Effective construction of quaternary stereocenters by highly enantioselective α-amination of branched aldehydes

Article abstract of DOI:10.1039/c0ob00406e

A highly efficient enantioselective α-amination of branched aldehydes with azadicarboxylates promoted by chiral proline-derived amide thiourea bifunctional catalysts was developed for the first time, affording the adducts bearing quaternary stereogenic centers with excellent yields (up to 99%) and enantioselectivities (up to 97% ee).

Full text of DOI:10.1039/c0ob00406e

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Effective construction of quaternary stereocenters by highly enantioselective
a-amination of branched aldehydes†
Ji-Ya Fu,a,b Xiao-Ying Xu,a Yan-Chun Li,a,b Qing-Chun Huanga and Li-Xin Wang*a
Received 9th July 2010, Accepted 6th August 2010
DOI: 10.1039/c0ob00406e
A highly efficient enantioselective a-amination of branched
aldehydes with azadicarboxylates promoted by chiral proline-
derived amide thiourea bifunctional catalysts was developed
for the first time, affording the adducts bearing quaternary
stereogenic centers with excellent yields (up to 99%) and
enantioselectivities (up to 97% ee).
Introduction
Optically active nitrogen-containing compounds are versatile and
fascinating building blocks in organic synthesis.1 Particularly,
those with chiral quaternary stereogenic centers are widely
used in the preparation of natural products, biologically active
molecules and pharmaceuticals.2 Over the past years, numer-
ous strategies have been developed for the construction of
Fig. 1 Secondary amine-thiourea bifunctional catalysts.
L-prolic amide skeleton haven’t drawn enough attention13 except
these interesting structures, typical examples include the reac-
tion of 2-oxindoles3 with azadicarboxylates, the enantioselective
a-amination of cyanoacetates,4 alkylidene cyanoacetates5 and
branched aldehydes.6,7 Among them, the amination of branched
aldehydes is one of the straightforward methods to access
nitrogen-containing compounds with quaternary stereocenters.8
In 2003, Bra¨se and co-workers6 first reported the a-amination
of branched aldehydes with azadicarboxylates catalyzed by 50
mol% L-proline in moderate results, and recently, an improved
result was obtained for the same reaction with the aid of
microwave irradiation.7 Barbas9 applied the a-amination of 3-
(4-bromophenyl)-2-methylpropanal catalyzed by chiral L-proline-
derived tetrazole to construct LFA-1 antagonist BIRT-377 in
95% yield and 80% ee, and the amino-aldehyde was obtained in
>99% ee after recrystallization. To the best of our knowledge,
the a-aminations of simple and unsubstituted chain aldehydes
are well established,10 while the highly effective reaction of a,a-
disubstituted aldehydes is less exploited and it is still highly
challenging and desirable to develop new efficient catalytic systems
for this transformation.
for in our recent works on asymmetric Michael additions and a-
amination of simple aldehydes.14a,14b,14e As a part of our continuing
interest in asymmetric synthesis,14 herein, we wish to report
the further application of these chiral proline amide-thiourea
bifunctional catalysts in the promotion of the enantioselective a-
amination of branched aldehydes with azodicarboxylates.
Results and discussion
To determine the optimal asymmetric a-amination reaction
conditions, 2-phenylpropionaldehyde (2a) and diethyl azadicar-
boxylate (DEAD) (3a) were used as model reactants and the
results are summarized in Table 1. All catalysts were screened
in CH3CN, moderate to excellent yields (75–96%) and good
enantioselectivities (46–85% ee) were achieved (Table 1, entries
1–4). Comparatively, catalyst 1a, bearing an R,R-linker, gave a
better yield and enantioselectivity (Table 1, entry 1) probably due
to the compatibility of the two catalytic chiral centers, and was
chosen for further optimization.
Bifunctional thiourea catalysts, which are powerful tools to
simultaneously activate both donors and acceptors, have been
investigated extensively in asymmetric reactions.11 Primary and
tertiary amine-thioureas have been well identified as powerful
catalysts,12 while the secondary amine-thioureas, especially cat-
alysts 1a–1d (Fig. 1) with two catalytic sites of chiral thiourea and
Then a series of solvents were evaluated and the results are
listed in Table 1. The results revealed that enantioselectivities and
yields are highly variable with solvents. In less polar solvents
such as CH2Cl2, DCE, CHCl3, 1a delivered excellent yields (up
to 96%) and good enantioselectivities (up to 87% ee) (Table 1,
entries 5–9). Comparatively, when the reaction was carried out in
polar solvent such as MeOH, only poor yield (35%) and moderate
enantioselectivity (66% ee) were obtained (Table 1, entry 14). These
results indicated that CH2Cl2 is a suitable candidate solvent for
this reaction (Table 1, entry 7). A wide range of acid and base
additives were also investigated.15 The results indicated that o-
hydroxybenzoic acid was the most promising additive and afforded
the best result in both yield and enantioselectivity (Table 1, entry
15, 99% yield and 90% ee) and was selected for further studies.
aKey Laboratory of Asymmetric Synthesis and Chirotechnology of Sichuan
Province, Chengdu Institute of Organic Chemistry, Chinese Academy
of Sciences, Chengdu, 610041, China, PR. E-mail: wlxioc@cioc.ac.cn;
Fax: +86-028-8525-5208
bGraduate University of Chinese Academy of Sciences, Beijing, 10039,
People’s Republic of China
† Electronic supplementary information (ESI) available: Experimental
details, NMR spectra and HPLC traces. See DOI: 10.1039/c0ob00406e
4524 | Org. Biomol. Chem., 2010, 8, 4524–4526
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Table 1 Optimizing the reaction conditionsa
Entry
Catalyst
Solvent
Additive
Temp./◦C
Cat. Loading (%)
Time/h
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19d
1a
1b
1c
1d
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
CH3CN
CH3CN
CH3CN
CH3CN
toluene
cyclohexane
DCM
CH2ClCH2Cl
CHCl3
Et2O
THF
dioxane
DMF
MeOH
DCM
DCM
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
2-OHPhCOOH
2-OHPhCOOH
2-OHPhCOOH
2-OHPhCOOH
2-OHPhCOOH
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
0
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
10
5
20.5
27
15.5
20.5
11
11
8.5
21
11
3.5
11
11
49
26
1
6
21.5
47.5
23
94
75
84
96
88
99
96
87
80
85
46
84
85
35
99
91
88
77
96
85(R)
49(R)
66(R)
46(R)
79
81
87
87
84
79
72
79
70
66
90
93
95
96
96
DCM
DCM
DCM
0
0
0
10
a Unless otherwise specified, all reactions were carried out with 2a (0.30 mmol), 3a (0.20 mmol), the catalyst 1 in the specified solvent (1.0 mL) and additive
(the same eq. as catalyst). b Isolated yield. c Determined by HPLC with a Chiralpak-AS column and the absolute configuration of 4a was assigned as R6c
d Additive (0.02 mmol).
Table 2 Scope of substratesa
Other parameters such as temperature, catalyst loading, amount
of 2a and additive loading were also investigated.15 The reaction
temperature has a slight effect on the enantioselectivities. When the
◦
reaction was carried out at 0 C, the enantioselectivity increased
slightly (Table 1, entry 16). Decreasing the catalyst loading to
10 mol% (Table 1, entry 17), the enantioselectivity was increased
to 95% ee. Acid additive loading also affected the yields, and
20 mol% o-hydroxybenzoic acid gave the best result (Table 1,
entries 17 vs. 19, 96% yield, 96% ee). Through those screenings,
the optimized reaction conditions were found to be reaction of 1.0
eq. azodicarboxylate with 1.5 eq. 2a, in the presence of 10 mol%
of 1a and 20 mol% of o-hydroxybenzoic acid in dichloromethane
at 0 ◦C.
Finally, the scope of the branched aldehydes with different
azodicarboxylates under the optimized reaction conditions were
evaluated and the results are shown in Table 2. Excellent yields (up
to 99%) and enantioselectivities (up to 97% ee) were obtained for a
wide range of aldehydes bearing electron-withdrawing or donating
groups on different sites.
Generally, aliphatic substituted aldehydes afforded lower yields
(Table 2. entries 3, 4) than aromatic substituted aldehydes (Table 2,
entries 5–20). The electronic properties on the aromatic ring
of aldehydes have no obvious effects on the enantioselectivities
(Table 2, entries 5–20), whereas steric hindrances of the sub-
stituents on the aromatic ring greatly affected the enantioselec-
tivities (Table 2, entries 11 vs. 13, 16 vs. 18). With diisopropyl
azodicarboxylate (DIAD) in hand, we also investigated its effect
on this reaction, good yields (up to 94%) and enantioselectivities
(up to 97% ee) were also obtained.
Entry R1
R2
Et
Time/h Product Yield (%)b Ee (%)c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Ph (2a)
23
4a-Et
4a-i-Pr 87
4b-Et 52
4b-i-Pr 54
4c-Et 93
4c-i-Pr 81
4d-Et 86
4d-i-Pr 92
4e-Et 99
4e-i-Pr 94
4f-Et 99
96
96
97
—
—
81
80
93
97
94
96
94
94
nd
97
93
93
96
nd
90
95
Ph (2a)
i-Pr 32
Et 45
i-Pr 45
Et 50
i-Pr 32
Et 24
i-Pr 32
Et 20
i-Pr 32
Et 20
i-Pr 32
Et 50
i-Pr 56
d
d
n-Pr (2b)
n-Pr (2b)
p-NO2Ph (2c)
p-NO2Ph (2c)
p-BrPh (2d)
p-BrPh (2d)
p-FPh (2e)
p-FPh (2e)
m-ClPh (2f)
m-ClPh (2f)
o-ClPh (2g)
o-ClPh (2g)
4f-i-Pr 90
4g-Et
trace
4g-i-Pr 30
p-CH3OPh (2h) Et
22
22
4h-Et
4i-Et
4i-i-Pr
4j-Et
4k-Et
80
80
85
nr
92
p-CH3Ph (2i)
p-CH3Ph (2i)
o-CH3Ph (2j)
2-Naph (2k)
2-Naph (2k)
Et
i-Pr 20
Et
Et
72
10
i-Pr 15.5
4k-i-Pr 90
a Unless otherwise specified, all reactions were carried out with 2
(0.3 mmol), 3 (0.20 mmol), the catalys◦t 1a (0.02 mmol) and 2-OHPhCOOH
(0.04 mmol) in DCM (1.0 mL) at 0 C. b Isolated yield. c Determined by
HPLC with Chiralpak column. d The ee could not be determined by GC
or HPLC with chiral stationary phase.
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In summary, we have successfully applied the secondary amine-
thiourea bifunctional catalysts 1a–1d to promote the direct asym-
metric a-amination of various branched aldehydes with azodicar-
boxylates in excellent yields (up to 99%) and enantioselectivities
(up to 97% ee) and provided an effective and enantioselective
method for the construction of quaternary stereocenters. Further
applications of these catalysts in other reactions are currently
underway in our laboratory.
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4526 | Org. Biomol. Chem., 2010, 8, 4524–4526
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