Catalytic asymmetric transfer hydrogenation of ketones using terpene-based chiral β-amino alcohols

Article abstract of DOI:10.1016/j.tetasy.2006.04.025

Catalytic asymmetric transfer hydrogenations of aromatic alkyl ketones have been studied using [RuCl₂(p-cymeme)]₂ and terpene-based β-amino alcohols. The limonene derived amino alcohol, (1S,2S,4R)-1-methyl-4-(1-methylethenyl)-2-(meth

Full text of DOI:10.1016/j.tetasy.2006.04.025

Tetrahedron: Asymmetry 17 (2006) 1301–1307
Catalytic asymmetric transfer hydrogenation of ketones
using terpene-based chiral b-amino alcohols
Cian Christopher Watts, Praveen Thoniyot, Frank Cappuccio, Joelle Verhagen,
Brain Gallagher and Bakthan Singaram*
Department of Chemistry and Biochemistry, University of California Santa Cruz, Santa Cruz, CA 95060, USA
Received 28 March 2006; accepted 25 April 2006
This paper is dedicated to the memory of Dr. Ronald Micetich
Abstract—Catalytic asymmetric transfer hydrogenations of aromatic alkyl ketones have been studied using [RuCl2(p-cymeme)]2 and
terpene-based b-amino alcohols. The limonene derived amino alcohol, (1S,2S,4R)-1-methyl-4-(1-methylethenyl)-2-(methylamino)cyclo-
hexanol gave the most promising results. Chiral secondary alcohols were obtained in good to excellent yields and moderate
enantioselectivities (up to 71%).
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
metric induction by increasing the steric bulk around the
amine moiety via N-alkylation (Scheme 1).3d
The advantages of asymmetric transfer hydrogenation
(ATH) using transition metal complexes as catalysts for a
variety of substrates, have been well documented in the lit-
erature.1 The development of new or improved asymmetric
reduction methodologies is important for meeting the
continuing need for enantiomerically pure secondary alco-
hols.2 The catalysts used in asymmetric transfer hydro-
genations are usually prepared from an achiral metal
complex and a chiral auxiliary. In order to achieve the
highest enantioselectivity possible, these catalysts should
have ideal steric and electronic properties in relation to
the substrate. In addition to chiral diamines,1 b-amino
alcohols are one of the most effective classes of chiral aux-
iliaries for asymmetric transfer hydrogenations.3 A variety
of b-amino alcohols have been successfully used to gener-
ate active catalysts in situ with [RuCl2(p-cymene)]2, provid-
ing moderate to excellent catalytic activity in the ATH
reduction of acetophenone. Patti et al. found that (R)-1-
N-benzylamino-2-hydroxy-3-ferrocenylpropane 1 provided
a 94% conversion and 70% ee (R) in 3 h at room tempera-
ture. Through optimization of the ligand structure, they
were generally able to improve the reaction rate and asym-
While examining the chiral directive effects of several
substituted 2-amino ethanol and norephedrine-based
ligands in ATH reactions, van Leeuwen reported that
(1R,2S)-N-benzyl-norephedrine 2 provided the highest
asymmetric induction.3i Andersson et al. were successful
in developing highly active and selective catalysts from 2-
azanorbornyl derivative 3.4 Reductions using amino alco-
hol 3 were fast, providing 96% conversion to the alcohol
and 96% ee with a S/C ratio of 5000 in 90 min. Amino alco-
hol (1R,2S)-cis-1-aminoindan-2-ol 4 was developed by
Wills et al. and has been evaluated for its effectiveness in
the reduction of various substrates.5 It should be pointed
out that when amino alcohols were used as chiral directors
in ATH reactions, the best results were achieved using
isopropanol as the hydride source. Several research groups
have reported on the incompatability of amino alco-
hols with formic acid/triethylamine as the hydride
source.1c,d,4c,5e
In a continuation of our interest in the development and
use of terpenes in catalytic asymmetric methodology, we
have synthesized several b-amino alcohols from limonene,
pinene and carene.6 Terpenes make ideal building blocks
for the development of chiral auxiliaries, because they
are naturally abundant, easily obtained and relatively
*
Corresponding author. Tel.: +1 831 459 3154; fax: +1 831 459 2935;
e-mail: singaram@chemistry.ucsc.edu
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.04.025

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C. C. Watts et al. / Tetrahedron: Asymmetry 17 (2006) 1301–1307
O
H
OH
0.5-2.0 mol % ligand 1-4
[RuCl2(p-cymene)]2
iPrOH, KOH or iPrOK, or tBuOK, rt
(1) 94% conv., 70% e.e. (R)
(2) 88% conv., 95% e.e. (R)
(3) 96% conv., 96% e.e. (S)
(4) 70% conv., 91% e.e. (S)
CH2Ph
NH2
CH3
NH
NHCH2Ph
O
Fe
OH
OH
O
NH
OH
OH
1
2
3
4
Scheme 1. Acetophenone reduction using amino alcohol ligands.
inexpensive. We reported that the cis- and trans-diastereo-
mers of (R)-(+)-limonene oxide can be isolated in enantio-
merically and diastereomerically pure forms from a
commercially available (1:1) diastereomeric mixture of lim-
onene oxides. Epoxide ring opening with a variety of
amines allows the formation of b-amino alcohols from
these chiral epoxides.6d Several of the amino alcohols we
synthesized, were found to provide good yields and moder-
ate enantioselectivities for the asymmetric addition of
phenylacetylene to aldehydes promoted by diethyl zinc,6a
as well as up to 87% ee for the diethyl zinc addition to alde-
hydes.6b Our recent encouraging results prompted us to
further explore the scope of these amino alcohols in asym-
metric catalysis. Herein, we report our results on the effec-
tiveness of terpene-based b-amino alcohols as chiral
auxiliaries for the catalytic asymmetric transfer hydrogena-
tion of ketones.
prepared from 3-carene oxide.7 Ligands 6–10 were derived
from trans-limonene oxide and were prepared as reported
earlier.6b
Amino alcohols derived from terpenes have not been
applied to asymmetric transfer hydrogenation as widely
as other chiral ligands, such as those based on ephedrine
or monotosylated diamines.1,3 Most of the amino alcohols
used for ATH have either primary or secondary alcohols,
whereas amino alcohols 5–10 are unique in that they have
tertiary hydroxyl groups. Under standard conditions, the
chiral catalysts were prepared in situ by refluxing
0.25 mol % [RuCl2(p-cymeme)]2 with 2.0 mol % of our
amino alcohols in isopropanol at 80 ꢁC for 1 h. The base
was then added (2.5 mol %) and stirred for 30 min, before
the addition of the substrate (0.1 M ketone). The reduction
of acetophenone was carried out at 25 ꢁC and the reaction
progress monitored by TLC. The product alcohol was
isolated and the enantiomeric excess determined by chiral
GC or HPLC analysis.
2. Results and discussion
For our study we used the representative b-amino alcohols
5–10 (Fig. 1). The primary amine amino alcohol 5, can be
Before screening our series of amino alcohols, we per-
formed an initial study using ligand 6 and acetophenone
OH
OH
H
OH
NH2
NH2
N
5
6
7
OH
OH
OH
H
N
H
Ph
N
N
3
8
9
10
Figure 1. Terpene-based b-amino alcohols for use in Ru(II)-catalyzed transfer hydrogenation of acetophenone.

C. C. Watts et al. / Tetrahedron: Asymmetry 17 (2006) 1301–1307
1303
to try and optimize the reaction conditions. Several differ-
ent bases are currently in use by a number of research
groups conducting research into ATH, including NaOH,
KOH, i-PrONa, and t-BuOK.1 Changing the base from
i-PrONa to t-BuOK lead to an increase in asymmetric
induction (Table 1, entries 1 and 2).
The terpene amino alcohols with primary amines, 5 and 6,
were both equally effective in terms of asymmetric induc-
tion for acetophenone. Limonene based ligand 6 has a
slight advantage over carene based ligand 5 in that the cat-
alyst derived from ligand 6 promoted a faster reaction (Ta-
ble 2, entries 1 and 2). As the steric bulk increased on the
amine with the addition of a methyl group in 7, the enantio-
selectivity also increased slightly to 63% ee with 99% con-
version after 72 h (entry 3). A further increase of the steric
bulk around the amine lead to a decline in the asymmetric
induction for ligands 8 and 9, decreasing from 50% down
to 33% (entries 4–6). Our attempt to use 10 as a ligand in
the ATH reduction of acetophenone was unsuccessful
due to the tertiary amine. Noyori and others have pointed
out that ligands having a tertiary amine group were unable
to catalyze the reduction of carbonyl compounds.1b–d
Table 1. Influence of the amount of base, ligand, and substrate on
conversion and enantioselectivity for the reduction of acetophenone using
ligand 6
Entry
Molar ratio of M:L*:t-BuOK
Conv. [%]
ee [%]
1
2
3
4
5
6
1:8:10a
1:8:10
99
99
68
61
92
42
20
50
35
33
27
26
1:8:20
1:8:40
1:40:10b
1:8:10c
With an increasing demand for environmentally friendly
chemistry, asymmetric transfer hydrogenation performed
in water has recently aroused great interest.8 We decided
to carry out a short investigation with our terpene-based
amino alcohols following two procedures recently pub-
lished in the literature, one taking place in water at
40 ꢁC8a and the other at room temperature.8b Both of these
procedures used sodium formate as the hydride source,
which is preferable over 2-propanol due to its irreversible
hydride delivery. In addition to [RuCl2(p-cymene)]2, we
explored the use of [Cp*RhCl2]2 and [Cp*IrCl2]2 with
ligands 6 and 7 under the reported conditions. Attempted
use of ligands 6 and 7 under these conditions for ATH with
acetophenone was unsuccessful.
a i-PrONa was used for base.
b 10 mol % of ligand was used.
c Substrate concentration was 0.5 M.
We also studied the effect of base and amino alcohol con-
centration on the reduction of acetophenone. These results
showed that increasing the amount of base in the reaction
had a negative effect on the asymmetric induction of the
product. The best molar ratio of Ru(II) to t-BuOK was
1:10 for our system (entry 2). Increasing the concentration
of the ligand by a factor of 5 led to a slight drop in conver-
sion, but a larger drop in enantioselectivity (entry 5). We
also tried changing the molarity of the reaction solution
by decreasing the amount of 2-propanol used for solvent.
After 48 h, only a 42% conversion and 26% ee were noted
when using a 0.5 M solution of ketone (entry 6). The reac-
tion progressed much faster when the ketone concentration
was 0.1 M (entry 2). This observation can be explained by a
change in the isopropanol to acetone equilibrium, which is
reversible.1b,1c,1d Decreasing the amount of 2-propanol
would shift the equilibrium away from the acetone product
back towards the 2-propanol reactant. With less 2-propa-
nol being converted to acetone, the active catalyst cannot
be formed as fast. Although the reduction itself can be car-
ried out at room temperature, the pre-catalyst is formed
during reflux at 80 ꢁC. When the reaction temperature
was changed from room temperature to 55 ꢁC, over 90%
of acetophenone was converted to 1-phenylethanol after
24 h, but the product was racemic. After our attempts at
optimization we screened the rest of the amino alcohols
under our standard conditions (Table 2).
While our work was in progress, Adolfsson reported an
effective amino acid conjugate of an amino alcohol, 11,
as a chiral ligand in ATH reactions (Fig. 2).9
In order to explore the utility of an amino acid conjugate
with our limonene amino alcohol system, we synthesized
compound 12 by coupling Boc-L-valine with ligand 6. Com-
pound 12 was not effective for catalytic ATH under our
reaction conditions. This could be attributed to the presence
of the tertiary alcohol moiety in 12 as compared to the
primary alcohol in 11. We explored further the amide deriv-
atives 13–15, which were synthesized using ligand 6 (Fig. 3).
However, none of the newly prepared compounds were
effective as chiral directors in our ATH reactions.
Based on our initial results (Table 2) with acetophenone,
we decided to explore the scope and limit of amino alcohols
Table 2. Asymmetric reduction of acetophenone using b-amino alcohols
5–10a
OH
Ph
O
H
N
NHBoc
NHBoc
Entry
b-Amino alcoholb
Time [h]
Conv. [%]
ee [%]
N
H
O
1
2
3
4
5
6
5
6
7
8
9
72
36
72
24
24
72
86
99
99
45
83
0
50 (S)
50 (S)
63 (S)
50 (S)
34 (S)
—
OH
11
12
10
a 0.1 M ketone.
b Ketone–ligand:[RuCl2(p-cymeme)]2–t-BuOK = 100:2:0.5:5; 25 ꢁC.
Figure 2. Adolfsson’s amino acid conjugate 11, and a terpene-based
conjugate of an amino alcohol 12.

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C. C. Watts et al. / Tetrahedron: Asymmetry 17 (2006) 1301–1307
OH
OH
OH
H
N
H
N
H
N
H
N
H
N
O
Ph
O
O
O
13
14
15
Figure 3. Terpene-based ligands containing amide moieties for ATH reduction of acetophenone.
Table 3. Asymmetric reduction of several ketones using ligands 6 and 7a
O
O
O
O
O
O
N
16
17
18
19
20
21
Entry
Ketoneb
6
7
Time [h]
Conv. [%]
ee [%]
Time [h]
Conv. [%]
ee [%]
1
2
3
4
5
6
16
17
18
19
20
21
72
24
72
48
48
24
0
99
56
58
10
99
—
48
72
72
36
48
24
94
0
56
75
10
83
22 (R)
—
0
71 (S)
40 (S)
0
12 (S)
48 (S)
68 (S)
53 (S)
14 (S)
a Ketone–ligand:[RuCl2(p-cymeme)]2–t-BuOK = 100:2:0.5:5, 25 ꢁC.
b Substrate concentration was 0.1 M.
6 and 7, which had provided the most encouraging results.
Several representative aromatic alkyl ketones were reduced
under our ATH conditions using ruthenium catalysts
derived from primary amine 6, and the N-methyl amine
7. These results are summarized in Table 3.
secondary alcohols. We have shown that terpene-based b-
amino alcohols can be used as ligands for catalytic ATH
with moderate success. The reduction takes place with
good to excellent conversion, and moderate asymmetric
induction. This could be attributed to the presence of a ter-
tiary hydroxyl group in the amino alcohol. Over the course
of our investigation, we noted that our amino alcohols
were not compatible with either the formic acid/triethyl-
amine or sodium formate systems as hydrogen sources.
The N-methyl limonene amino alcohol 7 catalyzed the
reduction of tetralone to provide the corresponding sec-
ondary alcohol in 75% conversion and 71% enantiomeric
excess for the (S)-enantiomer. This is the highest value re-
ported for an amino alcohol containing a tertiary alcohol
moiety. The terpene precursors of our chiral b-amino alco-
hols have the advantage of being abundant naturally
occurring starting materials, which keeps the cost low.
The non-aromatic ketone pinacolone was not reduced in
the presence of ligand 6, but in the presence of ligand 7
was reduced in excellent conversion (94%). However, the
asymmetric induction was poor (22% ee) (Table 3, entry 1).
Ligand 7 was unable to catalyze the reduction of heteroaro-
matic ketone, acetylpyridine, while ligand 6 provided an
excellent conversion (99%) but poor induction (12%) (entry
2). It is possible that the pyridine ring is coordinating to the
ruthenium thereby interfering with the asymmetric induc-
tion. In general, the primary amine containing limonene
amino alcohol 6 was more effective for the ketones exam-
ined in our study compared to ligand 7 containing a second-
ary amine moiety (entries 3–6). However, both ligands
provided their best catalytic activity in the reduction of tetr-
alone (entry 4). The N-methyl limonene amino alcohol pro-
vided the highest asymmetric induction of 71% ee for
tetralone, with 6 providing 68% ee for the same substrate.
4. Experimental
All reactions were carried out in oven-dried glassware
under an inert atmosphere of argon. Bis-dichlororuthe-
nium(II) p-cymene was obtained from Aldrich chemicals.
Isopropanol was distilled over calcium hydride under
argon and degassed using liquid N2. Ketones, if necessary,
were distilled over P2O5. Distillation, degassing and prepa-
ration of the base solution all took place immediately
before the reaction in order to minimize the effects of air
and water on the reaction. The NMR spectra were
recorded on a Varian 500 MHz spectrometer and are
3. Conclusion
The reduction of carbonyls under catalytic transfer hydro-
genation conditions with 2-propanol as a hydrogen source
is a mild and highly attractive route for the formation of

C. C. Watts et al. / Tetrahedron: Asymmetry 17 (2006) 1301–1307
1305
1
reported in parts per million (500 MHz for H, 125 MHz
for 13C). High-resolution mass spectra were obtained via
a positive ion ESI-TOF mass spectrometer. Optical
rotations were recorded on a Jasco DIP-371 polarimeter.
Conversion and enantiomeric excess of the product mix-
ture was determined by either GC or HPLC analysis. GC
analysis was accomplished with an HP 5890 gas chromato-
graph with a flame-ionization detector equipped with a
Supelco b-cyclodextrin 120 chiral GC column (30 m ·
0.25 mm). HPLC analysis was accomplished using the
Beckman System Gold HPLC system equipped with a
Daicel Chiralcel OD column. Elution took place with 5%
i-PrOH in hexanes at 1.0 mL/min unless otherwise indi-
cated, and detection was at 254 nm. Crude products were
compared to the racemic alcohol, from the NaBH4 reduc-
tion of the appropriate ketone. Product alcohols were also
compared with literature references.
CDCl3) d = 21.5, 25.8, 29.6, 32.4, 34.8, 38.8, 50.4, 53.8,
72.2, 110.0, 147.9, 157.8; HRMS (EI) (M+H)+ calcd for
C15H29N2O2 269.22420, found 269.22235.
4.1.3. 1-[(1S,2S,5R)-2-Hydroxy-2-methyl-5-(1-methylethen-
yl)cyclohexyl]-3-phenylurea, 14. To a solution of phenyl-
isocyanate (0.31 mL, 2.8 mmol) in toluene (15 mL, 0.2 M),
a
solution of (1S,2S,4R)-2-amino-1-methyl-4-(methyl-
ethenyl)cyclohexanol (0.500 g, 2.95 mmol) in dry toluene
(15 mL) was added dropwise at 80 ꢁC. After 1 h, the tolu-
ene was evaporated and the product dissolved in chloro-
form/methanol 2:1 (30 mL) to be poured into acetone/
acetonitrile 3:1 (200 mL). No precipitate formed at this
point. The solution was cooled overnight in a refrigerator
but no precipitate was observed. The solvent was removed
by rotary evaporation to give a clear yellow oil. The oil was
put under house vacuum overnight, but no change was
observed the next day. The oil was put under high vacuum
(100 mTorr) and the next day a highly bubbled solid had
formed. This was broken up to give 0.744 g of the title com-
pound (crude yield, 92%) as an off-white solid. The com-
pound was dissolved in a minimal amount of EtOAc/hex
for recrystallization and left at 0 ꢁC overnight. No crystals
had formed by the next day. The solvent was removed and
the oil dried on high vacuum over several days, giving
4.1. Preparation of b-amino alcohol derivatives
4.1.1. {(S)-1-[(1S,2S,5R)-2-Hydroxy-2-methyl-5-(1-methyl-
ethenyl)cyclohexylcarbamoyl]-2-methylpropyl}-carbamic acid
tert-butyl ester, 12. Boc protected valine (0.534 g,
2.5 mmol) was dissolved in THF (10 mL) along with
carbonyldiimidazole (0.524 g, 3.3 mmol) and stirred at
reflux for 5 h. (1S,2S,4R)-2-Amino-1-methyl-4-(methyl-
ethenyl)cyclohexanol (0.380 g, 2.2 mmol) in THF was
added dropwise to the solution over 10 min. The reaction
mixture was held at reflux for another 18 h, after which
the solvent was evaporated, to give an oil (0.838 g). The
oil was dissolved in diethyl ether and washed with satd
NaHCO3 solution and brine. After MgSO4 and filtration,
evaporation of the solvent gave an off-white solid
(0.838 g) of which 490 mg was recrystallized from diethyl
ether and dried on a high vac for 24 h to give 0.398 g of a
sticky white crystalline solid. A second batch (0.348 g) was
recrystallized from diethyl ether to give 0.324 g (total:
an off-white solid (88% yield). Mp = 73–76 ꢁC;
28
½aꢀD ¼ þ9:7 (c 2.0, methanol); 1H NMR (250 MHz,
CDCl3) d = 1.23 (s, 3H), 1.46 (s, 3H), 1.48–1.66 (m, 6H),
2.02–2.06 (m, 1H), 3.92 (m, 1H), 4.77–4.78 (d, 2H), 7.00
(m, 1H), 7.23 (m, 4H); 13C NMR (62.5 MHz, CDCl3)
d = 21.4, 25.7, 32.4, 35.0, 38.8, 41.5, 54.2, 72.4, 110.0,
120.9, 121.6, 123.4, 129.4, 129.5, 138.6, 147.7, 156.1;
HRMS (EI) (M+H)+ calcd for C17H25N2O2 289.19112,
found 289.19106.
4.1.4. [(1S,2S,5R)-2-Hydroxy-2-methyl-5-(1-methylethen-
yl)cyclohexyl]carbamic acid isobutyl ester, 15. To a solu-
tion of (1S,2S,4R)-2-amino-1-methyl-4-(1-methylethenyl)-
cyclohexanol (1.132 g, 7.0 mmol) in dry THF (20 mL),
isobutylchloroformate (0.95 mL, 7.3 mmol) was added
dropwise via syringe at ꢁ15 ꢁC. The reaction mixture was
warmed to room temperature and was stirred for a total
of 18 h. Water (50 mL) was added to the reaction mixture
and the product was extracted with ethyl ether (3 · 50 mL).
The combined organic layers were dried over MgSO4, fil-
0.722 g, 89% yield) of the sticky white crystalline solid.
28
Mp = 82–84 ꢁC; ½aꢀD ¼ þ18:1 (c 2.0, methanol); 1H
NMR (500 MHz, CDCl3) d = 0.94–1.00 (dd, 6H), 1.20 (s,
3H), 1.45 (s, 9H), 1.47–1.71 (m, 6H), 1.73 (s, 3H), 2.00
(dd, 1H), 2.19 (m, 1H), 3.81 (t, 1H), 4.07 (dd, 1H), 4.76
(s, 1H), 4.77 (s, 1H), 5.01 (br s, OH), 6.24 (d, NH); 13C
NMR (125.6 MHz, CDCl3) d = 17.8, 19.4, 21.1, 25.9,
27.4, 28.3, 30.1, 31.8, 34.7, 38.7, 53.2, 60.7, 70.9, 109.6
148.4, 163.3, 171.6; HRMS (EI) (M+H)+ calcd for
C20H37N2O4 369.27524, found 369.27478.
tered, and the solvent removed by roto-evaporation to give
28
1.403 g (78% yield) of a viscous colorless oil. ½aꢀD ¼ þ13:5
1
(c 1.0, methanol); H NMR (500 MHz, CDCl3) d = 0.94
4.1.2. 1-tert-Butyl-3-[(1S,2S,5R)-2-hydroxy-2-methyl-5-(1-
methylethenyl)cyclohexyl]urea, 13. To a solution of tert-
butylisocyanate (0.35 mL, 3 mmol) in toluene (20 mL,
0.15 M), a solution of (1S,2S,4R)-2-amino-1-methyl-4-(1-
methylethenyl)cyclohexanol (0.500 g, 2.95 mmol) in dry
toluene (15 mL) was added dropwise at 80 ꢁC. After 24 h,
the product was extracted by adding water and ethyl ether
to the toluene. The organic layer was dried, filtered, and
was evaporated to give 0.715 g (90% yield) of a white solid
(dd, 6H), 1.24 (s, 3H), 1.41–1.69 (m, 6H), 1.74 (s, 3H),
1.92 (m, 1H), 2.0 (dd, 1H), 3.80–3.90 (m, 3H), 4.76–4.77
(d, 2H); 13C NMR (125.6 MHz, CDCl3) d = 19.1, 21.1,
25.9, 28.1, 32.0, 34.7, 38.8, 54.8, 68.0, 71.3, 109.7, 148.5,
163.3; HRMS (EI) (M+H)+ calcd for C15H28NO3
270.20826, found 270.20637.
4.2. Typical procedure for the catalytic asymmetric transfer
hydrogenation of ketones
(powder) after 24 h on the high vac. Mp: 144–145 ꢁC;
28
½aꢀD ¼ þ22:4 (c 2.0, methanol); 1H NMR (500 MHz,
An oven-dried Schlenk-type flask with a magnetic stirrer
bar was cooled under argon and then charged with bis-
ruthenium dichloro-p-cymene (7.7 mg, 12.5 lmol) followed
by amino alcohol (100 lmol). Freshly distilled 2-propanol
CDCl3) d = 1.21 (s, 3H), 1.36 (dd, 9H), 1.49–1.66 (m,
6H), 1.72 (s, 3H), 2.06 (m, 1H), 3.75 (m, 1H), 4.21 (d,
NH), 4.37 (s, OH), 4.79 (d, 2H); 13C NMR (125.6 MHz,

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C. C. Watts et al. / Tetrahedron: Asymmetry 17 (2006) 1301–1307
(10 mL) was added via cannula. The contents of the flask
were degassed with liquid N2 (3 freeze–thaw cycles) and
flushed with argon. The reaction mixture was refluxed for
1 h during which time the color of the solution changed
depending on the ligand used. The solution was cooled to
room temperature and freshly prepared base, potassium
tertiary butoxide (0.5 mL, 0.25 M in 2-propanol) was
added. The solution was stirred for an additional 30 min.
2-Propanol (40 mL) and then ketone (5 mmol) were added
and the solution stirred at room temperature. The reaction
progress was monitored by TLC. After a significant
amount of alcohol could be seen (compared to ketone),
the contents of the flask were transferred to a separatory
funnel and hydrochloric acid (20 mL, 1 M) was added.
The aqueous layer was extracted with diethyl ether
(150 mL). The combined organic extracts were washed with
sodium bicarbonate (75 mL), brine (75 mL) and dried over
magnesium sulfate and filtered. The solvent was removed
by rotary evaporation leaving a crude oil, which was passed
through a small plug of silica gel to remove any remaining
transition metal. The resulting product was concentrated
and analyzed by either chiral HPLC or chiral gas
chromatography.
References
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4.2.1. (S)-1-Phenylethanol.1r Table 2, entry 3 product:
99% conversion, 63% ee (S) by HPLC (hexane/
i-PrOH = 90:10, 1.0 mL/min; tR(R isomer) = 7.5 min,
tR(S isomer) = 8.3 min).
4.2.2. (R)-3,3-Dimethylbutan-2-ol, 16.1g Table 3, entry 1
product: 94% conv., 22% ee (S) by GC (70 ꢁC, 20 min;
tR(R isomer) = 13.1 min, tR(S isomer) = 13.7 min).
4.2.3. (S)-1-(3-Pyridyl)ethanol, 17.1x Table 3, entry 2
product: 99% conv., 12% ee (S) by GC (140 ꢁC, 25 min;
tR(R isomer) = 19.5 min, tR(S isomer) = 20.3 min).
4.2.4. (S)-2,3-Dihydro-1H-inden-1-ol, 18.1r Table 3, entry
3 product: 56% conv., 48% ee (S) by GC (118 ꢁC, 60 min;
tR(R isomer) = 53.3 min, tR(S isomer) = 52.4 min).
4.2.5. (S)-1,2,3,4-Tetrahydronaphthealen-1-ol, 19.1r Table
3, entry 4 product: 75% conv., 71% ee (S), by GC (135 ꢁC,
50 min; tR(R isomer) = 47.8 min, tR(S isomer) = 46.8 min).
4.2.6. (S)-1-(2-Naphthyl)ethanol, 20.1r Table 3, entry 5
product: 10% conv., 53% ee (S), by HPLC (hexane/
i-PrOH = 95:5, 1.0 mL/min, tR(R isomer) = 24.1 min,
tR(S isomer) = 12.4 min).
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40.6 min).
Acknowledgements
The authors would like to thank the Dow Chemical Com-
pany for their financial support. We would also like to
thank Paul Ralifo for providing technical support.

C. C. Watts et al. / Tetrahedron: Asymmetry 17 (2006) 1301–1307
1307
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