Synthetic Studies on Imbricatine, a Sulfur-containing Benzyltetrahydroisoquinoline Alkaloid from the Starfish Dermasterias imbricata.

为了确定从海星中分离得到的四氢异喹啉生物碱imbricatine(1)的结构和绝对构型，我们进行了候选结构1.1的手性合成。N，N-二乙基-3，5-二甲氧基苯甲酰胺锂化后与元素硫和4-甲氧基苄氯反应生成硫化物，再用LiAlH4还原和ClCO2Et氯化生成氯化物2。关于Schollkopf开发的不对称合成α-氨基酸的应用，2以较好的产率提供了含硫的D-苯丙氨酸衍生物3。3与4-甲氧基苯乙酰氯发生肖顿-鲍曼反应制得酰胺，再与聚磷酸三甲基硅烷进行Bischler-Napieralski环合，在-78ﾟC用NaBH_4还原得到1，3-顺式苄基四氢异喹啉衍生物4.3。为了避免4在3位上的异构化，4的酯基用LiAlH_4还原得到氨基醇5。5转化为恶唑酮6后，用(CF_3CO_2)_2HG去保护6的4-甲氧基苄基，然后用NaBH_4处理，提供南半球的1作为硫醇7.4。应用我们合成5-芳硫基-3-甲基-L-组氨酸的一般路线，得到了3-甲基-L-组氨酸部分(北半球1)。然后，组氨酸衍生物8通过8的恶唑环的水解、两个氨基的保护、Swern氧化和MeOH中的碱性碘氧化转化为酯9，从而合成了具有1的母体骨架的倒数第二个酯9。9的脱保护目前正在进行中。

With a view to confirming the structure and absolute configuration of imbricatine (1), a benzyltetrahydroisoquinoline alkaloid, isolated from the starfish Dermasterias imbricata, we have undertaken the chiral synthesis of the candidate structure 1.1. Lithiation of N,N-diethyl-3,5-dimethoxybenzamide followed by successive treatment with elemental sulfur and 4-methoxybenzyl chloride provided the sulfide, which was then converted to the chloride 2 via reduction with LiAlH_4 and chlorination with ClCO_2Et. On application of asymmetric synthesis of alpha-amino acid developed by Schollkopf, 2 afforded the sulfur-containing D-phenylalanine derivative 3 in good yield.2. Schotten-Baumann reaction of 3 with 4-methoxyphenylacetyl chloride furnished the amide, which was subjected to Bischler-Napieralski cyclization with trimethylsily polyphosphate followed by reduction with NaBH_4 at-78ﾟC,giving the 1,3-cis-benzyltetrahydroisoquinoline derivative 4.3. In order to avoid epimerization of 4 at the 3-position, the ester group of 4 was reduced with LiAlH_4 to give the amino alcohol 5. After conversion of 5 into the oxazolone 6, deprotection of 4-methoxybenzyl group of 6 was performed with (CF_3CO_2)_2Hg followed by NaBH_4 treatment, providing the southern hemisphere of 1 as the thiol 7.4. Application of our general synthetic route for 5-arylthio-3-methyl-L-histidines to 7 led to the construction of 3-methyl-L-histidine portion (the northern hemisphere of 1). The histidine derivative 8 was then transformed to the ester 9 via hydrolysis of the oxazole ring of 8, protection of two amino groups, Swern oxidation, and alkaline iodine oxidation in MeOH.Thus, we have achieved the synthesis of the penultimate ester 9 possessing the parent framework of 1.Deprotection of 9 leading to 1 is currently under way.