References and Notes
1a
Chorev M.
Biopolymers
2005,
80:
67
1b
Fletcher MD.
Campbell MM.
Chem. Rev.
1998,
98:
763
1c
Zhao M.
Kleinman HK.
Mokotoff M.
J. Pept. Res.
1997,
49:
240
1d
Chorev M.
Goodman M.
Trends Biotechnol.
1995,
13:
438
1e
Chorev M.
Goodman M.
Acc. Chem. Res.
1993,
26:
266
2a
Davis SS. In Perspectives in Medicinal Chemistry
Testa B.
Kyburz E.
Fuhrer W.
Giger R.
Verlag Helvetica Chimica Acta;
Basel:
1993.
p.533
2b
Giannis A.
Kolter T.
Angew. Chem., Int. Ed. Engl.
1993,
32:
1244
3a
Biron Z.
Khare S.
Quadt SR.
Hayek Y.
Naider F.
Anglister J.
Biochemistry
2005,
44:
13602
3b
Schneider SE.
Bray BL.
Mader CJ.
Friedrich PE.
Anderson MW.
Taylor TS.
Boshernitzan N.
Niemi TE.
Fulcher BC.
Whight SR.
White JM.
Greene RJ.
Stoltenberg LE.
Lichty M.
J. Pept. Sci.
2005,
11:
744
3c
Veiga AS.
Santos NC.
Loura LMS.
Fedorov A.
Castanho MARB.
J. Am. Chem. Soc.
2004,
126:
14758
3d
Wiley RA.
Rich DH.
Med. Res. Rev.
1993,
13:
327
4a
Gante J.
Angew. Chem., Int. Ed. Engl.
1994,
33:
1699
4b
Grant SK.
Meek TD.
Metcalf BW.
Petteway SR.
Biomed. Appl. Biotechnol.
1993,
1:
325
5a
Trabocchi A.
Menchi G.
Guarna F.
Machetti F.
Scarpi D.
Guarna A.
Synlett
2006,
331
5b
Nefzi A.
Ostresh JM.
Yu J.
Houghten RA.
J. Org. Chem.
2004,
69:
3603
5c
Liu R.
Marik J.
Lam KS.
Methods Enzymol.
2003,
369:
271
5d
Lam KS.
Lehman AL.
Song A.
Doan N.
Enstrom AM.
Maxwell J.
Liu R.
Methods Enzymol.
2003,
369:
298
5e
Szostak JW.
Chem. Rev.
1997,
97:
347
6a
Gibert L.
Gonzalez A.
Granell J.
Lopez C.
Tetrahedron: Asymmetry
2002,
13:
983
6b
Fujii H.
Nishikawa N.
Komazawa H.
Suzuki M.
Kojima M.
Itoh I.
Obata A.
Ayukawa K.
Azuma I.
Saiki I.
Clin. Exp. Metastasis
1998,
16:
94
6c
Fujii H.
Nishikawa N.
Komazawa H.
Orikasa A.
Ono M.
Itoh I.
Murata J.
Azuma I.
Saiki I.
Oncol. Res.
1996,
8:
333
7
Pallai PV.
Richman S.
Struthers RS.
Goodman M.
Int. J. Pept. Protein Res.
1983,
21:
84
8a
Nishikawa N.
Komazawa H.
Orikasa A.
Yoshikane M.
Yamaguchi J.
Kojima M.
Ono M.
Itoh I.
Azuma I.
Fujii H.
Murata J.
Saiki I.
Bioorg. Med. Chem. Lett.
1996,
6:
2725
8b
Dalpozzo A.
Kanai K.
Kereszturi G.
Calabrese G.
Int. J. Pept. Protein Res.
1993,
41:
561
8c
Verdini AS.
Silvestri S.
Becherucci C.
Longobardi MG.
Parente L.
Peppoloni S.
Perretti M.
Pileri P.
Pinori M.
Viscomi GC.
Nencioni L.
J. Med. Chem.
1991,
34:
3372
9a
Kudo H.
Sanda F.
Endo T.
Tetrahedron Lett.
2001,
42:
7847
9b
Phanstiel OIV.
Lachicotte RJ.
Torres D.
Richardson M.
Matsui H.
Schaffer H.
Adar F.
Liu J.
Seconi D.
Chem. Mater.
2001,
13:
264
9c
Jain D.
Tripathi M.
Kohli DV.
Uppadhyay RK.
Arch. Pharmacol. Res
1992,
15:
184
10 IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN), Eur. J. Biochem.
1984,
138:
9
11
Gaber AE.-AM.
McNab H.
Synthesis
2001,
2059
12
Rigo B.
Fasseur D.
Cauliez P.
Couturier D.
Tetrahedron Lett.
1989,
30:
3073
13 The molar ratios of Meldrum’s acid to amino ester were a crucial point in order to avoid the undesired formation of a symmetric disubstituted malonamide.
14 By refluxing in toluene only the N-acetyl amino ester was obtained as a consequence of the decarboxylation reaction.
15 The reaction was monitored by IR and MS-Q-TOF every 30 min until completion.
16
Typical Experimental Procedure
Equimolar amounts (from 250 mg up to multigram scale) of a suitable amino ester hydrochloride and Et3N were stirred in THF (3 mL/mmol) at r.t. After 30 min, a twofold excess of Meldrum’s acid was added, and then the reaction mixture was allowed to reflux for 3 h. After filtration and solvent removal, the malonic acid monoamides were obtained as crude products and used as such. The crude malonic acid monoamides were dissolved in CH2Cl2 and equimolar amounts of a suitable amino ester hydrochloride and DMAP were added. After stirring for 15 min, an equimolar amount of DCC was added and the mixture was stirred for additional 12 h. After reaction completion, the crude mixture was filtered and the expected malonyl peptides were collected as pure compounds after chromatography on silica gel (eluent mixture: hexane-EtOAc = 5:95).
17
Representative Spectral Data for 3A{1-4}B1
Methyl (2
S
)-2-({3-[(2-Methoxy-2-oxoethyl)amino]-3-oxopropanoyl}amino)-3-phenylpropanoate (3A1B1)
Viscous oil. IR: 3442, 3328, 1739, 1679 cm-1.
1H NMR (300 MHz, CDCl3): δ = 2.92-3.18 (m, 2 H), 3.19 (s, 2 H), 3.64 (s, 3 H), 3.68 (s, 3 H), 3.96 (d, J = 5.4 Hz, 2 H), 4.71-4.82 (m, 1 H), 7.05-7.26 (m, 5 H), 7.62-7.76 (m, 2 H). 13C NMR (75 MHz, CDCl3): δ = 37.6, 41.0, 42.1, 52.1 (two), 53.5, 126.8, 128.3, 129.0, 135.8, 167.0, 167.3, 169.8, 171.5. HRMS (ES Q-TOF): m/z calcd for C16H21N2O6 [M + H]+: 337.1394; found: 337.1387
Methyl (2
S
)-2-({3-[(2-Methoxy-2-oxoethyl)amino]-3-oxopropanoyl}amino)propanoate (3A2B1)
Viscous oil. IR: 3424, 3326, 1744, 1678 cm-1.
1H NMR (300 MHz, CDCl3): δ = 1.36 (d, J = 7.2 Hz, 3 H), 3.28 (s, 2 H), 3.68 (s, 3 H), 3.69 (s, 3 H), 3.94-4.01 (m, 2 H), 4.42-4.56 (m, 1 H), 7.73 (d, J = 6.9 Hz, 1 H), 7.77-7.83 (m, 1 H). 13C NMR (75 MHz, CDCl3): δ = 17.6, 41.1, 42.1, 52.2 (two), 52.3, 166.9, 167.6, 169.9, 173.0. HRMS (ES Q-TOF): m/z calcd for C10H17N2O6 [M + H]+: 261.1081; found: 261.1079
Methyl 3-({3-[(2-Methoxy-2-oxoethyl)amino]-3-oxopropanoyl}amino)propanoate (3A3B1)
Viscous oil. IR: 3445, 3327, 1737, 1679 cm-1.
1H NMR (300 MHz, CDCl3): δ = 2.42-2.48 (m, 2 H), 3.17 (s, 2 H), 3.37-3.44 (m, 2 H), 3.58 (s, 3 H), 3.63 (s, 3 H), 3.92 (d, J = 5.4 Hz, 2 H), 7.60-7.65 (m, 1 H), 7.92-7.94 (m, 1 H).13C NMR (75 MHz, CDCl3): δ = 33.4, 34.8, 41.0, 42.2, 51.5, 51.9, 167.2, 167.7, 169.9, 172.2. HRMS (ES Q-TOF): m/z calcd for C10H17N2O6 [M + H]+: 261.1081; found: 261.1090
Methyl (2
S
)-2-({3-[(2-Methoxy-2-oxoethyl)amino]-3-oxopropanoyl}amino)-3-methylbutanoate (3A4B1)
Viscous oil. IR: 3425, 3326, 1742, 1679 cm-1.
1H NMR (300 MHz, CDCl3): δ = 0.88 (d, J = 6.6 Hz, 3 H), 0.90 (d, J = 6.6 Hz, 3 H), 2.10-2.20 (m, 1 H), 3.31 (s, 2 H), 3.70 (s, 3 H), 3.71 (s, 3 H), 4.00 (d, J = 5.4 Hz, 2 H), 4.41-4.48 (m, 1 H), 7.72 (d, J = 7.8 Hz, 1 H), 7.79 (d, J = 7.8 Hz, 1 H). 13C NMR (75 MHz, CDCl3): δ = 17.7, 18.9, 30.8, 41.0, 42.0, 52.0, 52.2, 57.5, 167.2, 167.7, 169.9, 172.2. HRMS (ES Q-TOF): m/z calcd for C12H21N2O6 [M + H]+: 289.1394; found: 289.1401.
18
Ceretti S.
Luppi G.
De Pol S.
Formaggio F.
Crisma M.
Toniolo C.
Tomasini C.
Eur. J. Org. Chem.
2004,
4188