First Total Synthesis of the Pyrrolizidine Alkaloid Amphorogynine C through Intramolecular Azide–Olefin Cycloaddition

Abstract

The first total synthesis of the natural alkaloid amphorogynine C is reported (2.9 % overall yield in 20 steps). The key steps include a Claisen–Johnson rearrangement and an intramolecular azide–olefin cycloaddition, followed by a reduction of the resulting imine. The construction of the pyrrolizidine skeleton was achieved by an alkoxide‐mediatedlactone ring opening and subsequent cyclization of a conveniently functionalized bicyclic amine. Finally, the proposed structure of amphorogynine C was confirmed by single‐crystal X‐ray diffraction analysis.

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

“…In the total synthesis of chaetominine, Evano and co-workers employed a selective reduction of the imine intermediate, which was accessed by isomerization of an amino epoxide . In 2012, the Mann group disclosed an interesting total synthesis of pyrrolizidine alkaloid amphorogynine C, featuring an intramolecular azide–olefin cycloaddition/imine formation via a nitrogen extrusion/selective reduction sequence …”

“…645 In 2012, the Mann group disclosed an interesting total synthesis of pyrrolizidine alkaloid amphorogynine C, featuring an intramolecular azide−olefin cycloaddition/imine formation via a nitrogen extrusion/selective reduction sequence. 646 The diastereoselective reduction of iminium ions generated in situ has complemented the reduction of preformed imines as a means of C−N bond construction in total synthesis. In the synthesis of (+)-kopsihainanine A, advanced intermediate 157-1 was cyclized to iminium salt 157-2 under Bischler−Napieralski conditions (Scheme 157a).…”

Recent Applications and Developments of Organic Azides in Total Synthesis of Natural Products

“…The key reaction was set in the last step of the synthesis and the cyclization precursor 126 derived from 125 by Mitsunobu azidation was successfully converted to acid-sensitive natural product 128 without a specific deprotection step. [68]. As reported in some articles [61,62], thermolysis of the unstable triazoline intermediate Staudinger/aza-Wittig reaction: Similar to Wittig reaction, the reactions with iminophosphoranes and carbonyls can provide imines (Scheme 30).…”

Pyrrolizidine alkaloids

“…The 6-epimer of (+)-amphorogynine A, (À)-amphorogynine C (Scheme 137) was prepared for the rst time recently. 242 Glycal 782, readily-obtained from D-glucose (three steps) was taken through a ve-step sequence to allyl glycoside 783 with overall conjugate displacement of acetate, and Mitsunobu inversion at C(4) as key steps. Johnson-Claisen rearrangement transferred the stereochemistry to C(2); subsequent azide cycloaddition (in 784) was accompanied by loss of N 2 with [1,2]-H migration, giving bicyclic pyrroline 785.…”