American Chemical Society
ja7b09929_si_001.pdf (5.02 MB)

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

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journal contribution
posted on 2017-10-23, 00:00 authored by Petra Lindovska, Mohammad Movassaghi
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.