The Chiral Pool in the Pictet–Spengler Reaction for the Synthesis of β-Carbolines

Abstract

Abstract:The Pictet-Spengler reaction (PSR) is the reaction of a β-arylethylamine with an aldehyde or ketone, followed by ring closure to give an aza-heterocycle. When the β-arylethylamine is tryptamine, the product is a β-carboline, a widespread skeleton in natural alkaloids. In the natural occurrence, these compounds are generally enantiopure, thus the asymmetric synthesis of these compounds have been attracting the interest of organic chemists. This review aims to give an overview of the asymmetric PSR, in which the chirality arises from optically pure amines or carbonyl compounds both from natural sources and from asymmetric syntheses to assemble the reaction partners.

The Pictet-Spengler Reaction Updates Its Habits

“…The conversion of the diketopiperazine THIQ 100 into unsaturated compound 101 was the first key step of the synthesis of renieramycin I and cribrostatin 4 (Figure 3) (2011) The P-S reaction got a lead role in the total syntheses of (+)-yohimbine [105], (−)corynantheidine [106,107], (+)-corynantheine, and (+)-dihydrocorynantheine [107] (active as antimicrobial against Staphylococcus aureus-induced infections [109]), which have been reviewed in Todd's paper [65]. Analogously, the total synthesis of (−)-affinisine oxindole [108] was reported previously in the paper of Dalpozzo [66].…”

“…A model P-S condensation of tryptophan (Trp) and [ 11 C]formaldehyde in neutral or acidic medium (TsOH or HCl) afforded the desired [1- 11 Some references on P-S-driven synthesis of THIQ [38,40] and THBC [43,45,53,55] have been cited and/or discussed in other reviews [65,66].…”

“…The construction of fused rings on the THIQ or THBC skeleton is a key step in most of the total syntheses of natural products (isoquinoline and indole alkaloids), such as ecteinascidin 743 (ET-743) and yohimbine ( Figure 2), which will be updated in the next section (vide infra). Some references on P-S-driven synthesis of THIQ [38,40] and THBC [43,45,53,55] have been cited and/or discussed in other reviews [65,66].…”

“…Phenanthroindolizidines (50 [71,72]), phenanthroquinolizidines (51 [72]), tetrahydroprotoberberines (53 [67,68]), pyrroloisoquinolines (55 [69,70]), and diketopiperazine-fused THIQs (65 [73], vide infra) embody the tetrahydroisoquinoline skeleton, while indolizinoindoles (57 [74,75]), THBC-imidazolinediones (59 [76]), THBC-piperazinedione (61 [77,78]), the tetracyclic indole alkaloids (S)-harmicine (pyrrole-fused THBC, [66,79]), and (S)-eleagnine (1-methyl THBC, [66,80] represent the THBC-containing polyheterocycles. The additional ring can be already present in the imine substrate before the P-S reaction (type A) or can be built on the THIQ/THBC skeleton exploiting the functionality of some substituents (type B).…”

“…Pictet-Spengler reaction in total synthesis of natural products. [103,104] (+)-yohimbine Figure 3 Reported in [65] - [105] (−)-corynantheidine Figure 3 Reported in [65] corynanthe alkaloids [106] (−)-corynantheine (−)-dihydrocorynantheine Figure 3 Reported in [65] corynanthe alkaloids [107] (−)-affinisine oxindole Figure 3 Reported in [66] - [108] (2011) Cyclization of 3-arylidene-6-methylpiperazinedione 75 with 2,2-diethoxyethyl benzoate afforded in two steps the P-S-adduct 76 as a single isomer (Scheme 21). The lactam 76 was used to construct the pentacyclic key intermediate framework (not shown) [82] and achieve the total synthesis of cribrostatin 4 [83] and renieramycin G ( Figure 3) [84,85].…”