Abstract
Piperazine scaffolds are amongst the most extensively used backbones
in medicinal chemistry and many bioactive compounds are built upon
this template. The physicochemical properties and the three-dimensional
structures of the different piperazine chemotypes are of utmost
importance to understanding its biological activities. Knowing the
synthetic access to this chemical space of piperazines is of great
importance to designing compounds with better properties. Isocyanide-based
multicomponent reactions (IMCRs) allow for the truly convergent
and efficient access to not less than 35 different piperazine derived
scaffolds. These are reviewed, and their scopes and limitations
are discussed.
1 Piperazine Scaffolds in Chemistry and Medicine
2 Chemical Space of Piperazines via Isocyanide-Based Multicomponent
Reactions
3 Monocyclic Piperazines
3.1 Piperazine
3.2 Ketopiperazine
3.3 2,5-Diketopiperazine
3.4 2,6-Diketopiperazine
4 Bicyclic Fused Piperazines
5 Polycyclic Fused Piperazines
6 Introduction of the Piperazine Moiety via a Starting Material
7 Conclusions and Outlook
Key words
piperazine - diketopiperazine - heterocycles - multicomponent reaction - isocyanide
References
1 Wishart DS.
Knox C.
Guo AC.
Cheng D.
Shrivastava S.
Tzur D.
Gautam B.
Hassanali M.
Nucleic Acids Res.
2008,
36:
D901
2 Borio P.
Minerva
Farm.
1953,
2:
141
3 Khoury, K.; Dömling, A.; ChemMedChem in press.
4 Dömling, A.; Wang, K.; Wang,
W. Chem. Rev. submitted for publication.
5 Wang W.
Herdtweck E.
Dömling A.
Chem.
Commun.
2010,
46:
770
6 Pirali T.
Callipari G.
Ercolano E.
Genazzani AA.
Giovenzana GB.
Tron GC.
Org.
Lett.
2008,
10:
4199
7 Dömling A.
Beck B.
Fuchs T.
Yazbak A.
J. Comb. Chem.
2006,
8:
872
8 Dömling A.
Ugi I.
Angew. Chem.
Int. Ed.
2000,
39:
3169
8 Isonitrile Chemistry
Ugi I.
Academic Press;
New
York:
1971.
9a El Kaïm L.
Grimaud L.
Oble J.
Angew.
Chem. Int. Ed.
2005,
44:
7961
9a El Kaïm L.
Grimaud L.
Mol. Divers.
2010, in
press; DOI: 10.1007/s11030-009-9175-3
10 Fischer PM.
J.
Pept. Sci.
2003,
9:
9
11 Horton DA.
Bourne GT.
Smythe ML.
Mol. Divers.
2002,
5:
289
12 Martins MB.
Carvalho I.
Tetrahedron
2007,
63:
9923
13 Dinsmore CJ.
Beshore DC.
Tetrahedron
2002,
58:
3297
14 Rossen K.
Sager J.
DiMichele LM.
Tetrahedron
Lett.
1997,
38:
3183
15 Rossen K.
Pye PJ.
DiMichele LM.
Volante RP.
Reider PJ.
Tetrahedron Lett.
1998,
39:
6823
16 Keung W.
Bakir F.
Patron AP.
Rogers D.
Priest CD.
Darmohusodo V.
Tetrahedron Lett.
2004,
45:
733
17 Shaabani A.
Maleki A.
Moghimi-Rad J.
J.
Org. Chem.
2007,
72:
6309
18 Kysil V.
Tkachenko S.
Khvat A.
Williams C.
Tsirulnikov S.
Churakova M.
Ivachtchenko A.
Tetrahedron
Lett.
2007,
48:
6239
19 Kysil V.
Khvat A.
Tsirulnikov S.
Tkachenko S.
Williams C.
Churakova M.
Ivachtchenko A.
Eur.
J. Org. Chem.
2010,
1525
20 Ilyin AP.
Trifilenkov AS.
Kurashvili ID.
Krasavin M.
Ivachtchenko AV.
J. Comb. Chem.
2005,
7:
360
21 Cheng J.-F.
Chen M.
Arrhenius T.
Nadzan A.
Tetrahedron Lett.
2002,
43:
6293
22 Faggi C.
Garcia-Valverde M.
Marcaccini S.
Pepino R.
Pozo MC.
Synthesis
2003,
1553
23 Illgen K.
Nerdinger S.
Fuchs T.
Friedrich C.
Weber L.
Herdtweck E.
Synlett
2004,
53
24 Hulme C.
Peng J.
Louridas B.
Menard P.
Krolikowski P.
Kumar NV.
Tetrahedron Lett.
1998,
39:
8047
25 Hulme C.
Cherrier MP.
Tetrahedron Lett.
1999,
40:
5295
26 Szardenings AK.
Burkoth TS.
Lu HH.
Tien DW.
Campbell DA.
Tetrahedron
1997,
53:
6573
27 Szardenings AK.
Antonenko V.
Campbell DA.
DeFrancisco N.
Ida S.
Shi LH.
Sharkov N.
Tien D.
Wang YW.
Navre M.
J. Med. Chem.
1999,
42:
1348
28 Cho S.
Keum G.
Kang SB.
Han SY.
Kim Y.
Mol. Divers.
2003,
6:
283
29a Liddle J.
Allen MJ.
Borthwick AD.
Brooks DP.
Davies DE.
Edwards RM.
Exall AM.
Hamlett C.
Irving WR.
Mason AM.
McCafferty GP.
Nerozzi F.
Peace S.
Philp J.
Pollard D.
Pullen MA.
Shabbir SS.
Sollis SL.
Westfall TD.
Woollard PM.
Wu C.
Hickey DMB.
Bioorg. Med. Chem. Lett.
2008,
18:
90
29b Hopkins AL.
Groom CR.
Alex A.
Drug Discovery Today
2004,
9:
430
30 Sollis SL.
J.
Org. Chem.
2005,
70:
4735
31a Borthwick AD.
Davies DE.
Exall AM.
Hatley RJD.
Hughes JA.
Irving WR.
Livermore DG.
Sollis SL.
Nerozzi F.
Valko KL.
Allen MJ.
Perren M.
Shabbir SS.
Woollard PM.
Price MA.
J. Med. Chem.
2006,
49:
4159
31b Borthwick AD.
Davies DE.
Exall AM.
Livermore DG.
Sollis SL.
Nerozzi F.
Allen MJ.
Perren M.
Shabbir SS.
Woollard PM.
Wyatt PG.
J.
Med. Chem.
2005,
48:
6956
31c Wyatt PG.
Allen MJ.
Borthwick AD.
Davies DE.
Exall AM.
Hatley RJD.
Irving WR.
Livermore DG.
Miller ND.
Nerozzi F.
Sollis SL.
Szardenings AK.
Bioorg.
Med. Chem. Lett.
2005,
15:
2579
31d Obrecht R.
Toure S.
Ugi I.
Heterocycles
1984,
21:
271
32 Rhoden CRB.
Westermann B.
Wessjohann LA.
Synthesis
2008,
2077
33 Demarest JF.
Sparks SS.
Schell K.
Shibayama S.
McDanal CB.
Fang L.
Adkison KK.
Shachoy-Clark A.
Piscitelli SC.
J. Clin. Pharmacol.
2008,
48:
1179
34 Habashita H.
Kokubo M.
Hamano S.
Hamanaka N.
Toda M.
Shibayama S.
Tada H.
Sagawa K.
Fukushima D.
Maeda K.
Mitsuya H.
J.
Med. Chem.
2006,
49:
4140
35 Nishizawa R.
Nishiyama T.
Hisaichi K.
Matsunaga N.
Minamoto C.
Habashitaa H.
Takaoka Y.
Toda M.
Shibayama S.
Tada H.
Sagawa K.
Fukushima D.
Maeda K.
Mitsuya H.
Bioorg. Med. Chem. Lett.
2007,
17:
727
36a Campbell J.
Blackwell HE.
J.
Comb. Chem.
2009,
11:
1094
36b Dikmans A.
Beutling U.
Schmeisser E.
Thiele S.
Frank R.
QSAR
Comb. Sci.
2006,
25:
1069
37 Lin Q.
Blackwell HE.
Chem. Commun.
2006,
2884
38a Marcaccini S.
Pepino R.
Pozo MC.
Tetrahedron Lett.
2001,
42:
2727
38b Marcaccini S.
Torroba T.
Nat. Protocols
2007,
2:
632
39 Bruttomesso AC.
Eiras J.
Ramirez JA.
Galagovsky LR.
Tetrahedron Lett.
2009,
50:
4022
40 Hulme C.
Morrissette MM.
Volz FA.
Burns CJ.
Tetrahedron
Lett.
1998,
39:
1113
41 Hulme C.
Chappeta S.
Dietrich J.
Tetrahedron
Lett.
2009,
50:
4054
42 Rhoden CRB.
Rivera DG.
Kreye O.
Bauer AK.
Westermann B.
Wessjohann LA.
J.
Comb. Chem.
2009,
11:
1078
43a Kreye O.
Westermann B.
Wessjohann LA.
Synlett
2007,
3188
43b Gilley CB.
Buller MJ.
Kobayashi Y.
Org. Lett.
2007,
9:
3631
44a Constabel F.
Ugi I.
Tetrahedron
2001,
57:
5785
44b Ugi IK.
Ebert B.
Horl W.
Chemosphere
2001,
43:
75
45 Ilyn AP.
Trifilenkov AS.
Tsirulnikov SA.
Kurashvily ID.
Ivachtchenko AV.
J. Comb. Chem.
2005,
7:
806
46 Tsirulnikov S.
Nikulnikov M.
Kysil V.
Ivachtchenko A.
Krasavin M.
Tetrahedron
Lett.
2009,
50:
5529
47 Ilyn AP.
Kuzovkova JA.
Potapov VV.
Shkirando AM.
Kovrigin DI.
Tkachenko SE.
Ivachtchenko AV.
Tetrahedron
Lett.
2005,
46:
881
48 Akritopoulou-Zanze I.
Gracias V.
Djuric SW.
Tetrahedron
Lett.
2004,
45:
8439
49 Nixey T.
Kelly M.
Hulme C.
Tetrahedron
Lett.
2000,
41:
8729
50 Umkehrer M.
Kolb J.
Burdack C.
Ross G.
Hiller W.
Tetrahedron
Lett.
2004,
45:
6421
51a Schöllkopf U.
Liebigs Ann. Chem.
1976,
1444
51b Bienaymé H.
Bouzid K.
Tetrahedron
Lett.
1998,
39:
2735
52 Nikulnikov M.
Tsirulnikov S.
Kysil V.
Ivachtchenko A.
K-Rasavin M.
Synlett
2009,
260
53 Nixey T.
Tempest P.
Hulme C.
Tetrahedron
Lett.
2002,
43:
1637
54 Zhang W.
Tempest P.
Tetrahedron Lett.
2004,
45:
6757
55 Neochoritis C.
Idou-Stephanatou JS.
Tsoleridis CA.
Synlett
2009,
302
56 Oblé J.
El Kaïm L.
Gizzi M.
Grimaud L.
Heterocycles
2007,
73:
503
57 Shaabani A.
Maleki A.
Mofakham H.
Khavasi HR.
J. Comb.
Chem.
2008,
10:
323
58 Li J.
Liu YJ.
Li CJ.
Jia XS.
Tetrahedron Lett.
2009,
50:
6502
59 Hili R.
Rai V.
Yudin AK.
J.
Am. Chem. Soc.
2010,
132:
2889
60 Golebiowski A.
Klopfenstein SR.
Shao X.
Chen JJ.
Colson AO.
Grieb AL.
Russell AF.
Org. Lett.
2000,
2:
2615
61 El Kaïm L.
Gageat M.
Gaultier L.
Grimaud L.
Synlett
2007,
500
62 Liu HX.
Dömling A.
J. Org. Chem.
2009,
74:
6895
63 Liu, H. X.; William, S.; Herdtweck,
E; Botros, S.; Dömling, A. Bioorg.
Med. Chem. submitted for publication.
64 Cao, H.; Liu, H. X.; Dömling,
A. Chem. Eur. J. in press
65 Franckevicius V.
Longbottom DA.
Turner RM.
Ley SV.
Synthesis
2006,
3215
67a Mayer J.
Umkehrer M.
Kalinski C.
Ross G.
Kolb J.
Burdack C.
Hiller W.
Tetrahedron Lett.
2005,
46:
7393
66b Dömling A.
Beck B.
Magnin-Lachaux M.
Tetrahedron Lett.
2006,
47:
4289
67 Kalinski C.
Umkehrer M.
Gonnard S.
Jäger N.
Ross G.
Hiller W.
Tetrahedron Lett.
2006,
47:
2041
68 Sandulenko Y.
Komarov A.
Rufanov K.
Krasavin M.
Tetrahedron Lett.
2008,
49:
5990
69 Takiguchi S.
Iizuka T.
Kumakura Y.-S.
Murasaki K.
Ban N.
Higuchi K.
Kawasaki T.
J. Org.
Chem.
2010,
75:
1126
70a Semple JE.
Wang PC.
Lysenko Z.
Joullié MM.
J. Am. Chem. Soc.
1980,
102:
7505
70b Endo A.
Yanagisawa A.
Abe M.
Tohma S.
Kan T.
Fukuyama T.
J. Am. Chem. Soc.
2002,
124:
6552
70c Mori K.
Rikimaru K.
Kan T.
Fukuyama T.
Org. Lett.
2004,
6:
3095
70d Rikimaru K.
Mori K.
Kan T.
Fukuyama T.
Chem. Commun.
2005,
394
71a Groebke K.
Weber L.
Mehlin F.
Synlett
1998,
661
71b Bienayme H.
Bouzid K.
Angew. Chem. Int. Ed.
1998,
37:
2234
71c Backburn C.
Tetrahedron
Lett.
1998,
39:
5469
71d Kercher T.
Rao C.
Bencsik JR.
Josey JA.
72 Giovenzana GB.
Tron GC.
Paola SD.
Menegotto IG.
Pirali T.
Angew.
Chem. Int. Ed.
2006,
45:
1099
73a Srivastava S.
Beck B.
Herdtweck E.
Khoury K.
Dömling A.
Heterocycles
2009,
77:
731
73b Beck B.
Srivastava S.
Khoury K.
Herdtweck E.
Dömling A.
Mol. Divers.
2010, in press; DOI: 10.1007/s11030-010-9249-2
74 Rivera DG.
Wessjohann LA.
J. Am. Chem. Soc.
2009,
131:
3721
75 Musonda CC.
Little S.
Yardley V.
Chibale K.
Bioorg. Med. Chem. Lett.
2007,
17:
4733
76 Sörensen B.
Rohde J.
Wang J.
Fung S.
Monzon K.
Chiou W.
Pan L.
Deng X.
Stolarik D.
Frevert EU.
Jacobson P.
Link JT.
Bioorg.
Med. Chem. Lett.
2006,
16:
5958
77 Akritopoulou-Zanze I, Wakefield BD, Mack H, Turner SC, Gasiecki AF, Gracias VJ, Sarris K, Kalvin DM, Michmerhuizen MJ, Shuai Q, Patel JR, Bakker M, Teusch N, Johnson ET, Kovar PJ, Djuric SW, Long AJ, Vasudevan A, Hobson A, St. John Moore N, Wang L, George D, Li B, and Frank K. inventors; US
Patent 65727.
78 Hulme C, Tempest P, Ma V, Nixey T, and Balow G. inventors; US Patent 26021.
