The Hancock Alkaloids (−)-Cuspareine, (−)-Galipinine, (−)-Galipeine, and (−)-Angustureine: Asymmetric Syntheses and Corrected ¹H and ¹³C NMR Data

Abstract

The asymmetric syntheses of all members of the Hancock alkaloid family based upon a 2-substituted Nmethyl-1,2,3,4-tetrahydroquinoline core is delineated. The conjugate addition of enantiopure lithium Nbenzyl-N-(α-methyl-p-methoxybenzyl)amide to 5-(o-bromophenyl)-N-methoxy-N-methylpent-2-enamide is used to generate the requisite C(2)-stereogenic center of the targets, whilst an intramolecular Buchwald-Hartwig coupling is used to form the 1,2,3,4-tetrahydroquinoline ring. Late-stage diversification completes construction of the C(2)-side chains. Thus, (−)-cuspareine, (−)-galipinine, (−)-galipeine and (−)-angustureine were prepared in overall yields of 30%, 28%, 15% and 39%, respectively, in nine steps from commercially available 3-(o-bromophenyl)propanoic acid in all cases. Unambiguously corrected 1 H and 13 C NMR data for the originally isolated samples of (−)-cuspareine, (−)-galipinine and (−)-angustureine are also reported, representing a valuable reference resource for these popular synthetic targets.

Continuous Flow Synthesis of Quinolines via a Scalable Tandem Photoisomerization‐Cyclization Process

“…The success of this telescoped flow sequence enabled us to furthermore apply our method to the synthesis of a target structure, namely the antimalarial natural product galipinine ( 14 ) which has seen considerable interest by the synthetic community in recent years . We envisioned that a suitable dienone precursor ( 9 ) prepared by a sequential aldol condensation process from 2‐nitrobenzaldehyde, acetone and piperonal could be subjected to the iron‐mediated nitro‐reduction to render the required amine building block ( 10 ) for our telescoped reaction sequence.…”

Asymmetric synthesis of the allocolchicinoid natural product N-acetylcolchinol methyl ether (suhailamine), solid state and solution phase conformational analysis

“…In order to form the corresponding ketone 17, addition of an arylmetal reagent (derived from 5bromo-1,2,3-trimethoxybenzene 14) to the Weinreb amide functionality of 13 was investigated. In preliminary studies, generation of the corresponding aryllithium reagent 15 from aryl bromide 14 upon treatment with either n-BuLi or t-BuLi (following previously reported procedures) 7,8 followed by addition to 13 was frustrated by low conversion to ketone 17, 9 although the generation and subsequent addition of the corresponding Grignard reagent 16 to Weinreb amide 13 proved more promising. Upon optimisation of this reaction, 17 was formed in quantitative yield after work-up (Scheme 3).…”

The Hancock Alkaloids Angustureine, Cuspareine, Galipinine, and Galipeine: A Review of their Isolation, Synthesis, and Spectroscopic Data

“…Unfortunately, some transcriptional errors from the original spectra occurred when the data were first reported. We have validated, and corrected as necessary, both the 1 H and 13 C NMR spectroscopic data for all of the original samples of these alkaloids , . In addition to correction of transcriptional errors, it should also be noted that much of the 13 C NMR data reported for cuspareine was unfortunately transposed with that of galipinine.…”

“…This cyclisation method did not prove applicable to the synthesis of the remaining members of the Hancock alkaloid family and therefore Davies et al, developed an alternative approach to enable access to all of the family members. Application of the revised synthesis to ( R )‐(–)‐angustureine 1 began with conjugate addition of lithium ( S )‐ N ‐benzyl‐ N ‐(α‐methyl‐ p ‐methoxybenzyl)amide 104 to α,β‐unsaturated Weinreb amide 105 , which gave β‐amino amide 106 in 99 % yield and >95:5 dr.…”

“…We subsequently became aware of anomalies and discrepancies in the spectroscopic data reported for the alkaloids, in particular with respect to those for galipeine 4 and purported synthetic samples thereof. We acquired copies of the 1 H and 13 C NMR spectra recorded for the samples of the alkaloids 1 – 4 isolated from the natural source by Jacquemond‐Collet et al, which allowed us to correct the reported spectroscopic data for all of these alkaloids , . We developed an independent synthetic route to the alkaloids and on the basis of these studies, the structure of galipeine 4 was duly corrected, as it was originally erroneously assigned as the regioisomer 5 (Figure ).…”