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【结 构 式】 
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【分子编号】64603 【品名】(4aR,7R,8R,8aS)-8-(benzyloxy)-2,2,7-trimethylhexahydropyrano[3,2-d][1,3]dioxine-6-carbaldehyde 【CA登记号】 |
【 分 子 式 】C18H24O5 【 分 子 量 】320.38556 【元素组成】C 67.48% H 7.55% O 24.97% |
合成路线1
该中间体在本合成路线中的序号：(X)Tetrahydropyran intermediate (X). The asymmetric addition of Ipc2B-crotyl to 4-(Tbdps-O)-2-butenal (I) gives the chiral secondary alcohol (II), which is protected with benzyl bromide and NaH to yield the benzyl ether (III). The desilylation of (III) by means of TBAF affords the primary alcohol (IV), which is submitted to a Sharpless asymmetric epoxidation to provide the epoxide (V). Ring opening of (V) by means of Ti(iPrO)4 and benzoic acid gives the benzoate ester (VI), which is cyclized by means of Hg(OAc)2 to yield the tetrahydropyran derivative (VII). Hydrolysis of the benzoate group of (VII) by means of MeONa affords the trihydroxy compound (VIII), which is treated with acetone and Ts-OH to provide the acetonide (IX). Finally, oxidation of the hydroxymethyl group of (IX) by means of Swern oxidant yields the target tetrahydropyran-2-carbaldehyde intermediate (X).
| 【1】 Smith, A.B. III; Zhuang, L.; Brook, C.S.; Boldi, A.M.; McBriar, M.D.; Moser, W.H.; Murase, N.; Nakayama, K.; Verhoest, P.R.; Lin, Q.; Spongistatin synthetic studies. 1. Construction of a C(29-48) subtarget. Tetrahedron Lett 1997, 38, 50, 8667. |
| 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) | 60351 | 4-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-2-butenal | C20H24O2Si | 详情 | 详情 | |
| (II) | 64595 | (3S,4R,5E)-7-{[tert-butyl(diphenyl)silyl]oxy}-3-methyl-1,5-heptadien-4-ol | C24H32O2Si | 详情 | 详情 | |
| (III) | 64596 | benzyl (1R,2E)-4-{[tert-butyl(diphenyl)silyl]oxy}-1-[(1S)-1-methyl-2-propenyl]-2-butenyl ether; {[(2E,4R,5S)-4-(benzyloxy)-5-methyl-2,6-heptadienyl]oxy}(tert-butyl)diphenylsilane | C31H38O2Si | 详情 | 详情 | |
| (IV) | 64597 | (2E,4R,5S)-4-(benzyloxy)-5-methyl-2,6-heptadien-1-ol | C15H20O2 | 详情 | 详情 | |
| (V) | 54598 | tert-butyl (1S,2R)-1-(sec-butyl)-2-methoxy-4-pentenyl(methyl)carbamate | C16H31NO3 | 详情 | 详情 | |
| (VI) | 64599 | (1R,2R,3S)-2-(benzyloxy)-1-[(1R)-1,2-dihydroxyethyl]-3-methyl-4-pentenyl benzoate | C22H26O5 | 详情 | 详情 | |
| (VII) | 64600 | (2R,3S,4R,5R)-2-[(acetyloxy)methyl]-4-(benzyloxy)-6-(hydroxymethyl)-5-methyltetrahydro-2H-pyran-3-yl benzoate | C24H28O7 | 详情 | 详情 | |
| (VIII) | 64601 | (2R,3S,4R,5R)-4-(benzyloxy)-2,6-bis(hydroxymethyl)-5-methyltetrahydro-2H-pyran-3-ol | C15H22O5 | 详情 | 详情 | |
| (IX) | 64602 | [(4aR,7R,8R,8aS)-8-(benzyloxy)-2,2,7-trimethylhexahydropyrano[3,2-d][1,3]dioxin-6-yl]methanol | C18H26O5 | 详情 | 详情 | |
| (X) | 64603 | (4aR,7R,8R,8aS)-8-(benzyloxy)-2,2,7-trimethylhexahydropyrano[3,2-d][1,3]dioxine-6-carbaldehyde | C18H24O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)Bis-tetrahydropyran intermediate (XXIV). The asymmetric addition of Ipc2B-crotyl to 5-benzyloxypentanal (XI) gives the secondary alcohol (XII), which is protected with Boc2O and NaHMDS in THF yielding the carbamate (XIII). The reaction of (XIII) with IBr in toluene affords the iodinated cyclic carbonate (XIV), which is converted into the epoxide (XV) by reaction with K2CO3 in methanol/water. The reaction of the epoxide (XV) with 1,3-dithiane (XVI) by means of BuLi in THF/HMPA provides the dihydroxy compound (XVII), which is converted into the acetonide (XIX) by reaction with 2,2-dimethoxypropane (XVIII) and PPTS . The condensation of (XIX) with the tetrahydropyran-2-carbaldehyde intermediate (X) by means of BuLi in ethyl ether/HMPA gives the bis acetonide derivative (XX) (1), which is deprotected by means of CSA, cyclized by means of Hg(ClO4)2 and acylated with Piv-Cl and pyridine to yield the bis tetrahydropyranyl intermediate (XXI). The silylation of the OH group of (XXI) by means of Tbdms-OTf, followed by debenzylation by means of HCOONH4 and Pd/C affords the butanol derivative (XXII), which is successively silylated, first with Tbdps-Cl /imidazole and then with Tes-OTf and lutidine to provide the fully silylated compound (XXIII). Finally, the elimination of the pivaloyl group of (XXIII) by means of DIBAL in THF, followed by reaction with I2, PPh3 and imidazole in toluene gives the iodomethyl bis tetrahydropyran intermediate (XXIV) (2).
| 【2】 Smith, A.B. III; Lin, Q.; Doughty, V.A.; Zhuang, L.; McBriar, M.D.; Kerns, J.K.; Brook, C.S.; Murase, N.; Nakayama, K.; The spongistatins: Architecturally complex natural products - Part two: Synthesis of the C(29-51) subunit, fragment assembly, and final elaboration to (+)-spongistatin 2. Angew Chem. Int Ed 2001, 40, 1, 196. |
| 【1】 Smith, A.B. III; Zhuang, L.; Brook, C.S.; Boldi, A.M.; McBriar, M.D.; Moser, W.H.; Murase, N.; Nakayama, K.; Verhoest, P.R.; Lin, Q.; Spongistatin synthetic studies. 1. Construction of a C(29-48) subtarget. Tetrahedron Lett 1997, 38, 50, 8667. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 64603 | (4aR,7R,8R,8aS)-8-(benzyloxy)-2,2,7-trimethylhexahydropyrano[3,2-d][1,3]dioxine-6-carbaldehyde | C18H24O5 | 详情 | 详情 | |
| (XI) | 64604 | 5-(benzyloxy)pentanal | C12H16O2 | 详情 | 详情 | |
| (XII) | 64605 | (3R,4R)-8-(benzyloxy)-3-methyl-1-octen-4-ol | C16H24O2 | 详情 | 详情 | |
| (XIII) | 64606 | (1R,2R)-1-[4-(benzyloxy)butyl]-2-methyl-3-butenyl tert-butyl carbonate | C21H32O4 | 详情 | 详情 | |
| (XIV) | 64607 | (4R,5R)-4-[4-(benzyloxy)butyl]-6-(iodomethyl)-5-methyl-1,3-dioxan-2-one | C17H23IO4 | 详情 | 详情 | |
| (XV) | 64608 | (1R)-5-(benzyloxy)-1-{(1R)-1-[(2S)oxiranyl]ethyl}pentyl methyl carbonate | C18H26O5 | 详情 | 详情 | |
| (XVI) | 42372 | 1,3-dithiane | 505-23-7 | C4H8S2 | 详情 | 详情 |
| (XVII) | 64609 | (2S,3S,4R)-8-(benzyloxy)-1-(1,3-dithian-2-yl)-3-methyl-2,4-octanediol | C20H32O3S2 | 详情 | 详情 | |
| (XVIII) | 64610 | 1,3-dimethoxy-2,2-dimethylpropane; 3-methoxy-2,2-dimethylpropyl methyl ether | C7H16O2 | 详情 | 详情 | |
| (XIX) | 64611 | (4R,5R,6S)-4-[4-(benzyloxy)butyl]-6-(1,3-dithian-2-ylmethyl)-2,2,5-trimethyl-1,3-dioxane; benzyl 4-[(4R,5R,6S)-6-(1,3-dithian-2-ylmethyl)-2,2,5-trimethyl-1,3-dioxan-4-yl]butyl ether | C23H36O3S2 | 详情 | 详情 | |
| (XX) | 64612 | (S)-[(4aR,7R,8R,8aS)-8-(benzyloxy)-2,2,7-trimethylhexahydropyrano[3,2-d][1,3]dioxin-6-yl][2-({(4S,5R,6R)-6-[4-(benzyloxy)butyl]-2,2,5-trimethyl-1,3-dioxan-4-yl}methyl)-1,3-dithian-2-yl]methanol | C41H60O8S2 | 详情 | 详情 | |
| (XXI) | 64613 | {(2R,3S,4R,5R,6R)-4-(benzyloxy)-6-[(S)-{(2R,4S,5R,6R)-6-[4-(benzyloxy)butyl]-4-hydroxy-2-methoxy-5-methyltetrahydro-2H-pyran-2-yl}(hydroxy)methyl]-3-hydroxy-5-methyltetrahydro-2H-pyran-2-yl}methyl pivalate | C38H56O10 | 详情 | 详情 | |
| (XXII) | 64614 | {(2R,3S,4R,5R,6R)-6-[(S)-[(2R,4S,5S,6R)-4-{[tert-butyl(dimethyl)silyl]oxy}-6-(4-hydroxybutyl)-2-methoxy-5-methyltetrahydro-2H-pyran-2-yl](hydroxy)methyl]-3,4-dihydroxy-5-methyltetrahydro-2H-pyran-2-yl}methyl 2,2-dimethylpropanoate | C30H58O10Si | 详情 | 详情 | |
| (XXIII) | 64615 | {(2R,3R,4R,5S,6R)-6-{(S)-[(2R,4S,5S,6R)-4-{[tert-butyl(dimethyl)silyl]oxy}-6-(4-{[tert-butyl(diphenyl)silyl]oxy}butyl)-2-methoxy-5-methyltetrahydro-2H-pyran-2-yl][(triethylsilyl)oxy]methyl}-5-methyl-3,4-bis[(triethylsilyl)oxy]tetrahydro-2H-pyran-2-yl}methyl 2,2-dimethylpropanoate | C64H118O10Si5 | 详情 | 详情 | |
| (XXIV) | 64616 | tert-butyl[((2R,4S,5S,6R)-6-(4-{[tert-butyl(diphenyl)silyl]oxy}butyl)-2-{(S)-{(2R,3S,4R,5R,6S)-6-(iodomethyl)-3-methyl-4,5-bis[(triethylsilyl)oxy]tetrahydro-2H-pyran-2-yl}[(triethylsilyl)oxy]methyl}-2-methoxy-5-methyltetrahydro-2H-pyran-4-yl)oxy]dimethylsilane; tert-butyl(dimethyl)silyl (2R,4S,5S,6R)-6-(4-{[tert-butyl(diphenyl)silyl]oxy}butyl)-2-{(S)-{(2R,3S,4R,5R,6S)-6-(iodomethyl)-3-methyl-4,5-bis[(triethylsilyl)oxy]tetrahydro-2H-pyran-2-yl}[(triethylsilyl)oxy]methyl}-2-methoxy-5-methyltetrahydro-2H-pyran-4-yl ether | C59H109IO8Si5 | 详情 | 详情 |