Catalytic Enantioselective Pictet–Spengler Reaction of α‐Ketoamides Catalyzed by a Single H‐Bond Donor Organocatalyst

Abstract

The asymmetric Pictet-Spengler reaction (PSR) with aldehydes is well known. However, PSR involving ketones as electrophilic partners is far-less developed. We report herein the first examples of catalytic enantioselective PSR of tryptamines with αketoamides. A new class of easily accessible prolyl-urea organocatalysts bearing a single H-bond donor function catalyzes the title reaction to afford 1,1-disubstituted tetrahydro-β-carbolines in excellent yields and enantioselectivities. The kinetic isotope effect using C2-deuterium-labelled tryptamine indicates that the rearomatization of the pentahydro-β-carbolinium ion intermediate might be the rate-and the enantioselectivity-determining step.

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)…”

“…Tryptamine and 111 a were mixed under the PÀ 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)…”

Accessing unnatural α-amino acids with tetrasubstituted stereogenic centersviacatalytic enantioselective reactions of ketimine-type α-iminoesters/α-iminoamides

“…In 2022, Zhu and co-workers reported the use of single-hydrogen-bond-donor organocatalyst 206 in enantioselective Pictet–Spengler reaction involving acyclic α-ketoamides 201b and tryptamines (Scheme 86). 139 206 acts as a bifunctional catalyst, with double hydrogen-bonding between 206 and the substrate facilitating highly controlled enantioselectivity. In addition, 2-nitrobenzoic acid is required to activate the electrophile while also stabilizing the transition state through π–π interactions with the aromatic groups of 206 .…”

Total synthesis of (S)-forphenicinol via asymmetric organocatalysis

“…3,4 Therefore, implementation of this innovative green methodology to medicinal chemistry practice and current pharmaceutical technologies is a hot topic. 5,6 (S)-Forphenicinol (active substance of Forfenimex s ), was first obtained from the natural product forphenicine, isolated from cultire filtrate of actinomyces, by means of chromatography 7 (Fig. 1).…”