Asymmetric Pauson-Khand reactions using camphor-derived chelating thiols as chiral controllers

Article abstract of DOI:10.1021/jo015790p

A convenient procedure for the preparation of enantiopure 10-(R-thio)-2-exo-bornanethiols from (1S)-camphor-10-thiol has been developed. The ethynyl derivatives of these thiols gave excellent diastereoselectivities (up to 98:2) in Pauson-Khand reactions with norbornene and norbornadiene through the intermediacy of a chelated dicobalt pentacarbonyl complex. Thermal reaction conditions starting from the preformed chelated complex gave better results than N-oxide-promoted runs with in situ generation of the chelated intermediate. The corresponding adducts have been elaborated through a protocol consisting of conjugate addition, samarium iodide-promoted cleavage of the chiral auxiliary, and retro-Diels-Alder reaction to afford 4-substituted 2-cyclopentenones in high enantiomeric purity.

Full text of DOI:10.1021/jo015790p

6400
J . Org. Chem. 2001, 66, 6400-6409
Asym m etr ic P a u son -Kh a n d Rea ction s Usin g Ca m p h or -Der ived
Ch ela tin g Th iols a s Ch ir a l Con tr oller s
Iolanda Marchueta, Elvira Montenegro, Dmitri Panov, Marta Poch, Xavier Verdaguer,
Albert Moyano, Miquel A. Perica`s,* and Antoni Riera*
Unitat de Recerca en S´ıntesi Asime`trica, Departament de Qu´ımica Orga`nica, Universitat de Barcelona,
Martı´ i Franque´s 1-11, 08028 Barcelona, Spain
a.riera@qo.ub.es
Received May 24, 2001
A convenient procedure for the preparation of enantiopure 10-(R-thio)-2-exo-bornanethiols from
(1S)-camphor-10-thiol has been developed. The ethynyl derivatives of these thiols gave excellent
diastereoselectivities (up to 98:2) in Pauson-Khand reactions with norbornene and norbornadiene
through the intermediacy of a chelated dicobalt pentacarbonyl complex. Thermal reaction conditions
starting from the preformed chelated complex gave better results than N-oxide-promoted runs with
in situ generation of the chelated intermediate. The corresponding adducts have been elaborated
through a protocol consisting of conjugate addition, samarium iodide-promoted cleavage of the chiral
auxiliary, and retro-Diels-Alder reaction to afford 4-substituted 2-cyclopentenones in high
enantiomeric purity.
The search for reliable asymmetric versions of the
Pauson-Khand reaction (PKR) is a subject of maximum
interest since this reaction has emerged as one of the
most powerful tools for the synthesis of cyclopenten-
ones.1,2 Leaving aside the use of chiral substrates,3 which
in many cases have exhibited high stereoselectivities,
several approaches have been explored in order to render
the classical cobalt-mediated cyclization enantioselec-
tive: (a) chiral phosphines,4 (b) chiral tertiary amine
N-oxides5 to promote the reaction, and (c) chiral auxil-
iaries bonded either to the alkene or to the alkyne.6-10
Although important progress has been recently achieved
through the use of chiral phosphines as a source of
chirality in PKR,4 the use of removable chiral auxiliaries
(1) Selected 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 Organo-
metallics 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. (g)
Chung, Y. K. Coordin. Chem. Rev. 1999, 188, 297-341. (h) Sugihara,
T.; Yamaguchi, M.; Nishizawa, M. Rev. Heteroat. Chem. 1999, 21, 179-
194. (i) Brummond, K. M.; Kent, J . L. Tetrahedron 2000, 56, 3263-
3283.
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by other metals: (a) Hicks, F. A.; Buchwald, S. L. J . Am. Chem. Soc.
1996, 118, 11688-11689. (b) Hicks, F. A.; Kablaoui, N. M.; Buchwald,
S. L. J . Am. Chem. Soc. 1996, 118, 9450-9451. (c) J eong, N.; Sung, B.
K.; Choi, Y. K. J . Am. Chem. Soc. 2000, 122, 6771-6772. (d) Shibata,
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1999, 121, 6072-6073. (b) Mukai, C.; Kim, J . S.; Uchiyama, M.;
Sakamoto, S.; Hanaoka, M. J . Chem. Soc., Perkin Trans. 1 1998, 2903-
2915. (c) Alcaide, B.; Polanco, C.; Sierra, M. A. J . Org. Chem. 1998,
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(f) Stolle, A.; Becker, H.; Salaun, J .; de Meijere, A. Tetrahedron Lett.
1994, 35, 3521-3524. (g)Naz, N.; Al-Tel, T. H.; Al-Abed, Y.; Voelter,
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Y. K.; Chung, Y. K. Organometallics 1995, 14, 3104-3107. (d) Castro,
J .; Moyano, A.; Perica`s, M. A.; Riera, A.; Alvarez Larena, A.; Piniella,
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T.; Kawagishi, R.; Abe, I. Tetrahedron Lett. 2000, 41, 891-895. (h)
Castro, J .; Moyano, A.; Perica`s, M. A.; Riera, A.; Alvarez-Larena, A.;
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X.; Moyano, A.; Perica`s, M. A.; Riera, A.; Maestro, M. A.; Mahia, J . J .
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(5) (a) Kerr, W. J .; Kirk, G. G.; Middlemiss, D. Synlett 1995, 1085-
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Organometallics 1995, 14, 4986-4988. (c) Kerr, W. J .; Lindsay, D. M.;
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3229-3233.
(6) (a) Poch, M.; Valent´ı, E.; Moyano, A.; Perica`s, M. A.; Castro
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.;
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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) Bernardes, V.; Verdaguer, X.; Kardos, N.; Riera,
A.; Moyano, A.; Perica`s, M. A.; Greene, A. E. Tetrahedron Lett. 1994,
35, 575-578. (f) Stolle, A.; Becker, H.; Salau¨n, J .; de Meijere, A.
Tetrahedron Lett. 1994, 35, 3521-3524. (g) Fonquerna, S.; Moyano,
A.; Perica`s, M. A.; Riera, A. Tetrahedron 1995, 51, 4239-4254. (h)
Balsells, J .; Moyano, A.; Perica`s, M. A.; Riera, A. Tetrahedron:
Asymmetry 1997, 8, 1575-1580. (i) Montenegro, E.; Poch, M.; Moyano,
A.; Perica`s, M. A.; Riera, A. Tetrahedron 1997, 53, 8651-8664. (j) Adrio,
J .; Carretero, J . C. J . Am. Chem. Soc. 1999, 121, 7411-7412. (k)
Balsells, J .; Vazquez, J .; Moyano, A.; Perica`s, M. A.; Riera, A. J . Org.
Chem. 2000, 65, 7291-7302. (m) Fletcher, A. J .; Rutherford, D. T.;
Christie, S. D. R. Synlett 2000, 1040-1042. (n) Hiroi, K.; Watanabe,
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(7) (a) Bernardes, V.; Kann, N.; Riera, A.; Moyano, A.; Perica`s, M.
A.; Greene, A. E. J . Org. Chem. 1995, 60, 6670-6671. (b) Tormo, J .;
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52, 14021-14040. (c) Castro, J .; Moyano, A.; Perica`s, M. A.; Riera, A.;
Greene, A. E.; Alvarez-Larena, A.; Piniella, J . F. J . Org. Chem. 1996,
61, 9016-9020. (d) Tormo, J .; Moyano, A.; Perica`s, M. A.; Riera, A. J .
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(8) Fonquerna, S.; Moyano, A.; Perica`s, M. A.; Riera, A. J . Am. Chem.
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(9) Fonquerna, S.; Rios, R.; Moyano, A.; Perica`s, M. A.; Riera, A.
Eur. J . Org. Chem. 1999, 12, 3459-3478.
10.1021/jo015790p CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/24/2001

Asymmetric Pauson-Khand Reactions
J . Org. Chem., Vol. 66, No. 19, 2001 6401
acetylenes must be prepared by a three-step protocol
involving the protection of the terminal acetylenic posi-
tion by a trimethylsilyl group, complexation, and de-
silylation.12 Since acetylenic thioethers exhibit higher
stability against hydrolysis than their oxygenated ana-
logues, can be converted without problem into their
dicobalt hexacarbonyl complexes, and are appropriate
substrates for Pauson-Khand reactions,13 it seemed
reasonable that the use of chiral thiols with a adequately
positioned thioether funtion (“chelating thiols”) as aux-
iliaries could improve the scope and selectivity exhibited
by their alcohol analogues.
We reasoned that an increase in the steric bulk near
the sulfur atom designed as an hemilabile ligand would
have a positive effect in the diastereoselectivity of the
corresponding PKR. We report here full details14 on the
Pauson-Khand reactions of the alkynyl sulfides derived
from the known15 chiral thiol 1a bearing a methyl
thioether arm able to coordinate to cobalt (“chiral chelat-
ing thiol”) as well as the synthesis and Pauson-Khand
reactions of a new, specifically designed, thiol 1b.
F igu r e 1. Schematic mode of action of chiral auxiliaries with
a thioether functionality able to coordinate to cobalt (“chelating
auxiliaries”).
Resu lts a n d Discu ssion
Enantiomerically pure thiol 1a was prepared from the
readily available (1S)-camphor-10-thiol16 2 through a
significant improvement of a described procedure15 that
involves alkylation with methyl iodide, treatment with
Lawesson’s reagent,17 and stereoselective reduction of the
resulting thione (Scheme 1). In the original procedure,
stereochemical control of the reduction step was only
possible by performing the reaction at -80 °C, with the
undesired cost of a very extended reaction time (12 days).
We have now found a more practical alternative for this
transformation involving reaction with DIBALH at -20
°C (2 h, 10:1 dr), formation of the p-nitrobenzoate of the
thiol, purification by simple crystallization, and final
saponification. Enantio- and diastereomerically pure 1a
is obtained in 35% overall yield by this protocol.
is still a reliable approach and, up to now, the only one
that has been used in the synthesis of natural products.6b,7
Whereas in the intramolecular version of the reaction
conventional chiral auxiliaries such as trans-phenyl-
cyclohexanol or neopentyloxyisoborneol gave good levels
of diastereoselection and, in many cases, separable
diastereomers, the intermolecular version proved to be
more difficult. Nevertheless, excellent results were
achieved using alkynyl derivatives of Oppolzer’s cam-
phorsultam,8 chiral oxazolidinone,s9 or chiral auxiliaries
such as 10-methylthioisoborneol10 with an adequately
positioned thioether function.
In earlier studies on the reaction by our group it has
been shown that the ability of sulfur to coordinate onto
the cobalt atom in the cobalt carbonyl complex was
crucial in order to achieve high diastereoselectivity.11 The
substitution of a carbonyl ligand in the hexacarbonyl
dicobalt complex by a sulfur atom leads to a new, more
reactive pentacarbonyl complex, wherein the diaste-
reotopic cobalt atoms of the cluster are highly differenti-
ated. In this way, the chirality of the auxiliary is
transmitted to the metal cluster which, in turn, efficiently
controls the absolute configuration of the cyclopentenone
product (Figure 1). We have proposed the term chelating
auxiliaries for species exhibiting such behavior.
For the preparation of the new thiol 1b, the original
synthetic sequence was employed since the reduction step
takes place in a more convenient way. Thus, (1S)-
(11) In the pioneering work of Marie E. Krafft, sulfur coordination
to cobalt was used to control the regioselectivity of the PKR. (a) Krafft,
M. E. J . Am. Chem. Soc. 1988, 110, 968-970. (b) Krafft, M. E.; J uliano,
C. A.; Scott, I. L.; Wright, C.; McEachin, M. D. J . Am. Chem. Soc. 1991,
113, 1693-1703. (c) Krafft, M. E.; J uliano, C. A. J . Org. Chem. 1992,
57, 5106-5115. (d) Krafft, M. E.; Scott, I. L.; Romero, R. H.; Feibel-
mann, S.; Van Pelt, C. E. J . Am. Chem. Soc. 1993, 115, 7199-7207.
(12) Bernardes, V.; Verdaguer, X.; Moyano, A.; Perica`s, M. A.; Riera,
A.; Greene, A. E. J . Organomet. Chem. 1994, 470, C12-C14.
(13) Montenegro, E.; Poch, M.; Moyano, A.; Perica`s, M. A.; Riera,
A. Tetrahedron 1997, 53, 8651-8664.
(14) A preliminary account of this work describing the Pauson-
Khand reactions of 1a , has appeared: Montenegro, E.; Poch, M.;
Moyano, A.; Perica`s, M. A.; Riera, A. Tetrahedron Lett. 1998, 39, 335-
338.
(15) Montenegro, E.; Echarri, R.; Claver, C.; Castillo´n, S.; Moyano,
A.; Perica`s, M. A.; Riera, A. Tetrahedron: Asymmetry 1996, 7, 3553-
3558.
One of the problems associated with the use of alcohols
as chiral auxiliaries in alkoxyacetylenes participating in
PKR is the high tendency of these substrates to undergo
polymerization during the preparation of the requisite
dicobalt hexacarbonyl complexes. To avoid this problem,
the cobalt carbonyl complexes of all terminal alkoxy-
(10) 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. (b) Verdaguer, X.; Vazquez, J .; Fuster, G.;
Bernardes-Genisson, V.; Greene, A. E.; Moyano, A.; Perica`s, M. A.;
Riera, A. J . Org. Chem. 1998, 63, 7037-7052.
(16) Oae, S.; Togo, H. Bull. Chem. Soc. J pn. 1983, 56, 3802-3812.
(17) (a) Scheibye, S.; Shabana, R.; Lawesson, S.-O.; Rømming, C.
Tetrahedron 1982, 38, 993-1001. (b) Thomsen, I.; Clausen, K.;
Scheibye, S.; Lawesson, S.-O. Org. Synth. 1984, 62, 158-164. (c) Cava,
M. P.; Levinson, M. I. Tetrahedron 1985, 41, 5061-5087.

6402 J . Org. Chem., Vol. 66, No. 19, 2001
Marchueta et al.
Sch em e 1a
Sch em e 2a
a
Key: (a) BrCH2CH(OEt)2, NaEtO, EtOH (6a , 80%); (b) LDA,
a
Key: (a) R-Br, MeOH, NaMeO (3a , 79%; 3b, 81%); (b)
diethyl ether (7a , 81%); (c) (i) KH, THF, (ii) Cl2CHCH2Cl, (iii)
n-BuLi (7a , 71% overall); (d) (i) KH, THF, (ii) Cl2CHCH2Cl (8b,
70%); (e) n-BuLi, diethyl ether (7b, 96%).
Lawesson’s reagent (4a , 78%; 4b, 74%); (c) DIBALH, diethyl ether,
-20 °C, 88%, 10:1 dr; (d) (i) PNB-Cl, CH2Cl2, Pyr, (ii) cryst. 69%
overall; (e) NaOH, MeOH, 95%; (f) DIBALH, diethyl ether, -40
°C, 90%.
As anticipated, the preparation of the dicobalt hexa-
carbonyl complexes of the acetylene thioethers was
simple and straightforward. By stirring a solution of the
alkynyl thioethers 7a ,b in hexanes at room temperature
with 1.05 equiv of octacarbonyl dicobalt, the dicobalt
hexacarbonyl complexes (9a ,b) were obtained almost
quantitatively. The thermal stability of these complexes
was clearly superior to that of their oxygenated ana-
logues,10 allowing complete characterization. However,
in their 1H and 13C spectra, a significative amount (ca.
2-5% in the case of 9a , 10-30% in the case of 9b) of
new cobalt complexes 10a ,b, presumably formed by
internal displacement of a carbonyl ligand by the sulfur
atom, was observed. As with the oxygenated analogues,10
an equilibrium appears to exist between hexacarbonyl
and chelated complexes. In this case, however, the
equilibrium can be almost completely shifted toward the
chelated pentacarbonyl species by simply heating the
hexane solution of the hexacarbonyl complex at 55 °C
under a smooth nitrogen stream or by addition of
N-methylmorpholine N-oxide (NMO) to a dichloromethane
solution of 9 at room temperature (Scheme 3). Although
both methods for the generation of the pentacarbonyl
complexes are almost equivalent in terms of yield (ther-
mal: 89%; NMO: 83% in the case of 10a ), there are
several experimental details that should be stressed.
First, the 1H NMR spectra of the thermally generated
complex 10a always showed a small amount (ca. 3-5%)
of the starting hexacarbonyl complex 9a . Conversely,
samples of 10a prepared under oxidative conditions were
camphor-10-thiol 2 was alkylated by treatment with
2,4,6-trimethylbenzyl bromide18 and sodium methoxide
in methanol to afford the mesytylmethyl derivative 3b
in 81% yield. Conversion of this ketone into the corre-
sponding thione 4b was accomplished uneventfully in
74% yield using Lawesson’s reagent.17 To our satisfaction,
in this case, the DIBALH reduction of the thione 4b was
completely stereoselective at -40 °C yielding diastereo-
merically pure (exo) thiol 1b in 90% yield after only 6 h
of reaction (Scheme 1). This simple and straightforward
preparation of 1b (54% overall yield from 2), together
with the applications that we have just developed (see
below), converts this chiral thiol into a potentially useful
chiral auxiliary.
For the purposes of this study, thiols 1a ,b had to be
converted into the corresponding acetylene thioethers.
The synthesis of ethynyl sulfide 7a was initially ac-
complished using the methodology developed by Cook-
son.19 Thus, the sodium thiolate of 1a was treated with
2-bromoacetaldehyde diethylacetal affording 1,1-diethoxy-
2-(R*-thio)ethane 6a in 80% yield. Subsequent double
elimination promoted by LDA yielded the corresponding
ethynyl sulfide 7a in 81% yield.
For small-scale preparations, the methodology devel-
oped by Greene starting from thichloroethylene and using
potassium hydride as a base20 was more convenient and
afforded (2R-exo)-10-methylthioisobornyloxyethyne 7a in
71% yield in a “one-pot” reaction from thiol 1a (Scheme
2). However, when this method was attempted with thiol
1b afforded very low yields of the acetylenic thioether
9b, the intermediate dichloroolefin 8b being the main
product of the reaction.
1
almost completely free of 9a by H NMR. As we will see,
this fact can be of some concern in reactivity studies.
Significantly, and despite the increased steric bulk of the
sulfur substituent, the thermal generation of 10b pro-
vided a crude reaction completely free of 9b.
In any case, this problem could be easily overcome by
treating 8b with butyllithium in diethyl ether to afford
almost quantitatively ethynyl sulfide 7b (Scheme 2).
It is worth noting that two diastereomeric pentacar-
bonyl complexes 10-(Co-pr o-S) and 10-(Co-pr o-R) can
be formed by chelation of the alkylthio group to each one
of the two diastereotopic cobalt atoms (Figure 2). How-
(18) Hauser, C. R.; Van Eenam, D. N. J . Am. Chem. Soc. 1957, 79,
5512-5518
1
ever, careful inspection of the H and 13C NMR spectra
(19) Cookson, R. C.; Gopalan, R. J . Chem. Soc., Chem. Commun.
1978, 924-925.
of both pentacarbonyl complexes 10a ,b, generated either
thermally or by treatment with NMO, revealed only one
(20) Nebois, P.; Kann, N.; Greene, A. E. J . Org. Chem. 1995, 60,
7690-7692.

Asymmetric Pauson-Khand Reactions
J . Org. Chem., Vol. 66, No. 19, 2001 6403
Sch em e 3a
s) prevented the observation of any NOE of this atom
with the rest of the molecule. The H NMR spectrum of
1
10b is clean from 5 to 6.8 ppm, showing only one signal
for the acetylenic hydrogen. Although the possibility of
a rapid equilibrium between diastereomers cannot be
absolutely ruled out, it is much likely that the steric bulk
of the mesitylmethyl substitutent is able to completely
shift the equilibrium toward one diastereomer, 10-(Co-
pr o-S) or 10-(Co-pr o-R), as represented in Figure 2.
The Pauson-Khand reactions of the cobalt carbonyl
complexes 9/10 prepared from alkynyl sulfides 7 were
next studied. The results are shown in Table 1. As a
control experiment, the thermal reaction between the
hexacarbonyl complex 9a with norbornadiene was per-
formed under a CO atmosphere to minimize the forma-
tion of the pentacarbonyl complex. At 0 °C (Table 1, entry
1) the reaction was extremely slow, and after 23 days,
only a 31% of a 67:33 diastereomeric mixture of bicyclic
cyclopentenones 11a could be isolated. The N-oxide-
promoted reaction conditions that had given the best
results with the ethynyl ether of 10-methylthioisoborneol10
were next studied. A solution of the pentacarbonyl
complex 10a , generated by treatment with an excess of
NMO (6 equiv) in dichloromethane at room temperature,
was cooled to -20 °C and treated with norbornadiene.
The reaction was complete in 2.5 days (Table 1, entry 2)
but, quite surprisingly, took place without any stereo-
selectivity leading to equal amounts of the two possible
exo adducts. It is worth noting that under the same
conditions the analogous oxygenated compound afforded
the Pauson-Khand adduct in 77% yield as a 92:8 mixture
of diastereomers.10 The reaction was next studied under
thermal conditions starting from the pentacarbonyl
complex 10a , generated in hexanes by heating 7a at 55
°C. Once the conversion to the pentacarbonyl complex
was complete by TLC, the solution was cooled to 0 °C,
and norbornadiene was added. After 24 h, the reaction
was complete and, in this case, took place with excellent
diastereoselectivity (92:8). A further decrease of the
reaction temperature (-20 °C, Table 1, entry 4) did not
significantly improve the selectivity (93:7), whereas the
reaction time increased to 6 days. It was clear from these
experiments that an excess of NMO has a deleterious
effect on diastereoselectivity (Table 1, entries 2 and 3).
On the other hand, it was conceivable that the small
amount of the hexacarbonyl complex 9a present in
admixture with 10a when the latter is generated by
thermal activation was responsible for the formation of
the minor stereoisomer. In an attempt to develop optimal
reaction conditions, 10a was generated in dichloromethane
by treatment with the minimum amount of NMO (3
equiv) and then purified by chromatography. A hexane
solution of 10a completely free of 9a obtained in this way
was subsequently exposed to the employed olefins at
different temperatures. At -10 °C, the norbornadiene
adduct was obtained in 65% yield and the selectivity
increased up to 95:5 (Table 1, entry 5). With norbornene
under the same reaction conditions, a 86:14 diastereo-
meric mixture was obtained in 66% yield after 5 days of
reaction (Table 1, entry 8). Thus, while the thermal
generation of 10a seems to be appropriate for achieving
high diastereoselectivities, the best results are obtained
using the pentacarbonyl complex 10a generated by
oxidative treatment of 9a followed by complete removal
of any excess of NMO or its reduction product.To check
whether the presence of the bulky mesitylmethyl group
a
Conditions and yields for Pauson-Khand reactions are shown
in Table 1.
F igu r e 2. Diastereomeric complexes 10 generated by internal
chelation of the sulfide to each diastereotopic cobalt atom.
set of signals. The electronic and geometric changes
associated to the conversion of 9a /9b into 10a /10b can
be readily appreciated by comparison of their NMR
spectra (see the Supporting Information). Thus, the main
change in the 1H NMR spectra corresponds to the AB
system of the -CH2S group, which shows a large increase
in the chemical shift difference of the diastereotopic
nuclei, probably reflecting the different geometrical ar-
rangement (axial-like or equatorial-like) of these two
protons in the chelated complex. Moreover, the signal of
1
the CH3S group in the H NMR spectrum of 10a appears
significantly shifted downfield (from 2.09 to 2.45 ppm),
thus reflecting the reduced electron density of the sulfur
atom. On the other hand, the acetylenic proton is
correspondingly shifted upfield (6.36/6.34 to 5.89/5.95
ppm) as a consequence of the more electronically rich
nature of the C2Co2 core. This signal, which appears in a
clean region of the spectrum, allows the estimation of the
ratio 9/10 after a thermal or oxidative treatment. In the
experiments devoted to the generation of 10a , a very
small singlet (ca. 2%) was observed in this zone that could
be assigned either to the minor diastereomer of 10a or
to an impurity. By recording the spectrum at low tem-
perature (down to -60 °C), no significant broadening
could be observed in either the major or the minor
signals. If we make the assumption that the large and
the small signals correspond to the major and minor
diastereomers of 10a , it comes out that interconversion
between them should be slow at room temperature.
Although NOESY studies were performed on 10a to
establish the stereochemistry of the major diastereomer,
the high relaxation time of the acetylenic proton (∼9.7

6404 J . Org. Chem., Vol. 66, No. 19, 2001
Ta ble 1. In ter m olecu la r P a u son -Kh a n d Rea ction s of R*-th ioa lk yn es w ith Alk en es
Marchueta et al.
a
Conditions: (A) stirring the dicobalt hexacarbonyl complex 9a ,b in hexane at the specified temperature; (B) generation of the
pentacarbonyl complex 10a ,b by addition of NMO (6 equiv) to a solution of 9a ,b in dichloromethane followed by addition of the olefin at
the specified temperature; (C) generation of the pentacarbonyl complex 10a ,b by heating the solution of 9a ,b in hexane at 55 °C followed
by addition of the olefin at the specified temperature; (D) generation of the pentacarbonyl complex 10a ,b by addition of NMO (3 equiv)
to a solution of 9a ,b in dichloromethane; purification of 10a ,b by chromatography in Al2O3 and reaction with the olefin in hexanes at the
b
specified temperature. By HPLC. c By 13C NMR.
attached to the chelating sulfur atom in the chiral
auxiliary had a positive influence on the diastereoselec-
tivity, the Pauson-Khand reactions of alkynyl sulfide 7b
were tested. As expected from the above-mentioned
results, the N-oxide-promoted reactions conducted in the
presence of excess NMO gave poor yields and selectivities.
Gratifyingly enough, however, the thermally generated
pentacarbonyl complex 10b afforded the norbornadiene
adduct in 60% yield in excellent diastereoselectivity (98:
2) by performing the reaction in hexane at 0 °C (Table 1,
entry 10). It is worth mentioning that with this substrate
the thermal conversion of the hexacarbonyl complex 9b
into the corresponding chelated species 10b is complete.
In this case, the preparation of 10b by treatment with
NMO followed by chromatography did not improve the
selectivity, which decreased to 95:5 (Table 1, entry 11).
With norbornene, the thermal reaction from the ther-
mally generated pentacarbonyl complex 10b also pro-
vided excellent diastereoselectivities (Table 1, entry 13).
Again, these results were not improved when complex
10b was prepared by treatment with NMO followed by
removal of the excess N-oxide (Table 1, entry 14). As a
general trend, thiol 1b behaves as a more efficient chiral
controller in intermolecular PKR mediated by internally
chelated species such as 10. Not only is the synthesis of
1b much simpler and efficient than that of 1a , but also
the experimental procedures associated to its use in
intermolecular PKR (i.e., purely thermal generation of
the pentacarbonyl complex 10b) are straightforward and
the achieved diastereoselectivities, higher.
applications of the Pauson-Khand adducts derived from
norbornadiene rely on the possibility of performing on
these molecules a retro Diels-Alder reaction leading to
a cyclopentenone. In the context of asymmetric Pauson-
Khand reactions of chiral enol or ynol ethers, protocols
consisting of conjugate addition, samarium iodide-
induced cleavage of the carbon-alkoxy linkage, and
retro-Diels-Alder reaction has allowed the preparation
of enantiomerically pure 4-substituted 2-cyclopentenones
and bicyclo[n.3.0]alkanones. This strategy has been suc-
cessfully applied, for instance, to the development of an
enantioselective synthesis of brefeldin A.7a With the aim
of applying the same protocol in the present case, bicyclic
adducts 11a and 11b were submitted to conjugate
addition21 with n-Bu2CuCNLi2 in diethyl ether. Although
the reactions took place cleanly by TLC, cyclopentanones
13a and 13b were very unstable and decomposed when
chromatographic purification or spectroscopic character-
ization was attempted. To circumvent this difficulty, the
reaction crudes were directly treated with samarium
iodide22 in THF/MeOH to afford the known tricyclic
cyclopentanone (-)-14. Starting from adduct 11a , the
yield of (-)-14 was 46% (two steps), 5-butyl-4-hydroxytri-
cyclo[5.2.1.02,6]deca-4,8-dien-3-one (16) being formed as
a significant byproduct (32% yield). On the other hand,
starting from 11b, the reaction was much cleaner and
the bicyclic cyclopentenone (-)-14 was isolated in 64%
yield. The starting thiol 1b could be recovered in 59%
yield [91% with respect to (-)-14]. The retro Diels-Alder
reaction of (-)-14 was conducted at low temperature (55
°C) under the Lewis acid-catalyzed conditions developed
Once the formation of the PK adducts was optimized,
our efforts were directed to the development of protocols
for their conversion into enantiomerically pure, syntheti-
cally useful cyclopentenone derivatives with simulta-
neous recovery of the chiral auxiliary. Most synthetic
(21) cf.: Lipschutz, B. H.; Ellsworth, E. L.; Siahaan, I. J .; Shirazi,
A. Tetrahedron Lett. 1988, 29, 6677-6680.
(22) Kende, A. S.; Mendoza, J . S. Tetrahedron Lett. 1991, 32, 1699-
1702.

Asymmetric Pauson-Khand Reactions
J . Org. Chem., Vol. 66, No. 19, 2001 6405
F igu r e 3. Mechanistic interpretation for the observed loss of stereoselectivity when performing the PKR in the presence of
NMO.
Sch em e 4a
by Grieco.23 In this way, (-)-4-butylcyclopentenone (-)-
15 was obtained in 90% yield.
The enantiomeric purity of (-)-15 was measured by
chiral GC (R-Dex). Samples of (-)-15 arising either from
diastereomerically enriched 11a or 11b showed high
enantiomeric excesses (94-96% ee) in good agreement
with the diasteriomeric ratio of the starting adducts, thus
confirming that no significant racemization takes place
in the retro-Diels-Alder step.The absolute configuration
of adducts 11a and 11b (as depicted in Scheme 4) could
be established from the sign of the specific rotation of
14, of known absolute configuration,10,24 by assuming the
universally observed exo configuration of the Pauson-
Khand adducts involving norbornene and norbornadiene.
The absolute configuration of the major diastereomer of
adducts 12a ,b was established by chemical correlation
since hydrogenation of the major stereoisomer of 11a ,b
led to the major stereoisomer of 12a ,b. It is worth noting
that the sense of the induction in the major Pauson-
a
Khand adducts 11a ,b and 12a ,b is the same as observed
using (2R)-10-methylthioisoborneol as a chiral auxil-
iary.10 This fact strongly suggests that an analogous
mechanism, which has been studied in detail,10b is
operating. According to this mechanism, the coordination
of the alkene is directed by the sulfur ligand to a precise
cobalt atom (the pro-R) which is the one involved in the
cobaltacycle formation. This selectivity, linked to the
clear energetic preference for the anti-type cobaltacycles
would be responsible for the high diastereoselectivity of
Key: (a) n-Bu2CuCNLi2/diethyl ether; (b) SmI2, THF/MeOH
(from 11a : 46% of (-)-14, 32% of 16; from 11b: 64% yield of (-)-
14); (c) MeAlCl2, maleic anhydride, CH2Cl2 (94%).
the process. If the present reactions are compared with
those of the analogous acetylenic ethers, the first re-
markable difference is in reaction rates. Thus, albeit in
a more stereoselective manner, the chelated complexes
10a ,b react with strained olefins at considerably lower
rates than their oxygenated counterparts. This is clearly
indicative of an increased stability of the chelated species,
as the possibility of a purely thermal generation or of
chromatographic separation also are. This superior sta-
bility of the chelated species could provide a clue for the
(23) Grieco, P. A.; Abood, N. J . Org. Chem. 1989, 54, 6008-6010.
(24) Ackroyd, J .; Karpf, M.; Dreiding, A. S. Helv. Chim. Acta 1985,
68, 338-344.

6406 J . Org. Chem., Vol. 66, No. 19, 2001
Marchueta et al.
washed with 10% NaHCO3, dried over MgSO4, and concen-
trated in vacuo. The crude oil was purified by column chro-
matography on Et3N-pretreated silica gel (2.5% v/v) eluting
with hexane to afford 3.1 g (88% yield) of a 10:1 mixture of
exo- and endo-(2R)-10-methylthio-2-bornanethiol 1a as a color-
less oil.
understanding of an apparently anomalous result: the
complete loss of stereoselectivity when the PKR is
conducted in the presence of excess NMO. Once the
pentacarbonyl complex is completely formed, if the equi-
librium between chelated and nonchelated forms is easily
established and a reactive olefin is present in the
medium, reaction is predominantly directed toward the
cobalt atom involved in chelation. On the other hand, if
the chelated form is less reactive and excess NMO is
present, further oxidative CO detachment can take place
at any of the two diastereotopic cobalt atoms, with the
undesired result of a nonselective reaction (Figure 3).
In summary, an extremely efficient asymmetric version
of the Pauson-Khand reaction has been developed using
camphor-derived chelating thiols. Among them, (2R)-10-
(mesitylmethylthio)-2-exo-bornanethiol 1b has proved to
be an excellent chiral auxiliary: It can be prepared in
high yield in only three steps from (1S)-camphor-10-thiol,
and its ethynyl derivative gives excellent diastereoselec-
tivities (up to 98:2 dr) in Pauson-Khand reactions with
norbornene and norbornadiene. These reactions are
carried out under purely thermal conditions, by simply
generating a stable, chelated pentacarbonyl complex at
55 °C, cooling to 0 °C, and finally adding the reacting
olefin at that temperature. The corresponding cyclo-
adducts have been elaborated through a protocol consist-
ing of conjugate addition, samarium iodide-induced cleav-
age of the chiral auxiliary and retro-Diels-Alder reaction
to afford 4-substituted-2-cyclopentenones of high enan-
tiomeric purity.
B. To a solution of 5a (0.1 g, 0.27 mmol) in methanol (3 mL)
was added 1% NaOH/MeOH (10 mL) under stirring at room
temperature. The reaction was monitored by TLC. After 5 min,
the reaction mixture was quenched with saturated NH4Cl
solution and extracted with hexane. The organic solution was
evaporated and chromatographed on Et3N-pretreated silica gel
(2.5% v/v) eluting with hexane to afford 56 mg (95% yield) of
diastereomerically pure 1a : [R]D ) - 97.3 (c 1.9, CHCl3); IR
(film) νmax ) 2940, 2540, 1450 cm-1; 1H NMR (200 MHz, CDCl3)
δ 3.8 (m, 1H), 2.97, 2.55 (AB, J ) 11.4 Hz, 2H), 2.4 (d, J ) 6.2
Hz, 1H), 2.15 (s, 3H), 2.0-1.1 (m, 7H), 1.04 (s, 3H), 0.87 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 52.0 (C), 48.7 (C), 46.2 (CH),
43.7 (CH), 39.5 (CH2), 36.1 (CH2), 34.7 (CH2), 27.2 (CH2), 21.1
(CH3), 20.1 (CH3), 17.3 (CH3); MS (CI-NH3) m/e ) 215 (M+
-
1, 100). Anal. Calcd for C11H20S2: C, 61.05; H, 9.32; S, 29.63.
Found: C, 61.09; H, 9.52; S, 29.58.
(1S ,2R )-7,7-Dim e t h yl-1-m e t h ylsu lfa n ylm e t h yl-2-(4-
n itr oth ioben zoyl)bicyclo[2.2.1]h ep ta n e (5a ). A solution of
a diastereomeric mixture (10:1) of thiol 1a (1.0 g, 4.67 mmol)
in dichloromethane (3 mL) was added, under nitrogen, to a
solution of 4-nitrobenzoyl chloride (1.73 g, 9.34 mmol) and
pyridine (0.76 mL, 9.34 mmol) in dichloromethane (60 mL).
The reaction mixture was stirred at room temperature for 24
h. The reaction was monitored by TLC until no starting
material could be observed by TLC. The mixture was then
treated with saturated NH4Cl (3 mL) and water (15 mL) to
dissolve all inorganic salts. The aqueous phase was extracted
with dichloromethane, dried, and concentrated in vacuo. The
crude reaction was chromatographed (3% diethyl ether/hexane)
to afford 1.57 g (91% yield) of 5a as a 10:1 mixture of exo and
endo isomers: 13C NMR (50 MHz, CDCl3) δ 190.0 (C), 151.0
(C), 143.0 (C), 128.3 (CH), 123.7 (CH), 53.5 (q), 48.5 (q, minor),
48.7 (q, major), 48.3 (CH), 46.3 (CH, major), 45.8 (CH, minor),
40.2 (CH2, major), 39.2 (CH2, minor), 36.6 (CH2, minor), 36.2
(CH2, major), 35.1 (CH2), 29.5 (CH2, minor), 30.0 (CH2, minor),
27.1 (CH2, major), 20.4 (CH3), 20.2 (CH3), 19.4 (CH3, minor),
17.8 (CH3).
The mixture of diastereomers was crystallized from 35 mL
of 40% diethyl ether/hexane at -20 °C yielding 1.17 g of pure
5a (69% overall yield) as yellow needles: mp 98-99 °C; [R]D
) -88.2 (c 1.6, CHCl3); IR (film) νmax ) 2993, 2939, 1667, 1605
cm-1; 1H NMR (200 MHz, CDCl3) δ 8.31, 8.27, 8.15, 8.01 (broad
s BB′, 4H), 4.1 (dd, 1H), 2.4-2.8 (AB, 2H), 2.07 (s, 3H), 2.1-
1.1 (complex signal, 6H), 1.01 (s, 3H), 0.94 (s, 3H); 13C NMR
(50 MHz, CDCl3) δ 190.0 (C), 151.0 (C), 143.0 (C), 128.3 (CH),
123.7 (CH), 53.5 (C), 48.7 (C), 48.3 (CH), 46.3 (CH), 40.1 (CH2),
36.2 (CH2), 35.1 (CH2), 27.1 (CH2), 20.4 (CH3), 20.2 (CH3), 17.7
(CH3). Anal. Calcd for C18H23 NO3S2: C, 59.15; H, 6.34; N, 3.83;
S, 17.55. Found: C, 59.06; H, 6.36; N, 3.88; S, 17.31.
Exp er im en ta l Section
Gen er a l Meth od s. Melting points were determined in open
capillary tubes and are uncorrected. Infrared spectra were
recorded in Fourier transform mode, using film (NaCl) or KBr
pellet techniques. 1H NMR spectra were recorded at 200, 300,
or 500 MHz in CDCl3 unless specified otherwise, with tetra-
methylsilane as internal standard. J values are given in Hertz.
13C NMR spectra were recorded at 50.3, 75.4, or 125.7 MHz
in CDCl3 unless specified otherwise. Signal multiplicities were
established by DEPT experiments. In all cases, chemical shifts
are in ppm downfield of TMS. Elemental analyses were
performed by the Servei d’Ana`lisis Elementals del CSIC de
Barcelona, and exact mass measurements (HRMS) were
performed by the Laboratori d’Espectrometria de Masses del
CSIC de Barcelona or by the Servicio de Espectrometria de
Masas, Universidad de Co´rdoba. THF and diethyl ether were
distilled from sodium benzophenone ketyl. Dichloromethane
was distilled from CaH2. Hexamethyl phosphoramide (HMPA)
was purified by distillation from CaH2 at reduced pressure and
stored over 4 Å molecular sieves. All reactions were performed
in flame- or oven-dried glassware under a N2 or Ar atmosphere.
Silica gel (70-230 mesh) was used for column chromatography.
(1S)-Camphor-10-thiol 2,16 (1R)-10-methylthiocamphorthione
4a ,15 and 2,4,6-trimethylbenzyl bromide18 were prepared by
literature procedures. All other reagents were purchased
commercially and used without further purification.
(2R-exo)-10-Met h ylt h io-2-b or n a n et h iol [(1R,2R)-7,7-
Dim eth yl-1-m eth ylsu lfa n ylm eth ylbicyclo[2.2.1]h ep ta n e-
2-th iol] (1a ). A. To a cold (-20 °C) solution of (1R)-10-
methylthiocamphorthione (4a ) (3.5 g, 16.3 mmol) in diethyl
ether (40 mL) was added dropwise under nitrogen a solution
of DIBAL-H (80 mL, 1 M in hexane). The reaction was
monitored by TLC. After 4-7 h of stirring at -20 °C, cold
diethyl ether (50 mL) and saturated NH4Cl solution (40 mL)
were carefully added, and the mixture was slowly allowed to
warm to 0 °C. Then, 2 M HCl (ca. 60 mL) was added until two
clear phases were formed. The aqueous layer was extracted
with diethyl ether and the combined organic phases were
(1S,4R)-7,7-Dim eth yl-1-[(2,4,6-tr im eth ylben zylsu lfan yl)-
m eth yl]bicyclo[2.2.1]h ep ta n e-2-on e (3b). To a suspension
of sodium methoxide (1.2 g, 22.2 mmol) in methanol (20 mL)
was added a solution of 2 (3.4 g, 18.5 mmol) in methanol (20
mL). After the mixture was stirred 30 min at room tempera-
ture, a solution of 2,4,6-trimethylbenzyl bromide (4.9 g, 21.4
mmol) in methanol (20 mL) was added. After the mixture was
stirred for 4 h, the solvent was evaporated and the product
was chromatographed on silica gel eluting with hexane to
afford 4.7 g of 3b (81% yield): mp 73.3-73.7 °C; [R]D ) 30.6 (c
1
1.2, CHCl3); IR (film) νmax ) 2900, 1710, 1590, 1420 cm-1; H
NMR (200 MHz, CDCl3) δ 6.82 (broad s, 2H), 3.81 (s, 2H), 2.90,
2.59 (AB, J ) 13.4 Hz, 2H), 2.39 (s, 6H), 2.23 (s, 3H), 2.45-
1.20 (complex signal, 7H), 1.02 (s, 3H), 0.89 (s, 3H); 13C NMR
(50 MHz, CDCl3) δ 136.9 (2C), 136.3 (C), 131.2 (C), 128.9
(2CH), 62.0 (C), 47.7 (C), 43.4 (CH), 43.1 (CH2), 33.6 (CH2 ),
29.7 (CH2), 26.8 (CH2), 26.6 (CH2), 20.9 (CH3), 20.2 (CH3), 20.1
(CH3), 19.6 (2CH3) ppm; MS (CI-NH3) m/e ) 334 (M+ + 18,
100). Anal. Calcd for C20H28OS: C, 75.90; H, 8.92; S, 10.13.
Found: C, 75.90; H, 9.01; S, 10.18.

Asymmetric Pauson-Khand Reactions
J . Org. Chem., Vol. 66, No. 19, 2001 6407
(1S,4R)-7,7-Dim eth yl-1-[(2,4,6-tr im eth ylben zylsu lfan yl)-
m eth yl]bicyclo[2.2.1]h ep ta n e-2-th ion e (4b). To a solution
of 3b (1.85 g, 5.86 mmol) in toluene (5 mL) was added via
syringe a solution of Lawesson’s reagent (3.5 g, 8.8 mmol) in
toluene (25 mL). The reaction mixture was heated under reflux
(125 °C) during 12 h, cooled to room temperature, and filtered.
The solution was concentrated, and the crude reaction was
chromatographed eluting with diethyl ether/hexane (2.5%) to
Cl solution. The aqueous layer was extracted with CH2Cl2, and
the combined organic phases were dried (Na2SO4) and evapo-
rated. The crude product was purified by column chromatog-
raphy on Et3N-pretreated silica gel (2.5% v/v) eluting with
diethyl ether/hexane mixtures of increasing polarity to yield
0.31 g of 7a (81%) as an oil.
Meth od B. To a suspension of oil-free KH (1.74 mmol) in
anhydrous THF (2 mL) was added, under nitrogen, a solution
of 1a (0.25 g, 1.16 mmol) in THF (3 mL). After hydrogen
evolution subsided (15 min), the mixture was cooled to -50
°C and a solution of trichloroethylene (0.116 mL, 1.28 mmol)
in THF (2 mL) was added dropwise. Then, 20 µL of methanol
was added, and the reaction mixture was allowed to warm to
room temperature. After 1.5 h of stirring, the mixture was
cooled to -70 °C and treated with 1 mL of a 2.5 M solution of
n-BuLi in hexane (2.5 mmol). After 0.5 h at -70 °C, the
reaction was slowly warmed to room temperature and stirred
for 1.5 h. Then, it was quenched with methanol (0.5 mL) and
poured into 6 mL of saturated NH4Cl solution. The product
was extracted with hexane. The combined organic extracts
were washed with water, dried, evaporated, and purified by
column chromatography (diethyl ether/hexanes 2.5%) yielding
0.20 g of 7a (71%) as an oil: [R]D ) -86.6 (c 1.9 CDCl3); IR
(film) νmax ) 3280, 2950, 2030, 1450 cm-1; 1H NMR (200 MHz,
CDCl3) δ 3.41 (dd, J ) 9 Hz, J ′) 5.7 Hz, 1H), 2.85 (s, 1H),
2.75, 2.58 (AB, J ) 12 Hz, 2H), 2.15 (s, 3H), 2.1-0.97 (m, 7H),
0.93 (s, 3H), 0.86 (s, 3H); 13C NMR (75.4 MHz, CDCl3) δ 82.3
(CH), 75.6 (C), 55.9 (CH), 53.5 (C), 48.4 (C), 46.2 (CH), 39.2
(CH2), 35.5 (CH2), 34.7 (CH2), 26.9 (CH2), 20.5 (CH3), 20.2
(CH3), 17.7 (CH3); MS (EI) m/e ) 240 (M+, 47), 135 (100);
HRMS calcd for C13H20S2 240.1006, found 240.1003.
yield 1.43 g of thione 4b as an orange oil (74% yield): [R]D
)
+74.26 (c 1.4, CHCl3); IR (film) νmax ) 2960, 1620, 1590 cm-1
;
1H NMR (200 MHz, CDCl3) δ 6.83 (broad s, 2H), 3,78 (s, 2H),
3.19, 2.73 (AB, J ) 11.6 Hz, 2H), 2.39 (s, 6H), 2.24 (s, 3H),
2.45-1.20 (complex signal, 7H), 1.09 (s, 3H), 0.85 (s, 3H); 13
C
NMR (50 MHz, CDCl3) δ ) 136.9 (2C), 136.5 (C), 131.5 (C),
128.9 (2CH), 72.1 (C), 55.3 (CH2), 49.9 (C), 45.7 (CH), 33.8
(CH2), 32.8 (CH2), 30.6 (CH2), 27.0 (CH2), 20.9 (CH3), 20.7
(CH3), 20.2 (CH3), 19.7 (2CH3) ppm; HRMS Calcd for C20H28S2
332.1632, found 332.1639.
(1S,2R,4R)-7,7-Dim eth yl-1-[(2,4,6-tr im eth ylben zylsu l-
fa n yl)m eth yl]bicyclo [2.2.1]h ep ta n e-2-th iol (1b). To a cold
(-60 °C) solution of thione 4b (1.06 g, 3.2 mmol) in anhydrous
diethyl ether (15 mL) was added via cannula a solution of
DIBALH (16 mL, 1 M in hexane). The reaction mixture was
allowed to warm to -40 °C and stirred at this temperature
until the orange color disappeared. After 6 h, diethyl ether
(11 mL) and saturated NH4Cl (8 mL) were added dropwise
with caution. When the gas evolution was finished, the
temperature was warmed to 0 °C and the dense mixture was
treated with 33 mL of 5% HCl to dissolve all the aluminum
salts. The organic layer was separated, and the aqueous phase
was extracted with diethyl ether. The combined organic layers
were dried and evaporated, yielding a crude that was purified
by column chromatography (hexane) to afford 0.96 g of 1b as
a colorless oil (90% yield): [R]D ) -73.1 (c 1.5, CHCl3); IR (film)
(1S,2R)-2-(1,2-Dich lor ovin ylsu lfa n yl)-7.7-d im et h yl-1-
(2,4,6-t r im e t h ylb e n zylsu lfa n yl)m e t h ylb icyclo[2.2.1]-
h ep ta n e (8b). To a stirred suspension of oil-free KH (0.57 g,
5 mmol) in anhydrous THF (10 mL) was added dropwise a
solution of thiol 1b (1.1 g, 3.32 mmol) in THF (10 mL). After
hydrogen evolution (20 min), the mixture was cooled to -50
°C and a solution of trichloroethylene (0.47 mL, 5 mmol) in
THF (2 mL) was added dropwise, followed by 10 µL of
methanol. The reaction mixture was allowed to warm to room
temperature (1.5 h) and stirred for 1 h. The reaction was
quenched with 1 mL of methanol and concentrated in vacuo.
Then, the mixture was treated with saturated NH4Cl solution
(5 mL) and extracted with hexane. The combined organic
layers were dried and evaporated. The crude was chromato-
graphed eluting with hexane to afford 0.96 g of 8b (70%
yield): [R]D ) -103.7 (c 1.3, CHCl3); IR (film) νmax ) 2956,
νmax ) 2950, 1730, 1620, 1580, cm-1 1H NMR (300 MHz,
;
CDCl3) δ 6.85 (broad s, 2H), 3.84-3.79 (AB, J ) 11.2 Hz, 2H),
3.25-2.75 (m, 1H), 3.10,2.67 (AB, J ) 11.1 Hz, 2H), 2.43 (s, 6
H), 2.38, 2.35 (d, 1H), 2.26 (s, 3H), 1.95-1.00 (complex signal,
7H), 1.07 (s, 3H), 0.90 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
136.8 (2C), 136.4 (C), 131.3 (C), 129.0 (2CH), 51.9 (C), 48.8
(C), 46.2 (CH), 43.8 (CH), 39.5 (CH2), 34.7 (CH2), 34.2 (CH2),
32.5 (CH2), 27.2 (CH2), 21.1 (CH3), 20.9 (CH3), 20.1 (CH3), 19.7
(2CH3) ppm; MS (CI-NH3) m/e ) 352 (M+ + 18, 100), 335 (M+
+ 1, 29); HRMS calcd for C20H30S2 334.1789, found 334.1803.
(1S,2R)-2-(2,2-Diet h oxyet h ylsu lfa n yl)-7,7-d im et h yl-1-
m eth ylsu lfa n ylm eth ylbicyclo[2.2.1]h ep ta n e (6a ). To a
stirred suspension of sodium ethoxide in ethanol (47 mg, 2.05
mmol of sodium in 5 mL of ethanol) was added dropwise a
solution of 1a (420 mg, 2.05 mmol) in ethanol (9 mL). After
45 min of stirring at room temperature, 2-bromo-1,1-diethoxy-
ethane (0.31 mL, 2.05 mmol) was added. The reaction mixture
was stirred under reflux 1.5 h and then poured into ice/water.
The aqueous layer was extracted with dichloromethane, and
the combined organic phases were dried (Na2SO4) and evapo-
rated. The crude product was purified by column chromatog-
raphy on Et3N-pretreated silica gel 6a as an oil: [R]D ) -36.8
1613, 1459, 1389 cm-1 1H NMR (200 MHz, CDCl3) δ 6.82
;
(broad s, 2H), 6.32 (s, CDCl3 1H), 3.77 (s, 2H), 3.60 (t, 1H),
2.94, 2.65 (AB, J ) 12.2 Hz, 2H), 2. 39 (s, 6H), 2.23 (s, 3H),
2.01-1.15 (m, 7H), 1.03 (s, 3H), 0.90 (s, 3H); 13C NMR (50
MHz, CDCl3) δ 136.9 (2C), 136.3 (C), 131.8 (C), 131.3 (C), 128.9
(2CH), 117.4 (CH), 53.5 (C), 52.5 (CH), 48.7 (C), 46.3 (CH),
40.4 (CH2), 35.0 (CH2), 33.8 (CH2), 32.9 (CH2), 27.1 (CH2), 20.9
(CH3), 20.6 (2CH3), 19.6 (2CH3); HRMS calcd for C22H30S2Cl2
428.1166, found 428.1149.
(c 2.1 CHCl3); IR (film) νmax ) 2950, 2870, 1450, 1125 cm-1
;
1H NMR (200 MHz, CDCl3) δ 4.61 (t, J ) 5.7 Hz, 1H), 3.85-
3.49 (m, 4H), 2.97, 2.49 (AB, J ) 11.7 Hz, 2H), 2.95, 2.81 (ABX,
J ) 13.5 Hz, J ′) 5.4 Hz, 2H), 2.89 (dd, J ) 7.8 Hz, 1H), 2.12
(s, 3H), 1.98-1.08 (m, 7H), 1.21 (dt, J ) 6.9 Hz, J ′) 2.4 Hz,
6H), 0.93 (s, 3H), 0.83 (s, 3H); 13C NMR (75.4 MHz, CDCl3) δ
103.2 (CH), 62.0 (CH2), 61.5 (CH2), 53.6 (C), 53.5 (CH), 48.2
(C), 46.2 (CH), 41.6 (CH2), 38.6 (CH2), 36.2 (CH2), 34.9 (CH2),
27.2 (CH2), 20.51 (CH3), 20.45 (CH3), 17.6 (CH3), 15.3 (CH3),
15.3 (CH3) ppm.; MS (CI-NH3) m/e ) 350 (M+ + 18, 6), 333
(M+ + 1, 1), 215 (100).
(1S,2R)-2-E t h yn ylsu lfa n yl-7,7-d im et h yl-1-m et h ylsu l-
fa n ylm eth ylbicyclo[2.2.1]h ep ta n e (7a ). Meth od A. To a
cold (60 °C) LDA solution (prepared from diisopropylamine
(0.73 mL, 5.2 mmol) and n-BuLi (3.6 mL, 1.45 M in hexane,
5.2 mmol) in diethyl ether (30 mL)) was added a solution of
6a (0.52 g, 1.57 mmol) in diethyl ether (7 mL). The tempera-
ture was allowed to warm to 0 °C and the mixture stirred for
3 h. The reaction was quenched by addition of saturated NH4-
(1S,2R)-2-Eth yn ylsu lfan yl-7,7-dim eth yl-1-(2,4,6-tr im eth -
ylben zylsu lfa n yl)m eth ylbicyclo[2.2.1]h ep ta n e (7b). To a
cold (-80 °C) solution of dichloroolefine 8b (315 mg, 0.74 mmol)
in of anhydrous diethyl ether (12 mL) was added a solution of
n-BuLi (0.65 mL, 2.5 M in hexanes, 1.62 mmol). The mixture
was stirred for 30 min at -40 °C, 5 min at 0 °C, and 20 min
at room temperature. Then, the reaction mixture was treated
with saturated NH4Cl solution (2 mL), the organic phase was
separated, and the aqueous layer was extracted with diethyl
ether. The combined organic phases were dried and evaporated
to afford 255 mg of 7b (96% yield): [R]D ) -40.9 (c 1.5, CHCl3);
1
IR (film) νmax ) 3300, 2960, 2050, 1620 cm-1; H NMR (200
MHz, CDCl3) δ 6.83 (broad s, 2H), 3.82 (s, 2H), 3.5-3.38 (m,
1H), 2.85 (s, 1H), 2.85, 2.65 (AB, J ) 11 Hz, 2H), 2.42 (s, 6H),
2.24 (s, 3H), 2.2-1.05 (complex signal, 7H), 0.97 (s, 3H), 0.88
(s, 3H); 13C NMR (50 MHz, CDCl3) δ 137.0 (2C), 136.4 (C),
131.2 (C), 128.9 (2CH), 82.5 (CH), 55.9 (CH), 53.4 (C), 48.5
(C), 46.3 (CH), 39.4 (CH2), 34.9 (CH2), 33.6 (CH2), 33.0 (CH2),

6408 J . Org. Chem., Vol. 66, No. 19, 2001
Marchueta et al.
27.0 (CH2), 20.9 (CH3), 20.6 (CH3), 20.3 CH3), 19.7 (2CH3) ppm;
HRMS calcd for C22H30S2 358.1789, found 358.1781.
of stirring at room temperature, only the pentacarbonyl
complex could be observed by TLC. The solution was used
without further purification. Evaporation of a sample allowed
its characterization: [R]D ) -853.3 (c 0.4, CHCl3); IR (film)
νmax ) 2956, 2063, 2012, 1962, 1654 cm-1; 1H NMR (300 MHz,
CDCl3) δ 6.88 (broad s, 2H), 5.95 (s, 1H), 4.02,3.80 (AB, J )
13.0 Hz, 2H), 3.31 (d, J ) 11.1 Hz, 1H), 2.9, 2.8 (m, 1H), 2.35
(s, 6H), 2.27 (s, 3H), 2.1-0.8 (m, 8H), 1.01 (s, 3H), 0.54 (s, 3H)
ppm; 13C NMR (75 MHz, CDCl3) δ 137.7 (C), 137.3 (2C), 129,4
(2CH), 128.7 (C), 78.5 (CH), 57.5 (CH), 54.1 (C), 48.6 (C), 46.6
(CH), 41.2 (CH2), 38.6 (CH2), 36.1 (CH2), 34.4 (CH2), 26.9 (CH2),
20.1 (2CH3), 20.1 (CH3), 19.8 (CH3) ppm; MS (FAB, NBA) 588
(M+ - CO, 2), 560 (M+ - 2CO, 30), 476 (M+ - 5CO, 100).
Gen er a l P r oced u r es for P a u son -Kh a n d Rea ction s.
Cycloa d d u ct of 7a w ith Nor bor n a d ien e. Rea ction Con -
d ition s A. To a solution of alkynyl thioether 7a (40 mg, 0.17
mmol) in hexanes (4 mL) in CO atmosphere was added Co2-
(CO)8 (61 mg, 0.18 mmol) in one portion. After 15 min of
stirring at room temperature, the dark red solution was cooled
to 0 °C, and 2,5-norbornadiene (0.17 mL, 1.7 mmol) was added.
The mixture was stored at 0-5 °C during 23 days. Then, the
crude reaction was filtered and the solvent was evaporated.
Flash column chromatography (2% v/v NEt3 pretreated SiO2,
hexanes/diethyl ether) afforded 19 mg (31% yield, two steps)
of 11a (67:33 diastereomeric ratio).
Rea ction Con d ition s B. To a solution of thioether 7a (40
mg, 0.17 mmol) in dichloromethane (4 mL) was added Co2-
(CO)8 (61 mg, 0.18 mmol) in one portion. After 15 min of
stirring at room temperature, NMO (119 mg, 1.02 mmol) was
added. After 10 min of stirring, the solution was cooled to 0
°C, and 2,5-norbornadiene (0.17 mL, 1.7 mmol) was added. The
mixture was stirred for 24 h at 0 °C, filtered, and chromato-
graphed yielding 39 mg (64% yield) of a 2.1:1 diastereomeric
mixture of adducts 11a . The same reaction conditions but
performing the reaction at -20 °C during 60 h afforded 41
mg (67% yield, two steps) of 11a (50:50 diastereomeric ratio).
Dicob a lt H exa ca r b on yl Com p lex of (1S,2R)-2-E t h -
ynylsulfanyl-7,7-dimethyl-1-(methylsulfanylmethyl)bicyclo-
[2.2.1]h ep ta n e (9a ). To a solution of 7a (80 mg, 0.33 mmol)
in hexanes (8 mL) was added, under CO atmosphere, Co2(CO)8
(118 mg, 0.35 mmol) in one portion. The mixture was stirred
for 15 min at room temperature (the reaction can be con-
veniently monitored by TLC). Then, it was filtered through a
short Al2O3 pad eluting with hexane. The solvent was evapo-
rated in vacuo yielding 160 mg (91%) of 9a : IR (film) νmax
)
2960, 2100, 2060, 2030, 1970 cm-1; 1H NMR (200 MHz, CDCl3)
δ 6.36 (s, 1H), 3.13 (dd, J ) 9 Hz, J ′) 6.3 Hz, 1H), 2.75, 2.57
(AB, J ) 11.7 Hz, 2H), 2.21-1.2 (m, 7H), 2.09 (s, 3H), 0.98 (s,
3H), 0.90 (s, 3H);13C NMR (75.4 MHz, CDCl3) δ 199.3 (C), 77.97
(C), 58.7 (CH), 53.9 (C), 48.4 (C), 46.4 (CH), 41.4 (CH2), 36.4
(CH2), 35.1 (CH2), 27.4 (CH2), 20.8 (CH3), 20.1 (CH3), 17.5
(CH3).
Dicob a lt H exa ca r b on yl Com p lex of (1S,2R)-2-E t h -
yn ylsu lfa n yl-7,7-d im et h yl-1-[(2,4,6-t r im et h ylb en zylsu l-
fa n yl)m eth yl]bicyclo[2.2.1]h ep ta n e (9b). To a solution of
7b (0.2 g, 0.57 mmol) in hexanes (9 mL) was added, under N2,
Co2(CO)8 (0.21 g, 0.61 mmol) in one portion. The mixture was
stirred for 20 min at room temperature (the reaction can be
conveniently monitored by TLC). The resulting solution was
used without further purification in the subsequent reactions.
Evaporation of a sample allowed its characterization although
some pentacarbonyl complex 10b was observed in the spec-
1
tra: IR (film) νmax ) 2958, 2092, 2063, 2012, 1962 cm-1; H
NMR (300 MHz, CDCl3) δ 6.81 (broad s, 2H), 6.34 (s, 1H),
3.80-3.67 (AB, J ) 11.55 Hz, 2H), 3.15 (dd, J ) 8.1 Hz, J ′)4.8
Hz, 1H), 2.95, 2.49 (AB, J ) 12.5 Hz, 2H), 2.36 (s, 6H), 2.23
(s, 3H), 2.2-0.8 (m, 7H), 0.99 (s, 3H), 0.88 (s, 3H) ppm; 13C
NMR (75 MHz, CDCl3) δ 136.8 (C), 136.2 (2C), 131.6 (C), 128.8
(2CH), 78.0 (CH), 58.8 (CH), 54.3 (C), 48.3 (C), 46.6 (CH), 41.3
(CH2), 35.2 (CH2), 34.4 (CH2), 33.1 (CH2), 27.3 (CH2), 20.9
(CH3), 20.2 (CH3), 20.1 (2CH3), 19.7 (CH3) ppm.
Rea ction Con d ition s C. To a solution of a thermally
generated pentacarbonyl complex 10a (146 mg, 0.29 mmol) in
hexanes (6 mL) at 0 °C was added 2,5-norbornadiene (0.29 mL,
2.9 mmol). The reaction was stirred 24 h at 0 °C. The mixture
was filtered through Celite washing with CH2Cl2. The solution
was concentrated and chromatographed to afford 55 mg (52%
yield) of a 92:8 diastereomeric mixture of 11a . The same
reaction conditions but performing the reaction at -20 °C
during 6 days afforded 57 mg (53% yield) of 11a (93:7
diastereomeric ratio).
Rea ction Con d ition s D. To a solution of an NMO-
generated pentacarbonyl complex 10a (451 mg, 0.9 mmol) in
hexanes (17 mL) was added 2,5-norbornadiene (0.95 mL, 9
mmol) at -10 °C. The reaction was stirred for 76 h at this
temperature. The mixture was filtered through Celite, con-
centrated, and chromatographed to afford 211 mg (65% yield)
of 11a (95:5 diastereomeric ratio).
4-[(1S,2R,4R)-7,7-Dim et h yl-1-m et h ylsu lfa n ylm et h yl-
bicyclo[2.2.1]h ep t-2-ylsu lfa n yl]tr icyclo[5.2.1.02,6]d eca -4,8-
d ien -3-on e (11a ): IR (film) νmax ) 3060, 2940, 1700, 1560
cm-1; 1H NMR (300 MHz, CDCl3) δ 7.15 (minor), 7.10 (major)
(d, J ) 3 Hz, 1H), 6.27-6.17 (m, 2H), 3.39 (minor), 3.33 (major)
(dd, J ) 8.7 Hz, J ′) 5.7 Hz, 1H), 2.92 (s, 1H), 2.84-2.5 (m,
2H), 2.77 (s, 1H), 2.69 (s, 1H), 2.36-2.34 (m, 1H), 2.08 (major),
2.05 (minor) (s, 3H), 2.04-1.18 (m, 9H), 1.02 (major), 0.99
(minor) (s, 3H), 0.88 (major), 0.87 (minor) (s, 3H); 13C NMR
(75.4 MHz, CDCl3) δ 206.1 (C), 153.7 (CH, minor), 153.5 (CH),
146.2 (C), 146.1 (C, minor), 138.3 (CH), 137.1 (CH), 53.7 (C),
52.6 (CH), 52.5 (CH, minor), 50.5 (CH), 50.2 (CH, minor), 48.7
(C), 48.6 (CH, minor), 48.6 (CH), 46.4 (CH), 46.3 (CH, minor),
44.0 (CH, minor), 43.9 (CH), 43.7 (CH, minor), 43.7 (CH), 41.6
(CH2), 41.5 (CH2, minor), 40.8 (CH2), 40.7 (CH2, minor), 35.9
(CH2, minor), 35.8 (CH2), 35.3 (CH2), 35.1 (CH2, minor), 27.4
(CH2), 27.3 (CH2, minor), 20.7 (CH3), 20.7 (CH3), 20.6 (CH3,
minor), 17.8 (CH3); MS (EI) m/e ) 360 (M+,16), 183 (100);
HRMS calcd for C21H28OS2 360.1582, found 360.1580; HPLC
analysis (Nucleosil C18, 25 cm) MeOH/H2O 80/20 (1 mL/min,
λ ) 220 nm) tR (major) ) 16.5 min, tR (minor) ) 17.3 min.
Dicob a lt P en t a ca r b on yl Com p lex of (1S,2R,4R)-2-
Eth yn ylsu lfa n yl-7,7-d im eth yl-1-(m eth ylsu lfa n ylm eth yl)-
bicyclo[2.2.1]h ep ta n e (10a ). Th er m a l Gen er a tion . A hex-
ane solution of dicobalt hexacarbonyl complex 9a prepared
from 7a (80 mg, 0.33 mmol) was heated at 55 °C under a
stream of anhydrous nitrogen during 1 h (the reaction can be
conveniently monitored by TLC; the red spot of the hexacar-
bonyl complex disappears while a brown, more polar complex
is formed). The mixture was filtered through Al2O3 eluting with
hexanes, and the solvent was removed in vacuo to afford 146
mg (89% yield, two steps) of the dicobalt pentacarbonyl
complex 10a .
NMO P r om oted . To a solution of dicobalt hexacarbonyl
complex 9a prepared from 7a (60 mg, 0.25 mmol) in CH2Cl2
(5 mL) was added, under nitrogen atmosphere, NMO (88 mg,
3 equiv, 0.75 mmol). After 10 min of stirring at room temper-
ature, only the pentacarbonyl complex could be observed by
TLC. Pentane (15 mL) was added to the mixture, and the
solution was concentrated to a final volume of ca. 5-10 mL.
The crude was chromatographed on Al2O3 eluting with pen-
tane, yielding 80 mg (65% yield, two steps) of 10a : IR (film)
νmax ) 2950, 2070, 2005, 1965 cm-1; 1H NMR (200 MHz, CDCl3)
δ 5.89 (s, 1H), 3.51, 2.44 (AB, J ) 11.4 Hz, 2H), 2.94 (dd, J )
9 Hz, J ′ ) 6.3 Hz, 1H), 2.45 (s, 3H), 2-1.26 (m, 6H), 1.07 (s,
3H), 0.98-0.95 (m, 1H), 0.89 (s, 3H); 13C NMR (75.4 MHz,
CDCl3) δ 200 (C), 77.8 (C), 57.7 (CH), 53.9 (C), 48.9 (C), 46.5
(CH), 44.4 (CH2), 36.1 (CH2), 34.8 (CH2), 28.7 (CH3), 27.1 (CH2),
20.5 (CH3), 19.8 (CH3).
Dicob a lt P en t a ca r b on yl Com p lex of (1S,2R,4R)-2-
Eth yn ylsu lfan yl-7,7-dim eth yl-1-[(2,4,6-tr im eth ylben zylsu l-
fa n yl)m eth yl]bicyclo[2.2.1]h ep ta n e (10b). Th er m a l Gen -
er a t ion . The procedure described in the generation of 10a
starting from 7b (0.2 g, 0.57 mmol) and Co2(CO)8 (0.21 g, 0.61
mmol) afforded a solution of 10b that was used without
purification.
NMO P r om oted . To a solution of hexacarbonyl complex
9b prepared as described above from 7b (0.119 g, 0.33 mmol)
was added NMO (0.24 g, 2.06 mmols, 6 equiv). After 20 min

Asymmetric Pauson-Khand Reactions
J . Org. Chem., Vol. 66, No. 19, 2001 6409
P a u son -Kh a n d R ea ct ion of 7a w it h Nor b or n en e.
Procedure B using as reagents 7a (50 mg, 0.21 mmol), Co2-
(CO)8 (75 mg, 0.22 mmol), NMO (147 mg, 1.25 mmol), and
norbornene (197 mg, 2.1 mmol) was followed. The reaction was
conducted at 0 °C during 48 h affording 50 mg (66% yield, two
mmol) to give 156 mg of an oil that was immediately used in
the next step without characterization.
(1R,2R,5S,6S,7S)-5-Bu t ylt r icyclo[5.2.1.02,6]-8-d ecen -3-
on e [(-)-14].10,23 F r om 13a . A solution of SmI2 was prepared
as follows: Samarium powder (259 mg, 1.72 mmol) and 1,2-
diiodoethane (485 mg, 1.72 mmol) were placed under argon
in a Schlenk flask.. Then THF (2.6 mL) was added and the
mixture vigorously stirred 2 h at room temperature. The crude
reaction 13a was dissolved in a mixture of THF/MeOH (2:1)
and added via cannula to a freshly prepared, cold (0 °C) SmI2
solution in THF. After 10-15 min, no starting material was
observed by TLC. Then, wet THF, hexane, and saturated Na2-
CO3 solution were sequentially added. The phases were
separated, and the aqueous layer was extracted with diethyl
ether. The combined organic extracts were dried (Na2SO4) and
evaporated yielding 0.18 g of a residue that was chromato-
graphed eluting with hexane/diethyl ether mixtures to afford
50 mg (46% yield, two steps) of (-)-14 [[R]D ) -115.8 (c 1.0,
CHCl3)] along with 20 mg of thiol 1a (17% yield), 47 mg of
disulfide (41% yield) and 37 mg of 5-butyl-4-hydroxytricyclo-
[5.2.1.02,6]deca-4,8-dien-3-one.
steps) of 12a (37:63 diastereomeric ratio as determined by 13
C
NMR).
Procedure C using as reagents 7a (50 mg, 0.21 mmol), Co2-
(CO)8 (75 mg, 0.22 mmol), and norbornene (197 mg, 2.1 mmol)
was followed. The reaction was conducted at 0 °C during 48 h
affording 34 mg (45% yield, two steps) of 12a (82:18 diaster-
eomeric ratio as determined by 13C NMR).
Procedure D using as reagents 10a (83 mg, 0.17 mmol), and
norbornene (167 mg, 1.7 mmol) was followed. The reaction was
conducted at -10 °C during 120 h affording 40 mg (66% yield,
two steps) of 12a (86:14 diastereomeric ratio as determined
by 13C NMR).
4-[(1S,2R,4R)-7,7-Dim et h yl-1-m et h ylsu lfa n ylm et h yl-
b icyclo[2.2.1]h ep t -2-ylsu lfa n yl]t r icyclo[5.2.1.02,6]d ec-4-
en -3-on e (12a ): IR (film) νmax ) 2960, 2880, 1705, 1570 cm-1
;
1H NMR (300 MHz, CDCl3) δ 7.08 (minor), 7.03 (major) (d, J
) 3 Hz, 1H), 3.39 (minor), 3.33 (major) (dd, J ) 9 Hz, J ′ ) 5.7
Hz, 1H), 2.83-2.78 (m, 1H), 2.66-2.63 (m, 1H), 2.6-2.5 (m,
1H), 2.41 (d, J ) 3.6 Hz, 1H), 2.26 (d, J ) 4.5 Hz, 1H), 2.18 (d,
J ) 4 Hz, 1H), 2.08 (major), 2.06 (minor) (s, 3H), 2.06-0.9 (m,
13H), 1.02 (major), 0.99 (minor) (s, 3H), 0.88 (major), 0.87
(minor) (s, 3H); 13C NMR (75.4 MHz, CDCl3) δ 207.4 (C), 153.5
(CH, minor), 153.2 (CH), 145.2 (C), 53.85 (CH, minor), 53.82
(CH), 53.6 (C), 50.4 (CH), 50.2 (CH, minor), 49.26 (CH), 49.20
(CH, minor), 48.63 (C), 48.58 (C, minor), 46.28 (CH), 46.23 (CH,
minor), 40.7 (CH2), 40.6 (CH2, minor), 39.3 (CH, minor), 39.2
(CH), 38.6 (CH, minor), 38.6 (CH), 35.8 (CH2, minor), 35.7
(CH2), 35.2 (CH2), 35.0 (CH2, minor), 31.3 (CH2), 31.3 (CH2,
minor), 28.8 (CH2, minor), 28.8 (CH2), 28.3 (CH2, minor), 28.3
(CH2), 27.2 (CH2), 27.2 (CH2, minor), 20.5 (CH3, minor), 20.6
F r om 13b. The crude reaction 13b was treated with 4 equiv
of SmI2 solution in THF prepared as described. Once the
reaction with SmI2 was complete, it was quenched by bubbling
oxygen into the reaction followed by addition of wet THF (4
mL) and saturated 10/1 K2CO3/potassium tartrate solution (4
mL). The mixture was extracted with hexane, and the organic
phases were dried (MgSO4), evaporated, and chromatographed
on NEt3 pretreated SiO2 eluting with 0.5% diethyl ether/
hexane to afford 38 mg (64% yield, two steps) of (-)-14 along
with 75 mg (59%) of thiol 1b. The spectroscopic data of 14 were
fully coincident with those described in ref 10.
(-)-(S)-4-Bu tyl-2-cyclop en ten on e (-)-15.10,24 In a round-
bottomed flask under nitrogen were placed (-)-14 (130 mg,
0.63 mmol), maleic anhydride (0.3 g, 3.1 mmol), and CH2Cl2
(4 mL). To this solution was added MeAlCl2 (1 M in hexane,
0.7 mL, 0.7 mmol) via syringe. The reaction mixture was then
heated at 55 °C for 2 h, cooled to room temperature, quenched
with saturated K2CO3 solution, and filtered through Celite.
The residue was purified by flash column chromatography (2%
v/v NEt3 pretreated SiO2, hexane/diethyl ether) and afforded
85 mg (90%) of (-)-(S)-4-butyl-2-cyclopentenone as a colorless
oil. Enantiomeric purity: CG (R-Dex 120) 30 m, 0.25 mm i.d.
45 min isocratic at 70 °C, then 0.2 °C/min until 90 °C; tR (min)
) 128.8 (maj), 133.5 (min). The product obtained from a sample
of 11a of 95% de showed an enantiomeric purity of 96% ee.
The product obtained from 11b (96% de) showed an enantio-
meric purity of 94% ee. Spectroscopic data of 15 were fully
coincident with those described in ref 10.
(CH3), 20.6 (CH3), 17.6 (CH3); MS (CI-CH4) m/e ) 363 (M+
1, 100).
+
(1R ,2R ,6S ,7S )-5-Bu t yl-4-[(1S ,2R ,4R )-7,7-d im e t h yl-1-
m et h ylsu lfa n ylm et h ylb icyclo[2.2.1]h ep t -2-ylsu lfa n yl]-
tr icyclo[5.2.1.02,6]d ec-8-en -3-on e (13a ). A solution of Bu2-
CuCNLi2 in diethyl ether was prepared as follows: To a cold
(-50 °C) suspension of CuCN (95 mg, 1.06 mmol) in deoxy-
genated diethyl ether (12 mL) was added, under argon, n-BuLi
(1.6 M in hexanes, 1.32 mL, 2.12 mmol), and the resulting
solution was stirred for 30 min at -30 °C. To this cuprate
solution, cooled to -78 °C, was added via cannula under argon
a solution of enone 11a (0.19 g, 0.53 mmol) in diethyl ether (2
mL). After 10 min of stirring, wet but deoxygenated diethyl
ether (6 mL) was added. The reaction mixture was allowed to
warm to 0 °C, and 10% NH4OH in saturated NH4Cl solution
(20 mL) was added. The reaction was vigorously stirred at
room temperature 30 min and extracted with dichloromethane.
The combined organic phases were dried (Na2SO4) and evapo-
rated yielding 0.2 g of an oil that was immediately used in
the next step without characterization.
Ack n ow led gm en t. Financial support from DGICYT
(PB98-1246) and from CIRIT (2000SGR-00019) is grate-
fully acknowledged.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
cobalt carbonyl complexes 9a ,b and 10a ,b. Experimental
procedures and product characterization of the Pauson-Khand
reactions of 7b. This material is available free of charge via
the Internet at http://pubs.acs.org.
(1R,2R,6S,7S)-5-Bu tyl-4-[(1S,2R,4R)-7,7-dim eth yl-1-(2,4,6-
t r im e t h ylb e n zylsu lfa n yl)m e t h ylb icyclo[2.2.1]h e p t -2-
ylsu lfa n yl]tr icyclo[5.2.1.02,6]d ec-8-en -3-on e (13b). The cu-
prate addition was performed following the procedure described
above for 13a but starting from adduct 11b (139 mg, 0.29
J O015790P