Enantioselective Mannich-type reaction catalyzed by a chiral Bronsted acid derived from TADDOL

Article abstract of DOI:10.1002/adsc.200505167

A novel cyclic dialkyl phosphate was synthesized starting from (+)-diethyl tartrate. Its catalytic activity as a chiral Bronsted acid has been examined in the Mannich-type reaction of a ketene silyl acetal with aldimines as a model reaction. The correspon

Full text of DOI:10.1002/adsc.200505167

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DOI: 10.1002/adsc.200505167
Enantioselective Mannich-Type Reaction Catalyzed
by a Chiral Brønsted Acid Derived from TADDOL
Takahiko Akiyama,* Youichi Saitoh, Hisashi Morita, Kohei Fuchibe
Department of Chemistry, Faculty of Science, Gakushuin University, 1-5-1 Mejiro, Toshima-ku, Tokyo 171-8588, Japan
Fax: þ81-3-5992-1029, e-mail: takahiko.akiyama@gakushuin.ac.jp
Received: April 22, 2005; Accepted: July 11, 2005
Abstract: A novel cyclic dialkyl phosphate was syn-
thesized starting from (þ)-diethyl tartrate. Its cata-
lytic activity as a chiral Brønsted acid has been ex-
amined in the Mannich-type reaction of a ketene sil-
yl acetal with aldimines as a model reaction. The cor-
responding b-amino acid esters were obtained with
high enantioselectivity.
scaffold (2) because the TADDOL scaffold is expected
to have different electronic and steric impacts in com-
parison with the BINOL scaffold. In this communica-
tion, we report the preparation of novel chiral phos-
phate 2 starting from (þ)-diethyl tartrate and its catalyt-
ic activity in the Mannich-type reaction.
The catalysts were prepared starting from methyli-
dene-protected (þ)-diethyl tartrate through Grignard
addition followed by phosphorylation (Scheme 1). Di-
rect transformation of TADDOL derivative 3 to cyclic
phosphate 2 by use of POCl3, which was effective for
the preparation of chiral phosphate 1 bearing the BI-
NOL scaffold,[5] was unsuccessful. Therefore, an alter-
native synthetic route was devised by treatment of 3
Keywords: asymmetric synthesis; Brønsted acid;
Mannich-type reaction; organic catalysis; TADDOL
The development of novel chiral catalysts continues to with PCl3 and subsequent oxidation of dialkyl phosphite
be an important goal of synthetic organic chemistry.[1]
Recently, small organic compounds have been recog-
4
[9] by I2, affording dialkyl phosphate 2 in good yields.
At the outset, the Mannich-type reaction of an ald-
nized as efficient chiral catalysts for a number of syn- imine 5 with ketene silyl acetal 6 was examined by use
thetic reactions.[2] As part of our ongoing program di- of 5 mol% of Brønsted acid 2 and the results are shown
rected towards the development of carbon-carbon in Table 1. When 2a (Ar¼Ph) was employed in toluene
bond forming reactions catalyzed by Brønsted acids,[3]
we focused on strong chiral Brønsted acids as the elec-
trophilic activator of carbon-nitrogen double bond.[4]
We designed the novel chiral phosphate (1) as a bifunc-
tional Brønsted acid, starting from (R)-BINOL, and
have demonstrated its catalytic activity in the enantiose-
lective Mannich-type reaction of ketene silyl acetal with
an aldimine.[5,6] Although Lewis acid catalysts[7] and or-
ganocatalysts such as l-proline[8] have been employed
for enantioselective Mannich-type and Mannich reac-
tions, chiral strong Brønsted acids had not been reported
as a chiral catalyst for this reaction. We next paid atten-
tion to chiral Brønsted acids based on the TADDOL
Scheme 1. Preparation of chiral catalysts; yields are given for
Ar¼p-CF3C6H4.
Figure 1. Plausible transition state.
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Table 1. Effect of the Brønsted acid.[a]
Entry
Ar
Acid
Time [h]
Yield [%]
ee [%]
1
2
3
4
Ph
2a
2b
2c
2d
24
66
26
21
0
47
63
97
–
31
34
73
p-C6H5C6H4
p-FC6H4
p-CF3C6H4
[a]
1.5 equivs. of ketene silyl acetal 6 and 5 mol % of Brønsted acid 2 were employed.
at ꢀ788C, no reaction took place and imine 5 was
We further screened the N-substituents of imine and
recovered (entry 1). Introduction of substituents on the results are shown inTable 3. As expected, 4-methoxy-
the aromatic rings had beneficial effects. When 2b phenyl group deteriorated the enantioselectivity (entry
(Ar¼p-C6H5C6H4) was employed, b-amino ester 7 was 1). Introduction of methyl group on the phenyl ring im-
obtained in 47% yield with 31% ee (entry 2). Use of proved the enantioselectivity[10] and 2-hydroxy-4-meth-
2d (R¼p-CF3C6H4) improved both chemical yield and ylphenyl group showed the highest enantioselectivity
enantioselectivity (73% ee) (entry 4). The stereochem- (entry 4).
istry of 7 was determined by comparison of the optical
rotation and retention time of the products by HPLC an- dimines with 6 catalyzed by 2d (5 mol %) are shown in
alysis.[5,7c]
Table 4. A range of aldimines derived from aromatic al-
The results of the Mannich-type reaction of various al-
Next, effect of the acetal moiety was examined by use dehydes gave b-amino esters in high yields with good to
of 2 (Ar¼p-CF3C6H4) and the results are shown in Ta- excellent enantioselectivities. Aldimines derived from
ble 2. It is noted that introduction of an alkyl or aryl moi- p-fluorobenzaldehyde and p-methylbenzaldehyde, in
ety on the methylene carbon decreased the enantiose- particular, gave b-amino esters 9 in 92% ee (entries 3
lectivity (entries 2–4). Variation of the aryl and acetal and 5). Although 10 mol % of the Brønsted acid 1, based
groups revealed that 2d was optimal for this purpose.
on the BINOL scaffold, was required,[5] the present
Table 2. Effect of the acetal moiety.[a]
Entry
R1, R2
Time [h]
Yield [%]
ee [%]
1
2
3
4
H, H
Me, Me
H, Ph
21
21
48
38
97
62
82
48
73
56
65
68
H, 1-naphthyl
[a]
1.5 equivs. of ketene silyl acetal 6 and 5 mol % of Brønsted acid 2 were employed.
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Enantioselective Mannich-Type Reaction
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Table 3. Effect of N-substituent.
Figure 2.
the imine and the phosphoryl oxygen interacted with
the hydrogen of the imineꢁs OH group by hydrogen
bonding (Figure 2).[11] The nucleophile attacked the
Re-face preferentially. Thus, 2 functioned as a bifunc-
tional Brønsted acid bearing a Brønsted basic site.
In summary, we have synthesized a novel chiral
Brønsted acid based on the TADDOL scaffold. In com-
parison to the Brønsted acid based on the BINOL scaf-
fold, the Mannich-type reaction was catalyzed at lower
loading (5 mol %) to give b-amino esters in higher enan-
tioselectivities (up to 92% ee). The present Brønsted
acid will add a new entry into the organocatalyst family
and its application to other asymmetric reactions is now
in progress in our laboratory.
Experimental Section
[a]
1.5 equivs. of ketene silyl acetal 6 and 5 mol % of Brønsted
acid 2d were employed.
Typical Procedure for the Mannich-Type Reactions
(Table 4, Entry 1)
Mannich-type reaction was catalyzed by lower loadings
(5 mol %) to afford b-amino esters in high yields.
Based on the above results, we surmise that the Man-
nich-type reaction took place via a 9-membered transi-
To a solution of N-benzylidene-2-hydroxy-4-methylaniline (8;
Ar¼C6H5) (31.7 mg, 0.150 mmol) and phosphate 2d (5.8 mg,
0.0075 mmol) in toluene (1 mL) was added dropwise a solution
tion state, wherein the phosphate hydrogen activated of ketene silyl acetal 6 (45 mL, 0.225 mmol) for 3 min at
Table 4. Results of the Mannich-type reactions catalyzed by 2d.[a]
Entry
Ar
Time [h]
Yield [%]
Ee [%]
1
2
3
4
5
Ph
30
51
48
51
48
100
81
95
85
96
89
85
92
89
92
4-ClC6H4
4-FC6H4
4-MeOC6H4
4-CH3C6H4
[a]
1.5 equiv of ketene silyl acetal 6 and 5 mol% of Brønsted acid 2d were employed.
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ꢀ 788C. After being stirred for 30 h at that temperature, the
mixture was quenched by successive addition of saturated
NaHCO3 (5 mL), saturated KF solution (3 mL), and MeOH/
THF (3 mL) at ꢀ788C and was kept stirring for further
30 min at room temperature. The mixture was extracted with
ethyl acetate. The combined organic layers were washed with
brine, dried over anhydrous Na2SO4, and concentrated to
dryness. The remaining solid was purified by TLC (SiO2,
hexane:ethyl acetate¼5:1 v:v) to give b-amino ester 9
(Ar¼C6H5); yield: 46.9 mg (0.150 mmol, 100%). The enantio-
meric excess was determined to be 89% on a Daicel Chiralpak
AD-H column.
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Acknowledgements
This work was supported by a Grant-in-Aid for Scientific Re-
search (No. 15550042 and 17550046) from the Ministry of Edu-
cation, Science, Sports, Culture, and Technology, Japan.
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