Enantioselective Mannich-type reaction catalyzed by a chiral phosphoric acid bearing an (S)-biphenol backbone

Article abstract of DOI:10.1055/s-0029-1217330

A novel chiral phosphoric acid bearing a biphenol backbone was synthesized and its catalytic activity was investigated in the enantioselective Mannich-type reaction of ketene silyl acetals with aldimines. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1217330

1664
CLUSTER
Enantioselective Mannich-Type Reaction Catalyzed by a Chiral Phosphoric
Acid Bearing an (S)-Biphenol Backbone
C
hira
l
Phospho
a
ic
A
cid Bea
k
r
ing
B
iphen
a
B
ackbon
h
iko Akiyama,*a Takuya Katoh,a Keiji Mori,a Kazuaki Kannob
a
Department of Chemistry, Faculty of Science, Gakushuin University, 1-5-1 Mejiro, Toshima-ku, Tokyo 171-8588, Japan
Fax +81(3)59921029; E-mail: takahiko.akiyama@gakushuin.ac.jp
Mitsubishi Chemical Group Science and Technology Research Center, Inc., 1000 Kamoshida-cho, Aoba-ku, Yokohama 227-8502, Japan
b
Received 23 January 2009
Ar
stereo-controlling site
Lewis basic site
Abstract: A novel chiral phosphoric acid bearing a biphenol back-
bone was synthesized and its catalytic activity was investigated in
the enantioselective Mannich-type reaction of ketene silyl acetals
with aldimines.
··
·
O
O
O
·
P
O
Brønsted acidic site
H
Key words: asymmetric synthesis, chiral Brønsted acid, Mannich-
type reaction, biphenol, phosphoric acid
Ar
1
Figure 1 Functional chiral catalyst
The development of efficient chiral catalysts continues to
be one of the most challenging topics in synthetic organic
chemistry.1 A number of organocatalysts2 as well as met-
al-based catalysts have been reported. We focused on
stronger Brønsted acid catalysts and synthesized a cyclic
phosphoric acid 1, using (R)-BINOL as the starting mate-
rial. Phosphoric acid 1a (Ar = 4-O2NC6H4) exhibited ex-
cellent catalytic activity as a chiral Brønsted acid catalyst
for the Mannich-type reaction of silyl enolate with aldi-
mines,3 which is a useful method for the preparation of b-
amino carbonyl compounds.4 We also demonstrated that
phosphoric acid 1 worked as a bifunctional chiral catalyst
bearing a Lewis basic site and a Brønsted acidic site (Fig-
ure 1).5 Recently, chiral phosphoric acid has drawn much
attention as an efficient chiral catalyst.6–8 A number of
phosphoric acids have been synthesized from BINOL and
their catalytic activities investigated. In contrast, other
backbones for chiral phosphoric acid have been little stud-
ied. For example, we synthesized a phosphoric acid bear-
ing a TADDOL scaffold and investigated its catalytic
activity in the Mannich-type reaction.9 Antilla and co-
workers developed a phosphoric acid starting from VA-
POL, bearing the biphenyl framework.10 We report herein
the preparation of a novel phosphoric acid bearing the bi-
phenol backbone and its application as a chiral Brønsted
acid in the Mannich-type reaction of silyl enolate with
aldimines.
Ar
Ar
O
O
O
O
O
P
P
OH
O
OH
Ar
Ar
1a Ar = 4-O2NC6H4
2a Ar = 4-O2NC6H4
Figure 2 Design of a novel chiral Brønsted acid catalyst
group at 3,3¢-position. Acid-promoted cleavage of the
MOM group followed by phosphorylation gave 2a (Fig-
ure 2).12
At the outset, the Mannich-type reaction of aldimines with
a ketene silyl acetal, derived from ethyl isobutyrate, was
studied by means of 10 mol% of 2a, and the results are
shown in Table 1. Corresponding b-amino esters were ob-
tained in excellent chemical yields with high enantio-
selectivities.13 It was found that 2a exhibited comparable
catalytic activity to 1a bearing the binaphthyl backbone.14
Next, the Mannich-type reaction of aldimines with a silyl
enolate that was derived from ethyl propionate was inves-
tigated and the results are shown in Table 2. Aldimines
derived from substituted benzaldehyde and cinnamalde-
hyde gave corresponding b-amino-2-methylpropionates
with high syn selectivity and high to excellent enantio-
selectivities: the enantioselectivity of the syn isomer was
as high as 93% (entry 5). It was found that 2a exhibited
higher enantioselectivities than 1a in entries 2, 4, and 5.15
We selected chiral (S)-biphenol derivative 3 as the chiral
scaffold11 and synthesized novel phosphoric acid 2a, bear-
ing the (S)-biphenol backbone in six steps. (Scheme 1)
These steps involved Lewis acid promoted dealkylation,
followed by protection of the OH group with MOM ether,
o-lithiation and introduction of boronic ester, and subse-
quent Suzuki–Miyaura coupling to install p-nitrophenyl
The present Mannich-type reaction is considered to pro-
ceed via a nine-membered transition state, as shown in
Figure 3. Phosphoric acid 1 played two roles: (1) phos-
phoric acid hydrogen activated aldimine by acting as a
Brønsted acid, and (2) phosphoryl oxygen formed a hy-
drogen bond with o-hydroxy group by acting as a Lewis
base, thereby fixing the transition state. Hence, the phos-
SYNLETT 2009, No. 10, pp 1664–1666
x
x
.x
x
.2
0
0
9
Advanced online publication: 02.06.2009
DOI: 10.1055/s-0029-1217330; Art ID: Y00209ST
© Georg Thieme Verlag Stuttgart · New York

CLUSTER
Chiral Phosphoic Acid Bearing Biphenol Backbone
1665
t-Bu
t-Bu
t-Bu
1) AlCl3 (5 equiv)
r.t., 2 h
1) n-BuLi, i-PrOBPin
OMOM
OH
OH
OMOM
2) MOMCl
2) Pd(0)
4-O2NC6H4Br
t-Bu
74%
3
NO2
NO2
O
1) 6 M HCl
2) POCl3
O
OMOM
OMOM
P
O
OH
2a
NO2
NO2
Scheme 1 Preparation of a phosphoric acid 2a
Table 1 Results of the Mannich-Type Reactions
H
O
O
O
O
P
OH
NH
OH
O–
OTMS
2a (10 mol%)
+
H
N+
N
OMe
toluene
–78 °C
R
CO2Me
Ar
Ar
Figure 3 Proposed transition state
Entry
Ar
Time (h)
Yield (%)
ee (%)
87
esters were obtained with high to excellent enantioselec-
tivities.
1
2
3
Ph
13
47
13
100
90
4-MeC6H4
4-FC6H4
86
86
77
Typical Experimental Procedure for the Mannich-Type Reac-
tion
Table 2 Results of the Mannich-Type Reactions
Ketene silyl acetal was added dropwise over 1 min to a soln of aldi-
mine (0.15 mmol) and phosphoric acid (0.015 mmol) in toluene (1
mL) at –78 °C. The reaction was stirred at this temperature. The
mixture was quenched by the addition of sat. NaHCO3 and KF at
–78 °C. After filtration over Celite, the filtrate was extracted with
EtOAc. The conbined organic layers were washed successively
washed with 10% aq HCl and brine, dried over anhyd Na2SO4, and
concentrated to dryness. The remaining solid was purified by TLC
(SiO2, hexane–EtOAc = 3:1) to give b-amino ester in high yield.
The ee was determined on a Daicel Chiralpak AS-H, AD-H or IA
column.
OH
NH
OH
OTMS
2a (10 mol%)
+
N
OEt
toluene
–78 °C
CO2Et
Ar
Ar
Entry
Ar
Yield (%)
100
syn/anti
86:14
81:19
87:13
86:14
94:6
ee (%)b
90
1
2
3
4
5
Ph
4-MeC6H4
4-MeOC6H4
4-FC6H4
PhCH=CH
87
87
References and Notes
100
82
(1) Comprehensive Asymmetric Catalysis; Jacobsen, E. N.;
Pfaltz, A.; Yamamoto, H., Eds.; Springer: Berlin, 1999.
(2) (a) Asymmetric Organocatalysis; Berkessel, A.; Gröger, H.,
Eds.; Wiley-VCH: Weinheim, 2005. (b) Enantioselective
Organocatalysis; Dalko, P. I., Ed.; Wiley-VCH: Weinheim,
2007.
93
90
94
93
a Ketene silyl acetal E/Z = 91:9.
b Of the syn-isomer.
(3) (a) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew.
Chem. Int. Ed. 2004, 43, 1566. (b) Itoh, J.; Fuchibe, K.;
Akiyama, T. Synthesis 2008, 1319.
(4) For reviews of Mannich reactions, see: (a) Friestad, G. K.;
Mathiesa, A. K. Tetrahedron 2007, 63, 2541. (b) Ting, A.;
Schaus, S. E. Eur. J. Org. Chem. 2007, 5797.
phoric acid 1 worked as a bifunctional catalyst16 bearing
both Brønsted acidic and Lewis basic sites.
In summary, we have synthesized a novel phosphoric acid
bearing the (S)-biphenol backbone and demonstrated its
catalytic activity in the Mannich-type reaction of ketene
silyl acetal with aldimines. The corresponding b-amino
(5) Yamanaka, M.; Itoh, J.; Fuchibe, K.; Akiyama, T. J. Am.
Chem. Soc. 2007, 129, 6756.
(6) For selected examples, see: (a) Uraguchi, D.; Terada, M.
J. Am. Chem. Soc. 2004, 126, 5356. (b) Uraguchi, D.;
Synlett 2009, No. 10, 1664–1666 © Thieme Stuttgart · New York

1666
T. Akiyama et al.
CLUSTER
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Akiyama, T.; Saitoh, Y.; Morita, H.; Fuchibe, K. Adv. Synth.
Catal. 2005, 347, 1523.
(10) For use of phosphoric acid derived from biphenol derivative,
see: (a) Rowland, G. B.; Zhang, H.; Rowland, E. B.;
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Soc. 2005, 127, 15696. (b) Li, G.; Liang, Y.; Antilla, J. C.
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(12) (S)-6,6¢-Dimethyl-3,3¢-bis(4-nitrophenyl)-1,1¢-biphenyl-
2,2¢-yl Phosphate (2a)
[a]D21 +365 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3):
d = 8.06–8.04 (m, 4 H), 7.55–7.53 (m, 4 H), 7.39–7.37 (m, 4
H), 2.58 (s, 1 H), 2.35 (s, 6 H). 31P NMR(400 MHz, CDCl3):
d = 0.74. 13C NMR (75 MHz, CDCl3): d = 146.9, 144.7,
143.1, 140.3, 130.2, 130.0, 129.7, 128.4, 127.7, 123.3, 20.0.
31P NMR (162 MHz, CDCl3): d = 0.74. Anal. Calcd (%) for
C26H19O8P: C, 60.24; H, 3.69; N, 5.40. Found: C, 60.13; H,
3.66; N, 5.45%.
Sorimachi, K. Synlett 2008, 1661. (r) Xu, S.; Wang, Z.;
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Angew. Chem. Int. Ed. 2008, 47, 4122. (t) Rueping, M.;
Antonchick, A. P. Angew. Chem. Int. Ed. 2008, 47, 5836.
(13) (R)-Methyl 3-(N-2-Hydroxyphenylamino)-2,2-dimethyl-
3-phenylpropionate
[a]D21 +1.4 (c 0.45, CHCl3; 87% ee); Rf = 0.4 (hexane–
EtOAc = 3:1). 1H NMR (400 MHz, CDCl3): d = 7.29–7.19
(m, 5 H), 6.69 (1 H, dd, J = 7.7, 1.5 Hz), 6.61 (1 H, ddd,
J = 7.7, 7.7, 1.5 Hz), 6.53 (1 H, ddd, J = 7.7, 7.7, 1.5 Hz),
6.38 (1 H, dd, J = 7.7, 1.5 Hz), 5.80 (br s, 1 H), 4.55 (br s, 1
H), 4.55 (s, 1 H), 3.69 (s, 3 H), 1.24 (s, 3 H), 1.22 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 177.7, 144.3, 139.0,
135.5, 128.3, 127.9, 127.41, 121.0, 117.9, 114.4, 113.9,
64.6, 52.2, 47.4, 24.4, 20.0.
(7) For reviews, see: (a) Connon, S. J. Angew. Chem. Int. Ed.
2006, 45, 3909. (b) Akiyama, T.; Itoh, J.; Fuchibe, K. Adv.
Synth. Catal. 2006, 348, 999. (c) Akiyama, T. Chem. Rev.
2007, 107, 5744. (d) Akiyama, T. In Acid Catalysis in
Modern Organic Synthesis; Yamamoto, H.; Ishihara, K.,
Eds.; Wiley-VCH: Weinheim, 2008, 62. (e) Terada, M.
Chem. Commun. 2008, 4097.
(8) For our reports, see: (a) Akiyama, T.; Tamura, Y.; Itoh, J.;
Morita, H.; Fuchibe, K. Synlett 2006, 141. (b) Akiyama, T.;
Morita, H.; Fuchibe, K. J. Am Chem. Soc. 2006, 128, 13070.
(c) Itoh, J.; Fuchibe, K.; Akiyama, T. Angew. Chem. Int. Ed.
2006, 45, 4796. (d) Itoh, J.; Fuchibe, K.; Akiyama, T.
Angew. Chem. Int. Ed. 2008, 47, 4016. (e) Akiyama, T.;
Honma, Y.; Itoh, J.; Fuchibe, K. Adv. Synth. Catal. 2008,
350, 399.
(14) When 1a was employed in the reaction with the aldimine
derived from benzaldehyde, the corresponding adduct was
obtained in 87% ee.3
(15) The enantioselectivities obtained with 1a: 96% (Ar = Ph),
81% (Ar = 4-MeC6H4), 88% (Ar = 4-MeOC6H4), 84%
(Ar = 4-FC6H4), 90% (Ar = PhCH=CHC6H4).3
(16) For bifunctional Lewis acids, see: Shibasaki, M.; Kanai, M.;
Funabashi, K. Chem. Commun. 2002, 1989.
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