Treatment of cis-oxazolidine derivative (I) with isobutyraldehyde (II), LDA and LiBr in THF yields aldol product (III), which is then converted into (IV) by first aminal cleavage by means of MeOH and TfOH, followed by silylation with Tbdms-Cl and imidazole in DMF. Reaction of (IV) with formaldehyde and TsOH in benzene gives oxazolidine system (V), which is then first reduced with LiBH4 in THF/MeOH and then oxidized by means of DMSO, oxalyl chloride and Et3N in CH2Cl2 to provide aldehyde (VI). Mukaiyama aldol coupling of (VI) and (VII) in CH2Cl2 with MgI2 as catalyst, followed by treatment with K2CO3 in MeOH, yields aldol product (VIII), which is then converted into hydroxy lactam (IX) by the sequence: i) N-benzyl cleavage by hydrogenolysis over Pd/C in EtOH in the presence of DIEA; ii) ring closure by heating in MeOH; and iii) desilylation by treatment with HF in acetonitrile. Conversion of alcohol (IX) into dihydroxy acid (X) is achieved by a first oxidation with DMSO, oxalyl chloride and Et3N in CH2Cl2, followed by reaction with NaClO2, NaH2PO4 in t-BuOH and 2-Me-butene and final N/O methylene bridge removal with 1,3-propanedithiol (A) catalyzed by HCl and TFA. Compound (X) undergoes beta-lactonization to omuralide (XI) by means of BOPCl and Et3N in CH2Cl2 and finally (XI) is coupled to N-acetyl-L-cysteine (XII) in CH2Cl2 in the presence of Et3N.

Sharpless epoxidation of (XIII) with cumene hydroperoxide, diisopropyl L-tartrate ((+)-DIPT) and Ti(O-i-Pr)4 affords epoxide (-)-(XIV), which is then treated with benzyl isocyanate and NaH in refluxing THF to yield oxazolidinone (XV). Oxidation of (XV) by means of CrO3 in H2SO4 (Jones reagent) in acetone gives the corresponding carboxylic acid (XVI), which is converted into methyl ester (XVII) via diazomethane esterification in Et2O. Exposure of (XVII) to ethanolic KOH affords the trans-acid (XVIII), which is then converted into (2R,3S)-hydroxyleucine (XIX) by treatment with KOH and hydrogenolysis over Pd(OH)2 in MeOH. Esterification of (XIX) by means of MeOH and HCl (gas) provides (XX), which is treated with methyl benzimidate (Ph(MeO)C=NH) or methyl orthobenzoate (PhC(OMe)3) in the presence of catalytic p-TsOH to yield trans-oxazoline (XXI). Aldol condensation of (XXI) with formaldehyde and LHMDS via the Seebach protocol gives (XXII), which is converted into (XXIII) via Moffat oxidation with DCC and TFA in benzene/DMSO. Brown asymmetric allylboration of (XIII) in THF with (E)-crotyl(diisopinocampheyl)borane (XXIV) in Et2O affords a homoallylic alcohol mixture from which diastereomer (-)-(XXV) is obtained. Ozonolysis of (-)-(XXV) and reductive treatment with dimethylsulfide (DMS), followed by oxidation with NaClO2, NaH2PO4 and 2-methyl-2-butene, provides carboxylic acid (XXVI), which is then converted into (X) by means of Pd and HCOONH4 in refluxing HOAc followed by saponification with NaOH. Lactam ester derivative (X) reacts with N-acetyl-L-cysteine allyl ester (XXVII), BOPCl and Et3N in CH2Cl2 to furnish (XVIII), which is finally deallylated by means of Pd(PPh3)4, HCO2H and Et3N in THF.

Methylation of bicyclic oxazolidine (XXIX) by means of LDA and MeI, followed by selenenylation with PhSeBr/LDA in THF and ozonolysis in CH2Cl2, affords unsaturated derivative (XXX). Treatment of (XXX) with Tbdms-OTf and 2,6-lutidine in CH2Cl2 yields silyloxypyrrole (XXXI), which is converted into (XXXII) by an aldol reaction with (II) in the presence of SnCl4 in Et2O. Acetylation of (XXXII) by means of Ac2O, pyridine followed by dihydroxylation with OsO4 and N-methylmorpholine N-oxide allows formation of diol (XXXIII), whose tertiary hydroxyl group is removed by means of N,N'-thiocarbonyldiimidazole, followed by reduction with Bu3SnH and catalytic AIBN in toluene to provide derivative (XXXIV). Treatment of (XXXIV) with NaOH in MeOH followed by hydrogenolysis over Pd/C in HCl yields derivative (XXXV), which is converted into (XXXVI) by protection of primary alcohol by means of Et3SiCl and acetylation of secondary alcohol by treatment with Ac2O in pyridine. Regeneration of primary alcohol by treatment of (XXXVI) with HF in CH3CN furnishes (XXXVII), which is then oxidized by means of Jones reagent to yield (XXXVIII). Finally, saponification of diacetate acid (XXXVIII) with NaOH gives lactam (X).

Treatment of allofuranose derivative (XXXIX) with Bu2SnO in toluene followed by treatment with benzyl bromide and CsF provides (XL), which is then oxidized with Jones reagent to afford ketone (XLI). Wittig reaction of (XLI) with (ethoxycarbonymethylene)triphenylphosphorane (XLII) in toluene yields olefin (XLIII), which is then reduced by means of DIBAL to give (XLIV). Alcohol (XLIV) is then converted into trichloroacetimidate (XLV) by treatment with NaH and trichloroacetonitrile (CCl3CN) in Et2O. Rearrangement of (XLV) by heating with toluene affords derivative (XLVI), which is hydrolyzed by means of TFA/H2O to yield a mixture of diols that are chromatographically separated, providing (XLVII). Oxidation of (XLVII) in MeOH by means of NaIO4 provides hemiaminal derivative (XLVIII), which is further oxidized with Jones reagent to afford lactam (IL). Removal of protecting (N-trichloroacetyl and O-formyl) groups by treatment of (IL) with NaBH4 in MeOH gives partially deprotected derivative (L).

Silylation of (L) by treatment with TBSOTf and 2,6-lutidine in CH2Cl2 furnishes (LI), whose benzyl group is removed by means of Na/NH3 in THF to yield (LII). Moffat oxidation of (LII) gives aldehyde (LIII), which is treated with isopropylmagnesium bromide (LIV) in THF to afford a mixture of adducts from which (LV) is chromatographically separated. Treatment of (LV) with TFA/H2O provides (LVI), which is then treated with O3 (DMS workup) and finally oxidized with HOSO2NH2, NaH2PO4 and NaClO2 to yield carboxylic acid (X).

Alternatively, intermediate omuralide (XI) can also be obtained by following this synthetic sequence: Methylsulfanyl derivative (LVII) is transformed into chiral mono ester (LVIII) by enantioselective hydrolysis with porcine liver esterase (PLE) followed by recrystallization of the quinine salt. Treatment of (LVIII) with oxalyl chloride in DMF, followed by coupling in dichloromethane with N-p-methoxybenzylglycinate (PMB-NHCH2COOMe) (B) and Et3N and subsequent Dieckmann cyclization with LDA in THF, affords keto lactam (LIX). Stereoselective alpha-hydroxymethylation of (LIX) by means of formalin and DBU in THF, followed by stereospecific reduction with NaBH(OAc)3 in AcOH, gives dihydroxy lactam (LX), which is then converted into TBDMS ether (LXI) by the following sequence: i) esterification of primary hydroxyl group by pivaloyl chloride (PivCl) in pyridine; ii) silylation of the secondary hydroxyl group by means of TBSOTf and 2,6-lutidine; and iii) cleavage of the pivalate ester by treatment with NaOMe in MeOH. Desulfurization of (LXI) with Ni Raney followed by Dess-Martin periodinane oxidation furnishes aldehyde (LXII), which then reacts with Grignard reagent (LXIII) and TMSCl to yield the addition product (LXIV). Hydrogenation of (LXIV) over Pd/C followed by desilylation with TFA/H2O produces (LXV), which is hydrolyzed by means of LiOH in THF/H2O and treated with BOP-Cl and Et3N, affording beta-lactone (LXVI). Finally, cleavage of the N-p-methoxybenzyl protecting group of (LXVI) with Ceric ammonium nitrate in acetonitrile/H2O yields omuralide (XI).

Alternatively, intermediate omuralide (XI) can also be obtained by following this synthetic sequence: Methylsulfanyl derivative (LVII) is transformed into chiral mono ester (LVIII) by enantioselective hydrolysis with porcine liver esterase (PLE) followed by recrystallization of the quinine salt. Treatment of (LVIII) with oxalyl chloride in DMF, followed by coupling in dichloromethane with N-p-methoxybenzylglycinate (PMB-NHCH2COOMe) (B) and Et3N and subsequent Dieckmann cyclization with LDA in THF, affords keto lactam (LIX). Stereoselective alpha-hydroxymethylation of (LIX) by means of formalin and DBU in THF, followed by stereospecific reduction with NaBH(OAc)3 in AcOH, gives dihydroxy lactam (LX), which is then converted into TBDMS ether (LXI) by the following sequence: i) esterification of primary hydroxyl group by pivaloyl chloride (PivCl) in pyridine; ii) silylation of the secondary hydroxyl group by means of TBSOTf and 2,6-lutidine; and iii) cleavage of the pivalate ester by treatment with NaOMe in MeOH. Desulfurization of (LXI) with Ni Raney followed by Dess-Martin periodinane oxidation furnishes aldehyde (LXII), which then reacts with Grignard reagent (LXIII) and TMSCl to yield the addition product (LXIV). Hydrogenation of (LXIV) over Pd/C followed by desilylation with TFA/H2O produces (LXV), which is hydrolyzed by means of LiOH in THF/H2O and treated with BOP-Cl and Et3N, affording beta-lactone (LXVI). Finally, cleavage of the N-p-methoxybenzyl protecting group of (LXVI) with Ceric ammonium nitrate in acetonitrile/H2O yields omuralide (XI).

Sharpless epoxidation of (XIII) with cumene hydroperoxide, diisopropyl L-tartrate ((+)-DIPT) and Ti(O-i-Pr)4 affords epoxide (-)-(XIV), which is then treated with benzyl isocyanate and NaH in refluxing THF to yield oxazolidinone (XV). Oxidation of (XV) by means of CrO3 in H2SO4 (Jones reagent) in acetone gives the corresponding carboxylic acid (XVI), which is converted into methyl ester (XVII) via diazomethane esterification in Et2O. Exposure of (XVII) to ethanolic KOH affords the trans-acid (XVIII), which is then converted into (2R,3S)-hydroxyleucine (XIX) by treatment with KOH and hydrogenolysis over Pd(OH)2 in MeOH. Esterification of (XIX) by means of MeOH and HCl (gas) provides (XX), which is treated with methyl benzimidate (Ph(MeO)C=NH) or methyl orthobenzoate (PhC(OMe)3) in the presence of catalytic p-TsOH to yield trans-oxazoline (XXI). Aldol condensation of (XXI) with formaldehyde and LHMDS via the Seebach protocol gives (XXII), which is converted into (XXIII) via Moffat oxidation with DCC and TFA in benzene/DMSO. Brown asymmetric allylboration of (XIII) in THF with (E)-crotyl(diisopinocampheyl)borane (XXIV) in Et2O affords a homoallylic alcohol mixture from which diastereomer (-)-(XXV) is obtained. Ozonolysis of (-)-(XXV) and reductive treatment with dimethylsulfide (DMS), followed by oxidation with NaClO2, NaH2PO4 and 2-methyl-2-butene, provides carboxylic acid (XXVI), which is then converted into (X) by means of Pd and HCOONH4 in refluxing HOAc followed by saponification with NaOH. Lactam ester derivative (X) reacts with N-acetyl-L-cysteine allyl ester (XXVII), BOPCl and Et3N in CH2Cl2 to furnish (XVIII), which is finally deallylated by means of Pd(PPh3)4, HCO2H and Et3N in THF.

Methylation of bicyclic oxazolidine (XXIX) by means of LDA and MeI, followed by selenenylation with PhSeBr/LDA in THF and ozonolysis in CH2Cl2, affords unsaturated derivative (XXX). Treatment of (XXX) with Tbdms-OTf and 2,6-lutidine in CH2Cl2 yields silyloxypyrrole (XXXI), which is converted into (XXXII) by an aldol reaction with (II) in the presence of SnCl4 in Et2O. Acetylation of (XXXII) by means of Ac2O, pyridine followed by dihydroxylation with OsO4 and N-methylmorpholine N-oxide allows formation of diol (XXXIII), whose tertiary hydroxyl group is removed by means of N,N'-thiocarbonyldiimidazole, followed by reduction with Bu3SnH and catalytic AIBN in toluene to provide derivative (XXXIV). Treatment of (XXXIV) with NaOH in MeOH followed by hydrogenolysis over Pd/C in HCl yields derivative (XXXV), which is converted into (XXXVI) by protection of primary alcohol by means of Et3SiCl and acetylation of secondary alcohol by treatment with Ac2O in pyridine. Regeneration of primary alcohol by treatment of (XXXVI) with HF in CH3CN furnishes (XXXVII), which is then oxidized by means of Jones reagent to yield (XXXVIII). Finally, saponification of diacetate acid (XXXVIII) with NaOH gives lactam (X).

Methylation of bicyclic oxazolidine (XXIX) by means of LDA and MeI, followed by selenenylation with PhSeBr/LDA in THF and ozonolysis in CH2Cl2, affords unsaturated derivative (XXX). Treatment of (XXX) with Tbdms-OTf and 2,6-lutidine in CH2Cl2 yields silyloxypyrrole (XXXI), which is converted into (XXXII) by an aldol reaction with (II) in the presence of SnCl4 in Et2O. Acetylation of (XXXII) by means of Ac2O, pyridine followed by dihydroxylation with OsO4 and N-methylmorpholine N-oxide allows formation of diol (XXXIII), whose tertiary hydroxyl group is removed by means of N,N'-thiocarbonyldiimidazole, followed by reduction with Bu3SnH and catalytic AIBN in toluene to provide derivative (XXXIV). Treatment of (XXXIV) with NaOH in MeOH followed by hydrogenolysis over Pd/C in HCl yields derivative (XXXV), which is converted into (XXXVI) by protection of primary alcohol by means of Et3SiCl and acetylation of secondary alcohol by treatment with Ac2O in pyridine. Regeneration of primary alcohol by treatment of (XXXVI) with HF in CH3CN furnishes (XXXVII), which is then oxidized by means of Jones reagent to yield (XXXVIII). Finally, saponification of diacetate acid (XXXVIII) with NaOH gives lactam (X).

Sharpless epoxidation of (XIII) with cumene hydroperoxide, diisopropyl L-tartrate ((+)-DIPT) and Ti(O-i-Pr)4 affords epoxide (-)-(XIV), which is then treated with benzyl isocyanate and NaH in refluxing THF to yield oxazolidinone (XV). Oxidation of (XV) by means of CrO3 in H2SO4 (Jones reagent) in acetone gives the corresponding carboxylic acid (XVI), which is converted into methyl ester (XVII) via diazomethane esterification in Et2O. Exposure of (XVII) to ethanolic KOH affords the trans-acid (XVIII), which is then converted into (2R,3S)-hydroxyleucine (XIX) by treatment with KOH and hydrogenolysis over Pd(OH)2 in MeOH. Esterification of (XIX) by means of MeOH and HCl (gas) provides (XX), which is treated with methyl benzimidate (Ph(MeO)C=NH) or methyl orthobenzoate (PhC(OMe)3) in the presence of catalytic p-TsOH to yield trans-oxazoline (XXI). Aldol condensation of (XXI) with formaldehyde and LHMDS via the Seebach protocol gives (XXII), which is converted into (XXIII) via Moffat oxidation with DCC and TFA in benzene/DMSO. Brown asymmetric allylboration of (XIII) in THF with (E)-crotyl(diisopinocampheyl)borane (XXIV) in Et2O affords a homoallylic alcohol mixture from which diastereomer (-)-(XXV) is obtained. Ozonolysis of (-)-(XXV) and reductive treatment with dimethylsulfide (DMS), followed by oxidation with NaClO2, NaH2PO4 and 2-methyl-2-butene, provides carboxylic acid (XXVI), which is then converted into (X) by means of Pd and HCOONH4 in refluxing HOAc followed by saponification with NaOH. Lactam ester derivative (X) reacts with N-acetyl-L-cysteine allyl ester (XXVII), BOPCl and Et3N in CH2Cl2 to furnish (XVIII), which is finally deallylated by means of Pd(PPh3)4, HCO2H and Et3N in THF.

Treatment of allofuranose derivative (XXXIX) with Bu2SnO in toluene followed by treatment with benzyl bromide and CsF provides (XL), which is then oxidized with Jones reagent to afford ketone (XLI). Wittig reaction of (XLI) with (ethoxycarbonymethylene)triphenylphosphorane (XLII) in toluene yields olefin (XLIII), which is then reduced by means of DIBAL to give (XLIV). Alcohol (XLIV) is then converted into trichloroacetimidate (XLV) by treatment with NaH and trichloroacetonitrile (CCl3CN) in Et2O. Rearrangement of (XLV) by heating with toluene affords derivative (XLVI), which is hydrolyzed by means of TFA/H2O to yield a mixture of diols that are chromatographically separated, providing (XLVII). Oxidation of (XLVII) in MeOH by means of NaIO4 provides hemiaminal derivative (XLVIII), which is further oxidized with Jones reagent to afford lactam (IL). Removal of protecting (N-trichloroacetyl and O-formyl) groups by treatment of (IL) with NaBH4 in MeOH gives partially deprotected derivative (L).

Silylation of (L) by treatment with TBSOTf and 2,6-lutidine in CH2Cl2 furnishes (LI), whose benzyl group is removed by means of Na/NH3 in THF to yield (LII). Moffat oxidation of (LII) gives aldehyde (LIII), which is treated with isopropylmagnesium bromide (LIV) in THF to afford a mixture of adducts from which (LV) is chromatographically separated. Treatment of (LV) with TFA/H2O provides (LVI), which is then treated with O3 (DMS workup) and finally oxidized with HOSO2NH2, NaH2PO4 and NaClO2 to yield carboxylic acid (X).

The condensation of isobutyraldehyde (I) with triethyl phosphonoacetate (II) by means of NaH in THF gives 4-methyl-2-pentenoic acid ethyl ester (III), which is reduced with DIBAL in THF to yield the allyl alcohol (IV). The Sharpless asymmetric epoxidation of (IV) by means of Ti(O-iPr)4, (+)-diethyl tartrate ((+)-DET) and tBu-OOH in toluene affords the epoxy alcohol (V), which is treated with trichloroacetonitrile and DBU to provide the acetimidate (VI). The cyclization of (VI) by means of triethyl aluminum chloride in dichloromethane gives the oxazoline (VII), which is silylated with Tbdms-OTf and TEA in dichloromethane to afford the silyl ether (VIII). The cleavage of the oxazoline ring of (VIII) by means of HCl in THF yields the chiral amino alcohol (IX), which is protected with Tbdms-OTf as before to afford the silylated amine (X). The monoalkylation of (X) with 1,3-dibromo-2-methylpropene (XI) and Cs-OH in DMF provides the secondary amine (XII). The cyclization of (XII) by means of KHMDS in toluene/ethyl ether gives the non isolated intermediate (XIII) that rearranges to the pyrroline (XIV). The reaction of (XIV) with TPAP and NMO in acetonitrile yields the cyclic imine (XV), which is oxidized with NaClO2 to the 1-chloropyrrolin-2-one (XVI). The dechlorination of (XVI) by means of NaBH4 affords the pyrrolinone (XVII), which is selectively monodesilylated with TBAF in THF to provide the primary alcohol (XVIII). The cyclization of (XVIII) with benzaldehyde dimethylacetal and Ts-OH in refluxing toluene gives the bicyclic pyrrolo oxazole (XIX), which is finally deprotected by means of TBAF in THF to yield the target bicyclic intermediate (XX) (see scheme no. 23327701c intermediate (XXXII)).