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【结 构 式】

【药物名称】Disermolide, Discodermolide, (+)-Discodermolide, NVP-XAA-296, XAA-296

【化学名称】6(S)-[14(S)-(Carbamoyloxy)-2(S),6(S),12(R)-trihydroxy-5(S),7(S),9,11(S),13(S),15(S)-hexamethyl-3(Z),8(Z),16(Z),18-nonadecatetraenyl]-4(S)-hydroxy-3(R),5(R)-dimethyltetrahydro-2H-pyran-2-one
　　　　　　Carbamic acid (3Z,5S,6S,7S,8R,9S,11Z,13S,14S,15S,16Z,18S)-8,14,18-trihydroxy-19-[(2S,3R,4S,5R)-4-hydroxy-3,5-dimethyl-6-oxotetrahydro-2H-pyran-2-yl]-5,7,9,11,13,15-hexamethylnonadeca-1,3,11,16-tetraen-6-yl ester

【CA登记号】127943-53-7

【 分 子 式 】C33H55NO8

【 分 子 量 】593.8082

【开发单位】Harbor Branch Oceanographic Institution (Originator), Kosan (Not Determined), Novartis (Licensee)

【药理作用】IMMUNOMODULATING AGENTS, Immunosuppressants, Oncolytic Drugs, Solid Tumors Therapy, Antimitotic Drugs, Microtubule-Stabilizing Agents

合成路线1合成路线2合成路线3合成路线4合成路线5合成路线6合成路线7合成路线8合成路线9合成路线10合成路线11合成路线12合成路线13合成路线14合成路线15合成路线16合成路线17合成路线18合成路线19合成路线20合成路线21合成路线22合成路线23合成路线24合成路线25合成路线26

合成路线1

The intermediate (XI) has been obtained as follows: The condensation of the chiral ketone (I) with unsaturated aldehyde (II) by means of chlorodicyclohexylborane (DCHBCl) gives the chiral heptenone (III), which is esterified with propanal and SmI3, yielding the ester (IV). The ketalization of (IV) with 2-(phenylselanyl)acetaldehyde diethyl acetal (V) by means of pyridinium p-toluenesulfonate (PPTS) affords the cyclic ketal (VI), which is oxidized with NaIO4 and condensed with the silylated enol ether (VII), providing the lactone (VIII). Methanolysis of the lactone (VII) with MeONa and silylation of the hydroxyester gives methyl ester (IX), which is hydrolyzed with KOH and reesterified with 2,6-dimethylphenol (X) and DCC, yielding the desired intermediate, the aryl ester (XI).

参考文献 中间体
【1】 Paterson, I.; et al.; Total synthesis of the antimicrotubule agent (+)-discodermolide using boron-mediated aldol reactions of chiral ketones. Angew Chem. Int Ed Engl 2000, 39, 2, 377.
【2】 Paterson, I.; Florence, G.J.; Synthesis of (+)-discodermolide and analogues by control of asymmetric induction in aldol reactions of gamma-chiral (Z)-enals. Tetrahedron Lett 2000, 41, 35, 6935.
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) 42614 (2S)-1-[(4-methoxybenzyl)oxy]-2-methyl-3-pentanone C14H20O3 详情 详情
(II) 11387 2-Methylacrylaldehyde; Methacrylaldehyde 78-85-3 C4H6O 详情 详情
(III) 42615 (2S,4S,5R)-5-hydroxy-1-[(4-methoxybenzyl)oxy]-2,4,6-trimethyl-6-hepten-3-one C18H26O4 详情 详情
(IV) 42616 (1R)-1-[(1R,2S,3S)-2-hydroxy-4-[(4-methoxybenzyl)oxy]-1,3-dimethylbutyl]-2-methyl-2-propenyl propionate C21H32O5 详情 详情
(V) 42617 1-[(2,2-diethoxyethyl)selanyl]benzene; 1-ethoxy-2-(phenylselanyl)ethyl ethyl ether C12H18O2Se 详情 详情
(VI) 42618 (4R,5S,6S)-4-isopropenyl-6-[(1S)-2-[(4-methoxybenzyl)oxy]-1-methylethyl]-5-methyl-2-[(phenylselanyl)methyl]-1,3-dioxane; (2S)-2-[(4S,5S,6R)-6-isopropenyl-5-methyl-2-[(phenylselanyl)methyl]-1,3-dioxan-4-yl]propyl 4-methoxybenzyl ether C26H34O4Se 详情 详情
(VII) 42619 tert-butyl[(1-methoxyvinyl)oxy]dimethylsilane; tert-butyl(dimethyl)silyl 1-methoxyvinyl ether C9H20O2Si 详情 详情
(VIII) 42620 (7S,8R)-8-[(1S)-2-[(4-methoxybenzyl)oxy]-1-methylethyl]-5,7-dimethyl-3,4,7,8-tetrahydro-2H-oxocin-2-one C20H28O4 详情 详情
(IX) 42621 methyl (Z,6S,7R,8S)-7-[[tert-butyl(dimethyl)silyl]oxy]-9-[(4-methoxybenzyl)oxy]-4,6,8-trimethyl-4-nonenoate C27H46O5Si 详情 详情
(X) 37388 2,6-dimethylphenol 576-26-1 C8H10O 详情 详情
(XI) 42622 2,6-dimethylphenyl (Z,6S,7R,8S)-7-[[tert-butyl(dimethyl)silyl]oxy]-9-[(4-methoxybenzyl)oxy]-4,6,8-trimethyl-4-nonenoate C34H52O5Si 详情 详情

合成路线2

The intermediate (XXI) has been obtained as follows: The condensation of the chiral benzylated hydroxypentanone (XII) with the chiral aldehyde (XIII) by means of DCHBCl gives the chiral hydroxyheptanone (XIV), which is protected at the OH group with p-methoxybenzyl trichloroacetimidate (Pmb-Tca), yielding the expected benzyl ether (XV). The reduction of the CO group of (XV) by means of LiAlH4, with simultaneous debenzylation affords the alpha-diol (XVI), which is oxidized with NaIO4 to provide the aldehyde (XVII). The condensation of (XVII) with the allyl compound (XVIII) by means of CrCl2 and KH in THF gives the octadiene compound (XIX), which is desilylated with camphorsulfonic acid (CSA) to yield the unsaturated alcohol (XX). Finally, this alcohol is oxidized with DMP to the desired intermediate aldehyde (XXI).

参考文献 中间体
【1】 Paterson, I.; Florence, G.J.; Synthesis of (+)-discodermolide and analogues by control of asymmetric induction in aldol reactions of gamma-chiral (Z)-enals. Tetrahedron Lett 2000, 41, 35, 6935.
【2】 Paterson, I.; et al.; Total synthesis of the antimicrotubule agent (+)-discodermolide using boron-mediated aldol reactions of chiral ketones. Angew Chem. Int Ed Engl 2000, 39, 2, 377.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XII) 42623 (1S)-1-methyl-2-oxobutyl benzoate C12H14O3 详情 详情
(XIII) 42624 (2S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methylpropanal C10H22O2Si 详情 详情
(XIV) 42625 (1S,3R,4R,5S)-6-[[tert-butyl(dimethyl)silyl]oxy]-4-hydroxy-1,3,5-trimethyl-2-oxohexyl benzoate C22H36O5Si 详情 详情
(XV) 42626 (1S,3R,4R,5S)-6-[[tert-butyl(dimethyl)silyl]oxy]-4-[(4-methoxybenzyl)oxy]-1,3,5-trimethyl-2-oxohexyl benzoate C30H44O6Si 详情 详情
(XVI) 42627 (2S,4S,5R,6S)-7-[[tert-butyl(dimethyl)silyl]oxy]-5-[(4-methoxybenzyl)oxy]-4,6-dimethyl-2,3-heptanediol C23H42O5Si 详情 详情
(XVII) 42628 (2R,3R,4S)-5-[[tert-butyl(dimethyl)silyl]oxy]-3-[(4-methoxybenzyl)oxy]-2,4-dimethylpentanal C21H36O4Si 详情 详情
(XVIII) 42629 (1-bromo-2-propenyl)(trimethyl)silane 94397-40-7 C6H13BrSi 详情 详情
(XIX) 42630 tert-butyl([(2S,3S,4S,5Z)-3-[(4-methoxybenzyl)oxy]-2,4-dimethyl-5,7-octadienyl]oxy)dimethylsilane; tert-butyl(dimethyl)silyl (2S,3S,4S,5Z)-3-[(4-methoxybenzyl)oxy]-2,4-dimethyl-5,7-octadienyl ether C24H40O3Si 详情 详情
(XX) 42631 (2S,3S,4S,5Z)-3-[(4-methoxybenzyl)oxy]-2,4-dimethyl-5,7-octadien-1-ol C18H26O3 详情 详情
(XXI) 42632 (2R,3S,4S,5Z)-3-[(4-methoxybenzyl)oxy]-2,4-dimethyl-5,7-octadienal C18H24O3 详情 详情

合成路线3

The intermediate (XXX) has been obtained as follows: The condensation of benzylated hydroxypentanone (XXII) with acetaldehyde (XXIII) by means of DCHBCl gives the hydroxyhexanone (XXIV), which is reduced with LiBH4, yielding the diol (XXV). The silylation of (XXV) with Tbdms-OTf affords the disilyl ether (XXVI), which is regioselectively monodesilylated with CSA, providing the alcohol (XXVII). The hydrogenolysis of (XXVII) with H2 over Pd/C gives the primary alcohol (XXVIII), which is treated with (COCl)2 and NaClO2 in order to oxidize the primary alcohol to carboxylic acid and the secondary alcohol to ketone to furnish the ketoacid (XXIX). Finally, this compound is esterified with diazomethane to afford the desired ester intermediate (XXX).

参考文献 中间体
【1】 Paterson, I.; Florence, G.J.; Synthesis of (+)-discodermolide and analogues by control of asymmetric induction in aldol reactions of gamma-chiral (Z)-enals. Tetrahedron Lett 2000, 41, 35, 6935.
【2】 Paterson, I.; et al.; Total synthesis of the antimicrotubule agent (+)-discodermolide using boron-mediated aldol reactions of chiral ketones. Angew Chem. Int Ed Engl 2000, 39, 2, 377.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXII) 42633 (2S)-1-(benzyloxy)-2-methyl-3-pentanone C13H18O2 详情 详情
(XXIII) 11974 Acetaldehyde 75-07-0 C2H4O 详情 详情
(XXIV) 42634 (2S,4S,5S)-1-(benzyloxy)-5-hydroxy-2,4-dimethyl-3-hexanone C15H22O3 详情 详情
(XXV) 42635 (2S,3S,4R,5S)-6-(benzyloxy)-3,5-dimethyl-2,4-hexanediol C15H24O3 详情 详情
(XXVI) 42636 benzyl (2S,3R,4S,5S)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethylhexyl ether; (5R,6S,7S)-5-[(1S)-2-(benzyloxy)-1-methylethyl]-2,2,3,3,6,7,9,9,10,10-decamethyl-4,8-dioxa-3,9-disilaundecane n/a C27H52O3Si2 详情 详情
(XXVII) 42637 (2S,3S,4R,5S)-6-(benzyloxy)-4-[[tert-butyl(dimethyl)silyl]oxy]-3,5-dimethyl-2-hexanol n/a C21H38O3Si 详情 详情
(XXVIII) 42638 (2S,3R,4S,5S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethyl-1,5-hexanediol C14H32O3Si 详情 详情
(XXIX) 42639 (2R,3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethyl-5-oxohexanoic acid C14H28O4Si 详情 详情
(XXX) 42640 methyl (2R,3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethyl-5-oxohexanoate C15H30O4Si 详情 详情

合成路线4

The target compound has been obtained as follows: The condensation of ester intermediate (XI) with aldehyde intermediate (XXI) by means of lithium 2,2,6,6-tetramethylpiperidide (Li-TMP) gives the addition compound (XXXI), which is reduced at the ester group with LiAlH4, yielding the carbinol (XXXII). The reduction of this carbinol by sulfonation with mesitylenesulfonyl chloride, followed by reduction with LiAlH4, affords the corresponding methyl derivative (XXXIII), which is silylated at the secondary OH group with TBDMS-Otf, providing the fully protected compound (XXXIV). Elimination of the Pmb protecting groups of (XXXIV) with DDQ yields the diol (XXXV), which is selectively oxidized at the primary OH group to the corresponding aldehyde (XXXVI) by means of TEMPO. The Wittig condensation of (XXXVI) with phosphonate (XXXVII) by means of K2CO3 and 18-C-6 affords the octadecatetraenoic ester (XXXVIII), which is treated with trichloroacetyl isocyanate and K2CO3 to provide the carbamate (XXXIX). The reduction of the ester group of (XXXIX) by means of DIBAL gives the primary alcohol (XL), which is finally oxidized with DMP to the expected intermediate aldehyde (XLI).

参考文献 中间体
【1】 Paterson, I.; et al.; Total synthesis of the antimicrotubule agent (+)-discodermolide using boron-mediated aldol reactions of chiral ketones. Angew Chem. Int Ed Engl 2000, 39, 2, 377.
【2】 Paterson, I.; Florence, G.J.; Synthesis of (+)-discodermolide and analogues by control of asymmetric induction in aldol reactions of gamma-chiral (Z)-enals. Tetrahedron Lett 2000, 41, 35, 6935.
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) 42622 2,6-dimethylphenyl (Z,6S,7R,8S)-7-[[tert-butyl(dimethyl)silyl]oxy]-9-[(4-methoxybenzyl)oxy]-4,6,8-trimethyl-4-nonenoate C34H52O5Si 详情 详情
(XXI) 42632 (2R,3S,4S,5Z)-3-[(4-methoxybenzyl)oxy]-2,4-dimethyl-5,7-octadienal C18H24O3 详情 详情
(XXXI) 42641 2,6-dimethylphenyl (2S,3S,4S,5S,6S,7Z)-2-[(Z,4S,5R,6S)-5-[[tert-butyl(dimethyl)silyl]oxy]-7-[(4-methoxybenzyl)oxy]-2,4,6-trimethyl-2-heptenyl]-3-hydroxy-5-[(4-methoxybenzyl)oxy]-4,6-dimethyl-7,9-decadienoate C52H76O8Si 详情 详情
(XXXII) 42642 (2R,3R,4S,5S,6S,7Z)-2-[(Z,4S,5R,6S)-5-[[tert-butyl(dimethyl)silyl]oxy]-7-[(4-methoxybenzyl)oxy]-2,4,6-trimethyl-2-heptenyl]-5-[(4-methoxybenzyl)oxy]-4,6-dimethyl-7,9-decadiene-1,3-diol C44H70O7Si 详情 详情
(XXXIII) 42643 (3Z,5S,6S,7S,8R,9S,11Z,13S,14R,15S)-14-[[tert-butyl(dimethyl)silyl]oxy]-6,16-bis[(4-methoxybenzyl)oxy]-5,7,9,11,13,15-hexamethyl-1,3,11-hexadecatrien-8-ol C44H70O6Si 详情 详情
(XXXIV) 42644 (5R,6S,7Z,10S,11R)-11-[(1R,2S,3S,4Z)-2-[(4-methoxybenzyl)oxy]-1,3-dimethyl-4,6-heptadienyl]-5-[(1S)-2-[(4-methoxybenzyl)oxy]-1-methylethyl]-2,2,3,3,6,8,10,13,13,14,14-undecamethyl-4,12-dioxa-3,13-disila-7-pentadecene; (2S,3R,4S,5Z,8S,9R,10R,11S,12S,13Z)-3,9-bis[[tert-butyl(dimethyl)silyl]oxy]-11-[(4-methoxybenzyl)oxy]-2,4,6,8,10,12-hexamethyl-5,13,15-hexadecatrienyl 4-methoxybenzyl ether n/a C50H84O6Si2 详情 详情
(XXXV) 42645 (2S,3R,4S,5Z,8S,9R,10R,11S,12S,13Z)-3,9-bis[[tert-butyl(dimethyl)silyl]oxy]-2,4,6,8,10,12-hexamethyl-5,13,15-hexadecatriene-1,11-diol n/a C34H68O4Si2 详情 详情
(XXXVI) 42646 (2R,3R,4S,5Z,8S,9R,10R,11S,12S,13Z)-3,9-bis[[tert-butyl(dimethyl)silyl]oxy]-11-hydroxy-2,4,6,8,10,12-hexamethyl-5,13,15-hexadecatrienal n/a C34H66O4Si2 详情 详情
(XXXVII) 41856 methyl 2-[bis(2,2,2-trifluoroethoxy)phosphoryl]acetate 88738-78-7 C7H9F6O5P 详情 详情
(XXXVIII) 42647 methyl (2Z,4S,5S,6S,7Z,10S,11R,12R,13S,14S,15Z)-5,11-bis[[tert-butyl(dimethyl)silyl]oxy]-13-hydroxy-4,6,8,10,12,14-hexamethyl-2,7,15,17-octadecatetraenoate n/a C37H70O5Si2 详情 详情
(XXXIX) 42648 methyl (2Z,4S,5S,6S,7Z,10S,11R,12R,13S,14S,15Z)-13-[(aminocarbonyl)oxy]-5,11-bis[[tert-butyl(dimethyl)silyl]oxy]-4,6,8,10,12,14-hexamethyl-2,7,15,17-octadecatetraenoate n/a C38H71NO6Si2 详情 详情
(XL) 42649 (1S,2R,3R,4S,6Z,8S,9S,10S,11Z)-3,9-bis[[tert-butyl(dimethyl)silyl]oxy]-13-hydroxy-2,4,6,8,10-pentamethyl-1-[(1S,2Z)-1-methyl-2,4-pentadienyl]-6,11-tridecadienyl carbamate C37H71NO5Si2 详情 详情
(XLI) 42650 (1S,2R,3R,4S,6Z,8S,9S,10S,11Z)-3,9-bis[[tert-butyl(dimethyl)silyl]oxy]-2,4,6,8,10-pentamethyl-1-[(1S,2Z)-1-methyl-2,4-pentadienyl]-13-oxo-6,11-tridecadienyl carbamate C37H69NO5Si2 详情 详情

合成路线5

The condensation of aldehyde (XLI) with the intermediate ketoester (XXX) by means of chloro-(+)-disopinocampheylborane ((+)-IPCBCl) gives the 5-oxotetracosatetraenoic ester (XLII), which is submitted to reduction of the 5-oxo group with Me3N-BH(OAc)3, yielding a mixture of the 5-hydroxyester (XLIV) and the corresponding lactone (XLIII). Finally, this mixture, without separation of its components, is submitted to desilylation, with simultaneous lactonization, by treatment with HF and pyridine in THF.

参考文献 中间体
【1】 Paterson, I.; et al.; Total synthesis of the antimicrotubule agent (+)-discodermolide using boron-mediated aldol reactions of chiral ketones. Angew Chem. Int Ed Engl 2000, 39, 2, 377.
【2】 Paterson, I.; Florence, G.J.; Synthesis of (+)-discodermolide and analogues by control of asymmetric induction in aldol reactions of gamma-chiral (Z)-enals. Tetrahedron Lett 2000, 41, 35, 6935.
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) 42640 methyl (2R,3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethyl-5-oxohexanoate C15H30O4Si 详情 详情
(XLI) 42650 (1S,2R,3R,4S,6Z,8S,9S,10S,11Z)-3,9-bis[[tert-butyl(dimethyl)silyl]oxy]-2,4,6,8,10-pentamethyl-1-[(1S,2Z)-1-methyl-2,4-pentadienyl]-13-oxo-6,11-tridecadienyl carbamate C37H69NO5Si2 详情 详情
(XLII) 42651 methyl (2R,3S,4R,7S,8Z,10S,11S,12S,13Z,16S,17R,18R,19S,20S,21Z)-19-[(aminocarbonyl)oxy]-3,11,17-tris[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-2,4,10,12,14,16,18,20-octamethyl-5-oxo-8,13,21,23-tetracosatetraenoate C52H99NO9Si3 详情 详情
(XLIII) 42652 (1S,2R,3R,4S,6Z,8S,9S,10S,11Z,13S)-3,9-bis[[tert-butyl(dimethyl)silyl]oxy]-14-((2S,3S,4S,5R)-4-[[tert-butyl(dimethyl)silyl]oxy]-3,5-dimethyl-6-oxotetrahydro-2H-pyran-2-yl)-13-hydroxy-2,4,6,8,10-pentamethyl-1-[(1S,2Z)-1-methyl-2,4-pentadienyl]-6,11-t C51H97NO8Si3 详情 详情
(XLIV) 42653 methyl (2R,3S,4S,5S,7S,8Z,10S,11S,12S,13Z,16S,17R,18R,19S,20S,21Z)-19-[(aminocarbonyl)oxy]-3,11,17-tris[[tert-butyl(dimethyl)silyl]oxy]-5,7-dihydroxy-2,4,10,12,14,16,18,20-octamethyl-8,13,21,23-tetracosatetraenoate C52H101NO9Si3 详情 详情

合成路线6

The intermediate (XV) has been obtained as follows: The reaction of methyl 3-hydroxy-2(S)-methylpropionate (I) with 4-methoxybenzyl trichloroacetimidate gives methyl 3-(4-methoxybenzyloxy)-2(S)-methylpropionate (II), which is reduced with LiAlH4, yielding the primary alcohol (III). The Swern oxidation of (III) affords the aldehyde (IV), which is condensed with the chiral imidazolidinone (V) to provide the adduct (VI). The transamidation of (VI) with N,O-dimethylhydroxylamine by means of Me3Al gives the methoxyamide (VII), which is debenzylated with DDQ to yield the diol (VIII). The reaction of (VIII) with 4-methoxybenzaldehyde diethylacetal (IX) and CSA affords the cyclic ketal (X), which is condensed with the propionyloxazolidinone (XI) by means of dibutylboron triflate to furnish the adduct (XII). The silylation of the OH group of (XII) with Tbdms-OTf gives the silyl ether (XIII), which is reduced at the amide group with LiBH4 to yield the primary alcohol (XIV). Finally, this compound is treated with I2 and PPH3 to afford the intermediate iodo derivative (XV).

参考文献 中间体
【1】 Smith, A.B. III; et al.; Gram-scale synthesis of (+)-discodermolide. Org Lett 1999, 1, 11, 1823.
【2】 Smith, A.B. III; et al.; Evolution of a gram-scale synthesis of (+)-discodermolide. J Am Chem Soc 2000, 122, 36, 8654.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 17128 Methyl (2S)-3-hydroxy-2-methylpropanoate 72657-23-9 C5H10O3 详情 详情
(II) 42654 methyl (2S)-3-[(4-methoxybenzyl)oxy]-2-methylpropanoate C13H18O4 详情 详情
(III) 42655 (2R)-3-[(4-methoxybenzyl)oxy]-2-methyl-1-propanol C12H18O3 详情 详情
(IV) 42656 (2S)-3-[(4-methoxybenzyl)oxy]-2-methylpropanal C12H16O3 详情 详情
(V) 42657 (4R,5S)-3-[(Z)-1-butoxy-1-propenyl]-4-methyl-5-phenyl-1,3-oxazolidin-2-one C17H23NO3 详情 详情
(VI) 42658 (4R,5S)-3-[(2R,3S,4S)-3-hydroxy-5-[(4-methoxybenzyl)oxy]-2,4-dimethylpentanoyl]-4-methyl-5-phenyl-1,3-oxazolidin-2-one C25H31NO6 详情 详情
(VII) 42659 (2R,3S,4S)-3-hydroxy-N-methoxy-5-[(4-methoxybenzyl)oxy]-N,2,4-trimethylpentanamide C17H27NO5 详情 详情
(VIII) 42660 (2R,3S,4S)-3,5-dihydroxy-N-methoxy-N,2,4-trimethylpentanamide C9H19NO4 详情 详情
(IX) 35670 1-(diethoxymethyl)-4-methoxybenzene; 4-(diethoxymethyl)phenyl methyl ether C12H18O3 详情 详情
(X) 42661 (2R)-N-methoxy-2-[(4S,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-N-methylpropanamide C17H25NO5 详情 详情
(XI) 10968 (4R)-3-Acetyl-4-benzyl-1,3-oxazolidin-2-one; (R)-(-)-3-Acetyl-4-benzyl-2-oxazolidinone 184363-65-3 C12H13NO3 详情 详情
(XII) 42662 (4R)-4-benzyl-3-[(2R,3S,4S)-3-hydroxy-4-[(4S,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-2-methylpentanoyl]-1,3-oxazolidin-2-one C28H35NO7 详情 详情
(XIII) 42663 (4R)-4-benzyl-3-[(2R,3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-[(4S,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-2-methylpentanoyl]-1,3-oxazolidin-2-one C34H49NO7Si 详情 详情
(XIV) 42664 (2S,3R,4R)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-[(4S,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-2-methyl-1-pentanol C24H42O5Si 详情 详情
(XV) 42665 tert-butyl(dimethyl)silyl (1S,2R)-3-iodo-1-[(1R)-1-[(4S,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]ethyl]-2-methylpropyl ether; tert-butyl[((1S,2R)-3-iodo-1-[(1R)-1-[(4S,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]ethyl]-2-methylpropyl)oxy]dimethylsilane C24H41IO4Si 详情 详情

合成路线7

The intermediate (XVIII) has been obtained as follows: The silylation of the intermediate methoxyamide (VII) with Tbdms-OTf gives the silylated methoxyamide (XVI), which is reduced with DIBAL yielding the aldehyde (XVII). Finally, this compound is condensed with ethyltriphenylphosphonium iodide and BuLi and treated with I2 and NaHMDS to afford the intermediate iodo derivative (XVIII). The intermediate (XXV) has been obtained as follows: The hydrogenolysis of intermediate (XVI) with H2 over Pd/C gives the primary alcohol (XIX), which is oxidized with SO3 and pyridine, yielding the aldehyde (XX). The condensation of (XX) with the silylated enol ether (XXI) by means of TiCl4 and TFA affords the lactone (XXII), which is reduced with K-Selectride to provide the chiral alcohol (XXIII). The silylation of (XXIII) with Tbdms-Cl and imidazole gives the silyl ether (XXIV), which is finally ozonolyzed with O3 and PPh3 to yield the target intermediate aldehyde (XXV).

参考文献 中间体
【1】 Smith, A.B. III; et al.; Gram-scale synthesis of (+)-discodermolide. Org Lett 1999, 1, 11, 1823.
【2】 Smith, A.B. III; et al.; Evolution of a gram-scale synthesis of (+)-discodermolide. J Am Chem Soc 2000, 122, 36, 8654.
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) 42659 (2R,3S,4S)-3-hydroxy-N-methoxy-5-[(4-methoxybenzyl)oxy]-N,2,4-trimethylpentanamide C17H27NO5 详情 详情
(XVI) 42666 (2R,3S,4S)-3-[[tert-butyl(dimethyl)silyl]oxy]-N-methoxy-5-[(4-methoxybenzyl)oxy]-N,2,4-trimethylpentanamide C23H41NO5Si 详情 详情
(XVII) 42667 (2R,3S,4S)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-[(4-methoxybenzyl)oxy]-2,4-dimethylpentanal C21H36O4Si 详情 详情
(XVIII) 42668 tert-butyl(dimethyl)silyl (1R,2S,3Z)-4-iodo-1-[(1S)-2-[(4-methoxybenzyl)oxy]-1-methylethyl]-2-methyl-3-pentenyl ether; tert-butyl[((1R,2S,3Z)-4-iodo-1-[(1S)-2-[(4-methoxybenzyl)oxy]-1-methylethyl]-2-methyl-3-pentenyl)oxy]dimethylsilane C23H39IO3Si 详情 详情
(XIX) 42669 (2R,3S,4S)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-hydroxy-N-methoxy-N,2,4-trimethylpentanamide C15H33NO4Si 详情 详情
(XX) 42670 (2R,3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxy]-N-methoxy-N,2,4-trimethyl-5-oxopentanamide C15H31NO4Si 详情 详情
(XXI) 42671 3-methyl-1-methylene-2-butenyl trimethylsilyl ether; trimethyl[(3-methyl-1-methylene-2-butenyl)oxy]silane C9H18OSi 详情 详情
(XXII) 42672 (3R,4S,5R,6S)-4-methoxy-3,5-dimethyl-6-(4-methyl-2-oxo-3-pentenyl)tetrahydro-2H-pyran-2-one C14H22O4 详情 详情
(XXIII) 42673 (3R,4S,5R,6S)-6-[(2S)-2-hydroxy-4-methyl-3-pentenyl]-4-methoxy-3,5-dimethyltetrahydro-2H-pyran-2-one C14H24O4 详情 详情
(XXIV) 42674 (3R,4S,5R,6S)-6-((2S)-2-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-3-pentenyl)-4-methoxy-3,5-dimethyltetrahydro-2H-pyran-2-one C20H38O4Si 详情 详情
(XXV) 42675 (2S)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-[(2S,3R,4S,5R)-4-methoxy-3,5-dimethyl-6-oxotetrahydro-2H-pyran-2-yl]propanal C17H32O5Si 详情 详情

合成路线8

The target compound has been obtained as follows: The reaction of intermediate iodo derivative (XV) with ZnCl2 and BuLi gives the organozinc compound (XXVI), which is condensed with intermediate iodo derivative (XVIII) by means of Pd(PPh3)4, yielding the adduct (XXVII). The selective deprotection of the Pmb group of (XXVII) with DDQ, followed by reprotection with Tr-Cl, affords the suitably protected adduct (XXVIII). Cleaving of the cyclic ketal group of (XXVIII) with DIBAL provides the primary alcohol (XXIX), which is oxidized with DMP, giving the aldehyde (XXX). The condensation of (XXX) with the titanium derivative (XXXI) yields the adduct (XXXII), which is selectively deprotected at the trityl group with chloro-catecholborane to afford the primary alcohol (XXXIII). The reaction of (XXXIII) with PPh3 , I2 and DIEA furnishes the phosphonium iodide (XXXIV).

参考文献 中间体
【1】 Smith, A.B. III; et al.; Evolution of a gram-scale synthesis of (+)-discodermolide. J Am Chem Soc 2000, 122, 36, 8654.
【2】 Smith, A.B. III; et al.; Gram-scale synthesis of (+)-discodermolide. Org Lett 1999, 1, 11, 1823.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XV) 42665 tert-butyl(dimethyl)silyl (1S,2R)-3-iodo-1-[(1R)-1-[(4S,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]ethyl]-2-methylpropyl ether; tert-butyl[((1S,2R)-3-iodo-1-[(1R)-1-[(4S,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]ethyl]-2-methylpropyl)oxy]dimethylsilane C24H41IO4Si 详情 详情
(XVIII) 42668 tert-butyl(dimethyl)silyl (1R,2S,3Z)-4-iodo-1-[(1S)-2-[(4-methoxybenzyl)oxy]-1-methylethyl]-2-methyl-3-pentenyl ether; tert-butyl[((1R,2S,3Z)-4-iodo-1-[(1S)-2-[(4-methoxybenzyl)oxy]-1-methylethyl]-2-methyl-3-pentenyl)oxy]dimethylsilane C23H39IO3Si 详情 详情
(XXVI) 42676 tert-butyl[(2R,3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-[(4S,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-2-methylpentyl]zinc C28H50O4SiZn 详情 详情
(XXVII) 42677 (5R,6S,7Z,10S,11R)-5-[(1S)-2-[(4-methoxybenzyl)oxy]-1-methylethyl]-11-[(1R)-1-[(4S,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]ethyl]-2,2,3,3,6,8,10,13,13,14,14-undecamethyl-4,12-dioxa-3,13-disila-7-pentadecene; 4-((4S,5S)-4-[(1R,2R,3S,5Z,7S,8R,9S)-2,8-bis[[tert-butyl(dimethyl)silyl]oxy]-10-[(4-methoxybenzyl)oxy]-1,3,5,7,9-pentamethyl-5-decenyl]-5-methyl-1,3-dioxan-2-yl)phenyl methyl ether C47H80O7Si2 详情 详情
(XXVIII) 42678 (5R,6S,7Z,10S,11R)-11-[(1R)-1-[(4S,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]ethyl]-2,2,3,3,6,8,10,13,13,14,14-undecamethyl-5-[(1S)-1-methyl-2-(trityloxy)ethyl]-4,12-dioxa-3,13-disila-7-pentadecene; (2S,3R,4S,5Z,8S,9R,10R)-3,9-bis[[tert-butyl(dimethyl)silyl]oxy]-10-[(4S,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-2,4,6,8-tetramethyl-5-undecenyl trityl ether C58H86O6Si2 详情 详情
(XXIX) 42679 (2S,3S,4R,5R,6S,8Z,10S,11R,12S)-5,11-bis[[tert-butyl(dimethyl)silyl]oxy]-3-[(4-methoxybenzyl)oxy]-2,4,6,8,10,12-hexamethyl-13-(trityloxy)-8-tridecen-1-ol C58H88O6Si2 详情 详情
(XXX) 42680 (2R,3R,4R,5R,6S,8Z,10S,11R,12S)-5,11-bis[[tert-butyl(dimethyl)silyl]oxy]-3-[(4-methoxybenzyl)oxy]-2,4,6,8,10,12-hexamethyl-13-(trityloxy)-8-tridecenal C58H86O6Si2 详情 详情
(XXXI) 42681 　 C39H34LiO4PTi 详情 详情
(XXXII) 42682 (2S,3R,4S,5Z,8S,9R,10R,11S,12S,13Z)-3,9-bis[[tert-butyl(dimethyl)silyl]oxy]-11-[(4-methoxybenzyl)oxy]-2,4,6,8,10,12-hexamethyl-5,13,15-hexadecatrienyl trityl ether; (5R,6S,7Z,10S,11R)-11-[(1R,2S,3S,4Z)-2-[(4-methoxybenzyl)oxy]-1,3-dimethyl-4,6-heptadienyl]-2,2,3,3,6,8,10,13,13,14,14-undecamethyl-5-[(1S)-1-methyl-2-(trityloxy)ethyl]-4,12-dioxa-3,13-disila-7-pentadecene C61H90O5Si2 详情 详情
(XXXIII) 42683 (2S,3R,4S,5Z,8S,9R,10R,11S,12S,13Z)-3,9-bis[[tert-butyl(dimethyl)silyl]oxy]-11-[(4-methoxybenzyl)oxy]-2,4,6,8,10,12-hexamethyl-5,13,15-hexadecatrien-1-ol C42H76O5Si2 详情 详情
(XXXIV) 42684 [(2R,3R,4S,5Z,8S,9R,10R,11S,12S,13Z)-3,9-bis[[tert-butyl(dimethyl)silyl]oxy]-11-[(4-methoxybenzyl)oxy]-2,4,6,8,10,12-hexamethyl-5,13,15-hexadecatrienyl](triphenyl)phosphonium iodide C60H90IO4PSi2 详情 详情

合成路线9

The condensation of (XXXIV) with the intermediate aldehyde (XXV) by means of NaHMDS gives the fully protected lactone derivative (XXXV), which is selectively deprotected at the Pmb group with DDQ, yielding the secondary alcohol (XXXVI). The reaction of (XXXVI) with trichloroacetyl isocyanate and Al2O3 affords the corresponding carbamate (XXXVII), which is finally desilylated with HCl in methanol.

参考文献 中间体
【1】 Smith, A.B. III; et al.; Evolution of a gram-scale synthesis of (+)-discodermolide. J Am Chem Soc 2000, 122, 36, 8654.
【2】 Smith, A.B. III; et al.; Gram-scale synthesis of (+)-discodermolide. Org Lett 1999, 1, 11, 1823.
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) 42675 (2S)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-[(2S,3R,4S,5R)-4-methoxy-3,5-dimethyl-6-oxotetrahydro-2H-pyran-2-yl]propanal C17H32O5Si 详情 详情
(XXXIV) 42684 [(2R,3R,4S,5Z,8S,9R,10R,11S,12S,13Z)-3,9-bis[[tert-butyl(dimethyl)silyl]oxy]-11-[(4-methoxybenzyl)oxy]-2,4,6,8,10,12-hexamethyl-5,13,15-hexadecatrienyl](triphenyl)phosphonium iodide C60H90IO4PSi2 详情 详情
(XXXV) 42685 (3R,4S,5R,6S)-4-methoxy-3,5-dimethyl-6-[(2S,3Z,5S,6S,7S,8Z,11S,12R,13R,14S,15S,16Z)-2,6,12-tris[[tert-butyl(dimethyl)silyl]oxy]-14-[(4-methoxybenzyl)oxy]-5,7,9,11,13,15-hexamethyl-3,8,16,18-nonadecatetraenyl]tetrahydro-2H-pyran-2-one C59H106O8Si3 详情 详情
(XXXVI) 42686 (3R,4S,5R,6S)-4-methoxy-3,5-dimethyl-6-((2S,3Z,5S,6S,7S,8Z,11S,12R,13R,14S,15S,16Z)-2,6,12-tris[[tert-butyl(dimethyl)silyl]oxy]-14-hydroxy-5,7,9,11,13,15-hexamethyl-3,8,16,18-nonadecatetraenyl)tetrahydro-2H-pyran-2-one C51H98O7Si3 详情 详情
(XXXVII) 42687 (1S,2R,3R,4S,6Z,8S,9S,10S,11Z,13S)-3,9,13-tris[[tert-butyl(dimethyl)silyl]oxy]-14-[(2S,3R,4S,5R)-4-methoxy-3,5-dimethyl-6-oxotetrahydro-2H-pyran-2-yl]-2,4,6,8,10-pentamethyl-1-[(1S,2Z)-1-methyl-2,4-pentadienyl]-6,11-tetradecadienyl carbamate C52H99NO8Si3 详情 详情

合成路线10

The intermediate (XVI) has been obtained as follows: The ozonolysis of (2S,3S,4S)-2,4-dimethyl-1-(tert-butyldimethylsilyloxy)-5-hexen-3-ol (I) with O3 in DMSO gives the aldehyde (II), which is condensed with phosphorane (III) to yield the chiral heptenoic acid methyl ester (IV). The reaction of (IV) with benzaldehyde (V) by means of KHMDS affords the cyclic ketal (VI), which is desilylated with HF to provide the carbinol (VII). The oxidation of (VII) in methanol gives the dimethylacetal (VIII), which is treated with CSA in methanol to yield the tetrahydropyranylacetic acid methyl ester (IX). The silylation of the OH group of (IX) with Tbdms-OTf affords the silyl ether (X), which is hydrolyzed with LiOH to the corresponding free acetic acid (XI). The condensation of (XI) with N,O-dimethylhydroxylamine (XII) by means of DCC and HOBT provides the methoxyamide (XIII), which is treated with phenylsulfanyltrimethylsilane (XIV), ZnI2 and tetrabutylammonium iodide to give the phenylsulfanyl derivative (XV). Finally, the methoxyamide group of (XV) is reduced with LiAlH4 to afford the target acetaldehyde derivative (XVI).

参考文献 中间体
【1】 Hung, D.T.; et al.; Syntheses of discodermolides useful for investigating microtubule binding and stabilization. J Am Chem Soc 1996, 118, 45, 11054.
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) 42688 (2S,3S,4S)-1-[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethyl-5-hexen-3-ol C14H30O2Si 详情 详情
(II) 42689 (2R,3R,4S)-5-[[tert-butyl(dimethyl)silyl]oxy]-3-hydroxy-2,4-dimethylpentanal C13H28O3Si 详情 详情
(III) 14689 Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate 2605-67-6 C21H19O2P 详情 详情
(IV) 42690 methyl (E,4S,5S,6S)-7-[[tert-butyl(dimethyl)silyl]oxy]-5-hydroxy-4,6-dimethyl-2-heptenoate C16H32O4Si 详情 详情
(V) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(VI) 42691 methyl 2-[(4S,5R,6R)-6-((1S)-2-[[tert-butyl(dimethyl)silyl]oxy]-1-methylethyl)-5-methyl-2-phenyl-1,3-dioxan-4-yl]acetate C23H38O5Si 详情 详情
(VII) 42692 methyl 2-[(4S,5R,6R)-6-[(1S)-2-hydroxy-1-methylethyl]-5-methyl-2-phenyl-1,3-dioxan-4-yl]acetate C17H24O5 详情 详情
(VIII) 42693 methyl 2-[(4S,5R,6S)-6-[(1R)-2,2-dimethoxy-1-methylethyl]-5-methyl-2-phenyl-1,3-dioxan-4-yl]acetate C19H28O6 详情 详情
(IX) 42694 methyl 2-[(2S,3R,4S,5R)-4-hydroxy-6-methoxy-3,5-dimethyltetrahydro-2H-pyran-2-yl]acetate C11H20O5 详情 详情
(X) 42695 methyl 2-((2S,3S,4S,5R)-4-[[tert-butyl(dimethyl)silyl]oxy]-6-methoxy-3,5-dimethyltetrahydro-2H-pyran-2-yl)acetate C17H34O5Si 详情 详情
(XI) 42696 2-((2S,3S,4S,5R)-4-[[tert-butyl(dimethyl)silyl]oxy]-6-methoxy-3,5-dimethyltetrahydro-2H-pyran-2-yl)acetic acid C16H32O5Si 详情 详情
(XII) 13361 (Methoxyamino)methane; N,O-Dimethylhydroxylamine 1117-97-1 C2H7NO 详情 详情
(XIII) 42697 2-((2S,3S,4S,5R)-4-[[tert-butyl(dimethyl)silyl]oxy]-6-methoxy-3,5-dimethyltetrahydro-2H-pyran-2-yl)-N-methoxy-N-methylacetamide C18H37NO5Si 详情 详情
(XIV) 42698 trimethyl(phenylsulfanyl)silane; phenyl trimethylsilyl sulfide 4551-15-9 C9H14SSi 详情 详情
(XV) 42699 2-[(2S,3S,4S,5R,6S)-4-[[tert-butyl(dimethyl)silyl]oxy]-3,5-dimethyl-6-(phenylsulfanyl)tetrahydro-2H-pyran-2-yl]-N-methoxy-N-methylacetamide C23H39NO4SSi 详情 详情
(XVI) 42700 2-[(2S,3S,4S,5R,6S)-4-[[tert-butyl(dimethyl)silyl]oxy]-3,5-dimethyl-6-(phenylsulfanyl)tetrahydro-2H-pyran-2-yl]acetaldehyde C21H34O3SSi 详情 详情

合成路线11

The intermediate (XXXIII) has been obtained as follows: The silylation of the OH group of (2S,3R,4S)-2,4-dimethyl-1-(tert-butyldimethylsilyloxy)-5-hexen-3-ol (XVII) with Tbdms-OTf gives the bis-silyl ether (XVIII), which is ozonolyzed with O3 to yield the aldehyde (XIX). The condensation of (XIX) with the phosphonate (XX) by means of KHMDS affords the methyl heptenoate (XXI), which is reduced with LiAlH4 to the carbinol (XXII). The esterification of (XXII) with pivaloyl chloride and pyridine affords the pivaloyl ester (XXIII), which is selectively desilylated with HF and pyridine to provide the primary alcohol (XXIV). The Swern oxidation of (XXIV) gives the aldehyde (XXV), which is condensed with the phosphonate (XXVI) to yield the terminal acetylene derivative (XXVII). Iodination of (XXVII) with I2 and morpholine affords the iodoacetylene (XXVIII), which is condensed with the already reported acetaldehyde intermediate (XVI) by means of NiCl2/CuCl2 to provide the acetylenic alcohol (XXIX). The reduction of the triple bond of (XXIX) with H2 over Pd/C gives the corresponding allyl alcohol derivative (XXX), which is silylated with Tbdms-OTf to the trisilylated compound (XXXI). Elimination of the pivaloyl protecting group of (XXXI) by means of DIBAL yields the primary alcohol (XXXII), which is treated first with MsCl and TEA and then with LiBr to furnish the target bromoderivative intermediate (XXXIII).

参考文献 中间体
【1】 Hung, D.T.; et al.; Syntheses of discodermolides useful for investigating microtubule binding and stabilization. J Am Chem Soc 1996, 118, 45, 11054.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XVI) 42700 2-[(2S,3S,4S,5R,6S)-4-[[tert-butyl(dimethyl)silyl]oxy]-3,5-dimethyl-6-(phenylsulfanyl)tetrahydro-2H-pyran-2-yl]acetaldehyde C21H34O3SSi 详情 详情
(XVII) 42701 (2S,3R,4S)-1-[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethyl-5-hexen-3-ol C14H30O2Si 详情 详情
(XVIII) 42381 (5S,6R)-2,2,3,3,6,9,9,10,10-nonamethyl-5-[(1R)-1-methyl-2-propenyl]-4,8-dioxa-3,9-disilaundecane; tert-butyl(dimethyl)silyl (2R,3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethyl-5-hexenyl ether C20H44O2Si2 详情 详情
(XIX) 42702 (2R,3S,4S)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethylpentanal C19H42O3Si2 详情 详情
(XX) 42703 methyl 2-[bis(2,2,2-trifluoroethoxy)phosphoryl]propanoate C8H11F6O5P 详情 详情
(XXI) 42704 methyl (Z,4S,5R,6S)-5,7-bis[[tert-butyl(dimethyl)silyl]oxy]-2,4,6-trimethyl-2-heptenoate C23H48O4Si2 详情 详情
(XXII) 42705 (Z,4S,5R,6S)-5,7-bis[[tert-butyl(dimethyl)silyl]oxy]-2,4,6-trimethyl-2-hepten-1-ol C22H48O3Si2 详情 详情
(XXIII) 42706 (Z,4S,5R,6S)-5,7-bis[[tert-butyl(dimethyl)silyl]oxy]-2,4,6-trimethyl-2-heptenyl pivalate C27H56O4Si2 详情 详情
(XXIV) 42707 (Z,4S,5R,6S)-5-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-2,4,6-trimethyl-2-heptenyl pivalate C21H42O4Si 详情 详情
(XXV) 42708 (Z,4S,5R,6R)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,4,6-trimethyl-7-oxo-2-heptenyl pivalate C21H40O4Si 详情 详情
(XXVI) 42709 Diazomethylphoshonic acid dimethyl ester 27491-70-9 C3H7N2O3P 详情 详情
(XXVII) 42710 (Z,4S,5R,6S)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,4,6-trimethyl-2-octen-7-ynyl pivalate C22H40O3Si 详情 详情
(XXVIII) 42711 (Z,4S,5R,6S)-5-[[tert-butyl(dimethyl)silyl]oxy]-8-iodo-2,4,6-trimethyl-2-octen-7-ynyl pivalate C22H39IO3Si 详情 详情
(XXIX) 42712 (Z,4S,5R,6S,9S)-5-[[tert-butyl(dimethyl)silyl]oxy]-10-[(2S,3S,4S,5R,6S)-4-[[tert-butyl(dimethyl)silyl]oxy]-3,5-dimethyl-6-(phenylsulfanyl)tetrahydro-2H-pyran-2-yl]-9-hydroxy-2,4,6-trimethyl-2-decen-7-ynyl 2,2-dimethylpropanoate C43H74O6SSi2 详情 详情
(XXX) 42713 (2Z,4S,5S,6S,7Z,9S)-5-[[tert-butyl(dimethyl)silyl]oxy]-10-[(2S,3S,4S,5R,6S)-4-[[tert-butyl(dimethyl)silyl]oxy]-3,5-dimethyl-6-(phenylsulfanyl)tetrahydro-2H-pyran-2-yl]-9-hydroxy-2,4,6-trimethyl-2,7-decadienyl 2,2-dimethylpropanoate C43H76O6SSi2 详情 详情
(XXXI) 42714 (2Z,4S,5S,6S,7Z,9S)-5,9-bis[[tert-butyl(dimethyl)silyl]oxy]-10-[(2S,3S,4S,5R,6S)-4-[[tert-butyl(dimethyl)silyl]oxy]-3,5-dimethyl-6-(phenylsulfanyl)tetrahydro-2H-pyran-2-yl]-2,4,6-trimethyl-2,7-decadienyl 2,2-dimethylpropanoate n/a C49H90O6SSi3 详情 详情
(XXXII) 42715 (2Z,4S,5S,6S,7Z,9S)-5,9-bis[[tert-butyl(dimethyl)silyl]oxy]-10-[(2S,3S,4S,5R,6S)-4-[[tert-butyl(dimethyl)silyl]oxy]-3,5-dimethyl-6-(phenylsulfanyl)tetrahydro-2H-pyran-2-yl]-2,4,6-trimethyl-2,7-decadien-1-ol n/a C44H82O5SSi3 详情 详情
(XXXIII) 42716 (5S,6Z,8S,9S)-9-[(1S,2Z)-4-bromo-1,3-dimethyl-2-butenyl]-5-[[(2S,3S,4S,5R,6S)-4-[[tert-butyl(dimethyl)silyl]oxy]-3,5-dimethyl-6-(phenylsulfanyl)tetrahydro-2H-pyran-2-yl]methyl]-2,2,3,3,8,11,11,12,12-nonamethyl-4,10-dioxa-3,11-disila-6-tridecene; (2S,3S,4S,5R,6S)-2-((2S,3Z,5S,6S,7S,8Z)-10-bromo-2,6-bis[[tert-butyl(dimethyl)silyl]oxy]-5,7,9-trimethyl-3,8-decadienyl)-3,5-dimethyl-6-(phenylsulfanyl)tetrahydro-2H-pyran-4-yl tert-butyl(dimethyl)silyl ether n/a C44H81BrO4SSi3 详情 详情

合成路线12

The intermediate (XLIII) has been obtained in two related ways: 1) The protection of (2S,3S,4S)-2,4-dimethyl-1-(tert-butyldimethylsilyloxy)-5-hexen-3-ol (I) with p-methoxybenzyl bromide and NaH gives the benzyl ether (XXXIV) which is ozonolyzed with O3, yielding the aldehyde (XXXV), which is condensed with the phosphonium salt (XXXVI) by means of KHMDS to afford the iodovinyl derivative (XXXVII). The homologation of (XXXVII) with vinylzinc bromide (XXXVIII) provides the octadiene derivative (XXXIX), which is desilylated with TFA, furnishing the primary alcohol (XL). The oxidation of (XL) with DMP gives the aldehyde (XLI), which is treated with CH3-MgBr, yielding the secondary alcohol (XLII). Finally, this alcohol is oxidized with DMP to the target intermediate ketone (XLIII). 2) The protection of (2S,3R,4S)-2,4-dimethyl-1-(tert-butyldimethylsilyloxy)-5-hexen-3-ol (XVII) with p-methoxybenzyl bromide and NaH gives the benzyl ether (XLIV), which is ozonolyzed with O3, yielding the aldehyde (XLV). The reaction of (XLV) with CH3-MgBr affords the secondary alcohol (XLVI), which is desilylated with TFA.

参考文献 中间体
【1】 Hung, D.T.; et al.; Syntheses of discodermolides useful for investigating microtubule binding and stabilization. J Am Chem Soc 1996, 118, 45, 11054.
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) 42608 [(1R,3S,4S)-4-aminospiro[2.2]pent-1-yl]methanol C6H11NO 详情 详情
(XXXIV) 42717 tert-butyl([(2S,3S,4S)-3-[(4-methoxybenzyl)oxy]-2,4-dimethyl-5-hexenyl]oxy)dimethylsilane; tert-butyl(dimethyl)silyl (2S,3S,4S)-3-[(4-methoxybenzyl)oxy]-2,4-dimethyl-5-hexenyl ether n/a C22H38O3Si 详情 详情
(XXXV) 42628 (2R,3R,4S)-5-[[tert-butyl(dimethyl)silyl]oxy]-3-[(4-methoxybenzyl)oxy]-2,4-dimethylpentanal C21H36O4Si 详情 详情
(XXXVI) 42718 (iodomethyl)(triphenyl)phosphonium iodide n/a C19H17I2P 详情 详情
(XXXVII) 42719 tert-butyl([(2S,3S,4S,5Z)-6-iodo-3-[(4-methoxybenzyl)oxy]-2,4-dimethyl-5-hexenyl]oxy)dimethylsilane; tert-butyl(dimethyl)silyl (2S,3S,4S,5Z)-6-iodo-3-[(4-methoxybenzyl)oxy]-2,4-dimethyl-5-hexenyl ether n/a C22H37IO3Si 详情 详情
(XXXVIII) 42720 bromo(vinyl)zinc n/a C2H3BrZn 详情 详情
(XXXIX) 42630 tert-butyl([(2S,3S,4S,5Z)-3-[(4-methoxybenzyl)oxy]-2,4-dimethyl-5,7-octadienyl]oxy)dimethylsilane; tert-butyl(dimethyl)silyl (2S,3S,4S,5Z)-3-[(4-methoxybenzyl)oxy]-2,4-dimethyl-5,7-octadienyl ether C24H40O3Si 详情 详情
(XL) 42631 (2S,3S,4S,5Z)-3-[(4-methoxybenzyl)oxy]-2,4-dimethyl-5,7-octadien-1-ol C18H26O3 详情 详情
(XLI) 42632 (2R,3S,4S,5Z)-3-[(4-methoxybenzyl)oxy]-2,4-dimethyl-5,7-octadienal C18H24O3 详情 详情
(XLII) 42721 (3S,4S,5S,6Z)-4-[(4-methoxybenzyl)oxy]-3,5-dimethyl-6,8-nonadien-2-ol C19H28O3 详情 详情
(XLIII) 42722 (3R,4S,5S,6Z)-4-[(4-methoxybenzyl)oxy]-3,5-dimethyl-6,8-nonadien-2-one C19H26O3 详情 详情

合成路线13

The diol (XLVII) has been obtained as follows: The Swern oxidation of the OH groups of (XLVII) gives the 5-oxohexanal derivative (XLVIII), which is condensed with the phosphonium salt (XXXVI) to yield the iodovinyl derivative (XLIX). Finally, this compound is homologated with vinylzinc bromide (XXXVIII) to afford the target intermediate ketone (XLIII).

参考文献 中间体
【1】 Hung, D.T.; et al.; Syntheses of discodermolides useful for investigating microtubule binding and stabilization. J Am Chem Soc 1996, 118, 45, 11054.
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) 42701 (2S,3R,4S)-1-[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethyl-5-hexen-3-ol C14H30O2Si 详情 详情
(XXXVI) 42718 (iodomethyl)(triphenyl)phosphonium iodide n/a C19H17I2P 详情 详情
(XXXVIII) 42720 bromo(vinyl)zinc n/a C2H3BrZn 详情 详情
(XLIII) 42722 (3R,4S,5S,6Z)-4-[(4-methoxybenzyl)oxy]-3,5-dimethyl-6,8-nonadien-2-one C19H26O3 详情 详情
(XLIV) 42723 tert-butyl(dimethyl)silyl (2S,3R,4S)-3-[(4-methoxybenzyl)oxy]-2,4-dimethyl-5-hexenyl ether; tert-butyl([(2S,3R,4S)-3-[(4-methoxybenzyl)oxy]-2,4-dimethyl-5-hexenyl]oxy)dimethylsilane C22H38O3Si 详情 详情
(XLV) 42724 (2R,3S,4S)-5-[[tert-butyl(dimethyl)silyl]oxy]-3-[(4-methoxybenzyl)oxy]-2,4-dimethylpentanal C21H36O4Si 详情 详情
(XLVI) 42725 (3S,4S,5S)-6-[[tert-butyl(dimethyl)silyl]oxy]-4-[(4-methoxybenzyl)oxy]-3,5-dimethyl-2-hexanol n/a C22H40O4Si 详情 详情
(XLVII) 42726 (2S,3S,4S)-3-[(4-methoxybenzyl)oxy]-2,4-dimethyl-1,5-hexanediol n/a C16H26O4 详情 详情
(XLVIII) 42727 (2R,3S,4R)-3-[(4-methoxybenzyl)oxy]-2,4-dimethyl-5-oxohexanal C16H22O4 详情 详情
(XLIX) 42728 (3R,4S,5S,6Z)-7-iodo-4-[(4-methoxybenzyl)oxy]-3,5-dimethyl-6-hepten-2-one C17H23IO3 详情 详情

合成路线14

The target compound has been obtained as follows: The condensation of bromo derivative intermediate (XXXIII) with the ketone intermediate (XLIII) by means of LDA gives the adduct (L), which is methylated with methyl iodide and (Tbdps)2N-Li to yield the pentamethyl compound (LI). The desulfuration of (LI) by reaction with HgCl2 followed by oxidation with Jones reagent affords the tetrahydroyranone derivative (LII), which is debenzylated by means of DDQ to furnish the secondary alcohol (LIII). The reaction of (LIII) with trichloroacetyl isocyanate gives the carbamate (LIV), which is reduced with LiAlH(OBu)3I, yielding the secondary alcohol (LV). Finally, this compound is desilylated by treatment with HCl in methanol.

参考文献 中间体
【1】 Hung, D.T.; et al.; Syntheses of discodermolides useful for investigating microtubule binding and stabilization. J Am Chem Soc 1996, 118, 45, 11054.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXXIII) 42716 (5S,6Z,8S,9S)-9-[(1S,2Z)-4-bromo-1,3-dimethyl-2-butenyl]-5-[[(2S,3S,4S,5R,6S)-4-[[tert-butyl(dimethyl)silyl]oxy]-3,5-dimethyl-6-(phenylsulfanyl)tetrahydro-2H-pyran-2-yl]methyl]-2,2,3,3,8,11,11,12,12-nonamethyl-4,10-dioxa-3,11-disila-6-tridecene; (2S,3S,4S,5R,6S)-2-((2S,3Z,5S,6S,7S,8Z)-10-bromo-2,6-bis[[tert-butyl(dimethyl)silyl]oxy]-5,7,9-trimethyl-3,8-decadienyl)-3,5-dimethyl-6-(phenylsulfanyl)tetrahydro-2H-pyran-4-yl tert-butyl(dimethyl)silyl ether n/a C44H81BrO4SSi3 详情 详情
(XLIII) 42722 (3R,4S,5S,6Z)-4-[(4-methoxybenzyl)oxy]-3,5-dimethyl-6,8-nonadien-2-one C19H26O3 详情 详情
(L) 42729 (3Z,5S,6S,7R,11Z,13S,14S,15S,16Z,18S)-14,18-bis[[tert-butyl(dimethyl)silyl]oxy]-19-[(2S,3S,4S,5R,6S)-4-[[tert-butyl(dimethyl)silyl]oxy]-3,5-dimethyl-6-(phenylsulfanyl)tetrahydro-2H-pyran-2-yl]-6-[(4-methoxybenzyl)oxy]-5,7,11,13,15-pentamethyl-1,3,11 C63H106O7SSi3 详情 详情
(LI) 42730 (3Z,5S,6S,7R,9S,11Z,13S,14S,15S,16Z,18S)-14,18-bis[[tert-butyl(dimethyl)silyl]oxy]-19-[(2S,3S,4S,5R,6S)-4-[[tert-butyl(dimethyl)silyl]oxy]-3,5-dimethyl-6-(phenylsulfanyl)tetrahydro-2H-pyran-2-yl]-6-[(4-methoxybenzyl)oxy]-5,7,9,11,13,15-hexamethyl-1, C64H108O7SSi3 详情 详情
(LII) 42731 (3R,4S,5S,6S)-6-[(2S,3Z,5S,6S,7S,8Z,11S,13R,14S,15S,16Z)-2,6-bis[[tert-butyl(dimethyl)silyl]oxy]-14-[(4-methoxybenzyl)oxy]-5,7,9,11,13,15-hexamethyl-12-oxo-3,8,16,18-nonadecatetraenyl]-4-[[tert-butyl(dimethyl)silyl]oxy]-3,5-dimethyltetrahydro-2H-pyr C58H102O8Si3 详情 详情
(LIII) 42732 (3R,4S,5S,6S)-6-((2S,3Z,5S,6S,7S,8Z,11S,13R,14S,15S,16Z)-2,6-bis[[tert-butyl(dimethyl)silyl]oxy]-14-hydroxy-5,7,9,11,13,15-hexamethyl-12-oxo-3,8,16,18-nonadecatetraenyl)-4-[[tert-butyl(dimethyl)silyl]oxy]-3,5-dimethyltetrahydro-2H-pyran-2-one C50H94O7Si3 详情 详情
(LIV) 42733 (1S,2R,4S,6Z,8S,9S,10S,11Z,13S)-9,13-bis[[tert-butyl(dimethyl)silyl]oxy]-14-((2S,3S,4S,5R)-4-[[tert-butyl(dimethyl)silyl]oxy]-3,5-dimethyl-6-oxotetrahydro-2H-pyran-2-yl)-2,4,6,8,10-pentamethyl-1-[(1S,2Z)-1-methyl-2,4-pentadienyl]-3-oxo-6,11-tetradec C51H95NO8Si3 详情 详情
(LV) 42734 (1S,2S,3R,4S,6Z,8S,9S,10S,11Z,13S)-9,13-bis[[tert-butyl(dimethyl)silyl]oxy]-14-((2S,3S,4S,5R)-4-[[tert-butyl(dimethyl)silyl]oxy]-3,5-dimethyl-6-oxotetrahydro-2H-pyran-2-yl)-3-hydroxy-2,4,6,8,10-pentamethyl-1-[(1S,2Z)-1-methyl-2,4-pentadienyl]-6,11-t C51H97NO8Si3 详情 详情

合成路线15

The intermediate (IV) has been obtained as follows: The condensation of silylated propionic aldehyde (I) with the mesylated acetylene (II) by means of Pd(PPh3)4 and Et2Zn in THF gives the hexanol (III), which is protected with chloromethyl (methyl)ether by means of DIEA and Bu4NI, yielding the desired acetylenic intermediate (IV) (1) The intermediate (XXII) has been obtained as follows: The desilylation of hexanol (III) with TBAF gives the acetylenic diol (V), which is protected with p-methoxy-benzaldehyde diethyl acetal (VI) catalyzed by CSA, affording the cyclic ketal (VII). The homologation of (VI) with formaldehyde and BuLi yields the propargyl alcohol (VIII), which is treated with Ac2O to provide the acetate (IX) (1). The partial hydrogenation of the triple bond of (IX) with Red-Al gives the allyl alcohol (X), which is asymmetrically epoxidated by the Sharpless method, yielding the epoxide (XI). The reduction of (XI) with Red-Al affords the chiral diol (XII), which is monoesterified with pivaloyl chloride and TEA to provide the pivalate (XIII). The silylation of (XIII) with Tbdms-OTf and lutidine furnishes the silylated pivalate (XIV), which is hydrolyzed with K2CO3 in methanol to give the primary alcohol (XV). The Swern oxidation of (XV) gives the aldehyde (XVI) (2), which is condensed with the intermediate acetylenic derivative (IV) by means of BuLi and LiBr in THF, yielding the adduct (XVII). The partial reduction of the triple bond of (XVII) with H2 over Pd/Pb/CaCO3 gives compound (XVIII) with a cis double bond. The protection of the OH group of (XVIII) as the methoxymethyl ether, followed by desilylation with HF in pyridine, yields the primary alcohol (XIX), which is oxidized with DMP to the corresponding aldehyde (XX). Finally, this compound is condensed with the iodophosphorane (XXI) to afford the target intermediate, the iodo compound (XXII).

参考文献 中间体
【1】 Marsshall, J.A.; et al.; Synthesis of discodermolide subunits by SE2' addition of nonracemic allenylstannanes to aldehydes. J Org Chem 1998, 63, 3, 817.
【2】 Marshall, J.A.; Hohns, B.A.; Total synthesis of (+)-discodermolide. J Org Chem 1998, 63, 22, 7885.
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) 42735 (2S)-2-methyl-3-[(triethylsilyl)oxy]propanal C10H22O2Si 详情 详情
(II) 42736 methyl(dimethylene)[[(1R)-1-methyl-2-propynyl]oxy]-lambda(6)-sulfane C7H12OS 详情 详情
(III) 42737 (2S,3S,4S)-2,4-dimethyl-1-[(triethylsilyl)oxy]-5-hexyn-3-ol C14H28O2Si 详情 详情
(IV) 42738 (2S,3S,4S)-3-(methoxymethoxy)-2,4-dimethyl-5-hexynyl triethylsilyl ether; (5S,6S)-9,9-diethyl-6-methyl-5-[(1S)-1-methyl-2-propynyl]-2,4,8-trioxa-9-silaundecane C16H32O3Si 详情 详情
(V) 42739 (2S,3S,4S)-2,4-dimethyl-5-hexyne-1,3-diol C8H14O2 详情 详情
(VI) 35670 1-(diethoxymethyl)-4-methoxybenzene; 4-(diethoxymethyl)phenyl methyl ether C12H18O3 详情 详情
(VII) 42740 methyl 4-[(2R,4S,5S)-5-methyl-4-[(1S)-1-methyl-2-propynyl]-1,3-dioxan-2-yl]phenyl ether; (2R,4S,5S)-2-(4-methoxyphenyl)-5-methyl-4-[(1S)-1-methyl-2-propynyl]-1,3-dioxane C16H20O3 详情 详情
(VIII) 42741 (4S)-4-[(2R,4S,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-2-pentyn-1-ol C17H22O4 详情 详情
(IX) 42742 (4S)-4-[(2R,4S,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-2-pentynyl acetate C19H24O5 详情 详情
(X) 42743 (E,4S)-4-[(2R,4S,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-2-penten-1-ol C17H24O4 详情 详情
(XI) 42744 ((2R,3R)-3-[(1S)-1-[(2R,4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]ethyl]oxiranyl)methanol C17H24O5 详情 详情
(XII) 42745 (3S,4S)-4-[(2R,4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-1,3-pentanediol C17H26O5 详情 详情
(XIII) 42746 (3S,4S)-3-hydroxy-4-[(2R,4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]pentyl pivalate C22H34O6 详情 详情
(XIV) 42747 (3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-[(2R,4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]pentyl pivalate C28H48O6Si 详情 详情
(XV) 42748 (3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-[(2R,4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-1-pentanol C23H40O5Si 详情 详情
(XVI) 42749 (3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-[(2R,4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]pentanal C23H38O5Si 详情 详情
(XVII) 42750 (5S,7S,10S,11S,12S)-15,15-diethyl-11-(methoxymethoxy)-5-[(1R)-1-[(2R,4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]ethyl]-2,2,3,3,10,12-hexamethyl-4,14-dioxa-3,15-disila-8-heptadecyn-7-ol C39H70O8Si2 详情 详情
(XVIII) 42751 (5S,7S,8Z,10S,11S,12S)-15,15-diethyl-11-(methoxymethoxy)-5-[(1R)-1-[(2R,4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]ethyl]-2,2,3,3,10,12-hexamethyl-4,14-dioxa-3,15-disila-8-heptadecen-7-ol C39H72O8Si2 详情 详情
(XIX) 42752 (2S,3S,4S,5Z,7S,9S,10R)-9-[[tert-butyl(dimethyl)silyl]oxy]-3,7-bis(methoxymethoxy)-10-[(2R,4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-2,4-dimethyl-5-undecen-1-ol C35H62O9Si 详情 详情
(XX) 42753 (2R,3S,4S,5Z,7S,9S,10R)-9-[[tert-butyl(dimethyl)silyl]oxy]-3,7-bis(methoxymethoxy)-10-[(2R,4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-2,4-dimethyl-5-undecenal C35H60O9Si 详情 详情
(XXI) 42754 (1-iodoethylidene)(triphenyl)phosphorane C20H18IP 详情 详情
(XXII) 42755 (5S,6S,7Z,9S,11S)-5-[(1S,2Z)-3-iodo-1-methyl-2-butenyl]-9-(methoxymethoxy)-11-[(1R)-1-[(2R,4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]ethyl]-6,13,13,14,14-pentamethyl-2,4,12-trioxa-13-sila-7-pentadecene; tert-butyl(dimethyl)silyl (1S,3S,4Z,6S,7S,8S,9Z)-10-iodo-3,7-bis(methoxymethoxy)-1-[(1R)-1-[(2R,4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]ethyl]-6,8-dimethyl-4,9-undecadienyl ether C37H63IO8Si 详情 详情

合成路线16

The intermediate (XLI) has been obtained as follows: The condensation of the silylated propionic aldehyde (I) with the chiral allene (XXIII) by means of BF3/Et2O gives the acetylenic alcohol (XXIV), which is desilylated with TBAF, yielding the diol (XXV). The reaction of (XXV) with p-methoxybenzaldehyde dimethyl acetal (XXVI) affords the cyclic ketal (XXVII), which is treated with Red-Al to provided the primary alcohol (XXVIII). The asymmetric Sharpless epoxidation of the double bond of (XXVIII) gives the epoxide (XXIX), which is methylated with Me2CuCNLi2, yielding the chiral diol (XXX). The regioselective acylation of (XXX) with pivaloyl chloride affords the monopivalate (XXXI), which is silylated with Tes-Otf, providing the silyl ether (XXXII). The reductive cleavage of the pivalate ester of (XXXII) with Red-Al furnishes the primary alcohol (XXXIII), which is oxidized with DMP to the aldehyde (XXXIV). The condensation of (XXXIV) with the bromoallyl compound (XXXV) gives the homoallyl alcohol (XXXVI), which is treated with NaH in THF to afford the conjugated diene (XXXVII) (2). The reductive cleavage of the cyclic ketal group of (XXXVII) with iBu2AlH gives the primary alcohol (XXXVIII), which is treated with I2 and PPh3 to yield the iodo derivative (XXXIX). Finally, this compound is condensed with 9-methoxy-9-borabicyclo[3,3,1]nonane (XL) by means of BuLi in THF/ethyl ether to furnish the desired intermediate, the lithium salt (XLI).

参考文献 中间体
【1】 Marshall, J.A.; Hohns, B.A.; Total synthesis of (+)-discodermolide. J Org Chem 1998, 63, 22, 7885.
【2】 Marsshall, J.A.; et al.; Synthesis of discodermolide subunits by SE2' addition of nonracemic allenylstannanes to aldehydes. J Org Chem 1998, 63, 3, 817.
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) 42735 (2S)-2-methyl-3-[(triethylsilyl)oxy]propanal C10H22O2Si 详情 详情
(XXIII) 42756 2-(tributylstannyl)-2,3-pentadienyl pivalate C22H42O2Sn 详情 详情
(XXIV) 42757 (4R,5S,6S)-5-hydroxy-4,6-dimethyl-7-[(triethylsilyl)oxy]-2-heptynyl pivalate C20H38O4Si 详情 详情
(XXV) 42758 (4R,5S,6S)-5,7-dihydroxy-4,6-dimethyl-2-heptynyl pivalate C14H24O4 详情 详情
(XXVI) 26485 1-(dimethoxymethyl)-4-methoxybenzene 2186-92-7 C10H14O3 详情 详情
(XXVII) 42759 (4R)-4-[(2R,4S,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-2-pentynyl pivalate C22H30O5 详情 详情
(XXVIII) 42760 (E,4R)-4-[(2R,4S,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-2-penten-1-ol C17H24O4 详情 详情
(XXIX) 42761 ((2S,3R)-3-[(1R)-1-[(2R,4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]ethyl]oxiranyl)methanol C17H24O5 详情 详情
(XXX) 42762 (2S,3S,4R)-4-[(2R,4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-2-methyl-1,3-pentanediol C18H28O5 详情 详情
(XXXI) 42763 (2S,3S,4R)-3-hydroxy-4-[(2R,4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-2-methylpentyl pivalate C23H36O6 详情 详情
(XXXII) 42764 (2S,3S,4S)-4-[(2R,4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-2-methyl-3-[(triethylsilyl)oxy]pentyl pivalate C29H50O6Si 详情 详情
(XXXIII) 42765 (2S,3S,4S)-4-[(2R,4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-2-methyl-3-[(triethylsilyl)oxy]-1-pentanol C24H42O5Si 详情 详情
(XXXIV) 42766 (2R,3R,4S)-4-[(2R,4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-2-methyl-3-[(triethylsilyl)oxy]pentanal C24H40O5Si 详情 详情
(XXXV) 42629 (1-bromo-2-propenyl)(trimethyl)silane 94397-40-7 C6H13BrSi 详情 详情
(XXXVI) 42767 (3S,4R,5S,6S,7S)-7-[(2R,4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-5-methyl-6-[(triethylsilyl)oxy]-3-(trimethylsilyl)-1-octen-4-ol C30H54O5Si2 详情 详情
(XXXVII) 42768 triethyl[((1S,2S,3Z)-1-[(1S)-1-[(2R,4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]ethyl]-2-methyl-3,5-hexadienyl)oxy]silane; 4-((2R,4R,5S)-4-[(1S,2S,3S,4Z)-1,3-dimethyl-2-[(triethylsilyl)oxy]-4,6-heptadienyl]-5-methyl-1,3-dioxan-2-yl)phenyl methyl ether C27H44O4Si 详情 详情
(XXXVIII) 42769 (2S,3R,4S,5S,6S,7Z)-3-[(4-methoxybenzyl)oxy]-2,4,6-trimethyl-5-[(triethylsilyl)oxy]-7,9-decadien-1-ol C27H46O4Si 详情 详情
(XXXIX) 42770 triethyl[((1S,2S,3Z)-1-[(1S,2S,3R)-4-iodo-2-[(4-methoxybenzyl)oxy]-1,3-dimethylbutyl]-2-methyl-3,5-hexadienyl)oxy]silane; (1S,2S,3Z)-1-[(1S,2S,3R)-4-iodo-2-[(4-methoxybenzyl)oxy]-1,3-dimethylbutyl]-2-methyl-3,5-hexadienyl triethylsilyl ether C27H45IO3Si 详情 详情
(XL) 42771 9-methoxy-9-borabicyclo[3.3.1]nonane 38050-71-4 C9H17BO 详情 详情
(XLI) 42772 　 C36H62BLiO4Si 详情 详情

合成路线17

The target compound has been obtained as follows: The condensation of the intermediate iodo compound (XXII) with the intermediate lithium salt (XLI) gives the adduct (XLII), which is treated with iBu2AlH to yield the primary alcohol (XLIII). The oxidation of (XLIII) with DMP and NaClO2, followed by esterification with trimethylsilyldiazomethane affords the methyl ester (XLIV), which is selectively desilylated (elimination of the Tes group) with Ts-OH, providing the secondary alcohol (XLV). The reaction of (XLV) with trichloroacetyl isocyanate gives the corresponding carbamate (XLVI), which is debenzylated with DDQ to afford the precursor. Finally, (XLVII) is fully deprotected with HCl in methanol.

参考文献 中间体
【1】 Marshall, J.A.; Hohns, B.A.; Total synthesis of (+)-discodermolide. J Org Chem 1998, 63, 22, 7885.
【2】 Marsshall, J.A.; et al.; Synthesis of discodermolide subunits by SE2' addition of nonracemic allenylstannanes to aldehydes. J Org Chem 1998, 63, 3, 817.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXII) 42755 (5S,6S,7Z,9S,11S)-5-[(1S,2Z)-3-iodo-1-methyl-2-butenyl]-9-(methoxymethoxy)-11-[(1R)-1-[(2R,4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]ethyl]-6,13,13,14,14-pentamethyl-2,4,12-trioxa-13-sila-7-pentadecene; tert-butyl(dimethyl)silyl (1S,3S,4Z,6S,7S,8S,9Z)-10-iodo-3,7-bis(methoxymethoxy)-1-[(1R)-1-[(2R,4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]ethyl]-6,8-dimethyl-4,9-undecadienyl ether C37H63IO8Si 详情 详情
(XLI) 42772 　 C36H62BLiO4Si 详情 详情
(XLII) 42773 (5S,7S,8Z,10S,11S,12S,13Z,16S,17R,18S,19S)-21,21-diethyl-17-[(4-methoxybenzyl)oxy]-7,11-bis(methoxymethoxy)-5-[(1R)-1-[(2R,4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]ethyl]-2,2,3,3,10,12,14,16,18-nonamethyl-19-[(1S,2Z)-1-methyl-2,4-pentadie; tert-butyl(dimethyl)silyl (1S,3S,4Z,6S,7S,8S,9Z,12S,13R,14S,15S,16S,17Z)-13-[(4-methoxybenzyl)oxy]-3,7-bis(methoxymethoxy)-1-[(1R)-1-[(2R,4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]ethyl]-6,8,10,12,14,16-hexamethyl-15-[(triethylsilyl)oxy]-4 C64H108O11Si2 详情 详情
(XLIII) 42774 (2S,3R,4R,5S,7S,8Z,10S,11S,12S,13Z,16S,17R,18S,19S,20S,21Z)-5-[[tert-butyl(dimethyl)silyl]oxy]-3,17-bis[(4-methoxybenzyl)oxy]-7,11-bis(methoxymethoxy)-2,4,10,12,14,16,18,20-octamethyl-19-[(triethylsilyl)oxy]-8,13,21,23-tetracosatetraen-1-ol C64H110O11Si2 详情 详情
(XLIV) 42775 methyl (2R,3S,4R,5S,7S,8Z,10S,11S,12S,13Z,16S,17R,18S,19S,20S,21Z)-5-[[tert-butyl(dimethyl)silyl]oxy]-3,17-bis[(4-methoxybenzyl)oxy]-7,11-bis(methoxymethoxy)-2,4,10,12,14,16,18,20-octamethyl-19-[(triethylsilyl)oxy]-8,13,21,23-tetracosatetraenoate C65H110O12Si2 详情 详情
(XLV) 42776 methyl (2R,3S,4R,5S,7S,8Z,10S,11S,12S,13Z,16S,17R,18R,19S,20S,21Z)-5-[[tert-butyl(dimethyl)silyl]oxy]-19-hydroxy-3,17-bis[(4-methoxybenzyl)oxy]-7,11-bis(methoxymethoxy)-2,4,10,12,14,16,18,20-octamethyl-8,13,21,23-tetracosatetraenoate C59H96O12Si 详情 详情
(XLVI) 42777 methyl (2R,3S,4R,5S,7S,8Z,10S,11S,12S,13Z,16S,17R,18S,19S,20S,21Z)-19-[(aminocarbonyl)oxy]-5-[[tert-butyl(dimethyl)silyl]oxy]-3,17-bis[(4-methoxybenzyl)oxy]-7,11-bis(methoxymethoxy)-2,4,10,12,14,16,18,20-octamethyl-8,13,21,23-tetracosatetraenoate C60H97NO13Si 详情 详情
(XLVII) 42778 methyl (2R,3S,4R,5S,7S,8Z,10S,11S,12S,13Z,16S,17R,18S,19S,20S,21Z)-19-[(aminocarbonyl)oxy]-5-[[tert-butyl(dimethyl)silyl]oxy]-3,17-dihydroxy-7,11-bis(methoxymethoxy)-2,4,10,12,14,16,18,20-octamethyl-8,13,21,23-tetracosatetraenoate C44H81NO11Si 详情 详情

合成路线18

The Grignard reaction of the chiral pentanamide (I) with methylmagnesium bromide in ether gives the hydroxyhexanamide (II), which is oxidized with SO3/pyridine in DMSO to yield the oxohexanamide (III). The aldol condensation of the oxohexanamide (III) with the chiral aldehyde (IV) by means of (+)-beta-chlorodiisopinocampheylborane and TEA in ethyl ether affords the aldol (V), which is reduced with tetramethylammonium triacetoxyborohydride in acetonitrile/acetic acid to provide the dihydroxyamide (VI). Finally, this compound is deprotected and lactonized by treatment with HCl in THF/water to furnish the target discodermolide.

参考文献 中间体
【1】 Kinder, F.R. (Novartis AG; Novartis-Erfindungen VmbH); Process for preparing discodermolide and analogues thereof. WO 0212220 .
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) 52184 (2R,3S,4R)-3-{[tert-Butyl(dimethyl)silyl]oxy}-N-methoxy-2,4-dimethyl-5-oxopentanamide C14H29NO4Si 详情 详情
(II) 52185 (2R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-hydroxy-N-methoxy-2,4-dimethylhexanamide C15H33NO4Si 详情 详情
(III) 52186 (2R,3S,4R)-3-{[tert-butyl(dimethyl)silyl]oxy}-N-methoxy-2,4-dimethyl-5-oxohexanamide C15H31NO4Si 详情 详情
(IV) 42650 (1S,2R,3R,4S,6Z,8S,9S,10S,11Z)-3,9-bis[[tert-butyl(dimethyl)silyl]oxy]-2,4,6,8,10-pentamethyl-1-[(1S,2Z)-1-methyl-2,4-pentadienyl]-13-oxo-6,11-tridecadienyl carbamate C37H69NO5Si2 详情 详情
(V) 52187 (1S,2R,3R,4S,6Z,8S,9S,10S,11Z,13S,16R,17S,18R)-3,9,17-tris{[tert-butyl(dimethyl)silyl]oxy}-13-hydroxy-19-(methoxyamino)-2,4,6,8,10,16,18-heptamethyl-1-[(1S,2Z)-1-methyl-2,4-pentadienyl]-15,19-dioxo-6,11-nonadecadienyl carbamate C52H100N2O9Si3 详情 详情
(VI) 52188 (1S,2R,3R,4S,6Z,8S,9S,10S,11Z,13S,15S,16S,17S,18R)-3,9,17-tris{[tert-butyl(dimethyl)silyl]oxy}-13,15-dihydroxy-19-(methoxyamino)-2,4,6,8,10,16,18-heptamethyl-1-[(1S,2Z)-1-methyl-2,4-pentadienyl]-19-oxo-6,11-nonadecadienyl carbamate C52H102N2O9Si3 详情 详情

合成路线19

Chiral 5-oxohexanoic ester intermediate (XI): The reaction of 3-hydroxy-2(S)-methylpropionic acid methyl ester (I) with benzyl trichloroacetimidate gives the benzyl ether (II), which is condensed with ethylmagnesium bromide in THF to yield the chiral ketone (III). The reaction of (III) with (c-hexyl)2B-Cl ad TEA affords the boron enolate (IV), which is condensed with acetaldehyde to provide the intermediate boron aldolate (V). The reduction of (V) with LiBH4 and H2O2 in aqueous methanol gives the chiral diol (VI), which is silylated by means of Tbdms-OTf to yield the bis-silyl ether (VII). The selective deprotection of (VII) by means of CSA in methanol/dichloromethane affords the alcohol (VIII), which is debenzylated by means of H2 over Pd/C in ethanol to provide the diol (IX). The oxidation of (IX) with (COCl)2 and DMSO in dichloromethane gives the intermediate oxoaldehyde that is oxidized with NaClO2 to yield the 5-oxohexanoic acid (X). Finally, this compound is methylated with diazomethane in ethyl ether to afford the target, chiral 5-oxohexanoic ester intermediate (XI).

参考文献 中间体
【1】 Paterson, I.; Florence, G.J.; Gerlach, K.; Scott, J.P.; Sereinig, N.; A practical synthesis of (+)-discodermolide and analogues: Fragment union by complex aldol reactions. J Am Chem Soc 2001, 123, 39, 9535.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 17128 Methyl (2S)-3-hydroxy-2-methylpropanoate 72657-23-9 C5H10O3 详情 详情
(II) 62835 methyl (2S)-3-(benzyloxy)-2-methylpropanoate C12H16O3 详情 详情
(III) 42633 (2S)-1-(benzyloxy)-2-methyl-3-pentanone C13H18O2 详情 详情
(IV) 62836 (E)-1-[(1S)-2-(benzyloxy)-1-methylethyl]-1-propenyl dicyclohexylborinate C25H39BO2 详情 详情
(V) 62837 　 C27H43BO3 详情 详情
(VI) 42635 (2S,3S,4R,5S)-6-(benzyloxy)-3,5-dimethyl-2,4-hexanediol C15H24O3 详情 详情
(VII) 42636 benzyl (2S,3R,4S,5S)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethylhexyl ether; (5R,6S,7S)-5-[(1S)-2-(benzyloxy)-1-methylethyl]-2,2,3,3,6,7,9,9,10,10-decamethyl-4,8-dioxa-3,9-disilaundecane n/a C27H52O3Si2 详情 详情
(VIII) 42637 (2S,3S,4R,5S)-6-(benzyloxy)-4-[[tert-butyl(dimethyl)silyl]oxy]-3,5-dimethyl-2-hexanol n/a C21H38O3Si 详情 详情
(IX) 42638 (2S,3R,4S,5S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethyl-1,5-hexanediol C14H32O3Si 详情 详情
(X) 42639 (2R,3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethyl-5-oxohexanoic acid C14H28O4Si 详情 详情
(XI) 42640 methyl (2R,3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethyl-5-oxohexanoate C15H30O4Si 详情 详情

合成路线20

Chiral pentanoic aldehyde intermediate (XIX): The reaction of the chiral benzoate ester (XII) with (c-Hex)2B-Cl and Me2EtN in ethyl ether gives the boron enolate (XIII), which is condensed with the propionaldehyde (XIV) to yield the benzoate ester (XV). The protection of the OH group of (XV) by means of p-methoxybenzyl trichloroacetimidate and Tf-OH affords the corresponding p-methoxybenzyl ether (XVI). The reduction of the ketonic group of (XVI) by means of LiAlH4 in THF or NaBH4 in methanol provides the alcohol (XVII), which is debenzoylated with K2CO3 in methanol to furnish the diol (XVIII). Finally the vicinal diol (XVIII) is oxidized with NaIO4 in aqueous methanol to obtain the target, chiral pentanoic aldehyde intermediate (XIX).

参考文献 中间体
【1】 Paterson, I.; Florence, G.J.; Gerlach, K.; Scott, J.P.; Sereinig, N.; A practical synthesis of (+)-discodermolide and analogues: Fragment union by complex aldol reactions. J Am Chem Soc 2001, 123, 39, 9535.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XII) 42623 (1S)-1-methyl-2-oxobutyl benzoate C12H14O3 详情 详情
(XIII) 62838 (1S,2E)-2-{[cyclohexyl(methyl)boryl]oxy}-1-methyl-2-butenyl benzoate C19H27BO3 详情 详情
(XIV) 42624 (2S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methylpropanal C10H22O2Si 详情 详情
(XV) 42625 (1S,3R,4R,5S)-6-[[tert-butyl(dimethyl)silyl]oxy]-4-hydroxy-1,3,5-trimethyl-2-oxohexyl benzoate C22H36O5Si 详情 详情
(XVI) 42626 (1S,3R,4R,5S)-6-[[tert-butyl(dimethyl)silyl]oxy]-4-[(4-methoxybenzyl)oxy]-1,3,5-trimethyl-2-oxohexyl benzoate C30H44O6Si 详情 详情
(XVII) 62839 (1S,3S,4R,5S)-6-{[tert-butyl(dimethyl)silyl]oxy}-2-hydroxy-4-[(4-methoxybenzyl)oxy]-1,3,5-trimethylhexyl benzoate C30H46O6Si 详情 详情
(XVIII) 42627 (2S,4S,5R,6S)-7-[[tert-butyl(dimethyl)silyl]oxy]-5-[(4-methoxybenzyl)oxy]-4,6-dimethyl-2,3-heptanediol C23H42O5Si 详情 详情
(XIX) 42628 (2R,3R,4S)-5-[[tert-butyl(dimethyl)silyl]oxy]-3-[(4-methoxybenzyl)oxy]-2,4-dimethylpentanal C21H36O4Si 详情 详情

合成路线21

Chiral octadienoic aldehyde intermediate (XXV): The reaction of the silylated allyl bromide (XX) with CrCl2 in THF gives the Cr derivative (XXI), which is condensed with the chiral pentanoic aldehyde intermediate (XIX) to yield the secondary alcohol (XXII). Elimination of the Tms group of (XXII) by means of KH in THF affords the desired (Z)-diene (XXIII), which is desilylated by means of CSA in methanol/dichloromethane to provide the primary alcohol (XXIV). Finally this compound is oxidized by means of DMP in dichloromethane to furnish the target, chiral octadienoic aldehyde intermediate (XXV).

参考文献 中间体
【1】 Paterson, I.; Florence, G.J.; Gerlach, K.; Scott, J.P.; Sereinig, N.; A practical synthesis of (+)-discodermolide and analogues: Fragment union by complex aldol reactions. J Am Chem Soc 2001, 123, 39, 9535.
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) 42628 (2R,3R,4S)-5-[[tert-butyl(dimethyl)silyl]oxy]-3-[(4-methoxybenzyl)oxy]-2,4-dimethylpentanal C21H36O4Si 详情 详情
(XX) 42629 (1-bromo-2-propenyl)(trimethyl)silane 94397-40-7 C6H13BrSi 详情 详情
(XXI) 62840 chloro[(E)-3-(trimethylsilyl)-2-propenyl]chromium C6H13ClCrSi 详情 详情
(XXII) 62841 (3R,4S,5S,6R,7S)-8-{[tert-butyl(dimethyl)silyl]oxy}-6-[(4-methoxybenzyl)oxy]-5,7-dimethyl-3-(trimethylsilyl)-1-octen-4-ol C27H50O4Si2 详情 详情
(XXIII) 46630 2,4,4-trimethyl-5,6-dihydro-4H-1,3-oxazine C7H13NO 详情 详情
(XXIV) 42631 (2S,3S,4S,5Z)-3-[(4-methoxybenzyl)oxy]-2,4-dimethyl-5,7-octadien-1-ol C18H26O3 详情 详情
(XXV) 42632 (2R,3S,4S,5Z)-3-[(4-methoxybenzyl)oxy]-2,4-dimethyl-5,7-octadienal C18H24O3 详情 详情

合成路线22

Synthesis of the target (+)-Discodermolide: The reaction of 3-hydroxy-2(S)-methylpropionic acid methyl ester (I) with p-methoxybenzyl trichloroacetimidate gives the benzyl ether (XXVI), which is condensed with ethylmagnesium bromide in THF to yield the chiral ketone (XXVII). The reaction of (XXVII) with 2-methylpropenal (XXVIII) by means of (c-Hex)2B-Cl and TEA in ethyl ether affords the chiral hydroxyketone (XXIX), which is reduced with SmI2 and propanal to provide the beta-diol monoester (XXX). The methanolysis of (XXX) by means of K2CO3 furnishes the diol (XXXI), which can also be obtained directly by reduction of (XXIX) with Me4NBH(OAc)3 in acetonitrile/AcOH. The reaction of (XXXI) with the diethylacetal (XXXII) and PPTS in refluxing toluene gives the phenylselenoacetal (XXXIII), which is oxidized with NaIO4 and treated with DBU to achieve a Claisen rearrangement and yield the eight member lactone (XXXIV). The hydrolysis of (XXXIV) with KOH in refluxing aqueous methanol affords the hydroxyacid (XXXV), which is esterified with 2,6-dimethylphenol (XXXVI) by means of DCC and DMAP in dichloromethane to provide the phenyl ester (XXXVII). The reaction of (XXXVII) with Tbdms-OTf and lutidine gives the silylated ester (XXXVIII). Alternatively, the methanolysis of the lactone (XXXIV) with NaOMe in methanol gives the hydroxyester (XXXIX), which is treated with Tbdms-OTf as before to yield the silylated ester (XL). The hydrolysis of the ester (XL) with KOH in refluxing aqueous methanol affords the silylated hydroxyacid (XLI), which is esterified with 2,6-dimethylphenol (XXXVI) by means of DCC and DMAP to provide the already reported phenyl ester (XXXVIII).

参考文献 中间体
【1】 Paterson, I.; Florence, G.J.; Gerlach, K.; Scott, J.P.; Sereinig, N.; A practical synthesis of (+)-discodermolide and analogues: Fragment union by complex aldol reactions. J Am Chem Soc 2001, 123, 39, 9535.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 17128 Methyl (2S)-3-hydroxy-2-methylpropanoate 72657-23-9 C5H10O3 详情 详情
(XXVI) 42654 methyl (2S)-3-[(4-methoxybenzyl)oxy]-2-methylpropanoate C13H18O4 详情 详情
(XXVII) 42614 (2S)-1-[(4-methoxybenzyl)oxy]-2-methyl-3-pentanone C14H20O3 详情 详情
(XXVIII) 11387 2-Methylacrylaldehyde; Methacrylaldehyde 78-85-3 C4H6O 详情 详情
(XXIX) 42615 (2S,4S,5R)-5-hydroxy-1-[(4-methoxybenzyl)oxy]-2,4,6-trimethyl-6-hepten-3-one C18H26O4 详情 详情
(XXX) 62842 (1R)-1-{(1R,2S,3S)-2-hydroxy-4-[(4-methoxybenzyl)oxy]-1,3-dimethylbutyl}-2-methyl-2-propenyl butyrate C22H34O5 详情 详情
(XXXI) 62843 (3R,4R,5S,6S)-7-[(4-methoxybenzyl)oxy]-2,4,6-trimethyl-1-heptene-3,5-diol C18H28O4 详情 详情
(XXXII) 62844 1-[(2,2-dipropoxyethyl)selanyl]benzene; 2-(phenylselanyl)-1-propoxyethyl propyl ether C14H22O2Se 详情 详情
(XXXIII) 42618 (4R,5S,6S)-4-isopropenyl-6-[(1S)-2-[(4-methoxybenzyl)oxy]-1-methylethyl]-5-methyl-2-[(phenylselanyl)methyl]-1,3-dioxane; (2S)-2-[(4S,5S,6R)-6-isopropenyl-5-methyl-2-[(phenylselanyl)methyl]-1,3-dioxan-4-yl]propyl 4-methoxybenzyl ether C26H34O4Se 详情 详情
(XXXIV) 42620 (7S,8R)-8-[(1S)-2-[(4-methoxybenzyl)oxy]-1-methylethyl]-5,7-dimethyl-3,4,7,8-tetrahydro-2H-oxocin-2-one C20H28O4 详情 详情
(XXXV) 62845 (Z,6S,7R,8S)-7-hydroxy-9-[(4-methoxybenzyl)oxy]-4,6,8-trimethyl-4-nonenoic acid C20H30O5 详情 详情
(XXXVI) 37388 2,6-dimethylphenol 576-26-1 C8H10O 详情 详情
(XXXVII) 62847 2,6-dimethylphenyl (Z,6S,7R,8S)-7-hydroxy-9-[(4-methoxybenzyl)oxy]-4,6,8-trimethyl-4-nonenoate C28H38O5 详情 详情
(XXXVIII) 42622 2,6-dimethylphenyl (Z,6S,7R,8S)-7-[[tert-butyl(dimethyl)silyl]oxy]-9-[(4-methoxybenzyl)oxy]-4,6,8-trimethyl-4-nonenoate C34H52O5Si 详情 详情
(XXXIX) 62846 methyl (Z,6S,7R,8S)-7-hydroxy-9-[(4-methoxybenzyl)oxy]-4,6,8-trimethyl-4-nonenoate C21H32O5 详情 详情
(XL) 42621 methyl (Z,6S,7R,8S)-7-[[tert-butyl(dimethyl)silyl]oxy]-9-[(4-methoxybenzyl)oxy]-4,6,8-trimethyl-4-nonenoate C27H46O5Si 详情 详情
(XLI) 62848 (Z,6S,7R,8S)-7-{[tert-butyl(dimethyl)silyl]oxy}-9-[(4-methoxybenzyl)oxy]-4,6,8-trimethyl-4-nonenoic acid C26H44O5Si 详情 详情

合成路线23

The reaction of (XXXVIII) with Li-TMP and LiBr in THF gives the lithium enolate (XLII), which is condensed with the chiral octadienoic aldehyde intermediate (XXV) in THF to yield the aldol adduct (XLIII). The reduction of the phenyl ester group of (XLIII) by means of LiAlH4 in THF affords the diol (XLIV), which is submitted to a regioselective esterification with mesitylenesulfonyl chloride (XLV) to provide the sulfonate (XLVI). The deoxygenation of (XLVI) by means of LiAlH4 gives the desired alcohol (XLVII), which is protected with Tbdms-OTf and TEA to yield the fully protected compound (XLVIII). The selective deprotection of (XLVIII) by means of DDQ in dichloromethane affords the diol (XLIX), which is selectively oxidated at the primary OH group with TEMPO and PhI(OAc)2 to provide the aldehyde (L). The condensation of (L) with phosphonate (LI) by means of K2CO3 and 18-C-6 in toluene furnishes the chiral octadecatetraenoic ester (LII).

参考文献 中间体
【1】 Paterson, I.; Florence, G.J.; Gerlach, K.; Scott, J.P.; Sereinig, N.; A practical synthesis of (+)-discodermolide and analogues: Fragment union by complex aldol reactions. J Am Chem Soc 2001, 123, 39, 9535.
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) 42632 (2R,3S,4S,5Z)-3-[(4-methoxybenzyl)oxy]-2,4-dimethyl-5,7-octadienal C18H24O3 详情 详情
(XXXVIII) 42622 2,6-dimethylphenyl (Z,6S,7R,8S)-7-[[tert-butyl(dimethyl)silyl]oxy]-9-[(4-methoxybenzyl)oxy]-4,6,8-trimethyl-4-nonenoate C34H52O5Si 详情 详情
(XLII) 62849 　 C34H51LiO5Si 详情 详情
(XLIII) 42641 2,6-dimethylphenyl (2S,3S,4S,5S,6S,7Z)-2-[(Z,4S,5R,6S)-5-[[tert-butyl(dimethyl)silyl]oxy]-7-[(4-methoxybenzyl)oxy]-2,4,6-trimethyl-2-heptenyl]-3-hydroxy-5-[(4-methoxybenzyl)oxy]-4,6-dimethyl-7,9-decadienoate C52H76O8Si 详情 详情
(XLIV) 42642 (2R,3R,4S,5S,6S,7Z)-2-[(Z,4S,5R,6S)-5-[[tert-butyl(dimethyl)silyl]oxy]-7-[(4-methoxybenzyl)oxy]-2,4,6-trimethyl-2-heptenyl]-5-[(4-methoxybenzyl)oxy]-4,6-dimethyl-7,9-decadiene-1,3-diol C44H70O7Si 详情 详情
(XLV) 41158 2,4,6-trimethylbenzenesulfonyl chloride 773-64-8 C9H11ClO2S 详情 详情
(XLVI) 62850 (2R,3R,4S,5S,6S,7Z)-2-{(Z,4S,5R,6S)-5-{[tert-butyl(dimethyl)silyl]oxy}-7-[(4-methoxybenzyl)oxy]-2,4,6-trimethyl-2-heptenyl}-3-hydroxy-5-[(4-methoxybenzyl)oxy]-4,6-dimethyl-7,9-decadienyl 2,4,6-trimethylbenzenesulfonate C53H80O9SSi 详情 详情
(XLVII) 42643 (3Z,5S,6S,7S,8R,9S,11Z,13S,14R,15S)-14-[[tert-butyl(dimethyl)silyl]oxy]-6,16-bis[(4-methoxybenzyl)oxy]-5,7,9,11,13,15-hexamethyl-1,3,11-hexadecatrien-8-ol C44H70O6Si 详情 详情
(XLVIII) 42644 (5R,6S,7Z,10S,11R)-11-[(1R,2S,3S,4Z)-2-[(4-methoxybenzyl)oxy]-1,3-dimethyl-4,6-heptadienyl]-5-[(1S)-2-[(4-methoxybenzyl)oxy]-1-methylethyl]-2,2,3,3,6,8,10,13,13,14,14-undecamethyl-4,12-dioxa-3,13-disila-7-pentadecene; (2S,3R,4S,5Z,8S,9R,10R,11S,12S,13Z)-3,9-bis[[tert-butyl(dimethyl)silyl]oxy]-11-[(4-methoxybenzyl)oxy]-2,4,6,8,10,12-hexamethyl-5,13,15-hexadecatrienyl 4-methoxybenzyl ether n/a C50H84O6Si2 详情 详情
(XLIX) 42645 (2S,3R,4S,5Z,8S,9R,10R,11S,12S,13Z)-3,9-bis[[tert-butyl(dimethyl)silyl]oxy]-2,4,6,8,10,12-hexamethyl-5,13,15-hexadecatriene-1,11-diol n/a C34H68O4Si2 详情 详情
(L) 42646 (2R,3R,4S,5Z,8S,9R,10R,11S,12S,13Z)-3,9-bis[[tert-butyl(dimethyl)silyl]oxy]-11-hydroxy-2,4,6,8,10,12-hexamethyl-5,13,15-hexadecatrienal n/a C34H66O4Si2 详情 详情
(LI) 27698 methyl 2-(diethoxyphosphoryl)acetate 1067-74-9 C7H15O5P 详情 详情
(LII) 42647 methyl (2Z,4S,5S,6S,7Z,10S,11R,12R,13S,14S,15Z)-5,11-bis[[tert-butyl(dimethyl)silyl]oxy]-13-hydroxy-4,6,8,10,12,14-hexamethyl-2,7,15,17-octadecatetraenoate n/a C37H70O5Si2 详情 详情

合成路线24

The reaction of the OH group of (LII) with trichloroacetyl isocyanate and K2CO3 in methanol gives the carbamate (LIII). The reduction of the ester group of (LIII) with DIBAL in dichloromethane yields the primary alcohol (LIV), which is oxidized with DMP to afford the aldehyde (LV). The condensation of (LV) with the boron enolate (LVI), (obtained by reaction of the 5-oxohexanoic ester intermediate (XI) with (c-Hex)2B-Cl), provides the chiral 5-oxotetracosatetraenoic ester (LVII), which is reduced with Me4HBH(OAc)3 in acetonitrile/AcOH to give the dihydroxyester (LVIII). Finally, this compound is lactonized and simultaneously deprotected by means of HF/pyridine in THF or HCl in methanol giving rise to the target (+)-Discodermolide.

参考文献 中间体
【1】 Paterson, I.; Florence, G.J.; Gerlach, K.; Scott, J.P.; Sereinig, N.; A practical synthesis of (+)-discodermolide and analogues: Fragment union by complex aldol reactions. J Am Chem Soc 2001, 123, 39, 9535.
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) 42640 methyl (2R,3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethyl-5-oxohexanoate C15H30O4Si 详情 详情
(LII) 42647 methyl (2Z,4S,5S,6S,7Z,10S,11R,12R,13S,14S,15Z)-5,11-bis[[tert-butyl(dimethyl)silyl]oxy]-13-hydroxy-4,6,8,10,12,14-hexamethyl-2,7,15,17-octadecatetraenoate n/a C37H70O5Si2 详情 详情
(LIII) 42648 methyl (2Z,4S,5S,6S,7Z,10S,11R,12R,13S,14S,15Z)-13-[(aminocarbonyl)oxy]-5,11-bis[[tert-butyl(dimethyl)silyl]oxy]-4,6,8,10,12,14-hexamethyl-2,7,15,17-octadecatetraenoate n/a C38H71NO6Si2 详情 详情
(LIV) 42649 (1S,2R,3R,4S,6Z,8S,9S,10S,11Z)-3,9-bis[[tert-butyl(dimethyl)silyl]oxy]-13-hydroxy-2,4,6,8,10-pentamethyl-1-[(1S,2Z)-1-methyl-2,4-pentadienyl]-6,11-tridecadienyl carbamate C37H71NO5Si2 详情 详情
(LV) 42650 (1S,2R,3R,4S,6Z,8S,9S,10S,11Z)-3,9-bis[[tert-butyl(dimethyl)silyl]oxy]-2,4,6,8,10-pentamethyl-1-[(1S,2Z)-1-methyl-2,4-pentadienyl]-13-oxo-6,11-tridecadienyl carbamate C37H69NO5Si2 详情 详情
(LVI) 62851 methyl (2R,3S,4R)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-[(dicyclohexylboryl)oxy]-2,4-dimethyl-5-hexenoate C27H51BO4Si 详情 详情
(LVII) 42651 methyl (2R,3S,4R,7S,8Z,10S,11S,12S,13Z,16S,17R,18R,19S,20S,21Z)-19-[(aminocarbonyl)oxy]-3,11,17-tris[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-2,4,10,12,14,16,18,20-octamethyl-5-oxo-8,13,21,23-tetracosatetraenoate C52H99NO9Si3 详情 详情
(LVIII) 42653 methyl (2R,3S,4S,5S,7S,8Z,10S,11S,12S,13Z,16S,17R,18R,19S,20S,21Z)-19-[(aminocarbonyl)oxy]-3,11,17-tris[[tert-butyl(dimethyl)silyl]oxy]-5,7-dihydroxy-2,4,10,12,14,16,18,20-octamethyl-8,13,21,23-tetracosatetraenoate C52H101NO9Si3 详情 详情

合成路线25

Synthesis of the chiral 5-oxopentanoic ester intermediate (XI): The reaction of 3-hydroxy-2(S)-methylpentanoic acid methyl ester (I) with 4-methoxybenzyl trichloroacetimidate gives the aryl ether (II), which is treated with ethylmagnesium bromide to yield the ketone (III). The condensation of (III) with formaldehyde by means of (c-Hex)2B-Cl and H2O2 affords the hydroxypentanone (IV), which is reduced by means of NaBH(OAc)3 in THF/AcOH to provide the diol (V). The regioselective oxidation of the primary alcohol of (V) with TEMPO and BAIB in dichloromethane gives the beta-hydroxyaldehyde (VI), which is further oxidized with NaClO2 yielding the carboxylic acid (VII). The esterification of (VII) by means of Me-I and K2CO3, or with TMS-CHN2 affords the methyl ester (VIII), which is treated with Tbdms-OTf and lutidine to provide the silyl ether (IX). The selective deprotection of (IX) by means of DDQ in dichloromethane furnishes the omega-hydroxyester (X), which is finally submitted to a Swern oxidation to yield the chiral 5-oxopentanoic ester intermediate (XI).

参考文献 中间体
【1】 Paterson, I.; Delgado, O.; Florence, G.J.; Lyothier, I.; Scott, J.P.; Sereinig, N.; 1,6-asymmetric induction in boron-mediated aldol reactions: Application to a practical total synthesis of (+)-discodermolide. Org Lett 2003, 5, 1, 35.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 17128 Methyl (2S)-3-hydroxy-2-methylpropanoate 72657-23-9 C5H10O3 详情 详情
(II) 42654 methyl (2S)-3-[(4-methoxybenzyl)oxy]-2-methylpropanoate C13H18O4 详情 详情
(III) 42614 (2S)-1-[(4-methoxybenzyl)oxy]-2-methyl-3-pentanone C14H20O3 详情 详情
(IV) 62852 (2S,4S)-1-hydroxy-5-[(4-methoxybenzyl)oxy]-2,4-dimethyl-3-pentanone C15H22O4 详情 详情
(V) 62853 (2S,3R,4S)-5-[(4-methoxybenzyl)oxy]-2,4-dimethyl-1,3-pentanediol C15H24O4 详情 详情
(VI) 62854 (2R,3S,4S)-3-hydroxy-5-[(4-methoxybenzyl)oxy]-2,4-dimethylpentanal C15H22O4 详情 详情
(VII) 62855 (2R,3S,4S)-3-hydroxy-5-[(4-methoxybenzyl)oxy]-2,4-dimethylpentanoic acid C15H22O5 详情 详情
(VIII) 62856 methyl (2R,3S,4S)-3-hydroxy-5-[(4-methoxybenzyl)oxy]-2,4-dimethylpentanoate C16H24O5 详情 详情
(IX) 62857 methyl (2R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-[(4-methoxybenzyl)oxy]-2,4-dimethylpentanoate C22H38O5Si 详情 详情
(X) 62858 methyl (2R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-hydroxy-2,4-dimethylpentanoate C14H30O4Si 详情 详情
(XI) 62859 methyl (2R,3S,4R)-3-{[tert-butyl(dimethyl)silyl]oxy}-2,4-dimethyl-5-oxopentanoate C14H28O4Si 详情 详情

合成路线26

Synthesis of the target (+)-Discodermolide: The selective oxidation of the chiral hexadecatrien-1,11-diol derivative (XII) with TEMPO and BAIB gives the hydroxyaldehyde (XIII), which is condensed with the phosphonate (XIV) by means of K2CO3 and 18-C-6 in toluene to yield the methyl ketone (XV). The reaction of the free OH group of (XV) with trichloroacetyl isocyanate and neutral alumina affords the carbamate (XVI), which is condensed with the chiral 5-oxopentanoic ester intermediate (XI) by means of (c-Hex)2B-Cl and TEA in ethyl ether to provide the chiral 5-hydroxy-7-oxotetracosatetraenoic ester (XVII). The cyclization of (XVII) by means of Ac-OH in aqueous THF furnishes the oxo- lactone (XVIII), which is reduced with K-Selectride in toluene/THF to give the hydroxy lactone (XIX). Finally, this compound is deprotected by means of HCl in methanol to provide the target (+)-Discodermolide.

参考文献 中间体
【1】 Paterson, I.; Delgado, O.; Florence, G.J.; Lyothier, I.; Scott, J.P.; Sereinig, N.; 1,6-asymmetric induction in boron-mediated aldol reactions: Application to a practical total synthesis of (+)-discodermolide. Org Lett 2003, 5, 1, 35.
【2】 Paterson, I.; Florence, G.J.; Gerlach, K.; Scott, J.P.; Sereinig, N.; A practical synthesis of (+)-discodermolide and analogues: Fragment union by complex aldol reactions. J Am Chem Soc 2001, 123, 39, 9535.
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) 62859 methyl (2R,3S,4R)-3-{[tert-butyl(dimethyl)silyl]oxy}-2,4-dimethyl-5-oxopentanoate C14H28O4Si 详情 详情
(XII) 42645 (2S,3R,4S,5Z,8S,9R,10R,11S,12S,13Z)-3,9-bis[[tert-butyl(dimethyl)silyl]oxy]-2,4,6,8,10,12-hexamethyl-5,13,15-hexadecatriene-1,11-diol n/a C34H68O4Si2 详情 详情
(XIII) 42646 (2R,3R,4S,5Z,8S,9R,10R,11S,12S,13Z)-3,9-bis[[tert-butyl(dimethyl)silyl]oxy]-11-hydroxy-2,4,6,8,10,12-hexamethyl-5,13,15-hexadecatrienal n/a C34H66O4Si2 详情 详情
(XIV) 62860 bis(2,2,2-trifluoroethyl) 2-oxopropylphosphonate C7H9F6O4P 详情 详情
(XV) 62861 (3Z,5S,6S,7S,8Z,11S,12R,13R,14S,15S,16Z)-6,12-bis{[tert-butyl(dimethyl)silyl]oxy}-14-hydroxy-5,7,9,11,13,15-hexamethyl-3,8,16,18-nonadecatetraen-2-one C37H70O4Si2 详情 详情
(XVI) 62862 (1S,2R,3R,4S,6Z,8S,9S,10S,11Z)-3,9-bis{[tert-butyl(dimethyl)silyl]oxy}-2,4,6,8,10-pentamethyl-1-[(1S,2Z)-1-methyl-2,4-pentadienyl]-13-oxo-6,11-tetradecadienyl carbamate C38H71NO5Si2 详情 详情
(XVII) 62863 methyl (2R,3S,4S,5S,8Z,10S,11S,12S,13Z,16S,17R,18R,19S,20S,21Z)-19-[(aminocarbonyl)oxy]-3,11,17-tris{[tert-butyl(dimethyl)silyl]oxy}-5-hydroxy-2,4,10,12,14,16,18,20-octamethyl-7-oxo-8,13,21,23-tetracosatetraenoate C52H99NO9Si3 详情 详情
(XVIII) 62864 (1S,2R,3R,4S,6Z,8S,9S,10S,11Z)-3,9-bis{[tert-butyl(dimethyl)silyl]oxy}-14-((2S,3S,4S,5R)-4-{[tert-butyl(dimethyl)silyl]oxy}-3,5-dimethyl-6-oxotetrahydro-2H-pyran-2-yl)-2,4,6,8,10-pentamethyl-1-[(1S,2Z)-1-methyl-2,4-pentadienyl]-13-oxo-6,11-tetradeca C51H95NO8Si3 详情 详情
(XIX) 42652 (1S,2R,3R,4S,6Z,8S,9S,10S,11Z,13S)-3,9-bis[[tert-butyl(dimethyl)silyl]oxy]-14-((2S,3S,4S,5R)-4-[[tert-butyl(dimethyl)silyl]oxy]-3,5-dimethyl-6-oxotetrahydro-2H-pyran-2-yl)-13-hydroxy-2,4,6,8,10-pentamethyl-1-[(1S,2Z)-1-methyl-2,4-pentadienyl]-6,11-t C51H97NO8Si3 详情 详情
Extended Information