合成路线:Synthesis of the intermediate chiral tetrahydropyran-carboxylic acid methyl ester (VII): The selective reduction of the exocyclic double bond of the glycoside (I) with H2 over Pd/C in ethanol gives a mixture of the equatorial epimer (II) along with some axial compound that is eliminated by crystallization.The cleavage of the benzylidene protecting group of (II) with H2,over Pd/C in EtOH,followed by selective monoesterification of the primary OH group with PPh3,DIAD and benzoic acid yields the benzoate ester (III).The protection of (III) with Tbdms-Cl and imidazole affords the silyl ether (IV),which is debenzoylated by means of DIBAL in dichloromethane to afford the hydroxymethyl compound (V).The oxidation of (V) by means of RuCl3 and NaIO4 pin acetonitrile/CCl4 provides the chiral carboxylic acid (VI),which is finally esterified with CH3-I and K2CO3 in DMF to furnish the desired tetrahydropyran-carboxylic acid methyl ester (VII).
合成路线:The reaction of the chiral propyl iodide (VIII) with KCN in hot DMF gives the chiral butyronitrile (IX),which is reduced with DIBAL in dichloromethane to yield the butyraldehyde (X).The reaction of (X) with CBr4,PPH3 and BuLi in THF/dichloromethane affords the chiral alkyne (XI),which is treated with Me3Al,Cp2ZrCl2 and BuLi in dichloroethane to provide the vinyl aluminate (XII).The condensation of (XII) with the chiral epoxide (XIII) in benzene gives the unsaturated 2-octenol (XIV),which is protected with BnBr and NaH to yield the benzyl ether (XV).The desilylation of (XV) by means of TBAF in THF afford the primary alcohol (XVI),which is treated with diphenyl disulfide and Bu3P in DMF to provide the thioether (XVII).The oxidation of (XVII) with oxone in THF/methanol/water gives the corresponding sulfone (XVIII),which is condensed with the intermediate desired tetrahydropyran-carboxylic acid methyl ester (VII) by means of BuLi in THF to yield the adduct (XIX).The removal of the sulfone group of (XIX) is performed by means of Bu3SnH and AIBN in refluxing toluene affording the ketonic intermediate (XX).
合成路线:The desilylation of (XX) by means of HF in pyridine gives the hydroxyketone (XXI),which is reduced with Me4NBH(OAc)3 and HOAc in acetonitrile to yield the chiral dihydroxy compound (XXII).The methylation of both OH groups of (XXII) by means of methyl iodide and NaH in DMF affords the fully methylated intermediate (XXIII),which is finally debenzylated in the usual way to provide the target chiral trihydroxyalkyl-tetrahydropyran intermediate (XXIV).
参考文献标题:An enantioselective synthesis of the C(10) to C(23) backbone of the potent immunosuppressant FK506
文献作者:Smith,A.B.III; Hale,K.J.
参考来源:Tetrahedron Lett 1989,30(9),1037
合成路线:The total synthesis of FK-506 is described:This synthesis was performed by previously constructing three building fragments (XX),(XXXII) and (XLVI),which later were coupled sequentially.First the synthesis of these fragments will be presented,and afterwards their sequential coupling will be described.1) (2RS,4R,6S,7R,8S,10R)-2-(Bis(dimethylamino)phosphono)-7-(tert-butyldimethylsilyloxy)-6,8-dimethoxy-10-(1,3-dithian-2-yl)-4-methylundecane (XX).The reaction of L-arabitol (I) with 2-acetoxyisobutyryl chloride in acetonitrile gives the diacetoxycompound (II),which by treatment with sodium methoxide in THF yields (2S,4S)-1,2:4,5-diepoxy-3-pentanol (III).The protection of (III) with TBS-Cl in THF affords the protected compound (IV),which is condensed with ethoxyacetylene (V) by means of butyllithium and boron trifluoride ethearate in THF giving the diacetylenic alcohol (VI).Cyclization of (VI) by means of HgCl2 and p-toluenesulfonic acid in refluxing ethanol yields the dilactone (VII),which is methylated by means of methyl iodide and lithium diisopropylamide in THF affording the methylated dilactone (VIII).The deprotection of (VIII) with HF in acetonitrile gives the hydroxydilactone (IX),which is benzylated with benzyl trichloroacetimidate and trifluoromethanesulfonic acid in dichloromethane-cyclohexane yielding the benzyl protected dilactone (X).The methanolysis of (X),followed by methylation with NaH and methyl iodide in DMF affords the nonanedioic ester (XI),which is debenzylated by hydrogenolysis with H2 over Pd/C in ethyl acetate giving the hydroxy diester (XII).The lactonization of (XII) with pyridinium p-toluenesulfonate in dichloromethane yields the lactone-methyl ester (XIII),which is selectively reduced with L-Selectride in THF affording the lactol-methyl ester (XIV).The reaction of (XIV) with propane-1,3-dithiol and boron trifluoride ethearate in dichloromethane gives the 1,3-dithiane derivative (XV),which by reduction of its lactone group with LiAlH4 in THF yields (2R,4S,5R,6S,8R)-8-(1,3-dithian-2-yl)-4,6-dimethoxy-2-methylnonane-1,5-diol (XVI).The reaction of (XVI) with I2,pyridine and triphenylphosphine in benzene affords the 1-iodo derivative (XVII),which is protected with TBS trifluoromethanesulfonate and triethylamine in dichloromethane giving the protected iodide (XVIII).Finally,this compound is condensed with ethylphosphonic acid bis(dimethylamide) (XIX) by means of butyllithium in THF to afford the first building fragment (XX).
合成路线:2) (2R,3S,5S(2'S,4'R))-5-(2-(iodomethyl)tetrahydrofuran-4-yl)-5-(4-methoxy benzyloxy)-2-methyl-3-(triisopropylsilyloxy)pentanal (XXXII).The regioselective reduction of methyl 5-(4-methoxybenzyloxy)-3-oxopentanoate (XXI) with H2 over Ru2Cl4((S)-BINAP)2(C2H5)3N in methanol gives the 3(S)-hydroxy derivative (XXII),which is condensed with ally bromide (XXIII) by means of lithium diisopropylamide THF-HMPA to yield the ally derivative (XXIV).The reduction of (XXIV) with LiAlH4 in THF affords the diol (XXV),which is cyclized to the ketal (XXVI) by means of DDQ in dichloromethane.The reaction of (XXVI) first with N-iodosuccinimide (NIS) and then with diisobutylaluminum hydride affords (3S(2'S,4'R))-3-(2-iodomethyl)tetrahydrofuran-4-yl)-3-(4-methoxybenzyl)-1-propanol (XXVII),which is oxidized to the corresponding aldehyde (XXVIII) by means of oxalyl chloride in dichloromethane.The condensation of (XXVIII) with 2(E)-butenyltriphenylstannane (XXIX) by means of boron trifluoride ethearate in dichloromethane gives the alcohol (XXX),which is protected with TIPS trifluoromethanesulfonate in dichloromethane yielding the fully protected diol (XXXI).Finally,the double bond of (XXXI) is oxidized with ozone in methanol - dichloromethane yielding the second building fragment (XXXII).
合成路线:3) (1R,2R,4R)-4-(2(E)-Bromo-1-propenyl)-2-methoxy-1-(triisopropylsilyloxy)cyclohexane (XLVII).- The catalytic asymetric epoxidation of divinylcarbinol (XXXIII) with titanium isopropoxide and L-(+)-diisopropyl tartrate in dichloromethane gives (2R,3S)-1,2-epoxy-4-penten-3-ol (XXXIV),which is protected with PMB-Br and tetrabutylammonium bromide in dichloromethane yielding the benzyl derivative (XXXV).The condensation of (XXXV) with ethoxyacetylene (V) by means of boron trifluoride ethearate in THF affords the acetylenic ether (XXXVI),which is treated with ethanol and HgCl2 giving ethyl (4R,5S)-5-hydroxy-4-methoxyhept-6-enoate (XXXVII).The lactonization of (XXXVII) by means of p-toluenesulfonic acid in benzene yields the lactone (XXXVIII),which is submitted to a Claisen rearrangement by means of TBS trifluoromethanesulfonate and the resulting acid was methylated with diazomethane to afford methyl (1R,3R)-3-methoxy-4-cyclohexene-1-carboxylate (XXXIX).Hydroboration of (XXXIX) with BH3 and NaOH gives methyl (1R,3R,4R)-4-hydroxy-3-methoxycyclohexane-1-carboxylate (XL),which is protected with TIPS trifluoromethanesulfonate in dichloromethane yielding ester (XLI).The reduction of (XLI) with LiAlH4 in THF affords the hydroxymethyl derivative (XLII),which is oxidized to the corresponding aldehyde (XLIII) by means of oxalyl chloride in dichloromethane - DMSO.The reaction of (XLIII) with dimethyl diazomethylphosphonate and potassium tert-butoxide in THF gives (1R,2R,4R)-4-ethynyl-2-methoxy-1-(triisopropylsilyloxy)cyclohexane (XLIV),which is methylated with methyl iodide and butyllithium in THF to yield the corresponding propynyl derivative (XLV).Finally,this compound is treated with NBS in benzene affording the third building fragment (XLVI) (Scheme 2).4) The first coupling reaction was the addition of vinyl bromide (XLVI) to aldehyde (XXXII).This was performed by reaction of (XLVI) with butyllithium and the resulting vinyllithium derivative was treated with aldehyde (XXXII) and catalytic amounts of MgBr giving the carbinol (XLVII),which was esterified with N-(tert-butoxycarbonyl)piperidine-2(S)-carboxylic acid (XLVIII) by means of DDC and 4-pyrrolidinopyridine,yielding the corresponding ester (XLIX).Treatment of (XLIX) with Zn dust and NH4Cl affords the 2-allyl substituted alcohol (L),which is oxidized with oxalyl chloride and DMSO in dichloromethane giving a fourth building block,the allyl substituted aldehyde (LI).
合成路线:5) A second coupling reaction was the addition of the phosphonamide (XX) to the aldehyde (LI) by means of butyllithium in THF to give the dithianylolefin (LII),which was treated first with TFIB and methanol and then with acetic acid,yielding the free aldeyde (LIII).The condensation of (LIII) with methyl 2-(2,4-dimethoxybenzyloxy)acetate (LIV) by means of lithium diisopropylamide in THF,followed by a treatment with LiOH affords the hydroxy acid (LV),which is protected with TES trifluoromethylsulfonate and treated with 2,6-dimethylpyridine to give the free amino acid (LVI),the open-chain precursor of FK-506.
合成路线:The cyclization of (LVI) by means of N-methyl-2-chloropyridinium iodide and triethylamine yields the macrocyclic lactam (LVII),which is selectively deprotected with trifluoroacetic acid in THF - water and oxidized with DMP in dichloromethane affording the beta-keto lactam (LVIII).Selective deprotection of (LVIII) with DDQ in dichloromethane - tert-butyl alcohol gives the diol (LIX),which is then oxidized with DMP in dichloromethane yielding the silylated FK-506 (LX).Finally,this compound is deprotected by treatment with HF in acetonitrile.
参考文献标题:Total synthesis of FK506 and an FKBP probe reagent,(C8,C9-13C2)-FK5
文献作者:Smith,D.B.; Schreiber,S.L.; Ragan,J.A.; Uehling,D.E.; Nakatsuka,M.; Sammakia,T.
参考来源:J Am Chem Soc 1990,112(14),5583
合成路线:The synthesis of the C22-C34 subunit (C12-C16 of the chemical name) of FK-506 has been reported:The condensation of the chiral aldehyde (I) with the (S)-allenyl stannane (II) by means of boron trifluoride ethearate in dichloromethane yields an epimeric mixture of the acetylenic alcohol (III),which by protection with p-methoxybenzyl (PMB) trichloroacetimidate,followed by chromatographic separation,gives the enantiomerically pure protected acetylenic diol (IV).The reduction of (IV) with bis(2-methoxyethoxy)aluminum hydride in THF affords the (E,E)-dienic alcohol (V),which is submitted to a Sharpless asymmetric epoxidation with (-)-diethyl tartrate [(-)-DETR],titanium tetraisopropoxide and tert-butyl hydroperoxide (TBHP) in dichloromethane,yielding the chiral epoxy alcohol (VI).The reduction of (VI) with bis(2-methoxyethoxy)aluminum hydride in THF affords the partially protected triol (VII),which is finally dehydrogenated with dichlorodicyanobenzoquinone (DDQ) in dichloromethane to give the chiral 1,3-dioxane (VIII),which is the desired intermediate.
合成路线:The starting compounds (I) and (II) are obtained as follows:Aldehyde (I): The esterification of (R,R)-dihydrobenzoin (IX) with acryloyl chloride (X) by means of triethylamine in dichloromethane gives the corresponding diester (XI),which by bis-cyclization with butadiene (XII) by means of TiCl4 in dichloromethane yields the bis(3-cyclohexenecarboxylic acid) ester (XIII).The hydrolysis of (XIII) with LiOH in methanol affords (R)-3-cyclohexenecarboxylic acid (XIV),which by reaction with I2,KI and NaHCO3 is converted to the iodolactone (XV).The reaction of (XV) with 1,5-diazabicyclo[5.4.0]-5-undecene (DBU) in refluxing THF affords the unsaturated lactone (XVI),which by treatment with NaHCO3 in anhydrous methanol yields (1R,3R)-3-hydroxy-4-cyclohexenecarboxylic acid methyl ester (XVII).The methylation of (XVII) with methyl trifluoromethanesulfonate and 2,6-di-tert-butyl-4-methylpyridine (DBMP) in dichloromethane gives the 3-methoxy ester (XVIII),which is selectively hydroxylated with BH3,H2O2 and NaOH to (1R,3R,4R)-4-hydroxy-3-methoxycyclohexanecarboxylic acid methyl ester (XIX).The protection of (XIX) with triisopropylsilyl (TIPS) trifluoromethanesulfonate (XX) and triethylamine in dichloromethane affords the protected ester (XXI),which is reduced with dibutylaluminum hydride (DIBAL) in hexane to the corresponding aldehyde (XXII).Finally,this compound is condensed with the N-tert-butylimine of 2-(triethylsilyl)propanol (XXIII) by means of butyllithium in THF to afford the desired aldehyde (I).
合成路线:The starting compounds (I) and (II) are obtained as follows:Aldehyde (I): The esterification of (R,R)-dihydrobenzoin (IX) with acryloyl chloride (X) by means of triethylamine in dichloromethane gives the corresponding diester (XI),which by bis-cyclization with butadiene (XII) by means of TiCl4 in dichloromethane yields the bis(3-cyclohexenecarboxylic acid) ester (XIII).The hydrolysis of (XIII) with LiOH in methanol affords (R)-3-cyclohexenecarboxylic acid (XIV),which by reaction with I2,KI and NaHCO3 is converted to the iodolactone (XV).The reaction of (XV) with 1,5-diazabicyclo[5.4.0]-5-undecene (DBU) in refluxing THF affords the unsaturated lactone (XVI),which by treatment with NaHCO3 in anhydrous methanol yields (1R,3R)-3-hydroxy-4-cyclohexenecarboxylic acid methyl ester (XVII).The methylation of (XVII) with methyl trifluoromethanesulfonate and 2,6-di-tert-butyl-4-methylpyridine (DBMP) in dichloromethane gives the 3-methoxy ester (XVIII),which is selectively hydroxylated with BH3,H2O2 and NaOH to (1R,3R,4R)-4-hydroxy-3-methoxycyclohexanecarboxylic acid methyl ester (XIX).The protection of (XIX) with triisopropylsilyl (TIPS) trifluoromethanesulfonate (XX) and triethylamine in dichloromethane affords the protected ester (XXI),which is reduced with dibutylaluminum hydride (DIBAL) in hexane to the corresponding aldehyde (XXII).Finally,this compound is condensed with the N-tert-butylimine of 2-(triethylsilyl)propanol (XXIII) by means of butyllithium in THF to afford the desired aldehyde (I) (Scheme 2).Allenyl stannane (II): The silylation of (R)-methyl lactate (XXIV) with tert-butyldimethylsilyl chloride (TBS-Cl) and imidazole in DMF gives the silyl ether (XXV),which is reduced with DIBAL to the corresponding aldehyde (XXVI).The reaction of (XXVI) with tetrabromomethane and triphenylphosphine in dichloromethane affords 3(R)-(tert-butyldimethysilyloxy)-1,1-dibromo-1-butene (XXVII),which by reaction with butyllithium and formaldehyde is converted to the corresponding 2-pentyn-1-ol (XXVIII).The esterification of (XXVIII) with pivaloyl (PIV) chloride and NaHCO3 in dichloromethane yields the pivaloyl ester (XXIX),which is desilylated with tetrabutylammonium fluoride (TBAF) in THF,giving the hydroxy ester (XXX).The mesylation of (XXX) with methanesulfonyl chloride and triethylamine in dichloromethane affords the sulfonate (XXXI),which is finally treated with the lithium derivative of tributylstannyl hydride,CuBr and dimethylsulfide in THF to afford the desired allenyl stannane (II).
参考文献标题:Synthesis of a C22-34 subunit of the immunosuppressant FK-506
文献作者:Marshall,J.A.; Xie,S.P.
参考来源:J Org Chem 1995,60(22),7230
合成路线:The synthesis of the C16-C34 fragment of tacrolimus (FK-506),the key intermediate on the total synthesis of tacrolimus has been described:1) The reaction of (Z)-2-butene (I) with (?-beta-methoxydiisopinocamphenylborane (IPCB-OCH3; II) by means of potassium tert-butoxide and butyllithium in THF gives the butenyl borane (III),which is condensed with 2-benzyl-acetaldehyde (IV) by means of BF3 ethearate in ether to yield the monobenzylated diol (V).The silylation of (V) with tert-butyldimethylsilyl chloride (TBDMS-Cl) and imidazole affords the fully protected olefine (VI),which is oxidized with OsO4 and N-methylmorpholine N-oxide (NMO) in acetone/water/benzene to give a diastereomeric mixture of the diols (VII) and (VIII) separated by column chromatography.The epoxidation of (VII) with NaH and tosyl imidazole in THF afforded epoxide (IX),which was condensed with the protected furfuryl alcohol (X) by means of butyllithium and BF3 ethearate in THF giving the diol (XI).The oxidation of (XI) with m-chloroperbenzoic acid (MCPBA) with simultaneous trapping of the intermediate with 2-methoxypropene (XII) afforded the spiroenone (XIII),which was condensed with alkyne (XIV) by means of trimethylaluminum and a zircornium complex yielding the expected spiroketone (XV).2) The alkyne intermediate (XIV) has been obtained by condensation of the chiral tosylate (XXVII) with lithium acetylide giving the chiral pentynol ether (XVIII).(XVIII) then was deprotected with p-toluenesulfonic acid and silylated with TBDMS-Cl.3) The undesired diol (VIII) can also be converted into the epoxide (IX) by reaction with benzoyl chloride and dimethylaminopyridine (DMAP) to give the expected benzoate,which was subsequently treated with methanesulfonyl chloride and DMAP,and finally epoxidized with sodium methoxide in methanol.4) The diol (VII) can be selectively obtained by reaction of methyl 5-O-benzyl-beta-D-ribofuranoside (XXIV) with methylmagnesium chloride and copper bromide giving methyl 5-O-benzyl-3-deoxy-3-C-methyl-beta-D-xylofuranoside (XXV).(XXV) was treated with ethanethiol and TBDMS-Cl in the presence of imidazole and a catalytic amount of DMAP affording the dithioacetal (XXVI).Finally,this compound is treated with HgCl2 and CaCO3,and reduced with NaBH4 in THF/methanol to afford the desired diol (VII).5) The intermediate vinyl bromide (XXIII) has been obtained according to a previously reported method (Ragan,J.A.et al.J Org Chem 1989,54(18): 4267) .
合成路线:Subsequent reduction of the ketonic group of (XV) with L-selectride in THF afforded the enantiomerically pure alcohol (XVI),which was treated with p-methoxybenzyl trichloroacetimide (XVII) and a catalytic amount of triphenylmethyl tetrafluoroborate to give the expected p-methoxybenzyl ether (XVIII).The desilylation of (XVIII) with tetrabutylammonium fluoride (TBAF) in THF gives the diol (XIX),which was selectively resilylated at the primary OH group yielding the se-condary alcohol (XX).The selective debenzylation of (XX) with H2 over W-2 RaNi in ethanol afforded the vicinal diol (XXI),which was submitted to cleavage with sodium per-iodate in THF to obtain the aldehyde (XXII).Finally,this compound is condensed with the vinyl bromide (XXIII) by means of butyllithium and magnesium bromide in THF to afford the desired C16-C34 fragment of FK-506,the key intermediate in the total synthesis described in Tetrahedron 1997,53(39): 13257.
合成路线:The completion of the total synthesis of FK-506,starting with the key intermediate C16-C34 fragment obtained as described in Tetrahedron 1997,53(39): 13221,has been presented:1) The silyl ether (I) was partially deprotected with tetrabutylammonium fluoride (TBAF) in THF giving the diol (II),which is selectively tosylated with tosyl chloride at the primary OH group yielding the monotosylate (III).The protection of the secondary alcohol of (III) with triethylsilyl chloride (TES-Cl) affords the protected tosylate (IV),which by treatment with lithium iodide and sodium benzenesulfinate is converted into the sulfone (V).The condensation of (V) with aldehyde (VI) by means of butyllithium followed by Dess-Martin oxidation gives a nonisolated ketosulfone intermediate,which was treated with tri-butyltin hydride and azobis(isobutyronitrile) (AIBN) yielding ketone (VII).
合成路线:The diastereoselective reduction of (VII) with NaBH4/CeCl3 in methanol/ethyl ether affords alcohol (VIII),which was methylated with trimethyloxonium tetrafluoroborate in dichloromethane giving the methyl ether (IX).The treatment of (IX) with lithium bis(trimethylsilyl)amide (Li-HMDS) and Mg(HMDS)2 causes enolization and ring opening affording alcohol (X),which was protected with tert-butyldimethylsilyl triflate yielding the fully silylated compound (XI).The hydrolysis of the ester group of (XI) with NaOH,followed by a selective elimination of the triethylsilyl group with trifluoroacetic acid and esterification of the resulting alcohol with piperidine-2(S)-carboxylic acid (XII) by means of dicyclohexylcarbodiimide (DCC) and dimethylaminopyridine (DMAP) afforded ester (XIII).
合成路线:Ester (XIII) was submitted to cyclization by means of triethylsilyl triflate and 2-chloro-1-methylpyridinium iodide (MCPI) in dichloromethane/methanol gaving the macrocyclic compound (XIV).Elimination of the p-methoxybenzyl group of (XIV) with dichlorodicyanobenzoquinone (DDQ) in dichloromethane yielded the alcohol (XV),which was converted into the iodo derivative (XVI) with I2,triphenylphosphine and imidazole in hot toluene.The reductive fragmentation of the spiroketal rings of (XVI) with zinc/silver-graphite in THF afforded compound (XVII) with the adequate configuration in the C21-C24 fragment.
合成路线:The 1,3-dioxole ring of (XVII) was cleaved by selective oxidation with dimethyldioxirane (DMD) in acetone giving the tricarbonyl compound (XVIII) (silylated FK-506),which was finally desilylated by means of HF in acetonitrile/ water.2) Aldehyde (VI) was prepared according to a previously reported method (Ireland,R.E.et al.J Org Chem 1992,57: 5071).
参考文献标题:Total synthesis of FK-506.1.Construction of the C16-C34 fragment
文献作者:Liu,L.B.; Roper,T.D.; Ireland,R.E.
参考来源:Tetrahedron 1997,53(39),13221
合成路线:The synthesis of the C16-C34 fragment of tacrolimus (FK-506),the key intermediate on the total synthesis of tacrolimus has been described:1) The reaction of (Z)-2-butene (I) with (?-beta-methoxydiisopinocamphenylborane (IPCB-OCH3; II) by means of potassium tert-butoxide and butyllithium in THF gives the butenyl borane (III),which is condensed with 2-benzyl-acetaldehyde (IV) by means of BF3 ethearate in ether to yield the monobenzylated diol (V).The silylation of (V) with tert-butyldimethylsilyl chloride (TBDMS-Cl) and imidazole affords the fully protected olefine (VI),which is oxidized with OsO4 and N-methylmorpholine N-oxide (NMO) in acetone/water/benzene to give a diastereomeric mixture of the diols (VII) and (VIII) separated by column chromatography.The epoxidation of (VII) with NaH and tosyl imidazole in THF afforded epoxide (IX),which was condensed with the protected furfuryl alcohol (X) by means of butyllithium and BF3 ethearate in THF giving the diol (XI).The oxidation of (XI) with m-chloroperbenzoic acid (MCPBA) with simultaneous trapping of the intermediate with 2-methoxypropene (XII) afforded the spiroenone (XIII),which was condensed with alkyne (XIV) by means of trimethylaluminum and a zircornium complex yielding the expected spiroketone (XV).2) The alkyne intermediate (XIV) has been obtained by condensation of the chiral tosylate (XXVII) with lithium acetylide giving the chiral pentynol ether (XVIII).(XVIII) then was deprotected with p-toluenesulfonic acid and silylated with TBDMS-Cl.3) The undesired diol (VIII) can also be converted into the epoxide (IX) by reaction with benzoyl chloride and dimethylaminopyridine (DMAP) to give the expected benzoate,which was subsequently treated with methanesulfonyl chloride and DMAP,and finally epoxidized with sodium methoxide in methanol.4) The diol (VII) can be selectively obtained by reaction of methyl 5-O-benzyl-beta-D-ribofuranoside (XXIV) with methylmagnesium chloride and copper bromide giving methyl 5-O-benzyl-3-deoxy-3-C-methyl-beta-D-xylofuranoside (XXV).(XXV) was treated with ethanethiol and TBDMS-Cl in the presence of imidazole and a catalytic amount of DMAP affording the dithioacetal (XXVI).Finally,this compound is treated with HgCl2 and CaCO3,and reduced with NaBH4 in THF/methanol to afford the desired diol (VII).5) The intermediate vinyl bromide (XXIII) has been obtained according to a previously reported method (Ragan,J.A.et al.J Org Chem 1989,54(18): 4267) .
参考文献标题:Total synthesis of FK-506.2.Completion of the synthesis
文献作者:Liu,L.B.; Roper,T.D.; Gleason,J.L.; Ireland,R.E.
参考来源:Tetrahedron 1997,53(39),13257
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