Vinylketene silyl acetal

The first systematic investigation toward Lewis acid catalyzed vinylogous Mukaiya ma Mannich reactions was reported by the group of Ojima in 1987 who showed that acyclic vinylketene silyl 0,0 acetals 10 reacted with imines activated by stoichio metric amounts of TiCU to furnish either 5 amino 2 alkenoates 11 or 5,6 dihydro pyridones 12 selectively in excellent yields depending upon the substitution of the silyl dienolate employed (Scheme 5.4) [5]. Although 2 methyl substituted vinylketene acetal 10a gave rise to acyclic 5 amino 2 alkenoates 11 exclusively, 3 methyl substi tuted vinylketene acetal 10b furnished 5,6 dihydropyridones 12 as the sole products. 

Scheme 5.9 Catalytic cycle for the vinylogous Mannich reaction of vinylketene silyl 0,0 acetal 30 developed by Schneider and Sickert [14a].

Lewis acid promoted reactions of silicon enolates, /.e., silyl enol ethers and ketene silyl acetals with various electrophiles have yielded a wealth of novel and selective synthetic methods. This combination of reagents has been used in the past to perform such reactions as aldol-condensations with aldehydes and acetals, imine-condensations, conjugate additions to a,P-enones, alkylations, electrophilic aminations, and Diels-Alder/cyclocondensations. Our own interest in this field has involved the use of titanium tetrachloride to promote the reaction of ketene silyl acetals with non-activated imines as an efficient route to P-lactams. This reaction has been applied to the asymmetric synthesis of P-lactams via a chiral imine-titanium tetrachloride template. We have also found that both ketene silyl acetals and vinylketene silyl acetals oxidativelly dimerize or cross-couple, in the presence of titanium tetrachloride to conveniently yield various diesters . Our present study concerns reactions of vinylketene silyl acetals with non-activated imines and vinylimines promoted by titanium and zirconium tetrachlorides. 

Vinylketene silyl acetals (VKSAs) (1) possess two reaction sites, a and y. Simple imines (2) have only one reaction site, but vinylimines (3) can accept either 1,2- or 1, /-addition by an incoming nucleophile. Conceptually, this leads to two types of adducts, i.e a- and y-adducts, for the reaction of VKSAs (I) with simple imines (2), but four different ones, i.e., a-1, 2, a-1, 4, y-/, 2, and y-/, 4, for the VESA (I)-vinylimine (3) combination (Chart 1). Those adducts may also have cyclic and acyclic variations. With this in mind we studied the reactions of VKSAs (1) with simple imines (2) and vinylimines (3) promoted by titanium tetrachloride and zirconium tetrachloride. We will describe here the scope of these new reactions including (i) substitution effects on the reactivity and regioselectivity of the reaction, (ii) formation of 2-pyridones and novel aminomethylidenecyclohexenones through a unique addition-cyclizadon pathway, and (iii) possible mechanisms of these reactions. 

Reactions of Vinylketene Silyl Acetals with Simple Imines... 

Yield determined by GLC, Conversion yield based on the imine consumed. Isolated yield. Vinylketene silyl acetal used in excess. 

Reactions of Vinylketene Silyl Acetals with Vinylimines 3.1. REACTIONS USING TiC AS THE PROMOTER... 

Giera DS, Sickert M, Schneider C (2008) Brfmsted Acid-Catalyzed, Enantioselective, Vinylogous Mannich Reaction of Vinylketene Silyl N,0-Acetals. Org Lett 10 4259... 

A silver salt dramatically reverses the diastereoselectivity of a titanium-chloride-mediated vinylogous Mukaiyama aldol reaction of a chiral vinylketene silyl N, 0-acetal with ethyl glyoxolate. ° ... 

Remote asymmetric induction can be obtained through the use of chiral auxiliaries, such as valine derived oxazolidinones, within the framework of the vinylogous Mukaiyama aldol reaction. During the synthesis of khafrefungin, an antifungal agent, Kobayashi and coworkers reacted the vinylketene silyl A. O-acetal 56 with the aldehyde 57 to yield the a r/-aldol adduct 58 in excellent yield (98%) and high diastereoselectivity (> 20 1). ... 

An asymmetric protocol using a covalently attached chiral auxiliary was reported by Kobayashi [51]. They used the Evans auxiliary to generate vinylketene silyl V,0-acetal 43 (Scheme 2.131). This nucleophile performs in an efficient and highly selective 1,7 asymmetric induction. The stereochemical outcome was rationalized by transition state 45 in which the isopropyl group of the auxiliary shields the upper face of the dienol and the aldehyde approaches from the least... 

The authors propose a transition state for the pivotal Mukaiyama aldol reaction that puts the aromatic ring of the substrate in an anti-orientation to the a-methyl group of the vinylketene silyl A,0-acetal. Thus the rational for the transition state follows the basic concept for this structural motif, and once more, the a-methyl group plays a pivotal role for the stereo-directing effects. 

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