Asymmetric reductive Mannich reaction to ketimines catalyzed by a Cu(I) complex

Article abstract of DOI:10.1021/ja8069727

A highly diastereoselective reductive Mannich coupling of ketimines and α,β-unsaturated esters was developed using CuOAc-PPh₃ or CuOAc-MePPh₂ complex as a catalyst (5 mol %) and pinacolborane as a reducing reagent. The reaction was easily conducted at room temperature, and the substrate generality was broad. This platform methodology was extended to the first catalytic asymmetric reductive Mannich reaction of ketimines using CuOAc-DIFLUORPHOS as the catalyst (10 mol %). Switching the reducing reagent from pinacolborane to (EtO)₃SiH was key to inducing the high enantioselectivity (82-93% ee). High diastereoselectivity was also maintained (3:1～30:1). Thus, products containing contiguous tetra- and trisubstituted carbons were catalytically synthesized with high stereoselectivities. Products were converted to α,β,β-trisubstituted (β²,^3,3) amino acid derivatives without any racemization and epimerization through simple treatment under acidic conditions. This method is the first entry of the catalytic asymmetric synthesis of β²,³,³-amino acid derivatives, which constitute important chiral building blocks of biologically significant molecules. Copyright

Full text of DOI:10.1021/ja8069727

Published on Web 11/11/2008
Asymmetric Reductive Mannich Reaction to Ketimines Catalyzed by a Cu(I)
Complex
Yao Du, Li-Wen Xu, Yohei Shimizu, Kounosuke Oisaki, Motomu Kanai,* and Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, Hongo, Bunkyo-ku, Tokyo113-0033, Japan
Received September 3, 2008; E-mail: mshibasa@mol.f.u-tokyo.ac.jp
Table 1. Catalytic Diastereoselective Reductive Mannich Reaction
of Ketimines
ꢀ-Amino acids are important building blocks for a wide variety
of natural products, pharmaceutical agents, and mimics of protein
structural motifs.1 The substitution pattern and stereochemistry at
the C-2 and/or C-3 positions strongly influence the structural,
chemical, and biologic characteristics of ꢀ-amino acids and their
oligomers (ꢀ-peptides). A particularly intriguing, but not well-
evaluated class of ꢀ-amino acids is the densely substituted amino
acids, including ꢀ,ꢀ-disubstituted (ꢀ3,3) and R,ꢀ,ꢀ-trisubstituted
(ꢀ2,3,3) amino acids. Asymmetric synthesis of these ꢀ-amino acids
is extremely challenging,2 which hampers the use of these amino
acids as components of functional molecules.
The catalytic asymmetric Mannich-type reaction of ketimines is
one of the most straightforward methods for accessing ꢀ,ꢀ-
disubstituted amino acids.3-6 We developed a catalytic enantiose-
lective Mannich-type reaction between nonactivated ketimines and
an acetate-derived silyl enolate using chiral Cu(I) complexes.7 This
reaction is the first example that can catalytically overcome the
low reactivity of ketimines (relative to aldimines, aldehydes, and
ketones) in enolate addition.8 The high catalyst performance is
attributed to the generation of reactive copper enolates through
transmetalation from silicon enolates.9 This method, however, is
limited to acetate-derived enolates as donors (i.e., no reaction using
propionate-derived enolates). Therefore, a new method is required
to achieve catalytic asymmetric synthesis of ꢀ2,3,3-amino acids
containing a substituent at the R-position. In this communication,
we describe the development of a catalytic asymmetric reductive
Mannich reaction of ketimines, which greatly expands the previous
scope of catalytic asymmetric ꢀ,ꢀ-disubstituted amino acid synthesis.
We first established the catalytic conditions to realize Mannich-
type addition of a propionate-derived enolate to ketimines in a
racemic system. After several unsuccessful attempts to increase the
reactivity of copper enolate, which was generated through trans-
metalation, with soft Lewis base additives or cuprate formation,
we focused on an alternative approach to increase the concentration
of active copper enolate.10 The conjugate addition of Cu-based
nucleophiles to R,ꢀ-unsaturated esters was an attractive candidate
for this purpose.11,12
The reductive Mannich coupling between ketimine 1b and ethyl
acrylate (2a) in the presence of CuOAc-PPh3 catalyst (5 mol %)
was selected as a model reaction for optimization of the condi-
tions.13 Although the yield and diastereoselectivity were not
satisfactory (yield ≈ 60%, dr ≈ 3:1) when using (EtO)3SiH as a
stoichiometric reducing reagent in the presence or absence of
previously identified additive accelerators ((EtO)3SiF7 or LiOiPr14),
the reaction proceeded smoothly using pinacolborane (PinBH),
affording the product (3ba) in excellent yield and diastereoselec-
tivity (92% yield, dr ) 50:1, Table 1, entry 2).15 Other Cu sources,
such as CuF and CuH, produced less satisfactory results.
We then studied the substrate scope of this highly diastereose-
lective reductive Mannich reaction of ketimines under the optimized
conditions (Table 1). Except for one entry using a linear aliphatic
a Combined yield of diastereomers. b Diastereomer ratio determined
by H NMR spectroscopy. c MePPh2 was used instead of Ph3P.
1
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16146 J. AM. CHEM. SOC. 2008, 130, 16146–16147
10.1021/ja8069727 CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
ketimine (entry 8), products containing contiguous tetra- and
trisubstituted carbons were produced from a wide range of ketimines
with excellent chemical yield and diastereoselectivity.16 The
generality of the donor R,ꢀ-unsaturated esters was also broad
(entries 9-12). When using ethyl fumarate (2d) as the donor, the
synthetically attractive γ-lactam 4bd was produced in one-pot with
complete diastereoselectivity (entry 12).
derivatives. Studies to improve the catalyst turnover and expand
the substrate generality are in progress.
Acknowledgment. Financial support was provided by Grant-
in-Aid for Scientific Research (S) and (B) from JSPS, and that for
Priority Areas ”Chemistry of Concerto Catalysis” from MEXT. L.X.
and Y.S. thank JSPS for research fellowships.
Supporting Information Available: Experimental procedures and
characterization of the products. This material is available free of charge
via the Internet at http://pubs.acs.org.
Table 2. Catalytic Asymmetric Reductive Mannich Reaction of
Ketimines
References
(1) For reviews, see: (a) Seebach, D.; Gardiner, J. Acc. Chem. Res. 2008, 41,
1366. (b) Cheng, R. P.; Gellman, S. H.; DeGrado, W. F. Chem. ReV. 2001,
101, 3219.
(2) For a general review of stereoselective synthesis of ꢀ-amino acids, see:
Liu, M.; Sibi, M. P. Tetrahedron 2002, 58, 7991.
(3) (a) A general diastereoselective enolate addition to chiral sulfinyl imines: Tang,
T. P.; Ellman, J. A. J. Org. Chem. 2002, 67, 7819. (b) An asymmetric
Mannich-type reaction to ketone-derived N-acyl hydrazones using a
stoichiometric chiral promoter: Notte, G. T.; Leighton, J. L. J. Am. Chem.
Soc. 2008, 130, 6676.
(4) A diastereoselective [3 + 2] cycloaddition to chiral substrates as an
alternative method for the Mannich reaction: Fuller, A. A.; Chen, B.; Minter,
A. R.; Mapp, A. K. J. Am. Chem. Soc. 2005, 127, 5376.
(5) An organo-catalyzed asymmetric Mannich reaction between special
R-ketimino esters (activated ketimines) and aldehydes: Zhuang, W.; Saaby,
S.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2004, 43, 4476.
(6) General reviews: (a) Kobayashi, S.; Ishitani, H. Chem. ReV 1999, 99, 1069.
(b) Marques, M. M. B. Angew. Chem., Int. Ed. 2006, 45, 348.
(7) Suto, Y.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2007, 129, 500.
(8) CuOAr-catalyzed direct asymmetric Mannich reaction of ketimines was
recently reported: (a) Yazaki, R.; Nitabaru, T.; Kumagai, N.; Shibasaki,
M. J. Am. Chem. Soc. 2008, 130, 14477. (b) The original use of
Cu-conjugated Brønsted base catalyst in direct asymmetric C-C bond-
formation: Suto, Y.; Tsuji, R.; Kanai, M.; Shibasaki, M. Org. Lett. 2005,
7, 3757.
entry
product
temp (°C) time (h)
yielda (drb)
eec
1
2
3
3aa
3ba
-50
-50
-50
41
42
41
95 (9/1) 85
90 (6/1) 91
88 (3/1) 86
3ia: R1 ) 2-naphthyl,
R3 ) H
3ga
3bb
4
5
6
-30
-30
-40
36
48
65
90 (9/1) 91
86 (5/1) 82
65 (17/1) 90
1
3bd: R ) 4-Cl-C6H4,
R3 ) CO2Et
7
3gd: R1 ) 1-cyclohexenyl,
R3 ) CO2Et
-50
36
47 (30/1) 93
a Combined yield of diastereomers. b Diastereomer ratio determined
by 1H NMR spectroscopy. c Enantiomeric excess of the major isomer
determined by chiral HPLC.
(9) For pioneering studies on transmetalation from a silyl enolate to a copper
enolate, see: Pagenkopf, B. L.; Kru¨ger, J.; Stojanovic, A.; Carreira, E. M.
Angew. Chem., Int. Ed. 1998, 37, 3124.
(10) Transmetalation from silicon enolate to copper enolate is the rate-
determining step in the Cu-catalyzed aldol reaction to ketones, and therefore
not very efficient: Oisaki, K.; Suto, Y.; Kanai, M.; Shibasaki, M. J. Am.
Chem. Soc. 2003, 125, 5644.
(11) This type of copper enolate formation was applied to catalytic asymmetric
reductive or alkylative aldol reactions of ketones. For selected examples,
see: (a) Lam, H. W.; Joensuu, P. M. Org. Lett. 2005, 7, 4225. (b) Deschamp,
J.; Chuzel, O.; Hannedouche, J.; Riant, O. Angew. Chem., Int. Ed. 2006,
45, 1292. (c) Zhao, D.; Oisaki, K.; Kanai, M.; Shibasaki, M. J. Am. Chem.
Soc. 2006, 128, 14440. (d) Oisaki, K.; Zhao, D.; Kanai, M.; Shibasaki, M.
J. Am. Chem. Soc. 2007, 129, 7439. (e) Lipshutz, B. H.; Amorelli, B.;
Unger, J. B. J. Am. Chem. Soc. 2008, 130, 14378. Reviews: (f) Deutsch,
C.; Krause, N.; Lipshutz, B. H. Chem. ReV. 2008, 108, 2916. (g) Rendler,
S.; Oestreich, M. Angew. Chem., Int. Ed. 2007, 46, 498.
(12) Reductive Mannich reactions of aldimines: (a) Nishiyama, H.; Ishikawa,
J.; Shiomi, T. Tetrahedron Lett. 2007, 48, 7841. (b) Prieto, O.; Lam, H. W.
Org. Biomol. Chem. 2008, 6, 55. (c) Garner, S. A.; Krische, M. J. J. Org.
Chem. 2007, 72, 5843. (d) Townes, J. A.; Evans, M. A.; Queffelec, J.;
Taylor, S. J.; Morken, J. P. Org. Lett. 2002, 4, 2537. (e) Muraoka, T.;
Kamiya, S.; Matsuda, I.; Itoh, K. Chem. Commun. 2002, 1284. Extension
to the catalytic asymmetric version has not been reported.
This platform reaction was then extended to catalytic asymmetric
variants using chiral phosphines. No appreciable enantio-induction
was produced, however, even after intensive screening of the chiral
ligands. In sharp contrast, enantioselectivity was markedly higher
when using silanes instead of PinBH as the reducing reagent.17
Although the reactions were slower when using silanes, compared
to using PinBH, product yield was significantly improved when
sterically less crowded bis-arylphosphines were used as ligands and
the reactions were performed at lower temperature. The optimized
conditions for the catalytic asymmetric reductive Mannich reaction
were identified: CuOAc-DIFLUORPHOS18 complex as a catalyst
and (EtO)3SiH as a reducing reagent at -30 °C or lower (Table
2).15 The substrate scope covers both aromatic and R,ꢀ-unsaturated
ketimines as acceptors, affording R-methyl-, ethyl-, and ethoxy-
carbonylmethyl-substituted products19 with high enantio- and
diastereoselectivities. The products were converted to enantiomeri-
cally enriched ꢀ2,3,3-amino acid derivatives in high yield without
any racemization and epimerization through cleavage of the
diphenylphosphinoyl group under acidic conditions (Scheme 1).20
(13) For the initial stage optimization, see Table S-1 in Supporting Information
(SI). N-Phosphinoyl ketimines produced more promising results than
N-benzyl and N-toluenesulfonyl ketimines.
(14) Wada, R.; Shibuguchi, T.; Makino, S.; Oisaki, K.; Kanai, M.; Shibasaki,
M. J. Am. Chem. Soc. 2006, 128, 7687.
(15) For determination of the relative and absolute configuration of the products,
see SI.
Scheme 1. Conversion to ꢀ2,3,3-Amino Acid Derivative
(16) There was no simple and general catalytic method for diastereoselective
synthesis of ꢀ2,3,3-amino acid derivatives, even in a racemic system.
(17) For example, a CuOAc-tol-BINAP catalyst produced 3ba with only 25%
ee using PinBH, but with 68% ee using (EtO)3SiH (0 °C). This sharp
difference might be due to switching of the reactive nucleophile (achiral
boron enolate vs. chiral copper enolate) depending on the reducing reagents
(see SI). The fact that enantiomeric excess of 3ba improved to 56% ee in
the presence of pyridine (1.8 equiv: possible deactivator of boron enolate)
using PinBH supports this consideration.
(18) Jeulin, S.; de Paule, S. D.; Ratovelomanana-Vidal, V.; Geneˆt, J.-P.;
Champion, N.; Dellis, P. Angew. Chem., Int. Ed. 2004, 43, 320.
(19) In Table 2, entries 6 and 7, no cyclized products such as 4bd were observed.
(20) See SI for more examples of product conversion.
(21) Reviews of Cu-catalyzed asymmetric tetrasubstituted carbon construction,
see: (a) Shibasaki, M.; Kanai, M. Chem. ReV. 2008, 108, 2853. (b) Riant,
O.; Hannedouche, J. Org. Biomol. Chem. 2007, 5, 873.
In conclusion, we developed the first catalytic asymmetric
reductive Mannich reaction to ketimines. Products containing
contiguous tetra- and trisubstituted stereocenters were produced with
high enantio- and diastereoselectivities.21 This methodology is the
first entry to the catalytic asymmetric synthesis of ꢀ2,3,3-amino acid
JA8069727
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