Concise Synthesis of (−)-Hodgkinsine, (−)-Calycosidine, (−)-Hodgkinsine B, (−)-Quadrigemine C, and (−)-Psycholeine via Convergent and Directed Modular Assembly of Cyclotryptamines

Abstract

The enantioselective total synthesis of (−)-hodgkinsine, (−)-calycosidine, (−)-hodgkinsine B, (−)-quadrigemine C, and (−)-psycholeine through a diazene-directed assembly of cyclotryptamine fragments is described. Our synthetic strategy enables multiple and directed assembly of intact cyclotryptamine subunits for convergent synthesis of highly complex bis- and tris-diazene intermediates. Photoextrusion of dinitrogen from these intermediates enables completely stereoselective formation of all C3a–C3a' and C3a–C7' carbon–carbon bonds and all the associated quaternary stereogenic centers. In a representative example, photoextrusion of three dinitrogen molecules from an advanced intermediate in a single-step led to completely controlled introduction of four quaternary stereogenic centers and guided the assembly of four cyclotryptamine monomers en route to (−)-quadrigemine C. The synthesis of these complex diazenes was made possible through a new methodology for synthesis of aryl-alkyl diazenes using electronically attenuated hydrazine-nucleophiles for a silver-promoted addition to C3a-bromocyclotryptamines. The application of Rh- and Ir-catalyzed C–H amination reactions in complex settings were used to gain rapid access to C3a- and C7-functionalized cyclotryptamine monomers, respectively, used for diazene synthesis. This convergent and modular assembly of intact cyclotryptamines offers the first solution to access these alkaloids through completely stereoselective union of monomers at challenging linkages and the associated quaternary stereocenters as illustrated in our synthesis of five members of the oligocyclotryptamine family of alkaloids.

Total Synthesis and Anti-Cancer Activity of All Known Communesin Alkaloids and Related Derivatives

“…Importantly, we anticipate this late-stage N1′-acylation will enable access to all members of this alkaloid class containing diverse N1′ substituents. Next, consistent with our diazene-directed strategy for complex fragment assembly, 3b,6 we projected that the critical C3a–C3a′ linkage in 19 could be assembled via photoextrustion of dinitrogen from unsymmetrical diazene 22 and recombination of the resulting radical fragments 20 and 21 . We expected to assemble diazene 22 from epoxide-bearing C3a-amino oxindole 23 and C3a′-sulfamate 24 .…”

Fragment Coupling Reactions in Total Synthesis That Form Carbon–Carbon Bonds via Carbanionic or Free Radical Intermediates

“…Irradiation of this intermediate led to expulsion of dinitrogen and formation of the two tertiary radicals ( 211 b ) that underwent a heterodimerization to generate the coupling product 212 in 70 % yield. This general strategy has been applied to the synthesis of numerous targets and is a powerful solution to the formation of the congested benzylic C –C bonds present in this class of alkaloids [107a, 119] …”

Concise Total Synthesis and Stereochemical Assignment of (–)-Psychotridine.

“…4,5 Herein, we report the first total synthesis and complete stereochemical assignment of (-)psychotridine (4). The application of our diazene-directed assembly of enantiomerically enriched cyclotryptamines 3,7,8 led to a highly convergent synthesis of the pentameric alkaloid 4, allowing its detailed structural assignment. Scheme 1.…”