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【结 构 式】 
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【分子编号】53694 【品名】(3S,8S,9S,10R,13R,14S,17R)-17-((1R)-4-{[tert-butyl(dimethyl)silyl]oxy}-1,5-dimethylhexyl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate 【CA登记号】n/a |
【 分 子 式 】C35H62O3Si 【 分 子 量 】558.96098 【元素组成】C 75.21% H 11.18% O 8.59% Si 5.02% |
合成路线1
该中间体在本合成路线中的序号：(VIII)Protection of 3-beta-hydroxy-5-cholenic acid (I) with 2,3-dihydropyran in the presence of pyridinium p-toluenesulfonate provided the bis-tetrahydropyranyl derivative (II). Reduction of the tetrahydropyranyl ester group of (II) with LiAlH4 gave alcohol (III), which was further oxidized to aldehyde (IV) under Swern conditions. Addition of isopropylmagnesium bromide to the aldehyde (IV) yielded the secondary alcohol (V). After silylation of alcohol (V) with t-butyldimethylsilyl chloride and imidazole to (VI), the tetrahydropyranyl protecting group was removed under acidic conditions to afford alcohol (VII). This was further esterified with Ac2O in pyridine to provide acetate ester (VIII).
| 【1】 Moriarty, R.M.; et al.; Synthesis of squalamine. A steroidal antibiotic from the shark. Tetrahedron Lett 1994, 35, 44, 8103. |
| 【2】 Pechulis, A.D.; et al.; Synthesis of 24xi-squalamine, an anti-infective steroidal polyamine. J Org Chem 1995, 60, 16, 5121. |
| 【3】 Moriarty, R.M.; Guo, L.; Tuladhar, S.M. (Genaera Corp.); Chemical synthesis of squalamine. WO 9419366 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 53687 | 5-Cholenic acid-3beta-ol; 3beta-Hydroxy-5-cholen-24-oic acid | 5255-17-4 | C24H38O3 | 详情 | 详情 |
| (II) | 53688 | tetrahydro-2H-pyran-2-yl (4R)-4-[(3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoate | n/a | C34H54O5 | 详情 | 详情 |
| (III) | 53689 | (4R)-4-[(3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-1-pentanol | n/a | C29H48O3 | 详情 | 详情 |
| (IV) | 53690 | (4R)-4-[(3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanal | n/a | C29H46O3 | 详情 | 详情 |
| (V) | 53691 | (6R)-6-[(3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-methyl-3-heptanol | n/a | C32H54O3 | 详情 | 详情 |
| (VI) | 53692 | tert-butyl(dimethyl)silyl (4R)-4-[(3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-1-isopropylpentyl ether; tert-butyl({(4R)-4-[(3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-1-isopropylpentyl}oxy)dimethylsilane | n/a | C38H68O3Si | 详情 | 详情 |
| (VII) | 53693 | (3S,8S,9S,10R,13R,14S,17R)-17-((1R)-4-{[tert-butyl(dimethyl)silyl]oxy}-1,5-dimethylhexyl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-ol | n/a | C33H60O2Si | 详情 | 详情 |
| (VIII) | 53694 | (3S,8S,9S,10R,13R,14S,17R)-17-((1R)-4-{[tert-butyl(dimethyl)silyl]oxy}-1,5-dimethylhexyl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate | n/a | C35H62O3Si | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIII)Allylic oxidation of (VIII) by means of t-butyl hydroperoxide and chromium hexacarbonyl produced enone (IX). Subsequent Birch reduction of (IX) employing lithium metal in liquid ammonia gave the saturated ketone (X), which was further reduced to alcohol (XI) with K-Selectride in cold THF. Removal of the acetate ester of (XI) was achieved by treatment with NaCN in MeOH, giving diol (XII). The 3-beta hydroxyl group of (XII) was then selectively oxidized to ketone (XIII) under Oppenauer conditions. Ketone (XIII) was converted to the primary amine (XV) via formation of the O-benzyl oxime (XIV), which was reduced by LiAlH4.
| 【1】 Moriarty, R.M.; et al.; Synthesis of squalamine. A steroidal antibiotic from the shark. Tetrahedron Lett 1994, 35, 44, 8103. |
| 【2】 Moriarty, R.M.; Guo, L.; Tuladhar, S.M. (Genaera Corp.); Chemical synthesis of squalamine. WO 9419366 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 53694 | (3S,8S,9S,10R,13R,14S,17R)-17-((1R)-4-{[tert-butyl(dimethyl)silyl]oxy}-1,5-dimethylhexyl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate | n/a | C35H62O3Si | 详情 | 详情 |
| (IX) | 53695 | (3S,8S,9S,10R,13R,14S,17R)-17-((1R)-4-{[tert-butyl(dimethyl)silyl]oxy}-1,5-dimethylhexyl)-10,13-dimethyl-7-oxo-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate | n/a | C35H60O4Si | 详情 | 详情 |
| (X) | 53696 | (3S,5R,8R,9S,10S,13R,14S,17R)-17-((1R)-4-{[tert-butyl(dimethyl)silyl]oxy}-1,5-dimethylhexyl)-10,13-dimethyl-7-oxohexadecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate | n/a | C35H62O4Si | 详情 | 详情 |
| (XI) | 53697 | (3S,5S,7R,8R,9S,10S,13R,14S,17R)-17-((1R)-4-{[tert-butyl(dimethyl)silyl]oxy}-1,5-dimethylhexyl)-7-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate | n/a | C35H64O4Si | 详情 | 详情 |
| (XII) | 53698 | (3S,5R,7R,8R,9S,10S,13R,14S,17R)-17-((1R)-4-{[tert-butyl(dimethyl)silyl]oxy}-1,5-dimethylhexyl)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-3,7-diol | n/a | C33H62O3Si | 详情 | 详情 |
| (XIII) | 53699 | (5S,7R,8R,9S,10S,13R,14S,17R)-17-((1R)-4-{[tert-butyl(dimethyl)silyl]oxy}-1,5-dimethylhexyl)-7-hydroxy-10,13-dimethylhexadecahydro-3H-cyclopenta[a]phenanthren-3-one | n/a | C33H60O3Si | 详情 | 详情 |
| (XIV) | 53700 | (5R,7R,8R,9S,10S,13R,14S,17R)-17-((1R)-4-{[tert-butyl(dimethyl)silyl]oxy}-1,5-dimethylhexyl)-7-hydroxy-10,13-dimethylhexadecahydro-3H-cyclopenta[a]phenanthren-3-one O-benzyloxime | n/a | C40H67NO3Si | 详情 | 详情 |
| (XV) | 53701 | (3S,5R,7R,8R,9S,10S,13R,14S,17R)-3-amino-17-((1R)-4-{[tert-butyl(dimethyl)silyl]oxy}-1,5-dimethylhexyl)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-7-ol | n/a | C33H63NO2Si | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VIII)In an alternative preparation of intermediate (VIII), 3-beta-acetoxy-5-cholenic acid (XXVII) was converted to the corresponding acid chloride, to which was added isopropylcadmium bromide, yielding ketone (XXVIII). Subsequent reduction of (XXVIII) with calcium borohydride in THF, followed by silylation of the resultant alcohol (XXIX), provided intermediate (VIII).
| 【1】 Moriarty, R.M.; et al.; Synthesis of squalamine. A steroidal antibiotic from the shark. Tetrahedron Lett 1994, 35, 44, 8103. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 53694 | (3S,8S,9S,10R,13R,14S,17R)-17-((1R)-4-{[tert-butyl(dimethyl)silyl]oxy}-1,5-dimethylhexyl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate | n/a | C35H62O3Si | 详情 | 详情 |
| (XXVII) | 53711 | (4R)-4-[(3S,8S,9S,10R,13R,14S,17R)-3-(acetyloxy)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoic acid | n/a | C26H40O4 | 详情 | 详情 |
| (XXVIII) | 53712 | (3S,8S,9S,10R,13R,14S,17R)-17-[(1R)-1,5-dimethyl-4-oxohexyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate | n/a | C29H46O3 | 详情 | 详情 |
| (XXIX) | 53713 | (3S,8S,9S,10R,13R,14S,17R)-17-[(1R)-4-hydroxy-1,5-dimethylhexyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate | n/a | C29H48O3 | 详情 | 详情 |