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
<A NAME="RE26610SS-1">1 </A>
Wishart DS.
Knox C.
Guo AC.
Cheng D.
Shrivastava S.
Tzur D.
Gautam B.
Hassanali M.
Nucleic Acids Res.
2008,
36:
D901
<A NAME="RE26610SS-2">2 </A>
Borio P.
Minerva
Farm.
1953,
2:
141
<A NAME="RE26610SS-3">3 </A>
Khoury, K.; Dömling, A.; ChemMedChem in press.
<A NAME="RE26610SS-4">4 </A>
Dömling, A.; Wang, K.; Wang,
W. Chem. Rev. submitted for publication.
<A NAME="RE26610SS-5">5 </A>
Wang W.
Herdtweck E.
Dömling A.
Chem.
Commun.
2010,
46:
770
<A NAME="RE26610SS-6">6 </A>
Pirali T.
Callipari G.
Ercolano E.
Genazzani AA.
Giovenzana GB.
Tron GC.
Org.
Lett.
2008,
10:
4199
<A NAME="RE26610SS-7">7 </A>
Dömling A.
Beck B.
Fuchs T.
Yazbak A.
J. Comb. Chem.
2006,
8:
872
<A NAME="RE26610SS-8">8 </A>
Dömling A.
Ugi I.
Angew. Chem.
Int. Ed.
2000,
39:
3169
<A NAME="RE26610SS-8">8 </A>
Isonitrile Chemistry
Ugi I.
Academic Press;
New
York:
1971.
<A NAME="RE26610SS-9A">9a </A>
El Kaïm L.
Grimaud L.
Oble J.
Angew.
Chem. Int. Ed.
2005,
44:
7961
<A NAME="RE26610SS-9A">9a </A>
El Kaïm L.
Grimaud L.
Mol. Divers.
2010, in
press; DOI: 10.1007/s11030-009-9175-3
<A NAME="RE26610SS-10">10 </A>
Fischer PM.
J.
Pept. Sci.
2003,
9:
9
<A NAME="RE26610SS-11">11 </A>
Horton DA.
Bourne GT.
Smythe ML.
Mol. Divers.
2002,
5:
289
<A NAME="RE26610SS-12">12 </A>
Martins MB.
Carvalho I.
Tetrahedron
2007,
63:
9923
<A NAME="RE26610SS-13">13 </A>
Dinsmore CJ.
Beshore DC.
Tetrahedron
2002,
58:
3297
<A NAME="RE26610SS-14">14 </A>
Rossen K.
Sager J.
DiMichele LM.
Tetrahedron
Lett.
1997,
38:
3183
<A NAME="RE26610SS-15">15 </A>
Rossen K.
Pye PJ.
DiMichele LM.
Volante RP.
Reider PJ.
Tetrahedron Lett.
1998,
39:
6823
<A NAME="RE26610SS-16">16 </A>
Keung W.
Bakir F.
Patron AP.
Rogers D.
Priest CD.
Darmohusodo V.
Tetrahedron Lett.
2004,
45:
733
<A NAME="RE26610SS-17">17 </A>
Shaabani A.
Maleki A.
Moghimi-Rad J.
J.
Org. Chem.
2007,
72:
6309
<A NAME="RE26610SS-18">18 </A>
Kysil V.
Tkachenko S.
Khvat A.
Williams C.
Tsirulnikov S.
Churakova M.
Ivachtchenko A.
Tetrahedron
Lett.
2007,
48:
6239
<A NAME="RE26610SS-19">19 </A>
Kysil V.
Khvat A.
Tsirulnikov S.
Tkachenko S.
Williams C.
Churakova M.
Ivachtchenko A.
Eur.
J. Org. Chem.
2010,
1525
<A NAME="RE26610SS-20">20 </A>
Ilyin AP.
Trifilenkov AS.
Kurashvili ID.
Krasavin M.
Ivachtchenko AV.
J. Comb. Chem.
2005,
7:
360
<A NAME="RE26610SS-21">21 </A>
Cheng J.-F.
Chen M.
Arrhenius T.
Nadzan A.
Tetrahedron Lett.
2002,
43:
6293
<A NAME="RE26610SS-22">22 </A>
Faggi C.
Garcia-Valverde M.
Marcaccini S.
Pepino R.
Pozo MC.
Synthesis
2003,
1553
<A NAME="RE26610SS-23">23 </A>
Illgen K.
Nerdinger S.
Fuchs T.
Friedrich C.
Weber L.
Herdtweck E.
Synlett
2004,
53
<A NAME="RE26610SS-24">24 </A>
Hulme C.
Peng J.
Louridas B.
Menard P.
Krolikowski P.
Kumar NV.
Tetrahedron Lett.
1998,
39:
8047
<A NAME="RE26610SS-25">25 </A>
Hulme C.
Cherrier MP.
Tetrahedron Lett.
1999,
40:
5295
<A NAME="RE26610SS-26">26 </A>
Szardenings AK.
Burkoth TS.
Lu HH.
Tien DW.
Campbell DA.
Tetrahedron
1997,
53:
6573
<A NAME="RE26610SS-27">27 </A>
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
<A NAME="RE26610SS-28">28 </A>
Cho S.
Keum G.
Kang SB.
Han SY.
Kim Y.
Mol. Divers.
2003,
6:
283
29a </A>
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 </A>
Hopkins AL.
Groom CR.
Alex A.
Drug Discovery Today
2004,
9:
430
<A NAME="RE26610SS-30">30 </A>
Sollis SL.
J.
Org. Chem.
2005,
70:
4735
31a </A>
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 </A>
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 </A>
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 </A>
Obrecht R.
Toure S.
Ugi I.
Heterocycles
1984,
21:
271
<A NAME="RE26610SS-32">32 </A>
Rhoden CRB.
Westermann B.
Wessjohann LA.
Synthesis
2008,
2077
<A NAME="RE26610SS-33">33 </A>
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
<A NAME="RE26610SS-34">34 </A>
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
<A NAME="RE26610SS-35">35 </A>
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 </A>
Campbell J.
Blackwell HE.
J.
Comb. Chem.
2009,
11:
1094
36b </A>
Dikmans A.
Beutling U.
Schmeisser E.
Thiele S.
Frank R.
QSAR
Comb. Sci.
2006,
25:
1069
<A NAME="RE26610SS-37">37 </A>
Lin Q.
Blackwell HE.
Chem. Commun.
2006,
2884
38a </A>
Marcaccini S.
Pepino R.
Pozo MC.
Tetrahedron Lett.
2001,
42:
2727
38b </A>
Marcaccini S.
Torroba T.
Nat. Protocols
2007,
2:
632
<A NAME="RE26610SS-39">39 </A>
Bruttomesso AC.
Eiras J.
Ramirez JA.
Galagovsky LR.
Tetrahedron Lett.
2009,
50:
4022
<A NAME="RE26610SS-40">40 </A>
Hulme C.
Morrissette MM.
Volz FA.
Burns CJ.
Tetrahedron
Lett.
1998,
39:
1113
<A NAME="RE26610SS-41">41 </A>
Hulme C.
Chappeta S.
Dietrich J.
Tetrahedron
Lett.
2009,
50:
4054
<A NAME="RE26610SS-42">42 </A>
Rhoden CRB.
Rivera DG.
Kreye O.
Bauer AK.
Westermann B.
Wessjohann LA.
J.
Comb. Chem.
2009,
11:
1078
43a </A>
Kreye O.
Westermann B.
Wessjohann LA.
Synlett
2007,
3188
43b </A>
Gilley CB.
Buller MJ.
Kobayashi Y.
Org. Lett.
2007,
9:
3631
44a </A>
Constabel F.
Ugi I.
Tetrahedron
2001,
57:
5785
44b </A>
Ugi IK.
Ebert B.
Horl W.
Chemosphere
2001,
43:
75
<A NAME="RE26610SS-45">45 </A>
Ilyn AP.
Trifilenkov AS.
Tsirulnikov SA.
Kurashvily ID.
Ivachtchenko AV.
J. Comb. Chem.
2005,
7:
806
<A NAME="RE26610SS-46">46 </A>
Tsirulnikov S.
Nikulnikov M.
Kysil V.
Ivachtchenko A.
Krasavin M.
Tetrahedron
Lett.
2009,
50:
5529
<A NAME="RE26610SS-47">47 </A>
Ilyn AP.
Kuzovkova JA.
Potapov VV.
Shkirando AM.
Kovrigin DI.
Tkachenko SE.
Ivachtchenko AV.
Tetrahedron
Lett.
2005,
46:
881
<A NAME="RE26610SS-48">48 </A>
Akritopoulou-Zanze I.
Gracias V.
Djuric SW.
Tetrahedron
Lett.
2004,
45:
8439
<A NAME="RE26610SS-49">49 </A>
Nixey T.
Kelly M.
Hulme C.
Tetrahedron
Lett.
2000,
41:
8729
<A NAME="RE26610SS-50">50 </A>
Umkehrer M.
Kolb J.
Burdack C.
Ross G.
Hiller W.
Tetrahedron
Lett.
2004,
45:
6421
51a </A>
Schöllkopf U.
Liebigs Ann. Chem.
1976,
1444
51b </A>
Bienaymé H.
Bouzid K.
Tetrahedron
Lett.
1998,
39:
2735
<A NAME="RE26610SS-52">52 </A>
Nikulnikov M.
Tsirulnikov S.
Kysil V.
Ivachtchenko A.
K-Rasavin M.
Synlett
2009,
260
<A NAME="RE26610SS-53">53 </A>
Nixey T.
Tempest P.
Hulme C.
Tetrahedron
Lett.
2002,
43:
1637
<A NAME="RE26610SS-54">54 </A>
Zhang W.
Tempest P.
Tetrahedron Lett.
2004,
45:
6757
<A NAME="RE26610SS-55">55 </A>
Neochoritis C.
Idou-Stephanatou JS.
Tsoleridis CA.
Synlett
2009,
302
<A NAME="RE26610SS-56">56 </A>
Oblé J.
El Kaïm L.
Gizzi M.
Grimaud L.
Heterocycles
2007,
73:
503
<A NAME="RE26610SS-57">57 </A>
Shaabani A.
Maleki A.
Mofakham H.
Khavasi HR.
J. Comb.
Chem.
2008,
10:
323
<A NAME="RE26610SS-58">58 </A>
Li J.
Liu YJ.
Li CJ.
Jia XS.
Tetrahedron Lett.
2009,
50:
6502
<A NAME="RE26610SS-59">59 </A>
Hili R.
Rai V.
Yudin AK.
J.
Am. Chem. Soc.
2010,
132:
2889
<A NAME="RE26610SS-60">60 </A>
Golebiowski A.
Klopfenstein SR.
Shao X.
Chen JJ.
Colson AO.
Grieb AL.
Russell AF.
Org. Lett.
2000,
2:
2615
<A NAME="RE26610SS-61">61 </A>
El Kaïm L.
Gageat M.
Gaultier L.
Grimaud L.
Synlett
2007,
500
<A NAME="RE26610SS-62">62 </A>
Liu HX.
Dömling A.
J. Org. Chem.
2009,
74:
6895
<A NAME="RE26610SS-63">63 </A>
Liu, H. X.; William, S.; Herdtweck,
E; Botros, S.; Dömling, A. Bioorg.
Med. Chem. submitted for publication.
<A NAME="RE26610SS-64">64 </A>
Cao, H.; Liu, H. X.; Dömling,
A. Chem. Eur. J. in press
<A NAME="RE26610SS-65">65 </A>
Franckevicius V.
Longbottom DA.
Turner RM.
Ley SV.
Synthesis
2006,
3215
67a </A>
Mayer J.
Umkehrer M.
Kalinski C.
Ross G.
Kolb J.
Burdack C.
Hiller W.
Tetrahedron Lett.
2005,
46:
7393
66b </A>
Dömling A.
Beck B.
Magnin-Lachaux M.
Tetrahedron Lett.
2006,
47:
4289
<A NAME="RE26610SS-67">67 </A>
Kalinski C.
Umkehrer M.
Gonnard S.
Jäger N.
Ross G.
Hiller W.
Tetrahedron Lett.
2006,
47:
2041
<A NAME="RE26610SS-68">68 </A>
Sandulenko Y.
Komarov A.
Rufanov K.
Krasavin M.
Tetrahedron Lett.
2008,
49:
5990
<A NAME="RE26610SS-69">69 </A>
Takiguchi S.
Iizuka T.
Kumakura Y.-S.
Murasaki K.
Ban N.
Higuchi K.
Kawasaki T.
J. Org.
Chem.
2010,
75:
1126
70a </A>
Semple JE.
Wang PC.
Lysenko Z.
Joullié MM.
J. Am. Chem. Soc.
1980,
102:
7505
70b </A>
Endo A.
Yanagisawa A.
Abe M.
Tohma S.
Kan T.
Fukuyama T.
J. Am. Chem. Soc.
2002,
124:
6552
70c </A>
Mori K.
Rikimaru K.
Kan T.
Fukuyama T.
Org. Lett.
2004,
6:
3095
70d </A>
Rikimaru K.
Mori K.
Kan T.
Fukuyama T.
Chem. Commun.
2005,
394
71a </A>
Groebke K.
Weber L.
Mehlin F.
Synlett
1998,
661
71b </A>
Bienayme H.
Bouzid K.
Angew. Chem. Int. Ed.
1998,
37:
2234
71c </A>
Backburn C.
Tetrahedron
Lett.
1998,
39:
5469
71d </A>
Kercher T.
Rao C.
Bencsik JR.
Josey JA.
<A NAME="RE26610SS-72">72 </A>
Giovenzana GB.
Tron GC.
Paola SD.
Menegotto IG.
Pirali T.
Angew.
Chem. Int. Ed.
2006,
45:
1099
73a </A>
Srivastava S.
Beck B.
Herdtweck E.
Khoury K.
Dömling A.
Heterocycles
2009,
77:
731
73b </A>
Beck B.
Srivastava S.
Khoury K.
Herdtweck E.
Dömling A.
Mol. Divers.
2010, in press; DOI: 10.1007/s11030-010-9249-2
<A NAME="RE26610SS-74">74 </A>
Rivera DG.
Wessjohann LA.
J. Am. Chem. Soc.
2009,
131:
3721
<A NAME="RE26610SS-75">75 </A>
Musonda CC.
Little S.
Yardley V.
Chibale K.
Bioorg. Med. Chem. Lett.
2007,
17:
4733
<A NAME="RE26610SS-76">76 </A>
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
<A NAME="RE26610SS-77">77 </A>
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.
<A NAME="RE26610SS-78">78 </A>
Hulme C,
Tempest P,
Ma V,
Nixey T, and
Balow G. inventors; US Patent 26021.
