T. M. Vishwanatha et al. / Tetrahedron Letters 52 (2011) 5620–5624
5623
in the Chemical Synthesis of Antibiotics and Related Microbial Products; Luckacs,
G., Ed.; Springer: Berlin, 1993; Vol. 2, p 621; (c) Tamas, S.; Janos, P.; Peter, B.;
Jozsef, T. Bioorg. Med. Chem. Lett. 2005, 15, 3086–3090.
of the present protocol, a series of b-lactam derivatives were pre-
pared by varying the isonitriles derived from Nb-Fmoc-amino acids
and aldehyde components (3a–j) keeping H-Asp-OMe as a common
reactant.26 All the reactions were complete with in 24–28 h under rt,
resulting in the b-lactam derivatives in moderate to good yield with
diastereomeric ratio varying from 100:0 to 85:15 (Table 1). It is
known from the literature, a good diastereoselectivity is achieved
during b-lactam synthesis through Ugi 4C-3CR due to the formation
of seven membered oxapinone intermediate. Further, an attempt to
decrease the reaction time and to improve the yields of the Ugi ad-
11. Palomo, C.; Aizpurua, I.; Ganboa, I.; Oiarbide, M. Amino Acids 1999, 16, 321–
343.
12. (a) Podlech, J.; Linder, M. R. J. Org. Chem. 1997, 62, 5873–5883; (b) Mandell, G.
L.; Petri, W. A.; Hardman, J. G.; Limberd, L. E.; Molinoff, P. B.; Ruddon, R. W. In
Goodman and Gilman’s the Pharmacological Basis of Therapeutics; Gilman,
Goodman., Ed.; Mcgraw Hill: New York, 1996; p 1073.
13. (a) Hatanaka, N.; Ojima, I. Chem. Lett. 1981, 231–234; (b) Ruhland, B.; Bhandari,
A.; Gordon, E. M.; Gallop, M. A. J. Am. Chem. Soc. 1996, 118, 253–254.
14. (a) Benaglia, M.; Cinquini, M.; Cozzi, F. Tetrahedron Lett. 1999, 40, 2019–2020;
(b) Schunk, S.; Enders, D. Org. Lett. 2000, 2, 907–910.
15. (a) Linder, M. R.; Podlech, J. Org. Lett. 1999, 1, 869–871; (b) Podlech, J. Synlett
1996, 582–584; (c) Podlech, J.; Steurer, S. Synthesis 1999, 650–654.
16. Palomo, C.; Aizpurua, J. M.; Balentova, E.; Jimenez, A.; Oyarbide, J.; Fratila, R.
M.; Miranda, J. I. Org. Lett. 2007, 9, 101–104.
ducts was undertaken with compound Nb-Fmoc-Phe-
w[CH2NC] 2c
as the model reactant. The reaction was also carried out at reflux
for 8–10 h or ultrasonication at 80 °C for 7–9 h during which com-
plete disappearance of the isonitrile was observed, but these condi-
tions did not improve the yield significantly or the
diastereoselectivity. Hence, mild conditions were eventually chosen
to synthesize title molecules (Scheme 3). Isonitriles derived from
several side chain functionalized amino acids viz Fmoc-Ser(OBn)-
OH, Fmoc-Asp(b-OBn)-OH, Fmoc-Lys(Z)-OH were also used in the
reaction and the products were obtained in good yield without the
formation of byproducts.
17. (a) Domling, A.; Kehagia, K.; Ugi, I. Tetrahedron 1995, 51, 9519–9522; (b)
Kehagia, K.; Ugi, I. Tetrahedron 1995, 51, 9523–9530.
18. (a) Brahmachary, E.; Ling, F. H.; Svec, F.; Frechet, Jean M. J. J. Comb. Chem. 2003,
5, 441–450; (b) Isenring, H. P.; Hofheinz, W. Synthesis 1981, 385–387; (c) Sato,
A.; Hirata, T.; Nakamizo, N. Agric. Biol. Chem. 1983, 47, 799–806; (d) Geday, S.;
Eycken, J. V. d.; Fulop, F. Org. Lett. 2002, 4, 1967–1969; (e) Pirrung, M.; Sarma,
K. D. Synlett 2004, 1425–1427; (f) Pirrung, M. C.; Sarma, K. D. J. Am. Chem. Soc.
2004, 126, 444–445; (g) Janos, P.; Townsend, C. A. Bioorg. Med. Chem. Lett. 1997,
7, 3129–3134; (h) Isenrling, H. P.; Hofheinz, W. Tetrahedron 1983, 39, 2591–
2597.
19. (a) Zhu, J.; Wu, X.; Danishefsky, S. Tetrahedron Lett. 2009, 50, 577–579; (b)
Zhdanko, A. G.; Nenajdenko, V. G. J. Org. Chem. 2009, 74, 884–887.
20. Sureshbabu, V. V.; Narendra, N.; Nagendra, G. J. Org. Chem. 2009, 74, 153–157.
21. Typical procedure for preparation of H-Asp-Phe-OMe: Z-Asp(b-OBn)-OH
(3.57 g, 1.0 mmol) was dissolved in dry THF (5 mL), and cooled to ꢀ15 °C,
EtOCOCl (0.1 mL, 1.0 mmol) and TEA (0.1 mL, 1.0 mmol) were added to the
above solution and stirred for 10 min. While maintaining the temperature at
ꢀ10 °C, the reaction mixture was treated with the neutralized solution of
phenylalanine methyl ester hydrochloride salt (2.34 g, 1.0 mmol and equimolar
TEA was added) in THF (5.0 mL) solution and the reaction mixture was allowed
to stir for 6 h (monitored by TLC). The THF was evaporated under reduced
pressure and the residue was dissolved in CH2Cl2 (15.0 mL), washed with 5%
Na2CO3 (3 ꢁ 10 mL), 10% citric acid (10 mL, two times), water (10 mL, two
times) and brine (10 mL), and dried over anhydrous sodium sulfate. Solvent was
removed under reduced pressure. n-Hexane was added to obtain pure Z-Asp(b-
OBn)-Phe-OMe (4.76 g) as white solid. The later product (2.0 g) was dissolved in
MeOH (20.0 mL), Pd/C (400 mg, 20%/wt) was added and the reaction mixture
was stirred for 4 h under hydrogen atmosphere. After complete deprotection
(TLC analysis), Pd/C was filtered out and the filtrate was evaporated under
reduced pressure. Recrystallization of the crude product with MeOH:ether
(5:4 mL/200 mg of the crude product) afforded H-Asp-Phe-OMe.
Encouraged by these results, additional set of peptidomimetics
3i–m, bearing endo-b-lactam units were prepared by utilizing pep-
tide esters with N-terminal Asp residue 1b–e. Ugi reaction was car-
ried out by varying all the three components. Compared to the
reactions involving 1a as b-amino acid component, those involving
1b–e were sluggish and even after running the reaction to 48 h,
only moderate yields were obtained (Fig. 2).27 All the compounds
were isolated as stable ones and characterized through IR, mass,
1H NMR and 13C NMR analyses.
In conclusion, we have accomplished the first application of
chiral Nb-Fmoc-amino alkyl isonitriles in Ugi multi component
reactions through the synthesis of peptide mimics with b-lactam
units. b-Lactams have been synthesized in solution through Ugi
4C-3CR through one-pot condensation of Nb-Fmoc-amino alkyl
isonitriles, L-aspartic acid a-methyl ester/ peptide ester, and com-
mercially available aldehydes.
Spectroscopic data: ½ ꢂ +27.9 (c = 1, aq HCl); IR (KBr): m 3320, 1741,
a 2D0
1670 cmꢀ1; mp 248–249 °C; 1H NMR (CDCl3, 300 MHz) d 10.66 (s, 1H), 7.22–
7.45 (m, 5H), 5.81 (s, br, 1H), 4.41–4.72 (m, 1H), 3.68–3.91 (m, 1H), 3.56 (s, 3H),
3.46 (dd, 1H, J = 2.8, 7.1 Hz), 3.15 (dd, 1H, J = 3.6, 8.2 Hz), 2.78 (dd, 1H, J = 4.9,
9.1 Hz), 2.49 (dd, 1H, J = 2.5, 8.6 Hz), 2.13 (s, br, 2H); 13C NMR (CDCl3, 100 MHz)
d 176.3, 171.3, 171.2, 136.5, 129.0, 128.7, 127.5, 127.1, 126.0, 52.8, 51.2, 48.5,
42.4, 36.5; HRMS calcd for C14H18N2O5 m/z 295.1216 [M+H+], found 295.1208
[M+H+].
Acknowledgment
We thank the Department of Science and Technology, Govt. of
India (Grant No.SR/S1/OC-26/2008) for financial assistance.
22. Typical procedure for H-Asp-OMe: Z-Asp(b-OBn)-OH (1.0 mmol, 357.2 mg)
was dissolved in anhydrous THF and ethereal solution of diazomethane
(3.0 mmol, 305 mg) was added at 0 °C. The mixture was stirred for about 3 h
until the completion of the reaction. Solvent was then evaporated in vacuo and
the residue was dissolved in CH2Cl2. The organic layer was washed with 5%
Na2CO3 (10 mL, two times), 10% citric acid (10 mL, two times), water (10 mL,
two times) and brine (10 mL), and dried over anhydrous sodium sulfate. CH2Cl2
was removed under reduced pressure to obtain the corresponding methyl ester
as white solid almost quantitatively. The resulted methyl ester was then
dissolved in MeOH and was treated with Pd/C (20%/wt) under hydrogen
atmosphere, and the reaction mixture was stirred for 3 h till complete
deprotection of both Z and Bn groups. Evaporation of MeOH in vacuo was
followed by recrystallization of the residue with ether. THF afforded 1a in
References and notes
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quantitative yield. Spectroscopic data:
169 °C; IR (KBr):
3320, 1735 cmꢀ1 1H NMR (CDCl3, 300 MHz) d 10.25 (s, 1H),
4.01 (dd, 1H, J = 2.6, 5.8 Hz), 3.67 (s, 3H), 2.68–2.99 (m, 2H), 2.86 (s, br, 2H); 13
NMR (CDCl3, 100 MHz) 177.0, 170.6, 51.4, 49.0, 41.2; ESI-MS calcd for
C5H5NO4 m/z 148.12 [M+H+], found 148.06 [M+H+].
½ ꢂ +15.3 (c = 2, H2O); mp: 168–
a 2D0
m
;
C
d
23. General procedure for Ugi reaction: To a stirred solution of b-amino acid
component 1a–e (15.0 mmol) in methanol (15 mL) at room temperature was
added aldehyde (15.0 mmol) at once and stirred for 1 h to ensure imine
formation. The isonitrile 2 (15.5 mmol) was added and the reaction was stirred
at the same temperature for several hours (TLC analysis). After completion of
the reaction, methanol was evaporated under reduced pressure and the crude
product was dissolved in excess CH2Cl2 (20.0 mL). Organic layer was washed
with 5% Na2CO3 (10 mL, two times), 10% citric acid (10 mL, two times), water
(10 mL, two times) and brine (10 mL), and dried over anhydrous sodium
sulfate. Solvent was removed under reduced pressure and the crude product
was purified through column chromatography (silica gel 100–200 mesh size;
CHCl3: MeOH system 9.5:0.5).
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