Discoveries and diversions in natural product synthesis

Our lab. seeks to discover, develop, and study new chem. reactions within the context of natural product total synthesis. The chem. synthesis of natural products enables the study of their biol. properties, and can provide access to synthetic derivs. with improved therapeutic properties or that can serve as mechanistic probes. Importantly, these synthetic undertakings often highlight shortcomings of the existing state-of-the-art and inspire the discovery of new chem. Our lab. has ongoing research programs targeting the chem. syntheses of several natural products, including members of the epidithiodiketopiperazines, the ent-kauranoids, and the acutumine alkaloids. The densely packed arrays of heteroatoms and stereogenic centers that constitute these polycyclic targets challenge the limits of current synthetic methodol. This seminar will describe our latest progress in both our methodol. and target-directed synthesis endeavors

Rapid Assembly of the Salvileucalin B Norcaradiene Core

Preparation of the polycyclic core of the cytotoxic natural product salvileucalin B is described. The key feature of this synthetic strategy is a copper-catalyzed intramolecular arene cyclopropanation to provide the central norcaradiene. These studies lay the foundation for continued investigations toward an enantioselective total synthesis of 1

Enantioselective Total Synthesis of (+)-Salvileucalin B

An enantioselective total synthesis of the diterpenoid natural product (+)-salvileucalin B is reported. Key findings include a copper-catalyzed arene cyclopropanation reaction to provide the unusual norcaradiene core and a reversible retro-Claisen rearrangement of a highly functionalized norcaradiene intermediate

A Concise Total Synthesis of (--)-Maoecrystal Z

The first total synthesis of (--)-maoecrystal Z is described. The key steps of the synthesis include a diastereoselective Ti^(III)-mediated reductive epoxide coupling reaction and a diastereoselective Sm^(II)-mediated reductive cascade cyclization reaction. These transformations enabled the preparation of (--)-maoecrystal Z in only 12 steps from (--)-γ-cyclogeraniol

Enantioselective Total Synthesis of (-)-Lansai B and (+)-Nocardioazines A and B

The concise total syntheses of the bis(pyrroloindolines) (−)-lansai B and (+)- nocardioazines A and B are reported. The key pyrroloindoline building blocks are rapidly prepared by enantioselective formal [3+2] cycloaddition reactions. The macrocycle of (+)-nocardioazine A is constructed by an unusual intramolecular diketopiperazine formation

Enantioselective Total Synthesis of (—)-Acetylaranotin, a Dihydrooxepine Epidithiodiketopiperazine

The first total synthesis of the dihydrooxepine-containing epidithiodiketopiperazine (ETP) (−)-acetylaranotin (1) is reported. The key steps of the synthesis include an enantioselective azomethine ylide (1,3)-dipolar cycloaddition reaction to set the absolute and relative stereochemistry, a rhodium-catalyzed cycloisomerization/chloride elimination sequence to generate the dihydrooxepine moiety, and a stereoretentive diketopiperazine sulfenylation to install the epidisulfide. This synthesis provides access to (−)-1 in 18 steps from inexpensive, commercially available starting materials. We anticipate that the approach described herein will serve as a general strategy for the synthesis of additional members of the dihydrooxepine ETP family

Nickel-Catalyzed Asymmetric Reductive Cross-Coupling Between Vinyl and Benzyl Electrophiles

A Ni-catalyzed asymmetric reductive cross-coupling between vinyl bromides and benzyl chlorides has been developed. This method provides direct access to enantioenriched products bearing aryl-substituted tertiary allylic stereogenic centers from simple, stable starting materials. A broad substrate scope is achieved under mild reaction conditions that preclude the pregeneration of organometallic reagents and the regioselectivity issues commonly associated with asymmetric allylic arylation

Nickel-Catalyzed Asymmetric Reductive Cross-Coupling between Heteroaryl Iodides and α-Chloronitriles

A Ni-catalyzed asymmetric reductive cross-coupling of heteroaryl iodides and α-chloronitriles has been developed. This method furnishes enantioenriched α,α-disubstituted nitriles from simple organohalide building blocks. The reaction tolerates a variety of heterocyclic coupling partners, including pyridines, pyrimidines, quinolines, thiophenes, and piperidines. The reaction proceeds under mild conditions at room temperature and precludes the need to pregenerate organometallic nucleophiles