Diastereoselective intermolecular Pauson-Khand reactions of chiral cyclopropenes

Article abstract of DOI:10.1021/ol051456u

(Chemical Equation Presented) In this Letter, it is demonstrated that the unusual reactivity of cyclopropenes can increase the scope and utility of intermolecular Pauson-Khand reactions. The well-defined chiral environment of cyclopropenes has a powerful

Full text of DOI:10.1021/ol051456u

ORGANIC
LETTERS
2005
Vol. 7, No. 16
3593-3595
Diastereoselective Intermolecular
Pauson Khand Reactions of Chiral
−
Cyclopropenes
Mahesh K. Pallerla and Joseph M. Fox*
Brown Laboratories, Department of Chemistry and Biochemistry,
UniVersity of Delaware, Newark, Delaware 19716
jmfox@udel.edu
Received June 22, 2005
ABSTRACT
In this Letter, it is demonstrated that the unusual reactivity of cyclopropenes can increase the scope and utility of intermolecular Pauson
−
Khand reactions. The well-defined chiral environment of cyclopropenes has a powerful influence on the diastereoselectivity of the reactions
and leads to the production of a single cyclopentenone in each of the described cases. The cyclopropane ring strongly influences the
stereochemistry of reactions at the enone, and the three-membered ring can subsequently be cleaved under mild conditions.
The Pauson-Khand cyclocarbonylation is one of the most
powerful reactions of the past century,1 and since its
discovery2 it has been recognized that strained alkenes are
usually the “best substrates” for the reaction.3 Since the
original report,2 there has been a tremendous effort to
improve the scope of the reaction and to develop catalytic1b,4
and asymmetric variants.1a,d,5 Although the scope of the
intramolecular Pauson-Khand reaction has increased dra-
matically,1 improving intermolecular protocols to include
unstrained alkenes has presented a greater challenge.1b
A
notable exception is the elegant “directed Pauson-Khand”
reaction pioneered by Krafft,6 in which a ligand for cobalt
is tethered to the alkene.1a,b,5b,6 That advance increased the
scope of the intermolecular to include mono- and disubsti-
tuted alkenes. Still, the development of alternative approaches
(e.g., traceless tethers from intramolecular Pauson-Khand
reactions)7 is an active area of investigation because of the
clear need to increase the scope of the intermolecular
protocol.
(1) Selected reviews: (a) Brummond, K. M.; Kent, J. L. Tetrahedron
2000, 56, 3263. (b) Gibson, S. E.; Mainolfi, N. Angew. Chem., Int. Ed.
2005, 44, 3022. (c) Gibson, S. E.; Stevenazzi, A. Angew. Chem., Int. Ed.
2003, 42, 1800. (d) Alcaide, B.; Almendros, P. Eur. J. Org. Chem. 2004,
3377. (e) Ingate, S. T.; Marco-Contelles, J. Org. Prep. Proced. Int. 1998,
30, 121. (e) Shore, N. E. Org. React. 1991, 40, 1.
A philosophically different approach to improving the
intermolecular Pauson-Khand reaction is to embrace the
(2) Khand, I. U.; Knox, G. R.; Pauson, P. L.; Watts, W. E.; Foreman,
M. I. J. Chem. Soc., Perkin Trans. 1 1973, 977.
(3) Theory on alkene reactivity in Pauson-Khand reactions: (a) Perica´s,
M. A.; Balsells, J.; Castro, J.; Marchueta, I.; Moyano, A.; Riera, A.;
Va´zquez, J.; Verdaguer, X. Pure Appl. Chem. 2002, 74, 167. (b) de Bruin,
T. J. M.; Milet, A.; Greene, A. E.; Gimbert, Y. J. Org. Chem. 2004, 69,
1075.
(4) (a) Pagenkopf, B. L.; Livinghouse, T. J. Am. Chem. Soc. 1996, 118,
2285. (b) Belanger, D. B.; Livinghouse, T. Tetrahedron Lett. 1998, 39,
7641. (c) Krafft, M. E.; Hirosawa, C.; Bonaga, L. V. R. Tetrahedron Lett.
1999, 40, 9177.
(5) Enantioselective PKR lead references: (a) Verdaguer, X.; Lledo, A.;
Lopez-Mosquera, C.; Maestro, M. A.; Pericas, M. A.; Riera, A. J. Org.
Chem. 2004, 69, 8053. (b) Rivero, M. R.; de la Rosa, J. C.; Carretero, J. C.
J. Am. Chem. Soc. 2003, 125, 14992. (c) Hicks, F. A.; Buchwald, S. L. J.
Am. Chem. Soc. 1996, 118, 11688.
(6) (a) Krafft, M. E.; Juliano, C. A.; Scott, I. L.; Wright, C.; McEachin,
M. D. J. Am. Chem. Soc. 1991, 113, 1693. (b) Krafft, M. E.; Juliano, C. A.
J. Org. Chem. 1992, 57, 5106. (c) Itami, K.; Mitsudo, K.; Yoshida, J. Angew.
Chem. Int. Ed. 2002, 41, 3481. (d) Itami, K.; Mitsudo, K.; Fujita, K.; Ohashi,
Y.; Yoshida, J. J. Am. Chem. Soc. 2004, 126, 11058.
10.1021/ol051456u CCC: $30.25
© 2005 American Chemical Society
Published on Web 07/14/2005

unusual reactivity of strained molecules. The most developed
of such approaches is the allenic Pauson-Khand reaction,1a,d,8
which uses the strain that is inherent to allenes (∼10 kcal/
mol) to drive reactivity. This stereospecific8a approach has
been especially effective for increasing the scope of intramo-
lecular Pauson-Khand reactions. Methylenecyclopropanes9
and cyclobutenes10 are further examples of strained alkenes
that serve as useful coupling partners in Pauson-Khand-
type reactions.
Cyclopropenes are intriguing substrates for synthesis11
because they are easily prepared and handled but at the same
time possess remarkable strain energy (∼55 kcal/mol)12 and
unusual reactivity. Because the chiral environment is compact
and well defined, it is particularly suitable for diastereo-
selective transformations.11a In recent years, the synthetic
utility of cyclopropenes has been augmented by efficient
preparations of enantiomerically enriched derivatives13 and
by the development of facially selective reactions of chiral
cyclopropenes.14 Although it would seem that cyclopropenes
would also be excellent substrates for intermolecular Pau-
son-Khand reactions, there are few examples in the litera-
ture.15
Reactions carried out in hexane were inferior. However, the
reported yields were low,16 the protocol calls for an excess
(2 equiv) of the cyclopropene, and the diastereoselectivity
of the reaction was unclear.16 We decided to thoroughly
investigate the reactivity of cyclopropene Pauson-Khand
reactions and report here that such reactions can proceed with
exceptional efficiency in the presence of sulfide17a or
N-oxide17b,c promoters. The well-defined chiral environment
of cyclopropenes has a powerful influence on diastereose-
lectivity: a single cyclopentenone was isolated in each of
the reactions described in Scheme 1. exo-Diastereoselectivity
Scheme 1. Pauson-Khand Reactions of Chiral Cyclopropenes
Percias and co-workers have elegantly demonstrated that
cyclopropene itself is a good substrate for intermolecular
Pauson-Khand reactions.15b Pauson-Khand reactions of
chiral cyclopropenes have been addressed in a single study
by Smit, Nefedov, and co-workers.15a In that work, the methyl
ester of cyclopropene 1 was reported to react with dicobal-
thexacarbonyl complexes of alkynes on dry silica gel.
(7) Traceless PKR lead references: (a) Reichwein, J. F.; Iacono, S. T.;
Patel, M. C.; Pagenkopf, B. L. Tetrahedron Lett. 2002, 43, 3739. (b)
Brummond, K. M.; Sill, P. C.; Rickards, B.; Geib, S. J. Tetrahedron Lett.
2002, 3735.
(8) Allenic PKR lead references: (a) Brummond, K. M.; Kerekes, A.
D.; Wan, H. J. Org. Chem. 2002, 67, 5156. (b) Brummond, K. M.; Chen,
H.; Fisher, K. D.; Kerekes, A. D.; Rickards, B.; Sill, P. C.; Geib, S. J. Org.
Lett. 2002, 4, 1931. (c) Antras, F.; Ahmar, M.; Cazes, B. Tetrahedron Lett.
2001, 42, 8157.
(9) (a) Smit, W. A.; Kireev, S. L.; Nefedov, O. M.; Tarasov, V. A.
Tetrahedron Lett. 1989, 30, 4021. (b) Stolle, A.; Becker, H.; Salaun, J.;
Demeijere, A. Tetrahedron Lett. 1994, 35, 3521. (c) Stolle, A.; Becker, H.;
Salaun, J.; Demeijere, A. Tetrahedron Lett. 1994, 35, 3517. (d) Corlay, H.;
Fouquet, E.; Magnier, E.; Motherwell, W. B. Chem. Commun. 1999, 183.
(10) Lead reference for cyclobutene PKR: Gibson, S. E.; Mainolfi, N.;
Kalindjian, S. B.; Wright, P. T Angew. Chem., Int. Ed. 2004, 43, 5680.
(11) Reviews on cyclopropenes in synthesis: (a) Fox, J. M.; Yan, N.
Curr. Org. Chem. 2005, 9, 719. (b) Baird, M. S. Top. Curr. Chem. 1988,
144, 137. (c) Nakamura, M.; Isobe, H.; Nakamura, E. Chem. ReV. 2003,
103, 1295.
a Alternate conditions: BuSMe or Et2S, 100 °C, dioxane. All
yields are the average of two runs.
(12) Bach, R. D.; Dmitrenko, O. J. Am. Chem. Soc. 2004, 126, 4444.
(13) (a) Doyle, M. P.; Protopopova, M.; Mu¨ller, P.; Ene, D.; Shapiro, E.
A. J. Am. Chem. Soc. 1994, 116, 8492. (b) Davies, H. M. L.; Lee, G. H.
Org. Lett. 2004, 6, 1233 (c) Liao, L.-a.; Zhang, F.; Dmitrenko, O.; Bach,
R. D.; Fox, J. M. J. Am. Chem. Soc. 2004, 126, 4490. (d) Liao, L.-a.; Zhang,
F.; Yan, N.; Golen, J. A.; Fox, J. M. Tetrahedron 2004, 60, 1803. (e) Liao,
L.-a.; Yan, N.; Fox, J. M. Org. Lett. 2004, 6, 4937. (f) Chuprakov, S.;
Rubin, M.; Gevorgyan, V. J. Am. Chem. Soc. 2005, 127, 3714. (g) Lou,
Y.; Horikawa, M.; Kloster, R. A.; Hawryluk, N. A.; Corey, E. J. J. Am.
Chem. Soc. 2004, 126, 8916.
(14) Lead examples of diastereoselective reactions of cyclopropenes: (a)
Rubina, M.; Rubin, M.; Gevorgyan, V. J. Am. Chem. Soc. 2004, 126, 3688.
(b) Zohar, E.; Marek, I. Org. Lett. 2004, 6, 341. (c) Liao, L.-a.; Fox, J. M.
J. Am. Chem. Soc. 2002, 124, 14322. (d) Araki, S.; Tanaka, T.; Hirashita,
T.; Setsune, J.-i. Tetrahedron Lett. 2003, 44, 8001.
was rigorously assigned by X-ray crystallography for a
derivative of 9 and by NOE studies for 4. 2-Silyl-3-
alkylcyclopropene-1-carboxylates are particularly good sub-
strates for the Pauson-Khand chemistry. Ethyl 2-hexylcy-
clopropene-1-carboxylategivesthecomplementaryregioisomer,
but the reaction was less efficient and gave 12 in only 22%
isolated yield. Although a number of uncharacterized materi-
(16) Kireev et al.15a assigned endo selectivity for adducts prepared on
silica. In solvent, we observe exo adducts. Also, the highest yield reported
in the paper does not agree with the amounts given in the experimental
section.
(17) (a) Sugihara, T.; Yamada, M.; Yamaguchi, M. Nishiizawa, M. Synlett
1991, 771. (b) Shambayati, S.; Crowe, W. E.; Schreiber, S. L. Tetrahedron
Lett. 1990, 31, 5289. (c) Jeong, N.; Chung, Y. K.; Lee, B. Y.; Lee, S. H.;
Yoo, S. E. Synlett 1991, 204.
(15) (a) Kireev, S. L.; Smit, V. A.; Ugrak, B. I.; Nefedov, O. M. Bull.
Acad. Sci. USSR (Engl Transl) 1991, 2240. (b) Marchueta, I.; Verdaguer,
X.; Moyano, A.; Perica`s, M. A.; Riera, A. Org. Lett. 2001, 3, 3193. (c)
Nu¨ske, H.; Bra¨se, S.; de Meijere, A. Synlett 2000, 1467 (d) Witulski, B.;
Go¨ssman, M. Synlett 2000, 1793.
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Org. Lett., Vol. 7, No. 16, 2005

als accompanied the formation of 12, it was free from
isomeric Pauson-Khand adducts. As the cyclopropene is the
more valuable of the two reaction partners, all protocols in
Scheme 1 use it as the limiting reagent. The best results were
obtained when a large excess of promoter was utilized, and
while BuSEt was the promoter used for most studies, we
demonstrated that inexpensive Et2S was equally effective for
the synthesis of 3. While most of the reactions in Scheme 1
were carried out with racemic materials, enones 9-11 were
prepared in enantiomerically enriched form from readily
available, resolved starting materials.
Scheme 2. Diastereoselective Synthesis of Cyclopentanones
The bicyclic enones that are reported here are significant
in their own right, as a number of drug candidates share the
core structure.18 Furthermore, cyclopropene Pauson-Khand
reactions provide straightforward access to complex cyclo-
pentanones: the three-membered ring strongly influences the
stereochemistry of reactions at the enone, and the three-
membered ring can be cleaved under mild conditions. For
example, Scheme 2 shows that desilylation and hydrogena-
tion provides 13â with high diastereoselectivity, Reductive
ring cleavage15b gives cyclopentanone 14â, which bears all
carbon-quaternary and -tertiary stereocenters. The comple-
mentary diastereomer 14r can be obtained by epimerizing
13â to 13r prior to SmI2 reduction. Notably, the types of
products that are accessible via cyclopropene Pauson-
Khand/reductive cleavage complement those that can be
formed using directed Pauson-Khand methodology.6
In summary, cyclopropenes are a powerful tool for
promoting regio- and stereoselective intermolecular Pauson-
Khand reactions, and we believe that they will find applica-
tions in a host of cycloaddition processes. In future studies,
the many opportunities for stereocontrolled synthesis (e.g.,
stereoselective cuprate additions; specific enolate trapping
upon cyclopropane cleavage) will be explored. Further work
will also be focused on target directed synthesis and
mechanistic understanding of the origin of regio- and
stereoselectivity in the cyclopropene Pauson-Khand reac-
tion.
Acknowledgment. For financial support of this work we
thank NIGMS (NIH R01 GM068650-01A1).
Supporting Information Available: Full experimental
1
and characterization details and H and 13C NMR spectra;
X-ray data in CIF format, 2D-NMR and NOE data are
provided for stereochemical assignments. This material is
available free of charge via the Internet at http://pubs.acs.org.
(18) Schoepp, D. D.; Johnson, B. G.; Wright, R. A.; Salhoff, C. R.;
Mayne, N. G.; Wu, S.; Cockerman, S. L.; Burnett, J. P.; Belegaje, R.;
Bleakman, D.; Monn, J. A. Neuropharmacology 1996, 36, 1.
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