Short and efficient synthesis of Homo-Freidinger lactams: An olefin metathesis approach towards conformationally restricted β-amino acid analogues

Article abstract of DOI:10.1055/s-2002-31916

Peptide coupling of the N-allyl or N-homoallyl α-amino acid esters 6a-d with enantiomerically pure β-C-allylglycine gave access to the dienes 7a-d which were subjected to an olefin metathesis reaction. Thus, the novel lactam bridged peptide mimics 8a-d we

Full text of DOI:10.1055/s-2002-31916

1014
LETTER
Short and Efficient Synthesis of Homo-Freidinger Lactams: An Olefin
Metathesis Approach Towards Conformationally Restricted -Amino Acid
Analogues
Synthesis of
Ho
o
mo-Freiding
b
er Lactam
s
ias Hoffmann, Peter Gmeiner*
Department of Medicinal Chemistry, Emil Fischer Center, Friedrich-Alexander University, Schuhstr. 19, 91052 Erlangen, Germany
Fax +49(9131)8522585; E-mail: gmeiner@pharmazie.uni-erlangen.de
Received 27 March 2002
were developed, representing conformationally con-
Abstract: Peptide coupling of the N-allyl or N-homoallyl -amino
strained -amino acid equivalents.8 As a part of our pro-
acid esters 6a–d with enantiomerically pure -C-allylglycine gave
gram established for the design of -analogues9 of the
access to the dienes 7a–d which were subjected to an olefin
metathesis reaction. Thus, the novel lactam bridged peptide mimics
dopamine D2 receptor modulating peptide Pro-Leu-Gly-
8a–d were obtained in good overall yield. Modifications in ring size NH2 (PLG),10 Homo-Freidinger lactam derived tripeptide
and substitution pattern of the Homo-Freidinger lactams were dem-
onstrated.
mimics were shown to adopt -turn related structures and
to induce an increase of affinity at the dopamine D2 recep-
tor.11 As an extension of our studies towards the synthesis
Key words: -amino-acids, lactams, metathesis, peptide mimics,
ruthenium
of enantiopure -amino acid derivatives and the design of
secondary structure model systems,12 we wish to present
our results concerning the synthesis of unsaturated Homo-
Constrained peptides offer a fascinating challenge to gain Freidinger lactams of type B (Scheme 1), when an olefin
insight into molecular recognition processes between pep- metathesis is employed as the key reaction step.
tide ligands and bio-receptors. Thus, the incorporation of
peptide backbones into cyclic structures has attracted tre-
mendous efforts on the synthesis of enzyme inhibitors,
peptide hormones and neuroreceptor ligands.1,2 Among
numerous examples, especially Freidinger lactams
(Scheme 1, formula A, n = 0) were proven successful.3,4 In
addition, the application of the olefin metathesis reaction5
to the synthesis of Freidinger lactams and other cyclic
amino acid derivatives was recently demonstrated,6 thus
constraining the backbone of -amino acids by an olefin
linker.
Scheme 2 a) 4-nitrobenzenesulfonyl chloride, NEt3, CH2Cl2, 0 °C
(70–80%); b) allyl bromide, K2CO3, DMF for 5a (92%) and for 5b
(95%), 3-bromo-2-methyl-1-propene, K2CO3, DMF for 5c (94%), 3-
butene-1-ol, DEAD, PPh3, CH2Cl2 (76%) for 5d; c) PhSH, K2CO3,
Scheme 1
DMF (50–80%); d) DCC, HOBt, (S)-N-Boc-3-amino-5-hexenoic
acid, CH2Cl2 (40–94%); e) 9a (10 mol%) or 9b (5 mol%), see Table.
On the other hand, the remarkable metabolic stability and
the interesting structural properties of -amino acid de-
rived peptide mimics are well-known.7 Based on these
findings, Homo-Freidinger lactams (formula A, n = 1)
Following our plan of synthesis as indicated for B, the
metathesis precursors 7a–d were prepared by DCC–
HOBt induced peptide coupling of (S)-N-Boc-3-amino-5-
hexenoic acid13 with the N-allyl and N-homoallyl amino
acid esters 6a–c and 6d, (Scheme 2). In turn, the second-
ary amines 6a–d were readily available from the natural
Synlett 2002, No. 6, 04 06 2002. Article Identifier:
1437-2096,E;2002,0,06,1014,1016,ftx,en;G07702ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
Synthesis of Homo-Freidinger Lactams
1015
amino acid derivatives 4a,b by sulfonylation, alkylation studies in medicinal chemistry. The catalyst 9b is known
of the respective sulfonamides and subsequent thiol-as- to tolerate different substitution patterns of the participat-
sisted deprotection of the alkylation products 5a–d. This ing double bonds in metathesis reactions.19 In fact, start-
strategy was first developed by Fukuyama14 and recently ing from the isopropenyl derivative 7c, the cycloolefin 8c
applied by Reichwein and Liskamp.15 Starting from the could be obtained in 82% yield (entry 3). Variation of the
cyclization precursors 7, we tried to prepare differently ring size of lactam based templates is of particular interest
sized Homo-Freidinger lactams to evaluate the synthetic for investigating the conformational behavior of peptide
scope of our approach. The results of the RCM reaction of mimics.12 Thus, we were happy to accomplish the synthe-
the dienes 7a–d are summarized in the Table.
sis of the 9-membered azoninone 8d in 47% and 64%
yield from the precursor 7d renouncing any conforma-
tional predispositions which might have accelerating ef-
fects (entry 4). According to the NMR spectra, the
endocyclic double bond of 8d shows cis-geometry, exclu-
sively. Oligomerization products were not observed.
Table Results of the Metathesis Reaction of the Dienes 7a–d
(2 mM, Reflux, DCE)
En- Diene
try
Cycloolefin
Catalyst
(yield)
In summary, we have developed a valuable and widely ap-
plicable synthetic procedure to lactam-bridged dipeptide
mimics exploiting the combination of ex-chiral-pool syn-
thesis and olefin metathesis reaction. The strategy enables
the synthesis of the hitherto unknown unsaturated Homo-
Freidinger lactams. Further investigations are ongoing in
our laboratory.
1
2
3
4
9a (44%)
9b (65%)
7a
7b
7c
7d
8a
9a (61%)
9b (82%)
Acknowledgement
This work was supported by the BMBF and the Fonds der Chemi-
schen Industrie. Dr. R. Waibel is acknowledged for helpful discus-
sions.
8b
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Waibel, R.; Gmeiner, P. Heterocycles 1999, 51, 1389.
The olefin metathesis experiments were performed em-
ploying the ruthenium-based catalysts 9a or 9b.16 Since it
is well known that elevated temperatures facilitate ring
closure to medium sized rings,17 1,2-dichloro ethane
(DCE) at reflux temperature (81 °C) was utilized for all
metathesis reactions. In addition, we chose a substrate
concentration of 2 mM since this concentration has
proved to be sufficient to prevent possible oligomeriza-
tion processes.12 As a matter of fact, all cyclizations suc-
ceeded without any detectable by-products.18 The
synthesis of the azocinone 8a from the diene 7a proceeded
with satisfying yield when promoted by Grubbs’ catalyst
9a (entry 1). Running the same reaction with the highly
active ruthenium complex 9b bearing a N-heterocyclic
carbene ligand, an increase of the yield was observed. Af-
ter this first encouraging results we were happy to obtain
the alanine derived azacycle 8b (entry 2), thus showing
the possibility to introduce various side chains into the tar-
get dipeptidic structures which will be of interest for SAR
Synlett 2002, No. 6, 1014–1016 ISSN 0936-5214 © Thieme Stuttgart · New York

1016
T. Hoffmann, P. Gmeiner
LETTER
(9) Thomas, C.; Ohnmacht, U.; Niger, M.; Gmeiner, P. Bioorg.
Med. Chem. Lett. 1998, 8, 2885.
(10) Chiu, S.; Paulose, C. S.; Mishra, R. K. Science (Washington
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(11) Weber, K.; Ohnmacht, U.; Gmeiner, P. J. Org. Chem. 2000,
65, 7406.
(12) Hoffmann, T.; Lanig, H.; Waibel, R.; Gmeiner, P. Angew.
Chem. Int. Ed. 2001, 40, 3361; Angew. Chem. 2001, 113,
3465.
(13) Obtained from PepTechCorp, Cambridge, 02140 MA and
used without further purification.
(14) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett.
1995, 36, 6373.
(15) (a) Reichwein, J. F.; Liskamp, R. M. J. Eur. J. Org. Chem.
2000, 2335. (b) Reichwein, J. F.; Liskamp, R. M. J.
Tetrahedron Lett. 1998, 39, 1243.
(16) (a) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem.
Soc. 1996, 118, 100. (b) Scholl, M.; Ding, S.; Lee, C. W.;
Grubbs, R. H. Org. Lett. 1999, 1, 953.
8.03; N, 8.58. Found: C, 59.05; H, 8.21; N, 8.43. TLC: Rf
0.12 (ligroin–EtOAc, 6:4).
8b: colorless oil, [ ]D22 –25.7 (0.07, CHCl3). 1H NMR (360
MHz, CDCl3): 1.39 (d, J = 7.1 Hz, 3 H, CH3), 1.44 (s, 9 H,
tert-Bu), 2.35–2.47 (m, 3 H, H-5a,b/H-3a), 2.95 (dd, J =
12.2, 5.5 Hz, 1 H, H-3b), 3.69 (s, 3 H, OCH3), 3.82–3.95 (m,
1 H, H-8a), 4.05–4.15 (m, 2 H, H-8b/H-4), 5.30 (d, J = 8.5
Hz, 1 H, NH), 5.36 (q, J = 7.1 Hz, 1 H, -CH), 5.45–5.55 (m,
1 H, CH=), 5.70–5.80 (m, 1H, CH=). 13C NMR (CDCl3, 91
MHz): = 14.8, 28.6, 29.4, 36.9, 47.7, 49.4, 52.1, 60.4, 79.3,
126.1, 128.9, 154.9, 160.4, 172.0. IR(film): 3318, 2978,
1741, 1708, 1641, 1502, 1475 cm–1. MS (EI): m/z 326 [M+].
Anal. Calcd for C16H26N2O5: C, 58.88; H, 8.03; N, 8.58.
Found: C, 58.73; H, 8.11; N, 8.31. TLC: Rf 0.11 (ligroin–
EtOAc 6:4).
8c: colorless oil, [ ]D20 +31.6 (0.19, CHCl3). 1H NMR
(CDCl3, 360 MHz): 1.28 (t, J = 7.1 Hz, 3 H, CH3), 1.42 (s,
9 H, tert-Bu), 1.67 (s, 3 H, CH3), 2.35–2.40 (m, 3 H, H-5a,b/
H-3a), 2.98 (dd, J = 12.4, 5.3 Hz, 1 H, H-3b), 3.64 (d, J =
17.8 Hz, 1 H, -CH2), 4.20 (q, J = 7.2 Hz, 2 H, OCH2), 4.28
(d, J = 17.5 Hz, 1 H, -CH2), 4.75–4.95 (m, 2 H, H-8a,b),
5.24 (d, J = 8.5 Hz, 1 H, NH), 5.48–5.55 (m, 1 H, H-4), 5.55–
5.60 (m, 1 H, CH=). 13C NMR (CDCl3, 91 MHz): 14.1,
19.9, 23.3, 28.4, 29.7, 36.9, 50.0, 56.3, 61.3, 79.2, 121.9,
135.2, 154.9, 169.3, 173.1. IR(film): 3340, 2978, 2935,
1745, 1708, 1646, 1504 cm–1. MS (EI): m/z 340 [M+]. Anal.
Calcd for C17H28N2O5 1/4 H2O: C, 58.94; H, 8.14; N, 8.09.
Found: C 58.87; H, 8.56; N, 7.57. TLC: Rf 0.18 (ligroin–
EtOAc 1:1).
(17) Alkene Metathesis in Organic Synthesis: Fürstner, A. Top.
Organomet. Chem. 1998, 1, 37.
(18) General Procedure for the Ring-Closing Olefin
Metathesis Reaction: Catalyst 9a (10 mol%) or 9b (5
mol%), was added to a 2 mM solution of the diene 8 in
degassed 1,2-dichloro ethane under an atmosphere of dry
nitrogen employing flame-dried glass ware. Subsequently,
the mixture was heated to reflux until TLC indicated
completion of the reaction. After evaporation of the solution
the resulting residue was purified by column
chromatography on Merck silica gel (230-400 mesh, ASTM)
using freshly distilled solvents. All RCM-products were
fully characterized by spectroscopic methods and
microanalysis:
8d: colorless oil, [ ]D22 +9.2 (0.13, CHCl3). 1H NMR
(DMSO-d6, 360 MHz, 353 K): 1.20 (t, J = 7.1 Hz, 3 H,
CH3), 1.40 (s, 9 H, tert-Bu), 2.15–2.25 (m, 2 H, CH2), 2.28–
2.39 (m, 2 H, CH2), 2.40–2.50 (m, 2 H, CH2), 3.45–3.60 (m,
2 H, H-9a,b), 3.70–3.85 (m, 1 H, H-4), 3.97 (d, J = 17.0 Hz,
1 H, -CH2), 4.07 (d, J = 17.0 Hz, 1 H, -CH2), 4.11 (q, J =
7.1 Hz, 2 H, OCH2), 5.62 (ddd, J = 8.5, 10.6, 8.5 Hz, 1 H,
CH=), 5.76 (ddd, J = 8.1, 10.6, 8.1 Hz, 1 H, CH=), 6.28 (br
s, 1 H, NH). 13C NMR (DMSO-d6, 91 MHz): = 13.9, 26.0,
28.1, 31.3, 40.8, 49.6, 49.9, 50.3, 60.3, 79.1, 128.4, 130.2,
154.3, 169.3, 171.7. IR(film): 3385, 2979, 2933, 1747, 1706,
1630, 1487 cm–1. MS (EI): m/z 340 [M+]. Anal. Calcd for
C17H28N2O5: C, 59.98; H, 8.29; N, 8.23. Found: C, 59.61; H,
8.48; N, 7.93. TLC: Rf 0.13 (ligroin/EtOAc 6:4).
8a: colorless oil, [ ]D21 +5.3 (0.19, CHCl3). 1H NMR (360
MHz, CDCl3): 1.28 (t, J = 7.1 Hz, 3 H, CH3), 1.43 (s, 9 H,
tert-Bu), 2.35–2.46 (m, 3 H, H-5a,b/H-3a), 3.01 (dd, J =
12.4, 5.3 Hz, 1 H, H-3b), 3.78–3.89 (m, 1 H, H-8a), 4.00–
4.10 (m, 1 H, H-4), 4.16 (d, J = 17.4 Hz, 1 H, -CH2), 4.20
(q, J = 7.2 Hz, 2 H, OCH2), 4.24 (d, J = 17.4 Hz, 1 H, -CH2),
4.31–4.45 (m, 1 H, H-8b), 5.30 (d, J = 8.2 Hz, 1 H, NH),
5.48–5.66 (m, 1 H, CH=), 5.72–5.83 (m, 1 H, CH=). 13
C
NMR (CDCl3, 91 MHz): 14.1, 28.3, 29.8, 36.8, 48.9, 49.8,
52.6, 61.3, 79.2, 126.3, 128.5, 154.8, 169.2, 171.0. IR(film):
3324, 2977, 2931, 1747, 1712, 1700, 1643 cm–1. MS (EI):
m/z 326 [M+]. Anal. Calcd for C16H26N2O5: C, 58.88; H,
(19) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18.
Synlett 2002, No. 6, 1014–1016 ISSN 0936-5214 © Thieme Stuttgart · New York