Direct amidation of unprotected amino acids using B(OCH2CF3)3

Article abstract of DOI:10.1039/c6cc05147b

A commercially available borate ester, B(OCH₂CF₃)₃, can be used to achieve protecting-group free direct amidation of α-amino acids with a range of amines in cyclopentyl methyl ether. The method can be applied to the synthesis of medicinally relevant compounds, and can be scaled up to obtain gram quantities of products.

Full text of DOI:10.1039/c6cc05147b

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Karaluka, M. Sabatini, P. Starkov, M. Badland, L. Boulton and T. Sheppard, Chem. Commun., 2016, DOI:
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Direct Amidation of Unprotected Amino Acids using B(OCH2CF3)3
Rachel M. Lanigan,#a Valerija Karaluka,#a Marco T. Sabatini,#a Pavel Starkov,¥a Matthew Badland,b
Lee Boultonc and Tom D. Sheppard*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A commercially available borate ester, B(OCH2CF3)3, can be used to purification materials. A more straightforward approach would
achieve protecting-group free direct amidation of α-amino acids be the direct amidation of the free amino acid to give the
with a range of amines in cyclopentyl methyl ether. The method amino amide in a single step. This has rarely been achieved,
can be applied to the synthesis of medicinally relevant however, with only scattered reports in the literature that
compounds, and can be scaled up to obtain gram quantities of have not been widely applied.4 The only reasonably effective
products.
method involves reaction of the amino acid with the highly
toxic gas hexafluoroacetone, followed by subsequent reaction
with an amine.5 Although great progress has been made in
recent years on the development of new amidation methods6
which make use of low-cost reagents7-8 or catalysts9 that are
easy to separate from the amide products, few of these
methods are applicable to highly functionalized compounds
and none have been applied to the direct amidation of free
amino acids.10
Amino acids are valuable renewable chemical building blocks
for the synthesis of a wide range of natural products,
pharmaceuticals and agrochemicals, and can serve as a source
of chirality for a range of ligands and catalysts. However, their
use in synthesis relies heavily on protecting group chemistry,1
with either the amine or the carboxylic acid requiring
protection before key bond-forming processes are carried out.
Amidation is one of the most common transformations used in
the synthesis of many industrially important molecules,2 and
amino acid amides form part of the core of numerous globally
important pharmaceuticals including Sitagliptin, Ramipril and
Lacosamide (Scheme 1).3 The synthesis of amino acid amides
Pharmaceuticals containingamino acid amides:
CF3
Ph
O
H
H
F
N
Ph
N
H
N
N
N
N
OEt
H
N
N
O
H
MeO
Lacosamide
anti-epileptic
NH2
O
HO2C
O
O
F
typically proceeds via
a three step sequence involving
Sitagliptin
DPP IV inhibitor
Ramipril
ACE Inhibitor
F
protection of the nitrogen atom with a carbamate (Boc, Fmoc,
Cbz) before amidation of the carboxylic acid and subsequent
deprotection. Nitrogen protection is usually essential as self-
reaction of the free amino acid can lead to the formation of
diketopiperazines, oligomers or polymers. The use of
carbamate protecting groups is highly inefficient as they have
a relatively high molecular weight in comparison to the amino
acid itself (Boc 101; Fmoc 223; Cbz 135), and their introduction
and removal requires additional reagents, solvents and
Synthetic routes to amino acid amides:
This work (one step)
O
O
R2
R2
NH2
Deprotection
NH2
NH2
N
HO
H
B(OCH2CF3)3
R1
R1
O
H
O
R2
O
H
NH2
N
OR'
R2
N
OR'
HO
N
R'O
X
H
Coupling
reagent
R1
O
R1
Existing methods(three steps)
O
Scheme 1 Important amino acid amides and the typical synthetic
route used to prepare them.
a.Department of Chemistry, University College London, Christopher Ingold
Laboratories, 20 Gordon St, London, WC1H 0AJ, UK;
Email: tom.sheppard@ucl.ac.uk
We have recently reported the use of borate esters, and
11
B(OCH2CF3)3 in particular, for the direct amidation of a wide
range of acids and amines, including functionalized examples.8
An important advantage of this method is the ease with which
the amide products can be purified using a simple filtration
work-up involving commercially available resins, which
scavenge unreacted acid and amine as well as any boron-
containing byproducts. In this paper, we demonstrate that
B(OCH2CF3)3 is a highly effective reagent for the direct
b.Pfizer Global Pharmaceutical Sciences, Discovery Park, Ramsgate Road, Sandwich,
Kent, CT13 9NJ, UK
c. GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage,
Herts, SG1 2NY, UK
#These authors contributed equally.
¥Current address: Department of Chemistry, Tallinn University of Technology, 15
Akadeemia Rd, 12618 Tallinn, Estonia.
Electronic Supplementary Information (ESI) available: Full experimental procedures
and 1H and 13C data for all compounds. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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Chemical Communications
amidation of unprotected amino acids to give useful
amide products in a single step. This has the potential to valine, leucine, proline and isoleucine also underwent direct
significantly shorten the synthesis of many pharmaceutically amidation in high yield (5c 5g), although in the case of
relevant compounds. isoleucine a significant amount of epimerization was observed,
α-amino amino acids containing alkyl/aryl side chains including glycine,
-
We began our investigation (Scheme 2, Table 1) by which could be reduced by reduction of the reaction time and
exploring the direct amidation of alanine 1a with benzylamine by adding the borate reagent dropwise.
2
(entry 1). Under our previous amidation conditions (MeCN,
3 eq
B(OCH2CF3)3
reflux),8 addition of a base (diisopropylethylamine
3) was
O
O
NH2
NH2
necessary to solubilise alanine in the reaction. We observed a
promising 35% conversion to the desired amide using one
nPrHN
H2N
HO
CPME, 80
3-15 h
C
3 eq
R
R
1a-1z
5a-5z
equivalent of B(OCH2CF3)3
4, with little evidence for significant
O
O
O
O
self-reaction of the amino acid. Addition of excess borate
4
NH2
NH2
NH2
NH2
nPrHN
nPrHN
nPrHN
nPrHN
increased the conversion to 71% (entry 2). Crucially, in the
absence of the borate reagent no conversion to the amino
amide was observed (entry 3). As the amidation product
derived from alanine was extremely polar and time-consuming
to isolate, we switched our attention to the direct amidation of
Ph
5aa,b 71%
ier 93:7
O
5b 90%b, 95%m
5c 71%
5d 83%d,e
jer 91:9
O
ier 94:6
O
O
H
NH2
NH2
NH2
nPrHN
N
nPrHN
nPrHN
nPrHN
phenylalanine 1b with benzylamine
2. Under similar
conditions, this amide was obtained in 61% yield (entry 4). A
screen of different solvents,12 led us to identify cyclopentyl
NH
5h 79%d
5e 73%; 87%m
5f 91%
5g 90%c (dr 75:25)
methyl ether (CPME)13 as
a promising solvent for the
jer >99:1
O
jer >99:1
O
76%c,d (dr 83:17)
O
jer 92:8
O
amidation reaction (entry 5). A significant improvement in the
yield was seen by increasing the number of equivalents of
NH2
NH2
NH2
NH2
OH
nPrHN
nPrHN
nPrHN
OH
nPrHN
benzylamine
2 used (entry 6), and with excess benzylamine an
N
additional base was no longer required. The importance of
using B(OCH2CF3)3 as the coupling reagent was underlined by
8a
SMe
NH
5i
ier 96:4
O
5j
5k 23%d
5la
81%
27%
56%
the fact that B(OMe)3 led to only 9% conversion under
ler 85:15
O
dr >95:5
O
otherwise identical reaction conditions (entry 7). As observed
previously with alanine, no product was formed in the absence
O
H
NH2
NH2
NH2
N
nPrHN
nPrHN
nPrHN
nPrHN
of the borate reagent 4 (entry 8).
O
O
O
NHnPr
NH2
H2N
O
5mj
5n
ker >99:1
O
5oa
5pa,h
68%,b,f (er 81:19),
79%
(16%)
(21%)
71%d,f (er 89:11)
O
O
O
NH2
NH2
NH2
NH2
nPrHN
nPrHN
nPrHN
HN
Scheme 2 Direct amidation of alanine or phenyalanine using
SH
OH
NH
benzylamine.
H2N
N
H
Table 1 Direct amidation of 1a or 1b and 2 under a variety of conditions.
5qc
5ra,g
5s
(62%)
(44%)
(0%)
5t
(0%)
Entry
R
Solvent
MeCN
MeCN
MeCN
MeCN
CPME
CPME
CPME
CPME
2 (eq) 3 (eq) 4 (eq)
Yielda
(35)
(71)
(0)
O
O
O
1
2
3
4
5
6
7
8
Me
Me
Me
Bn
Bn
Bn
Bn
Bn
1
1
1
1
1
3
3
3
1
1
1
1
1
0
0
0
1
3
0
NH
NH2
NH2
nPrHN
NH2 nPrHN
nPrHN
5ua 68%
5vb 84%
5wc 70%
3
61
O
O
O
3
65
NH2
NH2
3
95
(9)
(0)
nPrHN
nPrHN
nPrHN
3b
0
MeO
5xc 58%
5y 83%d
jer 94:6
5z, 83%
aYields measured by 1H NMR using naphthalene as an internal standard;
conversions are shown in parentheses. bB(OMe)3 was used instead of 4.
Scheme 3 Direct amidation of unprotected amino acids with
propylamine; Isolated yields (NMR yields shown in parentheses);
aReaction carried out in MeCN; bIsolated as HCl salt; c125 °C;
With an effective procedure in hand, we then went on to
examine the scope with regard to the amino acid component
(Scheme 3). In order to facilitate purification of the products
we used n-propylamine as the amine so the products could be
purified via a simple solid-phase work-up and subsequent
evaporation of the volatile materials. The direct amidation
products 5a-5b derived from alanine and phenylalanine were
obtained in 71% and 95% isolated yield respectively. Other
dBorate 4 was added dropwise over 1 h; e110 °C; f4 eq of 4 and 6 eq
propylamine; gNo propylamine; h15% yield of 5n also observed;
iDetermined using imine formation with a chiral aldehyde;15
jDetermined using Marfey’s reagent;16 kDetermined using a chiral
shift reagent;17 lDetermined by HPLC of a derivative using a chiral
stationary phase; m1g scale.
2 | J. Name., 2012, 00, 1-3
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Pleasingly, tryptophan (5h) and methionine (5i) were also with benzylamine, followed by acylation with acetic
good substrates for the direct amidation reaction, giving high anhydride.20
yields of the corresponding amides. Even amino acids with
functionalized side chains were compatible with the reaction
conditions, with the amides derived from tyrosine (5j) and
histidine (5k) being obtained in moderate yield, and threonine
undergoing direct amidation in an impressive yield of 56%,
despite the presence of the free hydroxyl group (5l). Aspartic
acid underwent double amidation in the presence of excess
amine/borate to give the diamide 5m 18
, whereas in the case of
glutamic acid, lactam formation took place alongside
amidation to give 5n. A small improvement in both the yield
and enantiopurity was seen by adding the borate dropwise to
the reaction mixture. Asparagine and glutamine were poor
substrates for the reaction giving only low conversions to the
desired amides 5o-5p. Whilst reaction of cysteine led to a good
conversion to the desired amide 5q, we were unable to purify
this amide despite numerous attempts. Lactamisation of lysine
outcompeted the desired amidation reaction with 5r being the
only product observed either in the presence or absence of
propylamine. Direct amidation of serine and arginine did not
give any of the expected amino amide. The reaction of serine
led to a complex mixture of products with no observable
amide 5s, a surprising result given the successful amidation of
threonine. Arginine was insoluble in the reaction mixture and
no 5t was observed. Non-proteinogenic amino acids also
underwent direct amidation under these conditions (5u
with -alanine, sarcosine and -aminoisobutyric acid giving
the corresponding amides 5u 5w in good yield. Relatively
-5z)
β
α
-
hindered cyclopentyl amino acid amide 5x was obtained in
moderate yield, whereas 2-aminobutyric acid and O-
Scheme 4 Direct amidation reactions of amino acids with various
methylserine gave the corresponding amides 5y
-
5z in excellent
a
amines; 125 °C; bBorate 4 was added dropwise over 1 h.
yield. Pleasingly, the vast majority of the amides 5a
-5z were
obtained in high purity from a simple filtration without the
need for chromatography or an aqueous work-up.
Furthermore, scale-up of two amidation reactions (5b
, 5e) to 1
g
scale resulted in improved yieldd of products whilst
maintaining the same level of enantiopurity, demonstrating
the synthetic utility of this procedure. Whilst a small degree of
racemisation was observed with some amino acids, it should
be noted that the amino amides (or simple derivatives such as
their HCl salts) are usually crystalline so recrystallization could
potentially be used to obtain enantiopure material if needed.
The scope of the reaction with regard to the amine
component was investigated next (Scheme 4), through the
preparation of amides derived from a selection of different
Scheme 5 Possible mechanism for the direct amidation of
unprotected amino acids.
A plausible mechanism for the amidation reactions is
shown in Scheme 5. Coordination of both the amine and the
carboxylic acid to the borate reagent should lead to cyclic
amines. Simple aliphatic amines
(
6a-
6f
)
including an
intermediate 8 4a,4b
amine partner to form the boron-bound amino amide
.
This can then undergo reaction with the
. In
unsaturated example (6c) worked well in the reaction. Amides
9
could also be prepared from cyclic secondary amines in good
cases where the amino acid and/or the amine are less reactive,
racemisation could occur via borate-assisted deprotonation of
yield (6g
dipeptide derivatives using amino acid tert-butyl esters as the
nucleophile (6k 6l). The methodology was then applied to the
synthesis of the previously reported anti-convulsant amino
amides 6m
6n19 to demonstrate the application of the
methodology. Finally, synthesis of the anti-epileptic
Lacosamide was carried out by direct amidation of (R) 1z
-6j). Importantly, it was also possible to prepare two
intermediate
8 by the amine, leading to the formation of the
-
formally aromatic heterocyclic enolate 10
.
In summary, we have developed a practical and general
method for the protecting-group free direct amidation of free
amino acids. The amidation reaction is successful with 14 of
the 20 common proteinogenic amino acids as well as six
-
a
7
-
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We would like to thank the Engineering and Physical
Sciences Research Council (EPSRC Advanced Research
Fellowship to TDS; studentship to PS; Grant reference
EP/E052789/1), the Department of Chemistry, University
College London (studentship funding to RML and MS), Pfizer
(EPSRC CASE award to VK) and GlaxoSmithKline (studentship
support to MS). We would also like to acknowledge the EPSRC
National Mass Spectrometry Facility at Swansea University for
providing analytical services.
,
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