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【结 构 式】 
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【分子编号】32438 【品名】(3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-iodo-4-methyl-4-pentenal 【CA登记号】 |
【 分 子 式 】C12H23IO2Si 【 分 子 量 】354.30339 【元素组成】C 40.68% H 6.54% I 35.82% O 9.03% Si 7.93% |
合成路线1
该中间体在本合成路线中的序号：(XXVI)The reaction of 5-iodo-4-methyl-3-(tert-butydimethylsilyloxy)-4-pentenal (XXVI) with methyl iodide and CrCl2 in dioxane/THF gives the diiodohexenal (XXVII), which is desilylated with TBAF in THF yielding the secondary alcohol (XXVIII). The esterification of (XXVIII) with protected perhydropyridazinecarboxylic acid (XXIX) by means of EDC and DIEA in dichloromethane affords the carboxylic ester (XXX), which is deprotected with TFA in dichloromethane to give the unprotected ester (XXXI). The condensation of (XXXI) with carboxylic acid (XXXII) by means of 1-hydroxy-7-azabenzotriazole (HOAt) and EDC in dichloromethane yields the protected amide (XXXIII), which is deprotected with TFA affording (XXXIV) with a free amino group. The condensation of (XXXIV) with the acid (XXXV) (obtained by oxidation of carbinol (XXXVI) with tetrapropylammonium perruthenate (TPAP)) by means of O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) and DIEA in DMF provides the amide (XXXVII), which is cyclized by means of triphenylarsine and Pd dibenzylideneacetone complex yielding the cyclic intermediate (XXXVIII).
| 【1】 Nicolaou, K.C.; et al.; Total synthesis of sanglifehrin A. Angew Chem. Int Ed Engl 1999, 38, 16, 2447. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXVI) | 32438 | (3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-iodo-4-methyl-4-pentenal | C12H23IO2Si | 详情 | 详情 | |
| (XXVII) | 32439 | tert-butyl([(1S,3E)-4-iodo-1-[(E)-2-iodo-1-methylethenyl]-3-butenyl]oxy)dimethylsilane; tert-butyl(dimethyl)silyl (1S,3E)-4-iodo-1-[(E)-2-iodo-1-methylethenyl]-3-butenyl ether | C13H24I2OSi | 详情 | 详情 | |
| (XXVIII) | 32440 | (1E,3S,5E)-1,6-diiodo-2-methyl-1,5-hexadien-3-ol | C7H10I2O | 详情 | 详情 | |
| (XXIX) | 32441 | (3S)-1,2-bis(tert-butoxycarbonyl)hexahydro-3-pyridazinecarboxylic acid | C15H26N2O6 | 详情 | 详情 | |
| (XXX) | 32442 | 1,2-di(tert-butyl) 3-[(1S,3E)-4-iodo-1-[(E)-2-iodo-1-methylethenyl]-3-butenyl] (3S)tetrahydro-1,2,3-pyridazinetricarboxylate | C22H34I2N2O6 | 详情 | 详情 | |
| (XXXI) | 32443 | (1S,3E)-4-iodo-1-[(E)-2-iodo-1-methylethenyl]-3-butenyl (3S)hexahydro-3-pyridazinecarboxylate | C12H18I2N2O2 | 详情 | 详情 | |
| (XXXII) | 32444 | (2S)-2-([(2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoyl]amino)-3-(3-hydroxyphenyl)propionic acid | C19H28N2O6 | 详情 | 详情 | |
| (XXXIII) | 32445 | (1S,3E)-4-iodo-1-[(E)-2-iodo-1-methylethenyl]-3-butenyl (3S)-1-[(2S)-2-([(2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoyl]amino)-3-(3-hydroxyphenyl)propanoyl]hexahydro-3-pyridazinecarboxylate | C31H44I2N4O7 | 详情 | 详情 | |
| (XXXIV) | 32446 | (1S,3E)-4-iodo-1-[(E)-2-iodo-1-methylethenyl]-3-butenyl (3S)-1-[(2S)-2-[[(2S)-2-amino-3-methylbutanoyl]amino]-3-(3-hydroxyphenyl)propanoyl]hexahydro-3-pyridazinecarboxylate | C26H36I2N4O5 | 详情 | 详情 | |
| (XXXV) | 32447 | (3R,4S,5R,6R)-1,4-dimethyl-3-[(E)-2-(tributylstannyl)ethenyl]-2,9-dioxabicyclo[3.3.1]nonane-6-carboxylic acid | C24H44O4Sn | 详情 | 详情 | |
| (XXXVI) | 32448 | [(3R,4S,5S,6S)-1,4-dimethyl-3-[(E)-2-(tributylstannyl)ethenyl]-2,9-dioxabicyclo[3.3.1]non-6-yl]methanol | C24H46O3Sn | 详情 | 详情 | |
| (XXXVII) | 32449 | (1S,3E)-4-iodo-1-[(E)-2-iodo-1-methylethenyl]-3-butenyl (3S)-1-[(2S)-2-([(2S)-2-[([(3R,4S,5R,6R)-1,4-dimethyl-3-[(E)-2-(tributylstannyl)ethenyl]-2,9-dioxabicyclo[3.3.1]non-6-yl]carbonyl)amino]-3-methylbutanoyl]amino)-3-(3-hydroxyphenyl)propanoyl]hexahydro-3-pyridazinecarboxylate; (1S,3E)-4-iodo-1-[(E)-2-iodo-1-methylethenyl]-3-butenyl (3S)-1-[(2S)-2-([(2S)-2-[([(3R,4S,5R,6R)-1,4-dimethyl-3-[(E)-2-(tributylstannyl)ethenyl]-2,9-dioxabicyclo[3.3.1]non-6-yl]carbonyl)amino]-3-methylbutanoyl]amino)-3-(3-hydroxyphenyl)propanoyl]hexahydro-3-pyridazinecarboxylate | C50H78I2N4O8Sn | 详情 | 详情 | |
| (XXXVIII) | 32450 | (4R,7S,10S,16S,19S,25S,26R,27R)-10-(3-hydroxybenzyl)-19-[(E)-2-iodo-1-methylethenyl]-7-isopropyl-1,26-dimethyl-18,28,29-trioxa-6,9,12,30-tetraazatetracyclo[23.3.1.1(12,16).0(4,27)]triaconta-21,23-diene-5,8,11,17-tetrone; (4R,7S,10S,16S,19S,25S,26R,27R)-10-(3-hydroxybenzyl)-19-[(E)-2-iodo-1-methylethenyl]-7-isopropyl-1,26-dimethyl-18,28,29-trioxa-6,9,12,30-tetraazatetracyclo[23.3.1.1(12,16).0(4,27)]triaconta-21,23-diene-5,8,11,17-tetrone | C38H51IN4O8 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XLIV)The condensation of 3-hydroxybenzaldehyde (XXXIV) with phosphonate (XXXV) by means of DBU in dichloromethane gives the propenoic ester (XXXVI), which is enanthioselectively reduced catalyzed by (+)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene(1,5-cyclooctadiene)rhodium (I) trifluoromethanesulfonate ((S,S)-DuP-Rh+OTf-) yielding the L-phenylalanine derivative (XXXVII). The deprotection of (XXXVII) by hydrogenation as usual affords the free amino acid (XXXVIII), which is condensed with Boc-L-valine (XXXIX) by means of EDC and HOAt to afford the dipeptide (XL). Hydrolysis of the ester group of (XXXIX) with LiOH in THF/water affords the N-protected amino acid (XLI), which is condensed with the perhydropyridazine (XLII) by means of EDC and HOAt to give the protected intermediate (XLIII). Finally, this compound is deprotected with TFA in dichloromethane to afford the desired intermediate the bis(iodovinyl) compound (XXXI). The intermediate perhydropyridazine (XLII) has been obtained as follows: The reaction of the iodoaldehyde (XLIV) with iodoform and CrCl2 in dioxane/THF gives the 1,6-diiodohexadiene (XLV), which, previous desilylation with TBAF, is condensed with the protected hexahydropyridazinecarboxylic acid (XLVI) by means of EDC, 4-Ppy and DIEA in dichloromethane to provide the protected diiodo ester (XLVII). Finally, this compound is deprotected with TFA in dichloromethane to yield the desired intermediate the perhydropyridazine (XLII).
| 【1】 Nicolaou, K.C.; et al.; Total synthesis of the novel immunosuppressant Sanglifehrin A. J Am Chem Soc 2000, 122, 16, 3830. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXXI) | 32446 | (1S,3E)-4-iodo-1-[(E)-2-iodo-1-methylethenyl]-3-butenyl (3S)-1-[(2S)-2-[[(2S)-2-amino-3-methylbutanoyl]amino]-3-(3-hydroxyphenyl)propanoyl]hexahydro-3-pyridazinecarboxylate | C26H36I2N4O5 | 详情 | 详情 | |
| (XXXIV) | 28537 | 3-hydroxybenzaldehyde | 100-83-4 | C7H6O2 | 详情 | 详情 |
| (XXXV) | 35887 | methyl 2-[[(benzyloxy)carbonyl]amino]-2-(diethoxyphosphoryl)acetate | C15H22NO7P | 详情 | 详情 | |
| (XXXVI) | 35888 | methyl (E)-2-[[(benzyloxy)carbonyl]amino]-3-(3-hydroxyphenyl)-2-propenoate | C18H17NO5 | 详情 | 详情 | |
| (XXXVII) | 35889 | methyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-(3-hydroxyphenyl)propanoate | C18H19NO5 | 详情 | 详情 | |
| (XXXVIII) | 35890 | methyl (2S)-2-amino-3-(3-hydroxyphenyl)propanoate | C10H13NO3 | 详情 | 详情 | |
| (XXXIX) | 19733 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid | C10H19NO4 | 详情 | 详情 | |
| (XL) | 35891 | methyl (2S)-2-([(2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoyl]amino)-3-(3-hydroxyphenyl)propanoate | C20H30N2O6 | 详情 | 详情 | |
| (XLI) | 32444 | (2S)-2-([(2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoyl]amino)-3-(3-hydroxyphenyl)propionic acid | C19H28N2O6 | 详情 | 详情 | |
| (XLII) | 32443 | (1S,3E)-4-iodo-1-[(E)-2-iodo-1-methylethenyl]-3-butenyl (3S)hexahydro-3-pyridazinecarboxylate | C12H18I2N2O2 | 详情 | 详情 | |
| (XLIII) | 32445 | (1S,3E)-4-iodo-1-[(E)-2-iodo-1-methylethenyl]-3-butenyl (3S)-1-[(2S)-2-([(2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoyl]amino)-3-(3-hydroxyphenyl)propanoyl]hexahydro-3-pyridazinecarboxylate | C31H44I2N4O7 | 详情 | 详情 | |
| (XLIV) | 32438 | (3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-iodo-4-methyl-4-pentenal | C12H23IO2Si | 详情 | 详情 | |
| (XLV) | 32439 | tert-butyl([(1S,3E)-4-iodo-1-[(E)-2-iodo-1-methylethenyl]-3-butenyl]oxy)dimethylsilane; tert-butyl(dimethyl)silyl (1S,3E)-4-iodo-1-[(E)-2-iodo-1-methylethenyl]-3-butenyl ether | C13H24I2OSi | 详情 | 详情 | |
| (XLVI) | 32441 | (3S)-1,2-bis(tert-butoxycarbonyl)hexahydro-3-pyridazinecarboxylic acid | C15H26N2O6 | 详情 | 详情 | |
| (XLVII) | 32442 | 1,2-di(tert-butyl) 3-[(1S,3E)-4-iodo-1-[(E)-2-iodo-1-methylethenyl]-3-butenyl] (3S)tetrahydro-1,2,3-pyridazinetricarboxylate | C22H34I2N2O6 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XXV)Chiral tetracyclic macrolactone (XXXVI): The condensation of the chiral aldehyde (XXV) with phosphonate (XXVI) in the usual way gives the nonatrienoic ester (XXVII), which is reduced with DIBAL to the corresponding alcohol and oxidized with MnO2 to the carbaldehyde (XXVIII). The condensation of (XXVIII) with the chiral oxazolidinone intermediate (VI) through its boron enolate yields the expected adduct (XXIX), which is reduced with Me4NBH(OAc)3 to afford the dihydroxy compound (XXX). The dethioacetalization of (XXX) by means of PhI(OCOCF3)2 in dichloromethane provides the cyclic ketal (XXXI). The regiocontrolled reduction of (XXXI) by means of NaBH4 in THF/water cleaves the chiral auxiliary to yield the carbinol (XXXII), which is successively oxidized with DMP and NaClO2 to afford the carboxylic acid (XXXIII) (1). The condensation of (XXXIII) with the chiral tripeptide intermediate (XV) by means of TBAF, HATU and DIEA in acetonitrile provides the corresponding amide (XXXIV), which is submitted to macrocyclization by means of LiOH, EDC and DIEA in dichloromethane to give the polycyclic macrolactone (XXXV). Finally, the Boc protecting group of (XXXV) is removed by means of Tms-OTf and lutidine in dichloromethane to afford the target chiral tetracyclic macrolactone (XXXVI)
| 【1】 Duan, M.S.; Paquette, L.A.; Enantioselective total synthesis of the cyclophilin-binding immunosuppressive agent sanglifehrin A. Angew Chem. Int Ed 2001, 40, 19, 3632. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 60104 | (2R)-1-[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-2-[2-(2-methyl-1,3-dithian-2-yl)ethyl]-1,3-pentanedione | C22H29NO4S2 | 详情 | 详情 | |
| (XV) | 60112 | methyl (3S)-1-((2S)-2-{[(2S)-2-amino-3-methylbutanoyl]amino}-3-{3-[(tert-butoxycarbonyl)oxy]phenyl}propanoyl)hexahydro-3-pyridazinecarboxylate | C25H38N4O7 | 详情 | 详情 | |
| (XXV) | 32438 | (3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-iodo-4-methyl-4-pentenal | C12H23IO2Si | 详情 | 详情 | |
| (XXVI) | 60121 | methyl (E)-4-(dipropoxyphosphoryl)-2-butenoate | C11H21O5P | 详情 | 详情 | |
| (XXVII) | 60122 | methyl (2E,4E,7S,8E)-7-{[tert-butyl(dimethyl)silyl]oxy}-9-iodo-8-methyl-2,4,8-nonatrienoate | C17H29IO3Si | 详情 | 详情 | |
| (XXVIII) | 60123 | (2E,4E,7S,8E)-7-{[tert-butyl(dimethyl)silyl]oxy}-9-iodo-8-methyl-2,4,8-nonatrienal | C16H27IO2Si | 详情 | 详情 | |
| (XXIX) | 60124 | (2R,4S,5S,6E,8E,11S,12E)-1-[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-11-{[tert-butyl(dimethyl)silyl]oxy}-5-hydroxy-13-iodo-4,12-dimethyl-2-[2-(2-methyl-1,3-dithian-2-yl)ethyl]-6,8,12-tridecatriene-1,3-dione | C38H56INO6S2Si | 详情 | 详情 | |
| (XXX) | 60125 | (4S)-4-benzyl-3-{(2R,3R,4S,5S,6E,8E,11S,12E)-11-{[tert-butyl(dimethyl)silyl]oxy}-3,5-dihydroxy-13-iodo-4,12-dimethyl-2-[2-(2-methyl-1,3-dithian-2-yl)ethyl]-6,8,12-tridecatrienoyl}-1,3-oxazolidin-2-one | C38H58INO6S2Si | 详情 | 详情 | |
| (XXXI) | 60126 | (4S)-4-benzyl-3-{[(3S,4R,5R,6R)-3-((1E,3E,6S,7E)-6-{[tert-butyl(dimethyl)silyl]oxy}-8-iodo-7-methyl-1,3,7-octatrienyl)-1,4-dimethyl-2,9-dioxabicyclo[3.3.1]non-6-yl]carbonyl}-1,3-oxazolidin-2-one | C35H50INO6Si | 详情 | 详情 | |
| (XXXII) | 60127 | [(3S,4R,5S,6S)-3-((1E,3E,6S,7E)-6-{[tert-butyl(dimethyl)silyl]oxy}-8-iodo-7-methyl-1,3,7-octatrienyl)-1,4-dimethyl-2,9-dioxabicyclo[3.3.1]non-6-yl]methanol | C25H43IO4Si | 详情 | 详情 | |
| (XXXIII) | 60128 | (3S,4R,5R,6R)-3-((1E,3E,6S,7E)-6-{[tert-butyl(dimethyl)silyl]oxy}-8-iodo-7-methyl-1,3,7-octatrienyl)-1,4-dimethyl-2,9-dioxabicyclo[3.3.1]nonane-6-carboxylic acid | C25H41IO5Si | 详情 | 详情 | |
| (XXXIV) | 60129 | methyl (3S)-1-[(2S)-3-{3-[(tert-butoxycarbonyl)oxy]-1,3-cyclohexadien-1-yl}-2-({(2S)-2-[({(3S,4R,5R,6R)-3-[(1E,3E,6S,7E)-6-hydroxy-8-iodo-7-methyl-1,3,7-octatrienyl]-1,4-dimethyl-2,9-dioxabicyclo[3.3.1]non-6-yl}carbonyl)amino]-3-methylbutanoyl}amino)propanoyl]hexahydro-3-pyridazinecarboxylate | C44H65IN4O11 | 详情 | 详情 | |
| (XXXV) | 60130 | tert-butyl 3-({(4R,7S,10S,16S,19S,25S,26R,27R)-19-[(E)-2-iodo-1-methylethenyl]-7-isopropyl-1,26-dimethyl-5,8,11,17-tetraoxo-18,28,29-trioxa-6,9,12,30-tetraazatetracyclo[23.3.1.1~12,16~.0~4,27~]triaconta-21,23-dien-10-yl}methyl)phenyl carbonate | C43H59IN4O10 | 详情 | 详情 | |
| (XXXVI) | 32450 | (4R,7S,10S,16S,19S,25S,26R,27R)-10-(3-hydroxybenzyl)-19-[(E)-2-iodo-1-methylethenyl]-7-isopropyl-1,26-dimethyl-18,28,29-trioxa-6,9,12,30-tetraazatetracyclo[23.3.1.1(12,16).0(4,27)]triaconta-21,23-diene-5,8,11,17-tetrone; (4R,7S,10S,16S,19S,25S,26R,27R)-10-(3-hydroxybenzyl)-19-[(E)-2-iodo-1-methylethenyl]-7-isopropyl-1,26-dimethyl-18,28,29-trioxa-6,9,12,30-tetraazatetracyclo[23.3.1.1(12,16).0(4,27)]triaconta-21,23-diene-5,8,11,17-tetrone | C38H51IN4O8 | 详情 | 详情 |