Synthesis of 5-thiodidehydropyranylcytosine derivatives as potential anti-HIV agents Yuichi Yoshimura a,⇑ , Yoshiko Yamazaki a,b , Yukako Saito a , Yoshihiro Natori a , Tomozumi Imamichi c , Hiroki Takahata a,⇑ a Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan b Research and Development Department, SEED CO. Ltd, 1030-7 Fukuro, Kounosu, Saitama 369-0131, Japan c Laboratory of Human Retrovirology, Applied and Development Research Program, National Institute of Allergy and Infectious Diseases at Frederick, Science Applications International Corporation-Frederick, Inc., Frederick, MD 21702, USA article info Article history: Received 19 February 2011 Revised 2 April 2011 Accepted 5 April 2011 Available online 9 April 2011 Keywords: Nucleoside 4 0 -Thionucleoside Anti-HIV Antiviral Pummerer reaction abstract As a part of our ongoing efforts to identify new anti-HIV agents, a 5 0 -thiopyrano-nucleoside derivative 4, designed based on 4 0 -thioD4C 1 and cyclohexenylnucleoside 3, was synthesized. The dihydrothiopyran skeleton of 4 was constructed by the ring closing metathesis of 21 which was synthesized from but-2-yne-1,4-diol. After converting the protecting group from MOM to TBS followed by oxidation, a Pummerer-type thioglycosylation reaction of 24 with persilylated uracil gave the desired 5-thiodihydro- thiopyranyluracils 25 and 26 as a mixture of anomers. The conversion of 25 to a cytosine derivative and subsequent deprotection gave a 5-thiodidehydropyranosylcytosine derivative 4 in good yield. The anti-HIV activity of 4 was also evaluated. Ó 2011 Elsevier Ltd. All rights reserved. HAART (Highly Active Anti-Retroviral Therapy) is the most suc- cessful AIDS treatment to date for controlling HIV replication and has greatly improved the lifespan of AIDS patients. 1 However, the emergence of drug resistant viruses during the course of chemo- therapy for AIDS continues to be a serious problem even after the establishment of HAART. 2 The HAART protocol involves the use of a cocktail of anti-HIV drugs including nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcrip- tase inhibitors (NNRTIs), and protease inhibitors (PIs). 1 Since NRTIs play an important role in HAART, 2 the development of an effective NRTI for HIV, which is also effective for a drug-resistant AIDS virus, would be highly desirable. As a result, a number of nucleoside ana- logues that are effective for treating HIV have been reported to date. 3 Our efforts in this area have involved attempts to prepare new antiviral nucleoside derivatives that have the potential for use in HIV therapy. Our strategy involved the construction of a novel pseudosugar skeleton that could serve as a structurally novel NRTI. Such a compound could then be used in place of currently used NRTIs that are ineffective against viruses that are resistant to the NRTIs now in use. 4 We previously reported on the synthesis of dihydrothiopyrano-nucleoside 2 4c,e which was designed based on the known anti-HIV L-4 0 -thioD4C 1. 5 Unfortunately, dihydro- thiopyrano-nucleoside 2 did not show anti-HIV activity. Cyclohex- enylcytosine 3, however, was found to have weak anti-HIV activity. 4d Although these results were insufficient to obtain antiviral nucleosides, we hypothesized that the transformation of the carbocyclic derivative 3 into its 5 0 -thio counterpart might potentiate anti-HIV activity. To confirm this, we envisioned syn- thesizing a dihydrothiopyranocytosine derivative 4 as a potential HIV-nucleoside. In this Letter, we report on the synthesis of a race- mic mixture of 5-thio-2,3-didehydropyranosylcytosine 4 starting HO HO S N N O NH 2 HO HO N N O NH 2 HO S N N O NH 2 N N O NH 2 S HO 1 2 3 4 Chart 1. 0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2011.04.006 ⇑ Corresponding authors. E-mail address: yoshimura@tohoku-pharm.ac.jp (Y. Yoshimura). Bioorganic & Medicinal Chemistry Letters 21 (2011) 3313–3316 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl