Communication
[
[
[
[
1] G. F. Gause, M. G. Brazhnikova, Nature 1944, 154, 703.
Table 3. Synthesis of enantiopure homodiketopiperazines.
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[
[
6] D. H. Copp, Oral Surg. Oral Med. Oral Pathol. 1963, 16, 872.
7] J. Thundimadathil, J. Amino Acids 2012, 967347.
Entry
R
T [°C]
Product
Yield [%][a]
1
2
3
4
5
6
7
8
Ph
Bn
Bn
Ph
Ph
Bn
Bn
r.t.
50
50
r.t.
50
r.t.
r.t.
r.t.
cyclo-[Phe-ꢀAla]
cyclo-[Phe-ꢀAla]
cyclo-[Val-ꢀAla]
cyclo-[Leu-ꢀAla]
cyclo-[Leu-ꢀAla]
cyclo-[Trp-ꢀAla]
cyclo-[Lys(Z)-ꢀAla]
cyclo-[Ser(Bn)-ꢀAla]
51
49
23
[8] J. Luo, J. M. Otero, C. Yu, S. K. T. S. Warmlander, A. Graslund, M. Overhand,
J. P. Abrahams, Chem. Eur. J. 2013, 19, 17338.
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[10] S. H. Joo, Biomol. Ther. 2012, 20, 19.
[11] A. T. Bockus, C. M. McEwen, R. S. Lokey, Curr. Trends Med. Chem. 2013,
13, 821.
[12] H. Kawagashi, A. Somoto, J. Kuranari, A. Kimura, S. Chiba, Tetrahedron
Lett. 1993, 34, 3439.
[b]
–
42
63
45
52
[
c]
[
c]
Ph
[
13] Y. Li, A. Yongye, M. Giulianotti, K. Martinez-Mayorga, Y. Yu, R. A.
Houghten, J. Comb. Chem. 2009, 11, 1066.
[
[
a] Isolated yields after flash chromatography. [b] Mainly cyclic dimer formed.
c] MeCN was used instead of THF.
[
[
14] C. J. White, A. K. Yudin, Nat. Chem. 2011, 3, 509.
15] a) H. Bieräugel, H. Schoemaker, H. Hiemstra, J. H. van Maarseveen, Org.
Biomol. Chem. 2003, 1, 1830; b) J. Springer, T. P. Jansen, S. Ingemann, H.
Hiemstra, J. H. van Maarseveen, Eur. J. Org. Chem. 2008, 361; c) J. P. A.
Rutters, Y. Verdonk, R. de Vries, S. Ingemann, H. Hiemstra, V. Levacher,
J. H. van Maarseveen, Chem. Commun. 2012, 48, 8084.
It is important to note that the presence of buffer proved
to be crucial for successful lactamization, because dimers and
oligomers were barely detected.
[
16] E. Jiménez-González, C. G. Ávila-Ortiz, R. González-Olvera, J. Vargas-Capo-
rali, G. Dewynter, E. Juaristi, Tetrahedron 2012, 68, 9842.
Conclusions
[
17] O. David, W. J. N. Meester, H. Bieraugel, H. E. Schoemaker, H. Hiemstra,
J. H. van Maarseveen, Angew. Chem. Int. Ed. 2003, 42, 4373; Angew. Chem.
Efficient synthetic methodology providing seven-membered
bislactams containing an α-amino acid and ꢀ-alanine was de-
veloped. These lactams are difficult to access because the linear
precursors are reluctant to ring-closure and therefore a good
model for difficult peptide cyclizations. The synthesis of enanti-
opure racemization-prone peptide thioester lactamization pre-
cursors was achieved using DCC in respectable yields and very
high ee values. Conditions were found that drive the delicate
balance of the kinetics of lactamization, hydrolysis, racemiza-
tion, and oligomerization to lactamization. During difficult
lactamizations of peptides with a chiral C-terminal residue race-
mization can be avoided by choosing 4-methoxythiophenol es-
ter activation at pH 6.8. Linear peptide thioesters seem to be a
good choice as precursors obviating the need for additional
auxiliaries or backbone-amide alkylation to facilitate ring clo-
sure. Studies are ongoing to further broaden the scope by intro-
ducing substituted ꢀ-alanines and moving towards larger cyclic
peptides that are reluctant to ring-closure.
2
003, 115, 4509.
[
18] K. Ha, J. M. Monbaliu, B. C. Williams, G. G. Pillai, C. E. Ocampo, M. Zeller,
C. V. Stevens, A. R. Katritzky, Org. Biomol. Chem. 2012, 10, 8055.
[19] S. Popovic, H. Bieräugel, R. J. Detz, A. M. Kluwer, J. A. A. Koole, D. E.
Streefkerk, H. Hiemstra, J. H. van Maarseveen, Chem. Eur. J. 2013, 19,
1
6934.
[
20] Other papers describing the lactamization to give 2. Using backbone
alkylation 2 was prepared as described in two publications. No isolated
yield or optical purity was determined, see: a) J. Giovannoni, G. Subra,
M. Amblard, J. Martinez, Tetrahedron Lett. 2001, 42, 5389; b) J. Constanze,
D. Müller-Hartwieg, K. G. Akyel, J. Zimmerman, J. Pept. Sci. 2003, 9, 187.
Homodiketopiperazine 2 was also prepared via Staudinger reaction me-
diated ring-closure in 66 % yield (optical purity not determined), see: c)
K. Ha, J.-C. M. Monbaliu, B. C. Williams, G. G. Pillai, C. E. Ocampo, M.
Zeller, C. V. Stevens, A. R. Katritzky, Org. Biomol. Chem. 2012, 10, 8055.
Auxiliaries that give 2 via a ring-contraction strategy gave 2 in yields up
to 51 % (ref.[ ), 61 % (ref.
15a]
[15b]
) and 35 % (ref. ). Also cyclo-[Trp-ꢀAla]
[17]
was prepared in 67 % yield (partly racemized, see ref.[ ).
21] T. Wieland, E. Bokelmann, L. Bauer, H. U. Lang, H. Lau, Justus Liebigs Ann.
Chem. 1953, 583, 129.
15c]
[
[22] J. H. Chen, J. D. Warren, B. Wu, G. Chen, Q. Wan, S. J. Danishefsky, Tetrahe-
dron Lett. 2006, 47, 1969.
[
[
[
23] P. E. Dawson, T. W. Muir, I. Clarklewis, S. B. H. Kent, Science 1994, 266,
76.
24] Y. Li, A. Yongye, M. Giulianotti, K. Martinez-Mayorga, Y. Yu, R. A.
Houghten, J. Comb. Chem. 2009, 11, 1066.
Acknowledgments
The National Research School Combination Catalysis is kindly
acknowl- edged for a research grant to S. P. The Netherlands
Research Council (NWO) is acknowledged for financial support
7
25] N. Stuhr-Hansen, N. Bork, K. Stromgaard, Org. Biomol. Chem. 2014, 12,
5
745.
(
ECHO grant) to L. W. The authors also thank Dr. Steen Inge-
[26] During the course of this work, a study demonstrated an efficient syn-
thesis of peptide thioesters using PyBOP, which differed from our experi-
ments in solvent only (DMSO vs. DCM), see: P. Agrigento, F. Albericio, S.
Chamoin, I. Dacquignies, H. Koc, M. Eberle, Org. Lett. 2014, 16, 3922.
mann and Mr. Han Peeters for analytical assistance.
Keywords: Peptides · Cyclization · Peptide thioesters ·
Lactamization
Received: October 26, 2015
Published Online: December 21, 2015
Eur. J. Org. Chem. 2016, 443–446
www.eurjoc.org
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