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【结 构 式】 
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【分子编号】57282 【品名】methyl (2S,3S,5R,6S)-3-{[tert-butyl(dimethyl)silyl]oxy}-6-methoxy-5-methyltetrahydro-2H-pyran-2-carboxylate 【CA登记号】 |
【 分 子 式 】C15H30O5Si 【 分 子 量 】318.4857 【元素组成】C 56.57% H 9.49% O 25.12% Si 8.82% |
合成路线1
该中间体在本合成路线中的序号：(VII)Synthesis of the intermediate chiral tetrahydropyran-carboxylic acid methyl ester (VII): The selective reduction of the exocyclic double bond of the glycoside (I) with H2 over Pd/C in ethanol gives a mixture of the equatorial epimer (II) along with some axial compound that is eliminated by crystallization. The cleavage of the benzylidene protecting group of (II) with H2, over Pd/C in EtOH, followed by selective monoesterification of the primary OH group with PPh3, DIAD and benzoic acid yields the benzoate ester (III). The protection of (III) with Tbdms-Cl and imidazole affords the silyl ether (IV), which is debenzoylated by means of DIBAL in dichloromethane to afford the hydroxymethyl compound (V). The oxidation of (V) by means of RuCl3 and NaIO4 pin acetonitrile/CCl4 provides the chiral carboxylic acid (VI), which is finally esterified with CH3-I and K2CO3 in DMF to furnish the desired tetrahydropyran-carboxylic acid methyl ester (VII).
| 【1】 Smith, A.B. III; Hale, K.J.; An enantioselective synthesis of the C(10) to C(23) backbone of the potent immunosuppressant FK506. Tetrahedron Lett 1989, 30, 9, 1037. |
| 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) | 57276 | (4aR,6S,8aS)-7-methylene-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-6-yl methyl ether; (4aR,6S,8aS)-6-methoxy-7-methylene-2-phenylhexahydropyrano[3,2-d][1,3]dioxine | C15H18O4 | 详情 | 详情 | |
| (II) | 57277 | (4aR,6S,7R,8aS)-6-methoxy-7-methyl-2-phenylhexahydropyrano[3,2-d][1,3]dioxine; (4aR,6S,7R,8aS)-7-methyl-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-6-yl methyl ether | C15H20O4 | 详情 | 详情 | |
| (III) | 57278 | [(2R,3S,5R,6S)-3-hydroxy-6-methoxy-5-methyltetrahydro-2H-pyran-2-yl]methyl benzoate | C15H20O5 | 详情 | 详情 | |
| (IV) | 57279 | ((2R,3S,5R,6S)-3-{[tert-butyl(dimethyl)silyl]oxy}-6-methoxy-5-methyltetrahydro-2H-pyran-2-yl)methyl benzoate | C21H34O5Si | 详情 | 详情 | |
| (V) | 57280 | ((2R,3S,5R,6S)-3-{[tert-butyl(dimethyl)silyl]oxy}-6-methoxy-5-methyltetrahydro-2H-pyran-2-yl)methanol | C14H30O4Si | 详情 | 详情 | |
| (VI) | 57281 | (2S,3S,5R,6S)-3-{[tert-butyl(dimethyl)silyl]oxy}-6-methoxy-5-methyltetrahydro-2H-pyran-2-carboxylic acid | C14H28O5Si | 详情 | 详情 | |
| (VII) | 57282 | methyl (2S,3S,5R,6S)-3-{[tert-butyl(dimethyl)silyl]oxy}-6-methoxy-5-methyltetrahydro-2H-pyran-2-carboxylate | C15H30O5Si | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VII)The reaction of the chiral propyl iodide (VIII) with KCN in hot DMF gives the chiral butyronitrile (IX), which is reduced with DIBAL in dichloromethane to yield the butyraldehyde (X). The reaction of (X) with CBr4, PPH3 and BuLi in THF/dichloromethane affords the chiral alkyne (XI), which is treated with Me3Al, Cp2ZrCl2 and BuLi in dichloroethane to provide the vinyl aluminate (XII). The condensation of (XII) with the chiral epoxide (XIII) in benzene gives the unsaturated 2-octenol (XIV), which is protected with BnBr and NaH to yield the benzyl ether (XV). The desilylation of (XV) by means of TBAF in THF afford the primary alcohol (XVI), which is treated with diphenyl disulfide and Bu3P in DMF to provide the thioether (XVII). The oxidation of (XVII) with oxone in THF/methanol/water gives the corresponding sulfone (XVIII), which is condensed with the intermediate desired tetrahydropyran-carboxylic acid methyl ester (VII) by means of BuLi in THF to yield the adduct (XIX). The removal of the sulfone group of (XIX) is performed by means of Bu3SnH and AIBN in refluxing toluene affording the ketonic intermediate (XX).
| 【1】 Smith, A.B. III; Hale, K.J.; An enantioselective synthesis of the C(10) to C(23) backbone of the potent immunosuppressant FK506. Tetrahedron Lett 1989, 30, 9, 1037. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 57282 | methyl (2S,3S,5R,6S)-3-{[tert-butyl(dimethyl)silyl]oxy}-6-methoxy-5-methyltetrahydro-2H-pyran-2-carboxylate | C15H30O5Si | 详情 | 详情 | |
| (VIII) | 57283 | tert-butyl{[(2R)-3-iodo-2-methylpropyl]oxy}diphenylsilane; tert-butyl(diphenyl)silyl (2R)-3-iodo-2-methylpropyl ether | C20H27IOSi | 详情 | 详情 | |
| (IX) | 57284 | (3S)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-methylbutanenitrile | C21H27NOSi | 详情 | 详情 | |
| (X) | 57285 | (3S)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-methylbutanal | C21H28O2Si | 详情 | 详情 | |
| (XI) | 57286 | tert-butyl(diphenyl)silyl (2S)-2-methyl-4-pentynyl ether; tert-butyl{[(2S)-2-methyl-4-pentynyl]oxy}diphenylsilane | C22H28OSi | 详情 | 详情 | |
| (XII) | 57287 | lithium butyl((E,4S)-5-{[tert-butyl(diphenyl)silyl]oxy}-2,4-dimethyl-1-pentenyl)dimethylaluminate(1-) | C29H46AlLiOSi | 详情 | 详情 | |
| (XIII) | 25266 | benzyl [(2S,3S)-3-[(benzyloxy)methyl]oxiranyl]methyl ether; (2S,3S)-2,3-bis[(benzyloxy)methyl]oxirane | C18H20O3 | 详情 | 详情 | |
| (XIV) | 57288 | (2S,3S,4E,7S)-1-(benzyloxy)-3-[(benzyloxy)methyl]-8-{[tert-butyl(diphenyl)silyl]oxy}-5,7-dimethyl-4-octen-2-ol | C41H52O4Si | 详情 | 详情 | |
| (XV) | 57289 | ({(2S,4E,6S,7S)-7,8-bis(benzyloxy)-6-[(benzyloxy)methyl]-2,4-dimethyl-4-octenyl}oxy)(tert-butyl)diphenylsilane; benzyl (2S,3S,4E,7S)-2-(benzyloxy)-3-[(benzyloxy)methyl]-8-{[tert-butyl(diphenyl)silyl]oxy}-5,7-dimethyl-4-octenyl ether | C48H58O4Si | 详情 | 详情 | |
| (XVI) | 57290 | (2S,4E,6S,7S)-7,8-bis(benzyloxy)-6-[(benzyloxy)methyl]-2,4-dimethyl-4-octen-1-ol | C32H40O4 | 详情 | 详情 | |
| (XVII) | 57291 | 1-({[(2S,3S,4E,7S)-2-(benzyloxy)-3-[(benzyloxy)methyl]-5,7-dimethyl-8-(phenylsulfanyl)-4-octenyl]oxy}methyl)benzene; benzyl (2S,3S,4E,7S)-2-(benzyloxy)-3-[(benzyloxy)methyl]-5,7-dimethyl-8-(phenylsulfanyl)-4-octenyl ether | C38H44O3S | 详情 | 详情 | |
| (XVIII) | 57292 | (2S,4E,6S,7S)-7,8-bis(benzyloxy)-6-[(benzyloxy)methyl]-2,4-dimethyl-4-octenyl phenyl sulfone; {(2S,4E,6S,7S)-7,8-bis(benzyloxy)-6-[(benzyloxy)methyl]-2,4-dimethyl-4-octenyl}(dioxo)phenyl-lambda~6~-sulfane | C38H44O5S | 详情 | 详情 | |
| (XIX) | 57293 | (3S,5E,7S,8S)-8,9-bis(benzyloxy)-7-[(benzyloxy)methyl]-1-((2S,3S,5R,6S)-3-{[tert-butyl(dimethyl)silyl]oxy}-6-methoxy-5-methyltetrahydro-2H-pyran-2-yl)-3,5-dimethyl-2-(phenylsulfonyl)-5-nonen-1-one | C52H70O9SSi | 详情 | 详情 | |
| (XX) | 57294 | (3S,5E,7S,8S)-8,9-bis(benzyloxy)-7-[(benzyloxy)methyl]-1-((2S,3S,5R,6S)-3-{[tert-butyl(dimethyl)silyl]oxy}-6-methoxy-5-methyltetrahydro-2H-pyran-2-yl)-3,5-dimethyl-5-nonen-1-one | C46H66O7Si | 详情 | 详情 |