Synthesis and biological evaluation of cremastrine and an unnatural analogue

Abstract

In this Letter, we describe the first total synthesis of cremastrine, a pyrrolizidine alkaloid from Cremastra appendiculata, with anticholinergic activity as well as an unnatural analogue. The streamlined synthesis proceeds in 9 steps, 7 steps longest linear sequence, in 25.2% overall yield, and features novel methodology to construct the pyrrolizidine core. Biological evaluation of cremastrine and the unnatural analogue indicated that both are pan-mAChR functional antagonists.

Cutting-Edge and Time-Honored Strategies for Stereoselective Construction of C–N Bonds in Total Synthesis

“…Related one-pot indium-mediated allylation of the sulfenimine derived from tert -butanesulfinamide and 3-indolecarboxaldehyde (87% yield, dr 10:1) has been used extensively as the first step in the enantioselective synthesis of Strychnos and Aspidosperma alkaloids (−)-leuconicine A and B, unusual dihydroazepine Aspidosperma alkaloid (−)-melotenine A, and anticancer alkaloids (−)-akuammicine, (−)-norfluorocurarine, and (−)-dihydroakuammicine . Tricyclic aminal alkaloids tetraponerines T3 and T4 from Pseodomyrmecine ants and pyrrolizidine alkaloid cremastrine were also prepared by early-stage indium-mediated allylation of tert -butanesulfinamide-derived imines. Addition of allylmagnesium bromide to an imine derived from tert -butanesulfinamide and an aromatic aldehyde, carried out in dichloromethane for best stereoselectivity, was used in the synthesis of neuroactive plant alkaloid (−)-dihydrotetrabenazine and Carduus crispus quinolizidine alkaloids (−)-crispine A, (−)-benzo­[ a ]­quinolizidine, and (−)-salsolidine …”

Pyrrolizidine alkaloids

“…The synthesis of (À)-cremastrine (Scheme 29) followed strategically similar lines. 114 Here, the two stereogenic centres in the necine base were installed by diastereoselective allylation of sulfoximine 270 (dr ¼ 4 : 1). Alkene oxidation, then cyclisation and esterication afforded functionalised pyrrolidine 272; deprotection and intramolecular reductive amination generated (À)-cremastrine, the rst total synthesis.…”

Total Syntheses and Configuration Assignments of JBIR-06 and Related Depsipeptides

“…Mechanistic studies suggest that the transesterification of β-keto esters proceeds via the corresponding acyl ketene intermediate; , that is, the other ester moieties in 9 and 10 would not be effective during the conversion into 8 . Compound 9 would be obtained by the condensation of 11 , which is derived from l -isoleucine, with β-ketoester 12 .…”