The stereocontrolled reaction of 3-pentanone (I) with 2-methylpropionaldehyde (II) by means of (+)-bis(diisopinocampheyl)borane triflate and DIEA in THF, followed by silylation with Tes-Cl and imidazole gives the silylated heptenone (III), which is condensed with 3-benzyloxypropionaldehyde (IV) by means of chlorodicyclohexylborane yielding the diol (V). The protection of the hydroxy groups of (V) with 2,2-dimethoxypropane and camphorsulfonic acid (CSA) with simultaneous desilylation affords the isopropylidene ketal (VI), which is acylated with propionic anhydride and triethylamine giving the propionate (VII). The Claisen rearrangement of (VII) by means of LDA and TBDMS-Cl in HMPT yields the carboxylic acid (VIII), which by regio- and stereoselective hydroboration of its double bond with BH3, followed by oxidation with N-methylmorpholine N-oxide (NMO) and tetrapropylammonium perruthenate (TPAP) in dichloromethane affords the lactone (IX). The reaction of (IX) with Me2Al-NH2, followed by debenzylation with H2 over Pd/C provides the dihydroxyamide (X), which is oxidized with Dess-Martin periodinane (DMP) in dichloromethane giving the keto aldehyde (XI). The cyclization of (XI) with HF in acetonitrile yields the spiro carbaldehyde (XII), which is silylated with Tes-OTf in dichloromethane providing the silyl ether (XIII).

The condensation of (XIII) with the chiral borane (XIV) gives the addition product (XV), which is silylated with TBDMS-OTf affording (XVI). Ozonolysis of the double bond of (XVI) with O3 yields the aldehyde (XVII), which is condensed with TMS-CH2CH=N-t-Bu to provide he unsaturated aldehyde (XVIII).

The hydrogenation of the double bond of (XVIII) with H2 and Lindlar catalyst affords the corresponding saturated aldehyde (XIX), which is condensed with the diazophosphonate (XX) giving the acetylenic derivative (XXI). The bromination of (XXI) with N-bromosuccinimide (NBS) and AgNO3 yields the bromoacetylenic compound (XXII), which is desilylated with HF and TBAF affording the dihydroxy derivative (XXIII). The resilylation of (XXIII) with CF3CO-N(Me)-Tms gives the bis(trimethylsilyl) derivative (XXIV), which is finally converted into the desired intermediate, the stannane (XXV) by reaction with tributyltin hydride, PPh3 and Pd dibenzylideneacetone complex.

The reaction of 5-iodo-4-methyl-3-(tert-butydimethylsilyloxy)-4-pentenal (XXVI) with methyl iodide and CrCl2 in dioxane/THF gives the diiodohexenal (XXVII), which is desilylated with TBAF in THF yielding the secondary alcohol (XXVIII). The esterification of (XXVIII) with protected perhydropyridazinecarboxylic acid (XXIX) by means of EDC and DIEA in dichloromethane affords the carboxylic ester (XXX), which is deprotected with TFA in dichloromethane to give the unprotected ester (XXXI). The condensation of (XXXI) with carboxylic acid (XXXII) by means of 1-hydroxy-7-azabenzotriazole (HOAt) and EDC in dichloromethane yields the protected amide (XXXIII), which is deprotected with TFA affording (XXXIV) with a free amino group. The condensation of (XXXIV) with the acid (XXXV) (obtained by oxidation of carbinol (XXXVI) with tetrapropylammonium perruthenate (TPAP)) by means of O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) and DIEA in DMF provides the amide (XXXVII), which is cyclized by means of triphenylarsine and Pd dibenzylideneacetone complex yielding the cyclic intermediate (XXXVIII).

The condensation of intermediate (XXV) with intermediate (XXXVIII) by means of triphenylarsine and Pd dibenzylideneacetone complex in DMF gives the addition compound (XXXIX), which is desilylated with TBAF in THF yielding the immediate precursor (XL). Finally, the cyclic ketal group of (XL) is opened by means of H2SO4 in THF/water.

The condensation of intermediates tributyl stannane (I) with iodovinyl compound (II) by means of Pd2(dba)3 and AsPh3 in chloroform gives precursor (III), which is then treated with aqueous H2SO4 in order to open the cyclic ketal group of (III).

The regiocontrolled condensation of 3-pentanone (IV) with methacrolein (V) catalyzed by (+)-Ipc2B-OTf and DIEA in THF gives the chiral 3-heptenone (VI), which is reductocondensed with 3-benzyloxypropanal (VII) by means of Cy2BCl, Et3N and LiBH4 in ethyl ether to afford the partially protected tetrol (VIII). The ketalization of (VIII) with 2,2-dimethoxypropane and CSA in acetone provides the desilylated cyclic ketal (IX), which is esterified with butyric anhydride and Et3N to the butyrate (X). The isomerization of (X) by means of LDA, and TBDMS-Cl in HMPA/THF, followed by a treatment in hot toluene yields the chiral undecenoic acid (XI), which is reduced by means of borane in THF to the undecanediol (XII). The lactonization of (XII) by means of NMO and tetrapropylammonium perruthenate (TPAP) in dichloromethane affords the lactone (XIII), which is treated with Me2Al-NH2 in dichloromethane to give the amide (XIV). The debenzylation of (XIV) with H2 over Pd(OH)2 in ethanol yields the dihydroxyamide (XV), which is oxidized with Dess Martin periodinane (DMP) and pyridine in dichloromethane affording the ketoaldehyde (XVI). Spirocyclization of (XVI) catalyzed by HF in acetonitrile gives the aldehydic spirolactam (XVII). Alternatively, the oxidation of the secondary alcohol of (XIV) with pyridinium dichromate (PDC) in dichloromethane yields the ketoamide (XVIII), which is submitted to spirocyclization with HF as before, and hydrogenolytic debenzylation to afford the intermediate spirolactam (XIX). The oxidation of (XIX) with O2 catalyzed by RuCl2 (PPh)3 in benzene gives the previously reported aldehydic spirolactam (XVII).

The regiocontrolled condensation of (spirolactam (XVII) with the chiral borane (+)(Z)-crotyl-diisopinocampheylborane (XX) in THF gives the diol (XXI), which is silylated with TBDMS-OTf and lutidine in dichloromethane yielding the bis(silyloxy) compound (XXII). The ozonolysis of the terminal double bond of (XXII) with O3 in dichloromethane affords the aldehyde (XXIII), which is condensed with the silyl aldimine (XXIV) by means of LDA in THF giving the unsaturated aldehyde (XXV). Hydrogenation of the double bond of (XXV) yields aldehyde (XXVI), which is condensed with the diazo phosphonate (XXVII) by means of K2CO3 in methanol providing the terminal acetylenic compound (XXVIII). The reaction of (XXVIII) with TBAF in THF gives the desilylated acetylenic compound (XXIX), which is brominated with NBS and AgNO3 in acetone yielding the omega-bromoacetylenic compound (XXX). Finally, this compound is treated with tributyltin hydride, Pd2(dba)3 and PPh3 in chloroform to afford the desired tributyl stannane intermediate (I).

The condensation of the amine group of bis(iodovinyl) compound (XXXI) with the carboxy group of tributylstannane (XXXII) by means of O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) and DIEA in DMF gives the corresponding amide (XXXIII), which is cyclized by means of Pd2(dba)3, AsPh3 and DIEA in CHCl3/DMF to afford the desired intermediate iodovinyl compound (II).

The condensation of 3-hydroxybenzaldehyde (XXXIV) with phosphonate (XXXV) by means of DBU in dichloromethane gives the propenoic ester (XXXVI), which is enanthioselectively reduced catalyzed by (+)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene(1,5-cyclooctadiene)rhodium (I) trifluoromethanesulfonate ((S,S)-DuP-Rh+OTf-) yielding the L-phenylalanine derivative (XXXVII). The deprotection of (XXXVII) by hydrogenation as usual affords the free amino acid (XXXVIII), which is condensed with Boc-L-valine (XXXIX) by means of EDC and HOAt to afford the dipeptide (XL). Hydrolysis of the ester group of (XXXIX) with LiOH in THF/water affords the N-protected amino acid (XLI), which is condensed with the perhydropyridazine (XLII) by means of EDC and HOAt to give the protected intermediate (XLIII). Finally, this compound is deprotected with TFA in dichloromethane to afford the desired intermediate the bis(iodovinyl) compound (XXXI). The intermediate perhydropyridazine (XLII) has been obtained as follows: The reaction of the iodoaldehyde (XLIV) with iodoform and CrCl2 in dioxane/THF gives the 1,6-diiodohexadiene (XLV), which, previous desilylation with TBAF, is condensed with the protected hexahydropyridazinecarboxylic acid (XLVI) by means of EDC, 4-Ppy and DIEA in dichloromethane to provide the protected diiodo ester (XLVII). Finally, this compound is deprotected with TFA in dichloromethane to yield the desired intermediate the perhydropyridazine (XLII).

The silylation of hydroxyester (XLVIII) with Tips-Cl and imidazole in THF gives the fully protected compound (XLIX), which is reduced with DIBAL in dichloromethane to the carbinol (L).The epoxidation of the double bond of (L) with MCPBA in dichloromethane yields the epoxide (LI), which is condensed with the Grignard reagent (LII) by means of CuI in ethyl ether/THF affording the diol (LIII). Esterification of the primary OH group of (LIII) with pivaloyl chloride gives the ester (LIV), which is desilylated with TBAF in THF providing the diol (LV). The cyclic ketalization of (LV) catalyzed by PdCl2 and benzoquinone yields the cyclic ketal (LVI), which is debenzylated as usual affording the primary alcohol (LVII). The oxidation of (LVII) with TPAP and NMO in dichloromethane gives the aldehyde (LVIII), which is condensed with diazophosphonate (XXVII) by means of K2CO3 in methanol yielding the ethynyl derivative (LIX), with simultaneous hydrolysis of the pivaloyl ester. The reaction of (LIX) with tributyltin hydride and PdCl2 in dichloromethane affords the vinyl stannane derivative (LX). Finally, the hydroxymethyl group of (LX) is oxidized with TPAP, NMO and NaClO2 to the corresponding carboxylic group of the desired tributylstannane intermediate (XXXII).

The regiocontrolled condensation of the silylated propargyl aldehyde (LXI) with the chiral borane (LXII) gives the secondary alcohol (LXIII), which is silylated with TBDMS-OTf and lutidine in dichloromethane to the silyl ether (LXIV). The ozonolysis of the terminal double bond of (LXIV) with O3 in dichloromethane yields the aldehyde (LXV), which is condensed with the phosphonate (LXVI) by means of NaH in THF affording the unsaturated heptanoic ester (LXVII). The reduction of the ester group of (LXVII) with DIBAL in THF gives the alcohol (LXVIII), which is epoxidized with MCPBA as usual to the epoxide (LXIX). The condensation of (LXIX) with the Grignard reagent (LXX) in THF yields the diol (LXXI), which is selectively esterified with pivaloyl chloride affording the monopivalate (LXXII). The cyclic transketalization of (LXXII) catalyzed by HF in acetonitrile/water gives the cyclic ketal (LXXII), which is finally hydrolyzed by means of K2CO3 in methanol to provide the desired intermediate, the ethynyl derivative (LIX).

Chiral oxazolidinone intermediate (VI): The oxidation of the terminal double bond of the chiral acyl oxazolidinone (I) with O2 catalyzed by CuCl and PdCl2 in DMF/water gives the ketone (II), which is ketalized with propane-1,3-dithiol (III) and Ts-OH in AcOH to yield the thioketal (IV). Finally, the stereocontrolled acylation of (IV) with propionyl chloride (V) by means of LDA in THF affords the target oxazolidinone intermediate (VI)

Chiral tripeptide intermediate (XV): The deprotection of perhydropyridazine carboxylic acid methyl ester (VII) with TFA in dichloromethane gives ester (VIII), which is condensed with N-(benzyloxycarbonyl)-3-hydroxy-L-tyrosine (IX) by means of HBTU and TEA in acetonitrile to yield the dipeptide (X). The protection of the phenolic OH group of (X) with Boc2O and TEA In dichloromethane affords (XI), which is selectively deprotected with H2 over Pd/C in ethanol to provide dipeptide (XII). The condensation of (XII) with N-(benzyloxycarbonyl)-L-valine (XIII) by means of HBTU as before gives the protected tripeptide (XIV), which is finally treated with H2 over Pd/C in ethanol to provide the target tripeptide intermediate (XV)

Chiral acetylenic ketone intermediate (XXIV): The oxidation of 6-(trimethylsilyl)-5-hexyn-1-ol (XVI) with PCC in DMF gives the carboxylic acid (XVII), which is condensed with the chiral auxiliary (XVIII) by means of Piv-Cl and TEA in THF to yield the acyloxazolidine (XIX). The diastereoselective methylation of (XIX) with Me-I and NaHMDS in THF affords the methylated compound (XX), which by reductive elimination of the chiral auxiliary with LiBH4 in ethyl ether provides the chiral alcohol (XXI). The oxidation of (XXI) with (COCl)2 and DMSO in dichloromethane leads to the aldehyde (XXII), which by a Grignard reaction with Me-MgBr in ethyl ether is converted into the secondary alcohol (XXIII). Finally, this compound is oxidized with (COCl)2 as before to yield the chiral acetylenic ketone intermediate (XXIV)

Chiral tetracyclic macrolactone (XXXVI): The condensation of the chiral aldehyde (XXV) with phosphonate (XXVI) in the usual way gives the nonatrienoic ester (XXVII), which is reduced with DIBAL to the corresponding alcohol and oxidized with MnO2 to the carbaldehyde (XXVIII). The condensation of (XXVIII) with the chiral oxazolidinone intermediate (VI) through its boron enolate yields the expected adduct (XXIX), which is reduced with Me4NBH(OAc)3 to afford the dihydroxy compound (XXX). The dethioacetalization of (XXX) by means of PhI(OCOCF3)2 in dichloromethane provides the cyclic ketal (XXXI). The regiocontrolled reduction of (XXXI) by means of NaBH4 in THF/water cleaves the chiral auxiliary to yield the carbinol (XXXII), which is successively oxidized with DMP and NaClO2 to afford the carboxylic acid (XXXIII) (1). The condensation of (XXXIII) with the chiral tripeptide intermediate (XV) by means of TBAF, HATU and DIEA in acetonitrile provides the corresponding amide (XXXIV), which is submitted to macrocyclization by means of LiOH, EDC and DIEA in dichloromethane to give the polycyclic macrolactone (XXXV). Finally, the Boc protecting group of (XXXV) is removed by means of Tms-OTf and lutidine in dichloromethane to afford the target chiral tetracyclic macrolactone (XXXVI)

Synthesis of the target Sanglifehrin A: The condensation of the chiral ketone (XXXVII) with aldehyde (XXXVIII) by means of Sn(OTf)2 and TEA in dichloromethane gives the beta-hydroxyketone (XXXIX), which is reduced with Me4NBH3CN to yield the diol (XL). The ketalization of (XL) by means of DDQ, followed by ration with Tes-Cl and imidazole affords the silylated ketal (XLI), which is cleaved with iBu2AlH and oxidized with (COCl)2 to provide the protected carbaldehyde (XLII). The stereocontrolled condensation of aldehyde (XLII) with the chiral acetylenic ketone intermediate (XXIV) by means of (+)-DIPCl and TEA in ethyl ether leads to the acetylenic ketone (XLIII). This is reduced with Me4NBH3CN and ketalized by means of 2,2-dimethoxypropane and PPTS (simultaneous desilylation takes place) to give the dihydroxy ozonide (XLIV). The protection of the primary OH group of (XLIV) by means of Piv-Cl, pyridine and DMAP yields the pivalate (XLV), which is silylated with Tes-Cl and imidazole and deprotected with iBu2AlH to afford the acetylenic alcohol (XLVI). The sequential oxidation of (XLVI) with DMP and with NaClO2, followed by methylation with diazomethane affords the methyl ester (XLVII), which is treated with Me2AlNH2 in dichloromethane to provide the corresponding amide (XLVIII). The desilylation of (XLVIII) by means of TBAF, followed by oxidation with DMP gives the delta-ketoester (XLIX), which is submitted to and acid ring closure with CSA to yield the spirolactam (L)

The elimination of the Pmb protecting group of (L) by means of DDQ in dichloromethane affords compound (LI), which is brominated with NBS and AgNO3 in acetone to provide the bromoacetylene derivative (LII). The reaction of (LII) with tributyltin hydride, Pd2(dba)3 and PPh3 leads to the vinylstannane (LIII), which is condensed with the chiral tetracyclic macrolactone intermediate (XXXVI) by means of PdCl2(CH3CN)2 in DMF to give the cyclic precursor (LIV). Finally, this compound is submitted to an acidic hydrolysis by means of TsOH and BO3H3 in THF to provide the target Sanglifehrin A