chiral aldehyde’s epimerization. Greater benefits reagents, which which also the chiral aldehyde’s epimerization. Superior outcomes were obwere obtained with a modified Julia ocienski 72, typically used for (E)-selective olefinatained with a modified Julia ocienski reagent reagent 72, typically utilised for (E)-selective olefination [77]. these situations, the desired unsaturated constructing block block 73 could tion [77]. Beneath Under these circumstances, the preferred unsaturated building73 could be obbe obtained just about epimerization-free. Saponification and change N-protecting group tained pretty much epimerization-free. Saponification and transform within the inside the N-protecting group provided acid 74. provided amino amino acid 74.Mar. Drugs 2021, 19, 446 Mar. Drugs 2021, 19, x FOR PEER Assessment ugs 2021, 19, x FOR PEER REVIEW17 of16 of 27 17 ofScheme 14. synthesis of unsaturated amino acid 69 (developing block ). Scheme 14. Synthesis of unsaturated amino acid 69amino acid 69 (constructing block 7 ). Scheme 14. Synthesis of unsaturated (cIAP-2 medchemexpress building block ).With all essential creating blocks synthesized, thethe cyclomarins A and With all necessary creating blocks synthesized, linear synthesis of and With all required developing blocks synthesized, the linear synthesis of linear synthesis of cyclomarins A cyclomarins A C began with protected CA I list N-methylleucine 75 () to cyclize the linear heptapeptide at the very same and C started with protected N-methylleucine 75 ( 6 ) to cyclize in the very same C started with protected N-methylleucine 75 () to cyclize the linear heptapeptide the linear heptapeptide at position as accomplished by Yao et al. (Scheme 15) [47,56]. 15) [47,56].approach was selected was choto prevent exactly the same position as achieved by Yao et al. (Scheme The linear The to avoid position as achieved by Yao et al. (Scheme 15) [47,56]. The linear method was selected linear strategy epimerizations throughout fragment couplings, andcouplings, and 3 building blocks building three in the uncommon in the uncommon were insen to fragment couplings, and 3 with the unusual developing blocks have been inepimerizations duringavoid epimerizations throughout fragment corporated atincorporated at the finish of theallowing for modificationfor these creating blocks blocks were the finish of the synthesis, also synthesis, also allowing of modification of those corporated in the finish in the synthesis, also enabling for modification of these constructing blocks and to acquire derivatives for structure-activity connection (SAR)relationship (SAR) research. studies. creating for structure-activity partnership (SAR) research. and to get derivatives blocks and to get derivatives for structure-activityScheme 15. Syntheses of cyclomarin A and C. Scheme 15. Syntheses and C. Scheme 15. Syntheses of cyclomarin A of cyclomarin A and C.Mar. Drugs 2021, 19, x FOR PEER Critique Mar. Drugs 2021, 19,18 of 28 17 ofThe hydrogenolysis with the Cbz-protecting group in dipeptide 76 was not a trivial task. The hydrogenolysis in the Cbz-protecting group in dipeptide 76 was not a trivial The reaction essential an H2 stress of 20 bar to proceed, and two equivalents of HCl had process. added to prevent diketopiperazine formation. The hydrochloride salt was directly couto be The reaction needed an H2 stress of 20 bar to proceed, and two equivalents of HCl had to beactivated amino acid 32 inside the presence of excess base. The following measures were pled with the added to avoid diketopiperazine formation. The hydrochloride salt was straight coupled with all the activate
