A Protocol for NMR Analysis of the Enantiomeric Excess of Chiral Diols Using an Achiral Diboronic Acid Template

Article abstract of DOI:10.1021/acs.joc.6b01005

A practically simple derivatization protocol for determining the enantiopurity of chiral diols by ¹H NMR spectroscopic analysis is described. Diols were treated with 0.5 equiv of 1,3-phenyldiboronic acid to afford mixtures of diastereomeric boronate esters whose homochiral/heterochiral ratios are an accurate reflection of the diol's enantiopurity.

Full text of DOI:10.1021/acs.joc.6b01005

Subscriber access provided by University of Sussex Library
Note
A Protocol for NMR Analysis of the Enantiomeric Excess
of Chiral Diols Using an Achiral Diboronic Acid Template
David A. Tickell, Emma V. Lampard, John P. Lowe, Tony D. James, and Steven D. Bull
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01005 • Publication Date (Web): 06 Jul 2016
Downloaded from http://pubs.acs.org on July 11, 2016
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 14
The Journal of Organic Chemistry
1
2
3
4
5
6
A Protocol for NMR Analysis of the Enantiomeric Excess of Chiral Diols Using an Achiral
Diboronic Acid Template
7
8
9
David A. Tickell, Emma V. Lampard, John P. Lowe, Tony D. James* and Steven D. Bull*
Department of Chemistry, University of Bath, Claverton Down, Bath, BA2 7AY, U.K.
Email: t.d.james@bath.ac.uk; s.d.bull@bath.ac.uk.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ABSTRACT:
HO
OH
O
O
O
O
B
B
B
3Å mol. sieves
MeOH, 20 min
HA
HB
+
(rac)-diol
+
OH
O
O
1
B
B
B
OH
O
O
Homochiral
Heterochiral
A practically simple derivatization protocol for determining the enantiopurity of chiral diols by
1H NMR spectroscopic analysis is described. Diols were treated with 0.5 equivalents of 1,3ꢀ
phenyldiboronic acid to afford mixtures of diastereomeric boronate esters whose
homochiral:heterochiral ratios are an accurate reflection of the diol’s enantiopurity.
NMR spectroscopic analysis has proven itself to be an effective technique for determining the
enantiomeric excess (ee) of chiral substrates, with a wide range of chiral solvating agents and
chiral derivatization agents having been developed for this purpose.1ꢀ3 The Horeau concept of
statistical amplification has also been employed to develop efficient dimerization protocols that
enable the ee of chiral substrates to be determined by NMR spectroscopy.4,5 In this approach the
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 14
1
2
3
4
5
6
7
8
9
enantiomers of a chiral substrate react with 0.5 equivalents of an achiral bifunctional substrate.
This affords a mixture of diastereomeric homochiral and heterochiral (meso) dimers, whose
diastereomeric excess (de) is then determined by NMR spectroscopic analysis. As long as no
kinetic resolution occurs in the derivatisation process, then the measured de can be used to
calculate the enantiopurity of the parent diol.ǂ A range of different achiral bifunctional templates
have been developed that enable the ee of chiral alcohols,4ꢀ8 thiols,7ꢀ9 amines,10,11 amino esters,12
phosphiranes12 and carboxylic acids13ꢀ15 to be accurately determined. Further to these reports, we
now report a new Horeau based NMR protocol that employs an achiral bisꢀboronic acid template
to determine the ee of chiral diols.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
We have recently reported effective 3ꢀcomponent chiral derivatisation protocols to determine the
ee of chiral diols, amines, amino alcohols, diamines and hydroxylamines.16ꢀ26 These approaches
rely on the efficient formation of diastereomeric boronate esters from a 3ꢀcomponent reaction of
a chiral analyte with 2ꢀformylꢀphenyl boronic acid templates and a chiral auxiliary.16ꢀ26 Inspired
by the efficiency of these complexation reactions, we were intrigued to determine whether an
achiral bisꢀboronic acid could be used as an achiral template to develop a Horeau based
dimerization protocol to determine the ee of chiral diols. In this approach, we envisaged that
reaction of a chiral diol with 0.5 equivalents of a bisꢀboronic acid template would afford a
mixture of homochiral and heterochiral bisꢀboronate esters whose diastereomeric ratio could then
1
be determined by H NMR spectroscopy. Provided no kinetic resolution occurs, then this
diastereomeric ratio could then be used to determine the ee of the parent diol.
ACS Paragon Plus Environment

Page 3 of 14
The Journal of Organic Chemistry
1
2
3
4
DimethylꢀDLꢀtartrate 1a (1.0 equiv) was first reacted with 1,3ꢀphenyldiboronic acid (0.5 equiv)
5
6
in methanol in the presence of 3Å molecular sieves. This derivatisation reaction was complete
7
8
9
1
after 20 minutes, with H NMR spectroscopic analysis in CDCl3, revealing clean formation of a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
pair of diastereomeric heterochiral and homochiral bisꢀboronate esters in a statistical 50:50 ratio
(Scheme 1).
Scheme 1 ꢀ Reaction of dimethylꢀDLꢀtartrate with 1,3ꢀphenyldiboronic acid affords a 50:50
mixture of diastereomeric homochiral and heterochiral bisꢀboronate esters.
1
This was confirmed by the presence of two singlet resonances in the 500 MHz H NMR
spectrum at δ 8.50 and δ 8.48 corresponding to the HA and HB aryl ring protons of the
homochiral and heterochiral boronate esters respectively (Figure 1A). A pair of baseline resolved
singlet resonances centred at δ 3.91 ppm (OCHC and OCHD ) were also present, corresponding
3
3
to the methoxy ester protons of the homochiral and heterochiral boronate esters. These
assignments were confirmed by repeating the derivatisation reaction using enantiopure dimethylꢀ
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 14
1
2
ꢀtartrate which gave a clean 1H NMR spectrum exhibiting singlet resonances at δ 8.50 (HA) and
3
4
L
5
6
δ 3.91 (OCHC ) that were assigned to the homochiral boronate ester complex (Figure 1B).
3
7
8
HA/HB
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
HA
Figure 1 ꢀ (A) Expansion of the 500 MHz 1H NMR spectrum of the diastereomeric mixture
formed from dimethylꢀDLꢀtartrate 1a and 1,3ꢀphenyldiboronic acid; (B) Expansion of the
500 MHz H NMR spectrum of the homochiral boronate ester complex formed from
1
enantiopure dimethylꢀLꢀtartrate and 1,3ꢀphenyldiboronic acid.
In order to determine the scope and limitation of this new Horeau dimerization protocol, a series
of racemic chiral diols were derivatized with 1,3ꢀphenyldiboronic acid in the presence of 3Å
molecular sieves in methanol. Derivatization of (rac)ꢀdiols 1bꢀe with 1,3ꢀphenyldiboronic acid
gave 50:50 mixtures of their corresponding homochiral and heterochiral boronate esters in
quantitative yield (Table 1). 500 MHz 1H NMR spectroscopic analysis of these mixtures revealed
that the resonances for the aryl protons HA and HB of each pair of homochiral and heterochiral
complexes were baseline resolved in each case.
ACS Paragon Plus Environment

Page 5 of 14
The Journal of Organic Chemistry
1
2
3
4
Table 1 ꢀ Reaction of 1,3ꢀphenyldiboronic acid with a range of chiral diols 1aꢀf
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
Examination of the H NMR spectrum of the 50:50 mixture of homochiral and heterochiral
boronate esters derived from dibenzylꢀDLꢀtartrate 1f revealed partial overlap of the diagnostic
singlets for their HA and HB protons at δ 8.46 ppm (Figure 2A). We reasoned that the broadness
of these singlets might be due to long range coupling with aryl protons and as a consequence it
was decided to carry out a proton decoupled (1H{1H}) experiment in an attempt to eliminate
these coupling effects.27 It was found that selective irradiation of the aryl resonances centred at δ
8.05 ppm using a low power pulse during acquisition and Gaussian enhancement removed these
long range couplings. This resulted in significant sharpening of the diastereomeric HA and HB
proton singlets that enabled baseline resolution of these resonances to be achieved (Figure 2B).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 14
1
2
3
4
HA/HB
5
6
7
8
9
HA/HB
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
Figure 2 ꢀ Expansion of the aryl region of the 500 MHz H NMR spectrum of the 50:50
mixture of homochiral:heterochiral diastereomers formed from reaction of racemic
dibenzylꢀDLꢀtartrate with 1,3ꢀphenyldiboronic acid. (A) Poor resolution observed for
HA/HB resonances using standard H NMR processing techniques; (B) Baseline resolution
1
observed for HA/HB resonances using Gaussian enhancement of a H{1H} decoupling
1
experiment.
In order to determine the accuracy of this new Horeau protocol for determining ee, scalemic
samples of methylꢀ2,3ꢀdihydroxyꢀ3ꢀphenylpropionate 1b of 95%, 80%, and 60% ee were
derivatized with 1,3ꢀphenyldiboronic acid in methanol in the presence of 3Å molecular sieves.
Analysis of the resultant H NMR spectra revealed that the integrals of the diastereomeric HA
1
and HB resonances of the homochiral and heterochiral complexes at δ 8.59 ppm and δ 8.57 ppm
could be used to accurately measure the de of the heterochiral complex (Figure 3). In contrast to
1
conventional H NMR chiral derivatization protocols, the de’s measured using a Horeauꢀtype
derivatization protocol do not relate directly to the ee’s of the chiral analyte. Instead, the ee must
be calculated using a curve (See SI, Graph 1) which takes into account the quadratic relationship
that exists between the de of the homochiral/heterochiral complexes and the ee of the chiral
analyte. Therefore, the de’s of 88%, 61% and 32% measured for the integral ratios of the
homochiral/heterochiral complexes, were shown to correlate to calculated values of 94%, 78%
and 58% ee respectively. These measured ee values are in excellent agreement with the known
enantiopurities of the starting diols of 95%, 80%, and 60% ee respectively, indicating that no
ACS Paragon Plus Environment

Page 7 of 14
The Journal of Organic Chemistry
1
2
3
4
kinetic resolution occurs during the diol derivatization process. These values are well within the
5
6
1
5% error limit normally accepted for determining ee using H NMR spectroscopy, thus
7
8
9
demonstrating that this Horeau derivatization protocol is effective for determining the ee of diols.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
HA
HB
0.94
0.06
HA
HB
0.81
0.19
HA
HB
0.66
0.34
1
Figure 3 ꢀ Expansion of the 500 MHz H NMR spectra of the diastereomeric aryl
resonances centred at δ 8.58 ppm formed from derivatization of scalemic 1b with 1,3ꢀ
phenyldiboronic acid. Expansions of H NMR spectra shown for derivatization of scalemic
samples of diol 1b of 95%, 80% and 60% ee respectively. Values in red refer to measured
homochiral/heterochiral diastereomeric ratios.
1
It should be noted that whilst this Horeau derivatisation approach can be used to determine ee, it
cannot be used to determine which enantiomer is present in excess within a scalemic sample.
However, this information is easily obtainable from comparison of the sign of the optical rotation
of the scalemic diol with known literature values of its specific rotation.
Energy minimisation and equilibrium geometry calculations were carried out using a semiꢀ
empirical (PM3) method to calculate the lowest energy conformations of the heterochiral and
homochiral boronate esters derived from 1ꢀphenylꢀ1,3ꢀpropanediol 1c. It can be seen for the
heterochiral complex, that the aryl rings of both diol fragments are directed towards the HB
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 14
1
2
3
4
5
6
proton that is flanked by both boronate ester functionalities (Figure 4A). The shielding effects of
both these phenyl rings combine to result in a relative shift of the HB resonance to a lower δ
7
8
9
1
value in the H NMR spectrum. In contrast, the homochiral model has one of its aryl rings
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
pointing away from the aryl HA proton and as a consequence the shielding it experiences is less
than for the heterochiral system, potentially resulting in a higher chemical shift value for HA
(Figure 4B).
Figure 4 ꢀ (A) Lowest energy conformation of the (meso)ꢀheterochiral complex of diol 1c;
(B) Lowest energy conformation of the (R,R)ꢀhomochiral complex of diol 1c.
In conclusion, a new Horeau protocol has been developed to determine the ee of chiral diols
involving their reaction with 0.5 equivalents of an achiral bifunctional boronic acid template to
afford a mixture of heterochiral and homochiral diastereomers whose ratio can be accurately
1
determined by H NMR spectroscopic analysis. This diastereomeric ratio may then be used to
calculate the ee of the parent diol. The simplicity of this approach, and the inexpensive achiral
bisꢀboronic acid template employed, means it represents a versatile approach for determining the
ee of chiral diols produced in asymmetric reactions.
EXPERIMENTAL SECTION
All racemic diols 1 were commercially available, except for 1d which was prepared using the
Sharpless dihydroxylation protocol described below.
ACS Paragon Plus Environment

Page 9 of 14
The Journal of Organic Chemistry
1
2
Synthesis of (rac)ꢀ1ꢀphenylpropaneꢀ1,2ꢀdiol 1d.28 ADꢀmixꢀα (0.70 g) and ADꢀmixꢀβ (0.70 g)
were dissolved in 1:1 tertꢀbutanol:water (10 mL) and stirred at room temperature to produce two
clear phases. Methanesulfonamide (95 mg, 1.00 mmol) was then added and the mixture cooled to
0 °C. transꢀβꢀMethylstyrene (1.00 mmol) was then added and the reaction stirred vigorously at 0
°C for 24 hours. Sodium sulfite was added and the reaction allowed to warm to room
temperature and stirred for a further hour. The reaction mixture was extracted with
dichloromethane (3 x 10 mL) and the combined organic layers washed with 2 M potassium
hydroxide solution. The combined organic layers were dried over magnesium sulphate and the
solvent evaporated under reduced pressure. The crude product was purified by silica gel flash
column chromatography (ethyl acetate/hexane) to afford the desired racemic diol 1d as a white
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
solid (128 mg, 84%). mp 54ꢀ55 °C; IR (film / cmꢀ1) ν = 3340 cmꢀ1 (OH); H NMR (300 MHz;
CDCl3): δH = 7.42ꢀ7.32 (5H, m), 4.39 (1H, d, J = 7.3 Hz), 3.89 (1H, quin, J = 6.7 Hz), 2.72 (1H,
13
br s), 2.56 (1H, br s), 1.09 (3H, d, J = 6.4 Hz); C NMR (75 MHz; CDCl3): δC = 141.0, 128.5,
128.2, 126.9, 79.5, 72.3, 18.8; HRMS (ES): m/z calculated for C9H11O2 [M ꢀ H]ꢀ: 151.0759;
found: 151.0773.
General Horeau Derivatization Protocol for Determining the Enantiomeric Excess of
Chiral Diols. A chiral diol (0.24 mmol) was added to a solution of 1,3ꢀphenyldiboronic acid (20
mg, 0.12 mmol) suspended in MeOH in the presence of 3Å molecular sieves and the suspension
stirred for 20 minutes at room temperature, before filtering and evaporation of the solvent under
reduced pressure. The resultant mixture of heterochiral and homochiral diol products was then
dissolved in CDCl3 before acquiring a 500 MHz 1H NMR spectrum.
50:50 Mixture of homochiral and heterochiral 2,2'ꢀ(1,3ꢀphenylene)bis(1,3,2ꢀdioxaborolaneꢀ
4,5ꢀdicarboxylates). The title compounds were prepared according to the general Horeau
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 14
1
2
3
4
derivatisation procedure using racemic diol 1a to afford a 50:50 mixture of homochiral and
5
6
1
heterochiral diboronate esters as a white solid. H NMR (500 MHz; CDCl3): δH = 8.50 and 8.48
7
8
9
(1H, app d, ꢁδ = 0.020 ppm, BCCHCB), 8.09 (2H, d, J = 7.4 Hz), 7.51 (1H, t, J = 7.5 Hz), 5.16
(4H, s), 3.92 and 3.91 (12H, app d, ꢁδ = 0.010 ppm); 11B NMR (96 MHz; CDCl3): δB = 31.8; 13C
NMR (125 MHz; CDCl3): δC = 169.8, 142.5, 142.4, 139.0, 127.5, 77.9, 53.1.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
50:50 Mixture of homochiral and heterochiral dimethyl 2,2'ꢀ(1,3ꢀphenylene)bis(5ꢀphenylꢀ
1,3,2ꢀdioxaborolaneꢀ4ꢀcarboxylates). The title compounds were prepared according to the
general Horeau derivatisation protocol using racemic diol 1b to afford afford a 50:50 mixture of
1
homochiral and heterochiral diboronate esters as a white solid. H NMR (500 MHz; CDCl3): δH
= 8.59 and 8.57 (1H, app d, ꢁδ = 0.020 ppm), 8.14 (2H, d, J = 7.4 Hz), 7.53 (1H, t, J = 7.5 Hz),
7.47ꢀ7.40 (8H, m), 7.40ꢀ7.37 (2H, m), 5.65 (2H, dd, J1 = 2.9 Hz, J2 = 6.1 Hz), 4.90 (2H, d, J =
6.1 Hz), 3.90 (6H, s); 11B NMR (96 MHz; CDCl3): δB = 30.7; 13C NMR (125 MHz; CDCl3): δC =
171.0, 142.4, 140.3, 138.8, 128.9, 128.6, 127.6, 125.4, 125.3, 82.6, 81.9, 52.8; HRMS (ES): m/z
calculated for C26H24B2O8Na [M + Na]+: 509.1554; found: 509.1540.
50:50 Mixture of homochiral and heterochiral 1,3ꢀbis(4ꢀphenylꢀ1,3,2ꢀdioxaborinanꢀ2ꢀ
yl)benzenes. The title compounds were prepared according to the general Horeau derivatisation
protocol using racemic diol 1c to afford a 50:50 mixture of homochiral and heterochiral
1
diboronate esters as a white solid. H NMR (500 MHz; CDCl3): δH = 8.47 and 8.45 (1H, app d,
ꢁδ = 0.020 ppm), 8.03 (2H, d, J = 7.3 Hz), 7.47ꢀ7.41 (9H, m), 7.37ꢀ7.33 (2H, m), 5.33 (2H, app
dd, J1 = 9.2 Hz, J2 = 3.1 Hz), 4.30ꢀ4.24 (2H, m), 4.23ꢀ4.17 (2H, m), 2.36 (2H, dq, J1 = 14.2 Hz,
11
13
J2 = 4.1 Hz), 2.13ꢀ2.05 (2H, m); B NMR (96 MHz; CDCl3): δB = 30.5; C NMR (125 MHz;
CDCl3): δC = 142.7, 142.6, 139.7, 139.6, 136.4, 128.5, 127.5, 127.0, 125.3, 72.8, 61.0, 60.9,
35.4; HRMS (ES): m/z calculated for C24H24B2O4Na [M + Na]+: 421.1758; found: 421.1764.
ACS Paragon Plus Environment

Page 11 of 14
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
50:50 Mixture of homochiral and heterochiral 1,3ꢀbis(4ꢀmethylꢀ5ꢀphenylꢀ1,3,2ꢀ
dioxaborolanꢀ2ꢀyl)benzenes. The title compounds were prepared according to the general
Horeau derivatisation protocol using racemic diol 1d to afford a 50:50 mixture of homochiral
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
and heterochiral diboronate esters as a white solid. H NMR (500 MHz; CDCl3): δH = 8.51 and
8.50 (1H, app d, ꢁδ = 0.012 ppm), 8.07 (2H, d, J = 7.4 Hz), 7.49 (1H, t, J = 7.5 Hz), 7.42ꢀ7.40
(8H, m), 7.38ꢀ7.35 (2H, m), 5.07 (2H, d, J = 7.5 Hz), 4.50 (2H, quin, J = 6.2 Hz), 1.57 (6H, d, J
11
13
= 6.2 Hz); B NMR (160 MHz; CDCl3): δB = 30.6; C NMR (125 MHz; CDCl3): δC = 142.0,
141.9, 140.6, 140.5, 138.1, 128.7, 128.3, 127.4, 125.7, 125.6, 86.1, 81.7, 21.2.
50:50 Mixture of homochiral and heterochiral 1,3ꢀbis(4,5ꢀdiphenylꢀ1,3,2ꢀdioxaborolanꢀ2ꢀ
yl)benzenes. The title compounds were prepared according to the general Horeau derivatisation
protocol using racemic diol 1e to afford a 50:50 mixture of homochiral and heterochiral
1
diboronate esters as a white solid. H NMR (500 MHz; CDCl3): δH = 8.65 and 8.63 (1H, app d,
ꢁδ = 0.024 ppm), 8.16 (2H, d, J = 7.5 Hz), 7.53 (1H, t, J = 7.3 Hz), 7.42ꢀ7.34 (20H, m), 5.36
11
13
(4H, s, CH); B NMR (96 MHz; CDCl3): δB = 30.2; C NMR (125 MHz; CDCl3): δC = 141.5,
140.3, 138.6, 128.8, 128.4, 125.9, 125.8, 87.0.
50:50 Mixture of homochiral and heterochiral tetrabenzyl 2,2'ꢀ(1,3ꢀphenylene)bis(1,3,2ꢀ
dioxaborolaneꢀ4,5ꢀdicarboxylates). The title compounds were prepared according to the
general Horeau derivatisation protocol using racemic diol 1f to afford a 50:50 mixture of
1
homochiral and heterochiral diboronate esters as a white solid. H NMR (500 MHz; CDCl3): δH
= 8.46 (1H, br s), 8.06 (2H, d, J = 8.8 Hz), 7.46 (1H, t, J = 9.4 Hz), 7.43ꢀ7.39 (20H, m), 5.32ꢀ
5.26 (8H, m) 5.15 (4H, s); 11B NMR (96 MHz; CDCl3): δB = 32.0; 13C NMR (125 MHz; CDCl3):
δC = 171.4, 169.1, 142.5, 142.4, 139.1, 134.9, 128.7, 128.6, 128.4, 128.3, 78.0, 72.1, 68.1, 67.7.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 14
1
2
3
4
5
6
7
8
9
ASSOCIATED CONTENT
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Supporting Information. H and 13C NMR spectra of bisꢀboronate complexes formed from
reaction of diols 1aꢀf with 1,3ꢀphenyldiboronic acid as well as a graphical representation and
discussion of the quadratic relationship seen between the enantiomeric excess of the chiral diol
and diastereomeric excess (homochiral – heterochiral) of the corresponding bisꢀboronate
complex. Output files from energy minimisation and equilibrium geometry calculations using a
semiꢀempirical (PM3) method to calculate the lowest energy conformations of the heterochiral
(meso) and homochiral boronate esters (RR and SS) derived from 1ꢀphenylꢀ1,3ꢀpropanediol 1c.
All data created during this research (including NMR and MS data) are openly available from the
University of Bath data archive at http://doi.org/10.15125/BATHꢀ00211
1
ACKNOWLEDGMENT
We would like to thank the EPSRC and the University of Bath for funding. EVL thanks the
EPSRC Doctoral Training Centre in Sustainable Chemical Technologies: EP/G03768X/1 for a
studentship.
ACS Paragon Plus Environment

Page 13 of 14
The Journal of Organic Chemistry
1
2
3
4
NOTES AND REFERENCES
5
6
7
ǂ All values reported are absolute ee values. Using this method it is not possible to define which
8
9
enantiomer is in excess.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(1)
(2)
(3)
Parker, D. Chem. Rev. 1991, 91, 1441.
Wenzel, T. J.; Wilcox, J. D. Chirality 2003, 15, 256.
M. E. Powell, C. D. E., S. D. Bull, T. D. James and P. S. Fordred Comprehensive
Chirality 2012, 8, 571.
(4)
(5)
(6)
(7)
Vigneron, J. P.; Dhaenens, M.; Horeau, A. Tetrahedron 1973, 29, 1055.
Horeau, A.; Guette, J. P. Tetrahedron 1974, 30, 1923.
Feringa, B. L.; Smaardijk, A.; Wynberg, H. J. Am. Chem. Soc. 1985, 107, 4798.
Feringa, B. L.; Smaardijk, A. A.; Wynberg, H.; Strijtveen, B.; Kellogg, R. M.
Tetrahedron Lett. 1986, 27, 997.
(8)
(9)
Strijtveen, B.; Feringa, B. L.; Kellogg, R. M. Tetrahedron 1987, 43, 123.
Pasquier, M. L.; Marty, W. Angew. Chem., Int. Ed. 1985, 24, 315.
(10) Feringa, B. L.; Strijtveen, B.; Kellogg, R. M. J. Org. Chem. 1986, 51, 5484.
(11) Grotjahn, D. B.; Joubran, C. Tetrahedron-Asymmetry 1995, 6, 745.
(12) Marinetti, A.; Mathey, F.; Ricard, L. Organometallics 1993, 12, 1207.
(13) Alvarez, C.; Barkaoui, L.; Goasdoue, N.; Daran, J. C.; Platzer, N.; Rudler, H.;
Vaissermann, J. J. Chem. Soc., Chem. Commun. 1989, 1507.
(14) Heumann, A.; Loutfi, A.; Ortiz, B. Tetrahedron-Asymmetry 1995, 6, 1073.
(15) Coulbeck, E.; Eames, J. Tetrahedron-Asymmetry 2009, 20, 635.
(16) Kelly, A. M.; PerezꢀFuertes, Y.; Arimori, S.; Bull, S. D.; James, T. D. Org. Lett. 2006, 8,
1971.
(17) PerezꢀFuertes, Y.; Kelly, A. M.; Johnson, A. L.; Arimori, S.; Bull, S. D.; James, T. D.
Org. Lett. 2006, 8, 609.
(18) Kelly, A. M.; Bull, S. D.; James, T. D. Tetrahedron-Asymmetry 2008, 19, 489.
(19) Powell, M. E.; Kelly, A. M.; Bull, S. D.; James, T. D. Tetrahedron Lett. 2009, 50, 876.
(20) PerezꢀFuertes, Y.; Kelly, A. M.; Fossey, J. S.; Powell, M. E.; Bull, S. D.; James, T. D.
Nat. Protoc. 2008, 3, 210.
(21) Kelly, A. M.; PerezꢀFuertes, Y.; Fossey, J. S.; Yeste, S. L.; Bull, S. D.; James, T. D. Nat.
Protoc. 2008, 3, 215.
(22) PerezꢀFuertes, Y.; Taylor, J. E.; Tickell, D. A.; Mahon, M. F.; Bull, S. D.; James, T. D. J.
Org. Chem. 2011, 76, 6038.
(23) Fordred, P. S.; Bull, S. D. Tetrahedron Lett. 2013, 54, 27.
(24) Tickell, D. A.; Mahon, M. F.; Bull, S. D.; James, T. D. Org. Lett. 2013, 15, 860.
(25) Archer, R. M.; Hutchby, M.; Winn, C. L.; Fossey, J. S.; Bull, S. D. Tetrahedron 2015,
71, 8838.
(26) Shcherbakova, E. G.; Minami, T.; Brega, V.; James, T. D.; Anzenbacher, P. Angew.
Chem., Int. Ed. 2015, 54, 7130.
(27) Kessler, H.; Mronga, S.; Gemmecker, G. Magn. Reson. Chem. 1991, 29, 527.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 14
1
2
3
4
5
6
(28) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.; Hartung, J.; Jeong, K. S.;
Kwong, H. L.; Morikawa, K.; Wang, Z. M.; Xu, D. Q.; Zhang, X. L. J. Org. Chem. 1992, 57,
2768.
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment