Dirhodium tetraprolinate-catalyzed asymmetric cyclopropanations with high turnover numbers

Article abstract of DOI:10.1021/ol034002a

(Matrix presented) The bridged dirhodium tetraprolinate Rh ₂(S-biTISP)₂ (2) catalyzes the asymmetric cyclopropanation reaction between methyl phenyldiazoacetate and styrene at room temperature with high turnover number (92 000) and t

Full text of DOI:10.1021/ol034002a

ORGANIC
LETTERS
2003
Vol. 5, No. 9
1403-1406
Dirhodium Tetraprolinate-Catalyzed
Asymmetric Cyclopropanations with
High Turnover Numbers
Huw M. L. Davies* and Chandrasekar Venkataramani
Department of Chemistry, UniVersity at Buffalo, The State UniVersity of New York,
Buffalo, New York 14260-3000
hdaVies@acsu.buffalo.edu
Received January 2, 2003
ABSTRACT
The bridged dirhodium tetraprolinate Rh2(S-biTISP)2 (2) catalyzes the asymmetric cyclopropanation reaction between methyl phenyldiazoacetate
and styrene at room temperature with high turnover number (92 000) and turnover frequency (4000 per h).
The metal-catalyzed decomposition of diazo compounds to
transient metal carbenoids is a very versatile reaction in
organic synthesis.1 A wide variety of catalysts have been
developed leading to highly enantioselective cyclopropana-
tions,2 C-H insertions,3 and dipolar cycloadditions.4 Car-
benoids containing an electron acceptor ester group and a
donor group such as aryl, vinyl, or alkynyl are much more
chemoselective than the traditional carbenoids.5 They are far
less susceptible to carbene dimerization,6 routinely result in
highly diastereoselective cyclopropanation,7 and are capable
of highly regioselective intermolecular C-H activation by
means of carbenoid-induced C-H insertion.3b Furthermore
these carbenoids are very effective in solid-phase chemistry.8
In this paper, we report that donor/acceptor carbenoids can
also undergo intermolecular cyclopropanation with very high
catalyst turnover number (TON).
One of the most important future goals of transition metal-
catalyzed asymmetric reactions will be the development of
catalysts that are capable of very high TON. This will not
only improve the economy of the catalytic process but also
limit the problems of product contamination. Certain reac-
tions such as catalytic asymmetric hydrogenation9 can be
conducted with very low catalyst loadings, but the majority
of catalytic asymmetric reactions are still conducted with at
least 1 mol % catalyst. The metal-catalyzed transformations
of diazo compounds appear to be ideally suited for low
catalyst loading because many of the catalysts are very active
and have good stability, while product inhibition is generally
not an issue. Even so, 1 mol % catalyst tends to be used in
metal carbenoid reactions, and reports of much lower catalyst
loading are rare.10,11
(1) (a) Doyle, M. P.; McKervey, M. A.; Ye, T. In Modern Catalytic
Methods for Organic Synthesis with Diazo Compounds; Wiley-Inter-
science: New York, 1998; pp 112-162. (b) Mass, G. In Topics in Current
Chemistry; Springer-Verlag: New York; 1987; Vol. 137, pp 75-254.
(2) Davies, H. M. L.; Antoulinakis, E. G. Org. React. 2001, 59, 1-302.
(3) (a) Sulikowski, G. A.; Cha, K. L.; Sulikowski, M. M. Tetrahedron:
Asymmetry 1998, 9, 3145. (b) Davies, H. M. L. J. Mol. Catal. A 2002, 189,
125.
(4) Hodgson, D. M.; Pierard, F. Y. T. M.; Stupple, P. A. Chem. Soc.
ReV. 2001, 30, 50.
(5) Davies, H. M. L.; Panaro, S. A. Tetrahedron 2000, 56, 4871.
(6) Davies, H. M. L.; Hodges, L. M.; Matasi, J. J.; Hansen, T.; Stafford,
D. S. Tetrahedron Lett. 1998, 39, 4417.
In our own experience, dirhodium tetracarboxylates are
kinetically very active initially, but this high activity may
(8) (a) Nagashima, T.; Davies, H. M. L. J. Am. Chem. Soc. 2001, 123,
2695. (b) Nagashima, T.; Davies, H. M. L. Org. Lett. 2002, 4, 1989. (c)
Davies, H. M. L.; Walji, A. M. Org. Lett. 2003, 5, 479.
(7) Davies, H. M. L.; Clark, T. J.; Church, L. A. Tetrahedron Lett. 1989,
30, 5057.
(9) Ohkuma, T.; Koizumi, M.; Muniz, K.; Hilt, G.; Kabuto, C.; Noyori,
R. J. Am. Chem. Soc. 2002, 124, 6508.
10.1021/ol034002a CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/10/2003

Table 1. Optimization of Cyclopropanation with Low Catalyst Loading
entry
catalyst (solvent)
substrate/catalyst ratio
additiveb
yield, %
ee, %
time, h
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
1 (hexanes)
1 (hexanes)
1 (hexanes)
1 (hexanes)
1 (hexanes)
1 (hexanes)
2 (CH2Cl2)
2 (CH2Cl2)
2 (CH2Cl2)
2 (CH2Cl2)
2 (CH2Cl2)
2 (CH2Cl2)
2 (CH2Cl2)
2 (CH2Cl2)
2 (CH2Cl2)
2 (CH2Cl2)
1000
1000
10 000
A
B
A
B
A
B
A
B
A
B
A
B
C
D
C
D
98
97
62
96
15
14
72
82
80
79
90
91
25
85
11
10
89
89
89
89
1
1
>60a
16
>192a
>192a
1
10 000
100 000
100 000
1000
1000
10 000
1
6
3
10 000
100 000
100 000
100 000
100 000
1 000 000
1 000 000
>144a
>144a
42
82
85
63
75
65
83
62
74
28
>240a
>240a
a Reaction did not go to completion. b A: no additives. B: methyl benzoate (1 equiv). C: 4 Å molecular sieves. D: methyl benzoate (1 equiv) and 4 Å
molecular sieves.
not continue throughout the reaction. Rhodium prolinates
such as Rh2(S-DOSP)4 1 and the bridged structure Rh2(S-
biTISP)2 2 are exceptional catalysts for the cyclopropanation
chemistry of donor/acceptor carbenoids, active even at -50
°C.12 The vast majority of our studies with these catalysts
have used 1 mol % catalyst. In one brief study with Rh2(S-
DOSP)4, the problems with the use of lower catalyst loading
were demonstrated (Scheme 1).13 Increasing the substrate/
catalyst ratio to 1000 instead of 100 in the cyclopropanation
of the vinyldiazoacetate 3 to form 4 resulted in a drop in
enantioselectivity from 92 to 87% ee.13 The effect was even
more severe when a substrate/catalyst ratio of 10 000 was
used, as this resulted in an incomplete transformation and a
large drop in enantioselectivity to 50% ee.13 These results
indicate that the catalyst is being slowly modified under the
reaction conditions to some other species that catalyzes the
reaction with very different enantioselectivity. Although, the
mechanism for catalyst degeneration is not known, one
possibility would be the dissociation of the carboxylate
ligands. Therefore, we considered that a comparison of the
catalytic efficiency of Rh2(S-DOSP)4 and Rh2(S-biTISP)2
would be worthwhile, because the bridging ligands in Rh2-
(S-biTISP)2 may make it a more robust catalyst.
(10) For examples of asymmetric carbenoid reactions using < 1 mol %
catalyst loading, see (a) Che, C.-M.; Huang, J.-S.; Lee, F.-W.; Li, Y.; Lai,
T.-S.; Kwong, H.-L.; Teng, P.-F.; Lee, W.-S.; Lo, W.-C.; Peng, S.-M.; Zhou,
Z.-Y. J. Am. Chem. Soc. 2001, 123, 4119. (b) Doyle, M. P.; Dyatkin, A.
B.; Tedrow, J. S.; Tetrahedron Lett. 1994, 35, 3853. (c) Doyle, M. P.; Zhou,
Q. -L. Tetrahedron: Asymmetry 1995, 6, 2157. (d) Doyle, M. P.; Austin,
R. E.; Bailey, A. S.; Dwyer, M. P.; Dyatkin, A. B.; Kalinin, A. V.; Kwan,
M. M. Y.; Liras, S.; Oalmann, C. J.; Pieters, R. J.; Protopopova, M. N.;
Raab, C. E.; Roos, G. H. P.; Zhou, Q.-L.; Martins, S. F. J. Am. Chem. Soc.
1995, 117, 5763. (e) Doyle, M. P.; Kalinin, A. V. J. Org. Chem. 1996, 61,
2179. (f) Evans, D. A.; Woerpel, K. A.; Hinman, M. M.; Faul, M. M. J.
Am. Chem. Soc. 1991, 113, 726.
The test reaction that was used to evaluate the limitations
of catalyst loading was the cyclopropanation of styrene (2
equiv) with methyl phenyldiazoacetate (5) at 23 °C to form
6 (Table 1). The reaction catalyzed by Rh2(S-DOSP)4 (1) in
hexane14 was very successful (98% yield, 90% ee) when a
substrate catalyst ratio of 1000 was used, but the yield and
(11) While preparing this manuscript, we became aware of a study by
Hashimoto on asymmetric intramolecular C-H insertion using low catalyst
loading: Tsutsui, H.; Yamaguchi, Y.; Kitagaki, S.; Nakamura, S.; Ananda,
M.; Hashimoto, S. Tetrahedron: Asymmetry 2003, in press.
(12) Davies, H. M. L. Eur. J. Org. Chem. 1999, 2459.
(13) Davies, H. M. L.; Bruzinski, P.; Hutcheson, D. K.; Kong, N.; Fall,
M. J. J. Am. Chem. Soc. 1996, 118, 6897.
(14) Hydrocarbons are the optimum solvent for high enantioselectivty
for Rh2(S-DOSP)4-catalyzed reactions, while CH2Cl2 is the ideal solvent
for Rh2(S-biTISP)2-catalyzed reactions. The Rh2(S-DOSP)4-catalyzed reac-
tions give preferentially the (2S)-cyclopropanes, while the Rh2(S-biTISP)2-
catalyzed reactions give preferentially the (2R)-cyclopropanes: see ref 12
for details.
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Org. Lett., Vol. 5, No. 9, 2003

Scheme 1a
Table 2. Comparison of Additive Effects on Cyclopropanation
entry
additive
none
PhCO2Me
(Me2N)2CdO
(i-Pr)2NEt
OP(Oct)3
yield, %
ee, %
time, h
1
2
3
4
5
82
85
48
5
65
83
74
42
28
>36a
>36a
>36a
a Reaction did not go to completion.
36
78
a Reaction did not go to completion.
enantioselectivity dropped considerably (62% yield, 25% ee)
when a substrate/catalyst ratio of 10 000 was used. Prior to
our development of chiral catalysts for the donor/acceptor
carbenoids, we had found that R-hydroxyesters were excep-
tional chiral auxiliaries for these carbenoid systems15 and,
furthermore, the ester of the auxiliary enhanced the carbenoid
chemoselectivity.16 On the basis of this phenomenon, we
explored the effect of methyl benzoate as an additive on this
chemistry. Addition of 1 equiv of methyl benzoate greatly
enhanced the catalytic reaction because at a substrate/catalyst
ratio of 10 000, the reaction was complete in 16 h and 6
was formed in 96% yield and 85% ee. Attempts at further
lowering of the Rh2(S-DOSP)4 loading failed because the
reaction using a substrate/catalyst ratio of 100 000 was not
effective with or without methyl benzoate.
enantioselectivity of dirhodium tetraprolinate-catalyzed cy-
clopropanations under slightly hydrous conditions is greatly
improved by the addition of tri-n-octylphosphine oxide (OP-
(Oct)3).18 A comparison of the effect of these additives with
methyl benzoate revealed that methyl benzoate was far
superior. DIPEA virtually blocked the catalytic process, while
the reaction in the presence of TMU or OP(Oct)3 was
considerably slower. Although the actual role of methyl
benzoate in these reactions is uncertain, it is possible that it
stabilizes the rhodium carbenoid complex either by coordina-
tion to the carbenoid or to the other rhodium center.
The cyclopropanation reactions of Rh2(S-biTISP)2 (2) were
even more impressive as illustrated in Table 1 (entries 7-16).
Reactions using a substrate/catalyst ratio of 10 000 in CH2-
Table 3. Asymmetric Cyclopropanation by Various
Aryldiazoacetates
14
Cl2 were uniformly effective with or without methyl
benzoate. A further improvement was obtained by conducting
the reaction in the presence of molecular sieves, as this
enabled an efficient reaction to be conducted using a
substrate/catalyst ratio of 100 000. The presence of both
methyl benzoate and molecular sieves as additives was
optimal, and under these conditions, 6 could be obtained in
85% yield and 83% ee. Indeed, 6 was formed in 75% yield
and 74% ee when a substrate/catalyst ratio of 1 000 000 was
used, but with this low loading, the reaction did not reach
completion even after 10 days. Rh2(S-biTISP)2 has also been
shown to be more robust than Rh2(S-DOSP)4 when used as
a recoverable solid-supported catalyst.8b,c
Additives have been used previously to optimize various
carbenoid transformations. Nelson and co-workers reported
that the yield in a rhodium carbenoid-mediated intermolecular
O-H insertion reaction was considerably enhanced by
addition of tetramethyl urea (TMU) or diisopropylethylamine
(DIPEA).17 Jessop and co-workers have described that the
(15) Davies, H. M. L.; Huby, N. J. S.; Cantrell, W. R., Jr.; Olive, J. L.
J. Am. Chem. Soc. 1993, 115, 9468.
(16) Davies, H. M. L.; Matasi, J. J.; Thornley, C. Tetrahedron Lett. 1995,
36, 7205
(17) Nelson, T. D.; Song, Z. J.; Thompson, A. S.; Zhao, M.; DeMarco,
A.; Reamer, R. A.; Huntington, M. F.; Grabowski, E. J. J.; Reider, P. J.
Teterahedron Lett. 2000, 41, 1877.
a S/C ratio ) 10 000.
Org. Lett., Vol. 5, No. 9, 2003
1405

The cyclopropanation chemistry is applicable to large-scale
synthesis as illustrated in Scheme 2. The Rh2(S-biTISP)2
catalyzed cyclopropanation can be readily carried out on a
0.2 mol scale with 0.001 mol % catalyst. Under these
conditions the green catalyst is so dilute that it appears
colorless in solution. The reaction can be monitored by
simply observing the gradual disappearance of the yellow
color of methyl phenyldiazoacetate. As carbene dimerization
is rarely a problem with the donor/acceptor carbenoids, there
is no need to use very slow addition of the diazo compound.
The reaction is complete in 24 h, which means that the
catalyst is operating at very high TON (92 000) and turnover
frequency (4000 per h). After filtration of the molecular
sieves and removal of volatiles, no contaminants are visible
in the NMR of the crude material, which can be readily
enriched by recrystallization to give 6 in 75% isolated yield
and 99.3% ee.
Table 4. Cyclopropanation of Other Substrates
Scheme 2
The asymmetric cyclopropanation with low catalyst load-
ing (substrate/catalyst ratio of 100 000) may be applied to
various aryldiazoacetates as illustrated in Table 3 (entries
1-5). In all instances, the reactions were complete in 24-
36 h and the cyclopropanes were obtained in good yield (76-
91%) and enantioselectivity (80-94% ee). In the case of
the phenylvinyldiazoacetate cyclopropanation (entry 6), the
lowest effective catalyst loading was 10 000:1. This may be
due to the fact that methyl phenylvinyldiazoacetate slowly
undergoes a 6π electrocyclization to a pyrazole,15 and a
pyrazole is likely to partially poison the catalyst. This
improvement in catalyst loading is significant because the
resulting vinylcyclopropane 4 has been used for the asym-
metric synthesis of phenylcyclopropane amino acids13 and
the antidepressant (+)-sertraline.19
In summary, the bridged prolinate catalyst Rh2(S-biTISP)2
has been shown to be a superior catalyst over our first
generation catalyst Rh2(S-DOSP)4 in terms of low catalyst
loading. This may indicate that the design of new high TON
catalysts for carbenoid chemistry would benefit from the use
of bridging dicarboxylate ligands. Molecular sieves and
methyl benzoate have a beneficial effect on the stability of
the catalyst under the reaction conditions. Under optimized
conditions, room temperature cyclopropanations with a
substrate/catalyst ratio of 100 000 are readily achieved.
Two other examples of the cyclopropanation with low
catalyst loading are the reactions with 1-phenylbutadiene and
1,1-diphenylethylene in Table 4. These reactions give
comparable results in terms of yield and enantioselectivity
to the standard reaction with 1 mol % catalyst. Once again,
the reactions are faster when methyl benzoate is used as an
additive. These examples indicate that low catalyst loading
could be used in the asymmetric [3 + 4] cycloaddition
between vinyldiazoacetates and dienes,20 and in the asym-
metric synthesis of cyclopropane amino acids21 as well as
cyclopropyl analogues of tamoxifen.22
Acknowledgment. Financial support of this work by the
National Science Foundation (CHE-0092490) is gratefully
acknowledged. We thank Qihui Jin for his preliminary studies
with methyl benzoate in C-H activation reactions, which
encouraged us to use it as an additive in this study.
Supporting Information Available: Experimental data
for the cyclopropanation reactions. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL034002A
(18) Wynne, D. C.; Olmstead, M. M.; Jessop, P. G. J. Am. Chem. Soc.
2000, 122, 7638.
(19) Corey, E. J.; Grant, T. J. Tetrahedron Lett. 1994, 35, 5373.
(20) Davies, H. M. L.; Stafford, D. G.; Doan, B. D.; Houser, J. H. J.
Am. Chem. Soc. 1998, 120, 3326.
(21) Moye-Sherman, D.; Welch, M. B.; Reibenspies, J.; Burgess, K. J.
Chem. Soc., Chem. Commun. 1998, 2377.
(22) Davies, H. M. L.; Nagashima, T.; Klino, J. L., III. Org. Lett. 2000,
2, 823.
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