Abstract
A review of the Michael-type addition as one of the convenient
synthetic methods to N-functionalisation of the uracil ring - against
the background of other typical alkylation methods - is presented.
The topic of N1- versus N3-regioselectivity in alkylation reactions
is emphasised since this differentiation is essential in the various,
especially medicinal, applications of substituted uracils. Specifically,
the addition of uracils to acrylic acceptors at the N1-position
is frequently used in the first stage of the synthesis of pyrimidinic
acyclic nucleosides. In turn, the N3-position of the uracil ring
is useful in further transformations, like anchoring of biologically
active fragments in conjugates for radiochemotherapy or carriage
of covalently bonded drug molecules. Nevertheless, N3-substituted
derivatives of pyrimidine nucleosides can, themselves, play various
therapeutic roles. Fundamental theoretical premises are also detailed,
with regard to the rationale behind the orientation of alkylation.
1 Uracils in Medicine
2 Reactivity of the Uracil Ring
2.1 Electronic Structure and Tautomerism
2.2 Uracil Derivatives as N -H Acids
3 Alkylation of Uracils
3.1 Alkylation of Uracils in the Formation of N-Glycosidic Bonds
3.2 Synthesis of Acyclic Nucleosides
3.3 Alkylation of Uracils with Selected Electrophiles
3.4 N1- and N3-Alkylation of Uracils via Michael-type Addition
3.5 Synthesis of Michael-type Uracil N3 Adduct Analogues
4 Conclusions and Perspectives
Key words
nucleobases - nucleosides - Michael addition - alkylation - regioselectivity
References
1 Longley DB.
Harkin DP.
Johnston PG.
Nat. Rev. Cancer
2003,
3:
330
2 Al Safarjalani ON.
Zhou XJ.
Ras RH.
Shi J.
Schinazi RF.
Naguib FN.
El Kouni MH.
Cancer Chemother.
Phamacol.
2005,
55:
541
3 Kennedy BJ.
Torkelson JL.
Torlakovic E.
Cancer
1999,
85:
2265
4 Porter DJ.
Chestunt WG.
Merril BM.
Spector T.
J. Biol. Chem.
1992,
267:
5236
5 Seth A.
Misra A.
Umrigar D.
Pharm. Dev.
Technol.
2004,
9:
277
6 Otto S.
J.
Intraven. Nurs.
1998,
21:
335
7 Hertel LW.
Boder GB.
Kroin JS.
Rinzel SM.
Poore GA.
Todd GC.
Grindey GB.
Cancer Res.
1990,
50:
4417
8 De Clercq E.
Nature
Rev. Microbiol.
2004,
2:
704
9 Dolman NP.
More JCA.
Alt A.
Knauss JL.
Troop HM.
Bleakman D.
Collingridge GL.
Jane DE.
J. Med. Chem.
2006,
49:
2579
10 Maruyama T.
Kozai S.
Shimizu T.
Kimura T.
Watanabe K.
Yamamoto I.
Nucleic Acids Res.
2003,
Suppl.
3:
25
11 Maruyama T.
Kozai S.
Demizu Y.
Witvrouw M.
Pannecouque C.
Balzarini J.
Snoecks R.
Andrei G.
De Clercq E.
Chem.
Pharm. Bull.
2006,
54:
325
12 Daly JS.
Giehl TJ.
Brown NC.
Zhi Ch.
Wright GE.
Ellison RT.
Antimicrob.
Agents Chemother.
2000,
2217
13 Aspland SE.
Ballatore C.
Castillo R.
Desharnais J.
Eustaquio T.
Goelet P.
Guo Z.
Li Q.
Nelson D.
Sun Ch.
Castellino AJ.
Newman MJ.
Bioorg. Med. Chem. Lett.
2006,
16:
5194
14 Tjarks W.
Tiwari R.
Byun Y.
Narayanasamy S.
Barth RF.
Chem.
Commun.
2007,
4978
15 Mukhopadhyay U.
Soghomonyan S.
Yeh HH.
Flores LG.
Shavrin A.
Volgin AY.
Gelovani JG.
Alauddin MM.
Nucl.
Med. Biol.
2008,
35:
697
16 Undheim K.
Benneche T.
Pyrimidines
and Their Benzo Derivatives, In Comprehensive
Heterocyclic Chemistry
Vol. VI:
Kratitzky AR.
Rees CW.
Scriven EFV.
Pergamon;
Oxford:
1996.
p.97
17 Shishkin OV.
Gorb L.
Leszczynski J.
Int.
J. Mol. Sci.
2000,
1:
17
18 Gould IR.
Hillier IH.
J. Chem. Soc., Perkin
Trans. 2
1990,
329
19 Katritkzy AR.
Karelson M.
J. Am. Chem. Soc.
1991,
113:
1561
20 Borkovec M.
Koper GJM.
Anal. Chem.
2000,
72:
3272
21 Hague DN.
Moreton AD.
J. Chem. Soc., Perkin
Trans. 2
1994,
265
22 Chandra AK.
Uchimaru T.
Zeegers-Huyskens T.
J.
Mol. Struct.
2002,
605:
213
23 Suwiński J.
Walczak K.
Synthesis
2001,
225
24 Jang YH.
Sowers LC.
Çagin T.
Goddard WA.
J. Phys. Chem. A
2001,
105:
274
25 Ganguly S.
Kundu KK.
Can. J. Chem.
1994,
72:
1120
26 Yoshida M.
Makino K.
Morita H.
Terato H.
Ohyama Y.
Ide H.
Nucleic Acids Res.
1997,
25:
1570
27 Mikstis UJ.
Smolova NT.
Veveris AV.
Zh. Anal. Khim.
1977,
32:
362
28 Privat EJ.
Sowers LC.
Mutat. Res. Fund.
Mol. Mech. Mutagen.
1996,
354:
151
29 Zhuk RA.
Popelis YuA.
Hiller SA.
Khim. Geterotsikl. Soedin.
1970,
6:
546
30 Jonáš J.
Gut J.
Collect. Czech.
Chem. Commun.
1962,
27:
716
31 Bensaude O.
Aubard J.
Dreyfus M.
Dodin G.
Dubois JE.
J.
Am. Chem. Soc.
1978,
100:
2823
32 Driggers PH.
Beattie KL.
Biochemistry
1988,
27:
1729
33 Yu H.
Eritja R.
Bloom LB.
Goodman MF.
J. Biol. Chem.
1993,
268:
15935
34 Kurinovich MA.
Lee JK.
J. Am. Soc. Mass Spectrom.
2002,
13:
985
35 Drohat AC.
Strivers JT.
J. Am. Chem. Soc.
2000,
122:
1840
36 Cleaves HJ.
Astrobiology
2002,
2:
403
37 Wempen I.
Fox JJ.
J. Am. Chem. Soc.
1964,
86:
2474
38 Luyten I.
Pankiewicz KW.
Watanabe KA.
Chattopadhyaya J.
J.
Org. Chem.
1998,
63:
1033
39 Psoda A.
Kazimierczuk Z.
Shugar D.
J.
Am. Chem. Soc.
1974,
96:
6832
40 Kimura E.
Kitamura H.
Koike T.
Shiro M.
J. Am. Chem. Soc.
1997,
119:
10909
41 Wierzchowski KL.
Litońska E.
Shugar D.
J.
Am. Chem. Soc.
1965,
87:
4621
42 Montgomery JA.
Thomas HJ.
J. Org. Chem.
1963,
28:
2304
43 Robins MJ.
Robins RK.
J. Am. Chem. Soc.
1965,
87:
4934
44 Walczak K.
Pedersen EB.
Synthesis
1991,
959
45 Chow K.
Danishefsky S.
J. Org. Chem.
1990,
55:
4211
46 Cusack NJ.
Hildick BJ.
Robinson DH.
Rugg PW.
Shaw G.
J. Chem. Soc., Perkin Trans. 1
1973,
1720
47 Gondela A.
Walczak K.
Carbohydr. Res.
2005,
340:
1379
48 Vorbrueggen H.
Ruh-Pohlenz C.
Org. React.
2000,
55:
1
49 El-Barbary AA.
Khodair AI.
Pedersen EB.
J. Org. Chem.
1993,
58:
5994
50 Koshkin AA.
Singh SK.
Nielsen P.
Rajwanshi VK.
Kumar R.
Meldgaard M.
Olsen CE.
Wengel J.
Tetrahedron
1998,
54:
3607
51 Zemlicka J.
Allenols
derived from nucleic acid bases - A new class of anti-HIV agents:
Chemistry and biological activity, In Nucleosides and Nucleotides
as Antitumor and Antiviral Agents
Chu CK.
Baker DC.
Plenum Press;
New
York:
1993.
p.73
52 Lin TS.
Liu ACh.
Synthesis and anticancer
and antiviral activity of certain pyrimidine nucleoside analogues, In Nucleosides
and Nucleotides as Antitumor and Antiviral Agents
Chu CK.
Baker DC.
Plenum
Press;
New York:
1993.
p.177
53 Martin JC.
Smee DF.
Verheyden JPH.
J. Org. Chem.
1985,
50:
755
54 Lee K.-H.
Chen Y.-L.
Huang B.-R.
Zhu Q.-Y.
Chou T.-Ch.
Tzeng Ch.-Ch.
Nucleosides, Nucleotides
Nucleic Acids
1991,
10:
1407
55 El Kattan Y.
Gosselin G.
Imbach J. L.
J.
Chem. Soc., Perkin Trans. 1
1994,
1289
56 Harnden MR.
Wyatt PG.
Boyd MR.
Sutton D.
J. Med. Chem.
1990,
33:
187
57 Wong JL.
Fuchs DS.
J. Org. Chem.
1971,
36:
848
58 Wong JL.
Fuchs DS.
J. Org. Chem.
1970,
35:
3786
59 Nawrot B.
Michalak O.
Olejniczak S.
Wieczorek MW.
Lis T.
Stec WJ.
Tetrahedron
2001,
57:
3979
60 Copik A.
Suwiński J.
Walczak K.
Bronikowska J.
Czuba Z.
Król W.
Nucleosides, Nucleotides
Nucleic Acids
2002,
21:
377
61 Jane DE.
Hoo K.
Kamboj R.
Deverill M.
Bleakman D.
Mandelzys A.
J. Med. Chem.
1997,
40:
3645
62 Krivogonov VP.
Myshkin VA.
Kozlova GG.
Chernyshenko YuN.
Savlukov AI.
Plechev VV.
Ibatullina RB.
Abdrakhmanov IB.
Spirikhin LV.
Russ.
J. Org. Chem.
2006,
42:
1711
63 Orgel LE.
Lohrmann R.
Acc. Chem. Res.
1974,
7:
368
64 Paegle RA.
Lidak MYu.
Shvachkin YuP.
Khim. Geterotsikl. Soedin.
1966,
2:
316
65 Crippa S.
Di Gennaro P.
Lucini R.
Orlandi M.
Rindone B.
Gazz.
Chim. Ital.
1993,
123:
197
66 Cai Y.
Wu JY.
Wang N.
Sun X.-F.
Lin X.-F.
Chin. Chem.
Lett.
2004,
15:
594
67 Cai Y.
Sun X.-F.
Wang N.
Lin X.-F.
Synthesis
2004,
671
68 Xu J.-M.
Qian Ch.
Liu B.-K.
Wu Q.
Lin X.-F.
Tetrahedron
2007,
63:
986
69 Peshakova L.
Kalcheva V.
Z. Chem.
1990,
30:
438
70 Peshakova L.
Kalcheva V.
Madzhova L.
Izv.
Khim.
1991,
24:
91
71 Guillarme S.
Legoupy S.
Aubertin A.-M.
Olicard C.
Bourgougnon N.
Huet F.
Tetrahedron
2003,
59:
2177
72 Esposito A.
Perino MG.
Taddei M.
Eur.
J. Org. Chem.
1999,
931
73 Ouchi T.
Jokei S.
Chikashita H.
J.
Heterocycl. Chem.
1982,
19:
935
74 Ouchi T.
Jokei S.
Fujie H.
Chikashita H.
J. Heterocycl. Chem.
1984,
21:
1023
75 Nollet AJH.
Koomen GJ.
Grose WFA.
Pandit UK.
Tetrahedron
Lett.
1969,
53:
4607
76 Scheiner P.
Geer A.
Bucknor A.-M.
Imbach J.-L.
Schinazi RF.
J.
Med. Chem.
1989,
32:
73
77 Dai H.-X.
Yao S.-P.
Wang J.
Biotechnol.
Lett.
2006,
28:
1503
78 Lazrek HB.
Khaïder H.
Rochdi A.
Barascut J.-L.
Imbach J.-L.
Tetrahedron
Lett.
1996,
37:
4701
79 Prévost N.
Rouessac F.
Tetrahedron Lett.
1997,
38:
4215
80 Prévost N.
Rouessac F.
Synth. Commun.
1997,
27:
2325
81 Chambers RW.
Biochemistry
1965,
4:
219
82 Ramzaeva N.
Rosemeyer H.
Leonard P.
Mühlegger K.
Bergmann F.
von der Eltz H.
Seela F.
Helv. Chim. Acta
2000,
83:
1108
83 Nollet AJH.
Pandit UK.
Tetrahedron
Lett.
1969,
53:
4605
84 Nováček A.
Lissnerová M.
Collect.
Czech. Chem. Commun.
1968,
33:
1003
85 Nováček A.
Collect. Czech. Chem. Commun.
1971,
36:
1964
86 Boncel S.
Walczak K.
Lett. Org. Chem.
2006,
3:
534
87 Boncel S.
Osyda D.
Walczak K.
Beilstein
J. Org. Chem.
2007,
3:
40
88 Kokko JP.
Mandell L.
Goldstein JH.
J.
Am. Chem. Soc.
1962,
84:
1042
89 Crystallographic data for this compound
were deposited in The Cambridge Crystallographic Data Centre under reference
number CCDC-656160.
90 Crystallographic data for this compound
were deposited in The Cambridge Crystallographic Data Centre under reference
number CCDC-728270.
91 Ueda T.
Fox JJ.
J. Org. Chem.
1964,
29:
1762
92 Jaime-Figueroa S.
Zamilpa A.
Guzmán A.
Morgans DJ.
Synth.
Commun.
2001,
31:
3739
93 Nagase T.
Seike K.
Shiraishi K.
Yamada Y.
Ozaki S.
Chem.
Lett.
1988,
1381
