Lithium enolate (II), generated from chiral ester (I) and LDA at -84 C, was cyclocondensed with imine (III) to furnish azetidinone (IV). The N-p-methoxyphenyl group of (IV) was then removed by oxidative treatment with ceric ammonium nitrate at -10 C, and the resulting azetidinone (V) was protected with Boc2O to afford tert-butyl carbamate (VI).
The C-7 hydroxyl group of 10-deacetyl baccatin III (VII) was selectively protected with triethylsilyl chloride and imidazole to yield silyl ether (VIII). Subsequent selective acylation of (VIII) at C-10 hydroxyl group with propionyl chloride in the presence of LiN(SiMe3)2 afforded ester (IX). The title taxoid was then obtained by further coupling with b-lactam (VI) using LiN(SiMe3)2 in THF at low temperature, followed by desilylation with HF in pyridine.
Lithium enolate (II), generated from chiral ester (I) and LDA at -84 C, was cyclocondensed with imine (III) to furnish azetidinone (IV). After removal of the triisopropylsilyl group of (IV) using HF in pyridine, the resulting lactam was treated with CH2I2 and Et2Zn in 1,2-dichloroethane to give the dimethylcyclopropyl azetidinone (V). The C-3 hydroxyl group was reprotected as the triisopropylsilyl ether (VI). Then, the N-p-methoxyphenyl group of (VI) was removed by oxidative treatment with ceric ammonium nitrate at -10 C, and the resulting azetidinone was N-protected with Boc2O to afford tert-butyl carbamate (VII).
The C-7 hydroxyl group of 10-deacetyl baccatin III (VIII) was selectively protected with triethylsilyl chloride and imidazole to yield silyl ether (IX). Subsequent selective acetylation of (IX) at C-10 hydroxyl group with acetyl chloride in the presence of LiN(SiMe3)2 afforded ester (X). The title taxoid was then obtained by further coupling of (X) with b-lactam (VII) using LiN(SiMe3)2 in THF at low temperature, followed by desilylation with HF in pyridine.
The C-7 hydroxyl group of 10-deacetyl baccatin III (VIII) was selectively protected with triethylsilyl chloride and imidazole to yield silyl ether (IX). Subsequent selective acylation of (IX) at C-10 hydroxyl group with cyclopropanecarbonyl chloride (X) in the presence of LiN(SiMe3)2 afforded ester (XI). The title taxoid was then obtained by further coupling of (XI) with b-lactam (VII) using LiN(SiMe3)2 in THF at low temperature, followed by desilylation with HF in pyridine.
Lithium enolate (II), generated from chiral ester (I) and LDA at -84 C, was cyclocondensed with imine (III) to furnish azetidinone (IV). Ozonolysis of the olefinic bond of (IV) at -78 C in CH2Cl2-MeOH, followed by reductive workup using Me2S afforded aldehyde (V). Subsequent treatment of (V) with diethylaminosulfur trifluoride in CH2Cl2 at r.t. yielded the difluoromethyl lactam (VI). Then, the N-p-methoxyphenyl group of (VI) was removed by oxidative treatment with ceric ammonium nitrate at -5 C, and the resulting azetidinone was N-protected with Boc2O to afford tert-butyl carbamate (VII)
The C-7 hydroxyl group of 10-deacetyl baccatin III (VIII) was selectively protected with triethylsilyl chloride and imidazole to yield silyl ether (IX). Subsequent selective acylation of (IX) at C-10 hydroxyl group with acid chloride (X) in the presence of LiN(SiMe3)2 afforded ester (XI). The title taxoid was then obtained by further coupling of (XI) with b-lactam (VII) using LiN(SiMe3)2 in THF at low temperature, followed by desilylation with HF in pyridine
Reaction of benzyloxyacetyl chloride (I) with (-)-trans-2-phenylcyclohexanol (II) afforded chiral ester (III). Subsequent removal of the benzyl group by hydrogenolysis, followed by protection with triisopropylsilyl chloride and imidazole in DMF provided silyl ether (IV). Treatment of (IV) with LDA in THF at -85 C generated the corresponding enolate, which was cyclocondensed with imine (VII), (obtained from 3-methylbutenal (V) and p-anisidine (VI)), to produce azetidinone (VIII). Then, the N-p-methoxyphenyl group was removed by treatment with cerium ammonium nitrate in cold ACN-H2O, and the resulting azetidinone (IX) was coupled with di-tert-butyl dicarbonate in the presence of DMAP and Et3N to yield (X).
Protection of 14b-hydroxy-10-deacetylbaccatin (XI) with triethylsilyl chloride in pyridine-DMF provided the 7-silyl ether (XII). This compound was condensed with phosgene in CH2Cl2 to give cyclic carbonate (XIII), which was deprotonated with lithium hexamethyldisilazide (LiHMDS) in THF at -40 C, and then selectively acetylated at the 10 hydroxyl group with AcCl. The resulting baccatin derivative (XIV) was coupled with azetidinone (X) in the presence of LiHMDS in THF at -40 C to provide ester (XV), which was then desilylated by treatment with HF. Finally, the resulting isobutenyl compound (XVI) was hydrogenated in the presence of Pd/C to produce the target isobutyl derivative.