Various new routes for the large-scale synthesis of Ro-31-8959 have been described: 1) The condensation of N-protected-L-phenylalanine (I) with the Mg salt of malonic acid monoethyl ester (II) gives the keto ester (III), which is enantioselectively reduced with NaBH4 to yield the hydroxy ester (IV). The reaction of (IV) with 2,2-dimethoxypropane (V) by means of p-toluenesulfonic acid affords the oxazolidine (VI), which is hydrolyzed with NaOH in ethanol/water to the corresponding acid (VII). The treatment of (VII) with oxalyl chloride, mercaptopyridine-N-oxide (MPO) and bromotrichloromethane affords the bromomethyloxazolidine (VIII), which, without isolation, is treated with acetic acid to give the N-protected 3(S)-amino-2-bromo-4-phenyl-2(S)-butanol (IX). The reaction of (IX) with KOH in methanol yields the epoxide (X), which is condensed with (3S,4aS,8aS)-N-tert-butyldecahydroisoquinoline-3-carboxamide (XI), yielding the protected condensation product (XII). The deprotection of the amino group of (XII) by hydrogenation with H2 over Pd/C affords the amino derivative (XIII), which is condensed with N-benzyloxycarbonyl-asparagine (XIV) in the usual way, giving the protected peptide (XV). The deprotection of (XV) as before yields compound (XVI), with a free amino group that is finally condensed with quinoline-2-carboxylic acid (XVII) by means of dicyclohexylcarbodiimide and hydroxybenzotriazole.
2) The condensation of N-phthaloyl-L-phenylalaninyl chloride (XVIII) with 1,1,2-tris(trimethylsilyloxy)ethylene (TMS) (XIX) at 90-100 C followed by acidic hydrolysis with HCl gives the acid (XX), which, without isolation, is decarboxylated, yielding 1-hydroxy-3(S)-phthalimido-4-phenyl-2-butanone (XXI). Sequential protection of the OH- group with dihydropyran, reduction of the CO group with NaBH4, mesylation of the resulting OH group with methanesulfonyl chloride and deprotection of the primary OH group gives 2(R)-(methanesulfonyloxy)-4-phenyl-3(S)-phthalimido-1-butanol (XXII). The epoxidation of (XXII) with potassium tert-butoxide yields the epoxide (XXIII), which is condensed with the decahydroisoquinoline (XI) as before, affording the protected condensation product (XXIV). The elimination of the phthalimido group of (XXIV) with methylamine and HCl gives the amino derivative (XIII), already obtained in scheme 16810301a.
3) The condensation of N-(tert-butoxycarbonyl)-L-phenylalaninal (XXV) with 2-(trimethylsilyl)thiazole (XXVI) by means of tetrabutylammonium fluoride gives the thiazole derivative (XXVII), which is cleaved by reaction with methyl iodide (formation of the thiazolium derivative) and treated with NaBH4 and HgCl2 to afford the protected 3(S)-amino-2(S)-hydroxy-4-phenylbutanal (XXVIII). Finally, this compound is reductocondensed with isoquinoline (XI) by means of sodium cyanoborohydride to yield the protected condensation product (XII), already obtained in scheme 16810301a.
4) The selective esterification of 3(S)-azido-4-phenylbutane-1,2(S)-diol (XXIX) with 2,4,6-triiosopropylbenzenesulfonyl chloride (XXX) gives the sulfonate ester (XXXI), which by treatment with KOH is converted to the azido epoxide (XXXII). The condensation of (XXXII) with decahydroisoquinoline (XI) affords the azido condensation product (XXXIII), which is finally hydrogenated with H2 over Pd/C to the amino condensation product (XIII), already obtained in scheme 16810301a. 5) The reaction of (XXIX) with SOCl2 and RuCl3 gives the dioxathiole dioxide (XXXIV), which is condensed with decahydroisoquinoline (XI) to afford the azido condensation product (XXXIII), already obtained.
The intermediate (3R,4S)-4-[N-(tert-butoxycarbonyl)-N-methylamino]-5-phenyl-3-(tert-butyldimethylsilyloxy)pentanoic acid (VII) has been obtained as follows: The condensation of N-(tert-butoxycarbonyl)-L-phenylalanine (I) with the Mg salt of malonic acid monoethyl ester (II) by means of CDI gives the beta-ketoester (III), which is reduced with NaBH4 to yield (3R,4S)-4-(tert-butoxycarbonylamino)-3-hydroxy-5-phenylpentanoic acid ethyl ester (IV). The protection of the OH group of (IV) with Tbdms-Cl and imidazole in DMF affords the silylated ester (V), which is hydrolyzed with NaOH to provide the corresponding carboxylic acid (VI). Finally, this compound is N-methylated by means of Me-I and NaH in THF to obtain the target intermediate (VII).
The condensation of the chiral oxazolidinone (VIII) with octanal (IX) by means of Bu2B-OTf and TEA in dichloromethane gives the chiral adduct (X), which is treated with benzyl alcohol and BuLi to yield the benzyl ester (XI). The esterification of the OH group of (XI) with the intermediate carboxylic acid (VIII) by means of DCC and DMAP in dichloromethane affords the corresponding ester (XII), whose benzyl ester is hydrogenolyzed with H2 over Pd(OH)2 in ethanol to provide the carboxylic acid (XIII). The esterification of (XIII) with the chiral hydroxyester (XIV) by means of DCC and DMAP as before gives the expected triester (XV), which is treated first with Pd(PPh3)4 and then with TFA (elimination of the allyl, Boc and Tbdms protecting groups) to yield the open-chain precursor (XVI). Finally, this compound is submitted to macrocyclization by means of DPPA and DIEA to afford the target macrocyclic compound.
Boron enolate obtained from chiral propionyloxazolidinone (I) and dibutylboron triflate (Bu2BOTf) was condensed with n-octanal (II) to produce the syn aldol compound (III), which was protected as the silyl ether (IV) with tert-butyldimethylsilyl triflate. Then, removal of the chiral auxiliary by hydrolysis with lithium peroxide afforded the (2S,3R)-beta-(silyloxy)acid (V). After activation as the mixed anhydride (VII) with 2,4,6-trichlorobenzoyl chloride (VI), esterification with benzyl (S)-2-hydroxy-3-methylbutyrate (VIII) gave diester (IX). Subsequent removal of the silyl group using HF in acetonitrile provided intermediate (X).
Treatment of N-Boc-L-phenylalanine (XI) with carbonyl diimidazole, followed by condensation with the lithium enolate of ethyl acetate provided the beta-ketoester (XII). Then, reduction with NaBH4 in EtOH at -78 C furnished the anti aminoalcohol (XIII) as the major isomer. Subsequent reaction with formaldehyde in the presence of p-toluenesulfonic acid in boiling toluene produced the cis oxazolidine (XIV). Basic hydrolis of the ester group yielded carboxylic acid (XV) which, after activation as the mixed anhydride with 2,4,6-trichlorobenzoyl chloride (VI), was coupled to hydroxyester (X) to give triester (XVI). Reduction of the oxazolidine with NaBH3CN in the presence of trifluoroacetic acid afforded the N-methylated derivative (XVII). Then, hydrogenolysis of the benzyl ester in the presence of Pd/C produced acid (XVIII), which was finally cyclized using DPPA.
The condensation of the choral oxazolidinone (I) with octanal (II) by means of Bu2B-OTf and TEA in dichloromethane gives the chiral alcohol (III), which is protected with DHP and PPTS, yielding the tetrahydropyranyl ether (IV). The cleavage of the chiral adjuvant of (IV) by means of LiOH and H2O2 affords the carboxylic acid (V), which is esterified with (2S)-hydroxy-3-methylbutyric acid benzyl ester (VI) by means of trichlorobenzoyl chloride and TEA to provide the adduct (VII). Elimination of the tetrahydropyranyl protecting group of (VII) by means of Ts-OH gives the hydroxyester (VIII), which is condensed with the chiral amino acid (IX) by means of trichlorobenzoyl chloride as before to yield the triester compound (X). Elimination of the Mom protecting group of (X) by means of Tms-Cl and tetrabutylammonium bromide affords the hydroxy compound (XI), which is hydrogenated with H2 over Pd(OH)2 to provide the carboxylic acid (XII). Elimination of the Boc protecting group of (XII) by means of TFA gives the amino acid (XII), which is finally submitted to a macrocyclization by means of DPPA and DIEA in DMF to yield the target hapalosin.