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【结 构 式】 
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【分子编号】35670 【品名】1-(diethoxymethyl)-4-methoxybenzene; 4-(diethoxymethyl)phenyl methyl ether 【CA登记号】 |
【 分 子 式 】C12H18O3 【 分 子 量 】210.27312 【元素组成】C 68.55% H 8.63% O 22.83% |
合成路线1
该中间体在本合成路线中的序号：(IX)The intermediate (XV) has been obtained as follows: The reaction of methyl 3-hydroxy-2(S)-methylpropionate (I) with 4-methoxybenzyl trichloroacetimidate gives methyl 3-(4-methoxybenzyloxy)-2(S)-methylpropionate (II), which is reduced with LiAlH4, yielding the primary alcohol (III). The Swern oxidation of (III) affords the aldehyde (IV), which is condensed with the chiral imidazolidinone (V) to provide the adduct (VI). The transamidation of (VI) with N,O-dimethylhydroxylamine by means of Me3Al gives the methoxyamide (VII), which is debenzylated with DDQ to yield the diol (VIII). The reaction of (VIII) with 4-methoxybenzaldehyde diethylacetal (IX) and CSA affords the cyclic ketal (X), which is condensed with the propionyloxazolidinone (XI) by means of dibutylboron triflate to furnish the adduct (XII). The silylation of the OH group of (XII) with Tbdms-OTf gives the silyl ether (XIII), which is reduced at the amide group with LiBH4 to yield the primary alcohol (XIV). Finally, this compound is treated with I2 and PPH3 to afford the intermediate iodo derivative (XV).
| 【1】 Smith, A.B. III; et al.; Gram-scale synthesis of (+)-discodermolide. Org Lett 1999, 1, 11, 1823. |
| 【2】 Smith, A.B. III; et al.; Evolution of a gram-scale synthesis of (+)-discodermolide. J Am Chem Soc 2000, 122, 36, 8654. |
| 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) | 17128 | Methyl (2S)-3-hydroxy-2-methylpropanoate | 72657-23-9 | C5H10O3 | 详情 | 详情 |
| (II) | 42654 | methyl (2S)-3-[(4-methoxybenzyl)oxy]-2-methylpropanoate | C13H18O4 | 详情 | 详情 | |
| (III) | 42655 | (2R)-3-[(4-methoxybenzyl)oxy]-2-methyl-1-propanol | C12H18O3 | 详情 | 详情 | |
| (IV) | 42656 | (2S)-3-[(4-methoxybenzyl)oxy]-2-methylpropanal | C12H16O3 | 详情 | 详情 | |
| (V) | 42657 | (4R,5S)-3-[(Z)-1-butoxy-1-propenyl]-4-methyl-5-phenyl-1,3-oxazolidin-2-one | C17H23NO3 | 详情 | 详情 | |
| (VI) | 42658 | (4R,5S)-3-[(2R,3S,4S)-3-hydroxy-5-[(4-methoxybenzyl)oxy]-2,4-dimethylpentanoyl]-4-methyl-5-phenyl-1,3-oxazolidin-2-one | C25H31NO6 | 详情 | 详情 | |
| (VII) | 42659 | (2R,3S,4S)-3-hydroxy-N-methoxy-5-[(4-methoxybenzyl)oxy]-N,2,4-trimethylpentanamide | C17H27NO5 | 详情 | 详情 | |
| (VIII) | 42660 | (2R,3S,4S)-3,5-dihydroxy-N-methoxy-N,2,4-trimethylpentanamide | C9H19NO4 | 详情 | 详情 | |
| (IX) | 35670 | 1-(diethoxymethyl)-4-methoxybenzene; 4-(diethoxymethyl)phenyl methyl ether | C12H18O3 | 详情 | 详情 | |
| (X) | 42661 | (2R)-N-methoxy-2-[(4S,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-N-methylpropanamide | C17H25NO5 | 详情 | 详情 | |
| (XI) | 10968 | (4R)-3-Acetyl-4-benzyl-1,3-oxazolidin-2-one; (R)-(-)-3-Acetyl-4-benzyl-2-oxazolidinone | 184363-65-3 | C12H13NO3 | 详情 | 详情 |
| (XII) | 42662 | (4R)-4-benzyl-3-[(2R,3S,4S)-3-hydroxy-4-[(4S,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-2-methylpentanoyl]-1,3-oxazolidin-2-one | C28H35NO7 | 详情 | 详情 | |
| (XIII) | 42663 | (4R)-4-benzyl-3-[(2R,3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-[(4S,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-2-methylpentanoyl]-1,3-oxazolidin-2-one | C34H49NO7Si | 详情 | 详情 | |
| (XIV) | 42664 | (2S,3R,4R)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-[(4S,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-2-methyl-1-pentanol | C24H42O5Si | 详情 | 详情 | |
| (XV) | 42665 | tert-butyl(dimethyl)silyl (1S,2R)-3-iodo-1-[(1R)-1-[(4S,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]ethyl]-2-methylpropyl ether; tert-butyl[((1S,2R)-3-iodo-1-[(1R)-1-[(4S,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]ethyl]-2-methylpropyl)oxy]dimethylsilane | C24H41IO4Si | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)The intermediate (IV) has been obtained as follows: The condensation of silylated propionic aldehyde (I) with the mesylated acetylene (II) by means of Pd(PPh3)4 and Et2Zn in THF gives the hexanol (III), which is protected with chloromethyl (methyl)ether by means of DIEA and Bu4NI, yielding the desired acetylenic intermediate (IV) (1) The intermediate (XXII) has been obtained as follows: The desilylation of hexanol (III) with TBAF gives the acetylenic diol (V), which is protected with p-methoxy-benzaldehyde diethyl acetal (VI) catalyzed by CSA, affording the cyclic ketal (VII). The homologation of (VI) with formaldehyde and BuLi yields the propargyl alcohol (VIII), which is treated with Ac2O to provide the acetate (IX) (1). The partial hydrogenation of the triple bond of (IX) with Red-Al gives the allyl alcohol (X), which is asymmetrically epoxidated by the Sharpless method, yielding the epoxide (XI). The reduction of (XI) with Red-Al affords the chiral diol (XII), which is monoesterified with pivaloyl chloride and TEA to provide the pivalate (XIII). The silylation of (XIII) with Tbdms-OTf and lutidine furnishes the silylated pivalate (XIV), which is hydrolyzed with K2CO3 in methanol to give the primary alcohol (XV). The Swern oxidation of (XV) gives the aldehyde (XVI) (2), which is condensed with the intermediate acetylenic derivative (IV) by means of BuLi and LiBr in THF, yielding the adduct (XVII). The partial reduction of the triple bond of (XVII) with H2 over Pd/Pb/CaCO3 gives compound (XVIII) with a cis double bond. The protection of the OH group of (XVIII) as the methoxymethyl ether, followed by desilylation with HF in pyridine, yields the primary alcohol (XIX), which is oxidized with DMP to the corresponding aldehyde (XX). Finally, this compound is condensed with the iodophosphorane (XXI) to afford the target intermediate, the iodo compound (XXII).
| 【1】 Marsshall, J.A.; et al.; Synthesis of discodermolide subunits by SE2' addition of nonracemic allenylstannanes to aldehydes. J Org Chem 1998, 63, 3, 817. |
| 【2】 Marshall, J.A.; Hohns, B.A.; Total synthesis of (+)-discodermolide. J Org Chem 1998, 63, 22, 7885. |
| 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) | 42735 | (2S)-2-methyl-3-[(triethylsilyl)oxy]propanal | C10H22O2Si | 详情 | 详情 | |
| (II) | 42736 | methyl(dimethylene)[[(1R)-1-methyl-2-propynyl]oxy]-lambda(6)-sulfane | C7H12OS | 详情 | 详情 | |
| (III) | 42737 | (2S,3S,4S)-2,4-dimethyl-1-[(triethylsilyl)oxy]-5-hexyn-3-ol | C14H28O2Si | 详情 | 详情 | |
| (IV) | 42738 | (2S,3S,4S)-3-(methoxymethoxy)-2,4-dimethyl-5-hexynyl triethylsilyl ether; (5S,6S)-9,9-diethyl-6-methyl-5-[(1S)-1-methyl-2-propynyl]-2,4,8-trioxa-9-silaundecane | C16H32O3Si | 详情 | 详情 | |
| (V) | 42739 | (2S,3S,4S)-2,4-dimethyl-5-hexyne-1,3-diol | C8H14O2 | 详情 | 详情 | |
| (VI) | 35670 | 1-(diethoxymethyl)-4-methoxybenzene; 4-(diethoxymethyl)phenyl methyl ether | C12H18O3 | 详情 | 详情 | |
| (VII) | 42740 | methyl 4-[(2R,4S,5S)-5-methyl-4-[(1S)-1-methyl-2-propynyl]-1,3-dioxan-2-yl]phenyl ether; (2R,4S,5S)-2-(4-methoxyphenyl)-5-methyl-4-[(1S)-1-methyl-2-propynyl]-1,3-dioxane | C16H20O3 | 详情 | 详情 | |
| (VIII) | 42741 | (4S)-4-[(2R,4S,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-2-pentyn-1-ol | C17H22O4 | 详情 | 详情 | |
| (IX) | 42742 | (4S)-4-[(2R,4S,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-2-pentynyl acetate | C19H24O5 | 详情 | 详情 | |
| (X) | 42743 | (E,4S)-4-[(2R,4S,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-2-penten-1-ol | C17H24O4 | 详情 | 详情 | |
| (XI) | 42744 | ((2R,3R)-3-[(1S)-1-[(2R,4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]ethyl]oxiranyl)methanol | C17H24O5 | 详情 | 详情 | |
| (XII) | 42745 | (3S,4S)-4-[(2R,4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-1,3-pentanediol | C17H26O5 | 详情 | 详情 | |
| (XIII) | 42746 | (3S,4S)-3-hydroxy-4-[(2R,4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]pentyl pivalate | C22H34O6 | 详情 | 详情 | |
| (XIV) | 42747 | (3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-[(2R,4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]pentyl pivalate | C28H48O6Si | 详情 | 详情 | |
| (XV) | 42748 | (3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-[(2R,4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-1-pentanol | C23H40O5Si | 详情 | 详情 | |
| (XVI) | 42749 | (3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-[(2R,4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]pentanal | C23H38O5Si | 详情 | 详情 | |
| (XVII) | 42750 | (5S,7S,10S,11S,12S)-15,15-diethyl-11-(methoxymethoxy)-5-[(1R)-1-[(2R,4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]ethyl]-2,2,3,3,10,12-hexamethyl-4,14-dioxa-3,15-disila-8-heptadecyn-7-ol | C39H70O8Si2 | 详情 | 详情 | |
| (XVIII) | 42751 | (5S,7S,8Z,10S,11S,12S)-15,15-diethyl-11-(methoxymethoxy)-5-[(1R)-1-[(2R,4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]ethyl]-2,2,3,3,10,12-hexamethyl-4,14-dioxa-3,15-disila-8-heptadecen-7-ol | C39H72O8Si2 | 详情 | 详情 | |
| (XIX) | 42752 | (2S,3S,4S,5Z,7S,9S,10R)-9-[[tert-butyl(dimethyl)silyl]oxy]-3,7-bis(methoxymethoxy)-10-[(2R,4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-2,4-dimethyl-5-undecen-1-ol | C35H62O9Si | 详情 | 详情 | |
| (XX) | 42753 | (2R,3S,4S,5Z,7S,9S,10R)-9-[[tert-butyl(dimethyl)silyl]oxy]-3,7-bis(methoxymethoxy)-10-[(2R,4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-2,4-dimethyl-5-undecenal | C35H60O9Si | 详情 | 详情 | |
| (XXI) | 42754 | (1-iodoethylidene)(triphenyl)phosphorane | C20H18IP | 详情 | 详情 | |
| (XXII) | 42755 | (5S,6S,7Z,9S,11S)-5-[(1S,2Z)-3-iodo-1-methyl-2-butenyl]-9-(methoxymethoxy)-11-[(1R)-1-[(2R,4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]ethyl]-6,13,13,14,14-pentamethyl-2,4,12-trioxa-13-sila-7-pentadecene; tert-butyl(dimethyl)silyl (1S,3S,4Z,6S,7S,8S,9Z)-10-iodo-3,7-bis(methoxymethoxy)-1-[(1R)-1-[(2R,4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]ethyl]-6,8-dimethyl-4,9-undecadienyl ether | C37H63IO8Si | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)The acetalization of Hecogenyl beta-O-cellobioside (I) with 4-methoxybenzaldehyde diethyl acetal (II) by means of pyridinium tosylate in THF gives the acetal (III), which is acylated with 2-methoxyacetyl chloride (IV) by means of pyridine and DMAP in dichloromethane yielding the pentaacetate (V). The elimination of the acetal group of (V) with H2 over Pd/C in ethyl acetate affords the dihydroxy compound (VI).
| 【1】 Urban, F.J.; et al.; Process research and large-scale synthesis of 4'',6''-bis((2-fluorophenyl)carbomoyl)hecogenyl beta-O-cellobioside: A potent cholesterol absorption inhibitor. Org Process Res Dev 1998, 2, 2, 66. |
| 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) | 35669 | Pamaqueside | 150332-35-7 | C39H62O14 | 详情 | 详情 |
| (II) | 35670 | 1-(diethoxymethyl)-4-methoxybenzene; 4-(diethoxymethyl)phenyl methyl ether | C12H18O3 | 详情 | 详情 | |
| (III) | 35671 | C47H68O15 | 详情 | 详情 | ||
| (IV) | 13429 | 2-Methoxyacetyl chloride; Methoxyacetyl chloride | 38870-89-2 | C3H5ClO2 | 详情 | 详情 |
| (V) | 35672 | C62H88O25 | 详情 | 详情 | ||
| (VI) | 35673 | C54H82O24 | 详情 | 详情 |