Chemoselective oxygen-centered radical cyclizations onto silyl enol ethers

Article abstract of DOI:10.1021/ol802142k

(Chemical Equation Presented) A new oxygen-centered radical cyclization onto silyl enol ethers has been developed and utilized for the synthesis of versatile siloxy-substituted tetrahydrofurans. The reactions display excellent chemoselectivity for cyclization onto the electron-rich silyl enol ether when competing terminal alkene cyclization, 1,5-hydrogen abstraction, and β-fragmentation pathways are present. The increased chemoselectivity also allows for the synthesis of tetrahydropyrans, a challenging substrate class to access using oxygen-centered radical alkene cyclizations due to competing 1, 5-hydrogen abstractions.

Full text of DOI:10.1021/ol802142k

ORGANIC
LETTERS
2008
Vol. 10, No. 21
5083-5086
Chemoselective Oxygen-Centered
Radical Cyclizations onto Silyl Enol
Ethers
Maria Zlotorzynska, Huimin Zhai, and Glenn M. Sammis*
Department of Chemistry, 2036 Main Mall, UniVersity of British Columbia,
VancouVer, British Columbia V6T 1Z1, Canada
gsammis@chem.ubc.ca
Received September 12, 2008
ABSTRACT
A new oxygen-centered radical cyclization onto silyl enol ethers has been developed and utilized for the synthesis of versatile siloxy-substituted
tetrahydrofurans. The reactions display excellent chemoselectivity for cyclization onto the electron-rich silyl enol ether when competing terminal
alkene cyclization, 1,5-hydrogen abstraction, and ꢀ-fragmentation pathways are present. The increased chemoselectivity also allows for the
synthesis of tetrahydropyrans, a challenging substrate class to access using oxygen-centered radical alkene cyclizations due to competing
1,5-hydrogen abstractions.
Oxygen-containing heterocycles are common motifs in
natural products and pharmaceuticals, and the synthesis of
these compounds remains an important challenge in total
synthesis. A direct method for their synthesis is the cycliza-
tion of an oxygen-centered radical onto an olefin as alkoxy
radicals add rapidly and irreversibly to alkenes (R ) H, alkyl,
aryl).1 Advances in oxygen-centered radical cyclizations have
enabled the formation of a wide range of tetrahydrofurans
including several simple tetrahydrofuran-containing natural
products.1,2 Despite progress in the field, alkoxy-radical
cyclizations are still not as highly utilized in natural product
synthesis compared to carbon-centered cyclization ana-
logues3,4 as methods based on oxygen-centered radicals are
not sufficiently developed for the synthesis of complex
substrates. The synthetic utility of the cyclization product
can be increased by trapping carbon radical 2 with functional
groups such as halogen1b,c,5 or sulfur6 but it is difficult to
access R-hydroxylated rings, a motif common in bioactive
tetrahydrofuran- and tetrahydropyran-containing natural prod-
ucts.7 Furthermore, it is difficult to control the high reactivity
of the oxygen-centered radicals as they readily undergo 1,5-
hydrogen abstraction8 and ꢀ-fragmentation pathways9 (Scheme
1).
(1) For the first example of oxygen-centered radical cyclizations, see:
(a) Surzur, J. M.; Bertrand, M. P.; Nougier, R. Tetrahedron Lett. 1969, 48,
4197–4200. For recent reviews, see: (b) Hartung, J. Eur. J. Org. Chem.
ˇ
2001, 619–632. (c) Hartung, J.; Gottwald, T.; Spehar, K. Synthesis 2002,
(4) For reviews, see: (a) Curran, D. P. Synthesis 1988, 417–439. (b)
Curran, D. P. Synthesis 1988, 440–513. (c) Jasperse, C. P.; Curran, D.;
Fevig, T. L. Chem. ReV. 1991, 91, 1237–1286, and references therein.
(5) For representative examples, see: (a) Hartung, J.; Kneuer, R. Eur.
J. Org. Chem. 2000, 1677–1683. (b) Hartung, J.; Kopf, T. M.; Kneuer, R.;
1469–1498, and references therein.
(2) For a representative example of the use of oxygen-centered radicals
for the formation of natural products, see: Hartung, J.; Kneuer, R.
Tetrahedron: Asymmetry 2003, 14, 3019–3031
.
(3) For reviews on carbon-radical cyclizations, see: (a) Ramaiah, M.
Tetrahedron 1987, 43, 3541–3676. (b) Curran, D. P. In ComprehensiVe
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford,
1991; Vol. 4,Chapter 4.1, pp 715-777. (c) Giese, B.; Kopping, B.; Go¨bel,
T.; Dickhaut, J.; Thoma, G.; Kulicke, K. J.; Trach, F. In Organic Reactions;
Paquette, L. A., Ed.; John Wiley & Sons, Inc., New York, 1996; Vol.
48,Chapter 2, pp 303-856. (d) Gans¨auer, A.; Bluhm, H. Chem. ReV. 2000,
Schmidt, P. C. R. Acad. Sci. Paris, Chem./Chem. 2001, 649–666.
(6) Hartung, J.; Gallou, F. J. Org. Chem. 1995, 60, 6706–6716.
(7) For representative examples of bioactive tetrahydrofuran and tet-
rahydropyran-containing natural products with oxygenation alpha to the ring,
see: Bermejo, A.; Figade`re, B.; Zafra-Polo, M.-C.; Barrachina, I.; Estornell,
E.; Cortes, D. Nat. Prod. Rep. 2005, 22, 269–303.
(8) Barton, D. H. R.; Beaton, J. M.; Geller, L. E.; Pechet, M. M. J. Am.
Chem. Soc. 1961, 83, 4076–4083.
100, 2771–2788, and references therein
.
10.1021/ol802142k CCC: $40.75
Published on Web 10/15/2008
2008 American Chemical Society

Scheme 1
.
Oxygen-Centered Radical Reaction Pathways
Scheme 2
.
Alkoxy Radical Generation via Deprotection of
N-Alkoxyphthalimides
We were interested in investigating a substituent on the
alkene that could provide a versatile synthetic handle for
further functionalization as well as lead to increased rates
of cyclization. Introduction of an oxygen substituent (R )
OTBS) addresses both of these issues. The oxygen-radical
cyclization would provide oxacycles with a modular pro-
tected primary alcohol substituent. Furthermore, the increased
electron density of the olefinic acceptor should increase
cyclization rates because alkoxy-radicals are electron defi-
cient10 and have been shown to cyclize more rapidly onto
alkenes with increasing alkyl substitution.11 Herein, we report
the successful application of this approach for chemoselective
oxygen-centered radical cyclizations onto electron-rich silyl
enol ether acceptors.12 This provides a general method for
the preparation of siloxy-functionalized tetrahydrofurans as
well as a route to tetrahydropyrans, a challenging class of
substrates to access using oxygen-centered radical cycliza-
tions due to rapid 1,5-hydrogen abstraction pathways.
or tris(trimethylsilyl)silane16 and azobisisobutyronitrile (AIBN)
resulted in the desired 5-exo cyclization in quantitative
1
conversion by H NMR spectroscopy (Scheme 3).
Photochemically induced cleavage of N-alkoxypyridineth-
ione 13also leads to cyclization onto the silyl enol ether
(Scheme 4). In the absence of a source of hydrogen atom
the initial carbon-centered radical cyclized product is quenched
with pyridinethione17,18 to afford tetrahydrofuran 14. This
route provides both an alternative to using reductive stannyl
and silyl hydrides as well as a direct route to protected
aldehydes.
A common strategy for the generation of oxygen-centered
radicals is the cleavage of weak oxygen-heteroatom bonds
in protecting groups such as N-alkoxyphthalmide (PhthOR),13
N-alkoxypyridinethione,14 and N-alkoxythiazolethione.15 We
began our investigations with alkoxy-radical generation via
cleavage of N-alkoxyphthalimides as these groups can be
readily incorporated into a compound and are stable under
a wide range of reaction conditions. N-alkoxyphthalimides,
such as 8, can be converted to an oxygen-centered radical
through the reaction with stannyl or silyl radicals (Scheme
2).13a This should result in homolytic cleavage of the
oxygen-nitrogen bond to afford oxygen-centered radical 10,
which should then add to the π-system. Hydrogen atom
abstraction by the resulting carbon radical in 11 propagates
the radical and should provide tetrahydrofuran 12. Indeed,
treatment of silyl enol ether 8a with either tributyltin hydride
With the basic reactivity established, we next focused on
examining the chemo- and diastereoselectivities in oxygen-
centered radical cyclizations onto silyl enol ethers for a wide
range of substitution patterns (Table 1).19 Simple unsubsti-
(12) To the best of our knowledge, there is only one example of the
use of a silyl enol ether as an acceptor for an oxygen-centered radical
cyclization. In the course of a study on ꢀ-fragmentations, there is one
example of an oxygen-centered radical addition to a silyl enol ether in which
the system is directed to cyclize onto the carbon R to the siloxy substituent.
Kim, S.; Kim, K. H.; Cho, J. R. Tetrahedron Lett. 1997, 38, 3915–3918.
(13) (a) Kim, S.; Lee, T. A.; Song, Y. Synlett 1998, 471–472. (b) Okada,
K.; Okamoto, K.; Oda, M. J. Am. Chem. Soc. 1998, 110, 8736–8738. (c)
Barton, D. H. R.; Blundell, P.; Jaszberenyi, J. C. Tetrahedron Lett. 1989,
30, 2341–2344
.
(14) (a) Beckwith, A. L. J.; Hay, B. P. J. Am. Chem. Soc. 1988, 110,
4415–4416. (b) Hay, B. P.; Beckwith, A. L. J. J. Org. Chem. 1989, 54,
4330–4334
(15) Hartung, J.; Kneuer, R.; Schwarz, M.; Svoboda, I.; Fueb, H. Eur.
J. Org. Chem. 1999, 97–106
.
.
(16) For the development of tris(trimethylsilyl)silane as a radical
reducing agent, see: (a) Chatgilialoglu, C.; Griller, D.; Lesage, M. J. Org.
Chem. 1988, 53, 3641–3642. (b) Chatgilialoglu, C. Chem.sEur. J. 2008,
14, 2310–2320. For the use of tris(trimethylsilyl)silane in the generation of
oxygen-centered radicals, see ref 13a.
(9) For representative examples, see: (a) Walling, C.; Padwa, A. J. Am.
Chem. Soc. 1963, 85, 1593–1597. (b) Boto, A.; Herna´dez, D.; Sua´rez, Eur.
J. Org. Chem. 2003, 68, 5310–5319.
(17) For a review on the use of thiohydroxamic esters in carbon-radical
cyclizations with concomitant sulfur trapping, see: Barton, D. H. R.; Zard,
(10) Curran, D. P. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 4, Chapter 4.2.5, pp
811-814.
S. Z. Pure Appl. Chem. 1986, 58, 675–684
.
(18) For a representative example of the use of N-alkoxypyridinethiones
(11) For kinetic experiments demonstrating increased rates with increased
alkyl substitution, see: (a) Hartung, J.; Hiller, M.; Schmidt, P. Liebigs Ann.
1996, 1425–1436. (b) Hartung, J.; Kneuer, R.; Rummey, C.; Bringmann,
G. J. Am. Chem. Soc. 2004, 126, 12121–12129.
in oxygen-centered radical cyclizations with concomitant sulfur trapping,
see: Hartung, J.; Gallou, F. J. Org. Chem. 1995, 60, 6706–6716
.
(19) Substrates 8a-h are Z-enriched. See the Supporting Information
for E/Z ratios.
5084
Org. Lett., Vol. 10, No. 21, 2008

Scheme 3
.
Tin- or Silyl-Mediated Oxygen-Centered Radical
Table 1. Oxygen-Centered Radical Cyclization To Form
Substituted Tetrahydrofurans
Cyclization onto a Silyl Enol Ether from an
N-Alkoxyphthalimide
Scheme 4. Photolysis of an N-Alkoxypyridinethione Derivative
tuted silyl enol ethers derived from aldehydes (entry 1) and
ketones (entry 2) cyclized to the corresponding tetrahydro-
furans in good yield. Cyclization of secondary oxygen-
centered radicals (entries 4 and 5) also proceeded in good
yields. These cyclizations displayed comparable diastereo-
selectivity to what was observed with oxygen-centered
radical cyclizations onto terminal alkenes.1,6,20
Substrates 8d-g (entries 4-7) were used to examine the
effects siloxy-substitution on the alkene has on the rates of
possible ꢀ-fragmentation and 1,5-hydrogen transfer path-
ways. Fragmentation was not observed in substrates that
could undergo ꢀ-scission to secondary carbon radicals
(entries 4 and 5).21 Both 8d and 8e chemoselectively cyclized
to the tetrahydrofurans 12d and 12e in excellent yield. Even
substrate 8f, which can fragment to a benzyl radical, afforded
tetrahydrofuran 12f as the dominant product (84:16 cycliza-
tion/fragmentation).
Substrates 8e and 8g reacted to give tetrahydrofurans 12e
and 12g exclusively in high yields (entries 5 and 7).
Consistent with increased alkyl substitution,11 this suggests
that the activation provided by the siloxy substitutent to the
olefinic acceptor results in a rate of cyclization that is faster
than the rate of a possible 1,5-hydrogen abstraction pathway.
Furthermore, the cyclization of 8g occurred in high diaste-
reoselectivity.22 Increasing the steric bulk of the substituent
from a methyl (8g) to a phenyl group (8h) led to comparable
yields, but with even higher diastereoselectivity (entry 8).
For this cyclization methodology to be a valuable synthetic
tool, it must be highly chemoselective in the presence of
a Reactions were carried out on a >0.25 mmol scale. b The relative
stereochemistry was determined by conversion of 12b, 12c, 12f, and 12h
to the known alcohols. See the Supporting Information for experimental
details. c Isolated yields of the mixture of diastereomers after flash
chromatography. d The diastereomeric ratio was determined by 1H NMR
spectroscopy of crude reaction mixtures. e The product was obtained in
1
>95% conversion by H NMR spectroscopy with no other side products.
f
1
None of the minor isomers could be detected by H NMR.
Scheme 5. Competition Experiment To Examine the Relative
Rate of Cyclization onto a Silyl Enol Ether versus a Terminal
Olefin
(20) For representative diastereoselectivity studies, see: (a) Hartung, J.;
Hiller, M.; Schmidt, P. Chem.sEur. J. 1996, 2, 1014–1023. (b) Hartung,
ˇ
J.; Kneuer, R.; Laug, S.; Schmidt, P.; Spehar, K.; Svoboda, I.; Fuess, H.
Eur. J. Org. Chem. 2003, 4033–4052. (c) Hartung, J.; Stowasser, R.; Vin,
D.; Bringmann, G. Angew. Chem., Int. Ed. Engl. 1996, 35, 2820–2823
.
reactive functional groups. Therefore, we next investigated
the degree of chemoselectivity of cyclization onto a silyl enol
ether relative to a simple alkene. This was accomplished
using a competition experiment in which the oxygen-centered
radical could undergo a 5-exo cyclization with either a silyl
(21) Unless mentioned in the text, no products resulting from 1,5-
hydrogen abstraction or ꢀ-fragmentation pathways were observed in crude
1H NMR mixtures. Therefore, it is still possible that they are present in
<5% overall yield.
(22) The diastereoselectivity dropped to 88:12 when E-enriched silyl
enol ether 8g was used.
Org. Lett., Vol. 10, No. 21, 2008
5085

Scheme 6. Synthesis of Substituted Tetrahydropyrans
enol ether or a terminal olefin (Scheme 5). The oxygen-
centered radical generated from 15 displayed complete
chemoselectivity for addition to the silyl enol ether. Thus,
cyclization exclusively formed product 16.
to allow for a synthetically useful method for the formation
of substituted tetrahydropyrans. Gratifyingly, our experiments
demonstrate that we can successfully cyclize silyl enol ether
17b to substituted tetrahydropyran 19b in a 74% isolated
yield with an 8:1 preference for cyclization versus 1,5-
hydrogen abstraction.
A traditional limitation of oxygen-centered radical cy-
clizations onto alkenes is the formation of six-membered ring
systems because the high reactivity of the oxygen-centered
radical often leads to a 1,5-hydrogen abstraction of the allylic
hydrogen.23,24 Consistent with previous attempts, cyclization
of N-alkoxyphthalimide 17a resulted in exclusive formation
of 1,5-hydrogen abstraction product 5-hexen-1-ol (Scheme
6). Previous studies have demonstrated that the rate of
cyclization can be increased via gem-dialkyl substituents23c
or alkyl substitution23a on the alkene receptor, but the
tetrahydropyrans can only be formed in a maximum of 39%
yield.23a Complete mass balance experiments indicate that
the major product results from a 1,5-hydrogen abstraction
pathway.23 We hypothesized that the silyl enol ether may
be sufficiently electron-rich to increase the rate of cyclization
In summary, we have found that oxygen-centered radicals
chemoselectively cyclize onto silyl enol ethers with fewer
side reactions than with alkenes to provide a synthetically
general method for the formation of both tetrahydrofurans
and tetrahydropyrans. This high selectivity for heteroatom-
centered radicals has the potential to provide a reliable and
predictable new reaction for use in total synthesis. Efforts
to explore the newly uncovered reactivity in the context of
natural product synthesis are currently underway.
Acknowledgment. This work was supported by the
University of British Columbia, Merck-Frosst, the Natural
Sciences and Engineering Research Council of Canada
(NSERC), and a doctoral fellowship from NSERC to M.Z.
(23) For representative examples of attempts to form tetrahydropyrans
using 6-exo oxygen-centered radical cyclizations, see: (a) Hartung, J.;
Gottwald, T. Tetrahedron Lett. 2004, 45, 5619–5621. (b) Johns, A.; Murphy,
J. A. Tetrahedron Lett. 1988, 29, 837–840. (c) Bertrand, M. P.; Surzur,
Supporting Information Available: Complete experi-
mental procedures and characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
J. M.; Boyer, M.; Milhailovic´, M. L. Tetrahedron 1979, 35, 1365–1372
.
(24) Tetrahydropyrans can be formed in high yield from oxygen-centered
radical 6-exo cyclizations when the allylic position is fully substituted and
there are no allylic hydrogen atoms available for abstraction. For representa-
tive examples, see refs 10 and 23b
OL802142K
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Org. Lett., Vol. 10, No. 21, 2008