Synthesis of peptidomimetics containing a β-lactam moiety using peptidic diazoketones and imines in a staudinger reaction

Article abstract of DOI:10.1021/ol9908171

(equation presented) Rearrangement of α-amino acid or oligopeptide derived diazoketones in the presence of N-benzylbenzaldimine, a-amino acid, or tripeptide derived imines, respectively, led to peptidyl-substituted β-lactams. The trans-substituted diaster

Full text of DOI:10.1021/ol9908171

ORGANIC
LETTERS
1999
Vol. 1, No. 6
869-871
Synthesis of Peptidomimetics
Containing a â-Lactam Moiety Using
Peptidic Diazoketones and Imines in a
Staudinger Reaction
Michael R. Linder and Joachim Podlech*
Institut fu¨r Organische Chemie der UniVersita¨t Stuttgart, Pfaffenwaldring 55,
D-70569 Stuttgart, Germany
joachim.podlech@po.uni-stuttgart.de
Received July 15, 1999
ABSTRACT
Rearrangement of r-amino acid or oligopeptide derived diazoketones in the presence of N-benzylbenzaldimine, r-amino acid, or tripeptide
derived imines, respectively, led to peptidyl-substituted â-lactams. The trans-substituted diastereoisomers are formed exclusively.
The utilization of R-amino acids for the preparation of
â-lactams has been explored in our group.1 The photochemi-
cal decomposition of R-amino acid derived diazoketones2
in the presence of imines leads to the formation of â-lactams;
nearly all suitably protected amino acids can be employed
in this reaction. Only two of the four possible diastereoiso-
mers were found in which the substituents in positions C-3
and C-4 were trans-arranged (Scheme 1).
trinem,4 or meropenem5 antibiotics. The trans-substitution
swhich is usually hard to achieve6swas found to be
responsible for the special activity of these antibiotics against
resistant bacterial strains. The incorporation of â-lactam
moieties in oligopeptide strands is of additional interest. The
small ring should lead to a conformational restraint,7 the
(1) (a) Podlech, J. Synlett 1996, 582. (b) Podlech, J.; Linder, M. R. J.
Org. Chem. 1997, 62, 5873. (c) Podlech, J.; Linder, M. R. In New
PerspectiVes in Bioorganic Chemistry; Diederichsen, U., Lindhorst, T. K.,
Westermann, B., Wessjohann, L., Eds.; Wiley-VCH: Weinheim, 1999; in
press. (d) Podlech, J.; Steurer, S. Synthesis 1999, 650.
(2) (a) Podlech, J.; Seebach, D. Angew. Chem. 1995, 107, 507; Angew.
Chem., Int. Ed. Engl. 1995, 34, 471. (b) Podlech, J.; Seebach, D. Liebigs
Ann. 1995, 1217. (c) Guibourdenche, C.; Podlech, J.; Seebach, D. Liebigs
Ann. 1996, 1121. (d) Matthews, J. L.; Braun, C.; Guibourdenche, C.;
Overhand, M.; Seebach, D. In EnantioselectiVe Synthesis of â-Amino Acids;
Juaristi, E., Ed.; Wiley-VCH: New York, 1997; p 105.
Scheme 1
(3) Page, M. I. The Chemistry of â-Lactams; Blackie Academic &
Professional: London, 1992.
(4) (a) Di Modugno, E.; Erbetti, I.; Ferrari, L.; Galassi, G.; Hammond,
S. M.; Xerri, L. Antimicrob. Agents Chemother. 1994, 38, 2362. (b) Wise,
R.; Andrews, J. M.; Brenwald, N. Antimicrob. Agents Chemother. 1996,
40, 1248. (c) Singh, K. V.; Coque, T.; Murray, B. E. Antimicrob. Agents
Chemother. 1996, 40, 2142.
(5) (a) Nishimura, T.; Igarashi, J.-E.; Sasaki, A.; Sunagawa, M. Bioorg.
Med. Chem. 1998, 6, 367. (b) Shin, K. J.; Yoo, K. H.; Kim, D. J.; Park, S.
W.; Ko, B. S.; Lee, S. J.; Huh, J. D.; Park, S. Y. Bioorg. Med. Chem. Lett.
1998, 8, 1607.
(6) Georg, G. I.; Ravikumar, V. T. In The Organic Chemistry of
â-Lactams; Georg, G. I., Ed.; VCH: New York, 1993; p 295.
The resulting aminoalkyl-substituted â-lactams are useful
precursors for the preparation of possibly biologically active
compounds such as the similarly substituted carbapenem,3
10.1021/ol9908171 CCC: $18.00 © 1999 American Chemical Society
Published on Web 08/31/1999

Table 1. Preparation of â-Lactams from Peptidic Starting Materials9
entry
diazoketone
imine
lactam
ratio a /b
yield (%)
1
2
3
4
5
6
7
8
9
Cbz-Ala-Ala-CHN2
Cbz -Ala-Val-CHN2
Boc-Ala-Leu-CHN2
Cbz -Ala-CHN2
Cbz -Ala-CHN2
Cbz -Ile-CHN2
Cbz -Ala-CHN2
Cbz -Tle-CHN2
Fmoc-Ala-CHN2
PhCHdNBn (1)
PhCHdNBn (1)
PhCHdNBn (1)
PhCH<Leu-OMe (2)
PhCH<Ala-Ala-Ala-OMe (3)
PhCH<Ala-Ala-Ala-OMe (3)
PhCH<Val-Ala-Val-OMe (4)
PhCH<Val-Ala-Val-OMe (4)
2-thienyl-CH<Ile-Gly-Val-OMe (5)
6a ,b
7a ,b
8a ,b
9a ,b
10a ,b
11a ,b
12a ,b
13a ,b
14a ,b
4:1
4:1
4:1
2:1
11:1
2:1
>19:1
>19:1
>19:1
76
47
76
78
45
42
66
74
73
conformation being dependent on the relative configuration
of the stereogenic centers in the â-lactam ring. Therefore,
we wish to present a useful modification of our â-lactam
synthesis in which we utilize peptidic starting materials.
First, we used diazoketones derived from oligopeptides
in our â-lactam synthesis. Following a published procedure,2a,8
we synthesized diazoketones starting from Cbz-Ala-Ala-OH,
Cbz-Ala-Val-OH, and Boc-Ala-Leu-OH, respectively.9 Pho-
tochemical decomposition of these diazoketones in the
presence of N-benzylbenzaldimine 110 led to mixtures of two
diastereoisomers 6-8a,b, respectively, with yields ranging
from 45 to 75% (Scheme 2, Table 1, entries 1-3).
For the preparation of R-amino acid and peptide derived
imines 2-5, we used a very mild method developed by
Texier-Boullet in which equimolar amounts of amine and
aldehyde were condensed in the presence of activated
alumina.12 Addition of small amounts of benzene or meth-
ylene chloridesto allow for a better stirringsgave faster
reactions.13 This protocol led to the quantitative formation
of the corresponding imines without any racemization
(epimerization) or tautomerization (as checked by 1H NMR
spectroscopy).
Irradiation of the amino acid derived diazoketones in the
presence of imines 2-5 yielded the corresponding â-lactams
9-14a,b with yields ranging from 42 to 78% (Figure 1). As
Scheme 2
a NEt3, ClCO2Et, CH2N2, THF.8 b PhCHdNBn, hν, Et2O,
-20 °C. See Table 1 for specification of substituents.
Figure 1. Imines derived from amino acids and peptides as used
for the preparation of â-lactams.
The ratios of the isomers were determined by HPLC and
1H NMR spectroscopy, and separation of the products by
MPLC yielded the pure isomers.11 The trans-configuration
in previous investigations,1 we observed an influence of the
additional stereogenic centers introduced with the imine
moieties. Selectivities up to >95:5 could be obtained with
peptidic imines 4 and 5 (entries 7-9). No second isomer
could be detected in these cases, neither in the NMR spectra
of the crude products nor during MPLC separation and
purification.
1
was established by H NMR spectroscopy, and the relative
configuration of the â-lactams was determined by comparison
with previously prepared, similar compounds.1
(7) (a) Srivastava, L. K.; Bajwa, S. B.; Johnson, R. L.; Mishra, R. K. J.
Neurochem. 1988, 50, 960. (b) Sreenivasan, U.; Mishra, R. K.; Johnson,
R. L. J. Med. Chem. 1993, 36, 256. (c) Yu, K. L.; Rajakumar, G.; Srivastava,
L. K.; Mishra, R. K.; Johnson, R. L. J. Med. Chem. 1988, 31, 1430.
(8) Caution: The generation and handling of diazomethane requires
special precaution: DeBoer, T. J.; Backer, H. J. Organic Syntheses;
Wiley: New York, 1963; Collect. Vol. 4, p 250.
(9) Common abbreviations for amino acids and protecting groups were
used: Tle ) tert-leucine. Eur. J. Biochem. 1984, 138, 9.
(10) Juday, R.; Adkins, H. J. Am. Chem. Soc. 1955, 77, 4559.
(11) All new compounds were characterized by NMR, IR, MS, [R]D,
and elemental analyses.
(12) Texier-Boullet, F. Synthesis 1985, 679.
(13) Kra¨mer, B.; Franz, T.; Picasso, S.; Pruschek, P.; Ja¨ger, V. Synlett
1997, 295.
(14) (a) Drey, C. N. C.; Ridge, R. J.; Mtetwa, E. J. Chem. Soc., Perkin
Trans. 1 1980, 378. (b) Drey, C. N. C.; Ridge, R. J. J. Chem. Soc., Perkin
Trans. 1 1981, 2468. (c) Drey, C. N. C.; Mtetwa, E. J. Chem. Soc., Perkin
Trans. 1 1982, 1587.
(15) Allinger, N. L. J. Am. Chem. Soc. 1977, 99, 8127. The calculations
have been performed with PCModel for Windows, version 6.00; Serena
Software: Bloomington, IN, 1996.
870
Org. Lett., Vol. 1, No. 6, 1999

Fortunately, a previously observed intramolecular stabiliza-
tion2a of peptidic ketenes A seems to play no role with our
reaction conditions or, what is much more likely, is not fast
enough to compete with the attack of the imine. Obviously,
dihydrooxazinones such as 1514 would not lead to the
formation of â-lactams (Scheme 3).
Scheme 3
Figure 2. Tripeptide analogon stabilized by a hydrogen bond
(MM2 calculation).
We performed MM2 calculations15 with peptide analogues
accessible with our protocol and found that â-lactams should
be able to stabilize â-turns. Depending on the configuration
of the trans-substituted â-lactam, the conformation is either
a type I or a type II â-turn (Figure 2). These â-turn mimics
bear up to three residues in the turn area. This is advanta-
geous in comparison with previously presented â-turn
mimics,16 since this might allow for a better tuning of
possible biological activities.17 Work in this direction is
ongoing in our laboratories.
Acknowledgment. This work was supported by the Fonds
der Chemischen Industrie and the Deutsche Forschungsge-
meinschaft. We thank the Degussa AG for the kind donation
of amino acids. The generous help of Prof. Dr. V. Ja¨ger and
Prof. Dr. Dr. h. c. F. Effenberger is gratefully acknowledged.
OL9908171
(17) (a) Olson, G. L.; Bolin, D. R.; Bonner, M. P.; Bo¨s, M.; Cook, C.
M.; Fry, D. C.; Graves, B. J.; Hatada, M.; Hill, D. E.; Kahn, M.; Madison,
V. S.; Rusiecki, V. K.; Sarabu, R.; Sepinwall, J.; Vincent, G. P.; Voss, M.
E. J. Med. Chem. 1993, 36, 3039. (b) Kessler, H. Angew. Chem. 1982, 94,
509; Angew. Chem., Int. Ed. Engl. 1982, 21, 512. (c) Liskamp, R. M. J.
Recl. TraV. Chim. Pays-Bas 1994, 113, 1.
(16) (a) Richardson, J. S. In AdVances in Protein Chemistry; Anfinsen,
C. B., Edsall, J. T., Richards, F. M., Eds.; Academic Press: New York,
1981; Vol. 34, p 167. (b) Ball, J. B.; Alewood, P. F. J. Mol. Recognit.
1990, 3, 55. (c) Smith, J. A.; Pease, L. G. Crit. ReV. Biochem. 1980, 8,
315.
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