Uniting C1-Ammonium Enolates and Transition Metal Electrophiles via Cooperative Catalysis: The Direct Asymmetric α-Allylation of Aryl Acetic Acid Esters.

The direct, catalytic, asymmetric α-functionalization of acyclic esters constitutes a significant challenge in the area of asymmetric catalysis, particularly where the configurational integrity of the products is problematic. Through the unprecedented merger of two independent, yet complementary, catalysis events it has been possible to facilitate the direct asymmetric α-allylation of readily available aryl acetic acid esters. Since enantioselection is determined by the nucleophile, this conceptual approach to cooperative catalysis constitutes a potentially general solution to the direct catalytic asymmetric α-functionalization of acyclic esters.

Intramolecular Diels-Alder (IMDA) Studies toward the Synthesis of Australifungin. Stereocontrol in the Acetate Aldol Reaction of ß,ß'-Branched Aldehydes.

Studies of australifungin illustrate an enantiocontrolled synthesis of the trans-decalin core 28 via an intramolecular [4π + 2π] cycloaddition. This strategy utilizes the nitroalkene dienophile of 27 as a surrogate ketene equivalent. Stereocontrol at C-2 is critically important for an effective intramolecular Diels-Alder (IMDA) process. Our studies report high asymmetric induction using a nonracemic Duthaler titanium enolate in the acetate aldol reaction with ß,ß'-branched aldehyde 13 to introduce the required C-2 chirality.

Studies toward Australifungin. A Synthesis Dilemma of Regioselective Keto-Enol Tautomerization.

Studies have advanced a stereocontrolled pathway for the synthesis of australifungin. Elaboration of the trans-fused IMDA product 4 led to the cis-diol 15, which produced the α-hydroxyenone 19 upon oxidation. Computational studies on model systems indicate that the keto-enol tautomer shown for 19 is higher in energy than the keto-enol tautomer represented by the natural product 1. The reactivity of 19 does not permit mild isomerization and subsequent deprotection to yield 1. These findings raise new questions regarding the synthesis and bioactivity of australifungin and related natural products.

Studies of intramolecular Diels-Alder reactions of nitroalkenes for the stereocontrolled synthesis of trans-decalin ring systems.

Studies of thermal IMDA cyclizations of (1E,7E)-1-nitro-deca-1,7,9-trienes and (1E,3Z,7E)-1-nitro-deca-1,3,7,9-tetraenes have been examined. Reactions of these nitroalkenes proceed via transition states featuring characteristics of asymmetric stretch asynchronicity and result in stereoselective formation of trans-fused decalin products. A substantial rate acceleration is observed for IMDA cyclizations exemplified by triene 14 due to steric repulsions of substituents in the tethering chain which promote facile stereocontrolled formation of trans-fused 26.