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TOWARDS THE REGIO- AND STEREOSPECIFIC SYNTHESIS OF DAUNOMYCINONE AND ANALOGS
Abstract
A DC(B)A approach to synthesize the potent anticancer drug Daunomycinone and analogs was investigated. 5-methoxynaphthol and 86 were chosen as the CD and A-ring synthons. Except thallic nitrate oxidation, all attempts gave low yields of Juglone. 1,4-naphthoquinonmonoxime failed to form an isoxazole. The challenge was to introduce a ketomethyl side chain and a cis-1,3 glycol to 115. The reduction of trimethoxybenzoic acid to 86 was improved. The side chain was introduced by adding Li-119 on 108a. Moving to a nonpolar solvent reduced 1,4-polarization of (beta)-ketoenolether, a vinylogus ester, and produced more positive charge on cyclic ketone than free ester in 108. The ratio of desired 121 over useless 122 was thus improved from 4.5:1 to 9:1. Chromatography of the mixture was simplified. One attempt to introduce a one-carbon unit to 123, did not succeed. Epoxidation of 94, with the hope of reducing the (alpha)-ketoepoxide to 115 did not succeed. 121 was reduced to 131 with 9-BBN. Hydroxylamine was found very effective in work-up. Various A-ring synthons, 94, 131, and 111 failed to introduce the 9-OH group through a (gamma)-lactone under exhaustive variations. Evidence for 121 was observed but attempts to convert it to 115 led only to 121. The 1,3-dithiane in 121 and 131 were exchanged with 1,2-dioxolane protecting group. A new reaction of conjugate reduction of (beta)-ketoenolethers into (beta)-alkoxyketones in presence of an ester group was developed. Bulky esters of 108 were used to control stereoselectivity. Birch reduction of m-anisic acid was improved to give 85% yield of the enone acid 111. Use of larger R(,1) in 112 and non-polar solvent, produced a stereoselective 1,2-addition of 119. The major product was the allylic alcohol 193, which was cis to the ester and formed a (gamma)-lactone. A new method for converting an allylic alcohol into cis-1,3-glycol was developed. This could of adapted for other cis relations and is of large synthetic value. The 5-methoxynaphthol ester of 111 was prepared to undergo a regiospecific photo-Fries rearrangement to produce daunomycinone and analogs.
Subject Area
Organic chemistry
Recommended Citation
BASU, SWAPAN KUMAR, "TOWARDS THE REGIO- AND STEREOSPECIFIC SYNTHESIS OF DAUNOMYCINONE AND ANALOGS" (1981). ETD collection for University of Nebraska-Lincoln. AAI8208342.
https://digitalcommons.unl.edu/dissertations/AAI8208342