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【结 构 式】 
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【分子编号】14956 【品名】tert-butyl[[(2R,3R)-3-methyloxiranyl]methoxy]diphenylsilane; tert-butyl(diphenyl)silyl [(2R,3R)-3-methyloxiranyl]methyl ether 【CA登记号】 |
【 分 子 式 】C20H26O2Si 【 分 子 量 】326.51074 【元素组成】C 73.57% H 8.03% O 9.8% Si 8.6% |
合成路线1
该中间体在本合成路线中的序号：(III)Synthesis of the intermediate butyraldehyde (X): The Sharpless asymmetric epoxidation of 2(E)-buten-1-ol by means of t-Bu-OOH and D-(-9-diisopropyl tartrate gives the epoxy alcohol (II), which is treated with Tbdps-Cl, TEA and DMAP to yield the silyl ether (III) The condensation of (III) with 1,3-dithiane (IV) by means of BuLi in THF/HMPA affords the cyclic thioketal (V), which is deprotected by means of TBAF in THF, affording the diol (VI). The reaction of (VI) with 4-methoxybenzaldehyde dimethylacetal (VII) by means of TsOH in DMF provides the benzylidene ketal (VIII), which is submitted to a selective opening by means of DIBAL in dichloromethane to give the secondary benzyl ether (IX). Finally this compound is oxidized with SO3/Pyridine and TEA in DMSO/dichloromethane to obtain the target intermediate, the chiral butyraldehyde (X).
| 【1】 Chen, K.; Formal total synthesis of (-)-FK506. Diss Abstr Int B - Sci Eng 1993, 53, 9, 4663. |
| 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) | 54882 | 2-Butene-1-ol; Crotyl Alcohol; trans-Propenylcarbinol | 504-61-0 | C4H8O | 详情 | 详情 |
| (II) | 57330 | [(2R,3R)-3-methyloxiranyl]methanol | C4H8O2 | 详情 | 详情 | |
| (III) | 14956 | tert-butyl[[(2R,3R)-3-methyloxiranyl]methoxy]diphenylsilane; tert-butyl(diphenyl)silyl [(2R,3R)-3-methyloxiranyl]methyl ether | C20H26O2Si | 详情 | 详情 | |
| (IV) | 42372 | 1,3-dithiane | 505-23-7 | C4H8S2 | 详情 | 详情 |
| (V) | 57331 | (2S,3S)-1-{[tert-butyl(diphenyl)silyl]oxy}-3-(1,3-dithian-2-yl)-2-butanol | C24H34O2S2Si | 详情 | 详情 | |
| (VI) | 57332 | (2S,3S)-3-(1,3-dithian-2-yl)-1,2-butanediol | C8H16O2S2 | 详情 | 详情 | |
| (VII) | 26485 | 1-(dimethoxymethyl)-4-methoxybenzene | 2186-92-7 | C10H14O3 | 详情 | 详情 |
| (VIII) | 57333 | (4S)-4-[(1S)-1-(1,3-dithian-2-yl)ethyl]-2-(4-methoxyphenyl)-1,3-dioxolane; 4-{(4S)-4-[(1S)-1-(1,3-dithian-2-yl)ethyl]-1,3-dioxolan-2-yl}phenyl methyl ether | C16H22O3S2 | 详情 | 详情 | |
| (IX) | 57334 | (2S,3S)-3-(1,3-dithian-2-yl)-2-[(4-methoxybenzyl)oxy]-1-butanol | C16H24O3S2 | 详情 | 详情 | |
| (X) | 57335 | (2S,3S)-3-(1,3-dithian-2-yl)-2-[(4-methoxybenzyl)oxy]butanal | C16H22O3S2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)A partial synthesis of rapamycin has been reported: The condensation of sulfone (I) with epoxide (II) by means of butyllithium followed by desulfonation with Na/Hg gives the partially protected diol (III), which is treated with methanesulfonyl chloride and NaH to afford the epoxide (IV). Ring opening of epoxide (IV) with LiI and BF3.Et2O followed by protection of the resulting alcohol with PMBOC(NH)CCl3 yields the primary iodo compound (V). The condensation of (V) with the fully protected dihydroxyaldehyde (VI) (see later) by means of butyllithium in THF/HMPT gives the fully protected trihydroxyketone (VII), which is hydrolyzed with camphorsulfonic acid (CSA) to the corresponding gemdiol and reprotected with pivaloyl chloride (the primary alcohol) and tert-butyldimethylsilyl trifluoromethanesulfonate (the secondary alcohol), yielding a new fully protected trihydroxyketone (VIII). Elimination of the pivaloyl group with DIBAL and the dithiane group with MeI/CaCO3 affords the hydroxyketone (IX), which is finally oxidized with oxalyl chloride to the ketoaldehyde (X), the C(27)-C(42) fragment [the C(12)-C(15) fragment with the C(12)-substituent based on the IUPAC nomenclature recommendations]. The fully protected dihydroxyaldehyde (VI) is obtained as follows: The reaction of methyl 3-hydroxy-2(R)-methylpropionate (XI) with BPSCl followed by reduction with LiBH4 to the corresponding alcohol and oxidation with oxalyl chloride gives the aldehyde (XII), which is protected with propane-1,3-dithiol and BF3.Et2O to afford the dithiane compound (XIII). Elimination of the silyl group with TBAF followed by esterification with tosyl chloride, reaction with NaI and, finally, with sodium phenylsulfinate gives the sulfone (XIV), which is condensed with the partially protected dihydroxyaldehyde (XV), oxidized with oxalyl chloride and desulfonated with Al/Hg to afford the dithianyl ketone (XVI). The reaction of (XVI) with lithium hexamethyldisilylazane gives the corresponding enolate, which is treated with dimethyllithium cuprate to yield the fully protected unsaturated dihydroxyaldehyde (VI).
| 【1】 Leahy, J.W.; Smith, A.B.; McCauley, J.A.; Condon, S.M.; Leazer, J.L.; Maleczka, R.E.; Rapamycin synthetic studies. 1. Construction of the C(27)-C(42) subunit. Tetrahedron Lett 1994, 35, 28, 4907. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 52385 | [4-(methyloxy)phenyl]methyl 2,2,2-trichloroethanimidoate | C10H10Cl3NO2 | 详情 | 详情 | ||
| (I) | 14955 | triisopropyl([(1R,2R,4R)-2-methoxy-4-[(phenylsulfonyl)methyl]cyclohexyl]oxy)silane; [(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]methyl phenyl sulfone | C23H40O4SSi | 详情 | 详情 | |
| (II) | 14956 | tert-butyl[[(2R,3R)-3-methyloxiranyl]methoxy]diphenylsilane; tert-butyl(diphenyl)silyl [(2R,3R)-3-methyloxiranyl]methyl ether | C20H26O2Si | 详情 | 详情 | |
| (III) | 14957 | (2S,3R)-1-[[tert-butyl(diphenyl)silyl]oxy]-4-[(1S,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-3-methyl-2-butanol | C37H62O4Si2 | 详情 | 详情 | |
| (IV) | 14958 | triisopropyl[((1R,2R,4S)-2-methoxy-4-[(2R)-2-[(2S)oxiranyl]propyl]cyclohexyl)oxy]silane; (1R,2R,4S)-2-methoxy-4-[(2R)-2-[(2S)oxiranyl]propyl]cyclohexyl triisopropylsilyl ether | C21H42O3Si | 详情 | 详情 | |
| (V) | 14959 | [((1R,2R,4S)-4-[(2R,3R)-4-iodo-3-[(4-methoxybenzyl)oxy]-2-methylbutyl]-2-methoxycyclohexyl)oxy](triisopropyl)silane; (1R,2R,4S)-4-[(2R,3R)-4-iodo-3-[(4-methoxybenzyl)oxy]-2-methylbutyl]-2-methoxycyclohexyl triisopropylsilyl ether | C29H51IO4Si | 详情 | 详情 | |
| (VI) | 14960 | (4R)-4-[(E,3R)-3-(1,3-dithian-2-yl)-1-methyl-1-butenyl]-2,2-dimethyl-1,3-dioxolane | C14H24O2S2 | 详情 | 详情 | |
| (VII) | 14961 | (1R,2R,4S)-4-[(2R,3S)-4-(2-[(1R,2E)-3-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-1-methyl-2-butenyl]-1,3-dithian-2-yl)-3-[(4-methoxybenzyl)oxy]-2-methylbutyl]-2-[(triisopropylsilyl)oxy]cyclohexanol | C42H72O6S2Si | 详情 | 详情 | |
| (VIII) | 14962 | (2R,3E,5R)-2-[[tert-butyl(dimethyl)silyl]oxy]-5-[2-((2S,3R)-2-[(4-methoxybenzyl)oxy]-4-[(1S,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-3-methylbutyl)-1,3-dithian-2-yl]-3-methyl-3-hexenyl pivalate | C51H92O7S2Si2 | 详情 | 详情 | |
| (IX) | 14963 | (2R,3S,6R,7E,9R)-9-[[tert-butyl(dimethyl)silyl]oxy]-10-hydroxy-3-[(4-methoxybenzyl)oxy]-1-[(1S,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-2,6,8-trimethyl-7-decen-5-one | C43H78O7Si2 | 详情 | 详情 | |
| (X) | 14964 | (2R,3E,5R,8S,9R)-1-[[tert-butyl(dimethyl)silyl]oxy]-7-[(4-methoxybenzyl)oxy]-9-[(1S,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-2,4,8-trimethyl-5-oxo-3-decenoic 1,1-dimethylpropionic anhydride | C48H84O9Si2 | 详情 | 详情 | |
| (XI) | 14965 | methyl 3-hydroxy-2-methylpropanoate; METHYL (S)-(+)-3-HYDROXY-2-METHYLPROPIONATE | 80657-57-4 | C5H10O3 | 详情 | 详情 |
| (XII) | 14966 | (2R)-3-[[tert-butyl(diphenyl)silyl]oxy]-2-methylpropanal | C20H26O2Si | 详情 | 详情 | |
| (XIII) | 14967 | tert-butyl[[(2R)-2-(1,3-dithian-2-yl)propyl]oxy]diphenylsilane; tert-butyl(diphenyl)silyl (2R)-2-(1,3-dithian-2-yl)propyl ether | C23H32OS2Si | 详情 | 详情 | |
| (XIV) | 14968 | (2R)-2-(1,3-dithian-2-yl)propyl phenyl sulfone; 2-[(1R)-1-methyl-2-(phenylsulfonyl)ethyl]-1,3-dithiane | C13H18O2S3 | 详情 | 详情 | |
| (XV) | 14969 | (4S)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde | 22323-80-4 | C6H10O3 | 详情 | 详情 |
| (XVI) | 14970 | (3R)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-3-(1,3-dithian-2-yl)-1-butanone | C13H22O3S2 | 详情 | 详情 |