecular seives (650 mg), and PPTS (1.00
g, 3.97 mmol). The reaction mixture was stirred for 24 h at rt, then filtered through a pad of Celite
which was washed with CH2Cl2. The combined filtrate was concentrated to afford a colorless oil
that was purified by flash column chromatography on silica gel (gradient 2.5% to 5%
EtOAc/hexanes) to provide the O-TBS-oxime 122 as a separable ~2.2:1 mixture of diastereomers
(9.25 g total, 85%): 1H NMR (300 MHz, CDCl3) δ (major) 7.48 (d, J = 9.3 Hz, 1H), 7.19-7.36 (m,
5H), 5.53 (d, J = 15.0 Hz, 1H), 4.35 (t, J = 9.3 Hz, 1H), 3.63 (d, J = 15.0 Hz, 1H), 3.10-3.21 (m,
2H), 2.74-2.86 (m, 1H), 2.20-2.25 (m, 1H), 1.13-2.05 (m, 11H), 0.98 (s, 9H), 0.23 (s, 3H), 0.21 (s,
3H); 1H NMR (minor) δ 7.18-7.65 (m, 5H), 7.04 (d, J = 8.8 Hz, 1H), 5.09-5.18 (m, 2H), 3.86 (d,
J = 14.7 Hz), 3.01-3.13 (m, 2H), 2.74-2.80 (m, 1H), 2.17-2.31 (m, 1H), 1.16-1.87 (m, 11H), 0.95
(s, 9H), 0.22 (s, 3H), 0.19 (s, 3H); 13C NMR (75 MHz, CDCl3) δ (major) 175.4. 155.0, 138.2,
129.0, 128.1 127.6, 62.7, 51.0, 47.1, 46.8, 46.1, 35.3, 26.4, 25.8, 25.4, 22.4, 20.9, 19.4, 18.4, -4.5,
-4.8; (minor) 175.3, 153.3, 137.8, 128.9, 128.1, 127.6, 53.8, 51.0, 47.1, 46.9, 46.2, 35.3, 26.3, 25.8,
25.5, 22.3, 20.9, 19.3, 18.4, -4.7, -4.9; HRMS-ES+ (C25H40N2O2SiCl) (major) calcd 463.2548
(MH+), found 463.2551; (minor) calcd 463.2548 (MH+), found 463.2543.
NCO2Me
NH
CO2Me
O
OH
Bn
123a/b
H
Dimethyl-2-((E/Z)-1-(2-Benzyl-1-oxo-2-azaspiro[5.5]undecan-7-yl)-2-
(hydroxyimino)ethyl)malonate (123a/b). To a stirred solution of dimethyl malonate (1.21 mL,
123
10.6 mmol) in dry THF (60 mL) at -78 °C was added dropwise LiHMDS (1 M in THF, 10.6 mL,
10.6 mmol) and the resulting yellow solution was stirred for 30 min at that temperature. A solution
of O-TBS-oxime 122 (~2.2:1 mixture of C7-diastereomers, 4.10 g, 8.9 mmol) in dry THF (30 mL)
was added dropwise over 5 min followed by the dropwise addition of TBAF (1 M in THF, 17.7
mL, 17.7 mmol) over 5 min. The reaction mixture was immediately warmed to 0 °C via transfer
to an ice bath and stirred for 4 h at that temperature. The mixture was diluted with saturated NH4Cl
(aq) and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine,
dried over anhydrous MgSO4, and concentrated in vacuo to give an oil that was purified by flash
chromatography on silica gel (10% Et2O in CH2Cl2) to afford oximes 123a/b (~5:1 mixture of E-
and Z-oxime geometric isomers, 3.66 g, 93%) as a white solid. The geometric isomers 123a (E)
and 123b (Z) (~5 mg of solid from column fractions near the beginning and end of the elution,
respectively) were each recrystallized from a minimal amount of Et2O via slow evaporation to
afford clear prisms that were analyzed by X-ray crystallography. All attempts to purify a sufficient
quantity of the minor isomer (123b) by chromatography for NMR analysis were unsuccessful: 1H
NMR (300 MHz, CDCl3) (major (123a)) δ 7.72-7.77 (m, 2H), 7.23-7.36 (m, 5H), 4.80 (d, J = 14.6
Hz, 1H), 4.39 (d, J = 14.6 Hz, 1H), 3.90 (d, J = 5.6 Hz, 1H), 3.77 (s, 3H), 3.73 (s, 3H), 3.14-3.31
(m, 2H), 2.79-2.86 (m, 1H), 2.55 (dt, J = 13.1, 3.2 Hz, 1H), 1.06-1.93 (m, 12H). 13C NMR (75
MHz, CDCl3) (major (123a)) δ 175.2, 169.1, 168.9, 152.6, 137.8, 129.0, 128.4, 127.7, 55.7, 53.1,
52.7, 51.1, 47.8, 47.4, 44.1, 42.2, 35.1, 26.5, 25.1, 23.1, 20.8, 19.5; HRMS-ES+ (C24H33N2O6)
(mixture) calcd 445.2339 (MH+), found 445.2342.
124
NCO2Me
CNH
CO2Me
O
BnH
125
Dimethyl 2-(2-Benzyl-1-oxo-2-azaspiro[5.5]undecan-7-yl)(cyano)methyl)malonate
(125). To a stirred solution of oximes 123a/b (284 mg, 0.64 mmol) in dry CH2Cl2 (8 mL) were
added CuSO4·5H2O (100 mg), Et3N (0.16 mL, 1.54 mmol), and pyridine (0.51 mL, 6.4 mmol).
DCC (158 mg, 0.77 mmol) was then added in one portion and the reaction mixture was stirred for
14 h at rt, and diluted with 1 N HCl (aq). The mixture was extracted with CH2Cl2 (3 x 50 mL) and
the combined organic layers were washed with brine, dried over anhydrous MgSO4, and
concentrated in vacuo. The crude product was purified by flash column chromatography on silica
gel (20% EtOAc/hexanes) to provide nitrile 125 (263 mg, 96%) as a white waxy solid: 1H NMR
(300 MHz, CDCl3) δ 7.21-7.61 (m, 5H), 4.57 (dd, J = 19.4, 14.5 Hz, 2H), 3.83 (s, 3H), 3.82 (s,
3H), 3.77 (d, J = 5.9 Hz, 1H), 3.16-3.33 (m, 2H), 3.07 (dd, J = 7.8, 1.2 Hz, 1H), 2.51 (dd, J = 12.1,
3.1 Hz, 1H), 2.04-2.15 (m, 1H), 1.32-1.94 (m, 11H); 13C NMR (75 MHz, CDCl3) δ 174.3, 167.4,
166.7, 137.7, 129.1, 128.3, 127.8, 119.2, 54.3, 53.7, 53.4, 51.3, 47.8, 47.5, 42.0, 34.8, 34.5, 26.0,
24.7, 23.5, 20.6, 19.2; IR (neat) 2242, 1741, 1625, 1201 cm-1; HRMS-ES+ (C24H31N2O5) calcd
427.2233 (MH+), found 427.2215.
125
N
CNH
CO2Me
O
BnH
126
Methyl 3-(2-Benzyl-1-oxo-2-azaspiro[5.5]undecan-7-yl)-3-cyanopropanoate (126). To
a stirred solution of nitrile 125 (2.22 g, 5.2 mmol) in DMSO (50 mL) and H2O (25 mL) was added
LiCl (2.21 g, 52.1 mmol) and the reaction mixture was heated at 155 °C for 24 h, and then cooled
to rt. The mixture was extracted with EtOAc (3 x 200 mL) and the combined organic layers were
washed with H2O, brine, dried over anhydrous MgSO4, and concentrated in vacuo. The crude
product was purified by flash column chromatography on silica gel (20% EtOAc/hexanes) to
furnish ester 126 (1.41 g, 73%) as a clear colorless gum: 1H NMR (300 MHz, CDCl3) δ 7.18-7.32
(m, 5H), 4.64 (d, J = 14.5 Hz, 1H), 4.44 (d, J = 14.5 Hz, 1H), 3.71 (s, 3H), 3.14-3.25 (m, 2H), 2.80
(dd, J = 10.6, 3.6 Hz, 1H), 2.75 (dd, J = 26.0, 10.6 Hz, 1H), 2.59 (dd, J = 14.6, 3.5 Hz, 1H), 2.40
(dd, J = 12.8, 3.6 Hz, 1H), 1.23-2.07 (m, 12H); 13C NMR (75 MHz, CDCl3) δ 174.3, 170.2, 137.3,
128.2, 127.9, 127.4, 120.7, 52.1, 50.9, 47.2, 47.1, 43.6, 37.6, 34.4, 30.5, 25.6, 23.8, 22.9, 20.2,
18.7; IR (neat) 2239, 1739, 1623, 1203 cm-1; HRMS-ES+ (C22H29N2O3) calcd 369.2178 (MH+),
found 369.2188.
126
N
CNH
O
BnH OH
127
2-(2-Benzyl-1-oxo-2-azaspiro[5.5]undecan-7-yl)-4-hydroxybutanenitrile (127). To a
stirred suspension of LiBH4 (21 mg, 0.95 mmol) in dry THF (3 mL) at rt was added dropwise a
solution of ester 126 (250 mg, 0.68 mmol) in dry THF (5 mL). The reaction mixture was stirred
for 15 h at rt and diluted with brine. The mixture was extracted with EtOAc (3 x 50 mL), dried
over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified by flash
column chromatography on silica gel (40% EtOAc/hexanes) to afford alcohol 127 (203 mg, 88%)
as a clear gum: 1H NMR (300 MHz, CDCl3) δ 7.20-7.37 (m, 5H), 4.77 (d, J = 14.5 Hz, 1H), 4.37
(d, J = 14.5 Hz, 1H), 3.84-3.93 (m, 1H), 3.61-3.72 (m, 1H), 3.49-3.59 (m, 1H), 3.21-3.36 (m, 2H),
2.53-2.59 (m, 2H), 1.30-2.18 (m, 14H); 13C NMR (75 MHz, CDCl3) δ 176.3, 137.2, 129.2, 128.3,
128.0, 122.6, 59.0, 51.6, 47.7, 47.6, 40.4, 34.7, 30.2, 26.1, 23.5, 23.1, 20.7, 18.8; HRMS-ES+
(C21H29N2O2) calcd 341.2229 (MH+), found 341.2219.
N
CNH
O
BnH OMs
128
Methanesulfonic Acid 3-(2-Benzyl-1-oxo-2-azaspiro[5.5]undec-7-yl)-3-cyano-propyl
Ester (128). To a stirred solution of alcohol 127 (28 mg, 0.085 mmol) in dry CH2Cl2 (1.5 mL)
127
was added Et3N (0.022 mL, 0.17 mmol) and methanesulfonyl chloride (0.015 mL, 0.17 mmol).
The reaction mixture was stirred for 3 h at rt and then 1 N HCl (aq) was added. The mixture was
extracted with CH2Cl2 (3 x 10 mL) and the combined organic layers were washed with brine, dried
over anhydrous MgSO4, and concentrated in vacuo. The crude product was purified via flash
column chromatography on silica gel (35% EtOAc/hexanes) to afford mesylate 128 (23 mg, 64%)
as a clear colorless gum: 1H NMR (300 MHz, CDCl3) δ 7.21-7.63 (m, 5H), 4.69 (d, J = 14.6 Hz,
1H), 4.30-4.47 (m, 3H), 3.16-3.36 (m, 2H), 3.05 (s, 3H), 2.54 (td, J = 7.6, 1.3 Hz, 1H), 2.43 (ddd,
J = 14.9, 3.3, 1.3 Hz, 1H), 2.05-2.13 (m, 3H), 1.36-1.98 (m, 11H); 13C NMR (75 MHz, CDCl3) δ
174.8, 137.6, 129.2, 128.2, 127.9, 121.1, 67.3, 51.3, 47.6, 47.4, 43.6, 37.8, 34.8, 32.4, 30.9, 30.1,
26.1, 24.0, 23.3, 20.7, 19.1.
N
CNH
O
BnH CN
129
2-(2-Benzyl-1-oxo-2-azaspiro[5.5]undec-7-yl)-pentanedinitrile (129). To a stirred
solution of mesylate 128 (23 mg, 0.055 mmol) in dry MeCN (1 mL) was added 4Å molecular
seives (100 mg) and Et4NCN (60 mg, 0.39 mmol). The reaction mixture was heated at 60 °C for
15 h then cooled to rt and passed through a pad of Celite that was washed with EtOAc. The total
filtrate was washed with 1 M NaHCO3 (aq) and brine, dried over anhydrous MgSO4 and
concentrated in vacuo. The crude product was purified via flash column chromatography on silica
gel (20% EtOAc/hexanes) to afford dinitrile 129 (20 mg, 99%) as a clear gum: 1H NMR (300
MHz, CDCl3) δ 7.23-7.37 (m, 5H), 4.77 (d, J = 14.5 Hz, 1H), 4.38 (d, J = 14.5 Hz, 1H), 3.23-
128
3.38 (m, 2H), 2.35-2.60 (m, 4H), 1.22-2.13 (m, 14H); 13C NMR (75 MHz, CDCl3) δ 174.7, 137.6,
129.1, 128.4, 127.9, 120.6, 118.7, 51.5, 47.7, 47.5, 43.6, 34.5, 33.6, 28.9, 26.0, 24.2, 23.3, 20.6,
19.1, 15.8.
N
CNH
O
HH OH
131
4-Hydroxy-2-(1-oxo-2-azaspiro[5.5]undecan-7-yl)butanenitrile (131). Liquid ammonia
(ca. 10 mL) was condensed at -78 °C and Na metal (83 mg, 3.6 mmol) was added until the reaction
had developed a deep purple coloration. A solution of alcohol 127 (122 mg, 0.36 mmol) in dry
Et2O (10 mL) was added dropwise, the reaction mixture was stirred for 45 min, and then quenched
by the addition of solid NH4Cl (~200 mg). The mixture was warmed to rt, saturated NH4Cl (aq) was
added, and the resulting biphasic mixture was extracted with EtOAc (3 x 50 mL). The combined
organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo.
The crude product was purified by flash chromatography on silica gel (gradient 5% to 10%
MeOH/EtOAc) to afford N-H lactam alcohol 131 (76 mg, 87%) as a white solid: 1H NMR (300
MHz, CDCl3) δ 6.15 (br s, 1H), 3.82-3.93 (m, 1H), 3.71 (dt, J = 12.3, 4.9 Hz, 1H), 3.28-3.46 (m,
2H), 2.66 (dd, J = 10.2, 4.9 Hz, 1H), 2.45 (dd, J = 12.6, 3.4 Hz, 1H), 2.07-2.15 (m, 1H), 1.24-2.06
(m, 14H); 13C NMR (75 MHz, CDCl3) δ 178.6, 122.4, 59.1, 47.3, 42.5, 40.7, 34.8, 34.5, 30.2, 26.1,
23.3, 23.1, 20.6, 18.8; HRMS-ES+ (C14H23N2O2) calcd 251.1760 (MH+), found 251.1752.
129
N
CNH
O
HH OMs
132
3-Cyano-3-(1-oxo-2-azaspiro[5.5]undecan-7-yl)propyl Methanesulfonate (132). To a
stirred solution of N-H lactam alcohol 131 (76 mg, 0.31 mmol) in dry CH2Cl2 (5 mL) at rt was
added Et3N (0.083 mL, 0.62 mmol) and MsCl (0.047 mL, 0.37 mmol) and the mixture was stirred
for 4 h at that temperature. The reaction mixture was diluted with brine and extracted with CH2Cl2,
(3 x 50 mL). The combined organic layers were dried over anhydrous MgSO4, and concentrated
in vacuo. The crude product was purified by flash column chromatography on silica gel (5%
MeOH/EtOAc) to furnish mesylate 132 (92 mg, 91%) as a clear gum: 1H NMR (300 MHz, CDCl3)
δ 6.61 (br s, 1H), 4.28-4.43 (m, 2H), 3.23-3.36 (m, 2H), 3.07 (s, 3H), 2.59 (td, J = 7.8, 1.3 Hz, 1H),
2.28 (ddd, J = 12.7, 3.5, 1.2 Hz, 1H), 2.03-2.10 (m, 3H), 1.20-1.88 (m, 11H); 13C NMR (75 MHz,
CDCl3) δ 177.1, 121.0, 67.5, 47.0, 43.3, 42.3, 37.8, 34.6, 32.4, 30.9, 26.0, 23.8, 23.1, 20.5, 19.0;
HRMS-ES+ (C15H25N2O4S) calcd 329.1535 (MH+), found 329.1536.
N
CNH
O
HH CN
130
2-(1-Oxo-2-azaspiro[5.5]undecan-7-yl)pentanedinitrile (130). To a solution of mesylate
132 (92 mg, 0.28 mmol) in dry MeCN (10 mL) was added Et4NCN (308 mg, 1.96 mmol) and 4 Å
molecular seives (100 mg). The reaction mixture was heated at 60 °C for 12 h and cooled to rt.
130
The mixture was filtered through a Celite pad which was rinsed with EtOAc. The combined filtrate
was washed with 1 M NaHCO3 (aq) and brine, dried over anhydrous MgSO4 and concentrated in
vacuo. The resulting orange oil was purified by flash column chromatography on silica gel (40%
EtOAc/Et2O) to afford dinitrile 130 (71 mg, 97%) as a yellowish gum: 1H NMR (300 MHz, CDCl3)
6.59 (br s, 1H), 3.30-3.41 (m, 2H), 2.49-2.68 (m, 3H), 2.29 (dd, J = 12.8, 2.9 Hz, 1H), 1.18-2.13
(m, 19H); 13C NMR (75 MHz, CDCl3) δ 177.1, 120.5, 118.7, 47.0. 43.2, 42.4, 34.4, 33.6, 29.0,
26.0, 24.0, 23.2, 20.5, 19.0, 15.8; IR (neat) 2242, 2159, 1649 cm-1; HRMS-ES+ (C15H22N3O) calcd
260.1763 (MH+), found 260.1750.
N
CNH
OMe
CN
133
2-(1-Methoxy-2-azaspiro[5.5]undec-1-en-7-yl)pentanedinitrile (133). To a stirred
solution of dinitrile 130 (7.5 mg, 0.029 mmol) in dry CH2Cl2 (1 mL) was added methyl
trifluoromethanesulfonate (0.0144 mL, 0.087 mmol) and the reaction mixture was stirred for 10 h
at rt. CH2Cl2 was added and the mixture was washed with 1 M NaHCO3 (aq) and brine. The organic
layer was dried over anhydrous Na2SO4, and concentrated in vacuo. The crude material was
purified by flash chromatography on silica gel (40% EtOAc/Et2O) to afford methyl imidate 133
(6.3 mg, 79%) as a clear gum: 1H NMR (850 MHz, CDCl3) δ 3.64 (s, 3H), 3.62 (dd, J = 16.7, 3.6
Hz, 1H), 3.44 (pentet, J = 7.7 Hz, 1H), 2.58-2.62 (m, 1H), 2.51-2.54 (m, 1H), 2.44 (dd, J = 9.0,
8.9 Hz, 1H), 2.15 (dd, J = 12.5, 3.3 Hz, 1H), 2.05-2.08 (m, 1H), 2.02 (dt, J = 9.8, 3.9 Hz, 1H), 1.92
(pentet, J = 7.3 Hz, 1H), 1.88 (br d, J = 13.2 Hz, 1H), 1.80 (br d, J = 13.7 Hz, 1H), 1.72-1.75 (m,
131
1H), 1.61-1.68 (m, 5H), 1.57-1.59 (m, 1H), 1.51 (qt, J = 9.7, 3.9 Hz, 1H), 1.36 (qt, 13.2, 4.2 Hz,
1H); 13C NMR (212.5 MHz, CDCl3) δ 165.1, 120.0, 118.1, 52.6, 46.8, 43.3, 43.1, 33.8, 33.0, 28.8,
25.8, 23.7, 23.5, 20.2, 19.5, 15.5; HRMS-ES+ (C16H24N3O) calcd 274.1919 (MH+), found
274.1906.
N
CNH
O
BnH
144
O
N
Me
OMe
3-(2-Benzyl-1-oxo-2-azaspiro[5.5]undec-7-yl)-3-cyano-N-methoxy-N-methyl-
propionamide (144). To a stirred suspension of N,O-dimethylhydroxylamine hydrochloride (260
mg, 2.7 mmol) in dry CH2Cl2 (300 mL) at 0 °C was added dropwise dimethylaluminum chloride
(1 M in hexane, 2.7 mL, 2.7 mmol). The reaction mixture was warmed to rt and stirred for 2 h. A
solution of ester 126 (200 mg, 0.54 mmol) in dry CH2Cl2 (5 mL) was added and the mixture was
stirred for 24 h at rt. An equal volume of saturated aqeuous potassium sodium tartrate solution was
added and the resulting biphasic mixture was stirred for 2 h at rt. The aqueous layer was extracted
with CH2Cl2 (3 x 25 mL). The combined organic layers were washed with brine, dried over
anhydrous MgSO4, and concentrated in vacuo to afford a brownish oil. This material was purified
via flash column chromatography on silica gel (50% EtOAc/hexanes) to afford N-methoxy-N-
methylamide 144 (183 mg, 85%) as a light yellow gum: 1H NMR (300 MHz, CDCl3) δ 7.18-7.37
(m, 5H), 4.89 (d, J =14.6 Hz, 1H), 4.25 (d, J = 14.5 Hz, 1H), 3.71 (s, 3H), 3.14-3.38 (m, 4H), 2.91-
3.09 (m, 2H), 2.64 (dd, J = 15.8, 3.6 Hz, 1H), 2.49 (dd, J = 12.7, 3.2 Hz, 1H), 1.05-2.18 (m, 13H).
132
N
CNH
O
BnH
CHO
145
2-(2-Benzyl-1-oxo-2-azaspiro[5.5]undec-7-yl)-4-oxobutyronitrile (145). To a stirred
solution of N-methoxy-N-methyl amide 144 (60 mg, 0.15 mmol) in dry THF (10 mL) at -40 °C
was added LiAlH4 (23 mg, 0.61 mmol) in one portion. The reaction mixture was stirred for 30 min
at that temperature then quenched via dropwise addition of MeOH followed by 1 N NaOH (aq).
CH2Cl2 (50 mL) and an equal volume of saturated aqueous potassium sodium tartrate solution
were added and the mixture was stirred overnight at rt. The organic layer was washed with brine,
dried over anhydrous MgSO4 then concentrated in vacuo. The crude material was purified via flash
column chromatography on silica gel (40% EtOAc/hexanes) to afford aldehyde 145 (50 mg, 93%)
as a clear colorless gum: 1H NMR (300 MHz, CDCl3) δ 9.73 (s, 1H), 7.21-7.37 (m, 5H), 4.68 (d,
J = 14.5 Hz, 1H), 4.44 (d, J = 14.5 Hz, 1H), 3.22-3.33 (m, 2H), 2.97 (dd, J = 17.1, 9.7 Hz, 1H),
2.85 (ddd, J = 8.4, 4.2, 1.1 Hz, 1H), 2.71 (dd, J = 17.0, 4.1 Hz, 1H), 2.41 (dd, J = 12.9, 2.7 Hz,
1H), 2.05-2.09 (m, 1H), 1.36-1.94 (m, 12H); 13C NMR (75 MHz, CDCl3) δ 198.0, 174.7, 137.6,
129.1, 128.3, 127.9, 120.9, 51.5, 47.7, 47.6, 46.9, 44.1, 34.7, 27.8, 26.0, 24.2, 23.2, 20.6, 19.1.
133
N
CNH
O
BnH
147
2-(2-Benzyl-1-oxo-2-azaspiro[5.5]undec-7-yl)-pent-4-enenitrile (147). To a stirred
solution of aldehyde 145 (123 mg, 0.33 mmol) in dry THF (4 mL) and HMPA (0.13 mL) at rt was
added phenyltetrazoylmethyl sulfone 146 (78 mg, 0.35 mmol) followed by the dropwise addition
of LiHMDS (1 M in THF, 0.66 mL, 0.66 mmol). The reaction mixture was stirred at rt for 20 min
then diluted with saturated NH4Cl (aq). The mixture was extracted with EtOAc (3 x 25 mL) and the
combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated
in vacuo. The crude product was purified via flash column chromatography on silica gel (10%
EtOAc/hexanes) to afford olefin 147 (36 mg, 32%) as a clear colorless gum: 1H NMR (300 MHz,
CDCl3) δ 7.22-7.35 (m, 5H), 5.78-5.87 (m, 1H), 5.18-5.23 (m, 2H), 4.58 (s, 2H), 3.23-3.28 (m,
2H), 2.33-2.48 (m, 4H), 2.01-2.11 (m, 2H), 1.11-1.91 (m, 10H); 13C NMR (75 MHz, CDCl3) δ
174.9, 137.9, 134.0, 129.1, 128.4, 127.9, 121.8, 118.9, 51.5, 47.8, 47.6, 44.1, 37.5, 34.7, 30.1, 26.0,
24.0, 23.6, 29.8, 19.3.
NCO2Me
CHOH
CO2Me
O
BnH
149
Dimethyl 2-(1-(2-Benzyl-1-oxo-2-azaspiro[5.5]undecan-7-yl)-2-oxoethyl)malonate
(149). To a stirred solution of the aldoxime E/Z isomer mixture 123a/b (1.06 g, 2.4 mmol) in dry
134
THF (34 mL) at 0 °C was added Zn metal dust (1.58 g, 23.9 mmol) followed by the dropwise
addition of TiCl4 (1.37 mL, 11.9 mmol). The reaction mixture was stirred at 0 °C for 10 min, then
carefully quenched with saturated NaHCO3 (aq). The mixture was filtered through a sintered glass
frit and the filter cake was washed with CH2Cl2. The aqueous layer was extracted with CH2Cl2 (3
x 200 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4,
and concentrated in vacuo to yield a yellow oil that was purified by flash column chromatography
on silica gel (20% EtOAc/hexanes) to give aldehyde 149 (651 mg, 63%) as a white fluffy solid:
1H NMR (300 MHz, CDCl3) δ 9.92 (s, 1H), 7.23-7.35 (m, 5H), 4.60 (d, J = 14.5 Hz, 1H), 4.50 (d,
J = 14.5 Hz, 1H), 3.93 (d, J = 7.7 Hz, 1H), 3.80 (s, 3H), 3.78 (s, 3H), 3.21-3.35 (m, 2H), 2.86 (dt,
J = 7.7, 2.1 Hz, 1H), 2.70 (dt, J = 13.3, 2.5 Hz, 1H), 2.02-2.16 (m, 1H), 1.26-1.89 (m, 11H); 13C
NMR (75 MHz, CDCl3) δ 202.9, 174.8, 169.5, 169.0, 137.8, 129.2, 128.3, 127.8, 53.7, 53.4, 53.1,
52.5, 51.2, 47.6, 47.5, 43.9, 34.8, 26.7, 24.7, 24.6, 20.8, 19.5; IR (neat) 1734, 1627 cm-1; HRMS-
ES+ (C24H32NO6) calcd 430.2230 (MH+), found 430.2235.
N
CO2Me
HO
Bn
O
O
H
150
Methyl 4-(2-Benzyl-1-oxo-2-azaspiro[5.5]undecan-7-yl)-2-oxotetrahydrofuran-3-
carboxylate (150). To a stirred solution of aldehyde 149 (1.18 g, 2.7 mmol) in MeOH (60 mL)
and CH2Cl2 (5 mL) at 0 °C was added NaBH4 (102 mg, 2.7 mmol) in one portion. The reaction
mixture was stirred at 0 °C for 5 min and then diluted with saturated NH4Cl (aq). The mixture was
extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine, dried
135
over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified by flash
column chromatography on silica gel (20% EtOAc/hexanes) to afford α-carbomethoxylactone 150
(879 mg, 81%) as a white crystalline solid: mp 110-112 ºC; 1H NMR (300 MHz, CDCl3) δ 7.22-
7.35 (m, 5H), 5.34 (d, J = 14.6 Hz, 1H), 4.50 (t, J = 8.6 Hz, 1H), 4.02 (t, J = 9.3 Hz, 1H), 3.87 (s,
3H), 3.77 (d, J = 10.1 Hz, 1H), 3.69 (d, J = 14.7 Hz, 1H), 3.15-3.20 (m, 2H), 3.02 (pentet, J = 8.4
Hz, 1H), 2.58-2.62 (m, 1H), 1.28-2.09 (m, 12H); 13C NMR (75 MHz, CDCl3) δ 174.9, 173.0,
168.9, 137.9, 129.0, 128.2, 127.8, 71.5, 53.6, 51.3, 50.8, 47.1, 45.9, 44.8, 41.1, 35.2, 26.2, 24.8,
22.5, 20.5, 18.8; IR (neat) 1764, 1727, 1617, 1149 cm-1; HRMS-ES+ (C23H30NO5) calcd 400.2124
(MH+), found 400.2118.
N
HO
Bn
OO
H
151
2-Benzyl-7-(5-oxotetrahydrofuran-3-yl)-2-azaspiro[5.5]undecan-1-one (151). To a
solution of α-carbomethoxylactone 150 (879 mg, 2.2 mmol) in DMSO (45 mL) and H2O (16 mL)
was added LiCl (4.59 g, 110.0 mmol) and the reaction mixture was heated in an oil bath at 155-
160 °C for 24 h (additional water was added periodically to maintain the solvent). The mixture
was cooled to rt, brine was added, and the mixture was extracted with EtOAc (3 x 100 mL). The
combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated
in vacuo to give a yellowish oil that was purified by flash column chromatography on silica gel
(gradient 20% to 30% EtOAc/hexanes) to furnish butyrolactone 151 (676 mg, 90%) as a white
crystalline solid: mp 136-139 ºC; 1H NMR (400 MHz, CDCl3) δ 7.24-7.36 (m, 5H), 5.02 (d, J =
136
14.4 Hz, 1H), 4.41 (t, J = 7.3 Hz, 1H), 4.12 (d, J = 14.5 Hz, 1H), 3.94 (t, J = 8.8 Hz, 1H), 3.17-
3.24 (m, 2H), 2.42-2.53 (m, 3H), 2.18 (dd, J = 16.0, 6.7 Hz, 1H), 1.97 (dt, J = 13.8, 3.2 Hz, 1H),
1.11-1.89 (m, 11H); 13C NMR (100 MHz, CDCl3) δ 177.7, 175.4, 137.4, 129.1, 128.6, 127.9, 73.2,
51.3, 47.7, 45.7, 44.5, 39.5, 35.5, 33.3, 30.1, 25.9, 23.6, 20.7, 19.5; IR (neat) 1765, 1609, 1188 cm-
1; HRMS-ES+ (C21H28NO3) calcd 342.2069 (MH+), found 342.2068.
N
HO
Bn
O
H
OH
152
2-Benzyl-7-(5-hydroxytetrahydrofuran-3-yl)-2-azaspiro[5.5]undecan-1-one (152). To
a stirred solution of butyrolactone 151 (97 mg, 0.28 mmol) in dry THF (10 mL) at -78 °C was
added dropwise DIBAL-H (1 M in THF, 2.8 mmol, 2.8 mL) over 20 min. The reaction was
quenched with MeOH at -78 °C, warmed to rt and an equal volume of CH2Cl2 and saturated
aqueous potassium sodium tartrate solution were added. The mixture was stirred for 1 h, and was
extracted with CH2Cl2 (3 x 50 mL). The combined organic layers were washed with brine, dried
over anhydrous MgSO4, and concentrated in vacuo. The crude product was purified by flash
column chromatography on silica gel (20% Et2O/CH2Cl2) to afford the lactol 152 (80 mg, 83%)
as a ~4:1 mixture of C9-diastereomers: 1H NMR (400 MHz, CDCl3) δ (mixture) 7.23-7.33 (m,
5H), 5.35-5.38 (m, 1H), 4.88-4.93 (m, 1H), 3.95-4.31 (m, 1H), 3.71-3.94 (m, 1H), 3.47-3.55 (m,
1H), 3.21-3.32 (m, 2H), 2.30-2.52 (m, 3H), 1.18-2.03 (m, 14H); 13C NMR (75 MHz, CDCl3) δ
(major) 176.0, 137.8, 128.9, 128.7, 127.7, 99.2, 73.2, 51.4, 47.8, 46.1, 44.8, 39.7, 37.9, 35.6, 27.4,
26.3, 23.5, 21.0, 19.6; (minor) 176.9, 137.4, 129.0, 128.7, 127.9, 99.5, 71.3, 51.4, 47.7, 44.2, 42.2,
137
39.7, 38.1, 35.6, 30.1, 27.3, 23.5, 20.9, 19.4; HRMS-ES+ (C21H30NO3) calcd 344.2226 (MH+),
found 344.2236.
N
HO
Bn
OH
H
153
2-Benzyl-7-(1-hydroxypent-4-en-2-yl)-2-azaspiro[5.5]undecan-1-one (153). To a
stirred suspension of MePPh3Br (recrystallized from THF/CH2Cl2, 1.22 g, 3.18 mmol) in dry THF
(15 mL) at 0 °C was added n-butyllithium (1.6 M in hexanes, 2.1 mL, 3.2 mmol) and the resulting
yellow orange solution was stirred for 30 min at 0 °C. A solution of lactol 152 (218 mg, 0.64
mmol) in dry THF (13 mL) was added dropwise over ca. 5 min and the mixture was slowly warmed
to rt over 12 h. The mixture was diluted with saturated NH4Cl (aq) then extracted with EtOAc (3 x
50 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, and
concentrated in vacuo. The crude product was purified by flash column chromatography on silica
gel (20% EtOAc/hexanes) to furnish terminal olefin 153 (169 mg, 77%) as a clear gum: 1H NMR
(400 MHz, CDCl3) δ 7.24-7.33 (m, 5H), 5.81-5.92 (m, 1H), 4.98-5.10 (m, 2H), 4.68 (d, J = 14.5
Hz, 1H), 4.47 (d, J = 14.5 Hz, 1H), 3.51-3.59 (m, 2H), 3.16-3.28 (m, 2H), 2.42 (dt, J = 9.7, 3.2 Hz,
1H), 2.24-2.28 (m, 1H), 2.10-2.13 (m, 1H), 1.87-1.96 (m, 1H), 1.19-1.86 (m, 13H); 13C NMR (75
MHz, CDCl3) δ 176.4, 138.5, 137.9, 128.8, 128.5, 127.7, 116.4, 64.0, 51.4, 47.8, 47.4, 44.2, 43.8,
37.4, 35.8, 26.9, 24.5, 24.2, 21.2, 19.6; HRMS-ES+ (C22H32NO2) calcd 342.2433 (MH+), found
342.2431.
138
N
HO
Bn
OMOM
H
154
2-Benzyl-7-(1-methoxymethoxy)pent-4-en-2-yl)-2-azaspiro[5.5]undecan-1-one (154).
To a stirred solution of terminal olefin alcohol 153 (181 mg, 0.53 mmol) in dry CH2Cl2 (20 mL)
at 0 °C was added DIEA (0.41 mL, 2.65 mmol) and MOMCl (0.14 mL, 1.59 mmol). The mixture
was stirred for 28 h at rt, then diluted with 1 M NaHCO3 (aq). The mixture was extracted with
CH2Cl2 (3 x 50 mL) and the combined organic layers were washed with brine, dried over
anhydrous MgSO4, and concentrated in vacuo. The crude product was purified by flash column
chromatography on silica gel (10% EtOAc/hexanes) to furnish MOM ether 154 (189 mg, 93%) as
a clear oil: 1H NMR (300 MHz, CDCl3) δ 7.24-7.31 (m, 5H), 5.81-5.95 (m, 1H), 5.01-5.11 (m,
2H), 4.67 (d, J = 14.5 Hz, 1H), 4.56 (s, 2H), 4.49 (d, J = 14.5 Hz, 1H), 3.57 (dd, J = 9.8, 4.0 Hz,
1H), 3.31-3.39 (m, 4H), 3.13-3.24 (m, 1H), 2.42 (dt, J = 12.8, 3.0 Hz, 1H), 2.21-2.28 (m, 1H),
1.84-1.96 (m, 1H), 1.16-1.83 (m, 14H); 13C NMR (75 MHz, CDCl3) δ 175.7, 138.2, 137.4, 128.9,
128.5, 127.5, 116.4, 96.9, 69.0, 55.6, 51.3, 47.9, 47.8, 44.3, 40.3, 38.1, 35.5, 26.8, 24.2, 23.3, 21.2,
19.7; HRMS-ES+ (C24H36NO3) calcd 386.2695 (MH+), found 386.2687.
N
HO
H
OMOM
H
155
7-(1-(Methoxymethoxy)pent-4-en-2-yl)-2-azaspiro[5.5]undecan-1-one (155). Liquid
ammonia (ca. 25 mL) was condensed at -78 °C and Na metal (113 mg, 4.91 mmol) was added until
139
the reaction had developed a deep purple coloration. A solution of MOM ether 154 (189.4 mg,
0.491 mmol) in dry Et2O (10 mL) was added dropwise and the mixture was stirred for 1 h. Solid
NH4Cl was added and the mixture was warmed to rt. Brine was added and the mixture was
extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried
over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified by flash
column chromatography on silica gel (gradient 50% to 75% Et2O/CH2Cl2) to provide N-H lactam
155 (127 mg, 88%) as a clear colorless gum: 1H NMR (300 MHz, CDCl3) δ 5.81-5.95 (m, 2H),
5.01-5.11 (m, 2H), 4.59-4.63 (m, 2H), 3.60 (dd, J = 9.8, 3.9 Hz, 1H), 3.27-3.41 (m, 6H), 2.23-2.34
(m, 3H), 1.11-2.01 (m, 13H); 13C NMR (75 MHz, CDCl3) δ 178.0, 137.3, 116.5, 97.1, 69.0, 55.7,
43.9, 42.8, 40.3, 38.1, 35.3, 30.1, 26.7, 24.0, 23.0, 21.1, 19.7; HRMS-ES+ (C17H30NO3) calcd
296.2226 (MH+), found 296.2238.
N
HO
Ts
OMOM
H
156
7-(1-Methoxymethoxy)pent-4-en-2-yl)-2-tosyl-2-azaspiro[5.5]undecan-1-one (156).
To a stirred solution of N-H lactam 155 (127 mg, 0.43 mmol) in dry THF (15 mL) at 0 °C was
added LiHMDS (1 M in THF, 1.3 mL, 1.3 mmol) and the mixture was stirred for 1 h at that
temperature. TsCl (278 mg, 1.3 mmol) was added and the reaction mixture was stirred for 20 h at
rt. 1 M NaHCO3 (aq) was added and the mixture was extracted with EtOAc (3 x 50 mL). The
combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated
in vacuo. The crude product was purified by flash column chromatography on silica gel (20%
140
EtOAc/hexanes) to furnish N-tosyllactam 156 (170 mg, 88%) as a white solid: 1H NMR (300 MHz,
CDCl3) δ 7.89 (d, J = 8.3 Hz, 2H), 7.27 (d, J = 4.2 Hz, 2H), 5.35-5.48 (m, 1H), 4.82-4.92 (m, 2H),
4.52-4.54 (m, 2H), 4.16-4.21 (m, 1H), 3.59-3.68 (m, 1H), 3.43 (dd, J = 9.9, 4.4 Hz, 1H), 3.24-3.35
(m, 4H), 2.43 (s, 3H), 2.12 (dt, J = 9.8, 3.2 Hz, 1H), 1.05-1.93 (m, 15H); 13C NMR (75 MHz,
CDCl3) δ 176.5, 144.9, 136.8, 136.7, 129.6, 129.1, 116.5, 97.0, 68.5, 55.7, 50.3, 47.5, 44.6, 40.3,
37.5, 35.7, 26.4, 23.8, 23.4, 22.0, 21.0, 20.5; HRMS-ES+ (C24H39N2O5S) calcd 467.2580
(MNH4+), found 267.2585.
N
H
Ts
157
OMOM
7-((Methoxymethoxy)methyl)-4-tosyl-2,3,4,6,7,7a,8,9,10,11-decahydro-1H-
benzo[e]quinoline (157). TiCl4 (0.37 mL, 3.3 mmol) was dissolved in dry CH2Cl2 (6 mL) at 0 °C
followed by the addition of dry THF (1.7 mL, 19.3 mmol) and TMEDA (2.8 mL, 19.3 mmol). The
reaction mixture was stirred for 20 min at rt, followed by the addition of activated Zn dust (washed
with 1 N HCl (aq), acetone, then dried in vacuo at 100 ºC for 24 h) (468 mg, 7.2 mmol) and PbCl2
(104 mg, 0.38 mmol). The mixture was stirred for 5 min at rt and a solution of N-tosyllactam 156
(45 mg, 0.1 mmol) and Br2CHCH3 (0.41 mL, 4.5 mmol) in dry CH2Cl2 (3 mL) was added dropwise.
The reaction mixture was heated at 55 °C for 30 min, and cooled to 0 °C, treated with saturated
K2CO3 (aq) (0.8 mL) and stirred for 30 min. The resulting yellowish mixture was filtered through a
sintered glass frit that was washed with CH2Cl2. The combined filtrate was concentrated in vacuo
and the residue was chromatographed on silica gel (15% EtOAc/hexanes) to afford
141
enesulfonamide 157 (23 mg, 55%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.74 (d, J = 8.3
Hz, 2H), 7.29 (d, J = 8.3 Hz, 2H), 5.56 (dd, J = 5.9, 2.7 Hz, 1H), 4.60 (s, 2H), 4.00 (dd, J = 11.6,
4.1 Hz, 1H), 3.35-3.58 (m, 6H), 2.96 (td, J = 4.2, 3.5 Hz, 1H), 2.11-2.20 (m, 1H), 1.20-2.10 (m,
17H); 13C NMR (213 MHz, CDCl3) δ 144.6, 142.8, 138.8, 129.5, 127.2, 120.1, 96.7, 69.9, 65.9,
55.3, 50.2, 46.7, 39.4, 32.5, 32.2, 29.8, 29.7, 28.0, 26.3, 22.3, 21.5, 20.6, 20.6; HRMS-ES+
(C23H34NO4S) calcd 420.2209 (MH+), found 420.2217.
N
HO
SES
OMOM
H
160
7-(1-Methoxymethoxy)pent-4-en-2-yl)-2-((2-trimethylsilyl)ethyl)sulfonyl-2-
azaspiro[5.5]undecan-1-one (160). To a stirred solution of N-H lactam 155 (45 mg, 0.15 mmol)
in dry THF (5 mL) at 0 °C was added LiHMDS (1 M in THF, 0.45 mL, 0.45 mmol) and the mixture
was stirred for 1 h at that temperature. SES-Cl (0.087 mL, 0.45 mmol) was added and the reaction
mixture was stirred for 24 h at rt. 1 M NaHCO3 (aq) was added and the mixture was extracted with
EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous
MgSO4 and concentrated in vacuo. The crude product was purified by flash column
chromatography on silica gel (20% EtOAc/hexanes) to furnish N-sulfonyllactam 160 as a clear
colorless gum (55 mg, 78%): 1H NMR (300 MHz, CDCl3) δ 5.73-5.87 (m, 1H), 5.01-5.07 (m, 2H),
4.57 (s, 2H), 3.94-3.97 (m, 1H), 3.46-3.57 (m, 3H), 3.35-3.40 (m, 4H), 2.13-2.33 (m, 3H), 0.88-
1.97 (m, 19H), 0.04 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 178.1, 136.8, 131.7, 127.9, 117.0, 97.1,
142
68.6, 55.7, 51.4, 50.6, 47.5, 44.2, 40.7, 37.9, 36.2, 26.4, 26.4, 24.1, 23.2, 21.1, 20.5, -1.6; HRMS-
ES+ (C22H45N2O5SSi) calcd 477.2818 (MNH4+), found 477.2849.
N
H
SES
161
OMOM
7-((Methoxymethoxy)methyl)-4-(2-trimethylsilyl)ethyl)sulfonyl)-
2,3,4,6,7,7a,8,9,10,11-decahydro-1H-benzo[e]quinoline (161). TiCl4 (0.37 mL, 3.3 mmol) was
dissolved in dry CH2Cl2 (4 mL) at 0 °C followed by the addition of dry THF (1.7 mL, 19.3 mmol)
and TMEDA (2.7 mL, 19.3 mmol). The reaction mixture was stirred for 20 min at rt, followed by
the addition of activated Zn dust (washed with 1 N HCl (aq), acetone, then dried in vacuo at 100 ºC
for 24 h) (468 mg, 7.2 mmol) and PbCl2 (104 mg, 0.38 mmol). The mixture was stirred for 5 min
at rt, and a solution of N-sulfonyllactam 160 (43 mg, 0.1 mmol) and Br2CHCH3 (0.41 mL, 4.5
mmol) in dry CH2Cl2 (2 mL) was added dropwise. The reaction mixture was heated at 55 °C for
30 min, cooled to 0 °C, then treated with saturated K2CO3 (aq) (0.5 mL) and stirred for 30 min. The
resulting yellowish mixture was filtered through a sintered glass frit that was washed with CH2Cl2.
The combined filtrate was concentrated in vacuo and the residue was chromatographed on silica
gel (15% EtOAc/hexanes) to afford enesulfonamide 161 (33 mg, 83%) as a clear gum: 1H NMR
(300 MHz, CDCl3) δ 5.72 (dd, J = 6.3, 2.0 Hz, 1H), 4.61 (s, 2H), 3.96 (dd, J = 11.9, 4.5 Hz, 1H),
3.55 (dd, J = 9.4, 4.1 Hz, 1H), 3.36-3.40 (m, 4H), 2.95-3.07 (m, 3H), 0.79-2.29 (m, 18H), 0.06 (s,
9H); 13C NMR (75 MHz, CDCl3) δ 145.2, 121.6, 97.1, 70.2, 55.7, 51.0, 50.2, 47.2, 33.0, 32.8,
143
30.3, 30.1, 28.5, 26.7, 22.7, 21.1, 20.9, 10.9, -1.56; HRMS-ES+ (C21H40NO4SSi) calcd 430.2447
(MH+), found 430.2453.
N
CNH
O
BnH OH
176
2-(2-Benzyl-1-oxo-2-azaspiro[5.5]undec-7-yl)-4-hydroxyhex-5-enenitrile (176). To a
stirred solution of aldehyde 145 (50 mg, 0.14 mmol) in dry THF (5 mL) at rt was added
vinylmagnesium bromide (1 M in THF, 0.56 mL, 0.56 mmol) and the reaction mixture was stirred
for 15 min then quenched with saturated NH4Cl (aq). The mixture was extracted with EtOAc (3 x
25 mL) and the combined organic layers were washed with brine, dried over anhydrous MgSO4
and concentrated in vacuo. The crude product was purified by flash column chromatography on
silica gel (25% EtOAc/hexanes) to afford allylic alcohol 176 as a separable ~4:1 mixture of
diastereomers (23 mg total, 45%): 1H NMR (300 MHz, CDCl3) δ (major) 7.23-7.35 (m, 5H), 5.81-
5.94 (m, 1H), 5.33 (dt, J = 17.2, 1.3 Hz, 1H), 5.14 (dt, J = 11.7, 1.4 Hz, 1H), 4.63 (d, J =14.4 Hz,
1H), 4.49 (d, J = 14.5 Hz, 1H), 4.17 (br s, 1H), 3.21-3.36 (m, 2H), 2.52-2.68 (m, 2H), 1.95-2.13
(m, 1H), 1.27-1.94 (m, 14H); (minor) δ 7.23-7.35 (m, 5H), 5.81-5.94 (m, 1H), 5.35 (dt, J = 17.2,
1.4 Hz, 1H), 5.15 (dt, J = 13.7, 1.4 Hz, 1H), 4.88 (d, J = 14.4 Hz, 1H), 4.28 (d, J = 14.5 Hz, 1H),
4.05 (br. s, 1H), 3.21-3.36 (m, 2H), 2.52-2.68 (m, 2H), 1.95-2.13 (m, 1H), 1.27-1.94 (m, 14H); 13C
NMR (75 MHz, CDCl3) (major) δ 175.6, 140.5, 137.5, 129.1, 128.4, 127.9, 122.2, 115.4, 71.5,
51.5, 47.7, 47.6, 43.7, 40.2, 34.7, 31.9, 26.0, 23.9, 23.2, 20.7, 19.0; (minor) δ 176.5, 139.7, 137.0,
129.2, 128.3, 128.0, 122.6, 115.5, 68.3, 51.4, 47.6, 47.5, 40.4, 38.9, 30.1, 29.9, 26.1, 23.4, 23.0,
20.7, 18.7.
144
N
CNH
O
BnH OAc
177
Acetic Acid 3-(2-Benzyl-1-oxo-2-azaspiro[5.5]undec-7-yl)-3-cyano-1-vinylpropyl
Ester (177). To a stirred solution of allylic alcohol diastereomeric mixture 176 (17 mg, 0.046
mmol) in dry CH2Cl2 (1.5 mL) at rt was added acetic anhydride (0.013 mL, 0.14 mmol), Et3N
(0.0195 mL, 0.14 mmol), and DMAP (ca. 0.5 mg, cat.). The reaction mixture was stirred at rt for
2 h then diluted with brine. The mixture was extracted with CH2Cl2 (3 x 10 mL) and the combined
organic fractions were dried over anhydrous MgSO4 and concentrated in vacuo. The crude residue
was purified by flash column chromatography on silica gel (15% EtOAc/hexanes) to afford allyl
acetates 177 (13.8 mg, 73%) as an inseparable ~4:1 diastereomeric mixture: 1H NMR (300 MHz,
CDCl3) δ 7.22-7.36 (m, 5H), 5.74-5.92 (m, 1H), 5.23-5.43 (m, 3H), 4.41-4.78 (m, 2H), 4.00-4.02
(m, 1H), 3.18-3.33 (m, 2H), 2.25-2.48 (m, 2H), 1.28-2.08 (m, 16H).
N
CNH
O
BnH OMs
178
Methanesulfonic Acid 3-(2-Benzyl-1-oxo-2-azaspiro[5.5]undec-7-yl)-3-cyano-1-
vinylpropyl Ester (178). To a stirred solution allylic alcohol diastereomeric mixture 176 (69 mg,
0.15 mmol) in dry CH2Cl2 (2.5 mL) at rt was added methanesulfonyl chloride (0.024 mL, 0.17
mmol) and Et3N (0.038 mL, 0.29 mmol). The reaction mixture was stirred for 3 h then brine was
145
added. The mixture was extracted with CH2Cl2 (3 x 10 mL) and the combined organic layers were
dried over anhydrous MgSO4 and concentrated in vacuo. The crude residue was purified by flash
column chromatography on silica gel (25% EtOAc/hexanes) to furnish allylic mesylate 178 (30
mg, 47%) as an inseparable ~4:1 diastereomeric mixture: 1H NMR (300 MHz, CDCl3) δ 7.19-
7.35 (m, 5H), 5.78-5.92 (m, 1H), 5.17-5.60 (m, 3H), 4.30-4.89 (m, 2H), 2.08-3.20 (m, 6H), 2.15-
2.54 (m, 3H), 1.23-2.04 (m, 12H).
N
HO
Bn
OH
H
O
NOMeMe
180
3-(2-Benzyl-1-oxo-2-azaspiro[5.5]undecan-7-yl)-4-hydroxy-N-methoxy-N-
methylbutanamide (180). To a stirred suspension of N,O-dimethylhydroxylamine hydrochloride
(2.57 g, 29.7 mmol) in dry CH2Cl2 (25 mL) at 0 °C was added dropwise dimethylaluminum
chloride (0.9 M in heptane, 33.0 mL, 29.7 mmol) and the resulting mixture was stirred for 2 h at
rt. A solution of butyrolactone 151 (676 mg, 2.0 mmol) in dry CH2Cl2 (10 mL) was added dropwise
and the reaction mixture was stirred for 24 h at rt. The mixture was diluted with an equal volume
of saturated aqueous potassium sodium tartrate solution and the resulting biphasic mixture was
stirred for 1 h at rt. The aqueous layer was extracted with CH2Cl2 (3 x 100 mL) and the combined
organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo.
The crude product was purified via flash column chromatography on silica gel (gradient 50% to
100% Et2O/CH2Cl2) to afford amide alcohol 180 (681 mg, 86%) as an off-white fluffy solid: 1H
NMR (300 MHz, CDCl3) δ 7.15-7.39 (m, 5H), 4.78 (d, J = 14.6 Hz, 1H), 4.38 (d, J = 14.6 Hz,
146
1H), 4.10 (br s, 1H), 3.70-3.74 (m, 4H), 3.47-3.54 (m, 1H), 3.15-3.29 (m, 5H), 1.28-2.81 (m, 16H);
13C NMR (75 MHz, CDCl3) δ 176.0, 175.4, 138.0, 129.1, 128.2, 127.6, 65.4, 61.8, 51.2, 47.9, 47.7,
46.2, 40.3, 35.4, 32.6, 26.9, 23.6, 23.3, 21.2, 20.7, 19.5; HRMS-ES+ (C23H35N2O4) calcd 403.2597
(MH+), found 403.2600.
N
HO
Bn
OMOM
H
O
NOMeMe
181
3-(2-Benzyl-1-oxo-2-azaspiro[5.5]undecan-7-yl)-N-methoxy-4-(methoxymethoxy)-N-
methylbutanamide (181). To a stirred solution of amide alcohol 180 (681 mg, 1.7 mmol) in dry
CH2Cl2 (20 mL) at 0 °C was added MOMCl (0.75 mL, 8.5 mmol) and DIEA (2.62 mL, 16.9 mmol).
The reaction mixture was stirred for 24 h at rt, then diluted with saturated NaHCO3 (aq), and
extracted with EtOAc (3 x 100 mL). The combined extract washed with brine, dried over
anhydrous MgSO4 and concentrated in vacuo. The resulting crude oil was purified via flash column
chromatography on silica gel (gradient 20% to 100% Et2O/CH2Cl2) to afford MOM ether 181 (596
mg, 80%) as a light yellow gum: 1H NMR (300 MHz, CDCl3) δ 7.19-7.29 (m, 5H), 4.85 (d, J =
14.6 Hz, 1H), 4.51 (s, 2H), 4.20 (d, J = 14.6 Hz, 1H), 3.64 (s, 3H), 3.56 (dd, J = 15.9, 5.6 Hz, 1H),
3.44-3.50 (m, 1H), 3.29 (s, 3H), 3.07-3.20 (m, 5H), 2.59-2.78 (m, 1H), 2.31-2.42 (m, 2H), 1.10-
2.06 (m, 13H); 13C NMR (75 MHz, CDCl3) δ 175.9, 138.1, 128.9, 128.3, 127.5, 97.0, 69.1, 61.6,
55.7, 50.9, 47.4, 44.6, 37.3, 35.9, 35.5, 32.7, 30.7, 26.8, 23.7, 23.6, 21.1, 19.5; HRMS-ES+
(C25H39N2O5) calcd 447.2859 (MH+), found 447.2870.
147
N
H
CHO
O
Bn
OMOM
H
182
3-(2-Benzyl-1-oxo-2-azaspiro[5.5]undecan-7-yl)-4-(methoxymethoxy)butanal (182).
To a stirred solution of MOM ether 181 (596 mg, 1.3 mmol) in dry THF (50 mL) at -40 °C was
added lithium aluminum hydride (169 mg, 5.4 mmol) in one portion and the resulting suspension
was stirred for 1 h at that temperature. Methanol was added carefully followed by 1 N NaOH (aq),
the mixture was warmed to rt and further diluted with brine. The reaction mixture was extracted
with Et2O (3 x 100 mL). The combined organic extracts were washed with brine, dried over
anhydrous MgSO4 and concentrated in vacuo to afford aldehyde 182 as a clear colorless gum that
was used in the next step without further purification: 1H NMR (300 MHz, CDCl3) δ 9.57 (dd, J =
3.4, 1.8 Hz, 1H), 7.22-7.33 (m, 5H), 4.63 (d, J = 14.4 Hz, 1H), 4.43-4.54 (m, 3H), 3.64 (dd, J =
9.7, 3.8 Hz, 1H), 3.21-3.33 (m, 6H), 2.42-2.49 (m, 2H), 2.32-2.37 (m, 1H), 1.08-2.01 (m, 13H);
13C NMR (75 MHz, CDCl3) δ 203.2, 175.6, 137.9, 128.9, 128.5, 127.7, 96.8, 69.7, 55.8, 51.4, 49.1,
47.8, 45.0, 36.7, 35.3, 30.7, 26.7, 23.9, 23.1, 21.0, 19.4; HRMS-ES+ (C23H34NO4) calcd 388.2488
(MH+), found 388.2490.
148
N
HO
Bn
OMOM
H OH
183
2-Benzyl-7-(3-hydroxy-1-methoxymethoxymethylpent-4-enyl)-2-
azaspiro[5.5]undecan-1-one (183). To a stirred solution of aldehyde 182 (85 mg, 0.22 mmol) in
dry THF (5 mL) at rt was added vinylmagnesium bromide (1 M in THF, 1,1 mL, 1.1 mmol) and
the reaction mixture was stirred for 5 min then quenched with saturated NH4Cl (aq). The mixture
was extracted with EtOAc (3 x 25 mL) and the combined organic layers were washed with brine,
dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified by flash
column chromatography on silica gel (20% EtOAc/hexanes) to afford allylic alcohol 183 as a
separable ~10:1 mixture of diastereomers (57 mg total, 58%): 1H NMR (300 MHz, CDCl3) (major)
δ 7.23-7.52 (m, 5H), 5.90 (ddd, J = 17.1, 9.4, 4.6 Hz, 1H), 5.24-5.34 (m, 2H), 5.04 (dt, J = 10.5,
1.7 Hz, 1H), 4.77 (d, J = 14.5 Hz, 1H), 4.55-4.59 (m, 2H), 4.42 (d, J = 14.5 Hz, 1H), 4.19 (br s,
1H), 3.67 (dd, J = 9.5, 2.3 Hz, 1H), 3.31 (s, 3H), 3.16-3.28 (m, 3H), 2.62 (dd, J = 13.1, 2.9 Hz,
1H), 1.95-2.03 (m, 1H), 1.06-1.87 (m, 14H); 13C NMR (75 MHz, CDCl3) (major) δ 177.1, 142.1,
137.7, 129.0, 128.4, 127.7, 113.3, 96.9, 73.4, 70.8, 55.7, 51.4, 48.4, 47.8, 44.4, 41.5, 40.3, 35.6,
26.8, 24.3, 21.9, 21.1, 19.2.
149
N
HO
Bn
OMOM
H OH
184
Acetic Acid 3-(2-Benzyl-1-oxo-2-azaspiro[5.5]undec-7-yl)-4-methoxymethoxy-1-
vinylbutyl Ester (184). To a stirred solution of the major diastereomer of allylic alcohol 183 (10.0
mg, 0.024 mmol) in dry CH2Cl2 (0.5 mL) at rt was added acetic anhydride (0.004 mL, 0.036 mmol),
Et3N (0.015 mL, 0.12 mmol), and DMAP (ca. 0.5 mg, catalytic amount). The reaction mixture was
stirred at rt for 12 h, then diluted with brine. The mixture was extracted with CH2Cl2 (3 x 5 mL)
and the combined organic layers were dried over anhydrous MgSO4 and concentrated in vacuo.
The crude residue was purified by flash column chromatography on silica gel (15%
EtOAc/hexanes) to afford allyl acetate 184 (10.2 mg, 91%) as a clear gum: 1H NMR (300 MHz,
CDCl3) δ 7.22-7.32 (m, 5H), 5.78 (ddd, J = 16.8, 12.9, 6.7 Hz, 1H), 5.45 (q, J = 6.5 Hz, 1H), 5.30
(d, J = 17.2 Hz, 1H), 5.13 (d, J = 10.4 Hz, 1H), 4.95 (d, J = 14.6 Hz, 1H), 4.58 (s, 2H), 4.20 (d, J
= 14.5 Hz, 1H), 3.63 (dd, J = 10.0, 3.5 Hz, 1H), 3.33 (s, 3H), 3.03-3.30 (m, 2H), 2.43 (dt, J = 10.1,
3.0 Hz, 1H), 2.05 (s, 1H), 1.09-2.04 (m, 18H).
N
HO
BnH
SiMe3
OMOM
187
2-Benzyl-7-(E/Z)-1-(methoxymethoxy)-6-(trimethylsilyl)hex-4-en-2-yl)-2-
azaspiro[5.5]undecan-1-one (187). To a stirred solution of 2-
trimethylsilylethyltriphenylphosphonium iodide (2.66 g, 5.4 mmol) in dry THF (35 mL) at rt was
150
added dropwise PhLi (1.8 M in dibutyl ether, 3.05 mL, 5.5 mmol). The resulting deep crimson
solution was stirred at rt for 5 min, then a solution of aldehyde 182 (519 mg, 1.3 mmol) in dry
THF (5 mL) was added dropwise. The reaction mixture was stirred for 12 h at rt and diluted with
saturated NH4Cl (aq). The mixture was extracted with Et2O (3 x 100 mL). The combined extract
was washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The crude
product was purified via flash column chromatography on silica gel (gradient 8% to 10%
EtOAC/hexanes) to afford allylsilane 187 (470 mg, 74%) as an inseparable ~2.2:1 mixture of E/Z-
olefin isomers: 1H NMR (300 MHz, CDCl3) δ 7.21-7.35 (m, 5H), 5.25-5.54 (m, 2H), 4.79 (d, J =
14.5 Hz, 1H), 4.68 (d, J = 14.4 Hz, 1H), 4.56 (s, 2H), 4.48 (d, J = 14.4 Hz, 1H), 4.38 (d, J = 14.5
Hz, 1H), 3.58 (dd, J = 9.8, 4.1 Hz, 1H), 3.48-3.52 (m, 1H), 3.32-3.38 (m, 4H), 3.10-3.27 (m, 2H),
2.41 (dt, J = 12.8, 2.4 Hz, 1H), 2.05-2.28 (m, 2H), 1.11-1.97 (m, 16H), 0.01 (s, 9H), 0.001 (s, 9H);
13C NMR (75 MHz, CDCl3) δ 175.9, 175.8, 138.3, 138.2, 129.7, 128.9, 128.9, 128.6, 128.5, 128.3,
127.5, 126.9, 126.7, 126.0, 119.8, 115.9, 55.6, 55.6, 51.3, 51.2, 48.0, 47.9, 47.8, 47.7, 44.7, 44.6,
40.8, 40.6, 36.8, 35.6, 35.4, 30.8, 29.8, 26.9, 26.8, 24.3, 24.1, 23.6, 23.3, 23.3, 21.3, 21.2, 19.8,
19.7, 18.9, -1.3, -1.4; HRMS-ES+ (C28H46NO3Si) calcd 472.3247 (MH+), found 472.3272.
189
N
OMOMH
Ts
SiMe3
O
7-(E/Z)-1-(Methoxymethoxy)-6-(trimethylsilyl)hex-4-en-2-yl)-2-tosyl-2-
azaspiro[5.5]undecan-1-one (189). Anhydrous ammonia (15 mL) was condensed into a flask at
-78 °C and Na metal (158 mg, 6.9 mmol) was added portionwise until the mixture had developed
151
a dark blue color. A solution of N-Bn lactam/allylsilane E/Z mixture 187 (324 mg, 0.69 mmol) in
anhydrous Et2O (15 mL) was added dropwise and the reaction mixture was stirred at -78 °C. When
the reaction was determined to be complete via TLC (about 2 h), solid NH4Cl was added in one
portion and the mixture was warmed to rt. Additional Et2O and brine were added, and the layers
were separated. The aqueous layer was extracted with Et2O (3 x 50 mL), the combined organic
layers were dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was
purified via flash column chromatography on silica gel (10% Et2O/CH2Cl2) to afford unstable
N-H lactam 188 (inseparable mixture of E/Z-olefin geometric isomers) (207 mg, 79%) as a clear
colorless gum: 1H NMR (300 MHz, CDCl3) δ 5.84 (br s, 1H), 5.34-5.50 (m, 2H), 4.60 (s, 2H), 3.59
(dd, J = 9.7, 3.9 Hz, 1H), 3.28-3.41 (m, 5H), 2.14-2.32 (m, 3H), 0.87-1.97 (m, 16H), 0.00 (s, 9H),
-0.002 (s, 9H).
To a stirred solution of N-H lactam 188 (207 mg, 0.54 mmol) in dry THF (30 mL) at 0 °C
was added dropwise LiHMDS (1 M in THF, 1.63 mL, 1.6 mmol) and the mixture was stirred for
30 min at that temperature. TsCl (509 mg, 2.7 mmol) and DMAP (20 mg, 0.16 mmol) were added
and the reaction mixture was stirred for 11 h at rt. The mixture was then diluted with saturated
NaHCO3 (aq) and extracted with Et2O (3 x 50 mL). The combined organic extract was washed with
brine, dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified
via flash column chromatography on silica gel (gradient 10% to 20% EtOAc/hexanes) to afford N-
tosyllactam 189 (inseparable mixture of E/Z-olefin geometric isomers) (251 mg, 87%) as a clear
colorless gum: 1H NMR (300 MHz, CDCl3) δ 7.91 (d, J = 10.4 Hz, 2H), 7.30 (d, J = 12.7 Hz, 2H),
5.15-5.40 (m, 1H), 4.80-4.98 (m, 1H), 4.52-4.61 (m, 2H), 4.13-4.19 (m, 1H), 3.62-3.72 (m, 1H),
3.45 (dd, J = 9.9, 4.7 Hz, 1H), 3.33-3.38 (m, 3H), 3.24 (dd, J = 8.4, 7.1 Hz, 1H), 2.37 (s, 3H),
1.93-2.11 (m, 1H), 0.75-1.94 (m, 16H), -0.02 (s, 9H), -0.03 (s, 9H); 13C NMR (75 MHz, CDCl3) δ
152
176.6, 176.5, 144.7, 144.6, 136.9, 136.7, 131.9, 130.8, 129.5, 129.0, 129.0, 128.6, 127.0, 126.2,
125.3, 96.9, 96.9, 68.8, 68.3, 55.7, 55.7, 50.6, 50.2, 47.5, 47.5, 45.1, 44.6, 40.7, 40.6, 36.2, 35.6,
35.6, 30.7, 30.5, 30.1, 29.6, 26.5, 26.4, 24.0, 23.7, 23.2, 23.1, 22.1, 22.0, 21.1, 21.1, 20.6, 20.5,
18.7, -1.4, -1.5; HRMS-ES+ (C28H46NO5SiS) calcd 536.2866 (MH+), found 536.2877.
191
N
OMOMH
Ts
H
H
9-((Methoxymethoxy)methyl)-1-tosyl-11-vinyldodecahydro-1H-benzo[e]quinoline
(191). To a stirred solution of N-tosyllactam 189 (50 mg, 0.095 mmol) in dry CH2Cl2 (20 mL) at -
78 °C was added dropwise DIBAL-H (1 M in PhMe, 1.4 mL, 1.4 mmol). The reaction mixture
was stirred for 45 min, then anhydrous FeCl3 (150 mg, 0.95 mmol) was added in one portion and
the mixture was warmed to 5 ºC over 1.5 h (formation of a slightly turbid green solution indicated
that the reaction had gone to completion). An equal volume of saturated aqueous potassium sodium
tartrate solution was added and the resulting biphasic mixture was stirred for 2 h at rt. The aqueous
layer was extracted with CH2Cl2 (3 x 25 mL). The combined organic layers were washed with
brine, dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified
via flash column chromatography on silica gel (8:1:1 hexanes/CH2Cl2/Et2O) to afford tricycle 191
(33 mg, 78%) as a clear colorless gum: 1H NMR (850 MHz, CDCl3) δ 7.68 (d, J = 8.2 Hz, 2H),
7.23 (d, J = 8.1 Hz, 2H), 5.50-5.55 (m, 1H), 4.86 (dd, J = 17.0, 1.1 Hz, 1H), 4.63 (dd, J = 10.1, 1.6
Hz, 1H), 4.60 (d, J = 6.5 Hz, 1H), 4.58 (d, J = 6.5 Hz, 1H), 3.60 (dd, J = 13.8, 5.3 Hz, 1H), 3.48-
3.50 (m, 2H), 3.35-3.38 (m, 4H), 2.91 (td, J = 13.5, 3.4 Hz, 1H), 2.75-2.79 (m, 1H), 2.42-2.47 (m,
153
1H), 2.41 (s, 3H), 2.18 (br d, J = 13.9 Hz, 1H), 1.85 (dt, J = 13.2, 3.7 Hz, 1H), 1.74 (br d, J = 13.9
Hz, 2H), 1.66-1.70 (m, 2H), 1.54-1.61 (m, 5H), 1.49 (br d, J = 13.3 Hz, 1H), 1.41 (br d, J = 13.9
Hz, 1H), 1.22- 1.33 (m, 7H), 1.14 (ddd, J = 25.6, 12.9, 3.9 Hz, 1H), 0.97 (td, J = 13.3, 3.0 Hz, 1H);
13C NMR (75 MHz, CDCl3) δ 142.7, 141.6, 139.4, 129.4, 127.3, 115.2, 97.0, 70.6, 66.4, 55.6, 47.8,
40.5, 39.9, 37.5, 36.9, 35.7, 34.4, 26.7, 23.5, 21.9, 21.1, 20.3, 20.1; HRMS-ES+ (C25H38NO4S)
calcd 448.2522 (MH+), found 448.2536.
N
OMOMHH
Ts
OHH
192
9-((Methoxymethoxy)methyl)-1-tosyldodecahydro-1H-benzo[e]quinolin-11-
yl)methanol (192). Ozone gas was bubbled through a stirred solution of tricyclic alkene 191 (33
mg, 0.074 mmol) in dry CH2Cl2 (10 mL) at -78 °C for 5 min until a blue color was observed. PPh3
(58 mg, 0.22 mmol) was added to the reaction mixture which was subsequently warmed to rt over
10 h. The mixture was diluted with MeOH (4 mL), cooled to 0 °C, and NaBH4 (20 mg, 0.53 mmol)
was added in one portion. The reaction mixture was stirred for 5 min then diluted with an equal
volume of saturated NH4Cl (aq) solution causing two layers to form. The aqueous layer was
extracted with CH2Cl2 (3 x 10 mL) and the combined organic layers were washed with brine, dried
over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified via flash
column chromatography on silica gel (gradient 25% to 35% EtOAc/hexanes) to afford tricyclic
alcohol 192 (30 mg, 91%) as a clear colorless gum: 1H NMR (300 MHz, CDCl3) δ 7.73 (d, J = 8.3
Hz, 2H), 7.30 (d, J = 7.9 Hz, 2H), 4.60 (q, J = 6.6 Hz, 2H), 3.90 (dd, J =12.1, 2.8 Hz, 1H), 3.70
154
(br d, J = 14.4 Hz, 1H), 3.34-3.52 (m, 7H), 2.98-3.12 (m, 1H), 2.44 (s, 3H), 2.15 (br t, J = 10.0
Hz, 1H), 1.91 (dd, J = 9.8, 3.9 Hz, 1H), 0.52-1.69 (m, 16H); 13C NMR (75 MHz, CDCl3) δ 143.4,
138.7, 129.9, 127.3, 97.1, 70.8, 63.4, 55.7, 47.8, 40.9, 37.6, 35.9, 35.8, 35.1, 32.9, 30.1, 26.5, 23.5,
21.9, 21.0, 19.9, 19.9; HRMS-ES+ (C24H38NO5S) calcd 452.2471 (MH+), found 452.2445.
N
OHHH
Ts
OHH
194
[9-Hydroxymethyl-5-(toluene-4-sulfonyl)-5-azatricyclo[8.4.0.01,6]tetradec-7-yl]-
methanol (194). To a stirred solution of MOM-ether 192 (5 mg, 0.011 mmol) in THF (0.5 mL)
was added 6 N HCl (aq) (0.25 mL) and the mixture was heated at 50 ºC for 1.5 h and then cooled to
rt. Saturated NaHCO3 (aq) was added and the mixture was extracted with CH2Cl2 (3 x 10 mL). The
combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated
in vacuo. The crude product was purified via flash column chromatography on silica gel (40% to
75% Et2O/CH2Cl2) to afford diol 194 as a clear gum (4.5 mg, 100%): 1H NMR (400 MHz, CDCl3)
δ 7.72 (d, J = 6.7 Hz, 2H), 7.28 (d, J = 7.1 Hz, 2H), 3.91 (dd, J =12.2, 2.7 Hz, 1H), 3.67-3.73 (m,
2H), 3.43-3.49 (m, 2H), 2.98-3.09 (m, 2H), 2.44 (s, 3H), 2.14-2.19 (m, 1H), 1.88 (dd, J = 9.8, 4.2
Hz, 1H), 1.12-1.75 (m, 16H), 0.66 (t, J = 12.9 Hz, 1H).
155
196
N
OMOMH
SES
SiMe3
O
7-(1-Methoxymethoxymethyl-5-trimethylsilanylpent-3-enyl)-2-(2-trimethylsilanyl-
ethanesulfonyl)-2-azaspiro[5.5]undecan-1-one (196). To a stirred solution of N-H lactam 188
(38 mg, 0.10 mmol) in dry THF (2 mL) at 0 °C was added dropwise LiHMDS (1 M in THF, 0.30
mL, 0.30 mmol) and the mixture was stirred for 30 min at that temperature. SESCl (0.100 mL,
0.50 mmol) was added and the reaction mixture was stirred for 12 h at rt. The mixture was then
diluted with saturated NaHCO3 (aq) and extracted with Et2O (3 x 50 mL). The combined organic
extract was washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The crude
product was purified via flash column chromatography on silica gel (gradient 5% to 7%
EtOAc/hexanes) to afford N-SES lactam 196 (inseparable mixture of E/Z-olefin geometric
isomers) (40 mg, 73%) as a clear colorless gum: 1H NMR (300 MHz, CDCl3) δ 5.04-5.54 (m, 2H),
4.59 (s, 2H), 3.95-3.98 (m, 1H), 3.37-3.63 (m, 5H), 3.37 (s, 3H), 0.96-2.34 (m, 20H), 0.07 (s, 9H),
0.01 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 178.2, 178.0, 129.1, 127.6, 126.0, 125.2, 69.0, 68.4,
55.8, 51.4, 50.9, 50.6, 47.5, 44.6, 44.4, 41.3, 41.2, 36.9, 36.4, 36.1, 30.8, 30.7, 30.1, 26.6, 26.5,
24.3, 24.0, 23.6, 23.3, 23.1, 21.2, 20.6, 18.9, 10.5, -1.3, -1.4, -1.6.
197
N
OMOMHH
SES
156
9-Methoxymethoxymethyl-5-(2-trimethylsilanylethanesulfonyl)-7-vinyl-5-aza-
tricyclo[8.4.0.01,6]tetradecane (197). To a stirred solution of N-SES lactam 196 (10.0 mg, 0.018
mmol) in dry CH2Cl2 (4 mL) at -78 °C was added dropwise DIBAL-H (1 M in PhMe, 0.28 mL,
0.28 mmol). The reaction mixture was stirred for 45 min, then anhydrous FeCl3 (28 mg, 0.18
mmol) was added in one portion and the mixture was warmed to 5 ºC over 1.5 h (formation of a
slightly turbid green solution indicated that the reaction had gone to completion). An equal volume
of saturated aqueous potassium sodium tartrate solution was added and the resulting biphasic
mixture was stirred for 2 h at rt. The aqueous layer was extracted with CH2Cl2 (3 x 10 mL). The
combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated
in vacuo. The crude product was purified via flash column chromatography on silica gel (8%
EtOAc/hexanes) to afford tricycle 197 (2.2 mg, 27%) as a clear colorless gum: 1H NMR (300
MHz, CDCl3) δ 5.64-5.76 (m, 1H), 5.13 (dd, J = 17.1, 1.3 Hz, 1H), 4.99 (dd, J = 11.8, 1.8 Hz, 1H),
4.62 (dd, J = 8.0, 1.5 Hz, 2H), 3.41-3.50 (m, 3H), 3.35-3.40 (m, 6H), 2.81-3.14 (m, 4H), 2.35-2.40
(m, 1H), 0.89-1.95 (m, 15H), 0.045 (s, 9H); HRMS-ES+ (C23H44NO4SSi) calcd 458.2760 (MH+),
found 458.2810.
199
N
OMOMH
Ns
SiMe3
O
7-(1-Methoxymethoxymethyl-5-trimethylsilanylpent-3-enyl)-2-(4-nitro-
benzenesulfonyl)-2-azaspiro[5.5]undecan-1-one (199). To a stirred solution of N-H lactam 188
157
(57 mg, 0.15 mmol) in dry THF (4 mL) at 0 °C was added dropwise LiHMDS (1 M in THF, 0.45
mL, 0.45 mmol) and the mixture was stirred for 30 min at that temperature. Solid 4-
nitrobenzenesulfonyl chloride (166 mg, 0.75 mmol) was added and the reaction mixture was stirred
for 14 h at rt. The mixture was then diluted with saturated NaHCO3 (aq) and extracted with Et2O (3
x 20 mL). The combined organic extract was washed with brine, dried over anhydrous MgSO4 and
concentrated in vacuo. The crude product was purified via flash column chromatography on silica
gel (gradient 10% to 40% EtOAc/hexanes) to afford N-Ns lactam 199 (mixture of E/Z-olefin
geometric isomers) (60 mg, 72%) as a clear colorless gum: 1H NMR (300 MHz, CDCl3) δ 8.35 (d,
J = 9.2 Hz, 2H), 8.22 (d, J = 7.0 Hz, 2H), 5.19-5.39 (m, 1H), 4.77-4.86 (m, 1H), 4.54-4.56 (m,
2H), 4.18-4.26 (m, 1H), 3.60-3.75 (m, 1H), 3.23-3.49 (m, 5H), 1.09-1.99 (m, 21H), 0.0062 (s, 9H);
13C NMR (75 MHz, CDCl3) (major) δ 177.1, 150.8, 145.5, 130.4, 127.6, 124.8, 124.2, 97.1, 68.8,
55.8, 50.8, 47.8, 45.1, 44.4, 41.2, 35.8, 30.6, 26.4, 23.8, 23.0, 21.0, 20.5, 18.9, -1.48.
202
N
OMOMH
pbf
SiMe3
O
7-(1-Methoxymethoxymethyl-5-trimethylsilanyl-pent-3-enyl)-2-(2,2,4,6,7-
pentamethyl-2,3-dihydrobenzofuran-5-sulfonyl)-2-aza-spiro[5.5]undecan-1-one (202). To a
stirred solution of N-H lactam 188 (68 mg, 0.18 mmol) in dry THF (3 mL) at 0 °C was added
158
dropwise LiHMDS (1 M in THF, 0.34 mL, 0.34 mmol) and the mixture was stirred for 30 min at
that temperature. Solid 2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-sulfonyl chloride (97 mg,
0.34 mmol) and DMAP (6.3 mg, 0.05 mmol) were added and the reaction mixture was stirred for
14 h at rt. The mixture was then diluted with saturated NaHCO3 (aq) and extracted with Et2O (3 x
25 mL). The combined organic extract was washed with brine, dried over anhydrous MgSO4 and
concentrated in vacuo. The crude product was purified via flash column chromatography on silica
gel (gradient 10% to 15% EtOAc/hexanes) to afford N-pbf lactam 202 (mixture of E/Z-olefin
geometric isomers) (62 mg, 63%) as a clear colorless gum: 1H NMR (300 MHz, CDCl3) δ 5.22-
5.49 (m, 1H), 4.66-4.93 (m, 1H), 4.56-4.62 (m, 2H), 4.06-4.10 (m, 1H), 3.72-3.80 (m, 1H), 3.47-
3.61 (m, 1H), 3.38 (s, 3H), 3.20-3.27 (m, 1H), 3.01 (br s, 2H), 2.59 (d, J = 2.5 Hz, 3H), 2.50 (s,
3H), 2.11 (s, 3H), 0.83-2.10 (m, 24H), -0.02 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 177.0, 176.9,
160.61, 160.58, 140.3, 140.2, 136.9, 136.6, 128.9, 128.72, 128.65, 128.2, 127.0, 125.9, 125.4,
125.3, 118.2, 118.1, 97.12, 97.10, 87.30, 87.28, 69.4, 69.0, 55.72, 55.69, 50.6, 50.5, 46.0, 45.9,
44.8, 44.7, 43.5, 40.5, 40.2, 35.2, 35.0. 34.8, 30.5, 30.2, 29.11, 29.06, 29.0, 26.5, 26.4, 24.1, 23.9,
23.4, 23.1, 22.9, 21.1, 21.0, 20.20, 20.17, 20.09, 19.61, 19.57, 18.8, 17.9, 17.8, 13.2, 12.8, 12.7, -
1.3, -1.4.
204
N
OMOMH
Cbz
SiMe3
O
7-(1-Methoxymethoxymethyl-5-trimethylsilanylpent-3-enyl)-1-oxo-2-
azaspiro[5.5]undecane-2-carboxylic Acid Benzyl Ester (204). To a stirred solution of N-H
159
lactam 188 (57 mg, 0.15 mmol) in dry THF (4 mL) at -78 °C was added dropwise n-butyllithium
(1.6 M in hexanes, 0.11 mL, 0.18 mmol) and the mixture was stirred for 10 min at that temperature.
Benzyl chloroformate (0.10 mL, 0.75 mmol) was added and the reaction mixture was warmed to
rt and stirred for 1 h. The mixture was then diluted with saturated NH4Cl (aq) and extracted with
Et2O (3 x 20 mL). The combined organic extract was washed with brine, dried over anhydrous
MgSO4 and concentrated in vacuo. The crude product was purified via flash column
chromatography on silica gel (gradient 15% to 25% EtOAc/hexanes) to afford N-Cbz lactam 204
(mixture of E/Z-olefin geometric isomers) (35 mg, 58%) as a clear colorless gum: 1H NMR (300
MHz, CDCl3) δ 7.35-7.54 (m, 5H), 5.29-5.41 (m, 1H), 5.21 (s, 2H), 4.78-4.90 (m, 1H), 4.53-4.55
(m, 2H), 4.12-4.23 (m, 1H), 3.63-3.79 (m, 1H), 3.33-3.49 (m, 6H), 1.14-2.15 (m, 20H), 0.003 (s,
9H).
N
OMOMHH
Ts
OMOM
206
H
9,11-bis((Methoxymethoxy)methyl)-1-tosyldodecahydro-1H-benzo[e]quinoline (206).
To a stirred solution of alcohol 192 (24.3 mg, 0.053 mmol) in dry CH2Cl2 (2 mL) at 0 °C was
added MOMCl (20 μL, 0.22 mmol) and DIEA (70 μL, 0.44 mmol). The reaction mixture was
stirred overnight at rt then diluted with saturated NaHCO3 (aq) solution. The aqueous layer was
160
extracted with CH2Cl2 (3 x 10 mL) and the combined organic layers were washed with brine, dried
over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified via flash
column chromatography on silica gel (15% EtOAc/hexanes) to afford bis-MOM ether 206 (22 mg,
80%) as a clear colorless gum: 1H NMR (300 MHz, CDCl3) δ 7.73 (d, J = 8.3 Hz, 2H), 7.28 (d, J
= 6.9 Hz, 2H), 4.60 (q, J = 6.6 Hz, 2H), 4.47 (q, J = 6.4 Hz, 2H), 3.69 (dd, J = 13.5, 3.6 Hz, 1H),
3.38-3.53 (m, 3H), 3.37 (s, 3H), 3.30 (s, 3H), 3.15 (t, J = 9.4 Hz, 1H), 2.97 (td, J = 11.9, 3.5 Hz,
1H), 2.30-2.43 (m, 4H), 2.05-2.18 (m, 2H), 0.86-1.76 (m, 15H); 13C NMR (75 MHz, CDCl3) δ
142.9, 139.2, 129.7, 127.3, 97.0, 97.0, 70.7, 70.5, 63.9, 55.6, 55.5, 47.9, 40.6, 37.6, 35.6, 34.6,
34.3, 34.1, 30.7, 30.1, 26.7, 23.6, 21.8, 21.1, 20.3, 20.1; HRMS-ES+ (C26H45N2O6S) calcd
513.2998 (MNH4+), found 513.3034.
N
OMOMHH
H
OMOM
207
H
9,11-bis((Methoxymethoxy)methyl)dodecahydro-1H-benzo[e]quinoline (207).
Anhydrous ammonia (ca.7.5 mL) was condensed into a flask at -78 °C and Li metal (25 mg, 3.5
mmol) was added until a blue color persisted. A solution of bis-MOM ether 206 (68 mg, 0.136
mmol) in dry Et2O (8 mL) was added dropwise and the mixture was stirred for 1 min at -78 °C,
then quenched with NH4Cl (s) at that temperature. The reaction mixture was warmed to rt, diluted
with CH2Cl2, filtered through a sintered glass frit, and concentrated in vacuo. The crude product
161
was purified via flash column chromatography on silica gel (gradient 1:1 Et2O/CH2Cl2 to
1:1:0.1:0.01 Et2O/CH2Cl2/MeOH/TEA) to afford tricyclic amine 207 (37 mg, 81%) as a clear
colorless gum: 1H NMR (400 MHz, CDCl3) δ 4.64 (q, J = 6.4 Hz, 2H), 4.58 (q, J = 6.6 Hz, 2H),
3.68 (dd, J = 9.8, 4.4 Hz, 1H), 3.57 (dd, J = 9.7, 6.8 Hz, 1H), 3.48 (dd, J = 9.5, 3.5 Hz, 1H), 3.38
(s, 3H), 3.34 (s, 3H), 3.18 (br d, J = 12.2 Hz, 1H), 2.92-2.97 (m, 1H), 2.75 (br d, J = 13.2 Hz, 1H),
2.70 (br d, J = 11.6 Hz, 1H), 2.43-2.55 (m, 1H), 1.87-1.98 (m, 2H), 0.81-1.86 (m, 15H); 13C NMR
(75 MHz, CDCl3) δ 97.1, 97.0, 72.7, 69.8, 65.8, 56.4, 55.8, 46.7, 39.5, 35.1, 34.2, 32.3, 32.1, 30.1,
26.2, 23.1, 20.4, 18.2, 17.7; HRMS-ES+ (C19H36NO4) calcd 342.2644 (MH+), found 342.2649.
N
OHHH
HO
(±)-19
Racemic Myrioneurinol ((±)-19). To a stirred solution of tricyclic amine 207 (36.9 mg,
0.11 mmol) in THF (25 mL) was added 6 N HCl (aq) (14 mL). The reaction mixture was heated at
50 °C for 90 min and then cooled to rt. The mixture was and basified with Na2CO3 (aq) to a pH of
>10. The mixture was extracted with CH2Cl2 (3 x 10 mL). The combined organic layers were
washed with a small amount of brine, dried over anhydrous MgSO4, and concentrated in vacuo.
The crude product was purified via flash column chromatography on silica gel (gradient 66% to
100% Et2O/CH2Cl2) to afford racemic myrioneurinol ((±)-19, 22 mg, 75%) as a clear colorless
gum: 1H NMR (850 MHz, CDCl3) δ 4.47 (d, J = 10.2 Hz, 1H), 4.42 (d, J = 10.2 Hz, 1H), 3.91 (dd,
162
J = 11.1, 4.3 Hz, 1H), 3.64 (dd, J = 11.1, 4.3 Hz, 1H), 3.48 (dd, J = 10.2, 6.0 Hz, 1H), 3.28 (td, J
= 13.6, 4.3 Hz, 1H), 3.21 (t, J = 11.1 Hz, 1H), 2.67 (dd, J = 11.9, 5.1 Hz, 1H), 2.49 (br d, J = 12.8
Hz, 1H), 2.46 (qt, J = 12.8, 4.3 Hz), 2.28 (d, J = 11.1 Hz, 1H), 1.74-1.80 (m, 2H), 1.68 (br d, J =
13.6 Hz, 1H), 1.59 (dd, J = 12.8, 2.6 Hz, 1H), 1.56 (dt, J = 12.8, 3.4 Hz, 2H), 1.48-1.53 (m, 2H),
1.35-1.45 (m, 2H), 1.24-1.30 (m, 1H), 1.20 (qd, J = 12.8, 3.4 Hz, 1H), 1.14 (td, J = 11.1, 2.6 Hz,
1H), 0.87 (td, J = 14.5, 3.4 Hz, 1H), 0.80 (q, J = 11.9 Hz, 1H); 13C NMR (150 MHz, CDCl3, APT)
δ 86.8 (CH2), 73.6 (CH2), 69.6 (CH), 65.4 (CH2), 47.7 (CH), 45.0 (CH2), 37.1 (CH), 36.3 (C), 34.4
(CH2), 31.1 (CH2), 27.2 (CH), 26.7 (CH2), 23.1 (CH2), 20.5 (CH2), 20.5 (CH2), 19.8 (CH2); IR
(neat) 3399, 1028 cm-1; HRMS-ES+ (C16H28NO2) calcd 266.2120 (MH+), found 266.2132.
163
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VITA
Anthony J. Nocket
Anthony J. Nocket was born in 1987 and raised in Schuylkill Haven, Pennsylvania. After
graduation from Blue Mountain High School in 2005, he attended Franklin and Marshall College
where he earned his B.A. (magna cum laude) in chemistry in 2009. His undergraduate research
under the supervision of Professor Phyllis A. Leber focused upon the synthesis and thermal study
of model compounds to probe the thermal [1,3] sigmatropic rearrangement of bicyclic
vinylcyclobutane derivatives. These substrates were shown to undergo some degree of the
cyclopropylcarbinyl to homoallylic (CPC) radical clock rearrangement, thus providing ‘indirect’
evidence of singlet diradical intermediates in this pathway. In the fall of 2009, he joined the
laboratory of Steven M. Weinreb at Penn State where he completed the first total synthesis of the
tetracyclic antimalarial alkaloid myrioneurinol in racemic form. Upon completion of his
graduate studies, Anthony will seek employment in the pharmaceutical industry.
![Synthesis of highly functionalized benzo[h]quinoline and ...shodhganga.inflibnet.ac.in/bitstream/10603/39020/17/17...quinoline ) (16 ) and tetracyclic quinoline (3-(epimin omethano)](https://img.pdfslide.us/doc/110x75/606a70077d4f6141007ad728/synthesis-of-highly-functionalized-benzohquinoline-and-quinoline-16.jpg)
