SB-T-12130301

Chemical Name: 3-Methoxybenzoic acid (2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-12b-acetoxy-9-[3(S)-(tert-butoxycarboxamido)-2(R)-hydroxy-5-methyl-4-hexenoyloxy]-4,11-dihydroxy-6-[2-(4-methoxyphenyl)acetoxy]-4a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodeca
项目整合开发状态: Biological Testing
项目研究机构: Roswell Park Cancer Institute (Originator), State University of New York,Stony Brook (Originator)
合成路线:Ring opening of cyclohexene oxide (I) with phenylmagnesium bromide in the presence of CuI,followed by acetylation of the resulting alcohol (II) gave the racemic trans-2-phenylcyclohexyl acetate (III).Enzymatic resolution of (III) using porcine liver acetone powder yielded the desired (-)-alcohol (II) along with unreacted (+)-acetate (III).Condensation of the sodium alkoxide of benzyl alcohol with bromoacetic acid (IV) afforded benzyloxyacetic acid (V),which was then coupled with the chiral alcohol (-)-(II) to give ester (VI).Hydrogenolysis of the O-benzyl group of (VI),followed by silylation of the resulting hydroxyacetate ester (VII) with triisopropylsilyl chloride,furnished (VIII).Imine (XI) was prepared by condensation of 3-methyl-2-butenal (IX) with p-anisidine (X).The asymmetric cyclocondensation reaction of the lithium enolate derived from ester (VIII) with imine (XI) yielded the chiral beta-lactam (XII).Oxidative removal of the p-methoxyphenyl protecting group of (XII) and then reprotection of the lactam N atom with Boc2O furnished the intermediate N-Boc lactam (XIII).

合成路线:10-Deacetylbaccatin III (XIV) was protected by treatment with triethylsilyl chloride and imidazole,and the resulting trisilylated compound (XV) was debenzoylated to diol (XVI) by using Red-Al(R).Selective coupling of (XVI) with m-anisic acid (XVII) yielded the m-methoxybenzoate ester (XVIII).Complete desilylation of (XVIII) with HF-pyridine,followed by selective resilylation at C-7,furnished (XIX).The 10-hydroxyl group was then selectively acylated with p-methoxyphenylacetyl chloride (XX) to afford ester (XXI).Finally,coupling of the modified baccatin (XXI) with the intermediate lactam (XIII) in the presence of lithium hexamethyldisilazide,and then deprotection with HF-pyridine,gave rise to the desired taxoid.