electron transfer initiated cyclization reactions are practicable
because of the significant and selective benzylic carbon-
carbon σ-bond weakening that results from radical cation
formation.7 During the course of this study we demonstrated
that exposing epoxide 1 to our standard cyclization conditions
(hν, 2 equiv of NMQPF6, NaOAc, dichloroethane, tert-
butylbenzene) provides hydroxy-tetrahydropyranyl ether 3
in moderate yield (Figure 1). This result is consistent with
Figure 1. Epoxonium ion formation and hydration under oxidative
conditions.
Figure 2. Heterogenerative cascade cyclization reactions.
the intermediacy of epoxonium ion 2, which upon reaction
with adventitious water provides 3. We believed that the mild
conditions employed for these reactions and the intra-
molecular epoxide activation portended well for the use of
this method to initiate cascade cyclization processes that lead
to polyether structures related to biologically active natural
products such as the Annonaceous acetogenins8 and other
marine toxins.9
catalytic aerobic procedure10 to this reaction (hν, 0.025 equiv
of NMQPF6, gentle aeration, NaOAc, Na2S2O3, dichloro-
ethane, toluene) provided 7 in 73% yield, again as a 1:1
mixture at the anomeric center. Isomeric epoxide 9 underwent
cyclization with comparable efficiency to provide 10 as a
1:1 mixture of anomers in 78% yield under stoichiometric
conditions and in 80% yield under catalytic conditions,
demonstrating that cis- and trans-epoxides react with com-
parable efficiency. Lactone 11 was formed by oxidizing each
anomer of 10 with Jones reagent, again confirming the
stereospecificity of epoxonium ion opening.
The successful utilization of the THP-ether as a nucleo-
phile in opening epoxonium ions suggested that other ethers,
including epoxides, could serve in the same capacity. To test
this proposal we prepared 12, in which the absolute stereo-
chemistry of the two epoxide groups was established through
the use of a double Shi epoxidation11 on the diene precursor,12
and subjected it to our standard cyclization conditions (Figure
3). This reaction provided bistetrahydrofuran 16 in 64%
isolated yield (82% at 78% conversion) as a 3:2 ratio of
anomers under stoichiometric conditions and in 66% yield
under catalytic conditions. We propose that the conversion
of 12 to 16 proceeds through initial formation of epoxonium
ion 13 followed by reaction with the distal epoxide group to
provide epoxonium ion 14. In contrast to termination through
tetrahydrofuran formation, we chose to open this epoxonium
ion with an alkoxy group transfer process13 that proceeds
through nucleophilic attack by the distal oxygen of the mixed
acetal group to produce oxonium ion 15. Hydrolysis of 15
To test this proposal we subjected unstable hydroxy
epoxide 4a (Figure 2) to our standard cyclization conditions.
This procedure resulted in the isolation of a 1:3 mixture of
bistetrahydrofurans 6 and 7 in 51% combined yield as the
result of a competition between endo- and exo-cyclization
pathways from epoxonium ion 5 (pathways a and b,
respectively, Figure 2). Replacing NaOAc with the soluble,
oxidatively inert base 2,6-dichloropyridine provided a 1:1
mixture of 6 and 7 in 64% combined yield. We hypothesized
that the regioselectivity of the process would be affected by
changing the nucleophilic group. Thus, stable tetrahydro-
pyranyl ether 4b was subjected to standard cyclization
conditions to form 7 in 83% yield as a 1:1 mixture of epimers
at the anomeric center. No trace of 6 could be detected in
this reaction. Oxidation of each epimer of the product with
Jones’ reagent provided a single lactone 8, confirming that
the stereochemical difference between the products results
from the initial reaction between the epoxide group and the
oxidatively generated oxonium ion and not from solvolysis
of the intermediate epoxonium ion. Application of our
(7) For discussions of the reactivity patterns of radical cations, see: (a)
Schmittel, M.; Burghart, A. Angew. Chem., Int. Ed. Engl. 1997, 36, 2551.
(b) Baciocchi, E.; Bietti, M.; Lanzalunga, O. Acc. Chem. Res. 2000, 33,
243. (c) Schmittel, M.; Ghorai, M. K. In Electron Transfer in Chemistry;
Balzani, V., Ed.; Wiley-VCH: Weinheim, 2001; Vol. 2, Organic Molecules,
pp 5-54. (d) Mella, M.; Fagnoni, M.; Freccero, M.; Fasani, E.; Albini, A.
Chem. Soc. ReV. 1998, 27, 81.
(8) (a) Alali, F. Q.; Liu, X.-X.; McLaughlin, J. L. J. Nat. Prod. 1999,
62, 504. (b) Hoppe, R.; Scharf, H.-D. Synthesis 1995, 1447.
(9) Yasumoto, T.; Murata, M. Chem. ReV. 1993, 93, 1897.
(10) Kumar, V. S.; Aubele, D. L.; Floreancig, P. E. Org. Lett. 2001, 3,
4123.
(11) (a) Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am.
Chem. Soc. 1997, 119, 11224. (b) Tu, Y.; Wang, Z.-X.; Shi, Y. J. Am.
Chem. Soc. 1996, 118, 9806.
(12) For a related approach to the enantioselective synthesis of bisep-
oxides, see ref 3b.
(13) Barresi, F.; Hindsgaul, O. J. Am. Chem. Soc. 1991, 113, 9376.
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