Enantioselective addition of diethylzinc to aldehydes catalyzed by diastereomeric 1,4-amino alcohols with o-xylylene skeleton

Article abstract of DOI:10.1246/cl.141113

Two diastereomeric 1,4-amino alcohols with o-xylylene structure (S,R)-2 and (S,S)-3, synthesized from chiral 1,4-diol (S,S)-1, were utilized as chiral ligands for the enantioselective addition of diethylzinc to aldehydes. The stereochemical outcome of the reactions was controlled solely by the absolute configuration of the benzylic carbon bearing amino group, and both enantiomers of 1-substituted propanol were obtained with up to 98% (S) and 96% (R) enantiomeric excesses.

Full text of DOI:10.1246/cl.141113

Received: December 3, 2014 | Accepted: December 9, 2014 | Web Released: December 19, 2014
CL-141113
Enantioselective Addition of Diethylzinc to Aldehydes Catalyzed
by Diastereomeric 1,4-Amino Alcohols with o-Xylylene Skeleton
Masatoshi Asami,* Atsushi Nagai, Yukihiro Sasahara, Ken-ichi Ichikawa, Suguru Ito, and Naoya Hosoda
Department of Advanced Materials Chemistry, Graduate School of Engineering, Yokohama National University,
79-5 Tokiwadai, Hodogaya-ku, Yokohama, Kanagawa 240-8501
(E-mail: m-asami@ynu.ac.jp)
Two diastereomeric 1,4-amino alcohols with o-xylylene
structure (S,R)-2 and (S,S)-3, synthesized from chiral 1,4-diol
(S,S)-1, were utilized as chiral ligands for the enantioselective
addition of diethylzinc to aldehydes. The stereochemical
outcome of the reactions was controlled solely by the absolute
configuration of the benzylic carbon bearing amino group, and
both enantiomers of 1-substituted propanol were obtained with
up to 98% (S) and 96% (R) enantiomeric excesses.
Chiral 1,2- and 1,3-amino alcohols have been widely
investigated as chiral ligands and chiral auxiliaries in various
asymmetric transformations.1 Catalytic enantioselective addition
of organozinc compounds to aldehydes is a well-studied
asymmetric reaction using amino alcohol ligands. Since the
initial report by Oguni and Omi in 1984,2 a number of chiral 1,2-
and 1,3-amino alcohols have been utilized as chiral ligands in
the reaction.3-5 On the other hand, 1,4-amino alcohols have been
less investigated and the induction of high levels of enantiose-
lectivity is generally difficult owing to relatively flexible seven-
membered chelate ring structures in active chiral catalysts
prepared in situ from organozinc compounds and 1,4-amino
alcohol ligands.6 Previously, we reported the synthesis of a
chiral 1,4-diol with o-xylylene structure, 1,2-bis(1-hydroxypro-
pyl)benzene (1),7 and the derivatization to a novel chiral N-
heterocyclic carbene ligand8a,8b as well as its use in asymmetric
reactions as chiral auxiliary.8c,8d We expected that 1,4-amino
alcohols derived from 1 would form a rigid seven-membered
chelate ring structure due to the o-xylylene backbone, and
therefore should act as effective chiral ligands for various
asymmetric reactions. Herein, we report the synthesis of two
diastereomers of o-xylylene-type 1,4-amino alcohols (S,R)-2
and (S,S)-3, and their use in the enantioselective addition of
diethylzinc to aldehydes.
Novel diastereomeric 1,4-amino alcohols (S,R)-2 and (S,S)-
3 were synthesized from enantiomerically pure 1,4-diol 17
(Scheme 1). The selective methoxymethylation of one of the
two benzylic hydroxy group of (S,S)-1 by butyllithium and
chloromethyl methyl ether afforded monomethoxymethyl ether
(S,S)-4 in 92% yield. Stereoinversion of the remaining hydroxy
group of (S,S)-4 by Mitsunobu azidation followed by the
reduction of azide group and the stepwise methylation of the
resulting primary amino group gave tertiary amine (S,R)-5 in
71% yield from (S,S)-4. The methoxymethyl group of (S,R)-5
was removed by treating with 4 M aqueous HCl to give 1,4-
amino alcohol (S,R)-2 in 81% yield. Similarly, 1,4-amino
alcohol (S,S)-3, which is the diastereomer of (S,R)-2 at the chiral
carbon bearing amino group, was also synthesized from (S,S)-1.
At first, the chiral carbon bearing free hydroxy group of (S,S)-4
was inverted by the Mitsunobu esterification, and the hydrolysis
Scheme 1. Synthesis of diastereomeric 1,4-amino alcohols 2
and 3. (a) n-BuLi, MOMCl, Et2O, ¹78 °C to rt, 92%; (b) PPh3,
EtO2CN=NCO2Et, (PhO)2P(O)N3, THF, ¹20 °C or ¹20 °C to
rt; (c) H2, 10% Pd/C, MeOH, rt, then HCO2Et, rt; (d) LiAlH4,
THF, reflux, then (HCHO)n, H2, 10% Pd/C, MeOH, rt, 71%
from (S,S)-4, 62% from (S,R)-6; (e) 4 M aq. HCl, rt, 81% from
(S,R)-5, 75% from (S,S)-7; (f) PPh3, EtO2CN=NCO2Et,
PhCO2H, THF, ¹20 °C; (g) 4 M aq. NaOH, THF, rt, 70% from
(S,S)-4.
of the resulting ester group afforded (S,R)-6 in 70% yield. The
alcohol (S,R)-6 was then stereospecifically converted to (S,S)-7
in 62% yield by using the same manner as the one used for
the preparation of (S,R)-5, and the removal of the methoxy-
methyl group of (S,S)-7 gave 1,4-amino alcohol (S,S)-3 in 75%
yield.
Enantioselective addition of diethylzinc to benzaldehyde
was examined by using 1,4-amino alcohol (S,R)-2. In the
presence of 10 mol % of (S,R)-2, benzaldehyde and 2.0 equiv-
alents of diethylzinc in toluene were stirred at 0 °C for 18 h to
give (S)-1-phenyl-1-propanol in 83% yield with high enantio-
meric excess (96% ee, Table 1, Entry 1). After the screening of
the reaction solvents (Entries 2-4), the best result was obtained
by using Et2O (84%, 97% ee, Entry 3).9 The reaction was then
examined by using 1,4-amino alcohol (S,S)-3 in place of (S,R)-2
under the same reaction conditions, and (R)-1-phenyl-1-propanol
was obtained with almost the same enantioselectivity (95% ee,
Entry 5). These results indicate that the enantioselectivity of
the reaction is controlled solely by the absolute configuration of
the benzylic carbon having an amino group, and the stereo-
chemistry of another benzylic carbon bearing a hydroxy group
has little influence on the stereochemical outcome of the
reaction.10 The results are in contrast with the results obtained
by diastereomeric 1,2-amino alcohols where the enantioselec-
tivity of the products was usually determined by a hydroxy-
containing chiral carbon.3,11
Chem. Lett. 2015, 44, 345–347 | doi:10.1246/cl.141113
© 2015 The Chemical Society of Japan | 345

Table 1. Enantioselective addition of diethylzinc to benzalde-
hyde catalyzed by 1,4-amino alcohols 2 and 3
Yield
/%a
ee
/%b
Entry Solvent
Amino alcohol
1
2
3
4
5
Toluene
Cyclohexane
Et2O
THF
Et2O
(S,R)-2
(S,R)-2
(S,R)-2
(S,R)-2
(S,S)-3
83
86
84
36
84
96 (S)
73 (S)
97 (S)
96 (S)
95 (R)
b
aIsolated yield. Determined by HPLC analysis.
Table 2. Enantioselective addition of diethylzinc to various
aldehydes catalyzed by 1,4-amino alcohols 2 and 3
Yield
/%a
ee
/%b
Entry
R
Amino alcohol
Figure 1. Proposed reaction mechanism for enantioselective
addition of diethylzinc to aldehydes using (S,R)-2 and (S,S)-3.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
2-BrC6H4
(S,R)-2
(S,S)-3
(S,R)-2
(S,S)-3
(S,R)-2
(S,S)-3
(S,R)-2
(S,S)-3
(S,R)-2
(S,S)-3
(S,R)-2
(S,S)-3
(S,R)-2
(S,S)-3
88
86
85
78
92
87
67
78
80
74
70
85
86
95
94 (S)
94 (R)
95 (S)
95 (R)
95 (S)
92 (R)
87 (S)
88 (R)
98 (S)
96 (R)
76 (S)
69 (R)
80 (S)
77 (R)
1-Naphthyl
2-MeOC6H4
4-MeOC6H4
c-C6H11
summarized in Figure 1.6,12 Initially, the zinc catalyst A with a
seven-membered ring is generated by the reaction of 1,4-amino
alcohol ligand (S,R)-2 or (S,S)-3 with diethylzinc. In both cases,
the most suitable conformation of the seven-membered ring
would be a pseudo boat conformation for the coordination of
another diethylzinc and aldehyde from the less hindered side of
the complex to form a transition structure B and C. The ethyl
group of the benzylic carbon bearing the amino group is thought
to occupy the pseudo-equatorial position to avoid the steric
hindrance of the dimethylamino group, and the absolute
configuration of the benzylic carbon having a hydroxy group
has little influence on the formation of the boat structure. As a
result, both S- and R-chiral secondary alcohols should selec-
tively be obtained from the transition state B and C generated
from (S,R)-2 and (S,S)-3, respectively.
(E)-PhCH=CH
PhCH2CH2
b
aIsolated yield. Determined by HPLC analysis.
As both enantiomers of 1-phenyl-1-propanol were obtained
with high enantioselectivities by using the two diastereomeric
1,4-amino alcohols (S,R)-2 and (S,S)-3, the reactions of various
aldehydes were then examined (Table 2). In all cases, the
corresponding chiral secondary alcohols with S and R config-
urations were obtained predominantly by using (S,R)-2 and
(S,S)-3, respectively. The reactions of aromatic aldehydes with
bromo or methoxy groups, 1-naphthaldehyde, and cyclohex-
anecarboxaldehyde afforded the corresponding chiral secondary
alcohols with high enantioselectivities, and the values of the
enantiomeric excesses were almost the same between the
reactions using (S,R)-2 and (S,S)-3 (Entries 1-10). Although
the reported enantioselectivities of products were often low in
the reactions of sterically less-hindered (E)-cinnamaldehyde and
3-phenylpropanal using 1,4-amino alcohols,6 the corresponding
products were obtained with good enantioselectivities by using
(S,R)-2 and (S,S)-3 (Entries 11-14).
In conclusion, both enantiomers of 1-substituted 1-
propanols were obtained by the enantioselective addition of
diethylzinc to various aldehydes in the presence of two
diastereomeric 1,4-amino alcohols (S,R)-2 and (S,S)-3, both of
which were obtained from the same chiral source (S,S)-1. The
stereochemical outcome of the reaction was controlled solely by
the absolute configuration of the benzylic carbon bearing amino
group. Further studies are now in progress on the use of the
novel 1,4-amino alcohols for other asymmetric reactions.
This work was supported by JSPS KAKENHI Grant
Number 24550113. The authors are grateful to Mr. Shinji
Ishihara and Dr. Hironari Kurihara (Instrumental Analysis
Center, Yokohama National University) for their technical
assistance in the elemental analyses and the high-resolution
mass spectrometric analyses.
The proposed catalytic cycles and transition-state structures
for the enantioselective addition using (S,R)-2 or (S,S)-3 are
Supporting Information is available electronically on J-STAGE.
346 | Chem. Lett. 2015, 44, 345–347 | doi:10.1246/cl.141113
© 2015 The Chemical Society of Japan

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Typical experimental procedure: To an Et2O (3.0 mL)
solution of (S,R)-2 (33 mg, 0.15 mmol) under an atmosphere
of argon was added a hexane solution of diethylzinc (1 M,
3.0 mL) through a syringe at 0 °C, and the mixture was
stirred at room temperature for 30 min. After the mixture was
cooled to 0 °C, an Et2O (2.0 mL) solution of benzaldehyde
(160 mg, 1.5 mmol) was added and the reaction mixture was
stirred at 0 °C for 18 h. Saturated ammonium chloride
solution (2 mL) and 2 M HCl (10 mL) were added to the
reaction mixture. The organic layer was separated and the
aqueous layer was extracted with ether three times. The
combined organic layer was washed with water and brine,
and dried over anhydrous sodium sulfate. After removal
of the solvent under reduced pressure, crude product was
purified by preparative TLC (hexane/Et2O = 2:1) to give
(S)-1-phenyl-1-propanol (171 mg, 84%). The ee was deter-
mined to be 97% by HPLC analysis using a chiral column
(Daicel Chiralcel OD-H (25 cm © 0.46 cm i.d.); 254 nm UV
detector; eluent, hexane/i-PrOH = 97/3; flow rate, 0.5
mL min¹1; t, 18.4 min for minor peak, 22.1 min for major
peak).
5
6
10 Similar results were obtained in the reactions using
ferrocenyl 1,4-amino alcohols.6i
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Chem. Lett. 2015, 44, 345–347 | doi:10.1246/cl.141113
© 2015 The Chemical Society of Japan | 347