Published on Web 04/17/2007
Practical Synthesis of Enantiomerically Pure â2-Amino Acids
via Proline-Catalyzed Diastereoselective Aminomethylation of
Aldehydes
Yonggui Chi, Emily P. English, William C. Pomerantz, W. Seth Horne, Leo A. Joyce,
Lane R. Alexander, William S. Fleming, Elizabeth A. Hopkins, and
Samuel H. Gellman*
Contribution from the Department of Chemistry, UniVersity of Wisconsin,
Madison, Wisconsin 53706
Received January 4, 2007; E-mail: gellman@chem.wisc.edu
Abstract: Proline-catalyzed diastereoselective aminomethylation of aldehydes using a chiral iminium ion,
generated from a readily prepared precursor, provides R-substituted-â-amino aldehydes with 85:15 to 90:
10 dr. The R-substituted-â-amino aldehydes can be reduced to â-substituted-γ-amino alcohols, the major
diastereomer of which can be isolated via crystallization or column chromatography. The amino alcohols
are efficiently transformed to protected â2-amino acids, which are valuable building blocks for â-peptides,
natural products, and other interesting molecules. Because conditions for the aminomethylation and
subsequent reactions are mild, â2-amino acid derivatives with protected functional groups in the side chain,
such as â2-homoglutamic acid, â2-homotyrosine, and â2-homolysine, can be prepared in this way. The
synthetic route is short, and purifications are simple; therefore, this method enables the preparation of
protected â2-amino acids in useful quantities.
We recently reported a new route to protected â2-amino acids8
Introduction
that is based on enantioselective aminomethylation of aldehydes9
via an organocatalytic Mannich reaction.10-12 The Mannich
reaction involves diphenylprolinol TMS ether (1) as catalyst
and a formaldehyde-derived iminium generated in situ from
N,O-acetal 2 as the electrophile. Our route to protected â2-amino
â2-Amino acids are 3-aminopropanoic acids bearing a single
substituent adjacent to the carboxylic acid group. â2-Amino acid
residues can be found embedded within natural products that
exhibit interesting biological activities.1 In addition, â2-residues
are essential for the formation of specific â-peptide secondary
structures2 (e.g., 12/10-helix, â2/â3 reverse turn3). Designed
â-peptides containing â2-residues display useful functions
including mimicry of somatostatin signaling4 and inhibition of
viral infection.5 Many routes to enantio-enriched â2-amino acids
or protected derivatives have been described; however, most
of these routes involve tedious chromatographic purifications
(e.g., isolation of diastereomers from alkylation of chiral
enolates), and few of these synthetic approaches are amenable
to large-scale synthesis or diversity in side-chain functionality.6,7
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Tetrahedron 2002, 58, 7991. For selected examples: (d) Lee, H.-S.; Park,
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Moumne, R.; Lavielle, S.; Karoyan, P. J. Org. Chem. 2006, 71, 3332. (f)
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B. L. J. Am. Chem. Soc. 2003, 125, 3700. (b) Huang, H.; Liu, X.; Deng,
J.; Qiu, M.; Zheng, Z. Org. Lett. 2006, 8, 3359. (c) Swiderska, M. A.;
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J. AM. CHEM. SOC. 2007, 129, 6050-6055
10.1021/ja070063i CCC: $37.00 © 2007 American Chemical Society