Improved Synthesis of (E)-12-Nitrooctadec-12-enoic acid, a Potent PPARγ Activator. Development of a “Buffer-Free” Enzymatic Method for Hydrolysis of Methyl Esters

Abstract

Endogenous nitro-fatty acids, acting as partial agonist of PPARγ, are able to lower the insulin and glucose levels without the side effects associated with common antidiabetic drugs. (E)-12-Nitrooctadec-12-enoic acid, a potent activator of this peroxisome receptor, was synthesized in a very efficient sequence via a Henry-retro-Claisen ring fragmentation, followed by a novel enzymatic cleavage of methyl esters. The latter method was then applied in the last step of the synthesis of a few labile natural products, such as prostaglandins, isoprostanes, and phytoprostanes.

A Divergent Enantioselective Synthesis of 9‐J1‐Phytoprostane and 9‐A1‐Phytoprostane Methyl Ester

“…Finally, two consecutive deprotection steps, namely O ‐TBS ether cleavage with aq. HF, and methyl ester hydrolysis under our “buffer‐free” conditions,14 delivered the expected 9‐J 1 ‐PhytoP ( 1 ), [ α ] D 20 = –170.4 ( c = 0.55, CH 2 Cl 2 ), in 84 % yield over two steps. Following the same synthetic sequence used for the transformation of 4 into enone 19 , sulfone 5 gave the expected enone (i.e., 20 ; see Supporting Information), from which the O ‐TBS ether was detached using NH 4 F in MeOH instead of aq.…”

General Approach to Prostanes B1 by Intermolecular Pauson–Khand Reaction: Syntheses of Methyl Esters of Prostaglandin B1 and Phytoprostanes 16‐B1‐PhytoP and 9‐L1‐PhytoP

“…The cleavage of prostane methyl esters can be easily performed by enzymatic hydrolysis 27. Since the hydrolysis of the methyl esters of 16‐B 1 ‐PhytoP ( 16a ), and 9‐L 1 ‐PhytoP ( 16c ) has been described,27a our approach constitutes a formal synthesis of these compounds.…”

Nitro Fatty Acids (NO2-FAs): An Emerging Class of Bioactive Fatty Acids

“…In 2010, Zanoni reported a much more efficient synthetic route to (E)-12-nitrooctadec-12-enoic acid (24) in 4 steps (overall yield 50%), outperforming the previously reported methodology of Gorczynski [70], which had a 4.8% overall yield (Scheme 19) [112]. This high-yield synthesis of nitroalkene 24 began with a one-pot consecutive Henry reaction of 2-nitrocyclododecanone (75) with hexanal (76), followed by a retro-Claisen ring cleavage, affording this way the resulting nitro hydroxy acid 77.…”