A Chiral Pentenolide-Based Unified Strategy toward Dihydrocorynantheal, Dihydrocorynantheol, Protoemetine, Protoemetinol, and Yohimbane

Abstract

An organocatalytic cross-aldol reaction of formaldehyde (formalin) with alkyl aldehydes, followed by the Z-selective Horner-Wadsworth-Emmons (HWE) reaction and immediate lactonization, afforded γ-alkylated pentenolides in good overall yields and excellent enantioselectivities. Based on this scalable sequence, five quinolizidine alkaloids were synthesized in a unified and concise manner. The development of an in situ activation of a tertiary amide to improve the efficiency of the Bischler-Napieraiski (B-N) reaction was also noteworthy due to the generality to sensitive substrates for a variety of target molecules.

Enantioselective Syntheses of Yohimbine Alkaloids: Proving Grounds for New Catalytic Transformations

“…The second catalytic enantioselective synthesis of (–)-yohimbane was reported by Hong and co-workers in 2017. 54 Instead of employing enzymatic catalysis like Ghosh, they envisioned using organocatalysis, specifically the asymmetric enamine aldol reaction. Their overall synthetic strategy diverges from the previously discussed approaches, while also sharing many similarities.…”

A Bridge to Alkaloid Synthesis

“…With the synthetically practical method in hand, we selected melinonine-E and strychnoxanthine [34] as target molecules due to the characteristic morphan skeleton as well as there being no absolute configurations defined yet, which could be essential in identifying the pertinence of some elements of the biogenesis for specific alkaloid subfamilies [35] (Scheme 11A). The synthesis commenced from γ-substituted-δ-lactone, which was originally developed by Boeckman and coworkers [36] and applied in our previous syntheses for five quinolizidine alkaloids [37] (Scheme 11B). Accordingly, conjugate allylation of 92 promoted by copper reagent smoothly introduced a β-allyl group, and the corresponding bisallyl compound was subjected to ring-closing metathesis (RCM) with a Grubbs-II catalyst.…”

Salient features of the aza-Wacker cyclization reaction

“…36,37 Cyclization precursor 8 was constructed from chiral lactone 7 in 2 steps; this lactone had previously been synthesized by Hong and co-workers as a key intermediate in the construction of other alkaloid natural products. 38 Interestingly, the N-substituent had a marked effect on the success of the aza-Wacker cyclization. When the OMe group was replaced by a tosyl substituent, the yield dropped signicantly (Fig.…”