Convergent enantioselective synthesis of vinigrol, an architecturally novel diterpenoid with potent platelet aggregation inhibitory and antihypertensive properties. 1. Application of anionic sigmatropy to construction of the octalin substructure

Article abstract of DOI:10.1021/jo0301301

The coupling of building blocks 15 and 36e in the presence of MgBr₂·OEt₂ at 0 °C proceeds with an exo stereoselectivity (3.2:1) considerably more advantageous for the acquisition of carbinol 37e than in the absence of the additive (exo/endo = 1:5.7). The pivotal transformation that sets all of the relevant stereocenters of the cis-octalin 55 is the oxyanionic-accelerated [3,3]-sigmatropic rearrangement of 37e. A salient feature is the structurally enforced adoption of a boatlike transition state that serves to properly set four vicinal methine hydrogens in an all-cis arrangement. The ensuing conversion of 55 into iodo sulfone 62 has permitted X-ray crystallographic confirmation of all absolute stereochemical assignments since the isopropyl substituent was initially installed enantioselectively via the Evans oxazolidinone protocol. No intramolecular anionic cyclization of 62 to generate the tricyclic framework was seen. This absence of reactivity is attributed to conformational factors that inhibit attainment of the proper S_N2 reaction trajectory.

Full text of DOI:10.1021/jo0301301

Con ver gen t En a n tioselective Syn th esis of Vin igr ol, a n
Ar ch itectu r a lly Novel Diter p en oid w ith P oten t P la telet
Aggr ega tion In h ibitor y a n d An tih yp er ten sive P r op er ties. 1.
Ap p lica tion of An ion ic Sigm a tr op y to Con str u ction of th e Octa lin
Su bstr u ctu r e
Leo A. Paquette,* Ronan Guevel,1a Shuichi Sakamoto,1b In Ho Kim,1c and J ason Crawford1d
Department of Chemistry, The Ohio State University, Columbus, Ohio 43210
paquette.1@osu.edu
Received April 14, 2003
The coupling of building blocks 15 and 36e in the presence of MgBr2‚OEt2 at 0 °C proceeds with an
exo stereoselectivity (3.2:1) considerably more advantageous for the acquisition of carbinol 37e
than in the absence of the additive (exo/endo ) 1:5.7). The pivotal transformation that sets all of
the relevant stereocenters of the cis-octalin 55 is the oxyanionic-accelerated [3,3]-sigmatropic
rearrangement of 37e. A salient feature is the structurally enforced adoption of a boatlike transition
state that serves to properly set four vicinal methine hydrogens in an all-cis arrangement. The
ensuing conversion of 55 into iodo sulfone 62 has permitted X-ray crystallographic confirmation of
all absolute stereochemical assignments since the isopropyl substituent was initially installed
enantioselectively via the Evans oxazolidinone protocol. No intramolecular anionic cyclization of
62 to generate the tricyclic framework was seen. This absence of reactivity is attributed to
conformational factors that inhibit attainment of the proper SN2 reaction trajectory.
Fungi have been the source of a wide variety of
structurally unique and pharmacologically active com-
pounds. In 1987/1988, a group of scientists from the
Fujisawa Pharmaceutical Co. reported the isolation from
Virgaria nigra and the structural elucidation of a diter-
penoid, the antihypertensive and platelet-inhibiting prop-
erties of which held unusual promise.2 Spectroscopic
studies, capped by an X-ray crystallographic analysis,
established this substance, named vinigrol, to possess a
totally unprecedented decahydro-1,5-butanonaphthalene
framework as defined by 1. These unusual structural
features, and the subsequent discovery that vinigrol is
also a powerful tumor necrosis factor antagonist and an
agent capable of arresting the progression of the AIDS-
related complex to AIDS,3 have fueled interest in 1 as a
challenging synthetic objective.4-6 Despite the application
of several imaginative strategies to this problem, a de
novo route to 1 has not yet been achieved. Herein we
describe, with full experimental detail, a route to an
advanced precursor of vinigrol. The present investigation
highlights the utility of anionic oxy-Cope chemistry for
constructing an extensively functionalized octalin ring
system having the dual R configuration present in
appendages housing both C9 and C12.
(1) Current addresses: (a) CRIT-Pharma, 24 Avenue J ean J aures,
69153 Decines, France. (b) Yamanouchi Pharmaceutical Co. Ltd., 21
Miyukigaoka, Tsukuba Ibaraki, 205-8585 J apan. (c) Laboratory of
Bioorganic Chemistry, National Institute of Diabetes, Digestive and
Kidney Diseases, NIH, Bethesda, MD 20892. (d) AnorMED Inc., 200-
20353 64th Ave., Langley, B.C., Canada V2Y IN5.
(2) (a) Uchida, I.; Ando, T.; Fukami, N.; Yoshida, K.; Hashimoto,
M.; Tada, T.; Koda, S.; Morimoto, Y. J . Org. Chem. 1987, 52, 5292. (b)
Ando, T.; Tsurumi, Y.; Ohata, N.; Uchida, I.; Yoshida, K.; Okuhara,
M. J . Antibiot. 1988, 41, 25. (c) Ando, T.; Yoshida, K.; Okuhara, M. J .
Antibiot. 1988, 41, 31.
(3) Norris, D. B.; Depledge, P.; J ackson, A. P. PCT Int. Appl. W0 91
07 953; Chem Abstr. 1991, 115, 64776h.
(4) (a) Devaux, J .-F.; Hanna, I.; Lallemand, J .-Y. J . Org. Chem. 1993,
58, 2349. (b) Devaux, J .-F.; Fraisse, P.; Hanna, I.; Lallemand, J .-Y.
Tetrahedron Lett. 1995, 36, 9471. (c) Devaux, J .-F.; Hanna, I.; Lalle-
mand, J .-Y. J . Org. Chem. 1997, 62, 5062. (d) Gentric, L.; Hanna, I.;
Ricard, L. Org. Lett. 2003, 5, 1139.
Resu lts a n d Discu ssion
Retr osyn th etic An a lysis. In line with our long-range
plan to advance to 1 in nonracemic fashion, the strategy
as defined in Scheme 1 was based on the expectation that
the cyclization of 3 or a close relative thereof would lead
via 2 to the enantiopure diterpenoid target. With the
focus on 3, proper access to this intermediate by meth-
odology capable of accommodating the proper juxtaposi-
tioning of six contiguous stereogenic centers was accorded
attention. It was reasoned that this important objective
(6) (a) Kito, M.; Sakai, T.; Haruta, N.; Shirahama, H.; Matsuda, F.
Synlett 1996, 1057. (b) Matsuda, F.; Kito, M.; Sakai, T.; Okada, N.;
Miyashita, M.; Shirahama, H. Tetrahedron 1999, 55, 14369.
(5) Mehta, G.; Subba Reddy, K. Synlett 1996, 625.
10.1021/jo0301301 CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/26/2003
6096
J . Org. Chem. 2003, 68, 6096-6107

Enantioselective Synthesis of Vinigrol
SCHEME 1
involving the use of lithium benzyl mercaptide was
effective on a 100 mg scale,13 only a 12% yield of 9 was
realized at the 10 g level. In contrast, the hindered acyl
oxazolidinone responded well to the action of lithium
borohydride in THF containing 1 equiv of ethanol.14 The
absence of racemization during formation of alcohol 9 was
15
ascertained by Mosher ester analysis (>97% ee).
Protection of 9 as the tert-butyldimethylsilyl ether
followed by ozonolysis afforded aldehyde 11. While the
direct alkylation of aldehydes is recognized to be sluggish
and competitive with concomitant operation of unwanted
aldol condensations or Cannizarro type reactions,16 prior
conversion to an enamine, hydrazone, or imine derivative
has been reported to allow alkylations to proceed ef-
ficiently.17 From these options, the pyrrolidine enamine
alternative proved most successful in conjunction with
methyl vinyl ketone, giving rise to 12 in 84% yield. The
best conditions uncovered for the cyclization of the
resulting keto aldehyde were adapted from those devel-
oped in Burke’s quadrone synthesis.18 Following the
heating of 12 with potassium hydroxide and dibenzo-18-
crown-6 in benzene, there was isolated 46% of 13 (dr )
1.7:1) and 47% of the intermediate â-hydroxy ketones.
Resubmission of the latter to the basic reaction conditions
resulted in an increase of the overall yield of cyclohex-
enones to 80%.
could be realized in a single step by anionic oxy-Cope
rearrangement7 of the tertiary bicyclo[2.2.2]octenol 4.
Another attractive feature of 4 is the convenient allow-
ance provided by it for convergent assembly. Thus, we
envisioned that ketones such as 5 and appropriately
substituted vinylic halides would serve as reaction part-
ners. Proper delineation of the stereoselectivity associ-
ated with the coupling of these building blocks was also
mandated. Nucleophilic addition to 5 from the π surface
opposite the unsaturated bridge would give rise to a
diastereomer having olefinic centers too remote for
possible engagement in charge-accelerated [3,3]sigma-
tropic rearrangement. We therefore hoped to skirt its
formation. The degree of control available from solvent,
temperature, and precise nature of the organometallic
reagent was not a priori predictable, and we planned to
launch a systematic study in order to define conditions
leading to maximum exo stereoselectivity. The impact of
changes in the chemical nature of the XR substituent was
also to be probed.
Following the R′-monomethylation of 13, compound 14
so obtained was subjected to a double-Michael reaction19
involving phenyl vinyl sulfoxide as the co-reactant.
Without purification, the intermediate bicyclic adducts
were heated in toluene containing calcium carbonate in
order to induce the direct thermal extrusion of benzene-
sulfenic acid.20 Although the overall yield in which 15
and 16 were formed was modest (41%), these diastere-
(12) (a) Evans, D. A.; Bilodeau, M. T.; Somers, T. C.; Clardy, J .;
Cherry, D.; Kato, Y. J . Org. Chem. 1991, 56, 5750. (b) Evans, D. A.;
Black, W. C.; J . Am. Chem. Soc. 1992, 114, 2260. (c) Mavunkel, B. J .;
Lu, Z.; Kyla, D. J . Tetrahedron Lett. 1993, 34, 2255.
(13) (a) Damon, R. E.; Coppola, G. M. Tetrahedron Lett. 1990, 31,
2849. (b) Shapiro, G.; Chengzhi, C. Tetrahedron Lett. 1992, 33, 2447.
(14) (a) Penning, T. D.; Djuric, S. W.; Haack, R. A.; Kalish, V. J .;
Miyashiro, J . M.; Rowell, B. W.; Yu, S. S. Synth. Commun. 1990, 20,
307. (b) Chibale, K.; Warren, S. Tetrahedron Lett. 1992, 33, 4369.
(15) (a) Ward, D. E.; Rhee, C. K. Tetrahedron Lett. 1991, 32, 7165.
(b) Dale, J . A.; Dull, D. L.; Mosher, H. S. J . Org. Chem. 1969, 34, 2543.
(16) (a) House, H. O.; Liang, W. C.; Weeks, P. D. J . Org. Chem. 1974,
39, 3102. (b) Dietl, H. K.; Brannock, K. C. Tetrahedron Lett. 1973, 1273.
(17) Whitesell, J . K.; Whitesell, M. A. Synthesis 1983, 517.
Syn t h esis of R ep r esen t a t ive Bicyclo[2.2.2]oc-
ten on es. After brief, unprofitable encounters with routes
to 5 based on Diels-Alder and Ireland-Claisen protocols
as key transformations,8 attention was directed instead
to a pathway featuring a Michael-Michael sequence for
elaboration of the structural framework. The route began
by acylation of the lithiated form of (S)-oxazolidinone 69
with isovaleryl chloride (Scheme 2).10 Excellent levels of
diastereoselectivity (dr > 95:5) were subsequently real-
ized in the alkylation11 of 7 with allyl bromide. Traces of
the minor reaction component were conveniently removed
by preparative HPLC to give 8 of very high quality (>99%
ee). Some difficulties were experienced in removing the
chiral auxiliary resident in 8.12 The use of LiAlH4 resulted
in the formation of a significant amount of ring-cleaved
amino alcohol. Although Damon’s two-step procedure
(18) Burke, S. D.; Murtiashaw, C. W.; Saunders: J . O.; Oplinger, J .
A.; Dike, M. S. J . Am. Chem. Soc. 1984, 106, 4558.
(19) (a) Ihara, M.; Toyota, M.; Fukumoto, K.; Kametani, T. Tetra-
hedron Lett. 1984, 25, 3235. (b) For activation of sulfoxide in Diels-
Alder reactions, see: Ronan, B.; Kagan, H. B. Tetrahedron: Asymmetry
1992, 3, 115. (c) For a review on MIMIRC, see: Posner, G. H. Chem.
Rev. 1986, 86, 831. (d) For a review on the intramolecular double
Michael reaction, see: Ihara, M.; Fukumoto, K. Angew. Chem., Int.
Ed. Engl. 1993, 32, 1010. (e) Oare, D. A.; Heathcock, C. H. In Topics
in Stereochemistry; Eliel, E. L., Wilen, S. H., Eds.; Wiley: New York,
1989; Vol. 19, 374. (f) Brown, P. J .; J ones, D. N.; Khan, M. A.;
Meanwell, N. A.; Richards, P. J . J . Chem. Soc., Perkin Trans. 1 1984,
2049. (g) J ones, D. N.; Meanwell, N. A.; Mirza, S. M. J . Chem. Soc.,
Perkin. Trans. 1 1985, 145. (h) Yamazaki, T.; Ishikawa, N.; Iwatsubo,
H.; Kitazume, T. J . Chem. Soc., Chem. Commun. 1987, 1340. (i) Seki,
K.; Ohnuma, T.; Oishi, T.; Ban, Y. Tetrahedron Lett. 1975, 723. (j) Cory,
R. M.; Chan, D. M. T. Tetrahedron Lett. 1975, 4441. (k) Cory, R. M.;
Chan, D. M.; Naguib, Y. M. A.; Rastall, M. H.; Renneboog, R. M. J .
Org. Chem. 1980, 45, 1852. (l) Montgomery, J .; Overman, L. E. J . Org.
Chem. 1993, 58, 6476.
(7) (a) Paquette, L. A. Tetrahedron 1997, 53, 13971. (b) Paquette,
L. A. Synlett 1990, 67. (c) Paquette, L. A. Angew. Chem., Int. Ed. Engl.
1990, 29, 609.
(8) Guevel, R. Ph.D. Dissertation, The Ohio State University, 1994.
(9) (a) Evans, D. A.; Bartoli, J .; Shih, T. L. J . Am. Chem. Soc. 1981,
103, 2127. (b) Evans, D. A.; Ennis, M. D.; Mathre, D. J . J . Am. Chem.
Soc. 1982, 104, 1737.
(10) (a) Spaltenstein, A.; Carpino, P. A.; Miyake, F.; Hopkins, P. B.
J . Org. Chem. 1987, 52, 2, 3759. (b) Iseki, K.; Nagai, T.; Kobayashi, Y.
Tetrahedron Lett. 1993, 34, 2169. (c) Thom, C.; Kocienski, P. Synthesis
1992, 582.
(11) (a) Trimble, L. A.; Vederas, J . C. J . Am. Chem. Soc. 1986, 108,
6397. (b) Fadel, A.; Salaun, J . Tetrahedron Lett. 1988, 29, 6257. (c)
Herold, P.; Duthaler, R.; Rihs, G.; Angst, C. J . Org. Chem. 1989, 54,
1178.
(20) (a) Koppel, G. A.; Kinnick, M. D. J . Chem. Soc., Chem. Commun.
1975, 473. (b) Kametani, T.; Yukuwa, H.; Honda, T. J . Chem. Soc.,
Perkin Trans. 1 1990, 571. (c) De Groot, A.; J ansen, B. J . M.; Reuvers,
J . T. A.; Tedjo, E. M. Tetrahedron Lett. 1981, 22, 4137.
J . Org. Chem, Vol. 68, No. 16, 2003 6097

Paquette et al.
SCHEME 2
SCHEME 3
aldehydes were stored for any extended time period, even
at low temperatures. Immediate submission of 21 to the
Takai reaction25 was observed to lead almost exclusively
to the E vinyl iodide 22. At this point, effort was expended
for the purpose of determining the extent of configura-
tional loss during the reaction sequence. To this end, the
unstable vinyl iodide 22a was hydrogenated over plati-
(22) (a) Tsukuda, T.; Kakisawa, H.; Tetrahedron Lett. 1989, 30, 4245
(SEM). (b) White, J . D.; Kawasaki, M. J . Org. Chem. 1992, 57, 5292
(Bn). (c) Rinehart, K. L.; Harada, K.-I.; Namikoshi, C. C.; Harvis, C.
A.; Munro, M. H. G.; Blunt, J . W.; Mulligan, P. E.; Beasley, V. R.;
Dahlem, A. M.; Carmichael, W. W. J . Am. Chem. Soc. 1988, 110, 8557
(EE). (d) Roush, W. R.; Palkowitz, A. D.; Ando, K. J . Am. Chem. Soc.
1990, 112, 6348 (TBDMS, TBDPS, Bn). (e) Nagaoka, H.; Kishi, Y.
Tetrahedron 1981, 37, 3873. (f) Meyers, A. I.; Babiak, K. A.; Campbell,
A. L.; Comins, D. L.; Fleming, M. P.; Henning, R.; Heuschmann, M.;
Hudspeth, J . P.; Kane, J . M.; Reider, P. J .; Roland, D. M.; Shimizu,
K.; Tomioka, K.; Walkup, R. D. J . Am. Chem. Soc. 1983, 105, 5015. (g)
White, J . D.; Amedio, J . C.; Gut, S.; Ohira, S.; J ayasinghe, L. R. J .
Org. Chem. 1992, 57, 2270 (SEM). (h) Romo, D.; J ohnson, D. D.;
Plamondon, L.; Miwa, T.; Schreiber, S. L. J . Org. Chem. 1992, 57, 5060
(Bn). (i) See: Aldrichim. Acta 1984, 17, 42. (j) Naoshima, Y.; Ka-
mezawa, M.; Tachibana, H.; Munakata, Y.; Fujita, T.; Kihara, K.; Raku,
T. J . Chem. Soc., Perkin. Trans. 1 1993, 557 (MOM). (k) Baker, R.;
O’Mahony, M. J .; Swain, C. J . Tetrahedron Lett. 1986, 27, 3059 (THP).
(l) Boeckman, R. K., Charette, A. B.; Asberom, T.; J ohnston, B. J . Am.
Chem. Soc. 1987, 109, 7553 (MOM). (m) Hori, K.; Hikage, N.; Inagaki,
A.; Mori, S.; Nomura, K.; Yoshii, E. J . Org. Chem. 1992, 57, 2888 (EE).
(n) Paterson, I.; Lister, M. A.; Ryan, G. R. Tetrahedron Lett. 1991, 32,
1749.
omeric â,γ-unsaturated ketones were conveniently ame-
nable to chromatographic separation.
Deprotection of 15 with TBAF smoothly gave 17 and
made possible the ensuing conversion to the phenylthio
derivative 18 through the combined action of diphenyl
disulfide and tri-n-butylphosphine21 (Scheme 3). We were
now in a good position to examine the possible role of
different heteroatomic groups on π-face diastereoselec-
tion.
Con str u ction of th e Nu cleop h ilic Syn th on s. A rich
collection of O-substituted derivatives of methyl (R)-2-
(hydroxymethyl) propionate has been described in the
prior art.22 Of these, 19a -e were selected for evaluation
(Scheme 4). Reduction of these esters with LiAlH4 or
Dibal-H furnished the corresponding alcohols. Subse-
quent careful oxidation of intermediates 20 under Swern
conditions23 or with the perruthenate reagent24 was
implemented without any obvious epimerization. How-
ever, stereochemical integrity could not be ensured if the
(23) (a) Mancuso, A. J .; Huang, S. L.; Swern, D. J . Org. Chem. 1978,
43, 2480. (b) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651. (c)
For this specific example, consult: Shimizu, S.; Nakamura, S.; Nakada,
M.; Shibasaki, M. Tetrahedron 1996, 52, 13363.
(24) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D. J .
Chem. Soc., Chem. Commun. 1987, 1625.
(21) (a) Nakagawa, I.; Hata, T. Tetrahedron Lett. 1975, 1409. (b)
Marshall, J . A.; Cleary, D. G. J . Org. Chem. 1986, 51, 858.
(25) Takai, K.; Nitta, K.; Utimoto, K. J . Am. Chem. Soc. 1987, 109,
951.
6098 J . Org. Chem., Vol. 68, No. 16, 2003

Enantioselective Synthesis of Vinigrol
SCHEME 4
SCHEME 6
realized in anhydrous THF at -78 to 0 °C, proceeded with
minimal competing enolization. Column chromatography
conveniently separated the less polar 28 (53%) from its
more polar counterpart 29 (24%) (Scheme 6). The exo
orientation of the vinyl substituent in 28 was easily
recognized on the basis of NOE studies. The significant
amount of 29 formed under these circumstances was not
entirely expected because of the postulate that the bulky
group projected to the endo surface might well sterically
impede approach from this direction.
SCHEME 5
The literature precedent in this area is limited and
rather disparate. At one extreme such as that involving
the conjugate reduction of 31 with LiAlH4, hydride
delivery occurs stereospecifically from the exo direction
to give 32.29 In a related alkylation example, treatment
of ketone 33 with LDA and 1-iodobutane produced the
exo product (75%), equilibration of which with methanolic
sodium hydroxide produced a 73:27 exo/endo mixture.30
Where direct addition to the carbonyl is involved, product
ratios are significantly less imbalanced. For example, the
coupling of vinylmagnesium bromide to parent ketone 34
gives rise to a 2:1 mixture of the exo adduct and its
epimer.31 Higher levels of substitution as in 35, a ketone
more structurally allied to 15b, have little obvious impact
on product distribution. The exposure of 35 to 2-lithiodi-
hydropyran has been reported to lead to a 1.5:1 distribu-
tion of exo and endo carbinols.32
num oxide in the presence of triethylamine.26a This
process gave rise to 23, which was independently pre-
pared from pure (S)-(-)-2-methyl-1-butanol.27 Compari-
son of [R]D values indicated the enantiomeric excess to
be 75%. The same sample of 22a was treated as well with
anhydrous tetra-n-butylammonium fluoride at 80 °C
under reduced pressure26b to provide alcohol 24. Mosher
ester analysis of 25 by 1H and 19F NMR established more
reliably that the enantiomeric excess was greater than
90% and therefore suited for further deployment. Parallel
behavior was seen with 22b and 22c.
To gain greater quantitative appreciation of the ste-
reoselectivity of nucleophilic capture by bicyclic ketones
15 and 18, the alkynes 27a , 27d , and 27e were also
produced (Scheme 5). The Corey-Fuchs procedure28 was
selected among several options and found to be satisfac-
tory for our purposes.
Ster eoch em ica l Cou r se of th e Cou p lin g Rea c-
tion s. The ultimate acquisition of 4 requires that 1,2-
addition to the carbonyl group in 15 and 18 occur
predominantly from the direction syn to the double bond.
The consequences of methyl substitution at the proximal
bridgehead site and of the endo-oriented side chain on
reaction trajectories were not known. Consequently,
feasibility studies involving vinylmagnesium bromide
were initially undertaken. The conversion to 28 and 29,
(26) (a) Paquette, L. A.; Barrett, J . H.; Spitz, R. P.; Pitcher R. J .
Am. Chem. Soc. 1965, 87, 3417. (b) Sugimura, T.; Paquette, L. A. J .
Am. Chem. Soc. 1987, 109, 3017.
(27) Lipshutz, B. H.; Pegram, J . J . Tetrahedron Lett. 1980, 21, 3343.
(28) (a) Corey, E. J .; Fuchs, P. L. Tetrahedron Lett. 1972, 3769. (b)
Aoyagi, S.; Wang, T.-C.; Kibayashi, C. J . Am. Chem. Soc. 1993, 115,
11393.
(29) (a) Williams, R. V.; Chauhan, K.; Gadgil, V. R. J . Chem. Soc.,
Chem Commun. 1994, 1739. (b) Williams, R. V.; Gadgil, V. R.; Garner,
G. G.; Williams, J . D.; Vij, A. Tetrahedron Lett. 1999, 40, 2689.
(30) Kim, D.; Hong, S. W.; Park, C. W. Chem. Commun. 1997, 2263.
J . Org. Chem, Vol. 68, No. 16, 2003 6099

Paquette et al.
TABLE 1. Ster eoch em ica l Cou r se of 1,2-Ad d ition to
Bicyclo[2.2.2]octen on es 15 a n d 18 (THF , -78 °C)
on the isomer distribution. The replacement of THF by
ether led to extensive enolization of 15 and 18, resulting
in low-yielding conversion to addition products. The
ability of methylaluminum bis(2,6-di-tert-butyl-4-meth-
ylphenoxide) (MAD) to influence facial selectivity is well
recognized.35 However, the precomplexation of 18 with
MAD did not result in a change of product composition
at very short exposure times. When reactions were
allowed to proceed beyond 20 min at -78 °C, extensive
decomposition was noted.
Although recourse to the vinyl cerates36 and zincates37
was also ineffective and lithium acetylides afforded no
advantage, Grignard reagents proved more ideally suited
to preferred exo addition, provided that proper conditions
were employed (Table 1, expts 7-10). Although the direct
entrainment method involving the metalation of alkyne
27e with ethylmagnesium bromide in THF failed to give
rise to a useful distribution of 40 and 41 (expt 7),
significant improvements were noted when sonication of
the vinyl iodides in the presence of magnesium metal and
1,2-dibromoethane was utilized (expt 8). More serviceable
yet were those conditions involving exposure of the vinyl
iodide 22e to tert-butyllithium followed by magnesium
bromide etherate (expts 9 and 10). The 3.2:1 exo/endo
ratio observed in the last of these experiments accorded
us the opportunity to access reasonable quantities of 37e
for the continuation of our studies as discussed in the
sequel.
P r obe of P ossible Cya n oh yd r in a n d En ol Eth er
Alter n a tives. Although the preceding results proved to
be reproducible, we simultaneously probed other possible
means for stereocontrolled carbinol synthesis. The alter-
native interim goal was the construction of R-hydroxy
aldehydes of the type 46, 47, or 52, which possess an exo
carbonyl group potentially suited to Wittig and related
condensations. To this end, 15 was treated with tert-
butyldimethylsilyl cyanide38 in the presence of a catalytic
As a result of the above, we defined as an interim goal
a clearer definition of those conditions most conducive
to production of the appropriate exo isomers. The com-
patibility of those structural feature resident in 28 to a
potential synthesis of vinigrol was brought to the fore
when its sigmatropic rearrangement to 30 was found to
occur readily at room temperature in the presence of
potassium hydride and 18-crown-6 in tetrahydrofuran.
The ready availability of the lithiated alkenes 36 by
metal-halogen exchange involving tert-butyllithium in
THF at -78 °C33 prompted their initial exploitation.
Following chromatographic separation of the less polar
37 from the more polar 38, it was possible to ascertain
by NOE analysis that the preferred π-facial stereoselec-
tivity was in fact opposite to that observed with vinyl-
magnesium bromide (Table 1). The proportion of 38
varied from 3.5:1 when R was the SEM protecting group
to 5.7:1 for the p-methoxybenzyl (PMB) derivative.
Recourse to HMPA as cosolvent on the basis of its
capability to disrupt lithium aggregates34 had no effect
(34) Chang, N.-C.; Day, H. M.; Lu, W. F. J . Org. Chem. 1989, 54,
4083.
(35) (a) Maruoka, K.; Itoh, T.; Yamamoto, H. J . Am. Chem. Soc.
1985, 107, 4573. (b) Hirukawa, T.; Shudo, T.; Kato, T. J . Chem. Soc.,
Perkin Trans. 1 1993, 217. (c) Preparation of MAD: Stern, A. J .; Rohde,
J . J .; Swenton, J . S. J . Org. Chem. 1989, 54, 4413.
(36) (a) Imamoto, T.; Sugiura, Y.; Takiyama, N. Tetrahedron Lett.
1984, 25, 4233. (b) Imamoto, T.; Sugiura, Y. J . Organomet. Chem. 1985,
285, C21. (c) Paquette, L. A.; Oplinger, J . A. Tetrahedron 1989, 45,
107. (d) Greeves, N.; Lyford, L. Tetrahedron Lett. 1992, 33, 4759.
(37) Williams, D. R.; Kissel, W. S. J . Am. Chem. Soc. 1998, 120,
11198.
(31) Berson, J . A.; J ones, M., J r. J . Am. Chem. Soc. 1964, 86, 5019.
(32) (a) Oplinger, J . A.; Paquette, L. A. Tetrahedron Lett. 1987, 28,
5441. (b) For a more recent pertinent example, consult: Kim, D.; Shim,
P. J .; Lee, J .; Park, C. W.; Hong, S. W.; Kim, S. J . Org. Chem. 2000,
65, 4864.
(33) Evans, D. A.; Thomas, R. C.; Walker, J . A. Tetrahedron Lett.
1976, 1427.
6100 J . Org. Chem., Vol. 68, No. 16, 2003

Enantioselective Synthesis of Vinigrol
SCHEME 7
SCHEME 8
SCHEME 9
amount of zinc iodide. Chromatography on silica gel was
necessary to separate the nonpolar adducts 42 and 43,
which were formed quantitatively in a reasonably favor-
able 2:1 ratio. These isomers were distinguished spec-
troscopically and on the basis of the readiness with which
43 was converted to 15 in the presence of 0.05 N NaOH
in aqueous methanol (Scheme 7).
The desired isomer 42 proved inert to these conditions
during overnight stirring.
generation of the desired olefin. In the first instance,
modest amounts of aldehyde 50 were isolated in addition
to the starting ketone 15. On this basis, it would appear
that the mechanistic pathway shown in Scheme 8 may
be operative.41 This fragmentative option results in the
expulsion of silyl enol ether 49, the hydrolysis of which
gave rise to 50.
Our requirements for highly controlled exo orientation
of the unsaturated side chain at C-2 of the bicyclooctanol
were also met by homologation of 15 to enol ether 51 with
dimethyl diazomethylphosphonate42 and oxidation of the
latter with m-chloroperbenzoic acid43 (Scheme 9). These
conditions afforded 52 and 53 as a 3:1 mixture in good
Therefore, the recycling process could, if warranted,
be used advantageously to produce exclusively the exo
nitrile 42, the reduction of which to aldehyde 46 with
Dibal-H was conveniently accomplished in 72% yield.
Comparable exposure of 18 to trimethylsilyl cyanide39
gave rise to a less favorable 1.4:1 mixture of 44 and 45.
As expected, these adducts and the derived aldehyde 47
proved to be somewhat more sensitive compounds as a
result of the sterically smaller, more reactive nature of
the protecting group. The hydrolysis leading to 45 during
chromatography is noteworthy.
The attempted homologation of 46 and 47 to 37 and
48, respectively, proved to be unsuccessful. Neither
Wittig methylenation nor J ulia olefination40 resulted in
(41) Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863.
(42) Gilbert, J . C.; Weerasooriya, V.; Wiechman, B.; Ho, L. Tetra-
hedron Lett. 1980, 21, 5003.
(43) (a) Martin, S. F.; White, J . B.; Wagner, R. J . Org. Chem. 1982,
47, 3190. (b) Martin, S. F.; Assercq, J .-M.; Austin, R. E.; Dan-
tanarayana, A. P.; Fishpaugh, J . R.; Gluchowski, C.; Guinn, D. E.;
Hartmann, M.; Tanaka, T.; Wagner, R.; White, J . B. Tetrahedron 1995,
51, 3455.
(38) Narasaka, K.; Iwakura, K.; Okauchi, T. Chem. Lett. 1991, 423.
(39) (a) Lidy, W.; Sundermeyer, W. Chem. Ber. 1973, 106, 587. (b)
Evans, D. A.; Carroll, G. L.; Truesdale, L. K. J . Org. Chem. 1974, 39,
914.
(40) Marko, I. E.; Murphy, F.; Dolan, S. Tetrahedron Lett. 1996, 37,
2089 and relevant references therein.
J . Org. Chem, Vol. 68, No. 16, 2003 6101

Paquette et al.
SCHEME 10
yield. The sensitivity of these compounds to acidic and
basic conditions precluded their chromatographic separa-
tion. Furthermore, all attempts to protect their tertiary
hydroxyl group or to effect chain extension generally
resulted in operation of an R-ketol rearrangement to give
54. This result prompted cessation of this phase of the
effort and solidified the stance that further advance
would be made via the route defined by experiment 10
in Table 1.
Con str u ction of th e Octa lin Cor e. Given the ease
with which 28 was noted to undergo oxyanionic sigma-
tropy to form 30, the expectation was that 37e and its
congeners would likewise rearrange at or slightly above
room temperature. Quite to the contrary, exposure of 37e
to potassium hexamethyldisilazide and 18-crown-6 in
THF between -78 and 30 °C induced only gradual
degradation of the carbinol. After considerable experi-
mentation, it was determined that rapid heating of such
samples to 120 °C in sealed tubes for 1 h with subsequent
rapid cooling provided 55 in yields exceeding 70% (Scheme
10). That a structurally enforced boatlike transition state
had been adopted to set the four contiguous methine
hydrogens of the newly crafted octalin ring system in a
rigorous all-cis relationship was ultimately confirmed by
X-ray crystallographic studies (see below).
To develop the functional group array in 55 while
simultaneously addressing the unconfirmed stereochem-
ical issues, we chose to venture forward via the acetal
56. Following temporary masking of the ketone carbonyl
in this manner, desilylation was implemented and the
hydroxyl group so uncovered was transformed via tosy-
late 58 to sulfone 59. A comparable few steps transformed
the p-methoxybenzyloxy-terminated side chain into a
primary iodide. These advances made available the
highly crystalline substance 62, single crystal X-ray
analysis of which confirmed the original stereochemical
assumptions while simultaneously defining its solid state
conformational features (Figure 1). This rigorous evi-
dence establishes all stereogenic centers to be of the
proper vinigrol absolute configuration as a consequence
of their relative relationship to C-17, which was installed
in enantiocontrolled fashion. Beyond that, the pair of
heavily functionalized side chains are clearly seen to be
strongly directed to the equatorial plane. A major con-
sequence of this orientational preference, the origins of
which are obviously steric in nature, is to position the
incipient nucleophilic center neighboring the sulfone
sulfur (viz. C-21) remotely from the electrophilic carbon
bonded to iodine (C-15). Although it is quite likely that
this conformation of 62 or a closely related variant is also
preferentially adopted in solution, no information is
available concerning the topological flexibility of this cis-
octalin. cis-Decalins are well recognized to be mobile
systems subject to being biased toward one of two chair-
chair arrangements depending on the locus of substitu-
tion.44 In cis-octalins, the situation is somewhat more
complex since the double bond introduces an added
degree of rigidification.
Attem p ted Tr icycle F or m a tion via In tr a m olecu -
la r Nu cleop h ilic Disp la cem en t. The next major goal
in the synthesis was cyclization to close the eight-
membered ring. The various basic reagents that we chose
to employ, ranging from potassium hexamethyldisilazide
to potassium hydride, proved to be uniformly incapable
of generating 63. Depending on the specific conditions,
either unreacted 62 was returned or elimination of HI
was seen. Based on these results, it would appear that
intramolecular nucleophilic attack is impeded by an
inability of the reaction centers to orient themselves
properly along the necessary collinear trajectory. We
recognize that SN2 displacement reactions represent
perhaps the most stereoelectonically demanding carbon-
carbon bond-forming reactions. For that reason, recourse
to this tactic for medium-ring construction has been most
often applied only when favorable low energy conforma-
tions are populated.45 MM2 transition structures based
(44) Stereochemistry of Organic Compounds; Eliel, E. L., Wilen, S.
H., Mander, L. M., Eds.; J ohn Wiley and Sons: New York, 1994; pp
776-781.
(45) Takahashi, T. Stud. Nat. Prod. Chem. 1991, 8, 175-204.
6102 J . Org. Chem., Vol. 68, No. 16, 2003

Enantioselective Synthesis of Vinigrol
complicating factor. These and related protocols are
currently under active investigation.
Exp er im en ta l Section
[(4S)-N-(3-Meth ylbu ta n oyl)-4-(1-m eth yleth yl)-2-oxa zo-
lid in on e (7). To a solution of (4S)-4-isopropyl-2-oxazolidinone
(6, 100 g, 0.78 mol) in THF (1000 mL) was added 1.6 M
n-butyllithium in hexanes (509 mL, 0.81 mol) at -60 °C. After
being vigorously stirred for 20 min at -50 °C, the thick white
slurry was slowly treated with isovaleryl chloride (100 g, 0.85
mol). The resulting homogeneous reaction mixture was stirred
for 1 h at 0 °C and treated with saturated K2CO3 solution (300
mL). The aqueous layer was extracted with several portions
of CH2Cl2. The combined organic layers were washed with
brine, dried, and concentrated in vacuo. Purification of the
residue by distillation gave 157 g (95%) of 7 as a colorless oil:
1
bp 112-115 °C (1 Torr); IR (neat, cm-1) 1780, 1700; H NMR
(300 MHz, CDCl3) δ 4.45 (dt, J ) 8, 4 Hz, 1H), 4.24 (dd, J )
9, 8 Hz, 1H), 4.17 (dd, J ) 9, 4 Hz, 1H), 2.93 (dd, J ) 18, 7 Hz,
1H), 2.67 (dd, J ) 18, 8 Hz, 1H), 2.35 (heptet x d, J ) 7, 4 Hz,
1H), 2.16 (heptet, J ) 7 Hz, 1H), 0.98 (d, J ) 5 Hz, 3H), 0.96
(d, J ) 5 Hz, 3H), 0.90 (d, J ) 7 Hz, 3H), 0.86 (d, J ) 7 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 172.5 (s), 153.9 (s), 63.1 (t),
58.2 (d), 43.8 (t), 28.3 (d), 25.1 (d), 22.4 (q), 22.2 (q), 17.8 (q),
F IGURE 1. Perspective plot of 62 in the solid state.
14.5 (q); MS m/z (M+) calcd 213.1365, obsd 213.1368; [R]20
D
+79.5 (c 1.60, CHCl3).
[(4S)-4-Isop r op yl-3-[(2S)-2-isop r op yl-4-p en t en oyl]-2-
oxa zolid in on e (8). To an LDA solution prepared at 0 °C from
diisopropylamine (66 mL, 0.70 mol) and 1.6 M n-butyllithium
in hexanes (320 mL, 0.51 mmol) in THF (1500 mL) was slowly
added at -65 °C a solution of 7 (100 g, 0.47 mol) in THF (500
mL). The resulting yellow reaction mixture was vigorously
stirred at -65 °C for 3 h, warmed to 0 °C over 1 h, cooled back
to -65 °C, and treated with freshly distilled allyl bromide (120
mL, 1.41 mol). The resulting solution was stirred at 0 °C
overnight and quenched at -50 °C with saturated NH4Cl
solution (500 mL). The resulting aqueous layer was extracted
with CH2Cl2 (300 mL). The combined organic phases were
dried and concentrated in vacuo. Purification of the residue
by chromatography (silica gel, elution with 10% ethyl acetate
in hexanes) afforded 110 g (93%) of 8 as a colorless oil (de
>95%): IR (neat, cm-1) 1780, 1700, 1640; 1H NMR (300 MHz,
CDCl3) δ 5.77 (m, 1H), 5.03 (br d, J ) 17 Hz, 1H), 4.96 (br d,
J ) 10 Hz, 1H), 4.45 (m, 1H), 4.18 (m, 2H), 3.86 (m, 1H), 2.36
(m, 3H), 1.92 (octet, J ) 7 Hz, 1H), 0.94 (d, J ) 5 Hz, 3H),
0.92 (d, J ) 5 Hz, 3H), 0.88 (d, J ) 7 Hz, 3H), 0.83 (d, J ) 7
Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 175.7 (s), 153.8 (s), 135.5
(d), 116.7 (t), 62.8 (t), 58.6 (d), 48.1 (d), 33.9 (t), 30.2 (d), 28.3
(d), 20.8 (q), 19.2 (q), 18.0 (q), 14.5 (q); MS m/z (M+) calcd
F IGURE 2. Energy separating the diequatorial and diaxial
conformers of 64.
253.1678, obsd 253.1683; [R]20 +92.2 (c 1.06, CHCl3).
D
on ab initio calculations hold reasonably good predictive
ability. Our modeling of the structural prototype 64 has
provided indication that the diequatorial conformer is
approximately 12.5 kcal/mol less strained than the di-
axial arrangement (Figure 2). These considerations pro-
vide insight into the extent to which the framework
resident in 62 is precluded from aligning the two reacting
centers suitably for intramolecular backside displace-
ment. This restriction can be expected to apply to other
anionic C-C bond-forming reactions that have been used
for medium-ring construction such as the aldol reaction
and conjugate additions.46,47 Somewhat greater latitude
is recognized to be associated with radical cyclizations,47,48
samarium(II)- and manganese(III)-mediated processes,47
and ring-closing olefin metatheses,47,49 since comparably
high levels of stereoalignment no longer lurk as a
Anal. Calcd for C14H23NO3: C, 66.37; H, 9.15. Found: C,
66.63; H, 9.31.
(2S)-2-Isop r op yl-4-p en ten -1-ol (9). To a solution of 8 (27.6
g, 0.109 mol) in ether (600 mL) were added absolute ethanol
(6.1 mL, 0.11 mol) and a 2.0 M solution of lithium borohydride
in THF (60 mL, 0.12 mol) at 0 °C under N2. The reaction
mixture was stirred at 0-5 °C overnight under N2, quenched
with 1 M NaOH solution, stirred until both layers were clear,
and poured into ether and water. The ether layer was washed
with brine, dried, and concentrated in vacuo. Chromatography
of the residue on TLC grade silica gel (elution with 10% ethyl
acetate in petroleum ether) or by MPLC (silica gel, elution with
(49) (a) Grubbs, R. H.; Miller, S. J .; Fu, G. C. Acc. Chem. Res. 1995,
28, 446. (b) Schmalz, H.-G. Angew. Chem., Int. Ed. Engl. 1995, 34,
1833. (c) Fu¨rstner, A. Topics Catal. 1997, 4, 285. (d) Armstrong, S. K.
J . Chem. Soc., Perkin Trans. 1 1998, 371. (e) Pariya, C.; J ayaprakash,
K. N.; Sarkar, A. Coord. Chem. Rev. 1998, 168, 1 (f) Randall, M. L.;
Snapper, M. L. J . Mol. Catal. A.: Chem. 1998, 133, 29 (g) Grubbs, R.
H.; Chang, S. Tetrahedron 1998, 54, 4413. (h) Ivin, K. J . Mol. Catal.
A.: Chem. 1998, 133, 1. (i) Wright, D. L. Curr. Org. Chem. 1999, 3,
211.
(46) Petasis, N. A.; Patane, M. A. Tetrahedron 1992, 48, 5757.
(47) Mehta, G.; Singh, V. Chem. Rev. 1999, 99, 881.
(48) Yet, L. Tetrahedron 1999, 55, 9349.
J . Org. Chem, Vol. 68, No. 16, 2003 6103

Paquette et al.
30% ether and 10% CH2Cl2 in petroleum ether) afforded 10.04
To a solution of the above enamine (15.0 g, 50.5 mmol) in
dry benzene (300 mL) was added freshly distilled methyl vinyl
ketone (22.2 mL, 266 mmol). The resulting pale yellow reaction
mixture, which became darker yellow as the reaction pro-
g (72%) of 9 as a colorless liquid: IR (neat, cm-1) 3400 (br),
1
1635; H NMR (300 MHz, CDCl3) δ 5.83 (m, 1H), 5.05 (br d,
J ) 17 Hz, 1H), 4.99 (br d, J ) 10 Hz, 1H), 3.57 (m, 2H), 2.15
(m, 1H), 2.03 (m, 1H), 1.78 (m, 1H), 1.74 (br s, 1H), 1.42 (m,
1H), 0.90 (d, J ) 7 Hz, 3H), 0.89 (d, J ) 7 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ 138.1 (d), 115.8 (t), 63.6 (t), 46.4 (d), 32.9
(t), 27.9 (d), 19.8 (q), 19.3 (q); MS m/z (M+) calcd 128.1201,
ceeded, was refluxed for 48 h under N2
, treated at 0 °C with
aqueous oxalic acid solution (13 g in 200 mL of distilled water),
and stirred for 1 h. The aqueous phase was extracted with
several portions of ether (3 × 200 mL). The combined organic
layers were washed with brine (200 mL), dried, and concen-
trated in vacuo. Chromatography of the residue (Florisil,
elution with 10% ether in petroleum ether) gave 14.1 g (84%)
of 12 as a colorless, oily, inseparable 1.2:1 diastereomeric
mixture: IR (neat, cm-1) 1725, 1470, 1410, 1390; 1H NMR (300
MHz, CDCl3) δ 9.69 (d, J ) 2 Hz, 1H), 9.57 (br s, 1H), 3.60 (m,
1H), 3.52 (dd, J ) 10, 5.5 Hz, 1H, minor), 3.40 (dd, J ) 10, 9.1
Hz, 1H, major), 2.38 (m, 1H), 2.14 (m, 2H), 1.98-1.70 (series
of m, 2H), 1.69 (m, 1H), 1.68 (s, 3H, major), 1.67 (s, 3H, minor),
1.53 (m, 1H, major), 1.38 (m, 1H, minor), 0.98 (s, 9H), 0.91 (d,
J ) 6.7 Hz, 3H, minor), 0.89 (d, J ) 6.8 Hz, 3H, major), 0.84
(d, J ) 6.7 Hz, 3H, minor), 0.83 (d, J ) 6.8 Hz, 3H, major),
0.07 (s, 6H); 13C NMR (75.5 MHz, CDCl3) (major isomer) δ
205.8 (s), 202.8 (d), 61.9 (t), 51.0 (d), 47.9 (d), 41.5 (t), 29.0 (q),
27.0 (d), 25.6 (q, 3C), 21.3 (q), 20.5 (q), 18.0 (s), 17.9 (t), -6.0
(q, 2C); (minor isomer) δ 205.5 (s), 202.7 (d), 60.5 (t), 51.2 (d),
49.6 (d), 40.9 (t), 29.0 (q), 26.4 (d), 25.6 (q, 3C), 21.2 (t), 21.2
(q), 19.5 (q), 18.0 (s), -6.0 (q, 2C); MS m/z (M+) calcd 314.2277,
obsd 314.2304.
obsd 128.1187; [R]20 +10.2 (c 0.49, CHCl3).
D
Anal. Calcd for C8H16O: C, 74.94; H, 12.58. Found: C, 74.84;
H, 12.63.
ter t-Bu tyl[[(2R)-2-isop r op yl-3-bu ten yl]oxy]d im eth ylsi-
la n e (10). To a solution of 9 (11.67 g, 0.09 mol) and imidazole
(18.62 g, 0.27 mol) in dry DMF (10 mL) was added tert-
butyldimethylsilyl chloride (20.61 g, 0.14 mol). The viscous
reaction mixture was stirred for 2 days under N2 at rt, poured
into distilled water (150 mL), and extracted thoroughly with
several portions of pentane. The combined organic layers were
dried and concentrated in vacuo. Purification of the residue
by column chromotagraphy (silica gel, elution with petroleum
ether) afforded 19.8 g (90%) of 10 as a colorless liquid: IR
(neat, cm-1) 1645, 1470, 1440, 1395; 1H NMR (300 MHz,
CDCl3) δ 5.78 (m, 1H), 5.01 (br d, J ) 17 Hz, 1H), 4.96 (br d,
J ) 10 Hz, 1H), 3.53 (d, J ) 5.6 Hz, 2H), 2.06 (m, 2H), 1.80
(m, 1H), 1.37 (m, 1H), 0.90 (d, J ) 6.8 Hz, 3H), 0.89 (s, 9H),
0.88 (d, J ) 6.8 Hz, 3H), 0.03 (s, 6H); 13C NMR (75 MHz,
CDCl3) δ 138.3 (d), 115.3 (t), 63.0 (t), 46.4 (d), 32.4 (t), 27.7
(d), 25.9 (q, 3C), 19.9 (q), 19.5 (q), 18.3 (s), -5.4 (q, 2C); MS
4-[1-(ter t-Bu tyldim eth ylsiloxy)m eth yl]-2-m eth ylpr opyl]-
2-cycloh exen -1-on e (13). To a vigorously stirred solution of
the above enamine (14.1 g, 44.9 mmol) (1.2:1 ratio) in dry
benzene (1600 mL) was added a finely ground suspension of
KOH (three crushed pellets) and dibenzo-18-crown-6 (0.4 g,
1.1 mmol). The reaction mixture was stirred under N2 for 64
h, treated with saturated NH4Cl solution (300 mL), and
extracted with several portions of ether (4 × 200 mL). The
combined organic layers were dried and concentrated in vacuo.
The crude residue was filtered through a pad of silica gel to
remove most of the dibenzo-18-crown-6 (elution with 15% ether
in petroleum ether) and purified by column chromatography
(silica gel, elution with 15% ether in petroleum ether) to give
6.1 g (46%) of 13 (1.7:1 ratio) as a very pale yellow oil and 6.8
g (47%) of â-hydroxy ketone isomers, which were resubjected
to the previous reaction conditions for 3 days. After one
recycling, a total of 10.6 g (80%) of 13 (1.5:1 ratio of diastereo-
m/z (M+) calcd 242.2066, obsd 242.2038; [R]20 +11.9 (c 1.08,
D
CHCl3).
Anal. Calcd for C14H30OSi: C, 69.35; H, 12.47. Found: C,
69.72; H, 12.56.
The 19F signals for the Mosher esters in (CDCl3) were seen
at -72.74 and -73.04 ppm.
(3S)-3-[(ter t-Bu tyld im eth ylsiloxy)m eth yl]-4-m eth ylva l-
er a ld eh yd e (11). Ozone was bubbled through a solution of
10 (4.0 g, 17 mmol) in acid-free MeOH (10 mL) and CH2Cl2
(45 mL) buffered with NaHCO3 at -78 °C until the appearance
of a persistent deep blue color. The reaction mixture was
subsequently purged with a flow of dry N2, treated with methyl
sulfide (8 mL) at -78 °C, slowly warmed to rt, and stirred
overnight. The volatiles were removed in vacuo, and the
residue was purified by column chromatography on Florisil
(elution with 10% ether in petroleum ether) to give 3.8 g (91%)
of 11 as a colorless oil: IR (neat, cm-1) 1735, 1470, 1395, 1260;
1H NMR (300 MHz, C6D6) δ 9.57 (dd, J ) 2, 1 Hz, 1H), 3.51
(dd, J ) 10, 5.1 Hz, 1H), 3.40 (dd, J ) 10, 6.9 Hz, 1H), 2.14
(ddd, J ) 16.3, 8.5, 2.7 Hz, 1H), 2.01 (ddd, J ) 16.3, 4.4, 1.4
Hz, 1H), 1.90 (m, 1H), 1.62 (septet, J ) 5 Hz, 1H), 0.98 (s,
9H), 0.76 (d, J ) 7 Hz, 3H), 0.72 (d, J ) 7 Hz, 3H), 0.60 (s,
6H); 13C NMR (75 MHz, C6D6) δ 200.9 (s), 64.5 (t), 43.6 (t),
42.1 (d), 28.5 (d), 26.0 (q, 3C), 20.2 (q), 19.3 (q), 18.4 (s), -5.5
1
isomers) was obtained: IR (neat, cm-1) 1680, 1470, 1390; H
NMR (300 MHz, CDCl3) δ 7.07 (br d, J ) 10.3 Hz, 0.4H), 6.94
(br d, J ) 10.3 Hz, 0.6H), 5.96 (m, 1H), 3.67 (m, 2H), 2.76 (m,
1H), 2.51 (m, 1H), 2.34 (m, 1H), 1.98 (m, 2H), 1.84 (m, 1H),
1.47 (m, 0.6H), 1.34 (m, 0.4H), 0.97 (m, 6H), 0.86 (s, 9H), 0.02
(s, 6H); 13C NMR (75.5 MHz, CDCl3) (major diastereoisomer)
δ 200.2 (s), 157.1 (d), 128.5 (d), 61.5 (t), 50.4 (d), 37.9 (t), 37.3
(d), 25.5 (t), 26.9 (d), 25.8 (q, 3C), 21.8 (q), 20.3 (q), 18.1 (s),
-5.6 (q, 2C); (minor isomer) δ 200.1 (s), 156.1 (d), 128.3 (d),
60.9 (t), 50.5 (d), 38.0 (t), 36.7 (d), 27.6 (t), 26.9 (d), 25.8 (q,
(q, 2C); MS m/z (M+) calcd 244.1859, obsd 244.1828; [R]20
+16.8 (c 1.02, CHCl3).
D
3C), 21.5 (q), 20.3 (q), 18.1 (s), -5.5 (q, 2C); MS m/z (M+
t-Bu) calcd 239.1467, obsd 239.1402.
-
Anal. Calcd for C13H28O2Si: C, 63.88; H, 11.55. Found: C,
63.50; H, 11.54.
Anal. Calcd for C17H32O2Si: C, 68.86; H, 10.88. Found: C,
69.19; H, 10.94.
2-[(R)-1-[(ter t-Bu tyld im eth ylsiloxy)m eth yl]-2-m eth yl-
p r op yl]-5-oxoh exa n a l (12). Water was azeotropically re-
moved from a refluxing solution of 11 (13.0 g, 53.2 mmol) and
freshly distilled (from Na) pyrrolidine (18 mL, 215 mmol) in
benzene (400 mL) via a Dean-Stark apparatus for 24 h. The
resulting solution was concentrated in vacuo to give 15 g (95%)
of a moisture-sensitive, pale yellow oil which was used in the
next step without further purification: IR (neat, cm-1) 3060,
4-[1-(ter t-Bu tyldim eth ylsiloxy)m eth yl]-2-m eth ylpr opyl]-
6-m eth yl-2-cycloh exen -1-on e (14). To an LDA solution
prepared at 0 °C from diisopropylamine (3.1 mL, 22.2 mmol)
and a 1.3 M solution of n-butyllithium (14.7 mL, 19 mmol) in
THF (120 mL) was slowly added at 0 °C a solution of 13 (4.7
g, 16 mmol) in THF (50 mL). After being stirred for 15 min,
the reaction mixture was treated with purified methyl iodide
(1.3 mL, 20 mmol), treated 1.5 h later with saturated NH4Cl
solution (100 mL), and extracted with several portions of ether.
The combined organic layers were washed with brine, dried,
and concentrated in vacuo. Chromatography of the residue on
silica gel (elution with 5% ether in petroleum ether) gave 240
mg (5%) of the axial methylated epimer as a pale yellow oil,
3.7 g (75%) of the equatorial isomer 14 as a pale yellow oil
1
2940, 1650, 1465, 1390, 1370, 1260, 1100, 940, 850, 780; H
NMR (300 MHz, C6D6) δ 6.22 (d, J ) 13.6 Hz, 1 H), 4.03 (dd,
J ) 13.6, 9.2 Hz, 1 H), 3.75 (m, 2 H), 2.86 (m, 4 H), 2.20 (m,
1 H), 1.52 (m, 4 H), 1.12 (d, J ) 7 Hz, 3 H), 1.07 (s, 9 H), 1.06
(d, J ) 7 Hz, 3 H), 0.16 (s, 6 H); 13C NMR (50 MHz, C6D6) ppm
137.7 (d), 95.3 (d), 66.9 (t), 50.3 (d), 49.1 (t, 2C), 28.2 (d), 26.2
(q, 3C), 25.0 (t, 2C), 21.7 (q), 18.6 (s), 17.9 (q), -5.4 (q), -5.2
(q).
6104 J . Org. Chem., Vol. 68, No. 16, 2003

Enantioselective Synthesis of Vinigrol
(1.5:1 ratio of 2 diastereoisomers) and 987 mg (20%) of more
1.00 (dd, J ) 13, 6 Hz, 1H), 0.92 (s, 9H), 0.87 (d, J ) 7 Hz,
3H), 0.71 (d, J ) 7 Hz, 3H), 0.00 (s, 6H); 13C NMR (75 MHz,
C6D6) δ 210.7 (s), 138.9 (d), 133.5 (d), 61.3 (t), 49.2 (d), 49.1
(s), 38.7 (d), 37.0 (t), 34.9 (t), 34.5 (d), 28.5 (d), 25.9 (q, 3C),
22.4 (q), 18.2 (s), 18.1 (q), 17.1 (q), -5.5 (q), -5.6 (q); MS m/z
(M+) calcd 336.2485, obsd 336.2482; [R]20D +278 (c 1.1, CHCl3).
Anal. Calcd for C20H36O2Si: C, 71.37; H, 10.78. Found: C,
71.51; H, 10.78.
(1S,4S,8R)-8-[(1R)-1-(Hydr oxym eth yl)-2-m eth ylpr opyl]-
1-m eth ylbicyclo[2.2.2]oct-5-en -2-on e (17). To a solution of
15 (200 mg, 0.6 mmol) in THF (20 mL) was added at 0 °C a 1
M solution of TBAF in THF (1.4 mL, 1.4 mmol). After being
stirred at 0 °C for 5 h and at rt for 10 h, the reaction mixture
was treated with saturated NH4Cl solution (30 mL). The
aqueous layer was extracted with ether (5 × 60 mL) and the
combined organic layers were dried. Purification of the residue
by chromatography (Florisil, elution with 10% ethyl acetate
in petroleum ether) gave 113 mg (85%) of 17 as a colorless oil;
IR (neat, cm-1) 3446 (br), 1714, 1616, 1453; 1H NMR (300 MHz,
C6D6) δ 6.19 (dd, J ) 8, 7 Hz, 1H), 5.63 (br d, J ) 8 Hz, 1H),
3.35 (m, 2H), 2.44 (m, 1H), 1.99 (br d, J ) 18 Hz, 1H), 1.76 (br
d, J ) 18 Hz, 1H), 1.64 (m, 2H), 1.47 (dd, J ) 13, 10.5 Hz,
1H), 1.23 (br s, 1H), 1.22 (s, 3H), 1.15 (dd, J ) 13, 6 Hz, 1H),
0.91 (d, J ) 7 Hz, 3H), 0.91 (m, 1 H), 0.80 (d, J ) 7 Hz, 3H);
13C NMR (75 MHz, C6D6) δ 211.3 (s), 138.4 (d), 133.8 (d), 61.5
(t), 49.3 (s), 49.0 (d), 37.1 (t), 36.6 (d), 34.5 (t) 33.8 (d), 27.8
(d), 21.7 (q), 18.0 (q), 17.5 (q); MS m/z (M+) calcd 222.1620,
obsd 222.1619.
polar unreacted 13 which can be recycled.
1
For 14: IR (neat, cm-1), 1690, 1625, 1480, 1400; H NMR
(250 MHz, CDCl3) δ 7.01 (dd, J ) 10.3, 2.8 Hz, 1H, minor),
6.90 (dd, J ) 10.2, 2.8 Hz, 1H, major), 5.91 (m, 1H), 3.67 (m,
2H), 2.80 (m, 1H), 2.55 (m, 1H), 2.10 (m, 1H), 1.84 (m, 2H),
1.50 (m, 1H, major), 1.41 (m, 1H, minor), 1.15 (d, J ) 7 Hz,
3H, minor), 1.13 (d, J ) 7 Hz, 3H, major), 0.98 (d, J ) 6.8 Hz,
3H), 0.95 (d, J ) 6.8 Hz, 3H, major), 0.94 (d, J ) 6.8 Hz, 3H,
minor), 0.86 (s, 9H), 0.02 (s, 6H); 13C NMR (62 MHz, CDCl3)
(major diastereoisomer) δ 203.2 (s), 155.1 (d), 127.7 (d), 61.5
(t), 49.8 (d), 39.3 (d), 33.4 (d), 32.1 (t), 27.1 (d), 25.8 (q, 3C),
21.8 (q), 19.9 (q), 18.1 (s), 15.5 (q), -5.6 (q, 2C); (minor isomer)
δ 203.0 (s), 154.8 (d), 127.4 (d), 61.0 (t), 49.9 (d), 39.4 (d), 33.7
(t), 32.8 (d), 27.4 (d), 25.8 (q, 3C), 21.6 (q), 19.6 (q), 18.1 (s),
15.6 (q), -5.6 (q, 2C); MS m/z (M+ - CH3) calcd 295.2093, obsd
295.2119.
Anal. Calcd for C18H34O2Si: C, 69.62; H, 11.04. Found: C,
69.88; H, 11.13.
(1S,4S,8R)-8-[(R)-1-[(ter t-Bu tyld im eth ylsiloxy)m eth yl]-
2-m eth ylpr opyl]-1-m eth ylbicyclo[2.2.2]oct-5-en -2-on e (15)
a n d (1R,4R,8S)-8-[(R)-1-[(ter t-Bu tyld im eth ylsiloxy)m eth -
yl]-2-m e t h ylp r op yl]-1-m e t h ylb icyclo[2.2.2]oct -5-e n -2-
on e (16). To a cold (0 °C) solution of hexamethyldisilazane
(8.2 mL, 38.9 mmol) in THF (36 mL) was added n-butyllithium
in hexanes (20.1 mL, 32.2 mmol). After 30 min, 14 (4.0 g, 12.9
mmol) dissolved in dry THF (515 mL) was introduced, and the
brownish mixture was stirred at 0 °C for 30 min, treated with
phenyl vinyl sulfoxide (4.12 g, 27.1 mmol) in THF (65 mL) via
a syringe pump during 3 h at 3-6 °C, and quenched with
saturated NH4Cl solution (40 mL). The aqueous phase was
extracted several times with ether, and the combined organic
layers were dried and concentrated. The residue was taken
up in ether, filtered through a pad of Celite, and concentrated.
The residue was dissolved in toluene (40 mL), calcium carbon-
ate (2.6 g, 26 mmol) was added, and the yellow suspension
was heated at reflux for 24 h. After filtration of the cooled
mixture through a pad of Celite, the filtrate was evaporated
and the residue was chromatographed on silica gel (elution
with 9% ethyl acetate in hexanes) to give 2.5 g (58%) of a
mixture of 15 and 16. Further purification by MPLC afforded
1.16 g (27%) of pure 15 and 609 mg (14%) of 16.
Anal. Calcd for C14H22O2: C, 75.63; H, 10.03. Found: C,
75.84; H, 10.03.
(1S,4S,8R)-8-[(1R)-1-(P h en ylth iom eth yl)-2-m eth ylp r o-
p yl]-1-m eth ylbicyclo[2.2.2]oct-5-en -2-on e (18). A solution
of 17 (500 mg, 2.25 mmol) and diphenyl disulfide (970 mg, 4.44
mmol) in toluene (5 mL) was treated with tri-n-butylphosphine
(1.1 mL, 4.4 mmol), stirred overnight at rt, and directly
charged onto a column of silica gel. Elution with 0-10% of
ethyl acetate in hexanes gave 18 (650 mg, 92%) as a white
1
solid: mp 82.5-83.5 °C; H NMR (300 MHz, CDCl3) δ 7.32-
7.24 (m, 4H), 7.19-7.14 (m, 1H), 6.53 (t, J ) 7.4 Hz, 1H), 5.83
(d, J ) 7.4 Hz, 1H), 2.95 (dd, J ) 5.7, 12.4 Hz, 1H), 2.89 (m,
1H), 2.82 (ddd, J ) 1.0, 3.6, 12.4 Hz, 1H), 2.17 (ddd, J ) 1.0,
1.7, 18.5 Hz, 1H), 2.11-1.80 (m, 3 H), 1.69-1.49 (m, 1H), 1.40-
1.35 (m, 2 H), 1.18 (s, 3 H), 1.02 (d, J ) 6.9 Hz, 3 H), 0.96 (d,
J ) 6.9 Hz, 3 H); 13C NMR (75 MHz, CDCl3) δ 212.8, 138.2,
137.7, 133.7, 129.3 (2C), 128.8 (2C),126.0, 49.2, 46.9, 39.6, 37.0,
34.5, 33.9 (2C), 28.4, 21.0, 17.5, 16.9; MS m/z (M+) calcd
For 15: colorless solid; mp 38-40 °C; IR (neat, cm-1) 1730,
1470, 1415, 1390; 1H NMR (300 MHz, C6D6) δ 6.21 (dd, J ) 8,
7 Hz, 1H), 5.83 (br d, J ) 8 Hz, 1H), 3.55 (dd, J ) 10.5, 3 Hz,
1H), 3.39 (dd, J ) 10.5, 5 Hz, 1H), 2.48 (m, 1H), 2.01 (dd, J )
18, 2 Hz, 1H), 1.88-1.76 (series of m, 2H), 1.67 (septet × d,
J ) 7, 3 Hz, 1H), 1.59 (dd, J ) 13, 10.5 Hz, 1H), 1.26 (s, 3H),
1.24 (dd, J ) 13, 6 Hz, 1H), 0.99 (m, 1H), 0.92 (d, J ) 7 Hz,
3H), 0.91 (s, 9H), 0.87 (d, J ) 7 Hz, 3H), 0.00 (s, 6H); 1H NMR
(300 MHz, CDCl3) δ 6.54 (dd, J ) 7.4, 7.1 Hz, 1H), 5.83 (d,
J ) 7.7 Hz, 1H), 3.68 (dd, J ) 10.5, 3.5 Hz, 1H), 3.61 (dd, J )
10.5, 5 Hz, 1H), 2.88 (br s, 1H), 2.17 (dd, J ) 18.5, 1.6 Hz,
1H), 1.90 (ddd, J ) 18.5, 3.3, 1.6 Hz, 1H), 1.88 (m, 1H), 1.69
(dd, J ) 13.2, 10.5 Hz, 1H), 1.37 (dd, J ) 13.2, 6 Hz, 1H), 1.24
(m, 2H), 1.19 (s, 3H), 0.99 (d, J ) 7 Hz, 3H), 0.90 (d, J ) 7 Hz,
3H), 0.86 (s, 9H), 0.02 (s, 6H); 13C NMR (75 MHz, C6D6) δ 210.4
(s), 138.4 (d), 133.9 (d), 61.7 (t), 49.3 (s), 48.6 (d), 37.2 (t), 36.3
(d), 34.5 (t), 33.8 (d), 27.9 (d), 26.0 (q, 3C), 21.8 (q), 18.3 (s),
18.1 (q), 17.8 (q), -5.5 (q), -5.6 (q); 13C NMR (75 MHz, CDCl3)
δ 213.5 (s), 138.5 (d), 133.5 (d), 61.6 (t), 49.4 (s), 48.7 (d), 37.1
(t), 36.4 (d), 34.7 (t), 33.6 (d), 27.7 (d), 25.9 (q, 3C), 21.7 (q),
18.1 (s), 17.6 (q), 17.5 (q), -5.5 (q), -5.6 (q); MS m/z (M+) calcd
346.1780, obsd 346.1768; [R]20 +303 (c 6.6, CHCl3).
D
Anal. Calcd for C20H26OS: C, 76.38; H, 8.33. Found: C,
76.34; H, 8.37.
Meth yl (2R)-3-(p-Meth oxyben zyloxy)-2-m eth ylp r op i-
on a te (19e). To an ice-cold suspension of sodium hydride (500
mg, 20 mmol) in dry ether (25 mL) was added dropwise a
solution of p-methoxybenzyl alcohol (25 g, 0.20 mol) in dry
ether (40 mL) over a 15 min period. After an additional 30
min, trichloroacetonitrile (19 mL, 0.89 mol) was introduced
dropwise at ice-bath temperature. The mixture was stirred
overnight and concentrated to leave the imidate as an oil (46.4
g, 90%).
To a mixture of methyl (R)-2-(hydroxymethyl)propionate
(10.0 g, 0.085 mol) and the freshly prepared imidate (46 g) in
CH2Cl2 (20 mL) and petroleum ether (40 mL) was added at 0
°C a solution of triflic acid (0.024 mL, 0.094 mmol) in CH2Cl2
(2 mL) under N2. The reaction mixture was stirred for 30 min
at rt, diluted with ice-water, and filtered with the aid of
hexane. The aqueous layer of the filtrate was extracted with
hexanes, and the combined organic phases were washed with
brine, dried, and evaporated. Purification by chromatography
on silica gel gave 19e (9.6 g, 47%) as a colorless oil: 1H NMR
(300 MHz, CDCl3) δ 7.12 (d, J ) 9.0 Hz, 2H), 6.76 (d, J ) 9.0
Hz, 2H), 4.34 (s, 2H), 3.69 (s, 3H), 3.57 (s, 3H), 3.52 (dd, J )
9.1, 7.4 Hz, 1H), 3.35 (dd, J ) 9.1, 5.9 Hz, 1H), 2.67 (ddd, J )
7.4, 7.1, 5.9 Hz, 1H), 1.06 (d, J ) 7.1 Hz, 3H).
336.2485, obsd 336.2481; [R]20 -273 (c 1.35, CHCl3).
D
Anal. Calcd for C20H36O2Si: C, 71.37; H, 10.78. Found: C,
71.56; H, 10.87.
For 16: IR (neat) 1730, 1470, 1415, 1390; 1H NMR (300
MHz, C6D6) δ 6.33 (dd, J ) 8, 7 Hz, 1H), 5.66 (br d, J ) 8 Hz,
1H), 3.46 (dd, J ) 10.5, 3 Hz, 1H), 3.40 (dd, J ) 10.5, 4.5 Hz,
1H), 2.89 (m, 1H), 2.30 (dd, J ) 18, 2 Hz, 1H), 1.96 (ddd, J )
18, 3.5, 2 Hz, 1H), 1.77 (m, 1H), 1.57 (septet x d, J ) 7, 3 Hz,
1H), 1.42 (dd, J ) 13, 10.5 Hz, 1H), 1.25 (s, 3H), 1.05 (m, 1H),
J . Org. Chem, Vol. 68, No. 16, 2003 6105

Paquette et al.
p -Met h oxyb en zyl (2S,3E)-4-Iod o-2-m et h yl-3-b u t en yl
Eth er (22e). A cold (-78 °C) solution of 19e (480 mg, 2.01
mmol) in dry ether (10 mL) was treated dropwise with a
solution of diisobutylaluminum hydride in hexanes (2.1 mL
of 1 M, 2.1 mmol), stirred at -78 °C for 1.5 h, quenched with
saturated NH4Cl solution, and allowed to warm to rt. The
product was extracted into ethyl acetate, the combined organic
layers were washed with brine, dried, and evaporated, and the
residual aldehyde (420 mg) was used immediately.
appeared. After 10 min of stirring, magnesium bromide
etherate (excess) and a solution of 15 (95 mg, 0.28 mmol) were
introduced at this temperature, and the reaction mixture was
allowed to warm to 0 °C over 2 h. After the reaction mixture
was quenched with saturated NH4Cl solution (1 mL), the
mixture was diluted with ether, and the organic phase was
washed with brine, dried, and concentrated. Chromatography
of the residue as above afforded 60 mg (39%) of 37e and 32
mg (21%) of 38e.
To a cold (0 °C) suspension of dry chromium(II) chloride (1.4
g) in anhydrous THF (10 mL) and dioxane (4 mL) was added
dropwise a solution of the above aldehyde and iodoform (1.5
g, 3.8 mmol) in dry THF (8 mL). The reaction mixture was
stirred at 0 °C for 1 h and at rt for 4 h prior to being quenched
with saturated NH4Cl solution and extracted with ethyl
acetate. The combined organic layers were washed with brine,
dried and concentrated. Purification of the residue on silica
gel (elution with 0-3% ethyl acetate in hexanes) gave 322 mg
(42% over two steps) of 22e as a colorless oil: 1H NMR (300
MHz, CDCl3) δ 7.23 (d, J ) 8.9 Hz, 2H), 6.88 (d, J ) 8.9 Hz,
2H), 6.51 (dd, J ) 7.4, 14.5 Hz, 1H), 6.08 (d, J ) 14.5 Hz, 1H),
4.43 (s, 2H), 3.81 (s, 3H), 3.30 (m, 2H), 2.50 (m, 1H), 1.02 (d,
J ) 6.9 Hz, 3H); MS m/z (M+) calcd 332.0273, obsd 332.0266;
C. Use of Ma gn esiu m Br om id e Eth er a te a t 0 °C. A cold
(-78 °C) solution of 22e (101 mg, 0.30 mmol) in dry ether (2
mL) was treated with tert-butyllithium (0.4 mL of 1.7 M in
pentane, 0.68 mmol) until a pale yellow color appeared. After
10 min of stirring, magnesium bromide etherate (excess) was
introduced at this temperature and the reaction mixture was
warmed directly to 0 °C, stirred for 20 min, and treated with
a solution of 15 (51 mg, 0.15 mmol) in THF (2 mL). After 2 h
of stirring at 0 °C, the above workup was applied, and there
was isolated 52 mg (63%) of 37e and 16 mg (20%) of 38e.
Com p ou n d 55. To a cold (0 °C) solution of 37e (177 mg,
0.326 mmol) and 18-crown-6 (86 mg, 0.33 mmol) in dry THF
(6 mL) was added potassium hexamethyldisilazide (2 mL of
0.5 M in toluene, 1 mmol). After being stirred for 5 min at 0
°C, the yellowish mixture was directly heated at 120 °C for 1
h in a sealed tube, returned to 0 °C, quenched with saturated
NH4Cl solution, and diluted with ether. The organic phase was
washed with brine, dried, and concentrated. The residue was
purified by chromatography on silica gel (elution with 8:1
ether/hexanes) to give 127 mg (72%) of 55: colorless oil; IR
[R]20 -4.2 (c 0.17, CHCl3).
D
(1S ,2S ,4S ,8R )-2-[(1E ,3S )-4-(p -Me t h oxyb e n zyloxy)-3-
m eth yl-1-bu ten yl]-8-[(1R)-1-[(ter t-bu tyld im eth ylsiloxy)-
m eth y]-2-m eth ylp r op yl]-1-m eth ylbicyclo[2.2.2]oct-5-en -
2-ol (37e) a n d (1S,2R,4S,8R)-2-[(1E,3S)-4-(4-Met h oxy-
ben zyloxy)-3-m eth yl-1-bu ten yl]-8-[(1R)-1-[(ter t-bu tyld i-
m eth ylsiloxy)m eth yl]-2-m eth ylp r op yl]-1-m eth ylbicyclo-
[2.2.2]oct-5-en -2-ol (38e). A. By Ba r bier -Typ e Rea ction .
A mixture of magnesium turnings (270 mg, 0.81 mmol), 1,2-
dibromoethane (0.03 mL, 0.35 mmol), 22e (270 mg, 0.81 mmol),
and 15 (95 mg, 0.28 mmol) in dry THF (3 mL) was sonicated
for 2 h at 15-20 °C. After being cooled to 0 °C, the reaction
mixture was quenched with saturated NH4Cl solution (1 mL)
and diluted with ether. The organic phase washed with brine,
dried, and concentrated to leave a residue that was purified
chromatographically (silica gel, elution with 5% ethyl acetate
in hexanes) to give 31 mg (20%) of 37e and 20 mg (13%) of
38e.
1
(neat, cm-1) 1710, 1510, 1460; H NMR (300 MHz, CDCl3) δ
7.24 (br d, J ) 8.6 Hz, 2H), 6.86 (br d, J ) 8.6 Hz, 2H), 5.35
(br s, 1H), 4.47 (d, J ) 11.6 Hz, 1H), 4.40 (d, J ) 11.6 Hz, 1H),
3.79 (s, 3H), 3.69-3.62 (m, 2H), 3.48 (dd, J ) 9.1, 3.7 Hz, 1H),
3.38 (dd, J ) 9.0, 6.2 Hz, 1H), 2.61(br s, 1H), 2.31 (br d, J )
11.6 Hz, 1H), 2.20-2.02 (m, 6H), 1.94-1.70 (m, 4H), 1.70 (br
s, 3H), 1.12-1.07 (m, 1H), 1.02 (d, J ) 6.6 Hz, 3H), 0.97 (d,
J ) 6.9 Hz, 3H), 0.89 (s, 9H), 0.89 (d, J ) 7.0 Hz, 3H), 0.05 (br
s, 6H); 13C NMR (75 MHz, CDCl3) δ 212.7, 159.1, 136.9, 130.7,
129.0 (2C), 118.1, 113.7 (2C), 73.1, 72.8, 60.4, 55.2, 46.7, 43.7,
41.5, 38.2, 37.3, 37.0, 36.6, 34.7, 32.1, 26.7, 25.9 (3C), 23.7,
21.7, 18.1, 17.5, 16.2, -5.5, -5.7; MS m/z (M+ - CH3) calcd
For 37e: colorless oil; IR (CHCl3, cm-1) 3400, 1627, 1439;
1H NMR (300 MHz, C6D6) δ 7.28 (d, J ) 6.8 Hz, 2H), 6.81 (d,
J ) 6.8 Hz, 2H), 6.27 (dd, J ) 8.0, 7.1 Hz, 1H), 5.88 (d, J )
8.0 Hz, 1H), 5.58 (m, 2H), 4.31 (br s, 2H), 3.76 (dd, J ) 10.5,
2.5 Hz, 1H), 3.72 (dd, J ) 10.5, 4.1 Hz, 1H), 3.32 (s, 3H), 3.28
(m, 1H), 3.20 (m, 1H), 2.51 (br q, J ) 6.0 Hz, 1H), 2.42 (br s,
1H), 2.02 (dd, J ) 13, 4.5 Hz, 1H), 1.87 (m, 1H), 1.75 (m, 2H),
1.55 (ddd, J ) 13, 2.1, 1.3 Hz, 1H), 1.40-1.20 (m, 3H), 1.08
(d, J ) 7.0 Hz, 3H),1.06 (d, J ) 6.3 Hz, 3H), 1.02 (s, 3H), 0.96
(s, 9H), 0.93 (d, J ) 7.0 Hz, 3H), 0.02 (s, 6H); 13C NMR (75
MHz, C6D6) δ 159.4 (s), 138.4 (s), 138.1 (d), 135.8 (d), 129.0
(s), 128.7 (d, 2C), 127.4 (d), 113.7 (d, 2C), 77.2 (s), 75.2 (t), 72.6
(t), 62.3 (t), 54.4 (d), 47.7 (d), 41.9 (s), 38.0 (t), 36.9 (d), 36.1
(d), 34.0 (t), 32.7 (d), 27.9 (d), 25.6 (q, 3C), 21.8 (q), 18.9 (q),
527.3557, obsd 527.3536; [R]23 +5.9 (c 1.60, CHCl3).
D
Com p ou n d 56. A solution of 55 (185 mg, 0.34 mmol),
ethylene glycol (0.38 mL, 6.8 mmol), and p-toluenesulfonic acid
(19 mg, 0.1 mmol) in benzene (4 mL) was refluxed for 4 h under
a Dean-Stark trap, cooled to rt, and quenched with saturated
NaHCO3 solution. After dilution with ether, the organic phase
was washed with additional bicarbonate solution, dried, and
evaporated. Chromatography of the residue on silica gel
(elution with 10:1 hexanes/ethyl acetate) afforded 168 mg
(84%) of 56: colorless oil; IR (neat, cm-1) 1610, 1510, 1450;
1H NMR (300 MHz, CDCl3) δ 7.26 (br d, J ) 8.4 Hz, 2H), 6.86
(br d, J ) 8.3 Hz, 2H), 5.22 (br s, 1H), 4.47 (d, J ) 11.6 Hz,
1H), 4.40 (d, J ) 11.6 Hz, 1H), 3.93 (br s, 4H), 3.80 (s, 3H),
3.70-3.60 (m, 2H), 3.54 (dd, J ) 9.0, 3.5 Hz, 1H), 3.32-3.26
(m, 1H), 2.40 (br s, 1H), 2.09-1.91 (m, 4H), 1.84-1.58 (m, 4H),
1.64 (br s, 3H), 1.43-1.16 (m, 4H), 1.05 (d, J ) 6.5 Hz, 3H),
0.99 (d, J ) 6.9 Hz, 3H), 0.89 (br s, 9H), 0.88 (d, J ) 7.9 Hz,
3H), 0.05 (br s, 6H); 13C NMR (75 MHz, CDCl3) δ 159.0, 135.9,
131.0, 129.0 (2C), 118.7, 113.6 (2C), 109.9, 73.5, 72.6, 64.1, 63.9,
60.9, 55.2, 46.9, 40.8, 38.1, 36.4, 34.5, 34.2, 34.0, 32.6, 29.3,
26.7, 25.9 (3C), 23.7, 21.6, 18.1, 17.8, 16.4, -5.5, -5.6; MS m/z
18.4 (s), 17.5 (q), 17.4 (q), -5.5 (q), -5.7 (q); MS m/z (M+
-
C8H9O) calcd 421.3138, obsd 421.3128; [R]20 -71 (c 1.8,
D
CHCl3).
Anal. Calcd for C33H54O4Si; C, 73.01; H, 10.03. Found: C,
72.93; H, 10.07.
For 38e: colorless oil; 1H NMR (300 MHz, CDCl3) δ 6.55 (t,
J ) 8.4 Hz, 1H), 5.90 (d, J ) 8.4 Hz, 1H), 5.63 (m, 2H), 3.62
(dd, J ) 6.9, 2.1 Hz, 1H), 3.51 (dd, J ) 6.8, 3.1 Hz, 1H), 3.39
(dd, J ) 8.1, 4.1 Hz, 1H), 2.55 (br s, 1H), 2.41 (m, 1H), 1.85
(m, 3H), 1.55 (m, 1H), 1.26-1.20 (m, 1H), 1.21 (br s, 3H), 1.05
(d, J ) 6.9 Hz, 3H), 1.03 (d, J ) 6.8 Hz, 3H), 0.88 (2s, 18H),
0.81 (d, J ) 7.1 Hz, 3H), 0.05 (4s, 12H); MS m/z (M+ - C8H9O)
calcd 421.3138, obsd 421.3142.
(M+) calcd 586.4054, obsd 586.4023; [R]23 +10.2 (c 1.40,
D
CHCl3).
Com p ou n d 57. A solution of 56 (54 mg, 0.092 mmol) in
dry THF (4 mL) was treated with a 1 M solution of TBAF in
THF (0.28 mL, 0.28 mmol), stirred at rt for 14 h, diluted with
hexanes, and filtered through a short plug of silica gel. The
evaporated filtrate was purified by chromatography (silica gel,
elution with 2:1 hexanes/ethyl acetate) to give 57 (43 mg,
100%) as a colorless oil: IR (neat, cm-1) 3420, 1600, 1500, 1430;
1H NMR (300 MHz, CDCl3) δ 7.24 (br d, J ) 8.4 Hz, 2H), 6.85
B. Use of Ma gn esiu m Br om id e E t h er a t e a t -78 f
0 °C. A cold (-78 °C) solution of 22e (186 mg, 0.56 mmol) in
dry ether (3 mL) was treated with tert-butyllithium (0.75 mL
of 1.7 M in pentane, 1.28 mmol) until a pale yellow color
6106 J . Org. Chem., Vol. 68, No. 16, 2003

Enantioselective Synthesis of Vinigrol
(br d, J ) 8.6 Hz, 2H), 5.21 (br s, 1H), 4.45 (d, J ) 11.7 Hz,
1H), 4.37 (d, J ) 11.7 Hz, 1H), 3.91 (br s, 4H), 3.79 (s, 3H),
3.77-3.67 (m, 2H), 3.49 (dd, J ) 9.0, 3.6 Hz, 1H), 3.28 (dd,
J ) 9.0, 7.1 Hz, 1H), 2.37 (br s, 1H), 2.11-1.83 (m, 4H), 1.82-
1.57 (m, 4H), 1.64 (br s, 3H), 1.43-1.18 (m, 5H), 1.02 (d, J )
6.5 Hz, 3H), 1.01 (d, J ) 6.9 Hz, 3H), 0.89 (d, J ) 7.0 Hz, 3H);
13C NMR (75 MHz, CDCl3) δ 159.0, 135.6, 130.9, 129.0 (2C),
118.9, 113.6 (2C), 109.8, 73.3, 72.6, 64.2, 63.9, 61.2, 55.2, 47.4,
40.7, 38.0, 36.5, 34.5, 34.1, 34.0, 32.7, 29.2, 26.5, 23.7, 21.6,
17.7, 16.4; MS m/z (M+ + H) calcd 473.3267, obsd 473.3285;
J ) 8.3 Hz, 2H), 7.35 (br d, J ) 8.2 Hz, 2H), 5.18 (br s, 1H),
3.95-3.91 (m, 4H), 3.67 (dd, J ) 10.6, 3.3 Hz, 1H), 3.47 (dd,
J ) 10.5, 6.0 Hz, 1H), 3.06 (dd, J ) 15.2, 4.4 Hz, 1H), 2.85
(dd, J ) 15.2, 3.8 Hz, 1H), 2.67 (d, J ) 8.7 Hz, 2H), 2.44 (s,
3H), 2.35 (br s, 1H), 2.09-1.96 (m, 1H), 1.95-1.90 (m, 2H),
1.78-1.52 (m, 5H), 1.55 (s, 3H), 1.30-1.20 (m, 3H), 0.99 (d,
J ) 6.2 Hz, 3H), 0.86 (d, J ) 6.9 Hz, 3H), 0.72 (d, J ) 6.8 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 144.5, 137.6, 135.8, 129.8
(2C), 128.2 (2C), 118.5, 109.5, 65.9, 64.2, 64.0, 56.4, 40.1, 40.0,
39.9, 38.1, 35.8, 34.7, 34.5, 32.5, 28.9, 27.1, 23.5, 21.6, 20.5,
[R]23 +7.6 (c 1.53, CHCl3).
16.2, 15.6; MS m/z (M+) calcd 490.2753, obsd 490.2754; [R]23
D
D
Com p ou n d 58. To a stirred solution of 57 (43 mg, 0.091
mmol) and DMAP (67 mg, 0.55 mmol) in CH2Cl2 (4 mL) was
added p-toluenesulfonyl chloride (52 mg, 0.27 mmol), and the
mixture was stirred overnight at rt, quenched with saturated
NaHCO3 solution, and extracted with ether. The combined
organic phases were dried and evaporated to leave a residue
that was chromatographed on silica gel. Elution with 2.5:1
hexanes/ethyl acetate gave 52 mg (91%) of tosylate as a
colorless gum: IR (neat, cm-1) 1590, 1505, 1440, 1350; 1H NMR
(300 MHz, CDCl3) δ 7.79 (br d, J ) 8.2 Hz, 2H), 7.34 (br d,
J ) 8.1 Hz, 2H), 7.24 (br d, J ) 8.5 Hz, 2H), 6.86 (br d, J )
8.6 Hz, 2H), 5.18 (br s, 1H), 4.45 (d, J ) 11.7 Hz, 1H), 4.23 (d,
J ) 11.7 Hz, 1H), 4.09-3.29 (series of m, 2H), 3.89 (br s, 4H),
3.79 (s, 3H), 3.47 (dd, J ) 9.0, 3.5 Hz, 1H), 3.26 (dd, J ) 8.8,
7.2 Hz, 1H), 2.45 (s, 3H), 2.34 (br s, 1H), 2.00-1.80 (m, 3H),
1.76-1.48 (m, 5H), 1.54 (br s, 3H), 1.43-1.15 (m, 4H), 1.00 (d,
J ) 6.5 Hz, 3H), 0.87 (d, J ) 6.9 Hz, 3H), 0.81 (d, J ) 7.0 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 159.0, 144.7, 135.0, 132.9,
130.8, 129.8 (2C), 129.0 (2C), 128.0 (2C), 119.0, 113.6 (2C),
109.6, 73.2, 72.6, 68.9, 64.1, 63.9, 55.2, 44.6, 40.6, 37.8, 35.9,
34.4, 34.0, 33.6, 32.1, 29.1, 26.2, 23.4, 21.6, 21.2, 17.2, 16.3;
MS m/z (M+ - CH3) calcd 611.3043, obsd 611.3054; [R]23D +9.2
(c 2.43, CHCl3).
-4.1 (c 1.78, CHCl3).
Com p ou n d 61. To a mixture of 60 (32 mg, 0.065 mmol)
and DMAP (48 mg, 0.39 mmol) in CH2Cl2 (3 mL) was added
p-toluenesulfonyl chloride (37 mg, 0.19 mmol). After being
stirred overnight at rt, the reaction mixture was quenched with
saturated NaHCO3 solution and extracted with ether. The
combined organic layers were dried and concentrated to leave
a residue that was purified by flash chromatography (silica
gel, elution with 2.5:1 hexanes/ethyl acetate). There was
isolated 34 mg (81%) of 61 as a colorless gum: IR (neat, cm-1
)
1590, 1440, 1340; 1H NMR (300 MHz, CDCl3) δ 7.79 (br d,
J ) 8.3 Hz, 2H), 7.75 (br d, J ) 8.4 Hz, 2H), 7.35 (br d, J )
8.1 Hz, 2H), 7.31 (br d, J ) 8.1 Hz, 2 H), 4.98 (br s, 1H), 4.05
(dd, J ) 9.4, 3.4 Hz, 1H), 3.93-3.85 (m, 5H), 3.07 (dd, J )
15.2, 4.3 Hz, 1H), 2.84 (dd, J ) 15.0, 3.7 Hz, 1H), 2.45 (s, 3H),
2.43 (s, 3H), 2.18 (br s, 1H), 2.04-1.96 (m, 1H), 1.94-1.67 (m,
4H), 1.66-1.47 (m, 3H), 1.53 (br s, 3H), 1.47-1.14 (m, 4H),
0.92 (d, J ) 6.5 Hz, 3H), 0.86 (d, J ) 6.8 Hz, 3H), 0.72 (d, J )
6.7 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 144.6, 144.5, 137.6,
136.4, 133.1, 129.9 (2C), 129.7 (2C), 128.2 (2C), 127.9 (2C),
117.5, 109.2, 73.2, 64.2, 64.1, 56.3, 39.93, 39.89, 39.82, 37.7,
34.5, 34.3, 33.3, 32.5, 28.9, 27.1, 23.5, 21.61, 21.57, 20.4, 16.2,
15.6; MS m/z (M+) calcd 644.2841, obsd 644.2863; [R]23 -3.0
D
Com p ou n d 59. A mixture of 58 (52 mg, 0.083 mmol) and
sodium iodide (124 mg, 0.83 mmol) in methyl ethyl ketone (5
mL) was refluxed for 1.5 h under N2, cooled to rt, diluted with
ether, and washed with saturated sodium thiosulfate solution.
The organic phase was dried and evaporated. The residue was
taken up in DMF (4 mL), treated with sodium p-toluenesulfi-
nate (148 mg, 0.83 mmol), and heated at 110 °C for 11 h. The
cooled reaction mixture was diluted with ether and washed
with brine. The aqueous phase was extracted with ether, and
the combined organic layers were dried and concentrated.
Purification of the product was accomplished by flash chro-
matography on silica gel (elution with 3:1 hexanes/ethyl
acetate) to furnish 42 mg (82%) of 59 as a colorless gum: IR
(c 2.49, CHCl3).
Com p ou n d 62. A mixture of 61 (12 mg, 0.019 mmol) and
sodium iodide (28 mg, 0.19 mmol) in methyl ethyl ketone (3
mL) was heated at reflux temperature for 1.5 h, cooled to rt,
diluted with ether, and washed with saturated sodium thio-
sulfate solution. The organic phase was dried and evaporated,
and the residue was purified by flash chromatography (silica
gel, elution with 4:1 hexanes/ethyl acetate) to furnish 9 mg
(82%) of 62 as a white solid: mp 193 °C; IR (neat, cm-1)1580,
1
1420, 1360; H NMR (300 MHz, CDCl3) δ 7.80 (br d J ) 8.2
Hz, 2H), 7.36 (br d, J ) 8.0 Hz, 2H), 5.10 (br s, 1H), 3.94 (br
s, 4H), 3.34 (dd, J ) 9.8, 2.6 Hz, 1H), 3.22 (dd, J ) 9.7, 5.2 Hz,
1H), 3.08 (dd, J ) 15.2, 4.3 Hz, 1H), 2.86 (dd, J ) 15.1, 3.8
Hz, 1H), 2.45 (s, 3H), 2.38 (br s, 1H), 2.15-1.90 (m, 3H), 1.84-
1.50 (m, 5H), 1.58 (br s, 3H), 1.46-1.20 (m, 4H), 1.01 (d, J )
6.3 Hz, 3H), 0.87 (d, J ) 6.9 Hz, 3H), 0.74 (d, J ) 6.8 Hz, 3H);
13C NMR (75 MHz, CDCl3) δ 144.5, 137.7, 136.6, 129.9 (2C),
128.2 (2C), 117.6, 109.4, 64.3, 64.1, 56.4, 42.6, 40.04, 39.96,
37.5, 34.4, 34.3, 33.5, 32.6, 28.9, 27.2, 23.5, 21.6, 20.4, 19.7,
1
(neat, cm-1) 1590, 1460, 1440; H NMR (300 MHz, CDCl3) δ
7.79 (br d, J ) 8.2 Hz, 2H), 7.35 (br d, J ) 8.0 Hz, 2H), 7.25
(br d, J ) 8.9 Hz, 2H), 6.86 (br d, J ) 8.6 Hz, 2H), 5.16 (br s,
1H), 4.45 (d, J ) 11.7 Hz, 1H), 4.35 (d, J ) 11.7 Hz, 1H), 3.95-
3.86 (m, 4H), 3.78 (br s, 3H), 3.45 (dd, J ) 9.0, 3.5 Hz, 1H),
3.25 (dd, J ) 8.9, 7.0 Hz, 1H), 3.07 (dd, J ) 15.2, 4.3 Hz, 1H),
2.86 (dd, J ) 15.2, 3.7 Hz, 1H), 2.44 (s, 3H), 2.34 (br s, 1H),
2.13-2.04 (m, 1H), 1.93-1.90 (m, 2H), 1.80-1.49 (m, 5H), 1.54
(br s, 3H), 1.46-1.17 (m, 4H), 1.00 (d, J ) 6.5 Hz, 3H), 0.86
(d, J ) 6.8 Hz, 3H), 0.73 (d, J ) 6.8 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 159.0, 144.5, 137.6, 135.3, 130.8, 129.8 (2C),
129.0 (2C), 128.2 (2C), 118.8, 113.6 (2C), 109.5, 73.3, 72.6, 64.2,
64.0, 56.4, 55.2, 40.6, 40.01, 39.96, 38.1, 34.6, 34.4, 34.0, 32.5,
29.0, 27.1, 23.5, 21.5, 20.4, 16.3, 16.2; MS m/z (M+) calcd
17.5, 16.2; MS m/z (M+) calcd 600.1770, obsd 600.1761; [R]23
+7.6 (c 0.87, CHCl3).
D
Ack n ow led gm en t. Financial support was provided
in part by the National Institutes of Health. In addition,
we thank Prof. Robin Rogers (University of Alabama)
for the X-ray crystallographic analysis, Dr. Scott Ed-
mondson for the molecular mechanics calculations, and
Dr. Kurt Loening for assistance with nomenclature.
610.3328, obsd 610.3292; [R23 +1.1 (c 2.00, CHCl3).
D
Com p ou n d 60. A mixture of 59 (42 mg, 0.069 mmol) and
DDQ (23 mg, 0.1 mmol) in 18:1 CH2Cl2/H2O (4 mL) was stirred
at rt for 1.5 h, quenched with saturated NaHCO3 solution, and
diluted with ether. The aqueous phase was extracted with
ether, and the combined organic layers were dried and
concentrated. The residue was purified by flash chromatog-
raphy (silica gel, elution with 1:1 hexanes/ethyl acetate) to
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails for those compounds not involved in the direct route to
62, tables of the X-ray crystal data, atomic coordinates, and
equivalent isotropic displacement parameters, and positional
parameters for the hydrogen atoms of 62. This material is
available free of charge via the Internet at http://pubs.acs.org.
provide 32 mg (94%) of 60 as a colorless gum: IR (neat, cm-1
3460, 1590, 1370; 1H NMR (300 MHz, CDCl3) δ 7.88 (br d,
)
J O0301301
J . Org. Chem, Vol. 68, No. 16, 2003 6107