Condensation of protected ketone (I) with 2-benzyloxy-1-trimethylsilyloxyphenoxyethane (II) by means of Sn(OTf)2 and chiral amine (III) in propionitrile affords aldolic reaction product (IV), which is then dehydroxylated by treatment with thiocarbonyl diimidazole (A) in THF followed by reduction with Bu3SnH in refluxing toluene to provide the protected hydroxyester (V). Reduction of the ester group of (V) with DIBAL in CH2Cl2 followed by Swern oxidation with (COCl)2, DMSO and Et3N in dichloromethane yields aldehyde (VI), which is then condensed with 2-methoxypropene (VII) and 2-methoxyaniline (VIII) in the presence of yterbium triflate (Yb(OTf)3) in THF/H2O to furnish a mixture of diastereoisomers from which anti-(IX) is separated. Derivative anti-(IX) is treated with HF in THF for TBS removal and cyclization is induced by reaction with PPh3 and CBr4 in CH2Cl2, affording piperidine (X). Next, treatment of (X) with cerium ammonium nitrate (CAN) in acetonitrile/H2O allows N-protecting group removal, giving piperidine derivative (XI). Alternatively, (XI) can be obtained as follows: Treatment of aldehyde (VI) with 2-methoxyaniline (VIII) and PMB-protected 2-methoxypropene (XII) in the presence of scandium trisdodecylsulfate (STDS) in THF/H2O yields a mixture of diastereoisomers from which anti-(XIII) is separated. Derivative anti-(XIII) is then converted into (XI) by following the same procedure as for the conversion of anti-(IX) into (XI). Derivative (XI) is then subjected to: (i) N-protection by means of Boc2O; (ii) treatment with lithium hexamethyl disilazide (LHMDS) followed by trimethylsilyl chloride (TMSCl); (iii) oxidation of the silylenol ether by means of MCPBA; and (iv) bromination with PPh3 and CBr4. After all these steps bromo derivative (XIV) is obtained. Finally, coupling of (XIV) with 4-hydroxyquinazoline (XV) using KOH followed by Boc removal by treatment with refluxing HCl furnishes the target compound.

The enantioselective condensation of the silylated 4-hydroxy-2-butanone (I) with the silylated enol ester (II) by means of Sn(OTf)2 and the chiral pyrrolidine (III) gives the chiral benzylated trihydroxyester (IV), which is partially dehydroxylated with thiocarbonyl diimidazole (TCDI) and tributyltin hydride in refluxing toluene to yield the protected dihydroxy ester (V). The reduction of (V) with DIBAL in dichloromethane affords the corresponding alcohol (VI), which is oxidized with oxalyl chloride and TEA in DMSO/dichloromethane to provide the aldehyde (VII). The condensation of (VII) with the enol ether (IX) and 2-methoxyaniline (VIII) by means of Yb(OTf)3 in THF/water gives the beta aminoketone (X), which is cyclized by means of HF, PPh3, CBr4 and cerium ammonium nitrate (CAN) in acetonitrile/water to yield the chiral piperidine (XI). The bromination of (XI) with Br2 and HBr in HOAc affords the bromo derivative (XII), which is treated with Boc2O to provide the N-protected piperidine (XIII). The condensation of (XIII) with quinazolin-4(3H)-one (XIV) by means of KOH gives the adduct (XV), which is finally deprotected and cyclized by treatment with refluxing 6N HCl to afford the target isofebrifugine.

Condensation of protected ketone (I) with 2-benzyloxy-1-trimethylsilyloxyphenoxyethane (II) by means of Sn(OTf)2 and chiral amine (III) in propionitrile affords aldolic reaction product (IV), which is then dehydroxylated by treatment with thiocarbonyl diimidazole (A) in THF followed by reduction with Bu3SnH in refluxing toluene to provide the protected hydroxyester (V). Reduction of the ester group of (V) with DIBAL in CH2Cl2 followed by Swern oxidation with (COCl)2, DMSO and Et3N in dichloromethane yields aldehyde (VI), which is then condensed with 2-methoxypropene (VII) and 2-methoxyaniline (VIII) in the presence of yterbium triflate (Yb(OTf)3) in THF/H2O to furnish a mixture of diastereoisomers from which anti-(IX) is separated. Derivative anti-(IX) is treated with HF in THF for TBS removal and cyclization is induced by reaction with PPh3 and CBr4 in CH2Cl2, affording piperidine (X). Next, treatment of (X) with cerium ammonium nitrate (CAN) in acetonitrile/H2O allows N-protecting group removal, giving piperidine derivative (XI). Alternatively, (XI) can be obtained as follows: Treatment of aldehyde (VI) with 2-methoxyaniline (VIII) and PMB-protected 2-methoxypropene (XII) in the presence of scandium trisdodecylsulfate (STDS) in THF/H2O yields a mixture of diastereoisomers from which anti-(XIII) is separated. Derivative anti-(XIII) is then converted into (XI) by following the same procedure as for the conversion of anti-(IX) into (XI). Derivative (XI) is then subjected to: (i) N-protection by means of Boc2O; (ii) treatment with lithium hexamethyl disilazide (LHMDS) followed by trimethylsilyl chloride (TMSCl); (iii) oxidation of the silylenol ether by means of MCPBA; and (iv) bromination with PPh3 and CBr4. After all these steps bromo derivative (XIV) is obtained. Finally, coupling of (XIV) with 4-hydroxyquinazoline (XV) using KOH followed by Boc removal by treatment with refluxing HCl furnishes the target compound.

The enantioselective condensation of the silylated 4-hydroxy-2-butanone (I) with the silylated enol ester (II) by means of Sn(OTf)2 and the chiral pyrrolidine (III) gives the chiral benzylated trihydroxyester (IV), which is partially dehydroxylated with thiocarbonyl diimidazole (TCDI) and tributyltin hydride in refluxing toluene to yield the protected dihydroxy ester (V). The reduction of (V) with DIBAL in dichloromethane affords the corresponding alcohol (VI), which is oxidized with oxalyl chloride and TEA in DMSO/dichloromethane to provide the aldehyde (VII). The condensation of (VII) with the enol ether (IX) and 2-methoxyaniline (VIII) by means of Yb(OTf)3 in THF/water gives the beta aminoketone (X), which is cyclized by means of HF, PPh3, CBr4 and cerium ammonium nitrate (CAN) in acetonitrile/water to yield the chiral piperidine (XI). The bromination of (XI) with Br2 and HBr in HOAc affords the bromo derivative (XII), which is treated with Boc2O to provide the N-protected piperidine (XIII). The condensation of (XIII) with quinazolin-4(3H)-one (XIV) by means of KOH gives the adduct (XV), which is finally deprotected and cyclized by treatment with refluxing 6N HCl to afford the target isofebrifugine.

The dihydroxylation of 2-[3-(tert-butyldimethylsilyloxy)-1-propenyl]furan (I) with OsO4 and NMO gives the racemic diol (II), which is oxidized with MCPBA to yield the dhydropyranone (III). The cyclization of (III) by means of Ts-OH affords the racemic bicyclic enone (IV), which is reduced with NaBH4 to the racemic alcohol (V). The reaction of (V) with Ac2O and pyridine provides the racemic acetate (VI), which is treated with Lipase PS and vinyl acetate, furnishing a mixture of unreacted chiral acetate (-)-(VI) and the chiral alcohol (+)-(VII), which are easily separated. The reduction of (-)-(VII) with H2 over PtO2 gives the bicyclic alcohol (VIII), which is treated with Ms-Cl and TEA to yield the mesylate (IX). The reaction of (IX) with sodium azide in THF affords the azido derivative (X), which is reduced with LiAlH4 in THF to provide the bicyclic amine (XI). The protection of (XI) with benzyl chloroformate gives the carbamate (XII), which is alkylated with allyl bromide (XIII) and NaH in DMF to yield the N-allyl carbamate (XIV). The desilylation of (XIV) with TBAF, followed by a treatment with Ms-Cl and TEA, affords the mesylate (XV). The reaction of (XV) with LiI, and then reaction of the intermediate iodide with Zn/HOAc, provides the hemiacetal (XVI), which is further reduced with NaBH4 in ethanol to give the dihydroxydiene (XVII). The ring-closing metathesis reaction of (XVII) by means of Grubbs' catalyst yields the tetrahydropyridine (XVIII), which is reduced with H2 over PtO2 to afford the chiral dihydroxy piperidine (XIX). The reaction of (XIX) with diphenyl disulfide and tributyl phosphine provides the thioether (XX), which is treated with benzyl bromide and NaH to give the piperidin benzyl ether (XXI).

The desulfurization of (XXI) with H2O2 and CaCO3 gives the chiral allylpiperidine (XXII), which is epoxidized by oxidation with OsO4, reaction of Ts-OH and treatment with K2CO3 to yield the epoxide (XXIII). The condensation of (XXIII) with quinazolinone (XXIV) by means of KOH in methanol affords the substituted propanol (XXV), which is oxidized with DMP to provide the propanone derivative (XXVI). Finally, compound (XXVI) is deprotected by treatment with refluxing 6N HCl to give the target febrifugine.

The enantioselective reduction of 2-allyl-1-(benzyloxycarbonyl)piperidin-3-one (I) by means of Baker's yeast and sucrose in ethanol/water gives a mixture of unreacted (R)-piperidinone (II) and the desired (2S,3S)-piperidinol (III), which are easily separated by chromatography. The bromination of (III) with NBS in acetonitrile yields the furo piperidine (IV), which is treated with potassium tert-butoxide and NBS in methanol to afford the methoxy compound (V). The condensation of (V) with quinazolinone (VI) by means of K2CO3 in DMF provides the adduct (VII), which is deprotected by hydrogenation with H2 over Pd/C in methanol to give isofebrifugine (VIII). Finally, this compound is converted into the target febrifugine by treatment with water at 80 C.

The enantioselective reduction of 2-allyl-1-(benzyloxycarbonyl)piperidin-3-one (I) by means of Baker's yeast and sucrose in ethanol/water gives a mixture of unreacted (R)-piperidinone (II) and the desired (2S,3S)-piperidinol (III), which are easily separated by chromatography. The bromination of (III) with NBS in acetonitrile yields the furo piperidine (IV), which is treated with potassium tert-butoxide and NBS in methanol to afford the methoxy compound (V). The condensation of (V) with quinazolinone (VI) by means of K2CO3 in DMF provides the adduct (VII), which is deprotected by hydrogenation with H2 over Pd/C in methanol to give the target isofebrifugine.

Aldehyde (II) was prepared by mono-benzylation of 1,4-butanediol (I) followed by Swern oxidation. Subsequent addition of ethynylmagnesium bromide (III) to the aldehyde function of (II) provided propargyl alcohol (IV). Kinetic resolution of the racemic alcohol (IV) by lipase-mediated acetylation in the presence of vinyl acetate produced a mixture of the (S)-acetate (V) and the unreacted (R)-alcohol (VI). The required (S)-propargyl acetate (V) was subjected to partial hydrogenation using Lindlar catalyst to furnish allyl acetate (VII), which was further hydrolyzed to the chiral alcohol (VIII). After protection of (VIII) as the silylated derivative (IX), reductive removal of the benzyl ether using lithium naphthalenide afforded the primary alcohol (X). This was then treated with methanesulfonyl chloride and triethylamine to give mesylate (XI). Ozonolysis of the double bond of (XI), followed by reductive work-up with dimethyl sulfide, yielded aldehyde (XII). This was reacted with hydroxylamine hydrochloride and Et3N in allyl alcohol (XIII) to produce the intermediate nitrone (XIV), which underwent simultaneous 1,3-dipolar cycloaddition to allyl alcohol to furnish the isoxazolopyridine (XV) as a mixture of three diastereoisomers. This mixture was then subjected to hydrogenolytic N-O bond fission, producing piperidine (XVI).

After protection of (XVI) as the N-Boc derivative (XVII), the diol function was cyclized to epoxide (XIX) by treatment with N-tosyl imidazole (XVIII) in the presence of NaH. Epoxide (XIX) opening with the potassium salt of 4-quinazolinone (XX) gave alcohol (XXI). Subsequent Dess-Martin oxidation of (XXI) yielded the epimeric mixture of ketones (XXII). Acid hydrolysis of this mixture furnished the title trans-piperidine along with the cis-isomer, which was isolated in the cyclic hemiacetal form (XXIII). The title compound was also obtained by isomerization of (XXIII) in refluxing MeOH).

Aldehyde (II) was prepared by mono-benzylation of 1,4-butanediol (I) followed by Swern oxidation. Subsequent addition of ethynylmagnesium bromide (III) to the aldehyde function of (II) provided propargyl alcohol (IV). Kinetic resolution of the racemic alcohol (IV) by lipase-mediated acetylation in the presence of vinyl acetate produced a mixture of the (S)-acetate (V) and the unreacted (R)-alcohol (VI). The required (S)-propargyl acetate (V) was subjected to partial hydrogenation using Lindlar catalyst to furnish allyl acetate (VII), which was further hydrolyzed to the chiral alcohol (VIII). After protection of (VIII) as the silylated derivative (IX), reductive removal of the benzyl ether using lithium naphthalenide afforded the primary alcohol (X). This was then treated with methanesulfonyl chloride and triethylamine to give mesylate (XI). Ozonolysis of the double bond of (XI), followed by reductive work-up with dimethyl sulfide, yielded aldehyde (XII). This was reacted with hydroxylamine hydrochloride and Et3N in allyl alcohol (XIII) to produce the intermediate nitrone (XIV), which underwent simultaneous 1,3-dipolar cycloaddition to allyl alcohol to furnish the isoxazolopyridine (XV) as a mixture of three diastereoisomers. This mixture was then subjected to hydrogenolytic N-O bond fission, producing piperidine (XVI).

After protection of (XVI) as the N-Boc derivative (XVII), the diol function was cyclized to epoxide (XIX) by treatment with N-tosyl imidazole (XVIII) in the presence of NaH. Epoxide (XIX) opening with the potassium salt of 4-quinazolinone (XX) gave alcohol (XXI). Subsequent Dess-Martin oxidation of (XXI) yielded the epimeric mixture of ketones (XXII). Acid hydrolysis of this mixture furnished the trans-piperidine (XXIII) along with the title cis-isomer, which was isolated in the cyclic hemiacetal form.

The dihydroxylation of 2-[3-(tert-butyldimethylsilyloxy)-1-propenyl]furan (I) with OsO4 and NMO gives the racemic diol (II), which is oxidized with MCPBA to yield the dhydropyranone (III). The cyclization of (III) by means of Ts-OH affords the racemic bicyclic enone (IV), which is reduced with NaBH4 to the racemic alcohol (V). The reaction of (V) with Ac2O and pyridine provides the racemic acetate (VI), which is treated with Lipase PS and vinyl acetate, furnishing a mixture of unreacted chiral acetate (-)-(VI) and the chiral alcohol (+)-(VII), which are easily separated. The reduction of (-)-(VII) with H2 over PtO2 gives the bicyclic alcohol (VIII), which is treated with Ms-Cl and TEA to yield the mesylate (IX). The reaction of (IX) with sodium azide in THF affords the azido derivative (X), which is reduced with LiAlH4 in THF to provide the bicyclic amine (XI). The protection of (XI) with benzyl chloroformate gives the carbamate (XII), which is alkylated with allyl bromide (XIII) and NaH in DMF to yield the N-allyl carbamate (XIV). The desilylation of (XIV) with TBAF, followed by a treatment with Ms-Cl and TEA, affords the mesylate (XV). The reaction of (XV) with LiI, and then reaction of the intermediate iodide with Zn/HOAc, provides the hemiacetal (XVI), which is further reduced with NaBH4 in ethanol to give the dihydroxydiene (XVII). The ring-closing metathesis reaction of (XVII) by means of Grubbs' catalyst yields the tetrahydropyridine (XVIII), which is reduced with H2 over PtO2 to afford the chiral dihydroxy piperidine (XIX). The reaction of (XIX) with diphenyl disulfide and tributyl phosphine provides the thioether (XX), which is treated with benzyl bromide and NaH to give the piperidin benzyl ether (XXI).