The first total synthesis of the (±)-17-methyl-trans-4,5-methyleneoctadecanoic acid and related analogs with antileishmanial activity

Abstract

The first total synthesis of the marine cyclopropane fatty acid (±)-17-methyltrans-4,5-methyleneoctadecanoic acid was accomplished in 8 steps and in 9.1% overall yield starting from 1-bromo-12-methyltridecane. The cis analog (±)-17-methyl-cis-4,5-methyleneoctadecanoic acid was also synthesized but in 7 steps and in 16.4% overall yield. With the two isomeric cyclopropane fatty acids at hand it was possible to unequivocally corroborate the trans relative configuration of the naturally occurring fatty acid by gas chromatographic co-elution of the corresponding methyl esters. The cis isomer was cytotoxic to Leishmania donovani promastigotes with an IC 50 of 300.2 ± 4.2 µM. KeywordsAntileishmanial activity; Cyclopropane fatty acids; Sponges; Synthesis Cyclopropane fatty acids (CFAs) are widespread in nature and they have been identified in many organisms ranging from bacteria to seed oils. 1 The earliest known example is lactobacillic acid (cis-11,12-methyleneoctadecanoic acid), but several structural variants have been isolated since. 1 One interesting compound is the 17-methyl-cis-9,10-methyleneoctadecanoic acid, from the protozoan Herpetomonas megaseliae, which incorporates both methyl and cyclopropyl branching in the chain. 2 While most of the known CFAs incorporate a cis cyclopropyl group in the acyl chain, just a few trans CFAs are known, such as the recently discovered 17-methyl-trans-4,5-methyleneoctadecanoic acid (1a) and the 18-methyl-trans-4,5-methylenenonadecanoic acid, which were identified in the phospholipids of the Caribbean sponge Pseudospongosorites suberitoides. 3 These marine fatty acids are quite interesting since they incorporate an unusual trans 4,5-cyclopropane in addition to iso methyl branching. However, the characterization of 1a in the sponge extract was done by gas chromatography-mass spectrometry on suitable volatile derivatives Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors maybe discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript followed by 1 H NMR of the total mixture of fatty acids. Therefore, a more rigorous confirmation of the structure of 1a is warranted. For this purpose, a total synthesis of 1a would not only serve to confirm the unusual trans cyclopropyl arrangement of the natural fatty acid, but also to report the total characterization of 1a, as well as to provide the necessary expertise to synthesize analogs for biological screening. Therefore, herein we report the first total synthesis of both the naturally occurring (±)-17-methyl-trans-4,5-methyleneoctadecanoic acid (1a) and the correspon...

First total synthesis of the (±)-2-methoxy-6-heptadecynoic acid and related 2-methoxylated analogs as effective inhibitors of the Leishmania topoisomerase IB enzyme

“…Since we do not expect a big difference between the geometries of acids 2 and 3 , and we consider the fact that a fatty acid with a cis cyclopropane group does not inhibit Ld TopIB [13], other factors, such as intermolecular cation-π interactions, might be significant near the binding sites of the fatty acids with Ld TopIB. One could hypothesize that the ammonium groups (R-NH 3 + or R 2 C=NH 2 + ) in amino acids such as lysine (K) and/or arginine (R), known to be present in the active sites of these TopIB enzymes [14], might interact with the double or triple bonds in these fatty acids.…”

Simmons–Smith Cyclopropanation: A Multifaceted Synthetic Protocol toward the Synthesis of Natural Products and Drugs: A Review

“…In 2010, Carballeira et al performed the first total synthesis of (±)-17-methyl-trans-4,5-methyleneoctadecanoic acid 278 and its analogue, (±)-17-methyl-cis-4,5-methyleneoctadecanoic acid 279, in eight steps (9.1% overall yield) and seven steps (16.4% overall yield), respectively, by employing Simmons-Smith cyclopropanation as a key step. 1-Bromo-12-methyltridecane 270 was used as the starting material, and both the synthesized isomers were evaluated for anti-leishmanial activity [131]. In the first step of their synthetic route, 1-bromo-12-methyltridecane 270 was allowed to react with trimethylsilyl acetylene 271 in the presence of n-BuLi and subsequently desilylated to produce 14-methylpentadec-1-yne 272 (in a 100% yield), which was processed by reaction with 273, followed by deprotection by using p-TSA and subsequent reduction, to furnish compound 274 in a 94% yield.…”

Screening Marine Natural Products for New Drug Leads against Trypanosomatids and Malaria

“…LTopIB was described as a potential target in Trypanosomatids due to its anomalous heterodimeric structure and differential expression in the parasite [319]. Therefore, other unsaturated fatty acids were synthesized to target it [320][321][322]. Within this series, the 2-octadecynoic acid (2-ODA) (53), 2-hexadecynoic acid (2-HDA) (54) and 2-tetradecynoic acid (2-TDA) (55) were studied on the three major Trypanosomatids.…”