Enantioselective alkylation of aldehydes promoted by (S)-tyrosine-derived β-amino alcohols

Article abstract of DOI:10.1016/S0957-4166(02)00469-X

Two (S)-tyrosine-derived β-amino alcohols exhibiting a secondary and tertiary amino moiety, respectively, were employed in the enantioselective alkylation of aldehydes using diethylzinc. The enantioselectivity, catalytic activity and substrate specificity of these precatalysts were compared by high-throughput screening of benzaldehyde, cyclohexanecarboxaldehyde and hexanal. The homochiral catalysts were found to exhibit opposite chiral induction. The secondary amino alcohol favors the formation of (S)-alcohols, whereas the tertiary amino alcohol provides (R)-alcohols. Enantioselectivity and sense of chiral induction obtained with the secondary amino alcohol was proven to depend on the choice of solvent and experimental procedure. The mechanism of the enantioselective ethylation of benzaldehyde promoted by (S)-tyrosine-derived β-amino alcohols was studied by stoichiometric experiments and MM2 computations.

Full text of DOI:10.1016/S0957-4166(02)00469-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 1733–1741
Enantioselective alkylation of aldehydes promoted by
(S)-tyrosine-derived b-amino alcohols
Christian Wolf,* Christopher J. Francis, Pili A. Hawes and Mirage Shah
Department of Chemistry, Georgetown University, Washington, DC 20057, USA
Received 13 June 2002; accepted 30 July 2002
Abstract—Two (S)-tyrosine-derived b-amino alcohols exhibiting a secondary and tertiary amino moiety, respectively, were
employed in the enantioselective alkylation of aldehydes using diethylzinc. The enantioselectivity, catalytic activity and substrate
specificity of these precatalysts were compared by high-throughput screening of benzaldehyde, cyclohexanecarboxaldehyde and
hexanal. The homochiral catalysts were found to exhibit opposite chiral induction. The secondary amino alcohol favors the
formation of (S)-alcohols, whereas the tertiary amino alcohol provides (R)-alcohols. Enantioselectivity and sense of chiral
induction obtained with the secondary amino alcohol was proven to depend on the choice of solvent and experimental procedure.
The mechanism of the enantioselective ethylation of benzaldehyde promoted by (S)-tyrosine-derived b-amino alcohols was studied
by stoichiometric experiments and MM2 computations. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
catalysts is that the phenol group provides an anchor
remote from the asymmetric center, which might allow
one to covalently attach such a catalyst to a soluble
The enantioselective alkylation of aldehydes promoted
by b-amino alcohols is one of the most important CꢀC
bond forming reactions.1 Due to the slow achiral back-
ground reaction and the ease of operation, a variety of
catalysts that utilize organozinc reagents to produce
chiral secondary alcohols from aldehydes have been
developed in recent years.2 To date, the catalytic perfor-
mance of a number of b-amino alcohols derived from
amino acids has been investigated.3 In general, solvents
such as hexanes, toluene, dichloromethane or diethyl
ether can be used at ambient temperature without
compromising yield and enantioselectivity. Therefore,
the enantioselective alkylation of aldehydes provides an
excellent opportunity for developing soluble nanosize
catalysts for continuous operation in a membrane reac-
tor.4 Thus, advantages of homogeneous catalysis (high
yield, selectivity, reproducibility and catalyst activity
under mild reaction conditions) may be combined with
those of heterogeneous catalysis (simple product isola-
tion and catalyst recycling). Incorporation of a catalyst
into a dendrimer or polymer support requires an addi-
tional functional group within the catalyst for immobi-
lization. An important feature of tyrosine-derived
support
stereoselectivity.
without
decreasing
its
activity
or
To investigate the potential of tyrosine-derived b-amino
alcohols as catalyst precursors for the enantioselective
alkylation of aliphatic and aromatic aldehydes using
diethylzinc, we synthesized (2S)-3-(4-benzyloxyphenyl)-
2-butylamino-1,1-diphenylpropanol, 1, and (2S)-3-(4-
benzyloxyphenyl)-2-dibutylamino-1,1-diphenylpropanol,
2 (Fig. 1). Reductive cleavage of the benzyl group of 1
and 2, respectively, would allow immobilization of the
b-amino alcohol on a suitable dendrimer or polymer
support.
* Corresponding author. Tel.: (+1)-202-687-3468; fax: (+1)-202-687-
6209; e-mail: cw27@georgetown.edu
Figure 1. Structure of tyrosinols 1 and 2.
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00469-X

1734
C. Wolf et al. / Tetrahedron: Asymmetry 13 (2002) 1733–1741
The ability of catalyst precursors 1 and 2 to promote
the enantioselective alkylation of linear and branched
aliphatic as well as aromatic aldehydes with diethylzinc
was investigated. Benzaldehyde, 3, cyclohexanecarbox-
aldehyde, 4, and hexanal, 5, were chosen as representa-
tive substrates that exhibit a wide range of different
reactivity and steric demand (Fig. 2).
benzyltyrosine methyl ester, 12, in 70% overall yield.
Flash chromatography allowed purification of the
amino esters 11 and 12 and recovery of 25% starting
material 10. Amino esters 11 and 12 were converted to
b-amino alcohols 1 and 2, respectively, using phenyl-
magnesium chloride. The Grignard reaction was carried
out under mild reaction conditions to avoid racemiza-
tion.
2. Results and discussion
We have recently reported a high-throughput screening
(HTS) protocol that allows rapid evaluation of enan-
tioselective catalysts.5 Following this procedure, we
determined the enantioselectivity, substrate specificity,
sense of chiral induction and catalytic activity of amino
alcohols 1 and 2 in a single screening experiment using
representative aldehydes 3–5 at room temperature
(Table 1). Each run was performed in a mixture of
diethyl ether and hexanes (1:2) and quenched after 16 h
to allow comparison of catalytic activity and substrate
Both catalyst precursors 1 and 2 were synthesized in
five steps from (S)-tyrosine methyl ester, 9 (Fig. 3). The
use of standard Boc2O protection/deprotection proce-
dures allowed selective benzylation of the phenol
moiety of 9 in high yields. Alkylation of (S)-O-benzyl-
tyrosine methyl ester hydrochloride, 10, using butyl
iodide afforded a 1:1 mixture of (S)-N-butyl-O-benzyl-
tyrosine methyl ester, 11, and (S)-N,N-dibutyl-O-
Figure 2. Enantioselective alkylation of aldehydes 3–5 promoted by precatalysts 1 and 2.
Figure 3. Synthesis of b-amino alcohols 1 and 2.
Table 1. High-throughput screening of precatalysts 1 and 2 using aldehydes 3–5
Run
b-Amino alcohol
Aldehyde
% Yielda
% eeb
Configurationb
1
1
1
2
2
2
1
1
1
2
2
2
3
4
5
3
4
5
\99c
86
96
89
84
59
26
60
22
32
18
(S)
(S)
(S)
(R)
(R)
(R)
88
a Yields are calculated based on GC analysis using naphthalene as the internal standard.
b The enantiomeric excess of alcohols 6–8 was determined by enantioselective GC using octakis(6-O-methyl-2,3-di-O-pentyl)-g-cyclodextrin as the
chiral stationary phase. The elution order of enantiomers of alcohols 6–8 was known from previous studies.5
c No starting material was detected.

C. Wolf et al. / Tetrahedron: Asymmetry 13 (2002) 1733–1741
1735
specificity of b-amino alcohols 1 and 2. Both catalysts
were found to exhibit high activity towards aromatic
and linear aliphatic aldehydes. Employing tyrosinol 1
as the precatalyst gave benzaldehyde, 3, and hexanal, 5,
in almost quantitative yield within 16 h. Slightly lower
yields, i.e. 89 and 88%, were observed for the ethylation
of aldehydes 3 and 5 using precatalyst 2. Both catalysts
afford decreased catalytic activity towards cyclohexane-
carboxaldehyde, 4, which may be attributed to
increased steric hindrance in the transition state. How-
ever, employing amino alcohol 1 and 2, respectively, in
the alkylation of aldehydes with diethylzinc provides
only moderate to good enantioselectivities. Precatalyst
1 affords (S)-1-phenylpropanol, 6, and (S)-3-octanol, 8,
with 59 and 60% ee, whereas (S)-1-cyclohexylpropanol,
7, was obtained in only 26% ee. By contrast, b-amino
alcohol 2 exhibits higher enantioselectivity for branched
aliphatic aldehydes such as 4 than for less sterically
hindered substrates 3 and 5. However, ees observed are
only moderate. A decrease in temperature to 0°C did
not improve enantioselectivities of both catalysts. Nota-
bly, the homochiral tyrosinols afford opposite chiral
induction under the same reaction conditions. The use
of b-amino alcohol 1 favors Si-face attack of diethyl-
zinc on the prochiral aldehyde resulting in formation of
the corresponding (S)-alcohols, whereas 2 affords (R)-
alcohols 6–8. Moreover, the chirality induced by the
catalyst derived from b-amino alcohol 1 was found to
depend significantly on the solvents used. In hexanes,
(S)-6 and (S)-8 were obtained with only 23 and 46%
enantioselectivity, respectively, whereas (R)-7 was pro-
duced in 8% ee. In addition, employing 1 in the enan-
tioselective alkylation of prochiral aldehydes requires
the use of freshly distilled aldehydes since small
amounts of impurities exhibit dramatic effects on the
catalytic performance resulting in reversed chiral induc-
tion. Enantioselectivity and sense of chiral induction of
the alkylation of aldehydes 3–5 was also found to
depend on the experimental procedure. Treatment of a
solution of precatalyst 1 in diethyl ether with diethyl-
zinc prior to addition of the aldehyde mixture resulted
in formation of (S)-alcohols (Table 1). By contrast,
reversal of the addition order, i.e. addition of aldehydes
3–5 prior to addition of diethylzinc, led to formation of
(R)-alcohols with low enantioselectivity. This might be
attributed to the formation of catalytically active enam-
ine derivatives of 4 and 5 that promote the alkylation of
aldehydes 3–6 with opposite enantioselectivity. To
prove this hypothesis we performed an individual
screening experiment in which tyrosinol 1 was treated
with benzaldehyde, 3, at room temperature for 1 h
prior to the addition of diethylzinc at 0°C. Since benz-
aldehyde and b-amino alcohol 1 cannot undergo reac-
tion to form an enamine, the formation of (S)-6 was
still favored, i.e. the observed yield and enantioselectiv-
ity did not depend on the experimental procedure.
Based on the low enantioselectivity and opposite chiral
induction observed with b-amino alcohols 1 and 2, we
decided to verify the HTS results by individual screen-
ing of each aldehyde (Table 2). Again, high catalytic
activity but only moderate to good enantioselectivities
were observed. Yields and enantioselectivities obtained
by simultaneous screening of aldehydes 3–5 using pre-
catalyst 2 are in excellent agreement with individual
screening results. However, tyrosinol 1 showed signifi-
cantly better enantioselectivity for aldehyde 3 in the
absence of aldehydes 4 and 5. Given the sensitivity of
b-amino alcohol 1 to small amounts of impurities and
reaction conditions as described above, the variations in
enantioselectivity observed following different screening
protocols were somehow expected.
The opposite chiral induction observed for the enan-
tioselective alkylation of aldehydes 3–5 prompted us to
further investigate the mechanism of the ethylation of
benzaldehyde promoted by b-amino alcohols 1 and 2.
First, the effect of the stoichiometry of b-amino alco-
hol, benzaldehyde and diethylzinc on reactivity was
examined (Table 3). No sign of reaction was observed
using equimolar amounts of amino alcohol and
diethylzinc (entries 1 and 3). Both precatalysts 1 and 2
require 3 equiv. of organozinc reagent to promote the
alkylation of 2 equiv. of benzaldehyde (entries 2 and 5).
Our findings are in good agreement with similar studies
Table 2. Individual screening results of precatalysts 1 and
2
b-Amino
alcohol
Aldehyde
% Yielda
% eeb Configurationb
1
1
1
2
2
2
3
4
5
3
4
5
97
69
88
85
19
63
22
34
18
(S)
(S)
(S)
(R)
(R)
(R)
\99c
79
90
a Yields are calculated based on GC analysis using naphthalene as the
internal standard.
b The enantiomeric excess of alcohols 6–8 was determined by enan-
tioselective GC using octakis(6-O-methyl-2,3-di-O-pentyl)-g-
cyclodextrin as the chiral stationary phase. The elution order of
enantiomers of alcohols 6–8 was known from previous studies.5
c No starting material was detected.
Table 3. Effect of stoichiometry of b-amino alcohol, aldehyde 3 and diethylzinc on reactivity
Entry
b-Amino alcohol
Ratio (b-amino alcohol/3/Et2Zn)
% Yield
% ee
1
2
3
4
5
1
1
2
2
2
1/2/1
1/2/3
1/2/1
1/2/2
1/2/3
No reaction
94
No reaction
50
92
–
86 (S)
–
28 (R)
31 (R)

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C. Wolf et al. / Tetrahedron: Asymmetry 13 (2002) 1733–1741
and the nucleophilicity of one alkyl group of diethyl-
zinc are increased in the syn(Si) and anti(Re) transition
states.9
reported by Kitamura et al. using of (−)-3-exo-
(dimethylamino)isoborneol as the
precatalyst.1a
Accordingly, the first equivalent of diethylzinc is
required to form the active catalyst, whereas the second
equivalent can undergo reaction with an aldehyde upon
activation. An important atom economical limitation of
the investigated reaction is that only one alkyl group of
diethylzinc can be utilized (compare entries 4 and 5).
Our stoichiometric experiments also show that the pro-
ton of the secondary amine moiety of precatalyst 1 does
Optimization of the favored diastereomeric transition
states by MM2 computations allows rationalization of
chiral induction and selectivity of both tyrosinol-
derived catalysts. Comparison of transition states
derived from 1 reveals that the syn(Si) geometry should
indeed be significantly more stable than the anti(Re)
structure. The latter exhibits enhanced steric repulsion
between aldehyde 3 and both the ethyl group on the
zinc atom in the five-membered ring and the n-butyl
moiety on the ring nitrogen (Fig. 5). The preference
for the syn transition state favors a Si-face attack
on benzaldehyde and thus explains the observed forma-
tion of (S)-1-phenylpropanol with good enantio-
selectivity.
1
not react with diethylzinc. Similarly, H NMR studies
using tyrosinols 1 and 2, respectively, and various
amounts of dimethyl zinc revealed formation of 1
equiv. of methane in both cases. Attempts to elucidate
1
the structure of active catalyst species by H and 13C
NMR spectroscopy were not successful due to the
fluxional behavior of organozinc species in solution.
Recently, the origin of enantioselectivity observed in
b-amino alcohol catalyzed alkylations of aldehydes
using organozinc reagents has been rationalized by
By contrast, transition states derived from tyrosinol 2
are more sterically crowded and do not differ signifi-
cantly in stability. The two n-butyl groups seem to
shield the chiral information of 2 and therefore dimin-
ish chiral induction. Repulsion between the ethyl group
on the five-membered ring zinc atom and the adjacent
n-butyl group on the nitrogen atom should equally
destabilize both transition states. As a consequence of
the overcrowded structure, the syn(Si) geometry is fur-
ther destabilized by repulsive interactions between one
n-butyl group and the adjacent aldehyde moiety. Simi-
larly, the anti(Re) geometry suffers from repulsion
between the adjacent zinc ethyl moiety and the coordi-
nating benzaldehyde (Fig. 6). As a result, the anti(Re)
transition state is slightly preferred, i.e. 2 favors forma-
tion of (R)-1-phenylpropanol with moderate enantio-
selectivity.
computational studies.6 Following
a
qualitative
approach to better understand the opposite chiral
induction obtained with homochiral precatalysts 1 and
2, we optimized the structure of the five-membered
chelate ring that is formed upon reaction of the b-
amino alcohol with 1 equiv. of diethylzinc using MM2
computations. It is assumed that coordination of the
second equivalent of diethylzinc and benzaldehyde, 3,
results in a tricyclic transition state. The geometry of
the four-membered m-oxo ring as well as the approach
of the aldehyde was adapted from computations
reported by Vidal-Ferran and co-workers (Fig. 4).7
It is assumed that the approaching aldehyde preferen-
tially coordinates from the less hindered face of the
five-membered chelate ring.6,7 Thus, aldehyde 3 forms a
m-oxo four-membered ring opposite to the 4-benzyloxy-
benzyl moiety of the chiral amino alcohol. Based on the
geometry of the four-membered ring, one can imagine
two low energy m-oxo transition states exhibiting the
bulky phenyl group of 3 in less crowded positions to
minimize steric repulsion with the ethyl group attached
to the zinc atom in the five-membered ring and the
n-butyl group(s) attached to the nitrogen atom, respec-
tively.8 Thus, both the electrophilicity of the aldehyde
3. Conclusion
Tyrosinols 1 and 2 exhibiting a secondary and tertiary
amino function, respectively, were prepared from (S)-
tyrosine in good overall yields and employed in the
enantioselective alkylation of benzaldehyde, cyclohex-
anecarboxaldehyde, and hexanal using diethylzinc.
High yields but only moderate to good enantioselectiv-
Figure 4. Postulated favored transition states derived from b-amino alcohols 1 and 2.

C. Wolf et al. / Tetrahedron: Asymmetry 13 (2002) 1733–1741
1737
Figure 5. Stereoview of syn(Si) and anti(Re) geometry of transition states derived from precatalyst 1 obtained by MM2
calculations. Hydrogens are omitted for clarity.
ites were obtained with both catalysts following a high-
throughput screening protocol that allows simultaneous
screening of representative substrates. Tyrosinol 1 was
found to promote formation of (S)-alcohols, whereas
tertiary amino alcohol 2 favors (R)-alcohols. However,
precatalyst 1 yielded (R)-alcohols in low ees when hexane
was used as the reaction solvent. Also, addition of
enolizable aldehydes to 1 prior to addition of diethylzinc
was found to induce (R)-configuration. This was
attributed to the formation of enamine derivatives that
exhibit some catalytic activity but opposite chiral induc-
tion than b-amino alcohol 1. Stoichiometric experiments
from 1 and 1 equiv. of diethylzinc favors formation of
a syn(Si) transition state with a second equivalent of
diethylzinc and benzaldehyde 3 to yield (S)-1-phenyl-
propanol with good enantioselectivity. By contrast, the
anti(Re) transition state derived from tyrosinol 2 is
slightly favored over the diastereomeric syn(Si) geome-
try. Accordingly, 2 promotes the formation of (R)-1-
phenylpropanol with low enantioselectivity.
4. Experimental
1
and H NMR experiments revealed that both amino
All chemicals were of reagent grade and were purchased
from Aldrich. Flash chromatography was carried out on
silica gel (Merck Kieselgel 60, particle size 0.032–0.063
mm). NMR spectra were obtained at 300 MHz (1H
NMR) and 75 MHz (13C NMR) on a Varian FT NMR
spectrometer using CDCl3 as the solvent, if not stated
otherwise.
alcohols utilize 1 equiv. of the dialkyl zinc reagent to
form the active catalyst species. The catalyst takes
advantage of only one alkyl moiety of the organozinc
reagent to alkylate the aldehyde, i.e. the atom economy
of this reaction is inherently limited to 50%. MM2
computational analysis suggests that the catalyst derived

1738
C. Wolf et al. / Tetrahedron: Asymmetry 13 (2002) 1733–1741
Figure 6. Stereoview of syn(Si) and anti(Re) geometry of transition states derived from precatalyst 2 obtained by MM2
calculations. Hydrogens are omitted for clarity.
room temperature and quenched with saturated NH4Cl
(5 ml). The aqueous layer was extracted three times
with CH2Cl2. The organic layers were combined
analysed by GC.
4.1. General procedure for the enantioselective alkyla-
tion of aldehydes
To a solution of the catalyst (0.02 mmol, 8 mol%) in
anhydrous diethyl ether (1 ml) was added diethylzinc (1
M in hexanes, 1.1 mmol). After 40 min, the solution
was cooled to 0°C and a mixture of naphthalene and
the aldehyde (0.26 mmol) in hexanes (1 ml) was added
dropwise. The reaction mixture was stirred for 16 h at
4.1.1. GC analysis. Naphthalene, aldehydes 3, 4 or 5 as
well as the enantiomers of the corresponding alcohols
6–8 were separated in one GC run using octakis(6-O-
methyl-2,3-di-O-pentyl)-g-cyclodextrin (60% in OV

C. Wolf et al. / Tetrahedron: Asymmetry 13 (2002) 1733–1741
1739
1701, 30 m) as the chiral stationary phase.10 Tempera-
ture program: 90°C for 5 min, then 7°C/min to 115°C.
Enantioselectivity a: 1.02 (6), 1.02 (7), 1.04 (8). Individ-
ual response factors [area(aldehyde)×mg(standard)/
area(standard)×mg(aldehyde)] were determined for all
three aldehydes by GC analysis of the individual reac-
tion mixtures containing one aldehyde and naphthalene
as the internal standard. Determination of the ratio of
the area of the aldehyde to the area of naphthalene
obtained from a second GC run of the product mixture
containing naphthalene, the remaining aldehyde and
the corresponding chiral alcohol allowed the calculation
of yields. Dilution experiments revealed excellent linear-
ity of aldehyde responses over the concentration range
obtained in reaction and product mixtures. Since the
total area% of side products proved to be less than 2%
in all cases, we were able to calculate chemical yields
based on aldehyde conversion.
was washed with dioxane and dried in vacuo to give
white crystals (7.8 g, 24.3 mmol, 77%). 1H NMR
(DMSO-d6): l=3.13 (m, 2H), 3.67 (s, 3H), 4.24 (t,
J=7.4 Hz, 1H), 5.08 (s, 2H), 6.96 (d, J=8.4 Hz, 2H),
7.13 (d, J=8.4 Hz, 2H), 7.18 (m, 5H), 8.42 (bs, 3H).
13C NMR (DMSO-d6): 35.1, 52.7, 53.5, 69.3, 114.9,
126.7, 127.7, 127.9, 128.5, 130.6, 137.1, 157.5, 169.3.
4.5. Preparation of (S)-N-butyl-O-benzyltyrosine
methyl ester, 11 and (S)-N,N-dibutyl-O-benzyltyrosine
methyl ester, 12
To a solution of (S)-O-benzyltyrosine methyl ester, 10
(4.93 g, 15 mmol) in anhydrous acetonitrile (120 ml)
was added K2CO3 (12.65 g, 90 mmol). The reaction
mixture was heated to 60°C and butyl iodide (5.94 g,
32.3 mmol) was added. The mixture was heated under
reflux for 24 h, acetonitrile was removed under reduced
pressure and the residue was partitioned between
CH2Cl2 and water. The combined organic layers were
dried over MgSO4 and CH2Cl2 was removed in vacuo.
After purification by flash chromatography (CH2Cl2/
EtOAc, 20:1) 11 (1.76 g, 5.15 mmol, 34%) and 12 (2.17
g, 5.4 mmol, 36%) were obtained as light yellow oils.
4.2. Preparation of (S)-N-(tert-butoxycarbonyl)tyrosine
methyl ester
To a solution of (S)-tyrosine methyl ester hydrochlo-
ride, 9 (10.0 g, 43.2 mmol) and NaHCO3 (7.25 g, 86
mmol) in THF/methanol (200 ml/60 ml) was added
di-tert-butyl dicarbonate (9.40 g, 43.2 mmol) dissolved
in THF (20 ml). The solution was stirred at room
temperature for 22 h. The solvents were removed in
vacuo. The residue was dissolved in CH2Cl2, washed
with water and dried over MgSO4. The filtrate was
concentrated under reduced pressure. Recrystallization
of the residue from CH2Cl2 provided white crystals
1
4.5.1. (S)-N-Butyl-O-benzyltyrosine methyl ester, 11. H
NMR: l=0.87 (t, J=7.2 Hz, 3H), 1.29 (m, 2H), 1.39
(m, 2H), 2.46 (m, 1H), 2.56 (m, 1H), 2.89 (m, 2H), 3.47
(t, J=9.0 Hz, 1H), 3.63 (s, 3H), 5.04 (s, 2H), 6.89 (d,
J=8.5 Hz, 2H), 7.09 (d, J=8.5 Hz, 2H), 7.4 (m, 5H).
13C NMR: 13.9, 20.3, 32.1, 38.8, 47.8, 51.5, 63.2, 69.8,
114.6, 127.2, 127.7, 128.3, 129.3, 129.9, 136.8, 157.3,
174.8.
1
(12.5 g, 42.3 mmol, 98%). H NMR: l=1.42 (s, 9H),
3.08 (m, 2H), 3.71 (s, 3H), 4.59 (m, 1H), 5.00 (bs, 1H),
5.10 (bs, 1H), 6.76 (d, J=8.4, 2H), 6.98 (d, J=8.4, 2H).
13C NMR: 28.4, 37.6, 52.3, 54.6, 80.2, 115.4, 127.2,
130.2, 155.0, 155.2, 172.5.
4.5.2. (S)-N,N-Dibutyl-O-benzyltyrosine methyl ester,
1
12. H NMR: l=0.88 (t, J=7.2 Hz, 6H), 1.32 (m, 8H),
2.43 (m, 2H), 2.62 (m, 2H), 2.77 (dd, J=7.0 Hz,
J=12.4 Hz, 1H), 3.00 (dd, J=9.0 Hz, J=12.4 Hz, 1H),
3.53 (dd, J=7.0 Hz, J=9.0 Hz, 1H), 3.60 (s, 3H), 5.03
(s, 2H), 6.88 (d, J=8.7 Hz, 2H), 7.10 (d, J=8.7 Hz,
2H), 7.38 (m, 5H). 13C NMR: 14.2, 20.4, 30.9, 35.2,
50.9, 65.4, 69.9, 114.4, 127.3, 127.7, 128.4, 130.0, 131.0,
137.0, 157.0, 172.9.
4.3. Preparation of (S)-N-(tert-butoxycarbonyl)-O-ben-
zyltyrosine methyl ester
To a solution of (S)-N-(tert-butoxycarbonyl)tyrosine
methyl ester (10.19 g, 34.5 mmol) dissolved in acetone
(30 ml) was added K2CO3 (5.32 g, 38 mmol) and benzyl
bromide (4.68 ml, 39.4 mmol). The reaction mixture
was heated to reflux for 6 h. Acetone was removed and
the residue was partitioned between CH2Cl2 and 5%
NaOH. The combined organic layers were dried over
MgSO4 and CH2Cl2 was evaporated. Purification by
flash chromatography (CH2Cl2) yielded white crystals
4.6. Preparation of (2S)-3-(4-benzyloxyphenyl)-2-butyl-
amino-1,1-diphenylpropanol, 1
(S)-N-Butyl-O-benzyltyrosine methyl ester, 11 (300 mg,
0.88 mmol) was dissolved in anhydrous THF (3 ml)
under a nitrogen atmosphere. A solution of PhMgCl (2
M in hexanes 1.8 ml, 3.6 mmol) was added dropwise at
0°C. The mixture was stirred for 4 h at 0°C and then
quenched with saturated aqueous NH4Cl at 0°C. The
mixture was extracted with CH2Cl2. The combined
organic layers were dried over MgSO4, and CH2Cl2 was
removed. Flash chromatography (CH2Cl2/EA/TEA,
200:1:1) gave light yellow crystals (190 mg, 0.41 mmol,
1
(12.5 g, 32.4 mmol, 94%). H NMR: l=1.42 (s, 9H),
3.03 (m, 2H), 3.71 (s, 3H), 4.54 (m, 1H), 4.97 (bs, 1H),
5.04 (s, 2H), 6.90 (d, J=8.7, 2H), 7.04 (d, J=8.7 Hz,
2H), 7.40 (m, 5H). 13C NMR: 28.3, 37.5, 52.2, 54.5,
69.9, 79.8, 114.8, 127.3, 127.8, 128.1, 128.4, 130.1,
136.8, 154.9, 157.7, 172.2.
1
4.4. Preparation of (S)-O-benzyltyrosine methyl ester
hydrochloride, 10
46.6%). H NMR: l=0.60 (t, J=6.9 Hz, 3H), 0.93 (m,
4H), 2.83 (m, 1H), 2.97 (m, 1H), 2.23 (dd, J=10.6 Hz,
J=14.5 Hz, 1H), 2.81 (dd, J=3.1 Hz, J=14.5 Hz, 1H),
3.81 (dd, J=3.1 Hz, J=10.6 Hz, 1H), 5.04 (s, 2H), 6.90
(d, J=8.7 Hz, 2H), 7.08 (d, J=8.7 Hz, 2H), 7.16 (dd,
J=8.5 Hz, J=8.5 Hz, 2H), 7.38 (m, 9H), 7.61 (dd,
(S)-N-(tert-Butoxycarbonyl)-O-benzyltyrosine methyl
ester (12.1 g, 31.5 mmol) was dissolved in 4 M HCl in
dioxane (130 ml) and stirred for 2 h. The precipitate

1740
C. Wolf et al. / Tetrahedron: Asymmetry 13 (2002) 1733–1741
J=1.5 Hz, J=8.4 Hz, 2H), 7.70 (dd, J=1.5 Hz, J=8.4
Hz, 2H). 13C NMR: 14.4, 20.4, 32.8, 37.5, 49.9, 66.8,
70.7, 115.5, 126.2, 126.5, 126.8, 127.0, 128.0, 128.4,
128.5, 128.6, 129.0, 130.3, 132.3, 137.5, 145.7, 148.3,
157.8. Anal. calcd for C32H35NO2: C, 82.54; H, 7.58; N,
3.01. Found: C, 82.39; H, 7.37; N, 3.00%.
Tetrahedron: Asymmetry 1993, 4, 1473–1474; (j) Cho, B.
T.; Kim, N. Tetrahedron Lett. 1994, 35, 4115–4118; (k)
Cho, B. T.; Kim, N. Synth. Commun. 1996, 26, 855–
865; (l) Soai, K.; Hayase, T.; Takai, K.; Sugiyama, T.
J. Org. Chem. 1994, 59, 7908–7909; (m) Cho, B. T.;
Kim, N. Synth. Commun. 1996, 26, 2273–2280; (n) Cho,
B. T.; Kim, N. J. Chem. Soc., Perkin Trans. 1 1996,
2901–2907; (o) Cho, B. T.; Chun, Y. S. Tetrahedron:
Asymmetry 1998, 25, 1489–1492; (p) Reddy, K. S.;
Sola`, L.; Moyano, M. A.; Perica`s, M. A.; Riera, A. J.
Org. Chem. 1999, 64, 3969–3974; (q) Dangel, B. D.;
Polt, R. Org. Lett. 2000, 2, 3003–3006; (r) Okamoto,
K.; Kimachi, T.; Ibuka, T.; Takemoto, Y. Tetrahedron:
Asymmetry 2001, 12, 463–467; (s) Panev, S.; Linden,
A.; Dimitrov, V. Tetrahedron: Asymmetry 2001, 12,
1313–1321; (t) Superchi, S.; Mecca, T.; Giorgio, E.;
Rosini, C. Tetrahedron: Asymmetry 2001, 12, 1235–
1239; (u) Bastin, S.; Agbossou-Niedercorn, F.; Brocard,
J.; Pelinski, L. Tetrahedron: Asymmetry 2001, 12, 2399–
2408; (v) Liu, D. X.; Zhang, L. C.; Wang, Q.; Da, C.
S.; Xin, Z. Q.; Wang, R.; Choi, M. C. K.; Chan, A. S.
C. Org. Lett. 2001, 3, 2733–2735; (w) Sato, I.; Urabe,
H.; Ishii, S.; Tanji, S.; Soai, K. Org. Lett. 2001, 3,
3851–3854; (x) Le Goanvic, D.; Holler, M.; Pale, P.
Tetrahedron: Asymmetry 2002, 13, 119–121; (y) Priego,
J.; Mancheno, O. G.; Cabrera, S.; Carretero, J. C. J.
Org. Chem. 2002, 67, 1346–1353; (z) Ruzziconi, R.;
Piermatti, O.; Ricci, G.; Vinci, D. Synlett 2002, 747–
750.
4.7. Preparation of (2S)-3-(4-benzyloxyphenyl)-2-
dibutylamino-1,1-diphenylpropanol, 2
A solution of PhMgCl (2 M in hexanes, 1.0 ml, 2.0
mmol) was added dropwise to (S)-N,N-dibutyl-O-ben-
zyltyrosine methyl ester, 12 (300 mg, 0.76 mmol) in
anhydrous THF (3 ml) at 0°C under a nitrogen atmo-
sphere. The solution was stirred for 5 h. Following the
work-up procedure described for 1, purification of the
residue by flash chromatography (CH2Cl2/EA/TEA,
400:2:2) afforded a white oil (220 mg, 0.42 mmol, 56%).
1H NMR: l=0.77 (t, J=7.2 Hz, 6H), 1.06 (m, 4H),
1.22 (m, 2H), 1.40 (m, 2H), 2.04 (m, 4H), 2.77 (dd,
J=12.4 Hz, J=15.9 Hz, 1H), 3.06 (dd, J=1.3 Hz,
J=15.91 Hz, 1H), 3.94 (dd, J=1.3 Hz, J=12.4 Hz,
1H), 5.04 (s, 2H), 6.18 (s, 1H), 6.88 (d, J=8.8 Hz, 2H),
7.11 (d, J=8.8 Hz, 2H), 7.35 (m, 11H), 7.56 (d, J=8.4
Hz, 4H). 13C NMR: 14.1, 20.4, 31.9, 33.4, 52.7, 70.0,
71.4, 114.7, 126.6, 127.1, 127.3, 127.6, 127.8, 128.0,
128.4, 129.9, 136.9, 144.2, 145.8, 157.0. Anal. calcd for
C36H43NO2: C, 82.87; H, 8.31; N, 2.68. Found: C,
82.94; H, 7.99; N, 2.93%.
3. (a) Soai, K.; Ookawa, A.; Ogawa, K.; Kaba, T. J.
Chem. Soc., Chem. Commun. 1987, 467–468; (b) Soai,
K.; Ookawa, A.; Kaba, T.; Ogawa, K. J. Am. Chem.
Soc. 1987, 109, 7111–7115; (c) Soai, K.; Niwa, S.
Chem. Lett. 1989, 481–484; (d) Soai, K.; Watanabe, M.;
Koyano, M. J. Chem. Soc., Chem. Commun. 1989, 534–
536; (e) Itsuno, S.; Sakurai, Y.; Ito, K.; Maruyama, T.;
Nakahama, S.; Fre´chet, J. M. J. J. Org. Chem. 1990,
55, 304–310; (f) Soai, K.; Watanabe, M.; Yamamoto,
A.; Yamashita, T. J. Mol. Catal. 1991, 64, L27–L30;
(g) Delair, P.; Einhorn, C.; Einhorn, J.; Luche, J. L.
Tetrahedron 1995, 51, 165–172; (h) Liu, G.; Ellman, J.
A. J. Org. Chem. 1995, 60, 7712–7713; (i) Beliczey, J.;
Giffels, G.; Kragl, U.; Wandrey, C. Tetrahedron: Asym-
metry 1997, 8, 1529–1539; (j) Prasad, K. R. K.; Joshi,
N. N. J. Org. Chem. 1997, 62, 3770–3771; (k) Kossen-
jans, M.; Pennemann, H.; Martens, J.; Juanes, O.;
Rodr´ıguez-Ubis, J. C.; Brunet, E. Tetrahedron: Asym-
metry 1998, 9, 4123–4125; (l) Sola`, L.; Reddy, K. S.;
Vidal-Ferran, A.; Moyano, A.; Perica`s, M. A.; Riera,
A.; Alvarez-Larena, A.; Piniella, J.-F. J. Org. Chem.
1998, 63, 7078–7082; (m) Yang, X.; Shen, J.; Da, C.;
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Acknowledgements
C.J.F. and M.S. gratefully acknowledge support from
the Georgetown Undergraduate Research Opportuni-
ties Program (GUROP). C.W. thanks Georgetown Uni-
versity for a Summer Academic Grant.
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