A Stereoselective Synthesis of C26-C36 Fragment of Arenicolide A

Abstract

Scheme 2. Synthesis of C26-C36 Fragment (4). (a) n-Bu2BOTf (1.5 eq), Et3N (1.6 eq), butyraldehyde (2.0 eq), CH2Cl2, ‐78 C, 4 hr, 96%. (b) TBSOTf (1.2 eq), 2,6-lutidine (2.0 eq), CH2Cl2, ‒78 C, 3 hr, 84%. (c) LiBH4 (1.12 eq), water (1.12 eq), ether, rt, 45 min, 94%. (d) (COCl)2 (2.5 eq), DMSO (4.5 eq), Et3N (7.5 eq), CH2Cl2, ‒78 C, 1.5 hr, 91%. (e) Ph3P=C(Me)CO2Et (2.5 eq), benzene, reflux, overnight, 92%. (f) DIBAL (5.0 eq), CH2Cl2, ‒78 C, 2 hr, 94%. (g) mCPBA (1.5 eq), K2HPO4 (3.0 eq), CH2Cl2, rt, 18 hr, 72%. (h) (COCl)2 (2.0 eq), DMSO (4.0 eq), Et3N (5.0 eq), CH2Cl2, ‒78 C, 40 min, 88%. (i) (-)Ipc2BOMe (1.2 eq), allylmagnesium bromide (2.0 eq), ether, ‒100 C, 3 hr, 67%. (j) TBSOTf (1.5 eq), 2,6-lutidine (2.0 eq), CH2Cl2, ‒78 C, 30 min, 88%. Recently, arenicolides A (1) and B (2) were isolated from the large-scale fermentation of the S. arenicola strain CNR005 and its relative stereochemical relationship except C-12, C-30, and C-31 chiral centers was proposed by H NMR, C NMR, Mass, IR, UV, CD, chemical degradation methods. Arenicolides A (1) and B (2) are 26-membered macrolides with three conjugated dienes and nine chiral centers in the ring. There is one side chain which comprises the C-26 ~ C-36 carbon chain with five consecutive chiral centers. Arenicolide A (1) also showed moderate anti-cancer activity toward the human colon adenocarcinoma cell line HCT-116 (IC50; 30 μg/ mL) and three cell lines in the National Cancer Institute, and no activity against antimicrobial assay using methicillinresistant S. aureus (MRSA) and vancomycinresistant E. faecium (VREF).