合成路线1
该中间体在本合成路线中的序号:
(XII) The reduction of 2-methylthiazole-4-carboxylic acid ethyl ester (IX) with DIBAL in dichloromethane gives the corresponding aldehyde (X), which is condensed with the phosphorane (XI) in refluxing benzene to yield 2-methyl-3-(2-methylthiazol-4-yl)-2-propenal (XII). The alkylation of (XII) with (+)-diisopinocampheyl(allyl)borane (II) in ethyl ether affords the chiral secondary alcohol (XIII) (1), which is esterified with the intermediate tridecenoic acid (VIII) by means of EDC and DMAP in dichloromethane to provide the ester (XIV). Ring-closing metathesis of (XIV) catalyzed by a Ru catalyst gives the macrolactone (XV), which is desilylated by means of TFA in dichloromethane, yielding the dihydroxymacrolactone (XVI). Finally, the double bond of (XVI) is epoxidized by means of dimethyldioxirane (DMDO) or MCPBA in chloroform.
【1】
Nicolaou, K.C.; et al.; The olefin metathesis approach to epothilone A and its analogues. J Am Chem Soc 1997, 119, 34, 7960.
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(II) |
44449 |
allyl[bis[(1R,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]]borane
|
|
C23H39B |
详情 |
详情
|
(VIII) |
44453 |
(3S,6R,7S,8S)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-4,4,6,8-tetramethyl-5-oxo-12-tridecenoic acid
|
|
C23H44O5Si |
详情 |
详情
|
(IX) |
44454 |
ethyl 2-methyl-1,3-thiazole-4-carboxylate
|
6436-59-5 |
C7H9NO2S |
详情 | 详情
|
(X) |
44455 |
2-methyl-1,3-thiazole-4-carbaldehyde
|
|
C5H5NOS |
详情 |
详情
|
(XI) |
39940 |
2-(triphenylphosphoranylidene)propanal
|
|
C21H19OP |
详情 |
详情
|
(XII) |
44456 |
(E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal
|
|
C8H9NOS |
详情 |
详情
|
(XIII) |
43171 |
(1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol
|
|
C11H15NOS |
详情 |
详情
|
(XIV) |
44457 |
(1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl (3S,6R,7S,8S)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-4,4,6,8-tetramethyl-5-oxo-12-tridecenoate
|
|
C34H57NO5SSi |
详情 |
详情
|
(XV) |
43176 |
(4S,7R,8S,9S,16S)-4-[[tert-butyl(dimethyl)silyl]oxy]-8-hydroxy-5,5,7,9-tetramethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione
|
|
C32H53NO5SSi |
详情 |
详情
|
(XVI) |
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2
该中间体在本合成路线中的序号:
(X) The intermediate phosphonium salt (XVI) has been obtained as follows: The reduction of 2-methylthiazole-4-carboxylic acid ethyl ester (VII) with DIBAL in dichloromethane gives the corresponding aldehyde (VIII), which is condensed with the phosphorane (IX) in refluxing benzene to yield 2-methyl-3-(2-methylthiazol-4-yl)-2(E)-propenal (X). The allylation of (X) with (+)-diisopinocampheyl(allyl)borane (II) affords the chiral secondary alcohol (XI), which is protected with Tbdms-Cl and imidazole in DMF, providing the silyl ether (XII). The oxidation of the terminal double bond of (XII) with OsO4 and Pb(OAc)4 in THF/tert-butanol/water gives rise to the aldehyde (XIII), which is reduced with NaBH4 in methanol to give the corresponding primary alcohol (XIV). The reaction of (XIV) with I2, PPh3 and imidazole in ethyl ether/acetonitrile yields the expected iodo derivative (XV), which is finally condensed with PPh3 at 100 C to afford the desired intermediate phosphonium salt (XVI).
【1】
Nicolaou, K.C.; et al.; Total syntheses of epothilones A and B via a macrolactonization-based strategy. J Am Chem Soc 1997, 119, 34, 7974.
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(II) |
44449 |
allyl[bis[(1R,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]]borane
|
|
C23H39B |
详情 |
详情
|
(VII) |
44454 |
ethyl 2-methyl-1,3-thiazole-4-carboxylate
|
6436-59-5 |
C7H9NO2S |
详情 | 详情
|
(VIII) |
44455 |
2-methyl-1,3-thiazole-4-carbaldehyde
|
|
C5H5NOS |
详情 |
详情
|
(IX) |
39940 |
2-(triphenylphosphoranylidene)propanal
|
|
C21H19OP |
详情 |
详情
|
(X) |
44456 |
(E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal
|
|
C8H9NOS |
详情 |
详情
|
(XI) |
43171 |
(1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol
|
|
C11H15NOS |
详情 |
详情
|
(XII) |
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
|
(XIII) |
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
|
(XIV) |
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
|
(XV) |
44458 |
tert-butyl(dimethyl)silyl (1S,2E)-1-(2-iodoethyl)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenyl ether; 4-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-iodo-2-methyl-1-pentenyl)-2-methyl-1,3-thiazole
|
|
C16H28INOSSi |
详情 |
详情
|
(XVI) |
44459 |
[(3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-pentenyl](triphenyl)phosphonium iodide
|
|
C34H43INOPSSi |
详情 |
详情
|
合成路线3
该中间体在本合成路线中的序号:
(XVII) Synthesis of the thiazole intermediate (XXVI): The Grignard reaction of 2-methyl-3-(2-methylthiazol-4-yl)-2(E)-propenal (XVII) with vinylmagnesium bromide (XVIII) in THF gives the racemic secondary alcohol (XIX), which is submitted to enzymatic optical resolution with Pseudomonas AK lipase and vinyl acetate to yield the desired (S)-secondary alcohol (XX) along with the (R)-acetate, which is easily separated by chromatography. The silylation of (XX) with Tbdms-Cl and imidazole in DMF affords the silyl ether (XXI). The selective hydroboration of the terminal double bond of (XXI) with dicyclohexylborane followed by oxidation with H2O2 provided the primary alcohol (XXII), which is oxidized with DMP in dichloromethane to give the corresponding aldehyde (XXIII). The reaction of (XXIII) with the iodomethyl phosphonium salt (XXIV) by means of NaHMDS in THF yields the cis-iodovinyl compound (XXV), which is desilylated with aqueous HF in acetonitrile, affording the corresponding alcohol (XXVI). Finally, this alcohol is treated with acetic anhydride, TEA and DMAP to provide the desired thiazole intermediate (XXVII).
【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 |
(XVII) |
44456 |
(E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal
|
|
C8H9NOS |
详情 |
详情
|
(XVIII) |
16524 |
bromo(vinyl)magnesium
|
1826-67-1 |
C2H3BrMg |
详情 | 详情
|
(XIX) |
44488 |
(1E)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,4-pentadien-3-ol
|
|
C10H13NOS |
详情 |
详情
|
(XX) |
44489 |
(1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,4-pentadien-3-ol
|
|
C10H13NOS |
详情 |
详情
|
(XXI) |
44490 |
tert-butyl(dimethyl)silyl (1S,2E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-1-vinyl-2-propenyl ether; 4-((1E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1,4-pentadienyl)-2-methyl-1,3-thiazole
|
|
C16H27NOSSi |
详情 |
详情
|
(XXII) |
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
|
(XXIII) |
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
|
(XXIV) |
42718 |
(iodomethyl)(triphenyl)phosphonium iodide
|
n/a |
C19H17I2P |
详情 | 详情
|
(XXV) |
44491 |
4-((1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-iodo-2-methyl-1,5-hexadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl ether
|
|
C17H28INOSSi |
详情 |
详情
|
(XXVI) |
44492 |
(1E,3S,5Z)-6-iodo-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol
|
|
C11H14INOS |
详情 |
详情
|
(XXVII) |
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
|
合成路线4
该中间体在本合成路线中的序号:
(XXII) Synthesis of the thiazole intermediate (XXXIV): The reaction of 2-methyl-3-(2-methylthiazol-4-yl)-2(E)-propenal (XXII) with trimethylsilyl cyanide and Et2AlCl catalyzed by a chiral bidentate phosphine oxide catalyst gives the chiral alpha-hydroxybutenenitrile (XXIII), which is hydrolyzed to the corresponding carboxylic ester (XXIV) by means of HCl in hot ethanol/water. The reaction of (XXIV) with Tbdms-Cl and imidazole yields the silylated hydroxyester (XXV), which is reduced with DIBAL in toluene, affording the aldehyde (XXVI). The reaction of (XXVI) with lithium trimethylsilylacetylide (A) in THF provides the adduct (XXVII), which is esterified with methyl chloroformate (XXVIII), furnishing the carbonate (XXIX). The reduction of (XXIX) by means of Pd(OAc)2, Bu3P and ammonium formate gives the protected acetylenic compound (XXX). The selective reduction of the triple bond of (XXX) by means of Ti(OiPr)4 and iPr-MgBr in ethyl ether yields the cis-silylated vinyl compound (XXXI), which is iodinated with I2 in dichloromethane to afford the cis-iodovinyl compound (XXXII). The desilylation of (XXXII) with HF and pyridine in THF gives the secondary alcohol (XXXIII), which is finally acetylated with Ac2O, TEA and DMAP in CH2Cl2 to yield the target thiazole intermediate (XXXIV).
【1】
Sawada, D.; et al.; Enantioselective total synthesis of epothilones A and B using multifunctional asymmetric catalysis. J Am Chem Soc 2000, 122, 43, 10521.
|
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) |
16299 |
Lithium (trimethylsilyl)acetylide; [2-(Trimethylsilyl)ethynyl]lithium
|
54655-07-1 |
C5H9LiSi |
详情 | 详情
|
(XXII) |
44456 |
(E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal
|
|
C8H9NOS |
详情 |
详情
|
(XXIII) |
44520 |
(2R,3E)-2-hydroxy-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenenitrile
|
|
C9H10N2OS |
详情 |
详情
|
(XXIV) |
44521 |
ethyl (2R,3E)-2-hydroxy-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenoate
|
|
C11H15NO3S |
详情 |
详情
|
(XXV) |
44522 |
ethyl (2R,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenoate
|
|
C17H29NO3SSi |
详情 |
详情
|
(XXVI) |
44523 |
(2R,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenal
|
|
C15H25NO2SSi |
详情 |
详情
|
(XXVII) |
44524 |
(4R,5E)-4-[[tert-butyl(dimethyl)silyl]oxy]-5-methyl-6-(2-methyl-1,3-thiazol-4-yl)-1-(trimethylsilyl)-5-hexen-1-yn-3-ol
|
|
C20H35NO2SSi2 |
详情 |
详情
|
(XXVIII) |
16993 |
methyl chlorocarbonate;Carbonochloridic acid methyl ester;[(chlorocarbonyl)oxy]methane;methyl chloroformate |
79-22-1 |
C2H3ClO2 |
详情 | 详情
|
(XXIX) |
44525 |
(2R,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-1-[2-(trimethylsilyl)ethynyl]-3-butenyl methyl carbonate
|
|
C22H37NO4SSi2 |
详情 |
详情
|
(XXX) |
44526 |
4-[(E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-6-(trimethylsilyl)-1-hexen-5-ynyl]-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4-(trimethylsilyl)-3-butynyl ether
|
|
C20H35NOSSi2 |
详情 |
详情
|
(XXXI) |
44527 |
tert-butyl(dimethyl)silyl (1S,3Z)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4-(trimethylsilyl)-3-butenyl ether; 4-[(1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-6-(trimethylsilyl)-1,5-hexadienyl]-2-methyl-1,3-thiazole
|
|
C20H37NOSSi2 |
详情 |
详情
|
(XXXII) |
44491 |
4-((1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-iodo-2-methyl-1,5-hexadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl ether
|
|
C17H28INOSSi |
详情 |
详情
|
(XXXIII) |
44492 |
(1E,3S,5Z)-6-iodo-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol
|
|
C11H14INOS |
详情 |
详情
|
(XXXIV) |
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
|
合成路线5
该中间体在本合成路线中的序号:
(III) Synthesis of thiazole intermediate (IX): The reaction of 2-methylthiazole-4-carbaldehyde (I) with triphenylphosphorane (II) in refluxing benzene gives 2-methyl-3-(2-methyl-4-thiazolyl)-2-propenal (III), which is enantioselectively allylated with ally(tributyl)stannane (IV) catalyzed by (S)(-)-BINOL and Ti(O-iPr)4 in dichloromethane to yield the chiral homoallyl alcohol (V). The reaction of (V) with acetic anhydride TEA and DMAP in dichloromethane affords the acetate (VI), which is oxidized at its terminal double bond with OsO4 and NaIO4 to provide the aldehyde (VII). Finally, this compound is condensed with triphenylphosphorane (VIII) to give the desired thiazole intermediate (IX).
【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 |
(I) |
44455 |
2-methyl-1,3-thiazole-4-carbaldehyde
|
|
C5H5NOS |
详情 |
详情
|
(II) |
39940 |
2-(triphenylphosphoranylidene)propanal
|
|
C21H19OP |
详情 |
详情
|
(III) |
44456 |
(E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal
|
|
C8H9NOS |
详情 |
详情
|
(IV) |
40599 |
Allyltributyltin; Tributyl-2-propenylstannane |
24850-33-7 |
C15H32Sn |
详情 | 详情
|
(V) |
43171 |
(1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol
|
|
C11H15NOS |
详情 |
详情
|
(VI) |
44530 |
(1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate
|
|
C13H17NO2S |
详情 |
详情
|
(VII) |
44531 |
(1S,2E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-1-(2-oxoethyl)-2-propenyl acetate
|
|
C12H15NO3S |
详情 |
详情
|
(VIII) |
44532 |
(iodomethylene)(triphenyl)phosphorane
|
|
C19H16IP |
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
|
合成路线6
该中间体在本合成路线中的序号:
(XIX) The aldol condensation of 2-methyl-3-(2-methylthiazol-4-yl)-2-propenal (XIX) with acetone (XX) catalyzed by antibody 38C2 gives the chiral aldol (XXI), which is protected with Tbdms-Cl and imidazole, yielding the silyl ether (XXII). The reaction of (XXII) with Tbdms-OTf, followed by oxidation with MCPBA and reduction with NaBH4, affords the vicinal diol (XXIII), which is cleaved with Pb(OAc)4 to provide the aldehyde (XXIV). The Wittig condensation of (XXIV) with phosphonium salt (XV) gives olefinic silyl ether (XXV), which is desilylated with TBAF in THF to yield the homoallylic alcohol (XXVI). The esterification of alcohol (XXVI) with the previously described carboxylic acid (XVIII) by means of EDC in dichloromethane affords the ester (XXVII), which is submitted to a ring-closing metathesis by means of Grubb's catalyst to provide the macrolactone (XXVIII). The desilylation of (XXVIII) with HF and pyridine furnishes the precursor (XXIX), which is finally epoxidated with trifluoroacetone and oxone to give the target epothilone A.
【1】
Sinha, S.C.; Barbas, C.F. III; Lerner, R.A.; The antibody catalysis route to the total synthesis of epothilones. Proc Natl Acad Sci USA 1998, 95, 25, 14603.
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(XV) |
13484 |
Methyl(triphenyl)phosphonium iodide; Methyltriphenylphosphonium iodide
|
2065-66-9 |
C19H18IP |
详情 | 详情
|
(XVIII) |
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
|
(XIX) |
44456 |
(E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal
|
|
C8H9NOS |
详情 |
详情
|
(XX) |
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
|
(XXI) |
45552 |
(4S,5E)-4-hydroxy-5-methyl-6-(2-methyl-1,3-thiazol-4-yl)-5-hexen-2-one
|
|
C11H15NO2S |
详情 |
详情
|
(XXII) |
45553 |
(4S,5E)-4-[[tert-butyl(dimethyl)silyl]oxy]-5-methyl-6-(2-methyl-1,3-thiazol-4-yl)-5-hexen-2-one
|
2815-95-4 |
C17H29NO2SSi |
详情 | 详情
|
(XXIII) |
45554 |
(4S,5E)-4-[[tert-butyl(dimethyl)silyl]oxy]-5-methyl-6-(2-methyl-1,3-thiazol-4-yl)-5-hexene-1,2-diol
|
|
C17H31NO3SSi |
详情 |
详情
|
(XXIV) |
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
|
(XXV) |
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
|
(XXVI) |
43171 |
(1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol
|
|
C11H15NOS |
详情 |
详情
|
(XXVII) |
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
|
(XXVIII) |
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
|
(XXIX) |
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7
该中间体在本合成路线中的序号:
(IV) The synthesis of the intermediate chiral aldehyde (XVIII) has been obtained as follows: The reduction of 2-methylthiazole-4-carboxylic acid methyl ester (I) with DIBAL in dichloromethane gives the aldehyde (II), which by condensation with phosphorane (III) in refluxing benzene yields the unsaturated aldehyde (IV). The condensation of (IV) with the chiral borane (V) in ethyl ether affords the chiral unsaturated alcohol (VI), which is treated with Tbdms-Cl and imidazole to provide the sill ether (VII). The oxidation of the terminal double bond of (VIII) with OsO4 and Pb(OAc)4 in THF/tBuOH/water gives the aldehyde (VIII), which is condensed with the phosphorane (IX) in refluxing benzene to yield the carboxylic acid (X). The reduction of (X) with DIBAL in THF affords the carbinol (XI), which is reduced by reaction with CCl4 and PPh3, followed by a reductive dechlorination with LiBHEt3, to furnish the dimethylated olefin (XII). Hydroxylation of the terminal double bond of (XII) with 9-BBN in THF gives the primary alcohol (XIII), which is treated with I2 and PPh3 in ethyl ether/CH3CN to yield the iodo derivative (XIV). The condensation of (XIV) with the chiral 1-(propylideneamino)pyrrolidine (XV) by means of LDA in THF affords intermediate (XVI), which is converted into the nitrile (XVII) by reaction with monoperoxyphthalic acid magnesium salt (MMPP) in MeOH. Finally this compound is reduced with DIBAL in toluene to afford the target aldehyde intermediate (XVIII).
【1】
Nicolaou, K.C.; et al.; Total syntheses of epothilones A and B via a macrolactonization-based strategy. J Am Chem Soc 1997, 119, 34, 7974.
|
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) |
44454 |
ethyl 2-methyl-1,3-thiazole-4-carboxylate
|
6436-59-5 |
C7H9NO2S |
详情 | 详情
|
(II) |
44455 |
2-methyl-1,3-thiazole-4-carbaldehyde
|
|
C5H5NOS |
详情 |
详情
|
(III) |
39940 |
2-(triphenylphosphoranylidene)propanal
|
|
C21H19OP |
详情 |
详情
|
(IV) |
44456 |
(E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal
|
|
C8H9NOS |
详情 |
详情
|
(V) |
44449 |
allyl[bis[(1R,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]]borane
|
|
C23H39B |
详情 |
详情
|
(VI) |
43171 |
(1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol
|
|
C11H15NOS |
详情 |
详情
|
(VII) |
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
|
(VIII) |
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
|
(IX) |
46110 |
methyl 2-(triphenylphosphoranylidene)-4-pentenoate
|
|
C24H23O2P |
详情 |
详情
|
(X) |
46113 |
4-((1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-1,5,8-nonatrienyl)-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]-3,6-heptadienyl ether
|
|
C21H35NOSSi |
详情 |
详情
|
(XI) |
46114 |
(4Z,7S,8E)-7-[[tert-butyl(dimethyl)silyl]oxy]-4,8-dimethyl-9-(2-methyl-1,3-thiazol-4-yl)-4,8-nonadien-1-ol
|
|
C21H37NO2SSi |
详情 |
详情
|
(XII) |
46115 |
4-((1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-9-iodo-2,6-dimethyl-1,5-nonadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S,3Z)-7-iodo-4-methyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-heptenyl ether
|
|
C21H36INOSSi |
详情 |
详情
|
(XIII) |
46116 |
(2R)-N-[(Z,2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienylidene]-2-methoxy-1-pyrrolidinamine; N-[(Z,2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienylidene]-N-[(2R)-2-methoxypyrrolidinyl]amine |
|
C29H51N3O2SSi |
详情 |
详情
|
(XIV) |
46117 |
(2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienenitrile
|
|
C24H40N2OSSi |
详情 |
详情
|
(XV) |
44460 |
N-[(2R)-2-methoxypyrrolidinyl]-N-[(E)propylidene]amine; (2R)-2-methoxy-N-[(E)propylidene]-1-pyrrolidinamine
|
|
C8H16N2O |
详情 |
详情
|
(XVI) |
46118 |
(3S,6R,7S,8S,12Z,15S,16E)-3,15-bis[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid
|
|
C39H71NO6SSi2 |
详情 |
详情
|
(XVII) |
46119 |
tert-butyl(dimethyl)silyl (3S,6R,7S,8S,12Z,15S,16E)-3,7,15-tris[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoate
|
|
C51H99NO6SSi4 |
详情 |
详情
|
(XVIII) |
40829 |
(2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienal
|
|
C24H41NO2SSi |
详情 |
详情
|
合成路线8
该中间体在本合成路线中的序号:
(X) The intermediate phosphonium salt (XVI) has been obtained as follows: The reduction of 2-methylthiazole-4-carboxylic acid ethyl ester (VII) with DIBAL in dichloromethane gives the corresponding aldehyde (VIII), which is condensed with the phosphorane (IX) in refluxing benzene to yield 2-methyl-3-(2-methylthiazol-4-yl)-2(E)-propenal (X). The allylation of (X) with (+)-diisopinocampheyl(allyl)borane (II) affords the chiral secondary alcohol (XI), which is protected with Tbdms-Cl and imidazole in DMF, providing the silyl ether (XII). The oxidation of the terminal double bond of (XII) with OsO4 and Pb(OAc)4 in THF/tert-butanol/water gives rise to the aldehyde (XIII), which is reduced with NaBH4 in methanol to give the corresponding primary alcohol (XIV). The reaction of (XIV) with I2, PPh3 and imidazole in ethyl ether/acetonitrile yields the expected iodo derivative (XV), which is finally condensed with PPh3 at 100 C to afford the desired intermediate phosphonium salt (XVI).
【1】
Nicolaou, K.C.; et al.; Total syntheses of epothilones A and B via a macrolactonization-based strategy. J Am Chem Soc 1997, 119, 34, 7974.
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(II) |
44449 |
allyl[bis[(1R,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]]borane
|
|
C23H39B |
详情 |
详情
|
(VII) |
44454 |
ethyl 2-methyl-1,3-thiazole-4-carboxylate
|
6436-59-5 |
C7H9NO2S |
详情 | 详情
|
(VIII) |
44455 |
2-methyl-1,3-thiazole-4-carbaldehyde
|
|
C5H5NOS |
详情 |
详情
|
(IX) |
39940 |
2-(triphenylphosphoranylidene)propanal
|
|
C21H19OP |
详情 |
详情
|
(X) |
44456 |
(E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal
|
|
C8H9NOS |
详情 |
详情
|
(XI) |
43171 |
(1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol
|
|
C11H15NOS |
详情 |
详情
|
(XII) |
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
|
(XIII) |
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
|
(XIV) |
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
|
(XV) |
44458 |
tert-butyl(dimethyl)silyl (1S,2E)-1-(2-iodoethyl)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenyl ether; 4-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-iodo-2-methyl-1-pentenyl)-2-methyl-1,3-thiazole
|
|
C16H28INOSSi |
详情 |
详情
|
(XVI) |
44459 |
[(3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-pentenyl](triphenyl)phosphonium iodide
|
|
C34H43INOPSSi |
详情 |
详情
|
合成路线9
该中间体在本合成路线中的序号:
(XXII) Synthesis of the thiazole intermediate (XXXIII):
The reaction of 2-methyl-3-(2-methylthiazol-4-yl)-2(E)-propenal (XXII) with trimethylsilyl cyanide and Et2AlCl catalyzed by a chiral bidentate phosphine oxide catalyst gives the chiral alpha-hydroxybutenenitrile (XXIII), which is hydrolyzed to the corresponding carboxylic ester (XXIV) by means of HCl in hot ethanol/water. The reaction of (XXIV) with Tbdms-Cl and imidazole yields the silylated hydroxyester (XXV), which is reduced with DIBAL in toluene, affording the aldehyde (XXVI). The reaction of (XXVI) with phosphonium salt (XXVII), LHMDS, Hg(OAc)2 and tetrabutylammonium iodine (TBAI) in THF provides the olefin (XXX), which is iodinated with I2 and NaHMDS in THF to give the iodinated olefin (XXXI). The desilylation of (XXXI) with HF and pyridine in THF yields the secondary alcohol (XXXII), which is acylated with Ac2O, TEA and DMAP in dichloromethane to afford the target thiazole intermediate (XXXIII).
【1】
Sawada, D.; et al.; Enantioselective total synthesis of epothilones A and B using multifunctional asymmetric catalysis. J Am Chem Soc 2000, 122, 43, 10521.
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(XXII) |
44456 |
(E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal
|
|
C8H9NOS |
详情 |
详情
|
(XXIII) |
44520 |
(2R,3E)-2-hydroxy-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenenitrile
|
|
C9H10N2OS |
详情 |
详情
|
(XXIV) |
44521 |
ethyl (2R,3E)-2-hydroxy-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenoate
|
|
C11H15NO3S |
详情 |
详情
|
(XXV) |
44522 |
ethyl (2R,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenoate
|
|
C17H29NO3SSi |
详情 |
详情
|
(XXVI) |
44523 |
(2R,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenal
|
|
C15H25NO2SSi |
详情 |
详情
|
(XXVII) |
39163 |
(methoxymethyl)(triphenyl)phosphonium chloride
|
4009-98-7 |
C20H20ClOP |
详情 | 详情
|
(XXVIII) |
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
|
(XXIX) |
46122 |
ethyl(triphenyl)phosphonium iodide
|
|
C20H20IP |
详情 |
详情
|
(XXX) |
46123 |
tert-butyl(dimethyl)silyl (1S,3E)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-pentenyl ether; 4-((1E,3S,5E)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1,5-heptadienyl)-2-methyl-1,3-thiazole
|
|
C18H31NOSSi |
详情 |
详情
|
(XXXI) |
26246 |
tert-butyl(dimethyl)silyl (1S,3Z)-4-iodo-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]-6-iodo-2-methyl-1,5-heptadienyl)-2-methyl-1,3-thiazole
|
|
C18H30INOSSi |
详情 |
详情
|
(XXXII) |
46124 |
(1E,3S,5Z)-6-iodo-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-heptadien-3-ol
|
|
C12H16INOS |
详情 |
详情
|
(XXXIII) |
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
|
合成路线10
该中间体在本合成路线中的序号:
(III) Synthesis of thiazole intermediate (IX): The reaction of 2-methylthiazole-4-carbaldehyde (I) with triphenylphosphorane (II) in refluxing benzene gives 2-methyl-3-(2-methyl-4-thiazolyl)-2-propenal (III), which is enantioselectively allylated with ally(tributyl)stannane (IV) and catalyzed by (S)-(-)-BINOL and Ti(O-iPr)4 in dichloromethane to yield the chiral homoallyl alcohol (V). The reaction of (V) with acetic anhydride TEA and DMAP in dichloromethane affords the acetate (VI), which is oxidized at its terminal double bond with OsO4 and NaIO4 to provide the aldehyde (VII). Finally, this compound is condensed with triphenylphosphorane (VIII) to gives the desired thiazole intermediate (IX).
【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 |
(I) |
44455 |
2-methyl-1,3-thiazole-4-carbaldehyde
|
|
C5H5NOS |
详情 |
详情
|
(II) |
39940 |
2-(triphenylphosphoranylidene)propanal
|
|
C21H19OP |
详情 |
详情
|
(III) |
44456 |
(E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal
|
|
C8H9NOS |
详情 |
详情
|
(IV) |
40599 |
Allyltributyltin; Tributyl-2-propenylstannane |
24850-33-7 |
C15H32Sn |
详情 | 详情
|
(V) |
43171 |
(1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol
|
|
C11H15NOS |
详情 |
详情
|
(VI) |
44530 |
(1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate
|
|
C13H17NO2S |
详情 |
详情
|
(VII) |
44531 |
(1S,2E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-1-(2-oxoethyl)-2-propenyl acetate
|
|
C12H15NO3S |
详情 |
详情
|
(VIII) |
42754 |
(1-iodoethylidene)(triphenyl)phosphorane
|
|
C20H18IP |
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
|
合成路线11
该中间体在本合成路线中的序号:
(X) The allylation of 2-(2-methylthiazol-4-ylmethylene)propionaldehyde (X) with allyl(diisopinocampheyl)borane gives the chiral secondary alcohol (XI), which is protected with Tbdms-Cl, yielding the silyl ether (XII). The oxidation of the terminal double bond of (XII) with OsO4 and NaIO4 affords the chiral aldehyde (XIII), which is condensed with the intermediate iodovinyl compound (IX) by means of Ni/Cr to provide the allyl alcohol derivative (XIV). The reaction of (XIV) with SOCl2 gives the rearranged chloromethyl compound (XV), which is treated with LiEt3BH to cleave the oxazolidine chiral auxiliary and dechlorinate the chloromethyl group, yielding the primary alcohol (XVI). The controlled oxidation of the OH group of (XVI) with PCC affords the aldehyde (XVII), which is submitted to an aldol condensation with the intermediate ketone (VI) by means of LDA to provide the aldol (XVIII). The protection of the OH group of (XVIII) with Tbdms-Cl gives the fully silylated compound (XIX), which is regioselectively monodesilylated with camphorsulfonic acid (CSA) to yield the primary alcohol (XX).
【1】
Chen, Y.; Taylor, R.E.; Total synthesis of epothilones B and D. Org Lett 2001, 3, 14, 2221.
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(VI) |
40830 |
(5S)-5,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-3-heptanone
|
|
C21H46O3Si2 |
详情 |
详情
|
(IX) |
52569 |
3-(6-iodo-2-methyl-6-heptenoyl)-4-(phenylmethyl)-1,3-oxazolidin-2-one
|
|
C18H22INO3 |
详情 |
详情
|
(X) |
44456 |
(E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal
|
|
C8H9NOS |
详情 |
详情
|
(XI) |
43171 |
(1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol
|
|
C11H15NOS |
详情 |
详情
|
(XII) |
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
|
(XIII) |
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
|
(XIV) |
52571 |
3-[9-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-7-hydroxy-2,10-dimethyl-6-methylidene-11-(2-methyl-1,3-thiazol-4-yl)-10-undecenoyl]-4-(phenylmethyl)-1,3-oxazolidin-2-one
|
|
C34H50N2O5SSi |
详情 |
详情
|
(XV) |
52570 |
3-[6-(chloromethyl)-9-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-2,10-dimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienoyl]-4-(phenylmethyl)-1,3-oxazolidin-2-one
|
|
C34H49ClN2O4SSi |
详情 |
详情
|
(XVI) |
40828 |
(2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadien-1-ol
|
|
C24H43NO2SSi |
详情 |
详情
|
(XVII) |
40829 |
(2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienal
|
|
C24H41NO2SSi |
详情 |
详情
|
(XVIII) |
40831 |
(7S,10R,11S,12S,16Z,19S)-7-[[tert-butyl(dimethyl)silyl]oxy]-11-hydroxy-2,2,3,3,8,8,10,12,16,21,21,22,22-tridecamethyl-19-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,20-dioxa-3,21-disila-16-tricosen-9-one
|
|
C45H87NO5SSi3 |
详情 |
详情
|
(XIX) |
40832 |
(7S,10R,11S,12S,16Z,19S)-7,11-bis[[tert-butyl(dimethyl)silyl]oxy]-2,2,3,3,8,8,10,12,16,21,21,22,22-tridecamethyl-19-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,20-dioxa-3,21-disila-16-tricosen-9-one
|
|
C51H101NO5SSi4 |
详情 |
详情
|
(XX) |
40833 |
(5S,8R,9S,10S,14Z,17S)-9-[[tert-butyl(dimethyl)silyl]oxy]-5-(2-hydroxyethyl)-2,2,3,3,6,6,8,10,14,19,19,20,20-tridecamethyl-17-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,18-dioxa-3,19-disila-14-henicosen-7-one
|
|
C45H87NO5SSi3 |
详情 |
详情
|
合成路线12
该中间体在本合成路线中的序号:
(IV) The synthesis of the intermediate chiral aldehyde (XVIII) has been obtained as follows: The reduction of 2-methylthiazole-4-carboxylic acid methyl ester (I) with DIBAL in dichloromethane gives the aldehyde (II), which by condensation with phosphorane (III) in refluxing benzene yields the unsaturated aldehyde (IV). The condensation of (IV) with the chiral borane (V) in ethyl ether affords the chiral unsaturated alcohol (VI), which is treated with Tbdms-Cl and imidazole to provide the sill ether (VII). The oxidation of the terminal double bond of (VIII) with OsO4 and Pb(OAc)4 in THF/tBuOH/water gives the aldehyde (VIII), which is condensed with the phosphorane (IX) in refluxing benzene to yield the carboxylic acid (X). The reduction of (X) with DIBAL in THF affords the carbinol (XI), which is reduced by reaction with CCl4 and PPh3, followed by a reductive dechlorination with LiBHEt3, to furnish the dimethylated olefin (XII). Hydroxylation of the terminal double bond of (XII) with 9-BBN in THF gives the primary alcohol (XIII), which is treated with I2 and PPh3 in ethyl ether/acetonitrile to yield the iodo derivative (XIV). The condensation of (XIV) with the chiral 1-(propylideneamino)pyrrolidine (XV) by means of LDA in THF affords intermediate (XVI), which is converted into the nitrile (XVII) by reaction with monoperoxyphthalic acid magnesium salt (MMPP) in methanol. Finally, this compound is reduced with DIBAL in toluene to afford the target aldehyde intermediate (XVIII).
【1】
Nicolaou, K.C.; et al.; Total syntheses of epothilones A and B via a macrolactonization-based strategy. J Am Chem Soc 1997, 119, 34, 7974.
|
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) |
44454 |
ethyl 2-methyl-1,3-thiazole-4-carboxylate
|
6436-59-5 |
C7H9NO2S |
详情 | 详情
|
(II) |
44455 |
2-methyl-1,3-thiazole-4-carbaldehyde
|
|
C5H5NOS |
详情 |
详情
|
(III) |
39940 |
2-(triphenylphosphoranylidene)propanal
|
|
C21H19OP |
详情 |
详情
|
(IV) |
44456 |
(E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal
|
|
C8H9NOS |
详情 |
详情
|
(V) |
44449 |
allyl[bis[(1R,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]]borane
|
|
C23H39B |
详情 |
详情
|
(VI) |
43171 |
(1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol
|
|
C11H15NOS |
详情 |
详情
|
(VII) |
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
|
(VIII) |
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
|
(IX) |
46110 |
methyl 2-(triphenylphosphoranylidene)-4-pentenoate
|
|
C24H23O2P |
详情 |
详情
|
(X) |
46113 |
4-((1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-1,5,8-nonatrienyl)-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]-3,6-heptadienyl ether
|
|
C21H35NOSSi |
详情 |
详情
|
(XI) |
46114 |
(4Z,7S,8E)-7-[[tert-butyl(dimethyl)silyl]oxy]-4,8-dimethyl-9-(2-methyl-1,3-thiazol-4-yl)-4,8-nonadien-1-ol
|
|
C21H37NO2SSi |
详情 |
详情
|
(XII) |
46115 |
4-((1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-9-iodo-2,6-dimethyl-1,5-nonadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S,3Z)-7-iodo-4-methyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-heptenyl ether
|
|
C21H36INOSSi |
详情 |
详情
|
(XIII) |
46116 |
(2R)-N-[(Z,2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienylidene]-2-methoxy-1-pyrrolidinamine; N-[(Z,2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienylidene]-N-[(2R)-2-methoxypyrrolidinyl]amine |
|
C29H51N3O2SSi |
详情 |
详情
|
(XIV) |
46117 |
(2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienenitrile
|
|
C24H40N2OSSi |
详情 |
详情
|
(XV) |
44460 |
N-[(2R)-2-methoxypyrrolidinyl]-N-[(E)propylidene]amine; (2R)-2-methoxy-N-[(E)propylidene]-1-pyrrolidinamine
|
|
C8H16N2O |
详情 |
详情
|
(XVI) |
46118 |
(3S,6R,7S,8S,12Z,15S,16E)-3,15-bis[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid
|
|
C39H71NO6SSi2 |
详情 |
详情
|
(XVII) |
46119 |
tert-butyl(dimethyl)silyl (3S,6R,7S,8S,12Z,15S,16E)-3,7,15-tris[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoate
|
|
C51H99NO6SSi4 |
详情 |
详情
|
(XVIII) |
40829 |
(2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienal
|
|
C24H41NO2SSi |
详情 |
详情
|
合成路线13
该中间体在本合成路线中的序号:
(X) The intermediate phosphonium salt (XVI) has been obtained as follows: The reduction of 2-methylthiazole-4-carboxylic acid ethyl ester (VII) with DIBAL in dichloromethane gives the corresponding aldehyde (VIII), which is condensed with the phosphorane (IX) in refluxing benzene to yield 2-methyl-3-(2-methylthiazol-4-yl)-2(E)-propenal (X). The allylation of (X) with (+)-diisopinocampheyl(allyl)borane (II) affords the chiral secondary alcohol (XI), which is protected with Tbdms-Cl and imidazole in DMF to provide the silyl ether (XII). The oxidation of the terminal double bond of (XII) with OsO4 and Pb(OAc)4 in THF/tert-butanol/water gives rise to the aldehyde (XIII), which is reduced with NaBH4 in methanol to give the corresponding primary alcohol (XIV). The reaction of (XIV) with I2, PPh3 and imidazole in ethyl ether/acetonitrile yields the expected iodo derivative (XV), which is finally condensed with PPh3 at 100 C to afford the desired intermediate phosphonium salt (XVI).
【1】
Nicolaou, K.C.; et al.; Total syntheses of epothilones A and B via a macrolactonization-based strategy. J Am Chem Soc 1997, 119, 34, 7974.
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(II) |
44449 |
allyl[bis[(1R,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]]borane
|
|
C23H39B |
详情 |
详情
|
(VII) |
44454 |
ethyl 2-methyl-1,3-thiazole-4-carboxylate
|
6436-59-5 |
C7H9NO2S |
详情 | 详情
|
(VIII) |
44455 |
2-methyl-1,3-thiazole-4-carbaldehyde
|
|
C5H5NOS |
详情 |
详情
|
(IX) |
39940 |
2-(triphenylphosphoranylidene)propanal
|
|
C21H19OP |
详情 |
详情
|
(X) |
44456 |
(E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal
|
|
C8H9NOS |
详情 |
详情
|
(XI) |
43171 |
(1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol
|
|
C11H15NOS |
详情 |
详情
|
(XII) |
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
|
(XIII) |
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
|
(XIV) |
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
|
(XV) |
44458 |
tert-butyl(dimethyl)silyl (1S,2E)-1-(2-iodoethyl)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenyl ether; 4-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-iodo-2-methyl-1-pentenyl)-2-methyl-1,3-thiazole
|
|
C16H28INOSSi |
详情 |
详情
|
(XVI) |
44459 |
[(3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-pentenyl](triphenyl)phosphonium iodide
|
|
C34H43INOPSSi |
详情 |
详情
|
合成路线14
该中间体在本合成路线中的序号:
(XXII) Synthesis of the thiazole intermediate (XXXIII):
The reaction of 2-methyl-3-(2-methylthiazol-4-yl)-2(E)-propenal (XXII) with trimethylsilyl cyanide and Et2AlCl catalyzed by a chiral bidentate phosphine oxide catalyst gives the chiral alpha-hydroxybutenenitrile (XXIII), which is hydrolyzed to the corresponding carboxylic ester (XXIV) by means of HCl in hot ethanol/water. The reaction of (XXIV) with Tbdms-Cl and imidazole yields the silylated hydroxyester (XXV), which is reduced with DIBAL in toluene, affording the aldehyde (XXVI). The reaction of (XXVI) with phosphonium salt (XXVII), LHMDS, Hg(OAc)2 and tetrabutylammonium iodine (TBAI) in THF provides the olefin (XXX), which is iodinated with I2 and NaHMDS in THF to give the iodinated olefin (XXXI). The desilylation of (XXXI) with HF and pyridine in THF yields the secondary alcohol (XXXII), which is acylated with Ac2O, TEA and DMAP in dichloromethane to afford the target thiazole intermediate (XXXIII).
【1】
Sawada, D.; et al.; Enantioselective total synthesis of epothilones A and B using multifunctional asymmetric catalysis. J Am Chem Soc 2000, 122, 43, 10521.
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(XXII) |
44456 |
(E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal
|
|
C8H9NOS |
详情 |
详情
|
(XXIII) |
44520 |
(2R,3E)-2-hydroxy-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenenitrile
|
|
C9H10N2OS |
详情 |
详情
|
(XXIV) |
44521 |
ethyl (2R,3E)-2-hydroxy-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenoate
|
|
C11H15NO3S |
详情 |
详情
|
(XXV) |
44522 |
ethyl (2R,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenoate
|
|
C17H29NO3SSi |
详情 |
详情
|
(XXVI) |
44523 |
(2R,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenal
|
|
C15H25NO2SSi |
详情 |
详情
|
(XXVII) |
39163 |
(methoxymethyl)(triphenyl)phosphonium chloride
|
4009-98-7 |
C20H20ClOP |
详情 | 详情
|
(XXVIII) |
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
|
(XXIX) |
46122 |
ethyl(triphenyl)phosphonium iodide
|
|
C20H20IP |
详情 |
详情
|
(XXX) |
46123 |
tert-butyl(dimethyl)silyl (1S,3E)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-pentenyl ether; 4-((1E,3S,5E)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1,5-heptadienyl)-2-methyl-1,3-thiazole
|
|
C18H31NOSSi |
详情 |
详情
|
(XXXI) |
26246 |
tert-butyl(dimethyl)silyl (1S,3Z)-4-iodo-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]-6-iodo-2-methyl-1,5-heptadienyl)-2-methyl-1,3-thiazole
|
|
C18H30INOSSi |
详情 |
详情
|
(XXXII) |
46124 |
(1E,3S,5Z)-6-iodo-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-heptadien-3-ol
|
|
C12H16INOS |
详情 |
详情
|
(XXXIII) |
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
|
合成路线15
该中间体在本合成路线中的序号:
(III) Synthesis of thiazole intermediate (IX): The reaction of 2-methylthiazole-4-carbaldehyde (I) with triphenylphosphorane (II) in refluxing benzene gives 2-methyl-3-(2-methyl-4-thiazolyl)-2-propenal (III), which is enantioselectively allylated with ally(tributyl)stannane (IV) catalyzed by (S)(-)-BINOL and Ti(O-iPr)4 in dichloromethane to yield the chiral homoallyl alcohol (V). The reaction of (V) with acetic anhydride TEA and DMAP in dichloromethane affords the acetate (VI), which is oxidized at its terminal double bond with OsO4 and NaIO4 to provide the aldehyde (VII). Finally, this compound is condensed with triphenylphosphorane (VIII) to gives the desired thiazole intermediate (IX)
【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 |
(I) |
44455 |
2-methyl-1,3-thiazole-4-carbaldehyde
|
|
C5H5NOS |
详情 |
详情
|
(II) |
39940 |
2-(triphenylphosphoranylidene)propanal
|
|
C21H19OP |
详情 |
详情
|
(III) |
44456 |
(E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal
|
|
C8H9NOS |
详情 |
详情
|
(IV) |
40599 |
Allyltributyltin; Tributyl-2-propenylstannane |
24850-33-7 |
C15H32Sn |
详情 | 详情
|
(V) |
43171 |
(1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol
|
|
C11H15NOS |
详情 |
详情
|
(VI) |
44530 |
(1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate
|
|
C13H17NO2S |
详情 |
详情
|
(VII) |
44531 |
(1S,2E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-1-(2-oxoethyl)-2-propenyl acetate
|
|
C12H15NO3S |
详情 |
详情
|
(VIII) |
42754 |
(1-iodoethylidene)(triphenyl)phosphorane
|
|
C20H18IP |
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
|
合成路线16
该中间体在本合成路线中的序号:
(X) The allylation of 2-(2-methylthiazol-4-ylmethylene)propionaldehyde (X) with allyl(diisopinocampheyl)borane gives the chiral secondary alcohol (XI), which is protected with Tbdms-Cl, yielding the silyl ether (XII). The oxidation of the terminal double bond of (XII) with OsO4 and NaIO4 affords the chiral aldehyde (XIII), which is condensed with the intermediate iodovinyl compound (IX) by means of Ni/Cr to provide the allyl alcohol derivative (XIV). The reaction of (XIV) with SOCl2 gives the rearranged chloromethyl compound (XV), which is treated with LiEt3BH to cleave the oxazolidine chiral auxiliary and dechlorinate the chloromethyl group, yielding the primary alcohol (XVI). The controlled oxidation of the OH group of (XVI) with PCC affords the aldehyde (XVII), which is submitted to an aldol condensation with the intermediate ketone (VI) by means of LDA to provide the aldol (XVIII). The protection of the OH group of (XVIII) with Tbdms-Cl gives the fully silylated compound (XIX), which is regioselectively monodesilylated with camphorsulfonic acid (CSA) to yield the primary alcohol (XX).
【1】
Chen, Y.; Taylor, R.E.; Total synthesis of epothilones B and D. Org Lett 2001, 3, 14, 2221.
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(VI) |
40830 |
(5S)-5,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-3-heptanone
|
|
C21H46O3Si2 |
详情 |
详情
|
(IX) |
52569 |
3-(6-iodo-2-methyl-6-heptenoyl)-4-(phenylmethyl)-1,3-oxazolidin-2-one
|
|
C18H22INO3 |
详情 |
详情
|
(X) |
44456 |
(E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal
|
|
C8H9NOS |
详情 |
详情
|
(XI) |
43171 |
(1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol
|
|
C11H15NOS |
详情 |
详情
|
(XII) |
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
|
(XIII) |
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
|
(XIV) |
52571 |
3-[9-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-7-hydroxy-2,10-dimethyl-6-methylidene-11-(2-methyl-1,3-thiazol-4-yl)-10-undecenoyl]-4-(phenylmethyl)-1,3-oxazolidin-2-one
|
|
C34H50N2O5SSi |
详情 |
详情
|
(XV) |
52570 |
3-[6-(chloromethyl)-9-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-2,10-dimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienoyl]-4-(phenylmethyl)-1,3-oxazolidin-2-one
|
|
C34H49ClN2O4SSi |
详情 |
详情
|
(XVI) |
40828 |
(2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadien-1-ol
|
|
C24H43NO2SSi |
详情 |
详情
|
(XVII) |
40829 |
(2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienal
|
|
C24H41NO2SSi |
详情 |
详情
|
(XVIII) |
40831 |
(7S,10R,11S,12S,16Z,19S)-7-[[tert-butyl(dimethyl)silyl]oxy]-11-hydroxy-2,2,3,3,8,8,10,12,16,21,21,22,22-tridecamethyl-19-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,20-dioxa-3,21-disila-16-tricosen-9-one
|
|
C45H87NO5SSi3 |
详情 |
详情
|
(XIX) |
40832 |
(7S,10R,11S,12S,16Z,19S)-7,11-bis[[tert-butyl(dimethyl)silyl]oxy]-2,2,3,3,8,8,10,12,16,21,21,22,22-tridecamethyl-19-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,20-dioxa-3,21-disila-16-tricosen-9-one
|
|
C51H101NO5SSi4 |
详情 |
详情
|
(XX) |
40833 |
(5S,8R,9S,10S,14Z,17S)-9-[[tert-butyl(dimethyl)silyl]oxy]-5-(2-hydroxyethyl)-2,2,3,3,6,6,8,10,14,19,19,20,20-tridecamethyl-17-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,18-dioxa-3,19-disila-14-henicosen-7-one
|
|
C45H87NO5SSi3 |
详情 |
详情
|
合成路线17
该中间体在本合成路线中的序号:
(IV) The reduction of 2-methylthiazole-4-carboxylic acid ethyl ester (I) with DIBAL in dichloromethane gives the corresponding carbaldehyde (II), which is condensed with phosphorane (III) in refluxing benzene to yield the propionaldehyde (IV). The diastereocontrolled condensation of (IV) with (+)-allyl-di(isopinocampheyl)borane (V) in ethyl ether affords the chiral homoallyl alcohol (VI), which is silylated with Tbdms-Cl and imidazole to provide the silyl ether (VII).The oxidation of the terminal double bond of (VII) by means of OsO4, NaIO4 and 4-methylmorpholine N-oxide gives the 4-pentenal derivative (VIII), which is condensed with the phosphorane (IX) in refluxing benzene to yield the methyl heptadienoate (X). The reduction of (X) with DIBAL in THF affords the carbinol (XI), which is protected with trityl chloride and DMAP to provide the trityl ether (XII). The Hydroxylation of the terminal double bond of (XII) with 8-BBN and H2O2 gives the primary alcohol (XIII), which is treated with I2 and PPh3 to yield the iodo compound (XIV). The condensation of (XIV) with the hydrazone (XV) by means of LDA affords the chiral undecadienylhydrazone (XVI), which is treated with monoperoxyphthalic magnesium salt (MMPP) to provide the undecadienenitrile (XVII). The reduction of (XVII) with DIBAL in toluene gives the corresponding aldehyde (XVIII).
【1】
Nicolaou, K.C.; et al.; Total synthesis of 26-hydroxy-epothilone B and related analogs via a macrolactonization based strategy. Tetrahedron 1998, 54, 25, 7127.
|
【2】
Nicolaou, K.C.; et al.; Total syntheses of epothilones A and B via a macrolactonization-based strategy. J Am Chem Soc 1997, 119, 34, 7974.
|
【3】
He, Y.; Yang, Z.; Nicolaou, C.K.; Ninkovic, S.; Pastor, J.; Roschangar, F.; Sarabia, F.; Vallberg, H.; Vourloumis, D.; Winssinger, N.; King, N.P.; Finlay, M.R.V. (Novartis AG; Scripps Research Institute); Epothilone analogs. JP 2001504856; WO 9825929 . |
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) |
44454 |
ethyl 2-methyl-1,3-thiazole-4-carboxylate
|
6436-59-5 |
C7H9NO2S |
详情 | 详情
|
(II) |
44455 |
2-methyl-1,3-thiazole-4-carbaldehyde
|
|
C5H5NOS |
详情 |
详情
|
(III) |
39940 |
2-(triphenylphosphoranylidene)propanal
|
|
C21H19OP |
详情 |
详情
|
(IV) |
44456 |
(E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal
|
|
C8H9NOS |
详情 |
详情
|
(VI) |
43171 |
(1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol
|
|
C11H15NOS |
详情 |
详情
|
(VII) |
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
|
(VIII) |
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
|
(IX) |
46110 |
methyl 2-(triphenylphosphoranylidene)-4-pentenoate
|
|
C24H23O2P |
详情 |
详情
|
(X) |
46111 |
methyl (2E,5S,6E)-2-allyl-5-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-7-(2-methyl-1,3-thiazol-4-yl)-2,6-heptadienoate
|
|
C22H35NO3SSi |
详情 |
详情
|
(XI) |
46112 |
(2E,5S,6E)-2-allyl-5-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-7-(2-methyl-1,3-thiazol-4-yl)-2,6-heptadien-1-ol
|
|
C21H35NO2SSi |
详情 |
详情
|
(XII) |
54771 |
(2E,5S,6E)-2-allyl-5-{[tert-butyl(dimethyl)silyl]oxy}-6-methyl-7-(2-methyl-1,3-thiazol-4-yl)-2,6-heptadienyl trityl ether; 4-{(1E,3S,5E)-3-{[tert-butyl(dimethyl)silyl]oxy}-2-methyl-6-[(trityloxy)methyl]-1,5,8-nonatrienyl}-2-methyl-1,3-thiazole
|
|
C40H49NO2SSi |
详情 |
详情
|
(XIII) |
54772 |
(4E,7S,8E)-7-{[tert-butyl(dimethyl)silyl]oxy}-8-methyl-9-(2-methyl-1,3-thiazol-4-yl)-4-[(trityloxy)methyl]-4,8-nonadien-1-ol
|
|
C40H51NO3SSi |
详情 |
详情
|
(XIV) |
54773 |
tert-butyl(dimethyl)silyl (1S,3E)-7-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4-[(trityloxy)methyl]-3-heptenyl ether; 4-{(1E,3S,5E)-3-{[tert-butyl(dimethyl)silyl]oxy}-9-iodo-2-methyl-6-[(trityloxy)methyl]-1,5-nonadienyl}-2-methyl-1,3-thiazole |
|
C40H50INO2SSi |
详情 |
详情
|
(XV) |
44460 |
N-[(2R)-2-methoxypyrrolidinyl]-N-[(E)propylidene]amine; (2R)-2-methoxy-N-[(E)propylidene]-1-pyrrolidinamine
|
|
C8H16N2O |
详情 |
详情
|
(XVI) |
54774 |
(2R)-N-{(Z,2S,6E,9S,10E)-9-{[tert-butyl(dimethyl)silyl]oxy}-2,10-dimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6-[(trityloxy)methyl]-6,10-undecadienylidene}-2-methoxy-1-pyrrolidinamine; N-{(Z,2S,6E,9S,10E)-9-{[tert-butyl(dimethyl)silyl]oxy}-2,10-dimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6-[(trityloxy)methyl]-6,10-undecadienylidene}-N-[(2R)-2-methoxypyrrolidinyl]amine |
|
C48H65N3O3SSi |
详情 |
详情
|
(XVII) |
54775 |
(2S,6E,9S,10E)-9-{[tert-butyl(dimethyl)silyl]oxy}-2,10-dimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6-[(trityloxy)methyl]-6,10-undecadienenitrile
|
|
C43H54N2O2SSi |
详情 |
详情
|
(XVIII) |
54776 |
(2S,6E,9S,10E)-9-{[tert-butyl(dimethyl)silyl]oxy}-2,10-dimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6-[(trityloxy)methyl]-6,10-undecadienal
|
|
C43H55NO3SSi |
详情 |
详情
|
合成路线18
该中间体在本合成路线中的序号:
(XII) The reduction of 2-methylthiazole-4-carboxylic acid ethyl ester (IX) with DIBAL in dichloromethane gives the corresponding aldehyde (X), which is condensed with the phosphorane (XI) in refluxing benzene to yield 2-methyl-3-(2-methylthiazol-4-yl)-2-propenal (XII). The alkylation of (XII) with (+)-diisopinocampheyl(allyl)borane (II) in ethyl ether affords the chiral secondary alcohol (XIII) (1), which is esterified with the intermediate tridecenoic acid (VIII) by means of EDC and DMAP in dichloromethane to provide the ester (XIV). Ring-closing metathesis of (XIV) catalyzed by a Ru catalyst gives the macrolactone (XV), which is finally desilylated by means of TFA in dichloromethane, yielding the target epothilone C.
【1】
Nicolaou, K.C.; et al.; The olefin metathesis approach to epothilone A and its analogues. J Am Chem Soc 1997, 119, 34, 7960.
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(II) |
44449 |
allyl[bis[(1R,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]]borane
|
|
C23H39B |
详情 |
详情
|
(VIII) |
44453 |
(3S,6R,7S,8S)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-4,4,6,8-tetramethyl-5-oxo-12-tridecenoic acid
|
|
C23H44O5Si |
详情 |
详情
|
(IX) |
44454 |
ethyl 2-methyl-1,3-thiazole-4-carboxylate
|
6436-59-5 |
C7H9NO2S |
详情 | 详情
|
(X) |
44455 |
2-methyl-1,3-thiazole-4-carbaldehyde
|
|
C5H5NOS |
详情 |
详情
|
(XI) |
39940 |
2-(triphenylphosphoranylidene)propanal
|
|
C21H19OP |
详情 |
详情
|
(XII) |
44456 |
(E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal
|
|
C8H9NOS |
详情 |
详情
|
(XIII) |
43171 |
(1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol
|
|
C11H15NOS |
详情 |
详情
|
(XIV) |
44457 |
(1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl (3S,6R,7S,8S)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-4,4,6,8-tetramethyl-5-oxo-12-tridecenoate
|
|
C34H57NO5SSi |
详情 |
详情
|
(XV) |
43176 |
(4S,7R,8S,9S,16S)-4-[[tert-butyl(dimethyl)silyl]oxy]-8-hydroxy-5,5,7,9-tetramethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione
|
|
C32H53NO5SSi |
详情 |
详情
|
合成路线19
该中间体在本合成路线中的序号:
(X) The intermediate phosphonium salt (XVI) has been obtained as follows: The reduction of 2-methylthiazole-4-carboxylic acid ethyl ester (VII) with DIBAL in dichloromethane gives the corresponding aldehyde (VIII), which is condensed with the phosphorane (IX) in refluxing benzene to yield 2-methyl-3-(2-methylthiazol-4-yl)-2(E)-propenal (X). The allylation of (X) with (+)-diisopinocampheyl(allyl)borane (II) affords the chiral secondary alcohol (XI), which is protected with Tbdms-Cl and imidazole in DMF, providing the silyl ether (XII). The oxidation of the terminal double bond of (XII) with OsO4 and Pb(OAc)4 in THF/tert-butanol/water gives rise to the aldehyde (XIII), which is reduced with NaBH4 in methanol to give the corresponding primary alcohol (XIV). The reaction of (XIV) with I2, PPh3 and imidazole in ethyl ether/acetonitrile yields the expected iodo derivative (XV), which is finally condensed with PPh3 at 100 C to afford the desired intermediate phosphonium salt (XVI).
【1】
Nicolaou, K.C.; et al.; Total syntheses of epothilones A and B via a macrolactonization-based strategy. J Am Chem Soc 1997, 119, 34, 7974.
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(II) |
44449 |
allyl[bis[(1R,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]]borane
|
|
C23H39B |
详情 |
详情
|
(VII) |
44454 |
ethyl 2-methyl-1,3-thiazole-4-carboxylate
|
6436-59-5 |
C7H9NO2S |
详情 | 详情
|
(VIII) |
44455 |
2-methyl-1,3-thiazole-4-carbaldehyde
|
|
C5H5NOS |
详情 |
详情
|
(IX) |
39940 |
2-(triphenylphosphoranylidene)propanal
|
|
C21H19OP |
详情 |
详情
|
(X) |
44456 |
(E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal
|
|
C8H9NOS |
详情 |
详情
|
(XI) |
43171 |
(1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol
|
|
C11H15NOS |
详情 |
详情
|
(XII) |
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
|
(XIII) |
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
|
(XIV) |
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
|
(XV) |
44458 |
tert-butyl(dimethyl)silyl (1S,2E)-1-(2-iodoethyl)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenyl ether; 4-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-iodo-2-methyl-1-pentenyl)-2-methyl-1,3-thiazole
|
|
C16H28INOSSi |
详情 |
详情
|
(XVI) |
44459 |
[(3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-pentenyl](triphenyl)phosphonium iodide
|
|
C34H43INOPSSi |
详情 |
详情
|
合成路线20
该中间体在本合成路线中的序号:
(XVII) Synthesis of the thiazole intermediate (XXVI): The Grignard reaction of 2-methyl-3-(2-methylthiazol-4-yl)-2(E)-propenal (XVII) with vinylmagnesium bromide (XVIII) in THF gives the racemic secondary alcohol (XIX), which is submitted to enzymatic optical resolution with Pseudomonas AK lipase and vinyl acetate to yield the desired (S)-secondary alcohol (XX) along with the (R)-acetate, which is easily separated by chromatography. The silylation of (XX) with Tbdms-Cl and imidazole in DMF affords the silyl ether (XXI). The selective hydroboration of the terminal double bond of (XXI) with dichlohexylborane followed by oxidation with H2O2 provides the primary alcohol (XXII), which is oxidized with DMP in dichloromethane to give the corresponding aldehyde (XXIII). The reaction of (XXIII) with the iodomethyl phosphonium salt (XXIV) by means of NaHMDS in THF yields the cis-iodovinyl compound (XXV), which is desilylated with aqueous HF in acetonitrile affording the corresponding alcohol (XXVI). Finally, this alcohol is treated with acetic anhydride, TEA and DMAP to provide the desired thiazole intermediate (XXVII).
【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 |
(XVII) |
44456 |
(E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal
|
|
C8H9NOS |
详情 |
详情
|
(XVIII) |
16524 |
bromo(vinyl)magnesium
|
1826-67-1 |
C2H3BrMg |
详情 | 详情
|
(XIX) |
44488 |
(1E)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,4-pentadien-3-ol
|
|
C10H13NOS |
详情 |
详情
|
(XX) |
44489 |
(1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,4-pentadien-3-ol
|
|
C10H13NOS |
详情 |
详情
|
(XXI) |
44490 |
tert-butyl(dimethyl)silyl (1S,2E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-1-vinyl-2-propenyl ether; 4-((1E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1,4-pentadienyl)-2-methyl-1,3-thiazole
|
|
C16H27NOSSi |
详情 |
详情
|
(XXII) |
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
|
(XXIII) |
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
|
(XXIV) |
42718 |
(iodomethyl)(triphenyl)phosphonium iodide
|
n/a |
C19H17I2P |
详情 | 详情
|
(XXV) |
44491 |
4-((1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-iodo-2-methyl-1,5-hexadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl ether
|
|
C17H28INOSSi |
详情 |
详情
|
(XXVI) |
44492 |
(1E,3S,5Z)-6-iodo-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol
|
|
C11H14INOS |
详情 |
详情
|
(XXVII) |
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
|
合成路线21
该中间体在本合成路线中的序号:
(XXII) Synthesis of the thiazole intermediate (XXXIV): The reaction of 2-methyl-3-(2-methylthiazol-4-yl)-2(E)-propenal (XXII) with trimethylsilyl cyanide and Et2AlCl catalyzed by a chiral bidentate phosphine oxide catalyst gives the chiral alpha-hydroxybutenenitrile (XXIII), which is hydrolyzed to the corresponding carboxylic ester (XXIV) by means of HCl in hot ethanol/water. The reaction of (XXIV) with Tbdms-Cl and imidazole yields the silylated hydroxyester (XXV), which is reduced with DIBAL in toluene, affording the aldehyde (XXVI). The reaction of (XXVI) with lithium trimethylsilylacetylide (A) in THF provides the adduct (XXVII), which is esterified with methyl chloroformate (XXVIII), furnishing the carbonate (XXIX). The reduction of (XXIX) by means of Pd(OAc)2, Bu3P and ammonium formate gives the protected acetylenic compound (XXX). The selective reduction of the triple bond of (XXX) by means of Ti(OiPr)4 and iPr-MgBr in ethyl ether yields the cis-silylated vinyl compound (XXXI), which is iodinated with I2 in dichloromethane to afford the cis-iodovinyl compound (XXXII). The desilylation of (XXXII) with FH and pyridine in THF gives the secondary alcohol (XXXIII), which is finally acetylated with Ac2O, TEA and DMAP in dichloromethane to yield the target thiazole intermediate (XXXIV).
【1】
Sawada, D.; et al.; Enantioselective total synthesis of epothilones A and B using multifunctional asymmetric catalysis. J Am Chem Soc 2000, 122, 43, 10521.
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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) |
16299 |
Lithium (trimethylsilyl)acetylide; [2-(Trimethylsilyl)ethynyl]lithium
|
54655-07-1 |
C5H9LiSi |
详情 | 详情
|
(XXII) |
44456 |
(E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal
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|
C8H9NOS |
详情 |
详情
|
(XXIII) |
44520 |
(2R,3E)-2-hydroxy-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenenitrile
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|
C9H10N2OS |
详情 |
详情
|
(XXIV) |
44521 |
ethyl (2R,3E)-2-hydroxy-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenoate
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|
C11H15NO3S |
详情 |
详情
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(XXV) |
44522 |
ethyl (2R,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenoate
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|
C17H29NO3SSi |
详情 |
详情
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(XXVI) |
44523 |
(2R,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenal
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|
C15H25NO2SSi |
详情 |
详情
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(XXVII) |
44524 |
(4R,5E)-4-[[tert-butyl(dimethyl)silyl]oxy]-5-methyl-6-(2-methyl-1,3-thiazol-4-yl)-1-(trimethylsilyl)-5-hexen-1-yn-3-ol
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|
C20H35NO2SSi2 |
详情 |
详情
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(XXVIII) |
16993 |
methyl chlorocarbonate;Carbonochloridic acid methyl ester;[(chlorocarbonyl)oxy]methane;methyl chloroformate |
79-22-1 |
C2H3ClO2 |
详情 | 详情
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(XXIX) |
44525 |
(2R,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-1-[2-(trimethylsilyl)ethynyl]-3-butenyl methyl carbonate
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|
C22H37NO4SSi2 |
详情 |
详情
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(XXX) |
44526 |
4-[(E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-6-(trimethylsilyl)-1-hexen-5-ynyl]-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4-(trimethylsilyl)-3-butynyl ether
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|
C20H35NOSSi2 |
详情 |
详情
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(XXXI) |
44527 |
tert-butyl(dimethyl)silyl (1S,3Z)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4-(trimethylsilyl)-3-butenyl ether; 4-[(1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-6-(trimethylsilyl)-1,5-hexadienyl]-2-methyl-1,3-thiazole
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|
C20H37NOSSi2 |
详情 |
详情
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(XXXII) |
44491 |
4-((1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-iodo-2-methyl-1,5-hexadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl ether
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|
C17H28INOSSi |
详情 |
详情
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(XXXIII) |
44492 |
(1E,3S,5Z)-6-iodo-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol
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|
C11H14INOS |
详情 |
详情
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(XXXIV) |
44493 |
(1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate
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|
C13H16INO2S |
详情 |
详情
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合成路线22
该中间体在本合成路线中的序号:
(III) Synthesis of thiazole intermediate (IX): The reaction of 2-methylthiazole-4-carbaldehyde (I) with triphenylphosphorane (II) in refluxing benzene gives 2-methyl-3-(2-methyl-4-thiazolyl)-2-propenal (III), which is enantioselectively allylated with ally(tributyl)stannane (IV) catalyzed by (S)(-)-BINOL and Ti(O-iPr)4 in dichloromethane to yield the chiral homoallyl alcohol (V). The reaction of (V) with acetic anhydride TEA and DMAP in dichloromethane affords the acetate (VI), which is oxidized at its terminal double bond with OsO4 and NaIO4 to provide the aldehyde (VII). Finally, this compound is condensed with triphenylphosphorane (VIII) to give the desired thiazole intermediate (IX).
【1】
Meng, D.; et al.; Total syntheses of epothilones A and B. J Am Chem Soc 1997, 119, 42, 10073.
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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) |
44455 |
2-methyl-1,3-thiazole-4-carbaldehyde
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|
C5H5NOS |
详情 |
详情
|
(II) |
39940 |
2-(triphenylphosphoranylidene)propanal
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|
C21H19OP |
详情 |
详情
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(III) |
44456 |
(E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal
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|
C8H9NOS |
详情 |
详情
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(IV) |
40599 |
Allyltributyltin; Tributyl-2-propenylstannane |
24850-33-7 |
C15H32Sn |
详情 | 详情
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(V) |
43171 |
(1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol
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|
C11H15NOS |
详情 |
详情
|
(VI) |
44530 |
(1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate
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|
C13H17NO2S |
详情 |
详情
|
(VII) |
44531 |
(1S,2E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-1-(2-oxoethyl)-2-propenyl acetate
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|
C12H15NO3S |
详情 |
详情
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(VIII) |
44532 |
(iodomethylene)(triphenyl)phosphorane
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|
C19H16IP |
详情 |
详情
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(IX) |
44493 |
(1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate
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|
C13H16INO2S |
详情 |
详情
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合成路线23
该中间体在本合成路线中的序号:
(XIX) The aldol condensation of 2-methyl-3-(2-methylthiazol-4-yl)-2-propenal (XIX) with acetone (XX) catalyzed by antibody 38C2 gives the chiral aldol (XXI), which is protected with Tbdms-Cl and imidazole, yielding the silyl ether (XXII). The reaction of (XXII) with Tbdms-OTf, followed by oxidation with MCPBA and reduction with NaBH4, affords the vicinal diol (XXIII), which is cleaved with Pb(OAc)4 to provide the aldehyde (XXIV). The Wittig condensation of (XXIV) with phosphonium salt (XV) gives olefinic silyl ether (XXV), which is desilylated with TBAF in THF to yield the homoallylic alcohol (XXVI). The esterification of alcohol (XXVI) with the already described carboxylic acid (XVIII) by means of EDC in dichloromethane affords the ester (XXVII), which is submitted to a ring-closing metathesis by means of Grubb's catalyst to provide the macrolactone (XXVIII). Finally, the desilylation of (XXVIII) with HF and pyridine furnishes the target epothilone C.
【1】
Sinha, S.C.; Barbas, C.F. III; Lerner, R.A.; The antibody catalysis route to the total synthesis of epothilones. Proc Natl Acad Sci USA 1998, 95, 25, 14603.
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中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(XV) |
13484 |
Methyl(triphenyl)phosphonium iodide; Methyltriphenylphosphonium iodide
|
2065-66-9 |
C19H18IP |
详情 | 详情
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(XVIII) |
44438 |
(3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-12-tridecenoic acid
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|
C29H58O5Si2 |
详情 |
详情
|
(XIX) |
44456 |
(E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal
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|
C8H9NOS |
详情 |
详情
|
(XX) |
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
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(XXI) |
45552 |
(4S,5E)-4-hydroxy-5-methyl-6-(2-methyl-1,3-thiazol-4-yl)-5-hexen-2-one
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|
C11H15NO2S |
详情 |
详情
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(XXII) |
45553 |
(4S,5E)-4-[[tert-butyl(dimethyl)silyl]oxy]-5-methyl-6-(2-methyl-1,3-thiazol-4-yl)-5-hexen-2-one
|
2815-95-4 |
C17H29NO2SSi |
详情 | 详情
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(XXIII) |
45554 |
(4S,5E)-4-[[tert-butyl(dimethyl)silyl]oxy]-5-methyl-6-(2-methyl-1,3-thiazol-4-yl)-5-hexene-1,2-diol
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|
C17H31NO3SSi |
详情 |
详情
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(XXIV) |
40822 |
(3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-pentenal
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|
C16H27NO2SSi |
详情 |
详情
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(XXV) |
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
|
(XXVI) |
43171 |
(1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol
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|
C11H15NOS |
详情 |
详情
|
(XXVII) |
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
|
(XXVIII) |
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
|