Regioselectivity in the formation of small- and medium-sized cyclic ethers by diene-ene ring-closing metathesis

Article abstract of DOI:10.1021/jo052367y

In the formation of medium-sized ethers by diene-ene ring-closing metathesis, the formation of cyclic allyl ethers with a smaller ring size and of pentadienyl ethers with a larger ring size compete with each other. In the competition between six- and eight-membered and seven- and nine-membered ring formation, the smaller rings are formed exclusively, whereas in the competition between the five- and seven-membered rings, both products are formed in comparable amounts.

Full text of DOI:10.1021/jo052367y

SCHEME 1. Strategy for the Synthesis of Medium-Sized
Cyclic Ethers by Means of Diene-ene RCM, Employing
Differently Substituted Pentadienyl Ethers as Substrates
Regioselectivity in the Formation of Small- and
Medium-Sized Cyclic Ethers by Diene-Ene
Ring-Closing Metathesis
Sudipta Basu and Herbert Waldmann*
Max-Planck-Institut fu¨r molekulare Physiologie, Otto-Hahn
Strasse 11, 44227 Dortmund, Germany, and UnVersita¨t
Dortmund, Fachbereich Chemische Biologie, Otto-Hahn-Str. 6,
44227 Dortmund, Germany
the larger dienyl ethers 2 or the smaller monounsaturated ethers
3 was of particular interest.
herbert.waldmann@mpi-dortmund.mpg.de
ReceiVed NoVember 16, 2005
Results and Discussion
The substrates for the decisive ring-closing reaction were
synthesized via aldehyde 6 as the central intermediate, as shown
in Scheme 2. Commercially available oct-1-yne-3-ol 4 was
converted nearly quantitatively to the alkinyl iodide by treatment
with NIS in the presence of AgNO3,4 and the alcohol was then
alkylated by treatment with bromoacetic acid ethyl ester after
deprotonation with NaH.5
Stereoselective reduction of the alkyne to the Z olefin with
diimide prepared in situ gave vinyl iodide 5 in high yield.4,6
After a Stille reaction with vinyltributyl tin, the resulting dienyl
ether was converted into aldehyde 6 in 75% yield by means of
reduction of the ester to the aldehyde with DIBAL-H in diethyl
ether for 20 min at -78 °C. Aldehyde 6 was then converted
into pentadienyl ethers 7, 10, and 13 by means of established
methods (Scheme 2).4,7 Compounds 10 and 13 embody a free
or a protected alcohol to determine a possible influence of a
coordinating group on the course of the ring-closing reaction.
When subjected to RCM with either 10 mol % of first-
generation Grubbs catalyst 16 or 5 mol % of second-generation
catalyst 17 in refluxing dichloromethane (DCM), dienyl allyl
ether 7 yielded the five- and seven-membered cyclic ethers 8
and 9 in a ratio of 2:3. However, under similar conditions, dienyl
homoallyl ether 10 yielded exclusively the six-membered ether
11, and the formation of the eight-membered ring cyclic ether
12 was not observed at all. While the latter result was not
unexpected, the formation of the seven-membered ring in a
nearly equal amount as the five-membered cyclic ether was
surprising. To investigate whether a seven-membered ring was
also formed predominantly in competition to ring closure to a
In the formation of medium-sized ethers by diene-ene ring-
closing metathesis, the formation of cyclic allyl ethers with
a smaller ring size and of pentadienyl ethers with a larger
ring size compete with each other. In the competition
between six- and eight-membered and seven- and nine-
membered ring formation, the smaller rings are formed
exclusively, whereas in the competition between the five-
and seven-membered rings, both products are formed in
comparable amounts.
Seven-, eight-, and nine-membered oxygen heterocycles with
one or two double bonds embedded into the heterocyclic ring
systems are characteristic structural frameworks of various
natural products.1 In the course of a project aimed at the
synthesis of such natural product frameworks, we became
interested in their synthesis, employing the ring-closing me-
tathesis (RCM) reaction as the key transformation.2 In particular,
the diene-ene RCM reaction employing pentadinenyl ethers 1
as substrates (Scheme 1) attracted our interest because it would
give rise to seven- to nine-membered cyclic dienes that would
be amenable to substantial structural variation by means of
various transformations. The diene-ene RCM has been used
several times in natural-product synthesis3 but not for the
synthesis of small- and medium-sized cyclic ethers. In this
context, the regioselectivity of the reaction giving rise to either
(3) (a) Cabrejas, L. M. M.; Rohrbach, S.; Wagner, D.; Kallen, J.; Zenke,
G.; Wagner, J. Angew Chem., Int. Ed. 1999, 38, 2443-2446. (b) Yang,
Z.-Q.; Danishefsky, S. J. J. Am. Chem. Soc. 2003, 125, 9602-9603 and
the references therein. (c) Biswas, K.; Lin, H.; Njardarson, J. T.; Chappell,
M. D.; Chou, T.-C.; Guan, Y.; Tong, W. P.; He, L.; Horwitz, S. B.;
Danishefsky, S. J. J. Am. Chem. Soc. 2002, 124, 9825-9832. (d) Barluenga,
S.; Lopez, P.; Mpolin, E.; Winssinger, N. Angew Chem., Int. Ed. 2004, 43,
3467-3470. (e) Evano, G.; Schaus, J. V.; Panek, J. S. Org. Lett. 2004, 6,
525-528. (f) Wang, X.; Porco, J. A., Jr. J. Am. Chem. Soc. 2003, 125,
6040-6041.
(4) (a) Shair, M. D.; Yoon, T.; Danishefsky, S. J. J. Org. Chem. 1994,
59, 3755-3757. (b) Bialy, L.; Waldmann, H. Angew Chem., Int. Ed. 2002,
41, 1748-1751. (c) Bialy, L.; Waldmann, H. Chem.sEur. J. 2004, 10,
2759-2780.
* Corresponding author. Fax: (+49) 321-133-2499.
(1) (a) Faulkner, D. J. Nat. Prod. Rep. 1986, 3, 1-33. (b) Himara, M.;
Rainder, J. D. Tetrahedron 2002, 58, xi.
(2) (a) Fu, G. C.; Grubbs, R. H. J. Am. Chem. Soc. 1992, 114, 5426-
5427. (b) Fu, G. C.; Nguyen, S. T.; Grubbs, R. H. J. Am. Chem. Soc. 1993,
115, 9856-9857. (c) Crimmins, M. T.; Choy, A. L. J. Org. Chem. 1997,
62, 7548-7549. (d) Crimmins, M. T.; Choy, A. L. J. Am. Chem. Soc. 1999,
121, 5653-5660. (e) Deiters, A.; Martin, S. F. Chem. ReV. 2004, 104, 2199-
2238. (f) Crimmins, M. T.; McDougall, P. J.; Emmitte, K. A. Org. Lett.
2005, 7, 4033-4036.
(5) Crimmins, M. T.; DeBaillie, A. C. Org. Lett. 2003, 5, 3009-3011.
(6) (a) Denmark, S. E.; Yang, S.-M. J. Am. Chem. Soc. 2002, 124,
15196-15197 (b) Denmark, S. E.; Yang, S.-M. J. Am. Chem. Soc. 2004,
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10.1021/jo052367y CCC: $33.50 © 2006 American Chemical Society
Published on Web 04/14/2006
J. Org. Chem. 2006, 71, 3977-3979
3977

SCHEME 2. Synthesis of the Substrates and Attempted RCM Reactions
nine-membered ring, pentadienyl ether 13 was treated with either
one of the Grubbs catalysts and also with 5 mol % of the
phosphine-free second-generation Hoveyda-Grubbs catalyst 18
in refluxing DCM, and indeed, exclusive formation of the seven-
membered cyclic ether 14 in 65% yield was observed.
catalyst in refluxing toluene did not lead to the formation of
the desired eight- or nine-membered cyclic ethers 20 and 23.
Instead, in both cases, the unreacted starting material was
reisolated. To ascertain that the initial formation of the ruthenium
carbene had occurred, diene 19 was subjected to cross metathesis
with methyl acrylate. Cross metathesis reactions with this
electron-poor olefin proceed via initial carbene formation with
the more electron-rich olefin.8 When 19 was treated with methyl
acrylate and 10 mol % of second-generation Grubbs catalyst in
refluxing DCM, cross metathesis product 21 was isolated in
60% yield. To investigate whether the hydroxyl group in the
substrates 10 or 13 has a determinant role directing the RCM
reaction toward the formation of an alkene rather than a diene,
we synthesized a deoxygenated analogue to 10 by means of
established Wittig homologation and Wittig olefination from
These results indicate that the reaction starts via ruthenium
carbene complex formation at the site of the isolated double
bond, and then the ring closes with a preference for formation
of the smaller ring except in the competition between the five-
and seven-membered rings. Consequently, formation of the
larger rings should occur if the ruthenium carbene would initially
be formed at the diene unit. To investigate this possibility,
aldehyde 6 was converted into pentadienyl ethers 19 and 22 by
means of established methods (Scheme 3). Ethers 19 and 22
carry additional methyl groups at the terminal olefin carbon to
direct the attack of the ruthenium catalyst to the less-substituted
terminal olefin of the diene unit. Treatment of the pentadienyl
ethers 19 and 22 with 20 mol % of second-generation Grubbs
(8) Chatterjee, A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R. H. J. Am.
Chem. Soc. 2000, 122, 3782-3784.
3978 J. Org. Chem., Vol. 71, No. 10, 2006

SCHEME 3. Synthesis of Dienyl Ethers 19 and 22 and Attempted RCM To Yield Eight- and Nine-Membered Cyclic Ethers 20
and 23
aldehyde 6 and subjected it to the RCM conditions using both
16 (10 mol %) or 17 (5 mol %). In these experiments, compound
24 was obtained as the sole product in 62% yield after two steps,
indicating that the hydroxyl does not direct the RCM reaction.
Finally, to investigate whether the ring-closing reaction was
kinetically or thermodynamically controlled, two further experi-
ments were carried out. On one hand, the formation of five-
and seven-membered ethers 8 and 9 was followed by means of
GC-MS. The treatment of dienyl ether 7 with first-generation
Grubbs catalyst 16 in refluxing DCM within 5 min led to
complete consumption of the starting material, and the initially
determined product ratio did not change if the refluxing was
continued for 1 h. At room temperature, the reaction required
2 h to proceed to completion with the product ratio showing
the same distribution. If the seven-membered cyclic dienyl ether
9 was subjected to the conditions of the RCM, that is, reflux in
DCM in the presence of 10 mol % of first-generation Grubbs
catalyst and in the mixture of ethylene for 3 h, formation of the
five-membered cyclic ether 8 was observed by GC-MS. As-
suming that the five-membered ring ether is more stable than
the seven-membered ring ether, these results indicate that this
RCM reaction is thermodynamically controlled. We note that
this may be different for the analogous formation of 11 or 12
from 10 and of 14 or 15 from intermediate 13.
In conclusion, we have shown that in the attempted formation
of medium-sized cyclic ethers by means of the diene-ene RCM,
with the exception of the competition between five- and seven-
membered rings, the smaller ring sizes are formed.
Experimental Section
General Procedure for the Ring-Closing Metathesis: The
triene was dissolved in dry degassed DCM (0.002M) in a two-
neck round-bottom flask under argon. The Grubbs catalyst was
added, and the solution was stirred at reflux until the starting
material was totally consumed (monitored by TLC). The solvent
was evaporated, and the crude product was subjected to column
chromatography.
Acknowledgment. This research was financially supported
by the International Max-Planck Research School in Chemical
Biology (IMPRS-CB).
Supporting Information Available: Full experimental details
and spectral characterization of all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO052367Y
J. Org. Chem, Vol. 71, No. 10, 2006 3979