A Unified Strategy for the Synthesis of 7-Membered-Ring-Containing Lycopodium Alkaloids

Abstract

A unique subset of the Lycopodium alkaloid natural products share a 7-membered-ring substructure and may potentially arise from a common biosynthetic precursor. To both explore and exploit these structural relationships, we sought to develop a unified biosynthetically inspired strategy to efficiently access these complex polycyclic alkaloids through the use of a cascade sequence. In pursuit of these goals, the first total synthesis of (+)-fastigiatine (2) was accomplished via a series of cascade reactions; we describe herein a full account of our efforts. Insight from these endeavors led to critical modifications of our synthetic strategy, which enabled the first total syntheses of (-)-himeradine A (1), (-)-lycopecurine (3), and (-)-dehydrolycopecurine (4), as well as the syntheses of (+)-lyconadin A (5) and (-)-lyconadin B (6). Our approach features a diastereoselective one-pot sequence for constructing the common 7-membered-ring core system, followed by either a biomimetic transannular Mannich reaction to access himeradine A (1), lycopecurine (3), and dehydrolycopecurine (4) or an imine reduction for lyconadins A (5) and B (6). This strategy may potentially enable access to all 7-membered-ring-containing Lycopodium alkaloids and provides additional insight into their biosynthetic origin.

Enantioselective Total Syntheses of Lyconadins A–E through a Palladium‐Catalyzed Heck‐Type Reaction

“…We then focused on the construction of tetracycle 9 via a key C6−N bond‐forming reaction of amine 11 . A previous approach, relying on a double‐deprotonation/oxidation strategy to stitch the C6 and N atoms, proved fruitless in our hands, due to the presence of the hydroxy motif of amine 11 . Masking this primary alcohol of 11 with TBS followed by treatment with LHMDS and I 2 under anhydrous and cryogenic conditions successfully formed the C6−N bond, but the poor efficiency of this tactic (three steps from 11 , low overall yield) motivated us to look for more productive approach.…”

“…With favorable bioactivity and impressive structural complexity, these lycopodium alkaloids has served as attractive targets in the chemistry community . Remarkable total synthetic triumphs have been achieved by Smith ( 1 , 2 ), Sarpong ( 1 ), Fukuyama ( 1 – 3 ), Waters ( 3 ), Dai ( 1, 3 ), Shair ( 1 , 2, 6 – 8 ), Rychnovsky ( 8 ), but total syntheses of lyconadins D and E ( 4 , 5 ) has not been realized. Considering the structure diversity of alkaloids 1 – 8 , a divergent synthetic strategy that may address all of their constructions seems tempting yet quite challenging.…”

Enantioselective Total Syntheses of Lyconadins A–E through a Palladium‐Catalyzed Heck‐Type Reaction

“…We then focused on the construction of tetracycle 9 via a key C6−N bond‐forming reaction of amine 11 . A previous approach, relying on a double‐deprotonation/oxidation strategy to stitch the C6 and N atoms, proved fruitless in our hands, due to the presence of the hydroxy motif of amine 11 . Masking this primary alcohol of 11 with TBS followed by treatment with LHMDS and I 2 under anhydrous and cryogenic conditions successfully formed the C6−N bond, but the poor efficiency of this tactic (three steps from 11 , low overall yield) motivated us to look for more productive approach.…”

“…With favorable bioactivity and impressive structural complexity, these lycopodium alkaloids has served as attractive targets in the chemistry community . Remarkable total synthetic triumphs have been achieved by Smith ( 1 , 2 ), Sarpong ( 1 ), Fukuyama ( 1 – 3 ), Waters ( 3 ), Dai ( 1, 3 ), Shair ( 1 , 2, 6 – 8 ), Rychnovsky ( 8 ), but total syntheses of lyconadins D and E ( 4 , 5 ) has not been realized. Considering the structure diversity of alkaloids 1 – 8 , a divergent synthetic strategy that may address all of their constructions seems tempting yet quite challenging.…”

The chemistry of the carbon-transition metal double and triple bond: Annual survey covering the year 2014

“…Several papers report on the cross metathesis of inexpensive low molecular weight α,β-unsaturated carbonyl compounds with other more precious alkenes, including cross metatheses of: (1) acrolein with a 22-carbon α,ω-diene derivative for preparation of miyakosyne A and stereoisomers [440], with allylic alcohols for six-membered ring carbohydrate syntheses [441], and with an allylpiperidine derivative (e.g. 135) for total synthesis of himeradine A [442]; (2) methacrolein with an alkene spiroacetal for total synthesis of bistramide A [443]; (3) methyl vinyl ketone with allylic alcohols as part of a general arylamine synthesis route [444]; (4) various enones, acrylates, and allylic alcohols with 4-pentylpyranones [445]; (5) various acrylate esters with undeca-1,9-dien-6-ol derivatives (e.g.…”