Progress toward a Convergent, Asymmetric Synthesis of Jervine.

Progress toward a convergent approach for the enantioselective synthesis of the Veratrum alkaloid jervine is presented. The two requisite fragments were stereoselectively and efficiently fashioned from economical and readily available reagents. Key reactions include (a) a highly diastereoselective Ireland-Claisen rearrangement to establish the necessary cis-relationship between the amine and methyl group on the tetrahydrofuran E-ring; (b) a diastereoselective selenoetherification reaction that enabled the assembly of the D/E oxaspiro[4.5]decene in the needed configuration; and (c) an enzymatic desymmetrization of an abundant achiral diol en route to a key four-carbon building block as a practical alternative to a protected Roche ester reduction.

Formation of Complex α-Imino Esters via Multihetero-Cope Rearrangement of α-Keto Ester Derived Nitrones.

A sequential benzoylation and multihetero-Cope rearrangement of α-keto ester derived nitrones has been developed. The reaction furnishes a diverse array of complex α-imino ester derivatives. The products can be transformed into amino alcohols via LiAlH4 reduction.

Direct Zinc(II)-Catalyzed Enantioconvergent Additions of Terminal Alkynes to α-Keto Esters.

The addition of terminal alkynes to racemic ß-stereogenic α-keto esters was achieved in high levels of stereoselectivity, affording versatile tertiary propargylic alcohols containing two stereocenters. This environmentally benign enantioconvergent reaction proceeds with perfect atom economy, requires no solvent, and is catalyzed by a non-toxic zinc salt. The alkyne moiety can be leveraged in downstream transformations including hydrogenation to the corresponding saturated tertiary alcohol, which represents the product of a formal enantioconvergent aliphatic nucleophile addition.

Palladium-Catalyzed ß-Arylation of α-Keto Esters.

A catalyst system derived from commercially available Pd2(dba)3 and PtBu3 has been applied to the coupling of α-keto ester enolates and aryl bromides. The reaction provides access to an array of ß-stereogenic α-keto esters. When the air-stable ligand precursor PtBu3·HBF4 is employed, the reaction can be carried out without use of a glovebox. The derived products are of broad interest given the prevalence of the α-keto acid substructure in biologically important molecules.

Asymmetric Organocatalytic Reductive Coupling Reactions between Benzylidene Pyruvates and Aldehydes.

An organocatalytic three-component reductive coupling reaction between dimethyl phosphite, benzylidene pyruvates, and aldehydes is reported. A chiral triaryliminophosphorane catalyst promotes Pudovik addition, which is followed by phospha-Brook rearrangement to transiently generate enolates that are trapped stereoselectively by aldehydes. This reductive coupling provides vicinal polyfunctionalized stereocenters from readily available prochiral starting materials with excellent diastereoselectivity, enantioselectivity, and yield.

Synthesis of substituted 2-aminoimidazoles via Pd-catalyzed alkyne carboamination reactions. Application to the synthesis of preclathridine natural products.

A new method for the synthesis of 2-aminoimidazole products is described. The heterocyclic products are generated in good yields via Pd-catalyzed carboamination reactions of N-propargyl guanidines and aryl triflates. This methodology generates both a C-N and C-C bond during the annulation step and facilitates the rapid construction of 2-aminoimidazole products with different aryl groups. The utility of this methodology was demonstrated in the total synthesis of preclathridine A, preclathridine B, and dorimidazole B from a single intermediate.

Synthesis of cyclic guanidines via Pd-catalyzed alkene carboamination.

A new approach to the synthesis of substituted 5-membered cyclic guanidines is described. Palladium-catalyzed alkene carboamination reactions between acyclic N-allyl guanidines and aryl or alkenyl halides provide these products in good yield. This method allows access to a number of different cyclic guanidine derivatives in only two steps from readily available allylic amines.