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药物详细合成路线

Name Intaxel(from Himalayan Yew);Paclitaxel;MPI-5018(with Matrixs anhydrous delivery system);BMS-181339;NSC-125973;Xorane;Genaxol;Pacligel;Paxceed;Genexol;Paxoral(oral formulation);Paxene;Yewtaxan;Anzatax;Taxol
Chemical Name [2aR-[2aalpha,4beta,4abeta,6beta,9alpha(2R,3S),11beta,12alpha,12aalpha,12balpha]]-6,12b-Diacetoxy-9-(3-benzamido-2-hydroxy-3-phenylpropionyloxy)-12-(benzoyloxy)-4,11-dihydroxy-4a,8,13,13-tetramethyl-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-1H-7,11-methanocyclodeca[3,4]benzo[1,2-b]oxet-5-one
      3(S)-Benzamido-2(R)-hydroxybenzenepropionic acid (2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-6,12b-diacetoxy-12-(benzoyloxy)-4,11-dihydroxy-4a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-1H-7,11-methanocyclodeca[3,4]benzo[1,2-b]oxet-9-yl ester
CAS 33069-62-4
Related CAS
Formula C47H51NO14
Structure
Formula Weight 853.92882
Stage 上市-1993
Company Bristol-Myers Squibb (Originator), National Cancer Institute (Not Determined), Alcon (Licensee), Amersham (Licensee), Angiotech (Licensee), Ferring (Licensee), Galena (Licensee), Hauser (Licensee), Mayne (Licensee), Pharmachemie (Licensee), Viventia Biote
Activity/Mechanism Antiarthritic Drugs, Antipsoriatics, Breast Cancer Therapy, Cognition Disorders, Treatment of, DERMATOLOGIC DRUGS, Gastric Cancer Therapy, Immunologic Neuromuscular Disorders, Treatment of, Kaposis Sarcoma Therapy, Leukemia Therapy, Lung Cancer Therapy, Multiple Sclerosis, Agents for, NEUROLOGIC DRUGS, Non-Small Cell Lung Cancer Therapy, OCULAR MEDICATIONS, Oncolytic Drugs, Ophthalmic Drugs, Ovarian Cancer Therapy, Rheumatoid Arthritis, Treatment of, Solid Tumors Therapy, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, Angiogenesis Inhibitors, Antimitotic Drugs, Microtubule-Stabilizing Agents, Taxanes
Syn. Route 59
Route 1
a process for the preparation of taxol has been described:the acylation of baccatin iii (i) with 2,2,2-trichloroethyl chloroformate in pyridine yields the chloroformate (ii), which is acylated with cinnamic acid (iii) by means of oxalyl chloride of dicyclohexylcarbodiimide to the cinnamate (iv). the oxidative addition of tert-butyl n-chlorocarbamate (v) to (iv) by means of oso4 in water affords the protected amino hydroxyester (vi), which is deprotected with iodotrimethylsilane in acetonitrile to give the free aminoester (vii). the benzoylation of (vii) with benzoyl chloride in pyridine affords the protected n-benzoyl derivative (viii), which is finally deprotected by treatment with zn and acetic acid to eliminate the trichloroethoxycarbonyl group.
List of intermediates No.
(2r,3r,4r,5r,6r)-3-(acetamido)-5-(acetoxy)-2-(1-ethylpropoxy)-6-(hydroxymethyl)tetrahydro-2h-pyran-4-yl acetate (i)
(2r,3r,4r,5r,6s)-3-(acetamido)-5-(acetoxy)-2-(1-ethylpropoxy)-6-formyltetrahydro-2h-pyran-4-yl acetate (ii)
(2s,3r,4s)-3-(acetamido)-4-(acetoxy)-2-(1-ethylpropoxy)-3,4-dihydro-2h-pyran-6-carboxylic acid (iii)
methyl (2r,3r,4s)-3-(acetamido)-4-(acetoxy)-2-(1-ethylpropoxy)-3,4-dihydro-2h-pyran-6-carboxylate (iv)
methyl (3ar,4r,7ar)-4-(1-ethylpropoxy)-2-methyl-3a,7a-dihydro-4h-pyrano[3,4-d][1,3]oxazole-6-carboxylate (vi)
methyl (2r,3r,4s)-3-(acetamido)-4-azido-2-(1-ethylpropoxy)-3,4-dihydro-2h-pyran-6-carboxylate (vii)
methyl (2r,3r,4s)-3-(acetamido)-4-amino-2-(1-ethylpropoxy)-3,4-dihydro-2h-pyran-6-carboxylate (viii)
(3-amino-1-benzofuran-2-yl)(4-methoxyphenyl)methanone
Reference 1:
    colin, m.; guenard, d.; gueritte-voegelein, f.; potier, p. (aventis sa); process for the preparation of taxol and 10-deacetyltaxol. us 4857653 .

Route 2
a new partial synthesis for taxol has been reported:the cyclization of n-(4-methoxyphenyl)benzylideneimine (i) with acetoxyacetyl chloride (ii) by means of triethylamine in dichloromethane gives cis-3-acetoxy-1-(4-methoxyphenyl)-4-phenylazetidin-2-one (iii), which is treated with ceric ammonium nitrate in acetonitrile to afford cis-3-acetoxy-4-phenylazetidin-2-one (iv). hydrolysis of (iv) with koh in thf-water yields cis-3-hydroxy-4-phenylazetidin-2-one (v), which is submitted to optical resolution giving the (3r,4s)-isomer (vi). the reaction of (vi) with ethyl vinyl ether (vii) by means of methanesulfonic acid in thf affords (3r,4s)-3-(1-ethoxyethoxy)-4-phenylazetidin-2-one (viii), which is benzoylated with benzoyl chloride (ix) and butyllithium in hexane to give (x). opening of the azetidine ring of (x) with koh in thf-water gives (2r,3s)-3-(benzamido)-2-(1-ethoxyethoxy)propanoic acid (xi), which is cyclized with potassium tert-butoxide and methanesulfonyl chloride to (4s,5r)-5-(1-ethoxyethoxy)-2,4-diphenyl-5,6-dihydro-4h-1,3-oxazin-6-one (xii). finally, this compound is condensed with 7-o-(triethylsilyl)baccatin iii (xiv) [prepared from 10-deacetylbaccatin iii (xiii) by successive reaction with triethylsilyl chloride and acetyl chloride] by means of dimethylaminopyridine (dmap) in pyridine.
List of intermediates No.
benzhydryl (2r,3r,4s)-3-(acetamido)-4-[(tert-butoxycarbonyl)amino]-2-formyl-3,4-dihydro-2h-pyran-6-carboxylate (i)
trimethyl[(2e)-2,4-pentadienyl]stannane (ii)
benzhydryl (2r,3r,4s)-3-(acetamido)-4-[(tert-butoxycarbonyl)amino]-2-[(1r)-1-hydroxy-2-vinyl-3-butenyl]-3,4-dihydro-2h-pyran-6-carboxylate (iii)
benzhydryl (2r,3r,4s)-3-(acetamido)-4-[(tert-butoxycarbonyl)amino]-2-[(1r,3e)-1-hydroxy-3,5-hexadienyl]-3,4-dihydro-2h-pyran-6-carboxylate (iv)
benzhydryl (2r,3r,4s)-3-(acetamido)-4-[(tert-butoxycarbonyl)amino]-2-[(1r)-2-ethyl-1-hydroxybutyl]-3,4-dihydro-2h-pyran-6-carboxylate (vi)
2-methoxyphenacyl bromide; 2-bromo-1-(4-methoxyphenyl)-1-ethanone (viii)
(3-amino-1-benzofuran-2-yl)(4-methoxyphenyl)methanone (ix)
2,2,2-trifluoro-n-[2-(4-methoxybenzoyl)-1-benzofuran-3-yl]acetamide (x)
2-(chloromethyl)-4-methoxyphenyl methyl ether; 2-(chloromethyl)-1,4-dimethoxybenzene (xi)
[3-[(2,5-dimethoxybenzyl)amino]-1-benzofuran-2-yl](4-methoxyphenyl)methanone (xii)
ethyl 3-[(2,5-dimethoxybenzyl)[2-(4-methoxybenzoyl)-1-benzofuran-3-yl]amino]-3-oxopropanoate (xiii)
ethyl 1-(2,5-dimethoxybenzyl)-4-(4-methoxyphenyl)-2-oxo-1,2-dihydro[1]benzofuro[3,2-b]pyridine-3-carboxylate (xiv)
1-[(2r,4s,5r)-4-(benzyloxy)-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-iodo-2,4(1h,3h)-pyrimidinedione (vii)
Reference 1:
    holton, r.a. (university of florida); method for preparation of taxol using an oxazinone. us 5015744 .

Route 3
two new syntheses of taxol have been described:1) the oxidative cleavage of 10-deacetyltaxol-7-xyloside (i) with sodium periodate in methanol - chloroform gives 10-deacetyltaxol (ii), which is then acetylated with acetic anhydride and pyridine.2) by deacetylation of 2-acetyltaxol (iii) by means of dimethylamine in aqueous methanol.
List of intermediates No.
5-nitro-2,3-dihydro-1,4-benzodioxine (i)
2,3-dihydro-1,4-benzodioxin-5-amine; 2,3-dihydro-1,4-benzodioxin-5-ylamine; 5-amino-1,4-benzodioxane (ii)
benzhydryl (6r,7r)-7-amino-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (iii)
Reference 1:
    rao, k.v. (university of florida); process for the preparation of taxol and 10-deacetyltaxol. us 5200534 .

Route 4
the synthesis of tritium-labeled taxol [3-3h]-taxol has been described:the reaction of baccatin iii (i) with chlorotriethylsilane in pyridine gives the protected compound (ii), which is condensed with cis-1-benzoyl-4-(3-bromophenyl)-3-(triethylsilyloxy)azetidin-2-one (iii) by means of butyllithium in thf, yielding 3-bromo-2,7-bis-o-(triethylsilyl)taxol (iv). the deprotection of (iv) with pyridine and 48% hf in thf affords 3-bromotaxol (v), which is finally debrominated with tritium by means of pd/c and triethylamine in thf.the starting azetidinone (iii) is obtained as follows: the condensation of 3-bromobenzaldehyde (vi) with 4-methoxyaniline (vii) in refluxing benzene gives the enamine (viii), which is cyclized with acetoxyacetyl chloride (ix) by means of triethylamine in dichloromethane, yielding cis-3-acetoxy-4-(3-bromophenyl)-1-(4-methoxyphenyl)azetidin-2-one (x). the reaction of (x) with ceric ammonium nitrate (can) in acetonitrile affords cis-3-acetoxy-4-(3-bromophenyl)azetidin-2-one (xi), which is deacetylated with koh in thf-water giving cis-4-(3-bromophenyl)-3-hydroxyazetidin-2-one (xii). the silylation of (xii) with chlorotriethylsilane in pyridine yields cis-4-(3-bromophenyl)-3-(triethylsilyloxy)azetidin-2-one (xiii), which is finally benzoylated with benzoyl chloride (xiv) and butyllithium in thf to afford the desired azetidinone (iii).
List of intermediates No.
(2r,3r,4r,5r,6r)-3-(acetamido)-5-(acetoxy)-2-(1-ethylpropoxy)-6-(hydroxymethyl)tetrahydro-2h-pyran-4-yl acetate (i)
trimethyl[(2e)-2,4-pentadienyl]stannane (ix)
(3-amino-1-benzofuran-2-yl)(4-methoxyphenyl)methanone (xiv)
benzhydryl (6r,7r)-7-[[4-bromo-2-(hydroxyimino)-3-oxobutanoyl]amino]-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (ii)
benzhydryl (6r,7r)-7-[[2-(2-amino-1,3-thiazol-4-yl)-2-(hydroxyimino)acetyl]amino]-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (iii)
5-amino-2,4,6-triiodoisophthalic acid (iv)
5-cyano-2,4,6-triiodoisophthalic acid (v)
5-(aminocarbonyl)-2,4,6-triiodoisophthalic acid (vi)
2,4,6-triiodo-1,3,5-benzenetricarboxylic acid (vii)
2,4,6-triiodo-1,3,5-benzenetricarbonyl trichloride (viii)
6-amino-2,2-dimethyl-1,3-dioxepan-5-ol (x)
1-hydroxy-n-(6-hydroxy-2,2-dimethyl-1,3-dioxepan-5-yl)-2,2,5,5-tetramethyl-3-pyrrolidinecarboxamide (xi)
1-chloro-1-[(chlorocarbonyl)oxy]ethane (xii)
potassium (7r)-7-[[2-(2-amino-1,3-thiazol-4-yl)acetyl]amino]-3-[([1-[2-(dimethylamino)ethyl]-1h-1,2,3,4-tetraazol-5-yl]sulfanyl)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (xiii)
Reference 1:
    taylor, g.f.; thornton, s.s.; tallent, c.r.; kepler, j.a.; synthesis of [3-3h]taxol and [13-3h]taxol. j label compd radiopharm 1993, 33, 6, 501.

Route 5
the synthesis of tritium-labeled taxol [13-3h]-taxol (b) has been described:the oxidation of baccatin iii (i) with mno2 in chloroform gives 13-oxobaccatin iii (xv), which is silylated with chlorotriethylsilane in pyridine yielding 13-oxo-7-o-(triethylsilyl)baccatin iii (xvi). the reduction of (xvi) with tritiated borane (prepared from tritiated sodium borohydride and bf3) in thf affords [13-3h]-7-o-(triethylsilyl)baccatin iii (xvii), which is condensed with (3s-cis)-1-benzoyl-4-phenyl-3-(trimethylsilyloxy)azetidin-2-one (xviii) by means of butyllithium in thf to give [13-3h]-2,7-bis-o-(triethylsilyl)taxol (xix). finally, this compound is deprotected with 48% hf and pyridine in thf.
List of intermediates No.
(2r,3r,4r,5r,6r)-3-(acetamido)-5-(acetoxy)-2-(1-ethylpropoxy)-6-(hydroxymethyl)tetrahydro-2h-pyran-4-yl acetate (i)
sodium 4-(methylamino)-4-piperidinecarboxylate (xv)
1-[(benzyloxy)carbonyl]-4-(methylamino)-4-piperidinecarboxylic acid (xvi)
benzyl 1-methyl-2,4-dioxo-3-oxa-1,8-diazaspiro[4.5]decane-8-carboxylate (xvii)
benzyl 4-[(2,6-dimethylanilino)carbonyl]-4-(methylamino)-1-piperidinecarboxylate (xviii)
benzyl 4-(dimethylamino)-4-[(2,6-dimethylanilino)carbonyl]-1-piperidinecarboxylate (xix)
4-(benzyloxy)-3-hydroxybenzonitrile (xvii)
ethyl 2-[2-(benzyloxy)-5-cyanophenoxy]-6-chloroisonicotinate (xix)
Reference 1:
    taylor, g.f.; thornton, s.s.; tallent, c.r.; kepler, j.a.; synthesis of [3-3h]taxol and [13-3h]taxol. j label compd radiopharm 1993, 33, 6, 501.

Route 6
a new partial synthesis of taxol has been described: the esterification of (1s,2r)-2-phenylcyclohexanol (i) with benzyloxyacetyl chloride (ii) gives the corresponding chiral ester (iii), which is deprotected by hydrogenolysis to the hydroxy ester (iv). silylation of (iv) with triisopropylsilyl chloride affords the silylated ester (v), which is cyclized with trimethylsilylbenzaldimine (vi) [obtained from benzaldehyde (vii) and hexamethyldisilazane (hmsa)] by means of butyllithium in thf giving (3r,4s)-3-(triisopropylsilyloxy)-4-phenylazetidin-2-one (viii). the deprotection of (viii) with tetrabutylammonium fluoride affords (3r,4s)-3-hydroxy-4-phenylazetidin-2-one (ix), which is treated with ethyl vinyl ether to give the 1-ethoxyethyl ether (x). the benzoylation of (x) with benzoyl chloride (xi) by means of dimethylaminopyridine and triethylamine yields (3r,4s)-1-benzoyl-3-(1-ethoxyethoxy)-4-phenylazetidin-2-one (xii), which is condensed with 7-o-(triethylsilyl)baccatin iii (xiii) by means of nah in thf, affording 2-o-(1-ethoxyethyl)-7-o-(triethylsilyl)taxol (xiv). finally, this compound is deprotected with hcl in ethanol.
List of intermediates No.
benzhydryl (2r,3r,4s)-3-(acetamido)-4-[(tert-butoxycarbonyl)amino]-2-[(1r)-2-ethyl-1-hydroxybutyl]-3,4-dihydro-2h-pyran-6-carboxylate (ix)
2-methoxyphenacyl bromide; 2-bromo-1-(4-methoxyphenyl)-1-ethanone (x)
(3-amino-1-benzofuran-2-yl)(4-methoxyphenyl)methanone (xi)
2,2,2-trifluoro-n-[2-(4-methoxybenzoyl)-1-benzofuran-3-yl]acetamide (xii)
benzhydryl (6r,7r)-7-[[4-bromo-2-(hydroxyimino)-3-oxobutanoyl]amino]-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (xiii)
4-(dimethylamino)-n-(2,6-dimethylphenyl)-4-piperidinecarboxamide (i)
diethyl 2-(3-oxopropyl)malonate (ii)
diethyl 2-[[5-amino-4-(2-chlorobenzoyl)-2-thienyl]methyl]malonate (iii)
methyl 3-[5-amino-4-(2-chlorobenzoyl)-2-thienyl]propanoate (iv)
methyl 3-[5-[(2-bromoacetyl)amino]-4-(2-chlorobenzoyl)-2-thienyl]propanoate (v)
methyl 3-[5-(2-chlorophenyl)-2-oxo-2,3-dihydro-1h-thieno[2,3-e][1,4]diazepin-7-yl]propanoate (vii)
methyl 3-[5-(2-chlorophenyl)-2-thioxo-2,3-dihydro-1h-thieno[2,3-e][1,4]diazepin-7-yl]propanoate (viii)
3,4-dimethoxyphenol (xiv)
4,5-dimethoxy-2-(2-methoxy-5-methyl-4-nitrophenoxy)benzaldehyde (vi)
Reference 1:
    habus, i.; zhao, m.; brigaud, t.; zucco, m.; ojima, i.; sun, c.m.; park, y.h.; new and efficient approaches to the semisynthesis of taxol and its c-13 side chain analogs by means of beta-lactam synthon method. tetrahedron 1992, 48, 34, 6985.

Route 7
a new synthesis of paclitaxel starting from baccatin iii has been described: the cyclocondensation of the oppolzers chiral auxiliary esterified with silylated glycolic acid (i) with benzaldehyde trimethylsilylimine (ii) by means of lithium diisopropylamide (lda) in thf gives (3r,4s)-3-(tert-butyldimethylsilyloxy)-4-phenylazetidin-2-one (iii), which is benzoylated with benzoyl chloride and triethylamine/dimethylaminopyridine (dmap) in dichloromethane, yielding (3r,4s)-1-benzoyl-3-(tert-butyldimethylsilyloxy)-4-phenylazetidin-2-one (iv). the condensation of (iv) with 7-o-(triethylsilyl)baccatin iii (v) by means of nah in thf affords silylated paclitaxel (vi), which is finally deprotected with hf in pyridine.
List of intermediates No.
benzhydryl (6r,7r)-7-[[4-bromo-2-(hydroxyimino)-3-oxobutanoyl]amino]-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (v)
2-(3,4-dimethoxyphenoxy)-4-methyl-5-nitrophenyl methyl ether; 1-(3,4-dimethoxyphenoxy)-2-methoxy-5-methyl-4-nitrobenzene (i)
4,5-dimethoxy-2-(2-methoxy-5-methyl-4-nitrophenoxy)benzaldehyde (ii)
6,7-dimethoxy-2-methyl-3,4-dihydroisoquinolinium iodide (iii)
2-(5-[[(1s)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro-1-isoquinolinyl]methyl]-2-methoxy-4-nitrophenoxy)-4,5-dimethoxybenzaldehyde (iv)
2-[[(1s)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro-1-isoquinolinyl]methyl]-4-[2-(1,3-dioxolan-2-yl)-4,5-dimethoxyphenoxy]-5-methoxyphenylamine; 2-[[(1s)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro-1-isoquinolinyl]methyl]-4-[2-(1,3-dioxolan-2-yl)-4,5-dimethoxyphenoxy]-5-methoxyaniline (vi)
Reference 1:
    hepperle, m.; park, h.; georg, g.i.; cheruvallath, z.s.; harriman, g.c.b.; an efficient semisynthesis of taxol from (3r,4s)-n-benzoyl-3-[(t-butyldimethylsilyl)oxy]-4-phenyl-2-azetidinone and 7-(triethylsilyl)baccatin iii. bioorg med chem lett 1993, 3, 11, 2467.

Route 8
a total synthesis of paclitaxel has been reported: 1) the starting material is the previously known bicyclic diol ester (i), which is silylated with tert-butyldimethylsilyl trifluoromethylsulfonyl (tbstf) and reduced with lialh4 in ether at 0 c to give the hydroxy lactone (ii). the reaction of (ii) with camphorsulfonic acid (csa) and then with tert-butyldiphenylsilyl chloride (tpscl) followed by a treatment with benzyl bromide and kh in ether yields the fully protected lactone (iii), which is reductively opened with lialh4 in ether at 25 c (a simultaneous partial desilylation takes place), affording the triol (iv). the reaction of (iv) with 2,2-dimethoxypropane and csa gives the acetonide (v), which is oxidized with tetrapropylammonium perruthenate (tpap) to the aldehyde (vi). the condensation of (vi) with the previously known sulfonyl hydrazone (vii) by means of buli in thf gives the methanol derivative (viii), which is epoxidized with vo(acac)2 and tert-butyl hydroperoxide in benzene, yielding the epoxide (ix). opening of the epoxide (ix) with lialh4 in ether affords the 1,2-diol (x), which is treated with phosgene and kh to give the cyclic carbonate (xi). the desilylation of (xi) with tetrabutylammonium fluoride (tbaf) followed by oxidation with tpap in acetonitrile/dichloromethane yields the dialdehyde (xii), which is cyclized by means of ticl3 and zn-cu, affording the racemic vicinal diol (xiii); the suitable active enantiomer is obtained by optical resolution with 1(s)-(-)-camphanic acid chloride. selective acetylation of (xiii) with acetic anhydride and dimethylaminopyridine (dmap) followed by oxidation with tpap and n-methylmorpholine n-oxide (nmo) gives the acetoxy ketone (xiv). the hydroboration of (xiv) with bh3 followed by oxidation with h2o2 and hydrolysis of the acetonide group with hcl yields the trihydroxy compound (xv).
List of intermediates No.
7-hydroxy-6-methoxy-2-methyl-3,4-dihydroisoquinolinium iodide (i)
(1s)-1-[5-(3,4-dimethoxyphenoxy)-4-methoxy-2-nitrobenzyl]-6-methoxy-2-methyl-1,2,3,4-tetrahydro-7-isoquinolinol (ii)
(1s)-1-[2-amino-5-(3,4-dimethoxyphenoxy)-4-methoxybenzyl]-6-methoxy-2-methyl-1,2,3,4-tetrahydro-7-isoquinolinol (iii)
(6as)-9-(3,4-dimethoxyphenoxy)-2,10-dimethoxy-6-methyl-5,6,6a,7-tetrahydro-4h-dibenzo[de,g]quinolin-1-ol (iv)
(6as)-9-(3,4-dimethoxyphenoxy)-1,10-dimethoxy-6-methyl-5,6,6a,7-tetrahydro-4h-dibenzo[de,g]quinolin-2-yl methyl ether; (6as)-9-(3,4-dimethoxyphenoxy)-1,2,10-trimethoxy-6-methyl-5,6,6a,7-tetrahydro-4h-dibenzo[de,g]quinoline (v)
2-[[(6as)-1,2,10-trimethoxy-6-methyl-5,6,6a,7-tetrahydro-4h-dibenzo[de,g]quinolin-9-yl]oxy]-4,5-dimethoxybenzaldehyde (vi)
2-benzoyl-6,7-dimethoxy-1,2-dihydro-1-isoquinolinecarbonitrile (vii)
(6as)-9-[2-[(6,7-dimethoxy-1-isoquinolinyl)methyl]-4,5-dimethoxyphenoxy]-1,10-dimethoxy-6-methyl-5,6,6a,7-tetrahydro-4h-dibenzo[de,g]quinolin-2-yl methyl ether (viii)
(6as)-9-(2-[[(1s)-6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinyl]methyl]-4,5-dimethoxyphenoxy)-1,10-dimethoxy-6-methyl-5,6,6a,7-tetrahydro-4h-dibenzo[de,g]quinolin-2-yl methyl ether (ix)
p-methylpropiophenone; 4-methylpropiophenone; 1-(4-methylphenyl)-1-propanone (x)
1-(4-methyl-3-nitrophenyl)-1-propanone (xi)
1-(3-amino-4-methylphenyl)-1-propanone (xii)
1-(3-hydroxy-4-methylphenyl)-1-propanone (xiii)
1-[3-(benzyloxy)-4-methylphenyl]-1-propanone (xiv)
1-[3-(benzyloxy)-4-methylphenyl]-2-bromo-1-propanone (xv)
Reference 1:
    yang, z.; liu, j.j.; nicolaou, k.c.; et al.; total synthesis of taxol. nature 1994, 367, 6464, 630.

Route 9
compound (xv) is selectively acetylated with acetic anhydride and dmap to the diol (xvi). the replacement of the benzyl protecting group by a triethylsilyl (tes) group in (xvi) by debenzylation with h2 over pd(oh)2/c followed by treatment with tescl in pyridine and deacetylation with k2co3 in methanol affords the silylated triol (xvii). the formation of the oxetane ring is carried out by treatment of (xvii) with trimethylsilyl chloride (tmscl) and pyridine (silylation of the primary alcohol), subsequent reaction with tf2o (activation of the secondary alcohol), and cyclization by acidic treatment with csa to give compound (xviii) with the oxetane ring and a tertiary oh group. the acetylation of (xviii) with acetic anhydride and dmap affords compound (xix) with the tertiary acetoxy group. the reaction of (xix) with phenyllithium gives the benzoyloxy derivative (xx), which is oxidized with pyridinium chlorochromate (pcc) to yield the diketone (xxi). the reduction of (xxi) with nabh4 in methanol affords compound (xxii) with the appropriate secondary hydroxy group, which is acylated with ojimas beta-lactam (xxiii) by means of sodium bis(trimethylsilyl)amide to give the silylated paclitaxel (xxiv). finally, this compound is deprotected with hf/pyridine.
List of intermediates No.
benzhydryl (6r,7r)-7-[[4-bromo-2-(hydroxyimino)-3-oxobutanoyl]amino]-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (xxii)
1-[(benzyloxy)carbonyl]-4-(methylamino)-4-piperidinecarboxylic acid (xxi)
benzyl 4-[(2,6-dimethylanilino)carbonyl]-4-(methylamino)-1-piperidinecarboxylate (xxiii)
1-[3-(benzyloxy)-4-methylphenyl]-2-bromo-1-propanone (xv)
1-[3-(benzyloxy)-4-methylphenyl]-2-[benzyl(3-phenylpropyl)amino]-1-propanone (xvi)
3,5-dichloro-4-[1,2-diamino-2-(2,6-dichloro-4-hydroxyphenyl)ethyl]phenol (xvii)
2-[1,2-diamino-2-(2-hydroxyphenyl)ethyl]phenol (xviii)
2,6-dichloro-4-methoxybenzaldehyde (xix)
2-[[(1,2-bis(2,6-dichloro-4-methoxyphenyl)-2-[[(e)-(2-hydroxyphenyl)methylidene]amino]ethyl)imino]methyl]phenol (xx)
1-(4-ethylphenyl)-1-propanone (xxiv)
Reference 1:
    yang, z.; liu, j.j.; nicolaou, k.c.; et al.; total synthesis of taxol. nature 1994, 367, 6464, 630.

Route 10
1) the selective protection of 10-deacetylbaccatin iii (i) with triethylsilyl chloride (tescl) gives the monosilylated compound (ii), which is acetylated with acetic anhydride and pyridine to yield baccatin iii (iii). the condensation of (iii) with (2r,3s)-3-benzamido-2-(1-ethoxyethoxy)-3-phenylpropionic acid (iv) by means of di-2-pyridyl carbonate (dpc) and dimethylaminopyridine (dmap) affords protected paclitaxel (v), which is finally deprotected with hcl in ethanol/water. (denis, j.-n. and greene, a.e. j amer chem soc 1988, 110: 5917).
List of intermediates No.
2-(chloromethyl)-4-methoxyphenyl methyl ether; 2-(chloromethyl)-1,4-dimethoxybenzene (iv)
ethyl 3-[(2,5-dimethoxybenzyl)[2-(4-methoxybenzoyl)-1-benzofuran-3-yl]amino]-3-oxopropanoate (i)
benzhydryl (6r,7r)-7-[[4-bromo-2-(hydroxyimino)-3-oxobutanoyl]amino]-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (iii)
6,7-dimethoxy-3-methyl-1-(4-nitrophenyl)-3,4-dihydro-1h-isochromene; 6-methoxy-3-methyl-1-(4-nitrophenyl)-3,4-dihydro-1h-isochromen-7-yl methyl ether (ii)
methyl (5r)-5-methyl-4-oxotetrahydro-3-thiophenecarboxylate (v)
Reference 1:
    guy, r.k.; nicolaou, k.c.; dai, w.m.; chemistry and biology of taxol. angew chem. int ed engl 1994, 33, 1, 15.

Route 11
2) the condensation of (3r,4s)-1-benzoyl-3-(1-ethoxyethyl)-4-phenyloxazolidin-2-one (i) with monosilylated baccatin iii (ii) by means of dmap in pyridine (or nah) gives the protected paclitaxel precursor (iii), which is easily deprotected by treatment with hcl in ethanol/water. (holton, r.a. ep 400971).
List of intermediates No.
2,2,2-trifluoro-n-[2-(4-methoxybenzoyl)-1-benzofuran-3-yl]acetamide (i)
benzhydryl (6r,7r)-7-[[4-bromo-2-(hydroxyimino)-3-oxobutanoyl]amino]-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (ii)
methyl (5r)-5-methyl-4-oxotetrahydro-3-thiophenecarboxylate (iii)
Reference 1:
    guy, r.k.; nicolaou, k.c.; dai, w.m.; chemistry and biology of taxol. angew chem. int ed engl 1994, 33, 1, 15.

Route 12
3) the condensation of (4s,5r)-3-(bromoacetyl)-4-methyl-5-phenyloxazolidin-2-one (i) with benzaldehyde (ii) by means of dibutylboron triflate gives intermediate (iii), which by treatment with lithium ethoxide yields (r,r)-3-phenyloxirane-2-carboxylic acid ethyl ester (iv). the reaction of (iv) with sodium azide in ethanol affords the hydroxy ester (v), which is hydrogenated with h2 over pd/c in ethyl acetate, giving the amino ester (vi). the protection of (vi) with tert-butoxycarbonyl anhydride affords the protected amino ester (vii), which is treated with 2-methoxypropene and pyridinium p-toluenesulfonate to give the oxazolidine (viii). the hydrolysis of (viii) with lioh in ethanol/water yields (4s,5r)-3-(tert-butoxycarbonyl)-2,2-dimethyl-4-phenyloxazolidine-5-carboxylic acid (ix), which is condensed with the protected baccatin iii (x) by means of dicyclohexylcarbodiimide (dcc) and dmap to afford the oxazolidine ester (xi). the treatment of (xi) with formic acid gives the amino ester (xii), which is benzoylated with benzoyl chloride and nahco3 to the protected paclitaxel (xiii). finally, this compound is deprotected by treatment with zn/acetic acid. (commercon, a. et al. tetrahedron lett 1992, 33(36): 5185).
List of intermediates No.
(2r,3r,4r,5r,6s)-3-(acetamido)-5-(acetoxy)-2-(1-ethylpropoxy)-6-formyltetrahydro-2h-pyran-4-yl acetate (x)
methyl 3-[5-(2-chlorophenyl)-2-oxo-2,3-dihydro-1h-thieno[2,3-e][1,4]diazepin-7-yl]propanoate (ii)
2-[4-(3,4-dichlorophenyl)-1-piperazinyl]ethyl 3-oxobutanoate (i)
2,4-dichloro-5-fluorobenzoyl chloride (iii)
diethyl 2-(2,4-dichloro-5-fluorobenzoyl)malonate (iv)
ethyl 3-(2,4-dichloro-5-fluorophenyl)-3-oxopropanoate (v)
ethyl (z)-2-(2,4-dichloro-5-fluorobenzoyl)-3-ethoxy-2-propenoate (vi)
ethyl (e)-3-(cyclopropylamino)-2-(2,4-dichloro-5-fluorobenzoyl)-2-propenoate (vii)
7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (viii)
1-cyclopropyl-6-fluoro-4-oxo-7-(1-piperazinyl)-1,4-dihydro-3-quinolinecarboxylic acid (ix)
methyl (e)-3-(cyclopropylamino)-2-(2,4-dichloro-5-fluorobenzoyl)-2-propenoate (xi)
2-[5-(1-cyanoethyl)-2-(phenylsulfanyl)phenyl]acetic acid (xii)
2-(10-oxo-10,11-dihydrodibenzo[b,f]thiepin-2-yl)propanenitrile (xiii)
Reference 1:
    guy, r.k.; nicolaou, k.c.; dai, w.m.; chemistry and biology of taxol. angew chem. int ed engl 1994, 33, 1, 15.

Route 13
the first part of a total synthesis of paclitaxel has been published: the silylation of tricyclic diol (i) (readily available from camphor) with triethylsilyl chloride (tescl) gives compound (ii), which is submitted to epoxy alcohol fragmentation followed by silylation to yield the silylated cyclic ketone (iii). the magnesium enolate of (iii) is submitted to an aldol condensation with 4-pentenal (iv) to afford the ketol (v), which is protected with cocl2 and etoh, giving the carbonate ester (vi). the hydroxylation of (vi) with lithium diisopropylamide (lda) and (+)-camphorsulfonyl oxaziridine (vii) yields the alpha-hydroxy ketone (viii), which is reduced with red-al in toluene, affording the alpha-diol (ix). the reaction of (ix) with cocl2 in pyridine gives the cyclic carbonate (x), which is oxidized with the swern oxidant to the ketone (xi). the rearrangement of (xi) with lithium 2,2,6,6-tetramethylpiperidide (ltmp) yields the hydroxy lactone (xii), which is reduced with samarium diiodide to the stable enol (xiii), which by treatment with silica gel gives a mixture of cis- and trans-oxolactones (cis-xiv + trans-xiv) that can be separated by crystallization. (trans-xiv) does not react with ltmp, but can be reverted to (xiii) with t-buok in order to increase the yield in (cis-xiv). on the other hand, the reaction of (cis-xiv) with ltmp and (+)-camphorsulfonyl oxaziridine (vii) affords a mixture of cis- and trans-hydroxy-oxolactones (cis-xv + trans-xv) that can be separated by chromatography. the reduction of (cis-xv) with red-al followed by a basic workup gives the alpha-diol with trans-configuration in the lactone ring (xvi), and the reduction of (trans-xv) with samarium diiodide affords the same alpha-diol isomer (xvi). this alpha-diol (xvi) is protected with cocl2 in pyridine to give the cyclic carbonate (xvii). (for the second part, see holton, r.a. et al. j amer chem soc 1994, 116(4): 1599).
List of intermediates No.
ethyl 8-nitro-4-oxo-4h-chromene-2-carboxylate (i)
8-nitro-4-oxo-4h-chromene-2-carboxamide (ii)
8-nitro-4-oxo-4h-chromene-2-carbonitrile (iii)
8-nitro-2-(1h-1,2,3,4-tetraazol-5-yl)-4h-chromen-4-one (iv)
8-amino-2-(1h-1,2,3,4-tetraazol-5-yl)-4h-chromen-4-one (v)
4-(4-phenylbutoxy)benzoic acid (vi)
1-(3-chlorophenyl)piperazine (vii)
2-[4-(3-chlorophenyl)-1-piperazinyl]-1-ethanol (viii)
2-(4-isobutylphenyl)propanoyl chloride (ix)
2-chloroethyl 2-(4-isobutylphenyl)propanoate (x)
2,3,4-trimethoxybenzaldehyde (xi)
6-chloro-2h-1,4-benzoxazine-2,3(4h)-dione (xii)
3,6-dichloro-2h-1,4-benzoxazin-2-one (xiii)
2-ethoxy-1-ethanol (trans-xiv)
n,n-diethyl-n-[(9s)-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinolin-9-yl]urea (cis-xiv)
3-(4-methylphenyl)thiophene (trans-xv)
3-[4-(bromomethyl)phenyl]thiophene (cis-xv)
2-[4-(3-thienyl)phenyl]acetonitrile (xvi)
2-[4-(3-thienyl)phenyl]propanenitrile (xvii)
Reference 1:
    kim, h.-b.; somoza, c.; holton, r.a.; et al.; first total synthesis of taxol. 1. functionalization of the b ring. j am chem soc 1994, 116, 4, 1597.

Route 14
the ozonolysis of the terminal double bond of cyclic carbonate (xvii) with o3 in methanol/naoh followed by oxidation of the resulting aldehyde with kmno4 and methylation with diazomethane gives the ester (xviii), which is submitted to a dieckman cyclization by means of lithium diisopropylamide (lda) in thf, yielding the tetracyclic ester (xix). the protection of the free hydroxy group of (xix) with 2-methoxypropene and p-toluenesulfonic acid affords the enol ester (xx), which is decarboxylated with potassium phenylthiolate in hot dmf, affording the tetracyclic ketone (xxi). selective deprotection of (xxi) in acidic medium gives the hydroxy ketone (xxii), which is protected again with a stronger protecting group, benzyloxymethyl chloride (bomcl) ethyl(diisopropyl)amine, giving the ketone (xxiii). enolization of (xxiii) with trimethylsilyl chloride (tmscl) and lda yields the enol-silyl ether (xxiv), which is oxidized with m-chloroperbenzoic acid (mcpba) in hexane to the alpha-silyloxy ketone (xxv). the grignard reaction of (xxv) with methylmagnesium bromide affords the tertiary alcohol (xxvi), which is dehydrated with the burgess reagent to the methylene compound (xxvii). this compound is either mesylated with mesyl chloride and osmylated with oso4 to the monomesylated triol (xxviii), or osmylated with oso4 followed by silylation with tmscl, tosylated with p-toluenesulfonyl chloride and desilylated to give the monotosylated triol (xxix). both compounds (xxviii) and (xxix) are cyclized by means of 1,8 diazabicyclo[5.4.0]undec-7-ene (dbu) in hot toluene to the hydroxyoxetane (xxx), which is acetylated with acetic anhydride in dimethylaminopyridine (dmap) to the acetoxyoxetane (xxxi). selective desilylation of (xxxi) with hf in pyridine yields the secondary alcohol (xxxii).
List of intermediates No.
2-[4-(3-thienyl)phenyl]propionic acid (xviii)
10-(1-azabicyclo[2.2.2]oct-3-ylmethyl)-10h-phenothiazine (xix)
2-[[2-[bis(carboxymethyl)amino]-1-methylethyl](carboxymethyl)amino]acetic acid (xx)
4-[2-(3,5-dioxo-1-piperazinyl)propyl]-2,6-piperazinedione (xxi)
1-(4-fluorophenyl)hydrazine (xxii)
ethyl 8-fluoro-1,3,4,5-tetrahydro-2h-pyrido[4,3-b]indole-2-carboxylate (xxiii)
3-(3-bromopropyl)pyridine (xxiv)
2-amino-5-(4-chlorophenyl)-6-ethyl-4-pyrimidinylamine; 5-(4-chlorophenyl)-6-ethyl-2,4-pyrimidinediamine (xxv)
5-(4-chloro-3-nitrophenyl)-6-ethyl-2,4-pyrimidinediamine; 2-amino-5-(4-chloro-3-nitrophenyl)-6-ethyl-4-pyrimidinylamine (xxvi)
2-amino-5-(3-amino-4-chlorophenyl)-6-ethyl-4-pyrimidinylamine; 5-(3-amino-4-chlorophenyl)-6-ethyl-2,4-pyrimidinediamine (xxvii)
2-amino-5-(3-azido-4-chlorophenyl)-6-ethyl-4-pyrimidinylamine; 5-(3-azido-4-chlorophenyl)-6-ethyl-2,4-pyrimidinediamine (xxviii)
ethyl 4-(methylamino)-1-piperidinecarboxylate (xxix)
1-isothiocyanatobenzene; phenyl isothiocyanate (xxx)
ethyl 4-[(anilinocarbothioyl)(methyl)amino]-1-piperidinecarboxylate (xxxi)
Reference 1:
    kim, h.-b.; holton, r.a.; somoza, c.; et al.; first total synthesis of taxol. 2. completion of the c and d rings. j am chem soc 1994, 116, 4, 1599.

Route 15
the secondary alcohol (xxxii) is treated with phenyllithium in thf (to open the cyclic carbonate and form the benzoyloxy group) and oxidized with tetrapropylammonium perruthenate (tpap) to give the benzoyloxyketone (xxxiii). enolization of ketone (xxxiii) with potassium tert-butoxide affords the potassium enolate (xxxiv), which is oxidized with phenylseleninic anhydride and acetylated with acetic anhydride in dmap to give the alpha-acetoxyketone (xxxv). further desilylation of (xxxv) with tris(diethylamino)sulfoxonium difluorotrimethylsiliconate (tasf) in thf yields the secondary alcohol (xxxvi), which is condensed with ojimas beta-lactam (xxxvii) by means of lithium hexamethyldisilazane (lhmds) in thf to afford protected paclitaxel (xxxviii). finally, this compound is deprotected first with hf in pyridine to eliminate the triethylsilyl (tes) group and then hydrogenated with h2 over pd/c in ethanol to eliminate the bom group.
List of intermediates No.
benzyl 4-[(2,6-dimethylanilino)carbonyl]-4-(methylamino)-1-piperidinecarboxylate (xxxvii)
ethyl 4-[1,3-benzothiazol-2-yl(methyl)amino]-1-piperidinecarboxylate (xxxii)
2-[(4-fluorophenoxy)methyl]oxirane; 4-fluorophenyl 2-oxiranylmethyl ether (xxxiii)
4-chloro-3-pyridinesulfonamide (xxxiv)
cyclooctanamine; cyclooctylamine (xxxv)
4-(cyclooctylamino)-3-pyridinesulfonamide (xxxvi)
methyl 2-methyl-1-azulenecarboxylate (xxxviii)
Reference 1:
    kim, h.-b.; holton, r.a.; somoza, c.; et al.; first total synthesis of taxol. 2. completion of the c and d rings. j am chem soc 1994, 116, 4, 1599.

Route 16
a new synthesis of paclitaxel starting from baccatin (iii) has been described: the esterification of 7-o-(triethylsilyl)baccatin iii (i) with (4s,5r)-2,4-diphenyl-2-oxazoline-5-carboxylic acid (ii) by means of dicyclohexylcarbodiimide (dcc) and 4-(4-pyrrolidinyl)pyridine (ppyr) in dry toluene gives the intermediate ester (iii), which is then hydrolyzed with diluted hcl.
List of intermediates No.
benzhydryl (6r,7r)-7-[[4-bromo-2-(hydroxyimino)-3-oxobutanoyl]amino]-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (i)
3-benzoyl-2-methyl-1-azulenecarboxylic acid (ii)
(2-methyl-1-azulenyl)(phenyl)methanone (iii)
Reference 1:
    chaudhary, a.g.; kingston, d.g.i.; middleton, m.; gunatilaka, a.k.l.; synthesis of taxol from baccatin iii via an oxazoline intermediate. tetrahedron lett 1994, 35, 26, 4483.

Route 17
a new synthesis of paclitaxel has been reported: the cyclization of the 4-methoxyphenylimine of benzaldehyde (i) with acetoxyacetyl chloride (ii) by means of triethylamine gives cis-3-acetoxy-1-(4-methoxyphenyl)-4-phenylazetidin-2-one (iii), which is treated with ceric ammonium nitrate to afford cis-3-acetoxy-4-phenylazetidin-2-one (iv). the hydrolysis of (iv) with koh in thf/water affords the corresponding hydroxy compound (v), which is submitted to optical resolution by crystallization of the 2-methoxy-2-[2-(trifluoromethyl)phenyl]acetic esters. the (3r,4s)-regioisomer (vi) is protected with ethyl vinyl ether, giving the 1-ethoxyethyl derivative (vii), which is benzoylated with benzoyl chloride and butyllithium to afford (3r,4s)-1-benzoyl-3-(1-ethoxyethoxy)-4-phenylazetidin-2-one (viii). the condensation of (viii) with baccatin iii (ix) by means of dimethylaminopyridine (dmap) in pyridine yields the protected paclitaxel derivative (x), which is finally deprotected with hcl in ethanol/water.
List of intermediates No.
benzhydryl (2r,3r,4s)-3-(acetamido)-4-[(tert-butoxycarbonyl)amino]-2-formyl-3,4-dihydro-2h-pyran-6-carboxylate (i)
trimethyl[(2e)-2,4-pentadienyl]stannane (ii)
benzhydryl (2r,3r,4s)-3-(acetamido)-4-[(tert-butoxycarbonyl)amino]-2-[(1r)-1-hydroxy-2-vinyl-3-butenyl]-3,4-dihydro-2h-pyran-6-carboxylate (iii)
benzhydryl (2r,3r,4s)-3-(acetamido)-4-[(tert-butoxycarbonyl)amino]-2-[(1r,3e)-1-hydroxy-3,5-hexadienyl]-3,4-dihydro-2h-pyran-6-carboxylate (iv)
benzhydryl (2r,3r,4s)-3-(acetamido)-4-[(tert-butoxycarbonyl)amino]-2-[(1r)-2-ethyl-1-hydroxybutyl]-3,4-dihydro-2h-pyran-6-carboxylate (vi)
2-methoxyphenacyl bromide; 2-bromo-1-(4-methoxyphenyl)-1-ethanone (vii)
(3-amino-1-benzofuran-2-yl)(4-methoxyphenyl)methanone
2,2,2-trifluoro-n-[2-(4-methoxybenzoyl)-1-benzofuran-3-yl]acetamide (viii)
benzhydryl (6r,7r)-7-[[4-bromo-2-(hydroxyimino)-3-oxobutanoyl]amino]-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (ix)
3,4-dimethoxyphenol (x)
Reference 1:
    holton, r.a. (university of florida); method for preparation of taxol. ep 0400971; us 5336785 .

Route 18
a new synthesis of paclitaxel has been described: the condensation of oppolzers l-(+)-2,10-camphorsultam (i) with 2-(4-methoxybenzyloxy)acetyl chloride (ii) by means of nah gives the corresponding substituted sultam (iii), which is condensed with n-benzoylbenzaldehydeimine (iv) by means of lithium bis(trimethylsilyl)amide, yielding the protected side-chain (v) of paclitaxel. the reaction of (v) with ddq affords oxazolidine (vi), which is hydrolyzed with lioh/h2o2 to the free oxazolidine-carboxylic acid (vii). the esterification of (vii) with baccatin iii (viii) by means of dicyclohexylcarbodiimide (dcc) affords the protected paclitaxel derivative (ix), which is finally treated with hcl in ethanol.
List of intermediates No.
benzhydryl (6r,7r)-7-[[4-bromo-2-(hydroxyimino)-3-oxobutanoyl]amino]-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (viii)
1-[[(6-bromohexyl)oxy]methyl]benzene; benzyl 6-bromohexyl ether (i)
[6-(benzyloxy)hexyl](bromo)magnesium (ii)
3-chloro-9h-fluoren-9-one (iii)
9-[6-(benzyloxy)hexyl]-3-chloro-9h-fluoren-9-ol (iv)
6-(3-chloro-9h-fluoren-9-yl)-1-hexanol (v)
6-(3-chloro-9h-fluoren-9-yl)hexanal (vi)
6-(3-chloro-9h-fluoren-9-yl)hexanal oxime (vii)
Reference 1:
    kanazawa, a.m.; greene, a.e.; denis, j.-n.; direct, stereoselective synthesis of the protected paclitaxel (taxol) side chain and high-yield transformation to paclitaxel. j chem soc chem commun 1994, 2591.

Route 19
1) the reaction of the known ketoketal (i) with n-phenyltrifluoromethanesulfonimide and khmds in thf gives the enol triflate (ii), which is condensed with vibusn using tetrakis(triphenylphosphine)palladium(0) as catalyst in thf, yielding the diene (iii). the reaction of (iii) with 9-bbn in thf affords the alcohol (iv) and, after protection with tbdms-cl in dichloromethane, the silyl ether (v), which is oxidized with cro3 and dmp in dichloromethane to the enone (vi). the stereoselective reduction of (vi) with bh3/thf catalyzed with the chiral borane (vii) yields the alcohol (viii), which is protected with tbdms-cl as before to give (ix). selective deprotection of (ix) affords the primary alcohol (x), which is oxidized with oxalyl chloride in dmso to the aldehyde (xi). the condensation of (xi) with the vinyl iodide (xii) catalyzed by nicl2 and crcl2 gives the allyl alcohol (xiii), which is oxidized with oxalyl chloride as before to the enone (xiv). the oxidation of (xiv) with 3-phenyl-2-(phenylsulfonyl)oxaziridine and khmds yields the hydroxy ketone (xv), which is further oxidized with oxalyl chloride as before to afford the unsaturated dione (xvi). the diels-alder condensation between (xvi) and the diene (xvii) gives compound (xviii) or (xix), depending on the reaction conditions. the oxidation of the primary alcohol of (xix) with oxalyl chloride as usual yields the aldehyde (xx), which by elimination of the ketal group in acidic medium affords the tetraketonic aldehyde (xxi).
List of intermediates No.
dimethyl 2-[7-(3-chloro-9h-fluoren-9-yl)-2-hydroxyheptyl]-2-hydroxysuccinate (i)
(2r)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropionic acid (ii)
(2r)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-phenylpropionic acid (iii)
(s)-(+)-1-amino-2-propanol; (2s)-1-amino-2-propanol (iv)
tert-butyl (1r)-1-benzyl-2-[[(2s)-2-hydroxypropyl]amino]-2-oxoethyl(methyl)carbamate (v)
(2r)-n-[(2s)-2-hydroxypropyl]-2-(methylamino)-3-phenylpropanamide (vi)
(2r)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-(2-naphthyl)propionic acid (vii)
(2r)-n-((1r)-1-benzyl-2-[[(2s)-2-hydroxypropyl]amino]-2-oxoethyl)-n-methyl-2-(methylamino)-3-(2-naphthyl)propanamide (viii)
(e)-5-[(tert-butoxycarbonyl)amino]-5-methyl-2-hexenoic acid (ix)
tert-butyl (e)-5-[[(1r)-2-[((1r)-1-benzyl-2-[[(2s)-2-hydroxypropyl]amino]-2-oxoethyl)(methyl)amino]-1-(2-naphthylmethyl)-2-oxoethyl](methyl)amino]-1,1-dimethyl-5-oxo-3-pentenylcarbamate (x)
3-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid (xi)
tert-butyl 3-hydroxy-1,1-dimethylpropylcarbamate (xii)
tert-butyl 1,1-dimethyl-3-oxopropylcarbamate (xiii)
2,4-dichlorobenzaldehyde (xiv)
(e)-7-(2,4-dichlorophenyl)-6-heptenoic acid (xv)
methyl (e)-7-(2,4-dichlorophenyl)-6-heptenoate (xvi)
(e)-7-(2,4-dichlorophenyl)-6-hepten-1-ol (xvii)
7-(2,4-dichlorophenyl)-1-heptanol (xviii)
7-(2,4-dichlorophenyl)heptanal (xix)
7-(2,4-dichlorophenyl)heptanal oxime (xx)
Reference 1:
    danishefsky, s.j.; bornmann, w.g.; queneau, y.; magee, t.v.; krol, w.j. (sloan-kettering institute); total synthesis of taxol. us 5416225 .

Route 20
the intramolecular pinacolic cyclization of (xxi) by means of smi2 yields the compound (xxii) with the basic abc subskeleton of paclitaxel. selective acetylation and silylation of (xxii) with acetic anhydride/pyridine and tbdms-cl gives the trihydroxy compound (xxiii), which is oxidized with oxalyl chloride as usual to the trione (xxiv). selective reduction of (xxiv) with zn(bh4)2 yields the dihydroxydione (xxv), which is selectively benzoylated and, after benzyl protection of the remaining hydroxy groups, affords the protected dione (xxvi). selective reduction of (xxvi) with l-selectride followed by oxidation of the sulfanyl group to sulfinyl and its elimination by heating gives a methylene double bond, which is oxidized in situ with mcpba and oso4 to the vicinal triol (xxvii). the cyclization of (xxvii) according to tetrahedron lett 1991, 47: 9823 affords the hydroxy ketone (xxviii) with the basic skeleton of paclitaxel. acetylation of (xxviii) with acetic anhydride/pyridine followed by selective elimination of the tbdms group affords the secondary alcohol (xxix). the attachment of the propenoyl side-chain of paclitaxel to (xxix) according to j amer chem soc 1988, 110: 5917 gives the protected paclitaxel derivative (xxx), which is finally deprotected by hydrogenolysis with h2 over pd/c.
List of intermediates No.
dimethyl 2-[8-(2,4-dichlorophenyl)-2-oxooctyl]-2-hydroxysuccinate (xxii)
dimethyl 2-[8-(2,4-dichlorophenyl)-2-hydroxyoctyl]-2-hydroxysuccinate (xxiii)
2-[8-(2,4-dichlorophenyl)-2(r)-hydroxyoctyl]-2-hydroxysuccinic acid disodium salt (xxiv)
2-oxepanone (xxv)
2-oxepanol (xxvi)
methyl 3-(5-hydroxypentyl)-5-(2-methoxy-2-oxoethyl)-4,5-dihydro-5-isoxazolecarboxylate (xxvii)
methyl 5-(2-methoxy-2-oxoethyl)-3-(5-oxopentyl)-4,5-dihydro-5-isoxazolecarboxylate (xxviii)
(2,4-dichlorobenzyl)(triphenyl)phosphorane (xxix)
methyl 3-[(e)-6-(2,4-dichlorophenyl)-5-hexenyl]-5-(2-methoxy-2-oxoethyl)-4,5-dihydro-5-isoxazolecarboxylate (xxx)
Reference 1:
    danishefsky, s.j.; bornmann, w.g.; queneau, y.; magee, t.v.; krol, w.j. (sloan-kettering institute); total synthesis of taxol. us 5416225 .

Route 21
2) the silylation of the hydroxyketal (xxxi) with tbdms-tf in dichloromethane gives the corresponding silyl ether (xxxii), which is treated sequentially with borane in thf, with h2o2 and tetrapropylammonium perruthenate catalyst to afford ketone (xxxiii). the reaction of (xxxiii) with khmds and tfnp in anhydrous thf yields the enol triflate (xxxiv), which by addition of co catalyzed by triphenylphosphine and pd(oac)2 in methanol is converted to the methyl ester (xxxv). the reduction of (xxxv) with dibal in hexane gives the alcohol derivative (xxxvi), which by oso4 oxidation in acetone/water gives the triol (xxxvii). the dehydration of (xxxvii) by previous silylation with tms-cl and reaction with trifluoromethanesulfonic anhydride in dichloromethane affords the oxetane derivative (xxxviii), which is submitted to deketalization with clts to yield the ketone (xxxix). the dehydrogenation of (xxxix) by reaction with lithium diisopropylamide tms-cl and pd(oac)2 in thf gives the enone (xl), which is silylated with tbdms-cl in dmf to the fully silylated enone (xli). the enolization of (xli) with butyllithium and tms-cl followed by ozonolysis with o3 in dichloromethane yields the dialdehyde (xlii), which is submitted to a selective ketalization of the less hindered aldehyde group, affording the monoketal (xliii). the addition of the lithium dithiane derivative (xliv) to (xliii) followed by a swern oxidation of the intermediate alcohol gives the ketone (xlv), which is deketalized in acidic medium to yield the keto aldehyde (xlvi). the addition of the vinyllithium compound (xlvii) to (xlvi) gives the diels-alder precursor (xlviii), which is submitted to cyclization by heating to afford the polycyclic compound (ii) with the basic skeleton of paclitaxel.
List of intermediates No.
dimethyl 2-[(e)-8-(2,4-dichlorophenyl)-2-oxo-7-octenyl]-2-hydroxysuccinate (xxxi)
methyl 11-(2,4-dichlorophenyl)-5-hydroxy-3-oxoundecanoate (xxxii)
methyl 3-cyano-11-(2,4-dichlorophenyl)-3,5-dihydroxyundecanoate (xxxiii)
(2s)-2-[(2r)-8-(2,4-dichlorophenyl)-2-hydroxyoctyl]-2-hydroxybutanedioic acid (xxxiv)
6-hydroxyhexanal oxime (xxxv)
4-bromobenzaldehyde (xxxvi)
4-(4-fluorophenoxy)benzaldehyde (xxxvii)
cycloheptanamine; cycloheptylamine (xxxviii)
n-cycloheptyl-n-[4-(4-fluorophenoxy)benzyl]amine; n-[4-(4-fluorophenoxy)benzyl]cycloheptanamine (xxxix)
2,4,6-trimethyl-3-pyridinylamine; 2,4,6-trimethyl-3-pyridinamine (xl)
phenyl 2,4,6-trimethyl-3-pyridinylcarbamate (xli)
6-methyl-2,4-bis(methylsulfanyl)-3-pyridinylamine; 6-methyl-2,4-bis(methylsulfanyl)-3-pyridinamine (xlii)
n-cycloheptyl-n-[4-(4-fluorophenoxy)benzyl]-n-[6-methyl-2,4-bis(methylsulfanyl)-3-pyridinyl]urea (xliii)
4-iodophenol (xliv)
(4-iodophenoxy)(trimethyl)silane; 4-iodophenyl trimethylsilyl ether (xlv)
4-[2-(trimethylsilyl)ethynyl]phenol (xlvi)
tert-butyl 4-(3-hydroxypropyl)-1h-imidazole-1-carboxylate (xlvii)
tert-butyl 4-(3-[4-[2-(trimethylsilyl)ethynyl]phenoxy]propyl)-1h-imidazole-1-carboxylate (xlviii)
4-(3-[4-[2-(trimethylsilyl)ethynyl]phenoxy]propyl)-1h-imidazole; 3-(1h-imidazol-4-yl)propyl 4-[2-(trimethylsilyl)ethynyl]phenyl ether (il)
(1r,4as,10ar)-7-isopropyl-1,4a-dimethyl-6-sulfo-1,2,3,4,4a,9,10,10a-octahydro-1-phenanthrenecarboxylic acid
Reference 1:
    danishefsky, s.j.; bornmann, w.g.; queneau, y.; magee, t.v.; krol, w.j. (sloan-kettering institute); total synthesis of taxol. us 5416225 .

Route 22
the stereoselective reduction of the lesshindered ketonic group of (ii) followed by benzoylation yields the polycyclic ketone (l), which is submitted to an allylic oxidation to afford the unsaturated dione (li). the sequential selective reduction of the less hindered ketone with a bulky borohydride gives an alpha-alcohol, which is then benzylated with benzyl chloride and finally treated with h2 and raney nickel to eliminate the dithiane group and afford the polycyclic ketone (lii). the regioselective franklin davis hydroxylation of (lii) followed by desilylation with tbaf and peracetylation with acetic anhydride yields the triacetoxy ketone (liii), which is debenzylated by hydrogenation with h2 over pd/c to the secondary alcohol (liv). the attachment of the propenoyl side-chain of paclitaxel to (liv) according to j amer chem soc 1988, 110: 5917 gives the protected paclitaxel derivative (lv), which is submitted to a selective deacetylation to the paclitaxel precursor (lvi). finally, this compound is deprotected to paclitaxel.
List of intermediates No.
4-(3-[4-[2-(trimethylsilyl)ethynyl]phenoxy]propyl)-1h-imidazole; 3-(1h-imidazol-4-yl)propyl 4-[2-(trimethylsilyl)ethynyl]phenyl ether (il)
4-ethynylphenyl 3-(1h-imidazol-4-yl)propyl ether; 4-[3-(4-ethynylphenoxy)propyl]-1h-imidazole (l)
(2s)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutyric acid (li)
benzyl (2s)-2-amino-4-methylpentanoate; benzyl (s)-leucinate (lii)
benzyl (2s)-2-([(2s)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutanoyl]amino)-4-methylpentanoate (liii)
benzyl (2s)-2-[[(2s)-2-amino-3,3-dimethylbutanoyl]amino]-4-methylpentanoate (liv)
(2s)-2-[[(9h-fluoren-9-ylmethoxy)carbonyl]amino]-3-(2-methylphenyl)propionic acid (lv)
benzyl (5s,8s,11s)-8-(tert-butyl)-1-(9h-fluoren-9-yl)-11-isobutyl-5-(2-methylbenzyl)-3,6,9-trioxo-2-oxa-4,7,10-triazadodecan-12-oate (lvi)
Reference 1:
    danishefsky, s.j.; bornmann, w.g.; queneau, y.; magee, t.v.; krol, w.j. (sloan-kettering institute); total synthesis of taxol. us 5416225 .

Route 23
a new synthesis of [14c]-labeled paclitaxel has been published: the protection of l-threonine methyl ester (i) with tert-butoxydiphenylchlorosilane (bps-cl) gives the compound (ii), which is condensed with [14c]-labeled benzaldehyde (iii), yielding the imine (iv). the cyclization of (iv) with acetoxyacetyl chloride (v) by means of triethylamine affords the azetidinone (vi), which is deprotected with tetrabutylammonium fluoride to the hydroxy ester (vii). the dehydration of (vii) with p-toluenesulfonyl chloride and triethylamine affords the unsaturated ester (viii), which by ozonolysis is converted to the oxalimide (ix). elimination of the oxalyl group with hydrazine gives the labeled azetidinone (x), which is deacetylated to the hydroxyazetidinone (xi) and protected with triethylchlorosilane (tes-cl) to (xii). the benzoylation of (xii) with benzoyl chloride (xiii) and dimethylaminopyridine (dmap) yields the corresponding benzoylated compound (xiv), which is then condensed with triethylsilyl-baccatin iii (xv) by means of butyllithium to afford silylated labeled paclitaxel (xvi). finally, this compound is deprotected with hcl. the intermediate silylated baccatin iii (xv) is obtained from paclitaxel (xvii) by hydrogenolysis with nabh4 to baccatin iii (xviii) and silylation with triethylsilyl chloride to (xv).
List of intermediates No.
(2r,3r,4r,5r,6r)-3-(acetamido)-5-(acetoxy)-2-(1-ethylpropoxy)-6-(hydroxymethyl)tetrahydro-2h-pyran-4-yl acetate (xviii)
trimethyl[(2e)-2,4-pentadienyl]stannane (v)
benzhydryl (2r,3r,4s)-3-(acetamido)-4-[(tert-butoxycarbonyl)amino]-2-[(1r)-2-ethyl-1-hydroxybutyl]-3,4-dihydro-2h-pyran-6-carboxylate (xi)
(3-amino-1-benzofuran-2-yl)(4-methoxyphenyl)methanone (xiii)
benzhydryl (6r,7r)-7-[[4-bromo-2-(hydroxyimino)-3-oxobutanoyl]amino]-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (xv)
methyl 3-[5-(2-chlorophenyl)-2-oxo-2,3-dihydro-1h-thieno[2,3-e][1,4]diazepin-7-yl]propanoate (iii)
methyl 2-methyl-1-azulenecarboxylate (xvii)
benzyl (2s)-2-[((2s)-2-[[(2s)-2-amino-3-(2-methylphenyl)propanoyl]amino]-3,3-dimethylbutanoyl)amino]-4-methylpentanoate (i)
(2s)-5-(tert-butoxy)-2-[[(9h-fluoren-9-ylmethoxy)carbonyl]amino]-5-oxopentanoic acid (ii)
(2s)-4-(tert-butoxy)-2-[[(9h-fluoren-9-ylmethoxy)carbonyl]amino]-4-oxobutyric acid (iv)
4-(tert-butoxy)-4-oxobutyric acid (vi)
1-benzyl 19-(tert-butyl) (2s,5s,8s,11s,14s)-14-[2-(tert-butoxy)-2-oxoethyl]-11-[3-(tert-butoxy)-3-oxopropyl]-5-(tert-butyl)-2-isobutyl-8-(2-methylbenzyl)-4,7,10,13,16-pentaoxo-3,6,9,12,15-pentaazanonadecane-1,19-dioate (vii)
(2s,5s,8s,11s,14s)-14-[2-(tert-butoxy)-2-oxoethyl]-11-[3-(tert-butoxy)-3-oxopropyl]-5-(tert-butyl)-2-isobutyl-21,21-dimethyl-8-(2-methylbenzyl)-4,7,10,13,16,19-hexaoxo-20-oxa-3,6,9,12,15-pentaazadocosan-1-oic acid (viii)
4-tert-butoxysuccinyl-(4-o-tert-butyl)-l-aspartyl-(5-o-tert-butyl)-l-glutamyl-(2-methyl)-l-phenylalanyl-l-tert-leucyl-l-leucine isobutoxycarbonyl anhydride; 4-tert-butoxysuccinyl-(4-o-tert-butyl)-l-aspartyl-(5-o-tert-butyl)-l-glutamyl-(2-methyl)-l-phenylalanyl-l-tert-leucyl-l-leucine isobutoxycarbonyl anhydride (ix)
2-(dichloromethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (x)
2-(1-chloropropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (xii)
tert-butyl (6s,9s,12s,15s,18s)-18-[2-(tert-butoxy)-2-oxoethyl]-15-[3-(tert-butoxy)-3-oxopropyl]-9-(tert-butyl)-6-isobutyl-12-(2-methylbenzyl)-5,8,11,14,17,20-hexaoxo-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,7,10,13,16,19-hexaazatricosan-23-oate (xiv)
tert-butyl (6s,9s,12s,15s,18s)-6-[2-(tert-butoxy)-2-oxoethyl]-9-[3-(tert-butoxy)-3-oxopropyl]-15-(tert-butyl)-18-isobutyl-12-(2-methylbenzyl)-4,7,10,13,16,19-hexaoxo-21-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,8,11,14,17,20-hexaaza-23-tetracosen-1-oate (xvi)
ethyl 2-[2-(benzyloxy)-5-cyanophenoxy]-6-[3-(1-methyl-4,5-dihydro-1h-imidazol-2-yl)phenoxy]isonicotinate (iii)
(7r)-7-{(3as,7s,7ar)-3a-methyl-7-[(triethylsilyl)oxy]-3a,4,5,6,7,7a-hexahydro-1h-inden-3-yl}-2,2-dimethyl-3-octanone (iv)
Reference 1:
    walker, d.g.; swigor, j.e.; standridge, r.t.; synthesis of paclitaxel-c3-c-14. j label compd radiopharm 1995, 36, 5, 479.

Route 24
a new total synthesis of paclitaxel has been described: this synthesis starts from 2-methyl-2-(3-oxobutyl)cyclohexane-1,3-dione (i), which by a multistep synthesis (helv chim acta 1950, 33: 2215) yields (s)-wieland miesher ketone (ii). this compound is converted by a known process (j org chem 1992, 57: 3274) to the ketal (iii), which by reaction with trimethylsulfonium iodide and potassium hexamethyldisilazide (khmds) affords the hydromethyl derivative (iv). the cyclization of (iv) according to j org chem 1992, 57: 3274 yields the oxetane derivative (v), which is benzylated and deprotected, affording the ketone (vi). a multistep ring cleavage of (vi) according to angew chem int ed engl 1995, 34: 452 gives the aldehyde (vii), which is condensed with the lithium compound (viii) (obtained from the corresponding iodo compound (ix) and buli) to afford the dienic ketone (x). the epoxidation of (x) with m-chloroperbenzoic acid (m-cpba) followed by reduction with h2 over pd/c yields compound (xi) with a tertiary hydroxy group, which by reaction with carbonyl diimidazole (cdi) and nah affords the cyclic carbonate (xii). the reduction of (xii) with l-selectride in thf gives the saturated ketone (xiii), which is converted to the corresponding vinyl trifluoromethanesulfonate (xiv) by known methods. the cleavage of the dimethyl acetal group with pyridinium p-toluenesulfonate (ppts) followed by chain elongation with methylenetriphenylphosphorane affords the allyl derivative (xv), which is submitted to cyclization with palladium triphenylphosphine complex, affording compound (xvi) with the basic ring system of paclitaxel. the previous change of the tert-butyldimethylsilyl (tbdms) protecting group to a triethylsilyl (tes) group (less difficult to remove when the functionality of the tetracyclic structure is more complex) is performed with tetrabutylammonium fluoride (tbaf) and tes-tf, yielding compound (xvii). the epoxidation of (xvii) with m-cpba as usual affords epoxide (xviii).
List of intermediates No.
methyl 3-cyano-11-(2,4-dichlorophenyl)-3,5-dihydroxyundecanoate (iii)
4-bromobenzaldehyde (iv)
cycloheptanamine; cycloheptylamine (v)
cyclopropyl bromide; 1-(bromomethyl)cyclopropane (i)
4,5-dibromo-3(2h)-pyridazinone (ii)
2-benzyl-4-bromo-5-hydroxy-3(2h)-pyridazinone (vi)
1-benzyl-5-bromo-6-oxo-1,6-dihydro-4-pyridazinyl trifluoromethanesulfonate (vii)
2-benzyl-4-bromo-5-[4-(methylsulfanyl)phenyl]-3(2h)-pyridazinone (viii)
2-benzyl-4-bromo-5-[4-(methylsulfonyl)phenyl]-3(2h)-pyridazinone (ix)
4-fluoro-2-nitrophenylamine; 4-fluoro-2-nitroaniline (x)
3-(4-fluoro-2-nitroanilino)propanenitrile (xi)
3-(2-amino-4-fluoroanilino)propanenitrile (xii)
ethyl 2-[1-(2-cyanoethyl)-5-fluoro-1h-benzimidazol-2-yl]acetate (xiii)
ethyl 3-[2-(2-ethoxy-2-oxoethyl)-5-fluoro-1h-benzimidazol-1-yl]propanoate (xiv)
ethyl 7-fluoro-3-oxo-1,2,3,5-tetrahydropyrido[1,2-a]benzimidazole-4-carboxylate (xv)
2-fluorophenylamine; 2-fluoroaniline (xvi)
7-fluoro-n-(2-fluorophenyl)-3-oxo-1,2,3,5-tetrahydropyrido[1,2-a]benzimidazole-4-carboxamide (xvii)
(2r,3r,4r,5r)-4-(acetoxy)-2-[(acetoxy)methyl]-5-(2-amino-6-chloro-9h-purin-9-yl)tetrahydro-3-furanyl acetate (xviii)
Reference 1:
    masters, j.j.; young, w.b.; snyder, l.b.; link, j.t.; danishefsky, s.j.; a total synthesis of taxol. angew chem. int ed engl 1995, 34, 16, 1723.

Route 25
epoxide (xviii) is debenzylated by hydrogenation and acetylated with acetic anhydride and dimethylaminopyridine (dmap) to compound (xix). the ring opening of the cyclic carbonate group of (xix) with phenyllithium affords compound (xx) with the secondary benzoate group and the tertiary hydroxy substituent of paclitaxel. the oxidation of the methylene group of (xx) with oso4 and lead tetraacetate affords the epoxy ketone (xxi). the deoxygenation of the epoxy group of (xxi) is performed with smi2 and acetic anhydride, and after oxidation, alpha-ketol interchange and acetylation, compound (xxii) with almost all the functionality of paclitaxel is obtained. the allylic oxidation of (xxii) with pyridinium chlorochromate (pcc) followed by reduction with nabh4 affords triethylsilyl-baccatin iii (xxiii), which is deprotected with hf.pyridine to baccatin iii (xxiv). finally, both compounds (xxiii) and (xxiv) are converted to paclitaxel by known methods (j org chem 1991, 56: 1681).
List of intermediates No.
(2r,3r,4r,5r,6r)-3-(acetamido)-5-(acetoxy)-2-(1-ethylpropoxy)-6-(hydroxymethyl)tetrahydro-2h-pyran-4-yl acetate (xxiv)
benzhydryl (6r,7r)-7-[[4-bromo-2-(hydroxyimino)-3-oxobutanoyl]amino]-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (xxiii)
2-[[(1,2-bis(2,6-dichloro-4-methoxyphenyl)-2-[[(e)-(2-hydroxyphenyl)methylidene]amino]ethyl)imino]methyl]phenol (xxii)
(2r,3r,4r,5r)-4-(acetoxy)-2-[(acetoxy)methyl]-5-(2-amino-6-chloro-9h-purin-9-yl)tetrahydro-3-furanyl acetate (xviii)
6-chloro-9-(2-o,3-o,5-o-triacetyl-beta-d-ribofuranosyl)purine-2-diazonium cation (xix)
(2r,3r,4r,5r)-4-(acetoxy)-2-[(acetoxy)methyl]-5-[6-chloro-2-(propylsulfanyl)-9h-purin-9-yl]tetrahydro-3-furanyl acetate (xx)
(2r,3r,4s,5r)-2-[6-amino-2-(propylsulfanyl)-9h-purin-9-yl]-5-(hydroxymethyl)tetrahydro-3,4-furandiol (xxi)
Reference 1:
    masters, j.j.; young, w.b.; snyder, l.b.; link, j.t.; danishefsky, s.j.; a total synthesis of taxol. angew chem. int ed engl 1995, 34, 16, 1723.

Route 26
a new method for the synthesis of paclitaxel side chain has been developed: the esterification of (s)-phenylglycine (i) with socl2 and methanol gives the corresponding methyl ester (ii), which is acylated with benzoyl chloride and pyridine to the benzoyl derivative (iii). the reduction of (iii) with dibutylaluminum hydride (dibal) in toluene yields the corresponding aldehyde (iv), which is condensed with 2-(trimethylsilyl)thiazole (v) by means of tetrabutylammonium fluoride (tbaf) to afford the (1r,2s)-n-[2-hydroxy-1-phenyl-2-(2-thiazolyl)ethyl]benzamide (vi) with a 95% enantiomeric purity. the cyclization of (vi) with 2,2-dimethoxypropane (vii) catalyzed by camphosulfonic acid (csa) gives (4s,5r)-3-benzoyl-2,2-dimethyl-4-phenyl-5-(2-thiazolyl)oxazolidine (viii), which is treated with methyl trifluoromethanesulfonate to afford (4s,5r)-3-benzoyl-2,2-dimethyl-4-phenyloxazolidine-5-carbaldehyde (ix). finally, this compound is oxidized with kmno4 in tert-butanol/aqueous potassium phosphate buffer to yield (4s,5r)-3-benzoyl-2,2-dimethyl-4-phenyloxazolidine-5-carboxylic acid (x), the side chain of paclitaxel suitably protected.
List of intermediates No.
(3-amino-1-benzofuran-2-yl)(4-methoxyphenyl)methanone
(2r,3r,4s,5r)-2-(6-amino-2-sulfanyl-9h-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol (i)
3-chloro-1,1,1-trifluoropropane (ii)
(2r,3r,4s,5r)-2-[6-amino-2-[(3,3,3-trifluoropropyl)sulfanyl]-9h-purin-9-yl]-5-(hydroxymethyl)tetrahydro-3,4-furandiol (iii)
(2r,3r,4r,5r)-2-[6-(acetamido)-2-[(3,3,3-trifluoropropyl)sulfanyl]-9h-purin-9-yl]-4-(acetoxy)-5-[(acetoxy)methyl]tetrahydro-3-furanyl acetate (iv)
1-iodo-2-(methylsulfanyl)ethane; 2-iodoethyl methyl sulfide (v)
(2r,3r,4r,5r)-2-[6-[acetyl[2-(methylsulfanyl)ethyl]amino]-2-[(3,3,3-trifluoropropyl)sulfanyl]-9h-purin-9-yl]-4-(acetoxy)-5-[(acetoxy)methyl]tetrahydro-3-furanyl acetate (vi)
(2r,3s,4r,5r)-2-(hydroxymethyl)-5-[6-[[2-(methylsulfanyl)ethyl]amino]-2-[(3,3,3-trifluoropropyl)sulfanyl]-9h-purin-9-yl]tetrahydro-3,4-furandiol (vii)
((2r,3s,4r,5r)-3,4-dihydroxy-5-[6-[[2-(methylsulfanyl)ethyl]amino]-2-[(3,3,3-trifluoropropyl)sulfanyl]-9h-purin-9-yl]tetrahydro-2-furanyl)methyl dihydrogen phosphate (viii)
((2r,3s,4r,5r)-3,4-dihydroxy-5-[6-[[2-(methylsulfanyl)ethyl]amino]-2-[(3,3,3-trifluoropropyl)sulfanyl]-9h-purin-9-yl]tetrahydro-2-furanyl)methyl hydrogen 1h-imidazol-1-ylphosphonate (ix)
1-(3,4-dihydroxyphenyl)-1-ethanone (x)
Reference 1:
    semola, t.; dondoni, a.; perrone, d.; synthesis of taxol and taxotere side chains by 2-(trimethylsilyl)thiazole based homologation of l-phenylglycine. synthesis 1995, 2, 2, 181.

Route 27
three partial syntheses of taxol are described starting from taxol analogues such as taxol c or taxol b (cephalomannine):1) the reaction of taxol c (i) with triethylsilyl chloride (tes-cl) in pyridine gives the bis(triethylsilyl) derivative (ii), which by reduction with zirconocene chloride hydride [bis(cyclopentadienyl)zirconium chloride hydride] in dry thf yields compound (iii). the hydrolytic cleavage of (iii) with simultaneous desilylation by means of hcl in ethanol affords [2ar-[2aalpha,4beta,4abeta,6beta,9alpha(2r,3s),11beta,12alpha,12aalpha,12balpha]]-6,12b-diacetoxy-9-(3-amino-2-hydroxy-3-phenylpropionyloxy)-1 2-benzoyloxy-4,11-dihydroxy-4a,8,13,13-tetramethyl-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-1h-7,11-methanocyclodeca[3,4]benz[1,2-b]oxet-5-one (iv) with a free amino group, which is benzoylated with benzoyl chloride (v) and pyridine to taxol.
List of intermediates No.
(3-amino-1-benzofuran-2-yl)(4-methoxyphenyl)methanone (v)
2-(bromomethyl)-1,3-difluorobenzene (i)
1-[4-[(2,6-difluorobenzyl)oxy]-3-hydroxyphenyl]-1-ethanone (ii)
ethyl 2-[5-acetyl-2-[(2,6-difluorobenzyl)oxy]phenoxy]acetate (iii)
diethyl 2-(diethylamino)-2-oxoethylphosphonate (iv)
Reference 1:
    young, t.h. (hauser, inc.); preparation of taxol and docetaxel through primary amines. ep 0852581; wo 9623780 .

Route 28
2) the silylation of taxol b (vi) with triethylsilyl chloride as before gives the bis(triethylsilyl) compound (vii), which by reduction with zirconocene chloride hydride as described yields compound (viii). finally, the hydrolytic cleavage of (viii) with simultaneous desilylation with hcl in ethanol affords the previously reported compound (iv) with its free amino group easily benzoylated to taxol. 3) the ozonolysis of the silylated taxol b (vii) with o3 in methanol gives compound (ix), which is reduced with zirconocene as before yielding the 2-oxopropylideneimine (x). finally, the hydrolytic cleavage of (x) with simultaneous desilylation with hcl in ethanol affords the previously reported compound (ix) with its free amino group easiely benzoylated to taxol.
List of intermediates No.
diethyl 2-(diethylamino)-2-oxoethylphosphonate (iv)
2-(2-hydroxyphenyl)acetic acid (vi)
ethyl 2-(5-bromo-2-hydroxyphenyl)acetate (vii)
ethyl 2-[5-bromo-2-[(2,6-difluorobenzyl)oxy]phenyl]acetate (viii)
(e)-n,n-diethyl-2-butenamide (ix)
ethyl 2-[5-[(e)-3-(diethylamino)-1-methyl-3-oxo-1-propenyl]-2-[(2,6-difluorobenzyl)oxy]phenyl]acetate (x)
Reference 1:
    young, t.h. (hauser, inc.); preparation of taxol and docetaxel through primary amines. ep 0852581; wo 9623780 .

Route 29
a partial synthesis of taxol starting from deacetyl baccatin iii (xi) has been developed:the starting compounds, the acid (i) and the silylated baccatin iii (ii) have been obtained as follows:a) the reaction of 3(s)-amino-2(r)-hydroxy-3-phenylpropionic acid ethyl ester (viii) with benzyloxycarbonyl chloride and na2co3 in ethyl or tert-butyl ether/water gives 3(s)-(benzyloxycarbonylamino)-2(r)-hydroxy-3-phenylpropionic acid ethyl ester (ix), which is condensed with benzyloxymethyl chloride by means of buli in thf yielding the fully protected ester (x). the hydrolysis of (x) with lioh in ethanol/water affords the desired acid (i).b) the silylation of (deacetyl baccatin iii) (xi) with triethylsilyl chloride in pyridine gives the monosilylated deacetyl baccatin iii (xii), which is then acetylated with acetyl chloride in pyridine or buli in thf to afford the desired silylated baccatin iii (ii).
List of intermediates No.
ethyl 3-[(2,5-dimethoxybenzyl)[2-(4-methoxybenzoyl)-1-benzofuran-3-yl]amino]-3-oxopropanoate (xi)
ethyl (z)-2-(2,4-dichloro-5-fluorobenzoyl)-3-ethoxy-2-propenoate (viii)
3-[(1r)-6,7-dimethoxy-2-methyl-1-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydro-2lambda(5)-isoquinolin-2-yl]-1-propanol (i)
3-[(1s)-6,7-dimethoxy-2-methyl-1-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydro-2lambda(5)-isoquinolin-2-yl]-1-propanol (ii)
(z)-2-chloro-2-butenedioyl dichloride (iii)
2-[(2-amino-6-chloro-9h-purin-9-yl)methoxy]-1,3-propanediol (iv)
2-[(2-amino-6-fluoro-9h-purin-9-yl)methoxy]-1,3-propanediol (ix)
1-methylpropionic anhydride (x)
4-[(3-aminopropyl)amino]-1-butanol (xii)
Reference 1:
    sisti, n.j.; swindell, c.s.; chander, m.c. (napro biotherapeutics, inc.); paclitaxel synthesis from precursor compounds and methods of producing the same. us 5675025 .

Route 30
the benzoylation of (iv) with benzoyl chloride (v) and triethylamine in ethyl acetate affords the fully protected taxol derivative (vi), which is desillylated with hf in acetonitrile giving the partially protected taxol derivative (vii). finally, this compound is fully deprotected by hydrogenation with h2 over pd/c in isopropanal at 40 atm to give taxol.
List of intermediates No.
(3-amino-1-benzofuran-2-yl)(4-methoxyphenyl)methanone (v)
diethyl 2-(diethylamino)-2-oxoethylphosphonate (iv)
4-((tert-butoxycarbonyl)[3-[(tert-butoxycarbonyl)amino]propyl]amino)butyl methanesulfonate (vi)
tert-butyl 4-aminobutyl[3-[(tert-butoxycarbonyl)amino]propyl]carbamate (vii)
Reference 1:
    sisti, n.j.; swindell, c.s.; chander, m.c. (napro biotherapeutics, inc.); paclitaxel synthesis from precursor compounds and methods of producing the same. us 5675025 .

Route 31
a new synthesis of paclitaxel has been reported: the esterification of (2r,3s)-2,3-epoxy-3-phenylpropionic acid (i) with 2-(trimethylsilyl)ethanol (ii) by means of 1,8-diazabicyclo[5.4.0]undec-7-ene (dbu) in hot toluene gives the expected ester (iii), which is treated with libr in acetic acid to yield the (2r,3r)-3-bromo-2-hydroxy ester (iv). the reaction of (iv) with sodium azide in hot dmf affords the corresponding azido derivative (v), which is reduced with ammonium formate or h2 over pd/c giving the (2r,3s)-3-amino-2-hydroxy ester (vi). the amidation of (vi) with benzyl chloroformate (vii) yields the corresponding benzyloxycarbonylamino compound (viii), which is esterified with benzoyl chloride (ix) and triethylamine affording (2r,3s)-2-(benzoyloxy)-3-(benzyloxycarbonylamino)-3-phenylpropionic acid 2-(trimethylsilyl)ethyl ester (x). the condensation of the ester (x) with 7-o-(triethylsilyl)baccatin (xi) by means of 4-(1-pyrrolidinyl)-piperidine (4-pp) and dicyclohexylcarbodiimide (dcc) in hot toluene gives the mixed ester (xii). finally, this compound is hydrogenated with ammonium formate and pd/c to obtain a free amino group to which the benzoyl group of the a-position is transferred by a treatment with formic acid yielding pure paclitaxel.
List of intermediates No.
[5-[3-benzoyl-2,4-dioxo-5-vinyl-3,4-dihydro-1(2h)-pyrimidinyl]-3-(benzoyloxy)tetrahydro-2-furanyl]methyl benzoate (vii)
(3-amino-1-benzofuran-2-yl)(4-methoxyphenyl)methanone (ix)
n(1)-(2-bromoethyl)-1,3-propanediamine; n-(3-aminopropyl)-n-(2-bromoethyl)amine (i)
3-(bromomethyl)-1,2-benzisoxazole (ii)
sodium 1,2-benzisoxazol-3-ylmethanesulfonate (iii)
1,2-benzisoxazol-3-ylmethanesulfonyl chloride (iv)
tert-butyl phenylcarbamate (v)
2-[(tert-butoxycarbonyl)amino]benzoic acid (vi)
tert-butyl (2s,3s)-2-[(2-[[2-([[(1s,2s)-1-(tert-butoxycarbonyl)-2-methylbutyl]amino]carbonyl)phenyl]disulfanyl]benzoyl)amino]-3-methylpentanoate (viii)
(2s,3s)-2-[(2-[[2-([[(1s,2s)-1-carboxy-2-methylbutyl]amino]carbonyl)phenyl]disulfanyl]benzoyl)amino]-3-methylpentanoic acid (x)
dichlorophosphoric acid 4-methoxyphenyl ester (xi)
methyl 2-[[chloro(4-methoxyphenoxy)phosphoryl]amino]propanoate (xii)
Reference 1:
    gao, y.; zepp, c.m. (sepracor inc.); taxol process and cpds.. us 5760251 .

Route 32
a new synthesis of the side chain of paclitaxel has been described: the reaction of 2,3-epoxy-3-phenylpropionic acid methyl ester (i) with sodium azide in hot methanol/dmf/water gives 3-azido-2-hydroxy-3-phenylpropionic acid methyl ester (ii), which is oxidized with jones reagent yielding 3-azido-2-oxo-3-phenylpropionic acid methyl ester (iii). the reduction of (iii) with bakers yeast in water affords 3(rs)-azido-2(r)-hydroxy-3-phenylpropionic acid methyl ester (iv) as a diastereomeric mixture, which is resolved by spinning-plate chromatography in silicagel using ethyl acetate/pentane as solvent. the resulting (2r, 3s)-isomer (iv) is converted into the target compound by known methods (adam, w. et al tetrahedron asymmetry, 1995, 6: 1047).
List of intermediates No.
benzyl 4-iodobutyl ether; 1-[(4-iodobutoxy)methyl]benzene (ii)
n-[(e,2s)-6-(benzyloxy)-2-methylhexylidene]-n-[(2r)-2-methoxypyrrolidinyl]amine; (2r)-n-[(e,2s)-6-(benzyloxy)-2-methylhexylidene]-2-methoxy-1-pyrrolidinamine (iii)
(2s)-6-(benzyloxy)-2-methylhexanal (iv)
(2s)-6-(benzyloxy)-2-methyl-1-hexanol (v)
benzyl (5s)-6-[[tert-butyl(dimethyl)silyl]oxy]-5-methylhexyl ether; [[(2s)-6-(benzyloxy)-2-methylhexyl]oxy](tert-butyl)dimethylsilane
diethyl (3r,4r,5s,6s)-5-(benzyloxy)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,2,4,6-tetramethyloctanedioate (i)
Reference 1:
    kayser, m.m.; et al.; bakers yeast-mediated reductions of alpha-keto esters and an alpha-keto-beta-lactam. two routes to the paclitaxel side chain. j org chem 1999, 64, 18, 6603.

Route 33
the condensation of the chiral aldehyde (i) with the phenyllithium compound (ii) in the presence of magnesium ion gives, after protection of the resulting vicinal diol as a boronate, the cyclization precursor (iii). the cyclization of (iii) by means of ticl2 in dichloromethane yields the tricarbocyclic compound (iv), which is silylated at the vicinal diol with butyllithium and di-tert-butylsilyl chloride in thf, reduced with dibal in dichloromethane and silylated with tbs-otf to afford intermediate (v). singlet oxygen oxygenation of the diene moiety of (v), followed by a treatment with tributyl tin hydride produced the peroxide bonds cleavage and removal of the phenylsulfanyl group; and elimination of the benzyl protecting group by hydrogenation, followed by reprotection of the vicinal diol with benzaldehyde dimethylacetal gave a mixture of two diastereoisomers (vi). this mixture was treated with diethylzinc/chloroiodomethane, only the beta-isomer underwent the cyclopropanation, followed by dess-martin periodinane (dmp), affording the ketone (vii). elimination of the benzylidene group of (vii), followed by reaction with triphosgene, and desilylation with tbaf provided the cyclic carbonate (viii). the reprotection of the free hydroxy groups of (viii) with benzaldehyde dimethylacetal, followed by hydrolysis of the cyclic carbonate group affords intermediate (ix). this compound was treated with samarium iodide and tbaf to induce the cleavage of the cyclopropane ring resulting in a mixture of enol (x) and ketone (xi). the enol was treated with naome to complete the ketonization to (xi). the vicinal diol of (xi) was initially protected as a boronate with phenylboronic acid and the remaining hydroxy group was silylated with tbs-otf. after removal the boron-protecting group, selective dess martin oxidation and protection of the remaining hydroxy group with 2-methoxypropene, the dione (xii) was obtained. the reaction of (xii) with khmds and phntf2 yielded the corresponding enol, which was reacted with trimethylsilyl magnesium chloride in ether to give the allylsilane (xiii). the reaction of (xiii) with n-chlorosuccinimide (ncs) and 2-methoxypropene yielded the chlorinated compound (xiv), which was treated successively with lda to generate the enol, oxidized with moo5, and acetylated with acetic anhydride to provide the acetoxy derivative (xv). the oxidation of the exocyclic double bond of (xv) with oso4 and pyridine gave the corresponding diol, which by treatment with dbu in refluxing toluene and silylation with tes-cl yielded the oxetane derivative (xvi).
List of intermediates No.
1-carboxy-3-nitrobenzene; m-nitrobenzoic acid; 3-nitrobenzoic acid; 3-nitrodracylic acid (i)
(5s)-6-[[tert-butyl(dimethyl)silyl]oxy]-5-methyl-1-hexanol (ii)
4-((1e,3s,5z,10s)-3,11-bis[[tert-butyl(dimethyl)silyl]oxy]-2,10-dimethyl-1,5-undecadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (2s,6z,9s,10e)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,10-dimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienyl ether (iii)
(2s,6z,9s,10e)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,10-dimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadien-1-ol (iv)
(2s,6z,9s,10e)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,10-dimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienal (v)
(3s,6r,7s,8s,12z,15s,16e)-3,15-bis[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid (vi)
tert-butyl(dimethyl)silyl (3s,6r,7s,8s,12z,15s,16e)-3,7,15-tris[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoate (vii)
(3s,6r,7s,8s,12z,15s,16e)-3,7,15-tris[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid (viii)
(3s,6r,7s,8s,12z,15s,16e)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-15-hydroxy-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid (ix)
methyl (3s,4e)-3-[dimethyl(phenyl)silyl]-4-hexenoate (x)
2-[[tert-butyl(diphenyl)silyl]oxy]acetaldehyde (xi)
methyl (e,5s,6r)-6-(benzyloxy)-7-[[tert-butyl(diphenyl)silyl]oxy]-5-methyl-3-heptenoate (xii)
(2r,3r)-3-(benzyloxy)-4-[[tert-butyl(diphenyl)silyl]oxy]-2-methylbutanal (xiii)
1-ethoxy-2-methyl-1-propenyl trimethylsilyl ether; [(1-ethoxy-2-methyl-1-propenyl)oxy](trimethyl)silane (xiv)
ethyl (3r,4s,5r)-5-(benzyloxy)-6-[[tert-butyl(diphenyl)silyl]oxy]-3-hydroxy-2,2,4-trimethylhexanoate (xv)
ethyl (3r,4r,5r)-5-(benzyloxy)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-[[tert-butyl(diphenyl)silyl]oxy]-2,2,4-trimethylhexanoate (xvi)
Reference 1:
    morihira, k.; et al.; enantioselective total synthesis of taxol. j am chem soc 1998, 120, 49, 12980.

Route 34
the debenzylation of (xvi) by hydrogenation, and subsequent reaction with triphosgene afforded the cyclic carbonate (xvii), which was acetylated with acetic anhydride and treated with phenyllithium in thf to open the cyclic carbonate giving the benzoate (xviii). compound (xviii) was submitted to a deprotection protection cycle, first with hf and pyridine followed by a treatment with troc-cl in the same solvent, providing intermediate (xix). finally, compound (xix) was desilylated with tasf in thf, condensed with azetidinone (xx) and deprotected with zn/acetic acid to provide taxol.
List of intermediates No.
benzyl 4-[(2,6-dimethylanilino)carbonyl]-4-(methylamino)-1-piperidinecarboxylate (xx)
ethyl (3r,4r,5r)-5-(benzyloxy)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-[[tert-butyl(diphenyl)silyl]oxy]-2,2,4-trimethylhexanoate (xvi)
ethyl (3r,4r,5r)-5-(benzyloxy)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-hydroxy-2,2,4-trimethylhexanoate (xvii)
ethyl (3r,4r,5r)-5-(benzyloxy)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,2,4-trimethyl-6-oxohexanoate (xviii)
diethyl (e,4s,5r,6r)-4-(benzyloxy)-6-[[tert-butyl(dimethyl)silyl]oxy]-5,7,7-trimethyl-2-octenedioate (xix)
Reference 1:
    morihira, k.; et al.; enantioselective total synthesis of taxol. j am chem soc 1998, 120, 49, 12980.

Route 35
1) the selective protection of baccatin iii (i) with 2,2,2-trichloroethoxycarbonyl chloride and li-hmds in dmf gives 7-o-(2,2,2-trichloroethoxycarbonyl)baccatin iii (ii), which is condensed with the chiral oxazolidine (iii) by means of dcc and dmap in toluene affording the 13-o-oxazolidinyl derivative (iii). finally, this compound is submitted to deprotection with zn/acetic acid and to cleavage of the oxazolidine ring with trifluoroacetic acid/acetic acid.
List of intermediates No.
(2r,3r,4r,5r,6r)-3-(acetamido)-5-(acetoxy)-2-(1-ethylpropoxy)-6-(hydroxymethyl)tetrahydro-2h-pyran-4-yl acetate (i)
(2r,3r,4r,5r,6s)-3-(acetamido)-5-(acetoxy)-2-(1-ethylpropoxy)-6-formyltetrahydro-2h-pyran-4-yl acetate (ii)
3-benzoyl-2-methyl-1-azulenecarboxylic acid (iii)
(3s,4s,5r,6r)-4-(benzyloxy)-6-[[tert-butyl(dimethyl)silyl]oxy]-8-hydroxy-3,5,7,7-tetramethyloctanal (iv)
Reference 1:
    gibson, f.s. (bristol-myers squibb co.); synthesis of paclitaxel baccatin iii by protecting the 7-hydroxyl using a strong base and an electrophile. wo 9945001 .

Route 36
2) the selective protection of baccatin iii (i) with benzyloxycarbonyl anhydride and li-hmds in dmf gives 7-o-(benzyloxycarbonyl)baccatin iii (v), which is condensed with the chiral oxazolidine (iii) by means of dcc and dmap in toluene affording the 13-o-oxazolidinyl derivative (vi). finally, this compound is deprotected by hydrogenation with h2 over pd/c in ethanol, and treated with trifluoroacetic acid/acetic acid as before.
List of intermediates No.
(2r,3r,4r,5r,6r)-3-(acetamido)-5-(acetoxy)-2-(1-ethylpropoxy)-6-(hydroxymethyl)tetrahydro-2h-pyran-4-yl acetate (i)
3-benzoyl-2-methyl-1-azulenecarboxylic acid (iii)
(3s,4s,5r,6r)-4-(benzyloxy)-6,8-bis[[tert-butyl(dimethyl)silyl]oxy]-3,5,7,7-tetramethyloctanal (v)
(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 (vi)
Reference 1:
    gibson, f.s. (bristol-myers squibb co.); synthesis of paclitaxel baccatin iii by protecting the 7-hydroxyl using a strong base and an electrophile. wo 9945001 .

Route 37
3) the selective protection of baccatin iii (i) with tert-butoxycarbonyl anhydride and li-hmds in dmf gives 7-o-(tert-butoxycarbonyl)baccatin iii (vii), which is condensed with the chiral oxazolidine (iii) by means of dcc and dmap in toluene affording the 13-o-oxazolidinyl derivative (viii). finally, this compound is deprotected with formic or acetic acids, and the oxazolidine ring is cleaved with trifluoroacetic acid/acetic acid.
List of intermediates No.
(2r,3r,4r,5r,6r)-3-(acetamido)-5-(acetoxy)-2-(1-ethylpropoxy)-6-(hydroxymethyl)tetrahydro-2h-pyran-4-yl acetate (i)
3-benzoyl-2-methyl-1-azulenecarboxylic acid (iii)
(1e)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,4-pentadien-3-ol (vii)
(1e,3s)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,4-pentadien-3-ol (viii)
Reference 1:
    gibson, f.s. (bristol-myers squibb co.); synthesis of paclitaxel baccatin iii by protecting the 7-hydroxyl using a strong base and an electrophile. wo 9945001 .

Route 38
4) the selective protection of baccatin iii (i) with 2,2,2-trichloroethoxycarbonyl chloride and li-hmds in dmf gives 7-o-(2,2,2-trichloroethoxycarbonyl)baccatin iii (ii), which is condensed with the chiral azetidinone (ix) by means of lithium tert-butoxide or li-hmds in thf and the reaction product, without isolation, is treated with trifluoroacetic acid and acetic acid to afford the protected taxol derivative (x). finally, this compound is deprotected with zn and acetic acid.
List of intermediates No.
(2r,3r,4r,5r,6r)-3-(acetamido)-5-(acetoxy)-2-(1-ethylpropoxy)-6-(hydroxymethyl)tetrahydro-2h-pyran-4-yl acetate (i)
(2r,3r,4r,5r,6s)-3-(acetamido)-5-(acetoxy)-2-(1-ethylpropoxy)-6-formyltetrahydro-2h-pyran-4-yl acetate (ii)
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 (ix)
(1e,3s,5z)-6-iodo-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol (x)
Reference 1:
    gibson, f.s. (bristol-myers squibb co.); synthesis of paclitaxel baccatin iii by protecting the 7-hydroxyl using a strong base and an electrophile. wo 9945001 .

Route 39
5) the selective protection of baccatin iii (i) with benzyloxycarbonyl anhydride and li-hmds in dmf gives 7-o-(benzyloxycarbonyl)baccatin iii (v), which is condensed with the chiral azetidinone (ix) by means of lithium tert-butoxide or li-hmds in thf and the reaction product, without isolation, is treated with trifluoroacetic acid and acetic acid to afford the protected taxol derivative (xi). finally, this compound is deprotected by hydrogenation with h2 over pd/c in ethanol.
List of intermediates No.
(2r,3r,4r,5r,6r)-3-(acetamido)-5-(acetoxy)-2-(1-ethylpropoxy)-6-(hydroxymethyl)tetrahydro-2h-pyran-4-yl acetate (i)
(3s,4s,5r,6r)-4-(benzyloxy)-6,8-bis[[tert-butyl(dimethyl)silyl]oxy]-3,5,7,7-tetramethyloctanal (v)
(1e)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,4-pentadien-3-ol (ix)
(1s,3z)-4-iodo-1-[(e)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate (xi)
Reference 1:
    gibson, f.s. (bristol-myers squibb co.); synthesis of paclitaxel baccatin iii by protecting the 7-hydroxyl using a strong base and an electrophile. wo 9945001 .

Route 40
6) the selective protection of baccatin iii (i) with tert-butoxycarbonyl anhydride and li-hmds in dmf gives 7-o-(tert-butoxycarbonyl)baccatin iii (vii), which is condensed with the chiral azetidinone (ix) by means of lithium tert-butoxide or li-hmds in thf and the reaction product, without isolation, is treated with trifluoroacetic acid and acetic acid.
List of intermediates No.
(2r,3r,4r,5r,6r)-3-(acetamido)-5-(acetoxy)-2-(1-ethylpropoxy)-6-(hydroxymethyl)tetrahydro-2h-pyran-4-yl acetate (i)
(1e)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,4-pentadien-3-ol (vii)
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 (ix)
Reference 1:
    gibson, f.s. (bristol-myers squibb co.); synthesis of paclitaxel baccatin iii by protecting the 7-hydroxyl using a strong base and an electrophile. wo 9945001 .

Route 41
the condensation of verbenone (i) with 1-bromo-3-methyl-2-butene (ii) by means of t-buok in dme, followed by ozonolysis of the aliphatic double bond gives acetaldehyde (iii), which is isomerized with uv light in methanol to the chrysanthenone derivative (iv). the condensation of (iv) with ethyl propynoate (v) by means of lda in thf, followed by silylation with tmscl affords the silylated 4-hydroxy-2-pentynoate (vi), which is cyclized by means of me2culi in ethyl ether giving the methanonaphthalene derivative (vii). the oxidation of the secondary oh group of (vii) with dess martin periodinane (dmp) yields the ketoester (viii), which is hydroxylated with davis oxaziridine to the ketonic dihydroxyester (ix). the reduction of the ester group of (ix) with lialh4 in ethyl ether affords the tetrahydroxy compound (x), which is protected by silylation with tbdms-cl and imidazole and ketalization with ppts and 2-methoxypropene providing the silylated acetonide (xi). the rearrangement of (xi) by means of mcpba, followed by silylation with tips-otf gives (xii) with the a-b-bicycle of taxol. the hydroxylation of (xii) with t-buok and oxygen, followed by reduction of its ketonic group with nabh4 yields the trihydroxy compound (xiii), which is stereoselectively reduced with h2 and crabtree catalyst, silylated with tmscl and treated with triphosgene to afford the cyclic carbonate (xiv). the oxidation of (xiv) with pyridinium chlorochromate (pcc) in dichloromethane gives the carbaldehyde (xv), which is condensed with methoxymethyl(triphenyl)phosphorane to yield the acetaldehyde derivative (xvi). the selective silylation of (xvi) with tes-cl, followed by oxidation of the remaining secondary oh group with dess martin periodinane (dmp) and methylenation acetaldehyde ch2 group with me2n-ch2-i affords the substituted propenoic aldehyde (xvii).
List of intermediates No.
phenyl (2s)-2-[[chloro(phenoxy)phosphoryl]amino]propanoate (ii)
2-amino-2-imino-n-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]ethanimidamide
2-[5-nitro-6-oxo-2-phenyl-1(6h)-pyrimidinyl]acetaldehyde (i)
2-amino-1-[5-(tert-butyl)-1,3,4-oxadiazol-2-yl]-3-methyl-1-butanone (iii)
n-(1-[[5-(tert-butyl)-1,3,4-oxadiazol-2-yl]carbonyl]-2-methylpropyl)-2-[5-nitro-6-oxo-2-phenyl-1(6h)-pyrimidinyl]acetamide (iv)
(3s,6r,7s,8s)-11-[(2r,3s)-3-[(2s,3e)-2-azido-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]-2-methyloxiranyl]-3,7-dihydroxy-4,4,6,8-tetramethyl-5-oxoundecanoic acid (v)
(3s,6r,7s,8s)-11-[(2r,3s)-3-[(2s,3e)-2-amino-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]-2-methyloxiranyl]-3,7-dihydroxy-4,4,6,8-tetramethyl-5-oxoundecanoic acid (vi)
(2r)-1-butyl-n-(2,6-dimethylphenyl)-2-piperidinecarboxamide (vii)
8-aminooctanoic acid (viii)
trimethylsilyl 8-[(trimethylsilyl)amino]octanoate (ix)
trimethylsilyl 8-[(2-hydroxybenzoyl)amino]octanoate (x)
2-chloro-1-[(2r)-4-(4-fluorobenzyl)-2-methylpiperazinyl]-1-ethanone (xi)
n-(5-chloro-2-hydroxyphenyl)urea (xii)
6-(benzyloxy)-1-hexyn-3-ol (xiii)
(1s)-1-[3-(benzyloxy)propyl]-2-propynyl acetate (xiv)
(3r)-6-(benzyloxy)-1-hexyn-3-ol (xv)
(1s)-1-[3-(benzyloxy)propyl]-2-propenyl acetate (xvi)
(3s)-6-(benzyloxy)-1-hexen-3-ol (xvii)
6,7-difluoro-1-[(1r,2s)-2-fluorocyclopropyl]-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid
3-{[(difluoroboryl)oxy]carbonyl}-6,7-difluoro-1-[(1r,2s)-2-fluorocyclopropyl]-8-methoxy-4(1h)-quinolinone
Reference 1:
    wender, p.a.; et al.; the pinene path to taxanes. 5. stereocontrolled synthesis of a versatile taxane precursor. j am chem soc 1997, 119, 11, 2755.
Reference 2:
    wender, p.a.; et al.; the pinene path to taxanes. 6. concise stereocontrolled synthesis of taxol. j am chem soc 1997, 119, 11, 2757.

Route 42
the grignard reaction of aldehyde (xvii) with allylmagnesium bromide in presence of zncl2, followed by protection of the resulting alcohol with benzyloxymethyl chloride (bom-cl) gives the intermediate (xviii), which by desilylation of nh4f; cleavage of the cyclic carbonate with ph-li and acylation of the oh group with ac2o yields the benzoate ester (xix). the transposition of the acetoxyketone grouping, catalyzed by the cyclic guanidine (xx) provides (xxi) with the correct stereochemistry of taxol. the ozonolysis of the terminal double bond of (xxi) gives aldehyde (xxii), which is cyclized by means of dmap in dichloromethane yielding the tricyclic alcohol (xxiii). the protection of the oh group of (xxiii) with 2,2,2-trichloroethyl chloroformate (troc-cl) affords the expected carbonate (xxiv), which is treated with nai and hcl in order to eliminate the bom protecting group to give the secondary alcohol (xxv). the reaction of (xxv) with ms-cl yields the mesylate (xxvi), which by reaction with libr is converted into the bromide (xxvii). the oxidation of (xxvii) with oso4, followed by a treatment with triphosgene affords the glycol (xxviii), which is cyclized with means of kcn and diea and acetylated with ac2o providing (xxix) with the oxetane ring of taxol.
List of intermediates No.
4-methyl-2h-oxet-2-one
(3s)-6-(benzyloxy)-1-hexen-3-ol (xvii)
([(1s)-1-[3-(benzyloxy)propyl]-2-propenyl]oxy)(tert-butyl)diphenylsilane; benzyl (4s)-4-[[tert-butyl(diphenyl)silyl]oxy]-5-hexenyl ether (xviii)
(4s)-4-[[tert-butyl(diphenyl)silyl]oxy]-5-hexen-1-ol (xix)
(4s)-4-[[tert-butyl(diphenyl)silyl]oxy]-5-hexenyl methanesulfonate (xx)
(4s)-4-[[tert-butyl(diphenyl)silyl]oxy]-5-oxopentyl methanesulfonate (xxi)
(5s)-5-[[tert-butyl(diphenyl)silyl]oxy]-2,3,4,5-tetrahydro-1-pyridiniumolate (xxii)
((4s)-4-[[tert-butyl(diphenyl)silyl]oxy]hexahydro-2h-isoxazolo[2,3-a]pyridin-2-yl)methanol (xxiii)
3-((3s)-3-[[tert-butyl(diphenyl)silyl]oxy]piperidinyl)-1,2-propanediol (xxiv)
tert-butyl (3s)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-(2,3-dihydroxypropyl)-1-piperidinecarboxylate (xxv)
1-[(4-methylphenyl)sulfonyl]-1h-imidazole (xxvi)
tert-butyl (3s)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-(2-oxiranylmethyl)-1-piperidinecarboxylate (xxvii)
tert-butyl (3s)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-[2-hydroxy-3-[4-oxo-3(4h)-quinazolinyl]propyl]-1-piperidinecarboxylate (xxviii)
tert-butyl (3s)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-[2-oxo-3-[4-oxo-3(4h)-quinazolinyl]propyl]-1-piperidinecarboxylate (xxix)
Reference 1:
    wender, p.a.; et al.; the pinene path to taxanes. 6. concise stereocontrolled synthesis of taxol. j am chem soc 1997, 119, 11, 2757.

Route 43
the deprotection of (xxix) with tris(diethylamino)sulfoxonium difluoro-trimethylsilyconate (tasf), followed by opening of the carbonate ring with ph-li gives baccatin iii (xxx), which can be converted into taxol by known methods.
List of intermediates No.
(2r,3r,4r,5r,6r)-3-(acetamido)-5-(acetoxy)-2-(1-ethylpropoxy)-6-(hydroxymethyl)tetrahydro-2h-pyran-4-yl acetate (xxx)
tert-butyl (3s)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-[2-oxo-3-[4-oxo-3(4h)-quinazolinyl]propyl]-1-piperidinecarboxylate (xxix)
Reference 1:
    wender, p.a.; et al.; the pinene path to taxanes. 6. concise stereocontrolled synthesis of taxol. j am chem soc 1997, 119, 11, 2757.

Route 44
the asymmetric dihydroxylation of methyl cinnamate (i) with ad-alpha reagent in tert-butanol/water gives the (2r,3s)-dihydroxyester (ii), which is treated with trimethyl orthobenzoate (iii) and tsoh in dichloromethane yielding the benzoate (iv). this compound, without isolation, is treated with acetyl bromide affording (2s,3r)-2-(benzoyloxy)-3-bromo-3-phenylpropionic acid methyl ester (v), which is treated with sodium azide in dmf to give the corresponding (2r,3s)-azido compound (vi). finally, this compound is reduced with h2 over pd/c in methanol to the corresponding amine that suffers a benzoyl transposition yielding the target side chain (vii).
List of intermediates No.
diacetyl [7-[(3s,4s)-3-amino-4-(fluoromethyl)pyrrolidinyl]-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinyl]carbonyl borate (i)
(3,5-diaminophenyl)methanol (iii)
[3-amino-5-[(7-chloro-4-quinolinyl)amino]phenyl]methanol (ii)
2-chloro-n-[3-[(7-chloro-4-quinolinyl)amino]-5-(hydroxymethyl)phenyl]acetamide (iv)
n-[3-[(7-chloro-4-quinolinyl)amino]-5-(hydroxymethyl)phenyl]-2-(1-piperidinyl)acetamide (v)
n-[3-[(7-chloro-4-quinolinyl)amino]-5-formylphenyl]-2-(1-piperidinyl)acetamide (vi)
Reference 1:
    hu, z.; et al.; utilization of a benzoyl migration to effect an expeditious synthesis of the paclitaxel c-13 side chain. org process res dev 1997, 1, 5, 387.

Route 45
2(r),3(s)-dihydroxy-3-phenylpropionic acid methyl ester, an intermediate in the paclitaxel side chain synthesis, can be prepared by the sharpless catalytic asymmetric dihydroxylation of methyl cinnamate (i) with k2oso4, n-methylmorpholine n-oxide (nmo) and a catalytic amount of 1,4-bis(9-o-dihydroquinine)phthalazine [(dhq)2phal] in tert-butanol/water. this reaction has been tested successfully in a 50-kg industrial process.
List of intermediates No.
diacetyl [7-[(3s,4s)-3-amino-4-(fluoromethyl)pyrrolidinyl]-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinyl]carbonyl borate (vii)
[3-amino-5-[(7-chloro-4-quinolinyl)amino]phenyl]methanol (ii)
Reference 1:
    lu, x.; et al.; process development of the sharpless catalytic asymmetric dihydroxylation reaction to prepare methyl (2r,3s)-2,3-dihydroxy-3-phenylpropionate. org process res dev 2000, 4, 6, 575.

Route 46
a novel semisynthetic method for the production of paclitaxel from 10-deacetylbaccantin-iii using dialkyldichlorosilanes has been reported:the protection of the 7-oh of 10-deacetylbaccatin-iii (i) by reaction first with dichlorodiethylsilane (ii) and imidazole and then with methanol gives 7-o-[diethyl(methoxy)silyl]baccatin-iii (iii), which is regioselectively acetylated at the 10-oh with acetylimidazole and lihmds to yield the acetate (iv). the esterification of (iv) with the chiral oxazolinecarboxylic acid (v) by means of lihmds affords the corresponding ester (vi), which is treated with tfa in hoac/water in order to perform desilylation and open the oxazoline ring to furnish paclitaxel. other silylating agents, such as dimethyldichlorosilane, dipropyldichlorosilane, diisopropyldichlorosilane, dibutyldichlorosilane and diphenyldichlorosilane, and other alcohols, such as etoh, proh, i-proh, t-buoh, 3,3,3-trifluoroethanol and others, can also be used in the silylation step.
List of intermediates No.
ethyl 3-[(2,5-dimethoxybenzyl)[2-(4-methoxybenzoyl)-1-benzofuran-3-yl]amino]-3-oxopropanoate (i)
3-benzoyl-2-methyl-1-azulenecarboxylic acid (v)
(1s,2s,3r,6s)-6-[((2r,3s,4s,5r,6r)-6-{[(2r,3s,4r,5r,6s)-6-{[(1r,2s,3r,4r,5r)-3,4-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-2-yl]oxy}-4,5-dihydroxy-2-(hydroxymethyl)tetrahydro-2h-pyran-3-yl]oxy}-4,5-dihydroxy-2-methyltetrahydro-2h-pyran-3-yl)amino]-4-(hydroxymethyl)-4-cyclohexene-1,2,3-triol (ii)
(1s,2s,3r,6s)-6-[((2r,3r,4r,5r,6r)-2-{[(2r,3s,4r,5r,6s)-6-{[(1r,2s,3r,4r,5r)-3,4-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-2-yl]oxy}-4,5-dihydroxy-2-(hydroxymethyl)tetrahydro-2h-pyran-3-yl]oxy}-3,5-dihydroxy-6-methyltetrahydro-2h-pyran-4-yl)amino]-4-(hydroxymethyl)-4-cyclohexene-1,2,3-triol (iii)
(2r,3r,4s,5r,6r)-3-(acetyloxy)-6-[(acetyloxy)methyl]-2-{[(1r,2r,3s,4r,5r)-3,4-bis(acetyloxy)-6,8-dioxabicyclo[3.2.1]oct-2-yl]oxy}-5-{[(2r,3r,4s,5r,6r)-3,4-bis(acetyloxy)-6-methyl-5-({(1s,4r,5s,6s)-4,5,6-tris(acetyloxy)-3-[(acetyloxy)methyl]-2-cyclohexen-1-yl}amino)tetrahydro-2h-pyran-2-yl]oxy}tetrahydro-2h-pyran-4-yl acetate (iv)
(2r,3r,4s,5r,6r)-3-(acetyloxy)-6-[(acetyloxy)methyl]-5-{[(2r,3r,4s,5r,6r)-3,4-bis(acetyloxy)-6-methyl-5-({(1s,4r,5s,6s)-4,5,6-tris(acetyloxy)-3-[(acetyloxy)methyl]-2-cyclohexen-1-yl}amino)tetrahydro-2h-pyran-2-yl]oxy}-2-({(2r,3r,4s,5r)-4,5,6-tris(acetyloxy)-2-[(acetyloxy)methyl]tetrahydro-2h-pyran-3-yl}oxy)tetrahydro-2h-pyran-4-yl acetate (vi)
Reference 1:
    dillon, j.l. jr.; vemishetti, p.; gibson, f.s. (bristol-myers squibb co.); semi-synthesis of paclitaxel using dialkyldichlorosilanes. wo 0073293 .

Route 47
a new synthesis of (3r,4s)-1-benzyl-4-phenyl-3-(triethylsilyloxy)azetidin-2-one (xiii), a precursor of the side chain of paclitaxel, has been described:the reaction of ethyl l-tartrate (i) with benzaldehyde and tsoh followed, by reduction with lialh4 and alcl3 gives the monobenzylated tretraol (ii), which is submitted to an oxidative cleavage of the alpha-diol bond with naio4 to yield the aldehyde (iii). reaction of (iii) with benzylamine affords the imine (iv), which is submitted to a grignard addition of phenylmagnesium bromide in ether providing a 1:9 mixture of aminoalcohols (vi) and (vii) separated by chromatography. oxidation of the desired major isomer (vii) with cro3/h2so4 gives the corresponding acid (viii), which is then esterified with tms-cl in refluxing methanol to the methyl ester (ix). deprotection of compound (ix) by hydrogenolysis with reluxing hco2h over pd/c yields 3(s)-amino-2(r)-hydroxy-3-phenylpropionic acid methyl ester (x), which is silylated at the oh group of with tes-cl and tea in ether/thf to afford the silyl ether (xi). cyclization of (xi) by means of lhmds in thf provides the beta-lactam (xii), which is finally benzoylated with benzoyl chloride and tea in the usual way.
List of intermediates No.
benzyl 4-[(2,6-dimethylanilino)carbonyl]-4-(methylamino)-1-piperidinecarboxylate (xiii)
2-(1-chloropropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (xii)
1-(2,6-dihydroxyphenyl)-1-ethanone (iv)
(2,3-dichloro-6-nitrophenyl)methanamine (i)
(1s,2s,3r,6s)-6-amino-4-(hydroxymethyl)-4-cyclohexene-1,2,3-triol (ii)
(4r,5s,6r)-4,5,6-trihydroxy-3-(hydroxymethyl)-2-cyclohexen-1-one (iii)
(2r,3r,4r,5s,6r)-5-{[(2s,3r,4r,5s,6r)-5-{[(2r,3r,4s,5s,6r)-5-amino-3,4-dihydroxy-6-methyltetrahydro-2h-pyran-2-yl]oxy}-3,4-dihydroxy-6-(hydroxymethyl)tetrahydro-2h-pyran-2-yl]oxy}-6-(hydroxymethyl)tetrahydro-2h-pyran-2,3,4-triol (v)
calcium (2s)-2-{[4-({[(6s)-2-amino-5-formyl-4-oxo-1,4,5,6,7,8-hexahydro-6-pteridinyl]methyl}amino)benzoyl]amino}pentanedioate (vi)
calcium (2s)-2-{[4-({[(6r)-2-amino-5-formyl-4-oxo-1,4,5,6,7,8-hexahydro-6-pteridinyl]methyl}amino)benzoyl]amino}pentanedioate (vii)
(6as)-3-amino-8-[4-({[(1s)-1,3-dicarboxypropyl]amino}carbonyl)phenyl]-1-oxo-1h,4h,5h,6h,6ah,7h,8h-imidazo[1,5-f]pteridin-10-ium (viii)
(6ar)-3-amino-8-[4-({[(1s)-1,3-dicarboxypropyl]amino}carbonyl)phenyl]-1-oxo-1h,4h,5h,6h,6ah,7h,8h-imidazo[1,5-f]pteridin-10-ium (ix)
(2s)-2-[(4-{[(2-amino-4-oxo-1,4-dihydro-6-pteridinyl)methyl]amino}benzoyl)amino]pentanedioic acid (x)
(2s)-2-[(4-{[(2-amino-4-oxo-1,4,7,8-tetrahydro-6-pteridinyl)methyl]amino}benzoyl)amino]pentanedioic acid (xi)
Reference 1:
    kim, h.-k.; kim, s.-c.; synthesis of new taxol side chain precursor from l-tartaric ester. bull korean chem soc 2000, 21, 10, 1047.

Route 48
the condensation of the acetylenic tetrahydropyranyl ether (i) with propionaldehyde (ii) by means of buli in thf gives 6-(tetrahydropyranyloxy)-4-hexyn-3-ol (iii), which by reduction with h2 over lindlar catalyst in hexane yields compound (iv). the swern oxidation of (iv) with oxalyl chloride in dichloromethane affords enone (v), which is condensed with the lithium enolate (vi) in thf to afford the addition keto ester (vii). cyclization of (vii) by means of potassium tert-butoxide, followed by acylation with pivaloyl chloride gives the cyclohexenone (viii). elimination of the tetrahydropyranyl protecting group of (viii) with tsoh in methanol yields the carbinol (ix), which is oxidized with oxalyl chloride and tea in dichloromethane to afford the carbaldehyde (x). the enolization of the aldehyde group of (x) with tipsotf, dbu and dmap in dichloromethane provides exclusively the (e)-enol ether (xi), which is submitted to a sharpless asymetric dihydroxylation using dhq-phn as a chiral ligand to give the chiral alpha-hydroxy aldehyde (xii). elimination of the pivaloyl group of (xii) with n,n-dimethylethylenediamine and potassium methoxide in refluxing benzene, followed by reprotection with tipscl in thf provides aldehyde (xiii). the reaction of the ketonic group of (xiii) with phsch(li)tms in thf affords the dienol silyl ether (xiv), which by condensation with 2-bromo-4,5-dihydrobenzaldehyde dibenzyl acetal (xv) by means of t-buli in the presence of t-bumgcl furnishes the expected addition compound (xvi) as a single isomer. protection of the vicinal diol of (xvi) with trimethyl borate and pyridine in benzene gives the boronic ester (xvii), which is cyclized by means of (i-pro)2ticl2 in dichloromethane to yield the polycyclic compound (xviii). the hydrolysis of the boronic ester of (xviii) with pinacol and dmap in benzene, followed by silylation with t-bu2sihcl and buli in thf affords the cyclic silyl ether (xix). reduction of the ketonic group of (xix) with dibal in dichloromethane, followed by silylation with tbdms-otf affords the silyl ether (xx), which is dihydroxylated by oxidation with o2 and light using tpp as catalyst, and desulfurized by treatment with bu3snh and aibn in refluxing benzene to provide diol (xxi).
List of intermediates No.
(2r)-5-[[amino(imino)methyl]amino]-2-[(tert-butoxycarbonyl)amino]pentanoic acid (ii)
1-carboxy-3-nitrobenzene; m-nitrobenzoic acid; 3-nitrobenzoic acid; 3-nitrodracylic acid (xiv)
4-((1e,3s,5z,10s)-3,11-bis[[tert-butyl(dimethyl)silyl]oxy]-2,10-dimethyl-1,5-undecadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (2s,6z,9s,10e)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,10-dimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienyl ether (xvii)
(2s)-2-{[4-({[(6s)-2-amino-4-oxo-1,4,5,6,7,8-hexahydro-6-pteridinyl]methyl}amino)benzoyl]amino}pentanedioic acid (i)
(2s)-2-{[4-({[(6s)-2-amino-5-({[(1r,2s,5r)-2-isopropyl-5-methylcyclohexyl]oxy}carbonyl)-4-oxo-1,4,5,6,7,8-hexahydro-6-pteridinyl]methyl}amino)benzoyl]amino}pentanedioic acid (iii)
(2s)-2-[(4-{[(2-amino-4-oxo-1,4,5,6,7,8-hexahydro-6-pteridinyl)methyl]amino}benzoyl)amino]pentanedioic acid (iv)
methyl (2s)-2-(benzylamino)-3-hydroxypropanoate (v)
(2s)-2-(benzylamino)-3-hydroxypropanamide (vi)
(2r)-3-amino-2-(benzylamino)-1-propanol (vii)
2-amino-6-chloro-5-nitro-4(1h)-pyrimidinone (viii)
2-amino-6-{[(2r)-2-(benzylamino)-3-hydroxypropyl]amino}-5-nitro-4(1h)-pyrimidinone (ix)
tert-butyl (1r)-2-[(2-amino-5-nitro-6-oxo-3,6-dihydro-4-pyrimidinyl)amino]-1-(hydroxymethyl)ethyl(benzyl)carbamate (x)
tert-butyl (1r)-2-[(2-amino-5-nitro-6-oxo-3,6-dihydro-4-pyrimidinyl)amino]-1-formylethyl(benzyl)carbamate (xi)
(2s)-2-[(4-aminobenzoyl)amino]pentanedioic acid (xii)
(2s)-2-[(4-{[(2s)-3-[(2-amino-5-nitro-6-oxo-3,6-dihydro-4-pyrimidinyl)amino]-2-(benzylamino)propyl]amino}benzoyl)amino]pentanedioic acid (xiii)
(2s)-2-{[4-({(2s)-2-amino-3-[(2,5-diamino-6-oxo-3,6-dihydro-4-pyrimidinyl)amino]propyl}amino)benzoyl]amino}pentanedioic acid (xv)
(2s)-2-{[4-({(2s)-2-amino-3-[(2-amino-5-imino-6-oxo-5,6-dihydro-4-pyrimidinyl)amino]propyl}amino)benzoyl]amino}pentanedioic acid (xvi)
(2s)-2-{[4-({(2s)-2-amino-3-[(2-amino-5,6-dioxo-5,6-dihydro-4-pyrimidinyl)amino]propyl}amino)benzoyl]amino}pentanedioic acid (xviii)
(2s)-2-{[4-({[(6r)-2-amino-4-oxo-1,4,5,6,7,8-hexahydro-6-pteridinyl]methyl}amino)benzoyl]amino}pentanedioic acid (xix)
(2s)-2-({4-[{[(6r)-2-amino-4-oxo-1,4,5,6,7,8-hexahydro-6-pteridinyl]methyl}(formyl)amino]benzoyl}amino)pentanedioic acid (xx)
Reference 1:
    kashima, h.; kusama, h.; hara, r.; morihira, k.; nakamura, n.; kuwajima, i.; kawahara, s.; nishimori, t.; enantioselective total synthesis of (-)-taxol. j am chem soc 2000, 122, 16, 3811.

Route 49
hydrogenation of (xxi) with h2 over pd/c in ethanol gives the triol (xxii), which is treated with benzaldehyde dimethyl acetal and camphorsulfonic acid (csa) in dichloromethane yielding the cyclic ketal (xxiii). the cyclopropanation of (xxiii) with chloro(iodo)methane and et2zn in toluene affords compound (xxiv), which is oxidized with dess-martin periodinane (dmpi) in dichloromethane providing the ketonic compound (xxv). the deproctection of (xxv) with h2 over pd(oh)2 in ethanol in order to remove the benzylidene ketal group, followed by reaction with triphosgene in order to form a cyclic carbonate and finally selective desilylation of the cyclic silyl ether with tbaf, furnishes diol (xxvi). the protection of the diol moiety of (xxvi) with benzaldehyde dimethylacetal, followed by cleavage of the cyclic carbonate with k2co3 in methanol provides the diol (xxvii), which is submitted to cyclopropane ring-opening with smi2 and tbaf in thf giving the enol (xxviii). enol-keto isomerization of (xxviii) by treatment with naome in methanol yields ketone (xxix), which is treated with phenylboronic acid and pyridine to afford the cyclic phenylboronic ester (xxx). silylation of the remaining hydroxy group of (xxx) with tbdms-otf gives the silyl ether (xxxi), which is then treated with h2o2 and nahco3 in water/ethyl acetate to remove the boron-protecting group and yielding diol (xxxii). the selective oxidation of diol (xxxii) with dess-martin periodinane in dichloromethane, followed by protection of the remaining oh group as a 2-methoxy-2-propyl (mop) ether by reaction with 2-methoxypropene (xxxiii) and ppts in thf gives diketone (xxxiv), which is enolized with phntf2 and khmds in thf yielding the enol triflate (xxxv).
List of intermediates No.
2-amino-2-imino-n-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]ethanimidamide (xxxiii)
2-[[tert-butyl(diphenyl)silyl]oxy]acetaldehyde (xxix)
(2s)-2-({4-[(8ar)-5-amino-1,7,8,8a-tetrahydro-3-oxa-2,4,6,7,8b-pentaazacyclopenta[bc]acenaphthylen-2(2ah)-yl]benzoyl}amino)pentanedioic acid (xxi)
(2s)-2-({4-[(8as)-5-amino-1,7,8,8a-tetrahydro-3-oxa-2,4,6,7,8b-pentaazacyclopenta[bc]acenaphthylen-2(2ah)-yl]benzoyl}amino)pentanedioic acid (xxii)
(2s)-2-{[4-({[(6s)-2-amino-5-formyl-4-oxo-1,4,5,6,7,8-hexahydro-6-pteridinyl]methyl}amino)benzoyl]amino}pentanedioic acid (xxiii)
(2s)-2-{[4-({[(6r)-2-amino-5-formyl-4-oxo-1,4,5,6,7,8-hexahydro-6-pteridinyl]methyl}amino)benzoyl]amino}pentanedioic acid (xxiv)
(4s)-4-{[4-({[(6s)-2-amino-5-formyl-4-oxo-1,4,5,6,7,8-hexahydro-6-pteridinyl]methyl}amino)benzoyl]amino}-5-[(2,6-dichlorobenzyl)oxy]-5-oxopentanoic acid (xxv)
1,3-diamino-2,2-dimethylpropane; neopentandiamine (xxvi)
3-[(3-{[(e)-2-(hydroxyimino)-1-methylpropylidene]amino}-2,2-dimethylpropyl)imino]-2-butanone oxime (xxvii)
(3s)-3-[(3-{[(1r)-2-(hydroxyimino)-1-methylpropyl]amino}-2,2-dimethylpropyl)amino]-2-butanone oxime (xxviii)
(3r)-3-[(3-{[(1r)-2-(hydroxyimino)-1-methylpropyl]amino}-2,2-dimethylpropyl)amino]-2-butanone oxime (xxx)
(6ar,9s)-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (xxxi)
(6ar,9s)-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinolin-9-yl isocyanate; (6ar,9s)-9-isocyanato-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline (xxxii)
n-[(6ar,9s)-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinolin-9-yl]-n,n-diethylurea (xxxiv)
n-[(6ar,9s,10as)-7-methyl-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinolin-9-yl]-n,n-diethylurea (xxxv)
Reference 1:
    kashima, h.; kusama, h.; hara, r.; morihira, k.; nakamura, n.; kuwajima, i.; kawahara, s.; nishimori, t.; enantioselective total synthesis of (-)-taxol. j am chem soc 2000, 122, 16, 3811.

Route 50
the introduction of a methylene group in (xxxv) by reaction with the grignard reagent tmsch2mgcl and pd(pph3)3 as catalyst in ethyl ether, affords the trimethylsilylmethyl compound (xxxvi), which is chlorinated with n-chlorosuccinimide (ncs) in methanol and treated with 2-methoxypropene (xxxiii) and ppts to provide the chloro derivative (xxxvii). regioselective hydroxylation of (xxxvii) is performed by enolization with lda, followed by oxidation with moo5/pyridine in hmpa and final acylation with ac2o to give the alpha-acetoxy compound (xxxviii). this acetate (xxxviii) is isomerized to the corresponding beta-isomer (xxxix) by heating with a base such as dbn. the dihydroxylation of the exo-methylene moiety of (xxxix) with oso4 and pyridine in ethyl ether yields the corresponding dihydroxy compound (xl), which is cyclized with dbu in refluxing toluene in order to form the oxetane ring of (xli). the removal of the mop group of (xli) with ppts, followed by reprotection with tes-cl in dmf gives the triethylsilyl ether (xlii). cleavage of the cyclic benzylidene ketal of (xlii) with h2 over pd(oh)2, followed by reaction with triphosgene and pyridine yields the cyclic carbonate (xliii), which is acetylated at the tertiary oh group of with acetic anhydride and dmap to yield the acetoxy compound (xliv). reaction of (xliv) with phenyl lithium in thf gives the benzoate (xlv), which is selectively desilylated with hf/pyridine and reprotected with 2,2,2-trichloroethyl chloroformate (troc-cl) yielding the intermediate (xlvi). compound (xlvi) is again desilylated with tris(diethylamino)sulfoxonium difluorotrimethylsiliconate (tasf) affording the secondary alcohol (xlvii).
List of intermediates No.
(2r,3r,4r,5r,6s)-3-(acetamido)-5-(acetoxy)-2-(1-ethylpropoxy)-6-formyltetrahydro-2h-pyran-4-yl acetate (xlvii)
2-amino-2-imino-n-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]ethanimidamide (xxxiii)
n-[(6ar,9s,10as)-7-methyl-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinolin-9-yl]-n,n-diethylurea (xxxv)
(6ar,9s,10ar)-7-methyl-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carboxamide (xxxvi)
(6ar,9s,10ar)-7-methyl-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carbohydrazide (xxxvii)
(6ar,9s,10ar)-7-methyl-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carbonyl azide (xxxviii)
(6ar,9s,10ar)-9-isocyanato-7-methyl-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline; (6ar,9s,10ar)-7-methyl-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinolin-9-yl isocyanate (xxxix)
1-(4-bromobutyl)-4,4-dimethyl-2,6-piperidinedione (xl)
3-[1-(4-fluorophenyl)-5-iodo-1,3-dihydro-2-benzofuran-1-yl]-n,n-dimethyl-1-propanamine; n-{3-[1-(4-fluorophenyl)-5-iodo-1,3-dihydro-2-benzofuran-1-yl]propyl}-n,n-dimethylamine (xli)
4-methyl-2-(1-phenylvinyl)phenol (xlii)
3-(2-hydroxy-5-methylphenyl)-3-phenylpropanal (xliii)
2-[(e)-3-(diisopropylamino)-1-phenyl-2-propenyl]-4-methylphenol (xliv)
copper (i) cyanide; cuprous cyanide (xlv)
(xlvi)
Reference 1:
    kashima, h.; kusama, h.; hara, r.; morihira, k.; nakamura, n.; kuwajima, i.; kawahara, s.; nishimori, t.; enantioselective total synthesis of (-)-taxol. j am chem soc 2000, 122, 16, 3811.

Route 51
condensation of (xlvii) with the chiral azetidinone (xlviii) by means of lihmds in thf provides the protected paclitaxel precursor (lix), which is finally deprotected with zn in hoac/water.
List of intermediates No.
(2r,3r,4r,5r,6s)-3-(acetamido)-5-(acetoxy)-2-(1-ethylpropoxy)-6-formyltetrahydro-2h-pyran-4-yl acetate (xlvii)
benzyl 4-[(2,6-dimethylanilino)carbonyl]-4-(methylamino)-1-piperidinecarboxylate (xlviii)
1,2-dichloro-3-{cyano[(z)-2-(diaminomethylene)hydrazono]methyl}benzene (xlix)
Reference 1:
    kashima, h.; kusama, h.; hara, r.; morihira, k.; nakamura, n.; kuwajima, i.; kawahara, s.; nishimori, t.; enantioselective total synthesis of (-)-taxol. j am chem soc 2000, 122, 16, 3811.

Route 52
alternatively, condensation of the dienol silyl ether intermediate (xiv) with 2-bromobenzaldehyde dibenzyl acetal (l) by means of t-buli in the presence of t-bumgcl in thf furnishes the expected addition compound (li).protection of the vicinal diol moiety of (li) with trimethyl borate and pyridine in benzene gives the boronic ester (lii), which is cyclized by means of sncl4 in dichloromethane to yield the tricarbocyclic compound (liii). hydrolysis of the boronic ester of (liii) with pinacol and dmap in benzene affords the vicinal diol (liv), which is reduced at the keto group with dibal in dichloromethane and silylated at the resulting alcohol with tbdms-otf in the same solvent to give the fully protected intermediate (lv). elimination of the phenylthio group of (lv) by means of bu3snh and aibn in refluxing benzene yields the tricyclic compound (lvi), which is debenzylated with h2 over pd/c and treated with swern oxidant to provide ketone (lvii). selective hydrogenation of (lvii) with potassium in liquid ammonia in the presence of 2,2,4-trimethyl-3-isopropyl-3-pentanol furnishes the dihydro intermediate (lviii), which is selectively desilylated with tbaf in thf to yield the vicinal diol (lix). silylation of diol (lix) with t-bu2sihcl and buli in thf affords the cyclic silyl ether (lx), which is reduced at the carbonyl group with nabh4 and cecl3 in methanol giving the secondary alcohol (lxi). finally, this compound is dihydroxylated by oxidation with o2, light and rose bengal as photoinductor to furnish the triol (xxii), already reported.
List of intermediates No.
1-carboxy-3-nitrobenzene; m-nitrobenzoic acid; 3-nitrobenzoic acid; 3-nitrodracylic acid (xiv)
(2s)-2-({4-[(8as)-5-amino-1,7,8,8a-tetrahydro-3-oxa-2,4,6,7,8b-pentaazacyclopenta[bc]acenaphthylen-2(2ah)-yl]benzoyl}amino)pentanedioic acid (xxii)
potassium cyanide (l)
cyanopotassium (li)
cyanocopper (lii)
2-(2,3-dichlorophenyl)-2-oxoacetonitrile (liii)
thiourea (liv)
{[amino(imino)methyl]sulfanyl}methane (lv)
hydrazine (lvi)
(lvii)
1,2-dichloro-3-{cyano[(z)-2-(diaminomethylene)hydrazono]methyl}benzene (lviii)
bis(4-fluorophenyl)methyl 2-iodoethyl ether; 1-fluoro-4-[(4-fluorophenyl)(2-iodoethoxy)methyl]benzene (lix)
(2r,3r,4r,5r)-4-(benzoyloxy)-5-[(benzoyloxy)methyl]-3-{[(trifluoromethyl)sulfonyl]oxy}tetrahydro-2-furanyl benzoate (lx)
(2r,3s,4r,5r)-4-(benzoyloxy)-5-[(benzoyloxy)methyl]-3-fluorotetrahydro-2-furanyl benzoate (lxi)
Reference 1:
    kashima, h.; kusama, h.; hara, r.; morihira, k.; nakamura, n.; kuwajima, i.; kawahara, s.; nishimori, t.; enantioselective total synthesis of (-)-taxol. j am chem soc 2000, 122, 16, 3811.

Route 53
the reaction of baccatine iii (i) with trichloroacetyl chloride in pyridine gives 7-o-(trichloroacetyl)baccatine iii (ii), which is condensed with 2,3-epoxy-3-phenylpropionic acid (iii) by means of dcc and dmap in toluene to yield the ester (iv). opening of the epoxide ring of (iv) by means of sodium azide and methyl formate in methanol affords the expected hydroxy azide (v), which is reduced with pph3 in dichloromethane/water to provide the corresponding amino derivative (vi). finally, the amino group of (vi) is benzoylated with benzoyl chloride (vii) and nahco3 in ethyl acetate/water to furnish the target paclitaxel.
List of intermediates No.
(2r,3r,4r,5r,6r)-3-(acetamido)-5-(acetoxy)-2-(1-ethylpropoxy)-6-(hydroxymethyl)tetrahydro-2h-pyran-4-yl acetate (i)
(3-amino-1-benzofuran-2-yl)(4-methoxyphenyl)methanone (vii)
diethyl 2-(diethylamino)-2-oxoethylphosphonate (vi)
3-chloro-4-(4-chlorobutyl)-1,4-benzoxazepin-5(4h)-one (iii)
3-[1-(3,5-dimethoxybenzyl)-4-piperidinyl]-6-fluoro-1,2-benzisoxazole; 3-[[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]methyl]-5-methoxyphenyl methyl ether (ii)
Reference 1:
    bombardelli, e.; pontiroli, a.; battaglia, a.; dambruoso, p.; guerrini, a. (indena spa); a process for the preparation of paclitaxel. wo 0246177 .

Route 54
the asymmetric dihydroxylation of trans-cinnamic acid ethyl ester (i) with ad mix alpha gives (2r,3s)-2,3-dihydroxy-3-phenylpropionic acid ethyl ester (ii), which is submitted to the cyclic iminocarbonate rearrangement protocol with bu4sno, phco-ncs and mgi2 to yield the chiral oxazolidinone (iii). the hydrolysis of (iii) in refluxing 10% hcl affords (2r,3s)-3-amino-2-hydroxy-3-phenylpropionic acid (iv), which is finally n-benzoylated by means of benzoyl chloride and naoh to provide the target side chain acid (v).
List of intermediates No.
benzyl (5s)-6-[[tert-butyl(dimethyl)silyl]oxy]-5-methylhexyl ether; [[(2s)-6-(benzyloxy)-2-methylhexyl]oxy](tert-butyl)dimethylsilane (v)
Reference 1:
    cho, g.y.; et al.; improving the regioselectivity in the cyclic iminocarbonate rearrangement: enantioselective synthesis of the paclitaxel side chain. bull korean chem soc 2001, 22, 4, 432.

Route 55
the grignard reaction of phenylmagnesium bromide (i) with 11c labeled co2 (ii) in thf gives the radiolabeled benzoic acid (iii), which is treated with phthaloyl dichloride (iv) in the same solvent to yield radiolabeled benzoyl chloride (v). finally, this compound is treated with n-debenzoylated paclitaxel (vi) in acetonitrile to afford the target radiolabeled paclitaxel.
List of intermediates No.
4-methoxybenzyl (7r)-7-([2-([[(1s)-2-(benzhydryloxy)-1-methyl-2-oxoethyl]oxy]imino)-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetyl]amino)-8-oxo-3-[([1,3]thiazolo[4,5-c]pyridin-2-ylsulfanyl)methyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (iii)
(3-amino-1-benzofuran-2-yl)(4-methoxyphenyl)methanone (v)
diethyl 2-(diethylamino)-2-oxoethylphosphonate (vi)
2-chloro-1-[4-(2,3,4-trimethoxybenzyl)-1-piperazinyl]-1-ethanone (i)
1-(methylsulfonyl)-2-imidazolidinone (iv)
Reference 1:
    ravert, h.t.; et al.; radiosynthesis of [11c]paclitaxel. j label compd radiopharm 2002, 45, 6, 471.

Route 56
the reaction of (2r,3s)-phenylisoserine (i) with 2-propynyl chloroformate (ii) in aq. nahco3 gives the n-acylated compound (iii), which is treated with diazomethane in ethyl ether (cdi and methanol) to yield the corresponding methyl ester (iv). the reaction of (iv) with 2-methoxypropene (v) and pyridinium p-toluenesulfonate in toluene affords the oxazolidine (vi), which is treated with lioh in water to provide the oxazolidine-5-carboxylic acid (vii). the esterification of 7-o-(trichloroethoxycarbonyl)baccatin (viii) with acid (vii) by means of dcc in toluene gives the corresponding ester (ix), which is treated with ammonium tetrathiomolybdate to cleave the oxazolidine ring and yield the 3-amino-2-hydroxypropionyl ester (x). the reaction of (x) with benzoyl chloride (xi) and nahco3 in ethyl acetate affords the expected benzamido derivative (xii), which is finally deprotected by means of zn and acoh to afford the target paclitaxel.
List of intermediates No.
(2r,3r,4r,5r,6s)-3-(acetamido)-5-(acetoxy)-2-(1-ethylpropoxy)-6-formyltetrahydro-2h-pyran-4-yl acetate (viii)
(3-amino-1-benzofuran-2-yl)(4-methoxyphenyl)methanone (xi)
2-[5-(1-cyanoethyl)-2-(phenylsulfanyl)phenyl]acetic acid (x)
2-amino-2-imino-n-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]ethanimidamide (v)
Reference 1:
    sharma, a.p.; sarkar, s. (dabur india ltd.); method of preparation of paclitaxel (taxol) using 3-(alk-2-ynyloxy)carbonyl-5-oxazolidine carboxylic acid. wo 0266448 .

Route 57
the hydrogenation of the protected taxol derivative (i) with h2 over pd/c in aqueous thf in the presence of hcl gives the 3-amino-taxol derivative (ii), which is n-benzoylated by means of benzoyl chloride (iii) and tea to provide the target paclitaxel.
List of intermediates No.
(3-amino-1-benzofuran-2-yl)(4-methoxyphenyl)methanone (iii)
diethyl 2-(diethylamino)-2-oxoethylphosphonate (ii)
Reference 1:
    mcchesney, j.d.; zygmunt, j. (napro biotherapeutics, inc.); two-step conversion of protected taxane ester to paclitaxel. wo 0285878 .

Route 58
the hydrogenation of the protected taxol derivative (i) with h2 over pd/c in aqueous thf gives the 3-amino-2-o-bom protected taxol derivative (ii), which is n-benzoylated by means of benzoyl anhydride (iii) to provide the 2-o-bom protected taxol (iv). finally this compound is deprotected by hydrogenation with h2 over pd/c in thf/water in the presence of hcl or h2so4 to afford the target paclitaxel.
List of intermediates No.
tert-butyl 4-aminobutyl[3-[(tert-butoxycarbonyl)amino]propyl]carbamate (iv)
Reference 1:
    mcchesney, j.d.; zygmunt, j. (napro biotherapeutics, inc.); three-step conversion of protected taxane ester to paclitaxel. wo 0285879 .

Route 59
the cyclization of 2(r),3(s)-dihydroxy-3-phenylpropionic acid methyl ester (i) with benzonitrile (ii) by means of conc. h2so4 gives 2,4(s)-diphenyloxazolidine-5(s)-carboxylic acid methyl ester (iii). finally, this compound is submitted to an hydrolytic treatment with aq. h2so4 to afford the target 3(s)-benzamido-2(r)-hydroxy-3-phenylpropionic acid (iv).
List of intermediates No.
1,4-benzoxazepine-3,5(2h,4h)-dione (i)
1,2,3,4-tetrahydro[1]benzofuro[3,2-c]pyridine (ii)
benzyl (5s)-6-[[tert-butyl(dimethyl)silyl]oxy]-5-methylhexyl ether; [[(2s)-6-(benzyloxy)-2-methylhexyl]oxy](tert-butyl)dimethylsilane (iv)
Reference 1:
    voronkov, m.v.; et al.; improved large-scale synthesis of phenylisoserine and the taxol c-13 side chain. tetrahedron lett 2003, 44, 2, 407.

来源:药化网

作者:药化小编

摘要:本文合成路线介绍的是药物中文名紫杉醇;英文名Intaxel(from Himalayan Yew);Paclitaxel;MPI-5018(with Matrixs anhydrous delivery system);BMS-181339;NSC-125973;Xorane;Genaxol;Pacligel;Paxceed;Genexol;Paxoral(oral formulation);Paxene;Yewtaxan;Anzatax;Taxol;CAS[33069-62-4]

 
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