1,4-syn-Asymmetric induction in the titanium-mediated aldol reactions of chiral methyl a-silyloxy ketones Adriana Lorente, Miquel Pellicena, Pedro Romea * , Fèlix Urpí * Departament de Química Orgànica, Universitat de Barcelona, Martí i Franqués 1-11, 08028 Barcelona, Catalonia, Spain article info Article history: Received 4 November 2009 Revised 4 December 2009 Accepted 9 December 2009 Available online 13 December 2009 Keywords: Stereoselective reactions Acetate aldol reactions Titanium enolates Chiral ketones abstract Good levels of 1,4-syn asymmetric induction are obtained in the TiCl 4 -mediated aldol reaction of methyl a-silyloxy ketones with achiral aldehydes. Such methodology represents a new approach to the sub- strate-controlled acetate aldol reaction, which can be useful to design more efficient syntheses of natural products. Ó 2009 Elsevier Ltd. All rights reserved. In spite of the large number of highly stereoselective aldol methodologies 1 developed during the last decades and their suc- cessful application to the synthesis of natural products, 2 the acetate aldol reaction 3 is still a matter of concern. 1,4 Indeed, the lack of mechanistic models to understand the stereochemical outcome of these reactions 5,6 makes it difficult to use them for coupling large fragments in advanced steps of a synthesis. 7 Particularly, it is remarkable to note the scarce number of studies on aldol reac- tions from protected a-hydroxy methyl ketones. 8,9 In this context, we established that the titanium-mediated aldol reactions of chiral a-benzyloxy methyl ketones provide the corresponding 1,4-anti adducts in good yields and diastereomeric ratios. 10 More recently, Kalesse and co-workers reported that the enol borinates and the alkaline enolates from related a-silyloxy ketones show the same 1,4-anti asymmetric induction. 11,12 Thus, considering the impor- tance of this transformation and taking advantage of our experi- ence with chiral ethyl a-hydroxy ketones, 13 we envisaged that the appropriate choice of the titanium(IV) Lewis acid and the hydroxyl protecting group might give access to 1,4-syn-selective aldol reactions. Herein, we document that a-tert-butyldimethylsi- lyloxy methyl ketones 1–3 represented in Scheme 1 impart such asymmetric induction, which can be useful to design more flexible syntheses of structurally complex natural products. At first, we surveyed the influence of the titanium Lewis acid on the stereochemical outcome of the aldol reactions from lactate- derived ketone 1 14 and isobutyraldehyde (a). Disappointingly, pre- liminary experiments with mild (i-PrO) 2 TiCl 2 and (i-PrO)TiCl 3 Lewis acids furnished low yields of the desired 1,4-syn aldol 4a. In- deed, the experimental conditions optimized for related ethyl ke- tones 13c afforded aldol 7 as the major component of the reaction mixtures (see entries 1 and 2 in Table 1). Such unexpected results suggest that the enolization step is slow enough to allow the resulting enolate to attack the activated ketone and deliver the self-condensation adduct 7. Even the stronger TiCl 4 produced a sig- nificant amount of this adduct at À78 °C (see entry 3 in Table 1). Lowering the enolization temperature to À94 °C increased the overall yield (71%) of aldols 4 and 5 (1,4-syn and 1,4-anti, respectively) and minimized the formation of 7 (see entry 4 in Table 1). 15 However, it was then clear that tiny amounts of hemiacetal 6a were also formed during the aldol reaction and could be isolated after chromatographic purification as a single diastereomer. Hence, assuming that 6a arises from 4a, the 0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2009.12.046 * Corresponding authors. Tel.: +34 934039106; fax: +34 933397878 (P.R.); tel.: +34 934021247; fax: +34 933397878 (F.U.). E-mail addresses: pedro.romea@ub.edu (P. Romea), felix.urpi@ub.edu (F. Urpí). R 1 BnO O R 1) (i-PrO)TiCl 3 , i-Pr 2 NEt R 1 BnO O 2) RCHO 1,4-anti aldol R 1 O R 1) TiL 4 , i-Pr 2 NEt R 1 TBSO O 2) RCHO 1,4-syn aldol 1 R 1 : Me 2 R 1 : Bn 3 R 1 : i-Pr Ref. 10 This study TBSO OH OH 1 4 1 4 Scheme 1. Asymmetric induction in titanium-mediated aldol reactions from chiral a-hydroxy methyl ketones. Tetrahedron Letters 51 (2010) 942–945 Contents lists available at ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet