Design and synthesis of peptide-based macrocyclic cyclophilin inhibitors.

The efficient assembly of an 18-membered macrocyclic peptide core was realized by a straightforward and convergent approach utilizing ring-closing metathesis of the corresponding linear tetrapeptides as the key transformation. This approach allowed for the facile preparation of a focused library of novel macrocycles that culminated in the discovery of a cyclophilin A inhibitor with a K=5.4μM.

Evolution of a strategy for preparing bioactive small molecules by sequential multicomponent assembly processes, cyclizations, and diversification.

A strategy for generating diverse collections of small molecules has been developed that features a multicomponent assembly process (MCAP) to efficiently construct a variety of intermediates possessing an aryl aminomethyl subunit. These key compounds are then transformed via selective ring-forming reactions into heterocyclic scaffolds, each of which possesses suitable functional handles for further derivatizations and palladium-catalyzed cross coupling reactions. The modular nature of this approach enables the facile construction of libraries of polycyclic compounds bearing a broad range of substituents and substitution patterns for biological evaluation.

Concise total synthesis of (±)-actinophyllic acid.

A concise total synthesis of the complex indole alkaloid (±)-actinophyllic acid was accomplished by a sequence of reactions requiring only 10 steps from readily-available, known starting materials. The approach featured a Lewis acid-catalyzed cascade of reactions involving stabilized carbocations that delivered the tetracyclic core of the natural product in a single chemical operation. Optimal conversion of this key intermediate into (±)-actinophyllic acid required judicious selection of a protecting group strategy.

Synthesis of (±)-actinophyllic acid and analogs: applications of cascade reactions and diverted total synthesis.

Actinophyllic acid is a biologically active indole alkaloid with a unique structural framework that incorporates five contiguous stereocenters. A total synthesis of (±)-actinophyllic acid has been completed that proceeds in only 10 steps from readily available, known compounds and with the isolation of nine intermediates. The synthesis features a novel cascade of reactions of N-stabilized carbocations with π-nucleophiles to create the tetracyclic core of actinophyllic acid in a single chemical operation.

Multicomponent assembly processes for the synthesis of diverse yohimbine and corynanthe alkaloid analogues.

A strategy involving a Mannich-type multicomponent assembly process followed by a 1,3-dipolar cycloaddition has been developed for the rapid and efficient construction of parent heterocyclic scaffolds bearing indole and isoxazolidine rings. These key intermediates were then readily elaborated using well-established protocols for refunctionalization and cross-coupling to access a diverse 180-member library of novel pentacyclic and tetracyclic compounds related to the Yohimbine and Corynanthe alkaloids. Several other new multicomponent assembly processes were developed to access dihydro-β-carboline-fused benzodiazepines, pyrimidinediones, and rutaecarpine derivatives.

APPLICATIONS OF MULTICOMPONENT ASSEMBLY PROCESSES TO THE FACILE SYNTHESES OF DIVERSELY FUNCTIONALIZED NITROGEN HETEROCYCLES.

Several multicomponent assembly processes have been developed for the synthesis of intermediates that may be elaborated by a variety of cyclizations to generate a diverse array of highly functionalized heterocycles from readily-available starting materials. The overall approach enables the efficient preparation of libraries of small molecules derived from fused, privileged scaffolds.

Multicomponent assembly strategies for the synthesis of diverse tetrahydroisoquinoline scaffolds.

Several novel multicomponent assembly processes have been developed for the rapid and efficient assembly of various heterocyclic scaffolds bearing a tetrahydroisoquinoline core, each of which allows for facile derivatization to access a diverse array of compounds. This work led to the serendipitous discovery of a new method for the synthesis of a fused quinazolone ring system, which was applied to a one-step total synthesis of the quinazolinocarboline alkaloid rutaecarpine.