合成路线1

The first total synthesis of hyperzine A as racemic is carried out as follows: The reaction of pyrrolidine (I) with cyclohexane-1,4-dione monoethyleneketal (II) by means of p-toluenesulfonic acid in refluxing benzene gives the enamine (III), which is cyclized with acrylamide (IV) in refluxing dioxane affording the bicyclic pyridone (V). The benzylation of (V) with benzyl chloride and KH in THF yields the N-benzyl derivative (VI), which is dehydrogenated by means of phenylselenium chloride in THF, followed by a treatment with NaIO4 in refluxing methanol to give the protected pyridone (VII). The debenzylation of (VII) with Pd(OH)2 in acetic acid yields the free pyridone (VIII), which is aromatized with methyl iodide and silver carbonate to the 2-methoxypyridine (IX). Elimination of the ketal group of (IX) with HCl in refluxing acetone affords the tetrahydroquinolone (X), which is carboxylated by means of dimethyl carbonate and KH to give 2-methoxy-6-oxo-5,6,7,8-tetrahydroquinoline-5-carboxylic acid methyl ester (XI). The cyclization of (XI) with 2-methylacrolein (XII) by means of sodium methoxide in methanol or tetramethylguanidine in dichloromethane yields the tricyclic compound (XIII), which is mesylated with mesyl chloride to the mesylate (XIV). Elimination of the mesyl group of (XIV) with refluxing acetic acid - sodium acetate affords the olefinic compound (XV), which is submitted to a Wittig condensation with ethylidenetriphenylphosphorane in ether giving the diolefinic compound (XVI) as a mixture of the E- and Z-isomers. Selective hydrolysis of (XVI) with NaOH in THF - methanol yields acid (XVII) as the E-isomer, which is treated with SOCl2 and sodium azide in a modified Curtius reaction to obtain the urethane (XVIII). Lastly trimethylsilyl iodide is used to effect both N- and O-deprotection.

合成路线2

This compound can be prepared by several different ways: 1) The reaction ot 4-(chloromethyl)pyridine (I) with NaCN in toluene - water gives 4-(cyanomethyl)pyridine (II), which is condensed with methyl acrylate (III) yielding dimethyl 4-cyano 4-(4-pyridyl)pimelate (IV). The hydrolysis and decarboxylation of (IV) atfords 4-(4-pyridyl)pimelic acid (V), which is cyclized by means of potassium tert-butoxide giving 4-(4-pyridyl)cyclohexanone (VI). The acetylation of (VI) with acetic anhydride or acetylimidazole affords 2-acetyl(4-4 pyridyl)cyclohexanone (VII), which is finally cyclized with acetylacetamide (VIII) by means of dimethylamine. 2) The cyclization of (VII) with cyanoacetamide (IX) by means of piperidine gives 4-cyano-1-methyl-7-(4-pyridyl)-5,6,7,8-tetrahydro-3(2H)-isoquinolinone (X), which is finally treated with methyl magnesium iodide in ether. 3) The condensation of 4 bromopyridine (XI) and cyclohexanedione monoethyleneketal (XII) by means of butyllithium in THF gives 4-hydroxy-4-(4-pyridyil)cyclohexanone ethyleneketal (XIII), which is dehydrated by treatment with SOCl2 and then with NaOH to afford 4-(4-pyridyl)-3-cyclohexenone ethyleneketal (XIV). Finally, this compound is hydrolyzed with HCl and reduced with H2 over Pd/C in 0.5 N HCl yielding cyclohexanone (VII), already obtained.

合成路线3

The synthesis of [14C]-labeled Bay-u-3405 by two closely related ways has been described: 1) [14C]-Labeled aniline (I) is diazotized and reduced with sodium sulfite, yielding the labeled hydrazine (II), which is condensed with the monoketal of cyclohexane-1,4-dione (III) under Fisher's indole synthesis (ZnCl2) to afford the tetrahydrocarbazole (IV). The hydrolysis of (IV) with HCl in THF/water yields 1,2,3,4-tetrahydrocarbazol-3-one (V), which is submitted to a reductive condensation with (S)-1-phenylethylamine (VI) by means of tetrabutylammonium borohydride, yielding preferentially the secondary amine (VII), which, after purification, is dealkylated with ammonium formate and Pd/C to afford 1,2,3,4-tetrahydrocarbazole-3(R)-amine (VIII). The acylation of (VIII) with 4-fluorophenylsulfonyl chloride (IX) gives the corresponding sulfonamide (X), which is condensed with acrylonitrile by means of NaH, yielding 3-[3(R)-(4-fluorophenylsulfonamido)-1,2,3,4-tetrahydrocarbazol-9-yl]pro pionitrile (XI). Finally, this compound is hydrolyzed in the usual way. 2) The condensation of the sulfonamide (X) with methyl acrylate by means of NaH as before gives 3-[3(R)-(4-fluorophenylsulfonamido)-1,2,3,4-tetrahydrocarbazol-9-yl]propionic acid methyl ester (XII), which is finally hydrolyzed in the usual way.

合成路线4

Aryl lithium reagent (II) (prepared by halogen-metal exchange of 1-chloro-4-iodobenzene (I) with tert-butyllithium at -60 C), was added to 1,4-cyclohexanedione mono-ethylene ketal (III) to yield tertiary alcohol (IV). Then, mild acid hydrolysis of (IV) with pyridinium tosylate in aqueous acetone provided ketone (V). Deoxygenation of the benzylic alcohol of (V) with P2I4 in refluxing benzene produced the arylcyclohexanone (VI), which was further reduced to the trans cyclohexanol (VII) with NaBH4 in MeOH. Subsequent acylation of (VIII) with oxalyl chloride, followed by an aqueous quench furnished the oxalic acid monoester (VIII). The free-radical decarboxylative coupling of (VIII) with 2-chloronaphthoquinone (IX), promoted by ammonium persulfate and a trace of AgNO3 under phase-transfer conditions, provided the desired cyclohexylquinone (X) together with the cyclohexyl ester (XI) as mixtures of cis and trans isomers, which were separated by flash chromatography. Finally, conversion of the trans-(X) to the target hydroxylated compound was performed by treatment with KOH in boiling MeOH.

合成路线5

The methylation of N-(tert-butoxycarbonyl)-L-tyrosine methyl ester (I) with methyl iodide and KOH gives the protected 4-O-methyl-L-tyrosine methyl ester (II), which is deprotected with TFA yielding (III). The Grundke oxidation of (III) affords the N-hydroxy derivative (IV), which is cyclocondensed with cyclohexane-1,4-dione monoethylene ketal (V) and ethyl acrylate (VI) in refluxing toluene to afford the spiroisoxazolidinone (VII). The reductive rearrangement of (VII) with H2 over Pd/C in acetic acid provides the spiropyrrolidinone (VIII), which is treated successively with tosyl chloride and with sodium azide to obtain the azido derivative (IX). The reduction of (IX) with H2 over Pd/C, protection of the resulting amine with Boc2O, and methylation of the resulting carbamate with NaH and methyl iodide affords the N-methylcarbamate (X). The reduction of the methoxycarbonyl group of (X) with LiBH4 in THF gives the carbinol (XI), which is oxidized with Dess-Martin periodinane to the aldehyde (XII). The rearrangement of (XII) by means of potassium tert-butoxide, followed by deprotection of the carbamate group yields the 7,10a-methanopyrrolo[1,2-a]azocin-8-one derivative (XIII), which is reduced at the carbonyl group with LiAlH4 in THF affords the 8(R)-hydroxy derivative (XIV). The protection of the amino group of (XIV) with benzyloxycarbonyl chloride and triethylamine yields the carbamate (XV).

合成路线6

11) Hassner and Belostotskii reported a simple synthesis of 7-alkyl-7-azabicyclo[2.2.1]heptanes. The starting aminoalcohols which were easily available from the monoethylene ketal of 1,4-cyclohexanedione (XLI) were treated with triphenylphosphine-carbon tetrachloride, leading to 7-alkyl-7-azabicyclo[2.2.1]heptanes (XLIII) in good yields. Recently, Davis et al. described the microbial hydroxylations of (XLIII) using the fungi Beauveria bassiana, Rhizopus nigricans, Aspergillus ochraceus and Rhizopus arrhizus as the primary organisms. Though the enantioselectivity was not high enough, these results demonstrated the potential of microbiological oxygenations to deliver enantioselective reactions.

合成路线7

Condensation of pyruvic aldehyde dimethyl acetal (V) with dimethylformamide dimethyl acetal produced enamino ketone (VI). Cyclization of (VI) with thiourea (VII), followed by methylation with iodomethane furnished the (methylsulfanyl)pyrimidine (VIII). Acid hydrolysis of the dimethyl acetal gave rise to aldehyde (IX). Cyclohexanedione monoketal (X) was converted to oxime (XI) and then hydrogenated to give amine (XII). This was condensed with aldehyde (IX) yielding imine (XIII). Reaction of imine (XIII) with sulfonyl isocyanide (IV) gave rise to imidazole (XIV). The methylsulfanyl group of (XIV) was then oxidized to sulfone (XV) employing oxone®. Further displacement of the methylsulfonyl group of (XV) with NaOMe produced the methoxy pyrimidine (XVI). After ketal (XVI) hydrolysis, reduction of the resulting ketone (XVII) with NaBH4 furnished the title alcohol.

合成路线8

Reduction of 3,4-dimethoxybenzaldehyde (I) with NaBH4 provided benzyl alcohol (II). After conversion of (II) to the benzyl chloride (III) using SOCl2, its reaction with PPh3 (IV) in refluxing xylene afforded phosphonium salt (V). Subsequent Wittig reaction of the corresponding ylide with 4,4-(ethylenedioxy)cyclohexanone (VI) produced the benzylidene derivative (VII), which was reduced to benzyl compound (VIII) by catalytic hydrogenation over Pd/C. The ketal protecting group of (VIII) was then removed by acid hydrolysis to yield cyclohexanone (IX). Finally, the target tetrahydroquinazoline was obtained by condensation of (IX) with cyanoguanidine (X) at 180 C.

合成路线9

Reduction of 3,4,5-trimethoxybenzaldehyde (I) with NaBH4 provided benzyl alcohol (II). After conversion of (II) to the benzyl chloride (III) using SOCl2, its reaction with PPh3 (IV) in refluxing xylene afforded phosphonium salt (V). Subsequent Wittig reaction of the corresponding ylide with 4,4-(ethylenedioxy)cyclohexanone (VI) produced the benzylidene derivative (VII), which was reduced to benzyl compound (VIII) by catalytic hydrogenation over Pd/C. The ketal protecting group of (VIII) was then removed by acid hydrolysis to yield cyclohexanone (IX). Finally, the target tetrahydroquinazoline was obtained by condensation of (IX) with cyanoguanidine (X) at 180 C.

合成路线10

The intermediate 4-(5-cyano-1H-indol-3-yl)cyclohexanone (V) has been obtained as follows: The condensation of 1H-indole-5-carbonitrile (VI) with cyclohexanone monoethyleneketal (VII) by means of KOH in refluxing methanol gives the cyclohexenone ethyleneketal (VIII), which is reduced with H2 over Pd/C in ethanol to yield 4-(5-cyano-1H-indol-3-yl)cyclohexanone ethyleneketal (IX). Finally, this compound is hydrolyzed to the target intermediate (V) with HCl in THF.

合成路线11

1,4-Cyclohexanedione mono-ethylene ketal (I) was converted to nitrile (II) upon treatment with p-tosylmethyl isocyanide. Reduction of the nitrile (II) by means of LiAlH4 gave rise to amino ketal (III). Ketal group hydrolysis in (III) with concomitant double Mannich reaction of the intermediate amino ketone (IV) with formaldehyde furnished the aza adamantanone (V). Knoevenagel condensation of ketone (V) with ethyl cyanoacetate and triethylamine produced the unsaturated cyano ester (VI), which was further reduced to (VII) by catalytic hydrogenation over Pd/C. The target thiadiazole derivative (VIII) was then obtained by nitrosation of (VII) with isoamyl nitrite, followed by reaction with sulfur monochloride. Selective dehalogenation of (VIII) was accomplished by catalytic hydrogenation over Pd/C yielding the mono-chloro derivative (IX). Chloride displacement in (IX) with sodium hydrogen sulfide generated the intermediate thiol (X), which was subsequently alkylated with propyl bromide to produce a mixture of s- (XI) and r-isomers (XII), separable by column chromatography.

合成路线12

Base-catalyzed condensation of 5-cyanoindole (I) with 1,4-cyclohexanedione mono-ethylene ketal (II) furnished the cyclohexenyl indole (III), which was further hydrogenated in the presence of Pd/C to the cyclohexyl analogue (IV). Subsequent hydrolysis of the ethylene ketal function of (IV) gave ketone (V).

合成路线13

Reduction of 1,4-cyclohexanedione mono-ethylene ketal (VII) with NaBH4 gives alcohol (VIII). This is then coupled with the pyrazolopyrimidine (VI) under Mitsunobu conditions to afford adduct (IX). Subsequent acidic ketal hydrolysis in (IX) leads to ketone (X). Finally, reductive condensation of (X) with N-methylpiperazine (XI) in the presence of NaBH(OAc)3 produces a mixture of cis and trans disubstituted cyclohexanes, from which the title trans isomer is isolated by flash column chromatography.

合成路线14

Treatment of 3-aminopyrazole-4-carbonitrile (I) with formamide at 180 C gives rise to the pyrazolopyrimidinyl amine (II). Subsequent iodination of (II) with N-iodosuccinimide in hot DMF affords 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (III). Reduction of 1,4-cyclohexanedione mono-ethylene ketal (IV) with NaBH4 furnishes alcohol (V). This is then subjected to Mitsunobu coupling with the pyrazolopyrimidine (III) to produce adduct (VI). Acidic hydrolysis of the ethylene ketal (VI) leads to the cyclohexanone (VII). The reductive amination of ketone (VII) with N-methylpiperazine (VIII), either employing NaBH(OAc)3 or via condensation in hot NMP, and then reduction of the resultant enamine with formic acid, produces a mixture of trans- (IX) and cis- (X) disubstituted cyclohexanes, with different ratios in each case.

合成路线15