The reaction of dimethyl malonate (I) with 3-(tert-butyldimethylsilyloxy)propyl iodide (II) by means of NaH in THF gives the alkylmalonate (III), which by a new alkylation with allyl bromide (IV) and NaH in DME affords the dialkylmalonate (V). The reduction of (V) with LiBH4 in THF yields the 1,3-propanediol (VI), which is cyclized with 2,2-dimethoxypropane and CSA in dichloromethane giving the 1,3-dioxane (VII). The ozonolysis of the double bond of (VII) with O3 in dichloromethane yields the aldehyde (VIII), which is protected by heating with cyclohexylamine (IX) to afford the imine (X).The condensation of (X) with 8(E)-decenal (XI) by means of LDA in ethyl ether gives the unsaturated aldehyde (XII), which is treated with Pmb-Cl and KH in DME/HMPA to yield the enol ether (XIII). The desilylation of (XIII) with TBAF in THF gives the propanol derivative (XIV), which is oxidized with SO3/pyridine to the corresponding aldehyde (XV). The condensation of (XV) with 4-(triisopropylsilyloxy)-1(E)-butenyl iodide (XVI) by means of BuLi in THF, followed by oxidation of the intermediate alcohol with SO3/pyridine provides the unsaturated ketone (XVII).

The cyclization of (XVII) by means of Me2AlCl in dichloromethane gives the tricyclic ketone (XVIII), which is desilylated with TBAF in THF yielding the ethanol (XIX). The oxidation of (XIX) with Dess Martin periodinane (DMP) in dichloromethane affords the corresponding aldehyde (XX), which is condensed with the lithium 1,3-dithiane (XXI) in THF to give the secondary alcohol (XXII). The silylation of this alcohol with Tes-OTf and NaH in THF yields the silyl ether (XXIII), which is treated with Ph-NTf2 and KHMDS in THF to afford the enol ether (XXIV). The reaction of (XXIV) with Pdo and CO in methanol gives the methyl ester (XXV), which is treated with PhI(OCOCF3)2 and methanol to afford the gem-dimethoxy compound (XXVI).

The reduction of the ester group of (XXVI) with DIBAL in toluene gives the carbinol (XXVII), which is treated with tert-butyl hydroperoxide and Et2Al-CN in toluene to yield the dihydroxy-carbonitrile (XXVIII). The sulfonation of the primary OH group of (XXVIII) with Ms-Cl affords the mesylate (XXIX), which is treated with K2CO3 in methanol providing the intermediate epoxide (XXX). The reaction of (XXX) with oxalic acid in ethanol/water affords the maleic anhydride derivative (XXXI), which by a selective hydrolysis with aqueous AcOH gives the alpha hydroxy ketone (XXXII). The silylation of the OH group of (XXXII) with TBDMS-OTf and lutidine in dichloromethane yields the silyl ether (XXXIII).

The intermediate aldehyde (XV) has been obtained as follows: The reaction of dimethyl malonate (I) with 3-(tert-butyldimethylsilyloxy)propyl iodide (II) by means of NaH in THF gives the alkylmalonate (III), which by a new alkylation with allyl bromide (IV) and NaH in DME affords the dialkylmalonate (V). The reduction of (V) with LiBH4 in THF yields the 1,3-propanediol (VI), which is cyclized with 2,2-dimethoxypropane and CSA in dichloromethane giving the 1,3-dioxane (VII). The ozonolysis of the double bond of (VII) with O3 in dichloromethane yields the aldehyde (VIII), which is protected by heating with cyclohexylamine (IX) to afford the imine (X). The condensation of (X) with 8(E)-decenal (XI) by means of LDA in ethyl ether gives the unsaturated aldehyde (XII), which is treated with PmbCl and KH in DME/HMPA to yield the enol ether (XIII). The desilylation of (XIII) with TBAF in THF gives the propanol derivative (XIV), which is oxidized with SO3.Pyr to the corresponding aldehyde (XV).

The condensation of (S)-glycidol (XVI) with trimethylsilylacetylene (XVII) by means of tert-butyllithium in THF, followed by quenching with TBDMS triflate gives the protected acetylenic diol (XVIII), which is iodinated with K2CO3, Cp2ZnCl and I2 yielding the vinyl iodide (XIX). The condensation of (XIX) with the intermediate aldehyde (XV) in THF, followed by oxidation with DMP affords the chiral ketone (XX), which is submitted to a diastereoselective cyclization catalyzed by dichloroaluminum phenoxide (XXI) in toluene to furnish the polycyclic ketone (XXII) as a 5.7:1 diastereomeric mixture. The desilylation of this mixture with TBAF in THF allowed the separation of the mayor diastereomeric diol (XXIII) by flash chromatography. The oxidation of (XXIII) with NaIO4 affords the corresponding aldehyde (XXIV), which is condensed with the lithium 1,3-dithiane (XXV) in THF to give the secondary alcohol (XXVI). The silylation of this alcohol with TES-OTf and NaH in THF yields the silyl ether (XXVII), which is treated with Ph-NTf2 and KHMDS in THF to afford the enol ether (XXVIII).

The reaction of (XXVIII) with Pd and CO in MeOH gives the methyl ester (XXIX), which is treated with PhI(OCOCF3)2 and MeOH to afford the gem-dimethoxy compound (XXX). The reduction of the ester group of (XXX) with DIBAL in toluene gives the carbinol (XXXI), which is treated with tert-butyl hydroperoxide and Et2Al-CN in toluene to yield the dihydroxycarbonitrile (XXXII). The sulfonation of the primary OH group of (XXXII) with MsCl affords the mesylate (XXXIII), which is treated with K2CO3 in MeOH providing the intermediate epoxide (XXXIV). The reaction of (XXXIV) with oxalic acid in EtOH/H2O affords the maleic anhydride derivative (XXXV).

The selective hydrolysis of (XXXV) with aqueous AcOH gives the alpha hydroxy ketone (XXXVI), which is silylated at the OH group with TBDMS-OTf and lutidine in dichloromethane yielding the silyl ether (XXXVII). The cleavage of the 4-methoxybenzyl group of (XXXVII) with DDQ in CH2Cl2/H2O gives the secondary alcohol (XXXVIII), which is oxidized with pyridinium dichromate (PDC) in dichloromethane yielding the corresponding ketone (XXXIX). The cyclization of (XXXIX) with AcOH affords the tetracyclic compound (XL), which is silylated at the carbinol group with TES-OTf and lutidine giving the silyl ether (XLI). The oxidation of (XLI) with DMP in refluxing benzene affords the carbinol (XLII), which is selectively desilylated and cyclized with TFA in CH2Cl2/H2O giving the pentacyclic compound (XLIII). The oxidation of the hydroxymethyl group of (XLIII) with DMP in CH2Cl2 yields corresponding aldehyde (XLIV).

The reaction of dimethyl malonate (I) with 3-(tert-butyldimethylsilyloxy)propyl iodide (II) by means of NaH in THF gives the alkylmalonate (III), which by a new alkylation with allyl bromide (IV) and NaH in DME affords the dialkylmalonate (V). The reduction of (V) with LiBH4 in THF yields the 1,3-propanediol (VI), which is cyclized with 2,2-dimethoxypropane and CSA in dichloromethane giving the 1,3-dioxane (VII). The ozonolysis of the double bond of (VII) with O3 in dichloromethane yields the aldehyde (VIII), which is protected by heating with cyclohexylamine (IX) to afford the imine (X).The condensation of (X) with 8(E)-decenal (XI) by means of LDA in ethyl ether gives the unsaturated aldehyde (XII), which is treated with Pmb-Cl and KH in DME/HMPA to yield the enol ether (XIII). The desilylation of (XIII) with TBAF in THF gives the propanol derivative (XIV), which is oxidized with SO3/pyridine to the corresponding aldehyde (XV). The condensation of (XV) with 4-(triisopropylsilyloxy)-1(E)-butenyl iodide (XVI) by means of BuLi in THF, followed by oxidation of the intermediate alcohol with SO3/pyridine provides the unsaturated ketone (XVII).

The cyclization of (XVII) by means of Me2AlCl in dichloromethane gives the tricyclic ketone (XVIII), which is desilylated with TBAF in THF yielding the ethanol (XIX). The oxidation of (XIX) with Dess Martin periodinane (DMP) in dichloromethane affords the corresponding aldehyde (XX), which is condensed with the lithium 1,3-dithiane (XXI) in THF to give the secondary alcohol (XXII). The silylation of this alcohol with Tes-OTf and NaH in THF yields the silyl ether (XXIII), which is treated with Ph-NTf2 and KHMDS in THF to afford the enol ether (XXIV). The reaction of (XXIV) with Pdo and CO in methanol gives the methyl ester (XXV), which is treated with PhI(OCOCF3)2 and methanol to afford the gem-dimethoxy compound (XXVI).

The reduction of the ester group of (XXVI) with DIBAL in toluene gives the carbinol (XXVII), which is treated with tert-butyl hydroperoxide and Et2Al-CN in toluene to yield the dihydroxy-carbonitrile (XXVIII). The sulfonation of the primary OH group of (XXVIII) with Ms-Cl affords the mesylate (XXIX), which is treated with K2CO3 in methanol providing the intermediate epoxide (XXX). The reaction of (XXX) with oxalic acid in ethanol/water affords the maleic anhydride derivative (XXXI), which by a selective hydrolysis with aqueous AcOH gives the alpha hydroxy ketone (XXXII). The silylation of the OH group of (XXXII) with Tbdms-OTf and lutidine in dichloromethane yields the silyl ether (XXXIII).

The intermediate aldehyde (XV) has been obtained as follows: The reaction of dimethyl malonate (I) with 3-(tert-butyldimethylsilyloxy)propyl iodide (II) by means of NaH in THF gives the alkylmalonate (III), which by a new alkylation with allyl bromide (IV) and NaH in DME affords the dialkylmalonate (V). The reduction of (V) with LiBH4 in THF yields the 1,3-propanediol (VI), which is cyclized with 2,2-dimethoxypropane and CSA in dichloromethane giving the 1,3-dioxane (VII). The ozonolysis of the double bond of (VII) with O3 in dichloromethane yields the aldehyde (VIII), which is protected by heating with cyclohexylamine (IX) to afford the imine (X).The condensation of (X) with 8(E)-decenal (XI) by means of LDA in ethyl ether gives the unsaturated aldehyde (XII), which is treated with Pmb-Cl and KH in DME/HMPA to yield the enol ether (XIII). The desilylation of (XIII) with TBAF in THF gives the propanol derivative (XIV), which is oxidized with SO3.Pyr to the corresponding aldehyde (XV).

The condensation of (S)-glycidol (XVI) with trimethylsilylacetylene (XVII) by means of tert-butyllithium in THF, followed by quenching with TBDMS triflate gives the protected acetylenic diol (XVIII), which is iodinated with K2CO3, Cp2ZnCl and I2 yielding the vinyl iodide (XIX). The condensation of (XIX) with the intermediate aldehyde (XV) in THF, followed by oxidation with DMP affords the chiral ketone (XX), which is submitted to a diastereoselective cyclization catalyzed by dichloroaluminum phenoxide (XXI) in toluene to furnish the polycyclic ketone (XXII) as a 5.7:1 diastereomeric mixture. The desilylation of this mixture with TBAF in THF allowed the separation of the mayor diastereomeric diol (XXIII) by flash chromatography. The oxidation of (XXIII) with NaIO4 affords the corresponding aldehyde (XXIV), which is condensed with the lithium 1,3-dithiane (XXV) in THF to give the secondary alcohol (XXVI). The silylation of this alcohol with TES-OTf and NaH in THF yields the silyl ether (XXVII), which is treated with Ph-NTf2 and KHMDS in THF to afford the enol ether (XXVIII).

The reaction of (XXVIII) with Pd and CO in MeOH gives the methyl ester (XXIX), which is treated with PhI(OCOCF3)2 and MeOH to afford the gem-dimethoxy compound (XXX). The reduction of the ester group of (XXX) with DIBAL in toluene gives the carbinol (XXXI), which is treated with tert-butyl hydroperoxide and Et2Al(CN) in toluene to yield the dihydroxycarbonitrile (XXXII). The sulfonation of the primary OH group of (XXXII) with MsCl affords mesylate (XXXIII), which is treated with K2CO3 in MeOH providing intermediate epoxide (XXXIV). The reaction of (XXXIV) with oxalic acid affords the maleic anhydride derivative (XXXV).

The selective hydrolysis of (XXXV) with aqueous AcOH gives the alpha hydroxy ketone (XXXVI), which is silylated at the OH group with TBDMS-OTf and lutidine in dichloromethane yielding the silyl ether (XXXVII). The cleavage of the 4-methoxybenzyl group of (XXXVII) with DDQ in dichloromethane/water gives the secondary alcohol (XXXVIII), which is oxidized with pyridinium dichromate (PDC) in dichloromethane yielding the corresponding ketone (XXXIX). The cyclization of (XXXIX) with AcOH affords the tetracyclic compound (XL), which is silylated at the carbinol group with TES-OTf and lutidine giving the silyl ether (XLI). The oxidation of (XLI) with DMP in refluxing benzene affords the carbinol (XLII), which is selectively desilylated and cyclized with TFA in dichloromethane/water giving the pentacyclic compound (XLIII). The oxidation of the hydroxymethyl group of (XLIII) with DMP in dichloromethane yields corresponding aldehyde (XLIV).

The cleavage of the 4-methoxybenzyl group of (XXXIII) with DDQ in dichloromethane/water gives the secondary alcohol (XXXIV), which is oxidized with pyridinium dichromate (PDC) in dichloromethane yielding the corresponding ketone (XXXV). The cyclization of (XXXV) with AcOH affords the tetracyclic compound (XXXVI), which is silylated at the carbinol group with Tes-OTf and lutidine giving the silyl ether (XXXVII). The oxidation of (XXXVII) with DMP in refluxing benzene affords the carbinol (XXXVIII), which is selectively desilylated and cyclized with TFA in dichloromethane/water giving the pentacyclic compound (XXXIX). The oxidation of the hydroxymethyl group of (XXXIX) with DMP in dichloromethane yields corresponding aldehyde (XL), which is silylated at the remaining OH group with Tbdms-OTf and lutidine in dichloromethane to afford the silyl ether (XLI). The oxidation of the aldehyde group of (XLI) with NaClO2 in tert-butanol/water gives the carboxylic acid (XLII).

The reaction of (XLII) with methanesulfonyl chloride and Et3N in THF gives the mixed anhydride (XLIII), which is treated with diazomethane in ethyl ether/THF to yield the diazoketone (XLIV). The rearrangement of (XLIV) with Ag2O in DMF/water affords the acetic acid derivative (XLV), which is condensed with indoline (XLVI) by means of EDC and DMAP in dichloromethane to provide the acyl indoline (XLVII). The desilylation of (XLVII) with TFA/water in dichloromethane gives the secondary alcohol (XLVIII), which is oxidized with DMP in dichloromethane to yield the corresponding ketonic compound (XLIX). The dehydrogenation of the indoline group of (XLIX) with chloranil in refluxing toluene affords the corresponding indole derivative (L).

Finally, compound (L) is treated with LiOH and NaH2PO4 in THF/water to provide the target compound.

The selective hydrolysis of (XXXV) with aqueous AcOH gives the alpha hydroxy ketone (XXXVI), which is silylated at the OH group with TBDMS-OTf and lutidine in dichloromethane yielding the silyl ether (XXXVII). The cleavage of the 4-methoxybenzyl group of (XXXVII) with DDQ in CH2Cl2/H2O gives the secondary alcohol (XXXVIII), which is oxidized with pyridinium dichromate (PDC) in dichloromethane yielding the corresponding ketone (XXXIX). The cyclization of (XXXIX) with AcOH affords the tetracyclic compound (XL), which is silylated at the carbinol group with TES-OTf and lutidine giving the silyl ether (XLI). The oxidation of (XLI) with DMP in refluxing benzene affords the carbinol (XLII), which is selectively desilylated and cyclized with TFA in CH2Cl2/H2O giving the pentacyclic compound (XLIII). The oxidation of the hydroxymethyl group of (XLIII) with DMP in CH2Cl2 yields corresponding aldehyde (XLIV).

The silylation at the remaining OH group of (XLIV) with TBDMS-OTf and lutidine in dichloromethane affords the silyl ether (XLV), which is oxidized at the aldehyde group with NaClO2 in tert-butanol/water giving the carboxylic acid (XLVI). The reaction of (XLVI) with methanesulfonyl chloride and Et3N in THF gives the mixed anhydride (XLVII), which is treated with diazomethane in ethyl ether/THF to yield the diazoketone (XLVIII). The rearrangement of (XLVIII) with Ag2O in DMF/water affords the acetic acid derivative (XLIX), which is condensed with indoline (L) by means of EDC and DMAP in CH2Cl2 to provide the acyl indoline (LI). The desilylation of (LI) with TFA/water in dichloromethane gives the secondary alcohol (LII).

The oxidation of (LII) with DMP in dichloromethane yields the corresponding ketonic compound (LIII), which is dehydrogenated at the indoline group with chloranil in refluxing toluene affording the corresponding indole derivative (LIV). Finally, compound (LIV) is treated with LiOH and NaH2PO4 in THF/water to provide the target compound.

The cleavage of the 4-methoxybenzyl group of (XXXIII) with DDQ in dichloromethane/water gives the secondary alcohol (XXXIV), which is oxidized with pyridinium dichromate (PDC) in dichloromethane yielding the corresponding ketone (XXXV). The cyclization of (XXXV) with AcOH affords the tetracyclic compound (XXXVI), which is silylated at the carbinol group with Tes-OTf and lutidine giving the silyl ether (XXXVII). The oxidation of (XXXVII) with DMP in refluxing benzene affords the carbinol (XXXVIII) (1), which is selectively desilylated and cyclized with TFA in dichloromethane/water giving the pentacyclic compound (XXXIX). The oxidation of the hydroxymethyl group of (XXXIX) with DMP in dichloromethane yields corresponding aldehyde (XL), which is silylated at the remaining OH group with Tbdms-OTf and lutidine in dichloromethane to afford the silyl ether (XLI). The oxidation of the aldehyde group of (XLI) with NaClO2 in tert-butanol/water gives the carboxylic acid (XLII).

The reaction of (XLII) with methanesulfonyl chloride and Et3N in THF gives the mixed anhydride (XLIII), which is treated with diazomethane in ethyl ether/THF to yield the diazoketone (XLIV). The rearrangement of (XLIV) with Ag2O in DMF/water affords the acetic acid derivative (XLV), which is condensed with indoline (XLVI) by means of EDC and DMAP in dichloromethane to provide the acyl indoline (XLVII). The desilylation of (XLVII) with TFA/water in dichloromethane gives the secondary alcohol (XLVIII), which is oxidized with DMP in dichloromethane to yield the corresponding ketonic compound (XLIX). The dehydrogenation of the indoline group of (XLIX) with chloranil in refluxing toluene affords the corresponding indole derivative (L).

Compound (L) is treated with LiOH and NaH2PO4 in THF/water to provide the dihydroxylated acetic acid derivative (LI), which is finally cyclized to the target compound by means of methanesulfonic acid in chloroform.

The selective hydrolysis of (XXXV) with aqueous AcOH gives the alpha hydroxy ketone (XXXVI), which is silylated at the OH group with TBDMS-OTf and lutidine in dichloromethane yielding the silyl ether (XXXVII). The cleavage of the 4-methoxybenzyl group of (XXXVII) with DDQ in dichloromethane/water gives the secondary alcohol (XXXVIII), which is oxidized with pyridinium dichromate (PDC) in dichloromethane yielding the corresponding ketone (XXXIX). The cyclization of (XXXIX) with AcOH affords the tetracyclic compound (XL), which is silylated at the carbinol group with TES-OTf and lutidine giving the silyl ether (XLI). The oxidation of (XLI) with DMP in refluxing benzene affords the carbinol (XLII), which is selectively desilylated and cyclized with TFA in dichloromethane/water giving the pentacyclic compound (XLIII). The oxidation of the hydroxymethyl group of (XLIII) with DMP in dichloromethane yields corresponding aldehyde (XLIV).

The silylation at the remaining OH group of (XLIV) with TBDMS-OTf and lutidine in dichloromethane affords the silyl ether (XLV), which is oxidized at the aldehyde group with NaClO2 in tert-butanol/water giving the carboxylic acid (XLVI). The reaction of (XLVI) with methanesulfonyl chloride and Et3N in THF gives the mixed anhydride (XLVII), which is treated with diazomethane in ethyl ether/THF to yield the diazoketone (XLVIII). The rearrangement of (XLVIII) with Ag2O in DMF/water affords the acetic acid derivative (XLIX), which is condensed with indoline (L) by means of EDC and DMAP in dichloromethane to provide the acyl indoline (LI). The desilylation of (LI) with TFA/water in dichloromethane gives the secondary alcohol (LII).

The oxidation of (LII) with DMP in dichloromethane yields the corresponding ketonic compound (LIII), which is dehydrogenated at the indoline group with chloranil in refluxing toluene affording the corresponding indole derivative (LIV). Compound (LIV) is treated with LiOH and NaH2PO4 in THF/water to provide the dihydroxylated acetic acid derivative (LV), which is finally cyclized to the target compound by means of methanesulfonic acid in chloroform.

The condensation of (S)-glycidol (XVI) with trimethylsilylacetylene (XVII) by means of tert-butyllithium in THF, followed by quenching with TBDMS triflate gives the protected acetylenic diol (XVIII), which is iodinated with K2CO3, Cp2ZnCl and I2 yielding the vinyl iodide (XIX). The condensation of (XIX) with the intermediate aldehyde (XV) in THF, followed by oxidation with DMP affords the chiral ketone (XX), which is submitted to a diastereoselective cyclization catalyzed by dichloroaluminum phenoxide (XXI) in toluene to furnish the polycyclic ketone (XXII) as a 5.7:1 diastereomeric mixture. The desilylation of this mixture with TBAF in THF allowed the separation of the mayor diastereomeric diol (XXIII) by flash chromatography. The oxidation of (XXIII) with NaIO4 affords the corresponding aldehyde (XXIV), which is condensed with the lithium 1,3-dithiane (XXV) in THF to give the secondary alcohol (XXVI). The silylation of this alcohol with TES-OTf and NaH in THF yields the silyl ether (XXVII), which is treated with Ph-NTf2 and KHMDS in THF to afford the enol ether (XXVIII).

The reaction of (XXVIII) with Pd and CO in MeOH gives the methyl ester (XXIX), which is treated with PhI(OCOCF3)2 and MeOH to afford the gem-dimethoxy compound (XXX). The reduction of the ester group of (XXX) with DIBAL in toluene gives the carbinol (XXXI), which is treated with tert-butyl hydroperoxide and Et2Al-CN in toluene to yield the dihydroxycarbonitrile (XXXII). The sulfonation of the primary OH group of (XXXII) with MsCl affords the mesylate (XXXIII), which is treated with K2CO3 in MeOH providing the intermediate epoxide (XXXIV). The reaction of (XXXIV) with oxalic acid in EtOH/H2O affords the maleic anhydride derivative (XXXV).

The selective hydrolysis of (XXXV) with aqueous AcOH gives the alpha hydroxy ketone (XXXVI), which is silylated at the OH group with TBDMS-OTf and lutidine in dichloromethane yielding the silyl ether (XXXVII). The cleavage of the 4-methoxybenzyl group of (XXXVII) with DDQ in CH2Cl2/H2O gives the secondary alcohol (XXXVIII), which is oxidized with pyridinium dichromate (PDC) in dichloromethane yielding the corresponding ketone (XXXIX). The cyclization of (XXXIX) with AcOH affords the tetracyclic compound (XL), which is silylated at the carbinol group with TES-OTf and lutidine giving the silyl ether (XLI). The oxidation of (XLI) with DMP in refluxing benzene affords the carbinol (XLII), which is selectively desilylated and cyclized with TFA in CH2Cl2/H2O giving the pentacyclic compound (XLIII). The oxidation of the hydroxymethyl group of (XLIII) with DMP in CH2Cl2 yields corresponding aldehyde (XLIV).

The silylation at the remaining OH group of (XLIV) with TBDMS-OTf and lutidine in dichloromethane affords the silyl ether (XLV), which is oxidized at the aldehyde group with NaClO2 in tert-butanol/water giving the carboxylic acid (XLVI). The reaction of (XLVI) with methanesulfonyl chloride and Et3N in THF gives the mixed anhydride (XLVII), which is treated with diazomethane in ethyl ether/THF to yield the diazoketone (XLVIII). The rearrangement of (XLVIII) with Ag2O in DMF/water affords the acetic acid derivative (XLIX), which is condensed with indoline (L) by means of EDC and DMAP in CH2Cl2 to provide the acyl indoline (LI). The desilylation of (LI) with TFA/water in dichloromethane gives the secondary alcohol (LII).

The oxidation of (LII) with DMP in dichloromethane yields the corresponding ketonic compound (LIII), which is dehydrogenated at the indoline group with chloranil in refluxing toluene affording the corresponding indole derivative (LIV). Finally, compound (LIV) is treated with LiOH and NaH2PO4 in THF/water to provide the target compound.

The condensation of (S)-glycidol (XVI) with trimethylsilylacetylene (XVII) by means of tert-butyllithium in THF, followed by quenching with TBDMS triflate gives the protected acetylenic diol (XVIII), which is iodinated with K2CO3, Cp2ZnCl and I2 yielding the vinyl iodide (XIX). The condensation of (XIX) with the intermediate aldehyde (XV) in THF, followed by oxidation with DMP affords the chiral ketone (XX), which is submitted to a diastereoselective cyclization catalyzed by dichloroaluminum phenoxide (XXI) in toluene to furnish the polycyclic ketone (XXII) as a 5.7:1 diastereomeric mixture. The desilylation of this mixture with TBAF in THF allowed the separation of the mayor diastereomeric diol (XXIII) by flash chromatography. The oxidation of (XXIII) with NaIO4 affords the corresponding aldehyde (XXIV), which is condensed with the lithium 1,3-dithiane (XXV) in THF to give the secondary alcohol (XXVI). The silylation of this alcohol with TES-OTf and NaH in THF yields the silyl ether (XXVII), which is treated with Ph-NTf2 and KHMDS in THF to afford the enol ether (XXVIII).

The reaction of (XXVIII) with Pd and CO in MeOH gives the methyl ester (XXIX), which is treated with PhI(OCOCF3)2 and MeOH to afford the gem-dimethoxy compound (XXX). The reduction of the ester group of (XXX) with DIBAL in toluene gives the carbinol (XXXI), which is treated with tert-butyl hydroperoxide and Et2Al(CN) in toluene to yield the dihydroxycarbonitrile (XXXII). The sulfonation of the primary OH group of (XXXII) with MsCl affords mesylate (XXXIII), which is treated with K2CO3 in MeOH providing intermediate epoxide (XXXIV). The reaction of (XXXIV) with oxalic acid affords the maleic anhydride derivative (XXXV).

The selective hydrolysis of (XXXV) with aqueous AcOH gives the alpha hydroxy ketone (XXXVI), which is silylated at the OH group with TBDMS-OTf and lutidine in dichloromethane yielding the silyl ether (XXXVII). The cleavage of the 4-methoxybenzyl group of (XXXVII) with DDQ in dichloromethane/water gives the secondary alcohol (XXXVIII), which is oxidized with pyridinium dichromate (PDC) in dichloromethane yielding the corresponding ketone (XXXIX). The cyclization of (XXXIX) with AcOH affords the tetracyclic compound (XL), which is silylated at the carbinol group with TES-OTf and lutidine giving the silyl ether (XLI). The oxidation of (XLI) with DMP in refluxing benzene affords the carbinol (XLII), which is selectively desilylated and cyclized with TFA in dichloromethane/water giving the pentacyclic compound (XLIII). The oxidation of the hydroxymethyl group of (XLIII) with DMP in dichloromethane yields corresponding aldehyde (XLIV).

The silylation at the remaining OH group of (XLIV) with TBDMS-OTf and lutidine in dichloromethane affords the silyl ether (XLV), which is oxidized at the aldehyde group with NaClO2 in tert-butanol/water giving the carboxylic acid (XLVI). The reaction of (XLVI) with methanesulfonyl chloride and Et3N in THF gives the mixed anhydride (XLVII), which is treated with diazomethane in ethyl ether/THF to yield the diazoketone (XLVIII). The rearrangement of (XLVIII) with Ag2O in DMF/water affords the acetic acid derivative (XLIX), which is condensed with indoline (L) by means of EDC and DMAP in dichloromethane to provide the acyl indoline (LI). The desilylation of (LI) with TFA/water in dichloromethane gives the secondary alcohol (LII).

The oxidation of (LII) with DMP in dichloromethane yields the corresponding ketonic compound (LIII), which is dehydrogenated at the indoline group with chloranil in refluxing toluene affording the corresponding indole derivative (LIV). Compound (LIV) is treated with LiOH and NaH2PO4 in THF/water to provide the dihydroxylated acetic acid derivative (LV), which is finally cyclized to the target compound by means of methanesulfonic acid in chloroform.

The condensation of 4-(ethylsulfanyl)-2-butynoic acid methyl ester (I) with the vinyl copper derivative (III) by means of DBU in THF gives the addition product (IV), which is treated with methyl chloroformate and LHMDS in THF yielding the malonic ester (V): The condensation of (V) with the chiral oxazolidinone (VI) by means of Cs2CO3 in acetonitrile affords the addition compound (VII), which is further condensed with the aldehyde (VIII) by means of Bu2B-OTf and TEA in dichloromethane giving the adduct (IX). The cyclization of (IX) by means of ZnCl2 and pyridine in dichloromethane yields the bicyclic compound (X), which is treated with allyl thioglycolate (XI) and LHMDS in ether producing the opening of the thiazolidinone ring. The resulting thiocarboxylic ester (XII) is submitted to cyclization by means of DBU in THF furnishing the tricyclic compound (XIII), which is selectively dehydrated and decarboxylated with Pd(OAc)2/PPh3 and pyr/Ac2O giving the tricyclic thiophenone (XIV). The oxidation of (XIV) with TBDMS-Cl, DBU and AgNO3 in hot DMSO affords the tricyclic thiophenedione (XV).

The successive treatment of (XV) with LiOH and Ba(OH)2 caused selective hydrolyses of the thiomaleic group and the less hindered methyl ester, yielding finally monocarboxylic acid (XVI). The conventional Arndt-Eister (oxalyl chloride, diazomethane and silver benzoate/tert-butanol) was used to convert acid (XVI) into the homologated ester (XVII). Careful oxidation of the sulfanyl group of (XVII) with MCPBA followed by a treatment with trifluoroacetic anhydride yields the ketone (XVIII), which is hydrolyzed and cyclized by means of 80% AcOH affording the cyclic acetal (XIX). Finally, this compound is oxidized with Jones reagent and the tert-butyl ester is deprotected with formic acid to provide the target compound.

The condensation of oxazolidinone (I) with the malonic ester derivative (II) by means of Cs2CO3 in hot acetonitrile gives the disubstituted malonic ester (III), which is condensed with the aldehyde (IV) by means of dibutyl boronic triflate as catalyst to yield the intermediate (V). The cyclization of (V) by means of SO3/pyridine and ZnCl2 in dichloromethane affords the bicyclic ketone (VI), which is treated with LiSEt in order to cleave the chiral auxiliary of (VI) and yield the thioester (VII). The reaction of (VII) with Ba(OH)2 causes selective hydrolysis of both the thioester group and one of the methyl ester groups to afford the dicarboxylic acid (VIII), which is selectively esterified with methyl chloroformate and TEA to provide the monocarboxylic acid (IX). The esterification of (IX) with allyl bromide and K2CO3 furnishes the allyl ester (X), which is treated with p-NO2-Ph-NTf2 to give the enol triflate (XI). The cleavage of the allyl ester group of (XI) by means of Pd(PPh3)4 and HCO2H yields the carboxylic acid (XII).

The reaction of (XII) with (COCl)2 in DMF affords the acyl chloride (XIII), which is submitted to homologation with diazomethane, PhCO2-Ag and t-BuOH to provide the tert-butyl acetate derivative (XIV). The oxidation of (XIV) with MCPBA and TFAA furnishes the bicyclic ketone (XV), which is submitted to a Pd(OAc)2 catalyzed carbonylation with P(2-furyl)3 and CO to give the cyclic maleic anhydride derivative (XVII) through the non isolated maleic monoester intermediate (XVI). The treatment of (XVII) with hot aqueous AcOH causes removal of the acetonide group and simultaneous cyclization to the lactone-acetal (XVIII). The oxidation of the hydroxymethyl group of (XVIII) with the Jones reagent gives the corresponding carboxylic acid (XIX), which is treated with (COCl)2 to yield the acyl chloride (XX). The reaction of (XX) with EtSH affords the thioester (XXI), which is condensed with (E)-3-pentenyl zinc iodide (XXII) to afford the hexenoyl derivative (XXIII). Finally, the tert-butyl ester group of (XXIII) is deprotected by means of formic acid to provide the target phomoidride B.