Decahydroquinoline Ring ¹³C NMR Spectroscopic Patterns for the Stereochemical Elucidation of Phlegmarine-Type Lycopodium Alkaloids: Synthesis of (−)-Serralongamine A and Structural Reassignment and Synthesis of (−)-Huperzine K and (−)-Huperzine M (Lycoposerramine Y)

Abstract

Analysis of 13 C NMR spectroscopic data of the phlegmarine subset of Lycopodium alkaloids revealed spectral patterns that allowed the stereochemical arrangement of the four stereogenic carbons in the decahydroquinoline core to be established. A relatively simple predictive set of chemical shift combinations is reported, providing a tool for the challenging stereochemical assignment of phlegmarine-type alkaloids. Based on the chemical shifts in their NMR spectroscopic profiles, the alkaloids huperzine K and huperzine M, formally reported as cis derivatives, were structurally reassigned as transdecahydroquinolines. The NMR spectroscopic data for huperzine M were identical to those reported for lycoposerramine Y and, hence, also implied the configurational reassignment of the latter. The revised structures of the above alkaloids were confirmed by enantioselective total synthesis. Additionally, the synthesis of (−)-serralongamine A via a common intermediate precursor is reported.

Deciphering the Biosynthetic Mechanism of Pelletierine in Lycopodium Alkaloid Biosynthesis

“…In addition, P01 is non-enzymatically condensed with another molecule of Δ 1 -piperideine to generate P03 (Scheme ). It should be noted that for the C 3 side chain in pelletierine and its biogenetically downstream products, phlegmarine-type alkaloids isolated from natural plants are coincidentally incorporated in nonstereospecific modes, which strongly supports that the condensation of Δ 1 -piperideine and 3-oxoglutaric acid in the biosynthesis of LAs is a non-enzymatic reaction. Although the biosynthetic mechanism of pelletierine reported here is similar to the biosynthesis of tropane alkaloids recently reported by Huang, this is the first study to decipher the biosynthetic mechanism of pelletierine with direct biochemical evidence.…”

Lycopodium Alkaloids from Thai Club Mosses

“…Cernuine (51) and lycocernuine (52), 58 isolated from both species Lycopodiella cernua and Lycopodium clavatum, are members of the quinolizidines, which were derived from phlegmarine-type alkaloids by C-9/N bond formation (Figure 7). Serratezomine E (53), 59 a known Nacdetylphlemarin-type alkaloid was isolated from Phlegmariurus squarrosus. 2-Piperidineacetic acid (54), 7,60 a known C7N1 alkaloid precursor, was first isolated from P. squarrosus, which was the first reported isolation of this compound from a natural source.…”

Recent Advances in Total Synthesis of Alkaloids from α,β‐Unsaturated Aldehydes

“…[10] Among these examples, the research team of Bradshaw and Bonjoch has done successful work on the synthesis of a number of tricyclic phlegmarine-type Lycopodium alkaloids (1-7) ( Figure 1). [11][12][13][14] Their powerful methodology included tandem sequence of synthetic steps is initiated by asymmetric Michael addition of β-ketoester 8 to an activated double bond of 2-butenal (9) in the presence of pyrrolidine type organocatalyst 10 and LiOAc as basic additive (Scheme 1). Then treatment of intermediate 11 with LiOH led to the tandem aldol condensation/intramolecular aza-Michael reaction to give cis-decahydroquinoline 12 (90 % ee).…”

“…The purity of intermediate 12 was increased to 99 % ee by simple recrystallization from MeOH. This cis-fused hydroquinoline 12 is easily transformed to library of azabicyclic cores, such as lycoposerramine Z, [11] (-)-cermizine B, [12] serrazomine E, (�)-serralongamine A, (-)-huperzine N, [13] (-)-huperzine K, (-)-huperzine M. [14] It should be noted that the advantages of this methodology are the available starting reagents, "pot economy", low catalyst loading, its high recovery (93 %), the possibility of a gram-scale synthesis of structurally related alkaloids.…”

“…In 2017, Zhao group reported another total synthesis of (�)-cermizine B (2) via reaction of methyl 4-methyl-6-oxocyclohex-1-ene-1-carboxylate (13), 2-picoline (14) and acrolein (15) (Scheme 2). [15] According to the mechanism nine-step synthesis of this heterocyclic scaffold includes two uninterrupted Michael additions, Krapcho decarboxylation, double reductive amination.…”