Cyrene as a bio-based solvent for HATU mediated amide coupling

Article abstract of DOI:10.1039/c8ob00653a

Amide bonds are one of the underpinning linkages in all living systems and are fundamental within drug discovery. Current methods towards their synthesis frequently rely on the use of dipolar aprotic solvents; however, due to increasingly stringent regula

Full text of DOI:10.1039/c8ob00653a

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DOI: 10.1039/C8OB00653A
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ART
Cyrene as a Bio-based Solvent for HATU Mediated Amide Coupling
a
b
a
c
Kirsty L. Wilson, Jane Murray, Craig Jamieson and Allan J. B. Watson *
Received 00th January 20xx,
Accepted 00th January 20xx
Amide bonds are one of the underpinning linkages in all living systems and are fundamental within drug discovery. Current
methods towards their synthesis frequently rely on the use of dipolar aprotic solvents; however, due to increasingly
stringent regulations and growing societal pressures, safe and more sustainable alternatives are highly sought after.
Herein, we evaluate the application of the bio-based solvent Cyrene™ in the HATU mediated synthesis of amides and
peptides. We found that Cyrene functioned as a competent replacement for DMF in the synthesis of a series of lead-like
compounds and dipeptides (25 examples, 63-100%).
DOI: 10.1039/x0xx00000x
www.rsc.org/
concern due to the safety issues they pose. Exposure to
solvents such as DMF and NMP is associated with reproductive
toxicity and, as such, have been placed on the Registration,
Introduction
The amide functionality is ubiquitous throughout the
natural world, forming the backbone of essential biomolecules
Evaluation, Authorisation and Restriction of Chemicals (REACH)
list of substances of very high concern with NMP additionally
(
e.g. proteins) as well as many widely used materials (e.g.
9
,10
1
,2
recommended for inclusion on the REACH authorisation list.
polyamides). Additionally, the amide moiety has profound
importance to modern pharmaceutical development. This is
clearly demonstrated throughout the chemical literature,
where amide bond formation is consistently highlighted as the
most frequently performed transformation in medicinal
In this respect, solvent selection and more specifically the
reduction in usage of dipolar aprotic solvents such as DMF and
NMP has been designated
a focal area by leading
11
pharmaceutical companies and academic groups. As such, a
number of tools and guides have been published to allow
chemists to identify suitable alternatives and make changes to
their reaction manifold to align with current environmental
3
-5
chemistry.
Indeed, Brown’s recent analysis of past and
present synthetic methodologies within medicinal chemistry
revealed that 50% of manuscripts surveyed (a representative
data set of 125 papers taken from J. Med. Chem. in 2014)
contained the transformation in the context of small molecule
synthesis. The authors also note that the amide functionality
occurs in >50% of pharmaceutical drug discovery patents and
1
2-17
advisory guidelines.
stringent regulations, the use of dipolar aprotic solvents is still
Despite these efforts and increasingly
1
8
widespread. This is due to the superior solubilising power of
DMF and NMP, which is why they are commonly encountered
in amide bond formation and, more specifically in the
synthesis of peptides.
3
journals (as calculated by the IBEX database). In addition to
these significant statistics within small molecule drug design,
the number of peptides being approved for therapeutic use is
growing dramatically. Analysis of the peptide drug market
carried out by Nuss revealed that, as of 2016, the number of
Efforts have been made towards highlighting direct solvent
replacement strategies within amide bond formation. We have
previously evaluated the use of selected alternative solvents
within four benchmark amide bond forming reactions,
peptides approved as drugs was 56 while a further 178 were
6
involved in clinical trials (Phase
2 2
demonstrating that CH Cl and DMF could successfully be
I
-
III). As such, efficient
1
9
replaced by more benign solvents. More recently, a series of
papers have been published detailing the replacement of
dipolar aprotic solvents within solid phase peptide synthesis
methods towards their formation are highly sought after.
Typically, amides are formed by the direct condensation of
carboxylic acids and amines, usually using an activator of some
kind, which is attractive due to the high abundance of starting
materials. Established methods employ coupling reagents such
2
0-24
(SPPS).
In addition to these important contributions,
emerging micellar technology has also allowed for the
5
formation of amide bonds in aqueous media.
2
7
8
as HATU and COMU, and commonly rely on the use of
dipolar aprotic solvents, the continued use of which is of great
O
Cyrene (1)
DMF
O
•
B. Pt.: 203 °C
• Density: 1.25 g/mL
Dipolarity (π*): 0.93
• B. Pt.: 153 °C
• Density: 0.94 g/mL
• Dipolarity (π*): 0.88
Me
O
H
N
O
•
Me
Figure 1. Physical properties of Cyrene and DMF
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ARTICLE
Journal Name
In addition to the safety aspects surrounding the use of consistency. We found that this was due to variable stirring rate and
conventional solvents, growing societal and political pressure as such, stringent control of this factor allowed us to establish
towards the greening of chemical industries places emphasis consistency (Entry 3). Upon increasing the stirring rate higher yields
on the reduction of petroleum based chemicals in favour of with little variance could be achieved (Entry 3-5). Cyrene is a
2
6
those derived from sustainable sources. To address this viscous liquid, which we believe gives rise to sub-optimal mixing at
movement, many Green Chemistry initiatives within academia slow stirring rates. However, by increasing the stoichiometry of
and industry are exploring solvents which can be obtained DIPEA we observed a decreased dependency of yield on stirring rate
2
7-35
TM
from biomass.
), which can be accessed from cellulose in two steps, has improvement on conversion (see ESI).
been shown to possess similar physical properties to DMF and We sought to investigate the utility of the optimized conditions
other dipolar aprotic solvents and is not currently associated (Table1, Entry 6) in the coupling of a range of carboxylic acids and
Dihydrolevoglucosenone (Cyrene , Figure (Entry 6). Variation of coupling reagent and base failed to offer any
1
3
4-40
with any harmful effects.
demonstrated successful
in addition
Cyrene has previously amines (Scheme 1). Variation of the carboxylic acid and amine
application
in
materials components was broadly successful (15 examples, 63-100%) with
4
1,42
chemistry,
transformations.
replacement strategies,
to synthetic
organic alkyl (e.g., 3g, 3j) and aryl (e.g., 3k, 3m) moieties of both coupling
4
3-45
Based on our interest in solvent partners tolerated. In addition to primary amines we found that
2
1,46-49
we are pleased to report the use both cyclic (e.g., 3c, 3i) and acyclic (e.g., 3f) secondary amines could
of Cyrene as a bio-based solvent in amide bond formation.
be coupled in high yields. In the cases where comparatively lower
yields were reported, such as 3n, we found that the remaining mass
balance was made up of unreacted activated ester.
Results and discussion
To investigate the capacity of Cyrene as a solvent in amide bond
formation we selected N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-
b]pyridin-
1-ylmethylene]-
N-methyl-
methanaminium
7
hexafluorophosphate N-oxide (HATU) as the coupling reagent in
the benchmark coupling of p-toluic acid 1a and aniline 2a (Table 1).
a
Table 1. Reaction Optimisation
Conversion
Entry
Reaction conditions
DIPEA (2 equiv.), 24 h
b
(µ ± σ %)
c
1
2
3
4
5
6
7
87 ± 13
c
DIPEA (2 equiv.), 1 h
84 ± 21
73 ± 3
71 ± 3
96 ± 7
92 ± 2
100 ± 0
DIPEA (2 equiv.), 1 h, 200 rpm
DIPEA (2 equiv.), 1 h, 400 rpm
DIPEA (2 equiv.), 1 h, 800 rpm
DIPEA (3 equiv.), 1 h, 400 rpm
Scheme 1. HATU mediated amide bond formation: Scope of the transformation.
Isolated yields. Acid (1 equiv., 0.25 mmol), amine (1.1 equiv., 0.275 mmol), HATU (1.2
equiv., 0.3 mmol), DIPEA (3 equiv., 0.75 mmol), Cyrene (1.25 mL, 0.2 M), rt, 1 h.
d
DIPEA (3 equiv.), 1 h, 400 rpm
a
We next applied these conditions in the synthesis of
peptides (Scheme 2). Again, high yields are reported in the
coupling of protected amino acids, with a broad scope of
functionality demonstrated (9 examples, 63-100%). In addition
to amino acids whose side chains bore alkyl and aryl
substituents (e.g., 6a and 6c), we found those containing
protected and unprotected heteroaromatic residues could also
be coupled in high yields (e.g. 6e and 6i). However, with some
p-Toluic acid (1 equiv., 0.25 mmol), aniline (1.1 equiv., 0.275 mmol), HATU
b
1
(
1.2 equiv., 0.3 mmol). % conversion calculated by H NMR using 1,4-
dinitrobenzene as an internal standard. Presented as an average with
c
d
standard deviation as a measure of consistency. n=3. Variable stirring rate.
DMF as solvent.
We found that the initial reaction proceeded smoothly allowing
a reduced reaction time of 1 h (Entry 2). However, whilst high yields
of 3a were recorded further repetitions failed to deliver
2
| J. Name., 2012, 00, 1-3
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examples (6b
ARTICLE
,
6d, and 6h) we found it necessary to increase
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Conflict of Interest
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2
2
3
4
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Cyrene® is sold (£83/100 mL) by Sigma-Aldrich (now Merck
KGaA).
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