Design of axially chiral dicarboxylic acid for asymmetric mannich reaction of arylaldehyde N-boc imines and diazo compounds

Article abstract of DOI:10.1021/ja0713375

An axially chiral dicarboxylic acid has been prepared as a new class of chiral hydrogen-bonding catalysts and applied to the highly enantioselective Mannich reaction of arylaldehyde N-Boc imines and diazo compounds. Copyright

Full text of DOI:10.1021/ja0713375

Published on Web 07/27/2007
Design of Axially Chiral Dicarboxylic Acid for Asymmetric Mannich Reaction
of Arylaldehyde N-Boc Imines and Diazo Compounds
Takuya Hashimoto and Keiji Maruoka*
Department of Chemistry, Graduate School of Science, Kyoto UniVersity, Sakyo, Kyoto 606-8502, Japan
Received February 26, 2007; E-mail: maruoka@kuchem.kyoto-u.ac.jp
The state-of-the-art asymmetric hydrogen-bonding catalysis
mainly relies on the use of thiourea, diol, and phosphoric acid as
hydrogen-bonding donors.1 Despite the fact that the key feature
of these catalyses is the choice of a catalyst with appropriate acidity,
the important class of moderate Brønsted acids, carboxylic acids,
Table 1. Asymmetric Mannich Reaction of Benzaldehyde N-Boc
Imine and tert-Butyl Diazoacetatea
,2
3
has rarely been employed in these catalyses. This is quite surprising
because carboxylic acids are often utilized as one of the most
4
promising acid catalysts in various organic transformations. We
assumed that the poor reactivity of the carboxylic acid and the
difficulty in building an effective chiral recognition site around the
carboxylic acid might be the main reasons for this deficiency. In
an effort to address this issue, we prepared chiral dicarboxylic acid
catalysts, which consist of two carboxylic acids and an axially chiral
binaphthyl moiety, and applied them to highly enantioselective
Mannich reaction of N-Boc imines and diazo compounds.
conditions
yield (%)b
ee (%)c
entry
catalyst (mol %)
(°C, h)
1
2
3
4
5
6
7
8
9
2-NpCO2H (20)
rac-4a (10)
rac-BNDHP (10)
(R)-4a (10)
(R)-4b (10)
(R)-4c (10)
(R)-4d (10)
(R)-4e (10)
(R)-4e (5)
(R)-4f (5)
rt, 40
rt, 40
rt, 0.5
rt, 20
rt, 6
rt, 20
rt, 20
rt, 16
0, 15
0, 38
0, 20
3
41
17 (22)e
33
5-7
Asymmetric addition of diazoacetate to imines
was selected
0
29
17
49
69
74
95
95
33
25
35
38
39
38
81
as a starting point of the research in conjunction with our interest
8
in the use of diazoacetate in organic synthesis (Table 1). The initial
attempt with benzaldehyde N-Boc imine 1 and tert-butyl diazo-
acetate under the influence of 2-naphthoic acid was not fruitful
and provided only a trace amount of the desired compound rac-2
1
1
0
1
d
(R)-4e (5) + MS4Å
(entry 1). To enhance the reactivity, a second carboxylic acid was
introduced into the catalyst since such a dual activation by two
acidic components in one catalyst is a commonly utilized approach
both in Lewis acid and hydrogen-bonding catalysis.1,9 Gratifyingly,
a
Reactions were performed with benzaldehyde N-Boc imine (0.10 mmol)
and tert-butyl diazoacetate (0.12 mmol) in the presence of a dicarboxylic
b
c
acid in CH2Cl2 (1 mL). Isolated yield. Determined by chiral HPLC
analysis. d With MS 4 Å (100 mg). e Isolated yield of 3.
the reaction catalyzed by rac-1,1′-binaphthyl-2,2′-dicarboxylic acid
Scheme 1. Preparation of the Dicarboxylic Acid (R)-4fa
4
2
2
a was found to be promising, providing rac-2 in 41% yield (entry
). As a comparison, the reaction catalyzed by 1,1′-binaphthyl-
,2′-diyl hydrogenphosphate (abbreviated as BNDHP in Table 1)
6
was examined, which was revealed to furnish not only rac-2 but
a considerable amount of side products, tentatively assigned as E/Z
isomers of the ene carbamates 3 (entry 3).10 These observations
clearly indicated the necessity to use the catalyst with the appropri-
ate acidity in hydrogen-bonding catalysis.
Capitalizing on the axially chiral nature of 4a, the reaction was
then conducted in the presence of optically pure (R)-4a.1 However,
no appreciable asymmetric induction was observed (Table 1, entry
a
Conditions: (a) (i) SOCl2; (ii) TMSCH2CH2OH, pyridine, THF, 97%;
1
(b) (i) Mg(TMP)2, THF; (ii) Br2, THF, 44%; (c) 2,6-Me2-4-t-Bu-
C6H2B(OH)2, Pd(OAc)2, 2-(2′,6′-dimethoxybiphenyl)dicyclohexylphosphine,
K3PO4, toluene, 62%; (d) TBAF, THF, 74%.
4). At this point, we turned our attention to the introduction of aryl
groups at the 3,3′-position of (R)-4a in consideration of our recent
report on the synthesis of 3,3′-diaryl-1,1′-binaphthyl-2,2′-dicar-
boxylic acid esters (Scheme 1).1
butyl group may impart the axial chirality of the binaphthyl moiety
to the substrate (entries 7, 8). Molecular sieves 4 Å would prevent
the imine hydrolysis.
2-14
15
After evaluation of some aryl groups, use of 3,3′-dimesityl
dicarboxylic acid (R)-4e was found to be encouraging, providing 2
in 38% yield with 69% ee (entry 8). The enantiomeric excess could
be improved by performing the reaction at 0 °C (entry 9). Further
With the optimized condition in hand, the scope of the Mannich
reaction with various arylaldehyde N-Boc imines was surveyed as
shown in Table 2. High enantiomeric excess was observed
regardless of the substituent pattern at the aryl group, although the
reaction rate dropped significantly when the o-tolyl imine was
utilized (entries 1-5). The reaction was general for both electron-
rich and electron-poor substrates, furnishing the corresponding
products in excellent ee (entries 6-9). In the case of imine bearing
a heteroaromatic group, slight decrease of the enantiomeric excess
was observed (entry 10).
experiments proved the effectiveness of 3,3′-bis(2,6-Me
2
-4-t-Bu-
6 2
C H
) dicarboxylic acid (R)-4f and molecular sieves 4 Å (entries
10, 11). Under this condition, the reaction could be carried out with
5
mol % of (R)-4f at 0 °C, leading to the adduct 2 in 81% yield
with 95% ee (entry 11). We speculate that 2,6-dimethyl groups
contribute to rigidify the flexible aryl-aryl bond axis, and the 4-tert-
10054
9
J. AM. CHEM. SOC. 2007, 129, 10054-10055
10.1021/ja0713375 CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Asymmetric Mannich Reaction of Arylaldehyde N-Boc
Imines and tert-Butyl Diazoacetate
acids in asymmetric catalysis is currently underway in our labora-
tory.
a
Acknowledgment. This work was partially supported by a
Grant-in-Aid for Scientific Research from the Ministry of Education,
Culture, Sports, Science and Technology, Japan.
entry
Ar
time (h)
yield (%)b
ee (%)c
Supporting Information Available: Experimental details and
characterization data for new compounds (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
1
2
3
4
5
6
7
8
9
Ph
o-tolyl
m-tolyl
p-tolyl
24
72
20
18
17
20
26
72
20
5
80
53
74
79
77
83
89
38
72
84
95 (R)d
90
92
95
94
95
96
95
95
2-Np
References
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Ar
time (h)
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1
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Ph
p-tolyl
p-FC6H4
p-ClC6H4
p-MeOC6H4
2-furyl
85
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46
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(
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a
Reactions were performed with arylaldehyde N-Boc imine (0.10 mmol)
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f (0.005 mmol) and MS 4 Å (100 mg) in CH2Cl2 (1 mL). Isolated yield.
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(
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Scheme 2. Derivatization of the Mannich Adducta
(
(
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a
Conditions: (a) Pd/C, H2 (balloon), MeOH; (b) CH2Cl2/TFA (10:1).
Our synthetic methodology was further exploited in the hitherto
unknown catalytic asymmetric Mannich reaction of N-Boc imines
and dimethyl diazomethylphosphonate (Table 3), as a means of
creating optically enriched â-aminophosphonate derivatives.1 The
identical reaction condition as described above was employed to
give the various R-diazo-â-aminophosphonates in a highly enan-
tioselective manner.
To demonstrate the synthetic utility and to establish the absolute
configuration,18 the adduct 5 was subjected to the catalytic
hydrogenation condition and deprotection. Consequently, dimethyl
â-phenyl-â-aminophosphonate 7 was obtained in good yield without
an erosion in the enantiomeric excess (Scheme 2).
(
10) In contrast to N-Boc imines, the reaction of N-acyl imines catalyzed by
this type of phosphoric acid catalysts provided the adduct cleanly; see ref
6.
(
11) Seki, M.; Yamada, S.; Kuroda, T.; Imashiro, R.; Shimizu, T. Synthesis
2000, 1677.
6,17
(
(
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T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J. Am. Chem.
Soc. 2005, 127, 4685.
(
(
14) For details, see Supporting Information.
15) BNDHP-catalyzed reaction re-evaluated in the presence of MS 4 Å
improved the total yield of the products (56%) with the same ratio of 2
and 3.
(
16) Juaristi, E., Soloshonok, V., Eds. EnantioselectiVe Synthesis of â-Amino
Acid, 2nd ed.; John Wiley and Sons: Hoboken, NJ, 2005.
17) For the base-catalyzed Mannich reaction of N-Ts imines and dimethyl
diazomethylphosphonate, see: Zhao, Y.; Jiang, N. Wang, J. Tetrahedron
Lett. 2003, 44, 8339.
(
In summary, we have developed asymmetric Mannich reactions
of diazo compounds catalyzed by a novel axially chiral dicarboxylic
acid. Further research to expand the utility of chiral dicarboxylic
(
18) Xu, C.; Yuan, C. Eur. J. Org. Chem. 2004, 4410.
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J. AM. CHEM. SOC.
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