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【结 构 式】

【分子编号】30484

【品名】Methyl(triphenyl)phosphonium bromide

【CA登记号】1779-49-3

【 分 子 式 】C19H18BrP

【 分 子 量 】357.229682

【元素组成】C 63.88% H 5.08% Br 22.37% P 8.67%
与该中间体有关的原料药合成路线共 22 条
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1

该中间体在本合成路线中的序号：(B)

The ketalization of 11alpha-hydroxy-18-methyl-DELTA4-estrene-3,17-dione (I) with ethylene glycol (A) by means of ethyl orthoformate and p-toluene sulfonic acid gives the diketal (II), which is oxidized with CrO3 in acetone yielding the ketone (III). The Wittig reaction of (III) with triphenylmethyl-phosphonium bromide (B) by means of NaH in benzene-DMSO affords 11-methylene-18-methyl-DELTA4-estren-3,17-dione diethyleneketal (IV), which is hydrolyzed with HCl in acetone to the diketone (V). The reaction of (V) with pyrrolidine (C) in methanol gives the N-pyrrolidinyl derivative (VI), which is condensed with potassium acetylide (D) in THF yielding 17alpha-ethynyl derivative (VII). Finally, this compound is hydrolyzed with acetic acid in methanol - water.

参考文献 中间体
合成目标
【1】 Van den Broek, A.J.; Novel 11,11-alkylidene steroids. DE 2361120; ES 421253; FR 2209577; GB 1455270; JP 50029548; US 3927046 .
【2】 Hillier, K.; Castaner, J.; ORG-3236. Drugs Fut 1978, 3, 9, 664.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(B) 30484 Methyl(triphenyl)phosphonium bromide 1779-49-3 C19H18BrP 详情 详情
(D) 33587 Potassium acetylide C2HK 详情 详情
(I) 33580 (8S,9S,10R,11R,13S,14S)-13-ethyl-11-hydroxy-7,8,9,10,11,12,13,14,15,16-decahydro-1H-cyclopenta[a]phenanthrene-3,17(2H,6H)-dione; 11alpha-Hydroxy-18-methyl-delta4-estrene-3,17-dione C19H26O3 详情 详情
(II) 33581 11alpha-Hydroxy-18-methylestr-4-ene-3,17-dione bis(ethyleneketal) C23H34O5 详情 详情
(III) 33582 18-Methylestr-4-ene-3,11,17-trione 3,17-bis(ethyleneketal) C23H32O5 详情 详情
(IV) 33583 11-Methylene-18-methyl-delta4-estren-3,17-dione diethyleneketal; 18-Methyl-11,11-methyleneestr-4-ene-3,17-dione bis(ethyleneketal) C24H34O4 详情 详情
(V) 33584 (8R,9S,10R,13S,14S)-13-ethyl-11-methylene-7,8,9,10,11,12,13,14,15,16-decahydro-1H-cyclopenta[a]phenanthrene-3,17(2H,6H)-dione C20H26O2 详情 详情
(VI) 33585 (8R,9S,10R,13S,14S)-13-ethyl-11-methylene-3-(1-pyrrolidinyl)-1,2,7,8,9,10,11,12,13,14,15,16-dodecahydro-17H-cyclopenta[a]phenanthren-17-one C24H33NO 详情 详情
(VII) 33586 (8R,9S,10R,13S,14S,17R)-13-ethyl-17-ethynyl-11-methylene-3-(1-pyrrolidinyl)-2,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-ol C26H35NO 详情 详情
(C) 11376 Pyrrolidine 123-75-1 C4H9N 详情 详情

合成路线2

该中间体在本合成路线中的序号：(VIII)

The methylation of 2,3,5-trimethylphenol (I) with NaH and Me-I in DMSO gives 1-methoxy-2,3,5-trimethylbenzene (II), which is condensed with DMF by means of POCl3 and NaOH to yield 4-methoxy-2,3,6-trimethylbenzaldehyde (III). The condensation of benzaldehyde (III) with acetone (IV) by means of NaOH affords the butenone (V). The condensation of (V) with methyl formate by means of NaOMe in ethyl ether provides the sodium enolate (VI), which is treated with MeOH and H2SO4 to obtain the dimethylacetal (VII). The condensation of (VII) with the phosphonium bromide (VIII) by means of tBu-OK in cyclohexane gives the methylene derivative (IX), which is hydrolyzed with formic acid to yield the aldehyde (X). The isomerization of (X) by means of TEA in ethyl ether affords the 5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-2,4-pentadienal as a mixture of (E,E) and (Z,E)-isomers that is separated by chromatography. The desired (E,E)-isomer (XI) is condensed with dimethyl isopropylidenemalonate (XII) by means of Triton B in methanol and hydrolyzed with HCl to provide the monoester (XIII), which is saponified with NaOH in methanol/water to give the malonic acid derivative (XIV). Finally, this compound is monodecarboxylated by means of pyridine in dichloromethane to yield the target Acitretin (Etretin).

参考文献 中间体
合成目标
【1】 Andriamialisoa, Z.; et al.; A new stereoselective synthesis of acitretin (=Soriatane(R), Neotigason(R)). Helv Chim Acta 2002, 85, 9, 2926.
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) 33479 2,3,5-trimethylphenol 697-82-5 C9H12O 详情 详情
(II) 33480 1-methoxy-2,3,5-trimethylbenzene; methyl 2,3,5-trimethylphenyl ether 20469-61-8 C10H14O 详情 详情
(III) 33481 4-methoxy-2,3,6-trimethylbenzaldehyde C11H14O2 详情 详情
(IV) 23199 2-Propanone; Acetone; beta-ketopropane; chevron acetone;propan-2-one； Dimethyl formaldehyde; Dimethyl ketone; dimethylketal; Ketone propane; Methyl ketone; Propanone; Pyroacetic acid; Pyroacetic ether 67-64-1 C3H6O 详情 详情
(V) 33482 (E)-4-(4-methoxy-2,3,6-trimethylphenyl)-3-buten-2-one 54757-47-0 C14H18O2 详情 详情
(VI) 58106 sodium (1E,4E)-5-(4-methoxy-2,3,6-trimethylphenyl)-3-oxo-1,4-pentadien-1-olate C15H17NaO3 详情 详情
(VII) 58107 (E)-5,5-dimethoxy-1-(4-methoxy-2,3,6-trimethylphenyl)-1-penten-3-one C17H24O4 详情 详情
(VIII) 30484 Methyl(triphenyl)phosphonium bromide 1779-49-3 C19H18BrP 详情 详情
(IX) 58108 2-[(1E)-3-(2,2-dimethoxyethyl)-1,3-butadienyl]-5-methoxy-1,3,4-trimethylbenzene; 4-[(1E)-3-(2,2-dimethoxyethyl)-1,3-butadienyl]-2,3,5-trimethylphenyl methyl ether C18H26O3 详情 详情
(X) 58109 (E)-5-(4-methoxy-2,3,6-trimethylphenyl)-3-methylene-4-pentenal C16H20O2 详情 详情
(XI) 58110 (2E,4E)-5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-2,4-pentadienal C16H20O2 详情 详情
(XII) 49671 dimethyl 2-(1-methylethylidene)malonate 22035-53-6 C8H12O4 详情 详情
(XIII) 58111 (2E,4E,6E,8E)-2-(methoxycarbonyl)-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoic acid C23H28O5 详情 详情
(XIV) 58112 2-[(2E,4E,6E)-7-(4-methoxy-2,3,6-trimethylphenyl)-1,5-dimethyl-2,4,6-heptatrienylidene]malonic acid C22H26O5 详情 详情

合成路线3

该中间体在本合成路线中的序号：

2) The epoxidation of nerol (XII) with tert-butyl peroxide and titanium isopropoxide gives the epoxide (XIII), which is benzylated with benzyl bromide to the protected epoxide (XIV). A stereo- and regioselective cleavage of the epoxide (XIV) with methanol yields the methoxy hydroxy derivative (XV), which is ozonolyzed in methanol dichloromethane to the aldehyde (XVI). The Wittig condensation of (XVI) with triphenylmethylphosphonium bromide and potassium tert-butoxide affords the methylene alcohol (XVII), which is protected with tert-butyldimethylsilyl chloride as before to give silyl derivative (XVIII). The hydrogenation of (XVIII) with H2 over Pd in ethyl acetate yields the saturated alcohol (XIX), which is oxidized with oxalyl chloride in DMSO to the aldehyde (XX).The reaction of (XX) with tetrabromomethane and triphenylphosphine affords the dibromovinyl compound (XXI), which by reaction with butyllithium in THF is converted into the acetylene (XXII). Finally, this compound is treated with tributylstannyl hydride and azobisisobutyronitrile to give the stannyl derivative (II).

参考文献 中间体
合成目标
【1】 Kolb, M.; Van Hijfte, L.; Ireland, R.E.; A highly convergent synthesis of mexiprostil: 16(R) 16-methoxy 16-methyl PGE1 methyl ester. Tetrahedron Lett 1988, 29, 51, 6769.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
30484 Methyl(triphenyl)phosphonium bromide 1779-49-3 C19H18BrP 详情 详情
(A) 12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(II) 21528 (1R,2R,3E)-1-butyl-2-[[tert-butyl(dimethyl)silyl]oxy]-1-methyl-4-(tributylstannyl)-3-butenyl methyl ether C28H60O2SiSn 详情 详情
(XII) 21538 (2Z)-3,7-dimethyl-2,6-octadien-1-ol 106-25-2 C10H18O 详情 详情
(XIII) 21539 [(2R,3S)-3-methyl-3-(4-methyl-3-pentenyl)oxiranyl]methanol C10H18O2 详情 详情
(XIV) 21540 (2S,3R)-3-[(benzyloxy)methyl]-2-methyl-2-(4-methyl-3-pentenyl)oxirane C17H24O2 详情 详情
(XV) 21541 (2R,3R)-1-(benzyloxy)-3-methoxy-3,7-dimethyl-6-octen-2-ol C18H28O3 详情 详情
(XVI) 21542 (4R,5R)-6-(benzyloxy)-5-hydroxy-4-methoxy-4-methylhexanal C15H22O4 详情 详情
(XVII) 21543 (2R,3R)-1-(benzyloxy)-3-methoxy-3-methyl-6-hepten-2-ol C16H24O3 详情 详情
(XVIII) 21544 ([(1R,2R)-1-[(benzyloxy)methyl]-2-methoxy-2-methyl-5-hexenyl]oxy)(tert-butyl)dimethylsilane C22H38O3Si 详情 详情
(XIX) 21545 (2R,3R)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methoxy-3-methyl-1-heptanol C15H34O3Si 详情 详情
(XX) 21546 (3R,4R)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methoxy-4-methyloctanal C16H34O3Si 详情 详情
(XXI) 21547 tert-butyl(dimethyl)silyl (1R)-3,3-dibromo-1-[(1R)-1-methoxy-1-methylpentyl]-2-propenyl ether C16H32Br2O2Si 详情 详情
(XXII) 21548 (1R,2R)-1-butyl-2-[[tert-butyl(dimethyl)silyl]oxy]-1-methyl-3-butynyl methyl ether C16H32O2Si 详情 详情

合成路线4

该中间体在本合成路线中的序号：(II)

A new method for the synthesis of pirbuterol hydrochloride has been described: By reaction of 2-phenyl-4H-1,3-dioxino[5,4-b]pyridine-6-carbaldehyde (I) with methyltriphenylphosphonium bromide (II) and NaOH in toluene to give 2-phenyl-6-vinyl-4H-1,3-dioxino[5,4-b]pyridine (III), which is treated with m-chloroperbenzoic acid (IV) in methylene chloride to give 6-(1,2-epoxyethyl)-2-phenyl-4H-1,3-dioxino[5,4-b]pyridine N-oxide (V). Compound (V) can also be obtained from 6-(1,2-epoxyethyl)-2-phenyl-4H-1,3-dioxino[5,4-b]pyridine (VI) by reaction with m-chloroperbenzoic acid (IV) as before. The reaction of (V) with tert-butylamine (VII) in methanol affords 6-(1-hydroxy-2-tert-butylaminoethyl)-2-phenyl-4H-1,3-dioxino[5,4-b]pyridine N-oxide (VIII), which is first treated with H2 over Pd/C in methanol and then with HCl in ethyl acetate to give pirbuterol hydrochloride.

参考文献 中间体
合成目标
【1】 Masset, S.S.; Cue, B.W. (Pfizer Inc.); Process and intermediates for preparing pirbuteol and analogs. EP 0058069; EP 0058070; EP 0058071; EP 0058072; JP 57150665 .
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) 30711 2-phenyl-4H-[1,3]dioxino[5,4-b]pyridine-6-carbaldehyde C14H11NO3 详情 详情
(II) 30484 Methyl(triphenyl)phosphonium bromide 1779-49-3 C19H18BrP 详情 详情
(III) 30712 2-phenyl-6-vinyl-4H-[1,3]dioxino[5,4-b]pyridine C15H13NO2 详情 详情
(V) 30713 6-(2-oxiranyl)-2-phenyl-4H-[1,3]dioxino[5,4-b]pyridin-5-ium-5-olate C15H13NO4 详情 详情
(VI) 30714 6-(2-oxiranyl)-2-phenyl-4H-[1,3]dioxino[5,4-b]pyridine C15H13NO3 详情 详情
(VII) 17895 2-Amino-2-methylpropane; tert-butylamine; 2-methyl-2-propanamine 75-64-9 C4H11N 详情 详情
(VIII) 30715 6-[2-(tert-butylamino)-1-hydroxyethyl]-2-phenyl-4H-[1,3]dioxino[5,4-b]pyridin-5-ium-5-olate C19H24N2O4 详情 详情

合成路线5

该中间体在本合成路线中的序号：(II)

By a Wittig reaction at naltrexone (I) with triphenylmethylphosphonium bromide (II) in DMSO by means of NaH as base.

参考文献 中间体
合成目标
【1】 Hahn, E.F.; Fishman, J.; Narcotic antagonists. 4. Carbon-6 derivatives of N-substituted noroxymorphones as narcotic antagonists. J Med Chem 1975, 18, 3, 259-262.
【2】 Hermann, E.C.; Lee, K.T.; Myers, M.J. (DuPont Pharmaceuticals Co.); 17-Substituted-6-desoxy-7,8-dihydro-6alpha-methylnoroxymorphone narcotic antagonists. EP 0039066; JP 167687; US 4322426 .
【3】 Serradell, M.N.; Castaner, J.; Nalmefene. Drugs Fut 1984, 9, 7, 518.
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) 25079 (1S,5R,13R,17S)-4-(cyclopropylmethyl)-10,17-dihydroxy-12-oxa-4-azapentacyclo[9.6.1.0(1,13).0(5,17).0(7,18)]octadeca-7(18),8,10-trien-14-one; Naltrexone 16590-41-3 C20H23NO4 详情 详情
(II) 30484 Methyl(triphenyl)phosphonium bromide 1779-49-3 C19H18BrP 详情 详情

合成路线6

该中间体在本合成路线中的序号：(IV)

The reaction of 5-methyluridine (I) with TrCl and pyridine gives the 5'-O-trityl derivative (II), which is oxidized with NaIO4 in ethanol/water to yield the dialdehyde (III). The Wittig reaction of (III) with methyltriphenylphosphonium bromide (IV) and t-BuOK in toluene to afford the bis vinyl compound (V), which is submitted to a ring closing metathesis reaction catalyzed by a Ru catalyst in dichloromethane to provide the unsaturated nucleoside (VI). Finally, this compound is deprotected by means of AcOH in water to furnish the target Stavudine.

参考文献 中间体
合成目标
【1】 Ewing, D.F.; et al.; Synthesis of acyclic bis-vinyl pyrimidines: A general route to d4T via metathesis. Tetrahedron 2003, 59, 7, 941.
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) 12206 1-[(2R,3R,4S,5R)-3,4-Dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione; 5-Methyluridine 1463-10-1 C10H14N2O6 详情 详情
(II) 41905 1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione C29H28N2O6 详情 详情
(III) 62190 (2R)-2-({(1R)-1-[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-2-oxoethyl}oxy)-3-(trityloxy)propanal C29H26N2O6 详情 详情
(IV) 30484 Methyl(triphenyl)phosphonium bromide 1779-49-3 C19H18BrP 详情 详情
(V) 62191 5-methyl-1-[(1R)-1-({(1S)-1-[(trityloxy)methyl]-2-propenyl}oxy)-2-propenyl]-2,4(1H,3H)-pyrimidinedione C31H30N2O4 详情 详情
(VI) 12199 5-Methyl-1-[(2R,5S)-5-[(trityloxy)methyl]-2,5-dihydro-2-furanyl]-2,4(1H,3H)-pyrimidinedione C29H26N2O4 详情 详情

合成路线7

该中间体在本合成路线中的序号：(V)

The reaction of 5-methyluridine (I) with trityl chloride (II) and pyridine gives the 5'-O-trityl analogue (III), which is submitted to an oxidative cleavage of the vicinal dihydroxy group by means of NaIO4 in EtOH/water to yield the dialdehyde (IV). The double Wittig olefination of (IV) by means of methyltriphenylphosphonium bromide (V) and t-BuOK in toluene affords the bis alkene (VI), which is submitted to a ring closing metathesis by means of the Grubb's catalyst in dichloromethane to provide the unsaturated nucleoside (VII). Finally, this compound was deprotected by means of 80% AcOH to furnish the target Stavudine.

参考文献 中间体
合成目标
【1】 Ewing, D.; Glacon, V.; Mackenzie, G.; Postel, D.; Len, C.; A novel approach to unsaturated acyclic nucleoside analogues and the first synthesis of d4T by ring closure metathesis. Tetrahedron Lett 2002, 43, 19, 3503.
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) 12206 1-[(2R,3R,4S,5R)-3,4-Dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione; 5-Methyluridine 1463-10-1 C10H14N2O6 详情 详情
(II) 28630 Triphenylchloromethane; 1-[Chloro(diphenyl)methyl]benzene; Trityl chloride 76-83-5 C19H15Cl 详情 详情
(III) 41905 1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione C29H28N2O6 详情 详情
(IV) 62190 (2R)-2-({(1R)-1-[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-2-oxoethyl}oxy)-3-(trityloxy)propanal C29H26N2O6 详情 详情
(V) 30484 Methyl(triphenyl)phosphonium bromide 1779-49-3 C19H18BrP 详情 详情
(VI) 62191 5-methyl-1-[(1R)-1-({(1S)-1-[(trityloxy)methyl]-2-propenyl}oxy)-2-propenyl]-2,4(1H,3H)-pyrimidinedione C31H30N2O4 详情 详情
(VII) 12199 5-Methyl-1-[(2R,5S)-5-[(trityloxy)methyl]-2,5-dihydro-2-furanyl]-2,4(1H,3H)-pyrimidinedione C29H26N2O4 详情 详情

合成路线8

该中间体在本合成路线中的序号：(IX)

The intermediate tricyclic carbaldehyde has been obtained by two different methods: 1. The dicarboxylic ester (I) is methylated with Me-I and Ag2O in dioxane to give the dimethoxy compound (II), which is reduced with LiAlH4 in THF to obtain the dicarbinol (III). Monoesterification of (III) with benzoyl chloride and pyridine in dichloromethane yields the monobenzoate (IV), which is oxidized with DMP to afford the carbaldehyde (V). The Grignard reaction of (V) with methylmagnesium bromide and MeLi in THF provides the diol (VI), which is oxidized with oxalyl chloride to furnish the desired intermediate carbaldehyde (VII). 2. The reaction of the tricyclic ketone (VIII) with phosphonium bromide (IX) by means of tBu-OK in THF gives methylene derivative (X), which by hydroboration with BH3 and H2O2 in THF yields the carbinol (XI). The oxidation of (XI) with DPP affords the carbaldehyde (XII), which is condensed with the 1-aminopyrrolidine (XIII) to afford the hydrazone (XIV). The acylation of (XIV) with acetyl chloride and LDA in THF provides the acetyl derivative (XV), which is finally treated with oxalic acid go give the desired intermediate carbaldehyde (VII).

参考文献 中间体
合成目标
【1】 Kita, Y.; et al.; Total synthesis of the antitumor antribiotic (±)-fredericamycin A by a linear approach. Chemistry (Weinheim) 2000, 6, 21, 3897.
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) 48755 dimethyl 9-hydroxy-3-methyl-1-oxo-1,2,6,7-tetrahydro-8H-cyclopenta[g]isoquinoline-8,8-dicarboxylate C17H17NO6 详情 详情
(II) 48756 dimethyl 1,9-dimethoxy-3-methyl-6,7-dihydro-8H-cyclopenta[g]isoquinoline-8,8-dicarboxylate C19H21NO6 详情 详情
(III) 48757 [8-(hydroxymethyl)-1,9-dimethoxy-3-methyl-7,8-dihydro-6H-cyclopenta[g]isoquinolin-8-yl]methanol C17H21NO4 详情 详情
(IV) 48758 [8-(hydroxymethyl)-1,9-dimethoxy-3-methyl-7,8-dihydro-6H-cyclopenta[g]isoquinolin-8-yl]methyl benzoate C24H25NO5 详情 详情
(V) 48759 (8-formyl-1,9-dimethoxy-3-methyl-7,8-dihydro-6H-cyclopenta[g]isoquinolin-8-yl)methyl benzoate C24H23NO5 详情 详情
(VI) 48760 1-[8-(hydroxymethyl)-1,9-dimethoxy-3-methyl-7,8-dihydro-6H-cyclopenta[g]isoquinolin-8-yl]-1-ethanol C18H23NO4 详情 详情
(VII) 48761 8-acetyl-1,9-dimethoxy-3-methyl-7,8-dihydro-6H-cyclopenta[g]isoquinoline-8-carbaldehyde C18H19NO4 详情 详情
(VIII) 48762 1,9-dimethoxy-3-methyl-6,7-dihydro-8H-cyclopenta[g]isoquinolin-8-one C15H15NO3 详情 详情
(IX) 30484 Methyl(triphenyl)phosphonium bromide 1779-49-3 C19H18BrP 详情 详情
(X) 48763 1,9-dimethoxy-3-methyl-8-methylene-7,8-dihydro-6H-cyclopenta[g]isoquinoline; 1-methoxy-3-methyl-8-methylene-7,8-dihydro-6H-cyclopenta[g]isoquinolin-9-yl methyl ether C16H17NO2 详情 详情
(XI) 48764 (1,9-dimethoxy-3-methyl-7,8-dihydro-6H-cyclopenta[g]isoquinolin-8-yl)methanol C16H19NO3 详情 详情
(XII) 46913 (2R)-2-(methoxymethyl)pyrrolidinylamine; (2R)-2-(methoxymethyl)-1-pyrrolidinamine 59983-39-0 C6H14N2O 详情 详情
(XIII) 48765 1,9-dimethoxy-3-methyl-7,8-dihydro-6H-cyclopenta[g]isoquinoline-8-carbaldehyde C16H17NO3 详情 详情
(XIV) 48766 N-[(E)-(1,9-dimethoxy-3-methyl-7,8-dihydro-6H-cyclopenta[g]isoquinolin-8-yl)methylidene]-N-[(2R)-2-(methoxymethyl)pyrrolidinyl]amine; (2R)-N-[(E)-(1,9-dimethoxy-3-methyl-7,8-dihydro-6H-cyclopenta[g]isoquinolin-8-yl)methylidene]-2-(methoxymethyl)-1-pyrrolidinamine C22H29N3O3 详情 详情
(XV) 19273 acetyl chloride 75-36-5 C2H3ClO 详情 详情
(XVI) 48767 1-[1,9-dimethoxy-8-([[(2R)-2-(methoxymethyl)pyrrolidinyl]imino]methyl)-3-methyl-7,8-dihydro-6H-cyclopenta[g]isoquinolin-8-yl]-1-ethanone C24H31N3O4 详情 详情

合成路线9

该中间体在本合成路线中的序号：(XV)

The silylation of 2-methyl-5-(tert-butyldimethylsilyloxy)-1-penten-3(s)-ol (VIII) with Tbdms-Cl and imidazole in DMF gives the disilylated compound (IX), which is treated with ozone and PPh3 in dichloromethane to yield the 2-pentanone (X). The condensation of (X) with phosphonate (XI) by means of BuLi in THF yields the fully silylated diol (XII), which is selectively monodesilylated with HF in acetonitrile to afford the primary alcohol (XIII). The oxidation of (XIII) with DMP in dichloromethane affords the aldehyde (XIV), which is methylenated with the phosphonium salt (XV) and NaNH2 in THF to provide the silylated hexadienol (XVI). The reaction of (XVI) with TBAF in THF gives the free secondary alcohol (XVII), which is esterified with the intermediate tridecenoic acid (VII) by means of DCC and DMAP in dichloromethane, yielding the ester (XVIII). Ring-closing metathesis of (XVIII), catalyzed by a Ru catalyst, affords the macrolactone (XIX), which is desilylated by means of HF in acetonitrile to furnish the dihydroxymacrolactone (XX). Finally, the double bond of (XX) is epoxidated with dimethyldioxirane (DMDO) in dichloromethane to provide the target epothilone A.

参考文献 中间体
合成目标
【1】 Schinzer, D.; et al.; Total synthesis of (-)-epothilone A. Angew Chem. Int Ed Engl 1997, 36, 5, 523.
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) 44438 (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-12-tridecenoic acid C29H58O5Si2 详情 详情
(VIII) 44439 (3S)-5-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1-penten-3-ol C12H26O2Si 详情 详情
(IX) 44440 (5S)-5-isopropenyl-2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecane; tert-butyl(dimethyl)silyl (1S)-1-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-2-methyl-2-propenyl ether C18H40O2Si2 详情 详情
(X) 44441 (3S)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-pentanone C17H38O3Si2 详情 详情
(XI) 44442 diethyl (2-methyl-1,3-thiazol-4-yl)methylphosphonate C9H16NO3PS 详情 详情
(XII) 44443 tert-butyl(dimethyl)silyl (1S,2E)-1-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenyl ether; 4-((E,3S)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1-pentenyl)-2-methyl-1,3-thiazole C22H43NO2SSi2 详情 详情
(XIII) 40821 (3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-penten-1-ol C16H29NO2SSi 详情 详情
(XIV) 40822 (3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-pentenal C16H27NO2SSi 详情 详情
(XV) 30484 Methyl(triphenyl)phosphonium bromide 1779-49-3 C19H18BrP 详情 详情
(XVI) 44444 4-((1E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1,5-hexadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl ether C17H29NOSSi 详情 详情
(XVII) 43171 (1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol C11H15NOS 详情 详情
(XVIII) 44445 (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-12-tridecenoate C40H71NO5SSi2 详情 详情
(XIX) 44446 (4S,7R,8S,9S,16S)-4,8-bis[[tert-butyl(dimethyl)silyl]oxy]-5,5,7,9-tetramethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione C38H67NO5SSi2 详情 详情
(XX) 44447 (4S,7R,8S,9S,16S)-4,8-dihydroxy-5,5,7,9-tetramethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione C26H39NO5S 详情 详情

合成路线10

该中间体在本合成路线中的序号：(XV)

Synthesis of intermediate (XVI): The condensation of 3(S)-(phenyldimethylsilyl)-4(E)-hexenoic acid methyl ester (I) with 2-(tert-butyldimethylsilyloxy)acetaldehyde (II) by means of Tms-OBn, Tms-OTf and BF3/Et2O in dichloromethane gives the 3(E)-heptenoic ester (III), which is ozonolyzed with O3 and pyridine in methanol/dichloromethane to yield the aldehyde (IV). The condensation of (IV) with the silyl ketal (V) by means of TiCl4 in dichloromethane affords the partially protected trihydroxyester (VI), which is silylated with Tbdms-OTf and lutidine in dichloromethane to provide the fully protected ester (VII). Regioselective monodesilylation of (VII) by means of TBAF/HOAc in THF gives the primary alcohol (VIII), which is oxidized with oxalyl chloride to the corresponding aldehyde (IX). The condensation of (IX) with phosphorane (X) in refluxing benzene yields the octenedioic diester (XI), which is methylated with Me2CuLi and Tms-Cl in THF, affording the tetramethyl diester (XII). The two ester groups of (XII) were easily differentiated by a reduction with DIBAL in dichloromethane, providing the 8-hydroxyoctanal derivative (XIII), which was silylated with TBdms-Cl and imidazole in DMF to give the fully protected aldehyde (XIV). Finally, this compound was subjected to a Wittig olefination reaction with methyltriphenylphosphonium bromide (XV) and NaHMDS in THF to yield the desired intermediate (XVI).

参考文献 中间体
合成目标
【1】 Panek, J.S.; Zhu, B.; Total synthesis of apothilone A. Org Lett 2000, 2, 17, 2575.
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) 44474 methyl (3S,4E)-3-[dimethyl(phenyl)silyl]-4-hexenoate C15H22O2Si 详情 详情
(II) 44475 2-[[tert-butyl(diphenyl)silyl]oxy]acetaldehyde C18H22O2Si 详情 详情
(III) 44476 methyl (E,5S,6R)-6-(benzyloxy)-7-[[tert-butyl(diphenyl)silyl]oxy]-5-methyl-3-heptenoate C32H40O4Si 详情 详情
(IV) 44477 (2R,3R)-3-(benzyloxy)-4-[[tert-butyl(diphenyl)silyl]oxy]-2-methylbutanal C28H34O3Si 详情 详情
(V) 44478 1-Ethoxy-2-methyl-1-trimethylsiloxypropene;1-Ethoxy-2-methyl-1-(trimethylsilyloxy)propene;1-Ethoxy-2-methyl-1-(trimethylsilyl)oxy-1-propene;1-ethoxy-2-methyl-1-propenyl trimethylsilyl ether; [(1-ethoxy-2-methyl-1-propenyl)oxy](trimethyl)silane ;dimethylketene ethyl trimethylsilyl acetal 31469-16-6 C9H20O2Si 详情 详情
(VI) 44479 ethyl (3R,4S,5R)-5-(benzyloxy)-6-[[tert-butyl(diphenyl)silyl]oxy]-3-hydroxy-2,2,4-trimethylhexanoate C34H46O5Si 详情 详情
(VII) 44480 ethyl (3R,4R,5R)-5-(benzyloxy)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-[[tert-butyl(diphenyl)silyl]oxy]-2,2,4-trimethylhexanoate C40H60O5Si2 详情 详情
(VIII) 44481 ethyl (3R,4R,5R)-5-(benzyloxy)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-hydroxy-2,2,4-trimethylhexanoate C24H42O5Si 详情 详情
(IX) 44482 ethyl (3R,4R,5R)-5-(benzyloxy)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,2,4-trimethyl-6-oxohexanoate C24H40O5Si 详情 详情
(X) 14182 ethyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate; (Carbethoxymethylene)triphenylphosphorane 1099-45-2 C22H21O2P 详情 详情
(XI) 44483 diethyl (E,4S,5R,6R)-4-(benzyloxy)-6-[[tert-butyl(dimethyl)silyl]oxy]-5,7,7-trimethyl-2-octenedioate C28H46O6Si 详情 详情
(XII) 44484 diethyl (3R,4R,5S,6S)-5-(benzyloxy)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,2,4,6-tetramethyloctanedioate C29H50O6Si 详情 详情
(XIII) 44485 (3S,4S,5R,6R)-4-(benzyloxy)-6-[[tert-butyl(dimethyl)silyl]oxy]-8-hydroxy-3,5,7,7-tetramethyloctanal C25H44O4Si 详情 详情
(XIV) 44486 (3S,4S,5R,6R)-4-(benzyloxy)-6,8-bis[[tert-butyl(dimethyl)silyl]oxy]-3,5,7,7-tetramethyloctanal C31H58O4Si2 详情 详情
(XV) 30484 Methyl(triphenyl)phosphonium bromide 1779-49-3 C19H18BrP 详情 详情
(XVI) 44487 (5R)-5-[(1R,2S,3S)-2-(benzyloxy)-1,3-dimethyl-5-hexenyl]-2,2,3,3,6,6,9,9,10,10-decamethyl-4,8-dioxa-3,9-disilaundecane; benzyl (1S,2S)-1-((1R,2R)-2,4-bis[[tert-butyl(dimethyl)silyl]oxy]-1,3,3-trimethylbutyl)-2-methyl-4-pentenyl ether C32H60O3Si2 详情 详情

合成路线11

该中间体在本合成路线中的序号：(XXV)

The cyclization of 3-(benzyloxy)-2(S)-methylpropenal (X) with the diene (XI) by means of TiCl4 in dichloromethane gives the dihydropyranone (XII), which is reduced with LiAlH4 in ethyl ether to yield the alcohol (XIII). The cyclopropanation of (XIII) by means of diiodomethane and Et2Zn in ethyl ether affords the cyclopropano derivative (XIV), which is cleaved by means of N-iodosuccinimide (NIS) in methanol, affording the iodomethyl derivative (XV). The dehalogenation of (XV) by means of Bu3SnH and AIBN in refluxing benzene provide the gem-dimethyltetrahydropyran (XVI), which is treated with triphenylchlorosilane and imidazole in DMF to give the silyl ether (XVII). Opening of the tetrahydropyran ring of (XVII) by means of propane-1,2-dithiol and TiCl4 in dichloromethane yields the 1,3-dithiolane derivative (XVIII), which is treated with Tbdms-OTf and lutidine to afford the disilylated compound (XIX). The debenzylation of (XIX) with DDQ in dichloromethane/water provides the primary alcohol (XX), which is oxidized with oxalyl chloride in DMSO/dichloromethane, furnishing the corresponding aldehyde (XXI). The condensation of (XXI) with the phosphonium salt (XXII) by means of KOtBu in THF gives the enol ether (XXIII), which is hydrolyzed to the corresponding aldehyde (XXIV) by means of TsOH in dioxane/water. The condensation of (XXIV) with phosphonium salt (XXV) by means of NaHMDS in toluene yields the terminal olefin (XXVI), which is treated with phenyliodonium trifluoroacetate in methanol/THF to afford the aldehyde dimethylacetal (XXVII). The condensation of (XXVII) with thiazole intermediate (IX) by means of 9-BBN, a Pd catalyst and Cs2CO3 in DMF/water gives the adduct (XXVIII).

参考文献 中间体
合成目标
【1】 Meng, D.; et al.; Total syntheses of epothilones A and B. J Am Chem Soc 1997, 119, 42, 10073.
【2】 Bertinato, P.; Danishefsky, S.J.; Su, D.-S.; Kamenecka, T.; Meng, D.F.; Sorensen, E.J.; Savin, K.A.; Chou, T.-C.; Balog, A. (Sloan-Kettering Institute); Synthesis of epothilones, intermediates thereto, analogues and uses thereof. JP 2001507716; US 6242469; WO 9901124 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXIIIa) 44545 tert-butyl(dimethyl)silyl (1S,2S,3E)-1-[(1R,2R)-3-(1,3-dithian-2-yl)-1,3-dimethyl-2-[(triphenylsilyl)oxy]butyl]-4-methoxy-2-methyl-3-butenyl ether; (3R,4R,5S)-3-[1-(1,3-dithian-2-yl)-1-methylethyl]-5-[(1S,2E)-3-methoxy-1-methyl-2-propenyl]-4,7,7,8,8-pentamethyl-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane C40H58O3S2Si2 详情 详情
(XXIIIa) 44546 (3R,4R,5S)-3-[1-(1,3-dithian-2-yl)-1-methylethyl]-5-[(1S,2Z)-3-methoxy-1-methyl-2-propenyl]-4,7,7,8,8-pentamethyl-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane; tert-butyl(dimethyl)silyl (1S,2S,3Z)-1-[(1R,2R)-3-(1,3-dithian-2-yl)-1,3-dimethyl-2-[(triphenylsilyl)oxy]butyl]-4-methoxy-2-methyl-3-butenyl ether C40H58O3S2Si2 详情 详情
(IX) 44493 (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate C13H16INO2S 详情 详情
(X) 44533 (2S)-3-(benzyloxy)-2-methylpropanal C11H14O2 详情 详情
(XI) 44534 (Z)-1-[(E)-2-methoxy-1-methylethenyl]-1-propenyl trimethylsilyl ether; ([(Z)-1-[(E)-2-methoxy-1-methylethenyl]-1-propenyl]oxy)(trimethyl)silane C10H20O2Si 详情 详情
(XII) 44535 (2S,3R)-2-[(1S)-2-(benzyloxy)-1-methylethyl]-3,5-dimethyl-2,3-dihydro-4H-pyran-4-one C17H22O3 详情 详情
(XIII) 44536 (2S,3S,4R)-2-[(1S)-2-(benzyloxy)-1-methylethyl]-3,5-dimethyl-3,4-dihydro-2H-pyran-4-ol C17H24O3 详情 详情
(XIV) 44537 (1R,3S,4S,5R,6R)-3-[(1S)-2-(benzyloxy)-1-methylethyl]-4,6-dimethyl-2-oxabicyclo[4.1.0]heptan-5-ol C18H26O3 详情 详情
(XV) 44538 (3R,4R,5S,6S)-6-[(1S)-2-(benzyloxy)-1-methylethyl]-3-(iodomethyl)-2-methoxy-3,5-dimethyltetrahydro-2H-pyran-4-ol C19H29IO4 详情 详情
(XVI) 44539 (4R,5S,6S)-6-[(1S)-2-(benzyloxy)-1-methylethyl]-2-methoxy-3,3,5-trimethyltetrahydro-2H-pyran-4-ol C19H30O4 详情 详情
(XVII) 44540 benzyl (2S)-2-[(2S,3R,4R)-6-methoxy-3,5,5-trimethyl-4-[(triphenylsilyl)oxy]tetrahydro-2H-pyran-2-yl]propyl ether; ([(4R,5R,6S)-6-[(1S)-2-(benzyloxy)-1-methylethyl]-2-methoxy-3,3,5-trimethyltetrahydro-2H-pyran-4-yl]oxy)(triphenyl)silane C37H44O4Si 详情 详情
(XVIII) 44541 (2S,3S,4R,5R)-1-(benzyloxy)-6-(1,3-dithian-2-yl)-2,4,6-trimethyl-5-[(triphenylsilyl)oxy]-3-heptanol C39H48O3S2Si 详情 详情
(XIX) 44542 (3R,4R,5S)-5-[(1S)-2-(benzyloxy)-1-methylethyl]-3-[1-(1,3-dithian-2-yl)-1-methylethyl]-4,7,7,8,8-pentamethyl-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane; benzyl (2S,3S,4R,5R)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-(1,3-dithian-2-yl)-2,4,6-trimethyl-5-[(triphenylsilyl)oxy]heptyl ether C45H62O3S2Si2 详情 详情
(XX) 44543 (2S,3S,4R,5R)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-(1,3-dithian-2-yl)-2,4,6-trimethyl-5-[(triphenylsilyl)oxy]-1-heptanol C38H56O3S2Si2 详情 详情
(XXI) 44544 (2R,3R,4R,5R)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-(1,3-dithian-2-yl)-2,4,6-trimethyl-5-[(triphenylsilyl)oxy]heptanal C38H54O3S2Si2 详情 详情
(XXII) 39163 (methoxymethyl)(triphenyl)phosphonium chloride 4009-98-7 C20H20ClOP 详情 详情
(XXIV) 44547 (3S,4S,5R,6R)-4-[[tert-butyl(dimethyl)silyl]oxy]-7-(1,3-dithian-2-yl)-3,5,7-trimethyl-6-[(triphenylsilyl)oxy]octanal C39H56O3S2Si2 详情 详情
(XXV) 30484 Methyl(triphenyl)phosphonium bromide 1779-49-3 C19H18BrP 详情 详情
(XXVI) 44548 (3R,4R,5S)-3-[1-(1,3-dithian-2-yl)-1-methylethyl]-4,7,7,8,8-pentamethyl-5-[(1S)-1-methyl-3-butenyl]-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane; tert-butyl(dimethyl)silyl (1S,2S)-1-[(1R,2R)-3-(1,3-dithian-2-yl)-1,3-dimethyl-2-[(triphenylsilyl)oxy]butyl]-2-methyl-4-pentenyl ether C40H58O2S2Si2 详情 详情
(XXVII) 44549 tert-butyl(dimethyl)silyl (1S,2S)-1-[(1R,2R)-4,4-dimethoxy-1,3,3-trimethyl-2-[(triphenylsilyl)oxy]butyl]-2-methyl-4-pentenyl ether; (3R,4R,5S)-3-(2,2-dimethoxy-1,1-dimethylethyl)-4,7,7,8,8-pentamethyl-5-[(1S)-1-methyl-3-butenyl]-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane C39H58O4Si2 详情 详情
(XXVIII) 44550 (1S,3Z,8S,9S,10R,11R)-9-[[tert-butyl(dimethyl)silyl]oxy]-13,13-dimethoxy-8,10,12,12-tetramethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-11-[(triphenylsilyl)oxy]-3-tridecenyl acetate C52H75NO6SSi2 详情 详情

合成路线12

该中间体在本合成路线中的序号：(XXV)

The cyclization of 3-(benzyloxy)-2(S)-methylpropenal (X) with the diene (XI) by means of TiCl4 in dichloromethane gives the dihydropyranone (XII), which is reduced with LiAlH4 in ethyl ether to yield the alcohol (XIII). The cyclopropanation of (XIII) by means of diiodomethane and Et2Zn in ethyl ether affords the cyclopropano derivative (XIV), which is cleaved by means of N-iodosuccinimide (NIS) in methanol, affording the iodomethyl derivative (XV). The dehalogenation of (XV) by means of Bu3SnH and AIBN in refluxing benzene provide the gem-dimethyltetrahydropyran (XVI), which is treated with triphenylchlorosilane and imidazole in DMF to give the silyl ether (XVII). Opening of the tetrahydropyran ring of (XVII) by means of propane-1,2-dithiol and TiCl4 in dichloromethane yields the 1,3-dithiolane derivative (XVIII), which is treated with Tbdms-OTf and lutidine to afford the disilylated compound (XIX). The debenzylation of (XIX) with DDQ in dichloromethane/water provides the primary alcohol (XX), which is oxidized with oxalyl chloride in DMSO/dichloromethane to furnish the corresponding aldehyde (XXI). The condensation of (XXI) with the phosphonium salt (XXII) by means of tBu-OK in THF gives the enol ether (XXIII), which is hydrolyzed to the corresponding aldehyde (XXIV) by means of Ts-OH in dioxane/water. The condensation of (XXIV) with phosphonium salt (XXV) by means of NaHMDS in toluene yields the terminal olefin (XXVI), which is treated with phenyliodonium trifluoroacetate in methanol/THF to afford the aldehyde dimethylacetal (XXVII). The condensation of (XXVII) with thiazole intermediate (IX) by means of 9-BBN, a Pd catalyst and Cs2CO3 in DMF/water gives the adduct (XXVIII).

参考文献 中间体
合成目标
【1】 Meng, D.; et al.; Total syntheses of epothilones A and B. J Am Chem Soc 1997, 119, 42, 10073.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXIIIa) 44545 tert-butyl(dimethyl)silyl (1S,2S,3E)-1-[(1R,2R)-3-(1,3-dithian-2-yl)-1,3-dimethyl-2-[(triphenylsilyl)oxy]butyl]-4-methoxy-2-methyl-3-butenyl ether; (3R,4R,5S)-3-[1-(1,3-dithian-2-yl)-1-methylethyl]-5-[(1S,2E)-3-methoxy-1-methyl-2-propenyl]-4,7,7,8,8-pentamethyl-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane C40H58O3S2Si2 详情 详情
(XXIIIb) 44546 (3R,4R,5S)-3-[1-(1,3-dithian-2-yl)-1-methylethyl]-5-[(1S,2Z)-3-methoxy-1-methyl-2-propenyl]-4,7,7,8,8-pentamethyl-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane; tert-butyl(dimethyl)silyl (1S,2S,3Z)-1-[(1R,2R)-3-(1,3-dithian-2-yl)-1,3-dimethyl-2-[(triphenylsilyl)oxy]butyl]-4-methoxy-2-methyl-3-butenyl ether C40H58O3S2Si2 详情 详情
(IX) 46125 (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-pentenyl acetate C14H18INO2S 详情 详情
(X) 44533 (2S)-3-(benzyloxy)-2-methylpropanal C11H14O2 详情 详情
(XI) 44534 (Z)-1-[(E)-2-methoxy-1-methylethenyl]-1-propenyl trimethylsilyl ether; ([(Z)-1-[(E)-2-methoxy-1-methylethenyl]-1-propenyl]oxy)(trimethyl)silane C10H20O2Si 详情 详情
(XII) 44535 (2S,3R)-2-[(1S)-2-(benzyloxy)-1-methylethyl]-3,5-dimethyl-2,3-dihydro-4H-pyran-4-one C17H22O3 详情 详情
(XIII) 44536 (2S,3S,4R)-2-[(1S)-2-(benzyloxy)-1-methylethyl]-3,5-dimethyl-3,4-dihydro-2H-pyran-4-ol C17H24O3 详情 详情
(XIV) 44537 (1R,3S,4S,5R,6R)-3-[(1S)-2-(benzyloxy)-1-methylethyl]-4,6-dimethyl-2-oxabicyclo[4.1.0]heptan-5-ol C18H26O3 详情 详情
(XV) 44538 (3R,4R,5S,6S)-6-[(1S)-2-(benzyloxy)-1-methylethyl]-3-(iodomethyl)-2-methoxy-3,5-dimethyltetrahydro-2H-pyran-4-ol C19H29IO4 详情 详情
(XVI) 44539 (4R,5S,6S)-6-[(1S)-2-(benzyloxy)-1-methylethyl]-2-methoxy-3,3,5-trimethyltetrahydro-2H-pyran-4-ol C19H30O4 详情 详情
(XVII) 44540 benzyl (2S)-2-[(2S,3R,4R)-6-methoxy-3,5,5-trimethyl-4-[(triphenylsilyl)oxy]tetrahydro-2H-pyran-2-yl]propyl ether; ([(4R,5R,6S)-6-[(1S)-2-(benzyloxy)-1-methylethyl]-2-methoxy-3,3,5-trimethyltetrahydro-2H-pyran-4-yl]oxy)(triphenyl)silane C37H44O4Si 详情 详情
(XVIII) 44541 (2S,3S,4R,5R)-1-(benzyloxy)-6-(1,3-dithian-2-yl)-2,4,6-trimethyl-5-[(triphenylsilyl)oxy]-3-heptanol C39H48O3S2Si 详情 详情
(XIX) 44542 (3R,4R,5S)-5-[(1S)-2-(benzyloxy)-1-methylethyl]-3-[1-(1,3-dithian-2-yl)-1-methylethyl]-4,7,7,8,8-pentamethyl-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane; benzyl (2S,3S,4R,5R)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-(1,3-dithian-2-yl)-2,4,6-trimethyl-5-[(triphenylsilyl)oxy]heptyl ether C45H62O3S2Si2 详情 详情
(XX) 44543 (2S,3S,4R,5R)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-(1,3-dithian-2-yl)-2,4,6-trimethyl-5-[(triphenylsilyl)oxy]-1-heptanol C38H56O3S2Si2 详情 详情
(XXI) 44544 (2R,3R,4R,5R)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-(1,3-dithian-2-yl)-2,4,6-trimethyl-5-[(triphenylsilyl)oxy]heptanal C38H54O3S2Si2 详情 详情
(XXII) 39163 (methoxymethyl)(triphenyl)phosphonium chloride 4009-98-7 C20H20ClOP 详情 详情
(XXIV) 44547 (3S,4S,5R,6R)-4-[[tert-butyl(dimethyl)silyl]oxy]-7-(1,3-dithian-2-yl)-3,5,7-trimethyl-6-[(triphenylsilyl)oxy]octanal C39H56O3S2Si2 详情 详情
(XXV) 30484 Methyl(triphenyl)phosphonium bromide 1779-49-3 C19H18BrP 详情 详情
(XXVI) 44548 (3R,4R,5S)-3-[1-(1,3-dithian-2-yl)-1-methylethyl]-4,7,7,8,8-pentamethyl-5-[(1S)-1-methyl-3-butenyl]-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane; tert-butyl(dimethyl)silyl (1S,2S)-1-[(1R,2R)-3-(1,3-dithian-2-yl)-1,3-dimethyl-2-[(triphenylsilyl)oxy]butyl]-2-methyl-4-pentenyl ether C40H58O2S2Si2 详情 详情
(XXVII) 44549 tert-butyl(dimethyl)silyl (1S,2S)-1-[(1R,2R)-4,4-dimethoxy-1,3,3-trimethyl-2-[(triphenylsilyl)oxy]butyl]-2-methyl-4-pentenyl ether; (3R,4R,5S)-3-(2,2-dimethoxy-1,1-dimethylethyl)-4,7,7,8,8-pentamethyl-5-[(1S)-1-methyl-3-butenyl]-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane C39H58O4Si2 详情 详情
(XXVIII) 46127 (1S,3Z,8S,9S,10R,11R)-9-[[tert-butyl(dimethyl)silyl]oxy]-13,13-dimethoxy-4,8,10,12,12-pentamethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-11-[(triphenylsilyl)oxy]-3-tridecenyl acetate C53H77NO6SSi2 详情 详情

合成路线13

该中间体在本合成路线中的序号：(XV)

The protection of the allyl alcohol (I) with dihydropyran and PPTS in dichloromethane gives the tetrahydropyranyl ether (II), which is condensed with the chiral oxazolidinone (III) by means of BuLi and CuCN in THF to yield the adduct (IV). The hydroxylation of (IV) with Davis' oxaziridine, NaHMDS and CSA affords the alcohol (V), which is silylated with Tbdms-OTf and lutidine to provide the silyl ether (VII). The hydrolysis of the oxazolidinone group of (VII) with Et-SH and Et-SK in THF gives the thioester (VIII), which is methylated with Me2CuLi in ethyl ether, yielding the methyl ketone (IX). The condensation of (IX) with phosphonate (X) by means of BuLi in THF affords the diene (XI), which is treated with MgBr2 in ethyl ether in order to eliminate the THP protecting group and obtain the primary alcohol (XII). The sulfonation of (XII) with Ms2O and TEA in dichloromethane gives the mesylate (XIII), which is treated with LiBr in acetone to yield the allyl bromide (XIV). Finally, (XIV) is condensed with methyltriphenylphosphonium bromide (XV) by means of BuLi in THF affording the desired intermediate phosphonium salt (XVI).

参考文献 中间体
合成目标
【1】 White, J.D.; Carter, R.G.; Sundermann, K.F.; Wartmann, M.; Total synthesis of epothilone B, epothilone D, and cis- and trans-9,10-dehydroepothilone D. J Am Chem Soc 2001, 123, 23, 5407.
【2】 White, J.D.; et al.; A highly stereoselective synthesis of epothilone B. J Org Chem 1999, 64, 3, 684.
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) 46138 (Z)-3-iodo-2-methyl-2-propen-1-ol C4H7IO 详情 详情
(II) 46139 (Z)-3-iodo-2-methyl-2-propenyl tetrahydro-2H-pyran-2-yl ether; 2-[[(Z)-3-iodo-2-methyl-2-propenyl]oxy]tetrahydro-2H-pyran C9H15IO2 详情 详情
(III) 40307 (4S)-3-acryloyl-4-benzyl-1,3-oxazolidin-2-one C13H13NO3 详情 详情
(IV) 46140 (4S)-4-benzyl-3-[(Z)-5-methyl-6-(tetrahydro-2H-pyran-2-yloxy)-4-hexenoyl]-1,3-oxazolidin-2-one C22H29NO5 详情 详情
(V) 31834 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine;2-(Phenylsulfonyl)-3-phenyloxaziridine;2-Benzenesulfonyl-3-phenyloxaziridine;3-Phenyl-2-phenylsulfonyloxaziridine;3-Phenyl-N-phenylsulfonyloxaziridine;N-(Phenylsulfonyl)phenyloxaziridine;N-Benzenesulfonyl-3-phenyloxaziridine 63160-13-4 C13H11NO3S 详情 详情
(VI) 46141 (4S)-4-benzyl-3-[(2S,4Z)-2-hydroxy-5-methyl-6-(tetrahydro-2H-pyran-2-yloxy)-4-hexenoyl]-1,3-oxazolidin-2-one C22H29NO6 详情 详情
(VII) 46142 (4S)-4-benzyl-3-[(2S,4Z)-2-[[tert-butyl(dimethyl)silyl]oxy]-5-methyl-6-(tetrahydro-2H-pyran-2-yloxy)-4-hexenoyl]-1,3-oxazolidin-2-one C28H43NO6Si 详情 详情
(VIII) 46143 S-ethyl (2S,4Z)-2-[[tert-butyl(dimethyl)silyl]oxy]-5-methyl-6-(tetrahydro-2H-pyran-2-yloxy)-4-hexenethioate C20H38O4SSi 详情 详情
(IX) 46144 (3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-7-(tetrahydro-2H-pyran-2-yloxy)-5-hepten-2-one C19H36O4Si 详情 详情
(X) 44442 diethyl (2-methyl-1,3-thiazol-4-yl)methylphosphonate C9H16NO3PS 详情 详情
(XI) 46145 4-[(1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-7-(tetrahydro-2H-pyran-2-yloxy)-1,5-heptadienyl]-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S,3Z)-4-methyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-5-(tetrahydro-2H-pyran-2-yloxy)-3-pentenyl ether C24H41NO3SSi 详情 详情
(XII) 40824 (2Z,5S,6E)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-7-(2-methyl-1,3-thiazol-4-yl)-2,6-heptadien-1-ol C19H33NO2SSi 详情 详情
(XIII) 46146 tert-butyl(dimethyl)silyl (1S,3Z)-4-methyl-5-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-pentenyl ether; 4-((1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-7-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-1,5-heptadienyl)-2-methyl-1,3-thiazole C22H39NO2S2Si 详情 详情
(XIV) 46147 4-((1E,3S,5Z)-7-bromo-3-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-1,5-heptadienyl)-2-methyl-1,3-thiazole; (1S,3Z)-5-bromo-4-methyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-pentenyl tert-butyl(dimethyl)silyl ether C19H32BrNOSSi 详情 详情
(XV) 30484 Methyl(triphenyl)phosphonium bromide 1779-49-3 C19H18BrP 详情 详情
(XVI) 46148 [(3Z,6S,7E)-6-[[tert-butyl(dimethyl)silyl]oxy]-3,7-dimethyl-8-(2-methyl-1,3-thiazol-4-yl)-3,7-octadienyl](triphenyl)phosphonium bromide C38H49BrNOPSSi 详情 详情

合成路线14

该中间体在本合成路线中的序号：(VI)

The Friedel Crafts condensation of 2,5-dichloro-2,2,5,5-tetramethylhexane (I) with toluene (II) by means of AlCl3 gives 1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (III), which is submitted to a new condensation with the pyridine-2-carbonyl chloride (IV) by means of AlCl3 in dichloromethane to yield the diaryl ketone (V). The reaction of (V) with methyltriphenylphosphonium bromide (VI) and NaNH2 affords the 1,1-diarylethylene (VII), which is treated with Et2Zn and Cl-CH2-I in dichloromethane to provide the 1,1-diarylcyclopropane (VIII). Finally, the ester group of (VIII) is hydrolyzed with KOH in methanol/water to yield the target carboxylic acid.

参考文献 中间体
合成目标
【1】 Faul, M.M.; Ratz, A.M.; Sullivan, K.A.; Trankle, W.G.; Winneroski, L.L.; Synthesis of novel retinoid X receptor-selective retinoids. J Org Chem 2001, 66, 17, 5772.
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) 35216 2,5-dichloro-2,5-dimethylhexane C8H16Cl2 详情 详情
(II) 12890 Toluene 108-88-3 C7H8 详情 详情
(III) 35217 1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphthalene C15H22 详情 详情
(IV) 64262 methyl 6-(chlorocarbonyl)nicotinate C8H6ClNO3 详情 详情
(V) 64263 methyl 6-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)carbonyl]nicotinate C23H27NO3 详情 详情
(VI) 30484 Methyl(triphenyl)phosphonium bromide 1779-49-3 C19H18BrP 详情 详情
(VII) 64264 methyl 6-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)vinyl]nicotinate C24H29NO2 详情 详情
(VIII) 64265 methyl 6-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)cyclopropyl]nicotinate C25H31NO2 详情 详情

合成路线15

该中间体在本合成路线中的序号：(XXV)

The cyclization of 3-(benzyloxy)-2(S)-methylpropenal (X) with the diene (XI) by means of TiCl4 in dichloromethane gives the dihydropyranone (XII), which is reduced with LiAlH4 in ethyl ether to yield the alcohol (XIII). The cyclopropanation of (XIII) by means of diiodomethane and Et2Zn in ethyl ether affords the cyclopropano derivative (XIV), which is cleaved by means of N-iodosuccinimide (NIS) in methanol, affording the iodomethyl derivative (XV). The dehalogenation of (XV) by means of Bu3SnH and AIBN in refluxing benzene provides the gem-dimethyltetrahydropyran (XVI), which is treated with triphenylchlorosilane and imidazole in DMF to give the silyl ether (XVII). Opening of the tetrahydropyran ring of (XVII) by means of propane-1,2-dithiol and TiCl4 in dichloromethane yields the 1,3-dithiolane derivative (XVIII), which is treated with Tbdms-OTf and lutidine to afford the disilylated compound (XIX). The debenzylation of (XIX) with DDQ in dichloromethane/water provides the primary alcohol (XX), which is oxidized with oxalyl chloride in DMSO/dichloromethane, furnishing the corresponding aldehyde (XXI). The condensation of (XXI) with the phosphonium salt (XXII) by means of tBu-OK in THF gives the enol ether (XXIII), which is hydrolyzed to the corresponding aldehyde (XXIV) by means of Ts-OH in dioxane/water. The condensation of (XXIV) with phosphonium salt (XXV) by means of NaHMDS in toluene yields the terminal olefin (XXVI), which is treated with phenyliodonium trifluoroacetate in methanol/THF to afford the aldehyde dimethylacetal (XXVII). The condensation of (XXVII) with thiazole intermediate (IX) by means of 9-BBN, a Pd catalyst and Cs2CO3 in DMF/water gives the adduct (XXVIII).

参考文献 中间体
合成目标
【1】 Meng, D.; et al.; Total syntheses of epothilones A and B. J Am Chem Soc 1997, 119, 42, 10073.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXIIIa) 44545 tert-butyl(dimethyl)silyl (1S,2S,3E)-1-[(1R,2R)-3-(1,3-dithian-2-yl)-1,3-dimethyl-2-[(triphenylsilyl)oxy]butyl]-4-methoxy-2-methyl-3-butenyl ether; (3R,4R,5S)-3-[1-(1,3-dithian-2-yl)-1-methylethyl]-5-[(1S,2E)-3-methoxy-1-methyl-2-propenyl]-4,7,7,8,8-pentamethyl-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane C40H58O3S2Si2 详情 详情
(XXIIIb) 44546 (3R,4R,5S)-3-[1-(1,3-dithian-2-yl)-1-methylethyl]-5-[(1S,2Z)-3-methoxy-1-methyl-2-propenyl]-4,7,7,8,8-pentamethyl-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane; tert-butyl(dimethyl)silyl (1S,2S,3Z)-1-[(1R,2R)-3-(1,3-dithian-2-yl)-1,3-dimethyl-2-[(triphenylsilyl)oxy]butyl]-4-methoxy-2-methyl-3-butenyl ether C40H58O3S2Si2 详情 详情
(IX) 46125 (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-pentenyl acetate C14H18INO2S 详情 详情
(X) 44533 (2S)-3-(benzyloxy)-2-methylpropanal C11H14O2 详情 详情
(XI) 44534 (Z)-1-[(E)-2-methoxy-1-methylethenyl]-1-propenyl trimethylsilyl ether; ([(Z)-1-[(E)-2-methoxy-1-methylethenyl]-1-propenyl]oxy)(trimethyl)silane C10H20O2Si 详情 详情
(XII) 44535 (2S,3R)-2-[(1S)-2-(benzyloxy)-1-methylethyl]-3,5-dimethyl-2,3-dihydro-4H-pyran-4-one C17H22O3 详情 详情
(XIII) 44536 (2S,3S,4R)-2-[(1S)-2-(benzyloxy)-1-methylethyl]-3,5-dimethyl-3,4-dihydro-2H-pyran-4-ol C17H24O3 详情 详情
(XIV) 44537 (1R,3S,4S,5R,6R)-3-[(1S)-2-(benzyloxy)-1-methylethyl]-4,6-dimethyl-2-oxabicyclo[4.1.0]heptan-5-ol C18H26O3 详情 详情
(XV) 44538 (3R,4R,5S,6S)-6-[(1S)-2-(benzyloxy)-1-methylethyl]-3-(iodomethyl)-2-methoxy-3,5-dimethyltetrahydro-2H-pyran-4-ol C19H29IO4 详情 详情
(XVI) 44539 (4R,5S,6S)-6-[(1S)-2-(benzyloxy)-1-methylethyl]-2-methoxy-3,3,5-trimethyltetrahydro-2H-pyran-4-ol C19H30O4 详情 详情
(XVII) 44540 benzyl (2S)-2-[(2S,3R,4R)-6-methoxy-3,5,5-trimethyl-4-[(triphenylsilyl)oxy]tetrahydro-2H-pyran-2-yl]propyl ether; ([(4R,5R,6S)-6-[(1S)-2-(benzyloxy)-1-methylethyl]-2-methoxy-3,3,5-trimethyltetrahydro-2H-pyran-4-yl]oxy)(triphenyl)silane C37H44O4Si 详情 详情
(XVIII) 44541 (2S,3S,4R,5R)-1-(benzyloxy)-6-(1,3-dithian-2-yl)-2,4,6-trimethyl-5-[(triphenylsilyl)oxy]-3-heptanol C39H48O3S2Si 详情 详情
(XIX) 44542 (3R,4R,5S)-5-[(1S)-2-(benzyloxy)-1-methylethyl]-3-[1-(1,3-dithian-2-yl)-1-methylethyl]-4,7,7,8,8-pentamethyl-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane; benzyl (2S,3S,4R,5R)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-(1,3-dithian-2-yl)-2,4,6-trimethyl-5-[(triphenylsilyl)oxy]heptyl ether C45H62O3S2Si2 详情 详情
(XX) 44543 (2S,3S,4R,5R)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-(1,3-dithian-2-yl)-2,4,6-trimethyl-5-[(triphenylsilyl)oxy]-1-heptanol C38H56O3S2Si2 详情 详情
(XXI) 44544 (2R,3R,4R,5R)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-(1,3-dithian-2-yl)-2,4,6-trimethyl-5-[(triphenylsilyl)oxy]heptanal C38H54O3S2Si2 详情 详情
(XXII) 39163 (methoxymethyl)(triphenyl)phosphonium chloride 4009-98-7 C20H20ClOP 详情 详情
(XXIV) 44547 (3S,4S,5R,6R)-4-[[tert-butyl(dimethyl)silyl]oxy]-7-(1,3-dithian-2-yl)-3,5,7-trimethyl-6-[(triphenylsilyl)oxy]octanal C39H56O3S2Si2 详情 详情
(XXV) 30484 Methyl(triphenyl)phosphonium bromide 1779-49-3 C19H18BrP 详情 详情
(XXVI) 44548 (3R,4R,5S)-3-[1-(1,3-dithian-2-yl)-1-methylethyl]-4,7,7,8,8-pentamethyl-5-[(1S)-1-methyl-3-butenyl]-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane; tert-butyl(dimethyl)silyl (1S,2S)-1-[(1R,2R)-3-(1,3-dithian-2-yl)-1,3-dimethyl-2-[(triphenylsilyl)oxy]butyl]-2-methyl-4-pentenyl ether C40H58O2S2Si2 详情 详情
(XXVII) 44549 tert-butyl(dimethyl)silyl (1S,2S)-1-[(1R,2R)-4,4-dimethoxy-1,3,3-trimethyl-2-[(triphenylsilyl)oxy]butyl]-2-methyl-4-pentenyl ether; (3R,4R,5S)-3-(2,2-dimethoxy-1,1-dimethylethyl)-4,7,7,8,8-pentamethyl-5-[(1S)-1-methyl-3-butenyl]-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane C39H58O4Si2 详情 详情
(XXVIII) 46127 (1S,3Z,8S,9S,10R,11R)-9-[[tert-butyl(dimethyl)silyl]oxy]-13,13-dimethoxy-4,8,10,12,12-pentamethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-11-[(triphenylsilyl)oxy]-3-tridecenyl acetate C53H77NO6SSi2 详情 详情

合成路线16

该中间体在本合成路线中的序号：(XV)

The protection of the allyl alcohol (I) with dihydropyran and PPTS in dichloromethane gives the tetrahydropyranyl ether (II), which is condensed with the chiral oxazolidinone (III) by means of BuLi and CuCN in THF, yielding the adduct (IV). The hydroxylation of (IV) with Davis' oxaziridine, NaHMDS and CSA affords the alcohol (V), which is silylated with Tbdms-OTf and lutidine, providing the silyl ether (VII). The hydrolysis of the oxazolidinone group of (VII) with Et-SH and Et-SK in THF gives the thioester (VIII), which is methylated with Me2CuLi in ethyl ether, yielding the methyl ketone (IX). The condensation of (IX) with phosphonate (X) by means of BuLi in THF affords the diene (XI), which is treated with MgBr2 in ethyl ether in order to eliminate the THP protecting group and obtain the primary alcohol (XII). The sulfonation of (XII) with Ms2O and TEA in dichloromethane gives the mesylate (XIII), which is treated with LiBr in acetone to yield the allyl bromide (XIV). Finally, (XIV) is condensed with methyltriphenylphosphonium bromide (XV) by means of BuLi in THF affording the desired intermediate phosphonium salt (XVI).

参考文献 中间体
合成目标
【1】 White, J.D.; Carter, R.G.; Sundermann, K.F.; Wartmann, M.; Total synthesis of epothilone B, epothilone D, and cis- and trans-9,10-dehydroepothilone D. J Am Chem Soc 2001, 123, 23, 5407.
【2】 White, J.D.; et al.; A highly stereoselective synthesis of epothilone B. J Org Chem 1999, 64, 3, 684.
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) 46138 (Z)-3-iodo-2-methyl-2-propen-1-ol C4H7IO 详情 详情
(II) 46139 (Z)-3-iodo-2-methyl-2-propenyl tetrahydro-2H-pyran-2-yl ether; 2-[[(Z)-3-iodo-2-methyl-2-propenyl]oxy]tetrahydro-2H-pyran C9H15IO2 详情 详情
(III) 40307 (4S)-3-acryloyl-4-benzyl-1,3-oxazolidin-2-one C13H13NO3 详情 详情
(IV) 46140 (4S)-4-benzyl-3-[(Z)-5-methyl-6-(tetrahydro-2H-pyran-2-yloxy)-4-hexenoyl]-1,3-oxazolidin-2-one C22H29NO5 详情 详情
(V) 31834 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine;2-(Phenylsulfonyl)-3-phenyloxaziridine;2-Benzenesulfonyl-3-phenyloxaziridine;3-Phenyl-2-phenylsulfonyloxaziridine;3-Phenyl-N-phenylsulfonyloxaziridine;N-(Phenylsulfonyl)phenyloxaziridine;N-Benzenesulfonyl-3-phenyloxaziridine 63160-13-4 C13H11NO3S 详情 详情
(VI) 46141 (4S)-4-benzyl-3-[(2S,4Z)-2-hydroxy-5-methyl-6-(tetrahydro-2H-pyran-2-yloxy)-4-hexenoyl]-1,3-oxazolidin-2-one C22H29NO6 详情 详情
(VII) 46142 (4S)-4-benzyl-3-[(2S,4Z)-2-[[tert-butyl(dimethyl)silyl]oxy]-5-methyl-6-(tetrahydro-2H-pyran-2-yloxy)-4-hexenoyl]-1,3-oxazolidin-2-one C28H43NO6Si 详情 详情
(VIII) 46143 S-ethyl (2S,4Z)-2-[[tert-butyl(dimethyl)silyl]oxy]-5-methyl-6-(tetrahydro-2H-pyran-2-yloxy)-4-hexenethioate C20H38O4SSi 详情 详情
(IX) 46144 (3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-7-(tetrahydro-2H-pyran-2-yloxy)-5-hepten-2-one C19H36O4Si 详情 详情
(X) 44442 diethyl (2-methyl-1,3-thiazol-4-yl)methylphosphonate C9H16NO3PS 详情 详情
(XI) 46145 4-[(1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-7-(tetrahydro-2H-pyran-2-yloxy)-1,5-heptadienyl]-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S,3Z)-4-methyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-5-(tetrahydro-2H-pyran-2-yloxy)-3-pentenyl ether C24H41NO3SSi 详情 详情
(XII) 40824 (2Z,5S,6E)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-7-(2-methyl-1,3-thiazol-4-yl)-2,6-heptadien-1-ol C19H33NO2SSi 详情 详情
(XIII) 46146 tert-butyl(dimethyl)silyl (1S,3Z)-4-methyl-5-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-pentenyl ether; 4-((1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-7-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-1,5-heptadienyl)-2-methyl-1,3-thiazole C22H39NO2S2Si 详情 详情
(XIV) 46147 4-((1E,3S,5Z)-7-bromo-3-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-1,5-heptadienyl)-2-methyl-1,3-thiazole; (1S,3Z)-5-bromo-4-methyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-pentenyl tert-butyl(dimethyl)silyl ether C19H32BrNOSSi 详情 详情
(XV) 30484 Methyl(triphenyl)phosphonium bromide 1779-49-3 C19H18BrP 详情 详情
(XVI) 46148 [(3Z,6S,7E)-6-[[tert-butyl(dimethyl)silyl]oxy]-3,7-dimethyl-8-(2-methyl-1,3-thiazol-4-yl)-3,7-octadienyl](triphenyl)phosphonium bromide C38H49BrNOPSSi 详情 详情

合成路线17

该中间体在本合成路线中的序号：(XXII)

Alternatively, the intermediate (Z)-ethylenic diol (XV) can also be obtained as follows: The reduction of 5,5-dimethyloxepan-2-one (XX) with iBu2AlH in THF gives 5,5-dimethyloxepan-2-ol (XXI), which is condensed with methyltriphenylphosphonium bromide (XXII) by means of tBu-OK in THF to yield 3,3-dimethyl-6-hepten-1-ol (XXIII). The Swern oxidation of the primary alcohol of (XIII) affords aldehyde (XXIV), which is condensed with CBr4 by means of PPh3 in CH2Cl2 to provide the dibromovinyl compound (XXV). The condensation of (XXV) with hexafluoroacetone (XII) by means of BuLi gives the acetylenic alcohol (XXVI), which is treated with hexylborane in THF to yield the acetylenic diol (XXVII). Finally, this compound is selectively reduced with H2 over Pd/C in EtOAc to afford the desired (Z)-ethylenic diol (XV).

参考文献 中间体
合成目标
【1】 Mohr, P.; Barbier, P.; Pirson, W.; Muller, M.; Bauer, F. (F. Hoffmann-La Roche AG); Cyclohexanediole derivs.. EP 1056716; WO 9943646 .
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) 44260 1,1,1,3,3,3-hexafluoroacetone 684-16-2 C3F6O 详情 详情
(XV) 49036 (Z)-10,10,10-trifluoro-5,5-dimethyl-9-(trifluoromethyl)-7-decene-1,9-diol C13H20F6O2 详情 详情
(XX) 49065 5,5-dimethyl-2-oxepanone C8H14O2 详情 详情
(XXI) 49066 5,5-dimethyl-2-oxepanol C8H16O2 详情 详情
(XXII) 30484 Methyl(triphenyl)phosphonium bromide 1779-49-3 C19H18BrP 详情 详情
(XXIII) 49067 3,3-dimethyl-6-hepten-1-ol C9H18O 详情 详情
(XXIV) 49068 3,3-dimethyl-6-heptenal C9H16O 详情 详情
(XXV) 49069 1,1-dibromo-4,4-dimethyl-1,7-octadiene C10H16Br2 详情 详情
(XXVI) 49070 1,1,1-trifluoro-6,6-dimethyl-2-(trifluoromethyl)-9-decen-3-yn-2-ol C13H16F6O 详情 详情
(XXVII) 49062 10,10,10-trifluoro-5,5-dimethyl-9-(trifluoromethyl)-7-decyne-1,9-diol C13H18F6O2 详情 详情

合成路线18

该中间体在本合成路线中的序号：(X)

The nitration of the dimeric benzoic acid (I) with 70% HNO3 gives the dimeric nitrobenzoic acid (II), which is treated with oxalyl chloride in THF to yield the acid chloride (III). The reaction of (III) with the pyrrolidine (IV) by means of TEA in the same solvent affords the diamide (V). The reduction of the nitro groups of (V) with RaNI and hydrazine in methanol provides the diamino compound (VI), which is protected with allyloxycarbonyl chloride (VII) and pyridine in dichloromethane to give the bis carbamate (VIII). The oxidation of the OH groups of (VIII) with oxalyl chloride and TEA in DMSO/dichloromethane yields the bis-pyrrolidinone (IX), which is allowed to react with methyl triphenylphosphonium bromide (X) and tBu-OK in THF to afford the bis exomethylene derivative (XI).

参考文献 中间体
合成目标
【1】 Gregson, S.J.; Howard, P.W.; Corcoran, K.E.; Jenkins, T.C.; Kelland, L.R.; Thurston, D.E.; Synthesis of the first example of a C2-C3/C2'-C3'-endo unsaturated pyrrolo[2,1-c][1,4]benzodiazepine dimer. Bioorg Med Chem Lett 2001, 11, 21, 2859.
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) 47736 4-[3-(4-carboxy-2-methoxyphenoxy)propoxy]-3-methoxybenzoic acid C19H20O8 详情 详情
(II) 47737 4-[3-(4-carboxy-2-methoxy-5-nitrophenoxy)propoxy]-5-methoxy-2-nitrobenzoic acid C19H18N2O12 详情 详情
(III) 47738 4-[3-[4-(chlorocarbonyl)-2-methoxy-5-nitrophenoxy]propoxy]-5-methoxy-2-nitrobenzoyl chloride C19H16Cl2N2O10 详情 详情
(IV) 62872 (3R,5S)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-pyrrolidinol C11H25NO2Si 详情 详情
(V) 62873 [(2S,4R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-hydroxypyrrolidinyl]{4-[3-(4-{[(2S,4R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-hydroxypyrrolidinyl]carbonyl}-2-methoxy-5-nitrophenoxy)propoxy]-5-methoxy-2-nitrophenyl}methanone C41H64N4O14Si2 详情 详情
(VI) 62874 {2-amino-4-[3-(5-amino-4-{[(2S,4R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-hydroxypyrrolidinyl]carbonyl}-2-methoxyphenoxy)propoxy]-5-methoxyphenyl}[(2S,4R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-hydroxypyrrolidinyl]methanone C41H68N4O10Si2 详情 详情
(VII) 38115 3-[(chlorocarbonyl)oxy]-1-propene 2937-50-0 C4H5ClO2 详情 详情
(VIII) 62875 allyl 5-[3-(5-{[(allyloxy)carbonyl]amino}-4-{[(2S,4R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-hydroxypyrrolidinyl]carbonyl}-2-methoxyphenoxy)propoxy]-2-{[(2S,4R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-hydroxypyrrolidinyl]carbonyl}-4-metho C49H76N4O14Si2 详情 详情
(IX) 62876 allyl 5-[3-(5-{[(allyloxy)carbonyl]amino}-4-{[(2S)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-oxopyrrolidinyl]carbonyl}-2-methoxyphenoxy)propoxy]-2-{[(2S)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-oxopyrrolidinyl]carbonyl}-4-methoxyphenylcarbam C49H72N4O14Si2 详情 详情
(X) 30484 Methyl(triphenyl)phosphonium bromide 1779-49-3 C19H18BrP 详情 详情
(XI) 62877 allyl 5-[3-(5-{[(allyloxy)carbonyl]amino}-4-{[(2S)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-methylenepyrrolidinyl]carbonyl}-2-methoxyphenoxy)propoxy]-2-{[(2S)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-methylenepyrrolidinyl]carbonyl}-4-methoxy C51H76N4O12Si2 详情 详情

合成路线19

该中间体在本合成路线中的序号：(A)

Reduction of 3-(4-fluorobenzoyl)propionic acid (I) by means of AlCl3 in CH2Cl2 and borane/tert-butylamine complex yields alcohol (II), which is then converted into aldehyde (IV) by reaction with 4-hydroxybenzaldehyde (III) in presence of PPh3 in THF and diethyl azodicarboxylate. Treatment of (IV) with a solution of methyltriphenylphosphonium bromide in THF and a solution of n-BuLi in hexane affords styrene derivative (V), which couples with 2’-hydroxy-3’-iodoacetophenone (VI) in presence of Et3N and Pd(OAc)2 in CH3CN to provide (VII). Cyclization of (VII) by means of a first treatment with NaOEt in EtOH followed by reaction with diethyl oxalate in Et2O/EtOH yields benzopyrane derivative (VIII) which is then hydrolyzed with NaOH in THF/MeOH to give (IX). Carboxylic acid (IX) is first converted into carboxamide (X) by treatment with a saturated NH3 solution in MeOH and then into carbonitrile (XI) by means of POCl3 in DMF. Finally, treatment of (XI) with a solution of NaN3, NH4Cl and DMF leads to the formation of the desired product.

参考文献 中间体
合成目标
【1】 Carganico, G.; Mauleon Casellas, D.; Pascual Avellana, J.; Garcia Perez, M.L.; Palomer Benet, A. (Menarini Industrie Farma Riunite srl); Benzopyran derivs. having leukotriene-antagonistic action. EP 0888327; ES 2127106; JP 2000506878; US 5990142; WO 9734885 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(B) 17571 Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate 95-92-1 C6H10O4 详情 详情
(A) 30484 Methyl(triphenyl)phosphonium bromide 1779-49-3 C19H18BrP 详情 详情
(I) 39863 4-(4-fluorophenyl)-4-oxobutyric acid 366-77-8 C10H9FO3 详情 详情
(II) 41474 4-(4-fluorophenyl)-1-butanol C10H13FO 详情 详情
(III) 13433 4-Hydroxybenzaldehyde; p-Hydroxybenzaldehyde 123-08-0 C7H6O2 详情 详情
(IV) 41475 4-[4-(4-fluorophenyl)butoxy]benzaldehyde C17H17FO2 详情 详情
(V) 41476 1-fluoro-4-[4-(4-vinylphenoxy)butyl]benzene; 4-(4-fluorophenyl)butyl 4-vinylphenyl ether C18H19FO 详情 详情
(VI) 27290 1-(2-hydroxy-3-iodophenyl)-1-ethanone C8H7IO2 详情 详情
(VII) 41477 1-[3-((E)-2-[4-[4-(4-fluorophenyl)butoxy]phenyl]ethenyl)-2-hydroxyphenyl]-1-ethanone C26H25FO3 详情 详情
(VIII) 41478 ethyl 8-((E)-2-[4-[4-(4-fluorophenyl)butoxy]phenyl]ethenyl)-4-oxo-4H-chromene-2-carboxylate C30H27FO5 详情 详情
(IX) 41479 8-((E)-2-[4-[4-(4-fluorophenyl)butoxy]phenyl]ethenyl)-4-oxo-4H-chromene-2-carboxylic acid C28H23FO5 详情 详情
(X) 41480 8-((E)-2-[4-[4-(4-fluorophenyl)butoxy]phenyl]ethenyl)-4-oxo-4H-chromene-2-carboxamide C28H24FNO4 详情 详情
(XI) 41481 8-((E)-2-[4-[4-(4-fluorophenyl)butoxy]phenyl]ethenyl)-4-oxo-4H-chromene-2-carbonitrile C28H22FNO3 详情 详情

合成路线20

该中间体在本合成路线中的序号：(XV)

The silylation of 2-methyl-5-(tert-butyldimethylsilyloxy)-1-penten-3(s)-ol (VIII) with Tbdms-Cl and imidazole in DMF gives the disilylated compound (IX), which is treated with ozone and PPh3 in dichloromethane to yield the 2-pentanone (X). The condensation of (X) with phosphonate (XI) by means of BuLi in THF yields the fully silylated diol (XII), which is selectively monodesilylated with HF in acetonitrile to afford the primary alcohol (XIII). The oxidation of (XIII) with DMP in dichloromethane affords the aldehyde (XIV), which is methylenated with the phosphonium salt (XV) and Na-NH2 in THF to provide the silylated hexadienol (XVI). The reaction of (XVI) with TBAF in THF gives the free secondary alcohol (XVII), which is esterified with the intermediate tridecenoic acid (VII) by means of DCC and DMAP in dichloromethane yielding the ester (XVIII). Ring-closing metathesis of (XVIII), catalyzed by a Ru catalyst, affords the macrolactone (XIX), which is finally desilylated by means of HF in acetonitrile to furnish the target epothilone C.

参考文献 中间体
合成目标
【1】 Schinzer, D.; et al.; Total synthesis of (-)-epothilone A. Angew Chem. Int Ed Engl 1997, 36, 5, 523.
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) 44438 (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-12-tridecenoic acid C29H58O5Si2 详情 详情
(VIII) 44439 (3S)-5-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1-penten-3-ol C12H26O2Si 详情 详情
(IX) 44440 (5S)-5-isopropenyl-2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecane; tert-butyl(dimethyl)silyl (1S)-1-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-2-methyl-2-propenyl ether C18H40O2Si2 详情 详情
(X) 44441 (3S)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-pentanone C17H38O3Si2 详情 详情
(XI) 44442 diethyl (2-methyl-1,3-thiazol-4-yl)methylphosphonate C9H16NO3PS 详情 详情
(XII) 44443 tert-butyl(dimethyl)silyl (1S,2E)-1-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenyl ether; 4-((E,3S)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1-pentenyl)-2-methyl-1,3-thiazole C22H43NO2SSi2 详情 详情
(XIII) 40821 (3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-penten-1-ol C16H29NO2SSi 详情 详情
(XIV) 40822 (3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-pentenal C16H27NO2SSi 详情 详情
(XV) 30484 Methyl(triphenyl)phosphonium bromide 1779-49-3 C19H18BrP 详情 详情
(XVI) 44444 4-((1E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1,5-hexadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl ether C17H29NOSSi 详情 详情
(XVII) 43171 (1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol C11H15NOS 详情 详情
(XVIII) 44445 (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-12-tridecenoate C40H71NO5SSi2 详情 详情
(XIX) 44446 (4S,7R,8S,9S,16S)-4,8-bis[[tert-butyl(dimethyl)silyl]oxy]-5,5,7,9-tetramethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione C38H67NO5SSi2 详情 详情

合成路线21

该中间体在本合成路线中的序号：(XV)

Synthesis of intermediate (XVI): The condensation of 3(S)-(phenyldimethylsilyl)-4(E)-hexenoic acid methyl ester (I) with 2-(tert-butyldimethylsilyloxy)acetaldehyde (II) by means of Tms-OBn, Tms-OTf and BF3/Et2O in dichloromethane gives the 3(E)-heptenoic ester (III), which is ozonolyzed with O3 and pyridine in methanol/dichloromethane to yield the aldehyde (IV). The condensation of (IV) with the silyl ketal (V) by means of TiCl4 in dichloromethane affords the partially protected trihydroxyester (VI), which is silylated with Tbdms-OTf and lutidine in dichloromethane to provide the fully protected ester (VII). Regioselective monodesilylation of (VII) by means of TBAF/AcOH in THF gives the primary alcohol (VIII), which is oxidized with oxalyl chloride to the corresponding aldehyde (IX). The condensation of (IX) with phosphorane (X) in refluxing benzene yields the octenedioic diester (XI), which is methylated with Me2CuLi and Tms-Cl in THF, affording the tetramethyl diester (XII). The two ester groups of (XII) were easily differentiated by a reduction with DIBAL in dichloromethane, providing the 8-hydroxyoctanal derivative (XIII), which was silylated with TBdms-Cl and imidazole in DMF to give the fully protected aldehyde (XIV). Finally, this compound was subjected to a Wittig olefination reaction with methyltriphenylphosphonium bromide (XV) and NaHMDS in THF to yield the desired intermediate (XVI).

参考文献 中间体
合成目标
【1】 Panek, J.S.; Zhu, B.; Total synthesis of apothilone A. Org Lett 2000, 2, 17, 2575.
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) 44474 methyl (3S,4E)-3-[dimethyl(phenyl)silyl]-4-hexenoate C15H22O2Si 详情 详情
(II) 44475 2-[[tert-butyl(diphenyl)silyl]oxy]acetaldehyde C18H22O2Si 详情 详情
(III) 44476 methyl (E,5S,6R)-6-(benzyloxy)-7-[[tert-butyl(diphenyl)silyl]oxy]-5-methyl-3-heptenoate C32H40O4Si 详情 详情
(IV) 44477 (2R,3R)-3-(benzyloxy)-4-[[tert-butyl(diphenyl)silyl]oxy]-2-methylbutanal C28H34O3Si 详情 详情
(V) 44478 1-Ethoxy-2-methyl-1-trimethylsiloxypropene;1-Ethoxy-2-methyl-1-(trimethylsilyloxy)propene;1-Ethoxy-2-methyl-1-(trimethylsilyl)oxy-1-propene;1-ethoxy-2-methyl-1-propenyl trimethylsilyl ether; [(1-ethoxy-2-methyl-1-propenyl)oxy](trimethyl)silane ;dimethylketene ethyl trimethylsilyl acetal 31469-16-6 C9H20O2Si 详情 详情
(VI) 44479 ethyl (3R,4S,5R)-5-(benzyloxy)-6-[[tert-butyl(diphenyl)silyl]oxy]-3-hydroxy-2,2,4-trimethylhexanoate C34H46O5Si 详情 详情
(VII) 44480 ethyl (3R,4R,5R)-5-(benzyloxy)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-[[tert-butyl(diphenyl)silyl]oxy]-2,2,4-trimethylhexanoate C40H60O5Si2 详情 详情
(VIII) 44481 ethyl (3R,4R,5R)-5-(benzyloxy)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-hydroxy-2,2,4-trimethylhexanoate C24H42O5Si 详情 详情
(IX) 44482 ethyl (3R,4R,5R)-5-(benzyloxy)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,2,4-trimethyl-6-oxohexanoate C24H40O5Si 详情 详情
(X) 14182 ethyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate; (Carbethoxymethylene)triphenylphosphorane 1099-45-2 C22H21O2P 详情 详情
(XI) 44483 diethyl (E,4S,5R,6R)-4-(benzyloxy)-6-[[tert-butyl(dimethyl)silyl]oxy]-5,7,7-trimethyl-2-octenedioate C28H46O6Si 详情 详情
(XII) 44484 diethyl (3R,4R,5S,6S)-5-(benzyloxy)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,2,4,6-tetramethyloctanedioate C29H50O6Si 详情 详情
(XIII) 44485 (3S,4S,5R,6R)-4-(benzyloxy)-6-[[tert-butyl(dimethyl)silyl]oxy]-8-hydroxy-3,5,7,7-tetramethyloctanal C25H44O4Si 详情 详情
(XIV) 44486 (3S,4S,5R,6R)-4-(benzyloxy)-6,8-bis[[tert-butyl(dimethyl)silyl]oxy]-3,5,7,7-tetramethyloctanal C31H58O4Si2 详情 详情
(XV) 30484 Methyl(triphenyl)phosphonium bromide 1779-49-3 C19H18BrP 详情 详情
(XVI) 44487 (5R)-5-[(1R,2S,3S)-2-(benzyloxy)-1,3-dimethyl-5-hexenyl]-2,2,3,3,6,6,9,9,10,10-decamethyl-4,8-dioxa-3,9-disilaundecane; benzyl (1S,2S)-1-((1R,2R)-2,4-bis[[tert-butyl(dimethyl)silyl]oxy]-1,3,3-trimethylbutyl)-2-methyl-4-pentenyl ether C32H60O3Si2 详情 详情

合成路线22

该中间体在本合成路线中的序号：(XXV)

The cyclization of 3-(benzyloxy)-2(S)-methylpropenal (X) with the diene (XI) by means of TiCl4 in dichloromethane gives the dihydropyranone (XII), which is reduced with LiAlH4 in ethyl ether to yield the alcohol (XIII). The cyclopropanation of (XIII) by means of diiodomethane and Et2Zn in ethyl ether affords the cyclopropano derivative (XIV), which is cleaved by means of N-iodosuccinimide (NIS) in methanol, affording the iodomethyl derivative (XV). The dehalogenation of (XV) by means of Bu3SnH and AIBN in refluxing benzene provides the gem-dimethyltetrahydropyran (XVI), which is treated with triphenylchlorosilane and imidazole in DMF to give the silyl ether (XVII). Opening of the tetrahydropyran ring of (XVII) by means of propane-1,2-dithiol and TiCl4 in dichloromethane yields the 1,3-dithiolane derivative (XVIII), which is treated with Tbdms-OTf and lutidine to afford the disilylated compound (XIX). The debenzylation of (XIX) with DDQ in dichloromethane/water provides the primary alcohol (XX), which is oxidized with oxalyl chloride in DMSO/dichloromethane, furnishing the corresponding aldehyde (XXI). The condensation of (XXI) with the phosphonium salt (XXII) by means of tBu-OK in THF gives the enol ether (XXIII), which is hydrolyzed to the corresponding aldehyde (XXIV) by means of Ts-OH in dioxane/water. The condensation of (XXIV) with phosphonium salt (XXV) by means of NaHMDS in toluene yields the terminal olefin (XXVI), which is treated with phenyliodonium trifluoroacetate in methanol/THF to afford the aldehyde dimethylacetal (XXVII). The condensation of (XXVII) with thiazole intermediate (IX) by means of 9-BBN, a Pd catalyst and Cs2CO3 in DMF/water gives the adduct (XXVIII).

参考文献 中间体
合成目标
【1】 Meng, D.; et al.; Total syntheses of epothilones A and B. J Am Chem Soc 1997, 119, 42, 10073.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXIIIa) 44545 tert-butyl(dimethyl)silyl (1S,2S,3E)-1-[(1R,2R)-3-(1,3-dithian-2-yl)-1,3-dimethyl-2-[(triphenylsilyl)oxy]butyl]-4-methoxy-2-methyl-3-butenyl ether; (3R,4R,5S)-3-[1-(1,3-dithian-2-yl)-1-methylethyl]-5-[(1S,2E)-3-methoxy-1-methyl-2-propenyl]-4,7,7,8,8-pentamethyl-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane C40H58O3S2Si2 详情 详情
(XXIIIb) 44546 (3R,4R,5S)-3-[1-(1,3-dithian-2-yl)-1-methylethyl]-5-[(1S,2Z)-3-methoxy-1-methyl-2-propenyl]-4,7,7,8,8-pentamethyl-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane; tert-butyl(dimethyl)silyl (1S,2S,3Z)-1-[(1R,2R)-3-(1,3-dithian-2-yl)-1,3-dimethyl-2-[(triphenylsilyl)oxy]butyl]-4-methoxy-2-methyl-3-butenyl ether C40H58O3S2Si2 详情 详情
(IX) 44493 (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate C13H16INO2S 详情 详情
(X) 44533 (2S)-3-(benzyloxy)-2-methylpropanal C11H14O2 详情 详情
(XI) 44534 (Z)-1-[(E)-2-methoxy-1-methylethenyl]-1-propenyl trimethylsilyl ether; ([(Z)-1-[(E)-2-methoxy-1-methylethenyl]-1-propenyl]oxy)(trimethyl)silane C10H20O2Si 详情 详情
(XII) 44535 (2S,3R)-2-[(1S)-2-(benzyloxy)-1-methylethyl]-3,5-dimethyl-2,3-dihydro-4H-pyran-4-one C17H22O3 详情 详情
(XIII) 44536 (2S,3S,4R)-2-[(1S)-2-(benzyloxy)-1-methylethyl]-3,5-dimethyl-3,4-dihydro-2H-pyran-4-ol C17H24O3 详情 详情
(XIV) 44537 (1R,3S,4S,5R,6R)-3-[(1S)-2-(benzyloxy)-1-methylethyl]-4,6-dimethyl-2-oxabicyclo[4.1.0]heptan-5-ol C18H26O3 详情 详情
(XV) 44538 (3R,4R,5S,6S)-6-[(1S)-2-(benzyloxy)-1-methylethyl]-3-(iodomethyl)-2-methoxy-3,5-dimethyltetrahydro-2H-pyran-4-ol C19H29IO4 详情 详情
(XVI) 44539 (4R,5S,6S)-6-[(1S)-2-(benzyloxy)-1-methylethyl]-2-methoxy-3,3,5-trimethyltetrahydro-2H-pyran-4-ol C19H30O4 详情 详情
(XVII) 44540 benzyl (2S)-2-[(2S,3R,4R)-6-methoxy-3,5,5-trimethyl-4-[(triphenylsilyl)oxy]tetrahydro-2H-pyran-2-yl]propyl ether; ([(4R,5R,6S)-6-[(1S)-2-(benzyloxy)-1-methylethyl]-2-methoxy-3,3,5-trimethyltetrahydro-2H-pyran-4-yl]oxy)(triphenyl)silane C37H44O4Si 详情 详情
(XVIII) 44541 (2S,3S,4R,5R)-1-(benzyloxy)-6-(1,3-dithian-2-yl)-2,4,6-trimethyl-5-[(triphenylsilyl)oxy]-3-heptanol C39H48O3S2Si 详情 详情
(XIX) 44542 (3R,4R,5S)-5-[(1S)-2-(benzyloxy)-1-methylethyl]-3-[1-(1,3-dithian-2-yl)-1-methylethyl]-4,7,7,8,8-pentamethyl-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane; benzyl (2S,3S,4R,5R)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-(1,3-dithian-2-yl)-2,4,6-trimethyl-5-[(triphenylsilyl)oxy]heptyl ether C45H62O3S2Si2 详情 详情
(XX) 44543 (2S,3S,4R,5R)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-(1,3-dithian-2-yl)-2,4,6-trimethyl-5-[(triphenylsilyl)oxy]-1-heptanol C38H56O3S2Si2 详情 详情
(XXI) 44544 (2R,3R,4R,5R)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-(1,3-dithian-2-yl)-2,4,6-trimethyl-5-[(triphenylsilyl)oxy]heptanal C38H54O3S2Si2 详情 详情
(XXII) 39163 (methoxymethyl)(triphenyl)phosphonium chloride 4009-98-7 C20H20ClOP 详情 详情
(XXIV) 44547 (3S,4S,5R,6R)-4-[[tert-butyl(dimethyl)silyl]oxy]-7-(1,3-dithian-2-yl)-3,5,7-trimethyl-6-[(triphenylsilyl)oxy]octanal C39H56O3S2Si2 详情 详情
(XXV) 30484 Methyl(triphenyl)phosphonium bromide 1779-49-3 C19H18BrP 详情 详情
(XXVI) 44548 (3R,4R,5S)-3-[1-(1,3-dithian-2-yl)-1-methylethyl]-4,7,7,8,8-pentamethyl-5-[(1S)-1-methyl-3-butenyl]-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane; tert-butyl(dimethyl)silyl (1S,2S)-1-[(1R,2R)-3-(1,3-dithian-2-yl)-1,3-dimethyl-2-[(triphenylsilyl)oxy]butyl]-2-methyl-4-pentenyl ether C40H58O2S2Si2 详情 详情
(XXVII) 44549 tert-butyl(dimethyl)silyl (1S,2S)-1-[(1R,2R)-4,4-dimethoxy-1,3,3-trimethyl-2-[(triphenylsilyl)oxy]butyl]-2-methyl-4-pentenyl ether; (3R,4R,5S)-3-(2,2-dimethoxy-1,1-dimethylethyl)-4,7,7,8,8-pentamethyl-5-[(1S)-1-methyl-3-butenyl]-1,1,1-triphenyl-2,6-dioxa-1,7-disilanonane C39H58O4Si2 详情 详情
(XXVIII) 44550 (1S,3Z,8S,9S,10R,11R)-9-[[tert-butyl(dimethyl)silyl]oxy]-13,13-dimethoxy-8,10,12,12-tetramethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-11-[(triphenylsilyl)oxy]-3-tridecenyl acetate C52H75NO6SSi2 详情 详情
Extended Information