Study on Synthesis of (s)-3-(t-butyIdimethylsilyloxy)-7,7-dichloro-2,2-dimethyloctanoicacid

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^. Lyngbyabellin A (14) is a new cytotoxic pepolides isolated from the marine cyanobacterium L.majuscula collected at Finger's Reef, Apra Harbor, Guam111. 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 P-hydroxy acid (9) and glycine t-butyl ester (11). Herein ,we report the synthesis of the dichlorinated P-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-l,l-dichloroetnane with 5-bromo-l-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)-P-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).