Stereoselective acetate aldol reactions of a-silyloxy ketones Adriana Lorente, Miquel Pellicena, Pedro Romea * ,F  elix Urpí * Departament de Química Org anica and Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona, Carrer Martí i Franqu es, 1-11, 08028 Barcelona, Catalonia, Spain article info Article history: Received 13 November 2014 Received in revised form 18 December 2014 Accepted 29 December 2014 Available online 3 January 2015 Keywords: Stereoselective reactions Acetate aldol reactions Titanium enolates Chiral ketones abstract TiCl 4 -mediated aldol reactions of chiral methyl a-silyloxy ketones with a variety of aldehydes provide the corresponding 1,4-syn aldol adducts with moderate to high stereocontrol. This transformation represents a new approach to substrate-controlled acetate aldol reactions and complements the 1,4-anti asymmetric induction produced by the related a-benzyloxy ketones. This new approach could be useful in the design of more efficient syntheses of natural products. Ó 2015 Elsevier Ltd. All rights reserved. 1. Introduction The coupling of elaborate fragments in the advanced steps of a synthesis requires full knowledge of the particular trends of the reacting species. 1,2 This is especially important in asymmetric synthesis, in which the configurations of the new chirality centres usually rely on subtle steric and electronic influences due to several groups within the reactants. 3 Acetate aldol reactions illustrate such a scenario. 4,5 Indeed, the resultant b-hydroxy carbonyl structures are found in a large array of natural products and, in principle, they could be easily synthesized by aldol addition of methyl ketones to aldehydes. 5,6 Nevertheless, and despite recent advances in catalytic asymmetric-based 5g,h,7 and chiral auxiliary-based 5g,h,8 approaches, there is still a shortage of methods to achieve such transformations both in structurally simple as well as structurally complex in- termediates in advanced steps of a synthesis. 9 Thus, substrate- controlled aldol reactions based on metal enolates from chiral methyl ketones are an appealing way to address this challenge provided that one has a thorough understanding of the asymmetric induction that the enolate and the aldehyde undergo. 5g,h,10e12 Un- fortunately, this is much more demanding than it is in related processes from ethyl ketones since metal enolate-mediated aldol reactions involving chiral methyl ketones can proceed through several six-membered cyclic transition states of similar energy. 13 Therefore, prediction of the stereochemical outcome of these reactions is always problematic and requires comprehensive anal- ysis of the influence of both the ketone and the aldehyde on the configuration of the new stereocentre. Keeping these challenges in mind, some years ago we launched a project to develop stereoselective aldol reactions from titaniu- m(IV) enolates of chiral methyl ketones. 14,15 These titanium(IV) enolates can be prepared by simple treatment of methyl ketones with titanium(IV) Lewis acids in the presence of a tertiary amine, 16,17 and they can react with a large array of aldehydes under mild conditions. Furthermore, we envisaged that the relatively short TieO distances and the possibility of attaching different li- gands to the metal might furnish the tight transition states that are essential for highly stereocontrolled transformations. 18 This proved to be the case in the aldol additions of b-as well as a-benzyloxy methyl ketones (see Eqs. 1 and 3 in Scheme 1). 14,15 A parallel pro- cess based on b-silyloxy methyl ketones turned out to be non stereoselective (Eq. 2 in Scheme 1), so the benzyl protecting group seemed to be crucial for the success of these reactions. Neverthe- less, preliminary studies of the addition of titanium(IV) enolates from a-tert-butyldimethylsilyloxy methyl ketones to aliphatic, aromatic and a,b-unsaturated aldehydes showed that the corre- sponding 1,4-syn aldols could be obtained in good yields (see Eq. 4 in Scheme 1). 19 Encouraged by these results, we have now carried out a comprehensive analysis of such a transformation that com- plements the 1,4-anti induction observed for the related a-benzy- loxy methyl ketones (compare Eqs. 3 and 4 in Scheme 1). Herein, we report our findings on the substrate-controlled titanium-me- diated aldol reactions of a-silyloxy methyl ketones that produce 1,4-syn aldol adducts with moderate to high diastereoselectivity depending on the steric hindrance of the R group and the aldehyde. * Corresponding authors. Tel.: þ34 93 4039106; fax: þ34 93 3397878 (P.R.); tel.: þ34 93 4021247; fax: þ34 93 3397878 (F.U.); e-mail addresses: pedro.romea@ ub.edu (P. Romea), felix.urpi@ub.edu (F. Urpí). Contents lists available at ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet http://dx.doi.org/10.1016/j.tet.2014.12.099 0040-4020/Ó 2015 Elsevier Ltd. All rights reserved. Tetrahedron 71 (2015) 1023e1035