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【结 构 式】 
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【分子编号】32415 【品名】Propione; Dimethylacetone; Diethyl ketone; 3-Pentanone 【CA登记号】96-22-0 |
【 分 子 式 】C5H10O 【 分 子 量 】86.1338 【元素组成】C 69.72% H 11.7% O 18.58% |
合成路线1
该中间体在本合成路线中的序号：(I)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).
| 【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
该中间体在本合成路线中的序号：(IV)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).
| 【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3
该中间体在本合成路线中的序号：(I)The Wadsworth-Emmons condensation of 3-pentanone (I) with phosphonate (II) affords the conjugated ester adduct (III). Subsequent double bond hydrogenation in (III), in the presence of Pd/C, leads to the saturated ester (IV). After basic hydrolysis of the ethyl ester group of (IV), the resultant carboxylic acid (V) is activated as the corresponding acid chloride (VI) upon treatment with SOCl2. Then, acylation of the silver acetylide of methyl propiolate (VII) with acid chloride (VI) gives rise to the oxo ester intermediate (VIII).
| 【1】 Mori, S.; Takechi, S.; Kida, S.; Mizui, T.; Ichihashi, T. (Shionogi & Co. Ltd.); Lignan analog, production thereof, and hypolipidemic drug. EP 0597107; EP 0701991; JP 1993310634; US 5731455; WO 9308155 . |
| 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) | 10019 | Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate | 867-13-0 | C8H17O5P | 详情 | 详情 |
| (III) | 57428 | ethyl 3-ethyl-2-pentenoate | C9H16O2 | 详情 | 详情 | |
| (IV) | 57429 | ethyl 3-ethylpentanoate | C9H18O2 | 详情 | 详情 | |
| (V) | 57433 | 3-ethylpentanoic acid | C7H14O2 | 详情 | 详情 | |
| (VI) | 57430 | 3-ethylpentanoyl chloride | C7H13ClO | 详情 | 详情 | |
| (VII) | 57431 | (3-methoxy-3-oxo-1-propynyl)silver | C4H3AgO2 | 详情 | 详情 | |
| (VIII) | 57432 | methyl 6-ethyl-4-oxo-2-octynoate | C11H16O3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)Treatment of ethyl N-Boc-(S)-pyroglutamate (I) with lithium hexamethyldisilazide in THF at -78 C, followed by aldol condensation of the resulting lithium enolate with 3-pentanone (II) in the presence of boron trifluoride etherate, furnished adduct (III). Dehydration of the alcohol group of (III) to produce olefin (IV) was achieved by treatment of (III) with methanesulfonyl chloride and triethylamine. Hydrolysis of the ester and lactam groups of (IV) by means of LiOH afforded diacid (V). The N-Boc group of (V) was finally cleaved with HCl in EtOH.
| 【1】 Bleakman, D.; Ezquerra, J.; Baker, S.R.; et al.; 4-Alkylidenyl glutamic acids, potent and selective GluR5 agonists. Bioorg Med Chem Lett 2000, 10, 16, 1807. |
| 【2】 Rubio Esteban, A.; Pedregal Tercero, C. (Lilly SA); Glutamic acid derivs. and pharmaceutical compsns. for the treatment of central nervous system disorders. EP 0867430; ES 2133095; JP 1998279542 . |
| 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) | 43914 | 1-(tert-butyl) 2-ethyl (2S)-5-oxo-1,2-pyrrolidinedicarboxylate | 144978-35-8 | C12H19NO5 | 详情 | 详情 |
| (II) | 32415 | Propione; Dimethylacetone; Diethyl ketone; 3-Pentanone | 96-22-0 | C5H10O | 详情 | 详情 |
| (III) | 43918 | 1-(tert-butyl) 2-ethyl (2S)-4-(1-ethyl-1-hydroxypropyl)-5-oxo-1,2-pyrrolidinedicarboxylate | C17H29NO6 | 详情 | 详情 | |
| (IV) | 43919 | 1-(tert-butyl) 2-ethyl (2S)-4-(1-ethylpropylidene)-5-oxo-1,2-pyrrolidinedicarboxylate | C17H27NO5 | 详情 | 详情 | |
| (V) | 43920 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-(1-ethylpropylidene)pentanedioic acid | C15H25NO6 | 详情 | 详情 |