Optical enrichment in enzyme-catalyzed resolution of 1-aryl-2,2-dimethyl-1,3-propanediols

Article abstract of DOI:10.1139/cjc-2016-0341

Novozym 435 efficiently catalyzed the chemo-, regio-, and enantioselective transesterification of 1-aryl-2,2-dimethyl-1,3-propanediols in different organic solvents with vinyl acetate as the acetyl donor at room temperature. This enzyme-catalyzed chemical

Full text of DOI:10.1139/cjc-2016-0341

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Optical Enrichment in Enzyme-catalyzed Resolution of
1-Aryl-2,2-dimethyl-1,3-propanediols
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Chandrani Mukherjee,a Prabhu P. Mohapatra,a Dani Youssef,a,b Amitabh Jha a,*
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aDepartment of Chemistry, Acadia University, Wolfville, NS, Canada, B4P 2R6
bScience Department, Universite Sainte-Anne, Church Point, NS, Canada, B0W 1M0
E-mail: amitabh.jha@acadiau.ca
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Telephone: 902-585-1515
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Abstract: Novozym® 435 efficiently catalyzed the chemoꢀ, regioꢀ, and enantioselective
transesterification of 1ꢀarylꢀ2,2ꢀdimethylꢀ1,3ꢀpropanediols in different organic solvents with
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vinyl acetate as the acetyl donor at room temperature. This enzymeꢀcatalyzed chemical
transformation method provides an efficient route for opticallyꢀenriched propanediol
derivatives.
Key words: 1ꢀArylꢀ2,2ꢀdimethylꢀ1,3ꢀpropanediols, kinetic resolution, Novozym® 435,
enantioselection, optical enrichment, biocatalysis, enzymeꢀassisted organic synthesis.
Introduction
Several mono and dicarbamate derivatives of 1,3ꢀpropanediols such as mebutamate,
meprobamate, tybamate, carisprodol, felbamate and methocarbamol (Fig. 1) are clinically
used as sedatives, tranquilizers, anxiolytic and muscle relaxing drugs.1–3 Mephenesin (Fig. 1),
a clinical muscle relaxant, has marked structural resemblance to methocarbamol but it is a
diol rather than a carbamate.4 Bronopol, 2ꢀbromoꢀ2ꢀnitroꢀ1,3ꢀpropanediol, is an antimicrobial
agent and used as a preservative in cosmetics.5 In addition to the pharmacological profile,
propanediols such as 2,2ꢀbis(bromomethyl)ꢀ1,3ꢀpropanediol is widely used as a flame
retardant.6 Recently, 1,3ꢀpropanediol has also emerged as an interesting polyester raw
material similar to homologs ethylene glycol and butanediol.7
For particular relevance to the current investigations are 1ꢀarylꢀ2,2ꢀdimethylꢀ1,3ꢀ
propanediols 1 (Figure 1). Monocarbamate derivatives of these compounds (2 and 3) have
been studied for sedative and tranquilizing activity.8,9 The esters, acetals, and ketals of 1ꢀarylꢀ
2,2ꢀdimethylꢀ1,3ꢀpropanediols possess good aroma; hence, they have the potential to be used
as essential oils in perfume industries.10
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Figure 1. Biologically active propanediol carbamates and related propanediols.
The significance of propanediol in different aspects of life has promoted the need to
develop efficient routes for their synthesis. The most common synthetic method involves the
hydroformylation of epoxides, which is generally accompanied with numerous side products,
thus resulting in a poor yield. Efforts to improve the yield have led to the evolution of several
metal catalysts and promoters.7,11,12 However, the present research is focused on developing
on developing enantiomerically pure 1ꢀarylꢀ2,2ꢀdimethylꢀ1,3ꢀpropanediols (1) from its aldolꢀ
crossed Cannizzaro reactionꢀderived racemic mixture using enzyme catalysis based
bioengineering techniques. It should be noted that all clinically used chiral drugs shown in
Fig. 1 are marketed in racemic form. The pharmacological activity of a pair of enantiomers
often differs from each other, and one enantiomer is often responsible for the desired activity
when racemic drug is administered. The unwanted enantiomer may have toxic properties.13
This has triggered the need for obtaining a drug molecule in an optically pure form. Optically
enriched 1,3ꢀpropanediol derivatives have been synthesized using the enzymatic
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desymmetrization of prochiral diols.14–16 Similar enantiomerically pure substrates, namely, 1ꢀ
(4ꢀphenyl)ꢀ2,2ꢀdimethylꢀ1,3ꢀpropanediol and 1ꢀ(4ꢀchlorophenyl)ꢀ2,2ꢀdimethylꢀ1,3ꢀ
propanediol, have been obtained as their chiral cyclic phosphonates from the corresponding
phosphoric acid derivatives. These chiral cyclic phosphonates have been used as the chiral
derivatizing agents for the enantiomeric excess (ee) determination of amines, alcohols, and
unprotected amino acids.17–21 However, none of the methods used green catalysts—
enzymes—for obtaining enantiomerically pure 1ꢀarylꢀ2,2ꢀdimethylꢀ1,3ꢀpropanediols in an
ecoꢀfriendly manner.
Novozym® 435 is a commercially available heterogeneous biocatalyst that consists
of Candida antarctica lipase B physically immobilized within a macroporous resin of
poly(methyl methacrylate) and is marketed by Novozymes and other chemical vendors.22
Owing to its in vitro transesterification potential, Novozym® 435 has been extensively
utilized for synthesizing esters from alcohols and phenols using an acyl group donor.23ꢀ25
In continuation of our interest in enzymeꢀassisted synthesis of chemical building
blocks and potential drug intermediates,24ꢀ28 we herein report Novozym® 435ꢀcatalyzed
enantioselective acetylation of a series of racemic 1ꢀarylꢀ2,2ꢀdimethylꢀ1,3ꢀpropanediols (1).
Results and Discussion
The compound of this investigation, namely, 1ꢀarylꢀ2,2ꢀdimethylꢀ1,3ꢀpropanediols 1,
was synthesized chemically as a racemic mixture by following a literature method involving
an aldolꢀcrossed Cannizzaro reaction between 1 equivalent of an aromatic aldehyde, 2
equivalent of isobutyraldehyde, and 1 equivalent of KOH in ethanol.17
To check the feasibility of the enzymeꢀcatalyzed enantioselective transesterification
process, three reactions on a model substrate 2,2ꢀdimethylꢀ1ꢀphenylꢀ1,3ꢀpropanediol 1a were
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carried out with vinyl acetate as acetyl group donor at room temperature in diisopropyl ether
(DIPE) as the solvent: a) in the absence of any enzyme (blank), b) in the presence of
Novozym® 435, and c) in the presence of Amano PS lipase. A nonpolar solvent (diisopropyl
ether) was selected as the solvent because both the starting material and product are soluble
in this solvent. No reaction was observed in the blank reaction and in presence of Amano PS
lipase even after 72 h of reaction time. However, in the presence of Novozyme® 435, it took
36 h to consume ~50% of the starting material and to form a new relatively nonꢀpolar
product as visualized qualitatively on TLC (Scheme 1). The reaction was quenched by
filtering the enzyme and the reaction mixture was purified by performing column
chromatography on silica gel to isolate unreacted starting material 1a and the product which
was characterized as 2,2ꢀdimethylꢀ1ꢀphenylꢀpropaneꢀ3ꢀacetateꢀ1ꢀol (4a) on the basis of 1H &
13C NMR and HRMS data. Thus, the reaction clearly displayed regioꢀ and chemoselectivity
in the sense that primary –OH group was exclusively acetylated. To ascertain the extent of
enantioselectivety, if any, optical rotation of the unreacted diol 1a and the corresponding
monoacetylated product 4a were measure in chloroform at room temperature. To our delight,
a nonꢀzero optical rotation of these compounds (−15.38o and +1.48o for unreacted 1a and
monoacetylated product 4a, respectively) were observed confirming some degree of
enantioselection. Encouraged by these results, optimization of the effect of solvent was
carried out for the kinetic resolution of the model substrate 1a was screened using
Novozym® 435 in several solvents of varying polarities. The variation in optical rotation
values, time required for 50% conversion, and chemical yields are listed in Table 1. As
expected, the Novozym® 435ꢀcatalyzed selective acetylation of 1a was found to be
enantioselective as well as regio and chemoselective in the case of all the solvents used for
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the reaction. The extent of optical enrichment measured as enantiomeric excess (ee) in the
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lipaseꢀcatalyzed reactions was determined by H NMR experimental studies using Eu(hfc)3
as the chiral lanthanide shift reagent (CLSR) in CDCl3 as the solvent. The 1H NMR peaks for
the diastereomeric mixtures were successfully separated, and the ee was calculated from the
integration of the peaks of respective acetoxy group singlets. This data is presented in Table
1. The addition of Eu(hfc)3 caused a downfield shift of all the protons in the 1H NMR spectra.
The absolute configuration assigned to the products in the scheme under Table 1 was based
on comparison of the sign of optical rotation of previously characterized optically pure
compounds reported in the literature.18
Scheme 1. Kinetic resolution of racemic 2,2ꢀdimethylꢀ1ꢀphenylꢀ1,3ꢀpropanediol 1a.
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Table 1 Stereoselective acetylation of racemic 1ꢀ(4ꢀmethoxyphenyl)ꢀ2,2ꢀdimethylꢀ1,3ꢀ
propanediol 1a in different solvents
Monoacetate (4a)
Unreacted Diol (1a)
% yieldb
[α]D
+1.48
+2.85
+12.0
% ee
% yieldb
[α]D
−15.38
−2.72
−27.0
% ee
Solvents
Time (h)
36
96
12
49
13
47
21
41
52
39
70
49
57
19
66
DIPE
Chloroform
THF
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21
29
41
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+2.0
+1.0
19
47
39
37
38
25
48
49
46
71
−7.33
−5.5
−6.2
−7.5
−3.0
30
26
61
28
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Toluene
Acetone
+1.18
+2.2
Acetonitrile
Dioxane
Ethyl acetatea
+2.66
120
a No vinyl acetate was added in the ethyl acetate reaction.
b Isolated yield.
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The effect of solvent polarity on enantioselective acylation of 1a is clearly evident in
the data presented in Table 1. In the case of THF as the reaction medium, best
enantioselection was obtained for unreacted diol 1a as well as the primary monoacylated
product 4a, 66% and 52% ee, respectively. However, the time required for enzymatic
reactions for ~50% conversion of racemic 1a to monoacetate 4a varied significantly from 12
to 96 h by changing the solvent. The reaction in THF again, was found to be the fastest;
~50% conversion of racemic 1a to 4a was achieved in ~12 h. The reactions in toluene,
acetone, acetonitrile, and dioxane needed 22ꢀ26 h for ~50% conversion. The reaction in
diisopropyl ether (DIPE) was comparatively slower; ~50% conversion was achieved in 36 h.
The reaction in chloroform attained only ∼20% conversion even after four days (96 h). The
reaction in ethyl acetate, which also acted as acetyl group donor, was also found to be equally
slow. Isomeric secondary acetoxy product (5a) was isolated in the THF reaction in trace
amounts. Optical activity of 5a was not recorded. The structure of the major acetylated
products 4a, where the acetate is at the Cꢀ3 position, was confirmed from the appearance of a
chiral center proton, namely, Cꢀ1H at δ 4.6 ppm compared to δ 5.8 ppm in the case of Cꢀ1ꢀ
acetylated product (5a).
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Having optimized the Novozyme® 435 catalyzed chemoꢀ, regioꢀ, and
enantioselective transesterification of model compound 1a in THF at room temperature with
vinyl acetate as the acyl donor, the enzyme reactions were carried out on a series of
differently phenylꢀsubstituted 1,3ꢀpropanediols 1b–j under identical conditions (Scheme 2).
As the customary, these reactions were stopped at the 50% conversion (qualitative, by tlc) by
filtering off the enzyme. The unreacted propanediols 1b–j and product monoacetates 4b–j
were separated by performing flash column chromatography over silica gel. The optical
rotation values, observed chemical yields, and time required for the half acetylation of
propanediols 1a–j to the corresponding acetates 4a–j are listed in Table 2. The enantiomeric
ratios (Eꢀvalues) of the reactions were calculated using Eq. 1 and are reported in Table 2.
ꢀꢁ [ꢂꢃꢄ (ꢂꢅꢆꢆ)]
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E =
Eq. 1
(
)
ꢀꢁ [ꢂꢃꢄ ꢂꢃꢆꢆ ]
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where c is the conversion of the reaction, and ee is the enantiomeric excess of the product.
Scheme 2. Kinetic resolution of racemic 1ꢀarylꢀ2,2ꢀdimethylꢀ1,3ꢀpropanediols 1a-j.
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Table 2 Stereoselective acetylation of 1ꢀarylꢀ2,2ꢀdimethylꢀ1,3ꢀpropanediols 1a-j in THF.
Monoacetate (4a–j)
Unreacted Diol (1a–j)
# Ar
Phenyl
% yield
47
% ee E % yield
% ee E
66 1
[αD]
[αD]
+12.0 52
1
49
a
−27.0
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4ꢀClꢀphenyl
35
41
42
37
41
66
41
44
28
+1.2
+6.4
+8.0
23
25
19
1
1
1
1
1
1
ꢀ
54
20
35
50
29
20
20
20
24
71
53
30
51
51
5
1
1
1
1
1
1
ꢀ
b
c
d
e
f
−15.6
−15.87
−4.0
4ꢀFꢀphenyl
4ꢀOMeꢀphenyl
4ꢀNO2ꢀphenyl
3,4ꢀOCH2Oꢀphenyl
3,4ꢀdiOMeꢀphenyl
Pyridinꢀ4ꢀyl
+12.4 57
+0.73 43
−1.2
−2.77
−4.0
+10.0
+1.60
+1.20
8
ꢀa
ꢀa
g
h
-i
j
ꢀa
−5.30
−18.4
−4.33
Pyridinꢀ2ꢀyl
ꢀ
ꢀa
ꢀ
Furanꢀ2ꢀyl
+1.83 25
1
40
1
155
a The ee could not be calculated owing to peak broadening in the 1H NMR experiments with
CLSR.
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Enantioselection was evident from the opposite signs and comparable values of
specific rotation for each pair of unreacted diols and the corresponding acetates. All the
unreacted diols showed a negative sign of rotation, whereas the acetates showed a positive
sign of rotation (Tables 1 and 2). Enantiopure 1a with R absolute stereochemistry has a
negative optical rotation (conc. 1g/100 mL of CHCl3, [α]D= − 49.9°).18 This indicates that the
unreacted diols 1a–j with negative optical rotations are optically enriched in favor of the R
isomers, whereas monoacetates 4a-j are optically enriched in favor of the S isomers.
The ee values were determined by 1H NMR experiments using Eu(hfc)3 as the chiral
1
lanthanide shift reagent in CDCl3 as the solvent (vide supra). The H NMR peaks for the
diastereomeric mixtures were successfully separated, and the ee was calculated from the
integration of the peaks of acetate, methyl, methoxy, or chiral center proton, whichever
worked the best in particular case. In the case of pyridineꢀsubstituted propanediols (1i and
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1j), addition of Eu(hfc)3 led to broadening of peaks in the respective H NMR spectra and
therefore, the ee could not be determined. Use of another chiral shift reagent, Eu(tfc)3, also
led to the same unfortunate outcome. In all these cases again, chemoꢀ and regioselectivity of
the transesterification reaction turned out to nearly exclusive in the favor of primary acetoxy
products 4b-j. The isomeric secondary acetoxy product was isolated in trace amounts (<5%
yield) when the starting material was 1d (4ꢀMeOꢀ substituted phenyl). The enantioselectivity,
however, ranged from 19ꢀ57% for 4a-j and 5ꢀ71% for unreacted recovered 1a-j.
The stereoselective deacetylation of one representative compound 1ꢀ(4ꢀ
methoxyphenyl)ꢀ2,2ꢀdimethylꢀ1,3ꢀpropanediacetate 6 was also studied using Novozym® 435
in different organic solvents for kinetic resolution using nꢀbutanol as the acetyl scavenger.
When monitored in anhydrous organic solvents, no deacetylation was observed.
Subsequently, waterꢀsaturated organic solvents were used to screen the catalytic activity of
Novozym® 435 as enzymes show better catalytic activity in aqueous medium. However, no
deacetylation of 6 was observed.
Conclusion
The Novozym® 435ꢀcatalyzed transesterification of 1ꢀarylꢀ2,2ꢀdimethylꢀ1,3ꢀ
propanediols using vinyl acetate as the acetyl donor in organic solvents exhibited nearly
exclusive regioꢀ, and chemoselectivity in favor of acetylating the primary hrdroxyl group
when the reaction was allowed to proceed until ~50% conversion. However, this resulted in
varying degrees of enantioselectivity. The rate of the acetylation was found to be fastest in
tetrahydrofuran.
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Experimental General
The melting points are reported in degrees Celsius, measured using a MELꢀTEMP II
capillary melting point apparatus, and are uncorrected. The H1 and C13 NMR spectra were
recorded using a Bruker AVꢀ300 spectrometer at 300 and 75.5 MHz, respectively. The
chemical shifts are reported in parts per million (ppm,
δ scale), downfield from internal
standard tetramethylsilane, and the coupling constants (J) are reported in Hz. The UV–visible
spectra were recorded using a LKB Biochrom Ultrospec Plus 4054 UV–visible
spectrophotometer. The optical rotations were recorded on ADP220 Polarimeter (Bellingham
Stanley Ltd.) using CHCl3 as the solvent. Precoated fluorescent silica gel thinꢀlayer
chromatography plates were used to monitor the progress of the reactions and determine the
Rf values. The progress of enzymeꢀcatalyzed reactions was monitored both by UV light
visibility and using methanolic FeCl3 reagent. Novozym® 435 (Candida antarctica lipase B
immobilized on acrylic acid resin) was purchased from Aldrich. All the solvents were dried
prior to use in the enzymeꢀcatalyzed reactions.
General procedure for synthesis of 1a–j
2,2ꢀDimethylꢀ3ꢀarylꢀ1,3ꢀpropanediols were prepared following a modified literature
procedure starting from isobutyraldehyde (20 mmol), an appropriate aromatic aldehyde (10
mmol), and KOH (10 mmol) in ethanol (150 mL).16 The pure products were obtained in 41–
69 % yields after column chromatography using a mixture of 20–30% EtOAc/hexane as the
eluent.
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1-Phenyl-2,2-dimethyl-1,3-propanediol (1a): It was obtained as a solid in 69% yield; m.p.
1
71–73 °C (lit. m.p.29 78–79 °C). Its H spectrum was found to be identical to the literature
report.29 13C NMR (75.5 MHz, CDCl
): δ 19.4, 23.2, 39.4, 72.4, 82.5, 127.9, 128.0, 128.1,
3
141.8. UV (MeOH) λmax: 215, 257 nm. HRMS (ESI) m/z: Found 203.1040 [M+Na]+; calcd.
for [C11H16O2+Na]+: 203.1048.
1-(4-Chlorophenyl)-2,2-dimethylpropane-1,3-diol (1b): It was obtained as a solid in 68%
1
yield; m.p. 93–95 °C; lit. m.p.10 89–90 °C. Its H spectrum was found to be identical to the
literature report.17 13C NMR (75.5 MHz, CDCl
): δ 19.4, 23.2, 39.4, 72.4, 82.5, 127.9, 128.0,
3
128.1, 141.8. UV (MeOH) λmax: 215, 257 nm. HRMS (ESI) m/z: Found 237.0662 [M+Na]+;
calcd. for [C11H15ClO2+Na]+: 237.0658.
1-(4-Fluorophenyl)-2,2-dimethylpropane-1,3-diol (1c): It was obtained as a solid in 54%
1
yield; m.p. 70–72 °C; H NMR (300 MHz, CDCl3) δ 0.79 and 0.82 (6H, s, 2 × CH
3
), 3.49–
3.52 (3H, m, CH2 and OH), 3.94 (1H, d, J = 2.7 Hz, OH), 4.58 (1H, d, J = 1.8 Hz, CH), 7.01
(2H, t, J = 8.7 Hz, ArH), 7.24–7.29 (2H, m, ArH); 13C NMR (75.5 MHz, CDCl
3
) δ 19.2,
23.1, 39.4, 72.4, 81.8, 114.9 (d, 2C, J = 21.8 Hz), 129.5 (d, 2C, J = 8.3 Hz), 137.5, 162.6 (d,
2C, J = 245.4 Hz); UV (MeOH) λmax: 213, 264, 271 nm. HRMS (ESI) m/z: Found 221.0945
[M+Na]+; calcd. for [C11H15FO2+Na]+: 221.0954.
1-(4-Methoxyphenyl)-2,2-dimethylpropane-1,3-diol (1d): It was obtained as a solid in
62% yield; m.p. 77–78 °C (lit. m.p.30 78–79 °C). Its 1H and 13C NMR spectra were found to
be identical to the literature report.30
1-(4-Nitrophenyl)-2,2-dimethylpropane-1,3-diol (1e): It was obtained as a solid in 54%
1
yield; m.p. 43–44 °C (lit. m.p.29 36–38 °C). Its H NMR spectrum was found to be identical
to the literature report.29 13C NMR (75.5 MHz, CDCl
) δ 19.1, 22.9, 39.6, 72.4, 81.3, 123.2,
3
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128.9, 147.7, 149.4; UV (MeOH) λmax: 203, 214, 275 nm. HRMS (ESI) m/z: Found 248.0905
[M+Na]+; calcd. for [C11H15NO4+Na]+: 248.0899.
1-(Benzol[d][1,3]dioxol-5-yl)-2,2-dimethylpropane-1,3-diol (1f): It was obtained as a solid
in 41% yield; m.p. 70–72 °C. Its 1H NMR spectrum was found to be identical to the literature
report.17 13C NMR (75.5 MHz, CDCl
) δ 19.4, 23.1, 39.6, 72.5, 82.3, 101.3, 107.9, 108.4,
3
121.3, 135.9, 147.2, 147.6; UV (MeOH) λmax: 209, 235, 285 nm. HRMS (ESI) m/z: Found
247.0940 [M+Na]+; calcd. for [C12H16O4+Na]+: 247.0946.
1-(3,4-Dimethoxyphenyl)-2,2-dimethylpropane-1,3-diol (1g): It was obtained as a red
1
liquid in 45% yield; H NMR (300 MHz, CDCl3) δ 0.79 (6H, s, 2 × CH
3), 3.45 (2H, q, J =
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247
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257
258
259
13.5 Hz, CH2), 3.70 (1H, br s, OH), 3.83 (6H, s, 2 × OCH3), 3.90 (1H, br s, OH), 4.50 (1H, s,
13
CH), 6.77 (2H, s, ArH), 6.84 (1H, s, ArH); C NMR (75.5 MHz, CDCl
3
) δ 19.3, 23.1, 39.4,
56.2 (2C), 72.4, 82.2, 110.8, 111.3, 120.3, 134.6, 148.6 (2C); UV (MeOH) λmax: 208, 229,
277 nm. HRMS (ESI) m/z: Found 263.1264 [M+Na]+; Calcd. for [C13H20O4+Na]+: 263.1260.
1-(Furan-2-yl)-2,2-dimethylpropane-1,3-diol (1h): It was obtained as a solid in 45.12%
yield; m.p. 53–55 °C. Its 1H and 13C NMR spectra were found to be identical to the literature
report.17
1-(Pyridin-4-yl)-2,2-dimethylpropane-1,3-diol (1i): It was obtained as a solid in 43% yield;
1
m.p. 120–122 °C; H NMR (300 MHz, DMSOꢀd6) δ 0.64 and 0.78 (3H each, s, 2 × CH3),
3.08 and 3.34 (1H each, d, J = 10.5 Hz each, CH2), 4.51 (1H, s, CH), 4.80 and 5.51 (1H each,
br s, OH), 7.28 (2H, d, J = 4.8 Hz, pyridylꢀH), 8.47 (2H, d, J = 4.2 Hz, pyridylꢀH); 13C NMR
(75.5 MHz, DMSOꢀd6) δ 20.3, 21.6, 40.1, 68.8, 75.8, 123.8 (2C), 149.3 (2C), 152.9; UV
(MeOH) λmax: 206, 257 nm. HRMS (ESI) m/z: Found 204.0997 [M+Na]+; calcd. for
[C10H15NO2+Na]+: 204.1001.
13

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274
275
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277
278
279
280
281
282
1-(Pyridin-2-yl)-2,2-dimethylpropane-1,3-diol (1j): It was obtained as a solid in 52% yield;
m.p. 52–55 °C; 1H NMR (300 MHz, CDCl3) δ 0.85 (6H, s, 2 × CH3), 3.41 (2H, s, CH2), 4.20
(1H, br s, OH), 4.68 (2H, br s, CH and OH), 7.19 (1H, d, J = 1.2 Hz, pyridylꢀH), 7.33 (1H, d,
13
J = 7.8 Hz, pyridylꢀH), 7.67 (1H, br s, pyridylꢀH), 8.47 (1H, d, J = 4.5 Hz, pyridylꢀH); C
NMR (75.5 MHz, CDCl ) δ 20.4, 21.7, 40.5, 71.5, 79.8, 122.9 (2C), 136.6, 148.3, 160.7; UV
3
(MeOH) λmax: 211, 261 nm. HRMS (ESI) m/z: Found 204.1008 [M+Na]+; calcd. for
[C10H15NO2+Na]+: 204.1001.
General procedure for the synthesis of enantiomerically-enriched 1-aryl-2,2-
dimethylpropane-3-acetate-1-ols (4a–j)
To a solution of propanediol (5 mmol) and vinyl acetate (5 mmol) in an appropriate
organic solvent (20 mL), Novozym® 435 (1 g) was added, and the resulting mixture was
shaken at room temperature. The reaction was stopped by filtering off the enzyme after
approximately 50% conversion (qualitatively based on TLC) of the diol into the
monoacetate. The solvent was removed under vacuum, and the unreacted diol and acetate
were separated by column chromatography over silica gel (230–400 mesh) using a mixture of
10–25% EtOAc/hexane as the eluent. In the case of 1a and 1d as starting materials, very
small amounts of monoacetates formed after transesterification of secondary hydroxyl groups
(5a and 5d) were also isolated.
1-Phenyl-2,2-dimethylpropane-3-acetate-1-ol (4a): It was obtained as a solid in 50% yield;
m.p. 62–64 °C; 1H NMR (300 MHz, CDCl3) δ 0.87 and 0.95 (3H each, s, 2 × CH3), 2.12 (3H,
s, OCOCH3), 2.40 (1H, d, J = 3.3 Hz, OH), 3.80 and 4.20 (1H each, d, J = 10.8 Hz each,
CH2), 4.59 (1H, d, J = 3.3 Hz, CH), 7.28–7.36 (5H, m, ArH); 13C NMR (75.5 MHz, CDCl
3
) δ
14

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284
285
286
287
19.7, 21.3, 21.8, 39.4, 71.2, 78.2, 127.9 (2C), 128.0 (2C), 128.1, 141.5, 171.6; UV (MeOH)
max: 213, 257 nm. HRMS (ESI) m/z: Found 245.1148 [M+Na]+; calcd. for [C13H18O3+Na]+:
λ
245.1154.
1-(4-Chlorophenyl)-2,2-dimethylpropane-3-acetate-1-ol (4b): It was obtained as a solid in
1
35% yield; mp 88–90 °C (lit. m.p.9 78.5–80 °C). H NMR (300 MHz, CDCl3) δ 0.83 and
288
289
290
291
292
293
294
295
296
297
298
299
300
301
302
303
304
305
0.89 (3H each, s, 2 × CH3), 2.10 (3H, s, OCOCH3), 2.69 (1H, brs, OH), 3.73 and 4.18 (1H
each, d, J = 11.1 Hz each, CH2), 4.53 (1H, s, CH), 7.23 and 7.29 (2H each, d, J = 7.2 Hz,
ArH); 13C NMR (75.5 MHz, CDCl
) δ 19.4, 21.3, 21.8, 39.4, 71.1, 128.2, 129.4, 133.6,
3
139.9, 171.7; UV (MeOH) λmax: 220 nm. HRMS (ESI) m/z: Found 279.0769 [M+Na]+; calcd.
for [C13H17ClO3+Na]+: 279.0764.
1-(4-Fluorophenyl)-2,2-dimethylpropane-3-acetate-1-ol (4c): It was obtained as a solid in
1
62% yield; mp 80–83 °C; H NMR (300 MHz, CDCl3) δ 0.84 and 0.91 (3H each, s, 2 ×
CH3), 2.11 (3H, s, OCOCH3), 2.55 (1H, d, J = 2.4 Hz, OH), 3.76 and 4.20 (1H each, d, J =
11.1 Hz each, CH2), 4.56 (1H, d, J = 2.1 Hz, CH), 7.01 (2H, t, J = 8.4 Hz, ArH), 7.27 (2H, t, J
= 8.1 Hz, ArH); 13C NMR (75.5 MHz, CDCl
) δ 19.5, 21.3, 21.9, 39.5, 71.1, 77.6, 114.9 (2C,
3
d, J = 21.1 Hz), 129.5 (2C, d, J = 7.5 Hz), 137.14, 162.6 (2C, d, J = 245.4 Hz), 171.72 ; UV
(MeOH) λmax: 212, 264, 270 nm. HRMS (ESI) m/z: Found 263.1055 [M+Na]+; calcd. for
[C13H17FO3+Na]+: 263.1059.
1-(4-Methoxyphenyl)-2,2-dimethylpropane-3-acetate-1-ol (4d): It was obtained as a solid
1
in 43% yield; m.p. 63–65 °C. H NMR (300 MHz, CDCl3) δ 0.84 and 0.93 (3H each, s, 2 ×
CH3), 2.10 (3H, s, OCOCH3), 2.40 (1H, d, J = 3.0 Hz, OH), 3.80 (3H, s, OCH3), 3.78 (1H, d,
J = 12.3 Hz, CHαHβ), 4.16 (1H, d, J = 10.8 Hz, CHαHβ), 4.53 (1H, d, J = 3.0 Hz, CH), 6.86
13
(2H, d, J = 8.4 Hz, ArH), 7.22 (2H, d, J = 8.4 Hz, ArH); C NMR (75.5 MHz, CDCl
3
) δ
15

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307
308
309
310
311
312
313
314
315
316
317
19.7, 21.3, 21.8, 39.5, 55.6, 71.2, 77.8, 113.5 (2C), 129.0 (2C), 133.6, 159.4, 171.6; UV
(MeOH) λmax: 225, 274, 281 nm. HRMS (ESI) m/z: Found 275.1260 [M+Na]+; calcd. for
[C14H20O4+Na]+: 275.1259.
1-(4-Nitrophenyl)-2,2-dimethylpropane-3-acetate-1-ol (4e): It was obtained as a solid in
1
37.13% yield; m.p. 90–92 °C. H NMR (300 MHz, CDCl3) δ 0.86 and 0.89 (6H, 2s, 2 ×
CH3), 2.12 (3H, s, OCOCH3), 2.93 (1H, d, J = 3.3 Hz, OH), 3.73 and 4.29 (1H each, d, J =
11.1 Hz each, CH2), 4.66 (1H, d, J = 3.3 Hz, CH), 7.49 (2H, d, J = 8.4 Hz, ArH), 8.17 (2H, d,
13
J = 8.4 Hz, ArH). C NMR (75.5 MHz, CDCl
3
) δ 19.2, 21.2, 22.0, 39.7, 70.9, 77.0, 123.2
(2C), 128.9 (2C), 147.7, 148.8, 171.8. UV (MeOH) λmax: 273 nm. HRMS (ESI) m/z:
290.0999 [M+Na]+; Calcd. for [C13H17NO5+Na]+: 290.1005.
1-(Benzo[d][1,3]dioxol-5-yl)-2,2-dimethylpropane-3-acetate-1-ol (3f): It was obtained as a
solid in 40.5% yield; mp 75–77 °C; 1H NMR (300 MHz, CDCl3) δ 0.85 and 0.93 (3H each, s,
318
319
320
321
322
323
324
325
326
327
2 × CH3), 2.04 (1H, s, OH), 2.11 (3H, s, OCOCH3), 3.77 and 4.17 (1H each, d, J = 10.8 Hz,
CH2), 4.51 (1H, s, CH), 5.95 (2H, s, OCH2O), 6.75 (2H, s, ArH), 6.84 (1H, s, ArH); 13C
NMR (75.5 MHz, CDCl ) δ 19.7, 21.3, 21.8, 39.5, 71.2, 78.0, 101.3, 107.8, 108.4, 121.3,
3
135.4, 147.2, 147.6, 171.7; UV (MeOH) λmax: 209, 234, 285 nm. HRMS (ESI) m/z 289.1048
[M+Na]+; Calcd. for [C14H18O5+Na]+: 289.1052.
1-(3,4-Dimethoxyphenyl)-2,2-dimethylpropane-3-acetate-1-ol (4g): It was obtained as a
1
liquid in 55.4% yield; H NMR (300 MHz, CDCl3) δ 0.86 and 0.95 (3H each, s, 2 × CH3),
2.12 (3H, s, OCOCH3), 2.37 (1H, br s, OH), 3.79 and 4.18 (1H each, d, J = 11.1 Hz, CH2),
13
3.88 (6H, s, 2 × OCH3), 4.54 (1H, s, CH), 6.82 (2H, br s, ArH), 6.88 (1H, br s, ArH); C
NMR (75.5 MHz, CDCl ) δ 19.8, 21.4, 21.9, 39.5, 56.2 (2C), 71.3, 78.0, 110.7, 111.1, 120.3,
3
16

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329
330
331
332
333
334
335
336
337
338
134.0, 148.7 (2C), 171.7; UV (MeOH) λmax: 204, 228, 274, 379 nm. HRMS (ESI) m/z:
305.1361 [M+Na]+; Calcd. for [C15H22O5+Na]+: 305.1365.
1-(Furan-2-yl)-2,2-dimethylpropane-3-acetate-1-ol (4h): It was obtained as a liquid in
28.11% yield. 1H NMR (300 MHz, CDCl3) δ 0.93 and 1.01 (3H each, s, 2 × CH3), 2.10 (3H,
s, OCOCH3), 2.44 (1H, d, J = 4.2 Hz, OH), 3.84 and 4.12 (1H each, d, J = 11.1 Hz each,
CH2), 4.58 (1H, d, J = 5.1 Hz, CH), 6.25 (1H, d, J = 3.0 Hz, furylꢀH), 6.34 (1H, d, J = 1.8 Hz,
13
furylꢀH), 7.37 (1H, s, furylꢀH); C NMR (75.5 MHz, CDCl
3
) δ 20.1, 21.3, 21.6, 39.5, 70.8,
72.7, 107.9, 110.5, 142.1, 155.0, 171.6; UV (MeOH) λmax: 217, 317 nm. HRMS (ESI) m/z
235.0942 [M+Na]+; Calcd. for [C11H16O4+Na]+: 235.0947.
1-(Pyridin-4-yl)-2,2-dimethylpropane-3-acetate-1-ol (4i): It was obtained as a solid in 40%
1
yield; mp 69–71 °C; H NMR (300 MHz, CDCl3) δ 0.83 and 0.88 (6H, 2s, 2 × CH3), 2.01
339
(1H, s, OH), 2.06 (3H, s, OCOCH3), 3.75 (1H, d, J = 10.8 Hz, CHαHβ), 4.19 (1H, d, J = 11.1
340
341
342
343
344
345
Hz, CHαH
β), 4.53 (1H, s, CH), 7.22 (2H, d, J = 5.1 Hz, ArH), 8.38 (2H, d, J = 5.1 Hz, ArH);
13C NMR (75.5 MHz, CDCl
3
) δ 19.3, 21.3, 21.8, 39.3, 70.8, 76.3, 123.4 (2C), 149.1 (2C),
151.2, 171.7; UV (MeOH) λmax: 257 nm. HRMS (ESI) m/z 246.1099 [M+Na]+; Calcd. for
[C12H17NO3+Na]+: 246.1106.
1-(Pyridin-2-yl)-2,2-dimethylpropane-3-acetate-1-ol (4j): It was obtained as a solid in
1
41% yield; mp 54–55 °C; H NMR (300 MHz, CDCl3) δ 0.88 and 0.93 (3H each, s, 2 ×
346
CH3), 2.07 (3H, s, OCOCH3), 3.88 (1H, d, J = 10.8 Hz, CHαHβ), 4.14 (1H, d, J = 10.5 Hz,
347
348
349
CHαH
β), 4.40 (1H, d, J = 9.0 Hz, OH), 4.62 (1H, d, J = 6.6 Hz, CH), 7.23 (2H, t, J = 7.5 Hz,
pyridylꢀH), 7.66 (1H, t, J = 6.0 Hz, pyridylꢀH), 8.57 (1H, d, J = 4.8 Hz, pyridylꢀH); 13C NMR
(75.5 MHz, CDCl ) δ 20.0, 21.3, 21.7, 39.9, 70.6, 76.5, 122.9, 123.0, 136.1, 148.4, 159.4,
3
17

Page 18 of 23
350
351
352
353
354
355
356
357
358
359
360
361
362
363
364
365
366
367
368
369
370
371
171.4; UV (MeOH) λmax: 261 nm. HRMS (ESI) m/z 246.1098 [M+Na]+; Calcd. for
[C12H17NO3+Na]+: 246.1106.
1-Phenyl-2,2-dimethylpropane-1-acetate-3-ol (5a): It was obtained as a liquid in 5% yield;
1H NMR (300 MHz, CDCl3) δ 0.90 and 0.95 (6H, s, 2 × CH3), 2.14 (3H, s, OCOCH3), 2.32
(1H, br s, OH), 3.26 and 3.46 (1H each, d, J = 11.4 Hz, CH2), 5.82 (1H, s, CH), 7.28–7.33
(5H, m, ArH); 13C NMR (75.5 MHz, CDCl
) δ 19.7, 21.5, 21.8, 40.3, 69.4, 79.3, 128.2 (5C),
3
137.9, 171.2; UV (MeOH) λmax: 207, 258 nm. HRMS (ESI) m/z 245.1150 [M+Na]+; Calcd.
for [C13H18O3+Na]+: 245.1154.
1-(4-Methoxyphenyl)-2,2-dimethylpropane-1-acetate-3-ol (5d): It was obtained as a liquid
1
in 2% yield; H NMR (300 MHz, CDCl3) δ 0.87 and 0.88 (6H, s, 2 × CH3), 2.12 (3H, s,
OCOCH3), 3.24 and 3.44 (1H each, d, J = 12.0 Hz, CH2), 3.81 (3H, s, OCH3), 5.77 (1H, s,
13
CH), 6.87 (2H, d, J = 8.7 Hz, ArH), 7.24 (2H, d, J = 8.4 Hz, ArH); C NMR (75.5 MHz,
CDCl ) δ 19.8, 21.6, 21.8, 40.4, 55.6, 69.4, 79.1; UV (MeOH) λmax: 225, 274, 281 nm.
3
HRMS (ESI) m/z 275.1262 [M+Na]+; Calcd. for [C14H20O4+Na]+: 275.1260.
Synthesis of 1-(4-methoxyphenyl)-2,2-dimethylpropane-1,3-diacetate (6):
To a stirred solution of 1ꢀ(4ꢀmethoxyphenyl)ꢀ2,2ꢀdimethylꢀ1,3ꢀpropanediol (80
mmol) in acetic anhydride (160 mmol), DMAP (catalytic amount) was added, and the
resulting mixture was stirred at room temperature for 48 h. Water was added to the reaction
mixture and extracted with ethyl acetate (3 × 100 mL). The organic layer was dried and
concentrated to afford a crude product which was purified by column chromatography (8%
EtOAc/hexane as the eluent). It was obtained as a colorless solid in 84% yield; mp 35–38 °C;
372
1H NMR (300 MHz, CDCl3) δ 0.91 and 0.99 (3H each, s, 2 × CH3), 2.08 and 2.10 (6H, 2s, 2
18

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374
375
376
377
378
379
380
381
382
383
384
385
386
387
388
× OCOCH3), 3.69 and 4.05 (1H each, d, J = 10.8 Hz, CH2), 3.80 (3H, s, OCOCH3), 5.68 (1H,
13
s, CH), 6.85 (2H d, J = 8.7 Hz, ArH), 7.20 (2H, d, J = 8.7 Hz, ArH); C NMR (75.5 MHz,
CDCl ) δ 20.7, 21.3, 21.5 (2C), 38.7, 55.6, 70.1, 78.7, 113.7 (2C), 129.2 (2C), 129.9, 159.5,
3
170.3, 171.4; UV (MeOH) λmax: 222, 274, 280 nm. HRMS (ESI) m/z 317.1357 [M+Na]+;
Calcd. for [C16H22O5+Na]+: 317.1365.
Acknowledgements
The authors thank the Natural Sciences and Engineering Research Council (NSERC) of
Canada financial support. Julie Richard, Mark Deveau and Jeffery Melanson of Universite
SainteꢀAnne are thanked for technical support.
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Tables and Figure Captions:
443
444
445
446
Figure 1. Biologically active propanediol carbamates and related propanediols.
Table 1. Stereoselective acetylation of racemic 1ꢀ(4ꢀmethoxyphenyl)ꢀ2,2ꢀdimethylꢀ1,3ꢀ
propanediol 1a in different solvents
Table 2. Stereoselective acetylation of 1ꢀarylꢀ2,2ꢀdimethylꢀ1,3ꢀpropanediols 1a-j in THF.
447
448
449
450
Scheme 1. Attempted Novozym® 435ꢀcatalyzed deacetylation reaction of racemic diacetate
6.
22

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Graphical Abstract:
Optical Enrichment in Enzyme-Catalyzed Resolution of 1-Aryl-2,2-Dimethyl-1,3-
Propanediols
454
455
Chandrani Mukherjee, Prabhu P. Mohapatra, Dani Youssef, Amitabh Jha*
456
457
23