We have already reported various asymmetric reactions
catalyzed by the chiral Pd-bisphosphine complexes 2 and
3,5 and we recently found that an R,â-unsaturated carbonyl
compound was reduced in ethanol in the presence of 2 or 3.
Pd hydride species have been proposed to be key intermedi-
ates in the Pd-catalyzed oxidation of alcohols, but they are
usually decomposed to Pd(0), which is reoxidized to
complete the catalytic cycle.6-7 We speculated that the Pd
hydride species generated under our conditions might act as
a reducing agent. While Pd-H species are known to be
important intermediates in several reactions,8 their use in the
asymmetric conjugate reduction of enones has, to the best
of our knowledge, not previously been reported.9 In this
paper, we describe an efficient enantioselective conjugate
reduction of enones using ethanol as a hydride source and
its application to the asymmetric synthesis of (S)-warfarin,
a clinically important anticoagulant.
acetophenone formation was observed in the reaction using
3 as a catalyst, which afforded 5a in quantitative yield with
74% ee (entry 3). The reaction in 2-propanol was consider-
ably slower (entry 4), and ethanol was found to give the
best result. No reduction of the carbonyl group was observed,
indicating high functional group selectivity (1,2 reduction
vs 1,4 reduction). Furthermore, when a mixture of 4a and
ethyl (E)-â-methylcinnamate 6 was subjected to the conjugate
reduction, only 4a was reduced, and the ester 6 was recovered
quantitatively (eq 1). It is noteworthy that this reaction does
not require the tedious Schlenck technique or special
equipment and proceeds even in an open flask.
With these results in hand, we next examined the reactions
of other substrates (Table 2). The reaction of the ethyl-
Initially, we examined the reaction of (E)-4-phenyl-3-
penten-2-one 4a in the presence of 5 mol % of chiral
Pd-bisphosphine complexes in ethanol (1 M) at ambient
temperature (Table 1). No reaction was observed when the
Table 2. Catalytic Asymmetric Conjugate Reduction of Enones
entry
R1
R2
Et
i-Pr
c-Hex
CF3
product 5 time (h) yielda (%) eeb (%)
Table 1. Optimization of the Reaction Conditions
1
2
3
4
5
Ph
Ph
Ph
Ph
5b
5c
5d
5e
5f
3
1
0.5
1
6
97
>99
97
85
>99
84 (R)
92 (S)
86
84
80
2-BrC6H4 Me
a Isolated yield. b Determined by chiral HPLC. c For determination of
the absolute stereochemistry, see Supporting Information.
entry
cat.
solvent
time (h)
yielda (%)
eeb (%)
1
2
3
4
1
2
3
3
EtOH
EtOH
EtOH
i-PrOH
24
6
12
12
c
88
>99
29
74
74
72
substituted substrate 4b was completed after 3 h in the
presence of 2.5 mol % of 3, affording 5b in 97% yield with
84% ee. Interestingly, as the bulkiness of the â-substituent
was increased, the reaction rate was significantly enhanced.
The reaction of the substrate bearing i-Pr or c-Hex was
completed within 1 h, affording the reduced products 5c and
5d in excellent yields in a highly enantioselective manner
a Isolated yield. b Determined by chiral HPLC analysis. c Recovery of
the starting material. d For determination of the absolute stereochemistry,
see Supporting Information.
chloride complex 1 was used as a catalyst (entry 1). However,
when the aqua complex 2 was used, the reaction was
complete after 6 h to give 5a in 88% yield with 74% ee
(entry 2). In entry 2, a small amount (8%) of acetophenone
was isolated as a byproduct, probably due to hydration of
the enone followed by a retro-aldol reaction. In contrast, no
(6) (a) Peterson, K. P.; Larock, R. C. J. Org. Chem. 1998, 63, 3185-
3189. (b) Nishimura, T.; Onoue, T.; Ohe, K.; Uemura, S. J. Org. Chem.
1999, 64, 6750-6755. (c) Jensen, D. R.; Pugsley, J. S.; Sigman, M. S. J.
Am. Chem. Soc. 2001, 123, 7475-7476. (d) Ferreira, E. M.; Stoltz, B. M.
J. Am. Chem. Soc. 2001, 123, 7725-7726.
(7) Mechanistic studies on formation of Pd hydride in oxidation of
alcohols: (a) Mueller, J. A.; Goller, C. P.; Sigman, M. S. J. Am. Chem.
Soc. 2004, 126, 9724-9734. (b) Konnick, M. M.; Gandhi, B. A.; Guzei, I.
A.; Stahl, S. S. Angew. Chem., Int. Ed. 2006, 45, 2904-2907 and references
therein.
(8) Tsuji, J., Ed. Palladium Reagents and Catalysts: New PerspectiVes
for the 21st Century; John Wiley & Sons: Chichester, UK, 2004.
(9) Putative Pd hydride species generated from Pd(0) and metal hydrides
were used in non-enantioselective conjugate reduction. Haskel, A.; Keinan,
E. In Handbook of Organopalladium Chemistry in Organic Synthesis;
Negishi, E., Ed.; John Wiley & Sons: New York, 2002; Vol. 2, Chapter
VII 2.3, pp 2767-2782.
(4) Organocatalysis: (a) Yang, J. W.; Fonseca, M. T. H.; Vignola, N.;
List, B. Angew. Chem., Int. Ed. 2005, 44, 108-110. (b) Ouellet, S. G.;
Tuttle, J. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 32-33.
(5) (a) Fujii, A.; Hagiwara, E.; Sodeoka, M. J. Am. Chem. Soc. 1999,
121, 5450-5458. (b) Hamashima, Y.; Hotta, D.; Sodeoka, M. J. Am. Chem.
Soc. 2002, 124, 11240-11241. (c) Hamashima, Y.; Yagi, K.; Takano, H.;
Tama´s, L.; Sodeoka, M. J. Am. Chem. Soc. 2002, 124, 14530-14531. (d)
Hamashima, Y.; Suzuki, T.; Takano, H.; Shimura, Y.; Sodeoka, M. J. Am.
Chem. Soc. 2005, 127, 10164-10165. (e) Sodeoka, M.; Hamashima, Y.
Pure Appl. Chem. 2006, 78, 477-494 and references therein.
4852
Org. Lett., Vol. 8, No. 21, 2006