Lithioarene Cycliacylation and Pd-Catalyzed Aminoethylation/Cyclization to Access Electronically Diverse Saturated Isoquinoline Derivatives.

We report operationally facile methods for the synthesis of substituted dihydroisoquinolinones and tetrahydroisoquinolines from readily accessible -bromobenzyl bromides and -bromobenzaldehydes, respectively. While classical electrophilic aromatic substitution reactions are tailored to the construction of saturated isoquinolines derived from electron-rich precursors, we demonstrate efficient syntheses from electronically diverse substrates to produce cyclized products as single regioisomers.

General Asymmetric Synthesis of Densely Functionalized Pyrrolidines via -Selective [3+2] Cycloaddition of β-Quaternary-Substituted Nitroalkenes and Azomethine Ylides.

A scalable -selective synthesis of 2,3,4,5-tetrasubstituted pyrrolidines via cycloaddition of nitroalkenes and azomethine ylides is reported using a P,N-type ferrocenyl ligand and [Cu(OTf)]·CH. The robust method is tolerant of a wide range of functionalities, including rarely reported quaternary nitroalkene substitution and heteroaromatic and hindered -substituted arenes on the azomethine ylide. Subsequent transformations highlight the utility of the method in the synthesis of densely functionalized small molecules suitable for fragment-based drug discovery and the cystic fibrosis C2-corrector clinical candidate ABBV-3221.

Syntheses of Cyclopropyl Analogues of Disorazoles A and B and Their Thiazole Counterparts.

Modular syntheses of disorazoles A and B analogues in which the epoxide moieties of the natural products were replaced with cyclopropyl units have been achieved. Targeted as part of a structure-activity relationships study, these syntheses were successfully extended to the thiazole counterparts of these analogues. The retrosynthetically defined fragments were assembled through Yamaguchi esterification, Cu/Pd-catalyzed cross-coupling, Yamaguchi macrolactonization, and Cu-catalyzed cross-coupling as the key reactions.

Enantioselective Total Synthesis of Antibiotic CJ-16,264, Synthesis and Biological Evaluation of Designed Analogues, and Discovery of Highly Potent and Simpler Antibacterial Agents.

An improved and enantioselective total synthesis of antibiotic CJ-16,264 through a practical kinetic resolution and an iodolactonization reaction to form the iodo pyrrolizidinone fragment of the molecule is described. A series of racemic and enantiopure analogues of CJ-16,264 was designed and synthesized through the developed synthetic technologies and tested against drug-resistant bacterial strains. These studies led to interesting structure-activity relationships and the identification of a number of simpler, and yet equipotent, or even more potent, antibacterial agents than the natural product, thereby setting the foundation for further investigations in the quest for new anti-infective drugs.

Total Syntheses of Disorazoles A₁ and B₁ and Full Structural Elucidation of Disorazole B₁.

Described herein are the first total syntheses of naturally occurring antitumor agents disorazoles A and B and the full structural assignment of the latter. The syntheses were achieved through convergent strategies employing enantioselective constructions of the required building blocks, including a novel Sharpless epoxidation/enzymatic kinetic resolution of stannane-containing substrates that led selectively to both enantiomeric forms of an epoxy vinyl stannane, and a series of coupling reactions, including a Wittig reaction, a Suzuki coupling, a Stille coupling, a Yamaguchi esterification and a Yamaguchi macrolactonization.

Asymmetric Syntheses of (+)-Preussin B, the C(2)-Epimer of (-)-Preussin B, and 3-Deoxy-(+)-preussin B.

Efficient de novo asymmetric syntheses of (+)-preussin B, the C(2)-epimer of (-)-preussin B, and 3-deoxy-(+)-preussin B have been developed, using the diastereoselective conjugate addition of lithium (S)-N-benzyl-N-(α-methylbenzyl)amide to tert-butyl 4-phenylbut-2-enoate and diastereoselective reductive cyclizations of γ-amino ketones as the key steps to set the stereochemistry. Conjugate addition followed by enolate protonation generated the corresponding β-amino ester. Homologation using the ester functionality as a synthetic handle gave the corresponding γ-amino ketone.