Modern Synthesis and Chemistry of Stabilized, Ketene N,O-Acetals

Ketene N,O-acetals are robust and versatile synthons. Herein, we outline the synthesis of stable ketene N,O-acetals in the twenty-first century. In addition, we review recent developments in the chemistry of ketene N,O-acetals, as it applies to the vinylogous Mukaiyama aldol reaction, electrolysis, and pericyclic transformations. While dated reports rely on in situ use, modern methods of ketene N,O-acetal synthesis are heavily oriented towards producing products with high “bench” stability; moreover, in the present century, chemists typically enhance the stability of ketene N,O-acetals by positioning an electron-withdrawing group at the β-terminus or at the N-position. As propitious substrates in the vinylogous Mukaiyama aldol reaction, ketene N,O-acetals readily provide polyketide adducts with high regioselectivity. When exposed to electrolysis conditions, the title functional group forms a reactive radical cation and cleanly couples with a variety of activated olefins. Given their electron-rich nature, ketene N,O-acetals act as facile substrates in several rearrangement reactions; further, ketene N,O-acetals reserve the ability to act as either dienophiles or dienes in Diels-Alder reactions. Lastly, ketene N,O-acetals are seemingly more stable than their O,O- counterparts and more reactive than analogous N,N- or S,S-acetals; these factors, in combination, make ketene N,O-acetals advantageous substitutes for other ketene acetal homologs.

A Chiral, Dendralenic C–H Acid

We report the synthesis of a chiral dendralenic C–H acid (2), which contains three unsubstituted binaphthyl moieties. This motif and an achiral variant (1) can be made from their corresponding bis(sulfone) precursors in one step. Despite the presence of the enantiopure binaphthyl backbone, the newly designed chiral C–H acid showed only poor enantioselectivity in a Mukaiyama aldol reaction. First attempts toward the synthesis of 3,3’-hexasubstituted binaphthyl-based dendralenic acids are also reported.

Optimization of Two Steps in Scale-Up Synthesis of Nannocystin A

We have accomplished a 10-step (longest linear) total synthesis of nannocystin A on a four hundred milligram scale. The previously reported Kobayashi vinylogous Mukaiyama aldol reaction to connect C4 and C5 was unreproducible during the scaling up process. A more convenient and cost-efficient Keck asymmetric vinylogous aldol reaction was employed to improve this transformation.

Enantioselective vinylogous Mukaiyama aldol reaction of α-ketoesters under bifunctional organocatalysis

A highly enantioselective vinylogous Mukaiyama aldol reaction to ketoesters catalysed by a hydrogen-bond-donor based bifunctional organcatalysts is presented. The addition of silyloxy dienol ether gives rise to multifuncional chiral tertiary...

Mukaiyama aldol reaction catalyzed by (benz)imidazolium-based halogen bond donors

A Mukaiyama aldol reaction can be catalyzed by bidentate halogen bond donors with very high efficiency. The halogenated catalysts were stable over multiple consecutive runs, which supports the halogen-bond-based mode of catalysis.