One-pot chemoenzymatic synthesis of chiral 1,3-diols using an enantioselective aldol reaction with chiral Zn2+ complex catalysts and enzymatic reduction using oxidoreductases with cofactor regeneration

Article abstract of DOI:10.1002/asia.201100584

We previously reported on enantioselective aldol reactions of acetone and some aldehydes catalyzed by chiral Zn²⁺ complexes of L-prolyl-pendant [12]aneN₄ (L-ZnL¹) and L-valyl-pendant [12]aneN ₄ (L-ZnL²

Full text of DOI:10.1002/asia.201100584

FULL PAPERS
DOI: 10.1002/asia.201100584
One-pot Chemoenzymatic Synthesis of Chiral 1,3-Diols Using an
Enantioselective Aldol Reaction with Chiral Zn2+ Complex Catalysts and
Enzymatic Reduction Using Oxidoreductases with Cofactor Regeneration
Shotaro Sonoike,[a] Toshinari Itakura,[a] Masanori Kitamura,[a, b] and Shin Aoki*[a, b]
64
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2012, 7, 64 – 74

Abstract: We previously reported on
enantioselective aldol reactions of ace-
tone and some aldehydes catalyzed by
chiral Zn2+ complexes of l-prolyl-
pendant [12]aneN4 (l-ZnL1) and l-
valyl-pendant [12]aneN4 (l-ZnL2) in
aqueous solution. Here, we report on
the one-pot chemoenzymatic synthesis
of chiral 1,3-diols in an aqueous solvent
system at room temperature by a com-
bination of enantioselective aldol reac-
tions catalyzed by Zn2+ complexes of
tion of the aldol products using oxidor-
eductases with the regeneration of the
NADH (reduced form of nicotinamine
adenine dinucleotide) cofactor. The
findings indicate that all four stereoiso-
mers of 1,3-diols can be produced by
appropriate selection of a chiral Zn2+
-complex and an oxidoreductase com-
mercially available from the “Chir-
alscreen OH” kit.
l-
and
d-phenylalanyl-pendant
[12]aneN4 (l-ZnL3 and d-ZnL3) and
the successive enantioselective reduc-
Keywords: aldol reaction · asym-
metric catalysis
· biocatalysis ·
water chemistry · zinc
Introduction
Chiral 1,3-diols are important intermediates in the synthesis
of natural products, pharmaceutically active compounds, and
related materials.[1] To date, numerous publications have ap-
peared dealing with the stereoselective synthesis of 1,3-diols
that contain two stereogenic centers,[2] involving asymmetric
homogeneous and heterogeneous hydrogenation and diaste-
reoselective reduction,[2,3] radical chain elongation,[4] enzy-
matic and non-enzymatic asymmetrization,[5] dynamic kinet-
ic resolution,[6] and stereoselective aldol-Tishchenko reac-
tions.[7] However, there is still substantial demand for stereo-
selective synthetic methods to produce all possible stereoiso-
mers of chiral 1,3-diols.
We previously reported on chiral catalysts that are dually
functionalized with chiral amino acids and achiral Zn2+
complexes of 1,4,7,10-tetraazacyclododecane ([12]aneN4 or
cyclen) such as l-prolyl-pendant [12]aneN4 1 (l-ZnL1) and
l-valyl-pendant [12]aneN4 2 (l-ZnL2).[8] The findings indi-
cate that 1 and 2 catalyze aldol reactions of acetone (and de-
rivatives thereof) with benzaldehydes 3 such as 2-chloroben-
zaldehyde in aqueous solution to give the corresponding
Scheme 1. Enantioselective aldol reaction of acetone with benzaldehyde
catalyzed by chiral Zn2+ complexes.
aldol adducts
4 in good chemical and optical yields
(Scheme 1). A mechanistic study strongly suggested that the
amino acid portion and the Zn2+ ion of the catalysts act as a
base and a Lewis acid, respectively, to generate a Zn2+-eno-
late intermediate,[9] which is different from the enamine in-
termediate that is formed by organocatalysts such as l-pro-
line.[10,11] Moreover, it was suggested that an enolate of ace-
tone complexed with ZnL is more reactive than the enamine
intermediate formed from ketone and l-proline.[12]
selective reduction by an oxidoreductase in an aqueous sol-
vent. Despite the remarkable progress achieved in one-pot
multistep synthetic methodologies,[13–15] only a few attempts
have been made to combine a chemical catalyst and a bio-
catalyst in a one-pot multistep process.[16] For example,
Grçger et al. reported on the synthesis of chiral biaryl-con-
taining alcohols,[16e] the transformation of aromatic alde-
hydes into 1,3-diols[16c], and an enantioselective synthesis of
ethyl (S)-3-aminobutanoate by means of combinations of
chemical (enantioselective aldol reactions catalyzed by orga-
nocatalysts and cross-coupling reactions catalyzed by palla-
dium catalyst)[16b,d] and biocatalytic reactions (enantioselec-
tive reduction and aminolysis).[16a]
These results allowed us to develop a one-pot chemoenzy-
matic synthesis by the combined use of enantioselective
aldol reactions catalyzed by chiral Zn2+ catalysts and stereo-
Herein, we report on the selective synthesis of all possible
stereoisomers of 1,3-diols 7 in a one-pot manipulation in-
volving enantioselective aldol reactions of acetone with 3 to
give 4 using chiral ZnL complexes, l-phenylalanyl- and d-
phenylalanyl-pendant [12]aneN4 (5 (l-ZnL3) and 6 (d-
ZnL3)), and the successive enantioselective reduction of 4 to
give 7 using oxidoreductases, with the regeneration of the
NADH (reduced form of nicotinamine adenine dinucleo-
tide) cofactor (Scheme 2).[15a,17]
[a] S. Sonoike, T. Itakura, Dr. M. Kitamura, Prof. S. Aoki
Faculty of Pharmaceutical Sciences
Tokyo University of Science
2641 Yamazaki, Noda 278-8510 (Japan)
Fax : (+81)4-7121-3670
E-mail: shinaoki@rs.noda.tus.ac.jp
[b] Dr. M. Kitamura, Prof. S. Aoki
Center for Technologies against Cancer
Tokyo University of Science
2641 Yamazaki, Noda 278-8510 (Japan)
Chem. Asian J. 2012, 7, 64 – 74
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65

S. Aoki et al.
FULL PAPERS
NaOH in aqueous solution
(with I=0.1 (NaNO3)) is shown
as a dashed curve in Figure 1a.
Analysis of this curve using the
“BEST” program according to
acid–base equilibrium, Equa-
tions (1)–(4), gave pKa values
of <3 (pKa1), 5.5ꢀ0.1 (pKa2),
7.2ꢀ0.1 (pKa3), and 10.3ꢀ0.1
(pKa4), as summarized in
Scheme 4 and Table 1.[8] An in-
trinsic complexation constant,
log KsACHTNUGRTNEUNG
(ZnL3), and the deproto-
nation constant for the Zn2+
-bound H2O of l-ZnL3, pKa
(ZnL), defined by Equa-
tions (5) and (6) were deter-
mined to be 8.2 and 8.4, respec-
tively, by an analysis of the pH
titration curves for a mixture of
H4ACTHNUTRGNEUNG
(l-L3) and 1 mm ZnSO4
(solid line curve in Figure 1a).
The distribution diagram for a
Scheme 2. One-pot synthesis of optically active 1,3-diols 7 by chemoenzymatic synthesis in an aqueous solvent,
involving an enantioselective aldol reaction of acetone with 3 catalyzed by chiral Zn2+ complexes (ZnL) and
the successive enzymatic reduction of 4 with regeneration of the NADH cofactor.
Results and Discussion
Synthesis of Phenylalanyl-Ligands (l-L3 and d-L3) and
Their Deprotonation Constants and Zn2+ Complexation
Behavior
We previously reported that 1 (l-ZnL1) and 2 (l-ZnL2) cata-
lyze asymmetric aldol reactions of acetone with 2-chloro-
benzaldehyde (3a) in aqueous solution to give the corre-
sponding aldol adduct 4a (X=ortho-Cl) in 72–73% yield
with 80% to 89% ee (R). In this study, new chiral ligands,
11 (l-L3) and 12 (d-L3), were synthesized from 1,4,7-tris(-
tert-butyloxycarbonyl)cyclen 8 (3Boc-cyclen)[18] via 9 or 10,
as shown in Scheme 3, to evaluate the effect of an aromatic
ring on the side chain of the amino acid portion. The Zn2+
complexes of these ligands, 5 (l-ZnL3) and 6 (d-ZnL3), were
Scheme 3. Synthesis of chiral ligands, 11 (l-L3) and 12 (d-L3), and the
corresponding Zn2+ complexes, 5 (l-ZnL3) and 6 (d-ZnL3).
prepared in situ by reacting acid-free 11 (l-L3) or 12 (d-L3)
with Zn
(NO3)2 (1.5 equiv vs. L3), immediately before use.
The Zn2+ complexation properties of both enantiomers of
L3, 11(l-L3), and 12(d-L3), were studied by potentiometric
pH titration. A typical potentiometric pH titration curve at
258C for 1 mm H4A
(l-L3) (prepared from 1 mm l-L3·3TFA
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
mixture of 50 mm 11 (l-L3) and 50 mm Zn2+ in water is
T
shown in Figure 1b. The pKa, log Ks, and pKaACTHGUNTERNNU(G ZnL) values
(TFA=trifluoroacetic acid) and 1 mm HNO3) with 0.1m
of 11 (l-L3) and 12 (d-L3) were almost identical, as listed in
Table 1. The apparent complexation constants, defined by
Equations (7) and (8), log KappACTHNUTRGNEUNG
(ZnL) for 11 (l-L3) and 12
(d-L3), at pH 7.4 were determined to be 5.6 and 5.7, which
are almost the same as those of 1 (L1) and 2 (L2).
Abstract in Japanese:
H4L Ð H3LþHþ, Ka1 ¼ ½H3Lꢁ½Hþꢁ=½H4Lꢁ
H3L Ð H2LþHþ, Ka2 ¼ ½H2Lꢁ½Hþꢁ=½H3Lꢁ
H2L Ð HLþHþ, Ka3 ¼ ½HLꢁ½Hþꢁ=½H2Lꢁ
ð1Þ
ð2Þ
ð3Þ
66
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Chem. Asian J. 2012, 7, 64 – 74

One-pot Synthesis of Chiral 1,3-Diols
Table 1. Deprotonation constants (pKai) and complexation constants [log
sA
(ZnL)] of l-L1, l-L2, l-L3, and d-L3 with I=0.1 (NaNO3) at 258C.[a]
K CHTUNGTRENNUNG
l-L1[b]
l-L2[b]
l-L3
d-L3
pKa1
pKa2
pKa3
pKa4
log K
<3
5.7
8.8
9.7
7.6
<3
5.6
7.6
10.9
9.6
<3
5.5
7.2
10.3
8.2
<3
5.6
7.0
10.6
8.5
sACHTUNGTNER(NUNG ZnL)
A
A
pK
log K CTHGNUTRENNUNG
G
8.6
5.7
8.4
5.6
8.7
5.7
[a] See the text for definitions of pKa, log Ks (ZnL), and pKa (ZnL).
[b] From ref. [8].
ZnL ðH2OÞ Ð ZnL ðOHꢂÞþHþ,
ð6Þ
Ka ðZnLÞ ¼ ½ZnL ðOHꢂÞꢁ½Hþꢁ=½ZnL ðH2OÞꢁ
2þ
KappðZnLÞ ¼ ½ðZnL ðH2OÞþZnL ðOHꢂÞÞꢁ=½Lꢁfree½Zn
½Lꢁfree ¼ ½H4Lꢁþ½H3Lꢁþ½H2Lꢁþ½HLꢁþ½Lꢁ
ꢁ
free
ð7Þ
ð8Þ
Enantioselective Aldol Reactions in Aqueous Media Cata-
lyzed by Chiral Zn2+ Complexes
On the basis of the aforementioned Zn2+ complexation be-
havior, we carried out aldol reactions of acetone and 2-
chlorobenzaldehyde (3a), 4-chlorobenzaldehyde (3b), or 4-
nitrobenzaldehyde (3c) in acetone/H2O in the presence of
50 mm ZnL catalysts (it is considered that ZnL is formed
with >95% at this concentration). The results are summar-
ized in Table 2.
Figure 1. a) Typical potentiometric pH titration curves for a 1 mm 11 (H4-
ACHTUNGTRENNUNG CHTUNGTRENNUNG
(l-L3)) (dashed curve) and for a mixture of 1 mm H (l-L3) and 1 mm
4A
ZnSO4 (solid curve) with I=0.1 (NaNO3) at 258C. b) Speciation diagram
for a mixture of 50 mm 11 (H4A
(l-L3)) and 50 mm ZnSO4 as a function of
CTHUNGTRENNUNG
pH at 258C with I=0.1 (NaNO3).
As reported by List, Lerner, and Barbas III, l-proline
(20 mol% relative to the aldehyde) gave 4a in good chemi-
cal yield (85%) and enantioselectivity (67% ee (R)) in di-
methyl sulfoxide (DMSO; Table 2, entry 1),[8] while its
chemical and optical yields were lowered when an acetone/
H2O mixture was used (Table 2, entry 2). As previously re-
ported, 1 (l-ZnL1) and 2 (l-ZnL2) gave 4a with moderate
enantioselectivity (80–89% ee) in acetone/H2O (Table 2, en-
tries 3 and 4).[8] The new catalysts 5 (l-ZnL3) and 6 (d-
ZnL3) (5 mol% vs. 3a) gave 4a in somehow higher chemical
yields than those for 1 and 2 (Table 2, entries 3 and 4) with
almost the same enantioselectivity (91% ee (R) with 5 (l-
ZnL3) and 91% ee (S) with 6 (d-ZnL3)) (Table 2, entries 5
and 7). When the number of equivalents of 5 and 6 were in-
creased to 10 mol%, the product 4a was obtained in almost
quantitative yield (Table 2, entries 6 and 8). Similarly, 4-
chlorobenzaldehyde 3b and 4-nitrobenzaldehyde 3c gave
the corresponding 1,2-adducts 4b and 4c, with almost identi-
cal chemical and optical yields as 3a (Table 2, entries 9–12).
Scheme 4. Equilibria for deprotonation and Zn2+ complexation of 11 (l-
L3) and 12 (d-L3).
Enantioselective Reductions of b-Hydroxyketones 4a–c
HL Ð LþHþ, Ka4 ¼ ½Lꢁ½Hþꢁ=½H2Lꢁ
LþZn2þ Ð ZnL ðH2OÞ, Ks ¼ ½ZnL ðH2OÞꢁ=½Lꢁ½Zn2þꢁ
ð4Þ
ð5Þ
using Oxidoreductase
For the reduction of b-hydroxyketones 4a–c, we first chose
Bakerꢁs yeast alcohol dehydrogenase (ADH) and oxidore-
Chem. Asian J. 2012, 7, 64 – 74
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67

S. Aoki et al.
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Table 2. The results of asymmetric aldol reactions of acetone with benzaldehydes (3a–c) catalyzed by 1, 2, 5, and 6.
Entry
Aldehydes
Catalyst [mM][a]
mol%[b]
Solvent
Conditions
Product
(yield [%][c]
)
CTN[d]
ee [%][e]
U
1
2
3
4
5
6
7
8
3a
3a
3a
3a
3a
3a
3a
3a
3b
3b
3c
3c
l-proline (50)[f]
20
5
5
5
5
DMSO/acetone (4:1)
acetone/H2O (4:1)
acetone/H2O (4:1)
acetone/H2O (4:1)
acetone/H2O (4:1)
acetone/H2O (4:1)
acetone/H2O (4:1)
acetone/H2O (4:1)
acetone/H2O (4:1)
acetone/H2O (4:1)
acetone/H2O (4:1)
acetone/H2O (4:1)
4 h, 258C
4a (85)
4a (22)
4a (73)
4a (72)
4a (85)
4a (quant)
4a (85)
4a (quant)
4b (quant)
4b (quant)
4c (quant)
4c (quant)
4
4
67 (R)
48 (R)
80 (R)
89 (R)
91 (R)
90 (R)
91 (S)
90 (S)
90 (R)
90 (S)
90 (R)
90 (S)
l-proline (50)[f]
20 h, 258C
24 h, 258C
24 h, 258C
24 h, 258C
24 h, 308C
24 h, 258C
24 h, 308C
72 h, 308C
72 h, 308C
24 h, 308C
24 h, 308C
1 (l-ZnL1) (50)[g]
2 (l-ZnL2) (50)[g]
5 (l-ZnL3) (50)[g]
5 (l-ZnL3) (50)[g]
6 (d-ZnL3) (50)[g]
6 (d-ZnL3) (50)[g]
5 (l-ZnL3) (50)[g]
6 (d-ZnL3) (50)[g]
5 (l-ZnL3) (50)[g]
6 (d-ZnL3) (50)[g]
14
14
17
10
17
10
10
10
10
10
10
5
10
10
10
10
10
9
10
11
12
[a] Numbers in parentheses are the concentrations of catalyst in the solvent system (acetone/H2O). [b] Mol% of catalyst vs. aldehyde. [c] Isolated yield.
[d] Catalytic turnover number (=chemical yield/equivalents of catalyst). [e] Determined by HPLC analysis using a chiral column (Chiralpak AD-H for
4a, Chiralpak AD-H for 4b, and Chiralcel OJ-H for 4c). [f] From ref. [8]. [g] Chiral ligands were extracted with CHCl3 from an aq. NaOH (pH>12) so-
lution prior to use and mixed with ZnACTHNUTGRNEG(UN NO3)2 in situ.
ductases from Saccharomyces cerevisiae (S. cerevisiae) and
Lactobacillus kefir (L. kefir) because these enzymes have
been reported to catalyze the enantioselective reduction of
of 7a (99% ee), respectively, with respect to the stereogenic
center (position 3) in 7a.[22] It should also be noted that the
syn/anti ratios of 7a were almost 1:1, thus indicating that ki-
netic resolution negligibly occurred (except for E092). It
was also found that 4b and 4c are converted into 7b and 7c
by E001 and E039, respectively (Table 3, entries 14–17),[22]
and the reduction of (S)-4a (90% ee) with E001 exclusively
gave anti-7a ((1S,3S)-7a) as the main product (Table 3,
entry 18).[23]
4-phenyl-4-hydroxy-2-butanone
(4d).[5a,16c,19]
However,
Bakerꢁs yeast ADH and S. cerevisiae ADH were not very ef-
fective for the reduction of 4a (Table 3, entries 1 and 2). In
entries 3 and 4, it was found that the ADH from L. kefir is
effective for the stereoselective reduction of 4a and 4b,
albeit this enzyme produces only the (R)-form of 7a and 7b
(Table 3, entries 3 and 4).
We thus decided to test the Chiralscreen OH kit, which is
available from Daicel Co., Ltd, Japan,[20] and contains a li-
brary of recombinant NADH-dependent oxidoreductases.
Generally, oxidoreductases require an equivalent amount of
NAD(P)H (reduced form) for activity. The reductases in
Chiralscreen OH themselves can reduce NAD+ (oxidized
form) to NADH using 2-propanol as a hydride source, so
that the concentration of NADH can be reduced to a cata-
lytic amount.[17,20] It has been also reported that Chir-
alscreen OH can be used to catalyze the reduction of a vari-
ety of ketones even if the solubility of the substrate is low in
aqueous solution.[20a]
The results of the stereoselective reduction of racemic
4a–c using Chiralscreen OH enzymes in 100 mm phosphate
buffer (pH 7.2) at 308C are summarized in Table 3. Among
the nine enzymes of Chiralscreen OH tested (E001, 021,
031, 039, 041, 051, 057, 092, 119), four enzymes such as
E001, E031, E039, and E092, were found to be effective for
the reduction of 4a (Table 3, entries 5–13). In general, E001
and E039 gave better chemical yields than E031 and E092
(Table 3, entries 5 and 8 vs. entries 7 and 12).[21] Interesting-
ly, it was found that E001 and E039 gave (S)- and (R)-forms
One-pot Chemoenzymatic Synthesis of Optically Active 1,3-
Diols 7a–c from Acetone and Benzaldehydes 3a–c
Based on the aforementioned results dealing with enantiose-
lective chemical aldol reactions and enzymatic reductions,
we carried out the one-pot synthesis of 1,3-diols 7a–c from
acetone and benzaldehydes 3a–c. The enantioselective aldol
reaction of acetone and 3 with ZnL3 (l-ZnL3 or d-ZnL3)
(10 mol% relative to 2) was conducted in acetone/H2O to
give 4. The reaction mixture was then diluted with phos-
phate buffer (100 mm, pH 7.2), and the enzyme, NAD+, and
2-propanol were added for the reduction of the aldol prod-
uct 4.
The results are summarized in Table 4. The aldol reaction
of 3a with acetone in the presence of 5 (l-ZnL3) and succes-
sive reduction by E001 gave 7a in 88% yield with a syn/anti
ratio of approximately 4:96 ((1R,3S)-7a is the major isomer;
as listed in Table 4, entry 1). Employing E039 instead of
E001 switched the product to (1R, 3R)-7a (Table 4, entry 2).
The use of 6 (d-ZnL3) with E001 and E039 gave (1S,3S)-7a
and (1S,3R)-7a, respectively, with >99% ee (Table 4, en-
tries 3 and 4). These results suggest that all four stereoiso-
68
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Chem. Asian J. 2012, 7, 64 – 74

One-pot Synthesis of Chiral 1,3-Diols
Table 3. Results for the asymmetric reduction of b-hydroxyketones 4a–c catalyzed by oxidoreductase with NADH regeneration in 100 mm phosphate
buffer (pH 7.2) at 308C for 1 day.
Entry
Substrate
Oxidoreductase[a]
product[c]
(syn/anti)
Yield [%][b]
ee [%][c]
ACHTUNGTRENUN(NG syn/anti)
3R/3S[c]
U
1
2
rac-4a[d]
rac-4a[d]
Bakerꢁs yeast
ADH
–
–
trace
trace
–
–
–
–
from S. cerevisiae
ADH
from L. Kefir
ADH
3
4
rac-4a[d]
rac-4b[d]
7a (52/48)
7b (49/51)
quant
quant
>99% (1R, 3R)/>99% (1S, 3R)
>99% (1R, 3R)/>99% (1S, 3R)
>99/<1
>99/<1
from L. Kefir
5
6
7
8
rac-4a[d]
rac-4a[d]
rac-4a[d]
rac-4a[d]
rac-4a[d]
rac-4a[d]
rac-4a[d]
rac-4a[d]
rac-4a[d]
rac-4b[d]
rac-4b[d]
rac-4c[d]
rac-4c[d]
4a (90% ee (S))
E001[e]
7a (52/48)
–
7a (47/53)
7a (48/52)
–
quant
trace
50
quant
trace
trace
trace
64
trace
quant
quant
quant
quant
quant
>99% (1S, 3S)/>99% (1R, 3S)
–
95% (1S, 3S)/93% (1R, 3S)
>99% (1R, 3R)/>99% (1S, 3R)
–
–
–
<1/>99
–
3/97
>99/<1
–
–
–
1/99
–
<1/>99
>99/<1
<1/>99
>99/<1
<1/>99
E021[e]
E031[e]
E039[e]
9
E041[e]
10
11
12
13
14
15
16
17
18
E051[e]
–
–
E057[e]
E092[e]
7a (78/22)
–
>99% (1S, 3S)/94% (1R, 3S)
–
E119[e]
E001[e]
7b (50/50)
7b (49/51)
7c (50/50)
7c (48/52)
7a (95/5)
>99% (1S, 3S)/>99% (1R, 3S)
>99% (1R, 3R)/>99% (1S, 3R)
>99% (1S, 3S)/>99% (1R, 3S)
>99% (1R, 3R)/>99% (1S, 3R)
>99% (1S, 3S)/>99% (1R, 3S)
E039[e]
E001[e]
E039[e]
E001[e]
[a] Conditions for the enzymatic reductions: [ketone]=10 mm in 100 mm phosphate buffer, 24 h, 308C in the presence of 2-propanol (100 mm) and
NAD+ (2 mm). [b] Yield of isolated product. [c] Determined by 1H NMR and HPLC analysis using a chiral column (Chiralcel OD-H for 7a, Chiralcel
OJ-H for 7b, and Chiralpak AD-H for 7c). [d] Racemate of 4a was used as the substrate. [e] Enzyme of Chiralscreen purchased from Daicel Co., Ltd.
Table 4. Results for the one-pot chemoenzymatic synthesis of chiral 1,3-diols 7a–c in aqueous solvent at room temperature by the combined use of an
enantioselective aldol reaction catalyzed by chiral Zn2+-complex catalysts and an enantioselective reduction using Chiralscreen OH.
Entry
Substrate
ZnL[a]
Oxidoreductase[b]
(Chiralscreen OH)
Product
Yield [%][c]
Product ratio[d]
A
E
(1R, 3S)
ACHTUNGTRENNUNG(1S, 3S)
1
2
3
4
5
6
7
8
3a
3a
3a
3a
3b
3b
3b
3b
3c
3c
3c
3c
5 (l-ZnL3)
5 (l-ZnL3)
6 (d-ZnL3)
6 (d-ZnL3)
5 (l-ZnL3)
5 (l-ZnL3)
6 (d-ZnL3)
6 (d-ZnL3)
5 (l-ZnL3)
5 (L-ZnL3)
6 (d-ZnL3)
6 (d-ZnL3)
E001
E039
E001
E039
E001
E039
E001
E039
E001
E039
E001
E039
7a
7a
7a
7a
7b
7b
7b
7b
7c
7c
7c
7c
88
88
84
92
68
60
60
48
83
87
91
80
96
<1
4
<1
96
<1
5
<1
93
<1
4
4
<1
95
<1
5
<1
96
<1
4
<1
94
<1
4
5
<1
96
<1
4
<1
95
<1
7
<1
96
<1
95
<1
4
<1
96
<1
6
9
10
11
12
<1
96
<1
[a] ZnL complexes were formed in situ. [b] Conditions for reductions by enzymes: [ketone]=10 mm in 100 mm phosphate buffer (pH 7.2), 24 h, 308C in
the presence of 2-propanol (100 mm) and NAD+ (2 mm). [c] Yield of isolated product. [d] Determined by HPLC analysis of a mixture of all stereoiso-
mers by column chromatography using a chiral column (Chiralcel OD-H for 7a, Chiralpak AD-H for 7b, and Chiralcel OJ-H for 7c).
mers of 1,3-diols can be prepared by selecting the appropri-
ate chiral Zn2+-complexes and dehydrogenases. Similarly,
entries 5–8 and 9–12 indicate that 4-chlorobenzaldehyde 3b
and 4-nitrobenzaldehyde 3c can be converted into all possi-
Chem. Asian J. 2012, 7, 64 – 74
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
69

S. Aoki et al.
FULL PAPERS
AHCTUNGTRENNUNG
line
(300 MHz) and 13C (75 MHz) NMR
spectra were recorded on JEOL
of
sodium
(589 nm).
1H
a
Always 300 spectrometer. Chemical
shifts (d) in CDCl3 were determined
relative to an internal reference of tet-
ramethylsilane (TMS) (for 1H NMR)
or CDCl3 (for 13C NMR). Chemical
shifts (d) in D2O were determined rel-
ative to an external reference of
2,2,3,3-[D4]-3-(trimethylsilyl)propionic
(TSP) sodium salt for 1H NMR or
Scheme 5. Summary of the one-pot chemoenzymatic synthesis of 1,3-diols 7a–c from acetone and benzalde-
hydes 3a–c.
[D8]1,4-dioxane for 13C NMR. TMS
ble stereoisomers of the corresponding 1,3-diols, 7b and 7c
1
was used as an internal reference for H NMR measurements in CD3OD.
Thin-layer chromatography (TLC) and silica-gel column chromatography
were performed using aluminum-backed silica gel TLC plates (Merck-
5554) and FL-100D silica gel (Fuji Silysia Chemical Ltd.), respectively.
IR spectra were recorded at room temperature on a Spectrum 100 FT-IR
spectrophotometer (Perkin–Elmer). MS measurements were performed
on a JEOL JMX-SX102A and on a Varian 910 mass spectrometer.
(Scheme 5).[22]
Conclusions
In this work, we report on the one-pot synthesis of optically
active 1,3-diols 7 by enantioselective aldol reactions of ace-
tone with 3 catalyzed by chiral Zn2+ complexes, 5 and 6, to
afford the 1,2-adducts 4, and the successive reduction of 4
by a recombinant oxidoreductase from Chiralscreen OH.
For example, a one-pot chemoenzymatic synthesis from ace-
tone and 3a with 5 (l-ZnL3) and E039 afforded (1R, 3R)-7a
in 88% yield with 99% ee. Using these methodologies, all
possible stereoisomers of 7a–c were obtained by the appro-
priate selection of the ZnL aldol catalyst and dehydrogen-
ase. These results outline a strategy that can be useful for
the design of new one-pot methodologies for stereoselective
organic reactions in aqueous solutions.
1,4,7-Tris(tert-butyloxycarbonyl)-10-(N-tert-butyloxycarbonyl-(S)-
phenylalanyl-1,4,7,10-tetraazacyclododecane (9)
1-benzotriazolyloxy-tris(pyrollidino)phosphonium
(PyBop;
722 mg,
1.39 mmol) and iPr2NEt (356 mg, 2.76 mmol) were added to a solution of
8[18] (437 mg, 0.92 mmol), N-tert-butyloxycarbonyl-l-phenylalanine
(368 mg, 1.39 mmol), and HOBt (212 mg, 1.39 mmol) in anhydrous DMF
(10 mL) at 08C, and the entire reaction mixture was stirred at room tem-
perature for 72 h and then diluted with CHCl3. The organic layer was
washed with H2O, sat. aq. NaHCO3 and brine, dried over Na2SO4, fil-
tered, and concentrated under reduced pressure. The resulting residue
was purified by silica-gel column chromatography (hexane/AcOEt=3:1)
to give 9 as a colorless amorphous solid (519 mg, 83% yield). M.p. 109–
1118C; ½aꢁ2D3 =+55.0 (c=1.00, CHCl3); 1H NMR (300 MHz, CDCl3/
TMS): d=1.38–1.50 (m, 36H), 2.90–3.80 (br, 18H), 4.70 (d, J=7.6 1H),
5.28 (d, J=8.1 1H), 7.20–7.26 ppm (m, 5H); 13C NMR (75 MHz, CDCl3/
TMS): d=28.2, 28.3, 40.6, 49.0- 50.0 (br), 50.5, 50.9, 51.8, 79.2, 80.1, 80.2,
80.3, 126.8, 128.3, 129.3, 136.3, 154.3, 155.6, 156.7, 172.4 ppm; IR (ATR):
n˜ =3310, 3107, 2977, 2933, 1690, 1642, 1466, 1404, 1365, 1248, 1158, 1130,
Experimental Section
1105, 1048, 1037, 972, 862, 777, 701, 622, 506, 457, 209, 400, 393 cmꢂ1
HRMS (FAB+): calcd for C37H62N5O9, 720.4548; found, 720.4552.
;
General Procedures
All reagents and solvents were of the highest commercial quality and
were used without further purification, unless otherwise noted. Acetone
was dried over anhydrous CaSO4 and distilled. 2-Chlorobenzaldehyde
was washed with aqueous 10% Na2CO3 and then distilled. 4-Chloroben-
zaldehyde and 4-nitrobenzaldehyde were purified by sublimation. Zn-
1-(S)-Phenylalanyl-1,4,7,10-tetraazacyclododecane·3TFA salt (11·3TFA)
TFA (2 mL, 27 mmol) was added to a solution of 9 (519 mg, 0.72 mmol)
in CH2Cl2 (8 mL), and the resulting solution was stirred at room temper-
ature for 4 h. The mixture was concentrated under reduced pressure and
70
www.chemasianj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2012, 7, 64 – 74

One-pot Synthesis of Chiral 1,3-Diols
the resulting solid was recrystallized from EtOH/Et2O to afford 11·3TFA
salt (the number of TFA units was determined by potentiometric pH ti-
in H2O (50 mL) and acetone (0.2 mL), and the mixture was stirred for
10 min. Subsequently, aldehyde 3 (0.25 mmol) was added and the whole
reaction mixture was stirred for 20–72 h at 258C or 308C. The reaction
mixture was diluted with 6% aq. NH4Cl (2.5 mL) and extracted with
ethyl acetate (30 mLꢂ3). The combined organic layers were dried over
anhydrous Na2SO4, filtered, and concentrated under reduced pressure.
The resulting residue was purified by silica-gel column chromatography
(hexane/AcOEt) to provide 4a–c. The optical purities of the aldol prod-
ucts were determined by HPLC using a chiral HPLC column, as de-
scribed below.
22
tration; see Figure 1a) (450 mg, 94% yield). M.p. 108–1108C; ½aꢁD
=
+31.3 (c=1.00, H2O); 1H NMR (300 MHz, D2O/external TSP): d=3.21
(m, 18H), 4.00 (m, 1H), 4.80 (m, 2H), 7.33 (m, 2H), 7.45 ppm (m, 3H);
13C NMR (75 MHz, D2O): d=36.7, 43.1, 43.5, 44.0, 44.5, 45.9, 46.2, 46.9,
46.9, 51.9, 116.3 (q, JCꢂF =291.9), 128.3, 129.2, 129.5, 133.1 (q, JCꢂF =35.5),
171.3; IR (ATR): n˜ =3014, 2860, 1661, 1499, 1457, 1429, 1360, 1175, 1120,
1016, 966, 835, 797, 762, 720, 702, 597, 548, 518, 469, 442, 409, 395,
386 cmꢂ1
; , 320.2444; found,
HRMS (ESI+): calcd for C17H30N5O+1
320.2445.
General procedure for the enzymatic enantioselective reduction of b-
hydroxyketone 4a–c (Table 3)
1-(S)-Phenylalanyl-1,4,7,10-tetraazacyclododecane (11)
Aqueous 1n NaOH (1 mL) was added to a solution of 11·3TFA (13 mg,
0.2 mmol). Subsequently, the solution was extracted with CHCl3. The or-
ganic layer was dried over Na2SO4 and concentrated under reduced pres-
Cofactor NAD+ (36 mg, 0.05 mmol) and enzyme (10 mg) were added to
a mixture of 4 (50 mg, 0.25 mmol) in 100 mm phosphate buffer (pH 7.2,
25 mL) and 2-propanol (1 mL), and the resulting solution was stirred for
24 h at 308C. The entire reaction mixture was extracted with EtOAc
(30 mLꢂ3), and the combined organic layers were dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pressure. The resulting
residue was purified by silica-gel column chromatography (hexane/
AcOEt) to provide the 1,3-diol 7, the diastereo- and enantioselectivities
of which were determined by NMR spectrocopy and HPLC with a chiral
HPLC column, as described below.
1
sure to give 11 as a colorless oil. ½aꢁ2D3 =+43.6 (c=1.00, CHCl3); H NMR
(300 MHz, D2O/external TSP): d=2.40–2.81 (m, 15H), 2.98 (dd, J=13.0,
7.5 Hz, 1H), 3.13–3.40 (m, 3H), 3.51–3.67 (m, 1H), 3.94 (t, J=7.1 Hz,
1H), 7.09–7.24 ppm (m, 5H); 13C NMR (75 MHz, D2O): d=42.6, 44.6,
45.7, 47.1, 47.5, 47.7, 48.0, 48.4, 49.5, 53.3, 126.4 128.2, 129.3, 137.9,
176.3 ppm; IR (ATR): n˜ =3288, 2885, 2828, 1631, 1494, 1452, 1353, 1237,
1130, 1074, 1030, 895, 807, 744, 699, 661, 523, 419, 404, 398, 386 cmꢂ1
.
HRMS (ESI+): calcd for C17H30N5O+1, 320.2444; found, 320.2445.
General Procedure for the One-Pot Chemoenzymatic Synthesis of 1,3-
1,4,7-Tris(tert-butyloxycarbonyl)-10-(N-tert-butyloxycarbonyl-(R)-
diols 7a–c (Table 4)
phenylalanyl-1,4,7,10-tetraazacyclododecane (10)
A solution of ZnL (12.5 mmol) in acetone/H2O was prepared as described
above. The substrate aldehyde (0.125 mmol) was added and the entire re-
action mixture was stirred at 308C for 24–72 h. After confirming the com-
pletion of the aldol reaction by TLC, the reaction mixture was diluted
with 12.5 mL of 100 mm phosphate buffer (pH 7.2), to which 2-propanol
(0.5 mL), cofactor NAD+ (18 mg, 25 mmol), and enzyme (10 mg) were
added. After stirring the mixture at 308C for 24 h, the entire reaction
mixture was extracted with ethyl acetate (30 mLꢂ3). The combined or-
ganic layers were dried over anhydrous Na2SO4, filtered, and the solution
was concentrated under reduced pressure. The resulting residue was puri-
fied by silica-gel column chromatography (hexane/AcOEt) to provide the
pure product. The optical purities of the thus obtained 1,3-diols were de-
termined by NMR spectroscopy and HPLC using a chiral HPLC column.
This compound was prepared from 8 and N-tert-butyloxycarbonyl-d-phe-
nylalanine following a method similar to that used for 9. ½aꢁ2D2 =ꢂ52.5
(c=1.00, CHCl3); HRMS (FAB+): calcd for C37H62N5O9, 720.4548;
found, 720.4542.
1-(R)-Phenylalanyl-1,4,7,10-tetraazacyclododecane·3TFA salt (12·3TFA)
This compound was prepared following a method similar to that used for
11·3TFA. ½aꢁ2D3 =ꢂ30.3 (c=1.00, H2O); HRMS (ESI+): calcd for
C17H30N5O+1, 320.2444; found, 320.2445.
1-(3-(R)-Phenylalanyl-1,4,7,10-tetraazacyclododecane (12)
This compound was prepared following a method similar to that used for
11. ½aꢁ2D2 =ꢂ44.3 (c=1.00, CHCl3); HRMS (ESI+): calcd for
C17H30N5O+1, 320.2444; found, 320.2445.
4-(2-Chlorophenyl)-4-hydroxybutan-2-one (4a)[24]
1H NMR (300 MHz, CDCl3/TMS): d=2.23 (s, 3H), 2.64–3.01 (m, 2H),
3.61 (br, 1H), 5.51 (m, 1H), 7.18–7.63 ppm (m, 4H; ArH); HPLC
(Daicel Chiralpak AD-H column,10.46 cmꢂ25 cm, hexane/EtOH=
95:5, flow rate: 1 mLminꢂ1, l=254 nm, 258C): tR (S)=14.4 min, tR (R)=
19.4 min.
Potentiometric pH Titrations
The preparation of the test solutions and the calibration method for the
electrode system (Potentiometric Automatic Titrator AT-400 and Auto
Piston Buret APB-410, Kyoto Electronics Manufacturing, Co. Ltd.) with
a Combination pH Electrode 98100C171 (Kyoto Electronics Manufactur-
ing, Co.) were described in a previous report.[8] All test solutions (50 mL)
were kept under an argon (>99.999% purity) atmosphere. Potentiomet-
ric pH titrations were performed with I=0.10 (NaNO3) at 25.0ꢀ0.18C
(0.1n aq. NaOH was used as a base). Deprotonation constants of Zn2+
-bound water K’2 (=[OHꢂ-bound species] aH+/[H2O-bound species])
were determined by means of the software program BEST. All of the
sigma fit values defined in the program were smaller than 0.2. The Kw
4-(4-Chlorophenyl)-4-hydroxybutan-2-one (4b)[24]
1H NMR (300 MHz, CDCl3/TMS): d=2.20 (s, 3H), 2.80–2.85 (m, 2H),
3.37 (br, 1H), 5.10–5.16 (m, 1H), 7.26–7.35 ppm (m, 4H; ArH); HPLC
(Daicel Chiralpak AD-H column (10.46 cmꢂ25 cm), hexane/2-propa-
nol=97:3, flow rate: 1 mLminꢂ1, l=254 nm, 258C): tR (S)=26.1 min, tR
(R)=23.7 min.
4-(4-Nitrophenyl)-4-hydroxybutan-2-one (4c)[24]
ACTHNUTRGNEUNG
(equivalent to aH+aOH-), K’w (equivalent to [H+][OHꢂ]), and fH+ values
used at 258C were 10ꢂ14.00, 10ꢂ13.79, and 0.825, respectively. The corre-
sponding mixed constants, K2(=[OHꢂ-bound species]aH+/[H2O-bound
species]), were derived using [H+]=aH+/fH+. The species distribution
values (%) against pH (=ꢂlog[H+]+0.084) were obtained using the SPE
software program.
1H NMR (300 MHz, CDCl3/TMS): d=2.23 (s, 3H), 2.84–2.90 (m, 2H),
3.59 (d, J=3.2 Hz, 1H), 5.51 (m, 1H), 7.54 (d, J=7.0 Hz, 2H; ArH) ,
8.21 ppm (d, J=7.0 Hz, 2H; ArH); HPLC (Daicel Chiralcel OJ-H
column (10.46 cmꢂ25 cm), hexane/EtOH=95:5, flow rate: 1 mLminꢂ1
l=254 nm, 258C): tR (S)=37.6 min, tR (R)=32.1 min.
,
General Procedure for Catalytic Aldol Reactions of Acetone and
(1R,3R)-7a)[22]
ACHUTGTNRNEUG(N 1R, 3R)-1-(2-Chlorophenyl)-1,3-butanediol (ACHTUTGNRENNUGN
Aldehydes 3a–c (Table 2)
½aꢁ2D3 =+71.1 (c=0.50, CHCl3); 1H NMR (300 MHz, CDCl3/TMS): d =
1.21 (d, J = 6.3 Hz, 3H), 1.56–1.69 (m, 1H), 1.80–1.91 (m, 1H), 3.55 (br,
1H), 4.12 (br, 1H), 4.15–4.24 (m, 1H), 5.25–5.34 (m, 1H), 7.15–7.62 ppm
(m, 4H); 13C NMR (75 MHz, CDCl3): d=23.9, 45.0, 69.0, 71.5, 126.9,
127.2, 128.3, 129.2, 131.2, 141.7 ppm; IR (ATR): n˜ =3326, 3069, 2969,
2913, 1596, 1574, 1473, 1438, 1321, 1130, 1077, 1032, 929, 751, 703,
A given chiral ligand for the Zn2+ complex (TFA salt) (12.5 mmol) was
extracted from its 0.2m NaOH aqueous solution with CHCl3. After
drying the combined organic layer over anhydrous Na2SO4, the solution
was filtered and concentrated under reduced pressure. The remaining res-
idue was added to a solution of a mixture of ZnACHTUNGTRNEUNG(NO3)2·6H2O (18.7 mmol)
Chem. Asian J. 2012, 7, 64 – 74
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
71

S. Aoki et al.
FULL PAPERS
+1
460 cmꢂ1
;
HRMS (FAB+): calcd for C10H14ClO2
,
201.0677; found,
(1R,3R)-7c)[22]
ACHUTGTNRENNUG(1R, 3R)-1-(4-Nitrophenyl)-1,3-butanediol (ACHTUTGNRENNUGN
201.0681; HPLC (Daicel Chiralcel OD-H column (10.46 cmꢂ25 cm),
½aꢁ2D3 =+38.6 (c=0.50, CHCl3); 1H NMR (300 MHz, CDCl3/TMS): d=
1.26 (d, J=6.1 Hz, 3H; CH3), 1.75–1.86 (m, 2H; CH2), 2.50 (s, 1H; OH),
4.10 (s, 1H; OH), 4.14–4.24 (m, 1H; CHCH3), 5.06 (t, J=5.9 Hz, 1H;
CHCH2), 7.53 (d, J=8.3 Hz, 2H; ArH), 8.20 ppm (d, J=10.2 Hz, 2H;
ArH); 13C NMR (75 MHz, CDCl3): 24.5, 46.8, 69.2, 74.2, 123.7, 126.4,
146.9, 151.7 ppm; IR (ATR): n˜ =3351, 3117, 2971, 2954, 2908, 2879, 1602,
1514, 1336, 1124, 1074, 864, 749, 698 cmꢂ1; HRMS (FAB+): calcd for
C10H13NO4+1, 211.0845; found, 211.0763; HPLC (Daicel Chiralcel OJ-H
hexane/2-propanol=98:2, flow rate 1.0 mLminꢂ1
, l=254 nm): tR =
26.5 min.
(1S,3R)-7a)[22]
ACHTUNGTRENNUNG(1S, 3R)-1-(2-Chlorophenyl)-1,3-butanediol (ACHTUGNTRENNUGN
½aꢁ2D3 =ꢂ91.7 (c=0.50, CHCl3); 1H NMR (300 MHz, CDCl3/TMS): d =
1.22 (d, J = 6.3 Hz, 3H), 1.79–1.93 (m, 2H), 3.26 (br, 1H), 3.97–4.07 (m,
1H), 4.21 (br, 1H), 5.37–5.42 (m, 1H), 7.15–7.62 ppm (m, 4H); 13C NMR
(75 MHz, CDCl3): d=23.1, 43.3, 65.7, 68.5, 126.9, 127.2, 128.2, 129.3,
131.1, 141.5 ppm; IR (ATR): n˜ =3329, 3069, 2969, 2916, 1596, 1574, 1472,
1440, 1377, 1129, 1078, 1033, 975, 751, 703, 461 cmꢂ1; HRMS (FAB+):
calcd for C10H14ClO2+1, 201.0677; found, 201.0683; HPLC (Daicel Chiral-
cel OD-H column (10.46 cmꢂ25 cm), hexane/2-propanol=98:2, flow
rate 1.0 mLminꢂ1, l=254 nm): tR =34.0 min.
column (10.46 cmꢂ25 cm), hexane/EtOH=95:5, flow rate 1.0 mLminꢂ1
l=254 nm): tR =32.7 min.
,
(1S,3R)-7c)[22]
ACHUTNGREN(NUG 1S, 3R)-1-(4-Nitrophenyl)-1,3-butanediol (ACHTUTGNRENNUGN
½aꢁ2D3 =ꢂ54.9 (c=0.50, CHCl3); 1H NMR (300 MHz, CDCl3/TMS): d=
1.27 (d, 3H, J=6.1 Hz), 1.75–1.79 (m, 2H), 2.11 (br, 1H), 3.65 (br, 1H),
3.95–4.13 (m, 1H), 5.10–5.21 (m, 2H), 7.53 (d, J=8.4 Hz, 2H), 8.21 ppm
(d, J=8.3 Hz, 2H); 13C NMR (75 MHz, CDCl3): d=23.7, 45.5, 65.6, 71.0,
123.6, 126.3, 147.1, 152.0 ppm; IR (ATR): n˜ =3339, 2969, 2932, 1601,
1513, 1343, 1290, 1107, 1074, 1052, 853, 749, 698 cmꢂ1; HRMS (FAB+):
calcd for C10H13NO4+1, 211.0845; found, 211.0770; HPLC (Daicel Chiral-
cel OJ-H column (10.46 cmꢂ25 cm), hexane/EtOH=95:5, flow rate
1.0 mLminꢂ1, l=254 nm): tR =30.5 min.
(1R,3S)-7a)[22]
ACHTUNGTRENNUNG(1R, 3S)-1-(2-Chlorophenyl)-1,3-butanediol (ACHTUGNTRENNUGN
½aꢁ2D3 =+86.3 (c=0.50, CHCl3); 1H NMR (300 MHz, CDCl3/TMS): d =
1.24 (d, J = 6.6 Hz, 3H), 1.81–1.95 (m, 2H), 2.95 (br, 1H), 3.95 (br, 1H),
3.99–4.09 (m, 1H), 5.37–5.46 (m, 1H), 7.16–7.63 ppm (m, 4H); 13C NMR
(75 MHz, CDCl3): d=23.2, 43.3, 65.8, 68.6, 126.9, 127.2, 128.3, 129.3,
131.1, 141.6 ppm; IR (ATR): n˜ =3328, 3069, 2968, 2916, 1596, 1574, 1472,
1440, 1377, 1129, 1078, 1033, 975, 751, 703, 460 cmꢂ1; HRMS (FAB+):
calcd for C10H14ClO2+1, 201.0677; found, 201.0683; HPLC (Daicel Chiral-
cel OD-H column (10.46 cmꢂ25 cm), hexane/2-propanol=98:2, flow
rate 1.0 mLminꢂ1, l=254 nm): tR =28.4 min.
(1R,3S)-7c)[16c]
ACHUTNGREN(NUG 1R, 3S)-1-(4-Nitrophenyl)-1,3-butanediol (ACHTUTGNRENNUGN
1H NMR (300 MHz, CDCl3/TMS): d=1.27 (d, 3H, J=6.1 Hz), 1.75–1.79
(m, 2H), 2.01 (br, 1H), 3.61 (br, 1H), 4.14–4.24 (m, 1H), 5.04–5.07 (m,
1H), 7.53 (d, J=8.3 Hz, 2H), 8.18 ppm (d, J=8.3 Hz, 2H); HPLC
(Daicel Chiralcel OJ-H column (10.46 mmꢂ25 cm), hexane/EtOH=
95:5, flow rate 1.0 mLminꢂ1, l=254 nm): tR =28.4 min.
(1S,3S)-7a)[22]
ACHTUNGTRENNUNG(1S, 3S)-1-(2-Chlorophenyl)-1,3-butanediol (ACHTUGNTRENNUGN
½aꢁ2D3 =ꢂ81.5 (c=0.50, CHCl3); 1H NMR (300 MHz, CDCl3/TMS): d =
1.20 (d, J = 6.3 Hz, 3H), 1.57–1.70 (m, 1H), 1.80–1.92 (m, 1H), 3.34 (br,
1H), 3.95 (br, 1H), 4.15–4.25 (m, 1H), 5.25–5.33 (m, 1H), 7.15–7.63 ppm
(m, 4H); 13C NMR (75 MHz, CDCl3): 24.0, 45.1, 69.1, 71.5, 126.9, 127.2,
128.4, 129.2, 131.2, 141.7 ppm; IR (ATR): n˜ =3323, 3069, 2969, 2912,
(1S,3S)-7c)[22]
ACHUTNGREN(NUG 1S, 3S)-1-(4-Nitrophenyl)-1,3-butanediol (ACHTUTGNRENNUGN
½aꢁ2D3 =ꢂ30.5 (c=0.50, CHCl3); 1H NMR (300 MHz, CDCl3/TMS): d=
1.26 (d, J=6.1 Hz, 3H; CH3), 1.75–1.91 (m, 2H; CH2), 2.57 (s, 1H; OH),
4.10 (s, 1H; OH), 4.14–4.27 (m, 1H; CHCH3), 5.06 (t, J=5.9 Hz, 1H;
CHCH2), 7.53 (d, J=8.3 Hz, 2H; ArH), 8.20 ppm (d, J=10.2 Hz, 2H;
ArH); 13C NMR (75 MHz, CDCl3): d=24.5, 46.8, 69.2, 74.2, 123.7, 126.4,
146.9, 151.7 ppm; IR (ATR): n˜ =3351, 3117, 2971, 2954, 2908, 2879, 1602,
1514, 1336, 1124, 1074, 864, 749, 698 cmꢂ1; HRMS (FAB+): calcd for
C10H13NO4+1, 211.0845; found, 211.0763; HPLC (Daicel Chiralcel OJ-H
1596, 1574, 1473, 1438, 1320, 1130, 1076, 1033, 929, 751, 703, 460 cmꢂ1
;
+1
HRMS (FAB+): calcd for C10H14ClO2
, 201.0677; found, 201.0681;
HPLC (Daicel Chiralcel OD-H column (10.46 cmꢂ25 cm), hexane/2-
propanol=98:2, flow rate 1.0 mLminꢂ1, l=254 nm): tR =42.9 min.
(1R,3R)-7b)[16c]
ACHTUNGTRENNUNG(1R, 3R)-1-(4-Chlorophenyl)-1,3-butanediol (ACHTUGNTRENNUGN
1H NMR (300 MHz, CDCl3/TMS): d = 1.20 (d, J = 6.3 Hz, 3H), 1.57–
1.70 (m, 1H), 1.80–1.92 (m, 1H), 3.34 (br, 1H), 3.95 (br, 1H), 4.15–4.25
(m, 1H), 5.25–5.33 (m, 1H), 7.15–7.63 ppm (m, 4H); HPLC (Daicel Chir-
alpak AD-H column (10.46 cmꢂ25 cm), hexane/2-propanol=97:3, flow
rate 0.8 mLminꢂ1, l=254 nm): tR =35.7 min.
column
(10.46 mmꢂ25 cm),
hexane/EtOH=95:5,
flow
rate
1.0 mLminꢂ1, l=254 nm): tR =35.0 min.
(1S, 3R)-7b)[16c]
ACHTUNGTRENNUNG(1S, 3R)-1-(4-Chlorophenyl)-1,3-butanediol (ACHTUGNTRENNUGN
Acknowledgements
1H NMR (300 MHz, CDCl3/TMS): d=1.23 (d, J=6.2 Hz, 3H; CH3),
1.80–1.92 (m, 2H; CH2), 2.14 (s, 1H; OH), 3.11 (s, 1H; OH), 4.03–4.09
(m, 1H; CHCH3), 5.04 (dd, J=6.9 Hz, J=4.1 Hz, 1H; CHCH2), 7.25–
7.34 ppm (m, 4H; ArH); HPLC (Daicel Chiralpak AD-H column
This work was supported by Grants-in-Aid from the Ministry of Educa-
tion, Science and Culture in Japan (No. 19659026, 22390005, and
22659005) and an “Academic Frontier” project for private universities:
matching fund subsidy from MEXT, 2009–2013.
(10.46 cmꢂ25 cm), hexane/2-propanol=97:3, flow rate 0.8 mLminꢂ1
l=254 nm): tR =46.5 min.
,
(1R,3S)-7b)[16c]
ACHTUNGTRENNUNG(1R, 3S)-1-(4-Chlorophenyl)-1,3-butanediol (ACHTUGNTRENNUGN
[1] A. Kleemann, J. Engels, B. Kutscher, D. Reichert, Pharmaceutical
Substances: Syntheses, Patents, Applications, 4th ed., Thieme, Stutt-
gart, 2001.
[2] a) Modern Aldol Reactions (Ed.: R. Mahrwald), Wiley-VCH, Wein-
heim, 2004; b) S. E. Bode, M. Wolberg, M. Mꢃller, Synthesis 2006,
557–588; c) R. Noyori, Asymmetric Catalysts in Organic Synthesis
Wiley, New York, 1994; d) I. Ojima, Catalytic Asymmetric Synthesis
VCH, New York, 1993.
1H NMR (300 MHz, CDCl3/TMS): d=1.23 (d, J=6.2 Hz, 3H; CH3),
1.80–1.92 (m, 2H; CH2), 2.16 (s, 1H; OH), 3.13 (s, 1H; OH), 4.03–4.09
(m, 1H; CHCH3), 5.04 (dd, J=6.9 Hz, J=4.1 Hz, 1H; CHCH2), 7.25–
7.34 ppm (m, 4H; ArH); HPLC (Daicel Chiralpak AD-H column
(10.46 cmꢂ25 cm), hexane/2-propanol=97:3, flow rate 0.8 mLminꢂ1
l=254 nm): tR =43.5 min.
,
[3] a) Y. Hayashi, S. Aratake, T. Okano, J. Takahashi, T. Sumiya, M.
Shoji, Angew. Chem. 2006, 118, 5653–5655; Angew. Chem. Int. Ed.
2006, 45, 5527–5529; b) T. A. Davis, P. R. Chopade, G. Hilmersson,
R. A. Flowers II, Org. Lett. 2005, 7, 119–122; c) D. A. Evans, K. T.
Chapman, E. M. Carreira, J. Am. Chem. Soc. 1988, 110, 3560–3578;
d) D. A. Evans, K. T. Chapman, Tetrahedron Lett. 1986, 27, 5939–
5942.
(1S,3S)-7b)[16c]
ACHTUNGTRENNUNG(1S, 3S)-1-(4-Chlorophenyl)-1,3-butanediol (ACHTUGNTRENNUGN
1H NMR (300 MHz, CDCl3/TMS): d=1.24 (d, J=6.3 Hz, 3H; CH3),
1.68–1.87 (m, 2H; CH2), 2.67 (s, 1H; OH), 3.42 (s, 1H; OH), 4.12–4.20
(m, 1H; CHCH3), 4.92 (dd, J=9.5 Hz, J=3.3 Hz, 1H; CHCH2), 7.25–
7.34 ppm (m, 4H; ArH); HPLC (Daicel Chiralpak AD-H column
(10.46 cmꢂ25 cm), hexane/2-propanol=97:3, flow rate 0.8 mLminꢂ1
l=254 nm): tR =38.7 min.
,
[4] C. J. Sinz, S. D. Rychnovsky, Top. Curr. Chem. 2001, 216, 51–92.
72
www.chemasianj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2012, 7, 64 – 74

One-pot Synthesis of Chiral 1,3-Diols
[5] a) D. Acetti, E. Brenna, C. Fuganti, F. G. Gatti, S. Serra, Eur. J. Org.
Chem. 2010, 142–151; b) K. Chen, J. M. Richter, P. S. Baran, J. Am.
Chem. Soc. 2008, 130, 7247–7249; c) S. Bertelsen, P. Dinꢄr, R. L. Jo-
hansen, K. A. Jørgensen, J. Am. Chem. Soc. 2007, 129, 1536–1537;
d) J. T. Binder, S. F. Kirsch, Chem. Commun. 2007, 4164–4166;
e) H. M. L. Davies, S. J. Hedley, B. R. Bohall, J. Org. Chem. 2005,
70, 10737–10742; f) K. Ahmad, S. Koul, S. C. Taneja, A. P. Singh, M.
Kapoor, Riyaz-ul-Hassan, V. Verma, G. N. Qazi, Tetrahedron: Asym-
metry 2004, 15, 1685–1692.
[6] a) F. Levayer, C. Rabiller, C. Tellier, Tetrahedron: Asymmetry 1995,
6, 1675–1682; b) Z.-W. Guo, S.-H. Wu, C. S. Chen, G. Girdaukas,
C. J. Sih, J. Am. Chem. Soc. 1990, 112, 4942–4945; c) K. Yamamoto,
H. Ando, H. Chikamatsu, J. Chem. Soc. Chem. Commun. 1987, 334–
335.
[7] a) T. Ichibakase, M. Nakajima, Org. Lett. 2011, 13, 1579–1581; b) K.
Tanaka, T. Ueda, T. Ichibakase, M. Nakajima, Tetrahedron Lett.
2010, 51, 2168–2169; c) Y. Orito, S. Hashimoto, T. Ishizuka, M. Na-
kajima, Tetrahedron 2006, 62, 390–400; d) J. Mlynarski, Eur. J. Org.
Chem. 2006, 4779–4786; e) C. Schneider, M. Hansch, T. Weide,
Chem. Eur. J. 2005, 11, 3010–3021; f) V. Gnanadesikan, Y. Horiuchi,
T. Ohshima, M. Shibasaki, J. Am. Chem. Soc. 2004, 126, 7782–7783;
g) S, Kiyooka, H. Maeda, Tetrahedron: Asymmetry 1997, 8, 3371–
3374; h) A. Baramee, N. Chaichit, P. Intawee, C. Thebtaranonth, Y.
Thebtaranonth, J. Chem. Soc. Chem. Commun. 1991, 1016–1017;
i) D. A. Evans, A. H. Hoveyda, J. Am. Chem. Soc. 1990, 112, 6447–
6449.
basaki, J. Am. Chem. Soc. 2003, 125, 5644–5645; i) Y. Hamashima,
D. Sawada, H. Nogami, M. Kanai, M. Shibasaki, Tetrahedron 2001,
57, 805–814; j) N. Kumagai, S. Matsunaga, N. Yoshikawa, T. Ohshi-
ma, M. Shibasaki, Org. Lett. 2001, 3, 1539–1542; k) R. Mahrwald,
Chem. Rev. 1999, 99, 1095–1120.
[13] a) L. F. Tietze, G. Brasche, K. Gericke, Domino Reactions in Organ-
ic Synthesis, Wiley-VCH, Weinheim 2006; b) H. Ishikawa, T. Suzuki,
H. Orita, T. Uchimaru, Y. Hayashi, Chem. Eur. J. 2010, 16, 12616–
12626; c) H. Ishikawa, T. Suzuki, Y. Hayashi, Angew. Chem. 2009,
121, 1330–1333; Angew. Chem. Int. Ed. 2009, 48, 1304–1307;
d) K. C. Nicolaou, D. J. Edmonds, P. G. Bulger, Angew. Chem. 2006,
118, 7292–7344; Angew. Chem. Int. Ed. 2006, 45, 7134–7186.
[14] For review of one-pot and tandem or cascade reactions, see: a) C.
Vaxelaire, P. Winter, M. Christmann, Angew. Chem. 2011, 123,
3685–3687; Angew. Chem. Int. Ed. 2011, 50, 3605–3607; b) H. Pel-
lissier, Tetrahedron 2008, 64, 1563–1601; c) A. M. Walji, D. W. C.
MacMillan, Synlett 2007, 1477–1489; d) O. Pꢆmies, J.-E. Bꢇckvall,
Chem. Rev. 2003, 103, 3247; e) A. Bruggink, R. Schoevaart, T. Kie-
boom, Org. Process Res. Dev. 2003, 7, 622; f) B. M. Trost, Science
1991, 254, 1471–1477.
[15] For representative examples of multienzymatic synthesis in water,
see: a) C.-H. Wong, G. M. Whitesides, Enzymes in Synthetic Organic
Chemistry, Pergamon, Oxford, 1994; b) F. Lopez-Gallego, C.
Schmidt-Dannert, Curr. Opin. Chem. Biol. 2010, 14, 174–183; c) N.
ˇ
D’Antona, R. Morrone, P. Bovicelli, G. Gambera, D. Kubꢈc, L. Mar-
tꢉnkovꢈ, Tetrahedron: Asymmetry 2010, 21, 2448–2454; d) D. Monti,
E. E. Ferrandi, I. Zanellato, L. Hua, F. Polentini, G. Carrea, S. Riva,
Adv. Synth. Catal. 2009, 351, 1303–1311; e) S. Servi, D. Tessaro, G.
Pedrocchi-Fantoni, Coord. Chem. Rev. 2008, 252, 715–726; f) S. M.
Dean, W. A. Greenberg, C.-H. Wong, Adv. Synth. Catal. 2007, 349,
1308–1320; g) S. Takayama, G. J. McGarvey, C.-H. Wong, Chem.
Soc. Rev. 1997, 26, 407–415; h) C.-H. Wong, R. L. Halcomb, Y. Ichi-
kawa, T. Kajimoto, Angew. Chem. 1995, 107, 453–474; Angew.
Chem. Int. Ed. Engl. 1995, 34, 412–432; i) C.-H. Wong, R. L. Hal-
comb, Y. Ichikawa, T. Kajimoto, Angew. Chem. 1995, 107, 569–593;
Angew. Chem. Int. Ed. Engl. 1995, 34, 521–546.
[8] S. Itoh, M. Kitamura, Y. Yamada, S. Aoki, Chem. Eur. J. 2009, 15,
10570–10584.
[9] For representative examples of aldol reactions via Zn2+-enolates,
see: a) T. Darbre, M. Machuqueiro, Chem. Commun. 2003, 1090–
1091; b) J. Kofoed, M. Machuqueiro, J.-L. Reymond, T. Darbre,
Chem. Commun. 2004, 1540–1541; c) J. Kofoed, J.-L. Reymond, T.
Darbre, Org. Biomol. Chem. 2005, 3, 1850–1855; d) R. Fernandez-
Lopez, J. Kofoed, M. Machuqueiro, T. Darbre, Eur. J. Org. Chem.
2005, 5268–5276; e) J. Kofoed, T. Darbre, J.-L. Reymond, Chem.
Commun. 2006, 1482–1484; f) B. M. Trost, H. Ito, E. R. Silcoff, J.
Am. Chem. Soc. 2001, 123, 3367–3368; g) B. M. Trost, H. Ito, J. Am.
Chem. Soc. 2000, 122, 12003–12004.
[16] a) M. Weiß, T. Brinkmann, H. Grçger, Green Chem. 2010, 12, 1580–
1588; b) E. Burda, W. Bauer, W. Hummel, H. Grçger, ChemCatCh-
em 2010, 2, 67–72; c) K. Baer, M. Kraußer, E. Burda, W. Hummel,
A. Berkessel, H. Grçger, Angew. Chem. 2009, 121, 9519–9522;
Angew. Chem. Int. Ed. 2009, 48, 9355–9358; d) M. Weiß, H. Grçger,
Synlett 2009, 1251–1254; e) E. Burda, W. Hummel, H. Grçger,
Angew. Chem. 2008, 120, 9693–9696; Angew. Chem. Int. Ed. 2008,
47, 9551–9554; f) H. Grçger, W. Hummel, C. Rollmann, F. Chamou-
leau, H. Hꢃsken, H. Werner, C. Wunderlich, K. Abokitse, K. Drauz,
S. Buchholz, Tetrahedron 2004, 60, 633–640; g) S. Sgalla, G. Fabrizi,
R. Cirilli, A. Macone, A. Bonamore, A. Boffi, S. Cacchi, Tetrahe-
dron: Asymmetry 2007, 18, 2791–2796.
[17] a) Z. Shaked, G. M. Whitesides, J. Am. Chem. Soc. 1980, 102, 7104–
7105; b) C.-H. Wong, G. M. Whitesides, J. Am. Chem. Soc. 1981,
103, 4890–4899; c) C.-H. Wong, G. M. Whitesides, J. Org. Chem.
1982, 47, 2816–2818; d) C.-H. Wong, D. G. Drueckhammer, H. M.
Sweers, J. Am. Chem. Soc. 1985, 107, 4028–4031.
[10] a) B. List, R. A. Lerner, C. F. Barbas, III, J. Am. Chem. Soc. 2000,
122, 2395–2396; b) W. Notz, B. List, J. Am. Chem. Soc. 2000, 122,
7386–7387; c) K. Sakthivel, W. Notz, T. Bui, C. F. Barbas, III, J.
Am. Chem. Soc. 2001, 123, 5260–5267; d) B. List, Acc. Chem. Res.
2004, 37, 548–557; e) W. Notz, F. Tanaka, C. F. Barbas, III, Acc.
Chem. Res. 2004, 37, 580–591.
[11] For reviews of organocatalysts: a) M. Gruttadauria, F. Giacalone, R.
Noto, Adv. Synth. Catal. 2009, 351, 33–57; b) M. Raj, V. K. Singh,
Chem. Commun. 2009, 6687–6703; c) H. Kotsuki, H. Ikishima, A.
Okuyama, Heterocycles 2008, 75, 493–529; d) H. Kotsuki, H. Ikishi-
ma, A. Okuyama, Heterocycles 2008, 75, 757–797; e) K. Nakayama,
K. Maruoka, J. Am. Chem. Soc. 2008, 130, 17666–17667; f) S. Buch-
holz, H. Grçger in Biocatalysis in the Pharmaceutical and Biotech-
nology Industries (Ed.: R. N. Patel), CRC, New York, 2006,
chap. 32, p. 757; g) P. I. Dalko, L. Moisan, Angew. Chem. 2004, 116,
5248–5286; Angew. Chem. Int. Ed. 2004, 43, 5138–5175; h) C. Alle-
mann, R. Gordillo, F. R. Clemente, P. H.-Y. Cheong, K. N. Houk,
Acc. Chem. Res. 2004, 37, 558–569; i) S. Bahmanyar, K. N. Houk,
H. J. Martin, B. List, J. Am. Chem. Soc. 2003, 125, 2475–2479;
j) A. B. Northrup, D. W. C. MacMillan, J. Am. Chem. Soc. 2002, 124,
6798–6799.
[18] E. Kimura, S. Aoki, T. Koike, M. Shiro, J. Am. Chem. Soc. 1997,
119, 3068–3076.
[19] a) E. Brenna, C. Fuganti, F. G. Gatti, S. Serra, Chem. Rev. 2011, 111,
4036–4072; b) D. Pollard, M. Truppo, J. Pollard, C. Chen, J. Moore,
Tetrahedron: Asymmetry 2006, 17, 554–559.
[20] For review of Chiralscreen, see: a) M. Hayashi, J. Synth. Org. Chem.
Jpn. 2011, 69, 517–525; b) T. Ema, T. Kadoya, K. Akihara, T. Sakai,
J. Mol. Catal. B 2010, 66, 198–202; c) M. Hayashi, H. Yamamoto,
Asymmetric Synthesis and Application of a-Amino Acids (Eds.:
V. A. Soloshonok, K. Izawa), American Chemical Society, 2009.
[21] Chiralscreen OH contains formate dehydrogenases (FDH) mutants,
which are more stable than wild type, for the regeneration of
NADH (reduced form) from NAD+ (oxidized form) using formate
or d-glucose as a hydride source (see Scheme in Table 3). When
sodium formate was used as a reductant of NAD+, the results were
[12] For recent examles of catalytic reactions via metal enolates, see:
a) F. Dꢄnꢅs, A. P. -Luna, F. Chemla, Chem. Rev. 2010, 110, 2366–
2447; b) J. Mlynarski, J. Paradowska, Chem. Soc. Rev. 2008, 37,
1502–1511; c) D. Enders, A. A. Narine, J. Org. Chem. 2008, 73,
7857–7870; d) H. Yamamoto, Tetrahedron 2007, 63, 8377–8412;
e) D. Enders, M. Voith, A. Lenzen, Angew. Chem. 2005, 117, 1330–
1351; Angew. Chem. Int. Ed. 2005, 44, 1304–1325; f) Y. Suto, R.
Tsuji, M. Kanai, M. Shibasaki, Org. Lett. 2005, 7, 3757–3760; g) M.
Shibasaki, Y. Yamamoto, Multimetallic Catalysts in Organic Synthe-
sis, Wiley, New York, 2004; h) K. Oisaki, Y. Suto, M. Kanai, M. Shi-
Chem. Asian J. 2012, 7, 64 – 74
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
73

S. Aoki et al.
FULL PAPERS
almost identical (>99% yield, 3R/3S= <1/>99 for E001) as those
when 2-propanol was used.
spectively) by comparing with the syn-selective reduction of optical-
ly active 4a (91% ee (S)) and 4c (90% ee (S)) with NaBH4.
[23] The selectivity of oxidoreductase was almost identical when the re-
duction was conducted in different buffers such as 10 mm HEPES
buffer (pH 7.4).
[22] The relative configuration of 7a and 7c (syn/anti) was determined
by 1H NMR spectroscopy and HPLC (Daicel Chiralcel OD-H
column and Chiralcel OJ-H column, respectively) by comparing
with the products of the syn-selective reduction of racemic 4a and
4c with NaBH4 (in MeOH) and DIBAL-H (in CHCl3) (see, D. L.
Boger, Modern Organic Synthesis: Lecture Notes, The Scripps Re-
search Institute Press, San Diego, CA, 1999). The absolute configu-
ration of (1S,3S)- and (1S,3R)-7a and 7c was determined by HPLC
(Daicel Chiralcel OD-H column and Chiralcel OJ-H column, re-
[24] Z. Tang, F. Jiang, L.-T. Yu, X. Cui, L.-Z. Gong, A.-Q. Mi, Y.-Z.
Jiang, Y.-D. Wu, J. Am. Chem. Soc. 2003, 125, 5262–5263.
Received: June 30, 2011
Published online: December 15, 2011
74
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ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2012, 7, 64 – 74