Asymmetric approach to (+)-β-cuparenone by intramolecular Pauson-Khand reaction

Full text of DOI:10.1021/jo961190s

9016
J . Org. Chem. 1996, 61, 9016-9020
Asym m etr ic Ap p r oa ch to (+)-â-Cu p a r en on e
by In tr a m olecu la r P a u son -Kh a n d
Rea ction
J aume Castro,† Albert Moyano,*,† Miquel A. Perica`s,*,†
Antoni Riera,† Andrew E. Greene,‡
Angel Alvarez-Larena,§ and J oan F. Piniella§
F igu r e 1.
similar goal,5 our approximation has already been applied
to the enantioselective synthesis of complex natural
products such as (+)-hirsutene3b and (+)-brefeldin A.6 We
describe in the present paper how the Pauson-Khand
bicyclization of 1-alkoxy-4-thia-1-hepten-6-ynes can be
applied to the formation of enantioenriched cyclopen-
tanones with asymmetric quaternary carbon centers,7 as
exemplified by an enantioselective synthesis of (+)-â-
cuparenone.
Departament de Quı´mica Orga`nica, Facultat de Quı´mica,
Universitat de Barcelona, Martı´ i Franque`s 1-11, 08028
Barcelona, Spain, LEDSS 3, Universite´ J . Fourier, BP 53X,
38041 Grenoble, France, and Unitat de Cristal.lografia,
Facultat de Cie`ncies, Universitat Auto`noma de Barcelona,
08193 Bellaterra, Spain
Received J une 24, 1996
In tr od u ction
Resu lts a n d Discu ssion
The Pauson-Khand reaction1 has become the most
widely used among the transition-metal-promoted meth-
ods for the construction of five-membered carbocycles, as
evidenced by an ever increasing number of synthetic
applications.2 Well aware of the possibilities offered by
this reaction, which produces in a single step a 2-cyclo-
pentenone with up to two stereogenic carbon atoms, we
have devoted our efforts to the objective of rendering the
Pauson-Khand cyclization asymmetric. Our initial strat-
egy, based on the use of chiral alkoxy groups directly
linked either to the olefinic or the acetylenic components,
has resulted in the development of reliable, practical
asymmetric approaches for both the intramolecular3 and
the intermolecular4 versions of the Pauson-Khand reac-
tion. Contrasting to other methodologies aiming at a
Together with the regioisomeric R-cuparenones, (+)-
â-cuparenone (1), a 3,3,4,4-tetrasubstituted cyclopen-
tanone isolated from the essential oil of the “Mayur
pankhi” tree,8 has been the subject of much synthetic
effort, aimed generally to its preparation in racemic
form.9 Following the first enantioselective synthesis,10
other approaches to the enantiomerically pure compound
have relied upon the resolution of 2-methyl-2-(p-tolyl)-
succinic acid11 or the enzymatic hydrolysis of 2-methyl-
2-(p-tolyl) malonic esters12a,b and of 1-acetoxydicyclo-
pentadiene12c or on the ring contraction of optically active
5-(trimethylsilyl)-2-cyclohexenones.13
The key concept in the present chiral auxiliary-based
asymmetric intramolecular Pauson-Khand route to natu-
(5) (a) Bladon, P.; Pauson, P. L.; Brunner, H.; Eder, J . J . Organomet.
Chem. 1988, 353, 449-454. (b) Brunner, H.; Niederhuber, A. Tetra-
hedron: Asymmetry 1990, 1, 711-714. (c) Stolle, A.; Becker, H.; Salau¨n,
J .; de Meijere, A. Tetrahedron Lett. 1994, 35, 3521-3524. (d) Park,
H.-J .; Lee, B. Y.; Kang, Y. K.; Chung, Y. K. Organometallics 1995, 14,
3104-3107. (e) Kerr, W. J .; Kirk, G. G.; Middlemiss, D. Synlett 1995,
1085-1086. (f) Hay, A. M.; Kerr, W. J .; Kirk, G. G.; Middlemiss, D.
Organometallics 1995, 14, 4986-4988.
(6) Bernardes, V.; Kann, N.; Riera, A.; Verdaguer, X.; Moyano, A.;
Perica`s, M. A.; Greene, A. E. J . Org. Chem. 1995, 60, 6670-6671.
(7) For reviews and recent references, see: (a) Martin, S. F.
Tetrahedron 1980, 36, 419-460. (b) ApSimon, J . W.; Collier, T. L.
Tetrahedron 1986, 42, 5157-5254. (c) Asymmetric Synthesis; Morrison,
J . D., Ed.; Academic Press: New York, 1983; Vols. 2 and 3. (d) Nemoto,
H.; Ishibashi, H.; Nagamochi, M.; Fukumoto, K. J . Org. Chem. 1992,
57, 1707-1712. (e) Honda, T.; Kimura, N.; Tsubuki, M. Tetrahedron:
Asymmetry 1993, 4, 21-24. (f) Kataoka, Y.; Makihira, I.; Akiyama,
H.; Tani, K. Tetrahedron Lett. 1995, 36, 6495-6498 and references
therein.
(8) Chetty, G. L.; Dev, S. Tetrahedron Lett. 1964, 73-77.
(9) (a) Lansbury, P. T.; Hilfiker, F. R. J . Chem. Soc., Chem. Commun.
1969, 619-620. (b) Mane, R. B.; Rao, G. S. K. J . Chem. Soc., Perkin
Trans. 1 1973, 1806-1808. (c) Leriverend, P. Bull. Soc. Chim. Fr. 1973,
3498-3499. (d) Casares, A.; Maldonado. L. A. Synth. Commun. 1976,
6, 11-16. (e) Paquette, L. A.; Fristad, W. E.; Dime, D. S.; Bailey, T. R.
J . Org. Chem. 1980, 45, 3017-3018. (f) J ung, M. E.; Radcliffe, C. D.
Tetrahedron Lett. 1980, 21, 4397-4400. (g) Halazy, S.; Zutterman, F.;
Krief, A. Tetrahedron Lett. 1982, 23, 4385-4388. (h) Greene, A. E.;
Lansard, J .-P.; Luche, J .-L.; Petrier, C. J . Org. Chem. 1984, 49, 931-
932.
† Departament de Qu´ımica Orga`nica.
‡ LEDSS.
§ Unitat de Cristal.lografia; authors to whom correspondence re-
garding the X-ray diffraction study should be addressed.
(1) Reviews on the Pauson-Khand reaction: (a) Pauson, P. L.;
Khand, I. U. Ann. N.Y. Acad. Sci. 1977, 295, 2-14. (b) Pauson, P. L.
Tetrahedron 1985, 41, 5855-5860. (c) Pauson, P. L. In Organometallics
in Organic Synthesis. Aspects of a Modern Interdisciplinary Field; de
Meijere, A., tom Dieck, H., Eds.; Springer: Berlin, 1988; pp 233-246.
(d) Harrington, P. J . Transition Metals in Total Synthesis; Wiley: New
York, 1990; pp 259-301. (e) Schore, N. E. Org. React. 1991, 40, 1-90.
(f) Schore, N. E. In Comprehensive Organic Synthesis; Trost, B. M.,
Ed.; Pergamon Press: Oxford, 1991; Vol. 5, pp 1037-1064.
(2) For recent, miscellaneous synthetic applications of the Pauson-
Khand reaction, see: (a) J ohnstone, C.; Kerr, W. J .; Lange, U. J . Chem.
Soc., Chem. Commun. 1995, 457-458. (b) Halterman, R. L.; Ramsey,
T. M.; Pailes, N. A.; Khan, M. A. J . Organomet. Chem. 1995, 497, 43-
53. (c) Kent, J . L.; Wan, H.; Brummond, K. M. Tetrahedron Lett. 1995,
36, 2407-2410. (d) Costa, M.; Mor, A. Tetrahedron Lett. 1995, 36,
2867-2870. (e) Paquette, L. A.; Borrelly, S. J . Org. Chem. 1995, 60,
6912-6921. (f) Veretenov, A. L.; Koltun, D. O.; Smit, W. A.; Strelenko,
Y. A. Tetrahedron Lett. 1995, 36, 4651-4654.
(3) (a) Poch, M.; Valent´ı, E.; Moyano, A.; Perica`s, M. A.; Castro, J .;
De Nicola, A.; Greene, A. E. Tetrahedron Lett. 1990, 31, 7505-7508.
(b) Castro, J .; So¨rensen, H.; Riera, A.; Morin, C.; Moyano, A.; Perica`s,
M. A.; Greene, A. E. J . Am. Chem. Soc. 1990, 112, 9388-9389. (c)
Verdaguer, X.; Moyano, A.; Perica`s, M. A.; Riera, A.; Greene, A. E.;
Piniella, J .; Alvarez-Larena, A. J . Organomet. Chem. 1992, 433, 305-
310. (d) Castro, J .; Moyano, A.; Perica`s, M. A.; Riera, A.; Greene, A. E.
Tetrahedron: Asymmetry 1994, 5, 307-310. (e) Castro, J .; Moyano,
A.; Perica`s, M. A.; Riera, A. Tetrahedron 1995, 51, 6541-6556.
(4) (a) Bernardes, V.; Verdaguer, X.; Kardos, N.; Riera, A.; Moyano,
A.; Perica`s, M. A.; Greene, A. E. Tetrahedron Lett. 1994, 35, 575-578.
(b) Bernardes, V.; Verdaguer, X.; Moyano, A.; Perica`s, M. A.; Riera,
A.; Greene, A. E. J . Organomet. Chem. 1994, 470, C12-C14. (c)
Verdaguer, X.; Moyano, A.; Perica`s, M. A.; Riera, A.; Bernardes, V.;
Greene, A. E.; Alvarez-Larena, A.; Piniella, J . F. J . Am. Chem. Soc.
1994, 116, 2153-2154. See also: (d) Fonquerna, S.; Moyano, A.;
Perica`s, M. A.; Riera, A. Tetrahedron 1995, 51, 4239-4254.
(10) Greene, A. E.; Charbonnier, F.; Luche, M.-J .; Moyano, A. J . Am.
Chem. Soc. 1987, 109, 4752-4753.
(11) Gharpure, M. M.; Rao, A. S. Synth. Commun. 1989, 19, 679-
688.
(12) (a) Fadel, A.; Canet, J .-L.; Salau¨n, J . Synlett 1991, 60-62. (b)
Canet, J .-L.; Fadel, A.; Salau¨n, J . J . Org. Chem. 1992, 57, 3463-3473.
(c) Takano, S.; Moriya, M.; Ogasawara, K. Tetrahedron Lett. 1992, 33,
329-332.
(13) (a) Asaoka, M.; Hayashibe, S.; Sonoda, S.; Takei, H. Tetrahedron
Lett. 1990, 31, 4761-4764. (b) Sato, T.; Hayashi, M.; Hayata, T.
Tetrahedron 1992, 48, 4099-4114.
S0022-3263(96)01190-5 CCC: $12.00 © 1996 American Chemical Society

Notes
J . Org. Chem., Vol. 61, No. 25, 1996 9017
Sch em e 1
Sch em e 2a
a
Reaction conditions and yields: (a) NaH (1.1 equiv), THF,
reflux, 5 h; NBu4+I- (cat.), HCtCCH2Br (1.1 equiv), rt, 12 h (89%
based on recovered starting material); (b) KtBuO (1.5 equiv),
tBuOH, reflux, 2 h (80%); (c) HCtCCH2SH (1.3 equiv), HBF4‚Et2O
(cat.), CH2Cl2, -78 °C to rt, 12 h (77%); (d) Co2(CO)8 (1.1 equiv),
isooctane, rt, 30 min; reflux, 2.5 h (38%, 12:1 dr), or Co2(CO)8 (1.2
equiv), CH2Cl2, rt, 2 h; NMO (6 equiv), rt, 12 h (56%, 8:1 dr).
ral (+)-â-cuparenone, summarized in Scheme 1, lies on
the identification of the alkoxythiabicyclooctenone III,
arising from the cobalt-promoted bicyclization of an
alkoxythiaheptenyne such as II, as a suitable precursor
of the key cyclopentanone 2, whose conversion into 1
requires only the introduction of a methyl group at C-4.
Enantiopure (-)-(1R,2S)-2-phenylcyclohexanol was se-
lected as the chiral alcohol (I) of choice for this applica-
tion, on the basis both of its ready availability14 and of
the predictable sense and consistently high degree of
asymmetric induction that it imparts to the Pauson-
Khand bicyclization of other 1-alkoxy-1-hepten-6-ynes.3b,e
The required enyne II could be efficiently assembled
from the homochiral alkoxyallene 3 (prepared by base-
promoted isomerization15 of the corresponding propargyl
ether) and 2-propynethiol16 through a regio- and stereo-
selective acid catalyzed17 addition. In this way, (E)-1-
alkoxy-4-thiahepten-6-yne 4 was obtained in 77% yield
(Scheme 2) as a 9:1 mixture with the corresponding (Z)
isomer. Exposure of 4 to Co2(CO)8 in isooctane followed
by heating of the resulting dicobalt hexacarbonyl complex
(90 °C, 2.5 h) produced a ca. 12:1 mixture of diastereo-
meric bicyclo[3.3.0]octenones 5 from which the major one
could be isolated in moderate yield (33%) by column
chromatography; this yield could be considerably im-
proved by promoting the reaction with N-methylmorpho-
line N-oxide,18 at the cost of a slight decrease in diaste-
reoselectivity (56% yield, 8:1 diastereomeric ratio). In
no case were we able to detect products arising from the
cobalt-induced bicyclization of the (Z)-isomer of 4, in
accordance with the low Pauson-Khand reactivity ex-
hibited by other cis-alkoxyenynes.3b The (4R,5S) absolute
F igu r e 2.
configuration of the major diastereomer, established
through X-ray diffraction23 (Figure 2), turned out to be
fully coincident with that predicted by our working model
for the stereochemical outcome of the intramolecular
Pauson-Khand reaction of trans-2-phenylcyclohexanol-
derived enynes.3b,e On the other hand, H NMR spectra
1
show that, as expected, the minor diastereomer of 5 has
a (4S,5R) stereochemistry.
Since the chromatographic separation of synthetically
useful amounts of the diastereomeric bicyclooctenones 5
involved extended periods of time and was usually
accompanied by substantial losses due to partial product
decomposition, the synthesis was continued with the
readily available 8:1 diastereomeric mixture. In this
way, the cuprate reagent generated from p-tolyllithium
with cuprous iodide effected the desired conjugate addi-
tion on 5 to give in 41% yield after column chromatog-
raphy the 7-thiabicyclo[3.3.0]octanone 6 as a 8:1 diaste-
reomer mixture (Scheme 3). Subsequent Raney-Ni-
promoted transformation of the five-membered sulfur-
containing ring into a vic-dimethyl moiety (7, 95% yield
of a 8:1 diastereomer mixture), followed by reductive
removal (with 95% recovery) of the chiral auxiliary
accomplished with SmI2-MeOH,19 furnished (90% yield)
the key cyclopentanone 2, whose absolute configuration,
(14) Schwartz, A.; Madan, P.; Whitesell, J . K.; Lawrence, R. M. Org.
Synth. 1990, 69, 1-9.
(15) Rochet, P.; Vate`le, J .-M.; Gore´, J . Synthesis 1994, 8, 795-799.
(16) (a) Sato, K.; Miyamoto, O. Nippon Kagaku Zasshi 1956, 77,
1409-1411. (b) Conklin, G. W.; Morris, R. C. U. S. Pat. 2,707,714, 1953;
Chem. Abstr. 1956, 5018d. Complete experimental details for
a
convenient preparation of this unstable compound will be reported
separately.
(17) (a) Hoffmann, R. W.; Kemper, B. Tetrahedron Lett. 1981, 22,
5263-5266. (b) Hagen, J . P. J . Org. Chem. 1993, 58, 506-508.
(18) J eong, N.; Chung, Y. K.; Lee, B. Y.; Lee, S. H.; Yoo, S.-E. Synlett
1991, 204-206.
(19) Molander, G. A.; Hahn, G. J . Org. Chem. 1986, 51, 1135-1138.

9018 J . Org. Chem., Vol. 61, No. 25, 1996
Notes
on a Perkin-Elmer 241 MC polarimeter. The 1H NMR spectra
were recorded at 200 or 300 MHz in CDCl3 unless specified
otherwise. J values are given in Hz. The 13C NMR spectra were
recorded at 50.3 or 75.4 MHz in CDCl3 unless specified other-
wise. Signal multiplicities were established by DEPT experi-
ments. In all cases, chemical shifts are in ppm downfield of
TMS. Mass spectra were recorded at 70 eV ionizing voltage;
ammonia was used for chemical ionization (CI). Elemental
analyses were performed by the “Servei d’Ana`lisis Elementals
del CSIC de Barcelona”. THF and diethyl ether were distilled
from sodium benzophenone ketyl, and CH2Cl2 was distilled from
CaH2. All reactions were performed in flame or oven-dried
glassware under a N2 atmosphere. Reaction progress was
followed by TLC (Merck DC-Alufolien KIESELGEL 60 F254).
1-[(1R,2S)-(2-P h en ylcycloh exyl)oxy]-1,2-p r op a d ien e (3).
(a ) (1R,2S)-2-P h en ylcycloh exyl P r op a r gyl Eth er . To a cold
(0 °C), stirred suspension of sodium hydride (18.7 mmol, from
0.562 g of a 80% oil suspension) in dry THF (5 mL) was added
dropwise a solution of (-)-(1R,2S)-2-phenylcyclohexanol14 (3.00
g, 17.0 mmol) in THF (20 mL). The resulting mixture was
heated to reflux for 5 h, cooled to 0 °C, and treated with solid
tetrabutylammonium iodide (0.135 g). After 10 min at 0 °C, a
80% toluene solution of propargyl bromide (2.1 mL, 18.6 mmol)
was added dropwise; the reaction mixture was stirred overnight
at room temperature and poured into hexane/water. The
aqueous phase was separated and extracted with diethyl ether
(3 × 15 mL), and the combined organic phases were washed with
brine and dried over Na2SO4. Distillation of the solvents at
reduced pressure gave 4 g of a crude product which was purified
by column chromatography on silica gel (12 g), eluting with
hexane/diethyl ether mixtures of increasing polarity that allowed
the recovery of 1.79 g of the starting alcohol and the isolation of
2.08 g (89% yield based on the consumed chiral alcohol) of the
desired propargyl ether as a colorless oil: [R]23D ) -29.3 (c 5.93,
Sch em e 3a
a
Reaction conditions and yields: (a) p-Tolyllithium (5 equiv),
CuI (2.5 equiv), Et2O, -10 to 0 °C, 10 min; 6, rt, 12 h (41%); (b)
Ni-Raney, EtOH, reflux, 1 h (95%); (c) SmI2 (3.3 equiv), THF-
MeOH, -70 °C, 5 min (90%, 95% recovery of the chiral alcohol);
(d) LDA (1.1 equiv), THF, -78 °C, 20 min; PhSeBr (1.2 equiv),
-78 °C, 30 min; 0 °C, 1 h (85%); (e) H2O2 (6 equiv), AcOH-H2O,
rt, 1 h (90%); (f) (CH3)2Zn (5 equiv), Ni(acac)2 (cat.), Et2O, rt, 15 h
(86%, ref 10).
CCl4); IR (NaCl film) νmax ) 3300, 2100, 1600 cm-1 1H NMR
;
(200 MHz) δ 1.2-2.0 (m, 7H), 2.25 (t, J ) 2.5 Hz, 1H), 2.52 (td,
J ) 11.5 Hz, J ′ ) 7.5 Hz, 1H), 3.56 (td, J ) 12 Hz, J ′ ) 7.5 Hz,
1H), 3.75-3.90 (m, 2H), 7.10-7.40 (m, 5H); 13C NMR (50.3 MHz)
δ 25.0 (CH2), 25.9 (CH2), 32.2 (CH2), 34.1 (CH2), 51.0 (CH), 56.2
(CH2,), 73.4 (CH), 80.4 (Cq), 80.9 (CH), 126.1 (CH), 127.7 (2CH),
128.2 (2CH), 144.2 (Cq).
established by CD,20 showed that the conjugate addition
had taken place cis to the bridgehead hydrogen atom of
5, as expected. Accurate determination (both by 13C
NMR and HPLC analysis of the diastereomeric acetals
formed with both (-)- and (+)-2,3-butanediol)21 of the
enantiomeric composition of 2 indicated a 77% enantio-
meric excess, in agreement with the diastereomeric
composition of 5-7. Finally, when an enolate mixture
generated from 2 (LDA, THF, 0 °C) was treated with
phenylselenenyl bromide at -78 °C, the product arising
from deprotonation of the less hindered methylene group
was obtained in very high yield. This intermediate
selenide was then oxidized without further purification
to give (89% yield) the dextrorotatory cyclopentenone 8,
which has been previously converted to natural (+)-â-
cuparenone (1) by simple methyl conjugate addition.10,13
In summary, the intramolecular Pauson-Khand bicy-
clization of a 1-alkoxy-4-thia-1-hepten-6-yne derived from
a chiral alcohol provides a novel asymmetric approach
to â-cuparenone. Further synthetic applications and
methodological investigations of the asymmetric Pau-
son-Khand reaction are underway in our laboratories
and will be reported in due course.
(b) Ba se-P r om oted Isom er iza tion . A stirred suspension
of (1R,2S)-2-phenylcyclohexyl propargyl ether (2.0 g, 9.34 mmol)
and potassium tert-butoxide (1.57 g, 14.01 mmol) in tert-butyl
alcohol (25 mL) was heated to reflux for 2 h. At this point, the
reaction progress was monitored by TLC (hexane/ethyl acetate
5:1) and, if some propargyl ether still remained, 0.5 equiv of base
was added and heating was continued for 1 h, until complete
disappearance of the starting material. The reaction mixture
was cooled down to room temperature and poured into diethyl
ether/water (100 mL + 100 mL). After phase separation, the
aqueous one was extracted with diethyl ether (3 × 25 mL), and
the combined organic extracts were dried over Na2SO4. Elimi-
nation of solvents at reduced pressure gave a crude product
which was purified by column chromatography on Et3N pre-
treated (2.5% v/v) SiO2 (8 g) eluting with hexane, to afford 1.6 g
(80%) of alkoxyallene 3 as a white solid: Mp 50.0-51.4 °C; [R]23
D
) +130.2 (c 2.6, CCl4); IR (NaCl film) νmax ) 1960, 1610, 1500
cm-1; 1H NMR (200 MHz) δ 1.2-2.0 (m, 7H), 2.15-2.35 (m, 1H),
2.66 (td, 1H, J ) 10 Hz, J ′ ) 4.5 Hz), 3.8 (td, J ) 11 Hz, J ′ )
4.5 Hz, 1H), 5.25-5.40 (m, 2H), 6.40 (t, 1H, J ) 5.9 Hz), 7.10-
7.40 (m, 5H); 13C NMR (50.3 MHz) δ 24.5 (CH2), 25.8 (CH2), 31.6
(CH2), 34.2 (CH2), 50.2 (CH), 80.0 (CH,), 88.8 (CH2), 120.7 (CH),
126.2 (CH), 127.6 (2CH), 128.3 (2CH), 144.0 (Cq), 201.4 (Cq); MS
(CI-NH3) m/ e ) 215 (M+ + 1, 16%), 232 (M+ + 18, 21%). Anal.
Calcd for C15H18O: C 84.00%, H 8.46%. Found: C 84.32%, H
8.54%.
Exp er im en ta l Section
Gen er a l. Melting points were determined in an open capil-
(E)-1-[(1R,2S)-(2-P h en ylcycloh exyl)oxy]-4-th ia -1-h ep ten -
6-yn e (4). An anhydrous 0.34 M dichloromethane solution of
2-propynethiol16 (1 mL, 0.34 mmol) was added via cannula to a
cold (-78 °C) reaction flask containing solid alkoxyallene 3
(0.056 g, 0.26 mmol) and activated molecular sieves (dust; 3 Å);
4.4 µL (0.03 mmol) of HBF4‚Et2O was then added, and the
resulting mixture was stirred overnight at room temperature
and poured into dichloromethane/saturated aqueous NaHCO3.
After separation of the layers, the organic one was washed with
water, dried over Na2SO4, and stripped of solvents at reduced
pressure. The crude product was purified by column chroma-
lary tube and are uncorrected. Optical rotations were measured
(20) Negative Cotton effect, [θ]296 ) -4848 (c ) 2.47 × 10-3 M, CH2-
Cl2, 20 °C).
(21) Hiemstra, H.; Wynberg, H. Tetrahedron Lett. 1977, 18, 2183-
2186.
(22) Charbonnier, F. Ph.D. Thesis, Universite´ Scientifique, Tech-
nologique et Me´dicale de Grenoble, 1987.
(23) The author has deposited atomic coordinates for this structure
with the Cambridge Crystallographic Data Centre. The coordinates
can be obtained, on request, from the Director, Cambridge Crystal-
lographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK.

Notes
J . Org. Chem., Vol. 61, No. 25, 1996 9019
tography on Et3N-pretreated (2.5% v/v) SiO2, eluting with
hexane/diethyl ether mixtures of increasing polarity, to afford
0.057 g (77% yield) of a ca. 9:1 mixture of the (E)-enyne 4 and
were washed with brine. Drying over Na2SO4 and elimination
of the solvents at reduced pressure gave a crude product which
was purified by column chromatography on SiO2, eluting with
hexane/methylene chloride (5/1) to afford 0.108 g (41% yield) of
the bicyclic ketone 6, as a 8:1 mixture with its (1S,4S,5R)
its (Z) diastereomer, as a colorless oil. [R]23 ) -30.4 (c 0.028,
D
CH2Cl2); IR (NaCl film) νmax ) 3300, 1660, 1640 cm-1; 1H NMR
(200 MHz) δ 1.0-2.0 (m, 8H), 2.15 (t, J ) 2.5 Hz, 1H, acetylene),
2.62 (td, J ) 10.5 Hz, J ′ ) 4.5 Hz, 1H), 2.91 (dd, J ) 5.1 Hz, J ′
) 2.6 Hz, 2H), 3.03 (dd, J )7.6 Hz, J ′ ) 1.0 Hz, 2H), 3.79 (td,
J ) 10.5Hz, J ′ ) 4.5 Hz, 1H), 4.60 (dt, J ) 12.3 Hz, J ′ ) 7.8
Hz, 1H), 6.00 (d, J ) 12.3 Hz, 1H), 7.10-7.40 (m, 5H); [only the
signals corresponding to 4 are quoted, the (Z) diastereomer being
easily identified on the basis of a characteristic olefinic proton
signal: δ 5.90 (d, J ) 6 Hz, 1H)]; 13C NMR (50.3 MHz) δ 17.2
(CH2), 24.8 (CH2), 25.7 (CH2), 29.5 (CH2), 32.4 (CH2), 34.0 (CH2),
50.4 (CH), 70.6 (CH), 80.0 (Cq), 83.0 (CH), 99.4 (CH), 126.3 (CH),
127.5 (2CH), 128.2 (2CH), 143.4 (Cq), 148.0 (CH); MS (CI-NH3)
m/e ) 287 (M+ + 1, 100%), 304 (M+ + 18, 5%).
diastereomer, as a colorless oil. [R]23 ) -53 (c 1.69, CH2Cl2);
D
IR (NaCl film) νmax ) 1750, 1600, 1520 cm-1; 1H NMR (200 MHz,
major diastereomer) δ 1.0-2.0 (m, 8H), 2.29 (s, 3H), 2.1-2.8 (m,
6H), 3.20 (d, J ) 11.5 Hz, 1H), 3.56 (d, J ) 10 Hz, 1H), 3.60-
3.70 (m, 1H), 6.90-7.20 (m, 9H); 13C NMR (50.3 MHz, major
diastereomer) δ 20.8 (CH3), 25.2 (CH2), 25.8 (CH2), 29.7 (CH2),
33.3 (CH2), 33.7 (CH2), 34.4 (CH2), 44.0 (Cq), 48.8 (CH2), 51.8
(CH), 56.7 (CH), 85.7 (CH), 85.8 (CH), 125.2 (2CH), 126.5 (CH),
127.9 (2CH), 128.4 (2CH), 129.5 (2CH), 136.5 (Cq), 141.6 (Cq),
144.5 (Cq), 214.2 (CO); MS (CI-NH3) m/e ) 407 (M+ + 1, 2%),
424 (M+ + 18, 100%).
(2R,3S,4R)-3,4-Dim et h yl-2-[(1R,2S)-(2-p h en ylcycloh ex-
yl)oxy]-4-(p-tolyl)cyclop en ta n on e (7). A mixture of Raney
nickel (0.365 g from a 50% aqueous suspension, rinsed with
acetone and ethanol) and the ketone 6 (0.020 g, 0.05 mmol) in
ethanol (0.5 mL) was heated to reflux until TLC analysis showed
the complete disappearance of starting material (1 h). The
Raney nickel was then filtered off and thoroughly rinsed with
dichloromethane. Solvent evaporation at reduced pressure gave
an oil which was purified by column chromatography on SiO2,
eluting with hexane/methylene chloride (5/1) to afford 0.018 g
(95% yield) of 7, as a 8:1 mixture with its (2S,3R,4S) diastere-
When the reaction was effected on a larger scale (4.67 mmol
of allene), 4 was obtained with essentially the same yield (76%).
(4R,5S)-4-[(1R,2S)-(2-P h en ylcycloh exyl)oxy]-7-th iabicyclo-
[3.3.0]oct-1-en -3-on e (5). Th er m a l Rea ction . To a stirred
solution of Co2(CO)8 (0.050 g, 0.146 mmol) in isooctane (3 mL),
under argon, was added dropwise a solution of the enyne 4 (0.035
g, corresponding to 0.110 mmol of the (E) isomer) in isooctane
(3 mL), and the resulting solution was stirred at room temper-
ature until complete disappearance of the starting material
(TLC) and subsequently heated for 2.5 h at 90 °C. The reaction
mixture was cooled to room temperature and filtered through
Celite/SiO2, which was thoroughly washed with dichloromethane.
The solvents were distilled at reduced pressure, and the crude
product was purified by column chromatography on Et3N-
pretreated (2.5% v/v) SiO2 (6 g), eluting with hexane diethyl
ether mixtures of increasing polarity) to give: (a) 0.011 g (33%)
of pure, solid (4R,5S)-4-[(1R,2S)-(2-phenylcyclohexyl)oxy]-7-
thiabicyclo[3.3.0]oct-1-en-3-one, and (b) 0.002 g of a 1:1 mixture
of the same product with its (4S,5R) diastereomer. The overall
yield of the reaction was 38%.
omer, as an oil. [R]23 ) -78 (c 0.97, CH2Cl2); IR (NaCl film)
D
νmax ) 1748, 1603, 1514 cm-1 1H NMR (200 MHz, major
;
diastereomer) δ 0.30 (d, J ) 7 Hz, 3H), 0.40-2.20 (m, 10 H),1.06
(s, 3H), 2.28 (s, 3H), 3.25 (d, J ) 10 Hz, 1H), 3.75 (td, J ) 10
Hz, J ′ ) 4Hz, 1H), 6.90-7.20 (m, 9H); 13C NMR (50.3 MHz,
major diastereomer) δ 10.8 (CH3), 20.7 (CH3), 21.0 (CH3), 25.2
(CH2), 25.8 (CH2), 34.1 (CH2), 34.4 (CH2), 40.1 (Cq), 46.9 (CH),
51.9 (CH), 53.0 (CH2), 84.3 (CH), 86.2 (CH), 125.5 (2CH), 126.2
(CH), 128.1 (4CH), 128.9 (2CH), 135.6 (Cq), 143.3 (1Cq), 144.6
(1Cq), 216.4 (1Cq, CO); MS (CI-NH3) m/e ) 377 (M+ + 1, 1%),
394 (M+ + 18, 100%).
N-Oxid e-P r om oted Rea ction . To a stirred solution of Co2-
(CO)8 (0.093 g, 0.272 mmol) in dry dichloromethane (20 mL)
under Ar at room temperature was added dropwise a solution
of the enyne 5 (0.065 g, 0.204 mmol of the (E) isomer) in
dichloromethane (15 mL). After 2 h of stirring at room temper-
ature, solid N-methylmorpholine N-oxide (0.159 g, 1.36 mmol)
was added in one portion. Although the reaction was complete
after 1 h, as shown by TLC, the reaction mixture was left
overnight so that the violet Co precipitate settles out. Working
up and filtration through a short pad of Et3N-pretreated (2.5%
v/v) SiO2 afforded 0.035 g (56% yield) of a 8:1 diastereomer
mixture, which was subsequently used without further purifica-
tion.
(3R,4R)-3,4-Dim eth yl-3-(p-tolyl)cyclop en ta n on e (2). To
a cold (-70 °C) 0.1 M THF solution of SmI2 (Aldrich, 3.06 mL,
0.3 mmol) was added dropwise a solution of the alkoxy ketone 7
(0.045 g, 0.12 mmol) in anhydrous, degassed THF (0.50 mL) and
methanol (0.25 mL). After a short time, the progress of the
reaction was monitored by TLC and, if some 7 was still present,
more 0.1 M SmI2 solution (1.0 mL) was added and the disap-
pearance of 7 tested again. When the reaction was complete,
the remaining Sm(II) was destroyed by addition of moist THF;
the reaction mixture was diluted with pentane and treated with
aqueous saturated K2CO3 solution. The phases were separated,
the aqueous one was extracted three times with hexane, and
the combined organic extracts were dried over MgSO4. Solvents
were removed under vacuum, and the residue was purified by
column chromatography on SiO2, eluting with 1% ethyl acetate/
hexane, to afford 0.022 g (91% yield) of 2, of 77% enantiomeric
excess, as a colorless oil, and 0.020 g (95% recovery) of (1R,2S)-
Major diastereomer: [R]23D ) +24.6 (c 0.6, CH2Cl2); IR (KBr)
νmax ) 1720, 1630, 1600 cm-1 1H NMR (200 MHz) δ 1.2-2.0
;
(m, 7H), 2.30-2.70 (m, 4H), 3.32 (d, J ) 3 Hz, 1H), 3.57 (s, 2H),
3.50-3.80 (m, 1H), 5.85 (d, J ) 1.4 Hz, 1H), 7.10-7.40 (m, 5H);
13C NMR (50.3 MHz) δ 25.2 (CH2), 25.7 (CH2), 30.2 (CH2), 33.1
(CH2), 33.3 (CH2), 33.6 (CH2), 51.7 (CH), 53.7 (CH), 85.1 (CH),
86.5 (CH), 124.0 (CH), 126.4 (CH), 128.0 (2CH), 128.3 (2CH),
144.5 (Cq), 177.9 (Cq), 207.8 (CO); MS (CI-NH3) m/e ) 315 (M+
+ 1, 8%), 332 (M+ + 18, 100%).
2-phenylcyclohexanol. [R]23 ) -58 (c 0.5, CH2Cl2, 77% ee); IR
D
(NaCl film) νmax ) 1742, 1603, 1516 cm-1; H NMR (200 MHz)
1
δ 1.01 (d, J ) 6.6 Hz, 3H), 1.05-1.15 (m, 1H), 1.29 (s, 3H), 2.0-
2.8 (m, 4H), 2.34 (s, 3H), 7.0-7.2 (m, 4H); 13C NMR (50.3 MHz)
δ 14.3 (CH3), 20.0 (CH3), 20.8 (CH3), 29.7 (Cq), 40.8 (CH), 44.5
(CH2), 55.3 (CH2), 125.6 (2CH), 129.1 (2CH), 135.8 (1Cq), 143.4
(Cq), 217.9 (CO); MS (CI-NH3) m/e ) 220 (M+ + 18, 1%), 291
(M+ + 35, 1%), 310 (M+ + 90 + 18, 60%).
When the same reaction was run starting from 3.14 mmol of
the enyne, the yield was only 33%, mainly due to decomposition
during the chromatographic purification.
(1R,4R,5S)-1-p-Tolyl-4-[(1R,2S)-(2-ph en ylcycloh exyl)oxy]-
7-t h ia b icyclo[3.3.0]oct a n -3-on e (6). To a cold (-10 °C)
suspension of CuI (0.304 g, 1.6 mmol) in anhydrous diethyl ether
(0.5 mL) was added dropwise a 1.2 M diethyl ether solution of
p-tolyllithium (2.65 mL, 3.18 mmol, from p-bromotoluene and
lithium). After stirring for 10 min at 0 °C, the light green
suspension was cooled at -50 °C and treated with a solution of
5 (0.200 g, 0.637 mmol, 8:1 mixture of diastereomers from the
N-oxide-promoted reaction) in diethyl ether (0.5 mL). The
reaction mixture was slowly allowed to warm up to room
temperature, stirred overnight, and poured into a mixture of
diethyl ether (40 mL), aqueous saturated NH4Cl (40 mL), and
ice. The phases were separated and the organic one was washed
with aqueous saturated NH4Cl until no more blue color appeared
in the aqueous layer. The aqueous phases were extracted with
diethyl ether (2 × 20 mL), and the combined organic extracts
(4R)-3,4-Dim et h yl-4-(p -t olyl)-2-cyclop en t en on e (8).
A
solution of ketone 2 (0.029 g, 0.143 mmol) in anhydrous THF
(0.5 mL) was added via cannula to a cold (-78 °C), stirred 0.67
M solution of LDA in THF (0.235 mL, 0.158 mmol). The
resulting mixture was stirred for 20 min at the same temper-
ature and treated with a solution of phenylselenenyl bromide
(0.040 g, 0.170 mmol) in THF (0.5 mL). After 30 min at -78 °C
and 1 h at 0 °C, the reaction mixture was poured into an hexane/
saturated aqueous NH4Cl mixture (10 mL each). The phases
were separated, the aqueous one was extracted twice with
hexane, and the combined organic extracts were washed with
brine and dried over Na2SO4. Elimination of the solvents at
reduced pressure and subsequent purification by column chro-
matography on SiO2 (2 g), eluting with hexane, gave 0.037 g of

9020 J . Org. Chem., Vol. 61, No. 25, 1996
Notes
(2R,3S,4R)-(3,4-dimethyl)-2-(phenylselenyl)-4-(p-tolyl)cyclopen-
tanone (of 77% ee) and 0.008 g of starting material.
) +253 (c 1.7, CHCl3);10 [R]29 ) +233 (c 1.32, CHCl3)12c}; IR
D
(NaCl film) νmax ) 1710, 1625, 1515 cm-1; H-NMR (300 MHz)
1
r-P h en ylselen o Keton e: 1H NMR (200 MHz) δ 1.05 (d, J
) 6.6 Hz, 3H), 1.05-1.25 (m, 1H), 1.29 (s, 3H), 2.0-2.8 (m, 2H),
2.31 (s, 3H), 3.30 (d, J ) 10 Hz, 1H), 6.9-7.5 (m, 7H), 7.6-7.8
(m, 2H).
δ 1.63 (s, 3H), 1.82 (d, J ) 1.2 Hz, 3H), 2.32 (s, 3H), 2.59 (AB
system, 2H), 6.02 (q, J ) 1.2 Hz, 1H), 7.00-7.20 (m, 4H); 13C
NMR (75.4 MHz) δ 14.9 (CH3), 20.9 (CH3), 23.7 (CH3), 49.8 (Cq),
54.4 (CH2), 125.6 (2CH), 129.4 (2CH), 130.2 (CH), 136.3 (Cq),
141.2 (Cq), 184.70 (Cq), 208.6 (CO).
A solution of this 2-phenylseleno ketone (0.014 g, 0.039 mmol)
in THF (0.5 mL) was treated with water (30 µL), 33% hydrogen
peroxide (25 µL), and acetic acid (8 µL), stirred for 1 h at room
temperature, poured into a hexane/diethyl ether mixture (5 mL
each), and washed with water (3 × 10 mL) and aqueous
saturated NaHCO3 solution. The aqueous phase was extracted
twice with hexane, and the combined organic phases were first
washed with brine and then dried over Na2SO4. The solvents
were removed at reduced pressure, and the crude product was
purified by column chromatography on SiO2, eluting with
pentane/diethyl ether mixtures of increasing polarity, to afford
0.003 g of the starting 2-phenylseleno ketone and 0.0055 g (91%
overall yield, based on reacted starting material) of (4R)-3,4-
dimethyl-4-(p-tolyl)-2-cyclopentenone (8), whose spectral data
were fully coincident with those reported in the literature,22 as
Ack n ow led gm en t. We thank the CIRIT-CICYT
(Grant QFN 93-4407) and Mr. Llu´ıs Sola` for his techni-
cal assistance in the preparation of enantiopure (1R,2S)-
2-phenylcyclohexanol.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of compounds 2-8 (14 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
a colorless oil: [R]23D ) +211 (c 0.38, CHCl3, 77% ee) {lit.: [R]23
J O961190S
D