Bis Ring Closing Olefin Metathesis for the Synthesis of Unsaturated Polycyclic Ethers. O-Membered Ring Cyclization in Favor of C-Membered Ring Cyclization

Full text of DOI:10.1021/jo982098u

3354
J . Org. Chem. 1999, 64, 3354-3360
of relatively strained cycloalkenes,6 substituted cyclic
olefins,7 O- or N-containing heterocycles,8 and macro-
cycles.9 More recently, some selective olefin cross-meta-
theses10 have been introduced as well as solid-phase ring
closing metathesis reactions.11 To date, many total
syntheses of natural products have employed a meta-
thesis key step.12
Bis Rin g Closin g Olefin Meta th esis for th e
Syn th esis of Un sa tu r a ted P olycyclic
Eth er s. O-Mem ber ed Rin g Cycliza tion in
F a vor of C-Mem ber ed Rin g Cycliza tion
Christophe Baylon,† Marie-Pierre Heck,†,‡ and
Charles Mioskowski*,†,§,|
While the use of ring closing metathesis for the syn-
thesis of unsaturated oxygen and nitrogen heterocycles,4-8
phospholenes and cyclic phosphonates,13 cyclic silyloxy
olefins,14 and thiophenes15 is fully documented, these
methods are generally limited to a single cyclization step
CEA, CE-Saclay, Service des Mole´cules Marque´es, Baˆt 547,
De´partement de Biologie Cellulaire et Mole´culaire,
91191 Gif Sur Yvette, France, and Laboratoire de Synthe`se
Bio-Organique associe´ au CNRS, Faculte´ de Pharmacie,
Universite´ Louis Pasteur, 74 route du Rhin BP 24,
67401 Illkirch, France
(5) (a) Nguyen, S. T.; Grubbs, R. H.; Ziller, J . W. J . Am. Chem. Soc.
1993, 115, 9858. (b) Schwab, P.; France, M. B.; Ziller, J . W.; Grubbs,
R. H. Angew. Chem., Int. Ed. Engl. 1995, 34, 2039. (c) Wu, Z.; Nguyen,
S. T.; Grubbs, R. H.; Ziller, J . W. J . Am. Chem. Soc. 1995, 117, 5503.
(d) Schwab, P.; Grubbs, R. H.; Ziller, J . W. J . Am. Chem. Soc. 1996,
118, 100.
(6) (a) Tsuji, J . Tetrahedron Lett. 1980, 21, 2955. (b) Villemin, D.
Tetrahedron Lett. 1980, 21, 1715. (c) Schmalz, H.-G. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 1833. (d) Fu, G. C.; Grubbs, R. H. J . Am. Chem.
Soc. 1993, 115, 3800. (e) See ref 1. (f) McKervey, M. A.; Pitarch, M.
Chem. Commun. 1996, 1689. (g) Martin, S. F.; Chen, H.-J .; Courtney,
A. K.; Liao, Y.; Pa¨tzel, M.; Ramser, M. N.; Wagman, A. S. Tetrahedron
1996, 52, 7251.
Received October 19, 1998
In tr od u ction
Since first being reported more than thirty years ago,1
the metathesis of olefins to produce carbon-carbon
double bonds has been of great synthetic interest, notable
for ring opening metathesis polymerization (ROMP).2 In
recent years this metal-catalyzed exchange of alkylidene
groups has been further studied resulting in the develop-
ment of new catalysts, mainly by Osborn (tungsten),3
Schrock (tungsten and molybdenum),4 and Grubbs (ru-
thenium).5 These metals exhibit high metathesis activity
and stability toward functional groups, and since their
discovery, many reports have been published on the
subject of ring closing metathesis (RCM) for the formation
(7) Grubbs, R. H.; Kirkland, T. A. J . Org. Chem. 1997, 62, 7310 and
references cited therein.
(8) (a) Fujimura, O. F.; Fu, G. C.; Grubbs, R. H. J . Org. Chem. 1994,
59, 4029. (b) Fu, G. C.; Grubbs, R. H. J . Am. Chem. Soc. 1992, 114,
7324. (c) Fu, G. C.; Nguyen, S. T.; Grubbs, R. H. J . Am. Chem. Soc.
1993, 115, 9856. (d) Miller, S. J .; Blackwell, H. E.; Grubbs, R. H. J .
Am. Chem. Soc. 1996, 118, 9606. (e) Visser, M. S.; Heron, N. M.; Didiuk,
M. T.; Sagal, J . F.; Hoveyday, A. M. J . Am. Chem. Soc. 1996, 118, 4291.
(f) Nicolaou, K. C.; Postema, M. H. D.; Clairbone, C. F. J . Am. Chem.
Soc. 1996, 118, 1565. (g) Marsella, M. J .; Maynard, H. D.; Grubbs, R.
H. Angew. Chem., Int. Ed. Engl. 1997, 36, 1101. (h) Ghosh, A. K.;
Cappiello, J .; Shin, D. Tetrahedron Lett. 1998, 39, 4651.
(9) (a) Fu¨rstner, A.; Langemann, K. J . Org. Chem. 1996, 61, 3942.
(b) Winkler, J . D.; Stelmach, J . E.; Axten, J . Tetrahedron Lett. 1996,
37, 4317. (c) Huwe, C. M.; Kiehl, O.; Blechert, S. Synlett 1996, 65. (d)
Ho¨lder, S.; Blechert, S. Synlett 1996, 505. (e) Miller, S. J .; Kim, S.-H.;
Chen, Z.-R.; Grubbs, R. H. J . Am. Chem. Soc. 1995, 117, 2108. (f)
Fu¨rstner, A.; Langemann, K. Synthesis 1997, 792. (g) Fu¨rstner, A.;
Mu¨ller, T. Synlett 1997, 1010.
(10) (a) Crowe, W. E.; Zhang, Z. J . J . Am. Chem. Soc. 1993, 115,
10998. (b) Crowe, W. E.; Goldberg, D. R. J . Am. Chem. Soc. 1995, 117,
5162. (c) Crowe, W. E.; Goldberg, D. R.; Zhang, Z. J . Tetrahedron Lett.
1996, 37, 2117. (d) Barrett, A. G. M.; Beall, J . C.; Giles, M. R.; Walker,
G. L. P. Chem. Commun. 1996, 2229. (e) Snapper, M. L.; Tallarico, J .
A.; Randall, M. L. J . Am. Chem. Soc. 1997, 119, 1478. (f) Schneider,
M. F.; Blechert, S. Angew. Chem., Int. Ed. Engl. 1996, 35, 411. (g)
Bru¨mmer, O.; Ru¨ckert, A.; Blechert, S. Chem. Eur. J . 1997, 3, 441.
(11) (a) Schuster, M.; Pernerstorfer, J .; Blechert, S. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 1979. (b) van Maarseveen, J . H.; den Hartog,
J . A. J .; Engelen, V.; Finner, E.; Visser, G.; Kruse, C. G. Tetrahedron
Lett. 1996, 37, 8249. (c) Peters, J . U.; Blechert, S. Synlett 1997, 348.
(d) Boger, D. L.; Chai, W.; Ozer, R. S.; Andersson, C.-M. Bioorg. Med.
Chem. Lett. 1997, 7, 463. (e) Nicolaou, K. C.; Vourloumis, D.; Li, T.;
Pastor, J .; Winssinger, N.; He, Y.; Ninkovic, S.; King, N. P.; Finlay,
M. R. V.; Giannakakou, P.; Verdier-Pinard, P.; Hamel, E. Angew.
Chem., Int. Ed. Engl. 1997, 36, 2097.
(12) (a) Plugge, M. F. C.; Mol, J . C. Synlett 1991, 507. (b) Borer, B.
C.; Deerenberg, S.; Biera¨ugel, H.; Pandit, U. K. Tetrahedron Lett. 1994,
35, 3191. (c) Martin, S. F.; Liao, Y.; Wong, Y.; Rein, T. Tetrahedron
Lett. 1994, 35, 691. (d) Martin, S. F.; Wagman, A. L. Tetrahedron Lett.
1995, 36, 1169. (e) Xu, Z.; J ohannes, C. W.; Salman, S. S.; Hoveyda,
A. M. J . Am. Chem. Soc. 1996, 118, 10926. (f) Fu¨rstner, A.; Langemann,
K. J . Org. Chem. 1996, 61, 8746. (g) Lim, H.-J .; Sulikowski, G. A.
Tetrahedron Lett. 1996, 37, 5243. (h) Fu¨rstner, A.; Kindler, N.
Tetrahedron Lett. 1996, 37, 7005. (i) Ho¨lder, S.; Blechert, S. Synlett
1996, 505. (j) Nicolaou, K. C.; He, Y.; Vourloumis, D.; Vallberg, H.;
Yang, Z. Angew Chem., Int. Ed. Engl. 1996, 35, 2399. (k) Pandit, U.
K.; Borer, B. C.; Biera¨ugel, H. Pure Appl. Chem. 1996, 68, 659. (l)
Bertinalo, P.; Sorensen, E. J .; Meng, D.; Danishefsky, S. J . J . Org.
Chem. 1996, 61, 8000. (m) Fu¨rstner, A.; Langemann, K. J . Am. Chem.
Soc. 1997, 119, 9130. (n) Yang, Z.; He, Y.; Vourloumis, D.; Vallberg,
H.; Nicolaou, K. C. Angew Chem. Int. Ed. Engl. 1997, 36, 166. (o) Meng,
D.; Bertinalo, P.; Balog, A.; Su, D.-S.; Kamenecka, T.; Sorensen, E. J .;
Danishefsky, S. J . J . Am. Chem. Soc. 1997, 119, 10073.
† CEA.
‡ Phone: +33(0)169086352. e-mail: heck@dsvidf.cea.fr. Fax: +33-
(0)169087991.
§ Universite´ Louis Pasteur.
| Phone: +33(0)388676863. e-mail: mioskow@bioorga.u-strasbg.fr.
Fax: +33(0)388678891.
(1) (a) Calderon, N.; Chen, H. Y.; Scott, K. W. Tetrahedron Lett.
1967, 3327. (b) Calderon, N.; Ofstead, E. A.; Ward, J . P.; J udy, W. A.;
Scott, K. J . Am. Chem. Soc. 1968, 90, 4133. (c) Wang, J .-L.; Menapace,
H. R. J . Org. Chem. 1968, 33, 3794. (d) Herisson, J .-L.; Chauvin, Y.
Makromol. Chem. 1970, 141, 161. (e) Hocks, L. Bull. Soc. Chim. Fr.
1975, 1893. (f) Calderon, N.; Ofstead, E. A.; J udy, W. A. Angew. Chem.,
Int. Ed. Engl. 1976, 15, 401. (g) Grubbs, R. H.; Pine, S. H. In
Comprehensive Organic Synthesis, Vol. 5; Trost, B. M., Fleming, L.
A., Paquette, L. A., Eds.; Pergamon: New York, 1991; Chapter 9.3.
(h) Grubbs, R. H.; Tumas, W. Science 1989, 243, 907. (i) Grubbs, R.
H.; Miller, S. J .; Fu, G. C. Acc. Chem. Res. 1995, 28, 446. (j) Schuster,
M.; Blechert, S. Angew. Chem., Int. Ed. Engl. 1997, 36, 2036.
(2) (a) Natta, G.; Dall’asta, G.; Mazzanti, G. Angew. Chem., Int. Ed.
Engl. 1964, 3, 723. (b) Grubbs, R. H. In Comprehensive Organometallic
Chemistry; Wilkinson, G., Ed.; Pergamon: Oxford, 1982; Vol. 8, pp
499-551. (c) Grubbs, R. H.; Gilliom, L. R. J . Am. Chem. Soc. 1986,
108, 733. (d) Swager, T. M.; Grubbs, R. H. J . Am. Chem. Soc. 1987,
109, 894. (e) Schrock, R. R.; Feldman, J .; Cannizzo, L. F.; Grubbs, R.
H. Macromolecules 1987, 20, 1169. (f) Cannizo, L. F.; Grubbs, R. H.
Macromolecules 1987, 20, 1488. (g) Bazan, G. C.; Khosravi, E.; Schrock,
R. R.; Feast, W. J .; Gibson, V. C.; O’Regan, M. B.; Thomas, J . K.; Davis,
W. M. J . Am. Chem. Soc. 1990, 112, 8378. (h) Gorman, C. B.; Ginsburg,
E. J .; Grubbs, R. H. J . Am. Chem. Soc. 1993, 115, 1397.
(3) (a) Kress, J .; Osborn, J . A.; Amir-Ebrahimi, V.; Ivin, K. J .;
Rooney, J . J . J . Chem. Soc., Chem. Commun. 1988, 1164. (b) Ivin, K.
J .; Kress, J .; Osborn, J . A. J . Mol. Catal. 1988, 46, 351. (c) Greene, R.
M. E.; Ivin, K. J .; Rooney, J . J .; Kress, J .; Osborn, J . A. Makromol.
Chem. 1988, 189, 2797. (d) Kress, J .; Osborn, J . A.; Ivin, K. J . J . Chem.
Soc., Chem. Commun. 1989, 1234.
(4) (a) Schaverien, C. J .; Dewan, J . C.; Schrock, R. R. J . Am. Chem.
Soc. 1986, 108, 2771. (b) Schrock, R. R.; Feldman, J . Cannitzo, L. F.;
Grubbs, R. H. Macromolecules 1987, 20, 1172. (c) Schrock, R. R.;
Krouse, S. A.; Knoll, K.; Feldman, J .; Murdzek, J . S.; Yang, D. C. J .
Am. Chem. Soc. 1988, 110, 1423. (d) Schrock, R. R. Acc. Chem. Res.
1990, 23, 158. (e) Schrock, R. R.; Murdzek, J . S.; Bazan, G. C.; Robbins,
J .; DiMare, M.; O’Regan, M. J . Am. Chem. Soc. 1990, 112, 3875. (e)
Fox, H. H.; Yap, K. K. B.; Robbins, J .; Cai, S.; Schrock, R. R. Inorg.
Chem. 1992, 31, 2287. (f) Bazan, G. C.; Oskam, J . H.; Cho, H.-N.; Park,
L. Y.; Schrock, R. R. J . Am. Chem. Soc. 1991, 113, 6899.
10.1021/jo982098u CCC: $18.00 © 1999 American Chemical Society
Published on Web 04/02/1999

Notes
J . Org. Chem., Vol. 64, No. 9, 1999 3355
Sch em e 1. Ca ta lytic RCM of Tetr a en es
roperoxybenzoic acid followed by treatment with an
excess of dimethylsulfonium methylide23 afforded the
corresponding one-carbon homologated allyl alcohols (3a ,
3b) which were further transformed to allyl ethers (4a ,
4b). Alternatively, epoxides (2a , 2c24) were treated with
vinylmagnesium bromide under copper iodide catalysis
to provide alcohols (5a , 3c). Subsequent treatment with
allylbromide gave substrates (6a , 7a , 4c). Isomerization
of 4c using Wilkinson’s catalyst yielded to product 5c.
Compound 8a was prepared by refluxing 7a in ethyl vinyl
ether in the presence of mercury(II) acetate. Treatment
of epoxides (2b, 2c) with allylmagnesium bromide fur-
nished alcohols (5b, 3d ) which were converted to allyl
ethers (6b, 4d ).
All the substrates were submitted to the typical me-
tathesis reaction: the starting olefin was solubilized in
dry benzene and a catalytic amount of ruthenium catalyst
(0.05-0.1 equivalent) was added. The mixture was
stirred at room temperature for 30-60 min and subjected
to workup and purification. The results are summarized
in Table 1. Bis dihydrofuran rings linked by one carbon
(entries 1 and 2), two carbons (entry 3), or directly linked
(entry 8) were isolated in good yields (70-90%). The
reaction also allowed access to seven-membered cyclic
ethers (entries 5 and 9, 50-60% yield) and bis dihydro-
pyran rings linked by either two (entry 4, 94% yield) or
zero carbons (entry 7, 70% yield). Interestingly, an
asymmetric substrate allowed the incorporation of both
dihydrofuran and dihydropyran rings linked by two
carbons as illustrated in entry 6 (81% yield).
Mechanistically two products were conceivable from
the cyclization of substrates 4a , 4a ′, 4b, and 4c resulting
from competition between a single RCM reaction leading
to cycloalkenes 9b, 9b′,25 10b, and 12b (C-membered ring
cyclization) or two RCM reactions (O-membered ring
cyclization) yielding 9a , 9a ′,25 10a , and 12a . Our results
demonstrated that after consumption of the starting
substrate (30-60 min), bicyclic compounds were isolated
as major products (entry 1, 9a 76%; entry 2, 9a ′ 75%;
entry 3, 10a 72%; entry 7, 12a 45%), while cyclic alkenes
were obtained as minor products (entry 1, 9b 0%; entry
2, 9b′25 <9%; entry 3, 10b 0%; entry 7, 12b 19%). The
structure of 9b was unambiguously confirmed by com-
parison of its analytical data which were identical to
those found for an authentic substrate obtained from cis-
4-cyclopentene-1,3-diol.26,27 The metathesis reaction of
substrates 4a and 4a ′ was completed after 3 h at room
temperature with 10 mol % of catalyst to afford only the
bicyclic compounds in good yields (entries 1 and 2, 9a ,
leading to an unsaturated mono-heterocycle. Note, while
there is literature precedent for the preparation of bicyclic
compounds,16 these transformations involved either a
two-step sequence17 with introduction of the first ring
followed by an intramolecular metathesis cyclization or
a tandem ring opening-ring closing sequence18 at slightly
elevated temperature and in higher concentration condi-
tions.
In our efforts toward the synthesis of natural and non-
natural Annonaceous acetogenins19 and polyether anti-
biotics,20 we have developed an efficient application of
catalytic intramolecular olefin metathesis of acyclic tet-
raenes which allows the generation of a variety of poly-
unsaturated oxygen heterocycles. These polycyclic ethers,
and especially tetrahydrofuran units which are directly
linked, constitute the core motif of acetogenins whose
pharmacological activities have attracted serious atten-
tion from chemists21 and biologists.22
We report herein our preliminary results using ruthe-
nium alkylidene A as the catalyst in a double ring closing
metathesis reaction of acyclic tetraenes. In this process,
two rings and two carbon-carbon double bonds are
formed in a single step to yield polycyclic unsaturated
ethers (Scheme 1). This work completes the initial studies
reported by Grubbs18 for the preparation of bicyclic
molecules.
Resu lts a n d Discu ssion
The acyclic tetraenes were synthesized starting from
commercially available dienes (1a , 1b) as illustrated in
Scheme 2. Conversion to epoxides (2a , 2b) using 3-chlo-
(13) (a) Leconte, M.; J ourdan, I.; Pagano, S.; Lefebvre, F.; Basset,
J .-M. J . Chem. Soc., Chem. Commun. 1995, 857. (b) Hanson, P. R.;
Stoianova, D. S. Tetrahedron Lett. 1998, 39, 3939.
(14) (a) Chang, S.; Grubbs, R. H. Tetrahedron Lett. 1997, 38, 4757.
(b) Finkel’shtein, E. Sh.; Ushakov, N. V.; Portnykh, E. B. J . Mol. Catal.
1992, 76, 133. (c) Meyer, C.; Cossy, J . Tetrahedron Lett. 1997, 38, 7861.
(d) Evans, P. A.; Murthy V. S. J . Org. Chem. 1998, 63, 6768.
(15) (a) Amstrong, S. K.; Christie, B. A. Tetrahedron Lett. 1996, 37,
9373. (b) Couturier, J .-L.; Tanaka, K.; Leconte, M.; Basset, J .-M.;
Ollivier, J . Angew Chem., Int. Ed. Engl. 1993, 32, 112. (c) Leconte,
M.; Pagano, S.; Mutch, A.; Lefebvre, F.; Basset, J .-M. Bull. Soc. Chim.
Fr. 1995, 132, 1069. (d) ref 12. (e) Shon, Y. S.; Lee, T. R. Tetrahedron
Lett. 1997, 38, 1283.
(16) (a) Martin, S. F.; Liao, Y.; Chen, H.-J .; Pa¨tzel, M.; Ramser, M.
N. Tetrahedron Lett. 1994, 35, 6005. (b) Blechert, S.; Huwe, C. M.
Tetrahedron Lett. 1995, 36, 1621. (c) Martin, S. F.; Chen, H.-J . C.;
Courtney, A. K.; Liao, Y. Tetrahedron 1996, 52, 7251. (d) Barrett, A.
G. M.; Baugh, S. P. D.; Gibson, V. C.; Giles, M. R.; Marshall, E. L.;
Procopiou, P. A. Chem. Commun. 1996, 2231. (e) Overkleeft, H. S.;
Pandit, U. K. Tetrahedron Lett. 1996, 37, 547. (f) Dyatkin, A. B.
Tetrahedron Lett. 1997, 38, 2065. (g) Barrett, A. G. M.; Baugh, S. P.
D.; Gibson, V. C.; Giles, M. R.; Marshall, E. L.; Procopiou, P. A. Chem.
Commun. 1997, 155. (h) Hammer, K.; Undheim, K. Tetrahedron 1997,
53, 2309.
(20) Westley, J . W. Polyether Antibiotics: Naturally Occuring Acid
Ionophores; Dekker M: New York, 1983; Vols. 1 and 2.
(21) (a) Hanck, P.; Bernardi, A.; Romero, A. Lectures Heterocyl.
Chem. 1987, 9, 533. (b) Koert, V. Synthesis 1995, 115. (c) Hoppe, R.;
Scharf, H. D. Synthesis 1995, 1447.
(22) (a) Zeng, L.; Ye, Q.; Oberlies, N. H.; Shi, G.; Gu, Z. M.; He, K.;
McLaughlin, J . L. Nat. Prod. Report. 1996, 275. (b) Zafrapolo, M. C.;
Gonzalez, M. C.; Estornell, E.; Sahpaz, S.; Cortes, D. Phytochemistry
1996, 42, 253. (c) Morre, D. J .; de Cabo, R.; Farley, C.; Oberlies, N. H.;
McLaughlin, J . L. Life Sci. 1995, 56, 343. (d) Espositi, M. D.; Ghelli,
A.; Batta, M.; Cortes, D.; Estornell, E. Biochemistry 1994, 33, 161. (e)
Friedrich, T.; Van Heek P.; Leif H.; Ohmishi, T.; Forche, E.; Kunze,
B.; J ansen, R.; Trowitzsch-Kienast, W.; Ho¨fle, G.; Reichenbach, H.;
Wiss, H. Eur. J . Biochem. 1994, 219, 691.
(17) (a) Kim, S.-H.; Bowden, N.; Grubbs, R. H. J . Am. Chem. Soc.
1994, 116, 10801. (b) Kim, S.-H.; Zuercher, W. J .; Bowden, N. B.;
Grubbs, R. H. J . Org. Chem. 1996, 61, 1, 1073.
(18) Zuercher, W. J .; Hashimoto, M.; Grubbs, R. H. J . Am. Chem.
Soc. 1996, 118, 6634.
(19) (a) Figade`re, B.; Cave´ A. Studies in Natural Products Chemistry;
Atta-ur-Rahman, Ed.; Elsevier Science B. V.: Amsterdam, 1996, Vol.
18, pp 193-227. (b) Cave´, A.; Figade`re, B.; Laurens, A.; Cortes, D. In
Progress in the Chemistry of Organic Natural Products; Hertz, W. Ed.;
Springer-Verlag: Wien, New York, 1997; Vol. 70, p 81.
(23) Alcaraz, L. Harnett, J . J .; Mioskowski, C. Martel, J . P.; Le Gall,
T.; Shin D.-S.; Falck, J . R. Tetrahedron Lett. 1994, 35, 5449.
(24) (()-1,3-Butadiene diepoxide 2c was purchased from commercial
sources.
(25) The analytical data for compounds 9a ′ and 9b′ were previously
reported by Grubbs.18 9b′ was synthesized following the published
experimental procedure.18

3356 J . Org. Chem., Vol. 64, No. 9, 1999
Sch em e 2. Syn th esis of RCM Su bstr a tesa
Notes
a
Conditions: (a) m-CPBA, CH2Cl2, rt, 5-12 h; (b) (CH3)3SI, n-BuLi, THF, -10 °C f rt, 3 h; (c) CH2dCH-CH2Br, NaH, DMF/THF, rt,
6 h; (d) CH2dCHMgBr, CuI, THF, -30 °C, 1-2 h; (e) CH3CH2OCHdCH2, Hg(OAc)2, reflux 48 h; (f) CH2dCH-CH2MgBr, CuI, THF, -30
°C, 3 h; (g) RhCl(PPh3)3, EtOH, reflux 12 h.
9a ′: 90%). These results suggested that even if carbocycle
products 9b and 9b′ were formed, they were totally
transformed into bicyclic compounds 9a and 9a ′. Fur-
thermore, when 9b and 9b′ were submitted to the
metathesis reaction for 1 h at room temperature, bicyclic
products 9a and 9a ′ were formed respectively resulting
from a tandem ring opening-ring closing metathesis
similar to that previously observed by Grubbs.18-28 In
contrast to 4a ′ (entry 2), 4b yielded only the bicyclic ether
10a 29 (entry 3, 72% yield) and the cyclic olefin 10b was
never observed. Nevertheless, for substrate 4c the prod-
uct 12b was obtained in higher yield (entry 7, 19% yield)
compared to that of 9b′ (entry 2, <9% yield), but 12b was
totally transformed into the bicyclic compound 12a after
2 h at 60 °C. These conversions of carbocycle compounds
to bicyclic products are driven by the release of highly
volatile ethylene and by a gain in entropy. In the other
examples (entries 4, 5, 6, 8, and 9) the metathesis
products were polycyclic ethers (O-membered ring cy-
clization) 11a , 13a , 14a , 12a , 15a , and 16a which were
isolated as a mixture of diastereoisomers.
Interestingly, the results showed that when both O-
and C-membered ring cyclizations were possible by RCM
of the starting diene, the formation of a bis O-heterocycle
was preferred over C-ring giving an unsaturated bis-
cyclic ether as the major product.
These RCM results obtained under ruthenium carbene
A catalyst can be explained by two classical reaction
mechanisms resulting from the addition of the ruthenium
catalyst30 either to the less hindered double bond (mech-
anism 1, Scheme 3) or to the more hindered double bond
(mechanism 2, Scheme 4).
RCM following the same sequences yields intermediate
E which forms the second ring (intermediate F ) and
evolves to the bicycle 9a . We can note that the formation
of cyclic alkene 9b is not feasible with this mechanism
(without any ROM-RCM reaction18-28) and that inter-
mediate B leads directly to bicyclic ethers. The other
internal metathesis reactions starting from B which
would lead to seven- or nine-membered ring compounds
are unfavorable.
In mechanism 2, the initial metathesis occurs at the
other available olefin moiety of 4a to yield intermediate
B′. B′ is predicted to be minor compared to B (mechanism
1) due to steric hindrance. While two cyclizations paths
(a and b) are possible from B′, path a yielding intermedi-
ate C′ was believed to be the major pathway because
products D31 and 4a were isolated when the reaction was
stopped before completion. Path b leading to the C-cycli-
zation intermediate G was believed to be a minor path-
way because the resulting cyclic olefin 9b was obtained
in only low yields (Table 1, entry 2, 9b′ yield <9%), and
carbocycle l0b (Table 1, entry 3) was never isolated.
Furthermore, 9b was converted to the bicyclic ether 9a .28
Path a affords intermediate C′ and then compound D
which is similar to mechanism 1. A second diene RCM
(26) 9b was synthesized by monoalkylation of commercially avail-
able cis-4-cyclopentene-1,3-diol to give compound 17. Treatment of 17
under Mitsunobu conditions27 yielded ester 18 having complete inver-
sion of configuration. Hydrolysis of 18 followed by alkylation of alcohol
19 afforded 9b. For experimental details and analytical data, see the
Experimental Section.
(27) Mitsunobu, O. Synthesis 1981, 1.
(28) Complete conversion of 9b to 9a was observed after 45 min at
25 °C. The metathesis reaction for 9b′ was slower, and after 3 h at 25
°C product 9a ′ was isolated in 80% yield in addition to recovered 9b′.
Both products 9a and 9a ′ are the result of a tandem ring opening-
ring closing metathesis (ROM-RCM reaction).18
(29) 10a was isolated as a mixture of diastereoisomers.
(30) The reviewers had very helpful comments concerning the
reaction mechanism and the involved intermediates.
Mechanism 1 involves an initial intermolecular acyclic
metathesis of 4a with fixation of the ruthenium catalyst
at the terminal olefin of the allyl group to generate inter-
mediate B. B evolves to metallacyclobutane intermediate
C which after productive cleavage gives the carbene
(LnRudCH2) and the first ring of D.31 A second diene
(31) D was isolated and identified when the RCM reaction was
stopped before complete consumption of the starting material. Analyti-
cal data are reported in the Experimental Section.

Notes
J . Org. Chem., Vol. 64, No. 9, 1999 3357
Ta ble 1. Resu lts of th e RCM of Tetr a en es
Sch em e 4. Mech a n ism 2
bicycle 9a . In both mechanisms (mechanism 1, Scheme
3; mechanism 2, Scheme 4) the generation of compound
9a from product D can be rationalized by two routes,
through intermediate E or intermediate E′.
Noting that the bicyclic ethers were isolated as major
products (entries 1-9) and the addition of the ruthen-
ium catalyst on the olefin should be governed by steric
effects, mechanism 1 is expected to predominate over
mechanism 2. In entries 1-6 the ruthenium catalyst
added to the less hindered olefin of the allyl group, fol-
lowing mechanism 1. In entries 7-9 the differentiation
of the terminal olefins is more difficult and can explain
the C-cylization product (12b, 19% yield). This suggests
that the intermediate B′ in mechanism 2 is not excluded
and should evolve following path b. In the case of product
5c (entry 8), which is bearing substituted olefins, the Ru
catalyst adds on the unsubstituted olefins to give 15a as
single product, and as reported previously,6,7 any olefin
substitution appears to slow the RCM (15a : 70% yield
after 6 h at 60 °C). In entries 4-6, mechanism 2 following
path b would have generated eight- or ten-membered
rings which are not entropically favored.
Presumably, we can deduce that the RCM reaction of
acyclic tetraenes using A as the catalyst is occurring via
O-membered cyclization to yield bis polycyclic ethers as
major products following mechanism 1. When C-cycliza-
tion products were formed (path b, mechanism 2, Scheme
4) they were totally transformed to bicyclic compounds
owing to the release of highly volatile ethylene.
Sch em e 3. Mech a n ism 1
Con clu sion
In summary, we have presented herein metathesis-
based methodology for the construction of bis polycyclic
ethers or enol ethers linked by none, one, or two carbons
through a double metathesis reaction. We have shown
that RCM reactions of tetraenes bearing unsaturated
ether functions produce polycyclic ethers as major prod-
ucts. The application of this bis ring closing metathesis
reaction for the preparation of acetogenins and for the
synthesis of other substituted cyclic ethers is being
investigated.
Exp er im en ta l Section
Gen er a l Meth od s. All reagents were commercial grade and
were used as received without further purification. Bis(tricyclo-
hexylphosphine)benzylidine ruthenium(IV) dichloride was pur-
following the same sequence yields intermediate E′ which
generates the second ring (intermediate F ′) to afford the

3358 J . Org. Chem., Vol. 64, No. 9, 1999
Notes
chased from Strem Chemical INC. All reactions were performed
under an inert atmosphere, and anhydrous solvents were dried
and distilled before use. Thin layer chromatograms (TLC) and
flash chromatography separations were respectively performed
on precoated silica gel 60 F254 plates (Merck, 0.25 mm) and on
Merck silica gel 60 (230-400 mesh). 1H NMR spectra were
recorded at 300 MHz in CDCl3; shifts are relative to internal
TMS. 13C NMR spectra were obtained at 75 MHz with CDCl3
as internal reference. Mass spectra were recorded at 70 eV using
chemical ionization mode (CI-NH3). High-resolution mass spec-
tra HRMS:LSIMS+ were recorded on a Zabspec TOF Micromass
(matrix: 3-nitrobenzyl alcohol). IR spectra were recorded as casts
on an FT instrument.
Gen er a l P r oced u r e for Meta th esis Rea ction : P r ep a r a -
tion of 9a , 9a ′, 10a , 11a , 12a , 13a , 14a , a n d 16a . To a stirred
solution of tetraene (90 mg, 0.43 mmol) in 3 mL of dry benzene
at room temperature was added a solution of bis(tricyclohex-
ylphosphine)benzylidine ruthenium(IV) dichloride (18 mg, 0.022
mmol) in 2 mL of dry benzene. The reaction mixture was stirred
for 1 h at room temperature and was concentrated under vac-
uum. The crude product was purified by column chromatography
on silica gel with pentane/ether to yield the bicyclic compound.
1,4-P en ta d ien e Diep oxid e (2a ). To a stirred solution of 1,4-
pentadiene (7 mL, 67.6 mmol) in dry CH2Cl2 (150 mL) at 0 °C
was added m-chloroperoxybenzoic acid (48.6 g, 169 mmol, 57-
60% by wt.) in five portions. The reaction mixture was stirred
overnight at room temperature and was quenched with satu-
rated aqueous NaHCO3 solution (100 mL). The organic layer was
separated, washed with 1 M KOH (7 × 50 mL), dried (MgSO4),
and concentrated to give the diepoxide 2a (7.5 g, 98% yield)
which was used directly in the next step: 1H NMR (CDCl3) δ
3.09-2.99 (m, 2H), 2.80-2.75 (m, 2H), 2.56 (dd, J ) 2.8, 4.9 Hz,
1H), 2.50 (dd, J ) 2.8, 5.0 Hz, 1H), 1.77-1.70 (m, 2H); 13C NMR
(CDCl3) δ 49.1, 48.6, 46.6, 46.0, 35.6, 34.6; IR (neat, cm-1) 2997,
1218, 845; MS (DCI/NH3) m/z (MNH4+) ) 118.
1,6-Hep ta d ien e-3,5-d iol (3a ). To a stirred solution of tri-
methylsulfonium iodide (47 g, 230.7 mmol) in dry THF (400 mL)
at -10 °C was added dropwise butyllithium (140 mL, 1.6 M in
hexane). The reaction mixture was stirred at -10 °C for 1 h,
and a solution of diepoxide 2a (3.85 g, 38.45 mmol) in dry THF
(20 mL) was added. The reaction mixture was allowed to warm
to room temperature, and the white suspension was stirred
overnight. The mixture was treated with a saturated aqueous
NH4Cl solution (100 mL), extracted with CH2Cl2 (4 × 75 mL),
dried over MgSO4, and concentrated. The crude product was
purified on silica gel (pentane/ether 50/50) to yield the compound
3a (3.1 g, 65% yield):1H NMR (CDCl3) δ 5.90-5.79 (m, 2H), 5.25
(dd, J ) 3.2, 14.3 Hz, 2H), 5.11 (dd, J ) 2.9, 8.0 Hz, 2H), 4.40-
4.33 (m, 2H), 3.55 (br s, 1H), 3.20 (br s, 1H), 1.75-1.60 (m, 2H);
13C NMR (CDCl3) δ 140.6, 114.7, 114.6, 73.1, 70.3, 43.0, 42.1;
IR (neat, cm-1) 3357; 1425, 992, 925; MS (DCI/NH3) m/z (MH)+
) 129, (MNH4+) ) 146.
d l-3,5-Bis-a llyloxy-h ep ta -1,6-d ien e (4a ), m eso-3,5-Bis-a l-
lyloxy-h ep ta -1,6-d ien e (4a ′). To a stirred solution of diol 3a
(3.1 g, 24.19 mmol) in dry THF (150 mL) at 0 °C was added
sodium hydride (3.9 g, 96.75 mmol, 60% dispersion in mineral
oil). The reaction mixture was stirred at room temperature for
15 min and was cooled to 0 °C, and allyl bromide (8.4 mL, 96.75
mmol) in dry DMF (50 mL) was added. The reaction mixture
was stirred for 12 h at room temperature, hydrolyzed with
saturated NH4Cl (75 mL), extracted with Et2O, washed with
saturated NaCl (3 × 50 mL), and dried (MgSO4). After concen-
tration, the crude product was purified by column chromatog-
raphy (pentane/ether 97/3) to give 4a ′ (1.20 g, 24% yield), 4a +
4a ′ (1.45 g, 30% yield), and 4a (0.81 g, 16% yield). 4a : 1H NMR
(CDCl3) δ 5.96-5.84 (m, 2H), 5.74-5.62 (m, 2H), 5.28-5.12 (m,
8H), 4.08-3.93 (m, 4H), 3.80 (dd, J ) 5.6, 11.8 Hz, 2H), 1.68
(dd, J ) 6.2, 7. 2 Hz, 2H); 13C NMR (CDCl3) δ 139.0, 135.3, 116.7,
116.6, 76.7, 69.6, 42.1; IR (neat, cm-1) 3080, 2860, 1083, 993,
924; MS (DCI/NH3) m/z (MH)+ ) 209, (MNH4+) ) 226. 4a ′: 1H
NMR (CDCl3) δ 5.94-5.80 (m, 2H), 5.73-5.61 (m, 2H), 5.27-
5.10 (m, 8H), 4.01 (dd, J ) 1.5, 5.3 Hz, 2H), 3.86-3.73 (m, 4H),
2.06-1.96 (m, 1H), 1.60-1.51 (m, 1H); 13C NMR (CDCl3) δ 138.7,
135.2, 117.4, 116.6, 77.7, 69.3, 41.3; IR (neat, cm-1) 3080, 2861,
1081, 994, 924; MS (DCI/NH3) m/z (MH)+ )209, (MNH4+) ) 226.
d l-Bis-(5-oxa -2cyclop en ten yl) m m eth a n e (9a ). From 4a
(100 mg, 0.49 mmol), 9a was obtained (55 mg, 76% yield)
following the general procedure, or 9a (65 mg, 90% yield) when
the reaction mixture was stirred for 3 h at room temperature:
1H NMR (CDCl3) δ 5.86-5.79 (m, 4H), 4.97-4.91 (m, 2H), 4.65-
4.52 (m, 4H), 1.72 (dd, J ) 6.2, 6.3 Hz, 2H); 13C NMR (CDCl3) δ
130.4, 126.2, 83.6, 74.8, 42.6; IR (neat, cm-1) 2850, 1755, 1353,
1074; MS (DCI/NH3) m/z (MH)+ ) 153, (MNH4+) ) 170.
m eso-Bis-(5-oxa -2cyclop en ten yl)m eth a n e (9a ′). From 4a ′
(100 mg, 0.49 mmol), 9a ′ was obtained (55 mg, 75% yield)
following the general procedure, or 9a ′ (66 mg, 90% yield) when
the reaction mixture was stirred for 3 h at room temperature:
1H NMR (CDCl3) δ 5.86-5.80 (m, 4H), 4.92-4.90 (m, 2H), 4.66-
4.52 (m, 4H), 1.88-1.72 (m, 2H); 13C NMR (CDCl3) δ 130.0,
126.4, 83.3, 75.0, 41.8; IR (neat, cm-1) 2851, 1755, 1352, 1073.
MS (DCI/NH3) m/z (MH)+ ) 153, (MNH4+) ) 170; HRMS cald
for C19H12O2 )152,0837, found 152,0827.
d l-2-(2-Allyloxy-bu t-3-en yl)-2,5-d ih yd r ofu r a n (D). The
ether D was prepared in a manner similar to that of 9a ′ when
the reaction was stopped after 15 min. Purification of the crude
material gave 9a (45 mg, 60% yield) and D (8 mg, 10% yield).
D: 1H NMR (CDCl3) δ 5.98-5.64 (m, 4H), 5.28-5.17 (m, 4H),
5.16-5.12 (m, 1H), 4.64-4.59 (m, 2H), 4.07-3.82 (m, 3H), 1.82-
1.71 (m, 1H), 1.64-1.57 (m, 1H); 13C NMR (CDCl3) δ 139.1,
135.2, 130.5, 126.2, 116.8, 116.6, 83.7, 83.0, 74.8, 69.6, 42.6; IR
(neat, cm-1) 2926, 2855, 1741, 1075; MS (DCI/NH3) m/z (MH)+
) 181, (MNH4+) ) 198.
1,5-Hexa d ien e Diep oxid e (2b). To a stirred solution of 1,5-
hexadiene (3.6 mL, 30 mmol) in dry CH2Cl2 (60 mL) was added
at 0 °C m-chloroperbenzoic acid (12.95 g, 75 mmol, 57-86% by
wt) in four portions. After 24 h at room temperature, 15 mL of
water was added and the solution was extracted with CH2Cl2
(3 × 10 mL). The organic layer was washed with 1 N KOH (6 ×
25 mL), dried over MgSO4, and concentrated. Flash chromatog-
raphy (hexane/ether 70/30) gave the diepoxide 2b (2.16 g, 63%
yield): 1H NMR (CDCl3) δ 2.89-2.87 (m, 2H), 2.69 (dd, J ) 4.7,
4.7 Hz, 2H), 2.42 (dd, J ) 2.5, 4.9 Hz, 2H), 1.73-1.53 (m, 4H);
13C NMR (CDCl3) δ 51.8, 51.5, 46.9, 29.2, 28.7; IR (neat, cm-1
)
)
2991, 1262, 926, 837; MS (DCI/NH3) m/z (MH)+ ) 115, (MNH4
+
) 132.
Oct a -1,7-d ien e-3,6-d iol (3b ). To a stirred mixture of tri-
methylsulfonium iodide (6.12 g, 30 mmol) in 50 mL of dry THF
was added at -10 °C butyllithium (18 mL, 1.6 M in hexane).
The resulting mixture was stirred at -10 °C for 30 min, and a
solution of diepoxide 2b (570 mg, 5 mmol) in dry THF (5 mL)
was added. The reaction mixture was stirred at room temper-
ature for 3 h, hydrolyzed with saturated NH4Cl (15 mL),
extracted with CH2Cl2 (3 × 10 mL), dried over MgSO4, and
concentrated. The crude product was purified by column chro-
matography (hexane/ether 50/50) to yield compound 3b (360 mg,
50% yield): 1H NMR (CDCl3) δ 5.86-5.74 (m, 2H), 5.17 (dd, J
) 2.3, 16.1 Hz, 2H), 5.03 (dd, J ) 2.2, 2.9 Hz, 2H), 4.07-4.04
(m, 2H), 3.57 (br s, 1H), 3.44 (br s, 1H), 1.62-1.56 (m, 4H); 13C
NMR (CDCl3) δ 141.0, 114.6, 114.5, 72.9, 72.6, 33.2, 32.6; IR
(neat, cm-1) 3345, 1426, 990, 921; MS (DCI/NH3) m/z (MH)+
)143, (MNH4+) ) 160.
3,6-Bis-a llyloxy-octa -1,7-d ien e (4b). To a stirred solution
of diol 3b (250 mg, 1.76 mmol) in dry THF (10 mL) was added
at 0 °C sodium hydride (285 mg, 7.03 mmol, 60% dispersion in
mineral oil). The reaction mixture was stirred at room temper-
ature for 15 min and cooled to 0 °C. Allyl bromide (0.61 mL,
7.03 mmol) in dry DMF (10 mL) was added, and the mixture
was stirred at room temperature for 4 h. The reaction was
quenched with saturated NH4Cl (10 mL) and extracted with
CH2Cl2 (4 × 10 mL). The organic layer was dried over MgSO4
and concentrated. The crude product was purified by column
chromatography (hexane/ether 90/10) to yield 4b (390 mg, 99%
yield): 1H NMR (CDCl3) δ 5.94-5.81 (m, 2H), 5.68-5.58 (m, 2H),
5.26-5.10 (m, 8H), 4.01 (dd, J ) 5.2, 12.8 Hz, 2H), 3.79 (dd, J
) 6.6, 12.7 Hz, 2H), 3.70-3.65 (m, 2H), 1.72-1.48 (m, 4H); 13C
NMR (CDCl3) δ 139.0, 135.3, 117.0, 116.6, 80.7, 80.5, 69.2, 31.4,
31.2; IR (neat, cm-1) 2846, 1075; MS (DCI/NH3) m/z (MH)+
223, (MNH4+) ) 240.
)
1,2-Bis-(5-oxa -2-cyclop en ten yl) eth a n e (10a ). From 4b
(100 mg, 0.45 mmol) the bicycle 10a was obtained (51 mg, 72%
yield) following the general procedure: 1H NMR (CDCl3) δ 5.85-
5.82 (m, 2H), 5.74-5.72 (m, 2H), 4.84-4.80 (m, 2H), 4.65-4.52
(m, 4H), 1.68-1.50 (m, 4H); 13C NMR (CDCl3) δ 129.7, 126.6,

Notes
J . Org. Chem., Vol. 64, No. 9, 1999 3359
86.0, 85.8, 75.1, 31.4, 31.3; IR (neat, cm-1) 3079, 2925, 1079;
MS (DCI/NH3) m/z (MH)+ ) 167, (MNH4+) ) 184.
2b (600 mg, 5.26 mmol) in dry THF (6 mL) was added, and the
mixture was stirred at -30 °C for 30 min. The reaction mixture
was hydrolyzed with saturated NH4Cl (10 mL) and extracted
with Et2O (3 × 10 mL), and the organic layer was separated,
dried over MgSO4, and concentrated. The crude product was
purified by column chromatography (hexane/ether 50/50) to yield
the diol 5a (860 mg, 97% yield): 1H NMR (CDCl3) δ 5.83-5.72
(m, 2H), 5.11-5.06 (m, 4H), 3.65-3.61 (m, 2H), 2.90 (br s, 1H),
2.50 (br s, 1H), 2.27-2.14 (m, 4H), 1.68-1.46 (m, 4H); 13C NMR
(CDCl3) δ 134.9, 134.7, 118.2, 117.9, 71.2, 70.5, 42.2, 41.9, 33.5,
32.6; IR (neat, cm-1) 3352, 2928, 1434, 995, 914; MS (DCI/NH3)
m/z (MH)+ ) 171, (MNH4+) ) 188.
Octa -1,7-d ien e-4,5-d iol (3c). To cooled (-30 °C) copper(I)
iodide (4 g, 20 mmol) were added dropwise a solution of
vinylmagnesium bromide (200 mL, 200 mmol, 1 M in THF) and
commercially available (()-1,3-butadiene diepoxide 2c (5.2 mL,
66.7 mmol). The reaction mixture was stirred at -30 °C for 1 h,
hydrolyzed with saturated NH4Cl (50 mL), and extracted with
Et2O (3 × 40 mL). The organic layer was separated, dried over
MgSO4, and concentrated. The crude product was purified by
column chromatography (pentane/ether 50/50) to yield the diol
3c (9.3 g, 93% yield): 1H NMR (CDCl3) δ 5.90-5.76 (m, 2H),
5.16-5.08 (m, 4H), 3.55-3.44 (m, 2H), 2.51 (br s, 2H), 2.36-
4,7-Bis-a llyloxy-d eca -1,9-d ien e (6a ), 7-Allyloxy-4-d eca -
1,9-d ien -4-ol (7a ). To a stirred solution of diol 5a (380 mg, 2.23
mmol) in dry THF (10 mL) at 0 °C was added NaH (180 mg,
4.46 mmol, 60% dispersion in mineral oil). The reaction mixture
was stirred at room temperature for 15 min, cooled to 0 °C, and
added to a solution of allyl bromide (0.4 mL, 4.46 mmol) in 10
mL of dry DMF. The reaction mixture was stirred at room
temperature for 2 h , quenched with saturated NH4Cl (10 mL),
and extracted with Et2O (3 × 5 mL). The organic layer was dried
over MgSO4 and concentrated. The crude product was purified
on silica gel (hexane/ether 90/10) to yield 7a (210 mg, 45% yield)
2.20 (m, 4H); 13C NMR (CDCl3) δ 134.6, 118.1, 72.8, 38.3; IR
+
(neat, cm-1) 3397, 1642, 996, 916; MS (DCI/NH3) m/z (MNH4
) 160.
)
4,5-Bis-a llyloxy-octa -1,7-d ien e (4c). To a solution of diol
3c (500 mg, 3.52 mmol) in dry THF (30 mL) at 0 °C was added
NaH (425 mg, 10.55 mmol, 60% dispersion in mineral oil). The
resulting mixture was stirred at room temperature for 15 min
and cooled to 0 °C. A solution of allyl bromide (0.92 mL, 10.55
mmol) in dry DMF (10 mL) was added, and the mixture was
stirred at room temperature for 45 min. NaH (140 mg, 3.51
mmol) and allyl bromide (0.3 mL, 3.51 mmol) were added, and
the reaction mixture was stirred at room temperature for 4 h.
The mixture was hydrolyzed with saturated NH4Cl (25 mL) and
extracted with Et2O (3 × 25 mL). The organic layer was
separated and dried (MgSO4). The crude product was purified
by column chromatography (pentane/ether 95/5) to give 4c (650
mg, 88% yield): 1H NMR (CDCl3) δ 5.94-5.77 (m, 4H), 5.27-
5.01 (m, 8H), 4.09-3.99 (m, 4H), 3.42-3.36 (m, 2H), 2.42-2.33
(m, 2H), 2.28-2.19 (m, 2H); 13C NMR (CDCl3) δ 135.5, 116.8,
116.7, 79.8, 71.8, 34.8; IR (neat, cm-1) 3079, 2925, 1085, 996,
915; MS (DCI/NH3) m/z (MH)+ ) 223, (MNH4+) ) 240.
1
and 6a (110 mg, 20% yield). 6a : H NMR (CDCl3) δ 5.94-5.76
(m, 4H), 5.28-5.01 (m, 8H), 4.05-3.91 (m, 4H), 3.37-3.34 (m,
2H), 2.31-2.20 (m, 4H), 1.63-1.45 (m, 4H); 13C NMR (CDCl3) δ
135.5, 135.0, 117.0, 116.6, 78.7, 78.4, 70.1,, 38.5, 38.4, 29.6, 29.1;
IR (neat, cm-1) 3080, 2927, 1079, 995, 914; MS (DCI/NH3) m/z
(MH)+ ) 251, (MNH4+) ) 268. 7a : 1H NMR (CDCl3) δ 5.93-
5.79 (m, 3H), 5.28-5.02 (m, 6H), 4.04-3.95 (m, 3H), 3.65 (br s,
1H), 3.39-3.37 (m, 1H), 2.34-2.15 (m, 4H), 1.65-1.52 (m, 4H);
13C NMR (CDCl3) δ 135.1, 134.7, 117.7, 117.1, 116.8, 78.7, 78.5,
70.8, 70.1, 70.0, 42.0, 38.2, 32.6, 29.9; IR (neat, cm-1) 3404, 2927,
1070, 996, 914; MS (DCI/NH3) m/z (MH)+ ) 211, (MNH4+) )
228.
d l-5,5-Bis(6-oxa -2-cycloh exen e) (12a ). From 4c (100 mg,
0.45 mmol) 12a (53 mg, 70% yield) was prepared following the
general procedure except that the mixture was heated to 60 °C
for 2 h: 1H NMR (CDCl3) δ 5.82-5.67 (m, 4H), 4.30-4.15 (m,
4H), 3.55-3.47 (m, 2H), 2.14-2.07 (m, 2H), 1.93-1.84 (m, 2H);
d l-1,2-Bis(6-oxa -3 cycloh exen yl)eth a n e (11a ). From 6a (60
mg, 0.24 mmol) the bicycle 11a was obtained (47 mg, 94% yield)
following the general procedure: 1H NMR (CDCl3) δ 5.80-5.66
(m, 4H), 4.15 (br s, 4H), 3.52-3.43 (m, 2H), 2.00-1.97 (m, 4H),
1.70-1.51 (m, 4H); 13C NMR (CDCl3) δ 126.4, 124.4, 73.9, 73.4,
66.0, 32.3, 31.5, 31.3, 31.0; IR (neat, cm-1) 2912, 1181, 1091;
MS (DCI/NH3) m/z (MH)+ ) 195, (MNH4+) ) 212; HRMS cald
for C12H18O2 ) 194,1307, found 194,1310.
13C NMR (CDCl3) δ 126.6, 123.6, 75.8, 66.2, 26.5; IR (neat, cm-1
)
3034, 2927, 1183, 1098; MS (DCI/NH3) m/z (MH)+ ) 167,
(MNH4+) ) 184; HRMS cald for C10H14O2 ) 166,0994, found
166,0995.
tr a n s-4,5-Bis-a llyloxy-cycloh exen e (12b ). From 4c (100
mg, 0.45 mmol) 12a (34 mg, 45% yield) and 12b (16 mg, 19%)
were prepared following the general procedure. 12b: 1H NMR
(CDCl3) δ 5.99-5.86 (m, 2H), 5.53-5.52 (m, 2H), 5.27 (dd, J )
3.5, 18.9 Hz, 2H), 5.13 (dd, J ) 3.6, 10.3 Hz, 2H), 4.21-4.09 (m,
4H), 3.59-3.53 (m, 2H), 2.48-2.40 (m, 2H), 2.11-2.03 (m, 2H);
13C NMR (CDCl3) δ 135.5, 124.2, 116.3, 77.4, 71.1, 30.7; IR (neat,
cm-1) 3080, 2923, 1139, 1091, 994, 921; MS (DCI/NH3) m/z
(MH)+ ) 195, (MNH4+) ) 212.
4-Allyloxy-7-vin yloxy-d eca -1,9-d ien e (8a ). To a solution of
7a (192 mg, 0.87 mmol) in ethyl vinyl ether (5 mL) was added
mercury(II) acetate (140 mg, 0.44 mmol), and the mixture was
heated to reflux for 48 h. The solvent was removed under
vacuum, and the crude product was purified on silica gel
(hexane/ether 90/10) to give 8a (110 mg, 54% yield) and
recovered 7a (75 mg, 40% yield). 8a : 1H NMR (CDCl3) δ 6.30
(dd, J ) 6.6, 14.1 Hz, 1H), 5.89-5.74 (m, 3H), 5.29-5.02 (m,
6H), 4.26 (dd, J ) 1.6, 14.1 Hz, 1H), 4.01-3.95 (m, 3H), 3.78-
3.74 (m, 1H), 3.38-3.32 (m, 1H), 2.35-2.22 (m, 4H), 1.71-1.49
(m, 4H); 13C NMR (CDCl3) δ 151.3, 135.4, 134.6, 134.1, 117.5,
117.0, 116.5, 88.2, 79.6, 79.1, 78.5, 78.1, 70.0, 69.9, 38.6, 38.4,
38.3, 29.6, 29.5, 29.2, 29.0; IR (neat, cm-1) 3079, 2926, 1634,
1195, 996, 916; MS (DCI/NH3) m/z (MH)+ ) 237, (MNH4+) )
254.
4,5-Bis-p r op en yloxy-octa -1,7-d ien e (5c). To a solution of
4c (3.25 g, 14.6 mmol) in MeOH (100 mL) was added Wilkinson’s
catalyst (chlorotris(triphenylphosphine)rhodium(I), 950 mg, 1.02
mmol), and the resulting mixture was heated at 60 °C for 12 h.
The solution was concentrated under vacuum, and the crude
product was purified on silica gel (pentane/ether 97/3) to give
5c (2.65 g, 82% yield): 1H NMR (CDCl3) δ 6.10-5.94 (m, 2H),
5.86-5.74 (m, 2H), 5.13-5.04 (m, 4H), 4.94-4.86 (m, 2H), 3.71-
3.63 (m, 2H), 2.42-2.29 (m, 4H), 1.59-1.50 (m, 6H); 13C NMR
(CDCl3) δ 146.4, 145.5, 134.4, 134.3, 117.6, 117.5, 101.4, 101.1,
80.6, 80.0, 34.9, 34.4, 12.4; IR (neat, cm-1) 3080, 2923, 1674,
995, 918; MS (DCI/NH3) m/z (MH)+ ) 223, (MNH4+) ) 240.
d l-4,4′-Bis(5-oxa -1-cyclop en ten e) (15a ). From 5c (150 mg,
0.67 mmol) the bicycle 15a was obtained (65 mg, 70% yield)
following the general procedure except that the reaction mix-
turewas heated to 60 °C for 6 h: 1H NMR (CDCl3) δ 6.32-6.29
(m, 2H), 4.89-4.86 (m, 2H), 4.65-4.59 (m, 2H), 2.73-2.64 (m,
2H), 2.43-2.34 (m, 2H); 13C NMR (CDCl3) δ 145.5, 99.0, 82.2,
1,2-[5-Oxa-1 cyclopen ten yl][6-oxa-2 cycloh exen yl]eth an e
(14a ). From 8a (80 mg, 0.34 mmol) the bicycle 14a was obtained
(49 mg, 81% yield) following the general procedure: 1H NMR
(CDCl3) δ 6.25-6.22 (m, 1H), 5.80-5.66 (m, 2H), 4.84-4.80 (m,
1H), 4.56-4.48 (m, 1H), 4.17-4.13 (m, 2H), 3.51-3.47 (m, 1H),
2.72-2.63 (m, 1H), 2.28-2.19 (m, 1H), 2.02-1.96 (m, 2H), 1.73-
1.52 (m, 4H); 13C NMR (CDCl3) δ 145.0, 126.4, 124.3, 99.0, 81.7,
81.2, 73.7, 73.3, 66.0, 34.9, 34.7, 32.4, 32.1, 31.9, 31.5, 31.3, 31.2;
IR (neat, cm-1) 2926, 1619, 1091; MS (DCI/NH3) m/z (MH)+
)
181, (MNH4+) ) 198.
Dod eca -1,11-d ien e-5,8-d iol (5b). To a cooled solution (-30
°C) of copper(I) iodide (525 mg, 2.6 mmol) in dry Et2O (5 mL)
was added dropwise of allylmagnesium bromide (26.3 mL, 26.3
mmol, 1 M in THF), and the solution was stirred at -30 °C for
5 min. A solution of 2b (1 g, 8.76 mmol) in dry Et2O (5 mL) was
added, and the mixture was stirred at -30 °C for 2 h, hydrolyzed
with saturated NH4Cl (15 mL), and extracted with Et2O (3 ×
10 mL). The organic layer was separated, dried over MgSO4,
and concentrated. The crude product was purified by column
31.0; IR (neat, cm-1) 2931, 1622; MS (DCI/NH3) m/z (MH)+
)
139, (MNH4+) ) 173; HRMS cald for C8H10O2 ) 138,0681, found
138,0685.
Deca -1,9-d ien e-4,7-d iol (5a ). To cooled (-30 °C) copper(I)
iodide (315 mg, 1.58 mmol) was added dropwise vinylmagnesium
bromide (15.8 mL, 15.8 mol, 1 M in THF), and the reaction
mixture was stirred at -30 °C for 5 min. A solution of diepoxide

3360 J . Org. Chem., Vol. 64, No. 9, 1999
Notes
chromatography (hexane/ether 50/50) to yield the diol 5b (1.03
g, 60% yield): 1H NMR (CDCl3) δ 5.86-5.71 (m, 2H), 5.02-4.68
(m, 4H), 3.63-3.34 (m, 4H), 2.19-2.02 (m, 4H), 1.64-1.38 (m,
8H); 13C NMR (CDCl3) δ 138.6, 138.5, 114.7, 71.7, 71.1, 36.8,
36.3, 34.1, 33.0, 30.1; IR (neat, cm-1) 3354, 2928, 996, 910; MS
(DCI/NH3) m/z (MH)+ ) 199, (MNH4+) ) 216.
at 0 °C was added NaH (210 mg, 5.25 mmol, 60% dispersion in
mineral oil), and the reaction mixture was stirred at room
temperature for 15 min. A solution of allyl bromide (0.46 mL,
5.25 mmol) in dry DMF (30 mL) was added dropwise, and the
mixture was stirred at room temperature for 2 h. The reaction
mixture was hydrolyzed with saturated NH4Cl (25 mL), ex-
tracted with Et2O (2 × 20 mL), and washed with saturated NaCl
(3 × 10 mL). The organic layer was dried (MgSO4). The crude
product was purified by column chromatography (pentane/ether
90/10) to yield 17 (295 mg, 43% yield): 1H NMR (CDCl3) δ 5.98-
5.80 (m, 3H), 5.22 (dd, J ) 1.9, 15.2 Hz, 1H), 5.12 (dd, J ) 1.1,
10.3 Hz, 1H), 4.55 (br s, 1H), 4.35-4.30 (m, 1H), 4.03-3.91 (m,
5,8-Bis-a llyloxy-d od eca -1,11-d ien e (6b). To a solution of
diol 5b (200 mg, 1.01 mmol) in dry THF (3 mL) at 0 °C was
added NaH (80 mg, 2.02 mmol, 60% dispersion in mineral oil),
and the reaction mixture was stirred at room temperature for
15 min. The mixture was cooled to 0 °C, and allyl bromide (0.18
mL, 2.02 mmol) was added. After 1 h at room temperature were
added NaH (80 mg, 2.02 mmol) and allyl bromide (0.18 mL, 2.02
mmol), and the reaction mixture was stirred at room tempera-
ture for 2 h. The mixture was hydrolyzed with saturated NH4-
Cl (5 mL) and extracted with Et2O (3 × 10 mL). The organic
layer was separated and dried (MgSO4). The crude product was
purified by column chromatography (hexane/ether 90/10) to give
6b (170 mg, 65% yield): 1H NMR (CDCl3) δ 5.94-5.72 (m, 4H),
5.24 (dd, J ) 1.6, 18.8 Hz, 2H), 5.12 (dd, J ) 1.3, 10.4 Hz, 2H),
4.99 (dd, J ) 1.7, 21.0 Hz, 2H), 4.94 (dd, J ) 1.7, 15.8 Hz, 2H),
3.95 (dd, J ) 1.0, 5.1 Hz, 4H), 3.33-3.29 (m, 2H), 2.15-2.05 (m,
4H), 1.66-1.45 (m, 8H); 13C NMR (CDCl3) δ 138.7, 135.5, 116.4,
114.5, 78.5, 78.3, 70.0, 69.9, 33.2, 33.1, 29.7, 29.4, 29.0; IR (neat,
2H), 3.07 (br s, 1H), 2.65-2.55 (m, 1H), 1.58-1.50 (m, 1H); 13
C
NMR (CDCl3) δ 137.4, 134.9, 133.7, 117.1, 81.5, 74.6, 69.9, 40.8;
IR (neat, cm-1) 3387, 1061, 992; MS (DCI/NH3) m/z (MH)+
141, (MNH4+) ) 158.
)
tr a n s-Ben zoic Acid 4-Allyloxy-cyclop en t-2-en yl Ester
(18). To a solution of 17 (55 mg, 3.96 mmol) in dry THF (30
mL) were added triphenylphosphine (2.1 g, 7.92 mmol), benzoic
acid (970 mg, 7.92 mmol), and diethyl azodicarboxylate (1.25 mL,
7.92 mmol). The reaction mixture was stirred at room temper-
ature for 2 h, and the solvent was removed under vacuum. The
crude product was purified by column chromatography (pentane/
ether 90/10) to yield 18 (920 mg, 95% yield): 1H NMR (CDCl3)
δ 8.02-7.98 (m, 2H), 7.57-7.50 (m, 1H), 7.44-7.39 (m, 2H),
6.25-6.22 (m, 1H), 6.18-6.15 (m, 1H), 6.05-6.01 (m, 1H), 6.00-
5.88 (m, 1H), 5.29 (dd, J ) 1.3, 15.8 Hz, 1H), 5.19 (dd, J ) 1.3,
10.2 Hz, 1H), 4.84-4.80 (m, 1H), 4.05-3.99 (m, 2H), 2.37-2.21
(m, 2H); 13C NMR (CDCl3) δ 166.3, 137.6, 134.8, 133.5, 132.8,
129.5, 128.2, 117.0, 82.6, 79.4, 70.1, 37.7.
cm-1) 3078, 2937, 1081, 994, 914; MS (DCI/NH3) m/z (MH)+
)
279, (MNH4+) ) 296.
1,2-Bis(7-oxa -2 cycloh ep ta d ien yl)eth a n e (13a ). From 6b
(100 mg, 0.36 mmol) the bicycle 13a was obtained (48 mg, 60%
yield) following the general procedure: 1H NMR (CDCl3) δ 5.84-
5.76 (m, 2H), 5.66-5.61 (m, 2H), 4.26 (dd, J ) 4.6, 16.1 Hz, 2H),
4.00 (dd, J ) 4.7, 13.6 Hz, 2H), 3.60-3.52 (m, 2H), 2.38-2.30
(m, 2H), 2.17-2.13 (m, 2H), 1.93-1.63 (m, 2H), 1.71-1.45 (m,
6H); 13C NMR (CDCl3) δ 131.9, 130.2, 81.6, 80.9, 67.0, 66.9, 34.4,
34.3, 33.1, 32.4, 26.1, 26.0; IR (neat, cm-1) 3019, 2927, 1124;
MS (DCI/NH3) m/z (MH)+ ) 223, (MNH4+) ) 240; HRMS calcd
for C14H23O2 (MH+) ) 223,1698, found 223,1698.
tr a n s-4-Allyloxy-cyclop en t-2-en ol (19). To a solution of 18
(1.17 g, 4.6 mmol) in MeOH (25 mL) was added NaOMe (3.5
mL, 5.3 mL in MeOH), and the reaction mixture was stirred at
room temperature for 1 h. The mixture was treated with 1 N
HCl to reach pH ) 6 and was extracted with EtOAc (2 × 20
mL), dried (MgSO4), and concentrated under vacuum. The crude
product was purified by column chromatography (pentane/
ether 50/50) to give 19 (550 mg, 85% yield): 1H NMR (CDCl3) δ
6.04-5.98 (m, 2H), 5.94-5.81 (m, 1H), 5.23 (dd, J ) 1.0, 17.2
Hz, 1H), 5.14 (dd, J ) 1.1, 10.3 Hz, 1H), 4.98-4.94 (m, 1H),
4.72-4.68 (m, 1H), 3.96-3.93 (m, 2H), 2.41 (br s, 1H), 2.16-
2.08 (m, 1H), 1.97-1.88 (m, 1H); 13C NMR (CDCl3) δ 138.0,
Deca -1,9-d ien e-5,6-d iol (3d ). To a solution of allylmagne-
sium bromide (58 mL, 58.14 mmol, 1 M in THF) at -30 °C was
added copper iodide, and the resulting mixture was stirred at
-30 °C for 5 min. Commercially available (()-1,3-butadiene
diepoxide 2c (1.5 mL, 19.38 mmol) was added, and the solution
was stirred at -30 °C for 1 h. The reaction was quenched with
saturated NH4Cl (25 mL), extracted with Et2O, and dried
(MgSO4). The crude product was purified on silica gel (pentane/
ether 50/50) to yield 3d (2.4 g, 86% yield): 1H NMR (CDCl3) δ
5.87-5.73 (m, 2H), 5.06-4.93 (m, 4H), 3.43-3.38 (m, 2H), 2.84
(d, J ) 4.1 Hz, 2H), 2.26-2.07 (m, 4H), 1.62-1.49 (m, 4H); 13C
134.7, 134.0, 116.9, 82.9, 75.3, 69.8, 40.5; IR (neat, cm-1) 3381,
1357, 1062, 993, 927; MS (DCI/NH3) m/z (MH)+ ) 141, (MNH4
) 158.
)
+
tr a n s-3,5-Bis-a llyloxy-cyclop en ten e (9b). To a solution of
19 (500 mg, 3.57 mmol) in dry THF (20 mL) at 0 °C was added
NaH (215 mg, 5.35 mmol, 60% dispersion in mineral oil), and
the mixture was stirred for 30 min at room temperature. Allyl
bromide (0.46 mL, 5.35 mmol) in dry DMF (20 mL) was added,
and the reaction was stirred for 6 h at room temperature. NaH
(215 mg, 5.35 mmol) and allyl bromide (0.46 mL, 5.35 mmol)
were added, and the mixture was heated to 50 °C for 3 h. The
mixture was hydrolyzed with saturated NH4Cl (20 mL), ex-
tracted with Et2O (2 × 20 mL), and washed with saturated NaCl
(3 × 10 mL). The organic layer was dried (MgSO4). The crude
product was purified by column chromatography (pentane/ether
70/30) to afford 9b (490 mg, 77% yield): 1H NMR (CDCl3) δ
6.10-6.07 (m, 2H), 5.96-5.82 (m, 2H), 5.24 (dd, J ) 2.8, 19.2
Hz, 2H), 5.14 (dd, J ) 2.8, 8.8 Hz, 2H), 4.72-4.68 (m, 2H), 4.00-
3.90 (m, 4H), 2.04 (dd, J ) 6.6, 6.6 Hz, 2H); 13C NMR (CDCl3) δ
135.6, 135.0, 116.9, 83.0, 70.1, 38.0; IR (neat, cm-1) 3080, 1075,
922; MS (DCI/NH3) m/z (MNH4+) ) 198.
NMR (CDCl3) δ 138.4, 115.1, 74.0, 32.8, 30.0; IR (neat, cm-1
)
3377, 2940, 1437, 996, 913; MS (DCI/NH3) m/z (MNH4+) ) 188.
5,6-Bis-a llyloxy-d eca -1,9-d ien e (4d ). To a solution of diol
3d (500 mg, 2.94 mmol) in dry THF (30 mL) at 0 °C was added
NaH (470 mg, 11.76 mmol, 60% dispersion in mineral oil), and
the reaction mixture was stirred for 15 min at room temperature.
The mixture was cooled to 0 °C, and a solution of allyl bromide
(1.02 mL, 11.76 mmol) in dry DMF (10 mL) was added. The
reaction mixture was stirred for 3 h at room temperature,
hydrolyzed with saturated NH4Cl (20 mL), and extracted with
Et2O (3 × 25 mL). The organic layer was separated and dried
(MgSO4). The crude product was purified by column chroma-
tography (pentane/ether 90/10) to give 4d (650 mg, 88% yield):
1H NMR (CDCl3) δ 5.98-5.72 (m, 4H), 5.31-4.90 (m, 8H), 4.16-
3.90 (m, 4H), 3.50-3.30 (m, 2H), 2.33-2.00 (m, 4H), 1.74-1.42
(m, 4H); 13C NMR (CDCl3) δ 138.8, 135.6, 116.8, 114.8, 79.4, 71.9,
30.3, 29.3; IR (neat, cm-1) 3079, 2925, 1088, 994, 912; MS (DCI/
NH3) m/z (MH)+ ) 251, (MNH4+) ) 268.
Ack n ow led gm en t. The authors are thankful to Dr.
Tracy J . J enkins for proofreading this manuscript and
to Alain Valleix for running mass spectra.
d l-1,1′-Bis(oxa -5-cycloh ep ta d ien e) (16a ). From 4d (100
mg, 0.40 mmol) the bicycle 16a was obtained (39 mg, 50% yield)
following the general procedure: 1H NMR (CDCl3) δ 5.83-5.76
(m, 2H), 5.66-5.60 (m, 2H), 4.40 (dd, J ) 1.1, 4.1 Hz, 2H), 4.07
(dd, J ) 1.1, 4.7 Hz, 2H), 3.55-3.50 (m, 2H), 2.44-2.40 (m, 2H),
2.18-2.12 (m, 2H), 1.90-1.75 (m, 4H); 13C NMR (CDCl3) δ 131.5,
129.7, 83.8, 68.8, 30.4, 26.4; IR (neat, cm-1) 3018, 2926, 1137;
MS (DCI/NH3) m/z (MH)+ ) 195, (MNH4+) ) 212.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for compounds 2a , 3a , 4a , 4a ′, 9a , 9a ′, 9b, D, 2b, 3b,
4b, 10a , 3c, 4c, 12a , 12b, 5c, 15a , 5a , 6a , 7a , 8a , 11a , 14a ,
5b, 6b, 13a , 3d , 4d , 16a , 17, 18, and 19. This material is
available free of charge via the Internet at http://pubs.acs.org.
cis-4-Allyloxy-cyclop en t-2-en ol (17). To a solution of cis-
4-cyclopentene-1,3-diol (500 mg, 5 mmol) in dry THF (30 mL)
J O982098U