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【结 构 式】 
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【药物名称】Tacrolimus, Fujimycin, L-679934, FK-506, FR-900506, Protopy, Protopic, Prograf(as hydrate) 【化学名称】[3S-[3R*[E(1S*,3S*,4S*)],4S*,5R*,8S*,9E,12R*,14R*,15S*,16R*,18S*,19S*,26aR*]]-5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-Hexadecahydro-5,19-dihydroxy-3-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylethenyl]-14,16-dimethoxy-4,10,12,18-tetramethyl-8-(2-propenyl)-15,19-epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclotricosine-1,7,20,21(4H,23H)-tetraone 【CA登记号】104987-11-3, 109581-93-3 (monohydrate) 【 分 子 式 】C44H69NO12 【 分 子 量 】804.04003 |
【开发单位】Fujisawa (Orphan Drug), Sucampo Pharmaceuticals (Orphan Drug), Fujisawa (Originator), Roche (Licensee), Sucampo Pharma (Licensee), Sucampo Pharmaceuticals (Licensee), GlaxoSmithKline (Comarketer) 【药理作用】Antiallergic Ophthalmic Agents, Antiarthritic Drugs, Antipsoriatics, Asthma Therapy, Atopic Dermatitis, Agents for, Cerebrovascular Diseases, Treatment of, DERMATOLOGIC DRUGS, Dry Eye Syndrome, Treatment for, Eczema, Treatment of, GASTROINTESTINAL DRUGS, Immunologic Neuromuscular Disorders, Treatment of, IMMUNOMODULATING AGENTS, Immunosuppressants, Inflammatory Bowel Disease, Agents for, Myasthenia Gravis, Agents for, NEUROLOGIC DRUGS, Ocular Antiinflammatory and Antiinfective Agents, OCULAR MEDICATIONS, Ophthalmic Drugs, Other Ocular Medications, RESPIRATORY DRUGS, Rheumatoid Arthritis, Treatment of, Stroke, Treatment of, Systemic Lupus Erythematosus, Agents for, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, Treatment of Other Autoimmune Disorders, Treatment of Transplant Rejection, Calcineurin Inhibitors, INS Expression Inhibitors, Rotamase (FKBP12) Inhibitors |
合成路线1
The total synthesis of FK-506 is described: This synthesis was performed by previously constructing three building fragments (XX), (XXXII) and (XLVI), which later were coupled sequentially. First the synthesis of these fragments will be presented, and afterwards their sequential coupling will be described. 1) (2RS,4R,6S,7R,8S,10R)-2-(Bis(dimethylamino)phosphono)-7-(tert-butyldimethylsilyloxy)-6,8-dimethoxy-10-(1,3-dithian-2-yl)-4-methylundecane (XX). The reaction of L-arabitol (I) with 2-acetoxyisobutyryl chloride in acetonitrile gives the diacetoxycompound (II), which by treatment with sodium methoxide in THF yields (2S,4S)-1,2:4,5-diepoxy-3-pentanol (III). The protection of (III) with TBS-Cl in THF affords the protected compound (IV), which is condensed with ethoxyacetylene (V) by means of butyllithium and boron trifluoride ethearate in THF giving the diacetylenic alcohol (VI). Cyclization of (VI) by means of HgCl2 and p-toluenesulfonic acid in refluxing ethanol yields the dilactone (VII), which is methylated by means of methyl iodide and lithium diisopropylamide in THF affording the methylated dilactone (VIII). The deprotection of (VIII) with HF in acetonitrile gives the hydroxydilactone (IX), which is benzylated with benzyl trichloroacetimidate and trifluoromethanesulfonic acid in dichloromethane-cyclohexane yielding the benzyl protected dilactone (X). The methanolysis of (X), followed by methylation with NaH and methyl iodide in DMF affords the nonanedioic ester (XI), which is debenzylated by hydrogenolysis with H2 over Pd/C in ethyl acetate giving the hydroxy diester (XII). The lactonization of (XII) with pyridinium p-toluenesulfonate in dichloromethane yields the lactone-methyl ester (XIII), which is selectively reduced with L-Selectride in THF affording the lactol-methyl ester (XIV). The reaction of (XIV) with propane-1,3-dithiol and boron trifluoride ethearate in dichloromethane gives the 1,3-dithiane derivative (XV), which by reduction of its lactone group with LiAlH4 in THF yields (2R,4S,5R,6S,8R)-8-(1,3-dithian-2-yl)-4,6-dimethoxy-2-methylnonane-1,5-diol (XVI). The reaction of (XVI) with I2, pyridine and triphenylphosphine in benzene affords the 1-iodo derivative (XVII), which is protected with TBS trifluoromethanesulfonate and triethylamine in dichloromethane giving the protected iodide (XVIII). Finally, this compound is condensed with ethylphosphonic acid bis(dimethylamide) (XIX) by means of butyllithium in THF to afford the first building fragment (XX).
| 【1】 Smith, D.B.; Schreiber, S.L.; Ragan, J.A.; Uehling, D.E.; Nakatsuka, M.; Sammakia, T.; Total synthesis of FK506 and an FKBP probe reagent, (C8,C9-13C2)-FK5. J Am Chem Soc 1990, 112, 14, 5583. |
| 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) | 11442 | (2S,4S)-1,2,3,4,5-Pentanepentol; D-Arabinol | 488-82-4 | C5H12O5 | 详情 | 详情 |
| (II) | 11439 | [(3aR,5R,5aS,8aS,8bR)-2,2,7,7-tetramethyltetrahydro-3aH-di[1,3]dioxolo[4,5-b:4,5-d]pyran-5-yl]methyl 4-methylbenzenesulfonate | C19H26O8S | 详情 | 详情 | |
| (III) | 11444 | Di[(2S)oxiranyl]methanol | C5H8O3 | 详情 | 详情 | |
| (IV) | 11445 | tert-Butyl(dimethyl)silyl di[(2S)oxiranyl]methyl ether; tert-Butyl[di[(2S)oxiranyl]methoxy]dimethylsilane | C11H22O3Si | 详情 | 详情 | |
| (V) | 11446 | 1-Ethoxyacetylene; Ethyl ethynyl ether.; Ethoxyethyne | 927-80-0 | C4H6O | 详情 | 详情 |
| (VI) | 11447 | (4S,6S)-5-[[tert-Butyl(dimethyl)silyl]oxy]-1,9-diethoxy-1,8-nonadiyne-4,6-diol | C19H34O5Si | 详情 | 详情 | |
| (VII) | 11448 | (5S)-5-[[[tert-Butyl(dimethyl)silyl]oxy][(2S)-5-oxotetrahydro-2-furanyl]methyl]dihydro-2(3H)-furanone | C15H26O5Si | 详情 | 详情 | |
| (VIII) | 11449 | (3R,5S)-5-[[[tert-Butyl(dimethyl)silyl]oxy][(2S,4R)-4-methyl-5-oxotetrahydro-2-furanyl]methyl]-3-methyldihydro-2(3H)-furanone | C17H30O5Si | 详情 | 详情 | |
| (IX) | 11450 | (3R,5S)-5-[Hydroxy[(2S,4R)-4-methyl-5-oxotetrahydro-2-furanyl]methyl]-3-methyldihydro-2(3H)-furanone | C11H16O5 | 详情 | 详情 | |
| (X) | 11451 | 5-(2-Bromophenyl)-1-(4-nitrophenyl)-1H-1,2,3,4-tetraazole | C13H8BrN5O2 | 详情 | 详情 | |
| (XI) | 11452 | dimethyl (2R,4S,6S,8R)-5-(benzyloxy)-4,6-dimethoxy-2,8-dimethylnonanedioate | C22H34O7 | 详情 | 详情 | |
| (XII) | 11453 | dimethyl (2R,4S,6S,8R)-5-hydroxy-4,6-dimethoxy-2,8-dimethylnonanedioate | C15H28O7 | 详情 | 详情 | |
| (XIII) | 11454 | methyl (2R,4S)-4-methoxy-4-[(2S,3S,5R)-3-methoxy-5-methyl-6-oxotetrahydro-2H-pyran-2-yl]-2-methylbutanoate | C14H24O6 | 详情 | 详情 | |
| (XIV) | 11455 | methyl (2R,4S)-4-[(2S,3S,5R)-6-hydroxy-3-methoxy-5-methyltetrahydro-2H-pyran-2-yl]-4-methoxy-2-methylbutanoate | C14H26O6 | 详情 | 详情 | |
| (XV) | 11456 | (3R,5S,6R)-6-[(1S,3R)-3-(1,3-Dithian-2-yl)-1-methoxybutyl]-5-methoxy-3-methyltetrahydro-2H-pyran-2-one | C16H28O4S2 | 详情 | 详情 | |
| (XVI) | 11457 | (2R,4S,5R,6S,8R)-8-(1,3-Dithian-2-yl)-4,6-dimethoxy-2-methyl-1,5-nonanediol | C16H32O4S2 | 详情 | 详情 | |
| (XVII) | 11458 | (2R,4S,5S,6S,8R)-8-(1,3-Dithian-2-yl)-1-iodo-4,6-dimethoxy-2-methyl-5-nonanol | C16H31IO3S2 | 详情 | 详情 | |
| (XVIII) | 11459 | tert-Butyl([(1S,2S,4R)-1-[(1S,3R)-3-(1,3-dithian-2-yl)-1-methoxybutyl]-5-iodo-2-methoxy-4-methylpentyl]oxy)dimethylsilane; tert-Butyl(dimethyl)silyl (1S,2S,4R)-1-[(1S,3R)-3-(1,3-dithian-2-yl)-1-methoxybutyl]-5-iodo-2-methoxy-4-methylpentyl ether | C22H45IO3S2Si | 详情 | 详情 | |
| (XIX) | 11460 | Ethyl-N,N,N',N'-tetramethylphosphonic diamide | C6H17N2OP | 详情 | 详情 | |
| (XX) | 11491 | (3R,5S,6R,7S,9R)-6-[[tert-Butyl(dimethyl)silyl]oxy]-9-(1,3-dithian-2-yl)-5,7-dimethoxy-1,3-dimethyldecyl-N,N,N',N'-tetramethylphosphonic diamide | C28H61N2O4PS2Si | 详情 | 详情 |
合成路线2
2) (2R,3S,5S(2'S,4'R))-5-(2-(iodomethyl)tetrahydrofuran-4-yl)-5-(4-methoxy benzyloxy)-2-methyl-3-(triisopropylsilyloxy)pentanal (XXXII). The regioselective reduction of methyl 5-(4-methoxybenzyloxy)-3-oxopentanoate (XXI) with H2 over Ru2Cl4((S)-BINAP)2(C2H5)3N in methanol gives the 3(S)-hydroxy derivative (XXII), which is condensed with ally bromide (XXIII) by means of lithium diisopropylamide THF-HMPA to yield the ally derivative (XXIV). The reduction of (XXIV) with LiAlH4 in THF affords the diol (XXV), which is cyclized to the ketal (XXVI) by means of DDQ in dichloromethane. The reaction of (XXVI) first with N-iodosuccinimide (NIS) and then with diisobutylaluminum hydride affords (3S(2'S,4'R))-3-(2-iodomethyl)tetrahydrofuran-4-yl)-3-(4-methoxybenzyl)-1-propanol (XXVII), which is oxidized to the corresponding aldehyde (XXVIII) by means of oxalyl chloride in dichloromethane. The condensation of (XXVIII) with 2(E)-butenyltriphenylstannane (XXIX) by means of boron trifluoride ethearate in dichloromethane gives the alcohol (XXX), which is protected with TIPS trifluoromethanesulfonate in dichloromethane yielding the fully protected diol (XXXI). Finally, the double bond of (XXXI) is oxidized with ozone in methanol - dichloromethane yielding the second building fragment (XXXII).
| 【1】 Smith, D.B.; Schreiber, S.L.; Ragan, J.A.; Uehling, D.E.; Nakatsuka, M.; Sammakia, T.; Total synthesis of FK506 and an FKBP probe reagent, (C8,C9-13C2)-FK5. J Am Chem Soc 1990, 112, 14, 5583. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXI) | 11461 | methyl 6-(4-methoxyphenyl)-3-oxohexanoate | C14H18O4 | 详情 | 详情 | |
| (XXII) | 11462 | methyl (3S)-3-hydroxy-6-(4-methoxyphenyl)hexanoate | C14H20O4 | 详情 | 详情 | |
| (XXIII) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (XXIV) | 11464 | methyl (2S)-2-[(1S)-1-hydroxy-4-(4-methoxyphenyl)butyl]-4-pentenoate | C17H24O4 | 详情 | 详情 | |
| (XXV) | 11465 | (2R,3S)-2-Allyl-5-[(4-methoxybenzyl)oxy]-1,3-pentanediol | C16H24O4 | 详情 | 详情 | |
| (XXVI) | 11466 | (2R)-2-[(2S,4S)-2-(4-Methoxyphenyl)-1,3-dioxan-4-yl]-4-penten-1-ol | C16H22O4 | 详情 | 详情 | |
| (XXVII) | 11467 | (3S)-3-[(3S,5S)-5-(Iodomethyl)tetrahydro-3-furanyl]-4-(4-methoxyphenyl)-1-butanol | C16H23IO3 | 详情 | 详情 | |
| (XXVIII) | 11468 | (3S)-3-[(3S,5S)-5-(Iodomethyl)tetrahydro-3-furanyl]-4-(4-methoxyphenyl)butanal | C16H21IO3 | 详情 | 详情 | |
| (XXIX) | 11469 | (E)-2-Butenyl(triphenyl)stannane | C22H22Sn | 详情 | 详情 | |
| (XXX) | 11470 | (3S,4S,6S)-6-[(3S,5S)-5-(Iodomethyl)tetrahydro-3-furanyl]-7-(4-methoxyphenyl)-3-methyl-1-hepten-4-ol | C20H29IO3 | 详情 | 详情 | |
| (XXXI) | 11481 | ([(1S,2S)-1-[(2S)-2-[(3S,5S)-5-(Iodomethyl)tetrahydro-3-furanyl]-3-(4-methoxyphenyl)propyl]-2-methyl-3-butenyl]oxy)(triisopropyl)silane; (1S,2S)-1-[(2S)-2-[(3S,5S)-5-(Iodomethyl)tetrahydro-3-furanyl]-3-(4-methoxyphenyl)propyl]-2-methyl-3-butenyl triisopropylsilyl ether | C29H49IO3Si | 详情 | 详情 | |
| (XXXIII) | 11471 | 1,4-Pentadien-3-ol | 922-65-6 | C5H8O | 详情 | 详情 |
| (XXXIV) | 11472 | (1S)-1-[(2R)Oxiranyl]-2-propen-1-ol | C5H8O2 | 详情 | 详情 | |
| (XXXV) | 11473 | (2S)-2-[(1S)-1-(4-Methoxybenzyl)-2-propenyl]oxirane; Methyl 4-[(2S)-2-[(2S)oxiranyl]-3-butenyl]phenyl ether | C13H16O2 | 详情 | 详情 | |
| (XXXVI) | 11474 | (3S,4R)-7-Ethoxy-4-methoxy-3-(4-methoxybenzyl)-1-hepten-6-yne; 4-[(2S,3R)-6-Ethoxy-3-methoxy-2-vinyl-5-hexynyl]phenyl methyl ether | C18H24O3 | 详情 | 详情 | |
| (XXXVII) | 11475 | ethyl (4R,5S)-5-hydroxy-4-methoxy-6-heptenoate | C10H18O4 | 详情 | 详情 | |
| (XXXVIII) | 11476 | (5R,6S)-5-Methoxy-6-vinyltetrahydro-2H-pyran-2-one | C8H12O3 | 详情 | 详情 | |
| (XXXIX) | 11585 | methyl (1R,5R)-5-methoxy-3-cyclohexene-1-carboxylate | C9H14O3 | 详情 | 详情 | |
| (XL) | 11586 | methyl (1R,3R,4R)-4-hydroxy-3-methoxycyclohexanecarboxylate | C9H16O4 | 详情 | 详情 | |
| (XLI) | 11588 | methyl (1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexanecarboxylate | C18H36O4Si | 详情 | 详情 | |
| (XLII) | 11480 | [(1R,3R,4R)-3-Methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]methanol | C17H36O3Si | 详情 | 详情 | |
| (XLIII) | 11532 | (1R,3R,4R)-3-Methoxy-4-[(triisopropylsilyl)oxy]cyclohexanecarbaldehyde | C17H34O3Si | 详情 | 详情 |
合成路线3
3) (1R,2R,4R)-4-(2(E)-Bromo-1-propenyl)-2-methoxy-1-(triisopropylsilyloxy)cyclohexane (XLVII).- The catalytic asymetric epoxidation of divinylcarbinol (XXXIII) with titanium isopropoxide and L-(+)-diisopropyl tartrate in dichloromethane gives (2R,3S)-1,2-epoxy-4-penten-3-ol (XXXIV), which is protected with PMB-Br and tetrabutylammonium bromide in dichloromethane yielding the benzyl derivative (XXXV). The condensation of (XXXV) with ethoxyacetylene (V) by means of boron trifluoride ethearate in THF affords the acetylenic ether (XXXVI), which is treated with ethanol and HgCl2 giving ethyl (4R,5S)-5-hydroxy-4-methoxyhept-6-enoate (XXXVII). The lactonization of (XXXVII) by means of p-toluenesulfonic acid in benzene yields the lactone (XXXVIII), which is submitted to a Claisen rearrangement by means of TBS trifluoromethanesulfonate and the resulting acid was methylated with diazomethane to afford methyl (1R,3R)-3-methoxy-4-cyclohexene-1-carboxylate (XXXIX). Hydroboration of (XXXIX) with BH3 and NaOH gives methyl (1R,3R,4R)-4-hydroxy-3-methoxycyclohexane-1-carboxylate (XL), which is protected with TIPS trifluoromethanesulfonate in dichloromethane yielding ester (XLI). The reduction of (XLI) with LiAlH4 in THF affords the hydroxymethyl derivative (XLII), which is oxidized to the corresponding aldehyde (XLIII) by means of oxalyl chloride in dichloromethane - DMSO. The reaction of (XLIII) with dimethyl diazomethylphosphonate and potassium tert-butoxide in THF gives (1R,2R,4R)-4-ethynyl-2-methoxy-1-(triisopropylsilyloxy)cyclohexane (XLIV), which is methylated with methyl iodide and butyllithium in THF to yield the corresponding propynyl derivative (XLV). Finally, this compound is treated with NBS in benzene affording the third building fragment (XLVI) (Scheme 2). 4) The first coupling reaction was the addition of vinyl bromide (XLVI) to aldehyde (XXXII). This was performed by reaction of (XLVI) with butyllithium and the resulting vinyllithium derivative was treated with aldehyde (XXXII) and catalytic amounts of MgBr giving the carbinol (XLVII), which was esterified with N-(tert-butoxycarbonyl)piperidine-2(S)-carboxylic acid (XLVIII) by means of DDC and 4-pyrrolidinopyridine, yielding the corresponding ester (XLIX). Treatment of (XLIX) with Zn dust and NH4Cl affords the 2-allyl substituted alcohol (L), which is oxidized with oxalyl chloride and DMSO in dichloromethane giving a fourth building block, the allyl substituted aldehyde (LI).
| 【1】 Smith, D.B.; Schreiber, S.L.; Ragan, J.A.; Uehling, D.E.; Nakatsuka, M.; Sammakia, T.; Total synthesis of FK506 and an FKBP probe reagent, (C8,C9-13C2)-FK5. J Am Chem Soc 1990, 112, 14, 5583. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXXI) | 11481 | ([(1S,2S)-1-[(2S)-2-[(3S,5S)-5-(Iodomethyl)tetrahydro-3-furanyl]-3-(4-methoxyphenyl)propyl]-2-methyl-3-butenyl]oxy)(triisopropyl)silane; (1S,2S)-1-[(2S)-2-[(3S,5S)-5-(Iodomethyl)tetrahydro-3-furanyl]-3-(4-methoxyphenyl)propyl]-2-methyl-3-butenyl triisopropylsilyl ether | C29H49IO3Si | 详情 | 详情 | |
| (XXXII) | 11482 | (2R,3R,5S)-5-[(3S,5S)-5-(Iodomethyl)tetrahydro-3-furanyl]-6-(4-methoxyphenyl)-2-methyl-3-[(triisopropylsilyl)oxy]hexanal | C28H47IO4Si | 详情 | 详情 | |
| (XLIII) | 11532 | (1R,3R,4R)-3-Methoxy-4-[(triisopropylsilyl)oxy]cyclohexanecarbaldehyde | C17H34O3Si | 详情 | 详情 | |
| (XLIV) | 11483 | (1R,2R,4R)-4-Ethynyl-2-methoxycyclohexyl triisopropylsilyl ether; [[(1R,2R,4R)-4-Ethynyl-2-methoxycyclohexyl]oxy](triisopropyl)silane | C18H34O2Si | 详情 | 详情 | |
| (XLV) | 11484 | (1R,2R,4R)-2-Methoxy-4-(1-propynyl)cyclohexyl triisopropylsilyl ether; Triisopropyl[[(1R,2R,4R)-2-methoxy-4-(1-propynyl)cyclohexyl]oxy]silane | C19H36O2Si | 详情 | 详情 | |
| (XLVI) | 11485 | ([(1R,2R,4R)-4-[(E)-2-Bromo-1-propenyl]-2-methoxycyclohexyl]oxy)(triisopropyl)silane; (1R,2R,4R)-4-[(E)-2-Bromo-1-propenyl]-2-methoxycyclohexyl triisopropylsilyl ether | C19H37BrO2Si | 详情 | 详情 | |
| (XLVII) | 11486 | (E,3S,4S,5S,7S)-7-[(3S,5S)-5-(Iodomethyl)tetrahydro-3-furanyl]-8-(4-methoxyphenyl)-1-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-2,4-dimethyl-5-[(triisopropylsilyl)oxy]-1-octen-3-ol | C47H85IO6Si2 | 详情 | 详情 | |
| (XLVIII) | 11487 | (2S)-1-(tert-Butoxycarbonyl)hexahydro-2-pyridinecarboxylic acid | C11H19NO4 | 详情 | 详情 | |
| (XLIX) | 11488 | 1-(tert-butyl) 2-((1S,2E)-1-[(1S,2S,4S)-4-[(3S,5S)-5-(iodomethyl)tetrahydro-3-furanyl]-5-(4-methoxyphenyl)-1-methyl-2-[(triisopropylsilyl)oxy]pentyl]-3-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-2-methyl-2-propenyl) (2S)-1,2-piperidinedicarboxylate | C58H102INO9Si2 | 详情 | 详情 | |
| (L) | 11489 | 1-(tert-butyl) 2-[(1S,2S,3S,5S,6S)-6-(hydroxymethyl)-5-(4-methoxybenzyl)-1-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methylethenyl)-2-methyl-3-[(triisopropylsilyl)oxy]-8-nonenyl] (2S)-1,2-piperidinedicarboxylate | C58H103NO9Si2 | 详情 | 详情 | |
| (LI) | 11490 | 1-(tert-butyl) 2-[(1S,2S,3S,5S,6S)-6-formyl-5-(4-methoxybenzyl)-1-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methylethenyl)-2-methyl-3-[(triisopropylsilyl)oxy]-8-nonenyl] (2S)-1,2-piperidinedicarboxylate | C58H101NO9Si2 | 详情 | 详情 |
合成路线4
5) A second coupling reaction was the addition of the phosphonamide (XX) to the aldehyde (LI) by means of butyllithium in THF to give the dithianylolefin (LII), which was treated first with TFIB and methanol and then with acetic acid, yielding the free aldeyde (LIII). The condensation of (LIII) with methyl 2-(2,4-dimethoxybenzyloxy)acetate (LIV) by means of lithium diisopropylamide in THF, followed by a treatment with LiOH affords the hydroxy acid (LV), which is protected with TES trifluoromethylsulfonate and treated with 2,6-dimethylpyridine to give the free amino acid (LVI), the open-chain precursor of FK-506.
| 【1】 Smith, D.B.; Schreiber, S.L.; Ragan, J.A.; Uehling, D.E.; Nakatsuka, M.; Sammakia, T.; Total synthesis of FK506 and an FKBP probe reagent, (C8,C9-13C2)-FK5. J Am Chem Soc 1990, 112, 14, 5583. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 33696 | 3-[([1-[(1-[[(3-hydroxypropyl)amino]methyl]cyclohexyl)disulfanyl]cyclohexyl]methyl)amino]-1-propanol | C20H40N2O2S2 | 详情 | 详情 | ||
| (XX) | 11491 | (3R,5S,6R,7S,9R)-6-[[tert-Butyl(dimethyl)silyl]oxy]-9-(1,3-dithian-2-yl)-5,7-dimethoxy-1,3-dimethyldecyl-N,N,N',N'-tetramethylphosphonic diamide | C28H61N2O4PS2Si | 详情 | 详情 | |
| (LI) | 11490 | 1-(tert-butyl) 2-[(1S,2S,3S,5S,6S)-6-formyl-5-(4-methoxybenzyl)-1-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methylethenyl)-2-methyl-3-[(triisopropylsilyl)oxy]-8-nonenyl] (2S)-1,2-piperidinedicarboxylate | C58H101NO9Si2 | 详情 | 详情 | |
| (LII) | 11492 | 2-[(1S,2S,3S,5S,6S,7E,10S,12S,13R,14S,16R)-6-allyl-16-(1,3-dithian-2-yl)-12,14-dimethoxy-5-(4-methoxybenzyl)-1-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methylethenyl)-2,8,10-trimethyl-3,13-bis[(triisopropylsilyl)oxy]-7-heptadecenyl] 1-(tert-butyl) (2S)-1,2-piperidinedicarboxylate | C85H155NO11S2Si3 | 详情 | 详情 | |
| (LIII) | 11493 | 2-[(1S,2S,3S,5S,6S,7E,10S,12S,14R,15S,16R)-6-allyl-15-[[tert-butyl(dimethyl)silyl]oxy]-12,14-dimethoxy-5-(4-methoxybenzyl)-1-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methylethenyl)-2,8,10,16-tetramethyl-17-oxo-3-[(triisopropylsilyl)oxy]-7-heptadecenyl] 1-(tert-butyl) (2S)-1,2-piperidinedicarboxylate | C79H143NO12Si3 | 详情 | 详情 | |
| (LIV) | 57274 | methyl 2-[(2,4-dimethoxybenzyl)oxy]acetate | C12H16O5 | 详情 | 详情 | |
| (LV) | 11494 | 2-[(1S,2S,3S,6S,7E,10S,12S,13R,14S,16R)-6-allyl-13-[[tert-butyl(dimethyl)silyl]oxy]-18-[(2,4-dimethoxybenzyl)oxy]-17-hydroxy-12,14,19-trimethoxy-5-(4-methoxybenzyl)-1-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methylethenyl)-2,8,10,16-tetramethyl-19-oxo-3-[(triisopropylsilyl)oxy]-7-nonadecenyl] 1-(tert-butyl) (2S)-1,2-piperidinedicarboxylate | C91H159NO17Si3 | 详情 | 详情 | |
| (LVI) | 11495 | (4R,6S,7R,8S,10S,12E,14R,15S,17S,18S,19S,20E)-14-Allyl-7-[[tert-butyl(dimethyl)silyl]oxy]-2-[(2,4-dimethoxybenzyl)oxy]-6,8-dimethoxy-15-[(4-methoxybenzyl)oxy]-21-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-4,10,12,18,20-pentamethyl-19-[[(2S)piperidinylcarbonyl]oxy]-3-[(triethylsilyl)oxy]-17-[(triisopropylsilyl)oxy]-12,20-henicosadienoic acid | C91H163NO16Si4 | 详情 | 详情 |
合成路线5
The cyclization of (LVI) by means of N-methyl-2-chloropyridinium iodide and triethylamine yields the macrocyclic lactam (LVII), which is selectively deprotected with trifluoroacetic acid in THF - water and oxidized with DMP in dichloromethane affording the beta-keto lactam (LVIII). Selective deprotection of (LVIII) with DDQ in dichloromethane - tert-butyl alcohol gives the diol (LIX), which is then oxidized with DMP in dichloromethane yielding the silylated FK-506 (LX). Finally, this compound is deprotected by treatment with HF in acetonitrile.
| 【1】 Smith, D.B.; Schreiber, S.L.; Ragan, J.A.; Uehling, D.E.; Nakatsuka, M.; Sammakia, T.; Total synthesis of FK506 and an FKBP probe reagent, (C8,C9-13C2)-FK5. J Am Chem Soc 1990, 112, 14, 5583. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (LVI) | 11495 | (4R,6S,7R,8S,10S,12E,14R,15S,17S,18S,19S,20E)-14-Allyl-7-[[tert-butyl(dimethyl)silyl]oxy]-2-[(2,4-dimethoxybenzyl)oxy]-6,8-dimethoxy-15-[(4-methoxybenzyl)oxy]-21-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-4,10,12,18,20-pentamethyl-19-[[(2S)piperidinylcarbonyl]oxy]-3-[(triethylsilyl)oxy]-17-[(triisopropylsilyl)oxy]-12,20-henicosadienoic acid | C91H163NO16Si4 | 详情 | 详情 | |
| (LVII) | 11496 | (3S,4S,5S,8R,12S,14S,15R,16S,18R,26aS)-8-Allyl-15-[[tert-butyl(dimethyl)silyl]oxy]-20-[(2,4-dimethoxybenzyl)oxy]-14,16-dimethoxy-7-[(4-methoxybenzyl)oxy]-3-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methylethenyl)-4,10,12,18-tetramethyl-19-[(triethylsilyl)oxy]-5-[(triisopropylsilyl)oxy]-5,6,7,8,11,12,13,14,15,16,17,18,19,20,24,25,26,26a-octadecahydro-3H-pyrido[2,1-c][1,4]oxazacyclotricosine-1,21(4H,23H)-dione | C91H161NO15Si4 | 详情 | 详情 | |
| (LVIII) | 11497 | (3S,4S,5S,7S,8R,12S,14S,15R,16S,18R,26aS)-8-Allyl-15-[[tert-butyl(dimethyl)silyl]oxy]-20-[(2,4-dimethoxybenzyl)oxy]-14,16-dimethoxy-7-[(4-methoxybenzyl)oxy]-3-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methylethenyl)-4,10,12,18-tetramethyl-5-[(triisopropylsilyl)oxy]-5,6,7,8,11,12,13,14,15,16,17,18,24,25,26,26a-hexadecahydro-3H-pyrido[2,1-c][1,4]oxazacyclotricosine-1,19,21(4H,20H,23H)-trione | C85H145NO15Si3 | 详情 | 详情 | |
| (LIX) | 11498 | (3S,4S,5S,7S,8R,12S,14S,15R,16S,18R,26aS)-8-Allyl-15-[[tert-butyl(dimethyl)silyl]oxy]-7,20-dihydroxy-14,16-dimethoxy-3-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methylethenyl)-4,10,12,18-tetramethyl-5-[(triisopropylsilyl)oxy]-5,6,7,8,11,12,13,14,15,16,17,18,24,25,26,26a-hexadecahydro-3H-pyrido[2,1-c][1,4]oxazacyclotricosine-1,19,21(4H,20H,23H)-trione | C68H127NO12Si3 | 详情 | 详情 | |
| (LX) | 11499 | (3S,4S,5S,8R,12S,14S,15R,16S,18R,26aS)-8-Allyl-15-[[tert-butyl(dimethyl)silyl]oxy]-14,16-dimethoxy-3-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methylethenyl)-4,10,12,18-tetramethyl-5-[(triisopropylsilyl)oxy]-5,6,11,12,13,14,15,16,17,18,24,25,26,26a-tetradecahydro-3H-pyrido[2,1-c][1,4]oxazacyclotricosine-1,7,19,20,21(4H,8H,23H)-pentone | C68H123NO12Si3 | 详情 | 详情 |
合成路线6
A new total synthesis of FK-506 is described: This synthesis has been performed by previous construction of two building fragments (XXIV) and (LI), which later were coupled and cyclized. (Schemes 1-3): 1) (1R*S*,3R,5S,6R,7S,9R)-6-(tert-butyldimethylsilyloxy)-9-(1,3-dithian-2-yl)-5,7-dimethoxy-1-methyldecyl diphenyl phosphine oxide (XXIV). The Sharpless asymetric epoxidation of 1,4-pentadien-3-ol (I) with (-)-diisopropyltartrate and tert-butylhydroperoxide gives the epoxy alcohol (II) with high optical purity, which is benzylated in the usual way to (III). The reaction of (III) with lithioacetonitrile and then HCl yields lactone (IV), which is methylated with lithium diisopropylamide and methyl iodide to lactone (V) as major isomer (separated by chromatography on SiO2). The reduction of (V) with LiAlH4 affords the diol (VI), which is converted into the bis(tert-butyl carbonate) (VII) with 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (BOC-N). The reaction of (VII) with Br2 and K2CO3 in dichloromethane gives the bromocarbonate (VIII), which by selective saponification of the cyclic carbonate with NaOCH3 in methanol yields the epoxy alcohol (IX). Methylation of (IX) with NaH and methyl iodide affords the methyl ether (X), which is converted into the butyrolactone (XI) with lithioacetonitrile as before. The protection of the OH group of (XI) with TBS-Cl gives the silyl ether (XII), which by trans-selective methylation with lithium diisopropylamide and methyl iodide yields lactone (XIII). The reduction of (XIII) with LiAlH4 affords diol (XIV) as major isomer (separated by column chromatography). The selective esterification of the primary OH group of (XIV) with pivaloyl chloride gives the hydroxy ester (XV), which is methylated with NaH and methyl iodide as usual to the methoxy derivative (XVI). Debenzylation of (XVI) by hydrogenolysis with H2 over Pd/C yields the hydroxy ester (XVII), which is silylated with TBS-SO3CF3 to the fully protected compound (XVIII).
| 【1】 Jones, T.K.; Askin, D.; Mills, S.G.; Reamer, R.A.; Desmond, R.; Volante, R.P.; Tschaen, D.M.; Shinkai, I. (Merck & Co., Inc.); Process for synthesis of FK-506 and tricarbonyl intermediates. EP 0378318; JP 1990233643 . |
| 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) | 11471 | 1,4-Pentadien-3-ol | 922-65-6 | C5H8O | 详情 | 详情 |
| (II) | 11501 | (1R)-1-[(2S)Oxiranyl]-2-propen-1-ol | C5H8O2 | 详情 | 详情 | |
| (III) | 11502 | (2S)-2-[(1R)-1-(Benzyloxy)-2-propenyl]oxirane; benzyl (1R)-1-[(2S)Oxiranyl]-2-propenyl ether | C12H14O2 | 详情 | 详情 | |
| (IV) | 11503 | (5S)-5-[(1R)-1-(Benzyloxy)-2-propenyl]dihydro-2(3H)-furanone | C14H16O3 | 详情 | 详情 | |
| (V) | 11504 | (3R,5S)-5-[(1R)-1-(Benzyloxy)-2-propenyl]-3-methyldihydro-2(3H)-furanone | C15H18O3 | 详情 | 详情 | |
| (VI) | 11505 | (2R,4S,5R)-5-(Benzyloxy)-2-methyl-6-heptene-1,4-diol | C15H22O3 | 详情 | 详情 | |
| (VII) | 11506 | (2R,4S,5R)-5-(benzyloxy)-4-[(tert-butoxycarbonyl)oxy]-2-methyl-6-heptenyl tert-butyl carbonate | C25H38O7 | 详情 | 详情 | |
| (VIII) | 11507 | (2R)-3-[(4S,5S)-5-(benzyloxy)-6-(bromomethyl)-2-oxo-1,3-dioxan-4-yl]-2-methylpropyl tert-butyl carbonate | C21H29BrO7 | 详情 | 详情 | |
| (IX) | 11508 | (2R,4S,5S)-5-(benzyloxy)-4-hydroxy-2-methyl-5-[(2S)oxiranyl]pentyl tert-butyl carbonate | C20H30O6 | 详情 | 详情 | |
| (X) | 11509 | (2R,4S,5S)-5-(benzyloxy)-4-methoxy-2-methyl-5-[(2S)oxiranyl]pentyl tert-butyl carbonate | C21H32O6 | 详情 | 详情 | |
| (XI) | 11510 | (5S)-5-[(1S,2S,4R)-1-(Benzyloxy)-5-hydroxy-2-methoxy-4-methylpentyl]dihydro-2(3H)-furanone | C18H26O5 | 详情 | 详情 | |
| (XII) | 11511 | (5S)-5-((1S,2S,4R)-1,5-Bis[[tert-butyl(dimethyl)silyl]oxy]-2-methoxy-4-methylpentyl)dihydro-2(3H)-furanone | C23H48O5Si2 | 详情 | 详情 | |
| (XIII) | 11512 | (3R,5S)-5-((1S,2S,4R)-1-(Benzyloxy)-5-[[tert-butyl(dimethyl)silyl]oxy]-2-methoxy-4-methylpentyl)-3-methyldihydro-2(3H)-furanone | C25H42O5Si | 详情 | 详情 | |
| (XIV) | 11513 | (2R,4S,5R,6S,8R)-5-(Benzyloxy)-9-[[tert-butyl(dimethyl)silyl]oxy]-6-methoxy-2,8-dimethyl-1,4-nonanediol | C25H46O5Si | 详情 | 详情 | |
| (XV) | 11514 | (2R,4S,5R,6S,8R)-5-(benzyloxy)-9-[[tert-butyl(dimethyl)silyl]oxy]-4-hydroxy-6-methoxy-2,8-dimethylnonyl pivalate | C30H54O6Si | 详情 | 详情 | |
| (XVI) | 11515 | (2R,4S,5R,6S,8R)-5-(benzyloxy)-9-[[tert-butyl(dimethyl)silyl]oxy]-4,6-dimethoxy-2,8-dimethylnonyl pivalate | C31H56O6Si | 详情 | 详情 | |
| (XVII) | 11516 | (2R,4S,5R,6S,8R)-9-[[tert-butyl(dimethyl)silyl]oxy]-5-hydroxy-4,6-dimethoxy-2,8-dimethylnonyl pivalate | C24H50O6Si | 详情 | 详情 | |
| (XVIII) | 11517 | (2R,4S,5R,6S,8R)-5,9-bis[[tert-butyl(dimethyl)silyl]oxy]-4,6-dimethoxy-2,8-dimethylnonyl pivalate | C30H64O6Si2 | 详情 | 详情 |
合成路线7
Selective deprotection of (XVIII) with trifluoroacetic acid in THF - water affords the primary alcohol (XIX), which is oxidized with oxalyl chloride and DMSO in dichloromethane to the aldehyde (XX). The protection of the aldehyde group of (XX) with propane-1,3-dithiol and BF3 gives the dithiane derivative (XXI), which is resilylated with TBS-SO3CF3 as before to the dithiane (XXII). The pivaloyl group of (XXII) is eliminated with LiAlH4 in THF yielding the alcohol (XXIII), which is finally treated with benzenesulfonyl chloride and then with ethyl diphenylphosphine oxide and butyllithium in THF to obtain the first building group, the phosphine derivative (XXIV).
| 【1】 Jones, T.K.; Askin, D.; Mills, S.G.; Reamer, R.A.; Desmond, R.; Volante, R.P.; Tschaen, D.M.; Shinkai, I. (Merck & Co., Inc.); Process for synthesis of FK-506 and tricarbonyl intermediates. EP 0378318; JP 1990233643 . |
| 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) | 11517 | (2R,4S,5R,6S,8R)-5,9-bis[[tert-butyl(dimethyl)silyl]oxy]-4,6-dimethoxy-2,8-dimethylnonyl pivalate | C30H64O6Si2 | 详情 | 详情 | |
| (XIX) | 11518 | (2R,4S,5S,6S,8R)-5-[[tert-butyl(dimethyl)silyl]oxy]-9-hydroxy-4,6-dimethoxy-2,8-dimethylnonyl pivalate | C24H50O6Si | 详情 | 详情 | |
| (XX) | 11519 | (2R,4S,5R,6S,8R)-5-[[tert-butyl(dimethyl)silyl]oxy]-4,6-dimethoxy-2,8-dimethyl-9-oxononyl pivalate | C24H48O6Si | 详情 | 详情 | |
| (XXI) | 11520 | (2R,4S,5R,6S,8R)-8-(1,3-dithian-2-yl)-5-hydroxy-4,6-dimethoxy-2-methylnonyl pivalate | C21H40O5S2 | 详情 | 详情 | |
| (XXII) | 11521 | (2R,4S,5R,6S,8R)-5-[[tert-butyl(dimethyl)silyl]oxy]-8-(1,3-dithian-2-yl)-4,6-dimethoxy-2-methylnonyl pivalate | C27H54O5S2Si | 详情 | 详情 | |
| (XXIII) | 11522 | (2R,4S,5R,6S,8R)-5-[[tert-Butyl(dimethyl)silyl]oxy]-8-(1,3-dithian-2-yl)-4,6-dimethoxy-2-methyl-1-nonanol | C22H46O4S2Si | 详情 | 详情 | |
| (XXIV) | 11523 | (3R,5S,6R,7S,9R)-6-[[tert-Butyl(dimethyl)silyl]oxy]-9-(1,3-dithian-2-yl)-5,7-dimethoxy-1,3-dimethyldecyl(diphenyl)phosphine oxide; [(3R,5S,6R,7S,9R)-6-[[tert-Butyl(dimethyl)silyl]oxy]-9-(1,3-dithian-2-yl)-5,7-dimethoxy-1,3-dimethyldecyl](oxo)diphenylphosphorane | C36H59O4PS2Si | 详情 | 详情 |
合成路线8
2) [2S,3S,5S,6R,7S,8E,9(1'R,3'R,4'R)]-2-Allyl-3-(tert-butyldimethylsilylox y)-6,8-dimethyl-7-(triethylsilyloxy)-5-(triisopropylsilyloxy)-9-[3-meth oxy-4-(triisopropylsilyloxy)cyclohexyl]-8-nonenal (LI). Quinic acid (XXV) is converted into the lactone (XXVI) by known methods. Then this lactone is treated with thiocarbonyldiimidazole in refluxing dichloroethane yielding the bis(thiocarbonyl)lactone (XXVII), which by reaction with tributyltin hydride and AIBN in refluxing xylene is converted into the lactone (XXIX), either directly or through the intermediate thiocarbonyl-lactone (XXVIII). The silylation of (XXIX) with TIPS-SO3CF3 as usual affords the protected lactone (XXX). Opening of the lactone ring with methylchloroaluminum N-methoxy-N-methylamide gives the methoxyamide (XXXI), which is methylated with methyl trifluoromethylsulfonate to the methoxy-N-methoxyamide (XXXII). The reduction of (XXXII) with diisobutylaluminum hydride gives the aldehyde (XXXIII), which is condensed with 2-lithio-2-(triethylsilyl)propanal (XXXIV), yielding unsaturated aldehyde (XXXV). The condensation of (XXXV) with the boron enolate of oxazolidone (XXVI) affords the oxazolidone derivative (XXXVII), which is treated with methylchloroaluminum N-methoxy-N-methylamide to give the methoxyamide (XXXVIII). The silylation of (XXXVIII) with TES-SO3CF3 as usual yields the silylated amide (XXXIX), which is reduced with diisobutylaluminum hydride to the aldehyde (XL). The condensation of (XL) with chiral acetate (XLI) by means of lithium diisopropylamide in THF affords the hydroxy ester (XLII). Transesterification of (XLII) with NaOCH3 and methanol gives methyl ester (XLIII).
| 【1】 Jones, T.K.; Askin, D.; Mills, S.G.; Reamer, R.A.; Desmond, R.; Volante, R.P.; Tschaen, D.M.; Shinkai, I. (Merck & Co., Inc.); Process for synthesis of FK-506 and tricarbonyl intermediates. EP 0378318; JP 1990233643 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 63305 | di(1H-imidazol-2-yl)methanethione | C7H6N4S | 详情 | 详情 | ||
| 63306 | C3H9AlClNO | 详情 | 详情 | |||
| (XXV) | 11524 | D-Quinic acid; D-(-)-Chinic acid; D-(-)-Quinic acid; (3R,5R)-1,3,4,5-Tetrahydroxycyclohexanecarboxylic acid | 77-95-2 | C7H12O6 | 详情 | 详情 |
| (XXVI) | 11525 | (1S,3R,4R,5R)-1,3,4-Trihydroxy-6-oxabicyclo[3.2.1]octan-7-one | C7H10O5 | 详情 | 详情 | |
| (XXVII) | 11526 | O-[(1R,2S,6R)-9-oxo-4-thioxo-3,5,10-trioxatricyclo[6.2.1.0(2,6)]undec-8-yl] 1H-imidazole-1-carbothioate | C12H10N2O5S2 | 详情 | 详情 | |
| (XXVIII) | 11527 | (1R,2S,6R,8S)-4-Thioxo-3,5,10-trioxatricyclo[6.2.1.0(2,6)]undecan-9-one | C8H8O4S | 详情 | 详情 | |
| (XXIX) | 11528 | (1R,4R,5R)-4-Hydroxy-6-oxabicyclo[3.2.1]octan-7-one | C7H10O3 | 详情 | 详情 | |
| (XXX) | 11529 | (1R,4R,5R)-4-[(Triisopropylsilyl)oxy]-6-oxabicyclo[3.2.1]octan-7-one | C16H30O3Si | 详情 | 详情 | |
| (XXXI) | 11530 | (1R,3R,4R)-3-Hydroxy-N-methoxy-N-methyl-4-[(triisopropylsilyl)oxy]cyclohexanecarboxamide | C18H37NO4Si | 详情 | 详情 | |
| (XXXII) | 11531 | (1R,3R,4R)-N,3-Dimethoxy-N-methyl-4-[(triisopropylsilyl)oxy]cyclohexanecarboxamide | C19H39NO4Si | 详情 | 详情 | |
| (XXXIII) | 11532 | (1R,3R,4R)-3-Methoxy-4-[(triisopropylsilyl)oxy]cyclohexanecarbaldehyde | C17H34O3Si | 详情 | 详情 | |
| (XXXIV) | 11533 | [1-Methyl-1-[(4-methylphenyl)sulfonyl]-2-oxoethyl]lithium | C10H11LiO3S | 详情 | 详情 | |
| (XXXV) | 11534 | (E)-3-[(1R,3R,4R)-3-Methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-2-methyl-2-propenal | C20H38O3Si | 详情 | 详情 | |
| (XXXVI) | 11535 | (4S)-4-Isopropyl-3-propionyl-1,3-oxazolidin-2-one | 77877-19-1 | C9H15NO3 | 详情 | 详情 |
| (XXXVII) | 11536 | (4S)-3-((2S,3S,4E)-3-Hydroxy-5-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-2,4-dimethyl-4-pentenoyl)-4-isopropyl-1,3-oxazolidin-2-one | C29H53NO6Si | 详情 | 详情 | |
| (XXXVIII) | 11537 | (2S,3S,4E)-3-Hydroxy-N-methoxy-5-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-N,2,4-trimethyl-4-pentenamide | C25H49NO5Si | 详情 | 详情 | |
| (XXXIX) | 11538 | (2S,3S,4E)-N-Methoxy-5-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-N,2,4-trimethyl-3-[(triethylsilyl)oxy]-4-pentenamide | C31H63NO5Si2 | 详情 | 详情 | |
| (XL) | 11539 | (2S,3S,4E)-5-[(1R,3R,4R)-3-Methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-2,4-dimethyl-3-[(triethylsilyl)oxy]-4-pentenal | C29H58O4Si2 | 详情 | 详情 | |
| (XLI) | 11540 | (1S)-2-hydroxy-1,2,2-triphenylethyl acetate; (R)-(+)-1,1,2-Triphenyl-1,2-ethanediol 2-acetate | 95061-47-5 | C22H20O3 | 详情 | 详情 |
| (XLII) | 11541 | (1S)-2-hydroxy-1,2,2-triphenylethyl (3S,4R,5S,6E)-3-hydroxy-7-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-4,6-dimethyl-5-[(triethylsilyl)oxy]-6-heptenoate | C51H78O7Si2 | 详情 | 详情 | |
| (XLIII) | 11542 | methyl (3S,4R,5S,6E)-3-hydroxy-7-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-4,6-dimethyl-5-[(triethylsilyl)oxy]-6-heptenoate | C32H64O6Si2 | 详情 | 详情 |
合成路线9
(XLIII) is silylated with TIPS-SO3CF3 to the protected ester (XLIV). The reduction of (XLIV) with diisobutylaluminum hydride yields the primary alcohol (XLV), which is oxidized with the complex pyridine - SO3 to the aldehyde (XLVI). The condensation of (XLVI) with the boron enolate of the oxazolidone (XLVII) affords the oxazolidone derivative (XLVIII), which is treated with methylchloroaluminum N-methoxy-N-methylamide as before to give the methoxyamide (XLIX). Silylation of (XLIX) with TBS-SO3CF3 as usual yields the protected amide (L), which is finally reduced with diisobutylaluminum hydride to the second building group, the aldehyde (LI).
| 【1】 Jones, T.K.; Askin, D.; Mills, S.G.; Reamer, R.A.; Desmond, R.; Volante, R.P.; Tschaen, D.M.; Shinkai, I. (Merck & Co., Inc.); Process for synthesis of FK-506 and tricarbonyl intermediates. EP 0378318; JP 1990233643 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 63306 | C3H9AlClNO | 详情 | 详情 | |||
| (IL) | 11548 | (2S,3S,5S,6S,7S,8E)-2-Allyl-3-hydroxy-N-methoxy-9-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-N,6,8-trimethyl-7-[(triethylsilyl)oxy]-5-[(triisopropylsilyl)oxy]-8-nonenamide | C47H95NO7Si3 | 详情 | 详情 | |
| (XLIII) | 11542 | methyl (3S,4R,5S,6E)-3-hydroxy-7-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-4,6-dimethyl-5-[(triethylsilyl)oxy]-6-heptenoate | C32H64O6Si2 | 详情 | 详情 | |
| (XLIV) | 11543 | methyl (3S,4S,5S,6E)-7-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-4,6-dimethyl-5-[(triethylsilyl)oxy]-3-[(triisopropylsilyl)oxy]-6-heptenoate | C41H84O6Si3 | 详情 | 详情 | |
| (XLV) | 11544 | (3S,4S,5S,6E)-7-[(1R,3R,4R)-3-Methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-4,6-dimethyl-5-[(triethylsilyl)oxy]-3-[(triisopropylsilyl)oxy]-6-hepten-1-ol | C40H84O5Si3 | 详情 | 详情 | |
| (XLVI) | 11545 | (3S,4S,5S,6E)-7-[(1R,3R,4R)-3-Methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-4,6-dimethyl-5-[(triethylsilyl)oxy]-3-[(triisopropylsilyl)oxy]-6-heptenal | C40H82O5Si3 | 详情 | 详情 | |
| (XLVII) | 11546 | (4S)-4-Isopropyl-3-(4-pentenoyl)-1,3-oxazolidin-2-one | C11H17NO3 | 详情 | 详情 | |
| (XLVIII) | 11547 | (4S)-3-[(2S,3S,5S,6S,7S,8E)-2-Allyl-3-hydroxy-9-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-6,8-dimethyl-7-[(triethylsilyl)oxy]-5-[(triisopropylsilyl)oxy]-8-nonenoyl]-4-isopropyl-1,3-oxazolidin-2-one | C51H99NO8Si3 | 详情 | 详情 | |
| (L) | 11549 | (2S,3S,5S,6S,7S,8E)-2-Allyl-3-[[tert-butyl(dimethyl)silyl]oxy]-N-methoxy-9-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-N,6,8-trimethyl-7-[(triethylsilyl)oxy]-5-[(triisopropylsilyl)oxy]-8-nonenamide | C53H109NO7Si4 | 详情 | 详情 | |
| (LI) | 11550 | (2S,3S,5S,6S,7S,8E)-2-Allyl-3-[[tert-butyl(dimethyl)silyl]oxy]-9-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-6,8-dimethyl-7-[(triethylsilyl)oxy]-5-[(triisopropylsilyl)oxy]-8-nonenal | C51H104O6Si4 | 详情 | 详情 |
合成路线10
3) Coupling and cyclization process.- The condensation of the diphenylphosphine derivative (XXIV) with aldehyde (LI) by means of butyllithium in THF gives the hydroxy phosphine derivative (LII), which is treated with potassium hexamethyldisylazane (KHMDS) to afford dithiane (LIII). Partial desilylation of (LIII) with THF - water - trifluoroacetic acid gives alcohol (LIV), which is condensed with N-tert-butoxycarbonylpiperidine-2(S)-carboxylic acid (LV) by means of dicyclohexylcarbodiimide (DCC) and 4-(dimethylamino)pyridine in dichloromethane to yield the ester (LVI). Elimination of the dithiane ring of (LVI) with N-chlorosuccinimide and silver nitrate in anhydrous methanol affords the dimethyl acetal (LVII), which is hydrolyzed to the corresponding aldehyde (LVIII) with acetic acid. The condensation of (LVIII) with 4(S)-benzyl-3-[2-(4-methoxybenzyloxy)acetyl]oxazolidin-2-one (LIX) by means of dibutylboron trifluoromethylsulfonate in toluene gives the oxazolidone derivative (LX).
| 【1】 Jones, T.K.; Askin, D.; Mills, S.G.; Reamer, R.A.; Desmond, R.; Volante, R.P.; Tschaen, D.M.; Shinkai, I. (Merck & Co., Inc.); Process for synthesis of FK-506 and tricarbonyl intermediates. EP 0378318; JP 1990233643 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXIV) | 11523 | (3R,5S,6R,7S,9R)-6-[[tert-Butyl(dimethyl)silyl]oxy]-9-(1,3-dithian-2-yl)-5,7-dimethoxy-1,3-dimethyldecyl(diphenyl)phosphine oxide; [(3R,5S,6R,7S,9R)-6-[[tert-Butyl(dimethyl)silyl]oxy]-9-(1,3-dithian-2-yl)-5,7-dimethoxy-1,3-dimethyldecyl](oxo)diphenylphosphorane | C36H59O4PS2Si | 详情 | 详情 | |
| (LI) | 11550 | (2S,3S,5S,6S,7S,8E)-2-Allyl-3-[[tert-butyl(dimethyl)silyl]oxy]-9-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-6,8-dimethyl-7-[(triethylsilyl)oxy]-5-[(triisopropylsilyl)oxy]-8-nonenal | C51H104O6Si4 | 详情 | 详情 | |
| (LII) | 11553 | (1E,3S,4S,5S,7S,8R,9E,12S,14S,15R,16S,18R)-8-Allyl-7,15-bis[[tert-butyl(dimethyl)silyl]oxy]-18-(1,3-dithian-2-yl)-14,16-dimethoxy-1-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-2,4,10,12-tetramethyl-5-[(triisopropylsilyl)oxy]-1,9-nonadecadien-3-ol | C69H138O8S2Si4 | 详情 | 详情 | |
| (LIII) | 11552 | (5R,6S,8S,10E,12R,13S,15S,16S,17S)-12-Allyl-13-[[tert-butyl(dimethyl)silyl]oxy]-5-[(1S,3R)-3-(1,3-dithian-2-yl)-1-methoxybutyl]-19,19-diethyl-6-methoxy-17-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methylethenyl)-2,2,3,3,8,10,16-heptamethyl-15-[(triisopropylsilyl)oxy]-4,18-dioxa-3,19-disila-10-henicosene; (1S,3S,4R,5E,8S,10S,11R,12S,14R)-4-Allyl-3,11-bis[[tert-butyl(dimethyl)silyl]oxy]-14-(1,3-dithian-2-yl)-10,12-dimethoxy-1-[(1S,2S,3E)-4-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1,3-dimethyl-2-[(triethylsilyl)oxy]-3-butenyl]-6,8-dimethyl-5-pentadecenyl triisopropylsilyl ether | C75H152O8S2Si5 | 详情 | 详情 | |
| (LIV) | 11551 | (5R,6S,8R,12R,13S,15S,16S,17S)-12-allyl-13-[[tert-butyl(dimethyl)silyl]oxy]-9-(diphenylphosphoryl)-5-[(1S,3R)-3-(1,3-dithian-2-yl)-1-methoxybutyl]-19,19-diethyl-6-methoxy-17-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methyl | C87H163O10PS2Si5 | 详情 | 详情 | |
| (LV) | 11487 | (2S)-1-(tert-Butoxycarbonyl)hexahydro-2-pyridinecarboxylic acid | C11H19NO4 | 详情 | 详情 | |
| (LVI) | 11555 | 2-[(1S,2S,3S,5S,6R,7E,10S,12S,13R,14S,16R)-6-allyl-5,13-bis[[tert-butyl(dimethyl)silyl]oxy]-16-(1,3-dithian-2-yl)-12,14-dimethoxy-1-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methylethenyl)-2,8,10-trimethyl-3-[(triisopropylsilyl)oxy]-7-heptadecenyl] 1-(tert-butyl) (2S)-1,2-piperidinedicarboxylate | C80H155NO11S2Si4 | 详情 | 详情 | |
| (LVII) | 11556 | 2-[(1S,2S,3S,5S,6R,7E,10S,12S,13R,14S,16R)-6-allyl-5,13-bis[[tert-butyl(dimethyl)silyl]oxy]-12,14,17,17-tetramethoxy-1-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methylethenyl)-2,8,10,16-tetramethyl-3-[(triisopropylsilyl)oxy]-7-heptadecenyl] 1-(tert-butyl) (2S)-1,2-piperidinedicarboxylate | C79H155NO13Si4 | 详情 | 详情 | |
| (LVIII) | 11557 | 2-[(1S,2S,3S,5S,6R,7E,10S,12S,13R,14S,16R)-6-allyl-5,13-bis[[tert-butyl(dimethyl)silyl]oxy]-12,14-dimethoxy-1-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methylethenyl)-2,8,10,16-tetramethyl-17-oxo-3-[(triisopropylsilyl)oxy]-7-heptadecenyl] 1-(tert-butyl) (2S)-1,2-piperidinedicarboxylate | C77H149NO12Si4 | 详情 | 详情 | |
| (LIX) | 11558 | (4S)-4-Benzyl-3-[3-(4-methoxyphenyl)propanoyl]-1,3-oxazolidin-2-one | C20H21NO4 | 详情 | 详情 | |
| (LX) | 11559 | 2-[(1S,2S,3S,5S,6R,7E,10S,12S,13R,14S,16R,17R)-6-allyl-19-[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-5,13-bis[[tert-butyl(dimethyl)silyl]oxy]-17-hydroxy-12,14-dimethoxy-18-[(4-methoxybenzyl)oxy]-1-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methylethenyl)-2,8,10,16-tetramethyl-19-oxo-3-[(triisopropylsilyl)oxy]-7-nonadecenyl] 1-(tert-butyl) (2S)-1,2-piperidinedicarboxylate | C97H170N2O17Si4 | 详情 | 详情 |
合成路线11
(LX) is treated successively with H2O2 and LiOH, with triethylsilyl trifluoromethylsulfonate and with water to afford acid (LXI). Cyclization of (LXI) with 2-chloro-N-methylpyridinium iodide and triethylamine in dichloromethane yields the cyclic derivative (LXII), which is treated with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) to eliminate the 4-methoxybenzyl protecting group, so yielding alcohol (LXIII). A new partial deprotection of (LXIII) with trifluoroacetic acid affords the glycol (LXIV), which is oxidized with oxalyl chloride in DMSO to the vicinal triketone (LXV). Treatment of (LXV) with HF in acetonitrile gives the epoxy derivative (LXVI) with some free hydroxyl groups which are protected with triethylsilyl chloride, affording the compound (LXVII) with only one free hydroxy group. Oxidation of (LXVII) with Dess-Martin periodinane (DMP) in dichloromethane yields protected FK-506 (LXVIII), which is finally deprotected with HF in acetonitrile.
| 【1】 Jones, T.K.; Askin, D.; Mills, S.G.; Reamer, R.A.; Desmond, R.; Volante, R.P.; Tschaen, D.M.; Shinkai, I. (Merck & Co., Inc.); Process for synthesis of FK-506 and tricarbonyl intermediates. EP 0378318; JP 1990233643 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 34696 | 2-chloro-1-methylpyridinium iodide | 14338-32-0 | C6H7ClIN | 详情 | 详情 | |
| (LX) | 11559 | 2-[(1S,2S,3S,5S,6R,7E,10S,12S,13R,14S,16R,17R)-6-allyl-19-[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-5,13-bis[[tert-butyl(dimethyl)silyl]oxy]-17-hydroxy-12,14-dimethoxy-18-[(4-methoxybenzyl)oxy]-1-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methylethenyl)-2,8,10,16-tetramethyl-19-oxo-3-[(triisopropylsilyl)oxy]-7-nonadecenyl] 1-(tert-butyl) (2S)-1,2-piperidinedicarboxylate | C97H170N2O17Si4 | 详情 | 详情 | |
| (LXI) | 11560 | (2S,3R,4R,6S,7R,8S,10S,12E,14R,15S,17S,18S,19S,20E)-14-Allyl-7,15-bis[[tert-butyl(dimethyl)silyl]oxy]-6,8-dimethoxy-2-[(4-methoxybenzyl)oxy]-21-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-4,10,12,18,20-pentamethyl-19-[[(2S)piperidinylcarbonyl]oxy]-3-[(triethylsilyl)oxy]-17-[(triisopropylsilyl)oxy]-12,20-henicosadienoic acid | C88H167NO14Si5 | 详情 | 详情 | |
| (LXII) | 11561 | (3S,4S,5S,7S,8R,12S,14S,15R,16S,18R,19R,20S,26aS)-8-Allyl-7,15-bis[[tert-butyl(dimethyl)silyl]oxy]-14,16-dimethoxy-20-[(4-methoxybenzyl)oxy]-3-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methylethenyl)-4,10,12,18-tetramethyl-19-[(triethylsilyl)oxy]-5-[(triisopropylsilyl)oxy]-5,6,7,8,11,12,13,14,15,16,17,18,19,20,24,25,26,26a-octadecahydro-3H-pyrido[2,1-c][1,4]oxazacyclotricosine-1,21(4H,23H)-dione | C88H165NO13Si5 | 详情 | 详情 | |
| (LXIII) | 11562 | (3S,4S,5S,7R,8R,12S,14S,15R,16S,18R,19R,20S,26aS)-8-Allyl-7,15-bis[[tert-butyl(dimethyl)silyl]oxy]-20-hydroxy-14,16-dimethoxy-3-((E)-2-[(1R,3R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methylethenyl)-4,10,12,18-tetramethyl-19-[(triethylsilyl)oxy]-5-[(triisopropylsilyl)oxy]-5,6,7,8,11,12,13,14,15,16,17,18,19,20,24,25,26,26a-octadecahydro-3H-pyrido[2,1-c][1,4]oxazacyclotricosine-1,21(4H,23H)-dione | C80H157NO12Si5 | 详情 | 详情 | |
| (LXIV) | 11563 | (3S,4S,5S,7R,8R,12S,14S,15R,16S,18R,19R,20S,26aS)-8-Allyl-7,15-bis[[tert-butyl(dimethyl)silyl]oxy]-19,20-dihydroxy-14,16-dimethoxy-3-((E)-2-[(1R,3R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methylethenyl)-4,10,12,18-tetramethyl-5-[(triisopropylsilyl)oxy]-5,6,7,8,11,12,13,14,15,16,17,18,19,20,24,25,26,26a-octadecahydro-3H-pyrido[2,1-c][1,4]oxazacyclotricosine-1,21(4H,23H)-dione | C74H143NO12Si4 | 详情 | 详情 | |
| (LXV) | 11564 | (3S,4S,5S,7R,8R,12S,14S,15R,16S,18R,26aS)-8-Allyl-7,15-bis[[tert-butyl(dimethyl)silyl]oxy]-14,16-dimethoxy-3-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methylethenyl)-4,10,12,18-tetramethyl-5-[(triisopropylsilyl)oxy]-5,6,7,8,11,12,13,14,15,16,17,18,24,25,26,26a-hexadecahydro-3H-pyrido[2,1-c][1,4]oxazacyclotricosine-1,19,20,21(4H,23H)-tetrone | C74H139NO12Si4 | 详情 | 详情 | |
| (LXVI) | 11565 | (1R,9S,12S,13S,14S,16R,17R,21S,23S,24R,25S,27R)-17-Allyl-1,16-dihydroxy-23,25-dimethoxy-12-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triethylsilyl)oxy]cyclohexyl]-1-methylethenyl)-13,19,21,27-tetramethyl-14-[(triethylsilyl)oxy]-11,28-dioxa-4-azatricyclo[22.3.1.0(4,9)]octacos-18-ene-2,3,10-trione | C44H71NO12 | 详情 | 详情 | |
| (LXVII) | 11566 | (1R,9S,12S,13S,14S,16R,17R,21S,23S,24R,25S,27R)-17-Allyl-1,16-dihydroxy-23,25-dimethoxy-12-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triethylsilyl)oxy]cyclohexyl]-1-methylethenyl)-13,19,21,27-tetramethyl-14-[(triethylsilyl)oxy]-11,28-dioxa-4-azatricyclo[22.3.1.0(4,9)]octacos-18-ene-2,3,10-trione | C56H99NO12Si2 | 详情 | 详情 | |
| (LXVIII) | 11567 | (1R,9S,12S,13S,14S,17R,21S,23S,24R,25S,27R)-17-Allyl-1-hydroxy-23,25-dimethoxy-12-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triethylsilyl)oxy]cyclohexyl]-1-methylethenyl)-13,19,21,27-tetramethyl-14-[(triethylsilyl)oxy]-11,28-dioxa-4-azatricyclo[22.3.1.0(4,9)]octacos-18-ene-2,3,10,16-tetrone | C56H97NO12Si2 | 详情 | 详情 |
合成路线12
The synthesis of the C22-C34 subunit (C12-C16 of the chemical name) of FK-506 has been reported: The condensation of the chiral aldehyde (I) with the (S)-allenyl stannane (II) by means of boron trifluoride ethearate in dichloromethane yields an epimeric mixture of the acetylenic alcohol (III), which by protection with p-methoxybenzyl (PMB) trichloroacetimidate, followed by chromatographic separation, gives the enantiomerically pure protected acetylenic diol (IV). The reduction of (IV) with bis(2-methoxyethoxy)aluminum hydride in THF affords the (E,E)-dienic alcohol (V), which is submitted to a Sharpless asymmetric epoxidation with (-)-diethyl tartrate [(-)-DETR], titanium tetraisopropoxide and tert-butyl hydroperoxide (TBHP) in dichloromethane, yielding the chiral epoxy alcohol (VI). The reduction of (VI) with bis(2-methoxyethoxy)aluminum hydride in THF affords the partially protected triol (VII), which is finally dehydrogenated with dichlorodicyanobenzoquinone (DDQ) in dichloromethane to give the chiral 1,3-dioxane (VIII), which is the desired intermediate.
| 【1】 Marshall, J.A.; Xie, S.P.; Synthesis of a C22-34 subunit of the immunosuppressant FK-506. J Org Chem 1995, 60, 22, 7230. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 63307 | 1,1,1-trichloro-3-(4-methoxyphenyl)-2-propanimine | C10H10Cl3NO | 详情 | 详情 | ||
| (I) | 11534 | (E)-3-[(1R,3R,4R)-3-Methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-2-methyl-2-propenal | C20H38O3Si | 详情 | 详情 | |
| (II) | 11569 | 2-(tributylstannyl)-2,3-pentadienyl pivalate | C22H42O2Sn | 详情 | 详情 | |
| (III) | 11570 | (4R,6E)-5-hydroxy-7-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-4,6-dimethyl-6-hepten-2-ynyl pivalate | C30H54O5Si | 详情 | 详情 | |
| (IV) | 11571 | (4R,5S,6E)-5-[(4-methoxybenzyl)oxy]-7-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-4,6-dimethyl-6-hepten-2-ynyl pivalate | C38H62O6Si | 详情 | 详情 | |
| (V) | 11572 | (2E,4R,5S,6E)-5-[(4-Methoxybenzyl)oxy]-7-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-4,6-dimethyl-2,6-heptadien-1-ol | C33H56O5Si | 详情 | 详情 | |
| (VI) | 11573 | [(2R,3R)-3-((1S,2S,3E)-2-[(4-Methoxybenzyl)oxy]-4-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1,3-dimethyl-3-butenyl)oxiranyl]methanol | C33H56O6Si | 详情 | 详情 | |
| (VII) | 11574 | (3S,4R,5S,6E)-5-[(4-Methoxybenzyl)oxy]-7-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-4,6-dimethyl-6-heptene-1,3-diol | C33H58O6Si | 详情 | 详情 | |
| (VIII) | 11575 | 2-[(4S,5S,6S)-2-(4-Methoxyphenyl)-6-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methylethenyl)-5-methyl-1,3-dioxan-4-yl]-1-ethanol | C33H56O6Si | 详情 | 详情 |
合成路线13
The starting compounds (I) and (II) are obtained as follows: Aldehyde (I): The esterification of (R,R)-dihydrobenzoin (IX) with acryloyl chloride (X) by means of triethylamine in dichloromethane gives the corresponding diester (XI), which by bis-cyclization with butadiene (XII) by means of TiCl4 in dichloromethane yields the bis(3-cyclohexenecarboxylic acid) ester (XIII). The hydrolysis of (XIII) with LiOH in methanol affords (R)-3-cyclohexenecarboxylic acid (XIV), which by reaction with I2, KI and NaHCO3 is converted to the iodolactone (XV). The reaction of (XV) with 1,5-diazabicyclo[5.4.0]-5-undecene (DBU) in refluxing THF affords the unsaturated lactone (XVI), which by treatment with NaHCO3 in anhydrous methanol yields (1R,3R)-3-hydroxy-4-cyclohexenecarboxylic acid methyl ester (XVII). The methylation of (XVII) with methyl trifluoromethanesulfonate and 2,6-di-tert-butyl-4-methylpyridine (DBMP) in dichloromethane gives the 3-methoxy ester (XVIII), which is selectively hydroxylated with BH3, H2O2 and NaOH to (1R,3R,4R)-4-hydroxy-3-methoxycyclohexanecarboxylic acid methyl ester (XIX). The protection of (XIX) with triisopropylsilyl (TIPS) trifluoromethanesulfonate (XX) and triethylamine in dichloromethane affords the protected ester (XXI), which is reduced with dibutylaluminum hydride (DIBAL) in hexane to the corresponding aldehyde (XXII). Finally, this compound is condensed with the N-tert-butylimine of 2-(triethylsilyl)propanol (XXIII) by means of butyllithium in THF to afford the desired aldehyde (I).
| 【1】 Marshall, J.A.; Xie, S.P.; Synthesis of a C22-34 subunit of the immunosuppressant FK-506. J Org Chem 1995, 60, 22, 7230. |
| 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) | 11534 | (E)-3-[(1R,3R,4R)-3-Methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-2-methyl-2-propenal | C20H38O3Si | 详情 | 详情 | |
| (IX) | 11576 | (1S,2S)-1,2-Diphenyl-1,2-ethanediol; (S,S)-(-)-1,2-Diphenyl-1,2-ethanediol | 2325-10-2 | C14H14O2 | 详情 | 详情 |
| (X) | 11577 | Acryloyl chloride; Acrylyl chloride;2-Propenoyl chloride | 814-68-6 | C3H3ClO | 详情 | 详情 |
| (XI) | 11578 | (1R,2R)-2-(Acryloyloxy)-1,2-diphenylethyl acrylate | C20H18O4 | 详情 | 详情 | |
| (XII) | 11579 | 1,3-Butadiene; Butadiene | 106-99-0 | C4H6 | 详情 | 详情 |
| (XIII) | 11580 | (1R,2R)-2-[[(1R)-3-cyclohexen-1-ylcarbonyl]oxy]-1,2-diphenylethyl (1R)-3-cyclohexene-1-carboxylate | C28H30O4 | 详情 | 详情 | |
| (XIV) | 11581 | (1R)-3-Cyclohexene-1-carboxylic acid | C7H10O2 | 详情 | 详情 | |
| (XV) | 11582 | (1R,4R,5R)-4-Iodo-6-oxabicyclo[3.2.1]octan-7-one | C7H9IO2 | 详情 | 详情 | |
| (XVI) | 11583 | (1R,5R)-6-Oxabicyclo[3.2.1]oct-3-en-7-one | C7H8O2 | 详情 | 详情 | |
| (XVII) | 11584 | methyl (1R,5R)-5-hydroxy-3-cyclohexene-1-carboxylate | C8H12O3 | 详情 | 详情 | |
| (XVIII) | 11585 | methyl (1R,5R)-5-methoxy-3-cyclohexene-1-carboxylate | C9H14O3 | 详情 | 详情 | |
| (XIX) | 11586 | methyl (1R,3R,4R)-4-hydroxy-3-methoxycyclohexanecarboxylate | C9H16O4 | 详情 | 详情 | |
| (XX) | 11587 | triisopropylsilyl trifluoromethanesulfonate | 80522-42-5 | C10H21F3O3SSi | 详情 | 详情 |
| (XXI) | 11588 | methyl (1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexanecarboxylate | C18H36O4Si | 详情 | 详情 | |
| (XXII) | 11532 | (1R,3R,4R)-3-Methoxy-4-[(triisopropylsilyl)oxy]cyclohexanecarbaldehyde | C17H34O3Si | 详情 | 详情 | |
| (XXIII) | 11590 | N-(tert-Butyl)-N-[(E)-2-(triethylsilyl)propylidene]amine; 2-Methyl-N-[(E)-2-(triethylsilyl)propylidene]-2-propanamine | C13H29NSi | 详情 | 详情 |
合成路线14
The starting compounds (I) and (II) are obtained as follows: Aldehyde (I): The esterification of (R,R)-dihydrobenzoin (IX) with acryloyl chloride (X) by means of triethylamine in dichloromethane gives the corresponding diester (XI), which by bis-cyclization with butadiene (XII) by means of TiCl4 in dichloromethane yields the bis(3-cyclohexenecarboxylic acid) ester (XIII). The hydrolysis of (XIII) with LiOH in methanol affords (R)-3-cyclohexenecarboxylic acid (XIV), which by reaction with I2, KI and NaHCO3 is converted to the iodolactone (XV). The reaction of (XV) with 1,5-diazabicyclo[5.4.0]-5-undecene (DBU) in refluxing THF affords the unsaturated lactone (XVI), which by treatment with NaHCO3 in anhydrous methanol yields (1R,3R)-3-hydroxy-4-cyclohexenecarboxylic acid methyl ester (XVII). The methylation of (XVII) with methyl trifluoromethanesulfonate and 2,6-di-tert-butyl-4-methylpyridine (DBMP) in dichloromethane gives the 3-methoxy ester (XVIII), which is selectively hydroxylated with BH3, H2O2 and NaOH to (1R,3R,4R)-4-hydroxy-3-methoxycyclohexanecarboxylic acid methyl ester (XIX). The protection of (XIX) with triisopropylsilyl (TIPS) trifluoromethanesulfonate (XX) and triethylamine in dichloromethane affords the protected ester (XXI), which is reduced with dibutylaluminum hydride (DIBAL) in hexane to the corresponding aldehyde (XXII). Finally, this compound is condensed with the N-tert-butylimine of 2-(triethylsilyl)propanol (XXIII) by means of butyllithium in THF to afford the desired aldehyde (I) (Scheme 2). Allenyl stannane (II): The silylation of (R)-methyl lactate (XXIV) with tert-butyldimethylsilyl chloride (TBS-Cl) and imidazole in DMF gives the silyl ether (XXV), which is reduced with DIBAL to the corresponding aldehyde (XXVI). The reaction of (XXVI) with tetrabromomethane and triphenylphosphine in dichloromethane affords 3(R)-(tert-butyldimethysilyloxy)-1,1-dibromo-1-butene (XXVII), which by reaction with butyllithium and formaldehyde is converted to the corresponding 2-pentyn-1-ol (XXVIII). The esterification of (XXVIII) with pivaloyl (PIV) chloride and NaHCO3 in dichloromethane yields the pivaloyl ester (XXIX), which is desilylated with tetrabutylammonium fluoride (TBAF) in THF, giving the hydroxy ester (XXX). The mesylation of (XXX) with methanesulfonyl chloride and triethylamine in dichloromethane affords the sulfonate (XXXI), which is finally treated with the lithium derivative of tributylstannyl hydride, CuBr and dimethylsulfide in THF to afford the desired allenyl stannane (II).
| 【1】 Marshall, J.A.; Xie, S.P.; Synthesis of a C22-34 subunit of the immunosuppressant FK-506. J Org Chem 1995, 60, 22, 7230. |
| 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) | 11569 | 2-(tributylstannyl)-2,3-pentadienyl pivalate | C22H42O2Sn | 详情 | 详情 | |
| (XXIV) | 11591 | methyl (2R)-2-hydroxypropanoate | 17392-83-5 | C4H8O3 | 详情 | 详情 |
| (XXV) | 11592 | methyl (2R)-2-[[tert-butyl(dimethyl)silyl]oxy]propanoate | C10H22O3Si | 详情 | 详情 | |
| (XXVI) | 11593 | (2R)-2-[[tert-Butyl(dimethyl)silyl]oxy]propanal | C9H20O2Si | 详情 | 详情 | |
| (XXVII) | 11594 | tert-Butyl(dimethyl)silyl (1R)-3,3-dibromo-1-methyl-2-propenyl ether; tert-Butyl[[(1R)-3,3-dibromo-1-methyl-2-propenyl]oxy]dimethylsilane | C10H20Br2OSi | 详情 | 详情 | |
| (XXVIII) | 11595 | (4R)-4-[[tert-Butyl(dimethyl)silyl]oxy]-2-pentyn-1-ol | C11H22O2Si | 详情 | 详情 | |
| (XXIX) | 11596 | (4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-pentynyl pivalate | C16H30O3Si | 详情 | 详情 | |
| (XXX) | 11597 | (4R)-4-hydroxy-2-pentynyl pivalate | C10H16O3 | 详情 | 详情 | |
| (XXXI) | 11598 | (4R)-4-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-2-pentynyl pivalate | C13H22O3S | 详情 | 详情 |
合成路线15
The synthesis of the C16-C34 fragment of tacrolimus (FK-506), the key intermediate on the total synthesis of tacrolimus has been described: 1) The reaction of (Z)-2-butene (I) with ()-beta-methoxydiisopinocamphenylborane (IPCB-OCH3; II) by means of potassium tert-butoxide and butyllithium in THF gives the butenyl borane (III), which is condensed with 2-benzyl-acetaldehyde (IV) by means of BF3 ethearate in ether to yield the monobenzylated diol (V). The silylation of (V) with tert-butyldimethylsilyl chloride (TBDMS-Cl) and imidazole affords the fully protected olefine (VI), which is oxidized with OsO4 and N-methylmorpholine N-oxide (NMO) in acetone/water/benzene to give a diastereomeric mixture of the diols (VII) and (VIII) separated by column chromatography. The epoxidation of (VII) with NaH and tosyl imidazole in THF afforded epoxide (IX), which was condensed with the protected furfuryl alcohol (X) by means of butyllithium and BF3 ethearate in THF giving the diol (XI). The oxidation of (XI) with m-chloroperbenzoic acid (MCPBA) with simultaneous trapping of the intermediate with 2-methoxypropene (XII) afforded the spiroenone (XIII), which was condensed with alkyne (XIV) by means of trimethylaluminum and a zircornium complex yielding the expected spiroketone (XV). 2) The alkyne intermediate (XIV) has been obtained by condensation of the chiral tosylate (XXVII) with lithium acetylide giving the chiral pentynol ether (XVIII). (XVIII) then was deprotected with p-toluenesulfonic acid and silylated with TBDMS-Cl. 3) The undesired diol (VIII) can also be converted into the epoxide (IX) by reaction with benzoyl chloride and dimethylaminopyridine (DMAP) to give the expected benzoate, which was subsequently treated with methanesulfonyl chloride and DMAP, and finally epoxidized with sodium methoxide in methanol. 4) The diol (VII) can be selectively obtained by reaction of methyl 5-O-benzyl-beta-D-ribofuranoside (XXIV) with methylmagnesium chloride and copper bromide giving methyl 5-O-benzyl-3-deoxy-3-C-methyl-beta-D-xylofuranoside (XXV). (XXV) was treated with ethanethiol and TBDMS-Cl in the presence of imidazole and a catalytic amount of DMAP affording the dithioacetal (XXVI). Finally, this compound is treated with HgCl2 and CaCO3, and reduced with NaBH4 in THF/methanol to afford the desired diol (VII). 5) The intermediate vinyl bromide (XXIII) has been obtained according to a previously reported method (Ragan, J.A. et al. J Org Chem 1989, 54(18): 4267) .
| 【1】 Liu, L.B.; Roper, T.D.; Ireland, R.E.; Total synthesis of FK-506. 1. Construction of the C16-C34 fragment. Tetrahedron 1997, 53, 39, 13221. |
| 【2】 Liu, L.B.; Roper, T.D.; Gleason, J.L.; Ireland, R.E.; Total synthesis of FK-506. 2. Completion of the synthesis. Tetrahedron 1997, 53, 39, 13257. |
| 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) | 17343 | 2-Butene-cis; (Z)-2-butene | 590-18-1 | C4H8 | 详情 | 详情 |
| (II) | 63308 | methyl 2,7,7-trimethylbicyclo[4.1.0]hept-3-yl(5,7,7-trimethylbicyclo[4.1.0]hept-3-yl)borinate | C21H37BO | 详情 | 详情 | |
| (III) | 17345 | 2-butenyl(2,7,7-trimethylbicyclo[4.1.0]hept-3-yl)(5,7,7-trimethylbicyclo[4.1.0]hept-3-yl)borane | C24H41B | 详情 | 详情 | |
| (IV) | 17346 | Benzyloxyacetaldehyde; 2-(Benzyloxy)acetaldehyde | 60656-87-3 | C9H10O2 | 详情 | 详情 |
| (V) | 17347 | (2S,3R)-1-(benzyloxy)-3-methyl-4-penten-2-ol | C13H18O2 | 详情 | 详情 | |
| (VI) | 17348 | benzyl (2S,3R)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-pentenyl ether; ([(1S,2R)-1-[(benzyloxy)methyl]-2-methyl-3-butenyl]oxy)(tert-butyl)dimethylsilane | C19H32O2Si | 详情 | 详情 | |
| (VII) | 17349 | (2S,3R,4S)-5-(benzyloxy)-4-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-1,2-pentanediol | C19H34O4Si | 详情 | 详情 | |
| (VIII) | 17350 | (2R,3R,4S)-5-(benzyloxy)-4-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-1,2-pentanediol | C19H34O4Si | 详情 | 详情 | |
| (IX) | 17351 | benzyl (2S,3R)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-[(2R)oxiranyl]butyl ether; ([(1S,2R)-1-[(benzyloxy)methyl]-2-[(2R)oxiranyl]propyl]oxy)(tert-butyl)dimethylsilane | C19H32O3Si | 详情 | 详情 | |
| (X) | 17352 | 2-[(1-methoxy-1-methylethoxy)methyl]furan; 1-(2-furylmethoxy)-1-methylethyl methyl ether | C9H14O3 | 详情 | 详情 | |
| (XI) | 17353 | (2S,3R,4S)-5-(benzyloxy)-4-[[tert-butyl(dimethyl)silyl]oxy]-1-[5-(hydroxymethyl)-2-furyl]-3-methyl-2-pentanol | C24H38O5Si | 详情 | 详情 | |
| (XII) | 17354 | isopropenyl methyl ether; 2-methoxy-1-propene | 116-11-0 | C4H8O | 详情 | 详情 |
| (XIII) | 17355 | 4-((1R,2S)-3-(benzyloxy)-2-[[tert-butyl(dimethyl)silyl]oxy]-1-methylpropyl)-2,2-dimethyl-1,3,7-trioxaspiro[5.5]undec-10-en-9-one | C27H42O6Si | 详情 | 详情 | |
| (XIV) | 17356 | tert-butyl(dimethyl)[[(2S)-2-methyl-4-pentynyl]oxy]silane; tert-butyl(dimethyl)silyl (2S)-2-methyl-4-pentynyl ether | C12H24OSi | 详情 | 详情 | |
| (XV) | 17357 | 4-((1R,2S)-3-(benzyloxy)-2-[[tert-butyl(dimethyl)silyl]oxy]-1-methylpropyl)-11-((E,4S)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethyl-1-pentenyl)-2,2-dimethyl-1,3,7-trioxaspiro[5.5]undecan-9-one | C40H70O7Si2 | 详情 | 详情 | |
| (XVII) | 17358 | (2R)-3-methoxy-2-methylpropyl 4-methylbenzenesulfonate | C12H18O4S | 详情 | 详情 | |
| (XVIII) | 17359 | (4S)-5-methoxy-4-methyl-1-pentyne; methyl (2S)-2-methyl-4-pentynyl ether | C7H12O | 详情 | 详情 | |
| (XXIV) | 17360 | (1S,2R,4R,5R)-2-[(benzyloxy)methyl]-4-methoxy-3,6-dioxabicyclo[3.1.0]hexane; benzyl [(1S,2R,4R,5R)-4-methoxy-3,6-dioxabicyclo[3.1.0]hex-2-yl]methyl ether | C13H16O4 | 详情 | 详情 | |
| (XXV) | 17361 | (2R,3R,4R,5S)-5-[(benzyloxy)methyl]-2-methoxy-4-methyltetrahydro-3-furanol | C14H20O4 | 详情 | 详情 | |
| (XXVI) | 17362 | (2R,3R,4S)-5-(benzyloxy)-4-[[tert-butyl(dimethyl)silyl]oxy]-1,1-bis(ethylsulfanyl)-3-methyl-2-pentanol | C23H42O3S2Si | 详情 | 详情 |
合成路线16
Subsequent reduction of the ketonic group of (XV) with L-selectride in THF afforded the enantiomerically pure alcohol (XVI), which was treated with p-methoxybenzyl trichloroacetimide (XVII) and a catalytic amount of triphenylmethyl tetrafluoroborate to give the expected p-methoxybenzyl ether (XVIII). The desilylation of (XVIII) with tetrabutylammonium fluoride (TBAF) in THF gives the diol (XIX), which was selectively resilylated at the primary OH group yielding the se-condary alcohol (XX). The selective debenzylation of (XX) with H2 over W-2 RaNi in ethanol afforded the vicinal diol (XXI), which was submitted to cleavage with sodium per-iodate in THF to obtain the aldehyde (XXII). Finally, this compound is condensed with the vinyl bromide (XXIII) by means of butyllithium and magnesium bromide in THF to afford the desired C16-C34 fragment of FK-506, the key intermediate in the total synthesis described in Tetrahedron 1997, 53(39): 13257.
| 【1】 Liu, L.B.; Roper, T.D.; Ireland, R.E.; Total synthesis of FK-506. 1. Construction of the C16-C34 fragment. Tetrahedron 1997, 53, 39, 13221. |
| 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) | 17369 | (E,3S,4S)-4-[11-((E,4S)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethyl-1-pentenyl)-9-[(4-methoxybenzyl)oxy]-2,2-dimethyl-1,3,7-trioxaspiro[5.5]undec-4-yl]-1-((1R,3R,4R)-4-[[tert-butyl(diphenyl)silyl]oxy]-3-methoxycyclohexyl)-2-methyl-1-penten-3-ol | C60H92O9Si2 | 详情 | 详情 | |
| (XV) | 17357 | 4-((1R,2S)-3-(benzyloxy)-2-[[tert-butyl(dimethyl)silyl]oxy]-1-methylpropyl)-11-((E,4S)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethyl-1-pentenyl)-2,2-dimethyl-1,3,7-trioxaspiro[5.5]undecan-9-one | C40H70O7Si2 | 详情 | 详情 | |
| (XVI) | 17363 | 4-((1R,2S)-3-(benzyloxy)-2-[[tert-butyl(dimethyl)silyl]oxy]-1-methylpropyl)-11-((E,4S)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethyl-1-pentenyl)-2,2-dimethyl-1,3,7-trioxaspiro[5.5]undecan-9-ol | C40H72O7Si2 | 详情 | 详情 | |
| (XVII) | 17358 | (2R)-3-methoxy-2-methylpropyl 4-methylbenzenesulfonate | C12H18O4S | 详情 | 详情 | |
| (XVIII) | 17359 | (4S)-5-methoxy-4-methyl-1-pentyne; methyl (2S)-2-methyl-4-pentynyl ether | C7H12O | 详情 | 详情 | |
| (XIX) | 17364 | (2S,4E)-5-[4-[(1S,2S)-3-(benzyloxy)-2-hydroxy-1-methylpropyl]-9-[(4-methoxybenzyl)oxy]-2,2-dimethyl-1,3,7-trioxaspiro[5.5]undec-11-yl]-2,4-dimethyl-4-penten-1-ol | C36H52O8 | 详情 | 详情 | |
| (XX) | 17365 | (2S,3S)-1-(benzyloxy)-3-[11-((E,4S)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethyl-1-pentenyl)-9-[(4-methoxybenzyl)oxy]-2,2-dimethyl-1,3,7-trioxaspiro[5.5]undec-4-yl]-2-butanol | C42H66O8Si | 详情 | 详情 | |
| (XXI) | 17366 | (2S,3S)-3-[11-((E,4S)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethyl-1-pentenyl)-9-[(4-methoxybenzyl)oxy]-2,2-dimethyl-1,3,7-trioxaspiro[5.5]undec-4-yl]-1,2-butanediol | C35H60O8Si | 详情 | 详情 | |
| (XXII) | 17367 | (2R)-2-[11-((E,4S)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethyl-1-pentenyl)-9-[(4-methoxybenzyl)oxy]-2,2-dimethyl-1,3,7-trioxaspiro[5.5]undec-4-yl]propanal | C34H56O7Si | 详情 | 详情 | |
| (XXIII) | 17368 | (1R,2R,5R)-5-[(E)-2-bromo-1-propenyl]-2-[[tert-butyl(diphenyl)silyl]oxy]cyclohexyl methyl ether; ([(1R,2R,4R)-4-[(E)-2-bromo-1-propenyl]-2-methoxycyclohexyl]oxy)(tert-butyl)diphenylsilane | C26H35BrO2Si | 详情 | 详情 |
合成路线17
The completion of the total synthesis of FK-506, starting with the key intermediate C16-C34 fragment obtained as described in Tetrahedron 1997, 53(39): 13221, has been presented: 1) The silyl ether (I) was partially deprotected with tetrabutylammonium fluoride (TBAF) in THF giving the diol (II), which is selectively tosylated with tosyl chloride at the primary OH group yielding the monotosylate (III). The protection of the secondary alcohol of (III) with triethylsilyl chloride (TES-Cl) affords the protected tosylate (IV), which by treatment with lithium iodide and sodium benzenesulfinate is converted into the sulfone (V). The condensation of (V) with aldehyde (VI) by means of butyllithium followed by Dess-Martin oxidation gives a nonisolated ketosulfone intermediate, which was treated with tri-butyltin hydride and azobis(isobutyronitrile) (AIBN) yielding ketone (VII).
| 【1】 Liu, L.B.; Roper, T.D.; Gleason, J.L.; Ireland, R.E.; Total synthesis of FK-506. 2. Completion of the synthesis. Tetrahedron 1997, 53, 39, 13257. |
| 【2】 Liu, L.B.; Roper, T.D.; Ireland, R.E.; Total synthesis of FK-506. 1. Construction of the C16-C34 fragment. Tetrahedron 1997, 53, 39, 13221. |
| 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) | 17369 | (E,3S,4S)-4-[11-((E,4S)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethyl-1-pentenyl)-9-[(4-methoxybenzyl)oxy]-2,2-dimethyl-1,3,7-trioxaspiro[5.5]undec-4-yl]-1-((1R,3R,4R)-4-[[tert-butyl(diphenyl)silyl]oxy]-3-methoxycyclohexyl)-2-methyl-1-penten-3-ol | C60H92O9Si2 | 详情 | 详情 | |
| (II) | 17370 | (2S,4E)-5-[4-[(1S,2S,3E)-4-((1R,3R,4R)-4-[[tert-butyl(diphenyl)silyl]oxy]-3-methoxycyclohexyl)-2-hydroxy-1,3-dimethyl-3-butenyl]-9-[(4-methoxybenzyl)oxy]-2,2-dimethyl-1,3,7-trioxaspiro[5.5]undec-11-yl]-2,4-dimethyl-4-penten-1-ol | C54H78O9Si | 详情 | 详情 | |
| (III) | 17371 | (2S,4E)-5-[4-[(1S,2S,3E)-4-((1R,3R,4R)-4-[[tert-butyl(diphenyl)silyl]oxy]-3-methoxycyclohexyl)-2-hydroxy-1,3-dimethyl-3-butenyl]-9-[(4-methoxybenzyl)oxy]-2,2-dimethyl-1,3,7-trioxaspiro[5.5]undec-11-yl]-2,4-dimethyl-4-pentenyl 4-methylbenzenesulfonat | C61H84O11SSi | 详情 | 详情 | |
| (IV) | 17372 | (2S,4E)-5-[4-[(1R,2S,3E)-4-((1R,3R,4R)-4-[[tert-butyl(diphenyl)silyl]oxy]-3-methoxycyclohexyl)-1,3-dimethyl-2-[(triethylsilyl)oxy]-3-butenyl]-9-[(4-methoxybenzyl)oxy]-2,2-dimethyl-1,3,7-trioxaspiro[5.5]undec-11-yl]-2,4-dimethyl-4-pentenyl 4-methylbe | C67H98O11SSi2 | 详情 | 详情 | |
| (V) | 17373 | (2S,4E)-5-[4-[(1R,2S,3E)-4-((1R,3R,4R)-4-[[tert-butyl(diphenyl)silyl]oxy]-3-methoxycyclohexyl)-1,3-dimethyl-2-[(triethylsilyl)oxy]-3-butenyl]-9-[(4-methoxybenzyl)oxy]-2,2-dimethyl-1,3,7-trioxaspiro[5.5]undec-11-yl]-2,4-dimethyl-4-pentenyl benzenesul | C66H96O11SSi2 | 详情 | 详情 | |
| (VI) | 17374 | ethyl (4R,5S,7S,8S,10R)-7-formyl-8-methoxy-2,2,10-trimethyl-1,3,6-trioxaspiro[4.5]decane-4-carboxylate | C15H24O7 | 详情 | 详情 | |
| (VII) | 17375 | ethyl (4R,5S,7S,8S,10R)-7-((3S,5E)-6-[4-[(1R,2S,3E)-4-((1R,3R,4R)-4-[[tert-butyl(diphenyl)silyl]oxy]-3-methoxycyclohexyl)-1,3-dimethyl-2-[(triethylsilyl)oxy]-3-butenyl]-9-[(4-methoxybenzyl)oxy]-2,2-dimethyl-1,3,7-trioxaspiro[5.5]undec-11-yl]-3,5-dimethyl-5-hexenoyl)-8-methoxy-2,2,10-trimethyl-1,3,6-trioxaspiro[4.5]decane-4-carboxylate | C75H114O15Si2 | 详情 | 详情 |
合成路线18
The diastereoselective reduction of (VII) with NaBH4/CeCl3 in methanol/ethyl ether affords alcohol (VIII), which was methylated with trimethyloxonium tetrafluoroborate in dichloromethane giving the methyl ether (IX). The treatment of (IX) with lithium bis(trimethylsilyl)amide (Li-HMDS) and Mg(HMDS)2 causes enolization and ring opening affording alcohol (X), which was protected with tert-butyldimethylsilyl triflate yielding the fully silylated compound (XI). The hydrolysis of the ester group of (XI) with NaOH, followed by a selective elimination of the triethylsilyl group with trifluoroacetic acid and esterification of the resulting alcohol with piperidine-2(S)-carboxylic acid (XII) by means of dicyclohexylcarbodiimide (DCC) and dimethylaminopyridine (DMAP) afforded ester (XIII).
| 【1】 Liu, L.B.; Roper, T.D.; Gleason, J.L.; Ireland, R.E.; Total synthesis of FK-506. 2. Completion of the synthesis. Tetrahedron 1997, 53, 39, 13257. |
| 【2】 Liu, L.B.; Roper, T.D.; Ireland, R.E.; Total synthesis of FK-506. 1. Construction of the C16-C34 fragment. Tetrahedron 1997, 53, 39, 13221. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 17375 | ethyl (4R,5S,7S,8S,10R)-7-((3S,5E)-6-[4-[(1R,2S,3E)-4-((1R,3R,4R)-4-[[tert-butyl(diphenyl)silyl]oxy]-3-methoxycyclohexyl)-1,3-dimethyl-2-[(triethylsilyl)oxy]-3-butenyl]-9-[(4-methoxybenzyl)oxy]-2,2-dimethyl-1,3,7-trioxaspiro[5.5]undec-11-yl]-3,5-dimethyl-5-hexenoyl)-8-methoxy-2,2,10-trimethyl-1,3,6-trioxaspiro[4.5]decane-4-carboxylate | C75H114O15Si2 | 详情 | 详情 | |
| (VIII) | 17376 | ethyl (4R,5S,7R,8S,10R)-7-((1S,3S,5E)-6-[4-[(1R,2S,3E)-4-((1R,3R,4R)-4-[[tert-butyl(diphenyl)silyl]oxy]-3-methoxycyclohexyl)-1,3-dimethyl-2-[(triethylsilyl)oxy]-3-butenyl]-9-[(4-methoxybenzyl)oxy]-2,2-dimethyl-1,3,7-trioxaspiro[5.5]undec-11-yl]-1-hydroxy-3,5-dimethyl-5-hexenyl)-8-methoxy-2,2,10-trimethyl-1,3,6-trioxaspiro[4.5]decane-4-carboxylate | C75H116O15Si2 | 详情 | 详情 | |
| (IX) | 17377 | ethyl (4R,5S,7R,8S,10R)-7-((1S,3S,5E)-6-[4-[(1R,2S,3E)-4-((1R,3R,4R)-4-[[tert-butyl(diphenyl)silyl]oxy]-3-methoxycyclohexyl)-1,3-dimethyl-2-[(triethylsilyl)oxy]-3-butenyl]-9-[(4-methoxybenzyl)oxy]-2,2-dimethyl-1,3,7-trioxaspiro[5.5]undec-11-yl]-1-methoxy-3,5-dimethyl-5-hexenyl)-8-methoxy-2,2,10-trimethyl-1,3,6-trioxaspiro[4.5]decane-4-carboxylate | C76H118O15Si2 | 详情 | 详情 | |
| (X) | 17378 | ethyl 5-((1R,3S,4R,5S,7S,9E)-10-[4-[(1R,2S,3E)-4-((1R,3R,4R)-4-[[tert-butyl(diphenyl)silyl]oxy]-3-methoxycyclohexyl)-1,3-dimethyl-2-[(triethylsilyl)oxy]-3-butenyl]-9-[(4-methoxybenzyl)oxy]-2,2-dimethyl-1,3,7-trioxaspiro[5.5]undec-11-yl]-4-hydroxy-3,5-dimethoxy-1,7,9-trimethyl-9-decenyl)-2,2-dimethyl-1,3-dioxole-4-carboxylate | C76H118O15Si2 | 详情 | 详情 | |
| (XI) | 17379 | ethyl 5-((1R,3S,4R,5S,7S,9E)-4-[[tert-butyl(dimethyl)silyl]oxy]-10-[4-[(1R,2S,3E)-4-((1R,3R,4R)-4-[[tert-butyl(diphenyl)silyl]oxy]-3-methoxycyclohexyl)-1,3-dimethyl-2-[(triethylsilyl)oxy]-3-butenyl]-9-[(4-methoxybenzyl)oxy]-2,2-dimethyl-1,3,7-trioxaspiro[5.5]undec-11-yl]-3,5-dimethoxy-1,7,9-trimethyl-9-decenyl)-2,2-dimethyl-1,3-dioxole-4-carboxylate | C82H132O15Si3 | 详情 | 详情 | |
| (XII) | 17380 | (2S)hexahydro-2-pyridinecarboxylic acid; (S)-pipecolic acid | 3105-95-1 | C6H11NO2 | 详情 | 详情 |
| (XIII) | 17381 | 5-((1R,3S,4R,5S,7S,9E)-4-[[tert-butyl(dimethyl)silyl]oxy]-10-[4-((1R,2S,3E)-4-((1R,3R,4R)-4-[[tert-butyl(diphenyl)silyl]oxy]-3-methoxycyclohexyl)-1,3-dimethyl-2-[[(2S)piperidinylcarbonyl]oxy]-3-butenyl)-9-[(4-methoxybenzyl)oxy]-2,2-dimethyl-1,3,7-trioxaspiro[5.5]undec-11-yl]-3,5-dimethoxy-1,7,9-trimethyl-9-decenyl)-2,2-dimethyl-1,3-dioxole-4-carboxylic acid | C80H123NO16Si2 | 详情 | 详情 |
合成路线19
Ester (XIII) was submitted to cyclization by means of triethylsilyl triflate and 2-chloro-1-methylpyridinium iodide (MCPI) in dichloromethane/methanol gaving the macrocyclic compound (XIV). Elimination of the p-methoxybenzyl group of (XIV) with dichlorodicyanobenzoquinone (DDQ) in dichloromethane yielded the alcohol (XV), which was converted into the iodo derivative (XVI) with I2, triphenylphosphine and imidazole in hot toluene. The reductive fragmentation of the spiroketal rings of (XVI) with zinc/silver-graphite in THF afforded compound (XVII) with the adequate configuration in the C21-C24 fragment.
| 【1】 Liu, L.B.; Roper, T.D.; Gleason, J.L.; Ireland, R.E.; Total synthesis of FK-506. 2. Completion of the synthesis. Tetrahedron 1997, 53, 39, 13257. |
| 【2】 Liu, L.B.; Roper, T.D.; Ireland, R.E.; Total synthesis of FK-506. 1. Construction of the C16-C34 fragment. Tetrahedron 1997, 53, 39, 13221. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIII) | 17381 | 5-((1R,3S,4R,5S,7S,9E)-4-[[tert-butyl(dimethyl)silyl]oxy]-10-[4-((1R,2S,3E)-4-((1R,3R,4R)-4-[[tert-butyl(diphenyl)silyl]oxy]-3-methoxycyclohexyl)-1,3-dimethyl-2-[[(2S)piperidinylcarbonyl]oxy]-3-butenyl)-9-[(4-methoxybenzyl)oxy]-2,2-dimethyl-1,3,7-trioxaspiro[5.5]undec-11-yl]-3,5-dimethoxy-1,7,9-trimethyl-9-decenyl)-2,2-dimethyl-1,3-dioxole-4-carboxylic acid | C80H123NO16Si2 | 详情 | 详情 | |
| (XIV) | 17382 | (10S,12S,13R,14S,16R,28S,31S,32R)-13-[[tert-butyl(dimethyl)silyl]oxy]-31-[(E)-2-((1R,3R,4R)-4-[[tert-butyl(diphenyl)silyl]oxy]-3-methoxycyclohexyl)-1-methylethenyl]-12,14-dimethoxy-4-[(4-methoxybenzyl)oxy]-8,10,16,19,19,32,35,35-octamethyl-2,18,20,30,34,36-hexaoxa-23-azapentacyclo[31.3.1.0(1,6).0(17,21).0(23,28)]heptatriaconta-7,17(21)-diene-22,29-dione | C80H121NO15Si2 | 详情 | 详情 | |
| (XV) | 17383 | (10S,12S,13R,14S,16R,28S,31S,32R)-13-[[tert-butyl(dimethyl)silyl]oxy]-31-[(E)-2-((1R,3R,4R)-4-[[tert-butyl(diphenyl)silyl]oxy]-3-methoxycyclohexyl)-1-methylethenyl]-4-hydroxy-12,14-dimethoxy-8,10,16,19,19,32,35,35-octamethyl-2,18,20,30,34,36-hexaoxa-23-azapentacyclo[31.3.1.0(1,6).0(17,21).0(23,28)]heptatriaconta-7,17(21)-diene-22,29-dione | C72H113NO14Si2 | 详情 | 详情 | |
| (XVI) | 17384 | (10S,12S,13R,14S,16R,28S,31S,32R)-13-[[tert-butyl(dimethyl)silyl]oxy]-31-[(E)-2-((1R,3R,4R)-4-[[tert-butyl(diphenyl)silyl]oxy]-3-methoxycyclohexyl)-1-methylethenyl]-4-iodo-12,14-dimethoxy-8,10,16,19,19,32,35,35-octamethyl-2,18,20,30,34,36-hexaoxa-23-azapentacyclo[31.3.1.0(1,6).0(17,21).0(23,28)]heptatriaconta-7,17(21)-diene-22,29-dione | C72H112INO13Si2 | 详情 | 详情 | |
| (XVII) | 17385 | (9aS,12S,13R,14S,17R,21S,23S,24R,25S,27R)-17-allyl-24-[[tert-butyl(dimethyl)silyl]oxy]-12-[(E)-2-((1R,3R,4R)-4-[[tert-butyl(diphenyl)silyl]oxy]-3-methoxycyclohexyl)-1-methylethenyl]-14-hydroxy-23,25-dimethoxy-2,2,13,19,21,27-hexamethyl-7,8,9,9a,12,13,14,15,20,21,22,23,24,25,26,27-hexadecahydro-4H-[1,3]dioxolo[4,5-f]pyrido[2,1-c][1,4]oxazacyclotricosine-4,10,16(6H,17H)-trione | C69H107NO12Si2 | 详情 | 详情 |
合成路线20
The 1,3-dioxole ring of (XVII) was cleaved by selective oxidation with dimethyldioxirane (DMD) in acetone giving the tricarbonyl compound (XVIII) (silylated FK-506), which was finally desilylated by means of HF in acetonitrile/ water. 2) Aldehyde (VI) was prepared according to a previously reported method (Ireland, R.E. et al. J Org Chem 1992, 57: 5071).
| 【1】 Liu, L.B.; Roper, T.D.; Ireland, R.E.; Total synthesis of FK-506. 1. Construction of the C16-C34 fragment. Tetrahedron 1997, 53, 39, 13221. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVII) | 17385 | (9aS,12S,13R,14S,17R,21S,23S,24R,25S,27R)-17-allyl-24-[[tert-butyl(dimethyl)silyl]oxy]-12-[(E)-2-((1R,3R,4R)-4-[[tert-butyl(diphenyl)silyl]oxy]-3-methoxycyclohexyl)-1-methylethenyl]-14-hydroxy-23,25-dimethoxy-2,2,13,19,21,27-hexamethyl-7,8,9,9a,12,13,14,15,20,21,22,23,24,25,26,27-hexadecahydro-4H-[1,3]dioxolo[4,5-f]pyrido[2,1-c][1,4]oxazacyclotricosine-4,10,16(6H,17H)-trione | C69H107NO12Si2 | 详情 | 详情 | |
| (XVIII) | 17386 | (3S,4R,5S,8R,12S,14S,15R,16S,18R,26aS)-8-allyl-15-[[tert-butyl(dimethyl)silyl]oxy]-3-[(E)-2-((1R,3R,4R)-4-[[tert-butyl(diphenyl)silyl]oxy]-3-methoxycyclohexyl)-1-methylethenyl]-5-hydroxy-14,16-dimethoxy-4,10,12,18-tetramethyl-5,6,11,12,13,14,15,16,17,18,24,25,26,26a-tetradecahydro-3H-pyrido[2,1-c][1,4]oxazacyclotricosine-1,7,19,20,21(4H,8H,23H)-pentone | C66H101NO12Si2 | 详情 | 详情 |
合成路线21
The reaction of FK-506 (I) with Tbdms-Cl and imidazole gives the bis silylated compound (II), which is regioselectively monodesilylated by means of aq. HF in acetonitrile to yield the monosilylated compound (III). The silylation of (III) with 2-bromophenyldimethylsilyl chloride (IV) and imidazole affords the new disilylated compound (V), which is submitted to radical translocating/reducing conditions by means of Et3N/O2 or AIBN as radical initiator and Bu3Sn2H as deuterium source. Under these conditions a mixture of labeled compounds (VI) and (VII) is obtained.
| 【1】 Acemoglu, M.; et al.; Regio- and stereoselective preparation of ascomycin-d1 and FK 506-d1. J Label Compd Radiopharm 2002, 45, 5, 361. |
| 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),(VII) | 55703 | (1R,9S,12S,13S,14S,17R,21S,23S,24R,25S,27R)-17-allyl-14-{[tert-butyl(dimethyl)silyl]oxy}-12-[(E)-2-((1R,3R,4R)-4-{[dimethyl(phenyl)silyl]oxy}-3-methoxycyclohexyl)-1-methylethenyl]-1-hydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0~4,9~]octacos-18-ene-2,3,10,16-tetrone | C58H93NO12Si2 | 详情 | 详情 | |
| (I) | 47057 | (1R,9S,12S,13R,14S,17R,21S,23S,24R,25S,27R)-17-allyl-1,14-dihydroxy-12-[(E)-2-[(1R,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethenyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0(4,9)]octacos-18-ene-2,3,10,16-tetrone | C44H69NO12 | 详情 | 详情 | |
| (II) | 55697 | (1R,9S,12S,13S,14S,17R,21S,23S,24R,25S,27R)-17-allyl-14-{[tert-butyl(dimethyl)silyl]oxy}-12-[(E)-2-((1R,3R,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-3-methoxycyclohexyl)-1-methylethenyl]-1-hydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0~4,9~]octacos-18-ene-2,3,10,16-tetrone | C56H97NO12Si2 | 详情 | 详情 | |
| (III) | 55698 | (1R,9S,12S,13S,14S,17R,21S,23S,24R,25S,27R)-17-allyl-14-{[tert-butyl(dimethyl)silyl]oxy}-1-hydroxy-12-{(E)-2-[(1R,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethenyl}-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0~4,9~]octacos-18-ene-2,3,10,16-tetrone | C50H83NO12Si | 详情 | 详情 | |
| (IV) | 55699 | (2-bromophenyl)(chloro)dimethylsilane | C8H10BrClSi | 详情 | 详情 | |
| (V) | 55700 | (1R,9S,12S,13S,14S,17R,21S,23S,24R,25S,27R)-17-allyl-12-[(E)-2-((1R,3R,4R)-4-{[(2-bromophenyl)(dimethyl)silyl]oxy}-3-methoxycyclohexyl)-1-methylethenyl]-14-{[tert-butyl(dimethyl)silyl]oxy}-1-hydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0~4,9~]octacos-18-ene-2,3,10,16-tetrone | C58H92BrNO12Si2 | 详情 | 详情 | |
| (VI) | 55701 | (1R,9S,12S,13S,14S,17R,21S,23S,24R,25S,27R)-17-allyl-14-{[tert-butyl(dimethyl)silyl]oxy}-12-[(E)-2-((1R,3R,4R)-4-{[dimethyl(phenyl)silyl]oxy}-3-methoxycyclohexyl)-1-methylethenyl]-1-hydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0~4,9~]octacos-18-ene-2,3,10,16-tetrone | C58H93NO12Si2 | 详情 | 详情 | |
| (VII) | 55702 | (1R,9S,12S,13S,14S,17R,21S,23S,24R,25S,27R)-17-allyl-14-{[tert-butyl(dimethyl)silyl]oxy}-12-[(E)-2-((1R,3R,4R)-4-{[dimethyl(phenyl)silyl]oxy}-3-methoxycyclohexyl)-1-methylethenyl]-1-hydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0~4,9~]octacos-18-ene-2,3,10,16-tetrone | C58H93NO12Si2 | 详情 | 详情 |
合成路线22
This mixture is desilylated by means of aq. HOAc in THF to yield from a 41:59 up to a 68:32 mixture of labeled and unlabeled FK-506.
| 【1】 Acemoglu, M.; et al.; Regio- and stereoselective preparation of ascomycin-d1 and FK 506-d1. J Label Compd Radiopharm 2002, 45, 5, 361. |
| 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),(VII) | 55703 | (1R,9S,12S,13S,14S,17R,21S,23S,24R,25S,27R)-17-allyl-14-{[tert-butyl(dimethyl)silyl]oxy}-12-[(E)-2-((1R,3R,4R)-4-{[dimethyl(phenyl)silyl]oxy}-3-methoxycyclohexyl)-1-methylethenyl]-1-hydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0~4,9~]octacos-18-ene-2,3,10,16-tetrone | C58H93NO12Si2 | 详情 | 详情 | |
| (I) | 47057 | (1R,9S,12S,13R,14S,17R,21S,23S,24R,25S,27R)-17-allyl-1,14-dihydroxy-12-[(E)-2-[(1R,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethenyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0(4,9)]octacos-18-ene-2,3,10,16-tetrone | C44H69NO12 | 详情 | 详情 | |
| (VI) | 55701 | (1R,9S,12S,13S,14S,17R,21S,23S,24R,25S,27R)-17-allyl-14-{[tert-butyl(dimethyl)silyl]oxy}-12-[(E)-2-((1R,3R,4R)-4-{[dimethyl(phenyl)silyl]oxy}-3-methoxycyclohexyl)-1-methylethenyl]-1-hydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0~4,9~]octacos-18-ene-2,3,10,16-tetrone | C58H93NO12Si2 | 详情 | 详情 | |
| (VII) | 55702 | (1R,9S,12S,13S,14S,17R,21S,23S,24R,25S,27R)-17-allyl-14-{[tert-butyl(dimethyl)silyl]oxy}-12-[(E)-2-((1R,3R,4R)-4-{[dimethyl(phenyl)silyl]oxy}-3-methoxycyclohexyl)-1-methylethenyl]-1-hydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0~4,9~]octacos-18-ene-2,3,10,16-tetrone | C58H93NO12Si2 | 详情 | 详情 |
合成路线23
The intermediate chiral 2-bromovinyl cyclohexane (XVIII) has been obtained as follows: The asymmetric epoxidation of divinyl carbinol (I) by means of L-(+)-diisopropyl tartrate, Ti(O-iPr)4 and tBu-OOH gives the epoxy alcohol (II), which is protected with p-methoxybenzyl bromide and NaH in THF to yield the benzyl ether (III). The condensation of (III) with the lithium derivative of ethyl acetate (IV) by means of BF3/Et2O, followed by hydrolysis with LiOH affords the 6-heptenoic acid (V). The methylation of the OH group of (V) with methyl iodide and NaH provides the corresponding methoxy acid (VI), which is esterified with diazomethane to give the methyl ester (VII). The debenzylation of (VII) by means of DDQ in dichloromethane yields the hydroxyester (VIII), which is cyclized by means of Ts-OH in refluxing benzene to afford the chiral tetrahydropyranone (IX). The Claisen rearrangement of the lactone (IX) catalyzed by Tbdms-OTf in refluxing toluene provides the cyclohexane carboxylic acid (X), which is esterified with diazomethane to give the methyl ester (XI). The hydroboration of the double bond of (XI) with BH3/THF, followed by protection with Tips-OTf yield the silyl ether (XII). The reduction of the ester group of (XII) with LiAlH4 affords the carbinol (XIII), which is treated with the Swern oxidant to afford the carbaldehyde (XIV). The condensation of (XIV) with the diazophosphonate (XV) and tBuOK provides the ethynyl cyclohexane (XVI), which is methylated with methyl iodide and BuLi in THF to give the propynyl cyclohexane (XVII). Finally, this compound is brominated by means of NBS and Cp2ZrHCl to yield the target intermediate, the chiral 2-bromovinyl cyclohexane (XVIII).
| 【1】 Ragan, J.A.; The total synthesis of FK506 and an FKBP probe reagent, (C8,C9-13C2)-FK506. Diss Abstr Int B - Sci Eng 1991, 51, 8, 3849. |
| 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) | 11471 | 1,4-Pentadien-3-ol | 922-65-6 | C5H8O | 详情 | 详情 |
| (II) | 11472 | (1S)-1-[(2R)Oxiranyl]-2-propen-1-ol | C5H8O2 | 详情 | 详情 | |
| (III) | 57251 | 4-methoxybenzyl (1S)-1-[(2R)oxiranyl]-2-propenyl ether; (2R)-2-{(1S)-1-[(4-methoxybenzyl)oxy]-2-propenyl}oxirane | C13H16O3 | 详情 | 详情 | |
| (IV) | 44205 | (2-ethoxy-2-oxoethyl)lithium | C4H7LiO2 | 详情 | 详情 | |
| (V) | 57252 | (4R,5S)-4-hydroxy-5-[(4-methoxybenzyl)oxy]-6-heptenoic acid | C15H20O5 | 详情 | 详情 | |
| (VI) | 57253 | (4R,5S)-4-methoxy-5-[(4-methoxybenzyl)oxy]-6-heptenoic acid | C16H22O5 | 详情 | 详情 | |
| (VII) | 57254 | methyl (4R,5S)-4-methoxy-5-[(4-methoxybenzyl)oxy]-6-heptenoate | C17H24O5 | 详情 | 详情 | |
| (VIII) | 57255 | methyl (4R,5S)-5-hydroxy-4-methoxy-6-heptenoate | C9H16O4 | 详情 | 详情 | |
| (IX) | 11476 | (5R,6S)-5-Methoxy-6-vinyltetrahydro-2H-pyran-2-one | C8H12O3 | 详情 | 详情 | |
| (X) | 57256 | (1R,5R)-5-methoxy-3-cyclohexene-1-carboxylic acid | C8H12O3 | 详情 | 详情 | |
| (XI) | 11585 | methyl (1R,5R)-5-methoxy-3-cyclohexene-1-carboxylate | C9H14O3 | 详情 | 详情 | |
| (XII) | 11588 | methyl (1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexanecarboxylate | C18H36O4Si | 详情 | 详情 | |
| (XIII) | 11480 | [(1R,3R,4R)-3-Methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]methanol | C17H36O3Si | 详情 | 详情 | |
| (XIV) | 11532 | (1R,3R,4R)-3-Methoxy-4-[(triisopropylsilyl)oxy]cyclohexanecarbaldehyde | C17H34O3Si | 详情 | 详情 | |
| (XV) | 57257 | dimethyl diazomethylphosphonate | C3H7N2O3P | 详情 | 详情 | |
| (XVI) | 11483 | (1R,2R,4R)-4-Ethynyl-2-methoxycyclohexyl triisopropylsilyl ether; [[(1R,2R,4R)-4-Ethynyl-2-methoxycyclohexyl]oxy](triisopropyl)silane | C18H34O2Si | 详情 | 详情 | |
| (XVII) | 11484 | (1R,2R,4R)-2-Methoxy-4-(1-propynyl)cyclohexyl triisopropylsilyl ether; Triisopropyl[[(1R,2R,4R)-2-methoxy-4-(1-propynyl)cyclohexyl]oxy]silane | C19H36O2Si | 详情 | 详情 | |
| (XVIII) | 11485 | ([(1R,2R,4R)-4-[(E)-2-Bromo-1-propenyl]-2-methoxycyclohexyl]oxy)(triisopropyl)silane; (1R,2R,4R)-4-[(E)-2-Bromo-1-propenyl]-2-methoxycyclohexyl triisopropylsilyl ether | C19H37BrO2Si | 详情 | 详情 |
合成路线24
The intermediate chiral phosphonamide (XXXII) has been obtained as follows: The treatment of arabitol (XIX) with the Moffat reagent (alpha-acetoxy-isobutyric acyl chloride) (XX) gives the intermediate (XXI), which, without isolation, by treatment with NaOMe and with Tbdms-Cl yields the silylated diepoxide (XXII). The condensation of (XXII) with ethoxyethynyl lithium (XXIII) by means of BF3/Et2O, HgCl2 and Ts-OH affords the bis(lactone) (XXIV), which is methylated by means of methyl iodide and LDA to provide the dimethyl analogue (XXV). The hydrolysis and desilylation of (XXV) by means of HF, followed by reprotection with benzyl trichloroacetimidate, and exhaustive methylation with NaH and methyl iodide gives the chiral nonanedioic dimethyl ester (XXVI). The reductive cleavage of the benzyl ether group with H2 over Pd(OH)2, followed by cyclization by means of PPTS yields the lactone (XXVII). The reduction of (XXVII) with L-selectride, followed by protection with propane-1,3-dithiol and BF3/Et2O affords the 1,3-dithiane (XXVIII). The reduction of the lactone group of (XXVIII) with LiAlH4, followed by reaction with PPh3 and I2 provides the chiral nonyl iodide (XXIX). The protection of the OH group of (XXIX) by means of Tbdms-OTf gives the silyl ether (XXX), which is finally condensed with lithium derived ethylphosphonamide (XXXI) to yield the intermediate chiral phosphonamide (XXXII).
| 【1】 Ragan, J.A.; The total synthesis of FK506 and an FKBP probe reagent, (C8,C9-13C2)-FK506. Diss Abstr Int B - Sci Eng 1991, 51, 8, 3849. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIX) | 11442 | (2S,4S)-1,2,3,4,5-Pentanepentol; D-Arabinol | 488-82-4 | C5H12O5 | 详情 | 详情 |
| (XX) | 32808 | 2-chloro-1,1-dimethyl-2-oxoethyl acetate | 40635-66-3 | C6H9ClO3 | 详情 | 详情 |
| (XXI) | 57258 | (1R,3R)-3-(acetyloxy)-4-chloro-1-(chloromethyl)-2-hydroxybutyl acetate | C9H14Cl2O5 | 详情 | 详情 | |
| (XXII) | 11445 | tert-Butyl(dimethyl)silyl di[(2S)oxiranyl]methyl ether; tert-Butyl[di[(2S)oxiranyl]methoxy]dimethylsilane | C11H22O3Si | 详情 | 详情 | |
| (XXIII) | 55241 | (2-ethoxyethynyl)lithium | C4H5LiO | 详情 | 详情 | |
| (XXIV) | 11448 | (5S)-5-[[[tert-Butyl(dimethyl)silyl]oxy][(2S)-5-oxotetrahydro-2-furanyl]methyl]dihydro-2(3H)-furanone | C15H26O5Si | 详情 | 详情 | |
| (XXV) | 11449 | (3R,5S)-5-[[[tert-Butyl(dimethyl)silyl]oxy][(2S,4R)-4-methyl-5-oxotetrahydro-2-furanyl]methyl]-3-methyldihydro-2(3H)-furanone | C17H30O5Si | 详情 | 详情 | |
| (XXVI) | 11452 | dimethyl (2R,4S,6S,8R)-5-(benzyloxy)-4,6-dimethoxy-2,8-dimethylnonanedioate | C22H34O7 | 详情 | 详情 | |
| (XXVII) | 11454 | methyl (2R,4S)-4-methoxy-4-[(2S,3S,5R)-3-methoxy-5-methyl-6-oxotetrahydro-2H-pyran-2-yl]-2-methylbutanoate | C14H24O6 | 详情 | 详情 | |
| (XXVIII) | 11456 | (3R,5S,6R)-6-[(1S,3R)-3-(1,3-Dithian-2-yl)-1-methoxybutyl]-5-methoxy-3-methyltetrahydro-2H-pyran-2-one | C16H28O4S2 | 详情 | 详情 | |
| (XXIX) | 11458 | (2R,4S,5S,6S,8R)-8-(1,3-Dithian-2-yl)-1-iodo-4,6-dimethoxy-2-methyl-5-nonanol | C16H31IO3S2 | 详情 | 详情 | |
| (XXX) | 11459 | tert-Butyl([(1S,2S,4R)-1-[(1S,3R)-3-(1,3-dithian-2-yl)-1-methoxybutyl]-5-iodo-2-methoxy-4-methylpentyl]oxy)dimethylsilane; tert-Butyl(dimethyl)silyl (1S,2S,4R)-1-[(1S,3R)-3-(1,3-dithian-2-yl)-1-methoxybutyl]-5-iodo-2-methoxy-4-methylpentyl ether | C22H45IO3S2Si | 详情 | 详情 | |
| (XXXI) | 57259 | {1-[bis(dimethylamino)phosphoryl]ethyl}lithium | C6H16LiN2OP | 详情 | 详情 | |
| (XXXII) | 11491 | (3R,5S,6R,7S,9R)-6-[[tert-Butyl(dimethyl)silyl]oxy]-9-(1,3-dithian-2-yl)-5,7-dimethoxy-1,3-dimethyldecyl-N,N,N',N'-tetramethylphosphonic diamide | C28H61N2O4PS2Si | 详情 | 详情 |
合成路线25
The asymmetric reduction of 5-(4-methoxybenzyloxy)-3-oxopentanoic acid methyl ester (XXXIII) with H2 over a chiral Ru catalyst gives the chiral hydroxyester (XXXIV), which is alkylated by means of allyl bromide (XXXV) and LDA to yield the chiral 2-allyl-3-hydroxypentanoic ester (XXXVI). The reduction of (XXXVI) with LiAlH4, and then with DDQ affords the 1,3-dioxan-4-ylethanol (XXXVII), which is treated with NIS, NaHCO3 and reduced with DIBAL to afford the iodomethyl tetrahydrofuran (XXXVIII). The oxidation of the primary OH group of (XXXVIII) with oxalyl chloride provides the carbaldehyde (XXXIX), which is condensed with the propenylstannane (XL) by means of BF3/Et2O in dichloromethane to give the unsaturated alcohol (XLI). The protection of the OH group of (XLI) with TipsOTf yields the unsaturated silyl ether (XLII), which is ozonolyzed by means of O3, pyridine and Me2S to afford the carbaldehyde (XLIII). The condensation of (XLIII) with the chiral intermediate 2-bromovinyl cyclohexane (XVIII) by means of tBuLi and MgBr2 provides the alcohol (XLIV), which is esterified with 1-(tert-butoxycarbonyl)piperidine-2(S)-carboxylic acid (XLV) by means of DCC to give the expected ester (XLVI). The reaction of (XLVI) with Zn and NH4Cl yields the chiral alpha-allyl alcohol (XLVII), which is oxidized by means of oxalyl chloride to afford the corresponding carbaldehyde (XLVIII).
| 【1】 Ragan, J.A.; The total synthesis of FK506 and an FKBP probe reagent, (C8,C9-13C2)-FK506. Diss Abstr Int B - Sci Eng 1991, 51, 8, 3849. |
| 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) | 11485 | ([(1R,2R,4R)-4-[(E)-2-Bromo-1-propenyl]-2-methoxycyclohexyl]oxy)(triisopropyl)silane; (1R,2R,4R)-4-[(E)-2-Bromo-1-propenyl]-2-methoxycyclohexyl triisopropylsilyl ether | C19H37BrO2Si | 详情 | 详情 | |
| (XXXIII) | 57260 | methyl 5-[(4-methoxybenzyl)oxy]-3-oxopentanoate | C14H18O5 | 详情 | 详情 | |
| (XXXIV) | 57261 | methyl (3S)-3-hydroxy-5-[(4-methoxybenzyl)oxy]pentanoate | C14H20O5 | 详情 | 详情 | |
| (XXXV) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (XXXVI) | 57262 | methyl (2S)-2-{(1S)-1-hydroxy-3-[(4-methoxybenzyl)oxy]propyl}-4-pentenoate | C17H24O5 | 详情 | 详情 | |
| (XXXVII) | 11466 | (2R)-2-[(2S,4S)-2-(4-Methoxyphenyl)-1,3-dioxan-4-yl]-4-penten-1-ol | C16H22O4 | 详情 | 详情 | |
| (XXXVIII) | 57263 | (3S)-3-[(3R,5S)-5-(iodomethyl)tetrahydro-3-furanyl]-3-[(4-methoxybenzyl)oxy]-1-propanol | C16H23IO4 | 详情 | 详情 | |
| (XXXIX) | 57264 | (3S)-3-[(3R,5S)-5-(iodomethyl)tetrahydro-3-furanyl]-3-[(4-methoxybenzyl)oxy]propanal | C16H21IO4 | 详情 | 详情 | |
| (XL) | 11469 | (E)-2-Butenyl(triphenyl)stannane | C22H22Sn | 详情 | 详情 | |
| (XLI) | 57265 | (1S,3S,4S)-1-[(3R,5S)-5-(iodomethyl)tetrahydro-3-furanyl]-1-[(4-methoxybenzyl)oxy]-4-methyl-5-hexen-3-ol | C20H29IO4 | 详情 | 详情 | |
| (XLII) | 57266 | (1S,2S)-1-{(2S)-2-[(3R,5S)-5-(iodomethyl)tetrahydro-3-furanyl]-2-[(4-methoxybenzyl)oxy]ethyl}-2-methyl-3-butenyl triisopropylsilyl ether; [((1S,2S)-1-{(2S)-2-[(3R,5S)-5-(iodomethyl)tetrahydro-3-furanyl]-2-[(4-methoxybenzyl)oxy]ethyl}-2-methyl-3-butenyl)oxy](triisopropyl)silane | C29H49IO4Si | 详情 | 详情 | |
| (XLIII) | 57267 | (2R,3S,5S)-5-[(3R,5S)-5-(iodomethyl)tetrahydro-3-furanyl]-5-[(4-methoxybenzyl)oxy]-2-methyl-3-[(triisopropylsilyl)oxy]pentanal | C28H47IO5Si | 详情 | 详情 | |
| (XLIV) | 57268 | (E,3S,4S,5S,7S)-7-[(3R,5S)-5-(iodomethyl)tetrahydro-3-furanyl]-7-[(4-methoxybenzyl)oxy]-1-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-2,4-dimethyl-5-[(triisopropylsilyl)oxy]-1-hepten-3-ol | C47H85IO7Si2 | 详情 | 详情 | |
| (XLV) | 11487 | (2S)-1-(tert-Butoxycarbonyl)hexahydro-2-pyridinecarboxylic acid | C11H19NO4 | 详情 | 详情 | |
| (XLVI) | 57269 | 1-(tert-butyl) 2-((1S,2E)-1-{(1S,2S,4S)-4-[(3R,5S)-5-(iodomethyl)tetrahydro-3-furanyl]-4-[(4-methoxybenzyl)oxy]-1-methyl-2-[(triisopropylsilyl)oxy]butyl}-3-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-2-methyl-2-propenyl) (2S)-1,2-piperidinedicarboxylate | C58H102INO10Si2 | 详情 | 详情 | |
| (XLVII) | 57270 | 1-(tert-butyl) 2-{(1S,2S,3S,5S,6R)-6-(hydroxymethyl)-5-[(4-methoxybenzyl)oxy]-1-((E)-2-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-1-methylethenyl)-2-methyl-3-[(triisopropylsilyl)oxy]-8-nonenyl} (2S)-1,2-piperidinedicarboxylate | C58H103NO10Si2 | 详情 | 详情 | |
| (XLVIII) | 57271 | 1-(tert-butyl) 2-{(1S,2S,3S,5S,6S)-6-formyl-5-[(4-methoxybenzyl)oxy]-1-((E)-2-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-1-methylethenyl)-2-methyl-3-[(triisopropylsilyl)oxy]-8-nonenyl} (2S)-1,2-piperidinedicarboxylate | C58H101NO10Si2 | 详情 | 详情 |
合成路线26
The condensation of carbaldehyde (XLVIII) with the chiral intermediate phosphonamide (XXXII), by means of BuLi, gives the adduct (XLIX), which is treated with phenyliodonium trifluoroacetate and AcOH to cleave the 1,3-dithiane ring and yield the carbaldehyde (L). The cyclocondensation of (L) with 2-(2,4-dimethoxybenzyloxy)acetic acid methyl ester (LI) by means of LDA, LiOH, TesOTf and 2-chloro-1-methylpyridinium iodide (CMPI) affords the macrolactone (LII), which is submitted to a sequence of deprotection (DDQ), oxidation (DMP), deprotection (TFA) and oxidation (DMP) to provide the tricarbonyl compound (LIII). A similar sequence (TFA, DMP, DDQ, and DMP) can also be used to obtain the tricarbonyl compound (LIII). Finally this compound is fully desilylated by means of HF in acetonitrile to provide the target FK-506.
| 【1】 Ragan, J.A.; The total synthesis of FK506 and an FKBP probe reagent, (C8,C9-13C2)-FK506. Diss Abstr Int B - Sci Eng 1991, 51, 8, 3849. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXXII) | 11491 | (3R,5S,6R,7S,9R)-6-[[tert-Butyl(dimethyl)silyl]oxy]-9-(1,3-dithian-2-yl)-5,7-dimethoxy-1,3-dimethyldecyl-N,N,N',N'-tetramethylphosphonic diamide | C28H61N2O4PS2Si | 详情 | 详情 | |
| (XLVIII) | 57271 | 1-(tert-butyl) 2-{(1S,2S,3S,5S,6S)-6-formyl-5-[(4-methoxybenzyl)oxy]-1-((E)-2-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-1-methylethenyl)-2-methyl-3-[(triisopropylsilyl)oxy]-8-nonenyl} (2S)-1,2-piperidinedicarboxylate | C58H101NO10Si2 | 详情 | 详情 | |
| (XLIX) | 57272 | 2-{(1S,2S,3S,5S,6R,7E,10S,12S,13R,14S,16R)-6-allyl-13-{[tert-butyl(dimethyl)silyl]oxy}-16-(1,3-dithian-2-yl)-12,14-dimethoxy-5-[(4-methoxybenzyl)oxy]-1-((E)-2-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-1-methylethenyl)-2,8,10-trimet | C82H149NO12S2Si3 | 详情 | 详情 | |
| (L) | 57273 | 2-{(1S,2S,3S,5S,6R,7E,10S,12S,13R,14S,16R)-6-allyl-13-{[tert-butyl(dimethyl)silyl]oxy}-12,14-dimethoxy-5-[(4-methoxybenzyl)oxy]-1-((E)-2-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-1-methylethenyl)-2,8,10,16-tetramethyl-17-oxo-3-[(tr | C79H143NO13Si3 | 详情 | 详情 | |
| (LI) | 57274 | methyl 2-[(2,4-dimethoxybenzyl)oxy]acetate | C12H16O5 | 详情 | 详情 | |
| (LII) | 57275 | (3S,4S,5S,7S,8R,12S,14S,15R,16S,18R,26aS)-8-allyl-15-{[tert-butyl(dimethyl)silyl]oxy}-20-[(2,4-dimethoxybenzyl)oxy]-14,16-dimethoxy-7-[(4-methoxybenzyl)oxy]-3-((E)-2-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-1-methylethenyl)-4,10,12,18-tetramethyl-19-[(triethylsilyl)oxy]-5-[(triisopropylsilyl)oxy]-5,6,7,8,11,12,13,14,15,16,17,18,19,20,24,25,26,26a-octadecahydro-3H-pyrido[2,1-c][1,4]oxazacyclotricosine-1,21(4H,23H)-dione | C91H161NO15Si4 | 详情 | 详情 | |
| (LIII) | 11499 | (3S,4S,5S,8R,12S,14S,15R,16S,18R,26aS)-8-Allyl-15-[[tert-butyl(dimethyl)silyl]oxy]-14,16-dimethoxy-3-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methylethenyl)-4,10,12,18-tetramethyl-5-[(triisopropylsilyl)oxy]-5,6,11,12,13,14,15,16,17,18,24,25,26,26a-tetradecahydro-3H-pyrido[2,1-c][1,4]oxazacyclotricosine-1,7,19,20,21(4H,8H,23H)-pentone | C68H123NO12Si3 | 详情 | 详情 |
合成路线27
Synthesis of the intermediate chiral tetrahydropyran-carboxylic acid methyl ester (VII): The selective reduction of the exocyclic double bond of the glycoside (I) with H2 over Pd/C in ethanol gives a mixture of the equatorial epimer (II) along with some axial compound that is eliminated by crystallization. The cleavage of the benzylidene protecting group of (II) with H2, over Pd/C in EtOH, followed by selective monoesterification of the primary OH group with PPh3, DIAD and benzoic acid yields the benzoate ester (III). The protection of (III) with Tbdms-Cl and imidazole affords the silyl ether (IV), which is debenzoylated by means of DIBAL in dichloromethane to afford the hydroxymethyl compound (V). The oxidation of (V) by means of RuCl3 and NaIO4 pin acetonitrile/CCl4 provides the chiral carboxylic acid (VI), which is finally esterified with CH3-I and K2CO3 in DMF to furnish the desired tetrahydropyran-carboxylic acid methyl ester (VII).
| 【1】 Smith, A.B. III; Hale, K.J.; An enantioselective synthesis of the C(10) to C(23) backbone of the potent immunosuppressant FK506. Tetrahedron Lett 1989, 30, 9, 1037. |
| 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) | 57276 | (4aR,6S,8aS)-7-methylene-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-6-yl methyl ether; (4aR,6S,8aS)-6-methoxy-7-methylene-2-phenylhexahydropyrano[3,2-d][1,3]dioxine | C15H18O4 | 详情 | 详情 | |
| (II) | 57277 | (4aR,6S,7R,8aS)-6-methoxy-7-methyl-2-phenylhexahydropyrano[3,2-d][1,3]dioxine; (4aR,6S,7R,8aS)-7-methyl-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-6-yl methyl ether | C15H20O4 | 详情 | 详情 | |
| (III) | 57278 | [(2R,3S,5R,6S)-3-hydroxy-6-methoxy-5-methyltetrahydro-2H-pyran-2-yl]methyl benzoate | C15H20O5 | 详情 | 详情 | |
| (IV) | 57279 | ((2R,3S,5R,6S)-3-{[tert-butyl(dimethyl)silyl]oxy}-6-methoxy-5-methyltetrahydro-2H-pyran-2-yl)methyl benzoate | C21H34O5Si | 详情 | 详情 | |
| (V) | 57280 | ((2R,3S,5R,6S)-3-{[tert-butyl(dimethyl)silyl]oxy}-6-methoxy-5-methyltetrahydro-2H-pyran-2-yl)methanol | C14H30O4Si | 详情 | 详情 | |
| (VI) | 57281 | (2S,3S,5R,6S)-3-{[tert-butyl(dimethyl)silyl]oxy}-6-methoxy-5-methyltetrahydro-2H-pyran-2-carboxylic acid | C14H28O5Si | 详情 | 详情 | |
| (VII) | 57282 | methyl (2S,3S,5R,6S)-3-{[tert-butyl(dimethyl)silyl]oxy}-6-methoxy-5-methyltetrahydro-2H-pyran-2-carboxylate | C15H30O5Si | 详情 | 详情 |
合成路线28
The reaction of the chiral propyl iodide (VIII) with KCN in hot DMF gives the chiral butyronitrile (IX), which is reduced with DIBAL in dichloromethane to yield the butyraldehyde (X). The reaction of (X) with CBr4, PPH3 and BuLi in THF/dichloromethane affords the chiral alkyne (XI), which is treated with Me3Al, Cp2ZrCl2 and BuLi in dichloroethane to provide the vinyl aluminate (XII). The condensation of (XII) with the chiral epoxide (XIII) in benzene gives the unsaturated 2-octenol (XIV), which is protected with BnBr and NaH to yield the benzyl ether (XV). The desilylation of (XV) by means of TBAF in THF afford the primary alcohol (XVI), which is treated with diphenyl disulfide and Bu3P in DMF to provide the thioether (XVII). The oxidation of (XVII) with oxone in THF/methanol/water gives the corresponding sulfone (XVIII), which is condensed with the intermediate desired tetrahydropyran-carboxylic acid methyl ester (VII) by means of BuLi in THF to yield the adduct (XIX). The removal of the sulfone group of (XIX) is performed by means of Bu3SnH and AIBN in refluxing toluene affording the ketonic intermediate (XX).
| 【1】 Smith, A.B. III; Hale, K.J.; An enantioselective synthesis of the C(10) to C(23) backbone of the potent immunosuppressant FK506. Tetrahedron Lett 1989, 30, 9, 1037. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 57282 | methyl (2S,3S,5R,6S)-3-{[tert-butyl(dimethyl)silyl]oxy}-6-methoxy-5-methyltetrahydro-2H-pyran-2-carboxylate | C15H30O5Si | 详情 | 详情 | |
| (VIII) | 57283 | tert-butyl{[(2R)-3-iodo-2-methylpropyl]oxy}diphenylsilane; tert-butyl(diphenyl)silyl (2R)-3-iodo-2-methylpropyl ether | C20H27IOSi | 详情 | 详情 | |
| (IX) | 57284 | (3S)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-methylbutanenitrile | C21H27NOSi | 详情 | 详情 | |
| (X) | 57285 | (3S)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-methylbutanal | C21H28O2Si | 详情 | 详情 | |
| (XI) | 57286 | tert-butyl(diphenyl)silyl (2S)-2-methyl-4-pentynyl ether; tert-butyl{[(2S)-2-methyl-4-pentynyl]oxy}diphenylsilane | C22H28OSi | 详情 | 详情 | |
| (XII) | 57287 | lithium butyl((E,4S)-5-{[tert-butyl(diphenyl)silyl]oxy}-2,4-dimethyl-1-pentenyl)dimethylaluminate(1-) | C29H46AlLiOSi | 详情 | 详情 | |
| (XIII) | 25266 | benzyl [(2S,3S)-3-[(benzyloxy)methyl]oxiranyl]methyl ether; (2S,3S)-2,3-bis[(benzyloxy)methyl]oxirane | C18H20O3 | 详情 | 详情 | |
| (XIV) | 57288 | (2S,3S,4E,7S)-1-(benzyloxy)-3-[(benzyloxy)methyl]-8-{[tert-butyl(diphenyl)silyl]oxy}-5,7-dimethyl-4-octen-2-ol | C41H52O4Si | 详情 | 详情 | |
| (XV) | 57289 | ({(2S,4E,6S,7S)-7,8-bis(benzyloxy)-6-[(benzyloxy)methyl]-2,4-dimethyl-4-octenyl}oxy)(tert-butyl)diphenylsilane; benzyl (2S,3S,4E,7S)-2-(benzyloxy)-3-[(benzyloxy)methyl]-8-{[tert-butyl(diphenyl)silyl]oxy}-5,7-dimethyl-4-octenyl ether | C48H58O4Si | 详情 | 详情 | |
| (XVI) | 57290 | (2S,4E,6S,7S)-7,8-bis(benzyloxy)-6-[(benzyloxy)methyl]-2,4-dimethyl-4-octen-1-ol | C32H40O4 | 详情 | 详情 | |
| (XVII) | 57291 | 1-({[(2S,3S,4E,7S)-2-(benzyloxy)-3-[(benzyloxy)methyl]-5,7-dimethyl-8-(phenylsulfanyl)-4-octenyl]oxy}methyl)benzene; benzyl (2S,3S,4E,7S)-2-(benzyloxy)-3-[(benzyloxy)methyl]-5,7-dimethyl-8-(phenylsulfanyl)-4-octenyl ether | C38H44O3S | 详情 | 详情 | |
| (XVIII) | 57292 | (2S,4E,6S,7S)-7,8-bis(benzyloxy)-6-[(benzyloxy)methyl]-2,4-dimethyl-4-octenyl phenyl sulfone; {(2S,4E,6S,7S)-7,8-bis(benzyloxy)-6-[(benzyloxy)methyl]-2,4-dimethyl-4-octenyl}(dioxo)phenyl-lambda~6~-sulfane | C38H44O5S | 详情 | 详情 | |
| (XIX) | 57293 | (3S,5E,7S,8S)-8,9-bis(benzyloxy)-7-[(benzyloxy)methyl]-1-((2S,3S,5R,6S)-3-{[tert-butyl(dimethyl)silyl]oxy}-6-methoxy-5-methyltetrahydro-2H-pyran-2-yl)-3,5-dimethyl-2-(phenylsulfonyl)-5-nonen-1-one | C52H70O9SSi | 详情 | 详情 | |
| (XX) | 57294 | (3S,5E,7S,8S)-8,9-bis(benzyloxy)-7-[(benzyloxy)methyl]-1-((2S,3S,5R,6S)-3-{[tert-butyl(dimethyl)silyl]oxy}-6-methoxy-5-methyltetrahydro-2H-pyran-2-yl)-3,5-dimethyl-5-nonen-1-one | C46H66O7Si | 详情 | 详情 |
合成路线29
The desilylation of (XX) by means of HF in pyridine gives the hydroxyketone (XXI), which is reduced with Me4NBH(OAc)3 and HOAc in acetonitrile to yield the chiral dihydroxy compound (XXII). The methylation of both OH groups of (XXII) by means of methyl iodide and NaH in DMF affords the fully methylated intermediate (XXIII), which is finally debenzylated in the usual way to provide the target chiral trihydroxyalkyl-tetrahydropyran intermediate (XXIV).
| 【1】 Smith, A.B. III; Hale, K.J.; An enantioselective synthesis of the C(10) to C(23) backbone of the potent immunosuppressant FK506. Tetrahedron Lett 1989, 30, 9, 1037. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XX) | 57294 | (3S,5E,7S,8S)-8,9-bis(benzyloxy)-7-[(benzyloxy)methyl]-1-((2S,3S,5R,6S)-3-{[tert-butyl(dimethyl)silyl]oxy}-6-methoxy-5-methyltetrahydro-2H-pyran-2-yl)-3,5-dimethyl-5-nonen-1-one | C46H66O7Si | 详情 | 详情 | |
| (XXI) | 57295 | (3S,5E,7S,8S)-8,9-bis(benzyloxy)-7-[(benzyloxy)methyl]-1-[(2S,3S,5R,6S)-3-hydroxy-6-methoxy-5-methyltetrahydro-2H-pyran-2-yl]-3,5-dimethyl-5-nonen-1-one | C40H52O7 | 详情 | 详情 | |
| (XXII) | 57296 | (2R,3S,5R,6S)-2-{(1S,3S,5E,7S,8S)-8,9-bis(benzyloxy)-7-[(benzyloxy)methyl]-1-hydroxy-3,5-dimethyl-5-nonenyl}-6-methoxy-5-methyltetrahydro-2H-pyran-3-ol | C40H54O7 | 详情 | 详情 | |
| (XXIII) | 57297 | (2R,3S,5R,6S)-2-{(1S,3S,5E,7S,8S)-8,9-bis(benzyloxy)-7-[(benzyloxy)methyl]-1-methoxy-3,5-dimethyl-5-nonenyl}-3,6-dimethoxy-5-methyltetrahydro-2H-pyran; benzyl (2S,3S,4E,7S,9S)-2-(benzyloxy)-3-[(benzyloxy)methyl]-9-[(2R,3S,5R,6S)-3,6-dimethoxy-5-methyltetrahydro-2H-pyran-2-yl]-9-methoxy-5,7-dimethyl-4-nonenyl ether | C42H58O7 | 详情 | 详情 | |
| (XXIV) | 57298 | (2S,3S)-3-{(E,4S,6S)-6-[(2R,3S,5R,6S)-3,6-dimethoxy-5-methyltetrahydro-2H-pyran-2-yl]-6-methoxy-2,4-dimethyl-1-hexenyl}-1,2,4-butanetriol | C21H40O7 | 详情 | 详情 |
合成路线30
The intermediate (IX) has been obtained as follows: The reduction of the spiroenone (I) with Li(s-Bu)3BH gives the corresponding alcohol that is protected with Tbdms-Cl and imidazole to yield the silyl ether (II). The oxidation of the vinyl group of (II) with OsO4, NaIO4 and NMO affords the carbaldehyde (III), which is condensed with the vinyl bromide (IV) by means of t-BuLi to provide the alcohol (V). The esterification of the alcohol (V) with the chiral piperidine-2-carboxylic acid (VI) by means of DCC and DMAP gives the ester (VII), which is selectively monodesilylated by means of TBAF to yield the alcohol (VIII). Finally this alcohol is oxidized by means of Dess Martin periodinane (DMP) to afford the target spiroenone (IX).
| 【1】 Gleason, J.L.; The total synthesis of FK-506 and its spiroketal analogs. Diss Abstr Int B - Sci Eng 1994, 54, 12, Part 1, 6206. |
| 【2】 Ireland, R.E.; et al.; A total synthesis of FK-506. J Org Chem 1996, 61, 20, 6856. |
| 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) | 57299 | (4S,6R)-2,2-dimethyl-4-[(1S)-1-methyl-2-propenyl]-1,3,7-trioxaspiro[5.5]undec-10-en-9-one | C14H20O4 | 详情 | 详情 | |
| (II) | 57300 | tert-butyl(dimethyl)silyl (4S,6R,9R)-2,2-dimethyl-4-[(1S)-1-methyl-2-propenyl]-1,3,7-trioxaspiro[5.5]undec-10-en-9-yl ether; tert-butyl({(4S,6R,9R)-2,2-dimethyl-4-[(1S)-1-methyl-2-propenyl]-1,3,7-trioxaspiro[5.5]undec-10-en-9-yl}oxy)dimethylsilane | C20H36O4Si | 详情 | 详情 | |
| (III) | 57301 | (2R)-2-((4S,6R,9R)-9-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethyl-1,3,7-trioxaspiro[5.5]undec-10-en-4-yl)propanal | C19H34O5Si | 详情 | 详情 | |
| (IV) | 17368 | (1R,2R,5R)-5-[(E)-2-bromo-1-propenyl]-2-[[tert-butyl(diphenyl)silyl]oxy]cyclohexyl methyl ether; ([(1R,2R,4R)-4-[(E)-2-bromo-1-propenyl]-2-methoxycyclohexyl]oxy)(tert-butyl)diphenylsilane | C26H35BrO2Si | 详情 | 详情 | |
| (V) | 57302 | (E,3S,4S)-4-((4R,6R,9R)-9-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethyl-1,3,7-trioxaspiro[5.5]undec-10-en-4-yl)-1-((1R,3R,4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-methoxycyclohexyl)-2-methyl-1-penten-3-ol | C45H70O7Si2 | 详情 | 详情 | |
| (VI) | 11487 | (2S)-1-(tert-Butoxycarbonyl)hexahydro-2-pyridinecarboxylic acid | C11H19NO4 | 详情 | 详情 | |
| (VII) | 57303 | 1-(tert-butyl) 2-[(1S,2E)-1-[(1R)-1-((4R,6R,9R)-9-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethyl-1,3,7-trioxaspiro[5.5]undec-10-en-4-yl)ethyl]-3-((1R,3R,4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-methoxycyclohexyl)-2-methyl-2-propenyl] (2S)-1,2-piperid | C56H87NO10Si2 | 详情 | 详情 | |
| (VIII) | 57304 | 1-(tert-butyl) 2-((1S,2E)-3-((1R,3R,4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-methoxycyclohexyl)-1-{(1R)-1-[(4R,6R,9R)-9-hydroxy-2,2-dimethyl-1,3,7-trioxaspiro[5.5]undec-10-en-4-yl]ethyl}-2-methyl-2-propenyl) (2S)-1,2-piperidinedicarboxylate | C50H73NO10Si | 详情 | 详情 | |
| (IX) | 57305 | 1-(tert-butyl) 2-((1S,2E)-3-((1R,3R,4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-methoxycyclohexyl)-1-{(1R)-1-[(4R,6R)-2,2-dimethyl-9-oxo-1,3,7-trioxaspiro[5.5]undec-10-en-4-yl]ethyl}-2-methyl-2-propenyl) (2S)-1,2-piperidinedicarboxylate | C50H71NO10Si | 详情 | 详情 |
合成路线31
The selective protection of the primary OH group of hydroxymethyl tetrahydropyran-3-ol (X) with trityl chloride and pyridine gives the cyclohexanol (XI), which is methylated by means of methyl iodide and NaH to yield the dimethoxy derivative (XII). The cleavage of the trityl group of (XII) by means of HCl in methanol affords the methanol derivative (XIII), which is oxidized by means of DMP to the corresponding carbaldehyde (XIV). The condensation of (XIV) with 2(S)-methyl-5-(trimethylsilyl)-4-pentynyl iodide (XV) by means of t-BuLi and MgBr2 provides the acetylenic alcohol (XVI), which is methylated with methyl iodide and NaH giving the trimethoxy derivative (XVII). The hydrolysis of the acetal group of (XVII) with Ac-OH yields the hemiacetal (XVIII), which is olefinated with the phosphorane (XIX) in refluxing benzene to afford the unsaturated tridecanoic ester (XX). The reduction of (XX) with DIBAL provides the unsaturated diol (XXI), which is submitted to an asymmetric dihydroxylation by means of Ti(O-iPr)4, (+)-diethyl tartrate and tert-butyl hydroperoxide to give the chiral tetrahydropyran diol (XXII). The iodination of the triple bond of (XXII) with AlMe3, Cp2ZrCl2 and iodine yields the iodovinyl compound (XXIII), which is protected by means of Tbdms-Cl, DMAP and imidazole to afford the silylated compound (XXIV). The condensation of (XXIV) with the intermediate spiroenone (IX) by means of t-BuLi provides the open chain intermediate (XXV).
| 【1】 Gleason, J.L.; The total synthesis of FK-506 and its spiroketal analogs. Diss Abstr Int B - Sci Eng 1994, 54, 12, Part 1, 6206. |
| 【2】 Ireland, R.E.; et al.; A total synthesis of FK-506. J Org Chem 1996, 61, 20, 6856. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 57305 | 1-(tert-butyl) 2-((1S,2E)-3-((1R,3R,4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-methoxycyclohexyl)-1-{(1R)-1-[(4R,6R)-2,2-dimethyl-9-oxo-1,3,7-trioxaspiro[5.5]undec-10-en-4-yl]ethyl}-2-methyl-2-propenyl) (2S)-1,2-piperidinedicarboxylate | C50H71NO10Si | 详情 | 详情 | |
| (X) | 57306 | (2R,3S,5R,6S)-2-(hydroxymethyl)-6-methoxy-5-methyltetrahydro-2H-pyran-3-ol | C8H16O4 | 详情 | 详情 | |
| (XI) | 57307 | (2R,3S,5R,6S)-6-methoxy-5-methyl-2-[(trityloxy)methyl]tetrahydro-2H-pyran-3-ol | C27H30O4 | 详情 | 详情 | |
| (XII) | 57308 | (2S,3R,5S,6R)-2,5-dimethoxy-3-methyl-6-[(trityloxy)methyl]tetrahydro-2H-pyran; [(2R,3S,5R,6S)-3,6-dimethoxy-5-methyltetrahydro-2H-pyran-2-yl]methyl trityl ether | C28H32O4 | 详情 | 详情 | |
| (XIII) | 57309 | [(2R,3S,5R,6S)-3,6-dimethoxy-5-methyltetrahydro-2H-pyran-2-yl]methanol | C9H18O4 | 详情 | 详情 | |
| (XIV) | 57310 | (2S,3S,5R,6S)-3,6-dimethoxy-5-methyltetrahydro-2H-pyran-2-carbaldehyde | C9H16O4 | 详情 | 详情 | |
| (XV) | 57311 | [(4S)-5-iodo-4-methyl-1-pentynyl](trimethyl)silane | C9H17ISi | 详情 | 详情 | |
| (XVI) | 57312 | (1S,3S)-1-[(2R,3S,5R,6S)-3,6-dimethoxy-5-methyltetrahydro-2H-pyran-2-yl]-3-methyl-6-(trimethylsilyl)-5-hexyn-1-ol | C18H34O4Si | 详情 | 详情 | |
| (XVII) | 57313 | (1S,3S)-1-[(2R,3S,5R,6S)-3,6-dimethoxy-5-methyltetrahydro-2H-pyran-2-yl]-3-methyl-6-(trimethylsilyl)-5-hexynyl methyl ether; {(4S,6S)-6-[(2R,3S,5R,6S)-3,6-dimethoxy-5-methyltetrahydro-2H-pyran-2-yl]-6-methoxy-4-methyl-1-hexynyl}(trimethyl)silane | C19H36O4Si | 详情 | 详情 | |
| (XVIII) | 57314 | (3R,5S,6R)-5-methoxy-6-[(1S,3S)-1-methoxy-3-methyl-6-(trimethylsilyl)-5-hexynyl]-3-methyltetrahydro-2H-pyran-2-ol | C18H34O4Si | 详情 | 详情 | |
| (XIX) | 14182 | ethyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate; (Carbethoxymethylene)triphenylphosphorane | 1099-45-2 | C22H21O2P | 详情 | 详情 |
| (XX) | 57315 | ethyl (E,4R,6S,7R,8S,10S)-7-hydroxy-6,8-dimethoxy-4,10-dimethyl-13-(trimethylsilyl)-2-tridecen-12-ynoate | C22H40O5Si | 详情 | 详情 | |
| (XXI) | 57316 | (E,4R,6S,7R,8S,10S)-6,8-dimethoxy-4,10-dimethyl-13-(trimethylsilyl)-2-tridecen-12-yne-1,7-diol | C20H38O4Si | 详情 | 详情 | |
| (XXII) | 57317 | (1S)-1-{(2R,3R,5S,6R)-5-methoxy-6-[(1S,3S)-1-methoxy-3-methyl-6-(trimethylsilyl)-5-hexynyl]-3-methyltetrahydro-2H-pyran-2-yl}-1,2-ethanediol | C20H38O5Si | 详情 | 详情 | |
| (XXIII) | 57318 | (1S)-1-{(2R,3R,5S,6R)-6-[(1S,3S,5E)-6-iodo-1-methoxy-3,5-dimethyl-5-hexenyl]-5-methoxy-3-methyltetrahydro-2H-pyran-2-yl}-1,2-ethanediol | C18H33IO5 | 详情 | 详情 | |
| (XXIV) | 57319 | (2R,3S,5R,6R)-6-((1S)-1,2-bis{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-[(1S,3S,5E)-6-iodo-1-methoxy-3,5-dimethyl-5-hexenyl]-5-methyltetrahydro-2H-pyran-3-yl methyl ether; (5S)-5-{(2R,3R,5S,6R)-6-[(1S,3S,5E)-6-iodo-1-methoxy-3,5-dimethyl-5-hexenyl]-5-methoxy-3-methyltetrahydro-2H-pyran-2-yl}-2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecane | C30H61IO5Si2 | 详情 | 详情 | |
| (XXV) | 57320 | 2-[(1S,2E)-1-[(1R)-1-((4S,6R,11R)-11-{(E,4S,6S)-6-[(2R,3S,5R,6R)-6-((1S)-1,2-bis{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-methoxy-5-methyltetrahydro-2H-pyran-2-yl]-6-methoxy-2,4-dimethyl-1-hexenyl}-2,2-dimethyl-9-oxo-1,3,7-trioxaspiro[5.5]undec-4-yl)ethyl]-3-((1R,3R,4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-methoxycyclohexyl)-2-methyl-2-propenyl] 1-(tert-butyl) (2S)-1,2-piperidinedicarboxylate | C80H133NO15Si3 | 详情 | 详情 |
合成路线32
The selective desilylation of (XXV) by means of TBAF gives the diol (XXVI), which is oxidized by means of NaClO and NaClO2 to yield the hydroxyacid (XXVII), which is methylated with diazomethane to afford the methyl ester (XXVIII). The cyclization of (XXVIII) by means of LiOH and Tes-OTf provides the macrocyclic alpha-hydroxy ketonic intermediate (XXIX), which is oxidized with DMP to the alpha diketonic intermediate (XXX).
| 【1】 Gleason, J.L.; The total synthesis of FK-506 and its spiroketal analogs. Diss Abstr Int B - Sci Eng 1994, 54, 12, Part 1, 6206. |
| 【2】 Ireland, R.E.; et al.; A total synthesis of FK-506. J Org Chem 1996, 61, 20, 6856. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXV) | 57320 | 2-[(1S,2E)-1-[(1R)-1-((4S,6R,11R)-11-{(E,4S,6S)-6-[(2R,3S,5R,6R)-6-((1S)-1,2-bis{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-methoxy-5-methyltetrahydro-2H-pyran-2-yl]-6-methoxy-2,4-dimethyl-1-hexenyl}-2,2-dimethyl-9-oxo-1,3,7-trioxaspiro[5.5]undec-4-yl)ethyl]-3-((1R,3R,4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-methoxycyclohexyl)-2-methyl-2-propenyl] 1-(tert-butyl) (2S)-1,2-piperidinedicarboxylate | C80H133NO15Si3 | 详情 | 详情 | |
| (XXVI) | 57321 | 1-(tert-butyl) 2-((1S,2E)-3-((1R,3R,4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-methoxycyclohexyl)-1-{(1R)-1-[(4S,6R,11R)-11-((E,4S,6S)-6-{(2R,3S,5R,6R)-6-[(1S)-1,2-dihydroxyethyl]-3-methoxy-5-methyltetrahydro-2H-pyran-2-yl}-6-methoxy-2,4-dimethyl-1-hexenyl)-2,2-dimethyl-9-oxo-1,3,7-trioxaspiro[5.5]undec-4-yl]ethyl}-2-methyl-2-propenyl) (2S)-1,2-piperidinedicarboxylate | C68H105NO15Si | 详情 | 详情 | |
| (XXVII) | 57322 | (2R)-2-[(2R,3R,5S,6R)-6-((1S,3S,5E)-6-{(4S,6R,11R)-4-[(1R,2S,3E)-2-({[(2S)-1-(tert-butoxycarbonyl)piperidinyl]carbonyl}oxy)-4-((1R,3R,4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-methoxycyclohexyl)-1,3-dimethyl-3-butenyl]-2,2-dimethyl-9-oxo-1,3,7-trioxaspiro[5.5]undec-11-yl}-1-methoxy-3,5-dimethyl-5-hexenyl)-5-methoxy-3-methyltetrahydro-2H-pyran-2-yl]-2-hydroxyethanoic acid | C68H103NO16Si | 详情 | 详情 | |
| (XXVIII) | 57323 | 1-(tert-butyl) 2-((1S,2E)-3-((1R,3R,4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-methoxycyclohexyl)-1-{(1R)-1-[(4S,6R,11R)-11-((E,4S,6S)-6-{(2R,3S,5R,6R)-6-[(1R)-1-hydroxy-2-methoxy-2-oxoethyl]-3-methoxy-5-methyltetrahydro-2H-pyran-2-yl}-6-methoxy-2,4-dimethyl-1-hexenyl)-2,2-dimethyl-9-oxo-1,3,7-trioxaspiro[5.5]undec-4-yl]ethyl}-2-methyl-2-propenyl) (2S)-1,2-piperidinedicarboxylate | C69H105NO16Si | 详情 | 详情 | |
| (XXIX) | 57324 | (1R,6R,10S,12S,13R,14S,16R,17R,18R,25S,28S,29R,30R)-28-[(E)-2-((1R,3R,4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-methoxycyclohexyl)-1-methylethenyl]-18-hydroxy-12,14-dimethoxy-8,10,16,29,32,32-hexamethyl-2,27,31,33,35-pentaoxa-20-azapentacyclo[28.3.1.1~13,17~.0~1,6~.0~20,25~]pentatriacont-7-ene-4,19,26-trione | C63H93NO13Si | 详情 | 详情 | |
| (XXX) | 57325 | (1R,6R,10S,12S,13R,14S,16R,17R,25S,28S,29R,30R)-28-[(E)-2-((1R,3R,4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-methoxycyclohexyl)-1-methylethenyl]-12,14-dimethoxy-8,10,16,29,32,32-hexamethyl-2,27,31,33,35-pentaoxa-20-azapentacyclo[28.3.1.1~13,17~.0~1,6~.0~20,25~]pentatriacont-7-ene-4,18,19,26-tetrone | C63H91NO13Si | 详情 | 详情 |
合成路线33
The reduction of the tetrahydropyranone group of (XXX) by means of Li(s-Bu)3BH gives the tetrahydropyranol (XXXI), which is iodinated by means of PPh3 and iodine to give the iodo derivative (XXXII). The reaction of the alpha diketonic group of (XXXII) with KHMDS and TesCl yields the silyl enol ether (XXXIII). The fragmentation of the iodinated spiroketal group of (XXXIII) was achieved using a Zn-Ag couple, that was prepared in situ by reduction of ZnCl2 and AgOAc by means of C8K (a mixture of graphite and potassium heated at 150 C under argon) to provide the silylated precursor (XXXIV). Finally the silylated enol ether group of (XXXIV) is hydroxylated by means of dimethyldioxirane and desilylated by means of HF to afford the target FK-506.
| 【1】 Gleason, J.L.; The total synthesis of FK-506 and its spiroketal analogs. Diss Abstr Int B - Sci Eng 1994, 54, 12, Part 1, 6206. |
| 【2】 Ireland, R.E.; et al.; A total synthesis of FK-506. J Org Chem 1996, 61, 20, 6856. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXX) | 57325 | (1R,6R,10S,12S,13R,14S,16R,17R,25S,28S,29R,30R)-28-[(E)-2-((1R,3R,4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-methoxycyclohexyl)-1-methylethenyl]-12,14-dimethoxy-8,10,16,29,32,32-hexamethyl-2,27,31,33,35-pentaoxa-20-azapentacyclo[28.3.1.1~13,17~.0~1,6~.0~20,25~]pentatriacont-7-ene-4,18,19,26-tetrone | C63H91NO13Si | 详情 | 详情 | |
| (XXXI) | 57326 | (1R,4R,6R,10S,12S,13R,14S,16R,17R,25S,28S,29R,30R)-28-[(E)-2-((1R,3R,4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-methoxycyclohexyl)-1-methylethenyl]-4-hydroxy-12,14-dimethoxy-8,10,16,29,32,32-hexamethyl-2,27,31,33,35-pentaoxa-20-azapentacyclo[28.3.1.1~13,17~.0~1,6~.0~20,25~]pentatriacont-7-ene-18,19,26-trione | C63H93NO13Si | 详情 | 详情 | |
| (XXXII) | 57327 | (1R,4S,6R,10S,12S,13R,14S,16R,17R,25S,28S,29R,30R)-28-[(E)-2-((1R,3R,4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-methoxycyclohexyl)-1-methylethenyl]-4-iodo-12,14-dimethoxy-8,10,16,29,32,32-hexamethyl-2,27,31,33,35-pentaoxa-20-azapentacyclo[28.3.1.1~13,17~.0~1,6~.0~20,25~]pentatriacont-7-ene-18,19,26-trione | C63H92INO12Si | 详情 | 详情 | |
| (XXXIII) | 57328 | (1R,4S,6R,10S,12S,13R,14S,16R,25S,28S,29R,30R)-28-[(E)-2-((1R,3R,4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-methoxycyclohexyl)-1-methylethenyl]-4-iodo-12,14-dimethoxy-8,10,16,29,32,32-hexamethyl-18-[(triethylsilyl)oxy]-2,27,31,33,35-pentaoxa-20-azapentacyclo[28.3.1.1~13,17~.0~1,6~.0~20,25~]pentatriaconta-7,17-diene-19,26-dione | C69H106INO12Si2 | 详情 | 详情 | |
| (XXXIV) | 57329 | (9S,12S,13R,14S,17R,21S,23S,24R,25S,27R)-17-allyl-12-[(E)-2-((1R,3R,4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-methoxycyclohexyl)-1-methylethenyl]-14-hydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-2-[(triethylsilyl)oxy]-11,28-dioxa-4-azatricyclo[22.3.1.0~4,9~]octacosa-1,18-diene-3,10,16-trione | C66H101NO11Si2 | 详情 | 详情 |
合成路线34
Synthesis of the intermediate butyraldehyde (X): The Sharpless asymmetric epoxidation of 2(E)-buten-1-ol by means of t-Bu-OOH and D-(-9-diisopropyl tartrate gives the epoxy alcohol (II), which is treated with Tbdps-Cl, TEA and DMAP to yield the silyl ether (III) The condensation of (III) with 1,3-dithiane (IV) by means of BuLi in THF/HMPA affords the cyclic thioketal (V), which is deprotected by means of TBAF in THF, affording the diol (VI). The reaction of (VI) with 4-methoxybenzaldehyde dimethylacetal (VII) by means of TsOH in DMF provides the benzylidene ketal (VIII), which is submitted to a selective opening by means of DIBAL in dichloromethane to give the secondary benzyl ether (IX). Finally this compound is oxidized with SO3/Pyridine and TEA in DMSO/dichloromethane to obtain the target intermediate, the chiral butyraldehyde (X).
| 【1】 Chen, K.; Formal total synthesis of (-)-FK506. Diss Abstr Int B - Sci Eng 1993, 53, 9, 4663. |
| 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) | 54882 | 2-Butene-1-ol; Crotyl Alcohol; trans-Propenylcarbinol | 504-61-0 | C4H8O | 详情 | 详情 |
| (II) | 57330 | [(2R,3R)-3-methyloxiranyl]methanol | C4H8O2 | 详情 | 详情 | |
| (III) | 14956 | tert-butyl[[(2R,3R)-3-methyloxiranyl]methoxy]diphenylsilane; tert-butyl(diphenyl)silyl [(2R,3R)-3-methyloxiranyl]methyl ether | C20H26O2Si | 详情 | 详情 | |
| (IV) | 42372 | 1,3-dithiane | 505-23-7 | C4H8S2 | 详情 | 详情 |
| (V) | 57331 | (2S,3S)-1-{[tert-butyl(diphenyl)silyl]oxy}-3-(1,3-dithian-2-yl)-2-butanol | C24H34O2S2Si | 详情 | 详情 | |
| (VI) | 57332 | (2S,3S)-3-(1,3-dithian-2-yl)-1,2-butanediol | C8H16O2S2 | 详情 | 详情 | |
| (VII) | 26485 | 1-(dimethoxymethyl)-4-methoxybenzene | 2186-92-7 | C10H14O3 | 详情 | 详情 |
| (VIII) | 57333 | (4S)-4-[(1S)-1-(1,3-dithian-2-yl)ethyl]-2-(4-methoxyphenyl)-1,3-dioxolane; 4-{(4S)-4-[(1S)-1-(1,3-dithian-2-yl)ethyl]-1,3-dioxolan-2-yl}phenyl methyl ether | C16H22O3S2 | 详情 | 详情 | |
| (IX) | 57334 | (2S,3S)-3-(1,3-dithian-2-yl)-2-[(4-methoxybenzyl)oxy]-1-butanol | C16H24O3S2 | 详情 | 详情 | |
| (X) | 57335 | (2S,3S)-3-(1,3-dithian-2-yl)-2-[(4-methoxybenzyl)oxy]butanal | C16H22O3S2 | 详情 | 详情 |
合成路线35
Synthesis of the intermediate 14-iodo-10-tetradecenal dimethylacetal (XXI): The reaction of the chiral trihydroxy compound (XI) with 2,4-dimethyl-3-pentanone dimethyl acetal (XII) by means of TsOH in THF gives the ketal (XIII), which is treated with TsCl, TEA and DMAP in dichloromethane to yield the silyl ether (XIV). The condensation of (XIV) with ethynyl lithium (XV) in DMSO affords the propargyl derivative (XVI). The reduction of (XVI) with H2 over Lindlar catalyst in hexane containing quinoline provides the allyl derivative (XVII), which is condensed with propane-1,3-dithiol and BF3/Et2O in dichloromethane to give the chiral hydroxy dithiane (XVIII). The cleavage of the ketal group of (XVIII) by means of TsOH in methanol, followed by reaction of the intermediate diol with TsCl and pyridine yields the primary monotosylate (XIX), which is treated with Tbdms-OTf and lutidine in dichloromethane to afford the bis silyl ether (XX). Finally, this compound is iodinated by means of NaI, Cu and AgNO3 in hot acetonitrile/methanol to provide the desired intermediate 14-iodo-10-tetradecenal dimethylacetal (XXI).
| 【1】 Chen, K.; Formal total synthesis of (-)-FK506. Diss Abstr Int B - Sci Eng 1993, 53, 9, 4663. |
| 【2】 Smith, A.B. III; et al.; Formal total synthesis of FK506. Concise construction of the C(10)-C(34) segment via an effective coupling tactic. Tetrahedron Lett 1994, 35, 25, 4271. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 57298 | (2S,3S)-3-{(E,4S,6S)-6-[(2R,3S,5R,6S)-3,6-dimethoxy-5-methyltetrahydro-2H-pyran-2-yl]-6-methoxy-2,4-dimethyl-1-hexenyl}-1,2,4-butanetriol | C21H40O7 | 详情 | 详情 | |
| (XII) | 57336 | 3,3-dimethoxy-2,4-dimethylpentane; 1-isopropyl-1-methoxy-2-methylpropyl methyl ether | C9H20O2 | 详情 | 详情 | |
| (XIII) | 57337 | (2S,3E,6S,8S)-2-[(4S)-2,2-diisopropyl-1,3-dioxolan-4-yl]-8-[(2R,3S,5R,6S)-3,6-dimethoxy-5-methyltetrahydro-2H-pyran-2-yl]-8-methoxy-4,6-dimethyl-3-octen-1-ol | C28H52O7 | 详情 | 详情 | |
| (XIV) | 57338 | (2S,3E,6S,8S)-2-[(4S)-2,2-diisopropyl-1,3-dioxolan-4-yl]-8-[(2R,3S,5R,6S)-3,6-dimethoxy-5-methyltetrahydro-2H-pyran-2-yl]-8-methoxy-4,6-dimethyl-3-octenyl 4-methylbenzenesulfonate | C35H58O9S | 详情 | 详情 | |
| (XV) | 17461 | ethynyllithium | C2HLi | 详情 | 详情 | |
| (XVI) | 57339 | (2R,3S,5R,6S)-2-{(1S,3S,5E,7R)-7-[(4S)-2,2-diisopropyl-1,3-dioxolan-4-yl]-1-methoxy-3,5-dimethyl-5-decen-9-ynyl}-3,6-dimethoxy-5-methyltetrahydro-2H-pyran; (1S,3S,5E,7R)-7-[(4S)-2,2-diisopropyl-1,3-dioxolan-4-yl]-1-[(2R,3S,5R,6S)-3,6-dimethoxy-5-methyltetrahydro-2H-pyran-2-yl]-3,5-dimethyl-5-decen-9-ynyl methyl ether | C30H52O6 | 详情 | 详情 | |
| (XVII) | 57340 | (2R,3S,5R,6S)-2-{(1S,3S,5E,7R)-7-[(4S)-2,2-diisopropyl-1,3-dioxolan-4-yl]-1-methoxy-3,5-dimethyl-5,9-decadienyl}-3,6-dimethoxy-5-methyltetrahydro-2H-pyran; (1S,3S,5E,7R)-7-[(4S)-2,2-diisopropyl-1,3-dioxolan-4-yl]-1-[(2R,3S,5R,6S)-3,6-dimethoxy-5-methyltetrahydro-2H-pyran-2-yl]-3,5-dimethyl-5,9-decadienyl methyl ether | C30H54O6 | 详情 | 详情 | |
| (XVIII) | 57341 | (2R,4S,5R,6S,8S,10E,12R)-12-[(4S)-2,2-diisopropyl-1,3-dioxolan-4-yl]-2-(1,3-dithian-2-yl)-4,6-dimethoxy-8,10-dimethyl-10,14-pentadecadien-5-ol | C32H58O5S2 | 详情 | 详情 | |
| (XIX) | 57342 | (2S,3R,4E,7S,9S,10R,11S,13R)-3-allyl-13-(1,3-dithian-2-yl)-2,10-dihydroxy-9,11-dimethoxy-5,7-dimethyl-4-tetradecenyl 4-methylbenzenesulfonate | C32H52O7S3 | 详情 | 详情 | |
| (XX) | 57343 | (2S,3R,4E,7S,9S,10R,11S,13R)-3-allyl-2,10-bis{[tert-butyl(dimethyl)silyl]oxy}-13-(1,3-dithian-2-yl)-9,11-dimethoxy-5,7-dimethyl-4-tetradecenyl 4-methylbenzenesulfonate | C44H80O7S3Si2 | 详情 | 详情 | |
| (XXI) | 57344 | (1S,2R,3E,6S,8S,9R,10S,12R)-2-allyl-9-{[tert-butyl(dimethyl)silyl]oxy}-1-(iodomethyl)-8,10,13,13-tetramethoxy-4,6,12-trimethyl-3-tridecenyl tert-butyl(dimethyl)silyl ether; (5S,6R,7E,10S,12S,13R)-6-allyl-5-(iodomethyl)-12-methoxy-2,2,3,3,8,10,15,15,16,16-decamethyl-13-[(1S,3R)-1,4,4-trimethoxy-3-methylbutyl]-4,14-dioxa-3,15-disila-7-heptadecene | C36H73IO6Si2 | 详情 | 详情 |
合成路线36
The condensation of sultam (XXII) with propenoyl chloride (XXIII) by means of TEA in dichloromethane gives the acryloyl sultam (XXIV), which is submitted to a Diels Alder cyclization with butadiene (XXV) by means of EtAlCl2 in dichloromethane to yield the chiral cyclohexenylcarbonyl derivative (XXVI). The hydrolysis of (XXVI) with LiOH in THF affords 3-cyclohexene-1(R)-carboxylic acid (XXVII), which is treated with I2, KI, NaHCO3 and DBU to provide the bicyclic lactone (XXVIII). The reduction of (XXVIII) with LiAlH4 in THF gives the chiral diol (XXIX), which is treated with diphenyl disulfide and tributylphosphine to yield the phenyl thioether (XXX). The methylation of the OH group of (XXX) with methyl iodide and KOH in DMSO afford the methoxy derivative (XXXI). The oxidation of (XXXI) with oxone in THF/methanol provides the sulfone (XXXII), which is submitted to hydroboration with BH3/Me2S and tBu-OOH in THF to give the chiral 4-hydroxy-3-methoxycyclohexylmethyl sulfone (XXXIII). The reaction of (XXXIII) with Tbdps-Cl and imidazole in DMF yields the silyl ether (XXXIV), which is condensed with the intermediate butyraldehyde (X) by means of BuLi in THF to afford the chiral pentanol derivative (XXXV). The oxidation of (XXXV) with TFAA and DMSO in dichloromethane provides the corresponding ketone (XXXVI), which is desulfonated by means of aluminum amalgam in refluxing THF/water to give the ketone (XXXVII). The reaction of (XXXVII) with Tf2N-Ph and KHMDS in THF yields the triflate enol ester (XXXVIII), which is methylated with Me-Li and CuI in THF to afford the unsaturated dithiane derivative (XXXIX). The reaction of (XXXIX) with NaH and Tips-OTf in HMPA provides the triisopropylsilyl ether (XL) (1) (Scheme 12407109c). The condensation of (XL) with the intermediate 14-iodo-10-tetradecenal dimethylacetal (XXI) by means of BuLi in THF/HMPA gives the adduct (XLI), which is desulfurized by means of NCS and AgNO3 in acetone/THF/water to yield the ketonic product (XLII). The cleavage of the 4-methoxybenzyl group of (XLII) by means of DDQ in dichloromethane affords the beta-hydroxyketone (XLIII). The reduction of the ketonic group of (XLIII) with LiAlH4 and LiI in ethyl ether provides the dihydroxy compound (XLIV), which is selectively monoprotected with Tips-OTf and 2,6-lutidine in dichloromethane to give the intermediate (XLV).
| 【1】 Chen, K.; Formal total synthesis of (-)-FK506. Diss Abstr Int B - Sci Eng 1993, 53, 9, 4663. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 57335 | (2S,3S)-3-(1,3-dithian-2-yl)-2-[(4-methoxybenzyl)oxy]butanal | C16H22O3S2 | 详情 | 详情 | |
| (XXII) | 24401 | 1,7,7-Trimethylbicyclo[2,2,1]heptane-1',2-sultam; (1S)-(-)-2,10-Camphorsultam | C10H17NO2S | 详情 | 详情 | |
| (XXIII) | 11577 | Acryloyl chloride; Acrylyl chloride;2-Propenoyl chloride | 814-68-6 | C3H3ClO | 详情 | 详情 |
| (XXIV) | 57357 | 4-acryloyl-10,10-dimethyl-3lambda~6~-thia-4-azatricyclo[5.2.1.0~1,5~]decane-3,3-dione | C13H19NO3S | 详情 | 详情 | |
| (XXV) | 11579 | 1,3-Butadiene; Butadiene | 106-99-0 | C4H6 | 详情 | 详情 |
| (XXVI) | 57358 | 4-[(1R)-3-cyclohexen-1-ylcarbonyl]-10,10-dimethyl-3lambda~6~-thia-4-azatricyclo[5.2.1.0~1,5~]decane-3,3-dione | C17H25NO3S | 详情 | 详情 | |
| (XXVII) | 11581 | (1R)-3-Cyclohexene-1-carboxylic acid | C7H10O2 | 详情 | 详情 | |
| (XXVIII) | 11583 | (1R,5R)-6-Oxabicyclo[3.2.1]oct-3-en-7-one | C7H8O2 | 详情 | 详情 | |
| (XXIX) | 57345 | (1R,5R)-5-(hydroxymethyl)-2-cyclohexen-1-ol | C7H12O2 | 详情 | 详情 | |
| (XXX) | 57346 | (1R,5R)-5-[(phenylsulfanyl)methyl]-2-cyclohexen-1-ol | C13H16OS | 详情 | 详情 | |
| (XXXI) | 57347 | 1-({[(1R,5R)-5-methoxy-3-cyclohexen-1-yl]methyl}sulfanyl)benzene; methyl (1R,5R)-5-[(phenylsulfanyl)methyl]-2-cyclohexen-1-yl ether | C14H18OS | 详情 | 详情 | |
| (XXXII) | 57348 | {[(1R,5R)-5-methoxy-3-cyclohexen-1-yl]methyl}(dioxo)phenyl-lambda~6~-sulfane; [(1R,5R)-5-methoxy-3-cyclohexen-1-yl]methyl phenyl sulfone | C14H18O3S | 详情 | 详情 | |
| (XXXIII) | 57349 | (1R,2R,4R)-2-methoxy-4-[(phenylsulfonyl)methyl]cyclohexanol | C14H20O4S | 详情 | 详情 | |
| (XXXIV) | 57350 | ((1R,3R,4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-methoxycyclohexyl)methyl phenyl sulfone; tert-butyl({(1R,2R,4R)-2-methoxy-4-[(phenylsulfonyl)methyl]cyclohexyl}oxy)diphenylsilane | C30H38O4SSi | 详情 | 详情 | |
| (XXXV) | 57351 | (1S,3S,4S)-1-((1R,3R,4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-methoxycyclohexyl)-4-(1,3-dithian-2-yl)-3-[(4-methoxybenzyl)oxy]-1-(phenylsulfonyl)-2-pentanol | C46H60O7S3Si | 详情 | 详情 | |
| (XXXVI) | 57352 | (1S,3S,4S)-1-((1R,3R,4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-methoxycyclohexyl)-4-(1,3-dithian-2-yl)-3-[(4-methoxybenzyl)oxy]-1-(phenylsulfonyl)-2-pentanone | C46H58O7S3Si | 详情 | 详情 | |
| (XXXVII) | 57353 | (3S,4S)-1-((1R,3R,4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-methoxycyclohexyl)-4-(1,3-dithian-2-yl)-3-[(4-methoxybenzyl)oxy]-2-pentanone | C40H54O5S2Si | 详情 | 详情 | |
| (XXXVIII) | 57354 | (Z)-2-((1R,3R,4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-methoxycyclohexyl)-1-{(1S,2S)-2-(1,3-dithian-2-yl)-1-[(4-methoxybenzyl)oxy]propyl}ethenyl trifluoromethanesulfonate | C41H53F3O7S3Si | 详情 | 详情 | |
| (XXXIX) | 57355 | tert-butyl(diphenyl)silyl (1R,2R,4R)-4-{(E,3S,4S)-4-(1,3-dithian-2-yl)-3-[(4-methoxybenzyl)oxy]-2-methyl-1-pentenyl}-2-methoxycyclohexyl ether; tert-butyl[((1R,2R,4R)-4-{(E,3S,4S)-4-(1,3-dithian-2-yl)-3-[(4-methoxybenzyl)oxy]-2-methyl-1-pentenyl}-2-methoxycyclohexyl)oxy]diphenylsilane | C41H56O4S2Si | 详情 | 详情 | |
| (XL) | 57356 | [((1R,2R,4R)-4-{(E,3S,4S)-4-(1,3-dithian-2-yl)-3-[(4-methoxybenzyl)oxy]-2-methyl-1-pentenyl}-2-methoxycyclohexyl)oxy](triisopropyl)silane; (1S,2E)-1-[(1S)-1-(1,3-dithian-2-yl)ethyl]-3-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-2-methyl-2-propenyl 4-methoxybenzyl ether | C34H58O4S2Si | 详情 | 详情 |
合成路线37
The condensation of (XL) with the intermediate 14-iodo-10-tetradecenal dimethylacetal (XXI) by means of BuLi in THF/HMPA gives the adduct (XLI), which is desulfurized by means of NCS and AgNO3 in acetone/THF/water to yield the ketonic product (XLII). The cleavage of the 4-methoxybenzyl group of (XLII) by means of DDQ in dichloromethane affords the beta-hydroxyketone (XLIII). The reduction of the ketonic group of (XLIII) with LiAlH4 and LiI in ethyl ether provides the dihydroxy compound (XLIV), which is selectively monoprotected with Tips-OTf and 2,6-lutidine in dichloromethane to give the intermediate (XLV).
| 【1】 Smith, A.B. III; et al.; Formal total synthesis of FK506. Concise construction of the C(10)-C(34) segment via an effective coupling tactic. Tetrahedron Lett 1994, 35, 25, 4271. |
| 【2】 Chen, K.; Formal total synthesis of (-)-FK506. Diss Abstr Int B - Sci Eng 1993, 53, 9, 4663. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXI) | 57344 | (1S,2R,3E,6S,8S,9R,10S,12R)-2-allyl-9-{[tert-butyl(dimethyl)silyl]oxy}-1-(iodomethyl)-8,10,13,13-tetramethoxy-4,6,12-trimethyl-3-tridecenyl tert-butyl(dimethyl)silyl ether; (5S,6R,7E,10S,12S,13R)-6-allyl-5-(iodomethyl)-12-methoxy-2,2,3,3,8,10,15,15,16,16-decamethyl-13-[(1S,3R)-1,4,4-trimethoxy-3-methylbutyl]-4,14-dioxa-3,15-disila-7-heptadecene | C36H73IO6Si2 | 详情 | 详情 | |
| (XL) | 57356 | [((1R,2R,4R)-4-{(E,3S,4S)-4-(1,3-dithian-2-yl)-3-[(4-methoxybenzyl)oxy]-2-methyl-1-pentenyl}-2-methoxycyclohexyl)oxy](triisopropyl)silane; (1S,2E)-1-[(1S)-1-(1,3-dithian-2-yl)ethyl]-3-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-2-methyl-2-propenyl 4-methoxybenzyl ether | C34H58O4S2Si | 详情 | 详情 | |
| (XLI) | 57359 | 4-{[((1S,2E)-1-{(1S)-1-[2-((2R,3R,4E,7S,9S,10R,11S,13R)-3-allyl-2,10-bis{[tert-butyl(dimethyl)silyl]oxy}-9,11,14,14-tetramethoxy-5,7,13-trimethyl-4-tetradecenyl)-1,3-dithian-2-yl]ethyl}-3-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-2-methyl-2-propenyl)oxy]methyl}phenyl methyl ether | C70H130O10S2Si3 | 详情 | 详情 | |
| (XLII) | 57360 | (1E,3S,4S,7R,8R,9E,12S,14S,15R,16S,18R)-8-allyl-7,15-bis{[tert-butyl(dimethyl)silyl]oxy}-14,16,19,19-tetramethoxy-3-[(4-methoxybenzyl)oxy]-1-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-2,4,10,12,18-pentamethyl-1,9-nonadecadien-5-one | C67H124O11Si3 | 详情 | 详情 | |
| (XLIII) | 57361 | (1E,3S,4S,7R,8R,9E,12S,14S,15R,16S,18R)-8-allyl-7,15-bis{[tert-butyl(dimethyl)silyl]oxy}-3-hydroxy-14,16,19,19-tetramethoxy-1-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-2,4,10,12,18-pentamethyl-1,9-nonadecadien-5-one | C59H116O10Si3 | 详情 | 详情 | |
| (XLIV) | 57362 | (1E,3S,4R,5S,7R,8R,9E,12S,14S,15R,16S,18R)-8-allyl-7,15-bis{[tert-butyl(dimethyl)silyl]oxy}-14,16,19,19-tetramethoxy-1-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-2,4,10,12,18-pentamethyl-1,9-nonadecadiene-3,5-diol | C59H118O10Si3 | 详情 | 详情 | |
| (XLV) | 57363 | (1E,3S,4S,5S,7R,8R,9E,12S,14S,15R,16S,18R)-8-allyl-7,15-bis{[tert-butyl(dimethyl)silyl]oxy}-14,16,19,19-tetramethoxy-1-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-2,4,10,12,18-pentamethyl-5-[(triisopropylsilyl)oxy]-1,9-nonadecadien-3-ol | C68H138O10Si4 | 详情 | 详情 |
合成路线38
The silylation of the remaining OH group of (XLV) with Tes-OTf and lutidine in dichloromethane gives the fully silylated intermediate (XLVI), which is treated with a mild acid in order to cleave the 1,3-dithiane ring and yield the carbaldehyde (XLVII). The condensation of (XLVII) with the chiral piperidine carboxylic acid (XLVIII) by means of LDA in THF affords the adduct (XLIX). The oxidation of the OH group of (XLIX) provides the beta dioxo compound (L), which is treated with Ac-OH in THF/water to selectively cleave the triethylsilyl protecting group and yield the secondary alcohol (LI).
| 【1】 Chen, K.; Formal total synthesis of (-)-FK506. Diss Abstr Int B - Sci Eng 1993, 53, 9, 4663. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XLV) | 57363 | (1E,3S,4S,5S,7R,8R,9E,12S,14S,15R,16S,18R)-8-allyl-7,15-bis{[tert-butyl(dimethyl)silyl]oxy}-14,16,19,19-tetramethoxy-1-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-2,4,10,12,18-pentamethyl-5-[(triisopropylsilyl)oxy]-1,9-nonadecadien-3-ol | C68H138O10Si4 | 详情 | 详情 | |
| (XLVI) | 57364 | (1S,2R,3S,5S,7E,9R,10R,12S,13S,14S,15E)-9-allyl-2,10-bis{[tert-butyl(dimethyl)silyl]oxy}-1-[(2R)-3,3-dimethoxy-2-methylpropyl]-3-methoxy-16-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-5,7,13,15-tetramethyl-14-[(triethylsilyl)oxy]-12-[(triisopropylsilyl)oxy]-7,15-hexadecadienyl methyl ether | C74H152O10Si5 | 详情 | 详情 | |
| (XLVII) | 57365 | (2R,4S,5R,6S,8S,10E,12R,13R,15S,16S,17S,18E)-12-allyl-5,13-bis{[tert-butyl(dimethyl)silyl]oxy}-4,6-dimethoxy-19-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-2,8,10,16,18-pentamethyl-17-[(triethylsilyl)oxy]-15-[(triisopropylsilyl)oxy]-10,18-nonadecadienal | C72H146O9Si5 | 详情 | 详情 | |
| (XLVIII) | 57366 | (2S)-1-{2-[(4-methoxybenzyl)oxy]acetyl}-2-piperidinecarboxylic acid | C16H21NO5 | 详情 | 详情 | |
| (XLIX) | 57367 | (2S)-1-{(4R,6S,7R,8S,10S,12E,14R,15R,17S,18S,19S,20E)-14-allyl-7,15-bis{[tert-butyl(dimethyl)silyl]oxy}-3-hydroxy-6,8-dimethoxy-2-[(4-methoxybenzyl)oxy]-21-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-4,10,12,18,20-pentamethyl-19-[(triethylsilyl)oxy]-17-[(triisopropylsilyl)oxy]-12,20-henicosadienoyl}-2-piperidinecarboxylic acid | C88H167NO14Si5 | 详情 | 详情 | |
| (L) | 57368 | (2S)-1-{(4R,6S,7R,8S,10S,12E,14R,15R,17S,18S,19S,20E)-14-allyl-7,15-bis{[tert-butyl(dimethyl)silyl]oxy}-6,8-dimethoxy-2-[(4-methoxybenzyl)oxy]-21-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-4,10,12,18,20-pentamethyl-3-oxo-19-[(triethylsilyl)oxy]-17-[(triisopropylsilyl)oxy]-12,20-henicosadienoyl}-2-piperidinecarboxylic acid | C88H165NO14Si5 | 详情 | 详情 | |
| (LI) | 57369 | (2S)-1-{(4R,6S,7R,8S,10S,12E,14R,15R,17S,18S,19S,20E)-14-allyl-7,15-bis{[tert-butyl(dimethyl)silyl]oxy}-19-hydroxy-6,8-dimethoxy-2-[(4-methoxybenzyl)oxy]-21-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-4,10,12,18,20-pentamethyl-3-oxo-17-[(triisopropylsilyl)oxy]-12,20-henicosadienoyl}-2-piperidinecarboxylic acid | C82H151NO14Si4 | 详情 | 详情 |
合成路线39
The macrocyclization of (LI) by means of EDC and DMAP in dichloromethane gives the macrolactone (LII), which is treated with DDQ and oxidized with DMP in dichloromethane to yield the tricarbonyl compound (LIII). The cyclization and desilylation of (LIII) by means of HF in acetonitrile affords the tricyclic macrolactone (LIV), which is treated with Tes-Cl and oxidized with DMP to provide the silylated precursor (LV). Finally, this compound is desilylated with HF in acetonitrile to give the target FK-506.
| 【1】 Chen, K.; Formal total synthesis of (-)-FK506. Diss Abstr Int B - Sci Eng 1993, 53, 9, 4663. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (LI) | 57369 | (2S)-1-{(4R,6S,7R,8S,10S,12E,14R,15R,17S,18S,19S,20E)-14-allyl-7,15-bis{[tert-butyl(dimethyl)silyl]oxy}-19-hydroxy-6,8-dimethoxy-2-[(4-methoxybenzyl)oxy]-21-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-4,10,12,18,20-pentamethyl-3-oxo-17-[(triisopropylsilyl)oxy]-12,20-henicosadienoyl}-2-piperidinecarboxylic acid | C82H151NO14Si4 | 详情 | 详情 | |
| (LII) | 57370 | (3S,4S,5S,7R,8R,12S,14S,15R,16S,18R,26aS)-8-allyl-7,15-bis{[tert-butyl(dimethyl)silyl]oxy}-14,16-dimethoxy-20-[(4-methoxybenzyl)oxy]-3-((E)-2-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-1-methylethenyl)-4,10,12,18-tetramethyl-5-[(triisopropylsilyl)oxy]-5,6,7,8,11,12,13,14,15,16,17,18,24,25,26,26a-hexadecahydro-3H-pyrido[2,1-c][1,4]oxazacyclotricosine-1,19,21(4H,20H,23H)-trione | C82H149NO13Si4 | 详情 | 详情 | |
| (LIII) | 11564 | (3S,4S,5S,7R,8R,12S,14S,15R,16S,18R,26aS)-8-Allyl-7,15-bis[[tert-butyl(dimethyl)silyl]oxy]-14,16-dimethoxy-3-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methylethenyl)-4,10,12,18-tetramethyl-5-[(triisopropylsilyl)oxy]-5,6,7,8,11,12,13,14,15,16,17,18,24,25,26,26a-hexadecahydro-3H-pyrido[2,1-c][1,4]oxazacyclotricosine-1,19,20,21(4H,23H)-tetrone | C74H139NO12Si4 | 详情 | 详情 | |
| (LIV) | 11565 | (1R,9S,12S,13S,14S,16R,17R,21S,23S,24R,25S,27R)-17-Allyl-1,16-dihydroxy-23,25-dimethoxy-12-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triethylsilyl)oxy]cyclohexyl]-1-methylethenyl)-13,19,21,27-tetramethyl-14-[(triethylsilyl)oxy]-11,28-dioxa-4-azatricyclo[22.3.1.0(4,9)]octacos-18-ene-2,3,10-trione | C44H71NO12 | 详情 | 详情 | |
| (LV) | 11567 | (1R,9S,12S,13S,14S,17R,21S,23S,24R,25S,27R)-17-Allyl-1-hydroxy-23,25-dimethoxy-12-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triethylsilyl)oxy]cyclohexyl]-1-methylethenyl)-13,19,21,27-tetramethyl-14-[(triethylsilyl)oxy]-11,28-dioxa-4-azatricyclo[22.3.1.0(4,9)]octacos-18-ene-2,3,10,16-tetrone | C56H97NO12Si2 | 详情 | 详情 |
合成路线40
The reaction of tri(p-tolyl)phosphine (I) with 11C-methyl iodide (II) gives the labelled phosphonium salt (III), which is condensed with the carbaldehyde (IV) to yield the protected intermediate (V). Finally, this compound is desilylated by means of HF in acetonitrile to afford the target labelled compound.
| 【1】 Murakami, Y.; et al.; Rapid synthesis of 11C-labeled FK506 for positron emission tomography. Tetrahedron Lett 2003, 44, 4, 641. |
| 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) | 61752 | Tri-p-tolylphosphine; Phosphine, tris(4-methylphenyl)-; Tri(p-tolyl)phosphine; Phosphorus Tri-P-Tolyl; Tris(4-methylphenyl)phosphine; Tri(4-methylphenyl)phosphine; Tris(4-tolyl)phosphine; Tris(p-tolyl)phosphine; TPTP | 1038-95-5 | C21H21P | 详情 | 详情 |
| (II) | 58599 | iodomethane | CH3I | 详情 | 详情 | |
| (III) | 61753 | methyl[tris(4-methylphenyl)]phosphonium iodide | C22H24IP | 详情 | 详情 | |
| (IV) | 61754 | 2-{(1R,9S,12S,13S,14S,17R,21S,23S,24R,25S,27R)-14-{[tert-butyl(dimethyl)silyl]oxy}-12-[(E)-2-((1R,3R,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-3-methoxycyclohexyl)-1-methylethenyl]-1-hydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-2,3,10,16-tetraoxo-11,28-dioxa-4-azatricyclo[22.3.1.0~4,9~]octacos-18-en-17-yl}acetaldehyde | C55H95NO13Si2 | 详情 | 详情 | |
| (V) | 61755 | (1R,9S,12S,13S,14S,17R,21S,23S,24R,25S,27R)-17-allyl-14-{[tert-butyl(dimethyl)silyl]oxy}-12-[(E)-2-((1R,3R,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-3-methoxycyclohexyl)-1-methylethenyl]-1-hydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0~4,9~]octacos-18-ene-2,3,10,16-tetrone | C56H97NO12Si2 | 详情 | 详情 |