α-Hydroxy carboxylic acids as ligands for enantioselective diethylzinc additions to aromatic and aliphatic aldehydes

Article abstract of DOI:10.1016/j.tet.2004.07.060

The first examples of the enantioselective titanium-mediated diethylzinc additions to aromatic and aliphatic aldehydes catalyzed by optically active α-hydroxy acids are presented. The reactions proceed with very good yield and good asymmetric induction. Enantioselectivities up to 90% are obtained depending on ligand and aldehyde used. A stereochemical model for the reaction is proposed.

Full text of DOI:10.1016/j.tet.2004.07.060

Tetrahedron 60 (2004) 9163–9170
a-Hydroxy carboxylic acids as ligands for enantioselective
diethylzinc additions to aromatic and aliphatic aldehydes
*
Tomasz Bauer and Joanna Gajewiak
Department of Chemistry, Warsaw of University, u1. Pasteura 1, PL-02-093 Warsaw, Poland
Received 27 May 2004; revised 1 July 2004; accepted 23 July 2004
Available online 25 August 2004
Abstract—The first examples of the enantioselective titanium-mediated diethylzinc additions to aromatic and aliphatic aldehydes catalyzed
by optically active a-hydroxy acids are presented. The reactions proceed with very good yield and good asymmetric induction.
Enantioselectivities up to 90% are obtained depending on ligand and aldehyde used. A stereochemical model for the reaction is proposed.
q 2004 Elsevier Ltd. All rights reserved.
1
. Introduction
For the second coordination site, we chose the hydroxy
group so that our ligands belong to the readily accessible
family of a-hydroxy acids 1. Recently we have presented a
preliminary communication on the addition of diethylzinc
to benzaldehyde (2) catalyzed by a-hydroxy acids 1 and the
purpose of this paper is to give a full account on the
enantioselective diethylzinc addition to aromatic and
aliphatic aldehydes (Scheme 1).
The enantioselective organometallic addition to aldehydes
is a valuable method for the synthesis of optically active
secondary alcohols and several efficient catalysts have been
developed, various types of chiral ligands can be used for
such additions. Since 1986, when DAIB was introduced by
1
9
1
Noyori, the amount of very useful and efficient dialkyl-
2
amino alcohols has grown dramatically, and now includes
3
not only dialkylamino alcohols but also amino thiols,
4
–6
7,8
and even diols such as TADDOLs and
Further progress in enantioselective additions
2. Results and discussion
oxazolines
9
BINOLs.
–11
2.1. Synthesis of a-hydroxy acids
to aldehydes was achieved, when Ohno and co-workers
reported diethylzinc additions in the presence of titanium
tetraisopropoxide and a chiral bissulfonamide. Since then,
extensive synthetic studies were conducted and a-hydroxy
sulfonamides and bissulfonamides were proven to be very
1
2
2.1.1. Synthesis by diazotisation of a-amino acids. One of
the most straightforward, reliable and inexpensive methods
for the synthesis of a-hydroxy acids is diazotisation of
a-amino acids. The reaction proceeds with retention of
1
3–17
efficient ligands for additions of dialkylzincs.
Although
2
0,21
configuration,
and traces of the minor enantiomer, if
the exact mechanism of the process is not known, recent
structural and mechanistic investigations showed that the
active catalytic intermediates could be an ethyltitanium
species derived from the transfer of an ethyl group from zinc
to titanium or a bimetallic species containing an ethylzinc
compound. Both ligand accelerated diethylzinc additions
and alkyltitanium additions to carbonyl compounds exhibit
excellent chemoselectivity. For mixtures of aldehydes and
ketones, only addition to the aldehyde carbonyl group is
observed whilst ketones remain intact. This led us to the
2
2
present, can be removed by recrystallization. We have
chosen six amino acids 4b–g, which were treated at 0 8C
with excess of aqueous sodium nitrate(IV) in the presence
of 0.5 M sulfuric acid. The reaction mixture was stirred
1
5
1
8
conclusion that carboxylic acids could serve as ligands in
i
Ti(O Pr) catalyzed additions of diethylzinc to aldehydes.
4
Keywords: Diethylzinc; Titanium tetraisopropoxide; a-Hydroxy acids;
Aldehydes; Enantioselective.
*
Corresponding author. Tel.: C48-22-822-02-11x273; fax: C48-22-822-
9-96; e-mail: tbauer@chem.uw.edu.pl
Scheme 1. Diethylzinc addition to benzaldehyde in the presence of a-
hydroxy acids as chiral ligands.
5
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.07.060

9164
T. Bauer, J. Gajewiak / Tetrahedron 60 (2004) 9163–9170
Scheme 2. Synthesis of a-hydroxy acids by diazotisation.
overnight at room temperature, and after work-up, the
resulting a-hydroxy acids 1b–g were crystallized from
organic solvents (Scheme 2). For all thus prepared
compounds, specific rotations were in good agreement
with literature values, except the case of (S)-2-hydroxy-3,3-
dimethylbutanoic acid (1g). For the sample prepared by us
enantiomeric excess (77% ee in favor of the product with 1S
configuration) was determined by HPLC using a Chiracel
OD column.
After this first successful experiment we started a systematic
investigation of the factors influencing yield and asym-
metric induction in this reaction. First, we noted that the
2
2
we measured [a] ZC4.1 (cZ1.83, H O); commercially
D
2
2
2
i
available (Aldrich) compound had [a] ZC3.3 (c 2.25,
H O), while the literature value is [a] ZC4.5 (cZ1 or
cZ4 , H O). At this moment we are not able to say,
D
reaction performed in the absence of Ti(O Pr) is very
4
2
D
5
23
2
sluggish and proceeds with low asymmetric induction
(Table 1, entry 1). On the other hand, increased bulkiness
of the titanium reagent does not influence the reaction and in
2
4
2
whether the reason for this discrepancy is presence of the
minor enantiomer or chemical impurities. The enantiomeric
purity of (S)-2-hydroxy-3,3-dimethylbutanoic acid (1g), as
well as rest of the a-hydroxy acids used, will be confirmed
by other methods and the results will be reported in due
course. This has to be taken into account during analysis of
the results of diethylzinc addition.
t
the presence of Ti(O Bu) we obtained similar yield and ee
4
(
Table 1, entry 3). Addition of zinc and titanium reagents in
the reversed order did not influence enantioselectivity
Table 1, entry 2). To examine effect of the solvent the
(
reaction was carried out in five typical solvents. Methylene
chloride was the best one both for chemical yield and
asymmetric induction (Table 1, entries 4–8).
2
.1.2. Synthesis by diastereoselective Friedel–Crafts
alkylation. In addition to a-hydroxy acids synthesized
from a-amino acids we have also prepared two compounds
bearing substituted phenyl rings. Lewis acid catalyzed
addition of N-glyoxyloyl-(2R)-bornane-10,2-sultam (5) to
methoxy- and isopropoxy tert-butyl benzene (6a and 6b,
respectively) proceeded with good yield and diastereos-
electivity. Hydrolysis of the chiral auxiliary under mild
conditions gave hydroxy acids 1h and 1i (Scheme 3). The
Once the best solvent was found, we studied the influence of
the amount of the ligand and its concentration. The
asymmetric induction was only slightly influenced by
increased amount of ligand, while the chemical yield
dropped from 95 to 80% (Table 2). For further experiments,
a concentration of 0.044 mmol/mL and 0.2 equiv of ligand
was chosen. The next parameter studied was reaction
temperature. Table 3 shows the influence of the temperature
and the optimum regarding both yield and enantiomeric
excess was observed for room temperature (22 8C).
2
5
details of the synthesis are presented elsewhere.
2
2
.2. Enantioselective diethylzinc addition
.2.1. Enantioselective diethylzinc addition to aldehydes
The so-called ‘aging’ of the catalyst can seriously influence
the results of the reaction. In order to find out, whether our
system is prone to such phenomena we performed two series
of experiments in which we measured the enantiomeric
excess against time of the complexation with titanium and
zinc compounds. In the first series, showed that the optimum
complexation time for titanium tetraisopropoxide lies
in the presence of (S)-mandelic acid. In order to confirm
considerations presented above, we decided to use commer-
cially available (S)-mandelic acid 1a as a ligand and
benzaldehyde 2 as a model carbonyl compound. The
reaction was conducted at room temperature in methylene
chloride in the presence of 0.2 equiv of mandelic acid,
between 1 and 1.5 h. Therefore, in the next experiments,
for 1.5 h. For
i
the ligand was stirred with Ti(O Pr)
3
equiv of diethylzinc and 1.4 equiv of titanium tetra-
4
isopropoxide. The reaction was stirred overnight, and after
TLC showed complete conversion, quenched with aqueous
hydrochloric acid. After work-up and chromatography
diethylzinc this optimum was found after 45 min of
complexation. The results are presented in Tables 4 and 5.
1
-phenyl-1-propanol 3 was isolated in 88% yield. The
The last two parameters, the influence of which had to be

T. Bauer, J. Gajewiak / Tetrahedron 60 (2004) 9163–9170
9165
Scheme 3. Synthesis of a-hydroxy acids by diastereoselective Friedel–Crafts reaction.
Table 1. Diethylzinc addition in various solvents
Entry
Ligand
Solvent
Temperature (8C)
Time (h)
Yield (%)
ee (config.) (%)
a
1
1a
1a
1a
1a
1a
1a
1a
1a
CH
CH
CH
CH
Toluene
n-Hexane
THF
2
2
2
2
Cl
Cl
Cl
Cl
2
2
2
2
22
22
22
22
22
22
22
22
66
23
23
20
23
24
19
19
73
90
79
88
77
88
40
75
40 (S)
76 (S)
77 (S)
77 (S)
67 (S)
63 (S)
32 (S)
65 (S)
b
2
c
3
4
5
6
7
8
2
Et O
a
i
4
Reaction in the absence of Ti(O Pr) .
b
c
i
Addition order was reversed from Ti(O Pr)
Reaction in the presence of Ti(O Bu) instead of Ti(O Pr) .
4 4
i
Zn/Ti(O Pr)
4
/Et
2
Zn to Et
i
2
4
.
t
Table 2. Influence of the ligand amount on the enantiomeric excess
Entry
Ligand
Amount (equiv)
Concentration
(
Temperature
(8C)
Time (h)
Yield (%)
ee (config.) (%)
mmol/ml)
1
2
3
4
5
6
1a
1a
1a
1a
1a
1a
0.2
0.2
0.4
0.6
0.8
1.0
0.034
0.044
0.044
0.054
0.064
0.074
22
22
22
22
22
22
20
18
18
18
18
18
88
95
88
89
85
80
77 (S)
78 (S)
79 (S)
81 (S)
81 (S)
80 (S)
Table 3. Influence of the reaction temperature on the enantiomeric excess
Entry
Ligand
Temperature (8C)
Time (h)
Yield (%)
ee (config.) (%)
1
2
3
4
1a
1a
1a
1a
22
0
K20
K78
18
19
19
72
95
87
62
—
78 (S)
80 (S)
76 (S)
—
i
Table 4. Optimalization of the complexation time with Ti(O Pr)
4
Entry
Ligand
Amount (equiv)
Complexation time
h)
Reaction time (h)
Yield (%)
ee (config.) (%)
(
1
2
3
4
5
1a
1a
1a
1a
1a
0.2
0.2
0.2
0.2
0.2
0.5
1
1.5
2
18
18
18
18
18
90
94
95
87
90
77 (S)
78 (S)
78 (S)
78 (S)
77 (S)
2.5

9
166
T. Bauer, J. Gajewiak / Tetrahedron 60 (2004) 9163–9170
Zn
Table 5. Optimalization of the complexation time with Et
2
Entry
Ligand
Amount (equiv)
Complexation time
h)
Reaction time (h)
Yield (%)
ee (config.) (%)
(
1
2
3
4
5
6
1a
1a
1a
1a
1a
1a
0.2
0.2
0.2
0.2
0.2
0.2
0.5
0.75
1
1.5
2
18
18
19
18
18
18
95
96
94
95
87
90
78 (S)
79 (S)
78 (S)
75 (S)
75 (S)
75 (S)
2.5
i
Zn and Ti(O Pr)
Table 6. Optimalization of amounts of Et
2
4
sufficient for the efficient addition
i
Ti(O Pr)
Entry
Ligand
Amount of 1a
(
Et
2
Zn (equiv)
4
(equiv)
Time (h)
Yield (%)
ee (config.) (%)
equiv)
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1a
1a
1a
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
3
2.5
2
1.5
1
2
2
2
2
1.4
1.4
1.4
1.4
1.4
1.2
1
18
18
18
42
42
18
18
18
18
96
97
92
55
41
86
88
90
85
79 (S)
79 (S)
80 (S)
80 (S)
80 (S)
80 (S)
80 (S)
80 (S)
78 (S)
0.8
0.6
established, were amounts of diethylzinc and titanium
tetraisopropoxide sufficient for the good chemical yield
and asymmetric induction. The optimum was found to be
accompanied by longer reaction time and a serious drop of
chemical yield (entry 1 vs entries 2–5 in Table 9). The
reaction performed at 0 8C gave somewhat higher ee (entry 6),
but the reaction stops at lower temperatures (entries 7 and 8).
i
2
8
equiv of Et Zn and 0.8 equiv of Ti(O Pr) (Table 6, entry
4
). It is important to stress that substochiometric amounts
2
of titanium are sufficient to produce S-3 in 90% yield and
0% ee.
The enantioselective addition of diethylzinc to some
representative aromatic and aliphatic aldehydes was per-
formed in the presence of ligand 1h, which was easy to
obtain in high chemical and enantiomeric purity, despite its
multistep synthesis. The results are presented in Table 10. In
general, the results obtained in the presence of ligand 1h
were better than in the presence of 1a, with the exception of
aliphatic aldehydes 16 and 17 that gave substantially lower
enantiomeric excess.
8
Having established all the important parameters of the
reaction we carried out the enantioselective addition of
diethylzinc to some representative aromatic and aliphatic
aldehydes. As shown in the Table 7, for all but one aldehyde
(
cinnamaldehyde, entry 7) enantioselectivities were at
levels comparable with that obtained for benzaldehyde,
even for aliphatic and cycloaliphatic aldehydes (entries 8
and 9).
2
.2.3. Mechanistic considerations. The stereochemical
outcome of the reaction performed in the presence of a-
hydroxy acids can be rationalized as follows. The variation
of the addition order of titanium and zinc reagents, leading
to virtually identical asymmetric induction indicates a
monometallic transition state, which has been postulated
2
.2.2. Enantioselective diethylzinc addition to aldehydes
in the presence of various a-hydroxy acids. The positive
results presented above prompted us to synthesize and use
series of aromatic and aliphatic a-hydroxy acids with
various steric demands. The results are presented in Table 8.
The increased bulkiness of the acid substituent is reflected in
the increased asymmetric induction. The individual char-
acter of each ligand means that conditions optimized for
each one of them (e.g., mandelic acid 1a) are not good for
others (entry 1 vs 2, 3 vs 4, 10 vs 11), so we decided to use
2
6,27
several times in the literature for other ligands.
We
suggest that the reaction goes through one of the possible
model transition states I–III depicted in Figure 1. For
picture simplicity, addition of diethylzinc to benzaldehyde
in the presence of mandelic acid is analyzed. In the model I
re attack leads to products with the absolute configuration R,
‘
typical’ (widely used in the literature) conditions K3 equiv
of diethylzinc and 1.4 equiv of titanium tetraisopropoxide.
The best results were obtained for two ligands 1g and 1h.
Interestingly, ligand 1i with more bulky isopropyl sub-
stituent, gave lower asymmetric induction than 1h. Also, in
this study, the bulkiness of the titanium reagent (entry 5) had
an adverse effect on the asymmetric induction.
For relatively inexpensive and readily available ligand 1c
the influence of ligand amount and its concentration on ee
was established (Table 9). The increased amounts of ligand
1
c gives slightly better enantiomeric excess but this effect is
Figure 1. Stereochemical models for an ethylation of aldehydes.

T. Bauer, J. Gajewiak / Tetrahedron 60 (2004) 9163–9170
2
Zn addition to selected aldehydes in the presence of 1a
9167
Table 7. Et
Entry
1a (equiv)
Aldehyde
Temperature
Time (h)
Product
Yield (%)
ee (%)
(8C)
1
0.2
9
28
19
S-18
S-19
75
76
70
2
3
0.2
0.2
10
28
28
18
19
90
97
11
S-20
72
4
5
0.2
0.2
12
13
28
28
19
19
S-21
S-22
88
97
79
77
6
0.2
14
28
18
S-23
96
80
7
8
9
0.2
0.2
0.2
15
16
17
28
28
28
17
17
19
S-24
S-25
S-26
91
75
81
52
78
77
opposite to that observed in experiments. In models II and
III the si attack leads to the observed configuration, but the
apical position of the bulky isopropoxy group in the model
II is not very likely, due to a steric clash with the aryl (or
alkyl) moiety of the a-hydroxy acid. The model transition
state III in our opinion is the best explanation of the
observed asymmetric induction. In all three we postulate the
presence of hydrogen bonding between ligand’s a-oxygen
and formyl hydrogen of the coordinated aldehyde. Such
bonding was already postulated by Corey, and was proved
2
Table 8. Addition of Et Zn to benzaldehyde in the presence of acids 1b–i
Entry
Ligand
Amount of 1b–i
(
Amount of
i
Ti(O Pr)
Amount of
Et Zn (equiv)
Time (h)
Yield (%)
Ee (config.) (%)
equiv)
4
2
(
equiv)
1
2
3
4
1b
1b
1c
1c
1c
1d
1e
1f
1g
1h
1h
1i
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
1.4
0.8
1.4
0.8
1.4
1.4
1.4
1.4
1.4
1.4
0.8
1.4
3
2
3
2
3
3
3
3
3
3
2
3
19
24
19
24
45
19
20
20
20
20
18
20
80
90
85
95
67
73
71
88
95
95
74
95
85 (S)
83 (S)
85 (S)
80 (S)
78 (S)
80 (S)
83 (S)
77 (S)
88 (S)
87 (S)
79 (S)
79 (S)
a
5
6
7
8
9
1
1
1
0
1
2
a
t
i
4 4
Ti(O Bu) instead of Ti(O Pr)

9
168
T. Bauer, J. Gajewiak / Tetrahedron 60 (2004) 9163–9170
Zn to benzaldehyde
Table 9. Influence of ligand amount on the enantiomeric excess in the addition of Et
2
Entry
Ligand
Amount (equiv)
Concentration
(
Temperature
(8C)
Time (h)
Yield (%)
ee (%)
mmol/ml)
1
2
3
4
5
6
7
8
1c
1c
1c
1c
1c
1c
1c
1c
0.2
0.4
0.6
0.8
1.0
0.2
0.2
0.2
0.044
0.044
0.054
0.064
0.074
0.044
0.044
0.044
22
22
22
22
22
0
K23
K78
19
24
40
42
42
20
48
48
85
79
56
54
27
82
—
—
85 (S)
87 (S)
88 (S)
91 (S)
88 (S)
86 (S)
—
—
to be a very important factor influencing asymmetric
to enantioselective additions of diethylzinc to aldehydes.
We have shown that reactions in the presence of a-hydroxy
acids proceed with very good yield and good enantiomeric
excess up to 90%. a-Hydroxy acids can catalyze the
addition of diethylzinc to both aliphatic and aromatic
aldehydes, are relatively inexpensive and are readily
available. Further applications of a-hydroxy acids as ligands
for enantioselective metalloorganic additions are under
investigation and will be reported in due course.
2
8
induction in enantioselective reactions. Its presence
substantially rigidifies transition states leading to good
enantiomeric excess.
3. Conclusions
We have proposed a new class of chiral ligands applicable
Table 10. Et
2
Zn addition to selected aldehydes in the presence of 1h
Entry Amount of
1h (equiv)
Aldehyde
Temperature
(8C)
Time (h)
Product
Yield (%)
ee (%)
76
1
0.2
9
21
21
24
S-18
S-19
95
2
3
0.2
0.2
10
19
24
94
83
77
82
11
21
S-20
4
5
0.2
0.2
12
13
21
21
19
18
S-21
S-22
85
96
89
78
6
0.2
14
21
18
S-23
95
83
7
8
9
0.2
0.2
0.2
15
16
17
21
21
21
18
23
23
S-24
S-25
S-26
87
70
70
59
65
68

T. Bauer, J. Gajewiak / Tetrahedron 60 (2004) 9163–9170
9169
4
. Experimental
Tiny, colorless needles; yield 52% (0.69 g, 5.2 mmol). Mp
2
9
20
50–52 8C (ether–hexane) lit. : 52–54 8C. [a] ZC21.9
D
31 22
4
.1. General
(cZ1, CHCl ); lit. [a] ZC22 (cZ1, CHCl ).
3 D 3
Melting points were determined using a Kofler hot stage
apparatus and are uncorrected. Specific rotations were
recorded using a Perkin–Elmer PE-241 polarimeter with a
4
.2.5. (S)-2-Hydroxyhexanoic acid (1f). White crystals;
yield 30% (0.40 g, 3.0 mmol). Mp 59–60 8C (ether–hexane)
33
3
2
20
lit. : 60–61 8C. [a] ZK16.3 (cZ3.92, 1 M NaOH); lit.
D
1
13
2
5
thermally jacketed 10-cm cell. H and C NMR spectra
were recorded in CDCl using a Varian 200 Unity Plus and
[
a] ZK15.3 (cZ1.1, 1 M NaOH).
D
3
Varian 500 Unity Plus spectrometers. All chemical shifts
are quoted in parts per million relative to tetramethylsilane
4
.2.6. (S)-2-Hydroxy-3,3-dimethylbutanoic acid (1g).
Small colorless crystals; yield 47% (0.62 g, 4.7 mmol).
(
d, 0.00 ppm), and coupling constants (J) are measured in
Hertz. Mass spectra were recorded on a Mariner instrument
Biosystem) using the LSIMS technique. Infrared spectra
34
22
Mp 47–48 8C (ether–hexane) lit. : 49–51 8C. [a] ZC4.1
D
23
25
24
(
[
cZ1.83, H O); lit. [a] ZC4.5 (cZ1, H O); lit.
2 D 2
25
a] ZC4.5 (cZ4, H O).
(
D
2
were recorded using a Beckmann IR-240 spectrometer.
Reactions were carried under argon using Schlenk tech-
nique when necessary. Flash column chromatography was
made on silica gel (Kieselgel-60, Merck, 230–400 mesh).
High Performance Liquid Chromatography was conducted
on Merck Hitachi D-7000 with diode array detector L-7455
using chiral column Diacel Chiracel OD. Gas Chromato-
graphy was conducted on Hewlett–Packard 5890 series II
with FID detector using chiral column b-Dex, 30 m!
4.3. General procedure for the addition of diethylzinc to
aldehyde in the presence (S)-mandelic acid
In the oven dried Schlenk tube filled with argon and
equipped with the stirring bar was placed (S)-mandelic acid
(
(
30.2 mg, 0.2 mmol), followed by methylene chloride
4.5 mL), Ti(O Pr) (0.24 mL, 0.8 mmol). After 1.5 h the
i
4
solution was cooled to 0 8C and diethylzinc (1.1 M in
toluene, 1.8 mL, 2 mmol) was added. The stirring was
continued at this temperature for 45 min, aldehyde (1 mmol)
was added and after additional 30 min of stirring at 0 8C the
reaction mixture was allowed to warm up to room
temperature. The progress of the reaction was controlled
with TLC using CH Cl :MeOH 70:2. After completion the
0.25 mm I.D. (Supelco, Bellefonte, USA). Retention time is
given in minutes.
4.2. Preparation of a-hydroxy acids form a-amino acids
by diazotisation. General procedure
2
2
a-Amino acid (10 mmol) was dissolved in 0.5 M H SO
2
4
reaction was quenched with slow addition of 1 M HCl
CAUTION! Exothermic reaction). The precipitate was
(
40 mL, 20 mmol). This solution was cooled to 0 8C and a
solution of NaNO (4.14 g, 60 mmol) in H O (13.5 mL) was
(
3
2
filtered off using funnel with cotton plug and filtrate was
extracted three times with ethyl acetate (3!20 mL),
combined extracts were washed with brine (30 mL), dried
over anhydrous MgSO4 and evaporated in vacuo. The
resulting oil was purified by flash chromatography
added slowly with stirring, while temperature was main-
tained below 5 8C. The reaction was stirred at this
temperature for a further 3 h, and than allowed to warm
up to room temperature and left for 24 h. The reaction
mixture was extracted 3 times with ethyl ether (3!50 mL),
combined organic layers were washed with brine (50 mL)
and dried over anhydrous sodium sulfate. The drying agent
was filtered off, and ether was evaporated in vacuo. The
residual mass was recrystallized from hexane–ether to give
respective a-hydroxy acid. All compounds have been
previously reported and were characterized by comparison
with their reported physical and spectroscopic data.
(CH Cl /MeOH 200:3 as eluent). All compounds have
2 2
been previously reported and were characterized by
comparison with their reported physical and spectroscopic
data.
4
.3.1. (S)-1-Phenyl-1-propanol (S-3). HPLC: t Z12.1
S
i 20
t Z13.2 (hexane/ PrOH 97:3, flow 1 mL/min). [a] Z
R
D
K42.0 (cZ1.0, CHCl ); for enantiomer S with eeZ90.4%.
3
3
5
20
D
lit. [a] ZK44.4 (cZ1.01, CHCl ) for enantiomer S with
3
4
.2.1. (S)-2-Hydroxy-3-phenylpropanoic acid (1b). Tiny,
colorless needles with characteristic pleasant smell; yield
5% (1.08 g, 6.2 mmol). Mp 123–123 8C (ether–hexane);
eeZ95.5%.
6
2
2
20
29
4
.3.2. (S)-1-(2-Chlorophenyl)-1-propanol (S-18). GC:
lit. 123–124 8C. [a] ZK21.3 (cZ2.35, H O); lit.
D
2
t Z51.0, tSZ54.2 (TcolumnZ130 8C, PZ100 kPa).
[
a] ZK20.0 (cZ2, H O).
R
D
2
2
0
[
a] ZK48.6 (cZ1.25, benzene) for eeZ85%.
D
4.2.2. (S)-2-Hydroxy-3-methylbutanoic acid (1c). Tiny,
colorless needles with intensive unpleasant smell; yield
4.3.3. (S)-1-(3-Chlorophenyl)-1-propanol (S-19). HPLC:
3
0
i
3
6
1% (0.37 g, 3.1 mmol). Mp 61–62 8C (ether–hexane) lit.
t
S
Z2017.1 t
[a] ZK23.3 (cZ1.21, benzene) for enantiomer S with
eeZ78.8%. lit. [a]
R
Z18.6 (hexane/ PrOH 96:4, flow 0.5 mL/min).
2
0
29
2–63 8C. [a] ZC17.3 (cZ1.06, CHCl ); lit.
D
D
3
3
6
20
[
a] ZC17.3 (cZ1, CHCl ).
ZC26.6 (cZ2.36, benzene) for
D
D
3
enantiomer R with eeZ97%.
4
.2.3. (S)-2-Hydroxy-4-methylpentanoic acid (1d). Color-
less needles yield; 40% (0.53 g, 4.0 mmol). Mp 76–77 8C
4.3.4. (S)-1-(4-Chlorophenyl)-1-propanol (S-20). HPLC:
2
2
20
i
(
ether–hexane) lit. 78–80 8C. [a] ZK26.6 (cZ1.2, 1 M
t Z22.4 t Z24.3 (hexane/ PrOH 97:3, flow 0.5 mL/min).
D
S
R
2
9
20
NaOH); lit. [a] ZK25.9 (cZ1, 1 M NaOH).
[a] ZK23.6 (cZ1.77, benzene) for enantiomer S with
D
35 20
D
eeZ88.5%. lit. [a] ZK23.6 (cZ1.73, benzene) for
D
4
.2.4. (2S,3S)-2-Hydroxy-3-methylpentanoic acid (1e).
enantiomer S with eeZ93%.

9170
T. Bauer, J. Gajewiak / Tetrahedron 60 (2004) 9163–9170
4
.3.5. (S)-1-(2-Metoxyphenyl)-1-propanol (S-21). HPLC:
7. Schmidt, B.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1991,
30, 99–101.
i
t Z27.5 t Z29.6 (hexane/ PrOH 97:3, flow 0.5 mL/min).
S
R
20
[
a] ZK50.8 (cZ1.22, toluene) for enantiomer S with
8. Ito, Y. N.; Ariza, X.; Beck, A. K.; Bohac, A.; Ganter, C.;
Gawley, R. E.; Kuehnle, F. N.; Tuleja, J.; Wang, J. M.;
Seebach, D. Helv. Chim. Acta 1994, 77, 2071–2210.
D
3
5
22
eeZ89.1%. lit. [a] ZK52.9 (cZ1.02, toluene) for
enantiomer S with eeZ91%.
D
9
. Mori, M.; Nakai, T. Tetrahedron Lett. 1997, 38, 6233–6236.
4
.3.6. (S)-1-(3-Metoxyphenyl)-1-propanol (S-22). HPLC:
10. Zhang, F.-Y.; Yip, C.-W.; Cao, R.; Chan, A. S. C.
Tetrahedron: Asymmetry 1997, 8, 585–589.
i
t Z80.3 t Z76.6 (hexane/ PrOH 97:3, flow 0.3 mL/min).
S
R
20
[
a] ZK26.8 (cZ0.8, toluene)) for enantiomer S with eeZ
D
11. Kitajima, H.; Aoki, Y.; Katsuki, T. Bull. Chem. Soc. Jpn 1997,
9
2%.
7
0, 207–217.
1
1
1
1
2. Takahashi, H.; Kawakita, T.; Ohno, M.; Yoshioka, M.;
4
.3.7. (S)-1-(4-Metoxyphenyl)-1-propanol (S-23). HPLC:
Kobayashi, S. Tetrahedron 1992, 48, 5691–5700.
i
t Z38.1 t Z33.6 (hexane/: PrOH 97:3, flow 0.5 mL/min).
S
R
3. Knochel, P.; Perea, J.; Almena, J.; Jones, P. Tetrahedron 1998,
20
[
a] ZK28.7 (cZ1, benzene)) for enantiomer S with eeZ
D
5
4, 8275–8319.
4. Hwang, C.-D.; Uang, B.-J. Tetrahedron: Asymmetry 1998, 9,
979–3984.
5. Paquette, L. A.; Zhou, R. J. Org. Chem. 1999, 64, 7929–7934.
3
5
20
8
3%. lit. [a] ZK25.8 (cZ1.1, benzene) for enantiomer
D
S with eeZ74%.
.3.8. (S)-1-Phenyl-1-penten-3-ol (S-24). HPLC: t Z13.0
3
4
S
i
20
16. Ito, K.; Kimura, Y.; Okamura, H.; Katsuki, T. Synlett 1992,
573–574.
t Z9.0 (hexane/ PrOH 90:10, flow 1.0 mL/min). [a] Z
R
D
1
4
K4.87 (cZ1, CHCl ) for enantiomer S with eeZ63%. lit.
3
20
17. Pritchett, S.; Woodmansee, D. H.; Gantzel, P.; Walsh, P. J.
J. Am. Chem. Soc. 1998, 120, 6423–6424.
[
a] ZK6.3 (cZ1.73, CHCl ) for enantiomer S with eeZ
D
3
5
9%.
1
8. Reetz, M. T. Organotitanium Reagents in Organic Synthesis;
Springer: Berlin, 1986.
4
.3.9. (S)-3-Octanol (S-25). HPLC (as benzoate): t Z21.1
S
20
19. Bauer, T.; Tarasiuk, J. Tetrahedron Lett. 2002, 43, 687–689.
20. Brewster, P.; Hiron, F.; Hughes, D.; Ingold, C.; Rao, P. Nature
t Z23.1 (hexane, flow 0.5 mL/min). [a] ZC7.6 (cZ
R
D
3
5
1
.03, CHCl ); for enantiomer S with eeZ77%. lit.
3
20
(
London) 1950, 166, 178–180.
[
a] ZC5.87 (cZ1, CHCl ), for enantiomer S with eeZ
D
3
2
1. Winitz, M.; Bloch-Frankenthal, L.; Izumiya, N.; Birnbaum, S.;
6
0%.
Baker, C.; Greenstein, J. J. Am. Chem. Soc. 1956, 78,
2
423–2430.
4
.3.10. (S)-1-Cyclohexyl-1-propanol (S-26). HPLC (as
i
benzoate): t Z37.8 t Z35.9 (hexane/ PrOH 99.9:0.1, flow
0
mer S with eeZ82.5%. lit. [a] ZK6.39 (cZ1.05,
CHCl ), for enantiomer S with eeZ97%.
22. Degerbeck, F.; Fransson, B.; Grehn, L.; Ragnarsson, U.
J. Chem. Soc., Perkin Trans. 1 1993, 11–14.
S
R
2
0
.2 mL/min). [a] ZK5.43 (cZ1.14, CHCl ) for enantio-
D 3
35 24
23. Zhang, W.; Jakiela, D.; Maul, A.; Knors, Ch.; Lauher, J.;
Helquist, P.; Enders, D. J. Am. Chem. Soc. 1988, 110,
D
3
4
652–4660.
2
4. Masamune, S.; Reed, L.; Davis, J.; Choy, W. J. Org. Chem.
1983, 48, 4441.
Acknowledgements
2
5. Bauer, T.; Gajewiak, J. Synthesis 2004, 20–22.
Financial support from the State Committee for Scientific
Research (Grant
acknowledged.
26. Paquette, L.; Zhou, R. J. Org. Chem. 1999, 64, 7929–7934.
3 T09A 039 16) is gratefully
2
7. Pritchett, S.; Woodmansee, D.; Davis, T.; Walsh, P.
Tetrahedron Lett. 1998, 39, 5941–5942.
2
8. Corey, E. J.; Lee, T. Chem. Commun. 2001, 1321–1329.
9. Shin, I.; Lee, M.; Jung, M.; Lee, W.; Yoon, J. J. Org. Chem.
2
2
000, 65, 7667–7675.
30. Kim, H.; Olsen, R.; Choi, O. J. Org. Chem. 1987, 52,
531–4536.
References and notes
. Kitamura, M.; Suga, S.; Kawai, K.; Noyori, R. J. Am. Chem.
Soc. 1986, 108, 6071–6072.
4
1
2
31. Mimaki, Y.; Kuroda, M.; Kameyama, A.; Yokosuka, A.;
Sashida, Y. Chem. Pharm. Bull. 1998, 46, 298–303.
32. Brettle, R.; Latham, D. J. Chem. Soc. C 1968, 906–910.
33. Focella, A.; Bizzarro, F.; Exon, C. Synth. Commun. 1991, 21,
2165–2170.
. For reviews see: (a) Soai, K.; Niwa, S. Chem. Rev. 1992, 92,
833–856. (b) Pu, L.; Yu, H.-B. Chem. Rev. 2001, 101,
757–824.
3
. Kang, J.; Kim, D. S.; Kim, J. I. Synlett 1994, 842–844.
. Falorni, M.; Collu, C.; Conti, S.; Giacomelli, G. Tetrahedron:
Asymmetry 1996, 7, 293–299.
3
3
3
4. Draanen, N.; Arseniyadis, S.; Crimmins, M.; Heathcock, C.
J. Org. Chem. 1991, 56, 2499–2506.
4
5. Asami, M.; Watanabe, H.; Inoue, S. Tetrahedron: Asymmetry
5
6
. Aurich, H. G.; Biesemeier, F.; Geiger, M.; Harms, K. Liebiegs
Ann. Recl. 1997, 423.
1
998, 9, 4165–4173.
6. Dai, W.; Zhu, H.; Hao, X. Tetrahedron: Asymmetry 2000, 11,
315–2337.
. Seebach, D.; Pichota, A.; Beck, A. K.; Pinkerton, A. B.; Litz,
T.; Karjalainen, J.; Gramlich, V. Org. Lett. 1999, 1, 55–58.
2