Alkene substituents for selective activation of endo-regioselective polyepoxide oxacyclizations

Article abstract of DOI:10.1021/ol048212e

(Chemical equation presented) The presence of an alkenyl substituent on the terminal epoxide of a polyepoxide substrate enhances the yield of all-endo-regioselective tandem oxacyclization to trans-syn-trans-fused polycyclic ethers. For a substrate in which the epoxide and alkene functional groups are separated by two methylene substituents, a novel bromonium ion-induced endo-regioselective cyclization to bromooxepane is also described.

Full text of DOI:10.1021/ol048212e

ORGANIC
LETTERS
2004
Vol. 6, No. 24
4487-4489
Alkene Substituents for Selective
Activation of endo-Regioselective
Polyepoxide Oxacyclizations
Fernando Bravo,† Frank E. McDonald,* Wade A. Neiwert,‡ and
Kenneth I. Hardcastle‡
Department of Chemistry, Emory UniVersity, Atlanta, Georgia 30322
fmcdona@emory.edu
Received September 3, 2004
ABSTRACT
The presence of an alkenyl substituent on the terminal epoxide of a polyepoxide substrate enhances the yield of all-endo-regioselective
tandem oxacyclization to trans-syn-trans-fused polycyclic ethers. For a substrate in which the epoxide and alkene functional groups are
separated by two methylene substituents, a novel bromonium ion-induced endo-regioselective cyclization to bromooxepane is also described.
We recently demonstrated that the synthesis of fused poly-
cyclic ethers (both polyoxepanes1 and polypyrans2) can be
Scheme 1. endo-Selective Polyepoxide Cyclizations
achieved in a biomimetic and endo-regioselective fashion
by addition of a Lewis acid to the corresponding polyepoxide.
Boron trifluoride etherate was shown to be the best activator
for the oxacyclization cascade, and the reaction required nu-
cleophilic termination by a carbonyl oxygen such as carbon-
ate or carbamate. However, the polyoxacyclization yield de-
creased with increasing the number of epoxides and, con-
sequently, the number of rings formed. For instance, the
geraniol and farnesol-derived polyepoxides 1 and 2 provided
trans-syn-trans-fused oxacyclic products 5 and 6 in 60 and
52% isolated yields, respectively (Scheme 1), but only a 27%
yield of 7 was obtained for the tetraoxacyclization of the
tetraepoxide 3 derived from geranylgeraniol.1b The reaction
was also explored in the pentaepoxide case 4,3-5 which
afforded the pentacyclic product 8 in a single operation, but
only in 12% isolated yield, thus setting the limits of the
method.
† Current address: GlaxoSmith-Kline, Chemical Development, Verona,
Italy.
‡ Emory University X-ray Crystallography Laboratory.
(1) (a) McDonald, F. E.; Wang, X.; Do, B.; Hardcastle, K. I. Org. Lett.
We anticipated that some of the mass balance was lost in
activations of epoxides other than the terminal epoxide. With
this consideration in mind, we envisioned that the introduc-
tion of an activating group at the terminal epoxide could
increase the yield of the polyoxacyclization. As the activator,
2000, 2, 2917. (b) McDonald, F. E.; Bravo, F.; Wang, X.; Wei, X.; Toganoh,
M.; Rodr´ıguez, J. R.; Do, B.; Neiwert, W. A.; Hardcastle, K. I. J. Org.
Chem. 2002, 67, 2515.
(2) Bravo, F.; McDonald, F. E.; Neiwert, W. A.; Do, B.; Hardcastle, K.
I. Org. Lett. 2003, 5, 2123.
10.1021/ol048212e CCC: $27.50
© 2004 American Chemical Society
Published on Web 11/05/2004

we chose the vinyl group, which not only better stabilizes
the incipient positive charge at the terminal quaternary
position6 but might also act as a coordination site for an
appropriate Lewis acid. In addition, the alkene functional
group provides the opportunity for postcyclization transfor-
mations at the polycyclic ether terminus.
14 in significantly lower yield than observed for the
monoalkene substrate 11. Two slightly different routes were
explored for the formation of polyepoxide substrates: from
13, oxidation of the allylic alcohol with IBX and subsequent
Wittig methylenation was followed by Shi epoxidation10 of
the conjugated diene to afford diepoxide 15 as the major
product, although the yield for this final transformation (step
f) was only 55% yield. From 14, the allylic hydroxyl group
was employed for Sharpless epoxidation of the terminal
alkene, followed by Shi epoxidation of the internal alkene
(in this case, step f gave 90% yield), and vinyl-substituted
triepoxide 16 was then obtained by alcohol oxidation and
Wittig methylenation, in this case using potassium tert-
butoxide as a base.11
The cyclization precursors were synthesized as shown in
Scheme 2. Geraniol (9) and farnesol (10) were each selec-
Scheme 2. Synthesis of Vinyl-Substituted Di- and Triepoxides
15 and 16a
We proceeded to the optimization of cyclization condi-
tions, first with diepoxide substrate 15. Boron trifluoride
etherate as a Lewis acid produced the desired bicyclic product
17 from tandem endo,endo-regioselective cyclization in 65%
yield (Table 1, entry 1), which slightly improves the 60%
yield obtained with the Boc-protected geraniol diepoxide
(vide supra). This result is explained only by the better
stabilization of the positive charge that effects the vinyl group
in compound 15 in comparison with the methyl group, as
boron trifluoride, once coordinated to the epoxide, lacks
another free coordination site. Other Lewis acids with the
potential for coordination to multiple sites were explored,
in particular lanthanide Lewis acids. Lanthanum(III) triflate
afforded the cyclized product 17 in 63% yield (entry 4), a
result similar to that obtained with boron trifluoride. How-
ever, both gadolinium(III) triflate (77% yield of the bicyclic
product, entry 5) and ytterbium(III) triflate (73%, entry 3)
considerably increased the yield of the cyclization to provide
17,12 thus demonstrating the validity of our approach.13 From
the triepoxide substrate 16, the use of gadolinium(III) triflate
resulted in the formation of the all-trans-syn-trans-fused
tricyclic product 18 in 45% yield (entry 6), whereas
ytterbium(III) triflate proved to be a better choice, affording
compound 18 in 56% yield (entry 7).
a Conditions: (a) D-(-)-DIPT, Ti(O-i-Pr)4, t-BuOOH, CH2Cl2,
-18 °C, 12 h. (b) (Boc)2O, N3-Me-imidazole, toluene, 0 to 20 °C,
12 h. (c) SeO2 (10 mol %), t-BuOOH, H2O/CH2Cl2, 0 to 20 °C,
36-96 h. (d) IBX, DMSO, 20 °C, 30 min. (e) Ph3P+CH3Br-,
n-BuLi, THF, 20 °C, 12 h. (f) Shi ketone, Oxone, (CH3O)2CH2/
CH3CN/H2O, pH 11.4, 0 °C. (g) SO3-py, DMSO, CH2Cl2, NEt3, 0
°C, 3 h. (h) Ph3P+CH3Br-, t-BuOK, THF, 20 °C, 12 h.
tively epoxidized by Sharpless catalytic asymmetric epoxi-
dation,7 followed by protection of the alcohol as the Boc
carbonate.8 The terminal (E)-methyl substituents of 11 and
12 underwent Sharpless allylic oxidation with catalytic
selenium dioxide9 to afford the corresponding allylic alcohols
13 and 14. Not surprisingly, the diene 12 was converted into
In a continuing search for new methods to activate endo-
regioselective epoxide cyclizations, we also explored halo-
nium-promoted cyclization of epoxyalkene 11. We were
pleased to observe that bromonium di-sym-collidine per-
chlorate14 afforded predominantly endo,endo-selective cy-
clization to provide bromooxepanes 19/20 as a separable
mixture of diastereomers (Scheme 3).12,15,16
(3) Boc-protected pentaepoxide alcohol 4 was synthesized from the
corresponding pentaene alcohol in a sequence of reactions similar to the
ones described for geraniol, farnesol, and geranylgeraniol derivatives in
ref 1. The pentaene alcohol, in turn, was prepared by coupling of the
organobarium reagent derived from farnesyl chloride (see ref 4) with
8-bromo-1-O-tert-butyldiphenylsilyl-3,7-dimethyl-octa-2,6-dien-1-ol (ref 5).
See Supporting Information for details.
(4) (a) Yanagisawa, A.; Habaue, S.; Yamamoto, H. J. Am. Chem. Soc.
1991, 113, 5893. (b) Yanagisawa, A.; Habaue, S.; Yamamoto, H. J. Am.
Chem. Soc. 1991, 113, 8955. (c) Yanagisawa, A.; Hibino, H.; Hisada, Y.;
Yasue, K.; Yamamoto, H. Bull. Chem. Soc. Jpn. 1995, 68, 1263.
(5) Corey, E. J.; Shieh, W.-C. Tetrahedron Lett. 1992, 33, 6435.
(6) (a) Nicolaou, K. C.; Prasad, C. V. C.; Somers, P. K.; Hwang, C.-K.
J. Am. Chem. Soc. 1989, 111, 5330. (b) Nicolaou, K. C.; Prasad, C. V. C.;
Somers, P. K.; Hwang, C.-K. J. Am. Chem. Soc. 1989, 111, 5335. (c)
McDonald, F. E.; Wei, X. Org. Lett. 2002, 4, 593.
In conclusion, we note that the presence of terminal alkene
in polycyclic products 17 and 18 might be exploited in
(10) (a) Wang, Z.; Tu, Y.; Frohn, M.; Zhang, J.; Shi, Y. J. Am. Chem.
Soc. 1997, 119, 11224. (b) Cao, G.-A.; Wang, Z.-X.; Tu, Y.; Shi, Y.
Tetrahedron Lett. 1998, 39, 4425. (c) Zhu, Y.; Tu, Y.; Tu, H.; Shi, Y.
Tetrahedron Lett. 1998, 39, 7819. (d) Frohn, M.; Dalkiewicz, M.; Tu, Y.;
Wang, Z.-X.; Shi, Y. J. Org. Chem. 1998, 63, 2948.
(11) Use of n-butyllithium or phenyllithium in the Wittig reaction leading
to 16 considerably reduced the yield of the methylenation to 20-25%.
(12) See Supporting Information for essential data and thermal ellip-
soid diagrams for crystal structures obtained for compounds ent-17 and
19.
(13) Cyclization of diepoxide 1 (Scheme 1) under the optimized
conditions (ytterbium(III) triflate) gave the bicyclic product 5 in 52% yield,
demonstrating that the vinyl substituent in substrate 15 plays a significant
role in enhancing the cyclization yield.
(7) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.;
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765.
(8) Basel, Y.; Hassner, A. J. Org. Chem. 2000, 65, 6368.
(9) Umbreit, M. A.; Sharpless, K. B. J. Am. Chem. Soc. 1977, 99, 5526.
(14) Lemieux, R. U.; Morgan, A. R. Can. J. Chem. 1965, 43, 2190.
4488
Org. Lett., Vol. 6, No. 24, 2004

Table 1. Lewis Acid-Promoted Oxacyclizations of Polyepoxide Substrates 15 and 16
entry
substrate
product
Lewis acid
conditions
isolated yield
1
2
3
4
5
6
7
15
15
15
15
15
16
16
17
17
17
17
17
18
18
BF3-OEt2 (1 equiv)
Yb(OTf)3 (1 equiv)
Yb(OTf)3 (3 equiv)
La(OTf)3 (3 equiv)
Gd(OTf)3 (3 equiv)
Gd(OTf)3 (5 equiv)
Yb(OTf)3 (6 equiv)
-40 °C, 10 mina
-40 to 20 °C, 4 ha
20 °C, 1 ha
65%
59%
73%
63%
77%
47%
56%
20 °C, 2.5 ha
20 °C, 1 ha
20 °C, 4 hb
20 °C, 2 hc
a Solvent: CH2Cl2, 0.05 M. b CH2Cl2, 0.01 M. c CH2Cl2, 0.04 M.
troscopy, X-ray diffractometry) provided by grants from the
National Institutes of Health, the National Science Founda-
tion, and the Georgia Research Alliance. We also thank Dr.
John A. Hyatt (Eastman Chemical Company) for valuable
discussions regarding the chemistry of (E,E)-farnesol.
Scheme 3. endo,endo-Bromocyclization of Epoxyalkene 11
Supporting Information Available: Experimental pro-
cedures and characterization data for new compounds and
crystallographic data for compounds ent-17 and 19 (CIF).
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL048212E
(15) The only related synthesis of halooxepanes from hydroxyalkene
synthesis requires alkoxy-substituted alkenes in order to achieve endo-
regioselectivity: (a) Brunel, Y.; Rousseau, G. J. Org. Chem. 1996, 61, 5793.
(b) Simart, F.; Brunel, Y.; Robin, S.; Rousseau, G. Tetrahedron 1998, 54,
13557.
(16) In addition to CH2Cl2 as a solvent, the bromocyclization of 11 could
also be conducted in CH3CN with a similar outcome (51% combined yield
of 19 and 20, 3:2 ratio). Toluene, DMF, THF, and Et2O were not suitable
solvents for this transformation.
postcyclization functionalization.17 Further applications of
vinyl-substituted polyepoxide substrates to polycyclic ether
formation are in progress, including studies with transition-
metal catalysts for selective epoxide activation. We also note
that bromooxepane units similar to 19 and 20 are found in
the armatol family of natural products.18
(17) For examples of related postcyclization functionalization transforma-
tions, see: Kadota, I.; Takamura, H.; Sato, K.; Ohno, A.; Matsuda, K.;
Satake, M.; Yamamoto, Y. J. Am. Chem. Soc. 2003, 125, 11893.
(18) Ciavatta, M. L.; Wahidulla, S.; D’Souza, L.; Scognamiglio, G.;
Cimino, G. Tetrahedron 2001, 57, 617.
Acknowledgment. This research was supported by the
National Science Foundation (CHE-9982400). We also
acknowledge the use of shared instrumentation (NMR spec-
Org. Lett., Vol. 6, No. 24, 2004
4489