Rational design of an organocatalyst for peptide bond formation

Article abstract of DOI:10.1021/jacs.9b07742

Amide bonds are ubiquitous in peptides, proteins, pharmaceuticals, and polymers. The formation of amide bonds is a straightforward process: amide bonds can be synthesized with relative ease because of the availability of efficient coupling agents. However, there is a substantive need for methods that do not require excess reagents. A catalyst that condenses amino acids could have an important impact by reducing the significant waste generated during peptide synthesis. We describe the rational design of a biomimetic catalyst that can efficiently couple amino acids featuring standard protecting groups. The catalyst design combines lessons learned from enzymes, peptide biosynthesis, and organocatalysts. Under optimized conditions, 5 mol % catalyst efficiently couples Fmoc amino acids without notable racemization. Importantly, we demonstrate that the catalyst is functional for the synthesis of oligopeptides on solid phase. This result is significant because it illustrates the potential of the catalyst to function on a substrate with a multitude of amide bonds, which may be expected to inhibit a hydrogen-bonding catalyst.

Full text of DOI:10.1021/jacs.9b07742

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Article
Rational Design of an Organocatalyst for Peptide Bond Formation
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Handoko, Sakilam Satishkumar, Nihar Panigrahi, and Paramjit S. Arora
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b07742 • Publication Date (Web): 11 Sep 2019
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Rational Design of an Organocatalyst for Peptide Bond Formation
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Handoko, Sakilam Satishkumar, Nihar R. Panigrahi and Paramjit S. Arora*
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Department of Chemistry New York University, New York, NY 10003, U.S.A
ABSTRACT: Amide bonds are ubiquitous in peptides, proteins, pharmaceuticals and polymers. The formation of amide bonds is
a relatively straightforward process: amide bonds can be synthesized with relative ease because of the availability of efficient
coupling agents. However, there is a substantive need for methods that do not require excess reagents. A catalyst that condenses
amino acids could have an important impact by reducing the significant waste generated during peptide synthesis. We describe the
rational design of a biomimetic catalyst that can efficiently couple amino acids featuring standard protecting groups. The catalyst
design combines lessons learned from enzymes, peptide biosynthesis, and organocatalysts. Under optimized conditions, 5 mol%
catalyst efficiently couples Fmoc amino acids without significant racemization. Significantly, we demonstrate that the catalyst is
functional for the synthesis of oligopeptides on solid phase. This result is significant because it illustrates the potential of the
catalyst to function on a substrate with a multitude of amide bonds, which may be expected to inhibit a hydrogen bonding catalyst.
1
7-19
oxidative coupling of bromonitroalkanes with amines,
and
INTRODUCTION
α-ketoacid—hydroxylamine condensation.2
0,21
Atom efficient construction of amide bonds has become an
important challenge for organic chemists with the growing
popularity of peptides as biological reagents and therapeutics.
Contemporary approaches for peptide synthesis involve solid
1
phase methodology, which is a straightforward yet highly
wasteful process, with typical conditions utilizing three to five
equivalents of the coupling agents for every amide bond
synthesized. Various potential approaches for catalyst driven
peptide synthesis may be envisioned. Direct catalytic
activation of carboxylic acids with amines would provide the
most straightforward and efficient strategy. Catalytic
activation of carboxylic acids with boronic acids and
2-6
7,8
derivatives and zirconium salts has offered significant
promise. Carboxylic acid esters, which are more electrophilic
than carboxylic acids, provide an easily accessible alternative.
9
Condensation of esters with amines catalyzed by Zr(OtBu) ,
4
ruthenium-PNN complex,10 and N-heterocyclic carbenes
11
represent promising methods for obtaining amide bonds;
however, here the esters must be pre-formed limiting the
attractiveness of the approach. A recent report by Yamamoto
and coworkers describes intriguing results with substrate-
directed Lewis acid catalysts derived from titanium and
1
2
tantalum. Exciting approaches to obtain a native peptide
bond from non-standard reaction partners and reaction
pathways offer intriguing alternatives to carboxylic acids and
esters. For example, the Staudinger ligation utilizes an amino
Figure 1. Idealized depiction of a catalyst that covalently or
non-covalently engages the carboxylic acid and amine
nucleophile to coax amide bond formation. PG = protecting
group. b) Proposed catalytic cycle for the activation and
condensation of amino acids. The catalyst builds on a
reduction-oxidation condensation protocol where a transient
thioester or selenoester is formed between the catalyst and the
amino acid.
acid phosphine and azido amino acid derivative to afford a
native amide bond.1
3,14
Tang i ble success has al so been
obtained with nonclassical approaches which include
activation of reducible aldehydes with nucleophilic
15,16
carbenes,
umpolung amide synthesis that employs
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The above discussion highlights the various approaches synthesis of peptide bonds in nonribosomal peptide
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that are being pursued to develop an efficient catalyst for
synthesis, and (3) thioesters can be readily accessed from
carboxylic acids with disulfides and phosphorus (III)
12,21-25
oligopeptide synthesis.
We sought to build an
26
organocatalyst that would act upon Fmoc-amino acids—the
standard monomers in peptide synthesis—with the
hypothesis that for any new method to have significant impact
on the practice of peptide synthesis, minimal changes to the
existing protocols should be made. Our design builds on three
biomimetic and synthetic precedents: (1) the tetrahedral
intermediate for amide bond formation that is stabilized by
oxyanion holes in enzymes can be mimicked by urea catalysts.
(2) Carboxylic acids are routinely activated as thioesters for
reagents, as described by Mukaiyama in 1970. As illustrated
in Figure 1, we sought to combine these important precedents
with the concept of covalent catalysis. We envisioned a urea
catalyst covalently linking to the carboxylic acid via a thioester
bond; the thioester is then activated by the catalyst towards
amide bond formation.
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Figure 2. (a) Urea 1 efficiently condenses amino acid thioesters with amines. (b) Pseudo first order rate constants for dipeptide
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formation with urea 1 and designed controls 2-4. The kinetics of the amidation reaction between Fmoc-valine thiophenyl ester (10
mM) and alanine methyl ester (100 mM) in toluene are shown in the Table. The catalyst concentration was varied from 2.5 mol% to 10
mol%. (c) Proposed mechanism for amide bond formation catalyzed by catalyst 1. The mechanism is supported by the previously
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reported studies.
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Our proposed catalytic cycle has four key steps (Figure
The postulated catalytic cycle supported by these extensive
analyses is depicted in Figure 2c.
1
b). The first and second steps involve the formation of an
amino acid thioester from carboxylic acid, disulfide-linked
catalyst dimer and a phosphorus (III) reagent. In the third
step, the catalyst engages the amine nucleophile and the
thioester to yield an amide bond. The catalyst-thiol, liberated
from the prior step, then re-oxidizes to yield the disulfide for
the next cycle. We developed several designs that originate
from the proposed catalytic cycle. Here we illustrate the
preliminary success of this concept for the efficient coupling
of Fmoc-amino acids.
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DEVELOPMENT OF A CATALYST THAT COUPLES
CARBOXYLIC ACIDS AND AMINES
Catalyst 1 leads to an efficient formation of amide bonds from
amino acid thioesters and amines. The above studies provide
a foundation for our overall goal of developing a catalyst that
directly couples amino acids. Our approach is based on the
seminal work by Mukaiyama2 and others
6,42
43,44
who have
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utilized a reduction–oxidation condensation procedure to
synthesize amide bonds in a stoichiometric fashion.4 We
sought to make this approach more efficient by including a
urea derivative as an oxyanion hole mimic to catalyze acyl
transfer reactions.2
4-47
RESULTS
DESIGN OF AN ORGANOCATALYST THAT CONDENSES
THIOESTERS WITH AMINES27
8,29,34-39
Our goal requires the catalyst to first self-condense with
the carboxylic acid to form a thioester followed by amide bond
formation (Figure 1). Thioesters can be accessed from
carboxylic acids with disulfides and phosphorus (III)
reagents.26 We utilized tributylphosphine in these initial
studies after a preliminary investigation with different
phosphines. The oxidized form of the catalyst provides the
requisite disulfide.
We tested the potential of the disulfide form of 1, denoted
as 1-S in Figure 3, to couple toluic acid and benzylamine, as
model carboxylic acid and amine substrates for the formation
of Amide A. Detailed conditions for the model reaction are:
toluic acid (10 μmol), benzylamine (20 μmol), catalyst (0.5
μmol, 5 mol%), tributylphosphine (15 μmol), and 3Å
molecular sieves (30% w/v) in 1 mL acetonitrile at room
temperature. The reaction progress was monitored by HPLC
and percent conversion to amide A in comparison to an
internal standard is reported. We used millimolar
concentrations of the carboxylic acid and amine because these
concentrations are common in peptide synthesis.
We began our studies by developing a catalyst from first
principles that could accelerate condensation of thioesters
with amines, i.e. Step 3 of the catalytic cycle in Figure 1b. We
recently reported the iterative design of such a catalyst, which
combines elements of protease active sites and lessons learned
from peptide and protein ligation methodologies.27 The
salient results from the earlier study are shown in Figure 2.
Briefly, the catalyst was designed to mimic the oxyanion hole
to stabilize the tetrahedral intermediate.
28,29
Many hydrogen
30
29,31
bonding scaffolds including ureas, thioureas,
and
32,33
squaramides
have been described for their potential to
recognize anions. Several examples of hydrogen bonding
catalysts aiding acylation or deacylation chemistries are also
3
4-41
known.
We tested various scaffolds to arrive at the optimal
urea catalyst 1. The placement of the thiol and amine groups
proved to be critical. Modeling studies suggested that the
biphenyl/phenyl urea architecture provides the most
favorable positioning for the thiol group in relation to the urea
for efficient thioester exchange. Ter t iar y al ky l amines proved
to be superior bases. Figure 2b illustrates the dependence of
the reaction on the urea group, the tertiary amine and thiol
with negative controls 2-4 that are missing individual
components. The controls show a significantly diminished
rate for dipeptide bond formation between Fmoc-valine
thiophenylester and alanine methyl ester supporting the
hypothesis that a trifunctional catalyst is necessary for rate
acceleration.
We envisioned two key steps in the catalytic amide bond
formation by 1: The first step involves a transthioesterification
reaction between the thioester and 1. This step is postulated
to be mediated by hydrogen bonding with the urea group. The
catalyst•thioester complex then condenses with the amine
leading to amide bond formation. We tested the dependence
of the reaction on the concentration of the catalyst, thioester,
and the amine moieties. Analysis suggests that amide bond
2
7
Figure 3. Formation of Amide A after 20 minutes under
unoptimized reaction conditions: toluic acid (10 μmol),
benzylamine (20 μmol), catalyst (0.5 μmol, 5 mol%),
tributylphosphine (15 μmol), and 3Å molecular sieves (50%
w/v) in 1 mL acetonitrile. Reactions were conducted at room
temperature under open air.
1
9
formation is slower than transthioesterification. Careful F
NMR studies implicate the tertiary amine in both the
transthioesterification and the amide bond formation steps.
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side reactions that lead to the decomposition of the starting
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materials and phosphine reagent can be envisioned; however,
we postulated that oxidation of the selenol to the diselenide
(Step 3 of the catalytic cycle in Figure 1b) might be slow thus
limiting catalyst availability for the subsequent steps. We
envisioned that the rate of the diselenide formation could be
enhanced by linking the individual selenol units to increase
their effective concentration for oxidation. Accordingly, we
synthesized several macrocyclized analogs of 1-Se (Figure 5).
We chose to access the macrocycle by linking the individual
selenol units through the tertiary amine group because the
amine base and the diselenide group are attached to the same
aromatic ring.
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Figure 4. Comparison of 1-Se to diselenide controls 5 and 6
under the same reaction conditions as in Figure 3 with 5 mol%
of each diselenide. No reaction is observed in the absence of a
diselenide.
Gratifyingly, we found that 5 mol% 1-S provides 9% amide
formation after 20 minutes and the product formation slowly
increases to 65% after 4 hours (Supporting Information,
Figure S1). We next sought to improve upon this initial
success by testing the performance of the diselenide derivative
1-Se. We postulated that the selenium substitution may lead
to a more efficient catalyst due to the rate enhancement
provided by the diselenide in the selenoester and amide
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formation steps as well as in the reoxidation step to
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regenerate the diselenide (Step 3 in Figure 1). Diselenide 1-
Se leads to 36% product formation after 20 minutes, which is
a significant overall rate enhancement over 1-S.
We synthesized and evaluated two control diselenides to
gauge the contribution of the different components– the urea,
tertiary amine and the diselenide – that comprise catalyst 1-
Se. We compared the rates of the amide bond formation with
diphenyldiselenide 5 and diselenide 6. The latter derivative
5
0
was recently described by Liebeskind and coworkers as part
of their own significant efforts to develop an acylative
oxidation−reduction condensation system for amide bond
Figure 5. Comparison of diselenides 1-Se and 7 to macrocyclic
diselenides 8a–8c for catalysis of A under the same reaction
conditions as reported in Figure 3 caption. Bar graphs depict
product formation after 20 and 240 minutes with 5 mol% catalyst.
4
3,50,51
formation.
Both 5 and 6 serve as diselenide controls for
1-Se, with 6 also featuring a tertiary amine base. Both
derivatives allow us to gauge the contribution from the
designed urea component. Figure 4 demonstrates the
effectiveness of 1-Se as compared to the diselenide analogs.
Under the same reaction condition as described above,
diphenyldiselenide leads to roughly 20% product formation
after 20 minutes while diselenide 6 is less effective. As
expected, no reaction is seen in the absence of a diselenide.
We began by redesigning 1-Se to simplify the synthesis:
the alkyl tertiary amine base was appended to the biphenyl
group through an amide bond so we could optimize the linker
length by appending dialkylamines of different lengths. We
synthesized diselenide 7 as a control for 1-Se and compared
its activity to the parent compound after 20 and 240 minutes.
Roughly 40% of Amide A is formed in the presence of 5 mol%
1-Se after 20 minutes, with little further increase observed
after 240 minutes. With 5 mol% diselenide 7, we observe an
enhancement to 60% product formation after 240 minutes.
Replacement of the alkyl amine appendage from 1-Se to the
electron-withdrawing amide group in 7 lowers the pKa of the
ortho-selenol group, potentially accounting for the change in
the reaction profile.
Design of Macrocyclic Catalysts to Enhance Reoxidation
The above results provide a foundation for further
optimization of our designs. Although 1-Se leads to higher
product formation than diphenyldiselenide, the difference is
not significant. Importantly, we observed that while most of
the diselenides tested offer a burst in product formation over
2
0-30 minutes, reaction progress stalls after this initial rate
We next used three bis-amino linkers of varying lengths to
prepare macrocyclic derivatives 8a-8c. We designed 8a-8c
enhancement (Supporting Information, Figure S1). Many
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such that the tertiary amine will remain equidistant in all three
reaction employing P(OPh)
formation after 2 hours, Figure 6). Similar results were also
observed with other phosphites such as P(OEt) and
P(OiPr) . This result indicates that the electronic properties
of P(III) reagents play important roles in affecting the
turnover rate of the reaction. An electron-rich and less bulky
P(III) reagent is likely necessary to achieve efficient catalyst
turnover; however, these properties also cause the reagent to
be air sensitive. Tributylphosphine straddles the middle
ground between activity and resistance to oxidative
degradation and proved to be a suitable reducing partner for
catalyst 8a.
3
was slow (20% product
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scaffolds. Notably, these compounds exist as mixture of
oligomers of dimer that once reduced, become chemically
equivalent. (Supporting information, Figure S6–S7) The
profiles of these macrocycles are compared to 1-Se and 7 in
Figure 5. Macrocyclization provided further boost leading to
roughly 70% product formation after 4 h, with 8a proving to
be the most efficient catalyst.
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We next optimized each reaction component and
parameter, including solvent, temperature, time, the
dehydrating agent, and concentrations of the starting
carboxylic acid, amine, tributylphosphine, and catalyst 8a
(
Table 1). The reaction progress was monitored by HPLC and
percent conversion to amide A in comparison to an internal
standard is reported. We sought to determine the highest
conversion to the product under each reaction condition
within 24 hours of monitoring. In many cases, the reaction
progress halts before reaching full conversion, as discussed
earlier; in these instances, the time required to reach the
maximal conversion is noted. We found the reaction to be the
highest yielding in polar aprotic solvents such as acetonitrile
and DMF, with acetonitrile providing faster conversion (Table
Figure 6. Evaluation of phosphine and phosphites as reaction
partners for 8a. Less congested trialkylphosphines – PBu
3
and
– provided the highest yields of A after 2 hours under the
same reaction conditions as listed in Figure 3 caption.
i
P( Bu)
3
1
, Entries 1-6). We attribute this observation to DMF, which
features a hydrogen-bond acceptor, competing with the urea
moiety of 8a. These solvents are typically used in peptide
synthesis and suitable for dissolving protected amino acids.
Optimization of the Reaction Conditions for
Organocatalyst 8a
Encouraged by the above results, we next evaluated reaction
conditions to optimize the performance of 8a. We employed
tributylphosphine during the initial catalyst screening.
Repeated studies with different diselenides suggested that
A dehydrating agent is critical for the reaction progress, as
55-57
is also the case for catalytic Mitsunobu reactions.
We
surveyed various molecular sieves, alumina and anhydrous
magnesium sulfate (Entries 7-13), and found that 4 Å
molecular sieves lead to the highest conversion.
reaction progress stalled due to premature depletion of PBu
3
(
Supporting Information, Figure S2). We hypothesized that
Phosphine oxidation is a limiting factor in the reaction
progress. We determined the highest amount of
tributylphosphine required for quantitative conversion of
toluic acid to the product. At millimolar substrate
concentrations, such as those employed in standard peptide
synthesis protocols, three equivalents of tributylphosphine
lead to near quantitative yield of the amide A in four hours
(Entry 16). We tested the impact of slow addition of
phosphine on reaction progress. As expected, addition of fresh
batches of phosphine reduces its total amount required in the
reaction. Addition of 0.5 equivalent of phosphine in three
batches leads to enhanced conversion to A (Entries 17-19).
Lastly, we found that an increase in reaction temperature to 60
PBu is oxidized during the reaction, thus limiting catalytic
3
efficiency. We anticipated that the use of less air-sensitive
phosphines may lead to better reaction yield.
We screened various phosphines and phosphites with
diverse steric and electronic properties to identify an optimal
reaction partner for 8a (Figure 6). Electron density at the
phosphorus center of phosphines is related to their sensitivity
5
2
towards air oxidation. Disappointingly, we found that the
more oxidatively stable PPh leads to only 6% product after 2
hours as compared to 70% with PBu under the same reaction
conditions. We also screened electronically rich but sterically
bulky phosphines such as PCy and CyJohnPhos but found
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3
5
3
i
similarly low yield of product A. P( Bu)
3
, which has similar
°
C provides further boost to near quantitative conversion.
electronic properties to PBu produced similar yield.
3
Under optimized conditions, 2.5-5 mol% 8a catalyzes efficient
condensation of equimolar amounts of carboxylic acid and amine
partners (Entries 20-22).
To ident i f y a phosphor us(I I I) der ivat ive that i s less
sensitive to oxidation yet has similar steric properties to that
of PBu
3
, we next shifted our attention to P(OPh)
3
, which has
5
4
a similar Tolman cone angle to that of PBu
3
. We found that
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Table 1. Optimization of reaction conditions with 8a
.
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%
Conversion
Entry Toluic Ac id Benzylamine Catalyst PBu
3
Dehydrating Agenta Temperature Solventsb to A
(mM)
10
(mM)
20
(% mol) (mM) (% w/v)
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5%
15
3Å MS (50%)
RT
RT
MeCN
DMF
76% (6 h)
75% (24 h)
Dioxane 24% (6 h)
THF 22% (6 h)
Toluene 1% (24 h)
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8
9
0
DCE
25% (6 h)
75% (2 h)
59% (1 h)
13% (24 h)
No reaction
20% (6 h)
36% (10 min)
76% (1 h)
85% (2 h)
95% (4 h)
99% (4 h)
90% (2 h)
90% (2 h)
76% (2 h)
99% (1.5 h)
97% (4 h)
21% (6 h)
10
20
5%
15
4Å MS (50%)
5Å MS (50%)
13X MS (50%)
Alumina (50%)
MeCN
0
11
MgSO
4
(50%)
1
2
3
None
1
4Å MS (30%)
4Å MS (30%)
14
10
20
5%
20
25
30
RT
MeCN
1
5
6
1
17
10
10
20
10
20
10
10
10
5%
3 × 5d 4Å MS (30%)
3 × 5d 4Å MS (30%)
3 × 5d 4Å MS (30%)
3 × 5d 4Å MS (30%)
RT
MeCN
MeCN
MeCN
MeCN
1
8
9
5%
RT
1
5%
RT
20
5%
2.5%
1%
60°C
2
1
2
2
a
b
Molecular sieves were activated by microwave irradiation prior to reaction. Each solvent was dried overnight with the corresponding
c
dehydrating agent. Yield of amide A as monitored by HPLC using biphenyl as internal standard. Time to reach the indicated product
yield for each condition is listed in parentheses; we assayed each condition for maximum conversion. Tributylphosphine was added in
d
portions every 30 minutes.
Reaction profiles at various catalyst concentrations (0.5–
.5 mM) were obtained. Plotting of product concentration
against normalized time [8a] t reveals a first-order
dependence on catalyst 8a. Diselenide 8a is a dimer and urea-
ANALYSIS OF THE MECHANISM OF AMIDE BOND
CATALYSIS BY 8a
1
n
We rigorously analyzed the kinetics of the reaction with
respect to four different components – catalyst 8a, toluic acid,
benzylamine, and tributylphosphine – to gain insight into the
mechanism of the reaction. The reoxidation of selenols to
diselenide is mediated by atmospheric oxygen; we regarded
oxygen concentration as a constant in our calculations. The
kinetic studies and the proposed catalytic mechanism are
shown in Figure 7 and Supporting Information Figure S37–
S46. We analyzed the impact of varying concentrations of each
component on the initial rate of the reaction. We also utilized
the variable time normalization analysis described by Burés to
determine reaction orders for each component (Supporting
based organocatalysts often show a tendency to form higher
61-65
order aggregates,
but our analysis suggests that only one
molecule of reduced 8a (or any of its intermediates) is
involved in the rate determining step of the reaction.
Similar analysis for toluic acid also revealed first-order
dependence on the carboxylic acid component of the reaction
at lower concentration (5–12 mM). At higher concentrations,
saturation kinetics was observed as evidence from the
plateauing of initial rate versus toluic acid concentration curve
(
Supporting Information, Figure S44). This behavior is
consistent with rapid association and dissociation of the
58-60
Information).
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Figure 7. Dependence of reaction rate on concentrations of (a) catalyst 8a, (b) toluic acid, (c) benzylamine, and (d) tributylphosphine.
Variable time normalization analysis was utilized to elucidate the reaction orders from concentration profiles of the reaction (insets in
panels a-c).
We observed no rate dependence on amine concentration,
implying that nucleophilic attack of amine to activated ester is
fast and kinetically irrelevant. Owing to exceptional
nucleophilicity of selenolates and in analogy to mechanism of
PyBOP mediated coupling,6
6,67
we hypothesize the
involvement of selenoester intermediate (III) in the amide
bond formation step. The observation that the reaction rate
slows considerably when reaction solvent is changed from
acetonitrile to DMF (Table 1, Entr ies 1 and 2 and Supporting
Information, Figure S12) suggests that the assistance of
hydrogen bonding from the urea moiety is necessary for fast
conversion. Formation of the selenoester intermediate has
also been implicated by Singh, et al. in amide bond formation
with
stoichiometric
tributylphosphine
and
46
diphenyldiselenide.
Analysis of the initial rates of reaction with varying
tributylphosphine concentration (30–120 mM) suggests that
the reaction has a negative one-half rate order dependence on
phosphine (Supporting Information, Figure S46). We
rationalize this peculiar result to denote the complex role of
tributylphosphine in the reaction, which includes its
sensitivity to oxidation. Beyond the desired role of the
phosphine for catalyst reduction, we hypothesize that it also
inhibits catalyst reoxidation, presumably by reacting with
selenenic acid to form tributylphosphine oxide and bis-
selenolate V.
Figure 8. The proposed mechanism, supported by the kinetic
studies, is shown in black. The possible side reactions are
depicted in red and gray fonts.
carboxylate and selenophosphonium (Figure 7e: I-II). The
saturation kinetics at higher carboxylate concentrations
suggest that any of the succeeding reaction steps may be rate
limiting.
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Table 2. Potential of diselenide 8a to catalyze coupling diverse Fmoc-protected amino acids into dipeptides.
8
a
R
O
R1
R2
1
H
N
PBu3
OH
X
.
FmocHN
+
HCl H
2
N
FmocHN
X
4
Å MS (30% w/v)
O
O
O
R
2
6
0 °C
MeCN
t
X = -O Bu, -NH
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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6
7
8
9
0
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2
3
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5
6
7
8
9
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9
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9
0
Method A: Slow
Method B: One
Pot Reaction
Catalyst
% mol)
Addition of
c
Entry Dipeptides
Phosphineb
Epimerizatione
dr > 99:1
(
(% Conversiond) (%Conversiond)
t
86% (1 h)f
97% (1 h) f, h
95% (1 h) f
99% (1.5 h)g
1
2
3
4
5
6
7
8
9
10
FmocAlaAlaO Bu
2.5%
5.0%
5.0%
5.0%
5.0%
5.0%
5.0%
5.0%
5.0%
5.0%
5.0%
5.0%
5.0%
5.0%
-
92% (1 h)
99% (30 min)
98% (1 h)
96% (1 h)
69% (1 h)
73% (1 h)
87% (30 min)
90% (30 min)
82% (30 min)
89% (1 h)
81% (30 min)
53% (1.5 h)
-
t
FmocAlaPheO Bu
t
FmocAlaLys(Z)O Bu
t
99% (1 h) f
FmocAlaValO Bu
t
94% (2 h) g
99% (1 h) f
90% (1 h) f
90% (1 h) f
90% (2 h) g
99% (1.5 h) g
92% (2 h) g
91% (2 h) g
82% (2 h) g
FmocAlaProO Bu
FmocAlaTrpNH
2
t
FmocPheAlaO Bu
t
FmocLys(Boc)AlaO Bu
t
FmocProAlaO Bu
t
1
1
2
FmocArg(Pbf )AlaO Bu
t
1
FmocValAlaO Bu
dr = 99 :1
dr = 98 :2
t
13
FmocAibAlaO Bu
t
14
FmocPheProO Bu
a
t
Reaction condition: Fmoc-Xaa-OH (10 µmol), HCl•H-Xaa-O Bu or HCl•H-Xaa-NH
2
(11 µmol), DIEA (11 µmol), 8a, PBu , 4Å
3
b
MS (300 mg), in 1 mL ACN at 60°C. Method A: Two or three portions of PBu (5 µmol per portion) were added every 30 minutes.
Method B: PBu (11 µmol) was added in one portion. Conversions were monitored by HPLC using biphenyl as internal standard.
Time to reach maximum conversion is provided in parentheses. The amount of epimerization was quantified by HPLC. Reaction
reached maximum conversion after two 5-µmol portions of PBu
3
c
d
3
e
f
g
3
were added. Reaction required three 5-µmol portions of PBu
3
to reach
h
t
maximum conversion. The isolated yield for a 0.2 mmol scale synthesis of Fmoc-AlaAlaO Bu is 90%.
Based on our analysis and literature precedence,46,68-71 we
propose the catalytic cycle outlined in Figure 8. The
diselenide catalyst 8a is reduced by tributylphosphine to form
selenophosphonium I, which associates rapidly with the
carboxylate to form the pentacoordinated phosphorane II.
Intramolecular acyl transfer of II leads to selenoester III and
concomitant release of tributylphosphine oxide. Rapid
aminolysis of III leads to formation of the desired amide
product and release of bis-selenolate V, which oxidizes back to
catalyst 8a on exposure with air. Water and hydrogen peroxide
molecules produced as side products from selenolate
acyloxyphosphonium intermediate (IV) or exchange of the
acyloxyphosphonium back to selenoesters may also be in play.
The kinetic analysis suggests that the catalyst reoxidation is
the slow step in the cycle.
CATALYST 8a EFFICIENTLY COUPLES AMINO ACIDS
Our overall goal is to develop catalysts that act on protected
amino acids routinely used in solid phase synthesis. We
rationalized that a sub-stoichiometric reagent that can couple
Fmoc amino acids protected with standard protecting groups
would be useful in reducing waste in peptide synthesis.
Toward thi s end , we tested the potential of 8a on substrates
beyond the model compounds described above (Table 2).
oxidation are absorbed and decomposed respectively by
molecular sieves.5
5,57
Alternative mechanisms that involve
direct nucleophilic attack by the amine on
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We began by analyzing the rate of alanine dipeptide
formation. Commercially available amino acid esters or
amides were directly used. These amino acids are available as
HCl salts and equimolar N,N-diisopropylethylamine was
added to the reaction mixture to scavenge the acid.
Condensation of 10 mM Fmoc-alanine with 11 mM alanine t-
butyl ester in acetonitrile leads to 86% yield of Fmoc-Ala-Ala-
O-t-Bu dipeptide with 2.5 mol% 8a after 1 hour (Table 2,
Entry 1). The yield of the dipeptide product increases to 97%
with 5 mol% 8a (Table 2, Entry 2). These examples utilized
slow addition of tributylphosphine in two 5-µmol portions
(Method A in Table 2). One pot addition of 1.1 equivalent of
tributylphosphine with 5 mol% 8a provided 92% conversion
(Method B) – a slight decrease from the slow addition method
but still a highly encouraging result. We tested various amino
acid partners for Fmoc-alanine to gauge the scope of the
catalyst. We surveyed aromatic amino acids (phenylalanine
and tryptophan), protected lysine, valine and proline (Table 2,
Entries 3-7). In each case, high yields for the dipeptide
products were obtained. We were particularly gratified to learn
that the catalyst can couple amino acids with b-branching and
secondary amine.
2
3
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9
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0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 9. HPLC studies to determine potential epimerization
during peptide coupling mediated by 8a. (a) Comparison of
HPLC traces of authentic sample of racemic FmocAlaAlaO Bu
t
(top) and that of crude reaction mixture (bottom). (b)
Comparison of HPLC traces of authentic sample of (ʟʟ)-
t
t
FmocValAlaO Bu spiked with (ᴅʟ)-FmocValAlaO Bu (top) and
that of crude reaction mixture (bottom). HPLC condition:
®
Chiralcel OD 250 × 4.6 mm column; isocratic elution of 5%
isopropanol in hexanes; flow rate = 1.0 mL/min; detection
wavelength = 280 nm.
We next explored different Fmoc-amino acids as the
coupling partners (Table 2, Entries 8-13). We tested
phenylalanine, lysine and arginine with standard side chain
protecting groups, valine, proline and aminoisobutyric acid
(Aib). Fmoc-Aib provides a stringent test for probing the role
of amino acid sterics on catalytic efficiency. We were pleased
to learn that catalyst 8a can lead to a high conversion to the
dipeptide in every case; although, the bulkier amino acids
valine and Aib required longer reaction times.
Epimerization of amino acids is a major concern in peptide
synthesis. To rigorously quantify the amount of potential
epimerization resulting from the catalyst-mediated product
formation step, we prepared both ʟʟ and ᴅʟ epimer of
t
t
FmocAlaAlaO Bu and FmocValAlaO Bu dipeptides. We also
tested coupling of Fmoc-phenylalanine and proline-t-Bu, two
non-alanine amino acids that react slowly, to assess the impact
of the slow reaction on epimerization (Table 2, Entry 14).
Careful analysis showed less than 2% epimerization under the
reaction conditions for any of the dipeptides tested (Table 2,
Figure 9 and Supporting Information, Figure S3–S5).
Figure 10. (a) Protocol for solid phase synthesis mediated by
PBu
3
and 8a. (b) HPLC traces of crude peptide FmocFEKAG-
NH
2
synthesized using HBTU (top) and PBu and 8a(bottom).
3
HPLC condition: Poroshell 120 EC-C18 4.6 × 100 mm 2.7 µm
column; 0.1% TFA (v/v) in water (solvent A): acetonitrile
(solvent B); gradient 5–100% (solvent B) in 6 min; flow rate = 1.5
mL/min; detection wavelength = 220 nm.
Catalyst Mediated Solid Phase Peptide Synthesis
We next evaluated the potential of 8a to catalyze solid phase
peptide synthesis. We were interested in testing the potential
of the catalyst on solid phase because a catalyst that functions
through hydrogen bonding interactions and coordination
with carbonyl groups would be expected to be less efficient
with peptide substrates as compared to amino acids due to the
presence of multiple carbonyl groups and other coordinating
sites. As a proof of concept, we aimed to synthesize a
Fmoc-amino acids. The reaction progress was monitored
using the Kaiser test which indicates incomplete coupling of
resin-bound free amines. We utilized 1.1 equivalent of the
Fmoc-amino acid and 5 mol% of 8a in this study. After each
coupling step, molecular sieves were separated from the resin
support by use of buoyant force. As the peptide becomes
longer (beyond 3 residues), the complete reaction of the free
amine required two coupling cycles. The pentapeptide
prepared using 8a and standard coupling agents were then
pentapeptide (Fmoc-FEKAG-NH ) on resin using standard
2
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Page 10 of 12
cleaved from resin and analyzed by HPLC. Spectra of the
Synthesis, characterization, kinetic studies, and spectroscopy
data (PDF)
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crude cleaved products indicate that relatively pure peptide
was obtained after iterative synthesis on solid phase. The same
peptide synthesized using standard coupling agent HBTU is
provided as control (Figure 10b). Despite the inconveniences,
the performance of the catalyst for solid phase peptide
synthesis (SPPS) is highly encouraging.
AUTHOR INFORMATION
Corresponding Author
*arora@nyu.edu
ACKNOWLEDGMENT
CONCLUSION
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The authors thank the NSF (CHE-1807670) for financial
support of this work.
We describe efforts to develop an organocatalyst for amide
bond formation from commercially available Fmoc amino
acids featuring standard side chain protecting groups. The
catalyst design builds on urea-based hydrogen bonding
scaffolds and the concept of covalent catalysis. The proposed
catalytic cycle utilizes a reduction–oxidation condensation
procedure to activate the carboxylic acid as a selenoester. The
diselenide required for this transformation is a component of
the catalyst. The selenoester linkage reversibly connects the
amino acid to the organocatalyst which catalyzes amide bond
formation.
The studies described here provide a lead towards catalytic
peptide synthesis. We utilized an iterative design approach to
develop a macrocyclic diselenide catalyst that yields near
quantitative conversion of carboxylic acids and amines to their
amide products under optimized conditions. The catalyst is
active on a diverse range of amino acid substrates and shows
promise for solid phase peptide synthesis. Insignificant
epimerization of chiral amino acids was observed in the
catalyzed reaction. The result with oligomer synthesis is
particularly rewarding because hydrogen bonding catalysts
may not be expected to be efficient in the presence of multiple
amide bonds.
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ASSOCIATED CONTENT
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