A new method for stereocontrolled synthesis of substituted tetrahydrothiophenes

Article abstract of DOI:10.1021/ja001975m

A variety of substituted 3-acyltetrahydrothiophenes can be prepared with high stereoselectivity in 50-70% yield by acid-promoted condensation of mercapto allylic alcohols 1 (X = S) with aldehydes and ketones. The mercapto allylic alcohol must be substitut

Full text of DOI:10.1021/ja001975m

8672
J. Am. Chem. Soc. 2000, 122, 8672-8676
A New Method for Stereocontrolled Synthesis of Substituted
Tetrahydrothiophenes
Andre´s Molina Ponce and Larry E. Overman*
Contribution from the Department of Chemistry, 516 Rowland Hall, UniVersity of California,
IrVine, California 92697-2025
ReceiVed June 5, 2000
Abstract: A variety of substituted 3-acyltetrahydrothiophenes can be prepared with high stereoselectivity in
50-70% yield by acid-promoted condensation of mercapto allylic alcohols 1 (X ) S) with aldehydes and
ketones. The mercapto allylic alcohol must be substituted at the internal alkene carbon and the terminal alkene
carbon must be unsubstituted. This new synthesis of tetrahydrothiophenes will be most useful for preparing
3-acyltetrahydrothiophenes having cis side chains at C2 and C5. The complete preservation of enantiomeric
purity in the conversion of (4R)-9 to tetrahydrothiophene 22 is consistent with a cyclization-pinacol pathway
(24 f 25 f 26 f 27, Scheme 8).
Introduction
Scheme 1
The development of versatile methods for forming carbon-
carbon bonds under mild conditions is a central objective of
synthetic organic chemistry. Previous investigations in our
laboratories have shown that five-membered nitrogen and
oxygen heterocycles 3a and 3b can be prepared with high
stereoselectivity by acid-catalyzed condensations of allylic
alcohols 1a or 1b with carbonyl compounds, or by rearrange-
ments of 5-alkenyl oxazolidines 2a or 4-alkenyldioxolanes 2b
(Scheme 1).1 This pyrrolidine synthesis (X ) NR), often termed
the aza-Cope-Mannich reaction, constitutes a powerful method
for assembling complex nitrogen heterocycles and has served
as the cornerstone of total syntheses of a wide variety of
alkaloids.1,2 The related preparation of tetrahydrofurans also has
been developed extensively,1a,b,3 and shown to be effective at
solving formidable stereochemical problems in the assembly
of complex cyclic ethers.4
Substituted tetrahydrothiophenes find a number of uses. Biotin
is an essential coenzyme, which is produced on large scale by
chemical synthesis.5 Polysubstituted tetrahydrothiophenes are
reported to display various other biological activities, including
leukotriene antagonism,6a plant growth regulation,6b and anti-
oxidant activity.6c In addition, many tetrahydrothiophenes, or
their sulfoxide or sulfonium analogues, have been prepared as
mimics of natural and synthetic ligands for pharmacologically
important targets.7 The tetrahydrothiophene ring system is also
found in tetronothiodin, a structurally novel cholecystokinin
type-B receptor antagonist isolated from a Streptomyces strain,8
and also has served as a platform for developing new chiral
ligands for asymmetric catalysis.9 Despite their utility, few
stereocontrolled methods for forming substituted tetrahy-
drothiophenes have been developed.10,11
We report herein that a variety of 3-acyltetrahydrothiophenes
3c can be prepared by acid-promoted condensations of 1-mer-
capto-3-alken-2-ols 1c and carbonyl compounds, or by rear-
rangement of 5-alkenyl oxathiolanes 2c (Scheme 1). The
defining feature of this new tetrahydrothiophene synthesis is
use of a carbon-carbon bond-forming reaction to form the
cyclic thioether product and regulate stereochemical outcome.
This approach differs from most syntheses of substituted
(1) For short reviews, see: (a) Overman, L. E. Aldrichim. Acta 1995,
28, 107-120. (b) Overman, L. E. Acc. Chem. Res. 1992, 25, 352-359. (c)
Thebtaranonth, C.; Thebtaranonth, Y. Cyclization Reactions; CRC Press:
Boca Raton, 1994; pp 29-35.
(7) (a) Kim, B. M.; Bae, S. J.; Seomoon, G. Tetrahedron Lett. 1998, 39,
6921-6922. (b) Yamada, K.; Sakata, S.; Yoshimura, Y. J. Org. Chem. 1998,
63, 6891-6899. (c) Jones, M. F.; Noble, S. A.; Robertson, C. A.; Storer,
R. Tetrahedron Lett. 1991, 32, 247-250. (d) Morimoto, Y.; Achiwa, K.
Chem. Pharm. Bull. 1987, 35, 3845-3849. (e) Harrold, M. W.; Wallace,
R. A.; Farooqui, T.; Wallace, L. J.; Uretsky, N.; Miller, D. D. J. Med. Chem.
1989, 32, 874-888. (f) Popsavin, V.; Beric, O.; Velimirovic, S.; Miljkovic,
D. J. Serb. Chem. Soc. 1993, 58, 717-719. (g) Aloup, J. C.; Bouchaudon,
J.; Farge, D.; James, C.; Deregnaucourt, J.; Hardy-Houis, M. J. Med. Chem.
1987, 30, 24-29.
(8) Ohtsuka, T.; Kotaki, H.; Nakayama, N.; Itezono, Y.; Shimma, N.;
Kudoh, T.; Kuwahara, T.; Arisawa, M.; Yokose, K.; Seto, H. J. Antibiot.
1993, 46, 11-17.
(9) Hauptman, E.; Shapiro, R.; Marshall, W. Organometallics 1998, 17,
4976-4982.
(2) For one illustration, see: Knight, S. D.; Overman, L. E.; Pairaudeau,
G. J. Am. Chem. Soc. 1995, 117, 5776-5788.
(3) Martinet, P.; Mousset, G. Bull. Soc. Chim. Fr. 1970, 1071-1076.
(4) For one illustration, see: MacMillan, D. W. C.; Overman, L. E. J.
Am. Chem. Soc. 1995, 117, 10391-10392.
(5) For a recent commercial synthesis, see: Imwinkelried, R. Chimia
1997, 51, 300-302.
(6) (a) Chorghade, M. S.; Gurjar, M. K.; Palakodety, R. K.; Lalitha, S.
V. S.; Sadalapure, K.; Adhikari, S. S.; Murugaiah, A. M. S.; Rao, B. V.;
Talukdar, A.; Talukdar, A.; Islam, A.; Hariprasad, C.; Rao, A. V. R. Patent
Application WO 99-US15050, CAN 132:93203 (b) Tsygankova, V. A.;
Blume, Ya. B. Biopolim. Kletka 1997, 13, 484-492. (c) Kato, T.; Tsuzuki,
K. Patent Application JP 92-147881, CAN 120:106750.
10.1021/ja001975m CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/25/2000

Stereocontrolled Synthesis of Substituted Tetrahydrothiophenes
J. Am. Chem. Soc., Vol. 122, No. 36, 2000 8673
tetrahydrothiophenes that typically involve carbon-sulfur bond
Scheme 2
formation.10,11
Results
Preparation of Unsaturated Mercapto Alcohols. 1-Mer-
capto-3-alkene-2-ols 6 and 7 were prepared from allylic epoxides
412 and 513 by reaction with a slight excess of freshly prepared
anhydrous sodium hydrosulfide14 at room temperature (eq 1).
Scheme 3
Purification of the crude product by vacuum distillation provided
analytically pure 6 and 7 in ∼50% yield. The yield of 6 was
somewhat reduced when commercial sodium hydrosulfide
hydrate was employed. 2-Mercapto-4-alkene-3-ols 9 and 10
were synthesized from 3-hydroxy-2-butanone by activation with
methanesulfonyl chloride followed by displacement of the crude
mesylate with cesium benzylsulfide at room temperature
(Scheme 2).15 Addition of alkenyllithium reagents derived from
2-bromopropene or (E)-2-bromo-2-butene to R-mercapto ketone
8 provided the corresponding allylic alcohols. The benzyl
protecting group was removed from these crude intermediates
by reaction with sodium and ethanol in ammonia, and the
mercapto alcohol products were purified by vacuum distillation
to provide 9 and 10 in 30-50% overall yield from 3-hydroxy-
2-butanone. Mercapto alkenols 9 and 10 were 2:3 mixtures of
allylic alcohol epimers, which were not separated.
Formation of 3-Acyltetrahydrothiophenes by Rearrange-
ment of 5-Alkenyl Oxathiolanes. A two-step sequence for
preparing 3-acyltetrahydrothiophenes was examined initially. In
early scouting experiments, mercapto allylic alcohol 7 was
condensed with cinnamaldehyde to generate 5-alkenyl oxathi-
olane 11a (Scheme 3). When this condensation was conducted
in the presence of 0.1 equiv of p-toluenesulfonic acid at 0 °C
in CH2Cl2, a ∼2:1 mixture of 11a and dithioacetal 12 was
produced. Alkenyl oxathiolane 11a, a 2:1 mixture of C2 epimers,
showed diagnostic doublets at δ 5.78 (J ) 7.6 Hz) and δ 5.62
(J ) 7.9 Hz) for the C2 methine hydrogens, whereas dithioacetal
12 exhibited a doublet (J ) 7 Hz) at δ 4.4 for its methine
hydrogen. In an attempt to minimize formation of 12, the
condensation was conducted at various temperatures and in the
presence of several alternative acid catalysts (BF3‚OEt2, pyridine
p-toluenesulfonate, and oxalic acid).16 p-Toluenesulfonic acid
proved to be optimal, and conducting the reaction at -20 °C
somewhat minimized competing formation of 12.17 Under these
conditions,18 11a was isolated in 67% yield after purification
on silica gel.
Initial survey experiments showed that the rearrangement of
styrenyl oxathiolane 11a to the corresponding 3-acyltetrahy-
drothiophene was promoted in CH2Cl2 at temperatures ranging
from -50 to 0 °C by addition of 1 equiv of various Lewis
acids: BF3‚OEt2, SnCl4, TiCl4, MnCl2, AlCl3, and EtAlCl2.
Yields were highest with BF3‚OEt2; in the presence of this Lewis
acid, 11a was cleanly converted to crystalline 3-acyl-3-methyl-
5-styrenyltetrahydrothiophene 13a within 1 h at -20 °C. After
purification on silica gel, 13a was isolated in 90% yield.
Examination of the crude product by 1H NMR failed to reveal
the presence of other products showing an acetyl methyl singlet
in the vicinity of δ 2.0-2.4. The stereochemistry of 13a
(10) (a) For an early review, see: Wolf, E.; Folkers, K. Org. React. 1951,
6, 410-468. For representative recent syntheses, see: (b) Linderman, R.
J.; Cutshall, N. S.; Becicka, B. T. Tetrahedron Lett. 1994, 35, 6639-6642.
(c) Eames, J.; Kuhnert, N.; Jones, R. V. H.; Warren, S. Tetrahedron Lett.
1998, 39, 1247-1250. (d) Vlattas, I.; Dellureficio, J.; Cohen, D. S.; Lee,
W.; Clarke, F.; Dotson, R.; Mathis, J.; Zoganas, H. Bioorg., Med. Chem.
Lett. 1994, 4, 2067-2072. (e) Brånalt, J.; Kvarnstro¨m, I.; Svensson, C. T.;
Classon, B.; Samuelsson, B. J. Org. Chem. 1994, 59, 4430-4432. (f)
Uenishi, J.; Motoyama, M.; Takahashi, K. Tetrahedron: Asymmetry 1994,
5, 101-110. (g) Jones, M. F.; Noble, S. A.; Robertson, C. A.; Store, R.
Tetrahedron Lett. 1991, 32, 247-250. (h) Dyson, M. R.; Coe, P. L.; Walker,
R. T. J. Chem. Soc., Chem. Commun. 1991, 741-742. (i) Bredenkamp, M.
W.; Holzapfel, C. W.; Swanepoel, A. D. Tetrahedron Lett. 1990, 31, 2759-
2762.
1
followed unambiguously from large reciprocal H NMR nOe
enhancements observed between the C3-Me, H4R and H5. When
Lewis acids other than BF3‚OEt2 were employed, the yield of
13a was compromised by competing fragmentation of oxathi-
olane 11a to regenerate trans-cinnamaldehyde. For example,
when 11a was exposed to 1 equiv of TiCl4 in CH2Cl2 at -20
°C, acyltetrahydrothiophene 13a and trans-cinnamaldehyde were
isolated in yields of 65% and 18%, respectively.
(11) Tetrahydrothiophenes have been made by C-C bond-forming 1,3-
dipolar cycloadditions of thiocarbonyl ylides. For representative examples,
see: (a) Karlsson, S.; Hogberg, H.-E. Org. Lett. 1999, 1, 1667-1669. (b)
Terao, Y.; Aono, M.; Achiwa, K. Heterocycles 1986, 24, 1571-1574. (c)
Hojo, M.; Ohkuma, M.; Hosomi, A. Chem. Lett. 1992, 6, 1073-1076. (d)
Aono, M.; Terao, Y.; Achiwa, K. Heterocycles 1995, 40, 249-260. (e)
Aono, M.; Terao, Y.; Achiwa, K. Heterocycles 1986, 24, 313-315.
(12) (a) Johnston, B. D.; Oehlschlager, A. C. Can. J. Chem. 1984, 62,
2148-2154. (b) Overman, L. E.; Kakimoto, M.; Okazaki, M. E.; Meier,
G. P. J. Am. Chem. Soc. 1983, 105, 6622-6629.
(16) Facile rearrangement of 11a to acyltetrahydrothiophene 13a limited
possible condensation conditions.
(17) Under no conditions examined was competing formation of 12
minimized significantly.
(13) Annis, G. D.; Ley, S. V.; Self, C. R.; Sivaramakrishnan, R. J. Chem.
Soc., Perkin Trans. 1 1981, 270-277.
(14) Eibeck, R. E. Inorg. Synth. 1963, 7, 128-131.
(18) Small amounts (∼5%) of acyltetrahydrothiophenes were formed
(15) Stritjtveen, B.; Kellogg, R. M. J. Org. Chem. 1986, 51, 3664-3671.
under these conditions.

8674 J. Am. Chem. Soc., Vol. 122, No. 36, 2000
Ponce and OVerman
Scheme 4
Scheme 5
Qualitatively similar results were observed with alkenyl
oxathiolanes 11b and 11c, which were derived from representa-
tive aliphatic and aromatic aldehydes (Scheme 4). Rearrange-
ment of these intermediates with 1 equiv of BF3‚OEt2 and 2
equiv of MgSO4 at -20 °C in CH2Cl2 provided acetyltetrahy-
drothiophenes 13b and 13c in high yields. In marked contrast,
no acyltetrahydrothiophene products were observed when 5-vi-
nyloxathiolanes 14 were exposed to various Lewis acids under
a variety of reaction conditions (eq 2).19 This latter result shows
Scheme 6
that this tetrahydrothiophene synthesis is limited to precursors
having an alkene more nucleophilic than a terminal vinyl group.
Direct Formation of 3-Acyltetrahydrothiophenes by Con-
densation of Aldehydes and Unsaturated Mercapto Alcohols.
We soon discovered that 3-acyltetrahydrothiophenes could be
prepared more conveniently by direct condensation of mercapto
alkenols with aldehydes and ketones. As summarized in Scheme
5, condensation of 7 with 1 equiv of a representative set of
aliphatic, R,â-unsaturated and aromatic aldehydes in the pres-
ence of 1 equiv of BF3‚OEt2 and 2 equiv of MgSO4 at -20 °C
in CH2Cl2 provided the 3-acetyl-3-methyl-5-substituted tetrahy-
drothiophenes 13a-e in 51-71% yields. When these reactions
were monitored by TLC, the oxathiolane was detected as an
intermediate. As in the earlier rearrangements of related
oxathiolanes, only a single stereoisomer of 13, that having the
5-substituent and the acetyl groups cis, was isolated. The yield
of 13b, formed from the saturated aliphatic aldehyde hydro-
cinnamaldehyde, was improved by employing 1.5 equiv of BF3‚
OEt2. That this tetrahydrothiophene synthesis is not limited to
aldehydes was shown by formation of 1-thiaspiro[4.5]decane
16 in 65% yield from similar condensation of 7 and cyclohex-
anone. When the reaction of 7 and trans-cinnamaldehyde was
attempted in the presence of 1 equiv of the proton-selective base
2,6-di-tert-butyl-4-methylpyridine,20 13a was not detected after
12 h. This experiment suggests that a complex protic acid
formed by the reaction of BF3‚OEt2 with water, which is a
byproduct of the reaction, is the acid promoter for the reaction.
To pursue preparation of more highly substituted tetrahy-
drothiophenes, unsaturated mercapto alcohol 9 (a 3:2 mixture
of epimers) was condensed with two representative aldehydes
(Scheme 6). Reaction of 9 with trans-cinnamaldehyde under
standard conditions (BF3‚OEt2 and 2 equiv of MgSO4 at -20
°C) provided trisubstituted tetrahydrothiophenes 17a and 18a
in a 97:3 ratio and 48% combined yield. The stereochemistry
1
of the major stereoisomer 17a was secured by H NMR nOe
experiments. Particularly diagnostic were large enhancements
observed for H2, H4R, and H5 upon irradiation of the C3 methyl
singlet at δ 1.45, and for H4â upon irradiation of the C2 methyl
doublet at δ 1.24. The minor diastereoisomer 18a, which we
assign as the C2 epimer of 17a, showed diagnostic large nOe
enhancements between the C2 and C3 methyl groups and no
detectable nOe between H2 and the C3 methyl group. In similar
fashion, acid-promoted condensation of mercapto alcohol 9 with
anisaldehyde delivered 17b and 18b in a 95:5 ratio and 63%
combined yield.
Our attempts to extend this synthesis to preparation of
tetrahydrothiophenes containing substituents at each ring carbon
met with limited success. Thus, reaction of mercapto alkenol
10 (a 3:2 mixture of epimers) with trans-cinnamaldehyde under
standard conditions proceeded in low yield to give two
acyltetrahydrothiophene stereoisomers in a 96:4 ratio (eq 3).
1H-nOe studies were consistent with the major stereoisomer 19
being the product that would arise from incorporating the
trisubstituted alkene in a suprafacial sense.
(19) The following Lewis acids and reaction temperatures were surveyed
in CH2Cl2 for rearrangement of 14 (R ) CH2CH2Ph): BF3‚OEt2 (-50,
-20 and 23 °C), SnCl4 (-95, -50 and -20 °C), Me2AlCl (-20 and 23
°C), Et2AlCl (-25 °C), EtAlCl2 (-25 °C), and p-toluenesulfonic acid (23
°C). No reaction was observed with Me2AlCl at -20 °C or Et2AlCl at -25
°C. Under the other conditions, hydrocinnamaldehyde was the major product
produced. No singlets in the 1H NMR spectra of the crude reaction product
attributable to an acetyl methyl group were seen.
Preparation of Enantioenriched 3-Acyltetrahydrothio-
phenes. To pursue application of this chemistry to enantiose-
lective synthesis of tetrahydrothiophenes, as well as probe the
mechanism of the condensation rearrangement, (4R)-9 was
prepared as summarized in Scheme 7. Conversion of (S)-(-)-
(20) Brown, H. C.; Kanner, B. J. Am. Chem. Soc. 1966, 88, 986-987.

Stereocontrolled Synthesis of Substituted Tetrahydrothiophenes
J. Am. Chem. Soc., Vol. 122, No. 36, 2000 8675
Scheme 7
tion of mercapto allylic alcohols and aldehydes and ketones.
Alternatively, this tetrahydrothiophene synthesis can be ac-
complished by first condensing the mercapto allylic alcohol and
carbonyl compound to form the corresponding 5-alkenyl ox-
athiolane, followed by acid-promoted rearrangement of this
intermediate to the 3-acyltetrahydrothiophene. Even though the
rearrangement step of this latter sequence takes place in superb
yield (>85%), the overall efficiency of the two-step procedure
is no higher than that realized by more convenient direct
condensation of the mercapto allylic alcohol and carbonyl
compound in the presence of BF3‚OEt2. Although this synthesis
of substituted tetrahydrothiophene is highly stereoselective, its
scope is more limited than that of the related preparations of
3-acylpyrrolidines or 3-acyltetrahydrofurans.1 The alkene com-
ponent must be substituted at the internal alkene carbon, and
tetrahydrothiophene formation takes place in good yield only
when the terminal alkene carbon is unsubstituted. As a result,
the tetrahydrothiophene synthesis reported here will be most
useful for preparing 3-acyltetrahydrothiophenes having cis side
chains at C2 and C5. Since the stereochemistry of the side chains
evolves from a single stereocenter of the mercapto allylic alcohol
precursor, this reaction should be of particular utility for
enantioselective construction of substituted tetrahydrothiophenes.
5-Alkenyl oxathiolanes are undoubtedly intermediates in the
direct condensation of mercapto allylic alcohols and carbonyl
compounds to form 3-acyltetrahydrothiophenes. Two plausible
mechanisms for evolution of a 5-alkenyl oxathiolanes to a
3-acyltetrahydrothiophene are thionium ion-alkene cyclization24
followed by pinacol rearrangement, or 2-thionia[3,3]-sigmatropic
rearrangement25-27 followed by aldol-type condensation (Scheme
8). As we have discussed previously in our analysis of related
transformations in the nitrogen and oxygen series,28 a cycliza-
tion-pinacol sequence would proceed with retention of the
configuration at the homoallylic stereogenic center.29 In contrast,
a [3,3] sigmatropic rearrangement-aldol process would yield
racemic products, if R-thiocarbenium ion 28 contained no
stereogenic centers and the barrier for aldol cyclization were
higher than that of C-C single bond rotation.30 The complete
preservation of enantiomeric purity in the conversion of (4R)-9
to 22 (Scheme 7) is consistent with a cyclization-pinacol
pathway. As we saw in the related synthesis of 3-acyltetrahy-
drofurans, the rate of the cyclization step appears to be critical
in the success of this tetrahydrothiophene synthesis.31 When the
ethyl lactate (20) to its mesylate derivative and displacement
of this intermediate with cesium benzylsulfide gave R-thioester
21 in high enantiopurity.15,21 Reaction of 21 with an excess of
methyllithium in the presence of trimethylsilyl chloride at -105
°C, following a procedure developed by us earlier for a related
lactate-derived silyl ether,22 provided (R)-8 in 65% yield. Due
to the acidity of the methine hydrogen R to sulfur, racemization
of 8 under these conditions was a serious complication. Attempts
to prevent racemization by changing the order of addition of
reagents, reaction temperature, and workup conditions met with
limited success. Under the best conditions found, (R)-8 could
be generated in 80% ee.21 Condensation of (R)-8 of this
enantiopurity with 2-propenyllithium at -78 °C and cleavage
of the benzyl group with sodium and ethanol in liquid ammonia
yielded (4R)-9 as a 3:2 mixture of C3 epimers. The enantiomeric
purity of this intermediate was accurately determined to be 80
( 2% ee by conversion to the di-p-bromobenzoyl derivative
followed by HPLC analysis using a Diacel OD-H column.
Reaction of (4R)-9 with 2-methoxypropene in the presence
of 2 equiv of BF3‚OEt2 and excess MgSO4 at -20 °C in CH2-
Cl2 provided one predominant acyltetrahydrothiophene product
(+)-22, [R]D +149 (c 1, CH2Cl2), in 55% yield. Reduction of
(+)-22 with NaBH4 and 1H NMR analysis of the Mosher ester
23 of the resulting major alcohol diastereomer established that
there was no detectable loss of enantiomeric purity during the
conversion of (4R)-9 to 22.23 Although the absolute configu-
ration of 22 was not established, it likely has the 2R,3S
configuration as depicted in Scheme 7.
(24) For a review of carbon-carbon bond forming reactions of R-thio
carbocations, see: Ishibashi, H.; Ikeda, M. ReV. Heteroatom. Chem. 1992,
7, 191-213.
(25) To the best of our knowledge, this hetero-3,3-sigmatropic rear-
rangement has not been described. The related variant in the nitrogen series
(2-azonia-[3,3]-sigmatropic rearrangement) is well-established,26 and the
analogous rearrangement in the oxygen series has been proposed.27
(26) For reviews, see: (a) Heimgartner, H.; Hansen, H.-J.; Schmid, H.
In Iminium Salts in Organic Chemistry; Bo¨hme, H., Viehe, H. G., Eds.;
Wiley: New York, 1979; Part 2, pp 655-732. (b) Blechert, S. Synthesis
1989, 2, 71-82.
(27) Lolkema, L. D. M.; Semeyn, C.; Ashek, L.; Hiemstra, H.; Speckamp,
W. N. Tetrahedron 1994, 50, 7129-7140.
(28) Jacobsen, E. J.; Levin, J.; Overman, L. E. J. Am. Chem. Soc. 1988,
110, 4329-4335. (b) Hopkins, M. H.; Overman, L. E.; Rishton, G. M. J.
Am. Chem. Soc. 1991, 113, 5354-5365.
(29) For reviews of pinacol rearrangements, see: (a) Bartok, M.; Molnar,
A. In Chemistry of Ethers, Crown Ethers, Hydroxyl Compounds and Their
Sulfur Analogues; Patai, S., Ed.; New York, 1980; Part 2, pp 722-732. (b)
Rickborn, B. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon Press: Oxford, 1991; Vol. 3, pp 721-732.
(30) This is a reasonable assumption considering the low barriers of C-C
single bond rotations: Eliel, E. L.; Allinger, N. L.; Angyal, S. J.; Morrison,
G. A. Conformational Analysis; American Chemical Society; Washington,
DC, 1965; Chapters 2 and 3.
Discussion
A variety of substituted 3-acyltetrahydrothiophenes can be
prepared in 50-70% yield by simple acid-promoted condensa-
(21) The enantiomeric excess of this intermediate was determined by
1H NMR analysis in the presence of Eu(hfc)3.
(22) Overman, L. E.; Rishton, G. M. Organic Syntheses; Wiley: New
York, 1998; Collect. Vol. IX; pp 139-142.
(23) (a) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512-
519. (b) Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34,
2543-2549.
(31) For kinetic studies of the addition of stabilized carbenium ions to
alkenes, see: Mayr, H. Angew. Chem. 1990, 29, 1371-1384.

8676 J. Am. Chem. Soc., Vol. 122, No. 36, 2000
Ponce and OVerman
Scheme 8
cyclohexanone (74 mg, 0.75 mmol), MgSO4 (200 mg), and CH2Cl2
(15 mL) at -20 °C. The resulting mixture was maintained at -20 °C
for 28 h and then poured into saturated aqueous NH4Cl (30 mL). This
mixture was extracted with CH2Cl2 (3 × 20 mL) and the combined
organic layers were dried (MgSO4) and concentrated. The residue was
dissolved in CH2Cl2 (20 mL) and stirred overnight with aqueous
NaHSO3 (20 mL). The organic phase was separated, dried (MgSO4),
and concentrated, and the residue was purified by flash chromatography
(95:5 hexanes-EtOAc) to give 102 mg (64%) of 16 as a colorless oil:
1H NMR (500 MHz, CDCl3) δ 3.31 (d, J ) 11.7 Hz, 1H), 2.69 (d, J
) 11.7 Hz, 1H), 2.51 (d, J ) 13.3 Hz, 1H), 2.24 (s, 3H), 1.79-1.20
(m, 10H), 1.61 (d, J ) 13.3 Hz, 1H), 1.33 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 210.8, 60.3, 59.1, 52.4, 42.1, 41.1, 39.3, 25.2, 25.1,
25.0, 24.5, 24.4; IR (KBr) 1708 cm-1; HRMS (CI, isobutane) m/z
212.1234 (212.1234 calcd for C12H20OS, M). Anal. Calcd for C12H20-
OS: C, 67.87; H, 9.49; S, 15.10. Found: C, 68.15; H, 9.55; S, 14.83.
internal alkene carbon is unsubstituted, thionium ion-alkene
cyclization would lead to a relatively unstable secondary
carbenium ion intermediate 26 (R2 ) H). Apparently in this
case, 24 or its precursor mercapto allylic alcohol decomposes
more rapidly than 25 cyclizes to 26, most likely by ionization
of the tertiary allylic C-O bond.
The high stereoselectivity observed in this tetrahydrothiophene
synthesis can be rationalized as follows.The lowest energy chair
cyclization conformer derived by ring opening of 24 should be
25 having the thionium ion in a more stable E configuration32
and the R1 substituent quasiequatorial. This preference could
manifest irrespective of the relative stereochemistry of the
alcohol stereocenter. Pinacol rearrangement of 26 would then
yield acyltetrahydrothiophene 27. When R1 and R4 are both non-
hydrogen, the relative rates of pinacol rearrangement and
conformational dynamics of 26 would be expected not to affect
stereoselection, because chair tetrahydrothiopyranyl carbenium
ion conformer 26 would be considerably more stable than the
alternative chair conformer. More interesting is the high
stereoselectivity observed in the reactions reported in Schemes
3-5 where R1 and R3 are both hydrogen. In these cases, the
two chair conformers of a 4-thiatetrahydropyranyl cation
intermediate would be more similar in energy. The high
stereoselectivity observed in these transformations is consistent
with pinacol rearrangement of 26 occurring more rapidly than
conformational interconversion of this intermediate.33
Acknowledgment. This research was supported by a Javits
Neuroscience Investigator Award from NIH NINDS (NS-12389)
and a postdoctoral fellowship to A.M.P. from the Ministerio
de Educacion y Ciencia of Spain. Merck, Pfizer, Roche
Biosciences, and SmithKline Beecham provided additional
support. NMR and mass spectra were determined using instru-
ments acquired with the assistance of NSF and NIH shared
instrumentation grants.
Supporting Information Available: Experimental details
and characterization data for new compounds not reported in
the Experimental Section (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
Experimental Section34,35,36
General Procedure for Preparing 3-Acyltetrahydrothiophenes
by Direct Condensation of Mercapto Allylic Alcohols and Aldehydes
or Ketones. Preparation of (()-1-(3-Methyl-1-thiaspiro[4.5]dec-3-
yl)ethanone (16). Boron trifluoride etherate (190 µL, 1.5 mmol) was
added dropwise to a stirring mixture of 7 (99 mg, 0.75 mmol),
JA001975M
(34) Boron trifluoride etherate was distilled from CaH2 at atmospheric
pressure. Molarities indicated for organolithium reagents were established
by double titration using the Gilman procedure.35 1H NMR and 13C NMR
were measured at 500 MHz with Bruker Omega 500 and Bruker GN-500
spectrometers. Other general experimental details were recently described.36
(35) Gilman, H. J. Organomet. Chem. 1964, 2, 447-454.
(32) For examples of other reactions where the E stereoisomer of R-thio
carbenium ions are suggested to react preferentially, see: (a) Mori, I.;
Bartlett, P. A.; Heathcock, C. H. J. Am. Chem. Soc. 1987, 109, 7199-
7200. (b) Mori, I.; Bartlett, P. A.; Heathcock, C. H. J. Org. Chem. 1990,
55, 5966-5977.
(36) Metais, E.; Overman, L. E.; Rodriguez, M. I.; Stearns, B. A. J. Org.
Chem. 1997, 62, 9210-9216.
(33) Minor, K. P.; Overman, L. E. Tetrahedron 1997, 53, 8927-8940.