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【结 构 式】

【药物名称】Sanglifehrin A

【化学名称】(3S,6S,9R,10R,11S,12S,18S,21S)-18-[(1E,3E,7S,8S)-9-[(2S,3R,4S,5S,6R,9S,11S)-9-Ethyl-4-hydroxy-3,5,11-trimethyl-8-oxo-1-oxa-7-azaspiro[5.5]undec-2-yl]-8-hydroxy-1,7-dimethyl-1,3-nonadienyl]-10,12-dihydroxy-3-(3-hydroxybenzyl)-6-isopropyl-11-methyl-9-(3-oxobutyl)-19-oxa-1,4,7,25-tetraazabicyclo[19.3.1]pentacosa-13,15-diene-2,5,8,20-tetrone

【CA登记号】

【 分 子 式 】C60H91N5O13

【 分 子 量 】1090.41997

【开发单位】Novartis (Originator)

【药理作用】IMMUNOMODULATING AGENTS, Immunosuppressants, Non-Steroidal Antiinflammatory Drugs

合成路线1合成路线2合成路线3合成路线4合成路线5合成路线6合成路线7合成路线8合成路线9合成路线10合成路线11合成路线12合成路线13合成路线14合成路线15合成路线16合成路线17合成路线18

合成路线1

The stereocontrolled reaction of 3-pentanone (I) with 2-methylpropionaldehyde (II) by means of (+)-bis(diisopinocampheyl)borane triflate and DIEA in THF, followed by silylation with Tes-Cl and imidazole gives the silylated heptenone (III), which is condensed with 3-benzyloxypropionaldehyde (IV) by means of chlorodicyclohexylborane yielding the diol (V). The protection of the hydroxy groups of (V) with 2,2-dimethoxypropane and camphorsulfonic acid (CSA) with simultaneous desilylation affords the isopropylidene ketal (VI), which is acylated with propionic anhydride and triethylamine giving the propionate (VII). The Claisen rearrangement of (VII) by means of LDA and TBDMS-Cl in HMPT yields the carboxylic acid (VIII), which by regio- and stereoselective hydroboration of its double bond with BH3, followed by oxidation with N-methylmorpholine N-oxide (NMO) and tetrapropylammonium perruthenate (TPAP) in dichloromethane affords the lactone (IX). The reaction of (IX) with Me2Al-NH2, followed by debenzylation with H2 over Pd/C provides the dihydroxyamide (X), which is oxidized with Dess-Martin periodinane (DMP) in dichloromethane giving the keto aldehyde (XI). The cyclization of (XI) with HF in acetonitrile yields the spiro carbaldehyde (XII), which is silylated with Tes-OTf in dichloromethane providing the silyl ether (XIII).

参考文献 中间体
【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
(I) 32415 Propione; Dimethylacetone; Diethyl ketone; 3-Pentanone 96-22-0 C5H10O 详情 详情
(II) 11387 2-Methylacrylaldehyde; Methacrylaldehyde 78-85-3 C4H6O 详情 详情
(III) 32416 (4R,5R)-4,6-dimethyl-5-[(triethylsilyl)oxy]-6-hepten-3-one C15H30O2Si 详情 详情
(IV) 14688 3-(benzyloxy)propanal C10H12O2 详情 详情
(V) 32417 (3S,4S,5S,6S,7R)-1-(benzyloxy)-4,6,8-trimethyl-7-[(triethylsilyl)oxy]-8-nonene-3,5-diol C25H44O4Si 详情 详情
(VI) 31418 [6-(benzyloxy)-2-(4-hydroxyphenyl)-1-benzothiophen-3-yl][3-methoxy-4-(1-pyrrolidinylmethyl)phenyl]methanone C34H31NO4S 详情 详情
(VII) 31419 4-[6-(benzyloxy)-3-[3-methoxy-4-(1-pyrrolidinylmethyl)benzyl]-1-benzothiophen-2-yl]phenol C34H33NO3S 详情 详情
(VIII) 31420 methyl (2S)-3-hydroxy-2-(tritylamino)propanoate C23H23NO3 详情 详情
(IX) 32421 (3S,5S,6S)-6-((1S)-1-[(4S,5R,6S)-6-[2-(benzyloxy)ethyl]-2,2,5-trimethyl-1,3-dioxan-4-yl]ethyl)-3-ethyl-5-methyltetrahydro-2H-pyran-2-one C26H40O5 详情 详情
(X) 32422 (2S,4S,5S,6R)-2-ethyl-5-hydroxy-6-[(4R,5R,6S)-6-(2-hydroxyethyl)-2,2,5-trimethyl-1,3-dioxan-4-yl]-4-methylheptanamide C19H37NO5 详情 详情
(XI) 32423 (2S,4S,6S)-2-ethyl-4-methyl-5-oxo-6-[(4S,5R,6S)-2,2,5-trimethyl-6-(2-oxoethyl)-1,3-dioxan-4-yl]heptanamide C19H33NO5 详情 详情
(XII) 32424 2-[(2S,3R,4S,5S,6R,9S,11S)-9-ethyl-4-hydroxy-3,5,11-trimethyl-8-oxo-1-oxa-7-azaspiro[5.5]undec-2-yl]acetaldehyde C16H27NO4 详情 详情
(XIII) 32425 2-[(2S,3S,4S,5S,6R,9S,11S)-9-ethyl-3,5,11-trimethyl-8-oxo-4-[(triethylsilyl)oxy]-1-oxa-7-azaspiro[5.5]undec-2-yl]acetaldehyde C22H41NO4Si 详情 详情

合成路线2

The condensation of (XIII) with the chiral borane (XIV) gives the addition product (XV), which is silylated with TBDMS-OTf affording (XVI). Ozonolysis of the double bond of (XVI) with O3 yields the aldehyde (XVII), which is condensed with TMS-CH2CH=N-t-Bu to provide he unsaturated aldehyde (XVIII).

参考文献 中间体
【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
40677 N-(tert-butyl)-N-[(E)-2-(trimethylsilyl)ethylidene]amine; 2-methyl-N-[(E)-2-(trimethylsilyl)ethylidene]-2-propanamine C9H21NSi 详情 详情
(XIII) 32425 2-[(2S,3S,4S,5S,6R,9S,11S)-9-ethyl-3,5,11-trimethyl-8-oxo-4-[(triethylsilyl)oxy]-1-oxa-7-azaspiro[5.5]undec-2-yl]acetaldehyde C22H41NO4Si 详情 详情
(XIV) 32426 (E)-2-butenyl[bis[(1S,2R,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]]borane C24H41B 详情 详情
(XV) 32427 (2S,3S,4S,5S,6R,9S,11S)-9-ethyl-2-[(2S,3S)-2-hydroxy-3-methyl-4-pentenyl]-3,5,11-trimethyl-4-[(triethylsilyl)oxy]-1-oxa-7-azaspiro[5.5]undecan-8-one C26H49NO4Si 详情 详情
(XVI) 32428 (2S,3S,4S,5S,6R,9S,11S)-2-((2S,3S)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-pentenyl)-9-ethyl-3,5,11-trimethyl-4-[(triethylsilyl)oxy]-1-oxa-7-azaspiro[5.5]undecan-8-one C32H63NO4Si2 详情 详情
(XVII) 32429 (2R,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-[(2S,3S,4S,5S,6R,9S,11S)-9-ethyl-3,5,11-trimethyl-8-oxo-4-[(triethylsilyl)oxy]-1-oxa-7-azaspiro[5.5]undec-2-yl]-2-methylbutanal C31H61NO5Si2 详情 详情
(XVIII) 32430 (E,4S,5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-[(2S,3S,4S,5S,6R,9S,11S)-9-ethyl-3,5,11-trimethyl-8-oxo-4-[(triethylsilyl)oxy]-1-oxa-7-azaspiro[5.5]undec-2-yl]-4-methyl-2-hexenal C33H63NO5Si2 详情 详情

合成路线3

The hydrogenation of the double bond of (XVIII) with H2 and Lindlar catalyst affords the corresponding saturated aldehyde (XIX), which is condensed with the diazophosphonate (XX) giving the acetylenic derivative (XXI). The bromination of (XXI) with N-bromosuccinimide (NBS) and AgNO3 yields the bromoacetylenic compound (XXII), which is desilylated with HF and TBAF affording the dihydroxy derivative (XXIII). The resilylation of (XXIII) with CF3CO-N(Me)-Tms gives the bis(trimethylsilyl) derivative (XXIV), which is finally converted into the desired intermediate, the stannane (XXV) by reaction with tributyltin hydride, PPh3 and Pd dibenzylideneacetone complex.

参考文献 中间体
【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
21859 2,2,2-trifluoro-N-methyl-N-(trimethylsilyl)acetamide C6H12F3NOSi 详情 详情
(XVIII) 32430 (E,4S,5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-[(2S,3S,4S,5S,6R,9S,11S)-9-ethyl-3,5,11-trimethyl-8-oxo-4-[(triethylsilyl)oxy]-1-oxa-7-azaspiro[5.5]undec-2-yl]-4-methyl-2-hexenal C33H63NO5Si2 详情 详情
(XIX) 32431 (4S,5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-[(2S,3S,4S,5S,6R,9S,11S)-9-ethyl-3,5,11-trimethyl-8-oxo-4-[(triethylsilyl)oxy]-1-oxa-7-azaspiro[5.5]undec-2-yl]-4-methylhexanal C33H65NO5Si2 详情 详情
(XX) 32432 1-Diazo-2-oxopropylphosphonic acid dimethyl ester C5H9N2O4P 详情 详情
(XXI) 32433 (2S,3S,4S,5S,6R,9S,11S)-2-((2S,3S)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-6-heptynyl)-9-ethyl-3,5,11-trimethyl-4-[(triethylsilyl)oxy]-1-oxa-7-azaspiro[5.5]undecan-8-one C34H65NO4Si2 详情 详情
(XXII) 32434 (2S,3S,4S,5S,6R,9S,11S)-2-((2S,3S)-7-bromo-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-6-heptynyl)-9-ethyl-3,5,11-trimethyl-4-[(triethylsilyl)oxy]-1-oxa-7-azaspiro[5.5]undecan-8-one C34H64BrNO4Si2 详情 详情
(XXIII) 32435 (2S,3R,4S,5S,6R,9S,11S)-2-[(2S,3S)-7-bromo-2-hydroxy-3-methyl-6-heptynyl]-9-ethyl-4-hydroxy-3,5,11-trimethyl-1-oxa-7-azaspiro[5.5]undecan-8-one C22H36BrNO4 详情 详情
(XXIV) 32436 (2S,3R,4S,5S,6R,9S,11S)-2-[(2S,3S)-7-bromo-3-methyl-2-[(trimethylsilyl)methyl]-6-heptynyl]-9-ethyl-3,5,11-trimethyl-4-[(trimethylsilyl)methyl]-1-oxa-7-azaspiro[5.5]undecan-8-one C30H56BrNO2Si2 详情 详情
(XXV) 32437 (2S,3R,4S,5S,6R,9S,11S)-9-ethyl-3,5,11-trimethyl-2-[(2S,3S,6E)-3-methyl-7-(tributylstannyl)-2-[(trimethylsilyl)methyl]-6-heptenyl]-4-[(trimethylsilyl)methyl]-1-oxa-7-azaspiro[5.5]undecan-8-one C42H85NO2Si2Sn 详情 详情

合成路线4

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).

参考文献 中间体
【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5

The condensation of intermediate (XXV) with intermediate (XXXVIII) by means of triphenylarsine and Pd dibenzylideneacetone complex in DMF gives the addition compound (XXXIX), which is desilylated with TBAF in THF yielding the immediate precursor (XL). Finally, the cyclic ketal group of (XL) is opened by means of H2SO4 in THF/water.

参考文献 中间体
【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
(XXV) 32437 (2S,3R,4S,5S,6R,9S,11S)-9-ethyl-3,5,11-trimethyl-2-[(2S,3S,6E)-3-methyl-7-(tributylstannyl)-2-[(trimethylsilyl)methyl]-6-heptenyl]-4-[(trimethylsilyl)methyl]-1-oxa-7-azaspiro[5.5]undecan-8-one C42H85NO2Si2Sn 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
(XXXIX) 32451 (1R,4R,7S,10S,16S,19S,26R,27R)-19-{(1E,3E,7S,8S)-9-{(2S,3R,4S,5S,6R,9S,11S)-9-ethyl-3,5,11-trimethyl-8-oxo-4-[(trimethylsilyl)methyl]-1-oxa-7-azaspiro[5.5]undec-2-yl}-1,7-dimethyl-8-[(trimethylsilyl)methyl]-1,3-nonadienyl}-10-(3-hydroxybenzyl)-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 C68H109N5O10Si2 详情 详情
(XL) 32452 (4R,7S,10S,16S,19S,25S,26R,27R)-19-{(1E,3E,7S,8S)-9-[(2S,3R,4S,5S,6R,9S,11S)-9-ethyl-4-hydroxy-3,5,11-trimethyl-8-oxo-1-oxa-7-azaspiro[5.5]undec-2-yl]-8-hydroxy-1,7-dimethyl-1,3-nonadienyl}-10-(3-hydroxybenzyl)-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 C60H89N5O12 详情 详情

合成路线6

The condensation of intermediates tributyl stannane (I) with iodovinyl compound (II) by means of Pd2(dba)3 and AsPh3 in chloroform gives precursor (III), which is then treated with aqueous H2SO4 in order to open the cyclic ketal group of (III).

参考文献 中间体
【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
(I) 35874 (2S,3R,4S,5S,6R,9S,11S)-9-ethyl-4-hydroxy-2-[(2S,3S,6E)-2-hydroxy-3-methyl-7-(tributylstannyl)-6-heptenyl]-3,5,11-trimethyl-1-oxa-7-azaspiro[5.5]undecan-8-one C34H65NO4Sn 详情 详情
(II) 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
(III) 32452 (4R,7S,10S,16S,19S,25S,26R,27R)-19-{(1E,3E,7S,8S)-9-[(2S,3R,4S,5S,6R,9S,11S)-9-ethyl-4-hydroxy-3,5,11-trimethyl-8-oxo-1-oxa-7-azaspiro[5.5]undec-2-yl]-8-hydroxy-1,7-dimethyl-1,3-nonadienyl}-10-(3-hydroxybenzyl)-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 C60H89N5O12 详情 详情

合成路线7

The regiocontrolled condensation of 3-pentanone (IV) with methacrolein (V) catalyzed by (+)-Ipc2B-OTf and DIEA in THF gives the chiral 3-heptenone (VI), which is reductocondensed with 3-benzyloxypropanal (VII) by means of Cy2BCl, Et3N and LiBH4 in ethyl ether to afford the partially protected tetrol (VIII). The ketalization of (VIII) with 2,2-dimethoxypropane and CSA in acetone provides the desilylated cyclic ketal (IX), which is esterified with butyric anhydride and Et3N to the butyrate (X). The isomerization of (X) by means of LDA, and TBDMS-Cl in HMPA/THF, followed by a treatment in hot toluene yields the chiral undecenoic acid (XI), which is reduced by means of borane in THF to the undecanediol (XII). The lactonization of (XII) by means of NMO and tetrapropylammonium perruthenate (TPAP) in dichloromethane affords the lactone (XIII), which is treated with Me2Al-NH2 in dichloromethane to give the amide (XIV). The debenzylation of (XIV) with H2 over Pd(OH)2 in ethanol yields the dihydroxyamide (XV), which is oxidized with Dess Martin periodinane (DMP) and pyridine in dichloromethane affording the ketoaldehyde (XVI). Spirocyclization of (XVI) catalyzed by HF in acetonitrile gives the aldehydic spirolactam (XVII). Alternatively, the oxidation of the secondary alcohol of (XIV) with pyridinium dichromate (PDC) in dichloromethane yields the ketoamide (XVIII), which is submitted to spirocyclization with HF as before, and hydrogenolytic debenzylation to afford the intermediate spirolactam (XIX). The oxidation of (XIX) with O2 catalyzed by RuCl2 (PPh)3 in benzene gives the previously reported aldehydic spirolactam (XVII).

参考文献 中间体
【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
(IV) 32415 Propione; Dimethylacetone; Diethyl ketone; 3-Pentanone 96-22-0 C5H10O 详情 详情
(V) 11387 2-Methylacrylaldehyde; Methacrylaldehyde 78-85-3 C4H6O 详情 详情
(VI) 32416 (4R,5R)-4,6-dimethyl-5-[(triethylsilyl)oxy]-6-hepten-3-one C15H30O2Si 详情 详情
(VII) 14688 3-(benzyloxy)propanal C10H12O2 详情 详情
(VIII) 32417 (3S,4S,5S,6S,7R)-1-(benzyloxy)-4,6,8-trimethyl-7-[(triethylsilyl)oxy]-8-nonene-3,5-diol C25H44O4Si 详情 详情
(IX) 32418 (3R,4R)-4-[(4R,5R,6S)-6-[2-(benzyloxy)ethyl]-2,2,5-trimethyl-1,3-dioxan-4-yl]-2-methyl-1-penten-3-ol C22H34O4 详情 详情
(X) 32419 (1R)-1-((1S)-1-[(4S,5R,6S)-6-[2-(benzyloxy)ethyl]-2,2,5-trimethyl-1,3-dioxan-4-yl]ethyl)-2-methyl-2-propenyl butyrate C26H40O5 详情 详情
(XI) 32420 (2S,4E,6R)-6-[(4R,5R,6S)-6-[2-(benzyloxy)ethyl]-2,2,5-trimethyl-1,3-dioxan-4-yl]-2-ethyl-4-methyl-4-heptenoic acid C26H40O5 详情 详情
(XII) 35875 (2S,4S,5S,6R)-6-[(4R,5R,6S)-6-[2-(benzyloxy)ethyl]-2,2,5-trimethyl-1,3-dioxan-4-yl]-2-ethyl-4-methyl-1,5-heptanediol C26H44O5 详情 详情
(XIII) 32421 (3S,5S,6S)-6-((1S)-1-[(4S,5R,6S)-6-[2-(benzyloxy)ethyl]-2,2,5-trimethyl-1,3-dioxan-4-yl]ethyl)-3-ethyl-5-methyltetrahydro-2H-pyran-2-one C26H40O5 详情 详情
(XIV) 35876 (2S,4S,5S,6R)-6-[(4R,5R,6S)-6-[2-(benzyloxy)ethyl]-2,2,5-trimethyl-1,3-dioxan-4-yl]-2-ethyl-5-hydroxy-4-methylheptanamide C26H43NO5 详情 详情
(XV) 32422 (2S,4S,5S,6R)-2-ethyl-5-hydroxy-6-[(4R,5R,6S)-6-(2-hydroxyethyl)-2,2,5-trimethyl-1,3-dioxan-4-yl]-4-methylheptanamide C19H37NO5 详情 详情
(XVI) 32423 (2S,4S,6S)-2-ethyl-4-methyl-5-oxo-6-[(4S,5R,6S)-2,2,5-trimethyl-6-(2-oxoethyl)-1,3-dioxan-4-yl]heptanamide C19H33NO5 详情 详情
(XVII) 32424 2-[(2S,3R,4S,5S,6R,9S,11S)-9-ethyl-4-hydroxy-3,5,11-trimethyl-8-oxo-1-oxa-7-azaspiro[5.5]undec-2-yl]acetaldehyde C16H27NO4 详情 详情
(XVIII) 35877 (2S,4S,6S)-6-[(4S,5R,6S)-6-[2-(benzyloxy)ethyl]-2,2,5-trimethyl-1,3-dioxan-4-yl]-2-ethyl-4-methyl-5-oxoheptanamide C26H41NO5 详情 详情
(XIX) 35878 (2S,3R,4S,5S,6R,9S,11S)-9-ethyl-4-hydroxy-2-(2-hydroxyethyl)-3,5,11-trimethyl-1-oxa-7-azaspiro[5.5]undecan-8-one C16H29NO4 详情 详情

合成路线8

The regiocontrolled condensation of (spirolactam (XVII) with the chiral borane (+)(Z)-crotyl-diisopinocampheylborane (XX) in THF gives the diol (XXI), which is silylated with TBDMS-OTf and lutidine in dichloromethane yielding the bis(silyloxy) compound (XXII). The ozonolysis of the terminal double bond of (XXII) with O3 in dichloromethane affords the aldehyde (XXIII), which is condensed with the silyl aldimine (XXIV) by means of LDA in THF giving the unsaturated aldehyde (XXV). Hydrogenation of the double bond of (XXV) yields aldehyde (XXVI), which is condensed with the diazo phosphonate (XXVII) by means of K2CO3 in methanol providing the terminal acetylenic compound (XXVIII). The reaction of (XXVIII) with TBAF in THF gives the desilylated acetylenic compound (XXIX), which is brominated with NBS and AgNO3 in acetone yielding the omega-bromoacetylenic compound (XXX). Finally, this compound is treated with tributyltin hydride, Pd2(dba)3 and PPh3 in chloroform to afford the desired tributyl stannane intermediate (I).

参考文献 中间体
【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
(I) 35874 (2S,3R,4S,5S,6R,9S,11S)-9-ethyl-4-hydroxy-2-[(2S,3S,6E)-2-hydroxy-3-methyl-7-(tributylstannyl)-6-heptenyl]-3,5,11-trimethyl-1-oxa-7-azaspiro[5.5]undecan-8-one C34H65NO4Sn 详情 详情
(XVII) 32424 2-[(2S,3R,4S,5S,6R,9S,11S)-9-ethyl-4-hydroxy-3,5,11-trimethyl-8-oxo-1-oxa-7-azaspiro[5.5]undec-2-yl]acetaldehyde C16H27NO4 详情 详情
(XXI) 35879 (2S,3R,4S,5S,6R,9S,11S)-9-ethyl-4-hydroxy-2-[(2S,3S)-2-hydroxy-3-methyl-4-pentenyl]-3,5,11-trimethyl-1-oxa-7-azaspiro[5.5]undecan-8-one C20H35NO4 详情 详情
(XXII) 35880 (2S,3S,4S,5S,6R,9S,11S)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-((2S,3S)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-pentenyl)-9-ethyl-3,5,11-trimethyl-1-oxa-7-azaspiro[5.5]undecan-8-one C32H63NO4Si2 详情 详情
(XXIII) 35881 (2R,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-((2S,3S,4S,5S,6R,9S,11S)-4-[[tert-butyl(dimethyl)silyl]oxy]-9-ethyl-3,5,11-trimethyl-8-oxo-1-oxa-7-azaspiro[5.5]undec-2-yl)-2-methylbutanal C31H61NO5Si2 详情 详情
(XXV) 35882 (E,4S,5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-((2S,3S,4S,5S,6R,9S,11S)-4-[[tert-butyl(dimethyl)silyl]oxy]-9-ethyl-3,5,11-trimethyl-8-oxo-1-oxa-7-azaspiro[5.5]undec-2-yl)-4-methyl-2-hexenal C33H63NO5Si2 详情 详情
(XXVI) 35883 (4S,5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-((2S,3S,4S,5S,6R,9S,11S)-4-[[tert-butyl(dimethyl)silyl]oxy]-9-ethyl-3,5,11-trimethyl-8-oxo-1-oxa-7-azaspiro[5.5]undec-2-yl)-4-methylhexanal C33H65NO5Si2 详情 详情
(XXVII) 35884 diethyl 1-diazo-2-oxopropylphosphonate C7H13N2O4P 详情 详情
(XXVIII) 35885 (2S,3S,4S,5S,6R,9S,11S)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-((2S,3S)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-6-heptynyl)-9-ethyl-3,5,11-trimethyl-1-oxa-7-azaspiro[5.5]undecan-8-one C34H65NO4Si2 详情 详情
(XXIX) 35886 (2S,3R,4S,5S,6R,9S,11S)-9-ethyl-4-hydroxy-2-[(2S,3S)-2-hydroxy-3-methyl-6-heptynyl]-3,5,11-trimethyl-1-oxa-7-azaspiro[5.5]undecan-8-one C22H37NO4 详情 详情
(XXX) 32435 (2S,3R,4S,5S,6R,9S,11S)-2-[(2S,3S)-7-bromo-2-hydroxy-3-methyl-6-heptynyl]-9-ethyl-4-hydroxy-3,5,11-trimethyl-1-oxa-7-azaspiro[5.5]undecan-8-one C22H36BrNO4 详情 详情

合成路线9

The condensation of the amine group of bis(iodovinyl) compound (XXXI) with the carboxy group of tributylstannane (XXXII) by means of O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) and DIEA in DMF gives the corresponding amide (XXXIII), which is cyclized by means of Pd2(dba)3, AsPh3 and DIEA in CHCl3/DMF to afford the desired intermediate iodovinyl compound (II).

参考文献 中间体
【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
(II) 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
(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
(XXXII) 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
(XXXIII) 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

合成路线10

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).

参考文献 中间体
【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11

The silylation of hydroxyester (XLVIII) with Tips-Cl and imidazole in THF gives the fully protected compound (XLIX), which is reduced with DIBAL in dichloromethane to the carbinol (L).The epoxidation of the double bond of (L) with MCPBA in dichloromethane yields the epoxide (LI), which is condensed with the Grignard reagent (LII) by means of CuI in ethyl ether/THF affording the diol (LIII). Esterification of the primary OH group of (LIII) with pivaloyl chloride gives the ester (LIV), which is desilylated with TBAF in THF providing the diol (LV). The cyclic ketalization of (LV) catalyzed by PdCl2 and benzoquinone yields the cyclic ketal (LVI), which is debenzylated as usual affording the primary alcohol (LVII). The oxidation of (LVII) with TPAP and NMO in dichloromethane gives the aldehyde (LVIII), which is condensed with diazophosphonate (XXVII) by means of K2CO3 in methanol yielding the ethynyl derivative (LIX), with simultaneous hydrolysis of the pivaloyl ester. The reaction of (LIX) with tributyltin hydride and PdCl2 in dichloromethane affords the vinyl stannane derivative (LX). Finally, the hydroxymethyl group of (LX) is oxidized with TPAP, NMO and NaClO2 to the corresponding carboxylic group of the desired tributylstannane intermediate (XXXII).

参考文献 中间体
【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
(XXVII) 35884 diethyl 1-diazo-2-oxopropylphosphonate C7H13N2O4P 详情 详情
(XXXII) 35904 (4S,6R)-1,4-dimethyl-3-[(E)-2-(tributylstannyl)ethenyl]-2,9-dioxabicyclo[3.3.1]nonane-6-carboxylic acid C24H44O4Sn 详情 详情
(XLVIII) 35892 ethyl (E,4R,5R)-6-(benzyloxy)-5-hydroxy-4-methyl-2-hexenoate C16H22O4 详情 详情
(XLIX) 35893 ethyl (E,4R,5R)-6-(benzyloxy)-4-methyl-5-[(triisopropylsilyl)oxy]-2-hexenoate C25H42O4Si 详情 详情
(L) 35894 (E,4R,5R)-6-(benzyloxy)-4-methyl-5-[(triisopropylsilyl)oxy]-2-hexen-1-ol C23H40O3Si 详情 详情
(LI) 35895 ((2S,3R)-3-[(1R,2R)-3-(benzyloxy)-1-methyl-2-[(triisopropylsilyl)oxy]propyl]oxiranyl)methanol C23H40O4Si 详情 详情
(LII) 35896 bromo(3-butenyl)magnesium 7103-09-5 C4H7BrMg 详情 详情
(LIII) 35897 (2S,3S,4R,5R)-6-(benzyloxy)-2-(3-butenyl)-4-methyl-5-[(triisopropylsilyl)oxy]-1,3-hexanediol C27H48O4Si 详情 详情
(LIV) 35898 (2S)-2-[(1S,2R,3R)-4-(benzyloxy)-1-hydroxy-2-methyl-3-[(triisopropylsilyl)oxy]butyl]-5-hexenyl pivalate C32H56O5Si 详情 详情
(LV) 35899 (2S)-2-[(1S,2R,3R)-4-(benzyloxy)-1,3-dihydroxy-2-methylbutyl]-5-hexenyl pivalate C23H36O5 详情 详情
(LVI) 35900 [(4S,6S)-3-[(benzyloxy)methyl]-1,4-dimethyl-2,9-dioxabicyclo[3.3.1]non-6-yl]methyl pivalate C23H34O5 详情 详情
(LVII) 35901 [(4S,6S)-3-(hydroxymethyl)-1,4-dimethyl-2,9-dioxabicyclo[3.3.1]non-6-yl]methyl pivalate C16H28O5 详情 详情
(LVIII) 35902 [(4S,6S)-3-formyl-1,4-dimethyl-2,9-dioxabicyclo[3.3.1]non-6-yl]methyl pivalate C16H26O5 详情 详情
(LIX) 35903 [(4S,6S)-3-ethynyl-1,4-dimethyl-2,9-dioxabicyclo[3.3.1]non-6-yl]methanol C12H18O3 详情 详情
(LX) 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

合成路线12

The regiocontrolled condensation of the silylated propargyl aldehyde (LXI) with the chiral borane (LXII) gives the secondary alcohol (LXIII), which is silylated with TBDMS-OTf and lutidine in dichloromethane to the silyl ether (LXIV). The ozonolysis of the terminal double bond of (LXIV) with O3 in dichloromethane yields the aldehyde (LXV), which is condensed with the phosphonate (LXVI) by means of NaH in THF affording the unsaturated heptanoic ester (LXVII). The reduction of the ester group of (LXVII) with DIBAL in THF gives the alcohol (LXVIII), which is epoxidized with MCPBA as usual to the epoxide (LXIX). The condensation of (LXIX) with the Grignard reagent (LXX) in THF yields the diol (LXXI), which is selectively esterified with pivaloyl chloride affording the monopivalate (LXXII). The cyclic transketalization of (LXXII) catalyzed by HF in acetonitrile/water gives the cyclic ketal (LXXII), which is finally hydrolyzed by means of K2CO3 in methanol to provide the desired intermediate, the ethynyl derivative (LIX).

参考文献 中间体
【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
(LIX) 35903 [(4S,6S)-3-ethynyl-1,4-dimethyl-2,9-dioxabicyclo[3.3.1]non-6-yl]methanol C12H18O3 详情 详情
(LXI) 35905 3-(triethylsilyl)-2-propynal C9H16OSi 详情 详情
(LXIII) 35906 (3R,4R)-4-methyl-1-(triethylsilyl)-5-hexen-1-yn-3-ol C13H24OSi 详情 详情
(LXIV) 35907 ((3R,4R)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-hexen-1-ynyl)(triethyl)silane; tert-butyl(dimethyl)silyl (1R,2R)-2-methyl-1-[2-(triethylsilyl)ethynyl]-3-butenyl ether C19H38OSi2 详情 详情
(LXV) 35908 (2S,3R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-5-(triethylsilyl)-4-pentynal C18H36O2Si2 详情 详情
(LXVI) 35909 ethyl 3-(diethoxyphosphoryl)propanoate 3699-67-0 C9H19O5P 详情 详情
(LXVII) 35910 ethyl (E,4R,5R)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-7-(triethylsilyl)-2-hepten-6-ynoate C22H42O3Si2 详情 详情
(LXVIII) 35911 (E,4R,5R)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-7-(triethylsilyl)-2-hepten-6-yn-1-ol C20H40O2Si2 详情 详情
(LXIX) 35912 [3-[(1R,2R)-2-[[tert-butyl(dimethyl)silyl]oxy]-1-methyl-4-(triethylsilyl)-3-butynyl]-2-oxiranyl]methanol C20H40O3Si2 详情 详情
(LXX) 35913 bromo[2-(2-methyl-1,3-dioxolan-2-yl)ethyl]magnesium C6H11BrMgO2 详情 详情
(LXXI) 35914 (2S,3S,4R,5R)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-2-[2-(2-methyl-1,3-dioxolan-2-yl)ethyl]-7-(triethylsilyl)-6-heptyne-1,3-diol C26H52O5Si2 详情 详情
(LXXII) 35915 (2S,3S,4R,5R)-5-[[tert-butyl(dimethyl)silyl]oxy]-3-hydroxy-4-methyl-2-[2-(2-methyl-1,3-dioxolan-2-yl)ethyl]-7-(triethylsilyl)-6-heptynyl pivalate C31H60O6Si2 详情 详情
(LXXIII) 35916 [(4S,6S)-1,4-dimethyl-3-[2-(triethylsilyl)ethynyl]-2,9-dioxabicyclo[3.3.1]non-6-yl]methyl pivalate C23H40O4Si 详情 详情

合成路线13

Chiral oxazolidinone intermediate (VI): The oxidation of the terminal double bond of the chiral acyl oxazolidinone (I) with O2 catalyzed by CuCl and PdCl2 in DMF/water gives the ketone (II), which is ketalized with propane-1,3-dithiol (III) and Ts-OH in AcOH to yield the thioketal (IV). Finally, the stereocontrolled acylation of (IV) with propionyl chloride (V) by means of LDA in THF affords the target oxazolidinone intermediate (VI)

参考文献 中间体
【1】 Duan, M.S.; Paquette, L.A.; Highly diastereocontrolled synthesis of the C1-C25 domain of sanglifehrin A. Tetrahedron Lett 2000, 41, 20, 3789.
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) 60101 (4S)-4-benzyl-3-(5-hexenoyl)-1,3-oxazolidin-2-one C16H19NO3 详情 详情
(II) 60102 1-[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-1,5-hexanedione C16H19NO4 详情 详情
(III) 29729 1,3-propanedithiol; 3-sulfanylpropylhydrosulfide 109-80-8 C3H8S2 详情 详情
(IV) 60103 (4S)-4-benzyl-3-[4-(2-methyl-1,3-dithian-2-yl)butanoyl]-1,3-oxazolidin-2-one C19H25NO3S2 详情 详情
(V) 15967 propanoyl chloride; propionyl chloride 79-03-8 C3H5ClO 详情 详情
(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

合成路线14

Chiral tripeptide intermediate (XV): The deprotection of perhydropyridazine carboxylic acid methyl ester (VII) with TFA in dichloromethane gives ester (VIII), which is condensed with N-(benzyloxycarbonyl)-3-hydroxy-L-tyrosine (IX) by means of HBTU and TEA in acetonitrile to yield the dipeptide (X). The protection of the phenolic OH group of (X) with Boc2O and TEA In dichloromethane affords (XI), which is selectively deprotected with H2 over Pd/C in ethanol to provide dipeptide (XII). The condensation of (XII) with N-(benzyloxycarbonyl)-L-valine (XIII) by means of HBTU as before gives the protected tripeptide (XIV), which is finally treated with H2 over Pd/C in ethanol to provide the target tripeptide intermediate (XV)

参考文献 中间体
【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
(VII) 60105 1,2-di(tert-butyl) 3-methyl (3S)tetrahydro-1,2,3-pyridazinetricarboxylate C16H28N2O6 详情 详情
(VIII) 60106 methyl (3S)hexahydro-3-pyridazinecarboxylate C6H12N2O2 详情 详情
(IX) 60107 (2S)-2-{[(benzyloxy)carbonyl]amino}-3-(3-hydroxyphenyl)propanoic acid C17H17NO5 详情 详情
(X) 60108 methyl (3S)-1-[(2S)-2-{[(benzyloxy)carbonyl]amino}-3-(3-hydroxyphenyl)propanoyl]hexahydro-3-pyridazinecarboxylate C23H27N3O6 详情 详情
(XI) 60109 methyl (3S)-1-((2S)-2-{[(benzyloxy)carbonyl]amino}-3-{3-[(tert-butoxycarbonyl)oxy]phenyl}propanoyl)hexahydro-3-pyridazinecarboxylate C28H35N3O8 详情 详情
(XII) 60110 methyl (3S)-1-((2S)-2-amino-3-{3-[(tert-butoxycarbonyl)oxy]phenyl}propanoyl)hexahydro-3-pyridazinecarboxylate C20H29N3O6 详情 详情
(XIII) 49332 (2R)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutyric acid C13H17NO4 详情 详情
(XIV) 60111 methyl (3S)-1-((2S)-2-[((2S)-2-{[(benzyloxy)carbonyl]amino}-3-methylbutanoyl)amino]-3-{3-[(tert-butoxycarbonyl)oxy]phenyl}propanoyl)hexahydro-3-pyridazinecarboxylate C33H44N4O9 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

合成路线15

Chiral acetylenic ketone intermediate (XXIV): The oxidation of 6-(trimethylsilyl)-5-hexyn-1-ol (XVI) with PCC in DMF gives the carboxylic acid (XVII), which is condensed with the chiral auxiliary (XVIII) by means of Piv-Cl and TEA in THF to yield the acyloxazolidine (XIX). The diastereoselective methylation of (XIX) with Me-I and NaHMDS in THF affords the methylated compound (XX), which by reductive elimination of the chiral auxiliary with LiBH4 in ethyl ether provides the chiral alcohol (XXI). The oxidation of (XXI) with (COCl)2 and DMSO in dichloromethane leads to the aldehyde (XXII), which by a Grignard reaction with Me-MgBr in ethyl ether is converted into the secondary alcohol (XXIII). Finally, this compound is oxidized with (COCl)2 as before to yield the chiral acetylenic ketone intermediate (XXIV)

参考文献 中间体
【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
(XVI) 60113 6-(trimethylsilyl)-5-hexyn-1-ol C9H18OSi 详情 详情
(XVII) 60114 6-(trimethylsilyl)-5-hexynoic acid C9H16O2Si 详情 详情
(XVIII) 25351 (4R)-4-benzyl-1,3-oxazolidin-2-one; (R)-(+)-4-benzyl-2-oxazolidinone 102029-44-7 C10H11NO2 详情 详情
(XIX) 60115 (4S)-4-benzyl-3-[6-(trimethylsilyl)-5-hexynoyl]-1,3-oxazolidin-2-one C19H25NO3Si 详情 详情
(XX) 60116 (4S)-4-benzyl-3-[(2S)-2-methyl-6-(trimethylsilyl)-5-hexynoyl]-1,3-oxazolidin-2-one C20H27NO3Si 详情 详情
(XXI) 60117 (2S)-2-methyl-6-(trimethylsilyl)-5-hexyn-1-ol C10H20OSi 详情 详情
(XXII) 60118 (2S)-2-methyl-6-(trimethylsilyl)-5-hexynal C10H18OSi 详情 详情
(XXIII) 60119 (3S)-3-methyl-7-(trimethylsilyl)-6-heptyn-2-ol C11H22OSi 详情 详情
(XXIV) 60120 (3S)-3-methyl-7-(trimethylsilyl)-6-heptyn-2-one C11H20OSi 详情 详情

合成路线16

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)

参考文献 中间体
【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

合成路线17

Synthesis of the target Sanglifehrin A: The condensation of the chiral ketone (XXXVII) with aldehyde (XXXVIII) by means of Sn(OTf)2 and TEA in dichloromethane gives the beta-hydroxyketone (XXXIX), which is reduced with Me4NBH3CN to yield the diol (XL). The ketalization of (XL) by means of DDQ, followed by ration with Tes-Cl and imidazole affords the silylated ketal (XLI), which is cleaved with iBu2AlH and oxidized with (COCl)2 to provide the protected carbaldehyde (XLII). The stereocontrolled condensation of aldehyde (XLII) with the chiral acetylenic ketone intermediate (XXIV) by means of (+)-DIPCl and TEA in ethyl ether leads to the acetylenic ketone (XLIII). This is reduced with Me4NBH3CN and ketalized by means of 2,2-dimethoxypropane and PPTS (simultaneous desilylation takes place) to give the dihydroxy ozonide (XLIV). The protection of the primary OH group of (XLIV) by means of Piv-Cl, pyridine and DMAP yields the pivalate (XLV), which is silylated with Tes-Cl and imidazole and deprotected with iBu2AlH to afford the acetylenic alcohol (XLVI). The sequential oxidation of (XLVI) with DMP and with NaClO2, followed by methylation with diazomethane affords the methyl ester (XLVII), which is treated with Me2AlNH2 in dichloromethane to provide the corresponding amide (XLVIII). The desilylation of (XLVIII) by means of TBAF, followed by oxidation with DMP gives the delta-ketoester (XLIX), which is submitted to and acid ring closure with CSA to yield the spirolactam (L)

参考文献 中间体
【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
(XXXVII) 42614 (2S)-1-[(4-methoxybenzyl)oxy]-2-methyl-3-pentanone C14H20O3 详情 详情
(XXXVIII) 60131 (2S,4S)-4-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-methylhexanal C24H34O2Si 详情 详情
(XXXIX) 60132 (2S,4R,5S,6S,8S)-8-({[tert-butyl(diphenyl)silyl]oxy}methyl)-5-hydroxy-1-[(4-methoxybenzyl)oxy]-2,4,6-trimethyl-3-decanone C38H54O5Si 详情 详情
(XL) 60133 (2S,3S,4R,5S,6S,8S)-8-({[tert-butyl(diphenyl)silyl]oxy}methyl)-1-[(4-methoxybenzyl)oxy]-2,4,6-trimethyl-3,5-decanediol C38H56O5Si 详情 详情
(XLI) 60134 (6S,8S,9S)-6,11,11-triethyl-9-{(1S)-1-[(4S,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]ethyl}-2,2,8-trimethyl-3,3-diphenyl-4,10-dioxa-3,11-disilatridecane; tert-butyl(diphenyl)silyl (2S,4S,5S,6S)-2-ethyl-6-[(4S,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-4-methyl-5-[(triethylsilyl)oxy]heptyl ether C44H68O5Si2 详情 详情
(XLII) 60135 (2R,3R,4S,5S,6S,8S)-8-({[tert-butyl(diphenyl)silyl]oxy}methyl)-3-[(4-methoxybenzyl)oxy]-2,4,6-trimethyl-5-[(triethylsilyl)oxy]decanal C44H68O5Si2 详情 详情
(XLIII) 60136 (5S,8S,9S,10S,11S,12S,13S,15S)-15-({[tert-butyl(diphenyl)silyl]oxy}methyl)-8-hydroxy-10-[(4-methoxybenzyl)oxy]-5,9,11,13-tetramethyl-12-[(triethylsilyl)oxy]-1-(trimethylsilyl)-1-heptadecyn-6-one C55H88O6Si3 详情 详情
(XLIV) 60137 (2S,4S,5S,6R,7R,8R)-8-{(4S,6S)-2,2-dimethyl-6-[(1S)-1-methyl-4-pentynyl]-1,3-dioxan-4-yl}-2-ethyl-7-[(4-methoxybenzyl)oxy]-4,6-dimethyl-1,5-nonanediol C33H54O6 详情 详情
(XLV) 60138 (2S,4S,5S,6R,7R,8R)-8-{(4S,6S)-2,2-dimethyl-6-[(1S)-1-methyl-4-pentynyl]-1,3-dioxan-4-yl}-2-ethyl-5-hydroxy-7-[(4-methoxybenzyl)oxy]-4,6-dimethylnonyl pivalate C38H62O7 详情 详情
(XLVI) 60139 (2S,4S,5S,6S,7S,8R)-8-{(4S,6S)-2,2-dimethyl-6-[(1S)-1-methyl-4-pentynyl]-1,3-dioxan-4-yl}-2-ethyl-7-[(4-methoxybenzyl)oxy]-4,6-dimethyl-5-[(triethylsilyl)oxy]-1-nonanol C39H68O6Si 详情 详情
(XLVII) 60140 methyl (2S,4S,5S,6S,7S,8R)-8-{(4S,6S)-2,2-dimethyl-6-[(1S)-1-methyl-4-pentynyl]-1,3-dioxan-4-yl}-2-ethyl-7-[(4-methoxybenzyl)oxy]-4,6-dimethyl-5-[(triethylsilyl)oxy]nonanoate C40H68O7Si 详情 详情
(XLVIII) 60141 (2S,4S,5S,6S,7S,8R)-8-{(4S,6S)-2,2-dimethyl-6-[(1S)-1-methyl-4-pentynyl]-1,3-dioxan-4-yl}-2-ethyl-7-[(4-methoxybenzyl)oxy]-4,6-dimethyl-5-[(triethylsilyl)oxy]nonanamide C39H67NO6Si 详情 详情
(XLIX) 60142 (2S,4S,6S,7S,8R)-8-{(4S,6S)-2,2-dimethyl-6-[(1S)-1-methyl-4-pentynyl]-1,3-dioxan-4-yl}-2-ethyl-7-[(4-methoxybenzyl)oxy]-4,6-dimethyl-5-oxononanamide C33H51NO6 详情 详情
(L) 60143 (2S,3R,4S,5S,6R,9S,11S)-9-ethyl-2-[(2S,3S)-2-hydroxy-3-methyl-6-heptynyl]-4-[(4-methoxybenzyl)oxy]-3,5,11-trimethyl-1-oxa-7-azaspiro[5.5]undecan-8-one C30H45NO5 详情 详情

合成路线18

The elimination of the Pmb protecting group of (L) by means of DDQ in dichloromethane affords compound (LI), which is brominated with NBS and AgNO3 in acetone to provide the bromoacetylene derivative (LII). The reaction of (LII) with tributyltin hydride, Pd2(dba)3 and PPh3 leads to the vinylstannane (LIII), which is condensed with the chiral tetracyclic macrolactone intermediate (XXXVI) by means of PdCl2(CH3CN)2 in DMF to give the cyclic precursor (LIV). Finally, this compound is submitted to an acidic hydrolysis by means of TsOH and BO3H3 in THF to provide the target Sanglifehrin A

参考文献 中间体
【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
(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
(L) 60143 (2S,3R,4S,5S,6R,9S,11S)-9-ethyl-2-[(2S,3S)-2-hydroxy-3-methyl-6-heptynyl]-4-[(4-methoxybenzyl)oxy]-3,5,11-trimethyl-1-oxa-7-azaspiro[5.5]undecan-8-one C30H45NO5 详情 详情
(LI) 35886 (2S,3R,4S,5S,6R,9S,11S)-9-ethyl-4-hydroxy-2-[(2S,3S)-2-hydroxy-3-methyl-6-heptynyl]-3,5,11-trimethyl-1-oxa-7-azaspiro[5.5]undecan-8-one C22H37NO4 详情 详情
(LII) 32435 (2S,3R,4S,5S,6R,9S,11S)-2-[(2S,3S)-7-bromo-2-hydroxy-3-methyl-6-heptynyl]-9-ethyl-4-hydroxy-3,5,11-trimethyl-1-oxa-7-azaspiro[5.5]undecan-8-one C22H36BrNO4 详情 详情
(LIII) 35874 (2S,3R,4S,5S,6R,9S,11S)-9-ethyl-4-hydroxy-2-[(2S,3S,6E)-2-hydroxy-3-methyl-7-(tributylstannyl)-6-heptenyl]-3,5,11-trimethyl-1-oxa-7-azaspiro[5.5]undecan-8-one C34H65NO4Sn 详情 详情
(LIV) 32452 (4R,7S,10S,16S,19S,25S,26R,27R)-19-{(1E,3E,7S,8S)-9-[(2S,3R,4S,5S,6R,9S,11S)-9-ethyl-4-hydroxy-3,5,11-trimethyl-8-oxo-1-oxa-7-azaspiro[5.5]undec-2-yl]-8-hydroxy-1,7-dimethyl-1,3-nonadienyl}-10-(3-hydroxybenzyl)-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 C60H89N5O12 详情 详情
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