A glycine Schiff base Michael addition is used in sequence with free radical-mediated aryl amination to ultimately arrive at the ambiguine G ABC-tricycle convergently. Additionally, thermal DielsAlder cycloaddition of β-chloro methacrolein with Cohen's diene is used to diastereoselectively construct the D-cyclohexane ring bearing a neopentyl chloride.The blue-green algae Hapalosiphon delicatulus produces a variety of indoloterpenes, including the hapalindole, 1 fischerindole, 2 and welwitindolinone 3 classes of natural products ( Figure 1). The ambiguines have been isolated from this source as well, appearing formally as prenylated hapalindoles, and often bearing an additional element of complexity in the form of a fifth (fused) seven membered ring (e.g. ambiguine G, 1). 4 The entanglement between structural diversity and apparent homology within these natural products has led to the proposal that the individual biosynthesis pathways may overlap.In contrast to total syntheses within the first three classes, 5,6 the pentacyclic ambiguines and their highly ring-fused skeletons remain without approach, much less a synthetic solution. Ambiguine G (1) further attracted our attention by virtue of the challenge it poses on a strategic level to the development of a convergent synthesis. Of the nineteen atoms that comprise the structural core, eight (42%) are involved in ring fusions. This uncharacteristically high level of ring interdependence provides a unique challenge for traditional annulation approaches whose implementation might result in a rather linear approach. Figure 2 outlines the key elements of a global solution to this problem. Instead of reliance on an indole template, we targeted instead the construction of the BC-rings by a Buchner reaction, 7 followed by selective fragmentation of the norcaradiene intermediate. The A-ring would then be annulated using a jeffrey.n.johnston@vanderbilt.edu. † Current address: Department of Chemistry, University of Utah, Salt Lake City, UT 84102. sequence of carbon-carbon and aryl-nitrogen bond formations. Separately, we sought a means to validate the use of a Diels-Alder cycloaddition to establish the chiral chlorocyclohexane. NIH Public AccessWe targeted intermediate 4 as a template for design of a convergent indoline annulation. Our plan was to combine the operationally mild nature of free radical-mediated aryl amination 89 with conjugate addition of a glycine Schiff base (5) to a suitably functionalized β-tetralone (4).ortho-Bromobenzyl acetic acid (2) was homologated to α-diazo ketone 3 in 88% overall yield by treatment of the derived acid chloride with diazomethane. This intermediate was then treated with rhodium(II) acetate at elevated temperature to effect a formal aryl C-H insertion, proceeding through the intermediate norcaradiene and regioselective cyclopropane ring opening to deliver the β-tetralone. 10 Regioselective dimethylation at the more acidic benzylic methylene could be effected in 71% yield using potassium tert-butoxide in tert-butanol and met...

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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...

Serratezomine A is a member of the structurally diverse class of compounds known as the Lycopodium alkaloids. The key supporting studies and successful total synthesis of serratezomine A are described in this account. Significant features of the synthesis include the first application of free radical mediated vinyl amination and Hwu’s oxidative allylation in a total synthesis, and an intramolecular lactonization via a transannular SNi reaction. Minimal use of protecting groups and the highly diastereoselective formation of a hindered, quaternary stereocenter using an umpolung allylation are also highlights from a strategy perspective. Observation of quaternary carbon epimerization via a retro-Mannich/Mannich sequence highlights the additional challenge presented by the axial alcohol at C8 in serratezomine A.

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