Asymmetric synthesis of (-)-trichodiene. Generation of vicinal stereogenic quaternary centers via the thio-Claisen rearrangement

Article abstract of DOI:10.1021/ja9804159

The use of chiral bicyclic lactams, in their thiocarbonyl form 9, has been shown to serve as important intermediates for producing α-quaternary alkyl derivatives 8, which were readily transformed into the title compound (-)-1. The reversibility of the thi

Full text of DOI:10.1021/ja9804159

J. Am. Chem. Soc. 1998, 120, 5453-5457
5453
Asymmetric Synthesis of (-)-Trichodiene. Generation of Vicinal
Stereogenic Quaternary Centers via the Thio-Claisen Rearrangement
Rene´ M. Lemieux and A. I. Meyers*
Contribution from the Department of Chemistry, Colorado State UniVersity, Fort Collins, Colorado 80523
ReceiVed February 5, 1998
Abstract: The use of chiral bicyclic lactams, in their thiocarbonyl form 9, has been shown to serve as important
intermediates for producing R-quaternary alkyl derivatives 8, which were readily transformed into the title
compound (-)-1. The reversibility of the thio-Claisen rearrangement, 15h8, was clearly demonstrated and
appears to be unprecedented. Solvent effects to alter the equilibrium position were studied and found to have
only a moderate, but beneficial effect. The title compound was obtained in 14% overall yield in 10 steps from
bicyclic lactam, 9.
The sesquiterpene trichodiene, (+)-1, isolated from the
fermentation broth of the mycelium of Tricothecium roseum,1
is the postulated biogenetic precursor2 to the trichothecene
mycotoxins 2 which are fungal metabolites from the Fusarium
species.3 The trichothecene mycotoxins have been shown to
exhibit diverse biological activities.4 The biosynthesis of
trichodiene has been suggested to occur via cyclization of
farnesyl pyrophosphate mediated by trichodiene synthetase,5 an
enzyme isolated from the fungus T. roseum. Trichodiene,
although devoid of heteroatoms, presents an interesting challenge
to the synthetic chemist owing to the two vicinal stereogenic
quaternary carbons. Since its isolation, several racemic syn-
theses have appeared in the literature,6 and one report described
the preparation of the sesquiterpene in enantiomerically enriched
form (47% ee).6a To date, this sesquiterpene has eluded any
effort toward an asymmetric total synthesis. We report herein
the results of our efforts which culminated with the asymmetric
total synthesis of (-)-trichodiene (1).
We recently described the [3,3]-sigmatropic rearrangement
of the S-alkylthioenamine 3, derived from S-alkylation of a chiral
nonracemic bicyclic thiolactam 4 with various allylic halides.
This resulted in the formation of compounds (e.g., 5) bearing
vicinal quaternary centers or stereogenic quaternary-tertiary
centers.7 The further development of this potentially useful
synthetic method, e.g., transposing a C-S single bond for a
C-C single bond,8 had set the stage to synthesize more complex
(6) (a) Gilbert, J. C.; Selliah, R. D. J. Org. Chem. 1993, 58, 6255-
6265. (b) Tanaka, M.; Sakai, K. Tetrahedron Lett. 1991, 32, 5581-5584.
(c) Harding, K. E.; Clement, K. S.; Tseng, C.-Y. J. Org. Chem. 1990, 55,
4403-4410. (d) Pearson, A. J.; O′Brien, M. K. J. Org. Chem. 1989, 54,
4663-4673. (e) Gilbert, J. C.; Kelly, T. A. Tetrahedron Lett. 1989, 30,
4193-4196. (f) Snowden, R. L.; Brauchli, R.; Sonnay, P. HelV. Chim. Acta
1989, 72, 570-593. (g) Pearson, A. J.; O′Brien, M. K. J. Chem. Soc., Chem.
Commun. 1987, 1445-1447. (h) VanMiddlesworth, F. L. J. Org. Chem.
1986, 51, 5019-5021. (i) Gilbert, J. C.; Kelly, T. A. J. Org. Chem. 1986,
51, 4485-4488. (j) Kraus, G. A.; Thomas, P. J. J. Org. Chem. 1986, 51,
503-505. (k) Gilbert, J. C.; Wiechman, B. E. J. Org. Chem. 1986, 51,
258-260. (l) Harding, K. E.; Clement, K. S. J. Org. Chem. 1984, 49, 3870-
3871. (m) Snowden, R. L.; Sonnay, P. J. Org. Chem. 1984, 49, 1464-
1465. (n) Schlessinger, R. H.; Schultz, J. A. J. Org. Chem. 1983, 48, 407-
408. (o) Suda, M. Tetrahedron Lett. 1982, 23, 427-428. (p) Welch, S. C.;
Rao, A. S. C. P.; Gibbs, C. G.; Wong, R. Y. J. Org. Chem. 1980, 45, 4077-
4085. (q) Welch, S. C.; Rao, A. S. C. P.; Gibbs, C. G. Synth. Commun.
1976, 6, 485-488. (r) Welch, S. C.; Rao, A. S. C. P.; Wong, R. Y. Synth.
Commun. 1976, 6, 443-445.
(1) (a) Nozoe, S.; Machida, Y. Tetrahedron Lett. 1970, 31, 2671-2674.
(b) Nozoe, S.; Machida, Y. Tetrahedron 1972, 28, 5105-5111.
(2) (a) Hesketh, A. R.; Bycroft, B. W.; Dewick, P. M.; Gilbert, J.
Phytochemistry 1993, 32, 105-116. (b) Zamir, L. O.; Devor, K. A.; Morin,
N.; Sauriol, F. J. Chem. Soc., Chem. Commun. 1991, 1033-1034. (c)
Hesketh, A. R.; Gledhill, L.; Marsh, D. C.; Bycroft, B. W.; Dewick, P. M.;
Gilbert, J. J. Chem. Soc., Chem. Commun. 1990, 1184-1186. (d) Zamir,
L. O.; Gauthier, M. J.; Devor, K. A.; Nadeau, Y.; Sauriol, F. J. Chem.
Soc., Chem. Commun. 1989, 598-600. (e) Savard, M. E.; Blackwell, B.
A.; Grennhalgh, R. J. Nat. Prod. 1989, 52, 1267-1278. (f) VanMiddles-
worth, F.; Desjardins, A. E.; Taylor, S. L.; Plattner, R. D. J. Chem. Soc.,
Chem. Commun. 1986, 1156-1157.
(3) Fusarium: Mycotoxins, Taxonomy and Pathogenicity; Chelkowski,
J., Ed.; Elsevier Science: Amsterdam, 1989; Vol. 2.
(4) Joffe, A. Z. Fusarium Species: Their Biology and Toxicology; John
Wiley & Sons: New York, 1986.
(5) For leading references see: (a) Cane, D. E.; Yang, G. J. Org. Chem.
1994, 59, 5794-5798. (b) Cane, D. E.; Yang, G.; Coates, R. M.; Pyun,
H.-J.; Hohn, T. M. J. Org. Chem. 1992, 57, 3454-3462. (c) Cane, D. E.;
Pawlak, J. L.; Horak, R. M.; Hohn, T. M. Biochemistry 1990, 29, 5476-
5490. (d) Cane, D. E. Pure Appl. Chem. 1989, 61, 493-496. (e) Cane, D.
E.; Ha, H.-J. J. Am. Chem. Soc. 1988, 110, 6865-6870.
(7) Devine, P. N.; Meyers, A. I. J. Am. Chem. Soc. 1994, 116, 2633-
2634.
(8) For a recent review on the use of thiocarbonyl compounds in carbon-
carbon bond forming reactions, see: (a) Metzner, P. Synthesis 1992, 1185-
1199. For recent examples of thio-Claisen rearrangement, see: (b) Reference
7. (c) Sreekumar, R.; Padmakumar, R. Tetrahedron Lett. 1997, 38, 2413-
2416. (d) Jain, S.; Sinha, N.; Dikshit, D. K.; Anand, N. Tetrahedron Lett.
1995, 36, 8467-8468. (e) Smith, D. C.; Fuchs, P. L. J. Org. Chem. 1995,
60, 2692-2703. (f) Harvey, J. N.; Viehe, H. G. J. Chem. Soc., Chem.
Commun. 1995, 2345-2346. (g) Beslin, P.; Perrio, S. Tetrahedron 1993,
49, 3131-3142. (h) De´sert, S.; Metzner, P. Tetrahedron 1992, 48, 10327-
10338. (i) De´sert, S.; Metzner, P.; Ramdani, M. Tetrahedron 1992, 48,
10315-10326. (j) Reddy, K. V.; Rajappa, S. Tetrahedron Lett. 1992, 33,
7957-7960.
S0002-7863(98)00415-6 CCC: $15.00 © 1998 American Chemical Society
Published on Web 05/19/1998

5454 J. Am. Chem. Soc., Vol. 120, No. 22, 1998
Lemieux and Meyers
systems, such as carbon frameworks bearing vicinal stereogenic
quaternary centers found in trichodiene. We envisaged that (-)-
trichodiene (1) would be accessible from the chiral enone 6,
obtained in enantiomerically pure form, via a route similar to
that described by Pearson6d for rac-1. The nonracemic enone
6, in turn, would be derived from the keto-aldehyde 7 obtained
from hydrolysis of thiolactam 8 via a previously described
sequence.7 The cornerstone of the synthesis relied on the
successful preparation of thiolactam 8, which was anticipated
to arise via a diastereoselective [3,3]-sigmatropic rearrangement
of the S-alkylthioenamine (e.g., 3, or 15) derived from S-
alkylation of the thiolactam 9 (X ) S). This rearrangement
of cyclohexane provided the unsaturated ketone 13a (41%)
which was then oxidized (KOCl) to the corresponding carboxy-
lic acid 13b (52%). Reduction of the carboxylic acid with
LiAlH4 provided the known allylic alcohol 13c14 (75%) which
was subsequently transformed, using NBS-Me2S, into the highly
unstable allylic bromide 13d.15 Even though 13d could be
isolated in good yield (70%), it was generally stored for 1-2 h
at -20 °C until ready for use in the S-alkylation of the bicyclic
thiolactam 12.
Treatment of 12 with LDA (1.2 equiv, THF, 0 °C), to generate
the thioenolate 14, followed by addition of the allylic bromide
13d (1.2 equiv) resulted in the smooth formation of the crude
S-alkylthioenamine 15, contaminated, however, by halide 13d.
This was demonstrated by inspection of the 1H NMR spectrum
of the crude product which unequivocally showed that (a)
alkylation had occurred exclusiVely at sulfur and (b) that
thiophilic attack of the anion 14, derived from 12, occurred only
in a SN2 fashion with no SN2′ product being visible. The
formation of the S-alkylated thioenamine 15 augered well for
the original synthetic route that the key thiolactam 8 could
indeed arise via a [3,3]-sigmatropic rearrangement from 15.
would simultaneously establish the required relative and absolute
stereochemistry for the adjacent quaternary centers.9
The readily available, enantiomerically pure, chiral bicyclic
lactam 9 (X ) O)10 was transformed into the corresponding
methyl ether 10 (93%)11 which was converted into its enolate
and alkylated to produce the monomethyl derivative 11 as a
1.2:1 mixture of epimers in 87% yield. This mixture was of
no consequence since this newly introduced stereogenic center
would be rendered planar during a subsequent thioenolate
formation (vide infra). Treatment of bicyclic lactam 11 with
the Belleau reagent12 in refluxing toluene smoothly thionated
the carbonyl group to furnish the corresponding thiolactam 12,
as the same 2:1 mixture of epimers, in 87% yield. The requisite
allylic bromide 13d was readily prepared from a known13
Furthermore, the concern that alkylation of the thioenolate 14
at carbon with allylic bromide 13d in a SN2′ fashion would
compete, appears to be unfounded. First attempts at [3,3]-
sigmatropic rearrangement of the crude S-alkylthioenamine 15
under a variety of conditions (xylenes 140 °C, silylated
glassware, high dilution, etc.) failed to produce the rearranged
thiolactam 8 and yielded only complex mixtures of products.
In the event that excess reagents from the S-alkylation of 14,
which were still present with the thioenamine 15, were interfer-
ing with the rearrangement, it was decided to attempt the
purification of the sensitive substrate 15. Not unexpectedly,
chromatography of the latter using a variety of adsorbent and
solvent systems generally resulted in significant (∼35%) loss
of material. The thioenamine 15, obtained in pure form, was
subjected to the [3,3]-sigmatropic rearrangement; however, the
results were the same. This lack of rearrangement (15 f 8)
proved especially disappointing in light of the fact that related
systems had been shown earlier to undergo smooth thio-Claisen
rearrangement (THF at 25 °C or xylenes at 140 °C).7
Finally, after extensive experimentation, it was discovered
that S-alkylthioenamine 15 underwent [3,3]-sigmatropic rear-
rangement in refluxing DME (83 °C for 96 h) to produce the
desired bicyclic thiolactam 8. The 1H NMR spectrum derived
from the crude product mixture indicated the presence of only
two compounds in a 60:40 ratio, the thioenamine 15 and the
desired rearranged product 8, respectively. After chromatog-
raphy, pure 8 was obtained in 34% yield. The relative and
absolute stereochemistry depicted for 8 was assigned by analogy
to the [3,3]-sigmatropic rearrangements of related substances
cyclopentene precursor in four steps. Thus, direct acetylation
(9) For some recent examples of simultaneous generation of vicinal
quaternary centers, see: (a) Evans, D. A.; Trotter, B. W.; Barrow, J. C.
Tetrahedron 1997, 53, 8779-8794. (b) Roush, W. R.; Barda, D. A. J. Am.
Chem. Soc. 1997, 119, 7402-7403. (c) Kazmaier, U. J. Org. Chem. 1996,
61, 3694-3699. (d) Sieburth, S. M.; Siegel, B. J. Chem. Soc., Chem.
Commun. 1996, 2249-2250. (e) Lorthois, E.; Marek, I.; Meyer, C.;
Normant, J.-F. Tetrahedron Lett. 1995, 36, 1263-1266. (f) Gilbert, J. C.;
Selliah, R. D. Tetrahedron 1994, 50, 1651-1664. (g) Kno¨lker, H.-J.; Graf,
R. Tetrahedron Lett 1993, 34, 4765-4768. See also refs 6a and 7.
(10) Meyers, A. I.; Lefker, B. A. Tetrahedron 1987, 43, 5663-5676.
(11) Schwarz, J. B.; Devine, P. N.; Meyers, A. I. Tetrahedron 1997, 53,
8795-8806.
(14) For other preparations of 13c, see: Short, R. P.; Revol, J.-M.; Ranu,
B. C.; Hudlicky, T. J. Org. Chem. 1983, 48, 4453-4461. Inouye, Y.;
Inomata, S.; Ishihara, Y.; Kakisawa, H. Bull. Chem. Soc. Jpn. 1982, 55,
208-211.
(15) For alternative preparation of 13d and spectral data, see: Ziegler,
F. E.; Nangia, A.; Shulte, G. J. Am. Chem. Soc. 1987, 109, 3987-3991.
Kurth, M. J.; Decker, O. H. W. J. Org. Chem. 1985, 50, 5769-5775.
(12) Lajoie, G.; Le´pine, F.; Maziak, L.; Belleau, B. Tetrahedron Lett.
1983, 24, 3815-3818.
(13) Harding, K. E.; Clement, K. S. J. Org. Chem. 1984, 49, 2049-
2050.

Synthesis of (-)-Trichodiene
J. Am. Chem. Soc., Vol. 120, No. 22, 1998 5455
Table 1. Effect of Solvents and Temperature on the Equilibrium
of 15, 8
from prior studies from this laboratory. In those earlier studies,
the S-allylic moiety had rearranged to the exo(â) face of the
bicyclic system via a chair conformation.7 The failure to promote
the thio-Claisen rearrangement in xylenes and its success in
DME was initially unclear and therefore warranted further
investigation. Furthermore, the [3,3]-sigmatropic rearrangement
of the S-alkylthioenamine 15 into 8 in 34% yield certainly called
for some improvement.
entry
solvent
T (°C)
ratio 15:8a
1
2
xylenes
140
80
100:0
65:35
60:40
60:40
60:40
48:52
36:64
decb
MeCN
3
DME
dioxane
Bu2O
HMPA
DMF
DMSO
H2O:MeOH (3:1)
EtOH
83
4
101
140
100
90
5
6
7
The use of ethereal solvent (DME) to perform the [3,3]-
sigmatropic rearrangement allowed the transformation to become
experimentally simple. Indeed, when the reaction mixture
derived from the S-alkylation of 12 in DME was heated to
reflux, the initially formed 15 underwent in situ thio-Claisen
rearrangement into 8. However, when 15 was heated in various
ethereal solvents at reflux for longer periods of time (i.e., DME
(85 °C) 13 days, dioxane (101 °C) 84 h, Bu2O (140 °C) 48 h),
the thiolactam 8 was obtained in 38, 37, and 32% isolated yields,
respectively. The remainder of the thioenamine 15 remained
unchanged. Furthermore, only a single diastereomer was formed
during the [3,3]-sigmatropic rearrangement. It soon became
obvious that prolonged heating or heating the thioenamine 15
at higher temperature did not increase the conversion to the key
thiolactam 8. The lack of complete conversion of 15 into 8
suggested that an equilibrium may be in operation wherein the
rearrangement was reversible. Thus, thiolactam 8 was heated
in refluxing Bu2O (140 °C) for 3 h, and subsequent analysis of
the 1H NMR spectrum derived from the reaction mixture
indicated the presence of both the thiolactam 8 and S-
alkylthioenamine 15 in a 40:60 ratio, respectively, demonstrating
conclusively the reversibility of the system. Although Claisen
rearrangements are in principle reversible, the large driving force
created by generating the more stable carbonyl group allows
these reactions to be treated as irreversible.8a It has been reported
that thio-Claisen rearrangements derived from a thioketone were
found to be reversible.16 However, the [3,3] rearrangements
derived from the parent dithio esters and thioamides17 are not
known to be reversible and therefore, the equilibrium established
between 15 and 8 appears to be unprecedented. In the
O-Claisen rearrangement, it is known that O-alkylenol ethers
derived from strained γ,δ-unsaturated carbonyl compounds have
been observed to be reversible.18
8
80
9
90
dec
10
78
dec
a Ratio determined via integration of the benzylic protons of 15 and
8 in the 1H NMR spectrum of the crude reaction mixture. b dec )
decomposition.
Table 1. It is clear that the proportion of thiolactam 8 generally
increased with solvent polarity (entries 1-7), whereas DMSO
(entry 8) and the protic solvent systems (entries 9 and 10) led
only to complex mixture of products. Interestingly, the rear-
rangement of 15 in HMPA or DMF solutions could only be
conducted with purified material since the use of the crude
S-alkylthioenamine 15 resulted in decomposition. However, this
limitation was circumvented by adding K2CO3 (1.5 equiv) to
the crude thioenamine-DMF solution, which appeared to
neutralize any HBr that might have been released in the reaction
mixture, as a result of decomposition of the small excess of
allylic bromide 13d used in the preceding S-alkylation. From
the table it can be seen that nearly a 2:1 ratio of 8:15 was
achieved in DMF at 90 °C after 72 h.
In light of the limited, yet beneficial, influence of solvent on
the equilibrium mixture, it was possible to conduct the rear-
rangement in DMF which produced the desired thiolactam 8 in
50% isolated yield as well as 22% of 15. After separation,
resubjecting the latter substance under identical conditions
provided an additional 10% of the thiolactam 8. In this fashion,
a 60% overall yield of 8 was achieved.
Having access to reasonable yields of the thiolactam 8, the
chiral auxiliary now had to be removed. However, the thiolac-
tam proved to be resistant to reduction conditions previously
employed for related bicyclic lactam systems (Red-Al, low
temperature).19 By employing Meerwein’s reagent in refluxing
CH2Cl2, the thiolactam 8 formed the corresponding thioiminium
ion7 16, which was efficiently reduced with Red-Al (-78 °C)
in situ to the thioaminal 17. The latter material was subjected
to hydrolysis in EtOH/H2O/Bu4NH2PO4 to liberate the chiral
keto-aldehyde 7, which underwent spontaneous aldol condensa-
tion to the desired 4,4-disubstituted enone 6 in a reasonable
54% overall yield from 8. This material exhibited spectroscopic
data identical with that of Pearson’s racemic material,6d except
for chiroptical properties: [R]25D -131° (c ) 1.37/CHCl3). The
enone 6 was subsequently treated with methylene triphenylphos-
phorane in benzene at room temperature to afford the corre-
sponding triene 18 in 92% yield. Finally, dissolved metal
reduction (Na/NH3) of triene 18 at -78 °C afforded (-)-
trichodiene (1) along with the 1,2-reduction product 19 as an
85:15 mixture, respectively. Chromatography of the mixture
over AgNO3 impregnated silica afforded the volatile (-)-
trichodiene (1) in 65% isolated yield. This material exhibited
a rotation of -18 (CHCl3), which compares somewhat favorably
with the reported rotation for the natural trichodiene of +21.1
However, further confirmation of the enantiomeric purity was
sought. A sample of enantiomerically enriched (-)-trichodiene
was obtained from Professor Jack Gilbert; chiral GLC analysis
Having established that the reversibility of the thio-Claisen
process was responsible for the low (∼40%) conversion of the
thioenamine 15 to the key thiolactam 8, it now remained to
study means to force the equilibrium ratio in favor of the
product, 8. Attempts to remove thiolactam 8 from the equi-
librium via selective coordination of the thiocarbonyl moiety
with a variety of Lewis acids (Pd(II) salts, Cu(I), MgBr, etc.)
or via addition to the C-S double bond of 8 (KSCN, RMgBr,
(RO)3P, etc.) proved fruitless. A study to assess the effect of
solvent polarity on the equilibrium position are summarized in
(16) (a) Beslin, P.; Lagain, D.; Vialle, J. J. Org. Chem. 1980, 45, 2517-
2518. (b) Metzner, P.; Pham, T. N.; Vialle, J. NouV. J. Chim. 1978, 2, 179-
182. (c) Metzner, P.; Pham, T. N.; Vialle, J. J. Chem. Res. (S) 1978, 478-
479.
(17) For some recent examples of thio-Claisen rearrangements using
thioamides, see: (a) Welch, J. T.; Eswarakrishnan, S. J. Am. Chem. Soc.
1987, 109, 6716-6719. (b) Tamaru, Y.; Furukawa, Y.; Mizutani, M.; Kitao,
O.; Yoshida, Z. J. Org. Chem. 1983, 48, 3631-3639.
(18) For some recent examples of retro-Claisen rearrangements, see: (a)
Boeckman, R. K., Jr.; Reeder, M. R. J. Org. Chem. 1997, 62, 6456-6457.
(b) Boeckman, R. K., Jr.; Shair, M. D.; Vargas, J. R.; Stolz, L. A. J. Org.
Chem. 1993, 58, 1295-1297. (c) Boeckman, R. K., Jr.; Flann, C. J.; Poss,
K. M. J. Am. Chem. Soc. 1985, 107, 4359-4362. For a theoretical treatment
of pericyclic reactions see: (d) Burrows, C. J.; Carpenter, B. K. J. Am.
Chem. Soc. 1981, 103, 6984-6986. (e) Burrows, C. J.; Carpenter, B. K. J.
Am. Chem. Soc. 1981, 103, 6983-6984. (f) Carpenter, B. K. Tetrahedron
1978, 54, 1877-1884.
(19) Romo, D.; Meyers, A. I. Tetrahedron 1991, 47, 9503-9569.

5456 J. Am. Chem. Soc., Vol. 120, No. 22, 1998
Lemieux and Meyers
diluted with Et2O (500 mL) and the layers were separated. The organic
layer was washed with H2O (2 × 75 mL) and brine (50 mL), dried
over MgSO4, and then filtered; the solvent was removed under reduced
pressure. The residue was subjected to flash chromatography (4:1 to
1.5:1 Hex-EtOAc gradient) to afford 9.69 g (87%) of an epimeric
mixture (1.2:1) of the bicyclic lactam 11 as a colorless solid. Major
diastereomer: 1H NMR (300 MHz, CDCl3) δ 1.28 (d, 3H, J ) 7.2
Hz), 1.57 (s, 3H), 1.60-1.70 (m, 1H), 1.72-1.85 (m, 1H), 2.00-2.14
(m, 1H), 2.20 (dt, 1H, J ) 12.2, 2.7 Hz), 2.35-2.44 (m, 1H), 3.34 (s,
3H), 3.62 (dd, 1H, J ) 3.1, 10.2 Hz), 3.76 (dd, 1H, J ) 5.4, 10.2 Hz),
4.02-4.10 (m, 1H), 5.23 (d, 1H, J ) 6.8 Hz), 7.25-7.43 (m, 5H) 13
C
NMR (75 MHz, CDCl3) δ 18.8, 24.1, 26.4, 35.4, 36.8, 59.2, 63.3, 70.8,
78.5, 93.6, 126.6, 128.2, 128.5, 139.3, 172.6. IR (KBr pellet): 2930,
1641, 1403 cm-1. HRMS (FAB+) for C17H24NO3 (M + H)+: calcd
290.1756, found 290.1751.
Bicyclic Thiolactam 12. To a stirred solution of bicyclic lactam
11 (9.00 g, 31.1 mmol) in dry toluene (80 mL), was added Belleau’s
reagent12 (9.04 g, 17.1 mmol). The reaction mixture was heated to
reflux for 1 h, then cooled to room temperature, and the solvent was
removed under reduced pressure. The residue was filtered through
Florisil (CH2Cl2 as eluent) and the solvent was removed under reduced
pressure. The residue was purified via flash chromatography (13:1 to
6:1 Hex-EtOAc gradient) to afford 8.24 g (87%) of an epimeric
mixture (2:1) of the bicyclic thiolactam 12 as a colorless solid. Major
diastereomer: 1H NMR (300 MHz, CDCl3) δ 1.49 (d, 3H, J ) 6.6
Hz), 1.55-1.60 (m, 1H), 1.61 (s, 3H), 1.79-1.92 (m, 1H), 2.09-2.21
(m, 1H), 2.25 (dt, 1H, J ) 11.9, 3.3 Hz), 2.86-3.00 (m, 1H), 3.36 (s,
3H), 3.71 (dd, 1H, J ) 2.8, 10.6 Hz), 4.20 (dd, 1H, J ) 4.7, 10.6 Hz),
4.54-4.61 (m, 1H), 5.39 (d, 1H, J ) 7.9 Hz), 7.26-7.45 (m, 5H). 13
C
NMR (75 MHz, CDCl3) δ 22.6, 25.3, 26.1, 34.8, 44.5, 59.3, 68.2, 68.6,
of his sample showed the ratio of enantiomers to be 67:33. When
the synthetic sample obtained in this study was injected onto
the chiral column (Experimental Section), only the peak
corresponding to (-)-trichodiene was visible, indicating the
enantiomeric purity of 1 ([R]D ) -18) was indeed greater than
99%. The specific rotation, therefore, was subject to the usual
experimental errors that normally plague polarimetric determi-
nations. Furthermore, all other physical data (IR, NMR, m/e)
were in complete agreement with those reported for the natural
material.1a
In conclusion, we have achieved the asymmetric synthesis
of (-)-trichodiene in 10 steps and 14% overall yield from the
readily available bicyclic lactam 9. The thio-Claisen rearrange-
ment has proven to be a powerful synthetic tool in the
preparation of a key synthetic intermediate bearing vicinal
stereogenic quaternary centers. The [3,3]-sigmatropic transposi-
tion, derived from S-alkylthioenamine 15, was shown to be
reversible, and the equilibrium ratio of the rearranging partners
was shown to be somewhat solvent dependent. Further work
on the development of new synthetic methods to access chiral,
nonracemic, quaternary carbon substances via the thio-Claisen
rearrangement are in progresss.
77.7, 95.2, 126.7, 128.5, 128.6, 138.6, 203.4. IR (KBr pellet) 2923,
.
1441 cm-1 HRMS (FAB+) for C17H24NO2S (M + H)+: calcd
306.1528, found 306.1527. Anal. Calcd for C17H23NO2S: C, 66.85;
H, 7.59; N, 4.59. Found: C, 67.01; H, 7.50; N, 4.49.
(2-Methylcyclopent-1-yl)methanol (13c). To a cold (-78 °C)
stirred slurry of LiAlH4 (2.55 g, 67.2 mmol) in dry Et2O (150 mL)
was added carboxylic acid 13b13 (5.64 g, 44.8 mmol) portionwise over
20 min. The reaction mixture was warmed slowly to room temperature
and allowed to stir overnight. The mixture was cooled to 0 °C and
saturated aqueous NH4Cl (50 mL) was added cautiously. The
precipitate was filtered and rinsed with Et2O (2 × 20 mL). The
combined organic layers were washed with H2O (20 mL) and brine
(20 mL), dried over MgSO4, and filtered; the solvent was removed
under reduced pressure. The residue was distilled (85-86 °C/13
mmHg) to afford 3.74 g (75%) of the alcohol 13c14 as a clear colorless
oil. 1H NMR (300 MHz, CDCl3) δ 1.20 (s, 1H), 1.67 (s, 3H), 1.79
(quint, 2H, J ) 7.5 Hz), 2.26-2.35 (m, 2H), 2.38-2.37 (m, 2H), 4.16
(s, 2H). 13C NMR (75 MHz, CDCl3) δ 13.4, 21.4, 34.0, 38.6, 58.8,
134.1, 135.5. IR (thin film): 3320, 2841 cm-1
.
1-(Bromomethyl)-2-methylcyclopentene (13d). To a cold (0 °C)
stirred suspension of NBS (0.76 g, 4.3 mmol) in dry CH2Cl2 (20 mL)
was added Me2S (0.29 g, 0.34 mL, 4.7 mmol). The resulting yellow
suspension was stirred at 0 °C for 15 min; then the alcohol 13c (410
mg, 3.66 mmol) was added in CH2Cl2 (3 mL) via a cannula. The
reaction mixture was allowed to slowly warm to room temperature over
3.5 h. The mixture was diluted with hexanes (50 mL), washed with
H2O (2 × 10 mL) and brine (10 mL), dried over MgSO4, and then was
filtered. The solvent was removed under reduced pressure and the
residue was distilled (bulb-to-bulb, 35-40 °C/1 mmHg) from CaH2
and Cu wire into a receiving bulb cooled to -78 °C containing Cu
wire. Obtained was 445 mg (70%) of the unstable allylic bromide
13d15 as a light yellow oil, which was stored immediately at -20 °C
for a period not exceeding 2-3 h. 1H NMR (300 MHz, CDCl3) δ
1.68 (s, 3H), 1.82 (quint, 2H, J ) 7.4 Hz), 2.32 (m, 2H), 2.45 (m, 2H),
4.07 (s, 2H). 13C NMR (75 MHz, CDCl3) δ 13.9, 21.1, 29.9, 34.5,
Experimental Section
Thin-layer chromatography (TLC) and flash chromatography were
performed with E. Merck silica gel (230-400 mesh). TLC grade flash
chromatography was performed using Sigma Type H silica gel (10-
40 µm, no binder). All reagents were purchased from Aldrich. All
nonaqueous reactions were conducted under an argon atmosphere in
oven or flame-dried apparatus. All solvents and reagents were purified
using established procedures. Microanalyses were performed by
Atlantic Microlab, Inc., Norcross, GA.
Bicyclic Lactam 11. To a cold (-78 °C) stirred solution of LDA
(42.2 mmol) in dry THF (150 mL) was added bicyclic lactam 1011
(10.57 g, 38.4 mmol) in THF (40 mL) via a cannula. The reaction
mixture was allowed to stir for 15 min, then MeI (5.50 g, 2.51 mL,
38.8 mmol) was added. The solution was stirred for 15 min at -78
°C, warmed to room temperature, stirred for an additional 1 h, and
treated with saturated aqueous NH4Cl (50 mL). The mixture was
38.9, 131.3, 139.7. IR (thin film) 2953, 1664, 1446, 1198 cm-1
.
Bicyclic Thioenamine 15. To a cold (0 °C) stirred solution of LDA
(2.49 mmol) in dry THF (20 mL) was added the bicyclic thiolactam
12 (637 mg, 2.09 mmol) in THF (2.5 mL) via a cannula. The reaction
mixture was allowed to stir for 20 min, and 1-(bromomethyl)-2-
methylcyclopentene (13d, 436 mg, 2.49 mmol) was added in THF (2.5

Synthesis of (-)-Trichodiene
J. Am. Chem. Soc., Vol. 120, No. 22, 1998 5457
mL) via a cannula. The mixture was stirred at 0 °C for 5 min, then
warmed to room temperature and was allowed to stir for an additional
20 min. The solution was diluted with Et2O (50 mL), washed with 1
M NaOH (2 × 10 mL), H2O (10 mL) and brine (10 mL), dried over
K2CO3, and filtered; the solvent was removed under reduced pressure.
The thick yellow oil obtained was generally subjected to the [3,3]-
sigmatropic rearrangement without further purification owing to its
instability to chromatography. A sample from a related experiment
was purified via flash chromatography (33:1 Hex-EtOAc containing
0.3% Et3N) to provide the thioenamine 15 as a thick yellow oil. 1H
NMR (300 MHz, CDCl3) δ 1.38 (s, 3H), 1.60 (s, 3H), 1.67-1.93 (m,
8H; therein 1.89 (s, 3H)), 2.18-2.53 (m, 5H), 3.12 (d, 1H, J ) 12.8
Hz), 3.35 (s, 3H), 3.51 (d, 1H, J ) 12.8 Hz), 3.67 (ddd, 1H, J ) 3.9,
5.7, 8.2 Hz), 3.77 (dd, 1H, J ) 8.2, 9.2 Hz), 3.89 (dd, 1H, J ) 3.9, 9.2
Hz), 5.10 (d, 1H, J ) 5.7 Hz), 7.18-7.32 (m, 3H), 7.36-7.42 (m,
2H). 13C NMR (75 MHz, CDCl3) δ 14.0, 21.4, 21.5, 26.0, 27.2, 31.7,
34.2, 35.6, 38.5, 58.9, 69.5, 75.5, 79.8, 94.4, 120.8, 126.4, 127.2, 128.1,
2H), 2.53 (ddd, 1H, J ) 5.5, 14.2, 17.2 Hz), 4.86 (d, 1H, J ) 2.7 Hz),
5.04 (d, 1H, J ) 2.7 Hz), 5.91 (dd, 1H, J ) 1.0, 10.4 Hz), 6.98 (dd,
1H, J ) 2.1, 10.4 Hz). 13C NMR (75 MHz, CDCl3) δ 18.8, 23.2, 24.5,
29.4, 34.1, 37.2, 38.3, 41.5, 49.4, 107.5, 127.8, 156.9, 158.3, 199.5.
IR (thin film) 2958, 2871, 1682, 1612 cm-1
. HRMS (FAB+) for
C14H21O (M + H)+: calcd 205.1592, found 205.1586. [R]25 -131°
D
(c ) 1.37/CHCl3).
(1R)-1-Methyl-1-((1S)-1-methyl-2-methylcyclopent-1-yl)-4-meth-
ylenecyclohex-2-ene (18). To a stirred mixture of Ph3PCH2, prepared
from Ph3PCH3Br (0.18 g, 0.51 mmol) and a solution of n-BuLi (2.10
M in hexanes, 0.19 mL, 0.41 mmol), in dry benzene (10 mL) was added
the enone 6 (41.7 mg, 0.204 mmol) in benzene (2 mL) via a cannula.
The mixture was allowed to stir at room temperature for 2.5 h and
then diluted with hexanes (45 mL). The organic layer was washed
with H2O (2 × 5 mL) and brine (5 mL), dried over MgSO4, and then
filtered; the solvent was removed under reduced pressure. The residue
was subjected to flash chromatography (Hex) and the resulting oil was
distilled (bulb-to-bulb, 140-150 °C/0.8 mmHg) to afford 38 mg (92%)
of the triene 18 as a clear colorless oil.6d 1H NMR (300 MHz, CDCl3)
δ 1.06 (s, 3H), 1.07 (s, 3H), 1.32-1.56 (m, 3H), 1.58-1.88 (m, 3H),
2.17-2.52 (m, 4H), 4.73 (s, 1H), 4.76 (s, 1H), 4.83 (d, 1H, J ) 3.0
Hz), 4.98 (d, 1H, J ) 2.0 Hz), 5.85 (d, 1H, J ) 10.0 Hz), 6.07 (d, 1H,
J ) 10.0 Hz). 13C NMR (75 MHz, CDCl3) δ 20.7, 23.3, 24.5, 27.1,
30.2, 37.3, 38.5, 40.6, 49.5, 106.6, 109.8, 127.9, 137.0, 143.0, 159.5.
131.8, 133.6, 134.9, 142.0. IR (thin film) 2924, 1448, 1099 cm-1
.
Bicyclic Thiolactam 8. The crude thioenamine 15 (2.09 mmol)
prepared above was dissolved in dry DMF (21 mL), anhydrous K2CO3
(433 mg, 3.13 mmol) was added, and the reaction mixture was heated
to 90 °C for 72 h. The reaction mixture was cooled to room temperature
and poured into brine (200 mL). The aqueous layer was extracted with
Et2O (5 × 20 mL). The combined organic extracts were washed with
H2O (2 × 10 mL) and brine (10 mL), dried over K2CO3 and filtered;
the solvent was removed under reduced pressure. The residue, which
was shown (1H NMR) to be a mixture (36:64) of 15 and 8, respectively,
was subjected to flash chromatography (TLC grade silica gel,20 13:1
Hex-EtOAc) to afford 183 mg (22%) of thioenamine 15 as well as
414 mg (50%) of the bicyclic thiolactam 8 as a thick light yellow oil,
which solidified upon storage at -20 °C. The recovered thioenamine
was resubjected to thermal rearrangement under identical experimental
conditions as described above to provide an additional 85 mg (10%)
of the bicyclic thiolactam 8. 1H NMR (300 MHz, CDCl3) δ 1.38-
1.88 (m, 15H; therein 1.57 (s, 3H), 1.62 (s, 3H), 1.68 (s, 3H)), 1.91-
2.00 (m, 1H), 2.07-2.15 (m, 1H), 2.21-2.45 (m, 2H), 3.33 (s, 3H),
3.68 (dd, 1H, J ) 2.8, 10.5 Hz), 4.00 (dd, 1H, J ) 4.7, 10.5 Hz), 4.88
(ddd, 1H, J ) 2.8, 4.7, 8.2 Hz), 4.93 (d, 1H, J ) 2.8 Hz), 4.95 (d, 1H,
J ) 1.9 Hz), 5.36 (d, 1H, J ) 8.2 Hz), 7.25-7.40 (m, 5H). 13C NMR
(75 MHz, CDCl3) δ 22.1, 22.8, 25.3, 26.3, 29.8, 33.0, 37.9, 38.7, 51.4,
53.3, 59.0, 68.4, 68.7, 77.5, 95.6, 106.8, 126.7, 128.3, 128.5, 138.8,
159.2, 206.5. IR (thin film) 2958, 1394 cm-1. HRMS (FAB+) for
C24H34NO2S (M + H)+: calcd 400.2310, found 400.2315. Anal. Calcd
for C24H33NO2S: C, 72.14; H, 8.32; N, 3.51. Found: C, 72.00; H,
IR (thin film) 2954, 1642 cm-1. [R]25 -261° (c ) 1.59/CHCl3).
D
(-)-Trichodiene (1). To a cold (-78 °C) stirred solution of sodium
(12 mg, 0.52 mmol) in ammonia (predried from Na) was added a
solution of the triene 18 (25 mg, 0.12 mmol) in dry THF (2 mL) via
a cannula. The reaction mixture was stirred for 1 h, then treated with
t-BuOH (0.5 mL) and allowed to stir for an additional 5 min. The
flask was removed from the cooling bath and the ammonia was allowed
to evaporate. The residue was dissolved in hexanes (20 mL) and the
organic layer was washed with H2O (5 mL) and brine (5 mL), dried
over MgSO4, and then filtered; the solvent was removed under reduced
pressure to afford a mixture (85:15) of (-)-trichodiene (1) and the 1,2-
reduction product 19, respectively. This mixture was subjected to flash
chromatography (hexanes as eluent) over AgNO3 impregnated silica
(12.5% in CH3CN) and (-)-trichodiene (1) was isolated as the fast
running band. The derived oil was distilled (bulb-to-bulb, 180 °C/1
mmHg) to afford 16.3 mg (65%) of (-)-trichodiene (1) as a clear
colorless oil. 1H NMR (300 MHz, CDCl3) δ 0.85 (s, 3H), 1.04 (s,
3H), 1.32-1.51 (m, 3H), 1.56-2.08 (m, 10H; therein 1.64 (s, 3H)),
2.13-2.28 (m, 1H), 2.32 (dd, 1H, J ) 6.6, 14.0 Hz), 4.74 (d, 1H, J )
2.7 Hz), 4.96 (d, 1H, J ) 2.7 Hz), 5.27-5.33 (m, 1H). 13C NMR (75
MHz, CDCl3) δ 17.9, 23.3, 23.4, 24.0, 27.8, 28.1, 33.0, 36.8, 37.2,
38.9, 50.6, 106.8, 120.5, 132.3, 159.9. IR (thin film) 3065, 2958, 890
8.26; N, 3.44. [R]25 -281° (c ) 1.11/CHCl3).
D
(4R)-4-Methyl-4-((1S)-1-methyl-2-methylcyclopent-1-yl)-cyclohex-
2-enone (6). To a stirred solution of bicyclic thiolactam 8 (129 mg,
0.322 mmol) in dry CH2Cl2 (5 mL) was added Et3OBF4 (2 M in CH2-
Cl2, 0.39 mL, 0.77 mmol), and the mixture was heated to reflux for 2
h. The resulting red solution was cooled to -78 °C and a solution of
Red-Al (65% in toluene, 0.126 mL, 0.406 mmol) was added dropwise.
The mixture was allowed to stir for 20 min, then was treated with 1 M
NaOH (1 mL) and warmed to room temperature. The mixture was
diluted with Et2O (15 mL), washed with 1 M NaOH (2 × 2 mL), H2O
(2 mL) and brine (2 mL), dried over K2CO3, and then filtered; the
solvent was removed under reduced pressure. The residue acquired
was taken up in EtOH (3 mL)/H2O (3 mL)/Bu4NH2PO4 (1 M in H2O,
6 mL), and the solution was heated to reflux for 15 h. The mixture
was cooled to room temperature and the EtOH was removed under
reduced pressure. The aqueous layer was poured into brine (25 mL)
and was extracted with Et2O (5 × 5 mL). The combined organic layers
were washed with H2O (5 mL) and brine (5 mL), dried over K2CO3,
and filtered; the solvent was removed under reduced pressure. The
oil thus obtained was subjected to flash chromatography (19:1 Hex-
EtOAc) to afford 35.8 mg (54%) of the enone 6 as a clear colorless
oil.6d A pure sample for HRMS and optical rotation was obtained by
distillation (190-200 °C/0.6 mmHg). 1H NMR (300 MHz, CDCl3) δ
1.12 (s, 3H), 1.19 (s, 3H), 1.39-1.55 (m, 2H), 1.64-1.90 (m, 3H),
2.11 (dt, 1H, J ) 5.0, 13.8 Hz), 2.19-2.31 (m, 1H), 2.32-2.43 (m,
cm-1
.
HRMS (EI) calcd for C15H24 (M)+: calcd 204.1878, found
204.1872. [R]25 -18° (c ) 0.50/CHCl3), lit.1a (+)-trichodiene [R]D
D
+21°. Chiral GLC analysis (Chiraldex B-PH) proved the sample of
(-)-trichodiene to be >99% enantiomerically pure when compared to
a sample of enantiomerically enriched (-)-trichodiene6a exhibiting the
following retention times: (-)-trichodiene, 10.58 min (67%); (+)-
trichodiene, 15.43 min (33%). The sample from the present study
appeared at 10.58 min with no visible trace of the (+)-enantiomer.
Further mixing of the two samples gave only the peaks at 10.58
(enhanced) and 15.43 min.
Acknowledgment. This paper is dedicated to the memory
of Professor Antonino Fava who contributed so much to
organosulfur chemistry. The authors are grateful to the National
Institutes of Health for generous financial support of this
program. We wish to thank Professor J. C. Gilbert (University
of Texas) for generously providing a sample of enantiomerically
enriched (-)-trichodiene.
Supporting Information Available: Spectral data (1H and
13C) of all key intermediates and chiral GLC traces of the final
products (15 pages, print/PDF). See any current masthead page
for ordering information and Web access instructions.
(20) Taber, D. F. J. Org. Chem. 1982, 47, 1351-1352.
JA9804159