Asymmetric trialkylaluminium addition to aldehydes catalyzed by titanium complexes of N-sulfonylated amino alcohols with two stereogenic centers

Article abstract of DOI:10.1039/b103618c

The asymmetric methylation, ethylation and allylation of aldehydes using trialkylaluminium reagents catalyzed by titanium(IV) complexes of N-sulfonylated amino alcohols gave excellent enantioselectivities of up to 99% ee.

Full text of DOI:10.1039/b103618c

Asymmetric trialkylaluminium addition to aldehydes catalyzed by
titanium complexes of N-sulfonylated amino alcohols with two
stereogenic centers
Jing-Song You,† Sheng-Hsiang Hsieh and Han-Mou Gau*
Department of Chemistry, National Chung-Hsing University, Taichung, Taiwan 402.
E-mail: hmgau@dragon.nchu.edu.tw
Received (in Cambridge, UK) 23rd April 2001, Accepted 20th June 2001
First published as an Advance Article on the web 1st August 2001
The asymmetric methylation, ethylation and allylation of
aldehydes using trialkylaluminium reagents catalyzed by
titanium(IV) complexes of N-sulfonylated amino alcohols
gave excellent enantioselectivities of up to 99% ee.
chiral ligand, the asymmetric triethylaluminium addition to
benzaldehyde was examined to afford low ee values of 29% (R)
and 2% (S), respectively. The above results prompted us to
synthesize a series of amino alcohols with two stereogenic
centers, hoping to learn more about the structural factors that
influence the enantioselectivity. Based on the route described
by Reetz et al.,12 amino alcohols 2 with two stereogenic centers
starting from (S)-amino acids were synthesized. Compound 2
further reacted with arylsulfonyl chloride to give N-sulfonylated
amino alcohol derivatives (R,S)-3a, (R,S)-4a–c, and (S,S)-4a.
Asymmetric triethylaluminium additions to benzaldehyde
catalyzed by titanium(IV) complexes were conducted [eqn. (1)],
Catalytic asymmetric carbon–carbon bond formation has been
one of the most studied subjects in the past 10 years.1 In these
studies, the enantioselective additions of organozinc to alde-
hydes are one of the most reliable processes and thus gain much
attention from chemists.2–6 For alkylation reagents, trialk-
ylaluminium reagents are more interesting since they are
economically obtained in industrial scale.7 Therefore the
successful alkylation of aldehydes by trialkylaluminium should
have great potential for practical applications. Unlike the
diethylzinc addition to aldehydes which is extremely slow in the
absence of a catalyst, trialkylaluminium reagents themselves are
known to add to aldehydes at room temperature within hours.
Due to competing reactions, the development of enantiose-
lective catalysts for trialkylaluminium addition becomes much
more challenging. Recently, Chan et al. reported the first
example of asymmetric AlEt3 addition to aldehydes employing
titanium–BINOL systems with excellent ee’s.8 Subsequently,
two papers dealing with the asymmetric methylation9 and
ethylation10 of aldehydes by trialkylaluminium reagents were
also reported.
(1)
and the results are listed in Table 1.‡ While using 10 mol% of
N-sulfonylated b-amino alcohol (S)-1a or (S)-1b, the reaction
gave low ee values (entries 1 and 2). In using bidentate (R,S)-3a
with two stereogenic centers, the ee value dramatically
improved to 70% (entry 3). From entries 4–6, the tridentate
ligands (R,S)-4a were examined with variation of the amount of
Ti(O-i-Pr)4 added. Without the addition of Ti(O-i-Pr)4, the yield
of 1-phenylpropanol is 44% with ee value of only 4% (R) (entry
4). With the addition of 0.05 mmol Ti(O-i-Pr)4 (10 mol%),
which gives a molar ratio of 1+1 of Ti(O-i-Pr)4–(R,S)-4a, the ee
value improves to 45% (R) (entry 5). Similar to previous studies
of asymmetric diethylzinc addition to aldehydes, excess Ti(O-i-
Pr)4 is required in order to obtain the best enantioselectivity and,
in this study, the best ee value of 96% was obtained for a
catalytic system with a Ti(O-i-Pr)4–(R,S)-4a ratio of 18 (entry
Following our recent interest in titanium chemistry,11 we
herein report the synthesis of a family of amino alcohol
derivatives 1–4 with one or two stereogenic centers. For N-
sulfonylated amino alcohol derivative (S)-1a or (S)-1b as a
Table 1 Enantioselective addition of trialkylaluminium to benzaldehyde
catalyzed by in Situ-formed chiral ligand–Ti(O-i-Pr)4 catalytic systems in
THFa
Ti/O-i-Pr)4/ Yield
Entry
Compd. (mol%)
AlR3
mmol
(%)
% eeb
1
2
3
4
5
6
7
8
9
(S)-1a (10)
(S)-1b (10)
AlEt3
AlEt3
AlEt3
AlEt3
AlEt3
AlEt3
AlEt3
AlEt3
AlEt3
AlEt3
0.9
0.9
0.9
0
0.05
0.9
0.45
0.9
0.9
0.9
90
84
97
44
49
98
97
70
94
66
29 (R)
2 (S)
70 (R)
4 (R)
45 (R)
96 (R)
95 (R)
26 (S)
75 (R)
8 (S)
(R,S)-3a (10)
(R,S)-4a (10)
(R,S)-4a (10)
(R,S)-4a (10)
(R,S)-4a (5)
(S,S)-4a (10)
(R,S)-4b (10)
(R,S)-4c (10)
10
a Benzaldehyde, 0.5 mmol; trialkylaluminium, 1.25 mmol; reaction tem-
perature, 0 °C; reaction time, 12 h. b The ee values were determined by
HPLC with a chiral OD column.
† Postdoctoral research fellow from Department of Chemistry, Sichuan
University, P. R. China.
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Chem. Commun., 2001, 1546–1547
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b103618c

Table 2 Enantioselective addition of trialkylaluminium to aldehydes catalyzed by in situ-formed 10 mol% (R,S)-4a–Ti(O-i-Pr)4 catalytic systems in
THFa
Ti(O-i-Pr)4/
mmol
Entry
Aldehyde
AlR3
Yield (%)
% eeb
96 (R)
1
2
3
4
5
6
7
8
9
Benzaldehyde
AlEt3
AlEt3
AlEt3
AlEt3
AlEt3
AlEt3
AlMe3
AlMe3
AlMe3
AlMe3
(Allyl)AlEt2
(Allyl)AlEt2
0.9
0.9
0.9
0.9
0.9
0.9
0.9
0.9
0.9
0.9
0.9
0.9
98
100
94
100
100
54
100
95
100
99
4-Chlorobenzaldehyde
1-Naphthaldehyde
2-Naphthaldehyde
E-Cinnamaldehyde
Cyclohexanecarboxaldehyde
Benzaldehyde
1-Naphthaldehyde
Cyclohexanecarboxaldehyde
(E)-Cinnamaldehyde
Benzaldehyde
94 (R)
92 (R)
92 (R)
88 (R)
91 (R)c
98 (R)
96 (R)
91 (R)c
> 99 (R)
90 (R)
96 (R)
10
11
12
100
100
2-Naphthaldehyde
a Aldehyde, 0.5 mmol; trialkylaluminium, 1.25 mmol; Ti(O-i-Pr)4, 0.9 mmol; reaction temperature, 0 °C; reaction time, 12 h. b The ee values were determined
by HPLC with a chiral OD column. c Determined by HPLC with a chiralcel AS column after protecting as a benzoyl ester.
6). Even with the use of as little as 5 mol% of (R,S)-4a, 95% ee
was still obtained (entry 7). For chiral ligand (S,S)-4a which is
a diastereomer of (R,S)-4a, a much lower ee value of 26% was
aldehydes. Under a dry dinitrogen atmosphere, the ligand and Ti(O-i-Pr)4
Notes and references
‡ General procedures for the addition of trialkylaluminium reagents to
obtained (entry 8). When the substituent on the amino carbon
was replaced with a phenyl group ((R,S)-4b), the ee value
decreases to only 75% (entry 9). For (R,S)-4c with a tert-butyl
substituent instead of a phenyl group on the chiral alcoholic
carbon in (R,S)-4a, an ee value of 8% of S-configuration was
observed (entry 10). In the initial study of triethylaluminium
addition to benzaldehyde, a profound solvent effect was
observed, and only a coordinating solvent such as THF
prompted high enantioselectivities.
The enhanced unique reactivity of the N-sulfonylated amino
alcohol (R,S)-4a is suggested to arise from the following two
factors: (1) phenoxides are known to form strong bonds to group
4 transition metals, and with electron withdrawing halogen
groups, the phenoxide moiety may lead to enhance Lewis
acidity at the metal centre; (2) the phenolic ring provides
conformational rigidity which may be an important factor in the
transfer of asymmetry.
For examining the substrate generality, the best performing
(R,S)-4a–Ti(O-i-Pr)4 catalytic system was used (Table 2). Ee
values ranging from 92–96% (R) (entries 1–4) were recorded
for aromatic aldehydes with the best result observed for
benzaldehyde as a substrate. For the (E)-cinnamaldehyde, the ee
value is somewhat lower at 88% (entry 5). Interestingly, the
catalytic system catalyzed the ethylation of the aliphatic
cyclohexanecarboxaldehyde with an ee value of 91% (entry 6).
Though not many aldehydes were examined, the catalytic
system generally seems to work well for both aromatic and
aliphatic aldehydes.
In addition, other trialkylaluminium reagents such as AlMe3
and AlEt2(allyl)13 were also examined. AlMe3 was added to
aldehydes, to give exceptional ee values from 91 to 99% (entries
7–10). More interestingly, when allyldiethylaluminium was
used as an alkylation reagent, the allyl group rather than the
ethyl group selectively added to aldehydes to give the secondary
homoallyl alcohol with excellent ee values of 90% for
benzaldehyde (entry 11) and 96% for 2-naphthaldehyde (entry
12). For catalytic allylation reactions, this is the first example of
catalytically enantioselective allylation of aldehydes employing
the allyldialkylaluminium reagent, to the best of our knowl-
edge.
were mixed in 1.5 mL of dry THF at room temperature. After 1 hour, 1.25
mmol of AlEt3, AlMe3 or allyldiethylaluminum was added at 0 °C. After the
mixture was stirred for 30 min, the orange-colored solution was treated with
aldehyde (0.5 mmol) at 0 °C, kept at this temperature for 10 h, and quenched
with 1 M HCl. The aqueous phase was extracted with ethyl acetate (3 3 5
mL), dried over MgSO4, filtered and concentrated. Chromatography of the
residue on silica gel (elution with 5+1 hexane–ethyl acetate) gave the
alcohol. The enantiomeric purity of the product was determined by
HPLC.
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In summary, a family of N-sulfonylated amino alcohols have
been developed for asymmetric alkylation reactions. The (R,S)-
4a–Ti(O-i-Pr)4 system is an excellent catalyst for trialk-
ylaluminium addition to aldehydes at a convenient temperature
of 0 °C. Furthermore, the (R,S)-4a/Ti(O-i-Pr)4 catalytic system
shows a wide generality of trialkylaluminum reagents such as
AlEt3, AlMe3, or even (allyl)AlEt2.
We would like to thank the National Science Council of
Taiwan for financial support (NSC 89-2113-M-005-024).
13 T. Mukaiyama, N. Minowa, T. Oriyama and K. Narasaka, Chem. Lett.,
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