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【结 构 式】 
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【分子编号】55492 【品名】(6R)-6-{(E,3R,4R,6R)-6-{[tert-butyl(dimethyl)silyl]oxy}-8-iodo-4-[(4-methoxybenzyl)oxy]-3-methyl-3-[(triethylsilyl)oxy]-1-octen-7-ynyl}-5,6-dihydro-2H-pyran-2-one 【CA登记号】 |
【 分 子 式 】C34H53IO6Si2 【 分 子 量 】740.86669 【元素组成】C 55.12% H 7.21% I 17.13% O 12.96% Si 7.58% |
合成路线1
该中间体在本合成路线中的序号：(XVIII)The cyclization of 1-(benzyloxy)butadiene (I) with silylated propargyl aldehyde (II) by means of a chiral chromium catalyst gives the chiral dihydropyran (III), which is desilylated with TBAF and Ts-OH, yielding the acetylenic dihydropyran (IV). The reaction of (IV) with Ts-OH and isopropanol (V) affords the isopropoxy dihydropyran (VI). The optical resolution of the acetyloxirane (VII) by reaction with O2 and a chiral Co catalyst gives a mixture of (S)-3,4-dihydroxy-2-butanone (VIII) and (R)-acetyloxirane (IX) that is easily separated. The condensation of the chiral oxirane (IX) with the acetylenic dihydropyran (VI) by means of Cp2Zr(H)Cl and Me2Zn, yields the epoxyalcohol (X), which is protected with Tes-Cl and imidazole in DMF to afford the silyl ether (XI). Ring opening of the epoxy group of (XI) with acetylenic dithiolane (XII) by means of BuLi in THF provides the adduct (XIII), which is treated with PPTS to cleave the isopropyl group and oxidized with MnO2 to give the dihydropyranone compound (XIV). The cleavage of the dithiolane ring of (XIV) with bis(trifluoroacetoxy)iodobenzene (PIFA), followed by protection of the OH group with Pmb-trichloroimidate and BF3/Et2O, yields the protected acetylenic ketone (XV), which is submitted to a enantioselective reduction by transfer hydrogenation with isopropanol catalyzed by a chiral Ru catalyst, affording the chiral alcohol (XVI). The protection of the OH group of (XVI) with Tbdms-OTf and lutidine provides the fully protected compound (XVII), which is treated with AgNO3 and N-iodosuccinimide (NIS), giving the iodoethynyl compound (XVIII).
| 【1】 Jacobsen, E.N.; Chavez, D.E.; Total synthesis of fostriecin (CI-920). Angew Chem. Int Ed 2001, 40, 19, 3667. |
| 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) | 55477 | 1-{[(1E)-1,3-butadienyloxy]methyl}benzene; benzyl (1E)-1,3-butadienyl ether | C11H12O | 详情 | 详情 | |
| (II) | 55478 | 3-(triisopropylsilyl)-2-propynal | C12H22OSi | 详情 | 详情 | |
| (III) | 55479 | benzyl (2S,6R)-6-[2-(triisopropylsilyl)ethynyl]-5,6-dihydro-2H-pyran-2-yl ether; {2-[(2R,6S)-6-(benzyloxy)-3,6-dihydro-2H-pyran-2-yl]ethynyl}(triisopropyl)silane | C23H34O2Si | 详情 | 详情 | |
| (IV) | 55480 | (2R,6R)-6-(benzyloxy)-2-ethynyl-3,6-dihydro-2H-pyran; benzyl (2R,6R)-6-ethynyl-5,6-dihydro-2H-pyran-2-yl ether | C14H14O2 | 详情 | 详情 | |
| (V) | 19250 | 2-propanol | 67-63-0 | C3H8O | 详情 | 详情 |
| (VI) | 55481 | (2R,6R)-2-ethynyl-6-isopropoxy-3,6-dihydro-2H-pyran; (2R,6R)-6-ethynyl-5,6-dihydro-2H-pyran-2-yl isopropyl ether | C10H14O2 | 详情 | 详情 | |
| (VII) | 55493 | 1-(2-oxiranyl)-1-ethanone | C4H6O2 | 详情 | 详情 | |
| (VIII) | 55482 | (3S)-3,4-dihydroxy-2-butanone | C4H8O3 | 详情 | 详情 | |
| (IX) | 55483 | 1-[(2R)oxiranyl]-1-ethanone | C4H6O2 | 详情 | 详情 | |
| (X) | 55484 | (2R,3E)-4-[(2R,6R)-6-isopropoxy-3,6-dihydro-2H-pyran-2-yl]-2-[(2R)oxiranyl]-3-buten-2-ol | C14H22O4 | 详情 | 详情 | |
| (XI) | 55485 | (1R,2E)-3-[(2R,6R)-6-isopropoxy-3,6-dihydro-2H-pyran-2-yl]-1-methyl-1-[(2R)oxiranyl]-2-propenyl triethylsilyl ether; triethyl({(1R,2E)-3-[(2R,6R)-6-isopropoxy-3,6-dihydro-2H-pyran-2-yl]-1-methyl-1-[(2R)oxiranyl]-2-propenyl}oxy)silane | C20H36O4Si | 详情 | 详情 | |
| (XII) | 55486 | [2-(1,3-dithian-2-yl)ethynyl](trimethyl)silane | C9H16S2Si | 详情 | 详情 | |
| (XIII) | 55487 | (2R,3R,4E)-5-[(2R,6R)-6-isopropoxy-3,6-dihydro-2H-pyran-2-yl]-3-methyl-3-[(triethylsilyl)oxy]-1-{2-[2-(trimethylsilyl)ethynyl]-1,3-dithian-2-yl}-4-penten-2-ol | C29H52O4S2Si2 | 详情 | 详情 | |
| (XIV) | 55488 | (6R)-6-((E,3R,4R)-4-hydroxy-3-methyl-3-[(triethylsilyl)oxy]-5-{2-[2-(trimethylsilyl)ethynyl]-1,3-dithian-2-yl}-1-pentenyl)-5,6-dihydro-2H-pyran-2-one | C26H44O4S2Si2 | 详情 | 详情 | |
| (XV) | 55489 | (6R)-6-[(E,3R,4R)-4-[(4-methoxybenzyl)oxy]-3-methyl-6-oxo-3-[(triethylsilyl)oxy]-8-(trimethylsilyl)-1-octen-7-ynyl]-5,6-dihydro-2H-pyran-2-one | C31H46O6Si2 | 详情 | 详情 | |
| (XVI) | 55490 | (6R)-6-[(E,3R,4R,6R)-6-hydroxy-4-[(4-methoxybenzyl)oxy]-3-methyl-3-[(triethylsilyl)oxy]-8-(trimethylsilyl)-1-octen-7-ynyl]-5,6-dihydro-2H-pyran-2-one | C31H48O6Si2 | 详情 | 详情 | |
| (XVII) | 55491 | (6R)-6-[(E,3R,4R,6R)-6-{[tert-butyl(dimethyl)silyl]oxy}-4-[(4-methoxybenzyl)oxy]-3-methyl-3-[(triethylsilyl)oxy]-8-(trimethylsilyl)-1-octen-7-ynyl]-5,6-dihydro-2H-pyran-2-one | C37H62O6Si3 | 详情 | 详情 | |
| (XVIII) | 55492 | (6R)-6-{(E,3R,4R,6R)-6-{[tert-butyl(dimethyl)silyl]oxy}-8-iodo-4-[(4-methoxybenzyl)oxy]-3-methyl-3-[(triethylsilyl)oxy]-1-octen-7-ynyl}-5,6-dihydro-2H-pyran-2-one | C34H53IO6Si2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XVIII)The selective deprotection of the Pmb- group of (XVIII) with DDQ in dichloromethane gives the secondary alcohol (XIX), which is submitted to a highly selective diimide reduction of its ethynylene group by means of 2-nitrobenzenesulfonyl hydrazide (NBSH) in THF/iPr-OH to yield the cis-iodovinyl compound (XX). The condensation of the iodovinyl compound (XX) with tributylstannane (XXI) by means of PdCl2(acetonitrile)2 in DMF affords the adduct (XXII), which is treated with PCl3/pyridine and then oxidized with tBu-OOH and Pmb-OH to provide the phosphate ester (XXIII). Finally, this compound is deprotected with HF/pyridine in acetonitrile to give the target fostriecin.
| 【1】 Jacobsen, E.N.; Chavez, D.E.; Total synthesis of fostriecin (CI-920). Angew Chem. Int Ed 2001, 40, 19, 3667. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVIII) | 55492 | (6R)-6-{(E,3R,4R,6R)-6-{[tert-butyl(dimethyl)silyl]oxy}-8-iodo-4-[(4-methoxybenzyl)oxy]-3-methyl-3-[(triethylsilyl)oxy]-1-octen-7-ynyl}-5,6-dihydro-2H-pyran-2-one | C34H53IO6Si2 | 详情 | 详情 | |
| (XIX) | 55494 | (6R)-6-{(E,3R,4R,6R)-6-{[tert-butyl(dimethyl)silyl]oxy}-4-hydroxy-8-iodo-3-methyl-3-[(triethylsilyl)oxy]-1-octen-7-ynyl}-5,6-dihydro-2H-pyran-2-one | C26H45IO5Si2 | 详情 | 详情 | |
| (XX) | 55495 | (6R)-6-{(1E,3R,4R,6R,7Z)-6-{[tert-butyl(dimethyl)silyl]oxy}-4-hydroxy-8-iodo-3-methyl-3-[(triethylsilyl)oxy]-1,7-octadienyl}-5,6-dihydro-2H-pyran-2-one | C26H47IO5Si2 | 详情 | 详情 | |
| (XXI) | 55496 | tert-butyl(diphenyl)silyl (2E,4Z)-5-(trimethylstannyl)-2,4-pentadienyl ether; tert-butyl(diphenyl){[(2E,4Z)-5-(trimethylstannyl)-2,4-pentadienyl]oxy}silane | C24H34OSiSn | 详情 | 详情 | |
| (XXII) | 55497 | (6R)-6-{(1E,3R,4R,6R,7Z,9Z,11E)-6-{[tert-butyl(dimethyl)silyl]oxy}-13-{[tert-butyl(diphenyl)silyl]oxy}-4-hydroxy-3-methyl-3-[(triethylsilyl)oxy]-1,7,9,11-tridecatetraenyl}-5,6-dihydro-2H-pyran-2-one | C47H72O6Si3 | 详情 | 详情 | |
| (XXIII) | 55498 | (1R,3R,4Z,6Z,8E)-3-{[tert-butyl(dimethyl)silyl]oxy}-10-{[tert-butyl(diphenyl)silyl]oxy}-1-{(1R,2E)-1-methyl-3-[(2R)-6-oxo-3,6-dihydro-2H-pyran-2-yl]-1-[(triethylsilyl)oxy]-2-propenyl}-4,6,8-decatrienyl bis(4-methoxybenzyl) phosphate | C63H89O11PSi3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(X)The reaction of the iodovinyl compound (I) with BuLi and MgBr2 gives the organometallic compound (II), which is condensed with the acetylenic ketone (III) to yield the tertiary alcohol (IV). The selective monodesilylation of (IV) by means of HF affords the diol (V), which is selectively monoesterified with acryloyl chloride (VI) by means of DIEA to provide the acrylate (VII). The silylation of the free OH group of (VIII) with Tes-OTf gives the desilylated compound (VIII), which is submitted to a ring closing metathesis by means of (Pcy3)2RuCl2(=CH-PH) and Ti(O-iPr)4 in dichloromethane to yield the dihydropyranone (IX). The iodination of the terminal acetylene group of (IX) by means of NIS and AgNO3 in acetone affords the iodoacetylene (X), which is selectively deprotected at the Pmb protecting group by means of DDQ to provide the alcohol (XI). Finally the triple bond of (XI) is reduced by means of o-(NO2)C6H4-SO2-N=NH to obtain the target iodovinyl intermediate (XII) (see scheme no. 09093803b, intermediate (XX)).
| 【1】 Wang, Y.-G.; Kobayashi, Y.; Formal total synthesis of fostriecin. Org Lett 2002, 4, 26, 4615. |
| 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) | 60531 | (1R)-1-[(E)-2-iodoethenyl]-3-butenyl triethylsilyl ether; triethyl({(1R)-1-[(E)-2-iodoethenyl]-3-butenyl}oxy)silane | C12H23IOSi | 详情 | 详情 | |
| (II) | 60532 | bromo{(1E,3R)-3-[(triethylsilyl)oxy]-1,5-hexadienyl}magnesium | C12H23BrMgOSi | 详情 | 详情 | |
| (III) | 60533 | (3R,5R)-5-{[tert-butyl(dimethyl)silyl]oxy}-3-[(4-methoxybenzyl)oxy]-6-heptyn-2-one | C21H32O4Si | 详情 | 详情 | |
| (IV) | 60534 | (5R,6E,8R,9R,11R)-5-allyl-3,3-diethyl-11-ethynyl-9-[(4-methoxybenzyl)oxy]-8,13,13,14,14-pentamethyl-4,12-dioxa-3,13-disila-6-pentadecen-8-ol | C33H56O5Si2 | 详情 | 详情 | |
| (V) | 60535 | (4R,5E,7R,8R,10R)-10-{[tert-butyl(dimethyl)silyl]oxy}-8-[(4-methoxybenzyl)oxy]-7-methyl-1,5-dodecadien-11-yne-4,7-diol | C27H42O5Si | 详情 | 详情 | |
| (VI) | 11577 | Acryloyl chloride; Acrylyl chloride;2-Propenoyl chloride | 814-68-6 | C3H3ClO | 详情 | 详情 |
| (VII) | 60536 | (1R,2E,4R,5R,7R)-1-allyl-7-{[tert-butyl(dimethyl)silyl]oxy}-4-hydroxy-5-[(4-methoxybenzyl)oxy]-4-methyl-2-nonen-8-ynyl acrylate | C30H44O6Si | 详情 | 详情 | |
| (VIII) | 60537 | (1R,2E,4R,5R,7R)-1-allyl-7-{[tert-butyl(dimethyl)silyl]oxy}-5-[(4-methoxybenzyl)oxy]-4-methyl-4-[(triethylsilyl)oxy]-2-nonen-8-ynyl acrylate | C36H58O6Si2 | 详情 | 详情 | |
| (IX) | 60538 | (6R)-6-{(E,3R,4R,6R)-6-{[tert-butyl(dimethyl)silyl]oxy}-4-[(4-methoxybenzyl)oxy]-3-methyl-3-[(triethylsilyl)oxy]-1-octen-7-ynyl}-5,6-dihydro-2H-pyran-2-one | C34H54O6Si2 | 详情 | 详情 | |
| (X) | 55492 | (6R)-6-{(E,3R,4R,6R)-6-{[tert-butyl(dimethyl)silyl]oxy}-8-iodo-4-[(4-methoxybenzyl)oxy]-3-methyl-3-[(triethylsilyl)oxy]-1-octen-7-ynyl}-5,6-dihydro-2H-pyran-2-one | C34H53IO6Si2 | 详情 | 详情 | |
| (XI) | 55494 | (6R)-6-{(E,3R,4R,6R)-6-{[tert-butyl(dimethyl)silyl]oxy}-4-hydroxy-8-iodo-3-methyl-3-[(triethylsilyl)oxy]-1-octen-7-ynyl}-5,6-dihydro-2H-pyran-2-one | C26H45IO5Si2 | 详情 | 详情 | |
| (XII) | 55495 | (6R)-6-{(1E,3R,4R,6R,7Z)-6-{[tert-butyl(dimethyl)silyl]oxy}-4-hydroxy-8-iodo-3-methyl-3-[(triethylsilyl)oxy]-1,7-octadienyl}-5,6-dihydro-2H-pyran-2-one | C26H47IO5Si2 | 详情 | 详情 |