Ruthenium- and lipase-catalyzed DYKAT of 1,2-diols: an enantioselective synthesis of syn-1,2-diacetates

Article abstract of DOI:10.1016/j.tetasy.2006.02.011

Regio- and stereoselective lipase-catalyzed kinetic resolutions were investigated for some unsymmetrical, secondary/secondary syn-diols. Candida antarctica lipase B-catalyzed transesterifications of a few aryl/alkyl- and alkyl/alkyl 1,2-diols were coupled

Full text of DOI:10.1016/j.tetasy.2006.02.011

Tetrahedron: Asymmetry 17 (2006) 708–715
Ruthenium- and lipase-catalyzed DYKAT of 1,2-diols:
an enantioselective synthesis of syn-1,2-diacetates
Michaela Edin, Bel e´ n Mart ´ı n-Matute and Jan-E. B a¨ ckvall*
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden
Received 5 December 2005; accepted 10 February 2006
Abstract—Regio- and stereoselective lipase-catalyzed kinetic resolutions were investigated for some unsymmetrical, secondary/
secondary syn-diols. Candida antarctica lipase B-catalyzed transesterifications of a few aryl/alkyl- and alkyl/alkyl 1,2-diols were
coupled in one-pot for efficient ruthenium-catalyzed epimerization and intramolecular acyl migration to give a dynamic kinetic
asymmetric transformation (DYKAT) affording enantioenriched (ee up to >99%) syn-diacetates as the main diastereomers (syn:anti
ꢀ
2:1 to 10:1).
ꢀ
2006 Elsevier Ltd. All rights reserved.
1
. Introduction
etate.7 More recently, Lee and Ley screened seven
lipases (CALB not included) for the regioselective pro-
tection of syn-1a of the alcohol next to the phenyl
Chiral vicinal diols are important building blocks in
enantioselective synthesis. Highly enantioenriched syn-
8
group.
1
,2-diols are readily available by the Sharpless asymmet-
1
ric dihydroxylation (AD). Alternative ‘greener’ proto-
cols for the latter transformation are available, which
employ environmentally benign terminal oxidants, such
as hydrogen peroxide or molecular oxygen. Another
entry to enantioenriched diols is provided by lipase-
catalyzed resolution of racemic diols. Amongst the
structures containing the 1,2-diol motif, lipases have
been extensively used for selective protection and depro-
Kinetic resolutions are limited to a maximum yield of
50% of enantiopure product. In a kinetic asymmetric
transformation (KAT) of a diastereomeric 1:1 syn:anti
mixture, the maximum theoretical yield of one enantio-
mer is 25%. This is a severe drawback, and methods to
improve the yield of these reactions are of great impor-
tance. We recently reported on different types of
dynamic kinetic asymmetric transformations (DYKAT)
of symmetrically and unsymmetrically substituted 1,3-
2
3
4
tection in carbohydrates and terminal 1,2-diols, regio-
selective reactions of glycerides, and sequential
resolutions of symmetrical diols. However, neither nor-
5
9
and 1,4-diols. In the case of unsymmetrical 1,3-diols,
6
the DYKAT procedure relies on an intramolecular acyl
migration in an intermediate monoacetate. An efficient
approach toward enantiopure syn-1,2-diols would be
to combine a lipase-catalyzed transesterification, a
ruthenium-catalyzed epimerization, and an intramole-
cular acyl migration. Unsymmetrical diol 1 would be acyl-
ated by the enzyme preferentially at the hydroxyl group
closest to the small substituent (Scheme 1). In the pres-
ence of a ruthenium catalyst, epimerization should occur
and all of 1 would be transformed to 2, in which one
stereocenter is defined. If acyl migration in the syn-diol
monoacetate of 2 is favored over migration in the corre-
sponding anti-diol monoacetate, acetyl migration under
dynamic conditions will give only 3. Subsequently, 3
would be acylated again by the enzyme at the alcohol
released to give enantiopure syn-diacetate 4.
mal nor sequential lipase-catalyzed resolutions of
unsymmetrical acyclic vic-diols with two stereogenic
centers seem to have been much explored. To the best
of our knowledge, there are only two reports on the
kinetic resolution of 1-phenyl-1,2-propanediol 1a and
neither uses Candida antarctica lipase B (CALB). Kim
et al. performed the transesterification of anti-1a
using Pseudomonas cepacia lipase to obtain at 53% con-
version of one major monoacetate and one minor diac-
*
Corresponding author. Tel.: +46 8 6747178; fax: +46 8 154908;
e-mail: jeb@organ.su.se
Present address: Universidad Aut o´ noma de Madrid, Spain.
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.02.011

M. Edin et al. / Tetrahedron: Asymmetry 17 (2006) 708–715
709
lipase,
acyl migr.,
OH
OH
OAc
OAc
[Ru]
[Ru]
lipase
S
S
S
S
L
L
L
L
OH "dynamic
process"
OAc "dynamic
process"
OH
OAc
1
2
3
4
Scheme 1. DYKAT of unsymmetrical acyclic 1,2-diols containing one large substituent (L) and one small substituent (S).
Acyl migration in related 1,2-diols is an often observed
phenomenon and has been observed to occur, for exam-
From a controlled experiment, in which racemic syn-
monoacetate 3a was subjected to kinetic resolution, it
was concluded that the second acylation is somewhat
slower than the first acylation (29% diacetate in 70 min).
1
0
ple, during hydrolysis of terminal 1,2-diols and in
1
1
mono- and diglycerides, thus hampering the regio-
selectivity of lipases.
2.2. Ruthenium-catalyzed epimerization
Next, epimerization of racemic syn-diols 1 was success-
1
3
2
. Results and discussion
fully effected by ruthenium complex 5. This is a pre-
catalyst, which is best activated by t-BuOK. We recently
reported racemization of secondary alcohols catalyzed
by 5, in combination with lipase-catalyzed kinetic reso-
lution in a very efficient dynamic kinetic resolution
2
.1. Enzymatic transesterification
Enzymatic acylation of rac-syn-1a using CALB and iso-
propenyl acetate was studied in toluene at 50 ꢁC
Scheme 2). Surprisingly, not only monoacetate 2a
1
4
(DKR) operating at room temperature. Table 2 shows
that under the conditions employed for transesterifi-
cation of 1a (50 ꢁC, 0.5 M substrate concentration),
epimerization of diols 1a and 1b occurs easily (Table
2, entries 1 and 2). Efficient epimerization of diol 1c
required slightly more of catalyst 5 (3 mol %) and a
higher temperature (entry 3). In contrast, aliphatic diol
1d epimerized even at room temperature (entry 4).
Epimerization of diols 1e and 1f was performed at
50 ꢁC because of their low solubility in toluene at room
temperature (entries 5–6). The diastereomeric ratios
remained unchanged after prolonged reaction times.
The threo isomers are the thermodynamically most sta-
ble ones. In agreement with our mechanistic investiga-
(
formed, but also monoacetate 3a and the two monoace-
tates 2a and 3a in a ca. 3:1 ratio. At higher conversion,
small amounts of diacetate 4 were also observed. The
formation of 3a should occur via direct enzymatic acyl-
ation of the inner alcohol, since in a controlled experi-
ment it was shown that CALB does not catalyze any
significant acyl migration. The selectivity of acylation
at the inner alcohol is high and follows Kazlauskas’ rule.
For example, at 42% conversion (60 min) 3a was ob-
tained in 11% yield and 96% ee. At this conversion, no
diacetate 4a was formed.
1
2
1
5
In contrast, the formation of major monoacetate 2a is
less selective. At 13% conversion (24 min), 2a was ob-
tained in 10% yield and ꢀ86% ee (along with 3% yield
of 3a), which corresponds to E ꢀ14 (Table 1, entry 1).
Kinetic resolutions of a few more diols were investi-
gated. Interestingly, the ratio for 2:3 was significantly
larger for substrates rac-syn-1b (Table 1, entry 2), rac-
syn-1c (entry 3), and rac-syn-1d (entry 4). Acetate 2b
was obtained in 96% ee. Diol rac-syn-1e (entry 5)
behaved the same as 1a.
tions of the racemization process, analysis by NMR
spectroscopy showed only trace amounts of ketones.
Ph
Ph
Ph
[Ru] =
Ph
Ph
Ru
Cl
OC
CO
5
A prolonged reaction time was required for consecutive
acetylations to diacetate to occur (Scheme 2). The trans-
formation to diacetate is a KAT. After 21 h, 7% of 4a
was produced. Carrying out the reaction in the presence
of sodium carbonate (1 equiv) led to a faster production
of diacetate.
2
.3. Intramolecular acyl migration
To obtain information about the rate of acyl migration,
this process was studied separately. When syn-diol
monoacete rac-2a was heated in deuterated toluene at
1
6
50 ꢁC, no acyl migration occurred. Acyl transfer of
OH
OH
OAc
OAc
CALB
+
Ph
Ph
Ph
Ph
o
PhMe, 50 C
OAc
OH
syn-1a
OAc
2a
OH
OAc
rac
-
3a
4a
only observed at
long reaction times
3
:
1
Scheme 2. Kinetic asymmetric transformation of rac-syn-1a.

710
M. Edin et al. / Tetrahedron: Asymmetry 17 (2006) 708–715
a
Table 1. Kinetic resolution of syn-diols
OH
OH
OAc
lipase
R2
OH
rac-syn-1
R2
R2
R1
R1
+
R1
o
PhMe, 50 C
OAc
OAc
OH
2
3
1
2
b
c
d
Entry
Diol
R
R
Time (min)
Yield (%)
ee (%)
ꢀE
2
3
2
3
2
3
e
f
f
1
2
3
4
5
rac-syn-1a
rac-syn-1b
rac-syn-1c
rac-syn-1d
rac-syn-1e
Ph
n-Pentyl
Ph
n-Butyl
p-OMePh
Me
Me
CO
Et
24
7
210
20
24
10
20
26
10
13
3
86
96
n.d.
>92
86
96
14
61
n.d.
>26
15
n.c.
n.c.
3.8
3.4
n.d.
n.d.
n.d.
n.d.
g
2
Me
n.d.
n.d.
n.d.
h
i
1
Me
3
a
Isopropenyl acetate (3 equiv) was added to a mixture of diol and CALB (20 mg/mmol 1) in toluene (2 mL/mmol 1) and the reaction stirred at 50 ꢁC
under argon.
b
c
Determined by NMR.
ee measured by chiral GC or HPLC after separation by flash column chromatography and chemical acetylation to diacetate.
Since this is a parallel kinetic resolution, the E values are not readily calculated from the data. For the larger component, the E-value was estimated
d
as if it were an ordinary kinetic resolution.
Measured at 42% conversion.
n.c. = not calculated.
PCL ‘Amano’ II (80 mg/mmol 1) was used.
At 20% conversion (30 min) still only 1% 3d was detected.
Regioisomers 2d and 3d are inseparable on silica, hence the ee determination of 2d is disturbed by the small traces of 3d.
e
f
g
h
i
a
Table 2. Epimerization of syn-1
OH
OAc
Na CO3
2
OH
OH
R2
[Ru],
t
-BuOK
R2
R1
OAc
rac-2a
o
R1
PhMe-D , 50 C
OH
8
OH
rac-3a
OH
PhMe, Temp., 1 h
OH
OAc
1
2
1
1
1
1
1
1
a R = Ph, R = Me
Na CO3
2
1
2
b R =
n
-Pentyl, R = Me
OAc
rac-6a
o
1
2
PhMe-D , 50 C
OH
c R = Ph, R = CO Me
8
2
1
2
d R =
n
-Butyl, R = Et
rac-7a
1
2
e R =
p
-OMePh, R = Me
Scheme 3. Acyl migration in racemic syn- and anti-diol monoacetates.
f 1,2,3,4-tetrahydro-naphthalene-1,2-diol
b
Entry
Diol
Temp (ꢁC)
dr (syn/anti)
ratio remained constant showing that the acyl migration
had reached equilibrium.
c
1
1a
1b
1c
1d
1e
1f
50
50
80
rt
50
50
2:1
3:2
3:1
2:1
2:1
2
3
d
The DYKAT process outlined in Scheme 1 relies on a
4
5
6
faster acyl migration in the syn-diol monoacetate than
1
7
in the anti-diol monoacetate. The relative rate of acyl
migration in syn-diol monoacetate 2a and anti-diol
monoacetate 6a was therefore compared. The anti-deriv-
ative rac-6a was heated in toluene at 50 ꢁC in the pres-
ence of carbonate, as described for rac-2 above. The
ratios 3a/2a and 7a/6a from the two experiments,
respectively, were calculated and plotted as a function
of time (Fig. 1). This study shows that the acyl transfer
in syn-derivative 2a is almost three times as fast as in the
anti-derivative 6a.
e
f
5:2
a
Unless otherwise noted, t-BuOK (0.5 M in THF, 2 mol %) was added
to a solution of [Ru] (1 mol %) in toluene (1 mL). After 6 min, a
solution of diol 1 (1 mmol) in toluene (1 mL) was added and the
mixture was stirred and heated at the temperature indicated under an
argon atmosphere.
b
c
d
e
f
1
Diastereomeric ratio measured by H NMR.
2
3
2
mol % [Ru] and 4 mol % t-BuOK.
mol % [Ru] and 6 mol % t-BuOK.
mL of toluene was used because of the poor solubility of diol 1f.
After 16 h dr = 5:4.
2
.4. DYKAT of 1,2-diols
rac-2a was, however, observed in a similar experiment
run in the presence of 1 equiv of sodium carbonate
DYKAT of diol 1a was studied with 5 mol % of 5 and
5 mol % t-BuOK and in the presence of Na CO . After
2
3
(
Scheme 3); after 4 h, rac-2a:rac-3a = 57:43 and this
24 h, all of the diol had been consumed and ꢀ38% diac-

M. Edin et al. / Tetrahedron: Asymmetry 17 (2006) 708–715
711
0
0
0
0
0
0
0
0
.8
.7
.6
.5
.4
.3
.2
.1
0
of base to activate pre-catalyst 5 depended on the
amount of enzyme employed as well as the substrates
1
4
and hence, had to be optimized for each entry. The
acyclic diol 1b gave a high yield of diacetate 4 as a 2:1
syn:anti mixture (Table 4, entry 2). Both diastereoiso-
mers were of high ee. Interestingly, diol 1d mainly gave
syn-diacetate 4d (syn:anti = 10:1) in the DYKAT (entry
3) in high ee. The high diastereoselectivity obtained for
this diol in the DYKAT is explained by a more regio-
selective enzymatic acylation of the alcohol next to the
ethyl substituent together with a more syn-selective acyl
migration in the intermediate monoacetate. Diol 1e with
a p-methoxy on the aryl group also worked well in the
DYKAT and afforded diacetate 4d in a 2:1 syn:anti mix-
ture in high ee (entry 4). The non-optimized result
obtained for cyclic 1,2-diol 1f indicates a lower
diastereoselectivity for such substrates (entry 5). Kinetic
resolution of rac-syn-1f produced equimolar amounts of
regioisomeric monoacetates 2. The p-bromo substituted
diol 1g gave by use of 10 mol % t-BuOK only 61% diac-
etate 4g after 76 h (entry 6a). The reaction mixture in
this experiment turned green, indicating the decomposi-
tion of the ruthenium catalyst. When the amount of base
was raised to 11 mol %, the reaction mixture remained
an orange-color, indicating an active metal catalyst.
However, a more chemically acetylated product was ob-
tained (dr = 6:5 and 81% ee, entry 6b).
syn
anti
0
5
10
15
time (h)
Figure 1. Acyl migration in syn- versus anti-diol monoacetes. Ratios
a:2a (syn) and 7a:6a (anti) are plotted.
3
etate (of syn/anti ꢀ2:1) was obtained (Table 3, entry 1).
The reaction went to completion after a prolonged reac-
tion time (entry 2). An increased amount of enzyme gave
a faster reaction (entries 3 and 4). DYKAT run as in
entry 4, but at 70 ꢁC gave a similar result where the
1
H NMR spectroscopy indicated a somewhat greater
amount of ketones formed (not shown in the table).
That the system is sensitive to water is clearly demon-
strated in entries 5 and 6 where even more enzyme was
used, hence more water in the system, and a slow reac-
tion with lower ee was obtained. The higher dr of 4a is
further evidence that epimerization was inhibited, as
the starting material was pure syn-diol.
3. Conclusion
The long reaction time required for the quantitative for-
mation of diacetate in KAT and DYKAT seems to be
due to a combination of a slow acyl transfer and a not
very fast second acylation. The low dr obtained in DY-
KAT is ascribed to acyl migration in the anti-diol mono-
acetate (obtained from epimerization of 2a) and to the
formation of the monoacetate at the benzylic position
In conclusion, CALB-catalyzed transesterification of 1
has been demonstrated. Regioselective kinetic resolu-
tion, in combination with an intramolecular acyl migra-
tion and an efficient ruthenium-catalyzed epimerization
enantioselectively transforms a mixture of four diol iso-
mers in one-pot to diacetate in moderate to excellent
yield and enantioselectivity and in moderate to good
diastereoselectivity (ꢀ2:1–10:1). The present DYKAT
procedure provides a useful alternative to the Sharpless
AD reaction since the cost of ruthenium and CALB are
3
a with an (S)-configuration.
A few more diols were exposed to the DYKAT and the
results are summarized in Table 4. The required amount
1
8
not very high.
a
Table 3. DYKAT of 1-phenyl-1,2-propanediol
[Ru], t-BuOK,
OH
OAc
OAc
CALB, Na CO3
2
+
o
OH
rac-syn-1a
Enzyme (mg/mmol) t-BuOK (mol %)
PhMe, 50 C
OAc
OAc
OAc
syn-4a
anti-4a
b
b
b
c
Entry
Time (h)
% Conv.
% 4a
dr (syn:anti)
% ee (syn:anti)
1
2
3
4
5
6
6
6
20
20
60
60
5
5
8
8
5
5
24
12 d
24
72
20
100
100
100
100
100
100
ꢀ38
100
2:1
2:1
2:1
2:1
6:1
3:1
n.d.
99, >99
n.d.
98, 99
n.d.
72, n.d.
ꢀ67
100
<50
ꢀ60
44
a
2 3
Ru-catalyst 5 (5 mol %), CALB, Na CO (1 mmol), and t-BuOK were stirred in toluene (1 mL) for 6 min before adding the alcohol (1 mmol) in
toluene (1 mL). After 4 min, isopropenyl acetate (3 mmol) was added and the mixture stirred under an argon atmosphere at 50 ꢁC.
Determined by NMR.
Measured by chiral GC.
b
c

712
M. Edin et al. / Tetrahedron: Asymmetry 17 (2006) 708–715
a
Table 4. DYKAT of 1,2-diols
b
c
d
Entry
1
Substrate
OH
Product
OAc
t-BuOK (mol %)
Time (h)
72
Yield (%)
dr (syn:anti)
ee (syn, anti)
8
95
2:1
2:1
98, 99
96, 99
OH
OAc
1a
4a
OH
OAc
e
2
6
41
95
OH
4b
OAc
1b
f
OH
OAc
3
3
a
8
9
142
120
87
10:1
8:1
>99, >99
>99, >99
g
1
d
OH
4b
OAc
OAc
b
95 (87)
OH
4
5
9
9
72
65
77 (77)
26 (24)
2:1
7:5
98, 99
OH
OAc
MeO
MeO
4
e
1
e
OH
OAc
OH
OAc
>99, ꢀ30
1f
4f
OH
OAc
6
a
10
11
76
73
61 (61)
71 (66)
2:1
6:5
90, n.d.
81, n.d.
OH
OAc
Br
Br
1g
4g
6
b
a
2 3
Ru-catalyst 5 (5 mol %), CALB (20 mg), Na CO (1 mmol), and t-BuOK were stirred in toluene (1 mL) for 6 min before adding the alcohol
(
1 mmol) in toluene (1 mL). After 4 min, isopropenyl acetate (3 mmol) was added and the mixture stirred under an argon atmosphere at 50 ꢁC.
b
c
d
e
f
Determined by NMR or GC. Isolated yield in parenthesis.
Diastereomeric ratio measured by NMR or GC.
Enantiomeric excess determined by chiral GC or HPLC.
CALB: 6 mg.
THF from the t-BuOK solution was not evaporated, CALB: 12 mg.
CALB: 12 mg.
g
1
4. Experimental
benzaldehyde followed by dihydroxylation. H NMR
2
0
21
22
23
data of 1a, 1b, 1c, and 1e were in agreement with
4
.1. Reagents and materials
those reported in the literature. Racemic monoacetate
2
4
6
a was prepared by epoxidation and subsequent alka-
2
5
Unless otherwise noted, all reactions were carried out
under a dry argon atmosphere in flame-dried glassware.
Solvents were purified by standard procedures. Isopro-
penyl acetate was stirred over K CO overnight, dried
over CaCl2 and distilled under argon. C. antarctica
lipase B (CALB) was used as immobilized and thermo-
stable Novozyme 435. P. cepacia (PCL) was used as
immobilized PS-C Amano II. The enzymes were stored
in a sealed container with a saturated aqueous solution
of LiCl for a minimum of 24 h. Ruthenium complex 5
line hydrolysis of trans-b-methylstyrene, followed by
chemical monoacylation.
˚
Flash chromatography was carried out either on 60 A
2
3
1
(35–70 lm) silica gel or on an automated system. H
1
3
and
C NMR spectra were recorded at 400 or
300 MHz and at 100 or 75 MHz, respectively. Chemical
shifts (d) are reported in parts per million, using the
residual solvent peak in CDCl (dH 7.26 and d 77.00)
3
C
as internal standard, while coupling constants (J) are
given in hertz. Enantiomeric excess was determined by
analytical gas chromatography employing a CP-Chira-
sil-Dex CB column and temperature programming as
indicated below, or by HPLC employing a Daicel Chi-
1
4b
was prepared as previously reported. Diols 1a–f were
1
9
synthesized by osmium-catalyzed dihydroxylation of
commercially available alkenes, and diol 1g was pre-
pared by Wittig olefination of commercial p-bromo-

M. Edin et al. / Tetrahedron: Asymmetry 17 (2006) 708–715
713
ralcel OD-H column or a Daicel Chiralpak AS column
4.3. Kinetic resolution of syn-1,2-diols
along with solvents and flow rates as noted, using race-
mic and diastereomeric mixtures as references.
To a stirred mixture of diol 1a (152 mg, 1.0 mmol) and
CALB (20 mg) in toluene (2 mL) was added isopropenyl
acetate (332 lL, 3.0 mmol) and the reaction then heated
in an oil bath at 50 ꢁC. After 24 min, the reaction mix-
ture was filtered. The solvents were evaporated under re-
4
1
.2. Preparation of stereoisomeric mixtures of 1,2-diols:
-(4-bromophenyl)-propane-1,2-diol 1g
1
n-BuLi (1.6 M in hexane, 38 mL, 60.5 mmol) was added
dropwise to a stirred, white suspension of ethyltriphen-
ylphosphonium bromide (22.5 g, 60.5 mmol) in THF
duced pressure. H NMR showed 10% of monoacetate
2a and 3% of monoacetate 3a. Regioisomers 2a and 3a
were separated by flash chromatography. Enantiomeric
excess was determined after conversion into diacetates.
(
84 mL) at À5 ꢁC. The mixture turned red upon the
addition. After 1 h 40 min at À5 ꢁC, p-bromobenzalde-
hyde (9.33 g, 50.4 mmol) in THF (84 mL) was added
via cannula. The cooling bath was removed and the
reaction then allowed to reach room temperature. After
To a stirred solution of monoacetate 2a (17.7 mg,
0.091 mmol), DMAP (cat.), and triethylamine (0.127
mL, 0.91 mmol) in CH Cl (0.8 mL), acetic anhydride
2
2
2
5 h, the reaction was quenched by the addition of brine
(43 lL, 0.46 mmol) was added. The reaction was stirred
at rt overnight. TLC showed complete conversion and
the reaction mixture was treated with MeOH (five
drops). The mixture was diluted with CH Cl and was
and extracted with toluene. The combined organic
phases were washed with water and brine, dried over
MgSO , and concentrated. The resulting suspension
4
2
2
was diluted in Et O and the insoluble material was
removed by filtration. Evaporation of the solvent and
washed with 1 M aq HCl. The water phase was ex-
tracted with CH Cl and the organic phase was washed
2
2
2
flash chromatography of the oily residue gave a cis/
trans-mixture of 4-bromo-b-methylstyrene as a color-
with saturated aq NaHCO , water, and brine. After dry-
3
2
6
1
ing over MgSO and evaporation of solvent, H NMR
4
less oil (7.55 g, 76%).
showed pure diacetate 4a. Chiral GC: ee = 86%.
To a stirred solution of 4-bromo-b-methylstyrene
4.4. Epimerization of syn-1,2-diols
(
7.54 g, 38.3 mmol) and 4-methylmorpholine N-oxide
monohydrate (5.33 g, 38.3 mmol) in acetone/H O 3:1
2
To a Schlenk flask containing Ru complex 5 (6.5 mg,
.01 mmol) in toluene (1 mL) was added a solution of
(
40 mL), OsO (2.5 wt % solution in 2-methyl-2-propa-
4
0
nol, 4.80 mL, 0.38 mmol) was added at room tempera-
ture. The weak exotherm was controlled by a water
bath. The reaction was stirred under air overnight.
Sodium dithionite (2.3 g) and Mg-silicate (4.6 g) were
added and the mixture stirred for another 2.5 h before
it was filtered through Celite, which was then washed
with EtOAc. The filtrate was washed with brine and
the water layer was extracted with EtOAc. The
organic phase was concentrated under reduced
pressure. Flash chromatography of the residue afforded
diol 1g as a highly viscous oil (6.73 g, 76%, syn/anti =
t-BuOK (0.5 M in THF, 40 lL, 0.02 mmol) under an
argon atmosphere. After 6 min, a solution of rac-syn-
diol 1b (146 mg, 1.0 mmol) in toluene (1 mL) was added.
The reaction mixture was then heated in an oil bath at
5
0 ꢁC and samples were collected under a rigorous argon
1
atmosphere and were analyzed by H NMR.
4.5. General procedure for DYKAT
A solution of t-BuOK (0.5 M in THF, 180 lL,
0.09 mmol) was added to a 10 mL Schlenk flask. THF
was carefully removed under reduced pressure and the
flask was then filled with argon. Ru-catalyst (32 mg,
0.05 mmol), CALB (12 mg), and Na CO (106 mg,
2
7
1
6
2
0
0
0
3
:5 ). H NMR (300 MHz, CDCl ) d 7.46–7.51 (m,
3
H), 7.19–7.21 (m, 2H), 4.65 (app t, J = 3.7 Hz,
.45H), 4.34 (dd, J = 7.4, 3.3 Hz, 0.55H), 3.99 (m,
.45H), 3.80 (m, 0.55H), 2.77 (br d, J = 3.3 Hz,
.55H), 2.50 (br d, J = 3.6 Hz, 0.45H), 2.44 (br d, J =
.8 Hz, 0.55H), 1.95 (br d, J = 4.9 Hz, 0.45H), 1.05
2
3
1.0 mmol) were added quickly. The flask was evacuated
and filled with argon. Toluene (1 mL) was introduced
and the mixture was stirred for 6 min. Then rac-syn-diol
1d (146 mg, 1.0 mmol) in toluene (1 mL) was added, and
after 4 min isopropenyl acetate (332 lL, 3.0 mmol) was
added. After this, the reaction was heated in an oil bath
at 50 ꢁC and stirred for 120 h before the mixture was fil-
tered through Celite. The filter cake was washed with
EtOAc (25 mL) and the filtrate was concentrated and
analyzed by chiral GC (80 ꢁC cte. for 3 min then 3 ꢁC/
min to 140 ꢁC): 95% GC-yield, syn:anti = 8:1, ee (syn)
1
3
(
(
2 · d, 3H); C NMR (75 MHz, CDCl ) major isomer
syn): d 140.0, 131.6, 128.5, 121.9, 78.7, 72.0, 18.7; minor
3
isomer (anti) d: 139.2, 131.3, 128.3, 121.6, 76.6, 71.1,
1
6.9.
2
8
1
4
.2.1. syn-3,4-Octanediol 1d.
H NMR (300 MHz,
CDCl ) d 3.39–3.47 (m, 1H), 3.30–3.38 (m, 1H), 1.97
3
(
br s, 2H), 1.21–1.67 (m, 8H), 0.99 (t, J = 7.5 Hz, 3H),
0
.92 (t, J = 6.9 Hz, 3H).
>
99%, ee (anti) >99% [t (major) = 12.2 min, t (mi-
syn syn
4
1
1
.2.2. syn-1,2,3,4-Tetrahydro-1,2-dihydroxynaphthalene
2
nor) = 11.5 min, tanti(major) = 11.1 min, tanti(minor) =
3
1
f.
H NMR (400 MHz, CDCl ) d 7.42–7.47 (m,
10.9 min]. Flash chromatography furnished dia-
3
2
9
1
H), 7.21–7.28 (m, 2H), 7.11–7.16 (m, 1H), 4.71 (dd,
cetate 4d as an oil (200 mg, 87%). H NMR (300
J = 5.6, 4.1 Hz, 1H), 4.03 (m, 1H), 2.93–3.02 (m, 1H),
.75–2.85 (m, 1H), 2.29 (d, J = 6.9 Hz, 1H), 2.25
d, J = 5.9 Hz, 1H), 2.00–2.11 (m, 1H), 1.90–1.98 (m,
H).
MHz, CDCl ) syn/anti-mixture: d 4.88–4.98 (m, 1H),
4.99–5.06 (m, 1H), 2.08 (d, J = 2.5 Hz, 5.3H), 2.04 (d,
3
2
(
1
J = 2.7 Hz, 0.7H), 1.21–1.62 (m, 8H), 0.89 (m, 6H);
1
3
C NMR (75 MHz, CDCl ) major isomer: d 170.6,
3

714
M. Edin et al. / Tetrahedron: Asymmetry 17 (2006) 708–715
1
9
2
70.5, 75.1, 73.5, 30.4, 27.3, 23.8, 22.4, 20.9, 20.8, 13.8,
.6; minor isomer: d 170.7, 75.5, 73.9, 29.0, 27.6, 22.4,
1.0, 20.9, 13.9, 9.9 (two carbons are missing due to
Acknowledgments
Financial support from the Swedish Research Council,
the Swedish Foundation for Strategic Research and
the Ministereo de Educati o´ n y Ciencia of Spain is grate-
fully acknowledged.
overlapping with the major isomer).
3
0
4
.6. Characterization of products
References refer to previously reported spectral data of
known compounds.
References
syn/anti-1,2-Diacetoxy-1-phenylpropane 4a:31 1H NMR:
1
. Kolb, H. C.; VanNieuwenhenhze, M. S.; Sharpless, K. B.
9
5%, syn/anti ꢁ 2:1; chiral GC (80 ꢁC cte. for 30
Chem. Rev. 1994, 94, 2483–2547.
min then 2 ꢁC/min to 160 ꢁC): t (major) = 56.5 min,
2. (a) Jonsson, S. Y.; Adolfsson, H.; B a¨ ckvall, J.-E. Chem.
Eur. J. 2003, 9, 2783–2788; (b) Jonsson, S. Y.; F a¨ rne-
g a˚ rdh, K.; B a¨ ckvall, J.-E. J. Am. Chem. Soc. 2001, 123,
syn
t
(minor) = 56.3 min, tanti(major) = 55.0 min, tanti(mi-
syn
nor) = 55.2 min. The absolute configuration of the pure
syn diacetate 4a was established to be (R,R) from its spe-
cific rotation (negative rotation in chloroform). This is
in accordance with Kazlauskas’ rule.
1
365–1371; (c) Bergstad, K.; Jonsson, S. Y.; B a¨ ckvall,
3
2
J.-E. J. Am. Chem. Soc. 1999, 121, 10424–10425.
. (a) D o¨ bler, C.; Mehltretter, G. M.; Sundermeier, U.;
Beller, M. J. Am. Chem. Soc. 2000, 122, 10289–10297; (b)
D o¨ bler, C.; Mehltretter, G. M.; Beller, M. Angew. Chem.,
Int. Ed. 1999, 38, 3026–3028.
4. Bornscheuer, U. T.; Kazlauskas, R. J. Hydrolases in
Organic Synthesis. Regio- and Stereoselective Biotransfor-
mations; Wiley-VCH: Weinheim, 1999; pp 131–151.
3
syn/anti-2,3-Diacetoxyoctane 4b:33 chiral GC (120 ꢁC
cte. for 15 min): 95% yield, syn/anti = 2:1, tsyn(major) =
8
.5 min, tsyn(minor) = 8.3 min, tanti(major) = 7.6 min,
tanti(minor) = 7.8 min.
5
6
. Ref. 4, pp 156–167.
. Ref. 4, p 35 and references therein.
syn/anti-1,2-Diacetoxy-1-(4-methoxy-phenyl)-propane
3
4 1
7. Kim, M.-J.; Choi, G.-B.; Kim, J.-Y.; Kim, H.-J. Tetrahe-
dron Lett. 1995, 36, 6253–6256.
8
4
e: H NMR: 77% yield, syn/anti = 2:1; chiral HPLC
(
Chiralpak AS, iso-hexane/2-propanol 96:4, flow rate
. Lee, A.-L.; Ley, S. V. Org. Biomol. Chem. 2003, 1, 3957–
966.
0
3
.5 mL/min): tsyn(major) = 18.1 min, tsyn(minor) =
0.3 min, tanti(major + minor) = 16.5 min; chiral HPLC
3
9
. Symmetrical diols: (a) Persson, B. A.; Huerta, F. F.;
B a¨ ckvall, J.-E. J. Org. Chem. 1999, 64, 5237–5240;
Unsymmetrical 1,3-diols: (b) Edin, M.; Steinreiber, J.;
B a¨ ckvall, J.-E. Proc. Natl. Acad. Sci. U.S.A. 2004, 101,
(
Chiralcel OD-H, iso-hexane/2-propanol 99.5:0.5, flow
rate 0.5 mL/min): tanti(major) = 28.6 min, tanti(minor) =
3
1.9 min, tsyn(major) = 34.3 min, tsyn(minor) = 36.0 min.
5
761–5766; Unsymmetrical 1,4-diols: (c) Mart ´ı n-Matute,
B.; B a¨ ckvall, J.-E. J. Org. Chem. 2004, 69, 9191–9195.
0. Bisht, K. S.; Kumar, A.; Kumar, N.; Parmar, V. S. Pure
Appl. Chem. 1996, 68, 749–752.
1. Bornscheuer, U. T.; Kazlauskas, R. J. Hydrolases in
Organic Synthesis; Wiley-VCH: Weinheim, 1999; pp 163–
cis/trans-1,2-Diacetoxy-1,2,3,4-tetrahydro-naphthalene
3
5
1
1
1
4
f:
H NMR: 26% yield, syn/anti = 7:5; chiral GC
(
80 ꢁC cte. for 30 min then 1.5 ꢁC/min to 170 ꢁC):
t
syn
(major) = 78.9 min, t (minor) = 79.5 min, t (major)
syn
anti
1
=
78.7 min, tanti(minor) = 78.3 min. H NMR (300 MHz,
1
64.
CDCl ) syn/anti-mixture: d 6.94–7.32 (m, 4H), 6.18 (d,
3
1
2. After 2 h <5% migration was observed. After prolonged
time a mixture of monoacetates, diol, and diacetate was
formed.
13. Csjernyik, G.; Bog a´ rt, K.; B a¨ ckvall, J. E. Tetrahedron
Lett. 2004, 45, 6799–6802.
J = 3.6 Hz, 0.58H), 6.07 (d, J = 5.9 Hz, 0.42H), 5.15–
5
2
.29 (m, 1H), 2.82–3.12 (m, 2H), 1.92–2.35 (m, 6H),
.11 (s, 1.26H), 2.10 (s, 1.74H), 2.05 (s, 1.74H), 2.04
1
3
(
s, 1.26H); C NMR (75 MHz, CDCl ) syn/anti-mix-
3
ture: d 170.5, 170.4, 170.3, 136.6, 136.6, 132.7, 132.1,
14. (a) Mart ´ı n-Matute, B.; Edin, M.; Bog a´ r, K.; B a¨ ckvall,
J.-E. Angew. Chem., Int. Ed. 2004, 43, 6535–6539; (b)
Mart ´ı n-Matute, B.; Edin, M.; Bog a´ r, K.; Kaynak, F. B.;
B a¨ ckvall, J.-E. J. Am. Chem. Soc. 2005, 127, 8817–
1
7
2
30.0, 129.0, 128.7, 128.7, 128.5, 128.2, 126.5, 126.4,
1.4, 71.0, 70.1, 69.3, 27.1, 25.7, 24.9, 23.3, 21.1, 21.1,
1.0 (two carbons are missing due to overlapping).
8
825.
1
1
5. Ref. 14b and unpublished results from this laboratory.
6. Samples were withdrawn and analyzed by H NMR up to
syn/anti-1,2-Diacetoxy-1-(4-bromo-phenyl)-propane 4g:
H NMR: 61% yield, syn/anti = 2:1; chiral HPLC (Chi-
ralcel OD-H, iso-hexane/2-propanol 98:2, flow rate
1
1
2
8 h.
1
7. A rough estimation of the energy in syn- versus anti-diol
monoacetates approximated to 1,2-substituted cyclopen-
tanes made in Chem3D gave a difference of 2 kcal/mol.
0
1
.5 mL/min): tsyn(major) = 15.5 min, tsy n1 (minor) =
9.1 min, tanti(major + minor) = 13.6 min. H NMR
(
300 MHz, CDCl ) syn/anti-mixture: d 7.18–7.26 (m,
18. DSM in the Netherlands has recently developed a large
scale industrial process for dynamic kinetic resolution
3
2
5
1
1
6
H), 7.46–7.53 (m, 2H), 5.83 (d, J = 4.4 Hz, 0.35H),
.70 (d, J = 7.1 Hz, 0.65H), 5.14–5.27 (m, 1H), 2.13 (s,
.05H), 2.08 (s, 1.95H), 2.02 (s, 1.95H), 2.00 (s,
.05H), 1.17 (d, J = 6.6 Hz, 1.05H), 1.09 (d, J =
(
DKR) of secondary alcohols based on a ruthenium
catalyst and CALB: Verzijl, G. K. M.; De Vries J. G.;
Broxterman, Q. B. WO 0190396 A1 20011129.
9. VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron
Lett. 1976, 17, 1973–1976.
0. Closson, A.; Johansson, M.; B a¨ ckvall, J.-E. Chem. Com-
mun. 2004, 1494–1495.
1
2
1
3
.6 Hz, 1.95H); C NMR (75 MHz, CDCl ) major
3
isomer (syn): d 170.1, 169.8, 135.9, 131.7, 129.0, 122.6,
7
1
1
6.6, 71.0, 21.0, 20.9, 16.4; minor isomer (anti) d: 170.1,
69.7, 135.6, 131.5, 128.7, 122.2, 75.5, 71.2, 21.0, 21.0,
4.8.
21. Moussou, P.; Archelas, A.; Furstoss, R. Tetrahedron 1998,
54, 1563–1572.

M. Edin et al. / Tetrahedron: Asymmetry 17 (2006) 708–715
715
2
2
2
2
2. Plietker, B.; Niggemann, M. J. Org. Chem. 2005, 70, 2402–
29. syn-rac-4d: Sicher, T. Collect. Czech. Chem. Commun.
1958, 23, 2081–2088.
30. The assignment of absolute configurations of syn- and
anti-diacetates is made based on the assumption that the
enantioselectivity in the enzymatic acetylation is dictated
by Kazlauskas’ rule.
2
405.
3. Superchi, S.; Casarini, D.; Summa, C.; Rosini, C. J. Org.
Chem. 2004, 69, 1685–1694.
4. Ley, S. V.; Mitchell, C.; Pears, D.; Ramarao, C.; Yu, J.-Q.;
Zhou, W. Org. Lett. 2003, 5, 4665–4668.
5. (a) Zioudrou, C.; Chrysochou, P.; Karabatsos, G. J.;
Herlem, D.; Nipe, R. N. Tetrahedron Lett. 1972, 13, 5293–
31. Fristad, W. E.; Peterson, J. R. J. Org. Chem. 1985, 50, 10–
18.
5
296; (b) Berti, G.; Macchia, B.; Macchia, F. Tetrahedron
32. Takeshita, M.; Miura, M.; Unuma, Y.; Iwai, S.; Sato, I.;
Hongo, T.; Arai, T.; Kosaka, K. Heterocycles 1996, 42,
831–836.
33. Uemura, S.; Ohe, K.; Fukuzawa, S.-I.; Patil, S. R.; Sugita,
N. J. Organomet. Chem. 1986, 316, 67–78.
34. Ono, M.; Ito, Y.; Ishikawa, T.; Kitajima, J.; Tanaka, Y.;
Niiho, Y.; Nohara, T. Chem. Pharm. Bull. 1996, 44, 337–
342.
35. (a) Boyd, D. R.; Sharma, N. D.; Boyle, R.; Malone, J. F.;
Chima, J.; Dalton, H. Tetrahedron: Asymmetry 1993, 4,
1307–1324; (b) Kasai, M.; Kawai, K.; Imuta, M.; Ziffer,
H. J. Org. Chem. 1984, 49, 675–679.
Lett. 1965, 6, 3421–3427.
2
2
6. Zhang, L.; Dolbier, W. R.; Sheeller, B.; Ingold, K. U. J.
Am. Chem. Soc. 2002, 124, 6362–6366.
7. The major diastereomer is tentatively assigned as the syn-
1
diol based on (1) the similar H NMR shifts compared to
the known syn- and anti-chloro derivatives, and (2) that
the major isomer corresponds to the major diacetate
produced in DYKAT.
2
8. (a) Higashibayashi, S.; Kishi, Y. Tetrahedron 2004, 60,
1
4
1977–11982; (b) Bonini, C.; Righi, G. Tetrahedron 1992,
8, 1531–1538.