α,β-Unsaturated Diazoketones as Platforms in the Asymmetric Synthesis of Hydroxylated Alkaloids. Total Synthesis of 1-Deoxy-8,8a-diepicastanospermine and 1,6-Dideoxyepicastanospermine and Formal Synthesis of Pumiliotoxin 251D

Abstract

A versatile and concise approach for the stereoselective synthesis of mono-, di-, and trihydroxylated indolizidines is presented in four to six steps from Cbz-prolinal and a diazophosphonate. The key steps involved a Wolff rearrangement, followed by a stereoselective dihydroxylation/epoxidation reaction, from an α,β-unsaturated diazoketone. The strategy also permits extension to the synthesis of many natural hydroxylated indolizidine alkaloids as demonstrated in the formal synthesis of pumiliotoxin 251D.

Synthesis of 1‐Deoxy‐8,8a–di–epi–castanospermine, 1‐Deoxy‐6,7,8a–tri–epi–castanospermine and Formal Synthesis of Pumilotoxin 251D

“…The cyclization reaction could also be achieved with organic bases such as diisopropylethylamine and triethylamine; however the presence of these tertiary amines in the reaction mixture made the purification of the indolizidine derivative difficult. Stereochemistry of the product obtained was confirmed to be that of 1 , by comparing its spectral data and specific rotation with those available in the literature …”

“…Reduction of the double bond and the N−O bond using Pd/C in methanol under H 2 atmosphere gave the lactone 11 (Scheme ). The lactone 11 has already been used for the synthesis of Pumilotoxin 251D and other indolizidine alkaloids ,,…”

“…Majority of the synthesis to date are based on chiral pool approach using chirons derived from carbohydrates, heterocyclic compounds and amino acids ,. Burtoloso et al reported a six step synthesis of 1‐deoxy‐8,8a‐di‐epi‐castanospermine from prolinal and the diasteremeric ratio achieved in the key reaction is 8:2 …”

“…Recently, Burtoloso et al. reported the synthesis of 1‐deoxy‐8,8a‐diepicastanospermine from prolinal and Suh et al. reported the synthesis of 1‐deoxy‐6,8a‐di‐epi‐castanospermine and 1‐deoxy‐6‐epi‐castanospermine from homoprolinal .…”

A Two-Step Synthesis of the Bioprotective Agent JP4-039 from N-Boc-L-Leucinal.

“…Only one synthesis is described in the literature, which consists of six steps and involves a one-pot hydrozirconation-transmetalation-addition 1 to a chiral sulfinimine as the key step. As our group has been recently exploiting the chemistry of α,β-unsaturated diazoketones [2][3][4] , we were interested in investigating these platforms for the direct synthesis of β,γ-unsaturated amides and apply the methodology to prepare the bioprotective agent JP4-039 in just one step from them.…”