ORGANIC
LETTERS
2004
Vol. 6, No. 15
2507-2510
Asymmetric Synthesis of Quaternary r-
and â-Amino Acids and â-Lactams via
Proline-Catalyzed Mannich Reactions
with Branched Aldehyde Donors
Naidu S. Chowdari, Jeff T. Suri, and Carlos F. Barbas III*
The Skaggs Institute for Chemical Biology and the Departments of Chemistry and
Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road,
La Jolla, California 92037
Received April 23, 2004
ABSTRACT
L-Proline-catalyzed direct asymmetric Mannich reactions of N-PMP protected r-imino ethyl glyoxylate with various r,r-disubstituted aldehydes
affords quaternary â-formyl r-amino acid derivatives with excellent yields and enantioselectivities. The Mannich products are further converted
to the corresponding quaternary r- and â-amino acids and â-lactams.
Optically active R- and â-amino acids are fundamental
building blocks for the preparation of molecules important
for the pharmaceutical and agrochemical industries such as
peptides, proteins, and other natural products.1 Furthermore,
amino acids are extensively used as chiral auxiliaries and
catalysts in modern organic synthesis. The asymmetric
synthesis of quaternary amino acid derivatives is a difficult
and challenging task.2 Some of these unusual amino acids
are components of enzyme inhibitors, and their incorporation
into peptides is used to modulate secondary and tertiary
structural conformations.3 In particular, aspartic acid deriva-
tives are structural components of virus inhibitors.4
Recently, proline- and proline derivative-catalyzed asym-
metric aldol,5 Mannich,6 Michael,7 Diels-Alder,8 amination,9
oxidation,10 chlorination,11 Robinson annulation,12 and multi-
component or assembly reactions13 have been developed. In
(1) Ma, J. Angew. Chem., Int. Ed. 2003, 42, 4290.
(2) (a) Vachal, P.; Jacobsen, E. N. Org. Lett. 2000, 2, 867. (b) Trost, B.
M.; Dogra, K.; J. Am. Chem. Soc. 2002, 124, 7256. (c) Spino, C.; Gobdout,
C. J. Am. Chem. Soc. 2003, 125, 12106.
(3) (a) Shirlin, D.; Gerhart, F.; Hornsperger, J. M.; Harmon, M.; Wagner,
I.; Jung, M.; J. Med. Chem. 1988, 31, 30. (b) Karle, I.; Kaul, R.; Roa, R.
B.; Raghothama, S.; Balaram, P. J. Am. Chem. Soc. 1997, 119, 12048.
(4) Moss, N.; Ferland, J. M.; Goulet, S.; Guse, I.; Malenfant, E.;
Plamondon, L.; Plante, R.; Deziel, R. Synthesis 1997, 32.
(5) (a) List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 2000,
122, 2395. (b) Saktihvel, K.; Notz, W.; Bui, T.; Barbas, C. F., III. J. Am.
Chem. Soc. 2001, 123, 5260. (c) Co´rdova, A.; Notz, W.; Barbas, C. F., III.
J. Org. Chem. 2002, 67, 301. (d) Northrup, A. B.; MacMillan, D. W. C. J.
Am. Chem. Soc. 2002, 124, 6798. (e) Bogevig, A.; Kumaragurubaran, N.;
Jorgensen, K. A. Chem. Commun. 2002, 620. (f) Mase, N.; Tanaka, F.;
Barbas, C. F., III. Angew. Chem., Int. Ed. Engl. 2004, 43, 2420. (g) Torii,
H.; Nakadai, M.; Ishihara, K.; Saito, S.; Yamamoto, H. Angew. Chem., Int.
Ed. Engl. 2004, 43, 1983.
(6) (a) Notz, W.; Sakthivel, K.; Bui, T.; Barbas, C, F., III. Tetrahedron
Lett. 2001, 42, 199. (b) Co´rdova, A.; Notz, W.; Zhong, G.; Betancort, J.
M.; Barbas, C. F., III. J. Am. Chem. Soc. 2002, 124, 1842. (c) Co´rdova, A,
Watanabe, S.-i.; Tanaka, F.; Notz, W.; Barbas, C. F., III. J. Am. Chem.
Soc. 2002, 124, 1866. (d) Chowdari. N. S.; Ramachary, D. B.; Barbas, C.
F., III. Synlett. 2003, 1906. (e) Notz, W.; Tanaka, F.; Watanabe, S.-i.;
Chowdari, N. S.; Thayumanavan, R.; Barbas, C. F., III. J. Org. Chem. 2003,
68, 9624. (f) List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J. J. Am. Chem.
Soc. 2002, 124, 827.
(7) (a) Betancort, J. M.; Sakthivel, K.; Thayumanavan, R.; Barbas, C,
F., III. Tetrahedron Lett. 2001, 42, 4441. (b) Betancort, J. M.; Barbas, C,
F., III. Org. Lett. 2001, 3, 3737. (c) Enders, D.; Seki, A. Synlett 2002, 26.
(d) Alexakis, A.; Andey, O. Org. Lett. 2002, 4, 3611. (e) Mase, N.; Thayu-
manavan, R.; Tanaka, F.; Barbas, C. F., III. Org. Lett. 2004, 6, 2527.
10.1021/ol049248+ CCC: $27.50 © 2004 American Chemical Society
Published on Web 06/25/2004