(Z)- and (E)-2-((Hydroxymethyl)cyclopropylidene)methyladenine and -guanine. New Nucleoside Analogues with a Broad-Spectrum Antiviral Activity<SUP>1</SUP><BBR RID="jm9705723b00001">

New nucleoside analogues <BO>14</BO>−<BO>17</BO> based on a methylenecyclopropane structure were synthesized and evaluated for antiviral activity. Reaction of 2,3-dibromopropene (<BO>19</BO>) with adenine (<BO>18</BO>) led to bromoalkene <BO>20</BO>, which was benzoylated to give N⁶,N⁶-dibenzoyl derivative <BO>23</BO>. Attempts to convert <BO>20</BO> or <BO>23</BO> to bromocyclopropanes <BO>21</BO> and <BO>22</BO> by reaction with ethyl diazoacetate catalyzed by Rh<INF>2</INF>(OAc)<INF>4</INF> were futile. By contrast, 2,3-dibromopropene (<BO>19</BO>) afforded smoothly (E)- and (Z)-dibromocyclopropane carboxylic esters <BO>24</BO> + <BO>25</BO>. Alkylation of adenine (<BO>18</BO>) with <BO>24</BO> + <BO>25</BO> gave (E)- and (Z)-bromo derivatives <BO>21</BO> + <BO>22</BO>. Base-catalyzed elimination of HBr resulted in the formation of (Z)- and (E)-methylenecyclopropanecarboxylic esters <BO>26</BO> + <BO>27</BO>. More convenient one-pot alkylation−elimination of adenine (<BO>18</BO>) or 2-amino-6-chloropurine (<BO>30</BO>) with <BO>24</BO> + <BO>25</BO> afforded (Z)- and (E)-methylenecyclopropane derivatives <BO>26</BO> + <BO>27</BO> and <BO>31</BO> + <BO>32</BO>. The Z-isomers were always predominant in these mixtures (Z/E ~ 2/1). Reduction of <BO>26</BO> + <BO>27</BO> and <BO>31</BO> + <BO>32</BO> with DIBALH afforded (Z)- and (E)-methylenecyclopropane alcohols <BO>14</BO> + <BO>16</BO> and <BO>33</BO> + <BO>34</BO>. The latter were resolved directly by chromatography. Compounds <BO>14</BO> + <BO>16</BO> were converted to N⁶-(dimethylamino)methylene derivatives <BO>28</BO> and <BO>29 </BO>which were separated and deprotected to give <BO>14</BO> and <BO>16</BO>. Reaction of <BO>33</BO> and <BO>34</BO> with HCO<INF>2</INF>H led to guanine analogues <BO>15</BO> and <BO>17</BO>. The ¹H NMR spectra of the Z-analogues <BO>14</BO> and <BO>15 </BO>are consistent with an anti-like conformation of the nucleobases. By contrast, ¹H NMR and IR spectra of bromo ester <BO>21</BO> are indicative of syn-conformation of adenine. Several Z-(hydroxymethyl)methylenecyclopropanes exhibited in vitro antiviral activity in micromolar or submicromolar range against human and murine cytomegalovirus (HCMV and MCMV), Epstein−Barr virus (EBV), human herpes virus 6 (HHV-6), varicella zoster virus (VZV), and hepatitis B virus (HBV). Analogues <BO>14</BO>, <BO>15</BO>, and <BO>33</BO> were the most effective agents against HCMV (IC<INF>50</INF> 1−2.1, 0.04−2.1, and 0.8−5.6 μM), MCMV (IC<INF>50</INF> 2.1, 0.3, and 0.3 μM) and EBV in H-1 (IC<INF>50</INF> 0.2, 0.3, and 0.7 μM) and Daudi cells (IC<INF>50</INF> 3.2, 5.6, and 1.2 μM). Adenine analogue <BO>14</BO> was active against HBV (IC<INF>50</INF> 2 μM), VZV (IC<INF>50</INF> 2.5 μM), and HHV-6 (IC<INF>50</INF> 14 μM). Synadenol (<BO>14</BO>) and the E-isomer (<BO>16</BO>) were substrates of moderate efficiency for adenosine deaminase from calf intestine. The E-isomer <BO>16</BO> was more reactive than Z-isomer <BO>14</BO>. The deamination of <BO>14</BO> effectively stopped at 50% conversion. Synadenol (<BO>14</BO>) was also deaminated by AMP deaminase from aspergillus sp.