An interesting dichotomy in the cyclisation of exocyclic enamines with protected dehydroamino acids leading to different β-turn templates

Article abstract of DOI:10.1016/S0040-4039(02)02141-X

Two templates for the preparation of external β-turns have been synthesised. In the course of the synthetic studies an interesting dichotomy was observed in the PCl₃ catalysed reaction of exocyclic enamines such as 6 and 14 with protected dehyd

Full text of DOI:10.1016/S0040-4039(02)02141-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8963–8966
An interesting dichotomy in the cyclisation of exocyclic enamines
with protected dehydroamino acids leading to different
b-turn templates
Jane M. Berry, Paul M. Doyle and Douglas W. Young*
Sussex Centre for Biomolecular Design and Drug Development, CPES, University of Sussex, Falmer, Brighton, BN1 9QJ, UK
Received 14 August 2002; accepted 26 September 2002
Abstract—Two templates for the preparation of external b-turns have been synthesised. In the course of the synthetic studies an
interesting dichotomy was observed in the PCl3 catalysed reaction of exocyclic enamines such as 6 and 14 with protected
dehydroamino acids. When amide protected dehydroamino acids were condensed with 6 and 14 the expected 6/6 and 6/5 fused
bicyclic compounds such as 7 and 15 respectively were obtained, whereas when urethane protected dehydroamino acids were used,
the 5/6 and 5/5 fused products 9 and 18 were obtained. © 2002 Elsevier Science Ltd. All rights reserved.
We are prompted by the recent publication by Millet et
al.1 to report the results of studies on the synthesis of
beta-turn mimetics. Millet et al. used methodology
developed in our laboratory2 to prepare bicyclic com-
pounds of type 1 of defined stereochemistry. We now
report the synthesis of beta-turn templates of this type
and also of type 2, and the discovery of an interesting
dichotomy in this synthesis, which appears to depend on
the nature of the protecting group used.
prepared by Nagai5–7 was an early example of such a
compound and it was used successfully (a) to replace the
Pro-D-Phe dipeptide sequence in gramicidin S,6 (b) to
prepare mimetics of enkephalin and luteinising hormone
releasing factor (LRF) with biological activity,7 and (c)
to define a biological conformation in CGRP 8-37.8
During work on the synthesis of the bridged b-lactam 4,9
we developed2 a facile one-step synthesis of a series of
bicyclic compounds 7 by the method shown in Scheme
1. The products of this synthesis were all esters at C-4
and some (7a, b, c and d) were substituted at C-7 with
protected amino groups. It was evident, therefore, that
suitably protected derivatives of these compounds might
act as external b-turn mimetics, since selective deprotec-
tion might allow appropriate cyclic peptides to be built
on this template. The fact that the compounds 7 were not
homochiral was a problem that might be addressed by
separation of the diastereoisomers produced when the
turn was built up by reaction of the mimetic with
L-amino acids.
Reverse turns connect elements of protein secondary
structure such as a-helices and b-sheets and, since they
usually occur on the surface of the protein, these turns
can be important in molecular recognition processes.3,4
Since native proteins are large, have poor transport
properties and are prone to proteolysis, an interest has
developed in synthetic molecules which mimic the turns
in these proteins responsible for molecular recognition.
These can have the therapeutic effect of the protein they
mimic without any of the transport or other associated
problems. The external bicyclic turn mimetic BTD 3
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02141-X

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J. M. Berry et al. / Tetrahedron Letters 43 (2002) 8963–8966
Scheme 1. (i) PCl3 (7a 92%; 7b 90%; 7c 80%; 7d 81%; 7e 56%; 7f 39%).
Scheme 2. (i) PCl3 (9a 57%; 9b 53%).
B rather than by nucleophilic attack at C-3 of the
The benzyloxycarbonyl derivatives 7g and 7h were cho-
sen as the first targets and so 2-(benzyloxycarbonyl-
amino)-acrylic acid 8a10 was reacted with the esters 6c2
and 6d2 respectively in the presence of PCl3 as shown in
Scheme 2. The products were not the reduced pyrido-
thiazines 7g or 7h, expected by analogy to our previous
work,2 since the characteristic signals for H-7 and H-8,
seen in the analogous compounds 7a,b,c and d, were
1
enamine tautomer A, as shown in Scheme 2. The H
NMR spectrum of the urethane 8a suggested that some
of the imine tautomer
B might accumulate in
(C[2H3])2SO with time, as a singlet appeared at 1.89
ppm in the 1H NMR spectrum on standing in this
solvent. It is interesting to note that intramolecular
attack by a nitrogen nucleophile occurs in the dehy-
drodipeptide 10 at the a-carbon atom by the allowed
5-exo-trig cyclisation mode to give the product 11
(Scheme 3) even though the alternative 6-endo-trig
cyclisation is also allowed.12 Further, it has been shown
that reaction of a 2-(acetylamino)-acrylic ester with
HBr first gives the 2-bromo compound as the kinetic
1
not present in the H NMR spectra of the compounds.
1
An additional methyl singlet was observed in both H
NMR spectra. This suggested that the products were in
fact the pyrrolinothiazines 9a† and 9b,† an assignment
which was confirmed by single crystal X-ray structure
analysis of the methyl ester 9b.11
The well-tried synthesis of pyridothiazines2 had thus
proceeded in an anomalous manner when the dehy-
droamino acid used was protected as a urethane. The
structure of the product suggested that the reaction had
proceeded by nucleophilic attack on the imine tautomer
† These compounds had the expected analytical and spectroscopic
properties.
Scheme 3.

J. M. Berry et al. / Tetrahedron Letters 43 (2002) 8963–8966
8965
Scheme 4. (i) NCCH2CO2t Bu/NEt3 (58%); (ii) CF3CO2H (68%); (iii) 8b+PCl3/dioxane/benzene (41%); (iv) ortho-phenylenediamine
(43%); (v) 8a/PCl3 (21% 17+18).
product and that this then rearranges to the 3-bromo
compound, the product of thermodynamic control.13
The nitrogen lone pair is certainly more available in the
urethane derivative 8a to allow tautomerism to the
form B than it is in the compounds 5a and 5b which
form six membered ring products by preliminary
Michael attack on the thiazine 6a.
The mixed geometric isomers 14 were now reacted with
chloroacetylaminoacrylic acid 8b and PCl3 to afford the
protected hexahydroindolizine 15† in 41% yield, and
treatment of this with ortho-phenylenediamine gave the
template amino acid 16.†
The 6/6- and 6/5-bicyclic b-turn free amine templates
had now been prepared and it was interesting to see if
an ‘anomalous’ cyclisation reaction might be observed
in the reaction of 2-(benzyloxycarbonylamino)-acrylic
acid 8a with the enamine 14. When these compounds
were reacted in the presence of PCl3, a product was
obtained in 21% yield which appeared to be a mixture
of pairs of diastereoisomers of 17 and 18. The only pure
product to be obtained by repeated column chromato-
graphy was one of the diastereoisomers of the ‘anoma-
lous’ product 18. It is interesting that when Millet et
al.1 conducted the condensation of the dehydroamino
acid 8a with a very similar compound to our enamine
14 using 1-ethyl-3-(3%-dimethylaminopropyl)-carbodi-
imide, only the ‘normal’ condensation product
analogous to 17 was obtained. The PCl3 cyclisation
conditions are therefore important if the anomalous
condensation products are to be obtained.
Since the pyrrolinothiazines 9 might themselves be use-
ful b-turn mimetics, attempts were made to remove the
benzyloxycarbonyl group from 9a and 9b under a vari-
ety of conditions, but to no avail.
Because of the anomalous reaction observed when ure-
thane protection was used, the reaction was investi-
gated using the chloroacetyl group to protect the amine
function of the dehydroamino acid. The esters 6c2 and
6d2 were therefore reacted with 2-(chloroacetylamino)-
acrylic acid 8b14 in the presence of PCl3 as shown in
Scheme 2. The products obtained, 7i† and 7j,† were
those expected from ‘normal’ cyclisation, having spec-
tral and analytical characteristics of the other pyrido-
thiazines in Scheme 1. An attempt to resolve these
racemic products by selective hydrolysis of the L-
chloroacetamide using immobilised acylase I from
Aspergillus proved unsuccessful. The chloroacetylamine
7j was converted to the corresponding free amine† by
reaction with ortho-phenylenediamine.
Acknowledgements
One of us (J.M.B.) thanks the EPSRC and GlaxoWell-
come for a CASE award.
We now turned our attention to the synthesis of the
6/5-bicyclic system 1. The imino ether 12† was first
prepared from ethyl (2S)-pyroglutamate15 in 92% yield
using Meerwein’s reagent (Scheme 4). This was then
reacted with tert-butyl cyanoacetate and triethylamine
to yield the vinylogous urethane 13† as a single geomet-
rical isomer in 58% yield. This compound was assumed
to be the Z-isomer shown, as it would be expected to
be stabilised by hydrogen bonding. Treatment with
trifluoroacetic acid gave a 1:1 mixture of the E and Z
isomers 14,† the identity of the isomers in the mixture
being determined with the aid of a 2D-COSY spectrum
and nOe studies.
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J. M. Berry et al. / Tetrahedron Letters 43 (2002) 8963–8966
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9b:
C27H26N2O7S, M=522.57, monoclinic, space group P21/a
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,
(No14), a=9.799(2), b=19.412(2), c=14.241(1) A, i=