The Bull-James assembly as a chiral auxiliary and shift reagent in kinetic resolution of alkyne amines by the CuAAC reaction

Article abstract of DOI:10.1039/C6OB01623E

The Bull-James boronic acid assembly is used simultaneously as a chiral auxiliary for kinetic resolution and as a chiral shift reagent for in situ enantiomeric excess (ee) determination by ¹H NMR spectroscopy. Chiral terminal alkyne-containing amines, and their corresponding chiral triazoles formed via CuAAC, were probed in situ. Selectivity factors of up to s = 4 were imparted and measured, accurate to within ±3% when compared to chiral GC.

Full text of DOI:10.1039/C6OB01623E

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The Bull–James assembly as a chiral auxiliary and
shift reagent in kinetic resolution of alkyne amines
by the CuAAC reaction†‡
Cite this: DOI: 10.1039/c6ob01623e
Received 29th July 2016,
Accepted 15th August 2016
a,b
a,b
a,b
b
DOI: 10.1039/c6ob01623e
William D. G. Brittain,c Brette M. Chapin, Wenlei Zhai, aVincent M. Lynch,
b
Benjamin R. Buckley, Eric V. Anslyn* and John S. Fossey*
www.rsc.org/obc
The Bull–James boronic acid assembly is used simultaneously as a spectroscopy previously. One popular strategy is the use of
chiral auxiliary for kinetic resolution and as a chiral shift reagent chiral shift reagents, with the most common reagents being
1
6
3
for in situ enantiomeric excess (ee) determination by H NMR relatively expensive lanthanide-based complexes e.g. Eu(hfc) .
spectroscopy. Chiral terminal alkyne-containing amines, and their A weakly paramagnetic chiral lanthanide complex forms an
corresponding chiral triazoles formed via CuAAC, were probed in situ mixture of diastereoisomers whose diastereomeric ratio
6
c
in situ. Selectivity factors of up to s = 4 were imparted and (dr) is measured to determine the ee of the chiral analyte.
measured, accurate to within ±±3 when compared to chiral GC.
Chiral derivatisation of compounds to form distinguishable
diastereomers is one strategy for indirect determination of ee
via NMR spectroscopy. This technique was most notably
One of the bottlenecks in the analysis of asymmetric reaction
outcomes is the enantiomeric excess (ee) determination by
7
employed by Mosher (Mosher’s acid) for the analysis of
2
HPLC analysis using a chiral stationary phase. The develop-
8
enantiomer ratios of chiral alcohols and amines. However,
ment of enantiomer separation conditions, followed by often
lengthy elution times means that even a relatively fast reaction
can require hours to properly analyse the stereochemical
efficiency of the transformation. Therefore, the development of
high-throughput screening (HTS) techniques to determine ee
is important, especially where hundreds to thousands of reac-
tions need to be analysed swiftly in order to avoid holding up
this method requires one to sacrifice a small amount of
sample in order to carry out the analysis and is therefore less
9
than ideal for HTS applications.
1
A boronic acid-based supramolecular assembly for the H
NMR spectroscopic analysis of the enantiopurity of chiral
amines and diols were first reported by Bull, James and
10
co-workers. This system takes advantage of the diastereomeric
2
,3
industrial processes.
complexes formed from a boronic acid, chiral diol and a chiral
primary amine. Using a stereo-defined amine component, the
Nuclear magnetic resonance (NMR) spectroscopy is one
method that could be utilised in some cases as a HTS ee deter-
mination strategy. Proton NMR spectra can usually be
obtained in less than five minutes, whereas HPLC runs often
10a–e,g,k
ee of a chiral alcohol could be analysed, and vice versa.
The commercial availability and relatively inexpensive nature
of the Bull–James assembly components gives it an economic
edge over lanthanide-based chiral shift reagents.
4
require approximately tens of minutes. The increased
throughput in combination with circumvention of chiral
Following previously published work from some of the co-
authors of this report (Brittain, Buckley and Fossey), we
wished to tackle the difficult task of kinetic resolution (KR) of
terminal alkynes using copper catalysed azide alkyne cyclo-
additions (CuAACs) (Scheme 1). As there is, to the best of our
knowledge, only one reported example of this type of resolu-
1
chromatography method development makes H NMR spectro-
5
scopy an attractive approach for HTS. Determination of enan-
tiopurity has been successfully carried out via NMR
a
School of Chemistry, University of Birmingham, Edgbaston, Birmingham,
1
1
tion, we believed this to be a robust test of the Bull–James
sensing assembly in the challenging forum of kinetic resolu-
tion, where both the ee of starting material and of product are
simultaneously probed. Kinetic resolution takes advantage of
West Midlands, B15 2TT, UK. E-mail: j.s.fossey@bham.ac.uk
b
Department of Chemistry, The University of Texas at Austin, Austin, Texas, 78712,
USA. E-mail: anslyn@austin.utexas.edu
c
Department of Chemistry, Loughborough University, Loughborough, Leicestershire,
LE11 3TU, UK
11
the difference in rate of reaction of enantiomers and allows
1
†
‡
Dedicated to the 60th Birthday of Tony Czarnik.
for the recovery of enantioenriched starting materials and
products. Additionally, it is an asymmetric approach that has
been successfully used to obtain many enantioenriched
Electronic supplementary information (ESI) available. CCDC 1477891. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c6ob01623e
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nation of ee for this resolution. Unfortunately, we found that
the free base of amine 1 decomposed and was not suitable for
resolution using our previously reported system and that
1
1
research was suspended.
Since the imine in assembly 4 is more stable than the free
primary amine 1, we tested if it was possible to form the
assembly and then carry out a CuAAC reaction to measure con-
version and circumvent the stability issues of 1.
To our surprise, we found that combining 1, 2 and 3 to
form the assembly, followed by addition of half an equivalent
of benzyl azide and 10 mol% CuCl, led to formation of the tri-
azole assembly 5. Proton NMR spectroscopy revealed that inte-
grations corresponding to diastereomers of both alkyne and
triazole imine peaks (in 4 and 5 respectively) were not 1 : 1
(
Fig. 1). Since the reaction was carried out on a 1 : 1 mixture of
diastereomers of the assembly 4, the alkyne of one diastereo-
meric assembly is consumed more rapidly than the other.
Therefore, the Bull–James assembly was acting as a chiral
auxiliary for KR, simultaneously with its precedented use as an
ee determination tool. In addition, the reversible nature of
boron–diol binding means that after hydrolysis all of the
remaining alkyne 1 and formed triazole 6 could be recovered,
thus giving the approach an advantage over irreversible chiral
Scheme 1 Boronic acid assembly is used as a chiral auxiliary and an derivatisations such as Mosher’s acid. It should be noted that
17
in situ ee NMR determination methodology.
half an equivalent of benzyl azide was used, in accordance
with typical kinetic resolution reactions, in order to avoid full
conversion (full conversion would lead to 1 : 1 diastereomeric
assembly 5 and thus racemic triazole 6).
In order to confirm that NMR spectroscopic analysis was an
accurate measure of assembly dr (and thus ee) during the
1
2
species, including scaffolds with proven biological activity.
Enantioenriched, unreacted alkynes, as well as product tri-
azoles, can be obtained.
1
3
To test if the assembly was suitable for inference of ee for a kinetic resolution process, we first used chiral HPLC as a stan-
primary amine alkyne, 1-phenylprop-2-yn-1-amine was dard with which to compare the relative NMR peak inte-
1
required. The alkyne 1 was selected because it is an important grations. Thereby, we would be able to confirm that the
building block for several biologically active compounds such measured enantioenrichment of 1 and 6 following kinetic
1
3
14
as peptide isosteres, analogues of oxotremorine, and benzo resolution was accurate.
1
5
[
b]furan compounds. Additionally, the associated triazole
has previously been studied for its antimicrobial activity.
Hydrolysis of the mixture of assemblies 4 and 5 with 2 N
1
6
HCl and subsequent basic extraction led to the recovery of the
Therefore, kinetic resolution would allow access to compounds amine 1 and triazole 6 with minimal amounts of 2-FPBA and
and intermediates with previously proven biological activity in BINOL remaining (Scheme 1). The amine was then protected
an enantioenriched form.
using benzoyl chloride to give two pairs of HPLC-separable
Originally, the Bull–James three-component assembly was enantiomers (see ESI‡). The HPLC traces showed peaks with
selected for use as only a tool to measure the ee of 1 and 6 fol- the correct retention times for both benzoylated starting
lowing exposure of compound 1 to our previously reported material 1 and benzoylated product 6 (see ESI‡ for details).
resolution conditions, which had successfully resolved racemic The calculated ee’s from HPLC peak integrations were within
1
1
quaternary alkyne oxindoles. We had hoped to use the Bull–
James assembly to measure the ee of 1 and 6 simultaneously
and in situ during resolution using our previously developed
1
1
KR methodology. Upon mixing amine 1 with the assembly
components (to form 4), we observed signals corresponding to
1
imine diastereomers in the H NMR spectra (1 : 1 integration).
Thus, the imine signals (8.74 ppm and 8.88 ppm) were
selected for dr measurement and subsequent ee determination
of amine 1. Carrying out the same process with triazole 6 (to
form 5) we also observed clear imine signals (8.56 ppm and
9
.05 ppm, 1 : 1 integration) which did not overlap with reson-
ances of 4. The assembly was deemed suitable for the determi- Fig. 1 Imine region of NMR following assembly reaction.
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±
5% ee agreement with the level of enantioenrichment deter-
Next solvent effects were investigated to influence both
1
mined by in situ H NMR spectroscopic integration. As enantioselectivity and spectra analysis. We found that
additional evidence of accuracy, it was found that amine 1 was DMSO-d6 and DMF-d7 led to broad spectra, which were
suitable for chiral GC without need of benzoylation. The chiral difficult to integrate to give reliable values, even after drying
GC integration values were shown to be within ±3% ee of the over molecular sieves. To our surprise, we found that aceto-
NMR analysis method. The agreement of the ee values deter- nitrile-d3 and toluene-d8 both led to precipitation of the
mined by two methods of chiral chromatography with the assembly. On closer inspection of the acetonitrile case, only
1
H NMR integrations of the imine signals of the assemblies one diastereomer precipitated (R,R), which was recrystallised
allowed us to conclude that the assembly was successfully and analysed through XRD to obtain structure 7. We did not
doubling as a dual-function chiral auxiliary and ee measurement include dichloromethane-d2 in our screen due to the possi-
1
8
ensemble of both the starting material and product in situ.
bility of unwanted side reactions (Fig. 2). Chloroform-d was
After confirming that the three-component assembly was thus determined to be the best choice.
acting as a dual ee determination ensemble and chiral auxili-
We next varied the diol component to determine whether
ary, we began to screen reaction conditions in the hope of this had an effect on the observed enantioselectivity and ee
improving selectivity. First we varied the copper source, and a determination capability. However, after testing a range of
range of commercially available Cu(II), Cu(I) and Cu(0) sources diols it was confirmed that BINOL was the best choice for this
were tested. Of the copper sources tested, CuCl was confirmed system (see ESI‡). BINOL was found to have the correct solubi-
as superior in terms of selectivity (Table 1, entry 1) whilst lity and steric bulk to achieve selectivity; bulkier diols tried
giving reasonable conversion. CuBr gave slightly increased were found not to be soluble at the concentrations required for
conversion (34%) but with slightly reduced selectivity (s = 3.7) NMR analysis and thus were disregarded.
whilst CuI was very sluggish and required doubling of the reac-
tion time to give a reasonable conversion (39%) with poorer adventitious water led to the appearance of additional peaks
selectivity (s 2.4) (Table 1, entries and 3). in the proton NMR spectrum. We found that rigorous drying
Cu(OTf)·0.5toluene gave decreased selectivity (s = 2.8) (Table 1, of the BINOL and 2-FPBA and the addition of molecular sieves
entry 4). [Cu(CH CN) ]PF gave increased conversion (50%). to all solutions led to the minimisation of these side-products.
However, selectivity was lower (s = 3.0) (Table 1, entry 5). In These preliminary findings show that a chiral boronic acid-
addition to these a wide range of other copper sources were based assembly, designed for the analysis of ee of amines via
Due to the reversible nature of boronic acid–diol binding,
=
2
3
4
6
1
tested (see ESI‡) however none of them could improve on
H NMR spectroscopy, can also be used as a chiral auxiliary.
This allows for the catalysis and analysis of the reaction
mixture to be carried out by the same auxiliary. It was shown
that this assembly can effect, and accurately measure, the
enantioenrichment of primary amine alkynes and triazoles in
a kinetic resolution reaction. This system allows for rapid and
relatively accurate measurement of an on-going asymmetric
transformation in situ, thus analysis time is shortened com-
pared with standard chiral chromatography. We anticipate that
the concept of using a chiral appendage as both an asym-
metric induction unit and as an NMR chiral shift reagent will
be applicable to many other asymmetric transformations and
CuCl.
Table 1 Probing reaction conditions
19
we look forward to reporting on these in due course.
The authors thank Tony D. James and Steven D. Bull for
inventing and developing the ee analysis protocol. Without
a
b
b
Entry
Copper source
Conv. (%)
%ee 1
%ee 6
s
1
2
3
4
5
CuCl
CuBr
CuI
Cu(OTf)·0.5toluene
3 4 6
[Cu(CH CN) ]PF
30
34
39
31
50
23
25
21
18
36
39
48
13
31
16
4.1
3.7
2.4
2.8
3.0
c
c
a
1
Conversion was determined by integration of H NMR of the assem-
bly comparing the imine proton of the starting material and triazolic
b
Fig. 2 Crystal structure of assembly precipitated from mixture of com-
ponents in acetonitrile, chirality of the diastereoisomer (R,R) was calcu-
product. ee was determined via comparison of the integration values
of the imine region diastereomers in the H NMR spectrum of the
assembly as de = ee (see ESI). Reaction was slow, thus reaction time lated from the known chirality of the (R)-BINOL. Full details in ESI‡ and
1
c
was increased to 48 h.
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their breakthrough technology none of this work would have
been possible. WDGB and WZ are grateful to the University of
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Industry for travel grants. EVA also thanks the Welch Regents
Chair (F-0046) and the NIH (GM077437) for support. The
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2
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