Total Synthesis of Δ¹²‐Prostaglandin J₃, a Highly Potent and Selective Antileukemic Agent

Abstract

A catalytic asymmetric total synthesis of the potent and selective antileukemic Δ12-prostaglandin J3 (Δ12-PGJ3) is described. The convergent synthesis proceeded through intermediates 2 and 3, constructed enantioselectively from readily available starting materials and coupled through an aldol reaction followed by dehydration to afford stereoselectively the cyclopentenone alkylidene structural motif of the molecule.

Total Synthesis of Δ12‐Prostaglandin J3: Evolution of Synthetic Strategies to a Streamlined Process

“…The UV,H PLC, and mass spectrum were in agreement with those of the biosynthetically generated D 12 -PGJ 3 (1)b yt he Prabhu-Paulsont eam. [3a, 16] Furthermore, we were able to obtain a 1 HNMR spectrum of am inutea mount of as ample of D 12 -PGJ 3 (1)f rom these investigators, comparison of which with that of synthetic D 12 -PGJ 3 (1)r evealed the identity of the two samples (see Supporting Information of reference [16]). Next, as tabilityt est for D 12 -PGJ 3 (1)w as carried out and, interestingly, the natural D 12 -PGJ 3 (1)w as stable when stored neat at 25 8Cw ith only small amountso fd egradation products observed after one week (as judged by 1 Ha nd 13 CNMR spectroscopic analysis).…”

“…It was found after systematic experimentation (see Ta ble 1) that the combination of tBuOOH and catalytic amountso f[ Rh 2 (cap) 4 ], ac atalyst introduced by Doyle et al, [21] produced the desired regioisomer 20 in 48 %y ield. Other common conditions [e.g.,S eO 2 , tBuOOH-PDC, [22] tBuOOH-bleach, [23] Mn(OAc) 3 with or without O 2 atmosphere [24] ]p roved to be inferior.D uring our earlier investigations, [16] we had also studied the CÀHo xidation on alternative substrates with either aT BS-protectedp rimary alcohol( 15 b, entry 3, Ta ble 1) or ad imethyl acetal (15 c,e ntry 4, Table 1), both of which could be converted, in principle, to the C6 aldehyde for the upcoming Wittig olefination (vide infra). However, under identical conditions, theses ubstrates provided the trisubstituted enones 20 b and 20 c,r espectively (entries 3a nd 4, Ta ble 1), in which the CÀHo xidation occurred with concomitant olefin transposition.…”

Reoptimization of the Organocatalyzed Double Aldol Domino Process to a Key Enal Intermediate and Its Application to the Total Synthesis of Δ12‐Prostaglandin J3

“…In order to construct Δ 12 ‐PGJ 3, disconnection of the C12−C13 bond through an aldol/dehydration reaction sequence would require β‐boryl aldehyde 8 and enone 9 (Scheme B). This type of aldol/dehydration strategy was originally reported by Kobayashi and has subsequently been applied to the syntheses of Δ 12 ‐PGJ 3 3 , and other closely related prostaglandins . Boryl aldehyde 8 was selected as a masked hydroxy aldehyde equivalent because it can be easily prepared by catalytic enantioselective conjugate borylation, and subsequently unmasked later in the synthesis by stereospecific oxidation of the boronic ester.…”

Chemoenzymatic Synthesis towards the Active Agent Travoprost

“…[4] The increasing number of studies dealing with synthetic approaches towards the total synthesis of prostaglandins and their analogues stresses the growing demando ft hese active agents. [6] In this context,e xtensive efforts have been dedicated to the development of synthetic strategies, which have allowed an easy access to diverse prostaglandin derivatives, [7] for example, Woodward, [8] Corey, [5] Danishefsky, [9] Aggarwal, [2,10] Nicolaou, [11] and co-workers have developedn ew methods for establishing the complex structures of these diverse molecules. Previous approaches towards the synthesiso ft ravoprost (1) led to racemic (AE)-travoprost (1) [12] and those using the Corey method( in which the so-called Corey lactone 2 acts as an intermediate that is sequentially attached by two sidechains in aH orner-Emmons and Wittig alkenylation) [8] suffer from low selectivity in the late-stage reduction of the keto functiona t positon1 5i nthe w-side chain of intermediate 3 (Figure 1).…”

“…[3] An alternative synthetic strategy that avoidst he late-stage reduction in the w-side chain was reported by Lennon and co-workers. [13,36] Their route required three synthons:t he silyl-protected bicycle 9,t he enantiopure vinyl iodide 10,a nd the commerciallya vailableW ittig reagent (4-carboxybutyl)-triphenylphosphonium bromide (11), the latter of which gives access to the w-side chain (Figure 2). The first step in their sequential route is based on ac uprate-mediated coupling of compound 10 to the tricycle obtained from ketone 9 after treatment with base.…”