Stereoselective Total Synthesis of Natural (+)-Streptazolin via a Palladium-Catalyzed Enyne Bicyclization Approach

Abstract

The natural Z isomer of (+)-streptazolin (1), isolated from cultures of Streptomyces viridochromogenes, was synthesized in an optically pure form for the first time on the basis of a palladium-catalyzed enyne bicyclization approach in 12 steps and 4.3% overall yield from (3R,4R)-3,4-bis(benzyloxy)succinimide (5). The requisite enyne 13 for palladium-catalyzed bicyclization was prepared from 5 via N-acyliminium ion cyclization of the acetoxy lactam 9, partial reduction of 10 with DIBALH−BuLi, and conversion to the dibromo olefin 12. The best result in the palladium-catalyzed bicyclization was obtained when treated with 30 mol % Pd(OAc)2 and N,N ‘-bis(benzylidene)ethylenediamine (BBEDA) as the ligand in benzene at reflux, thus affording a 93:7 mixture of the 1,2,4a,7a,6,7-hexahydro-5H-1-pyrindine (Z)-14 along with its isomerized product (Z)-15 in 84% total yield. The isomerization of the 1,4-diene in (Z)-14 to the 1,3-diene was achieved by treatment with triiron dodecacarbonyl to generate the stable tricarbonyl(η4-1,3-diene)iron complex 16, which was then converted to the glycol 17. Treatment of 17 with sodium methoxide followed by ordinary chromatography on silica gel resulted in isolation of chemically and enantiomerically pure (+)-streptazolin (1).

Structure and Absolute Configuration of Secondary Metabolites from Two Strains of Streptomyces chartreusis Associated with Attine Ants

“…It is an unusual antibiotic and antifungal compound, 15 which possesses its major structural features composed by a 1,2,5,6-tetrahydropyridine ring system, a cyclourethane, and an exocyclic ethylidene side chain. 17 Structural variants of streptazolin (1) such as 3,9-dihydrostreptazolin and Diels-Alder adducts with naphthoquinones show enhanced antimicrobial and cytotoxic activity. 18 Recent studies have found that streptazolin increases bacterial killing and the elaboration of immunostimulatory cytokines by macrophages in vitro.…”

Synthetic Chemistry with N-Acyliminium Ions Derived from Piperazine-2,5-Diones and Related Compounds

“…N-Acyliminium ions show highly versatile reaction characteristics that are reflected in an impressive number of synthetic applications that have been comprehensively reviewed [24][25][26][27][28][29][30]. Both interand intramolecular carbon-carbon bond-forming reactions, including cyclizations onto olefins and arenes as well as reactions with heteroatom nucleophiles, are in continuous expansion [31][32][33][34][35][36][37][38][39][40][41][42][43]. However, even in some very comprehensive reviews dealing with N-acyliminium ions [28], references to these species derived from piperazine-2,5-diones are scarce.…”

Oxazolidin-2-one Ring, a Popular Framework in Synthetic Organic Chemistry: Part 1. The Construction of the Oxazolidin-2-one Ring

“…The treatment of 192d with BBr 3 at 0°C afforded, in enantiomerically pure form, the epoxy-ketone 190d which was finally converted to (+)-streptazolin by the three steps sequence developed by Kozikowski and Park [136]. The enantioselective synthesis of Kibayashi and coworkers [138], resting on a palladium-catalyzed enyne bicyclization, starts from the chiral succinimide derivative 193 (Scheme 100). The enyne 193c was prepared from 193a, through the Nacyliminium ion cyclization of the acetoxy lactam 193b, followed by partial reduction of the amide function, conversion into the dibromo olefin and final treatment with n-BuLi and then iodomethane.…”