Efficient enantioselective reduction of ketones with Daucus carota root

Article abstract of DOI:10.1021/jo010399p

A novel and efficient reduction of various prochiral ketones such as acetopehones, α-azido aryl ketones, β-ketoesters, and aliphatic acyclic and cyclic ketones to the corresponding optically acive secondary alcohols with moderate to excellent chemical yield was achieved by using Daucus carota, root plant cells under extremely mild and environmentally benign conditions in aqueous medium, has been described. Many of these optically active alcohols are the potential chiral building blocks for the synthesis of pharmaceutically important molecules and asymmetric chiral ligands. Hence, this biocatalytic approach is found to be the most suitable for the preparation of a wide range of chiral alcohols and gave inspiration for the development of a new biotechnological process.

Full text of DOI:10.1021/jo010399p

3900
J . Org. Chem. 2002, 67, 3900-3903
Sch em e 1
Efficien t En a n tioselective Red u ction of
Keton es w ith Da u cu s ca r ota Root
J . S. Yadav,* S. Nanda, P. Thirupathi Reddy, and
A. Bhaskar Rao
Organic Division, Indian Institute of Chemical Technology,
Hyderabad-500007, India
be straightforward. In baker’s yeast, sometimes reduction
of carbonyl compounds is carried out by enzymes requir-
ing costly cofactors (NADH, NADPH); thus, one condition
of their activity is the regeneration of oxidized cofactors.
The use of plant cells in biotechnology has been steadily
increasing over the past decade.5 Biotransformations of
organic xenobiotics, e.g., ethyl-3-oxobutanoate and aceto-
phenone by immobilized plant cell cultures of carrot6 have
been investigated. Recently, Baldassarre et al.,7 first
reported the use of whole plant cell, e.g., carrot root for
the asymmetric reduction of prochiral ketones.
yadav@iict.ap.nic.in
Received April 17, 2001
Abstr act: A novel and efficient reduction of various prochiral
ketones such as acetopehones, R-azido aryl ketones, â-ke-
toesters, and aliphatic acyclic and cyclic ketones to the
corresponding optically acive secondary alcohols with mod-
erate to excellent chemical yield was achieved by using
Daucus carota, root plant cells under extremely mild and
environmentally benign conditions in aqueous medium, has
been described. Many of these optically active alcohols are
the potential chiral building blocks for the synthesis of
pharmaceutically important molecules and asymmetric chiral
ligands. Hence, this biocatalytic approach is found to be the
most suitable for the preparation of a wide range of chiral
alcohols and gave inspiration for the development of a new
biotechnological process.
Herein, we describe for the first time our systematic
and well-defined investigation of the reduction of some
prochiral ketones with Daucus carota root.
We have performed the chiral reduction of various
compounds containing the keto functionality, e.g., aceto-
phenones, cyclic ketones, â-ketoesters, azidoketones, and
aliphatic ketones (Scheme 1). The reduction products in
all the cases lead to valuable chiral intermediates, which
can be further employed in the total synthesis of various
chiral drugs and agrochemicals. The general feature of
these reductions is, for most cases, well documented by
Prelog’s rule, which predicts that hydrogen transfer to
the prochiral ketone always occurs from the Re-face,8a
where L represents a large substituent and S a small
substituent adjacent to the carbonyl group (Scheme 2)
to yield chiral alcohols. But as Sih8b pointed out one
should exercise considerable caution when Prelog’s rule
is applied to intact cell systems.
(a ) Red u ction of Acetop h en on es. Acetophenone and
substituted acetophenones underwent the reduction in
a well-defined fashion. Several substituted acetophenones
were subjected to the reduction protocol (Table 1). In
almost all the cases, the reduction was completed within
40-50 h. Excellent chemical (70-80%) and optical purity
(>90%) was observed. The product alcohol had S config-
uration, which is in perfect agreement with Prelog’s rule.
In recent years, a great amount of attention has been
paid to asymmetric synthesis of chiral synthons, the
demand for which is increasing as precursors in the
development of modern drugs and agrochemicals. Chiral
alcohols are one of the many well-known synthons and
can be obtained from the corresponding prochiral ketones
by asymmetric reduction. Though numerous chemical1
and biocatalytic2 reductions are reported in the literature,
difficulties still remain in attaining high chemical and
optical yield. Asymmetric reduction by means of chemical
methods involves the use of expensive chiral reagents,
and environmentally hazardous heavy metals are often
employed.3 On the contrary, baker’s yeast is by far the
most widely used microorganism for the reduction of
prochiral ketones yielding the corresponding optically
active alcohols with fair to excellent enantioselectivity;
unfortunately,4 recovery of the desired product might not
* To whom correspondence should be addressed. Fax: +91-40-
7160512.
(1) (a) Itsuno, S. Enantioselective Reduction of Ketones. In Organic
Reactions; J ohn Wiley & Sons: New York, 1998; Vol. 52, pp 395-576.
(b) Corey, E. J .; Helal, C. J . Angew. Chem., Int. Ed. Engl. 1998, 91,
1986-2021. (c) Gaylore, N. G. Reduction with Complex Metal Hydrides;
Interscience: New York, 1956. (d) Hajos, A. Complex Hydrides in
Organic Synthesis; Elsevier: New York, 1979. (e) Hudlicky, M.
Reductions in Organic Chemistry; Ellis Harwood: Chichester, 1984;
Vols. 1 and 2.
(2) (a) Csuk, R.; Glanzer, B. Chem. Rev. 1991, 91, 49-97. (b) J ones,
J . B. In Comprehensive Organic Synthesis; Fleming, I., Trost, B. M.,
Eds.; Pergamon Press: Oxford, 1991; Vol. 8, p 183. (c) Servi, S.
Synthesis 1990, 1-25. (d) Wong, C. H.; Drueckhammer, D. G.; Sweers,
H. M. J . Am. Chem. Soc. 1985, 107, 4028. (e) Irwin, A. J .; J ones, J . B.
J . Am. Chem. Soc. 1976, 98, 8476. (f) Nakamura, K.; inoue, Y.; Ohno,
A. Tetrahedron Lett. 1995, 36, 265. (g) Fujisawa, T.; Mobele, B. I.;
Shimizu, M. Tetrahedron Lett. 1992, 33, 5567. (h) Dodds, D. R.; J ones,
J . B. J . Am. Chem. Soc. 1988, 110, 577.
(5) (a) Reinhard, E.; Alfermann, A. W. Adv. Biochem. Engg. 1980,
16, 49. (b) Dixon, R. A. Eds. Plant Cell Culture: A Practical Approach;
IRL Press: Eynsham, 1985. (c) Alfermann, A. W. Biocatalysis in
Organic Synthesis; Tramper, J ., Vander Plas, H. C., Linko, P., Eds.;
Elsevier: Amsterdam, 1985; p 25.
(6) (a) Naoshima, Y.; Akakabe, Y. J . Org. Chem. 1989, 54, 4237. (b)
Naoshima, Y.; Akakabe, Y. Phytochemistry 1991, 30, 3595. (c) Akakabe,
Y.; Takahasi, M.; Kamezawa, M.; Kikuchi, K.; Tachibana, H.; Ohtani,
T.; Naoshima, Y. J . Chem. Soc., Perkin Trans. 1 1995, 1295. (d)
Chadha, A.; Manohar, M.; Soundararajan, T.; Lokeswari, T. S.
Tetrahedron: Asymmetry 1996, 7, 1571.
(7) Baldassarre, F.; Bertoni, G.; Chiappe, C.; Marioni, F. J . Mol.
Catal. B: Enzym. 2000, 11, 55-58.
(8) (a) Prelog, V. Pure Appl. Chem. 1964, 9, 119. (b) Sih, C. J .; Zhou,
B.; Gopalan, A. S.; Shieh, W. R.; VanMiddlesworth, F. Selectivity, a
Goal for Synthetic Efficiency. In Proceedings, 14th Workshop Confer-
ence, Hoechst; Bartmann, W., Trost, B. M., Eds.; Verlag Chemie:
Weinhem, 1984; pp 250-261. (c) Simon, H.; Bader, J .; Gunther, H.;
Neumann, S.; Thomas, J . Angew. Chem., Int. Ed. Engl. 1985, 24, 539.
(d) MacLeod, R.; Prosser, H.; Fikentscher, L.; Lanyi, J .; Mosher, H. S.
Biochemistry 1964, 3, 838. (e) Cervinka, O.; Hub, L. Collect. Czech.
Chem. Commun. 1966, 31, 2615.
(3) a() Nayori, R. Asymmetric Catalysis in Organic Synthesis.
Wiley: New York, 1994. (b) Ohkuma, T.; Ooka, H.; Hashiguchi, S.;
Ikariya, T.; Nayori, R. J . Am. Chem. Soc. 1995, 117, 2675.
(4) Ward, O. P.; Young, C. S. Enzyme Microbiol. Technol. 1998, 12,
482.
10.1021/jo010399p CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/01/2002

Notes
J . Org. Chem., Vol. 67, No. 11, 2002 3901
Ta ble 3. Red u ction of â-Ketoester s w ith D. ca r ota Root
Sch em e 2
time of
conversion yield ee
entry
compd
(h)
(%) (%) config
16 ethyl acetoacetate
17 ethyl 4-chloro-3-oxobutanoate
18 ethyl 4-bromo-3-oxobutanoate
19 ethyl 4-azido-3-oxobutanoate
20 ethyl 3-oxo-3-phenyl-
propanoate
58
60
62
65
56
58 95
50 90
53 95
68 90
62 98
S
S
S
R
S
21 ethyl 4,4,4-trichloro-3-oxo-
butanoate
22 ethyl 4,4,4-trifluoro-3-oxo-
butanoate
23 ethyl 3-oxo-4-phenylsulfonyl-
butanoate
24 ethyl 2-oxo-1-cyclopentane-
carboxylate
70
56
66
60
62
51 88
72 78
70 98
S
R
R
Ta ble 1. Red u ction of Acetop h en on es w ith Da u ca s
ca r ota Root
time of
conversion yield ee
60 97 1R,2S
63 98 1R,2S
entry
compd
acetophenone
(h)
(%) (%) config
25 ethyl 2-oxo-1-cyclohexane-
carboxylate
1
2
3
4
5
6
7
8
9
40
42
48
41
40
50
45
47
49
42
73
76
61
80
82
75
72
73
70
78
92
95
95
90
96
92
94
91
97
98
S
S
S
S
S
S
S
S
S
S
p-chloroacetophenone
p-bromoacetophenone
p-fluoroacetophenone
p-nitroacetophenone
p-methylacetophenone
p-methoxyacetophenone
p-hydroxyacetophenone
1-(2-naphthyl)-1-ethanone
1-(6-methoxy-2-naphthyl)-
1-ethanone
toesters. When we employed D. carota root as the
biocatalyst, completed reduction was effected within 55-
70 h, yielding the products in high chemical and optical
yield (Table 3). Furthermore, the need for costly cofactor
recycling was avoided since the whole cell automatically
does it. The enantioselectivity of the reduction products
for the cyclic â-ketoesters are higher than that of open
chain â-ketoesters.
10
11
1-(2-furyl)-1-ethanone
50
65
92
S
When two racemic â-ketoesters (24 and 25) were
treated with carrot root, the (R)-isomer was reduced
faster than the (S)-enantiomer (the two esters are in
equilibrium under the reaction conditions), and the
hydrogen transfer took place preferentially from the
diastereotopic Re-face yielding (1R,2S) product with high
enantioselection. For compounds 24 and 25, the erythro
isomer was obtained as the major one due to equilibrium
by enolization (with concomitant racemization) of the
educt followed by kinetic resolution.2a A possible coordi-
nation through hydrogen bonded interaction between the
hydroxyl group and the carbonyl oxygen of the carbo-
ethoxy group also cannot be ruled out.
The general stereochemical feature of the reaction is,
for most cases, well explained by Prelog’s rule. However,
it was established that the absolute configuration and
the optical purity of the products depend strongly upon
both the nature and the size of the substituents adjacent
to the carbonyl group and that of the ester moiety. For
compounds 19, 22, and 23, the opposite stereochemistry
was observed as predicted by Prelog’s rule. The absolute
configuration of the reduced product (CF3-ester, 22) was
(R); thus, the hydride transfer to the keto group has
taken place from the Si-face. This is the opposite steric
course as compared with CCl3-ester (21), which is reduced
from the Re-face. It was assumed that CCl3 group is
sterically more demanding than the CF3 group. For
compounds 19 and 23, the configuration of final reduced
product alcohols were (R), which suggests that hydride
transfer occurs from the Si-face. It was concluded that,
like yeast, D. carota produces several enzymes, which are
able to distinguish between, in an enantiomeric way,
small and large groups; thus, hydrogen is delivered from
both the Re- and Si-faces.
Ta ble 2. Red u ction of Cyclic Keton es w ith D. ca r ota
Root
time of
conversion yield ee
entry
compd
1-tetralone
2-tetralone
6-methoxy-1-tetralone
1-indanone
(h)
(%) (%) config
12
13
14
15
70
72
69
78
52
58
60
57
96
95
93
98
S
S
S
S
It was observed that the presence of electron-donating
substituents in the aromatic ring (-Me, -OMe) slows
down the reaction rate. No influence on the steric course
of the reduction was observed. When compared to our
observation with fermentative reduction (yeast) of sub-
stituted acetophenones, (S)-1-arylethanols were obtained
in low to moderate yields and ee values between 82% and
96%.9
(b) Red u ction of Cyclic Alk a n on es. Different sub-
stituted tetralones and indanone were reduced efficiently
with D. carota root. The reduction was completed within
70-80 h (Table 2) as determined by GC. The absolute
configuration of the product alcohol was (S), as predicted
by Prelog’s rule. The enantioselectivity was >95% in all
the cases as determined by chiral HPLC.
(c) Red u ction of â-Ketoester s. Reduction of â-ke-
toesters is probably the most extensively studied small-
molecule microbial transformation leading to chiral
intermediates in asymmetric synthesis. Recently, some
discrepancies regarding the ee and chemical yield10 have
been reported for the yeast-mediated reduction of â-ke-
(9) (a) Deardorff, D. R.; Myles, D. C.; MacFerrin, K. D. Tetrahedron
Lett. 1985, 26, 5615. (b) Bucciarelli, M.; Forni, A.; Moretti, I.; Torre,
G. Synthesis 1983, 897. (c) Nakamura, K.; Ushio, K.; Oka, S.; Ohno,
A.; Yasui, S.; Tetrahedron Lett. 1984, 25, 3979. (d) Meese, C. O. Liebigs
Ann. Chem. 1986, 2004.
(d ) Red u ction of Azid ok eton es. In our continuing
interest for the synthesis of chiral azido alcohols11 that
(10) (a) Wipf, R.; Kupfer, E.; Bertazzi, R.; Leuenberger, H. G. Helv.
Chim. Acta. 1983, 66, 485. (b) Ehrler, J .; Giovannini, F.; Lamatsch,
B.; Seebach, D. Chim. 1986, 40, 172.(c) Seebach, D.; Sutter, M. A.;
Weber, R. H.; Zuger, M. F. Org. Synth. 1985, 63, 1.
(11) (a) Yadav, J . S.; Reddy, P. T.; Hashim, S. R. Synlett 2000, 7,
1049-1051. (b) Yadav, J . S.; Reddy, P. T.; Nanda, S.; Rao, A. B.
Tetrahedron: Asymmetry 2001, 12, 63.

3902 J . Org. Chem., Vol. 67, No. 11, 2002
Notes
Ta ble 6. Red u ction of Keton es on a P r ep a r a tive Sca le
Ta ble 4. Red u ction of Azid ok eton es w ith D. ca r ota Root
time of
conversion yield ee
isolated
yield (%)
substrate/carrot
(w/w)
ee
(%) config
substrate
entry
compd
(h)
(%) (%) config
acetophenone
tetralone
ethyl acetoacetate
2-azido-1-phenyl-
1-ethanone
75
68
65
40
1/100
1/100
1/100
1/100
90
95
92
94
S
S
S
R
26 2-azido-1-phenyl-1-ethanone
27 2-azido-1-(4-chlorophenyl)-
1-ethanone
28 2-azido-1-(4-methylphenyl)-
1-ethanone
29 2-azido-1-(4-methoxyphenyl-
1-ethanone
30 2-azido-1-(4-fluorophenyl)-
1-ethanone
42
40
70 100
R
R
72
71
58
65
77
62
98
98
99
95
97
99
58
78
60
66
78
R
R
R
R
R
2-hexanone
25
1/100
90
S
P r ep a r a tive Sca le Red u ction . Since several ketones
afforded high enantioselectivities for the reduction on a
small scale, it was decided to conduct the transformations
on a large scale to demonstrate the viability of this
protocol as industrially feasible. The isolated yields and
ee’s of the products are summarized in Table 6.
We have also performed the reduction of some ketones
with D. carota root in an aqueous-organic biphasic
reaction system. Common organic solvents, which are
immiscible with water, were investigated, e.g., ethyl
acetate, hexane, and cyclohexane. It was observed that
a significant amount of substrate was unconverted,
leading to a decrease in the yield of reduced product. The
propensity of organic solvents to cause serious damages
to microbial cells probably contributed to this decreased
reaction rate.12 They may destroy the lipid layer and
other structures of microbial cells and diminish their
activities of reduction.
In summation, we have described an ecofriendly and
environmental benign asymmetric reduction system em-
ploying D. carota root as a biocatalyst. The main advan-
tages of this reduction over the traditional yeast-
mediated reductions are easy isolation of the product,
elimination of the need of costly cofactor, and its recy-
cling, easy availability, and cheapness of the carrot root.
Further studies are in progress in order to obtain chiral
alcohols on an industrial scale by increasing the sub-
strate-catalyst contact surface area and by changing
other parameters such as pH, temperature and different
carrot cultivar.
31 2-azido-1-(4-bromophenyl)-
1-ethanone
32 2-azido-(4-tert-butyldimethyl-
silyloxyphenyl)-1-ethanone
33 2-azido-1-(2-furyl)-1-ethanone
34 2-azido-1-(2-thienyl)-
1-ethanone
52
69
69
58
92
94
S
S
35 2-azido-1-(2-naphthyl)-
1-ethanone
70
49
93
R
Ta ble 5. Red u ction of Op en -Ch a in Keton es w ith
D. ca r ota Root
time of
conversion yield ee
entry
compd
2-butanone
2-pentanone
2-hexanone
4-methyl-2-pentanone
3,3-dimethyl-2-butanone
2-heptanone
(h)
(%) (%) config
36
37
38
39
40
41
80
88
85
90
102
86
38
49
50
32
49
30
87
82
90
71
75
92
S
S
S
S
S
S
can be effectively employed in the total synthesis of
various drugs, we have investigated the reduction of
different substituted azidoketones with D. carota root.
All the azido ketones investigated were efficiently re-
duced with carrot root. The reaction was completed
within 40-78 h (Table 4). Both the chemical yield and
the optical purity of the product azido alcohols were
excellent. No influence on the steric course of the reduc-
tion was observed when the substituents were changed,
but the velocity of the reaction was decreased by electron-
donating substituents. Though high chemical yield and
low conversion time was reported for the reduction of
Exp er im en ta l Section
Exp er im en ta l Deta ils. All the ketones were obtained from
commercial suppliers. Carrots were obtained from
azidoketones with baker’s yeast in our earlier com-
munication,
a local
11b
it is noteworthy to mention that some-
market. To increase the contact of the substrate with the
biocatalyst, the external layer was removed and the rest was
carefully cut into small thin pieces (approximately 1 cm long
slice). Reactions were monitored by thin-layer chromatography
(TLC) carried out on 0.25 mm silica gel plates with UV light
and 2.5% ethanolic anisaldehyde (with 1% AcOH and 3%
concentrated H2SO4)-heat as developing agents. Silica gel 100-
200 mesh was used for column chromatography. Yields refer to
chromatographically and spectroscopically homogeneous materi-
als unless otherwise stated. NMR spectra were recorded on 200
MHz spectrometers at room temperature in CDCl3 using tetra-
methylsilane as internal standard, and the chemical shifts are
reported in δ. 13C NMR spectra were recorded with a complete
proton-decoupling instrument. Optical purity of all the com-
pounds (ee) was determined from chiral HPLC analysis as well
as measuring the optical rotations and comparing with literature
values. Solvents for HPLC use were spectrometric grade. The
column was 4.6 × 250 nm, Chiralcel OD column (Daicel). The
eluents were hexane-2-propanol (HPLC grade, 85:15) at 0.5 mL
per min flow rate and monitored at 254 nm wavelength.
times isolation of the desired product is intrinsically
messy, as the aqueous media contains the cellular mass,
nutrients, usual metabolites, and the azidoketones.
(e) Red u ction of Alip h a tic Keton es. It is difficult
to obtain pure simple aliphatic secondary alcohols by the
reduction of corresponding ketones by chemical methods
despite their utility as chiral building blocks. Our inves-
tigation demonstrated that the open-chain aliphatic
ketones can be reduced with D. carota root used as a
biocatalyst. The reduction time was usually longer for
these classes of compounds (Table 5). The chemical yield
of the products are often lower (30-50%) when compared
to the other ketones, as the product alcohols easily
evaporated during the purification process due to their
low boiling point. The absolute configuration of the
product alcohol was (S), which indicates the addition of
hydrogen follows the Prelog’s rule. Simple aliphatic
ketones were reduced by bakers’ yeast predominantly to
the (S)-configured alcohols, often with high ee, but poorer
yield (15-35%) was observed when compared with our
findings.
(12) a) Nelson, D. L.; Cox, M. M. Lehniger Principles of Biochemistry,
3rd ed.; Worth: New York, 2000; p 192. (b) Lapanje, S. Physicochemical
Aspects of Protein Denaturation; Wiley: New York, 1978; Chapters
1-3, 6.

Notes
Red u ction of Keton es w ith D. ca r ota Root. Ketones (100
J . Org. Chem., Vol. 67, No. 11, 2002 3903
Eth yl 4-br om o-3-h yd r oxy-(3S)-bu ta n oa te (18): [R]25
-10.1 (c ) 2.0, EtOH) (lit.20 ([R]D, NMR identical)).
Eth yl 4-a zid o-3-h yd r oxy-(3R)-bu ta n oa te (19): [R]25
)
)
)
D
mg) were added to a suspension of freshly cut carrot root (10 g)
in 70 mL of water, and the reaction mixtures were incubated in
an orbital shaker (150 rpm) at room temperature for the time
necessary to obtain the appropriate conversion. Finally, the
suspension was then filtered off, and carrot root was washed
three times with water. Filtrates were extracted with EtOAc
(3 × 125 mL). The organic phase was dried (Na2SO4) and then
evaporated in a vacuum. The final products were purified by
flash chromatography. If the ketone was solid, ethanolic solution
was added to the carrot root. For the preparative-scale reduction
ketones (1 g) were taken in a 2 L conical flask. Water (700 mL)
was added to it followed by addition of freshly cut carrot (100
g). The reaction mixture was stirred in an incubator shaker for
the required time. After that the product alcohol was isolated
as described before. It is important to note that the reaction
container should be large enough for efficient agitation.
Recyclin g of th e D. ca r ota Root. After completion of the
reduction, the reaction mixture was filtered and the carrot roots
were washed successively with water and then kept in distilled
water at 0 °C for 3 days. After that, water was decanted and
the carrot roots were wiped with soft tissue paper to remove
the remaining water. These roots were again used for another
reduction reaction. It was observed that the activity of the roots
was decreased significantly. Only 20% conversion was achieved
for acetophenone after 10 days incubation. So it was concluded
that the whole cell loses its activity significantly after one
reduction reaction.
D
-16.8 (c ) 1.8, H2O) (lit.20 ([R]D, NMR identical)).
Eth yl 3-h yd r oxy-(3S)-3-p h en ylp r op a n oa te (20): [R]25
D
-7.2 (c ) 3.0, CHCl3) (lit.21 ([R]D, NMR identical)).
E t h yl 4,4,4-t r ich lor o-3-h yd r oxy-(3S)-b u t a n oa t e (21):
[R]25 ) -18.3 (c ) 1.1, CHCl3) (lit.22 ([R], NMR identical)).
D
E t h yl 4,4,4-t r iflu or o-3-h yd r oxy-(3R)-b u t a n oa t e (22):
[R]25 ) 21.1 (c ) 0.9, MeOH) (lit.22 ([R]D, NMR identical)).
D
Eth yl 3-h yd r oxy-4-p h en ylsu lfon yl-(3R)-bu ta n oa te (23):
[R]25 ) -21.0 (c ) 1.5, CHCl3) (lit.23 ([R] D, NMR identical)).
D
Eth yl 2-h ydr oxy-(1R,2S)-cyclopen tan e-1-car boxylate (24):
[R]25 ) 15.0 (c ) 2.8, CHCl3) (lit.24 ([R]D, NMR identical)).
D
Eth yl 2-h ydr oxy-(1R,2S)-cycloh exan e-1-car boxylate (25):
[R]25 ) 28.9 (c ) 10.5, CHCl3) (lit.24 ([R]D, NMR identical)).
D
2-Azid o-1-p h en yl-(1R)-et h a n -1-ol (26): [R]25 ) -80.0
D
(c ) 1.0, CHCl3) (lit.11b ([R]D, NMR identical)).
2-Azid o-1-(4-ch lor op h en yl-(1R)-eth a n -1-ol (27): [R]25
-79.0 (c ) 1.25, CHCl3) (lit.11b ([R]D, NMR identical)).
2-Azid o-1-(4-m eth ylp h en yl-(1R)-eth a n -1-ol (28): [R]25
-28.9 (c ) 1.5, CHCl3) (lit.11b ([R]D, NMR identical)).
)
)
D
D
2-Azid o-1-(4-m eth oxyp h en yl-(1R)-eth a n -1-ol (29): [R]25
D
) -39.0 (c ) 1.2, CHCl3) (lit.11b ([R]D, NMR identical)).
2-Azid o-1-(4-flu or op h en yl-(1R)-eth a n -1-ol (30): [R]25
-14.5 (c ) 2.0, CHCl3) (lit.11b ([R]D, NMR identical)).
)
)
D
2-Azid o-1-(4-br om op h en yl-(1R)-eth a n -1-ol (31): [R]25
D
-35.9 (c ) 1.0, CHCl3) (lit.11b ([R]D, NMR identical)).
Sp ectr a l Da ta for th e Com p ou n d s. 1-P h en yl-(1S)-eth a n -
1-ol (1): [R]25 ) -39.1 (c ) 3.5, MeOH) (lit.13 ([R]D, NMR
D
2-Azido-(4-ter t-bu tyldim eth ylsilyloxyph en yl)-(1R)-eth an -
1-ol (32): 1H NMR 7.25 (d, J ) 7.2 Hz, 2H), 6.85 (d, J ) 7.2 Hz,
2H), 4.80 (m, 1H), 3.40 (m, 2H), 2.35 (brs, 1H), 1.0 (s, 9H), 0.2
(s, 6H); 13C NMR -4.46, 25.62, 58.1, 73.09, 120.24, 127.0, 127.1,
identical)).
1-(4-Ch lor op h en yl)-(1S)-et h a n -1-ol (2): [R]25 ) -41.2
D
(c ) 2.5, CHCl3) (lit.14 ([R] D, NMR identical)).
1-(4-Br om op h en yl)-(1S)-et h a n -1-ol (3): [R]25 ) -25.6
D
133.1; [R]25 ) -59.2 (c ) 1.0, CHCl3).
D
(c ) 3.4, CHCl3) (lit.14 ([R]D, NMR identical)).
2-Azid o-1-(2-fu r yl)-(1S)-et h a n -1-ol (33): [R]25 ) -28.9
D
1-(4-F lu or op h en yl)-(1S)-et h a n -1-ol (4): [R]25 ) -35.0
(c ) 2.0, CHCl3) (lit.11b ([R]D, NMR identical)).
D
(c ) 9.2, CHCl3) (lit.14 ([R]D, NMR identical)).
2-Azid o-1-(2-th ien yl)-(1S)-eth a n -1-ol (34): [R]25D ) -34.6
(c ) 1.5, CHCl3) (lit.11b ([R]D, NMR identical)).
1-(4-Nitr op h en yl)-(1S)-eth a n -1-ol (5): [R]25 ) -30.5 (c )
D
4.0, CHCl3) (lit.14 ([R] D, NMR identical)).
2-Azido-1-(2-n aph th yl)-(1R)-eth an -1-ol (35): [R]25D ) -79.5
(c ) 0.5, CHCl3) (lit.11b ([R]D, NMR identical)).
1-(4-Met h ylp h en yl)-(1S)-et h a n -1-ol (6): [R]25 ) -21.0
D
(c ) 1.5, CHCl3) (lit.13 ([R]D, NMR identical)).
(2S)-Bu ta n -2-ol (36): [R]25 ) 13.1 (c ) 6.0, MeOH) (lit.25
D
1-(4-Meth oxylp h en yl)-(1S)-eth a n -1-ol (7): [R]25 ) -30.0
D
([R]D, NMR identical)).
(c ) 1.75, CHCl3) (lit.13 ([R]D, NMR identical)).
(2S)-P en ta n -2-ol (37): [R]25D ) 14.0 (neat) (lit.26 ([R]D, NMR
1-(4-Hyd r oxyp h en yl)-(1S)-eth a n -1-ol (8): [R]25 ) -47.5
D
identical)).
(c ) 4.2, EtOH) (lit.16 ([R]D, NMR identical)).
1-(2-Na p h th yl)-(1S)-eth a n -1-ol (9): [R]25D ) -31.0 (c ) 3.5,
MeOH) (lit.15 ([R]D, NMR identical)).
(2S)-Hexa n -2-ol (38): [R]25 ) 10.4 (neat) (lit.27 ([R]D, NMR
D
identical)).
1,3-Dim eth yl-(1S)-bu tyl a lcoh ol (39): [R]25 ) 19.5 (c )
1-(6-Meth oxy-2-n a p h th yl)-(1S)-eth a n -1-ol (10): [R]25
-41.8 (c ) 1.5, CHCl3) (lit.17 ([R] D, NMR identical)).
)
D
D
3.5, MeOH) (lit.28 ([R]D, NMR identical)).
1,2,2-Tr im eth yl-(1S)-p r op yl a lcoh ol (40): [R]25 ) 18.5
1-(2-F u r yl)-(1S)-eth a n -1-ol (11): [R]25 ) -19.2 (c ) 3.0,
D
D
(neat) (lit.17 ([R]D, NMR identical)).
(2S)-Hep ta n -2-ol (41): [R]25D ) 10.1 (neat) (lit.15 ([R]D, NMR
identical)).
MeOH) (lit.15 ([R]D, NMR identical)).
(1S)-1,2,3,4-Tetr a h yd r o-1-n a p h th a len ol (12): [R]25D ) 24.5
(c ) 1.2, CHCl3) (lit.13 ([R]D, NMR identical)).
(2S)-1,2,3,4-Tetr ah ydr o-2-n aph th alen ol (13): [R]25D ) -58.2
(c ) 1.5, EtOH) (lit.18 ([R]D, NMR identical)).
Su p p or tin g In for m a tion Ava ila ble: NMR spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
6-Meth oxy-(1S)-1,2,3,4-tetr a h yd r o-1-n a p h th a len ol (14):
1H NMR 7.15 (m, 1H), 7.0 (m, 1H), 6.8 (m, 1H), 4.7 (m, 1H), 3.8
(s, 3H), 2.7 (m, 1H), 2.5 (m, 1H), 2.0 (m, 4H); [R]25 ) +10.1
D
J O010399P
(c ) 1.75, CHCl3).
(1S)-2,3-Dih yd r o-1H-1-in d en ol (15): [R]25D ) 29.8 (c ) 2.0,
CHCl3) (lit.13 ([R]D, NMR identical)).
(19) Nakamura, K.; Higaki, M.; Ushio, K.; Oka, S.; Ohno, A.
Tetrahedron Lett. 1985, 26, 4213.
(20) Fuganti, C.; Grasselli, P.; Casati, P.; Carmeno, M. Tetrahedron
Lett. 1985, 26, 101.
(21) Manzocchi, A.; Csati, R.; Fiecchi, A.; Santaniello, E. J . Chem.
Soc., Perkin Trans. 1 1986, 2753.
Eth yl 3-h yd r oxy- (3S)-bu ta n oa te (16): [R]25 ) 32.8 (c )
D
3.0, CHCl3) (lit.19 ([R]D, NMR identical)).
Eth yl 4-ch lor o-3-h yd r oxy-(3S)-bu ta n oa te (17): [R]25
-19.9 (c ) 3.8, CHCl3) (lit.20 ([R]D, NMR identical)).
)
D
(22) Seebach, D.; Renaud, P.; Schweizer, W. B.; Zuger, Max. F.;
Brienne, M. Helv. Chim. Acta 1984, 67, 1843.
(23) Nakamura, K.; Ushio, K.; Oka, S.; Ohno, A.; Yasui, S. Tetra-
hedron Lett. 1984, 24, 3979.
(24) Frater, V. G. Helv. Chim. Acta 1980, 63, 1383.
(25) Brown, H. C.; Ayyangar, N. R.; Zweifel, G. J . Am. Chem. Soc.
1964, 86, 397.
(26) Kim, Y. H.; Park, D. H.; Byun, S. Il. J . Org. Chem. 1993, 58,
4511.
(27) Quallich, G. J .; Woodall, T. M. Tetrahedron Lett. 1993, 34, 785.
(28) Yamamoto, K.; Fukushima, H.; Nakazaki, M. Chem. Commun.
1984, 1490.
(13) de Vries, E. F. J .; Brussee, J .; Kruse, C. G.; Van der Gen, A.
Tetrahedron: Asymmetry 1994, 5, 377.
(14) Mathre, D. J .; Thompson, A. S.; Douglas, A. W.; Hoogsteen, K.;
Carroll, J . D.; Corley, E. G.; Grabowski, E. J . J . Org. Chem. 1993, 58.
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(15) Cherng, Y.-J .; Fang J .-M.; Lu, T.-J . Tetrahedron: Asymme-
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(16) Clerici, A.; Porta, O. J . Org. Chem. 1985, 50, 76.
(17) Corey, E. J .; Bakshi, R. K.; Shibata, S.; Chen, C.-P.; Singh, V.
K. J . Am. Chem. Soc. 1987, 109, 7925.
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