Asymmetric catalysis on the intramolecular cyclopropanation of α-Diazo-β-keto sulfones

Article abstract of DOI:10.1021/ja029534l

This work describes the development of a highly enantioselective asymmetric catalysis on the intramolecular cyclopropanation of α-diazo-β-keto sulfones. We have found that the catalytic asymmetric intramolecular reactions of α-diazo-β-keto sulfones generally proceed with high enantioselectivity when the α-diazo-β-keto mesityl sulfone is used with the newly prepared ligand 2e. The absolute configuration of products has been determined by X-ray crystallographic analysis, and the outcome of the enantioselectivities is explained well by our proposed models A and B. The products possess great potential for natural product synthesis because (1) many different chemistries of cyclopropane, ketone, and sulfone are available, and (2) the products are generally highly crystalline, facilitating the supplies of enantiomerically pure synthetic intermediates. Copyright

Full text of DOI:10.1021/ja029534l

Published on Web 02/19/2003
Asymmetric Catalysis on the Intramolecular Cyclopropanation of
r-Diazo-â-keto Sulfones
Masahiro Honma, Takashi Sawada, Yuri Fujisawa, Masayuki Utsugi, Hideaki Watanabe,
Akinori Umino, Takehiko Matsumura, Takayuki Hagihara, Masashi Takano, and Masahisa Nakada*
Department of Chemistry, School of Science and Engineering, Waseda UniVersity,
3-4-1 Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan
Received December 1, 2002 ; E-mail: mnakada@waseda.jp
Since the pioneering work of Nozaki et al.,1 asymmetric catalysis
Table 1. Intramolecular Cyclopropanations of Sulfones 3a and 3b
on cyclopropanations has been studied,2 and some excellent
enantioselectivities have been reported for the catalytic asymmetric
intramolecular cyclopropanation of R-diazo ketones, R-diazo ace-
tates, and R-diazo acetamidates.2,3
However, only modest enantioselectivities have been found for
entry
product
ligand
ee (%)a,b
yield (%)c
temp (°C)
time (h)
R-diazo-â-keto esters, even with all of their versatile utilities.2,4
For example, the derivative of 2-oxobicyclo[3.1.0]hexane 1a was
obtained from the corresponding R-diazo-â-keto ester with 56%
ee, and the more-bulky ester 1b was obtained with 48% ee.5 We
surmised that such low selectivity might be attributed to the small
steric difference between the keto group and the ester group in the
substrates.
1
2
3
4
5
4a
4a
4a
4a
4a
2a
2b
2c
2d
2e
65 (1R)
75 (1R)
32 (1R)
72 (1R)
73 (1R)
91
67
61
67
61
rt
rt
50
rt
rt
2
2
5.5
5.5
2
6
7
8
9
10
4b
4b
4b
4b
4b
2a
2b
2c
2d
2e
83 (1R)
72 (1R)
31 (1R)
90 (1R)
93 (1R)
93
78
48
89
87
50
1.5
rt, 50d
50, 70d
rt, 50d
rt, 50d
2, 2d
2, 3d
2, 2d
2, 2.5d
a ee determined by HPLC. For HPLC conditions, see Supporting
Information. b Absolute configuration determined by X-ray crystallographic
analysis or the comparison of optical rotation. c Isolated yields. d Reaction
was carried out at the indicated temperatures for the indicated times,
respectively.
Hence, we started to investigate asymmetric catalysis on the
intramolecular cyclopropanation of R-diazo-â-keto sulfones because
(1) the sulfonyl group is apparently sterically different from the
keto group, implying that good enantioselectivity would emerge,
(2) the sulfonyl group would be a better surrogate for the ester
group because of its utility, and (3) R-diazo-â-keto sulfones are
easily prepared and stable, fulfilling the requirements for the
synthesis of natural products.
were gratified by these promising results (Table 1), and therefore
we began to investigate the reactions of other mesityl sulfones.
As summarized in Table 2, high enantioselectivities were
obtained for all substrates.8 It should be noted that 2e was a most
effective ligand on all substrates, and the reversal of enantioselection
was found in the reactions of 3e (entry 9-12).
Surprisingly, only one example has been reported for asymmetric
catalysis on the intramolecular cyclopropanation of R-diazo-â-keto
sulfones.6 Therefore, first we carried out the reaction of substrate
3a using the easily accessible ligand 2a.7a The intramolecular
cyclopropanation of 3a with the in situ prepared asymmetric catalyst
of (CuOTf)2C6H6 and ligand 2a afforded 4a (65% ee, 91% yield;
entry 1). We then examined the reactions of 3a with other ligands
2b,7b 2c,7a 2d,7c and a new ligand 2e. As shown in Table 1, the
enantioselectivity increased to 75% ee (entry 2) in the reaction of
3a with ligand 2b, and ligands 2d and 2e showed comparable results
of 72 and 73% ee, respectively.8 Interestingly, the reaction with
ligand 2c was slow and resulted in the worst selectivity.
Because 4a was obtained with better enantioselectivity as com-
pared to 1a, we were confident that the utility of sulfones is rational
as discussed above. Hence, we next examined the reaction of a
more bulky sulfone, mesityl sulfone 3b. The reaction of 3b with
2a did not proceed at ambient temperature, but proceeded smoothly
at 50 °C to afford 4b at 83% ee. Although a somewhat reduced
enantioselectivity (72% ee) was observed in the reaction with ligand
2b (Table 1), the enantioselectivities were increased markedly to
90% ee with 2d, and to 93% ee with 2e; thus, the combination of
the mesityl sulfone and the ligands was found to be crucial. We
We have also applied this protocol to substrates that will afford
tricyclic compounds. That is, the 2, 5-cyclohexadiene derivatives
5a, 5b, 7a, and 7b were prepared and subjected to this catalytic
asymmetric reaction.
The results in Table 3 clearly show that the tricyclic products
6b, 8a, and 8b were constructed with high enantioselectivities (entry
4-7). Reactions of 5a and 5b, forming tricyclo[4.3.0.0]nonene
derivatives (entry 1-4), showed the same trend in enantioselection
as summarized in Tables 1 and 2. That is, the highest ee was again
recorded by the combination of mesityl sulfone 5b with ligand 2e
(entry 4). To form tricyclo[4.4.0.0]decene derivatives with high
enantioselectivity, however, use of the less bulky phenyl sulfone
7a and ligand 2a was sufficient (entries 5, 7), and ligand 2e resulted
in a low yield (entries 6, 8). These results suggest that the
combination of the sulfone and the ligand is important, and therefore
this combination should be examined in each case to achieve high
enantioselectivity. Interestingly, the reversal of enantioselection was
again observed in the reactions of 6a and 6b (entries 1-4).
As all of the products in this study were crystalline, the absolute
structures have been determined successfully by X-ray crystal-
lographic analysis. Although further investigations are required to
deduce the mechanistic details, the outcome of the enantioselective
9
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J. AM. CHEM. SOC. 2003, 125, 2860-2861
10.1021/ja029534l CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Intramolecular Cyclopropanation of Mesityl Sulfones
3c-f
isopropyl group and also with the benzyl group of the ligand, with
steric repulsion. As a result, the si-face will be sterically hindered
during the cyclopropanation reactions. By contrast, the reaction at
the re-face would be preferred because the unfavorable interactions
with the aryl sulfonyl group would be negligible in the transition
states arising from models A and B. Thus, the aryl sulfonyl group
has a crucial role in the enantioselection. The high enantioselec-
tivities obtained for the mesityl sulfones are also well explained
by the increased unfavorable interactions with the mesityl group.
The reversal of enantioselection for 3e, 5a, and 5b would be
rationalized by model B because the steric strain with the substrates
would disfavor model A. The depicted orientation of the alkene
with respect to the re-face of the complex well explains the (1R,
5R) configuration for 4e, and the (1S, 5R, 6R, 7S) configuration
for 6a and 6b.
For 7a and 7b, model A would operate. As the steric strain with
the substrate is so large in this case, the use of a less bulky phenyl
sulfone might be sufficient for high enantioselectivity.
In summary, highly enantioselective asymmetric catalysis on the
intramolecular cyclopropanation of R-diazo-â-keto sulfones has
been developed. The products possess great potential for natural
product synthesis because (1) a variety of chemistries of cyclo-
propane, ketone, and sulfone are available, and (2) the products
are highly crystalline, facilitating the production of enantiomerically
pure synthetic intermediates.
entry product
ligand
ee (%)a,b
yield (%)c
temp (°C)
time (h)
1
2
3
4
4c
4c
4c
4c
2a
2b
2d
2e
81 (1R)
69 (1R)
87 (1R)
98 (1R)
96
98
94
90
50
1
rt, 50d
rt, 50d
50
2, 2.5d
2, 1.5d
2
5
6
7
8
4d
4d
4d
4d
2a
2b
2d
2e
92 (1S)
56 (1S)
95 (1S)
98 (1S)
68
44
43
63
50
50
50
50
1
1.5
1.5
2.5
9
10
11
12
4e
4e
4e
4e
2a
2b
2d
2e
74 (1R)e,f
71 (1R)e,f
76 (1R)e,f
92 (1R)e,f
74
77
54
84
50
50
50
rt
1.5
0.5
2
5
13
14
15
16
4f
4f
4f
4f
2a
2b
2d
2e
78 (1R)
73 (1R)
84 (1R)
91 (1R)
91
96
75
98
rt, 50, 70d 1.5, 12, 10d
50, 70d
10, 20d
rt, 50, 70d 3.5, 13, 5d
rt, 50, 70d 3.5, 13, 7d
a-d See the footnotes to Table 1. e The absolute structure is the opposite
of the depicted structure above. f CuOTf (20 mol %) and ligand (30 mol
%) were used because the reaction was sluggish.
Acknowledgment. We thank Messrs Kenji Namoto and Koichi
Yonezawa for early experiments, and Dr. M. Shiro of Rigaku for
assistance with X-ray crystallography. This work was financially
supported in part by 21COE “Practical Nano-Chemistry”.
Table 3. Enantioselective Formation of the Tricyclic Compounds
Supporting Information Available: Experimental details and
characterization data for all new compounds (PDF). An X-ray crystal-
lographic file is available in CIF format. This material is available free
of charge via the Internet at http://pubs.acs.org.
References
entry
product
ligand
ee (%)a,b
yield (%)c
temp (°C)
time (h)
(1) Nozaki, H.; Takaya, H.; Moriuti, S.; Noyori, R. Tetrahedron 1968, 24,
3655-3658.
1
2
3
4
6a
6a
6b
6b
2a
2e
2a
2e
33 (7S)e
66 (7S)e
79 (7S)e
93 (7S)e
quant.
81
76
rt
rt
0.5
5
(2) Reviews: (a) Davies, H. M. L. In ComprehensiVe Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 4, Chapter 4.8,
pp 1031-1067. (b) Doyle, M. P.; Protopopova, M. N. Tetrahedron 1998,
54, 7919-7946 and references therein. (c) Doyle, M. P. In Catalytic
Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; YHC Publishers: New
York, 2000; Chapter 5, pp 191-228 and references therein.
(3) Recent studies for R-diazo ketones: (a) Barberis, M.; Pe´rez-Prieto, J.;
Herbst, K.; Lahuerta, P. Organometallics 2002, 21, 1667-1673. (b)
Barberis, M.; Perez-Prieto, J.; Stiriba, S.-E.; Lahuerta, P. Org. Lett. 2001,
3, 3317-3319. (c) Park, S. W.; Son, J. H.; Kim, S. G.; Ahn, K. H.
Tetrahedron: Asymmetry 1999, 10, 1903-1911. (d) Kim, S. G.; Cho, C.
W.; Ahn, K. H. Tetrahedron 1999, 55, 10079-10086.
rt, 50d
rt, 50d
2, 20d
1, 27d
61
5
6
7
8
8a
8a
8b
8b
2a
2e
2a
2e
92 (7R)
90 (7R)
97 (7R)
87 (7R)
78
37
69
7
rt
3.5
rt, 50d
rt
1, 2d
27
rt, 50d
1, 29d
a-e See the footnotes to Table 1.
(4) (a) Dauben, W. G.; Hendricks, R. T.; Luzzio, M.; Ng, H. P. Tetrahedron
Lett. 1990, 48, 6969-6972. (b) Pique´, C.; Fa¨hndrich, B.; Pfaltz, A. Synlett
1995, 491-492. (c) Mu¨hler, P.; Bole´a, C. Synlett 2000, 6, 826-828. (d)
Mu¨hler, P.; Bole´a, C. HelV. Chim. Acta 2001, 84, 1093-1111.
(5) The same reaction condition of entry 1 in Table 1 was used. See Supporting
Information for the details.
(6) The highest ee observed for 4a was ca. 12% ee: Kennedy, M.; McKervey,
M. A.; Maguire, A. R.; Roos, G. H. P. J. Chem. Soc., Chem. Commun.
1990, 361-362.
(7) (a) Evans, D. A.; Woerpel, K. A.; Hinman, M. M.; Faul, M. M. J. Am.
Chem. Soc. 1991, 113, 726-728. (b) Denmark, S. E.; Nakajima, N.;
Nicaise, O. J.-C.; Faucher, A.-M.; Edwards, J. P. J. Org. Chem. 1995,
60, 4884-4892. (c) von Matt, P.; Lloyd-Jones, G. C.; Minidis, A. B. E.;
Pfaltz, A.; Macko, L.; Neuburger, M.; Zehnder, M.; Rueegger, H.;
Pregosin, P. S. HelV. Chim. Acta 1995, 78, 265-284.
Figure 1. Proposed models A and B.
reactions would be well explained by the proposed models A and
B (Figure 1).9
(8) Solvents other than toluene afforded diminished enantioselectivities.
(9) Models A and B are depicted on the basis of Pfaltz’s model10 and the
recent theoretical analysis.11
The cyclopropanation reactions are thought to occur preferentially
at the re-face (defined by the CudC-C arrangement) of the chiral
catalyst-carbene complexes, because steric hindrance will be
encountered during cyclopropanation reactions at the si-face. That
is, if the olefin approaches from the si-face, the resultant pyramidal
conformation of the carbene C atom in the transition state9 means
that the aryl sulfonyl group will interact unfavorably with the
(10) (a) Fritschi, H.; Leutenegger, U.; Phaltz, A. HelV. Chim. Acta 1988, 71,
1553-1565. (b) Phaltz, A. In Modern Synthetic Methods 1989; Scheffold,
R., Ed.; Springer: Berlin-Heidelberg, 1989; pp 199-248.
(11) Fraile, J. M.; Garc´ıa, J. I.; Mart´ınes-Merino, V.; Mayoral, J. A.; Salvatella,
L. J. Am. Chem. Soc. 2001, 123, 7616-7625.
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