New chiral ligands derived from mandelic acid: Synthesis and application in the asymmetric phenyl transfer reaction to an aromatic aldehyde

Article abstract of DOI:10.1055/s-2004-829184

Starting from inexpensive enantiopure (R)- and (S)-mandelic acid, a range of α-hydroxy-2-oxazolines has been prepared. The synthesis involves the condensation of the acid chloride with a vicinal amino alcohol, followed by intramolecular cyclization to form the oxazoline ring. The resulting compounds have been used as ligands in the asymmetric phenyl transfer reaction to 4-chlorobenzaldehyde, employing a mixture of triphenylborane and diethylzinc as the phenyl source. Good yields (up to 76%) and moderate enantioselectivities (up to 35%) have been achieved.

Full text of DOI:10.1055/s-2004-829184

PAPER
2173
New Chiral Ligands Derived from Mandelic Acid: Synthesis and Application
in the Asymmetric Phenyl Transfer Reaction to an Aromatic Aldehyde
Chiral
L
igands fr
a
om Mandel
r
ic
A
cid:
s
T
he
A
sym
t
metric
e
P
henyl
T
ra
n
nsfer Reaction to a
B
n Aldehyde olm,* Lorenzo Zani, Jens Rudolph, Ingo Schiffers
Institut für Organische Chemie der RWTH Aachen, Professor-Pirlet-Str. 1, 52056 Aachen, Germany
Fax +49(241)8092391; E-mail: carsten.bolm@oc.rwth-aachen.de
Received 17 May 2004
OH
OH
*
Abstract: Starting from inexpensive enantiopure (R)- and (S)-man-
delic acid, a range of a-hydroxy-2-oxazolines has been prepared.
N
CO2H
*
*
R
The synthesis involves the condensation of the acid chloride with a
vicinal amino alcohol, followed by intramolecular cyclization to
form the oxazoline ring. The resulting compounds have been used
as ligands in the asymmetric phenyl transfer reaction to 4-chlo-
robenzaldehyde, employing a mixture of triphenylborane and dieth-
ylzinc as the phenyl source. Good yields (up to 76%) and moderate
enantioselectivities (up to 35%) have been achieved.
O
1
2
Scheme 1 Conversion of mandelic acid into a-hydroxy-2-oxazo-
lines
transferred, this reaction gives rise to chiral diarylmetha-
nols 4, which are important intermediates in the synthesis
of biologically active substances.7 Over the past years
several investigations have focussed on the synthesis of
diarylmethanols by addition of phenylzinc reagents to al-
dehydes.8–12 Alternative methods employing arylboronic
acids,13 arylstannanes14 and arylsilanes15 have also been
reported. However, most of these protocols lack generali-
ty, and until recently, the asymmetric versions led to prod-
ucts with only moderate to good enantiomeric excesses. A
more general approach for the enantioselective catalytic
synthesis of diarylmethanols from aldehydes was intro-
duced by us, utilizing planar chiral ferrocene-derived hy-
droxyoxazoline 5 and a zinc species, generated in situ
from ZnEt2 and ZnPh2.11 The substrate scope has later
been increased by using arylboronic acids as aryl source
(Scheme 2).12
Key words: asymmetric catalysis, mandelic acid, organometallics,
oxazolines, phenyl transfer, zinc
Asymmetric metal catalysis is one of the most important
and rapidly growing research fields in organic chemistry.1
In the search for more efficient ligands for enantioselec-
tive transformations, the structural diversity of nature has
often been inspiring. Indeed, many natural molecules,
constituting the so-called chiral pool,2 represent an easily
accessible and cheap source of chiral starting materials,
which can be used in the preparation of ligands for asym-
metric metal-catalyzed reactions.3 Among those com-
pounds, hydroxy and amino acids are of enormous
synthetic value, and mandelic acid (1) appears particularly
attractive. It is inexpensive and available in both enantio-
meric forms. Moreover, its carboxyl group can easily be
converted into many different structural motifs. Now we
wondered about the transformation of mandelic acid into
a-hydroxy-2-oxazolines 2 (Scheme 1). Oxazolines have
originally been used as base-stable protecting groups for
carboxylic acids4 and more recently, they have found ex-
tensive applications as chiral auxiliaries4a and ligands in
asymmetric catalysis.5 In compounds of type 2, two natu-
ral products from the chiral pool (mandelic acid and b-
amino alcohols stemming from a-amino acids) are com-
bined to give a set of potential ligands with most interest-
ing properties: the stereogenic centers are adjustable (to
give matched and mismatched combinations) and the ster-
ics are tunable (by R-group modifications).
OH
1) ZnEt2, toluene, 60 °C, 12 h
2) Ar'CHO, DiMPEG (10 mol%),
B(OH)2
5 (10 mol%), 10 °C, 12 h
3) work-up
R1
R2
R1
3
4
O
yield up to 93%
ee up to 98%
N
OH
Fe
Ph
Ph
5
Scheme 2 Asymmetric aryl transfer reaction with arylboronic acids
as aryl source
The results of these studies, together with the recently re-
ported evidence that chiral hydroxyoxazolines can act as
effective ligands for the enantioselective addition of di-
ethylzinc towards aldehydes16 and activated imines,17
prompted us to investigate the potential of simple mandel-
ic acid-derived a-hydroxy-2-oxazolines 2 as ligands in
aryl transfer reactions towards aromatic aldehydes. Here-
in, we report the synthesis and the catalytic application of
such compounds.
In the field of metal-mediated transformations, the cata-
lyzed enantioselective addition of organozinc reagents to
carbonyl compounds, and in particular aldehydes, is one
of the most extensively investigated areas.6 When aromat-
ic aldehydes are used as substrates and an aryl group is
SYNTHESIS 2004, No. 13, pp 2173–2180
x
x.
x
x
.
2
0
0
4
Advanced online publication: 27.07.2004
DOI: 10.1055/s-2004-829184; Art ID: Z09404SS
© Georg Thieme Verlag Stuttgart · New York

2174
C. Bolm et al.
PAPER
Ligand Synthesis
OR
*
OAc
*
Cl
a
b
CO2H
Formally, a-hydroxy-2-oxazolines 2 are condensation
products of mandelic acid and b-amino alcohols. The
availability of both enantiomeric forms of the acid as well
as the b-amino alcohols, which are readily accessible by
reduction of a-amino acids, allows the introduction of a
considerable degree of structural diversity following a
very short reaction sequence. The reagents and the reac-
tion conditions, which have been applied in the synthesis
of 2, are depicted in Scheme 3.
O
7
1: R = H
6: R = Ac
OAc
H
OAc
*
N
R
N
c or d
*
*
*
R
O
O
OH
8
9
First, mandelic acid (1) was converted into acetyl-protect-
ed intermediate 618 by treatment of 1 with acetyl chloride
at room temperature. Subsequent addition of SOCl2 to 6
afforded 7 in quantitative yield. The reactions were per-
formed with both enantiomers of mandelic acid to give
(R)-7 and (S)-7, respectively. In the following step, enan-
tiopure 7 was treated with one equivalent of an amino al-
cohol in the presence of triethylamine as base to give
condensation products 8 as single diastereomers in good
yields (up to 78%). Formation of the oxazoline was then
achieved by treatment of amides 8 with mesyl chloride in
the presence of an excess of triethylamine. Starting from
either (R,S)-8b or (S,S)-8b [derived from both enantio-
mers of 1 and (S)-tert-leucinol] this protocol led to a-ace-
toxy-2-oxazolines (R,S)-9b and (S,S)-9b, respectively, as
single diastereoisomers. Unfortunately, however, the at-
tempted stereospecific ring-closures of the other four
amides [(R,R)-8a, (S,R)-8a, (R,R)-8c and (S,R)-8c derived
from both enantiomers of 1 and (R)-valinol or (R)-phe-
nylglycinol, respectively] occured with partial epimeriza-
tion leading to diastereomeric mixtures of 9a and 9c. The
difficulties encountered in the chromatographic separa-
tion of these diastereoisomers required the employment of
an alternative method for the oxazoline formation. After
screening of various protocols, the diethylaminosulfur tri-
OH
*
N
e
*
R
O
R = i-Pr, t-Bu, Ph
2
Scheme 3 Reagents and conditions: (a) AcCl, 2 h, r.t. (1 → 6), then
SOCl2, reflux, 3 h, 100%; (b) b-amino alcohol (1.0 equiv), Et3N (2.0
equiv), CH2Cl2, 0 °C to r.t., 17 h, 59–78%; (c) MsCl (3.0 equiv),
DMAP (10 mol%), Et3N–CH2Cl2 (3:1), 0 °C to r.t., 17 h, 62–67%; (d)
DAST (1.1 equiv), CH2Cl2, –78 °C, 1 h, 56–71%; (e) LiOH (3.0
equiv), MeOH, 0 °C, 3 h, 62–94%.
fluoride (DAST)-mediated cyclization19 was identified as
a method, which preserved the stereochemical features of
the starting materials and products. Thus with DAST, a-
acetoxy-2-oxazolines (R,R)-9a, (S,R)-9a, (R,R)-9c and
(S,R)-9c were obtained from the corresponding amides 8a
and 8c in diastereomerically pure form. In comparison to
the MsCl–Et3N method a minor decrease in yield had to
be accepted. Finally, the syntheses of all diastereomers of
target compounds 2a–c were completed by hydrolyses of
the ester groups of 8a–c under basic conditions, employ-
ing an excess of lithium hydroxide in methanol. In
Figure 1 the structures of all compounds are depicted and
the overall yields (after four steps, referring to the initial
amount of mandelic acid) are given.
amino alcohol
OH
OH
OH
mandelic acid
enantiomer
H2N
(R)-valinol
H2N
H2N
(S)-tert-leucinol
(R)-phenylglycinol
OH
OH
OH
N
OH
N
N
CO2H
O
O
O
(R,R)-2a
(R,S)-2b
(R,R)-2c
(R)-1
overall yield 35%
overall yield 31%
overall yield 31%
(R)-mandelic acid
OH
N
OH
N
OH
OH
N
CO2H
O
O
O
(S,R)-2a
(S,R)-2c
(S,S)-2b
(S)-1
overall yield 30%
overall yield 35%
overall yield 29%
(S)-mandelic acid
Figure 1 Diastereomerically pure a-hydroxy-2-oxazolines 2a–c prepared by the combination of (R)- and (S)-mandelic acid with three enan-
tiopure amino alcohols.
Synthesis 2004, No. 13, 2173–2180 © Thieme Stuttgart · New York

PAPER
Chiral Ligands from Mandelic Acid: The Asymmetric Phenyl Transfer Reaction to an Aldehyde
2175
Table 1 Catalyzed Asymmetric Phenyl Transfer to 4-Chlorobenzal-
dehyde (10) to Give Diarylmethanol 11
Next, the diastereomerically pure a-hydroxy-2-oxazo-
lines 2a–c were employed in the catalytic enantioselective
phenyl transfer reaction towards aromatic aldehydes. No-
tably, as a consequence of the chosen synthetic pathway,
it was possible to easily modify the structural features of
the ligand, either by changing the substituent on the ox-
azoline ring or by adjusting the configurations of the two
stereogenic centers. Moreover, the six a-hydroxy-2-ox-
azolines were prepared as couples of diastereoisomers,
thus allowing an evaluation of possible ‘match–mis-
match’ effects to be displayed during the catalytic reac-
tions.
Entry a-Hydroxy-
Procedure A
Procedure B
2-oxazoline
Yield
(%)a
ee
Yield
(%)a
ee
(%)b
(%)b
1
(R,R)-2a
(S,R)-2a
(R,S)-2b
(S,S)-2b
(R,R)-2c
(S,R)-2c
33
76
72
19
74
50
16 (R)
9 (S)
26
<5
54
20
74
35
21 (R)
n.d.c
2
3
32 (S)
32 (S)
rac
30 (S)
35 (S)
3 (R)
26 (S)
4
5d
6d
Asymmetric Aryl Transfer Reaction
24 (S)
a After column chromatography.
In order to evaluate the capability of the a-hydroxy-2-ox-
azolines to serve as chiral ligands in the phenyl transfer re-
action to aldehydes, two different protocols were
followed. In both, 4-chlorobenzaldehyde (10) was the test
substrate (Scheme 4). Procedure A involved mixtures of
diethylzinc and triphenylborane as the phenyl source.20
Procedure B made use of the recent discovery that the
presence of small quantities of DiMPEG had beneficial
effects on the enantioselectivity of the catalyzed aryl
transfer.12,21 Thus in procedure B a reagent combination
consisting of BPh3, ZnEt2 and DiMPEG was applied.
Table 1 summarizes the results.
b The enantiomer ratios of 11 were determined by HPLC using a
chiral Chiralcel OB-H column.
c Not determined.
d Use of the original protocol with mixtures of ZnPh2 and ZnEt2 gave
irreproducible results.
afforded S-configured 11 indicating that the absolute con-
figuration of the product was determined by the stereo-
genic center at the oxazoline group. In terms of catalytic
activity (R,S)-2b proved superior over (S,S)-2b as re-
vealed by the yield of 11. Catalysts based on a-hydroxy-
2-oxazolines 2a and 2c were less enantioselective
[eemax = 26% with (S,R)-2c; Table 1, entry 6] than those
derived of 2b. The yields were comparable and reached up
to 76% (Table 1, entry 2). We assume that the differences
in the enantioselectivities of catalysts stemming from 2a
and 2c on one side and 2b on the other originate from the
chemical properties of the corresponding a-hydroxy-2-
oxazolines. To our surprise, 2a and 2c showed a rather
limited solubility in toluene, which is the solvent of choice
for the catalyzed aryl transfer reactions. Probably, the
sterically bulky tert-butyl substituent at the oxazoline
group of 2b eases the dissolution of the a-hydroxy-2-ox-
azolines in the reaction medium and facilitates their con-
versions into the corresponding catalytically active
species. Due to partial or full decomposition during the
catalysis, none of the a-hydroxy-2-oxazolines 2 could be
recovered and reused.
procedure A
BPh3, ZnEt2,
catalyst (10 mol%)
O
OH
Ph
original protocol
H
ZnPh2, ZnEt2,
ferrocene 5 (10 mol%)
Cl
Cl
10
11
procedure B
BPh3, ZnEt2, DiMPEG (10 mol%),
catalyst (10 mol%)
A benefical effect of a small quantity of DiMPEG in the
reaction mixture on the enantioselectivity of the aryl
transfer reaction had been revealed in previous stud-
ies.12,21 Although the cause of this ‘MPEG-effect’ still
needs to be fully elucidated, it is assumed that the increase
in ee originates from a polyether-based deactivation of
catalytically active but achiral species, which otherwise
lower the enantioselectivity of the overall process by pro-
ducing racemic product.21 A similar trend was observed
here. Thus, compared to procedure A, the ee-values in-
creased slightly (with one exception) when the catalyses
were performed with DiMPEG as additive according to
procedure B (Table 1).
Scheme 4 Reagents and conditions: BPh3 (1.0 equiv), ZnEt2 (4.3
equiv), 2 (10 mol%), toluene, 12 h, 10 °C; work-up (procedure A);
BPh3 (1.0 equiv), ZnEt2 (4.3 equiv), 2 (10 mol%), DiMPEG (10
mol%; MW = 2500 g mol–1), toluene, 12 h, 10 °C, work-up (proce-
dure B).
Gratifyingly, most a-hydroxy-2-oxazolines led to catalyt-
ically active systems giving diarylmethanol 11 with up to
76% yield. Unfortunately, however, neither the enantiose-
lectivity in the formation of 11 nor the activity of the cat-
alysts exceeded those of the known systems.11,12 The
highest ee-values (ranging between 30 and 35%) were
achieved with catalysts originating from a-hydroxy-2-ox-
azoline 2b (Table 1, entries 3 and 4). Both diastereomers
Synthesis 2004, No. 13, 2173–2180 © Thieme Stuttgart · New York

2176
C. Bolm et al.
PAPER
13C NMR (100 MHz, CDCl3): d = 20.6 (CH3), 81.0 (CH), 128.4,
In summary, six a-hydroxy-2-oxazolines have been pre-
pared from mandelic acid in a straightforward manner fol-
lowing an easy to perform four-step reaction sequence.
The absolute and the relative stereochemistry of the prod-
ucts is dictated by the starting materials, which all stem
from the chiral pool. With the optimized protocol, neither
racemization nor epimerization was detected during the
synthesis, which allows a specific access of all stereoiso-
mers. The reaction sequence appears to be general and
should also be applicable to other hydroxy acid–amino al-
cohol combinations allowing the preparation of large a-
hydroxy-2-oxazoline libraries. The capability of such
compounds to serve as ligands in asymmetric catalysis
was demonstrated in the enantioselective phenyl transfer
to an aromatic aldehyde from a mixture of BPh3 and ZnEt2
in the presence of DiMPEG, which afforded an optically
active diarylmethanol. Although the enantioselectivity in
this process remained moderate (35% ee), improvements
are expected to result from ligand optimizations and an
extensive library screening.
129.2, 130.3, 130.8 (aryl), 169.9 (CO), 170.7 (CO).
(S)-O-Acetylmandelic Acid Chloride [(S)-7]18
Yield: 31.9 g (100%); yellow oil; [a]20D +183.2 (c 1.94 in CHCl3).
1H NMR (300 MHz, CDCl3): d = 2.21 (s, 3 H, CH3), 6.08 (s, 1 H,
CH), 7.38–7.53 (m, 5 H, Har).
13C NMR (75 MHz, CDCl3): d = 20.4 (CH3), 80.9 (CH), 128.4,
129.2, 130.3, 130.8 (aryl), 169.9 (CO), 170.8 (CO).
Condensation of Acid Chlorides 7 with Amino Alcohols to Give
Amides 8; General Procedure
In a flame-dried, round-bottom Schlenk flask under an inert atmo-
sphere of argon, the appropriate amino alcohol (50 mmol, 1.0 equiv)
and Et3N (10.12 g, 100 mmol, 2.0 equiv) were dissolved in CH2Cl2
(80 mL). The mixture was cooled to 0 °C and a solution of O-acetyl-
mandelic acid chloride (7) (10.63 g, 50 mmol, 1.0 equiv) in anhyd
CH2Cl2 (70 mL) was added dropwise over 10 min. The resulting re-
action mixture was allowed to warm to r.t., stirred for 17 h and then
washed with aq HCl (1 M; 2 × 100 mL). The combined aq phases
were extracted with CH2Cl2 (100 mL) and the combined organic
layers washed with sat. aq NaCl (2 × 100 mL). Drying (MgSO4) fol-
lowed by removal of the solvent in vacuo afforded 8 as crude prod-
uct. Pure 8 was obtained by recrystallization.
Air sensitive manipulations were carried out under an inert atmo-
sphere of Ar using standard Schlenk techniques. Triphenyl borane
and diethylzinc were donated by Bayer AG and Crompton Corp.
(previously Witco), respectively. D-valine, L-tert-leucine, D-phe-
nylglycine were provided by Degussa AG. Toluene was distilled
from sodium–benzophenone ketyl radical, and CH2Cl2 from calci-
um hydride prior to use. EtOAc, petroleum ether (PE, boiling frac-
tion 40–70 °C), pentane, and Et2O for column chromatograpy were
distilled before use. MeOH was HPLC grade and was used as re-
ceived. 1H and 13C NMR spectra were recorded on a Varian Gemini
300 spectrometer (300 and 75 MHz, respectively) and on a Varian
Inova 400 spectrometer (400 and 100 MHz, respectively). IR spec-
tra were measured on a Perkin-Elmer PE 1760 FT instrument as
KBr pellets or neat (in the case of liquid compounds); absorptions
are given in wavenumbers (cm–1). MS spectra were recorded on a
Varian MAT 212 or on a Finnigan MAT 95 spectrometer with EI
ionization. Optical rotation measurements were conducted at r.t.
with a Perkin-Elmer PE 241 polarimeter at a wavelength of 589 nm.
HPLC measurements were performed on a Dionex HPLC system
(previously Gynkotek) with autosampler Gina 50, UV-detector
UVD 170S, degasser DG 503 and gradient pump M480G. The
HPLC columns with chiral stationary phases were from Chiral
Technologies. Elemental analyses were performed using a Heraeus
CHN-O-Rapid instrument. Mps were measured in open capillaries
with a Buechi B-540 apparatus and are uncorrected. All experi-
ments were conducted at least twice to ensure reproducibilty.
(R,R)-O-Acetylmandelic Acid (1-Hydroxymethyl-2-methyl)pro-
pylamide [(R,R)-8a]
Prepared starting from (R)-7 and (R)-valinol (5.19 g, 50 mmol, 1.0
equiv). Purification by recrystallization from Et2O furnished pure
(R,R)-8a.
Yield: 8.36 g (30 mmol, 60%); white solid; mp 91–92 °C; [a]20
–41.4 (c 0.82 in CHCl3).
D
IR (KBr): 1052, 1238, 1563, 1663, 1747, 2962, 3284 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.88 (d, 3 H, J = 6.8 Hz, CH3),
0.93 (d, 3 H, J = 6.8 Hz, CH3), 1.90 (sept, 1 H, J = 6.8 Hz, CH), 2.17
(s, 3 H, CH3), 2.92 (br s, 1 H, OH), 3.56–3.73 (m, 3 H, CH2CH),
6.06 (s, 1 H, CH), 6.57–6.61 (m, 1 H, NH), 7.32–7.48 (m, 5 H, Har).
13C NMR (75 MHz, CDCl3): d = 18.9 (CH3), 19.6 (CH3), 21.0
(CH3), 29.0 (CH), 56.9 (CH), 62.9 (CH2), 75.8 (CH), 127.4, 128.8,
129.0, 135.6 (aryl), 169.0 (CO), 169.5 (CO).
MS (EI, 70 eV): m/z = 280 (M+ + 1), 149, 130, 108, 107, 77, 69.
Anal. Calcd for C15H21NO4: C, 64.50; H, 7.58; N, 5.01. Found: C,
64.70; H, 7.59; N, 5.21.
(S,R)-O-Acetylmandelic Acid (1-Hydroxymethyl-2-methyl)pro-
pylamide [(S,R)-8a]
Prepared starting from (S)-7 and (R)-valinol (5.19 g, 50 mmol, 1.0
equiv). Purification by recrystallization from Et2O furnished pure
(S,R)-8a.
O-Acetylmandelic Acid Chloride (7); General Procedure
Yield: 8.62 g (31 mmol, 62%); white solid; mp 88–89 °C;
In a flame-dried, round-bottomed flask (R)- or (S)-mandelic acid
(22.82 g, 0.15 mol) was dissolved in acetyl chloride (175 mL). After
stirring the solution at r.t. for 2 h, the excess of acetyl chloride was
removed under high vacuum to give 6. Thionyl chloride (100 mL)
was added to the oily residue. The resulting solution was stirred and
heated at reflux for an additional 3 h. After this time, the reaction
mixture was cooled to r.t., and excess thionyl chloride was removed
under high vacuum, to furnish pure O-acetyl mandelic acid chloride
(7) which was successively been used without further purification.
[a]20D +118.6 (c 1.00 in CHCl3).
IR (KBr): 1068, 1238, 1373, 1549, 1655, 1734, 3300, 3471 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.80 (d, 3 H, J = 6.8 Hz, CH3),
0.88 (d, 3 H, J = 6.8 Hz, CH3), 1.84 (sept, 1 H, J = 6.8 Hz, CH), 2.17
(s, 3 H, CH3), 3.59–3.78 (m, 3 H, CH2CH), 6.05 (s, 1 H, CH), 6.44
(br s, 1 H, NH), 7.32–7.40 (m, 3 H, Har), 7.42–7.50 (m, 2 H, Har).
13C NMR (75 MHz, CDCl3): d = 18.6 (CH3), 19.6 (CH3), 21.0
(CH3), 29.0 (CH), 56.9 (CH), 63.2 (CH2), 75.8 (CH), 127.6, 128.8,
129.1, 135.4, (aryl) 169.2 (CO), 169.8 (CO).
(R)-O-Acetylmandelic Acid Chloride [(R)-7]18
Yield: 31.9 g (100%); yellow oil; [a]20D –184.0 (c 1.96 in CHCl3).
MS (EI, 70 eV): m/z = 279 (M+), 149, 130, 108, 107, 91, 77, 69.
1H NMR (400 MHz, CDCl3): d = 2.20 (s, 3 H, CH3), 6.08 (s, 1 H,
CH), 7.37–7.52 (m, 5 H, Har).
Anal. Calcd for C15H21NO4: C, 64.50; H, 7.58; N, 5.01. Found: C,
64.15; H, 7.37; N, 4.99.
Synthesis 2004, No. 13, 2173–2180 © Thieme Stuttgart · New York

PAPER
Chiral Ligands from Mandelic Acid: The Asymmetric Phenyl Transfer Reaction to an Aldehyde
2177
(R,S)-O-Acetylmandelic Acid (1-Hydroxymethyl-2,2-dimeth-
yl)propylamide [(R,S)-8b]
(S,R)-O-Acetylmandelic Acid (2-Hydroxymethyl-1-phenyl)eth-
ylamide [(S,R)-8c]
Prepared starting from (R)-7 and (S)-tert-leucinol (5.86 g, 50 mmol,
1.0 equiv). Purification by recrystallization from EtOAc furnished
pure (R,S)-8b.
Prepared starting from (S)-7 and (R)-phenylglycinol (6.86 g, 50
mmol, 1.0 equiv). Purification by recrystallization from Et2O fur-
nished pure (S,R)-8c.
Yield: 11.44 g (39 mmol, 78%); white solid; mp 151–152 °C;
Yield: 9.24 g (29.5 mmol, 59%); white solid; mp 123–124 °C;
[a]20D –84.1 (c 0.84 in CHCl3).
[a]20D +31.5 (c 1.00 in CHCl3).
IR (KBr): 1052, 1233, 1370, 1576, 1659, 1742, 2968, 3079, 3297
cm–1.
1H NMR (400 MHz, CDCl3): d = 0.84 (s, 9 H, CH3), 2.17 (s, 3 H,
CH3), 2.83 (br s, 1 H, OH), 3.52–3.60 (m, 1 H, CH), 3.77–3.87 (m,
2 H, CH2), 6.07 (s, 1 H, CH), 6.47–6.51 (m, 1 H, NH), 7.32–7.37
(m, 3 H, Har) 7.46–7.52 (m, 2 H, Har).
13C NMR (100 MHz, CDCl3): d = 21.1 (CH3), 26.9 (CH3), 33.9
(Cq), 59.4 (CH), 62.3 (CH2), 76.0 (CH), 127.6, 128.8, 129.1, 135.4
(aryl), 169.3 (CO), 170.0 (CO).
IR (KBr): 1074, 1241, 1372, 1540, 1661, 1725, 3337, 3548 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.14 (s, 3 H, CH3), 2.75 (br s, 1 H,
OH), 3.75–3.84 (m, 2 H, CH2), 5.00–5.06 (m, 1 H, CH), 6.07 (s, 1
H, CH), 6.96–7.02 (m, 1 H, NH), 7.10–7.15 (m, 2 H, Har), 7.26–7.32
(m, 3 H, Har), 7.32–7.37 (m, 3 H, Har), 7.40–7.47 (m, 2 H, Har).
13C NMR (100 MHz, CDCl3): d = 20.9 (CH3), 55.3 (CH), 65.7
(CH2) 75.5 (CH), 126.3, 127.4, 127.6, 128.5, 128.6, 128.9, 135.0,
138.4 (aryl), 168.5 (CO), 169.5 (CO).
MS (EI, 70 eV): m/z = 314 (M+ + 1), 282, 255, 254, 226, 164, 91,
77.
MS (EI, 70 eV): m/z = 294 (M+ + 1), 262, 177, 174, 149, 144, 107,
91, 77, 57.
Anal. Calcd for C18H19NO4: C, 68.99; H, 6.11; N, 4.47. Found: C,
68.94; H, 6.24; N, 4.40.
Anal. Calcd for C16H23NO4: C, 65.51; H, 7.90; N, 4.77. Found: C,
65.41; H, 7.95; N, 4.74.
Formation of the Oxazoline Ring; General Procedure
Method A
(S,S)-O-Acetylmandelic Acid (1-Hydroxymethyl-2,2-dimeth-
yl)propylamide [(S,S)-8b]
Prepared starting from (S)-7 and (S)-tert-leucinol (5.86 g, 50 mmol,
1.0 equiv). Purification by recrystallization from Et2O furnished
pure (S,S)-8b.
In a flame-dried, round-bottomed Schlenk flask under an inert at-
mosphere of argon, the appropriate O-acetylmandelic acid amide 8
(10.0 mmol) was dissolved in a mixture of anhyd CH2Cl2–Et3N
(3:1; 160 mL). To this solution, DMAP (0.122 g, 1.0 mmol, 0.1
equiv) was added, and the reaction mixture was cooled to 0 °C. Sub-
sequently, mesyl chloride (3.44 g, 30 mmol, 3.0 equiv), dissolved in
anhyd CH2Cl2 (10 mL), was added dropwise, and the reaction was
stirred at r.t. overnight. The solvent was then removed by rotary
evaporation and replaced by a mixture of EtOAc and H2O (4:1; 150
mL). The aq phase was extracted with EtOAc (150 mL), and the
combined organic layers were washed with H2O (2 × 150 mL). Af-
ter drying (MgSO4), removal of the solvent in vacuo afforded crude
9 as a yellow-brown oil.
Yield: 9.33 g (32 mmol, 64%); white solid; mp 93–94 °C;
[a]20D +46.4 (c 1.00 in CHCl3).
IR (KBr): 1050, 1229, 1373, 1560, 1661, 1749, 2959, 3337, 3444
cm–1.
1H NMR (400 MHz, CDCl3): d = 0.93 (s, 9 H, CH3), 2.20 (s, 3 H,
CH3), 2.45 (br s, 1 H, OH), 3.53–3.62 (m, 1 H, CH), 3.75–3.84 (m,
2 H, CH2), 6.10 (s, 1 H, CH), 6.43 (br s, 1 H, NH), 7.32–7.41 (m, 3
H, Har), 7.42–7.48 (m, 2 H, Har).
13C NMR (100 MHz, CDCl3): d = 21.0 (CH3), 26.7 (CH3), 33.8
(Cq), 59.2 (CH), 62.4 (CH2), 75.8 (CH), 127.1, 128.6, 128.8, 135.4
(aryl), 169.0 (CO), 169.0 (CO).
Method B
In a flame-dried, round-bottomed Schlenk flask under an inert at-
mosphere of argon, the appropriate O-acetylmandelic acid amide 8
(10.0 mmol) was dissolved in anhyd CH2Cl2 (100 mL). The solution
was cooled to –78 °C and diethylaminosulfur trifluoride (DAST)
was added dropwise (1.44 mL, 11.0 mmol, 1.1 equiv) over 5 min.
After the addition, the reaction mixture was stirred at –78 °C for 1
h. Then, K2CO3 (2.07 g, 15 mmol, 1.5 equiv) was added in one por-
tion and the reaction was allowed to warm to r.t. Subsequently, the
reaction mixture was poured into sat. aq NaHCO3 (200 mL) and the
organic layer was collected. The aq layer was extracted once more
with CH2Cl2 (200 mL) and the combined organic layers were dried
(MgSO4). Removal of the solvent in vacuo afforded crude 9 as a
brown or yellow oil.
MS (EI, 70 eV): m/z = 278, 262, 177, 149, 144, 118, 107, 86, 77, 57.
Anal. Calcd for C16H23NO4: C, 65.51; H, 7.90; N, 4.77. Found: C,
65.67; H, 7.92; N, 4.65.
(R,R)-O-Acetylmandelic Acid (2-Hydroxymethyl-1-phenyl)eth-
ylamide [(R,R)-8c]
Prepared starting from (R)-7 and (R)-phenylglycinol (6.86 g, 50
mmol, 1.0 equiv). Purification by recrystallization from Et2O fur-
nished pure (R,R)-8c.
Yield: 9.49 g (30.5 mmol, 61%); white solid; mp 126–127 °C;
[a]20D –107.0 (c 1.00 in CHCl3).
IR (KBr): 1030, 1249, 1294, 1375, 1557, 1705, 3325, 3469 cm–1.
(R,R)-2-Acetoxyphenylmethyl-4-isopropyl-4,5-dihydro-ox-
azole [(R,R)-9a]
According to method B, the title compound was prepared starting
from (R,R)-8a (2.79 g, 10.0 mmol). Purification by flash column
chromatography (EtOAc–PE, 1:2) afforded pure (R,R)-9a.
Yield: 1.86 g (7.1 mmol, 71%); colorless oil; [a]20D +71.7 (c 0.47 in
CHCl3).
1H NMR (400 MHz, CDCl3): d = 2.15 (s, 3 H, CH3), 2.67 (br s, 1 H,
OH), 3.78–3.82 (m, 2 H, CH2), 5.02 (dt, 1 H, J = 4.7, 7.3 Hz, CH),
6.10 (s, 1 H, CH), 7.01–7.18 (m, 1 H, NH), 7.20–7.44 (m, 10 H, Har).
13C NMR (100 MHz, CDCl3): d = 20.9 (CH3), 55.3 (CH), 65.7
(CH2), 75.5 (CH), 126.4, 127.1, 127.6, 128.6, 128.8, 135.1, 138.4,
(aryl), 168.5 (CO), 169.2 (CO).
IR (neat): 1044, 1230, 1372, 1673, 1747, 2962 cm–1.
MS (EI, 70 eV): m/z = 314 (M+ + 1), 282, 223, 194, 165, 164, 149,
107, 91, 77.
1H NMR (300 MHz, CDCl3): d = 0.84 (d, 3 H, J = 6.8 Hz, CH3),
0.90 (d, 3 H, J = 6.8 Hz, CH3), 1.77 (dsept, 1 H, J = 1.1, 6.8 Hz,
CH), 2.18 (s, 3 H, CH3), 3.93–4.07 (m, 2 H, CH2), 4.21 (dd, 1 H,
J = 7.7, 9.4 Hz, CH), 6.28 (s, 1 H, CH), 7.31–7.42 (m, 3 H, Har),
7.45–7.53 (m, 2 H, Har).
Anal. Calcd for C18H19NO4: C, 68.99; H, 6.11; N, 4.47 Found: C,
68.63; H, 6.18; N, 4.41.
Synthesis 2004, No. 13, 2173–2180 © Thieme Stuttgart · New York

2178
C. Bolm et al.
PAPER
13C NMR (100 MHz, CDCl3): d = 17.8 (CH3), 18.5 (CH3), 20.9
(CH3), 32.4 (CH), 70.6 (CH), 70.9 (CH), 71.8 (CH2), 127.6, 128.7,
129.0, 135.3 (aryl), 163.8 (NCO), 169.8 (CO).
13C NMR (100 MHz, CDCl3): d = 20.9 (CH3), 25.6 (CH3), 33.8
(Cq), 69.4 (CH), 70.9 (CH), 75.4 (CH2), 127.4, 128.4, 128.8, 135.0
(aryl), 163.5 (NCO), 169.6 (CO).
MS (EI, 70 eV): m/z = 261 (M+), 218, 176, 158, 149, 107, 91, 77.
MS (EI, 70 eV): m/z = 275 (M+), 176, 159, 105, 77, 57.
Anal. Calcd for C15H19NO3: C, 68.94; H, 7.33; N, 5.36. Found: C,
68.60; H, 7.38; N, 5.30.
HRMS (EI): m/z calcd for C16H21NO3: 275.15214; found:
275.15213.
(S,R)-2-Acetoxyphenylmethyl-4-isopropyl-4,5-dihydro-oxazole
[(S,R)-9a]
(R,R)-2-Acetoxyphenylmethyl-4-phenyl-4,5-dihydro-oxazole
[(R,R)-9c]
According to method B, the title compound was prepared starting
from (S,R)-8a (2.79 g, 10.0 mmol). Purification by flash column
chromatography (EtOAc–PE, 1:2) afforded pure (S,R)-9a.
According to method B, the title compound was prepared starting
from (R,R)-8c (3.13 g, 10 mmol). Purification by flash column chro-
matography (EtOAc–PE, 1:2) afforded (R,R)-9c.
Yield: 1.46 g (5.6 mmol, 56%); colorless oil; [a]20D +89.1 (c 2.12 in
CHCl3).
Yield: 1.61 g (6.5 mmol, 65%); yellow oil; [a]20D –31.3 (c 0.78 in
CHCl3).
IR (neat): 1043, 1231, 1372, 1677, 1747, 2962, 3340 cm–1.
IR (neat): 1045, 1229, 1373, 1672, 1748, 3032, 2903 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.83 (d, 3 H, J = 6.9 Hz, CH3),
0.93 (d, 3 H, J = 6.9 Hz, CH3), 1.84 (dsept, 1 H, J = 1.1, 6.9 Hz,
CH), 2.17 (s, 3 H, CH3), 3.93–4.01 (m, 2 H, CH2), 4.18–4.31 (m, 1
H, CH), 6.29 (s, 1 H, CH), 7.32–7.41 (m, 3 H, Har), 7.47–7.53 (m, 2
H, Har).
13C NMR (100 MHz, CDCl3): d = 17.6, 18.8 (CH3), 21.0 (CH3),
32.1 (CH), 70.1 (CH2), 70.9 (CH), 71.8 (CH), 127.4, 128.4, 128.8,
135.3 (aryl), 163.5 (NCO), 169.6 (CO).
1H NMR (300 MHz, CDCl3): d = 2.20 (s, 3 H, CH3), 4.08 (t, 1 H,
J = 8.4 Hz, CH2), 4.66 (dd, 1 H, J = 8.4, 10.1 Hz, CH2), 5.18–5.27
(m, 1 H, CH), 6.37 (s, 1 H, CH), 7.14–7.46 (m, 8 H, Har), 7.53–7.61
(m, 2 H, Har).
13C NMR (75 MHz, CDCl3): d = 21.0 (CH3), 69.6 (CH), 71.0 (CH),
75.4 (CH2), 126.7, 127.6, 127.7, 128.7, 128.8, 129.2, 135.2, 141.7
(aryl), 165.4 (NCO), 170.0 (CO).
MS (EI, 70 eV): m/z = 295 (M+), 280, 252, 236, 174, 118, 91, 77.
MS (EI, 70 eV): m/z = 261 (M+), 246, 218, 176, 158, 105, 91, 77.
Anal. Calcd for C18H17NO3: C, 73.20; H, 5.80; N, 4.74. Found: C,
72.94; H, 6.00; N, 4.67.
Anal. Calcd for C15H19NO3: C, 68.94; H, 7.33; N, 5.36. Found: C,
68.84; H, 7.19; N, 5.69.
(S,R)-2-Acetoxyphenylmethyl-4-phenyl-4,5-dihydro-oxazole
[(S,R)-9c]
According to method B, the title compound was prepared starting
from (S,R)-8c (3.13 g, 10 mmol). Purification by flash column chro-
matography (EtOAc–PE, 1:2) afforded (S,R)-9c.
(R,S)-2-Acetoxyphenylmethyl-4-tert-butyl-4,5-dihydro-oxazole
[(R,R)-9b]
According to method A, the title compound was prepared starting
from (R,S)-8b (2.93 g, 10.0 mmol). Purification by flash column
chromatography (EtOAc–PE, 2:3 + 5% Et3N) afforded pure (R,S)-
9b.
Yield: 1.71 g (6.2 mol, 62%); yellow oil; [a]20D –94.0 (c 1.01 in
CHCl3).
IR (neat): 1046, 1230, 1570, 1678, 1748, 2957 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.88 (s, 9 H, CH3), 2.15 (s, 3 H,
CH3), 3.88 (ddd, 1 H, J = 1.1, 8.3, 10.1 Hz, CH), 4.03 (t, 1 H, J = 8.3
Hz, CH2), 4.20 (dd, 1 H, J = 8.7, 10.1 Hz, CH2), 6.30 (s, 1 H, CH),
7.29–7.41 (m, 3 H, Har), 7.45–7.54 (m, 2 H, Har).
13C NMR (75 MHz, CDCl3): d = 21.0 (CH3), 25.9 (CH3), 33.8 (Cq),
69.2 (CH), 71.1 (CH), 75.7 (CH2), 127.6, 128.6, 129.0, 135.6 (aryl)
163.5 (NCO), 169.8 (CO).
Yield: 1.89 g (6.4 mmol, 64%); white solid; mp 113–114 °C;
[a]20D +134.3 (c 1.03 in CHCl3).
IR (KBr): 1047, 1182, 1233, 1371, 1676, 1741, 2969, 3460 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.19 (s, 3 H, CH3), 4.07 (t, 1 H,
J = 8.4 Hz, CH2), 4.65 (dd, 1 H, J = 8.4, 10.3 Hz, CH2), 5.17–5.25
(m, 1 H, CH), 6.35 (s, 1 H, CH), 7.15–7.21 (m, 2 H, Har), 7.23–7.47
(m, 6 H, Har), 7.53–7.60 (m, 2 H, Har).
13C NMR (100 MHz, CDCl3): d = 20.9 (CH3), 69.5 (CH), 70.9
(CH), 75.3 (CH2), 126.5, 127.4, 127.5, 128.5, 128.6, 129.0, 135.0,
141.5 (aryl), 165.1 (NCO), 169.7 (CO).
MS (EI, 70 eV): m/z = 295 (M+), 280, 252, 236, 175, 118, 105, 91,
77.
MS (EI, 70 eV): m/z = 275 (M+), 218, 176, 159, 105, 77.
Anal. Calcd for C18H17NO3: C, 73.20; H, 5.80; N, 4.74. Found: C,
72.86; H, 5.94; N, 4.61.
HRMS (EI): m/z calcd for C16H21NO3: 275.15214; found:
275.15209.
a-Hydroxy-2-oxazolines 2; General Procedure
(S,S)-2-Acetoxyphenylmethyl-4-tert-butyl-4,5-dihydro-oxazole
[(S,S)-9b]
According to method A, the title compound was prepared starting
from (S,S)-8b (2.93 g, 10 mmol). Purification by flash column chro-
matography (EtOAc–PE, 4:5) afforded (S,S)-9b.
Yield: 1.85 g (6.7 mmol, 67%); pale yellow oil; [a]20D +6.0 (c 1.07
in CHCl3).
In a round-bottomed flask, the appropriate acetoxyoxazoline 9 (5.0
mmol) was dissolved in MeOH (30 mL). The solution was cooled
to 0 °C and aq LiOH solution (1 M; 15 mL, 3.0 equiv) was added
dropwise. The reaction mixture was stirred at 0 °C for 3 h and al-
lowed to warm to r.t. The mixture was then extracted with CH2Cl2
(2 × 50 mL), and the combined organic layers were washed with sat.
aq NaCl (2 × 50 mL). After drying (MgSO4) and evaporation of the
solvent crude a-hydroxy-2-oxazoline 2 was obtained as a yellow
solid or oil. Recrystallization afforded pure product.
IR (neat): 1048, 1232, 1678, 1747, 2956 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.84 (s, 9 H, CH3), 2.18 (s, 3 H,
CH3), 3.90 (dd, J = 9.9, 7.4 Hz, 1 H, CH), 4.11–4.18 (m, 2 H, CH2),
6.29 (s, 1 H, CH), 7.32–7.42 (m, 3 H, Har), 7.46–7.52 (m, 2 H, Har).
(R,R)-2-Hydroxyphenylmethyl-4-isopropyl-4,5-dihydro-
oxazole [(R,R)-2a]
Prepared starting from (R,R)-9a (1.31 g, 5.0 mmol). Recrystalliza-
tion from EtOAc gave pure (R,R)-2a.
Synthesis 2004, No. 13, 2173–2180 © Thieme Stuttgart · New York

PAPER
Chiral Ligands from Mandelic Acid: The Asymmetric Phenyl Transfer Reaction to an Aldehyde
2179
Yield: 898 mg (4.1 mmol, 82%); white crystalline solid; mp 73–
13C NMR (100 MHz, CDCl3): d = 25.9 (CH3), 33.8 (Cq), 69.7 (CH),
74 °C; [a]20D +7.4 (c 1.00 in CHCl3).
70.6 (CH2), 74.8 (CH), 126.6, 128.3, 128.5, 139.2 (aryl), 168.3
(NCO).
IR (KBr): 1089, 1200, 1266, 1673, 1741, 2909, 3174 cm–1.
MS (EI, 70 eV): m/z = 234, 233 (M+), 177, 146, 107, 91, 77.
1H NMR (300 MHz, CDCl3): d = 0.86 (d, 3 H, J = 6.7 Hz, CH3),
0.94 (d, 3 H, J = 6.7 Hz, CH3), 1.74 (sept, 1 H, J = 6.7 Hz, CH),
3.78–3.88 (m, 1 H, CH), 4.05 (t, 1 H, J = 8.5 Hz, CH2), 4.25 (dd, 1
H, J = 8.5, 9.6 Hz, CH2), 4.57 (br s, 1 H, OH), 5.32 (s, 1 H, CH),
7.27–7.40 (m, 3 H, Har), 7.42–7.49 (m, 2 H, Har).
13C NMR (75 MHz, CDCl3): d = 18.1 (CH3), 18.7 (CH3), 32.5 (CH),
69.7 (CH), 71.2 (CH), 71.8 (CH2), 126.7, 128.3, 128.5, 139.3 (aryl),
168.5 (NCO).
Anal. Calcd for C14H19NO2: C, 72.07; H, 8.21; N, 6.00. Found: C,
71.80; H, 7.88; N, 6.00.
(R,R)-2-Hydroxyphenylmethyl-4-phenyl-4,5-dihydro-oxazole
[(R,R)-2c]
Prepared starting from (R,R)-9c (1.48 g, 5.0 mmol). Recrystalliza-
tion from EtOAc gave pure (R,R)-2c.
Yield: 997 mg (3.9 mmol, 79% yield); white crystalline solid; mp
MS (EI, 70 eV): m/z = 219 (M+), 176, 146, 107, 91, 77.
108–109 °C; [a]20D –29.1 (c 1.01 in CHCl3).
Anal. Calcd for C13H17NO2: C, 71.21; H, 7.81; N, 6.39. Found: C,
71.03; H, 7.82; N, 6.36.
IR (KBr): 1080, 1177, 1454, 1664, 2871, 2967, 3138, 3390 cm–1.
1H NMR (400 MHz, CDCl3): d = 4.20 (t, 1 H, J = 8.7 Hz, CH2),
4.60 (dd, 1 H, J = 8.7, 10.0 Hz, CH2), 4.95 (br s, 1 H, OH), 5.09–
5.17 (m, 1 H, CH), 5.14 (s, 1 H, CH), 7.21–7.27 (m, 2 H, Har), 7.29–
7.41 (m, 6 H, Har), 7.42–7.47 (m, 2 H, Har).
13C NMR (100 MHz, CDCl3): d = 68.6 (CH), 69.4 (CH), 75.9
(CH2), 126.5, 126.6, 127.7, 128.2, 128.3, 128.6, 138.8, 141.3 (aryl),
169.8 (NCO).
(S,R)-2-Hydroxyphenylmethyl-4-isopropyl-4,5-dihydro-ox-
azole [(S,R)-2a]
Prepared starting from (S,R)-9a (1.31 g, 5.0 mmol). Recrystalliza-
tion from EtOAc gave pure (S,R)-9a.
Yield: 918 mg (4.2 mmol, 84%); white crystalline solid; mp 85–
86 °C; [a]20D +152.5 (c 0.97 in CHCl3).
IR (KBr): 1090, 1198, 1462, 1670, 2754, 2971, 3148 cm–1.
MS (EI, 70 eV): m/z = 255 (M+), 254, 236, 176, 120, 91, 77.
1H NMR (400 MHz, CDCl3): d = 0.84 (d, 3 H, J = 6.8 Hz, CH3),
0.93 (d, 3 H, J = 6.8 Hz, CH3), 1.74 (sept, 1 H, J = 6.8 Hz, CH),
3.90–4.01 (m, 1 H, CH2), 4.24–4.36 (m, 2 H, CH + OH), 5.26 (s, 1
H, CH), 7.28–7.38 (m, 3 H, Har), 7.41–7.47 (m, 2 H, Har).
13C NMR (100 MHz, CDCl3): d = 18.0 (CH3), 18.7 (CH3), 32.4
(CH), 69.7 (CH), 71.1 (CH), 71.6 (CH2), 126.6, 128.2, 128.3, 139.1
(aryl), 168.2 (NCO).
Anal. Calcd for C16H15NO2: C, 75.87; H, 5.97; N, 5.53. Found: C,
75.67; H, 6.07; N, 5.48.
(S,R)-2-Hydroxyphenylmethyl-4-phenyl-4,5-dihydrooxazole
[(S,R)-2c]
Prepared starting from (S,R)-2c (1.48 g, 5.0 mmol). Recrystalliza-
tion from EtOAc gave pure (S,R)-9c.
Yield: 1.11 g (4.7 mmol, 94%); white crystalline solid; mp 124–
MS (EI, 70 eV): m/z = 219 (M+), 176, 146, 107, 91, 77.
125 °C; [a]20D +175.3 (c 0.99 in CHCl3).
Anal. Calcd for C13H17NO2: C, 71.21; H, 7.81; N, 6.39. Found: C,
71.25; H, 7.86; N, 6.33.
IR (KBr): 1056, 1241, 1455, 1651, 2905, 2970, 3164 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.09 (t, 1 H, J = 8.4 Hz, CH2),
4.25 (br s, 1 H, OH), 4.68 (dd, 1 H, J = 8.4, 10.0 Hz, CH2), 5.15–
5.25 (m, 1 H, CH), 5.35 (s, 1 H, CH), 7.12–7.18 (m, 2 H, Har), 7.23–
7.40 (m, 6 H, Har), 7.43–7.50 (m, 2 H, Har).
13C NMR (75 MHz, CDCl3): d = 68.7 (CH), 69.9 (CH), 74.0 (CH2),
126.5, 126.7, 127.8, 128.5, 128.6, 128.8, 139.2, 141.6 (aryl), 169.9
(NCO).
(R,S)-2-Hydroxyphenylmethyl-4-tert-butyl-4,5-dihydro-ox-
azole [(R,S)-2b]
Prepared starting from (R,S)-9b (1.40 g, 5.0 mmol). Recrystalliza-
tion from EtOAc gave pure (R,S)-2b.
Yield: 769 mg (3.3 mmol, 65%); white solid; mp 123–124 °C;
[a]20D +1.5 (c 0.84 in CHCl3).
1H NMR (400 MHz, CDCl3): d = 0.87 (s, 9 H, CH3), 3.75–3.83 (m,
1 H, CH), 4.11–4.23 (m, 2 H, CH2), 4.49 (br s, 1 H, OH), 5.33 (s, 1
H, CH), 7.27–7.39 (m, 3 H, Har), 7.40–7.48 (m, 2 H, Har).
13C NMR (100 MHz, CDCl3): d = 25.9 (CH3), 33.8 (Cq), 69.7 (CH),
70.5 (CH2), 74.8 (CH), 126.6, 128.3, 128.5, 139.3 (aryl), 168.4
(NCO).
MS (EI, 70 eV): m/z = 255, 254 (M+), 236, 208, 176, 120, 107, 91,
77.
Anal. Calcd for C16H15NO2: C, 75.87; H, 5.97; N, 5.53. Found: C,
75.70; H, 6.03; N, 5.51.
Performed Catalysis; General Procedures
General Procedure A
MS (EI, 70 eV): m/z = 233 (M+), 219, 177, 146, 107, 91, 77.
In a glovebox under inert atmosphere, BPh3 (60 mg, 0.25 mmol)
was sealed in a flame-dried reaction vessel (18 × 50 mm). Toluene
(3 mL) was added, and the resulting solution was treated with ZnEt2
(110 mL, 1.075 mmol). After stirring for 15 min at r.t., a-hydroxy-
2-oxazoline 2 (0.025 mmol) was added as toluene solution (0.5 mL)
and stirring was continued for 30 min. at r.t. The resulting clear so-
lution was cooled to 10 °C, and 4-chlorobenzaldehyde (11) (35 mg,
0.25 mmol) in toluene (0.5 mL) was added in one portion. After
stirring at 10 °C for 12 h, the reaction mixture was quenched with
H2O (10 mL) and extracted with CH2Cl2 (3 × 20 mL). The com-
bined organic layers were dried (MgSO4), and the solvents were re-
moved under reduced pressure. The resulting oil was submitted to
flash chromatography (pentane–Et2O, 85:15) to give pure 12. The
enantiomeric excess was determined by HPLC using a chiral col-
umn [Chiralcel OB-H, 30 °C, 230 nm; heptane–i-PrOH, 90:10; 0.5
mL/min; tR = 25.7 min (R), 33.6 min (S)].
IR (KBr): 1029, 1101, 1411, 1671, 2869, 3195 cm–1.
Anal. Calcd for C14H19NO2: C, 72.07; H, 8.21; N, 6.00. Found: C,
71.95; H, 8.50; N, 5.99.
(S,S)-2-Hydroxyphenylmethyl-4-tert-butyl-4,5-dihydro-ox-
azole [(S,S)-2b]
Prepared starting from (S,S)-9b (1.31 g, 5.0 mmol). Recrystalliza-
tion from EtOAc gave pure (S,S)-9b.
Yield: 718 mg (3.1 mmol, 62%); white solid; mp 104–105 °C;
[a]20D –1.7 (c 1.05 in CHCl3).
IR (KBr): 1089, 1197, 1673, 2957, 3163 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.89 (s, 9 H, CH3), 3.82 (dd, 1 H,
J = 8.0, 9.9 Hz, CH), 4.12–4.24 (m, 3 H, CH2 + OH), 5.32 (s, 1 H,
CH), 7.28–7.39 (m, 3 H, Har), 7.42–7.48 (m, 2 H, Har).
Synthesis 2004, No. 13, 2173–2180 © Thieme Stuttgart · New York

2180
C. Bolm et al.
PAPER
(7) (a) Meguro, K.; Aizawa, M.; Sohda, T.; Kawamatsu, Y.;
General Procedure B
In a glovebox under inert atmosphere, BPh3 (60 mg, 0.25 mmol) and
DiMPEG (M = 2500 g/mol, 63 mg, 0.025 mmol) were sealed in a
flame dried reaction vessel (18 × 50 mm). Toluene (3 mL) was add-
ed, and the resulting mixture was treated with ZnEt2 (110 mL, 1.075
mmol) to give a clear solution containing small amouts of a white
precipitate. After stirring for 15 min at r.t., a-hydroxy-2-oxazoline
2 (0.025 mmol) was added as a toluene solution (0.5 mL) and stir-
ring was continued for 30 min. at r.t. The resulting solution was
cooled to 10 °C, and 4-chlorobenzaldehyde (11) (35 mg, 0.25
mmol) in toluene (0.5 mL) was added in one portion. From here on
the protocol followed general procedure A.
Nagaoka, A. Chem. Pharm. Bull. 1985, 33, 3787. (b) Toda,
F.; Tanaka, K.; Koshiro, K. Tetrahedron: Asymmetry 1991,
2, 873. (c) Stanev, S.; Rakovska, R.; Berova, N.; Snatzke, G.
Tetrahedron: Asymmetry 1995, 6, 183. (d) Botta, M.;
Summa, V.; Corelli, F.; Di Pietro, G.; Lombardi, P.
Tetrahedron: Asymmetry 1996, 7, 1263. (e) See also:
Bolshan, Y.; Chen, C.-Y.; Chilenski, J. R.; Gosselin, F.;
Mathre, D. J.; O’Shea, P. D.; Roy, A.; Tillyer, R. D. Org.
Lett. 2004, 6, 111.
(8) Soai, K.; Kawase, Y.; Oshio, A. J. Chem. Soc., Perkin Trans.
1 1991, 1613.
(9) Dosa, P. I.; Ruble, J. C.; Fu, G. C. J. Org. Chem. 1997, 62,
444.
(10) (a) Huang, W.-S.; Hu, Q.-S.; Pu, L. J. Org. Chem. 1999, 64,
7940. (b) Huang, W.-S.; Pu, L. Tetrahedron Lett. 2000, 41,
145.
(4-Chlorophenyl)phenylmethanol
1H NMR (300 MHz, CDCl3): d = 2.28 (br s, 1 H, OH), 5.80 (s, 1 H,
CH), 7.27–7.36 (m, 9 H, Har).
13C NMR (75 MHz, CDCl3): d = 75.91 (CH), 126.74, 128.08,
128.81, 128.86, 133.48, 142.39, 143.62 (aryl).
(11) (a) Bolm, C.; Muñiz, K. Chem. Commun. 1999, 1295.
(b) Bolm, C.; Hermanns, N.; Hildebrand, J. P.; Muñiz, K.
Angew. Chem. Int. Ed. 2000, 39, 3465. (c) Bolm, C.;
Kesselgruber, M.; Grenz, A.; Hermanns, N.; Hildebrand, J.
P. New J. Chem. 2001, 25, 13. (d) Bolm, C.; Hermanns, N.;
Kesselgruber, M.; Hildebrand, J. P. J. Organomet. Chem.
2001, 624, 157. (e) Bolm, C.; Kesselgruber, M.; Hermanns,
N.; Hildebrand, J. P. Angew. Chem. Int. Ed. 2001, 40, 1488.
(f) For a theoretical study on the competition between phenyl
and ethyl transfer in this reaction, see: Rudolph, J.;
Rasmussen, T.; Bolm, C.; Norrby, P.-O. Angew. Chem. Int.
Ed. 2003, 42, 3002. (g) For a recent application of this
protocol, see: Fontes, M.; Verdaguer, X.; Solà, L.; Pericàs,
M. A.; Riera, A. J. Org. Chem. 2004, 69, 2532.
(12) Bolm, C.; Rudolph, J. J. Am. Chem. Soc. 2002, 124, 14850.
(13) (a) Non-asymmetric: Ueda, M.; Miyaura, N. J. Org. Chem.
2000, 65, 4450. (b) Non-asymmetric: Fürstner, A.; Krause,
H. Adv. Synth. Catal. 2001, 343, 343. (c) Enantioselective:
Sakai, M.; Ueda, M.; Miyaura, N. Angew. Chem. Int. Ed.
1998, 37, 3279.
(14) Oi, S.; Moro, M.; Inoue, Y. Chem. Commun. 1997, 1621.
(15) (a) Oi, S.; Moro, M.; Inoue, Y. Organometallics 2001, 20,
1036. (b) Murata, M.; Shimazaki, R.; Ishikura, M.;
Watanabe, S.; Masuda, Y. Synthesis 2002, 717.
(16) Braga, A. L.; Rubim, R. M.; Schrekker, H. S.; Wessjohann,
L. A.; de Bolster, M. W. G.; Zeni, G.; Sehnem, J. A.
Tetrahedron: Asymmetry 2003, 14, 3291.
(17) Zhang, X.-M.; Zhang, H.-L.; Lin, W.-Q.; Gong, L.-Z.; Mi,
A.-Q.; Cui, X.; Jiang, Y.-Z.; Yu, K.-B. J. Org. Chem. 2003,
68, 6474.
All other analytical data are in agreement with those reported in the
literature.21,22
Acknowledgment
The Fonds der Chemischen Industrie and the Deutsche Forschungs-
gemeinschaft within the SFB 380 and the Graduiertenkolleg 440 are
gratefully acknowledged for financial support. We also thank De-
gussa AG and Bayer AG for the generous gift of chemicals.
References
(1) (a) Noyori, R. Asymmetric Catalysis in Organic Synthesis;
Wiley: New York, 1994. (b) Transition Metals for Organic
Synthesis; Beller, M.; Bolm, C., Eds.; Wiley-VCH:
Weinheim, 1998. (c) Comprehensive Asymmetric Catalysis;
Jacobsen, E. N.; Pfalz, A.; Yamamoto, H., Eds.; Springer:
Berlin, 1999. (d) Catalytic Asymmetric Synthesis, 2nd ed.;
Ojima, I., Ed.; Wiley-VCH: New York, 2000.
(2) Seebach, D.; Hungerbühler, E. In Modern Synthetic
Methods; Scheffold, R., Ed.; Salle and Sauerländer:
Frankfurt, 1980, 91.
(3) Blaser, H. U. Chem. Rev. 1992, 92, 935.
(4) (a) Meyers, A. I.; Gant, T. G. Tetrahedron 1994, 50, 2297.
(b) Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Chemistry; Wiley: New York, 1999.
(5) (a) Bolm, C. Angew. Chem., Int. Ed. Engl. 1991, 30, 542.
(b) Pfalz, A. Acc. Chem. Res. 1993, 26, 339. (c) Meyers, A.
I. J. Heterocycl. Chem. 1998, 35, 991. (d) Ghosh, A. K.;
Mathivanan, P.; Cappiello, J. Tetrahedron: Asymmetry
1998, 9, 1. (e) Johnson, J. S.; Evans, D. A. Acc. Chem. Res.
2000, 33, 325. (f) Braunstein, P.; Naud, F. Angew. Chem.
Int. Ed. 2001, 40, 680.
(6) (a) Soai, K.; Niwa, S. Chem. Rev. 1992, 92, 833. (b) Soai,
K.; Shibata, T. In Comprehensive Asymmetric Catalysis;
Jacobsen, E. N.; Pfalz, A.; Yamamoto, H., Eds.; Springer:
Berlin, 1999, 911. (c) Pu, L.; Yu, H.-B. Chem. Rev. 2001,
101, 757.
(18) (a) Schmidlin, T.; Wallach, D.; Tamm, C. Helv. Chim. Acta
1984, 67, 1998. (b) Babudri, F.; Fiandanese, V.; Marchese,
G.; Punzi, A. Tetrahedron 1999, 55, 2431.
(19) Phillips, A. J.; Uto, Y.; Wipf, P.; Reno, M. J.; Williams, D.
R. Org. Lett. 2000, 2, 1165.
(20) Rudolph, J.; Schmidt, F.; Bolm, C. Adv. Synth. Catal.,
accepted for publication.
(21) Rudolph, J.; Hermanns, N.; Bolm, C. J. Org. Chem. 2004,
69, 3997.
(22) (a) Wu, B.; Mosher, H. S. J. Org. Chem. 1986, 51, 1904.
(b) Lee, J.-S.; Velarde-Ortiz, R.; Guijarro, A.; Wurst, J. R.;
Rieke, R. D. J. Org. Chem. 2000, 65, 5428.
Synthesis 2004, No. 13, 2173–2180 © Thieme Stuttgart · New York