Enantioselective Mannich-type reaction catalyzed by a chiral Bronsted acid

Article abstract of DOI:10.1002/anie.200353240

No metal required: The Mannich-type reaction of ketene silyl acetals 2 with aldimines 1 proceeded highly enantioselectively to afford the syn isomer of β-aminoesters 3 with up to 96% ee under the influence of a chiral Bronsted acid 4 derived from (R)-BINO

Full text of DOI:10.1002/anie.200353240

Communications
Asymmetric Synthesis
Enantioselective Mannich-Type Reaction
Catalyzed by a Chiral Brønsted Acid**
Takahiko Akiyama,* Junji Itoh, Koji Yokota, and
Kohei Fuchibe
The enantioselective Mannich-type reaction of an enolate or
an enolate anion equivalent with aldimines constitutes a
useful method for the preparation of chiral b-amino carbonyl
compounds, which are the precursors of biologically impor-
tant compounds such as b-lactams and b-amino acids. The
development of chiral catalysts for the asymmetric Mannich-
type reaction has attracted the attention of synthetic organic
chemists.[1] Although stoichiometric amounts of chiral acid
were employed initially,[2] a number of enantioselective
catalysts such as chiral Lewis acid catalysts[3] and chiral base
catalysts[4] have been developed lately.
In addition to metal-based chiral catalysts,[5] the use of
small organic molecules as catalysts to promote asymmetric
reactions has emerged as a new frontier in reaction method-
ology.[6] Accordingly, l-proline derivatives[7] and peptide
derivatives[8] have been developed as catalysts for the
Mannich-type reactions. We previously reported that Man-
nich-type reactions[9] and the aza-Diels–Alder reaction[10]
proceed smoothly in the presence of a catalytic amount of a
strong Brønsted acid. We thus postulated that the use of a
chiral Brønsted acid, in which the proton is surrounded by
bulky substituents, may lead to effective asymmetric induc-
tion. We report herein an enantioselective Mannich-type
reaction of silyl enolates with aldimines catalyzed by a chiral
metal-free Brønsted acid.[11,12]
First, treatment of aldimine 1a (Scheme 1, R1 = Ph) and
ketene silyl acetal 2 (3.0 equiv) with 0.3 equivalents of the
chiral phosphate 4a[13,14,15] (which is readily prepared from
(R)-BINOL; Scheme 2) in toluene at À788C led to a smooth
Mannich-type reaction to give 3a (R1 = Ph). However, no
enantioselectivity was observed (Table 1, entry 1), as deter-
Scheme 1. Mannich-type reaction of aldimines 1 and ketene silyl
acetals 2 to form b-aminoesters 3.
[*] Prof. Dr. T. Akiyama, J. Itoh, K. Yokota, Dr. K. Fuchibe
Department of Chemistry, Faculty of Science
Gakushuin University
Mejiro, Toshima-ku, Tokyo 171-8588 (Japan)
Fax: (+81)-3-5992-1029
E-mail: takahiko.akiyama@gakushuin.ac.jp
[**] This work was supported by a Grant-in-Aid for Scientific Research
(No. 15550042) from the Ministry of Education, Science, Sports,
Culture, and Technology, Japan.
1566
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DOI: 10.1002/anie.200353240
Angew. Chem. Int. Ed. 2004, 43, 1566 –1568

Angewandte
Chemie
mined by HPLC analysis with a chiral stationary phase
column.[16] Next, we synthesized chiral phosphates 4b–e by
Suzuki coupling of bis(boronic acid) 5[17] followed by de-
methylation and subsequent phosphorylation, as shown in
Scheme 2. Introduction of aromatic groups at the 3,3’-
Aldimines derived from aromatic aldehydes afforded adducts
with good to high enantioselectivities. The chemical yields
were excellent in all cases.[19,20]
Next, other ketene silyl acetals were examined (Table 3).
Monosubstituted ketene silyl acetals led to high syn selectivity
Table 3: Diastereoselective Mannich-type reactions.[a]
Entry R1
R2
R3
Yield [%] syn/anti ee [%][b]
1
2
3
4
5
6
7
8
Ph
Me[c]
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
100
100
100
100
100
81
91
100
92
87:13
92:8
91:9
96
88
84
83
81
88
90
91
87
90
91
p-MeOC6H4 Me[c]
p-FC6H4
Me[c]
Me[c]
Me[c]
Me[c]
Me[c]
PhCH2
Scheme 2. Formation of chiral phosphates 4, readily available from
(R)-BINOL.
p-ClC6H4
p-MeC6H4
2-Thienyl
PhCH CH
Ph
p-MeOC6H4 PhCH2
PhCH CH
Ph
86:14
94:6
94:6
95:5
93:7
93:7
95:5
100:0
=
[d]
[d]
[d]
positions exerted a beneficial effect on the enantioselectivity.
Use of 4b as a chiral Brønsted acid in toluene increased the
enantiofacial selectivity to 27% ee (Table 1, entry 2). The
9
10
11
=
PhCH2
65
79
Ph3SiO[e] Me
[a] Aldimine 1 (1.0 equiv) and ketene silyl acetal 6 (1.5 equiv) were
treated with 4e (10 mol%) in toluene at À788C for 24 h. [b] ee value of
syn isomer. [c] E/Z=87:13. [d] E/Z=87:13. [e] E/Z=91:9.
Table 1: Effect of the aromatic substituents of 4.[a]
Entry
Ar
t [h]
Yield [%]
ee [%]
1
2
3
4
5
H
Ph
22
20
27
46
4
57
100
100
99
0
27
60
52
87
as well as excellent enantioselectivity. The ketene silyl acetal
derived from ethyl propionate furnished the corresponding
ester in 96% ee (Table 3, entry 1). Substituted aromatic,
heteroaromatic, and a,b-unsaturated aldimines also gave the
corresponding adducts with high enantioselectivities (Table 3,
entries 2–7). The reactions of ketene silyl acetals derived from
ethyl 3-phenylpropionate (Table 3, entries 8–10) and methyl
2-triphenylsilyloxyacetate (Table 3, entry 11) also exhibited
excellent syn selectivities[21] and high enantioselectivities.
Because the use of N-benzylideneaniline in place of 1a
(R1 = Ph) in the reaction with 2 lowered the enantioselectivity
to 39% ee, we concluded that the presence of the hydroxy
group in the ortho position of the aldimine is essential for the
present enantioselective Mannich-type reaction. This reaction
can be considered to proceed via an iminium salt, generated
from the aldimine and the Brønsted acid. Although the
precise mechanism has not been elucidated, it is supposed
that 3,3’-diaryl groups, which are not coplanar with the
naphthyl groups (see 8), would effectively shield the phos-
phate moiety, leading to efficient asymmetric induction.[22]
This is the first example of an enantioselective Mannich-type
reaction in which the carbon–nitrogen double bond is
2,4,6-Me3C6H2
4-MeOC6H4
4-NO2C6H4
96
[a] Aldimine 1a (R1 =Ph) (1.0 equiv) and 2 (3.0 equiv) were treated with
Brønsted acid 4 (30 mol%) in toluene at À788C.
introduction of 4-nitrophenyl groups (i.e. 4e) had a dual
effect: 1) improvement of enantioselectivity to 87% ee,
2) acceleration of reaction rate, thereby allowing the reaction
to go to completion in 4 h (Table 1, entry 5). The absolute
stereochemistry of 3a was determined by chiral HPLC
analysis by comparison of the retention time with that
found in the literature.[3c]
By further optimization of the reaction conditions, we
found that the use of aromatic solvents led to high enantio-
selectivities, whereas protic solvents gave racemates.[18] Fur-
thermore, a lower loading (10 mol%) of the Brønsted acid
was sufficient to retain the high enantioselectivity. The results
of the Mannich-type reaction of 2 with several aldimines
catalyzed by chiral Brønsted acid 4e are shown in Table 2.
Table 2: Catalytic enantioselective Mannich-type reactions.[a]
Entry
R1
Product
Yield [%]
ee [%]
1
2
3
4
Ph
3a
3b
3c
3d
98
100
100
100
89
89
85
80
p-MeC6H4
p-FC6H4
p-ClC6H4
[a] Aldimine 1 (1.0 equiv) and 2 (1.5 equiv) were treated with 4e
(10 mol%) in toluene at À788C for 24 h.
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Communications
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In summary, we have developed a chiral Brønsted acid
catalyzed enantioselective Mannich-type reaction of aldi-
mines with silyl enolates, and b-aminoesters were obtained
with high to excellent enantioselectivities under metal-free
conditions. This method adds a new entry to the catalogue
organo-catalyzed asymmetric reactions. This method can
potentially be extended to a variety of enantioselective
nucleophilic addition reactions to carbon–nitrogen double
bonds. Further investigations to clarify the reaction mecha-
nism and its application to other enantioselective reactions
are in progress.
Experimental Section
General procedure (Table 3, Entry 1): A solution of 6 (R2 = Me, R3 =
Et) (50 mL, 0.246 mmol) was added dropwise over 3 min to a solution
of 1 (R1 = Ph) (32.0 mg, 0.162 mmol) and 4e (9.5 mg, 0.0161 mmol) in
toluene (1 mL) at À788C. The reaction was stirred at this temperature
for 17 h. The mixture was quenched by the addition of saturated
solutions of NaHCO3 and KF at À788C. After filtration over celite,
the filtrate was extracted with ethyl acetate. The combined organic
layers were washed successively washed with HCl (1n) and brine,
dried over anhydrous Na2SO4, and concentrated to dryness. The
remaining solid was purified by TLC (SiO2, hexane/EtOAc 3:1) to
give 7 (45.6 mg, 0.155 mmol) in 100% yield. The enantiomeric excess
was determined on a Daicel Chiralpak AS-H column.
Received: November 3, 2003 [Z53240]
[11] For recent examples which claim the use of chiral Brønsted acids
as activators, see: B. L. Hodous, G. C. Fu, J. Am. Chem. Soc.
2002, 124, 10006; C. Palomo, M. Oiarbide, J. M. Garcia, A.
Gonzalez, A. Lecumberri, A. Linden, J. Am. Chem. Soc. 2002,
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2003, 125, 12094; Y. Huang, A. K. Unni, A. N. Thadani, V. H.
Rawal, Nature 2003, 424, 146.
[12] For a “Brønsted acid assisted chiral Lewis acid” promoted
Mannich-type reaction, see reference [2a], in which a Lewis acid
plays an important role.
Keywords: asymmetric synthesis · Brønsted acids ·
enantioselectivity · organocatalysis · Schiff bases
.
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[18] The enantiomeric excesses in other solvents were as follows:
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(EtOH).
[19] The absolute stereochemistry of 3a and 3d were assigned to be S
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1568
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