Dianion approach to chiral cyclopropene carboxylic acids

Article abstract of DOI:10.1021/ol047837+

(Chemical Equation Presented) In this Letter, we describe a general method for preparing the dianions of cyclopropene carboxylic acids, and we show that their subsequent reactions with electrophiles provide a general means for selectively introducing dive

Full text of DOI:10.1021/ol047837+

ORGANIC
LETTERS
2004
Vol. 6, No. 26
4937-4939
Dianion Approach to Chiral
Cyclopropene Carboxylic Acids
Lian-an Liao, Ni Yan, and Joseph M. Fox*
Brown Laboratories, Department of Chemistry and Biochemistry,
UniVersity of Delaware, Newark, Delaware 19716
jmfox@udel.edu
Received October 19, 2004
ABSTRACT
In this Letter, we describe a general method for preparing the dianions of cyclopropene carboxylic acids, and we show that their subsequent
reactions with electrophiles provide a general means for selectively introducing diverse types of functional groups. This provides a general
method for the synthesis of chiral 1,2-disubstituted cyclopropenes, and opens new avenues for the enantioselective preparation of cyclopropenes.
Cyclopropene carboxylic acids are easily prepared1 materials
with a diverse spectrum of applications in complex molecule
synthesis.2-4 Their usefulness has been increased significantly
by recent developments that have made chiral cyclopropene
carboxylic acids available in nonracemic form.5 In their
pioneering work, Doyle, Mu¨ller, and Shapiro first demon-
strated that high enantioselectivities could be obtained
through the catalytic cyclopropenation of alkynes with
diazoacetates.6 More recently, we7 as well as Davies8
addressed the problem of preparing enantiomerically pure
or enriched derivatives of cyclopropene carboxylic acids in
which C-3 is an all-carbon quaternary stereocenter. These
include a method of resolution with broad scope,7a a parallel
kinetic resolution strategy that is amenable to large scale,7b
and a very efficient catalytic enantioselective method using
Rh2(DOSP)4.8 These methods are highly complementary, and
(3) Recent, synthetically useful reactions of cyclopropenes. Hydrometa-
lation reactions: (a) Rubin, M.; Gevorgyan, V. Synthesis 2004, 796. (b)
Rubina, M.; Rubin, M.; Gevorgyan, V. J. Am. Chem. Soc. 2002, 124, 11566.
(c) Rubina, M.; Rubin, M.; Gevorgyan, V. J. Am. Chem. Soc. 2003, 125,
7198. (d) Rubina, M.; Rubin, M.; Gevorgyan, V. J. Am. Chem. Soc. 2004,
126, 3688. (e) Zohar, E.; Marek, I. Org. Lett. 2004, 6, 341. Carbometalation
reactions: (f) Fox, J. M.; Liao, L.-a. J. Am. Chem. Soc. 2002, 124, 14322.
(g) Araki, S.; Kenji, O.; Shiraki, F.; Hirashita, T. Tetrahedron Lett. 2002,
43, 8033 and references therein. Cyclizations and rearrangements: (h)
Padwa, A.; Kassir, J. M.; Xu, S. L. J. Org. Chem. 1997, 62, 1642. (i) Mu¨ller,
P.; Allenbach, Y. F.; Bernardinelli, G. HelV. Chim. Acta 2003, 86, 3164.
(j) Ma, S. M.; Zhang, J. L. J. Am. Chem. Soc 2003, 125, 12386. (k) Al-
Dulayymi, J.; Baird, M. S. Tetrahedron 1990, 46, 5703. Cycloadditions:
(l) Al Dulayymi, J. R.; Baird, M. S.; Hussain, H. H.; Alhourani, B. J.;
Alhabashna, A. M. Y.; Coles, S. J.; Hursthouse, M. B. Tetrahedron. Lett.
2000, 41, 4205. (m) Baird, M. S.; Huber, F. A. M.; Clegg, W. Tetrahedron
2001, 57, 9849. (n) Nuske, H.; Brase, S.; de Meijere, A. Synlett 2000, 1467.
(o) Marchueta, I.; Verdaguer, X.; Moyano, A.; Pericas, M. A.; Riera, A.
Org. Lett. 2001, 3, 3193. (p) Molchanov, A. P.; Diev, V. V.; Kopf, J.;
Kostikov, R. R. Russ. J. Org. Chem. 2004, 40, 431. (q) Orugunty, R. S.;
Wright, D. L.; Battiste, M. A.; Helmich, R. J.; Abboud, K. J. Org. Chem.
2004, 69, 406. (r) Orugunty, R. S.; Ghiviriga, I.; Abboud, K. A.; Battiste,
M. A.; Wright, D. L. J. Org. Chem. 2004, 69, 570. Ring-opening reactions:
(s) Ma, S. M.; Zhang, J. L.; Cai, Y. J.; Lu, L. H. J. Am. Chem. Soc. 2003,
125, 13954. (t) Nakamura, I.; Bajracharya, G. B.; Yamamoto, Y. J. Org.
Chem. 2003, 68, 2297. (u) Zohar, E.; Ram, M.; Marek, I. Synlett 2004,
1288.
(1) (a) Protopopova, M. N.; Shapiro, E. A. Russ. Chem. ReV. (Engl.
Transl.) 1989, 58, 667. (b) Diaz-Requejo, M. M.; Mairena, M. A.;
Belderrain, T. R.; Nicasio, M. C.; Trofimenko, S.; Perez, P. J. Chem.
Communn. 2001, 1804 and references therein.
(2) Reviews of cyclopropene formation and reactivity: (a) Halton, B.;
Banwell, M. G. In The Chemistry of the Cyclopropyl Group; Patai, S.,
Rappoport, Z., Eds.; Wiley: Chichester, 1987; p 1224. (b) Baird, M. S.
Top. Curr. Chem. 1988, 144, 137. (c) Baird, M. S.; Schmidt, T. In
Carbocyclic Three-Membered Ring Compounds, 4th ed.; de Meijere, A.,
Ed.; Georg Thieme Verlag: Stuttgart, 1996; Vol. E17a, p 114. (d) Baird,
M. S.; Bushby, R. J.; Schmidt, T. In Carbocyclic Three-Membered Ring
Compounds, 4th ed.; de Meijere, A., Ed.; Georg Thieme Verlag: Stuttgart,
1996; Vol. E17d, p 2695. (e) Hopf, H. In Carbocyclic Three-Membered
Ring Compounds, 4th ed.; de Meijere, A., Ed.; Georg Thieme Verlag:
Stuttgart, 1996; Vol. E17d, p 2745. (f) Padwa, A.; Fryxell, G. E. In AdVances
in Strain in Organic Chemistry; Halton, B., Ed.; Jai Press: Greenwich,
CT, 1991; Vol. 1.
10.1021/ol047837+ CCC: $27.50
© 2004 American Chemical Society
Published on Web 11/20/2004

although the field is still dynamic,9 it can be said that there
are good solutions to the problem of preparing “terminal”10
cyclopropenes 1 in a single enantiomer form (Figure 1). In
efficient for many types of cyclopropenes.12 Furthermore,
metalated cyclopropenes have been used as the nucleophiles
in Pd(0)-catalyzed cross-coupling reactions.13 Thus, it would
seem that the deprotonation of an enantiomerically pure
terminal cyclopropene 3 would provide simple access to
chiral, internal cyclopropenes 4 in high yield after the
addition of electrophiles (Scheme 1). It should also be
possible to break the symmetry of a prochiral cyclopropene,
ultimately in enantioselective fashion, and thereby provide
a route to diverse types of chiral cyclopropenes through the
reaction of electrophiles with a single, common precursor.
In practice, the transformations of anions 3 to internal
cyclopropenes 4 are not straightforward. The deprotonations
are followed by fragmentations to give ring-opened structures
(via 5) as shown in Scheme 1. To date, the only successful
transformations of anions of structure 3 are those in which
Me3GeCl or Me3SiCl is the electrophile,14 procedures that
are successful because of an inverse addition protocol that
allows the electrophile to trap the 1-lithiocyclopropene as
soon as it is formed. Our extensive efforts to broaden the
reaction scope of 3 to other electrophiles have been largely
unsuccessful.
Figure 1. Classification of “terminal” and “internal” cyclopropenes.
contrast, there is no general method for preparing enantio-
merically enriched “internal”10 cyclopropenes 2. Previous
attempts to prepare internal cyclopropenes by enantioselec-
tive catalysis were either unsuccessful or proceeded with low
enantiomeric excess.6,8
In the context of our program to develop synthetically
useful reactions of strained molecules,3f,7 we hoped to
develop a seemingly straightforward solution to the problem
of preparing chiral, internal cyclopropenes as shown in
Scheme 1. The alkene hydrogens of cyclopropenes are more
Upon further consideration of the problem, we speculated
that the dianion 6 might be more stable than monoanion 3.
We reasoned that the formation of 7 would be disfavored
because of increased Coulombic repulsion upon ring opening
(Scheme 2). We further speculated that the more reactive
carbanion would react in preference to the carboxylate to
selectively produce an internal cyclopropene of structure 8.
Scheme 1. Ring-Opening Is Generally Too Fast for Reactions
of Anions 3 to Provide a Useful Route to “Internal”
Cyclopropenes 4
Scheme 2. Dianion Strategy for Forming Internal
Cyclopropenes
In this Letter, we describe a general method for preparing
the dianions of cyclopropene carboxylic acids, and we show
acidic than those of unstrained alkenes,11 and it is well-known
that deprotonation and subsequent reaction with electrophiles
(e.g., alkyl halides, aldehydes, epoxides, silyl chlorides) are
(10) In analogy to the common nomenclature of alkynes, we refer to
cyclopropenes with a single alkene substituent as “terminal” cyclopropenes
and to those with two alkene substitutents as “internal” cyclopropenes. To
our knowledge, there are only two examples of resolutions for “internal”
cyclopropenes. See ref 7a and Arrowood, T. L.; Kass, S. R. J. Am. Chem.
Soc. 1999, 121, 7272.
(4) Reactions of cyclopropenone ketals: Nakamura, M.; Isobe, H.;
Nakamura, E. Chem. ReV. 2003, 103, 1295.
(5) For a comprehensive bibliography of nonracemic cyclopropene
synthesis, see ref 7a.
(11) Fattahi, A.; McCarthy, R. E.; Ahmad, M. R.; Kass, S. R. J. Am.
Chem. Soc. 2003, 125, 11746 and references therein.
(6) (a) Doyle, M. P.; Protopopova, M.; Mu¨ller, P.; Ene, D.; Shapiro, E.
A. J. Am. Chem. Soc. 1994, 116, 8492. (b) Mu¨ller, P.; Imogai, H.
Tetrahedron: Asymmetry 1998, 9, 4419. (c) Doyle, M. P.; Ene, D. G.;
Forbes, D. C.; Pillow, T. H. Chem. Commun. 1999, 1691. (d) Timmons, D.
J.; Doyle, M. P. J. Organomet. Chem. 2001, 617, 98. (e) Doyle, M. P.; Hu,
W. Tetrahedron Lett. 2000, 41, 6265. (f) Doyle, M. P.; Hu, W. H. Synlett
2001, 1364. (g) Imogai, H.; Bernardinelli, G.; Granicher, C.; Moran, M.;
Rossier, J. C.; Muller, P. HelV. Chim. Acta 1998, 81, 1754.
(7) (a) Liao, L.-a.; Zhang, F.; Yan, N.; Golen, J. A.; Fox, J. M.
Tetradedron 2004, 60, 1803. (b) Liao, L.-a.; Zhang, F.; Dmitrenko, O.;
Bach, R. D.; Fox, J. M. J. Am. Chem. Soc. 2004, 126, 4490. (c) Fox, J. M.;
Dmitrenko, O.; Liao, L.-a.; Bach, R. D. J. Org. Chem. 2004, 69, 7317.
(8) Davies, H. M. L.; Lee, G. H. Org. Lett. 2004, 6, 1233.
(12) Early examples of cyclopropene deprotonation/alkylation or depro-
tonation/silylation: see ref 4 and (a) Closs, G. L.; Closs, L. E. J. Am. Chem.
Soc. 1963, 85, 99. (b) Avezov, I. B.; Bolesov, I. G.; Levina, R. Y. J. Org.
Chem. (USSR), Engl. Trans. 1974, 10, 2129. (c) Isaka, M.; Matsuzawa, S.;
Yamago, S.; Ejiri, S.; Miyachi, Y.; Nakamura, E. J. Org. Chem. 1989, 54,
4727. (d) Kirms, M. A.; Primke, H.; Stohlmeier, M.; de Meijere, A. Recl.
TraV. Chim. Pays-Bas. 1986, 105, 462. (e) Schipperijn, A. J.; Smael, P.
Recl. TraV. Chim. Pays-Bas. 1973, 92, 1159.
(13) Cyclopropene deprotonation/cross-coupling: see refs 4, 12c and (a)
Gru¨ger, G.; Szeimies, G. Tetrahedron Lett. 1986, 27, 1563. (b) Unteidt, S.;
de Meijere, A. Chem. Ber. 1994, 127, 1511.
(14) (a) Zrinski, I.; Novak-Coumbassa, N.; Eckert-Maksic, M. Organo-
metallics 2004, 23, 2806. (b) Zrinski, I.; Eckert-Maksic, M. Synth. Commun.
2003, 33, 4071. (c) Zrinski, I.; Gadanji, G.; Eckert-Maksic, M. New J. Chem,
2003, 27, 1270.
(9) For a recent modification of the Doyle, Mu¨ller, Shapiro cyclopro-
penation system, see: Luo, Y.; Horikawa, M.; Kloster, R. A.; Hawryluk,
N. A.; Corey, E. J. J. Am. Chem. Soc. 2004, 126, 8916.
4938
Org. Lett., Vol. 6, No. 26, 2004

that their subsequent reactions with electrophiles provide a
general means for selectively introducing diverse types of
alkene functional groups. Scheme 3 shows the results
Scheme 5. Dianion Formation/Alkylation Occurs without Loss
of Stereochemical Integrity
Scheme 3. Cyclopropene Dianion Alkylation and Arylation
ously described parallel kinetic resolution strategy.7b The
enantiomeric excess did not diminish during course of
deprotonation/alkylation.
We have also shown that it is possible to use to use dianion
formation to break the symmetry of prochiral cyclopropenes
such as 11. As shown in Scheme 6, 13 and 14 were obtained
by the treatment of dianion 12 with benzaldehyde and 4-n-
butylphenyliodide/ZnCl2/Pd(0), respectively.
Scheme 6. Desymmetrization of a Cyclopropene Carboxylic
Acid
obtained when a number of different terminal cyclopropene
carboxylic acids were sequentially treated with 2.2 equiv of
MeLi and an electrophile. Good yields were obtained for
alkylations with MeI, MeOTs, or MEMCl. For reactions of
EtI, the best yields were obtained when 12-C-4 was added.
It was also shown that cyclopropene carboxylate dianions
can serve as the nucleophile in Pd(0)-catalyzed cross-
coupling chemistry:13 transmetalation with ZnCl2 followed
by the addition of catalytic Pd(PPh3)4 leads to arene bond
formation as shown in Scheme 3.
This tandem lithiation/transmetalation/cross-coupling cas-
cade could also be applied to the simultaneous introduction
of two aryl groups to alkyne-substitued cyclopropene 9.
Treatment of 9 with 3 equiv of MeLi forms a trilithiated
species that produces 10 when sequentially treated with
ZnCl2, p-iodotoluene, and Pd(PPh3)4 (Scheme 4).
In summary, we have shown that the dianions of cyclo-
propene carboxylic acids are stable and do not rearrange in
analogy to the corresponding monoanions of their esters.
Subsequent capture by electrophiles provides a general
synthesis of chiral “internal” cyclopropenes. The deproto-
nation/alkylation occurs with excellent transfer of absolute
stereochemistry. It was also demonstrated that prochiral
cyclopropenes could be desymmetrized via their dianions.
The development of an asymmetric version of that reaction
is underway.
Scheme 4. Trianion Formation/Pd-Catalyzed Arylation
Acknowledgment. For financial support of this work we
thank NIGMS (NIH R01 GM068650-01A1) and the NIH
COBRE Program of the National Center for Research
Resources (P20 RR017716-01).
Supporting Information Available: Full experimental
As shown in Scheme 5, the metalation/electrophilic capture
sequence is stereospecific. This was demonstrated for the
reaction of MeI with the dianion of (R)-1,3-diphenylcyclo-
propene carboxylic acid, a compound that could be obtained
in highly enantiomerically enriched form using our previ-
1
and characterization details and H and 13C NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL047837+
Org. Lett., Vol. 6, No. 26, 2004
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