An Iterative Approach to Fused Ether Ring Systems

Full text of DOI:10.1021/jo980996k

5310
J . Org. Chem. 1998, 63, 5310-5311
Sch em e 1
An Iter a tive Ap p r oa ch to F u sed Eth er Rin g
System s
J on D. Rainier* and Shawn P. Allwein
Department of Chemistry, The University of Arizona,
Tucson, Arizona 85721
Received May 26, 1998
Fused heterocyclic ring systems are the key skeletal
arrangement in a vast array of bioactive natural products.
The family of compounds which best illustrate this structural
feature are the marine “ladder” toxins whose skeletons
include cis- and trans-fused six-nine-membered oxygenated
heterocycles. Although the members of this family are most
commonly associated with neurotoxicity and “red tide”
catastrophes,1 some have shown potent antimicrobial activ-
ity and lack neurotoxicity (cf. gambieric acid).2,3 The very
interesting bioactivity of the members of this family when
coupled with their molecular complexity would seem to
warrant an efficient approach to their synthesis and/or to
the synthesis of analogues if they are to be fully evaluated.4
With this in mind, the regularity in these structures has
influenced many, including us, to believe that an iterative
strategy to the fused ether skeleton would be ideal. While
independent investigations from the laboratories of Mori,5
Clark,6,7 McDonald,8 and Martin9 approach this ideal, to date
there exist no general iterative strategies to synthesize six-
nine-membered cyclic ethers.
At the outset, we envisioned a novel three-flask protocol
toward fused ether ring systems. This strategy centered
around stereoselective cyclic enol ether epoxidations and
subsequent epoxide opening reactions with carbon nucleo-
philes (1 f 3, Scheme 1).10-13 While the epoxidation of C-3
substituted glycals appeared to be fairly well under-
stood,10,14,15 the lack of information regarding the stereose-
lective epoxidation of C-3 unsubstituted glycals as well as
more complex ring systems (bi- and tricyclic enol ethers,
medium sized rings) was a concern. Despite this, we decided
to pursue this approach because of the considerable flex-
ibility provided by the existence of a large number of
epoxidation protocols (vide infra). After C-C bond forma-
tion, annulation would result in a new cyclic enol ether and
thus complete the iterative pathway (cf. 3 f 4, Scheme 1).
Among the many possible methods that had the potential
to meet our cyclization needs, carbonyl-olefin and olefin-
olefin metathesis chemistry were particularly attractive as
they were capable of generating cyclic enol ethers from
pendant carbonyls and olefins.16,17 Additionally, these
methods of ring formation have been used in the synthesis
of fused ethers.6,7,18-21 Described herein are our preliminary
experiments in this area which utilize the paradigm il-
lustrated in Scheme 1.
The epoxidation of tribenzyl-D-glucal according to Dan-
ishefsky’s protocol15 followed by the addition of allylmagne-
sium chloride gives bis-homoallyl alcohol 7 (eq 1). We have
utilized a single-flask conversion of 6 f 7; concentration of
a CH2Cl2 solution of the intermediate epoxide, dissolution
of the resulting residue in THF, and coupling with allyl-
magnesium chloride at 0 °C provides 7. Thus far, the 6 f
7 transformation has proceeded in an overall yield of 82%
and can be accomplished in a matter of hours. The addition
of anions to the intermediate epoxide appears to be
general;10-13 propargylmagnesium chloride and vinylmag-
nesium bromide also add in respectable yields. Subsequent
conversion of the resulting alcohol to the corresponding
acetate or formate esters using acetic anhydride or benzoyl
chloride/DMF22 respectively gives 8 and 9 in high yield.
(1)
(1) Red Tides; Okaichi, T., Anderson, D. M., Nemoto, T., Ed.; Elsevier:
New York, 1989.
We have invested considerable time examining the 8 f
12 and 9 f 13 transformations; our best results to date are
illustrated (eq 2). Subjecting acetate 9 or formate 8 to
Takai’s conditions23 led to 65% and 28% yields of enol ethers
(2) Nagai, H.; Torigoe, K.; Satake, M.; Murata, M.; Yasumoto, J . J . Am.
Chem. Soc. 1992, 114, 1102-1103.
(3) Nagai, H.; Murata, M.; Torigoe, K.; Satake, M.; Yasumoto, T. J . Org.
Chem. 1992, 57, 7, 5448-5453.
(4) The Nicolaou group has been at the forefront of the synthetic efforts
toward this family. Their work has led to the total synthesis of brevetoxins
A and B.30-32
(5) Mori, Y.; Yaegashi, K.; Furukawa, H. J . Am. Chem. Soc. 1996, 118,
8158-8159.
(16) Grubbs, R. H.; Miller, S. J .; Fu, G. C. Acc. Chem. Res. 1995, 28,
446-452.
(6) Clark, J . S.; Kettle, J . G. Tetrahedron Lett. 1997, 38, 123-126.
(7) Clark, J . S.; Kettle, J . G. Tetrahedron Lett. 1997, 38, 127-130.
(8) Bowman, J . L.; McDonald, F. E. J . Org. Chem. 1998, 63, 3680-3682.
(9) Alvarez, E.; Diaz, M. T.; Perez, R.; Ravelo, J . L.; Regueiro, A.; Vera,
J . A.; Zurita, D.; Martin, J . D. J . Org. Chem. 1994, 59, 2848-2876.
(10) Lemieux, R. U.; Huber, G. J . Am. Chem. Soc. 1956, 78, 4117-4119.
(11) Bellosta, V.; Czernecki, S. J . Chem. Soc., Chem. Commun. 1989,
199-200.
(17) Despite the substantial work that has been accomplished in this
area, there exists considerable room for improvement as the current state
of the art involves the use of highly sensitive organometallic reagents, often
in stoichiometric quantities. For
a discussion of efficiency and organic
synthesis, see: Trost, B. M. Science 1991, 254, 1471-1477.
(18) Fu, G. C.; Grubbs, R. H. J . Am. Chem. Soc. 1993, 115, 3800-3801.
(19) Fujimura, O.; Fu, G. C.; Grubbs, R. H. J . Org. Chem. 1994, 59, 4029-
4031.
(12) Belosludtsev, Y. Y.; Bhatt, R. K.; Falck, J . R. Tetrahedron Lett. 1995,
33, 5881-5882.
(20) Nicolaou, K. C.; Postema, M. H. D.; Yue, E. W.; Nadin, A. J . Am.
Chem. Soc. 1996, 118, 10335-10336.
(13) Hanessian, S.; Liak, T. J .; Dixit, D. M. Carbohydr. Res. 1981, 88,
C14-C19.
(21) Nicolaou, K. C.; Postema, M. H. D.; Claiborne, C. F. J . Am. Chem.
Soc. 1996, 118, 1565-1566.
(14) Danishefsky, S. J .; McClure, K. F.; Randolph, J . T.; Ruggeri, R. B.
Science 1993, 260, 1307-1309.
(22) Barluenga, J .; Campos, P. J .; Gonzalez-Nunez, E.; Asensio, G.
Synthesis 1985, 426-429.
(15) Halcomb, R. L.; Danishefsky, S. J . J . Am. Chem. Soc. 1989, 111,
6661-6666.
(23) Takai, K.; Kakiuchi, T.; Kataoka, Y.; Utimoto, K. J . Org. Chem. 1994,
59, 2668-2670.
S0022-3263(98)00996-7 CCC: $15.00 © 1998 American Chemical Society
Published on Web 07/23/1998

Communications
J . Org. Chem., Vol. 63, No. 16, 1998 5311
11 and 10, respectively.24,25 Alternatively, enol ether 10 can
be generated in 58% yield directly from alcohol 7 through
the use of ethyl vinyl ether and Hg(OAc)2. The success of
the Takai procedure appears to be highly dependent upon
the amount of reagent present as four equiv of TiCl4 results
in the reisolation of starting material while the addition of
a fifth equivalent results in the yields indicated.26 As was
observed by Nicolaou utilizing the Tebbe and Petasis
reagents,20,21 we have also isolated cyclic enol ethers 12 and
13, albeit in low yield. Although we are currently attempt-
ing to optimize this potentially important cyclization reac-
tion,27 a more efficient approach to 12 and 13 in our hands
uses Grubbs’ two-step protocol and Schrock’s molybdenum
alkylidene 14.19 Exposure of enol ethers 10 and 11 to 14
(15 mol %) results in the isolation of cyclic ethers 12 and 13
in 85% and 76% yields, respectively. These results demon-
strate that an iterative approach to fused ethers which
employs cyclic enol ether epoxidations is possible. As these
experiments are preliminary, none of the reactions have
been optimized; we are confident that some of the moderate
yields that we have observed can be improved as would be
required for any truly successful iterative strategy.
the diastereomeric epoxide. Much to our delight, a minor
modification of Spilling’s epoxidation conditions29 resulted
in the desired vinyl acetate 16 as a 6:1 mixture of diaster-
eomers after allylmagnesium chloride addition to the inter-
mediate epoxide followed by acetylation (eq 4). The relative
stereochemistry at the newly formed centers in 16 was
determined from the H2, C-Ha coupling value of 11.8 Hz
along with the expected NOESY cross-peaks. These results
successfully demonstrate the flexibility of our approach to
these systems. We have been able to generate either epoxide
isomer by simply altering the oxidation protocol.
(4)
Utilizing the conditions which were successful in the
generation of bicycles 12 and 13, acetoxyolefin 16 was
transformed into tricycle 17 in 47% overall yield (eq 5).
Interestingly, as in the 8, 9 f 12, 13 transformations, the
Takai protocol resulted in the formation of the desired enol
ether along with a small amount of metathesis product 17.
(2)
(5)
To conclude, we have demonstrated that enol ether
epoxidations, when coupled with C-C bond formation and
ring-closing metathesis, can provide fused pyran ring sys-
tems. Current studies in this area are concentrating on the
optimization of this sequence, the incorporation of medium
sized rings, and the application of this strategy to the
synthesis of bioactive fused cyclic ethers.
Bicyclic enol ethers 12 and 13 lacking substitution at the
carbon adjacent to the enol ether have been exposed to the
pivotal epoxidation/epoxide opening sequence. The same
conditions utilized for the 6 f 9 transformation (dimethyl-
dioxirane; allylmagnesium chloride; acetic anhydride) re-
sulted in the formation of acetoxy olefin 15 in 19% overall
yield (eq 3). Unfortunately, 15 appeared to be the undesired
isomer on the basis of the H2, Ha,e coupling constant of 2.8
Hz.28
Ack n ow led gm en t. We gratefully acknowledge the
National Institutes of Health (GM56677), Research Cor-
poration, and the donors of the Petroleum Research Fund,
administered by the American Chemical Society, for partial
support of this work. Support from the Department of
Chemistry at The University of Arizona is also acknowl-
edged. The authors would like to thank Professor Robin
Polt for helpful discussions as well as the use of his
laboratory during the initial phases of this project and
Professor David Wigley and Mr. J eff Anthis for the use of
their glovebox. We would also like to thank Dr. Arpad
Somagyi for help with mass spectra and Dr. Neil J acobsen
and Ms. Carolyn Kriss for help with NMR experiments.
(3)
With the failure of dimethyldioxirane to deliver the
desired stereoisomer, we turned to halohydrins as epoxide
precursors as, in theory, they would allow us to synthesize
(24) Exposure of acetate 9 to the Tebbe or Petasis reagents has led only
to recovery of starting material or decomposition upon more vigorous
reaction conditions (110 °C).
Su p p or tin g In for m a tion Ava ila ble: Experimental proce-
dures and spectroscopic data for compounds 7-13 and 15-17 (33
pages).
(25) As has been discussed,23 catalytic quantities of PbCl2 have a dramatic
influence on these reactions as the absence of PbCl2 resulted in only 15%
of 11.
J O980996K
(26) We believe that this is due to coordination of the four oxygens about
the pyran ring with Ti. Addition of more than 5 equiv of reagent resulted
in the isolation of significant quantities of alcohol 7 after aqueous workup.
(27) Thus far, we have been able to isolate 13 in 15% yield by extending
the time of the reaction, completely decomposing enol ether 11 in the
process. The major component from this preliminary experiment appears
to be dimeric.
(28) We have tentatively identified the only other recognizable product
from this reaction as the exocyclic enol ether from deprotonation and epoxide
opening. Thus far, we have been unable to determine the relative stereo-
chemistry at the carbon bearing the hydroxyl group in this compound.
(29) Marzabadi, C. H.; Spilling, C. D. J . Org. Chem. 1993, 58, 3761-
3766.
(30) Nicolaou, K. C.; Theodorakis, E. A.; Rutjes, F. P. J . T.; Tiebes, J .;
Sato, M.; Untersteller; Xiao, X.-Y. J . Am. Chem. Soc. 1995, 117, 1171-
1172.
(31) Nicolaou, K. C.; Rutjes, F. P. J . T.; Theodorakis, E. A.; Tiebes, J .;
Sato, M.; Untersteller J . Am. Chem. Soc. 1995, 117, 1173-1174.
(32) Nicolaou, K. C.; Yang, Z.; Shi, G. Q.; Gunzner, J . L.; Agrios, K. A.;
Gartner, P. Nature 1998, 392, 264-269.