Enantioselective Syntheses of Corynanthe Alkaloids by Chiral Brønsted Acid and Palladium Catalysis

Abstract

Synergistic catalysis: Three indole alkaloids (−)‐corynantheidine, (+)‐corynantheine and (+)‐dihydro‐corynantheine were prepared following a short and common strategy based on the binol phosphoric acid catalyzed enantioselective Pictet–Spengler reaction, followed by closure of the final ring by an intramolecular Tsuji–Trost‐type Pd‐catalyzed allylic alkylation by using an α‐ketoester‐derived enolate as the nucleophile (see scheme).

The Pictet-Spengler Reaction Updates Its Habits

“…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].…”

“…Advances in support, protecting group strategies, and extensive optimization of chemical methodology have expanded the scope of solid phase chemistry from mere peptide preparation to the synthesis of pharmacologically relevant small molecules [110][111][112], as well as the total synthesis (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].…”

“…According to the results of previous studies [103], the treatment of the readily available compound 98 with trimethylsilyl chloride (TMSCl) in DCM in the presence of triethylamine afforded lactam intermediate 99, which, in turn, treated with 2,2-diethoxyethyl benzoate in the presence of trimethylsilyl triflate (TMSOTf) and Ac 2 O gave the P-S product 100 as a diastereomeric mixture (a/b: 10/3) in 92% yield (Scheme 28) [104]. 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].…”

Total syntheses of mitragynine, paynantheine and speciogynine via an enantioselective thiourea-catalysed Pictet–Spengler reaction

“…We recently reported an enantioselective total synthesis of Corynanthe alkaloids lacking the methoxy group by using an enantioselective Pictet-Spengler cyclisation as the key step with the chirality arising from a binaphthylphosphoric acid catalyst (Scheme 1). 10 In another key step the D-ring was closed via a Tsuji-Trost allylic alkylation with the use of an a-ketoester enolate as the nucleophile. 10 In this communication we wish to report efficient total syntheses of the three title alkaloids by a similar approach.…”

“…10 In another key step the D-ring was closed via a Tsuji-Trost allylic alkylation with the use of an a-ketoester enolate as the nucleophile. 10 In this communication we wish to report efficient total syntheses of the three title alkaloids by a similar approach. However, the presence of the methoxy group considerably influenced the Pictet-Spengler reaction and it appeared necessary to apply a different chiral organocatalyst than the binaphthyl-phosphoric acid used in our previous study.…”