Steven A. Weissman

Copper-Facilitated Suzuki Reactions: Application to 2-Heterocyclic Boronates

The palladium-catalyzed Suzuki-Miyaura reaction has been utilized as one of the most powerful methods for C-C bond formation. However, Suzuki reactions of electron-deficient 2-heterocyclic boronates generally give low conversions and remain challenging. The successful copper(I) facilitated Suzuki coupling of 2-heterocyclic boronates that is broad in scope is reported. Use of this methodology affords greatly enhanced yields of these notoriously difficult couplings. Furthermore, mechanistic investigations suggest a possible role of copper in the catalytic cycle.

Asymmetric hydrogenation of tetrahydropyrazines: Synthesis of (S)-piperazine-2-tert-butylcarboxamide, an intermediate in the preparation of the HIV protease inhibitor indinavir

Abstract Hydrogenation of tetrahydropyrazine 4g with [(R)-BINAP(COD)Rh]TfO gave piperazine 6g in 96% yield and 99% ee. Simple hydrogenolytic deprotection and crystallization afforded the key chiral (S)-N-Boc-piperazine MK-639 intermediate 1 in high yield and enantiomeric purity.

N-Bromosuccinimide/Dibromodimethylhydantoin in aqueous base: A practical method for the bromination of activated benzoic acids

A new bromination method employing NBS or dibromodimethylhydantoin in aqueous base is described for the synthesis of 3-bromo-2,6-dimethoxybenzoic acid (1) and other monobrominated alkoxybenzoic acids.

Asymmetric synthesis of (2S,3S)-3-hydroxy-2-phenylpiperidine via ring expansion

Abstract A catalytic highly enantioselective (99% ee) preparation of N - tert -butyloxycarbonyl-(2 S ,3 S )-3-hydroxy-2-phenyl-piperidine and N - tert -butyloxycarbonyl-(2 S )-2-phenyl-piperidin-3-one was developed using an intramolecular epoxide opening followed by ring expansion. The cis -epoxide starting material was available in high ee via Jacobsen epoxidation.

Crystallization-induced diastereoselection: asymmetric synthesis of substance P inhibitors.

A novel three-component condensation followed by a crystallization-induced asymmetric transformation is used to build this key substance P inhibitor intermediate in a short synthetic sequence.

Practical synthesis of a potent indolocarbazole-based, DNA topoisomerase inhibitor

Abstract DNA topoisomerase I inhibitors are currently under investigation as cancer chemotherapy agents of which indolocarbazole glycoside ( 1 ) has been identified as a promising candidate. A practical, scalable synthesis of 1 that limits the isolation of cytotoxic compounds to only that of the final product is described. The convergent process features a novel phase transfer-promoted glycosylation of aglycone core ( 4 ); subsequent hydrolysis provides anhydride ( 8 ). The hydrazine fragment ( 3 ), which is coupled with 8 , is synthesized via a modification of existing procedures. The coupled product ( 2 ) is subsequently hydrogenated to provide 1 in excellent purity via direct crystallization (>99.3 A%).

Cyclic imidate salts in acyclic stereochemistry: Diastereoselective syn-epoxidation of 2-alkyl-4-enamides to epoxyamides

Abstract Reaction of 2-alkyl-4-enamides with 1 + and aqueous sodium bicarbonate results in the diastereoselective formation of the corresponding iodohydrins with essentially no iodolactone by-product. The reaction appears to proceed through a cyclic imidate type intermediate. This methodology has been successfully employed for the synthesis of the epoxide intermediate of the orally active HIV-1 protease inhibitor MK-639 (indinavir sulfate).

Efficient synthesis of N-arylpiperazinones via a selective intramolecular Mitsunobu cyclodehydration

Abstract A practical two pot synthesis of N -arylpiperazinones from the corresponding aniline is described. The key transformation is a selective intramolecular Mitsunobu cyclodehydration of an amidoalcohol intermediate. A series of N -arylpiperazinones were prepared in yields up to 89%.