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【结 构 式】 
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【分子编号】32433 【品名】(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 【CA登记号】 |
【 分 子 式 】C34H65NO4Si2 【 分 子 量 】608.06544 【元素组成】C 67.16% H 10.77% N 2.3% O 10.52% Si 9.24% |
合成路线1
该中间体在本合成路线中的序号：(XV)The esterification of 4alpha-carboxymethyl-5beta-benzyloxymethyl-cyclopent-2-en-1alpha-ol (I) with methyl iodide and K2CO3 in acetone gives the corresponding methyl ester (II), which by reaction with triethyl - orthoacetate (III) at 145 C is converted into 3-ethoxycarbonylmethyl-4-methoxycarbonylmethyl-5-benzyloxymethyl-1-cyclopentene (IV). The cyclization of (IV) with potassium tert-butoxide in benzene yields 6-benzyloxymethyl-cis-bicyclo[3.3.0]oct-7-ene-3-one (V), which by reaction with N-bromosuccinimide in DMSO - water affords 6-benzyloxymethyl-7-hydroxy-8-bromo-cis-bicyclo[3.3.0]octan-3-one (VI). Debromination of (VI) with tributyltin hydride and azobisisobutyronitrile in benzene irradiated with UV light gives 6-benzyloxymethyl-7-hydroxy-cis-bicyclo[3.3.0]octan-3-one (VII), which is treated with dihydropyran and p-toluenesulfonic acid in methylene chloride yielding the corresponding protected compound (VIII). Elimination of the benzyl group of (VIII) with H2 over Pd/C in acetic acid affords 6-hydroxymethyl-7-(tetrahydropyranyloxy)-cis-bicyclo[3.3.0]octan-3-one (IX), which is submitted to a Wittig condensation with (4-carboxybutyl) triphenylphosphonium bromide (X) and the sodium salt of DMSO in this solvent, followed by a methylation with diazomethane, affording 3-(4-methoxycarbonylbutylidene)-6-hydroxymethyl-7-tetrahydropyranyloxy)-cis-bicyclo[3.3.0]octane (XI). Oxidation of (XI) with CrO3 in methylene chloride gives the corresponding 6-formyl derivative (XII), which is submitted to a new Wittig condensation with dimethyl 2-oxo-2-cyclopentylethylphosphonate (XIII) and NaH in THF yielding methyl 6,9-methano-11-(tetrahydropyranyloxy)-15-oxo-15-cyclopentyl-16,17,18,19,20-pentanorprosta-3,5-dienoate (XIV). Deprotection of (XIV) with acetic acid in THF - water gives the corresponding 11-hydroxy compound (XVI), which is reduced with NaBH4 in methanol affording the 11,15-dihydroxy ester (XVI). Finally, this compound is hydrolyzed with NaOH in methanol - water.
| 【1】 Hayashi, M.; Konishi, Y.; Arai, Y.; 6,9-Methano-PGI2 analogues. CH 639360; DE 2912409; FR 2422635; GB 2017699; IT 1113341; US 4479966 . |
| 【2】 Kottegoda, S.R.; Serradell, M.N.; Adaikan, P.G.; Castaner, J.; ONO-41483. Drugs Fut 1984, 9, 11, 833. |
| 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) | 34221 | 2-[(1S,4R,5S)-5-[(benzyloxy)methyl]-4-hydroxy-2-cyclopenten-1-yl]acetic acid | C15H18O4 | 详情 | 详情 | |
| (II) | 34222 | methyl 2-[(1S,4R,5S)-5-[(benzyloxy)methyl]-4-hydroxy-2-cyclopenten-1-yl]acetate | C16H20O4 | 详情 | 详情 | |
| (III) | 12940 | 1,1-Diethoxyethyl ethyl ether; 1,1,1-Triethoxyethane; Triethyl orthoacetate | 78-39-7 | C8H18O3 | 详情 | 详情 |
| (IV) | 34223 | methyl 2-[(1S,2R,5S)-2-[(benzyloxy)methyl]-5-(2-ethoxy-2-oxoethyl)-3-cyclopenten-1-yl]acetate | C20H26O5 | 详情 | 详情 | |
| (V) | 34224 | (3aS,4R,6aS)-4-[(benzyloxy)methyl]-3,3a,4,6a-tetrahydro-2(1H)-pentalenone | C16H18O2 | 详情 | 详情 | |
| (VI) | 34225 | (3aR,4S,5S,6aR)-4-[(benzyloxy)methyl]-6-bromo-5-hydroxyhexahydro-2(1H)-pentalenone | C16H19BrO3 | 详情 | 详情 | |
| (VII) | 34226 | (3aS,4S,5R,6aR)-4-[(benzyloxy)methyl]-5-hydroxyhexahydro-2(1H)-pentalenone | C16H20O3 | 详情 | 详情 | |
| (VIII) | 34227 | (3aS,4R,5R,6aR)-4-[(benzyloxy)methyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2(1H)-pentalenone | C22H30O4 | 详情 | 详情 | |
| (IX) | 34228 | (3aS,4R,5R,6aR)-4-(hydroxymethyl)-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2(1H)-pentalenone | C15H24O4 | 详情 | 详情 | |
| (X) | 13616 | (4-Carboxybutyl)triphenylphosphonium bromide | 17814-85-6 | C23H24BrO2P | 详情 | 详情 |
| (XI) | 34229 | methyl 5-[(3aS,4R,5R,6aR)-4-(hydroxymethyl)-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2(1H)-pentalenylidene]pentanoate | C21H34O5 | 详情 | 详情 | |
| (XII) | 34230 | methyl 5-[(3aS,4R,5R,6aR)-4-formyl-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2(1H)-pentalenylidene]pentanoate | C21H32O5 | 详情 | 详情 | |
| (XIII) | 34231 | dimethyl 2-cyclopentyl-2-oxoethylphosphonate | C9H17O4P | 详情 | 详情 | |
| (XIV) | 34232 | methyl 5-[(3aS,4S,5R,6aR)-4-[(E)-3-cyclopentyl-3-oxo-1-propenyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2(1H)-pentalenylidene]pentanoate | C28H42O5 | 详情 | 详情 | |
| (XV) | 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 | |
| (XVI) | 34234 | methyl 5-[(3aS,4S,5R,6aS)-4-[(E,3S)-3-cyclopentyl-3-hydroxy-1-propenyl]-5-hydroxyhexahydro-2(1H)-pentalenylidene]pentanoate | C22H34O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXI)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.
| 【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 |