Chiral spiroaminoborate ester as a highly enantioselective and efficient catalyst for the borane reduction of furyl, thiophene, chroman, and thiochroman-containing ketones

Article abstract of DOI:10.1016/j.tetasy.2009.11.009

Prochiral heteroaryl ketones containing furan, thiophene, chroman, and thiochroman moieties were successfully reduced in the presence of 1-10 mol % of spiroaminoborate ester 1 with different borane sources to afford non-racemic alcohols in up to 99% ee. In addition, modest enantioselectivity, around 80% ee, was achieved in the reduction of linear α,β-unsaturated heteroaryl ketones.

Full text of DOI:10.1016/j.tetasy.2009.11.009

Tetrahedron: Asymmetry 20 (2009) 2659–2665
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Chiral spiroaminoborate ester as a highly enantioselective and efficient
catalyst for the borane reduction of furyl, thiophene, chroman, and
thiochroman-containing ketones
Viatcheslav Stepanenko, Melvin De Jesús, Wildeliz Correa, Lorianne Bermúdez, Cindybeth Vázquez,
*
Irisbel Guzmán, Margarita Ortiz-Marciales
Department of Chemistry, University of Puerto Rico-Humacao, CUH Station, Humacao, PR 00791, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Prochiral heteroaryl ketones containing furan, thiophene, chroman, and thiochroman moieties were suc-
cessfully reduced in the presence of 1–10 mol % of spiroaminoborate ester 1 with different borane
sources to afford non-racemic alcohols in up to 99% ee. In addition, modest enantioselectivity, around
Received 31 August 2009
Revised 10 November 2009
Accepted 13 November 2009
Available online 5 December 2009
80% ee, was achieved in the reduction of linear
a
,b-unsaturated heteroaryl ketones.
Ó 2009 Elsevier Ltd. All rights reserved.
1
. Introduction
Heterocyclic fragments containing oxygen or sulfur in the ring
50% of the desired non-racemic alcohols. To overcome this limita-
tion, the quantitative chemoenzymatic reduction of ketones has
also been widely studied. Baker’s yeast reduction has been applied
8
are important cores found in natural and synthetic products used
in the flavor, fragrance, and pharmaceutical industry.1 Recently,
enantiomerically pure (R)-2-furanyl-2-ethanol was used as a build-
ing block by O’Doherty et al. to introduce chirality in the synthesis
effectively to obtain (S)-1-heteroarylethanols in high enantiopuri-
ty, however, the opposite enantiomer required a chemical transfor-
8
c
mation. Other limitations of biocatalysts are the lack of generality
and difficulties encountered in scaling-up the methods for pharma-
2
a
8
of the anthrax tetrasaccharide produced by Bacillus antharacis.
ceutical production. The Noyori asymmetric transfer hydrogena-
Other furfuryl enantiopure alcohols were used by the same group
to obtain iminosugar natural products.2b Benzofuran carbinols
are important units found in chiral drugs such as bufuralols, potent
nonselective b-blocker antagonists.2 In addition, sulfur heterocy-
cles are important intermediates in the synthesis of chiral biologi-
cally active compounds such as the antidepressant Duloxetine 2
tion method, which uses ruthenium diamino complexes, has
been successfully applied to the synthesis of heterocyclic enantio-
pure secondary alcohols.
2
,9
d,e
Asymmetric addition of boron, aluminum, and silicon hydrides
to the carbonyl group of prochiral ketones is an area of major inter-
est since these methods provide a less expensive, efficient, and
suitable access to a great variety of non-racemic alcohols with pre-
3
4
(
Cymbalta), and the carbonic anhydrase inhibitor, MK-0417 3,
1
0
used for the treatment of glaucoma (Fig. 1). Zileuton 4 from Abbott
and other related furan, thiophene, and benzofuran 5-lipoxygenase
inhibitors have been developed for the treatment of asthma and
dictable stereochemistry. Oxazaborolidines have been the most
widely used boron catalysts for the borane reduction of heteroaryl
1
1,12
ketones.
However, the oxazaborolidine reduction of ketones
5
other inflammatory deseases. In addition, chroman and thiochro-
containing oxygen, sulfur, and nitrogen have been observed in
some substrates, to provide inferior enantioselectivity, particularly
at the 2-position, possibly due to a competitive intramolecular
man carbinols are found in many drugs, such as 4-hydroxy tertalo-
6
lol 5, which is employed in the treatment of high blood pressure.
1
2a
Consequently, the synthesis of single isomeric heteroaryl carbi-
nols is currently a vast area of research. Although conventional
chemical resolutions of racemic drug precursors are still being
used to obtain enantiopure products, more efficient bioenzymatic
reduction by the heterocyclic–borane complex.
Recently, a series of novel stable aminoborate esters with
oxazaborolidine-like enantioselectivity were synthesized and char-
acterized by our group. The structure of some of these aminob-
7
13c,e
resolution methods are being developed. For example, the kinetic
orates esters was established by X-ray analysis.
The highly
resolution of racemic heterocyclic alcohols by lipases has been
demonstrated to be a useful tool since it provides high enantiopure
crystalline and stable spiroaminoborate complex 1, derived from
diphenylprolinol (Scheme 1) and ethylene glycol, was found to
be highly enantioselective and convenient catalysts for the asym-
7
a,b
heteroaryl ethanols.
Nevertheless, the maximum yield is still
1
3a–e
metric borane reduction of prochiral ketones.
As part of our
interest in the enantioselective synthesis of biologically active pre-
cursors, we decided to apply our spiroaminoborate methodology
*
Corresponding author. Tel.: +1 787 852 3222; fax: +1 787 850 9422.
E-mail address: ortiz@quimica.uprh.edu (M. Ortiz-Marciales).
0
957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.11.009

2
660
V. Stepanenko et al. / Tetrahedron: Asymmetry 20 (2009) 2659–2665
OH
S
H N
2
O
HO N
NH
HN
S
O
O
H
2
SO NH2
N
HO
S
S
S
O
2
2
3
4
5
Figure 1. Biologically active heterocyclic compounds containing sulfur.
for the asymmetric reduction of heteroaryl compounds containing
oxygen or sulfur.
Table 1
Reduction of ketones containing the furanyl ring and using spiroborate ester 1 in 10
and 1 mol %
a
2
. Results and discussion
OH
O
Cat. 1 (0.1-0.01 equiv)
In previous work, we have studied the borane-mediated reduc-
RL
RS
RL
RS
BH -DMS (0.7 equiv), THF, rt
3
tion of aryl and pyridyl ketones using different aminoborate
catalysts, and the process was optimized using different solvents,
borane sources, temperatures, and amount of catalyts.
Yieldb (%)
eec (%)
13a–c
Entry
Substrate
Cat. 1 (%)
To
assess the catalytic performance of 1, a curve of catalytic load vs.
enantiomeric excess was established using the acetophenone
reduction with borane–dimethyl sulfide in THF at 25 °C, as a mod-
el. The maximum enantioselectivity (99% ee) was attained with
1
2
O
O
10
1
63
65
95
95
2
2
-Acetylfuran
3
4
O
O
10
1
87d
91
91
85
1
0
0 mol % of aminoborate 1, and the catalytic cut-off was
.5 mol % obtaining 98% ee.13c Additionally, we have carried out
similar studies with the 3- and 4-acetyl pyridines observing excel-
-Acetyl-5-methylfuran
lent enantioselectivities, 98% ee and 99% ee, respectively, with
mol % of catalyst.1
3d
88d
95
96
96
1
5
6
O
O
10
1
Derivatives of 2-acetylfuran are important synthons for the
preparation of
a-hydroxy and other a-functionalized acids by
14
(benzofuran-2-yl)ethanone
O
ozonolysis of the furan ring. The reduction of 2-acetylfuran in
the presence of 10 mol % of 1 gave (+)-(R)-1-(furan-2-yl)ethanol
in 95% ee. When 1 mol % of catalyst was used, the selectivity was
still high, 95% ee. The yield was moderate probably due to the high
volatility of the alcohol causing product loss during distillation in
the purification process (Table 1, entries 1 and 2). Other commer-
cially available substrates with a furanyl fragment were studied
7
8
10
5
86d
78
92
92
d
O
benzofuran-3(2H)-one
O
(
entries 3–6). Unexpectedly, 2-acetyl-5-methylfuran provided the
corresponding alcohol with significantly lower selectivity with 1%
of catalyst, but with 10 mol %, the enantiopurity of the correspond-
ing alcohol increased to 91% ee (entry 3). The enantioselectivity for
the 2-acetyl benzofuran reduction was 96% ee using 1% and 10% of
9
10
82
>99e
O
Chroman-4-one
a
1, in good yield (entries 5 and 6).
The reaction was carried out using 0.7 equiv of borane DMS in THF at room
temperature.
The unstable and enolizable benzofuran-3(2H)-one afforded the
b
Yield after distillation in a Kugelrohr apparatus.
corresponding alcohol with good selectivity (92%) using 10% and
% of catalyst (entries 7 and 8 in Table 1). However, a lower level
c
d
e
Determined by GC of the acetate on a CP-Chirasil-Dex CB column.
Yield after column chromatography.
5
Determined by 31P NMR of a phosphonate (CDA) derivative.15
of asymmetric induction was observed with 1% of catalyst, obtain-
ing the dihydrobenzofuranol with less than 50% ee and in low yield
H
Ph
Ph
OH
O
cat. 1 (0.01 equiv)
Ph
N
O
Ph
(R)
BH -DMS (0.7 equiv), THF, rt
H
B
3
84% 98% ee
O
O
1
Scheme 1.

V. Stepanenko et al. / Tetrahedron: Asymmetry 20 (2009) 2659–2665
2661
(
33%). However, remarkable enantioselectivity was achieved for
parentheses in Table 2). However the yields were modest, possibly
duetothemorelaboriousDEAextractionprocessduringthework-up.
Chiralallylic alcoholsareveryimportantsynthonsinorganicsyn-
thesis and can be prepared by asymmetric reduction of the corre-
the 4-chromanone reduction with 10 mol % of catalyst 1, providing
the chromanol in >99% ee (entry 9).
Our study was then extended to the synthesis of representative
sulfur-containing heteroaryl alcohols. Prochiral thiophenyl ketones
and thiochromanones were, in general, successfully reduced to the
corresponding alcohols with 10 and even 1 mol % of catalyst 1
1
6
sponding unsaturated ketones. For the reduction of heteroaryl
,b-unsaturated ketones, we investigated the reaction of (E)-4-phe-
a
nylbut-3-en-2-one6 using differentamounts of catalyst1 anda vari-
ety of borane reagents (Table 3, entries 1–6). The optimal
enantiomeric excess (80%) was achieved using borane–DMS with
10% of 1. The reaction was conducted in THF at 0 °C, and no
reduction of the double bond was observed. The reduction of com-
mercially available enones containing thiophenyl and furyl substit-
uents 7 and 8 was studied with different catalytic loads of 1 using a
borane–DMS complex under the previous conditions. Similarly, using
10 mol % of catalyst 1 provided the optimal selectivity affording
(Table 2). Outstanding enantioselectivities (>96% ee) were attained
in most instances even with a low catalytic load, and the reactions
were completed in less than an hour. The products were easily iso-
lated in high yield and purified, usually, by a simple distillation. In
addition, we studied the reduction of some sulfur heterocyclic ketone
using borane diethylaniline (DEA) as a more stable borane sources.
In general, for the selected thiophene compounds, we observed high
1
5
enantioselectivity up to 99% ee with 10% catalyst 1 (as shown in
Table 2
a
Reduction of heteroaryl ketones containing sulfur using 1and 10 mol % of spiroaminoborate ester 1
Entry
Substrate
Cat. 1 (%)
Yieldb (%)
eec (%)
1
2
S
O
10
1
92
87
98
96
2
2
-acetylthiophene
3
4
10
1
91 (83)d
91
98 (99)d
98
O
Cl
S
-acetyl-5-chlorothiophene
O
5
6
10
1
75
97
86 (71)d
98 (82)
d
S
3
3
3
-acetylthiophene
7
8
O
10
1
90 (83)d
89
95 (99)d
96
S
-acetyl-2,5-dimethylthiophene
9
1
O
10
1
92 (76)d
92
99 (99)d
99
0
Cl
Cl
S
-acetyl-2,5-dichlorothiophe
1
1
1
2
O
10
1
92 (53)d
93
94.5 (94)d
94
S
6,7-Dihydro-5H-
benzo[b]thiophen-4-one
1
1
3
4
O
10
1
80c,d
92
93d
99 (92)
d
S
Thiochroman-4-one
1
1
5
6
O
10
1
85c
92
100
99
Cl
S
6
-chlorothiochroman-4-one
a
b
c
The reaction was carried out using 0.7 equiv of borane DMS in THF at room temperature.
Isolated yield after distillation in a Kugelrohr apparatus.
Determined by GC of the acetate on chiral column.
d
3
The reaction was carried out using BH –DEA

2
662
V. Stepanenko et al. / Tetrahedron: Asymmetry 20 (2009) 2659–2665
Table 3
Studies on the reduction of unsaturated ketones using spiroborate ester 1a
O
OH
Cat. 1 (0.25-0.01 equiv)
R
º
BH (0.6 equiv), THF, 0 C
3
R
6
7
8
: E, R = Ph
: E, R = 2-thiophenyl
: Z, R = 2-furyl
Entry
Substrate
Cat. (%)
Borane
Yieldb (%)
eec (%)
1
2
25
10
BH
BH
3
–DMS
–DMS
87g
73
79
80
3
3
4
5
6
1
BH
BH
BH
BH
3
3
3
3
–DMS
–DEA
73
70
67
72
74
O
d
10
10
10
—
—
e
d
–THF
(
E)-4-phenylbut-3-
en-2-one 6
f
d
–THF
—
7
8
9
O
25
10
1
BH
BH
BH
3
–DMS
–DMS
55g
83
87
72
80
62
3
S
3
–DMS
(
E)-4-(thiophen-2-
yl)but-3-en-2-one 7
1
1
0
1
O
25
10
BH
BH
3
–DMS
–DMS
73g
83
81
83
3
1
2
1
BH
3
–DMS
88
65
O
(
Z)-4-(furan-2-
yl)but-3-en-2-one 8
a
b
c
d
e
f
The reaction was carried out using 0.6 equiv of borane reagent in THF at 0 °C.
Yield after distillation in a Kugelrohr apparatus.
Determined by GC of the acetate on a chiral column.
The product was not isolated.
Borane–THF complex was stabilized by <0.005 M of NaBH .
4
Borane–THF complex was stabilized by <0.005 M of N-tert-butyl-N-isopropyl-methylamine.
g
Yield after column chromatography.
1
(
3
R,Z)-4-(furan-3-yl)but-3-en-1-ol and (R,E)-4-(thiophen-3-yl)but-
-en-2-ol (entries 8 and 11) in 80% and 83% ee, respectively. The
performed in a Perkin–Elmer Spectrum 100 FT-IR with ATR. H, 13C
NMR spectra were recorded on a Bruker Avance 400 MHz spectrom-
eter with standard pulse sequences operating at 400.152 MHz and
absolute configuration of the products was assigned based on
the comparison with the literature specific rotation values and by
the predicted stereochemistry outcome produced by catalyst 1.
100.627 MHz in CDCl
cessed on a Hewlett Packard GC 5890 equipped with a Chrompack
m). GC–MS
3
. Chiral gas chromatography analysis was pro-
Chiralsil-Dex-CB column (30 m ꢀ 0.25 mm ꢀ 0.25
l
analysiswas processedon a Finnegan TraceGC/PolarisQ Massdetec-
tor using a Restek RTX-5MS column. A Perking–Elmer Polarimeter,
Model 341, was used for optical rotation analysis.
3
. Conclusions
In general, the asymmetric borane reduction of prochiral furyl,
chroman, thiochromanyl, and thiophenyl ketones was successfully
achieved with high enantioselectivity using only 1 mol % of spirob-
orate ester 1 as a catalyst and under very mild and convenient con-
ditions, offering an efficient synthetic tool for the preparation of
enantiopure secondary alcohols. Although only moderate selectiv-
4
.1. General procedure for the preparation of racemic alcohols
To a solution of the ketone (1 mmol) in THF (3 mL) and MeOH
(
3 mL), solid sodium borohydride (37 mg, 1 mmol) was added at
0
°C. After the reaction mixture was stirred at 25 °C over 1 h, the
ity was achieved in the reduction of linear
a,b-unsaturated aro-
solvents were evaporated. The residue was dissolved in dichloro-
methane (DCM) (10 mL) and added into water (15 mL) in a separ-
atory funnel and extracted. The aqueous phase was extracted with
matic ketones, it is a facile method and further studies will be
considered to improve the enantiomeric purity.
DCM (2 ꢀ 10 mL) and dried over Na
2 4
SO . The solvents were
4
. Experimental part
removed under vacuum. The crude product was used for the prep-
aration of the O-acetyl derivative for the enantiopurity determina-
tion by GC-analysis.
All reactions were preformed in oven-dried glassware under an
2
N atmosphere. Air- and moisture-sensitive reagents and solvents
were transferred via syringe. All reagents were obtained commer-
cially from Aldrich unless otherwise noted. Common solvents were
dried and distilled by standard procedures.
4.2. General procedure for the preparation of O-acetyl
derivatives for GC-analysis of alcohols
Chromatographic purification of products was accomplished
using flash chromatography on Merck silica gel, 200–400 mesh, as
eluent: hexane/AcOEt 100:1 to 1:1 using HPLC grade solvents. Thin
layer chromatography (TLC) was performed on Merck silica plates.
The spots were visible under an UV lamp. Infrared analyses were
To a solution of the racemic or enantio-enriched alcohol
(0.5 mmol) in dry ethyl ether (3 mL,) in a 10 mL vial, neat triethyl-
amine (0.5 mL, 3.60 mmol), acetic anhydride (0.5 mL, 5.30 mmol),
and a small crystal of DMAP (2 mg, 0.02 mmol) were added. The

V. Stepanenko et al. / Tetrahedron: Asymmetry 20 (2009) 2659–2665
2663
mixture was left at 25 °C for 5 min, and then H
2
O (3 mL) and the
pump. After usual work-up, the crude residue was distilled in a Ku-
mixture were shaken for 5 min. Solid Na CO (3 g) was carefully
2
3
gelrohr apparatus under vacuum to give the final (+)-(R)-1-(benzo-
added in small portions and left for 5 min, shaking from time to
time. Extreme evolution of gas was observed. The O-acetyl deriva-
tive was extracted with additional diethyl ether (2 mL) and the or-
ganic phase was transferred with a Pasteur pipette to another vial.
Chiral gas chromatography analysis was processed on a Hewlett
Packard GC 5890 equipped with a Chrompack Chiralsil-Dex-CB col-
furan-2-yl)ethanol as a colorless oil (1.54 g, 95%). Bp: 220 °C/
1
0.5 mmHg H NMR (400 MHz, CDCl
3
): d 1.57 (d, J = 6.6 Hz, 3H,
Me), 2.88 (br s, 1H, OH), 4.94 (q, J = 6.4 Hz, CHMe), 6.53 (s, 1H,
C
C
3
0
H), 7.18–7.27 (m, 2H, C
7 3
H), 7.51 (d, J = 6.0 Hz, 1H, C H); C NMR (100 MHz, CDCl ): d
5 6
H and C H), 7.44 (dd, J = 8.0, 0.6 Hz,
0 0
1
3
0
0
4
21.4, 66.0, 101.7, 111.2, 121.0, 122.7, 124.1, 128.2, 154.7, 160.3.
Chiral GC of O-acetyl derivative at T = 90 °C (10 min), gradi-
ent = 1 °C/min, T = 150 °C (35 min): Rt
indicated 96% ee. ½
(c 1.0, CHCl ), 98.6% ee.
umn (30 m ꢀ 0.25 mm ꢀ 0.25
lm).
1
2
R
47.2 min; Rt
S
46.2 min,
¼ ꢁ16:6
2
D
3
7a
20
4
.3. General optimized method for the asymmetric reduction of
a
ꢂ
¼ þ18 (c 3, CHCl
3
). Lit. (S) ½
a
ꢂ
D
ketones using 1 mol % of spiroborate 1
3
Borane–SMe complex (10 M, 0.7 mL, 7.0 mmol) was added to a
2
4.3.4. Reduction of benzofuran-3(2H)-one using 10 mol % of
borate ester 1
solution of (S)-2-[(1,3,2-dioxaborolan-2-yloxy)diphenylmethyl]
pyrrolidine 1 (32 mg, 0.10 mmol) in dry THF (5 mL) at 25 °C and
the mixture was stirred for 1 h. A solution of ketone (10.0 mmol)
in THF (5 mL) was added for 1 h using an infusion pump. The reac-
tion mixture was stirred at 25 °C over 1 h, then cooled at 0 °C,
quenched with methanol (5 mL), and concentrated. The residue
was dissolved in methanol (10 mL) and refluxed over 3 h, concen-
trated, re-dissolved in methanol (5 mL), and concentrated again.
The residue was distilled in a Kugelrohr apparatus under vacuum
to give the final product.
To a dried 25 mL round flask under a nitrogen flow, spiroborate
1 (0.097 g, 0.3 mmol) was added and then, dry THF (5 mL) was
added to make a clear solution. Borane dimethyl sulfide complex
(0.21 mL, 10.0 M, 2.1 mmol) was added to the solution and the
mixture was stirred during 1 h. The initial cloudy mixture changed
to a colorless solution. Benzofuran-3(2H)-one (0.402 g, 3.0 mmol)
in dry THF (5.0 mL) was added to the solution over 1 h using an
infusion pump, and the mixture was allowed to stir for an addi-
tional 1 h. The reaction was then monitored by TLC using a silica
plate and hexane as eluent to confirm the substrate consumption.
The reaction was quenched with MeOH (2 mL) and the mixture
was stirred overnight. The solvents were removed in the rotova-
porator at 60 °C at approximately 20 mmHg and finally concen-
trated to afford a yellow oil. The crude product was treated with
4
.3.1. Reduction of 2-acetylfuran using 1 mol % of spiroborate
A solution of freshly redistilled 1-(furan-2-yl)ethanone (1.10 g,
0.0 mmol) in THF (5 mL) was added to the reaction flask. After fol-
1
lowing the general procedure, (+)-(R)-1-(furan-2-yl)ethanol was
obtained as colorless oil (730 mg, 65%). Bp: 150 °C/1 mmHg. IR
H
2
O (10 mL), extracted with methylene chloride (3 ꢀ 10 mL), dried
ꢁ1
(
cm ): 3335, 2981, 1505, 1148, 1066, 1008. MS m/z (relative
intensity, ion): 112.0 (28, M), 97.1 (46, M–CH ), 95.1 (100, M–
). H NMR (400 MHz, CDCl ): d
.48 (d, J = 6.6 Hz, 3H, Me), 3.08 (br s, 1H, OH), 4.81 (q, J = 6.6 Hz,
CHMe), 6.19 (dt, J = 3.3, 0.7 Hz, 1H, C H), 6.29 (dd, J = 3.2, 1.8 Hz,
H, C H), 7.33 (dd, J = 1.8, 0.8 Hz, 1H, C
H); 13C NMR (100 MHz,
CDCl ): d 21.3, 66.4, 105.1, 110.1, 141.8, 157.8. Chiral GC of O-acet-
yl derivative at T = 70 °C (10 min), gradient = 4 °C/min, T = 190 °C
over sodium sulfate, filtered, and concentrated in the rotovapora-
tor at 60 °C under vacuum. The crude product was purified by col-
umn chromatography using Silica Gel 60 Å mesh 70–130 and
hexane/EtOAc 1:1 as eluent to give (+)-(S)-2,3-dihydrobenzofu-
3
1
OH, –H), 69.2 (32, M-CHOHCH
3
3
1
ran-3-ol as a yellow solid, mp 48–50. (0.349 g, 86% yield). 1
H
0
3
1
4
0
5
0
NMR (400 MHz, CDCl
= 2.6 Hz, J = 10.6 Hz, 1H, CH
J = 4.8 Hz, 1H, HO-C-H); 6.99 (td, J
7.31 (td, J = 0.8 Hz, J = 8.0 Hz, 1H, Ar); C NMR (100 MHz, CDCl
d ppm: 72.2, 78.2, 110.6, 121.1, 125.5, 128.3, 130.8, 160.2. Chiral
GC of O-acetyl derivative at T = 70 °C (10 min), gradient = 4 °C/
min, T = 190 °C (35 min): Rt 21.3 min; Rt 19.9 min, indicated
92% ee. ½ ¼ þ13 (c 2.2, CHCl ). With 5% it was afforded 78%
chemical yield, 92% ee and similar specific rotation: ½
3
) d ppm: 2.24 (s, 1H, OH); 4.45 (dd,
); 4.56 (m, 1H, CH ); 5.36 (d,
= 0.8 Hz, J = 7.4 Hz, 1H, Ar);
3
J
1
2
2
2
1
2
1
2
2
2
13
(
(
35 min): Rt
c 1.45, CHCl
R
19.2 min; Rt
). Lit. (R): [
S
17.4 min, indicated 95% ee. ½
aꢂ
¼ þ21
1
2
3
)
D
7
d
3
a
]
D
= +22 (c 2.7, CHCl ), 95% ee.
3
1
4
1
.3.2. Reduction of 1-(5-methylfuran-2-yl)ethanone using
0 mol % of spiroborate
2
R
S
2
D
2
a
ꢂ
3
2
D
2
A solution of freshly redistilled 1-(5-methylfuran-2-yl)ethanone
a
ꢂ
¼ þ61
7
e
(
0.62 g, 5.00 mmol) in THF (5 mL) was added to the reducing mix-
3 D 3
(c 1.8, CHCl ). Lit. (R): [a] = +67 (c 0.63, CHCl ), >98% ee.
ture for 1 h using an infusion pump. After the usual work-up, the
crude product was distilled in a Kugelrohr apparatus under vacuum
to give the final product, (+)-(R)-1-(5-methylfuran-2-yl)ethanol as a
colorless oil (468 mg, 74%). Bp: 150 °C/1 mmHg. The reaction was
repeated to improve the yield and the crude product was purified
4.3.5. Reduction of chroman-4-one using 10 mol % of
spiroborate 1
To a 100 mL one neck round-bottomed flask, previously dried
and under nitrogen, was placed (S)-2-[(1,3,2-dioxaborolan-2-
yloxy)diphenylmethyl]pyrrolidine (1) (0.323 g, 1.0 mmol) and dis-
by column chromatography with Silica Gel 60 Å and hexane/EtOAc
1
gradients to give 0.546 g (87%). H NMR (400 MHz, CDCl
3
): d 1.49
Me), 2.45 (br s,
H, OH), 4.79 (q, J = 6.6 Hz, CHMe), 5.87–5.88 (m, 1H, C H), 6.07
d, J = 3.0 Hz, 1H, C ): d 13.5, 21.2,
H); 13C NMR (100 MHz, CDCl
2
solved in dry THF (40 mL). Borane–SMe complex (10 M, 2.0 mL,
(
d, J = 6.6 Hz, 3H, CHMe), 2.26 (d, J = 0.8 Hz, 3H, C
5
0
20 mmol) was added via an infusion pump during 30 min, and
the mixture was stirred at 25 °C for 1 h. A solution of chroman-4-
one (1.48 g, 10 mmol) in THF (5 mL) was added for 1 h using an
infusion pump. The reaction mixture was stirred at 25 °C over
3 h, then cooled at 0 °C, quenched with methanol (5 mL), and left
stirring overnight at room temperature. After the mixture was con-
centrated in the rotoevaporator at 70 °C, the residue was dissolved
in methanol (10 mL) and concentrated again. The residue was trea-
1
0
4
(
3
0
3
6
1
3.5, 105.9, 106.0, 151.6, 155.9. GC–MS m/z (relative intensity)
26 M (16%), 110 (32%), 109 (100%), 95 (52%), 81 (12%). Chiral GC
+
of O-acetyl derivative at T
1
= 70 °C (10 min), gradient = 4 °C/min,
16.9 min, indicated 91% ee,
T
2
= 190 °C (35 min): Rt 21.3 min, Rt
R
S
2
3
7d
determined from crude derivative. ½
a
ꢂ
3
¼ þ7:2 (c 1.25, CHCl ). Lit.
D
(R): [
a]
D
= +8.5 (c 2.2, CHCl
3
), 95% ee.
ted with NH
4 ꢀ 15 mL) and water (3 ꢀ 10 mL). The organic phases were col-
lected and dried with K CO3. After concentrating at 30 °C in the
4
Cl (20 mL), and extracted with diethyl ether
(
4
.3.3. Reduction of 2-acetylbenzofuran using 1 mol % of
2
spiroborate 1
rotoevaporator, the crude product was purified by flash column
chromatography on silica gel (45 g): ethyl acetate/hexane 1:5,
obtaining the (+)-(R)-4-chromanol as a white solid (1.23 g, 82%
A solution of freshly redistilled 2-acetylbenzofuran (1.60 g,
0.0 mmol) in THF (5 mL) was added for 1 h using an infusion
1

2
664
V. Stepanenko et al. / Tetrahedron: Asymmetry 20 (2009) 2659–2665
yield). 1H NMR (400 MHz, CDCl
CH ), 4.3 (m, 2H, CH ), 4.83 (m, 1H, CH–OH), 6.86 (d, J = 6.40, 1H,
Ar), 6.95 (t, J = 7.60, 1H, Ar), 7.24 (m, 1H, Ar), 7.35 (m, 1H, Ar);
was distilled to give (+)-(R)-1–2,5-dimethyl-3-yl)ethanol as a
3
): d 1.8 (s, 1H, OH), 2.5 (m, 2H,
1
2
2
white solid (1.395 g, 89%). Bp: 152 °C/9 mmHg; mp 83–84 °C. H
NMR (400 MHz, CDCl ): d 1.41 (d, J = 6.4 Hz, 3H, CHMe), 2.02 (br
s, 1H, OH), 2.33 (s, 3H, Me), 2.38 (s, 3H, Me), 4.86 (q, J = 6.6 Hz,
3
1
3
C NMR (100 MHz, CDCl
20.5, 130.1, 124; FT-IR
062(C–O, OH). GC R 6.97 min/MS m/z: 150 M (50%), 131
3
-d): d 63.5, 30.5, 62, 154.5, 116.8, 129,
ꢁ1
13
1
1
m
(cm ): 3434 (O-H), 3054, 2987,
1H, CHMe), 6.66 (s 1H, C
15.1, 23.9, 64.4, 123.6, 131.5, 136.0, 141.3. Chiral GC of O-acetyl
derivative at T = 70 °C (10 min), gradient = 4 °C/min, T = 190 °C
(35 min): Rt 27.4 min; Rt 27.2 min, indicated 95.6% ee.
4
0
H); C NMR (100 MHz, CDCl ): d 12.6,
3
+
t
(
100%), 95 (20%), 121 (80%). The alcohol was derivatized with the
1
2
1
5
31
CDA Alexakis reagent for P-NMR (161.992 MHz, CDCl
provide >99.8% ee.
3
): d 146
R
S
9c
2
D
0
9a
23
21
½
aꢂ
¼ þ61 (c 0.045, CHCl
3
). Lit.
(S):
½
aꢂ
¼ þ18 (c 3.5, CHCl
3
). Lit.
½
a
ꢂ
3
¼ þ7:0 (c 0.45, CHCl ), 97% ee.
D
D
2
D
5
½
a
ꢂ
¼ ꢁ60:5 (c 2.55, EtOH), 95% ee.
4
.3.10. Reduction of 2,5-dichloro-3-acetylthiophene using
4
.3.6. Reduction of 2-acetylthiophene using 1 mol % of borate
1 mol % of spiroborate 1
ester 1
A solution of freshly redistilled 2-acetylthiophene (1.26 g,
0.0 mmol) in THF (5 mL) was added for 1 h using an infusion
pump. After the usual work-up, the crude product was distilled
in a Kugelrohr apparatus under vacuum to give the final product
A solution of freshly redistilled 2,5-dichloro-3-acetylthiophene
(1.95 g, 10.00 mmol) in THF (5 mL) was added for 1 h using an infu-
sion pump. After the work-up, the crude was distilled to give (+)-
(R)-1-(5-chlorothiophen-2-yl)ethanol as a white solid (1.795 g,
1
1
91%). Bp: 143 °C/8 mmHg; mp 66–68 °C. H NMR (400 MHz,
(
+)-(R)-1-(thiophen-2-yl)ethanol as a colorless oil (1.109 g, 87%).
CDCl
J = 6.5 Hz, 1H, CHMe), 6.87 (s 1H, C
d. 23.2, 64.1, 121.4, 124.4, 126.9, 142.5. Chiral GC of O-acetyl deriv-
ative at = 90 °C (10 min), gradient = 4 °C/min, = 190 °C
(35 min): Rt 12.6 min; Rt 12.4 min, indicated 98.6% ee.
3
): d 1.42 (d, J = 6.5 Hz, 3H, CHMe), 2.25 (br s, 1H, OH), (q,
ꢁ
1
13
Bp: 200 °C/1 mmHg; IR (cm ) 3342 (OH), 2974 (CH
3
), 1435 (CH),
370 (CH), 1066 (C–O), 849 (C–S); 1H NMR (400 MHz, CDCl
): d
.53 (d, J = 6.4 Hz, 3H, Me), 2.91 (br s, 1H, OH), 5.04 (q, J = 6.4 Hz,
H and C H), 7.17–7.19 (m, 1H, C H);
): d 25.2, 66.0, 123.1, 124.3, 126.6,
50.0. GC–MS m/z128 M+ (10%), 113 (32%), 95 (20%), 85 (100%).
Chiral GC of O-acetyl derivative at T = 90 °C (10 min), gradi-
ent = 1 °C/min, T = 150 °C (35 min): Rt 20.2 min; Rt 17.4 min,
indicated 96% ee. ½ ). With 10% of 1, it was
4
0
H); C NMR (100 MHz, CDCl ):
3
1
1
3
T
1
T
2
Me), 6.91–6.93 (m, 2H, C
3
0
4
0
5
0
R
S
1
3
23
20
C NMR (100 MHz, CDCl
3
½
a
CHCl
ꢂ
¼ þ24 (c 3.8, CHCl
3
). For 99.8% ee: ½
a
ꢂ
¼ þ30 (c 0.011,
D
D
9b
21
D
1
3
). Lit.
½
a
ꢂ
¼ þ6:75 (c 0.2, CHCl ), 92.1% ee.
3
1
2
R
S
4.3.11. Reduction of 6,7-dihydrobenzo[b]thiophen-4(5H)-one
using 1 mol % of spiroborate 1
2
D
3
aꢂ
¼ þ27 (c 2.5, CHCl
3
2
D
3
7d
obtained 92% yield and 98% ee ½
a
ꢂ
¼ þ26 (c 2.0, CHCl
3
). Lit.
:
A solution of freshly redistilled 3-acetylthiophen (760 mg,
5.00 mmol) in THF (5 mL) was added for 1 h using an infusion
pump. After the work-up, the residue was distilled under vacuum
to give (+)-(R)-4,5,6,7-tetrahydrobenzo[b]thiophen-4-ol as a white
D 3
[a] = +24.2 (c 5, CHCl ), 100% ee.
4
1
.3.7. Reduction of 1-(5-chlorothiophen-2-yl)ethanone using
mol % of spiroborate 1
1
solid (716 mg, 93%). Bp: 152 °C/6 mmHg; mp 57–59 °C. H NMR
A solution of freshly redistilled 1-(5-chlorothiophen-2-yl)etha-
none (1.61 g, 10.0 mmol) in THF (5 mL) was added for 1 h using
an infusion pump. The crude product was distilled to give the
(400 MHz, CDCl
2.84 (m, 2H, C
7.08 (d, J = 5.2 Hz, C
32.3, 65.4, 122.7, 122.6, 138.0, 138.7. Chiral GC of O-acetyl deriva-
tive at = 110 °C (10 min), gradient = 1 °C/min, = 120 °C
(10 min), gradient = 0.5 °C/min, = 130 °C (20 min), gradi-
= 150 °C/min (20 min): Rt 43.4; Rt 43.8 min,
3
): d 1.1.75–2.10 (m, 5H, C
H), 4.76 (br s, 1H, C H), 7.01 (d, J = 5.2 Hz, C
H); C NMR (100 MHz, CDCl ): d 19.9, 25.0,
5
H, C
6
H and OH), 2.67–
7
4
3
H),
1
3
2
3
(
9
+)-(R)-1-(5-chlorothiophen-2-yl)ethanol as a white solid (1.49 g,
1
1%). Bp: 250 °C/1 mmHg. H NMR (400 MHz, CDCl
3
): d 1.53 (d,
T
1
1
T
2
J = 6.4 Hz, 3H, Me), 2.46 (br s, 1H, OH), 4.97 (q, J = 6.4 Hz, Me),
2
T
3
1
3
6
.70 (dd, J = 3.8, 0.8 Hz, 1H, C
3
0
H), 6.74 (d, J = 3.8 Hz, C
): d 25.0, 66.4, 122.4, 125.6, 129.0, 148.6.
= 70 °C (10 min), gradi-
4
0
H);
C
ent
3
= 10 °C/min, T
4
R
S
2
3
NMR (100 MHz, CDCl
3
indicated 94% ee. ½
a
ꢂ
¼ ꢁ7 (c 1, CHCl
3
).
D
Chiral GC of O-acetyl derivative at T
ent = 4 °C/min, T = 190 °C (35 min): Rt
indicated 98% ee.
1
2
R
28.8 min; Rt
S
28.0 min,
4.3.12. Reduction of thiochroman-4-one using 1 mol % of
spiroborate 1
2
D
3
10e
½
a
ꢂ
¼ ꢁ27:4 (c 1.8, CHCl
3
). Lit.
:
25
½
a
ꢂ
¼ ꢁ29:2 (c 2.1, CHCl
3
), 54% ee.
A solution of freshly redistilled thiochroman-4-one (1.64 g,
D
1
0.0 mmol) in THF (5 mL) was added for 1 h using an infusion
4
.3.8. Reduction of 3-acetylthiophene using 1 mol % of
pump. After the usual work-up, the residue was distilled under
spiroborate 1
vacuum to give (+)-(R)-thiochroman-4-ol as a white solid (1.53 g,
92%). Bp: 155 °C/4 mmHg; mp 78–80 °C. H NMR (400 MHz,
1
A solution of freshly redistilled 3-acetylthiophene (630 mg,
.00 mmol) in THF (5 mL) was added for 1 h using an infusion
5
CDCl
(m, 1H, C
4.72 (br t, J = 3.9 Hz, 1H, C
(m, 2H, C H and C H), 7.24–7.28 (m, 1H, C
(100 MHz, CDCl ): d 21.5, 30.0, 66.5, 124.2, 126.7,128.4, 129.7,
120.4, 133.2, 134.6; Chiral GC of O-acetyl derivative at T = 150 °C
gradient = 1 °C/min, T = 185 °C: Rt 14.97 min; Rt 15.5 min, indi-
cated 98.7% ee.
¼ þ134 (c 1.9, CHCl
3
): d 1.96–2.04 (m, 1H, C
H), 2.79–2.84 (m, 1H, C
H), 7.01–7.05 (m, 1H, C
H);
3
H), 2,21 (br s, 1H, OH), 2.24–2.31
H), 3.22–3.30 (m, 1H, C H),
H), 7.07–7.16
pump. After the usual work-up, the crude was distilled to give
+)-(R)-1-(thiophen-3-yl)ethanol as a colorless oil (550 mg, 86%).
3
2
2
(
4
8
1
13
Bp: 200 °C/1 mmHg. H NMR (400 MHz, CDCl
J = 6.5 Hz, 3H, Me), 2.82 (br s, 1H, OH), 4.86 (q, J = 6.4 Hz, CHMe),
.04 (dd, J = 5.0, 1.2 Hz, 1H, C H), 7.10–7.12 (m, 1H, C H), 7.24
): d 24.4,
6.3, 120.1, 125.7, 126.0, 147.3. Chiral GC of O-acetyl derivative
= 120 °C (10 min), gradient = 5 °C/min, T = 185 °C (3 min):
3
): d 1.45 (d,
7
6
5
C NMR
3
7
4
0
2
0
1
H); 1 C NMR (100 MHz, CDCl
3
(
dd, J = 5.0, 3.0 Hz, 1H, C
5
0
3
2
R
S
2
D
3
9a
6
½
a
ꢂ
3
). Lit.
(S):
2
5
at T
Rt 5.4 min; Rt
CHCl
1
2
½
aꢂ
¼ ꢁ113:1 (c 0.46, CHCl
3
), 90% ee.
D
2
D
3
R
S
5.15 min, indicated 98.4% ee. ½
aꢂ
¼ þ27 (c 1.5,
9
b
24
D
9c
3
). Lit.
½
a
ꢂ
¼ þ33:8 (c 0.43, EtOH), 91% ee and Lit.
4.3.13. Reduction of 6-chlorothiochroman-4-one using 1 mol %
of spiroborate 1
A solution of freshly redistilled 6-chlorothiochroman-4-one
(995 mg, 5.00 mmol) in THF (5 mL) was added for 1 h using an
infusion pump. After the work-up, the residue was distilled under
2
5
½
a
ꢂ
¼ þ44:7 (c 1.00, EtOH), 99.8% ee.
D
4
1
.3.9. Reduction of 2,5-dimethyl-3-acetylthiophene using
mol % of spiroborate 17d
A solution of freshly redistilled 2,5-dimethyl-3-acetylthiophen
1.54 g, 10.00 mmol) in THF (5 mL) was added to the reducing solu-
vacuum to give (+)-(R)-6-chlorothiochroman-4-ol as a white solid
1
(
(920 g, 92%). Mp 102–104 °C. H NMR (400 MHz, CDCl
3
): d 2.02–
tion for 1 h using an infusion pump. After the work-up, the crude
3 3
2.10 (m, 1H, C H), 2.24–2.30 (m, 1H, C H), 2.59 (br s, 1H, OH),

V. Stepanenko et al. / Tetrahedron: Asymmetry 20 (2009) 2659–2665
2665
2
3
2
.87–2.93 (m, 1H, C
.1 Hz, 1H, C H), 7.07 (d, J = 8.4 Hz, 1H, C
H); 1 C NMR (100 MHz,
.1 Hz, 1H, C H), 7.35 (d, J = 1.8 Hz, 1H, C
): d 21.8, 30.0, 66.4, 127.9, 128.5, 129.7, 129.9, 131.8, 136.3;
Chiral GC of O-acetyl derivative at T = 150 °C gradient = 1 °C/min,
= 185 °C: Rt 25.6 min; Rt 26.7 min, indicated 98.7% ee.
¼ þ79 (c 2.2, CHCl ).
2
H), 3.22–3.28 (m, 1H, C
2
H), 4.71 (dd, J = 4.9,
References
4
8
H), 7.15 (dd, J = 8.4,
3
1. (a) Bauer, K.; Garbe, D.; Horst, S. Common Fragrance and Flavor Materials, 3rd
ed.; Wiley-VCH: New York, 1997; (b)Annual Reports In Medicinal Chemistry;
Macor, J. E., Ed.; Elsevier Academic Press: Amsterdam, 2007; Vol. 42,.
2. (a) Abrams, J. N.; Babu, R. S.; Guo, H.; Le, D.; Le, J.; Osbourn, J. M.; O’Doherty, G.
A. J. Org. Chem. 2008, 73, 1935; (b) Guo, H.; O’Doherty, G. A. Org. Lett. 2006, 8,
1609; (c) Noyori, R.; Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97; (d) Hwang, S.-
K.; Juhasz, A.; Yoon, S.-H.; Bodor, N. J. Med. Chem. 2000, 43, 1525; (e)
Weerawarna, S. A.; Geisshusler, S. M.; Murthy, S. S.; Nelson, W. L. J. Med. Chem.
1991, 34, 3091.
7
5
CDCl
3
1
T
2
R
S
2
D
3
½a
ꢂ
3
4
.3.14. Reduction of (E)-4-phenylbut-3-en-2-one using 10% of
3.
Bymaste, F. P.; Beedle, E. E.; Findlay, J.; Gallagher, P. T.; Krushinski, J. H.;
Mitchell, S.; Robertson, D. W.; Thompson, D. C.; Wallace, L.; Wong, D. T. Bioorg.
Med. Chem. Lett. 2003, 13, 4477.
spiroborate 1
A solution of (E)-4-phenylbut-3-en-2-one (730 g, 5.0 mmol) in
THF (5 mL) was added at 0 °C for 1 h using an infusion pump.
The reaction mixture was stirred at 25 °C over 30 min, then cooled
at 0 °C, quenched with methanol (5 mL), and concentrated. The
residue was dissolved in methanol (10 mL) and refluxed over 5 h,
concentrated, re-dissolved in methanol (10 mL), and concentrated
again. The residue was distilled in a Kugelrohr apparatus under
vacuum to give (+)-(R,E)-4-phenylbut-3-en-2-ol as a pale yellow
4. Jones, T. K.; Mohan, J. J.; Xavier, L. C.; Blacklock, T. J.; Mathre, D. J.; Sohar, P. E.;
Turner Jones, T.; Reamer, R. A.; Roberts, F. E.; Grabowski, E. J. J. J. Org. Chem.
1991, 56, 763.
5.
(a) Ohemeng, K. A.; Appollina, M. A.; Nguyen, V. N.; Schwender, C. F.; Singer,
M.; Steber, M.; Ansell, J.; Argentieri, D.; Hageman, W. J. Med. Chem. 1994, 37,
3663; (b) Stewart, A. O.; Bhatia, P. A.; Martin, J. G.; Summers, J. B.; Rodriquez, K.
E.; Martin, M. B.; Holms, J. H.; Moore, J. L.; Craig, R. A.; James, D. T.; Ratajczyk,
K.; Mazdiyasni, H.; Kerdesky, F. A. J.; DeNinno, S. L.; Maki, R. G.; Bouska, J. B.;
Young, P. R.; Lanni, C.; Bell, R. L.; Carter, G. W.; Brooks, C. D. W. J. Med. Chem.
1
997, 40, 1955; (c) Bosiak, M. J.; Krzemi n´ ski, M. P.; Jaisankarand, P.; Zaidlewicz,
oil (543 mg, 73%). Chiral GC of O-acetyl derivative at T
dient = 4 °C/min, T
1
= 90 °C gra-
37.4 min; Rt 36.5 min,
= +27 (c
) 81% ee.
M. Tetrahedron: Asymmetry 2008, 19, 956.
2
= 190 °C (35 min: Rt
R
S
6.
Marchand, B.; Gargouil, Y. M. FR Pat 2588260, CAN 108:37647, 1987.
2
3
10g
indicated 80% ee. ½
a
ꢂ
¼ þ25:6 (c 4, CHCl
3
). Lit.
[
a
]
D
7. (a) Paizs, C.; Tosa, M.; Bódai, V.; Szakács, G.; Kmecz, I.; Simándi, B.; Majdik, C.;
Novák, L.; Irimie, F.-D.; Poppe, L. Tetrahedron: Asymmetry 2003, 14, 1943; (b)
To ßs a, M.; Pilbák, S.; Moldovan, P.; Paizs, C.; Szatzker, G.; Szakács, G.; Novák, L.;
Irimie, F.-D.; Poppe, L. Tetrahedron: Asymmetry 2008, 19, 1844; (c)
Drueckhammer, D. G.; Barbas, C. F., III; Nozaki, K.; Wong, C. H.; Wood, C.;
Ciufolini, Y.; Ciufolini, M. A. J. Org. Chem. 1988, 53, 1607; (d) Fantin, G.;
Fogagnolo, M.; Medici, A.; Pedrini, P.; Poli, S.; Gardini, F. Tetrahedron:
Asymmetry 1993, 4, 1607; (e) Boyd, D. R.; Sharma, N. D.; Boyle, R.; Malone, J.
F.; Chima, J.; Dalton, H. Tetrahedron: Asymmetry 1993, 4, 1307; (f) Szigeti, M.;
Toke, E. R.; Turoczi, M. C.; Nagy, V.; Szakacs, G.; Poppe, L. ARKIVOC 2008, 3, 54;
D
10f
0
.5, CHCl
3
) 84% ee, Lit. (S) [
a
]
D
= ꢁ32.2 (c 5, CHCl
3
4
.3.15. Reduction of (Z)-4-(furan-3-yl)but-3-en-2-one using
1
0% of spiroborate 1
A
solution of (Z)-4-(furan-2-yl)but-3-en-2-one (1.36 g,
1
0
0.0 mmol) in THF (5 mL) was added to the reducing solution at
°C for 1 h using an infusion pump. After the usual work-up, the
(
g) Kusakabe, M.; Kitano, Y.; Kobayashi, Y.; Sato, F. J. Org. Chem. 1989, 54, 2085.
crude was distilled in a Kugelrohr apparatus under vacuum to give
8
.
For an extensive review see: Nakamura, K.; Yamanaka, R.; Matsuda, T.; Harada,
T. Tetrahedron: Asymmetry 2003, 14, 2659; (b) Martín-Matute, B.; Edin, M.;
Bogár, K.; Kaynak, F. B.; Bäckvall, J.-E. J. Am. Chem. Soc. 2005, 127, 8817; (c) To sß a,
M. I.; Podea, P. V.; Paizs, C.; Irimie, F. D. Tetrahedron: Asymmetry 2008, 19, 2068.
(a) Evans, D. A.; Michael, F. E.; Tedrow, J. S.; Campos, K. R. J. Am. Chem. Soc. 2003,
1
(
R,Z)-4-(furan-2-yl)but-3-en-2-ol as a yellow oil (1.14 g, 83%). H
NMR (400 MHz, CDCl ): d 1.32 (d, J = 6.4 Hz, 1H), 2.26 (br s, 1H,
OH), 4.39–4.45 (m, 1H), 6.15–6.23 (m, 2H), 6.32–6.41 (m, 2H),
3
9.
7
1
.32 (d, J = 1.2 Hz, 1H); 13C NMR (100 MHz, CDCl
07.9, 111.3, 117.6, 132.4, 141.9, 152.5; Chiral GC of O-acetyl
= 90 °C gradient = 4 °C/min, = 190 °C: Rt
¼ þ24 (c 2.5, CHCl ).
3
): d 23.4, 68.3,
1
25, 3534; (b) Xu, Y.; Clarkson, G. C.; Docherty, G.; North, C. L.; Woodward, G.;
Wills, M. J. Org. Chem. 2005, 70, 8079; (c) Koizumi, M.; Yoshida, M.; Noyori, R.
Org. Lett. 2000, 2, 1749.
derivative at
8
T
1
T
2
R
2
D
3
10. Daverio, P.; Zanda, M. Tetrahedron: Asymmetry 2001, 12, 2225; (b) Kanth, J. V.
B.; Brown, H. C. Tetrahedron 2002, 58, 1069; Matteson, D. Stereodirected
Synthesis with Organoboranes; Springer: Berlin, 1995; (d) Singh, V. K. Synthesis
.5 min; Rt
S
7.7 min, indicated 83% ee. ½
aꢂ
3
1
(
1
992, 7, 605; (e) Cherng, Y.-J.; Fang, J.-M.; Lu, T.-J. J.Org. Chem. 1999, 64, 3207;
f) Brown, H. C.; Chandrasekharan, J.; Ramachandran, P. V. J. Am. Chem. Soc.
988, 110, 1539; (g) Mastranzo, V. M.; Quintero, L.; Anaya de Parrodi, C.;
4
1
.3.16. Reduction of (E)-4-(thiophen-3-yl)but-3-en-2-one using
0% of spiroborate 1
A
solution of (Z)-4-(thiophen-2-yl)but-3-en-2-one (1.52 g,
Juarist, E.; Walsh, P. J. Tetrahedron 2004, 60, 1781.
1
0.0 mmol) in THF (5 mL) was added at 0 °C for 1 h using an infu-
11. (a) Cho, B. T. Chem. Soc. Rev. 2009, 443; (b) Cho, B. T. Tetrahedron 2006, 62,
7621; (c) Glushkov, V. A.; Tolstikov, A. G. Russ. Chem. Rev. 2004, 73, 581; (d)
sion pump. After the work-up, the residue was distilled in a Kugel-
rohr apparatus under vacuum to give the (R,E)-4-(thiophen-2-
yl)but-3-en-2-ol as a yellow oil (1.14 g, 83%). H NMR (400 MHz,
CDCl
Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986.
1
2. (a) Quallich, J. G.; Woodall, T. M. Tetrahedron Lett. 1993, 34, 785; (b) Mathre, D.
J.; Thompson, A. S.; Douglas, A. W.; Hoogsteen, K.; Carroll, J. D.; Corley, E. G.;
Grabowski, E. J. J. J. Org. Chem. 1993, 58, 2880; (c) Bichlmaier, I.; Siiskonen, A.;
Finel, M.; Yli-Kauhaluoma, J. J. Med. Chem. 2006, 49, 1825.
1
3
): d 1.32 (d, J = 6.4 Hz, 1H), 2.26 (br s, 1H, OH), 4.36–4.43
(
6
2
m, 1H), 6.07 (dd, J = 15.8, 6.4 Hz), 6.65 (d, J = 15.8 Hz, 1H), 6.90–
1
3. (a) Stepanenko, V.; Ortiz-Marciales, M.; Correa, W.; De Jesús, M.; Espinosa, S.;
Ortiz, L. Tetrahedron: Asymmetry 2006, 17, 112; (b) Ortiz-Marciales, M.;
Stepanenko, V.; Correa, W.; De Jesús, M.; Espinosa, S. U.S. Patent Application
.94 (m, 2H), 7.11–7.12 (m, 1H); 13C NMR (100 MHz, CDCl
3.3, 68.4, 122.5, 124.2, 125.7, 127.3, 141.8; Chiral GC of O-acetyl
= 110 °C gradient = 1 °C/min, = 140 °C: Rt
¼ þ18:2 (c 2.3,
3
): d
11/512,599, August 30, 2006.; (c) Stepanenko, V.; De Jesús, M.; Correa, W.;
derivative at
2
CHCl
T
1
T
2
R
Vázquez, C.; Guzman, I.; Vazquez, C.; De la Cruz, W.; Ortiz-Marciales, M.;
Barnes, C. L. Tetrahedron Lett. 2007, 48, 5799; (d) Stepanenko, V.; Ortiz-
Marciales, M.; De Jesús, M.; Correa, W.; Vázquez, C.; Ortiz, L.; Guzmán, I.; De la
Cruz, W. Tetrahedron: Asymmetry 2007, 18, 2738; (e) Stepanenko, V.; Ortiz-
Marciales, M.; Barnes, C. L.; Garcia, C. Tetrahedron Lett. 2009, 50, 995; (f) Huang,
K.; Ortiz-Marciales, M.; Correa, W.; Pomales, E.; López, X. Y. J. Org. Chem. 2009,
2
D
3
5.3 min; Rt
S
24.2 min, indicated 80% ee. ½ ꢂ
a
9
c
25
D
3
). Lit.
½
aꢂ
¼ þ41:3 (c 0.49, CHCl
3
), 91% ee.
Acknowledgments
7
4, 4195.
4. Demir, A. S.; Sesenoglu, Ö.; Gerçek-Arkin, Z. Tetrahedron: Asymmetry 2001, 12,
309.
1
Financial support by the National Institute of Health through
their MBRS (GM 08216) and AABRE (NC P20 RR-016470) grants
is greatly appreciated. We express our special gratitude to the
NSF-MRI (01–07) and NIH-MBRS programs to have made possible
the acquisition of a 400 MHz NMR spectrometer. The NSF-PREM
2
15. (a) Alexakis, A.; Frutos, J. C.; Mutti, S.; Mangeney, P. J. Org. Chem. 1992, 57,
1224; (b) Alexakis, A.; Frutos, J. C.; Mutti, S.; Mangeney, P. J. Org. Chem. 1994,
5
9, 3326.
16. Corey, E. J.; Bakshi, R. K. Tetrahedron Lett. 1990, 31, 611.
(DMR-03537730), NIH-INBRE, NIH-RISE, NIH-MARC, and NSF-AMP
undergraduate student’s support is also gratefully acknowledged.