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【结 构 式】 
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【分子编号】26241 【品名】(2S)-2-methyl-4-pentenal 【CA登记号】 |
【 分 子 式 】C6H10O 【 分 子 量 】98.1448 【元素组成】C 73.43% H 10.27% O 16.3% |
合成路线1
该中间体在本合成路线中的序号：(III)Treatment of diketoester (I) with trimethylsilyl diazomethane and diisopropyl ethylamine produced enol ether (II). This was condensed with (S)-2-methyl-4-pentenal (III) in the presence of LDA at -120 C to afford the aldol condensation product (IV) as the major isomer. Protection of the 7-hydroxyl group of (IV) with trichloroethoxycarbonyl chloride gave carbonate (V). Enol ether of (V) was then hydrolyzed with p-TsOH in acetone to provide diketoester (VI). Hydroboration of the terminal olefin of (VI) with 9-borabicyclo[3.3.1]nonane gave organoborane (VII). Then, Suzuki coupling of (VII) with vinyl iodide (VIII), followed by acid hydrolysis of the silyl protecting group, provided the thiazolyl heptadecadienoate (IX). Asymmetric hydrogenation of 3-keto group of (IX) in the presence of the modified Noyori's catalyst [RuCl2(R)-BINAP)]2[Et3N] furnished the desired 3-(S) alcohol (X).
| 【1】 Harris, C.R.; et al.; New chemical synthesis of the promising cancer chemotherapeutic agent 12,13-desoxyepothilone B: Discovery of a surprising long-range effect on the diastereoselectivity of an aldol condensation. J Am Chem Soc 1999, 121, 30, 7050. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 13664 | 1,1,1-Trichloro-2-[(chlorocarbonyl)oxy]ethane; 2,2,2-Trichloroethyl chloroformate | 17341-93-4 | C3H2Cl4O2 | 详情 | 详情 | |
| (I) | 26239 | tert-butyl 4,4-dimethyl-3,5-dioxoheptanoate | C13H22O4 | 详情 | 详情 | |
| (II) | 26240 | tert-butyl (Z)-3-methoxy-4,4-dimethyl-5-oxo-2-heptenoate | C14H24O4 | 详情 | 详情 | |
| (III) | 26241 | (2S)-2-methyl-4-pentenal | C6H10O | 详情 | 详情 | |
| (IV) | 26242 | tert-butyl (2Z,6R,7S,8S)-7-hydroxy-3-methoxy-4,4,6,8-tetramethyl-5-oxo-2,10-undecadienoate | C20H34O5 | 详情 | 详情 | |
| (V) | 26243 | tert-butyl (2Z,6R,7S,8S)-3-methoxy-4,4,6,8-tetramethyl-5-oxo-7-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-2,10-undecadienoate | C23H35Cl3O7 | 详情 | 详情 | |
| (VI) | 26244 | tert-butyl (6R,7S,8S)-4,4,6,8-tetramethyl-3,5-dioxo-7-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-10-undecenoate | C22H33Cl3O7 | 详情 | 详情 | |
| (VII) | 26245 | tert-butyl (6R,7S,8S)-11-(9-borabicyclo[3.3.1]non-9-yl)-4,4,6,8-tetramethyl-3,5-dioxo-7-[[(2,2,2-trichloroethoxy)carbonyl]oxy]undecanoate | C30H48BCl3O7 | 详情 | 详情 | |
| (VIII) | 26246 | tert-butyl(dimethyl)silyl (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-pentenyl ether; 4-((1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-iodo-2-methyl-1,5-heptadienyl)-2-methyl-1,3-thiazole | C18H30INOSSi | 详情 | 详情 | |
| (IX) | 26247 | tert-butyl (6R,7S,8S,12Z,15S,16E)-15-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-3,5-dioxo-7-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-12,16-heptadecadienoate | C34H50Cl3NO8S | 详情 | 详情 | |
| (X) | 26248 | tert-butyl (3S,6R,7S,8S,12Z,15S,16E)-3,15-dihydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-7-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-12,16-heptadecadienoate | C34H52Cl3NO8S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)The chiral tetrahydropyran intermediate (XI) has been obtained as follows. The reaction of (-)-pseudoephedrine propionamide (I) with the allyl bromide (II) by the Myers' method gives pentenamide (III), which is reduced with LiNH2BH3 in THF to yield 2(S)-methyl-4-penten-1-ol (IV). Swern oxidation of (IV) affords the corresponding aldehyde (V), which is submitted to an asymmetric aldol condensation with the silyl enol ether (VI) catalyzed by Cu(OTf)2, (S)-Tol-BINAP and (Bu4N)Ph3SiF2 in THF to provide the adduct (VII). The methanolysis of (VII) with Me-OH in refluxing toluene gives the beta-keto ester (VIII), which is treated with Et2BOMe, NaBH4 and HF to yield the chiral hydroxy lactone (IX). The reduction of (IX) with DIBAL in THF affords the lactol (X), which is finally methylated with Ts-OH in refluxing methanol to provide the target tetrahydropyran intermediate (XI).
| 【1】 Bauer, M.; Maier, M.E.; Synthesis of the core structure of salicylihalamide A by intramolecular Suzuki reaction. Org Lett 2002, 4, 13, 2205. |
| 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) | 56935 | N-[(1R,2R)-2-hydroxy-1-methyl-2-phenylethyl]-N-methylpropanamide | C13H19NO2 | 详情 | 详情 | |
| (II) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (III) | 56936 | (2S)-N-[(1R,2R)-2-hydroxy-1-methyl-2-phenylethyl]-N,2-dimethyl-4-pentenamide | C16H23NO2 | 详情 | 详情 | |
| (IV) | 56937 | (2S)-2-methyl-4-penten-1-ol | C6H12O | 详情 | 详情 | |
| (V) | 26241 | (2S)-2-methyl-4-pentenal | C6H10O | 详情 | 详情 | |
| (VI) | 53651 | [(2,2-dimethyl-4-methylene-4H-1,3-dioxin-6-yl)oxy](trimethyl)silane; 2,2-dimethyl-4-methylene-4H-1,3-dioxin-6-yl trimethylsilyl ether | n/a | C10H18O3Si | 详情 | 详情 |
| (VII) | 56938 | 6-[(2R,3S)-2-hydroxy-3-methyl-5-hexenyl]-2,2-dimethyl-4H-1,3-dioxin-4-one | C13H20O4 | 详情 | 详情 | |
| (VIII) | 56939 | methyl (5R,6S)-5-hydroxy-6-methyl-3-oxo-8-nonenoate | C11H18O4 | 详情 | 详情 | |
| (IX) | 56940 | (4S,6R)-4-hydroxy-6-[(1S)-1-methyl-3-butenyl]tetrahydro-2H-pyran-2-one | C10H16O3 | 详情 | 详情 | |
| (X) | 56941 | (4S,6R)-6-[(1S)-1-methyl-3-butenyl]tetrahydro-2H-pyran-2,4-diol | C10H18O3 | 详情 | 详情 | |
| (XI) | 56942 | (4S,6R)-2-methoxy-6-[(1S)-1-methyl-3-butenyl]tetrahydro-2H-pyran-4-ol | C11H20O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XIV)The treatment of diketoester (XII) with trimethylsilyl diazomethane and DIEA gives enol ether (XIII), which is condensed with 2(S)-methyl-4-pentenal (XIV) by means of LDA to yield the aldol condensation product (XV) as the major isomer. The protection of the OH group of (XV) with Troc-Cl and pyridine affords the trichloroethyl carbonate (XVI), whose enol ether group is hydrolyzed with TsOH in acetone to provide the diketoester (XVII). The condensation of (XVII) with iodovinyl intermediate (XI) by means of BBN, (dppf)2PdCl2, AsPh3 and Cs2CO3 in THF/DMF/water gives adduct (XVIII), which is desilylated by means of HCl in methanol to yield the secondary alcohol (XIX). The asymmetric hydrogenation of (XIX) with H2 over a chiral Ru catalyst in acidic methanol affords the secondary diol (XX), which is silylated with Tes-OTf and lutidine to provide the bis-silyl ether (XXI). The selective desilylation of (XXI) with simultaneous hydrolysis of its tert-butyl ester by means of HCl in methanol gives the hydroxyacid (XXII) suitable for cyclization.
| 【1】 Zhang, X.-G.; Chappell, M.D.; Lee, C.B.; Kuduk, S.D.; Danishefsky, S.J.; Chou, T.-C.; Wang, Z.-G.; Stachel, S.J.; Total synthesis and antitumor activity of 12,13-dexoxyepothilone F: An unexpected solvolysis problem at C15, mediated by remote substitution at C21. J Org Chem 2000, 65, 20, 6525. |
| 【2】 Harris, C.R.; et al.; New chemical synthesis of the promising cancer chemotherapeutic agent 12,13-desoxyepothilone B: Discovery of a surprising long-range effect on the diastereoselectivity of an aldol condensation. J Am Chem Soc 1999, 121, 30, 7050. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 49358 | [4-((1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-iodo-2-methyl-1,5-heptadienyl)-1,3-thiazol-2-yl]methyl 2,2,2-trichloroethyl carbonate | C21H31Cl3INO4SSi | 详情 | 详情 | |
| (XII) | 26239 | tert-butyl 4,4-dimethyl-3,5-dioxoheptanoate | C13H22O4 | 详情 | 详情 | |
| (XIII) | 26240 | tert-butyl (Z)-3-methoxy-4,4-dimethyl-5-oxo-2-heptenoate | C14H24O4 | 详情 | 详情 | |
| (XIV) | 26241 | (2S)-2-methyl-4-pentenal | C6H10O | 详情 | 详情 | |
| (XV) | 26242 | tert-butyl (2Z,6R,7S,8S)-7-hydroxy-3-methoxy-4,4,6,8-tetramethyl-5-oxo-2,10-undecadienoate | C20H34O5 | 详情 | 详情 | |
| (XVI) | 26243 | tert-butyl (2Z,6R,7S,8S)-3-methoxy-4,4,6,8-tetramethyl-5-oxo-7-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-2,10-undecadienoate | C23H35Cl3O7 | 详情 | 详情 | |
| (XVII) | 26244 | tert-butyl (6R,7S,8S)-4,4,6,8-tetramethyl-3,5-dioxo-7-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-10-undecenoate | C22H33Cl3O7 | 详情 | 详情 | |
| (XVIII) | 49359 | tert-butyl (6R,7S,8S,12Z,15S,16E)-15-[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,12,16-hexamethyl-3,5-dioxo-7-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-17-[2-([[(2,2,2-trichloroethoxy)carbonyl]oxy]methyl)-1,3-thiazol-4-yl]-12,16-heptadecadienoate | C43H65Cl6NO11SSi | 详情 | 详情 | |
| (XIX) | 49360 | tert-butyl (6R,7S,8S,12Z,15S,16E)-15-hydroxy-4,4,6,8,12,16-hexamethyl-3,5-dioxo-7-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-17-[2-([[(2,2,2-trichloroethoxy)carbonyl]oxy]methyl)-1,3-thiazol-4-yl]-12,16-heptadecadienoate | C37H51Cl6NO11S | 详情 | 详情 | |
| (XX) | 49361 | tert-butyl (3S,6R,7S,8S,12Z,15S,16E)-3,15-dihydroxy-4,4,6,8,12,16-hexamethyl-5-oxo-7-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-17-[2-([[(2,2,2-trichloroethoxy)carbonyl]oxy]methyl)-1,3-thiazol-4-yl]-12,16-heptadecadienoate | C37H53Cl6NO11S | 详情 | 详情 | |
| (XXI) | 49362 | tert-butyl (3S,6R,7S,8S,12Z,15S,16E)-4,4,6,8,12,16-hexamethyl-5-oxo-7-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-17-[2-([[(2,2,2-trichloroethoxy)carbonyl]oxy]methyl)-1,3-thiazol-4-yl]-3,15-bis[(triethylsilyl)oxy]-12,16-heptadecadienoate | C49H81Cl6NO11SSi2 | 详情 | 详情 | |
| (XXII) | 49363 | (3S,6R,7S,8S,12Z,15S,16E)-15-hydroxy-4,4,6,8,12,16-hexamethyl-5-oxo-7-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-17-[2-([[(2,2,2-trichloroethoxy)carbonyl]oxy]methyl)-1,3-thiazol-4-yl]-3-[(triethylsilyl)oxy]-12,16-heptadecadienoic acid | C39H59Cl6NO11SSi | 详情 | 详情 |