Synthesis and reactivity of enediynyl amino acids and peptides: a novel concept in lowering the activation energy of Bergman cyclisation by H-bonding and electrostatic interactions.

Article abstract of DOI:10.1039/b308976m

Novel enediynyl amino acids and peptides 3 and 5-8 were synthesized and their thermal reactivity towards Bergman cyclization studied and compared with the earlier reported amino acid 4, which demonstrated, for the first time, the effect of H-bonding and e

Full text of DOI:10.1039/b308976m

Synthesis and reactivity of enediynyl amino acids and peptides: a novel
concept in lowering the activation energy of Bergman cyclisation by
H-bonding and electrostatic interactions†
Amit Basak,* Subhendu Sekhar Bag and Hussam M. M. Bdour
Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India.
E-mail: absk@chem.iitkgp.ernet.in
Received (in Cambridge, UK) 29th July 2003, Accepted 29th August 2003
First published as an Advance Article on the web 12th September 2003
Novel enediynyl amino acids and peptides 3 and 5–8 were
synthesized and their thermal reactivity towards Bergman
cyclization studied and compared with the earlier reported
amino acid 4, which demonstrated, for the first time, the
effect of H-bonding and electrostatic interactions in lowering
the activation energy of Bergman cyclization.
thereby lowering the c,d-distance and hence the activation
barrier for cycloaromatization. Metal ion coordination, in
general, has been shown to lower the activation barrier for BC
in acyclic enediynes5–8 through metal–ligand interactions.
To know the effect of the electrostatic and H-bonding
interactions on the c,d-distance, we carried out molecular
mechanics calculations in the gas phase on the amino acid 9
using the program Hyperchem Pro6 (Hypercube Inc., Scientific
Software). The energy minimized conformations were refined
by performing an optimized geometry calculation using aug-
mented MM force field parameters. Interestingly, although 9 is
an acyclic enediyne, the c,d-distance surprisingly came out to be
quite low, 3.298 Å, which is within the critical range for
spontaneous cyclization. We have also carried out similar
calculations on the peptides 7 and 8 (Fig. 1). The c,d-distance
for peptide 7 (3.902 Å) came out to be lower than that for
peptide 8 (4.067 Å).
During our studies1 on enediyne model systems, we became
interested in the synthesis of w-amino enediyne carboxylic acid
1. The reason for our curiosity was two fold: 1) we wished to
explore the influence of electrostatic and hydrogen bond
forming interactions between the carboxylic acid and the amino
group on the cycloaromatization process and 2) we were
interested in the possible elaboration of these amino acids into
b-turn mimetics as depicted in structure 2.
Although electrostatic or H-bond interactions will be differ-
ent in the solution phase, initial calculations predicted some
degree of reactivity difference in these compounds. Un-
fortunately, we could not synthesize the amino acid 9 as the
Sonogashira coupling9 involving propargylic esters created
problems. The higher homologous acid, 3-butynoic acid, could
not be used because of the problem of easy tautomerization to
the allenic acid. This prompted us to synthesize the amino acids
and the peptides from the commercially available 4-pentynoic
acid.
The synthesis of the amino acid 3 started with the Pd(0)-
catalysed coupling of cis-dichloroethylene and propargyl alco-
hol. The mono coupled product was then converted1 to amine
11, which was immediately t-Boc protected. A second round of
Pd(0)-mediated coupling with 4-pentynoic acid benzyl ester
gave the fully protected enediynyl amino acid 5, which was
isolated pure by column chromatography. The benzyl ester was
then removed by stirring in an alkaline methanol solution. Final
deprotection was done with TFA. The synthesis is shown in
Scheme 1.
Recently2 we have reported the synthesis and conformational
preferences of novel enediynyl tripeptides, which exist predom-
inantly in the intramolecularly H-bonded form, to be used as a
scaffold for b-turn mimetics. In this communication, we report
the effect of weak interactions, especially H-bonding and
electrostatic interactions, on the kinetics of Bergman cyclization
by studying the thermal reactivity of the enediynyl amino acid
in free (3 and 4) and protected forms (5 and 6) and also of the
dipeptides (7 and 8). Specifically, our intention was to
investigate the possibility of encouraging Bergman Cyclization
(BC) by pulling the reactive centers together with electrostatic
interactions. Incidentally, except for amino acid 4, all other
compounds are new and are reported here for the first time.
Among the various parameters that control the kinetics of
BC, the distance between the acetylenic carbon atoms under-
going covalent connection, commonly referred to as the c,d-
distance,3 has become extremely useful in spite of some
limitations.4 As compared to the cyclic ones, acyclic enediynes
have a comparatively high c,d-distance, which is much greater
than the critical distance range required for spontaneous
cyclization as proposed by Nicolaou and others.3 However, it is
not unreasonable to think that acyclic enediynyl amino acids
may form a cyclic network via intramolecular H-bond or
electrostatic interactions between the terminal zwitterions
Fig. 1 MM2 minimized structures of enediynes 7 and 9.
† Electronic supplementary information (ESI) available: optimised geome-
try of peptide 8, DSC curves of enediynes 3–6 and d vs. T curves for peptides
7 and 8. See http://www.rsc.org/suppdata/cc/b3/b308976m/
Scheme 1
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This journal is © The Royal Society of Chemistry 2003

The preparation of the higher homologous amino acid 4 has
already been reported.2 The enediyne-based dipeptides 7 and 8
were synthesized from 1,2-dibromobenzene. After the first
Pd(0)-mediated coupling with 4-pentynoic acid benzhydryl
ester, the resulting bromo eneyne 15 was deprotected with TFA
and then coupled with -alanine methyl ester. Another round of
L
coupling with N-t-Boc propargyl amine afforded the target
peptide 7. For the synthesis of the other peptide 8, the second
coupling was done with homopropargyl alcohol. The enediyne
alcohol 17 was then converted to the target peptide 8 via the
azide 19 as shown in Scheme 2.
Fig. 3 BC kinetics in DMSO. Insert: Temperature dependence of NH
The onset temperatures for BC for these enediynyl amino
acids and the peptides were determined using Differential
Scanning Calorimetric (DSC)10 measurements which were
recorded in the neat state without any solvent. For the fully
protected amino acids 5 and 6, which were viscous oils, the
onset temperature for BC came out to be ~ 111 and 133 °C
respectively. However when the same was recorded for the free
amino acids (semi-solids), both the onset temperatures were
lowered. For the amino acid 3, the onset temperature for BC
came out to be ~ 92 °C (a decrease of ~ 19 °C). For the higher
homologous amino acid 4, the exothermic rise started at ~ 99 °C
showing a lowering of the onset temperature of ~ 34 °C. For the
two peptides, the difference in onset temperature for BC is even
more striking. While the peptide containing the propargyl arm 7
showed an exothermic rise starting from ~ 121 °C, the higher
homologue 8 did not cyclize until being heated up to ~ 207 °C.
As representative examples, the DSC curves of peptides 7 and
8 (both viscous oils) are shown in Fig. 2.
We ascribe this large difference in reactivity towards BC to
the presence of stronger intramolecular H-bonding involving
the carbamate NH and the amide carbonyl. This has been
supported by the energy minimized geometry as well as by
variable temperature NMR11 experiments. The carbamate NH
showed very low temperature dependence in d6-DMSO (insert
of Fig. 3) and is within the Kessler limit12 of 23 ppb K21 thus
proving a high degree of intramolecular H-bonding in peptide 7.
Solution phase kinetics in DMSO in the presence of 1,4-CHD at
150 °C was also carried out, the rate of disappearance of the
enediynyl peptides were monitored by HPLC using an internal
standard (naphthalene).13 This also revealed higher reactivity of
peptide 7 (kobs = 12 3 1022 h21) as compared to peptide 8 (kobs
chemical shifts.
= 2.08 3 1022 h21) (Fig. 3). That the BC is the major process
occurring under these thermal conditions was evident from the
appearance of new aromatic peaks in the 1H-NMR which
corresponded to the cyclized product. However, the cyclized
product yields were low (15–25%) although most of the starting
material was consumed. The low yield is attributed to the
formation of polynaphthalene type compounds via BC followed
by polymerization.14 In general, cyclizations all have good mass
balance.
In conclusion, we have been able to demonstrate the
importance of H-bonding/electrostatic interactions in lowering
the activation energy of BC. Current studies are aimed towards
incorporating DNA-bases into the two arms of enediynes and
exploring their reactivity.
A. B. thanks DST, Government of India, for financial
assistance. S. S. B. is grateful to CSIR, Government of India, for
a research fellowship.
Notes and references
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Scheme 2 Reagents and conditions: a Pd(PPh3)4, benzhydryl 4-pentynoate,
CuBr2, NEt3, 76%; b
propargyl amine, Pd(PPh3)4, Cu2Br2, NEt3, 70%;
L
-alanine methyl ester, EDCl, DMF, 82%; c N-Boc
3-butyn-1-ol,
d
Pd(PPh3)4, Cu2Br2, NEt3, 70%; e NEt3, MsCl, CH2Cl2, 89%; f NaN3, DMF,
85%; g PPh3, H2O, THF then Boc2O, EtOAc, 80%.
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14 C.-S. Kim, C. Diez and K. C. Russel, Chem. Eur. J., 2000, 6, 1555.
Fig. 2 DSC of peptides 7 (left) and 8 (right).
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