The catalytic tandem oxidation/benzilic ester rearrangement (BER): insights into reaction mechanism and stereoselectivity Carolina Silva Marques, a Nuno M. M. Moura, a Anthony J. Burke a, * and Olı ´via R. Furtado b a Departamento de Quı ´mica and Centro de Quı ´mica de E ´ vora, Universidade de E ´ vora, Rua Roma ˜o Romalho 59, 7000 E ´ vora, Portugal b Departamento de Tecnologia de Indu ´ strias Quı ´micas, Instituto Nacional de Engenharia, Tecnologia e Inovac ¸a ˜o, Estrada do Pac ¸o do Lumiar, Edifı ´cio F, 1649-038 Lisboa, Portugal Received 7 July 2007; revised 16 August 2007; accepted 10 September 2007 Available online 14 September 2007 Abstract—This Letter describes an expeditious regiospecific and stereoselective approach to tertiary a-hydroxyesters via a simple one pot tandem catalytic oxidation/benzilic ester rearrangement of acyclic a-hydroxyketone substrates. Mechanistic studies confirming the regioselective nature of this reaction are discussed, including some insights into the nature of the stereoselectivity encountered in this reaction. Ó 2007 Elsevier Ltd. All rights reserved. The benzilic acid rearrangement (BAR) was discovered by Liebig in 1838 1 and since then both this (hydrox- ide = nucleophile) and the analogous benzilic ester rear- rangement (BER) (alkoxide = nucleophile) has been the subject of a plethora of experimental and theoretical studies over the last 50 years. 2,3 This 1,2-rearrangement has been applied to the synthesis of a number of impor- tant compounds. 4–6 For cyclic systems it is quite useful from a synthetic point in that, like such rearrangements as the Favorskii rearrangement, it leads to ring con- tracted products. As an approach to the creation of the tertiary a-hydroxy ester functionality, a unit which is present in a plethora of biologically active compounds like, oxybutynin 7 and topotecan, 8 we have recently introduced a simple highly efficient strategy based on the tandem stoichiometric oxidation/benzilic ester rearrangement of a-hydroxy- ketone substrates (Scheme 1). 9 We have shown that a-hydroxyketone substrates are readily oxidised in situ to intermediate a-diketones (this was confirmed by the isolation of a quinoxaline adduct upon adding 1,2- diaminobenzene to the reaction mixture 9 ) which subse- quently undergo stereoselective benzilic ester rearrange- ments affording tertiary a-hydroxy ester diastereomers when attacked by an appropriate nucleophile (e.g., methoxide or ethoxide, etc.). As far as we are aware, studies on the stereoselectivity of this rearrangement in acyclic systems are quite rare. In this Letter we report our very recent findings on the results of an experiment verifying the exclusive Ar O OH X Ph X = OMe, OEt or Me RO 2 C HO Ar Ph H X RO 2 C HO Ar Ph X H + anti syn Ar O X Ph O [O] ROH BER Scheme 1. 0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2007.09.066 Keywords: Benzilic acid rearrangment; Benzilic ester rearrangment; Isotopic label; Regioselectivity; Diastereoselectivity. * Corresponding author. Tel.: +351 266745310; fax: +351 266745303; e-mail: ajb@dquim.uevora.pt Tetrahedron Letters 48 (2007) 7957–7960