Access to a Stereoisomer Library of Solomonamide Macrocycles

Abstract

In an attempt towards understanding stereostructure activity relationships (SSARs), we have prepared eight possible stereoisomers of solomonamide macrocycles, in particular,b yc hanging the stereochemical pattern of non-peptidef ragment AHMOA. Here, we have demonstrated different ways to construct three contiguous chiral centers present in solomonamide Bm acrocycle using substrate/reagent-controlled methods.T hese methods involve Brown crotylation, NHK reactiona nd Evans aldol addition as key steps to synthesize key non-peptide fragment. Further,these non-peptidefragments were converted to their corresponding macrocycles via ligand-free intramolecular Heck reaction.Supporting information and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.

Heck Macrocyclization in Forging Non-Natural Large Rings including Macrocyclic Drugs

“…More often though, analogues of structurally validated natural products are prepared deliberately, rather than unexpectedly, in order to explore biologically relevant chemical space, wherein Heck macrocyclization again plays a substantial role. Earlier examples include conformationally restricted taxoids [80], side chain derivatives of mandelalide A [81], and stereodivergent solomonamides [82]. Recently, our total synthesis of highly antiproliferative nannocystin A through Heck macrocyclization [83,84] secured subsequent SAR investigations by facilely preparing dozens of non-natural analogues including 50-54 that deviate from the natural lead either stereochemically, along the macrocycle backbone, or at the peripheral substituent (Figure 8A) [85][86][87][88].…”

Brown Allylation: Application to the Synthesis of Natural Products

“…The allyl alcohol was obtained in 66 % yield as a mixture of diastereoisomers in a intermediate, later used for ligand-free intramolecular Heck reaction. [63] Disciformycin B ( 22) is a polyketide-derived macrolide, isolated in 2014 by Müller and co-workers from the myxobacterium Pyxidicoccus fallax strain AndGT8. [64] The biological assessment of this compound revealed significant antibacterial activity against Gram-positive bacteria, including methicillinand vancomycin-resistant Staphylococcus aureus (MRSA/VRSA) strains.…”

“…Starting with d‐methionine, treatment with (Ipc) 2 B‐(E)‐crotyl (2) afforded the desired crotylated compound with planned stereochemistry in good yield as a single isomer (Scheme 19). It then underwent acetonide protection, reductive ozonolysis and pyrolytic syn‐elimination to give the important intermediate, later used for ligand‐free intramolecular Heck reaction [63] …”

Comprehensive Study on Solomonamides: Total Synthesis, Stereochemical Revision, and SAR Studies toward Identification of Simplified Lead

“…The unique macrocyclic scaffold and interesting biological properties of the solomonamides have generated intense synthetic efforts from our group during the past decade . Ever since the disclosure of its structure, several synthetic attempts toward the total synthesis of target natural products have been published, mainly from the Chandrasekhar group, the Butler group, the Sarabia group, and a very recent report from the Unsworth group .…”