Anti-selective direct catalytic asymmetric Mannich-type reaction of hydroxyketone providing β-amino alcohols

Article abstract of DOI:10.1021/ja034787f

An anti-selective direct catalytic asymmetric Mannich-type reaction is described. The Et₂Zn/(S,S)-linked-BINOL 1 = 4/1 complex promoted a Mannich-type reaction of 2-hydroxy-2′-methoxyacetophenone (2) and N-diphenylphosphinoyl imines 3. Using as

Full text of DOI:10.1021/ja034787f

Published on Web 03/27/2003
anti-Selective Direct Catalytic Asymmetric Mannich-type Reaction of
Hydroxyketone Providing â-Amino Alcohols
Shigeki Matsunaga, Naoya Kumagai, Shinji Harada, and Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received February 21, 2003; E-mail: mshibasa@mol.f.u-tokyo.ac.jp
Chiral â-amino alcohol units are useful as chiral building blocks
for various biologically active compounds. Among the methods
available for their catalytic enantioselective syntheses,1 catalytic
asymmetric Mannich-type reactions2 of R-alkoxy enolate are of
particular interest, because two adjacent stereocenters are con-
Figure 1. Structures of (S,S)-linked-BINOL 1, 2-hydroxy-2′-methoxy-
acetophenone (2), and N-diphenylphosphinoyl(Dpp) imine 3.
structed simultaneously with a concomitant carbon-carbon bond
formation. Toward this end, Kobayashi reported pioneering work
on the Zr catalysis using preformed R-TBSO- and R-BnO-ketene
Table 1. Direct Catalytic Asymmetric Mannich-type Reaction of 3a
silyl acetals, which selectively provided either syn- or anti-â-amino
alcohol, respectively.3 Recently, more atom-economical processes,4
that is, the direct addition of unmodified R-hydroxyketone to imines,
were reported by List,5 Barbas,6 and Trost.7,8 Excellent selectivity
was achieved; however, only syn-amino alcohols were produced
in those systems.5-7 In addition, the requirement of harsh oxidizing
conditions for the cleavage of the N-protective groups would impose
some limitations on their synthetic utility. Thus, the development
of the complementary anti-selective direct catalytic asymmetric
Mannich-type reaction of unmodified R-hydroxyketone using an
easily removable N-protective group is in high demand. We report
a novel anti-selective direct catalytic asymmetric Mannich-type
reaction of 2-hydroxy-2′-methoxyacetophenone (2) and N-diphen-
ylphosphinoyl(Dpp) imines 3 using a Et2Zn/linked-BINOL 1
complex (Figure 1).9,10
with a Et2Zn/(S,S)-linked-BINOL 1 ) 4/1 Complex
ligand 1 ketone 2
temp time yielda
drb
(anti/syn)
ee (%)
(anti)
entry (× mol%)
(equiv)
additive
(°C)
(h)
(%)
1
2
3
4
5
6
5
3
1
1
1
1
2
2
2
1.1
1.1
2
MS 3A -20
MS 3A -20
MS 3A -20
2
3
9
97
95
98
87
97
93
94/6
94/6
96/4
96/4
88/12
96/4
98
98
98
98
95
98
MS 3A -20 24
MS 3A
none
0
8
-20 18
1
a Isolated yield. b Determined by the H NMR of the crude mixture.
As a part of our continuing project on asymmetric zinc catalysis,
we reported direct catalytic asymmetric syn-selective aldol10a,d,e and
Michael reactions10b,c of hydroxyketone 2 using the Et2Zn/linked-
BINOL 1 ) 4/1 complex and 3 Å molecular sieves (MS 3A). Thus,
we initiated screening using the Et2Zn/1 complex, 2, and imines
with various N-protective groups and determined that N-Dpp imine
3a was promising. As shown in Table 1, the addition of 2 to 3a
proceeded smoothly in the presence of 1 (5 mol %), Et2Zn (20
mol %), and MS 3A to afford 4a with high selectivity11 (anti/syn
) 94/6, 98% ee) in 97% yield (entry 1). The preferential formation
of the anti-isomer is particularly noteworthy, because the di-
astereoselectivity is complementary to that observed by others.5-7
The reaction reached completion even with reduced catalyst loading
to afford 4a 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 2, although there was a slight loss of
reactivity at -20 °C (entry 4). At 0 °C, the reaction was completed
using 1.1 equiv of 2 to afford 4a in 97% yield; the stereoselectivity,
however, decreased somewhat (entry 5). The presence of activated
MS 3A enhanced the reaction rate without affecting stereoselectivity
(entry 3 vs entry 6).
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, di-
astereoselectivity was improved at a lower reaction temperature
(entry 12, dr: 81/19 at -30 °C). Imine 3l also provided Mannich
adduct in high ee (99%) with modest anti-selectivity (entry 13).
To demonstrate the practical utility, the reaction was performed
on a gram scale with as little as 0.25 mol % of 1 (6.2 mg) to afford
4b in excellent yield (99%, 1.92 g), dr (>98/2), and ee (99%) after
6 h (entry 14). Commercial availability of both Et2Zn solution and
linked-BINOL 1 also makes the present system advantageous from
a practical viewpoint.9
The opposite diastereoselectivity between the present Mannich-
type reaction (anti-selective) and the previously reported aldol
reaction (syn-selective)10a using the same Et2Zn/1 complex is
interesting. Because the absolute configurations at the R-position
of both the aldol- and the Mannich-products are identical (2R),12
the facial selection of the Zn-enolate generated from 2 should be
same (Si-face shielding), and the electrophiles should approach in
a different manner in these two reactions. We speculate that the
anti-selectivity in the present Mannich-type reaction would be due
to the bulky Dpp group on the imine nitrogen. To avoid steric
repulsion, the Mannich-type reaction would proceed via the
transition state as shown in Figure 2, preferentially affording anti-
4.12
As summarized in Table 2, the present asymmetric zinc catalysis
was applicable to various imines 3. All reactions were performed
with 1 mol % of 1, 4 mol % of Et2Zn, and MS 3A. 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 98/2, entries 1-10). Ortho-substituents
Facile deprotection of the N-Dpp group and transformation of
the ketone to an ester produce a protected R-hydroxy-â-amino acid
9
4712
J. AM. CHEM. SOC. 2003, 125, 4712-4713
10.1021/ja034787f CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Direct Mannich-type Reaction with Various N-Dpp Imines
In summary, we developed a highly enantio- and diastereo-
selective direct catalytic asymmetric Mannich-type reaction to
provide anti-amino alcohols (yield up to 99%, dr up to >98/2, ee
up to >99.5%). The process worked well with from as little as
0.25 to 1 mol % of catalyst loading. The observed complementary
anti-selectivity, in combination with the facile removal of the Dpp
group, makes the present reaction synthetically useful. Detailed
mechanistic studies of the present reaction, especially to clarify
the origin of the anti-selectivity, are ongoing.
3a
ligand 1
(× mol %) product (°C) (h)
temp time yieldb
drc
ee (%)
entry
R
(%) (anti/syn) (anti)
1
2
3
4
5
6
7
8
9
4-MeC6H4 3a
2-MeC6H4 3b
1
1
1
1
1
1
1
1
1
1
1
1
1
4a -20
4b -20
4c -20
4d -20
4e -20
9
6
6
6
9
4
4
6
7
7
4
7
5
6
98
96/4
98
99
99
99
98
98
98
Acknowledgment. We are thankful for financial support by
RFTF and Grant-in-Aid for Encouragements for Young Scientists
(B) (for S.M.) from JSPS. N.K. thanks JSPS Research Fellowships
for Young Scientists. We thank Prof. S. Kobayashi at the University
of Tokyo for support in the X-ray analysis of 4b.
99 >98/2
C6H5
3c
98
97
96
97
97
97
95
98
98
97
98
96/4
95/5
97/3
97/3
95/5
4-MeOC6H4 3d
4-NO2C6H4 3e
4-ClC6H4
4-BrC6H4
3f
3g
4f
-20
4g -20
4h -20
Supporting Information Available: Experimental procedures,
characterization of the products, determination of absolute and relative
configurations of the products, and X-ray data of 4b (CIF and PDF).
This material is available free of charge via the Internet at http://
pubs.acs.org.
1-naphthyl 3h
2-naphthyl 3i
98/2 >99.5
94/6 99
4i
4j
-20
-20
10 2-furyl
11 (E)-cinnam 3k
12 3k
13 cyclo-propyl 3l
3j
96/4 >99.5
76/24 >99.5
81/19 >99.5
4k -20
4k -30
4l
-30
80/20
99
99
14d 2-MeC6H4 3b 0.25
4b -20
99 >98/2
References
(1) For reviews on asymmetric synthesis of vicinalamino alcohols, see: (a)
Bergmeire, S. C. Tetrahedron 2000, 56, 2561. (b) Kolb, H. C.; Sharpless,
K. B. In Transition Metals for Organic Synthesis; Beller, M., Bolm, C.,
Eds.; Wiley-VCH: Weinheim, 1998; p 243.
a 2 equiv of 2 was used. For less soluble imines, THF/CH2Cl2 mixed
solvent was used. See Supporting Information. b Isolated yield. c Determined
1
by the H NMR of the crude mixture. d 1.28 g of 3b was used.
(2) For reviews on catalytic asymmetric Mannich-type Reaction, see: (a)
Denmark, S. E.; Nicaise, O. J.-C. In ComprehensiVe Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999;
p 954. (b) Kobayashi, S.; Ishitani, H. Chem. ReV. 1999, 99, 1069. (c)
Taggi, A. E.; Hafez, A. M.; Lectka, T. Acc. Chem. Res. 2003, 36, 10.
(3) Kobayashi, S.; Ishitani, H.; Ueno, M. J. Am. Chem. Soc. 1998, 120, 431.
(4) Trost, B. M. Science 1991, 254, 1471.
(5) (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.
(6) Co´rdova, A.; Notz, W.; Zhong, G.; Betancort, J. M.; Barbas, C. F., III. J.
Am. Chem. Soc. 2002, 124, 1842.
(7) Trost, B. M.; Terrell, L. R. J. Am. Chem. Soc. 2003, 125, 338.
(8) For other examples of direct catalytic asymmetric Mannich reaction using
unmodified ketone and/or aldehyde as donors, see: (a) Yamasaki, S.; Iida,
T.; Shibasaki, M. Tetrahedron Lett. 1999, 40, 307. (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.
(9) 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. Linked-BINOL is also
commercially available from Wako Pure Chemical Industries, Ltd. Catalog
No. for (S,S)-1: No. 152-02431.
Figure 2. Working transition state model to afford anti-4 and X-ray
structure of anti-4b.
Scheme 1. Transformation of Mannich Adducta
(10) (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) Harada, S.; Kumagai, N.; Kinoshita, T.; Matsunaga, S.;
Shibasaki, M. J. Am. Chem. Soc. 2003, 125, 2582. (c) Kumagai, N.;
Matsunaga, S.; Shibasaki, M. Org. Lett. 2001, 3, 4251. (d) Kumagai, N.;
Matsunaga, S.; Yoshikawa, N.; Ohshima, T.; Shibasaki, M. Org. Lett.
2001, 3, 1539. (e) Yoshikawa, N.; Kumagai, N.; Matsunaga, S.; Moll,
G.; Ohshima, T.; Suzuki, T.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123,
2466.
a (i) Concentrated HCl(aq)/THF, room temperature, 1 h; (ii) triphosgene,
pyridine, CH2Cl2, -78 °C, 0.5 h, yield 84% (two steps); (iii) mCPBA,
Cl(CH2)2Cl, 60 °C, 3 h, yield 88%.
(11) Determined by NOE enhancement of cyclic carbamate synthesized from
4a.
in high yield. As shown in Scheme 1, 4b was readily converted to
cyclic carbamate 5b in 84% yield (two steps) after removal of the
N-Dpp group under acidic conditions,13 followed by treatment with
triphosgene. Baeyer-Villiger oxidation of 5b proceeded with
mCPBA to afford ester 6b in 88% yield without any epimerization,
as confirmed by NOE.
(12) The absolute configuration of 4b was determined by Mosher’s method.
Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512. The relative
configuration of 4b was determined by X-ray analysis (see Figure 2).
(13) Ramage, R.; Hopton, D.; Parrott, M. J. J. Chem. Soc., Perkin Trans. 1
1984, 1357.
JA034787F
9
J. AM. CHEM. SOC. VOL. 125, NO. 16, 2003 4713