Protecting-Group-Free Amidation of Amino Acids using Lewis Acid Catalysts

Article abstract of DOI:10.1002/chem.201800372

Amidation of unprotected amino acids has been investigated using a variety of ‘classical“ coupling reagents, stoichiometric or catalytic group(IV) metal salts, and boron Lewis acids. The scope of the reaction was explored through the attempted synthesis of amides derived from twenty natural, and several unnatural, amino acids, as well as a wide selection of primary and secondary amines. The study also examines the synthesis of medicinally relevant compounds, and the scalability of this direct amidation approach. Finally, we provide insight into the chemoselectivity observed in these reactions.

Full text of DOI:10.1002/chem.201800372

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Accepted Article
Title: Protecting-group-free amidation of amino acids using Lewis acid
catalysts
Authors: Marco Sabatini, Valerija Karaluka, Rachel Lanigan, Lee
Boulton, Matthew Badland, and Tom David Sheppard
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10.1002/chem.201800372
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Protecting-group-free amidation of amino acids using Lewis acid
catalysts
Marco T. Sabatini,[a] Valerija Karaluka,[a] Rachel M. Lanigan,[a] Lee T. Boulton,[b] Matthew Badland,[c]
Tom D. Sheppard*[a]
Abstract: The amidation of unprotected amino acids has been
investigated using a variety of ‘classical’ coupling reagents, and
stoichiometric or catalytic group(IV) metal salts and boron Lewis
acids. The scope of the reaction was explored through the attempted
synthesis of amides derived from twenty natural, and several
unnatural, amino acids, as well as a wide selection of primary and
secondary amines. The study also examines the synthesis of
medicinally relevant compounds, and the scalability of this direct
amidation approach. Finally, we provide insight into the
chemoselectivity observed in these reactions.
Introduction
Chemical reactions for the formation of amide bonds are among
the most commonly employed transformations in organic
chemistry; amides featuring in 25% of industrially important
Scheme 1. Chemoselective amidation of unprotected amino acids. (A)
Classical approach to the synthesis of amino amides (B) Chemoselective
amidation of an unprotected amino acid. (C) Potential pitfalls & Issues.
pharmaceuticals as well as a wide selection of bioactive natural
products and polymeric materials.[1] The synthesis of amides
derived from amino acids constitutes a major application of
amide bond formation chemistry. While the synthesis of amino
amides via the assembly of N-protected -amino acids and
Since then, there have been several reports of methods for the
[2]
amines is a well-known and accepted methodology,
the
synthesis of amides derived from amino acids employing a
transient activating group for the carboxylic acid that
simultaneously protects the amine (Scheme 2A). Burger et al.
synthesis of amides directly derived from unprotected amino
acids (Scheme 1 B) is rare, despite shortening the synthetic
sequence by two steps. This class of amidation reaction
presents issues relating to control of reactivity, but the lack of
research effort in this area is probably due to the preconception
that such a reaction simply would not work (Scheme 1, C).
Nevertheless, a small number of methods for direct amidation of
unprotected amino acids have been developed.
The first known method for the chemoselective amidation of
unprotected amino acids was developed by Leuchs, and
employed phosgene or derivatives thereof to generate reactive
N-carboxyanhydrides (NCA’s) for subsequent reaction with
amines (Scheme 2). [3] However the activation occurs to such an
extent that it leads to polymerization[4] and the amino acid still
requires protection for a fully selective monoacylation. [5]
reported the use of gaseous hexafluoroacetone (HFA) for the
[6-7]
formation of activated oxazolidinones,
which are reactive
towards amines. The applicability of this method was
demonstrated through the shortest synthesis of aspartame to
date (Scheme 2B). [6] Later, similar approaches were exploited
by Liskamp et al. using dichloroalkyl silanes[8] or boron
trifluoride[9] to produce activated Lewis acid conjugates in which
the amino acid was proposed to coordinate in a bidentate
fashion. Remarkably, Bristol-Meyers-Squibb have employed the
silane-based methodology for the synthesis of an amino amide
[10]
drug candidate,
demonstrating benefits with regard to both
[11]
cost-effectiveness and atom-economy (Scheme 2B).
recently, Sharma et al.
unprotected amino acids employing
More
[12]
reported the amidation of some
‘classical’ coupling
a
reagent, CDI, in water. Nevertheless, the method displayed
serious drawbacks with regard to scope, only succeeding in the
amidation of four amino acids (Scheme 2C).
We have recently reported that the borate ester B(OCH2CF3)3 is
an effective reagent for the direct synthesis of -amino amides
from unprotected amino acids and amines. [13-14] In this study, we
outline the full scope of the direct amidation of unprotected
amino acids employing both stoichiometric and catalytic
quantities of a variety of boron Lewis acids as well as group(IV)
metal salts and ‘classical’ coupling reagents.
[a]
M. T. Sabatini, Dr. V. Karaluka, Dr. R. M. Lanigan, Dr. T. D.
Sheppard
Department of Chemistry, University College London
Christopher Ingold Laboratories
20 Gordon Street, London, WC1H 0AJ (UK)
tom.sheppard@chem.ucl.ac.uk
www.tomsheppard.eu
[b]
[c]
Dr. L. T. Boulton
GlaxoSmithKline, Medicines Research Centre
GunnelsWood Road, Stevenage, Herts, SG12NY (UK)
Dr. M. Badland
Pfizer Global Pharmaceutical Sciences, Discovery Park, Ramsgate
Road, Sandwich, UK
Supporting information for this article is given via a link at the end of
the document.
1
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Scheme 2. Chemoselective amidation of unprotected amino acids. (A) One-pot chemoselective methods.[3-9, 13] (B) Applications to the synthesis of
drug/natural products[6,10] (C) ‘Classical’ coupling reagents with unprotected amino acids.[12]
Table 1. Classical’ coupling reagents in amidation of amino acids
Results and Discussion
Classical coupling reagents. The acylation of amines with
activated carboxylic acids is the most common way to make an
amide, as a consequence of the widespread availability and high
stability of both of these building blocks. In fact, based on
literature surveys, the most commonly used methods for
amidation involve the formation of intermediary acid chlorides,
O-acyl ureas or (mixed) anhydrides. [15] We therefore began our
investigation by looking at the efficiency of classical coupling
reagents for the chemoselective amidation of unprotected
phenylalanine with benzylamine. Using polar solvents with the
potential to partially solubilize unprotected amino acids (H2O,
EtOH), biphasic systems (CH2Cl2/H2O) as well as non-protic
solvents (DMF, CH2Cl2) we looked at the competency of
‘classical’ coupling reagents in amidation. In most cases, little or
no amino amide was produced (Table 1, entries 1-6). In the case
of amidation employing CDI in water (entry 7), the formation of
the desired amino amide was observed in small quantities,
accompanied by the formation of three other amide species,
highlighting issues relating to control of reactivity. Overall, we
believe that the lack of reactivity, as suggested previously, [12] is
mainly due to the poor solubility of zwitterionic -amino acids
both in organic solvents and in aqueous solution.
Entry
Coupling agent
EDC/HOBt
EDC.HCl/HOBt
EDC.HCl/HOBt
T3P®
Solvents
CH2Cl2/H2O
NMM, H2O
NMM, EtOH
DMF
Yield[a]
<5%
<5%
<5%
0%
1
2
3
4
5
6
7
HATU
DMF
0%
SOCl2
Et3N/CH2Cl2
H2O
0%
CDI
<10%
[a] 1,4-dimethoxybenzene was used as an internal standard. Complete reaction
conditions and spectra of crude reaction mixtures as can be found in the ESI
Stoichiometric amidation with Lewis acids. We have recently
reported the use of B(OCH2CF3)3 as an effective reagent for the
direct synthesis of -amino amides from unprotected amino
acids and excess amine. In most cases, the pure amino amide
could be obtained using a solid phase work-up to remove amino
acid and boron compounds, followed by evaporation of the
[13b]
volatile components.
All 20 common proteogenic amino
acids (entries 1-20, table 2) as well as six unnatural amino acids
2
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(entries 21-26, table 2) were evaluated in the reaction. Although
polar amino acids (namely arginine (2b), asparagine (2c) and
glutamine (2f)) did not efficiently undergo amidation, the method
was extremely successful with the less polar amino acids (2a,
2g-2o, 2q-2t). Overall, 60% of the natural amino acids and 5/6
of the unnatural amino acids (2u-2z) underwent amidation to
give amides in good yields and enantiomeric ratio (er) (>60%
yield and >90:10 er).
Table 3. Reducing racemization through the dropwise addition of
B(OCH2CF3)3 and by decreasing the reaction time.
Table 2. B(OCH2CF3)3-mediated amidation of free amino acids with
[13b]
propylamine.
Sarcosine (Sar), α-aminoisobutyric acid (AiB); Homoserine
(Hse); L-2-Aminobutyric acid (AABA). e.r. could not be determined for 2c, 2e,
2f, 2i, 2l
Entry
Reaction time
(h)
borate added
dropwise
Yield
e.r.
1
2
3
4
15
5
N
N
Y
Y
93%
87%
93%
83%
80:20
83:17
84:16
91:9
15
5
We have also attempted the reaction to synthesise 1a under
similar conditions with a variety of group (IV) metal salts (Table
4), as these types of species have been reported to be active
catalysts for amide bond formation in recent years. [16-17] While
reactions employing zirconium based reagents solidified and
produced only minor quantities of amide 1a, Ti(OiPr)4 was
identified as a suitable alternative amidation reagent. The
reactions were also attempted in the presence of molecular
sieves but the resulting yields were slightly lower. A selection of
amino amides were synthesised using 1 equiv. of Ti(OiPr)4
(Figure 1). Amide 2n was synthesised in high yield but with
significant racemisation. Although lower yields were seen for the
synthesis of 2r and 2t, the use of Ti(OiPr)4 furnished products
with higher enantiopurity (≥95:5 er) than the reactions mediated
by B(OCH2CF3)3. Hence, Ti(OiPr)4 represents an easily
accessible and lower cost alternative to our borate ester,
especially for more reactive amino acids.
Catalytic amidation employing Lewis acids. Having recently
developed a method for general amidation employing catalytic
B(OCH2CF3)3, [14] we wished to explore the applicability of this
approach in the amidation of unprotected amino acids. In the
optimisation of the general catalytic amidation reaction, we
screened a wide selection of organic solvents under Dean-Stark
conditions and identified tert-amyl methyl ether (TAME) as a
suitable alternative to CPME and PhMe, which crucially allows
for azeotropic removal of water to be conducted at lower
temperatures (86 °C). [14] Design of Experiments (DoE) reaction
optimisation[18] was then conducted to understand the factors
playing a role in the amidation of an unprotected amino acid,
and to maximise the yield of product 3a and minimise the
formation of diamide byproduct 4a, the product of amidation of
the amino acid with the desired aminoamide product. The
catalyst loading, amine loading and volume of solvent used were
investigated as factors.
Following this study, we went on to look at the reaction
conditions in more detail in order to minimize the levels of
racemization seen for some examples. The reaction of
tryptophan with propylamine was examined with various
conditions, and it was found that racemization could be
minimized by shortening the reaction time and/or by adding the
borate reagent dropwise (Table 3).
3
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Table 4. Ti/Zr in amidation of amino acids.
Entry
Lewis acid
B(OCH2CF3)3
Cp2ZrCl2
ZrCl4
Eq
3
Yield
85%
0%
1
2
3
4
5
Figure 1. Ti(OiPr)4 mediated amidation of free amino acids with
propylamine.
1
1
32%
85%
75%
Ti(OiPr)4
1
[a]
Ti(OiPr)4
1
[a]Reaction run with mol. sieves
Scheme 3. DoE study on the direct amidation reaction to form 3a. ‘Summary of Fit’ and ‘Coefficient’ plots for amide 3a and diamide 4a. The ‘Summary of Fit’ plots
demonstrate that the two models obtained from the DoE study provide a high quality fit to the data. The coefficient plots indicate the significant factors affecting
the yield of each product, showing the average effect on the yield of a product when a factor is increased from the value at the design centre point to the upper
limit of the design. Factors: Am (amine loading, 1-3 eq.); Cat (catalyst loading, 5-50 mol%); Sol (solvent: 4 to 12 volumes, equivalent to varying the reaction
concentration from 1.5 M to 0.5 M).
Good quality models for predicting the yield of both products
were obtained from the DoE study. The results indicated that
only the amine loading and catalyst loading had a significant
effect on the yield of the desired amino amide. Unsurprisingly,
4
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we found that excess amine was beneficial for minimising
byproduct formation. Increasing the catalyst loading led to
increased formation of both products. As a result of this study,
we were able to identify conditions to obtain high yields of the
desired amino amide by running the reactions with only 1.5 eq of
amine and 20 mol% B(OCH2CF3)3 catalyst. Lowering the
amounts of amine further led to increased formation of di-amino
amide 4a, although less than statistically expected (usually
ranging between 1-8%, separable during purification).
With effective conditions in hand for the use of catalytic
B(OCH2CF3)3 for the direct amidation of an unprotected amino
acid, we then went on to explore the use of alternative Lewis
acid catalysts under these conditions. The use of 2-Cl and 3,4,5-
trifluorophenylboronic acids (entries 2-3, 9) has been previously
reported to be effective for amidation under dehydrative
conditions. [19-20] Such catalysts are generally unsuccessful even
for amidation of protected amino acids, and to the best of our
knowledge they have never been explored with unprotected
amino acids. [19-21] To our surprise, these boronic acid catalysts
were reasonably effective for the amidation of Phe with
benzylamine under Dean-Stark conditions, however.
workup), most likely due to the formation of complexes between
amino amides and Zr and the formation of hydrochloride salts of
the amines present in the reaction mixture.
The high levels of conversion to 1a in these reactions prevents
accurate differentiation of the reactivity of the various catalysts,
so we went on to screen selected catalysts for the direct
amidation of valine, a much less reactive substrate. Again, the
amidation could be achieved chemoselectively with both
group(IV) catalysts and boron-based catalysts. Although
amidation employing ZrCl4 gave the highest level of conversion,
attempts at isolation failed due to issues relating to adduct/salt
formation (vide supra, for use of stoichiometric ZrCl4).
B(OCH2CF3)3 was therefore identified as the catalyst of choice,
but Ti(OiPr)4 is a suitable alternative for more reactive amino
acids.
Substrate scope of borate-catalysed amidation. With
B(OCH2CF3)3 as the catalyst, we explored the scope of the
amino acid component with benzylamine as the amine (Scheme
4). All 20 common proteinogenic, as well as 9 non-proteinogenic
amino acids were tested. In general, the less polar amino acids
were good substrates for the reaction, with two aromatic (1a, 1d)
and most aliphatic (1f-1i) amino acids yielding the corresponding
amide in good to excellent yields (Scheme 4A, 4B). The amide
derived from alanine and benzylamine could not be readily
separated from unreacted benzylamine during purification, so a
reaction was therefore performed with phenethylamine to give
amide 1f in excellent yield. The reaction with glycine led to the
formation of a mixture of the desired amide 1e and its di-amido
counterpart 5e under the standard conditions, so a larger excess
of amine had to be employed (3 equivalents) and only a
moderate yield of 1e was obtained. We were also able to use
catalytic quantities of Ti(OiPr)4 for the preparation of amino
amides derived from more reactive amino acids (e.g. 1a, 1g).
This catalyst was much less effective for more hindered amino
acids, however (e.g. 1b). Pleasingly, using B(OCH2CF3)3 we
were also able to access amides of more polar amino acids with
hydroxyl (1l-1m) and sulfur (1j,1k) moieties present, and good
conversions were observed (Scheme 4C). Amide 1k (from
cysteine) was partially oxidized to the corresponding disulfide
over the course of the reaction and upon exposure to air.
Table 5. Lewis acids in the catalytic amidation of unprotected amino acids
Entry
R =
Catalyst
Yield 4a[a]
1
Bn
Bn
Bn
Bn
Bn
iPr
iPr
iPr
iPr
iPr
iPr
B(OCH2CF3)3
o-ClC6H4B(OH)2
3,4,5-F3C6H2B(OH)2
Ti(OiPr)4
90%
63%
71%
85%
41%
40%
43%
8%
2
3
4
5
Zr(Cl)4
6
B(OCH2CF3)3
Zr(Cl)4
Acidic amino acids underwent amidation effectively (Scheme
4D), with glutamic acid cyclizing intramolecularly to give
pyroglutamide 1n and aspartic acid undergoing double
amidation to give a diamide (1o). The increased degree of
racemization for 1o is probably due to a competing dehydrative
7
8
B(OMe)3
9
o-ClC6H4B(OH)2
Ti(OiPr)4
7%
mechanism involving a 5-membered acid anhydride, known to
[24]
have a propensity for racemization.
The basic (1q-1s) and
10
11
13%
25%
amidic (1t-1u) amino acids were somewhat less reactive
(Scheme 4E, 4F), with only histidine giving an amide derived
from benzylamine (1r). As expected, lysine spontaneously
cyclized to form -aminocaprolactam 1s. -Amino acids
generally worked less well than their -amino counterparts
(Scheme 4G). As with glycine, -alanine underwent extensive
overreaction (1v), and even with 3 equivalents of amine did not
give a clean amino amide product. However, -amino acids
could be coupled successfully to give amides 1w-1x, albeit in
lower yields relative to their -amino acid counterparts.
Hf(Cp2)(Cl)2
Amino acid (5 mmol), benzylamine (7.5 mmol), 20 mol% catalyst, TAME (5
mL), Dean-Stark. [a]1,4-dimethoxybenzene was used as an internal standard
Group (IV) metals (Entries 4-5) were, as with the stoichiometric
conditions, suitable catalysts for this transformation, with
Ti(OiPr)4 a particularly cost-effective alternative to our borate
ester providing amide 1a in excellent yield. When employing
ZrCl4, isolation of the product was problematic (product lost in
5
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Amino acids with protected side chains were also tested
(Scheme 4H). Ester-protected glutamic acid and the methyl-
ether derivative of serine gave amides 1y and 1z respectively in
good yields, despite showing signs of significant racemization.
Protected cysteine formed desired amide 1aa along with minor
amounts of a rearranged product (see ESI); S-methyl cysteine
yielded amide 1bb in excellent yield, but with significant
the method showed similar trends in reactivity to the
stoichiometric approach (vide supra, Table 2). The relevance of
this chemistry can easily be exemplified by the fact that most of
the amides synthesized in Scheme 4 (or their enantiomers) are
members of a well-documented class of potent anticonvulsants
and agents for neuropathic pain treatment, commonly referred to
as primary amino acid derivatives (PAADs). [22-23]
racemization.
Sarcosine,
L--aminobutyric
acid
and
The scope of the reaction with regard to the amine component
was investigated next through the preparation of amides derived
phenylglycine all underwent successful amidation (Scheme 4H),
although the latter (1ee) underwent complete racemization, as
expected based on its known propensity to racemise even under
mild conditions (e.g. Cbz-PhGly + NH4Cl yields amide in 43%
yield, 46% ee using ethyl chloroformate, 5° C, 1 h[25]). Overall,
from
a
selection of different amines employing both
stoichiometric B(OCH2CF3)3 (denoted as [A]) and the catalytic
reaction conditions (denoted as [B], Scheme 5).
Scheme 4. Scope of amidation reaction with unprotected amino acids. (A) Aromatic amino acids (B) Aliphatic amino acids. (C) Hydroxylic and sulfur
containing amino acids (D) Acidic amino acids (E) Basic amino acids (F) Amidic amino acids. (G) β-amino acids. (H) Side chain-protected amino acids (I)
Unnatural amino acids. Enantiomeric/Diastereomeric ratios >95:5, unless otherwise stated. er for 1k, 1m and 1r could not be determined. Yields in
[
parentheses are calculated against an internal standard (see ESI). [a]3 eq amine used.
mol%) in CPME. [d]No benzylamine used. [e]10 mol% B(OCH2CF3)3.
30 mol% B(OCH2CF3)3. [c]reaction conducted with Ti(OiPr)4 (15
b]
6
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Simple aliphatic amines worked well under both sets of
conditions (6a-6g, Scheme 5A). However, the reaction of
isobutylamine with tryptophan under catalytic conditions resulted
in a low yield of amide most likely due to the volatility of the
amine, which is probably removed into the side arm of the Dean-
Stark apparatus. Benzylic and allylic amines were also
successful (Scheme 5B), with substituted benzylamines bearing
a methoxy group (6i, 6l), fluoride (6j) or polyfluoroalkane (6n)
giving good yields of the corresponding -amino amides under
both sets of conditions. Heterocyclic tryptamine (6m) and 2-
picolylamine (6o) also underwent amidation successfully, with
significant amounts of racemization in the latter case when
stoichiometric B(OCH2CF3)3 was used. Pleasingly, the degree of
racemization was significantly reduced under catalytic conditions.
Amino amides could also be prepared from reactive secondary
amines in good yield (6q-6s, 6u-6w, Scheme 5C), but only with
the stoichiometric method. The reactions with leucine and
phenylalanine with pyrrolidine required forcing reaction
Scheme 5. Scope of amine component for amidation of unprotected amino acids. (A) Aliphatic amine scope (B) Aromatic/allylic amine scope (C) Secondary
]
amine scope (D) Synthesis of di-peptides (E) Medicinally relevant substrates. Enantiomeric/diastereomeric ratios >95:5, unless otherwise stated. [a Reaction
]
]
]
]
run at 125 ºC. [b B(OCH2CF3)3 added dropwise. [c 2 eq of amine used. [d 3 eq of amine used. [e 30 mol% B(OCH2CF3)3.
7
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conditions which led to significant levels of racemization (6s, 6u).
When employing catalytic B(OCH2CF3)3 for the synthesis of a
tertiary amide, even with a large excess of amine (3 equiv.) the
reaction was not selective and led to further reaction of 6t to give
di-amide 7t. Under the catalytic set of conditions, glutamic acid
was the only amino acid to show selectivity for mono-amidation
with a secondary amine, due to intramolecular cyclisation.
Indeed, it was possible to synthesise 6w and the pharmaceutical
Fasoracetam 6z (Scheme 5E) in one step from glutamic acid.
It was also possible to prepare dipeptide derivatives using
glycine and alanine tert-butyl esters as the nucleophiles
(Scheme 5D, 5E). Reaction of both Phe (6y) and Pro (6aa) was
attempted with OtBu Gly, although only the latter gave a good
yield and enantiopurity, with phenylalanine undergoing
significant racemization (6y). Conveniently, 6aa is a precursor to
a marketed nootropic, Noopept, which can be accessed through
a
further condensation employing our catalytic amidation
[14]
conditions.
Glutamic acid also underwent successful
cyclisation/amidation with Ala-OtBu to give 6x in good yield. We
were also able to synthesize a benzodiazepine derivative 8,
which belongs to a class of anti-anxiolytic drugs, from 2-
aminobenzophenone and L-Phe in 52% yield, albeit under
forcing conditions, which again led to a near full racemisation of
the final product.
As the synthesis of tertiary amides was problematic in most
cases, we set out to explore an alternative protocol using
aminoboranes (Scheme 6), which have been previously
demonstrated to promote amidation of carboxylic acids26-27 and
esters.28 Commercially available tris-amino boranes were found
to be effective for direct amidation of unprotected amino acids,
affording amides in moderate yield and enantiopurity. Due to the
volatility of amines such as dimethylamine, these amides would
be difficult to prepare using the borate-mediated reactions
outlined above. Using equimolar amounts of aminoborane under
conditions analogous to the stoichiometric borate reaction,
amino amides 6u, 6s, and 6bb-6gg were synthesized in low to
good yields and with little signs of racemization. In acetonitrile,
the remarkable reactivity of these aminoboranes enabled the
synthesis of amides 6ff-6gg and 6ee under very mild conditions
at room temperature. This method is, however, limited by the
requirement to employ an excess of amine in the synthesis of
the tris-amino borane, something which is only likely to be
economically viable with low-cost readily available amines.
Scheme 6: tris-Aminoboranes in amidation. Enantiomeric/diastereomeric
ratios >95:5, unless otherwise stated.
Sequential amidation reactions. With a method to provide
direct access to amino amide derivatives, we reasoned that we
could use the free amine group in further transformations to
access useful compounds. We envisaged that the direct
synthesis of free amino-amides could be combined with our
previously reported amidation processes[13] to provide access to
relatively complex -amido amides in a simple operation.
We started by exploring sequential amidation reactions with our
stoichiometric reaction conditions. To this end, direct amidation
of a free amino acid with propylamine was followed by a filtration
work-up to remove unreacted amino acid and boron residues
and give the crude -amino amide. This was then subjected to
direct borate-mediated amidation with a carboxylic acid to give
an -amido amide which was purified by a second filtration
work-up (Table 6). The diamides 10a-10e were obtained
efficiently over the two-step sequence in all cases, with no
requirement for chromatographic purification.
8
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Table 6. Sequential double amidation reactions
Table 7. Sequential catalytic double amidation reactions (one-pot)
Amide
Yield
Amide
Step 1 yield
95%
step 2 yield
80%
57%
87:13 er
61%
85:15 dr
64%
98:2 er
94%
71%
71%
57%
77%
69%
98:2 er
(recryst)
73%
66:34 er (SM
er 94:6)
71%
63%
Sequential condensation reactions. Given that B(OCH2CF3)3
We then went on to explore an analogous transformation
employing the catalytic conditions in a one-pot procedure (Table
7). Following the standard protocol for direct amidation of a free
amino acid, a solution of carboxylic acid in TAME was added to
enable a second amidation reaction to take place. In general
these double amidation reactions gave high conversions,
although in the case of chiral substrates, significant
epimerization took place most likely due to the extended
reaction times. Purification for diamides 11 employing column
chromatography was particularly difficult, due to the formation of
amide side products from the reaction of the reactant amine with
the second carboxylic acid coupling partner. Nonetheless, the
one-pot synthesis of Lacosamide was successful with this
has previously been shown to promote imine formation when
[31]
used stoichiometrically,
we also explored a one-pot
unprotected amino acid amidation/condensation reaction in
order to provide access to imidazolidinones in a single step
(Scheme 7). In this case the cyclisation reaction was much
quicker (1-2 h), and yielded products with very little or no signs
of racemization. Imidazolidinones derived from a selection of
amino acids (Phe, Ala and Sar) were cyclized with aliphatic
(12c-d, 12g-I, 12k), benzylic (12a), heterocyclic (12b, 12j) and
hydroxyl containing (12a) aldehydes or ketones in good to
excellent yields. Only the reaction of camphor (12e) failed to
yield the desired heterocycle. We were also able to synthesise
precursors to two natural products (±)-Tricladin A and B from
alanine in one step. [32]
method, yielding desired amide 11d, albeit with
a low
enantiopurity. It is worth noting, however, that this substrate is
particularly prone to racemization,[29-30] and that the first step of
the amidation reaction (1z, Scheme 4) also showed erosion of
enantiopurity (vide supra).
9
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Phe-OH being available at what is often considered a nominal
cost, it is >20 times more expensive than the free amino acid
(198 €/mol vs 10 €/mol)! [33]
Scheme 7. Sequential condensation reactions for the synthesis of
imidazolidinones. Enantiomeric ratios >95:5, unless otherwise stated. The er
of 12f could not be determined.
Scalability and green metrics. As our goal was to develop a
highly efficient and scalable amidation protocol, we sought to
test the synthesis of a set of substrates on a larger scale. Both
the chemoselective amidation protocol (25-50 mmol) and the
sequential amidation/condensation procedures (250 mmol) were
amenable to scale up to access multigram quantities of material,
although in slightly lower yields than the smaller scale reactions
in the case of 1b and 1d (Figure 2). This is likely due to the
heterogeneity of the system, which makes adequate mixing
more difficult on a larger scale.
Scheme 8. Efficiency and cost-effectiveness of chemoselective amidation in
comparison to regular amide bond formation processes.
Figure 2: Scale up amidations and sequential condensations. See ESI for
It is clear on the basis of the total material input required in
terms of reagents and solvents, that the direct chemoselecitve
amidation route offers significant benefits. The literature route
from the free amino acid requires a total material input of 308
Kg/Kg of amide product, and the approach from the Boc-
protected amino acid requires an even larger material input (412
Kg/Kg amide product). In comparison, our chemoselective
amidation method requires a material input of only 5 Kg/Kg of
amide product obtained, ~60-80 times more efficient. As these
methods for the syntheses of amino amides employ column
detailed procedures. [a]40 mol% B(OCH2CF3)3
Next we set out to demonstrate the efficiency and cost-
effectiveness of our method by benchmarking it against
‘classical’ amide coupling approaches. We examined the
synthesis of amide 1a using our method, and using literature
approaches starting from either the free amino acid or the Boc-
protected derivative, which is also commercially available and
commonly used as a starting material. However, despite Boc-
10
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chromatographic purification, we are unable to calculate the
process mass intensities. [34] However, the synthesis of amide 1a
was carried out on a 25 mmol scale and crystallization was used
to obtain the product with high purity, though in a lower yield
(57%) than from chromatographic purification. Nevertheless, this
process proceeds with an impressive PMI of only 13, which
compares very favorably to established amidation methods
(Typical PMI values in the range of 150-300).[34]
Origins of chemoselectivity. The interactions between amino
acids and boron Lewis acids were investigated by NMR studies.
The NMR spectra suggest that the Lewis acid coordinates to the
amino acid to form a cyclic intermediate such as 13 or 14
(Scheme 9). A shift in the 11B NMR spectrum from the trigonal to
the tetrahedral region suggests the formation of a structure such
as 13 (Figure 3). The interaction between the borate species
and the amino acid effectively solubilizes the amino acid in
organic solvent, allowing it to react in an amidation reaction.
Scheme 10. Reactivity of amino acids with (A) carboxylic acids and (B)
themselves
From these observations, it can be deduced that, only small
quantities of amino acid will be solubilized when employing
catalytic amounts of Lewis acid, creating a system in which the
amine is in large excess to the solubilised amino acid, which is
not reactive as a nucleophile (Scheme 11). This explains how
self-condensation of the amino acid is prevented, and also
explains the lack of reactivity of the amino acid with a carboxylic
acid. The solubilized amino acid complex 13 is then able to
undergo boron-catalysed amidation with the amine to generate
the amino amide product coordinated to the catalyst, which then
undergoes exchange with another molecule of free amino acid
to continue the cycle. On the basis of our recent studies, [35] the
amidation of the amino acid complex is likely to be mediated by
interaction with a second catalyst molecule to form a species
with a bridging acylboron unit.
Scheme 9. Interaction of boron Lewis acids with amino acids
Figure 3. 11B NMR of the interaction of B(OCH2CF3)3 with phenylalanine
Interestingly, amino acids do not react with an external
carboxylic acid such as phenylacetic acid under our standard
catalytic amidation conditions (Scheme 10). This suggests that
complexes such as 13 are not reactive at the amine. Similarly, in
the absence of an amine reaction partner self condensation of
the amino acid to give diketopiperazine did not take place to any
significant extent (Scheme 10). Of all the amino acids screened,
only proline formed trace amounts of diketopiperazine when
subjected to the standard catalytic amidation conditions (<5%
yield over 24 h).
Scheme 11: Solubilization of amino acid into solution, and subsequent
acylation
11
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We would like to thank GSK and University College London,
Department of Chemistry for providing a PhD studentship (to
MTS), Pfizer and the Engineering and Physical Sciences
Research Council (EPSRC) for providing a CASE award to
support a PhD studentship (to VK), and University College
Conclusions
In summary, we have identified effective methods for the direct
amidation of unprotected amino acids with amines using
catalytic or stoichiometric quantities of boron or titanium Lewis
acids. In this study, a detailed exploration of the scope of these
reactions has been carried out, enabling the advantages and
limitations of each approach to be identified. In scheme 12 we
provide a flowchart to enable the best method for a particular
amidation reaction to be identified. We hope that this guide will
prove useful in promoting the direct amidation of amino acids as
a useful transformation for the chemistry community. With
burgeoning interest in the development of novel catalytic
methods for amide bond formation, [36] we anticipate that other
amidation catalysts may well be applicable to this reaction. We
also anticipate that implementation of this synthetic strategy in
the pharmaceutical sector can lead to improved cost-
effectiveness and reduced levels of waste in the synthesis of
complex medicinally relevant compounds.
London, Department of Chemistry for providing
a PhD
studentship (to RML). We would also like to thank the EPSRC
national mass spectrometry facility at Swansea University for
providing assistance with analysis of some samples.
Keywords: Amino acids • amides • catalysis • Boron • Green
Chemistry
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