Chemoenzymatic enantioselective synthesis of 2-substituted glycerol derivatives

Article abstract of DOI:10.1016/j.tetasy.2012.04.001

2-Substituted glycerol derivatives 4a-g were resolved by acylation with vinyl butyrate in the presence of lipases in organic media. The reverse reaction, the enzymatic hydrolysis of the corresponding butyrates 5a-g, was also highly stereoselective and pro

Full text of DOI:10.1016/j.tetasy.2012.04.001

Tetrahedron: Asymmetry 23 (2012) 428–433
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Chemoenzymatic enantioselective synthesis of 2-substituted
glycerol derivatives
Mélanie Bolduc a, Jérôme Bergeron a, Annie Michaud a, Nicholas Pelchat a, Pierre Morin a,
Mohammed Dasser b, Robert Chênevert a,
⇑
a Département de Chimie, Faculté des Sciences et de Génie, Université Laval, Québec (Qc), Canada G1V 0A6
b OmegaChem, 480 rue Perreault, St-Romuald (Qc), Canada G6W 7V6
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 January 2012
Accepted 3 April 2012
2-Substituted glycerol derivatives 4a–g were resolved by acylation with vinyl butyrate in the presence of
lipases in organic media. The reverse reaction, the enzymatic hydrolysis of the corresponding butyrates
5a–g, was also highly stereoselective and provided the opposite enantiomers. High enantioselectivities
(ee >90%) and good isolated yields were obtained for all substrates using the appropriate lipase. Pseudo-
monas cepacia lipase or the closely related Pseudomonas sp. lipase were the most efficient enzymes for the
resolution of substrates bearing smaller aliphatic groups. Candida antarctica lipase B was more suitable as
the biocatalyst in the resolution of more sterically demanding aromatic substrates. 2-Benzylglycerol
derivatives were resolved in the presence of Rhizopus sp. lipase.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Glycerol (1,2,3-propanetriol) occurs naturally in many lipids in
the form of phosphoric or fatty acid esters (glycerides). Tradition-
ally, glycerol is commercially produced by several processes: soap
manufacture, fatty acid or esters production, microbial fermenta-
tion, and chemical synthesis from propylene. Glycerol is utilized
in many commercial products or can be converted into a variety
of valuable chemicals or intermediates (dihydroxyacetone, epi-
chlorohydrin, acrylic acid, etc). Glycerol is currently available in
large surplus as a by-product in biodiesel production by the transe-
sterification of vegetal oils with simple alcohols, such as methanol.
Conversion of this abundant renewable resource into higher value-
added chemicals has recently attracted much interest.1–6
Chiral tertiary alcohols are important frameworks frequently
found in natural products and pharmaceuticals; however their
enantioselective synthesis remains a significant challenge.7–13
Desymmetrization of meso or resolution of chiral 2-substituted
glycerol derivatives by chemical14–17 or enzymatic18–25 methods
are valuable approaches to obtain optically active tertiary alcohols.
Of particular interest is the chemoenzymatic preparation of enan-
tiopure 2-methylglycerol derivatives reported by Wirz et al.24
Herein we report the synthesis of both enantiomers of a series of
2-substitued-1,2-isopropylidene glycerols via enzymatic transeste-
rification or hydrolysis.
2.1. Substrates preparation
Substrates 4a–g and 5a–g were synthesized as outlined in
Scheme 1. 1,3-Dihydroxyacetone bis-silyl ether 1 was prepared
as described in the literature.26 Grignard reactions with dihydroxy-
acetone derivative 1 in THF provided tertiary alcohols 2a–g in high
O
HO
R
HO
OH
R
a
b
OTBS OTBS
OTBS OTBS
OH
1
2a-g
3a-g
R
R
O
O
c
d
HO
O
O
n-Pr
O
4a-g
5a-g
O
a: R = CH3
e: R = Ph
f: R = 4-fluoro-Ph
g: R = CH2-Ph
b: R = CH=CH2
c: R = CH2-CH=CH2
d: R = C(CH3)=CH2
⇑
Corresponding author. Tel.: +1 418 656 3283; fax: +1 418 656 7916.
E-mail address: robert.chenevert@chm.ulaval.ca (R. Chênevert).
Scheme 1. Reagents and conditions: (a) RMgX, THF; (b) t-Bu4NF, THF; (c) acetone,
TsOH; (d) butyryl chloride, Et3N, CH2Cl2.
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.04.001

M. Bolduc et al. / Tetrahedron: Asymmetry 23 (2012) 428–433
429
yields. Desilylation of 2a–g with tetrabutylammonium fluoride
(TBAF) afforded triols 3a–g. 2-Methylglycerol 3a was also prepared
in one step by dihydroxylation of b-methallylic alcohol following a
known procedure.27 The diol functionality of 3a–g was protected
using acetone and p-toluenesulfonic acid (TsOH) to give acetals
4a–g. Esters 5a–g were obtained by acylation of 4a–g with butyryl
chloride in the presence of triethylamine.
and the hydrolysis of the corresponding racemic esters 5a–g are
complementary and lead to opposite enantiomers of both alcohol
and ester. When both the alcohol and the corresponding ester
are substrates for a hydrolase, acylation and hydrolysis are usually
complementary and give the opposite enantiomers. Although acyl-
ation and hydrolysis represent reactions in opposite directions, the
hydrolase favors the same enantiomer or the same prochiral group
in both cases. While this empirical rule applies to kinetic resolu-
tions and desymmetrizations, exceptions have been reported.29
The title compounds are valuable synthons in asymmetric syn-
thesis. For instance, compound 4c has been used as a chiral build-
ing block for the synthesis of a number of natural products or
biologically active compounds (Fig. 1) such as frontalin (insect
pheromone), malyngolide (antibiotic), daunomycinone, and rhodo-
mycinone derivatives (anthracyclinones, antitumor agents).30 Ahn
et al.31 reported the stereoselective transformation of (R)-4c into 2-
fluoroglycerol derivatives, en route to fluorinated nucleosides.
2.2. Enzymatic kinetic resolutions
We examined both the acylation (transesterification) of alco-
hols 4a–g and the hydrolysis of esters 5a–g in the presence of com-
mercially available lipases. The best reaction conditions reported
for the resolution of 4a were applied to the series of substrates.24
The reactions were monitored by GC or HPLC on a chiral phase col-
umn allowing the simultaneous determination of conversion (c)
and enantiomeric excesses (ee) of both product and remaining sub-
strate. The reactions were stopped at conversion close to 50% and
the E values were determined using Sih’s method.28
The best results of the enzymatic hydrolysis of esters 5a–g in a
phosphate buffer (pH 7.5) are shown in Table 1. Excellent enanti-
oselectivities (E >100) and good isolated yields were obtained for
all substrates using the appropriate lipase. Pseudomonas cepacia li-
pase (PCL) or the closely related Pseudomonas sp. lipase (PSL) were
the most efficient enzymes for the resolution of ester 5a–d bearing
smaller R groups (entries 1–4). Candida antarctica lipase B (CAL-B)
was more suitable as the biocatalyst in the resolution of more ste-
rically demanding substrates such as 4e,f (entries 5 and 6). In the
case of ester 5g, Rhizopus sp. lipase (RSL) gave the best results.
The absolute configurations of 4a–g were determined by compar-
ison or chemical correlation with compounds of known absolute
configurations. In most cases, the (R)-ester was the faster-reacting
enantiomer, yielding the (S)-alcohol in high ee and leaving the (S)-
ester as an enantiomerically pure unreacted enantiomer (entries
1–4, 7). In contrast, CAL-B catalyzed the hydrolysis of the aromatic
(S)-esters 5e,f selectively.
Compound (R)-4c is usually prepared in low yields from D-lac-
tose.30 The present procedure provides both enantiomers of alco-
hols 4a–g and esters 5a–g in good yields with high enantiomeric
excesses. Tertiary alcohols and their esters are poor substrates
for most of the commercially available hydrolases presumably
due to steric hindrance. Enzymes bearing the motif GGG(A)X
(G = glycine, A = alanine, X = any amino acid) in the oxyanion bind-
ing pocket of their active site are active toward acetates of some
tertiary alcohols.7 In primary alcohols and their esters with an
adjacent quaternary stereocenter bearing a protected alcohol, such
as 4a–g and 5a–g, the hindered stereocenter lies further from the
reactive group, and so lipase-catalyzed reactions are facilitated
considerably and more general.32
3. Experimental
3.1. General
NMR spectra were recorded on a Varian Inova AS400 spectrom-
eter (400 MHz). Infrared spectra were recorded on a Bomem MB-
100 spectrometer. Optical rotations were measured using a JASCO
DIP-360 digital polarimeter (c as grams of compound per 100 mL).
High resolution mass spectra (HRMS) were obtained by chemical
ionization (CI, NH3) or electrospray ionization (ESI). Flash column
The results of the lipase-catalyzed acylation of substrates 4a–g
using vinyl butyrate as the acyl donor in hexane are summarized in
Table 2. The esterification of 4a–g follows the same pattern as the
hydrolysis of 5a–g but the enantioselectivity (46 < E < 126) is lower
(entries 1–7). The least satisfying result was obtained with alcohol
4g; RSL showed good enantioselectivity but very low activity (en-
try 7). As expected, the transesterification of racemic alcohols 4a–g
chromatography was carried out using 40–63 lm (230–400 mesh)
silica gel. Pseudomonas sp. lipase (PSL) and P. cepacia lipase (PCL,
Table 1
Enzymatic resolution of 5a–g using lipases under hydrolysis conditions
R
O
R
O
R
phosphate buffer
O
pH 7.5
O
O
O
enzyme
O
O
OH
(S)-4
(S)-5
rac-5
O
O
Entry
Substrate
Enzymea
Time (h)
Alcohol 4
Ester 5
E
Eeb (%)
Abs. conf.
Yieldc (%)
Eeb (%)
Abs. Conf.
Yieldc (%)
1
2
3
4
5
6
7
5a
5b
5c
5d
5e
5f
PCL
PSL
PCL
PSL
CAL-B
CAL-B
RSL
1
2
9
99
97
99
98
94
94
94
(S)
(S)
(S)
(S)
(R)
(R)
(S)
46
49
40
40
43
41
47
99
97
99
98
94
94
94
(S)
(S)
(S)
(S)
(R)
(R)
(S)
49
44
48
37
39
41
46
>200
>200
>200
>200
115
9
20
52
18
115
115
5g
a
b
c
PCL (P. cepacia lipase), PSL (Pseudomonas sp. lipase), CAL-B (C. antarctica lipase B), RSL (Rhizopus sp. lipase).
Determined by GC or HPLC on a chiral phase.
Isolated yield.

430
M. Bolduc et al. / Tetrahedron: Asymmetry 23 (2012) 428–433
Table 2
Enzymatic resolution of 4a–g using lipases under esterification conditions
R
O
R
O
R
O
lipase
O
O
O
O
vinyl butyrate
hexane
OH
OH
(R)-4
rac-4
O
(R)-5
Entry
Substrate
Enzymea
Time (h)
Alcohol 4
Ester 5
E
Eeb (%)
Abs. conf.
Yieldc (%)
Eeb (%)
Abs. Conf.
Yieldc (%)
1
2
3
4
5
6
7
4a
4b
4c
4d
4e
4f
PCL
PCL
PCL
PCL
CAL-B
CAL-B
RSL
24
5
10
22
1.25
1
98
93
99
99
92
96
80
(R)
(R)
(R)
(R)
(S)
(S)
(R)
40
39
40
37
46
44
48
93
93
85
92
92
92
90
(R)
(R)
(R)
(R)
(S)
(S)
(R)
39
37
42
40
44
41
42
126
94
63
125
78
94
4g
648
46
a
b
c
PCL (P. cepacia lipase), CAL-B (C. antarctica lipase B), RSL (Rhizopus sp. lipase).
Determined by GC or HPLC on a chiral phase.
Isolated yield.
O
O
OH
OH
OH
O
OH
O
(-)-4-deoxy−γ-rhodomycinone
(-)-frontalin
HO
O
O
F
OBn
OH
HO
(R)-4c
(CH2)8CH3
O
O
(-)-malyngolide
OAc
BnO
O
F
Figure 1. Natural products and biologically active compounds synthesized from (R)-4c.30,31
renamed Burkholderia cepacia lipase) were from Fluka-Aldrich-Sig-
ma. Rhizopus sp. lipase (RSL, lipase F) was from Amano Interna-
purified by flash column chromatography (hexane/EtOAc, 95/5)
to give a yellow oil (yields: 76–94%).
tional Enzyme Co. and CAL-B (Candida antarctica lipase
B
(Chirazyme L2) was obtained from Boehringer Mannheim.
3.2.1. 1,3-Bis-[(tert-butyldimethylsilyloxy)methyl]-2-
methylpropan-2-ol 2a
3.2. General procedure for the synthesis of alcohols 2a–g
IR (neat) 3565, 3484, 2959–2862, 1472,1257,1089 cmꢁ1; 1H NMR
(400 MHz, CDCl3) d 0.06 (s, 12H), 0.90 (s, 18H), 1.10 (s, 3H), 2.58 (br s,
1H, OH), 3.40 (d, J = 9.3 Hz, 2H), 3.47 (d, J = 9.3 Hz, 2H); 13C NMR
(100 MHz, CDCl3) d ꢁ5.3, 18.4, 20.9, 26.1, 66.6, 72.6; HRMS (ESI)
Calcd for C16H39O3Si2 (M+H)+: 335.2438. Found: 335.2432.
To a solution of R-MgBr (66 mmol, 3 equiv) in anhydrous THF
(130 mL) was added a solution of 1 (22 mmol, 1 equiv) in THF
(15 mL). The mixture was stirred at room temperature and the pro-
gress of the reaction was monitored by TLC (hexane/AcOEt, 9:1).
The reaction mixture was cooled to 0 °C, quenched with a 3 M
HCl solution (29 mL), and extracted with Et2O (3 ꢀ 50 mL). The
combined extracts were washed with satd NaHCO3 (3 ꢀ 40 mL),
water, and brine. The organic extract was dried (MgSO4), filtered,
and concentrated under reduced pressure. The crude product was
3.2.2. 1-(tert-Butyldimethylsilyloxy)-2-[(tert-
butyldimethylsilyloxy)methyl]but-3-en-2-ol 2b
IR (neat) 3566, 3094, 2956, 2930, 2858, 1472, 1258, 1095 cmꢁ1
;
1H NMR (400 MHz, CDCl3) d 0.15 (s, 12H), 0.88 (s, 18H), 3.48 (d,
J = 9.5 Hz, 2H), 3.57 (d, J = 9.5 Hz, 2H), 5.18 (m, 1H), 5.41 (m, 1H),

M. Bolduc et al. / Tetrahedron: Asymmetry 23 (2012) 428–433
431
5.95 (m, 1H); 13C NMR (100 MHz, CDCl3) d ꢁ5.3, 18.5, 26.1, 65.8,
75.1, 115.0, 138.7. Spectroscopic data of compound 2b are in agree-
ment with that reported in the literature.33
by TLC (hexane/EtOAc, 70:30). The reaction was quenched by the
addition of NaHCO3 (24 mg, 0.28 mmol) and stirred for 15 min.
The mixture was diluted with ethyl acetate (50 mL), washed with
aqueous satd NaHCO3 (30 mL), dried (MgSO4), and evaporated.
The crude product was purified by flash chromatography (hex-
ane/EtOAc, 70:30) to give acetals 4a–g as colorless oils (yields:
70–85%).
3.2.3. 1-(tert-Butyldimethylsilyloxy)-2-[(tert-butyldimethyl-
silyloxy)methyl]pent-4-en-2-ol 2c
IR (neat) 3566, 3484, 3077, 2955–2861, 1642, 1465, 1257,
1085 cmꢁ1 1H NMR (400 MHz, CDCl3) d 0.06 (s, 12H), 0.90 (s,
;
18H), 2.23 (m, 2H), 2.58 (br s, 1H, OH), 3.41 (d, J = 9.3 Hz, 2H),
3.50 (d, J = 9.3 Hz, 2H), 5.08 (m, 1H), 5.10 (m, 1H), 5.86–5.94 (m,
1H); 13C NMR (100 MHz, CDCl3) d ꢁ5.3, 18.4, 26.1, 38.5, 65.1,
74.0, 118.0, 133.8; HRMS (ESI) Calcd for C18H41O3Si2 (M+H)+:
361.2594. Found: 361.2539.
3.4.1. 2,2,4-Trimethyl-1,3-dioxolan-4-yl methanol 4a
IR (neat) 3463, 2986, 2936, 2874, 1457, 1372, 1251, 1213 cmꢁ1
;
1H NMR (400 MHz, CDCl3) d 1.30 (s, 3H), 1.42 (s, 3H), 1.43 (s, 3H),
3.47 (d, J = 11.3 Hz, 2H), 3.52 (d, J = 11.3 Hz, 2H), 3.73 (d, J = 8.6 Hz,
1H), 3.98 (d, J = 8.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 22.4, 27.1,
27.3, 67.0, 71.2, 81.2, 109.8. Spectroscopic data are in agreement
with that reported in the literature.24
3.2.4. 1-(tert-Butyldimethylsilyloxy)-2-[(tert-butyldimethyl-
silyloxy)methyl]-3-methylbut-3-en-2-ol 2d
IR (neat) 3559, 2954, 2929, 2885, 2858, 1471, 1254, 1082 cmꢁ1
;
3.4.2. (4-Ethenyl-2,2-dimethyl-1,3-dioxolan-4-yl) methanol 4b
1H NMR (400 MHz, CDCl3) d 0.03 (s, 12H), 0.86 (s, 18H), 1.77 (m,
3H), 3.53 (d, J = 9.5 Hz, 2H), 3.65 (d, J = 9.5 Hz, 2H), 4.89 (m, 1H),
4.96 (m, 1H); 13C NMR (100 MHz, CDCl3) d ꢁ5.4, 18.4, 19.8, 26.0,
65.5, 76.4, 111.8, 146.3; HRMS (CI, NH3) Calcd for C18H41O3Si2
(M+H)+: 361.2594. Found: 361.2588.
IR (neat) 3478, 3094, 2988, 2935, 2876, 1372, 1212, 1056 cmꢁ1
;
1H NMR (400 MHz, CDCl3) d 1.43 (s, 3H), 1.47 (s, 3H), 3.54 (m, 2H),
3.88 (d, J = 8.6 Hz, 1H), 4.07 (d, J = 8.6 Hz, 1H), 5.25 (d, J = 11.8 Hz,
1H), 5.41 (d, J = 14.8 Hz, 1H), 5.90 (m, 1H); 13C NMR (100 MHz,
CDCl3) d 26.4, 27.2, 66.1, 70.3, 84.1, 110.4, 116.0, 138.4. Spectro-
scopic data are in agreement with that reported in the literature.15
3.2.5. 1,3-Bis-[(tert-butyldimethylsilyloxy)methyl]-2-phenyl-
propan-2-ol 2e
3.4.3. (2,2-Dimethyl-4-(prop-2-en-1-yl)-1,3-dioxolan-4-yl)
methanol 4c
IR (neat) 3555, 3484, 3061, 3032, 2955–2857, 1601, 1470, 1256,
1096 cmꢁ1; 1H NMR (400 MHz, CDCl3) d 0.01 (s, 12H), 0.88 (s, 18H),
3.15 (br s, 1H, OH), 3.72 (d, J = 9.4 Hz, 2H), 3.85 (d, J = 9.4 Hz, 2H),
7.24–7.50 (m, 5H); 13C NMR (100 MHz, CDCl3) d ꢁ5.34, ꢁ5.30,
18.5, 26.1, 66.8, 75.5, 126.0, 127.3, 127.9, 142.8; HRMS (ESI) Calcd
for C21H41O3Si2 (M+H)+: 397.2594. Found: 397.2589.
IR (neat) 3473, 3078, 2987, 2936, 2877, 1371, 1214, 1059 cmꢁ1
;
1H NMR (400 MHz, CDCl3) d 1.39 (s, 3H), 1.42 (s, 3H), 1.83 (br s, 1H,
OH), 2.39 (m, 2H), 3.54 (m, 2H), 3.82 (d, J = 8.6 Hz, 1H), 3.89 (d,
J = 8.6 Hz, 1H), 5.12 (m, 2H), 5.78 (m, 1H); 13C NMR (100 MHz,
CDCl3) d 26.5, 27.1, 39.9, 65.2, 69.3, 83.1, 109.5, 118.1, 133.8. Spec-
troscopic data are in agreement with that reported in the
literature.17
3.2.6. 1,3-Bis-[(tert-butyldimethylsilyloxy)methyl]-2-(4-fluoro-
phenyl)propan-2-ol 2f
IR (neat) 3356, 3020, 2967, 2900, 2876, 2845, 1661, 1216 cmꢁ1
;
3.4.4. (2,2-Dimethyl-4-(prop-1-en-2-yl)-1,3-dioxolan-4-yl)
methanol 4d
1H NMR (400 MHz, CDCl3) d 0.00 (s, 12H), 0.87 (s, 18H), 3.12 (d,
J = 7.6 Hz, 2H), 3.78 (d, J = 7.6 Hz, 2H), 6.98–7.02 (m, 2H), 7.50–
7.66 (m, 2H); 13C NMR (100 MHz, CDCl3) d ꢁ5.3, 18.5, 26.1, 66.7,
75.2, 114.6, 127.7, 139.1, 161.6; HRMS (ESI) Calcd for C21H39O3Si2F-
Na (M+Na)+: 437.2319. Found: 437.2310.
IR (neat) 3481, 3097, 3084, 2988, 2939, 2877, 1371, 1213,
1059 cmꢁ1 1H NMR (400 MHz, CDCl3) d 1.41 (s, 3H), 1.48 (s, 3H),
;
1.77 (s, 3H), 3.58 (m, 2H), 3.97 (d, J = 8.6 Hz, 1H), 4.04 (d,
J = 8.6 Hz, 1H), 4.99 (s, 1H), 5.10 (s, 1H); 13C NMR (100 MHz, CDCl3)
d 19.8, 26.0, 27.4, 65.9, 70.0, 86.5, 110.4, 112.6, 145.5. HRMS (CI,
NH3) Calcd for C9H17O3 (M+H)+: 173.1178. Found: 173.1174.
3.2.7. 1,3-Bis-[(tert-butyldimethylsilyloxy)methyl]-2-benzyl-
propan-2-ol 2g
IR (neat) 3559, 3064, 3030, 2954, 2929, 2885, 2858, 1471, 1254,
1082 cmꢁ1; 1H NMR (400 MHz, CDCl3) d 0.05 (s, 12H), 0.92 (s, 18H),
2.36 (s, 2H), 3.37 (d, J = 9.3 Hz, 2H), 3.45 (d, J = 9.3 Hz, 2H), 7.18–
7.30 (m, 5H); 13C NMR (100 MHz, CDCl3) d ꢁ5.3, 18.4, 26.1, 39.7,
64.7, 74.6, 126.4, 128.1, 130.9, 137.3; HRMS (CI, NH3) Calcd for
3.4.5. (2,2-Dimethyl-4-phenyl-1,3-dioxolan-4-yl) methanol 4e
IR (neat) 3404, 3061, 2922, 2851, 1637, 1048 cmꢁ1 1H NMR
;
(400 MHz, CDCl3) d 1.36 (s, 3H), 1.57 (s, 3H), 3.63 (d, J = 11.6 Hz,
1H), 3.70 (d, J = 11.6 Hz, 1H), 4.15 (d, J = 8.5 Hz, 1H), 4.40 (d,
J = 8.5 Hz, 1H), 7.28–7.37 (m, 5H); 13C NMR (100 MHz, CDCl3) d
26.1, 27.2, 68.3, 71.5, 85.5, 110.3, 125.6, 127.5, 128.4, 143.0. Spec-
troscopic data are in agreement with that reported in the
literature.17
C
22H43O3Si2 (M+H)+: 411.2751. Found: 411.2743.
3.3. General procedure for the synthesis of triol 3a–g
To a solution of 2a–g (12.5 mmol, 1 equiv) in THF (30 mL) was
added a solution of tetrabutylammonium fluoride in THF (1 M,
38 mmol, 3 equiv). The mixture was stirred overnight at room tem-
perature. The solvent was evaporated and the crude product was
purified by flash chromatography (EtOAc/hexane, 9:1 to pure
EtOAc) to afford 3a–g. All of the triols are known compounds that
exhibited spectroscopic data identical to that reported in the
literature.15,16,20,34
3.4.6. [4-(4-Fluorophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl]
methanol 4f
IR (neat) 3356, 3020, 2967, 2900, 2876, 1661, 1216 cmꢁ1 1H
;
NMR (400 MHz, CDCl3) d 1.35 (s, 3H), 1.58 (s, 3H), 3.65 (m, 2H),
4.11 (d, J = 8.5 Hz, 1H), 4.38 (d, J = 8.5 Hz, 1H), 7.02–7.05 (m, 2H),
7.32–7.35 (m, 2H); 13C NMR (100 MHz, CDCl3) d 26.1, 27.2, 68.2,
71.6, 85.2, 110.7, 115.5, 127.2, 127.3, 167.2. HRMS (CI, NH3) Calcd
for C12H15O3FNa (M+Na)+: 249.0897. Found: 249.0909.
3.4. General procedure for the synthesis of acetals 4a–g
3.4.7. (4-Benzyl-2,2-dimethyl-1,3-dioxolan-4-yl) methanol 4g
IR (neat) 3387, 3064, 3030, 2985, 2925, 2853, 1603, 1153,
Triol 3a–g (0.27 mmol, 1 equiv), p-toluenesulfonic acid
(0.03 mmol, 0.1 equiv), and Na2SO4 (0.058 mmol, 0.2 equiv) were
stirred in acetone at room temperature. The reaction was monitored
1048 cmꢁ1 1H NMR (400 MHz, CDCl3) d 1.32 (s, 3H), 1.41 (s, 3H),
;
1.64 (br s, 1H, OH), 2.94 (d, J = 13.6 Hz, 1H), 2.99 (d, J = 13.6 Hz,
1H), 3.47 (d, J = 11.2 Hz, 1H), 3.52 (d, J = 11.2 Hz, 1H), 3.85

432
M. Bolduc et al. / Tetrahedron: Asymmetry 23 (2012) 428–433
(d, J = 8.6 Hz, 1H), 3.99 (d, J = 8.6 Hz, 1H), 7.22–7.30 (m, 5H); 13C
NMR (100 MHz, CDCl3) d 27.0, 27.5, 41.8, 65.3, 69.5, 83.8, 110.2,
126.9, 128.5, 130.8, 136.7. Spectroscopic data are in agreement
with that reported in the literature.17
(d, J = 8.7 Hz, 1H), 4.24 (s, 2H), 4.36 (d, J = 8.7 Hz, 1H), 7.29–7.38
(m, 5H); 13C NMR (100 MHz, CDCl3) d 13.8, 18.5, 26.2, 27.2, 36.3,
68.5, 72.0, 83.7, 110.9, 125.7, 127.9, 128.5, 142.1, 173.6, HRMS
(CI, NH3) Calcd for C16H23O4 (M+H)+: 279.1596. Found: 279.1599.
3.5. General procedure for the synthesis of butyrates 5a–g
3.5.6. [4-(4-Fluorophenyl)-2,2-dimethyl-1,3-dioxolan-4-yl]
methyl butanoate 5f
To a solution of alcohol 4a–g (0.28 mmol, 1 equiv) in anhydrous
CH2Cl2 (2 mL) at 0 °C under a dry atmosphere were added anhy-
drous Et3N (1.4 mmol, 5 equiv) and butanoyl chloride (0.34 mmol,
1.2 equiv). The reaction mixture was stirred at room temperature
and monitored by TLC (hexane/EtOAc, 90:10). The reaction mixture
was quenched by the addition of water (5 mL) and extracted with
CH2Cl2 (3 ꢀ 40 mL). The organic layer was washed with water
(2 ꢀ 20 mL), satd NaHCO3 (2 ꢀ 30 mL), dried over MgSO4, and
evaporated. The crude product was purified by flash chromatogra-
phy (hexane/EtOAc, 95:5) to give esters 5a–g as colorless oils
(yields: 75–90%).
Crystallises on standing, mp. 50–52 °C; IR (neat) 3583, 2966,
2937, 2878, 1739, 1511, 1160 cmꢁ1 1H NMR (400 MHz, CDCl3) d
;
0.88 (t, J = 7.4 Hz, 3H), 1.35 (s, 3H), 1.55 (s, 3H), 1.55–1.62 (m,
2H), 2.27 (t, J = 7.5 Hz, 2H), 4.09 (d, J = 8.7 Hz, 1H), 4.21 (s, 2H),
4.34 (d, J = 8.7 Hz, 1H), 7.02–7.07 (m, 2H), 7.34–7.36 (m, 2H); 13C
NMR (100 MHz, CDCl3) d 13.8, 18.5, 26.1, 27.2, 36.3, 68.4, 71.9,
83.3, 110.0, 115.4, 127.5, 137.9, 162.5, 173.5. HRMS (CI, NH3) Calcd
for C16H21O4FNa (M+Na)+: 319.1322. Found: 319.1320.
3.5.7. (4-Benzyl-2,2-dimethyl-1,3-dioxolan-4-yl) methyl
butanoate 5g
IR (neat) 3064, 3031, 2965, 2936, 2876, 1740, 1176, 1090 cmꢁ1
;
3.5.1. (2,2,4-Trimethyl-1,3-dioxolan-4-yl) methyl butanoate 5a
1H NMR (400 MHz, CDCl3) d 0.98 (t, J = 6.7 Hz, 3H), 1.27 (s, 3H),
1.41 (s, 3H), 1.69 (m, 2H), 2.36 (t, J = 6.4 Hz, 3H), 2.95 (m, 2H),
3.88 (d, J = 8.6 Hz, 1H), 3.91 (d, J = 8.6 Hz, 1H), 3.97 (s, 2H), 7.21–
7.29 (m, 5H); 13C NMR (100 MHz, CDCl3) d 13.9, 18.5, 26.8, 27.4,
36.4, 41.6, 66.2, 70.1, 81.7, 110.5, 127.0, 128.5, 130.8, 136.3,
171.4; HRMS (CI, NH3) Calcd for C17H25O4 (M+H)+: 293.1753.
Found: 293.1758.
IR (neat) 2984, 2937, 2876, 1740, 1380, 1251, 1212, 1175,
1061 cmꢁ1 1H NMR (400 MHz, CDCl3) d 0.96 (t, J = 7.4 Hz, 3H),
;
1.32 (s, 3H), 1.41 (s, 6H), 1.64 (m, 2H), 2.32 (t, J = 7.4 Hz, 2H),
3.72 (d, J = 8.7 Hz, 1H), 3.95 (d, J = 8.7 Hz, 1H), 4.03 (m, 2H); 13C
NMR (100 MHz, CDCl3) d 13.2, 18.3, 22.1, 26.4, 26.7, 35.7, 67.4,
71.4, 79.5, 109.4, 172.6. Spectroscopic data are in agreement with
that reported in the literature.24
3.6. Typical procedure for enzymatic reactions
3.5.2. (4-Ethenyl-2,2-dimethyl-1,3-dioxolan-4-yl) methyl
butanoate 5b
3.6.1. Transesterification
IR (neat) 3096, 2987, 2968, 2938, 2878, 1742, 1372, 1173,
To a solution of alcohol 4e (80.5 mg, 0.39 mmol) in hexane
(5.7 mL) were added vinyl butyrate (73 lL, 0.58 mmol, 1.5 equiv)
1062 cmꢁ1
;
1H NMR (400 MHz, CDCl3) d 0.94 (t, J = 7.4 Hz, 3H),
1.40 (s, 3H), 1.46 (s, 3H), 1.63 (m, 2H), 2.32 (t, J = 7.5 Hz, 2H),
3.84 (d, J = 8.7 Hz, 1H), 4.03 (d, J = 8.7 Hz, 1H), 4.05 (d, J = 11.2 Hz,
1H), 4.11 (d, J = 11.2 Hz, 1H), 5.22 (d, J = 9.6 Hz, 1H), 5.43 (d,
J = 15.4 Hz, 1H), 5.91 (m, 1H); 13C NMR (100 MHz, CDCl3) d 13.8,
18.6, 26.3, 27.1, 36.3, 66.7, 70.9, 82.0, 110.7, 116.0, 137.6, 173.4.
HRMS (CI, NH3) Calcd for C12H21O4 (M+H)+: 229.1440. Found:
229.1428.
and lipase B from C. antarctica (CAL-B, 400 units). The reaction
course was monitored by chiral HPLC and when the conversion
reached 50% (75 min), the reaction was quenched by filtration of
the enzyme and the solvent evaporated. Flash chromatography of
the residue with hexane/EtOAc (90:10–80:20) gave alcohol (S)-4e
(37 mg, 46%, ee = 92%) and ester (S)-5e (48 mg, 44%, ee = 92%).
3.6.2. Hydrolysis
3.5.3. (2,2-Dimethyl-4-(prop-2-en-1-yl)-1,3-dioxolan-4-yl)
methyl butanoate 5c
Ester 5e (84 mg, 0.30 mmol) was suspended in a buffered aque-
ous solution (4.0 mL, phosphate pH 7.5). C. antarctica lipase B (400
units) was added and the pH maintained at its initial value by addi-
tion of 0.1 M aqueous NaOH. The reaction was monitored by chiral
HPLC and stopped at the 50%-of-hydrolysis point (20 h). The aque-
ous mixture was extracted with EtOAc and the organic layer was
dried over MgSO4 and concentrated. Flash chromatography of the
residue with hexane/EtOAc (90:10–80:20) gave alcohol (R)-4e
(27 mg, 43%, ee = 94%) and ester (R)-5e (32.6 mg, 39%, ee = 94%).
IR (neat) 3079, 2984, 2868, 2877, 1742, 1381, 1177, 1064 cmꢁ1
;
1H NMR (400 MHz, CDCl3) d 0.95 (t, J = 7.4 Hz, 3H), 1.41 (s, 6H),
1.65 (m, 2H), 2.33 (t, J = 7.4 Hz, 2H), 2.40 (m, 2H), 3.82 (d,
J = 8.8 Hz, 1H), 3.89 (d, J = 8.8 Hz, 1H), 4.05 (s, 2H), 5.13 (m, 2H),
5.80 (m, 1H); 13C NMR (100 MHz, CDCl3) d 13.2, 18.3, 26.4, 26.6,
35.7, 40.1, 65.8, 69.7, 81.1, 109.7, 118.1, 133.6, 172.5. HRMS (CI,
NH3) Calcd for C13H23O4 (M+H)+: 243.1596. Found: 243.1594.
3.5.4. [2,2-Dimethyl-4-(prop-1-en-2-yl)-1,3-dioxolan-4-yl]
methyl butanoate 5d
3.6.3. Determination of the enantiomeric excess and absolute
configuration
IR (neat) 3084, 2986, 2968, 2938, 2877, 1742, 1381, 1177,
Compounds 4a–5a: Chiral GC analysis on a Chiradex B-DM col-
1064 cmꢁ1
;
1H NMR (400 MHz, CDCl3) d 0.94 (t, J = 7.4 Hz, 3H),
umn; (S)-4a (from enzymatic hydrolysis, ee = 99%): ½a D22
¼ ꢁ5:6 (c
ꢂ
1.38 (s, 3H), 1.48 (s, 3H), 1.65 (m, 2H), 1.78 (s, 3H), 2.31 (t,
J = 7.4 Hz, 2H), 3.96 (d, J = 8.8 Hz, 1H), 4.03 (d, J = 8.8 Hz, 1H),
4.15 (s, 2H), 4.96 (s, 1H), 5.08 (s, 1H); 13C NMR (100 MHz, CDCl3)
d 13.8, 18.6, 19.7, 25.9, 27.2, 36.3, 66.4, 70.3, 84.5, 110.6, 112.7,
144.4, 173.6. HRMS (CI, NH3) Calcd for C13H23O4 (M+H)+:
243.1596. Found: 243.1594.
0.98, CH2Cl2), lit.35 (R)-4a: ½a D22
¼ þ5:5 (c 0.78, CH2Cl2); (S)-5a
ꢂ
(from enzymatic hydrolysis, ee = 99%): ½a D22
¼ ꢁ6:1 (c 1.02, EtOH).
ꢂ
Compounds 4b–5b: Chiral GC analysis on a Chiradex B-DM col-
umn; (S)-4b (from enzymatic hydrolysis, ee = 97%): ½a D22
¼ ꢁ11:9
ꢂ
(c 1.00, CHCl3); the absolute configuration was established by cor-
relation with 2-ethylglycerol monobenzyl ether of known absolute
configuration.36 Compound (S)-5b (from enzymatic hydrolysis,
3.5.5. (2,2-Dimethyl-4-phenyl-1,3-dioxolan-4-yl) methyl
butanoate 5e
ee = 97%): ½a 2D2
¼ þ31:1 (c 1.00, CHCl3).
ꢂ
Compounds 4c–5c: Chiral GC analysis on a Chiradex B-DM col-
IR (neat) 3101, 3006, 2965, 2878, 1740, 1370, 1221, 1095 cmꢁ1
;
umn; (S)-4c (from enzymatic hydrolysis, ee = 99%): ½a D22
¼ þ2:8 (c
ꢂ
1H NMR (400 MHz, CDCl3) d 0.89 (t, J = 7.4 Hz, 3H), 1.36 (s, 3H),
1.56 (s, 3H), 1.55–1.62 (m, 2H), 2.28 (t, J = 7.5 Hz, 2H), 4.12
1.15, CHCl3), lit.37 (R)-4c: ½a D22
¼ ꢁ3:0 (c 3.00, CHCl3); (S)-5c (from
ꢂ
enzymatic hydrolysis, ee = 99%): ½a D22
¼ ꢁ15:2 (c 1.05, CHCl3).
ꢂ

M. Bolduc et al. / Tetrahedron: Asymmetry 23 (2012) 428–433
8. Seebach, D. Angew. Chem., Int. Ed. 2011, 50, 96–101.
433
Compounds 4d–5d: Chiral GC analysis on a Chiradex B-DM col-
umn; (S)-4d (from enzymatic hydrolysis, ee = 98%): ½a D22
¼ ꢁ24:2
ꢂ
9. Stymiest, J. L.; Bagutski, V.; French, R. M.; Aggarwal, V. K. Nature 2008, 456,
778–783.
10. Cozzi, P. G.; Hilgraf, R.; Zimmermann, N. Eur. J. Org. Chem. 2007, 5969–5994.
11. Christoffers, J.; Baro, A. Quaternary Stereocenters, Challenges and Solutions for
Organic Synthesis; Wiley-VCH: Weinheim, 2005.
12. Denissova, I.; Barriault, L. Tetrahedron 2003, 59, 10105–10146.
13. Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37, 388–401.
14. Sano, S.; Tsumura, T.; Tanimoto, N.; Honjo, T.; Nakao, M.; Nagao, Y. Synlett
2010, 256–260.
15. Jung, B.; Kang, S. H. Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 1471–1475.
16. Jung, B.; Hong, M. S.; Kang, S. H. Angew. Chem., Int. Ed. 2007, 46, 2616–2618.
17. Harada, T.; Nakajima, H.; Ohnishi, T.; Takeuchi, M.; Oku, A. J. Org. Chem. 1992,
57, 720–724.
18. Chênevert, R.; Courchesne, G.; Pelchat, N. Bioorg. Med. Chem. 2006, 14, 5389–
5396.
19. Chênevert, R.; Duguay, D.; Touraille, F.; Caron, D. Tetrahedron: Asymmetry 2004,
15, 863–866.
20. Chênevert, R.; Simard, M.; Bergeron, J.; Dasser, M. Tetrahedron: Asymmetry
2004, 15, 1889–1892.
(c 1.09, CHCl3); the absolute configuration was established by cor-
relation with 2-isopropenylglycerol monoacetate of known abso-
lute configuration.20 Compound (S)-5d (from enzymatic
hydrolysis, ee = 98%): ½a D22
¼ þ29:1 (c 1.30, CHCl3).
ꢂ
Compounds 4e–5e: Chiral HPLC analysis on a Chiralcel OJ-H col-
umn; (R)-4e (from enzymatic hydrolysis, ee = 94%): ½a D22
¼ þ5:9 (c
ꢂ
1.03, CHCl3), lit.17 (R)-4e: ½a D22
¼ þ4:5 (c 2.51, CHCl3); (R)-5e (from
ꢂ
enzymatic hydrolysis, ee = 94%): ½a D22
¼ ꢁ18:7 (c 1.00, CHCl3).
ꢂ
Compounds 4f–5f: Chiral HPLC analysis on a (S,S)Whelk-O1 col-
umn; (S)-4f (from enzymatic acylation, ee = 96%): ½a D22
¼ ꢁ2:3 (c
ꢂ
2.57, CHCl3); the absolute configuration of 4f was tentatively as-
signed by close similarity of its structure and chiral HPLC chro-
matogram with that of 4e. Compound (S)-5f (from enzymatic
acylation, ee = 92%): ½a D22
¼ þ17:9 (c 1.51, CHCl3).
ꢂ
21. Chênevert, R.; Caron, D. Tetrahedron: Asymmetry 2002, 13, 339–342.
22. Chen, S. T.; Fang, J. M. J. Org. Chem. 1997, 62, 4349–4357.
23. Hof, R. P.; Kellogg, R. M. J. Org. Chem. 1996, 61, 3423–3427.
24. Wirz, B.; Barner, R.; Hübscher, J. J. Org. Chem. 1993, 58, 3980–3984.
25. Watanabe, N.; Sugai, T.; Ohta, H. Chem. Lett. 1992, 657–660.
26. Sodeoka, M.; Yamada, H.; Shibasaki, M. J. Am. Chem. Soc. 1990, 112,
4906–4911.
Compounds 4g–5g: Chiral HPLC analysis on a Chiralcel OJ-H col-
umn; (S)-4g (from enzymatic hydrolysis, ee = 94%): ½a D22
¼ þ7:7 (c
ꢂ
1.65, CHCl3), lit.17 (R)-4g: ½a D22
¼ ꢁ6:5 (c 1.34, CHCl3); (S)-5g (from
ꢂ
enzymatic hydrolysis, ee = 94%): ½a D22
¼ ꢁ10:9 (c 1.00, CHCl3).
ꢂ
27. Chrystal, E. J. T.; Haines, A. H.; Patel, R. Carbohydr. Res. 1989, 186, 320–325.
28. (a) Sih, C. J.; Wu, S. H. Resolution of Enantiomers via Biocatalysis In Topics in
Stereochemistry; Eliel, E. L., Wilen, S. H., Allinger, N. L., Eds.; Wiley: New York,
1989; Vol. 19, pp 63–125; (b) For a website see: http://www.orgc.tugraz.at/ (by
Faber, K.; Hönig, H.; Kleewein, A., 2006).
29. (a) Chênevert, R.; Lévesque, C.; Morin, P. J. Org. Chem. 2008, 73, 9501–9503; (b)
Chênevert, R.; Jacques, F.; Giguère, P.; Dasser, M. Tetrahedron: Asymmetry 2008,
19, 1333–1338; (c) Morgan, B.; Dodds, D. R.; Zaks, A.; Andrews, D. R.; Kleese, R.
J. J. Org. Chem. 1997, 62, 7736–7743.
Acknowledgement
We acknowledge the financial support of this work by the Nat-
ural Sciences and Engineering Research Council of Canada (NSERC).
References
30. Monneret, C.; Florent, J. C. Synlett 1994, 305–318.
31. Jeong, B. S.; Lee, J. W.; Son, H. J.; Kim, B. Y.; Ahn, S. K. Tetrahedron: Asymmetry
2005, 16, 3795–3801.
32. Bornscheuer, U. T.; Kazlauskas, R. J. Hydrolase in Organic Chemistry; Wiley-VCH:
Weinheim, 2006. pp 113–116.
33. Kraus, G. A.; Kempema, A. Synthesis 2010, 389–391.
34. You, Z.; Hoveyda, A. H.; Snapper, M. L. Angew. Chem., Int. Ed. 2009, 48, 547–550.
35. Avenoza, A.; Cativiela, C.; Peregrina, J. M.; Sucunza, D.; Zurbano, M. M.
Tetrahedron: Asymmetry 2001, 12, 1383–1388.
1. Dibenedetto, A.; Angelini, A.; Aresta, M.; Ethiraj, J.; Fragale, C.; Nocito, F.
Tetrahedron 2011, 67, 1308–1313.
2. Garcia, J. I.; Garcia-Marin, H.; Mayoral, J. A.; Perez, P. Green Chem. 2010, 12,
426–434.
3. Gu, Y.; Jérôme, F. Green Chem. 2010, 12, 1127–1138.
4. Zhou, C. H.; Beltramini, J. N.; Fan, Y. X.; Lu, G. Q. Chem. Soc. Rev. 2008, 37, 527–
549.
5. Behr, A.; Eilting, J.; Irawadi, K.; Leschinski, J.; Lindner, F. Green Chem. 2008, 10,
13–30.
36. Hale, K. J.; Manaviazar, S.; Peak, S. A. Tetrahedron Lett. 1994, 35, 425–428.
37. Florent, J. C.; Ughetto-Monfrin, J.; Monneret, C. J. Org. Chem. 1987, 52, 1051–
1056.
6. Pagliaro, M.; Ciriminna, R.; Kimura, H.; Rossi, M.; Della Pina, C. Angew. Chem.,
Int. Ed. 2007, 46, 4434–4440.
7. Kourist, R.; Bornscheuer, U. T. Appl. Microbiol. Biotechnol. 2011, 91, 505–517.