y Guo and Ye et al. [38]. In their very convergent strategy, the ilamycins had been synthesized from two parts (1 and 2) that have been linked in between 1 and 7 for the macrocyclic lactam (Scheme 1). The lower ideal tripeptide component 1 ( 1 three ) was prepared in five actions from Mar. Drugs 2021, 19, x FOR PEER Assessment 7 of 28 tryptophan, whilst the upper left tetrapeptide two ( four 7 ) required 13 actions from glutamic acid. Final oxidation in the -hydroxyleucine five resulted inside the described ilamycins.Scheme 1. Retrosynthesis of ilamycins (Guo and Ye). Scheme 1. Retrosynthesis of ilamycins (Guo and Ye).The synthesis of peptide HSPA5 web fragment 1 1 was rather simple (Scheme 2). 2of peptide fragment was rather straightforward (Scheme 2). 2-(TriThe (Trimethylsilyl)ethoxycarbonyl (Teoc)-protected tryptophan methylester 3 was subjected to methylsilyl)ethoxycarbonyl (Teoc)-protected tryptophan methylester three was subjected to a a Pd-catalyzed N-tert-prenylation in line with aprotocol created by Baran et al. [39]. Pd-catalyzed N-tert-prenylation according to a protocol CDK13 web developed by Baran et Saponification of the ester moiety of 4 and peptide coupling with N-methylated Leu-OMe Saponification of the ester moiety of four and peptide coupling with N-methylated Leu-OMe developed dipeptide 5, which was further elongated to tripeptide 1. developed dipeptide five, which was further elongated to tripeptide 1. For the larger fragment 2, glutamic acid was converted into protected eight (Scheme 3) as outlined by a synthetic route created in the course of the synthesis of dysithiazolamide [40]. The glutamic acid was converted into the dimethyl ester and N-Boc protected ahead of it was stereoselectively -methylated at the sterically least-hindered ester moiety [41,42]. For the chemoselective reduction from the -ester 6, a second N-Boc-protecting group was introduced, and also the sterically least-hindered ester functionality was decreased with DIBALH. Silyl protection of the primary alcohol and subsequent mono-Boc deprotection yielded 7. The methyl ester was saponified (to prevent -methylation), plus the Boc-amide was selectively N-methylated to 8 with NaH/MeI. The cost-free carboxylic acid eight was converted into the corresponding benzyl ester. TMSOTf/NEt3 was applied for selective cleavage in the N-Boc-protecting group devoid of affecting the OTBDPS group. The free amine couldScheme 1. Retrosynthesis of ilamycins (Guo and Ye).Mar. Drugs 2021, 19, 446 7 of 27 The synthesis of peptide fragment 1 was rather straightforward (Scheme 2). 2-(Trimethylsilyl)ethoxycarbonyl (Teoc)-protected tryptophan methylester 3 was subjected to a Pd-catalyzed N-tert-prenylation as outlined by a protocol developed by Baran et al. [39]. Saponification from the ester moiety of four and peptide coupling with N-methylated Leu-OMe be coupled with Fmoc-protected alanine, as well as the C-terminal benzyl ester was cleaved by made dipeptide five, which was the cost-free acid 9. catalytic hydrogenation to providefurther elongated to tripeptide 1.Mar. Drugs 2021, 19, x FOR PEER REVIEW8 ofBoc-protecting group without the need of affecting the OTBDPS group. The totally free amine might be coupled with Fmoc-protected alanine, along with the C-terminal benzyl ester was cleaved by catalytic hydrogenation peptide fragment 1. Scheme two. Synthesis ofto deliver the totally free acid 9. For the bigger fragment 2, glutamic acid was converted into protected eight (Scheme 3) in accordance with a synthetic route created during the synthesis of dysithiazolamide [40]. The glutamic acid was converted in to the dimethyl ester and N-Boc pro
