syn-selective direct catalytic asymmetric mannich-type reactions of aromatic and heteroaromatic hydroxy ketones promoted by Y[N(SiMe 3)2]3/linked-BINOL complexes

Article abstract of DOI:10.1246/bcsj.79.1906

Full details of syn-selective catalytic asymmetric direct Mannich-type reactions of aromatic and heteroaromatic hydroxy ketones promoted by Y[N(SiMe₃)₂]₃/linked-BINOL complexes are described. From a screening of various ra

Full text of DOI:10.1246/bcsj.79.1906

1906 Bull. Chem. Soc. Jpn. Vol. 79, No. 12, 1906–1912 (2006)
ꢀ 2006 The Chemical Society of Japan
syn-Selective Direct Catalytic Asymmetric Mannich-Type
Reactions of Aromatic and Heteroaromatic Hydroxy Ketones
Promoted by Y[N(SiMe3)2]3/Linked-BINOL Complexes
ꢀ
Akitake Yamaguchi, and Masakatsu Shibasaki
Shigeki Matsunaga, Mari Sugita, Noriyuki Yamagiwa, Shinya Handa,
ꢀ
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033
Received April 10, 2006; E-mail: mshibasa@mol.f.u-tokyo.ac.jp
Full details of syn-selective catalytic asymmetric direct Mannich-type reactions of aromatic and heteroaromatic
hydroxy ketones promoted by Y[N(SiMe3)2]3/linked-BINOL complexes are described. From a screening of various
rare-earth metals and linked-BINOL derivatives, a Y[N(SiMe3)2]3/TMS-linked-BINOL (1.7/1) complex was deter-
mined to be the most effective. Mannich-type reactions of aromatic and heteroaromatic hydroxy ketones with aryl
and alkenyl N-diphenylphosphinoylimines, catalyzed by 0.1 molar amount of Y[N(SiMe3)2]3 and 0.059 molar amount
of TMS-linked-BINOL, afforded syn-ꢀ-amino-ꢁ-hydroxy ketones in good yields (78–98%), high diastereoselectivity
(syn/anti = 81/19–96/4), and high enantioselectivity (86–98% ee).
Chiral ꢀ-amino alcohol units are useful building blocks
found in various natural products, compounds with pharmaco-
logically important activity, chiral auxiliaries, and chiral li-
gands.1 Various methods for enantioselective and diastereose-
lective preparation of ꢀ-amino alcohols have been developed
over the last decade.2 Among the methods available for their
catalytic enantioselective syntheses,3 catalytic asymmetric
Mannich-type reactions4 of ꢁ-alkoxy enolates are of particular
interest because two adjacent stereocenters are constructed
simultaneously with concomitant carbon–carbon bond for-
mation.5,6 To address this issue, direct catalytic asymmetric
Mannich reactions7,8 are ideal methods in terms of atom econ-
omy.9 In the direct Mannich-type reactions, either a nucleo-
philic enolate or an enamine is generated in situ using catalytic
amount of bifunctional metal complexes10 or organocata-
lysts.11 The reaction formally proceeds through simple proton
transfer from a nucleophile to an electrophile. Therefore, the
pre-activation of a nucleophile using stoichiometric amounts
of a strong base and a silylating reagent is not required, en-
abling to avoid producing stoichiometric amount of salt waste.
Difference between the direct Mannich-type reaction and the
Mannich-type reactions with pre-formed enolates is summariz-
ed in Scheme 1.
a) Direct Mannich-type reaction
PG
PG
O
NH
O
N
chiral cat.
H
+
*
R'
R'
R'
*
R
proton transfer
X
X
b) Mannich-type reaction with preformed enol silane
PG
OSiR'3
O
silylating reagent
base (1 equiv)
NH
O
chiral cat.
R'
R'
*
R'
R'
*
PG
X
X
N
X
salt (1 equiv)
R
Scheme 1. a) Direct catalytic asymmetric Mannich-type
reaction and b) Mannich-type reaction with preformed
enol silane.
X
X
O
HO
OH
OH
HO
X
X
X = H: (S,S)-linked-BINOL 1a
During the last decade, several research groups including us
realized the direct catalytic asymmetric Mannich-type reac-
tions of ꢁ-oxy-donors, and they include the addition of un-
modified ꢁ-hydroxy ketones,12,13 ꢁ-oxyaldehydes,14 and ꢁ-
hydroxy-N-acylpyrrole as an ester surrogate15,16 to imines.17,18
Among the Mannich-type reactions of ꢁ-hydroxy ketones, we
developed a Et2Zn/linked-BINOL 1a (Fig. 1)19,20 complex,
which efficiently catalyzed the Mannich-type reaction of 2-
hydroxy-1-(2-methoxyphenyl)ethanone (3a).13 By changing
the imine protective groups, either anti- or syn-ꢀ-amino-ꢁ-
hydroxy ketones were obtained (Scheme 2). A Mannich-type
reaction using diphenylphosphinoylimine (Dpp-imine 2)21 af-
X = -Si(CH ) : (S,S)-TMS-linked-BINOL 1b
3 3
X = -Br: (S,S)-Br-linked-BINOL 1c
Fig. 1. Structures of (S,S)-linked-BINOLs (1a, 1b, and 1c).
forded anti-products, whereas the use of a Boc-imine afforded
syn-products. Although high catalyst turnover number and
high ee were achieved, problems remained. 1) Modest syn-se-
lectivity with Boc-imine; diastereoselectivity strongly depend-
ed on the imines used.13b Especially, ꢁ,ꢀ-unsaturated imines
and heteroaromatic imines gave poor syn-selectivity. To the
best of our knowledge, there are no reports of highly diastereo-
Published on the web December 13, 2006; doi:10.1246/bcsj.79.1906

S. Matsunaga et al.
Bull. Chem. Soc. Jpn. Vol. 79, No. 12 (2006) 1907
Table 1. Screening of Various Rare-Earth Metal/Linked-
BINOL 1a Complexes Using Hydroxy Ketone 3b as a
Donor
O
O
OMe
O
PPh
2
Ph P
2
Et Zn/1a
2
NH
O
OMe
N
+
(x mol. amt.)
THF, MS 3 Å
−20 °C
O
Ar
Ar
OH
3a
O
metal (0.1 mol. amt.)
OH
4
Ph P
2
2
PPh
+
2
O
(S,S)-linked-BINOL 1a
NH
O
cat loading:
x = (0.02 − 1) x 10
mol. amt.
ee: 98−>99% ee
N
(0.05 mol. amt.)
-2
anti/syn: 80/20 − 99/1
Ph
Ph
Ph
Ph
THF, −20 °C
OH
OH
7ab
O
OMe
Boc
2a
3b (1.2 mol. amt.)
Boc
+
Et Zn/1a
NH
O
OMe
2
N
(x mol. amt.)
THF, MS 3 Å
−40 °C
Time YieldaÞ
drbÞ
(syn/anti) (syn)
ee (%)
Ar
Ar
Entry
Metal source
OH
3a
/h
/%
OH
ee: 89−>99% ee
syn/anti: 58/42 − 95/5
6
5
1
2
3
4
5
6
7
8
La(O-iPr)3
Gd(O-iPr)3
Y(O-iPr)3
Yb(O-iPr)3
La[N(SiMe3)2]3
Gd[N(SiMe3)2]3
Y[N(SiMe3)2]3
Yb[N(SiMe3)2]3
60
60
93
60
60
60
48
60
78
51
25
50
81
78
89
82
1
60/40
75/25
77/23
72/28
60/40
84/16
88/12
87/13
20
45
64
65
12
66
85
89
cat loading:
-2
x = (0.05 − 5) x 10
mol. amt.
Scheme 2. Direct catalytic asymmetric Mannich-type reac-
tion of hydroxy ketone 3a promoted by a Et2Zn/linked-
BINOL 1a complex.
and enantioselective (dr: >90=10, ee: >90% ee) direct catalyt-
ic asymmetric Mannich-type reactions of ꢁ,ꢀ-unsaturated
imines using hydroxy ketones as donors.22 2) Nucleophile gen-
erality: Use of ketone 3a was essential to achieve good selec-
tivity. The methoxyphenyl group in the Mannich adducts is
synthetically useful, because the methoxy group facilitates
efficient conversion of the Mannich adducts in Scheme 2 into
ꢀ-amino-ꢁ-hydroxycarboxylic esters through Baeyer–Villiger
oxidation;13a,13b however, zinc catalysis is not suitable for
the synthesis of various ꢀ-amino-ꢁ-hydroxy ketones. For
example, when using 2-hydroxyphenylethanone (3b) and 1-
(2-furyl)-2-hydroxyethanone (3f) without a methoxy group
on the aromatic ring, Mannich adducts are obtained in only
modest enantioselectivity.23 To overcome the modest syn-
selectivity and the lack of nucleophile generality of our zinc
catalyzed Mannich-type reactions, we previously communicat-
ed new Y[N(SiMe3)2]3/linked-BINOLs complexes (Fig. 1).24
Herein, we describe full details of the yttrium-catalyzed direct
enantioselective Mannich-type reactions. The Y[N(SiMe3)2]3/
TMS-linked-BINOL (1b) complex was applicable to various
aromatic and heteroaromatic hydroxy ketones, to afford
Mannich adducts syn-selectively in good yield (up to 98%),
and high enantio- and diastereoselectivity (up to 98% ee,
syn/anti = up to 96/4).
a) Isolated yield. b) Determined by H NMR analysis.
Table 2. Effects of Chiral Ligands 1a–1i
O
O
metal (0.1 mol. amt.)
(S,S)-ligand
(0.05 mol. amt.)
Ph P
2
PPh
+
2
O
NH
O
N
Ph
Ph
Ph
Ph
THF, −20 °C
OH
OH
7ab
2a
3b (1.2 mol. amt.)
Time YieldaÞ
drbÞ
(syn/anti)
ee (%)
(syn)
Entry
Ligand
/h
/%
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
48
48
88
88
87
87
88
88
88
88
89
89
95
54
91
18
29
91
93
84
90
24
88/12
93/7
85
94
38
10
14
5
14
25
13
2
64/36
64/36
53/47
43/57
59/41
55/45
57/43
50/50
45/55
10
11
BINOLcÞ
3
1
a) Isolated yield. b) Determined by H NMR analysis. c) 0.1
mol amt. of BINOL was used.
Results and Discussion
The rare-earth metal alkoxide/linked-BINOL 1a complexes
are useful in several asymmetric reactions,25 therefore we
screened various rare-earth metal/linked-BINOL 1a com-
plexes using Dpp-imine 2a and 1.2 molar amount of hy-
droxyketone 3b (Table 1). Using a 0.1 molar amount of a
metal source and 0.05 molar amount of linked-BINOL 1a, a
Mannich-type reaction was performed in THF at ꢁ20 ꢂC. In
contrast to our initial assumption based on results obtained
by the Et2Zn/linked-BINOL 1a complex (Scheme 1),13a the
reaction proceeded syn-selectively with rare-earth metal com-
plexes.26 The use of rare-earth metal alkoxides of La, Gd,
Y, and Yb afforded only modest enantioselectivity and reac-
tivity (Entries 1–4, 20–65% ee).27 Therefore, other rare-earth
metal sources were screened, and rare-earth metal hexamethyl-
disilazide [RE[N(SiMe3)2]3]27 had much better reactivity and
selectivity (Entries 5–8). Among RE[N(SiMe3)2]3 sources,
Y[N(SiMe3)2]3 and Yb[N(SiMe3)2]3 gave the best results
(Entry 7, 89% yield, syn/anti = 88/12, 85% ee; Entry 8, 82%
yield, syn/anti = 87/13, 89% ee). Because Y[N(SiMe3)2]3
was superior to Yb[N(SiMe3)2]3 in terms of reaction rate
(48 h vs 60 h), further optimization was performed using
Y[N(SiMe3)2]3 as the metal source.
Table 2 summarizes the results using different linked-
BINOL derivatives. Although ligands 1d–1j (Fig. 2), which
have one chiral moiety, were effective in the Et2Zn/linked-
BINOL-catalyzed reaction,13c ligands 1d–1j were unsatisfac-
tory when used with Y[N(SiMe3)2]3 (Table 2, Entries 4–10).

1908 Bull. Chem. Soc. Jpn. Vol. 79, No. 12 (2006)
Direct Catalytic Asymmetric Mannich Reaction
Me Si
3
R
O
a)
ref. 29
OH
OH
OH
OMOM
OMOM
HO
R =
HO
76%
Me Si
3
1d
(S)-BINOL
8
Me Si
Me Si
3
3
OH
Br
OH
OH
OH
b)
99%
OMOM
OMOM
OMOM
OMOM
OH
Me Si
3
Me Si
3
1e
1f
1g
9
10
t-Bu
Me Si
3
SiMe
SiMe
3
3
O
OH
OH
OH
c)
89%
OR RO
OR RO
t-Bu
1j
F C
CF
3
3
1h
1i
Me Si
3
11: R = MOM
1b: R = OH
d) 66%
Fig. 2. Structures of linked-BINOL derivatives 1d–1j for
screening.
Scheme 3. Synthetic scheme of (S,S)-TMS-linked-BINOL
1b. Reagents and conditions: a) 1. BuLi (1.1 mol amt.),
TMEDA (1.2 mol amt.), THF, 0 ꢂC, 1 h; then DMF (1.05
mol amt.), ꢁ78 ꢂC, 3 h; 2. NaBH4 (1.0 mol amt.), THF/
MeOH, 0 ꢂC, 30 min, 76% (2 steps); b) Ms2O (1.5
mol amt.), iPr2NEt (1.6 mol amt.), 25 ꢂC, 1 h; then LiBr
(5 mol amt.), DMF, 0 ꢂC, 10 h, 99%; c) B (1.0 mol amt.),
BINOL, itself, also afforded poor reactivity and selectivity
(Entry 11, 24% yield, 3% ee). The present Y[N(SiMe3)2]3
complex required two chiral BINOL units for high reactivity
and enantioselectivity (Entry 1, 89% yield, 85% ee). Modifi-
cation at the 6,60,600,6000-positions of linked-BINOL 1 improved
stereoselectivity. When TMS-linked-BINOL 1b (Fig. 1) was
used,28 Mannich adduct 7ab was obtained in 95% yield,
94% ee and syn/anti = 93/7 (Table 2, Entry 2). We speculate
that the bulky trimethylsilyl group at the 6,60-position of
binaphthyl affects the dihedral angle of the ligand, thereby
improving stereoselectivity. On the other hand, electron-
withdrawing groups at 6,60,600,6000-positions had adverse ef-
fects. The use of Br-linked-BINOL 1c resulted in poor yield,
diastereoselectivity and enantioselectivity (Entry 3). The syn-
NaH (1.2 mol amt.), 25 ꢂC, 3.5 h, 89%; d) pTsOH H2O
ꢃ
(0.2 mol amt.), CH2Cl2/MeOH, 35 ꢂC, 14 h, 66%.
thetic procedure for TMS-linked-BINOL 1b is summarized
in Scheme 3. Intermediate 8 was synthesized following the
reported procedure.29 Compound 9 was obtained in 76% yield
(2 steps) by formylation and reduction with NaBH4. Com-
pound 10 was obtained in 99% yield (2 steps from compound
Table 3. Effects of Y[N(SiMe3)2]3:Ligand Ratio, and Hydroxy Ketone 3b Amount on Diastereo-
selectivity and Enantioselectivity
Y[N(SiMe ) ]
3 2 3
(0.1 mol. amt.)
(S,S)-ligand 1
(x mol. amt.)
O
O
O
Ph P
2
PPh
2
NH
O
N
+
Ph
THF, −20 °C, 48 h
Ph
Ph
Ph
OH
3b
OH
7ab
2a
Y[N(SiMe3)2]3
:Ligand ratio
Ligand
(x mol amt.)
3b
(mol amt.)
YieldaÞ
/%
drbÞ
(syn/anti)
ee (%)
(syn)
Entry
1
2
3
4
5
6
7
8
2.0:1
1.7:1
1.5:1
1.3:1
1:1
1.7:1
1.7:1
1.7:1
1a (0.050)
1a (0.059)
1a (0.067)
1a (0.077)
1a (0.10)
1b (0.059)
1a (0.059)
1a (0.059)
1
1.2
1.2
1.2
1.2
1.2
1.2
3.0
1.0
89
97
94
95
92
98
98
90
88/12
90/10
84/16
76/24
68/32
94/6
85
91
86
63
26
95
82
95
83/17
95/5
a) Isolated yield. b) Determined by H NMR analysis.

S. Matsunaga et al.
Bull. Chem. Soc. Jpn. Vol. 79, No. 12 (2006) 1909
Table 4. Direct Catalytic Asymmetric Mannich-Type Reaction Using Hydroxy Ketones 3c–3g and Imines 2b–2f
O
O
Y[N(SiMe ) ] (0.1 mol. amt.)
3 2 3
O
Ph P
2
PPh
2
(S,S)-ligand 1 (0.059 mol. amt.)
NH
O
N
+
2
R
1
2
1
THF, −20 °C
R
R
R
OH
2 (1 mol. amt.)
3 (1 mol. amt.)
7
OH
Time
/h
YieldaÞ
/%
drbÞ
(syn/anti)
ee (%)
(syn)
Entry
Imine: R1
Ketone: R2
Product
Ligand
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
Ph- 2a
Ph- 2a
Ph- 2a
Ph- 2a
Ph- 2a
Ph- 2a
Ph- 2a
Ph- 2a
Ph- 2a
Ph- 2a
4-MeO-C6H4- 3c
4-MeO-C6H4- 3c
4-Me-C6H4- 3d
4-Me-C6H4- 3d
4-Cl-C6H4- 3e
4-ClC6H4- 3e
2-Furyl 3f
2-Furyl 3f
2-Thienyl 3g
2-Thienyl 3g
Ph- 3b
7ac
7ac
7ad
7ad
7ae
7ae
7af
1a
1b
1a
1b
1a
1b
1a
1b
1a
1b
1a
1b
1a
1b
1a
1b
1a
1b
1a
1b
1a
1b
1a
1b
1a
1b
82
84
65
63
60
48
60
60
89
36
60
48
89
84
60
39
61
39
66
60
65
42
40
60
65
42
43
89
84
91
70
94
68
94
65
95
73
78
69
90
90
93
83
95
86
87
93
94
94
92
87
89
94/6
91/9
91/9
91/9
81/19
81/19
82/18
94/6
90/10
95/5
88/12
94/6
89/11
95/5
93/7
95/5
93/7
96/4
96/4
96/4
96/4
95/5
92/8
93/7
96/4
96/4
96
98
92
96
80
86
74
93
74
92
92
95
86
94
95
96
95
97
96
95
94
93
92
91
94
94
7af
7ag
7ag
7bb
7bb
7cb
7cb
7db
7db
7eb
7eb
7fb
7fb
7gb
7gb
7hb
7hb
7ib
4-Cl-C6H4- 2b
4-Cl-C6H4- 2b
4-MeO-C6H4- 2c
4-MeO-C6H4- 2c
2-Furyl 2d
2-Furyl 2d
2-Thienyl 2e
2-Thienyl 2e
PhCH=CH- 2f
PhCH=CH- 2f
Ph- 3b
Ph- 3b
Ph- 3b
Ph- 3b
Ph- 3b
Ph- 3b
Ph- 3b
Ph- 3b
Ph- 3b
Ph- 3b
Ph- 3b
Ph- 3b
Ph- 3b
Ph- 3b
Ph- 3b
4-Cl-C6H4CH=CH- 2g
4-Cl-C6H4-CH=CH- 2g
4-Me-C6H4CH=CH- 2h
4-Me-C6H4CH=CH- 2h
2-FurylCH=CH- 2i
2-FurylCH=CH- 2i
7ib
1
a) Isolated yield. b) Determined by H NMR analysis.
9) by mesylation of 9, followed by treatment with LiBr. Cou-
pling reaction of compounds 9 and 10 and removal of MOM
group afforded linked-BINOL 1b.
adduct was obtained in 90% yield, even with an equimolar
amount of the nucleophile.
The Y[N(SiMe3)2]3/ligand 1a or 1b (1.7/1) complex was
useful with various aromatic and heteroaromatic hydroxy
ketones 3b–3g (Table 4). TMS-linked-BINOL 1b gave better
chemical yield, diastereoselectivity, and ee than linked-BINOL
1a in most entries. For hydroxy ketones 3c, linked-BINOL 1a
gave Mannich adduct 7ac in only 43% yield (Entry 1), while
linked-BINOL 1b gave 7ac in 89% yield (98% ee, Entry 2).
On the other hand, TMS-linked-BINOL 1b was required to
achieve good ee for hydroxy ketone 3e with an electron-with-
drawing group (Entry 5 vs 6). 1-(2-Furyl)-2-hydroxyethanone
(3f), which affords versatile chiral building blocks,30 was
also a suitable nucleophile. Mannich adduct 7af was obtained
in 94% yield, syn/anti = 94/6, 93% ee using linked-BINOL
1b (Entry 8), although only modest yield and ee were achieved
with linked-BINOL 1a (Entry 7, 74% ee). 2-Hydroxy-1-(2-
thienyl)ethanone (3g) also required TMS-linked-BINOL 1b
to achieve high yield and ee (Entry 10, 95% yield, 92% ee).
On the other hand, the present system is not applicable to ali-
phatic ketones such as hydroxyacetone. No reaction proceeded
with hydroxy acetone, probably due to slightly lower acidity of
ꢁ-proton in hydroxyacetone than in aromatic hydroxy ketones
The ratio of Y[N(SiMe3)2]3 and linked-BINOL 1a affected
both reactivity and stereoselectivity (Table 3, Entries 1–5).
Using a 0.1 molar amount of Y[N(SiMe3)2]3 and variable
amounts of linked-BINOL 1a (0.05–0.1 molar amount), the
Mannich-type reaction of 2a with 1.2 molar amount of 3b
was examined. The best diastereo- and enantioselectivity were
obtained when the ratio of Y[N(SiMe3)2]3/linked-BINOL 1a
was 1.7/1. With a catalyst prepared from Y[N(SiMe3)2]3/
1a = 1.7/1 ratio, Mannich adduct 7ab was obtained in 97%
yield, syn/anti = 90/10, and 91% ee (Entry 2). When TMS-
linked-BINOL 1b was used, Mannich adduct 7ab was obtained
in 98% yield, syn/anti = 94/6, and 95% ee (Entry 6). The
amount of hydroxy ketone 3b also affected stereoselectivity.
Excess hydroxy ketone 3b negatively affected enantio- and
diastereoselectivity. When 3 molar amounts of hydroxy ketone
3b was used, both diastereoselectivity and enantioselectivity
decreased (Entry 7, syn/anti = 83/17, 82% ee). Whereas
when using 1.0 molar amount of ketone 3b was used, 7ab
was obtained in syn/anti = 95/5 and 95% ee using ligand
1a as a ligand (Entry 8). It is noteworthy that the Mannich

1910 Bull. Chem. Soc. Jpn. Vol. 79, No. 12 (2006)
Direct Catalytic Asymmetric Mannich Reaction
O
O
Ph
Ph
O
Y[N(SiMe ) ]
3 2 3
(0.034 mol. amt.)
Ph
Ph
P
P
Ph P
2
N
N
PPh
+
O
2
O
NH
O
N
(S,S)-1b (0.02 mol. amt.)
S
H
R
H
R
S
Ph
Ph
THF, −20 °C, 61 h
7eb:
s-cis
s-trans
OH
OH
91% yield, 95% ee
syn/anti: 94/6
O
2e
3b
Ph
Ph
(1 mol. amt.) (1 mol. amt.)
P
NH
O
Scheme 4. Mannich-type reaction with reduced catalyst loading.
R
Ar
syn-7
OH
3b–3g. Entries 11–26 illustrate the scope of useable imine sub-
strates. Aromatic imines with an electron-withdrawing group
2b and an electron-donating group 2c were useable (Entries
11–14). Heteroaromatic imines 2d and 2e also afforded
Mannich adducts 7db and 7eb in high stereoselectivity
(Entries 15–18, 95–97% ee). ꢁ,ꢀ-Unsaturated imines 2f–2i
gave Mannich adducts in good yield and high diastereo- and
enantioselectivity (Entries 19–26: 86–94% yield, 91–96% ee,
syn/anti = 92/8–96/4). The high diastereoselectivity (Entries
19–26: 92/8–96/4) is noteworthy, because the Et2Zn/linked-
BINOL 1a complex gave only modest diastereoselectivity us-
ing ꢁ,ꢀ-unsaturated imines, even when using hydroxy ketone
3a.31 The Mannich adducts from ꢁ,ꢀ-unsaturated imines are
synthetically useful, because they are precursors for the ꢀ-
alkyl-ꢀ-amino-ꢁ-hydroxycarbonyl compounds. The use of
enolizable aliphatic imines was not successful in the present
yttrium catalysis.32 Catalyst loading was successfully reduced
as shown in Scheme 4. Using 0.02 molar amount of linked-
BINOL 1b and 0.034 molar amount of Y[N(SiMe3)2]3, the
Mannich-type reaction with imine 2e and hydroxy ketone 3b
gave 7eb in 91% yield and 95% ee after 61 h.
Fig. 3. Proposed acyclic anti-periplanar transition state
model to give syn-Mannich adduct.
linked-BINOL 1b complex for direct catalytic asymmetric
Mannich-type reactions of various aromatic and heteroaromat-
ic hydroxy ketones. Using the Y[N(SiMe3)2]3/1b (1.7/1) com-
plex, Mannich adducts were obtained syn-selectively in good
diastereomeric ratio (81/19–96/4), good yield (78–98%),
and high ee (86–98%). The present yttrium catalysis compen-
sates for the drawbacks of the previously reported Et2Zn/
linked-BINOL catalysis for syn-amino alcohol synthesis in
terms of nucleophile generality and diastereoselectivity with
ꢁ,ꢀ-unsaturated imine and heteroaromatic imines. Use of var-
ious aromatic and heteroaromatic hydroxy ketones as donors is
also complimentary to the Mannich reactions using organo-
catalyst11 in terms of the scope of useable nucleophiles. Fur-
ther applications of the new yttrium catalysis in other asym-
metric reactions are ongoing.
Experimental
General Procedure for Direct Mannich-Type Reaction. To
a stirred solution of linked-BINOL 1a or 1b (8.8 mmol, 5:86 ꢄ
10ꢁ2 molar amount) in THF (0.5 mL) at room temperature was
added Y[N(SiMe3)2]3 (8.55 mg, 0.015 mmol, 0.1 molar amount)
in THF (1.0 mL). The mixture was stirred at room temperature
for 10 min, then THF was removed in vacuo to remove HN(Si-
Me3)2. THF (0.4 mL) was added, and the mixture was cooled to
ꢁ20 ꢂC. To the mixture solution at ꢁ20 ꢂC were added imine 2
(0.15 mmol) and hydroxy ketone 3 (0.15 mmol) in THF (1.2 mL).
The resulting mixture was stirred at ꢁ20 ꢂC for indicated time
in Tables and quenched with aq 1 M (1 mol dmꢁ3) HCl. The mix-
ture was extracted with ethyl acetate (ꢄ3). The combined organic
layers were washed with brine and dried over Na2SO4. After re-
moving the solvent under reduced pressure, the residue was puri-
fied by flash silica-gel column chromatography to afford Mannich
adducts 7. Diastereomeric ratio of Mannich adducts was deter-
The yttrium complex should function as a Lewis acid–
Brønsted base bifunctional catalyst similar to other metal-
ꢀ
(Ar OH = linked-BINOL 1a or 1b) moiety would function
catalyzed direct Mannich-type reactions.12d,13,15 Y-OAr
ꢀ
as a Brønsted base to generate Y-enolate from hydroxy
ketones, and the Y center would function as a Lewis acid to
activate imines. Unfortunately, trials to elucidate the structure
of the Y[N(SiMe3)2]3/linked-BINOL complex failed. NMR
analysis and ESI-MS analysis of the Y[N(SiMe3)2]3/linked-
1
BINOL 1a complex with variable Y/1a ratio failed. H NMR
of Y[N(SiMe3)2]3/linked-BINOL 1a complex showed only
very broad peaks, suggesting complicated mixtures of oligo-
meric species. On the basis of previous mechanistic studies
involving rare-earth metal/linked-BINOL complexes,25b more
than two yttrium metals are probably involved in the active
species. In the direct Mannich-type reaction of Dpp-imines 2,
the Y[N(SiMe3)2]3/linked-BINOL complex gave syn-adducts,
while the Et2Zn/linked-BINOL complex gave anti-adducts.
Because the structure of the present yttrium complex is unclear,
it is difficult to discuss precisely the difference between Zn
and Y complexes. We assume that the coordination mode of
Dpp-imine 2 on a Lewis acidic metal is different. With more
oxophilic rare-earth metals,33 Dpp-imine 2 would coordinate
to yttrium through oxygen atom as shown in Fig. 3. Dpp-imine
2 favors s-cis conformation to avoid steric repulsion, and the
reaction would proceed via the acyclic anti-periplanar transi-
tion state to minimize gauche interactions between imine 2
and Y-enolate complex, affording the syn-product.
1
mined by H NMR analysis of the crude mixture before purifica-
tion. Ee of syn-isomer was determined by chiral HPLC analysis.
This work was supported by Grant-in-Aid for Specially
Promoted Research and Grant-in-Aid for Encouragements
for Young Scientists (B) (for SM) from JSPS and MEXT.
We thank Mr. T. Yoshida for his generous support in synthesis
of ligands 1d–1j.
Supporting Information
Detailed experimental procedures including Mannich-type
reaction and synthesis of ligand 1b, and spectroscopic data for
new compounds; these materials are available free of charge on
the web at http://www.csj.jp/journals/bcsj/.
In summary, we developed a new Y[N(SiMe3)2]3/TMS-

S. Matsunaga et al.
Bull. Chem. Soc. Jpn. Vol. 79, No. 12 (2006) 1911
15 S. Harada, S. Handa, S. Matsunaga, M. Shibasaki, Angew.
Chem., Int. Ed. 2005, 44, 4365.
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For a review on catalytic asymmetric Mannich-type
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For elegant pioneering works involving a Zr catalysis
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6
nucleophile, see also: T. Akiyama, J. Itoh, K. Yokota, K. Fuchibe,
For recent other example using ꢁ-oxy ketene silyl acetal as
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A review for direct Mannich reaction: a) A. Cordova,
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For related direct aldol reactions, see also reviews: a) B.
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19 For other applications of the Et2Zn/linked-BINOL 1a
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Kinoshita, S. Harada, S. Okada, S. Sakamoto, K. Yamaguchi,
M. Shibasaki, J. Am. Chem. Soc. 2003, 125, 2169. b) N.
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c) N. Kumagai, S. Matsunaga, N. Yoshikawa, T. Ohshima, M.
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Harada, N. Kumagai, T. Kinoshita, S. Matsunaga, M. Shibasaki,
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M. Shibasaki, Org. Lett. 2001, 3, 4251. f) S. Matsunaga, T.
Kinoshita, S. Okada, S. Harada, M. Shibasaki, J. Am. Chem.
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´
124, 827. c) A. Cordova, W. Notz, G. Zhong, J. M. Betancort,
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20 Synthesis of linked-BINOL 1a: S. Matsunaga, J. Das,
J. Roels, E. M. Vogl, N. Yamamoto, T. Iida, K. Yamaguchi, M.
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14 I. Ibrahem, A. Cordova, Tetrahedron Lett. 2005, 46, 2839.

1912 Bull. Chem. Soc. Jpn. Vol. 79, No. 12 (2006)
Direct Catalytic Asymmetric Mannich Reaction
21 Use of Dpp-imine is favorable because removal of protec-
tive group is relatively easy. A review for the use of Dpp-imines 2
in organic synthesis: S. M. Weinreb, R. K. Orr, Synthesis 2005,
1205.
22 Highly enantioselective catalytic Mannich-type reactions
using alkenyl imines: with enol silane and ketene silyl acetal
as donors: a) N. S. Josephsohn, M. L. Snapper, A. H. Hoveyda,
J. Am. Chem. Soc. 2004, 126, 3734. b) N. S. Josephsohn, E. L.
Carswell, M. L. Snapper, A. H. Hoveyda, Org. Lett. 2005, 7,
2711, and references therein. For direct Mannich-type reaction
of alkenyl imines with 2-hydroxy-N-acylpyrrole as a donor, see
Ref. 15.
27 Rare-earth metal alkoxides were purchased from Kojundo
(sales@kojundo.co.jp), RE[N(SiMe3)2]3 were purchased from
Aldrich.
28 Slightly positive effects of TMS-linked-BINOL 1b over
linked-BINOL 1a was previously reported in In(O-iPr)3/linked-
BINOL 1 complexes, see Ref. 15.
29 Y. Yamashita, H. Ishitani, H. Shimizu, S. Kobayashi,
J. Am. Chem. Soc. 2002, 124, 3292.
30 For use of 2-furyl group as a 4-oxygenated-2-enoic acid
synthon using mild oxidation conditions (NBS, pyridine), see:
a) Y. Kobayashi, M. Nakano, G. B. Kumar, K. Kishihara,
J. Org. Chem. 1998, 63, 7505. For use of 2-furyl group as an
ester synthon, see also: b) A. Dondoni, S. Franco, F. Junquera,
23 When using the Et2Zn/linked-BINOL 1a complex (0.05
molar amount of 1a), Mannich adducts were obtained in 58% ee
with 2-hydroxy-1-phenylethanone (3b) and in 36% ee with 2-
hydroxy-1-(2-furyl)ethanone (3c). See, Ref. 13b.
´
F. L. Merchan, P. Merino, T. Tejero, J. Org. Chem. 1997, 62,
5497. c) B. M. Trost, V. S. C. Yeh, Org. Lett. 2002, 4, 3513,
and references therein.
24 A portion of this article was communicated previously,
see: M. Sugita, A. Yamaguchi, N. Yamagiwa, S. Handa, S.
Matsunaga, M. Shibasaki, Org. Lett. 2005, 7, 5339.
25 a) Y. S. Kim, S. Matsunaga, J. Das, A. Sekine, T. Ohshima,
M. Shibasaki, J. Am. Chem. Soc. 2000, 122, 6506. b) K. Majima,
R. Takita, A. Okada, T. Ohshima, M. Shibasaki, J. Am. Chem.
Soc. 2003, 125, 15837.
26 The relative and absolute configuration of Mannich adduct
7ab were determined after conversion into dibenzoate 12ab. NMR
and optical rotation were compared with those of authentic sample
prepared from known compound 13. Absolute configuration of
7ab was also confirmed by Mosher’s method. For more detailed
information including determination of configurations of other
Mannich adducts, see Supporting Information. The relative and
absolute configuration of Mannich adducts 7ac, 7ae, 7ag, and
7bb were determined in a similar manner.
31 For the results using Et2Zn/linked-BINOL 1a, ꢁ,ꢀ-
unsaturated imine, and hydroxy ketone 3a (with Dpp-imine 2f:
syn/anti = 19/81, 99% ee, with Boc-imine derived from cinnam-
aldehyde: syn/anti = 63/37, 99% ee), see Ref. 13b. Although ee
was excellent, diastereoselectivity was only modest.
32 For metal-catalyzed direct asymmetric Mannich-type reac-
tions of isomerizable aliphatic imines, see Refs. 12h and 13d.
33 For evaluation of oxophilicity of rare-earth metals, see:
a) H. Tsuruta, K. Yamaguchi, T. Imamoto, Chem. Commun.
1999, 1703. For a example of utilizing oxophilic property of a
rare-earth metal in the presence of nitrogen-containing ligands,
see: b) M. Andruh, O. Kahn, J. Sainton, Y. Dromzee, S. Jeannin,
Inorg. Chem. 1993, 32, 1623.
Bz
Ph
Bz
Ph
1)HCl/MeOH
NH
O
NH
O
0 °C to RT
BzCl, Py
CH2Cl2
7ab
Ph
Ph
2) BzCl, Py
CH2Cl2
OBz
OH
12ab
13