Assembly of the target compound: The condensation of intermediates (XVI) and (XXXIII) by means of NaH in THF gives the adduct (XXXIV), which is treated with Zn/HOAc in THF, yielding the aminoalcohol (XXXV). The selective protection of the NH2 and OH groups of (XXXV) with TsCl/TEA and MsCl/TEA, respectively, affords the fully protected compound (XXXVI), which is treated with NaH and imidazole in refluxing THF to provide the aziridine derivative (XXXVII). The desilylation of (XXXVII) with HF and pyridine furnishes the diol (XXXVIII), which is oxidized with DMP in CH2Cl2 to give the dialdehyde (XXXIX). The cyclization of (XXXIX) by means of LiHMDS in THF, followed by reduction with NaBH4, yields the tricyclic diol (XL), which is selectively silylated at the primary OH group with Tbdps-Cl, TEA and DMAP in CH2Cl2 to afford the monosilylated compound (XLI). The oxidation of the secondary OH group of (XLI) with DMP provides the cyclic ketone (XLII), which is desilylated with HF and pyridine to give the (S)-hydroxymethyl compound (XLIII). The treatment of (XLIII) with DBU in THF yields a mixture of the starting (S)-isomer (XLIII) and the desired (R)-isomer (XLIV) that is resolved by chromatography.

The reduction of the carbonyl group of (XLIV) with NaBH4 in THF gives the diol (XLV), which is selectively silylated at the primary OH group with Tbdps-Cl, TEA and DMAP, yielding silyl ether (XLVI). Elimination of the Alloc protecting group with Pd(PPh3)4, PPh3 in THF affords compound (XLVII), which is carefully oxidized at the NH group with MCPBA in dichloromethane, providing the hydroyamine (XLVIII). The reaction of (XLVIII) with Ac2O gives the acetate (XLIX), which is oxidized with DMP to yield the ketone (L). The desilylation of (L) with HF and pyridine affords the hydroxyketone (LI), which by treatment with K2CO3 in methanol undergoes cyclization to the tetracyclic compound (LIII) through the intermediate dihydroxyketone (LII). The reaction of (LIII) with diphosgene and pyridine gives the cyclic carbonate (LIV), which is treated with ammonia in THF, yielding the carbamic ester (LV).

The reaction of (LV) with Ac2O and pyridine gives the acetate (LVI), which is detosylated with sodium naphthalenide in DME to yield compound (LVII). The hydrogenation of (LVII) with H2 over Pd/C in ethyl acetate eliminates the Bn and Bom protecting groups to afford dihydroxy compound (LVIII), which is oxidized at the carbinol group with oxalyl chloride to provide the aldehyde (LIX). Finally, the cleavage of the acetoxy group of (LIX) with ammonia in methanol furnishes the target compound.

Synthesis of oxazolidine intermediate (XVI): The reaction of dimethyl L-tartrate (I) with benzaldehyde and Ts-OH gives the benzylidene ketal (II), which is reduced with LiAlH4/AlCl3 to yield the monobenzylated tetrol (III). The reaction of (III) with 2,2-dimethoxypropane (IV) and TsOH affords the acetonide (V), which is protected at the primary OH group with Mpm-Cl and NaH to provide the corresponding ether (VI). The debenzylation of (VI) with H2 over Raney-Ni in ethanol, followed by reaction with MsCl and TEA in dichloromethane, gives the mesylate (VII), which is treated with HCl in methanol to yield the diol (VIII). The reaction of (VIII) with K2CO3 in methanol affords the epoxide (IX), which is opened with NaN3 in refluxing ethanol to provide the azide (X). The selective monosilylation of (X) with Tbdps-Cl, TEA and DMAP in dichloromethane furnishes the silyl ether (XI). The reduction of the azido group of (XI) with PPh3 in THF/water gives the amine (XII), which is protected with Troc-Cl and NaHCO3 to afford the carbamate (XIII). The reaction of (XIII) with 2,2-dimethoxypropane (IV) and TsOH provides the oxazolidine (XIV), which is selectively deprotected at the Mpm group with DDQ in dichloromethane, giving the primary alcohol (XV). Finally, this compound is esterified with Tf2O and TEA in CH2Cl2 to obtain the desired oxazolidine intermediate (XVI).

Synthesis of the aromatic intermediate (XXXIII): The esterification of the 5-hydroxyisophthalic acid (XVII) with SOCl2 and methanol gives the dimethyl ester (XVIII), which is treated with allyl bromide (XIX) and K2CO3 in refluxing acetone to yield the allyl ether (XX). The thermal isomerization of (XX) affords 4-allyl-5-hydroxyisophthalic acid dimethyl ester (XXI), which is treated with Bn-Br and K2CO3 in refluxing acetone to provide the benzyl ether (XXII). The hydrolysis of the ester groups of (XXII) with NaOH in THF gives the isophthalic acid (XXIII), which by reaction with Br2 and NaHCO3 yields the lactone (XXIV). The reduction of the carboxyl group of (XXIV) with isopropyl chloroformate and NaBH4 in THF/water affords the carbinol (XXV), which is protected with Bom-Cl and DIEA, providing compound (XXVI). The debromination of (XXVI) with Zn and NH4Cl in ethanol/water gives the 2-allylbenzoic acid (XXVII), which by a Curtius rearrangement with DPPA and TEA in refluxing tert-butanol yields the aryl carbamate (XXVIII). The reaction of (XXVIII) with OsO4 and NaIO4 in dioxane/water affords the indoline derivative (XXIX), which is treated with NaBH4 in EtOH to afford the 2-phenylethanol derivative (XXX). The reaction of (XXX) with Tbdms-Cl, TEA and DMAP provides the silyl ether (XXXI), which is treated with Tbdms-OTf and pyridine to give the aniline derivative (XXXII). Finally, this amine is reprotected with Alloc-Cl and NaHCO3 to yield the desired intermediate (XXXIII).

Synthesis of oxazolidine intermediate (XVI): The reaction of dimethyl L-tartrate (I) with benzaldehyde and Ts-OH gives the benzylidene ketal (II), which is reduced with LiAlH4/AlCl3 to yield the monobenzylated tetrol (III). The reaction of (III) with 2,2-dimethoxypropane (IV) and TsOH affords the acetonide (V), which is protected at the primary OH group with Mpm-Cl and NaH to provide the corresponding ether (VI). The debenzylation of (VI) with H2 over Raney-Ni in ethanol, followed by reaction with MsCl and TEA in dichloromethane, gives the mesylate (VII), which is treated with HCl in methanol to yield the diol (VIII). The reaction of (VIII) with K2CO3 in methanol affords the epoxide (IX), which is opened with NaN3 in refluxing ethanol to provide the azide (X). The selective monosilylation of (X) with Tbdps-Cl, TEA and DMAP in dichloromethane furnishes the silyl ether (XI). The reduction of the azido group of (XI) with PPh3 in THF/water gives the amine (XII), which is protected with Troc-Cl and NaHCO3 to afford the carbamate (XIII). The reaction of (XIII) with 2,2-dimethoxypropane (IV) and TsOH provides the oxazolidine (XIV), which is selectively deprotected at the Mpm group with DDQ in dichloromethane, giving the primary alcohol (XV). Finally, this compound is esterified with Tf2O and TEA in CH2Cl2 to obtain the desired oxazolidine intermediate (XVI).

Synthesis of the aromatic intermediate (XXXIII): The esterification of the 5-hydroxyisophthalic acid (XVII) with SOCl2 and methanol gives the dimethyl ester (XVIII), which is treated with allyl bromide (XIX) and K2CO3 in refluxing acetone to yield the allyl ether (XX). The thermal isomerization of (XX) affords 4-allyl-5-hydroxyisophthalic acid dimethyl ester (XXI), which is treated with Bn-Br and K2CO3 in refluxing acetone to provide the benzyl ether (XXII). The hydrolysis of the ester groups of (XXII) with NaOH in THF gives the isophthalic acid (XXIII), which by reaction with Br2 and NaHCO3 yields the lactone (XXIV). The reduction of the carboxyl group of (XXIV) with isopropyl chloroformate and NaBH4 in THF/water affords the carbinol (XXV), which is protected with Bom-Cl and DIEA, providing compound (XXVI). The debromination of (XXVI) with Zn and NH4Cl in ethanol/water gives the 2-allylbenzoic acid (XXVII), which by a Curtius rearrangement with DPPA and TEA in refluxing tert-butanol yields the aryl carbamate (XXVIII). The reaction of (XXVIII) with OsO4 and NaIO4 in dioxane/water affords the indoline derivative (XXIX), which is treated with NaBH4 in EtOH to afford the 2-phenylethanol derivative (XXX). The reaction of (XXX) with Tbdms-Cl, TEA and DMAP provides the silyl ether (XXXI), which is treated with Tbdms-OTf and pyridine to give the aniline derivative (XXXII). Finally, this amine is reprotected with Alloc-Cl and NaHCO3 to yield the desired intermediate (XXXIII).

Assembly of the target compound: The condensation of intermediates (XVI) and (XXXIII) by means of NaH in THF gives the adduct (XXXIV), which is treated with Zn/HOAc in THF, yielding the aminoalcohol (XXXV). The selective protection of the NH2 and OH groups of (XXXV) with TsCl/TEA and MsCl/TEA, respectively, affords the fully protected compound (XXXVI), which is treated with NaH and imidazole in refluxing THF to provide the aziridine derivative (XXXVII). The desilylation of (XXXVII) with HF and pyridine furnishes the diol (XXXVIII), which is oxidized with DMP in CH2Cl2 to give the dialdehyde (XXXIX). The cyclization of (XXXIX) by means of LiHMDS in THF, followed by reduction with NaBH4, yields the tricyclic diol (XL), which is selectively silylated at the primary OH group with Tbdps-Cl, TEA and DMAP in CH2Cl2 to afford the monosilylated compound (XLI). The oxidation of the secondary OH group of (XLI) with DMP provides the cyclic ketone (XLII), which is desilylated with HF and pyridine to give the (S)-hydroxymethyl compound (XLIII). The treatment of (XLIII) with DBU in THF yields a mixture of the starting (S)-isomer (XLIII) and the desired (R)-isomer (XLIV) that is resolved by chromatography.

The reduction of the carbonyl group of (XLIV) with NaBH4 in THF gives the diol (XLV), which is selectively silylated at the primary OH group with Tbdps-Cl, TEA and DMAP, yielding silyl ether (XLVI). Elimination of the Alloc protecting group with Pd(PPh3)4, PPh3 in THF affords compound (XLVII), which is carefully oxidized at the NH group with MCPBA in dichloromethane, providing the hydroyamine (XLVIII). The reaction of (XLVIII) with Ac2O gives the acetate (XLIX), which is oxidized with DMP to yield the ketone (L). The desilylation of (L) with HF and pyridine affords the hydroxyketone (LI), which by treatment with K2CO3 in methanol undergoes cyclization to the tetracyclic compound (LIII) through the intermediate dihydroxyketone (LII). The reaction of (LIII) with diphosgene and pyridine gives the cyclic carbonate (LIV), which is treated with ammonia in THF, yielding the carbamic ester (LV).

The reaction of (LV) with Ac2O and pyridine gives the acetate (LVI), which is detosylated with sodium naphthalenide in DME to yield compound (LVII). The hydrogenation of (LVII) with H2 over Pd/C in ethyl acetate eliminates the Bn and Bom protecting groups to afford dihydroxy compound (LVIII), which is oxidized at the carbinol group with oxalyl chloride to provide the aldehyde (LIX). Finally, the cleavage of the acetoxy group of (LIX) with ammonia in methanol furnishes the target compound.

Synthesis of oxazolidine intermediate (XVI): The reaction of dimethyl L-tartrate (I) with benzaldehyde and Ts-OH gives the benzylidene ketal (II), which is reduced with LiAlH4/AlCl3 to yield the monobenzylated tetrol (III). The reaction of (III) with 2,2-dimethoxypropane (IV) and TsOH affords the acetonide (V), which is protected at the primary OH group with Mpm-Cl and NaH to provide the corresponding ether (VI). The debenzylation of (VI) with H2 over Raney-Ni in ethanol, followed by reaction with MsCl and TEA in dichloromethane, gives the mesylate (VII), which is treated with HCl in methanol to yield the diol (VIII). The reaction of (VIII) with K2CO3 in methanol affords the epoxide (IX), which is opened with NaN3 in refluxing ethanol to provide the azide (X). The selective monosilylation of (X) with Tbdps-Cl, TEA and DMAP in dichloromethane furnishes the silyl ether (XI). The reduction of the azido group of (XI) with PPh3 in THF/water gives the amine (XII), which is protected with Troc-Cl and NaHCO3 to afford the carbamate (XIII). The reaction of (XIII) with 2,2-dimethoxypropane (IV) and TsOH provides the oxazolidine (XIV), which is selectively deprotected at the Mpm group with DDQ in dichloromethane, giving the primary alcohol (XV). Finally, this compound is esterified with Tf2O and TEA in CH2Cl2 to obtain the desired oxazolidine intermediate (XVI).

Synthesis of oxazolidine intermediate (XVI): The reaction of dimethyl L-tartrate (I) with benzaldehyde and Ts-OH gives the benzylidene ketal (II), which is reduced with LiAlH4/AlCl3 to yield the monobenzylated tetrol (III). The reaction of (III) with 2,2-dimethoxypropane (IV) and TsOH affords the acetonide (V), which is protected at the primary OH group with Mpm-Cl and NaH to provide the corresponding ether (VI). The debenzylation of (VI) with H2 over Raney-Ni in ethanol, followed by reaction with MsCl and TEA in dichloromethane, gives the mesylate (VII), which is treated with HCl in methanol to yield the diol (VIII). The reaction of (VIII) with K2CO3 in methanol affords the epoxide (IX), which is opened with NaN3 in refluxing ethanol to provide the azide (X). The selective monosilylation of (X) with Tbdps-Cl, TEA and DMAP in dichloromethane furnishes the silyl ether (XI). The reduction of the azido group of (XI) with PPh3 in THF/water gives the amine (XII), which is protected with Troc-Cl and NaHCO3 to afford the carbamate (XIII). The reaction of (XIII) with 2,2-dimethoxypropane (IV) and TsOH provides the oxazolidine (XIV), which is selectively deprotected at the Mpm group with DDQ in dichloromethane, giving the primary alcohol (XV). Finally, this compound is esterified with Tf2O and TEA in CH2Cl2 to obtain the desired oxazolidine intermediate (XVI).

Synthesis of oxazolidine intermediate (XVI): The reaction of dimethyl L-tartrate (I) with benzaldehyde and Ts-OH gives the benzylidene ketal (II), which is reduced with LiAlH4/AlCl3 to yield the monobenzylated tetrol (III). The reaction of (III) with 2,2-dimethoxypropane (IV) and TsOH affords the acetonide (V), which is protected at the primary OH group with Mpm-Cl and NaH to provide the corresponding ether (VI). The debenzylation of (VI) with H2 over Raney-Ni in ethanol, followed by reaction with MsCl and TEA in dichloromethane, gives the mesylate (VII), which is treated with HCl in methanol to yield the diol (VIII). The reaction of (VIII) with K2CO3 in methanol affords the epoxide (IX), which is opened with NaN3 in refluxing ethanol to provide the azide (X). The selective monosilylation of (X) with Tbdps-Cl, TEA and DMAP in dichloromethane furnishes the silyl ether (XI). The reduction of the azido group of (XI) with PPh3 in THF/water gives the amine (XII), which is protected with Troc-Cl and NaHCO3 to afford the carbamate (XIII). The reaction of (XIII) with 2,2-dimethoxypropane (IV) and TsOH provides the oxazolidine (XIV), which is selectively deprotected at the Mpm group with DDQ in dichloromethane, giving the primary alcohol (XV). Finally, this compound is esterified with Tf2O and TEA in CH2Cl2 to obtain the desired oxazolidine intermediate (XVI).

Synthesis of the aromatic intermediate (XXXIII): The esterification of the 5-hydroxyisophthalic acid (XVII) with SOCl2 and methanol gives the dimethyl ester (XVIII), which is treated with allyl bromide (XIX) and K2CO3 in refluxing acetone to yield the allyl ether (XX). The thermal isomerization of (XX) affords 4-allyl-5-hydroxyisophthalic acid dimethyl ester (XXI), which is treated with Bn-Br and K2CO3 in refluxing acetone to provide the benzyl ether (XXII). The hydrolysis of the ester groups of (XXII) with NaOH in THF gives the isophthalic acid (XXIII), which by reaction with Br2 and NaHCO3 yields the lactone (XXIV). The reduction of the carboxyl group of (XXIV) with isopropyl chloroformate and NaBH4 in THF/water affords the carbinol (XXV), which is protected with Bom-Cl and DIEA, providing compound (XXVI). The debromination of (XXVI) with Zn and NH4Cl in ethanol/water gives the 2-allylbenzoic acid (XXVII), which by a Curtius rearrangement with DPPA and TEA in refluxing tert-butanol yields the aryl carbamate (XXVIII). The reaction of (XXVIII) with OsO4 and NaIO4 in dioxane/water affords the indoline derivative (XXIX), which is treated with NaBH4 in EtOH to afford the 2-phenylethanol derivative (XXX). The reaction of (XXX) with Tbdms-Cl, TEA and DMAP provides the silyl ether (XXXI), which is treated with Tbdms-OTf and pyridine to give the aniline derivative (XXXII). Finally, this amine is reprotected with Alloc-Cl and NaHCO3 to yield the desired intermediate (XXXIII).

Assembly of the target compound: The condensation of intermediates (XVI) and (XXXIII) by means of NaH in THF gives the adduct (XXXIV), which is treated with Zn/HOAc in THF, yielding the aminoalcohol (XXXV). The selective protection of the NH2 and OH groups of (XXXV) with TsCl/TEA and MsCl/TEA, respectively, affords the fully protected compound (XXXVI), which is treated with NaH and imidazole in refluxing THF to provide the aziridine derivative (XXXVII). The desilylation of (XXXVII) with HF and pyridine furnishes the diol (XXXVIII), which is oxidized with DMP in CH2Cl2 to give the dialdehyde (XXXIX). The cyclization of (XXXIX) by means of LiHMDS in THF, followed by reduction with NaBH4, yields the tricyclic diol (XL), which is selectively silylated at the primary OH group with Tbdps-Cl, TEA and DMAP in CH2Cl2 to afford the monosilylated compound (XLI). The oxidation of the secondary OH group of (XLI) with DMP provides the cyclic ketone (XLII), which is desilylated with HF and pyridine to give the (S)-hydroxymethyl compound (XLIII). The treatment of (XLIII) with DBU in THF yields a mixture of the starting (S)-isomer (XLIII) and the desired (R)-isomer (XLIV) that is resolved by chromatography.

The reduction of the carbonyl group of (XLIV) with NaBH4 in THF gives the diol (XLV), which is selectively silylated at the primary OH group with Tbdps-Cl, TEA and DMAP, yielding silyl ether (XLVI). Elimination of the Alloc protecting group with Pd(PPh3)4, PPh3 in THF affords compound (XLVII), which is carefully oxidized at the NH group with MCPBA in dichloromethane, providing the hydroyamine (XLVIII). The reaction of (XLVIII) with Ac2O gives the acetate (XLIX), which is oxidized with DMP to yield the ketone (L). The desilylation of (L) with HF and pyridine affords the hydroxyketone (LI), which by treatment with K2CO3 in methanol undergoes cyclization to the tetracyclic compound (LIII) through the intermediate dihydroxyketone (LII). The reaction of (LIII) with diphosgene and pyridine gives the cyclic carbonate (LIV), which is treated with ammonia in THF, yielding the carbamic ester (LV).

The reaction of (LV) with Ac2O and pyridine gives the acetate (LVI), which is detosylated with sodium naphthalenide in DME to yield compound (LVII). The hydrogenation of (LVII) with H2 over Pd/C in ethyl acetate eliminates the Bn and Bom protecting groups to afford dihydroxy compound (LVIII), which is oxidized at the carbinol group with oxalyl chloride to provide the aldehyde (LIX). Finally, the cleavage of the acetoxy group of (LIX) with ammonia in methanol furnishes the target compound.

The reaction of 2,3-di-O-isopropylidene-L-threitol (I) with Tbdms-Cl and NaH gives the silyl ether (II), which is reacted with TEMPO, Pd(OAc)2 and dimethyl 1-diazo-2-oxopropyl phosphonate in methanol to yield the acetylene (III). The condensation of (III) with the aryl triflate (IV) by means of Pd(OAc)2, PPh3 and TEA in THF affords the aryl acetylene (V), which is treated with pyrrolidine (VI) to furnish the intermediate enamine (VII). The hydrolysis of (VII) with AcOH/water provides the expected ketone (VIII), which is stereoselectively reduced with zinc borohydride in ethyl ether to give the secondary alcohol (IX). The reaction of (IX) with Tips-OTf and lutidine in ethyl ether yields the fully protected tetrol (X). The selective hydrolysis of (X) with hot AcOH/water affords the monosilylated triol (XI), which is selectively monosilylated at the primary OH group by means of Tbdms-Cl, TEA and DMAP in dichloromethane to furnish the vicinal diol (XII).

The reaction of diol (XII) with TsCl and 1,4-diazabicyclo[2.2.2]octane (DABCO) provides the monotosylate (XIII), which is treated with NaH in DMF to give the epoxide (XIV). The selective deprotection of the primary silyl group of (XIV) by means of CSA in methanol yields the alcohol (XV), which is oxidized by means of DMP to afford the aldehyde (XVI). The reductocyclization of (XVI) by means of H2 over Pt/C in methanol provides the N-hydroxybenzazocine (XVII), which is protected as the 1-methoxy-1-methylethyl ether (XIX) by means of 2-methoxypropene (XVIII) and TsOH. The desilylation of (XIX) by means of TBAF in THF furnishes the secondary alcohol (XX), which is oxidized with oxalyl chloride to give the ketone (XXI). The hydroxymethylation of (XXI) by means of formaldehyde and LiOH in THF/water yields the non isolated intermediate (XXII).

The acidification of (XXII) with HCl gives the hemiacetal (XXIII), which is treated with 2-methoxypropene (XVIII) and PPTS to yield the corresponding acetonide (XXIV). The reduction of the ester group of (XXIV) by means of DIBAL in dichloromethane affords the hydroxymethyl derivative (XXV), which is protected with 4-methoxyphenol (XXVI), DEAD and PPh3 to provide the aryl ether (XXVII). The reaction of the epoxide ring of (XXVII) with LiN3 gives the hydroxyazide (XXVIII), which is treated with MsCl and TEA to yield the mesylate (XXIX). The hydrolysis of (XXIX) with TFA, followed by esterification with bis(trichloromethyl) carbonate affords the cyclic carbonate (XXX). The reaction of (XXX) with PCC provides the corresponding aldehyde that is protected with CSA and HCOOMe, and treated with PPh3 and DIEA in hot THF/water to construct the desired aziridine ring of (XXXI). The debenzylation of (XXXI) with H2 over Pd/C in ethanol, followed by cleavage of the dimethylacetal group by means of HClO4 furnishes the hydroxyaldehyde (XXXII). Finally, ammonolysis of the cyclic carbonate group of (XXXII) with ammonia in THF provides the carbamate ester of the target compound.