1,2-二硬脂酰基-sn-甘油-3-磷脂酰丝氨酸的全合成

Total synthesis of 1,2-distearoyl-sn-glycero-3-phosphatidylserine

摘要:

以易制备的(S)-2-[(苄氧羰基)氨基]-3-羟基丙酸苄酯（Ⅰ）为原料，经亚磷酸二苯酯处理得到(S)-2-[(苄氧羰基)氨基]-3-(苄基)丙基膦酸酯（Ⅱ）；通过一锅缩合-氧化法，将化合物Ⅱ经新戊酰氯介导活化后，与(S)-(+)-2,2-二甲基-1,3-二氧戊环-4-甲醇（Ⅲ）缩合，并由碘介导的氧化得到新化合物(R)-2,3-异亚丙基-sn-甘油基{(S)-2-[(苄氧羰基)氨基]-3-(苄基)-1-氧丙基}膦酸酯（Ⅳ）；然后在三氟乙酸（TFA）的作用下脱除异亚丙基保护基得到关键中间体(R)-2,3-二羟基丙基-sn-甘油基{(S)-2-[(苄氧羰基)氨基]-3-(苄基)-1-氧丙基}膦酸酯（Ⅴ）；再在1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐（EDCI）的作用下，将化合物Ⅴ与硬脂酸进一步乙酰化，以良好的产率得到(R)-2,3-双(硬脂酰基)丙酰基{(S)-2-[(苄氧羰基)氨基]-3-(苄基)-1-氧丙基}膦酸酯（Ⅵ）；氢解苄氧羰基（-Cbz）和苄基（-Bn）保护基得到1,2-二硬脂酰基-sn-甘油-3-磷脂酰丝氨酸（Ⅶ）；最后对其主要步骤进行了反应条件优化，并对其进行了验证和放大。共经历5步反应，总产率为57.0%。采用FTIR、HRMS和NMR对终产物Ⅶ的结构进行确证。

Abstract:

Firstly, (S)-2-[(benzyloxycarbonyl)amino]-3-(benzyloxy)propyl phosphonate (Ⅱ) was synthesized after diphenyl phosphite treatment of easily prepared (S)-benzyloxy-2-((benzyloxycarbonyl)amino)-3-hydroxypropanoate (Ⅰ). Secondly, a new compound (R)-2,3-isopropylidene-sn-glyceryl{(S)-2-[(benzyloxycarbonyl)amino]-3-(benzyloxy)-1-oxopropyl}phosph-onate (Ⅳ) was prepared by a one-pot condensation-oxidation procedure. After the pivaloyl chloride mediated activation of compound Ⅱ, condensation with (S)-(+)-2,2-dimethyl-1,3-dioxolane-4-methanol (Ⅲ), and obtained by iodine mediated oxidation. Then, the protective group of isopropylidene was removed by trifluoroacetic acid (TFA) to obtain the key intermediate, (R)-2,3-dihydroxypropoxy-sn-glyceryl{(S)-2-[(benzyloxycarbonyl)amino]-3-(benzyloxy)-1-oxopropyl}pho-sphonate (Ⅴ). Next, the compound Ⅴ was acetylated further with stearic acid at the function in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) to give (R)-2,3-bis(Stearoyloxy)popyl{(S)-2-[(benzyloxycarbonyl)amino]-3-(benzyloxy)-1-oxopropyl}phosphonate (Ⅵ) with a great yield. Finally, 1,2-distearoyl-sn-glycero-3-phosphatidylserine (Ⅶ) was synthesized by hydrogenolysis of benzyloxycarbonyl (-Cbz) and benzyloxy (-Bn) protective groups. Finally, the main steps were optimized for reaction conditions, and it was verified and amplified. The synthesis of compound Ⅶ was only 5 steps with a total yield of 57.0%. The structure of final compound Ⅶ was confirmed by FTIR, HRMS and NMR