Skip to main content
NCBI home page
ACS Medicinal Chemistry Letters logoLink to ACS Medicinal Chemistry Letters
. 2018 Nov 9;9(12):1211–1216. doi: 10.1021/acsmedchemlett.8b00374

Synthesis, Anti-HBV, and Anti-HIV Activities of 3′-Halogenated Bis(hydroxymethyl)-cyclopentenyladenines

Hiroki Kumamoto †,*, Shuhei Imoto ‡, Masayuki Amano §, Nobuyo Kuwata-Higashi ∥, Masanori Baba ⊥, Hiroaki Mitsuya §,∥,#, Yuki Odanaka ▽, Satoko Shimbara Matsubayashi ▽, Hiromichi Tanaka ▽, Kazuhiro Haraguchi †
PMCID: PMC6295849  PMID: 30613328

Abstract

graphic file with name ml-2018-003745_0007.jpg

Synthesis of 3′-halogeno analogues (5a–d) of 9-[c-4,t-5-bis(hydroxymethyl)-cyclopent-2-en-r-1-yl]-9H-adenine (BCA, 3) was accomplished by means of dual utilization of the vinyl sulfone functional moieties in both 10 and 16 utilizing a SN2′ conjugate-addition reaction and a sulfur-extrusive stannylation, respectively. Evaluation of the antiviral activities of 5a–d revealed that introduction of a halogeno-substituent into the 3′-position of (−)-BCA diminished its anti-HIV-1 activity but increased the inhibitory activity for the reverse transcriptase of HBV in that the 3′-fluorinated BCA 5d exhibited the highest activity without significant cytotoxicity.

Keywords: Carbocyclic nucleosides, halogeno-substituent, anti-HBV

Since the discovery of carbovir (1)1,2 and its prodrug abacavir (2),3 anti-HIV agents, carbocyclic nucleosides have been recognized as an important class of antiviral agents (Figure 1). In 1992, a novel anti-HIV active carbocyclic nucleoside, (±)-9-[c-4,t-5-bis(hydroxymethyl)-cyclopent-2-en-r-1-yl]-9H-adenine (BCA) (3)4−9 emerged as a hybrid derivative of 1 and carbocyclic oxetanocin (COXT, 4)10−12 Asymmetric synthetic studies of BCA revealed that the depicted (−)-enantiomer of 3 is the active stereoisomer.8,9 Although 3 shows promising anti-HIV activity, only one study concerning structure–activity relationships has been reported. Thus, 4′-branched derivatives have been synthesized on the basis of intramolecular SH2′ cyclization.13 With a view to expanding the medicinal chemistry of BCA, we have extended the studies toward the preparation of 3′-halogenated BCA analogues (5). We were particularly intrigued by the possibility of exploiting the mildness and wide scope of vinyl stannanes to elaborate a wide range of alkenes. In this Letter we describe the development of synthetic methods for the novel BCA derivatives 5 by utilizing vinyl stannane chemistry. In this study, we have found that 5a–d exhibited selective inhibitory activity against the reverse transcriptase (RT) of HBV.

Figure 1.

Figure 1

Open in a new tab

Structure of 1–5.

The retrosynthetic analysis for the target 5 is illustrated in Scheme 1. The vinylstannane A was selected as a key precursor for the synthesis of 5 because of its versatility as a synthon for synthesizing a variety of substituted alkenes. The key precursor A would be prepared from the vinyl sulfone B through radical-mediated sulfur-extrusive stannylation reaction14−20 and introduction of adenine base by an SN2 manner. For preparing B, we selected vinyl sulfone C as substrate. SN2′-addition elimination reaction of C with hydroxymethyl synthon Pg2OCH2Li would proceed efficiently, assisted by the electron withdrawing PhSO2 group, to give B via resonance-stabilized carbanion D in which the β′-dioxolanyl structure acts as a good leaving group to release its ring strain.

Scheme 1. Retrosynthetic Analysis.

Scheme 1

Open in a new tab

Initially, preparation of cyclopentenyl phenylsulfone 10 was examined (Scheme 2). Cyclopentenone 6, prepared from d-ribose according to the literature procedure,21 was converted to mesylate 7 by the following three step sequence: (1) hydrogenation of the double bond using 10% Pd/C, (2) NaBH4 reduction of the resulting ketone, and (3) mesylation of the formed secondary alcohol. Treatment of 7 with sodium thiophenolate (NaSPh) in refluxing MeCN gave sulfide 8 in 95% isolated yield. The sulfide 8 was oxidized to the corresponding sulfoxide with m-CPBA and subsequent Pummerer-type dehydrogenation of the sulfoxide by treatment with (F3CCO)2O/pyridine gave vinyl sulfide 9. Finally, the sulfide 9 was converted to the desired 10 in 99% yield.

Scheme 2. Preparation of Vinyl Phenylsulfone 10.

Scheme 2

Open in a new tab

We next examined PhSO2-assisted SN2′ β-addition–elimination reaction22−28 of 10 with organolithium species as carbon nucleophiles for introducing the 4′-β-hydroxymethyl unit of the target molecule 5, and the results are shown in Table 1. Initially, reaction with methoxymethyl-protected hydroxymethyl lithium (MOMOCH2Li) was examined (entry 1). When 10 was treated with MOMOCH2Li prepared in situ from MOMOCH2SnBu3 and n-BuLi at −80 °C in THF,29−31 the main pathway of the reaction was an unexpected substitution of the PhSO2 group via an α-addition–elimination mechanism to give 12a (23% isolated yield). The desired SN2′ product 11a was obtained in 18% yield as a single stereoisomer (entry 1). The β-configuration of the introduced carbon substituent in 11a was confirmed by NOE experiments (see Supporting Information). The stereochemical outcome is rationalized by a steric repulsion exerted by the sterically encumbered TBDPSOCH2 group at the neighboring γ-position. Similar results were observed when the reaction was carried out by increasing the amount of MOMOCH2Li (entries 2 and 3). To improve the isolated yield of 11, benzyl- and tert-butyl-protected hydroxymethyl lithium, BnOCH2Li29−31 (entry 4) and tert-BuOCH2Li31 (entry 5), were reacted with 10. However, these reactions also gave the undesired 12b or 12c as major products in 17% and 66% isolated yields, respectively, along with 11b (10%) and 11c (13%). In contrast to the above results, when styryllithium (PhCH=CHLi, generated in situ from PhCH=CHSnBu3 and BuLi)32 was utilized, the desired substitution product 11d could be obtained in 72% isolated yield as a sole product (entry 6). Similarly, vinyllithium (H2C = CHLi, prepared in situ from H2C = CHSnBu3 and BuLi)33,34 gave 11e in 81% isolated yield (entry 7). On the basis of the isolated yields of 11, the vinyl group-substituted 11e was found to be a suitable substrate for the synthesis of the target molecules, and we envisioned transforming the vinyl-substituent into a hydroxymethyl group at later stage.35,36

Table 1. Reaction of Vinylsulfone 10 with Organolithium Reagents.

graphic file with name ml-2018-003745_0006.jpg

entry R (equiv) yield [%] of 11 yield [%] of 11
1 CH2OCH2OCH3 (1.2) 18 23
2 CH2OCH2OCH3 (2.4) 18 36
3 CH2OCH2OCH3 (3.0) 27 43
4 CH2OBn (3.0) 10 17
5 CH2Ot-Bu (3.0) 13 66
6 (E)-CH=CHPh (3.0) 72  
7 CH=CH2 (3.0) 81  
Open in a new tab

It has been reported that α-oxyalkyl lithium derived from phenyloxetane reacted with cyclopropylmethyl bromide to give the ring-opened linear butenyl-substituted oxetane through an SET process.37 This fact suggested to us that the mechanism of the α-substitution of the phenylsulfanyl group of 10 observed in the reaction of alkoxymethyl lithium could be via radical coupling of alkoxymethyl radical with the vinyl radical. To confirm the possibility of the radical mechanism, 10 was treated with t-BuOCH2Li in the presence of an excess amount of radical scavenger galvinoxyl (3.0 equiv). However, the α-substitution product 12c was obtained in 63% yield, and the SET mechanism was ruled out. Another possible mechanism is addition–elimination initiated by α-attack of the carbon nucleophile at the vinyl sulfone; indeed, a similar reaction pathway has been proposed in C-ethynylation utilizing arylsulfonylacetylene.38,39 At the present time, the latter mechanism is thought to be via the α-substitution pathway.

With the precursor 11e for the carbohydrate moiety of 5 in hand, the radical-mediated sulfur-extrusive stannylation was examined (Scheme 3). When 11e was treated with Bu3SnH and AIBN in the presence of i-Pr2NEt in refluxing benzene for 4 h according to our previously reported procedure,19 the desired vinylstannane 13 was obtained in 36% yield along with unreacted 11e. An improved result was obtained in the stannylation of benzoyl-protected vinyl sulfone 14(20) to furnish 15 in 52% yield. This result led us to examine the reaction of nucleoside derivative 16. Nucleoside 16 was prepared in 86% yield by reacting 11e with N6-bis(Boc)adenine (17)40,41 in the presence of DIAD and Ph3P in THF.42 The stannylation reaction of 16 was carried out under the above reaction conditions, and the desired tributylstannane 18 could be obtained in better yield (54%) with the recovery of unchanged 16 (40%).

Scheme 3. Radical-Mediated Sulfur-Extrusive Stannylation of Sulfones 11e, 14, and 16.

Scheme 3

Open in a new tab

Next, halogenation of the tributylstannane 18 was examined (Scheme 4), and the results are shown in Table 2. Treatment of 18 with iodine gave the corresponding iodide 19a in quantitative yield (entry 1). Bromination of 18 with N-bromosuccinimide (NBS) gave 19b in 74% yield (entry 2). Likewise, when chlorination of 18 using N-chlorosuccinimide (NCS) was carried out, the chloride 19c was obtained in only 33% yield. The isolated yield could be improved to 51% yield by reacting with CuCl243 (entry 4). The fluoro derivative 19d was obtained in 61% yield by treatment of 18 with XeF2 in the presence of AgOTf and 2,6-di-tert-butyl-4-methylpyridine (DTBMP)44 (entry 5).

Scheme 4. Synthesis of 3′-Halogeno-BCA 5.

Scheme 4

Open in a new tab

Table 2. Halogenation of Vinylstannane 18.

entry condition product X yield [%]
1 I2/CCl4, 0 °C 19a I 98
2 NBS/THF, rt 19b Br 74
3 NCS/THF, reflux 19c Cl 33
4 CuCl2/THF, rt 19c Cl 51
5 XeF2, AgOTf, DTBMP/CH2Cl2, rt 19d F 61
Open in a new tab

Oxidative cleavage of the terminal olefin of the 3′-halogenated 19a–d was conducted under Lemieux–Johnson conditions in the presence of 2,6-lutidine,45 and subsequent NaBH4 reduction of the resulted aldehyde gave 20a–d (Scheme 4). It is noteworthy that in this transformation the internal trisubstituted alkene moiety of the substrate was stable to the oxidative cleavage and that the protected target molecules 20a–d were formed in moderate yields. Finally, removal of the Boc- and TBDPS-protecting groups of 20a–d was performed by the treatment with 3 M HCl at 50 °C to yield the target 3′-halogeno-BCA derivatives 5a–d in 79–99% isolated yields. For the comparison of the antiviral activities, the parent compound (−)-BCA (3) was prepared from 5a through radical reduction conditions. The 1H and 13C NMR spectra of the synthesized 3 were consistent with the reported data.8 This result supported the depicted structures of 5 synthesized in this study.

Finally, anti-HIV-1 activities of 5a–d were evaluated, and the results are summarized in Table 3. The reported anti-HIV-1 data of BCA was also listed in entry 5.4 Unfortunately, none of the compounds (5a–d) synthesized in this study showed significant anti-HIV-1 activity (>100 μM). This result suggests that the introduction of the halogeno-substituent at the 3′-position of BCA has adverse effects on the inhibition of reverse transcriptase of HIV-1. However, 5a–d were found to exhibit potent anti-HBV activities presumably due to inhibition of HBV reverse transcriptase. Furthermore, this study has shown that BCA itself possesses anti-HBV activity (entry 5). As can be seen with entry 4, 3′-fluoro-BCA (5d) was the most potent inhibitor in this study (EC50 = 0.019 μM). A striking feature of these novel compounds is that none show cytotoxicity to HepG2 cell up to 100 μM. Although the potency of the fluorinated BCA 5d is 5 times less than that of positive control entecavir (entry 6), entecavir was found to be more toxic than that of 3′-fluoro-BCA. This result could pave the way for developing novel nontoxic and potent anti-HBV agents.

Table 3. Anti-HIV and Anti-HBV Activities of Compounds 5a–d and 3.

      HIV-1IIIB
 HBVWTD
entry compd R EC50 (μM) CC50 (μM) (MT4) EC50 (μM) CC50 (μM) (HepG2)
1 5a I >1 >100b 0.436 ± 0.000 NDc
2 5b Br >1 >100b 0.029 ± 0.017 >100
3 5c Cl >1 >100b 0.146 ± 0.000 NDc
4 5d F >1 >100b 0.019 ± 0.003 >100
5 3 (BCA) H 0.77a 153 0.0457 ± 0.0002 >100
6 entecavir       0.0038 52.9
Open in a new tab
a

Data taken from ref (4).

b

MT2 cell.

c

Not determined.

Of note, HBV’s reverse transcriptase (RT) is extremely insoluble, and to date, no research has succeeded in preparing HBV-RT solution. Thus, it has been impossible for one to conduct reverse transcriptase assay with HBV-RT; no crystallographic analyses have been successful; and no detailed structure of HBV-RT’s active site is known. However, it is quite plausible that the nucleoside analogs discovered in the present study act against HBV-RT due to the fact that all the new compounds reported in the present work have the 2′,3′-dideoxynucleoside configuration.50,51 Indeed, in order to circumvent the notoriously high insolubility of HBV-RT, we have most recently generated “hybrid” reverse transcriptase species of HIV-1-RT and HBV-RT and have demonstrated that HIV-1-RT containing a Q151M substitution (151-Met is an HBV-RT’s critical active site amino acid) at the nucleotide-binding site (N-site) of HIV-1-RT serves as a tool for examining the interactions of anti-HBV nucleosides with HBV-RT.46−48,51

It is commonly seen that certain nucleoside analogs are highly active against HIV-1, but not against HBV.49 For example, azydothymidine (zidovudine) is potent against HIV-1, but basically inert against HBV,49 while entecavir, an FDA-approved anti-HBV therapeutic, is potent against HBV but not against HIV-1.49 Since 2′-fluoro-BCA (5d) exerted potent activity against HBV (Table 3), it is assumed that the compound was intracellularly well triphosphorylated and incorporated into the growing DNA chain of HBV genome being mediated by HBV-RT without exerting significant cytotoxicity (CC50 > 100 μM). Also, it should be noted that MT-2 cell line is of a human lymphocyte origin, while HepG2 is of a human hepatocytic tumor origin and their susceptibility to the cytotoxicity of certain agents could very often vary. Nevertheless, the CC50 of 5d with MT-2 cells was 100 μM and that with HepG2 was >100 μM, strongly suggesting that 5d’s toxicity is insignificant. Of note, the specificity index of 5d (CC50/EC50) is 5263.16, indicating that, categorically, 5d has no significant cytotoxicity. Since the amounts of compounds newly synthesized are often low and scarce and the concentrations of such novel compounds usually are not tested at >100 μM. Further testing of the anti-HBV activity against other HBV species and safety profiles of 5d are future topics.

In conclusion, a synthetic method for the novel 3′-halogeno-BCA derivatives has been developed. The method includes two key steps: (1) SN2′ reaction of β′-dioxolanylcyclopentenylphenylsulfone 10 with vinyl lithium and (2) tin-radical-mediated sulfur-extrusive stannylation of 3′-phenylsulfonylted BCA derivative 16 to lead to the formation of key precursor vinyl stannane 18 for the target molecules. The former SN2′ reaction has proceeded with high-β-face selectively due to the sterically encumbered TBDPS-oxylmethyl group substituted at the γ-psition of 10. Evaluation of antiviral activities revealed that introduction of halogeno-substituents into the 3′-position diminished the anti-HIV-1 activity of BCA. Interestingly, 3′-substitution of BCA with a halogen atom gave rise to an increase in the potency of inhibition of reverse-transcriptase of HBV. In general, halogenation of small molecular-weight compounds increases metabolic stability, delays inactivation of the compounds, and elongates their dosage periods because, chemically, carbon-and-halogen bonds are highly stable as compared to carbon-and-hydrogen bonds. Halogenation also increases lipophilicity due to its greater hydrophobicity, often increasing cell membrane penetration and oral bioavailability. It is not evident at this time whether the halogenation of the two compounds enhanced their cellular penetration, whether the triphosphorylated compounds intracellularly longer persisted and accumulated due to their possibly increased chemical stability, or whether halogenation strengthened their binding to the reverse transcriptase of HBV. The elucidation of the actual mechanism of the strengthened antiviral activity of the halogenated compounds against HBV is a topic of future studies.

Acknowledgments

This research was supported by AMED under Grant Number JP 16fk0310501 and JP18fk0310113. The authors are grateful to Dr. K. Fukuhara (Showa University) for useful suggestions.

Supporting Information Available

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsmedchemlett.8b00374.

  • Experimental procedures and full characterization for compounds 5, 7–20 (PDF)

Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

Financial supports from the Japan Society for the Promotion of Science (KAKENHI No. 24590144 to K.H.) and Health and Labour Sciences Research Grants (Practical Research on Hepatitis (Research on the innovative development and the practical application of new drugs for hepatitis B)) are gratefully acknowledged.

The authors declare no competing financial interest.

Supplementary Material

ml8b00374_si_001.pdf (9MB, pdf)

References

  1. Vince R.; Hua M. Synthesis and anti-HIV activity of carbocyclic 2’,3′-didehydro-27,3′-dideoxy 2,6-disubstituted purine nucleosides. J. Med. Chem. 1990, 33, 17. 10.1021/jm00163a004. [DOI] [PubMed] [Google Scholar]
  2. Daluge S. M.Therapeutic Nucleosides U.S. Patent 5,034,394, 1991.
  3. Huff J. R. Abacavir sulfate. Bioorg. Med. Chem. 1999, 7, 2667. 10.1016/S0968-0896(99)00242-4. [DOI] [PubMed] [Google Scholar]
  4. Katagiri N.; Nomura M.; Sato H.; Kaneko C.; Yusa K.; Tsuruo T. Synthesis ans anti-HIV activity of 9-[c-4,t-5-bis(hydroxymethyl)cyclopent-2-en-r-1-yl]-9H-adenine. J. Med. Chem. 1992, 35, 1882. 10.1021/jm00088a026. [DOI] [PubMed] [Google Scholar]
  5. Katagiri N.; Shiraishi T.; Sato H.; Toyota A.; Kaneko C.; Yusa K.; Ohhara T.; Tsuruo T. Resolution of 9-(c-4,t-5-bishydroxymethylcyclopent-2-en-r-1-yl)-9H-adenine and selective inhibition of human immunodeficiency virus by the (−) enantiomer. Biochem. Biophys. Res. Commun. 1992, 184, 154. 10.1016/0006-291X(92)91172-M. [DOI] [PubMed] [Google Scholar]
  6. Katagiri N.; Shiraishi T.; Toyota A.; Sato H.; Kaneko C.; Aikawa T. Synthesis of nucleosides and related compounds. XXXI. Resolution of 9-[c-4,t-5-bis(hydroxymethyl)cyclopent-2-en-r-1-yl]-9H-adenine [(±)-BCA] by means of high-pressure-mediated deamination with adenosine deaminase. Chem. Pharm. Bull. 1993, 41, 1027. 10.1248/cpb.41.1027. [DOI] [Google Scholar]
  7. Katagiri N.; Toyota A.; Shiraishi T.; Sato H.; Kaneko C. Synthesis of (1R,4S,5R)-9-(4,5-bishydroxymethylcyclopent-2-en-1-yl)-9H-adenine [(−)-BCA] and selective inhibition of human immunodeficiency virus. Tetrahedron Lett. 1992, 33, 3507. 10.1016/S0040-4039(00)92675-3. [DOI] [PubMed] [Google Scholar]
  8. Tanaka M.; Norimine Y.; Fujita T.; Suemune H. Chemenzymatic synthesis of antiviral carbocyclic nucleosides: asymmetric hydrolysis of meso-bis(acetoxymethyl)cyclopentens using Rhizopus delemar lipase. J. Org. Chem. 1996, 61, 6952. 10.1021/jo9608230. [DOI] [PubMed] [Google Scholar]
  9. Banerjee S.; Ghosh S.; Shinha S. Convenient route to both enantiomers of a highly functionalized trans-disubstituted cyclopentene. Synthesis of the carbocyclic core of the nucleoside BCA. J. Org. Chem. 2005, 70, 4199. 10.1021/jo0502504. [DOI] [PubMed] [Google Scholar]
  10. Norbeck D. W.; Kern E.; Hayashi S.; Rosenbrook W.; Sham H.; Herrin T.; Plattner J. J.; Erickson J.; Clement J.; Swanson R.; Shipkowitz N.; Hardy D.; Marsh K.; Arnett G.; Shanmon W.; Broder S.; Mitsuya H. Cyclobut-A and cyclobut-G: broad-spectrum antiviral agents with potential utility for the therapy of AIDS. J. Med. Chem. 1990, 33, 1281. 10.1021/jm00167a002. [DOI] [PubMed] [Google Scholar]
  11. Bisacchi B. S.; Braitman A.; Cianci C. W.; Clark J. M.; Field A. K.; Hagen M. E.; Hochstein D. R.; Malley M. F.; Mitt T.; Slusarchyk W. A.; Sundeen J. E.; Terry B. J.; Tuomari A. V.; Weaver E. R.; Yung M. G.; Zahler R. Symtnesis and antiviral activity of enantiomeric forms of cyclobutyl nucleoside. J. Med. Chem. 1991, 34, 1415. 10.1021/jm00108a026. [DOI] [PubMed] [Google Scholar]
  12. Shimada N.; Hasegawa S.; Harada T.; Tomisawa T.; Fujii A.; Takita T. Oxetanocin, a novel nucleoside from bacteria. J. Antibiot. 1986, 34, 1623. 10.7164/antibiotics.39.1623. [DOI] [PubMed] [Google Scholar]
  13. Kumamoto H.; Takahashi N.; Shimamura T.; Tanaka H.; Nakamura K. T.; Hamasaki T.; Baba M.; Abe H.; Yano M.; Kato N. Synthesis of (±)-9-[c-4,t-5-bis(hydroxymethyl)cyclopent-2-en-r-1-yl]-9H-adenine (BCA) derivatives branched at the 4’-position based on intramolecular SH2’ cyclization. Tetrahedron 2008, 64, 1494. 10.1016/j.tet.2007.11.038. [DOI] [Google Scholar]
  14. Watanabe Y.; Ueno Y.; Araki T.; Endo T.; Okawara M. A novel hemolytic substitution on vinylic carbon. A new route to vinyl stannane. Tetrahedron Lett. 1986, 27, 215. 10.1016/S0040-4039(00)83980-5. [DOI] [Google Scholar]
  15. Dubois E.; Beau J.-M. Arylation of 1-tributylstannyl glycals catalyzed by palladium: A synthetic route to the basic skeleton of the papulacandins and chaetiacandin. Tetrahedron Lett. 1990, 31, 5165. 10.1016/S0040-4039(00)97832-8. [DOI] [Google Scholar]
  16. McCarthy J. R.; Matthews D. P.; Stemerick D. M.; Huber E. W.; Bey P.; Lippert B. J.; Snyder R. D.; Sunkara P. S. Stereospecific method to E and Z terminal fluoro olefin and its application to the synthesis of 2’-deoxy-2’-fluoromethylene nucleosides and potential inhibitors of ribonucleoside diphosphate reductase. J. Am. Chem. Soc. 1991, 113, 7439. 10.1021/ja00019a061. [DOI] [Google Scholar]
  17. Wnuk S. F.; Robins M. J. Nucleic acid related compounds. 78. Stereocontrolled syntheses of 6′(E and Z)-halovinyl analogues from uridine-derived vinylsulfones via vinyltin intermediates. Can. J. Chem. 1993, 71, 192. 10.1139/v93-028. [DOI] [Google Scholar]
  18. McCarthy J. R.; Huber E. W.; Le T.-B.; Laskovics F. M.; Matthews D. P. Stereospecific synthesis of 1-fluoro olefins via (fluorovinyl)stannanes and an unequivocal NMR method for the assignment of fluoro olefin geometry. Tetrahedron 1996, 52, 45. 10.1016/0040-4020(95)00911-Q. [DOI] [Google Scholar]
  19. Onuma S.; Kumamoto H.; Kawato K.; Tanaka H. A versatile intermediate for the synthesis 3′-substituted 2’,3′-didehydro-2’,3′-dideoxyadenosine(d4A): preparation of 3′-C-stannyl-d4A via radical-mediated desulfonylative stannylation. Tetrahedron 2002, 58, 2497. 10.1016/S0040-4020(02)00153-9. [DOI] [Google Scholar]
  20. Kumamoto H.; Deguchi K.; Wagata T.; Furuya Y.; Odanaka Y.; Tanaka H. Radical-mediated stannylation of vinyl sulfones: access to novel 4’-modified neplanocin A analogues. Tetrahedron 2009, 65, 8007. 10.1016/j.tet.2009.07.039. [DOI] [Google Scholar]
  21. Choi W. J.; Moon H. R.; Kim H. O.; Yoo B. N.; Lee J. A.; Shin D. H.; Jeong L. S. Preparative and stereoselective synthesis of the versatile intermediate for carbocyclic nucleosides: Effects of the bulky protecting groups to enforce facial selectivity. J. Org. Chem. 2004, 69, 2634. 10.1021/jo0356762. [DOI] [PubMed] [Google Scholar]
  22. Saddler J. C.; Fuchs P. L. Enantioselective, synthesis of γ-substituted enones: organometallic SN2’ cojugate-addition of epoxy vinyl sulfones. J. Am. Chem. Soc. 1981, 103, 2112. 10.1021/ja00398a050. [DOI] [Google Scholar]
  23. Hutchinson D. K.; Fuchs P. L. Stereoselective, chemodirected formal SN2’ addition of organometallic reagents to β’-amino cyclopentenyl sulfone derivatives. J. Am. Chem. Soc. 1985, 107, 6137. 10.1021/ja00307a069. [DOI] [Google Scholar]
  24. Hutchinson D. K.; Fuchs P. L. J. Am. Chem. Soc. 1987, 109, 4755. 10.1021/ja00249a068. [DOI] [Google Scholar]
  25. Conrad P. C.; Kwiatkowski P. L.; Fuchs P. L. Rapid access to a series of highly functionalized α,β-unsaturated cyclopentenones. A caveat on aminospirocyclization. J. Org. Chem. 1987, 52, 586. 10.1021/jo00380a019. [DOI] [Google Scholar]
  26. Hutchinson D. K.; Fuchs P. L. Amelioration of the conjugate addition chemistry of a-alkoxycopper reagents: Application to the stereospecific synthesis of C-glycosides. J. Am. Chem. Soc. 1987, 109, 4930. 10.1021/ja00250a029. [DOI] [Google Scholar]
  27. Burkholder T. P.; Fuchs P. L. Total synthesis of dl-Cephalotaxine. The first example of an intramolecular 4 + 2 cycloaddition when the dienophile has been delivered from the face opposite to the tethering moiety. J. Am. Chem. Soc. 1988, 110, 2341. 10.1021/ja00215a076. [DOI] [Google Scholar]
  28. Burkholder T. P.; Fuchs P. L. Total synthesis of the Cephalotaxus alkaloids dl-Cephalotaxine, dl-11-hydroxycephalotaxine, and dl-Drupacine. J. Am. Chem. Soc. 1990, 112, 9601. 10.1021/ja00182a019. [DOI] [Google Scholar]
  29. Sawyer J. S.; Kucerovy A.; Macdonald T. L.; McGarvey G. J. Physical properties and synthetic utility of α-alkoxyorganolithium species as studied through ligand selectivity in tin-lithium exchange. J. Am. Chem. Soc. 1988, 110, 842. 10.1021/ja00211a024. [DOI] [Google Scholar]
  30. Di Bussolo V.; Fiasella A.; Romano M. R.; Favero L.; Pineschi M.; Crotti P. Stereoselective synthesis of 2,3-unsaturated-aza-O-glycosides via new diastereoisomeric N-Cbz-imino glycal-derived allyl epoxides. Org. Lett. 2007, 9, 4479. 10.1021/ol701836a. [DOI] [PubMed] [Google Scholar]
  31. Buchwald S. L.; Nielsen R. B.; Dewan J. C. Synthesis of (alkoxymethyl)zirconocene chlorides: stereochemistry of carbon-carbon bond formation in a zirconocene-Wittig rearrangement. Organometallics 1989, 8, 1593. 10.1021/om00109a002. [DOI] [Google Scholar]
  32. Rim C.; Son D. Y. Transmetalation as a route to novel styryllithium reagents. Org. Lett. 2003, 5, 3443. 10.1021/ol035193k. [DOI] [PubMed] [Google Scholar]
  33. Seyferth D.; Weiner M. A.; Vaughan L. G.; Raab G.; Welch D. E.; Cohen H. M.; Alleston D. L. Transmetalation reactions as a source of new organolithium reagent work at M.I.T. Bull. Soc. Chim. Fr. 1963, 1364. [Google Scholar]
  34. Halterman R. L.; Tretyakov A. Synthesis of camphor-derived chiral cyclopentadienes via the Nazarov cyclization: Preparation of chiral bis(cyclopentadienyl)zirconium and -titanium dicclorides. Tetrahedron 1995, 51, 4371. 10.1016/0040-4020(94)01126-K. [DOI] [Google Scholar]
  35. Yang M.; Ye W.; Schneller S. W. Preparation of carbocyclic S-adenosylazamethionine accompanied by a practical synthesis of (−)-aristeromycin. J. Org. Chem. 2004, 69, 3993. 10.1021/jo040119g. [DOI] [PubMed] [Google Scholar]
  36. Broggi J.; Kumamoto H.; Berteina-Raboin S.; Nolan S. P.; Agrofoglio L. A. Click azido-alkyne cyclosddition for the synthesis of D-1,4-disubstituted triazolo-carbanucleosides. Eur. J. Org. Chem. 2009, 2009, 1880. 10.1002/ejoc.200801124. [DOI] [Google Scholar]
  37. Coppi D. I.; Salomone A.; Perna F. M.; Capriati V. 2-Lithiated-2-phenyloxetane: a new attractive synthon for the preparation of oxetane derivatives. Chem. Commun. 2011, 47, 9918. 10.1039/c1cc13670d. [DOI] [PubMed] [Google Scholar]
  38. García Ruano J. L.; Alemán J.; Marzo L.; Alvarado C.; Tortosa M.; Díaz-Tendero S.; Fraile S. Arylsulfonylacetylenes as alkylating reagents of Csp2-H bonds activated with lithium bases. Angew. Chem., Int. Ed. 2012, 51, 2712. 10.1002/anie.201107821. [DOI] [PubMed] [Google Scholar]
  39. García Ruano J. L.; Alemán J.; Marzo L.; Alvarado C.; Tortosa M.; Díaz-Tendero S.; Fraile S. Expanding the scope of arylsulfonylacetylenes as alkylating reagents and mechanistic insights in the formation of Csp2 – Csp and Csp3-Csp bonds from organolithiums. Chem. - Eur. J. 2012, 18, 8414. 10.1002/chem.201200939. [DOI] [PubMed] [Google Scholar]
  40. Dey S.; Garner P. Synthesis of tert-butoxycarbonyl(Boc)-protected purines. J. Org. Chem. 2000, 65, 7697. 10.1021/jo000983i. [DOI] [PubMed] [Google Scholar]
  41. Yin X.; Li W.; Schneller S. W. An efficient Mitsunobu coupling to adenine-derived carbocyclic nucleosides. Tetrahedron Lett. 2006, 47, 9187. 10.1016/j.tetlet.2006.10.126. [DOI] [Google Scholar]
  42. Mitsunobu O. The use of diethylazodicarboxylate ant triphenylphosphine in synthesis and transformation of natural products. Synthesis 1981, 1981, 1. 10.1055/s-1981-29317. [DOI] [Google Scholar]
  43. Madec D.; Férézou J.-P. The application of [γ-(silyloxy)allylidene]ditin to the efficient synthesis of the chromophore of the Neocarzinostatin dihydroxycyclopentene-based dienediyne core. Eur. J. Org. Chem. 2006, 2006, 92. 10.1002/ejoc.200500353. [DOI] [Google Scholar]
  44. Tius M. A. Xenon difluoride in synthesis. Tetrahedron 1995, 51, 6605. 10.1016/0040-4020(95)00362-C. [DOI] [Google Scholar]
  45. Yu W.; Mei Y.; Kang Y.; Hua Z.; Jin Z. Improved procedure for the oxidative cleavage of olefins by OsO4-NaIO4. Org. Lett. 2004, 6, 3217. 10.1021/ol0400342. [DOI] [PubMed] [Google Scholar]
  46. Korba B. E.; Milman G. A cell culture assay for compounds which inhibit hepatitis B virus replication. Antiviral Res. 1991, 15, 217–228. 10.1016/0166-3542(91)90068-3. [DOI] [PubMed] [Google Scholar]
  47. Innaimo S. F.; Seifer M.; Bisacchi G. S.; Standring D. N.; Zahler R.; Colonno R. J. Identification of BMS-200475 as a potent and selective inhibitor of hepatitis B virus. Antimicrob. Agents Chemother. 1997, 41, 1444–1448. 10.1128/AAC.41.7.1444. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Aoki M.; Hayashi H.; Rao K. V.; Das D.; Higashi-Kuwata N.; Bulut H.; Aoki-Ogata H.; Takamatsu Y.; Yedidi R. S.; Davis D. A.; Hattori S.; Nishida N.; Hasegawa K.; Takamune N.; Nyalapatla P. R.; Osswald H. L.; Yarchoan R.; Misumi S.; Ghosh A. K.; Mitsuya H. A novel central nervous system-penetrating protease inhibitor overcomes human immunodeficiency virus 1 resistance with unprecedented aM to pM potency.A novel CNS-Penetrating protease inhibitor overcomes HIV-1 resistance with unprecedented potency. eLife 2017, 6, e28020 10.7554/eLife.28020. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Takamatsu Y.; Tanaka Y.; Kohgo S.; Murakami S.; Singh K.; Das D.; Venzon D. J.; Amano M.; Kuwata N.; Aoki M.; Delino N. S.; Hayashi S.; Takahashi S.; Haraguchi K.; Sarafianos S. G.; Maeda K.; Mitsuya H. 4’-Modified Nucleoside Analogs: Potent Inhibitors Active against Entecavir-resistant HBV. Hepatology 2015, 62, 1024–1036. 10.1002/hep.27962. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Kassianides C.; Hoofnagle J. H.; Miller R. H.; Doo E.; Ford H.; Broder S.; Mitsuya H. Inhibition of duck hepatitis virus replication by 2’, 3′-dideoxycytidine: A potent inhibitor of reverse transcriptase. Gastroenterology 1989, 97, 1275–1280. 10.1016/0016-5085(89)91699-5. [DOI] [PubMed] [Google Scholar]
  51. Yasutake Y.; Hattori S.-I.; Hayashi H.; Matsuda K.; Tamura N.; Kohgo S.; Maeda K.; Mitsuya H. (2018) HIV-1 with HBV-associated Q151M substitution in RT becomes highly susceptible to entecavir: structural insights into HBV-RT inhibition by entecavir. Sci. Rep. 2018, 8, 1624. 10.1038/s41598-018-19602-9. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

ml8b00374_si_001.pdf (9MB, pdf)

Articles from ACS Medicinal Chemistry Letters are provided here courtesy of American Chemical Society

RESOURCES