Subscribe to RSS
DOI: 10.1055/s-2007-968026
New Ugi/Pictet-Spengler Multicomponent Formation of Polycyclic Diketopiperazines from Isocyanides and α-Keto Acids
Publication History
Publication Date:
07 February 2007 (online)
![](https://www.thieme-connect.de/media/synlett/200703/lookinside/thumbnails/10.1055-s-2007-968026-1.jpg)
Abstract
A new four-component 1,4-diketopiperazine formation is described via an Ugi/Pictet-Spengler two-step procedure. The use of α-ketocarboxylic acids and homoveratryl isocyanide allows the formation of α-keto amides along with cyclised 6-hydroxypiperazines. The mixtures are not separated but directly treated with trifluoroactic acid to afford a tricyclic 2,5-diketopiperazine in a Pictet-Spengler-type cyclisation.
Key words
diketopiperazine - isocyanide - multicomponent reaction - Ugi - Pictet-Spengler
-
1a
Cui C.-B.Kakeya H.Osada H. Tetrahedron 1996, 52: 12651 -
1b
Cui C.-B.Kakeya H.Osada H. J. Antibiot. 1996, 49: 534 -
1c
Charlton PA.Faint RW.Bent F.Bryans J.Chicarelli-Robinson I.Mackie I.Machin S.Bevan P. Thromb. Haemost. 1996, 75: 808 -
1d
Funabashi Y.Horiguchi T.Iinuma S.Tanida S.Harada S. J. Antibiot. 1994, 47: 1202 -
1e
Barrow CJ.Musza LL.Cooper R. Bioorg. Med. Chem. Lett. 1995, 5: 377 - 2
Dinsmore CJ.Beshore DC. Tetrahedron 2002, 58: 3297 - For general reviews on isocyanide-based multicomponent reactions, see:
-
3a
Dömling A.Ugi I. Angew. Chem. Int. Ed. 2000, 39: 3168 -
3b
Dömling A. Chem. Rev. 2006, 106: 17 -
4a
Kennedy AL.Fryer AM.Josey JA. Org. Lett. 2002, 7: 1167 -
4b
Boehm JC.Kingsbury WD. J. Org. Chem. 1986, 51: 2307 -
4c
Fukuyama T.Robins BD.Sachleben RA. Tetrahedron Lett. 1981, 22: 4155 -
4d
Endo A.Yanagisawa A.Abe M.Tohma S.Kan T.Fukuyama T. J. Am. Chem. Soc. 2002, 124: 6552 -
4e
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 -
5a
Hulme C.Morrissette MM.Volz FA.Burns CJ. Tetrahedron Lett. 1998, 39: 1113 -
5b
Hulme C.Cherrier M.-P. Tetrahedron Lett. 1999, 40: 5295 - 6
Szardenings AK.Burkoth TS.Lu HH.Tien DW.Campbell DA. Tetrahedron 1997, 53: 6573 - 7
Cho S.Keum G.Soon BK.Han SY.Kim Y. Mol. Diversity 2003, 6: 283 - 8
Marcaccini S.Pepino R.Pozo C. Tetrahedron Lett. 2001, 42: 2727 - 9
Sollis SL. J. Org. Chem. 2005, 70: 4735 - 10 For a review, see:
Cox ED.Cook JM. Chem. Rev. 1995, 95: 1797 - 11 For a review, see:
Speckamp WN.Moolenaar MJ. Tetrahedron 2000, 56: 3817 -
13a
Pirrung MC.Sarma KD. Synlett 2004, 1425 -
13b
Harriman GCB. Tetrahedron Lett. 1997, 38: 5591 - 14
Nixey T.Tempest P.Hulme C. Tetrahedron Lett. 2002, 43: 1637 - 15
Sanudo M.Marcaccini S.Basurto S.Torroba T. J. Org. Chem. 2006, 71: 4578 - 16
Zawadzka A.Leniewski A.Maurin JK.Wojtasiewicz K.Czarnocki Z. Org. Lett. 2001, 3: 997
References and Notes
Typical Procedure (Given for 6a):
To a solution of 124 mg of o-nitrobenzaldehyde 2a (0.82 mmol, 1 equiv)and 60 mg of butylamine 3a (0.82 mmol,
1 equiv) in MeOH (800 µL, 1 M) were added 157 mg of homoveratryl isocyanide(4a) (0.82 mmol, 1 equiv) and
57 µL of pyruvic acid (1a, 0.82 mmol, 1 equiv) under inert argon atmosphere. The mixture was then stirred at r.t. during 2 h. After concentration under reduced pressure, the crude product was dissolved in 4 mL of TFA (0.2 M) and stirred at r.t. for 1 h. Flash chromatography (50-100% Et2O-petroleum ether gradient) afforded the desired diketo-piperazine in a 69% overall yield as a mixture of two diastereomers in a 1:1.2 ratio.
Spectroscopic Data for DKP 6a:
Major diastereomer: 1H NMR (400 MHz, CDCl3): δ = 7.94 (d, J = 7.8 Hz, 1 H), 7.78 (s, 1 H), 7.40 (dt, J = 3.8, 7.6 Hz, 2 H), 6.74 (d, J = 7.6 Hz, 1 H), 6.55 (s, 1 H), 6.25 (s, 1 H), 4.69 (q, J = 7.8 Hz, 1 H), 4.11 (q, J = 7.8 Hz, 1 H), 3.92 (s, 3 H), 3.86 (s, 3 H), 3.22 (dt, J = 4.3, 12.6 Hz, 1 H), 2.79-2.64 (m, 2 H), 2.60 (d, J = 10.6 Hz, 1 H), 2.02 (s, 3 H), 1.67-1.57 (m, 2 H), 1.39-1.27 (m, 2 H), 0.91 (t, J = 7.3 Hz). 13C NMR (100.6 MHz, CDCl3): δ = 167.8, 163.8, 150.6, 148.8, 147.8, 133.3, 133.1, 132.2, 129.7, 129.6, 126.1, 125.7, 111.9, 109.3, 62.8, 58.1, 56.4, 56.2, 46.2, 37.8, 31.5, 29.0, 27.7, 20.4, 14.2.
Minor diastereomer: 1H NMR (400 MHz, CDCl3): δ = 7.91 (d, J = 7.8 Hz, 1 H), 7.74 (s, 1 H), 7.64 (dt, J = 1.2, 7.8 Hz, 1 H), 7.53 (dt, J = 1.2, 7.8 Hz, 1 H), 7.26 (d, J = 7.8 Hz, 1 H), 6.50 (s, 1 H), 6.20 (s, 1 H), 4.65 (q, J = 7.8 Hz, 1 H), 4.05 (q, J = 7.8 Hz, 1 H), 3.99 (s, 3 H), 3.94 (s, 3 H), 3.05 (q, J = 9.8 Hz, 1 H), 2.79-2.64 (m, 2 H), 2.60 (d, J = 10.6 Hz, 1 H), 1.98 (s, 3 H), 1.67-1.57 (m, 2 H), 1.39-1.27 (m, 2 H), 0.83 (t, J = 7.3 Hz). 13C NMR (100.6 MHz, CDCl3): δ = 168.7, 163.73, 150.9, 148.8, 147.5, 133.2, 133.1, 131.5, 129.9, 129.1, 126.7, 126.1, 111.6, 111.3, 62.8, 58.4, 56.5, 56.2, 46.1, 37.8, 31.6, 29.0, 28.5, 20.3, 14.0. IR: ν = 2928, 2312, 1653, 1513, 1424, 1354, 1256 cm-1. HRMS: m/z calcd for C25H29O6N3: 467.2056; found: 467.2052.