Phenylalanine derivatives as catalysts in the enantioselective addition of diethylzinc to benzaldehydes

Article abstract of DOI:10.1016/S0957-4166(03)00497-X

A series of mono and bis β-amino alcohols derived from phenylalanine were synthesised and their application as chiral catalysts in the asymmetric ethylation of aromatic aldehydes in the presence of diethylzinc investigated.

Full text of DOI:10.1016/S0957-4166(03)00497-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 2369–2380
Phenylalanine derivatives as catalysts in the enantioselective
addition of diethylzinc to benzaldehydes
Ruxandra D. Ionescu,a,* Anna Blomb and Torbjo¨rn Frejdb
aHahnemann Pharmacology, Drexel University, Philadelphia, PA 19102, USA
bDepartment of Organic and Bioorganic Chemistry, Lund University, PO Box 124, 221 00 Lund, Sweden
Received 2 May 2003; accepted 17 June 2003
Abstract—A series of mono and bis b-amino alcohols derived from phenylalanine were synthesised and their application as chiral
catalysts in the asymmetric ethylation of aromatic aldehydes in the presence of diethylzinc investigated.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
One of the most common asymmetric reactions studied
is that of diethylzinc addition to benzaldehydes. Among
the numerous chiral catalysts developed1–5 for the
asymmetric organozinc additions, b-amino alcohols
hold a prominent position.5,6 Our group has been inter-
ested in the synthesis and properties of non-natural
derivatives of phenylalanine (Phe) such as phenyl-
trisalanine (Pta) and phenylbisalanine (Pba, Fig. 1).7–10
In this work, we aimed to determine the efficiency of
chiral catalysts of mono-, bis- and tris-b-amino alcohols
derived from phenylalanine. It was interesting to find
out what effect the presence of several arms in the
ligand had on the reaction.
The synthesis of the catalysts was easily accomplished
(Scheme 1) following a general procedure based on the
alkylation of free terminal amino groups with diverse
alkyl halides in DMF at 80°C to give the N,N%-disubsti-
tuted compounds in 30–73% yields after purification by
chromatography. The b-amino alcohols were then
obtained after reduction with LiAlH4 in 30–91% yields
(Scheme 1, for details, see Section 4). The starting
material for the tris-armed catalyst was 1,7 while the
isophthalic aldehyde served as a starting material for
the bis-armed analogues. The mono-armed catalysts
were derived from commercially available (S)-phenyl-
alanine methyl ester.
With the chiral catalysts in hand, the catalysis effect
was tested with benzaldehyde as the substrate using
standard conditions. The reaction was carried out in
dry toluene in the presence of the chiral catalyst at
room temperature, for 24 h. The reaction was quenched
with 5% aqueous HCl and the product isolated by
extraction and purified by chromatography over silica
gel. The ee was determined by HPLC analysis using a
chiral stationary phase.
The first test was performed with ligand 3a. As this
failed to give any product, despite the use of different
reaction conditions (solvents, temperature, reaction
time), it was assumed that this ligand formed a complex
with the metal such as the one proposed in Figure 2.
The structure of the diethylzinc–catalyst complex is
Figure 1. Phenyltrisalanine (Pta) and phenylbisalanine (Pba).
* Corresponding author. E-mail: ruxandra.d.ionescu@drexel.edu
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00497-X

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Scheme 1. Reagents and conditions: (i) RX, DMF, 80°C, 30–73%; (ii) LiAlH4, THF, 0°C to rt, 30–91%.
Figure 2. The standard diethylzinc-catalyst complex (left) and the proposed structure for the diethylzinc–3a complex (right).
usually described as depicted in Figure 2 (left).11 In our
case, we assume that the complex between 3a and
diethylzinc is as shown in Figure 2 (right). As all three
OH groups can coordinate to the Zn, there is no place
left for the aldehyde to coordinate.
As the results obtained with chiral ligands 6a and 8a
were the best ones, we decided to tune these structures
in order to improve their performance. The first
attempt was the introduction of diarylhydroxymethyl.
Due to the enhanced stereoselectivity in catalytic reac-
tions, this group has been called the ‘magic group’ in
catalyst design and has frequently been used in recent
years.6,13 Inspired by this, catalyst 9 (Scheme 2) was
synthesised in 61% yield by reacting 2a with PhLi at
0°C in THF. This catalyst was used in the addition
reaction, but the presence of the diarylhydroxymethyl
groups had a negative effect on the enantioselectivity as
only ca. 7% ee was obtained. It was speculated that this
was due to the effect of racemisation of the chiral
catalyst during the reaction conditions employed in the
synthesis. An NMR experiment was performed, where
the substrate was titrated with PhLi. The assumption
made was that if racemisation took place, the a-hydro-
gen of the substrate would be removed during the
course of the reaction. However, this was not observed
on the NMR spectra collected at different time inter-
vals; only the disappearance of the OMe-signal was
detected.
We know from previous coordination studies with Pta12
that a 1:1 complex forms where the metal ion is placed
on top of the aromatic ring, therefore we assume that the
same type of complex also forms in this case. NMR
studies were undertaken, but only the disappearance of
the protons of the OH groups was detected with no shift
changes. No crystals of the complex could be formed
either.
The ees obtained with the bis- and mono-armed catalysts
were promising, namely 65% (76% yield) for 6a and 68%
(51% yield) for 8a (Table 1). In the initial attempts to
improve the results, the order of addition of the reagents
was investigated. We discovered that the best ee and yield
values were obtained when benzaldehyde was added to
a solution containing the chiral catalyst and Et2Zn. The
other two ligand types, 6b–c and 8b–c, bearing different
substitution patterns, gave poor results (Table 1).

R. D. Ionescu et al. / Tetrahedron: Asymmetry 14 (2003) 2369–2380
2371
Table 1. Enantioselectivity induced by 6a–c and 8a–c in the addition of Et2Zn to benzaldehyde, initial studies
reaction was studied. Initially, a methyl substituent was
successively introduced in the ortho, meta and para
position. However catalyst 6d gave only 16% ee and 47%
yield (Table 2). Catalyst 6e gave a better ee (55%) and
a better yield (83%) while the best ee (70%) in this series
was obtained with catalyst 6f with a 78% yield. Catalyst
6g, bearing a Ph-substituent in the ortho-position, gave
54% ee. We tried out a different catalyst system, catalyst
6h, but this only gave 19% ee (Table 2).
A plausible explanation to the poor result obtained with
this catalyst may be the presence of too many phenyl
groups. In this case, steric interactions would be signifi-
cant factors controlling the outcome of the reaction.
The next attempts were concentrated on the substitution
pattern on the terminal nitrogens. Thus, phenyl rings
bearing different substitution patterns were attached to
these terminal nitrogens and their effect on the addition

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As previously mentioned, our goal was to investigate
the effect of multiple arms in Phe derivatives on the
reactivity and enantioselectivity of the chiral catalysts.
The intention was to determine what the active complex
looked like. We thought that by titrating 6a with Et2Zn
we might be able to determine the stoichiometry of the
active catalyst complex. However, during the performed
NMR titration, only the disappearance of the proton of
the OH group was observed upon addition of 1 equiv.
of Et2Zn. No shift changes were observed, not even
with increased amounts of titrant. Despite our efforts,
no crystals of the catalyst–Et2Zn complex were
obtained.
Scheme 2. Reagents and conditions: (i) PhLi, THF, 0°C to rt,
12 h, 61%.
An autocatalysis test was also carried out in order to
determine whether the chiral alcohol formed as product
was itself acting as a chiral catalyst. When (R)-1-
phenyl-1-propanol was used to catalyse the Et2Zn addi-
tion to p-chlorobenzaldehyde, chosen as substrate as we
wanted to be able to differentiate between the catalyst
and the formed product, no product was isolated, thus
the alcohol did not function as a chiral catalyst.
The same trend was observed with the mono-armed
catalysts, 20% ee with 8d, 67% ee with 8e and 72% ee
with 8f (Table 3). The yields of the reaction also
followed the same tendency as with the bis-armed cata-
lysts with 82% for 8d, 98% for 8e and 69% for 8f.
When the biphenyl analogue 8g was tried, it resulted in
54% ee and 64% yield, which is comparable to 6g. As
for catalyst 8h, 29% ee was obtained and 65% yield,
which was more than with the bis-armed catalyst.
3. Conclusions
The results obtained with both bis- and mono-armed
catalyst systems did not seem to follow any particular
pattern. As the best results were obtained with the
para-substituted catalysts, it was tempting to assume
that the methyl substituent positioned in the ortho-posi-
tion invoked steric hindrance in the proximity of the
reaction centre. When moving this group further from
the reaction centre, both the ee and the yield increased.
When introducing a Ph-substituent in the ortho-posi-
tion in catalysts 6g and 8g, the ees were better than in
the ortho-methyl substituent cases. An explanation to
this result is that the two phenyl rings of the biphenyl
group were placed perpendicular to each other, thus an
arrangement that did not disturb the reaction centre as
much.
A new series of chiral ligands based on Phe were
synthesised and used as catalysts in the addition reac-
tion of Et2Zn to benzaldehydes. In these reactions,
modest to good ee and yield values were obtained. The
catalysts that proved the most effective in this type of
reaction were those carrying a methyl substituent in the
para position of the phenyl on the terminal nitrogen.
We conclude from our studies that catalysts with C3-
symmetry do not function in this type of reaction and
that there is no significant difference between the results
obtained with the mono- and bis-armed catalysts. It is
probable that only one of the arms in the bis-armed
catalysts is involved in the reaction. Further develop-
ment of this type of catalyst derived from Phe and their
use as ligands in other catalytic reactions is in process
in our laboratory.
As chiral ligands 6f and 8f gave the best results, they
were used as catalysts in the enantioselective addition
to two other types of benzaldehydes, namely p-
chlorobenzaldehyde and p-anisaldehyde. For p-
chlorobenzaldehyde, the bis-armed catalyst 6f gave 69%
ee and 53% yield (Table 4). The mono-armed catalyst 8f
gave a slightly lower ee value, 61% and lower yield,
35% (Table 4). Both catalysts gave modest ees in the
addition reaction to p-anisaldehyde, 16% in both cases,
with slightly higher yields for the bis-armed catalyst,
31% versus 24%. These results were not unexpected
since in the case of the p-anisaldehyde, the methoxy
group placed in the para-position donates electrons to
the carbonyl carbon of the aldehyde functionality
through an inductive effect. The carbonyl carbon is
thus rendered less electrophilic and less prone to react
with a nucleophile (the ethylzinc reagent). This phe-
nomenon accounts for the lower ee and yields obtained
with this type of aldehyde. The chloro-substituent how-
ever has the reverse effect, thus the results should be
better with this type of aldehyde.
4. Experimental
4.1. General procedures
NMR spectra were recorded on a Bruker DRX 300 and
a Bruker DRX 400 instrument in CDCl3 or CD3OD, at
20°C. For H experiments, residual CHCl3 or MeOH at
1
l 7.27 and 3.31, respectively, were used as internal
standards, while the central peak of the CDCl3 triplet at
l 77.0 and the central peak of the CD3OD septet at l
49.5 were used for the 13C experiments. COSY spectra
were run for compounds with complicated coupling
patterns in order to determine the identity of the differ-
ent protons. IR spectra were recorded on a Shimadzu
8300 FTIR Instrument. Melting points were taken with
a Gallenkamp melting point microscope and are uncor-
rected. Precoated Merck silica gel 60 F254 plates were
used for TLC analyses and retention values (TLC Rf)
are given in the same solvent as used in the respective

R. D. Ionescu et al. / Tetrahedron: Asymmetry 14 (2003) 2369–2380
2373
Table 2. Enantioselectivity induced by 6d–h by addition of Et2Zn to benzaldehyde
chromatography unless otherwise stated. The TLC
plates were visualised under UV followed by spray-
prepared according to literature.15 The (S,S)-Et-
DuPHOS catalyst was available from Strem Chemi-
cals. (S)-Phenylalanine methyl ester was purchased
from Aldrich.
ing with
a
KMnO4 solution14 followed by
heating. {Rh(COD)[(S,S)-Et-DuPHOS]}+OTf− was

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R. D. Ionescu et al. / Tetrahedron: Asymmetry 14 (2003) 2369–2380
Table 3. Enantioselectivity induced by 8d–h in the addition of Et2Zn to benzaldehyde
Compound 1 was synthesised as previously described.7
Compound 8a was purchased from NSC Technologies
(a division of the NutraSweet Co.). Compound 8b and
8c were synthesised following the same procedure as for
the other compounds. The spectral data were in agree-
ment with literature values.16–18 Optical rotations were
measured with a Perkin–Elmer 241 LC polarimeter at
20°C. Freshly distilled benzaldehyde was used and tolu-
,
ene was dried over molecular sieves (4 A). HPLC
analyses were performed on a Chiralcel OD-H column
(0.46 cm×25 cm, 5 mm particle size) with n-hexane and
iPrOH as eluents.

R. D. Ionescu et al. / Tetrahedron: Asymmetry 14 (2003) 2369–2380
2375
Table 4. Enantioselectivity induced by 6f and 8f in the addition of Et2Zn to aldehydes
Entry
L*a
Aldehyde
Time (h)
Yield (%)b
Ee (%)c
Config.d
1
2
3
4
6f
8f
6f
8f
p-Chlorobenzaldehyde
p-Chlorobenzaldehyde
p-Anisaldehyde
24
24
24
24
53
35
31
24
69
61
16
16
R
R
R
R
p-Anisaldehyde
a The reactions were carried out in toluene at room temperature in the presence of 5 mol% catalyst.
b Based on isolated compound.
c Determined using a Chiralcel OD-H column and eluting with hexane/iPrOH (95:5) at the flow rate of 0.5 mL/min.
d Assigned according to the tR of the HPLC analysis.
4.2. General procedure for alkylation of the free amino
acid methyl ester compounds
substrate, 500 mg (0.92 mmol) was dissolved in 1:1
mixture of MeOH/EtOAc (50 mL) and the solution was
purged with N2 for 30 min. The catalyst (7 mmol) was
added and the mixture was hydrogenated at 40 psi at
room temperature overnight. The product, 47 mg (94%)
was obtained as an oil. [h]2D1=+30 (c 1.6, CHCl3); IR (w
cm−1): 3346.3, 3033.8, 1718.5; 1H NMR (400 MHz;
CDCl3): l 7.34 (br s, 10H), 7.21–7.16 (m, 1H), 6.99 (d,
1H, J=1.6 Hz), 6.97 (d, 1H, J=1.5 Hz), 6.85 (br s,
1H), 5.25 (d, 2H, J=7.9 Hz), 5.09 (s, 4H), 4.64 (q, 2H,
J=7.0 Hz), 3.69 (s, 6H), 3.06 (t, 4H, J=5.2 Hz); 13C
NMR (100 MHz; CDCl3): l 171.8, 155.6, 136.1, 130.3,
128.8, 128.5, 128.1, 66.9, 54.7, 52.3, 38.1; HRMS
(FAB+Na+): m/z calculated for C30H32N2O8Na
571.2056. Found 571.2056[M+Na].
Hu¨nig’s base (4.6 mmol) was added to a DMF solution
(5 mL) of free amine (1.0 mmol) and the mixture stirred
for 5 min at room temperature. The alkyl halide (4.6
mmol) was added and the stirring continued at reflux
temperature for 18 h. After cooling to ambient temper-
ature, the solvent was removed under reduced pressure.
The remains were redissolved in a minute amount of
EtOAc and purified by chromatography (SiO2, heptane/
EtOAc, 4:1).
4.2.1.
(S,S,S)-2-Dibenzylamino-3-[3,5-bis-(2-dibenzyl-
amino-2-hydroxypropyl)-phenyl]-propanoic acid methyl
ester 2. Following the general procedure for alkylation,
from 83 mg (0.21 mmol) of 1, 120 mg (45%) of product
were isolated as a colourless oil. IR (w cm−1): 3024.2,
The product obtained in the previous step was submit-
ted to hydrogenation with Pd/C as catalyst. The sub-
strate, 0.29 g (0.54 mmol) was dissolved in MeOH (25
mL) and the catalyst (50 mg, 0.3 mmol) added. The
slurry was hydrogenated at 1 atm, room temperature,
overnight. The title compound was obtained, 130 mg
(88%), as an oil after filtration through Celite. [h]2D1=
+28 (c 1.6, CHCl3); IR (w cm−1): 3301.9, 2922.0, 1735.8;
1H NMR (400 MHz; CDCl3): l 7.27 (s, 1H), 7.10 (d,
3H, J=7.6 Hz), 3.83–3.78 (m, 2H), 3.75 (s, 6H), 3.15–
2.86 (dd, 4H, J=13.7, 7.6 Hz); 13C NMR (100 MHz;
CDCl3): l 175.2, 137.4, 130.2, 128.7, 127.7, 55.6, 51.9,
40.8; HRMS (FAB+H+): m/z calculated for
C14H23N2O4 281.1502. Found 281.1502 [M+H].
1
2947.0, 2839.0, 1728.1; H NMR (400 MHz, CDCl3): l
7.23–7.16 (m, 30H), 6.52 (s, 3H), 3.90 (d, 6H, J=14
Hz), 3.60 (s, 9H), 3.54 (s, 3H, J=13.9 Hz), 3.02–2.82
(m, 6H); 13C NMR (100 MHz, CDCl3): l 172.7, 139.3,
137.8, 128.6, 128.1, 127.9, 62.4, 54.5, 50.9, 35.5; HRMS
(FAB+Na+) m/z calculated for C60H63N3O6Na
944.4610. Found 944.4595 [M+Na].
4.2.2.
(S,S)-2-Amino-3-[3-{(-2-amino-2-methoxycar-
bonyl)-ethenyl}-phenyl]-acrylic acid methyl ester 4. The
didehydroamino acid was synthesised as described10
from 0.50 g (3.73 mmol) of isophtalic aldehyde, using
N-benzyloxycarbonyl-2-(dimethoxyphosphinyl)-glycine
methyl ester19 as phosphonate. The product, 790 mg
(35%), was obtained as a white powder after chro-
matography (SiO2, heptane/EtOAc 2:3, Rf 0.4) and
recrystallisation from EtOAc/heptane. Mp 151.8–
4.2.3.
(S,S)-2-Dibenzylamino-3-[3-(2-dibenzylamino-2-
methoxycarbonyl-ethyl)-phenyl]-propionic acid methyl
ester 5a. Following the general procedure for alkyla-
tion, from 100 mg (0.36 mmol) of 4, 70 mg (30%) of 5a
were isolated as a colourless oil. IR (w cm−1): 2949.0,
1
153.6°C; IR (w cm−1): 3276.8, 1733.9, 1701.1, 1500.5; H
NMR (400 MHz; CDCl3): l 7.67 (s, 1H), 7.46 (s, 1H),
7.32 (br s, 11H), 6.31 (br s, 2H), 5.09 (s, 4H), 3.82 (s,
6H); 13C NMR (100 MHz; CDCl3): l 165.5, 135.8,
134.1, 130.4 (br s), 128.8, 128.5 (br), 128.3, 124.7, 67.6,
52.7; HRMS (FAB+Na+): m/z calculated for
C30H28N2O8Na 567.1746. Found 567.1734 [M+Na].
1
1732.0; H NMR (CDCl3): l 7.27 (m, 20H), 7.15 (d,
1H, J=7.6 Hz), 6.94 (d, 2H, J=7.6 Hz), 6.69 (s, 1H),
3.98 (d, 4H, J=14 Hz), 3.74 (s, 6H), 3.67 (d, 2H, J=7.6
Hz), 3.60 (d, 4H, J=14 Hz), 3.04 (m, 4H); 13C NMR
(100 MHz, CDCl3): l 172.7, 139.2, 127.9, 130.4, 128.6,
128.1, 127.9, 127.3, 126.8, 62.4, 54.9, 51.0, 35.6; HRMS
(FAB-H+) m/z calculated for C42H43N2O4 639.3222.
Found 639.3230 [M−H].
The didehydroamino acid obtained in the previous step
was submitted to asymmetric hydrogenation with
{Rh(COD)[(S,S)-Et-DuPHOS]}+OTf− as catalyst. The

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R. D. Ionescu et al. / Tetrahedron: Asymmetry 14 (2003) 2369–2380
4.2.4.
(S,S)-2-(2,6-Dioxo-piperidin-1-yl)-3-{3-[2-(2,6-
3.79–3.66 (m, 6H), 3.22–2.94 (m, 4H), 2.25 (s, 12H);
13C NMR (75.5 MHz, CDCl3): l 172.4, 138.0, 137.2,
136.5, 130.3, 130.2, 130.1, 129.9, 129.8, 127.9, 127.6,
127.4, 127.1, 126.8, 125.9, 125.5, 62.8, 52.4, 50.9,
34.9, 19.0; HRMS (FAB+H+) m/z calculated for
C46H53N2O4 697.4006. Found 697.4007 [M+H].
dioxopiperidin-1-yl)-2-methoxycarbonyl-ethyl]-phenyl}-
propionic acid methyl ester 5b. To a solution of 4 (150
mg, 0.52 mmol) in CH2Cl2 (300 mL) at 0°C was
added portion wise glutaric anhydride (70 mg, 0.58
mmol). The solution was then refluxed for 6 h, after
which acetyl chloride (2 mL) was added and the
reflux maintained for an additional 24 h. The solution
was allowed to reach room temperature and the sol-
vent removed under reduced pressure. Water (4 mL)
and CH2Cl2 (4 mL) were added to the crude product.
Saturated K2CO3 was added until neutralisation. The
aqueous phase was extracted with CH2Cl2 (3×4 mL).
The combined organic layers were dried over Na2SO4
and the solvent removed under reduced pressure. The
crude was chromatographed (SiO2, heptane/EtOAc,
1:9, Rf 0.3) to give 5b (150 mg, 61%). IR (w cm−1):
4.2.8. (S,S)-2-[Bis-(4-methyl-benzyl)-amino]-3-(3-{2-[bis-
(4-methyl-benzyl)-amino]-2-methoxycarbonyl-ethyl}-
phenyl)-propionic acid methyl ester 5f. Following the
general procedure of alkylation, from 90 mg (0.29
mmol) of 4, 110 mg (52%) of 5f were isolated as a
1
colourless oil. IR (w cm−1): 2964.4, 1734.9; H NMR
(300 MHz, CDCl3): l 7.32–7.11 (m, 17H), 6.91 (dd,
2H, J=1.5, 7.1 Hz), 6.63 (s, 1H), 3.92 (d, 4H, J=
20.2 Hz), 3.75 (s, 6H), 3.79–3.66 (m, 6H), 3.22–2.94
(m, 4H), 2.25 (s, 12H); 13C NMR (75.5 MHz,
CDCl3): l 172.4, 138.0, 137.2, 136.5, 130.3, 130.2,
130.1, 129.9, 129.8, 127.9, 127.6, 127.4, 127.1, 126.8,
125.9, 125.5, 62.8, 52.4, 50.9, 34.9, 19.0; HRMS
(FAB+H+) m/z calculated for C46H53N2O4 697.4006.
Found 697.4007 [M+H].
1
2951.8, 1731.0, 1678.9; H NMR (400 MHz, CDCl3):
l 7.14 (m, 1H), 6.97 (m, 2H), 6.85 (s, 1H), 5.56 (q,
2H, J=5.2, 5.4 Hz), 3.37 (s, 6H), 3.42 (m, 2H), 3.22
(m, 2H), 2.53 (m, 8H), 1,76 (m, 4H); 13C NMR (100
MHz, CDCl3): l 172.0, 169.9, 137.3, 130.5, 128.2,
127.6, 53.0, 52.5, 34.2, 32.5, 16.8; HRMS (FAB+Na+)
m/z calculated for C24H30N2O8Na 495.1744. Found
495.1773 [M+Na].
4.2.9.
(S,S)-2-(Bis-biphenyl-2-ylmethyl-amino)-3-{3-
[2-(bis-biphenyl-2-ylmethyl-amino)-2-methoxycarbonyl-
ethyl]-phenyl}-propionic acid methyl ester 5g. Follow-
ing the general procedure of alkylation, from 100 mg
(0.36 mmol) of 4, 200 mg (60%) of 5g were isolated
4.2.5. (S,S)-2-Dimethylamino-3-[3-(2-dimethylamino-2-
methoxycarbonyl-ethyl)-phenyl]-propionic acid methyl
ester 5c. Following the general procedure of alkyla-
tion, from 90 mg (0.32 mmol) of 4, 20 mg (18%) of
5c were obtained as a colourless oil after chromatog-
raphy (SiO2, heptane/EtOAc 7:3, Rf 0.7). IR (w cm−1):
1
as an oil. IR (w cm−1): 3023.3, 1729.1; H NMR (300
MHz, CDCl3): l 7.47–7.27 (m, 37H), 6.89 (d, 2H,
J=7.6 Hz), 6.69 (s, 1H), 3.73 (q, 8H, J=39.6 Hz),
3.49 (t, 2H, J=7.1 Hz) 3.29 (s, 6H), 3.00–2.63 (m,
4H); 13C NMR (75.5 MHz, CDCl3): l 172.3, 145.9,
142.1, 141.2, 138.1, 137.7, 136.3, 133.5, 130.7, 130.6,
130.2, 130.0, 129.8, 129.3, 128.9, 128.4, 128.2, 128.0,
127.9, 127.8, 127.7, 127.5, 127.3, 127.2, 126.7, 126.4,
62.9, 51.4, 50.4, 35.4, 31.8; HRMS (FAB+H+) m/z
calculated for C66H61N2O4 945.4632. Found 945.4636
[M+H].
1
2961, 1729; H NMR (400 MHz, CDCl3): l 7.21 (m,
1H), 7.05 (m, 3H), 3.62 (s, 8H), 3.04 (d, 4H, J=7.6
Hz), 2.53 (s, 12H); 13C NMR (100 MHz, CDCl3): l
170.7, 137.3, 129.9, 128.8, 127.6, 68.9, 51.5, 41.4,
35.4; HRMS (FAB+H+) m/z calculated for
C18H29N2O4 337.2128. Found 337.2140 [M+H].
4.2.6. (S,S)-2-[Bis-(2-methyl-benzyl)-amino]-3-(3-{2-[bis-
(2-methyl-benzyl)-amino]-2-methoxycarbonyl-ethyl}-
phenyl)-propionic acid methyl ester 5d. Following the
general procedure of alkylation, from 100 mg (0.36
mmol) of 4, 180 mg (73%) of the title compound
were obtained as a brown oil. IR (w cm−1): 2964.4,
4.2.10. (S,S)-2-(1H,3H-Benzo[de]isoquinolin-2-yl)-3-{3-
[2-(1H,3H-bezo[de]isoquinolin-2-yl)-2-hydroperoxycar-
bonyl-ethyl]-phenyl}-propionic acid methyl ester 5h.†
Following the general procedure of alkylation, from
100 mg (0.36 mmol) of 4, 50 mg (21%) of white solid
was obtained after chromatography (SiO2, heptane/
EtOAc, 1:1, TLC CH2Cl2/MeOH 30:1, Rf 0.4). Mp
1
1734.9; H NMR (300 MHz, CDCl3): l 7.32–7.11 (m,
17H), 6.91 (dd, 2H, J=1.5, 7.1 Hz), 6.63 (s, 1H),
3.92 (d, 4H, J=20.2 Hz), 3.75 (s, 6H), 3.79–3.66 (m,
6H), 3.22–2.94 (m, 4H), 2.25 (s, 12H); 13C NMR
(75.5 MHz, CDCl3): l 172.4, 138.0, 137.2, 136.5,
130.3, 130.2, 130.1, 129.9, 129.8, 127.9, 127.6, 127.4,
127.1, 126.8, 125.9, 125.5, 62.8, 52.4, 50.9, 34.9, 19.0;
HRMS (FAB+H+) m/z calculated for C46H53N2O4
697.4006. Found 697.4007 [M+H].
1
126.8–129.1°C; IR (w cm−1): 2950.9, 1739.9; H NMR
(300 MHz, CDCl3): l 8.44 (dd, 4H, J=1.0, 7.3 Hz),
8.16 (dd, 4H, J=1.0, 8.4 Hz), 7.68 (t, 4H, J=7.4
Hz), 7.12 (s, 1H), 6.92 (m, 3H), 5.93 (q, 2H, J=5.9,
9.3 Hz), 3.68 (s, 6H), 3.60–3.21 (m, 4H); 13C NMR
(75.5 MHz, CDCl3): l 170.1, 163.5, 137.5, 137.4,
135.3, 134.1, 133.3, 131.4, 130.4, 128.1, 128.08, 127.4,
127.3, 126.8, 122.0, 54.1, 52.3, 34.8; HRMS
(FAB+H+) m/z calculated for C39H29N2O8 641.1846.
Found 641.1921 [M+H].
4.2.7. (S,S)-2-[Bis-(3-methyl-benzyl)-amino]-3-(3-{2-[bis-
(3-methyl-benzyl)-amino]-2-methoxycarbonyl-ethyl}-
phenyl)-propionic acid methyl ester 5e. Following the
general procedure of alkylation, from 100 mg (0.36
mmol) of 4, 150 mg (62%) of 5e were isolated. IR (w
† The methyl ester product was difficult to purify and the final
product contained traces of starting material, 1,8-naphthalic anhy-
dride. The product was used in the LiAlH4 reduction after which
the chiral catalyst was easily purified.
1
cm−1): 2964.4, 1734.9; H NMR (300 MHz, CDCl3): l
7.32–7.11 (m, 17H), 6.91 (dd, 2H, J=1.5, 7.1 Hz),
6.63 (s, 1H), 3.92 (d, 4H, J=20.2 Hz), 3.75 (s, 6H),

R. D. Ionescu et al. / Tetrahedron: Asymmetry 14 (2003) 2369–2380
2377
1
4.2.11. (S)-2-[Bis-(2-methyl-benzyl)-amino]-3-phenyl-pro-
pionic acid methyl ester 7d. Following the general pro-
cedure of alkylation, from 100 mg (0.56 mmol) of
phenylalanine methyl ester, 160 mg (72%) of 7d were
obtained as a colourless oil. IR (w cm−1): 3026.1,
3029.9, 1738.7, 1661.6; H NMR (300 MHz, CDCl3):
l 8.51 (dd, 2H, J=1.0, 7.4 Hz), 8.18 (dd, 2H, J=1.1,
8.4 Hz), 7.70 (t, 2H, J=7.3 Hz), 7.24–7.05 (m, 5H),
6.06 (q, 1H, J=1.8 Hz), 3.76 (s, 3H), 3.73–3.45 (m,
2H); 13C NMR (75.5 MHz, CDCl3): l 170.2, 153.6,
137.3, 135.3, 134.2, 133.3, 131.5, 131.4, 129.2, 128.2,
128.0, 127.4, 126.8, 126.4, 121.9, 54.2, 34.9, 22.6;
HRMS (FAB+H+) m/z calculated for C22H17NO4
360.1237 Found 360.1265 [M+H].
1
2949.0, 1734.9; H NMR (300 MHz, CDCl3): l 7.39–
7.07 (m, 13H), 3.97 (d, 2H, J=13.7 Hz), 3.81 (br s,
4H, OMe+a-H), 3.77 (s, 1H), 3.21 (m, 2H), 2.29 (s,
6H); 13C NMR (75.5 MHz, CDCl3): l 172.4, 138.2,
137.3, 136.5, 130.1, 129.9, 129.2, 128.1, 127.2, 126.9,
126.1, 125.5, 62.8, 52.4, 50.9, 35.1, 19.1; HRMS
(FAB+H+) m/z calculated for C26H30NO2 388.2277.
Found 388.2289 [M+H].
4.3. (S,S)-2-Dibenzylamino-3-[3-(2-dibenzylamino-3-
hydroxy-3,3-diphenyl-propyl)-phenyl]-1,1-diphenyl-
propan-1-ol 9
4.2.12.
(S)-2-[Bis-(3-methyl-benzyl)-amino]-3-phenyl-
PhLi (39 mg, 0.46 mmol) was added to a solution of
2a (40 mg, 0.12 mmol) in dry THF (5 mL) under a
nitrogen atmosphere. The reaction was stirred at room
temperature for 18 h. Saturated NH4Cl solution was
added to pH ꢀ3. The aqueous layer was extracted
with diethyl ether (3×20 mL) followed by drying over
Na2SO4 and removal of the solvent under reduced
pressure. The crude was chromatographed (SiO2, hep-
tane/EtOAc 1:4, Rf 0.2) to give 9 (65 mg, 61%) as a
white semi-amorphous mass. [h]2D1=−20.5 (c 1.7,
proionic acid methyl ester 7e. Following the general
procedure of alkylation, from 100 mg (0.56 mmol) of
phenylalanine methyl ester, 110 mg (50%) of 7e were
obtained as a colourless oil. IR (w cm−1): 3026.1,
1
2949.0, 1734.9; H NMR (300 MHz, CDCl3): l 7.35–
7.04 (m, 13H), 4.02 (d, 2H, J=13.9 Hz), 3.83 (s, 3H),
3.80 (m, 1H), 3.60 (d, 2H, J=14 Hz), 3.24–3.06 (m,
2H), 2.38 (s, 6H); 13C NMR (75.5 MHz, CDCl3): l
172.8, 139.2, 138.1, 137.5, 129.5, 129.4, 128.0, 127.9,
127.5, 126.2, 125.7, 62.1, 54.3, 51.0, 35.7, 21.4; HRMS
(FAB+H+) m/z calculated for C26H30NO2 388.2277.
Found 388.2289 [M+H].
1
EtOH); IR (w cm−1): 3388.7, 1645.17; H NMR (300
MHz, CDCl3): l 7.78 (m, 4H), 7.40–7.00 (m, 40H),
5.19 (m, 2H), 3.36 (m, 12H, CH2Ph+b-H); 13C NMR
(75.5 MHz, CDCl3): l 145.6, 143.8, 141.2, 138.9,
129.6, 129.1, 128.3, 128.1, 127.9, 127.8, 127.3, 127.2,
127.1, 55.5, 31.7, 22.7, 14.1; HRMS (FAB+H+) m/z
calculated for C64H60N2O2Na 911.4553. Found
911.4550[M+Na].
4.2.13.
(S)-2-[Bis-(4-methyl-benzyl)-amino]-3-phenyl-
proionic acid methyl ester 7f. Following the general
procedure of alkylation, from 100 mg (0.56 mmol) of
phenylalanine methyl ester, 170 mg (79%) of 7f were
obtained as a yellow oil. IR (w cm−1): 3026.1, 2949.0,
1
1734.9; H NMR (300 MHz, CDCl3): l 7.38–7.16 (m,
4.4. General procedure for reduction of the methyl
ester with LiAlH4
13H), 4.07 (d, 2H, J=13.8 Hz), 3.85 (m, 4H, OMe+a-
H), 3.66 (d, 2H, J=13.9 Hz), 3.31–3.10 (m, 2H), 2.46
(s, 6H); 13C NMR (75.5 MHz, CDCl3): l 172.7, 138.1,
136.2, 136.1, 129.8, 129.7, 129.6, 129.3, 129.2, 129.0,
128.9, 128.8, 128.7, 128.5, 128.3, 128.2, 127.9, 126.1,
62.1, 53.9, 50.9, 35.6, 21.0; HRMS (FAB+H+) m/z
calculated for C26H30NO2 388.2277. Found 388.2289
[M+H].
Dry THF (15 mL) was added to LiAlH4 (10 mmol) at
0°C and the resulting slurry stirred for 10 min. The
methyl ester (1.0 mmol) was dissolved in dry THF (3
mL) and then slowly added to the slurry at 0°C. The
reaction mixture was stirred for 4 h at room tempera-
ture and then quenched by the addition of 0.1 M HCl
(10 mL) followed by further stirring for 1 h. The
mixture was filtered through Celite and the aqueous
phase extracted with diethyl ether (2×30 mL) followed
by drying (Na2SO4) and the solvent removed under
reduced pressure. The crude was purified by chro-
matography (diethyl ether/pentane, 4:1).
4.2.14. (S)-2-(Bis-biphenyl-2-ylmethyl-amino)-3-phenyl-
propionic acid methyl ester 7g. Following the general
procedure of alkylation, from 100 mg (0.56 mmol) of
phenylalanine methyl ester, 240 mg (84%) of 7g were
obtained as a yellow oil. IR (w cm−1): 3059.9, 1732.9;
1H NMR (300 MHz, CDCl3): l 7.60–7.10 (m, 23H),
3.98 (d, 2H, J=14.5 Hz), 3.70 (m, 3H, CH2Ph+a-H),
3.41 (s, 3H), 3.15–2.75 (m, 2H); 13C NMR (75.5 MHz,
CDCl3): l 172.5, 142.4, 141.4, 138.5, 136.5, 133.7,
130.8, 130.2, 129.9, 129.5, 129.3, 129.2, 128.9, 128.6,
128.4, 128.3, 127.9, 127.9, 127.7, 127.5, 126.9, 126.6,
126.3, 63.1, 51.6, 50.7, 35.6; HRMS (FAB+H+) m/z
calculated for C36H33NO2 512.2590. Found 512.2595
[M+H].
4.4.1.
(S,S,S)-2-Dibenzylamino-3-[3,5-bis-(2-dibenzyl-
amino-2-hydroxy-propyl)-phenyl]-propan-1-ol 3a. Fol-
lowing the general procedure for reduction with
LiAlH4, from 60 mg (0.09 mmol) of 2, 26 mg (50%) of
the title compound were obtained as a colourless oil.
[h]2D1=+16 (c 1.2, EtOH); IR (w cm−1): 3386.8, 2935.5,
1
2856.4, 1600.8; H NMR (400 MHz, CD3OD): l 7.22
(m, 30H), 6.67 (s, 3H), 4.59 (s, 3H), 3.71 (m, 12H),
3.44 (m, 3H), 2.92 (m, 6H), 2.56 (m, 3H); 13C NMR
(100 MHz, CD3OD): l 141.8, 130.4, 128.7, 128.4, 62.9,
62.4, 55.2, 34.8, 30.6; HRMS (FAB+Na+) m/z calcu-
lated for C57H63N3O3Na 860.4767. Found 860.4758
[M+Na].
4.2.15.
(S)-2-(1H,3H-Benzo[de]isoquinolin-2-yl)-3-
phenyl-propionic acid methyl ester 7h.† Following the
general procedure of alkylation, from 100 mg (0.56
mmol) of phenylalanine methyl ester, 100 mg (51%) of
7h were obtained as a pink semi-solid. IR (w cm−1):

2378
R. D. Ionescu et al. / Tetrahedron: Asymmetry 14 (2003) 2369–2380
4.4.2. (S,S)-2-Dibenzylamino-3-[3-(2-dibenzylamino-3-
hydroxypropyl)-phenyl]-propan-1-ol 6a. Following the
general procedure for reduction with LiAlH4, from 100
mg (0.16 mmol) of 5a, 70 mg (80%) of 6a were obtained
as a colourless oil. [h]2D1=+16.3 (c 1.1, EtOH); IR (w
1H), 4.68 (s, 1H, OH), 3.69 (m, 10H, CH2Ph+a-H),
3.32 (m, 2H), 3.08 (m, 6H), 2.36 (s, 12H); 13C NMR
(75.5 MHz, CDCl3) l 139.5, 138.5, 138.1, 130.0, 129.8,
128.7, 128.4, 128.0, 126.8, 126.1, 60.9, 60.3, 53.3, 31.6,
21.4; HRMS (FAB+H+) m/z calculated for C44H53N2O2
641.4029. Found 641.4091 [M+H].
1
cm−1): 3301.9, 2911.0; H NMR (400 MHz, CD3OD): l
7.34 (d, 1H, J=6.0 Hz), 7.22 (m, 20H), 6.93 (d, 2H,
J=7.5 Hz), 6.82 (s, 1H), 3.71 (m, 8H), 3.45 (m, 2H),
2.95 (m, 4H), 2.61 (m, 2H); 13C NMR (100 MHz,
CD3OD): l 141.9, 141.8, 130.4, 129.7, 128.4, 62.9, 62.4,
55.2, 34.9; HRMS (FAB+Na+) m/z calculated for
C40H45N2O2 607.3301. Found 607.3299 [M+Na].
4.4.7. (S,S)-2-[Bis-(4-methyl-benzyl)-amino]-3-(3-{2-[bis-
(4-methyl-benzyl)-amino]-3-hydroxypropyl}-phenyl)-
propan-1-ol 6f. Following the general procedure for
reduction with LiAlH4, from 110 mg (0.16 mmol) of 5f,
90 mg (91%) of 6f were obtained as a colourless oil.
[h]2D1=+17.9 (c 1.4, EtOH); IR (w cm−1): 3427.3, 2915.2;
1H NMR (300 MHz, CDCl3): l 7.19–7.04 (m, 19H),
6.85 (dd, 2H, J=1.5, 7.6 Hz), 6.75 (s, 1H), 3.58 (m,
8H), 3.40 (t, 2H, J=3.8 Hz), 3.20 (dd, 2H, J=3.9, 10.4
Hz), 2.98 (d, 6H, J=11.8 Hz), 2.26 (m, 12H); 13C NMR
(75.5 MHz, CDCl3): l 139.5, 136.9, 135.9, 129.2, 128.9,
126.82, 126.8, 60.3, 60.2, 52.8, 31.6, 21.1; HRMS
(FAB+H+) m/z calculated for C44H53N2O2 641.4029.
Found 641.4091 [M+H]. Anal. calcd for C44H52N2O2:
C, 82.46; H, 8.18; N, 4.37. Found: C, 82.32; H, 8.11; N,
4.26%.
4.4.3.
(S,S)-3-[3-(3-Hydroxy-2-piperidin-1-yl-propyl)-
phenyl)-phenyl]-2-piperidin-1-yl-propan-1-ol 6b. Follow-
ing the general procedure for reduction with LiAlH4,
from 120 mg (0.25 mmol) of 5b, 30 mg (30%) of 6b
were obtained as a yellow oil. [h]2D1=+13.1 (c 1.9,
EtOH); IR (w cm−1): 3401.2, 2930.6; 1H NMR (400
MHz, CD3OD): l 7.25–7.03 (m, 5H, a-H+CH2OH),
2.72 (m, 13H), 1.52 (m, 12H); 13C NMR (100 MHz,
CD3OD): l 169.6, 159.1, 157.5, 155.9, 97.5, 88.9, 79.2,
61.5, 55.4, 53.7; HRMS (FAB+H+) m/z calculated for
C22H37N2O2 361.2856. Found 361.2845 [M+H].
4.4.8. (S,S)-2-(Bis-biphenyl-2-ylmethyl-amino)-3-{3-[2-
(bis-biphenyl-2-ylmethyl-amino)-3-hyroxypropyl]-
4.4.4. (S,S)-2-Dimethylamino-3-[3-(2-dimethylamino-3-
hydroxypropyl)-phenyl]-propan-1-ol 6c. Following the
general procedure for reduction with LiAlH4, from 30
mg (0.09 mmol) of 5c, 35 mg (72%) of 6c were obtained
as a yellow oil. The product could not be chro-
matographed because it decomposed on the column.
[h]2D1=+0.2 (c 3.2, EtOH); IR (w cm−1): 2359.7, 2330.8;
1H NMR (400 MHz, CD3OD): l 7.34–7.05 (m, 4H),
3.50 (m, 4H), 2.81 (m, 2H), 2.71 (m, 4H), 2.40 (s, 12H);
13C NMR (100 MHz, CD3OD): l 141.6, 131.3, 129.8,
128.1, 69.0, 61.3, 41.5, 33.1; HRMS (FAB+H+) m/z
calculated for C16H29N2O2 281.2230. Found 281.2239
[M+H].
phenyl}-propan-1-ol 6g. Following the general procedure
for reduction with LiAlH4, from 140 mg (0.15 mmol) of
5g, 70 mg (51%) of 6g were obtained as a white powder.
Mp 84.4–86.2°C; [h]D21=+16 (c 1.2, EtOH); IR (w cm−1):
1
3388.7, 3022.2, 2858.3; H NMR (300 MHz, CDCl3): l
7.24–7.21 (m, 36H), 6.95 (t, 1H, J=7.6 Hz), 6.47 (d,
2H, J=7.6 Hz), 6.32 (s, 1H), 3.65 (m, 8H), 3.13 (t, 2H,
J=10.3 Hz), 3.03 (m, 2H), 2.67 (m, 2H), 2.48 (m, 2H),
1.99 (q, 2H, J=13.3 Hz); 13C NMR (75.5 MHz,
CDCl3): l 142.2, 141.2, 138.8, 136.0, 130.2, 129.8,
129.7, 129.2, 128.3, 128.1, 127.6, 127.0, 126.8, 126.3,
61.3, 60.4, 50.4, 30.9; HRMS (FAB+H+) m/z calculated
for C64H61N2O2 889.4734. Found 889.4745 [M+H].
4.4.5. (S,S)-2-[Bis-(2-methyl-benzyl)-amino]-3-(3-{2-[bis-
(2-methyl-benzyl)-amino]-3-hydroxypropyl}-phenyl)-
propan-1-ol 6d. Following the general procedure for
reduction with LiAlH4, from 110 mg (0.16 mmol) of 5d,
50 mg (50%) of 6d were obtained as a colourless oil.
[h]2D1=+29.8 (c 1.6, EtOH); IR (w cm−1): 3427.3, 2915.2;
1H NMR (300 MHz, CDCl3): l 7.41–7.18 (m, 19H),
6.99 (dd, 2H, J=1.5, 6.1 Hz), 6.91 (s, 1H), 4.73 (s, 1H,
OH), 3.80 (m, 8H), 3.57 (t, 2H, J=10.7 Hz), 3.29 (m,
4H), 3.09 (m, 2H), 2.51 (m, 2H), 2.29 (s, 12H); 13C
NMR (75.5 MHz, CDCl3): l 139.4, 137.0, 136.3, 130.6,
130.4, 130.2, 129.9, 128.8, 127.7, 127.4, 127.37, 126.7,
126.0, 125.8, 125.5, 63.4, 60.9, 60.4, 51.0, 31.1, 30.3,
29.7, 19.1; HRMS (FAB+H+) m/z calculated for
C44H53N2O2 641.4029. Found 641.4091 [M+H].
4.4.9. (S,S)-2-(1H,3H-Benzo[de]isoquinolin-2-yl)-3-{3-[2-
(1H,3H-benzo[de]isoquinolin-2-yl)-3-hydroxypropyl]-
phenyl}-propan-1-ol 6h. Following the general procedure
for reduction with LiAlH4, from 47 mg (0.073 mmol) of
5h, 20 mg (41%) of 6h were obtained as a colourless oil.
[h]2D1=−20.8 (c 1.6, CHCl3); IR (w cm−1): 3442.7, 2926.8,
1700.0, 1657.7; 1H NMR (400 MHz, CDCl3): l 8.17 (m,
2H), 7.73 (d, 4H, J=8.0 Hz), 7.42 (q, 2H, J=6.9, 7.8
Hz), 7.19 (m, 3H), 7.09 (d, 1H, J=6.9 Hz), 6.94 (d, 1H,
J=6.6 Hz), 5.75–5.68 (m, 1H), 4.27–3.96 (m, 6H),
3.40–3.16 (m, 6H), 3.01–2.41 (m, 6H); 13C NMR (100
MHz, CDCl3): l 138.9, 138.5, 134.1, 133.7, 133.5,
131.4, 129.8, 128.6, 128.1, 128.05, 127.3, 127.1, 127.0,
126.1, 125.6, 121.8, 66.5, 63.6, 59.9, 54.5, 51.9; HRMS
(FAB+H+) m/z calculated for C36H36N2O2 529.2856.
Found 529.5856 [M+H].
4.4.6. (S,S)-2-[Bis-(3-methyl-benzyl)-amino]-3-(3-{2-[bis-
(3-methyl-benzyl)-amino]-3-hydroxypropyl}-phenyl)-
propan-1-ol 6e. Following the general procedure for
reduction with LiAlH4, from 70 mg (0.11 mmol) of 5e,
40 mg (59%) of the title compound were obtained as a
colourless oil. [h]D21=+23.2 (c 1.9, EtOH); IR (w cm−1):
4.4.10.
(S)-2-[Bis-(2-methyl-benzyl)-amino]-3-phenyl-
propan-1-ol 8d. Following the general procedure for
reduction with LiAlH4, from 100 mg, 0.26 mmol) of 7d,
90 mg (99%) of 8d were isolated as a colourless oil.
[h]2D1=+43.8 (c 8.0, CHCl3); IR (w cm−1): 3388.7, 2922.9;
1H NMR (300 MHz, CDCl3): l 7.41–7.17 (m, 13H)
1
3427.3, 2915.2; H NMR (300 MHz, CDCl3): l 7.26–
7.08 (m, 19H), 6.95 (dd, 2H, J=1.6, 6.0 Hz), 6.85 (s,

R. D. Ionescu et al. / Tetrahedron: Asymmetry 14 (2003) 2369–2380
2379
3.98 (d, 2H, J=13.1 Hz), 3.68 (d, 2H, J=13.1 Hz), 3.61
(d, 1H, J=10 Hz), 3.36 (m, 2H), 3.16 (m, 1H), 2.59 (q,
1H, J=10.5, 13.2 Hz), 2.32 (s, 6H); 13C NMR (75.5
MHz, CDCl3): l 139.1, 136.9, 136.3, 130.5, 130.4,
130.2, 128.9, 128.5, 127.6, 127.3, 126.2, 125.8, 125.5,
60.8, 60.3, 50.8, 31.1, 19.0; HRMS (FAB+H+) m/z
calculated for C25H30NO 360.2328. Found 360.2333
[M+H].
(m, 1H, OH); 13C NMR (75.5 Hz, CDCl3): l 138.9,
133.9, 133.7, 133.2, 129.1, 128.9, 128.6, 128.3, 128.1,
126.9, 126.3, 126.1, 125.5, 121.7, 66.7, 60.0, 51.9, 32.0;
HRMS (FAB+H+) m/z calculated for C21H22NO
304.1702. Found 304.1692 [M+H].
4.5. General procedure for the chiral catalyst-promoted
addition of Et2Zn to aldehydes
4.4.11.
(S)-2-[Bis-(3-methyl-benzyl)-amino]-3-phenyl-
To a solution of the chiral catalyst (0.05 equiv.) in dry
toluene (3 mL/0.95 mmol benzaldehyde) under nitrogen
atmosphere was added a solution of Et2Zn (1.73 mL,
1.1 M in toluene, 2 equiv.) via syringe. After stirring for
10 min, freshly distilled benzaldehyde (1 equiv.) was
added into the mixture via syringe. The resulting mix-
ture was stirred for 24 h at room temperature and the
reaction quenched by the addition of NH4Cl solution (4
mL) on an ice bath. The aqueous phase was extracted
with diethyl ether (3×6 mL) washed with NaHSO3 (3×8
mL), dried over Na2SO4 followed by the removal of the
solvent under reduced pressure. The crude was chro-
matographed (pentane/diethyl ether, 6:4) to give the
pure product.
propan-1-ol 8e. Following the general procedure for
reduction with LiAlH4, from 100 mg (0.26 mmol) of 7e,
90 mg (97%) of 8e were isolated as a colourless oil.
[h]2D1=+20.3 (c 7.2, EtOH); IR (w cm−1): 3388.7, 2922.9;
1H NMR (300 MHz, CDCl3): l 7.37–7.13 (m, 13H),
3.97 (d, 2H, J=13.2 Hz), 3.54 (m, 3H, CH2Ph+a-H),
3.42 (q, 1H, J=4.4, 10.7 Hz), 3.16 (m, 2H), 2.41 (s,
6H); 13C NMR (75.5 MHz, CDCl3): l 139.2, 138.9,
137.9, 129.8, 128.9, 128.4, 128.3, 127.9, 126.1, 126.0,
125.5, 60.7, 60.2, 53.1, 31.6, 21.4; HRMS (FAB+H+)
m/z calculated for C25H30NO 360.2328. Found
360.2333 [M+H].
4.4.12.
(S)-2-[Bis-(4-methyl-benzyl)-amino]-3-phenyl-
propan-1-ol 8f. Following the general procedure for
reduction with LiAlH4, from 170 mg (0.44 mmol) of 7f,
150 mg (94%) of 8f were obtained as a colourless oil.
[h]D21=+12.7 (c 11.3, CHCl3); IR (w cm−1): 3388.7,
4.6. General conditions for HPLC analysis of chiral
alcohols
Method A: Chiralcel OD-H column eluted with n-hex-
ane/iPrOH (97.5:2.5) at 0.5 mL/min using an UV detec-
tor operating at 254 nm.
1
2922.9; H NMR (300 MHz, CDCl3): l 7.39–7.19 (m,
13H), 3.97 (d, 2H, J=13.2 Hz), 3.58 (d, 1H, J=10.5
Hz), 3.52 (d, 2H, J=13.2 Hz), 3.41 (m, 1H), 3.17 (m,
2H), 2.42 (s, 6H); 13C NMR (75.5 MHz, CDCl3): l
139.1, 136.7, 135.9, 129.1, 129.05, 129.0, 128.9, 128.8,
128.7, 128.6, 128.4, 126.9, 126.1, 125.4, 60.4, 60.1, 52.7,
30.2, 21.0; HRMS (FAB+H+) m/z calculated for
C25H30NO 360.2328. Found 360.2333 [M+H]. Anal.
calcd for C25H29NO: C, 83.52; H, 8.13; N, 3.90. Found:
C, 83.39; H, 8.08; N, 3.84%.
Method B: Chiralcel OD-H column eluted with n-hex-
ane/iPrOH (95:5) at 0.5 mL/min using an UV detector
operating at 254 nm.
1-Phenyl-1-propanol
Method A: tR=23.2 min for (R) and tR=26.2 min for
(S)
1-(4%-Chlorophenyl)-1-propanol
Method B: tR=14.5 min for (R) and tR=15.3 min for
(S)
1-(4%-Methoxyphenyl)-1-propanol
Method B: tR=19.1 min for (R) and tR=22.7 min for
(S).
4.4.13. (S)-2-(Bis-biphenyl-2-ylmethyl-amino)-3-phenyl-
propan-1-ol 8g. Following the general procedure for
reduction with LiAlH4, from 200 mg (0.39 mmol) of 7g,
200 mg (99%) of 8g were obtained as a yellow-white
semi-solid. [h]D211=+16.7 (c 24, CHCl3); IR (w cm−1):
3389.7, 3025.1; H NMR (300 MHz, CDCl3): l 7.53–
6.83 (m, 23H), 3.93 (d, 2H, J=13.7 Hz), 3.62 (d, 2H,
J=13.7 Hz), 3.27 (m, 2H), 2.81 (m, 1H), 2.66 (dd, 1H,
J=3.6, 13.2 Hz), 2.19 (q, 1H, J=10.1, 13.2 Hz); 13C
NMR (75.5 Hz, CDCl3): l 142.1, 141.1, 138.9, 136.1,
130.2, 129.9, 129.8, 129.2, 129.0, 128.8, 128.6, 128.3,
128.2, 128.1, 128.0, 127.5, 127.4, 127.1, 126.9, 126.8,
125.8, 125.4, 62.8, 61.5, 50.3, 30.2; HRMS (FAB+H+)
m/z calculated for C35H34NO 484.2641. Found
484.2635 [M+H].
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4.4.14.
(S)-2-(1H,3H-Benzo[de]isoquinolin-2-yl)-3-
phenyl-propan-1-ol 8h. Following the general procedure
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1
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