【结 构 式】 |
【分子编号】47844 【品名】3-((3S)-3-[[tert-butyl(diphenyl)silyl]oxy]piperidinyl)-1,2-propanediol 【CA登记号】 |
【 分 子 式 】C24H35NO3Si 【 分 子 量 】413.63234 【元素组成】C 69.69% H 8.53% N 3.39% O 11.6% Si 6.79% |
合成路线1
该中间体在本合成路线中的序号:(XVI)Aldehyde (II) was prepared by mono-benzylation of 1,4-butanediol (I) followed by Swern oxidation. Subsequent addition of ethynylmagnesium bromide (III) to the aldehyde function of (II) provided propargyl alcohol (IV). Kinetic resolution of the racemic alcohol (IV) by lipase-mediated acetylation in the presence of vinyl acetate produced a mixture of the (S)-acetate (V) and the unreacted (R)-alcohol (VI). The required (S)-propargyl acetate (V) was subjected to partial hydrogenation using Lindlar catalyst to furnish allyl acetate (VII), which was further hydrolyzed to the chiral alcohol (VIII). After protection of (VIII) as the silylated derivative (IX), reductive removal of the benzyl ether using lithium naphthalenide afforded the primary alcohol (X). This was then treated with methanesulfonyl chloride and triethylamine to give mesylate (XI). Ozonolysis of the double bond of (XI), followed by reductive work-up with dimethyl sulfide, yielded aldehyde (XII). This was reacted with hydroxylamine hydrochloride and Et3N in allyl alcohol (XIII) to produce the intermediate nitrone (XIV), which underwent simultaneous 1,3-dipolar cycloaddition to allyl alcohol to furnish the isoxazolopyridine (XV) as a mixture of three diastereoisomers. This mixture was then subjected to hydrogenolytic N-O bond fission, producing piperidine (XVI).
【1】 Ooi, H.e; et al.; A concise enantioselective synthesis of antimalarial febrifugine alkaloids. Org Lett 2001, 3, 6, 953. |
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) | 43160 | 1,4-butanediol;1,4-Dihydroxybutane;1,4-Butylene glycol;Tetramethylene glycol | 110-63-4 | C4H10O2 | 详情 | 详情 |
(II) | 46170 | 4-(benzyloxy)butanal | C11H14O2 | 详情 | 详情 | |
(III) | 17778 | ETHYNYLMAGNESIUM BROMIDE; bromo(ethynyl)magnesium | 4301-14-8 | C2HBrMg | 详情 | 详情 |
(IV) | 47833 | 6-(benzyloxy)-1-hexyn-3-ol | C13H16O2 | 详情 | 详情 | |
(V) | 47834 | (1S)-1-[3-(benzyloxy)propyl]-2-propynyl acetate | C15H18O3 | 详情 | 详情 | |
(VI) | 47835 | (3R)-6-(benzyloxy)-1-hexyn-3-ol | C13H16O2 | 详情 | 详情 | |
(VII) | 47836 | (1S)-1-[3-(benzyloxy)propyl]-2-propenyl acetate | C15H20O3 | 详情 | 详情 | |
(VIII) | 47837 | (3S)-6-(benzyloxy)-1-hexen-3-ol | C13H18O2 | 详情 | 详情 | |
(IX) | 47838 | ([(1S)-1-[3-(benzyloxy)propyl]-2-propenyl]oxy)(tert-butyl)diphenylsilane; benzyl (4S)-4-[[tert-butyl(diphenyl)silyl]oxy]-5-hexenyl ether | C29H36O2Si | 详情 | 详情 | |
(X) | 47839 | (4S)-4-[[tert-butyl(diphenyl)silyl]oxy]-5-hexen-1-ol | C22H30O2Si | 详情 | 详情 | |
(XI) | 47840 | (4S)-4-[[tert-butyl(diphenyl)silyl]oxy]-5-hexenyl methanesulfonate | C23H32O4SSi | 详情 | 详情 | |
(XII) | 47841 | (4S)-4-[[tert-butyl(diphenyl)silyl]oxy]-5-oxopentyl methanesulfonate | C22H30O5SSi | 详情 | 详情 | |
(XIII) | 12234 | 2-Propen-1-ol; Allyl alcohol | 107-18-6 | C3H6O | 详情 | 详情 |
(XIV) | 47842 | (5S)-5-[[tert-butyl(diphenyl)silyl]oxy]-2,3,4,5-tetrahydro-1-pyridiniumolate | C21H27NO2Si | 详情 | 详情 | |
(XV) | 47843 | ((4S)-4-[[tert-butyl(diphenyl)silyl]oxy]hexahydro-2H-isoxazolo[2,3-a]pyridin-2-yl)methanol | C24H33NO3Si | 详情 | 详情 | |
(XVI) | 47844 | 3-((3S)-3-[[tert-butyl(diphenyl)silyl]oxy]piperidinyl)-1,2-propanediol | C24H35NO3Si | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(XVI)After protection of (XVI) as the N-Boc derivative (XVII), the diol function was cyclized to epoxide (XIX) by treatment with N-tosyl imidazole (XVIII) in the presence of NaH. Epoxide (XIX) opening with the potassium salt of 4-quinazolinone (XX) gave alcohol (XXI). Subsequent Dess-Martin oxidation of (XXI) yielded the epimeric mixture of ketones (XXII). Acid hydrolysis of this mixture furnished the title trans-piperidine along with the cis-isomer, which was isolated in the cyclic hemiacetal form (XXIII). The title compound was also obtained by isomerization of (XXIII) in refluxing MeOH).
【1】 Ooi, H.e; et al.; A concise enantioselective synthesis of antimalarial febrifugine alkaloids. Org Lett 2001, 3, 6, 953. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(XVI) | 47844 | 3-((3S)-3-[[tert-butyl(diphenyl)silyl]oxy]piperidinyl)-1,2-propanediol | C24H35NO3Si | 详情 | 详情 | |
(XVII) | 47845 | tert-butyl (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-(2,3-dihydroxypropyl)-1-piperidinecarboxylate | C19H39NO5Si | 详情 | 详情 | |
(XVIII) | 47846 | 1-[(4-methylphenyl)sulfonyl]-1H-imidazole | 2232-08-8 | C10H10N2O2S | 详情 | 详情 |
(XIX) | 47847 | tert-butyl (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-(2-oxiranylmethyl)-1-piperidinecarboxylate | C19H37NO4Si | 详情 | 详情 | |
(XX) | 14634 | 4(3H)-quinazolinone | C8H6N2O | 详情 | 详情 | |
(XXI) | 47848 | tert-butyl (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-[2-hydroxy-3-[4-oxo-3(4H)-quinazolinyl]propyl]-1-piperidinecarboxylate | C27H43N3O5Si | 详情 | 详情 | |
(XXII) | 47849 | tert-butyl (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-[2-oxo-3-[4-oxo-3(4H)-quinazolinyl]propyl]-1-piperidinecarboxylate | C27H41N3O5Si | 详情 | 详情 | |
(XXIII) | 38272 | 3-[[(3aS,7aS)-2-hydroxyoctahydrofuro[3,2-b]pyridin-2-yl]methyl]-4(3H)-quinazolinone | C16H19N3O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(XVI)Aldehyde (II) was prepared by mono-benzylation of 1,4-butanediol (I) followed by Swern oxidation. Subsequent addition of ethynylmagnesium bromide (III) to the aldehyde function of (II) provided propargyl alcohol (IV). Kinetic resolution of the racemic alcohol (IV) by lipase-mediated acetylation in the presence of vinyl acetate produced a mixture of the (S)-acetate (V) and the unreacted (R)-alcohol (VI). The required (S)-propargyl acetate (V) was subjected to partial hydrogenation using Lindlar catalyst to furnish allyl acetate (VII), which was further hydrolyzed to the chiral alcohol (VIII). After protection of (VIII) as the silylated derivative (IX), reductive removal of the benzyl ether using lithium naphthalenide afforded the primary alcohol (X). This was then treated with methanesulfonyl chloride and triethylamine to give mesylate (XI). Ozonolysis of the double bond of (XI), followed by reductive work-up with dimethyl sulfide, yielded aldehyde (XII). This was reacted with hydroxylamine hydrochloride and Et3N in allyl alcohol (XIII) to produce the intermediate nitrone (XIV), which underwent simultaneous 1,3-dipolar cycloaddition to allyl alcohol to furnish the isoxazolopyridine (XV) as a mixture of three diastereoisomers. This mixture was then subjected to hydrogenolytic N-O bond fission, producing piperidine (XVI).
【1】 Ooi, H.e; et al.; A concise enantioselective synthesis of antimalarial febrifugine alkaloids. Org Lett 2001, 3, 6, 953. |
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) | 43160 | 1,4-butanediol;1,4-Dihydroxybutane;1,4-Butylene glycol;Tetramethylene glycol | 110-63-4 | C4H10O2 | 详情 | 详情 |
(II) | 46170 | 4-(benzyloxy)butanal | C11H14O2 | 详情 | 详情 | |
(III) | 17778 | ETHYNYLMAGNESIUM BROMIDE; bromo(ethynyl)magnesium | 4301-14-8 | C2HBrMg | 详情 | 详情 |
(IV) | 47833 | 6-(benzyloxy)-1-hexyn-3-ol | C13H16O2 | 详情 | 详情 | |
(V) | 47834 | (1S)-1-[3-(benzyloxy)propyl]-2-propynyl acetate | C15H18O3 | 详情 | 详情 | |
(VI) | 47835 | (3R)-6-(benzyloxy)-1-hexyn-3-ol | C13H16O2 | 详情 | 详情 | |
(VII) | 47836 | (1S)-1-[3-(benzyloxy)propyl]-2-propenyl acetate | C15H20O3 | 详情 | 详情 | |
(VIII) | 47837 | (3S)-6-(benzyloxy)-1-hexen-3-ol | C13H18O2 | 详情 | 详情 | |
(IX) | 47838 | ([(1S)-1-[3-(benzyloxy)propyl]-2-propenyl]oxy)(tert-butyl)diphenylsilane; benzyl (4S)-4-[[tert-butyl(diphenyl)silyl]oxy]-5-hexenyl ether | C29H36O2Si | 详情 | 详情 | |
(X) | 47839 | (4S)-4-[[tert-butyl(diphenyl)silyl]oxy]-5-hexen-1-ol | C22H30O2Si | 详情 | 详情 | |
(XI) | 47840 | (4S)-4-[[tert-butyl(diphenyl)silyl]oxy]-5-hexenyl methanesulfonate | C23H32O4SSi | 详情 | 详情 | |
(XII) | 47841 | (4S)-4-[[tert-butyl(diphenyl)silyl]oxy]-5-oxopentyl methanesulfonate | C22H30O5SSi | 详情 | 详情 | |
(XIII) | 12234 | 2-Propen-1-ol; Allyl alcohol | 107-18-6 | C3H6O | 详情 | 详情 |
(XIV) | 47842 | (5S)-5-[[tert-butyl(diphenyl)silyl]oxy]-2,3,4,5-tetrahydro-1-pyridiniumolate | C21H27NO2Si | 详情 | 详情 | |
(XV) | 47843 | ((4S)-4-[[tert-butyl(diphenyl)silyl]oxy]hexahydro-2H-isoxazolo[2,3-a]pyridin-2-yl)methanol | C24H33NO3Si | 详情 | 详情 | |
(XVI) | 47844 | 3-((3S)-3-[[tert-butyl(diphenyl)silyl]oxy]piperidinyl)-1,2-propanediol | C24H35NO3Si | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号:(XVI)After protection of (XVI) as the N-Boc derivative (XVII), the diol function was cyclized to epoxide (XIX) by treatment with N-tosyl imidazole (XVIII) in the presence of NaH. Epoxide (XIX) opening with the potassium salt of 4-quinazolinone (XX) gave alcohol (XXI). Subsequent Dess-Martin oxidation of (XXI) yielded the epimeric mixture of ketones (XXII). Acid hydrolysis of this mixture furnished the trans-piperidine (XXIII) along with the title cis-isomer, which was isolated in the cyclic hemiacetal form.
【1】 Ooi, H.e; et al.; A concise enantioselective synthesis of antimalarial febrifugine alkaloids. Org Lett 2001, 3, 6, 953. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(XVI) | 47844 | 3-((3S)-3-[[tert-butyl(diphenyl)silyl]oxy]piperidinyl)-1,2-propanediol | C24H35NO3Si | 详情 | 详情 | |
(XVII) | 47845 | tert-butyl (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-(2,3-dihydroxypropyl)-1-piperidinecarboxylate | C19H39NO5Si | 详情 | 详情 | |
(XVIII) | 47846 | 1-[(4-methylphenyl)sulfonyl]-1H-imidazole | 2232-08-8 | C10H10N2O2S | 详情 | 详情 |
(XIX) | 47847 | tert-butyl (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-(2-oxiranylmethyl)-1-piperidinecarboxylate | C19H37NO4Si | 详情 | 详情 | |
(XX) | 14634 | 4(3H)-quinazolinone | C8H6N2O | 详情 | 详情 | |
(XXI) | 47848 | tert-butyl (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-[2-hydroxy-3-[4-oxo-3(4H)-quinazolinyl]propyl]-1-piperidinecarboxylate | C27H43N3O5Si | 详情 | 详情 | |
(XXII) | 47849 | tert-butyl (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-[2-oxo-3-[4-oxo-3(4H)-quinazolinyl]propyl]-1-piperidinecarboxylate | C27H41N3O5Si | 详情 | 详情 | |
(XXIII) | 47850 | 3-[3-[(2R,3S)-3-hydroxypiperidinyl]-2-oxopropyl]-4(3H)-quinazolinone | C16H19N3O3 | 详情 | 详情 |