Absolute Configuration Assignment by Asymmetric Syntheses of the Homalium Alkaloids (−)‑(R,R,R)‑Hoprominol and (−)-(4′S,4″R,2‴R)‑Hopromalinol

• Published in: Journal of organic chemistry 2012-11, Vol.77 (21), p.9724-9737
• Main Authors: Davies, Stephen G, Lee, James A, Roberts, Paul M, Stonehouse, Jeffrey P, Thomson, James E
• Format: Article
• Language: English
• Subjects: Alkaloids - chemical synthesis; Alkaloids - chemistry; Amides - chemistry; Chemistry; Exact sciences and technology; Heterocyclic compounds; Heterocyclic Compounds - chemical synthesis; Heterocyclic Compounds - chemistry; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings; Lithium Compounds - chemistry; Molecular Structure; Organic chemistry; Preparations and properties; Stereoisomerism
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo301830j

The conjugate addition of lithium (R)-N-(3-chloropropyl)-N-(α-methylbenzyl)amide to α,β-unsaturated esters was used as the key step in the syntheses of all possible diastereoisomers of the homalium alkaloids hoprominol and hopromalinol. Comparison of the specific rotation data for these synthetic samples with those of samples isolated from the natural source enabled the absolute configurations within these alkaloids to be confidently assigned for the first time as (−)-(R,R,R)-hoprominol and (−)-(4′S,4″R,2‴R)-hopromalinol. The asymmetric syntheses of (−)-(R,R,R)-hoprominol (in 10 steps and 4.0% overall yield) and (−)-(4′S,4″R,2‴R)-hopromalinol (in 10 steps and 9.3% overall yield), from commercially available starting materials in each case, therefore represent the first total asymmetric syntheses of these alkaloids to be reported.