Assembly of 3a-Arylperhydroindoles by the Intramolecular Cycloaddition of 2-Azaallyl Anions with Alkenes. Total Syntheses of (±)-Crinine, (±)-6-Epicrinine, (−)-Amabiline, and (−)-Augustamine

Abstract

The 2-azaallyl anion route to pyrrolidines was used for the concise synthesis of alkaloids featuring the 3a-arylperhydroindole nucleus. The brevity and efficiency of the syntheses described are particularly notable. The key transformations involved the tin−lithium exchange of (2-azaallyl)stannanes to 2-azaallyl anions, which participated in intramolecular [π4s + π2s] cycloadditions with styrenes to produce the requisite 3a-arylperhydroindoles. (±)-Crinine was synthesized in eight steps in 20% overall yield, with the key cycloaddition producing a single stereoisomer of the perhydroindole in 80% yield. (±)-6-Epicrinine was an intermediate in this synthesis. The key cycloaddition involved the use of a diene as the anionophile. The first asymmetric syntheses of (−)-amabiline and (−)-augustamine were accomplished in overall yields of 43% (in eight steps) and 42% (in nine steps), respectively, confirming or determining the absolute stereochemistry of the natural products. The key cycloadditions produced the perhydroindoles in 83% and 74% yields, respectively, with reasonable stereocontrol. The highly stereoselective cycloaddition leading to a trans-dialkoxyperhydroindole in 75% yield was consistent with stereochemical predictions. These studies contribute to a growing body of knowledge on the scope and stereochemistry of 2-azaallyl anion cycloadditions.

Potentially Biomimetic Total Synthesis and Relative Stereochemical Assignment of (±)‐Gracilamine

“…Fortunately, cleavage of the amide by treatment with NaOEt in ethanol delivered the cyclization product 27. [11] Finally, reduction of 27 with NaBH 4 furnished the target molecule, whose structure was confirmed by X-ray analysis. [11] Because the analytical data of our synthetically obtained gracilamine were in agreement with those reported for naturally ocurring gracilamine, we could fully establish the relative configuration of gracilamine (Scheme 6).…”

Alkaloid synthesis via [3+2] cycloadditions

“…Examples include the total synthesis of crinine [12,13], amabiline [13,14] mine [13,14], and an approach to 6a-epipretazettine [15]. Three additional examples of these efforts are briefly described below.…”

Cycloadditions of Nonstabilized2-Azaallyllithiums (2-Azaallyl Anions) and Azomethine Ylides withAlkenes: [3+2] Approaches to Pyrrolidinesand Application to Alkaloid Total Synthesis

“…55,56 The aldehyde 121 was prepared in optically active form in only a few steps from the commercially available acetonide of D-erythronolactone. As shown in Scheme 29, we were able to achieve the first total syntheses of these compounds.…”

“…56,58 The necessary (2-azaallyl)stannane 146 was formed from the alcohol 145 by a Swern oxidation followed by condensation with (aminomethyl)tri-n-butyl stannane. 56,58 The necessary (2-azaallyl)stannane 146 was formed from the alcohol 145 by a Swern oxidation followed by condensation with (aminomethyl)tri-n-butyl stannane.…”