Asymmetric Co(II)-catalyzed cyclopropanation with succinimidyl diazoacetate: General synthesis of chiral cyclopropyl carboxamides

Article abstract of DOI:10.1021/ol9005882

[Co(P1)] is an effective catalyst for asymmetric cyclopropanation with succinimidyl diazoacetate. The Co(II)-catalyzed reaction is suitable for various olefins, providing the desired cyclopropane succinimidyl esters in high yields and excellent diastereo-

Full text of DOI:10.1021/ol9005882

ORGANIC
LETTERS
2009
Vol. 11, No. 11
2273-2276
Asymmetric Co(II)-Catalyzed
Cyclopropanation with Succinimidyl
Diazoacetate: General Synthesis of
Chiral Cyclopropyl Carboxamides
Joshua V. Ruppel,† Ted J. Gauthier,† Nicole L. Snyder,‡ Jason A. Perman,† and
X. Peter Zhang*,†
Department of Chemistry, UniVersity of South Florida, Tampa, Florida 33620-5250,
and Department of Chemistry, Hamilton College, Clinton, New York 13323
pzhang@cas.usf.edu
Received March 19, 2009
ABSTRACT
[Co(P1)] is an effective catalyst for asymmetric cyclopropanation with succinimidyl diazoacetate. The Co(II)-catalyzed reaction is suitable for
various olefins, providing the desired cyclopropane succinimidyl esters in high yields and excellent diastereo- and enantioselectivity. The
resulting enantioenriched cyclopropane succinimidyl esters can serve as convenient synthons for the general synthesis of optically active
cyclopropyl carboxamides.
The well-documented importance of cyclopropanes in nu-
merous fundamental and practical applications has stimulated
vast efforts for the synthesis of these smallest carbocycles.1
Metal-catalyzed asymmetric cyclopropanation of alkenes
with diazo reagents constitutes the most direct and general
approach for the stereoselective construction of these unique
all-carbon triangular structures.2 A number of outstanding
chiral catalysts have been reported to achieve high diastereo-
and enantioselectivity for several classes of cyclopropanation
reactions, most of which employed diazoacetates.1-3 Ongo-
ing endeavors in the field aim at further expanding the
substrate scope to include a broader variety of alkenes as
(3) For select examples of asymmetric cyclopropanation with diazocar-
bonyls, see: (a) Hu, W.; Timmons, D. J.; Doyle, M. P. Org. Lett. 2002, 4,
901. (b) Niimi, T.; Uchida, T.; Irie, R.; Katsuki, T. AdV. Syn. Catal. 2001,
343, 79. (c) Davies, H. M. L. Eur. J. Org. Chem. 1999, 2459. (d) Lo, M. M.-
C.; Fu, G. C. J. Am. Chem. Soc. 1998, 120, 10270. (e) Davies, H. M. L;
Bruzinski, P. R.; Lake, D. H.; Kong, N.; Fall, M. J. J. Am. Chem. Soc.
1996, 118, 6897. (f) Nishiyama, H.; Itoh, Y.; Matsumoto, H.; Park, S.-B.;
Itoh, K. J. Am. Chem. Soc. 1994, 116, 2223. (g) Doyle, M. P.; Winchester,
W. R.; Hoorn, J. A. A.; Lynch, V.; Simonsen, S. H.; Ghosh, R. J. Am.
Chem. Soc. 1993, 115, 9968. (h) Evans, D. A.; Woerpel, K. A.; Hinman,
M. M.; Faul, M. M. J. Am. Chem. Soc. 1991, 113, 726. (i) Fritschi, H.;
† University of South Florida.
‡ Hamilton College.
(1) (a) Pietruszka, J. Chem. ReV. 2003, 103, 1051. (b) Wessjohann, L. A.;
Brandt, W.; Thiemann, T. Chem. ReV. 2003, 103, 1625. (c) Donaldson,
W. A. Tetrahedron 2001, 57, 8589. (d) Salaun, J. Chem. ReV. 1989, 89,
1247.
(2) (a) Lebel, H.; Marcoux, J.-F.; Molinaro; Charette, A. B. Chem. ReV
2003, 103, 977. (b) Davies, H. M. L.; Antoulinakis, E. Org. React. 2001,
57, 1. (c) Doyle, M. P.; Forbes, D. C. Chem. ReV. 1998, 98, 911. (d) Padwa,
A.; Krumpe, K. E. Tetrahedron 1992, 48, 5385. (e) Doyle, M. P. Chem.
ReV. 1986, 86, 919.
Leutenegger, U.; Pfaltz, A. Angew. Chem., Int. Ed. Engl. 1986, 25, 1005
.
10.1021/ol9005882 CCC: $40.75
Published on Web 05/04/2009
 2009 American Chemical Society

well as to utilize more challenging classes of diazo reagents
for use in asymmetric cyclopropanation.
In contrast to the large body of excellent results
achieved with diazoacetates,1-3 diazoacetamides have not
been successfully employed for asymmetric intermolecular
cyclopropanation (Scheme 1)4 except for the Rh2-based
1 with excellent diastereo- and enantioselectivities. As a
result of the highly reactive hydroxysuccinimide esters
present, 1 could serve as convenient synthons for the general
preparation of chiral amides 2 through reactions with a range
of different amines and without loss of pre-established
enantiomeric purity.
Structurally well-defined cobalt(II) complexes of D2-
symmetric chiral porphyrins ([Co(Por*)]) have emerged as
a class of effective catalysts for asymmetric cyclopropanation
reactions,11-13 with both electron-sufficient12a,b and electron-
deficient12c olefins using diazoacetates,12b,c diazosulfones,12d
and R-nitro diazoacetates.12e Among this family of [Co-
(Por*)],12 a group of six derivatives [Co(P1)]-[Co(P6)]
(Figures 1 and S1 (Supporting Information)), possessing
Scheme 1. Routes to Chiral Cyclopropyl Carboxamides
intramolecular reactions by Doyle and co-workers.5,6 The
absence of effective intermolecular asymmetric cyclopropa-
nation with diazoacetamides may be attributed to two major
factors: (i) inherent low reactivity of the resulting metal-
carbene intermediate due to reduced electrophilicity and
increased steric hindrance and (ii) complications resulting
from competitive intramolecular C-H insertion.7 Inspired
by their important biomedical applications,8 we envisioned
a postderivatization approach to synthesize chiral cyclopropyl
carboxamides 2 in enantioenriched form through reacting
preformed cyclopropyl chiral building blocks 1 with various
amines (Scheme 1).9 Herein, we report a cobalt-catalyzed
asymmetric cyclopropanation process with succinimidyl
diazoacetate (N2CHCO2Su),10 which forms cyclopropanes
Figure 1. D2-Symmetric chiral cobalt(II) porphyrins.
diverse electronic, steric, and chiral environments, were
evaluated as potential catalysts for the asymmetric cyclo-
propanation of styrene with the sterically bulky N2CHCO2Su
(Table 1). As a practical attribute of [Co(Por)]-catalyzed
cyclopropanation,14a these reactions were carried out in a
one-pot fashion with alkene as limiting reagent and without
the occurrence of the common dimerization side reaction.
Upon examination of the results (Table 1), it was evident
that the steric bulkiness of the carbene source governed the
reactivity difference of these catalysts. For example, no
(4) For nonasymmetric cyclopropanation with R-diazoacetamides, see:
(a) Doyle, M. P.; Dorow, R. L.; Terpstra, J. W.; Rodenhouse, R. A. J. Org.
Chem. 1985, 50, 1663. (b) Jeganathan, A.; Richardson, S. K.; Mani, R. S.;
Haley, B. E.; Watt, D. S. J. Org. Chem. 1986, 51, 5362. (c) Doyle, M. P.;
Loh, K.-L.; DeVries, K. M.; Chinn, M. S. Tetrahedron Lett. 1987, 28, 833.
(d) Haddad, N.; Galili, N. Tetrahedron: Asymmetry 1997, 8, 3367. (e) Gross,
Z.; Galili, N.; Simkhovich, L. Tetrahedron Lett. 1999, 40, 1571. (f)
Muthusamy, S.; Gunanathan, C. Synlett 2003, 1599.
(5) (a) 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.; Martin,
S. F. J. Am. Chem. Soc. 1995, 117, 5763. (b) Doyle, M. P.; Kalinin, A. V.
J. Org. Chem. 1996, 61, 2179. (c) Doyle, M. P.; Eismont, M. Y.;
(9) For an example of ineffective asymmetric cyclopropanation directly
with diazoacetamides by current Co(II)-based catalytsts, see Scheme S1,
Supporting Information.
(10) The solid N2CHCO2Su, which is stable and can be handled safely,
has not been previously employed for asymmetric cyclopropanation. For a
single report on Ru-catalyzed nonasymmetric cyclopropanation with
N2CHCO2Su, see: (a) Werle, T.; Maas, G. AdV. Synth. Catal. 2001, 343,
37. For the use of N2CHCO2Su to synthesize diazo derivatives, see: (b)
Ouihia, A.; Rene, L.; Guilhem, J.; Pascard, C.; Badet, B. J. Org. Chem.
1993, 58, 1641. (c) Fuerst, D. E.; Stoltz, B. M.; Wood, J. L. Org. Lett.
2000, 2, 3521. (d) Clark, J. P.; Middleton, M. D. Org. Lett. 2002, 4, 765.
(e) Grohmann, M.; Buck, S.; Schaffler, L.; Maas, G. AdV. Synth. Catal.
2006, 348, 2203. (f) Reference 5.
Protopopova, M. N.; Kwan, M. M. Y. Tetrahedron 1994, 50, 1665
.
(6) For a recent exmple on asymmetric cyclopropanation of R-ami-
dodiazoacetates, see: Marcoux, D.; Charette, A. B. Agnew. Chem. Int. Ed.
2008, 47, 10155
.
(7) For select examples of intramolecular carbene C-H insertion of
R-diazoacetamides, see: (a) Brown, D. S.; Elliott, M. C.; Moody, C. J.;
Mowlem, T. J.; Marino, J. P.; Padwa, A. P. J. Org. Chem. 1994, 59, 2447.
(b) Gois, P. M. P.; Afonso, C. A. M. Eur. J. Org. Chem. 2004, 3773. (c)
Grohmann, M.; Buck, S.; Schaffler, L.; Maas, G. AdV. Synth. Catal. 2006,
348, 2203.
(11) Doyle, M. P. Agnew. Chem. Int. Ed. 2009, 48, 850
.
(12) (a) Chen, Y.; Fields, K. B.; Zhang, X. P. J. Am. Chem. Soc. 2004,
126, 14718. (b) Chen, Y.; Zhang, X. P. J. Org. Chem. 2007, 72, 5931. (c)
Chen, Y.; Ruppel, J. V.; Zhang, X. P. J. Am. Chem. Soc. 2007, 129, 12074.
(d) Zhu, S.; Ruppel, J. V.; Lu, H.; Wojtas, L.; Zhang, X. P. J. Am. Chem.
Soc. 2008, 130, 5042. (e) Zhu, S.; Perman, J. A.; Zhang, X. P. Agnew.
(8) For select recent examples, see: (a) Garrido, D. M.; Corbett, D. F.;
Dwornik, K. A.; Goetz, A. S.; Littleton, T. R.; McKeown, S. C.; Mills,
W. Y.; Smalley, T. L.; Briscore, C. P.; Peat, A. J. Bioorg. Med. Chem.
Lett. 2006, 16, 1840. (b) Jiang, T.; Kuhen, K. L.; Wolff, K.; Yin, H.; Bieza,
K.; Caldwell, J.; Bursulaya, B.; Wu, T. Y.-H.; He, Y. Bioorg. Med. Chem.
Lett. 2006, 16, 2105. (c) Sandanayaka, V. P.; Prashad, A. S.; Yang, Y.;
Williamson, T.; Lin, Y. I.; Mansour, T. S. J. Med. Chem. 2003, 46, 2569.
(d) Morain, P.; Lestage, P.; De Nanteuil, G.; Jochemsen, R.; Robin, J.-L.;
Guez, D.; Boyer, P.-A. CNS Drug ReV. 2002, 8, 31. (e) Graham, D. W.;
Ashton, W. T.; Barash, L.; Brown, J. E.; Brown, R. D.; Canning, L. F.;
Chen, A.; Springer, J. P.; Rogers, E. F. J. Med. Chem. 1987, 30, 1074.
Chem. Int. Ed. 2008, 47, 8460
.
(13) For other contributions on [Co(Por)]-catalyzed cyclopropanation,
see: (a) Penoni, A.; Wanke, R.; Tollari, S.; Gallo, E.; Musella, D.; Ragaini,
F.; Demartin, F.; Cenini, S. Eur. J. Inorg. Chem. 2003, 1452. (b) Caselli,
A.; Gallo, E.; Ragaini, F.; Ricatto, F.; Abbiati, G.; Cenini, S. Inorg. Chim.
Acta 2006, 359, 2924. (c) Fantauzzi, S.; Gallo, E.; Rose, E.; Raoul, N.;
Caselli, A.; Issa, S.; Ragaini, F.; Cenini, S. Organometallics 2008, 27, 6143
.
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Org. Lett., Vol. 11, No. 11, 2009

Table 1. Asymmetric Cyclopropanation of Styrene with
Succinimidyl Diazoacetate by D2-Symmetric Chiral Cobalt(II)
Porphyrinsa
Table 2. [Co(P1)]-Catalyzed Diastereo- and Enantioselective
Cyclopropanation of Different Alkenes with N2CHCO2Sua
entry [Co(Por*)]b additive solvent yieldc,i (%) trans:cisd eee (%)
1
[Co(P1)]
[Co(P2)]
[Co(P3)]
[Co(P4)]
[Co(P5)]
[Co(P6)]
[Co(P1)]
[Co(P1)]
[Co(P1)]
[Co(P1)]
[Co(P1)]
[Co(P1)]
DMAP C6H5Me
DMAP C6H5Me
DMAP C6H5Me
DMAP C6H5Me
DMAP C6H5Me
DMAP C6H5Me
DMAP C6H5Me
C6H5Me
C6H5Me
DMAP C6H5Me
DMAP C6H5Me
DMAP C6H5Cl
86
70
10
0
>99:1
>99:1
>99:1
92
96
63
2
3
4
5
0
6
0
7f
74
85
86
66
64
67
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
91
88
88
91
91
87
8f
NMI
9f
10f,g
11f,h
12f
a Performed at rt for 48 h using 5 mol % of [Co(Por*)] under N2
with 1.0 equiv of styrene and 1.5 equiv of N2CHCO2Su in the presence
of 0.5 equiv of additive; [styrene] ) 0.25 M. b See Figures 1 and S1
(Supporting Information) for structures. c Isolated yields. d Determined
by HPLC. e Trans isomer ee determined by chiral HPLC. f 1.2 equiv of
N2CHCO2Suc. g 24 h. h 2 mol % of [Co(P1)]. i Similar olefin conversions
with no side reactions.
reactions were observed with the more sterically demanding
catalysts [Co(P4)], [Co(P5)], and [Co(P6)] (entries 4-6).
Furthermore, the yields of the desired cyclopropane 1a by
the less steric catalysts [Co(P1)], [Co(P2)], and [Co(P3)]
were correlated well with the relative hindrance of the ligand
environment (entries 1-3). For these reactions, outstanding
diastereoselectivities were achieved, with trans-1a produced
as the sole diastereomer. While the best ee was attained by
[Co(P2)], the use of [Co(P1)] afforded the best yield in
addition to high enantioselectivity. Reduction of the
N2CHCO2Su from 1.5 to 1.2 equiv gave similarly high
diastereo- and enantioselectivity for the [Co(P1)]-catalyzed
reaction but resulted in decreased yields (entries 1 and 7).
As demonstrated previously,14b a more positive trans effect
of DMAP on enantioselectivity was observed (entries 7-9).
Although selectivity was not affected, by lowering catalyst
loading or reducing reaction time, decrease in the overall
product yield was observed (entries 10 and 11). Finally,
toluene seemed to be the solvent of choice as the use of
other solvents such as chlorobenzene led to lower yields and
decreased enantioselectivities (entry 12).
Under the optimized reaction conditions, different olefin
substrates were subject to catalytic cyclopropanation using
N2CHCO2Su. As shown with select examples (Table 2),
both electron-sufficient and electron-deficient olefins could
be successfully cyclopropanated by [Co(P1)]. For ex-
ample, asymmetric cyclopropanation of styrene derivatives
bearing various substituents, including alkyl and halide
groups as well as electron-donating and -withdrawing
groups, could be catalyzed by [Co(P1)] to form the
corresponding cyclopropanes 1a-f in good to high yields
with outstanding diastereoselectivities and excellent enan-
tioselectivities (entries 1, 3, 5, 7, 9, and 11). Further
a Performed at rt for 48 h using 5 mol % of [Co(P1)] under N2 with
1.0 equiv of styrene and 1.5 equiv of N2CHCO2Su in the presence of
0.5 equiv of DMAP; [styrene] ) 0.25 M. b Isolated yields. c Trans:cis
ratio determined by NMR or HPLC. d Trans isomer ee determined by
chiral HPLC. e Sign of optical rotation. f [Co(P2)] as catalyst. g [1R,2R]
absolute configuration by X-ray crystal structural analysis and optical
rotation. h Similar olefin conversions with no side reactions.
improvement in enantioselectivity was achieved uniformly
for all these substrates when the relatively bulkier [Co(P2)]
was employed as the catalyst, albeit in lower yields for
most of the cases (entries 2, 4, 6, 8, 10, and 12). In
addition, the Co-based catalytic process exhibited func-
tional group tolerance as demonstrated with the reactions
of acetoxy- and nitro-substituted styrenes to form 1g,h
(entries 13 and 14). Due to the steric bulkiness of
N2CHCO2Su, the catalytic system was shown to be less
efficient for large aromatic olefins as exemplified by the
[Co(P1)]-catalyzed cyclopropanation reaction of 2-vinyl-
naphthalene, offering 1i in 33% yield with 98% de and
91% ee (entry 15). In addition to aromatic olefins, the
[Co(P1)]/N2CHCO2Su-based system could also selectively
cyclopropanate challenging electron-deficient olefins such
as R,ꢀ-unsaturated esters, amides, and ketones (entries
16-18). It is worth noting that the cyclopropanes prepared
from these olefins (1j,l) are highly electrophilic in nature
Org. Lett., Vol. 11, No. 11, 2009
2275

and have proven to be valuable synthetic intermediates
for a variety of applications.15
chiral R-amino acids such as methyl (S)-phenylalaninate
as well as chiral ꢀ-amino alcohols such as (S)-phenyla-
laninol and (R)-valinol (2af, 2ag, and 2ah). The resulting
multifunctional cyclopropyl amides 2af, 2ag, and 2ah,
bearing three stereogenic centers, could be isolated as
single diastereomers in good to excellent yields.
With the established availability of enantioenriched
succinimidyl cyclopropyl carboxylate derivatives 1 through
the [Co(P1)]-catalyzed asymmetric cyclopropanation with
N2CHCO2Su, their potential application as chiral building
blocks for the synthesis of cyclopropyl carboxamides 2
(Scheme 1) was subsequently explored. Using (1R,2R)-
1a as a representative synthon, a range of different amines
were examined for the postderivatization synthetic ap-
proach (Scheme 2). Both aliphatic and aromatic amines
Scheme 2. Post-Derivatization Approach for Synthesis of Chiral
Cyclopropyl Carboxamides via Reaction with Different Aminesa
To further demonstrate the utility of this synthetic ap-
proach, (1R,2R)-1a was allowed to react with the unprotected
tripeptide (S)-H2N-Gly-Gly-Ala-COOH at room temperature
in a mixture of water and THF in the presence of Et3N (eq
1). The corresponding cyclopropyl tripeptide (1R,2R,3S)-2ai
was isolated as single diastereomer in 60% yield without
affecting the carboxylic acid functionality.
The versatility and functional group tolerance of the
synthetic approach was further highlighted with the
reaction of (1R,2R)-1a with D-(+)-glucosamine without
protecting the hydroxyl groups (eq 2). The reaction
proceeded smoothly under mild conditions, forming the
desired cyclopropyl carboxamide of the amino sugar
(1R,2R,D)-2aj in 47% yield.
In summary, a highly diastereo- and enantioselective Co-
catalyzed asymmetric cyclopropanation of alkenes with
N2CHCO2Su has been established for the first time, and the
resulting enantioenriched succinimidyl cyclopropylcarboxylates
have proven to be valuable synthons for general synthesis of
optically active cyclopropyl carboxamide derivatives. The key
attributes of the post-derivatization approach include versatility
and a high degree of functional group tolerance. Together with
the suitability of various olefins for the asymmetric cyclopro-
panation process, this two-step synthetic scheme should permit
straightforward access to a wide range of chiral cyclopropyl
carboxamides.8
a Isolated yields; de determined by NMR or HPLC; ee determined by
chiral HPLC b 24 h. c In dioxane. d 1 h. e In THF/H2O with Et3N. f Isolated
as single diastereomer.
reacted with 1a smoothly, affording the desired cyclo-
propyl carboxamides 2a with retention of configuration
(2aa and 2ab). Cyclic amines, such as pyrrolidine and
morpholine, could also be effectively converted to the
corresponding amides in high yields with complete
preservationofthestereochemistry(2acand2ad). Thetrans-
formation of 1a into the corresponding primary amide
using ammonia also occurred in a high yield without loss
of diastereo- and enantioselectivity (2ae). Owing to the
mild and neutral reaction conditions, the postderivatization
approach was able to tolerate a number of different
functional groups as exemplified by the reactions with
Acknowledgment. We are grateful to USF (Startup Funds),
ACS-PRF (AC Grant), NSF (CAREER Award), and NSF
(CRIF: MU-0443611, Mass Facility) for financial support.
(14) (a) Huang, L.; Chen, Y.; Gao, G.-Y.; Zhang, X. P. J. Org. Chem.
2003, 68, 8179. (b) Chen, Y.; Zhang, X. P. Synthesis 2006, 1697.
(15) (a) Gnad, F.; Reiser, O. Chem. ReV. 2003, 103, 1603. (b) Cativiela,
C.; Diaz-de-Villegas, M. D. Tetrahedron: Asymmetry 2000, 11, 645. (c)
Wong, H. N. C.; Hon, M.-Y.; Tse, C.-W.; Yip, Y.-C.; Tanko, J.; Hudlicky,
T. Chem. ReV. 1989, 89, 165. (d) Danishefsky, S. Acc. Chem. Res. 1979,
12, 66.
Supporting Information Available: Experimental proce-
dures and analytical data for all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
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