Date of Award:
Doctor of Philosophy (PhD)
Chemistry and Biochemistry
Richard K. Olsen
Syntheses of diaryl ethers were approached by use of a Diels-Alder reaction employing a new type of diene attached with an aryloxy group. Thus, 2-methyl-3-phenoxybutadiene (90b ), 2- methoxy-3-phenoxybutadiene (92b) and (4S)-3-(t- butyloxycarbony1)-2 ,2-dimethyl-4-( 4-(3-methoxy-1,3 -butadienyl-2- oxy )phenylmethyl]oxazolidine (93b) were synthesized in ~65% yields by methylenation of the carbonyl function in the corresponding 2- substituted acrylate aryl ester using Tebbe's reagent. The 1,3- bis[(trimethylsilyl)oxy ]-2-phenoxybutadiene (105) was made from 1-phenoxy-2-propanone (101) by a sequence of formylation and enolsilylation. Methyl propiolate (107) and dimethyl acetylenedicarboxylate (113) were heated at reflux with diene 9 0 b and 92b in toluene to provide the cyclohexadiene adducts, which were easily oxidized to the corresponding diaryl ethers using DDQ in ~90% yields. Alkyne 107 was also reacted with diene 105 to provide 3-hydroxy-4-phenoxybenzoic acid methyl ester (116) m 49% yield. The diaryl ethers were characterized by IR, 1^ H NMR, l 3^C NMR and elemental analyses.
N-Cbz-O-methyl-L-tyrosinol (129a) and (1R,2R)-N-Cbz-O-methyl- B-hydroxytyrosinol (136b) were synthesized by the condensation of Danishefsky's diene (124) with an acetylenic ketone, benzyl (R)-4-( 1-oxo-2-propynyl)-2,2-dimethyl-3- oxazolidinecarboxylate (120), which was derived from D-serine. Reduction of the ketone function in the adduct using NaBH_4 at 0°C provided 136b. Deoxygenation of the alcohol function in 136b via Barton's procedure gave the optically pure tyrosinol 129a.
The synthesis of the fully differentiated (L,L)-isodityrosinol, ( 4R)-3-benzyloxycarbonyl-2,2-dimethyl-4- [3-[ 4-[ (2S)-2-( t-butyloxycarbonyl)amino-3-hydroxypropyl]phenoxy ]-4- methoxyphenylmethyl] oxazolidine (169) was also approached by a sequence of cycloaddition, aromatization and reduction. The cycloaddition between ketone 120 and diene 93b resulted in formation, in 91% yield, of an equal mixture of two regioisomers that were separated by flash chromatography on silica gel. The aromatization of the required cyclohexadiene adduct using DDQ gave (4R)-3-benzy loxycarbonyl-2,2-dimethyl-4-[3-[ 4-( 4S )-(3-t-butyloxycarbony 1-2,2-dimethy loxazolidin-4-yl)methyl phenoxy ]-4- methoxyphenyloxo] oxazolidine (145a), which was a precursor to isodityrosinol 169. The fortuitous selective methanolysis of one of the oxazolidine rings in 145a and reduction of the ketone function in the resulting monoalcohol via Barton's procedure gave isodityrosinol 169 in good overall yield (37%). The structure of isodityrosinol 169 was confirmed by l^H NMR, 13^C NMR, IR and elemental analyses. The diastereomeric purity of isodityrosinol 169 was proved by use of Mosher's acid.
A new synthetic approach to K-13 was also described. Isodityrosinol 169 was oxidized by RuCl_3 + NalO_4, followed by coupling with tyrosine methyl ester to provide, in 56% overall yield, N-[N-( t-butyloxy )carbonyl]-O-[ (R)-5-(3-benzyloxy carbonyl-2,2- dimethyloxazolidin-4-y1-methy 1)-2-methoxypheny l]-L-tyrosyl]-O- methyl-L-tyrosine a-methyl ester (174 ), which was a precursor to K- 13. Cyclization of the resulting amino acid derived from the tripeptide 174 was unsuccessful, and more research on the cyclization is needed.
Feng, Xianqi, "New Syntheses of Diaryl Ethers, Tyrosinols, B-Hydroxytyrosinols, L,L-Isodityrosinol and L,L-Isodityrosine-Derived Agents via the Diels-Alder Reaction" (1992). All Graduate Theses and Dissertations. 7214.
Copyright for this work is retained by the student. If you have any questions regarding the inclusion of this work in the Digital Commons, please email us at .