(R)-(−)- and (S)-(+)-Synadenol:  Synthesis, Absolute Configuration, and Enantioselectivity of Antiviral Effect

• Published in: Journal of medicinal chemistry Vol. 41; no. 26; pp. 5257 - 5264
• Main Authors: Qiu, Yao-Ling, Hempel, Andrew, Camerman, Norman, Camerman, Arthur, Geiser, Fiona, Ptak, Roger G, Breitenbach, Julie M, Kira, Toshiko, Li, Ling, Gullen, Elizabeth, Cheng, Yung-Chi, Drach, John C, Zemlicka, Jiri
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 17.12.1998; Amer Chemical Soc
• Subjects: Adenine - analogs & derivatives; Adenine - chemical synthesis; Adenine - chemistry; Adenine - pharmacology; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Biological and medical sciences; Cells, Cultured; Cercopithecus aethiops; Chemistry, Medicinal; Chromatography, High Pressure Liquid; Circular Dichroism; Crystallography, X-Ray; Cyclopropanes - chemical synthesis; Cyclopropanes - chemistry; Cyclopropanes - pharmacology; Cytomegalovirus - drug effects; Cytomegalovirus - growth & development; enantioselectivity; Epstein-Barr virus; Fibroblasts; Hepatitis B virus - drug effects; Hepatitis B virus - growth & development; Herpesvirus 3, Human - drug effects; Herpesvirus 3, Human - growth & development; Herpesvirus 4, Human - drug effects; Herpesvirus 4, Human - growth & development; HIV-1 - drug effects; HIV-1 - growth & development; Human cytomegalovirus; Human immunodeficiency virus 1; Humans; Inhibitory Concentration 50; Life Sciences & Biomedicine; Medical sciences; Mice; Molecular Conformation; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Science & Technology; Simplexvirus - drug effects; Simplexvirus - growth & development; Stereoisomerism; Synadenol; Varicella-zoster virus; Vero Cells; Viral Plaque Assay; ENANTIOMERS; REPLICATION; INHIBITION; Human; Varicella zoster virus; Cytomegalovirus; Purine nucleoside; Cyclopropane derivatives; Herpesviridae; Alphaherpesvirinae; Retroviridae; Betaherpesvirinae; Lentivirus; In vitro; Biological activity; Primary alcohol; Virus; Herpesvirus hominis 1; Herpesvirus hominis 2; Analog; Enantiomer; Absolute configuration; Antiviral; Human immunodeficiency virus; Chemical synthesis; Ethylenic compound
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm980323u

Synthesis of (R)-(−)- and (S)-(+)-synadenol (1a and 2a, 95−96% ee) is described. Racemic synadenol (1a + 2a) was deaminated with adenosine deaminase to give (R)-(−)-synadenol (1a) and (S)-(+)-hypoxanthine derivative 5. Acetylation of the latter compound gave acetate 6. Reaction with N,N-dimethylchloromethyleneammonium chloride led to 6-chloropurine derivative 7. Ammonolysis furnished (S)-(+)-synadenol (2a). Absolute configuration of 1a was established by two methods:  (i) synthesis from (R)-methylenecyclopropanecarboxylic acid (8) and (ii) X-ray diffraction of a single crystal of (−)-synadenol hydrochloride. Racemic methylenecyclopropanecarboxylic acid (10) was resolved by a modification of the described procedure. The R-enantiomer 8 was converted to ethyl ester 13 which was brominated to give vicinal dibromides 14. Reduction with diisobutylaluminum hydride then furnished alcohol 15 which was acetylated to the corresponding acetate 16. Alkylation−elimination procedure of adenine with 16 yielded acetates 17 and 18. Deprotection with ammonia afforded a mixture of Z- and E-isomers 1a and 19 of the R-configuration. Comparison with products 1a and 2a by chiral HPLC established the R-configuration of (−)-synadenol (1a). These results were confirmed by X-ray diffraction of a single crystal of (−)-synadenol hydrochloride. The latter forms a pseudosymmetric dimer with adenine−adenine base pairing in the lattice with the nucleobase in an anti-like conformation. Enantiomers 1a and 2a exhibit varied enantioselectivity toward different viruses. Both enantiomers are equipotent against human cytomegalovirus (HCMV) and varicella zoster virus (VZV). The S-enantiomer 2a is somewhat more effective than R-enantiomer 1a in herpes simplex virus 1 and 2 (HSV-1 and HSV-2) assays. By contrast, enantioselectivity of antiviral effect is reversed in Epstein-Barr virus (EBV) and human immunodeficiency virus type 1 (HIV-1) assays where the R-enantiomer 1a is preferred. In these assays, the S-enantiomer 2a is less effective (EBV) or devoid of activity (HIV-1).