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【结 构 式】 
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【分子编号】25713 【品名】(4S)-4-benzyl-3-propionyl-1,3-oxazolidin-2-one 【CA登记号】 |
【 分 子 式 】C13H15NO3 【 分 子 量 】233.26704 【元素组成】C 66.94% H 6.48% N 6% O 20.58% |
合成路线1
该中间体在本合成路线中的序号：(I)Boron enolate obtained from chiral propionyloxazolidinone (I) and dibutylboron triflate (Bu2BOTf) was condensed with n-octanal (II) to produce the syn aldol compound (III), which was protected as the silyl ether (IV) with tert-butyldimethylsilyl triflate. Then, removal of the chiral auxiliary by hydrolysis with lithium peroxide afforded the (2S,3R)-beta-(silyloxy)acid (V). After activation as the mixed anhydride (VII) with 2,4,6-trichlorobenzoyl chloride (VI), esterification with benzyl (S)-2-hydroxy-3-methylbutyrate (VIII) gave diester (IX). Subsequent removal of the silyl group using HF in acetonitrile provided intermediate (X).
| 【1】 Wagner, B.; et al.; Total synthesis and conformational studies of hapalosin, N-desmethylhapalosin and 8-deoxyhapalosin. Bioorg Med Chem 1999, 7, 5, 737. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 40666 | tert-butyl(dimethyl)silyl trifluoromethanesulfonoperoxoate | C7H15F3O4SSi | 详情 | 详情 | ||
| (I) | 25713 | (4S)-4-benzyl-3-propionyl-1,3-oxazolidin-2-one | C13H15NO3 | 详情 | 详情 | |
| (II) | 25714 | octanal | 124-13-0 | C8H16O | 详情 | 详情 |
| (III) | 25715 | (4S)-4-benzyl-3-[(2S,3R)-3-hydroxy-2-methyldecanoyl]-1,3-oxazolidin-2-one | C21H31NO4 | 详情 | 详情 | |
| (IV) | 25716 | (4S)-4-benzyl-3-((2S,3R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyldecanoyl)-1,3-oxazolidin-2-one | C27H45NO4Si | 详情 | 详情 | |
| (V) | 25717 | (2S,3R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyldecanoic acid | C17H36O3Si | 详情 | 详情 | |
| (VI) | 25718 | 2,4,6-trichlorobenzoyl chloride | 4136-95-2 | C7H2Cl4O | 详情 | 详情 |
| (VII) | 25719 | (2S,3R)-2-[[tert-butyl(dimethyl)silyl]oxy]-1-methyldecanoic 2,4,6-trichloro-1-benzenecarboxylic anhydride | C24H37Cl3O4Si | 详情 | 详情 | |
| (VIII) | 25720 | benzyl (2S)-2-hydroxy-3-methylbutanoate | C12H16O3 | 详情 | 详情 | |
| (IX) | 25721 | (1S)-1-[(benzyloxy)carbonyl]-2-methylpropyl (2S,3R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyldecanoate | C29H50O5Si | 详情 | 详情 | |
| (X) | 25722 | (1S)-1-[(benzyloxy)carbonyl]-2-methylpropyl (2S,3R)-3-hydroxy-2-methyldecanoate | C23H36O5 | 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 condensation of the choral oxazolidinone (I) with octanal (II) by means of Bu2B-OTf and TEA in dichloromethane gives the chiral alcohol (III), which is protected with DHP and PPTS, yielding the tetrahydropyranyl ether (IV). The cleavage of the chiral adjuvant of (IV) by means of LiOH and H2O2 affords the carboxylic acid (V), which is esterified with (2S)-hydroxy-3-methylbutyric acid benzyl ester (VI) by means of trichlorobenzoyl chloride and TEA to provide the adduct (VII). Elimination of the tetrahydropyranyl protecting group of (VII) by means of Ts-OH gives the hydroxyester (VIII), which is condensed with the chiral amino acid (IX) by means of trichlorobenzoyl chloride as before to yield the triester compound (X). Elimination of the Mom protecting group of (X) by means of Tms-Cl and tetrabutylammonium bromide affords the hydroxy compound (XI), which is hydrogenated with H2 over Pd(OH)2 to provide the carboxylic acid (XII). Elimination of the Boc protecting group of (XII) by means of TFA gives the amino acid (XII), which is finally submitted to a macrocyclization by means of DPPA and DIEA in DMF to yield the target hapalosin.
| 【1】 Hermann, C.; et al.; Total synthesis of hapalosin and two ring expanded analogs. Tetrahedron 2000, 56, 43, 8461. |
| 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) | 25713 | (4S)-4-benzyl-3-propionyl-1,3-oxazolidin-2-one | C13H15NO3 | 详情 | 详情 | |
| (II) | 25714 | octanal | 124-13-0 | C8H16O | 详情 | 详情 |
| (III) | 25715 | (4S)-4-benzyl-3-[(2S,3R)-3-hydroxy-2-methyldecanoyl]-1,3-oxazolidin-2-one | C21H31NO4 | 详情 | 详情 | |
| (IV) | 50327 | Cyanoethane; Ethyl cyanide; Propionitrile | 107-12-0 | C26H39NO5 | 详情 | 详情 |
| (V) | 50328 | (2S,3R)-2-methyl-3-(tetrahydro-2H-pyran-2-yloxy)decanoic acid | C16H30O4 | 详情 | 详情 | |
| (VI) | 25720 | benzyl (2S)-2-hydroxy-3-methylbutanoate | C12H16O3 | 详情 | 详情 | |
| (VII) | 50329 | (1S)-1-[(benzyloxy)carbonyl]-2-methylpropyl (2S,3R)-2-methyl-3-(tetrahydro-2H-pyran-2-yloxy)decanoate | C28H44O6 | 详情 | 详情 | |
| (VIII) | 25722 | (1S)-1-[(benzyloxy)carbonyl]-2-methylpropyl (2S,3R)-3-hydroxy-2-methyldecanoate | C23H36O5 | 详情 | 详情 | |
| (IX) | 50330 | (3R,4S)-4-[(tert-butoxycarbonyl)(methyl)amino]-3-(methoxymethoxy)-5-phenylpentanoic acid | C19H29NO6 | 详情 | 详情 | |
| (X) | 50331 | benzyl (6S,7R,11R,12S,15S)-6-benzyl-11-heptyl-15-isopropyl-7-(methoxymethoxy)-2,2,5,12-tetramethyl-4,9,13-trioxo-3,10,14-trioxa-5-azahexadecan-16-oate | C42H63NO10 | 详情 | 详情 | |
| (XI) | 50332 | benzyl (6S,7R,11S,12S,15S)-6-benzyl-11-heptyl-7-hydroxy-15-isopropyl-2,2,5,12-tetramethyl-4,9,13-trioxo-3,10,14-trioxa-5-azahexadecan-16-oate | C40H59NO9 | 详情 | 详情 | |
| (XII) | 50333 | (6S,7R,11R,12S,15S)-6-benzyl-11-heptyl-7-hydroxy-15-isopropyl-2,2,5,12-tetramethyl-4,9,13-trioxo-3,10,14-trioxa-5-azahexadecan-16-oic acid | C33H53NO9 | 详情 | 详情 | |
| (XIII) | 50334 | (2S)-2-[((2S,3R)-3-[[(3R,4S)-3-hydroxy-4-(methylamino)-5-phenylpentanoyl]oxy]-2-methyldecanoyl)oxy]-3-methylbutyric acid | C28H45NO7 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)Preparation of fragment (VIII) is illustrated in Scheme 24509401a. Aldol condensation of aldehyde (I) with (R)-4-benzyl-3-propionyl-2-oxazolidinone (II) mediated by dibutylboron triflate gives the syn aldol adduct (III). This is converted to the Weinreb amide (IV) by treatment with N,O-dimethyl hydroxylamine in the presence of trimethylaluminium. After silylation of the secondary hydroxyl group of (IV), the resultant bis-silyl ether (V) is selectively desilylated at the primary hydroxyl group with p-toluenesulfonic acid and tetrabutylammonium bisulfate, to afford alcohol (VI). Dess-Martin oxidation of (VI) gives the aldehyde (VII), which is then subjected to Corey-Fuchs olefination with CBr4 and PPh3 to produce the gem-dibromo olefin (VIII)
| 【1】 Evans, D.A.; Starr, J.T.; A cascade cycloaddition strategy leading to the total synthesis of (-)-FR182877. Angew Chem. Int Ed 2002, 41, 10, 1787. |
| 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) | 60194 | 7-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-4-methyl-4-heptenal | C14H28O2Si | 详情 | 详情 | |
| (II) | 25713 | (4S)-4-benzyl-3-propionyl-1,3-oxazolidin-2-one | C13H15NO3 | 详情 | 详情 | |
| (III) | 60195 | (4R)-4-benzyl-3-((2R,3S,6E)-9-{[tert-butyl(dimethyl)silyl]oxy}-3-hydroxy-2,6-dimethyl-6-nonenoyl)-1,3-oxazolidin-2-one | C27H43NO5Si | 详情 | 详情 | |
| (IV) | 60196 | 9-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-3-hydroxy-N,2,6-trimethyl-N-(methyloxy)-6-nonenamide | C19H39NO4Si | 详情 | 详情 | |
| (V) | 60197 | 3,9-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-N,2,6-trimethyl-N-(methyloxy)-6-nonenamide | C25H53NO4Si2 | 详情 | 详情 | |
| (VI) | 60198 | 3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-9-hydroxy-N,2,6-trimethyl-N-(methyloxy)-6-nonenamide | C19H39NO4Si | 详情 | 详情 | |
| (VII) | 60199 | 3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-N,2,6-trimethyl-N-(methyloxy)-9-oxo-6-nonenamide | C19H37NO4Si | 详情 | 详情 | |
| (VIII) | 60352 | 10,10-dibromo-3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-N,2,6-trimethyl-N-(methyloxy)-6,9-decadienamide | C20H37Br2NO3Si | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)The boron enolate aldol condensation between aldehyde (IX) and the chiral oxazolidinone (II) affords adduct (X). After conversion to the Weinreb amide (XI), addition of magnesium acetylide (XII) leads to alkynone (XIII). Diastereoselective reduction of (XIII) using DIBAL in THF furnishes diol (XIV) as the major isomer. After protection of diol (XIV) as the bis-silyl ether (XV), hydroboration of its triple bond with catecholborane, followed by alkaline work-up gives rise to the boronic acid fragment (XVI).
| 【1】 Evans, D.A.; Starr, J.T.; A cascade cycloaddition strategy leading to the total synthesis of (-)-FR182877. Angew Chem. Int Ed 2002, 41, 10, 1787. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 25713 | (4S)-4-benzyl-3-propionyl-1,3-oxazolidin-2-one | C13H15NO3 | 详情 | 详情 | |
| (IX) | 60351 | 4-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-2-butenal | C20H24O2Si | 详情 | 详情 | |
| (X) | 60353 | 3-(6-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-3-hydroxy-2-methyl-4-hexenoyl)-4-(phenylmethyl)-1,3-oxazolidin-2-one | C33H39NO5Si | 详情 | 详情 | |
| (XI) | 60354 | 6-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-3-hydroxy-N,2-dimethyl-N-(methyloxy)-4-hexenamide | C25H35NO4Si | 详情 | 详情 | |
| (XII) | 17778 | ETHYNYLMAGNESIUM BROMIDE; bromo(ethynyl)magnesium | 4301-14-8 | C2HBrMg | 详情 | 详情 |
| (XIII) | 60355 | 8-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-5-hydroxy-4-methyl-6-octen-1-yn-3-one | C25H30O3Si | 详情 | 详情 | |
| (XIV) | 60356 | 8-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-4-methyl-6-octen-1-yne-3,5-diol | C25H32O3Si | 详情 | 详情 | |
| (XV) | 60357 | 4,6-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-5-methyl-2-octen-7-ynyl (1,1-dimethylethyl)(diphenyl)silyl ether; 8-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-10-ethynyl-2,2,9,12,12,13,13-heptamethyl-3,3-diphenyl-4,11-dioxa-3,12-disila-6-tetradecene | C37H60O3Si3 | 详情 | 详情 | |
| (XVI) | 60358 | 3,5-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-8-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-4-methyl-1,6-octadienylboronic acid | C37H63BO5Si3 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)The condensation of the chiral oxazolidinone (I) with 2,4-difluorophenacyl bromide (II) by means of NaHMDS in THF/Et2 O gives the chiral oxirane (III), which is treated with LiOH and H2O2 to eliminate the chiral auxiliary, yielding the carboxylic acid (IV). The cleavage of the oxirane ring of (IV) with 1,2,4-triazole (V) and NaH in hot DMF affords the chiral hydroxyacid (VI), which is submitted to Curtius rearrangement by means of DPPA in hot pyridine to provide the chiral oxazolidinone (VII). The cleavage of the oxazolidinone ring of (VII) by means of refluxing aq. HCl gives the chiral aminoalcohol (VIII), which is condensed with 2-amino-4-chlorobenzoic acid (IX) by means of DCC and HOBt to yield the corresponding amide (X). Finally, this compound is cyclized to the target quinazolinone by reaction with triethyl orthoformate in hot dioxane/NMP.
| 【1】 Bartroli, J.; et al.; Aldol condensation of Evans chiral enolates with acetophenones. Its application to the stereoselective synthesis of homochiral antifungal agents. J Org Chem 1995, 60, 10, 3000. |
| 【2】 Bartroli, J.; et al.; New azole antigungals. 3. Synthesis and antifungal activity of 3-substituted-4(3H)-quinazolinones. J Med Chem 1998, 41, 11, 1869. |
| 【3】 Bartrolí, J.; Turmo, E.; Anguita, M. (J. Uriach & Cía., SA); New pyrimidone derivs. with antifungal activity. EP 0783501; ES 2107376; ES 2120885; JP 1998508317; US 5807854; WO 9705130 . |
| 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) | 25713 | (4S)-4-benzyl-3-propionyl-1,3-oxazolidin-2-one | C13H15NO3 | 详情 | 详情 | |
| (II) | 47646 | 2-bromo-1-(2,4-difluorophenyl)-1-ethanone | C8H5BrF2O | 详情 | 详情 | |
| (III) | 56711 | (4S)-4-benzyl-3-{(2R)-2-[(2R)-2-(2,4-difluorophenyl)oxiranyl]propanoyl}-1,3-oxazolidin-2-one | C21H19F2NO4 | 详情 | 详情 | |
| (IV) | 56712 | (2R)-2-[(2R)-2-(2,4-difluorophenyl)oxiranyl]propanoic acid | C11H10F2O3 | 详情 | 详情 | |
| (V) | 13135 | 1H-1,2,4-Triazole; 1,2,4-Triazole | 288-88-0 | C2H3N3 | 详情 | 详情 |
| (VI) | 56713 | (2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanoic acid | C13H13F2N3O3 | 详情 | 详情 | |
| (VII) | 56714 | (4R,5R)-5-(2,4-difluorophenyl)-4-methyl-5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-oxazolidin-2-one | C13H12F2N4O2 | 详情 | 详情 | |
| (VIII) | 56715 | (2R,3R)-3-amino-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol | C12H14F2N4O | 详情 | 详情 | |
| (IX) | 52504 | 4-Chloro-2-aminobenzoic acid; 2-Amino-4-chlorobenzoic acid; 2-Carboxy-5-chloroaniline; 3-Amino-4-carboxy-1-chlorobenzene; 4-Chloroanthranilic acid | 89-77-0 | C7H6ClNO2 | 详情 | 详情 |
| (X) | 56716 | 2-amino-4-chloro-N-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]benzamide | C19H18ClF2N5O2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(III)Preparation of the 15-methylerythromycin A precursor (XI) is accomplished by a chemobiosynthetic approach, utilizing the diketide surrogate (IX). Synthesis of (IX) is carried out as follows. Acylation of (S)-4-benzyl-2-oxazolidinone (I) with propionyl chloride (II) affords the N-propionyl oxazolidinone (III). Diastereoselective aldol condensation of (III) with butyraldehyde (IV) employing dibutylboron triflate leads to adduct (V). Deacetylation of cysteamine hydrochloride (VI) with Ac2O provides (VII). Then, selective hydrolysis of the thioester function of (VII) under alkaline conditions provides thiol (VIII). Condensation of the acyl oxazolidinone (V) with thiol (VIII) in the presence of AlMe3 gives rise to the thioester substrate (IX) (1). Incubation of a recombinant Streptomyces coelicolor strain with the diketide surrogate (IX) leads to the production of 6-deoxy-15-methylerythronolide B (X). Subsequent bioconversion of the aglycone (X) in a Saccharopolyspora erythraea strain affords the desired 15-methylerythromycin A (XI).
| 【1】 Macielag, M.; Abbanat, D.; Ashley, G.; Foleno, B.; Fu, H.; Li, Y.; Wira, E.; Bush, K.; Structure-activity studies of 15-methyl ketolides: Optimization of the heterocyclic substituent. 42nd Intersci Conf Antimicrob Agents Chemother (Sept 27 2002, San Diego) 2002, Abst F-1662. |
| 【2】 Hlasta, D.; Khosla, C.; Chu, D.T.W.; Ashley, G.; Henninger, T.C.; Grant, E.B. (Ortho-McNeil Pharmaceutical, Inc.); Ketolide antibacterials. WO 0232918 . |
| 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) | 14694 | (S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone | 90719-32-7 | C10H11NO2 | 详情 | 详情 |
| (II) | 15967 | propanoyl chloride; propionyl chloride | 79-03-8 | C3H5ClO | 详情 | 详情 |
| (III) | 25713 | (4S)-4-benzyl-3-propionyl-1,3-oxazolidin-2-one | C13H15NO3 | 详情 | 详情 | |
| (IV) | 23694 | butyraldehyde | 123-72-8 | C4H8O | 详情 | 详情 |
| (V) | 62287 | (4S)-4-benzyl-3-[(2S,3R)-3-hydroxy-2-methylhexanoyl]-1,3-oxazolidin-2-one | C17H23NO4 | 详情 | 详情 | |
| (VI) | 13186 | 2-Aminoethanethiol; 2-Amino-1-ethanethiol; 2-Aminoethylhydrosulfide; Cysteamine | 60-23-1 | C2H7NS | 详情 | 详情 |
| (VII) | 62288 | Ethanethioic acid, S-[2-(acetylamino)ethyl] ester; N,S-DIACETYLCYSTEAMINE; (TM)S-(2-(ACETYLAMINO)ETHYL) ETHANETHIOATE}; N,S-DIACETYL-BETA-MERCAPTOETHYLAMINE; N,s-Diacetylcysteamine; N-2-Mercaptoethylacetamide-acetate; {S-[2-(ACETYLAMINO)ETHYL] ETHANETHIOATE}; N,S-DIACETYLCYSTEAMINE*; N,S-Diacetyl-.beta.-mercaptoethylamine | 1420-88-8 | C6H11NO2S | 详情 | 详情 |
| (VIII) | 20034 | N-(2-sulfanylethyl)acetamide | 1190-73-4 | C4H9NOS | 详情 | 详情 |
| (IX) | 62289 | S-[2-(acetylamino)ethyl] (2S,3R)-3-hydroxy-2-methylhexanethioate | C11H21NO3S | 详情 | 详情 | |
| (X) | 62290 | (3R,4S,5R,6S,7S,9R,11R,12S,13R,14R)-4,6,12-trihydroxy-3,5,7,9,11,13-hexamethyl-14-propyl-2,10-oxacyclotetradecanedione | C22H40O6 | 详情 | 详情 | |
| (XI) | 62291 | (3R,4S,5R,6R,7S,9R,11R,12R,13S,14R)-6-{[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-7,12,13-trihydroxy-4-{[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-14-pr | C38H69NO13 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(III)Protection of (S)-3-hydroxy-2-methylpropionic acid methyl ester (I) as the corresponding silyl ether, followed by reduction with DIBAL provides the aldehyde (II). Diastereoselective aldol condensation of (II) with the chiral N-propionyl oxazolidinone (III) in the presence of dibutylboron triflate leads to adduct (IV), which is then reduced with LiBH4 to give the diol (V). The diol (V) is protected as the cyclic ketal (VII) by treatment with anisaldehyde dimethylacetal (VI) in the presence of pyridinium p-toluenesulfonate (PPTS). Desilylation of (VII) using tetrabutylammonium fluoride yields the alcohol (VIII). Subsequent iodination of (VIII) with I2/PPh3, followed by displacement of alkyl iodide (IX) with PPh3 in refluxing benzene, furnishes the phosphonium salt (X).
| 【1】 Choy, N.; Shin, Y.; Nguyen, P.Q.; Curran, D.P.; Balachandran, R.; Madiraju, C.; Day, B.W.; Simplified discodermolide analogues: Synthesis and biological evaluation of 4-epi-7-dehydroxy-14,16-didemethyl-(+)-discodermolides as microtubule-stabilizing agents. J Med Chem 2003, 46, 14, 2846. |
| 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) | 17128 | Methyl (2S)-3-hydroxy-2-methylpropanoate | 72657-23-9 | C5H10O3 | 详情 | 详情 |
| (II) | 42624 | (2S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methylpropanal | C10H22O2Si | 详情 | 详情 | |
| (III) | 25713 | (4S)-4-benzyl-3-propionyl-1,3-oxazolidin-2-one | C13H15NO3 | 详情 | 详情 | |
| (IV) | 64732 | 3-(5-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-3-hydroxy-2,4-dimethylpentanoyl)-4-(phenylmethyl)-1,3-oxazolidin-2-one | C23H37NO5Si | 详情 | 详情 | |
| (V) | 64733 | 5-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-2,4-dimethyl-1,3-pentanediol | C13H30O3Si | 详情 | 详情 | |
| (VI) | 26485 | 1-(dimethoxymethyl)-4-methoxybenzene | 2186-92-7 | C10H14O3 | 详情 | 详情 |
| (VII) | 64734 | (1,1-dimethylethyl)(dimethyl)[(2-{5-methyl-2-[4-(methyloxy)phenyl]-1,3-dioxan-4-yl}propyl)oxy]silane; (1,1-dimethylethyl)(dimethyl)silyl 2-{5-methyl-2-[4-(methyloxy)phenyl]-1,3-dioxan-4-yl}propyl ether | C21H36O4Si | 详情 | 详情 | |
| (VIII) | 64735 | 2-{5-methyl-2-[4-(methyloxy)phenyl]-1,3-dioxan-4-yl}-1-propanol | C15H22O4 | 详情 | 详情 | |
| (IX) | 64736 | 4-(2-iodo-1-methylethyl)-5-methyl-2-[4-(methyloxy)phenyl]-1,3-dioxane; 4-[4-(2-iodo-1-methylethyl)-5-methyl-1,3-dioxan-2-yl]phenyl methyl ether | C15H21IO3 | 详情 | 详情 | |
| (X) | 64737 | (2-{5-methyl-2-[4-(methyloxy)phenyl]-1,3-dioxan-4-yl}propyl)(triphenyl)phosphonium iodide | C33H36IO3P | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(III)Mono-protection of 1,4-butanediol (XI) by means of 4-methoxybenzyl chloride, followed by Swern oxidation with DMSO/SO3-Pyr, leads to the aldehyde (XII). Condensation of (XII)with the boron enolate of the N-propionyl oxazolidinone (III) and subsequent silylation with tert-butyldimethylsilyl triflate furnishes the N-acyl oxoazolidinone (XIII), which is reduced by LiBH4 to the primary alcohol (XIV), which is then subjected to Swern oxidation to produce the aldehyde (XV). Further condensation of (XV) with acyl oxazolidinone (III) leads to adduct (XVI). The free hydroxyl group of (XVI) is alkylated with chloromethyl methyl ether to produce the O-methoxymethyl derivative (XVII), which under desilylation conditions with HF-pyridine cyclizes to the lactone (XVIII).
| 【1】 Choy, N.; Shin, Y.; Nguyen, P.Q.; Curran, D.P.; Balachandran, R.; Madiraju, C.; Day, B.W.; Simplified discodermolide analogues: Synthesis and biological evaluation of 4-epi-7-dehydroxy-14,16-didemethyl-(+)-discodermolides as microtubule-stabilizing agents. J Med Chem 2003, 46, 14, 2846. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 25713 | (4S)-4-benzyl-3-propionyl-1,3-oxazolidin-2-one | C13H15NO3 | 详情 | 详情 | |
| (XI) | 46190 | (1R,2R,6S)-1-[(2S,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]-2-hydroxy-2,6-dimethyl-7-octenyl methanesulfonate | C26H47NO5S2Si | 详情 | 详情 | |
| (XII) | 64738 | 4-({[4-(methyloxy)phenyl]methyl}oxy)butanal | C12H16O3 | 详情 | 详情 | |
| (XIII) | 64739 | 3-[3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-2-methyl-6-({[4-(methyloxy)phenyl]methyl}oxy)hexanoyl]-4-(phenylmethyl)-1,3-oxazolidin-2-one | C31H45NO6Si | 详情 | 详情 | |
| (XIV) | 64740 | 3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-2-methyl-6-({[4-(methyloxy)phenyl]methyl}oxy)-1-hexanol | C21H38O4Si | 详情 | 详情 | |
| (XV) | 64741 | 3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-2-methyl-6-({[4-(methyloxy)phenyl]methyl}oxy)hexanal | C21H36O4Si | 详情 | 详情 | |
| (XVI) | 64742 | C34H51NO7Si | 详情 | 详情 | ||
| (XVII) | 64743 | 3-[5-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-2,4-dimethyl-3-{[(methyloxy)methyl]oxy}-8-({[4-(methyloxy)phenyl]methyl}oxy)octanoyl]-4-(phenylmethyl)-1,3-oxazolidin-2-one | C36H55NO8Si | 详情 | 详情 | |
| (XVIII) | 64744 | 3,5-dimethyl-4-{[(methyloxy)methyl]oxy}-6-[3-({[4-(methyloxy)phenyl]methyl}oxy)propyl]tetrahydro-2H-pyran-2-one | C20H30O6 | 详情 | 详情 |