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【结 构 式】 
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【分子编号】19020 【品名】(1R,4S)-4-[1-Hydroxy-1-[4-(3-methyl-2-butenyloxy)phenyl]methyl]-2-methyldispiro[2,5-diazabicyclo[3,2,1]octane-6,1'-cyclohexane-4',2''-[1,3]-dioxolan]-3-one 【CA登记号】 |
【 分 子 式 】C26H36N2O5 【 分 子 量 】456.58232 【元素组成】C 68.4% H 7.95% N 6.14% O 17.52% |
合成路线1
该中间体在本合成路线中的序号：(XVI)Alkylation of acid (I) with allyl bromide in the presence of two equivalents of lithium diisopropylamide (LDA) in THF gave (II). Curtius rearrangement of acid (II) using diphenylphosphoryl azide (DPPA), followed by treatment of the intermediate isocyanate with benzyl alcohol afforded benzyl carbamate (III). Dihydroxylation of (III) with N-methylmorpholine-N-oxide (NMO) and a catalytic amount OsO4 provided diol (IV), which was selectively tosylated at the primary hydroxyl group with p-toluenesulfonyl chloride in the presence of dimethylaminopyridine (DMAP). Protection of secondary hydroxyl group of the resulting tosylate (V) was effected with tert-butyldimethylsilyl chloride in the presence of imidazole, affording silyl ether (VI). Then, benzyl carbamate was removed by hydrogenolysis using palladium on carbon in methanol to give free amine (VII), and further cyclization in the presence of 1,8-diazabicycloundec-7-ene (DBU) in refluxing benzene afforded azaspiro compound (VIII). This was alkylated with ethyl bromoacetate in the presence of K2CO3, followed by deprotection of the silyl ether with tetrabutylammonium fluoride to give (IX). Alcohol (IX) was then converted into azide (X) under Mitsunobu's conditions, and subsequently reduced to primary amine (XI) by catalytic hydrogenation. Hydrolysis of ester (XI) with LiOH gave acid (XII), which was cyclized by treatment with diphenylphosphoryl azide and triethylamine to give rise to the tetracyclic system (XIII). Treatment of (XIII) with iodomethane in the presence of sodium hydride provided the N-methylated compound (XIV). Condensation of (XIV) with aldehyde (XV) was performed using LDA as a base in THF at -78 C to form two separable aldol adducts (XVI), which were determined to be epimeric at the benzylic position.
| 【1】 Nagumo, S.; et al.; Total synthesis of antimuscarinic alkaloid, (±)-TAN1251A. Tetrahedron 2002, 58, 24, 4917. |
| 【2】 Nagumo, S.; et al.; Total synthesis of (±)-TAN1251A. Tetrahedron Lett 1998, 39, 25, 4493. |
| 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) | 19005 | 1,4-dioxaspiro[4.5]decane-8-carboxylic acid | C9H14O4 | 详情 | 详情 | |
| (II) | 19006 | 8-allyl-1,4-dioxaspiro[4.5]decane-8-carboxylic acid | C12H18O4 | 详情 | 详情 | |
| (III) | 19007 | benzyl 8-allyl-1,4-dioxaspiro[4.5]dec-8-ylcarbamate | C12H18O4 | 详情 | 详情 | |
| (IV) | 19008 | benzyl 8-(2,3-dihydroxypropyl)-1,4-dioxaspiro[4.5]dec-8-ylcarbamate | C19H27NO6 | 详情 | 详情 | |
| (V) | 19009 | 3-(8-[[(benzyloxy)carbonyl]amino]-1,4-dioxaspiro[4.5]dec-8-yl)-2-hydroxypropyl 4-methylbenzenesulfonate | C26H33NO8S | 详情 | 详情 | |
| (VI) | 19010 | 3-(8-[[(benzyloxy)carbonyl]amino]-1,4-dioxaspiro[4.5]dec-8-yl)-2-[[tert-butyl(dimethyl)silyl]oxy]propyl 4-methylbenzenesulfonate | C32H47NO8SSi | 详情 | 详情 | |
| (VII) | 19011 | 3-(8-amino-1,4-dioxaspiro[4.5]dec-8-yl)-2-[[tert-butyl(dimethyl)silyl]oxy]propyl 4-methylbenzenesulfonate | C24H41NO6SSi | 详情 | 详情 | |
| (VIII) | 19012 | tert-butyl(dimethyl)silyl 1,4-dioxa-9-azadispiro[4.2.4.2]tetradec-11-yl ether; 11-[[tert-butyl(dimethyl)silyl]oxy]-1,4-dioxa-9-azadispiro[4.2.4.2]tetradecane | C17H33NO3Si | 详情 | 详情 | |
| (IX) | 19013 | ethyl 2-(11-hydroxy-1,4-dioxa-9-azadispiro[4.2.4.2]tetradec-9-yl)acetate | C15H25NO5 | 详情 | 详情 | |
| (X) | 19014 | ethyl 2-(11-azido-1,4-dioxa-9-azadispiro[4.2.4.2]tetradec-9-yl)acetate | C15H24N4O4 | 详情 | 详情 | |
| (XI) | 19015 | ethyl 2-(11-amino-1,4-dioxa-9-azadispiro[4.2.4.2]tetradec-9-yl)acetate | C15H26N2O4 | 详情 | 详情 | |
| (XII) | 19016 | 2-(11-amino-1,4-dioxa-9-azadispiro[4.2.4.2]tetradec-9-yl)acetic acid | C13H22N2O4 | 详情 | 详情 | |
| (XIII) | 19017 | Dispiro[2,5-diazabicyclo[3,2,1]octane-6,1'-cyclohexane-4',2''-[1,3]-dioxolan]-3-one | C13H20N2O3 | 详情 | 详情 | |
| (XIV) | 19018 | 2-Methyldispiro[2,5-diazabicyclo[3,2,1]octane-6,1'-cyclohexane-4',2''-[1,3]-dioxolan]-3-one | C14H22N2O3 | 详情 | 详情 | |
| (XV) | 19019 | 4-[(3-methyl-2-butenyl)oxy]benzaldehyde | C12H14O2 | 详情 | 详情 | |
| (XVI) | 19020 | (1R,4S)-4-[1-Hydroxy-1-[4-(3-methyl-2-butenyloxy)phenyl]methyl]-2-methyldispiro[2,5-diazabicyclo[3,2,1]octane-6,1'-cyclohexane-4',2''-[1,3]-dioxolan]-3-one | C26H36N2O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XVI)Mesylation of either isomer, followed by elimination in mesylate (XVII) with potassium tert-butoxide gave enone (XVIII). Reduction of carbonyl group was then effected with AlH3, prepared from lithium aluminum hydride and aluminum chloride yielding (XIX), and finally, deprotection of acetal (XIX) with HCl in acetone afforded the desired compound.
| 【1】 Nagumo, S.; et al.; Total synthesis of antimuscarinic alkaloid, (±)-TAN1251A. Tetrahedron 2002, 58, 24, 4917. |
| 【2】 Nagumo, S.; et al.; Total synthesis of (±)-TAN1251A. Tetrahedron Lett 1998, 39, 25, 4493. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVI) | 19020 | (1R,4S)-4-[1-Hydroxy-1-[4-(3-methyl-2-butenyloxy)phenyl]methyl]-2-methyldispiro[2,5-diazabicyclo[3,2,1]octane-6,1'-cyclohexane-4',2''-[1,3]-dioxolan]-3-one | C26H36N2O5 | 详情 | 详情 | |
| (XVII) | 19021 | (1R,4S)-4-[1-(Methanesulfonyloxy)-1-[4-(3-methyl-2-butenyloxy)phenyl]methyl]-2-methyldispiro[2,5-diazabicyclo[3,2,1]octane-6,1'-cyclohexane-4',2''-[1,3]-dioxolan]-3-one | C27H38N2O7S | 详情 | 详情 | |
| (XVIII) | 19022 | (1R,4S)-2-Methyl-4-[4-(3-methyl-2-butenyloxy)benzylidene]dispiro[2,5-diazabicyclo[3,2,1]octane-6,1'-cyclohexane-4',2''-[1,3]-dioxolan]-3-one | C26H34N2O4 | 详情 | 详情 | |
| (XIX) | 19023 | (1R,4S)-2-Methyl-4-[4-(3-methyl-2-butenyloxy)benzylidene]dispiro[2,5-diazabicyclo[3,2,1]octane-6,1'-cyclohexane-4',2''-[1,3]-dioxolane] | C26H36N2O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XVII)The reaction of L-tyrosine (I) with methyl chloroformate (II) by means of NaOH in water gives the carbamate (III), which is methylated at the remaining phenol and carboxylic groups with dimethyl sulfate and K2CO3 in refluxing acetone to yield the 4-O-methyl tyrosine derivative (IV). The hydrolysis of the methyl ester of (IV) with NaOH in dioxane/water, followed by reaction with O-methylhydroxylamine by means of DCC and HOBT, affords the methyl hydroxamate (V). The cyclization of (V) by means of bis(trifluoroacetoxy)iodobenzene in dichloromethane/methanol provides the spirodienone (VI), which is hydrogenated with H2 over Pd/C in ethyl acetate to give the saturated ketone (VII). The protection of the ketonic group of (VII) with ethyleneglycol and PPTS yields the cyclic ketal (VIII), which is reduced with LiAlH4 in THF to afford the methoxyamine (IX). The protection of the N-methylamine of (IX) with benzyl chloroformate and TEA provides the carbamate (X), which is treated with Zn in acetic acid in order to cleave the N-methoxyamine group and yield the spiropyrrolidine (XI). The alkylation of the pyrrolidine NH with benzyl chloroformate (XII) and K2CO3 in warm acetonitrile affords the adduct (XIII), which is treated with H2 over Pd/C in methanol in order to remove the benzyl and benzyloxycarbonyl protecting groups, providing the amino acid (XIV). The cyclization of (XIV) by means of DPPA and NaHCO3 in DMF/dichloromethane gives the tetracyclic compound (XV), which is condensed with 4-(prenyloxy)benzaldehyde (XVI) by means of LDA in THF yielding the aldol condensation product (XVII).
| 【1】 Basak, A.; Wardrop, D.J.; N-methoxy-N-acylnitrenium ions: Application to the formal synthesis of (-)-TAN1251A. Org Lett 2001, 3, 7, 1053. |
| 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) | 48794 | (S)-(-)-Tyrosine; (S)-2-Amino-3-(4-hydroxyphenyl)propionic acid; 3-(4-Hydroxyphenyl)-L-alanine; L-(-)-Tyrosine; L-3-(4-Hydroxyphenyl)alanine; L-4-Hydroxy-17O-phenylalanine; L-beta-(p-Hydroxyphenyl)alanine; L-Hydroxy Phenyl Alanine; L-tyrosine | 60-18-4 | C9H11NO3 | 详情 | 详情 |
| (II) | 16993 | methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate | 79-22-1 | C2H3ClO2 | 详情 | 详情 |
| (III) | 48795 | (2S)-3-(4-hydroxyphenyl)-2-[(methoxycarbonyl)amino]propionic acid | C11H13NO5 | 详情 | 详情 | |
| (IV) | 48796 | methyl (2S)-2-[(methoxycarbonyl)amino]-3-(4-methoxyphenyl)propanoate | C13H17NO5 | 详情 | 详情 | |
| (V) | 48797 | methyl (1S)-2-(methoxyamino)-1-(4-methoxybenzyl)-2-oxoethylcarbamate | C13H18N2O5 | 详情 | 详情 | |
| (VI) | 48798 | methyl (3S)-1-methoxy-2,8-dioxo-1-azaspiro[4.5]deca-6,9-dien-3-ylcarbamate | C12H14N2O5 | 详情 | 详情 | |
| (VII) | 48799 | methyl (3S)-1-methoxy-2,8-dioxo-1-azaspiro[4.5]dec-3-ylcarbamate | C12H18N2O5 | 详情 | 详情 | |
| (VIII) | 48800 | methyl (11S)-9-methoxy-10-oxo-1,4-dioxa-9-azadispiro[4.2.4.2]tetradec-11-ylcarbamate | C14H22N2O6 | 详情 | 详情 | |
| (IX) | 48801 | (11S)-9-methoxy-N-methyl-1,4-dioxa-9-azadispiro[4.2.4.2]tetradecan-11-amine; N-[(11S)-9-methoxy-1,4-dioxa-9-azadispiro[4.2.4.2]tetradec-11-yl]-N-methylamine | C13H24N2O3 | 详情 | 详情 | |
| (X) | 48802 | benzyl (11S)-9-methoxy-1,4-dioxa-9-azadispiro[4.2.4.2]tetradec-11-yl(methyl)carbamate | C21H30N2O5 | 详情 | 详情 | |
| (XI) | 48803 | benzyl (11S)-1,4-dioxa-9-azadispiro[4.2.4.2]tetradec-11-yl(methyl)carbamate | C20H28N2O4 | 详情 | 详情 | |
| (XII) | 12869 | benzyl 2-bromoacetate | 5437-45-6 | C9H9BrO2 | 详情 | 详情 |
| (XIII) | 48804 | benzyl 2-[(11S)-11-[[(benzyloxy)carbonyl](methyl)amino]-1,4-dioxa-9-azadispiro[4.2.4.2]tetradec-9-yl]acetate | C29H36N2O6 | 详情 | 详情 | |
| (XIV) | 48805 | 2-[(11S)-11-(methylamino)-1,4-dioxa-9-azadispiro[4.2.4.2]tetradec-9-yl]acetic acid | C14H24N2O4 | 详情 | 详情 | |
| (XV) | 48806 | C14H22N2O3 | 详情 | 详情 | ||
| (XVI) | 19019 | 4-[(3-methyl-2-butenyl)oxy]benzaldehyde | C12H14O2 | 详情 | 详情 | |
| (XVII) | 19020 | (1R,4S)-4-[1-Hydroxy-1-[4-(3-methyl-2-butenyloxy)phenyl]methyl]-2-methyldispiro[2,5-diazabicyclo[3,2,1]octane-6,1'-cyclohexane-4',2''-[1,3]-dioxolan]-3-one | C26H36N2O5 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XVII)The reaction of aldol (XVII) with Ms-Cl and TEA in dichloromethane gives the mesylate (XVIII), which is treated with tBu-OK in THF to obtain the unsaturated amide (XIX). The reduction of the amide group of (XIX) with AlH3 in ethyl ether yields the corresponding unsaturated enamine (XX), which is finally deprotected by treatment with HCl in acetone.
| 【1】 Basak, A.; Wardrop, D.J.; N-methoxy-N-acylnitrenium ions: Application to the formal synthesis of (-)-TAN1251A. Org Lett 2001, 3, 7, 1053. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVII) | 19020 | (1R,4S)-4-[1-Hydroxy-1-[4-(3-methyl-2-butenyloxy)phenyl]methyl]-2-methyldispiro[2,5-diazabicyclo[3,2,1]octane-6,1'-cyclohexane-4',2''-[1,3]-dioxolan]-3-one | C26H36N2O5 | 详情 | 详情 | |
| (XVIII) | 19021 | (1R,4S)-4-[1-(Methanesulfonyloxy)-1-[4-(3-methyl-2-butenyloxy)phenyl]methyl]-2-methyldispiro[2,5-diazabicyclo[3,2,1]octane-6,1'-cyclohexane-4',2''-[1,3]-dioxolan]-3-one | C27H38N2O7S | 详情 | 详情 | |
| (XIX) | 48807 | C26H34N2O4 | 详情 | 详情 | ||
| (XX) | 48808 | C26H36N2O3 | 详情 | 详情 |