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【结 构 式】 
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【分子编号】42735 【品名】(2S)-2-methyl-3-[(triethylsilyl)oxy]propanal 【CA登记号】 |
【 分 子 式 】C10H22O2Si 【 分 子 量 】202.36898 【元素组成】C 59.35% H 10.96% O 15.81% Si 13.88% |
合成路线1
该中间体在本合成路线中的序号：(I)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2
该中间体在本合成路线中的序号：(I)The intermediate (XLI) has been obtained as follows: The condensation of the silylated propionic aldehyde (I) with the chiral allene (XXIII) by means of BF3/Et2O gives the acetylenic alcohol (XXIV), which is desilylated with TBAF, yielding the diol (XXV). The reaction of (XXV) with p-methoxybenzaldehyde dimethyl acetal (XXVI) affords the cyclic ketal (XXVII), which is treated with Red-Al to provided the primary alcohol (XXVIII). The asymmetric Sharpless epoxidation of the double bond of (XXVIII) gives the epoxide (XXIX), which is methylated with Me2CuCNLi2, yielding the chiral diol (XXX). The regioselective acylation of (XXX) with pivaloyl chloride affords the monopivalate (XXXI), which is silylated with Tes-Otf, providing the silyl ether (XXXII). The reductive cleavage of the pivalate ester of (XXXII) with Red-Al furnishes the primary alcohol (XXXIII), which is oxidized with DMP to the aldehyde (XXXIV). The condensation of (XXXIV) with the bromoallyl compound (XXXV) gives the homoallyl alcohol (XXXVI), which is treated with NaH in THF to afford the conjugated diene (XXXVII) (2). The reductive cleavage of the cyclic ketal group of (XXXVII) with iBu2AlH gives the primary alcohol (XXXVIII), which is treated with I2 and PPh3 to yield the iodo derivative (XXXIX). Finally, this compound is condensed with 9-methoxy-9-borabicyclo[3,3,1]nonane (XL) by means of BuLi in THF/ethyl ether to furnish the desired intermediate, the lithium salt (XLI).
| 【1】 Marshall, J.A.; Hohns, B.A.; Total synthesis of (+)-discodermolide. J Org Chem 1998, 63, 22, 7885. |
| 【2】 Marsshall, J.A.; et al.; Synthesis of discodermolide subunits by SE2' addition of nonracemic allenylstannanes to aldehydes. J Org Chem 1998, 63, 3, 817. |
| 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 | |
| (XXIII) | 42756 | 2-(tributylstannyl)-2,3-pentadienyl pivalate | C22H42O2Sn | 详情 | 详情 | |
| (XXIV) | 42757 | (4R,5S,6S)-5-hydroxy-4,6-dimethyl-7-[(triethylsilyl)oxy]-2-heptynyl pivalate | C20H38O4Si | 详情 | 详情 | |
| (XXV) | 42758 | (4R,5S,6S)-5,7-dihydroxy-4,6-dimethyl-2-heptynyl pivalate | C14H24O4 | 详情 | 详情 | |
| (XXVI) | 26485 | 1-(dimethoxymethyl)-4-methoxybenzene | 2186-92-7 | C10H14O3 | 详情 | 详情 |
| (XXVII) | 42759 | (4R)-4-[(2R,4S,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-2-pentynyl pivalate | C22H30O5 | 详情 | 详情 | |
| (XXVIII) | 42760 | (E,4R)-4-[(2R,4S,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-2-penten-1-ol | C17H24O4 | 详情 | 详情 | |
| (XXIX) | 42761 | ((2S,3R)-3-[(1R)-1-[(2R,4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]ethyl]oxiranyl)methanol | C17H24O5 | 详情 | 详情 | |
| (XXX) | 42762 | (2S,3S,4R)-4-[(2R,4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-2-methyl-1,3-pentanediol | C18H28O5 | 详情 | 详情 | |
| (XXXI) | 42763 | (2S,3S,4R)-3-hydroxy-4-[(2R,4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-2-methylpentyl pivalate | C23H36O6 | 详情 | 详情 | |
| (XXXII) | 42764 | (2S,3S,4S)-4-[(2R,4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-2-methyl-3-[(triethylsilyl)oxy]pentyl pivalate | C29H50O6Si | 详情 | 详情 | |
| (XXXIII) | 42765 | (2S,3S,4S)-4-[(2R,4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-2-methyl-3-[(triethylsilyl)oxy]-1-pentanol | C24H42O5Si | 详情 | 详情 | |
| (XXXIV) | 42766 | (2R,3R,4S)-4-[(2R,4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-2-methyl-3-[(triethylsilyl)oxy]pentanal | C24H40O5Si | 详情 | 详情 | |
| (XXXV) | 42629 | (1-bromo-2-propenyl)(trimethyl)silane | 94397-40-7 | C6H13BrSi | 详情 | 详情 |
| (XXXVI) | 42767 | (3S,4R,5S,6S,7S)-7-[(2R,4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-5-methyl-6-[(triethylsilyl)oxy]-3-(trimethylsilyl)-1-octen-4-ol | C30H54O5Si2 | 详情 | 详情 | |
| (XXXVII) | 42768 | triethyl[((1S,2S,3Z)-1-[(1S)-1-[(2R,4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]ethyl]-2-methyl-3,5-hexadienyl)oxy]silane; 4-((2R,4R,5S)-4-[(1S,2S,3S,4Z)-1,3-dimethyl-2-[(triethylsilyl)oxy]-4,6-heptadienyl]-5-methyl-1,3-dioxan-2-yl)phenyl methyl ether | C27H44O4Si | 详情 | 详情 | |
| (XXXVIII) | 42769 | (2S,3R,4S,5S,6S,7Z)-3-[(4-methoxybenzyl)oxy]-2,4,6-trimethyl-5-[(triethylsilyl)oxy]-7,9-decadien-1-ol | C27H46O4Si | 详情 | 详情 | |
| (XXXIX) | 42770 | triethyl[((1S,2S,3Z)-1-[(1S,2S,3R)-4-iodo-2-[(4-methoxybenzyl)oxy]-1,3-dimethylbutyl]-2-methyl-3,5-hexadienyl)oxy]silane; (1S,2S,3Z)-1-[(1S,2S,3R)-4-iodo-2-[(4-methoxybenzyl)oxy]-1,3-dimethylbutyl]-2-methyl-3,5-hexadienyl triethylsilyl ether | C27H45IO3Si | 详情 | 详情 | |
| (XL) | 42771 | 9-methoxy-9-borabicyclo[3.3.1]nonane | 38050-71-4 | C9H17BO | 详情 | 详情 |
| (XLI) | 42772 | C36H62BLiO4Si | 详情 | 详情 |