Study on Synthesis of (s)-3-(t-Butyldimethylsilyloxy)-7,7-Dichloro-2,2-Dimethyloctanoic Acid

摘要

(s)-3-(t-butyldimethylsilyloxy)-7,7-dichloro-2,2-dimethyloctanoic acid (9), a segment of the new cyclodepsipeptide lyngbyabellin A[1] (14), which exhibits moderate cytotoxycity against human cancer cell lines, was synthesized through six steps. The key stereoselective synthesis of (9) was achieved by the enantioselective aldol reaction developed by Kiyooka[2]. Lyngbyabellin A (14) is a new cytotoxic pepolides isolated from the marine cyanobacterium L.majuscula collected at Finger’s Reef, Apra Harbor, Guam[1]. It exhibited moderate cytotoxic properties against human cancer cell lines, KB cells (a human nasopharyngeal carcinoma cell line) and LoVo cells (a human colon adenocarcinoma cell line), with IC50 values of 0.03 μg/mL and 0.50 μg/mL, respectively. In additon, because of its encouraging biological activities and highly unusual bis-thiazole containing structure, we viewed it as a significant and challenging synthetic target. By our retrosynthetic analysis (Figure 1), we got two thiazole fragments (12) and (13), the dichlorinated β-hydroxy acid (9) and glycine t-butyl ester (11). Herein,we report the synthesis of the dichlorinated β-hydroxy acid (9). Aldehyde (5) and commercially available methyl trimethylsiyl ketene acetal (6) served as the starting materials for the aldol reaction. Aldehyde (5) was prepared via a sequence of reactions shown in scheme 1. Alkylation of lithio-1,1-dichloroetnane with 5-bromo-1-pentene (1) gave linear dichloroheptene (3)[3]. Without further purification, (3) was oxidized to afford diol (4) using osmium tetraoxide and NMO in a two phase system. The overall yield for these two steps is 50%. Subsequent oxidative cleavage of (4) using improved silica gel-supported sodium metaperiodate[4], provided the desired aldehyde (5) (scheme 1). Aldehyde (5) was then reacted with methyl trimethylsilyl kentene acetal (6) in the presence of one equivalent of the R-valine derived oxazaborolidinone (10),to produce (s)-β-hydroxy ester (7) in 60% yield[2]. Hydrolysis of the ester liberated the corresponding acid (8), and this was protected as its TBDMS ether using TBDMSOTf and 2,6-lutidine, to give (9) (70% yield) in preparation for the later stages of the synthesis (scheme 2).