Substrate-Controlled Michael Additions of Chiral Ketones to Enones Mireia Fa ̀ bregas, † Alejandro Gó mez-Palomino, † Miquel Pellicena, † Daniel F. Reina, † Pedro Romea,* ,† Fe ̀ lix Urpí,* ,† and Merce ̀ Font-Bardia ‡ † Departament de Química Orga ̀ nica and Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona, Carrer Martí i Franque ́ s 1-11, 08028 Barcelona, Catalonia, Spain ‡ Unitat de Difracció de RX. CCiTUB, Universitat de Barcelona, Carrer Sole ́ i Sabarís 1-3, 08028 Barcelona, Catalonia, Spain * S Supporting Information ABSTRACT: Substrate-controlled Michael additions of the titanium- (IV) enolate of lactate-derived ketone 1 to acyclic α,β-unsaturated ketones in the presence of a Lewis acid (TiCl 4 or SnCl 4 ) provide the corresponding 2,4-anti-4,5-anti dicarbonyl compounds in good yields and excellent diastereomeric ratios. Likely, the nucleophilic species involved in such additions are bimetallic enolates that may add to enones through cyclic transition states. Finally, further studies indicate that a structurally related β-benzyloxy chiral ketone can also participate in such stereocontrolled conjugate additions. C omprehensive studies carried out in the 1980s on the conjugate addition of metal enolates to α,β-unsaturated compounds, the venerable Michael reaction, provided a reasonably good understanding of the key elements that determine the relative configuration of the resultant adducts. 1,2 Despite these early achievements and the ensuing exploitation of this transformation in the synthesis of natural products, there is still a shortage of asymmetric Michael methodologies. 3,4 Highly enantioselective catalyzed intermolecular additions of esters or ketones to α,β-unsaturated compounds have recently been reported, but they only cover a small range of substrates. Indeed, their scope is usually restricted to the most easily enolizable carbonyl compounds and the best acceptors; furthermore, just a few of them have succeeded in the simultaneous installation of two new chiral centers (R 1 ≠ R 2 and R 3 ≠ R 4 in Scheme 1). 5,6 Therefore, the stereoselective construction of 1,5-dicarbonyl structures through conjugate intermolecular additions of simple carbonyl derivatives to α,β-unsaturated ketones or esters is still a challenging transformation. In this context, classical chiral auxiliary-like approaches based on chiral hydrazines 7 or oxazolidinones 8 have been reported, but their scope is often narrower than that attained in other representative C-C bond- forming reactions. Moreover, and to the best of our knowledge, no substrate-controlled Michael reactions from chiral ketones have been reported to date. Considering that highly reactive titanium(IV) enolates could fill this void, we envisaged that substrate-controlled Michael additions of titanium(IV) enolates from lactate-derived α-benzyloxy ethyl ketone 1 9 to enones might produce 1,5-diketones containing up to two new stereocenters. Herein, we describe conjugate additions of titanium enolates of 1 to a wide range of enones in the presence of a second equivalent of a Lewis acid. These reactions give the corresponding adducts in a highly stereocontrolled manner and good yield. Preliminary experiments showed that the dibutylboron enolate from 1 was unable to undergo conjugate additions to methyl vinyl ketone (a) and the starting material 1 was recovered unchanged even after long reaction times (entry 1, Table 1). In turn, the lithium enolate counterpart turned out to be more reactive, but it only afforded tiny amounts of the Michael adduct 2a (entry 2, Table 1). 10-12 Thus, we were pleased to observe that the titanium(IV) enolate of 1 afforded 2a as a single diastereomer, albeit in a low 23% yield (entry 3, Table 1). 13 Encouraged by such an outstanding stereocontrol and taking advantage of our experience with these titanium enolates, we assessed the influence of a second equivalent of TiCl 4 . 14 Under these conditions, the reaction with 1.2 equiv of a proceeded smoothly and 2a was obtained with excellent diastereoselectivity (dr >97:3) and yields of 70% and 80% after 2 and 5 h respectively (entries 4 and 5, Table 1). Longer reaction times, higher temperatures, and a higher loading of enone did not improve this result (entries 4-7, Table 1). Instead, such conditions led to a more elaborate Michael adduct (3a), arising from the subsequent conjugate addition of a putative titanium enolate intermediate. It was obtained in variable yields and with a moderate diastereoselectivity (entries 6 and 7, Table 1). Importantly, the addition of the second equivalent of TiCl 4 at the beginning of the enolization (see entries 4-7 of Table 1) simplified the experimental procedure. Received: October 29, 2014 Published: November 25, 2014 Scheme 1. Michael Additions of Metal Enolates Letter pubs.acs.org/OrgLett © 2014 American Chemical Society 6220 dx.doi.org/10.1021/ol503133j | Org. Lett. 2014, 16, 6220-6223