Disulfonimide-catalyzed asymmetric vinylogous and bisvinylogous Mukaiyama aldol reactions.

The term vinylogy, which describes a unique property of p systems where the electron density and reactivity is amplified along conjugated bonds, was proposed 75 years ago by Fuson. The principle becomes particularly relevant in the context of the aldol reaction: While metal dienolates often furnish mixtures of aand g-addition products, the corresponding dienolsilanes react with high selectivity at the remote g position. Asymmetric vinylogous Mukaiyama aldol reactions furnish structural subunits commonly occurring in natural products, as illustrated by the research groups of Carreira, Denmark, Kalesse, and others. Several catalytic, asymmetric versions have been developed over the last few years. However, general and highly stereoselective methods that tolerate a wide range of unactivated substrates are still needed. Moreover, bisvinylogous aldol additions, potentially furnishing a,b,g,d-unsaturated esters in a single step, have to our knowledge not been successfully developed to date. Herein we report asymmetric vinylogous aldol additions, catalyzed by our recently introduced pre-Lewis acidic disulfonimide catalysts 1. We also describe the unprecedented extension of the Mukaiyama aldol addition towards a bisvinylogous e-selective and highly enantioselective variant. Initial computational studies revealed the expected reactivity trends of the extended ketene acetals (Scheme 1). DFT calculations for attack by an electrophile (f (r)) provided the corresponding condensed Fukui functions (CFF), and the electrostatic potentials (ESP). The data obtained for nucleophiles of type 3 were in line with those previously reported, thus suggesting the reaction occurred preferentially in the g position (a= 0.09, g= 0.14). Interestingly for nucleophiles of type 4, compounds that have been obtained previously though never studied in terms of their application in aldol additions, the calculations point to nucleophilic attack from the terminal position as well (a= 0.07, g= 0.07, e= 0.11). However, the values for the different positions vary less than for nucleophiles of type 3, possibly suggesting a less distinct selectivity. Furthermore, the nature of the aldehyde should also influence the outcome of the reaction. Despite the advancements in the asymmetric catalysis of vinylogous Mukaiyama aldol reactions, organocatalytic systems proved to be more challenging to establish. Probably the best system to date was reported byDenmark and co-workers, who described the Lewis base activation of Lewis acids by utilizing chiral hexamethylphosphoramide (HMPA) derivatives in combination with SiCl4. [10] However, even this method has its limitations, either in scope or reactivity, and requires stoichiometric amounts of the Lewis acid. As a starting point for our experimental work we explored our chiral disulfonimide catalyst 1 in the reaction of 2-naphthaldehyde with crotonate-derived nucleophile 3a in different solvents at different temperatures. These studies revealed that Et2O at 78 8C was optimal (see the Supporting Scheme 1. Reactivity and calculated nucleophilic properties of vinylogous nucleophiles for the Mukaiyama aldol reaction. The isosurfaces correspond to values of 0.025 a.u. (ESP) and 0.01 and 0.005 a.u. for Fukui functions. TBS= tert-butyldimethylsilyl.