Direct catalytic asymmetric Mannich-type reaction of hydroxyketone using a Et2Zn/linked-BINOL complex: Synthesis of either anti- or syn-β-amino alcohols

Article abstract of DOI:10.1021/ja0482435

Full details of a direct catalytic asymmetric Mannich-type reaction of a hydroxyketone using a Et₂Zn/(S,S)-linked-BINOL complex are described. By choosing the proper protective groups on imine nitrogen, either anti- or syn-β-amino alcohol was obtained in good diastereomeric ratio, yield, and excellent enantiomeric excess using the same zinc catalysis. N-Diphenylphosphinoyl (Dpp) imine 3 gave anti-β-amino alcohols in anti/syn = up to >98/2, up to >99% yield, and up to >99.5% ee, while Boc-imine 4 gave syn-β-amino alcohols in anti/syn = up to 5/95, up to >99% yield, and up to >99.5% ee. The high catalyst turnover number (TON) is also noteworthy. Catalyst loading was successfully reduced to 0.02 mol % (TON = up to 4920) for the anti-selective reaction and 0.05 mol % (TON = up to 1760) for the syn-selective reaction. The Et₂Zn/(S,S)-linked-BINOL complex exhibited far better TON than in previous reports of catalytic asymmetric Mannich-type reactions. Mechanistic studies to clarify the reason for the high catalyst efficiency as well as transformations of Mannich adducts are also described.

Full text of DOI:10.1021/ja0482435

Published on Web 06/26/2004
Direct Catalytic Asymmetric Mannich-type Reaction of
Hydroxyketone Using a Et2Zn/Linked-BINOL Complex:
Synthesis of Either anti- or syn-â-Amino Alcohols
Shigeki Matsunaga, Takamasa Yoshida, Hiroyuki Morimoto, Naoya Kumagai, and
Masakatsu Shibasaki*
Contribution from the Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo,
Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received March 27, 2004; E-mail: mshibasa@mol.f.u-tokyo.ac.jp
Abstract: Full details of a direct catalytic asymmetric Mannich-type reaction of a hydroxyketone using a
Et2Zn/(S,S)-linked-BINOL complex are described. By choosing the proper protective groups on imine
nitrogen, either anti- or syn-â-amino alcohol was obtained in good diastereomeric ratio, yield, and excellent
enantiomeric excess using the same zinc catalysis. N-Diphenylphosphinoyl (Dpp) imine 3 gave anti-â-
amino alcohols in anti/syn ) up to >98/2, up to >99% yield, and up to >99.5% ee, while Boc-imine 4 gave
syn-â-amino alcohols in anti/syn ) up to 5/95, up to >99% yield, and up to >99.5% ee. The high catalyst
turnover number (TON) is also noteworthy. Catalyst loading was successfully reduced to 0.02 mol % (TON
) up to 4920) for the anti-selective reaction and 0.05 mol % (TON ) up to 1760) for the syn-selective
reaction. The Et2Zn/(S,S)-linked-BINOL complex exhibited far better TON than in previous reports of catalytic
asymmetric Mannich-type reactions. Mechanistic studies to clarify the reason for the high catalyst efficiency
as well as transformations of Mannich adducts are also described.
Scheme 1. Catalytic Enantio- and Diastereoselective Synthesis of
â-Amino Alcohol via the Mannich-type Reaction
Introduction
Chiral â-amino alcohol units are useful chiral building blocks
found in various natural products, compounds with pharmaco-
logically important activity, chiral auxiliaries, and chiral ligands.1
Various methods have been developed over the past decade for
enantioselective and diastereoselective preparation of â-amino
alcohols.2 Among the methods available for their catalytic
enantioselective syntheses,3 catalytic asymmetric Mannich-type
reactions4 of R-alkoxy enolate are of particular interest because
two adjacent stereocenters are constructed simultaneously with
a concomitant carbon-carbon bond formation. As shown in
Scheme 1, either anti- or syn-â-amino alcohol is obtained in an
optically active form using suitable chiral catalysts, imines, and
nucleophiles. Toward this end, Kobayashi reported pioneering
work on the Zr catalysis using preformed R-TBSO- and R-BnO-
ketene silyl acetals, which selectively provided either anti- or
syn-â-amino alcohol, respectively.5 By changing the face
selection of enolate, stereoselective synthesis of either syn- or
anti-â-amino alcohol was achieved by the same Zr-catalysis.
syn-Mannich and anti-Mannich adducts had the same absolute
configuration at the â-position of the carbonyl group. Akiyama
et al. reported the syn-selective Mannich-type reaction of an
R-Ph3SiO-ketene silyl acetal using a chiral Brønsted acid
catalyst.6 Recently, more atom-economical processes,7 that is,
the direct addition of unmodified R-hydroxyketone8 to imines,
were reported by List,9 Barbas,10 and Trost.11,12 Excellent
selectivity was achieved; however, only syn-amino alcohols were
produced in those systems.9-11 The development of an anti-
(1) (a) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. ReV. 1996, 96, 835. (b)
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; ComprehensiVe Asym-
metric Catalysis, 1st ed.; Springer: Berlin, 1999. (c) Ojima, I., Ed.; Catalytic
Asymmetric Synthesis, 2nd ed.; Wiley-VCH: New York, 2000.
(2) For reviews on asymmetric synthesis of vicinalamino alcohols, see: (a)
Bergmeire, S. C. Tetrahedron 2000, 56, 2561. (b) Reetz, M. Chem. ReV.
1999, 99, 1121.
(6) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem., Int. Ed. 2004,
43, 1566.
(7) Trost, B. M. Science 1991, 254, 1471.
(8) For the use of unmodified hydroxyketones as a donor in asymmetric
carbon-carbon bond forming reactions, see, with catalytic antibodies: (a)
Hoffmann, T.; Zhong, G.; List, B.; Shabat, D.; Anderson, J.; Gramatikova,
S.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 1998, 120, 2768
and references therein. For examples with small molecular catalysts, see
reviews on direct aldol reactions: (b) Alcaide, B.; Almendros, P. Eur. J.
Org. Chem. 2002, 1595. (c) List, B. Tetrahedron 2002, 58, 5573.
(9) (a) List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J. J. Am. Chem. Soc.
2002, 124, 827. (b) List, B. J. Am. Chem. Soc. 2000, 122, 9336.
(10) Co´rdova, A.; Notz, W.; Zhong, G.; Betancort, J. M.; Barbas, C. F., III. J.
Am. Chem. Soc. 2002, 124, 1842.
(3) Reviews: (a) Kobayashi, S.; Ishitani, H. Chem. ReV. 1999, 99, 1069. (b)
Kolb, H. C.; Sharpless, K. B. In Transition Metals for Organic Synthesis;
Beller, M., Bolm, C., Eds.; Wiley-VCH: Weinheim, 1998; p 243.
(4) For a review on the catalytic asymmetric Mannich-type reaction, see: (a)
Kobayashi, S.; Ueno, M. In ComprehensiVe Asymmetric Catalysis; Jacobsen,
E. N., Pfaltz, A., Yamamoto, H., Eds.; Supplement 1; Springer: Berlin,
2003; Chapter 29.5, p 143. See also ref 3a and: (b) Taggi, A. E.; Hafez,
A. M.; Lectka, T. Acc. Chem. Res. 2003, 36, 10.
(5) Kobayashi, S.; Ishitani, H.; Ueno, M. J. Am. Chem. Soc. 1998, 120, 431.
(11) Trost, B. M.; Terrell, L. R. J. Am. Chem. Soc. 2003, 125, 338.
9
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J. AM. CHEM. SOC. 2004, 126, 8777-8785
8777

A R T I C L E S
Matsunaga et al.
selective direct catalytic asymmetric Mannich-type reaction of
R-hydroxyketone has remained problematic. In addition, catalyst
loading remained unsatisfactory in the above-mentioned
examples.9-11 In the Mannich-type reaction using metal cataly-
sis, â-amino carbonyl adducts often interact strongly with
asymmetric metal complexes. Product inhibition is a formidable
problem in asymmetric Mannich-type reactions. Although recent
progress in asymmetric Mannich-type reactions with ketene silyl
acetals and enol silyl ethers enabled catalytic use of chiral
promoters (1-5 mol %) to achieve high yield (>90%),4,13 the
asymmetric catalysts for the direct Mannich-type reaction, in
most cases, still require 5-20 mol % of catalyst loading
(substrate/catalyst ) <20) to achieve good conversion (>90%
yield).9-11,12 Thus, the development of an asymmetric catalysis
that has high catalyst efficiency for direct asymmetric Mannich-
type reactions is desirable. To improve the substrate/catalyst
ratio, catalysts should be compatible with â-amino carbonyl
adducts.
Figure 1. Structures of (S,S)-linked-BINOL 1, 2-hydroxy-2′-methoxy-
acetophenone (2a), N-diphenylphosphinoyl(Dpp) imine 3, and N-tert-
butoxycarbonyl (Boc) imine 4.
Scheme 2. Direct Asymmetric Aldol Reaction and Michael
Reaction Catalyzed by the Et2Zn/(S,S)-Linked-BINOL 1 Complex
After a preliminary report14 on anti-selective direct catalytic
asymmetric Mannich-type reactions of hydroxyketone 2a using
a Et2Zn/linked-BINOL 1 complex (Figure 1),15-17 we continued
studies to broaden the reaction scope and to improve the catalyst
turnover number (TON). Here, we report full details of
asymmetric zinc catalysis in direct catalytic asymmetric Man-
nich-type reactions using the Et2Zn/linked-BINOL 1 complex.
By selecting the proper protective group of imines, either anti-
or syn-â-amino alcohols were selectively obtained in good
diastereomeric ratio, yield, and ee while using the same zinc
catalyst and ketone 2a. Dpp-imine 3 gave anti-adducts in anti/
syn ) up to >98/2, up to >99% yield, and up to >99.5% ee,
while Boc-imine 4 gave syn-adducts in anti/syn ) up to 5/95,
up to >99% yield, and up to >99.5% ee. It is noteworthy that
catalyst loading was successfully reduced to 0.02 mol % for
the anti-selective reaction (TON ) up to 4920) and 0.05 mol
% for the syn-selective reaction (TON ) up to 1760).
Mechanistic studies revealed that the rate-determining step
differed depending on the imines used. The effects of â-amino
alcohol adducts on the zinc catalysis were also discussed.
(12) For other examples of direct catalytic asymmetric Mannich(-type) reactions
using unmodified ketone and/or aldehyde as donors, see a review: (a)
Co´rdova, A. Acc. Chem. Res. 2004, 37, 102. For selected examples, see
also: (b) Notz, W.; Sakthivel, K.; Bui, T.; Zhong, G.; Barbas, C. F., III.
Tetrahedron Lett. 2001, 42, 199. (c) Juhl, K.; Gathergood, N.; Jørgensen,
K. A. Angew. Chem., Int. Ed. 2001, 40, 2995. (d) Co´rdova, A.; Watanabe,
S.-i.; Tanaka, F.; Notz, W.; Barbas, C. F., III. J. Am. Chem. Soc. 2002,
124, 1866. (e) Co´rdova, A.; Barbas, C. F., III. Tetrahedron Lett. 2002, 43,
7749. (f) Watanabe, S.-i.; Co´rdova, A.; Tanaka, F.; Barbas, C. F., III. Org.
Lett. 2002, 4, 4519. (g) Hayashi, Y.; Tsuboi, W.; Shoji, M.; Suzuki, N. J.
Am. Chem. Soc. 2003, 125, 11208. (h) Hayashi, Y.; Tsuboi, W.; Ashimine,
I.; Urushima, T.; Shoji, M.; Sakai, K. Angew. Chem., Int. Ed. 2003, 42,
3677. For related examples, see: (i) Bernardi, L.; Gothelf, A. S.; Hazell,
R. G.; Jørgensen, K. A. J. Org. Chem. 2003, 68, 2583. (j) Marigo, M.;
Kjærsgaard, A.; Juhl, K.; Gathergood, N.; Jørgensen, K. A. Chem.-Eur. J.
2003, 9, 2359. (k) Uraguchi, D.; Terada, M. J. Am. Chem. Soc. 2004, 126,
5356 and references therein.
Results and Discussion
(13) For selected leading references, see: (a) Ishitani, H.; Ueno, M.; Kobayashi,
S. J. Am. Chem. Soc. 1997, 119, 7153. (b) Ishitani, H.; Ueno, M.;
Kobayashi, S. J. Am. Chem. Soc. 2000, 122, 8180. (c) Ferraris, D.; Young,
B.; Dudding, T.; Lectka, T. J. Am. Chem. Soc. 1998, 120, 4548. (d)
Josephsohn, N. S.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc.
2004, 126, 3734. (e) Xue, S.; Yu, S.; Deng, Y.; Wulff, W. D. Angew. Chem.,
Int. Ed. 2001, 40, 2271. (f) Kobayashi, S.; Matsubara, R.; Nakamura, Y.;
Kitagawa, H.; Sugiura, M. J. Am. Chem. Soc. 2003, 125, 2507. For examples
with metal enolate, see: (g) Hagiwara, E.; Fujii, A.; Sodeoka, M. J. Am.
Chem. Soc. 1998, 120, 2474. (h) Fujii, A.; Hagiwara, E.; Sodeoka, M. J.
Synth. Org. Chem. Jpn. 2000, 58, 728. (i) Fujieda, H.; Kanai, M.; Kambara,
T.; Iida, A.; Tomoika, K. J. Am. Chem. Soc. 1997, 119, 2060. For an
example with organocatalyst, see: (j) Wenzel, A. G.; Jacobsen, E. N. J.
Am. Chem. Soc. 2002, 124, 12964.
(14) A portion of the results in this Article was reported previously as a
preliminary communication: Matsunaga, S.; Kumagai, N.; Harada, S.;
Shibasaki, M. J. Am. Chem. Soc. 2003, 125, 4712.
(15) For the synthesis of linked-BINOL 1, see: (a) Matsunaga, S.; Das, J.; Roels,
J.; Vogl, E. M.; Yamamoto, N.; Iida, T.; Yamaguchi, K.; Shibasaki, M. J.
Am. Chem. Soc. 2000, 122, 2252. (b) Matsunaga, S.; Ohshima, T.;
Shibasaki, M. AdV. Synth. Catal. 2002, 344, 4. Both enantiomers of linked-
BINOL are also commercially available from Wako Pure Chemical
Industries, Ltd. Catalog No. for (S,S)-5, No. 152-02431; and for (R,R)-5,
No. 155-02421.
(16) Et2Zn/linked-BINOL 1 complex in direct aldol reaction: (a) Kumagai, N.;
Matsunaga, S.; Kinoshita, T.; Harada, S.; Okada, S.; Sakamoto, S.;
Yamaguchi, K.; Shibasaki, M. J. Am. Chem. Soc. 2003, 125, 2169. (b)
Kumagai, N.; Matsunaga, S.; Yoshikawa, N.; Ohshima, T.; Shibasaki, M.
Org. Lett. 2001, 3, 1539. (c) Yoshikawa, N.; Kumagai, N.; Matsunaga, S.;
Moll, G.; Ohshima, T.; Suzuki, T.; Shibasaki, M. J. Am. Chem. Soc. 2001,
123, 2466.
(17) Et2Zn/linked-BINOL 1 complex in direct Michael reaction: (a) Harada,
S.; Kumagai, N.; Kinoshita, T.; Matsunaga, S.; Shibasaki, M. J. Am. Chem.
Soc. 2003, 125, 2582. (b) Kumagai, N.; Matsunaga, S.; Shibasaki, M. Org.
Lett. 2001, 3, 4251.
(A) Development of Enantio- and Diastereoselective Man-
nich-type Reactions. In our continuing investigation of a direct
catalytic asymmetric aldol reaction16 and a Michael reaction17
of hydroxyketones, a Et2Zn/linked-BINOL 1 complex was
determined to be effective for shielding the Re-face of the zinc-
enolate generated from ketone 2a. Absolute configurations of
products at the R-position of the carbonyl group were identical
(2R) in aldol adducts and Michael adducts, as shown in Scheme
2. We anticipated that an efficient enantioface selection of the
enolate would be applicable to other electrophiles, such as
imines. Face selection of imines is important to achieve high
diastereoselectivity. As shown in Figure 2, we hypothesized that
either anti- or syn-Mannich adducts would be selectively
obtained by choosing the proper protective group of imines
(Scheme 3) that favored the Si-face or Re-face approach toward
the Zn/linked-BINOL 1/ketone 2a complex, respectively. There-
fore, our strategy is different from that of Kobayashi et al.
employed in Zr catalysis.5 Previous mechanistic studies on the
Et2Zn/linked-BINOL 1 complex revealed that active Zn/linked-
BINOL 1/ketone 2a had an oligomeric structure, containing
presumably seven Lewis acidic zinc centers.16a We assumed that
the multinuclear zinc complex would enable flexible facial
selection of imines depending on the protective groups. Screen-
9
8778 J. AM. CHEM. SOC. VOL. 126, NO. 28, 2004

Mannich-type Reaction of Hydroxyketone
A R T I C L E S
Table 1. Optimization of the anti-Selective Direct Catalytic
Asymmetric Mannich-type Reaction
ligand 1
entry (×mol %)
ketone 2a
(equiv)
time
(h)
yielda
(%)
drb
(anti/syn)
ee (%)
(anti)
additive
1
2
3
4
5
5
3
1
1
1
2
2
2
1.1
2
MS 3 Å
MS 3 Å
MS 3 Å
MS 3 Å
none
2
3
9
24
18
97
95
98
87
93
94/6
94/6
96/4
96/4
96/4
98
98
98
98
98
Figure 2. Strategy to achieve enantio- and diastereoselective Mannich-
type reactions.
Scheme 3. Effects of Protective Group on Imine Nitrogen
1
a Isolated yield. b Determined from the H NMR spectrum of the crude
mixture.
Table 2. Effects of Hydroxyketones in the anti-Selective Direct
Catalytic Asymmetric Mannich-type Reaction
ing of various imines revealed that Dpp-imines18 afforded anti-
â-amino alcohol, while Boc-imines19 afforded syn-â-amino
alcohol (Scheme 3).20 Optimization of the reaction conditions,
scopes, and limitations of substrates, and trials to reduce catalyst
loading for both the anti- and the syn-selective reactions are
described in this section.
ligand 1
ee (%)
entry
ketone:Ar2
(×mol %) time (h) yielda (%) drb (anti/syn) (anti)
1
2
3
4
5
2a: 2′-MeO-C6H4
2b: 4′-MeO-C6H4
2c: C6H5
2d: 4′-Me-C6H4
2e: 2-furyl
1
5
5
5
5
6
24
24
24
24
99
81
83
89
84
>98/2
91/9
72/28
81/19
85/15
99
92
58
65
36
Optimization of the reaction conditions for Dpp-imine 3a is
summarized in Table 1. The addition of 2a to 3a proceeded
smoothly in the presence of 5 mol % of 1, 20 mol % of Et2Zn,
and MS 3 Å, to afford 5a anti-selectively (anti/syn ) 94/6) in
97% yield and 98% ee (anti-5a) (entry 1). The reaction reached
completion even with reduced catalyst loading to afford 5a
without any loss of diastereo- or enantioselectivity (entry 2, 3
mol %; entry 3, 1 mol %). The reaction proceeded well with
only 1.1 equiv of 2a, although there was a slight loss of
reactivity at -20 °C (entry 4). The presence of activated MS 3
Å enhanced the reaction rate without affecting stereoselectivity
(entry 3 vs entry 5). The effects of hydroxyketones are
summarized in Table 2. As expected from previous results in
the direct aldol reaction using Et2Zn/(S,S)-linked-BINOL 1
complex,16a ketones 2a gave the best results (Table 2, entry 1).
With 4′-methoxy-substituted ketone 2b, the reaction rate
decreased, while good ee and dr were obtained (entry 2, 92%
1
a Isolated yield. b Determined from the H NMR spectrum of the crude
mixture.
ee, dr ) 91/9). With ketones without methoxy substituents, both
ee and dr were only modest (entries 3-5). These results
suggested that hydroxyketones are involved in active species
affecting the stereoselectivity, as was suggested in the previous
mechanistic studies in the direct aldol reaction.16a Although
applicable hydroxyketones were limited, Mannich adducts
should be useful as chiral building blocks when considering
the methoxy-phenyl group as an ester synthon. The methoxy
substituent of 2a is supposed to assist conversion of Mannich
adducts 5 into â-amino-R-hydroxy esters through Baeyer-
Villiger oxidation (see section C).
As summarized in Table 3, the present asymmetric zinc
catalysis was applicable to various Dpp-imines 3. All reactions
were performed with 1 mol % of 1, 4 mol % of Et2Zn, and MS
3 Å. The enantiomeric excesses were uniformly high (98 f
99.5% ee) with imines derived from R-nonenolizable aldehydes.
Imines from aromatic aldehydes having various substituents
(3a-3j) afforded products with high anti-selectivity (dr: 94/6
f 99/1, entries 1-10). ortho-Substituents on the aromatic rings
resulted in almost exclusive formation of the anti-adducts (dr:
>98/2, entry 2 and 98/2, entry 8). Although imine 3k from R,â-
unsaturated aldehyde had less anti-selectivity, diastereoselec-
tivity was improved at a lower reaction temperature (entry 12,
dr: 81/19 at -30 °C). Imine 3l also provided the Mannich
adduct in high ee (99%) with modest anti-selectivity (entry 13).
Diastereoselectivity was improved by increasing the bulkiness
of the protective group. As shown in Scheme 4, di(o-tolyl)-
phosphinoyl imine 3m21 gave product 5m in better anti-
(18) Dpp-imine was prepared by following the reported procedure. Jennings,
W. B.; Lovely, C. J. Tetrahedron 1991, 47, 5561.
(19) Boc-imine was prepared by following the reported procedure. Kanazawa,
A. M.; Denis, J.; Greene, A. E. J. Org. Chem. 1994, 59, 1238. See also ref
13j.
(20) Other imines, such as Ts-imine, PMP-imine, and Cbz-imine, gave less
satisfactory results in terms of diastereoselectivity, reaction rate, and
enantioselectivity.
9
J. AM. CHEM. SOC. VOL. 126, NO. 28, 2004 8779

A R T I C L E S
Matsunaga et al.
Table 3. anti-Selective Direct Catalytic Asymmetric Mannich-type
Table 4. Trials To Reduce Catalyst Loading in the anti-Selective
Mannich-type Reaction
Reaction with Various N-Dpp-iminesa
temp time yieldb
drc
(anti/syn)
ee (%)
(anti)
ligand 1
(×mol %)
ketone 2a
(equiv)
temp
(°C)
time
(h)
yielda
(%)
drb
(anti/syn)
ee (%)
(anti)
entry
R
product (°C)
(h)
(%)
entry
1
2
3
4
5
6
7
8
9
4-MeC6H4
2-MeC6H4
C6H5
4-MeOC6H4 3d
4-NO2C6H4 3e
4-ClC6H4
4-BrC6H4
1-naphthyyl 3h
3a
3b
3c
5a
5b
5c
5d
5e
5f
5g
5h
5i
-20
-20
-20
-20
-20
-20
-20
-20
-20
-20
-20
-30
-30
9
6
6
6
9
4
4
6
7
7
4
7
5
98
99
98
97
96
97
97
97
95
98
98
97
98
96/4
>98/2
96/4
95/5
97/3
97/3
95/5
98/2
94/6
96/4
98
99
99
99
98
98
98
>99.5
99
1
2
3
4
5
6
7c
1
0.25
0.5
2
2
-20
6
6
2
6
14
6
99
99
>99
95
89
>99
98
>98/2
>98/2
95/5
96/4
97/3
99
99
99
99
97
96
97
-20
1.1
1.1
1.1
1.5
1.5
0
0
0
0
0
0.1
0.05
0.05
0.02
3f
3g
94/6
98/2
24
a Isolated yield. b Determined from the H NMR spectrum of the crude
1
2-naphthyl
3i
3j
3k
3k
mixture. c Reaction was performed on the 25 mmol scale at 1.1 M on imine.
10 2-furyl
11 (E)-cinnam
12
5j
>99.5
5k
5k
5l
76/24 >99.5
81/19 >99.5
Table 5. Optimization of the syn-Selective Direct Catalytic
Asymmetric Mannich-type Reaction
13 cyclo-propyl 3l
80/20
99
a Two equivalents of 2a was used. For less soluble imines, THF/CH2Cl2
mixed solvent was used. See the Supporting Information. b Isolated yield.
1
c Determined from the H NMR spectrum of the crude mixture.
Scheme 4. Substituent Effects of the N-Phosphinoyl Group on
Diastereoselectivity
ligand 1
(×mol %)
ketone 2a
(equiv)
temp
(°C)
time
(h)
yielda
(%)
drb
(syn/anti)
ee (%)
(syn/anti)
entry
1
2
3
4
5
6
7
8
5
5
1
1
2
1.1
2
1.1
2
2
-40 19
-40 40
-40 36
-40 40
94
>99
91
90
84
86
90
88
88/12
79/21
89/11
84/16
87/13
86/14
83/17
84/15
99/95
97/92
99/95
95/94
98/93
99/ND
99/ND
98/ND
1
-20
-20
1.5
2.5
0.5
0.1
0.05
2
2
-20 15
-20 48
selectivity (89/11, Scheme 4 vs 80/20, Table 3, entry 13),
although reactivity decreased slightly.
1
a Isolated yield. b Determined from the H NMR spectrum of the crude
mixture.
The results of attempts to reduce catalyst loading are
summarized in Table 4. The reactions were completed within
6 h using 0.25 mol % catalyst to afford product 5b in excellent
yield, dr, and ee (entry 2). Importantly, diastereoselectivity and
enantioselectivity remained high when the reaction was per-
formed at 0 °C (entries 3-7). Thus, the catalyst loading was
reduced at 0 °C, because a higher reaction rate was observed at
0 °C. At 0 °C, the reaction proceeded smoothly with as little as
1.1 equiv of ketone 2a using 0.5 mol % (entry 3) and 0.1 mol
% catalyst (entry 4). High yield (entry 3, >99%; entry 4, 95%)
and ee (entry 3, 99%; entry 4, 99%) were achieved. The reaction
rate, however, decreased slightly with 0.05 mol % catalyst and
1.1 equiv of 2a (entry 5). Thus, 1.5 equiv of 2a was used to
achieve a good reaction rate. As shown in entry 6, the reaction
was completed within 6 h using 0.05 mol % catalyst, affording
the product in >99% yield, anti/syn ) 94/6, and 96% ee. The
high catalyst turnover frequency (>300 h-1) is noteworthy. In
entry 7, the reaction was performed on a >10 g scale with 0.02
mol % catalyst; 11.9 g of 5b (TON ) 4920, yield 98.4%, anti/
syn ) 98/2, 97% ee) was obtained using 3.1 mg of (S,S)-linked-
BINOL 1 (0.005 mmol) and 20 µL of Et2Zn in hexanes (0.02
mmol). The TON of the present reaction (up to 4920) was far
better than in previous reports of catalytic asymmetric Mannich-
type reactions. The commercial availability of both (S,S)-linked-
BINOL 115 and Et2Zn solution is also practically useful.
Boc-imine 4 was most promising for syn-selective reactions.
The attempts to optimize the reaction conditions are summarized
in Table 5. The best diastereoselectivity was achieved at -40
°C using 2 equiv of ketone 2a (entry 1, 88/12; entry 3, 89/11).
The diastereoselectivity and enantioselectivity decreased with
1.1 equiv of 2a, although good yield was achieved (entries 2
and 4). At -20 °C, the reaction rate was much higher, albeit
with slightly decreased diastereoselectivity (entries 5-8). Trials
to reduce catalyst loading were performed at -20 °C, because
turnover frequency of the zinc catalyst was rather slow at -40
°C. At -20 °C, the reaction reached completion within 1.5-
2.5 h with 1 mol % (entry 5) and 0.5 mol % (entry 6) catalyst.
The syn-adduct was obtained in high ee (98-99% ee) and good
dr (83/17-86/14) using 0.5 mol % (entry 6), 0.1 mol % (entry
7), and 0.05 mol % (entry 8) catalyst loading. Although syn-
selectivity of the present reaction was not as high as a previous
report of direct catalytic asymmetric Mannich-type reactions,9-11
the far better TON in the present system is noteworthy. Another
advantage of the present reaction is the use of Boc-imine as a
substrate, because the Boc group is one of the most frequently
used protective groups for amines.
Substrate scope and limitations were examined at -40 °C
with 5 mol % catalyst and 2 equiv of 2a, which afforded the
best diastereoselectivity (Table 5). The results are summarized
(21) Positive effects of sterically demanding di(o-tolyl)phosphinoyl imine over
Dpp-imine were reported. Miyazaki, D.; Nomura, K.; Yamashita, T.;
Iwakura I.; Ikeno, T.; Yamada, T. Org. Lett. 2003, 5, 3555 and references
therein.
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Mannich-type Reaction of Hydroxyketone
A R T I C L E S
Table 6. syn-Selective Direct Catalytic Asymmetric Mannich-type
Reaction with Various N-Boc-imines 4
Figure 3. X-ray structures of anti-5b and syn-6h.
1
a Isolated yield. b Determined from the H NMR spectrum of the crude
mixture. c 4m was used as E/Z ) (85/15) mixture. Product was obtained in
E-syn/E-anti/Z-syn/Z-anti ) 70/16/10/4 as determined (syn/anti ) 80/20)
by NMR analysis.
in Table 6. syn-Adducts were obtained in good yield (entries
1-11: 80->99%), dr (entries 1-11: syn/anti ) 83/17-95/5),
and ee (entries 1-11: 98 f 99.5% ee) using imines prepared
from aromatic aldehydes. For selected examples, the reaction
was also performed with 1 mol % catalyst and still afforded a
good yield, dr, and ee (entries 2, 4, and 8). Heteroaromatic
imines were also applicable (entries 12-14). Imines 4i and 4j
had good reactivity and enantioselectivity, although 4k with a
3-pyridyl group resulted in a modest yield (67%) and ee (89%).
Imines 4l, 4m, and 4n from R,â-unsaturated aldehydes gave
products in high ee, although the diastereoselectivity was poor
to modest (entries 15-17).
(B) Mechanistic Studies. In the present Mannich-type
reactions, either anti- or syn-â-amino alcohol was selectively
obtained using the same Et2Zn/linked-BINOL 1 complex. In
addition, a high catalyst TON was achieved in both anti- and
syn-selective reactions. The results summarized in Tables 4 and
5 suggest that the Et2Zn/linked-BINOL 1 complex is compatible
with both anti- and syn-â-amino alcohols. In our previous studies
on the direct aldol16a and Michael reaction17a of ketone 2a using
the Et2Zn/linked-BINOL 1 complex, the strong affinity of ketone
2a over aldol and Michael adducts had a key role in achieving
a high catalyst TON. Because â-amino alcohols are often utilized
as good ligands for zinc complexes,1 investigations on the effects
of the Mannich adducts on the Et2Zn/linked-BINOL 1 complex
were essential to clarify the origin of the high catalyst efficiency.
Relative configurations of Mannich adducts, anti-5b and syn-
6h, were unequivocally determined by X-ray crystallographic
Figure 4. Transition state models of Mannich-type reactions.
analysis as shown in Figure 3.22,23 Absolute configurations were
determined using the MTPA method or by derivatization into
known compounds (vide infra, section C).23 As expected, the
absolute configurations at the R-position of the carbonyl group
were identical in both anti-5 and syn-6, supporting our working
hypothesis (see Figure 2). Figure 4 illustrates the postulated
transition state models for the anti-selective reaction from Dpp-
imine 3 and for the syn-selective reaction from Boc-imine 4.
The anti-selectivity with Dpp-imine might be due to the bulky
Dpp-group on the imine nitrogen. To avoid steric repulsion
between the Dpp-group and zinc-enolate, the Mannich-type
reaction would proceed via transition state A in Figure 4,
preferentially affording anti-adducts. The positive effects of the
sterically more hindered di-o-tolyl-phosphinoyl group on dia-
stereoselectivity (Scheme 4) also support our assumption. When
using less sterically demanding Boc-imine 4, the facial selectiv-
ity of imine should be opposite. To avoid steric repulsion
between a substituent (R) of imine and zinc-enolate, the
Mannich-type reaction would proceed via transition state B in
Figure 4, giving syn-adducts.24
(22) CIF files of 5b and 6h are available as Supporting Information.
(23) Relative configurations of 5a, 5b, 5j, 5k, 5l, 6e, 6g, and 6i were determined
by NOE experiments of corresponding cyclic carbamates. Absolute and
relative configurations of 6a and 6b were determined by comparison of
R
D value and NMR after conversion into 10 and 12 (Scheme 9). Absolute
configurations of 5b, 6h, 6j, and 6l were determined by Mosher’s method.
Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512.
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A R T I C L E S
Matsunaga et al.
Scheme 5. Initial Rate Kinetics of Mannich-type Reactions with
(A) Dpp-imine 3b and (B) Boc-imine 4a
Figure 5. Reaction profiles of Mannich-type reactions.
The reaction profiles of anti- and syn-selective Mannich-type
reactions are summarized in Figure 5. When the Mannich-type
reactions of imines 3c and 4a derived from benzaldehyde were
performed under identical conditions [2 mol % of Et2Zn, 0.5
mol % of (S,S)-linked-BINOL, 2 equiv of 2a, 0.194 M, at -20
different tendency. As summarized in Figure 6 and Scheme 5,25
the reaction rate of the anti-selective Mannich-type reaction of
Dpp-imine 3b had 1.0 order dependency on the concentration
of the zinc catalyst, 0.09 order dependency on the concentration
of the Dpp-imine 3b, and 1.3 order dependency on the
concentration of ketone 2a (Scheme 5A). On the other hand,
the reaction rate of the syn-selective Mannich-type reaction of
°C], Boc-imine 4a had a 1.9-fold higher reaction rate (VBoc
)
4.27 mM min-1 vs VDpp ) 2.30 mM min-1) at the initial stage
(yield < 30%). Interestingly, the initial rate kinetic studies of
anti- and syn-selective Mannich-type reactions had a completely
Figure 6. Initial rate kinetics of Mannich-type reactions.
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8782 J. AM. CHEM. SOC. VOL. 126, NO. 28, 2004

Mannich-type Reaction of Hydroxyketone
A R T I C L E S
Scheme 7. Proposed Catalytic Cycle of the syn-Selective
Scheme 6. Proposed Catalytic Cycle of the anti-Selective
Mannich-type Reaction of Dpp-imine 3
Mannich-type Reaction of Boc-imine 4
Boc-imine 4a had 1.0 order dependency on the concentration
of the zinc catalyst, 0.86 order dependency on the concentration
of the Boc-imine 4a, and -0.03 order dependency on the
concentration of ketone 2a (Scheme 5B). These results indicate
that the rate-determining step of the Mannich-type reaction is
different depending on the imine used. The proposed catalytic
cycle of the Mannich-type reactions is summarized in Scheme
6 (anti-selective) and Scheme 7 (syn-selective). On the basis of
detailed mechanistic studies of the direct aldol reaction,16a the
active species of Et2Zn/(S,S)-linked-BINOL 1 are postulated to
be a Zn/linked-BINOL/ketone oligomeric, probably hepta-
nuclear, complex [Ar*OZn (I), in Schemes 6 and 7].26 Zinc-
phenoxide would act as a Brønsted base to deprotonate the
R-proton of the ketone, affording a zinc-enolate (II). Zinc would
also function as a Lewis acid to activate imines (III), and then
1,2-addition would give (IV). Subsequent protonation and ligand
exchange of (IV) with ketone 2a would regenerate (I). The rate-
determining step in Scheme 6 is the product dissociation step
[from (IV) to (I)], while the rate-determining step in Scheme 7
is the 1,2-addition step [from (III) to (IV)].
of (2R,3S)-syn-â-amino alcohol 6 would proceed smoothly.
Thus, the high TON observed in the syn-selective Mannich-
type reaction of Boc-imine 4 is reasonable. The mechanistic
studies of the direct Michael reaction of methyl vinyl ketone
using the Et2Zn/(S,S)-linked-BINOL 1 complex revealed the
same tendency previously.28 On the other hand, initial rate
kinetics indicated that the dissociation of (2R,3R)-anti-â-amino
alcohol 5 is the rate-determining step and that the affinity of
anti-â-amino alcohol 5 to the Et2Zn/(S,S)-linked-BINOL 1
complex is stronger than that of syn-â-amino alcohol 6. To
evaluate whether anti-â-amino alcohol 5 had negative or positive
effects on the Mannich-type reaction, we performed further
mechanistic studies.
During the initial rate kinetics studies, we found that initiation
time existed in the anti-selective Mannich-type reaction of Dpp-
imine 3. The reaction profile of the reaction at the initial stage
(yield < 8%, with 0.25 mol % ligand loading) is shown in Figure
7. Acceleration of the reaction was observed after 15 min. We
hypothesized that anti-â-amino alcohol 5 accelerated the reac-
tion. The experiments shown in Figure 8 indicated that anti-â-
amino alcohol had positive effects on the reaction rate. When
the reaction rate was compared with and without additional
product (20 mol %) using 0.5 mol % (S,S)-linked-BINOL 1
and 2 mol % of Et2Zn, the reaction rate increased 1.4-fold in
the presence of 20 mol % of 5b (Figure 8, 0.112 mM min-1 vs
0.078 mM min-1). When the Mannich-type reaction of 3d and
2a (3 equiv) was performed using 8 mol % of Et2Zn, and 1
equiv of optically active anti-â-amino alcohol 5b [(2R,3R)
prepared by (S,S)-cat: 99% ee], in the absence of (S,S)-linked-
BINOL 1, reaction proceeded at a much lower reaction rate than
The difference in the initial rate kinetics between Dpp-imine
3 and Boc-imine 4 is not explained well by the difference in
the reactivity of the imines.27 The different observed kinetic
tendencies might derive from the difference in interactions
between amino alcohol adducts and the Et2Zn/(S,S)-linked-
BINOL 1 complex. Initial rate kinetics indicated that syn-â-
amino alcohol 6 would have a relatively weak affinity for the
Et2Zn/(S,S)-linked-BINOL 1 complex and that the dissociation
(24) The precise coordination mode of imines to Zn catalyst is unclear. Imines
would possibly coordinate to Zn through either the oxygen atom of the
protective group or the nitrogen atom of imines. Because the present Zn/
linked-BINOL/ketone 2a complex is oligomeric with as much as seven
zinc metals, flexible coordination of imines to the Zn/linked-BINOL/ketone
2a complex seems possible.
(25) For detailed results of initial rate kinetics, see the Supporting Information.
(26) Although mechanistic studies including X-ray crystallography, mass, and
kinetic profiles suggested oligomeric active species (see ref 16a), a linear
relationship between the ee of linked-BINOL and the ee of product was
observed. The linear relationship would suggest that the formation of hetero-
complex from (S,S)-1 and (R,R)-1 would be negligible. See the Supporting
Information for the detailed results.
(27) Both Dpp-imine 3 and Boc-imine 4 are known as highly electrophilic imines.
On the basis of its stability on silica gel against hydrolysis (Dpp-imine,
stable; Boc-imine, decomposed), we speculate Boc-imine 4 would be more
electrophilic than Dpp-imine 3.
(28) In the mechanistic studies of Michael reaction of 2a, we found that Zn-
(S,S)-linked-BINOL catalyst recognized the absolute configuration of
R-hydroxyketone unit well, and therefore the affinity of the Michael adduct
to zinc catalyst was low. Thus, high catalyst TON was achieved in the
Michael reaction of 2a and methyl vinyl ketone. See ref 17a.
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A R T I C L E S
Matsunaga et al.
Scheme 9. Transformations of Mannich Adducts to
R-Hydroxy-â-amino Carboxylic Acid Derivative 8, a Side Chain of
Taxotere 10, and epi-Cytoxazone 12a
Figure 7. Reaction profile (yield < 8%) of the anti-selective Mannich-
type reaction of Dpp-imine 3b.
a Conditions: (a) concentrated HCl(aq)/THF, room temperature, 1 h; (b)
triphosgene, pyridine, CH2Cl2, -78 °C, 0.5 h, yield 84% (two steps); (c)
mCPBA, NaH2PO4, Cl(CH2)2Cl, 60 °C, 3 h, yield 88%; (d) Ac2O, cat.
DMAP, Py, 25 °C, 12 h, yield 94%; (e) mCPBA, Na2HPO4, 4,4′-thiobis(6-
tert-butyl-m-cresol), Cl(CH2)2Cl, 60 °C, 10 h, yield 97%; (f) K2CO3,
CH3OH, 25 °C, yield quant; (g) TFA, anisole, 25 °C, 2 h; (h) triphosgene,
Py, CH2Cl2, -78 °C, 2 h, yield 92% (two steps); (i) mCPBA, NaH2PO4,
Cl(CH2)2Cl, 60 °C, 3 h, yield 63%; (j) NaBH4, AcOH, THF, 25 °C, 2 h,
yield 88%.
ee [(2R,3R)-major]. Because the Mannich-type reaction in Tables
2 and 3 gave products in 99% ee, the possibility of asymmetric
autocatalysis29 without the participation of (S,S)-linked-BINOL
1 was ruled out. The difference in ee value (99% ee vs 15%
ee) suggested that the affinity of (S,S)-linked-BINOL 1 to Zn
metal is strong enough even in the presence of a large excess
amount of (2R,3R)-anti-â-amino alcohol 5. On the basis of these
results, we speculated that anti-â-amino alcohol 5b would be
involved in the active species consisting of Zn/(S,S)-linked-
BINOL 1/ketone 2a and that (2R,3R)-anti-â-amino alcohol had
positive effects on the reaction rate when using (S,S)-linked-
BINOL 1. For achieving high TON, the affinity of ketone 2a
to Zn catalyst should be strong enough to regenerate active
species via exchange with (2R,3R)-anti-â-amino alcohol 5.
Although the exact role of the coordinated anti-â-amino alcohol
is not clear, we suppose that the steric bulkiness of the (2R,3R)-
anti-â-amino alcohol coordinated to Zn catalyst might have
positive effects on the exchange process between another bulky
(2R,3R)-anti-â-amino alcohol and less sterically demanding
ketone 2a. Thus, product inhibition with anti-â-amino-alcohol
was negligible in the anti-selective Mannich-type reaction of
imine 3, and high catalyst efficiency (TON up to 4920) was
achieved.
Figure 8. Effects of anti-â-amino alcohol 5b on the initial reaction rate of
the anti-selective Mannich-type reaction.
Scheme 8 anti-Selective Mannich-type Reaction of Imine 3d Using
anti-â-Amino Alcohol 5b and Et2Zn, in the Absence of
(S,S)-Linked-BINOL 1
(C) Transformation of Mannich Adducts. Facile depro-
tection of the N-Dpp and N-Boc groups and transformation of
the ketone to an ester should make the present Mannich-type
reactions synthetically more useful. As shown in Scheme 9, anti-
Mannich adduct 5b was readily converted to cyclic carbamate
7 in 84% yield (two steps) after removal of the N-Dpp group
under acidic conditions, followed by treatment with triphosgene.
in the presence of (S,S)-linked-BINOL 1 (Scheme 8 vs Table
3). Product 5d was obtained in approximately 20% yield after
6 h at -20 °C, and the ee value of the product was only 15%
(29) Review: Soai, K.; Shibata, T. In Catalytic Asymmetric Synthesis, 2nd ed.;
Ojima, I., Ed.; Wiley-VCH: New York, 2000; Chapter 9, p 699.
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Mannich-type Reaction of Hydroxyketone
A R T I C L E S
Baeyer-Villiger oxidation of 7 proceeded with mCPBA to
afford ester 8 in 88% yield without any epimerization, as
confirmed by NOE. syn-Mannich adducts are also synthetically
useful, because the Boc group is one of the most frequently
utilized protective groups for amines. syn-Mannich adduct 6a
was readily converted into a side chain of Taxotere 10. For the
Baeyer-Villiger oxidation of acetylated adduct of 6a, the
addition of 4,4′-thiobis(6-tert-butyl-m-cresol) was effective,30
affording 9 in 97% yield. 10 was obtained in quantitative yield
by treatment with K2CO3 in CH3OH.31 Baeyer-Villiger oxida-
tion of cyclic carbamate derived from syn-Mannich adduct 6b
afforded 11 in 63% yield, and successive treatment with NaBH4/
AcOH gave epi-cytoxazone 12 in 88% yield.32
hydroxyketone using a Et2Zn/linked-BINOL complex. Dpp-
imine 3 gave anti-â-amino alcohols in anti/syn ) up to >98/2,
up to >99% yield, and up to >99.5% ee, while Boc-imine 4
gave syn-â-amino alcohols in anti/syn ) up to 5/95, up to >99%
yield, and up to >99.5% ee. It is noteworthy that the high
catalyst TON was achieved in both anti- and syn-selective
Mannich-type reactions (TON ) up to 4920 for anti and up to
1760 for syn). Mechanistic studies provided clues to the origin
of the high TON. Application of asymmetric zinc catalysis to
other reactions such as carbon-carbon bond forming reactions
using unmodified carboxylic acid derivatives is in progress.
Acknowledgment. We are thankful for financial support from
a Grant-in-Aid for Specially Promoted Research, Grant-in-Aid
for Encouragements for Young Scientists (B) (S.M.) from JSPS
and MEXT, and a JSPS Research Fellowship for Young
Scientists (N.K.). We thank Prof. S. Kobayashi and Mr. S.
Harada at the University of Tokyo for support in X-ray analysis.
In summary, we achieved highly efficient direct catalytic
enantio- and diastereoselective Mannich-type reactions of a
(30) Kishi, Y.; Aratani, M.; Tanino, H.; Fukuyama, T.; Goto, T.; Inoue, S.;
Sugiura, S.; Kakoi, H. J. Chem. Soc., Chem. Commun. 1972, 64.
(31) [R]24 -6.1 (c 1.4, CHCl3); spectral data matched well with the reported
data.Dlit. [R]24 -7 (c 1.2, CHCl3): (a) Denis, J.-N.; Correa, A.; Greene,
A. E. J. Org.DChem. 1990, 55, 1957. [R]20 -6.81 (c 1.0, CHCl3): (b)
Hamamoto, H.; Mamedov, V. A.; KitamotoD, M.; Hayashi, N.; Tsuboi, S.
Tetrahedron: Asymmetry 2000, 11, 4485.
Supporting Information Available: Experimental procedures,
characterization of the products, detailed data for the reaction
kinetic studies, and CIF files. This material is available free of
charge via the Internet at http://pubs.acs.org.
(32) [R]25D -27.2 (c 1.1, MeOH); spectral data matched well with the reported
data. lit. [R]28D -30.4 (c 1.0, MeOH): Sakamoto, Y.; Shiraishi, A.; Seonhee,
J.; Nakata, T. Tetrahedron Lett. 1999, 40, 4203.
JA0482435
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