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【结 构 式】 
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【药物名称】Hapalosin 【化学名称】(2S,5S,6R,10R,11S)-5-Benzyl-10-heptyl-6-hydroxy-2-isopropyl-4,11-dimethyl-1,9-dioxa-4-azacyclododecane-3,8,12-trione 【CA登记号】159542-04-8 【 分 子 式 】C28H43NO6 【 分 子 量 】489.65801 |
【开发单位】Keio University (Originator) 【药理作用】Modulators of the Therapeutic Activity of Antineoplastic Agents, Multidrug Resistance Modulators, ONCOLYTIC DRUGS |
合成路线1
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
Treatment of N-Boc-L-phenylalanine (XI) with carbonyl diimidazole, followed by condensation with the lithium enolate of ethyl acetate provided the beta-ketoester (XII). Then, reduction with NaBH4 in EtOH at -78 C furnished the anti aminoalcohol (XIII) as the major isomer. Subsequent reaction with formaldehyde in the presence of p-toluenesulfonic acid in boiling toluene produced the cis oxazolidine (XIV). Basic hydrolis of the ester group yielded carboxylic acid (XV) which, after activation as the mixed anhydride with 2,4,6-trichlorobenzoyl chloride (VI), was coupled to hydroxyester (X) to give triester (XVI). Reduction of the oxazolidine with NaBH3CN in the presence of trifluoroacetic acid afforded the N-methylated derivative (XVII). Then, hydrogenolysis of the benzyl ester in the presence of Pd/C produced acid (XVIII), which was finally cyclized using DPPA.
| 【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 |
|---|---|---|---|---|---|---|
| (VI) | 25718 | 2,4,6-trichlorobenzoyl chloride | 4136-95-2 | C7H2Cl4O | 详情 | 详情 |
| (X) | 25722 | (1S)-1-[(benzyloxy)carbonyl]-2-methylpropyl (2S,3R)-3-hydroxy-2-methyldecanoate | C23H36O5 | 详情 | 详情 | |
| (XI) | 12874 | (2R)-2-[(tert-Butoxycarbonyl)amino]-3-phenylpropionic acid; N-alpha-t-BOC-L-Phenylalanine | 13734-34-4 | C14H19NO4 | 详情 | 详情 |
| (XII) | 12876 | ethyl (4S)-4-[(tert-butoxycarbonyl)amino]-3-oxo-5-phenylpentanoate | C18H25NO5 | 详情 | 详情 | |
| (XIII) | 25723 | ethyl (3R,4S)-4-[(tert-butoxycarbonyl)amino]-3-hydroxy-5-phenylpentanoate | C18H27NO5 | 详情 | 详情 | |
| (XIV) | 25724 | tert-butyl (4S,5R)-4-benzyl-5-(2-ethoxy-2-oxoethyl)-1,3-oxazolidine-3-carboxylate | C19H27NO5 | 详情 | 详情 | |
| (XV) | 25725 | 2-[(4S,5R)-4-benzyl-3-(tert-butoxycarbonyl)-1,3-oxazolidin-5-yl]acetic acid | C17H23NO5 | 详情 | 详情 | |
| (XVI) | 25726 | tert-butyl (4S,5R)-4-benzyl-5-[2-([(1S)-1-[(1S)-2-([(1S)-1-[(benzyloxy)carbonyl]-2-methylpropyl]oxy)-1-methyl-2-oxoethyl]octyl]oxy)-2-oxoethyl]-1,3-oxazolidine-3-carboxylate | C40H57NO9 | 详情 | 详情 | |
| (XVII) | 25727 | (1S)-1-[(benzyloxy)carbonyl]-2-methylpropyl (2S,3S)-3-[[(3R,4S)-3-hydroxy-4-(methylamino)-5-phenylpentanoyl]oxy]-2-methyldecanoate | C35H51NO7 | 详情 | 详情 | |
| (XVIII) | 25728 | (2S)-2-[((2S,3S)-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
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4
The intermediate (3R,4S)-4-[N-(tert-butoxycarbonyl)-N-methylamino]-5-phenyl-3-(tert-butyldimethylsilyloxy)pentanoic acid (VII) has been obtained as follows: The condensation of N-(tert-butoxycarbonyl)-L-phenylalanine (I) with the Mg salt of malonic acid monoethyl ester (II) by means of CDI gives the beta-ketoester (III), which is reduced with NaBH4 to yield (3R,4S)-4-(tert-butoxycarbonylamino)-3-hydroxy-5-phenylpentanoic acid ethyl ester (IV). The protection of the OH group of (IV) with Tbdms-Cl and imidazole in DMF affords the silylated ester (V), which is hydrolyzed with NaOH to provide the corresponding carboxylic acid (VI). Finally, this compound is N-methylated by means of Me-I and NaH in THF to obtain the target intermediate (VII).
| 【1】 Rich, D.H.; Maibaum, J.; A facile synthesis of statine and analogues by reduction of beta-keto esters derived from Boc-protected amino acids. HPLC analyses of their enantiomeric purity. J Org Chem 1988, 53, 4, 869. |
| 【2】 Ohmori, K.; et al.; Synthetic study on hapalosin, a cyclic depsipeptide possessing multidrug resistance reversing activities. Tetrahedron Lett 1996, 37, 20, 3467. |
| 【3】 Parkes, K.E.B.; Bushnell, D.J.; Crackett, P.H.; et al.; Studies toward the large-scale synthesis of the HIV proteinase inhibitor Ro 31-8959. J Org Chem 1994, 59, 13, 3656. |
| 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) | 12874 | (2R)-2-[(tert-Butoxycarbonyl)amino]-3-phenylpropionic acid; N-alpha-t-BOC-L-Phenylalanine | 13734-34-4 | C14H19NO4 | 详情 | 详情 |
| (II) | 14507 | Malonic acid monoethyl ester magnesium salt | C5H6MgO4 | 详情 | 详情 | |
| (III) | 12876 | ethyl (4S)-4-[(tert-butoxycarbonyl)amino]-3-oxo-5-phenylpentanoate | C18H25NO5 | 详情 | 详情 | |
| (IV) | 50335 | ethyl (3R,4S)-4-[(tert-butoxycarbonyl)amino]-3-[[tert-butyl(dimethyl)silyl]oxy]-5-phenylpentanoate | C24H41NO5Si | 详情 | 详情 | |
| (V) | 50336 | (3R,4S)-4-[(tert-butoxycarbonyl)amino]-3-[[tert-butyl(dimethyl)silyl]oxy]-5-phenylpentanoic acid | C22H37NO5Si | 详情 | 详情 | |
| (VI) | 50337 | (3R,4S)-4-[(tert-butoxycarbonyl)(methyl)amino]-3-[[tert-butyl(dimethyl)silyl]oxy]-5-phenylpentanoic acid | C23H39NO5Si | 详情 | 详情 |
合成路线5
The condensation of the chiral oxazolidinone (VIII) with octanal (IX) by means of Bu2B-OTf and TEA in dichloromethane gives the chiral adduct (X), which is treated with benzyl alcohol and BuLi to yield the benzyl ester (XI). The esterification of the OH group of (XI) with the intermediate carboxylic acid (VIII) by means of DCC and DMAP in dichloromethane affords the corresponding ester (XII), whose benzyl ester is hydrogenolyzed with H2 over Pd(OH)2 in ethanol to provide the carboxylic acid (XIII). The esterification of (XIII) with the chiral hydroxyester (XIV) by means of DCC and DMAP as before gives the expected triester (XV), which is treated first with Pd(PPh3)4 and then with TFA (elimination of the allyl, Boc and Tbdms protecting groups) to yield the open-chain precursor (XVI). Finally, this compound is submitted to macrocyclization by means of DPPA and DIEA to afford the target macrocyclic compound.
| 【1】 Ohmori, K.; et al.; Synthetic study on hapalosin, a cyclic depsipeptide possessing multidrug resistance reversing activities. Tetrahedron Lett 1996, 37, 20, 3467. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 50338 | (4S,5R)-4-methyl-5-phenyl-3-propionyl-1,3-oxazolidin-2-one | C13H15NO3 | 详情 | 详情 | |
| (IX) | 25714 | octanal | 124-13-0 | C8H16O | 详情 | 详情 |
| (X) | 50339 | (4S,5R)-3-[(2S,3R)-3-hydroxy-2-methyldecanoyl]-4-methyl-5-phenyl-1,3-oxazolidin-2-one | C21H31NO4 | 详情 | 详情 | |
| (XI) | 50340 | benzyl (2S,3R)-3-hydroxy-2-methyldecanoate | C18H28O3 | 详情 | 详情 | |
| (XII) | 50337 | (3R,4S)-4-[(tert-butoxycarbonyl)(methyl)amino]-3-[[tert-butyl(dimethyl)silyl]oxy]-5-phenylpentanoic acid | C23H39NO5Si | 详情 | 详情 | |
| (XIII) | 50341 | benzyl (2S,3R)-3-[((3R,4S)-4-[(tert-butoxycarbonyl)(methyl)amino]-3-[[tert-butyl(dimethyl)silyl]oxy]-5-phenylpentanoyl)oxy]-2-methyldecanoate | C41H65NO7Si | 详情 | 详情 | |
| (XIV) | 50342 | (2S,3R)-3-[((3R,4S)-4-[(tert-butoxycarbonyl)(methyl)amino]-3-[[tert-butyl(dimethyl)silyl]oxy]-5-phenylpentanoyl)oxy]-2-methyldecanoic acid | C34H59NO7Si | 详情 | 详情 | |
| (XV) | 37830 | allyl (2S)-2-hydroxy-3-methylbutanoate | C8H14O3 | 详情 | 详情 | |
| (XVI) | 50343 | allyl (6S,7R,11R,12S,15S)-6-benzyl-7-[[tert-butyl(dimethyl)silyl]oxy]-11-heptyl-15-isopropyl-2,2,5,12-tetramethyl-4,9,13-trioxo-3,10,14-trioxa-5-azahexadecan-16-oate | C42H71NO9Si | 详情 | 详情 | |
| (XVII) | 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 |