Multicomponent Strategy for the Synthesis of Prostaglandin E₂ Methyl Ester under Anion Relay Chelation Control

Abstract

Starting with four components, the enantioselective synthesis of prostaglandin E2 methyl ester has been achieved through a highly stereoselective heteroatom-directed conjugate addition reaction and cyclopentanone ring cyclization as the key steps. This asymmetric strategy includes (i) an asymmetric Reformatsky reaction; (ii) conjugate addition of a chiral vinyllithium reagent; (iii) cyclization to form a sulfonylated cyclopentanone in one-pot; followed by (iv) allylation of the side chain. Four carbon-carbon bond-forming processes and three stereogenic centers were established, with the steps from (ii) to (iii) being achieved in a one-pot process.

Recent developments in the asymmetric Reformatsky-type reaction

“…More recently, excellent results were also reported by Isobe et al for a diastereoselective SmI 2 -mediated Reformatsky reaction constituting the key step of a highly economical total synthesis of prostaglandin E 2 methyl ester [ 23 ]. As shown in Scheme 7 , the reaction occurred between achiral aldehyde 17 and chiral oxazolidinone 18 in the presence of SmI 2 in THF at −78 °C to give the corresponding chiral secondary alcohol 19 in high yield (88%) combined with excellent diastereoselectivity (>95% de).…”

Scale-Up Investigation of Aggarwal Enal Bicyclic Intermediate Synthesis

“…Corey’s synthesis was later commercialized with the introduction of very cost-effective synthesis of Corey lactone by Tomoskozi et al in 1976, which is still used today in various improved formats. , In 2012, Aggarwal group described remarkably shortened seven-step synthesis of prostaglandin PGF 2α . This achievement has started a renaissance in this synthesis field with several groups reporting elegant and short access to various prostanoids . With respect to potential industrial application of newly reported routes, it is instructive to compare cost effectiveness of latest reported syntheses of commercially most successful prostanoid drug–latanoprost.…”

A Highly Regio- and Diastereoselective Four-Component Reaction to Construct Polycyclic Bispiroindolines from 2-Isocyanoethylindoles and Isocyanates

“…Multicomponent reactions involving cascade processes provide powerful strategies for the total synthesis of natural products and synthetically useful building blocks. , Among them, isocyanide-based multicomponent reactions are particularly important. , Recently, 2-isocyanoethylindoles, bearing a nucleophilic isocyanide at the C3-position of the indoles, have been used as precursors for the rapid construction of spiroindolines . Because the chemoselective synthesis of spiroindolines and pyrroles have been achieved by using a 2-isocyanoethylindole-based domino reaction, , a number of chemo- and enantioselective synthetic methods have been established for the dearomatization of 2-isocyanoethylindoles to afford spiroindolines.…”