Rhodium-catalyzed enantioselective reductive aldol reaction [11]

Full text of DOI:10.1021/ja9944453

4528
J. Am. Chem. Soc. 2000, 122, 4528-4529
Table 1. Rh-Catalyzed Asymmetric Reductive Aldol Reaction with
Rhodium-Catalyzed Enantioselective Reductive Aldol
Reaction
Varied Acrylate Componenta
Steven J. Taylor, Matthew O. Duffey, and James P. Morken*
Department of Chemistry
Venable and Kenan Laboratories
entry
R
syn:antib ee syn (configc) ee anti (config) % yield
The UniVersity of North Carolina at Chapel Hill
Chapel Hill, North Carolina 27599-3290
1
2
3
Me
t-Bu
Ph
1.7:1
1.4:1
3.4:1
91 (2R,3R)
58 (nd)
87 (2R,3R)
88 (2R,3S)
38 (nd)
34 (nd)
37
21
72
ReceiVed December 21, 1999
a All reactions were carried out at room temperature for 24 h in
dichloroethane solvent using the procedure described in the text.
b Stereoisomer ratios determined by chiral GC analysis of the unpurified
esters. c Absolute configuration established by comparison to reported
optical rotation for entry 1 and by independent synthesis for entry 3.
Catalytic enantioselective carbon-carbon coupling reactions,
particularly those that form C(sp3)-C(sp3) bonds from readily
available prochiral substrates, are useful tools for the synthesis
of natural products and commodity chemicals. Such a mode of
bond formation is available for the asymmetric synthesis of
â-hydroxy carbonyls through catalytic enantioselective aldol
processes.1,2 With the exception of reports by Nelson,3 Shibasaki,4
and Watanabe,5 methods for the catalytic asymmetric synthesis
of â-oxygenated carbonyls derive reactivity from latent enolates
which must be prepared, in advance, in a stoichiometric fashion.6
We recently reported a diastereoselective catalytic reductive aldol
reaction that may provide an alternative to such Mukaiyama aldol
processes.7-9 The reductive aldol reaction does not require
preformation of metal enolates or silyl enol ethers; catalytic
condensation between an activated alkene, an aldehyde, and a
silane directly furnishes protected propionate products. Challenges
to the development of effective reductive aldol catalysts include
reaction stereoselection and also product selectivity; late transition
metal-catalyzed condensations between aldehydes and silanes
(carbonyl hydrosilation10) and between acrylates and silanes
(alkene hydrosilation11) are well-known processes and are potential
competing reaction pathways. Herein we report the first asym-
metric catalytic reductive aldol reaction; a complex derived from
[(cod)RhCl]2 and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl
(BINAP)12 effects catalytic diastereoselective and enantioselective
reductive aldol reaction between acrylate esters and aldehydes
with good to excellent levels of enantioselectivity.13
Our initial studies with 192 independent catalyst systems
identified [(cod)RhCl]2-R-BINAP-Et2MeSiH as one catalyst sys-
tem able to effect room-temperature catalytic enantioselective
reductive aldol reaction between methyl acrylate and benzalde-
hyde. While enantioselectivity in the initial microscale assay was
low (20% enantiomeric excess), it was noted that reaction in the
presence of ligand was less efficient than the reaction with metal
salt alone (4% relative yield versus 16% relative yield, data not
shown). We surmised that during the microscale reaction,
inefficient complexation of the ligand to the metal might leave
uncomplexed metal salt available to effect relatively rapid and
nonselective transformation. Upon scale-up in the presence of
excess R-BINAP (1.3:1 ligand/metal; 2.5 mol % [(cod)RhCl]2)
the catalytic reductive aldol reaction between methyl acrylate,
benzaldehyde, and diethylmethylsilane occurs to provide a
diastereomeric mixture (1.7:1 syn:anti) of â-hydroxy esters in
good enantiomeric excess (91% ee syn; 88% ee anti, 37% yield;
see Table 1, entry 1).14 Notably, loss of diastereoselection occurs
from lack of stereocontrol in bond formation to the prochiral
carbonyl; the sense and level of stereoselection at CR is maintained
with good fidelity.
(1) For an excellent review on enantioselective aldol reactions with latent
enolates see: Nelson, S. G. Tetrahedron Asymmetry 1998, 9, 357.
(2) For recent lead references on catalytic asymmetric aldol reactions using
latent enolates, see: (a) Denmark, S. E.; Stavenger, R. A.; Wong, K.-T.; Su,
X. J. Am. Chem. Soc. 1999, 121, 4982. (b) Evans, D. A.; Kozlowski, M. C.;
Murray, J. A.; Burgey, C. S.; Campos, K. R.; Connell, B. T.; Staples, R. J. J.
Am. Chem. Soc. 1999, 121, 669. (c) Evans, D. A.; Burgey, C. S.; Kozlowski,
M. C.; Tregay, S. W. J. Am. Chem. Soc. 1999, 121, 686. (d) Fujimura, O. J.
Am. Chem. Soc. 1998, 120, 10032. (e) Kruger, J.; Carreira, E. M. J. Am. Chem.
Soc. 1998, 120, 837. (f) Evans, D. A.; MacMillan, D. W. M.; Campos, K. R.
J. Am. Chem. Soc. 1997, 119, 10859. (g) Keck, G. E.; Krishnamurthy, D. J.
Am. Chem. Soc. 1995, 117, 2363. (h) Carreira, E. M.; Lee, W.; Singer, R. A.
J. Am. Chem. Soc. 1995, 117, 3649. (i) Uotsu, K.; Sasai, H.; Shibasaki, M.
Tetrahedron Asymmetry 1995, 6, 71. (j) Sodeoka, M.; Ohrai, K.; Shibasaki,
M. J. Org. Chem. 1995, 60, 2648. (k) Mikami, K.; Matsuka, S. J. Am. Chem.
Soc. 1994, 116, 4077.
The impact of acrylate and aldehyde structure on stereoselection
was examined with the following experimental procedure: Under
a dry and oxygen-free nitrogen atmosphere, 2.5 mol % [(cod)-
RhCl]2 was stirred with 6.5 mol % R-BINAP in dichloroethane
at room temperature for 1 h. Diethylmethylsilane was then added
and the mixture stirred for an additional 30 min. After addition
of carbonyl substrates, the reaction was allowed to proceed for
(3) Nelson, S. G.; Peelen, T. J.; Wan, Z. J. Am. Chem. Soc. 1999, 121,
9742.
(4) (a) Yamada, Y. M. A.; Yoshikawa, N.; Sasai, H.; Shibasaki, M. Angew.
Chem., Int. Ed. Engl. 1997, 36, 1871. (b) Yoshikawa, N.; Yamada, Y. M. A.;
Das, J.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc. 1999, 121, 4168.
(5) Nakagawa, M.; Nakao, H.; Watanabe, K.-I. Chem. Lett. 1985, 391.
(6) For relevant methods involving catalytic enantioselective functional-
ization of unmodified carbonyls or their equivalent see: (a) Ito, Y.; Sawamura,
M.; Hayashi, T. J. Am. Chem. Soc. 1986, 108, 6405. (b) Evans, D. A.; Nelson,
S. G. J. Am. Chem. Soc. 1997, 119, 6452. (c) Ji, J.; Barnes, D. M.; Zhang, J.;
King, S. A.; Wittenberger, S. J.; Morton, H. E. J. Am. Chem. Soc. 1999, 121,
10215.
(11) For transition metal catalyzed hydrosilation of unsaturated esters,
see: (a) Appella, D. H.; Moritani, Y.; Shintani, R.; Ferreira, E. M.; Buchwald,
S. L. J. Am. Chem. Soc. 1999, 121, 9473. (b) Lipshutz, B. H.; Keith, J.; Papa,
P.; Vivian, R. Tetrahedron Lett. 1998, 39, 4627. (c) Ito, H.; Ishizuka, T.;
Arimoto, K.; Miura, K.; Hosomi, A. Tetrahedron Lett. 1997, 38, 8887. (d)
Zheng, G. Z.; Chan, T. H. Organometallics 1995, 14, 70. (e) Doyle, M. P.;
Devora, G. A.; Nefedov, A. O.; High, K. G. Organometallics 1992, 11, 549.
(f) Keinan, E.; Perez, D. J. Org. Chem. 1987, 52, 2576. (g) Takeshita, K.;
Seki, Y.; Kawamoto, K.; Murai, S.; Sonoda, N. J. Org. Chem. 1987, 52, 4864.
(h) Keinan, E.; Greenspoon, N. J. Am. Chem. Soc. 1987, 109, 7314.
(12) Miyashita, A.; Yasuda, A.; Takaya, H.; Toriumi, K.; Ito, T.; Souchi,
T.; Noyori, R. J. Am. Chem. Soc. 1980, 102, 7932.
(13) For Rh(I)-BINAP catalyzed conjugate addition of boronic esters to
unsaturated carbonyls, see: Takaya, Y.; Ogasawara, M.; Hayashi, T.; Sakai,
M.; Miyaura, N. J. Am. Chem. Soc. 1998, 120, 5579.
(14) Along with an increase in enantioselectivity in the presence of excess
ligand, the reaction in a flask also provides an increase in reaction yield
compared to reaction in a microtitre plate. We attribute this disparity to the
fact that reaction in the plate was unstirred; unstirred reactions in a flask
reproducibly provide <10% product yield.
(7) Taylor, S. J.; Morken, J. P. J. Am. Chem. Soc. 1999, 121, 12202.
(8) (a) Revis, A.; Hilty, T. K. Tetrahedron Lett. 1987, 28, 4809. (b) Isayama,
S.; Mukaiyama, T. Chem. Lett. 1989, 2005. (c) Kiyooka, S.; Shimizu, A.;
Torii, S. Tetrahedron Lett. 1998, 39, 5237. For a reductive aldol reaction with
unsaturated ketones, see: Matsuda, I.; Takahashi, K.; Sato, S. Tetrahedron
Lett. 1990, 31, 5331.
(9) Catalytic enantioselective tandem conjugate addition-aldol reaction
involving enones has been reported, see: Barrett, A. G. M.; Makimura, A. J.
Chem. Soc., Chem. Commun. 1995, 1755.
(10) For transition metal-catalyzed hydrosilation of carbonyls, see: Ojima,
I. Catalytic Asymmetric Synthesis; VCH Publishers: New York, 1993; Chapter
6.
10.1021/ja9944453 CCC: $19.00 © 2000 American Chemical Society
Published on Web 04/25/2000

Communications to the Editor
J. Am. Chem. Soc., Vol. 122, No. 18, 2000 4529
Table 2. Rh-Catalyzed Asymmetric Reductive Aldol Reaction with
Scheme 1
Varied Aldehyde Componenta
anecarboxaldehyde (5 g) was subjected to the reductive aldol
reaction conditions with 0.5 mol % [(cod)RhCl]2 and R-BINAP
ligand. After aqueous nonacidic workup, the silyl-protected aldol
adduct was isolated in 45% yield as a 3.7:1 mixture of syn:anti
diastereomers in good enantiomeric excess (82% ee syn).
Preliminary mechanistic experiments indicate that the silane
hydrogen is transferred to the acrylate â-carbon: when the
reductive aldol reaction in Table 2, entry 1, is carried out with
phenyldimethylsilyldeuteride in place of diethylmethylsilane, 13
C
NMR analysis shows partial deuteration of the C2 methyl
group.15,16 Experiments also suggest that the [(cod)RhCl]2-(R)-
BINAP catalyzed reductive aldol reaction does not proceed by
initial conversion of the silane and acrylate to a silyl ketene acetal;
treatment of phenyl acrylate with diethylmethylsilane in the
presence of the [(cod)RhCl]2-(R)-BINAP catalyst provides <5%
silylketene acetal after 24 h. It is also of note that <5% reductive
aldol adduct is formed from independently prepared silylketene
acetal and benzaldehyde under the catalytic reaction conditions.
While these experiments suggest that silicon enolates are not
involved, the intermediacy of a rhodium enolate may not be ruled
out. At present we expect that after oxidative addition of silane
to rhodium, the reaction is likely to proceed either by insertion
of the aldehyde into a Rh-Si bond followed by insertion of the
acrylate into the resulting Rh-C bond or by insertion of the
acrylate into a Rh-H bond followed by aldol addition of the
derived rhodium enolate to the aldehyde.17 Ongoing mechanistic
studies are addressing this issue and will be the subject of a
forthcoming report.
a All reactions were carried out at room temperature for 24 h in
dichloroethane solvent using the procedure described in the text.
b Percent yield is of isolated material after silica gel chromatography.
Satisfactory elemental analysis was obtained for all reaction products.
c Stereochemical ratios were determined by chiral GC or HPLC analysis,
see Supporting Information for details. d Configuration of syn reaction
products was determined by comparison to reported optical rotation or
by synthesis of authentic enantiomers.
While propionate synthesis with the current catalytic reductive
aldol reaction does not yet rival the high diastereo- and enanti-
oselectivity (>20:1 d.r., >97% ee) often observed2 in direct
catalytic asymmetric addition of silyl enol ethers to carbonyls,
we expect improvements may be gained by fine-tuning the
acrylate ester substituent and the silane component. As a note in
proof, initial studies reveal that enantioselective transformation
is not limited to use of diethylmethylsilane.15 That a variety of
silanes might be employed and retained as protecting groups for
the â-hydroxyl should also prove useful for propionate synthesis.
24 h at room temperature before being subjected to aqueous acidic
(4 M HCl) workup. Examination of the data in Table 1 reveals a
substantial dependence of stereoselectivity on acrylate structure;
whereas reaction with methyl acrylate provides product in good
enantiopurity, reaction with tert-butyl acrylate exhibits diminished
absolute stereoselection (Table 1, entries 1 and 2). Electronic
effects in the acrylate component appear to be important as phenyl
acrylate, with a steric size between that of tert-butyl acrylate and
methyl acrylate, reacts with high enantioselectivity, modest
diastereoselectivity and in the highest yield.
Acknowledgment. The authors are grateful to Amoco Chemicals for
unrestricted research funding. J.P.M. gratefully acknowledges receipt of
an NSF CAREER award, a Packard Foundation Fellowship, and a DuPont
Young Professor Grant. S.J.T. and M.O.D. gratefully acknowledge receipt
of Burroughs-Wellcome graduate student fellowships. The authors would
like to thank Professor Michael T. Crimmins (UNC) and Kleem
Chaudhary for valuable advice.
As shown in Table 2, catalytic reductive aldol reaction with
both aromatic and nonaromatic aldehydes proceeds in an enan-
tioselective fashion with phenyl acrylate and diethylmethylsilane.
In contrast to our previously reported catalyst system ([(cod)-
RhCl]2-DuPhos-Cl2MeSiH) where low yields were obtained with
aliphatic aldehydes bearing an R-hydrogen, with [(cod)RhCl]2-
BINAP-Et2MeSiH aliphatic aldehydes give useful product yields
and, except for pivaldehyde, react with good enantioselectivity.
Also in contrast to our earlier report, enals (entry 6) give no
reductive aldol product and return the unsaturated aldehyde and
acrylate unaffected. In all cases, the syn diastereomer is favored
and the major enantiomer of the syn isomer has the R configu-
ration at C-2. Notably, in these reactions a decrease in both
diastereomer ratio and syn enantiomer ratio is accompanied by
an increase in anti enantiomer ratio as substrate size is increased
(entries 2-4).
Supporting Information Available: Characterization data for all
compounds (Tables 1 and 2) and experimental details (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
JA9944453
(15) [(cod)RhCl]2-(R)-BINAP catalyzed reductive aldol reaction with
benzaldehyde, phenyl acrylate, and dimethylphenylsilane provides 60% yield
of the 2R,3R adduct with 3.9:1 syn:anti selectivity and 89% ee.
(16) Incomplete deuteration requires a pathway involving exchange of
hydrogen atoms. Accordingly, treatment of phenyl acrylate with phenyldim-
ethylsilyldeuteride, in the presence of [(cod)RhCl]2-(R)-BINAP, results in
nonselective deuterium incorporation at the â-carbon of the acrylate.
(17) Neither mechanism is without precedent: the first scenario is analogous
to that proposed by Wright for Rh-catalyzed silylformylation of aldehydes
(Wright, M. E.; Cochran, B. B. J. Am. Chem. Soc. 1993, 115, 2059) and, as
required by the second, rhodium enolates are known to undergo aldol addition
reactions (Slough, G. A.; Bergman, R. G.; Heatchcock, C. H. J. Am. Chem.
Soc. 1989, 111, 938).
The catalytic reductive aldol reaction is attractive because it
allows preparation of aldol adducts via operationally simple, room
temperature condensation between inexpensive commercially
available substrates. The “scale-up” experiment described in
Scheme 1 exemplifies the ease with which larger scale reactions
may be performed. At 0.9 M substrate concentration, cyclohex-