Atom Economic and Highly Syn‐selective Prolinamide‐Catalyzed Cross‐aldol Addition of Hydroxyacetone to Aromatic Aldehydes

Abstract

The highly selective cross‐aldol addition of hydroxyacetone (HA) to p‐nitro and m‐nitrobenzaldehyde is reported; the reaction is catalyzed by three different di‐ or tripeptides all containing D‐Pro in the N‐terminal position and one or two residues of β³‐homophenylglycine (β³‐hPhg): H‐D‐Pro‐(R)‐β³‐hPhg‐OBn, H‐D‐Pro‐(R)‐β³‐hPhg‐(S)‐β³‐hPhg‐OBn and H‐D‐Pro‐[(S)‐β³‐hPhg]₂‐OBn. Several reaction conditions have been tested, always in the absence of a protecting group on the HA hydroxyl. This reaction affords the desired compounds with complete regioselectivities being the other regioisomer completely avoided. Furthermore high enantioselectivities and satisfactory diastereoselectivities, always favouring the syn diastereoisomers, were obtained. The stereochemistry of the diols was further confirmed by the analysis of the ¹H NMR spectrum of the corresponding carbonates, obtained by reaction of the syn/anti mixtures with triphosgene in presence of dimethylamino‐pyridine (DMAP).

Keywords:

• Cross‐aldol addition
• organocatalysis
• β‐peptides
• hydroxyacetone
• diastereoselectivity

Acknowledgment

We thank Ministero dell'Università e della Ricerca (Progetto di Rilevante Interesse Nazionale 2006) (MIUR) (PRIN 2006), Consiglio Nazionale delle Ricerche-Istituto per la Sintesi Organica e la Fotoreattività (CNR‐ISOF), and the University of Bologna (funds for selected topics) for financial support.