Synthesis of C14–C21 acid fragments of cytochalasin Z₈via anti-selective aldol condensation and B-alkyl Suzuki–Miyaura cross-coupling

Abstract

An efficient synthesis of the C14-C21 acid fragment of cytochalasin Z 8 was accomplished in 10 steps with 14% overall yield. Boron-mediated anti-selective aldol condensation and Pd(OAc) 2 -Aphos-Y-catalysed Balkyl Suzuki-Miyaura cross-coupling were employed to construct the requisite C17 and C18 stereogenic centres and alkene subunit.Cytochalasins are secondary fungal metabolites with a wide range of biological activities that target cytoskeletal processes. 1Cytochalasins Z 7 -Z 9 (1-3, Chart 1) were isolated from the marine-derived fungus Spicaria elegans, and their structures and absolute congurations were established by Zhu et al. Cytochalasin Z 8 (2, Chart 1) is structurally related to cytochalasins Z 7 and Z 9 and features highly substituted hydroisoindol-1-one fused with a 12-membered macrolactone ring at the C-8 and C-9 positions. Cytochalasin Z 8 has been reported to exert cytotoxicity against P388 and A-549 cell lines with IC50 values of 56 and 21 mM, respectively, and therefore has signicant potential in cell biology and medicine. A number of laboratories have worked towards total synthesis of the cytochalasin family and developed linear 3 or convergent 4 strategies for their total synthesis. Total synthesis of cytochalasin congeners was accomplished by the laboratories of Stork, 3a,4a Thomas, 3b,3c,3e,3f Trost, 4d Vedejs (zygosporin E), 4b,4c,4e Myers, 5 Liu and Tang (periconiasins A-E) 6 and Nay (periconiasin G).7 To the best of our knowledge, total synthesis of cytochalasin with a 12-membered macrocyclic ring has not been reported. The intriguing molecular architecture and potent biological activity of cytochalasin Z 8 prompted us to pursue its total synthesis and render it to be readily available for biological investigations.The retrosynthetic strategy is depicted in Scheme 1. Intramolecular ring-closing metathesis (RCM) strategy 8 which is a promising tool for constructing macrolactone is oen used for synthesising macrolides. 9 We envisioned an RCM reaction at C13 and C14 positions and an esterication for assembling a 12-membered macrolactone. Thus, acid fragment 4 was required for the total synthesis of 2. Our strategy was exible and it allowed rapid access to structural analogues. In this study, we report the synthesis of C14-C21 acid fragment 4 via a highly anti-selective aldol condensation 10 of aldehyde 6 with Abiko's chiral norephedrine-derived propionate (1R,2S)-7 (ref. 11) and B-alkyl Suzuki-Miyaura cross-coupling 12 of chiral alkyl iodide 5 with (Z)-1-bromoprop-1-ene.Our rst task was to construct C16-C18 syn-anti stereotriad.13 The aldehyde functionality in 6 was expected to undergo an anti-selective aldol reaction with the (E)-boron enolate generated from Abiko's chiral propionate 7 for installing C17-C18 anti stereochemistry according to our synthetic strategy in Scheme 1. We initially prepared crude aldehyde 6 from commercially available (S)-methyl 3-hydroxy-2-methyl propionate (Roche ester) 14 by tosylation and partial ester reduction 15(Scheme 2). The unstable crude aldeh...

Cinnamomeoventrolide – Double-bond Regioisomerism in Frog Semiochemcials

“…Preparation of methyl (S)-2-methyl-3-(tosyloxy)propanoate (7). Triethylamine (2.45 ml, 1.79 g, 17.7 mmol, 1.3 equiv), DMAP (249 mg, 2.04 mmol, 0.15 equiv) and tosyl chloride (3.11 g, 16.3 mmol, 1.2 equiv) were added sequentially to a solution of methyl (S)-3-hydroxy-2-methylpropanoate ((S)-Roche ester, 6, 1.61 g, 13.6 mmol, 1.0 equiv) in dry DCM (20 ml) at 0°C (Han 2018). After stirring for 4.5 h at rt, water (100 ml) was added, the phases were separated, and the aq.…”

“…R f = 0.46 (pentane/diethyl ether 1:2); CH a H b ), 3.51 (dd, J = 11.0, 6.5 Hz, 1H, CH a H b ), 2.45 (s, 3H, CH 3 ), 2.08-1.93 (m, 1H, CH), 1.76 (br. s, 1H, OH), 0.92 (d, J = 7.0 Hz, 3H, CH 3 ); 13 C NMR (75 MHz, CDCl 3 ) δ 144.8 (C q ), 132.9 (C q ), 129.9 (2C, CH), 127.9 (2C, CH), 71.9 (CH 2 ), 63.6 (CH 2 ), 35.5 (CH), 21.6 (CH 3 ), 13.0 (CH 3 ); EIMS m/z (%) 203 (8), 173 (75), 155 (28), 139 (2), 107 (15), 91 (100), 77 (9), 72 (22), 65 (36), 62 (2), 57 (11), 51 (4), 39 (12).…”

“…The residue was puri ed by column chromatography (silica gel, pentane/diethyl ether 1:1) to afford (S)-2-methylhex-5-en-1-ol ( 9 (m, 2H, CH 2 ), 1.44 (br. s, 1H, OH), 1.30-1.11 (m, 1H, CH), 0.93 (d, J = 6.7 Hz, 3H, CH 3 ); 13 C NMR (75 MHz, CDCl 3 ) δ 138.9 (CH), 114.4 (CH 2 ), 68.2 (CH 2 ), 35.2 (CH), 32.3 (CH 2 ), 31.2 (CH 2 ), 16.4 (CH 3 ); EIMS m/z (%) 114 (< 1) [M] + , 96 (11) [M-H 2 O] + , 82 (6), 81 (86), 79 (9), 71 (31), 68 (13), 67 (28), 58 (17), 57 (33), 56 (15), 55 (100), 54 (74), 53 (16), 51 (6), 45 (7), 43 (30), 42 (21), 41 (94), 40 (9), 39 (55).…”

Recent Advances in Metal-Catalyzed Alkyl–Boron (C(sp3)–C(sp2)) Suzuki-Miyaura Cross-Couplings

“…B-alkyl SMC, in particular, was likewise applied in the synthesis of beneficial products [130][131][132]. Two examples are shown in Scheme 16: Cytochalasin Z 8 and Ieodomycin D, which belong to the family of secondary fungal metabolite with a wide range of biological activities that target cytoskeletal processes [133][134][135]. Scheme 16 also includes examples of complex molecules that were achieved by synthetic routes involving SMCs with C(sp 2 )-B reagents; namely Michellamine (an anti-HIV viral replication receptor) and (-)-steganone (an antileukemic lignan precursor) [136,137].…”

“…Catalysts 2020, 10, x FOR PEER REVIEW 18 of 24 cytoskeletal processes [133][134][135]. Scheme 16 also includes examples of complex molecules that were achieved by synthetic routes involving SMCs with C(sp 2 )-B reagents; namely Michellamine (an anti-HIV viral replication receptor) and (-)-steganone (an antileukemic lignan precursor) [136,137].…”