Regiospecific and Stereoselective Syntheses of (±)-Reserpine and (−)-Reserpine

Abstract

Full details of three approaches to an entirely regio- and stereoselective synthesis of the well-known target reserpine are described, culminating in a total synthesis which efficiently meets these requirements.

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

“…Of note, the latter observation is in line with the observed diastereoselectivity for the thermal cyclization of aminonitrile 3 in refluxing acetonitrile reported by Stork. 12,13 …”

“…1,2,3,4,5,6,7,8 While there have been many elegant syntheses to arrive at specific members of this class, 9,10,11,12,13,14,15,16,17,18,19,20 especially the archetypal member, reserpine ( 2 , Figure 1), a unified approach to these molecules remains an unsolved problem. 21 In the realm of complex molecule assembly, the total synthesis of 2 by R. B. Woodward and co-workers is well recognized as a milestone event.…”

“…In 1989, Stork reported an inventive solution to the reserpine C(3) problem, that took advantage of the ionization of an intermediate aminonitrile (i.e., 3 , Figure 1). 12,13 The subtleties in stereocontrol in the Pictet-Spengler reaction afforded by aminonitriles allowed Stork to selectively access the undesired as well as the desired C(3) epimer necessary for the total synthesis of reserpine. While the Stork approach sets the foundation to address the C(3) problem, it remained unclear whether this tactic could be extended to the synthesis of other yohimbinoid natural products given the significant influence of the indole nucleophile on the diastereoselectivity of the Pictet-Spengler ring closure from an aminonitrile as discovered in our own work ( vide infra ).…”

Natural Products and Their Mimics as Targets of Opportunity for Discovery

“…76 Stork later also relied upon a similar analysis in his synthesis of reserpine. 77 Unfortunately, some of the reserpine thus produced underwent oxidation under the reaction conditions to generate the iminium ion 164 . Although reduction of 164 with hydride ion provides isoreserpine with high stereoselectivity, the zinc metal promoted reduction of 164 had been reported to give reserpine with high selectivity under certain conditions.…”

Enantioselective Synthesis of α-Quaternary Amino Acids by Alkylation of Deprotonated α-Aminonitriles

“…[8][9][10][11][12][13][14][15][16][17][18] The pioneering chemical synthesis of α-amino acids reported by Adolph Strecker in 1850 made use of their close relationship with α-aminonitriles and even today, the Strecker synthesis is still used for the industrial scale synthesis of α-amino acids like methionine. 19 Due to the strong anion stabilizing capacity of the nitrile group and the latent iminium ion reactivity, [20][21][22][23] α-aminonitriles are not only useful precursors to amino acids but also versatile building blocks for the synthesis of a wide variety of nitrogen-containing compounds 24, 25 including diverse N-heteroarenes, [26][27][28] aliphatic amine derivatives 29,30 or alkaloids [31][32][33][34][35][36][37][38][39] . We found that N-mono-and N-unsubstituted α-aminonitriles derived from aromatic or heteroaromatic aldehydes can be deprotonated quantitatively in α-position to furnish stabilized α-aminocarbanion equivalents and in contrast to their counterparts derived from aliphatic aldehydes, no N-protection is required.…”