Nitrenium Ion-Mediated Alkene Bis-Cyclofunctionalization: Total Synthesis of (−)-Swainsonine

Abstract

The total synthesis of (-)-swainsonine from 2,3-O-isopropylidene-D-erythrose in 12 steps and an overall yield of 28% is reported. The pivotal transformation in our route to this indolizidine alkaloid is the formation of the pyrrolidine ring and C-8a/8 stereodiad through the diastereoselective, bis-cyclofunctionalization of an γ,δ-unsaturated O-alkyl hydroxamate. This transformation is believed to proceed via the intramolecular capture of an N-acyl-N-alkoxyaziridinium ion generated by the diastereoselective addition of a singlet acylnitrenium ion to the pendant alkene.

Nitrenium Ions from Amine‐Iodine(III) Combinations

“…Based on PIFA‐mediated nitrenium ion cyclization reactions, Wardrop made an eminent contribution by introducing a series of developments for synthesizing complex molecular structures as shown in Figure (selected examples). These reports include the synthesis of (+)‐Kishi lactam, fasicularin, (−)‐Dysibetaine, (−)‐swainsonine, (+)‐Castanospermine and some other complex structural motifs . (+)‐Kishi lactam, a complex molecule that was synthesized through formation of an acylnitrenium ion to enable azaspirocyclization of N ‐methoxy‐γ‐arylbutanamide on reaction with PIFA.…”

The Orthoester Johnson–Claisen Rearrangement in the Synthesis of Bioactive Molecules, Natural Products, and Synthetic Intermediates – Recent Advances

“…[141] Swainsonine showed selective strain inhibition of infected mammalian prions [142] and is the first inhibitor of glycoprotein processing to be selected for clinical trials. The total synthesis of (-)swainsonine (257), based on a nitrenium-ion-mediated alkene bis-cyclofunctionalization protocol, [144] was reported by Wardrop et al [145] The allyl alcohol 254, derived from lactone 253, was subjected to Johnson-Claisen rearrangement to afford the anticipated ester 255 in high yield and with excellent E selectivity. Synthesis of 7,11-cyclobotryococca-5,12, 26-triene. interesting synthetic targets.…”

“…These compounds display greater metabolic stability to phosphorylase enzymes. [89] Carbovir [90] (144, Scheme 31) and abacavir [91] (145) are such carbocyclic nucleosides, exhibiting potent anti-HIV properties. Stimulated by this finding, Hong and co-workers [92] developed 4Јcyclopropylated carbovir analogues with the aid of Johnson-Claisen rearrangement and ring-closing metathesis.…”

“…Synthesis of 7,11-cyclobotryococca-5,12, 26-triene. interesting synthetic targets. The total synthesis of (-)swainsonine (257), based on a nitrenium-ion-mediated alkene bis-cyclofunctionalization protocol, [144] was reported by Wardrop et al [145] The allyl alcohol 254, derived from lactone 253, was subjected to Johnson-Claisen rearrangement to afford the anticipated ester 255 in high yield and with excellent E selectivity. Ester 255 was elaborated through nitrenium-ion-mediated alkene bis-cyclofunctionalization to lactone bis-cyclization product 256.…”

Asymmetric Formal Synthesis of (–)‐Swainsonine by a Highly Regioselective and Diastereoselective Allylic Amination Using Chlorosulfonyl Isocyanate

“…One synthesis relies on a series of asymmetric synthetic reactions to construct the stereogenic centers 17. In a recent example that uses a carbohydrate as a chiral pool, Wardrop and co‐workers reported the total synthesis of 1 from 2,3‐ O ‐isopropylidene‐ D ‐erythrose through the diastereoselective addition of an acylnitrenium ion to an alkene to form the pyrrolidine framework 15h. In another example that uses a chiral pool, Chemla et al described the asymmetric total synthesis of 1 from readily available D ‐erythronolactone through the addition of allenylmetals to chiral α,β‐alkoxy sulfinylimines 15i.…”