|
【结 构 式】 
|
【分子编号】43443 【品名】(4S,4aR,6R,8S,8aR)-8-methoxy-7,7-dimethyl-6-[[(4S)-2-oxo-1,3-dioxolan-4-yl]methyl]hexahydropyrano[3,2-d][1,3]dioxine-4-carboxylic acid 【CA登记号】 |
【 分 子 式 】C15H22O9 【 分 子 量 】346.33428 【元素组成】C 52.02% H 6.4% O 41.58% |
合成路线1
该中间体在本合成路线中的序号：(XIV)The methylation of the homoallyl alcohol (I) with methyl iodide and NaH in DMF gives the methyl ether (II), which is oxidized with O3, yielding the aldehyde (III). The diastereoselective allylation of (III) with the chiral borane (IV) in ethyl ether affords the homoallyl alcohol (V), which is epoxidized to the epoxide (VI). The cleavage of the epoxide (VI) with trichloromethyl carbonate provides the cyclic carbonate (VII), which is protected with Troc-Cl and pyridine and then oxidized with NaIO4, furnishing the aldehyde (VIII). The asymetric allylation of (VIII) with the chiral boronate (IX) gives the new homoallyl alcohol (X), which is treated with dimethyldioxirane (XI) to yield the epoxide (XII). Elimination of the Troc- group of (XII) with Zn/HOAc, followed by selective silylation with Tbdps-Cl and imidazole, affords the cyclized tetrahydropyran derivative (XIII), which is cyclized with P2O5 and formaldehyde, and oxidized with CrO3 and sulfuric acid to provide the bicyclic carboxylic acid (XIV).
| 【1】 Roush, W.R.; Marron, T.G.; Diastereoselective synthesis of N-benzoyl mycalamine, the fully elaborated trioxadecalin nucleus of mycalamide A. Control of the key N-acyl aminal stereocenter via carbamate acylation. Tetrahedron Lett 1995, 36, 10, 1581. |
| 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) | 43431 | (1S)-1-[(4R)-2,2-diethyl-1,3-dioxolan-4-yl]-2,2-dimethyl-3-buten-1-ol | C13H24O3 | 详情 | 详情 | |
| (II) | 43432 | (4R)-2,2-diethyl-4-[(1S)-1-methoxy-2,2-dimethyl-3-butenyl]-1,3-dioxolane; (1S)-1-[(4R)-2,2-diethyl-1,3-dioxolan-4-yl]-2,2-dimethyl-3-butenyl methyl ether | C14H26O3 | 详情 | 详情 | |
| (III) | 43433 | (3S)-3-[(4R)-2,2-diethyl-1,3-dioxolan-4-yl]-3-methoxy-2,2-dimethylpropanal | C13H24O4 | 详情 | 详情 | |
| (IV) | 43434 | allyl[bis[(1R,2R,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]]borane | C23H39B | 详情 | 详情 | |
| (V) | 43435 | (1S,3R)-1-[(4R)-2,2-diethyl-1,3-dioxolan-4-yl]-1-methoxy-2,2-dimethyl-5-hexen-3-ol | C16H30O4 | 详情 | 详情 | |
| (VI) | 43436 | (2R,4S)-4-[(4R)-2,2-diethyl-1,3-dioxolan-4-yl]-4-methoxy-3,3-dimethyl-1-[(2S)oxiranyl]-2-butanol | C16H30O5 | 详情 | 详情 | |
| (VII) | 43437 | (4S)-4-[(2R,4S)-4-[(4R)-2,2-diethyl-1,3-dioxolan-4-yl]-2-hydroxy-4-methoxy-3,3-dimethylbutyl]-1,3-dioxolan-2-one | C17H30O7 | 详情 | 详情 | |
| (VIII) | 43438 | (1R,3S)-3-methoxy-2,2-dimethyl-4-oxo-1-[[(4S)-2-oxo-1,3-dioxolan-4-yl]methyl]butyl 2,2,2-trichloroethyl carbonate | C14H19Cl3O8 | 详情 | 详情 | |
| (IX) | 43439 | diethyl (4R,5R)-2-[(E)-3-(trimethylsilyl)-2-propenyl]-1,3,2-dioxaborolane-4,5-dicarboxylate | C14H25BO6Si | 详情 | 详情 | |
| (X) | 43440 | (1R,3S,4R,5S)-4-hydroxy-3-methoxy-2,2-dimethyl-1-[[(4S)-2-oxo-1,3-dioxolan-4-yl]methyl]-5-[(trimethylsilyl)oxy]-6-heptenyl 2,2,2-trichloroethyl carbonate | C20H33Cl3O9Si | 详情 | 详情 | |
| (XI) | 31501 | 3,3-dimethyl-1,2-dioxirane | C3H6O2 | 详情 | 详情 | |
| (XII) | 43441 | (1R,3S,4R)-4-hydroxy-4-[(2S,3R)-3-(hydroxymethyl)oxiranyl]-3-methoxy-2,2-dimethyl-1-[[(4S)-2-oxo-1,3-dioxolan-4-yl]methyl]butyl 2,2,2-trichloroethyl carbonate | C17H25Cl3O10 | 详情 | 详情 | |
| (XIII) | 43442 | (4S)-4-[[(2R,4S,5R,6R)-6-((1R)-2-[[tert-butyl(diphenyl)silyl]oxy]-1-hydroxyethyl)-5-hydroxy-4-methoxy-3,3-dimethyltetrahydro-2H-pyran-2-yl]methyl]-1,3-dioxolan-2-one | C30H42O8Si | 详情 | 详情 | |
| (XIV) | 43443 | (4S,4aR,6R,8S,8aR)-8-methoxy-7,7-dimethyl-6-[[(4S)-2-oxo-1,3-dioxolan-4-yl]methyl]hexahydropyrano[3,2-d][1,3]dioxine-4-carboxylic acid | C15H22O9 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIV)The Curtius degradation of carboxylic acid (XIV) with Ph2PON3 and 2-(trimethylsilyl)ethanol (A) gives the carbamate (XV), which is acylated with 2-(benzyloxy)acetyl chloride (XVI) and LiHMDS in THF, yielding the imide (XVII). The condensation of (XVII) with aldehyde (XVIII) by means of TiCl4 and DIEA in dichloromethane affords the expected adduct (XIX), which is oxidized with TFAA and DMSO in dichloromethane/DIEA, providing the beta-ketoimide (XX) as a diastereomeric mixture at the benzyloxy group. The cyclization of (XX) by means of CSA in methanol, followed by separation of the diastereomeric mixture, furnished the hydroxy tetrahydropyran derivative (XXI), which is submitted to a Swern oxidation to give the trahydropyranone (XXII). The reaction of (XXII) with diiodomethane, TiCl4 and Zn yields the exo-methylene compound (XXIII), which is desilylated with TBAF in DMF to afford intermediate (XXIV). Finally, this compound is submitted to a reductive cleavage of the benzyloxy and cyclic carbonate groups with Na/NH3 in THF/ethyl ether to furnish the target compound.
| 【1】 Roush, W.R.; Pfeifer, L.A.; Total synthesis of mycalamide A and 7-epi-mycalamide A. Org Lett 2000, 2, 6, 859. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 20323 | 2-(trimethylsilyl)-1-ethanol | 2916-68-9 | C5H14OSi | 详情 | 详情 |
| (XIV) | 43443 | (4S,4aR,6R,8S,8aR)-8-methoxy-7,7-dimethyl-6-[[(4S)-2-oxo-1,3-dioxolan-4-yl]methyl]hexahydropyrano[3,2-d][1,3]dioxine-4-carboxylic acid | C15H22O9 | 详情 | 详情 | |
| (XV) | 43444 | 2-(trimethylsilyl)ethyl (4S,4aS,6R,8S,8aR)-8-methoxy-7,7-dimethyl-6-[[(4S)-2-oxo-1,3-dioxolan-4-yl]methyl]hexahydropyrano[3,2-d][1,3]dioxin-4-ylcarbamate | C20H35NO9Si | 详情 | 详情 | |
| (XVI) | 10493 | 2-(Benzyloxy)acetyl chloride; Benzyloxyacetyl chloride | 19810-31-2 | C9H9ClO2 | 详情 | 详情 |
| (XVII) | 43445 | 2-(trimethylsilyl)ethyl (4S,4aS,6R,8S,8aR)-8-methoxy-7,7-dimethyl-6-[[(4S)-2-oxo-1,3-dioxolan-4-yl]methyl]hexahydropyrano[3,2-d][1,3]dioxin-4-yl[2-(benzyloxy)acetyl]carbamate | C29H43NO11Si | 详情 | 详情 | |
| (XVIII) | 43446 | (3R,4S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-4-methylhexanal | C19H42O3Si2 | 详情 | 详情 | |
| (XIX) | 43447 | 2-(trimethylsilyl)ethyl (4S,4aS,6R,8S,8aR)-8-methoxy-7,7-dimethyl-6-[[(4S)-2-oxo-1,3-dioxolan-4-yl]methyl]hexahydropyrano[3,2-d][1,3]dioxin-4-yl((2R,5R,6S,7R)-2-(benzyloxy)-5,7-bis[[tert-butyl(dimethyl)silyl]oxy]-3-hydroxy-6-methyloctanoyl)carbamate | C48H85NO14Si3 | 详情 | 详情 | |
| (XX) | 43448 | 2-(trimethylsilyl)ethyl (4S,4aS,6R,8S,8aR)-8-methoxy-7,7-dimethyl-6-[[(4S)-2-oxo-1,3-dioxolan-4-yl]methyl]hexahydropyrano[3,2-d][1,3]dioxin-4-yl((5R,6S,7R)-2-(benzyloxy)-5,7-bis[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-3-oxooctanoyl)carbamate | C48H83NO14Si3 | 详情 | 详情 | |
| (XXI) | 43449 | 2-(trimethylsilyl)ethyl (4S,4aS,6R,8S,8aR)-8-methoxy-7,7-dimethyl-6-[[(4S)-2-oxo-1,3-dioxolan-4-yl]methyl]hexahydropyrano[3,2-d][1,3]dioxin-4-yl[(2S)-2-(benzyloxy)-2-[(2R,4R,5R,6R)-4-hydroxy-2-methoxy-5,6-dimethyltetrahydro-2H-pyran-2-yl]ethanoyl]ca | C37H57NO14Si | 详情 | 详情 | |
| (XXII) | 43450 | 2-(trimethylsilyl)ethyl (4S,4aS,6R,8S,8aR)-8-methoxy-7,7-dimethyl-6-[[(4S)-2-oxo-1,3-dioxolan-4-yl]methyl]hexahydropyrano[3,2-d][1,3]dioxin-4-yl[(2S)-2-(benzyloxy)-2-[(2R,5S,6R)-2-methoxy-5,6-dimethyl-4-oxotetrahydro-2H-pyran-2-yl]ethanoyl]carbamate | C37H55NO14Si | 详情 | 详情 | |
| (XXIII) | 43451 | 2-(trimethylsilyl)ethyl (4S,4aS,6R,8S,8aR)-8-methoxy-7,7-dimethyl-6-[[(4S)-2-oxo-1,3-dioxolan-4-yl]methyl]hexahydropyrano[3,2-d][1,3]dioxin-4-yl[(2S)-2-(benzyloxy)-2-[(2R,5R,6R)-2-methoxy-5,6-dimethyl-4-methylenetetrahydro-2H-pyran-2-yl]ethanoyl]car | C38H57NO13Si | 详情 | 详情 | |
| (XXIV) | 43452 | (2S)-N-((4S,4aS,6R,8S,8aR)-8-methoxy-7,7-dimethyl-6-[[(4S)-2-oxo-1,3-dioxolan-4-yl]methyl]hexahydropyrano[3,2-d][1,3]dioxin-4-yl)-2-(benzyloxy)-2-[(2R,5R,6R)-2-methoxy-5,6-dimethyl-4-methylenetetrahydro-2H-pyran-2-yl]ethanamide | C32H45NO11 | 详情 | 详情 |