1) The cyclization of phloroglucinol (I) with butyrylacetic acid ethyl ester (II) by means of concentrated sulfuric acid gives 5,7-dihydroxy-4-propyl-2H-1-benzopyran-2-one (III), which is condensed with propionyl chloride by means of AlCl3 in nitrobenzene, yielding the 8-propionyl derivative (V). The cyclization of (V) with 3-hydroxy-3-methylbuytyraldehyde dimethylacetal (VI) in refluxing pyridine affords the benzodipyran (VII), which is cyclized again with paraldehyde or acetaldehyde dimethylacetal by means of p-toluenesulfonic acid and trifluoroacetic acid in pyridine at 140 C to give a mixture of the diastereomeric racemates (VIII) and (IX), which are separated by column chromatography. The reduction of racemate (VIII) with NaBH4 /CeCl3 in ethanol yields a new mixture of the racemic hydroxy epimers (X) (racemic calanolide A) and (XI), which are separated by semipreparative HPLC. Racemic calanolide A (X) is finally submitted to optical resolution by semipreparative chiral HPLC.
Calanolide A (I), a compound isolated from the tropical tree Calophyllym lanigerum, was selectively hydrogenated at the 7,8-double bond employing PtO2 poisoned with NH4OH to afford the title compound.
2) The condensation of 5,7-dihydroxy-4-propyl-2H-1-benzopyran-2-one (III) with N-methylformanilide (XII) by means of POCl3 in hot dichloromethane gives the carbaldehyde (XIII), which is cyclized with 3-chloro-3-methyl-1-butyne (XIV) by means of ZnCl2 /K2CO3 in hot 2-butanone/DMF, yielding the benzodipyran-carbaldehyde (XV). The enantioselective reaction of (XV) with 2(E)-butene and the chiral borane (+)-(E)-crotyldiisopinocamphenylborane (XVI) affords the single (R, R)-enatiomer (XVII). The selective silylation of (XVII) with TBDMS-Cl as usual gives the monosilyl ether (XVIII), which is cyclized by means of mercuric acetate and NaBH4 in THF, yielding the silylated (10R,11R,12R)-benzotripyran (XIX). The desilylation of (XIX) with tetrabutylammonium fluoride in THF gives the (10R,11S,12R)-benzotripyran (XX) (calanolide B), which is converted into calanolide A by inversion of the C-12 OH-group carried out with a modified Mitsunobu reaction with dimethyl azodicarboxylate (DEAD)/trimethylphosphine/chloroacetic acid in toluene/THF, followed by treatment with NH4OH in methanol.
The cyclization of phloroglucinol (I) with 3-oxohexanoic acid methyl ester (II) by means of conc. sulfuric acid gives the benzopyranone (III), which is acylated with 2-methyl-2-butenoyl chloride (IV) and AlCl3 in dichloroethane to yield the 5-hydroxy-7-(2-methyl-2-butenoyloxy)-4-propylbenzopyran-2-one (V). This compound, without isolation, rearranges under the reaction conditions to afford 5,7-dihydroxy-8-(2-methyl-2-butenoyloxy)-4-propylbenzopyran-2-one (VI). The cyclization of (VI) with 3-methyl-2-butenal (VII) in refluxing pyridine provides the benzo-tripyran-2,12-dione derivative (VIII) -alternatively, conversion of (VI) into (VIII) can be performed by first cyclization of (VI) by means of TEA to furnish compound (IX), which is then subjected to cyclization with 3-methyl-2-butenal (VII)-. Finally, reduction of (VIII) with LiAlH(OBu)3 in THF provides the target calanolide A.
5) Synthesis of [14C]-labeled calanolide A: The aldol condensation of benzodipyran (VII) with [1,2-14C]-labeled acetaldehyde catalyzed by TiCl4/lithium diisopropylamide (LDA) in heptane/THF/ethylbenzene gives a racemic mixture of enantiomers (XXXV) and (XXXVI), which is enzymatically resolved with lipase-AK and vinyl acetate in tert-butyl methyl ether to yield a mixture of unchanged 3(S)-hydroxy-2(R)-methylbutyryl enantiomer (XXXVI) and acetylated enantiomer (XXXVII), which are easily separated by column chromatography. The cyclization of (XXXVI) by means of triphenylphosphine and diethyl azodicarboxylate (DEAD) in THF gives the (10R,11R)-precursor (XXXVIII), which is finally reduced with NaBH4/triphenylphosphine oxide /CeCl3 in ethanol and purified by chiral HPLC.
3) Synthesis of ent-Calanolide A, (-)-calanolide A: The Clemensen reduction of 5,7-dihydroxy-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-4-one (XXI) with Zn/HCl in methanol gives 5,7-dihydroxy-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran (XXII), which is condensed with methyl 2-hexynoate (XXIII) using the palladium catalyst Pd2dba3 to yield dihydrobenzodipyran (XXIV). The regio- and enantioselective allylic alkylation of (XXIV) with 2-methyl-2(E)-butenyl carbonate (XXV) catalyzed by Pd2dba3 using a chiral ligand affords the chiral dihydrobenzodipyran ether (XXVI), which is dehydrogenated with dichlorodicyanobenzoquinone (DDQ) in dioxane to (XXVII). The chemoselective hydroboration of (XXVII) with 9-BBN and H2O2 gives the alcohol (XXVIII) with high diastereomeric selectivity. The Dess-Martin oxidation of (XXVIII) yields the expected aldehyde (XXIX), which is cyclized to (10S,11R,12R)-benzotripyran (XXX) (ent-calanolide B). Finally, this compound is converted into ent-calanolide A by inversion of the C-12 hydroxy group carried out with a modified Mitsunobu reaction with dimethyl azodicarboxylate (DEAD)/trimethylphosphine/chloroacetic acid in toluene/THF, followed by treatment with NH4OH in methanol. The authors indicate that Calanolide A can be synthesized in the same way by simply using the mirror image of the chiral ligand in the addition of carbonate (XXV) to dihydrobenzodipyran (XXIV).
4) The aldol condensation of the previously described benzodipyran (VII) with acetaldehyde catalyzed by TiCl4/lithium diisopropylamide (LDA) in heptane/THF/ethylbenzene gives a racemic mixture of the enantiomers (XXXI) and (XXXII), which is enzymatically resolved with lipase PS-30 or lipase-AK and vinyl acetate in tert-butyl methyl ether to yield a mixture of unchanged 3(S)-hydroxy-2(R)-methylbutyryl-enantiomer (XXXI) and acetylated enantiomer (XXXIII), which are easily separated by column chromatography. The cyclization of (XXXI) by means of triphenylphosphine and diethyl azodicarboxylate (DEAD) in THF gives the (10R,11R)-precursor (XXXIV), which is finally reduced with NaBH4/triphenylphosphine oxide /CeCl3 in ethanol and purified by chiral HPLC.
An improved synthesis of 5,7-dihydroxy-8-propionyl-4-propyl-2H-1-benzopyran-2-one, a key intermediate in the synthesis of (+)-calanolide A, has been reported: Friedel-Crafts acylation of 5,7-dihydroxy-4-propyl-2H-1-benzopyran-2-one (I) with propionic anhydride (II) by means of AlCl3 in refluxing nitromethane.
An enantioselective total synthesis of (+)-calanolide A has been reported: The silylation of 2'-hydroxy-4',6'-dimethoxybutyrophenone (I) with TIPS-Cl by means of benzylltriethylammonium chloride and NaOH in benzene gives the silyl ether (II), which is demethylated with BCl3 in dichloromethane yielding 2'-hydroxy-4'-methoxy-6'-(triisopropylsilyloxy)butyrophenone (III). The Wittig condensation of (III) with the phosphorane (IV) in N,N-diethylaniline with simultaneous cyclization, affords the benzopyranone (V), which is submitted to a Friedel-Crafts condensation with the acyl chloride (VI) by means of SnCl4 in dichloromethane to provide the 8-acylbenzopyranone (VII). The desilylation of (VII) by means of TBAF in THF/dichloromethane gives the 5-hydroxy compound (VIII) which is submitted to a propargylation with alcohol (IX) and DBU and then to a Claisen rearrangement with N,N-diethylaniline affording the pyrano-benzopyran (X). Demethylation of (X) with MgI2 in refluxing benzene gives the phenol (XI), which is submitted to a (-)-quinine-catalyzed asymmetric intramolecular oxo-Michael addition in chlorobenzene yielding an 80:20 mixture of the chiral cis- and trans-benzotripyrans (XII) (94% ee) and (XIII), respectively. Since the desired compound is the minor component (XIII), the preceding mixture is treated with MgI2 in refluxing benzene to afford an equilibrated 50:50 mixture that is separated by chromatography, and the undesired cis-isomer can be recycled by repeating the MgI2 treatment. The enantiomerically rich trans-isomer (XIII) is finally reduced with LiAlH(Ot-Bu)3 in THF.
The reaction of 5,7-dihydroxy-4-propyl-2H-1-benzopyran-2-one (I) with TsCl (or MsCl) and pyridine gives the ditosylate (II), which is selectively desulfonated by means of TBAF in THF at 0 C to yield monotosylate (III). The cyclization of (III) with 3-chloro-3-methyl-1-butyne (IV) by means of K2CO3, Bu4N+I- and ZnCl2 in butanone/DMF affords the benzodipyran (V), which is detosylated with TBAF in THF at 20 C to provide the hydroxy derivative (VI). Finally, the OH group of (VI) is enantioselectively alkylated with the mixed carbonate ester (VII) by means of Pd2dba3 ,Cs2CO3 and a (S,S)-chiral ligand in THF to furnish the target chiral intermediate (VIII) (see scheme no. 20433103a, intermediate (XXVII)).