Direct catalytic asymmetric Mannich-type reactions of isomerizable aliphatic imines: chemoselective enolate formation from a hydroxyketone by a Zn-catalyst

Article abstract of DOI:10.1016/j.tetlet.2006.04.016

A direct catalytic asymmetric Mannich-type reaction of isomerizable aliphatic imines is described. A Et₂Zn/(S,S)-linked-BINOL complex was suitable for chemoselective enolate formation from a hydroxyketone in the presence of isomerizable aliphat

Full text of DOI:10.1016/j.tetlet.2006.04.016

Tetrahedron Letters 47 (2006) 3985–3989
Direct catalytic asymmetric Mannich-type reactions of
isomerizable aliphatic imines: chemoselective enolate
formation from a hydroxyketone by a Zn-catalyst
Akitake Yamaguchi, Shigeki Matsunaga* and Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan
Received 6 March 2006; revised 5 April 2006; accepted 7 April 2006
Available online 2 May 2006
Abstract—A direct catalytic asymmetric Mannich-type reaction of isomerizable aliphatic imines is described. A Et2Zn/(S,S)-linked-
BINOL complex was suitable for chemoselective enolate formation from a hydroxyketone in the presence of isomerizable aliphatic
N-diphenylphosphinoyl imines. The reaction proceeds smoothly and b-alkyl-b-amino-a-hydroxyketones were obtained in good yield
and high enantioselectivity (up to 99% ee), albeit in modest to low diastereoselectivity.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Chiral b-amino alcohols are important building blocks,
found in natural products, pharmaceuticals, chiral auxil-
O
iaries, and chiral ligands.1 Tremendous effort has, there-
fore, been devoted to the synthesis of chiral b-amino
alcohols.2 Among the methods available, catalytic
asymmetric Mannich-type reactions3 of a-oxy donors
effectively provide chiral b-amino alcohols with a con-
comitant carbon–carbon bond-forming reaction. Vari-
ous methods are developed utilizing a-oxy donors in
the Mannich-type reaction.4 Recently, direct catalytic
asymmetric Mannich-type reactions,5 in which unmodi-
fied a-oxy donors rather than preformed latent enolates
such as a ketene silyl acetal are utilized, have been inten-
sively studied. High diastereoselectivities and enantio-
selectivities have been realized using organo-catalysts6,7
and metal complexes,8,9 including our metal/linked-
BINOL (1, Fig. 1) complexes.9–12 Most of the examples
reported to date are, however, limited to non-enolizable
aryl imines. The use of isomerizable aliphatic imines is
rare. Notable achievements were reported by Barbas
and co-workers using proline as a catalyst.6f With both
a branched aliphatic imine and an a-benzyloxy imine,
good yields (70–74%) and high ees (91–93%) were real-
ized using hydroxyacetone as a donor (2 examples). A
OHHO
OHHO
(S,S)-linked-BINOL 1
Figure 1. Structure of linked-BINOL 1.
linear unbranched imine, however, still resulted in mod-
est chemical yield (46%). Enders and co-workers realized
high yield and excellent ee using branched aliphatic
imines and an a-benzyloxy imine, when 2,2-dimethyl-
1,3-dioxan-5-one was used as a donor.6f
In the metal-catalyzed direct Mannich-type reaction, the
chiral metal-catalyst functions as a Brønsted base to
deprotonate the a-proton of a ketone donor, generating
a metal enolate in situ. When using isomerizable imines,
a chemoselectivity issue arises. Deprotonation of the a-
proton of a-oxy donor is required for the desired reac-
tion. However, the Brønsted basic catalyst could also
effect a-deprotonation of the aliphatic imine, leading
to undesired enamine or enamide formation. Quite re-
cently, the report of a successful metal-catalyzed direct
catalytic asymmetric Mannich-type reaction of isomeriz-
able aliphatic imines by Trost and co-workers prompted
us to report our preliminary results on this matter.13,14
In this manuscript, we describe a Et2Zn/linked-BINOL
Keywords: Asymmetric catalysis; Mannich; b-amino alcohol; Zinc;
Linked-BINOL.
*
Corresponding authors. Tel.: +81 3 5841 4830; fax: +81 3 5684 5206
(M.S.); e-mail addresses: mshibasa@mol.f.u-tokyo.ac.jp; smatsuna@
mol.f.u-tokyo.ac.jp
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.04.016

3986
A. Yamaguchi et al. / Tetrahedron Letters 47 (2006) 3985–3989
1 complex15 catalyzed chemoselective enolate formation
from a hydroxyketone in the presence of isomerizable
imines,16 including non-branched linear aliphatic imi-
nes. Mannich-type reactions proceeded in high enantio-
selectivity (up to 99%) and good yield (up to 92% yield),
albeit in modest diastereoselectivity.
without purification (Scheme 1, Table 1, entries 2–6).
N-Dpp imine 2a was readily generated by treatment of
3a with K2CO3 and Na2SO4 in CH3CN at room temper-
ature; however, the Mannich reaction gave only modest
yield probably due to impure imine 2a (entry 2). The use
of polymer-supported amine18 also failed in the present
system (entry 3). Conditions reported for aliphatic N-
Ts-imine synthesis19 were suitable for N-Dpp imines;
an aq NaHCO3/CH2Cl2 biphasic system gave pure
imine 2a20 and showed the best results in the Mannich
reaction (entry 4, 82% yield). Isolated yield of Mannich
adduct 5a improved slightly at 0 ꢁC (entry 5: 89%, syn/
anti = 76/24). Isolated yield decreased when the amount
of Et2Zn increased, probably because excess Et2Zn
caused undesired imine isomerization (entry 6).
Because we previously reported the direct Mannich-type
reaction of non-enolizable N-diphenylphosphinoyl imi-
nes (N-Dpp imine) and hydroxyketones,9 we initiated
our study using aliphatic N-Dpp imines 2. Aliphatic
imines were synthesized by the method reported by
Charette and co-workers with a slight modification.17
a-Amino sulfones 3 were synthesized from p-toluene-
sulfinic acid, aldehydes, and diphenylphosphinamide
(Scheme 1). Although the precedent reports utilize 3 to
generate aliphatic imines in situ in the presence of excess
base and chiral catalyst,16,17 that strategy was not appli-
cable to our system. With 1.1 equiv of Et2Zn and
5 mol % of linked-BINOL 1, both yield and ee were
unsatisfactory (Table 1, entry 1). Therefore, conditions
for isolating aliphatic N-Dpp imine 2a were examined.
Because aliphatic N-Dpp imines are relatively unstable,
isolated imine 2a was used for the Mannich reaction
The optimized reaction conditions were applicable to
several aliphatic imines as summarized in Table 2.21
With imine 2a, reaction proceeded smoothly with re-
duced catalyst loading (2 mol %, entry 2), affording the
product in 92% yield, syn/anti = 82/18, and 98% ee
(syn). It is noteworthy that the Mannich reaction pro-
ceeded even using linear unbranched imines 2b and 2c
(entries 3 and 4), which are especially prone to isomeri-
zation to enamides under basic conditions. With imine
2c, the reaction was performed at ꢀ30 ꢁC to avoid unde-
sired imine isomerization. The results in Table 2 sug-
gested that the Et2Zn/linked-BINOL 1 complex was
effective for chemoselective enolate formation from
hydroxyketone 4. Our previous mechanistic studies in
direct aldol reactions suggested that the active species
of the reaction would consist of Zn, linked-BINOL 1,
and hydroxyketone 4.15a We assume that high chemo-
selectivity was realized because of the high affinity of
hydroxyketone 4 toward Zn complex. On the other
hand, in contrast to our previous report using non-enol-
izable N-Dpp imines,9a diastereoselectivity for the pres-
ent aliphatic N-Dpp imines was low to modest, although
enantioselectivity was high in all entries. Diastereoselec-
tivity was strongly dependent on the imine substituent
(syn/anti = 82/18–35/65).22 The similar absolute config-
O
P
O
P
O
P
Ph
Ph
Ph
Ph
Ph
Ph NH
H N
2
base
N
HO S p-tol
2
p-tol
+
R
S
ref. 17
R
O
3
O
RCHO
2
O
-
without purification
3a: R = (CH ) CHCH
3 2
2
Ph
Ph
P
O
OMe
NH
O
OMe
cat. Et Zn/(S,S)-1
2
R
THF
OH
4
OH
5
Scheme 1. General scheme for preparation of enolizable aliphatic
N-Dpp imines 2 and application to Mannich-type reaction.
Table 1. Optimization of reaction conditions
O
Ph P
2
O
PPh
Et Zn (x mol %)
2
O
OMe
2
(S,S)-1
(5 mol %)
N
NH
O
OMe
OH
4 (2 equiv)
THF, MS 3
Å
OH
syn-5a
2a
Entry
Et2Zn (mol %)
Imine synthesisa
Temp (ꢁC)
Time (h)
Yieldb (%)
drc (syn/anti)
ee (syn/anti)
1
2
3
4
5
6
110
10
10
10
10
20
A
B
C
D
D
D
ꢀ20
ꢀ20
ꢀ20
ꢀ20
0
12
16
21
19
19
19
15
61/39
71/29
—
70/30
76/24
88/12
12/67
92/99
—
96/99
96/97
98/94
63d
Traced
82
89
76
0
a Imine preparation conditions: A: in situ generation from 3a, THF/CH2Cl2; B: 3a, K2CO3, Na2SO4, CH3CN; C: 3a, polymer-supported piperidine,
CH2Cl2; D: 3a, aq NaHCO3, CH2Cl2. See, Ref. 20.
b Isolated yield.
c Determined by 1H NMR analysis of crude mixtures.
d Imine was not pure.

A. Yamaguchi et al. / Tetrahedron Letters 47 (2006) 3985–3989
3987
Table 2. Direct catalytic asymmetric Mannich-type reactions of various aliphatic imines 2a–f
O
Ph P
Ph
O
Ph P
Ph
cat. Et Zn (2x mol %)
2
O
P Ph
Ph
O
OMe
(S,S)-linked-BINOL 1
NH
O
OMe
NH
O
OMe
(x mol %)
N
+
R
R
+
R
R
S
R
OH
THF, MS 3Å
R
OH
syn-5
OH
anti-5
2
4 (2 equiv)
Entry
Imine (R)
Product
(S,S)-1 (xmol %)
Temp (ꢁC)
Time (h)
Yielda (%)
drb (syn/anti)
eec (syn/anti)
1
2
5a
5a
5
2
0
0
18
24
89
92
76/24
82/18
96/97
98/97
2a
2b
2c
3
4
5b
5c
5
5
0
19
13
85
79
56/44
65/35
95/98
ꢀ30
>99/99
5
5d
5
0
19
89
52/48
97/94
2d
6
7
5e
5f
5
5
0
0
18
15
77
88
55/45
35/65
90/99
96/99
2e
2f
a Isolated yield.
b Determined by 1H NMR analysis of crude mixture.
c Determined by chiral HPLC analysis.
urations of the major enantiomers of syn-5 (2R,3S) and
anti-5 (2R,3R) suggest that enantioface selection of Zn-
enolate generated in situ from ketone 4 and the Et2Zn/
linked-BINOL 1 complex is good. Low diastereoselec-
tivity is, therefore, ascribed to the low facial selectivity
of imines 2. Further trials to improve the diastereoselec-
tivity are ongoing.
linked-BINOL 1 complex (2–5 mol %) effectively pro-
moted the Mannich-type reaction, affording b-alkyl-b-
amino-a-hydroxy ketones in high enantioselectivity
(90–>99% ee) and good yield (77–92%), albeit in modest
to low diastereoselectivity (88/12–35/65).
Acknowledgements
The usefulness of Mannich adducts 5 is enhanced by the
presence of a 2-methoxyphenyl group—a placeholder
for further conversion. As shown in Scheme 2,
Baeyer–Villiger oxidation23 of carbamate 6a proceeded
smoothly with the aid of the electron donating methoxy
group, affording b-alkyl-b-amino-a-hydroxy ester 7a in
60% yield.
This work was supported by Grant-in-Aid for Specially
Promoted Research and Grant-in-Aid for Encourage-
ments for Young Scientists (B) (for S.M.) from JSPS
and MEXT.
References and notes
In summary, we succeeded in chemoselective enolate
formation from hydroxyketone 4 in the presence of
isomerizable aliphatic N-Dpp imines 2. The Et2Zn/
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O
O
OMe
HN
O
HN
O
a
b
5a
O
6a
7a
O
OMe
O
Scheme 2. Transformation of Mannich adduct 5a. Reagents and
conditions: (a) (i) concd aq HCl/dioxane, rt, 3 h; (ii) triphosgene,
pyridine, ꢀ78 to ꢀ40 ꢁC, 0.5 h, 69% (two steps); (b) mCPBA, Na2HPO4,
4,40-thiobis(6-tert-butyl-m-cresol), Cl(CH2)2Cl, 60 ꢁC, 13 h, 60%.
´
4. A review for direct Mannich reaction: (a) Cordova, A.
Acc. Chem. Res. 2004, 37, 102; (b) Marques, M. M. B.
Angew. Chem., Int. Ed. 2006, 45, 348.

3988
A. Yamaguchi et al. / Tetrahedron Letters 47 (2006) 3985–3989
5. Excellent dr and ee were achieved in Mannich-type
Fuentes, A. Org. Lett. 2005, 7, 3433; (o) Mitsumori, S.;
Zhang, H.; Cheong, P. H. Y.; Houk, K. N.; Tanaka, F.;
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the 125th annual meeting of Pharmaceutical Society of
Japan (Tokyo), held in March 2005.
´
Cordova, A.; Notz, W.; Zhong, G.; Betancort, J. M.;
15. For other applications of the Et2Zn/linked-BINOL 1
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7. a-Oxy aldehydes as donors: Ibrahem, I.; Cordova, A.
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16. For a related phase-transfer catalyzed asymmetric aza-
Henry reaction using in situ generated enolizable N-
carbamoyl imines; see: (a) Fini, F.; Sgarzani, V.; Petter-
son, D.; Herrera, R. P.; Bernardi, L.; Ricci, A. Angew.
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17. (a) Coˆte, A.; Boezio, A. A.; Charette, A. B. Proc. Natl.
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´
10. Synthesis of linked-BINOL 1: Matsunaga, S.; Das, J.;
Roels, J.; Vogl, E. M.; Yamamoto, N.; Iida, T.; Yama-
guchi, K.; Shibasaki, M. J. Am. Chem. Soc. 2000, 122, 2252.
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reactions using metal catalysts: ketones as donors (a)
Yamasaki, S.; Iida, T.; Shibasaki, M. Tetrahedron Lett.
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20. Representative procedure for imine 2 synthesis: To a
mixture of sulfinic adduct 3 (0.2 mmol) in CH2Cl2
(4 mL) at room temperature was added freshly prepared
satd aq NaHCO3 (4 mL). The mixture was stirred for
2–5 h at 20 ꢁC. The organic phase was separated and
the aqueous phase was extracted with CH2Cl2 (·2). The
combined organic layers were dried over Na2SO4. After
evaporation under reduced pressure, the residue (imine 2)
was used for the Mannich-type reaction without
purification.
12. For selected other examples of direct Mannich reactions
using unmodified ketone and/or aldehyde donors with
organocatalysts, (a) Notz, W.; Sakthivel, K.; Bui, T.;
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´
199; (b) Cordova, A.; Watanabe, S.-i.; Tanaka, F.; Notz,
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˚
W., ; Barbas, C. F., III. J. Am. Chem. Soc. 2002, 124, 1866;
(c) Notz, W.; Tanaka, F.; Watanabe, S; Chowdari, N. S.;
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Miyauchi, K.; Nagata, K.; Ohsawa, A. Org. Lett. 2003, 5,
2): A test tube with 40 mg of MS 3 A was flame-dried and
heated at 160 ꢁC for 3 h under reduced pressure. After
cooling down to room temperature, (S,S)-linked BINOL 1
(0.01 mmol) in THF (0.2 mL) was added and the mixture
was cooled to the indicated reaction temperature (0 or
ꢀ30 ꢁC). To the mixture was added successively Et2Zn
(20 lL, 0.02 mmol, 1.0 M in hexanes), hydroxylketone 4
(0.4 mmol) in THF (0.45 mL), and then imine (0.2 mmol)
in THF (0.5 mL). The reaction mixture was stirred for the
indicated time in Table 2, and quenched with satd aq
NH4Cl. The mixture was extracted with ethyl acetate (·2).
Combined organic layers were washed with brine and
dried over Na2SO4. After evaporation, the residue was
purified by flash silica gel column chromatography to
afford Mannich adduct.
´
4301; (f) Cordova, A. Chem. Eur. J. 2004, 10, 1987, and
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22. Absolute configurations of syn-5a, anti-5a, syn-5c, anti-5c,
syn-5e, and anti-5e, were determined by Mosher’s method
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´
´
´

A. Yamaguchi et al. / Tetrahedron Letters 47 (2006) 3985–3989
3989
configurations of Mannich adducts 5c, 5d, 5e, and 5f were
determined after conversion to the corresponding cyclic
carbamates and NOE measurement.
23. Kishi, Y.; Aratani, M.; Tanino, H.; Fukuyama, T.; Goto,
T.; Inoue, S.; Sugiura, S.; Kakoi, H. J. C.S. Chem.
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