1) The isomerization of (-)-beta-pinene (I) with potassium 3-aminopropylamide (KAPA) gives (-)-alpha-pinene (II), which is dihydroxylated with OsO4, trimethylamine oxide and NaHSO3 in tert-butanol/pyridine/water yielding (1R,2R,3S,5R)-(-)-pinanediol (III) that is used as chiral director. The trans-esterification of (III) with 4-bromobutylboronic acid dimethyl ester (IV) [obtained by treatment of 4-bromo-1-butene (V) with BCl3, methanol and triethylsilane] affords the pinane boronic ester (VI), which is treated with dichloromethane and butyllithium in THF forming the intermediate lithium salt (VII). This salt, without isolation, is treated with anhydrous ZnCl2 to give 5-bromo-1(S)-chloropentylboronic acid pinanediol ester (VIII), which is then treated with methylmagnesium bromide in THF affording 5-bromo-1(S)-methylpentylboronic acid pinanediol ester (IX). The reaction of (IX) with 3,7-dimethylxanthine (X) by means of NaH in DMSO gives the corresponding condensation product (XI), which is finally treated with KOH and H2O2 in THF/water to eliminate the boronic group yielding the desired lisofylline.
2) Other chiral directors, such as (S,S)-1,2-dicyclohexylethane-1,2-diol (XII), have also been used. Thus, the trans-esterification of boronate (IV) with diol (XII) gives the cyclic boronate (XIII), which was submitted to the previously described homologation with dichloromethane and butyllithium in THF to the intermediate (XIV). The treatment of (XIV) with anhydrous ZnCl2 as before yields the corresponding 5-bromo-1-chloroboronate (XV), which is methylated with methylmagnesium bromide as before affording the 5-bromo-1-methylboronate (XVI). The oxidative cleavage of (XVI) with Na2CO3 and H2O2 in THF affords 6-bromohexan-2(R)-ol (XVII), which is finally condensed with 3,7-dimethylxanthine (X) by means of NaH in DMSO.
5) The enantioselective microbial reduction of 3,7-dimethyl-1-(5-oxohexyl)xanthine (pentoxifylline) (XXXIV) with Rhodotorula rubra DSM 5436 in isopropanol gives 1-[5(S)-hydroxyhexyl]-3,7-dimethylxanthine (XXXV), which is then submitted to optical inversion with benzoic acid, triphenylphosphine and diethyl azodicarboxylate in THF to afford 5'-O-benzoyllisofylline (XXXVI). Finally, this compound is debenzoylated with K2CO3 in methanol.
3) The tosylation of (S)-lactic acid ethyl ester (XVIII) with tosyl chloride and triethylamine gives the corresponding tosylate (XIX), which is reduced with NaBH4, diisobutylaluminum hydride (DIBAL) or borane.THF complex yielding 2(S)-(tosyloxy)-1-propanol (XX). The epoxidation of (XX) with KOH in water or NaH in DMSO/THF affords (R)-propylene oxide (XXI), which is condensed with 1-(benzyloxy)-2-propynyl (XXII) [obtained by benzylation of propargyl alcohol (XXIII) with benzyl chloride and NaOH] by means of butyllithium in THF or lithium amide in DMSO to give 6-benzyloxy-4-hexyn-2(R)-ol (XXIV). The acetylation of (XXIV) with acetic anhydride yields the corresponding acetate (XXV), which is reduced with H2 over Raney Nickel in ethanol to afford the expected 2(R),6-hexanediol derivative (XXVI). The debenzylation of (XXVI) by hydrogenation with H2 over Pd/C in acetic acid gives 5(R)-acetoxy-1-hexanol (XXVII), which is treated with SOCl2 to yield the corresponding hexyl chloride (XXVIII). The condensation of (XXVIII) with 3,7-dimethylxanthine (X) by means of sodium methoxide in DMSO affords the 5'-O-acetyllisofylline (XXIX), which is finally deacetylated by treatment with HCl in methanol/water. 4) The 5(R)-acetoxy-1-hexanol (XXVII) can also be obtained as follows: The addition of chiral epoxide (XXI) to acetaldehyde ethyl propargyl acetal (XXX) by means of lithium amide in DMSO gives 6-(1-ethoxyethoxy)-4-hexyn-2(R)-ol (XXXI), which is acetylated with acetic anhydride as before to the acetate (XXXII). The hydrogenation of (XXXII) with H2 over Raney Nickel in ethanol yields the corresponding saturated acetate (XXXIII), which is finally deprotected with aqueous HCl to the expected 5(R)-acetoxy-1-hexanol (XXVII) already reported.