|
【结 构 式】 
|
【分子编号】51427 【品名】D-Pantolactone; R(-)-2-Hydroxy-3,3-dimethyl-gamma-butyrolactone 【CA登记号】599-04-2 |
【 分 子 式 】C6H10O3 【 分 子 量 】130.1436 【元素组成】C 55.37% H 7.74% O 36.88% |
合成路线1
该中间体在本合成路线中的序号：(X)The C1-C6 building block (V) (segment A) can be obtained as follows. Protection of (–)-pantolactone (X) as the tetrahydropyranyl ether (XI) using dihydropyran and pyridinium tosylate, followed by reduction of the lactone ring with DIBAL in cold toluene, gives the lactol (XII). Subsequent Wittig reaction of the cyclic hemiacetal (XII) with methylene triphenylphosphorane affords the hydroxy olefin (XIII), which is protected as the benzyl ether (XIV) by treatment with benzyl bromide and potassium tert-butoxide. Hydroboration of olefin (XIV) followed by quenching with alkaline H2O2 provides the primary alcohol (XV) as the major isomer, which is converted to the acetonide (XVI) by treatment with 2,2-dimethoxypropane and p-toluenesulfonic acid. After catalytic hydrogenolysis of the benzyl ether (XVI), the deprotected alcohol (XVII) is oxidized to aldehyde (XVIII) under Swern conditions. Then, addition of 3-butenylmagnesium bromide (XIX) to the aldehyde (XVIII) provides alcohol (XX), which is oxidized to the target ketone (V) by treatment with N-methylmorpholine N-oxide and a catalytic amount of tetrapropylammonium perruthenate (3). Scheme 2.
| 【3】 Klar, U., Rohr, B., Kuczynski,F., Schwede, W., Berger, M., Skuballa, W., Buchmann, B. Efficient chiral pool synthesis of the C1-C6 fragment of epothilone. Synthesis 2005, (2): 301-5. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 65648 | C14H24O3 | 详情 | 详情 | ||
| (X) | 51427 | D-Pantolactone; R(-)-2-Hydroxy-3,3-dimethyl-gamma-butyrolactone | 599-04-2 | C6H10O3 | 详情 | 详情 |
| (XI) | 65653 | C11H19O4 | 详情 | 详情 | ||
| (XII) | 65654 | C11H21O4 | 详情 | 详情 | ||
| (XIII) | 65655 | C12H23O3 | 详情 | 详情 | ||
| (XIV) | 65656 | C19H28O3 | 详情 | 详情 | ||
| (XV) | 65657 | C19H31O4 | 详情 | 详情 | ||
| (XVI) | 65658 | C17H26O3 | 详情 | 详情 | ||
| (XVII) | 65659 | C10H20O3 | 详情 | 详情 | ||
| (XVIII) | 65660 | C10H18O3 | 详情 | 详情 | ||
| (XIX) | 35896 | bromo(3-butenyl)magnesium | 7103-09-5 | C4H7BrMg | 详情 | 详情 |
| (XX) | 65661 | C14H26O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)The synthesis of the chiral 3-heptanone intermediate has been obtained as follows: The protection of the OH group of the chiral lactone (I) with Tbdms-Cl and imidazole gives the silyl ether (II), which is reduced with DIBAL to yield the lactol (III).The reaction of (III) with the Tebbe reagent affords the pentenol derivative (IV), which is oxidized with Dess-Martin periodinane (DMP), affording the aldehyde (V). The Grignard synthesis of (V) with ethylmagnesium bromide (VI) provides the 3-heptanol derivative (VII), which is hydroxylated at the terminal double bond by means of BH3/THF and H2O2, giving the diol (VIII). The selective protection of the primary OH group of (VIII) with Dmt-Cl, DIEA and DMAP yields the trityl ether (IX), which is finally oxidized with DMP to afford the desired chiral heptanone (X)
| 【1】 Martin, N.; Thomas, E.J.; Total syntheses of epothilones B and D: Applications of allylstannanes in organic synthesis. Tetrahedron Lett 2001, 42, 47, 8373. |
| 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) | 51427 | D-Pantolactone; R(-)-2-Hydroxy-3,3-dimethyl-gamma-butyrolactone | 599-04-2 | C6H10O3 | 详情 | 详情 |
| (II) | 51428 | (3R)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyldihydro-2(3H)-furanone | C12H24O3Si | 详情 | 详情 | |
| (III) | 51429 | (3R)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyltetrahydro-2-furanol | C12H26O3Si | 详情 | 详情 | |
| (IV) | 51430 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,2-dimethyl-4-penten-1-ol | C13H28O2Si | 详情 | 详情 | |
| (V) | 51431 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,2-dimethyl-4-pentenal | C13H26O2Si | 详情 | 详情 | |
| (VI) | 24239 | bromo(ethyl)magnesium；ethylmagnesium bromide | 925-90-6 | C2H5BrMg | 详情 | 详情 |
| (VII) | 51432 | (5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-6-hepten-3-ol | C15H32O2Si | 详情 | 详情 | |
| (VIII) | 51433 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-1,5-heptanediol | C15H34O3Si | 详情 | 详情 | |
| (IX) | 51434 | (5S)-7-[bis(4-methoxyphenyl)(phenyl)methoxy]-5-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-3-heptanol | C36H52O5Si | 详情 | 详情 | |
| (X) | 51435 | (5S)-7-[bis(4-methoxyphenyl)(phenyl)methoxy]-5-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-3-heptanone | C36H50O5Si | 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 synthesis of the chiral 3-heptanone intermediate has been obtained as follows: The protection of the OH group of the chiral lactone (I) with Tbdms-Cl and imidazole gives the silyl ether (II), which is reduced with DIBAL to yield the lactol (III).The reaction of (III) with the Tebbe reagent affords the pentenol derivative (IV), which is oxidized with Dess-Martin periodinane (DMP), affording the aldehyde (V). The Grignard synthesis of (V) with ethylmagnesium bromide (VI) provides the 3-heptanol derivative (VII), which is hydroxylated at the terminal double bond by means of BH3/THF and H2O2, giving the diol (VIII). The selective protection of the primary OH group of (VIII) with Dmt-Cl, DIEA and DMAP yields the trityl ether (IX), which is finally oxidized with DMP to afford the desired chiral heptanone (X).
| 【1】 Martin, N.; Thomas, E.J.; Total syntheses of epothilones B and D: Applications of allylstannanes in organic synthesis. Tetrahedron Lett 2001, 42, 47, 8373. |
| 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) | 51427 | D-Pantolactone; R(-)-2-Hydroxy-3,3-dimethyl-gamma-butyrolactone | 599-04-2 | C6H10O3 | 详情 | 详情 |
| (II) | 51428 | (3R)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyldihydro-2(3H)-furanone | C12H24O3Si | 详情 | 详情 | |
| (III) | 51429 | (3R)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyltetrahydro-2-furanol | C12H26O3Si | 详情 | 详情 | |
| (IV) | 51430 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,2-dimethyl-4-penten-1-ol | C13H28O2Si | 详情 | 详情 | |
| (V) | 51431 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,2-dimethyl-4-pentenal | C13H26O2Si | 详情 | 详情 | |
| (VI) | 24239 | bromo(ethyl)magnesium；ethylmagnesium bromide | 925-90-6 | C2H5BrMg | 详情 | 详情 |
| (VII) | 51432 | (5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-6-hepten-3-ol | C15H32O2Si | 详情 | 详情 | |
| (VIII) | 51433 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-1,5-heptanediol | C15H34O3Si | 详情 | 详情 | |
| (IX) | 51434 | (5S)-7-[bis(4-methoxyphenyl)(phenyl)methoxy]-5-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-3-heptanol | C36H52O5Si | 详情 | 详情 | |
| (X) | 51435 | (5S)-7-[bis(4-methoxyphenyl)(phenyl)methoxy]-5-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-3-heptanone | C36H50O5Si | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IV)3-Phthalimidopropionyl chloride (I) is condensed with n-nonylamine to produce the corresponding amide (II). Subsequent hydrazinolysis of phthalimide (II) furnishes the aminopropanamide (III), which is condensed with D-pantonolactone (IV) to yield the desired compound.
| 【1】 Clifton, G.; Bryant, S.R.; Skinner, C.G.; N1-(Substituted) pantothenamides, antimetabolites of pantothenic acid. Arch Biochem Biophys 1970, 137, 2, 523. |
| 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) | 53390 | 3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propanoyl chloride | n/a | C11H8ClNO3 | 详情 | 详情 |
| (II) | 64801 | 3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-N-nonylpropanamide | C20H28N2O3 | 详情 | 详情 | |
| (III) | 64802 | 3-amino-N-nonylpropanamide | C12H26N2O | 详情 | 详情 | |
| (IV) | 51427 | D-Pantolactone; R(-)-2-Hydroxy-3,3-dimethyl-gamma-butyrolactone | 599-04-2 | C6H10O3 | 详情 | 详情 |