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The Development of New Oxabicycle-Based Strategies for the Synthesis
of Tram-Fused [43.0], [ S A @ ] Bicycles and Derslin-Derived
Tricycles with Diverse Functionalities
A thesis submitted in confonnity with the requirements
for the degree of Master of Science
Graduate Department of Chemistry
University of Toronto
O Copyright by Jianqing Chen (1999)
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The Development of New Oxabicycle-Based Strategies for the Synthesis
of Trans-Fused [43.0], [SA01 Bicycles and Decalin-Derived
Tricycles with Diverse Functionalities
ubmitted in confonnity with the requirements
for the degree of Master of Science
Graduate Department of Chemistry
University of Toronto
1999
ABSTRACT
The oxabicyclo[2.2.1] aldehyde and methyl ketone were examinecl in S a - , -
promoted radical cyclization reactions. Both gave a cyclued product but the subsequent ring
oprning did not take place. These results suggested that the radical intemediate produced in
the cyciization was not reactive enough to trigger the ring opening even in the presence of
additional equivalents of Sm&.
Anionic cyclization and ring opening reactions of oxabicyclo~.2.1], 13.2.11 and
oxatricycl0[6.2.1.~~] systems were dso studied. The oxabicyclo[2.2.1], [3.2.1] and
oxatricyc10[6.2.1.@~] stannanes were prepared from the corresponding aldehydes by n-
BusSnLi and MOMCl(2 steps) in good yields.
The anionic intramolecuiar ring opening of these stannane compounds by MeLi via
tin-lithium exchange and anionic cyclization was efficicent and occurred in g w d yields.
B icyclo[4.3.O 1, [5 -3.0 ] and decaiin-derived tricyclo systems were generated with complete
regio- and stereocontrol except at the carbon bearing the MOM group.
The primary objective of this study was to detennhe the mctivity of oxabicyclic
compounds in anionic ring closing-ring opening reactions, in particular the effect of
substitution on the carbanionic carbon which initiates the cyciization sequence. Trans-hsed
l4.3 .O], [5.3 .O] bicycles and decalin-derived tricycles with diverse fiuictionalities were the
desired products of this sequence.
Foliowing the successful synthesis of oxabicyclo[S.S.l] aldehyde and methyl
ketone substrates, the first objective was to explore the scope of S$-promoted radical
cyclization on the substrates. The investigation was mdy focused on the possibiities of
wheather the oxabicyclo[2.2.1] substrats could uadergo radical cyclization and sequential
tandem ring opening to forrn the tram-fused 14.3.01 bicycles with diverse fuoctionalities.
The reactivity of Sm& in different temperature and solvent system(THF/HMPA) were also
studied in the processes.
The second objective was to investigate the possibility of anionic cyclization of
oxabicyclo[2.2.1] aldehyde substrate via stannylation and tin-lithium exchange to initiate the
ring opening and form the trans-hsed [4.3.0] bicycles with diverse functionalities. The
emphasis was placed on the synthesis of a-alkoxy stannane fiom the cornpondhg
aldehyde and the reactivity of the staamne in anionic cyclization and sequential ring
opening reac tions.
Our third objective, the synthetic methodology of oxabicyclo[6.2.1.0 r7] stannane
substrate was exploited to fhd a convergent and practical way to prepare this khd of
compound. The reactivity of oxabicycl0[6.2.l.O *'] stannane in anionic cyclization and
sequential ring opening reactions was also investigated to extend the xope of the reaction.
Finaliy, as part of our effects directed toward the total synthesis of phorbols vce
intended to demonstrate the synthetic strategy on the oxabicyclo~.2.1] substrate to fom
trans-fused [5.3.0] bicycles with diverse functionalities. Syntheses of [3+4] cycloadduct,
oxabicyclo[3.2.1] aldehyde and stannane were investigated. The reactivity of the stannane in
anionic cyclization and ring opening reactions were also studied.
Acknowledgements
First of all, 1 would like to express my gratitude to Professor Mark Lautens for bis
guidance, insight and encouragement throughout my course of study, and for giving me this
opportunity to work in his group. His support and encouragement helped me qWckIy
familiarize myself with a dynamic and advanced academic environment I have learned a
great many things from him, both in chemistry and in the general life.
1 would Iike to thank Arjan Van Oeveren, Eric F i o n , Nicholas Smith, John Colucci,
Tom Rovis, Greg Hughes, Gilliane Bouchain, Masanon Tdchoto, Keith Fagnou, Valentin
Zunic, Sheldon Hiebert, John Mancuso, Ti Stammers, Wwseok Han and whole Lautens'
group for the fkiendship, support, advices and many helpfui discssions throughout the
project.
1 would also like to thank al l the Department staff that 1 came in contact with, for
their invaluable help, in particular Dr. Patricia Aroca-Oullette and Dr. Tim Burrows for
NMR help, Dr. Alex Young for mass spectrometry assistance, and Dr. Alan Lou& for X-
ray crystdographic analysis. Thanks to Dariene Gorzo for ali of her help with
administrative things. The chem Club is thanked for providing many interesthg activïties
and an enriched life in the department.
And the last but not the least, University of Toronto and the Department of
Chemistry are thanked for financial support.
To my wife Lu Li and my son KangLi, without whose love and support
this would not be possible.
Table of Contents
Abstract
Objectives
Acknowledgements
Dedication
Table of Contents
List of Abbreviations
List of Tables
INTRODUCTION
5 1. Synthetic Strategies Based on Sm&-Romoted Radical Cyciization
5 1.1. History and Background
*-
Il
.-. Ill
v
vi
vn X
xii
1
1
1
5 1.2. Strategies Based on Oxabicyclo[2.2.1] Aldehyde and Methyl Ketone Substrates 7
$ 2. Synthetic Strategies Based on Tin-Lithium Exchange and Anionic Cyciization 10
5 2.1. History and Background 10
5 2.2. Strategies Based on the a-Alkoxy Stannanes 13
RESULTS AND DISSCUSION
5 1. Preparation of the Oxabicyclo[2.2.1] Aldehyde Derivative 16
5 2. Attempts to Synthesize [4.3.0] Bicycles by S$-Promoted Radical Cycbt ion 17
6 2.1. Preparation of 0.1 M Sm& Solution in THF 17
5 2.2. C2.2.11 Oxabicycle Aldehyde Substrate
5 2.3. [2.2-11 Oxabicycle Methyl Ketone Substrate
5 2.4. Summary
Q 3. Anionic Intmnolecular Ring Opening of an Oxabicycio[Z.S. 1 .] Compound
5 3.1. Preparation of 0.34 M n-BhSnLi Solution in THF
5 3.2. Preparation of a-Aikoxy Tnbutylstannane Intermediate
5 3.3. Tin-Lithium Exchange and Anionic Cyclizattion
9 3.4- Confirmation of Two Isomeric Cyclized Roducts
$3.5. Summary
Q 4. Anionic Intramolecular Ring Opening of an OxatrïcycIo[6.2.1 .O "1 Compound
5 4.1. Attempt with Aldehyde intermediaie
5 4.2. Attempt with Aldehyde Acetal Intermediate
5 4.3. S ynthetic Route with a-Alkoxy Tributylstannyl Furan Derivative
5 4.4. Attempts to Hydrolyze the MOM-Group and Protect the Tertiary Alcohol
5 4.5. Reduction of the Cyclized Compounds
9 4.6. Summary
8 5. Anionic Inîramolecular Ring Opening of an OxabicycioP.2.1.] Compound
§ 5.1. [3+4] Cycloaddition
Q 5.2. Preparation of Aldehyde Intermediate
5 5.3. Preparation of an a-Alkoxy Tributylstannane intermediate
5 5.4. Tin-Lithium Exchange and Anioaic Cyclization
5 5.5. Hydrolysis of the MOM-Group in the Cyclized Products
5 5.6. Summary
EXPERIMENTAL SECTlON
General Experiments
Solvents and Reagents
Experiments
REFERENCES AND NOTES
APPENDIX 1 SELECTED SPECI'RA OF REPRESENTA'ITVE COMPQUMIS 9 1
APPENDIX 2 X-RAY CRYSTAL DATA FOR COMPOUND 43.44
Single Crystal X-Ray Detennination of 43
Single Crystal X-Ray Determination of 44
List of Abbreviations
Ac
Bn
Ca.
calcd
DHP
dr
DIB AL-H
DMPU
DMF
DMS
E
e9
E;T
GC
HMPA
HRMS
i-Bu
i-Pr
IR
LA
LDA
L-Selectride
LUMO
Me
MOM
acetyl
benzvl
appmximately
calculated
dihydropvran
diastereoisomeric ratio
diisobutylaluminum hydride
1,3-dimethy l-3,4,5,6-tetrahydro-2(1 H)- pyrimidinone
NB-dimethy lformamide
dimethyl suifide
generic ester group
equivalent
Fourier transform
gas chromatography
hexamethylphosphoric triamide
high resolution mass spectmm
isobuty 1
isoprop y1
infrared
Lewis acid
lithium diisopropyl amide
lithium tri-sec-butyl borohydride
lowest unoccupied moiecular orbital
methyl
methoxymethyl
mP
Ms
n-Bu
NMO
NMR
P
PDC
Ph
PETS
PY=
R
It
TBDMS
t-B u
Tf
TFA
TEIF
THP
TLC
TMEDA
TMS
TPAP
p-TS
X
melting point
mesyl, methanesulfonyi
n-butyl
4-methylmorpholine N-oxide
nuclear magnetic resonance
generic protecting p u p
pyridinium dichromate
phenyl
pyridinium ptohenesulfonate
pyridine
generic alS.1 p u p
room temperature
tert-buty ldimethy lsilyl
te#- butyl
trifluoromethanesulfony 1
trifiuoroacetic acid
tetrahydtofuran
te@ahy*pyran
thin layer chromatography
tetrame thylethy lene diamine
trimethylsily 1
tetrapropylammoniurn pemthenate
p-toluensulfony l
generic halogen atom
List of Tables
Table 2.î Sa-promoted radical cyciizattion of [2-2-11 aldehyde substrate
Table 3.1 Anionic cyclization of L2.2.11 substrates
Table 4.1 Acetalization of furan aldehyde
Table 4 2 Diels-Aider reactions of furan aldehyde acetd
Table 4.3 Anionic cyclization of [6.2.l.O "1 substrate
Table 4.4 Attempts to pmtect the tertiary alcohol
Table 4.5 Hydrogen transfer reduction of vinyl group
INTRODUCTION
9 1. S ynthetic S trategies Based on Sm.&-Promoted Radical Cyclization
8 1.1. History and Background
Samarium diiodide (Sm13 was first introduced by Kagan and coworkeal in 1980
as a selective one electron transfer reagent in organic chemistry. It has rapidly become
the standard for a variety of individual reductions2 and reductive coupling reactions'. The
versitility of the reagent makes it an ideal candidate for sequential processes. Both radical
and anionic reactions (e.g. radical cyclizations, ketyl-olefin coupling reactions and
carbonyl addition reactions etc.) are observed in yields and selectivities usually superior
to those using more traditional reductants. Moreover, the reactivity and/or selectivity of
Sm& can be modified by the addition of catalysts4, by solvent effecd, by photochernical
enhancement6, or through other modification of the reaction conditions7. Furthemore, in
appropriately designed substrates, sequential reactions involving diverse intermediates
can be carried out in any orde?, for example, sequential radical reactions have been
developed, anionic cascades are feasible, and both radicdanion and aniodradical
domino processes have k e n reaiized. This is a broad research area which had attracted
interest from many groups all over the world.
Here, we will bnefly review some related advances in the area of SmI,-promoted
radical cyclization and sequential tandem reactions. A variety of Sn&-promoted radical
cyclization reactions have attained synthetic importance owing to their high
stereoselectivity and the ability to undergo sequential reaction~?~* l0
Radical addition reactions that terminate in an elimination process comprise
perhaps the simplest example of a sequenced radical process. For these reactions the
cyclized radical initiaiiy forrned subsequently undergoes reduction to an organosamarium
species, inducing the fkiimination process. The elimbation does not necessary increase
molecular codexity, but cm be utilized to retain functionality in the final product and to
convey stereochemical ùiformation in the process.
Different leaving groups have been used in the eliminating component. In studies
of alkyl radicals derived from carbohydrate precursors, both acetates and hydroxy groups
have been utilized (eq 1-2)." Interestingly, no h i idna t ion occurs at the initial reaction
center which indicates the cyclization is clearly a radical process. In the case of allylic
alcohol acceptors, the generation of a Lewis acid species undoubtedly facilitates
departure of the normaUy reluctant hydroxy leaving group. The overall process results in
an efficient, enantiocontrolled synthesis of highly functionalized cyclopentane
derivatives.
4 Smlp
- - OH THF, HMPA, MeOH - -
-78 OC, 2 h; O OC, 1.3 h
A good leaving group has been employed for a two-fold purpose in an unusual
cyclooctenol synthesis employing a Smk-promoted cyclization/elimination sequence.12
Initial studies in cyclooctenol syntheses demonstrated the feasibility of an 8-endo ketyl-
olefin cyclization with unactivated aikenes. Yields in these initiai studies were modest.
That the process occurred at ali could be ascnbed to the persistence of the ketyl radical
anions generated under the reaction conditions.Thus, ke tyl radical anions are postulateci
to form reversibly in the presence of s~I , ." Additionally. these radical anions do not
undergo further reduction. Furthemore. ketyls are not particularly prone to quenching by
hydrogen atom abstraction from the solvent. disproportionation, or other means.'*
Consequently, the lifetime of these species is significantly enhanced as compared with
less highly stablized radicais. The combination of these features is apparently unique to
the Sm&-promoted processl' which provides a pseudo-dilution effect for the generation
of the ketyls and an adequate Lifetime for the slow cyclization to take place. To improve
the yields, it was rationalized that electron-wiîhdrawing groups on the alkene or at the
dy l i c position would enhance the cyclization rate of the reaction by lowering the LUMO
of the alkene radical acceptor. This tumeci out to be the case. By choosing a group that
aIso served as a leaving group afier the cyclization event, hnctionality was also retained
in the newly formed ring (eq 3).
Epoxides have also served as effective "leaving groups" in radical
cyclization/fiagmentation processes (eq 4-6).16 The use of the allylic alcohol epoxides as
radical acceptors retained not only the double bond, but also an alcohol for tùrther
functioalization. Enantioselective syntheses were achieved by utilizing readily available,
enentiomerically pure epoxides for the reactions. Interestingly, the reactions were
completely diastereoselective with regard to stereocenten created at the olefin (compare
eqs 5 and 6). Unfortunately, the method appears to be limited to 5-exo cyclizations.
2 Sm12 - THF, HMPA, R " " 6 0 " ( 6 )
It is noted that only a single radicalhadical sequential
has been reported (eq 7)."
process promoted
1. Sm12, THF, DMPU, O OC
O 2. p-TSA, acetone
Much more cornmon are sequential cyclizationlnucleophilic addition or - substitution reactions. In these processes the radical generated upon cyclization is
reduced under the reaction conditions to generate an organosamarium species. The later
have been trapped intramoiecularly by a pendant electrophile. Altematively, electrophiles
can be added to the reaction mixture to quench the resulting anion. Both alkyl and ketyl
radicals have been employed as intermediates in the first step of these reactions.
One of the more successful classes of substrates for sequential radical
cyclization/nucleophilic sequences with Sm[, are aryl halides (Scheme 1).""
Scheme 1
70%
55%
I
THF, HMPA
1 76%
PhNCO J d 0 w m
' O
Aryl radicals are reasonably resistent to reduction by SmI,,'' providing them with
an adequate lifetime for cyclization. Furthermore, acyl radicals cyclize in a 5-exo mode
with measured rate constants of up to 4 x 109 s- ' . '~~ The combination of these two factors
provides for a reasonably generai cyclization process. There are. however, some
limitations in the overail process. For exarnple, only pnmary and secondary radicais
generated in the cyciization process can be reduced to organosamariums. Furthermore,
the lack of nucleophilicity of the resulting organosamarium species limits the cascade
process to some degree. Thus allylic halides, benzylic halides, epoxides, ethyl
bromoacetate, acetonitrile, and aLkylating agents fail to undergo reaction in acceptable
yields." Carboxylic acid chlorides, TMSCI, and TsCl also fail to react, presumably
because they facilitate the ring opening of THF under the reaction conditions." in spite of
the limitaions, a number of electrophiles have been trapped by the organosamarium
intermediate, leading to a versatile process for the elabdation of dihydrobenzofurans.
As stated above, the organosamarium species generated in sequential processes
reacted with only a limited number of electrophiles. Extension of the range of
electophiles that c m be utilized in Su&-promoted sequentiai reactions has been achieved
by transmetdation to the corresponding organocopper species (eq 8):' Utilizing this
strategy, a$-unsaturated ketones have been employed as the terminating electrophiles.
trapping the organoçopper species in a conjugate addition reaction.
1.2.1 Sm12, THF, HMPA ' / 2. CuBr. OMS
O 3. Methyl vinyl ketone ' 0 TMSCl
92%
Five-membered ring cyclizations are
embered rings can also be generated pro
sufficientl y rapid (eq 10- 1 l)?
the most efficacious (eq 9) , but six-
lvided the 6-exo cyclization rates are
S
?Y- 1.2.2 Sm12, THF, HMPA
2. PhSeSePh ' "8'
1.2.2 Sm12, THF, HMPA
2. PhSeSeeh
O
k 1.2.2 Sml2, THF, HMPA
2PhSeSePh ( 1 1 )
H H
5 1.2. Strategies Based on Oxabicyclo[2.2.1] Aldehyde and Methyl Ketone Substrates
The presence of cyciic components in natural products has led ring construction
via cyclization reactions to be one of the most studied and uulized strategies in organic
synthesis. Cyclization reactions c m be classified into four main types, those involving
cationic, radical, anionic and metai complex intermediates which may be stable species or
transien t intermediates.=
Recently, Sd,-promoted radical reactions showed great potential in the syntheses
of many polycycles, and the full potential of the reaction has not been realized. Motivated
by the examples iisted above, we designed the oxabicyclo[2.2.1] aldehyde and methyl
ketone substrates to test the Sm1,-promoted radical cyclization and sequential ring
opening reaction. The possible pathways of the reactions are shown in Scheme 2.
Scheme 2
OMe
target products
,4 ,
#
#
Oxabicyclo[2.2.1] substrates are common substrates in the syntheses of many
poIycycles using an anionic/anioaic processes developed in our group. We wanted to see
if it is possible to undergo a radicaVradica1 or radicaVanionic sequential process by Sr&-
promoted radical cyclization with these substrates. The research wiii be initiaily canied
out with three carbon tethered aldehyde because the 5-exo cyclization is most favored.
The differences between two substrates oxabicyclo[2.2.1] aldehyde and methyl ketone
will also be examined.
The reactions may undergo a radicdradical sequences or a radical/anionic
sequences. W e hoped that both or either of the pathways may lead to the target products.
tram-fused 14-3-01 bicycles with diverse functionalities. If it becomes possible, this route
have the foilowing advantages: 1) It is very efficacious. Three steps cm be finished in a
one-pot process and many functionaiities are produced or retained in the reactions. 2) It is
highly stereoselective. A transfused hydroindene may be formed and probably only one
HO-isomer wili be produced in the cyclization because of the selectivity of Sm[,.
If this is not possible, we thought b a t the organosamarium intermediates could be
trapped by diphenyl disulfide. Foilowing the synthetic route shown in Scheme 3. the
sulfides could be oxidized by OXONE to form the corresponding sulfone and cleaved by
basic alumina. It may still be possible to obtain the target products by this less direct
route.
Scheme 3
R = H; CH3
target products
5 2. Synthetic Strategies Baseci on Tin-Lithium Exchange and Anionic Cyclization
2.1. History and Background
Anionic cyclization is a common approach to ring construction. The most
frequently used strategy involves the intramolecular attack of an anionic species on an
electrophile via an SN^ or SNT r e a ~ t i o n . ~ ~ A vast array of nucleophiles and electrophiles
have been utilized in the anionic cyclization reaction. We were particularly interested in
the cyclization of reactive anionic centers ont0 unactivated olefinic bonds, mainly due to
growing interest in this field and its unexploited potential in organic synthesis.
The anionic cyclization onto unactivated olefinic bonds remained, until very
recently, unprecedented. In the 19Ws, and 70's, some authors reported the cyclization of
organomagnesium,~ ~ r ~ a n o a l u m i n i u r n , ~ ~ ~rganoli thiurn,~~ and organornerc~q?~ onto
unactivated 01efins.~~ In these primary snidies. the main problems were associated with
the generation of the initial alkenylrnetal.
In 1987, Bailey and coworkers reported the generation of aiicenyUithiums and their
cyclization products (Scheme 4).' It was shown that the treatment of 6-iodo-1-hexene
with t-BuLi in pentaneEt20, with or without TMEDA at -78 OC, quantitatively effected
lithium-iodide exchange to give an organolithium which cm be trapped by various
electrophiles. On wanning to room temperature, however, the anion cyclized in a 5-exo-
trig fashion thus affording an anion which can subsequently be trapped by electrophilic
species. Bailey extended this preliminary work to tandem carboiithiation reactions for the
construction of complex carbocyclic compounds? The group of Bailey unequivocaüy
proved the anionic nature of the reaction rather than a radical cyclization process followed
by a second electron tran~fer?~
Scheme 4
Substituted tetrahydrofurans were prepared by Broka and coworkers by anionic
cyclization of a-alkoxy anions ont0 unactivateci olefins (Scheme s)." The aLkenyIlithium
was generated fiom the alkenyltin via tin-lithium exchange. The reactions were highly
diastrereoselective but iimited to the utilization of terminal olefins; 1,2-disubstituted
olefins being inert to the carbolithiation reaction. They improved the efficiency of the
reaction by performing the cyclization ont0 allylic ethers. For example, when 1 was
treated with n-BuLi, the tetrahydrofuran derivative 2 was generated in high
diastereoselectivity via an S@ reaction with concomitant lost of lithium methoxide and
formation of a terminal olefin.
Scheme 5
n-BuLi, THF e ml-kx dR O
-78 OC tO O OC R = H, 54%, predominantiy ci3-isomer R = Me, no cyclized product observed
*BuLi, THF
Lautens and Kumanovic have reported the intramolecular anionic ring opening of
oxabicyclo[3.2.1] systems as a route to bicyclo[5.3.0]decenes (Scheme 6)." The
generality of this methodology was demonstrated by using a variety of tethered
oxabicyclic cornpounds. The organoiithium was generated either from the iodide or
tributyltin derivatives 3. The most important feature of this cyclization is the exclusive
attack from the ex0 face leading to rrans-fused bicyclo[5.3.O]decenes 4 bearing a textiary
alcohol.
Scherne 6
Lautens and Fillion have also extended the scope of the reactions to
oxabicyclo[2.2.1] systerns to synthesize the [4.3.0] bicycles? Similarly, the organolithium
was generated either fkom the iodide or tributyltin derivatives. The cyclization of 5-
membered rings were very effective (80-83%), but the cyclization of 6-membered rings
seemed quite difficult and the cycclied product was obtained in 25% yield. The two-
carbon tethered iodide produced the spiro 15.2.01 bicycle 5 in 62% yield when treated with
r-BuLi. Interestingly, when oxabicyclo [S.S. l] butyronitrile was reacted with KHMDS at
rt for 1 h, selective production of the oniy W N isomer 6 occurred in 34% yield (Scheme
7). This is the fmt example of carbopotassiation reaction in an anionic/anionic processes
using a stablized anion.
Scbeme 7
5 2.2. Strategies Based on the a-Alkoxy Stannanes
From the results stated above and the expertise developed in our laboratones, we
were interested in fiuther exploring the anionic cyciization of oxabicyclo [2.2.1], [3.2.1] and
oxatricyclo[6.2.1.0 2*7] systems to prepare the tram-fused [4.3.0], [5.3.0] bicycles and
decalin-derived tricycles with diverse functionalites, especially the products bearing
hydroxy groups next to the bridgehead carbons (Scheme 8).
Scheme 8
5 6 /
&OMe H@>oMe HO OMe 8
OH OH 9 3
OH 2 3 2 1 (OH)
Here in particular, we want to mention that the 5,7-fused ring system is found in
many natural products? A recent review on sesquiterpenes States that of the more than
500 new sesquiterpenes, about 100 possess the 5,7-fused ring fram~ork.~' Interesting
biologicai activity has been found in phorbols (tumor promoting), daphnanes and
grayanoxins (Scheme 9). So the tram-fused [5.3.0] bicycles bearing hydroxy groups at
C-1 and C-3 are mostly interested since selective oxidation and fklimination would
yield the enone found in the phorbols.
Scheme 9
P horbol Oaphnane Grayanotoxin
Still reported that alkyl-substituted a-ailcoxy organolithium reagents can be
prepared in high yield from the corresponding aldehydes via an a-alkoxy organostannane?
Tributylstann y llithium is prepared from tributyl tin hyàride and lithium diisopropy lamide.
Addition of tributylstannyllithium to an alkyl or aryl aldehyde yields an a-hydroxy
stannane (RCH(OH)Sn(n-Bu),) which is then protected with a-chloroethyl ethyl ether to
give the ethoxyethyl derivative in >90% yield. On treatment with n-butyllithium, the
corresponding a-alkoxy organolithium reagent (RCH(0R')Li) is formed. These reagents
may incorporate a variety of conventional hydroxy protecting groups and are synthetically
useful.
We thought that if we can use the corresponding aldehydes to prepare the
organolithium reagents via stannylaaon, protection and tin-lithium exchange and to
initiate the intramolecular anionic/anionic processes, the potential 1-(or 3-)hydmxy group
should be readily furnished in the molecules. After hydrolysis the fiee hydroxy group
could be obtained. So we designed a synthetic route shown in scheme 10 as the general
procedure. Our goal was to prepare the target products starting fiom corresponding
aldehydes via an anionic cyclization and sequential ring opening reactioas.
Scbeme 10
OMOM
hydrolysis MOM -------------a- *
OH
RESULTS AND DISSCWSSION
8 1. Preparation of the Oxabicyclo[2.2.1] Aldehyde Denvative
3-Bromo- 1-propanol was protected as its THP derivative 7 and reacted with 2-
lithiofuran at O OC to give the alkylated furan 8 in 92% yield (Scheme 1.1). The hiran
denvative 8 was reacted with maleic anhydride at rt for 12 h to give the anhydride
cycloadduct via Diels-Alder reaction which was readily reduced to the di01 9 after
reaction with L i m in THF. The exo dioi was observed as the major product and the
minor endo di01 (<IO%) was easily removed by column chromatography. The diols were
isolated as equimolar mixtures of inseparable diastereomers, due to the presence of the
THP protecting group on the furan moieties. The di01 9 was deprotonated using NaH and
Scheme 1.1
1) DHP, PPTS, CH& Br-OH * n,-,OTHP 1) y y a
O 2) LiAIH4, THF
8 92%
NaH, THF
F o y Y - PPTS, MeOH
THPû THPO
g 52% 10 83%
Dess-Martin
11 81% 12 99%
methylated to yield the dialkoxide 10 in 83% yield. The THP ether was cleaved using
PPTS/MeOH to give the frre alcohol 11 in 81% yield? The alcohol 11 was oxidized by
the Dess-Martin reagent to give the key oxabicyclo[2.2.1] aldehyde intermediate 12 in
99% ~ i e l d ? ~
From this synthetic route, the oxabicyclo[2.2.1] aldehyde 12 bearing a three-
carbon tether is available in 7 steps starting fiom furan via a Diels-Alder reaction.
5 2. Attempts to S ynthesize 14.3 .O 1 Bicycles by Se-Promoted Radical Cyclization
5 2.1. Reparation of 0.1 M Sm12 Solution in THF1
Sm powder (2 eq) was heated in a flask with a flame, then THF and 1,2-
diiodoethane (1 eq) were added at rt with stirring. After 3 h a dark blue solution of SmI,
(0.1 M) was formed which was used directly in the next step. The SmI, soiution can be
stored at 4 OC for about one week but better results were obtained with freshly prepared
solutions.
Scheme 2.1
THF Sm + ICH2CHd (0.iM) Sm12
5 2.2. 12.2.13 Oxabicycle Aidehyde Substrate
The [2.2.1] oxabicycle aldehyde 12 was treated with Sd, (1.48 eq) in THF and
HMPA (12 eq) at rt to give a cyclized compound 13 in 28% yield as a single isomer
(Scheme 2.2).""' Possibly it was a-OH isomer but this was not rigorously proven.
Clearly it was not the desired compound, because the bridging C-O bond was still
present.
Scheme 2.2
/ OHC
12
Sm12 (1.48 eq), THF
HMPA (1 2 q), -78OC HO, ,.
In order to promote the ring opening, additional equivalents of Sm12 were added
to the r e a c t i ~ n . ' ~ When SmI, (2.2 eq) and HMPA (8 eq) was used. and reacted at rt, a
dimer (based on a peak in the MS at 479, structure unknown) was formed. The 'H NMR
and "C NMR spectra of the cornpound were not clear enough to elucidate the structure.
Further oxidation of the produced dimer with TPAP showed no reaction.
When 12 was treated with SmI, (2.5 eq) in THF and HMPA (12 eq) at -78 OC the
cyclized a-OH isomer 13 was formed but in only 37% yield. If HMPA was omitted, the
yield of the cyclized compound was very Iow (4%). A cornparison of the effect of
additives is shown in table 2.1.
Table 2.1 S~2-pmmoted radid cyclization of [2.2.1] aldehyde substrate
entry substrate condi tionsa products yieid
1 12 Sm-&( 1.48eq), HMPA(12eq), -78 OC 13 28%
4 12 Sm12(2.Seq), -78 OC to rt 13 4% a THF was u s 4 as solvent in ail the reactions.
To c o d m that only one isomer was produced in the reaction, 13 was oxidized
using TPAP to give the ketone compound 14 which upon reduction by NaBH, gave 15
in 6395 yield (Scheme 2.3)." The reaction was very selective and gave only one product
which we assigned to the p-OH isomer. The Ievel of the selectivity observed in the
reduction indicates that the accessibility of two faces of the ketone are very different,
probably due to the rigidity of the bicyclic skeleton.
Scbem 23
TPAP, NMO
Attempts to trap the radical intermediate with PhSSPh was not successful."
In the original literature, the subtrates used in the Sd,-promoted radical
cyclization were ketone olefin compounds, we thought that the methyl ketone substrate
may be better than the aldehyde substrate.
5 2.3. [2.2.1] Oxabicycle Methyl Ketone Substrate
The oxabicyclo methyl ketone 17 was prepared from ddehyde 12 by reaction
with a grinard reagent CH,MgI (2 eq) to give the secondary alcohol 16 in 46% yield
which was not optimized? Oxidation by the Dess-Martin ragent led ?o 17 in 85% yield
(Scheme 2.4) ?9
Scheme 2.4
Des-Martin
17 85%
The Sd,-promoted radical cyclization reaction was carried out using SmI, (2.2
eq) in THF and HMPA (20 eq) at rt for 1.5 h. One isomer (a or &OH isomer, possibly
OH isomer) 18 was obtained but in only 10% yield (Scheme 2.5).IUt And the bridging O
bond was still intact based on 'H m. Scheme 2.5
Smlz, HMPA
THF, rt
Although the number of the substrates examineci was limited the results showed
that neither the radical intermediate nor the subsequent organosarnarium species formed
upon transfer of a second eIectron was not reactive enough to cleave the bridging C-O
bond even when additional equivalents of Sr& were used in the reaction.
5 2.4. Summary
In this section, oxabicyclo[2.2.1] aldehyde and methyl ketone were examined in
Sm&-promoted radical cyclization reactions. Both substrates were cyciïzed but the
subsequent tandem ring opening did not take place. The olefin underwent
carbometaUatioa and the bndging C-O bond was stili present. These results primarily
suggested that a different metal was needed to trigger the ring opening reaction.
5 3. Anionic Intrarnolecular Ring Opening of an Oxatricyclo[2.2.1.] Compound
5 3.1. Preparation of 0.34 M n-Bu,Sdi Solution in THF
Method A: Using the procedure developed by Still.)8 the preparation of a solution
of n-Bu,SnLi in THF was attempted. Hexabutylditin and n-butyl lithium (Scheme 3.1)
were mixed at O OC, but the resulting n-Bu,SnLi solution gave poor results when reacted
with aldehyde 12.
Method 8: Wr2NH + n-BuLi
THF n-Suli n-BuSnLi + n-BySn
Method B: The second method was that reported by Still wherein," Lithium
diisopropylamide and tributyltin hydride were mixed in THF at O OC and within minutes
the product was formed as judged by formation of a pale yellow solution which was
directly used in the next step. Aithough it can be stored at 4 O C for about one week it was
better to use it immediately for the best result.
5 3.2. Preparation of a-Alkoxy Tributylstannane Intermediate
a-Akoxy-tributylstannane intermediate 23 was prepared in two steps? Aldehyde
12 was first reacted with a solution of n-Bu,SnLi (prepared by method A) at -78 OC for
20 min to give the trïbutylstannylcarbinol22. This adduct was found to be a rather labile
compound which could be chromatographed but which decomposed on contact with acid
(acidic silica gel), high temperature or on prolongeci standing. For this reason, the crude
adduct was immediately converted to the MOM ether. TributyIstannylcarbinoI 22 was
treated with MOMCl and PhNMe, in CH,Cl, at O O C for 1 h to give a-methoxymethoxy
tributylstannane 23 in 30% yield (two steps) (Scheme 3.3). It should be mentioned here
that this procedure for the protection of acid-sensitive alcohols is an extremely mild and
general method aliowing derivatization of many primary, secondary and tertiary alcohols.
n-Bu,SnLi prepared using method B gave the same product in 35% yield over two
steps. Unlike the intermediate tributylstannylcarbinol22, MOM-protected stannane S i s
quite stable and can be purified, or stored for many months under nitrogen.
In order to improve the yield, the following mode1 reactions (Scheme 3.2) were
carried out to check the reaction conditions.
Cyclohexanecarboxaldehyde was reacted with n-Bu,SnLi and then protected with
MOMCl to give the a-methoxymethoxy stannane 20 in 8296 yield.
Scheme 3.2
The protecting group effect was bnefly examined using a-chloroethyl ethyl ether
which was synthesized from ethyl aldehyde, ethanol and hydrogen chloride gas in 60%
yield? As it is volatile and toxic, it should be tightly seaied and stored after use.
Cyclohexanecarboxddehyde was treated with n-Bu,SnLi and then protected with
a-chIoroethy1 ethyl ether to give the a-akoxy stannane 21 in 87% yieid. From the result
we cm see that the yield was a Little bit higher, but its 'H NMR spectrum was much more
complicated than the MOM-protected stannane 20, because two diastereomers were
produced. To make the NMR analysis in the further research easier, we decided to use
MOMCl as the protecting group.
Having optimized the reaction condition, substrate 12 was tried again and a 56%
yield was obtained in two steps (Scheme 3.3). We also found that it is essential to have
fieshly distilled solvents in order to get high yield in this two step procedure.
Scheme 33
OMe n-BuaLi OMe MOMCl - - OHC
J 12 OMOM
23 56%
Attempts to use the recycled aldehyde 12 showed that on desired product was
produced in the reaction.
5 3.3. Tin-Lithium Exchange and Aaionic ~yc1ization~- 35
Anionic intrarnolecular ring opening of oxabicyclic[2.2.1] substrate 23 was
carried out by treatment with 3 equiv. of MeLi at -78 OC in THF. Tin-Lithium exchange
took place in minutes and upon warrning to room temperature the cyclized products 24,
25 were formed in 84% yield (a : =1:1) (Scheme 3.4). The reaction mixture should be
slowly and gradually warmed up to n. Since a rapid inscrease in temperature led to
decomposition and a low yield. The attack of the nuclephile is believed to occur
exclusively from exo face leading to the tram ring junction althruogh this was not
rigorously proven.
Scheme 3.4
MeLi was chosen as the transmetalation agent since the previous research in our
group showed that it does not induce ring opening in bridged substituted systems. This
eliminated any intermolecular coupling and avoided the need for high dilution or other
precautions during the transmetaiarion.
Table 3.1 Anionic cyclization of [2.2.1] su bstrates
Entry Subtrate MeLi Results
1 23 5~ No desired products
2 23 4eq 18% yield of isomer-2
3 23 3 eq û4% yield of 2 isomers (a$ =1: 1)
4 23 2eq No reaction
In our attempts to optimize the reaction conditions, different molar ratios of MeLi
were exarnined. More than 3 equivaients of MeLi gave no desired product (5 eq), or
decreased yield (4 eq), whereas less than 3 equivalent of MeLi showed Little reaction (2
eq) (Table 3.1). 3 Equivalents of MeLi was the optimal amount for the exchange step to
go to the completion and not to cause the decomposition of the cyclized products,
9 3.4. Confirmation of Two Isorneric Cyciized Products
The two cyclized isomers were separated by column chromatography.
The structure of isomer-1 24 was clearly determined by spectmscopy ('H NMR,
13c NMR, MS). It was hydrolyzed by PPTS in MEK to remove the MOM-group which
generated the di01 26 in 65% yield? Further oxidation by the Dess-Maxtin r a g e n t gave
the ketone 27 (from isomer- 1) in 75% yield (Scheme 3 .5)?9
Scheme 3 J
PPTS, MEK M O M O ~ ~ E OH 80°C. 38hrs
Dess-Martin - 75% (from isomer-1 )
The structure of the other product was quite difficult to differentiate between 25
or the spiro compound 28 (Scheme 3.6). The two olefin hydrogens were overlapping in
die 'H NMR spectmn so it was hard to determine if the other product was isomer-2 25.
Scheme 3.6
25 isomer-2 28 spiro cornpound
The alcohol was treated with MnO, and the Dess-Martin reagent, whereas the
spiro compound contains a secondary alcohol and isomer-2 contains a teniary alcohol.
So the spiro compound can be oxidized to fonn a ketone and isomer-2 will not be
oxidized. Both reactions showed no change with the starting material suggesting that this
compound was isomer-2.
Further confirination was carrîed out in the similar route with isomer-1. komer-2
25 was hydrolyzed by LiBF, to remove the MOM-group and generate the di01 29 in
45%45 yield. Oxidation of the di01 with the Dess-Martin reagent gave the ketone
compound 27 (from isomer-2) in 38% yield (Scheme 3.7).
Scheme 3.7
UBF4 OMe
70°C. CH3CN
Dess-Martin
27 38% (from isomer-2)
Both ketone compounds (ftom isomer-1 and isomer-2) are identical in al1 the
spectra ('H NhiIR, I3C NMR, IR, MS). So we can conclude that two products from the
anionic cyclization were stereoisomers (85%, a$ = 1:I).
5 3.5. Summary
In this section, we have demonstrated that the preparation of a-alkoxy
tributylstannane with n-Bu,SnLi and MOMCI in two steps was an effective way to obtain
a precursor to an a-&oxy organolithium reagent. The anionic intramolecular ring
opening of oxabicyclo[2.2.1] tin-compound by MeLi via tin-lithium exchange and
anionic cyclization was efficient and occuned in good yield. A bicyclo[4.3.0] system was
generated with complete regio- and stereocontrol except at the centre bearing the MOM
group. Further studies will be carried out on the application of this process to the
synthesis of natural products.
5 4. Anionic Intramolecular Ring Opeoing of an Oxatricyclo[6.2.1.0 "1 Compound
5 4.1. Attempt with Aldehyde Intermediate
We successfully did the anionic cyclization from oxabicyclo[2.2.1] aldehyde
substrate 12 via srannylation and iin-Lithium exchange. This synthetic strategy providecl a
very useful and general method to synthesize fused 5,6-membered bicyclic compounds
with diverse functionalities. We attempted to extend the scope to the oxatricyclo[6.2.1.0
"1 aldehyde substrate 32 with the same strategy.
The synthesis of oxatricyclo[6.2.1.0 substsrate was initially tried using a
similar route witb an oxabicyclo[2.2.1] substrate 12. Furan denvative 28 was reacted
with benzyne arising from the reaction of 1.2-dibromobenzene and n-BuLi to give the
Diels-Alder adduct 30 in 64% yield.' Then the THP-protecting group was removed by
hydrolysis (PPTS, MeOH) which generated the free alcohol31 in 94% yield. The dcohol
31 was treated with the Dess-Martin reagent but none of desired product was obtained
(Scheme 4.1).
Scheme 4.1
n-guti (1 eq) Br
PPTS, MeOH - toluene, -78 OC
) THPO
These results suggested that the oxatricycIo[6.2.1.0 "1 aldehyde substrate 32 may
be forrned in the reaction. But it was very unstable, especiaily in acid conditions. One
spot was separated after work-up in 15% yield. The structure of this compound 34 is
shown in Scheme 4.2. In 'H NMR it has 6 aromatic hydrogens and 6 aliphatic hydrogens.
13C NMR showed that the skeleton of the compound has very similar chernical shifts with
1,4-naphthoquinone. In IR it has a strong peak at 1666 cm-' indicating a ketone group.
HRMS showed that the molecular weight is right for the compound.
Scheme 4.2
chernical shifts in 13c NMR
The possible mechanism for the formation of this by-product was beiieved in the
foLlowing pathway (Scheme 4.3). Althrough it was not ngorously proven.
Scheme 4 3
In the presence of H' or LA, the epoxy ring of 31 was cleaved and a
tetrahydrofuran ring was formed to give the intermediate 33. Further oxidation of this
intermediate produced the separated by-product 34.
We also tried the oxidation with the Dess-Martin reagent in neutral and basic
solutions and even TPAP, Swem and PDC etc. in ali these cases no desired product was
obtained.
$ 4.2. Attempt with Aldehyde Acetal Intermediate
From the above experiments we learned that it was impossible to directly oxidize
oxatricyclo[6.2.1 .O 27] alcohol substsrate 31 to aldehyde 32. Therefore we designed a
second synthetic route using furan aldehyde acetal 37 as the diene and 1,2-
dibromobeozene to generate the benzene-fused acetal aldehyde 38. The product could be
hydrolyzed to give the desired aldehyde compound 39 (Scheme 4.4).
Scheme 4.4
The furan aldehyde acetal37 was prepared fiom the same starting materiai 8 as in
ouf previous route to the [2.2.1] subtrate 12. Furan denvative 8 was hydrolyzed to
remove the THP-protecting group, and then the free dcohol 35 was oxidized by the
Dess-Martin reagent to give the aldehyde 36 in -100% yield (Scheme 4.5).
Scheme 4.5
Dess-Martin - 7' A few conditions were tried to synthesize aldehyde acetal 37. The derails of the
reactions tried are Iisted in Table 3. The acetalization of the aldehyde 36 was best carried
out using Lac!, (1 eq) and trimethyl orthoformate (10 eq) in methanol at rt for 4.5 h." A
quantitative yield of the acetal37 was obtained under the optimïzed condition (Scheme
4.6, Table 4.1).
Scheme 4.6
\ CHO
Table 4.1 Acetalization of furan aldeh yde
Entry Subtrate Condi tionsa Yields
1 36 pTsOH(O.03 eq), (CH,O),CH(7.6 eq), Reflux 37, 12%
2 36 p-TsOH(0.03 eq), (CH,O),CH( IO eq), Reflux 37, 17%
4 36 LaC13(1 eq), (CH30),CH(10 eq), Reflux 37, -100%
a Methanol was used as the solvent in al1 the reactions.
The aldehyde acetal 37 was subjected to benzyne prepared from 1,2-
dibromobenzene and n-BuLi in THF at -78 O C . No desired product was obtained. So
other benzyne-generating methods were trïed. Aldehyde acetai 37 was reacted with 2-
aminobenzoic acid in isoamylnitrile and DMF at 60 O C . But it did not give the desired
product.
In order to try solve the problem. solvent and temperature effects were briefly
examined (Table 4). When the reactions were carried out in THF, Et,O at -78 O C or -78
OC to rt or in pentane or hexane at 4 0 OC, no desired product was obtained. When
hexane was used as the solvent and the reaction was carried out at -78 OC, a 36% of
desired product 38 was obtaiaed. The yield descreased to 29% if the concentration was
halved (Scheme 4.7, Table 4.2).
Scheme 4.7
Table 4.2 Diels-Alder reactions of furan aldehyde acetd
Entr~ Subtrate Conditions Results
1 37 THF, -78 OC
2 37 EbO, -78 OC
3 37 Hexane, -40 OC
NDP"
NDP
NDP
4 37 Pentane, -40 OC NDP
5 37 Hexane, -78 OC 38,36%
6 37 Hexane(diluted), -78 OC 38,29% a NDP stands for no desired product
The benzene-fused aldehyde acetai 38 was hydrolyzed using LiBF, (2 eq; 7 eq) in
CH,CN (2% H,O) at dg No aldehyde 39 was produced. A complex mixture was
obtained and the situation was very similar to Dess-Martin oxidation of substrate 31
(Scheme 4.8).
Scheme 4.8
5 4.3. Synthetic Route with a-Akoxy Tributylstannyl Furan Derivative
From the above experiments, we Iearned that the aldehyde 39 was dificult to
synthesize because of its instability. To overcome the difficulty, we thought that furan
aldehyde 36 could be directly used to prepare a-alkoxy stannane 41, and then to do the
benzyne cycloaddition to fonn oxatricycl0[6.2.l.O "1 compound 42. If the stannane 42
could be obtained, we expected that the cyciization should be straightforward. And in this
way it can Save two steps for protection and deprotection of the aldehyde.
Furan aldehyde 36 was treated with n-Bu,SnLi and MOMCl to give furan
a-alkoxy satnnane 41 over 55% yield (two steps)? It was successfdly reacted with
benzyne prepared fkom 1,2-dibromobenzene and n-BuLi in toluene at -78 OC to give the
Diels-Aider adduct 42 in 67% yield. It was a pleasant surprise to observe that stannane 41
was quite stable to the reaction conditions. During the separation process the starting
materid sablnane 41 was readily recovered, and used in the reaction for a second time
(50% yield), and third time (35% yield). The accumulated yield reached 89% (Scheme
4.9).
Scheme 4.9
1 ) nBu3SnLi, THF
2) MOMCI, CH& 7 Bu3& OMOM
41 55%
(two steps)
toluene, -78°C
42 67%
(recycled SM, 89%)
The cyciization was carried out in a similar way to that previously found for
oxabicyclo[2.2.1] substrate 23. Stannane 42 was reacted with MeLi in THF at -78 OC for
30 min to give the cyclized compounds 43,44 (two isomers a : =1:1) in 81% yield
(Scheme 4.10, TabIe 4.3). Warrning-up to rt pnor to the quench (NH,Cl) led to a
decreased yield (49%) by preferential decomposition of isomer-1 (entry 2, table 4.3). By
warming-up to -30 OC the yield was siightiy lower (77%) (entry 1, table 4.3).
Scheme 4.10
Table 4.3 Anionic cycliuoon of [6.2.1.0 substmte
E n t r ~ Subtrate Conditions Products & yield
1 42 MeLi, THF, -78 O to -30 OC 2 isomers, 77%
2 42 MeLi, THF, -78 O to O OC Isomer-2.49%
3 42 MeLi, THF, -78 O C 2 isomers, 8 1 %
WhiIe both isomers were produced in a good yield isomer-1 43 was not stable to
silica gel and could not be obtained in pure form. It is a cis-isomer (confirmed by the
later X-ray crystaiiographic anaiysis). It has both MOM- and OH-groups at the top of the
molecule. Because the energy barrier is high and it causes its instability. Isomer-2 44 is a
trans-isomer. It is quite stable on column and can be separated.
In order to get isomer-1 43 in pure form. 2% Et,N-neutralized silica gel
chromatography was used.
Both isomer-1 43 and isomer-2 44 are white crystalline soiids which were grown
in an E~O/pentane mixture. X-ray crystallographic data was obtained and the results
showed that the stereochemistly of the two isomers was as we predicted by their stability
(Appendk 2, page 120): isomer- 1 43 is a cis-isomer and isomer-2 44 is a tram-isomer.
These results showed that a convergent route to 42 and cyclized compounds (43,
44) was possible.
5 4.4. Attempts to Hydrolyze the MOM-Group and Protect the Tertiary Alcohol
Further studies on the cyclized compounds were camed out to remove the MOM-
group. Because the cyclized compounds contain an aromatic ring they could be readily
dehydrated to form the naphthelene denvatives. Some very mild conditions (SnCl,,
ZnBr2, ZnI, and LiBF, etc.) were tested on isomer-2 44 which is more stable than
isomer-1 4315.50 In al1 the cases the SM 44 was rapidly dehydrated to form the
naphthelene denvative 47, rather than the hydrolyzed product 46. The dehydration was
very fast and it was completed in 5 to 10 min. The hydrolysis was much slower using
LiBF, in CH,CN/2% H,O at 40 OC for 1 day but some dehydrated product was also
formed (Scheme 4.1 1). From these observations we thought that it could be better to
protect the tertiary alcohol first and then to do the hydrolysis to remove the MOM-group.
Scheme 4.11
rt, 5 - 10 min
4û°C, 1 day * Hot**-w
Attempts to protect the tertiary alcohol with TMSCl and TMSOTf in different
reaction conditions showed that no desired products were produced. but some dehydrated
naphthelene derivative 47 was formed (Scheme 4.12. Table 4.4)?lR
Scheme 4.12
TMSCI, Et3N MOMO,,.
THF, fi, 8 h
Table 4.4 Attempts to protect the tertiary alcohol
Entry Substrate Condi tionsa Results
1 44 TMSCl, THF, rt, 8 h NDP, 47,6496
2 4f4 TMSCI, CH2Cl,, rt, 8 h NDP
3 44 TMSCI, ClCH,CH,Cl, rt, 8 h NDP
4 44 TMSOTf, CH2CI2, -10 OC, 2.5 h NDP
5 44 TMSOTf, C1CH2CH2Cl, -10 OC, 2.5 h NDP
6 44 TMSOTf, CH2C12, O O-25 OC, 2.5 h NDP
a Et,N was used in al1 the reactions.
5 4.5. Reduction of the Cyclized Compounds
With the difficulties in hydrolysis and protection of tertïary alcohol. we thought
that reducing the olefin first may be necessary. Hydrogen transfer reduction was first
tried on isomer-2 44 at rt for 1 to 3 days." Cyclohexene and cyclohexenol were used as
the hydrogen donors and 5% PdC, 10% Pd/C, 5% Pd/CaC03 and 5% Pt were utilized as
the catalysts in the reactions. In most cases no reaction took place. But in some cases (5%
PtK, 10% PdK) small amount of 50 was produced. Increasing the reaction temperature
to 50 OC or reflux (80 O C ) did not accelerate the reduction, but did promote the
dehydration to give only the naphthelene derivative 47 (Scheme 4.13, Table 4.5).
Scheme 4.13
MOMQ-q 5% PdiC. cyclohuene
OH MeOH, rt, 48 h ---- M O M O , , - p
OH
MOMor,-p 5Oh PdC. cycloCxene MOMOr,.
OH MeOH, 50°C, 24 h
Table 4.5 Hydrogen transfer reduction of vhy1 p u p
Entry Substrate Conditions Results
5% P a , cyclohexenol, EtOH, rt, 48 h
10% Pd/C, cyclohexenol, EtOH, rt, 48 h
5% Pd/CaCO,, cyclohexenol, EtOH, rt, 48 h
5% WC, cyclohexenol, EtOH, rt, 48 h
5% PdK, cyclohexene, MeOH, rt, 48 h
10% PdK, cyclohexene, MeOH, rt, 48 h
5% WC, cyclohexene, MeOH, rt, 48 h
5% WC, H,, EtOAc, rt, 48 h
5% PdK, cyclohexenol, EtOH, 80 OC, 24 h
5% PdK, cyclohexene, MeOH, 50 OC, 24 h
No reaction
No reaction
No reaction
Some 50
No reaction
Some 50
Some 50
Dehydra ted 47
Dehydrated 47
Dehydrated 47
Finally, Lindlar's cataiyst was employed in the reduction? Isomer-2 44 was
dissolved in methanol and reacted under hydrogen atmosphere at r t for 3 days. The
reduced isomer-2 50 was obtained in 48% yield. The same rnethod was applied to
isomer-1 43 and the reduced isomer-149 was obtained in 47% yield (Scheme 4.14). The
yields of the reductions were not optimized.
Scheme 4.14 LCJMow Undlafs catalyst. [Hl
methanol OH
- MOMO#,. methanol
5 4.6. Summary
In this section, we have demonstrated that furan a-alkoxy stannane 42 was
available in 4 steps from furan denvative 8. Furan a-alkoxy stannane 42 underwent
cycloaddition with benzyne prepared from 12-dibromobenzene and n-BuLi to give the
benzene-fused oxatricyclic compound. A convergent synthetic route to prepare
oxatricyclo[6.2.1.0 "1 compounds was developed. Anionc cyclization of stannane 42 was
efficient and gave a good yield of the cyclized products. Isomer-1 43 is very labile, but it
can be isolated fiom 2% Et,N silica gel column. The stereochemistry of the two isomers
were detennined by X-ray crystallography. The reduction of the alkene functionalities in
43 and 44 by Lindlar's catalyst was chemoselective. Further studies wiiI be carried out to
apply this strategy to the total syntheis of biologically active molecules.
5 5. Anionic Intramolecular Ring Openhg of an Oxabicyclo[3.2.1.] Cornpound
8 5.1. [3+4] Cycloaddition
The [3+4] cycloaddition was carried out between the furan 8 and 1,1,3,3-
tetrabromoacetone in the presence of Zn-Ag couple. After work-up the crude dibromo-
oxabicyclo[3.2.1] adduct was directly reduced by Zn-Cu couple in saturated amnomiuni
chloride solution in rnethan01.~~ The oxabicyclo[3.2.1] ketone 52 was obtained in 30%
yield over two steps (Scheme 5.1).
Scheme 5.1
1. Zn-Ag O - 4; + 2. Zn-Cu THPO ,+?O
52 30%
(two steps)
Tetrabromoacetone was prepared by literature procedure. Furan derivative 8 was
synthesized by the method shown in Scheme 1 .l . Zn-Ag and Zn-Cu couples were freshiy
prepared before use by the procedure in the experimental section.
in order to improve the yield, nonacarbonyl diiron (0.5, 1 eq) was used as the
promoter in the ~~cloaddition." Furan derivative 8 was used in various molar ratios (1,2,
3 eq) with 1,1,3,3-tetrabroboacetone) in THF. In d cases no desired product was
obtained (Scheme 5.2).
Scheme 5.2
2. Zn-Cu
In another methoci , diethyl zinc was utiiized as the promoter, but only 22% yield
of [ 3 4 ] cycloadduct 52 was obtained? Increasing the amount of diethyl zinc form 1.33
to 2 eq gave a very modest improvement (15% yield) (Scheme 5.3).
Scheme 53
1. Et2Zn - 2. Zn-Cu
THrn 52 15%
(two steps)
From these reaction results, we can see that althrough the yieid of [3+4]
cycloaddition is low. The classic rnethod (Zn-Afin-Cu) stiii seemed a practical way to
prepare this kind of compound.
8 5.2. Preparation of Aldehyde Intermediate
The oxabicyclo[3.2.1] ketone 52 was first subjected to DlBAL in THF at -78 O C
to rt for 24 h to give the reduced products 53,54 in 6 1 1 yield (a:$ = 85:15)? The a$-
OH isomers have the same Rf value and they cannot be separated by column
chromatography. Thus L-selechide was used as the reducing agent which produced only
the a-OH isomer 53 in 9 1% yield (Scheme 5.4)"
Scheme 5.4
DISAL
THPO TH PO
OH THPO
Isomer 53 was treated with sodium hydride and methyl iodide to give the methyl
ether 55 in 95% yield (two steps). THP group was hydrolyzed using PPTS in ethanof to
give the alcohol56 in 92% yield. Which was oxidized by the Dess-Martin ragent to give
the key aldehyde intemediate 57 in 99% yield (Scheme 5.5).3539
Scheme 5.5
NaH, THF
Dess-Martin OMe CHO O M ~
PPTS, EtûH -
5 5.3. Preparation of an a-Aikoxy Tribut- 1s tannane Intermediate
In our initial studies, we encountered the similar problems as we had seen in
reactions in the 12.2.11 senes. The aldehyde 57 was treated with n-Bu,SnLi aud MOMCl
to give the a-alkoxy starnane 59 but in only 20% yield. Use of freshly prepared n-
Bu,SnLi and weU-dried solvents and reagents caused the yield to increase to 64% in w o
steps (Scheme 5.6)."
Scheme 5.6
BU~S&OH OMe
(two steps)
We attempted to recycle the recovered aldehyde 57 but no desired product was
obtained.
§ 5.4. Tin-Lithium Exchange and Anionic Cyclization
The a-alkoxy stannane 59 was treated with MeLi (3 eq) in THF at -78 OC for 30
min. Then the reactioo was quenched by adding saturated ammonium chloride solution.
Two isomers 60.61 (a:$ = 1:l) were produced in 82% yield (Scheme 5.7). Warming up
to -30 OC before it was quenched led to a dark brown mixture and a lower yield (5 1%).
Scheme 5.7
ôû,61 82%
(two isomers)
(a$ = 1:l)
The two isomers have very similar Rf values, so the separation was difficult.
Furthemore, isomer-1 60 (possibly a cis-isomer, p-MOM isomer) was not very stable
and aiways partially dehydrated in the process of work-up and separation. Even on a 2%
Et,N-neutraiized silica gel column it was still partially dehydrated. We concluded that it
rnay be easier to separate this isomer afier removing the MOM-group.
Isomer-2 61 (possibly a trans-isomer, a-MOM isomer) was quite stable and it
was successfully separated by the column.
5 5.5. Hydrolysis of the MOM-Group in the Cyclized Products
The lability of 60 demanded that we find very mild hydrO1ysis conditios. Isomer-1
60 and isomer-2 61 were treated with PPTS in MEK, or LiBF, in CH,CN (2% H,o).'"
At rt no reaction took place. Whereas at 40 OC and 60 OC both isorners were partiaily
hydrolyzed but the hydrolysis process was very slow. At 70 OC, PPTS in MEK caused
both isomen to decompose. The best conditions were using LiBF, in CH3CN (2% H,O).
Isomer-1 60 was hydrolyzed to give a alcoho1 62 in 25% yield and isomer-2 60 was
hydrolyzed to give a alcohol 63 in 39% yield (Scheme 5.8, Table 8). Further studies are
required to optimize the yields.
Scheme 5.8
In an attempt to obtain crystals of the hydrolyzed products 62 and 63,
crystallization was tried in many solvents (EQO/pentane, Et20/hexane, Et20/CH,CI,,
CHCI,, CH,COCH,, CH$H,OH, CH,OH). In most cases they oiled out or gave very fine
particles.
§ 5.6. Surnmary
In this section, we have demonstrated that oxabicyclo[33.1] aldehyde compound
57 bearing a three-carbon tether was availabie in 6 steps starting fiom furan derivative 8
and 1,1,3,3-tetrabrornoacetone via a [3+4] cycloaddition. Preparation of a-alkoxy
trîbutylstannane with n-Bu,SnLi and MOMCl in two steps was an effective way to obtain
the precursor of the a-alkoxy organoiithium reagent. The anionic intramolecular ring
opening of oxabicyclo[3.2.1] stannane via tin-üthium exchange and anionic cyclization
was efficient and occurred in good yield. The bicyclo[5.3.0] sysiem was generated with
complete regio- and stereocontrol except the centre bearing the MOM group. Further
studies about the application of this strategy on the oxabicyclo[3.2.1] aldehyde bearing a
potential hydroxy group next to the bridgehead could lead to the total synthesis of naniral
product Phorbol.
EXPERIMENTAL SECTION
General Experiments
The following general experimental details apply to aU subsequent experiments.
Analytical thin-layer chromatography (TLC) was performed on precoated
aluminum-backed silica gel (Merck 60F-254). Hash chrornatography was performed as
described by StillS1 using 230-400 mesh silica gel. Melting points were recorded with a
Fisher-Johns melting point apparatus and are uncorrected. Bulb-to-bulb distillations were
performed on a Kugelrohr apparatus; boiling point refers to air bath temperatures which are
uncorrected. Infrared spectra were recorded on a Nicoiet 8210E Fï-IR or Bomem
Michelson Senes Fï-IR spectrophotorneter as a KBr pellet, solution in CHC13, CH2C12 and
paraffin oil or a neat film between NaCI plates. IH and 13C NMR spectra were recorded on
a Varian Gemini-200 or VXR-40 spectrorneter. Chernical shifts are reported in parts per
million (6) fiom tetramethylsilane with the solvent resonance as the interna1 standard (1H
NMR, chlorofonn: 6 7.24 ppm, "C NMR, deuterochloroform: 6 77.23 ppm). Spectral
features are tabulated in the following order: chernical shift (6. ppm); number of protons;
muttiplicity (s-singlet, d-doublet, t-triplet, q-quartet, qu-quintet, m-complex multiplet, b-
broad). High resolution mass spectra were obtained on a VG 70-250s spectrorneter.
Elemen ta1 analyses were performed by Canadian Microanal ytical Service Ltd., Del ta, B .C.
Al1 glassware was flame dried under an atmosphere of dry nitrogen. Solvents and solutions
were transferred with syringes and canulae using standard inert atmosphere techniques.
Solvents and Reagents
Unless stated otherwise, commercial reagents were used without purification.
Tetrahydrofuran and diethyl ether were distilled immediately prïor to use from
sodiudbenzophenone. Diisopropylamine, dichloromethane, dimethyl sulfoxide,
triethylamine and toluene were distilleci immediately prior to use fiom calcium hydride.
The protection was carried out by stirring 3-bromo-1-propanol(15.0 g, 1 10 mmol),
DHP (23.7 rnL, 260 mmol), and PPTS (2.7 g, 11 mmol) in CH2C12(50 mL) at rt for 5 h. It
was quenched by adding 50 mL of saturated aqueous NaHCO, solution and extrated with
CE&Cl, (3x3. The combined organic layers were washed with brine (3X), dried (MgSO,)
and concentrated to give 32 g of residual oïl. Bulb-to-bulb distillation (0.50 m g , 50-60
OC) of the residual oil yielded 2-(3-bromo-propoxy)-tetrahydro-pyran 7 (25.0 g, -100%)
as a colorless oil: Rf = 0.31 on silica gel (hexane-EtOAc 9:l); 1H NMR (200 MHz,
CDC13) 6 4.55 (lH, m), 3.87-3.62 (2H, m), 3.49-3.33 (2H, m), 3.24 (2H, t, J = 6.8 Hz),
2.03 (2H, quintet, J = 6.3 Hz), 1.78-1.46 (6H, m); 13c NMR (50 MHz, CDC13) 6 98.6,
66.6,62.0,33.4,30.4,25.3, 19.3,3.3.
A solution of n-butyliithium (29.7 mL, 2.5 M solution in hexanes, 74.3 mmol)
was added dropwise to a solution of furan (5.9 mL, 8 1.1 mmol) in THF (250 mL) at O OC.
The mixture was stirred for 1 h at O OC and for an additional 1 h at rt. The reaction was
then cooled to O OC prior to the dropwise addition of a solution of 2-(3-bromo-propoxy)-
tetrahydro-pyran 7 (15.0 g, 67.6 mmol) in THF (20 mL) over 1 hou. After the addition
was complete, stirring was continued at rt for an additional 15 h. The reaction was
quenched by the addition of water (10 mL) and the solvent was removed in vacuo. The
aqueous layer was extracted (3x) with Et20 and then the combined organic layers were
washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Bulb-to-bulb
distillation (1.0 mmHg, 80 OC) of the residual oil gave 8 (13.1 g, 92%) as a colorless oil:
Rf=0.55 on silica gel (hexane-EtOAc 9: 1); IR (neat) 3 114,2938,2875, 1595, 1448, 1384,
1131 cm-l; lH NMR (200 MHz, CDC13) 6 7.28 (lH, d, J = 1.8 Hz), 6.26 (lH, dd, J = 3.1,
1.9 Hz), 5.98 (lH, d, J = 3.0 Hz), 4.58 (lH, t, J = 2.9 Hz), 3.87-3.73 (2H, m), 3.53-3.40
(2H, m), 2.72 (2H, t, 3 = 7.3 Hz), 2.05-1.49 (8HT m); 13C NMR (50 MHz, CDC13) 6 156.3.
141.3, 110.5, 105.3, 99.3, 67.1, 62.7, 31.2, 28.7, 26.0, 25.3, 20.1; HRMS calcd for
C12Hxg03 m+ 2 10.1255, found 210.1255.
Maleic anhydride (9.34 g, 95.2 mmol) was added to a solution of 8 (20.0 g, 95.2
mmol) in Eh0 (40mL). The mixture was stirred until the maleic anhydride was
completely dissolved and Et@ was then removed in vacuo. The resulting solution was
stirred for 12 h at rt during which tirne the matenal crystallized. The cmde mixture was
dissolved in THF (350mL) and added via a canula to a suspension of LiAlHJ7.23 g, 190.4
mmol) in THF (350 d) at O OC. The mixture was stirred for an additional 15 h at rt, The
reaction was quenched by the portionwise addition of potassium sodium tartrate
tetrahydrate (53.74 g, 190.4 m o l ) followed by water (50 mL). The mixture was stirred
for another 5 h at rt. Then the suspension was filtered and the residue was washed several
times with boiling THE The filtrate was concentrated and the resulting oil was
purification by flash chromatography (EtOAc-MeOH 955) to yield a mixture of
diastereornenc diols 9 (14.75 g, 52%) as a colorless oil: Rf = 0.27 on siiica gel (EtOAc-
MeOH 955); IR (neat) 3364, 2916, 1452, 1366, 1259, 1140, 1044 cm-1; IH NMR (400
MHz, CDC13) 6 6.38 (2H, dd, J = 5.7, 1.7 Hz), 6.23 (2H, d, J = 5.9 HZ), 4.61 (ZH, d, J =
1.1 Hz), 4.594.56 (2H, m), 3.95-3.66 (12H, m), 3.52-3.37 (4H, m), 3.06 (4H, bs), 2.10-
2.05 (2H, m), 2.03-1.92 (2H, m), 1.88-1.68 (124 m), 1.58- 1.50 (8H. m); 1 3 ~ NMR (100
MHz, CDC13) 6 137-9, 136.0,98.99 and 98.78,90.7, 80.9,67.4 and 67.3, 63.1,62.44 and
62.41, 60.3, 44.8, 44.1, 30.67 and 30.64,26.4, 25.71 and 25.67, 25.4, 19.6; HRMS calcd
for C1@2605 - THPI+ 213.1 127, found 213-1 1%.
NaH, THF then Mel
TH PO THP 10
A solution of 9 (28.25 g, 94.8 mmol) in THF (80mL) was added to a suspension of
NaH (6.82 g, 50% in oil, 284.3 m o l ) (washed 3 times with pentane) in THF (600 mL) at
0°C and the mixture was s h e d for 1 h at rt. After the dropwise addition of Me1 (23.59
mi,, 379.0 mmol) at O OC, the mixture was stirred for 1 h at rt and heated at reflux for an
additional 1 h. The reaction was quenched with several drops of MeOH and the solution
was diluted with water. THF was removed in vacuo and the aqueous layer was extracted
(3X) with Et20. The combined organic layers were dried(MgSO,), filtered and
concentrated. Purification by flash chromatography (hexane-EtOAc 2: 1) yielded 10
(25.65 g, 832) as a colorless oil: Rf = 0.53 on siiica gel (hexane-EtOAc 1 : 1); IR (neat)
3072,2938,2875,2812, 1455, 1258, 1202, 1124, 1103, 1033 cm-'; 1H NMR (400 MHz,
CDC13) 6 6.28 (2H, dd, J = 5.7, 1.6 Hz), 6.15 (2H, d, J = 5.5 Hz), 4.75 (2H, d, J = 1.5 Hz),
4.56 (2H, t, J = 3.5 Hz), 3.86-3.68 (4H, m), 3.57 (2H, d 4 J = 8.8,4.7 Hz), 3.49-3.22 (IOH,
m), 3.32 (6H, s), 3.27 (3H, s), 3.26 (3H, s), 2.00-1.46 (24H, m); ' 3 ~ NMR (100 MHz,
CDC13) 6 137.8, 135.8, 98.6, 98.5, 90.6, 80.0, 72.1, 70.6, 67.6, 67.5, 62.2, 62.1, 58.9,
58.6, 42.4, 41.6, 41.5, 30.8, 30.7, 26.5, 25.9, 25.8, 25.5, 19.6, 19.5; HRMS calcd for
C1gH3005 - CH30m+ 294.183 1, found 294-1833,
A solution of 10 (25.53 g, 78.21 mmol) in MeOH (255 mL) was treated with PVrS
(1.97 g, 7.82 m o l ) and stirred for 24 h at n. The reaction was quenched by the addition of
a saturated NaHC03 aqueous solution. MeOH was removed in vacuo and the aqueous
layer was extracted (3X) with Et2O. The combined organic Iayers were dried (MgS04).
filtered and concentrated. Puntikation by flash chromatography (hexane-EtOAc 1:2) gave
11 (1 5.4 g, 8 1 8 ) as a colorless oil: Rf = 0.26 on silica gel (hexane-EtOAc 12); IR (neat)
3416,2908,2810,1453,1193, 1108 cm-1; 1~ NMR (400 MHz, C D Q ) 6 6.31 (lH, dd, J =
5.9, 0.8 Hz), 6.17 (lH, d, J = 5.8 Hz), 4.80 (IH, d, J = 1.8 Hz), 3.70-3.60 (SH, m), 3.57
(lH, dd, J = 8.8, 5.2 Hz), 3.43 ClH, dd, J = 9.4, 7.2 Hz), 3.37-3.33 (lH, m), 3.35 (3H, s),
3.30 (3H, s), 3.29 (lH, dd, / = 10.3, 8.8 Hz), 2.11-1.98 (3H, m), 1.92-1.71 (4H, m); 13C
NMR (IO0 MHz, CDCl3) S 137.7, 135.6,90.6,79.9,71.9,70.4,62.5, 58.6,58.3,42.2,41.5,
28.5,26.3; HRMS calcd for C13H2204 @l - OH]+ 225.149 1, found 225- 1497.
(ZS*,4R*$R*,6S*)-3-(5,6-BiS-methoxgmetby 1-7-axa- bicyc10[2.2.1fhept-2-en-yl)-
propionaldehyde (U).
'OMe Dess-Martin
OHC ,J 12
Dess-Martin periodinate (3.149 g, 7.4283 m o l ) was added to a solution of 11 (1.5
g. 6.1902 mmol) in CH2C12 (60 mL) at O OC and the mixture was stirred for 1 h at d9 The
reaction was quenched by the addition of an aqueous NaHCe saturated solution. The
aqueous layer was extracted with Et20 (3X) and the combined organic layers were dried
(MgS04), filtered, and concentrated. Purification by flash chromatograph y (hexane-EtOAc
1.5:l) gave 12 (1.47 g, 99%) as a yeliowish oil: Rf = 0.40 on silica gel (hexane-EtOAc
1.51); IR (neat) 2928, 2892, 2811, 1723, 1450, 1389, 1321, 1193, 1103, 962 cm-1; 1H
NMR (400 MHz, CDC13) 6 9.76 (lH, t, J=1.3Hz), 6.29 (lH, d, J=5.3Hz), 6.04 (lH, d, J
=5.9Hz), 4.74 (IH, d, J =l.SHz), 3.50 (lH, dd, J =8.9, 5-OHz), 3.37-3.22 (lOH, m), 2.61-
2.55 (lH, m), 2.26-2.19 (1H. m). 2.08-1.95 (2H. m), 1.89-1.83 (lH, m); 1% NMR (100
MHz, CDCl3) 6 201.9, 137.2, 136-2,90.1,80.0,71.9,70.4,58.8,58.5,42.5,41.6,40.2,21.9
- 1 - (2eq) Mg, CH34 €40
A solution of CHJ (1.12g, 7.884 mmol) in Eh0 (2SmL) was slowly added to a
flame-dried reaction flask containing Mg tumings (191.6 mg, 7.884 mmol)." The reaction
mixture was warmed until the reaction was initiated- A crystal of iodine may be added if the
reaction does not start readily. When the addition of CH,I solution was cornpleted, the
reaction mixture was heated under reflux for 1 h. Then it was cooled to O OC and 12 (947.2
mg, 3.94 mmol) in Et@ (7 mL) was added dropwise to the fonned Grinard reagent. The
reaction mixture was stirred at O OC for 1 h. Then it was heated under reflux for another 1 h.
The reaction was quenched by adding saturated ammonium chloride solution (50mL). Some
white precipitate was fomed and filtered off. The mixture was extracted with Eh0 (3X).
The combined organic layers were dried (MgS04), fiitered, and concentrated. Purification
by flash chromatography (hexane-EtOAc 1:2) gave alcohol 16 (464.3 mg, 46%) as a
colorless oil: Rf = 0.45 on silica gel (EtOAc-CH30H 19:l); IR (neat) 3444, 2810, 1460.
1387, 1318,1195,1103,1043,975,916 cm-1; lH NMR (400 MHz, CDCI3) 6 6.25 (lH, d, J
=5.8 Hz), 6.12 (IH, d, J = 5.7 Hz), 4.74 (lH, dd, J = 5.3, 1.4 Hz), 3.81-3.70 (lH, m), 3.55-
3.47 (lH, m), 3.43-3.37 (lH, m), 3.32-3.20 (4H, m), 3.30 (3H, s), 3.25 (3H, s), 2.57 (lH, br.
s), 2.00-1.92 (2H, m), 1.87-1.70 (IH, m), 1.70-1.40 (lH, m), 1.12 (3H, dd, J=6.2,2.2 Hz);
13C NMR (100 MHz, CDClî) 8 137.7, 137.6, 135.6, 135.5, 90.6, 90.5, 79.9, 79.87, 72.0,
71.9,70.5,70.45,68.0,67.3,58.6,58.4,42.3,42.2,41.5,41.4.34.9,34.8,26.3,25.4,23.35,
23.3; HRMS calcd for C14H24Q [1Ml+ 256.1675, found 256.168 1.
Dess-Martin periodinate (921 mg, 2.17 m o l ) was added to a solution of 16 (464
mg, 1.8 1 m o l ) in CHzC12 (1 8 m.) at O O C and the mixture was stirred for 90 min at d9
The reaction was quenched by the addition of an aqueous NaHC03 saturateci solution. The
aqueous layer was extracted with Et20 (3X) and the combined organic layers were dried
(MgS04), filtered, and concentrated. Purification by flash chromatography (hexane-EtOAc
1.5: 1) gave 17 (391 mg, 85%) as a colorless oil: Rf = 0.41 on silica gel (hexane-EtOAc
1:2); IR (neat) 2928,2892,2810. 1716, 1449. 1356, 1319,1197, 1165, 1103,963,913 cm-1;
1H NMR (400 MHz, CDCI3) 6 6.27 (IH, ddd, J = 5.8, 1.6, 1.0 Hz), 6.03 (lH, d, J = 5.7
Hz), 4.74(1H, d, J = 1.6 Hz), 3.53 (IH, dd, J=8.9,4.8 Hz), 3.40-3.21 (3H, m), 3.31 (3H,
s), 3.27 (3H, s), 2.64-2.47 (2H, m), 2.21-2.14 (lH, ddd, J = 17.5,9.4,5.4 Hz), 2.09 (3H, s),
1.994.9 1 (2H, m), 1.87-1.8 1 (lH, m); "C NMR (100 MHz, CDCl3) 6 208.1, 137.4, 136.2,
90.0, 79.9, 71.9, 70.3, 58.6, 58.4, 42.3,41.5, 39.5, 29.9, 23.2; HlWS calcd for C1&2204
m+HJ+ 255.1596, found 255.1589.
Preparation of 0.1 M Sm& solution in THF.
THF Sm + ICH2CHd (0.1M) Sm12
rt
A reaction flask contaùling Sm powder (1.2 g, 8 mmol) was dned using a flame
under N2. After it was cooled down to rt, THF (40 mL) was added into the flask under
stimng. I,2-Diiodoethane was added in one portion and the reaction mixture was stirred
vigorously at rt for 0.5 h. The reaction mixture became green, deposited a yellow precipitate
(SmI,) and evolved heat. Further stirrïng at rt for 2.5 h generated a deep blue solution of
SmI, (0.1 M) with no visible yeliow precipitate.'
(lS*, 4S*, SR*, 7R*, SR*, 9S*)-8,9-Bis-methoxymethy1-10-oxa-tricyclo[5.2.1.0
1s]decan4-ol (13).
Sm12 (1 A8 eq), THF
HMPA (1 2 eq), -78 OC HOIS-
To a flarne-dried reaction flask was added 12 (107 mg, 0.45 mmol), THF (19.5 mL)
and HMPA (0.9 rnL).i2U The reaction flask was coled to -78 OC under N,. 0.1 M Sd,
solution (6.6 mi.) was added dropwise over 10 mins to the rapidly stirred solution, each
drop producing a transient purple colour which dissipated in -1 S. After 2 h TLC showed
that the reaction was completed. The resulting purple solution was aiiowed to wami to O OC
over 0.5 h before it was poured into 50 mL of brine, extracted with EtOAc (3X), washed
with water (2X) and brine (lx), dried (N%SO,), filtered and concentrated. Purification by
flash chromatography (hexane-EtOAc 1: 1) gave the product 13 (30 mg, 28%) as a colorless
oil: Rf = 0.39 on silica gel (EtOAc-CH,OH 19: 1); IR (neat) 3440, 2932,145 1, 1390, 1347,
1 192, 1 105, 1006, 823, 755 cm-'; 1H NMR (400 MHz, CDCl3) G 4.30 (lH, d, J =4.9Hz),
3.88-3.83 (IH, m), 3.45 (lH, dd, J=9.0, 4.7Hz), 3.34 (lH, dd, J =9.3, 6.6Hz), 3.31-3.17
(2H, rn), 3.29 (3H, s), 3.26 (3H, s), 2.24-2.07 (4H, m), 1.89-1.83 (4H, m), 1.74-1.62 (2H,
m); 13c NMR (100 MHz, CDCIj) 6 96.7,79.2.79.0.71.1,70.6,58.4,58.1, 56.8.46.5,45.1,
38.3, 35.4,25.5 HRMS cdcd for C13H2204 w-)Il+ 241.1440, found 241.1433.
(lS*, SR*, 7R*, BR*, 9S*)-8,9-Bis-methoxymethy~-10-0~a-tricyc1o[5~2.1~0
' J]decan40ne (14).
Solid TPAP (5.85 mg, 0.017 mmol) was added in one portion to a stirred mixture of
13 (80 mg, 0.33 mmol), NMO (58.52 mg, 0.50 mmol) and powdered 4A molecular sieves
(166 mg) in CH2CI, (4 mL) at rt under N,.*' After 2 h the reaction was completed. The
mixture was filtered through a short pad of silica gel and eluted with EtOAc (50 mi,). The
filrate was concentrated in vacuo. Purification by flash chromatography (hexane-EtOAc
1: 1) gave the product 14 (65 mg, 81%) as a colorless oil: Rf = 0.37 on silica gel (hexane-
EtOAc 1:2); IR (neat) 2926, 1740, 1460, 1390, 1282, 1199, 1101, 1024,987,916,840 cm-
l; IH NMR (400 MHz, CDCI3) 5 4.37 (IH, d, J =4.8Hz), 3.45-3.41 (2H, m), 3.36 (lH* dd, J
=9.4, 5.7Hz), 3.31 (3H, s), 3.30 (3H, s), 3-24 (lH, t, J =9.3Hz), 2.56-2-22 (7H, m), 2.01-
1.88 (2H, m); 13c NMR (100 MHz, CDCl3) 6 219.5, 94.3, 79.7, 71.4, 70.3, 59.1, 58.9,
56-6, 47.5, 44-9, 37.5, 37.2, 23.9 H R M S calcd for C13H2004 @l]+ 240.1362, found
240.1353.
(lS*, 4R*, SR*, 7R*, SR*, 9S*)-8,9-Bis-meth0xymethyl~leO~a-tncyclo~
'"]decan40i (15).
14 (80 mg, 0.33 m o l ) was dissolved in 3 mL of methanol and cooled to O OC.
NaBH, was added and the reaction mixture was stirred for 15 mins. The solvent was
removed by rotavaporation and the residue was dissolved in EtOAc (20 mL) and filtered
through a short silica gel column using EtOAc (200 mL) as the eluent. Conceniration and
purification by flash chromatography (hexane-EtOAc 1: 1) gave the product 15 (5 1 mg,
63%) as a colorless oil: Rf = 0.45 on silica gel (EtOAc-CH,OH 19: 1); IR (neat) 3454,
2931,1451, 1391, 1347, 1191. 1102. 916, 760 cm-l; NMR (400 MHz, CDC13) S 4.35
(lH, d, J =5.4Hz), 3.92-3.89 (lH, m), 3.43 (lH, ddd, J=8.9,5.3, 1.4Hz), 3.34 (lH, ddd, J
=9.6, 6.6, 1.5Hz), 3.30-3.19 (2H, m), 3.29 (3H, s), 3.26 (3H, s), 2.30 (lH, bras), 2.24 (IH,
td, J =9.5, 5.3Hz) 2.18-1.98 (7H, m), 1.59 (LH, ddd, J -12.5, 8.8, 1.5Hz); 1 3 ~ NMR (100
MHz,CDC13)6 98.4, 79.4, 73.2, 71.4, 70.8.58-8, 58.5,52.4,47.4, 45.2, 36.7, 31.3, 23.9
HRMS calcd for C 13H22O4 M+H]+ 243-1596, found 243-1594.
(IS*, 4R*, SR*, 7R*, SR*, 9S*)-4-Methy1-8,9-bis-methoxgmethyI-lO-oxa-
tricyclo[52.1.0 ]decan401(18).
Sml2, HMPA
H THF, it
To 8.65 mL of a 0.1 M SmI, solution in THF was added HMPA(l.283 g, 7.86
mmol) and N, was bubbled through the solution for 10 rnins.'= A solution of 17 (100 mg,
0.39mmol) in 18 mL of THF was added over 1.5 h. After the starting material was
consumed. The reaction was quenched by adding 10 mL of water, extracted with EtOAc
(3X), dried (Na,SO,), filtered and concentrated. mirification by flash chromatography
(hexane-EtOAc 1:l) gave the product 18 (10 mg, 10%) as a colorless oil: Rf = 0.22 on silica
gel (EtOAc-CH,OH 19:l); IR (neat) 3447, 2929, 2873, 2810, 1460, 1389, 1285, 1193,
L 109, 1010, 929, 892, 827, 805 cm-'; lH NMR (400 MHz, CDCi3) 6 4.27 (lH, d, J
=4.8Hz), 3.48 (lH, dd, J=8.9,4.7Hz), 3.38-3.19 (3H, m), 3.31 (3H, s), 3.26 (3H, s), 2.23-
1.49 (IOH, m), 1.20 (3H, s); I3C NMR (100 MHz, CDCi3) 6 97.5, 79.5, 78.9, 71.5, 71.0,
59.6, 58.8, 58.5, 46.6, 45.7, 42.4, 35.9, 26.4, 26.1 HRMS calcd for C13H2404 [M+H]+
257.1753, found 257.1740.
Preparation of 0.34 M n-Bu,SnLi solution in THE
THF n-BwSn H CPrzNti + n - B U CPr2NLi - n-Busnti
0°C 0°C
Anhydrous THF (10 mL) and diisopropylamine (0.8 m . , 6.10 mmol) were stirred
under nitrogen at O O C while n-butyliithiurn (2 mL of a 2.5 M hexane solution, 5 mmol) was
added dropwise. The resulting solution was stirred for an additional 5 min and tribuyltin
hydride (1.45 g, 1-32 mL, 5 m l ) was added via syringe. After ca. 15 min at O OC a pale
yellow solution of 0.34 M n-Bu,SnLi in THF was obtained which was used in the next
s tep?
2) MOMCI, CH2C)L BUJS
OHC 12 OMOM
To a solution of 12 (103.6 mg, 0.43 11 mmol) in THF (1.5 mL), 1.27 mL of 0.34M
n-Bu,SnLi in THF was added dropwise at -78 OC." The reaction mixture was stirred for
additional 20 mins. Then it was quenched by adding 10 mL diluted NH,Cl solution,
extracted with hexane (3X), dned @aZS04), filtered and concentrated (temperature < 30°C)
to give 137.7 mg of the crude a-hydroxy organostannane. The resulting oil was dissolved
in 2 mL of C H Q , containing N,N-dimethyl aniline (53.8 mg, 0.4436 mmol) and cooled to
O OC. MOMCl(208.2 mg, 2.5866 -01) was added and after 1 h the reaction mixture was
poured into 50 mL of hexane and washed successively with ice-cold 0.5 M aqueous
hydrochloric acid (SX), water, and saturated aqueous sodium bicarbonate. The organic
phase was dned (NafiO,), filtered and concentrated. Purification by flash c hromatography
(hexane-EtOAc SA) gave 23 (137.7 mg, 565) as a colorless oil: Rf = 0.26 on silica gel
(hexane-EtOAc 5:l); IR (neat) 2925,1463,1377,1197,1103, 1035,961,919,866,757 cm-
1; l H NMR (400 MHz, CDCb) 6 6.28 (lH, dd, J =5.7, l.SHz), 6.14 (lH, dd, J =5.6,
1.3Hz), 4.76 (lH, t, J =1.9Hz), 4.58 (lH, dd, J =6.6, 1.4Hz), 4.52 (IH, dd, J =6.5, 4.4Hz),
4.08-4.02 (rH, m), 3.59-3.55 (lH, m), 3.40-3.38 (lH, m), 3.33-3.23 (13H, m), 2.00-1.83
(4H, m), 1.5L-1.43 (6H, m), 1.32-1.24 (6H, m), 0.89-0.79 (lSH, m); 13C N M R (100 MHz,
CDCI3) S 137.94, 137.89, 135.79, 135.77,96.39,96.24, 90.64, 9û.58, 80.07, 80.03, 73.85,
72.19, 70.75, 58-79, 58.54, 55.43, 55.40, 40.35, 40.36, 41.76, 41.66, 30.88, 30.69, 29.27,
29.17, 29.06, 28.27, 28.15, 27.73, 27.46, 27.19, 13.62, 9.26, 9.15; HRMS calcd for
C ~ ~ H S ~ O ~ S ~ N - C ~ H ~ ] + 5 19.2132, found 5 19.2127.
(lS*, 3aS*, 4S*, SR*, 7aR*)-1-Methoxymethoxy-4,s-bis-methoxymethyl-
2 J Ja,4~,7a-heX8hydro-LH-inden-3a-o1 (PMOM-isomer) (24) and (IR*, Jas*, 4S*,
MoM*g~~ OH
MeLi, THF 24 isomer-1
-78°C +
OMOM
A solution of oxabicyclic compound 23 (21 3 mg, 0.37 mmol) in THF (3.5 mL) was
cooled to -78 OC and aûated with a solution of MeLi (0.79 m., 1.4M solution in EbO, 1.1 1
rn rn~l )?~~ The reaction mixture was stirred at -78 OC for 15 mins then it was slowly
warmed to O OC ( 2 h ) and stirred for 30 mins. The reaction was quenched by adding
saturated ammonium chloride solution (2 mL). Then extracted with Eh0 (3X). The
cornbined organic phase was dried (Na2S0,), filiered and concentrated. Rirification by flash
chromatography (hexane-EtOAc 2:l) gave two isomers 24 and 25 (89.2 mg, 84.296, a$ =
1: 1):
isomer-1 ($-MOM-isomer) 24 (46.1 mg, 44%) as a colorless oil: Rf = 0.57 on silica
gel (hexane-EtOAc 1:2); IR (neat) 3428,2927, 1450, 1416, 1380, 1290, 1190, 11 12, 1049,
1013,986,944,918,847,803 cm-l; lH NMR (400 MHz, CDQ) 6 5.95 (lH, dt, Jz10.1,
2.1Hz), 5.67 (lH, dt, J=10.1,3.OHz), 4.66 (2H, dd, J=17.4,6.6Hi), 4.48 (1H. s), 4.12-4.06
(IH, m), 3.63-3.45 (4H, m), 3.35-3.26 (9H, m), 2.27-2.66 (lH, m), 2.42-2.31 (2H, m), 2.27-
2.23 (IH, m), 1.79-1.62 (3H, m); 13C NMR (LOO MHz, CDCl3) 6 130.2, 126.9, 96.3, 79.8,
75.3, 71.9, 71.0, 58.8, 58.7, 55.3, 54.0, 45.9, 38.3, 33.9, 29.8; HRMS calcd for
C iSH2605~-H20]+ 268.1675, found 268-1675,
isomer-2 (a-MOM-isomer) 25 (43.1 mg, 41%) as a colorless oil: Rf= 0.46 on silica
gel (hexane-EtOAc 1:2); LR (neat) 3520,3438, 2927,2893,2823, 1739, 1450. 1370, 1240,
L 109, 1043, 975 cm-l; 1H NMR (400 MHz, CDCl3) 8 5.87-5.81 (2H, m), 4.64 (2H, dd, J
=33.7, 7.OHz), 4.28 (lH, td, J ~6.9 , 2.1Hz). 3.89 (lH, br. s), 3.62 (lH, dd, J =9.4.5.4Hz),
3.55-3.48 (3H, m), 3.35 (3H. s), 3.33 (3H, s), 3.31 (3H, s), 2.69-2.67 (lH, m), 2.27-2.18
(3H, m), 2.04-1.92 (2H, m), 1.44-1.36 (lH, m); 13C NMR (100 MHz, CDCl3) 6 131.7,
123.7, 95.5,77.4,76.7,73.0, 71.4,58.6,55.4,52.5,45.8,38.5, 35.8,32.0; HRMScalcdfor
Ci5H260sw+H]+ 287.1858, found 287.1852
(IR*, 3aS*, a*, SR*, 7aR*)4~-bis-metEioxgmetbyI-2~~a,49,'7a-he~ydm lH-inden-l,3a-diol (a-OH-isomer) (26).
PPfS
OH MEK, reflux
To a solution of 24 (196.7 mg, 0.69 mrnol) in MEK (10 mL) was added PPTS
(172.6 mg, 0.69 m m ~ l ) . ~ The reaction mixture was heated to reflux (at 80 OC) for 38 h.
After the reaction was completed, MEK was removed at reduced pressure. The residue was
extracted with Et,O (3X), dried (MgSO,), filtered and concentrated. Purification by flash
chromatography (hexane-EtOAc L:2) gave 26 (108.8 mg, 65%) as a colorless oii: Rf= 0.26
on silica gel (hexane-EtOAc 1:2); IR (neat) 34û6, 2899, 1738, 1644, 1459, 1421, 1378,
133 1, 1291, 1234, 1189, 1109,986,944, 803,755 cm-'; lH NMR (400 MHz. CDCh) 6
5.91 (lH, d, J =10.1 Hz), 5.64 (IH, d, J =10.1 Hz), 4.41 (lH, s), 4.18 (lH, dt, J =13.4,4.6
Hz), 3.59-3.41 (4H, m), 3.31 (3H, s), 3.30 (3H, s), 2.66-2.63 (IH, m), 2.40-2.30 (2H, m),
2.20 (lH, s), 2.1 1 (1H. d, J =9.9 Hz), 1.71 (ZR t, J =7.6 Hz), 1.59-1.50 (lH, m); 13C NMR
(100 MHz, CDC13) 6 130.2, 126.4,75.7, 73.9,71.9,70.9,58.8,58.6,55.8,45.9, 38.2,33.8,
32.3; HRMS calcd for Ci3H&@l-Om+ 225.149 1, found 225.1487.
Dess-Martin periodinate (1 14.8 mg, 0.27 mmol) was added to a solution of 26 (64.6
mg, 0.23 mmol) in CH2Cl2 (3 mL) at O O C and the mixture was stirred for 90 min at dg
The reaction was quenched by the addition of an aqueous NaHCOg saturated solution. The
aqueous layer was extracted with Et20 (3X) and the combined organic layers were dried
(MgSO4), filtered, and concentrated. Purification by flash chromatography (hexane-EtOAc
2: 1) gave 27 (37.6 mg, 7546) as a colorless oil: Rf = 0.59 on silica gel (hexane-EtOAc 1:2);
IR (neat) 2926, 1699, 160 , 1450, 1384, 127 1, 1 192, 1 102,954, 820,754 cm-1; 1H NMR
(400 MHz, CDC13) S 6.23 (1 H, d, J ~ 9 . 5 HZ), 5.69 (1 H, dd, J =9.5, 3.1 Hz), 3.54-3.27
(lOH, m), 2.97-2.87 (2H, m), 2.76-2.60 (2H, m), 2.42 (2H. t, J 4.6 Hz); 1 3 ~ NMR (100
MHz, CDCI3) 6 205.2, 174.2, 136.4, 128.5, 118.2, 72.0, 70.0, 58.8, 58.7, 39.3, 37.5, 35.3,
28.9; HRMS calcd for Ci3H1803m+ 222.1256, found 222.1268.
(lS*, 3aS*, 4S*, SR", 7aR*)4$-bis-methoxymethyl-2~~a,4~,7a-hex~ydro-
m-hden-lJa-diol(lp-OH-isomer) (29).
To a solution of 25 (21.5 mg, 0.075 mmol) in CH,CN (1.7 mL) (containing 4%
H,O) was added LiBF, (50.4 mg, 0.58 mmol) in one portion.'' The reaction mixture was
heated at 72 OC with stirring for 2 h, then cooled to rt and poured into 20 mL of water. The
aqueous solution was extracted with Eh0 (329, dried (MgSO,), filtered and concentrated,
Purification by flash cbmatography (hexane-EtOAc 1: 1) gave 29 (8.1 mg, 45%) as a
colorless oïl: Rf = 0.39 on silica gel (hexane-EtOAc 1:2); IR (neat) 3363, 2928, 1741,
1449, 1274, 1198, 1109, 1151, 962, 836, 753 cm-1; 1~ NMR (400 MHz, CDCl3) 6 6.01
(lH, dt, J =10.1, 2.2 HZ), 5.74 (IH, dt, J =10.1, 3.1 HZ), 5.15 (lH, d, J ~ 2 . 6 HZ), 4.21-4.15
(IR, m), 3.75 (lH, d, J =11.7 Hz), 3.63 (lH, dd, J =9.5, 4.6 Hz), 3.58-3.45 (3H, m), 3.36
(3H, s), 3.34 (3H, s), 2.73-2.67 (lH, m), 2.37-2.25 (2H, m), 2.03-1.95 (3H, m), 1.48-1.37
(lH, m); 13~NMR(100MHz, CDC13)6 131.1, 126.0, 78.1,72.8, 71.9, 71.1, 58.9, 58.7,
5 1.8, 45.6, 38.2, 35.1, 34.8; HRMS calcd for Cl3H22O4W-H,O]+ 224-1412, found
224.141 1.
O
HOI,. OMe Dess-Martin
Dess-Martin periodinate (95.3 mg, 0.22 mmol) was added to a solution of 29 (45.4
mg, 0.19 mmol) in CH2C12 (2 mL) at O OC and the mixture was stirred for 90 min at d9
The reaction was quenched by the addition of an aqueous NaHCO3 saturateci solution. The
aqueous layer was extracted with Et20 (3X) and the combined organic layers were dried
(MgS04). filtered, and concentrated. muif-~cation by flash chromatography (hexane-EtOAc
1: 1) gave 27 (15.8 mg, 38%) as a colorless oil: Rf = 0.53 on silica gel (hexane-EtOAc 1:2);
IR (neat) 2924, 1698, 1600, 1460, 1386, 1294, 1192, 1109,951,916,789,752 cm-1; 1H
NMR (400 MHz, CDCI3) 6 6.25 (IH, dd. J =9.6, 2.1 Hz), 5.70 (lH, dd, J =9.5, 3.3 Hz),
3.57-3.29 (lOH, m), 2.98-2.89 (2H, m), 2.78-2.62 (2H, m), 2.43 (2H, t, J =4.6 Hz); 13C
NMR (100 MHz, CDCS) 6 205.3, 174.3, 136.4, 128.5, 118.3, 72.1, 70.0, 58.81, 58.78,
39.3, 37.6,35.3,28.9; HRMS calcd for C I ~ H ~ ~ O ~ M + 222.1256, found 222.1254.
n-Buli
Br toluene, -78°C
THPO THPO
8 30
To a suspension of 8 (6.27 g, 29.84 -01) and 1,S-dibromobenzene (7.04 g, 29.84
mrnol) in toluene ( 1 0 d) at -78 OC under N, was added dropwise 1 1-94 rnL (2.5 M in
hexane, 29.84 mmol) of n-BuLi in 31 rnL of toluene? After 2 h the reaction mixture was
warmed to rt and quenched with 1 mL of methmol, diluted with 150 mi, of EtOAc,
washed with H,O (3X), dried (MgSO,) and concentrated. Purification by flash
chromatography (hexane-EtOAc 5:l) gave 30 (5.47 g, 64%) as a yellowish oil: Rf= 0.30
on silica gel (hexane-EtOAc 5:l); IR (neat) 2943, 2870, 1453, 1352, 1261, 1242, 1200,
1 182, 1076, 1033,982,954 c d ; 'H NMR (400 MHz, CM313) 6 7.20-7.14 (2& m), 6.98
(lH, dd, J = 5.5, 1.8 Hz), 6.97-6.91 (2H, m), 6.77 (lH, dd, J = 5-4, 1.5 Hz), 5.63 (lH, d, J
= 1.8 Hz), 4.62-5.59 (lH, m), 3.91-3.81 (2H, m), 3.56-3.47 (2H, m), 2.50-2.28 (2H, m),
1.98- 1.79 (3H. m), 1.76- 1.68 (lH, m), 1.63- 1.48 (4H, m); 13C NMR (100 MHz, CDCl3) G
150.8, 150.5, 150.4, 144.5, 144.4, 124.8, 124.6, 119.8, 119.21, 119.19, 98.81, 98.79,
92.58, 81.6, 67.33, 67.31, 62.4, 62.3, 30.7, 25.97, 25.94, 25.46, 25.08, 19.65, 19.62;
HRMS calcd for C18H2203 M+ 286.1569, found 286-1584,
PPTS, MeOH - f
THPO
A solution of 30 (5.47 g, 19.10 mmol) in MeOH (92 mL) was treated with PPTS
(0.48 g, 1.91 mmol) and stirred for 24 h at rt. The reaction was quenched by the addition of
a saturated NaHC03 aqueous solution. MeOH was removed in vacuo and the aqueous
layer was extracted (3X) with Et20. The combined organic layers were dried (MgS04),
filtered and concentrated. Purification by flash chromatography (hexane-EtOAc 1: 1) gave
31 (3.63 g, 94%) as a yeiiowish oil: Rf = 0.36 on silica gel (hexane-EtOAc 1:l); IR (neat)
3317,3012,2944,2877, 1587, 1517, 1453, 1381,1354, 1275, 1246, 1148, 1053,996,826,
754 cm-1; IN: NMR (400 MHz, CDCl3) 8 8.24-8.22 (lH, m), 7.95 (lH, dd, J = 7.4, 1.7 Hz),
7.52-7.43 (2H, m), 7.09 (lH, d, J = 7.6 Hz), 6.68 (lH, d, J = 7.5 Hz), 6.25 (IH, br. s), 3.73
(2H, t. J =6.3 Hz), 3.04 (2H, t, J ~ 7 . 6 Hz), 2.01-1.93 (2H, m), 1.80 (lH, br. s ); 1 3 ~ NMR
(100 MHz, CDC13) 6 150.3, 132.7, 129.9, 126.3, 125.8, 124.9, 124.8, 123.7, 122.4, 108.1,
62.6,33.4,28.6; HRMS calcd for C13H1402 H+ 202.0994, found 202.0986.
Dess-Martin
Dess-Martin periodinate (616.4 mg, 1.45 mmol) was added to a solution of 31 (245
mg, 1.21 m o l ) in CH2CI2 (10 mL) at O OC and the mixture was stirred at rt under N, for 90
min.39 The reaction was quenched by the addition of an aqueous NaHCOs saturated
solution. The aqueous layer was extracted with Et20 (3X) and the combined organic layers
were dtied (MgS04), filtered, and concentrated. Purification by flash chromatography
(hexane-EtOAc 5:l) gave 34 (36 mg, 15%) as a colorless oil: Rf = 0.48 on silica gel
(hexane-EtOAc 1: 1); IR (neat) 2978, 1666, 1601, 1457, 1386, 1301, 1153, 1035, 946, 838,
765 cm-1; 1H NMR (400 MHz, -3) 6 8.08 (lH, d, J =7.1 Hz), 7.62-7.57 (2H, m), 7.44-
7.40 (lH, m), 7.03 (IH, d, J =10.3 Hz), 6.30 (lH, d, J 40 .2 Hz), 4.39-4.34 (1H, m), 4.26-
4.20 (lH, m), 2.34-2.17 (4H, m); 13c NMR (100 MHz, CDClj) 8 184.5, 150.7, 147.0,
133.0, 130.2, 127.8, 126.30, 126.26, 125.9, 79.2, 70.1, 41.6, 26.8; HRMS calcd for
C13H1202m+ 200.0837, found 200.0833.
A solution of 8 (13.0 g, 6 1.88 mmol) in MeOH (360 mL) was treated with PPTS
(1.82 g, 6.19 mmol) and stirred for 24 h at rt. The reaction was quenched by the addition
of a saturated NaHC03 aqueous solution. MeOH was removed in vacuo and the aqueous
layer was extracted (3X) with Et20. The combined organic layers were dried (MgSO4),
filtered and concentrated. Purification by flash chromatography (hexane-EtOAc 3: 1) gave
35 (6.89 g, 88%) as a colorlas oil: Rf rO.3 1 on silica gel (hexane-EtOAc 3: 1); IR (neat)
3356,2947, 1597, 1508, 1447, 1146, 1007,930,885,802,732,600 cm-1; 1H NMR (200
MHz, CDC13) 6 7.28 (lH, t, J = 1.0 Hz), 6.26-6.25 (lH, m), 5.99-5.98 (lH, m), 3.64 (2H,
t, J = 6.3 Hz), 2.70 (2H. f J = 7.5 Hz), 198 (LH, br. s), 1.91-1.84 (2H, m); 13C NMR (50
MHz, CDC13) 6 155.5, 140.9, 110.1, 104.9, 61.9, 30.9, 24.2; HRMS calcd for C7HL&
Ml+ 126.068 1, found 126.0675.
O Dess-Martin
CHO HO
36 35
Dess-Martin periodinate (3.87 g, 9.13 mmol) was added to a solution of 35 (960
mg, 7.61 mmol) in CH2C12 (40 mL) at O OC and the mixture was stirred for 90 min at rt.39
The reaction was quenched by the addition of a sanirated aqueous NaHC03 solution. The
aqueous layer was extracted with Et20 (3X) and the combined organic layers were dried
(MgS04), filtered and concenaated. Purification by flash chromatography (hexane-
EtOAc 10: 1) gave 36 (956 mg, -100%) as a colorless oil: Rf 4 - 6 1 on silica gel (hexane-
EtOAc 3:l); IR (neat) 2929,2730, 1724, 1597, 1508, 1391, 1008,885, 805,736 cm-1; 1H
NMR (200 MHz, CDCl3) 6 9.79 (lH, br. s), 7.28 (lH, d, J = 1.4 Hz), 6.25 (1H, dd, J =2.9,
NMR (50 MHz, CDCl3) 6 201.1, 153.8, 141.3, 110.2, 105.4,41.8, 20.6; HRMS calcd for
C 7 H g e @fJ+ 124.0524, found 124.0525
LaCI3, ( Me0)aCH
MeOH
CHO * Me0 7 OMe
36 37
36 (100 mg, 0.81 mmol) was dissolved in a 0.4 M methanol solution of
LaC1,-6H20 (284.6 mg, 0.81 mmol) and trîmethyl orthoformate (854.8 mg, 0.88 mi,. 8.1
mmol) was dropwise added to the reaction mixture?' It was stirred at ri for 4.5 h. The
reaction was quenched by adding 20 mL of 5% NaHCO, solution, extracted with Et20
(3 X), dried (Na,SO,), filtered and concentrated. Purification b y flash chroma tography
(hexane-EtOAc 20: 1) gave 37 (137 mg, -100%) as a colorless oil: Rf a .42 on silica gel
(hexane-EtOAc 10:l); IR (neat) 2930, 1738, 1597, 1508, 1467, 1382, 1241, 1126, 1057,
1007, 964,932 cm-l; lH NMR (200 MHz, CDCb) 6 7.28 (lH, t J = 0.9 Hz), 6.25 (1H.
dd, J =2.9, 2.1 HZ), 5-98 (lH, d, J =3-1 HZ), 4-37 (lH, t, J = 5.8 HZ), 3.3 1 (6H9 s), 2.67
(2H, t, J = 7.8 HZ), 1.95-1.89 (2H9 m); 13C NMR (50 MHz, CDCb) G 155-3, 140.9, 110.1,
104.9, 103.6,52.8,30.8,23.2; HRMS calcd for CgH1403 @tj+ 170.0943, found 170.0949.
+ n-&ili
Br hexane, -78°C
A Me0 OMe A Me0 OMe
To a suspension of 37 (101.8 mg, 0.60 mmol) and 1,2-dibromobenzene (141.1 mg,
0.60 m o l ) in hexane (2 mL) at -78 OC under N, was added dropwise n-BuLi (0.5 mL of
2.5 M in hexane, 0.60 rn~nol).'~ After 2 h the reaction mixture was warmed to rt,
quenched with 1 mL of methanol, diluted with 150 mL of EtOAc, washed with H20 (3X),
dried (MgSO,) and concentrated. Purification by flash chromatography (hexane-EtOAc
20:l) gave 38 (53.2 mg, 3696) as a yeilowish oïl: Rf =OS1 on silica gel (hexane-EtOAc
5: 1); IR (neat) 2938,2830, 1453, 1363, 1281, 1192, 1129, 1069, 1006,932,864,794,759,
693 cm-'; IH NMR (200 MHz, CDC13) 6 7.20 (1H. dd, J = 5.6, 1.7 Hz), 7.16 (lH, dd, J =
5-9, 1.5 Hz), 7.02 (lH, dd, J =5.5, 1.6 Hz), 7.00-6.92 (2H, m), 6.76 (fH, d, J d . 5 Hz),
5.64 (lH, d, J = 1.7 Hz), 4.50 (lH, t, J = 5.6 Hz), 3.36 (6H, s), 2.45-2.28 (2H, m), 1.99-
1.82 (2H, m); 1 3 ~ NMR (50 MHz, CDC13) 6 150.7, 150.2, 144.5, 144.3, 124.9, 124.7,
119.9, 119.2, 104.2,92.3, 81.7,53.0,52.7,27.7,23.9
1) nBu&U. THF
2) MOMCI. CH2C)L
\ CHO
36
To a solution of 36 (1.09 g, 8.81 mmol) in THF (2 mL), 25.91 mL of 0.34M n-
Bu,SnLi in THF was added dropwise at -78 OC. The reaction mixture was stirred for
additional 20 min^.^' Then it was quenched by adding 50 ml diluted NH4Cl solution,
extracted with hexane (3 x 50 ml), dried (bh$04), Ntered and concentrated (temperature
< 30 OC) to give 4.65 g crude a-hydroxy organostannane intermediate. The crude product
was dissolved in 22 mL of CH,Cl, containing N,N-dimethyl aniline (1.1 g, 9.07 mmol)
and cooled to O OC. The solution was stirred and MOMCl (7.09 mg, 88.1 1 m o l ) were
added. After 1 hour, the reaction mixture was poured into 100 ml of hexane and washed
successively with ice-cold 0.5 M aqueous hydrochlonc acid (2X), water, and saturated
aqueous sodium bicarbonate. The organic phase was dried (Na,SO,), filtered and
concentrated. Purification by flash chromatography (hexane-EtOAc 20: 1) gave 41 (2.21 g,
55%) as a colorless oil: Rfd.37 on silica gel (hexane-EtOAc MA); IR (neat) 2960,2921,
2892,2842,1592,1504,1465,1376,1146,1097,1033,915,793,719 cm-l; lH NMR (200
MHz, CDCl3) 6 7.28 (lH, t, J = 0.9 Hz), 6.25 (lH, dd, J=2.9, 2.1 Hz), 5.98 (IR, d, J=3.1
Hz), 4.37 (IH, t, J= 5.8 Hz), 3.31 (6H, s), 2.67 ( 2 8 t, J = 7.8 Hz), 1.95-1.89 (2H, m); 13C
NMR (50 MHz, CDC13) 6 155.9, 140.8, 110.0, 104.7, 96.6, 73.0, 55.5, 33.7, 29.2, 27.5,
26.5, 13.7,9.2; HRMS calcd for C 2 1 w 3 S n W-C&]+ 403.1295, found 403.1304.
n-BU + -
Br toluene, -78°C A
BuSn OMOM
41
To a suspension of 41 (2.09 g, 4.56 mmol) and 1,2-dibromobenzene (1.07 g, 4.56
mmol) in toluene (20 mL) at -78 OC under N, was added dropwise 1.8 m . (2.5 M in
hexane, 4.56 mmol) of n-BuLi in 8 mL of toluene? After 2 h the reaction mixture was
warmed to rt and quenched with 1 rnL of methanol, diluted with 100 mL of EtOAc,
washed with H,O (3X), dried (MgSO,) and concentrated. Purification by flash
chromatography (hexane-EtOAc 20: 1) gave 42 (1.92 g, 67%) as a colorless oil: Rf4.26
on silica gel (hexane-EtOAc 20: 1); IR (neat) 2923, 1742, 1594, 1462, 1377, 1292, 1 148,
1093, 1038,924, 758.69 1 cm-'; 1H NMR (200 MHz, CDCl3) 6 7.2 1 (IH, dd, J = 5.9, 1.8
Hz), 7.15 (lH, td, J = 6.2, 1.7 Hz), 7.19 (IH, d, J =5.5 Hz), 7.00-6.93 (2H1 m), 6.78 (lH,
d, J =5.5 Hz), 5.65 (lH, d, J = 1.8 Hz), 4.66 (lH, dd, J = 6.6,2.0 Hz), 4.60 (lH, d, J = 6.6
Hz), 4.19-4.14 (lH, m), 3.39 (3H, s), 2.58-2.26 (2H, m), 2.19-2.00 (2H, m), 1.55-1.46
(6H, m), 1.36- 1.27 (6H. m), 0.97-0.87 (15H. m); 13C NMR (50 MHz, CDCl3) 6 150.84,
150.79, 150.66, 150.51, 144.58, 144.45, 144.36, 144.34, 124.84, 124.68, 124.66, 119.91,
119.17, 119.09, 96.41, 96.39, 92.61, 92.60, 81.68, 77.31, 73.62, 55.56, 29.95, 29.89,
29.29, 29.19, 29.10, 27.79, 27.61, 27.50, 27.23, 13.70, 9.27, 9.23; HRMS calcd for
C27H4403Sn N-C&Ig]+ 479.1608, found 479.1599.
(3R*, 3aR*, 9bS*)-3-Methonymethoxy-1,23Ji-tetrahydro-cyclopen~(a]-
naphthalen9b-ol (p-MOM-isomer, isomer-1) (43) and (3S*, 3aR*, 9 bS*)-3-
Methoxy- methoxy-1,2,3,3a-tetrahydro-cyclopent[a]- naphthalen-9b-01 (a-MOM-
isomer, isomer-2) (44).
MeLi (3 eq) - THF, -78%
& n-Bu3S OMOM
A solution of oxabicyclic compound 42 (200 mg, 0.37 rnmol) in THF (4 mi,) was
cooIed to -78 OC and treated with a solution of MeLi (0.80 mL, 1.4M solution in Et,O, 1.1 1
mmol). The reaction mixiure was stirred at -78 OC for 20 mins then it was quenched by
adding saturated ammonium chioride solution (2 mL). It was extracted with Eh0 (3X). The
combined organic phase was dried (N*SO,), filtered and concen trated. Purification b y flash
chromatography (hexane-EtOAc 2:l) gave two isomers 43 and 44 (74.2 mg, 818, a$ =
1: 1):
Isomer- 1 (8-MOM-isomer) 43 as a white crystailine solid: m.p. 84-86 OC(CHCI,),
Rf = 0.48 on silica gel (hexane-EtOAc 1:l); IR (Nujol) 3462, 2925, 2727, 1460, 1377,
1276, 1 1 18, 1046,906, 846.8 13,763 cm-'; 'H NMR (400 MHz, CDCl3) 8 7.30-7.17 (4H,
m), 6.65 (lH, dd, J=9.5, 3.1 Hz), 6.26 (lH, ddJS.4, 2.1Hz),4.73 (2H, dd, J=17.1, 6.7
Hz),4.40(1H9 td, J=9.0,5.1Hz), 3.40(3H, s), 2.75 (lH, dt, J-9.9, 2.6 Hz), 2.62-2.57(1H,
m), 2.24-2.19 (3H. m), 1.92-1.85 (lH, m); l3C NMR (100 MHz, CDCl3) 6 139.7, 133.3,
129.5, 128.5, 128.3, 128.2, 127.5, 123.7, 96.6, 78.7, 78.3, 55.5, 53.8, 31.1, 30.5; HRMS
calcd for CisHlg03[M-Hl+ 245.1 178, found 245.1 175.
Isomer-2 (a-MOM-isomer) 44 as a white crysialluie solid: m.p. 83-85 "C(CHC1,).
Rf = 0.38 on silica gel (hexane-EtOAc 1:l); IR (Nujol) 3442, 2965, 2104, 1652, 1463,
1377, 1152, 1040,722 cm-l; NMR (400 MHz, Cm13) 6 7.33-7.18 (4H, m), 6.69 (IH,
dd, J =9.4, 2.8Hz), 6.23 (lH, d, 1 =9.4 Hz), 4.784.67 (2H, m), 4.51 (lH, s), 3.50 (lH, s),
3.43 (3H. s), 2.65 (lH, s), 2.47-2.25 ( 3 8 m), 2.07-1.98 (IH, m); l3C NMR (100 MHz,
CDCl3) 6 138.8, 133.8, 130.0, 128.1, 127.7, 127.2, 125.6, 124.2, 95.3, 79.5, 76.6, 55.6,
52.3,33.8,3 1.6; HRMS calcd for ClsHla03w-H20]+ 228-1150, found 228.1 154
To a solution of 43 (34.5 mg, 0.14 m o l ) in methanol(1.5 mL) was added the
Lindlar catalyst (3.45 mg), The reaction mixture was stirred under a hydrogen filled
balloon for 3 days." M e r the reaction was complete, the mixture was filtered through a
pad of celite. The solvent was evaporated and the residue was punfied by flash
chromatography (hexane-EtOAc 3:l) to give 49 (16.3 mg, 47%), isomer-1 (PMOM-
isomer), as a white crystalline solid: m.p. 79-81 *C(CHCb), Rf = 0.35 on silica gel
(hexane-EtOAc 3: 1); IR (Nujol) 3463, 2924, 146% 1377, 1301, 1272, 1220, 1148, 1105,
1041, 900, 769 cm-1; 1H NMR (400 MHz, CDCI3) 8 7.33 (lH, d, J =6.6 Hz), 7.26-7.16
(3H, m), 4.70 (2H, dd, J =21.2, 6.6 Hz), 4.194.13 (lH, m), 3.39 (3H, s), 3.04-2.86 (2H,
m), 2.52-2.42 ( lH, m), 2.33-2.27 (lH, m), 2.12-1.92 (4H, m), 1.80-1.72 (lH, m), 1-48
(lH, br. s); 13C NMR (100 MHz, CDC13) 6 141.3, 136.9, 129.6, 128.1, 126.3, 125.6,96.5,
80.7, 77.6, 55.5, 51.9, 34.2, 29.8, 29.6, 20.1; HRMS calcd for CIsH20031M]+ 248.1412,
found 248.1412.
M o M o , , . p Lindlar's catalyst, [Hl
OH methanol m M O M O , , . - ' p OH
qq isomer-2 50
To a solution of 44 (28.9 mg, 0.12 m o l ) in methanol(l.2 mL) was added the
Lindlar catalyst (2.89 mg), The reaction mixture was stirred under a hydrogen filled
balloon for 3 days? TLC monitored the reaction. After the reaction was complete, the
mixture was filtered through a pad of celite and the solvent was evaporated. Purification
by Rash chromatography (hexane-EtOAc 3: 1) gave 50 (20 mg, 48%), isomer-2 (a-MOM-
isomer), as a white crystalline soiid: m.p. 66-68 OC(CHCl,), Rf = 0.30 on silica gel
(hexane-EtOAc 3:l); IR (Nujol) 3486, 2923, 1465, 1377, 1271, 1214, 1147, 1092, 1035,
949, 936, 783, 762, 722 cm-1; lH NMR (400 MHz, CDC13) 8 7.39 (lH, d, J =6.6 Hz),
7.26-7.12 (3H, m), 4.68 (2H, dd, J =36.0,6.6 Hz), 4.36 (lH, t, J =5.1 Hz), 3.43 (lH, s),
3.40 (3H, s), 3.14-3.08 (lH, m), 2.98-2.89 (lH, m), 2.61-2.55 (lH, m), 2.37-2.07 (3H, m),
1.97-1.82 (3H, s); 13C NMR (100 MHz, CDCI3) 8 140.9, 136.7, 129.3, 127.8, 126.4,
l26.0,95.2, 79.2, 78.9,55.7,50.3,36.3,3 1.2,29.9, 17.9; HRMS calcd for C1~H2003m]+
248.1412, found 248.1407
Preparation of Zinc-Silver couple.
Aqueous 10% hydroçhioric acid (10 mL) was added to zinc dust (2. lg, 3 1.5 mmol)
and the resulting suspension was shaken periodically. After severai minutes, the
supernatant Liquid was decanted and the zinc was washed with acetone (2X) and ether
( lx) . A suspension of silver acetate (65 mg) in boiling acetic acid (10 mL) was added.
After the mixture was stirred for 1 min, the supernatant was decanted and the black ZdAg
couple was washed with acetic acid (lx), ether (4X), and methmol (lx). The moist
couple can be directly used in the next step?
Preparation of Zinc-Copper couple.
To a hot (nearly refluxing) solution of cupnc acetate monohydrate (0.5 g) in
glacial acetic acid (50 mL) was added zinc dust (35 g). The mixture was shaken for 1 to 3
min, keeping it hot during this p e n d to prevent prrcipitation of zinc acetate. The acetic
acid was decanted and the zinc-copper couple was washed with glaciai acetic acid (LX)
and ether (3X). The ZnKu couple was typicdy shaken with each washing solution for 1
min. The ether-rnoistened couple cm be directly used in the next step, or it can be fked of
ether using a Stream of nitrogen?
To a solution of 8 (10.7 g, 50.93 mmol) in 64 mL of THF was added Zn-Ag couple
(5.0 g, 76.40 mmol) at -7 OC, and then 1,1,3,3-tetrabromoacetone (19.03 g, 50.93 mmol)
slowly over 1 h." The reaction mixture was stirred at -7 OC for 4 h, then warmed up to n
and stirred ovemight. The reaction mixture was filtered through a pad of celite and
concentrated to give 26.5 g of the crude brornide which was dissolved in a saturated
W4Cl solution in methanol(220 mL). Zn-Cu couple (20.88 g, 3 14.10 mmol) was added
portionwise to it at O OC, then the reaction mixture was stirred for 2 h. It was exothennic
during the reaction. The mixture was filtered through a pad of celite and washed with
saturated NH,Cl solution ( l x ) and water (lx). The filtrate was extracted with CH2Cl,
(3X). The organic layer was washed with brine (lx), dried (MgSO,), filtered and
concentrated. Purification by flash chromatography (hexane-EtOAc 3: 1) gave 52 (4.29 g,
30%) as a yeLiowish oil: Rf= 0.24 on silica gel (hexane-EtOAc 3: 1); IR (neat) 2943,2859,
17 14, 1442, 1402, 1343, 1279, 1 198, 1124, 1 121, 1076, 1021 cm-1; IH NMR (400 MHz,
CDC13) 6 6.19 ( 1 s dd, J = 6.0, 1.8 Hz), 6.06 (lH, d, J = 5.9 Hz), 5.05 (lH, d, J = 5.1 Hz),
4.58 (IH, dd, J=4.4, 2.5 Hz), 3.89-3.74 (2H, m), 3.54-3-40 (2H, m), 2.69 (lH, dd, J =
16.3, 5.1 Hz), 2.54 (lH, d, J = 16.2 Hz), 2.38 (1H, d, J =16.1 Hz), 2.30 (IH, d, J = 16.3
Hz), 1.90-1.49 (lOH, m); 13C NMR (100 MHz, CDCl3) 6 206.2, 135.0, 133.4, 98.82,
98.75, 86.1, 77.3, 67.3, 67.2, 62.34,62.29, 51.24, 51.23, 45.38, 32.96, 32.94, 30.6, 25.4,
24.2, 19.58, 19.55; HRMS calcd for C15H2204 @fj+ 266.1518, found 266.1522.
To a solution of 52 (3.06 g, 11.49 mmo) in THF (23 mL) was added 1.0 M L-
selectride (23 mL, 22.98 mmol) at -78 OC. The reaction mixture was stirred for 2 h, then
warmed to O The reaction was quenched by adding 5.0 M aqueous NaOH solution (5
mL), followed by 30% H,O, (5 mL). The aiixture was allowed to warm to rt and the
aqueous layer was extracted with Et@ (3X). The combined organic layers were dried
(MgSO,), filtered and concentrated. Purification by flash chromatography (hexane-EtOAc
1 :2) gave 53 (2.8 1 g, 9 1%) as a colorless oil: Rf = 0.27 on silica gel (hexane-EtOAc 1 :2);
IR (neat) 3460,2942, 2870, 1442, 1348, 1261, 1201, 1184, 1076, 103 1,906, 870, 815,
732, 691 c d ; 1H NMR (400 MHz, CDCl3) 6 6.36 (lH, dd, J = 5.9, 1.5 Hz), 6.18 (LH, d,
J = 5.8 Hz), 4.74(1H, br. s),4.52 (IH, br. s), 3.96 (IH, br. s), 3.84-3.77 (lH, m), 3.74-
3.66 (IH, m), 3.48-3.33 (2H, m), 2.30 (LH, br. s), 2.17-2.10 (lH, m), 2.00 (lH, dd, J =
14.7, 5.9 Hz), 1.80-1.43 (12H, m); 13C NMR (100 MHz, CDCI3) 6 137.4, 136.0, 98.7,
98.6, 85.3, 78.5, 67.49, 67.46, 65.6, 62.24, 62.21, 41.0, 35.5, 33.76, 33.75, 30.6, 25.4,
24.0, 19.5; HRMS calcd for C 15H2404 m+H]+ 269-1753, found 269.1759.
(IR*, 3S*, SS*)-3-Methoxy-l-[3-(tetr~ydro-pyrm-2-y10xy)-propyIJ-8-0xa-
NaH, THF then Mel
THPO TH PO 53 55
A solution of 53 (1.96 g, 7.3 1 mmol) in THF (8 m . ) was added to a suspension of
NaH (263.28 mg, 50% in oil, 10.97 m o l ) (washed 3 times with pentane) in THF (32 mL)
at O "C and the mixture was stirred for 1 h at rt. After the dropwise addition of Me1 (3.1 1
g, 1.37 mL, 21.94 mmol) at O OC, the mixture was stirred for 1 h at rt and heated at reflux
for an additional 1 h. The reaction was quenched with drops of MeOH and the solution
was diluted with water. THF was removed in vacuo and the aqueous layer was extracted
(3X) with EbO. The combined organic layers were dried (MgSO,), filtered and
concentrated. Purification by flash chromatography (hexane-EtOAc 3: 1) yielded 55 (1.97
g, 95%) as a colorless oil: Rf = 0.37 on silica gel (hexane-EtOAc 3:l); IR (neat) 2941,
1454, 1442, 1366, 1347, 1261, 1201, 1078, 1033, 988, 870, 815 cm-'; 1H NMR (400
MHz, CDC13)6 6.13 (lH, dd, J = 5 . 9 , 1.6Hz), 5.97 (lH, d, J=6 .1 Hz), 4.68 ( lH, t, J =
1.8 Hz), 4.53 (lH, t, J = 3.4 Hz), 3.84-3.78 (IH, m), 3.74-3.66 (IH, m), 3-50 ( lH, t, J =
5.6 Hz), 3.47-3.33 (2H, m), 3.17 (3H, s), 2.03-1.96 (IH, m), 1.88-1.43 (13H, m); 13C
NMR (100 MHz, CDCLj) 6 135.3, 133.9, 98.7,98.6, 84.9, 78.3, 74.5, 67.61,67.57,62.2,
56.3, 36.6, 34.0, 31.1, 30.7, 25.4, 24.1, 19.5; HRMS calcd for C1&12604 [M+H]+
283.1909, found 283.1897.
PPTS, EtOH
THPO 55 - HO fioMe 56
A solution of 55 (LOO mg, 0.35 m o l ) in EtOH (4 mL) was treated with PFTS
(4.45 mg, 0.018 mmol) and heated at 55 OC for 5 h. The reaction was quenched by the
addition of a saturated aqueous NaHC03 solution. EtOH was removed in vacuo and the
aqueous Iayer was extracted with Et20 (3X). The combined organic layers were dried
(MgS04), filtered and concentrated. Purification by flash chrornatography (hexane-EtOAc
1:3) gave 56 (64.7 mg, 92%) as a colorless oil: Rf = 0.22 on silica gel (hexane-EtOAc
1:2); IR (neat) 3434,2930,1602,1446, 1347, 1299,1260, 121 1, 1080,939,875,8 15 cm-
'; 'H NMR (400 MHz, CDCl3) 8 6.14 (IH, dd* J = 6-09 1.7 HZ), 5.95 (1& d, J = 6.0 HZ),
4.71 ( lH, t, J = 2.0 Hz), 3.60-3.55 (2H, m), 3.51 (IH, td, J = 6.0, 0.9 Hz), 3.17 (3H, s),
2.78 (LH, br. s), 2.02-1.95 ( 2 8 m), 1.88 (lH, dd, J-14.5.6.1 Hz), 1.75-1.56 (5H, m); 13C
NMR (100 MHz, CDCl3) 8 135.3, 133.9, 85.1, 78.5, 74.4, 63.0, 56.3, 36.8, 34.2, 30.9,
27.0; HRMS calcd for Ci rH1803 FI-OCH,l+ 167.1072, found 167.1057.
( 1 JS*, SS*)-3-(3-Methoxy-8-oxa-bicyclo[3~2~l]oct-6-en-l-y1)-
propionaldehyde (57).
O Dess-Martin --
CHO O M ~
57
Dess-Martin periodinate (2.13 g, 5.02 mmol) was added to a solution of 56 (830
mg, 4.19 rnmol) in CH2C12 (33 mL) at O OC and the mixture was stirred for 90 min at d9
The reaction was quenched by the addition of an aqueous NaHC03 saturated solution.
The aqueous layer was extracted with Et20 (3X) and the combined organic layers were
dried (MgS04), filtered and concentrated. Purification by flash chromatography (hexane-
EtOAc 1.5: 1) gave 57 (8 10-9 mg, 99%) as a colorless oil: Rf= 0.30 on silica gel (hexane-
EtOAc 1.51); IR (neat) 2920, 2820, 2722, 1724, 1602, 1440, 1369, 1347, 1299, 1242,
1084, 1029, 939, 874 cm-'; lH NMR (400 MHz, CDClj) 6 9.70 (lH, t, J =1.3 Hz), 6.12
( lH, dd, J = 5.8, 2.0 Hz), 5.83 (IH, dd, J = 5.9,2.6 Hz), 4.64 (IH, br. s), 3.47 (lH, t, J =
5.8 Hz), 3.14 (3H, d, J =2.7 Hz), 2.54-2.33 (2H, m), 1.98-1.60 (6H. m); 1 3 ~ NMR (100
MHz, CDC13) 8 202.3, 134.9, 134.5, 84.2, 78.4,74.2, 56.3, 38.3, 36.9, 30.9, 29.0; HRMS
calcd for C 1 lH1603 w+ 196-1099, found 196.1 102.
1) rrBu3SnLi
CHO OMe 2) MOMCl Bu
To a solution of 57 (50 mg, 0.25 mmol) in THF (1 mi,) at -78 OC was added 0.75
mL of 0.34M n-Bu,SnLi in The reaction mixture was stirred for 20 mins, then
quenched by adding 10 mL of dilute NRCI solution. The aqueous layers were extracted
with hexane (3X), dried (Na,SO,), filtered and concentrated (temperature < 30 OC) to give
203.5 mg of the crude a-hydroxy organostannane. The oil was dissolved in 1 mL of
CH,Cl, containing N,N-dimethyl aniline (31.8 mg, 0.26 mmol) and cooled to O O C . The
solution was stirred and MOMC1 (123.1 mg, 1.53 mmol) were added. After 1 h the
reaction mixture was poured into 50 ml of hexane and washed successively with ice-cold
0.5 M aqueous hydrochloric acid (2X). water, and saturated aqueous sodium bicarbonate.
The organic phase was dried (Na$O,), filtered and concentrated. Purification by flash
chromatography (hexane-EtOAc 7: 1) gave 59 (85.9 mg, 642) as a colorless oil: Rf g.28
on silica gel (hexane-EtOAc 7:l); IR (neat) 2925, 1464, 1375, 1346, 1294, 1229, 1145,
1096,1029,918,874,818,734,688 cm-1; IH NMR (200 MHz, CDCl3) 6 6.12 (lH, d, J =
6.1 Hz), 5.96 (lH, d, J = 5.9 Hz), 4.76 (lH, t, J =1.9 Hz), 4.55 (lH, dd, J =6.6, 0.7 Hz),
4.49 (lH, dd, J ~6.6 , 1.5 Hz), 4-00 (IH, t, J = 6.4 HZ), 3-50 (lH, t, J = 5-8 HZ), 3.29 (3H,
s), 3.17 (3H, s), 2.10-1.60 (8H, m), 1.49-1.38 (6H, m), 1.30-1.21 (6H, m), 0.88-0.80 (lSH,
III); 13C NMR (50 MHz, CDCl3) G 135.34. 135.18, 133.88, 133.82, 96.21, 96.169 84.93,
84.85, 78.28, 74.55, 73.69,73.65,56.33,55.39, 36.93, 36.72, 35.79, 35.56, 30.96,29.21,
29.12, 29.02, 28.99, 28.89, 27.43, 13.63, 9.12, 9.10; HRMS calcd for C25H4804Sn [M-
CJ39]+ 475.1870, found 475.1883.
(IR*, 3aR*, SS*, 8aR*)-5-Methoxy-1-methoxymethoxy-2,3,4,5,6,8a-
hexahydro-IH-den-3a-01($-MOM-isomer, isomer-1) (60) and (lS*, 3aR*,
SS*, 8aR*)-5-Methoxy-1-methog4miethoxy-2~,4~,6,8a-hexahydro-~-azulen-3a-ol
(a-MOM-isomer, isomer-2) (61).
A solution of oxabicyclic compound 59 (459.1 mg, 0.86 mmol) in THF (12 mL)
was cooled to -78 OC and treated with a solution of MeLi (1.85 mL, 1.4M solution in EbO,
2.59 m o l ) . The reaction mixture was stirred at -78 OC for 30 mins then it was quenched
by adding saturated ammonium chloride (15 mL) and then extracted with Eh0 (3X). The
combined organic phase was dried (Na,SO,), fdtered and concentrated. i?urification by flash
chromatography (hexane-EtOAc 1 : 1) gave two isomers 60 and 61 (f3- and a-MOM-
isomers) (170.6 mg, 82%, a$ = 1:l):
Isorner-l (PMOM-isomer) 60 cannot be separated from an unhowu impurity.
The mixture was directly used in the hydrolysis step.
Isomer-2 (a-MOM-isomer) 61 as a colourIess oil: Rf = 0.20 on silica gel (hexane-
EtOAc 1: 1); IR (neat) 3479,2932, 1448, 1351, 1255, 1191, 1041,983,917, 863, 829,694
cm-1; IH NMR (400 MHz, CDClj) 6 6.01-5.94 (lH, m), 5.71 (lH, dt, /=10.4,3.2Hz), 4.61
(2H, dd, J=23.3,6.8Hz),4.224.17 (lH, m), 3.31 (3H,s), 3.29 (3H, s), 3.17-3.10(1H, m),
2.65-2.60 (lH, m),2.55-2.49(lH, m), 2.44-2.39(1H, m), 2.28-2.11 (2H, m), 1.82(2HT t, J
=7.9 Hz), 1.65-1.52 (3H, m); 1 3 ~ NMR (100 MHz, CDCl3) 6 132.1, 130.2, 95.7, 83.2, 78.5,
73.9,56.2,55.3,55.0,48.8,38.5,34.0,28.8
To a solution of 60 (48.8 mg, 0.20 mmol) in CH,CN (2 mL) (containing 4% H20)
was added LiBF, (67.6 mg, 0.72 mmol) in one portion." The reaction mixture was heated at
70 OC with stunng for 24 h, then cooied to rt and poured into 20 mL of water. The aqueous
solution was extracted with Et,O (3X), dried (MgSO,), filtered and concentrated.
Purification by flash chromatography (hexane-EtOAc 1:l) gave 62 (10 mg, 25%) as a
colorless oil: Rf = 0.25 on silica gel (hexane-EtOAc 1:2); IR (neat) 3416,2935, 1715, 1651,
1449, 1349, 1300, 1220, 1 192, 1150, 1082,990,932,878. 826,753 cm-'; IH NMR (400
MHz, CDCI3) 6 6.00-5.97 (2H, m), 4.24 (1H. br. s), 3.32 (3H. s), 3.22 (lH, tt, J =10.5,2.7
Hz), 2.61-2.48 (4H, m), 2.40 (IH, br. s), 2.20-2.02 (3H, m), 1.97-1.88 (LH, m), 1.76-1.68
(lH, m), 1.58-1.51 (LH, dd, J t13.4, 11.1 Hz); I3c NMR (100 MHz, CDCl3) 6 129.1,
128.8, 81.1, 76.4, 74.0, 56.3,52.8,48.6, 39.7, 34.3, 33.4; HRMS calcd for CllHls03FI]+
198.1256, found 198-1249
To a solution of 61 (75.6 mg, 0.31 m o l ) in CH,CN (3 mL) (containing 4% H,O)
was added LiBF, (58.5 mg, 0.62 mmol) in one portion.45 The reaction mixture was heated at
55 OC with stirring for 3 days, then cooled to r t and poured into 20 mL of water. The
aqueous solution was extracted with Eh0 (3X), dried (MgSO,), filtered and concentrated.
Purification by flash chromatography (hexane-EtOAc 1:2) gave 63 (24.4 mg, 39%) as a
colorless oïl: Rf = 0.10 on silica gel (hexane-EtOAc 1 :2); IR (neat) 34 18,2943, 17 16, 1446,
1369, 1348, 1300, 1241, 1216, 1075, 939, 875, 815, 755, 691, 666 cm-1; IH NMR (400
MHz, CDCl3) 6 6.16 (IH, dd, J =6.1, 1.7 Hz), 5.97 (lH, d, J =6.0 Hz), 4.74 (1H. br. s),
3.66-3.56(2H, m),3J3 (lH,t, J=5.9Hz),3.19(3H,s), 2.31 (lH, br. s), 2.04-1.98 (LH,m),
1.91 (LH, dd, J =14.5, 6.1 Hz), 1.77-1.58 (6H, m); l3C NMR (100 MHz, CDCl3) G 135.4,
134.0, 85.1, 78.6, 74.5, 63.1, 56.4, 36.8, 34.3, 30.9, 27.1; HRMS calcd for
C l I H 1 8 0 3 ~ + ~ + 199.1334, found 199-1335
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APPENDLX 1
SELECTED SPECTRA OF REPRESENTATIVE COMPOUNDS
OHC J
12
Y-
U-.. U-11
OMOM
(from isomer-1)
(from isomer-2)
/ OMe THPO
HO OMe
56
CHO OMe
-. Il. sr
it.n
- Il*
APPENDIX 2
X-RAY CRYSTAL DATA FOR COMPOUND 43,44
SINGLE CRYSTAL X-RAY DETERMINATION OF 43
PL'osorp cion coefficient
F(000)
Crystal site
Theta range for data coIlection
index ranges
Independent reflections
Completeness to theta = 27-48"
Absorption correction
Max. and min. transmission
Refinemenc method
Data / resuainu / parameters
Goodness-o f- fit on F
Final R indices [I > 2 s i p ( I ) J
R indices (a11 data)
Extinction coefficient
Largest diff. peak and hole
Table 1. Crystal data and structure refmement for k9994.
Identification code Hg94
Empirical fomuia C1S Hl8 03
Formula weight 246.29
Temperature 100.0(1) K
Wavelength 0.71073 A Crystai system Monaclinic
Space group P2(1)/n
Unit ce11 dimensions a = 6.7392(3) a a= 90"-
b = 7.1787(3) A = 95.442(2) O .
c = 27.1178(12) À y = 90".
1306.01(10) A3
4
1.233 Mg/m3
0.086 m m x
528
0.25 x O. 10 x 0.05 mm3
4.14 to 27-38".
O < = h < = 8 , O < = k < = 9 , -35<=1<=35
13868
2975 pqrnt) = 0.1011
99.3 R
muiti-scan (Denzo-SMN)
0.9957 and 0.9788
Fdl-mauix ieast-squares on F2
2975 / 0 / 166
O. 852
RI = 0.0407. wR2 = 0.0831
RI = 0.1025. wR2 = 0.0953
0.0049(15)
0.180 and -0.225 e.À-3
Table 2. Atomic coordinates ( x IO4) and equivalent isotropie displacement parameters (Azx 103)
for k9994. U(eq) is defined as one third of the trace of the onhogonzlized UiJ tensor.
Table 3. Bond 1en;rhs [À] and angles [O] for k9994.
Symmetry t r a n s f o d o n s u e d to generate quivalent atoms:
Table 4. - Ankocropic displacement parameters (À2r 10)) for 18994. The anisouopic
displacement factor exponent takes the fom: -2x2[ h2 a*2U1 + . . . t 2 h k a* b* UiZ 1
TabIe 5. Hydrogen coordinates ( x 104) and isotropie displacement parameten (À2x 10 3,
for k9994.
Table 6. Hydrogen bonds for kg994 [A and "1 -
D-H.. .A d@-ff) d(H...A) d(D ... A) <@HA)
S ymmetry uansformauons used to generate equivalent arorns:
$1 &y-1 ,z
SINGLE CRYSTAL X-RAY DETERMINATION OF 44
Volume
Absorption coefficient
Theta range for data collection
Index ranges
independent reflections
Completeness to theta = 27.49"
Absorption correction
Max. and min- transmission
Refmement method
Data / resuaints / parameten
Goodness-of-fit on F' Final R indices CI > &igma(I)]
R indices (al1 data)
Extinction coefficient
Largest diff. peak and hoIe
Table 1. CrystaI data and structure refmernent for k9993-
idenufication code kg993
Ernpiricai formda CL5 H l 8 03
Fornula weight 246.29
Temperature LOO.O(I) K
Wavelength 0.71073 A Crystal system Monociinic
Space group P2(1)/n
Unit ceIl dimensions z = 8 -6775(3) a a= 90".
b = 10-3061(3) a p = 102.971(2)"-
c = 14.5936(4) A y = 90".
1271.82(7) a3 4
1.286 Mg/m3
0.088 mm-'
528
0.35 x 0.34 x 0.30 mm3
4.21 to 27-49".
OC=h<=l I . O<=k<=13, -18<=1<=18
13889
2909 m(int) = 0.0421
99.6 '%
muiti-scan (Derno-SMN)
0.9740 and 0.9697
Full-matrix least-squares on F2
2909 / O / 166
1 .O64
RI = 0.0397, wR2 = 0.1020
Ri = 0.0561, wR2 = 0.1073
0 .Oû2(3)
0.258 and -0.193 e.A-3
Table 3. Bond lengths [A] and angles [O] for k9993.
Symmetry transformations used to generate equivaient atoms:
Table 4. hisotropic displacement parameters (a'x 103) for k9993. The anisouopic
displacement factor exponent cakes the fom: -2&[ h2 a*'UX1 + .+. i 2 h k a* b* UI2 3
Table 5- Hydrogen coordinates ( x IO4) and isotropie displacement panmeters (À2x 10 3,
for k9993.
Table 6. Hydrogen bonds for kg993 [À and O ] .
Symrnetry transformations used to generate equivaient atoms:
# l -x+ l /2 ,y+ 1 /2 , -~+3/2
