| Budget Amount *help |
¥2,000,000 (Direct Cost: ¥2,000,000)
Fiscal Year 1995: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 1994: ¥1,300,000 (Direct Cost: ¥1,300,000)
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| Research Abstract |
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.
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