Chiral (R)- and (S)-allylic alcohols via a one-pot chemoenzymatic synthesis

Article abstract of DOI:10.1016/j.tetasy.2007.10.043

Chiral (R)- and (S)-allylic alcohols with an enantiomeric excess exceeding 99% have been prepared in good to high overall isolated yields through a two-step one-pot chemoenzymatic process based on the palladium-catalyzed Heck reaction of aryl iodides with

Full text of DOI:10.1016/j.tetasy.2007.10.043

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 18 (2007) 2791–2796
Chiral (R)- and (S)-allylic alcohols via a one-pot
chemoenzymatic synthesis
a
a
b
c
Simona Sgalla, Giancarlo Fabrizi, Roberto Cirilli, Alberto Macone,
c
c
a,
*
Alessandra Bonamore, Alberto Boffi and Sandro Cacchi
a
Dipartimento di Studi di Chimica e Tecnologia delle Sostanze Biologicamente Attive, Universit a` degli Studi ‘La Sapienza’,
P.le A. Moro 5, 00185 Rome, Italy
b
Istituto Superiore di Sanit a` , Viale Regina Elena 299, 00161 Rome, Italy
Dipartimento di Scienze Biochimiche, Universit a` degli Studi ‘La Sapienza’, P.le A. Moro 5, 00185 Rome, Italy
c
Received 3 October 2007; accepted 31 October 2007
Available online 28 November 2007
Abstract—Chiral (R)- and (S)-allylic alcohols with an enantiomeric excess exceeding 99% have been prepared in good to high overall
isolated yields through a two-step one-pot chemoenzymatic process based on the palladium-catalyzed Heck reaction of aryl iodides with
butenone followed by an enzymatic reduction of the resultant vinylic substitution products. Alcohol dehydrogenases from Lactobacillus
brevis and Thermoanaerobacter species were used to attain (R)- and (S)-stereoselectivity, respectively.
ꢀ
2007 Elsevier Ltd. All rights reserved.
1
. Introduction
hols, the development of alternative methods for their
preparation is highly desirable. The development of a
new chemoenzymatic process leading to the preparation
of this class of compounds via the construction of the
desired carbon framework followed by a direct stereoselec-
tive reduction step appeared particularly attractive. Based
on the versatility of palladium catalysis for C–C bond
forming reactions and on the ability of alcohol dehydro-
genases to perform stereoselective reduction reactions of
Chiral allylic alcohols in enantiomerically pure form are
useful building blocks in organic synthesis and have found
applications in the preparation of biologically active
compounds. Accordingly, the development of efficient
approaches to the synthesis of this class of compounds is
currently of great interest. Some of the most practical pro-
cedures available are based on kinetic resolution via asym-
1
2
3
8
metric enzymatic acylation of racemic allylic alcohols and
ketones, we focused on a sequential procedure, which
on dynamic kinetic resolution methods. Chemoenzymatic
dynamic kinetic resolution has been applied to racemic
allylic alcohols, which are enantioselectively acylated by
entails the formation of the required carbon skeleton via
the Heck reaction of aryl iodides with butenone, in the first
step, and the generation of enantiomerically pure allylic
alcohols 4, in the second step, through the enzyme-cata-
lyzed enantioselective reduction of the resultant benzalace-
tones 2 (Scheme 1).
4
a lipase in the presence of a ruthenium complex catalyzing
the racemization of the unreacted substrate, and to racemic
5
allylic acetates, using a lipase as biocatalyst and a palla-
dium complex as the racemization catalyst. The stereoselec-
tive reduction of a,b-unsaturated ketones has also been
One of the main tasks of this project was to circumvent the
intermediate purification and isolation steps by developing
a one-pot protocol. One-pot syntheses are a subject of great
current interest because of their economical and environ-
mental advantages. However, a one-pot synthesis based
on transition metal and enzyme catalysts can be extremely
challenging, especially when the transition metal-catalyzed
step involves a C–C bond forming reaction. Metal or
reagent inhibition of the enzyme is not uncommon and
suitable water/organic solvent mixtures need to be
6
attempted by using whole cell bioconversion and Ir(I)-
7
,8
and Ru(II)-catalyzed hydrogenation.
All these procedures are based on the conversion of the
preformed carbon framework into the desired chiral allylic
alcohols. Due to the importance of enantiopure allylic alco-
*
Corresponding author. Tel.: +39 (06) 4991 2795; fax: +39 (06) 4991
780; e-mail: sandro.cacchi@uniroma1.it
2
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.10.043

2792
S. Sgalla et al. / Tetrahedron: Asymmetry 18 (2007) 2791–2796
O
O
tantly, no enzyme inhibition was observed due to the pres-
ence of palladium or other reagents in the reaction medium.
O
Pd cat
ArI
Ar
Ar
Me
Ar
Me
Me
1
2
3
The experiment was repeated by adding the enzyme (LB-
ADH) solution to the crude reaction mixture derived from
the Heck reaction after concentration at a reduced pressure.
Under these conditions, the desired allylic alcohol was iso-
lated in 80% overall yield with the enantiomeric excess
exceeding 99%. 50 U (instead of 100 U) of enzyme was nec-
essary to obtain full substrate conversion, due to the removal
of the competing butenone substrate during the concentra-
tion process. The absolute configuration of the allylic car-
bon, expected to be (R) on the grounds of the reported
enzyme
H OH
Me
4
Scheme 1.
8
d
optimized. It is also essential that the C–C bond forming
step does not yield by-products, which can be reduced
stereoselectively by the enzyme such as, for example,
hydroarylation (conjugate addition-type) derivatives 3.
Even modest amounts of these by-products would either
require a wasteful and expensive purification of the reac-
tion mixture derived from the Heck reaction (thus impair-
ing the development of a one-pot process) or make the
isolation of pure chiral allylic alcohols inconvenient.
activity of the enzyme with dialkyl ketones, was confirmed
by circular dichroism (CD) spectroscopy using enantiomers
0
10
4d and 4d as reference samples of known stereochemistry.
A similar result was obtained with T-ADH, reported to give
0
(S)-alkyl alcohols: (S)-4a was isolated in 77% overall yield.
Having established the best conditions for our two-step
one-pot route to chiral allylic alcohols, we extended the
reaction to other aryl iodides. As shown by the results
summarized in Table 1, a variety of aryl iodides afforded
the corresponding (R)- (with LB-ADH) and (S)- (with
T-ADH) allylic alcohols usually in good to high overall iso-
lated yields with enantiomeric excess exceeding 99% with
all the substrates investigated. Only with 1g were the corre-
In general, the vinylic substitution of aryl iodides with bute-
none may form variable amounts of 3, depending on reac-
9
9
tion conditions. However, we recently reported that a
variety of benzalacetones can be prepared in good to excel-
lent yields from aryl iodides and butenone under solvent-
free conditions in the presence of a high affinity proton
acceptor (proton sponge). Thus, a reaction mixture com-
0
sponding allylic alcohols 4g and 4g isolated in low yields
0
(Table 1, entry 7). In this case, 5g and 5g , formed via
stereoselective reduction of both the ketonic groups, were
isolated as the main reaction products along with minor
posed of Pd(OAc) , tris-(2,4,6-trimethoxyphenyl)phosphine
ttmpp) and 1,8-bis(dimethylamino)naphthalene (proton
sponge) allows compound 2 formation with no detectable
amounts of 3. Consequently, these experimental conditions
appeared to be particularly suited for the chemoenzymatic
approach to chiral allylic alcohols presented herein.
2
0
(
amounts of 6g and 6g (Scheme 2). The absolute configura-
0 0 0
tions of the stereogenic centers of 4a–f,i and 4a –f ,i were
0
9
assigned using 4d and 4d as reference samples and those
0
0
of 4h, 4h , 5g and 5g were assigned by derivatization of
1
0
the alcohol groups with Mosher’s acid. The configuration
of 4g, 4g , 6g and 6g was assigned based on the configura-
0
0
tions of all the other chiral products prepared.
2
. Results and discussion
The two-step, one-pot reaction was carried out as follows.
In the first step (Heck reaction), compound 1a was added
to 3 equiv of butenone in the presence of 0.05 equiv of
3. Conclusions
The present results set the basis for a novel chemoenzy-
matic synthesis of chiral allylic alcohols starting from sim-
ple aryl halides and vinyl ketones using a two-step one-pot
method that entails the coupling of a palladium-catalyzed
Heck reaction to a stereoselective enzyme-catalyzed reduc-
tion. The method proves to be superior in product yield
and enantioselectivity to conventional dynamic kinetic
resolution methods and paves the way for a number of
applications by coupling the versatility of palladium
catalyst to the appropriate use of alcohol dehydrogen-
ases/ketoreductases with different substrate specificity.
Pd(OAc) , 0.1 equiv of ttmpp and 1.1 equiv of proton
2
sponge at 80 ꢁC for 16 h. In the second step, after cooling
the reaction mixture to room temperature, the raw product
was resuspended in 4.5 mL methoxyethanol/isopropanol
(
1/2 v/v); then 100 mM phosphate buffer, pH 7.0 contain-
ing 4.45 lmol of NADP+ and 100 U enzyme [alcohol
dehydrogenase enzyme from Lactobacillus brevis (LB-
ADH) or alcohol dehydrogenase enzyme from Thermo-
anaerobacter species (T-ADH)] was added to a final volume
of 9 mL. The reaction was carried out at room temperature
for 6–8 h. The corresponding allylic alcohols were isolated
in 78–80% overall yield.
4
. Experimental
+
Both enzymes are able to recycle NADPH from NADP by
oxidizing isopropanol to acetone while catalyzing the stereo-
selective reduction of the a,b-unsaturated ketone. The rela-
tively high amount of the enzyme was needed because of
the excess free butenone still present in the reaction mixture,
which is reduced to the corresponding allylic alcohol. Impor-
4.1. Materials and methods
Alcohol dehydrogenase enzymes from Lactobacillus bre-
vis (LB-ADH) and from Thermoanaerobacter species
(T-ADH) were obtained from Julich fine Chemicals (now

S. Sgalla et al. / Tetrahedron: Asymmetry 18 (2007) 2791–2796
2793
Table 1. Preparation of (R)- and (S)-allylic alcohols from aryl iodides and butenone through a one-pot palladium-catalyzed Heck reaction followed by
alcohol dehydrogenase-catalyzed reduction step
a,b
Yield (%)
Entry
Aryl iodide 1
t (h) 1st-step
t (h) 2nd-step
(R)-4
(S)-4
O N
2
0
0
1
2
1a
1b
16
16
2
2
80
84
4a
77
79
4a
4b
Me
I
Cl
I
4b
MeO
0
3
4
5
1c
1d
1e
24
16
92
4
2
4
77
85
67
4c
4d
4e
70
80
66
4c
4d
4e
I
0
PhI
Me
0
I
F3C
0
6
7
1f
16
18
16
4
4
74
4f
70
9
4f
I
c
0
0
MeCO
I
1g
21
4g
4g
4h
8
9
EtOOC
I
1h
1i
2
2
60
74
4h
4i
80
70
d
0
MeOCHN
I
—
4i
a
b
c
Yields are given for isolated products.
The ee was determined by enantioselective HPLC analysis and was found to always exceed 99%.
0
0
Allylic alcohols 5g (42%) and 5g (50%), formed via stereoselective reduction of both the ketonic groups, and 6g (16%) and 6g (13%) were also isolated
(
Scheme 2).
d
Enzyme-catalyzed reductions with LB-ADH and T-ADH were carried out on the isolated vinylic substitution product.
I
O
Me
Me
Me
1g
O
OH
Me
OH
Me
Me
O
Me
Me
O
OH
(
OH
LB-ADH
T-ADH
(
R) 4g (21%)
R,R) 5g (42%)
S,S) 5g' (50%)
(
(
R
) 6g (16%)
(S) 4g' (9%)
(
S) 6g' (13%)
Scheme 2.
CODEXIS inc., Redwood City, CA, USA). NADP sodium
salt was purchased from Sigma Aldrich Co. Units were
determined for each enzyme on acetophenone according
to published procedures. Melting points were determined
with a B u¨ chi B-545 apparatus and are uncorrected. Reac-
tion products were purified on axially compressed columns,
packed with SiO 25–40 lm (Macherey Nagel), connected
2
to a Gilson solvent delivery system and to a Gilson refrac-
tive index detector, and eluting with n-hexane/ethyl acetate
mixtures. IR spectra were recorded with a Jasco FT/IR-430
8
a

2794
S. Sgalla et al. / Tetrahedron: Asymmetry 18 (2007) 2791–2796
1
13
0
spectrometer. H NMR spectra (400 MHz), C NMR
90/10, k = 3.16 (R)-(+)-4a, k = 4.11 (S)-(ꢀ)-4a ; Chiral-
1
2
1
9
spectra (100.6 MHz), and F NMR spectra (376.3 MHz)
were recorded with a Bruker Avance 400 spectrometer.
Low resolution mass spectra were recorded with a Shima-
dzu GC–MS QP-2010S spectrometer. Enantioselective
HPLC analyses were performed by using stainless-steel
Chiralcel OB-H (250 · 4.6 mm I.D.), Chiralpak AS-H
cel OB-H/n-hexane-2-propanol 90/10, k = 0.86 (S)-(ꢀ)-
1
0
4b , k = 1.13 (R)-(+)-4b; Chiralcel OB-H/n-hexane-2-pro-
2
0
panol 90/10, k = 2.44 (S)-(ꢀ)-4c , k = 2.97 (R)-(+)-4c;
1
2
Chiralcel OD/n-hexane-2-propanol 90/10, k = 1.94 (R)-
1
0
(+)-4d, k = 3.34 (S)-(ꢀ)-4d ; Chiralpak AS-H/n-hexane-
2
2-propanol 90/10, k = 0.82 (R)-(+)-4e, k = 1.07 (S)-(ꢀ)-
1
2
0
(
250 · 4.6 mm I.D.), and Chiralcel OD (250 · 4.6 mm
4e ;
Chiralpak
AS-H/n-hexane-2-propanol
90/10,
0
I.D. and 250 · 10 mm I.D.) (Daicel, Chemical Industries,
Tokyo, Japan) columns. HPLC-grade solvents were sup-
plied by Carlo Erba (Milan, Italy). HPLC apparatus con-
sisted of a Perkin Elmer (Norwalk, CT, USA) 200 lc
pump equipped with a Rheodyne (Cotati, CA, USA) injec-
tor, a 200-lL sample loop, a HPLC Perkin Elmer oven,
and a Perkin Elmer 290 detector. The signal was acquired
and processed by Clarity software (DataApex, Prague,
The Czech Republic).
k = 0.61 (R)-(+)-4f, k = 0.81 (S)-(ꢀ)-4f ; Chiralpak AS-
1
2
H/n-hexane-2-propanol 50/50, k = 1.72 (S)-(ꢀ)-4g,
1
0
k = 2.50 (R)-(+)-4g ; Chiralcel OB-H/n-hexane-2-propa-
2
0
nol 50/50, k = 0.37 (S)-(ꢀ)-4h , k = 0.98 (R)-(+)-4h; Chi-
1
2
ralcel OB-H/n-hexane-2-propanol 50/50, k = 0.24 (S)-(ꢀ)-
1
0
4i , k = 0.46 (R)-(+)-4i; Chiralpak AS-H/n-hexane-2-pro-
2
0
panol 50/50, k = 0.37 (R)-(+)-5g, k = 0.56 (S)-(ꢀ)-5g ;
1
2
Chiralpak AS-H/n-hexane-2-propanol 50/50, k = 1.43
1
0
(R)-(+)-6g, k = 1.69 (S)-(ꢀ)-6g .
2
Specific rotations were measured at a wavelength of
4.4. GC/MS
5
89 nm by a Perkin Elmer polarimeter model 241 equipped
with a Na lamp. The volume of the cell was 1 mL and the
optical path was 10 cm. The system was maintained at the
temperature of 20 ꢁC by a Neslab RTE 740 cryostat.
GC/MS analyses were performed on an Agilent 6850A gas
chromatograph coupled to a 5973N quadrupole mass selec-
tive detector (Agilent Technologies, Palo Alto, CA, USA).
Gas-chromatographic separations were carried out on an
Agilent HP-5MS fused-silica capillary column (30 m ·
0.25 mm I.D., film thickness, 0.25 lm). Injection mode:
splitless at a temperature of 260 ꢁC. Column temperature
program: 70 ꢁC (1 min) then to 280 ꢁC at a rate of 10 ꢁC/
min and held for 15 min. The carrier gas was helium at a
constant flow of 1.0 mL/min. The spectra were obtained
in electron impact mode at 70 eV ionization energy and a
mass range scan from m/z 30 to 500; ion source tempera-
ture, 280 ꢁC; ion source vacuum 10–5 Torr.
The CD spectra of enantiomers of chiral analytes, dis-
solved in a n-hexane/2-propanol 90/10 mixture (concentra-
tion about 0.2 mg/mL) in a quartz cell (0.1 cm-path length)
at 25 ꢁC, were measured by using a Jasco (Jasco, Ishikawa-
cho, Hachioji City, Tokyo, Japan) Model J-700 spectro-
polarimeter in the 350–220 nm spectral range. The spectra
are average computed over three instrumental scans and
the intensities are presented in terms of [U] values (mdeg).
4
.2. Absolute configuration assignment
4.5. Typical procedure for the one-pot synthesis of enantio-
pure allylic alcohols 4a–h and 4a –4h
0
0
0
0
The absolute configuration of enantiomers 4a, 4a , 4b, 4b ,
4
0 0 0 0
c, 4c , 4e, 4e , 4f, 4f , and 4i, 4i was empirically assigned
by comparison of their CD spectra with those of enantio-
mers 4d and 4d . The enantioseparation of the reference
A
mixture of 1a (0.263 g, 1 mmol), 3-buten-2-one
0
(0.250 mL, 3 mmol), Pd(OAc) (0.011 g, 0.05 mmol), 1,8-
2
compound was obtained on semipreparative scale by
HPLC using a Chiralcel OD CSP column and n-hexane/
bis(dimethylamino)naphthalene (0.236 g, 1.1 mmol) and
ttmpp (0.053 g, 0.1 mmol) was warmed at 80 ꢁC with stir-
ring for 16 h. After this time, the reaction mixture was
cooled at room temperature and concentrated under a
reduced pressure. The residue was resuspended in 4.5 mL
methoxyethanol/isopropanol (1/2 v/v). Then 100 mM
phosphate buffer, pH 7.0 containing 4.45 lmol NADP+
and 100 U enzyme (LB-ADH) was added to a final volume
of 9 mL. The reaction was carried out at room temperature
(25 ꢁC) for 2 h. A 50 lL aliquot of the reaction mixture was
extracted with 200 lL AcOEt and analyzed by GC/MS.
The reaction mixture was then diluted with AcOEt, washed
twice with a saturated NH Cl solution, dried over Na SO
4
2
-propanol 90/10 (v/v) as eluent. As reported in the litera-
9
ture, under these conditions, the (R)-(+)-enantiomer was
eluted before the (S)-(ꢀ)-enantiomer. The CD spectrum
of (R)-(+)-4d showed a single diagnostic positive band at
2
51 nm. The CD pattern of (+)-enantiomers of unknown
stereochemistry was very similar with a positive CD band
located around 250 nm. In all cases, the (ꢀ)-enantiomers
exhibited the corresponding CD mirror-images. The abso-
0
0
lute configurations of 4h, 4h , 5g and 5g were assigned by
1
1
derivatization of the alcohol groups with Mosher’s acid.
4
2
4.3. HPLC conditions for the determination of enantiomeric
excess
and concentrated under reduced pressure. The residue was
purified by chromatography (SiO , 35 g; n-hexane/AcOEt
2
6
5/35 v/v) to give 0.166 g (80% yield) of (2R,3E)-4-(3-
20
Enantiomeric excesses were determined by enantioselective
HPLC using polysaccharide-based chiral stationary phases
nitro,4-methylphenyl)-3-buten-2-ol 4a: oil; ½aꢁ ¼ þ17:0
D
(c 0.16, MeOH). IR (neat): 3375, 2971, 1665, 1526,
ꢀ1
1
(
CSPs). The CSP/eluent system and the corresponding
1348 cm . H NMR (CDCl ) d: 7.95 (s, 1H), 7.48 (d,
3
chromatographic data for each compound analyzed are
J = 7.9 Hz, 1H), 7.27 (d, J = 4.3 Hz, 1H), 6.57 (d,
1
summarized as follows (k and k are the retention factors
J = 15.9 Hz, 1H), 6.33 (dd, J = 15.9 Hz, J = 5.9 Hz,
1
2
1
2
of the less retained and the more retained enantiomer,
respectively): Chiralpak AS-H/n-hexane-2-propanol
1H), 4.53–4.50 (m, 1H), 2.57 (s, 3H), 1.89 (sb, 1H) 1.38
1
3
(d, J = 6.4 Hz, 3H). C NMR (CDCl ) d: 149.4, 136.2,
3

S. Sgalla et al. / Tetrahedron: Asymmetry 18 (2007) 2791–2796
2795
1
35.9, 133.0, 132.5, 130.6, 126.8, 122.3, 68.5, 23.5, 20.3.
6.39 (dd, J1 = 15.9 Hz, J2 = 6.0 Hz, 1H), 4.55 (t,
J = 6.2 Hz, 1H), 2.6 (s, 3H), 1.8 (sb, 1H), 1.41 (d,
Anal. Calcd for C H NO , C, 63.76; H, 6.32; N, 6.76.
Found C, 63.70; H, 6.26; N, 6.70. MS m/z (relative inten-
sity) 207 (M , 3%), 43 (100%), 115 (28%).
1
1
13
3
1
3
J = 6.4 Hz, 3H). C NMR (CDCl ) d: 197.6, 141.4,
3
+
136.5, 136.0, 128.7, 128.1, 126.5, 68.6, 26.5, 23.3. Anal.
Calcd for C H O : C, 75.76; H, 7.42. Found C, 75.70;
1
2
14
2
+
4
6
.5.1. (2R,3E)-4-(4-Chlorophenyl)-3-buten-2-ol 4b. Mp:
H, 7.39. MS m/z (relative intensity): 190 (M , 10%), 43
1
2
20
0–62 ꢁC {lit. mp: 61–61 ꢁC}. ½aꢁ ¼ þ17:5 (c 0.18,
(100%), 147 (12%).
D
1
2
22
D
20
D
MeOH) {lit. ½aꢁ ¼ þ27:3 (c 0.6, CHCl ), ½aꢁ ¼ þ17:7
3
(
c 1.5, CH Cl )}.
4.5.7.
(2R,3E)-4-(4-Ethoxycarbonylphenyl)-3-buten-2-ol
20
2
2
4h. Mp 66–68 ꢁC. ½aꢁ ¼ þ16:0 (c 0.12, MeOH). IR
D
ꢀ
1 1
4
.5.2. (2R,3E)-4-(3-Methoxyphenyl)-3-buten-2-ol 4c. Oil.
(KBr): 3484, 2972, 1715, 1698 cm . H NMR (CDCl ) d:
3
2
0
½
aꢁ ¼ þ18:6 (c 0.19, MeOH). IR (neat): 3389, 2968,
7.98 (d, J = 8.3 Hz 2H), 7.40 (d, J = 8.3 Hz, 2H), 6.59 (d,
D
ꢀ
1
1
1
1
597, 1579, 1487 cm . H NMR (CDCl ) d: 7.25 (q,
3
J = 15.9 Hz, 1H), 6.37 (dd, J = 15.9 Hz, J = 6.0 Hz,
1
2
H), 6.99 (d, J = 7.8 Hz, 1H), 6.93 (s, 1H), 6.82 (d,
1H) 4.52–4.50 (m, 1H), 4.40–4.34 (m, 2H), 2.24 (sb, 1H),
1
3
J = 5.8 Hz, 1H), 6.54 (d, J = 15.9 Hz, 1H), 6.27 (dd,
J = 15.9 Hz, J = 6.3 Hz, 1H); 4.52–4.48 (m, 1H), 2.07
1.40–1.37 (m, 6H). C NMR (CDCl ) d: 166.5, 141.2,
3
136.3, 129.9, 129.3, 128.2, 126.3, 68.6, 61.0, 23.4, 14.3.
1
2
1
3
(
sb, 1H), 1.39 (d, J = 6.4 Hz, 3H). C NMR (CDCl ) d:
Anal. Calcd for C H O : C, 70.89; H, 7.32. Found C,
3
13 16
3
+
1
5
59.8, 138.2, 133.9, 129.6, 129.2, 119.2, 113.3, 111.8, 68.8,
5.2, 23.4. Anal. Calcd for C H O : C, 74.13; H, 7.92.
70.85; H, 7.29. MS m/z (relative intensity): 220 (M ,
15%), 43 (100%), 105 (27%).
1
1
14
2
Found C, 73.99; H, 7.85. MS m/z (relative intensity): 178
+
(
M , 36%), 115 (46%), 135 (100%).
4.5.8. (2R,3E)-4-(4-Acetamidophenyl)-3-buten-2-ol 4i. Mp
2
0
1
03–105 ꢁC. ½aꢁ ¼ þ31:0 (c 0.11, MeOH). IR (KBr):
D
ꢀ
1 1
4
.5.3. (2R,3E)-4-Phenyl-3-buten-2-ol 4d. Mp 57–59 ꢁC.
3295, 2923, 1665, 1536 cm . H NMR (CDCl ) d: 7.4 (d,
3
2
0
½
aꢁ ¼ þ18:3 (c 0.36, MeOH). IR (KBr): 3390, 2976,
J = 8.3 Hz, 2H), 7.3 (d, J = 8.2 Hz, 2H), 6.5 (d,
D
ꢀ
1
1
2
965, 1492 cm
.
H NMR (CDCl ) d: 7.40–7.23 (m,
3
J = 15.9 Hz, 1H),6.19 (dd, J = 15.9 Hz, J = 6.4 Hz,
1
2
5
H), 6.58 (d, J = 16.0 Hz, 1H), 6.27 (dd, J = 15.9 Hz,
1H), 4.48 (t, J = 6.2 Hz, 1H), 2.1 (s, 3H), 1.25 (d,
1
1
3
J = 6.4 Hz, 1H), 4.53–4.47 (m, 1H), 1.87 (sb, 1H), 1.39
J = 6.2 Hz, 3H). C NMR (CDCl ) d: 168.3, 137.3,
2
3
1
3
(
d, J = 6.4 Hz, 3H). C NMR (CDCl ) d: 136.7, 133.6,
132.9, 132.8, 128.7, 127.0, 119.9, 68.9, 24.5, 23.4. Anal.
3
1
29.4, 128.6, 127.7, 126.5, 68.9, 23.5. Anal. Calcd for
Calcd for C H NO : C, 70.22; H, 7.37; N 6.82. Found
1
2
15
2
C H O: C, 81.04; H, 8.16. Found C, 81.09; H, 8.20.
MS m/z (relative intensity): 148 (M , 47%), 43 (100%),
C, 70.25; H, 7.34; N 6.79. MS m/z (relative intensity):
205 (M , 14%), 43 (100%), 145 (21%).
1
0
12
+
+
1
31 (20%).
0
4
.5.9. (2S,3E)-4-(3-Nitro,4-methylphenyl)-3-buten-2-ol 4a .
2
0
4
.5.4. (2R,3E)-4-(3-Methylphenyl)-3-buten-2-ol 4e. Oil.
½aꢁ ¼ ꢀ16:0 (c 0.15, MeOH).
D
2
0
½
aꢁ ¼ þ20:5 (c 0.31, MeOH). IR (neat): 3363, 2967,
D
ꢀ
1
1
0
20
2
3
6
1
923, 1383 cm
.
H NMR (CDCl ) d: 7.30–7.21 (m,
4.5.10. (2S,3E)-4-(4-Chlorophenyl)-3-buten-2-ol 4b . ½aꢁD
ꢀ18:0 (c 0.17, MeOH).
¼
3
H), 7.08 (d, J = 6.2 Hz, 1H), 6.55 (d, J = 15.9 Hz, 1H),
.26 (dd, J = 15.9 Hz, J = 6.4 Hz, 1H), 4.53–4.46 (m,
H), 2.36 (s, 3H), 1.46 (sb, 1H), 1.33 (d, J = 6.4 Hz, 3H).
1
2
0
4.5.11.
(2S,3E)-4-(3-Methoxyphenyl)-3-buten-2-ol
4c .
1
3
20
C NMR (CDCl ) d: 138.2, 136.7, 133.4, 129.5, 128.5,
½aꢁD = ꢀ18.8 (c 0.19, MeOH).
3
1
28.4, 127.2, 123.7, 69.0, 23.4, 21.4. Anal. Calcd for
0
20
C H O: C, 81.44; H, 8.70. Found C, 81.37; H, 8.79.
MS m/z (relative intensity): 162 (M , 36%), 129 (100%),
4.5.12. (2S,3E)-4-Phenyl-3-buten-2-ol 4d . ½aꢁD ¼ ꢀ19:5 (c
1
1
14
+
0.49, MeOH).
9
1 (35%).
0
20
4
.5.13. (2S,3E)-4-(3-Methylphenyl)-3-buten-2-ol 4e . ½aꢁD
¼
4
4
2
1
.5.5.
(2R,3E)-4-(3-Trifluoromethylphenyl)-3-buten-2-ol
20
ꢀ21:0 (c 0.28, MeOH).
f. Oil. ½aꢁ ¼ þ11:3 (c 0.23, MeOH). IR (neat): 3349,
D
ꢀ
1
1
974, 2874, 1591 cm
H),7.53–7.39 (m, 3H), 6.60 (d, J = 15.9 Hz, 1H), 6.34
.
H NMR (CDCl ) d: 7.61 (s,
4.5.14.
0
(2S,3E)-4-(3-Trifluoromethylphenyl)-3-buten-2-ol
20
3
4f . ½aꢁD ¼ ꢀ10:4 (c 0.28, MeOH).
(
dd, J = 15.9 Hz, J = 6.1 Hz, 1H), 4.53–4.50 (m, 1H),
1 2
1
3
0
20
2
.11 (sb, 1H), 1.39 (d, J = 6.4 Hz, 3H). C NMR (CDCl3)
4.5.15. (2S,3E)-4-(4-Acetylphenyl)-3-buten-2-ol 4g . ½aꢁD
ꢀ18:9 (c 0.05, MeOH).
¼
d: 137.6, 135.6, 131.1 (q, J = 32 Hz), 129.6, 129.1, 127.9,
24.1 (q, J = 3.8 Hz), 124.0 (q, J = 272 Hz), 123.1 (q,
1
1
9
J = 3.8 Hz), 68.6, 23.5. F NMR (CDCl ) d: ꢀ62.8. Anal.
4.5.16.
0
(2S,3E)-4-(4-Ethoxycarbonylphenyl)-3-buten-2-ol
20
3
Calcd for C H F O: C, 61.11; H, 5.13. Found C, 61.00;
4h . ½aꢁD ¼ ꢀ16:5 (c 0.11, MeOH).
1
1
11 3
+
H, 5.05. MS m/z (relative intensity): 216 (M , 10%), 43
100%), 129 (17%).
0
(
4.5.17. (2S,3E)-4-(4-Acetamidophenyl)-3-buten-2-ol 4i .
½
2
0
aꢁ ¼ ꢀ22:0 (c 0.15, MeOH).
D
4
6
1
2
.5.6. (2R,3E)-4-(4-Acetylphenyl)-3-buten-2-ol 4g. Mp 59–
20
1 ꢁC. ½aꢁ ¼ þ22:2 (c 0.06, MeOH). IR (KBr): 3263, 2981,
4.5.18. (2R,3E)-4-[4-((R)-1-Hydroxyethyl)phenyl]-3-buten-
D
ꢀ
1
1
20
678, 1601 cm . H NMR (CDCl ) d: 7.93 (d, J = 8.3 Hz,
2-ol 5g. Mp 94–98 ꢁC. ½aꢁ ¼ þ64:8 (c 0.05, MeOH); IR
3
D
ꢀ
1 1
H), 7.47 (d, J = 8.3 Hz, 2H), 6.64 (d, J = 15.9 Hz, 1H),
(KBr): 3339, 2965, 2868, 1574 cm . H NMR (CDCl ) d:
3

2796
S. Sgalla et al. / Tetrahedron: Asymmetry 18 (2007) 2791–2796
7
.36–7.28 (m, 4H), 6.54 (d, J = 15.8 Hz, 1H), 6.24 (dd,
2. (a) Bach, J.; Berenguer, R.; Garcia, J.; Vilarrasa, J. Tetra-
hedron Lett. 1995, 36, 3425; (b) Aleu, J.; Bergamo, B.;
Brenna, E.; Fuganti, C.; Serra, S. Eur. J. Org. Chem. 2000,
3031–3038; (c) Brenna, E.; Fuganti, C.; Grasselli, P.; Serra, S.
Eur. J. Chem. 2001, 1349.
J = 15.9 Hz, J = 6.4 Hz, 1H), 4.90–4.86 (m, 1H), 4.48
1
2
(
t, J = 6.0 Hz, 1H), 2.32 (sb, 1H), 2.08 (sb, 1H), 1.48 (d,
1
3
J = 6.4 Hz, 3H), 1.37 (d, J = 6.3 Hz, 3H). C NMR
CDCl ) d: 145.3, 136.0, 133.5, 129.0, 126.6, 125.7, 70.1,
(
3
3
. (a) Burgess, K.; Jennings, L. D. J. Am. Chem. Soc. 1991, 113,
6
8
1
8.9, 25.1, 23.4. Anal. Calcd for C H O : C, 74.97; H,
12 16 2
6
129–6139; (b) Itoh, T.; Akasaki, E.; Nishimura, Y. Chem.
.39. Found C, 74.95; H, 8.35. MS m/z (relative intensity):
Lett. 2002, 154; (c) Ghanem, A.; Schurig, V. Tetrahedron:
Asymmetry 2003, 14, 57–62; (d) Lindner, E.; Ghanem, A.;
Warad, I.; Eichele, K.; Mayer, H. A.; Schurig, V. Tetra-
hedron: Asymmetry 2003, 14, 1045–1053; (e) Kamal, A.;
Sandbhor, M.; Shaik, A. A.; Sravanthi, V. Tetrahedron:
Asymmetry 2003, 14, 2839–2844.
+
92 (M , 7%), 91 (100%), 177 (25%).
4
.5.19. (2S,3E)-4-[4-((S)-1-Hydroxyethyl)phenyl]-3-buten-2-
0
20
ol 5g . ½aꢁD ¼ ꢀ51:1 (c 0.06, MeOH).
4
. Lee, D.; Huh, E. A.; Kim, M.; Jung, H. M.; Koh, J. H.; Park,
J. Org. Lett. 2000, 2, 2377–2379.
Acknowledgments
5
. (a) Allen, J. V.; Williams, J. M. J. Tetrahedron Lett. 1996, 37,
1
859–1862; (b) Choi, Y. K.; Suh, J. H.; Lee, D.; Lim, I. T.;
Jung, J. W.; Kim, M. J. J. Org. Chem. 1999, 64, 8423–
424.
This work was carried out in the framework of FIRB 2003
and of the National Project ‘Stereoselezione in Sintesi
Organica. Metodologie ed Applicazioni’ and was sup-
ported by the Ministero dell’Universit a` e della Ricerca Sci-
entifica e Tecnologica and by the University ‘La Sapienza’.
8
6
7
. Hage, A.; Petra, D. G. I.; Field, J. A.; Schipper, D.; Wijnberg,
J. B. P. A.; Kamer, P. C. J.; Reek, J. N. H.; Leeuwen, P. W.
N. M.; Wever, R.; Schoemaker, H. E. Tetrahedron: Asym-
metry 2001, 12, 1025–1034.
. For a review on Ru-catalyzed hydrogenation of ketones,
including the asymmetric hydrogenation of a,b-unsaturated
ketones, see: Noyori, R.; Ohkuma, T. Angew. Chem., Int. Ed.
2001, 40, 40–73.
8. (a) Wolberg, M.; Hummel, W.; Muller, M. Chemistry 2001, 7,
4562–4565; (b) Findrik, Z.; Vasic-Racki, D.; Lutz, S.;
Daussmann, T.; Wandey, C. Biotecnol. Lett. 2005, 27,
1087–1092; (c) Trivedi, A. H.; Spoess, A. C.; Daussmann,
T.; Buchs, J. Bitechnol. Prog. 2006, 22, 454–460; (d) Zhu, D.;
Rios, B. E.; Rozzel, J. D.; Hua, L. Tetrahedron: Asymmetry
2005, 16, 1541–1546.
9. Cacchi, S.; Fabrizi, G.; Goggiamani, A. Arkivoc 2003, 58–
66.
10. Kano, T.; Sasaki, K.; Maruoka, K. Org. Lett. 2005, 7, 1347–
1349.
11. For a review on the assignement of the absolute configuration
of alcohols, amines, and carboxylic acids by NMR, see: Seco,
J. M.; Qui n˜ o a´ , E.; Riguera, R. Tetrahedron: Asymmetry 2001,
12, 2915–2925.
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