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Stereoselective synthesis of daunomycinone and its analogues
Abstract
Total synthesis of doxorubicin has attracted the attention of many synthetic chemists. Daunomycinone (1), a key fragment of doxorubicin, has been synthesized in many different ways. The basic strategies of these approaches involve (1) anthraquinone approaches with ring A synthesis (DCBA), (2) juglone approaches with ring B formation (DCAB), (3) tetralone approaches with construction of ring C (ABDC) and (4) formation of ring D (ABCD). Wheeler and co-workers have worked on the synthesis of daunomycinone for more than a decade. This work has involved a synthesis using the DCAB approach with a stereochemically fixed ring A and a stepwise connection of ring B in controlling the stereo- and regiochemistry in the total synthesis. Stereoselective synthesis of ring A (2) was completed in 5 steps and 70% overall yield from m-anisic acid. The key reaction involved in the synthesis of ring A was the Sharpless epoxidation of 3. Use of molecular sieves reduced a number of by-products from the epoxidation and improved the reaction yield. It was also found that the addition of nitromethane to ring A precursor (2) was catalyzed by hydrogen bond acceptors, such as DMSO, Me$\sb3$NO and Ph$\sb3$PO. Regioselective synthesis of the ring CD precursor (4) was completed in 3 steps and 50% overall yield from 1,5-dihydroxynapthalene. This synthesis involved as a key step an oxidation of 5-methoxynaphthol by iodobenzene diacetate. The tetracyclic system (5) was synthesized from (4) and the acetonide of the adduct of 2 and nitromethane by a stepwise Michael addition, Dieckmann cyclization and demethanolation. The Nef reaction of transforming the nitro group to ketone failed. Alternatively, oxidative aromatization of 5 and manipulation of functional groups gave the daunomycinone in 13 steps and 6.4% overall yield. The oxidative aromatization by cerium ammonium nitrate (CAN) and a catalytic amount of dichlorodicyanoquinone (DDQ) provided a new feature in which the organic oxidizing reagent was regenerated by an inorganic oxidizing reagent (e.g. CAN) in-situ. Daunomycinone and several of its analogues were synthesized from 5. 6-Desoxy-6-nitrodaunomycine was synthesized in 12 steps from m-anisic acid. We have also converted 5 into 6,11-diamino-6,11-didesoxy, 11-amino-6,11-didesoxy-6-nitro and 6,11-didesoxy-11-fluoro-6-nitrodaunomycinones.
Subject Area
Organic chemistry|Pharmacology|Surgery
Recommended Citation
Fu, Xiaoping, "Stereoselective synthesis of daunomycinone and its analogues" (1993). ETD collection for University of Nebraska-Lincoln. AAI9314402.
https://digitalcommons.unl.edu/dissertations/AAI9314402