Table 2 Lewis base-catalyzed reductive aldol reactiona
Preliminary studies using a chiral Lewis base (BINAPO)11
revealed a high potential for enantioselective catalysis of the
reactions (Scheme 2). Although HMPA required an extended
reaction time at rt for the reduction of enone 1g (see Table 1,
entry 7), the asymmetric reduction using BINAPO proceeded
smoothly at 0 1C to give a high enantioselectivity. On the other
hand, the asymmetric reductive aldol reaction of b-ionone (1f)
with benzaldehyde at À78 1C provided both high diastereo-
and enantioselectivities. The syn-diastereoselectivity can be as-
cribed to the formation of the (Z)-trichlorosilyl enolate9
followed by Lewis base-catalyzed aldol reaction via a chair-like
transition state.11,12
Entry Enone R5
Catalyst Conditions Yieldb (%)
1
2
3
4
5
6
7
8
a
1b
1b
1b
1b
1b
1c
1f
Ph
Ph
HMPA
Ph3PQO 0 1C, 4 h
0 1C, 4 h
52
78
69
72
19
70
65
39
p-MeOC6H4 Ph3PQO 0 1C, 4 h
p-NO2C6H4
Ph(CH2)2
Ph
Ph
Ph
Ph3PQO 0 1C, 4 h
Ph3PQO rt, 24 h
Ph3PQO 0 1C, 4 h
Ph3PQO 0 1C, 5 h
In summary, we have demonstrated Lewis base-catalyzed
conjugate reduction of a,b-unsaturated ketones with trichloro-
silane and subsequent one-pot reactions with aldehydes.
Further studies on the enantioselective catalysis as well
as extension to other related reactions are currently in
progress.
1h
HMPA
rt, 24 h
All reactions were carried out by addition of trichlorosilane (1.0 mmol)
to a solution of an enone (0.5 mmol), an aldehyde (0.6 mmol) and a Lewis
b
base-catalyst (0.1 mmol) in CH2Cl2 (2 mL) at 0 1C or rt. Isolated as
diastereomeric mixtures except for entry 8.
Notes and references
1 For leading references on metal-catalyzed reductive aldol reac-
tions, see: (a) A. Revis and T. K. Hilty, Tetrahedron Lett., 1987, 28,
4809; (b) S. Isayama and T. Mukaiyama, Chem. Lett., 1989, 2005;
(c) S. Kiyooka, A. Shimizu and S. Torii, Tetrahedron Lett., 1998,
39, 5237; (d) T. Ooi, K. Doda, D. Sakai and K. Maruoka,
Tetrahedron Lett., 1999, 40, 2133; (e) C.-X. Zhao, M. O. Duffey,
S. J. Taylor and J. P. Morken, Org. Lett., 2001, 3, 1829; (f) H.-Y.
Jang, R. R. Huddleston and M. J. Krische, J. Am. Chem. Soc.,
2002, 124, 15156; (g) I. Shibata, H. Kato, T. Ishida, M. Yasuda
and A. Baba, Angew. Chem., Int. Ed., 2004, 43, 711.
2 (a) J. W. Yang, M. T. H. Fonseca and B. List, Angew. Chem., Int.
Ed., 2004, 43, 6660; (b) J. W. Yang, M. T. H. Fonseca, N. Vignola
and B. List, Angew. Chem., Int. Ed., 2005, 44, 108; (c) S. G. Ouellet,
J. B. Tuttle and D. W. C. MacMillan, J. Am. Chem. Soc., 2005,
127, 32; (d) N. J. A. Matrin and B. List, J. Am. Chem. Soc., 2006,
128, 13368; For related reactions based on non-metal-catalyzed
hydrostannation, see: (e) T. Kawakami, M. Miyatake, I. Shibata
and A. Baba, J. Org. Chem., 1996, 61, 376; (f) D. S. Hays, M.
Scholl and G. C. Fu, J. Org. Chem., 1996, 61, 6751.
Scheme 2 Enantioselective catalysis.
gave the 1,4-reduction products in high yields with exclusive
1,4-selectivity (entries 1–6), while b- and/or a-disubstituted
enones required extended reaction time (entries 7, 8 and 11).
The 1,4-reduction of one enone moiety proceeded regioselec-
tively even when substrates had an additional olefin moiety
(entries 4, 5, 6 and 10). Exocyclic enones gave 1,4-reduction
products smoothly (entries 9, 10 and 11), whereas an endo-
cyclic enone, 3-phenyl-2-cyclohexenone, showed low reactiv-
ity. These observations strongly suggest the importance of the
s-cis configuration in the transition state.9
3 A catalytic asymmetric reductive Michael cyclization has been
reported, see: J. W. Yang, M. T. H. Fonseca and B. List, J. Am.
Chem. Soc., 2005, 127, 15036.
4 Trichlorosilane has been utilized for (asymmetric) 1,2-reduction of
aldehydes, ketones, aldimines and ketimines in combination with
(chiral) Lewis base-catalysts. For leading references, see: (a) S.
Kobayashi, M. Yasuda and I. Hachiya, Chem. Lett., 1996, 407;
(b) F. Iwasaki, O. Onomura, K. Mishima, T. Maki and Y.
Matsumura, Tetrahedron Lett., 1999, 40, 7507; (c) Y. Matsumura,
K. Ogura, Y. Kouchi, F. Iwasaki and O. Onomura, Org. Lett.,
2006, 8, 3789; (d) A. V. Malkov, A. Mariani, K. N. MacDougall
and P. Kocovsky
P. Stewart Liddon, P. Ramı
P. Kocovsky, Angew. Chem., Int. Ed., 2006, 45, 1432; (f) L. Zhou,
´
, Org. Lett., 2004, 6, 2253; (e) A. V. Malkov, A. J.
HMPA or Ph3PQO scarcely promoted the 1,2-reduction of
benzaldehyde under these conditions. Thus, three-component
reactions of enones, aldehydes and trichlorosilane (reductive
aldol reactions) proceeded smoothly in the presence of a Lewis
base-catalyst to afford the corresponding aldol products in
good yield (Table 2).10 For the reaction of chalcone (1b) with
benzaldehyde, Ph3PQO catalyst showed better activity than
HMPA (entries 1 and 2). Reactions of 1b with electron-
donating and -withdrawing benzaldehyde derivatives also
afforded good yields, but reaction with an aliphatic aldehyde
gave a low yield (entries 3–5). Reactive enones 1c and 1f
provided good results (entries 6 and 7), but enone 1h having
low reduction activity resulted in a low yield (entry 8).
´
rez-Lopez, L. Bendova, D. Haigh and
´
´
´
Z. Wang, S. Wei and J. Sun, Chem. Commun., 2007, 2977.
5 Cobalt(II) chloride-catalyzed 1,4-reduction of enones or acryl esters
with trichlorosilane has been reported, see: M. Chauhan and P.
Boudjouk, Can. J. Chem., 2000, 78, 1396. For a palladium-
catalyzed reductive aldol reaction with trichlorosilane, see ref. 1c.
6 A patent that describes a formamide-catalyzed conjugate reduction
of enones with the silane has been reported, see: Y. Matsumira and
F. Iwasaki, Jpn. Pat., JP 2003171334 A. However, this patent does
not describe the effect of Lewis bases other than formamides.
Formamides are generally effective in the reduction of aldehydes
with trichlorosilane, see ref. 4.
7 For a pioneering study on aldol reaction of trichlorosilyl enolates,
see: S. E. Denmark, K.-T. Wong and R. A. Stavenger, J. Am.
Chem. Soc., 1997, 119, 2333.
ꢀc
This journal is The Royal Society of Chemistry 2008
4310 | Chem. Commun., 2008, 4309–4311