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Conformationally constrained amino acids: Synthesis of novel 3,4-cyclised tryptophans
TurcJlcdron Lutera, Vol. 35. No. 6. pp. 939-940.1994 Elsevia Scicrre L.td Printad in Great Britain #IO-4039M S~.ODUMN~
WKMl039(93)Eo349-0
Confonnationally
Constrained Amino Acids: Synthesis of Novel 3,4Cyclised Tryptophans. David C Horwell, Pti
Parke-Davis
D. Nichols and Edwud Robe**
Neuroscience Research Centra. Addanbrookes Hospital, Hills Road, Cambridge. CB2 2QB. U.K.
Key Words.- Conformational; Abstract: The synthesis of novel conformationally
Tryptophan; 3.4cyclisation;
constrained tryptophan derivatives
a-substituted
The development
of potential
Synthesis; Heck. via a Heck-type
cyclisation
of an unusual
amino acid is described.
therapeutic
based on the structure of peptides has stimulated
agents
keen interest in the design and synthesis of unusual and unnatural amino acids.‘.’ When incorporated peptide of interest, these surrogates making them non-peptidic, amino acid analogues
may infer conformational
constraint
as well as increasing
been
reported
in the literature
which
include
Many cyclic
of cyclic
a number
into the
biostability
rather peptoidic, and suitable for potential use as drug candidates6
have
a
ttyptophan
derivatives.7*“V Cyclic derivatives into peptides isomerism partner.
without
that have the a-nitrogen
perturbing
and the removal
consequence,
considered
was a Heck-type
according
Dehydration
of the formamide was realised
protection
of the a-nitrogen the palladium
6 with methanolic amine
according
scheme.
lithium
yielded
cyclisation
the indole
cyclisation proceeded using standard Heck methodology. after being separated
phase
NOESY
silica.
elemental
Detailed
analysis
and COSY
was
by medium
then
were used to assign the structural
acid we 8.
protected
as the
Boc
derivative.
for a-alkylation.
ally1 bromide
interference
3 was
in 45%
yield.
The
(Z) group.
This
from the isonitrile. the amine.
This a-
Treatment
Protection
The
of compounds
which were identified
liquid chromatography
(IvIPLC) over reverse
coupled
formulae
of
of the free
precursor 8, ready to attempt the cyclisation.
pressure
939
As a
compounds
group to the benzyloxycarbonyl
A 2: 1 mixture
experiments,
strategy to such
5 ready
Boc group and generated
gave the required
as 1 and 2 respectively
nitrogen
without
effects.
The 4-bromo-Na-formyltryptophan
diisopropylamide
to proceed
these
of 4-bromo-a-allyl-tryptophan
the isonitrile
from the isonitrile
as possible
both the amino and carboxylic
the synthesis
The indole
triphosgene
changed
with benzyloxycarbonylchloride
as much
bond
the nitrogen and a suitable
between
(1, 2) in which
to the synthetic
using
HCI both removed
to minimise
This would involve
procedures.”
was
bond formation
project
ring cannot be included
of the peptide through cis- ~tzuas- amide
to the 3,4- ring. One cyclisation
by the use of
catalysed
hydrogen
was considered
coupling.
to standard
alkylation
enabled
molecules
were exocyclic
This was achieved prepared
of the present
a set of target
groups on the a-carbon
the global conformation
of any possible
It was the intention
incorporated into the constraining
with
mass
to the compounds
spectrometry, (supplemental
W,
IR, and
material).
940
COO+&
NC
6
\BOC
co,hle
NH2
EJ
+
1
I>
’
Ii
Reagents
2b
Pa
1
and Conditions: i) Di-t-butyl carbonate, DMAP (cat.), DMF, RT, 18h. 94%; ii) Trrphosgene,
Et,N. CH,CI,, O”C.1Sh, 87%; iii) LDA, THF, -78oC. 0.5h. then ally1 bromide, RT,45%; iv) MeOH.HCI, 0°C to RT, 4h. s959%; v) Benzyl chlorofonnate, THF, pyridine. 18h, 70%; vi) Palladium acetate, Et,N, tri-o-tolylphosphine, acetomtrile,A, 6h. 88%
These data also revealed that 2 was a mixture of two isomers in equilibrium, which the double
bond has migrated.
tryptophan-containing
Compounds
peptides. These derivatives
designated
1. 2a and tb can act as surrogates and their biological
activities
2a and fb in
for tryptophan
in
will be reported elsewhere.
Acknowledgement The authors gratefully Refenaces
1. 2. 3. 4. 5.
6. 7. 8. 9.
10.
acknowledge
the N’MR determinations
carried out by Dr. G.S Ratcliffe.
and Notes:
Schiller, P.W.; Weltrowska, G.; Nguyen, T.M.D.; Lemieux, C.; Chung, N.N.; Marsden, B.J.; Wilkes, B.C., J Med. Chem., 1991, 34, 3125-3132. Webb, T.R.; Eigenbrot. C., J 0%. Chem., 1991, 56, 3009-15. Deeks, T.; Crooks, P.A.; Waigh, R.D., J. Med. Chem., 1983, 26, 762-765. Verschueren, K.; Toth, G; Lebl. M.; Van Binst, G.; Hruby, V.J., Synthesis, 1992, 458-460. Stammer, C.H., Termhedron, 1990, 46, 2231-2254. Horwell. DC; Hughes, J.; Hunter, J.C.; Pritchard, M.C.; Richardson, R.S.; Roberts, E.; Woodruff, G.N., 1 Med. Chem., 1991, 34, 404-414. Morgan, B.A.; Singh, J.; Baizman, E.; Bently, H.; Keifer, D.; Ward, S., in Proceedings offhe 10th. American Peptide Syniposium, Marshall, G.R. Ed.; Escom, Leiden, 1988; pp. 508-509. Chung, J.Y.L.; Wasicak, J.T.; Nadzan, A.M., Synthetic Commun., 1992, 22, 1039-1048. Nadzan, A.M.; Garvey, D.S.; Holladay, M.W.; Shiosaki, K.; Tufano, M.D.; Shue, Y.K.; Chung, J.Y.L.; May, P.D.; May, C.S.; Lin, C.W.; Miller, T.R.; Witte, D.G.; Bianchi, B.R.; Wolfram, C.A.W.; Burt, S.; Hutchins, C.W., in Proceedings of the 12th. American Peptide Symposium, Smith, J.; R_ivier, J.E , Eds.; Escom, Leiden, 1992, pp. 1OO- 102. Moyer, M.P.; Shiurba, J.F.; Rapoport, H., J Org. Chem., 1986, 51, 5106-5110.
(Received in UK 8 November 1993; revised 26 November
1993; accepted
3 December
1993)
WKMl039(93)Eo349-0
Confonnationally
Constrained Amino Acids: Synthesis of Novel 3,4Cyclised Tryptophans. David C Horwell, Pti
Parke-Davis
D. Nichols and Edwud Robe**
Neuroscience Research Centra. Addanbrookes Hospital, Hills Road, Cambridge. CB2 2QB. U.K.
Key Words.- Conformational; Abstract: The synthesis of novel conformationally
Tryptophan; 3.4cyclisation;
constrained tryptophan derivatives
a-substituted
The development
of potential
Synthesis; Heck. via a Heck-type
cyclisation
of an unusual
amino acid is described.
therapeutic
based on the structure of peptides has stimulated
agents
keen interest in the design and synthesis of unusual and unnatural amino acids.‘.’ When incorporated peptide of interest, these surrogates making them non-peptidic, amino acid analogues
may infer conformational
constraint
as well as increasing
been
reported
in the literature
which
include
Many cyclic
of cyclic
a number
into the
biostability
rather peptoidic, and suitable for potential use as drug candidates6
have
a
ttyptophan
derivatives.7*“V Cyclic derivatives into peptides isomerism partner.
without
that have the a-nitrogen
perturbing
and the removal
consequence,
considered
was a Heck-type
according
Dehydration
of the formamide was realised
protection
of the a-nitrogen the palladium
6 with methanolic amine
according
scheme.
lithium
yielded
cyclisation
the indole
cyclisation proceeded using standard Heck methodology. after being separated
phase
NOESY
silica.
elemental
Detailed
analysis
and COSY
was
by medium
then
were used to assign the structural
acid we 8.
protected
as the
Boc
derivative.
for a-alkylation.
ally1 bromide
interference
3 was
in 45%
yield.
The
(Z) group.
This
from the isonitrile. the amine.
This a-
Treatment
Protection
The
of compounds
which were identified
liquid chromatography
(IvIPLC) over reverse
coupled
formulae
of
of the free
precursor 8, ready to attempt the cyclisation.
pressure
939
As a
compounds
group to the benzyloxycarbonyl
A 2: 1 mixture
experiments,
strategy to such
5 ready
Boc group and generated
gave the required
as 1 and 2 respectively
nitrogen
without
effects.
The 4-bromo-Na-formyltryptophan
diisopropylamide
to proceed
these
of 4-bromo-a-allyl-tryptophan
the isonitrile
from the isonitrile
as possible
both the amino and carboxylic
the synthesis
The indole
triphosgene
changed
with benzyloxycarbonylchloride
as much
bond
the nitrogen and a suitable
between
(1, 2) in which
to the synthetic
using
HCI both removed
to minimise
This would involve
procedures.”
was
bond formation
project
ring cannot be included
of the peptide through cis- ~tzuas- amide
to the 3,4- ring. One cyclisation
by the use of
catalysed
hydrogen
was considered
coupling.
to standard
alkylation
enabled
molecules
were exocyclic
This was achieved prepared
of the present
a set of target
groups on the a-carbon
the global conformation
of any possible
It was the intention
incorporated into the constraining
with
mass
to the compounds
spectrometry, (supplemental
W,
IR, and
material).
940
COO+&
NC
6
\BOC
co,hle
NH2
EJ
+
1
I>
’
Ii
Reagents
2b
Pa
1
and Conditions: i) Di-t-butyl carbonate, DMAP (cat.), DMF, RT, 18h. 94%; ii) Trrphosgene,
Et,N. CH,CI,, O”C.1Sh, 87%; iii) LDA, THF, -78oC. 0.5h. then ally1 bromide, RT,45%; iv) MeOH.HCI, 0°C to RT, 4h. s959%; v) Benzyl chlorofonnate, THF, pyridine. 18h, 70%; vi) Palladium acetate, Et,N, tri-o-tolylphosphine, acetomtrile,A, 6h. 88%
These data also revealed that 2 was a mixture of two isomers in equilibrium, which the double
bond has migrated.
tryptophan-containing
Compounds
peptides. These derivatives
designated
1. 2a and tb can act as surrogates and their biological
activities
2a and fb in
for tryptophan
in
will be reported elsewhere.
Acknowledgement The authors gratefully Refenaces
1. 2. 3. 4. 5.
6. 7. 8. 9.
10.
acknowledge
the N’MR determinations
carried out by Dr. G.S Ratcliffe.
and Notes:
Schiller, P.W.; Weltrowska, G.; Nguyen, T.M.D.; Lemieux, C.; Chung, N.N.; Marsden, B.J.; Wilkes, B.C., J Med. Chem., 1991, 34, 3125-3132. Webb, T.R.; Eigenbrot. C., J 0%. Chem., 1991, 56, 3009-15. Deeks, T.; Crooks, P.A.; Waigh, R.D., J. Med. Chem., 1983, 26, 762-765. Verschueren, K.; Toth, G; Lebl. M.; Van Binst, G.; Hruby, V.J., Synthesis, 1992, 458-460. Stammer, C.H., Termhedron, 1990, 46, 2231-2254. Horwell. DC; Hughes, J.; Hunter, J.C.; Pritchard, M.C.; Richardson, R.S.; Roberts, E.; Woodruff, G.N., 1 Med. Chem., 1991, 34, 404-414. Morgan, B.A.; Singh, J.; Baizman, E.; Bently, H.; Keifer, D.; Ward, S., in Proceedings offhe 10th. American Peptide Syniposium, Marshall, G.R. Ed.; Escom, Leiden, 1988; pp. 508-509. Chung, J.Y.L.; Wasicak, J.T.; Nadzan, A.M., Synthetic Commun., 1992, 22, 1039-1048. Nadzan, A.M.; Garvey, D.S.; Holladay, M.W.; Shiosaki, K.; Tufano, M.D.; Shue, Y.K.; Chung, J.Y.L.; May, P.D.; May, C.S.; Lin, C.W.; Miller, T.R.; Witte, D.G.; Bianchi, B.R.; Wolfram, C.A.W.; Burt, S.; Hutchins, C.W., in Proceedings of the 12th. American Peptide Symposium, Smith, J.; R_ivier, J.E , Eds.; Escom, Leiden, 1992, pp. 1OO- 102. Moyer, M.P.; Shiurba, J.F.; Rapoport, H., J Org. Chem., 1986, 51, 5106-5110.
(Received in UK 8 November 1993; revised 26 November
1993; accepted
3 December
1993)