Triple Ring Closing Metathesis Reaction: Synthesis of Adjacent Cyclic Ethers

Article abstract of DOI:10.1021/ol0159625

(formula presented) Adjacent tris(cyclic ethers) and enol ethers have been synthesized in good yields for the first time via a triple olefin metathesis reaction using Grubbs' catalyst RuCl₂(=C(H)Ph)(PCy₃)₂ (Cy = cyclohexyl

Full text of DOI:10.1021/ol0159625

ORGANIC
LETTERS
2001
Vol. 3, No. 13
1989-1991
Triple Ring Closing Metathesis
Reaction: Synthesis of Adjacent Cyclic
Ethers
,†
Marie-Pierre Heck,* Christophe Baylon,† Steven P. Nolan,§ and
,†,‡
Charles Mioskowski*
CEA-CE Saclay, SerVice des Mole´cules Marque´es, Baˆt 547, De´partement de Biologie
Cellulaire et Mole´culaire, F-91191 Gif sur YVette cedex, France
heck@dsVidf.cea.fr
Received April 9, 2001
ABSTRACT
Adjacent tris(cyclic ethers) and enol ethers have been synthesized in good yields for the first time via a triple olefin metathesis reaction using
Grubbs’ catalyst RuCl2(dC(H)Ph)(PCy3)2 (Cy ) cyclohexyl), and the 1,3-dimesitylimidazol-2-ylidene ruthenium benzylidene catalyst RuCl2(d
C(H)Ph)(PCy3)(IMes) ((IMes) ) 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene). The latter proved to be the most efficient catalyst in these
transformations.
Although there are many methods for preparing cyclic
structures in organic chemistry,1 the ring closing metathesis
(RCM)2 of R,ω-dienes has emerged as a powerful synthetic
tool for the construction of various ring systems. This is
mainly due to the discovery of highly reactive (molybdenum
alkylidene) and more stable (ruthenium alkylidene) catalysts.3
Recent reports from our laboratory and others have shown
a catalytic tetraene double ring closing metathesis reaction
to be a useful protocol for the formation of bicyclic ethers.4
To extend the scope of these studies, we explored the possible
formation of triadjacent cyclic ethers by a ring closing
metathesis reaction involving an acyclic hexaene system as
outlined in Scheme 1. Acyclic hexaenes can formally
undergo ring closing metathesis through two different modes,
leading to two different types of products: contiguous
tris(cyclic ethers) stemming from selective triple metathesis
through mode a or/and bicyclic carbocycles resulting from
a double cyclization through mode b. In our previous studies
on the cyclization of tetraene by RCM,4a we found that the
formation of five- and six-membered ring cyclic ethers was
favored over the formation of carbocycles.
† CEA-CE Saclay, France.
§ Department of Chemistry, University of New Orleans, New Orleans,
LA 70148.
‡ Laboratoire de Synthe`se Bio-organique, Faculte´ de Pharmacie, Uni-
versite´ Louis Pasteur, 74 route du Rhin BP24, F-67401. E-mail: mioskow@
aspirine.u-strasbg.fr.
(1) (a) Yet, L. Chem. ReV. 2000, 100, 2963-3007. (b) Elliot, M. C. J.
Chem. Soc., Perkin Trans. 1 2000, 1291-1318.
(2) For recent reviews, see: (a) Grubbs, R. H.; Chang, S. Tetrahedron
1998, 54, 4413-4450. (b) Armstrong, S. K. J. Chem. Soc., Perkin Trans.
1 1998, 371-388. (c) Schuster, M.; Blechert, S. Angew. Chem., Int. Ed.
Engl. 1997, 36, 2036-2056. (d) Fu¨rstner, A. Angew. Chem., Int. Ed. 2000,
39, 3012-3043.
(3) (a) Schrock, R. R.; Murdzek, J. S.; Bazan, G. C.; Robin, J.; Dimane,
M.; O’Regan, M. J. Am. Chem. Soc. 1990, 112, 3875-3886. (b) Schwab,
P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996, 118, 100-110. (c)
Huang, J.; Stevens, E. D.; Nolan, S. P. J. Am. Chem. Soc. 1999, 121, 2674-
2678. (d) Scholl, M.; Trnka, T. M.; Morgan, J. P.; Grubbs, R. H. Tetrahedron
Lett. 1999, 121, 2674-2678. (e) Ackermann, L.; Fu¨rstner, A.; Weskamp,
T.; Kohl, F. J.; Herrmann, W. A. Tetrahedron Lett. 1999, 40, 4787-4790.
(f) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953-956. (g) Jafarpour, L.; Huang, J.; Stevens, E. D.; Nolan, S. P.
Organometallics 1999, 18, 3760-3763. (h) Jafarpour, L.; Nolan, S. P.
Organometallics 2000, 11, 2055-2057. (i) Jafarpour, L.; Nolan, S. P. AdV.
Organomet. Chem. 2000, 46, 181-222. (j) Jafarpour, L.; Nolan, S. P. J.
Organomet. Chem. 2001, 617, 17-27.
(4) (a) Baylon, C.; Heck, M.-P.; Mioskowski, C. J. Org. Chem. 1999,
64, 3354-3360. (b) Bassindale, M. J.; Hamley, P.; Leitner, A.; Harrity, J.
P. A. Tetrahedron Lett. 1999, 40, 3247-3250. (c) Wallace, D. J.; Cowden,
C. J.; Kennedy, D. J.; Ashwood, M. S.; Cottrell, I. F.; Dolling, U. H.
Tetrahedron Lett. 2000, 41, 2027-2029. (d) Lautens, M.; Hughes, G.
Angew. Chem., Int. Ed. 1999, 38, 129-131. (e) Clark, J. S.; Hamelin, O.
Angew. Chem., Int. Ed. 39, 372-374.
10.1021/ol0159625 CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/07/2001

Scheme 1. RCM Reactions of Acyclic Hexaene
Scheme 3. Preparation of the Acyclic Hexaenes
We now extend this study to the reactivity of acyclic
hexaenes and find similar results indicating that mode a
(Scheme 1), leading only to adjacent tris(cyclic ethers), is
the preferred reaction pathway. Interestingly, we observe that
formation of these three contiguous ring systems proceeds
either through simultaneous or consecutive triple RCM
reactions. Using Grubbs’ catalyst A, RuCl2(dC(H)Ph)(PCy3)2
(Cy ) cyclohexyl), or the ruthenium-based imidazolinylidene
complex B, RuCl2(dC(H)Ph)(PCy3)(IMes) (IMes ) 1,3-bis-
(2,4,6-trimethylphenyl)imidazol-2-ylidene), adjacent tris-
(cyclic ethers) were prepared in good yields and generated
as single products (Scheme 2).
3. Treatment of 3 with 3,4-dimethoxybenzyl alcohol
(DMPMOH)10 yielded the easily separable mixture of
alcohols 4 and 5. Alkylation of compound 4 with allyl
bromide gave 6 which was deprotected with DDQ to afford
vinyl alcohol 7. Stereo-and regiospecific ring opening of
epoxide 3 with 7 gave 10 which was alkylated to the
corresponding hexaene 11. Isomerization of 11 using Wilkin-
son’s catalyst afforded hexaenes 12 and 13. Hexaene 9 was
prepared by deprotection of alcohol 5 with DDQ, followed
by dialkylation with allyl bromide.
The four acyclic hexaenes 9, 11, 12, and 13 were then
submitted to our typical metathesis reaction conditions.11 The
results obtained are summarized in Table 1 and constitute
the first examples of a triple RCM reaction.
First, we investigated the reactivity of hexaene 9 with
Grubbs’ catalyst A (entry 1). After 2 h, a single product was
isolated and identified as a compound bearing three contigu-
ous cyclic ethers 14 resulting from a triple RCM (65% yield).
Then substrate 11 was subjected to Grubbs’ catalyst A under
identical conditions (entry 2). Surprisingly, only the bicyclic
ether 15 (69% yield) resulting from a double metathesis
reaction was obtained. In this case, the central diallyl ether
Scheme 2. RCM Catalysts
Cyclic polyethers are interesting structures due to their
ability to chelate metallic cations, conferring them ionophore
properties.5 Moreover, the three contiguous tetrahydrofuranic
motive (n ) 0) constitute the core structure of natural type
D acetogenin which reveals a wide variety of biological
activities.6
The syntheses of the acyclic hexaenes are outlined in
Scheme 3. The strategy involves the preparation of vinyl
epoxide 3, followed by its ring opening with various alcohols.
The precursor 2,5-hexadien-1-ol 1 was synthesized in two
steps from propargylic alcohol following a described pro-
cedure.7 Asymmetric epoxidation of 1 using the Sharpless
process8 gave epoxy alcohol 29 which was oxidized and
submitted to Wittig olefination to afford vinyl epoxide
(8) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.;
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765-5780.
(9) 19F NMR of Mosher’s esters showed ee’s >99% for 2.
(10) Prestat, G.; Baylon, C.; Heck, M.-P.; Mioskowski, C. Tetrahedron
Lett. 2000, 41, 3829-3831.
(11) Representative procedure: A solution of acyclic hexaene in dry
solvent (typical concentration 0.02 M in CH2Cl2 or toluene) with a catalytic
amount of ruthenium benzylidene A or B (5 mol %) was stirred at room
temperature or 80 °C (see Table 1). After disappearance of the starting
material, the reaction mixture was concentrated and purified on silica gel
to yield the tricyclic compound.
(5) Wang, X.; Erickson, S. D.; Iimori, T.; Still, W. C. J. Am. Chem.
Soc. 1992, 114, 4128-4137.
(6) (a) Figade`re, B.; Cave´, A. Studies in Natural Products Chemistry. In
StereoselectiVe Synthesis; Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, 1996;
Vol. 18, pp 193-227. (b) Gu, Z.-m.; Fang, X.-p.; Zeng, L.; McLaughlin,
J. L. Tetrahedron Lett. 1994, 35, 5367-5368.
(7) For experimental procedure, see: (a) Appa Rao, J.; Cava, M. P. J.
Org. Chem. 1989, 54, 2751-2753. (b) Taber, D. F.; You, K. J. Org. Chem.
1995, 60, 139-142.
1990
Org. Lett., Vol. 3, No. 13, 2001

found to be a more effective RCM catalyst for cyclizing the
central five-membered ring. Using Grubbs’ catalyst A, we
have shown that the RCM of the two lateral cycles 6-5-
membered rings (entry 1) or 6-6-membered rings (entry 2)
were rapidly completed. Nonetheless, the cyclization of the
central five-membered ring system (entry 2) was rather
sluggish compared to the formation of the central six-
membered ring (entry 1). In this case, catalyst B was required
to achieve useful dihydrofuran cyclization (entry 4).
We completed our studies by subjecting hexaenes 12 and
13 to RCM reaction with catalyst B. In both cases tricon-
tiguous cyclic ethers 17 and enol ether 18 were isolated as
single products in 55% and 62% yields, respectively (entries
5 and 6). The use of Grubbs’ catalyst A with these substrates
leads to incomplete cyclizations. It is noteworthy that
compound 18 possesses three adjacent five-membered ring
ethers which are present in several natural type D acetoge-
nins.
Table 1. Results of the RCM of Hexaenes
In conclusion, the first selective triple RCM reaction of
acyclic hexaenes leading to triadjacent cyclic ethers in good
yields (55-75%) is reported. The 1,3-dimesitylimidazol-2-
ylidene-modified ruthenium benzylidene catalyst proved to
be more efficient for tricyclization reactions of various
hexaenes than Grubbs’ catalyst.
Further studies aimed at probing the general use of this
triple RCM reaction for the synthesis of poly-THF products
and for the use of the very efficient ruthenium-based
imidazolylidene complex catalyst in a variety of metathesis
reactions are ongoing.
did not undergo cyclization to form the expected 2,5-
dihydrofuran. Under prolonged reaction time and by further
catalyst additions, no tris-(cyclic) compound was observed
in situ. However, when bicyclic compound 15 was isolated
and resubmitted to RCM conditions with successive additions
of catalyst A (30% mol), compound 16 resulting from a triple
RCM was isolated in 59% yield after 8 days (entry 3).
In view of the increased thermal stability and higher
reactivity displayed by olefin metathesis catalyst B, the RCM
reaction was performed on substrate 11 using the imidazol-
2-ylidene-modified ruthenium catalyst. This RCM reaction
afforded directly the triadjacent cyclic ether 16 in 75% yield
after only 4 h in toluene at 70 °C (entry 4). Catalyst B was
Acknowledgment. S.P.N. acknowledges the National
Science Foundation, the Louisiana Board of Regents, and
the Petroleum Research Fund, administered by the American
Chemical Society, for partial support of this work. The
authors thank Alain Valleix for mass spectra data and helpful
discussions.
Supporting Information Available: Experimental pro-
cedure and 1H NMR, 13C NMR, MS, and IR for compounds
2-18. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL0159625
Org. Lett., Vol. 3, No. 13, 2001
1991