Total Syntheses of (−)‐Strictosidine and Related Indole Alkaloid Glycosides

Abstract

A collective synthesis of glycosylated monoterpenoid indole alkaloids is reported. A highly diastereoselective Pictet–Spengler reaction with α‐cyanotryptamine and secologanin tetraacetate as substrates, followed by a reductive decyanation reaction, was developed for the synthesis of (−)‐strictosidine, which is an important intermediate in biosynthesis. This two‐step chemical method was established as an alternative to the biosynthetically employed strictosidine synthase. Furthermore, after carrying out chemical and computational studies, a transition state for induction of diastereoselectivity in our newly discovered Pictet–Spengler reaction is proposed. Having achieved the first enantioselective total synthesis of (−)‐strictosidine in just 10 steps, subsequent bioinspired transformations resulted in the concise total syntheses of (−)‐strictosamide, (−)‐neonaucleoside A, (−)‐cymoside, and (−)‐3α‐dihydrocadambine.

Total Syntheses of (+)‐Villocarine A, (−)‐Apogeissoschizine, and (+)‐Geissoschizine

“…The newly proposed synthetic strategy for 1 from 6 via 3 is shown in Scheme 3. 6 , which has a 3 S configuration, can be prepared by the diastereoselective Pictet−Spengler cyclization that we developed from 13 and ( R )‐α‐cyanotryptamine ( 23 ), followed by a reductive decyanation sequence [7,15b,16] . To prevent the formation of 5 from 6 , we elected to carry out the N1−C17 bond formation at an early stage.…”

Bioinspired Total Syntheses of Secologanin-Related Natural Products: A Demonstration of the Power of Secologanin in the Flask

“…Finally, 34 was converted into strictosidine ( 3 ) by solvolysis, and here the first total synthesis of 3 over 1 g was achieved (20% over ten steps from 13 ). 8a On the other hand, when 34 was heated under neutral conditions, intramolecular lactamization occurred, and the total synthesis of strictosamide ( 35 ), 16 which has several reported biological activities, 16m 17 was accomplished by removal of the acetyl groups.…”

Pictet–Spengler-Based Multicomponent Domino Reactions to Construct Polyheterocycles

“…The Pictet–Spengler reaction, discovered in 1911 by Amé Pickett and Theodore Spengler, is originally a cyclization of a phenethylamine 1 and a formaldehyde dimethyl acetal 2 to produce 1,2,3,4-tetrahydroisoquinoline 3 in the presence of hydrochloric acid ( Scheme 1 ). 1 After that, a variety of modified reaction systems for the Pictet–Spengler reaction have been developed for the construction of valuable heterocyclic scaffolds, 2 such as Brønsted acids, 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 Lewis acids, 39 40 41 transition metal catalysts, 42 43 44 45 46 organocatalysts, 26 27 47 48 and enzyme strictosidine synthases. 13 49 Meanwhile, the use of suitably substituted amine derivatives such as β-arylethylamines, tryptamines, or functionalized aromatic amines with an aldehyde or ketone is essential for the progress of the Pictet–Spengler reaction.…”