Synthesis of new chiral hydroxy oxazolines and their use in the catalytic asymmetric phenyl transfer to aldehydes

Article abstract of DOI:10.1016/j.tetasy.2005.01.038

Starting either from benzoylformic acid or ethyl oxamate and enantiopure β-amino alcohols, several chiral α-hydroxy oxazolines have been prepared by short synthetic routes. Subsequently, they have been employed in the catalytic asymmetric phenyl transfer to various aldehydes, using a mixture of triphenylborane and diethylzinc as the phenyl source. The corresponding secondary alcohols were obtained with good enantioselectivities (up to 81% ee) and up to 92% yield.

Full text of DOI:10.1016/j.tetasy.2005.01.038

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 1367–1376
Synthesis of new chiral hydroxy oxazolines and their use in
the catalytic asymmetric phenyl transfer to aldehydes
Carsten Bolm,* Frank Schmidt and Lorenzo Zani
Institut fu¨r Organische Chemie der RWTH Aachen, Landoltweg 1, 52074 Aachen, Germany
Received 22 December 2004; accepted 24 January 2005
Abstract—Starting either from benzoylformic acid or ethyl oxamate and enantiopure b-amino alcohols, several chiral a-hydroxy
oxazolines have been prepared by short synthetic routes. Subsequently, they have been employed in the catalytic asymmetric phenyl
transfer to various aldehydes, using a mixture of triphenylborane and diethylzinc as the phenyl source. The corresponding secondary
alcohols were obtained with good enantioselectivities (up to 81% ee) and up to 92% yield.
ꢀ 2005 Elsevier Ltd. All rights reserved.
O
1. Introduction
O
OH
*
N
N
N
OH
OH
Asymmetric catalysis is one of the most active research
areas in organic chemistry.1 Among the various reac-
tions that can be conducted in a catalytic asymmetric
manner, C–C bond forming processes have always
attracted considerable attention due to their synthetic util-
ity. One of the most studied enantioselective carbon–
carbon single bond forming reactions is the addition
of alkylzinc reagents to carbonyl compounds, in partic-
ular aldehydes.2 On the other hand, the corresponding
aryl transfer reactions have remained under-represented
for a long time. Following the pioneering studies of Soai
et al.3 and Fu et al.,4 major developments in the field
have been recently reported, both by our group5 and
others.6–8 The first catalytic systems, introduced by us
for the enantioselective synthesis of diarylmethanols
from aromatic aldehydes, utilized planar chiral metall-
ocenyl hydroxy oxazolines 1 and 2 as pre-catalysts and
a nucleophilic arylzinc species generated in situ from
mixtures of ZnEt2 and ZnPh2 (Scheme 1).5
R
*
O
Fe
Re
Ph
Ph
CO
Ph
Ph
OC
OC
R = t-Bu, i-Pr, Ph
1
2
3
O
OH
ZnPh2 (0.65 eq.), ZnEt2 (1.3 eq.)
metallocene 1 or 2 (10 mol%)
toluene, 10 ˚C, 12 h
R
R
5
4
yield 64-99%
ee 91-98%
Scheme 1. Asymmetric catalytic phenyl transfer reaction to aromatic
aldehydes employing a mixture of ZnEt2 and ZnPh2 as the phenyl
source.
air-stable arylboronic acids could also be used as the
aryl source, which furthermore allows the preparation
of chiral diarylmethanols substituted on both aromatic
rings with excellent enantioselectivities in high yields.9
Later, triphenylborane was found to be an ideal substi-
tute for diphenylzinc, due to its superior stability, easier
handling and lower cost.10 By using additives such as
mono- or dimethylpolyethyleneglycol (MPEG and
DiMPEG, respectively), a reduction of the catalyst load-
ing became possible while maintaining high enantio-
selectivities.11
Despite its effectiveness, this approach still had some
disadvantages: first, diphenylzinc is an air-sensitive and
expensive compound, and its use limits the reaction
scope to the transfer of simple phenyl groups. Second,
the enantioselectivity of the process relies on the use of
rather complex metallocenes 1 or 2, which have to be ap-
plied in substantial amounts (usually 10 mol %). A solu-
tion for the first problem was provided by finding that
*
In light of these developments, which predominantly
focus on the optimization of reagents and reaction
Corresponding author. Tel.: +49 241 809 4675; fax: +49 241 809
2391; e-mail: carsten.bolm@oc.rwth-aachen.de
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.01.038

1368
C. Bolm et al. / Tetrahedron: Asymmetry 16 (2005) 1367–1376
conditions, the introduction of new, effective and more
easily accessible catalysts for the asymmetric aryl trans-
fer reaction has remained highly desirable. In our first
attempt to meet this demand, we recently utilized man-
delic acid for the synthesis of a series of hydroxy oxazo-
lines 3 and applied those as N–O ligands for the same
reaction.12 Unfortunately, although reasonable yields
of the products were generally obtained, the enantio-
meric excesses remained low (eemax: 35%) and the cata-
lysts underwent partial or complete decomposition
during the catalytic process. Following the same strat-
egy and hoping for an improvement of the catalyst sys-
tem, novel hydroxy oxazolines 11a–k have now been
prepared and tested in the phenyl transfer reaction.
The results of these investigations are reported herein.
7a–d. After screening various oxazoline formation pro-
tocols, it was found that the reaction of hydroxy amides
7 with SOCl2 followed by treatment of the resulting
chloro amides with sodium carbonate in hot N,N0-
dimethylformamide (DMF) furnished the highest yields
of 2-benzoyl oxazolines 8a–c. These products were final-
ly converted into hydroxy oxazolines 11a–c by reacting
them with excess phenyl magnesium chloride.
Although this sequence was quite convenient, difficulties
were encountered in the oxazoline formation starting
from hydroxy amide 7d derived from (R)-phenylglycinol
(yield <20%). Furthermore, in order to prepare hydroxy
oxazolines with different structural and electronic prop-
erties, the possibility of obtaining compounds with sub-
stituents other than simple phenyl groups at the a-
position was desirable. After a brief survey of the litera-
ture, it was found that ethyl oxazoline-2-carboxylates 10
could be prepared in a single step starting from ethyl
oxamate 9, following a procedure reported by Pfaltz
and co-workers.15 This involved an activation of the
starting material by a triethyloxonium salt, followed
by transamidation and ring closure. Thus, compounds
10a and 10b bearing a phenyl and a tert-butyl group,
respectively, on the oxazoline ring were readily synthe-
sized. The ability to obtain the products in a single step
from a simple starting material compensated for the
drawback of the moderate yields (34–36%) obtained.
Subsequent treatment of esters 10a and 10b with Grig-
nard reagents used in excess afforded hydroxy oxazo-
lines 11d–k (Scheme 2, method B). Table 1 summarizes
all structural data of the final products.
2. Results and discussion
2.1. Synthesis of the ligands
A possible explanation for the poor enantioselectivity
observed in the asymmetric phenyl transfer reaction
with catalysts based on 3 could involve the destruction
of the ligand by oxidation or epimerization at the benz-
ylic position under the strongly basic reaction condi-
tions. A solution to this problem was expected from
the preparation of hydroxy oxazolines 11 containing a
quaternary hydroxyl-bearing carbon. Although the loss
of one stereogenic center, when compared to 3, pre-
vented the exploitation of possible match–mismatch
effects, the resulting compounds should exhibit
mproved stability, thus allowing better results to be ob-
tained in the catalysis. The reagents and conditions that
have been applied in the synthesis of 11 are depicted in
Scheme 2.
It is noteworthy that the developed synthetic routes
(Scheme 2) allowed the introduction of a high degree
of structural diversity in the products after a few syn-
thetic steps. The choice of the amino alcohol determined
the absolute configuration of the stereogenic center as
well as the structure of the oxazoline ring, and by
employing different Grignard reagents, several substitu-
ents could be easily placed at the a-position. Next,
In the first approach (method A),13 commercially avail-
able benzoylformic acid 6 was reacted with enantiopure
amino alcohols under standard peptide coupling condi-
tions,14 affording the corresponding hydroxy amides
Method A
O
O
O
H
a
b
N
N
*
COOH
OH
R
*
O
O
R
8a R = s-Bu (S)
8b R = i-Pr (S)
8c R = t-Bu (S)
6
7a R = s-Bu (S)
7b R = i-Pr (S)
7c R = t-Bu (S)
7d R = Ph (R)
c
Method B
O
O
O
OH
e
d
NH2
O
N
N
R'
O
R
R
R'
*
O
*
O
10a R = Ph (R)
10b R = t-Bu (S)
9
11
Scheme 2. Reagents and conditions: (a) HOBt (1.0 equiv), amino alcohol (1.0 equiv), DMAP (0.1 equiv), DCC (1.1 equiv), CH2Cl2, 0 ꢁC to rt, 16 h,
61–63%; (b) SOCl2 (5.0 equiv), CH2Cl2, rt, 16 h, then Na2CO3 (5.0 equiv), DMF, 85 ꢁC, 24 h, 62–71%; (c) PhMgCl (1.2 equiv), THF, rt, 2–12 h, 41–
53%; (d) Et3OBF4 (1.2 equiv), 1,2-DCE, rt, 24 h, then amino alcohol (1.2 equiv), reflux, 24 h, 34–36%; (e) R0MgX (3.0 equiv), THF, rt, 16 h, 60–86%.

C. Bolm et al. / Tetrahedron: Asymmetry 16 (2005) 1367–1376
1369
Table 1. Hydroxy oxazolines 11a–k prepared in this study
Entry Compound Method Config.
R0
s-Bu Ph
i-Pr Ph
t-Bu Ph
Ph Ph
selectivity, leading in most cases to an increased ee of
the product. Unfortunately, however, this positive effect
was generally accompanied by a decrease in yield.
R
1
11a
11b
11c
11d
11e
11f
11g
11h
11i
A
A
A
B
B
B
B
B
B
B
B
S
S
S
R
S
S
S
S
S
S
S
2
In the first set of experiments, the impact of the substitu-
ent on the oxazoline ring was assessed, with all hydroxy
oxazolines having two phenyl groups as substituents at
the benzylic position (Table 2, entries 1–4). While 11a
and 11d derived from (S)-leucinol and (R)-phenylgly-
cinol, respectively, furnished only racemic products
(entries 1 and 4), a low enantioselectivity (14% ee) was
found in the catalysis with 11b, derived from (S)-valinol
(entry 2). The best result was obtained with hydroxy
oxazoline 11c bearing a tert-butyl group at the oxazoline
ring, which led to the formation of diaryl methanol 5a
with 43% ee in 56% yield in the presence of the additive
(entry 3). Although both ee and yield were still moderate,
this result was already superior to those obtained in the
same reaction with mandelic acid-derived ligands 3.12
3
4
5
t-Bu Me
6
t-Bu 4-MeO–Ph
t-Bu 3,5-(CF3)2Ph
t-Bu 2-Me–Ph
t-Bu 3,5-(Me)2Ph
t-Bu 2,4,6-(Me)3Ph
t-Bu 2-MeO–Ph
7
8
9
10
11
11j
11k
hydroxy oxazolines 11a–k were employed in catalytic
asymmetric phenyl transfer reactions to aldehydes.
2.2. Asymmetric phenyl transfer reactions
In order to study the capability of hydroxy oxazolines
11a–k to yield catalysts for the title reaction, a series
of experiments were carried out under the previously
optimized reaction conditions7,10–12 with 10 mol % of
11, p-chlorobenzaldehyde 4a as the test substrate and
a mixture of triphenylborane and diethylzinc as the phe-
nyl source. Furthermore, since a positive effect on the
enantioselectivity had previously been observed upon
the addition of polyethyleneglycols to the reaction mix-
ture,11 two series of experiments were performed. One
involved reactions without the additive, the other uti-
lized 13 mol % of DiMPEG (MW = 2000 g molꢀ1) as
additive. The results obtained are shown in Table 2.
Having established the positive effect of the tert-butyl
group on the enantioselectivity, several (S)-tert-leu-
cinol-derived hydroxy oxazolines were then tested.
When the phenyl groups at the hydroxyl-bearing carbon
were changed to methyl substituents (hydroxy oxazoline
11e), the racemic product was obtained in moderate
yield (entry 5).16 While the introduction of electron
donating (entry 6) or electron withdrawing (entry 7)
groups on the phenyl rings at the a-position had little
effect on the enantioselectivity, a variation of the steric
hindrance was more effective. Thus 11h, having two 2-
methylphenyl substituents, was in fact able to produce
the final product with a promising 71% ee in 80% yield
(entry 8; in the presence of DiMPEG). Unfortunately,
using hydroxy oxazolines with more sterically hindered
aryls did not lead to further improvements. For exam-
ple, the introduction of two methyl groups at the meta
positions of the aryl rings (hydroxy oxazoline 11i)
showed almost no effect on the enantioselectivity
Two general points became immediately clear: first,
all hydroxy oxazolines led to active catalysts, furnishing
products with varying enantioselectivities (up to 71%
ee) in good to excellent yields (up to 92%). Second, the
presence of DiMPEG had a beneficial effect on enantio-
Table 2. Asymmetric phenyl transfer reaction to 4-chlorobenzaldehyde 4a catalyzed by hydroxy oxazolines 11a–k
O
OH
*
BPh3 (1.0 eq.), ZnEt2 (4.0 eq.),
11a-k (10 mol %)
toluene, 10 ˚C, 16 h
Cl
Cl
5a
4a
Entry
Ligand
Without additive
With additive (13 mol % DiMPEG)
% Yield of 5aa
% Ee of 5a (config.)b
% Yield of 5aa
% Ee of 5a (config.)b
1
11a
11b
11c
11d
11e
11f
11g
11h
11i
74
74
91
87
43
83
92
81
84
76
80
rac
44
50
56
48
65
74
80
80
72
72
70
rac
2
12 (S)
27 (S)
rac
14 (S)
43 (S)
rac
3
4
5
rac
rac
6
31 (S)
17 (S)
68 (S)
24 (S)
rac
35 (S)
30 (S)
71 (S)
39 (S)
rac
7
8
9
10
11
11j
11k
26 (R)
20 (R)
a After column chromatography.
b Determined by chiral HPLC (see Experimental for details).

1370
C. Bolm et al. / Tetrahedron: Asymmetry 16 (2005) 1367–1376
(entry 9) in comparison to the use of a,a-diphenyl com-
pound 11c. Applying a,a-dimesityl-substituted 11j was
even worse leading to racemic alcohol 5a (entry 10).
Presumably, the extreme bulk of the mesityl groups
forced the ligand into a different conformation, which
resulted in a lack of asymmetric induction.
kind of transformation, was subjected to the reaction,
diarylmethanol 5d was obtained with only 55% ee albeit
in good yield (entry 4). Finally, as demonstrated with
cyclohexyl carbaldehyde 4e, aliphatic aldehydes also re-
acted, but in this case the enantioselectivity was very low
(20% ee, entry 5).
Finally, we tried to combine steric and electronic effects
by employing hydroxy oxazoline 11k having two 2-
MeO-substituted phenyl rings at the a-position. The re-
sult (entry 11) was unusual: first, the use of DiMPEG
did not increase, but lowered the enantioselectivity,
and second, the absolute configuration of the product
was opposite to the ones obtained with all other ligands.
Thus, the (R)-enantiomer of 5a was formed in excess,
whereas in the other cases, (S)-5a was predominantly
obtained. It is most likely that a coordination of the
metal by the methoxy groups on the phenyl rings played
a key role in the reversal of enantioselectivity.
3. Conclusions
The synthesis of new hydroxy oxazolines 11a–k, derived
from chiral amino alcohols and benzoylformic acid or
ethyl oxamate, and their application in the catalytic asym-
metric phenyl transfer to aromatic and aliphatic alde-
hydes have been reported. Two synthetic pathways have
been developed, which proved to be remarkably flexible,
allowing the introduction of a high degree of structural
diversity in very few steps. Although the results obtained
in these reactions cannot compete with the best ones re-
ported in the literature, promising enantioselectivities
have been obtained with hydroxy oxazoline 11h in the
phenyl transfer to para-substituted benzaldehydes, with
a maximum of 81% ee for 4-methoxybenzaldehyde 4c.
These results are far superior to those obtained with man-
delic acid-derived hydroxy oxazolines 3, thus confirming
our initial assumption that a variation of the benzylic po-
sition of 11 would result in more active and selective cata-
lysts. Considering the ease of preparation of the present
class of hydroxy oxazolines, improvements are expected
to arise from further optimization of ligand structure, as
well as reaction conditions.
Since hydroxy oxazoline 11h led to the best results in the
test reaction, the scope of the asymmetric phenyl trans-
fer to aldehydes was briefly examined (Table 3).
4-Methylbenzaldehyde 4b reacted smoothly under the
standard conditions giving the corresponding alcohol
5b with 77% ee in 89% yield (Table 3, entry 2). 4-Meth-
oxybenzaldehyde 4c furnished the product in 81% ee
with a slightly decreased yield (60%; entry 3). Unfortu-
nately, when the 2-bromo-substituted aldehyde 4d,
which is known to be a challenging substrate for this
Table 3. Asymmetric phenyl transfer reaction to differently substituted aldehydes catalyzed by hydroxy oxazoline 11h
BPh3 (1.0 eq.), ZnEt2 (4.0 eq.),
OH
11h (10 mol%)
RCHO
R
DiMPEG (13 mol%),
toluene, 10 ˚C, 16 h
4a-e
5a-e
Entry
1
Starting material
Product
% Yielda
80
% Eeb
O
OH
4a
5a
71 (S)
Cl
Cl
O
OH
2
3
4b
5b
89
60
77 (S)
81 (S)
Me
Me
OH
O
4c
5c
MeO
Br
MeO
O
O
Br OH
4
5
4d
4e
5d
5e
85
65
55 (S)
20 (R)
OH
a After column chromatography.
b Determined by chiral HPLC (see Experimental for details).

C. Bolm et al. / Tetrahedron: Asymmetry 16 (2005) 1367–1376
1371
4. Experimental
4.1. General remarks
matography (PE–EtOAc 1:1) afforded pure 7a as a col-
orless oil. Yield 3.03 g (12.2 mmol, 61%); ½aꢁ ¼ ꢀ19:1
20
D
(c 0.50, CHCl3); IR (neat): 3339, 2956, 2872, 1662,
1
1529, 1251, 1221 cmꢀ1; H NMR (400 MHz, CDCl3):
Air sensitive manipulations were carried out under an
argon atmosphere using either standard Schlenk tech-
niques or a glovebox. THF and toluene were distilled
from the sodium-benzophenone ketyl radical and
CH2Cl2 from calcium hydride prior to use. Ethyl acetate,
diethyl ether, petroleum ether (PE) and pentane for col-
umn chromatography were distilled before use. Dichlo-
roethane and DMF were HPLC grade and used as
received. 1H and 13C NMR spectra were recorded either
on a Varian Gemini 300 spectrometer (300 and 75 MHz,
respectively) or on a Varian Inova 400 spectrometer (400
and 100 MHz, respectively). IR spectra were measured
on a Perkin–Elmer PE 1760 FT instrument as KBr pel-
lets or neat (in case of liquid compounds); absorptions
are given in wavenumbers (cmꢀ1). MS spectra were re-
corded on a Varian MAT 212 or on a Finnigan MAT
95 spectrometer with EI ionization. Optical rotation
measurements were conducted at room temperature with
a Perkin–Elmer PE 241 polarimeter at a wavelength of
589 nm. HPLC measurements were performed on a
Merck-Hitachi HPLC apparatus (L-7400 UV-detector,
L-7100 pump and D-7000 integrator) or on a Gynkotek
HPLC system (Gina 50 autosampler, UVD 170S UV-
detector, DG 503 degasser and M480G pump), using
columns with chiral stationary phase purchased from
Chiral Technologies Ltd. Elemental analyses were
performed using a Heraeus CHN-O-Rapid instrument.
Melting points were measured in open capillaries with
a Buechi B-540 apparatus and are uncorrected.
8.28 (d, J = 8.4 Hz, 2H, Har), 7.61 (t, J = 8.4 Hz, 2H,
Har), 7.46 (t, J = 8.0 Hz, 1H, Har), 7.22–7.27 (m, 1H,
NH), 4.11–4.21 (m, 1H, CH), 3.76 (dd, J = 9.3 Hz,
J = 3.6 Hz, 1H, CH2), 3.63 (dd, J = 9.3 Hz, J = 5.5 Hz,
1H, CH2), 2.80 (br s, 1H, OH), 1.67 (dsept, J = 6.4 Hz,
J = 2.1 Hz, 1H, CH), 1.48–1.56 (m, 1H, CH2), 1.38–
1.47 (m, 1H, CH2), 0.96 (s, 3H, CH3), 0.94 (s, 3H,
CH3). 13C NMR (100 MHz, CDCl3): 22.3, 23.2, 25.1,
40.1, 50.2, 65.5, 128.5, 131.1, 133.3, 134.4, 162.2,
187.9; MS (EI, 70 eV): m/z = 249 [M]+, 218, 144, 105,
83, 77, 55; HRMS (EI): m/z calcd for C14H19NO3:
249.1365; found 249.1364.
4.2.2. (S)-N-(1-iso-Propyl-2-hydroxyethyl)benzoylform-
amide 7b. Prepared starting from (S)-valinol
(20.0 mmol, 2.06 g). Purification by flash column chro-
matography (PE–EtOAc 1:1) afforded pure 7b as a col-
20
D
(c 0.18, CHCl3); IR (neat): 3358, 2964, 2878, 1663,
orless oil. Yield 2.97 g (12.6 mmol, 63%); ½aꢁ ¼ ꢀ13:7
1
1525, 1270, 1219 cmꢀ1. H NMR (300 MHz, CDCl3):
8.25–8.28 (m, 2H, Har), 7.57–7.65 (m, 1H, Har), 7.41–
7.50 (m, 2H, Har), 7.29–7.39 (m, 1H, NH), 3.79–3.89
(m, 1H, CH), 3.73–3.78 (m, 2H, CH2), 2.78 (br s, 1H,
OH), 1.99 (sept, J = 6.8 Hz, 1H, CH), 1.01 (d, J =
6.8 Hz, 3H, CH3), 0.98 (d, J = 6.8 Hz, 3H, CH3). 13C
NMR (75 MHz, CDCl3): 18.8, 19.6, 29.1, 57.2, 63.2,
128.5, 131.2, 133.3, 134.5, 162.6, 188.1. MS (EI,
70 eV): m/z = 235 [M]+, 204, 130, 105, 87, 77, 69. HRMS
(EI): m/z calcd for C13H17NO3: 235.1208; found
235.1208.
4.2. General procedure for the condensation of benzoyl-
formic acid 6 with amino alcohols to give oxo hydroxy
amides 7
4.2.3. (S)-N-(1-tert-Butyl-2-hydroxyethyl)benzoylform-
amide 7c. Prepared starting from (S)-tert-leucinol
(20.0 mmol, 2.34 g). Purification by flash column chro-
In a flame-dried, round-bottom Schlenk flask under an
inert atmosphere of argon, benzoylformic acid 6
(20.0 mmol, 3.00 g) was dissolved in dry CH2Cl2
(150 mL) and 1-hydroxybenzotriazol (HOBt, 20.0 mmol,
2.70 g) added in one portion. The mixture was stirred at
room temperature for 30 min, and then 4-dimethylami-
nopyridine (DMAP, 2.0 mmol, 244 mg) and the appro-
priate amino alcohol (20 mmol) added. The resulting
mixture was cooled to 0 ꢁC and a solution of N,N0-di-
cyclohexylcarbodiimide (DCC, 22.0 mmol, 4.54 g) in
dry CH2Cl2 (100 mL) added dropwise. The reaction mix-
ture was stirred for 1 h at 0 ꢁC, and then allowed to warm
to room temperature and stirred overnight. The solvent
was then removed under reduced pressure and replaced
with EtOAc (250 mL). The precipitate thus formed was
filtered off on a short pad of Celiteꢂ, and the organic
layer washed in sequence with aq HCl (1 M, 200 mL),
satd aq NaHCO3 (200 mL) and brine (200 mL) and final-
ly dried over MgSO4. Evaporation of the solvent affor-
ded 7 as a crude product, which was purified by flash
column chromatography.
matography (PE–EtOAc 1:1) afforded pure 7c as a col-
orless oil. Yield 2.78 g (12.0 mmol, 60%); ½aꢁ ¼ ꢀ60:2
;
1661, 1325, 1234, 1064 cmꢀ1 1H NMR (300 MHz,
CDCl3): 8.24–8.28 (m, 2H, Har), 7.55–7.64 (m, 1H,
Har), 7.40–7.48 (m, 2H, Har), 7.28–7.38 (m, 1H, NH),
3.86–3.97 (m, 2H, CH2), 3.60–3.70 (m, 1H, CH), 2.78
(br s, 1H, OH), 1.00 (s, 9H, CH3). 13C NMR
(75 MHz, CDCl3): 26.9, 33.9, 59.9, 62.3, 128.5, 131.2,
133.3, 134.5, 163.0, 188.2. MS (EI, 70 eV): m/z = 249
[M]+, 218, 164, 144, 105, 86, 77, 69, 57. HRMS (EI):
m/z calcd for C9H10NO2 [C14H19NO3–C5H9O]:
164.0712; found 164.0711.
20
D
(c 1.03, CHCl3); IR (neat): 3257, 3170, 3095, 2958,
4.3. General procedure for the synthesis of 2-benzoyl-
oxazolines 8
In a flame-dried, round-bottom Schlenk flask under an
inert atmosphere of argon, a solution of the appropriate
oxo hydroxy amide 7 (2.0 mmol) in dry CH2Cl2 (20 mL)
was prepared. The solution was cooled to 0 ꢁC and
SOCl2 (10.0 mmol, 1.19 g, 0.73 mL) added dropwise
over 10 min. The reaction mixture was warmed to room
temperature and stirred overnight. The solvent and ex-
cess SOCl2 were then evaporated and replaced with
4.2.1. (S)-N-(1-sec-Butyl-2-hydroxyethyl)benzoylform-
amide 7a. Prepared starting from (S)-leucinol
(20.0 mmol, 2.34 g). Purification by flash column chro-

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C. Bolm et al. / Tetrahedron: Asymmetry 16 (2005) 1367–1376
DMF (20 mL). Solid Na2CO3 (10.0 mmol, 1.06 g) was
added in one portion at room temperature and the reac-
tion mixture heated to 85 ꢁC and stirred for 24 h. The
heterogeneous mixture was then diluted with AcOEt
(20 mL) and the organic phase washed with water
(5 · 20 mL). The aqueous phase was extracted with
AcOEt (20 mL). The combined organic layers were
washed with brine (2 · 20 mL) and dried over MgSO4.
Removal of the solvent under reduced pressure afforded
crude 8, which was then purified by flash column
chromatography.
2-benzoyloxazoline 8 (1.0 mmol) in dry THF (15 mL)
was prepared. The solution was cooled to 0 ꢁC and
PhMgCl (2.0 M solution in THF, 1.1 mmol, 0.55 mL)
then added dropwise over 5 min. The reaction mixture
was then warmed to room temperature and stirred for
2 h. The reaction was quenched with satd aq NH4Cl
(15 mL) and extracted with CH2Cl2 (3 · 15 mL). The
combined organic layers were washed with water
(25 mL) and dried over MgSO4. Removal of the solvent
under reduced pressure afforded crude 11, which was
then purified either by recrystallization or flash column
chromatography.
4.3.1. (S)-2-Benzoyl-4-sec-butyloxazoline 8a. Prepared
starting from 7a (2.0 mmol, 0.499 g). Purification by
flash column chromatography (PE–EtOAc 4:1) afforded
4.4.1. (S)-2-(Diphenylhydroxy)methyl-4-sec-butyloxazo-
line 11a. Prepared starting from 8a (1.0 mmol,
0.231 g). Purification by flash column chromatography
pure 8a. Yield 0.329 g (1.42 mmol, 71%); colorless oil;
20
D
½aꢁ ¼ ꢀ31:0 (c 1.06, CHCl3); IR (neat): 3257, 3170,
(PE–EtOAc 4:1) afforded pure 11a. Yield 0.144 g
20
D
CHCl3); IR (neat): 3065, 2953, 2892, 2792, 1655, 1450,
2958, 1661, 1326, 1233, 1064 cmꢀ1
.
1H NMR
(0.47 mmol, 47%); colorless oil; ½aꢁ ¼ ꢀ57:2 (c 0.67,
(300 MHz, CDCl3): 8.25–8.32 (m, 2H, Har), 7.57–7.66
(m, 1H, Har), 7.43–7.52 (m, 2H, Har), 4.40–4.58 (m,
2H, CH2), 4.03 (t, J = 7.3 Hz, 1H, CH), 1.70–1.92 (m,
2H, CH2), 1.40–1.52 (m, 1H, CH), 1.00 (d, J = 6.4 Hz,
3H, CH3), 0.98 (d, J = 6.5 Hz, 3H, CH3). 13C NMR
(75 MHz, CDCl3): 22.7, 22.8, 25.6, 45.2, 66.3, 73.0,
128.5, 130.7, 134.2, 134.9, 159.1, 183.7. MS (EI,
70 eV): m/z = 231 [M]+, 174, 105, 77, 51.
1
1224, 1179 cmꢀ1; H NMR (300 MHz, CDCl3): 7.38–
7.49 (m, 4H, Har), 7.25–7.37 (m, 6H, Har), 4.90 (s, 1H,
OH), 4.49 (dd, J = 8.9 Hz, J = 7.9 Hz, 1H, CH2), 4.06–
4.19 (m, 1H, CH), 4.02 (t, J = 7.9 Hz, 1H, CH2), 1.68–
1.83 (m, 1H, CH2), 1.50–1.66 (m, 1H, CH2), 1.24–1.35
(m, 1H, CH), 0.93 (d, J = 6.4 Hz, 3H, CH3), 0.91 (d,
J = 6.4 Hz, 3H, CH3).13C NMR (75 MHz, CDCl3):
22.7, 22.8, 25.4, 45.3, 63.8, 75.6, 77.3, 127.3, 127.4,
127.6, 127.9, 128.0, 128.1, 142.9, 143.1, 170.1. MS (EI,
70 eV): m/z = 309 [M]+, 232, 183, 165, 105, 77. Anal.
Calcd for C20H23NO2: C, 77.64; H, 7.49; N, 4.53.
Found: C, 77.60; H, 7.44; N, 4.20.
4.3.2. (S)-2-Benzoyl-4-iso-propyloxazoline 8b. Prepared
starting from 7b (2.0 mmol, 0.471 g). Purification by
flash column chromatography (PE–EtOAc 3:1) afforded
pure 8b. Yield 0.270 g (1.24 mmol, 62%); colorless oil;
20
½aꢁ ¼ þ112:7 (c 0.97, CHCl3); IR (neat): 2964, 1739,
D
1
1607, 1194, 1174 cmꢀ1; H NMR (400 MHz, CDCl3):
8.27–8.32 (m, 2H, Har), 7.58–7.65 (m, 1H, Har), 7.45–
7.52 (m, 2H, Har), 4.46 (dd, J = 9.6 Hz, J = 8.3 Hz,
1H, CH2), 4.21–4.30 (m, 1H, CH), 4.17 (t, J = 8.3 Hz,
1H, CH2), 1.85–199 (m, 1H, CH), 1.06 (d, J = 6.9 Hz,
1H, CH3), 0.98 (d, J = 6.9 Hz, 1H, CH3); 13C NMR
(100 MHz, CDCl3): 18.6, 19.1, 32.8, 70.2, 73.7, 128.5,
130.7, 134.2, 134.9, 159.1, 183.7; MS (EI, 70 eV): m/z =
217 [M]+, 173, 144, 104, 77, 70, 55. HRMS (EI): m/z
calcd for C13H15NO2: 217.1103; found 217.1103.
4.4.2. (S)-2-(Diphenylhydroxy)methyl-4-iso-propyloxazo-
line 11b. Prepared starting from 8b (1.0 mmol,
0.217 g). Purification by recrystallization from n-hex-
ane/CH2Cl2 afforded pure 11b. Yield 0.120 g
(0.41 mmol, 41%); colorless crystals; mp 91–92 ꢁC;
20
½aꢁ ¼ ꢀ58:9 (c 0.95, CHCl3); IR (KBr): 3093, 2959,
D
2893, 2870, 1659, 1451, 1228, 1181 cmꢀ1
.
1H NMR
(400 MHz, CDCl3): 7.40–7.48 (m, 4H, Har), 7.25–7.37
(m, 6H, Har), 5.00 (br s, 1H, OH), 4.38–4.47 (m, 1H,
CH2), 4.13–4.20 (m, 1H, CH2), 3.80–3.90 (m, 1H,
CH), 1.68–1.81 (m, 1H, CH), 0.95 (d, J = 6.8 Hz, 3H,
CH3), 0.86 (d, J = 6.7 Hz, 3H, CH3). 13C NMR
(100 MHz, CDCl3): 18.4, 18.9, 32.8, 71.0, 73.0, 77.4,
127.3, 127.4, 127.8, 128.0, 143.0, 143.1, 170.2. MS (EI,
70 eV): m/z = 295 [M]+, 222, 218, 165, 105, 77. Anal.
Calcd for C19H21NO2: C, 77.26; H, 7.17; N, 4.74.
Found: C, 77.42; H, 7.34; N, 4.52.
4.3.3. (S)-2-Benzoyl-4-tert-butyloxazoline 8c. Prepared
starting from 7c (2.0 mmol, 0.499 g). Purification by
flash column chromatography (PE–EtOAc 3:1) afforded
pure 8c. Yield 0.315 g (1.36 mmol, 68%); colorless oil;
20
D
½aꢁ ¼ þ219:8 (c 0.80, CHCl3); IR (neat): 2960, 2907,
1741, 1608, 1476, 1176, 1054 cmꢀ1
;
1H NMR
(300 MHz, CDCl3): 8.28–8.35 (m, 2H, Har), 7.58–7.66
(m, 1H, Har), 7.43–7.53 (m, 2H, Har), 4.34–4.46 (m,
1H, CH), 4.16–4.29 (m, 2H, CH2), 1.01 (s, 9H, CH3);
13C NMR (75 MHz, CDCl3): 26.1, 34.0, 68.7, 77.4,
128.5, 130.8, 134.2, 135.0, 159.2, 183.7; MS (EI,
70 eV): m/z = 231 [M]+, 175, 158, 130, 104, 84, 77, 69,
57; HRMS (EI): m/z calcd for C14H17NO2: 231.1259;
found 231.1260.
4.4.3. (S)-2-(Diphenylhydroxy)methyl-4-tert-butyloxazo-
line 11c. Prepared starting from 8c (1.0 mmol, 0.231 g).
Purification by recrystallization from n-hexane afforded
pure 11c. Yield 0.166 g (0.54 mmol, 54%); colorless nee-
20
D
(KBr): 3062, 2957, 2895, 2868, 1657, 1451, 1227, 1181,
dles; mp 130–131 ꢁC; ½aꢁ ¼ ꢀ59:7 (c 0.87, CHCl3); IR
1060 cmꢀ1 1H NMR (400 MHz, CDCl3): 7.38–7.49
.
(m, 4H, Har), 7.25–7.36 (m, 6H, Har), 4.98 (br s, 1H,
OH), 4.36–4.44 (m, 1H, CH2), 4.28 (t, J = 8.5 Hz, 1H,
CH2), 3.89 (dd, J = 10.1 Hz, J = 8.4 Hz, 1H, CH), 0.89
(s, 9H, CH3). 13C NMR (100 MHz, CDCl3): 26.0,
34.0, 71.7, 74.4, 77.1, 127.3, 127.4, 127.8, 127.8, 128.0,
128.0, 142.7, 143.0, 170.6. MS (EI, 70 eV): m/z = 309
4.4. General procedure for the addition of phenylmagne-
sium chloride to 2-benzoyloxazolines 8
In a flame-dried, round-bottom Schlenk flask under an
inert atmosphere of argon, a solution of the appropriate

C. Bolm et al. / Tetrahedron: Asymmetry 16 (2005) 1367–1376
1373
[M]+, 232, 222, 183, 105, 77. Anal. Calcd for
C20H23NO2: C, 77.64; H, 7.49; N, 4.53. Found: C,
77.89; H, 7.71; N, 4.21.
(P3.0 mmol) in THF or Et2O added dropwise over
5 min. The reaction mixture was warmed to room tem-
perature and stirred for 16–24 h. The reaction was
quenched by the addition of satd aq NH4Cl (10 mL).
The aqueous phase was extracted with CH2Cl2
(3 · 10 mL). The combined organic layers were washed
with brine (20 mL) and dried over MgSO4. Removal
of the solvent under reduced pressure afforded crude
11, which was then purified either by recrystallization
or flash column chromatography.
4.5. General procedure for the synthesis of ethyl oxazo-
line-2-carboxylates 10 from ethyl oxamate 9
In a flame-dried, round-bottom Schlenk flask under an
inert atmosphere of argon, a solution of triethyloxo-
nium tetrafluoroborate (15.1 mmol, 2.87 g) in 1,2-
dichloroethane (DCE, 80 mL) was prepared. To this
solution, ethyl oxamate 9 (15.1 mmol, 1.77 g) was added
in one portion at room temperature. The reaction mix-
ture was stirred at room temperature for 24 h and then
the appropriate amino alcohol (17.1 mmol) added in
one portion. The reaction mixture was heated to reflux
and stirred for an additional 24 h. It was then cooled
to room temperature and poured into ice-cold satd aq
NH4Cl (25 mL). Dichloromethane was added (80 mL)
and the organic layer washed with satd aq NH4Cl
(2 · 25 mL), and brine (25 mL), and finally dried over
MgSO4. Removal of the solvent under reduced pressure
afforded crude 10, which was then purified by flash col-
umn chromatography.
4.6.1. (R)-2-(Diphenylhydroxy)methyl-4-phenyloxazoline
11d. Prepared starting from ethyl (R)-4-phenyloxazo-
line-2-carboxylate 10a (1.0 mmol, 0.219 g) and PhMgCl
(2.0 M solution in THF, 3.0 mmol, 1.5 mL). Purification
by flash column chromatography (PE–EtOAc 7:2) afford-
ed pure 11d. Yield 0.284 g (0.86 mmol, 86%); white
20
D
(KBr): 3062, 3027, 1736, 1655, 1494, 1450, 1220, 1172,
solid; mp 84–85 ꢁC; ½aꢁ ¼ þ113:9 (c 0.99, CHCl3); IR
1057 cmꢀ1 1H NMR (400 MHz, CDCl3): 7.46–7.54
.
(m, 4H, Har), 7.25–7.40 (m, 9H, Har), 7.16–7.22 (m,
2H, Har), 5.16–5.25 (m, 1H, CH2), 4.88 (s, 1H, OH),
4.77–4.86 (m, 1H, CH2), 4.26–4.33 (m, 1H, CH). 13C
NMR (100 MHz, CDCl3): 68.3, 77.1, 77.4, 126.3,
127.1, 127.2, 127.6, 127.8, 127.8, 127.9, 127.9, 128.6,
141.2, 142.4, 142.6, 171.5. MS (EI, 70 eV): m/z = 329
[M]+, 252, 183, 105, 77. Anal. Calcd for C22H19NO2:
C, 80.22; H, 5.81; N, 4.25. Found: C, 80.16; H, 5.55;
N, 3.98.
4.5.1. Ethyl (R)-4-phenyloxazoline-2-carboxylate 10a. Pre-
pared starting from (R)-phenylglycinol (17.1 mmol,
2.35 g). Purification by flash column chromatography
(PE–EtOAc 4:3) afforded pure 10a. Yield 1.141 g
20
D
CHCl3); IR (neat): 3358, 1745, 1697, 1529, 1306,
(5.2 mmol, 34%); yellow oil; ½aꢁ ¼ ꢀ38:3 (c 0.48,
4.6.2. (S)-2-(Dimethylhydroxy)methyl-4-tert-butyloxazo-
line 11e. Prepared starting from ethyl (S)-4-tert-butyl-
oxazoline-2-carboxylate 10b (1.0 mmol, 0.199 g) and
MeMgCl (3.0 M solution in Et2O, 3.0 mmol, 1.0 mL).
Purification by recrystallization from n-hexane afforded
pure 11e. Yield 0.110 g (0.60 mmol, 60%); white solid;
1188 cmꢀ1 1H NMR (400 MHz, CDCl3): 7.29–7.41
.
(m, 2H, Har), 7.23–7.29 (m, 3H, Har), 5.41 (dd,
J = 10.5 Hz, J = 9.0 Hz, 1H, CH2), 4.83 (dd,
J = 10.6 Hz, J = 8.9 Hz, 1H, CH2), 4.36–4.46 (m, 2H,
CH2), 4.32–4.38 (t, J = 8.9 Hz, 1H, CH), 1.40 (t,
J = 7.1 Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3):
14.0, 63.0, 70.3, 75.4, 126.6, 127.9, 128.7, 140.1, 156.5,
157.3. MS (EI, 70 eV): m/z = 219 [M]+, 189, 144, 117,
90, 77.
20
D
1
mp 86–87 ꢁC; ½aꢁ ¼ ꢀ28:9 (c 1.02, CHCl3); H NMR
(300 MHz, CDCl3): 4.15–4.35 (m, 2H, CH2), 3.86 (dd,
J = 9.9 Hz, J = 7.4 Hz, 1H, CH), 3.40 (s, 1H, OH),
1.44 (s, 6H, CH3), 0.90 (s, 9H, CH3). 13C NMR
(75 MHz, CDCl3): 25.6, 27.7, 28.1, 33.7, 68.8, 70.6,
75.0, 172.4. All the other data are in agreement with
those previously reported in the literature.16
4.5.2. Ethyl (S)-4-tert-butyloxazoline-2-carboxylate
10b. Prepared
(17.1 mmol, 2.00 g). Purification by flash column chro-
starting
from
(S)-tert-leucinol
matography (PE–EtOAc 3:2) afforded pure 10b. Yield
20
D
4.6.3.
(S)-2-[Di-(40-methoxyphenyl)hydroxy]methyl-4-
1.050 g (5.3 mmol, 36%); colorless oil; ½aꢁ ¼ ꢀ74:7 (c
1
tert-butyloxazoline 11f. Prepared starting from ethyl
(S)-4-tert-butyloxazoline-2-carboxylate 10b (1.0 mmol,
0.199 g) and [4-(MeO)Ph]MgBr (0.5 M solution in
THF, 3.0 mmol, 6.0 mL). Purification by double recrys-
tallization from Et2O afforded pure 11f. Yield 0.320 g
1.02, CHCl3); H NMR (400 MHz, CDCl3): 4.40 (dd,
J = 10.6 Hz, J = 1.9 Hz, 1H, CH), 4.34–4.42 (m, 2H,
CH2), 4.25 (t, J = 8.8 Hz, 1H, CH2), 4.09 (dd, J =
10.6 Hz, J = 8.8 Hz, 1H, CH2), 1.39 (t, J = 7.3 Hz, 3H,
CH3), 0.95 (s, 9H, CH3); 13C NMR (100 MHz, CDCl3):
14.2, 26.0, 33.9, 62.9, 69.8, 76.7, 155.4, 157.6. All the
other data are in agreement with those previously
reported in the literature.15
(0.86 mmol, 86%); light brown solid; mp 136–137 ꢁC;
20
½aꢁ ¼ ꢀ48:3 (c 0.78, CHCl3); IR (KBr): 3175, 2956,
D
2898, 1650, 1508, 1466, 1247, 1175, 1075 cmꢀ1
.
1H
NMR (400 MHz, CDCl3): 7.29–7.41 (m, 4H, Har),
6.80–6.89 (m, 4H, Har), 4.90 (br s, 1H, OH), 4.40 (dd,
J = 10.0 Hz, J = 8.8 Hz, 1H, CH2), 4.27 (t, J = 8.5 Hz,
1H, CH2), 3.90 (dd, J = 10.0 Hz, J = 8.5 Hz, 1H, CH),
3.795 (s, 3H, CH3), 3.790 (s, 3H, CH3), 0.90 (s, 9H,
CH3). 13C NMR (100 MHz, CDCl3): 26.0, 33.9, 55.35,
55.37, 71.7, 74.4, 77.1, 113.29, 113.31, 128.5, 128.6,
135.1, 135.3, 159.0, 159.1, 171.0. MS (EI, 70 eV): m/z =
369 [M]+, 262, 151, 135, 107, 77. Anal. Calcd for
4.6. General procedure for the addition of Grignard
reagents to ethyl oxazoline-2-carboxylates 10
In a flame-dried, round-bottom Schlenk flask under an
inert atmosphere of argon, a solution of the appropriate
ethyl oxazoline-2-carboxylate 10 (1.0 mmol) in dry THF
(10 mL) was prepared. The solution was cooled to 0 ꢁC
and a solution of the appropriate Grignard reagent

1374
C. Bolm et al. / Tetrahedron: Asymmetry 16 (2005) 1367–1376
C22H27NO4: C, 71.52; H, 7.37; N, 3.79. Found: C, 71.22;
H, 7.09; N, 3.54.
260, 133, 105, 77, 57. Anal. Calcd for C24H31NO2: C,
78.87; H, 8.55; N, 3.83. Found: C, 78.66; H, 8.83; N,
3.58.
4.6.4.
(S)-2-[Di-(30,50-di(trifluoromethyl)phenyl)hydr-
oxy]methyl-4-tert-butyloxazoline 11g. Prepared start-
ing from ethyl (S)-4-tert-butyloxazoline-2-carboxylate
10b (1.0 mmol, 0.199 g) and 3,5-(CF3)2PhMgBr
(approx. 1.0 M solution in THF, 5.0 mmol, 5.0 mL,
prepared according to the literature17). Purification by
flash column chromatography (PE–EtOAc 4:1) afforded
pure 11g. An analytical sample was obtained by recrys-
4.6.7. (S)-2-[Di-(20,40,60-trimethylphenyl)hydroxy]methyl-
4-tert-butyloxazoline 11j. Prepared starting from ethyl
(S)-4-tert-butyloxazoline-2-carboxylate 10b (1.0 mmol,
0.199 g) and 2,4,6-(Me)3PhMgBr (1.0 M solution in
THF, 3.0 mmol, 3.0 mL). Purification by flash column
chromatography (PE–EtOAc 13:1) afforded pure 11j.
Yield 0.223 g (0.57 mmol, 57%); yellow oil;
20
D
tallization from n-hexane. Yield 0.510 g (0.88 mmol,
½aꢁ ¼ ꢀ157:7 (c 1.02, CHCl3); IR (CHCl3): 3429,
20
D
(c 1.06, CHCl3); IR (KBr): 3420, 2968, 1660, 1372,
88%); white solid; mp 121–122 ꢁC; ½aꢁ ¼ ꢀ28:5
2958, 2870, 1646, 1477, 1382, 1220, 1057 cmꢀ1
.
1H
NMR (400 MHz, CDCl3): 6.73 (s, 2H, Har), 6.70 (s,
2H, Har), 5.05 (br s, 1H, OH), 4.40 (dd, J = 10.0 Hz,
J = 8.9 Hz, 1H, CH2), 4.15 (t, J = 9.1 Hz, 1H, CH2),
3.84 (t, J = 10.0 Hz, 1H, CH), 2.21 (s, 3H, CH3), 2.20
(s, 3H, CH3), 2.12 (s, 6H, CH3), 2.10 (s, 6H, CH3),
0.88 (s, 9H, CH3). 13C NMR (100 MHz, CDCl3): 20.7,
22.0, 23.5, 26.3, 27.1 33.8, 71.6, 74.4, 79.7, 131.4,
131.5, 136.0, 136.1, 136.2, 136.9, 138.3, 139.8, 172.8.
MS (EI, 70 eV): m/z = 393 [M]+, 360, 259, 202, 147,
119, 91, 57. Anal. Calcd for C26H35NO2: C, 79.35; H,
8.96; N, 3.56. Found: C, 79.65; H, 9.24; N, 3.35.
1
1283, 1176, 1137 cmꢀ1. H NMR (400 MHz, CDCl3):
7.97 (s, 2H, Har), 7.86–7.92 (m, 4H, Har), 5.27 (br s,
1H, OH), 3.92–4.02 (m, 1H, CH2), 4.46–4.54 (m, 1H,
CH2), 4.36–4.44 (m, 1H, CH), 0.90 (s, 9H, CH3). 13C
NMR (100 MHz, CDCl3): 25.7, 34.0, 72.6, 74.6, 76.0,
122.6, 122.6, 123.04 (q, J = 70.8 Hz), 123.08 (q,
J = 70.9 Hz), 127.2, 127.4, 131.8 (q, J = 33.0 Hz), 131.9
(q, J = 33.4 Hz), 143.6, 144.4, 167.5. MS (EI, 70 eV):
m/z = 581 [M]+, 562, 525, 455, 241, 213, 163, 70, 57.
Anal. Calcd for C24H19NO2F12: C, 49.58; H, 3.29; N,
2.41. Found: C, 49.97; H, 3.49; N, 2.40.
4.6.8.
(S)-2-[Di-(20-methoxyphenyl)hydroxy]methyl-4-
4.6.5. (S)-2-[Di-(20-methylphenyl)hydroxy]methyl-4-tert-
butyloxazoline 11h. Prepared starting from ethyl (S)-
4-tert-butyloxazoline-2-carboxylate 10b (1.0 mmol,
0.199 g) and 2-MePhMgCl (1.0 M solution in THF,
3.0 mmol, 3.0 mL). Purification by recrystallization
from n-hexane afforded pure 11h. Yield 0.266 g
tert-butyloxazoline 11k. Prepared starting from ethyl
(S)-4-tert-butyloxazoline-2-carboxylate 10b (1.0 mmol,
0.199 g) and 2-MeO–PhMgBr (1.0 M solution in THF,
3.0 mmol, 3.0 mL). Purification by flash column chro-
matography (PE–EtOAc 4:1, then 2:1) afforded pure
11k. Yield 0.235 g (0.64 mmol, 64%); pale yellow oil;
20
D
(0.79 mmol, 79%); white solid; mp 188–189 ꢁC;
½aꢁ ¼ ꢀ14:7 (c 0.96, CHCl3); IR (CHCl3): 3495, 2956,
20
½aꢁ ¼ ꢀ52:3 (c 0.96, CHCl3); IR (KBr): 3167, 2957,
1662, 1488, 1464, 1243, 1030 cmꢀ1
.
1H NMR
D
1654, 1483, 1461, 1218, 1049 cmꢀ1
.
1H NMR
(300 MHz, CDCl3): 7.27–7.39 (m, 2H, Har), 6.83–7.05
(m, 6H, Har), 5.52 (br s, 1H, OH), 4.14–4.32 (m, 2H,
CH2), 3.98 (dd, J = 10.2 Hz, J = 7.8 Hz, 1H, CH), 3.81
(s, 3H, CH3), 3.74 (s, 3H, CH3), 0.93 (s, 9H, CH3).
13C NMR (75 MHz, CDCl3): 26.0, 33.9, 55.6, 55.7,
69.8, 75.4, 84.1, 111.4, 111.6, 120.8, 120.8, 128.6,
129.1, 129.3, 129.3, 130.0, 130.2, 157.3, 157.5,
171.2. MS (EI, 70 eV): m/z = 369 [M]+, 338, 262, 238,
135, 121, 91, 77. Anal. Calcd for C22H27NO4: C,
71.52; H, 7.37; N, 3.79. Found: C, 71.60; H, 7.44; N,
3.63.
(300 MHz, CDCl3): 7.06–7.30 (m, 8H, Har), 4.94 (br s,
1H, OH), 4.38–4.49 (m, 1H, CH2), 4.21–4.32 (m, 1H,
CH2), 3.87–3.99 (m, 1H, CH), 2.15 (s, 3H, CH3), 2.13
(s, 3H, CH3), 0.92 (s, 9H, CH3). 13C NMR (75 MHz,
CDCl3): 21.5, 21.7, 26.1, 33.8, 71.6, 74.5, 79.4, 125.4,
125.5, 127.4, 127.6, 127.8, 127.9, 132.3, 132.3, 137.9,
137.9, 140.7, 140.8, 171.4. MS (EI, 70 eV): m/z = 337
[M]+, 304, 231, 192, 128, 119, 91, 65, 57. Anal. Calcd
for C22H27NO2: C, 78.30; H, 8.06; N, 4.15. Found: C,
77.92; H, 8.22; N, 3.91.
4.6.6. (S)-2-[Di-(30,50-dimethylphenyl)hydroxy]methyl-4-
tert-butyloxazoline 11i. Prepared starting from ethyl
(S)-4-tert-butyloxazoline-2-carboxylate 10b (1.0 mmol,
0.199 g) and 3,5-(Me)2PhMgBr (approx. 1.0 M solution
in THF, 5.0 mmol, 5.0 mL, prepared according to the
literature18). Purification by recrystallization from PE
4.7. General procedure for the phenyl transfer reaction on
aldehydes catalyzed by compounds 11a–k
4.7.1. General procedure without additive. In a glove-
box under an inert atmosphere of argon, BPh3
(0.25 mmol, 60 mg) was sealed in a flame-dried reaction
vessel (18 · 50 mm). Toluene (2 mL) was added and the
resulting solution treated with Et2Zn (1.0 M solution in
heptane, 1.0 mmol, 1.0 mL). After stirring at room tem-
perature for 30 min, the appropriate hydroxy oxazoline
11 (0.025 mmol) was added as toluene solution
(1.0 mL) and stirring continued for further 45–60 min
at room temperature. The resulting clear solution was
cooled to 10 ꢁC and the appropriate aldehyde 4
(0.25 mmol), dissolved in toluene (1.0 mL), was slowly
added. After stirring at 10 ꢁC for 12–18 h, the reaction
mixture was quenched with water (10 mL). Aqueous
afforded pure 11i. Yield 0.256 g (0.70 mmol, 70%); white
20
D
(KBr): 3152, 2957, 2867, 1660, 1602, 1467, 1218, 1151,
solid; mp 115–116 ꢁC; ½aꢁ ¼ ꢀ33:8 (c 1.06, CHCl3); IR
1
1100, 1037 cmꢀ1. H NMR (300 MHz, CDCl3): 6.84–
7.13 (m, 6H, Har), 4.81 (br s, 1H, OH), 4.35–4.46 (m,
1H, CH2), 4.23–4.34 (m, 1H, CH2), 3.89 (dd,
J = 10.0 Hz, J = 8.3 Hz, 1H, CH), 2.29 (s, 6H, CH3),
2.27 (s, 6H, CH3), 0.92 (s, 9H, CH3). 13C NMR
(75 MHz, CDCl3): 21.4, 21.5, 25.9, 33.9, 71.6, 74.4,
77.4, 125.18, 125.21, 129.5, 129.5, 137.3, 137.4, 142.5,
143.1, 170.9. MS (EI, 70 eV): m/z = 365 [M]+, 347, 278,

C. Bolm et al. / Tetrahedron: Asymmetry 16 (2005) 1367–1376
1375
AcOH (10%) was added (10 mL) and the aqueous layer
extracted with CH2Cl2 (3 · 15 mL). The combined
organic layers were washed with brine (25 mL) and dried
over MgSO4. Evaporation of the solvent furnished crude
alcohols 5, which were then purified by flash column
chromatography.
13C NMR (100 MHz, CDCl3): 74.8, 122.8, 127.1, 127.8,
128.5, 128.6 129.1, 129.6, 132.8, 142.2, 142.6. HPLC sep-
aration conditions: Chiralcel OD, 230 nm, heptane/i-
PrOH 90:10, 0.8 mL/min; tr = 10.3 min (R), 13.2 min (S).
4.7.7. (R)-Cyclohexylphenylmethanol 5e. Obtained
from cyclohexylcarbaldehyde 4e (0.25 mmol, 28 mg).
Purification by flash column chromatography (pen-
4.7.2. General procedure with additive. In a glovebox
under an inert atmosphere of argon, BPh3 (0.25 mmol,
60 mg) and DiMPEG (M = 2000 g molꢀ1, 0.032 mmol,
63 mg) were sealed in a flame-dried reaction vessel
(18 · 50 mm). Toluene (2 mL) was added, and the
resulting solution treated with Et2Zn (1.0 M solution
in heptane, 1.0 mmol, 1.0 mL), to give a clear solution
containing a small quantity of precipitate. After stirring
at room temperature for 30 min, hydroxy oxazoline 11
(0.025 mmol) was added as a toluene solution (1.0 mL)
and stirring continued for further 45–60 min at room
temperature. The resulting mixture was cooled to
10 ꢁC and the appropriate aldehyde 4 (0.25 mmol) dis-
solved in toluene (1.0 mL) slowly added. From hereon,
the protocol followed the procedure reported above
for the reactions performed without additive.
1
tane–Et2O 8:2) furnished pure 5e as a yellow solid. H
NMR (300 MHz, CDCl3): 7.17–7.37 (m, 5H, Har), 4.34
(d, 1H, J = 7.2 Hz, CH), 2.85 (br s, 1H, OH), 1.93–
2.04 (m, 1H, Hal), 1.53–1.80 (m, 4H, Hal), 0.85–1.42
(m, 6H, Hal). 13C NMR (75 MHz, CDCl3): 26.1, 26.1,
26.5, 28.9, 29.3, 45.0, 79.5, 126.7, 127.3, 128.2, 143.6.
HPLC separation conditions: Chiralcel OD, 254 nm,
heptane/i-PrOH 95:5, 0.5 mL/min; tr = 14.2 min (R),
15.6 min (S).
Acknowledgements
We thank the Fonds der Chemischen Industrie and the
Deutsche Forschungsgemeinschaft (DFG) within the
SFB 380 for financial support. We are also grateful to
DEGUSSA AG and BAYER AG for the generous dona-
tion of amino acids and triphenylborane, respectively.
4.7.3. (S)-(4-Chlorophenyl)phenylmethanol 5a. Obtained
from 4-chlorobenzaldehyde 4a (0.25 mmol, 35 mg). Puri-
fication by flash column chromatography (pentane–Et2O
85:15) furnished pure 5a as a white solid. 1H NMR
(300 MHz, CDCl3): 7.23–7.45 (m, 9H, Har), 5.78 (s, 1H,
CH), 2.50 (br s, 1H, OH). 13C NMR (75 MHz, CDCl3):
75.7, 126.6, 127.9, 127.9, 128.7, 128.8, 133.3, 142.3,
143.5. HPLC separation conditions: Chiralcel OB-H,
230 nm, heptane/i-PrOH 90:10, 0.5 mL/min; tr = 24.1 min
(R), 30.4 min (S).
References
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fication by flash column chromatography (pentane–Et2O
1
85:15) furnished pure 5c as a colorless liquid. H NMR
(400 MHz, CDCl3): 7.21–7.38 (m, 7H, Har), 6.81–6.88 (m,
2H, Har), 5.77 (s, 1H, CH), 3.76 (s, 3H, CH3), 2.35 (br s,
1H, OH). 13C NMR (100 MHz, CDCl3): 55.4, 75.9, 113.9,
126.4, 127.3, 127.9, 128.4, 136.2, 144.0, 159.0. HPLC sepa-
ration conditions: Chiralcel OJ, 230 nm, heptane/i-PrOH
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fication by flash column chromatography (pentane–Et2O
8:2) furnished pure 5d as a yellow liquid. 1H NMR
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(m, 7H, Har), 6.18 (s, 1H, CH), 2.81 (br s, 1H, OH).
`
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