Synthesis of bridged inside-outside bicyclic ethers through oxidative transannular cyclization reactions

Article abstract of DOI:10.1021/ol301720u

The classical geometry of the 6-endo transition state for nucleophilic additions into oxocarbenium ions can be perturbed by incorporating the reactive groups into medium-sized rings, leading to the formation of 2,6-trans-dialkyl tetrahydropyrans. The bicy

Full text of DOI:10.1021/ol301720u

ORGANIC
LETTERS
2012
Vol. 14, No. 14
3808–3811
Synthesis of Bridged InsideÀOutside
Bicyclic Ethers through Oxidative
Transannular Cyclization Reactions
Xun Han and Paul E. Floreancig*
Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260,
United States
florean@pitt.edu
Received June 22, 2012
ABSTRACT
The classical geometry of the 6-endo transition state for nucleophilic additions into oxocarbenium ions can be perturbed by incorporating the
reactive groups into medium-sized rings, leading to the formation of 2,6-trans-dialkyl tetrahydropyrans. The bicyclic products exhibit
insideÀoutside stereoisomerism, as seen in numerous macrolide natural products.
Intramolecular nucleophilic 6-endo additions into oxo-
carbenium ions provide cis-2,6-disubstituted tetrahydro-
pyrans due to the favorable chair transition state in which
the oxocarbenium ion has E-geometry and the substitu-
tents occupy equatorial orientations.1 2,6-trans-Disubsti-
tuted tetrahydropyrans could, in principle, be accessed by
switching the geometry of the oxocarbenium ion or forcing
a substitutent into an axial orientation (Scheme 1). Acces-
sing the trans-isomer as the major product is quite rare,
however, with Loh’s reports2 of the axial preference for
carboalkoxy groups being notable exceptions. The trans-
stereochemical orientation is present in a number of
biologically active macrolide natural products in which
the tetrahydropyran is embedded in the macrocyclic core,
including the cytotoxins apicularen A3 and leucascandro-
lide A.4 Notably, these compounds exhibit insideÀoutside
stereoisomerism5 in which one bridgehead hydrogen
points into the macrocycle and one points outside. The
biological activity of these structures and their structurally
unique features provides ample justification for the devel-
opment of new protocols for their synthesis.
Scheme 1. Transition States for 6-Endo Cyclizations into
Oxocarbenium Ions
We have been engaged in the synthesis of tetrahydro-
pyrans and related structures in which carbocation forma-
tion proceeds through oxidative carbonÀhydrogen bond
cleavage.6 Our application of this oxidative method to the
formation of macrocyclic oxocarbenium ions6b is particu-
larly relevant to the synthesis of 2,6-trans-disubstituted
tetrahydropyrans. We hypothesized that we could exploit
the geometric constraints of macrocyclic cores to direct the
(1) For recent reviews, see: (a) Olier, C.; Kaafarani, M.; Gastaldi, S.;
Bertrand, M. P. Tetrahedron 2010, 66, 413. (b) Clarke, P. A.; Santos, S.
Eur. J. Org. Chem. 2006, 2045.
(2) (a) Luo, H.-Q.; Hu, X.-H.; Loh, T.-P. Tetrahedron Lett. 2010, 51,
1041. (b) Hu, X.-H.; Liu, F.; Loh, T.-P. Org. Lett. 2009, 11, 1741.
€
(3) Kunze, B.; Jansen, R.; Sasse, F.; Hofle, G.; Reichenbach, H.
J. Antibiot. 1998, 51, 1075.
(4) D’Ambrosio, M.; Guerriero, A.; Debitus, C.; Pietra, F. Helv.
Chim. Acta 1996, 79, 51.
(5) Alder, R. W.; East, S. P. Chem. Rev. 1996, 96, 2097.
r
10.1021/ol301720u
Published on Web 07/11/2012
2012 American Chemical Society

formation of these structures. This plan was predicated on
the notion that, for certain tether lengths, oxocarbenium
ion precursors to the trans-isomers would be thermodyna-
mically favored over the corresponding precursors to the
cis-isomers, particularly if the macrocycle contained a
strain-inducing element such as an alkyne or an E-alkene
(Figure 1). Oxidative carbonÀhydrogen bond cleavage is
well-suited for this objective since the requisite strained
oxocarbenium ion intermediates would be difficult to
access through conventional ionization-based protocols.7
In this paper, we report that propargyl ether-containing
macrocycles undergo oxidative carbonÀhydrogen bond
cleavage to provide oxocarbenium ions that react with
appended nucleophiles in a transannular manner to yield
2,6-trans-disubstituted tetrahydropyrans.8
modestly contrasteric result was initially surprising, the
axial orientation is consistent with our recent postulate6e of
an attractive interaction between π-electrons and the par-
tial positive charge9 on the hydrogen of the oxocarbenium
ion. The observation that the level of diastereocontrol was
lower when the reaction was run in the polar solvent
CH3NO2 is consistent with the electrostatic model. Addi-
tional support for this weak attractive interaction is pro-
vided by the increased selectivity in the cyclization of 8 to 9,
in which the intermediate cation is destabilized relative to 7,
and in the diminished selectivity in the cyclization of 10 to
11, in which the ester group reduces the ability of the
alkynyl group to engage in an electrostatic interaction.
Scheme 2. Alkynes in the Synthesis of 2,6-Trans-Disubstituted
Tetrahydropyrans
Figure 1. Macrocyclic precursor to 2,6-cis- and 2,6-trans-disub-
stituted tetrahydropyrans.
Successinthisventurerequiresthatthe Z-oxocarbenium
ion or the axial substituent not cause a prohibitive ener-
getic penalty. We reasoned that alkynyl groups could
satisfy this requirement based on their sterically un-
demanding nature. We have reported6d that E- and
Z-substituted oxocarbenium ions differ in energy by only
∼0.4 kcal/mol, as shown by the conversion of 1 to a 1.6:1
mixture of 2 and 3 (Scheme 2). We preparedether 4 asa test
substrate to determine whether an axially oriented alkynyl
group would be energetically accessible in an oxidative
cyclization reaction. Subjecting 4 to 2,3-dichloro-5,6-
dicyano-1,4-benzoquinone (DDQ) in 1,2-dichloroethane
(DCE) resulted in the formation of tetrahydropyrones 5
and 6. Remarkably, the 2,6-trans-diastereomer 5 was the
major product in this reaction, demonstrating that the
alkynyl group shows a slight preference for an axial
orientation, as shown by transition state 7. Although this
(6) (a) Tu, W.; Liu, L.; Floreancig, P. E. Angew. Chem., Int. Ed. 2008,
47, 4184. (b) Tu, W.; Floreancig, P. E. Angew. Chem., Int. Ed. 2009, 48,
4567. (c) Liu, L.; Floreancig, P. E. Org. Lett. 2009, 11, 3152. (d) Liu, L.;
Floreancig, P. E. Angew. Chem., Int. Ed. 2010, 49, 3069. (e) Liu, L.;
Floreancig, P. E. Angew. Chem., Int. Ed. 2010, 49, 5894. (f) Brizgys, G. J.;
Jung, H. H.; Floreancig, P. E. Chem. Sci. 2012, 3, 438. (g) Cui, Y.;
Floreancig, P. E. Org. Lett. 2012, 14, 1720.
(7) For recent representative examples of 2,6-cis-disubstituted tetra-
hydropyran synthesis through macrocyclic oxocarbenium ion forma-
tion; see: (a) Crane, E. A.; Scheidt, K. A. Angew. Chem., Int. Ed. 2010,
49, 8316. (b) Custar, D. W.; Zabawa, T. P.; Scheidt, K. A. J. Am. Chem.
Soc. 2008, 130, 804. (c) Woo, S. K.; Kwon, M. S.; Lee, E. Angew. Chem.,
Int. Ed. 2008, 47, 3242. (d) Yadav, J. S.; Kumar, G. G. K. S. N.
Tetrahedron 2010, 66, 480. (e) Bahnck, K. B.; Rychnovsky, S. D.
J. Am. Chem. Soc. 2008, 130, 13177. (f) Wender, P. A.; Schrier, A. J.
J. Am. Chem. Soc. 2011, 133, 9228.
The successful demonstrations that alkynyl groups show
a slight preference for an axial orientation and that alky-
nyl-substituted oxocarbenium ions can access a Z-config-
uration without accruing a significant energetic penalty
provide two options for preparing bridged bicyclic tetra-
hydropyrans with insideÀoutside stereochemical relation-
ships. In consideration of the lower reactivity of propargylic
ethers toward DDQ relative to benzylic and allylic ethers6d
we initially examined substrates in which the alkynyl group
is designed to adapt an axial alignment in the cyclization
transition state. The results of these studies are shown in
Table 1.
(8) For other examples of transannular cyclizations to form insideÀ
€
outside bridged ethers, see: (a) Kuhnert, S. M.; Maier, M. E. Org. Lett.
2002, 4, 643. (b) Hilli, F.; White, J. M.; Rizzacasa, M. A. Org. Lett. 2004, 6,
1289. (c) Li, M.; O’Doherty, G. A. Org. Lett. 2006, 8, 6087.
(9) Corey, E. J.; Lee, T. W. Chem. Commun. 2001, 1321.
Org. Lett., Vol. 14, No. 14, 2012
3809

A values. The formation of the 2,6-cis-disubstituted isomer
was not observed until the cyclization substrate contained
a 19-membered ring (entry 3), in accord with the analysis in
Figure 1. Allylic ethers are also effective promoters of
macrocyclic oxocarbenium ion formation, although the
reactions are slower in comparison to the electron-rich
benzylic ethers (entry 1 vs entry 4). Of note, E-alkene
substrate 20 reacted quite slowly and changed configura-
tion during the reaction (entry 5). This result can also be
attributed to the formation of strained intermediates and
shows that alkene rotational barriers of carbonÀcarbon
π-bonds are significantly dimished in oxocarbenium ions.
The addition of an aryl group to the alkene promotes a
much faster cyclization reaction that proceeds quite
efficiently.
Table 1. Stereoselective Formation of InsideÀOutside Bridged
Bicyclesa
We also explored the possibility of preparing these
bicyclic structures through the intermediacy of alkynyl-
substituted oxocarbenium ions. The results from this study
are shown in Table 2. Propargylic ethers oxidize more
slowly than allylic and benzylic ethers,6d resulting in lower
yields of desired products and the need to heat these
reactions for prolonged periods of time. The modest yields
appear to result from nonspecific decomposition of the
strained oxocarbenium ions rather than overoxidation,
although the reactions were not run with lower DDQ
loadings because they were not kinetically viable under
those conditions. All reactions produced the 2,6-trans-
disubstituted stereoisomer as the major or exclusive pro-
duct, with the cis-product only being observed for the
cyclization of 16-membered ring substrate 27 (entry 3).
Stereochemical assignments were based on 1H NMR
coupling constants, and the structure of 24 was confirmed
by crystallography.11 As noted in the reaction from
Table 1, the reactions were marginally more efficient for
substrates with larger rings (entry 1 vs entry 3). Stereo-
selectivity was also observed in the formation of tertiary
ethers (entries 4 and 5). The difference in rates for sub-
strates 29 and 31 can be attributed to the greater capacity
of the proximal carbonyl group in 29 to destabilize the
intermediate carbocation relative tothe oxygen atom in 31.
The reactions that proceed through the more highly sub-
stituted oxocarbenium ions can be conducted at lower
temperatures, though no improvement is seen in the yield.
While the inductive effect that arises from the carbonyl
group being proximal to the oxocarbenium ion has a
significant impact on reaction rates, increasing the distance
between the carbocation intermediate and the oxygen of
the lactone group has a negligible impact on cyclization
efficiency (entry 1 vs entry 2). Although all the results in
this discussion are consistent with reasonable thermo-
dynamic analyses of the intermediate oxocarbenium ions,
kinetic effects might also play a role in the oxidation rates
since macrocyclic constraints could limit access to the
proper geometry for carbonÀhydrogen bond cleavage.12
Alkynes are not common structures in natural products
or medicinal agents, but they are extremely versatile as
precursors to numerous functional groups. To illustrate,
a Representative procedure: DDQ (2À3 equiv) was added to a 0.1 M
solution of the substrate (1 equiv), LiClO4 (0.2 equiv), and 2,6-dichloro-
pyridine (4 equiv) in DCE at rt. The reaction was stirred at rt for the
indicated period for the indicated time. Please see the Supporting
Information for details. b Please see the Supporting Information for
details on substrate syntheses. c Combined yield of diastereomers.
d Determined by integrating characteristic signals in the 1H NMR
spectrum.
These reactions all proceed at room temperature, and
many provide good yields of the desired products. The
reactions proceed more quickly when longer tether lengths
are employed (entries 1À3). This most likely results from a
reduction in the strain that results from the formation of
the intermediate oxocarbenium ion, and is consistent with
studies10 showing that cation stability is an important
determinant in the rate of oxidative carbonÀhydrogen
bond cleavage. Stereochemical assignments were made
1
based on coupling constants in H NMR spectra. The
coupling constants also confirmed that the alkynyl groups
occupy an axial orientation, as expected on the basis of
(10) Jung, H. H.; Floreancig, P. E. Tetrahedron 2009, 65, 10830.
(11) See the Supporting Information for details.
3810
Org. Lett., Vol. 14, No. 14, 2012

strong preference for the alkenyl group to occupy an equatorial
orientation in the cyclization transition state, but the use of the
alkynyl group for the cyclization followed by selective reduction
makes this compound accessible. Moreover the vinylsilane
intermediate can serve as a precursor to other functional groups
through cross-coupling15 and oxidative16 transformations.
Table 2. Reactions through Alkynyl-Stabilized Oxocarbenium
Ionsa
Scheme 3. Selective Alkyne Functionaliaztion
We have shown that bridged ethers that show insideÀ
outside stereoisomerism can be prepared through transan-
nular cyclizations of macrocyclic propargylic ethers. Oxi-
dative carbonÀhydrogen bond cleavage was employed to
generate the strained oxocarbenium ion intermediates in
this study. These cyclizations are possible because the
macrocycle constrains the geometry of the transition state
and because of the sterically undemanding nature of
alkynes. Two approaches to this objective were developed.
One approach proceeds through the oxidation of a benzylic
or allylic ether, where the alkynyl group adapts an axial
orientation in the transition state, as is slightly preferred
due to a possible electrostatic interaction. The other ap-
proach proceeds through the oxidation of propargylic
ethers to form slighly disfavored but energetically accessible
Z-oxocarbenium ion intermediates. The capacity of al-
kynes to act as versatile precursors to a number of func-
tional groups makes the products of these reactions useful
intermediates for the preparation of a range of compounds.
a Representative procedure: DDQ (3À4 equiv) was added to a 0.1 M
solution of the substrate (1 equiv), LiClO4 (0.2 equiv), and 2,6-dichloro-
pyridine (4 equiv) in DCE at rt. The reaction was stirred at the indicated
temperature for the indicated period for the indicated time. See the
Supporting Information for details. b See the Supporting Information
for details on substrate syntheses. c Combined yield of diastereomers.
d Determined by integrating characteristic signals in the 1H NMR
spectrum.
Acknowledgment. We thank the National Institutes of
Health (GM062924) for generous support of this work and
for a grant (1S10RR031789-01) for a diffractometer pur-
chase. We thank Dr. Steve Geib (University of Pittsburgh)
for crystallographic studies.
alkyne 13 was subjected to the two-step hydrosilylation/
desilylation-based reduction that was reported by the
Trost group13 to form E-alkene 33 (Scheme 3).14 This
compound would be difficult to form directly due to the
Supporting Information Available. Synthetic schemes
for substrate syntheses, experimental procedures for cou-
pling reactions, stereochemical determinations, crystal-
lographic information, and characterization data for all
new compounds. This information is available free of
charge via the Internet at http://pubs.acs.org.
(12) For discussions of the stereoelectronic requirements for efficient
bond cleavage reactions of radical cations, see: (a) Tolbert, L. M.;
Khanna, R. K.; Popp, A. E.; Gelbaum, L.; Bottomley, L. A. J. Am.
Chem. Soc. 1990, 112, 2373. (b) Perrott, A. L.; de Lijser, H. J. P.; Arnold,
D. R. Can. J. Chem. 1997, 75, 384. (c) Freccero, M.; Pratt, A.; Albini, A.;
Long, C. J. Am. Chem. Soc. 1998, 120, 284.
€
(13) Trost, B. M.; Ball, Z. T.; Joge, T. J. Am. Chem. Soc. 2002, 124,
7922.
(14) For other examples of hydrosilylation-based alkyne reduction in
(15) (a) Hatanaka, Y.; Hiyama, T. Tetrahedron Lett. 1990, 31, 2719.
(b) Denmark, S. E.; Sweis, R. F. Acc. Chem. Res. 2002, 35, 835.
(16) Jones, G. R.; Landais, Y. Tetrahedron 1996, 52, 7599.
€
macrocycles, see: (a) Furstner, A.; Radkowski, K. Chem. Commun. 2002,
€
2182. (b) Furstner, A.; Bonnekessel, M.; Blank, J. T.; Radkowski,
K.; Seidel, G.; Lacombe, F.; Gabor, B.; Mynott, R. Chem.;Eur. J.
€
2007, 13, 8762. (c) Micoine, K.; Furstner, A. J. Am. Chem. Soc. 2010,
132, 14064.
The authors declare no competing financial interest.
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