2 ,3 -Didehydro-2 ,3 -dideoxynucleosides

In addition to the three anti-HIV agents [AZT (zidovudine), DDI (dida-nosine) and DDC (zalcitabine)] that have been formally approved by the U.S. Food and Drug Administration for the treatment of HIV infections, several other 2, 3 -dideoxynucleoside (ddN) analogues (Fig. 5), including 3 -fluoro-2, 3 -didcoxy-5-chlorouridine (FddClUrd) and 2, 3 -didehydro-... 

Figure 5 Dideoxynucleoside (ddN) analogues 2, 3 -dideoxycytidine (DDC), 3 -azido-2, 3 -dideoxythymidine (AZT), 3 -fluoro-2, 3 -dideoxythymidine (FLT), 2, 3 -didehydro-2, 3 -dideoxythymidine (D4T), 3 -thia-2, 3 -dideoxycytidine (3TC), 3 -thia-2, 3 -dideoxy-5-fluorocytidine (FTC), and 2, 3 -dideoxy-L-cytidine (l-DDC).

In the past, various serendipitous discoveries have capitalized on the differential expression of enzymes by host and viral infected cells. For example, the prodrug Acyclovir, used widely for the treatment of herpes simplex and herpes zoster infections, is selectively activated through phosphorylation by viral thymidine kinase to acyclovir monophosphate which is then converted to the triphosphate, which inhibits DNA polymerase, by host cellular enzymes. Similarly several 2, 3 -dideoxynucleoside analogs such as Zidovudine (azidothymidine, AZT) and 2, 3 -didehydro-3 -deoxythymidine (D4T) have potent antiviral activity against human immunodeficiency vims (HIV). These compounds are selectively phosphoiylated intracellularly to the 5 -triphosphate derivatives which inhibit the viral reverse transcriptase. 

Stereoselective Glycosylation 2, 3 -Dideoxy and 2, 3 -Didehydro-2, 3 -dideoxynucleoside Synthesis... 

Dideoxy- and 2, 3 -didehydro-2, 3 -dideoxynucleosides are potent antiviral drugs that are effective against human immunodeficiency virus (HIV), especially in combination therapies. In synthesizing such compounds, stereochemical control of the glycosylation reaction is key (see Table 12). Selenium moieties provide such control presumably owing to their formation of seleniranium salts 68, as shown in Scheme 10. 

Several 2, 3 -dideoxynucleosides are given to patients with HIV. These analogs include 3 -azido-2, 3 -dideoxythymidine (zidovudine, AZT), 2, 3 -dideoxycytidine (zalcitabine, ddC), 2, 3 -dideoxyinosine (didanosine, ddl), 2, 3 -didehydro-3 -deoxythymidine (stavudine, d4T), and (-)-2 -deoxy-3 -thiacytidine (lamivudine, 3TC). A related molecule is abacavir (ABC), which contains a cyclopentene-methanol moiety instead of the dideoxyribose moiety of the above-mentioned... 

S)mthesis of 2, 3 -didehydro-2, 3 -dideoxynucleosides having variations at either or both of the 2 - and 3 -positions 06T9085. 

Dideoxy-P-D- /ycero-pent-2-enofuranosyl nucleosides 78 (2, 3 -unsaturated nucleosides, 2, 3 -didehydro-2, 3 -dideoxynucleosides) (Fig. 13) are less stable than regular nucleosides. The main source of reactivity is the 2, 3 -double bond which may undergo the reactions characteristic of olefins and enhances the... 

In the area of 2, 3 -didehydro-2, 3 -dideoxynucleosides, a new route to compounds of this type in the pyrimidine series is outlined in Scheme 4. The thioglycoside 54 was produced directly from deoxyribose and thiophenol in acidic conditions, and the condensations to form the nucleoside derivatives were P-selective by about 2 l/ A full account has been given of the formation of 2, 3 -didehydro-2, 3 -dideoxy systems from 2, 3 -dimesylates, protected at 0-5, by treatment with telluride anion (see Vol. 27, p. 247)7 Treatment of the furanoid glycal 55, made by cyclization of an acetylenic alcohol (Chapter 13), with silylated thymine in the presence of iodine, followed by sodium methoxide, provides a new route to d4T (56)7 A new synthesis of d4T (56) from 5-methyluridine has also been described, as has a route to d4T labelled with at C-1, which starts from [l- C]-ribose and proceeds via [r- C]-5-methyluridine, convertible in very high yield to [l - C]-d4T. ... 

---