The reaction of the chiral epoxide (I) with 4-methoxybenzaldehyde (II) by means of NaAl(OMe)3H in THF gives the 1,3-dioxane (III), which is opened by reduction with DIBAL in dichloromethane to yield the chiral benzyl ether (IV). The oxidation of the primary alcohol of (IV) with DMP in dichloromethane affords the corresponding aldehyde (V), which is condensed with the boronate (VI) and S,S-diisopropyl tartrate in toluene to provide the unsaturated alcohol (VII).The protection of (VII) with Tbdps-Cl and imidazole yields the fully protected triol (VIII), which is oxidized at the terminal double bond with 9-BBN in THF to give the primary alcohol (IX). The oxidation of (IX) with DMP in dichloromethane affords the aldehyde (X), which is condensed with methylenetriphenylphosphorane (XI) in THF to provide the terminal olefin (XII). Elimination of the Pmb protecting group of (XII) with DDQ in dichloromethane gives the alcohol (XIII), which is esterified with 2-allyl-6-methoxybenzoic acid (XIV)(obtained by allylation of 2-methoxybenzoic acid (XV) with allyl bromide (XVI), BuLi and MgBr2) by means of DEAD and PPh3 yielding the ester (XVII). The cyclization of (XVII) by means of a metathesis reaction catalyzed by a ruthenium catalyst in refluxing dichloromethane affords the bicyclic lactone (XVIII), which is treated with BBr3 in dichloromethane to provide the dihydroxylated lactone (XIX).
The oxidation of the primary alcohol of (XIX) with TPAP and NMO in dichloromethane gives the corresponding aldehyde (XX), which is condensed with (Z,Z)-2,4-heptadienamide (XXI) by means of Tms-OTf in dichloroethane to yield the N,N-acylated aminal (XXII). This compound undergoes elimination when treated with NaH in hot trifluoromethylbenzene affording enamide (XXIII) as a mixture of (Z) and (E) isomers, which is treated with TBAF in THF undergoing elimination of the Tips protecting group only and providing the monosilylated compound (XXIV). Removal of the remaining silyl group requires more drastic conditions (TBAF in THF/HMPA) that cause isomerization of the enamide double bond yielding a mixture of the target compound Salicylhalamide A along with its isomer Salicylhalamide B that are separated by HPLC chromatography. The intermediate (Z,Z)-2,4-heptadienamide (XXI) has been obtained as follows: The oxidation of (Z)-2-penten-1-ol (XXV) with TPAP and NMO in dichloromethane gives the corresponding aldehyde (XXVI), which is condensed with phosphonate (XXVII) by means of KH in THF to yield methyl (Z,Z)-2,4-heptadienoate (XXVIII). The hydrolysis of (XXVIII) with Ba(OH)2 in methanol/water affords (Z,Z)-2,4-heptadienoic acid (XXIX), which is finally treated with ethyl chloroformate and ammonia to provide the target amide (XXI).
The condensation of aldehyde (I) with boronate (II) in toluene gives the chiral alcohol (III), which is treated with Tbdms-OTf and TEA to yield the silyl ether (IV). The hydroxylation of the terminal double bond of (IV) by means of 9-BBN in refluxing THF affords the primary alcohol (V), which is oxidized by means of the Swern oxidant to provide the aldehyde (VI). The homologation of (VI) with methyltriphenylphosphonium iodide (VII) and NaHMDS gives the unsaturated compound (VIII), which is deprotected at the ketonide group by means of TFA in dichloromethane to afford the diol (IX). The dehydration of (IX) by means of tosylimidazole (X) and NaH in THF provides the epoxide (XI), which is condensed with the Grignard reagent (XIII) (obtained by reaction of the tributyltin derivative (XII) with MgBr2) to give the secondary alcohol (XIV). The reaction of 2-allyl-6-methoxybenzamide (XV) with I2 in THF/water gives the lactone (XVI), which is treated with Zn and AcOH to yield 2-allyl-6-methoxybenzoic acid (XVII). The esterification of acid (XVII) with alcohol (XIV) by means of DEAD and PPH3 affords the corresponding ester (XVIII), which is submitted to a ring closing metathesis reaction by means of a Ru catalyst to provide the macrolactone (XIX). The cleavage of the Pmb protecting group of (XIX) by means of DDQ gives the primary alcohol (XX), which is oxidized to the aldehyde (XXI) by means of DMP oxidant.
The demethylation of (XXI) by means of BBr3 gives the hydroxyaldehyde (XXII), which is oxidized to the corresponding carboxylic acid (XXIII) by means of NaClO2. The protection of the phenolic OH group of (XXIII) by means of Tbdms-OTf and TEA yields the silyl ether (XXIV), which is submitted to a Curtius rearrangement by means of isobutyl chloroformate, NaN3 and 2-(trimethylsilyl)ethanol, affording the carbamate (XXV). The acylation of carbamate (XXV) with heptadienoyl chloride (XXVI) and NaHMDS provides the advanced intermediate (XXVII), which is finally deprotected by successive treatments with TBAF and with HF/pyridine to provide the target Salicylhalamide A.
The chiral tetrahydropyran intermediate (XI) has been obtained as follows. The reaction of (-)-pseudoephedrine propionamide (I) with the allyl bromide (II) by the Myers' method gives pentenamide (III), which is reduced with LiNH2BH3 in THF to yield 2(S)-methyl-4-penten-1-ol (IV). Swern oxidation of (IV) affords the corresponding aldehyde (V), which is submitted to an asymmetric aldol condensation with the silyl enol ether (VI) catalyzed by Cu(OTf)2, (S)-Tol-BINAP and (Bu4N)Ph3SiF2 in THF to provide the adduct (VII). The methanolysis of (VII) with Me-OH in refluxing toluene gives the beta-keto ester (VIII), which is treated with Et2BOMe, NaBH4 and HF to yield the chiral hydroxy lactone (IX). The reduction of (IX) with DIBAL in THF affords the lactol (X), which is finally methylated with Ts-OH in refluxing methanol to provide the target tetrahydropyran intermediate (XI).
The Stille coupling of the benzodioxanone (XII) with allyltributyltin (XIII) by means of trifurylphosphine (TFP) and Pd2(dba)3 gives the 6-allylsalicylic acid (XIV), which is esterified with the intermediate (XI) by means of DEAD and PPH3 in ethyl ether to yield the ester (XV). Hydrolysis of the lactol group of (XV) with Ac-OH affords the carbaldehyde (XVI), which is condensed with the phosphorane (XVII) to provide the unsaturated ester (XVIII). The silylation of the free OH groups of (XVIII) with Tbdms-OTf and lutidine gives the protected compound (XIX), which is submitted to a rig closing metathesis reaction catalyzed by a Ru catalyst in dichloromethane to yield the macrolactone (XX). The selective hydrolysis of the methyl ester group of (XX) by treatment with (Bu3Sn)2O in refluxing toluene affords the unsaturated carboxylic acid (XXI), which is treated with DPPA in refluxing benzene to provide the corresponding isocyanate (XXII). The reaction of the isocyanate group of (XXII) with (1Z,3Z)-hexadienyl cuprate, prepared in situ by reaction of Et-Li, CuBr/Me2S and acetylene, gives the silylated heptadienamide (XXIII), along with some pentanamide and nonatrienamide derivatives that are separated by chromatography. Finally, compound (XXIII) is desilylated by means of HF and pyridine in THF to provide the target salicylhalamide A.
The stereoselective allylation of aldehyde (I) by means of allylmagnesium bromide (II) catalyzed by (-)-Ipc2BOMe gives the alcohol (III), which is protected with Tbdms-Cl and imidazole to yield the silyl ether (IV). The oxidation of the terminal double bond of (IV) by means of OsO4, NMO and NaIO4 affords the carbaldehyde (V), which is diastereoselectively condensed with the chiral bornanesultam (VI) by means of TiCl4 and DIEA in dichloromethane to provide the adduct (VII). The protection of the OH group of (VII) with Mom-Cl, NaI and DIEA in refluxing DME gives the Mom-ether (VIII). The reductive cleavage of the chiral auxiliary by means of LiEt3BH in THF yields the carbinol (IX), which is treated with Ts-Cl, TEA and DMAP in dichloromethane to afford the tosylate (X). The reductive cleavage of the tosyl group of (X) by means of LiEt3BH in THF provides the chiral methylated compound (XI), which is desilylated by means of TBAF in THF to give the corresponding alcohol (XII). The reaction of (XII) with benzoic acid (XIII) by means of DEAD and PPh3 in refluxing ethyl ether yields the benzoate ester (XIV), which is submitted to a ring closing metathesis (RCA) reaction by means of a Ru catalyst to afford the macrolactone (XV). The selective monodeprotection of (XV) by means of DDQ in dichloromethane/water provides the ethanol derivative (XVI), which is oxidized by means of DMP in dichloromethane to give the carbaldehyde (XVII). The homologation of (XVII) by means of a Horner-Wadsworth-Emmons reaction with phosphonate (XVIII) by means of NaH in THF yields the unsaturated allyl ester (XIX), which is treated with BBr3 in dichloromethane to eliminate the methoxy and methoxymethoxy protecting group, yielding the dihydroxy compound (XX).
The reaction of the dihydroxy compound (XX) with Tbdms-Cl and imidazole gives the disilylated compound (XXI), which is deallylated by means of Pd(PPh3)4 to yield the 2-butenoic acid derivative (XXII). The reaction of (XXII) with the phosphoryl azide (XXIII) by means of TEA in benzene affords the butenoyl azide (XXIV), which is converted into the isocyanate (XXV) by heating in refluxing benzene. The reaction of (XXV) with 1,3-hexadienyl bromide (XXVI) by means of t-BuLi in THF provides the 2,4-heptadienoyl amide (XXVII), which is finally desilylated by means of HF and pyridine in THF to obtain the target Salicylihalamide A.