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The Synthesis of the C24C32 Subunit of (+)-Ionomycin
Lisa Cameron
A thesis submitted in conformity with the requirements for the Degree of Master of Science, Graduate Department of Chemistry,
University of Toronto
8 Copyright by Lisa Cameron 1998
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Abstract
The Synthesis of the C24-C32 Subunit of (+) -1onomycin Master of Science, 1996, Lisa Cameron
Graduate Department of Chemistry, University of Toronto
Described herein is the Lautens/Colucci total synthesis of ( + )
ionomycin, with specific attention being paid to the synthesis of
the C24-C32 tetrahydrofuranyl subunit. To date, two previous total
syntheses of ( + ) ionomycin, to be discussed, have been published by
the groups of Evans and Hanessian. Also described is the general
chemistry of the formation of tetrahydrofuran rings.
This tetrahydrofuranyl subunit, ring B of ionomycin, is derived
from a geranyl acetate backbone. Sharpless asymmetric epoxidation
and a diastereoselective epoxidation-cyclization sequence are the
key manipulations applied to install the desired stereocentres.
Each of the other three acyclic fragments of ionomycin arise from
exploitation of the versatile chemistry of [ 3 .2.1] oxabicycles,
Chemistry developed in this laboratory which provides
enantiospecific nucleophilic ring opening effects further skeletal
elaboration,
Acknowledgments
I would like to gratefully acknowledge my advisor, Professor Mark
Lautens. His support and encouragement were invaluable throughout
my time spent in the Lautens group. I have learnt a great deal
because of Dr. Lautens, and for that I would like to express my
sincere gratitude.
It is also important for me to thank the members of the Lautens
group, each of whom were eager to lend help and share knowledge.
Their support and friendship is appreciated more than I can say.
Special thanks to Dr. Giliane Bouchard, Jianqing Chen, Greg Hughes,
Dr. Tornislav Rovis, dr. Nick Smith, and lastly, Dr. John Colucci,
who provided the basis for this work.
Finally I would like to thank my family and friends, who always
lead me back on track, wherever it may be.
Abstract Acknowledgments Table of Contents
iii iv
CHAPTER 1 INTRODUCTION TO THE CLASS OF POLYETKER ANTIBIOTICS AND (+ ) IONOMYCIN
1 Introduction 1.1 Introduction to Polyether Antibiotics 1.2 Introduction to the Polyether Antibiotic (+)
Ionomycin 1.3 References and Notes
CHAPTER 2 INTRODUCTION TO THE CHEMISTRY OF ( + ) IONOMYCIN 2 The Chemistry of Ionomycin 2.1 Introduction 2.2 Syntheses of the C1-C9/10 Fragment 2.2.1 Evans Synthesis of the C1-C10 Fragment 2.2.2 Hanessian Synthesis of the C1-C10 Fragment 2.2.3 Lautens/Colucci Synthesis of the C1-C9 Fragment 2.3 Syntheses of the C10/11-C16 Fragment 2.3.1 Evans Synthesis of the Cll-C16 Fragment 2 . 3 . 2 Hanessian Synthesis of the Cll-C16 Fragment 2.3.3 Lautens/Colucci Synthesis of the C10-C16 Fragment 2.4 Syntheses of the C17-C22/23 Fragment 2.4.1 Evans Synthesis of the C17-C22 Fragment 2.4.2 Hanessian Synthesis of the C17-C22 Fragment 2.4.3 Lautens/Colucci Synthesis of the C17-C23 Fragment 2 - 5 References and Notes
CHAPTER 3 THE CHEMISTRY OF THE TETMYDRO-L SUBUNIT 3 The Chemistry of the Tetrahydrofuranyl Subunit 3.1 Synthetic Developments Towards Tetrahydrofuran
Synthesis 3.1.1 Diastereoselective Epoxidation of a Bis
homoallylic Alcohol Followed by Acid Catalyzed Ring Closure
3-1.2 Oxidative Cyclization of 1,s-Dienes 3.1.3 Oxabicyclo [3.2,1] Octenones 3.1.4 Halocyclization 3.1.5 Polyepoxide Cyclization 3-1.6 Miscellaneous Routes to Tetrahydrofurans 3.2 Synthetic Developments Towards the Tetrahydrofuran
Moiety of (+ ) Ionomycin 3.2.1 Wuts 3 . 2 . 2 Spino and Weiler 3.2.3 Evans 3.2-4 Hanessian 3.3 References and Notes
CHAPTER 4 OUR SYNTHESIS OF THE C24-C32 FRAGMENT OF (+) IONOMYCIN
4 Our Synthesis of C24-C32 4.1 Synthetic Strategy and Discussion of Route 4.2 Experimental 4 . 3 References and Notes
CHAPTER 1
INTRODUCTION TO THE CLASS OF
POLmTHER ANTIBIOTICS
AND
(+) -1ONOMYCIN
Introduction
1.1 Introduction to Polyether Antibiotics
Monocarboxylic acid ionophores, also referred to as polyether
antibiotics are a large group of natural products which act to
chelate cations. These ionophores are comparable to crown ethers
in their cation binding ability, but differ significantly in
specificity. Crown ethers complex cations according to relative
dimension of cation and macrocyclic cavity, while polyether
antibiotics are able to chelate cations of varying sizesi. This
class of compounds, derived from various strains of streptomyces
organisms', has stirred much interest in scientific circles, The
interest stems from their unique ability to translocate inorganic
cations through hydrophobic lipid bilayers, which results in a wide
variety of biological functions. Some of these include
antimicrobial agents3, growth promoters in ruminants4, and the
initiation of cardiovascular responses in mammals5.
Although the first polyether antibiotic was isolated in 1950" it
was not until 1967 that a structural elucidation of a member of
this class was achieved7. The makeup of polyether antibiotics
typically consists of a carboxylate group along with several
additional oxygen ligandsa . Substituted tetrahydrofuran and
tetrahydropyran rings, as well as spiroketal functions' are
prevalent in the architecture of these molecules.
The 70 polyether antibiotics that have been isolated to date
present a formidable challenge to synthetic chemists. The
differing stereochemical arrangement of functional groups has
resulted in an unceasing flow of investigation and development of
elegant methodology. Scheme I depicts a small selection from the
class of polyether antibiotics.
Scheme I
Lasalocid A
Monensin
% 5
lRUllIlll
MeHN
Calcirnycin
1.2 In t roduc t ion to the Polyether A n t i b i o t i c (+) -1onomycin
( + I -Ionornycin, (Scheme 2 , was f i r s t i s o l a t e d from t h e fe rmenta t ion
broths of Streptomyces c o n g o b l a t ~ s ~ ~ i n 1978. Ionomycin i s d i s t i n c t
f rom the o t h e r members of t h e p o l y e t h e r antibiotic f a m i l y i n
s e v e r a l impor tan t ways. F i r s t l y , i t i s doubly charged, and
t h e r e f o r e h i g h l y s e l e c t i v e f o r divalent i o n s . T h i s p r o p e r t y i s i n
d i r e c t c o n t r a s t t o the monobasic c h e l a t i n g e f f e c t s o f other
p o l ye ther a n t i b i o t i c s and allows ionomycin t o c h e l a t e d i v a l e n t ions
a s a d i b a s i c a c id i n an oc tahedra l coo rd ina t i on system, as a 1:1
charge-neutral complex." Calcimycin is the only other ionophore
to similarly distinguish between monovalent and divalant cations,
differentiating between calcium and magnesium as its 2:1
ligand/metal complex.12 A second anomaly is present in the P- dicarbonyl functionality at C,-C,,, a rarity in natural products.
This moiety accounts for two of the six charged ligation points,13
and the intense W absorption band at 280 nm that is exhibited by
ionomycin.14 Lastly, while the backbone of ionomycin consists of
one long acyclic chain, and two furanoid rings, other ionophores of
simillar size are of a more polycyclic nature?
Scheme 2
The structure of ( + ) -ionornycin was elucidatsd in 1979 by Gougoutas
et al. l"trructura1 determination was achieved by X-ray
cyrstallography as well 'H and 13C NMR spectroscopic studies. The
dianion salt of ionomycin exhibits an octahedral coordination to
the central cation, typically, ca2+.
1 .Shultz, W - J - ; Etter, M. C.; Pocius, A, V.; Pocius, S. S. J. Am. Chem. SOC. 1980, 102, 7981
2. Westley, J, W. Polyether Antibiotics; Ed. ; Marcel Dekker: New York, 1982; Vol, 1-2
3.M. D. Ruff, Polyether Antibiotics; Naturally Occuring Acid Ionophores (Edited by J. W, Westley) , Vol. I, Ch. 6, Marcel Dekker, New York (1982)
4,M. D o Ruff, Polyether Antibiotics; Naturally Occuring Acid Ionophores (Edited by J. W. Westley) , Vol. I, Ch. 6. Marcel Dekker, New York (1982)
5.H. G . Hanley and J. D. Slack, Ref, 4, Ch. 8; P. W. Reed and G. M. Bokock, R e f . 4, Ch. 9; M. W. Osborne, J. Wenger, M. Zanko, F. Kovzelove and M. R. Cohen, Ref. 4, Ch 10
6-Berger, J. ; Rachlin, A. I.; Scott, W. E.; Sterback, L. H. ; Goldberg, M. W. J. Am. Chem. Soc. 1952, 7 3 , 5295
7 .Monensin: Agatrap, A. ; Chamberlin, J, W. ; Pinkerton, M. ; Steinrauf, L, J. Am. Chem. Soc, 1967, 89, 5737
8 .Evans, D. A. ; Dow, R. L. ; Shih, T. L. ; T a k a c s , J. M, ; Zahler, R J. Am. Chem. Soc. 1990, 112, 5290
9.Boivin, T. L . B. Tetrahedron, 1987, 15, 3309
lO,Liu, C.M.; Herrnann, T, E. J. B i o l . Chem. 1978, 2 5 3 , 5892
Il.Westley, J. W. Adv. Appl . Microbial. 1977, 2 2 , 1 7 7
12.Chaney, M. 0 . ; Demarco, P. V.; Jones, N. D.; Occolowitz, J. I,. J. Am. Chem. Soc. 1974, 96, 1932
13 .Evans, D. A. ; Dow, R. L. ; Shih, T. L. ; Takacs, J. M.; Zahler, R. J. Am. Chem. Soc. 1990, 112, 5290
14 ,Evans, D. A. ; Dow, R. L. ; Shih, T. L. ; Takacs, J. M. ; Zahler, R J. Am. Chem. Soc. 1990, 112, 5290
1 5 . W ~ t . s ~ P. G , M.; DfCosta, R.; Butler, W. J. Org. Chem, 1984, 49, 2582
16-Toeplitz, B. K- ; Cohen, A. I. ; Funke, P. T. ; Parker, W. L.; Gougoutas, J. Z . J. Am. Chem. Soc. 1979, 101, 3344
CHAPTER 2
INTRODUCTION TO THE CHEMISTRY OF
(+) IONOMYCIN
2 T h e Chemistry of Ionomycin
2.1 Introduction
(+) -1onomycin is constructed of a 32 carbon skeleton. Of these
carbon centers, 14 exhibit asymmetry. Both a cis and a trans
2,2,5-substituted tetrahydro furanyl ring system are present , as
wel l as a trans disubstituted olefin, and three hydroxyl groups.
A P-diketone and a carboxylic acid group complete the list of
functionality. Also noteworthy are the alternating methyl groups
from C1 to C16 and the propionate derived sequence that forms C17
to C 2 2 ,
Scheme l
TrO 0'
OTMS
TrO /' 17 F G
Constructing the ionornycin backbone with correct relative, and
absolute stereochemistry, is a formidable challenge. A convergent
synthetic approach readily simplifies this challenge. This
strategy entails the construction of smaller, simpler pieces of the
whole, which can then be joined with stereospecificity. Although
the controlled combining of fragments is not always as
straightforward as is hoped, and the final stages of any synthesis
is a poor time to experience problems, covergency is still an
excellent strategy.
Scheme Il
Another advantage of a convergent synthesis the ability to create
functionality upon appending of subunits. Although risky, this
approach is often desirable. In this way, the requisite functional
groups do not necessarily need to exist within the individual
f ragrnents . The retrosyntheses of all groups involved, i. e. Evans,
Hanessian, (Scheme I) , and Lautens/Colucci, (Scheme 11) illustrate this.
Both of the previously published total syntheses of ionomycin
employed similar strategies. Evans and Hanessian applied identical
disconnections in the construction of the ionomycin backbone; C1-
C10, Cll-C16, C17-C22, and C23-C32. In addition, the mode of
coupling of the individually constructed fragments, and the order
of coupling were identical. Different approaches to the individual
subunits make each of the previous synthetic efforts distinct.
2.2 Syntheses of the cI-c~/C~O Fragment
The C9-Cll P-dicarbonyl region of ( + ) ionomycin is an obvious point
of disconnection. Evans and Hanessian chose to make the C1-C9
fragment which could be coupled via aldol condensation of the C10
enolate to the C11 aldehyde. Colucci on the other hand, opted to
construct the C1-C10 fragment, after which the C10 enolate could be
coupled to the C 9 aldehyde.
Once the choice of disconnections was made, the focus was turned to
the stereochemically controlled installation of the syn-1,3-anti-
3,5 methyl triad on the carbon backbone.
2.2.1 Evans Synthesis of the C1-CIO Fragment
A u~lique synthetic approach was used to introduce each of the three
stereocentres of this fragment, C4, C6, and C8. First, Evans used
a chiral aldol reaction developed within their laboratory.' The
boron enolate of the norephedrine-based chiral carboximide', 2, was
added to acetaldehyde, as seen in Scheme 111. This reaction
proceeded highly selectively, with a diastereorneric excess
exceeding 985, and in good yield (93%) to give the P- hydroxycarbonyl, 3. Transesterification with lithium benzyloxide3
affected the removal of the chiral auxiliary. This ester was then
reduced to the diol before Swern oxidation to the aldehyde.
Reduction to the primary allylic alcohol was followed by
condensation with (carbethoxyethylidene) triphenylphosphorane, to
give an a$-unsaturated ester. A second,reduction led to a primary
allylic alcohol which was then iodinated to give compound 4 .
Scheme Ill
Next, the C4 center was established using the same propionate
chiral auxiliary in an asmymetric alkylation approach, also
developed in the Evans laboratory.' The allylic alcohol was first
converted to i tr s corresponding allylic iodide, via Landauer-Rydon
methodology' using methyltriphenoxyphosphonium iodide in DMF. The
alkylated product, 5, was obtained in 73% yield, with a
diastereomeric excess of 96%. A final two carbon extension was
performed using the same sequence outlined directly above to give
the full C1-C10 backbone. Installation of the correct
stereochemistry at C6 remained before completion of the fragment 6.
In order to install the correct stereocentre at C6, the C 9 carbonyl
was carried through the sequence as the corresponding secondary
alcohol. This hydroxyl group could then be exploited in a directed
hydrogenation reaction6 to give the requisite 1,3-syn-dimethyl
relationship. Cationic rhodium catalyst, [m (NBD) (DIPHOS) -41 BF,',
5 mol%, afforded the hydrogenated product in 96% yield, with a
diastereomeric ratio of 94 : 6, favouring the desired stereochemical
orientation at C 6 - This selectivity is assumed to arise from 1,3
strain conformational effectse at the allylic position.
The C1-C10 fragment was obtained in 17 steps starting from (IS, 2 R ) - norephedrine .
2.2.2 Hanessian Synthesis of the C1-C10 Fragment
Hanessian employed two butenolide templates, each derived from L-
glutamic acid, to stereoselectively construct the C1-C10 skeleton,
Scheme IV. (Pheny1thio)methane provided the one remaining carbon
necessary to complete the 10 carbon fragment.
The L-glutamic acid derivative, lactone 7 , has a methyl group which
corresponds to one of the syn-oriented methyl groups in the desired
fragment. A second methyl group was necessary at the ring oxygen
bearing carbon. This was seen to arise from direct nucleophilic
displacement.
Scheme N
L-Glutamic Acid RO
OR --kp
OTBDMS OTBDMS OTBDMS OR -
Epoxide 8 was obtained from the lactone in four steps. Epoxide
opening with (phenylthiomethyl) lithium assisted by DABCO' followed
by protection provided the tosylate, 9. Direct nucleophilic
displacement of the tosylate, with complete inversion of
stereochemistry, was affected by a sulfur assisted1* reaction with
lithium dimethylcuprate." The presence of the sulfide proved to
be pivotal. If a sulfoxide group or an alkyl group were present in
lieu of the sulfide, competitive elimination resulted. Next,
elimination of the thioether group was performed, resulting in a
C9-C10 olefin which underwent Wacker oxidation, unselective
reduction and protection to give silyl ether 10.
In preparation for a Peterson olefination with a second L-glutamic
acid derivative, 11, the primary hydroxyl group was next oxidized
to the aldehyde. The mixture of olefins was hydrogenated to
produce the corresponding saturated lactone, 12, as a mixture of C 9
epimers. The bis (phenylthio) ether was formed via the diol derived
from the lactone, 13. Desulfurization using Raney-nickel gave the
doubly deoxygenated product, which was then oxidized to give
ionomycin f ragnent 1 4 .
The Hanessian synthesis of the C1-C10 fragment of ( + ) ionomycin
required 26 steps from the starting L-glutamic acid.
2.2.3 Colucci/Lautens Synthesis of the C1-C9 Fragment
It was noted early on that the Cl-C9 fragment of ionomycin
contained the 1,3-syn-3,5-anti methyl triad orientation that was
obtained after methylithium induced nucleophilic ring opening of
(3.2.11 oxabicyclic alkenes followed by ozonolysis . "
Scheme V
2 Steps, 65% yield *
- - - - - - 1 Step followed by . d ~ e - 6 ~ e - - -
3 - - - - chromatographic
17 15 seperation, 45% yield 16 - T'ps(&+ - - -
-- - 4 Steps, 39% yield 3 Steps, 84Oh yield = 3 Steps, 77% yield - - - - - - - - - -
Monocycle 15 was obtained from nucleophilic attack (methyl lithium)
at the C7 position of a well known oxabicycle", Scheme V.
Resolution of the resulting diol proceeded by esterification with
a chiral acid. The mandelate ester used served two additional
purposes; to act as a protecting group, and as a hold to
differentiate the two ends of the acyclic fragment after ozonolysis
with reductive workup.
Ozonolytic cleavage resulted in a mixture of hydroxy lactols, 17.
The primary hydroxyl was selectively protected as the s i l y l ether
before removal of the mandelate ester, which was achieved by
treatment with DIBAL-H. At this point, a two carbon extension is
required to complete the 9 C backbone, and to this end,
triphenylcarbo-t-butoxymethylenephosphorane was used, to yield the
monoprotected trio1 18.
The dideoxy product was obtained via application of Barton
conditions. Formation of the thiocarbonate led anly to
deoxygenation at C 7 , and not CS: Barton had previously determined
that simultaneous deoxygenation would not occurT4 and so a
sequential approach was undertaken. To accomplish the task at
hand, namely the second deoxygenation, Rasmus senr s protocol15 was
applied to produce a CS thiocarbonylinidazolide which was then
reduced. It remained for the functionality at both terminals to be
adjusted. This was accomplished in three additional steps.
Treatment with TBAF resulted in deprotection of the silyl ether.
Transesterification was effected by refluxing conc. H2S04 in
methanol. Finally oxidation gave the aldehyde 19 in a total of 17
steps starting from furan, with an overall yield of 2.56.
2.3 Syntheses of the ClO/Cll-C16 Fragment
Evans and Hanessian both constructed the Cll-C16 fragment of
ionomycin, while the Colucci/Lautens synthesis involved the
construction of a CI0-C16 fragment. As with Evans and Hanessian,
Colucci intended to couple the C16 and C17 termini via
Lythqoe'"eaction. Ail three syntheses also sought to use
coupling to join the C1-CIO fragment to CII, or the C1-C9
to C 1 0 as the case may be: A regioselective enolizationi7
a Julia-
the same
f ragmeni
followed
by an aldol condensation to give the desired bond formation, Three
stereocencers ex is^ in each of the two described fragments, C11,
C X , a c C14-
2.3.1 Evans Synthesis of the Cll-C16 Fragment
12 t h e i r ccnstruction of the C11-Cl6 fragment of ionomycin, the
E v m s grccp again used two chiral propionate enolates, Scheme VI.
C r n r a m y l brcmicie was added to t h e Lithium enolate of 20 with
9 8 . 3 : 1 . 7 c i a s t e r e o s e ~ e c t i v i c y . The chiral auxiliary was removed by
redzcion with lithium aluminum h y a r i d e .
Scheme VI
Mesylation of the resulting primary alcohol followed by treatment
with sodium iodide afforded ally1 iodide 22. Due to its greater
nucleophilicity, the prolinol amide enolate was applied to the next
alkylation applied, resulting in a diastereomeric ratio of 97: 3.
The corresponding carboxylic acid was obtained after internally
assisted hydrolysis and treatment with sodium hydroxide. Less than
1% epimerization was observed upon reduction to the Cl1 alcohol
with lithium aluminum hydride, to give 24 . This alcohol was
protected before manipulation of the C16 position. Ozonolysis
followed by reductive workup, provides a handle for further
functionalization; formation of either the phosphonium salt or the
s u l f o n e , 25, to participate in trans olefination through Schlosser-
WittigL8 or 3ulia19 reactions.
2.3.2 Hanessian Synthesis of the C11-C16 Fragment
Hanessian- began his work on ionomycin early on, as did Evans, with
a paper published in 1986" detailing the construction of two
fragments of ionomycin; C2-C10, and Cll-C22, from butenolide
templates. These early routes were not considered synthetically
viable. In 1990, Hanessian published a synthetic route to the C11-
C16 fragmentz2, and it is this approach, illustrated by Scheme VII,
that was later used in their total synthesis.
A series of four steps from L-glutamic acid afforded the chiral
compound 26. Conjugate addition resulted from treatment of 26 with
trithiomethyl lithium to give a diastereomeric ratio of 99:l in
favour of the desired isomer. Installation of a hydroxyl group
alpha to the carbonyl was achieved by trapping of the enolate with
an oxodiperoxornolybdenum (IV) -pyridine-HMPA ~ornplex*~. Raney Nickel
reduction effected the removal of the three C12 thiomethyl groups.
Scheme VII
OTBDPS
k2r0 OTBDPS OTBDPS f
o+ V (M~s)~c''' b" -k2+
OH ,**. OH
28
4-0 29
,,S'K~- 27 30 0
The second butenolide template was formed in s i t u . The epoxide
formed from 28 underwent nucleophilic attack by the sulfone anion
30 to give the hydroxy acid butenolide precursor 31. Lactone
formation was accomplished by treatment with EDCI and DMAP. The
sulfide was oxidized to the sulfoxide which then underwent
elimination to give the butenolide. Treatment with lithiodimethyl
cupr~te effected the second conjugate addition which gave compound
32 with the newly installed stereocentre at C14- A further 8 steps
afforded alcohol 33.
The C16 functional handle remained to be introduced. Sulfonation
of 33 was accomplished by mesylation and subsequent displacement
with lithium thiophenoxide. Oxidation with mCPBA yielded the
targeted compound 34 in a total of 25 steps, starting from L-
glutamic acid. This methylation-hydroxylation sequence is the same
methodology used in the Hanessian synthesis of the C17-C22 fragment
of ionomycin .
2.3-3 ~olucci/Lautens Synthesis of the C10-C16 Fragment
A complete racemic synthesis of the C10-C16 fragment was achieved
by Colucci in 10 steps starting from furan, with an overall yield
of 10%. The more important enantiopure approach, Scheme VIII, was
less direct.
Scheme Vlll
a) 5 moI0h (S)-BINAP. 10 molOk Ni(COD)2, PhMe, 65%. 1-1 equiv. DIBAL-H added via syringe pump over 20 hours; ( b)
KHMDS, PMBCI. cat. "BuNhl , THF, rt; (c)cat. 0s04, NMO, THF, water; (d) Na104, t-butanol, water, NaHCQ ; (e)
(PPH&RhCI. PhH. rt; (f) (Et0)2POCl+S02Ph, DBU, UCI, CYCN. OOC to R; (g) EtOH. Raney Nik, rt; (h) TBAF, THF, rt;
(h) TCDI, THF, refluy (i) (TMS)3SiH, PhMe, cat. AIBN. 1000 C
The enantioselective desymmetrization developed by ~ o v i s ~ ~ was
applied to known oxabicycle 35, prepared in 3 steps from furan.
Selective protection of the ring opened product as the para-
methoxybenzyl ether gave cycloheptenol 36. The choice of PMB as the
protecting group is accredited to i t ' s ability to be selectively
cleaved at a later stage.
Lemiuex oxidation2( was applied to the diprotected cyclic olefin 36,
in lieu of ozonolysis which resulted in partial oxidation of the
PMB group. Diol formation followed by oxidative cleavage to give
the dialdehyde 37, proceeded smoothly with an overall yield of 90%.
An observation made by ~suji~' in 1965 was then applied to the
dialdehyde as a selective means of decarbonylation. He observed
that the pressence of branching alpha to an aldehyde, caused a
decrease in the rate of decarbonylation using stoichiometric
Wilkinsonr s catalyst. With this information in hand, the desired
monaldehyde 38 was obtained in 78% yield over two steps. A
stabilized Wittig reaction under Roush conditiond6 provided the
unsaturated sulfone 39, which was directly reduced to the saturated
sulf one 40, under Raney-nickel catalysis, leaving the PMB ether
intact. Deprotection of the silyl ehter preceded deoxygenation
under Rasmussen' s condition^'^ which afforded the target molecule 41. This piece was accomplished in 13 steps, in an impressive
overall yield of 18.3%.
2 - 4 Syntheses of the ~ 1 7 - ~ 2 2 / ~ 2 4 Fragment of Ionomycin
The C17-C22/C23 fragment consists of four adjacent stereocentres
(C18, C19, C 2 0 , and C Z l ) , with alternating orientation in space.
This propionate derived molecule, having anti anti anti
substitution pattern, lends itself to many synthetic approaches.
Three are outlined below.
2-4.1 Evans Synthesis of the C l 7 - C 2 2 Fragment
Developments in the Evans laboratory showed that addition of the
boryl enolate of crotylimides to aldehydes results in a syn, a-
vinyl adduct. This observation was applied to install the C19 and
C20 stereocentres of ionomycin with high diastereoselectivity via
an aldol condensation, Scheme IX. Reaction of crotylimide 42 with
(S)-0-benzyl-2-methyl-3-hydroxypropionaldehyde, to give 43 in 588
overall yield, based on the alcohol precursor to the aldehyde. The
removal of the chiral auxiliary poses a problem. The competing
electrophilicity of the endocyclic carbonyl moiety necessitates the
activation of the exocyclic carbonyl. This is accomplished by
reformation of the boron aldolate ." Reaction with tri-n-
butylborane and glacial acetic acid followed by reduction gives
the monoprotected trio1 44 with the newly corrected stereochemistry
at C 2 0 . Tosylation and reduction with lithium triethylborohydride"
effected the deoxygenation of the methyl substituent at C20, to
give olefin 45.
Application of Upjohn condition^^^ resulted in a C21 diastereorneric mixture of C21, C22 diols. The primary hydroxyl of both
diastereomers were selectively protected as the silyl ether, so
that the desired 3,s-acetonide could be formed selectively.
Deprotection and oxidation to the aldehyde was carried out before
equilibration of the trans acetonide 49 to the thermodynamically
more stable counterpart 48. Deprotection of the silyl ether, the
thirteenth and final step of this sequence, afforded syn acetonide
50, in a 98:2 equilibration mixture.
Scheme lX
2 . 4 - 2 Hanessian Synthesis of the C17-C22 Fragment
The Hanessian synthesis of C17-C22 involved the same strategy seen
in their synthesis of the Cll-C16 fragment, the selective
methylation of two chiral butenolide templates." Here,
installation of a hydroxyl functionality alpha to the carbonyl
follows methylation in each case, (Scheme X) . Opening of the ring, selective protection of the primary hydroxyl function, and
epoxidation, installed the correct stereochemistry at C19. The
method of acetate extension and replication of the butenolide
template, to afford 55 is described in previous reports.32
Scheme X
Again, conjugate addition of a methyl nucleophile was used to
introduce t h e second methyl group. The syn product was formed
exclusively. Oxidation under the previously applied conditions
resulted in an epirneric mixture of alcohols at the C21 position.
The unwanted diastereomer was favoured in a ratio of 1.7:l. Both
diastereomers of 56 were carried through to the target aldehyde in
a 5 step sequence; reduction of the lactone, formation of the
primary pivalate ester, acetalization, cleavage of the pivalate
esters 57 and 58, and finally Swern oxidatiod3 to afford aldehydes
59 and 60. The undesired enantiomer 59 was easily epimerized to
t h e thermodynamically favoured acetal 60. It is of interest to
note the application of the same equilibration strategy by the
Evans group3' in their synthesis of this fragment.
The synthesis of the C17-C22 fragment was finally accomplished in
25 s t e p s starting f r o m L-glutamic acid.
2 . 4 . 3 Colucci/Lautens Synthesis of the C17-C23 Fragment
The work of ~spiotis" provides us with a route to the known
enarrtiopure dihydroxylated cycloheptenol 61, Oxidative cleavage of
this monoprotected ring system affords the backbone of the C17-C23
fragment- The immediate challenges are inversion of the C21
centre, and differentiation of the dialdehyde that arises from
oxidative cleavage,
Scheme XI
OTlPS OTlPS
Y Y o
OTlPS ?TIPS
OTlPS H"vLL f ,o&o 18 g z0 e i 1 - - TIPSO 0-0 TIPSO OPMB
H ~ P M B
HO 65 66 67
(a) DMSO, (COC1)2, NEt3, CkCr;?, -78%; (b) PhMe,DIBAL-H, -76'~; (c) THF, KHMDS, PMBCI; (d) Q, MeOHICl-&h, -78'~ then
NaBb, rt: (e) CH2Ch, DDQ, Mol. Sieves, rt; (f)TrCI, NEb, DMAP, CYCh, then C k C h , DIBAL-H, - 7 f f ' ~ to PC, then DMSO,
(COCih, NEt3, CH2Ch, -78OC
In response to failed attempts at a Mitsonobu reaction, a simple
oxidation-stereospecific reduction sequence (DIBAL-H) effects the
inversion, leading to a diastereorneric ratio >3O: 1 in favour of the
syn alcohol. Para-methoxybenzyl protection is the final stage
before reductive ozonolysis was carried out. Further reduction
gives the tetrol 65,
Specific manipulation of the C17 aldehyde made use of the
observation of ~ i k a w a ~ ~ et al. Specifically, that anhydrous
oxidation of the benzylic position of para-methoxybenzyl ethers
will result in cyclization onto the cation if an appropriately
positioned hydroxyl group exists. Treatment of 65 with DDQ in
dichloromethane afforded the cyclization product, acetal 66, in 88%
yield. This elegant differentiation was followed by hydroxyl
protection at C17, and reduction of the acetal under Takano's
protocol using DIBAL-H.~' Swern oxidation gave fragment 67 in 12
steps from furan, with an overall yield of 19.6%.
1-Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981,
Z.Evans, D. A,; Bartroli, J.;Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127
3.Evans1 D. A.; Ennis, M. D,; Mathre, D. J. J. Am. Chem. Soc. 1982, 104, 1737
4.Evans, D. A,; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982, 104, 1737
5-Landauer, S. R.; Rydon, H. N, J. Chem. Soc, 1953, 2224
6.Brown, J. M. Angew. Chem., Int. Ed. Engl. 1987, 26, 190-203
7.Brownf J. M. Angew. Chem., Int. Ed. Engl. 1987, 26, 190-203
8.Hoffmannf R. W. Chem. Rev. 1989, 89, 1841
9.Marshal1, 3 . 11.; Andrew,R. C . J. Org. Chem. 1985, 50, 1602
10 .Alexakis, A. ; Mangeney, P. ; Ghribi, A. ; Marek, S . ; Sedrani, R.; Guir, C . ; Normant, J. Pure Appl. Chem. 1989, 45, 425
11. (a) Lipshutz, B. H. Synthesis, 1987, 3 2 5 (b) Lipshutz, B. H.; Koxlowski, M. A. Tetrahedron, 1984, 40, 5005
12.Coluccif J. Ph. D. Dissertation, University of Toronto, 1987
Prepared in two steps from the cycloaddition of furan and DBK to yield the oxabicyclic ketone followed stereoselective reduction with L-Selectride to give the , ~ ~ ~ ~ O l l l e , u
Cnem. Soc. 1972, 94, 7159 axial alcohol; Brown, H C.; Krishnamurthy, S.; J. Am.
14,Barton, D. H, R.; McCombie, S. J. Chem. Soc.; Perkin Trans. 1 1975, 1574.
15-Rasrnussen, J. R.; Slinger, C . J-; Kordish, R , J.; Newman- Evans, D. D- J. Org. Chem, 1981, 46, 4843
6 a , M.; Paris, J.-M. Tetrahedron Lett. 1973, 14, 4833
17,Mukaiyama, T.; Iwasawa, N,; Stevens, R. W.; Haga, T. Tetrahedron 1984, 40, 1381
18,Schlosser, M,; Christrnann, K, F- Angew. Chem., Int . Ed. Engl. 1966, 5 , 126
19 . Julia, M. ; Paris, J. -M. Tetrahedron Lett. 1973, 14, 4833
2O,Hanessian, S.; Murray, P. J. Can. J. Chern. 1986, 64, 2231
21.Hanessian, S.; Cooke, N. G.; Dehoof, B.; Sakito, Y. J. Am. Chem. SOC. 1990, 112, 5276
22.HanessianI S.; Sahoo, S. P.; Murray, P. J. Tetrahedron Lett. 1985, 26, 2631
23.LautensI M.; Rovis, T. J. Am. Chem. Soc. 1997, 119, 0000
24.VanRheenenf V , ; Kelly, R. C , ; Cha, D. Y. Tetrahedron Lett. 1976, 17, 1973
25.Tsujif J. ; Ohno, K. Tetrahedron Lett. 1965, 3969
26.Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.; Masamunie, S. ; Roush, W. R. ; Sakai, T. Tetrahedron Lett. 1984, 25, 2183
27.Rasmussenf J. R.; slinger, C. J.; Kordish, R. J.; Newrnan- Evans, D. D. J. Org. Chem. 1981, 46, 4843
28.Bartroli, J. Ph.D. Thesis, California Institute of Technology, 1984.
29.Krishnamurthy, S.; Brouwn, H. C. J. Org. Chem 1976, 41, 3064
30.VanRheene11, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976, 17, 1973
31.~tork, G.; Rychnovsky, S. P u r e A p p l . Chem. 1987, 59, 345,
32.Hanessian, S.; Hodges, P. J.; Murray, P. J.; Sahoo, S. P. J. Cnem. Soc., Chem. Commun. 1986, 734
33 .Mancuso, A. J.; Huang, S.-L. ; Swern, D. J. Org. Chem. 1978, 43, 2480
3 4 .Dow, R. L. Ph.D. Dissertation, Harvard University, 1985
35 .Aspiotis, R. Masters Degree, University of Toronto, 1997
36. Oikawa, Y. ; Yoshioka, T. ; Yonernitsu, 0 . Tetrahedron Lett. 1982, 23, 885
37.Takan0, S.; Akiyama, M.; Sato, S.; Ogasawara, K. Chem. Lett. 1983, 1593
CHAPTER 3
CHEMISTRY OF THE TE TRAHYDROFURANYL SUBUNI T
3 The Chemistry of the Tetrahydrofuranyl Subunit
3.1 Synthetic Developments Towards Tetrahydrofuran Synthesis
As stated by Boivin, the construction of a polyether antibiotic is,
to a large extent, an exercise in the preparation of substituted
oxygen heterocycles Total synthetic efforts towards various
polyether antibiotics, over the past forty or so years, has
necessitated the development of new synthetic strategies towards
the tetrahydrofuranyl ring system, As a result, a variety of
regio, chemo, and stereoselective routes to many substituted
tetrahydrofuran moieties', including the cis-2,2,5-trisubstituted
tetrahydrofuranyl subunit of interest, have been put forth,
It should be noted however, that in most cases, the focus has been
on the formation of disubstituted ring systems, and a large gulf
remains between development and our practice, since the B ring of
ionomycin is a 2,2,5-trisubstituted system.
3.1.1 Diastereoselective Epoxidation of a Bis Homoallylic
Alcohol Followed by Acid Catalyzed Ring Closure
Probably the most widely used approach to tetrahydrofuran synthesis
is the epoxidation of a bis homoallylic alcohol followed by acid
catalyzed ring closure. A look at representative developments in
this area follows,
The construction of ether rings through intramolecular attack of
hydroxyl groups on epoxides, has often been applied in the total
syntheses of polycyclic ethers3, such as monensin4, lasalocid A',
and ~varicin.~ Consequently, the development of methodology using
different parameters, such as olef in geometry, solvent, and
epoxidation catalyst, to control the nature of diastereoselectivity
has remained an important synthetic endeavour.
An important advance in epoxidation-cyclization methodology was
reported by Kishi in 1978.7 a,&-unsaturated alcohols were treated
with t-BuOOH in the presence of VO (acac), according to Sharpless'
protocol. The trans 2,5-disubstituted ring product predominated in
a greater than 20:l ratio upon addition of acetic acid. Kishi
invoked two transition state conformations to account for the
observed selectivity, Scheme I. This Kishi transition state model,
has been widely and successfully applied to both predict and
explain the stereoselectivity of epoxidation-cyclization
sequences ?Determination of the favoured product is based on
minimized steric congestion. Factors such as Alr"train, as well
as the bulk, orientation and number of substituents must all be
considered.
Scheme I
This newly developed methodology was applied by Kishi et al. in the
first total synthesis of lasalocid A', Scheme 11. An asymmetric
epoxidation cyclization successfully formed the first trans ring.
The second epoxidation proceeded, as expected, to give the trans
epoxy-alcohol which, upon ring closure, would afford the trans-
tetrahydrofuran. However, in this case it is the cis-ring closing
that is required. Although inversion of the epoxide is possible,
it is a tedious process, and another more direct route was
developed.
Scheme ll
In 1988 Nicolaou et al. sought to better define the stereospecific
construction of oxirane systems, lo again using the Sharpless
asymmetric epoxidation to give chiral materials and intramolecular
epoxide opening via a primary hydroxyl nucleophile. A versatile
synthetic route to monosubstituted 0-heterocycles was developed.
The regioselectivity of cyclizations, whether 6-endo or 5-exo", was
found to be dependant on the electronic nature of the substituent.
As expectedi2, it was found that a p-orbital adjacent to the epoxide
unit activates the carbon-oxygen bond to nucleophilic attack,
resulting in a 6-endo cyclization. The 5-exo cyclization
predominates in the absence of a p-orbital.
After a systematic look at epoxidation-cyclization reactions, it
was concluded that by varying the geometry of the allylic
substrate, the stereochemistry of the epoxide and the nature of the
substituent, any of the mono-substituted oxacycles, shown in Scheme
111, could, to a greater or lesser degree, be formed.
Scheme Ill
Although these studies established well-defined and predictable
routes to mono-substitued THF and THP systems of predesigned
stereochemistry, a reliable route to higher substituted
tetrahydrofuran ring systems remained elusive.
In 1990, the first total synthesis of Teurilene, a polyether
containing 3 tetrahydrofuran moieties, was published by Hashimoto
et al., Scheme IV.I3 In this synthesis, two simultaneous
vanadium (V) catalyzed oxidation-cyclization reactions were
elegantly employed to form two tetrahydrofuran rings with differing
stereoselectivities. Two developments were key to the
stereocontrol of this approach. Firstly, Kishi' s findings that
vanadium(V)-catalyzed epoxidation-cyclization of 4-substituted 4-
en-1-01 systems result in an anti epoxy alcohol which cyclyzes
under standard acid catalysis to afford the trans 2,2,5-
tetrahydrofuranyl ring. And secondly, a developement in their own
total synthesis of thyrsiferol14, that under identical conditions,
5-substituted 4-en-1-01 systems form syn epoxy alcohols which
cyclize to form a c i s fused ring.
Scheme IV
I
34Or6,7 steps 17
.)
. *OMOM
19 25 O h , 70 steps
VO(aca~ )~ , TBHP,
AcOH, benzene
50°C, 7 h - 25%, 1 step
MOM
* 31 %, 4 steps
HO'
The desired cyclization precursor 19 was obtained after
approximately 20 steps. Although arduous, the high yields make the
sequence viable. Simultaneous epoxidation afforded 25% of the bis
epoxide. In addition, 308 of the material underwent
monoepoxidation at the 4-substituted en01 to give the trans
tetrahydrofuran. Tetrahydrofuran 20 could then easily be
transformed into 21, resulting in an overall product yield of 56%
over 2 steps. The third oxacycle was prepared via monomesylation
of 20 at the 4-position, followed by treatment with potassium
carbonate in methanol, to give teuriline, 21. Overall, this
synthesis is an impressive display of stereocontrol manipulation.
3-1.2 Oxidative Cyclization of 1,5-Dienes
In 1965, Klein and Rojahn reported that upon treatment with
potassium penanganate, 1,s-dienes are oxidized to substituted
tetrahydrofurans in lieu of the expected tetrol. This reaction
which spawns 4 new stereocentres, Scheme V, is limited to the
formation of cis oxacycles, as well as by the number of available
diene precursors.
Scheme V
The search for workable routes to polyether antibiotics in the late
1 9 7 0 ' s caused a renewed interest in this methodology. Klein and
Rojahn explored a very limited number of substrates, only those
structurally similar to geraniol and nerol , Walba et . a1 . expanded the applicataions by looking at the extent of stereospecificity in
unsymmetrically substituted olefinic carbons. " In all cases
complete stereospecificity was maintained leading both Walba and
Baldwin, who was doing parallel research", to posit mechanisms to
explain the phenomena.
3.1.3 Oxabicyclo[3,2,I]octenones
The variety of synthetic pathways to [3,2,1] oxabicycles is
extensive .I6 The most common method is probably the stereospecif ic
addition of oxoallyl cations to furans through an endo, boat-like
transition state, with the oxoallyl cation adopting the W
conf~rrnation.~~ Due to the ease and versatility of large scale
production of the starting cycloadduct, the use of these oxabicyles
is particularly attractive. The formation of 2,5-substituted
tetrahydrofurans is just one of the many synthetically valuable
applications of [3,2,1] oxabicyclic ketones, developed in this lab
and others.
Scheme VI
EtOH NaOMe MeOH,rt
OH COQMe
One approach involves treatment of the oxabicyle to Bayer-Villager
conditions. The resulting lactone can then be hydrolyzed to give
a 2,s-substituted tetrahydrofuran. In 1975, White and co-workers
synthesized ( k ) -nonactic acid, a macrocyclic antibiotic with
biological activity as a potassium ionophore by this route (Scheme
VI) .'' Also notable is the work by Noyori et dl., in preparing the
first 2,s-disubstituted ribo-C-nucleosides, published in 1 9 8 0 .2'
Previous work in this area had applied manipulation of readily
available carbohydrates, but Noyori sought stereocontrolled
precursors from bicyclic ketonesOz2 Oxidation of the double bond
of the oxabicyle to give the diol affords a ribose skeleton upon a-
cleavage. In 1982, Hoffman et al, used this same rnethodclogy in
their synthesis of lilac alcohol.23
Molander arrived at the 2,2,5-tetrahydrofuranyl unit with the
relative stereochemistry of ionomycin by applying a Bayer-Villiger
oxidation to a [3 , 2, l] oxabicycle, followed by stereocentre
manipulation and transesterification." Treatment with m-CPBA and
NaHCO, afforded the lactone in 67% yield (89% based on recovered
starting material), which, after functional group manipulation, was
reduced to yield a tetrol tetrahydrofuran, 35 (Scheme VII) . A
notable advantage of this route is the ability to incorporate
substituents directly onto the THF ring, using a substituted
dicarbonyl precursor.
Scheme VII
+ OTMS
An alternative to a-cleavage of the carbonyl, is the Beckmann
rearrangement of the cycloadduct, seen in (Scheme VIII'~). This
method again provides a 2,5-substituted tetrahydrofuranyl moiety.
With the advent of controlled cleavage of [3,2,1] oxabicyles,
another route to natural products presents itself.26
Scheme VllI
0 N-OH 0 8 NI+H.HCI, 80%) - 6 (60%) - a AH'*cwNb
MeSQH, P205 aq. HCI NaOAc, EtOH
3.1.4 Halocyclization
Bartlett et al. Found that y,b-unsaturated alcohols, and ether
derivatives c y c l i z e at O°C with iodine in a~etonitrile.~~ The
stereoselectivity of this reaction is dependant upon the nature of
the oxygen; a free hydroxy cyclizes to form a trans-2,5-
tetrahydrofuan, while the corresponding 0-alkylated product
produces a cis substituted ring. The difference in
stereoselectivity can be accounted for by the steric bulk of the
oxygen protecting group, non-bonding interactions must be minimized
in each case. To date, this approach has not been applied i n a
synthesis of ( + ) -ionomycin-
3.1.5 Polyepoxide Cyclization
Another approach to polyether antibiotics is one developed by
Westley and Cane in their examination of the biosynthesis of
ionoph~res.'~ They proposed that in vivo synthesis occurs via
simultaneous epoxidation of the ene moieties followed by epoxide
opening. With this approach, it is the construction of a backbone
containing necessary stereocentres, that presents the largest
challenge. Idealy, stereoselectivity can arise from chirality
residing in the chair, instead of hydroxyl group directed
epoxidation. This approach was explored in the synthesis of
monensin B, Scheme IX .29 By X-ray analysis, the two trisubstituted
epoxides have the stereochemistry required for monensin B, while
the third epoxide is epimeric. Although the desired fragment was
not reached, it is evident that with fine tuning this synthetic
strategy could prove to be very powerful, having many potential
applications.
Scheme IX
Tris tetrahydrofuran segment of Monensin 6
3.1.6 Miscellaneous Routes to Tetrahydrofurans
While the above described routes to tetrahydrofurans give an idea
of the synthetic developements to this point, it is by no means a
complete list. Further examples are mentioned here.
In her report
spir~ketals~~,
on synthetic routes to 5/6 membered oxacycles, and
Boivin described examples of each of the following;
ring contraction of tetrahydropyrans, ester enolate Claisen
rearrangement, mercuricyclization and cyclization of 1,4-diols.
One more example involves the substitution at the 2 and 5 positions
of a furan followed by catalytic hydrogenation which proceeds to
give a single cis stereois~mer.~'
3.2 Synthetic Developments Towards the Tetrahydrofuran Moiety of
(+) Ionomycin
3.2-1 Wuts
I n t h e i r s y n t h e s i s of t h e t e t r ahydro fu rany l subunit of ( + )
ionomycin pub l i shed i n 1 9 8 4 ~ ~ , Wuts e t al. i n i t i a l l y planned t o
app ly t h e Sharp less Asymmetric s pox id at ion" t o a geraniol a c e t a t e
backbone. I t w a s thought t h a t a l l necessa ry c h i r a l i t y could be
in t roduced and t h a t the d e s i r e d r e l a t i v e s t e r e o c h e m i s t r y could be
e a s i l y manipulated via a s e r i e s of c o n t r o l l e d epoxide opening
r e a c t i o n s .
Scheme X
(a) Se*. t-BuOOh, salicylic acid; (b)TBSCi, DMF, imidazole; (c) MeOH, K2C03; (d)mBuli, TsCI, THF; (e)UEt3BH; (9 n-BU,NF; (g)Ti(O-CPrh. (+)diethyl-(L)-tartrate, t-BuOOH; (h) PhNCO, EbN, CHzCh; (i)HC104,H20, CH3CN; @ mC PBA; (k) VO(acach, t-BuOOH, AcOH
The t r ans format ion , (Scheme X ) , began with a l l y l i c ox ida t i on , which
s e rved two purposes, f i r s t l y t o p rov ide t h e s u b s t r a t e necessa ry f o r
t h e SAE, and secondly t o s e rve as an at tachment p o i n t f r o m which t o
b u i l d t h e ionomycin ske le ton . The c o r r e c t oxidation s t a t e a t C 3 2
was achieved e a r l y on i n a one p o t reaction by removal of the
a c e t y l groupt and reduction of the resulting hydroxyl group.
Removal of the remaining protecting group and Sharpless Asymmetric
Epoxidation afforded the desired chiral epoxide. As planned, the
centers at C 2 5 , C 2 6 and C27 were achieved by a c i d catalyzed opening
of the epoxide, Epoxidation w i t h m-CPBA and ring closure proceeded
with little stereoselectivity.
Scheme XI
OCONHPh AcO- HO-'
(a) Ti(O-CPr)4. (-)diethybD-tartrate, t-BuOOH; (b)PhNCO, Et3N, C k C b , PCb; (e) K2C03, MeOH. Dowex w; (f) TsCI,
pyridine, O'C; (g) Nal, 2-butanone; (h)B ySnH, AIBN, EtOH; (i) t-BuPbSiCI, DMF, imidazole; (j) LiAIH4; (k) K2C03, MeOH;
(I)C&=CHCY-MgCI, THF, room temperature
As predicted following Kishi's transition state models, the use of
VO (acac) resulted in a 20: 1 ratio, favouring the wrong isomer.
At this stage the problem of selectivity might be overlooked, but
the inability to separate the two isomers formed forced a new
approach, Scheme XI.
The C32 hydroxyl group was then realized to be potentially
invaluable in directing the chirality of the epoxide- An ideal
scenario involves the selective opening of a bisepoxide at the
right-nand epoxide before an internal hydroxyl group affects an
opening of the left-hand epoxide to afford the desired furanO3' In
actuality, the required selectivity could not be achieved and a
much less elegant procedure, involving the formation and opening of
one epoxide, and then the other, was initiated. The final
sequence, features the following steps; asymmetric epoxidation,
formation of the phenyl urethane , conversion to the cyclic
carbonate via perchloric acid, protection, base-catalyzed
hydrolysis of the acetate, deprotection followed by a second
asymmetric epoxidation, and finally a Lewis acid catalyzed
cyclization. With the successful completion of the tetrahydro furan
successfully formed, the target molecule was then easily prepared.
While the desired ring closure was achieved in 6 steps, this
alternative route features many redundant functional group
manipulations before the left quarter of ionomycin was obtained.
In total, 14 transformations, with an overall yield of 6% were
required,
3.2.2 Spino 6 Weiler
Spino and Weiler took a different approach to the tetrahydrofuran
subunit of ionomycin, taking advantage of earlier advances made in
the oxidative cyclizations of 1,5-dienes by Klein and Ro j ahn. 3s
Namely, that 1,5-dienes such as geranyl acetate, and neryl acetate,
could be induced t~ undergo cyclization to give a cis-
tetrahydrof uran product. 36 Further advances by Walba et a1. 37 showed
that the stereochemistry of the resulting disubstitued oxacycle was
dependant on the geometry of the diene starting material (Scheme
XII) .
Scheme XI1
The required diene was prepared stereospecifically in 8 steps as
seen in Scheme XIII, applying methodology recently developed in the
Weiler group.38 The selective formation of the E-enolate followed
by formation of the E-en01 phosphate by trapping with
diethylchlorophosphate gives the Z-alkene upon treatment with a
magnesium cuprate. A second dianion alkylation and enol-phosphate
cuprate coupling affords the 1,5-diene 64. Oxidative ring
formation proceeds to give >95% of one isomer, assumed to be the
c i s product based on Walba's work, in 53% isolated yield.
Reduction of the ester group and tosylation, followed by a hydridic
displacement of the tosyl group affected the deoxygenation. At
this stage, a resolution was performed, (attempts to separate the
isomers at an earlier stage had met with little success). Compound
66 was condensed with mandelic acid and the diastereomers were
separated by flash chromatography. The resolving group was then
hydrolyzed. Protection followed by conversion t o the phosphonium
salt completed the synthesis of the tetrahydrofuran fragment.
Scheme Xlll
OMOM
OMOM
COOMe h.ii _ k 67 Ph
OH OH +
OMOM
OTBDMS TBDMS
(a) NaH, n-BuLi. THF, O'C to rt, then MOMO-CH2CH2Br; (b) TEA, DMAP, HMPA, CIPO(OEt)2, -20'~ to rt; (c) MeMgClm MeLi, Cul, THF, -45'~; (d) OIBAL, OOC; (e)PPh3, CBr4, CH2CI;I, - 78 '~ to rt; (f) -CH2COCH-COOMe, THF, OOC to rt; (g) KMN04, acetondH 20, C02, -25'~; (h) LAH, THF, O'C; (i) TsCI, pyn'dine, O'C; (j) LAH, THF, heat; (k) (S)-(+)-O-acetyi mandelic acid, DCC,
DMAP, CH2CI2, O°C, chromatographic seperation
The overall transformation was accomplished in a series of 19
steps, many of which had unreported yields. The lengthiness of the
route coupled with the undesireable formation of a racemic product
that was kinetically resolved at a very late stage, prove to be
significant limitations to this synthetic effort of Spino and
Weiler ,
3-2-3 Evans
In 1990, Evans published his asymmetric total synthesis of
i~nomycin.~' The C 2 2 - C 2 3 bond was planned to be a point of
disconnection, fixing the C 2 3 stereocentre upon subunit assemblage,
With this skeletal breakdown, the tetrahydrofuranyl subunit of
interest extended from C23 to C32. The addition of the boryl
enolate of 12 and the aldehyde illustrated in Scheme XIV, provided
the 10 carbon framework, utilising Evans chiral auxilaries to
direct the stereochemistry at C 2 7 ,
To form the oxacycle, Evans applied the Sharpless VO(acac)?
epoxiaation, resulting, as expected by Kishi, and later Wuts, in
a 4:l selectivity for the wrong diastereomer. Although attempts
were made to invert the stereochernistry, their lack of success
forced an unselective epoxidation with m-CPBA. This course of
action was deemed acceptable due to the high chemical yield and
ease of separation of the two diasteromers. Epoxidation and acid
catalyzed cyclization with the hydroxyl group at C 2 7 acting as an
internal nucleophile was accomplished before attention was directed
to the chirality at C 2 6 .
Scheme XIV
1.,1",1
R BnO 0 OAc
(a) BuzBOTf, Et3N, CH2CI2, - 7 8 ' ~ ~ 68%; (b) MCPBA, EtOAc, 45% based on desired isomer; (c) PhMgBr, THF; 79%; (d)
Cp2TiCI(CH2)AlMe2, Pyridine, THFKoluene, -45 OC to -20°c; 94%; (e) PPTS,CH 2CI2;1 00%; (f) 0 3 , CH2CbMeOH. - 7 8 ' ~ ,
Me2S; 55% over 2 steps (g)MeMgBr, GH2C121Et20, -78'~; (h) TBSOTf, Et3N, C h C b , O'C; 94% (i) H2, PdIC, EtOAc; ( j)
MeS02CI E~JN, CH2Ch, O'C; Nal, NaHC03, Me2CO; 99% (k) PPhs, TolueneJMeCN, 75 OC, 78%
Lactonization which, in addition to removing the chiral auxiliary,
provides an intermediate, that will readily lead to the desired
decarboxylated product. Tebbe methylenation, acid catalyzed
isomerization to the more thermodynamically stable internal enol,
and ozonolysis followed by reductive workup, gives a C26 carbonyl
group which can then undergo diastereoselective nucleophilic
addition. Simple functional group manipulations gave the final
group which can then undergo diastereoselective nucleophilic
addition, Simple functional group manipulations gave the final
C23-C32 subunit as a phosphonium salt which could easily be
transformed into the corresponding ylide to be used in the
appending of subunits, An overall yield of 9% over I1 steps was
achieved.
3 .2 .4 Hanessian
Hanessian' s total synthesis of + ion~mycin~~, seen in Scheme XV,
was received for publication less than one month after Evans' total
synthesis, (although initial work was published by R. Dow in a 1985
Ph.D. thesis). Both syntheses featured a simillar approach to the
tetrahydrofuranyl ring system. The epoxidation-cyclization motif
was once again applied, again with hopes of stereocontrol.
Hanessian chose to use an optically active epoxide, and like Wuts,
geraniol, to form the skeleton of the C23-C32 chain. The terminal
2-methylpropenyl group would be cleaved at a later time to give
Scheme XV
TBMSO d ______)
OTBMS
OTBMS
(a) (D)-Diisopropyl tartrate, Ti(0iPr) 4. TBHP, CH2Cb, 4 A sieves, -20 OC, 30 h, then Me2% -20°c, 62%; (b) 1. EtMgBr, THF, then add Li anion of 86, THF-HMPA, -78 OC to -25%. 18 h, 71 %; (c) 1.03, then excess NaBH 4, MeOH, -78% to -25'C, 3h,
87%; 2 Ac20, Et3N, catalyst DMAP, CH2C12, O°C, 0.5 h, 62% overall; 3. Na, liquing NH 3, -33'~~ 69%; (d) 1. TBHP,
VO(acac)*, 3 A sieves, hexanes 24 h, 94%; (e) 1 . LiAIH 4, ether, -25 OC, 20 min, 86%; 2. PP h 3, imidazole, 1 2, CH2Cb, 91 %
Next, the use of the sulfone anion of geraniol in the pressence of
one equivalent of ethyl magnesium bromide41 was explored. The
coupling proceeded to give a mixture of two seperable
diastereomers, in 41 and 30% yields, Since the sulfone
functionality was removed by reduction with sodium in liquid
ammonia after protection and ozonolysis, both diastereorners were
carried through.
With the backbone constructed, the next challenge was
stereocontrolled ring closure to form the cis trisubstituted
tetrahydro furan. The VO (acac) catalyzed epoxidation-cyclization
sequence persued by Wuts and Evans was again explored, this time
with an impressive degree of success. Whereas Wuts, Evans and
Kishi, attempted this cyclization with a secondary hydroxyl group
as the internal nucleophile, the substrate that Hanessian presented
involved attack at the epoxide by a tertiary hydroxyl group,
Under optimized conditions it was found that the less polar the
solvent, the greater the stereoselectivity, culminating in a ratio
of 9: I cis:trans, when hexanes were used. Yields were
consistently between 70 and 808, with preference for cis decreasing
to 4-5:l with other solvents such as dichloromethane, toluene or
benzene. Three simple functional group manipulations give the
requisite cis-disubstituted tetrahydrofuran subunit in a total of
10 steps with an overall yield of 7 8 ,
For the sake of comparison, the original transition state models
proposed by K i ~ h i ~ ~ applied to the tetrahydrofuran precursors are
illustrated below, (Schemes XVI-XVIII), The observed selectivity
in each of the three scenarios is made apparent.
Scheme XXI: Wuts Transition States
Favoured
OH 46
Disfavoured
t-BuO' OH OR 45
Scheme XVII: Evans Transition States
Scheme XVIII: Hanessian Transition States
Favoured
Ha Fi 89
LBoivin, T, L. B. Tetrahedron, 1987, 43, 3309
2. (a) Nakata, T.; Schmid, G.; Vranesic, B.; Okigawa, M.; Srnith- Palmer, T.; Kishi, Y. J. Am. Chem. Soc. 1978, 100, 2933 (b)Fukayama, T.; Akasaka, K.; Karanewsky, D.S.; Wang, C.-L. J.; Schmid, G.; Kishi, Y. J. Am. Chem. Soc. 1979, 101, 259
3 .Hashimotof M I ; Kan, T . ; Nozaki, K. ; Yanagiya, M. ; Shirahama, H.; Matsumoto, T. J. Org. Chem. 1990, 56, 2299
4 . S W.C.; Romero, A. G. J. Am. Chem. Soc. 1986, 108, 2105
5-Nakata, T. ; Schmid, G.; Vranesic, B.; Okigawa, MI; Smith- Palmer, T.; Kishi, Y. J. A m . Chem. Soc. 1978, 100, 2933
6.Hoye, T.R.; Suhadonic, J . C . Tetrahedron Lett. 1986, 26,2885
7. Fukuyama, T . ; Vranesi, B; Negri, D. P. ;Kishi, Y. Tetrahedron Lett. 1978, 2741
8 .An illustrative sample (a) Wuts, P. G. M.; DrCosta, R.; Butler, W. 2. Org. Chem. 1984, 49, 2582; (b) Evans, D. A.; Dow, R. L.; Shih, T. L.; Takacs, J. M.; Zahler, R. J. Am. Chem. Soc. 1990, 112, 5290; (c) Hanessian, S.; Cooke, N. G.; DeHoff, B.; Sakito, Y. J. A m . Chem. Soc. 1990, 112, 5276
9.Nakataf T.; Schmid, G.; Vranesic, B.; Okigawa, M.; Smith- Palmer, T.; Kishi, Y. J. Am. Chem. Soc. 1978, 100, 2933
lO.Nicolau, K. C.; Prasad, C. V. C.; Somers, P. K.; Hwang, C. K.; J. Am. Chem. Soc. 1989, 111, 5330, 5335
ll.Baldwin, J. E. J. Chem. Soc. . Chem, Commun, 1976, 734
12.Storkf G.; Cama, L.D.; Coulson, D. R. J. Am. Chem. Soc. 1974, 96, 5268
13.Hashimot0, M.; Harigaya, H.; Yanagiya, M.; Shirahama, H. J. O r g . Chem. 1991, 56, 2299
14. (a) Hashimoto, M. ; Kan, T. ; Yanagiya, M. ; Shirahama, H. ; Matsumoto, T. Tetrahedron Lett. 1987, 28, 5665. (b) Hashimoto, M.; Kan, T.; Nozaki, K.; Yanagiya, M.; Shirahama, H.; Matsumoto, T. Tetrahedron Lett. 1988, 29, 1143. (c)Kan, T.; Hashimoto, M.; Yanagiya, M. ; Shirahama, H. Tetrahedron Lett. 1988, 29, 5471. (d) Hashimoto, M. ; Kan, T. ;Nozaki, K. ; Yanagiya, M. ; Shirahama, H. ; Matsumoto, T. J. Org. Chem. 1990, 55, 5088.
lS.Molander, G. A.; Swallow, S. J. Org. Chem. 1994, 59, 7148
16.Walba, D. M.; Wand, M. D.; Wilkes, M. C . J. Am. Chem. Soc. 3979, 101, 4396
17 .Baldwin, J. E,; Crossley, M. J.; Lehtoner,, E.-M. M. Chem. Corn. 1979, 918
18. (a) Hosomi, A.; Tominagaa, Y. [4+3] Cycloadditions. Comprehensive Organic Synthesis; Trost, B. M. ; Fleming, I. (Ed) Pergamon: Oxford, U.K. , 1991, Vol. 5, 593 (b) Mann, J. Tetrahedron, 42, 1986, 4611
19.Arc0, M. J.; Trammell, M. H.; White, J. Do J. Org. Chem. 1976, 42, 2073
20 .Arco, M. J. ; Trarnmell, M. H. ; White, J. Do J. Org. Chem. 1975, 41, 2075
21.Sat0, T; Watanabe, M.; Noyori, R. Chem. Lett. 1980, 679
22.Noyori, R.; Sato, R.; Hayakawa, Y, J. Am. Chem. Soc. 1978, 100, 2561
2 3 . Rabe, S Diplomarbeit, Universitat Hannover, 1982
24.Molandert GI A.; Swallow, S. J. Org. Chem. 1994, 59, 7148
25.Cowlingr A. P I ; Mann, J.; Usrnani, A. A, Perkin Trans. 1981, I2116
26.Mann, J. Tetrahedron, 42, 1986, 4611
27.Rychnovsky, S. D., Bartlett, P. A. J. Am- Chem. Soc. 1981, 103, 3963
31.Cane, D, E.; Liang, T. C.; Hasler, H. J. Am. Chem. Soc. 1982, 104, 7274
29.Sti11, W. C.; Romero, A. G. J. Am. Chem. Soc. 1986, 108, 2105
3O.Boivin, T, L. B. Tetrahedron, 1987, 43, 3309
31.Arc0, M. J.; Trammell, M. H. White, J. D, J. Org. Chem. 1976, 41, 2075
32.Wuts, P. G. M. ; DfCosta, R.; Butler, W. J. Org. Chem. 1984, 49, 2582
33.Umbreitf M, A , ; Sharpless, K. B, J. Am. Chem. Soc. 1977, 99, 5526
34.Boivinf T, L, B. Tetrahedron, 1987, 43, 3309
35.Spin0, C.; Weiler, L. TetrahedronLett. 1987, 28, 731
36.Kleinf E. ; Rojahn, W, Tetrahedron, 1965, 21, 2353
37.Walba, D. M.; Wand, M. D.; Wilkes, M. C. J. Am. Chem. Soc. 1979, 101, 4396
3 8 - (a) Sum, F. W.; Weiler, L. Tetrahedron, 1981, 31 Supp I, 303; (b)Alderdice, M. ; Spino, C . ; Weiler, L. T e t r a h e d r o n - 1 9 8 4 , 2 5 , 1 6 4 3
39 .Evans, D. A. ; Dow, R. L.; Shih, T. L. ; Takacs, J. M.; Zahler, R . J. Am. Chem. Soc. 1990, 112, 5290
40.Hanessianf S.; Cooke, N. G.; DeHoff, B.; Sakito, Y. J. Am. Chem. Soc. 1990, 112, 5276
41.Kocienskif P. J.; Lytgoe, B e ; Ruston, S . J. C h e m . Soc. Perkin Trans, 1 1978, 829
42. Fukayama, T. ; Vranesic, B. ; Negri, D. P , ; Kishi, Y. Tetrahedron Lett. 1978, 26, 2741
CHAPTER 4
OUR SYNTHESIS
OF THE C24-C32 FRAGMENT OF
(+) IONOMYCIN
4 Introduct ion
4.1 Synthetic Strategy and Discussion of the Route
The following synthetic route to the C24-C32 subunit of (+ )
ionomycin was developed by John Coluccil in the Lautens group. In
designing this sequence, Colucci considered several important
factors, such as installation of appropriate stereocenters at C31
and C 2 6 , functionality at C24 suitable to allow easy appendage to
the neighbouring subunit, length of route and of course achieving
a ring closure with the required absolute stereochemistry.
Previous synthetic efforts towards the tetrahydrofuranyl subunit of
ionomycin have provided invaluable information, which was
incorporated into the development of the strategy described below.
Scheme l
viii
The retrosynthesis, shown in Scheme I, illustrates the key
transformation en route to ionomycin. The skeleton of this subunit
is derived from geranyl acetate, which, although one carbon short
of the desired 9 carbon chain, has inherently correct positioning
of the two methyl groups, as well as olefin moieties which can be
functionalized. The architecture of geraniol has proven to be an
excellent point of departure in many previous syntheses of
polyether antibiotics, including ionomycin, as mentioned earlier.2
First, selenium catalyzed allylic oxidation3 of the geranyl acetate
starting material, using a text-butyldihydroperoxide co-oxidant , was performed in order to functionalize the carbon destined to be
C25. It was anticipated that the addition of a methyl-phenyl-
sulfone anion to this centre would provide not only the missing
carbon atom, but an appropriate linkage precursor. The ease of
formation of the sulfone anion makes it ideal for nucleophilic
attack to the planned aldehyde at C23 via a Julia-Lythgoe reaction"
to give an E-olefin, which could then be used in the construction
of the A ring. Of equal importance is the assumed ease with which
the sulphone moiety could be removed following attachment.'
Eventually, cleavage was effected by oxidation of the coupled C17-
C23 and C24-C32 fragments, followed by reduction with SrnI,.
Another foreseen advantage of this approach was the ability to
exploit the penchant of sulfone anion to attack carbonyls. A
greater number of anion equivalents could cleave the acetate, via
nucleophilic attack, leaving a free hydroxyl group to act as a
handle for the planned Sharpless asymmetric epoxidation to follow.
In order to attach the methyl-phenyl-sulfone, the existing hydroxyl
group was first converted to the bromide iii - At this point simple
nucleophilic displacement by the sulfone anion, formed by the
addition of butyllithium to phenyl methyl sulfone in THF at OCC,
afforded iv in 655 yield, along with the dimer as an undesired side
product. The common problem of dialkylation of sulfone-stabilized
carbanions, was investigated by by Pine et a1. . The assumed mode
of action is deprotonation of the mono-alkylated product, Scheme
11. The resultant anion then acts as the new nucleophile to
displace the bromide on the second C24-C32 chain.
Scheme ll
The division between mono and polyalkylated product is believed to
be under thermodynamic control. Although the monosubstituted
sulfone is alkylated much more readily than the unsubstituted
precursor, the monoalkylated anion is thermodynamically less stable
than the phenyl-methyl-sulfone anion.
The possibility that aggregation about the lithium cation could
come into play was also considered by the Pine group. If this were
the case, aggregation would increase as the bulk of the substrate
decreased, reducing the likelyhood of alkylation. Obviously, the
unalkylated iii is less sterically congested than the corresponding
monoalkylated product, iv. Since it is known that the degree of
ion association decreases with potassium in relation to lithium7,
a change in counterion should result in an increase in
monosubstituted product. Pine found this to be true as the base
was switched from butyl-lithium to potassium hydride.
Unfortunately, in our case, such a change in base did not result in
any degree of improvement in the ratio of mono to dialkylated
product. Other variables that were examined without success
include; temperature, rate of addition, the number of equivalents
phenyl sulfone relative
Colucci on the other hand,
the original experimental
The Sharpless asymmetric
to base, and the order of addition.
did not report dialkylation products in
work.
epoxidation, which has proven to be of
pivotal import in the previous syntheses of both ionomycin and
tetrahydrofuran rings, was next applied, Colucci found that with
substrate iv, the catalytic version of the Sharpless asymmetric
epoxidation6 resulted in a decrease in both the yield and
stereoselectivity of the reaction. This compromise could not be
made and allylic alcohol iv was subjected to stoichiometric amounts
of (+)-diisopropyltartrate, titanium isopropoxide and tert-
butylhydroperoxide - Under these conditions, the enantiomeric
excess was found to be >97% by Mosher's ester analysis.' Our
results were in full agreement with this analysis.
It is important to note that a proper workup was found to be
critical to the yields of this reaction. As proposed by Sharpless,
a solution of ferrous sulfate and tartaric acid was used to break
down the titanium isopropoxide. The resulting titanium salts could
then be removed by separation of the aqueous layer. If a trace of
Lewis acidic titanium remained, the epoxide v was found to
decompose at an alarming rate, especially upon concentration.
Next, the epoxide had to be manipulated into the necessary
precursor for the cyclization-epoxidation reaction. Tosylation of
the epoxy-alcohol proceeded without event. This relatively
unstable molecule vi, was then directly subjected to acid catalyzed
opening of the epoxide to form a monotosylated triol. Here,
stereospecific bimolecufar nucleophilic attack occured at the
tertiary centre, resulting in an inversion of stereochemistry.
This backside attack was required to achieve the correct relative
and absolute orientation of stereocentres. Selective protection of
the secondary hydroxyl of viii as the tert-butyldimethylsilyl ether
was the final step in preparation for the ring formation.
The approach decided upon followed Hanessian's beautifully laid
path. We similarly pursued a substrate directed epoxidation,
followed by acid catalyzed cyclization of a 5-substittuted-4-en-l-
01. In this case however, a problem of solvent was encountered.
The use of hexanes as described by Hanessian was not a possibility
due to insolubility. A solution of 3:l heptanes to dichloronethane
was finally found to be suitable, resulting in the best
selectivity, while maintaining solubility. Catalytic amounts of
VO (acac) and 4 equivalents of the co-oxidant, tert-
butylhydroperoxide, were added to the substrate solution twice, at
a 12 h interval. After this period, a catalytic amount of
pyridinium para-toluenesulfonate was added to aid the ring closure.
A final ratio of 7.8: 1 cis/trans was obtained, rivaling Hanessian's
own %I. The two isomers, ix along with itf s counterpart, were
carried through the synthesis together, the separation to be
performed at a later stage.
The deoxygenation at C32 of ix next presented itself. Direct
nucleophilic hydride displacernentlhas impossible due to the
incompatibility of the sulfone group, which suffered various
degrees of reduction as well as displacement. Conversion to the
iodide followed by a radical based reduction lead to the desired
reduced product. The displacement of the tosylate was carried out
in 2-butanone, facilitated by the presence of 18-c-6, to give x.
The diastereomeric tetrahydrofuran mixture was then deiodinated
under standard radical conditions, refluxing toluene, tributyltin
hydride and AIBN as the radical initiator. It was at this point
that separation of the two diastereomers could be accomplished.
The quality of tributyltin hydride was found to be of the utmost
importance. Any degree of contamination could result in
decomposition of the valuable starting material, lowering the yield
from 91% which was possible under optimum conditions.
The final step in the sequence of the C24-C32 chain was the
protection of the hydroxyl group in xi as the labile trimethylsilyl
ether, using the corresponding triflate at -78°C. The fragment xii
could then be coupled as prescribed to the other subunits.
4 - 2 EXPERIMENTAL,
All glassware was flame dried under nitrogen gas and cooled before
use. Solvents and solutions were transferred with syringes and
needles or canulae under standard inert atmosphere techniques.
THF and toluene were distilled from sodium/benzophenone ketyl.
Dichloromethane was distilled from calcium hydride before use.
Both 'H NMR, and 13c NMR spectra were recorded at a 400 MHz Varian
XL400 spectrometer with CDC1, as reference standard (6=7 - 2 4 ppm f o r
'H NMR, and 6=77.O ppm for 13c NMR). Spectral features are
tabulated in the following order: chemical shift (6, pprn); number
of protons; multiplicity (s-singlet, d-doublet, t-triplet, q-
quartet, qn-quintet, sp-septet, rn-complex multiplet, br-broad);
coupling constants (J, Hz) . " C NMR were recorded at 50 or 100 MHz.
Gas chromatography was performed on a Hewlett Packard 5890 gas
chromatograph using an HP-20 carbowax column, and chiral column P-
TA and y-TA. Analytical TLC was performed using EM Separations
precoated silica gel 0.2 mrn layer W 254 fluorescent sheets.
Column chromatography was performed as "Flash Chromatography" as
reported by still1' using (200-400 mesh) Merck grade silica gel.
Phenyl-methyl-sulfone was prepared in a procedure described by
Trost, by oxidation of phenyl methyl sulfide.'*
Since the 'H NMR and 13c NMR data obtained was in full agreement with previous experimental data, no further characterization was
performed. For IR, [a], and HRMS data, see Ph D thesis of John
Colucci, University of Toronto, 1997.
[2Er6E]-Acetic acid 8-hydroxy-3,7-dimethyl-octa-2,6-dienylester
To E sc lu t io -? of salicylic acid (3.52 g, 25.5 m o l ) , selenium
dioxide (565 ng, 5 mmol), and tert-butyl hydroperoxide (127 mL 705
s o l u t i o r , in w a t e r , 917 m o l ) in 90 mL dichloromethane, w a s added
g e r a n y l acetate (50 g, 2 5 5 m o l ) at 10cC, as prescribed by
Sharpless'?. The resulting solution was stirred at rcom temperature
for 4E h. A c this point dimethyl sulfoxide ( 5 0 mL, 917 rnrnol), and
200 rnL of water were added to the reaction. The aqueous pnase was
seperated, extracted with ether (3 x 200 mL) , dried over anhydrous MgSO;, filtered and concentrated in vzcuo. Purification by flash
chromztography ( 1 0 - 4 0 % e thedhexanes ) on silica gel gave known
compound iil' as a yellow oil ( 2 8 - 2 g, 5 2 % )
[2E, 6E j -Acetic acid 8-broma-3,7-dimethyl-octa-2 , 6-dienylester
Br iii
N-brcmosuccinirnide ( 2 1 . 5 g, 121 mmol) w a s added t o a solution of
alcohol ii and triphenylphosphine" ( 3 2 . 6 g, 1 2 4 . 4 m o l ) in 2 2 5 mL
of dichloroneihane s r i r r i n g in a cryobath at -20°C. The s o l i r t i o n
w a s stirred at -2QCC for 2 . 5 h . I n vzcuo c o n c e n t r a t i o n t o
eliminate solvent and flash chromatography of r e s u l t i n g orange
r e s i ~ u e (5-1 04 e t h e r / h e x a n e s on silica gel) gave the known zllyl
brcmide iii'" (23.76 q, 7 6 . 5 % I as a yellow o i l .
I Br iii
THF
To a solution of me thy l p h e n y l s u l f o n e ( 4 3 . 8 g, 280 m o l ) i n 560 r n l
THE' ai O X , w a s added n - b u t y l l i t h i u m ( 1 1 2 . 3 r n l , 280 m r n c l ) via
c a n n u l a . The r e s u l t i n g y e l l o w p r e c i p i t a t e was s t i r r e d f o r 30 min
a t 0°C a n d 1 h a t room temperature. The r e a c t i o n m i x t u r e w a s
c o o l e d t o -20°C and a l l y 1 bromide iii ( 1 6 . 5 g , 6 0 . 1 mmol ) , i n 120
m l o f TEF was added s l o w l y via c a n n u l a , over a p e r i o d o f 30
m i n u t e s . T h e solution w a s s t i r r e d for 2 h as t h e c o o l i n g b a t h
gradually w a r m e d t o room t e m p e r a t u r e . S a t u r a t e d NH,C1 s o l u t i o n ,
( 2 0 0 r n l o f ) , w a s added t o the y e l l o w s o l u t i o n . A f t e r v i g o r o u s
shaking, t h e aqueous l a y e r was s e p a r a t e d , and e x t r a c t e d w i t h e t h y l
a c e t a t e ( 3 x 250 ml) and CH,C12 (1 x 200 ml). The combined o r g a n i c
e x t r a c t s w e r e d r i e d o v e r a n h y d r o u s MgSO: and c o n c e n t r a t e d i n vacuo .
Flash ch roma tog raphy on s i l i c a ge l (30-805 ether/hexanes) g a v e t h e
sulfone i v as a p a l e y e l l o w o i l ( 1 2 . 0 3 g, 65%) .
'H NMR (400 MHz, CDC1,)G 7.90-7 .50 (5H, rn) , 5.34 ( l H r t r J = ~ . O H Z )
5 . 0 9 ( l H f t J = 6 . 6 H z ) , 1 ( l H , m), 3 .13 (2H, m ) , 2 . 3 2 (2H, m),
2 .10-1 .90 (4Hr m), 1.61 (3H, s ) , 1.5s (3H, s ) , 1 . 4 1 ( l H , m ) ; " C NMR
( 1 0 0 MHz, CDC13)6 139 .0 , 138 .8 , 1 3 3 . 6 , 1 3 0 . 9 , 129 .2 , 1 2 8 . 0 , 126 .4 ,
1 2 3 . 6 , 59 .2 , 5 5 . 0 , 3 9 - 0 , 32 .2 , 26.1, 1 6 . 2 , 15 .9 .
To a solution of (+ j -diisopropyltartrate (5.9 mL, 27.6 rnmol,
distilled m d kept under vacuum) and crushed molecular sieves (1 g )
in 2 2 5 r n l dicnlorometnane at -20°C (cryobath) , was added titanicin isoprcpoxide (7.8 m l , 25.8 mmol, freshly distilled), according to
Sharpless protocol. The resulting solution was stirred for 20 min
followed by s l o w addition of sx lphone iv ( 7 - 9 g, 25.8 rnmol) in 55
mL dicnlorrnechane and crushed molecular sieves (0.79 g ) vi a
cannula. This solutior! was again s t i r r e d for 20 min before
addition of tert-butyl hydroperoxide that had been pre-dried over
3 A molecular sieves for 30 min. After stirring overnight (14 h) , at -2OCC, the reaction was warmed to 0°C. A solution of tartaric
acid (58.6 g , 3 9 0 rnmol) and ferrous sulfate (170 g, 611 mmol) in
1.25 L of distilled H,O was prepared and cooled to O°C. The
reaccion mixcure was slowly poured into the stirring aqueous
solution. After stirring for 10 min, the aqueous layer was
separated and e x t r a c t e d with e the r ( 2 x 75 mL). The combined
organic extracts were once again cooled to O°C, and 130 mL of a
precooled solution (0°C) of 30% NaOH in saturated brine was added.
The biphasic solution was stirred vigorously for 1 h at O°C before
separation and extraction of aqueous phase with ether (3 x 100 mlT;)
and dicnloromethane (1 x 100 mL) .I7 Purification by flash
chromatography on silica gel (30-50% etheyl acetate /hexanes) gave
epoxy alcohol v (5.73 g, 69% yield) . Analysis by gas
chromatography revealed an enantiomeric excess of approximately
95%. This is in agreement with earlier experimental result^.'^
[a] = +7.2O (~=2.0, CHC1,) ; 'H NMR (400 MHz, CDC~,) 6 7.88-7.45 ( 5 H r
m), 5-11 (lH, dt, J=0.7, 7.0 Hz), 3 - 7 7 (IH, dd, J= 4-8, 12.1 Hz),
3.67 (lH, dd, J=6.6, 12.1 Hz), 3.15 (2H, m), 2-92 (lH, dd, J=4.8,
6.6 Hz), 2.37 (ZH, m) , 2.03 (2H, rn), 1.72 (IH, m) , 1.61 (lH, ddd,
J=6.6, 8-1, 13-6 Hz), 1.55 (3H, s), 1.46 (lH, ddd, J=7.3, 9.2, 13.9
HZ) , 12.6 ( 3 H f s ) ; 13C NMR (100 MHz, CDC13)6 139.0, 138.8, 133.6,
130-9, 129.2, 128-0, 126.4, 123.6, 59.2, 55.0, 39.0, 32.2, 26.1,
16.2, 15.9.
[ZR, 3R, 3 (3E) -Toluene-4-sulfonic acid 3- (6-benzenesulfonyl-4-methyl-
hex-3-enyl)-3-rnethyl-oxiran-2-ylmethyl ester
The epoxy a l c o h o l v ( 5 . 3 g , 16.24 nmcl) was d i s s o l v e d i n 30 mL of
dichlormethane and stirred at -10°C. To this solution was added
p y r i d i n e ( 2 . 2 mL, 2 7 . 1 mrnol) and f r e s h l y r e c r y s t a l l i z e d pa ra -
toluenesulfor.yl c h l o r i d e (5.2 g, 27 rnmol) . This s o l u t i o n was
stirred for 48 h b e f o r e a second addition of p y r i d i n e ( 0 . 2 2 mL) and
p a r a - t o l u e n e s u l f o n y l chloride ( 0 . 5 2 g ) . A f t e r 1 h , 1 0 0 ml o f water
w a s added and the aqueous l a y e r was s e p e r a t e d and e x t r a c t e d w i t h
dichloromethane ( 3 x 2 0 0 mL) . The organic extracts were dried over
anhydrous Na ,SO, , filtered, and concentrated i n vzcuo. Flash
chroma~oqraphy on silica gel ( 10-40:; ethyl acetate/hexanes gave
t o s y l a t e vi ( 7 . 3 g, 9 3 % ) as a p a l e ye l low oil.
E m . (400 MHz, C D C I , ) G 7.88-7.30 (5H, rn), 4.09 (lH, dd, J'11.1,
5.5 Hz), 4.05 (lH, dd, J=11.1, 5.9 Hz), 3.13 (2H, m), 2 . 9 4 (lH, dd,
J=5.9, 5.5 Hz), 2 . 4 4 (3H, s), 2.36 (3H,s), 1.98 (2H, q, J=7.7 Hz),
1.60-1.38 (4H, m), 1 . 3 (3H, s ) , 1.17 (3H, s ) ; 13c NMR ( 1 0 0 MHz,
c D c ~ : ) ~ 1 4 5 . 0 , 138.9, 133.6, 132.5, 131.6, 129.8, 129.1, 127.9,
127.8, 125.5, 68.4, 60.7, 58.6, 54 .8 , 37.4, 32.1, 23.3, 21.6, 16.6,
15.9.
[2R, 3S, 6E ] -Toluene-4 -SUM onicacid-9-benzenesulfonyl-2,3-dihydroxy-
3,7-dimethyl-non-6-enyl ester
vii
To a rocm temperature solution of t o s y l a t e vi 6 8 g, 3 4 - 5 m o l l
in 1 7 0 m i of a 3 : 1 THF/I-:,O s o l u t i o n was added p r r c h l o r i c acid (0.67
mL, 7 0 % aqueous s o l u t i o n ) . The r e z c t i o n m i x t u r e w a s then heated a t
reflux ( 7 O C C ) for 3 h . The s o l u t i o n w a s cooled t o room temperature
b e f o r e addition of saturated aqueous NH,Cl s o l u t i o n ( 2 0 0 mL) . The
aqueous l a y e r w a s separated and extracted w i t h e t h y l acetate ( 3 x
100 m L ) . The combined organic e x t r a c t s were dried o v e r anhydrous
Na-S04 , filtered, and c o n c e n t r a t e d i n vacuo before purification by
flash chromatograpny on s i l i c a g e l ( 2 0 - 5 0 % ethyl a c e t a t e / h e x a n e s ! . Diol v i i w a s ob ta ined ( 1 2 . 2 g, 72 %)as a pale, milky, o i l .
[ZR, 3S, 6E ] -Toluene-4-sulfonicacid-9-benzenesulfonyl-2- ( (1, l-
dimethylethyl)dimethylsiloxy)-3-hydroxy-3,7-dimethyl-non-6-enyl
ester
viii
T o a s o l u t i o n of d ie1 vii ( 1 2 . 2 g , 2 4 . 6 m o 1 ) i n 4 3 mL of
d i c h l o r o r n e t h a n e a t -2OSC, w a s added 2 , 6 - l u t i d i n e ( 6 . 6 mL, 5 9 m o l ) . T h e s o l u t i o n was s t i r r e d f o r 1 0 min a t -20°C be fo re s l o w a d d i t i o n
cf c21i-bucLyldirnetnylsily1 trifluoromethanesulfonate ( 6 . 6 mL, 2 9
m r n c l ) . The s o l u t i o r , was s t i r r e d a t -20°C f o r 1 h, a f t e r wh ich i t
w a s warned t o 0°C. 1 2 0 rnL o f s a t u r a t e d NH.,Cl s o l u t i o n w a s added.
The aqueous p h a s e w a s s e p a r a t e d and e x t r a c t e d w i t h d i c h l o r o m e t h a n e
( 3 x 1 5 0 mL). The combined o r g a n i c e x t r a c t s w e r e w a s h e d w i t h 1 2 0
mi, o f 0 . 5 M K C 1 s o l u t i o n , a n d 1 2 0 mL of s a t u r a t e d b r i n e s o l u t i o n .
T h e a q u e o u s washes w e r e t h e n e x t r a c t e d w i t h d i c h l o r o m e t h a n e ( 3 x 50
m L i , and t h e combined o r g a n i c extracts were d r i ed o v e r a n h y d r o u s
Na,SO,, f i l t e r e d a n d c o n c e n t r a t e d in v a c u o . P u r i f i c a t i o n b y f l a s h
c h r o m a t o g r a p h y o n s i l i c a gel (20-705 ethyl a c e t a t e / h e x a n e s ) g a v e
t h e s i l y l e t h e r v i i i ( 1 0 . 9 g, 7 3 % ) as a pa l e y e l l o w o i l .
'H NMR ( 4 0 0 MHz, ~ ~ ~ 1 , ) 6 7 . 8 8 - 7 . 3 (9H, m) , 5 . 0 7 ( l H , t , J = 7 . 3 H z ) , 4 - 2 1
(lH, dd, J=10 .3 , 3 . 3 H z ) , 3 . 8 2 ( I H , dd , J=10.3, 3 . 3 H z ) , 3 / 6 6 (lH,
dd, J = 1 0 . 3 , 3 . 3 H z ) , 3 . 6 6 (lH, dd, J=7.3, 2.9 H z ) , 3 . 1 5 (ZH, m),
2 . 4 5 (3H, s ) , 2 . 3 6 (3H, s ) , 1 . 9 8 (3E, m ) , 1 . 5 4 (3H, s ) , 1 . 2 4 ( l H ,
m.), 1 . 0 8 (3E, s ) , 0 . 8 5 (9B, s ) , 0 . 0 8 (3H, s ) , 0 . 0 6 (3H, sl ; I3c NMR
( 1 0 0 MHz, C D C 1 3 ) 6 1 4 4 . 9 , 1 3 9 . 0 , 1 3 3 . 6 , 1 3 1 . 1 , 129.8 , 129.2 , 128 .0 ,
1 2 7 . 9 , 1 2 6 . 6 , 1 2 6 . 5 , 7 6 . 8 , 7 3 . 5 , 7 1 1 5 4 . 9 , 3 7 . 0 , 3 2 . 2 , 25.9,
2 3 . 1 , 2 1 . 8 , 21 .7 , 1 8 . 1 , 1 5 . 9 , - 4 . 0 , - 4 . 9 .
[2R,2 (2S,SR,5 (IS) ) j Benzenesulfonic acid 2-[5-(3-benzenesulfonyl-1-
hydroxy-l-methyl-propyl)-2-methyl-tetrahydro-furan-2-yl]-2-(1-
( ( 1 , l - d i m e t h y l e t h y l ) dirnethylsiloxy) -ethyl ester
viii
Vanady-l z c e t y l a c e t o n a t e ( 3 1 3 no, 1 . 2 mmol) and :A m o l e c u l a r s i e v e s
w e r e a d d e d t o a s o l u t i c n o f s i l y l e t h e r v i i i ( 4 - 8 g , 7 . 9 mmol) i~
4 8 m i of 3 : 1 heptanes /CHZCl2. The g r e e n s c l u t i o n i s s t i r r e d for 3 0
m i r ! a f z e r which t e r t - b u t y l h y d r o p e r o x i d e ( 2 . 8 6 mL of a 5 . 5 M
s o l u t i o n i n ciecane, 15 .71 mmol) , which had b e e n p r e d r i e d o v e r
m o l e c u l a r s ieves f o r 30 m i n , i s added d r o p w i s e . T h e d a r k p u r p l e
s o l u t i o n i s s t i r r e d for 1 2 h . At t h i s t i m e , the s o l u t i o n is a
b r i c k red, and a s e c o n d a d d i t i o n o f vanadyl a c e t y l a c e t o n a t e and
t e r t - b u t y l h y d r o p e r o x i d e (313 mg, and 2 - 0 6 mL r e s p e c t i v e l y ) i s made
t o r egenera te t h e p u r p l e c o l o u r - A f t e r anocher 1 2 h, p y r i d i n i u m
p a r a - t o l i l e n s u l f o n a t e ( 2 0 0 rng, 0 . 8 mmol) i s added. After 4 h of
stirring, the r e a c t i o n mixture i s p u r i f i e d d i r e c t l y b y f l a s h
c h r o m a t o g r a p h y on s i l i c a g e l (20-503 e t h e d h e x a n e s ) . F n
i n s e p a r a b l e m i x t u r e o f cis ix, a n d trans p r o d u c t s ( 3 . 5 g, 718) are
o b t a i n e d as a p a l e y e l l o w o i l i n a r a t i o o f cis t o t r a n s , 7 . 7 : l .
'H NMR ( 4 0 0 MHz, C D C ~ , ) ~ 7 .88-7 .30 (9H, m ) , 4 . S O (lH, dd, 5=10.6 ,
1.8 H z ) , 3 .78 (2H, m), 3.67 ( l H , dd, J=7.3 , 1 3 H z ) , 3 . 3 6 ( l H , ddd,
J=16.8, 1 2 . 5 , 4 . 4 H z ) , 3 . 1 8 ( l H , d t , 5=12.5, 8 . 1 H z ) , 2 . 4 5 (3H, s ) ,
2.20-1.50 (7H, s ) , 1 .16 (3H, s ) , 1 . 0 8 (3H, s ) , 0 . 8 5 (9H, s ) , 0.07
( 6 , s ) ; " C NMR (100 MHz, CDCI,)6 144 .8 , 1 3 9 . 1 , 1 3 3 . 6 , 132 .8 ,
1 2 9 . 8 , 129 .2 , 1 2 7 . 9 , 1 2 7 . 7 , 85.3, 8 4 . 0 , 7 5 . 9 , 7 2 . 9 , 71 .2 , 51 .5 ,
36-3, 2 9 . 8 , 25.8, 24.9, 24 .0 , 21.7, 20.7 , 1 8 - 0 , -3-9, -5.1.
69
[2S,2(2Rt5S,5(1R)) I I-iodo-(4-Benzenesulfonyl-2-15-(1-((1,I-
dimethylethyl) dimethylsiloxy) -ethyl) -5-methyl -tetrahydro-furan-2 - yl] -butan-2-01
OH OTBS
Nal, 2-butanone, 18-c-6 - reflux, 16 h
OH OTBS X
The mixture of ~etrahyarof u r a n y l ether ix and its diastereomer,
( 3 . 5 g, 5.6 mnol) w s s disolved in 12 mL cf 2-butanone before the
sdaicion of sodium iodide (8.4 g, 5 5 . 8 mmol) and 18-c-6 (1- 5 g, 5 - 6 m o l l . The slurry was heated t o a gentle reflux and stirred for I6
h, after which t h e s o l u t i o n was cooled t o room temperature, and 100
mL of saturated brine solution was added. The aqueous phase was
s e p e r a t e d and extracted w i t h ether (3 x 100 ml), dried over
a n h y d r o u s Na,SO,, and c o n c e n t r a t e d i n vacuo. Purification by f l a s h
chromaZography ( 2 0 - 5 0 5 ethyl acetate/hexanes) gave an inseparable
m i x t u r e o f c i s x , and c r a n s iodides ( 2 . 6 ~ 3 80%) as a pale y e l l o w
o i l .
[2s,2(2Rl5Sf5(1R)) 1 (4-Benzenesulfonyl-2- [ S - (1- ( (1,l-
dimethylethyl) dimethylsiloxy) -ethyl) -5-methyl-tetrahydro-furan-Z-
yl 1 -butan-2 -01
Bu3SnH, AlEN , toluene
OH OTBS OH OTBS
r
refl w. 6 h
The mixture of iodides were dissolved in 9.2 mL of toluene. First
tributyltin nydride ( 2 . 5 mL, 9 rnmol) , and then AIBN ( 1 8 - 5 mg, 0.14
mmol} were added, and the mixture was heated to reflux for 6 fi.
Direct purification by flash chromatography on silica gel (5%-30%
e~her/toluene) prov ided the desired cis isomer xi, (1.2 g, 59%) as
a colourless oil.
'H W R (400 MEz, c D c I J ~ 7.90-7.50 (SH, m ) , 3.78 (lH, t, J=7-3 Hz),
3.58 (IH, q, J=6.2 Hz), 3.32 (lH, ddd, J=4.4, 12.5, 16.8 Hz), 3.16
(lH, dc, J=4.8, 12.8 H z ) , 2.21 (1H, s ) , 2.00-1.50 (6, m) 1.09 ( 3 H ,
s ) , 1.07 (3H, s), 1.05 (3H, d, J=6.2 Hz), 0.85 (9H, s), 0.05 (3E,
S) , 0.03 (3H, s ) ; " C NMR (100 MHz, C D C ~ , ) ~ 139.1, 133.6, 129.2,
127.9, 85-0, 84.2, 73.0, 72.1, 51.6, 34.3, 29.6, 25.9, 25.5, 23-8,
20.5, 18-53, 18.0, -4.0, -4.5.
71
[ 2 S , 2 (2R) , SR, 5 (1s) ] -5- [3-Benzenesulfonyl-I- (trimethylsilyloxy) -I- methyl-propyl ] -2- (1 - ( (I, 1-dimethylethyl) dimethylsiIoxy) -ethyl) -2- methyl-tetrahydrofuran
OH OTBS
NEt3, TMSOTf
S02Ph qJ+ a+ OTMS OTBS
xii
First trietnylamine ( 0 . 9 7 mL, 41 mmol) and then trimethylsilyl
trif Iuorornechanesulfonate ( 0 . 6 5 mL, 3 . 3 6 rnrnol) w e r e added to a
solution of alcohol xi in 1 8 mL of dichloromethane at -78OC. After
3h of scirring at - 7 8 " C , 1 mL of methanol was added to the reaction
mixture. The solution was then warmed to room temperature and 100
rnL of saturated brine solution was added. The aqueous phase was
seperaiea, extracted with dichloromethane (3 x 200 mL), dried over
a n h y d r o ~ s N a , S O , , fil terea, and concentrated in vacuo, Purification
by flash chromatcgraphy on silica gel (20-40% ethyl acetate/hexanes
w i t h 5 % triethyl mine) gave fragment xii as a colourless oil (1.3
g, 9 3 % ) .
'H NMR ( 4 0 0 MHz, CDCl,)6 7 .90 -7 .50 ( S H , m ) , 3 . 6 5 (lH, t, J=7 - 0 H z ) ,
3 . 4 3 (lH, q, J=6.2 Hz) 3 . 2 0 (2H, m), 1 . 9 5 - 1 . 5 0 (6H, m ) , 1 . 0 6 (3H,
s ) , 1 - 0 0 (3H, s ) , 0 . 9 9 (3H, d, J=6.2 H z ) , 0 . 8 4 (9H, s ) , 0 . 0 2 (3H,
s ) , - 0 . 0 1 (9H, s ) ; I3c NMR (100 MHz, CDc13)6 1 3 9 . 1 , 1 3 3 . 4 , 1 2 9 . 1 ,
1 2 8 . 0 , 8 5 . 7 , 82 .8 , 7 5 . 7 , 73 .4 , 5 2 - 0 , 3 5 . 9 , 32 .7 , 2 6 . 3 , 2 5 . 8 , 23 .0 ,
1 8 . 9 , 18.4, 1 7 . 9 , 2.4, -3 .9 , - 4 . 8 .
1-Colucci, J. Ph. D. Dissertation, University of Toronto, 1997
2. (a) Hashimoto, M. ; Harigaya, H. ; Yanagiya, M. ; Shiragama, H I J. Org. Chem. 1991, 56, 2299 (b) Wuts, P. G. M.; D'Costa, R. Butler, W. J. Org. Chem. 1984, 49, 2582 (c) Hanessian, S.; DeHoff, B.; Sakito, Y. J. A m . . Chem. Soc. 1990, 112, 5276
3.Umbreit, M. A*; Sharpless, K. B. J. Am. Chem. Soc. 1977, 99, 5526
44a) Julia, M.; Paris, J-M. Tetrahedron Lett. 1973, 14, 4833 (b) Kocienski, P. J. ; Lythgoe, B.; Waterhouse, I. J. Chem. Soc., Perkin Trans. I 1978, 829
5.(a) Molander, G. A.; Hahn, G. J. Org. Chem. 1986, 51, 1135 (b) Smith, 111, A. B. ; Hale, K. J.; McCauley, Jr., J. P. Tetrahedron Lett. 1989, 30, 1037
6.Pine, S. H.; Shen, G.; Bautista, J.; Sutton, Jr., C . ; Yamada, W-; Apodaca, L. J. 0rg. Chern. 1990, 55, 2234
TArnett, E. M.; Maroldo, S. G . ; Schriver, G. W.; Schilling, S. L.; Troughton, E. B. J. Am. Chem. Soc. 1985, 107, 2091
8.Ga0, Y. ; Hanson, R. M. ; Klunder, J. M. ; KO, S . Y . ; Masamuni, H-; Sharpless, K. B. 3. Am. Chem. Soc. 1987, 109, 5765
9-Colucci, J. Ph. D. Dissertation, University of Toronto, 1997
lO.Krishnamurthy, S.; Brown, H. C. J. Org. Chem. 1980, 45, 849
l S t , W. C.; Kahn, M.; Miltra, A. J. Org. Chem. 1978, 43, 2923
12.Trost, B. M.; Curran, D. P. Tetrahedron Lett. 1981, 22, 3455
13.Umbreit, M.A.; Sharpless, K.B. %Am. Chem. Soc. 1977, 99, 5526
14.Umbreit, M.A.; Sharpless, K.B. % A m . Chem. Soc. 1977, 99, 5526
15.0ehlschlagerf A. C.; Wong, J. W.; Verigin, V. G.; Pierce, H- D. Jr. J. Org. Chem, 1983, 48, 5009
16.0ehlschlager, A. C * ; Wong, J. W.; Verigin, V. G , ; Pierce, H. D. Jr. J. Org. C h m , 1983, 48, 5009
17.Ga0, Y.; Hanson, R.M.; Klunder, J.M.; KO, S.Y,; Masamune, H.; Sharpless, K. B, J, Am. Chem. Soc. 1987, 109, 5765
18.Coluccif J. Ph. D. Dissertation, University of Toronto, 1997
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