Intramolecular vinylsilane-oxocarbenium condensations: Concise assembly of cis-bicyclic ether arrays

Article abstract of DOI:10.1021/ol071349v

Lewis acid-mediated intramolecular attack of vinylsilanes at tethered oxonium precursors 1 results in a rapid assembly of the cis-fused bicyclic ether species 3, with complete regio- and stereospecific control, and in some cases near-quantitative yield. C

Full text of DOI:10.1021/ol071349v

ORGANIC
LETTERS
2007
Vol. 9, No. 18
3507-3510
Intramolecular Vinylsilane−Oxocarbenium
Condensations: Concise Assembly of
Cis-Bicyclic Ether Arrays†
,
|
Stephen Philip Fearnley*,‡, and Pedro Lory§,
Department of Chemistry & Physics, Lamar UniVersity, P.O. Box 10022,
Beaumont, Texas, 77710, and Department of Chemistry, The City UniVersity of
New York-The Graduate Center & York College, 94-20 Guy R. Brewer BlVd.,
Jamaica, New York 11451
fearnley@york.cuny.edu
Received June 7, 2007
ABSTRACT
Lewis acid-mediated intramolecular attack of vinylsilanes at tethered oxonium precursors 1 results in a rapid assembly of the cis-fused
bicyclic ether species 3, with complete regio- and stereospecific control, and in some cases near-quantitative yield. Continued investigation
suggests a general approach to a variety of such ether frameworks.
In recent years a large number of natural products containing
fused polycyclic ether arrays have surfaced and synthetic
endeavors to address these complex and often biologically
potent targets have quite rightly attracted much effort and
attention. Foremost among these are the brevetoxins,1 which
themselves have inspired a profusion of approaches to
systems of this overall type and pattern.2
strategies and thereby general methodologies for construction
of the corresponding cis-systems have proved less prevalent.3
This is not to say that many structurally complex and/or
bioactive examples of this distinct subclass do not exist per
se. In fact, these include a number of valid bicyclic natural
product targets, as illustrated by Figure 1, with this feature
further extrapolated to such intricate polycyclic architectures
as the halichondrins and maitotoxin.
However, as a result, efforts to date have focused primarily
on ether arrays with an all-trans-arrangement, whereas
We recently chose to develop a general route to this
common structural motif, involving the intramolecular attack
of a proximally tethered vinylsilane at an oxocarbenium
moiety, generated in situ from the corresponding cyclic acetal
under appropriate Lewis acid activation, Scheme 1. We
envisaged that the constrained intramolecular nature of the
delivery would yield cis-ring junctions in exclusive fashion.
Similar reactions utilizing a variety of equivalent electrophilic
species4 provide ample precedent, in particular the elegant
studies of Overman.5 By direct comparison, this particular
† Dedicated to the memory of Professor Shawn B. Allin [1966-2006]s
scholar, scientist, and friend.
‡ Present address: The City University of New York-The Graduate
Center & York College.
Lamar University.
| The City University of New York-The Graduate Center & York
College.
§ Present address: Tibotec BVBA, Gen. De Wittelaan L 11B 3, 2800
Mechelen, Belgium.
(1) For example, Nicolau’s landmark synthesis of brevetoxin B: Nicolau,
K. C.; Theodorakis, E. A.; Rutjes, F. P. J. T.; Tiebes, J.; Sato, M.;
Untersteller, E.; Xiao, X.-Y. J. Am. Chem. Soc. 1995, 117, 1171-1172.
Nicolau, K. C.; Rutjes, F. P. J. T.; Theodorakis, E. A.; Tiebes, J.; Sato, M.;
Untersteller, E. J. Am. Chem. Soc. 1995, 117, 1173-1174. For an intriguing
personalized account of these efforts see: Nicolau, K. C. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 589-607.
(2) (a) Alvarez, E.; Candenas, M. L.; Pere´z, R.; Ravelo, J. L.; Martin, J.
D. Chem. ReV. 1995, 95, 1953-1980. (b) Marmsa¨ter, F. P.; West, F. G.
Chem. Eur. J. 2002, 8, 4347-4353. (c) Evans, P. A.; Delouvrie´, B. Curr.
Opin. Drug DiscoVery DeV. 2002, 5, 986-998.
(3) One such example with potential for broader application features ring-
closing metathesis in carbohydrate-derived systems: (a) Leeuwenburgh, M.
A.; Overkleeft, H. S.; van der Marel, G. A.; van Boom, J. H. Synlett 1997,
1263-1264. (b) Leeuwenburgh, M. A.; Kulker, C.; Duynstee, H. I.;
Overkleeft, H. S.; van der Marel, G. A.; van Boom, J. H. Tetrahedron 1999,
55, 8253-8262.
10.1021/ol071349v CCC: $37.00
© 2007 American Chemical Society
Published on Web 08/04/2007

examples of this typesthe instability of the resulting allylic
ether products to the prevailing reaction conditions.9 We
predicted that construction of bicyclic systems would allay
this problem, due to increased resilience arising from the
usual inherent entropic factors.
Proof of concept required a facile construction of the
requisite precursors, via simple Williamson-type ether cou-
pling of the appropriate R-hydroxylated acetal with corre-
sponding vinylsilane fragments. The first example in our
study employed the synthesis of a [6,6]-cis-fused pyranopy-
ran system, and is illustrative of our overall strategy, Scheme
2. Mild epoxidation of dihydropyran in the presence of
Scheme 2. Precursor Synthesis and Cyclization
Figure 1. Representative cis-fused bicyclic ether natural products.
proposed cyclization would represent a 6-exo-trig closure at
an exocyclic oxocarbenium initiator with endocyclic vinyl-
silane as the terminating group.6
Scheme 1. Generalized Approach to Cis-Bicyclic Ether Arrays
methanol yielded the 3-hydroxy-2-methoxyacetal 2a as
essentially pure trans isomer.10 Well aware of the oft-times
critical role of olefin stereochemistry in these processes,11
we chose to proceed directly via the Z-silane in order to
expedite our investigation; this fragment was readily con-
structed by using a modification of the known literature
procedure.12 Coupling ensued to afford the key substrate 3a
in overall satisfactory yield,13 and cyclization studies could
begin.
In the event, a brief survey of Lewis acid vs reaction
conditions revealed BF3-promoted cyclization to be both
sufficiently rapid and essentially quantitative (GC-MS analy-
sis). Furthermore, the reaction proceeded in exclusive fashion
to furnish a single diastereomeric product, though isolated
yield did drop somewhat due to inherent volatility.14
Although comparison with similar known trans compounds
proved suggestive of a cis system, stereochemistry was not
Surprisingly, this class of cyclization has not previously
been utilized in synthesis,7 although an early example of
monocyclic reactivity was investigated by Fleming.8 This
study exposed one plausible reason for the scarcity of
(4) Acid chlorides: Burke, S. D.; Murtiashaw, C. W.; Dike, M. S.; Smith
Strickland, S. M.; Saunders, J. O. J. Org. Chem. 1981, 46, 2400-2402.
Nakamura, E.; Fukuzaki, K.; Kuwajima, I. J. Chem. Soc., Chem. Commun.
1983, 499-501. Mikami, K.; Kishi, N.; Nakai, T. Tetrahedron Lett. 1983,
24, 795-798. Denmark, S. E.; Germanas, J. P. Tetrahedron Lett. 1984, 25,
1231-1234. Fukuzaki, K.; Nakamura, E.; Kuwajima, I. Tetrahedron Lett.
1984, 25, 3591-3594. Aldehydes: McIntosh, M. C.; Weinreb, S. M. J.
Org. Chem. 1991, 56, 5010-5012. McIntosh, M. C.; Weinreb, S. M. J.
Org. Chem. 1993, 58, 4823-4832. Ketones: Hoflack, J.; De Clercq, P. J.
Bull. Soc. Chim. Belg. 1983, 92, 407-408. Thioacetals: Trost, B. M.;
Murayama, E. J. Am. Chem. Soc. 1981, 103, 6529-6530.
(5) Overman, L. E.; Casten˜ada, A.; Blumenkopf, T. A. J. Am. Chem.
Soc. 1986, 108, 1303-1304. Overman, L. E.; Blumenkopf, T. A.; Casten˜ada,
A.; Thompson, A. S. J. Am. Chem. Soc. 1986, 108, 3516-3517. However,
these latter studies have not always involved full participation of the silyl
moiety, having invoked an alternative polar ene mechanism.
(8) Chow, H.-F.; Fleming, I. J. Chem. Soc., Perkin Trans. I 1984, 1815-
1819.
(9) This possibility has not been overlooked, as elegantly exploited by
Tius in a novel benzene annulation process: Tius, M. A. Tetrahedron Lett.
1981, 22, 3335-3338. Tius, M. A.; Ali, S. J. Org. Chem. 1982, 47, 3163-
3166.
(10) Sweet, F.; Brown, R. K. Can. J. Chem. 1966, 44, 1571-1576.
(11) In one rate study, an E-vinylsilane reacted >7000 times faster than
its corresponding Z-counterpart: Overman, L. E.; Burk, R. M. Tetrahedron
Lett. 1984, 25, 5739-5742. A similar observation was noted by Fleming,
see ref 7.
(12) Heimstra, H.; Klaver, W. J.; Speckamp, W. N. Recl. TraV. Chim.
Pays-Bas 1986, 105, 299-306.
(6) A recent analogous approach to bridged oxabicyclics, employing both
silicon- and sulfur-activated olefins, proceeded via ene and Prins pathways,
respectively: Sasmal, P. K.; Maier, M. E. Org. Lett. 2002, 4, 1271-1274.
(7) By contrast the related reaction of iminium ions is a well-established
strategy for alkaloid synthesis: Blumenkopf, T.; Overman, L. E. Chem.
ReV. 1986, 86, 857-873.
(13) All new compounds were fully characterized by a wide range of
analytical techniques, including 1H and 13C NMR, IR, MS, combustion
analysis, and/or HRMS AMM.
(14) Similar low isolated yields (40%) have been reported in the trans-
series: Alvarez, E.; Delgado, M.; Diaz, M. T.; Hanxing, L.; Pe´rez, R.;
Martin, J. D. Tetrahedron Lett. 1996, 37, 2865-2868.
3508
Org. Lett., Vol. 9, No. 18, 2007

Table 1. Synthesis of Cis-Fused Bicyclic Ether ArrayssInitial Representative Surveya
a Depicted stereochemistry of all products is relative, except for entry g. b General procedure: dropwise addition of BF3‚OEt2 [2.5 equiv] to a stirred
solution of precursor in CH2Cl2 at 0 °C, followed by warming to rt. c Cyclization performed at reflux.
readily obvious due to occluded signals in the initial NMR
analysis, further complicated by long-range allylic interac-
tions. Only after extensive decoupling studies in d5-pyridine
was a 2.6 Hz 3J coupling revealed across the newly formed
ring junction, thus allowing confirmation as cis.
Suitably encouraged, we subsequently adapted this method
to a typical range of oxacyclic systems by simple exchange
of the initial enol ether framework, Table 1. Similar exposure
of dihydrofuran 1b and tetrahydrooxepine 1c15 to our
oxidation-etherification protocol afforded the requisite
precursors. These underwent smooth cyclization to the [5,6]
and [7,6] bicyclic arrays accordingly. In each case the cis-
ring junction proved exclusive and was confirmed by
subsequent NMR studies, with typical coupling values in the
2.5-4.6 Hz range.
stereodivergent control of the process. Readily available
benzyl ether 1d16 was subjected to nonspecific epoxidation
with peracetic acid, yielding a mixture of three alcohol
diastereoisomers.17 Careful separation followed by etherifi-
cation of each yielded both anti-anomers, 3d and 3e, along
with syn-precursor 3f. Cyclization thus allowed access to both
cis-fused ether arrays accordingly, with overall complemen-
tary stereochemistry, albeit differing degree of success.
Whereas both anti-precursors cyclized in near quantitative
yield, syn-3f required more forcing conditions, under which
competitive debenzylation led to formation of an anhydro-
pyranose derivative as the major byproduct. Therefore it does
appear evident the scope of the reaction will be susceptible
(16) Synthesis of the benzyl ether: Boschi, A.; Chiappe, C.; De Rubertis,
A.; Ruasse, M. F. J. Org. Chem. 2000, 65, 8470-8477.
Introduction of a simple substituent into the initial
heterocyclic moiety served to probe overall potential for
(17) These were obtained after acetylation of the initial crude mix,
separation by flash chromatography, identification by extensive 1H and 13
C
(15) Synthesis of the oxepin system: Oakes, F. T.; Yang, F.-A.;
Sebastian, J. F. J. Org. Chem. 1982, 47, 3094-3097.
NMR studies (including 1J C-H anomeric coupling values), and finally,
hydrolysis to re-yield each diastereoisomeric alcohol as a single isomer.
Org. Lett., Vol. 9, No. 18, 2007
3509

to the usual stereoelectronic factors prevalent in pyranose-
type systems.18
In summary, we have demonstrated an expeditious entry
to cis-fused [n,6] bicyclic ether arrays from cyclic enol ethers,
in complete regio- and stereospecific fashion. We are
currently developing this methodology further to the comple-
mentary [n,m] systems by simple increase of tether length
accordingly. In addition we hope to apply this strategy to
the total synthesis of several bioactive natural products
containing these important structural motifs.
Extension of this methodology to carbohydrate-type
candidates was successfully demonstrated with trimethyl-D-
glucal derivative 1g.19 Cyclization once again proceeded
smoothly to yield pyranoglucose-system 4g.20 In this case
the key cis-ring junction coupling rose to 6.2 Hz, indicative
4
of a slightly flattened C1 cis-fused chair, as previously
observed in the related pyranoisochroman systems.21
In these latter examples, it is important to note that in each
case the relative stereochemistry of the ring junction is a
direct consequence of the epoxidation step, for which many
selective technologies have arisen in recent years.22
Acknowledgment. We thank The Robert A. Welch
Foundation for generous support of this work (Individual
Award V-1450). S.P.F. is also grateful to the Gill Foundation
for a Science Faculty Development Award, and The City
University of New York for provision of start-up funds (Vice-
Chancellor’s Award).
(18) Deslongchamps, P. Stereoelectronic Effects in Organic Chemistry;
Baldwin, J. E., Ed.; Pergamon Press: Oxford, U.K., 1983.
(19) Synthesized from D-glucal in two steps: (a) Permethylation:
Dunkerton, L. V.; Adair, N. K.; Euske, J. M.; Brady, K. T.; Robinson, P.
D. J. Org. Chem. 1988, 53, 845-850. (b) Epoxidation/methanolysis:
Chiappe, C.; Lo Moro, G.; Munforte, P. Tetrahedron: Asymmetry 1997, 8,
2311-2317.
(20) The analogous perbenzylated compound has been reported (ref 3b).
(21) Verlhac, P.; Leteux, C.; Toupet, L.; Veyrie`res, A. Carbohydr. Res.
1996, 291, 11-20. Bu¨rli, R.; Vasella, A. HelV. Chim. Acta 1996, 79, 1159-
1168.
Supporting Information Available: General experimen-
1
tal procedure for cyclization; H and 13C NMR spectra and
data and confirmatory analyses for all cis-fused bicyclic ether
products (4a through 4g). This material is available free of
charge via the Internet at http://pubs.acs.org.
(22) For example, Gin’s complementary sulfonium-mediated oxidative
glycosylations: Kim, J-Y.; Di Bussolo, V.; Gin, D. Y. Org. Lett. 2001, 3,
303-306.
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