Nucleophile generation via decarboxylation: Asymmetric construction of contiguous trisubstituted and quaternary stereocenters through a Cu(I)-catalyzed decarboxylative mannich-type reaction

Article abstract of DOI:10.1021/ja9036675

(Chemical Equation Presented) The first catalytic asymmetric decarboxylative Mannich-type reaction between aldimines and cyanocarboxylic acids was developed. α,α,β-Trisubstituted β-amino nitriles containing contiguous trisubstituted and all-carbon quatern

Full text of DOI:10.1021/ja9036675

Published on Web 06/25/2009
Nucleophile Generation via Decarboxylation: Asymmetric Construction of
Contiguous Trisubstituted and Quaternary Stereocenters through a
Cu(I)-Catalyzed Decarboxylative Mannich-Type Reaction
Liang Yin, Motomu Kanai,* and Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received May 6, 2009; E-mail: mshibasa@mol.f.u-tokyo.ac.jp
Table 1. Optimization of the Reaction Conditions
Catalytic asymmetric construction of contiguous trisubstituted
and all-carbon quaternary stereocenters represents a particularly
difficult challenge.1,2 For the success of such a catalytic methodol-
ogy, carbon-carbon bond formation with high diastereo- and
enantiocontrol using sterically congested substrates is a prerequisite.
With the aim of expanding the scope of asymmetric catalysis,3 we
investigated the asymmetric synthesis of linear ꢀ-amino-R,R-
disubstituted carboxylic acids (ꢀ2,2,3-amino acids) containing con-
tiguous R-quaternary and ꢀ-trisubstituted chiral carbons. These
amino acids and their derivatives are important chiral building
blocks for biologically active molecules, but there are few examples
of their catalytic asymmetric synthesis.1a,b,4 We report herein a
general method for accessing ꢀ2,2,3-amino acid derivatives through
the development of a Cu-catalyzed decarboxylative asymmetric
Mannich-type reaction.
entry
Cu catalyst (X mol %)
2/3a yield (%)
dra
ee (%)b
1c
2c
3d
4d
5e
6f
CuOtBu-(S)-Ph-Taniaphos (10)
2
2
3a
3a
3a
3a
87
58
83
30
91
98
1:1.6
1:1.3
3.5:1
7.0:1
7.0:1
7.0:1
<5
<5
37g
87
87
87
CuOtBu-(R)-5 (10)
CuOAc-(S)-tol-BINAP (10)
CuOAc-(R)-5 (10)
CuOAc-(R)-5 (10)
CuOAc-(R)-5 (5)
a
Diastereomeric ratio determined by H NMR. b Enantiomeric excess
1
of 4aa determined by chiral HPLC. c Using 1.5 equiv of 2. d Using 1.5
equiv of 3a. e With syringe-pump addition of 1.5 equiv of 3a over 7 h.
Total reaction time ) 12 h. f With syringe-pump addition of 2.5 equiv
of 3a over 7 h. Total reaction time ) 12 h. g The enantiomer of 4aa
was obtained.
Our previous studies revealed that Cu(I)-catalyzed transmetalation
of silylated reagents and deprotonation of nitriles are two valuable
nucleophile activation methods for asymmetric C-C bond forma-
tion at sterically hindered positions (tetrasubstituted carbon syn-
thesis).3 Because it is difficult to control the enolate geometry in
R,R-disubstituted silicon enolate synthesis,1c we initially studied a
catalytic asymmetric direct Mannich-type reaction5 between aldi-
mine 1a and 2-phenylpropionitrile (2: racemic) using nucleophile
generation via chiral CuOtBu complex-catalyzed deprotonation.6
Products (4aa + its diastereomer) were obtained in moderate to
high yields, but the diastereo- and enantioselectivity were quite low
(up to 1:1.6 dr and less than 5% ee of 4aa) using various chiral
phosphines (Table 1, entries 1 and 2).7
maintained (entry 5). The reaction successfully proceeded in the
presence of lower catalyst loading (5 mol %) using 2.5 equiv of
3a (entry 6).
The optimized reaction conditions were evaluated using a range
of combinations of imines and cyanocarboxylic acids (Table 2). In
regard to imines, aromatic imines containing either electron-
donating or -withdrawing substituents at the para position were
tolerated, as were heteroaromatic imines (entries 1-12). The
reaction proceeded with complete chemoselectivity to the imine
functionality in the presence of a ketone group (entry 7). Sterically
congested ortho-substituted aromatic imines afforded excellent
enantioselectivity, although the yield and diastereoselectivity were
slightly decreased (entries 9 and 10). Remarkably, aliphatic imines
containing acidic R-protons and thus sensitive to basic conditions
were competent substrates in this decarboxylative Mannich-type
reaction (entries 13-17) because of the mild reaction conditions.
The diastereoselectivity, however, was moderate for aliphatic
imines, which must be overcome in future studies. As for the
cyanocarboxylic acids, the enantio- and diastereoselectivity de-
creased slightly according to the size of the R-substituents (entries
1-3, 13-15). Nevertheless, products containing a synthetically
useful allyl group at the quaternary center were produced with
meaningful efficiency (entries 3 and 15). It is also noteworthy that
this method was applicable to cyanoacetic acid without an aromatic
substituent, affording the products with reasonable enantioselectivity
(entries 18 and 19). To our knowledge, this is the first general
catalytic asymmetric method to access ꢀ2,2,3-amino acid derivatives
with both aromatic and aliphatic substituents at the R- and/or
ꢀ-position.
Thus, we next examined the Cu(I)-catalyzed extrusion of CO2
from carboxylic acids as an alternative nucleophile-generation
method that proceeds under neutral to weakly acidic conditions.
Although this type of nucleophile generation is a well-known
process in nature,8 it has not been utilized in artificially catalyzed
asymmetric carbon-carbon bond formation.9-12 Currently, there
is an intensive focus on this method as a novel catalytic nucleophile-
activation method that does not require stoichiometric organome-
tallic reagents.13-15
Using 10 mol % CuOAc-(S)-tol-BINAP complex as a catalyst,
we studied the decarboxylative Mannich-type reaction between 1a
and racemic cyanocarboxylic acid 3a (Table 1, entry 3).16 Products
were obtained in 83% combined yield with a 3.5:1 dr, with the
major diastereomer 4aa in 37% ee. Subsequent phosphine-ligand
screening indicated that DTBM-SEGPHOS (5) was the best ligand
in terms of diastereo- and enantioselectivity (7:1 dr and 87% ee;
entry 4). The yield, however, decreased to 30%. A significant
amount of 2, generated through decarboxylative protonation of 3a,
was recovered in this case. Therefore, we tried slow addition of 3a
to a mixture of the catalyst and 1a. As expected, the yield improved
to 91% while the high enantio- and diastereoselectivity were
The products were converted to enantiomerically enriched ꢀ2,2,3
amino acid derivatives without any racemization and epimerization
-
9
9610 J. AM. CHEM. SOC. 2009, 131, 9610–9611
10.1021/ja9036675 CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Catalytic Asymmetric Decarboxylative Mannich-Type
Reaction
with synthetically useful enantio- and diastereoselectivity. Detailed
mechanistic studies and expansion of this catalytic nucleophile-
activation method to other asymmetric reactions are ongoing.
Acknowledgment. Financial support was provided by a Grant-
in-Aid for Scientific Research (B) from JSPS. We thank Dr. Shiro
of Rigaku Corporation for X-ray crystallography of 4ac.
Supporting Information Available: Experimental procedures,
characterization of the products, and crystallographic data (CIF) for
4ac. This material is available free of charge via the Internet at http://
pubs.acs.org.
References
(1) Examples of catalytic asymmetric construction of contiguous quaternary-
trisubstituted carbons: (a) Lee, E. C.; Hodous, B. L.; Bergin, E.; Shih, C.;
Fu, G. C. J. Am. Chem. Soc. 2005, 127, 11586. (b) Chowdari, N. S.; Suri,
J. T.; Barbas, C. F., III. Org. Lett. 2004, 6, 2507. (c) Denmark, S. E.; Wilson,
T. W.; Burk, M. T.; Heemstra, J. R., Jr. J. Am. Chem. Soc. 2007, 129,
14864. (d) Shintani, R.; Murakami, M.; Hayashi, T. J. Am. Chem. Soc.
2007, 129, 12356. (e) Lalonde, M. P.; Chen, Y.; Jacobsen, E. N. Angew.
Chem., Int. Ed. 2006, 45, 6366. (f) Poulsen, T. B.; Alemparte, C.; Saaby,
S.; Bella, M.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2005, 44, 2896. (g)
Hamashima, Y.; Sasamoto, N.; Hotta, D.; Somei, H.; Umebayashi, N.;
Sodeoka, M. Angew. Chem., Int. Ed. 2005, 44, 1525.
(2) A review of catalytic asymmetric synthesis of all-carbon quaternary
centers: Trost, B. M.; Jiang, C. Synthesis 2006, 369.
(3) Shibasaki, M.; Kanai, M. Chem. ReV. 2008, 108, 2853.
(4) (a) An asymmetric synthesis of ꢀ2,2,3-amino acids using a stoichiometric
chiral auxiliary: Tiong, E. A.; Gleason, J. L. Org. Lett. 2009, 11, 1725. (b)
A relevant aldol reaction using a chiral auxiliary: Das, J. P.; Chechik, H.;
Marek, I. Nat. Chem. 2009, 1, 128.
(5) Reviews of the catalytic asymmetric Mannich reaction: (a) Kobayashi, S.;
Ishitani, H. Chem. ReV. 1999, 99, 1069. (b) Marques, M. M. B. Angew.
Chem., Int. Ed. 2006, 45, 348.
(6) Suto, Y.; Tsuji, R.; Kanai, M.; Shibasaki, M. Org. Lett. 2005, 7, 3757.
(7) The low enantio- and diastereoselectivity observed in entries 1 and 2 of
Table 1 were due to the existence of a retro-Mannich reaction under the
direct reaction conditions. When a 7:1 mixture of 4aa (87% ee) and its
diastereomer 4aa′ was subjected to the conditions of entry 2 (10 mol %
CuOtBu-DTBM-SEGPHOS at 0 °C for 24 h), 4aa and 4aa′ were recovered
in 73% yield with 1:1.3 dr, along with imine 1a in 27% yield. The
enantiomeric excess of recovered 4aa was less than 5%.
(8) Polyketide synthase and fatty acid synthase are typical catalysts that utilize
decarboxylative nucleophile generation: Dewick, P. M. Medicinal Natural
Products; Wiley: West Sussex, U.K., 2001.
(9) (a) A catalytic asymmetric aldol reaction using malonic acid half-thioesters:
Magdziak, D.; Lalic, G.; Lee, H. M.; Fortner, K. C.; Aloise, A. D.; Shair,
M. D. J. Am. Chem. Soc. 2005, 127, 7284. (b) This reaction proceeds
through aldol addition followed by decarboxylation: Fortner, K. C.; Shair,
M. D. J. Am. Chem. Soc. 2007, 129, 1032.
(10) Catalytic asymmetric decarboxylative protonation of carboxylic acids has
been reported: (a) Brunner, H.; Schmidt, P. Eur. J. Org. Chem. 2000, 2119.
(b) Amere, M.; Lasne, M.-C.; Rouden, J. Org. Lett. 2007, 9, 2621.
(11) Allyl esters or their derivatives are the main substrates for decarboxylative
nucleophile generation in asymmetric catalysis. Examples: (a) Behenna,
D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2004, 126, 15044. (b) Trost, B. M.;
Xu, J. J. Am. Chem. Soc. 2005, 127, 2846. Also see ref 1d.
(12) Although decarboxylative nucleophile generation was proposed in the
following reports, on the basis of Shair’s mechanistic studies (ref 9) it is
likelythatthesereactionsproceedthroughadditionfollowedbydecarboxylation:(a)
Lubkoll, J.; Wennemers, H. Angew. Chem., Int. Ed. 2007, 46, 6841. (b)
Ricci, A.; Pettersen, D.; Bernardi, L.; Fini, F.; Fochi, M.; Herrera, R. P.;
Sgarzani, V. AdV. Synth. Catal. 2007, 349, 1037.
a Isolated, combined yield of diastereomers. b Diastereomeric ratio
determined by 1H NMR. c Enantiomeric excess of 4 determined by
chiral HPLC. d The absolute and relative configurations were determined
by X-ray crystallography (see the Supporting Information).
(13) Examples of catalytic decarboxylative nucleophile generation in cross-
coupling reactions: (a) Goossen, L. J.; Deng, G.; Levy, L. M. Science 2006,
313, 662. (b) Wang, C.; Piel, I.; Glorius, F. J. Am. Chem. Soc. 2009, 131,
4194. (c) Shang, R.; Fu, Y.; Li, J.-B.; Zhang, S.-L.; Guo, Q.-X.; Liu, L.
J. Am. Chem. Soc. 2009, 131, 5738. (d) Review: Goossen, L. J.; Rodr´ıguez,
N.; Goossen, K. Angew. Chem., Int. Ed. 2008, 47, 3100.
Scheme 1. Conversion to ꢀ2,2,3-Amino Acid Derivatives
(14) Examples of Pd-catalyzed decarboxylative nucleophile generation from allyl
esters (racemic reactions): (a) Shimizu, I.; Yamada, T.; Tsuji, J. Tetrahedron
Lett. 1980, 21, 3199. (b) Tsuda, T.; Chujo, Y.; Nishi, S.; Tawara, K.;
Saegusa, T. J. Am. Chem. Soc. 1980, 102, 6381. (c) Lou, S.; Westbrook,
J. A.; Schaus, S. E. J. Am. Chem. Soc. 2004, 126, 11440. (d) Waetzig,
S. R.; Tunge, J. A. J. Am. Chem. Soc. 2007, 129, 14860.
(15) Use of enzymes or catalytic antibodies: (a) Bjo¨rnestedt, R.; Zhong, G.;
Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 1996, 118, 11720. (b)
Serafimov, J. M.; Gillingham, D.; Kuster, S.; Hilvert, D. J. Am. Chem.
Soc. 2008, 130, 7798.
(16) 3a was readily synthesized from commercially available ethyl phenylcy-
anoacetate in two steps. Cyanoacetate derivatives were utilized on the basis
of our hypothesis that the soft-soft interaction between Cu(I) and nitriles
would facilitate decarboxylation (see ref 6). N-Phosphinoyl imines produced
better results than N-sulfonyl and N-Boc imines.
through hydrolysis of the N-diphenylphosphinoyl moiety and the
cyano group under acidic conditions (Scheme 1).
In conclusion, we have developed a catalytic asymmetric
decarboxylative Mannich-type reaction involving nucleophile gen-
eration via Cu(I)-catalyzed extrusion of CO2 from cyanocarboxylic
acids. This method affords ꢀ2,2,3-amino acid precursors containing
contiguous trisubstituted and all-carbon quaternary stereocenters
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