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【结 构 式】 
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【分子编号】48420 【品名】methyl 2-[(2R,4aS,6S,7R,8S,8aS)-7,8-bis[[tert-butyl(dimethyl)silyl]oxy]-6-((1S,2E)-1-[[tert-butyl(dimethyl)silyl]oxy]-3-iodo-2-propenyl)octahydropyrano[3,2-b]pyran-2-yl]acetate 【CA登记号】 |
【 分 子 式 】C32H63IO7Si3 【 分 子 量 】771.00899 【元素组成】C 49.85% H 8.24% I 16.46% O 14.53% Si 10.93% |
合成路线1
该中间体在本合成路线中的序号：(XXXIV)The aldehyde building block (XXXV) was obtained by DIBAL reduction of the previously described methyl ester (XXXIV). Lithiation of alkyl iodide (XXXIII) by means of tert-BuLi and then addition to aldehyde (XXXV) furnished the carbinol adduct (XXXVI). The methoxytrityl protecting group of (XXXVI) was then removed by acidic treatment, yielding (XXXVII). Oxidation of both free hydroxyl groups of (XXXVII) with Dess-Martin periodinane reagent gave rise to the keto aldehyde (XXXVIII).
| 【1】 Littlefield, B.A.; Zheng, W.; Seletsky, B.M.; Yu, M.J.; Palme, M.H.; Towle, M.J. (Eisai Co., Ltd.); Macrocyclic analogs and methods of their use and preparation. US 6214865; WO 9965894 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXXIII) | 52396 | C59H89IO8Si2 | 详情 | 详情 | ||
| (XXXIV) | 48420 | methyl 2-[(2R,4aS,6S,7R,8S,8aS)-7,8-bis[[tert-butyl(dimethyl)silyl]oxy]-6-((1S,2E)-1-[[tert-butyl(dimethyl)silyl]oxy]-3-iodo-2-propenyl)octahydropyrano[3,2-b]pyran-2-yl]acetate | C32H63IO7Si3 | 详情 | 详情 | |
| (XXXV) | 52397 | C31H61IO6Si3 | 详情 | 详情 | ||
| (XXXVI) | 52398 | C90H151IO14Si5 | 详情 | 详情 | ||
| (XXXVII) | 52399 | C70H135IO13Si5 | 详情 | 详情 | ||
| (XXXVIII) | 52400 | C70H131IO13Si5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXXIV)The previously referenced vinyl iodide intermediate (XXXIV) was obtained as follows: The reaction of L-mannonic acid gamma-lactone (XLVIII) with cyclohexanone (XLIX) by means of H2SO4 in toluene gave the bis-cyclohexylidene ketal (L), which was reduced with DIBAL in dichloromethane to yield the lactol (LI). The condensation of (LI) with the phosphonium chloride (LII) by means of t-Bu-OK in refluxing THF afforded the vinyl ether (LIII), which was hydroxylated with OsO4 and dihydroquinidine-4-chlorobenzoate as chiral ligand and acylated with acetic anhydride and pyridine to provide the diacetate (LIV). The condensation of (LIV) with the functionalized allyl silane (LV) by means of BF3/Et2O in acetonitrile gave the adduct (LVI), which was submitted to cyclization by means of Triton B(OMe) in THF/methyl acetate to yield the perhydropyrano[3,2-b]pyran derivative (LVII). The selective hydrolysis of the exocyclic cyclohexylidene ketal of (LVII) with hot AcOH/water afforded the diol (LVIII), which by oxidative cleavage with NaIO4 in THF afforded the aldehyde (LIX). The coupling of (LIX) with the silylated vinyl iodide (LX), catalyzed by NiCl2 and CrCl2 in DMSO, gave the silylated allyl alcohol (LXI), which was submitted to cleavage of the cyclohexylidene ketal by means of AcOH/TFA to yield the trihydroxy compound (LXII). The protection of the three OH groups of (LXII) with Tbdms-OTf and lutidine in dichloromethane afforded the tris-Tbdms protected vinyl silane (LXIII), which was finally iodinated with N-iodosuccinimide (NIS) in acetonitrile/chloroacetonitrile to provide the target vinyl iodide intermediate (XXXIV).
| 【1】 Kishi, Y.; Stamos, D.P.; Synthetic studies on halichondrins: A practical synthesis of the C.1-C.13 segment. Tetrahedron Lett 1996, 37, 48, 8643. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXXIV) | 48420 | methyl 2-[(2R,4aS,6S,7R,8S,8aS)-7,8-bis[[tert-butyl(dimethyl)silyl]oxy]-6-((1S,2E)-1-[[tert-butyl(dimethyl)silyl]oxy]-3-iodo-2-propenyl)octahydropyrano[3,2-b]pyran-2-yl]acetate | C32H63IO7Si3 | 详情 | 详情 | |
| (XLVIII) | 25665 | (3R,4S,5S)-5-[(1S)-1,2-dihydroxyethyl]-3,4-dihydroxydihydro-2(3H)-furanone | C6H10O6 | 详情 | 详情 | |
| (XLIX) | 11059 | Cyclohexanone | 108-94-1 | C6H10O | 详情 | 详情 |
| (L) | 52411 | C18H26O6 | 详情 | 详情 | ||
| (LI) | 52412 | C18H28O6 | 详情 | 详情 | ||
| (LII) | 39163 | (methoxymethyl)(triphenyl)phosphonium chloride | 4009-98-7 | C20H20ClOP | 详情 | 详情 |
| (LIII) | 52413 | C20H32O6 | 详情 | 详情 | ||
| (LIV) | 52414 | C23H34O9 | 详情 | 详情 | ||
| (LV) | 52423 | methyl 3-(trimethylsilyl)-4-pentenoate | C9H18O2Si | 详情 | 详情 | |
| (LVI) | 52415 | C27H40O9 | 详情 | 详情 | ||
| (LVII) | 52416 | C25H38O8 | 详情 | 详情 | ||
| (LVIII) | 52417 | C19H30O8 | 详情 | 详情 | ||
| (LIX) | 52418 | C18H26O7 | 详情 | 详情 | ||
| (LX) | 52419 | (2-iodoethenyl)(trimethyl)silane | C5H11ISi | 详情 | 详情 | |
| (LXI) | 52420 | C23H38O7Si | 详情 | 详情 | ||
| (LXII) | 52421 | methyl 2-{(2R,4aS,6S,7S,8R,8aR)-7,8-dihydroxy-6-[(E)-1-hydroxy-3-(trimethylsilyl)-2-propenyl]octahydropyrano[3,2-b]pyran-2-yl}acetate | C17H30O7Si | 详情 | 详情 | |
| (LXIII) | 52422 | methyl 2-{(2R,4aS,6S,7R,8S,8aS)-7,8-bis{[tert-butyl(dimethyl)silyl]oxy}-6-[(1S,2E)-1-{[tert-butyl(dimethyl)silyl]oxy}-3-(trimethylsilyl)-2-propenyl]octahydropyrano[3,2-b]pyran-2-yl}acetate | C35H72O7Si4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XXXIV)The aldehyde building block (XXXV) was obtained by DIBAL reduction of the previously described methyl ester (XXXIV). Lithiation of alkyl iodide (XXXIII) by means of tert-BuLi and then addition to aldehyde (XXXV) furnished the carbinol adduct (XXXVI). The methoxytrityl protecting group of (XXXVI) was then removed by acidic treatment, yielding (XXXVII). Oxidation of both free hydroxyl groups of (XXXVII) with Dess-Martin periodinane reagent gave rise to the keto aldehyde (XXXVIII).
| 【1】 Littlefield, B.A.; Zheng, W.; Seletsky, B.M.; Yu, M.J.; Palme, M.H.; Towle, M.J. (Eisai Co., Ltd.); Macrocyclic analogs and methods of their use and preparation. US 6214865; WO 9965894 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXXIII) | 52396 | C59H89IO8Si2 | 详情 | 详情 | ||
| (XXXIV) | 48420 | methyl 2-[(2R,4aS,6S,7R,8S,8aS)-7,8-bis[[tert-butyl(dimethyl)silyl]oxy]-6-((1S,2E)-1-[[tert-butyl(dimethyl)silyl]oxy]-3-iodo-2-propenyl)octahydropyrano[3,2-b]pyran-2-yl]acetate | C32H63IO7Si3 | 详情 | 详情 | |
| (XXXV) | 52397 | C31H61IO6Si3 | 详情 | 详情 | ||
| (XXXVI) | 52398 | C90H151IO14Si5 | 详情 | 详情 | ||
| (XXXVII) | 52399 | C70H135IO13Si5 | 详情 | 详情 | ||
| (XXXVIII) | 52400 | C70H131IO13Si5 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XXXIV)The previously referenced vinyl iodide intermediate (XXXIV) was obtained as follows: The reaction of L-mannonic acid gamma-lactone (LI) with cyclohexanone (LII) by means of H2SO4 in toluene gave the bis-cyclohexylidene ketal (LIII), which was reduced with DIBAL in dichloromethane to yield the lactol (LIV). The condensation of (LIV) with the phosphonium chloride (LV) by means of t-Bu-OK in refluxing THF afforded the vinyl ether (LVI), which was hydroxylated with OsO4 and dihydroquinidine-4-chlorobenzoate as chiral ligand and acylated with acetic anhydride and pyridine to provide the diacetate (LVII). The condensation of (LVII) with the functionalized allyl silane (LVIII) by means of BF3/Et2O in acetonitrile gave the adduct (LIX), which was submitted to cyclization by means of Triton B(OMe) in THF/methyl acetate to yield the perhydropyrano[3,2-b]pyran derivative (LX). The selective hydrolysis of the exocyclic cyclohexylidene ketal of (LX) with hot HOAc/water afforded the diol (LXI), which by oxidative cleavage with NaIO4 in THF afforded the aldehyde (LXII). The coupling of (LXII) with the silylated vinyl iodide (LXIII), catalyzed by NiCl2 and CrCl2 in DMSO, gave the silylated allyl alcohol (LXIV), which was submitted to cleavage of the cyclohexylidene ketal by means of HOAc/TFA to yield the trihydroxy compound (LXV). The protection of the three OH groups of (LXV) with Tbdms-OTf and lutidine in dichloromethane afforded the tris-Tbdms protected vinyl silane (LXVI), which was finally iodinated with N-iodosuccinimide (NIS) in acetonitrile/chloroacetonitrile to provide the target vinyl iodide intermediate (XXXIV).
| 【1】 Kishi, Y.; Stamos, D.P.; Synthetic studies on halichondrins: A practical synthesis of the C.1-C.13 segment. Tetrahedron Lett 1996, 37, 48, 8643. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXXIV) | 48420 | methyl 2-[(2R,4aS,6S,7R,8S,8aS)-7,8-bis[[tert-butyl(dimethyl)silyl]oxy]-6-((1S,2E)-1-[[tert-butyl(dimethyl)silyl]oxy]-3-iodo-2-propenyl)octahydropyrano[3,2-b]pyran-2-yl]acetate | C32H63IO7Si3 | 详情 | 详情 | |
| (LI) | 25665 | (3R,4S,5S)-5-[(1S)-1,2-dihydroxyethyl]-3,4-dihydroxydihydro-2(3H)-furanone | C6H10O6 | 详情 | 详情 | |
| (LII) | 11059 | Cyclohexanone | 108-94-1 | C6H10O | 详情 | 详情 |
| (LIII) | 52411 | C18H26O6 | 详情 | 详情 | ||
| (LIV) | 52412 | C18H28O6 | 详情 | 详情 | ||
| (LV) | 39163 | (methoxymethyl)(triphenyl)phosphonium chloride | 4009-98-7 | C20H20ClOP | 详情 | 详情 |
| (LVI) | 52413 | C20H32O6 | 详情 | 详情 | ||
| (LVII) | 52414 | C23H34O9 | 详情 | 详情 | ||
| (LVIII) | 52415 | C27H40O9 | 详情 | 详情 | ||
| (LIX) | 52423 | methyl 3-(trimethylsilyl)-4-pentenoate | C9H18O2Si | 详情 | 详情 | |
| (LX) | 52416 | C25H38O8 | 详情 | 详情 | ||
| (LXI) | 52417 | C19H30O8 | 详情 | 详情 | ||
| (LXII) | 52418 | C18H26O7 | 详情 | 详情 | ||
| (LXIII) | 52419 | (2-iodoethenyl)(trimethyl)silane | C5H11ISi | 详情 | 详情 | |
| (LXIV) | 52420 | C23H38O7Si | 详情 | 详情 | ||
| (LXV) | 52421 | methyl 2-{(2R,4aS,6S,7S,8R,8aR)-7,8-dihydroxy-6-[(E)-1-hydroxy-3-(trimethylsilyl)-2-propenyl]octahydropyrano[3,2-b]pyran-2-yl}acetate | C17H30O7Si | 详情 | 详情 | |
| (LXVI) | 52422 | methyl 2-{(2R,4aS,6S,7R,8S,8aS)-7,8-bis{[tert-butyl(dimethyl)silyl]oxy}-6-[(1S,2E)-1-{[tert-butyl(dimethyl)silyl]oxy}-3-(trimethylsilyl)-2-propenyl]octahydropyrano[3,2-b]pyran-2-yl}acetate | C35H72O7Si4 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XI)Dess-Martin oxidation of alcohol (I) in CH2Cl2 yields aldehyde (II), which is then subjected to a Horner-Emmons reaction with phosphonate (III) in THF in the presence of NaH to provide compound (IV). Enone (IV) is then converted into intermediate (V) by first conjugate reduction by the Stryker reagent, reduction with NaBH4 in MeOH of the resulting saturated ketone, separation of the two possible diastereomers obtained and final mesylation by means of Ms2O and Et3N. Dess-Martin oxidation of the primary alcohol (VI) affords aldehyde (VII), which is then coupled to mesylate (V) by means of NiCl2-CrCl2 in DMF/THF. The resulting product is subjected to cyclization by means of KH in DME to furnish tetrahydropyran derivative (VIII). Reduction of (VIII) with LiAlH4 in Et2O yields alcohol (IX), which is then oxidized by the Dess Martin reagent to give aldehyde (X). Coupling of (X) with compound (XI) by means of NiCl2-CrCl2 in DMF/THF affords ketone (XII).
| 【1】 Aicher, T.D.; et al.; Total synthesis of halichondrin B and norhalichondrin B. J Am Chem Soc 1992, 114, 8, 3162. |
| 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) | 48410 | 3-[(2S,5R)-5-(hydroxymethyl)-4-methylenetetrahydro-2-furanyl]propyl pivalate | C14H24O4 | 详情 | 详情 | |
| (II) | 48411 | 3-[(2S,5R)-5-formyl-4-methylenetetrahydro-2-furanyl]propyl pivalate | C14H22O4 | 详情 | 详情 | |
| (III) | 48412 | dimethyl (4R)-5-iodo-4-methyl-2-oxo-5-hexenylphosphonate | C9H16IO4P | 详情 | 详情 | |
| (IV) | 48413 | 3-[(2S,5S)-5-[(1Z,5R)-6-iodo-5-methyl-3-oxo-1,6-heptadienyl]-4-methylenetetrahydro-2-furanyl]propyl pivalate | C21H31IO4 | 详情 | 详情 | |
| (V) | 48414 | 3-[(2S,5S)-5-((3R,5R)-6-iodo-5-methyl-3-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-6-heptenyl)-4-methylenetetrahydro-2-furanyl]propyl pivalate | C24H41IO4S | 详情 | 详情 | |
| (VI) | 48415 | 2-[(2S,3R,4R,4aS,6R,7R,8aS)-7-[[tert-butyl(dimethyl)silyl]oxy]-6-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-[(4-methoxybenzyl)oxy]-4-methyloctahydropyrano[3,2-b]pyran-2-yl]-1-ethanol | C32H58O7Si2 | 详情 | 详情 | |
| (VII) | 48416 | 2-[(2S,3R,4R,4aS,6R,7R,8aS)-7-[[tert-butyl(dimethyl)silyl]oxy]-6-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-[(4-methoxybenzyl)oxy]-4-methyloctahydropyrano[3,2-b]pyran-2-yl]acetaldehyde | C32H56O7Si2 | 详情 | 详情 | |
| (VIII) | 48417 | 3-((2S,5S)-5-[2-[(4R,6R)-2-([(2S,3R,4R,4aS,6R,7R,8aS)-7-[[tert-butyl(dimethyl)silyl]oxy]-6-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-[(4-methoxybenzyl)oxy]-4-methyloctahydropyrano[3,2-b]pyran-2-yl]methyl)-4-methyl-3-methylene-1,2-oxazinan-6-yl]ethyl]-4-methylenetetrahydro-2-furanyl)propyl 2,2-dimethylpropanoate | C52H89NO10Si2 | 详情 | 详情 | |
| (IX) | 48418 | 3-((2S,5S)-5-[2-[(4R,6R)-2-([(2S,3R,4R,4aS,6R,7R,8aS)-7-[[tert-butyl(dimethyl)silyl]oxy]-6-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-[(4-methoxybenzyl)oxy]-4-methyloctahydropyrano[3,2-b]pyran-2-yl]methyl)-4-methyl-3-methylene-1,2-oxazinan-6-yl]ethyl]-4-methylenetetrahydro-2-furanyl)-1-propanol | C47H81NO9Si2 | 详情 | 详情 | |
| (X) | 48419 | 3-((2S,5S)-5-[2-[(4R,6R)-2-([(2S,3R,4R,4aS,6R,7R,8aS)-7-[[tert-butyl(dimethyl)silyl]oxy]-6-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-[(4-methoxybenzyl)oxy]-4-methyloctahydropyrano[3,2-b]pyran-2-yl]methyl)-4-methyl-3-methylene-1,2-oxazinan-6-yl]ethyl]-4-methylenetetrahydro-2-furanyl)propanal | C47H79NO9Si2 | 详情 | 详情 | |
| (XI) | 48420 | methyl 2-[(2R,4aS,6S,7R,8S,8aS)-7,8-bis[[tert-butyl(dimethyl)silyl]oxy]-6-((1S,2E)-1-[[tert-butyl(dimethyl)silyl]oxy]-3-iodo-2-propenyl)octahydropyrano[3,2-b]pyran-2-yl]acetate | C32H63IO7Si3 | 详情 | 详情 | |
| (XII) | 48421 | C79H141NO16Si5 | 详情 | 详情 |