The tert-butylsulfinyl group as a highly efficient chiral auxiliary in asymmetric Pauson-Khand reactions [4]

Full text of DOI:10.1021/ja990546p

J. Am. Chem. Soc. 1999, 121, 7411-7412
7411
leading to conjugated dienes instead of cyclopentenones.12 Against
these precedents, the enyne dicobalt complexes of 1-3, readily
formed by treatment of 1-3 with Co2(CO)8 in CH2Cl2 at room
temperature, reacted under the usual thermal (CH3CN, 80 °C) or
amine N-oxide promoted conditions [6 equiv of N-methylmor-
pholine N-oxide (NMO), CH2Cl2, room temperature] to give the
PK diastereomeric aducts A and B13 in reasonable yields (46-
55%, Table 1) as the only isolated products after flash chroma-
tography. However, the most interesting outcome concerns the
dependence of the stereoselectivity with the substitution at
sulfur: although the cyclizations of both the p-tolylsulfoxide 1
and the potentially chelating o-dimethylaminophenylsulfoxide9,14
2 were moderately stereoselective, leading to a 3:1 mixture of A
and B isomers (compounds 4 and 5, entries 1-3), the PK reaction
of the tert-butyl sulfoxide 3 occurred with Very high stereocontrol
affording a crude mixture in which the B isomer could not be
The tert-Butylsulfinyl Group as a Highly Efficient
Chiral Auxiliary in Asymmetric Pauson-Khand
Reactions
Javier Adrio and Juan C. Carretero*
Departamento de Qu´ımica Orga´nica
Facultad de Ciencias
UniVersidad Auto´noma de Madrid, 28049 Madrid, Spain
ReceiVed February 22, 1999
The stoichiometric reaction of an alkene and an alkyne-
dicobalt hexacarbonyl complex, known as the Pauson-Khand
(PK) reaction, has become one of the most powerful methods
for cyclopentenone synthesis.1 Furthermore, the recent develop-
ments of new reaction conditions and catalytic versions of this
reaction are even increasing its synthetic utility.2 Regarding the
synthesis of optically active cyclopentenones by asymmetric PK
reactions, three different approaches have been envisaged: (a)
the use of a chiral auxiliary covalently attached either to the
alkyne3 or to the alkene component,4 (b) the generation of a chiral
C2Co2 core,5 and (c) the addition of a chiral promoter (a chiral
amine oxide).6 Up till now, the first approach, mainly developed
by Perica`s et al.,3,4 has led to the best results, especially when
the chiral auxiliary is bound to the alkyne.3 Although the sulfinyl
group has been widely used as a chiral auxiliary in important
reactions such as Diels-Alder reactions or nucleophile additions,7
it has been scarcely applied in transition-metal-catalyzed reac-
tions.8 In particular, we have recently reported the first examples
of vinyl sulfoxides in asymmetric Heck reactions.9 Extending its
use to other cornerstone metal-mediated reactions, here we report
that appropriately substituted sulfinylated enynes undergo in-
tramolecular PK reactions with exceptionally high stereoselec-
tivities.10
1
detected by H NMR (A:B ratio >98:<2, entries 4-5).
To apply this procedure in asymmetric synthesis, a variety of
(S)-tert-butylsulfinylated enynes (ee g96% by NMR)15 were
prepared by olefination of the corresponding alkynyl aldehyde
with (R)-diethyl tert-butylsulfinylmethylphosphonate (7, ee 98.5%
by HPLC).15 In Table 2 are summarized the results of the thermal
PK reactions of the major trans enynes (S)-8-13.
Remarkably, with all the terminal alkynes (entries 1-5) the
reactions took place again with complete stereoselectivity, provid-
ing the corresponding A adduct (6A and 14A-17A)13 as the only
isolated isomer (A:B ratio >98:<2). Furthermore, the optical
purity of the adducts (ee g96% by NMR)16 was as high as the
starting enynes, proving that the PK reactions occurred without
racemization at sulfur.10 Concerning the synthetic scope of the
method, the yields were somewhat higher in the case of the 4,4-
disubstituted 1,6-enynes 8 and 9 (65% and 60%, entries 2 and 3,
respectively) than in the unsubstituted case 3 (50%, entry 1) likely
due to the beneficial gem-dialkyl effect. Interestingly, the
procedure can also be applied to the synthesis of azabicyclo[3.3.0]-
octenones as is shown by the reaction of the aza-enyne 10 (60%,
First, to check the viability of the intramolecular PK reaction
of R,â-unsaturated sulfoxides, a series of differently substituted
racemic trans 1-sulfinylhept-1-en-6-ynes was prepared11 (sub-
strates 1-3). It is well-documented that alkenes substituted with
electron-withdrawing groups are unsuitable substrates in PK
reactions, because after the olefin insertion step the mechanism
evolves by â-H elimination rather than by carbonyl insertion,
(8) For sulfoxides as chiral auxiliaries in transition-metal-catalyzed reac-
tions, see: (a) Paley, R. S.; Rubio, M. B.; Ferna´ndez de la Pradilla, R.; Dorado,
R.; Hundal, G.; Mart´ınez-Ripoll, M. Organometallics 1996, 15, 4672. (b)
Villar, J. M.; Delgado, A.; Llebaria, A.; Moreto´, J. M. Tetrahedron: Asymmetry
1995, 6, 665. (c) Hiroi, K.; Arinaga, Y. Tetrahedron Lett. 1994, 35, 153. (d)
Chaigne, F.; Gotteland, J.-P.; Malacria, M. Tetrahedron Lett. 1989, 30, 1989.
For a recent report on the use of sulfoxides as chiral ligands, see: Hiroi, K.;
Suzuki, Y.; Kawagishi, R. Tetrahedron Lett. 1999, 40, 715 and references
therein.
(1) For recent reviews, see: (a) Geis, O.; Schmalz, H.-G. Angew. Chem.,
Int. Ed. Engl. 1998, 37, 911. (b) Schore, N. E. In ComprehensiVe Organo-
metallic Chemistry II; Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds.;
Elsevier: New York, 1995; Vol. 12, p 703.
(9) D´ıaz Buezo, N.; Alonso, I.; Carretero, J. C. J. Am. Chem. Soc. 1998,
120, 7129.
(2) See, for instance: (a) Belanger, D. B.; O’Mahony, D. J. R.; Livinghouse
Tetrahedron Lett. 1998, 39, 7637 (and 7641). (b) Sugihara, T.; Yamaguchi,
M. Synlett 1998, 1384. (c) Sugihara, T.; Yamaguchi, M. J. Am. Chem. Soc.
1998, 120, 10782 and references therein.
(3) Complete asymmetric inductions have been reported in the PK reaction
of alkynoyl derivatives of Oppolzer’s sultam with norbornadiene, see:
Fonquerna, S.; Moyano, A.; Perica`s, M. A.; Riera, A. J. Am. Chem. Soc. 1997,
119, 10225. See, also: Verdaguer, X.; Va´zquez, J.; Fuster, G.; Bernardes-
Ge´nisson, V.; Greene, A. E.; Moyano, A.; Perica`s, M. A.; Riera, A. J. Org.
Chem. 1998, 63, 7037 and references therein.
(4) (a) The best diastereoselectivities (up to 10:1 isomer ratio) have been
reported from alkenyl ethers derived from optically pure trans-2-phenylcy-
clohexanol, see: 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. See, also:
(b) Verdaguer, X.; Moyano, A.; Perica`s, M. A.; Riera, A.; Greene, A. E.;
Piniella, J. F.; Alvarez-Larena, A. J. Organomet. Chem. 1992, 433, 305. (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.
(5) (a) Brunner, H.; Niedernhuber, A. Tetrahedron: Asymmetry 1990, 1,
711. (b) Hay, A. M.; Kerr, W. J.; Kirk, G. G.; Middlemiss, D. Organometallics
1995, 14, 4986. (c) Park, H.-J.; Lee, B. Y.; Kang, Y. K.; Chung, Y. K.
Organometallics 1995, 14, 3104.
(10) During the editorial review process several examples of intermolecular
PK reactions of optically pure alkynyl p-tolyl sulfoxides have been pub-
lished: Montenegro, E.; Moyano, A.; Perica`s, M. A.; Riera, A.; Alvarez-
Larena, A.; Piniella, J.-F. Tetrahedron: Asymmetry 1999, 10, 457.
(11) Racemic trans enynes 1-3 were readily prepared from 5-hexynal by
either Wadsworth-Emmons olefination with a (()-sulfinylmethyl phosphonate
or by condensation with the anion of a (()-aryl methyl sulfoxide and further
dehydratation (MsCl, Et3N; then DBU). Both methods afforded cis + trans
mixtures of olefins (the trans R,â-sulfoxide as the major one) which were
easily separated by flash chromatography. Similarly, (R)-1 was prepared from
the readily available (R)-methyl p-tolyl sulfoxide (Solladie´, G.; Hunt, J.;
Girardin, A. Synthesis 1987, 13).
(12) (a) Smit, W. A.; Gybin, A. S.; Shashkov, A. S.; Strychkov, Y. T.;
Kizmina, L. G.; Mikaelian, G. S.; Caple, R.; Swanson, E. D. Tetrahedron
Lett. 1986, 27, 1241. (b) Khand, I. U.; Pauson, P. L. Heterocycles 1978, 11,
59. To the best of our knowledge, only some specific alkynyl enones have
led to successful results in cobalt-catalyzed PK reactions, see: (c) Veretenov,
A. L.; Smit, W. A.; Vorontsova, L. G.; Kurella, M. G.; Caple, R.; Gybin, A.
S. Tetrahedron Lett. 1991, 32, 2109. See, also: (d) Costa, M.; Mor, A.
Tetrahedron Lett. 1995, 36, 2867.
(13) The configuration of A and B isomers was established first by X-ray
difraction of enantiopure 6A (see Supporting Information) and confirmed
afterwards by chemical correlations: (a) The oxidation of either 4A or 4B
with MCPBA led to the same sulfone. (b) The desulfinylation (Zn, NH4Cl,
THF) of the enantiopure major isomer 4A obtained from the PK reaction of
(R)-1, and that of 6A obtained from (S)-3, led to opposite enantiomers of
enone 21a (Table 3). (c) The desulfinylation of enantiopure 14A [from (S)-8]
afforded the (R) enantiomer of the known enantiopure enone 21b19 (Table 3).
(6) (a) Kerr, W. J.; Kirk, G. G.; Middlemiss, D. Synlett 1995, 1085. (b)
Derdau, V.; Laschat, S.; Jones, P. G. Heterocycles 1998, 48, 1445. For an
outstanding catalytic and enantioselective titanocene-catalyzed cyclocarbo-
nylation of enynes, see: Hicks, F. A.; Buchwald, S. L. J. Am. Chem. Soc.
1996, 118, 11688.
(7) For a review, see: Carren˜o, C. Chem. ReV. 1995, 95, 1717.
10.1021/ja990546p CCC: $18.00 © 1999 American Chemical Society
Published on Web 08/03/1999

7412 J. Am. Chem. Soc., Vol. 121, No. 32, 1999
Table 1. PK Reactions of (() Trans Enynes 1-3
Communications to the Editor
Table 3. Optically Active Enones 21 Obtained by Desulfinylation
of A Adducts
yieldd
(%)
enyne
R
adduct
enone
[R]Da 21
A:B
enyne conditionsa,b adduct ratioc
entry
R
(R)-1
(S)-3
(S)-8
(S)-9
H
H
4A
6A
14A
15A
(S)-21a
(R)-21a
(R)-21b
(R)-21cc
-40 (c 0.6)
+41 (c 0.6)
+139 (c 0.6)b
+88 (c 0.4)
1
2
3
4
5
p-Tol
p-Tol
o-Me2NC6H4
t-Bu
1
1
2
3
3
a
b
a
a
b
4
4
5
6
6
75:25
73:27
71:29
>98:<2
>98:<2
52
49
55
50
46
Me
CO2Et
a
c
In CHCl3. b [R]D (ref 19) (S)-21b ) -141 (c 0.2, CHCl3). ee
t-Bu
96.5% by HPLC (Chiralpak AS column).
a CH3CN, 80 °C. b NMO‚H2O (6 equiv), CH2Cl2, room temperature.
c By 1H NMR on the crude mixtures after filtration of the cobalt
byproducts. d In pure adducts A and B. Isomers A and B were separated
by flash chromatography.
As the final step of this sulfinyl-mediated asymmetric PK
reaction, the reductive cleavage of the chiral auxiliary was simply
performed by desulfinylation of the A adducts with activated
zinc18 (sat NH4Cl, THF, room temperature) leading in very high
yields (92-96%) to the corresponding optically active bicyclo-
[3.3.0]oct-1-en-3-ones 21 (Table 3). In particular, the (R) enan-
tiomer of the known enantiomerically pure enone 21b19 was
obtained by desulfinylation of 14A, confirming otherwise the
configurational assignment of the PK adducts previously estab-
lished by X-ray difraction.13 Finally, the very high optical purity
of enones 21 [ee 96.5% by HPLC for (R)-21c] was confirmed,
proving that, as expected, the desulfinylation step occurs without
racemization at C-5.
In summary, it has been demonstrated that the sulfinyl group
can be used as a novel and efficient chiral auxiliary in intramo-
lecular asymmetric PK reactions. Especially, the PK reactions of
the readily available (S)-1-tert-butylsulfinylhept-1-en-6-ynes af-
forded a single isomer (dr >96%). This exceptionally high
stereoselectivity, coupled with the efficient final chiral auxiliary
elimination step, makes this procedure very appealing for the
synthesis of enantiopure bicyclo[3.3.0]oct-1-en-3-ones.
Table 2. Thermal PK Reactions of (S) Trans Enynes 3 and 8-13
entry enyne
X
n
R
T (°C) adduct yielda (%)
1
2
3
4
5
6
7
3
8
9
10
11
12
13
CH2
CMe2
C(CO2Et)2
NBOC
C(CO2Et)2
CH2
1
1
1
1
2
1
1
H
H
H
H
H
TMS
Ph
80
60
60
80
80
80
80
6A
14A
15A
16A
17A
18A
19A
50
65
60
60
30
b
CMe2
b
a In pure product after flash chromatography. b The starting enyne
was recovered unchanged.
Acknowledgment. This work was supported by the Ministerio de
Educacio´n y Cultura (DGICYT, project PB96-0021).
Scheme 1
Supporting Information Available: Experimental procedures and
characterization data of the new compounds and X-ray diffraction data
of 6A (PDF). This material is available free of charge via the Internet at
http://pubs.acs.org.
JA990546P
(14) (a) Krafft, M. E.; Juliano, C. A. J. Org. Chem. 1992, 57, 5106. (b)
Krafft, M. E.; Juliano, C. A.; Scott, I. L.; Wright, C.; McEachin, M. D. J.
Am. Chem. Soc. 1991, 113, 1693.
(15) The sulfinylation of the lithium carbanion of diethyl methylphosphonate
with the known (R)-tert-butyl tert-butanethiosulfinate (Cogan, D. A.; Liu, G.;
Kim, K.; Backes, B. J.; Ellman, J. A. J. Am. Chem. Soc. 1998, 120, 8011) in
THF at -100 °C provided (R)-7 in 70% yield ([R]D ) -106, c 1, CHCl3; ee
98.5%, HPLC, Chiralpak AS).
entry 4). In contrast, a poor yield was obtained in the reaction of
the 1,7-enyne 11 (30%, entry 5), and disappointingly, no reaction
at all was observed from substituted alkynes (entries 6 and 7).
Unexpected results were observed in the cobalt-meditated
reactions of the sulfinylated enynes of cis configuration (Scheme
1). Thus, whereas the aromatic sulfoxide (R)-cis-1 gave the
exocyclic diene 20 as the only characterized product (28% yield),
in fact the expected product from an electron poor alkene under
PK reaction conditions, the tert-butyl sulfoxides (S)-cis-3 and (S)-
cis-9 evolved by a very highly stereoselective PK reaction to give,
respectively, the same cyclopentenones 6A (41% yield) and 15A
(56% yield) obtained from the diastereomeric enynes (S)-trans-3
and (S)-trans-9.17 From a synthetic point of view this result is
particularly interesting because it allows the PK reaction to be
carried out with the cis + trans mixtures of enynes directly
obtained after the olefination step:15 thus, a 55:45 mixture of trans
+ cis olefins (S)-3 afforded 6A as the only isomer in 44% yield.
Deprotonation of (R)-7 (n-BuLi, THF, -78 °C) and addition of the corre-
sponding alkynyl aldehyde (-78 °C) led to the enynes (S)-3 and (S)-8-13 in
high yields (77-89%) as cis + trans mixtures of olefins, which were readily
separated by flash chromatography. On the other hand, we checked that the
1
optical purity of the enynes was very high as proved by H NMR [Yt(hfc)3]
in the case of (S)-3 and (S)-8 (ee g96%).
(16) A single enantiomer was observed by 1H NMR analysis of 6A and
14A in the presence of Eu(hfc)3 (ee g96%).
(17) A possible explanation justifying the same stereochemical outcome
of the PK reaction from trans and cis enynes might be that both vinyl sulfoxides
exhibit the same π-facial selectivity in the key olefin insertion step, and that
the initial cis substituted adduct obtained from the cis enyne epimerizes under
the reaction conditions to the most stable trans substituted cyclopentenone.
For previous cis to trans epimerizations of disubstituted cyclopentenones ad-
ducts in PK reactions, see: Krafft, M. E. J. Am. Chem. Soc. 1988, 110, 968.
(18) Holton, R. A.; Crouse, D. J.; Williams, A. D.; Kenedy, R. M. J. Org.
Chem. 1987, 52, 2317.
(19) Hua, D. H. J. Am. Chem. Soc. 1986, 108, 3836.