• English
  • 简体中文
Login Register
Current Location: Home > Feedback Help Print

【结 构 式】

【药物名称】Bryostatin 1, BMY-45618, NSC-339555

【化学名称】7beta-Acetoxy-5beta,9beta:11beta,15beta:19alpha,23alpha-triepoxy-3alpha,9alpha,19beta-trihydroxy-25beta-[1(R)-hydroxyethyl]-13,21-bis(methoxycarbonylmethylene)-8,8,18,18-tetramethyl-20alpha-[octa-2(E),4(E)-dienoyloxy]pentacosa-16(E)-enolide

【CA登记号】83314-01-6

【 分 子 式 】C47H68O17

【 分 子 量 】905.05581

【开发单位】GPC Biotech (Orphan Drug), Arizona State University (Originator), GPC Biotech (Originator), National Cancer Institute (Codevelopment)

【药理作用】Gastric Cancer Therapy, Leukemia Therapy, Lymphoma Therapy, Non-Hodgkin's Lymphoma Therapy, Oncolytic Drugs, Ovarian Cancer Therapy, Prostate Cancer Therapy, Solid Tumors Therapy, Antimitotic Drugs, Apoptosis Inducers, Protein Kinase C (PKC) Inhibitors

合成路线1

An asymmetric synthesis of the C(17)-C(27)-segment of bryostatin 1 has been described: The asymmetric dihydroxylation of 1,4(E)-hexadiene (I) with AD-mix-beta in tert-butanol gives the diol (II), which is protected with tert-butyldimethylsilyl chloride (TBDMS-Cl) and imidazole in DMF, yielding the bis(silyl) ether (III). The oxidation of (III) with OsO4 and NaIO4 affords the aldehyde (IV), which is condensed with triphenylphosphoranylideneacetic acid ethyl ester (V) in dichloromethane to give 5(R),6(R)-bis(tert-butyldimethylsilyloxy)-2(E)-heptenoic acid ethyl ester (VI). The reduction of (VI) with dibutylaluminum hydride (DIBAL-H) yields the primary alcohol (VII), which is epoxidized with (-)-DET, Ti(OPr)4 and tert-butyl peroxide in dichloromethane to the epoxy-alcohol (VIII). The reductive opening of the epoxide ring of (VIII) with REDAL affords the diol (IX), which by reaction with 4-methoxybenzaldehyde dimethylacetal [PMB(OMe)2] and PPTS in DMF is converted to the acetal (X). The reductive cleavage of (X) with DIBAL-H in dichloromethane affords 5(R),6(R)-bis(tert-butyldimethylsilyloxy)-3(S)-(4-methoxybenzyloxy)-1-h eptanol (XI), which is oxidized with oxalyl chloride to the corresponding aldehyde (XII). The condensation of (XII) with phosphorane (V) in dichloromethane gives 7(R),8(R)-bis(tert-butyldimethylsilyloxy)-5(S)-(4-methoxybenzyloxy)-2(E)-nonenoic acid ethyl ester (XIII), which is asymmetrically dihydroxylated with AD-mix-beta as before to the dihydroxy ester (XIV). The protection of (XIV) by reaction with 2,2-dimethoxypropane and PPTS yields the isopropylidene ketal (XV), which is submitted to a Claisen condensation with the lithium enolate of methyl isobutyrate, affording the keto ester (XVI). Selective deprotection of (XVI) with HF.pyridine affords the diol (XVII), which is acylated with pivaloyl chloride (Pv-Cl) and pyridine in dichloromethane, giving the bispivaloyloxy derivative (XVIII). A new selective deprotection of (XVIII) with DDQ in dichloromethane yields the hydroxy ester (XIX), which is submitted to cyclization with Amberlyst-15 H+ and acetyl chloride in methanol to afford the perhydrofuropyran derivative (XX). The oxidation of the hydroxy group of (XX) with RuCl3 and NaIO4 in acetonitrile/CCl4 gives the corresponding ketonic compound (XXI), which is finally submitted to a condensation with triphenylphosphoranylideneacetic acid methyl ester in dichloromethane to afford 2(E)-[5(S)-[2(R),3(R)-bis(pivaloyloxy)butyl]-3a(S)-methoxy-2,2-dimethyl-7a(S)-perhydrofuro[3,2-a]pyran-7-ylidene]acetic acid methyl ester (XXII), which includes the C(17)-C(27)-fragment of bryostatin 1 with the correct stereochemistry.

1 Manaviazar, S.; Lennon, J.A.; Javaid, M.H.; Hobbs, C.J.; Hale, K.J.; Asymmetric synthesis of the C17-C27 segment of the antineoplastic macrolide bryostatin 1. Tetrahedron Lett 1995, 36, 8, 1359.
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) 14178 (4E)-1,4-Hexadiene; 1,4-Hexadiene 592-45-0 C6H10 详情 详情
(II) 14179 (2R,3R)-5-Hexene-2,3-diol C6H12O2 详情 详情
(III) 14180 tert-Butyl(dimethyl)silyl (1R)-1-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-3-butenyl ether; (5R,6R)-5-Allyl-2,2,3,3,6,8,8,9,9-nonamethyl-4,7-dioxa-3,8-disiladecane C18H40O2Si2 详情 详情
(IV) 14181 (3R,4R)-3,4-Bis[[tert-butyl(dimethyl)silyl]oxy]pentanal C17H38O3Si2 详情 详情
(V) 14182 ethyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate; (Carbethoxymethylene)triphenylphosphorane 1099-45-2 C22H21O2P 详情 详情
(VI) 14183 ethyl (E,5R,6R)-5,6-bis[[tert-butyl(dimethyl)silyl]oxy]-2-heptenoate C21H44O4Si2 详情 详情
(VII) 14184 (E,5R,6R)-5,6-Bis[[tert-butyl(dimethyl)silyl]oxy]-2-hepten-1-ol C19H42O3Si2 详情 详情
(VIII) 14185 [(2R,3R)-3-((2R,3R)-2,3-Bis[[tert-butyl(dimethyl)silyl]oxy]butyl)oxiranyl]methanol C19H42O4Si2 详情 详情
(IX) 14186 (3S,5R,6R)-5,6-Bis[[tert-butyl(dimethyl)silyl]oxy]-1,3-heptanediol C19H44O4Si2 详情 详情
(X) 14187 (5R,6R)-5-[[(4S)-2-(4-Methoxyphenyl)-1,3-dioxan-4-yl]methyl]-2,2,3,3,6,8,8,9,9-nonamethyl-4,7-dioxa-3,8-disiladecane; 4-[(4S)-4-((2R,3R)-2,3-Bis[[tert-butyl(dimethyl)silyl]oxy]butyl)-1,3-dioxan-2-yl]phenyl methyl ether C27H50O5Si2 详情 详情
(XI) 14188 (3S,5R,6R)-5,6-Bis[[tert-butyl(dimethyl)silyl]oxy]-3-[(4-methoxybenzyl)oxy]-1-heptanol C27H52O5Si2 详情 详情
(XII) 14189 (3R,5R,6R)-5,6-Bis[[tert-butyl(dimethyl)silyl]oxy]-3-[(4-methoxybenzyl)oxy]heptanal C27H50O5Si2 详情 详情
(XIII) 14190 ethyl (E,5S,7R,8R)-7,8-bis[[tert-butyl(dimethyl)silyl]oxy]-5-[(4-methoxybenzyl)oxy]-2-nonenoate C31H56O6Si2 详情 详情
(XIV) 14191 ethyl (2S,3R,5S,7R,8R)-7,8-bis[[tert-butyl(dimethyl)silyl]oxy]-2,3-dihydroxy-5-[(4-methoxybenzyl)oxy]nonanoate C31H58O8Si2 详情 详情
(XV) 14192 ethyl (4S,5R)-5-[(2S,4R,5R)-4,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-[(4-methoxybenzyl)oxy]hexyl]-2,2-dimethyl-1,3-dioxolane-4-carboxylate C34H62O8Si2 详情 详情
(XVI) 14193 methyl 3-((4S,5R)-5-[(2S,4R,5R)-4,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-[(4-methoxybenzyl)oxy]hexyl]-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyl-3-oxopropanoate C37H66O9Si2 详情 详情
(XVII) 14194 methyl 3-((4S,5R)-5-[(2R,4R,5R)-4,5-dihydroxy-2-[(4-methoxybenzyl)oxy]hexyl]-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyl-3-oxopropanoate C25H38O9 详情 详情
(XVIII) 14195 methyl 3-((4S,5R)-5-[(2S,4R,5R)-4,5-bis[(2,2-dimethylpropanoyl)oxy]-2-[(4-methoxybenzyl)oxy]hexyl]-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyl-3-oxopropanoate C35H54O11 详情 详情
(XIX) 14196 methyl 3-((4S,5R)-5-[(2S,4R,5R)-4,5-bis[(2,2-dimethylpropanoyl)oxy]-2-hydroxyhexyl]-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyl-3-oxopropanoate C27H46O10 详情 详情
(XX) 14197 (1R,2R)-3-[(3aS,5S,7R,7aS)-7-hydroxy-3a-methoxy-3,3-dimethyl-2-oxohexahydro-2H-furo[3,2-b]pyran-5-yl]-2-[(2,2-dimethylpropanoyl)oxy]-1-methylpropyl pivalate C24H40O9 详情 详情
(XXI) 14198 (1R,2R)-3-[(3aS,5R,7aS)-3a-methoxy-3,3-dimethyl-2,7-dioxohexahydro-2H-furo[3,2-b]pyran-5-yl]-2-[(2,2-dimethylpropanoyl)oxy]-1-methylpropyl pivalate C24H38O9 详情 详情
(XXII) 14199 (1R,2R)-3-[(3aS,5S,7aS)-3a-methoxy-7-[(E)-2-methoxy-2-oxoethylidene]-3,3-dimethyl-2-oxohexahydro-2H-furo[3,2-b]pyran-5-yl]-2-[(2,2-dimethylpropanoyl)oxy]-1-methylpropyl pivalate C27H42O10 详情 详情

合成路线2

C1-C9 Fragment: The condensation of 2,2-dimethyl-4,4-diphenyl-3-butenal (I) with the chiral oxazolidinone (II) by means of dibutylboron triflate gives the chiral ketol (III), which is dechlorinated with Zn and AcOH in THF yielding the beta-hydroxyimide (IV). The reduction of (IV) with LiBH4 in methanol/THF affords the chiral diol (V), which is treated with 4-methoxybenzaldehyde dimethyl acetal and PPTS in dichloromethane to give the cyclic ketal (VI). The regioselective reduction of (VI) with DIBAL in dichloromethane yields the monoprotected diol (VII), which is oxidized to aldehyde (VIII) with oxalyl chloride in DMSO. The condensation of (VIII) with the bis(trimethylsilyl)dienol ether (IX) by means of TiCl2(i-PrO)2 in toluene affords the ketoester (X), which by stereoselective reduction with (AcO)3BHNMe4 in acetonitrile/acetic acid gives the dihydroxyester (XI) with high stereoselectivity. The lactonization of (XI) by means of PPTS in refluxing benzene yields the hydroxylactone (XII), which is silylated with TBDMS-OTf and 2,6-lutidine in dichloromethane affording the silylated lactone (XIII). Opening of the lactone ring with aniline and Me3Al in dichloromethane gives the monoprotected dihydroxyamide (XIV), which is ozonolyzed with O3 in CH2Cl2/MeOH yielding the cyclic lactol (XV). Acetylation of (XV) with acetic anhydride and pyridine affords the acetate (XVI), which by reaction with TMS-SPh, ZnI2 and tetrabutylammonium iodide is converted regioselectively into the phenylsulfanyl derivative (XVII). Finally, this compound is oxidized with m-chloroperbenzoic acid (MCPBA) in EtOAc to provide the desired C1-C9 subunit fragment (XVIII).

1 Lautens, M.; Prunet, J.A.; Carreira, E.M.; Carter, P.H.; Charette, A.B.; Evans, D.A.; Total synthesis of bryostatin 2. J Am Chem Soc 1999, 121, 33, 7540.
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) 39392 2,2-dimethyl-4,4-diphenyl-3-butenal C18H18O 详情 详情
(II) 39393 (4S)-4-benzyl-3-(2-chloroacetyl)-1,3-oxazolidin-2-one C12H12ClNO3 详情 详情
(III) 39394 (4S)-4-benzyl-3-[(2S,3R)-2-chloro-3-hydroxy-4,4-dimethyl-6,6-diphenyl-5-hexenoyl]-1,3-oxazolidin-2-one C30H30ClNO4 详情 详情
(IV) 39395 (4S)-4-benzyl-3-[(3S)-3-hydroxy-4,4-dimethyl-6,6-diphenyl-5-hexenoyl]-1,3-oxazolidin-2-one C30H31NO4 详情 详情
(V) 39396 (3S)-4,4-dimethyl-6,6-diphenyl-5-hexene-1,3-diol C20H24O2 详情 详情
(VI) 39397 4-[(4S)-4-(1,1-dimethyl-3,3-diphenyl-2-propenyl)-1,3-dioxan-2-yl]phenyl methyl ether; (4S)-4-(1,1-dimethyl-3,3-diphenyl-2-propenyl)-2-(4-methoxyphenyl)-1,3-dioxane C28H30O3 详情 详情
(VII) 39398 (3S)-3-[(4-methoxybenzyl)oxy]-4,4-dimethyl-6,6-diphenyl-5-hexen-1-ol C28H32O3 详情 详情
(VIII) 39399 (3S)-3-[(4-methoxybenzyl)oxy]-4,4-dimethyl-6,6-diphenyl-5-hexenal C28H30O3 详情 详情
(IX) 39400 (1Z)-1,3-bis[(trimethylsilyl)oxy]-1,3-butadienyl methyl ether; (Z)-4-methoxy-2,2,8,8-tetramethyl-6-methylene-3,7-dioxa-2,8-disila-4-nonene C11H24O3Si2 详情 详情
(X) 39401 methyl (5S,7S)-5-hydroxy-7-[(4-methoxybenzyl)oxy]-8,8-dimethyl-3-oxo-10,10-diphenyl-9-decenoate C33H38O6 详情 详情
(XI) 39402 methyl (3R,5R,7S)-3,5-dihydroxy-7-[(4-methoxybenzyl)oxy]-8,8-dimethyl-10,10-diphenyl-9-decenoate C33H40O6 详情 详情
(XII) 39403 (4R,6R)-4-hydroxy-6-[(2S)-2-[(4-methoxybenzyl)oxy]-3,3-dimethyl-5,5-diphenyl-4-pentenyl]tetrahydro-2H-pyran-2-one C32H36O5 详情 详情
(XIII) 39404 (4R,6S)-4-[[tert-butyl(dimethyl)silyl]oxy]-6-[(2S)-2-[(4-methoxybenzyl)oxy]-3,3-dimethyl-5,5-diphenyl-4-pentenyl]tetrahydro-2H-pyran-2-one C38H50O5Si 详情 详情
(XIV) 39405 (3R,5S,7S)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-hydroxy-7-[(4-methoxybenzyl)oxy]-8,8-dimethyl-N,10,10-triphenyl-9-decenamide C44H57NO5Si 详情 详情
(XV) 39406 (3R)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-[(2S,4S)-6-hydroxy-4-[(4-methoxybenzyl)oxy]-5,5-dimethyltetrahydro-2H-pyran-2-yl]-N-phenylbutanamide C31H47NO6Si 详情 详情
(XVI) 39407 (4S,6S)-6-((2R)-4-anilino-2-[[tert-butyl(dimethyl)silyl]oxy]-4-oxobutyl)-4-[(4-methoxybenzyl)oxy]-3,3-dimethyltetrahydro-2H-pyran-2-yl acetate C33H49NO7Si 详情 详情
(XVII) 39408 (3R)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-[(2S,4S,6R)-4-[(4-methoxybenzyl)oxy]-5,5-dimethyl-6-(phenylsulfanyl)tetrahydro-2H-pyran-2-yl]-N-phenylbutanamide C37H51NO5SSi 详情 详情
(XVIII) 63864 (3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-[(2S,4S,6R)-4-[(4-methoxybenzyl)oxy]-5,5-dimethyl-6-(phenylsulfonyl)tetrahydro-2H-pyran-2-yl]-N-phenylbutanamide C37H51NO7SSi 详情 详情

合成路线3

C10-C16 Fragment: The stereocontrolled reduction of ketoester (XIX) with Me4NHB(OAc)3 in acetonitrile/AcOH gives the dihydroxyester (XX), which is dehydrated to the lactone (XXI) with PPTS in refluxing benzene. The protection of (XXI) with triethylsilyl chloride as usual affords the fully silylated lactone (XXII), which is condensed with benzyloxymethyllithium in THF and reduced with BF3/Et2O and triethylsilane giving the benzyloxymethyl derivative (XXIII). The selective deprotection of (XXIII) with BF3/Et2O yields the 4-hydroxy derivative (XXIV), which is desilylated with TBAF in THF to give the diol (XXV). The silylation of (XXV) with TBDMS-OTf and lutidine in dichloromethane yields the fully protected compound (XXVI), which is debenzylated with H2 over Pd/C in acetic acid/ethyl acetate affording the carbinol (XXVII). Finally, this compound is oxidized with oxalyl chloride and triethylamine in DMSO to provide (XXVIII), the desired C10-C16 fragment.

1 Lautens, M.; Prunet, J.A.; Carreira, E.M.; Carter, P.H.; Charette, A.B.; Evans, D.A.; Total synthesis of bryostatin 2. J Am Chem Soc 1999, 121, 33, 7540.
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) 39410 methyl (5S)-5-hydroxy-3-oxo-6-[(triisopropylsilyl)oxy]hexanoate C16H32O5Si 详情 详情
(XX) 39411 methyl (3S,5S)-3,5-dihydroxy-6-[(triisopropylsilyl)oxy]hexanoate C16H34O5Si 详情 详情
(XXI) 39412 (4S,6S)-4-hydroxy-6-[[(triisopropylsilyl)oxy]methyl]tetrahydro-2H-pyran-2-one C15H30O4Si 详情 详情
(XXII) 39413 (4S,6S)-4-[(triethylsilyl)oxy]-6-[[(triisopropylsilyl)oxy]methyl]tetrahydro-2H-pyran-2-one C21H44O4Si2 详情 详情
(XXIII) 39414 benzyl ((2R,4S,6S)-4-[(triethylsilyl)oxy]-6-[[(triisopropylsilyl)oxy]methyl]tetrahydro-2H-pyran-2-yl)methyl ether; ([(2S,4S,6R)-6-[(benzyloxy)methyl]-4-[(triethylsilyl)oxy]tetrahydro-2H-pyran-2-yl]methoxy)(triisopropyl)silane C29H54O4Si2 详情 详情
(XXIV) 39415 (2R,4S,6S)-2-[(benzyloxy)methyl]-6-[[(triisopropylsilyl)oxy]methyl]tetrahydro-2H-pyran-4-ol C23H40O4Si 详情 详情
(XXV) 39416 (2R,4R,6S)-2-[(benzyloxy)methyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-4-ol C14H20O4 详情 详情
(XXVI) 39417 [((2S,4S,6R)-6-[(benzyloxy)methyl]-4-[[tert-butyl(dimethyl)silyl]oxy]tetrahydro-2H-pyran-2-yl)methoxy](tert-butyl)dimethylsilane; benzyl [(2R,4S,6S)-4-[[tert-butyl(dimethyl)silyl]oxy]-6-([[tert-butyl(dimethyl)silyl]oxy]methyl)tetrahydro-2H-pyran-2-yl]methyl ether C26H48O4Si2 详情 详情
(XXVII) 39418 [(2R,4S,6S)-4-[[tert-butyl(dimethyl)silyl]oxy]-6-([[tert-butyl(dimethyl)silyl]oxy]methyl)tetrahydro-2H-pyran-2-yl]methanol C19H42O4Si2 详情 详情
(XXVIII) 39419 (2R,4R,6S)-4-[[tert-butyl(dimethyl)silyl]oxy]-6-([[tert-butyl(dimethyl)silyl]oxy]methyl)tetrahydro-2H-pyran-2-carbaldehyde C19H40O4Si2 详情 详情

合成路线4

C17-C27 Fragment: The monotosylation of 2,2-dimethylpropane-1,3-diol (XXIX) with TsCl and pyridine in CH2Cl2 gives the monotosylate (XXX), which is condensed with thiophenol by means of NaH in hot DMF yielding the phenylsulfanyl derivative (XXXI). The oxidation of (XXXI) with MCPBA in dichloromethane affords the corresponding sulfone (XXXII), which is oxidized with oxalyl chloride in DMSO to give the aldehyde (XXXIII). The Grignard reaction of (XXXIII) with 4-pentenylmagnesium bromide (XXXIV) in ethyl ether/CH2Cl2 yields the secondary alcohol (XXXV), which is oxidized with oxalyl chloride in DMSO to the ketone (XXXVI). The dihydroxylation of the double bond of (XXXVI) with K2OsO4 in t-BuOH/H2O followed by oxidation with NaIO4 in t-BuOH/H2O/THF affords the keto aldehyde (XXXVII), which is condensed with the chiral butanone (XXXVIII) by means of (-)-diisopinocampheyl chloride ((-)-DIP-Cl) and Et3N in dichloromethane to give aldol (XXXIX). The SmI2 catalyzed Tishchenko reduction of (XXXIX) in the presence of 4-nitrobenzaldehyde yields the diastereomerically pure 4-nitrobenzoate (XL), which is silylated with TBDMS-OTf to afford the protected ketone (XLI). The hydrolysis of the 4-nitrobenzoate group of (XLI) with LiOH in THF/MeOH/H2O gives the alcohol (XLII), which is cyclized by means of camphorsulfonic acid (CSA) in refluxing benzene yielding the dihydropyran (XLIII), the desired C17-C27 fragment. The intermediate, the chiral butanone (XXXVIII) has been obtained as follows: The optical resolution of 3-methyl-4-phenyl-3-buten-2-ol (XLIV) with (+)-DIPT gives the (R)-isomer (XLV), which is protected with p-methoxybenzyl bromide and NaH yielding the benzyl ether (XLVI). Finally, (XLVI) is ozonolyzed with O3 in MeOH / CH2Cl2 dichloromethane to afford the desired intermediate (XXXVIII).

1 Lautens, M.; Prunet, J.A.; Carreira, E.M.; Carter, P.H.; Charette, A.B.; Evans, D.A.; Total synthesis of bryostatin 2. J Am Chem Soc 1999, 121, 33, 7540.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXIX) 12641 Neopentyl glycol; 2,2-Dimethyl-1,3-propanediol 126-30-7 C5H12O2 详情 详情
(XXX) 39420 3-hydroxy-2,2-dimethylpropyl 4-methylbenzenesulfonate C12H18O4S 详情 详情
(XXXI) 39421 2,2-dimethyl-3-(phenylsulfanyl)-1-propanol C11H16OS 详情 详情
(XXXII) 39422 2,2-dimethyl-3-(phenylsulfonyl)-1-propanol C11H16O3S 详情 详情
(XXXIII) 39423 2,2-dimethyl-3-(phenylsulfonyl)propanal C11H14O3S 详情 详情
(XXXIV) 39424 bromo(4-pentenyl)magnesium C5H9BrMg 详情 详情
(XXXV) 39425 2,2-dimethyl-1-(phenylsulfonyl)-7-octen-3-ol C16H24O3S 详情 详情
(XXXVI) 39426 2,2-dimethyl-1-(phenylsulfonyl)-7-octen-3-one C16H22O3S 详情 详情
(XXXVII) 39427 6,6-dimethyl-5-oxo-7-(phenylsulfonyl)heptanal C15H20O4S 详情 详情
(XXXVIII) 39428 (3R)-3-[(4-methoxybenzyl)oxy]-2-butanone C12H16O3 详情 详情
(XXXIX) 39429 (7S,10R)-7-hydroxy-10-[(4-methoxybenzyl)oxy]-2,2-dimethyl-1-(phenylsulfonyl)-3,9-undecanedione C27H36O7S 详情 详情
(XL) 39430 (1S)-1-[(2R,3R)-2-hydroxy-3-[(4-methoxybenzyl)oxy]butyl]-6,6-dimethyl-5-oxo-7-(phenylsulfonyl)heptyl 4-nitrobenzoate C34H41NO10S 详情 详情
(XLI) 39431 (1S)-1-[(2R,3R)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-[(4-methoxybenzyl)oxy]butyl]-6,6-dimethyl-5-oxo-7-(phenylsulfonyl)heptyl 4-nitrobenzoate C40H55NO10SSi 详情 详情
(XLII) 39432 (7S,9R,10R)-9-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-10-[(4-methoxybenzyl)oxy]-2,2-dimethyl-1-(phenylsulfonyl)-3-undecanone C33H52O7SSi 详情 详情
(XLIII) 39433 tert-butyl([(1R,2R)-1-([(2S)-6-[1,1-dimethyl-2-(phenylsulfonyl)ethyl]-3,4-dihydro-2H-pyran-2-yl]methyl)-2-[(4-methoxybenzyl)oxy]propyl]oxy)dimethylsilane; 2-((2S)-2-[(2R,3R)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-[(4-methoxybenzyl)oxy]butyl]-3,4-dihydro-2H-pyran-6-yl)-2-methylpropyl phenyl sulfone C33H50O6SSi 详情 详情
(XLIV) 39434 (E)-3-methyl-4-phenyl-3-buten-2-ol C11H14O 详情 详情
(XLV) 39435 (2R,3E)-3-methyl-4-phenyl-3-buten-2-ol C11H14O 详情 详情
(XLVI) 39436 (1R,2E)-1,2-dimethyl-3-phenyl-2-propenyl 4-methoxybenzyl ether; 1-([[(1R,2E)-1,2-dimethyl-3-phenyl-2-propenyl]oxy]methyl)-4-methoxybenzene C19H22O2 详情 详情

合成路线5

Fragment coupling: Coupling of the C10-C16 fragment (XXVIII) with the C17-C27 fragment (XLIII) by means of BuLi, Ac2O and Mg in THF gives (XLVII), which is selectively deprotected with TBAF yielding the carbinol (XLVIII). The reaction of (XLVIII) with triflic anhydride and lutidine in CH2Cl2 affords the triflate (IL), which is coupled with the C1-C9 fragment (XVIII) by means of n-BuLi in THF giving the tricyclic intermediate (L). The opening of the lactol ring of (L) with triethylsilyl chloride and imidazole yields the silylated hydroxyketone (LI), which is treated first with tert-butoxycarbonyl anhydride and then with the lithium salt of benzyl alcohol in order to convert the phenylcarboxamide of (LI) into the benzyl ester (LII). The epoxidation of the dihydropyran double bond of (LII) with MCPBA followed by epoxide opening with MeOH and oxidation of the resulting alcohol with DMP in CH2Cl2 gives the oxoketal (LIII).

1 Lautens, M.; Prunet, J.A.; Carreira, E.M.; Carter, P.H.; Charette, A.B.; Evans, D.A.; Total synthesis of bryostatin 2. J Am Chem Soc 1999, 121, 33, 7540.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
40733 lithium phenylmethanolate C7H7LiO 详情 详情
(IL) 39439 [(2S,4S,6R)-4-[[tert-butyl(dimethyl)silyl]oxy]-6-[(E)-3-((2S)-2-[(2R,3R)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-[(4-methoxybenzyl)oxy]butyl]-3,4-dihydro-2H-pyran-6-yl)-3-methyl-1-butenyl]tetrahydro-2H-pyran-2-yl]methyl trifluoromethanesulfonate C41H69F3O9SSi2 详情 详情
(XXVIII) 39419 (2R,4R,6S)-4-[[tert-butyl(dimethyl)silyl]oxy]-6-([[tert-butyl(dimethyl)silyl]oxy]methyl)tetrahydro-2H-pyran-2-carbaldehyde C19H40O4Si2 详情 详情
(XLIII) 39433 tert-butyl([(1R,2R)-1-([(2S)-6-[1,1-dimethyl-2-(phenylsulfonyl)ethyl]-3,4-dihydro-2H-pyran-2-yl]methyl)-2-[(4-methoxybenzyl)oxy]propyl]oxy)dimethylsilane; 2-((2S)-2-[(2R,3R)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-[(4-methoxybenzyl)oxy]butyl]-3,4-dihydro-2H-pyran-6-yl)-2-methylpropyl phenyl sulfone C33H50O6SSi 详情 详情
(XLVII) 39437 tert-butyl(dimethyl)silyl [(2S,4S,6R)-4-[[tert-butyl(dimethyl)silyl]oxy]-6-[(E)-3-((2S)-2-[(2R,3R)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-[(4-methoxybenzyl)oxy]butyl]-3,4-dihydro-2H-pyran-6-yl)-3-methyl-1-butenyl]tetrahydro-2H-pyran-2-yl]methyl ether; tert-butyl([(2S,4S,6R)-4-[[tert-butyl(dimethyl)silyl]oxy]-6-[(E)-3-((2S)-2-[(2R,3R)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-[(4-methoxybenzyl)oxy]butyl]-3,4-dihydro-2H-pyran-6-yl)-3-methyl-1-butenyl]tetrahydro-2H-pyran-2-yl]methoxy)dimethylsilane C46H84O7Si3 详情 详情
(XLVIII) 39438 [(2S,4S,6R)-4-[[tert-butyl(dimethyl)silyl]oxy]-6-[(E)-3-((2S)-2-[(2R,3R)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-[(4-methoxybenzyl)oxy]butyl]-3,4-dihydro-2H-pyran-6-yl)-3-methyl-1-butenyl]tetrahydro-2H-pyran-2-yl]methanol C40H70O7Si2 详情 详情
(L) 39440   C71H115NO12Si3 详情 详情
(LI) 39441   C77H129NO12Si4 详情 详情
(LII) 39442   C78H130O13Si4 详情 详情
(LIII) 39443   C79H132O15Si4 详情 详情

合成路线6

The reaction of (LIII) with HF in pyridine/methanol gives the desilylated tricyclic intermediate (LIV), which is resilylated with TESCl and DMAP in dichloromethane and debenzylated by reaction with 1,4-cyclohexadiene over Pd/C to afford the free hydroxyacid (LV). The cyclization of (LV) by means of 2,4,6-trichlorobenzoyl chloride, i-PrNEt2 and DMAP gives the macrocycle (LVI), which is selectively deprotected with PPTS in methanol/HC(OEt)3/dichloromethane, and oxidized with Dess Martin periodinane (DMP) in pyridine/dichloromethane yielding the diketone (LVII). The reaction of (LVII) with the Fuji's chiral phosphonate (LVIII) by means of NaHMDS in THF affords the C13 enoate (LIX), which is condensed with methyl glyoxylate by means of KHMDS in THF to give the C21 enoate (LX). The stereoselective reduction of the carbonyl group of (LX) with BH3/SMe2 catalyzed by the oxazaborolidine (A), followed by esterification with methoxyacetic anhydride provides the methoxyacetate (LXI).

1 Lautens, M.; Prunet, J.A.; Carreira, E.M.; Carter, P.H.; Charette, A.B.; Evans, D.A.; Total synthesis of bryostatin 2. J Am Chem Soc 1999, 121, 33, 7540.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
40732 methyl 2-oxoacetate 922-68-9 C3H4O3 详情 详情
(A) 39460 1-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole C18H20BNO 详情 详情
(LIII) 39443   C79H132O15Si4 详情 详情
(LIV) 39444   C56H78O15 详情 详情
(LV) 39445   C61H100O15Si2 详情 详情
(LVI) 39446   C61H98O14Si2 详情 详情
(LVII) 39447 (1S,3S,7R,11S,15S,17R,21R,23S,25S)-1,11-dimethoxy-25-[(4-methoxybenzyl)oxy]-17-[(1R)-1-[(4-methoxybenzyl)oxy]ethyl]-10,10,26,26-tetramethyl-21-[(triethylsilyl)oxy]-18,27,28,29-tetraoxatetracyclo[21.3.1.1(3,7).1(11,15)]nonacos-8-ene-5,12,19-trione C55H82O14Si 详情 详情
(LVIII) 39448 methyl 2-(2-oxo-2lambda(5)-dinaphtho[2,1-d:1,2-f][1,3,2]dioxaphosphepin-2-yl)acetate C23H17O5P 详情 详情
(LIX) 39449 methyl 2-[(1S,3S,7R,11S,15S,17R,21R,23S,25S)-1,11-dimethoxy-25-[(4-methoxybenzyl)oxy]-17-[(1R)-1-[(4-methoxybenzyl)oxy]ethyl]-10,10,26,26-tetramethyl-12,19-dioxo-21-[(triethylsilyl)oxy]-18,27,28,29-tetraoxatetracyclo[21.3.1.1(3,7).1(11,15)]nonacos-8-en-5-ylidene]acetate C58H86O15Si 详情 详情
(LX) 39450 methyl 2-[(1S,3S,7R,11S,15S,17R,21R,23S,25S)-1,11-dimethoxy-25-[(4-methoxybenzyl)oxy]-17-[(1R)-1-[(4-methoxybenzyl)oxy]ethyl]-13-[(E)-2-methoxy-2-oxoethylidene]-10,10,26,26-tetramethyl-12,19-dioxo-21-[(triethylsilyl)oxy]-18,27,28,29-tetraoxatetracyclo[21.3.1.1(3,7).1(11,15)]nonacos-8-en-5-ylidene]acetate C61H88O17Si 详情 详情
(LXI) 39451 methyl 2-[(1S,3S,7R,11S,12S,15S,17R,21R,23S,25S)-1,11-dimethoxy-12-[(2-methoxyacetyl)oxy]-25-[(4-methoxybenzyl)oxy]-17-[(1R)-1-[(4-methoxybenzyl)oxy]ethyl]-13-[(E)-2-methoxy-2-oxoethylidene]-10,10,26,26-tetramethyl-19-oxo-21-[(triethylsilyl)oxy]-18,27,28,29-tetraoxatetracyclo[21.3.1.1(3,7).1(11,15)]nonacos-8-en-5-ylidene]acetate C64H94O19Si 详情 详情

合成路线7

The desilylation and C9 demethylation of (LXI) with PPTS in THF/H2O gives the dihydroxy intermediate (LXII), which is deacetylated with Na2CO3 in MeOH to yield the trihydroxy intermediate (LXIII). The demethylation of the C19 methoxy group of (LXIII) with TsOH in CH3CN/H2O affords the tetrahydroxy compound (LXIV), which is selectively acylated at the C20 hydroxy group with 2(E),4(E)-octadienoic acid (LXV) by means of diisopropylcarbodiimidde (DIP) and DMAP in CH2Cl2 providing the ester (LXVI). The elimination of the 4-methoxybenzyl protecting groups of (LXVII) by means of DDQ in a buffered solution gives the precursor Bryostatin 2 (LXVII).

1 Lautens, M.; Prunet, J.A.; Carreira, E.M.; Carter, P.H.; Charette, A.B.; Evans, D.A.; Total synthesis of bryostatin 2. J Am Chem Soc 1999, 121, 33, 7540.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(LXI) 39451 methyl 2-[(1S,3S,7R,11S,12S,15S,17R,21R,23S,25S)-1,11-dimethoxy-12-[(2-methoxyacetyl)oxy]-25-[(4-methoxybenzyl)oxy]-17-[(1R)-1-[(4-methoxybenzyl)oxy]ethyl]-13-[(E)-2-methoxy-2-oxoethylidene]-10,10,26,26-tetramethyl-19-oxo-21-[(triethylsilyl)oxy]-18,27,28,29-tetraoxatetracyclo[21.3.1.1(3,7).1(11,15)]nonacos-8-en-5-ylidene]acetate C64H94O19Si 详情 详情
(LXII) 39452 methyl 2-[(1S,3S,7R,11S,12S,15S,17R,21R,23R,25S)-1,21-dihydroxy-11-methoxy-12-[(2-methoxyacetyl)oxy]-25-[(4-methoxybenzyl)oxy]-17-[(1R)-1-[(4-methoxybenzyl)oxy]ethyl]-13-[(E)-2-methoxy-2-oxoethylidene]-10,10,26,26-tetramethyl-19-oxo-18,27,28,29-tetraoxatetracyclo[21.3.1.1(3,7).1(11,15)]nonacos-8-en-5-ylidene]acetate C57H78O19 详情 详情
(LXIII) 39453 methyl 2-[(1S,3S,7R,11S,12S,15S,17R,21R,23R,25S)-1,12,21-trihydroxy-11-methoxy-25-[(4-methoxybenzyl)oxy]-17-[(1R)-1-[(4-methoxybenzyl)oxy]ethyl]-13-[(E)-2-methoxy-2-oxoethylidene]-10,10,26,26-tetramethyl-19-oxo-18,27,28,29-tetraoxatetracyclo[21.3.1.1(3,7).1(11,15)]nonacos-8-en-5-ylidene]acetate C54H74O17 详情 详情
(LXIV) 39454 methyl 2-[(1S,3S,7R,11S,12S,15S,17R,21R,23R,25S)-1,11,12,21-tetrahydroxy-25-[(4-methoxybenzyl)oxy]-17-[(1R)-1-[(4-methoxybenzyl)oxy]ethyl]-13-[(E)-2-methoxy-2-oxoethylidene]-10,10,26,26-tetramethyl-19-oxo-18,27,28,29-tetraoxatetracyclo[21.3.1.1(3,7).1(11,15)]nonacos-8-en-5-ylidene]acetate C53H72O17 详情 详情
(LXV) 39455 (2E,4E)-2,4-octadienoic acid C8H12O2 详情 详情
(LXVI) 39456 (1S,3S,7R,11S,12S,15S,17R,21R,23R,25S)-1,11,21-trihydroxy-25-[(4-methoxybenzyl)oxy]-17-[(1R)-1-[(4-methoxybenzyl)oxy]ethyl]-5,13-bis[(E)-2-methoxy-2-oxoethylidene]-10,10,26,26-tetramethyl-19-oxo-18,27,28,29-tetraoxatetracyclo[21.3.1.1(3,7).1(11,15)]nonacos-8-en-12-yl (2E,4E)-2,4-octadienoate C61H82O18 详情 详情
(LXVII) 39457 (1S,3S,7R,11S,12S,15S,17R,21R,23R,25S)-1,11,21,25-tetrahydroxy-17-[(1R)-1-hydroxyethyl]-5,13-bis[(E)-2-methoxy-2-oxoethylidene]-10,10,26,26-tetramethyl-19-oxo-18,27,28,29-tetraoxatetracyclo[21.3.1.1(3,7).1(11,15)]nonacos-8-en-12-yl (2E,4E)-2,4-octadienoate C45H66O16 详情 详情

合成路线8

The selective silylation of (LXVII) with TBMDSCl, Et3N and DMAP in DMF gives the 26-TBDMS ether (LXVIII), which is acetylated with Ac2O and pyridine yielding the 7-acetate (LXIX). Finally, (LXIX) is desilylated with HF in acetonitrile.

1 Pettit, G.R.; et al.; Synthetic conversion of bryostatin 2 to bryostatin 1 and related bryopyrans. Can J Chem 1991, 69, 856.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(LXVII) 39457 (1S,3S,7R,11S,12S,15S,17R,21R,23R,25S)-1,11,21,25-tetrahydroxy-17-[(1R)-1-hydroxyethyl]-5,13-bis[(E)-2-methoxy-2-oxoethylidene]-10,10,26,26-tetramethyl-19-oxo-18,27,28,29-tetraoxatetracyclo[21.3.1.1(3,7).1(11,15)]nonacos-8-en-12-yl (2E,4E)-2,4-octadienoate C45H66O16 详情 详情
(LXVIII) 39458 (1S,3S,7R,11S,12S,15S,17R,21R,23R,25S)-17-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-1,11,21,25-tetrahydroxy-5,13-bis[(E)-2-methoxy-2-oxoethylidene]-10,10,26,26-tetramethyl-19-oxo-18,27,28,29-tetraoxatetracyclo[21.3.1.1(3,7).1(11,15)]nonacos-8-en-12-yl (2E,4E)-2,4-octadienoate C51H80O16Si 详情 详情
(LXIX) 39459 (1S,3S,7R,11S,12S,15S,17R,21R,23R,25S)-25-(acetoxy)-17-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-1,11,21-trihydroxy-5,13-bis[(E)-2-methoxy-2-oxoethylidene]-10,10,26,26-tetramethyl-19-oxo-18,27,28,29-tetraoxatetracyclo[21.3.1.1(3,7).1(11,15)]nonacos-8-en-12-yl (2E,4E)-2,4-octadienoate C53H82O17Si 详情 详情
Extended Information