Asymmetric Vinylogous Aldol Reaction Catalyzed By Combined Lewis Acid

The asymmetric Vinylogous Aldol reaction has been emerging as one of the most important C-C bonds forming tools, as the obtained δ-hydroxy-p-keto esters or δ-hydroxy-a, P-unsaturated esters are versatile intermediates and structural motifs in total synthesis of natural products and commercial drugs. In the last two decades, several effective asymmetric catalysts have been developed for this transformation and a combination of those methodology has produced high reactivities and stereoselectivities with a wide range of the substrates. However, those methods still suffer from some drawbacks:unfriendly conditions, expensive reagents, or narrow substrates tolerance. To address these issues in this paper, we developed a novel bimetallic catalytic complex which was generated by a combination of the well-known BINOL-Ti complex and the achiral salt LiCl, and this combined Lewis acids proved to be a versatile catalyst for the vinylogous Mukiayama aldol reactions between aldehydes and various silyl dienolates.After elaborate investigation of the catalyst composition and the amount of LiCl, the combined-Lewis-acid catalytic system BTHL, BINOL-Ti-H2O-LiCl (1:1:1:1), was generated in situ from a sequential combination of BINOL, Ti(OiPr)4, H2O, and lithium chloride. Utilizing this BTHL catalyst, we realized the first example of highly asymmetric Vinylogous Aldol reaction of Brassard’s diene with aldehydes, affording the desired aldol products δ-hydroxy-p-methoxyacrylates in good yields (up to77%) and excellent enantioselectivities (up to99%ee). This method was handled under mild conditions, and it is suitable for various aromatic aldehydes but provides low reactivity for aliphatic aldehydes.An extension of the BTHL catalyst to the vinylogous aldol reaction of dioxinone-derived sliyl diene was then carried out, and perfect yields up to93%and enantioselectivities up to98%ee were obtained for both aromatic and aliphatic aldehydes. Using this method, a convenient and two-step total synthesis of the natural product (S)-(+)-dihydrokavain was accomplished in91%ee and71%overall yield.Finally, we revealed that the BTHL was also an effective catalyst for asymmetreic vinylogous aldol reaction with propionylacetate derived Brassard’s diene. Both aromatic and aliphatic aldehydes were well tolerated under this methodology in perfect yields (up to95%) with excellent stereoselectivities (ee up to99%, dr up to99:1), affording the corresponding δ-hydroxy-y-methyl-β-methoxyacrylates with syn vicinal stereogenic centers. And this methodology was then utilized in formal synthesis of the natural products, Melithiazole C and Cystothiazole A, featuring simultaneous formation of the vicinal stereogenic centers and the β-methoxy acrylate moiety with well controlled stereochemistry.