Heterobimetallic Catalysis in Asymmetric 1,4-Addition of O-Alkylhydroxylamine to Enones

Article abstract of DOI:10.1021/ja038688d

A heterobimetallic YLi₃tris(binaphthoxide) catalyst (YLB) promoted a 1,4-addition of O-methylhydroxylamine in high enantiomeric excess (up to 97% ee). Catalyst loading was reduced to as little as 0.5 mol %, still affording the 1,4-adduct in 96%

Full text of DOI:10.1021/ja038688d

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Heterobimetallic Catalysis in Asymmetric 1,4-Addition of
O-Alkylhydroxylamine to Enones
Noriyuki Yamagiwa, Shigeki Matsunaga, and Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received September 23, 2003; E-mail: mshibasa@mol.f.u-tokyo.ac.jp
Catalytic asymmetric 1,4-additions are one of the most important
fields of study in asymmetric catalysis,1 and various methods have
been reported during the past decade. 1,4-Addition of amines to
R,â-unsaturated carbonyl compounds provides a direct and attractive
strategy for the construction of optically active â-amino carbonyl
units,2 which are often found in biologically interesting compounds.
Among them, a few highly enantioselective Lewis acid catalyses
for 1,4-additions of O-alkylhydroxylamines were recently reported,3
providing versatile chiral building blocks. Although high enanti-
oselectivity was achieved, catalyst loading remained a problem.
For good yield and ee in the precedents, 10-30 mol % of catalysts
were necessary,3,4 probably because amines or products deactivated
the chiral Lewis acids. Thus, a practical, more amine-tolerant,
asymmetric catalysis for this useful reaction is desirable. Herein,
we demonstrate the utility of heterobimetallic multifunctional
catalysis5 in asymmetric 1,4-addition of O-alkylhydroxylamine.
High ee and yield were achieved using as little as 0.5-3 mol % of
a YLi3tris(binaphthoxide) (Figure 1, YLB 1a, 1.5-9 mol % based
on a chiral ligand).
Figure 1. Structure of YM3tris(binaphthoxide) (YLB, 1a and YPB, 1b).
Table 1. Optimization of the 1,4-Addition of O-Alkylhydroxylamine
with YLB 1a
catalyst
(×mol %)
time
(h)
yield
(%)
ee
(%)
entry
additive
amine: R
1
2
3
4
5
6
7
8
9
none
3a (Me-)
10
10
10
10
10
10
5
3
1
0.5
1
24
24
24
24
24
26
42
42
48
80
48
94
85
67
44
94
91
94
97
95
96
98
97
96
96
97
97
91
96
95
96
96
95
Initially, we screened various heterobimetallic complexes con-
taining rare earth metals and alkaline metals for the addition of 3a
to 2a, and YLB 1a gave the best reactivity and enantioselectivity.
As shown in Table 1, the reaction proceeded smoothly with 10
mol % of 1a at -20 °C to give 4a in 94% yield and 97% ee (entry
1). In contrast to the previous results using the YLB-H2O complex,6
the addition of H2O somewhat retarded the reaction. We speculated
that even a small amount of H2O derived from a possible side
reaction (oxime formation) would be problematic for reducing the
catalyst loading. Thus, various desiccants were screened to attain
good reproducibility (entries 2-5), and Drierite (CaSO4) gave the
best results (entry 5). BnONH2 also gave good results (entry 6).
With the optimal conditions (YLB, 3a: 1.2 equiv, Drierite), catalyst
loading was reduced. As summarized in entries 7-11, the reaction
proceeded without any problem with as little as 0.5-1 mol % of
1a, giving 4a in good yield and ee (entry 9, y. 95% and 96% ee;
entry 10, y. 96% and 96% ee). The low catalyst loading is
noteworthy. Other advantages of the present method are as
follows: (i) Commercially available, cheap O-methylhydroxylamine
gave high ee.7 (ii) Volumetric productivity of the present reaction
is high (2.1 M in entry 10, 2.5 M in entry 9). The result suggested
that inhibition of the Lewis acidic catalyst 1a by an amine or product
was negligible in the present system even under highly concentrated
conditions. Scalability of the reaction was also demonstrated in entry
11. The reaction proceeded without any problems on a 10 g scale
(2.1 M).
MS 3A
MS 4A
MS 5A
Drierite
Drierite
Drierite
Drierite
Drierite
Drierite
Drierite
3a
3a
3a
3a
3b (Bn-)
3a
3a
3a
3a
3a
10
11a
a 48 mmol scale (10 g of 2a was used).
substituents (entries 1-19) afforded 1,4-adducts in 81-96% ee and
85-98% yield. For the less reactive substrate, 2-3 equiv of 3a
was used. â-Heteroaromatic (entries 20-22) and â-aliphatic (entries
23-27) enones, and dienone (entry 28) also gave products in good
ee. At present, R1 of 2 is limited to an aromatic ring. To exemplify
the utility of the 1,4-adducts, 4a and 4s were converted into acyl
aziridines 5, 6,3c,d syn-1,3-amino alcohol 7, and anti-1,3-amino
alcohol 8, as summarized in Scheme 1.
Several preliminary experiments were performed to gain mecha-
nistic insight into the present catalysis. As summarized in Tables
2 and 3, neither the Li-BINOL nor the Y-BINOL complex
afforded products. YPB 1b (Figure 1) was also not effective. Only
YLB 1a promoted the reaction smoothly in high enantioselectivity.
Thus, the cooperative function of Y and Li metals (heterobimetallic
catalysis) was important to achieve high catalyst turnover in the
reaction. Initial rate kinetics suggested that only one catalyst is
involved in the reaction sequence.8 On the basis of previous
mechanistic studies on heterobimetallic catalysis,5b Y metal might
function as the Lewis acid that activates the enone. Considering
the pKa value of the amine proton, however, it is unlikely that Li-
binaphthoxide functions as a Brønsted base and activates the amine
We then examined the substrate scope of the reaction (Table 2).
For convenience, most reactions were performed with 3 mol % of
1a. For selected substrates including 2k with an electron-donating
substituent on the aromatic ring, reactions were also performed with
1 mol % of 1a, and similar results were obtained (entries 1, 3, 5,
12, 15 vs 2, 4, 6, 13, 16). â-Aryl substituted enones with various
9
16178
J. AM. CHEM. SOC. 2003, 125, 16178-16179
10.1021/ja038688d CCC: $25.00 © 2003 American Chemical Society

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C O M M U N I C A T I O N S
Table 2. Catalytic Asymmetric 1,4-Addition of
O-Methylhydroxylamine (3a) Promoted by YLB 1a
enone
YLB time yield ee
Figure 2. Postulated model for 1,4-addition of 3a catalyzed by YLB 1a.
1
2
entry
R
R
product (mol %) (h)
(%) (%)
1
2
3
4
5
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
2a
2a
2b
2b
2c
2c
2d
2e
2f
2g
2h
2i
2i
2j
4a
4a
4b
4b
4c
4c
4d
4e
4f
4g
4h
4i
4i
4j
4k
4k
4l
4m
4n
4o
4p
4q
4r
4s
3
1
3
1
3
1
3
3
3
3
3
3
1
3
3
1
3
3
3
3
3
3
3
3
3
3
3
3
42 97 95
48 95 96
42 96 96
46 92 96
54 97 96
65 91 96
48 96 94
74 91 96
48 96 92
48 95 94
78 96 93
48 92 92
78 97 93
48 96 96
82 85 95
74 85 95
42 98 81
48 95 92
122 92 82
84 80 92
48 96 95
60 91 85
84 96 84
48 95 93
78 97 86
48 98 82
96 57 82
84 91 95
2). The interaction between the oxygen atom of 3 and K in YPB
1b should be weaker than that with Li. Further mechanistic
investigations are necessary to clarify the role of Li in YLB.
In summary, we demonstrated the utility of heterobimetallic
catalysis in an enantioselective 1,4-addition of commercially
available O-methylhydroxylamine to enones. High catalyst turnover
(0.5-3 mol % of YLB 1a, 1.5-9 mol % based on a chiral ligand),
good yield (80-98%), and ee (81-96%) were achieved under
concentrated conditions (1.1-2.5 M), although the substrate scope
was somewhat limited. These results implied that neither amine
nor product inhibited the heterobimetallic catalysis, unlike standard
Lewis acid catalysis. Further investigation to broaden substrate
generality as well as mechanistic studies to clarify the origin of
high catalyst turnover are in progress.
4-Cl-C6H4
4-Cl-C6H4
4-F-C6H4
6a 4-F-C6H4
7
4-Me-C6H4 Ph
8a 4-MeO-C6H4 Ph
3-Me-C6H4 Ph
9
10a 2-furyl
11a 2-thienyl
12 Ph
13 Ph
14 Ph
15a Ph
16a Ph
17 Ph
18 Ph
19a Ph
20a Ph
21 Ph
22a Ph
23a Ph
24a Ph
25 Ph
26 Ph
27a Ph
28b Ph
Ph
Ph
4-Cl-C6H4
4-Cl-C6H4
4-Me-C6H4
4-MeO-C6H4
4-MeO-C6H4
3-NO2-C6H4
3-Cl-C6H4
2-Cl-C6H4
2-furyl
2-thienyl
4-pyridyl
n-C5H11
i-PrCH2
i-Pr
2k
2k
2l
2m
2n
2o
2p
2q
2r
2s
2t
Acknowledgment. We thank the RFTF and a Grant-in-Aid for
Encouragement for Young Scientists (B) for financial support.
Supporting Information Available: Experimental procedures,
characterization data for new compounds (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
4t
cyclo-hexyl
t-Bu
trans-PhCHdH 2w
2u
2v
4u
4v
4w
References
(1) Reviews for enantioselective conjugate addition: (a) Krause, N.; Hoff-
mann-Ro¨der, A. Synthesis 2001, 171. (b) Sibi, M. P.; Manyem, S.
Tetrahedron 2000, 56, 8033.
a 2 equiv of 3a was used. b 3 equiv of 3a was used.
Scheme 1. Transformations of 4
(2) For recent highly enantioselective examples (>90% ee) with nitrogen
nucleophiles; N3 ion: (a) Myers, J. K.; Jacobsen, E. N. J. Am. Chem.
Soc. 1999, 121, 8959. (b) Guerin, D. J.; Miller, S. J. J. Am. Chem. Soc.
2002, 124, 2134. Aromatic amine: (c) Zhuang, W.; Hazell, R. G.;
Jørgensen, K. A. Chem. Commun. 2001, 1240. Lithium amide: (d) Doi,
H.; Sakai, T.; Iguchi, M.; Yamada, K.; Tomioka, K. J. Am. Chem. Soc.
2003, 125, 2886 and references therein. For other methods for the
preparation of â-amino carbonyl segments, see reviews: (e) Liu, M.; Sibi,
M. P. Tetrahedron 2002, 58, 7991. (f) Taggi, A. E.; Hafez, A. M.; Lectka,
T. Acc. Chem. Res. 2003, 36, 10. (g) Kobayashi, S.; Ishitani, H. Chem.
ReV. 1999, 99, 1069.
(3) (a) Sibi, M. P.; Shay, J. J.; Liu, M.; Jasperse, C. P. J. Am. Chem. Soc.
1998, 120, 6615. (b) Jørgensen, K. A.; Falborg, L. J. Chem. Soc., Perkin
Trans. 1 1996, 2823. (c) Sugihara, H.; Daikai, K.; Jin, X. L.; Furuno, H.;
Inanaga, J. Tetrahedron Lett. 2002, 43, 2735. (d) Jin, X. L.; Sugihara,
H.; Daikai, K.; Takeishi, H.; Jin, Y. Z.; Furuno, H.; Inanaga, J. Tetrahedron
2002, 58, 8321. (e) Cardillo, G.; Gentilucci, L.; Gianotti, M.; Kim, H.;
Perciaccante, R.; Tolomelli, A. Tetrahedron: Asymmetry 2001, 12, 2395.
(4) During preparation of this manuscript, Sibi reported excellent results with
N-benzylhydroxylamine as nucleophile using 5 mol % catalyst. (a) Sibi,
M. P.; Prabagaran, N.; Ghorpade, S. G.; Jasperse, C. P. J. Am. Chem.
Soc. 2003, 125, 11796 and references therein. With N-benzylhydroxy-
lamine as a nucleophile, conversion of the 1,4-adduct into aziridine was
not reported. For difference in properties of O-alkylhydroxylamine and
N-alkylhydroxylamine, see: (b) Niu, D.; Zhao, K. J. Am. Chem. Soc. 1999,
121, 2456. (c) Sibi, M. P.; Liu, M. Org. Lett. 2000, 2, 3393.
(5) Review: (a) Shibasaki, M.; Yoshikawa, N. Chem. ReV. 2002, 102, 2187.
(b) Shibasaki, M.; Sasai, H.; Arai, T. Angew. Chem., Int. Ed. Engl. 1997,
36, 1236. For the preparation and structure of YLB 1a, see: (c) Aspinall,
H. C.; Dwyer, J. L.; Greeves, N.; Steiner, A. Organometallics 1999, 18,
1366.
Table 3. Catalytic Asymmetric 1,4-Addition of
O-Methylhydroxylamine (3a) Using Various Metal Complexes
entry
catalyst (×mol %)
time (h)
yield (%)
ee (%)
config
1
2
3
4
5
none
42
42
42
42
42
trace
11
29
19
97
BuLi/BINOL (9/9)
Y(HMDS)3/BINOL (3/9)
YPB 1b (3)
12
16
12
95
R
R
R
S
YLB 1a (3)
(6) (a) Tian, J.; Yamagiwa, N.; Matsunaga, S.; Shibasaki, M. Angew. Chem.,
Int. Ed. 2002, 41, 3636. (b) Tian, J.; Yamagiwa, N.; Matsunaga, S.;
Shibasaki, M. Org. Lett. 2003, 5, 3021.
moiety. Thus, the role of heterobimetallic catalysis appears to be
different from that in our previous reports.5 On the basis of the
different results obtained with Li (YLB) and K (YPB), the oxygen
atom of 3 might coordinate to Li. 3 would then be positioned close
to enone 4, and the addition reaction would be accelerated (Figure
(7) Inanaga achieved excellent ee (94-99% ee, ref 3d) using O-diphenylm-
ethylhydroxylamine, which is not commercially available.
(8) See the Supporting Information for the detailed results.
JA038688D
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J. AM. CHEM. SOC. VOL. 125, NO. 52, 2003 16179