|
【结 构 式】 
|
【分子编号】13712 【品名】(3R,4S,5S,6R)-5-Methoxy-4-[(2R,3R)-2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2.5]octan-6-ol 【CA登记号】 |
【 分 子 式 】C16H26O4 【 分 子 量 】282.38004 【元素组成】C 68.06% H 9.28% O 22.66% |
合成路线1
该中间体在本合成路线中的序号：(XXII)The second epoxide function was introduced into (XVIII) upon treatment with m-chloroperbenzoic acid, yielding (XIX). Oxidation of the primary alcohol of (XIX) to aldehyde (XX) was effected by means of Dess-Martin periodinane reagent. Subsequent Wittig reaction of aldehyde (XX) with isopropylidene triphenylphosphorane furnished olefin (XXI). The chiral fumagillol (-)-(XXII) was then obtained by hydrolysis of the benzoate ester (XXI) in the presence of methanolic K2CO3. Finally, condensation of alcohol (-)-(XXII) with the acid chloride (XXIII) led to the title compound.
| 【1】 Taber, D.F.; et al.; Synthesis of (-)-fumagillin. J Am Chem Soc 1999, 121, 23, 5589. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVIII) | 52845 | (3R,4S,5S,6R)-4-[(E)-4-hydroxy-1-methyl-1-butenyl]-5-methoxy-1-oxaspiro[2.5]oct-6-yl benzoate | C20H26O5 | 详情 | 详情 | |
| (XIX) | 52846 | (3R,4S,5S,6R)-4-[(2R,3R)-3-(2-hydroxyethyl)-2-methyloxiranyl]-5-methoxy-1-oxaspiro[2.5]oct-6-yl benzoate | C20H26O6 | 详情 | 详情 | |
| (XX) | 52847 | (3R,4S,5S,6R)-5-methoxy-4-[(2R,3R)-2-methyl-3-(2-oxoethyl)oxiranyl]-1-oxaspiro[2.5]oct-6-yl benzoate | C20H24O6 | 详情 | 详情 | |
| (XXI) | 52848 | (3R,4S,5S,6R)-5-methoxy-4-[(2R,3R)-2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2.5]oct-6-yl benzoate | C23H30O5 | 详情 | 详情 | |
| (XXII) | 13712 | (3R,4S,5S,6R)-5-Methoxy-4-[(2R,3R)-2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2.5]octan-6-ol | C16H26O4 | 详情 | 详情 | |
| (XXIII) | 52849 | (2E,4E,6E,8E)-2,4,6,8-decatetraenedioyl dichloride | C10H8Cl2O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXII)The primary alcohol group of (XXXIV) was selectively converted to mesylate (XXXV), which was subsequently treated with methanolic NaOH to afford the spiro-epoxide (XXXVI). Sharpless epoxidation of diene (XXXVI) in the presence of tert-butyl hydroperoxide and vanadyl acetylacetonate gave rise to the bis-epoxide (XXXVII) as the major diastereoisomer. Finally, regioselective hydroxyl group alkylation in (XXXVII) under Williamson's synthesis conditions furnished the racemic fumagillol (+/-)-(XXII).
| 【1】 Vosburg, D.A.; et al.; A concise synthesis of fumagillol. Angew Chem. Int Ed 1999, 38, 7, 971. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXII) | 13712 | (3R,4S,5S,6R)-5-Methoxy-4-[(2R,3R)-2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2.5]octan-6-ol | C16H26O4 | 详情 | 详情 | |
| (XXXIV) | 52861 | (1R,2S,3S,4R)-3-[(1E)-1,5-dimethyl-1,4-hexadienyl]-4-(hydroxymethyl)-1,2,4-cyclohexanetriol | C15H26O4 | 详情 | 详情 | |
| (XXXV) | 52862 | {(1R,2S,3S,4R)-2-[(1E)-1,5-dimethyl-1,4-hexadienyl]-1,3,4-trihydroxycyclohexyl}methyl methanesulfonate | C16H28O6S | 详情 | 详情 | |
| (XXXVI) | 52863 | (3R,4S,5S,6R)-4-[(1E)-1,5-dimethyl-1,4-hexadienyl]-1-oxaspiro[2.5]octane-5,6-diol | C15H24O3 | 详情 | 详情 | |
| (XXXVII) | 52864 | (3R,4S,5S,6R)-4-[(2R,3R)-2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2.5]octane-5,6-diol | C15H24O4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XIX)The cyclization of the chiral diene (I) with acrolein (II) by means of BF3/Et2O in dichloromethane gives the chiral cyclohexene (III), which is dihydroxylated under Upjohn conditions (OsO4) yielding the dihydroxy compound (IV). The reaction of (IV) with acetone (V) and TsOH affords the isopropylidene derivative (VI), which is treated with NaOH in THF/water to eliminate the chiral auxiliary to yield the cyclohexene carbaldehyde (VII). The regio- and diastereoselective condensation of (VII) with bromide (VIII) by means of t-BuLi and BF3/Et2O affords the adduct (IX), which is treated with N-cyclohexyl-hydroxylamine (X) to provide the nitrone (XI). The reaction of (XI) with acetyl chloride gives the alpha-acetoxy-N-cyclohexylimine (XIII), through the intermediate (XII). The hydrolysis of (XIII) with AcOH and NaOAc yields the carbaldehyde (XIV), which is reduced with LiAlH4 in ethanol to afford the hydroxymethyl derivative (XV). The hydrolysis of the acetoxy and isopropylidene groups of (XV) by means of HCl in THF provides the tetrahydroxy derivative (XVI), which is converted into the epoxide (XVII) by a treatment with MsCl, TEA, DMAP and NaOH in dichloromethane. A new epoxidation of (XVII) by means of VO(acac)2 and t-BuOOH in benzene gives the bis-epoxide compound (XVIII), which is finally monomethylated by means of t-BuONa and MeI in THF to yield the target intermediate fumagillol (XIX).
| 【1】 Vosburg, D.A.; et al.; Concise stereocontrolled routes to fumagillol, fumagillin, and TNP-470. Chirality 2003, 15, 2, 156. |
| 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) | 61435 | (4S)-3-[(1E)-1,3-butadienyl]-4-phenyl-1,3-oxazolidin-2-one | C13H13NO2 | 详情 | 详情 | |
| (II) | 17668 | acrylaldehyde; Acrolein | 107-02-8 | C3H4O | 详情 | 详情 |
| (III) | 61436 | (1R,2S)-2-[(4S)-2-oxo-4-phenyl-1,3-oxazolidin-3-yl]-3-cyclohexene-1-carbaldehyde | C16H17NO3 | 详情 | 详情 | |
| (IV) | 61437 | (1R,2S,3S,4R)-3,4-dihydroxy-2-[(3R,4S)-2-oxo-4-phenyltetrahydro-3-furanyl]cyclohexanecarbaldehyde | C17H20O5 | 详情 | 详情 | |
| (V) | 23199 | 2-Propanone; Acetone; beta-ketopropane; chevron acetone;propan-2-one； Dimethyl formaldehyde; Dimethyl ketone; dimethylketal; Ketone propane; Methyl ketone; Propanone; Pyroacetic acid; Pyroacetic ether | 67-64-1 | C3H6O | 详情 | 详情 |
| (VI) | 61438 | (3aS,4S,5R,7aR)-2,2-dimethyl-4-[(3R,4S)-2-oxo-4-phenyltetrahydro-3-furanyl]hexahydro-1,3-benzodioxole-5-carbaldehyde | C20H24O5 | 详情 | 详情 | |
| (VII) | 52852 | (3aS,7aR)-2,2-dimethyl-3a,6,7,7a-tetrahydro-1,3-benzodioxole-5-carbaldehyde | C10H14O3 | 详情 | 详情 | |
| (VIII) | 52853 | (2E)-2-bromo-6-methyl-2,5-heptadiene | C8H13Br | 详情 | 详情 | |
| (IX) | 52855 | (3aS,4S,5S,7aR)-4-[(1E)-1,5-dimethyl-1,4-hexadienyl]-2,2-dimethylhexahydro-1,3-benzodioxole-5-carbaldehyde | C18H28O3 | 详情 | 详情 | |
| (X) | 52856 | N-Cyclohexylhydroxylamine | C6H13NO | 详情 | 详情 | |
| (XI) | 61439 | ((Z)-{(3aS,4S,5S,7aR)-4-[(1E)-1,5-dimethyl-1,4-hexadienyl]-2,2-dimethylhexahydro-1,3-benzodioxol-5-yl}methylidene)(cyclohexyl)ammoniumolate | C24H39NO3 | 详情 | 详情 | |
| (XII) | 52858 | (3aS,4R,7aR)-5-{(E)-[(acetyloxy)(cyclohexyl)amino]methylidene}-4-[(1E)-1,5-dimethyl-1,4-hexadienyl]-2,2-dimethylhexahydro-1,3-benzodioxole | C26H41NO4 | 详情 | 详情 | |
| (XIII) | 61440 | (3aS,4S,5R,7aR)-5-[(cyclohexylimino)methyl]-4-[(1E)-1,5-dimethyl-1,4-hexadienyl]-2,2-dimethylhexahydro-1,3-benzodioxol-5-yl acetate | C26H41NO4 | 详情 | 详情 | |
| (XIV) | 61441 | (3aS,4S,5R,7aR)-4-[(1E)-1,5-dimethyl-1,4-hexadienyl]-5-formyl-2,2-dimethylhexahydro-1,3-benzodioxol-5-yl acetate | C20H30O5 | 详情 | 详情 | |
| (XV) | 61442 | (3aS,4S,5R,7aR)-4-[(1E)-1,5-dimethyl-1,4-hexadienyl]-5-(hydroxymethyl)-2,2-dimethylhexahydro-1,3-benzodioxol-5-yl acetate | C20H32O5 | 详情 | 详情 | |
| (XVI) | 52861 | (1R,2S,3S,4R)-3-[(1E)-1,5-dimethyl-1,4-hexadienyl]-4-(hydroxymethyl)-1,2,4-cyclohexanetriol | C15H26O4 | 详情 | 详情 | |
| (XVII) | 52863 | (3R,4S,5S,6R)-4-[(1E)-1,5-dimethyl-1,4-hexadienyl]-1-oxaspiro[2.5]octane-5,6-diol | C15H24O3 | 详情 | 详情 | |
| (XVIII) | 52864 | (3R,4S,5S,6R)-4-[(2R,3R)-2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2.5]octane-5,6-diol | C15H24O4 | 详情 | 详情 | |
| (XIX) | 13712 | (3R,4S,5S,6R)-5-Methoxy-4-[(2R,3R)-2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2.5]octan-6-ol | C16H26O4 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)By condensation of fumagillol [(3R,4S,5S,6R)-4-(1,2-epoxy-1,5-dimethyl4-hexenyl)-6-hydroxy-5-methoxy-1-oxaspiro[2.5]octane] (I) with chloroacetylisocyanate (II) by means of dimethylaminopyridine (DMAP) in dichloromethane.
| 【1】 Fujita, T.; Kanamaru, T.; Folkman, M.; Ingber, D. (Children's Med. Cent. Corp.; Takeda Chemical Industries, Ltd.); Angiogenesis inhibitory agent. EP 0357061 . |
| 【2】 Kishimoto, S.; Fujita, T. (Takeda Chemical Industries, Ltd.); Fumagillol derivs. EP 0359036; EP 0682020; JP 1991007270; US 5164410; US 5166172; US 5180738; US 5698586 . |
| 【3】 Kishimoto, S.; Marui, S.; Fujita, T. (Takeda Chemical Industries, Ltd.); Cyclohexanol derivs., production and use thereof. EP 0415294; JP 1991279376; US 5180735 . |
| 【4】 Marui, S.; Itoh, F.; Kozai, Y.; Sudo, K.; Kishimoto, S.; Chemical modification of fumagillin. I. 6-O-Acyl, 6-O-sulfonyl, 6-O-alkyl, and 6-O-(N-substituted-carbamoyl)fumagillols. Chem Pharm Bull 1992, 40, 1, 96-101. |
| 【5】 Mealy, N.; Prous, J.; Castaner, J.; AGM-1470. Drugs Fut 1994, 19, 11, 981. |
合成路线5
该中间体在本合成路线中的序号：(III)4-(2-Dimethylaminoethoxy)cinnamic acid (I) was converted to acid chloride (II) upon treatment with thionyl chloride in refluxing benzene. This was then coupled with the sodium alkoxide of fumagillol (III) in THF to furnish the title compound.
| 【1】 Chun, H.S.; Choi, N.S.; Lee, S.J.; Han, C.K.; Hong, C.I.; Hong, R.K.; Kim, J.W.; Moon, S.K.; Ahn, S.K. (Chong Kun Dang Corp.); Fumagillol derivs. and processes for preparing the same. US 6063812; WO 9959986 . |
| 【1】 Kim, J.W., Ahn, S.K., Hong, R.K. et al. (Chong Kun Dang Holdings Corp.) Fumagillol derivatives and processes for preparing the same. CA 2331873, EP 1077964, JP 2002515497, US 6063812, WO 1999059986. |
| 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) | 48095 | (E)-3-[4-[2-(dimethylamino)ethoxy]phenyl]-2-propenoic acid | C13H17NO3 | 详情 | 详情 | |
| (I) | 13712 | (3R,4S,5S,6R)-5-Methoxy-4-[(2R,3R)-2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2.5]octan-6-ol | C16H26O4 | 详情 | 详情 | |
| (II) | 48096 | (E)-3-[4-[2-(dimethylamino)ethoxy]phenyl]-2-propenoyl chloride | C13H16ClNO2 | 详情 | 详情 | |
| (II) | 48096 | (E)-3-[4-[2-(dimethylamino)ethoxy]phenyl]-2-propenoyl chloride | C13H16ClNO2 | 详情 | 详情 | |
| (III) | 13712 | (3R,4S,5S,6R)-5-Methoxy-4-[(2R,3R)-2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2.5]octan-6-ol | C16H26O4 | 详情 | 详情 | |
| (III) | 48095 | (E)-3-[4-[2-(dimethylamino)ethoxy]phenyl]-2-propenoic acid | C13H17NO3 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(I)4-(2-Dimethylaminoethoxy)cinnamic acid (I) was converted to acid chloride (II) upon treatment with thionyl chloride in refluxing benzene. This was then coupled with the sodium alkoxide of fumagillol (III) in THF to furnish the title compound.
| 【1】 Chun, H.S.; Choi, N.S.; Lee, S.J.; Han, C.K.; Hong, C.I.; Hong, R.K.; Kim, J.W.; Moon, S.K.; Ahn, S.K. (Chong Kun Dang Corp.); Fumagillol derivs. and processes for preparing the same. US 6063812; WO 9959986 . |
| 【1】 Kim, J.W., Ahn, S.K., Hong, R.K. et al. (Chong Kun Dang Holdings Corp.) Fumagillol derivatives and processes for preparing the same. CA 2331873, EP 1077964, JP 2002515497, US 6063812, WO 1999059986. |
| 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) | 48095 | (E)-3-[4-[2-(dimethylamino)ethoxy]phenyl]-2-propenoic acid | C13H17NO3 | 详情 | 详情 | |
| (I) | 13712 | (3R,4S,5S,6R)-5-Methoxy-4-[(2R,3R)-2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2.5]octan-6-ol | C16H26O4 | 详情 | 详情 | |
| (II) | 48096 | (E)-3-[4-[2-(dimethylamino)ethoxy]phenyl]-2-propenoyl chloride | C13H16ClNO2 | 详情 | 详情 | |
| (II) | 48096 | (E)-3-[4-[2-(dimethylamino)ethoxy]phenyl]-2-propenoyl chloride | C13H16ClNO2 | 详情 | 详情 | |
| (III) | 13712 | (3R,4S,5S,6R)-5-Methoxy-4-[(2R,3R)-2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2.5]octan-6-ol | C16H26O4 | 详情 | 详情 | |
| (III) | 48095 | (E)-3-[4-[2-(dimethylamino)ethoxy]phenyl]-2-propenoic acid | C13H17NO3 | 详情 | 详情 |