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【结 构 式】 
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【分子编号】24401 【品名】1,7,7-Trimethylbicyclo[2,2,1]heptane-1',2-sultam; (1S)-(-)-2,10-Camphorsultam 【CA登记号】 |
【 分 子 式 】C10H17NO2S 【 分 子 量 】215.31652 【元素组成】C 55.78% H 7.96% N 6.51% O 14.86% S 14.89% |
合成路线1
该中间体在本合成路线中的序号：(XXII)The condensation of sultam (XXII) with propenoyl chloride (XXIII) by means of TEA in dichloromethane gives the acryloyl sultam (XXIV), which is submitted to a Diels Alder cyclization with butadiene (XXV) by means of EtAlCl2 in dichloromethane to yield the chiral cyclohexenylcarbonyl derivative (XXVI). The hydrolysis of (XXVI) with LiOH in THF affords 3-cyclohexene-1(R)-carboxylic acid (XXVII), which is treated with I2, KI, NaHCO3 and DBU to provide the bicyclic lactone (XXVIII). The reduction of (XXVIII) with LiAlH4 in THF gives the chiral diol (XXIX), which is treated with diphenyl disulfide and tributylphosphine to yield the phenyl thioether (XXX). The methylation of the OH group of (XXX) with methyl iodide and KOH in DMSO afford the methoxy derivative (XXXI). The oxidation of (XXXI) with oxone in THF/methanol provides the sulfone (XXXII), which is submitted to hydroboration with BH3/Me2S and tBu-OOH in THF to give the chiral 4-hydroxy-3-methoxycyclohexylmethyl sulfone (XXXIII). The reaction of (XXXIII) with Tbdps-Cl and imidazole in DMF yields the silyl ether (XXXIV), which is condensed with the intermediate butyraldehyde (X) by means of BuLi in THF to afford the chiral pentanol derivative (XXXV). The oxidation of (XXXV) with TFAA and DMSO in dichloromethane provides the corresponding ketone (XXXVI), which is desulfonated by means of aluminum amalgam in refluxing THF/water to give the ketone (XXXVII). The reaction of (XXXVII) with Tf2N-Ph and KHMDS in THF yields the triflate enol ester (XXXVIII), which is methylated with Me-Li and CuI in THF to afford the unsaturated dithiane derivative (XXXIX). The reaction of (XXXIX) with NaH and Tips-OTf in HMPA provides the triisopropylsilyl ether (XL) (1) (Scheme 12407109c). The condensation of (XL) with the intermediate 14-iodo-10-tetradecenal dimethylacetal (XXI) by means of BuLi in THF/HMPA gives the adduct (XLI), which is desulfurized by means of NCS and AgNO3 in acetone/THF/water to yield the ketonic product (XLII). The cleavage of the 4-methoxybenzyl group of (XLII) by means of DDQ in dichloromethane affords the beta-hydroxyketone (XLIII). The reduction of the ketonic group of (XLIII) with LiAlH4 and LiI in ethyl ether provides the dihydroxy compound (XLIV), which is selectively monoprotected with Tips-OTf and 2,6-lutidine in dichloromethane to give the intermediate (XLV).
| 【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 |
|---|---|---|---|---|---|---|
| (X) | 57335 | (2S,3S)-3-(1,3-dithian-2-yl)-2-[(4-methoxybenzyl)oxy]butanal | C16H22O3S2 | 详情 | 详情 | |
| (XXII) | 24401 | 1,7,7-Trimethylbicyclo[2,2,1]heptane-1',2-sultam; (1S)-(-)-2,10-Camphorsultam | C10H17NO2S | 详情 | 详情 | |
| (XXIII) | 11577 | Acryloyl chloride; Acrylyl chloride;2-Propenoyl chloride | 814-68-6 | C3H3ClO | 详情 | 详情 |
| (XXIV) | 57357 | 4-acryloyl-10,10-dimethyl-3lambda~6~-thia-4-azatricyclo[5.2.1.0~1,5~]decane-3,3-dione | C13H19NO3S | 详情 | 详情 | |
| (XXV) | 11579 | 1,3-Butadiene; Butadiene | 106-99-0 | C4H6 | 详情 | 详情 |
| (XXVI) | 57358 | 4-[(1R)-3-cyclohexen-1-ylcarbonyl]-10,10-dimethyl-3lambda~6~-thia-4-azatricyclo[5.2.1.0~1,5~]decane-3,3-dione | C17H25NO3S | 详情 | 详情 | |
| (XXVII) | 11581 | (1R)-3-Cyclohexene-1-carboxylic acid | C7H10O2 | 详情 | 详情 | |
| (XXVIII) | 11583 | (1R,5R)-6-Oxabicyclo[3.2.1]oct-3-en-7-one | C7H8O2 | 详情 | 详情 | |
| (XXIX) | 57345 | (1R,5R)-5-(hydroxymethyl)-2-cyclohexen-1-ol | C7H12O2 | 详情 | 详情 | |
| (XXX) | 57346 | (1R,5R)-5-[(phenylsulfanyl)methyl]-2-cyclohexen-1-ol | C13H16OS | 详情 | 详情 | |
| (XXXI) | 57347 | 1-({[(1R,5R)-5-methoxy-3-cyclohexen-1-yl]methyl}sulfanyl)benzene; methyl (1R,5R)-5-[(phenylsulfanyl)methyl]-2-cyclohexen-1-yl ether | C14H18OS | 详情 | 详情 | |
| (XXXII) | 57348 | {[(1R,5R)-5-methoxy-3-cyclohexen-1-yl]methyl}(dioxo)phenyl-lambda~6~-sulfane; [(1R,5R)-5-methoxy-3-cyclohexen-1-yl]methyl phenyl sulfone | C14H18O3S | 详情 | 详情 | |
| (XXXIII) | 57349 | (1R,2R,4R)-2-methoxy-4-[(phenylsulfonyl)methyl]cyclohexanol | C14H20O4S | 详情 | 详情 | |
| (XXXIV) | 57350 | ((1R,3R,4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-methoxycyclohexyl)methyl phenyl sulfone; tert-butyl({(1R,2R,4R)-2-methoxy-4-[(phenylsulfonyl)methyl]cyclohexyl}oxy)diphenylsilane | C30H38O4SSi | 详情 | 详情 | |
| (XXXV) | 57351 | (1S,3S,4S)-1-((1R,3R,4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-methoxycyclohexyl)-4-(1,3-dithian-2-yl)-3-[(4-methoxybenzyl)oxy]-1-(phenylsulfonyl)-2-pentanol | C46H60O7S3Si | 详情 | 详情 | |
| (XXXVI) | 57352 | (1S,3S,4S)-1-((1R,3R,4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-methoxycyclohexyl)-4-(1,3-dithian-2-yl)-3-[(4-methoxybenzyl)oxy]-1-(phenylsulfonyl)-2-pentanone | C46H58O7S3Si | 详情 | 详情 | |
| (XXXVII) | 57353 | (3S,4S)-1-((1R,3R,4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-methoxycyclohexyl)-4-(1,3-dithian-2-yl)-3-[(4-methoxybenzyl)oxy]-2-pentanone | C40H54O5S2Si | 详情 | 详情 | |
| (XXXVIII) | 57354 | (Z)-2-((1R,3R,4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-methoxycyclohexyl)-1-{(1S,2S)-2-(1,3-dithian-2-yl)-1-[(4-methoxybenzyl)oxy]propyl}ethenyl trifluoromethanesulfonate | C41H53F3O7S3Si | 详情 | 详情 | |
| (XXXIX) | 57355 | tert-butyl(diphenyl)silyl (1R,2R,4R)-4-{(E,3S,4S)-4-(1,3-dithian-2-yl)-3-[(4-methoxybenzyl)oxy]-2-methyl-1-pentenyl}-2-methoxycyclohexyl ether; tert-butyl[((1R,2R,4R)-4-{(E,3S,4S)-4-(1,3-dithian-2-yl)-3-[(4-methoxybenzyl)oxy]-2-methyl-1-pentenyl}-2-methoxycyclohexyl)oxy]diphenylsilane | C41H56O4S2Si | 详情 | 详情 | |
| (XL) | 57356 | [((1R,2R,4R)-4-{(E,3S,4S)-4-(1,3-dithian-2-yl)-3-[(4-methoxybenzyl)oxy]-2-methyl-1-pentenyl}-2-methoxycyclohexyl)oxy](triisopropyl)silane; (1S,2E)-1-[(1S)-1-(1,3-dithian-2-yl)ethyl]-3-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-2-methyl-2-propenyl 4-methoxybenzyl ether | C34H58O4S2Si | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)The Horner-Emmons condensation of 3,5-dimethoxybenzaldehyde (I) with triethyl phosphonopropionate (II) gives the cinnamate ester (III), which is hydrolyzed, treated with SOCl2 and condensed with the chiral auxiliary acylsultam (IV) to yield the adduct (V). The enantioselective methylation of (V) with Me2CuLi gives compound (VI) as the major diastereomer. Subsequent hydrolysis of (VI) with LiOH furnishes carboxylic acid (VII). The reduction of (VII) with LiAlH4 gives alcohol (VIII). The reaction of (VIII) with Ts-Cl and pyridine affords the tosylate (IX), which is condensed with butylmagnesium bromide (X) by means of Li2CuCl4 in THF to provide the adduct (XI). The demethylation of (XI) with BBr3 in dichloromethane gives the resorcinol derivative (XII), which is condensed with 4-hydroxy-myrtenyl pivalate (XIII) by means of BF3-Et2O to yield the cannabinoid pivalate ester (XIV). Finally, the reductive cleavage of the ester group of (XIV) with LiAlH4 yields the target cannabinoid.
| 【1】 Huffman, J.W.; Liddle, J.; Enantioselective synthesis of 11-hydroxy-(1'S,2'R)-dimethylheptyl-DELTA8-THC, a very potent CB1 agonist. Tetrahedron 2001, 57, 36, 7607. |
| 【2】 Duncan, S.G. Jr.; Huffman, J.W.; Synthesis and pharmacology of the 1',2'-dimethylheptyl-DELTA8-THC isomers: Exceptionally potent cannabinoids. Bioorg Med Chem Lett 1997, 7, 21, 2799. |
| 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) | 21720 | 3,5-dimethoxybenzaldehyde | 7311-34-4 | C9H10O3 | 详情 | 详情 |
| (II) | 18816 | ethyl 2-(diethoxyphosphoryl)propanoate | 3699-66-9 | C9H19O5P | 详情 | 详情 |
| (III) | 24400 | ethyl (E)-3-(3,5-dimethoxyphenyl)-2-methyl-2-propenoate | C14H18O4 | 详情 | 详情 | |
| (IV) | 24401 | 1,7,7-Trimethylbicyclo[2,2,1]heptane-1',2-sultam; (1S)-(-)-2,10-Camphorsultam | C10H17NO2S | 详情 | 详情 | |
| (V) | 24402 | 4-[(E)-3-(3,5-dimethoxyphenyl)-2-methyl-2-propenoyl]-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione | C22H29NO5S | 详情 | 详情 | |
| (VI) | 24403 | 4-[(2S,3S)-3-(3,5-dimethoxyphenyl)-2-methylbutanoyl]-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione | C23H33NO5S | 详情 | 详情 | |
| (VII) | 24404 | (2S,3S)-3-(3,5-dimethoxyphenyl)-2-methylbutyric acid | C13H18O4 | 详情 | 详情 | |
| (VIII) | 24405 | (2S,3S)-3-(3,5-dimethoxyphenyl)-2-methyl-1-butanol | C13H20O3 | 详情 | 详情 | |
| (IX) | 51421 | (2S,3S)-3-(3,5-dimethoxyphenyl)-2-methylbutyl 4-methylbenzenesulfonate | C20H26O5S | 详情 | 详情 | |
| (X) | 42802 | bromo(butyl)magnesium | 693-03-8 | C4H9BrMg | 详情 | 详情 |
| (XI) | 51422 | 3-[(1S,2R)-1,2-dimethylheptyl]-5-methoxyphenyl methyl ether; 1-[(1S,2R)-1,2-dimethylheptyl]-3,5-dimethoxybenzene | C17H28O2 | 详情 | 详情 | |
| (XII) | 24406 | 5-[(1S,2R)-1,2-dimethylheptyl]-1,3-benzenediol | C15H24O2 | 详情 | 详情 | |
| (XIII) | 24407 | [(1R,5S)-4-hydroxy-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl]methyl pivalate | C15H24O3 | 详情 | 详情 | |
| (XIV) | 24408 | [(6aR,10aR)-3-[(1S,2R)-1,2-dimethylheptyl]-1-hydroxy-6,6-dimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-9-yl]methyl pivalate | C30H46O4 | 详情 | 详情 |