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【结 构 式】 
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【分子编号】56942 【品名】(4S,6R)-2-methoxy-6-[(1S)-1-methyl-3-butenyl]tetrahydro-2H-pyran-4-ol 【CA登记号】 |
【 分 子 式 】C11H20O3 【 分 子 量 】200.278 【元素组成】C 65.97% H 10.07% O 23.97% |
合成路线1
该中间体在本合成路线中的序号：(XI)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2
该中间体在本合成路线中的序号：(XI)The Stille coupling of the benzodioxanone (XII) with allyltributyltin (XIII) by means of trifurylphosphine (TFP) and Pd2(dba)3 gives the 6-allylsalicylic acid (XIV), which is esterified with the intermediate (XI) by means of DEAD and PPH3 in ethyl ether to yield the ester (XV). Hydrolysis of the lactol group of (XV) with Ac-OH affords the carbaldehyde (XVI), which is condensed with the phosphorane (XVII) to provide the unsaturated ester (XVIII). The silylation of the free OH groups of (XVIII) with Tbdms-OTf and lutidine gives the protected compound (XIX), which is submitted to a rig closing metathesis reaction catalyzed by a Ru catalyst in dichloromethane to yield the macrolactone (XX). The selective hydrolysis of the methyl ester group of (XX) by treatment with (Bu3Sn)2O in refluxing toluene affords the unsaturated carboxylic acid (XXI), which is treated with DPPA in refluxing benzene to provide the corresponding isocyanate (XXII). The reaction of the isocyanate group of (XXII) with (1Z,3Z)-hexadienyl cuprate, prepared in situ by reaction of Et-Li, CuBr/Me2S and acetylene, gives the silylated heptadienamide (XXIII), along with some pentanamide and nonatrienamide derivatives that are separated by chromatography. Finally, compound (XXIII) is desilylated by means of HF and pyridine in THF to provide the target salicylhalamide A.
| 【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 |
|---|---|---|---|---|---|---|
| (XI) | 56942 | (4S,6R)-2-methoxy-6-[(1S)-1-methyl-3-butenyl]tetrahydro-2H-pyran-4-ol | C11H20O3 | 详情 | 详情 | |
| (XII) | 56943 | 2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-5-yl trifluoromethanesulfonate | C11H9F3O6S | 详情 | 详情 | |
| (XIII) | 40599 | Allyltributyltin; Tributyl-2-propenylstannane | 24850-33-7 | C15H32Sn | 详情 | 详情 |
| (XIV) | 56944 | 2-allyl-6-hydroxybenzoic acid | C10H10O3 | 详情 | 详情 | |
| (XV) | 56945 | (4R,6R)-2-methoxy-6-[(1S)-1-methyl-3-butenyl]tetrahydro-2H-pyran-4-yl 2-allyl-6-hydroxybenzoate | C21H28O5 | 详情 | 详情 | |
| (XVI) | 56946 | (1R,3R,4S)-3-hydroxy-4-methyl-1-(2-oxoethyl)-6-heptenyl 2-allyl-6-hydroxybenzoate | C20H26O5 | 详情 | 详情 | |
| (XVII) | 14689 | Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate | 2605-67-6 | C21H19O2P | 详情 | 详情 |
| (XVIII) | 56947 | (1S,3R,4S)-3-hydroxy-1-[(E)-4-methoxy-4-oxo-2-butenyl]-4-methyl-6-heptenyl 2-allyl-6-hydroxybenzoate | C23H30O6 | 详情 | 详情 | |
| (XIX) | 56948 | (1S,3R,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-1-[(E)-4-methoxy-4-oxo-2-butenyl]-4-methyl-6-heptenyl 2-allyl-6-{[tert-butyl(dimethyl)silyl]oxy}benzoate | C35H58O6Si2 | 详情 | 详情 | |
| (XX) | 56949 | methyl (E)-4-((3S,5R,6S)-5,14-bis{[tert-butyl(dimethyl)silyl]oxy}-6-methyl-1-oxo-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-3-yl)-2-butenoate | C33H54O6Si2 | 详情 | 详情 | |
| (XXI) | 56950 | (E)-4-((3S,5R,6S)-5,14-bis{[tert-butyl(dimethyl)silyl]oxy}-6-methyl-1-oxo-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-3-yl)-2-butenoic acid | C32H52O6Si2 | 详情 | 详情 | |
| (XXII) | 56951 | (3S,5R,6S)-5,14-bis{[tert-butyl(dimethyl)silyl]oxy}-3-[(E)-3-isocyanato-2-propenyl]-6-methyl-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-1-one | C32H51NO5Si2 | 详情 | 详情 | |
| (XXIII) | 56952 | (2Z,4Z)-N-[(E)-3-((3S,5R,6S)-5,14-bis{[tert-butyl(dimethyl)silyl]oxy}-6-methyl-1-oxo-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-3-yl)-1-propenyl]-2,4-heptadienamide | C38H61NO5Si2 | 详情 | 详情 |