Kinetic Resolution and Double Stereodifferentiation in Catalytic Asymmetric C-H Activation of 2-Substituted Pyrrolidines

Article abstract of DOI:10.1021/ol015974q

(matrix presented) Dirhodium tetrakis(S-(N-dodecylbenzenesulfonyl)prolinate) (Rh₂(S-DOSP)₄) catalyzed decomposition of methyl aryldiazoacetates in the presence of 2-substituted pyrrolidines results in highly diastereoselective and en

Full text of DOI:10.1021/ol015974q

ORGANIC
LETTERS
2001
Vol. 3, No. 11
1773-1775
Kinetic Resolution and Double
Stereodifferentiation in Catalytic
Asymmetric C−H Activation of
2-Substituted Pyrrolidines
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 April 11, 2001
ABSTRACT
Dirhodium tetrakis(S-(N-dodecylbenzenesulfonyl)prolinate) (Rh2(S-DOSP)4) catalyzed decomposition of methyl aryldiazoacetates in the presence
of 2-substituted pyrrolidines results in highly diastereoselective and enantioselective C−H insertions. These reactions can proceed with impressive
levels of double stereodifferentiation and kinetic resolution, which allows for three stereocenters to be controlled during the C−H insertion
step.
In recent years there has been considerable interest in the
development of new methods for catalytic C-H activation.1
One particularly attractive method is the C-H insertion by
metal carbenoid intermediates.2 The intramolecular version
of this reaction is well established and has been elegantly
used in a number of total syntheses.2 Recently, the rhodium
carbenoids derived from aryldiazoacetates have been demon-
strated to be exceptional at intermolecular C-H insertion.3,4
A notable example is the Rh2(S-DOSP)4 catalyzed reaction
of N-BOC pyrrolidine which leads to a highly regio- and
stereoselective C-H activation (Scheme 1).3d This reaction
can be considered as a surrogate for an asymmetric Mannich
reaction.5
catalytic asymmetric C-H insertion step (Scheme 2).6 This
allows for three or even four stereocenters to be controlled
during the C-H insertion. These studies highlight the
remarkable stereoselectivity that is possible in the reactions
of aryldiazoacetates and offer considerable promise for their
utilization in organic synthesis.
Scheme 1
In this Letter we describe that impressive double stereo-
differentiation and kinetic resolution can occur during the
(1) (a) Shilov, A. E.; Shul′pin, G. B. Chem. ReV. 1997, 97, 2879. (b)
Arndtsen, B. A.; Bergman, R. G.; Mobley, T. A.; Peterson, T. H. Acc. Chem.
Res. 1995, 28, 154. (c) Waltz, K. M.; Hartwig, J. F. Science 1997, 277,
211.
(2) (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 133-162. (b) Lim, H.-J.; Sulikowski, G. A.
J. Org. Chem. 1995, 60, 2326.
10.1021/ol015974q CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/26/2001

Scheme 2
Scheme 4
To evaluate the effect of double stereodifferentiation on
the C-H activation, the reaction of both D and L proline
methyl ester (1) with methyl p-bromophenyldiazoacetate (2)
was examined. Rh2(S-DOSP)4-catalyzed decomposition of
2 (2 equiv) in the presence of D-1a in 2,2-dimethylbutane
as solvent at 50 °C resulted in a very clean transformation
(Scheme 3). After removal of the BOC group with TFA,
that the Rh2(S-DOSP)4-catalyzed C-H insertions on N-BOC-
pyrrolidine generate the (S) configuration at the stereogenic
center formed at the original carbenoid site.3d Thus, the
reaction with D-1a is the matched reaction, while the reaction
with L-1a is the mismatched reaction.
A predictive model has been developed to determine the
expected relative and absolute stereochemistry of these C-H
insertions (Figure 1). The C-H insertion is considered to
Scheme 3
the C-H insertion product 3 was formed as a single
diastereomer in 68% yield. The relative configuration of 3
was determined from NOE studies and distinctive chemical
shifts for the C-4 methylene proton,7 and this was confirmed
by X-ray crystallography.
In contrast to the above result, the Rh2(S-DOSP)4-catalyzed
reaction of 2 with L-1a generated a mixture of C-H insertion
products (Scheme 4). A mixture of ent-3 (31% yield) and
the second diastereomer 4 (14% yield) is formed. The
structure of 4 was determined on the basis of distinctive 1H
NMR chemical shifts and NOE studies. It is well-established
Figure 1. Predictive stereochemical models.
be a concerted and nonsynchronous process, occurring over
the position of the ester group.3,4 Although the actual
orientation of the substrates is not known, the arrangement
shown here, in which the alkane approaches from the front
with the large group (L) pointing up and away from the
catalyst, the medium group (M) pointing forward of the
catalyst, and the small group (S) points backward toward
the catalyst, has been successful in predicting the relative
stereochemistry of these reactions (eq 1). The extension of
this model to the matched reaction of 2-substituted pyrroli-
dines is shown in eq 2. The reaction with the D-pyrrolidine
derivatives is correctly predicted to be the matched reaction
and leads to the observed stereochemistry. In the mismatched
case, the pyrrolidine substituent would interfere with the site
of C-H insertion. This leads to low-yielding reactions and
unexpected stereochemistry as was seen with L-1a, which
generated ent-3.
(3) (a) Davies, H. M. L.; Hansen, T. J. Am. Chem. Soc. 1997, 119, 9075.
(b) Davies, H. M. L.; Stafford, D. G.; Hansen, T. Org. Lett. 1999, 1, 233.
(c) Davies, H. M. L.; Antoulinakis, E. G.; Hansen, T. Org. Lett. 1999, 1,
383. (d) Davies, H. M. L.; Hansen, T.; Hopper, D.; Panaro, S. A. J. Am.
Chem. Soc. 1999, 121, 6509. (e) Axten, J. M.; Ivy, R.; Krim, L.; Winkler,
J. D. J. Am. Chem. Soc. 1999, 121, 6511. (f) Davies, H. M. L.; Stafford, D.
G.; Hansen, T.; Churchill, M. R.; Keil, K. M. Tetrahedron Lett. 2000, 41,
2035. (g) Muller, P.; Tohill, S. Tetrahedron 2000, 56, 1725. (h) Davies, H.
M. L.; Hansen, T.; Churchill, M. R. J. Am. Chem. Soc. 2000, 122, 3063. (i)
Davies, H. M. L.; Antoulinakis, E. G. Org. Lett. 2000, 2, 4153. (j) Davies,
H. M. L.; Ren, P. J. Am. Chem. Soc. 2001, 123, 2071.
(4) For a general review, see: Davies, H. M. L.; Antoulinakis, E. G. J.
Organomet. Chem. 2001, 617-618, 45.
(5) For a general review, see: Denmark, S. E.; Nicaise, O. J.-C. In
ComprhensiVe Asymmetric Catalysis, Jacobsen, E. N., Pfaltz, A., Yamamoto,
H., Eds.; Springer-Verlag: Berlin, 1999; pp 954-958.
(6) Enantiomer differentitaion and double stereodifferentiation by use
of chiral catalysts have been reported for intramolecular cyclopropanation
and C-H insertion. (a) Doyle, M. P.; Dyatkin, A. B.; Kalinin, A. V.; Ruppar,
D. A.; Martin, S. F.; Spaller, M. R.; Liras, S. J. Am. Chem. Soc. 1995, 117,
11021. (b) Martin, S. F.; Spaller, M. R.; Liras, S.; Hartmann, B. J. Am.
Chem. Soc. 1994, 116, 4493. (c) Doyle, M. P.; Kalinin, A. V.; Ene, D. G.
J. Am. Chem. Soc. 1996, 118, 8837.
The matched reaction with a series of 2-substituted
pyrrolidines was then examined as summarized in Table 1.
(7) Davies, H. M. L.; Ren, P. Tetrahedron Lett., in press.
1774
Org. Lett., Vol. 3, No. 11, 2001

Table 1. Matched C-H Insertions of 2-Substituted
Pyrrolidines
Table 2. Kinetic Resolutions in C-H Insertions of
2-Substituted Pyrrolidines
R
equiv of (()-1
yield, %
ee, %
de, %
substrate
R
yield, %
de, %
a
b
c
d
CO2Me
2
4
2
4
2
4
2
64
66
58
60
58
62
85
77
79
83
87
88
94
98
86
86
>94
>94
76
78
>94
a
b
c
d
CO2Me
CO2 Bu
CH2OAc
CH2OTBDPS
83
85
85
85
>94
>94
>94
>94
t
t
CO2 Bu
CH2OAc
CH2OTBDPS
In each case a highly diastereoselective C-H insertion was
obtained in yields ranging from 83 to 85%. In contrast, the
mismatched reactions proceeded in poor yield. In the case
of the silyl ether L-1d, no C-H insertion product was
obtained, while with the tert-butyl proline L-1b, a mixture
of diastereomers was obtained in 22% overall yield. The
reaction with the acetyl derivative L-1c was most interesting
because in this case the major diastereomer was the cis-
substituted pyrrolidine 6 (Scheme 5).
catalyzed decomposition of methyl phenyldiazoacetate (8)
in the presence of (()-7 resulted in the formation of the C-H
insertion product 93d in 91% ee.
Scheme 6
Scheme 5
In summary, these results show that impressive levels of
kinetic resolution and double stereodifferentiation can occur
in Rh2(S-DOSP)4-catalyzed intermolecular C-H insertions.
In the matched case, highly diastereoselective reactions were
obtained by generating highly functionalized products con-
taining up to four stereogenic centers. These studies further
underscore the highly chemoselective nature of rhodium
carbenoids derived from aryldiazoacetates.
Having determined that the reaction with the 2-substituted
pyrrolidines displayed considerable double stereodifferen-
tiation, we then explored the possibility of kinetic resolution
in these reactions (Table 2). As the most useful aspect of
this work would be the asymmetric synthesis of the products
with three stereogenic centers rather than isolation of
enriched starting material, these reactions were carried out
with the (()-2-substituted pyrrolidines in excess (2-4 equiv).
In all instances, the C-H insertion products were produced
with moderate to high enantioselectivity (77-98% ee). The
high enantioselectivity in the formation of the C-H insertion
products 5 is due to a combination of the inherent kinetic
resolution and the enantiomer product differentiation by the
catalyst. Reaction of 2 with the silyl derivative 1d is most
impressive as the C-H insertion product 5d is formed in
85% yield, 98% ee, and >94% de.
Acknowledgment. Financial support of this work by the
National Science Foundation (CHE 0092490) and the
National Institutes of Health (GM57425) is gratefully
acknowledged. We thank Dr. Tore Hansen for some pre-
liminary studies in this area and Mr. Yuegang Zhang for
the X-ray structure determination.
Supporting Information Available: Full experimental
data of all new compounds and X-ray crystallographic data
for 3. This material is available free of charge via the Internet
at http://pubs.acs.org.
A final example of the kinetic resolution that is possible
is seen in the reaction with (()-7 (Scheme 6). Rh2(S-DOSP)4-
OL015974Q
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