Publisher Summary This chapter presents a review about the chemistry and developments of fluorinated carbohydrates. Because of the high C–F bond energy, glycosyl fluorides are stable in comparison to the other glycosyl halides, and this character has attracted much attention. Deoxyfluoro sugars labeled with fluorine-18 have important applications as imaging agents. Numerous 5-fluorouracil derivatives have been prepared as potential anticancer agents. Fluorine-18 is not known naturally (natural fluorine is all 19 F), but it may be prepared in a variety of artificial nuclear reactions. Several 1-phosphates of deoxyfluoro sugars have been prepared and their acid-catalyzed hydrolysis has been studied. The fluorination of aminoglycosides and anticancer antibiotics has been undertaken to obtain the derivatives of enhanced activity and decreased toxicity. The knowledge concerning the conformation of nucleosides is important in pursuing the relationship between the structure and biological activity of compounds containing fluorinated carbohydrates. Much effort has been devoted to preparing natural nucleoside analogs having effective antiviral (mostly antiherpetic) and antitumor activities with low cytotoxicity for the host cells.

Chemistry and Developments of Fluorinated Carbohydrates

Publisher Summary This chapter analyzes the synthesis of the anthracyclines and their importance as chemotherapeutic agents for the treatment of a broad spectrum of human cancers. The synthesis of the anthracyclines is divided into three parts: construction of the aglycones synthesis of the sugar residue and coupling of the two. The principal synthetic challenges posed by the aglycones include generation of the tetracyclic skeleton, introduction of the A-ring functionality, and achievement of the “correct” regiochemical juxtaposition of the substituents in the A– and D–rings. The demonstration that the natural, cis orientation of the 7- and 9-hydroxyl groups is thermodynamically preferred (∼6:1 ratio) and that epimerization of the C-7 position is affected by CF 3 COOH has attenuated the need to address aglycone stereochemistry directly. Nonetheless, efforts to achieve regiochemically controlled routes have led, inter alia, to a number of new methods of anthraquinone synthesis. In large measure, syntheses of aglycones have relied on the employment of one (or more) of the three general reaction classes: Friedel Crafts alkylations or acylations, nucleophilic condensations, and Diels Alder reactions. The search for effective solutions to aglycone regiochemistry has led to the development of a number of new methods for the construction of anthraquinones that involve anionic species in the regiochemically determining step. Efforts toward the synthesis of the anthracyclines have provided a chemical harvest that is already bounteous and continues to be reaped. Whether total (or partial) synthesis will emerge as the practical solution for the future is, however, a question whose ultimate answer depends on many, as yet, incompletely resolved factors that include: the relative economics of fermentative and total synthesis, the potential therapeutic superiority of non-natural anthracyclines, and the future advances in total synthesis.

Chapter 28 Synthetic Approaches to Anthracycline Antibiotics

Publisher Summary Doxorubicin is one member of the anthracycline group of antibiotics and is produced by a variant of the organism that produces daunorubicin (2) (trivial name, daunomycin), the latter drug being preferred in the treatment of acute leukemia, as it is equiactive and lower in cost. Despite its good antitumor activity, doxorubicin is far from an ideal drug as it has both pharmaceutical and toxicological limitations. This chapter focuses on synthetic routes to doxorubicin and other anthracyclines. It discusses the biochemical effects of doxorubicin and analogues of doxorubicin. Most of the work on synthetic routes to anthracyclines has concentrated on doxorubicin (1) and the related compounds, daunorubicin (2) and carminomycin (12). The stimulus has been the low yield of doxorubicin (1) from the fermentation process and the challenge of synthesis of a compound of such complexity. Only recently has attention really widened to synthesis of other natural anthracyclines. The major problem in design of a route is to obtain regiochemical and stereochemical control. New potentially clinically useful analogues have arrived by screening of natural products or by chemically based intuitive semisynthesis and synthesis, rather than by truly rational design.

Recent studies on doxorubicin and its analogues.

Stereoselective synthesis of α-linked 2-deoxysaccharides and furanosaccharides by use of 2-deoxy 2-pyridyl-1-thio pyrano- and furanosides as donors and methyl iodide as an activator

Synthesis and antitumor activity of 7-O-(3,4-di-O-acetyl-2,6-dideoxy-α-l-lyxo-hexopyranosyl)adriamycinone

Synthesis of 7-O-(2,6-dideoxy-α-l-lyxo-hexopyranosyl)daunomycinone, a functional analog of daunorubicin

Glycosidation of 2, 3, 6-trideoxy-3-trifluoroacclamido-4-O-tritluoroacetyl-α-D-arabino-hexopyranosyl chloride (19) (or the corresponding 4-p-nitrobenzoate, 20) with daunomycinone under KOENIGS-KNORR conditions afforded, after separation of the anomers and removal of the protecting groups, the individual target glycosides 8 (α anomer; major product) and 9 (β; minor) in acceptable yields. In contrast, the title diamino sugar, suitably protected with N-trifluoroacetyl and O-acetyl (or O-p-nitrobenzoyl) groups, underwent stereospecific coupling to the anthracycline aglycon by the glycal procedure to give, after deprotection, the α glycoside 12. All three analogs were assayed in vivo against P388 lymphocytic leukemia. They showed little (T/C 125 for 8; T/C 115 for 9) or no (compound 12) activity, but were essentially devoid of toxicity at the dose-levels tested.

New daunorubicin analogs. 3-Amino-2,3,6-trideoxy-alpha- and beta-D-arabino- and 3,6-diamino-2,3,6-trideoxy- alpha-D-ribo-hexopyranosides of daunomycinone.

Ernst-F. Fuchs

Papers

Synthesis of 7-O-(2,6-dideoxy-α-l-lyxo-hexopyranosyl)daunomycinone, a functional analog of daunorubicin

New daunorubicin analogs. 3-Amino-2,3,6-trideoxy-alpha- and beta-D-arabino- and 3,6-diamino-2,3,6-trideoxy- alpha-D-ribo-hexopyranosides of daunomycinone.