合成路线1

The cyclization of the chiral diene (I) with acrolein (II) by means of BF3/Et2O in dichloromethane gives the chiral cyclohexene (III), which is dihydroxylated under Upjohn conditions (OsO4) yielding the dihydroxy compound (IV). The reaction of (IV) with acetone (V) and TsOH affords the isopropylidene derivative (VI), which is treated with NaOH in THF/water to eliminate the chiral auxiliary to yield the cyclohexene carbaldehyde (VII). The regio- and diastereoselective condensation of (VII) with bromide (VIII) by means of t-BuLi and BF3/Et2O affords the adduct (IX), which is treated with N-cyclohexyl-hydroxylamine (X) to provide the nitrone (XI). The reaction of (XI) with acetyl chloride gives the alpha-acetoxy-N-cyclohexylimine (XIII), through the intermediate (XII). The hydrolysis of (XIII) with AcOH and NaOAc yields the carbaldehyde (XIV), which is reduced with LiAlH4 in ethanol to afford the hydroxymethyl derivative (XV). The hydrolysis of the acetoxy and isopropylidene groups of (XV) by means of HCl in THF provides the tetrahydroxy derivative (XVI), which is converted into the epoxide (XVII) by a treatment with MsCl, TEA, DMAP and NaOH in dichloromethane. A new epoxidation of (XVII) by means of VO(acac)2 and t-BuOOH in benzene gives the bis-epoxide compound (XVIII), which is finally monomethylated by means of t-BuONa and MeI in THF to yield the target intermediate fumagillol (XIX).

合成路线2

The oxidation of acetone (I) with butyl nitrite (II) with a catalytic amount of HCl gives methylglyoxal 1-oxime (III), which is then condensed with aminoguanidine (IV) in hot water acidified with HCl.

合成路线3

The condensation of 6-methoxy-2-naphthaldehyde (I) with acetone by means of NaOH in water gives 4-(6-methoxy-2-naphtyl)-3-buten-2-one (II), which is reduced with H2 over Pd/C in ethyl acetate.

合成路线4

By condensation of 2-cyanaziridine (I) [or a mixture of (I) and 2-carbamoylaziridine (II)] with acetone (III) by means of triethylamine.

合成路线5

The condensation of 1-ethyl-5-aminopyrazole (I) with diethyl ethoxymethylenemalonate (II) by heating at 120 C gives diethyl [((1-ethyl-5-pyrazolyl)amino)methylene]malonate (III), which by heating at 235-5 C in diphenyl ether is converted into ethyl 1-ethyl-4-hydroxy-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (IV). The reaction of (IV) with ethyl iodide (A) and K2CO3 in DMF affords ethyl 1-ethyl-4-ethoxy-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (V), which is condensed with hydrazine in refluxing ethanol with ZnCl2 yielding ethyl 1-ethyl-4-hydrazino-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (VI). Finally, (VI) is condensed with refluxing acetone (B).

合成路线6

The esterification of potassium phenoxymethylpenicillanate (I) with chloromethyl methyl ether (A) in methylene chloride-THF gives the methoxymethyl ester of penicilline V (II), which is then treated with dimethylaniline (B) in CH2Cl2 to afford methoxymethyl 6-aminopenicillanate (III). Finally, this product is condensed with phenylglycyl chloride (C) hydrochloride and acetone (D) by means of NaOH.

合成路线7

The condensation of acetone (VIII) with 2-methoxybenzaldehyde (IX) by means of NaOH gives 2-methoxybenzalacetone (X), which is reduced with H2 over Raney-Ni in ethanol to yield 4-(2-methoxyphenyl)-2-butanone (XI). The Grignard reaction of (XI) with methylmagnesium iodide in ether affords 1,1-dimethyl-3-(2-methoxyphenyl) propanol (XII), which by reaction with NaCN by means of H2SO4 in acetic acid affords N-[1,1-dimethyl-3-(2-methoxyphenyl)propyl]formamide (XIII). Finally, this compound is hydrolyzed with refluxing 5N NaOH to give (II).

合成路线8

By condensation of 5-(4-methoxy-2,3,6-trimethylphenyl)-3-methylpenta-2,4-diene-1-triphenylphosphonium bromide (I) with 3-formylcrotonic acid butyl ester (II) by means of NaH in DMF to yield 9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethylnona-2,4,6,8-tetraen-1-oic acid butyl ester (III), which is then hydrolyzed with KOH in refluxing ethanol - water. The starting products (I) and (II) are obtained as follows: 1) The methylation of 2,3,5-trimethylphenol (IV) with KOH and methyl iodide in refluxing aqueous ethanol gives 2,3,5-trimethylanisole (V), which is then carbonylated with POCl3 and DMF (A) to afford 4-methoxy-2,3,6-trimethylbenzaldehyde (VI). The condensation of (VI) with acetone (B) by means of NaOH gives 4-(4-methoxy-2,3,6-trimethylphenyl)-3-buten-2-one (VII), which by a Grignard reaction with ethynylmagnesium bromide (C) in THF is converted into 5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-3-hydroxy-4-penten-1-yne (VIII). The controlled hydrogenation of (VIII) with H2 over a Pd catalyst in hexane yields 5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-3-hydroxy-1,4-pentadiene (IX), which is finally treated with triphenylphosphonium bromide in benzene at 60 C to give the phosphonium salt (I). 2) The oxidation of dibutyl L-(+)-tartrate (X) with lead tetraacetate in benzene gives butyl glyoxalate (XI), which is then condensed with propionic aldehyde (D) by means of dibutylamine (E) to afford ester (II).

合成路线9

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

合成路线10

Reaction of 4-methylthiobenzaldehyde (I) with acetone (A) affords in a 90% yield E-4-methylmercaptophenyl-3-buten-2-one (II), which is oxidized by sodium periodate to the sulfoxide (III) in a 55% yield without forming any sulfone as byproduct. The sulfoxide then reacts with 4-hydroxycumarin without solvent at 140 C to form methylsulfinylwarifarin. The compound is purified by extraction from ether with a 1% sodium hydroxide solution and then precipitated with 10% hydrochloric acid. The yield of the last step is 30% of theory.

合成路线11

The reaction of 4-hydroxy-2-methyl-indole (V) with 1-(N-benzylisopropylamino)-3-chloro-2-propanol (D) by means of NaOH in refluxing aqueous dioxane yields the corresponding benzylamine (X), which is debenzylated by catalytic hydrogenation. The reaction of 4-hydroxy-2-methyl-indole (V) with epichlorohydrin (A) and benzylamine (B) gives 4-(3-benzylamino-2-hydroxypropoxy)-2-methyl-indole (XI), which is debenzylated by hydrogenolysis to 4-(3-amino-2-hydroxypropoxy)-2-methyl-indole (XII). The condensation of (XII) with refluxing acetone (C) affords the corresponding N-isopropylidene derivative (XIII), which is finally hydrogenated with H2 over Pd/C in methanol.

合成路线12

The methylation of 2,3,5-trimethylphenol (I) with MeI and KOH in 10% aqueous ethanol gives 2,3,5-trimethylanisole (II), which is formylated with DMF and POCl3 yielding 2,3,6-trimethyl-p-anisylaldehyde (III). The condensation of (III) with acetone (B) by means of NaOH affords 4-(4-methoxy-2,3,6-trimethylphenyl)but-3-en-2-one (IV), which by a Grignard reaction with ethynylmagnesium bromide (C) in THF is converted into the acetylenic alcohol (V). Partial hydrogenation of (V) with H2 over Pd/C in hexane gives dienic alcohol (VI), which is condensed with triphenylphosphine hydrobromide in benzene affording 5-(4-methoxy-2,3,6 trimethylphenyl)-3-methylpenta-2,4-diene-1-triphenylphosphonium bromide (VII). A Wittig condensation of (VII) with butyl 3-formylcrotonate (VIII) by means of NaH in DMF gives butyl 9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethylnona-2,4,6,8-tetraenoate (IX), which is hydrolyzed with KOH in refluxing ethanol-water yielding the corresponding free acid (X). This acid is converted into the acyl chloride (XI) by treatment with PCl3 in refluxing benzene. Finally, this compound is treated with ethylamine (E) in ether. The butyl 3-formylcrotonate (VIII) is obtained as follows: The oxidation of dibutyl tartrate (XII) with lead tetraacetate in benzene gives butyl glyoxalate (XIII), which is then condensed with propionaldehyde (XIV) by heating at 110 C with dibutyl-amine (D).

合成路线13

The reaction of 2,3,5-trimethylanisole (II) [prepared by alkylation of 2,3,5-trimethylphenol (I) with methyl iodide] with DMF and POCl3 affords 4-(4-methoxy-2,3,6-trimethylbenzaldehyde (V), which is condensed with propanone (B) in aqueous NaOH giving 4-(4-methoxy-2,3,6-trimethylphenyl)-but-3-en-2-one (VI). The Grignard reaction of (VI) with ethynylmagnesium bromide (C) in THF yields 5-(4-methoxy-2,3,6-trimethylphe-nyl)-3-methyl-3-hydroxypenta-4-en-1-yne (VII), which is partially hydrogenated with H2 over deactivated Pd in hexane to give 5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-3-hydroxypenta-1,4-diene (VIII). The reaction of (VIII) with triphenylphosphonium hydrobromide in benzene affords 5-(4-methoxy-2,3,6-trimethylphenyl)-3-methylpenta-2,4-diene-1-triphenylphosphonium bromide (IX). Finally, this compound is submitted to a Wittig reaction with ethyl 3,4-formylcrotonate (D) in DMF (NaH is used as base).

合成路线14

Condensation of D-mannitol (I) with acetone by means of zinc chloride gives 1,2,5,6-di-O isopropylidene-D-mannitol (II), which on treatment with dimethyl sulfate in DMSO in the presence of NaOH gives the 3,4-di-O-methyl derivative (III). Removal of the isopropylidene groups of (III) by HCl in boiling ethanol gives 3,4-di-O-methyl-o-mannitol (IV), a solution of which in pyridine is treated with methanesulfonyl chloride and subsequently with acetic anhydride to give 1,6-di-O-methylsulfonyl-2,5-di-O-acetyl-3,4-di-O-methyl-D-mannitol (V), deacetylation of which is carried out in methanol by means of hydrochloric acid.

合成路线15

The condensation of 3-methoxybenzaldehyde (I) with acetone (II) by means of NaOH gives 1-(3-methoxyphenyl)-1-buten-3-one (III), which is hydrogenated with H2 over Pd/C in methanol yielding 1-(3-methoxyphenyl)-3-butanone (IV). The iodination of (IV) with I2-silver acetate in acetic acid affords 1-(2-iodo-5-methoxyphenyl)-3-butanone (V), which is reductocondensed with methylamine and sodium cyanoborohydride in methanol giving 2-iodo-5-methoxy-N,alpha-dimethylphenylpropanamine (VI). The acylation of (VI) with 3,4-dimethoxyphenylacetyl chloride (VII) by means of triethylamine in dichloromethane yields the corresponding acetamide (VIII), which is reduced with borane-THF complex affording the corresponding tertiary amine (IX), which is finally condensed with phenylacetylene (X) by means of butyllithium in THF.

合成路线16

The Sandmeyer reaction of 4-(2',2'-dichlorocyclopropyl)aniline (I) first with NaNO2 and acetic acid and then with 33% aqueous H2SO4 at 100 C gives 4-(2',2'-dichlorocyclopropyl)phenol (II), which is then condensed with acetone (A) and CHCl3 by means of NaOH in refluxing acetone.

合成路线17

The condensation of 2-(bromomethyl)-2-(2,4-dichlorophenyl)-4-(benzoyloxymethyl)-1,3-dioxolane (I) with triazole (II) by means of NaH in DMSO, followed by hydrolysis with NaOH in dioxane water gives 2-(2,4-dichlorophenyl)-2-(1H)-1,2,4-triazol-1-ylmethyl)-1,3-dioxolane-4-methanol (III), which is acylated with methanesulfonyl chloride in pyridine affording the corresponding 4-mesyloxymethyldioxolane (IV). Finally, this compound is condensed with 4-(4-isopropylpiperazin-1-yl)phenol (V) by means of NaH in hot DMSO. Compound (V) is obtained as follows: 4-(4-methoxyphenyl)piperazine (VI) is reductocondensed with acetone (A) by means of H2 over Pd/C giving 1-isopropyl-4-(4-methoxyphenyl)piperazine (VII), which is then demethylated with refluxing aqueous 48% HBr yielding (V)

合成路线18

For the synthesis of umespirone the following synthesis pathway was chosen: Acetone is condensed with ethyl cyanoethanoate (I) to yield ethylisopropylidenecyanoacetate (II). This product is reacted with N-butylcyanoacetamide (III) in sodium methoxide solution to give N-butyl-2,4-dicyano-3,3-dimethylglutarimide (IV). The glutarimide (IV) is cyclized with phosphoric acid to yield 3-butyl-9,9-dimethyl-3,7-diazabicyclo[3.3.1]nonane-2,4,6,8-tetraone (V). The quaternary salt (VIII) (R = CH3), prepared from 1-(2-methoxyphenyl)piperazine (VI) and 1,4-dibromobutane (VII), undergoes reaction with (V) in the presence of potassium carbonate to afford the free base KC-9172 (IX) (R = CH3).

合成路线19

By condensation of 2,6-ditertbutyl-4-mercaptophenol (I) with acetone (II) in refluxing methanol with a catalytic amount of HCl.

合成路线20

Condensation of imidate (I) with glycine ethyl ester (II) in refluxing acetone yielded imidazolone (III). Subsequent alkylation with N-triphenylmethyl-5-[4'-bromomethyl)biphenyl-2-yl]tetrazole (IV) in the presence of potassium tert-butoxide in cold DMF provided (V), which was finally deprotected by refluxing in a methanolic solution of AcOH to afford the title compound.

合成路线21

Androstenedione (II) was converted to the C-17 cyanohydrin (III) by treatment with either KCN and AcOH or with acetone cyanohydrin and NaOH. Ketalization of the remaining 3-keto group with ethylene glycol and trimethyl orthoformate led to (IV). The C-17 hydroxyl was then protected by formation of the acetaldehyde mixed ketal (V) by treatment with butyl vinyl ether. Addition of methyllithium to the cyano group, followed by acidic ketal hydrolysis furnished the pregnenedione (VI). Subsequent iodination of (VI) by means of iodine and calcium oxide gave iodo ketone (VII), which was further displaced by potassium acetate yielding the C-21 acetate ester (VIII). Finally, dehydration of the C-17 alcohol employing 70% aqueous sulfuric acid produced the title compound.

合成路线22

A practical total synthesis of KRN-7000 has been reported: The reaction of D-lyxofuranose (I) with acetone and sulfuric acid gives the acetonide (II), which is tritiated with trityl chloride and pyridine in dichloromethane to the protected lyxose (III). The condensation of (III) with triphenyltridecylphosphonium bromide (IV) by means of butyllithium in THF yields the alcohol (V) with the suitable (2R,3S,4R)-configuration. The mesylation of (V) with mesyl chloride and pyridine affords the mesylate (VI), which is treated with aqueous HCl in dichloromethane to obtain the unsaturated triol (VII). The hydrogenation of (VII) with H2 over Pd-BaSO4 in THF affords (2R,3R,4R)-2-(methanesulfonyloxy)octadecane-1,3,4-triol (VIII), which by reaction with sodium azide in hot DMF yields the corresponding azide (IX). The protection of the primary alcohol of (IX) with trityl chloride and pyridine affords the azide diol (X), which is treated with benzyl bromide and NaH in DMF to give the fully protected triol (XI). The reduction of the azido group of (XI) with H2 over Pd/C in propanol/methanol affords the amine (XII), which is acylated with hexacosanoic acid (XIII) and WSC-HCl yielding the corresponding amide (XIV). Elimination of the trityl group of (XIV) with HCl in methanol/dichloromethane gives the primary alcohol (XV), which is condensed with tetra-O-benzyl-beta-D-galactopyranosyl bromide (XVI) by means of tetrahexylammonium bromide in toluene/DMF yielding the fully benzylated KRN-7000 (XVII). Finally, this compound is debenzylated by a treatment with Pd(OH)2 on charcoal and 4-methylcyclohexene in ethanol.

合成路线23

The aldol condensation of 2-methyl-3-(2-methylthiazol-4-yl)-2-propenal (XIX) with acetone (XX) catalyzed by antibody 38C2 gives the chiral aldol (XXI), which is protected with Tbdms-Cl and imidazole, yielding the silyl ether (XXII). The reaction of (XXII) with Tbdms-OTf, followed by oxidation with MCPBA and reduction with NaBH4, affords the vicinal diol (XXIII), which is cleaved with Pb(OAc)4 to provide the aldehyde (XXIV). The Wittig condensation of (XXIV) with phosphonium salt (XV) gives olefinic silyl ether (XXV), which is desilylated with TBAF in THF to yield the homoallylic alcohol (XXVI). The esterification of alcohol (XXVI) with the previously described carboxylic acid (XVIII) by means of EDC in dichloromethane affords the ester (XXVII), which is submitted to a ring-closing metathesis by means of Grubb's catalyst to provide the macrolactone (XXVIII). The desilylation of (XXVIII) with HF and pyridine furnishes the precursor (XXIX), which is finally epoxidated with trifluoroacetone and oxone to give the target epothilone A.

合成路线24

Activation of butyric acid derivative (I) with isobutyl chloroformate (II) by means of Et3N in THF, followed by coupling with ethylamine (III) in THF in the presence of Et3N, yields butyramide derivative (IV). Reduction of (IV) by means of (-)-B-chlorodiisopinocampheylborane (Ipc2BCl) in THF, followed by reaction with diethanolamine (A), affords hydroxy derivative (V), whose carbonyl group is removed by means of sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al) in toluene/THF, followed by treatment with H2SO4 to provide compound (VI) . Separately, the synthesis of intermediate (XIV) is performed as follows: condensation of pentamethylene chlorohydrin (VII) with 3,4-dihydro-2H-pyran (VIII) by means of p-toluenesulfonic acid in Et2O furnishes 5-chloropentyl-2-tetrahydropyranyl ether (IX), which is then subjected to reaction with acetone (X) in THF by means of Mg in the presence of 1,2-dibromoethane (B) to provide tetrahydropyranyl ether (XI). Conversion of hydroxy derivative (XI) into the corresponding fluoro derivative (XII) is performed by reaction with diethylaminosulfur trifluoride (DAST) in CH2Cl2, and posterior reaction of (XII) with pyridinium p-toluenesulfonate in EtOH furnishes 6-fluoro-6-methyl-1-heptanol (XIII). Finally, intermediate (XIV) is obtained by reaction of (XIII) with NBS and PPh3 in benzene. Condensation of secondary amine (VI) with intermediate (XIV) by means of NaHCO3 in refluxing acetonitrile provides methanesulfonamide (XV), which is finally converted into the target product by formation of the hemifumarate salt by treatment with fumaric acid (XVI) in acetone.

合成路线25

The reaction of 14C-labeled acetone (I) with O-benzylhydroxylamine (II) and pyridine in refluxing ethanol gives the corresponding oxime (III), which is methylated with MeLi and BF3.Et2O in toluene to yield labeled N-tert-butyl-O-benzylhydroxylamine (IV). The deprotection of (IV) by hydrogenation with H2 over Pd/C in methanol affords N-tert-butylhydroxylamine (V), which is finally condensed with benzaldehyde 2,4-disulfonic acid sodium salt (VI) in HOAc/water to give rise to the target imine oxide.

合成路线26

Condensation of 5-(benzyloxy)-2-hydroxyacetophenone (I) with acetone in the presence of pyrrolidine in toluene with azeotropical removal of water yielded chromanone (II). Subsequent aldol condensation of (II) with 2-methoxy-5-nitrobenzaldehyde (III), promoted by tetramethyl orthosilicate and KF, produced the benzylidenechromanone (IV). Palladium-catalysed hydrogenation of the benzylidene double bond of (IV), with concomitant benzyl ether cleavage and nitro group reduction, gave benzylchromanone (V). Then, the phenolic hydroxyl group of (V) was alkylated with 2-(chloromethyl)-7-chloroquinoline (VI) in the presence of NaH in DMF to afford ether (VII). Treatment of (VII) with trifluoromethanesulfonic anhydride and Et3N produced the bis(sulfonamide) (VIII), which after basic hydrolysis yielded the mono-trifluoromethylsulfonamide (IX). Subsequent reduction of (IX) with Super Hydride(R) afforded the racemic cis alcohol (X).

合成路线27

Condensation of 5-(benzyloxy)-2-hydroxyacetophenone (I) with acetone in the presence of pyrrolidine in toluene with azeotropical removal of water yielded chromanone (II). Subsequent aldol condensation of (II) with 2-methoxy-5-nitrobenzaldehyde (III), promoted by tetramethyl orthosilicate and KF, produced the benzylidenechromanone (IV). Palladium-catalysed hydrogenation of the benzylidene double bond of (IV) with concomitant benzyl ether cleavage and nitro group reduction, gave benzylchromanone (V). Then, the phenolic hydroxyl group of (V) was alkylated with 2-(chloromethyl)-5,6-difluorobenzothiazole (VI) in the presence of NaH in DMF to afford ether (VII). Treatment of (VII) with trifluoromethanesulfonic anhydride and Et3N produced the bis(sulfonamide) (VIII), which after basic hydrolysis yielded the mono-trifluoromethylsulfonamide (IX). Subsequent reduction of (IX) with Super Hydride(R) afforded the racemic cis alcohol (X).

合成路线28

The condensation of 3-[2-(hydroxymethyl)thiazol-4-yl]-2-methylpropenal (I) with acetone (II) gives the racemic aldol derivative (III), which is submitted to a enantioselective retroaldol reaction catalyzed by antibodies 84G3, 85H6 or 93F3, yielding the chiral aldol (IV) with 99% ee purity. The protection of the OH groups of (IV) with TbdmsCl and imidazole affords the bis silyl ether (V), which is oxidized with Tms-OTf, trifluoroacetone and oxone to provide the hydroxyketone (VI). The reduction of (VI) with NaBH4 in methanol gives the vicinal diol (VII), which is cleaved with Pb(OAc)4 to yield the aldehyde (VIII). The Wittig reaction of (VIII) with methyltriphenylphosphonium iodide (IX) and BuLi in THF affords the olefin (X), which is desilylated with TBAF in THF and selectively monosilylated at the primary alcohol with Tbdms-Cl and DIEA to give the secondary alcohol (XI). The esterification of (XI) with the known carboxylic acid (XII) (see later) by means of EDC in dichloromethane yields the ester (XIII), which is submitted to a ring-closing metathesis catalyzed by the Grubb's catalyst in dichloromethane to afford the protected macrolactone (XIV). The desilylation of (XIV) with HF and pyridine in THF gives the precursor (XV), which is finally epoxidated with H2O2 and KHCO3 in methanol to yield the target epothilone E.

合成路线29

Piperazine-2-carboxylic acid (VIII) was prepared by catalytic hydrogenation of pyrazine (VII). Sequential protection of the N-4 of (VIII) with 2-(t-butoxycarbonyloxyimino)-2-phenylacetonitrile and the N-1 with benzyl chloroformate provided the diprotected piperazinecarboxylic acid (X), which was subsequently esterified with diazomethane to give the methyl ester (XI). The N-benzyloxycarbonyl group of (XI) was selectively deprotected by hydrogenation in the presence of Pd/C to yield the N-Boc-piperazine (XII). Reductive alkylation of (XII) with isovaleraldehyde (XIII) afforded the corresponding N-isoamyl piperazine (XIV). After acid removal of the N-Boc group of (XIV) to yield (XV), a second reductive alkylation with acetone (XVI) produced the dialkyl piperazine (XVII). Hydrolysis of the methyl ester group of (XVII) under acidic conditions gave acid (XVIII). This was finally coupled with the intermediate piperidine (VI) in the presence of HBTU to provide the title compound.

合成路线30

The reaction of 2,4,5-trichlorophenol (I) with 1,3-dibromopropane (II) by means of refluxing 25% aqueous NaOH gives 3-(2,4,5-trichlorophenoxy)propyl bromide (III), which is condensed with benzhydroxamic acid (IV) by means of NaOH in refluxing methanol yielding 3-(2,4,5-trichlorophenoxy)propyl benzhydroxamate (V). The hydrolysis of (V) with HCl in refluxing methanol affords 3-(2,4,5-trichlorophenoxy)propyloxyamine (VI), which is then condensed with dicyandiamide (VII) in refluxing ethanol to give 3'-(2,4,5-trichlorophenoxy)propyloxydiguanide (VIII). Finally, this compound is cyclized with acetone (IX) by means of HCl.

合成路线31

Condensation of phenol (I) with acetone (II) in refluxing HOAc/HCl affords diol (III), which is finally converted into the desired compound by first reaction with chlorosulfonic acid in pyridine followed by treatment with aqueous KOH.

合成路线32

The aldol condensation of 2-methyl-3-(2-methylthiazol-4-yl)-2-propenal (XIX) with acetone (XX) catalyzed by antibody 38C2 gives the chiral aldol (XXI), which is protected with Tbdms-Cl and imidazole, yielding the silyl ether (XXII). The reaction of (XXII) with Tbdms-OTf, followed by oxidation with MCPBA and reduction with NaBH4, affords the vicinal diol (XXIII), which is cleaved with Pb(OAc)4 to provide the aldehyde (XXIV). The Wittig condensation of (XXIV) with phosphonium salt (XV) gives olefinic silyl ether (XXV), which is desilylated with TBAF in THF to yield the homoallylic alcohol (XXVI). The esterification of alcohol (XXVI) with the already described carboxylic acid (XVIII) by means of EDC in dichloromethane affords the ester (XXVII), which is submitted to a ring-closing metathesis by means of Grubb's catalyst to provide the macrolactone (XXVIII). Finally, the desilylation of (XXVIII) with HF and pyridine furnishes the target epothilone C.

合成路线33

Lithiation of 1,3-dimethoxybenzene (I), followed by addition of triisopropyl borate to the resultant lithio derivative (II) provided boronic acid (III). This was subjected to palladium-catalyzed Suzuki coupling with methyl 5-nitro-2-bromobenzoate (IV) to afford the biphenyl compound (V). Cleavage of the methyl ethers of (V) using boron tribromide gave rise to the tricyclic lactone (VI). After methylation of the hydroxyl group of (VI) with iodomethane and cesium carbonate, the resultant nitro derivative (VII) was reduced to amine (VIII) by catalytic hydrogenation. Iodine-catalyzed condensation of amine (VIII) with acetone at 105 ºC in a sealed vessel furnished the benzopyranoquinoline system (IX). The lactone function of (IX) was then reduced to the corresponding lactol (X) by means of DIBAL in cold dichloromethane. Subsequent treatment of (X) with methanol and p-toluenesulfonic acid produced acetal (XI). The acetal methoxy group of (XI) was finally displaced with allyl trimethylsilane (XII) in the presence of boron trifluoride etherate to furnish the title allyl derivative

合成路线34

Aldol condensation of 6-chloro-5-fluoroisatin (XIX) with acetone (XX) by means of Et2NH and K2CO3 gives the hydroxyl-ketone (XXI),which is protected with ethylene glycol (XXII) in the presence of HC(OEt)3 and p-TsOH in CH2Cl2 to yield the corresponding ketal (XXIII). Reduction of compound (XXIII) with Red-Al in THF, followed by treatment with aqueous HCl leads to 1-(6-chloro-5-fluoroindol-3-yl)acetone (XXIV). Alternatively, reduction of nitropropenyl intermediate (XVI) with H2 over Raney-Ni in MeOH/H2O or sequential reduction to oxime with H2 over Pt/C in EtOAc and then hydrolysis using NaHSO3 in EtOH furnishes ketone (XXIV). Enzymatic transamination of intermediate (XXIV) with isopropylamine hydrochloride (XXV) in the presence of transaminase SEQ ID 134 and pyridoxal-5’-phosphate (PLP) in H2O/PEG200 produces the corresponding (S)-amine, which is isolated as the camphorsulfonate salt (XXVI) by treatment with CSA in i-PrOAc. Condensation of tryptamine derivative (XXVI) with 5-chloroisatin (XII) in the presence of Et3N in refluxing i-PrOH and subsequent Pictet-Spengler cyclization in the presence of CSA provides cipargamin camphorsulfonate (XXVII), which is finally treated with Na2CO3 in EtOH/H2O .

合成路线35

N-Protection of 2-methylalanine with Boc2O, optionally in the presence of NaHCO3, in THF/H2O yields N-Boc-2-methylalanine (II) , which is then methylated with Me3SiCHN2 in MeOH/THF or with MeI using KHCO3 in DMF to give the methyl ester (III) . Reduction of the ester (III) by means of LiBH4 in THF /EtOH affords the primary alcohol (IV) , which can also be prepared from 2-amino-2-methyl-1-propanol (V) by N-protection with Boc2O in CH2Cl2 . After conversion of alcohol (IV) to the corresponding mesylate (VI) with MsCl and Et3N in CH2Cl2, N-deprotection with HCl in dioxane provides amine (VII), which by reaction with Na2SO3 in H2O yields the aminosulfonic acid (VIII) . Finally, compound (VIII) is N-chlorinated using trichloroisocyanuric acid , Cl2 , HOCl or NaOCl/HCl .
The aminosulfonic acid (VIII) can also be prepared by the following two strategies: Condensation of acetone (IX) with t-BuSONH2 by means of Ti(OEt)4 gives the N-sulfinylimine (X), which is then coupled with ethyl methanesulfonate (XI) in the presence of BuLi and HMPA in THF to produce the propanesulfonate derivative (XII). Finally, hydrolysis of the sulfonate ester (XII) with LiOH in THF/MeOH/H2O, followed by removal of the sulfinyl protecting group with HCl in MeOH furnishes aminosulfonic acid (VIII) .
Reduction of 2-hydroxy-2-methylpropanenitrile (XIII) by means of LiAlH4 yields 1-amino-2-methylpropan-2-ol (XIV), which is then Nprotected with Boc2O to give N-Boc-1-amino-2-methylpropan-2-ol (XV). Mesylation of the alcohol (XV) with MsCl using Et3N in CH2Cl2 and subsequent N-deprotection of the resulting mesylate (XVI) with HCl in dioxane affords the amino mesylate (XVII). Finally, substitution of the tertiary mesylate (XVII) with Na2SO3 occurs with rearrangement of the primary amino group generating aminosulfonic acid (VIII) .

合成路线36