Efficient Preparation of α-Ketoacetals.docVIP

Molecules 2012, 17, 13864-13878; doi:10.3390/molecules171213864 OPEN ACCESS molecules ISSN 1420-3049 /journal/molecules Article Efficient Preparation of α-Ketoacetals Francisco Ayala-Mata, Citlalli Barrera-Mendoza, Hugo A. Jiménez-Vázquez, Elena Vargas-Díaz and L. Gerardo Zepeda * Departamento de Química Orgánica, Escuela Nacional de Ciencias Biológicas del IPN, Prol. de Carpio y Plan de Ayala S/N, Col. Santo Tomás, Deleg. Gustavo A. Madero, México, DF 11340, Mexico * Author to whom correspondence should be addressed; E-Mail: lzepeda@woodward.encb.ipn.mx; Tel.: +52-55-5729-6300 (ext. 62412); Fax: +52-55-5396-3503. Received: 22 October 2012; in revised form: 31 October 2012 / Accepted: 19 November 2012 / Published: 22 November 2012 Abstract: The Weinreb amides 2a,b were prepared from the α,α-dimethoxyacetic acids 1c,d. A number of representative nucleophilic additions (RMgX and RLi) on 2 afforded α-ketoacetals 3a–j in 70–99% yield. These compounds represent a versatile arrangement of functional groups of significant synthetic value, as demonstrated in the synthesis of (±)-salbutamol. Keywords: α,α-dimethoxyacids; Weinreb amide; Grignard reagents; α-ketoacetals; salbutamol 1. Introduction The α-ketoacetals constitute a strategic array of functional groups of great value in synthetic organic chemistry. They offer the possibility of performing the selective functionalization of a keto group over the more reactive aldehyde, as the latter is protected as an acetal. For instance, α-ketoacetals are key intermediates in the preparation of chiral cyanohydrins [1], nicotine derivatives [2], chiral sulfoxides [3], α-hydroxy acetals [4–6], chiral 1,2-diols [7] and, of particular importance for our research group, of several myrtenal-derived chiral auxiliaries [8–10]. A number of methods have been described for the preparation of α-ketoacetals, including the classic acetalization of monoalkyl-substituted glyoxals with trialkylort