Synlett 2004(3): 558-560  
DOI: 10.1055/s-2004-817745
LETTER
© Georg Thieme Verlag Stuttgart · New York

5-Pyrrolidin-2-yltetrazole: A New, Catalytic, More Soluble Alternative to ­Proline in an Organocatalytic Asymmetric Mannich-type Reaction

Alexander J. A. Cobb, David M. Shaw, Steven V. Ley*
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
Fax: +44(1223)336442; e-Mail: svl1000@cam.ac.uk;
Further Information

Publication History

Received 9 January 2004
Publication Date:
06 February 2004 (online)

Abstract

A Mannich-type addition of ketones to N-PMP protected α-imino ethyl glyoxalate is catalyzed by a new proline analogue, 5-pyrrolidin-2-yltetrazole 1. The new organocatalyst has significant advantage over its parent in that it can be used in non-polar solvents without loss of enantioselectivity.

    References

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7

The tetrazole is not soluble in neat ketone.

8

General Procedure: N-PMP-protected α-imino ethyl glyoxalate (93.5 mg, 0.5 mmol) was dissolved in anhydrous CH2Cl2 (4 mL). Carbonyl-containing compound (1 mL, 20 vol%) was added to this solution followed by 5-pyrrolidin-2-yltetrazole (3.5 mg, 5 mol%) and the resulting mixture stirred under argon for 2-24 h. After this time, the mixture was quenched with sat. NH4Cl solution (10 mL) and the aqueous layer extracted with EtOAc (2 × 25 mL). The combined organic layers were dried (MgSO4), filtered and evaporated under reduced pressure to give a residue which was further purified by column chromatography using varying mixtures of EtOAc and petroleum ether 40-60 as eluent.

10

Determined by chiral HPLC (3): Chiralcel AS 0.7 mLmin-1, 6% 2-propanol: 94% hexane; tR(major) = 18 min, tR(minor) = 24 min. 5: Chiralcel AS 0.7 mLmin-1 94% hexane: 6% 2-propanol; tR(major) = 14 min, tR(minor) = 16 min. 6: Chiralcel AS 1 mLmin-1 85% hexane: 15% 2-propanol; tR(major) = 16 min, tR(minor) = 22 min. 7: Chiralcel OD 1 mLmin-1, 5% 2-propanol: 95% hexane; tR(major) = 13.5 min, tR(minor) = 19 min. 9 (lactone): Chiralcel AS 0.7 mLmin-1 94% hexane: 6% 2-propanol; tR(minor) = 43 min, tR(major) = 57 min. For retention times of 2, 4 and 8 see ref. 5a

11

In order to obtain separation on HPLC, the aldehyde was converted to the lactone by reduction with sodium borohydride (Scheme [3] ) before chromatography to avoid epimerization. This represents a good route to enantiopure functionalized 1-amino-2-alkyl-δ-lactones.

Scheme 3