On the reversible nature of the olefin cross metathesis reaction [8]

Full text of DOI:10.1021/ja003745d

990
J. Am. Chem. Soc. 2001, 123, 990-991
Scheme 1
On the Reversible Nature of the Olefin Cross
Metathesis Reaction
Amos B. Smith, III,* Christopher M. Adams, and
Sergey A. Kozmin†
Department of Chemistry
Monell Chemical Senses Center, and
Laboratory for Research on the Structure of Matter
UniVersity of PennsylVania
Philadelphia, PennsylVania 19104
ReceiVed October 23, 2000
The olefin ring-closing metathesis (RCM) reaction has emerged
as one of the most powerful transforms in organic synthesis.1
Indeed, the broad scope and reliability of this reaction has greatly
simplified the total synthesis of a wide variety of architecturally
complex natural and unnatural products.2 We first became
interested in the metathesis process during the synthesis of a
family of novel naturally occurring paracyclophanes known as
the cylindrocyclophanes (A-F).3,4
catalysts,5 with the Schrock catalyst furnishing the best yield
(72%).4c The observation of only one of the seven possible dimers
[(-)-3] suggested a cascade of reversible olefin metatheses,6 a
result supported by recent work from the Grubbs and Hoveyda
laboratories demonstrating the reversible nature of the olefin
metathesis reaction.7
To explore the observed selectivity of this olefin dimerization,
we carried out a series of Monte Carlo conformational searches8
using the MM2 force field9 (Macromodel 6.0). The calculations
indicated that the [7,7]-E,E-macrocycle (3) indeed possesses the
lowest-energy structure by ∼2.6-4.7 kcal/mol relative to the other
possible dimers (Figure 1),10 indicating that the naturally occurring
[7,7]-paracyclophane skeleton is the thermodynamically most
stable.
During the course of this venture we demonstrated that cross
metathesis dimerization (Scheme 1) provides an efficient tactic
for the construction of the C2-symmetric skeleton of the
cylindrocyclophanes.4c Of the seven possible cyclic dimers of (-)-
2, including those having either seven carbons between the
aromatic rings (3-5) or eight and six carbons (6-9), only (-)-3
was observed when subjected to either the Grubbs or Schrock
† Current address: Department of Chemistry, University of Chicago.
(1) For recent reviews on olefin metathesis, see: (a) Grubbs, R. H.; Chang,
S. Tetarhedron 1998, 54, 4413. (b) Armstrong, S. K. J. Chem. Soc., Perkin
Trans. 1 1998, 371. (c) Wright, D. L. Curr. Org. Chem. 1999, 3, 211. (d)
Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012.
Figure 1. Energy values for the lowest-energy conformation of the seven
possible geometrical/constitutional isomers (see Scheme 2).
(2) (a) Fu¨rstner, A.; Langemann, K. J. Org. Chem. 1996, 61, 8746 (b) Kim,
S. H.; Figueroa, I.; Fuchs, P. L. Tetrahedron Lett. 1997, 38, 2601. (c) Meng,
D.; Bertinato, P.; Balog, A.; Su, D.; Kamenecka, T.; Sorensen, E. J.;
Danishefsky, S. J. J. Am. Chem. Soc. 1997, 119, 10073. (d) Scholl, M.; Grubbs,
R. H. Tetrahedron Lett. 1999, 40, 1425. (e) Dixon, D. J.; Foster, A. C.; Ley,
S. V. Org. Lett. 2000, 2, 123. (f) Lee, D.; Sello, J. K.; Schreiber, S. L. J. Am.
Chem. Soc. 1999, 121, 10648 (g) Paquette, L. A.; Tae, J.; Arrington, M. P.;
Sadoun, A. H. J. Am. Chem. Soc. 2000, 122, 2742.
(3) (a) Moore, B. S.; Chen, J.-L.; Patterson, G. M.; Moore, R. M.; Brinen,
L. S.; Kato, Y.; Clardy, J. J. Am. Chem. Soc. 1990, 112, 4061. (b) Moore, B.
S.; Chen, J.-L.; Patterson, G. M.; Moore, R. E. Tetrahedron 1992, 48, 3001.
(c) Bobzin, S. C.; Moore, R. E. Tetrahedron 1993, 49, 7615.
(4) For recent syntheses of the cylindrocyclophanes see: (a) Smith, A. B.,
III; Kozmin, S. A.; Paone, D. V. J. Am. Chem. Soc. 1999, 121, 7423. (b)
Hoye, T. R.; Humpal, P. E.; Moon, B. J. Am. Soc. Chem. 2000, 122, 4982.
(c) Smith, A. B., III; Kozmin, S. A.; Adams, C. M.; Paone, D. V. J. Am.
Chem. Soc. 2000, 122, 4984.
To provide experimental evidence for the reversible cascade
of the olefin metatheses in the dimerization of (-)-2, we selected
trienes 14 and 15, both predisposed to form the [8,6]-macrocycle
(5) (a) Schrock R. R.; Murdzek, JS.; Bazan, G. C.; Robbins, J.; DiMare,
M.; O’Reagan, M. J. Am. Chem. Soc. 1990, 112, 3875. (b) Schwab, P.; France,
M. B.; Ziller, J. W. Grubbs, R. H. Angew. Chem., Int. Ed. Engl. 1995, 34,
2039. (c) Scholl, M.; Ding, S.; Lee, C. W. Grubbs, R. H.; Org. Lett. 1999, 1,
953.
(6) For another example see: Fu¨rstner, A.; Thiel, O. R.; Ackermann, L.
Org. Lett. 2001, 3, 449-452. We thank Professor Fu¨rstner for informing us
about his results prior to publication.
(7) (a) Marsella, N. J.; Maynard, H. D.; Grubbs, R. H. Angew. Chem., Int.
Ed. Engl. 1997, 36, 1101. (b) Xu, Z.; Johannes, C. W.; Houri, A. F.; La, D.
S.; Cogan, D. A.; Hofilena, G. E.; Hoveyda, A. H. J. Am. Chem. Soc. 1997,
119, 10302. (c) Lee, C. W.; Grubbs, R. H. Org. Lett. 2000, 2, 2145.
10.1021/ja003745d CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/12/2001

Communications to the Editor
J. Am. Chem. Soc., Vol. 123, No. 5, 2001 991
Scheme 2
Scheme 3
With experimental support for the reversibility of the cross
olefin metathesis in the dimerization of (-)-2, we sought to
explore the feasibility of preparing the high-energy [8,6]-
cyclophane congeners via olefin metathesis. Our intent was to
mask the C(4,5) olefin of (-)-14 as an epoxide, assemble the
[8,6]-paracyclophane via RCM, and then reinstall the C(4,5)
olefin. Toward this end, chemoselective epoxidation of the C(4,5)
disubstituted olefin in (-)-14 was envisioned (Scheme 4);
epoxidation from either face would give the same product, due
to the inherent C2-symmetry of (-)-14. Use of mCPBA in a
variety of solvents however led to (-)-16 in low yield (<25%)
due to competing oxidation of the electron-rich aromatic systems.
After significant experimentation we discovered that dimethyl-
dioxirane (DMDO) provided useful amounts of epoxide (-)-16,
albeit again in modest yield (43%, 66% based on recovered
starting material). Unfortunately, all attempts at RCM with either
the Schrock5a or the Grubbs catalysts5b,c led either to no reaction
or polymerization. This observation supports the Monte Carlo
calculations, indicating the relative high energy of the [8,6]-
paracyclophane skeleton.
via RCM (Scheme 2). The conversion of 14 and 15 to the [7,7]-
macrocycle (-)-3 instead of the analogous RCM products would
provide clear evidence for the proposed reversible cascade.
We envisioned that Kocienski-modified Julia11 and Wittig12
olefinations with (+)-11 would provide ready access to the
requisite Z and E trienes, 14 and 15, respectively. The required
common aldehyde (+)-11 was prepared in high yield via Dess-
Martin oxidation13 of known alcohol (+)-10.4a For the Wittig salt
(-)-12, iodination of (+)-10 (I2, PPh3, imidazole), followed by
treatment with PPh3 in acetonitrile at reflux furnished (-)-12 in
86% (two steps). For sulfone (-)-13, Mitsunobu reaction14 of
(+)-10 with 1-phenyl-1H-tetrazole-S-thiol followed by hydrogen
peroxide oxidation promoted by ammonium heptamolybdate
tetrahydrate15 led to (-)-13 in 83% (two steps). With the coupling
partners in hand, treatment of Wittig salt (-)-12 with KHMDS
at -78 °C followed by addition of aldehyde (+)-11 furnished
the Z-triene (-)-14 (88% yield, dr > 15:1). In a similar fashion,
deprotonation of sulfone (-)-13 with KHMDS followed by
addition of aldehyde (+)-11 furnished (-)-15 in 74% yield (dr
> 15:1).
Scheme 4
Both trienes were subjected to the Schrock catalyst (Scheme
3), employing conditions identical to the dimerization of (-)-2
(32-35 mol %, 20 °C, C6H6). Although the substrates were
predisposed to form the [8,6]-cyclophane, only the [7,7]-E,E-
paracyclophane (-)-3 was observed in yields ranging from 75 to
81%. Presumably both substrates undergo a cascade of reversible
olefin metathesis reactions which eventually led to the [7,7]-E,E-
paracyclophane.
In summary, the conversion of (-)-14 and (-)-15 to (-)-3
establishes unambiguously that the ring-closing metathesis pro-
tocol can lead to the thermodynamically most stable member of
a set of structurally related isomers. This self-editing process has
important strategic implications for the design and implementation
of future synthetic strategies.
(8) Mohamadi, F.; Richards, N. G. J.; Guida, W. C.; Liskamp, R.; Lipton,
M.; Caufield, C.; Chang, G.; Hendrickson, T.; Still, W. C. J. Comput. Chem.
1990, 11, 440.
Acknowledgment. We thank Professor Grubbs for a generous sample
of perhydroimidazolidine catalyst, and Professor Kozlowski for useful
comments regarding molecular modeling. Support was provided by the
National Cancer Institute through Grant CA 19033.
(9) Allinger, N. L. J. Am. Chem. Soc. 1977, 99, 8127
(10) To simplify the calculations the butyl chains, in isomers 3-9, were
replaced with methyl groups.
(11) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett
1998, 26.
(12) (a) Wittig, G.; Geissler, G. Liebigs Ann. Chem. 1953, 580, 44 (b)
Maryanoff, B. E. Reitz, A. B. Chem. ReV. 1989, 89, 863.
(13) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(14) (a) Loibnen, H.; Zbiral, E. HelV. Chim. Acta 1976, 59, 2100. (b)
Mitsunobu, O. Synthesis 1981, 1.
(15) Schultz, H. S.; Freyermuth, H. B.; Buc, S. R. J. Org. Chem. 1963,
28, 1140.
Supporting Information Available: Spectroscopic and analytical data
for compounds 3, 10-16 and selected experimental procedures. This
material is available free of charge via the Internet at http://pubs.acs.org.
JA003745D