Total Synthesis of (±)-Didehydrostemofoline (Asparagamine A) and (±)-Isodidehydrostemofoline

Abstract

The first total syntheses of (+/-)-didehydrostemofoline (1) and (+/-)-isodidehydrostemofoline (3) are reported. The synthesis begins with the Diels-Alder reaction of readily available pyrrole 9 and ethyl (E)-3-nitroacrylate, the latter serving as a regioinverted equivalent of ketene. After hydrogenation to prevent retro-Diels-Alder reaction, the major cycloadduct is transformed to 7-azabicyclo[2.2.1]heptanol 14. Aza-Cope-Mannich reaction of the formaldiminium derivative of 14 delivers 1-azatricyclo[5.3.0.04.10]decane 15, which in 15 additional steps is converted to 1 and 3.

<b>Synthesis of new &alpha;, &beta; -unsaturated butenolides</b>

“…The saturated analogues of these compounds are reported to act as signaling substances in bacteria [6] and enhance spore formation in streptomycetes or induce metabolite production [7]. There has been a continuous interest in the development of efficient and convenient methodologies for the synthesis of butenolides [8] because they are attractive building blocks in natural product synthesis and comprise structural moieties present in large number of significant compounds such as alkaloids [9], lignans [10], insect pheromones [11], cardenolides [2], flavour components [12] and large number of synthetic drug candidates with diverse biological activities [13]. These valid observations encouraged the authors to undertake the synthesis of some new substituted α,β-unsaturated butenolides (4-11a,b) by a simple and convenient method involving the use of easily accessible and inexpensive chemicals.…”

Masked Ketenes as Dienophiles in the Diels–Alder Reaction

“…Challenges arise when the inverse orientational selectivity of the DA reaction is desired, as demonstrated by Overman and coworkers in their synthesis of (AE)-didehydrostemofoline (asparagamine A) and (AE)-isodidehydrostemofoline (Scheme 12). [92] In their approach, an ideal route from pyrrole 82 to key intermediate 84 would employ a DA reaction with nitroethylene (45) (or equivalent); however, owing to the mismatched electronic properties of the two components, 83 is not accessible. Instead, a less direct route was taken, using dienophile 85.…”

Application of an intramolecular dipolar cycloaddition to an asymmetric synthesis of the fully oxygenated tricyclic core of the stemofoline alkaloids

“…6 Owing to their complex molecular architecture and intriguing biological activity, the stemofoline alkaloids have attracted considerable synthetic attention, 11-14 culminating in two racemic total syntheses. 15,16 The studies reported herein comprise the first non-racemic synthesis of the fully oxygenated tricyclic core of the stemofoline alkaloids.…”