A divergent approach to the synthesis of the yohimbinoid alkaloids venenatine and alstovenine

Abstract

The yohimbinoid alkaloids continue to receive considerable attention from the synthetic community because of their interesting chemical structures and varied biological activity. Although there are several elegant syntheses of certain members of this group of alkaloids, a truly unified approach has yet to be developed. In short, general approaches to this compound class are hampered by a lack of complete control in setting the C(3) stereocentre at a late stage. Herein, we report that a functionalized hydrindanone enables a divergent strategy that builds on existing precedent to address this long-standing challenge. Utilizing an aminonitrile intermediate, the stereochemistry at C(3) of the yohimbinoid skeleton can be controlled effectively in a Pictet-Spengler reaction. We applied this approach to the first total syntheses of the C(3) epimeric natural products venenatine and alstovenine.

Figure 1

Classic approaches to reserpine and selected yohimbine and berbane alkaloids. a) Classic approaches to closure of the C-ring and setting of the C-3 stereocenter of reserpine. b) Selected yohimbinoid natural products that vary in the substitution pattern of the indole ring. The ability to access a variety of yohimbine natural products from a common precursor would allow for a unified approach to this group of alkaloids. Me, methyl; Ac, acetyl

Figure 2

Retrosynthetic plan and synthesis of the aminonitrile Pictet-Spengler substrates. a) A variety of yohimbinoid natural products can be accessed from common hydrindanone precursor 18. b) The Diels-Alder cyclization between diene 19 and dienophile 20 provides hydrindanone 18 setting four contiguous stereocenters. Conversion of hydrindanone 18 into aldehyde 17 sets the stage for rapid formation of aminonitriles (16a-c) with varying substitution on the indole moiety. Bs, benzenesulfonyl; TBS, tert-butyldimethylsilyl; Bn, benzyl; PhMe, toluene; pyr, pyridine; DMAP, 4-dimethylaminopyridine; TBSOTf, tert-butyldimethylsilyl triflate; Oxone, potassium monopersulfate; DCM, dichloromethane.

Figure 3

Plausible reaction pathways for the thermal cyclization. Thermal cyclization of aminonitrile 16b leads to a diastereomeric mixture of pentacycles 23b and 24b. The diastereomeric ratio is dependent on the reaction conditions employed with nucleophilic solvents and additives favouring formation of the α-diastereomer 23b. Several mechanistic possibilities are presented. Nu, nucleophile; Bn, benzyl.

Figure 4

Synthesis of venenatine and alstovenine. Pd catalyzed deallylation/decarboxylation allows for allyl ester removal in 23b and 24b under mild conditions, minimizing β-hydroxy elimination. Treatment of 29 and 31 with BBr₃ leads to selective removal of the benzyl protecting group and access to venenatine and alstovenine respectively. PS, polymer supported; nOe, nuclear Overhauser effect; dba, dibenzylideneacetone; Bn, benzyl; DCM, dichloromethane.