Total Synthesis of the Lycopodium Alkaloid (+)-Serratezomine A

Abstract

The first total synthesis of (+)-serratezomine A is described. Key aspects of the synthesis include a) the first deployment of free radical-mediated vinyl amination -an intramolecular alkyne aminostannation -in a complex target synthesis, b) the use of a β-stannyl enamine as the lynchpin for convergent assembly of the natural product backbone, c) the use of an oxidative allylation promoted by cerium(IV) (CAN) to establish the all carbon quaternary chiral center with the proper configuration, and d) an intramolecular substitution reaction to form the sensitive bridging lactone. Overall, 15 steps (longest linear sequence) are required to prepare the natural product from a commercially available aldehyde, and assembly of the contiguous array of six stereocenters is accomplished with high stereocontrol.The Lycopodium alkaloids have provided some of the most intricately structured and stereochemically dense specimens among naturally occuring small molecules. 1 The attendant challenge for chemical synthesis, often combined with their promise as potential therapeutics, has led to broad interest in the total chemical synthesis of these targets. 2 Recent reports have detailed rather concise preparations of (−)-fawcettimine, 3 (+)-fawcettidine, 4 (−)-lycopodine, 5 lyconadin A and B, 6 and (−)-cernuine. 7,8 Importantly, valuable new chemical methods have been developed in nearly every case to solve specific synthetic challenges while also avoiding synthetic routes that would not address the important issue of supply. E-mail: jeffrey.n.johnston@vanderbilt.edu. Supporting Information Available: Preparations, spectral data, and structure elucidation for key intermediates. This material is available free of charge via the Internet at http://pubs.acs.org. Kobayashi isolated (+)-serratezomine A (1, as its trifluoroacetic acid salt) as part of a search for new therapeutics from the club moss L. serratum, from which the huperzine alkaloids were isolated. 9 The polycyclic structure merges a 5,6-fused ring system (an indolizidine) with a 6,6-spirocyclic ring and a bridging lactone. Kobayashi found that the lactone is subject to isomerization from O13 to O8, resulting in the thermodynamically favored fused γ-lactone. 10 Among the six contiguous stereogenic carbons, the axial alcohol at C8 -absent from the natural products listed above -sterically impinges upon the spirocyclic piperidine through a 1,3-diaxial interaction. Finally, all but two of the stereochemical elements overlap with a bridgehead or bicyclic union. We anticipated that these challenges might provide an opportunity to develop new chemistry to meet the goal of a convergent synthesis. In this Communication, we describe these developments in the context of the first total synthesis of (+)-serratezomine A. NIH Public AccessOur solution to the problem of convergency rested on the hypothesis that an exocyclic enamine of general type A (Figure 1), an unsaturated 2-methyl pyrrolidine, could provide a multiply nucleophilic C12 and serve as the synthesis lynchpin. The f...

Development of an Enantioselective Route toward the Lycopodium Alkaloids: Total Synthesis of Lycopodine

“…The Evans laboratory recently reported an elegant total synthesis of a similar alkaloid ring system (clavolonine) 10. Additionally, numerous other total syntheses of structural different lycopodium alkaloids have been reported over the past decade by Bosch,11 Chang,12 Comins,13 Dake,14 Johnston,15 Liao,16 Mukai,17 Overman,18 Sarpong,19 Siegel,20 Toste,21 Takahashi22 and Takayama 23. Herein, we disclose a full account of our work towards the alkaloid lycopodine.…”

Total Synthesis of the Lycopodium Alkaloid Serratezomine A Using Free Radical-Mediated Vinyl Amination to Prepare a β-Stannyl Enamine Linchpin

“…Combustion data analyzing C, H, and N were performed on select compounds. Compounds 5 , 7d , 14 , 16 , 25 , 68 , 69 , 70 , and 72 were reported in an earlier publication 8 as well as 9c and 11c . 14c …”

Radical Reactions in Alkaloid Synthesis: A Perspective from Carbon Radical Precursors

“…An intramolecular radical alkyne aminostannation from 30 leading to a pyrrolidine ring constitutes the initial ring‐closing step in the synthesis of the lycopodium alkaloid serratezomine A . The addition step giving β‐stannyl enamine 31 (Scheme ) was regiocontrolled electronically by the formation of the α‐aminomethyl radical and sterically by the disubstitution at the azomethine carbon.…”