Divergent Asymmetric Total Synthesis of (−)‐Voacafricines A and B

Abstract

A divergent asymmetric total synthesis of voacafricines A and B, hexacyclic monoterpene indole alkaloids, has been accomplished featuring the following key steps: a) a catalyst-controlled asymmetric Pictet-Spengler reaction of 6-methoxytryptamine with a chiral α-ketoester affording a 1,1-disubstituted tetrahydro-βcarboline in excellent yield and diastereoselectivity; b) oxidative cleavage of a 3,5-disubstituted cyclopentene furnishing a dialdehyde intermediate, which was effectively differentiated through spontaneous cyclization with the neighboring hydroxy and secondary amine functions; c) intramolecular nucleophilic addition of a tertiary amino nitrogen atom to the in situ generated oxonium species generating stereoselectively an unprecedented 8-alkyl octahydro- 2H-5,8-methanofuro[2,3b]azepin-8-ium motif bearing five contiguous stereocenters. The synthesis confirmed the absolute configuration of these two natural products.

Divergent Asymmetric Total Synthesis of (−)‐Voacafricines A and B

“…The reaction was performed on a gram scale without erosion of yield and diastereoselectivity. The 1 S configuration of the major diastereomer (1 S )‐ 16 a was assigned based on our previous results [13c] and was subsequently confirmed by X‐ray structural analysis of its downstream products.…”

“…We therefore turned our attention to the catalyst‐controlled process. Squaramides 17 a and 17 b [13c] stood out in our catalyst screening (see the Supporting Information, Table S2), affording the products 16 a and 16 b in a ratio of 7 : 1 (entry 2) and 8 : 1 (entry 3), respectively. Further fine‐tuning of the reaction conditions by varying the solvent (entry 4), the structure of acid co‐catalysts (entries 4–7) and the temperature (entry 8) allowed us to conclude that the reaction is best performed in trifluorotoluene in the presence of 17 b , 4‐nitrobenzoic acid ( 18 a ) and 5 Å molecular sieves at 0 °C.…”

Organocatalytic Enantioselective Pictet–Spengler Reaction of α‐Ketoesters: Development and Application to the Total Synthesis of (+)‐Alstratine A

“…She and co‐workers described a CPA catalyzed PSR of 3 with diisopropyl‐2‐oxopentanedioate (one single example) [13] aimed at developing a concise total synthesis of tabertinggine [14, 15] . In a more general context, catalytic enantioselective PSR of ketones [16–22] is known to be highly challenging and is unfortunately poorly developed in sharp contrast to that of aldehydes [23]…”

Organocatalyzed Asymmetric Pictet‐Spengler Reactions

“…Another molecule 173 b was refluxed in the presence of trifluoro acetic acid to form the tetracyclic molecule 176 through intramolecular amidation, which is the molecular core of the drug, tadalafil. Tryptamine and 111 a were mixed under the P−S reaction conditions, following in situ treatment with 1,1’‐carbonyldiimidazole under basic conditionsto delivera novel inhibitor of translationally controlled tumor protein (TCTP); 177 as thefinalproduct with 59 % yield and 91 % ee [52] . (Scheme 50)…”