Aziridine-Mediated Ligation at Phenylalanine and Tryptophan Sites

Article abstract of DOI:10.1002/asia.201700538

An efficient approach towards peptide synthesis that allows easy access to variety of small peptides via one-pot aziridine-mediated ligation/desulfurization strategy has been described. The protocol afforded a library of phenylalanine- and tryptophan-containing α-peptides in good yields by regioselective ring-opening of aziridine-3-aryl-2-carboxylates with peptide thioacids, followed by desulfurization.

Full text of DOI:10.1002/asia.201700538

CHEMISTRY
AN ASIAN JOURNAL
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Accepted Article
Title: Aziridine-Mediated Ligation at Phenylalanine and Tryptophan
Sites
Authors: Kiran Bajaj and Rajeev Sakhuja
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To be cited as: Chem. Asian J. 10.1002/asia.201700538
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Aziridine-Mediated Ligation at Phenylalanine and Tryptophan
Sites
Kiran Bajaj,*[a] and Rajeev Sakhuja[a]
This work is dedicated to Late Prof. Alan Roy Katritzky
Abstract: An efficient approach towards peptide synthesis has been
described that allows an easy access to variety of small peptides via
one-pot aziridine-mediated ligation-desulfurization strategy. The
present protocol afforded a library of phenylalanine and tryptophan
containing α-peptides in good yields by regioselective ring-opening
of aziridine-3-aryl-2-carboxylates with peptide thioacids followed by
desulfurization.
installation into different peptide units. Apart from this, other
modified ligation strategies such as α-ketoacid-hydroxylamine
ligation (KAHA),[22] salicylaldehyde ester-mediated ligation,[23]
oxime ligation,[24] and Staudinger ligation[25a-b] have also been
developed to eliminate the cysteine requirement for NCL.
As per the significance of all naturally-occurring amino acids,
phenylalanine (Phe) and tryptophan (Trp) are recognized for
their vibrant pharmacological profiles[26a-c] and their profound
applications in developing intelligent organic materials.[27]
Phenylalanine constitute an integral part of numerous naturally-
occurring peptides including β-casomorphin, Casoxin D, -
lactalbumin, β-lactoglobulin and β-amaloid.[28] On the other hand,
tryptophan although have low relative abundance in peptide and
protein sequences (≈1% of the amino acids), yet its presence is
critical for their activity.[29] Thus, the development of new
synthetic methodologies for synthesis of Phe- and Trp based
peptides is highly significant. Post ligation-desulfurization and
other modified NCL strategies including S- (or Se-) to N-peptidyl
migration-desulfurization method for Phe-ligation,[16a-c] and S- (or
N-) to N-peptidyl migration[20,30] for Trp-ligation have been
reported to generate Phe-and Trp-containing peptides. In spite
of significant advancements in ligation strategies, there is always
a scope for alternative synthetic protocols for accessing the
peptides of choice under mild reaction conditions.
In quest to explore the newer ligation approach for
phenylalanine and tryptophan based peptides, we envisaged to
extent the scope and reactivity of aziridine ring towards
developing a new ligation approach for accessing phenylalanine
and tryptophan based peptides. In this context, van der Donk
and Gin investigated site selective ring opening of aziridine-2-
carboxylic acid-containing peptides by various thiol nucleophiles
including carbohydrate thiols, farnesyl thiol, and biochemical
tags, both in solution and on solid support.[31a-b]
Amino acids and peptides are the natural building block of life
that have attracted immense attention as therapeutics due to
their high selectivity, potency and low toxicity towards biological
systems.[1-4] A large number of commercialized peptides have
proved their validity as active pharmaceutical ingredients and
are in various clinical phases.[5] Due to the tremendous
applicability of naturally-occurring and synthetic peptides in bio-
chemical interactions,[6] considerable progress have been
monitored towards the development of newer synthetic
methodologies for peptides in the past two decades.[7] However,
due to complex peptide multifunctional architecture, and their
increasing demands in emerging medicinal and material
chemistry, formulation of advance peptide bond-forming
strategies remains a challenging area. One of the major
breakthrough in peptide synthesis after Merrifield solid phase
peptide synthesis (SPPS)[8] was the introduction of Native
Chemical Ligation (NCL) by Kent's group,[9] that illustrated a
regio- and chemoselective strategy for longer peptide syntheses
by the reaction of a peptide-thioester with cysteine containing
peptide via rapid S- to N-acyl transfer. However, requirement of
an N-terminus cysteine residue restricted the applicability of
NCL at all naturally-occurring amino acid sites. Thereafter
modified ligation strategy involving post-ligation desulfurization
has been first introduced by Yan and Dawson[10] and further
explored by Wan and Danishefsky[11] that illustrated an excellent
application of converting the pivotal cysteine to an alanine
residue after ligation. This strategy have been well exemplified
to various suitably placed thiol and selenol-substituted unnatural
amino acids, and thus expanded the scope of NCL at
arginine,[12] aspartic acid,[13] glutamic acid,[14] glutamine,[15]
phenylalanine,[16a-c] valine,[17] lysine,[18] leucine,[19] tryptophan[20]
and proline[21] junctions. However, the major challenges for
implication of these modified NCL strategies are the multi-step
syntheses required for preparation of thiol (or selanol)-
functionalized amino acid auxiliaries and their selective
[a]
Dr Kiran Bajaj, Dr Rajeev Sakhuja
Department of Chemistry
Birla Institute of Technology and Sciences
Pilani 333031, India
E-mail: kbajaj26@gmail.com
Figure 1. Previous and present work on aziridine-mediated ligation.
Supporting information for this article is given via a link at the end of
the document.
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Yudin’s group[32] has displayed aziridine ring-opening approach
desulfurization in ethanol at 0 oC for slightly longer times (30
for peptidomimetic synthesis by incorporating the (2-
min.) also lead to decline in the yield of 5a due to its further
aziridin)methyl group at the N-side of a peptide chain (Figure 1a). reduction to α-dipeptidyl alcohol (entry 8). Formation of major
Garner’s group[33] have reported a two-step ligation strategy
yielding threonine-containing peptides via a Cu(II)-promoted
coupling of unprotected peptide with N-H aziridine-2-carbonyl
peptides followed by regioselective and stereoselective ring-
opening by water (Figure 1b). In present work, we have
explored phenyl and indolyl substituted aziridine-2-carboxylates
as synthetic electrophilic handles and displayed an aziridine-
mediated one-pot ligation-desulfurization strategy to afford
phenylalanine and tryptophan appended α-peptides in a regio-
and stereoselective manner (Figure 1c).
Our exploration of aziridine-mediated ligation at phenylalanine
and tryptophan sites commenced with the synthesis of 3-phenyl-
and 3-indolyl-substituted aziridin-2-carboxylates derivatives. For
this purpose, (2S,3R) β-hydroxy–α-azidophenylalanine[34] (1a)
and N-protected (2S,3R) β-hydroxy–α-azidotryptophan[35] (1b)
derivatives were synthesized using reported protocols.
Cyclization[36] of 1a and 1b using triphenylphosphine in DMF
amount of 5a (over 5a') (entry 5) clearly indicates that aziridine
ring opening by thioacid preferred C-3 attack (over C-2), thereby
triggering S-to-N aminoacyl group transfer via 5-membered
cyclic transition state which followed by desulfurization afforded
α-dipeptide regioselectively. To elucidate the stereochemistry of
the chiral centre at phenylalanine site in the synthesized α-
1
dipeptide (Boc-L-Val-Phe-OEt) (5a), its H NMR spectrum was
compared with dipeptides Boc-L-Val-L-Phe-OEt and racemic
Boc-L-Val-DL-Phe-OEt, that were obtained by coupling Boc-L-
Val-OH with L-Phe-OEt and DL-Phe-OEt, respectively using
EDC coupling strategy. 1H NMR of dipeptide 5a was in exact
agreement with the stereoisomer Boc-L-Val-L-Phe-OEt
suggesting that the aziridine ring-opening proceeded with the
retention of configuration at C-2 position, thereby generating an
L-phenylalanine residue at ligation junction (see supporting
information). The structure of β-phenylalanine peptide (5a') was
confirmed by its 1H-1H correlation spectrum (see supporting
information).
comfortably
afforded
(2S,3S)-ethyl
3-phenylaziridine-2-
carboxylate (2a) and N-protected (2S,3S)-methyl 3-(1H-indol-3-
yl)aziridine-2-carboxylate (2b) in 85% and 78% yields,
respectively with high diastereoselectivity (up to 95% as evident
from 1H NMR) (Scheme 1).
Table 1 Optimization of the Reaction Conditions for Synthesizing 5a.
Scheme 1. Synthesis of aziridin-2-carboxylates (2a-b).
Entry
Aziridine Ring
Opening & Ligation
(Step-I)[a]
Desulfurization
(Step-II)[b]
Overall
Yield [c]
(%)
In order to investigate the proposed one-pot ligation-
desulfurization strategy at phenylalanine site, aziridine ring-
opening reaction of 2a with thioacid, Boc-L-Val-SH (3a) (Table
1) was performed. The reaction of 2a and 3a in DMF at room
temperature leads to the complete consumption of the starting
materials and eventually formation of a new spot on TLC in 6 h.
Additive
Solve
nt
Reagent
Solvent
5a
5a'
1
2
-
-
-
-
DMF
DCM
THF
NaBH4/NiCl2.6H2O
NaBH4/NiCl2.6H2O
NaBH4/NiCl2.6H2O
NaBH4/NiCl2.6H2O
NaBH4/NiCl2.6H2O
-
MeOH
MeOH
MeOH
MeOH
EtOH
-
50
25
40
60
62
-
32
-
3
15
25
28
-
1
The H NMR of the crude mixture indicated the formation of a
4
EtOH
EtOH
DMF
DMF
EtOH
thiol-substituted dipeptide (Boc-L-Val-Phe(SH)-OEt) (4a) in
major amounts. Further reduction of this crude reaction mixture
using NiCl2.6H2O/NaBH4 in methanol at -10 oC yielded the
phenylalanine containing α-dipeptide (Boc-L-Val-Phe-OEt) (5a)
in 50% overall yield (entry 1). It is worth noticing that about 32%
of β-dipeptide (5a') was also obtained during this two-step one-
pot strategy (entry 1). A change of solvent to DCM and THF in
ring-opening-ligation step followed by reduction in methanol
leads to reduction in the yields of 5a (entries 2-3). However,
ethanol was found to be best solvent for the ligation step (entry
4), and an additive effect of performing the two steps in ethanol
was found to be most delightful reaction condition, yielding 5a
and 5a' in 62% and 28% yields respectively (entry 5). To further
increase the yield of C-3 regioisomer, the aziridine ring opening
was attempted with K2CO3 and BF3.OEt2 separately, however,
discouraging results were obtained as messy reaction mixtures
were observed on TLC in step-I only (entries 6-7). Performing
5
6[d]
7[d]
8[e]
K2CO3
BF3.OEt2
-
-
-
-
-
NaBH4/NiCl2.6H2O
EtOH
-
-
[a] Reaction conditions: 2a (0.52 mmol), 3a (0.63 mmol), additive (0.52 mmol),
solvent (10 mL). The reactions were performed at room temperature and
monitored via TLC till completion for 6-8 h; [b] Reaction conditions: 4a+4a'
(crude mixture), NaBH4 (4.70 mmol), NiCl2.6H2O (1.56 mmol), solvent (10 mL).
The reactions were performed at -10 oC and monitored via TLC till completion
for 15 min; [c] Isolated yield over two steps; [d] messy mixture on TLC in Step I
and thus step II was not performed; [e] (Step II) T = 0 oC for 30 min. Formation
of peptidyl alcohol was observed in crude 1H NMR spectra.
With optimized conditions in hand, the scope of the developed
two-step one-pot transformation at phenylalanine site was
exploited using a variety of peptide thioacids (3b-e). The
reaction proceeded smoothly with α-amino thioacids (3b-d) and
α-dipeptide thioacid (3e) affording phenylalanine containing α-
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dipeptides (5a-d) and α-tripeptide (5e) in good yields. In all
cases, a substantial amount of β-phenylalanine containing
peptides (5a'-e') were also obtained. The reaction tolerated a
variety of protecting groups (Fmoc-, Boc- and Cbz) on thioacids
(Scheme 2). All the synthesized compounds were purified by
column chromatography and characterized by detailed
spectroscopic analysis.
Scheme 3. Substrate scope for aziridine-mediated ligation at tryptophan site.
Scheme 4. Synthesis of aziridine based dipeptide precursor 7.
Application of one-pot ligation-desulfurization strategy to
aziridine embedded dipeptide precursor 7 and Cbz-Gly-SH
gratifyingly afforded α-tripeptide, Cbz-Gly-L-Phe-L-Phe-OEt (8)
Scheme 2. Substrate scope for aziridine-mediated ligation at phenylalanine
site.
in 68% yield (Scheme 5). The structure of α-tripeptide was
1
confirmed by detailed spectroscopic data including H NMR, 13
C
After thriving results obtained in phenylalanine based aziridine
ligation, we explored the scope of our developed one-pot
ligation-desulfurization methodology at tryptophan site.
Interestingly, the reaction of N-protected (2S,3S)-methyl 3-(1H-
indol-3-yl)aziridine-2-carboxylate (2b) with various α-amino
thioacids (3) were more regioselective affording their
corresponding native tryptophan containing α-peptides (6a-f) in
good yields (Scheme 3). In few cases, β-trytophan peptides (6a'
& 6e') were also isolated in very low yields (~10%).
NMR, 1H-1H COSY spectra (see supporting information).
Another peptide-peptide bond coupling using ligation-
desulfurization strategy successfully yielded α-pentapeptide (9)
in 70% yield by reacting Cbz-L-Ile-Gly-Gly-SH with 7 (Scheme 5).
Thus, the scope of aziridine-mediated ligation-desulfurization
protocol could be effectively used to regioselectively generate
tryptophan and phenylalanine containing α-peptides in high
yields.
In order to exemplify the developed methodology towards amide
bond formation between two peptidic fragments, the coupling
between aziridine embedded dipeptide and a peptide thioacid
was planned as a model reaction. Since Phe-Phe motif is found
as a core component of β-amyloid peptide and have shown
tremendous applications as a nano-material and pharmaceutical
persuit[37], we planned to affix L-phenylalanine to 3-phenyl
substituted aziridin-2-carboxylate (2a) via peptide bond. For this
purpose, lithiated salt of 2a was prepared by hydrolyzing 2a
using lithium hydroxide in MeOH-H2O, which on further coupling
with L-Phe-OEt using HBTU/Et3N in DMF yielded the novel
aziridine embedded dipeptide precursor 7 in 80% yield (Scheme
4).
Scheme 5. Exemplified synthesis of α-tripeptide and α-pentapeptide via
aziridine-mediated ligation-desulfurization strategy.
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To further explore the generality of the methodology for studying
ligation at a non-aromatic amino acid junction, (2S,3S)-diethyl
aziridine-2,3-dicarboxylate (2c)[38] was allowed to react with
peptide thioacids, Cbz-Gly-SH and Cbz-L-Ala-SH under our
optimized conditions in a two-step one-pot fashion. Pleasingly
Asp-based α-dipeptides, Cbz-Gly-L-Asp(OEt)-OEt (10a) and
Cbz-L-Ala-L-Asp(OEt)-OEt (10b) were obtained in 88% and 83%
yields respectively (Scheme 6). This clearly demonstrates the
potential of aziridine-mediated ligation towards synthesizing
peptides of choice using appropriate starting materials.
In summary, an epimerization free, regioselective route via
aziridine-mediated ligation–desulfurization technique has been
developed to synthesize native peptide through one-pot
approach at trytophan and phenylalanine junctions. This strategy
provided a new way to synthesize a series of tryptophan and
phenylalanine containing α-peptides in highly regioselective
manner. The inclusion of a derivatized aziridine to a peptide
backbone, and its efficiency to react with various peptide
thioacids illustrated a promising pathway to generate Phe- and
Trp-containing peptides in solution phase. With the recent
development of solid phase synthesis of long chain thioacids,
this methodology could also be extended to solid phase
synthesis of peptides and proteins of choice. We anticipate that
this methodology could also be extended to other amino acid
junctions.
Experimental Section
Scheme 6. Aziridine mediated ligation at aspartic acid junction.
The synthetic procedures and characterization of the compounds are
described in the Supporting Information.
To gain some insight Into the reaction mechanism, we
successfully isolated one of the thiol intermediate (4c/4c')
obtained by the reaction of 2a and Cbz-L-Ile-SH (3c). 1H NMR of
the isolated intermediate (4c+4c') clearly inferred it to be a
mixture of thiol substituted α- and β-regioisomers. (see
supporting Information). In addition, LC-HRMS of intermediate
(4c+4c') further confirmed it to the major product, along with the
presence of a small amount of oxidized (-S-S-) dimer (see
supporting information). Thus, from the above experiment and
literature reports,[32] the reaction could be believed to proceed by
nucleophilic (C-2/C-3) ring-opening of aziridine ring by amino
acyl thioacid to generate α- and β-aminoacyl thioesters (A & B),
which undergoes S- to -N aminoacyl group transfer via 5-
membered cyclic transition state to yield α- and β-thiol
substituted intermediates (4c & 4c'). Desulfurization of 4
afforded the ligated α-dipeptide & β-dipeptide (Scheme 7).
Acknowledgements
The authors acknowledge Department of Science and
Technology (DST-SERB), India for financial support under Grant
no. SB/FT/CS-140/2012.
Keywords: Aziridine • Amino acids • Tryptophan •
Phenylalanine • Ligation
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Entry for the Table of Contents
COMMUNICATION



Aziridine-mediated Ligation
Mild reaction conditions
Kiran Bajaj * and Rajeev Sakhuja
Page No. – Page No.
Facile access to Phe- and
Trp- peptides
Aziridine-Mediated Ligation at
Phenylalanine and Tryptophan Sites
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