Highly diastereoselective synthesis of 2-substituted-1,3-diols catalyzed by ketoreductases

Article abstract of DOI:10.1016/j.tet.2010.09.096

The stereoselective reduction of α-substituted-β-hydroxy ketones for the preparation of the corresponding optically pure 2-monosubstituted or 2-disubstituted-1,3-diols is described. These transformations proceed in high optical purities and yields. Ketoreductases were able to catalyze the formation of either the syn or the anti diol, depending on the enzyme. By replacing the α-alkyl substituent for an OAc moiety, in low conversion time (≤24 h), ketoreductases catalyzed the formation of the OAc-protected 1,2,3-triol, in high yield and with high optical purity (>99% de, >99% ee). This is a simple and highly stereoselective method for the synthesis of different diastereomers of chiral diols.

Full text of DOI:10.1016/j.tet.2010.09.096

Tetrahedron 66 (2010) 9431e9439
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Highly diastereoselective synthesis of 2-substituted-1,3-diols catalyzed
by ketoreductases
*
Dimitris Kalaitzakis, Ioulia Smonou
Department of Chemistry, University of Crete, Heraklio 71003, Crete, Greece
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 May 2010
Received in revised form 8 September 2010
Accepted 28 September 2010
Available online 26 October 2010
The stereoselective reduction of
sponding optically pure 2-monosubstituted or 2-disubstituted-1,3-diols is described. These trans-
formations proceed in high optical purities and yields. Ketoreductases were able to catalyze the
a-substituted-b-hydroxy ketones for the preparation of the corre-
formation of either the syn or the anti diol, depending on the enzyme. By replacing the a-alkyl sub-
stituent for an OAc moiety, in low conversion time (ꢀ24 h), ketoreductases catalyzed the formation of the
OAc-protected 1,2,3-triol, in high yield and with high optical purity (>99% de, >99% ee). This is a simple
and highly stereoselective method for the synthesis of different diastereomers of chiral diols.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Ketoreductase
Diastereoselective
Enantioselective
Enzymatic reduction
b
-Hydroxy ketones
Optically active 1,3-diols
1. Introduction
examples, the stereoselective formation of 1,3-diols is accom-
plished through enzymatic reductions or enzymatic resolutions.
Optically active 1,3-diols are very important compounds in
asymmetric synthesis, since they represent chiral building blocks
for many polyketide-derived natural products, and have frequently
been used as valuable intermediates in the synthesis of drugs and
natural products with important biological activity.1e8 Several
synthetic methods have been developed for the stereoselective
synthesis of 1,3-diols. In most of them, chiral catalysts or chiral
synthons were applied, usually the heavy metal catalysts or the
extreme conditions lead to low product yields or low optical
purities.9e26 These methods are frequently not generally applicable
for the synthesis of other structurally related compounds, or dif-
ferent diastereomers of the same compound. Therefore, the direct
assembly of chiral molecules with all possible 1,3-diol configura-
tions remains virtually unexplored, despite its significant synthetic
challenge. Consequently, it is highly demanding to develop syn-
thetic methodologies for the production of 1,3-diol chiral synthons
in all possible configurations.
However, the number of stereoisomers formed is limited, and the
substrates, which were used rarely bear a substituent at the 2-
carbon. Even in the very limited cases where an a-substituent ex-
ists, this substituent is mainly methyl and most importantly the
yield is very low due to kinetic resolution.27,30
In particular, the synthesis of optically active 1,3-diols can be
accomplished through enzymatic stereoselective reduction of 1,3-
diketones or
of 1,3-diketones in a single reduction step, rarely leads to 1,3-diols.
The major product from this reaction is usually a -hydroxy ketone,
as we and others have recently shown.28,35e38 These results in-
dicate that -hydroxy ketones are generally poor substrates for the
b-hydroxy ketones. However, the enzymatic reduction
b
b
synthesis of diols catalyzed by dehydrogenases.
2. Results and discussion
Isolated ketoreductases have been proved to be excellent cata-
lysts for the stereoselective synthesis of a-alkyl-b-hydroxy ketones.
We have recently demonstrated that a wide range of hydroxy ke-
tones can be accessed by using a variety of ketoreductases. Starting
Biocatalytic approaches have led to the synthesis of chiral 1,3-
diols using enzymes, such as oxidoreductases, hydrolases, and ly-
ases, either isolated or in the form of whole cells.9,27e34 In all these
from
a-alkyl-1,3-diketones, we achieved the formation of useful
chiral synthons, such as
a
-alkyl-b-hydroxy ketones, in high ster-
eoselectivity and regioselectivity.38e40 Representative examples are
shown in Scheme 1.
* Corresponding author. Tel.: þ30 2810 545010; fax: þ30 2810 545001; e-mail
address: smonou@chemistry.uoc.gr (I. Smonou).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.09.096

9432
D. Kalaitzakis, I. Smonou / Tetrahedron 66 (2010) 9431e9439
OH
OH
O
O
>99% ee
>99% de
conv >99%
OH
OH
O
>99% ee
>99% de
conv >99%
O
O
O
O
KRED-A1B
O
>99% ee
78% de
98% ee
94% de
conv 92%
conv >99%
OH
O
>99% ee
82% de
conv >99%
Scheme 1. Enzymatic reduction of 2-substituted and 2-disubstituted-1,3-diketones with NADPH-dependent ketoreductases.
It is possible to prepare single, different diastereomers of the
O
OH
OH OH
OH OH
R2
hydroxy ketones by tailoring the choice of enzyme. In addition, the
products are frequently formed in high yields. In most of the cases,
no diol was observed, whereas in a few cases, it was formed with
low optical purity.
Our continuing interest in the preparation of useful optically
pure synthons by biocatalytic methods led us to report herein a new
methodology that utilizes the enzymatic reduction of optically pure
R1
R2
R1
R2
R1
+
R3
O
R4
R3 R4
R4
R3
or
ketoreductase
NADPH
syn
anti
or
OH
NADP+
OH OH
R1
R2
OH OH
R3
R4
gluconic acid
R1
R2
R1
R2
+
GDH
R3 R4
a
-substituted-b-hydroxy ketones, for the direct stereoselective
R4
R3
glucose
synthesis of the corresponding 2-substituted-1,3-diols. We also
demonstrate that, under the proper enzyme selection, the stereo-
isomeric 1,3-diol of choice is formed in high optical purity and high
conversion. The general path of this synthetically useful reaction is
shown in Scheme 2.
Scheme 2. Enzymatic reduction of optically pure hydroxy ketones.
As shown in Table 1, for every
b
-hydroxy ketone tested, a few
positive enzymes were found, which were able to catalyze the
formation of either the syn or anti isomer of the corresponding 1,
3-diol, in high optical purity, depending on the enzyme. High
stereoselectivity in the 1,3-diol formation was achieved even by
enzymes that were not highly stereoselective in the first reduction
step of the same diketone, as shown previously. The characteriza-
tion syn/anti refers to the relative configuration between 1,3-hy-
droxy groups.
Nine mono-alkyl
a
-substituted
b
-hydroxy ketones 1e9, two
-substituted OAc-
a
-disubstituted -hydroxy ketones 10,11, and the a
b
protected hydroxy ketone 12, were used as substrates (Scheme 3) for
enzymatic reductions. All these optically pure compounds 1e11,
were produced by stereoselective reduction of the corresponding 2-
substituted-1,3-diketones, utilizing isolated ketoreductases.38
The data reported in Table 1 represent the best results obtained
after screening thirty-two commercially available ketoreductases.
OH
O
OH
O
OH
O
OH
O
2
3
1
4
OH
O
OH
O
OH
O
OH
O
OH
O
OH
O
2c
4a
2a
2b
4b
4c
OH
O
OH
O
OH
O
OH
O
OH
O
9
8
6
7
5
OH
O
OH
O
OH
O
OH
O
OH
O
OH
O
8a
8b
7a
7b
11
10
O
OAc
OH
OH
O
OH
O
12
11a
11b
Scheme 3. Optically pure a-substituted-b-hydroxy ketones submitted to enzymatic reduction.

D. Kalaitzakis, I. Smonou / Tetrahedron 66 (2010) 9431e9439
9433
Table 1
Enzyme-catalyzed stereoselective reduction of hydroxy ketones 1e11 to 1,3-diols
Substrate
Entry
KRED
Diastereomeric ratio
Conversion
Product
syna
antia
1
2
101,111
112,114,115
d
d
>99
>99
>99% (24 h)
50e70% (24 h)
1i
OH
O
1
3
A1B
95
5
>99% (2 h)
1ii
4
5
101,111,112,114,115
A1B
d
>99
90% (24 h)
95% (24 h)
2aib
2aii
2a
>99
d
6
7
8
9
101
111,115
112
10
d
5
90
>99
95
39% (24 h)
25e42% (24 h)
30% (24 h)
20% (24 h)
114
2
98
2b
10
A1B
98
2
>99% (24 h)
2bii
2ci
11
12
13
14
101
111,114,115
112
5
d
95
>99
96
53% (24 h)
26e34% (24 h)
60% (24 h)
70% (24 h)
2c
4
d
A1B
>99
15
16
17
101
111
112,114,115
2
d
98
>99
>99
70% (24 h)
10% (24 h)
40e50% (24 h)
3ci
3
d
18
A1B
>99
d
90% (24 h)
3cii
19
20
21
101
111,112,115
114
1
d
99
>99
97
90% (24 h)
43e60% (24 h)
90% (24 h)
4aib
4aii
3
4a
22
A1B
>99
d
>99% (24 h)
23
24
25
101
111,114
112,115
4
1
d
96
99
>99
95% (24 h)
>99% (24 h)
80e90% (24 h)
4bib
4bii
4b
4c
26
A1B
88
12
50% (24 h)
27
28
29
30
31
101,114
111
112
115
A1B
d
2
4
d
>99
98
96
d
30e45% (24 h)
10% (24 h)
65% (24 h)
<5% (24 h)
95% (24 h)
4ci
5i
d
>99
32
33
34
35
36
101
111,115
112
114
A1B
d
d
d
d
d
>99
d
15% (24 h)
5% (24 h)
35% (24 h)
60% (24 h)
0% (24 h)
5
>99
>99
d
d
37
38
39
101,111,112
114
115
d
d
d
>99
>99
>99
98% (24 h)
38% (24 h)
87% (24 h)
6i
6
40
A1B
>99
d
10% (24 h)
6ii
(continued on next page)

Table 1 (continued)
Substrate
Entry
KRED
Diastereomeric ratio
Conversion
Product
syna
antia
41
42
43
101,112
111,114
115
5
2
d
95
98
d
27e38% (24 h)
10% (24 h)
<5% (24 h)
7ai
7a
44
A1B
>99
d
45% (24 h)
7aii
7bi
45
101
d
>99
20% (24 h)
7b
46
47
111,112,114,115
A1B
d
d
d
d
<5% (24 h)
0% (24 h)
d
d
48
49
50
101,112
111
114,115
>99
>99
d
d
d
d
80e90% (24 h)
15% (24 h)
<5% (24 h)
8ai
d
8a
51
A1B
20
80
40% (24 h)
8aii
8bi
52
53
54
55
101,115
111
112,114
A1B
4
1
d
96
99
>99
d
33e50% (24 h)
75% (24 h)
15e22% (24 h)
0% (24 h)
8b
d
d
56
57
58
101,111
112,114
115
d
d
d
>99
>99
>99
>99% (24 h)
55e70% (24 h)
90% (24 h)
9i
9
59
A1B
98
2
>99% (2 h)
9ii
60
61
62
101,111,114,115
112
A1B
d
d
d
>99
>99
d
>99% (24 h)
50% (24 h)
0% (24 h)
10i
10
d
63
64
65
66
101,111
112,115
114
d
d
d
d
>99
>99
>99
d
40e52% (24 h)
25e29% (24 h)
>99% (24 h)
0% (24 h)
11aib
11bib
11a
A1B
d
d
67
68
69
101,111,114,115
112
A1B
d
d
d
>99
>99
d
>99% (24 h)
65% (24 h)
0% (24 h)
11b
a
The relative configuration between 1,3-hydroxy groups.
Produced diols 2ai and 2bi are identical, as well as 4ai with 4bi and 11ai with 11bi.
b
Table 2
The absolute configuration of the products was assigned by
Enzyme-catalyzed stereoselective reduction of (2S,3R)-2-acetoxy-3-hydroxy-3-
methyl-4-pentanone 12
analyzing the 1H NMR spectra without any transformation or de-
rivatization, since the absolute configuration of the starting b-hy-
Substrate
Entry
KRED
Diastereomeric ratio
Conversion
droxy ketones was already known.38 Only the product 9i, derived
from the enzymatic reduction of substrate 9, was converted to its
di-MPA ester in order to determine its absolute configuration.
Among all the enzymes screened, KRED-A1B proved to be the
most efficient catalyst for the selective formation of the syn diol
(meso-isomers with the exception of compounds 9ii, entry 59 Table
1, and 12a, entry 81 Table 2, which are optically active). However, in
the cases of substrates 2c, 4c, and 8a KRED-A1B catalyzed the for-
mation of the anti isomer (entries 14, 31 and 51, respectively). This
result indicates that the selectivity of this enzyme does not depend
on the configuration of the hydroxy stereocenter. Speciafically,
KRED-A1B always showed high selectivity toward the newly formed
stereogenic center with the R absolute configuration, regardless of
the preexisting R or S configuration of the OH-stereocenter. This
syna (12a)
antia (12b)
70
71
72
73
74
75
76
77
78
79
80
81
101
102
106
111
112,113
114
115
119
121
3
97
>99% (24 h)
>99% (24 h)
70% (24 h)
>99% (24 h)
>99% (24 h)
>99% (24 h)
90% (24 h)
30% (24 h)
70% (24 h)
46% (24 h)
20e52% (24 h)
>99% (24 h)
d
d
8
2
22
8
>99
>99
92
98
78
92
97
80
75
12
3
20
25
d
>99
123
130,131
A1B
>99
d
a
The relative configuration between the secondary hydroxy group and the
O-acetyl group.

D. Kalaitzakis, I. Smonou / Tetrahedron 66 (2010) 9431e9439
9435
result was not a surprise since KRED-A1B has shown anti-Prelog
selectivity in our previous studies.38,40 However, the selectivity of
the other positive enzymes was dependent on the hydroxy config-
in most cases (Table 2). However, KRED-A1B was able to catalyze
the formation of the syn stereoisomer, in high stereoselectivity
(>99%, entry 81) and conversion (>99%).
uration of the
b
-hydroxy ketones. When the preexisting hydroxy
The diastereomeric ratio of the products syn, 12a or anti, 12b
could not be assigned directly from their 1H NMR spectra, as for
those in Table 1, because the structure is not symmetrical and
bears three stereogenic centers. The 1H NMR spectra, as well as the
GC chromatograms of the mixture derived from the reduction of
12 by KRED-102 (entry 71), showed two products. However, re-
duction of 12 by KRED-A1B led to one product, which was not
identical to any of the two previous products derived from KRED-
102. This observation was unexpected, because the only possible
products from the reduction of 12 should be two. This can be ra-
tionalized by the fact that the produced isomer 12bi, from the
reduction catalyzed by KRED-102, is in equilibrium with its di-
astereomer 12bii, while the produced isomer 12ai, from the re-
action with KRED-A1B, is in equilibrium with its enantiomer 12aii,
which is not identical to the previous two diastereomers 12bi and
12bii. This is clearly illustrated in Scheme 4. Further acetylation of
the two secondary hydroxy groups led to the production of only
one isomer in both cases, 13a (meso) and 13b (Scheme 4). This
result clarifies the above mentioned equilibria and the absolute
configuration of the products.
group was S, ketoreductases KRED-101,111,112,114, and 115 showed
S selectivity, producing the anti stereoisomer, whereas in the case of
substrates 2c, 4c, and 7b, where the configuration of the already
existing hydroxy group was R, these enzymes showed R selectivity,
also producing the anti stereoisomer. The only exception to this
observation, was recorded in substrate 8a. Although in this case the
preexisting hydroxy group has the R configuration, the three posi-
tive enzymes for its reduction (KREDs-101, 111, 112), showed S se-
lectivity (entries 48 and 49, respectively), producing the meso
stereoisomer 8ai.
As a general rule, of the 32 enzymes that were screened, only
a few of them were able to catalyze the formation of optically pure
1,3-diols, indicating that b-hydroxy ketones are poor substrates for
dehydrogenases. Almosteveryenzyme tested showed lower activity
in the reduction of the hydroxy ketone compared to the reduction of
the corresponding diketone. The reactivity dependence on absolute
stereochemistry was also examined. Most enzymes were either in-
active or possessed low activity for the reduction of the hydroxy
ketone.
K2CO3
OH OAc
OAc OH
OAc OAc
DMAP
Ac2O
KRED-102
OH
12bi
OH
12bii
5 min
OH
O
OAc
OH
Diastereomers
Enantiomers
13b
K2CO3
DMAP
Ac2O
12
OH OAc
OAc OH
OAc OAc
KRED-A1B
OH
12ai
OH
OH
5 min
13a
12aii
Scheme 4. Enzymatic reduction of (2S,3R)-2-acetoxy-3-hydroxy-3-methyl-4-pentanone 12.
Besides being stereoselective, the positive enzymes showed
good to excellent activity. In some cases the reaction was complete
in only 2 h (entries 3 and 59), but predominantly, the maximum
reaction time was 24 h. In some cases, the activity of enzymes was
3. Conclusion
In conclusion, we have developed a straightforward enzymatic
method for the direct, stereoselective synthesis of 2-mono-
substituted or 2-disubstituted-1,3-diols in high optical purity and
yield. For this purpose, NADPH-dependent ketoreductases were
affected by the structure of the b-hydroxy ketone. For example,
KRED-A1B did not catalyze the reduction of disubstituted sub-
strates 10 and 11a, 11b. Furthermore, the enzyme activities with
substrates 3, 2b, 4c, 5, and 8b were relatively low (<75% conver-
sion) with the lowest observed in the case of 7a, 7b (entries 41e47).
Quantitative yields of product were obtained in 2 h of reaction
time, using 10% (w/w) of enzyme relative to substrate. For example,
hydroxy ketone 9 (50 mM, 507 mg) was reduced in larger scale
(78 mL) with KRED-101 affording optically pure diol (9i) in high
isolated yield and optical purities (95% yield, >99% ee). It is im-
portant to note here, that this specific product (9i) bears three
stereogenic centers. In every reaction discussed in this report, the
NADPH cofactor was used in catalytic amounts (1% relative to the
substrate) and was recycled in situ using glucose dehydrogenase
(GDH) and glucose as co-substrate.41
Finally, we examined the enzymatic reduction of substrate 12
(Table 2), which has different structure than all the previous sub-
strates utilized in this work. Many of the previously mentioned
enzymes (fourteen of them) showed good to excellent activity to-
ward the reduction of compound 12 (Table 2), leading to products
with the anti relative configuration (refers to the relative configu-
ration between the newly formed hydroxy group and the O-acetyl
group). The observed anti diastereoselectivity was excellent (>97%)
utilized for the stereoselective reduction of
a-substituted-b-hy-
droxy ketones. By this method either the syn or the anti diol can be
prepared dependent on the enzyme, demonstrating its significance
in asymmetric organic synthesis. Furthermore, ketoreductases cat-
alyzed theformation ofOAc-protected 1,2,3-triol (12a or12b)in high
yield, high optical purity (>99% de, >99% ee), and low conversion
time (ꢀ24 h). All the enzymatic transformations were clean, leading
to pure products with the absence of any byproducts. The isolation of
the produced diols was accomplished easily and no chromato-
graphic separation was necessary in the case of quantitative
reactions.
4. Experimental
4.1. General
Unlessotherwisenoted,solventsandreagentswerereagentgrade
from commercial suppliers (SigmaeAldrich) and used without any
further purification. The progress of the enzymatic reactions and the
selectivities were determined by gas chromatographical analysis of
crude EtOAc extracts (for the small scale reactions) and of isolated

9436
D. Kalaitzakis, I. Smonou / Tetrahedron 66 (2010) 9431e9439
products, using HP5890II gas chromatograph equipped with an FID
m chiral capillary col-
1.22 (3H, d, J 6.5, Me), 0.96 (3H, t, J 7.5, Me); dC (75 MHz; CDCl3;
Me4Si): 69.1, 68.0, 51.0, 22.4, 19.2, 19.0, 12.6; HRMS (ESI) calcd for
C7H16O2 m/z (MþH) 133.1229, obsd 133.1225; GC data: (column:
detector; (column: 30 mꢁ0.25 mmꢁ0.25
m
umn, 20% permethylated (R)-cyclodextrin HP Part No 19091G-8233).
1H and 13C NMR spectra were recorded on 300 and 500 MHz Bruker
spectrometers in CDCl3 solutions, by using Me4Si as an internal
standard. Chemical shifts are reported in parts per million downfield
from Me4Si. The enzymes-ketoreductases and glucose de-
hydrogenase-and NADPH are commercially available (Codexis).
30 mꢁ0.25 mmꢁ0.25
mm
chiral capillary column, 20% per-
methylated cyclodextrin 120 ꢂC for 3 min, rate: 10 ꢂC/min, final
temp: 210 ꢂC; carrier gas: N2, press 70 kPa). tR¼7.85 min (diol 2bi).
4.2.6. (2S,4R)-3-Ethyl-2,4-pentanediol (meso-diol 2bii). dH (500 MHz;
CDCl3; Me4Si): 3.95e4.02 (2H, m, 2ꢁCHOH), 2.91 (2H, br s, 2ꢁOH),
1.38e1.45 (2H, m, CH2), 1.24e1.30 (1H, m, CH), 1.27 (6H, d, J 6.5,
2ꢁMe), 0.86 (3H, t, J 7.5, Me); dC (75 MHz; CDCl3; Me4Si): 71.0, 52.1,
22.2, 17.1, 15.1; HRMS (ESI) calcd for C7H16O2 m/z (MþH) 133.1229,
4.2. Enzymatic reduction of hydroxy ketones (small scale)
In every enzymatic reaction the isolated and optically pure
substituted-
-hydroxy ketone was used as substrate.38 The second
reduction was performed as follows: in a phosphate buffer solution
(1 mL, 200 mM, pH 6.9), the -substituted- -hydroxy ketones
a-
b
obsd 133.1223; GC data: (column: 30 mꢁ0.25 mmꢁ0.25
mm chiral
capillary column, 20% permethylated cyclodextrin 120 ꢂC for 3 min,
rate: 10 ꢂC/min, final temp: 210 ꢂC; carrier gas: N2, press 70 kPa).
tR¼7.85 min (diol 2bii).
a
b
(25 mM), the corresponding ketoreductase (3e5 mg), glucose de-
hydrogenase (2 mg), NADPH (2 mg), and glucose (18 mg) were
added. The reactions were incubated at 37 ꢂC and reaction aliquots
were taken at various time points. After extraction with ethyl ac-
etate (3ꢁ1 mL), they were analyzed by GC chromatography and 1H
NMR spectroscopy.
4.2.7. (2R,4R)-3-Ethyl-2,4-pentanediol (diol 2ci). dH (500 MHz;
CDCl3; Me4Si): 4.21e4.26 (1H, m, CHOH), 4.00e4.05 (1H, m, CHOH),
2.83 (1H, br s, OH), 2.65 (1H, br s, OH), 1.40e1.49 (1H, m, CH),
1.29e1.37 (1H, m, CH2), 1.24e1.29 (1H, m, CH2), 1.27 (3H, d, J 6.5,
Me), 1.22 (3H, d, J 6.5, Me), 0.96 (3H, t, J 7.5, Me); dC (75 MHz; CDCl3;
Me4Si): 69.1, 68.0, 51.0, 22.4, 19.2, 19.0, 12.6; HRMS (ESI) calcd for
C7H16O2 m/z (MþH) 133.1229, obsd 133.1215; GC data: (column:
4.2.1. (2S,4S)-3-Methyl-2,4-pentanediol (diol 1i)42
. dH (500 MHz;
CDCl3; Me4Si): 4.08e4.14 (1H, m, CHOH), 3.83e3.89 (1H, m, CHOH),
2.81 (2H, br s, OH), 1.54e1.61 (1H, m, CH), 1.24 (3H, d, J 6.5, Me), 1.19
(3H, d, J 6.5, Me), 0.88 (3H, d, J 7.0, Me); dC (75 MHz; CDCl3; Me4Si):
71.0, 69.7, 44.5, 22.1, 19.0, 12.2; HRMS (ESI): calcd for C6H14O2 m/z
(MþH) 119.1072, obsd 119.1064; GC data: (column: 30 mꢁ0.25
30 mꢁ0.25 mmꢁ0.25
mm
chiral capillary column, 20% per-
methylated cyclodextrin 120 ꢂC for 3 min, rate: 10 ꢂC/min, final
temp: 210 ꢂC; carrier gas: N2, press 70 kPa). tR¼7.85 min (diol 2ci).
mmꢁ0.25
m
m chiral capillary column, 20% permethylated cyclo-
4.2.8. (2S,4S)-3-Propyl-2,4-pentanediol (diol 3ci). dH (500 MHz;
CDCl3; Me4Si): 4.19e4.25 (1H, m, CHOH), 3.96e4.03 (1H, m, CHOH),
2.81 (1H, br s, OH), 2.61 (1H, br s, OH), 1.23e1.45 (5H, m, CHCH2CH2),
1.27 (3H, d, J 6.5, Me), 1.21 (3H, d, J 6.5, Me), 0.92 (3H, t, J 7.0, Me); dC
(75 MHz; CDCl3; Me4Si): 69.5, 68.2, 49.0, 28.5, 22.4, 21.2, 19.3, 14.4;
HRMS (ESI) calcd for C8H18O2 m/z (MþH) 147.1385, obsd 147.1380; GC
dextrin 120 ꢂC for 3 min, rate: 10 ꢂC/min, final temp: 210 ꢂC; carrier
gas: N2, press 70 kPa). tR¼6.73 min (diol 1i).
4.2.2. (2S,4R)-3-Methyl-2,4-pentanediol (meso-diol 1ii). dH (500 MHz;
CDCl3; Me4Si): 4.08e4.14 (2H, m, 2ꢁCHOH), 2.35 (2H, br s, 2ꢁOH),
1.36e1.42 (1H, m, CH), 1.20 (6H, d, J 6.5, 2ꢁMe), 0.94 (3H, d, J 7.0, Me);
dC (75 MHz; CDCl3; Me4Si): 72.7, 43.5, 21.5, 3.8; HRMS (ESI): calcd for
C6H14O2 m/z (MþH) 119.1072, obsd 119.1068; GC data: (column:
data: (column: 30 mꢁ0.25 mmꢁ0.25
mm chiral capillary column, 20%
permethylated cyclodextrin 140 ꢂC for 3 min, rate: 10 ꢂC/min, final
temp: 210 ꢂC; carrier gas: N2, press 70 kPa). tR¼6.85 min (diol 3ci).
30 mꢁ0.25 mmꢁ0.25
mm chiral capillary column, 20% permethylated
cyclodextrin 120 ꢂC for 3 min, rate: 10 ꢂC/min, final temp: 210 ꢂC;
carrier gas: N2, press 70 kPa). tR¼6.43 min (meso-diol 1ii).
4.2.9. (2S,4R)-3-Propyl-2,4-pentanediol (meso-diol 3cii). dH (500 MHz;
CDCl3; Me4Si): 4.09e4.15 (2H, m, 2ꢁCHOH), 2.34 (2H, br s, 2ꢁOH),
1.37e1.46 (5H, m, CHCH2CH2),1.22 (6H, d, J 6.5, 2ꢁMe), 0.94 (3H, t, J 7.0,
Me); dC (75 MHz; CDCl3; Me4Si): 72.6, 49.2, 24.4, 23.6, 21.7,14.6; HRMS
(ESI) calcd for C8H18O2 m/z (MþH) 147.1385, obsd 147.1376; GC data:
4.2.3. (2S,4S)-3-Ethyl-2,4-pentanediol (diol 2ai). dH (500 MHz; CDCl3;
Me4Si): 4.21e4.26 (1H, m, CHOH), 4.00e4.05 (1H, m, CHOH), 2.83 (1H,
br s, OH), 2.65 (1H, br s, OH), 1.40e1.49 (1H, m, CH), 1.29e1.37 (1H, m,
CH2), 1.24e1.29 (1H, m, CH2), 1.27 (3H, d, J 6.5, Me), 1.22 (3H, d, J 6.5,
Me), 0.96 (3H, t, J 7.5, Me); dC (75 MHz; CDCl3; Me4Si): 69.1, 68.0, 51.0,
22.4, 19.2, 19.0, 12.6; HRMS (ESI) calcd for C7H16O2 m/z (MþH)
(column: 30 mꢁ0.25 mmꢁ0.25
mm chiral capillary column, 20% per-
methylated cyclodextrin 140 ꢂC for 3 min, rate: 10 ꢂC/min, final temp:
210 ꢂC; carrier gas: N2, press 70 kPa). tR¼6.62 min (meso-diol 2ci).
133.1229, obsd 133.1218; GC data: (column: 30 mꢁ0.25 mmꢁ0.25
m
m
4.2.10. (2S,4S)-3-Allyl-2,4-pentanediol (diol 4ai). dH (500 MHz;
CDCl3; Me4Si): 5.77e5.86 (1H, m, CH]CH2), 5.02e5.11 (2H, m, CH]
CH2), 4.23e4.28 (1H, m, CHOH), 4.01e4.06 (1H, m, CHOH), 2.90 (1H,
br s, OH), 2.57 (1H, br s, OH), 2.21e2.28 (1H, m, CH2), 2.08e2.14 (1H,
m, CH2), 1.44e1.48 (1H, m, CH), 1.28 (3H, d, J 6.5, Me), 1.22 (3H, d, J
6.5, Me); dC (75 MHz; CDCl3; Me4Si): 137.4, 116.3, 69.1, 67.7, 48.8,
30.8, 22.1, 19.4; HRMS (ESI) calcd for C8H16O2 m/z (MþH) 145.1229,
chiral capillary column, 20% permethylated cyclodextrin 120 ꢂC for
3 min, rate: 10 ꢂC/min, final temp: 210 ꢂC; carrier gas: N2, press
70 kPa). tR¼7.85 min (diol 2ai).
4.2.4. (2S,4R)-3-Ethyl-2,4-pentanediol (meso-diol 2aii). dH (500 MHz;
CDCl3; Me4Si): 4.09e4.14 (2H, m, 2ꢁCHOH), 2.33 (2H, br s, 2ꢁOH),
1.48e1.54 (2H, m, CH2),1.23 (6H, d, J 6.5, 2ꢁMe),1.14e1.18 (1H, m, CH),
1.02 (3H, t, J 7.5, Me); dC (75 MHz; CDCl3; Me4Si): 72.4, 51.4, 21.7, 15.8,
14.5; HRMS (ESI) calcd for C7H16O2 m/z (MþH) 133.1229, obsd
obsd 145.1219; GC data: (column: 30 mꢁ0.25 mmꢁ0.25
mm chiral
capillary column, 20% permethylated cyclodextrin 140 ꢂC for 3 min,
rate: 10 ꢂC/min, final temp: 210 ꢂC; carrier gas: N2, press 70 kPa).
tR¼6.82 min (diol 4ai).
133.1219; GC data: (column: 30 mꢁ0.25 mmꢁ0.25
mm chiral capillary
column, 20% permethylated cyclodextrin 120 ꢂC for 3 min, rate: 10 ꢂC/
min, final temp: 210 ꢂC; carrier gas: N2, press 70 kPa). tR¼7.50 min
(meso-diol 2aii).
4.2.11. (2S,4R)-3-Allyl-2,4-pentanediol (meso-diol 4aii). dH (500 MHz;
CDCl3; Me4Si): 5.92e6.00 (1H, m, CH]CH2), 4.97e5.12 (2H, m, CH]
CH2), 4.01e4.17 (2H, m, 2ꢁCHOH), 2.81 (2H, br s, 2ꢁOH), 2.28e2.36
(2H, m, CH2), 1.39e1.44 (1H, m, CH), 1.25 (6H, d, J 6.5, 2ꢁMe); dC
(75 MHz; CDCl3; Me4Si): 139.9,115.2, 72.2, 49.2, 26.7, 21.8; HRMS (ESI)
calcd for C8H16O2 m/z (MþH) 145.1229, obsd 145.1221; GC data:
4.2.5. (2S,4S)-3-Ethyl-2,4-pentanediol (diol 2bi). dH (500 MHz;
CDCl3; Me4Si): 4.21e4.26 (1H, m, CHOH), 4.00e4.05 (1H, m, CHOH),
2.83 (1H, br s, OH), 2.65 (1H, br s, OH), 1.40e1.49 (1H, m, CH),
1.29e1.37 (1H, m, CH2),1.24e1.29 (1H, m, CH2),1.27 (3H, d, J 6.5, Me),
(column: 30 mꢁ0.25 mmꢁ0.25
mm chiral capillary column, 20%

D. Kalaitzakis, I. Smonou / Tetrahedron 66 (2010) 9431e9439
9437
permethylated cyclodextrin 140 ꢂC for 3 min, rate: 10 ꢂC/min, final
temp: 210 ꢂC; carrier gas: N2, press 70 kPa). tR¼6.69 min (meso-diol
4aii).
10.4, 3.9; HRMS (ESI) calcd for C8H18O2 m/z (MþH) 147.1385, obsd
147.1377; GC data: (column: 30 mꢁ0.25 mmꢁ0.25
mm chiral cap-
illary column, 20% permethylated cyclodextrin 140 ꢂC for 3 min,
rate: 10 ꢂC/min, final temp: 210 ꢂC; carrier gas: N2, press 70 kPa).
tR¼6.72 min (meso-diol 8ai).
4.2.12. (2S,4S)-3-Allyl-2,4-pentanediol (diol 4bi). dH (500 MHz;
CDCl3; Me4Si): 5.76e5.86 (1H, m, CH]CH2), 5.02e5.11 (2H, m, CH]
CH2), 4.23e4.28 (1H, m, CHOH), 4.01e4.06 (1H, m, CHOH), 2.97 (1H,
br s, OH), 2.67 (1H, br s, OH), 2.21e2.28 (1H, m, CH2), 2.07e2.14 (1H,
m, CH2), 1.43e1.49 (1H, m, CH), 1.27 (3H, d, J 6.5, Me), 1.22 (3H, d, J
6.5, Me); dC (75 MHz; CDCl3; Me4Si): 137.4, 116.3, 69.1, 67.7, 48.8,
30.8, 22.1, 19.4; HRMS (ESI) calcd for C8H16O2 m/z (MþH) 145.1229,
4.2.18. (3S,5S)-4-Methyl-3,5-heptanediol (diol 8bi)43
. dH (500 MHz;
CDCl3; Me4Si): 3.82e3.87 (1H, m, CHOH), 3.55e3.60 (1H, m, CHOH),
2.52 (1H, br s, OH), 2.42 (1H, br s, OH),1.39e1.66 (5H, m, 2ꢁCH3CH2,
CH), 0.97 (3H, t, J 7.0, Me), 0.96 (3H, t, J 7.0, Me), 0.95 (3H, d, J 7.5,
Me); dC (75 MHz; CDCl3; Me4Si): 77.5, 74.1, 40.2, 28.2, 26.9,11.3,10.7,
10.0; HRMS (ESI) calcd for C8H18O2 m/z (MþH) 147.1385, obsd
obsd 145.1216; GC data: (column: 30 mꢁ0.25 mmꢁ0.25
mm chiral
capillary column, 20% permethylated cyclodextrin 140 ꢂC for 3 min,
rate: 10 ꢂC/min, final temp: 210 ꢂC; carrier gas: N2, press 70 kPa).
tR¼6.82 min (diol 4bi).
147.1380; GC data: (column: 30 mꢁ0.25 mmꢁ0.25
mm chiral cap-
illary column, 20% permethylated cyclodextrin 140 ꢂC for 3 min,
rate: 10 ꢂC/min, final temp: 210 ꢂC; carrier gas: N2, press 70 kPa).
tR¼6.55 min (diol 8bi).
4.2.13. (2S,4R)-3-Allyl-2,4-pentanediol(meso-diol 4bii). dH (500 MHz;
CDCl3; Me4Si): 5.68e5.80 (1H, m, CH]CH2), 5.02e5.12 (2H, m, CH]
CH2), 3.93e4.01 (2H, m, 2ꢁCHOH), 2.81 (2H, br s, 2ꢁOH), 2.15e2.22
(2H, m, CH2), 1.44e1.50 (1H, m, CH), 1.28 (6H, d, J 6.5, 2ꢁMe); dC
(75 MHz;CDCl3;Me4Si):135.5,116.8, 70.9, 50.9,33.0,22.3;HRMS(ESI)
calcd for C8H16O2 m/z (MþH) 145.1229, obsd 145.1218; GC data:
4.2.19. (2S,3R,4S)-3-Methyl-2,4-hexanediol (diol 9i). dH (500 MHz;
CDCl3; Me4Si): 4.09e4.17 (1H, m, CHOH), 3.55e3.63 (1H, m, CHOH),
2.84 (1H, br s, OH), 2.72 (1H, br s, OH),1.48e1.66 (3H, m, CH3CH2, CH),
1.18 (3H, d, J 7.0, Me), 0.96 (3H, t, J 7.5, Me), 0.91 (3H, d, J 7.0, Me); dC
(75 MHz; CDCl3; Me4Si): 76.7, 69.2, 41.9, 28.1, 19.5, 11.9, 9.8; HRMS
(ESI) calcd for C7H16O2 m/z (MþH) 133.1229, obsd 133.0758; GC data:
(column: 30 mꢁ0.25 mmꢁ0.25
mm chiral capillary column, 20% per-
methylated cyclodextrin 140 ꢂC for 3 min, rate: 10 ꢂC/min, final temp:
210 ꢂC; carrier gas: N2, press 70 kPa). tR¼7.10 min (meso-diol 4bii).
(column: 30 mꢁ0.25 mmꢁ0.25
mm chiral capillary column, 20%
permethylated cyclodextrin 120 ꢂC for 3 min, rate: 10 ꢂC/min, final
temp: 210 ꢂC; carrier gas: N2, press 70 kPa). tR¼7.35 min (diol 9i).
4.2.14. (2R,4R)-3-Allyl-2,4-pentanediol (diol 4ci). dH (500 MHz;
CDCl3; Me4Si): 5.76e5.86 (1H, m, CH]CH2), 5.02e5.11 (2H, m, CH]
CH2), 4.23e4.29 (1H, m, CHOH), 4.00e4.07 (1H, m, CHOH), 2.87 (1H,
br s, OH), 2.53 (1H, br s, OH), 2.21e2.28 (1H, m, CH2), 2.07e2.14 (1H,
m, CH2), 1.43e1.49 (1H, m, CH), 1.27 (3H, d, J 6.5, Me), 1.22 (3H, d, J
6.5, Me); dC (75 MHz; CDCl3; Me4Si): 137.4, 116.3, 69.1, 67.7, 48.8,
30.8, 22.1, 19.4; HRMS (ESI) calcd for C8H16O2 m/z (MþH) 145.1229,
4.2.20. (2S,3R,4R)-3-Methyl-2,4-hexanediol (diol 9ii). dH (500 MHz;
CDCl3; Me4Si): 4.06e4.13 (1H, m, CHOH), 3.75e3.80 (1H, m, CHOH),
2.55 (1H, br s, OH), 2.40 (1H, br s, OH),1.41e1.60 (3H, m, CH3CH2, CH),
1.20 (3H, d, J 6.5, Me), 0.93 (3H, t, J 7.5, Me), 0.91 (3H, d, J 7.0, Me); dC
(75 MHz; CDCl3; Me4Si): 78.7, 72.9, 41.4, 28.2, 21.5, 10.4, 3.8; HRMS
(ESI) calcd for C7H16O2 m/z (MþH) 133.1229, obsd 133.1220; GC data:
obsd 145.1221; GC data: (column: 30 mꢁ0.25 mmꢁ0.25
mm chiral
(column: 30 mꢁ0.25 mmꢁ0.25
mm chiral capillary column, 20%
capillary column, 20% permethylated cyclodextrin 140 ꢂC for 3 min,
rate: 10 ꢂC/min, final temp: 210 ꢂC; carrier gas: N2, press 70 kPa).
tR¼6.79 min (diol 4ci).
permethylated cyclodextrin 120 ꢂC for 3 min, rate: 10 ꢂC/min, final
temp: 210 ꢂC; carrier gas: N2, press 70 kPa). tR¼6.83 min (diol 9ii).
4.2.21. (2S,4S)-3-Ethyl-3-methyl-2,4-pentanediol (diol 10i). dH (500
MHz; CDCl3; Me4Si): 3.95e3.99 (1H, m, CHOH), 3.90e3.94 (1H, m,
CHOH), 3.02 (1H, br s, OH), 2.97 (1H, br s, OH), 1.59e1.66 (2H, m,
CH2CH3), 1.18 (3H, d, J 6.5, Me), 1.16 (3H, d, J 6.5, Me), 0.88 (3H, t, J 7.5,
CH2CH3), 0.80 (3H, s, CCH3); dC (75 MHz; CDCl3; Me4Si): 73.0, 72.4,
41.9, 24.5, 18.2, 17.7, 17.6, 7.6; HRMS (ESI) calcd for C8H18O2 m/z (MþH)
4.2.15. (2S,4S)-3-(3-Butenyl)-2,4-pentanediol (diol 6i). dH (500 MHz;
CDCl3; Me4Si): 5.76e5.84 (1H, m, CH]CH2), 4.95e5.05 (2H, m, CH]
CH2), 4.22e4.27 (1H, m, CHOH), 3.99e4.04 (1H, m, CHOH), 2.88 (1H,
br s, OH), 2.69 (1H, br s, OH), 2.12e2.20 (1H, m, CH2CH]CH2),
2.02e2.10 (1H, m, CH2CH]CH2), 1.47e1.55 (1H, m, CH), 1.33e1.44
(2H, m, CHCH2CH2), 1.28 (3H, d, J 6.5, Me), 1.21 (3H, d, J 6.5, Me); dC
(75 MHz; CDCl3; Me4Si): 138.5, 114.9, 69.2, 67.9, 48.3, 32.0, 25.2,
22.3, 19.4; HRMS (ESI) calcd for C9H18O2 m/z (MþH) 159.1385, obsd
147.1385, obsd 147.1378; GC data: (column: 30 mꢁ0.25 mmꢁ0.25
mm
chiral capillary column, 20% permethylated cyclodextrin 140 ꢂC for
3 min, rate: 10 ꢂC/min, final temp: 210 ꢂC; carrier gas: N2, press
70 kPa). tR¼7.15 min (diol 10i).
159.1378; GC data: (column: 30 mꢁ0.25 mmꢁ0.25
mm chiral capil-
lary column, 20% permethylated cyclodextrin 140 ꢂC for 3 min, rate:
10 ꢂC/min, final temp: 210 ꢂC; carrier gas: N2, press 70 kPa).
tR¼8.01 min (diol 6i).
4.2.22. (2S,4S)-3-Allyl-3-methyl-2,4-pentanediol (diol 11ai). dH (500
MHz; CDCl3; Me4Si): 5.87e5.96 (1H, m, CH]CH2), 5.08e5.16 (2H, m,
CH]CH2), 3.94e4.00 (1H, m, CHOH), 3.85e3.92 (1H, m, CHOH), 3.16
(1H, br s, OH), 2.74 (1H, br s, OH), 2.41e2.47 (1H, m, CH2), 1.92e1.98
(1H, m, CH2), 1.21 (3H, d, J 6.5, Me), 1.17 (3H, d, J 6.5, Me), 0.82 (3H, s,
CCH3); dC (75 MHz; CDCl3; Me4Si): 134.9, 117.7, 73.0, 72.6, 42.7, 36.9,
19.1, 17.5, 17.4; HRMS (ESI) calcd for C9H18O2 m/z (MþH) 159.1385,
4.2.16. (2S,4R)-3-(3-Methyl-2-butenyl)-2,4-pentanediol (meso-diol
7aii). dH (500 MHz; CDCl3; Me4Si): 5.18e5.23 (1H, m, CH]C(CH3)2),
4.08e4.14 (2H, m, 2ꢁCHOH), 2.20e2.26 (2H, m, CH2), 1.69 (3H, s,
Me),1.67 (3H, s, Me),1.33e1.38 (1H, m, CH),1.23 (6H, d, J 6.5, 2ꢁMe);
dC (75 MHz; CDCl3; Me4Si): 129.0, 120.0, 72.1, 50.3, 25.8, 21.8, 21.0,
17.8; HRMS (ESI) calcd for C10H20O2 m/z (MþH) 173.1542, obsd
obsd 159.1377; GC data: (column: 30 mꢁ0.25 mmꢁ0.25
mm chiral
capillary column, 20% permethylated cyclodextrin 140 ꢂC for 3 min,
rate: 10 ꢂC/min, final temp: 210 ꢂC; carrier gas: N2, press 70 kPa).
tR¼7.89 min (diol 11ai).
173.1538; GC data: (column: 30 mꢁ0.25 mmꢁ0.25
mm chiral capil-
lary column, 20% permethylated cyclodextrin 140 ꢂC for 3 min, rate:
10 ꢂC/min, final temp: 210 ꢂC; carrier gas: N2, press 70 kPa).
tR¼8.79 min (meso-diol 7aii).
4.2.23. (2S,4S)-3-Allyl-3-methyl-2,4-pentanediol (diol 11bi). dH (500
MHz; CDCl3; Me4Si): 5.86e5.95 (1H, m, CH]CH2), 5.07e5.15 (2H, m,
CH]CH2), 3.94e3.99 (1H, m, CHOH), 3.85e3.90 (1H, m, CHOH), 3.28
(1H, br s, OH), 2.91 (1H, br s, OH), 2.40e2.46 (1H, m, CH2), 1.91e1.96
(1H, m, CH2), 1.20 (3H, d, J 6.5, Me), 1.17 (3H, d, J 6.5, Me), 0.82 (3H, s,
CCH3); dC (75 MHz; CDCl3; Me4Si): 134.9, 117.7, 73.0, 72.6, 42.7, 36.9,
4.2.17. (3R,5S)-4-Methyl-3,5-heptanediol (meso-diol 8ai)43
. dH (500
MHz; CDCl3; Me4Si): 3.73e3.79 (2H, m, 2ꢁCHOH), 2.63 (2H, br s,
2ꢁOH), 1.41e1.61 (5H, m, 2ꢁCH3CH2, CH), 0.93 (6H, t, J 7.5, 2ꢁMe),
0.88 (3H, d, J 7.5, Me); dC (75 MHz; CDCl3; Me4Si): 78.9, 39.3, 28.1,

9438
D. Kalaitzakis, I. Smonou / Tetrahedron 66 (2010) 9431e9439
19.1, 17.5, 17.4; HRMS (ESI) calcd for C9H18O2 m/z (MþH) 159.1385,
36 mg), catalytic amount of DMAP and the reaction mixture was
stirred at 0 ꢂC for 6 h and at rt for 12 h. After completion of the
reaction the produced urea was filtered, the filtrate was evaporated,
and then chromatographed with 5/1 (v/v), Hex/EtOAc producing
the corresponding MPA-diester (38 mg, 90% isolated yield).
obsd 159.1379; GC data: (column: 30 mꢁ0.25 mmꢁ0.25
mm chiral
capillary column, 20% permethylated cyclodextrin 140 ꢂC for 3 min,
rate: 10 ꢂC/min, final temp: 210 ꢂC; carrier gas: N2, press 70 kPa).
tR¼7.87 min (diol 11bi).
4.2.24. Reduction of (2S,3R)-2-acetoxy-3-hydroxy-3-methyl-4-pen-
tanone 12 catalyzed by KRED-102 (diol 12bi in equilibrium with
12bii). dH (500 MHz; CDCl3; Me4Si): 5.10 (1H, q, J 6.5, CHOAc), 5.00
(1H, q, J 6.5, CHOAc), 3.61e3.67 (1H, m, CHOH), 3.55e3.61 (1H, m,
CHOH), 2.11 (3H, s, COMe), 2.09 (3H, s, COMe), 1.26 (3H, d, J 6.0, Me),
1.25 (3H, d, J 6.0, Me), 1.21 (3H, d, J 6.5, Me), 1.16 (3H, d, J 6.5, Me),
1.14 (3H, s, CCH3), 1.06 (3H, s, CCH3); HRMS (ESI) calcd for C8H16O4
m/z (MþH) 178.1205, obsd 178.1195; GC data: (column:
4.4.1. (R,R)-MPA-diester of (2S,3R,4S)-3-methyl-2,4-hexanediol. dH
(500 MHz; CDCl3; Me4Si): 7.28e7.45 (10H, m, 2ꢁCHC6H5),
5.04e5.09 (1H, m, CHO2C), 4.77e4.82 (1H, m, CHO2C), 4.76 (1H, s,
CHOMe), 4.75 (1H, s, CHOMe), 3.45 (3H, s, OMe), 3.44 (3H, s, OMe),
1.72e1.79 (1H, m, CHCH3),1.44e1.53 (1H, m, CH2),1.25e1.38 (1H, m,
CH2), 1.02 (3H, d, J 6.0, CH3CHO2C), 0.83 (3H, d, J 7.0, CH3CH), 0.43
(3H, t, J 7.5, CH3CH2).
30 mꢁ0.25 mmꢁ0.25
mm
chiral capillary column, 20% per-
4.4.2. (S,S)-MPA-diester of (2S,3R,4S)-3-methyl-2,4-hexanediol. dH
(500 MHz; CDCl3; Me4Si): 7.29e7.42 (10H, m, 2ꢁCHC6H5), 4.67e4.72
(1H, m, CHO2C), 4.69 (1H, s, CHOMe), 4.66 (1H, s, CHOMe), 4.45e4.50
(1H, m, CHO2C), 3.40 (3H, s, OMe), 3.39 (3H, s, OMe), 1.59e1.65 (1H,
m, CHCH3),1.23e1.32 (2H, m, CH2),1.09 (3H, d, J 6.0, CH3CHO2C), 0.64
(3H, t, J 7.5, CH3CH2), 0.55 (3H, d, J 7.0, CH3CH).
methylated cyclodextrin 120 ꢂC for 3 min, rate: 10 ꢂC/min, final
temp: 210 ꢂC; carrier gas: N2, press 70 kPa). tR¼8.76 min (diol 12bi),
tR¼9.26 min (diol 12bii).
4.2.25. Reduction of (2S,3R)-2-acetoxy-3-hydroxy-3-methyl-4-pen-
tanone 12 catalyzed by KRED-A1B (diol 12ai in equilibrium with
12aii). dH (500 MHz; CDCl3; Me4Si): 5.05 (1H, q, J 6.5, CHOAc),
3.72e3.78 (H, m, CHOH), 2.08 (3H, s, COMe),1.25 (3H, d, J 6.5, Me),1.14
(3H, d, J 6.5, Me),1.08 (3H, s, CCH3); HRMS (ESI) calcd for C8H16O4 m/z
(MþH) 178.1205, obsd 178.1199; GC data: (column: 30 mꢁ0.25
4.5. Enzymatic synthesis of (2S,3R,4S)-3-methyl-2,4-
hexanediol (diol 9i) in larger scale
In a phosphate buffer solution (78 mL, 200 mM, pH 6.9) were
added (4R,5S)-5-hydroxy-4-methyl-3-hexanone (9) (50 mM, 3.9
mmol, 507 mg), ketoreductase KRED-101 (50 mg), glucose (120
mM, 1.68 g), NADPH (0.5 mM, 0.039 mmol, 34 mg), glucose de-
hydrogenase (15 mg) and the mixture was stirred at 25 ꢂC. Peri-
odically the pH was readjusted to 6.9 with NaOH (2 M). After the
completion of the reaction, the product was isolated by extracting
the crude reaction mixture with EtOAc (80 mLꢁ3). The combined
organic layers were then dried over MgSO4 and evaporated to
dryness to give the corresponding diol (9i). Isolated yield 95%,
489 mg.
mmꢁ0.25
mm chiral capillary column, 20% permethylated cyclo-
dextrin 120 ꢂC for 3 min, rate: 10 ꢂC/min, final temp: 210 ꢂC; carrier
gas: N2, press 70 kPa). tR¼9.71 min (diol 12ai and 12aii).
4.3. Acetylation of diols 12ai, 12aii and 12bi, 12bii
In EtOAc (5 mL) were added the product from the enzymatic
reduction of keto alcohol 12 catalyzed by KRED-102 or by KRED-
A1B (7 mg, 0.04 mmol), small quantities of K2CO3 (0.06 mmol,
8 mg), Ac2O (0.1 mmol,10 mL), and DMAP (cat.) and the mixture was
stirred at 0 ꢂC for 10 min. After the completion of the reaction,
water (5 mL) was added to the mixture and the aquatic phase was
extracted with EtOAC (2ꢁ5 mL). The combined organic layer was
washed with saturated NaHCO3 and brine, dried over MgSO4, and
evaporated to dryness (8 mg, 90%).
dH (500 MHz; CDCl3; Me4Si): 4.09e4.17 (1H, m, CHOH), 3.55e3.63
(1H, m, CHOH), 2.84 (1H, br s, OH), 2.72 (1H, br s, OH), 1.48e1.66 (3H,
m, CH3CH2, CH),1.18(3H, d,J7.0, Me), 0.96(3H, t,J7.5,Me), 0.91(3H, d,J
7.0, Me); dC (75 MHz;CDCl3;Me4Si):76.7, 69.2, 41.9, 28.1,19.5,11.9,9.8;
HRMS (ESI) calcd for C7H16O2 m/z(MþH)133.1229,obsd133.0758;GC
data: (column:30 mꢁ0.25 mmꢁ0.25
mm chiralcapillarycolumn, 20%
permethylated cyclodextrin 120 ꢂC for 3 min, rate: 10 ꢂC/min, final
temp: 210 ꢂC; carrier gas: N2, press 70 kPa). tR¼7.35 min (diol 9i).
4.3.1. (2S,4S)-2,4-Diacetoxy-3-methyl-3-pentanol 13b. dH (500 MHz;
CDCl3; Me4Si): 4.97 (1H, q, J 6.5, CHOAc), 4.92 (1H, q, J 6.5, CHOAc),
3.04 (1H, s, OH), 2.05 (3H, s, COMe), 2.02 (3H, s, COMe), 1.25 (3H, d, J
6.5, Me), 1.24 (3H, d, J 6.5, Me), 1.14 (3H, s, CCH3); dC (75 MHz; CDCl3;
Me4Si): 170.3, 170.2, 74.8, 72.0, 71.5, 21.1, 21.0, 17.3, 14.2, 14.0; HRMS
(ESI) calcd for C10H18O5 m/z (MþH) 219.1233, obsd 219.1227; GC
Acknowledgements
Financial support for this work came from the Greek Secretariat
of Research and Technology (Pythagoras 2004 and PENED 2003)
and ELKE of University of Crete (RG2752). D.K. thanks the Greek
National Scholarships Foundation (IKY) for providing a three year
fellowship. We are also thankful to the ProFI (Proteomics Facility at
IMBB-FORTH) for performing all the HRMS analyses.
data: (column: 30 mꢁ0.25 mmꢁ0.25
mm chiral capillary column,
20% permethylated cyclodextrin 120 ꢂC for 3 min, rate: 10 ꢂC/min,
final temp: 210 ꢂC; carrier gas: N2, press 70 kPa). tR¼9.73 min (13b).
4.3.2. (2R,4S)-2,4-Diacetoxy-3-methyl-3-pentanol
meso-13a. dH
(500 MHz; CDCl3; Me4Si): 4.98 (2H, q, J 6.5, 2ꢁCHOAc), 3.03 (1H, s,
OH), 2.10 (6H, s, 2ꢁCOMe),1.20 (6H, d, J 6.5, 2ꢁMe),1.11 (3H, s, CCH3);
dC (75 MHz; CDCl3; Me4Si): 170.8, 75.8, 73.0, 21.3, 17.3, 14.8; HRMS
(ESI) calcd for C10H18O5 m/z (MþH) 219.1233, obsd 219.1225; GC
Supplementary data
Supplementary data provide the 1H NMR spectra of all the
compounds. Supplementary data associated with this article can be
found in online version at 10.1016/j.tet.2010.09.096. These data
include MOL files and InChIKeys of the most important compounds
described in this article.
data: (column: 30 mꢁ0.25 mmꢁ0.25
mm chiral capillary column,
20% permethylated cyclodextrin 120 ꢂC for 3 min, rate: 10 ꢂC/min,
final temp: 210 ꢂC; carrier gas: N2, press 70 kPa). tR¼9.82 min (13a).
4.4. Preparation of MPA-diester of (2S,3R,4S)-3-methyl-2,4-
hexanediol
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