Cascade approach to stereoselective polycyclic ether formation: Epoxides as trapping agents in the transposition of allylic alcohols

Article abstract of DOI:10.1002/anie.201208132

Complexity from simplicity: Polycyclic ethers are synthesized by cascade reactions involving the use of epoxides as electrophilic traps in the transposition of allylic alcohols. Stereogenic centers are created by functionalizing prochiral sites under ther

Full text of DOI:10.1002/anie.201208132

Angewandte
Chemie
DOI: 10.1002/anie.201208132
Cascade Reactions
Cascade Approach to Stereoselective Polycyclic Ether Formation:
Epoxides as Trapping Agents in the Transposition of Allylic Alcohols**
Youwei Xie and Paul E. Floreancig*
Cascade reactions[1] facilitate complex molecule synthesis
through their capacity to generate multiple target-relevant[2]
bonds and stereocenters in a single operation.[3] The use of
thermodynamic control to dictate product formation further
streamlines molecular synthesis by minimizing the need to set
multiple stereocenters in the substrates. Rhenium oxide
mediated allylic alcohol transpositions[4] are useful in the
design of thermodynamically controlled reactions because
regiochemistry[5] and stereochemistry[6] are influenced by
structural changes. Thus, they are being used increasingly in
complex molecule synthesis.[7] A schematic of the process that
is consistent with experimental observations and computa-
tional studies[8] is shown in Scheme 1.
can act as electrophiles to liberate nucleophilic hydroxy
groups upon ring opening[9] or as nucleophiles to create
electrophilic epoxonium ions upon reacting with a cation.[10]
Moreover, several methods are commonly employed to
prepare epoxides in enantiomerically pure form.[11] These
attributes have led to the development of numerous epoxide-
opening cascade reactions.[12] Herein, we report that epoxides
can be used as trapping agents for allylic alcohols in rhenium
oxide mediated transposition reactions. These reactions are
used as the basis for a number of cascade processes in which
several electrophiles can be used as trapping agents. Ketones
are shown to be effective stereochemical conduits, that allow
remote stereoinduction and bidirectional stereogenesis in the
synthesis of polycyclic structures. Stereocenters are generated
by functionalizing prochiral centers, in contrast to standard
epoxide cascade reactions in which an equivalent number of
stereocenters are present in the substrates and products.
Additionally we show that Re2O7 can be adsorbed on silica gel
to provide an easily handled and measured source of the
catalyst.
The capacity of epoxides to act as trapping agents was
demonstrated (Scheme 2) by treating 1 with Re2O7 (5 mol%)
to produce tetrahydropyrans 2 and 3 in 51% and 38% yields,
respectively, after 4 h at room temperature. Resubjection of
the isomers to the reaction conditions resulted in no reaction,
thereby establishing that this result arises from kinetic control
rather than thermodynamic equilibration. The reaction of
Scheme 1. Rhenium oxide mediated allylic alcohol transposition.
We have begun a program in which Re2O7-catalyzed
allylic alcohol transposition reactions[5c] initiate stereoselec-
tive ring-forming processes that proceed through trapping the
hydroxyl group with a pendent electrophile followed by
thermodynamically controlled equilibration. Initial studies
employed achiral acetal electrophiles, thereby a stereogenic
center in the tether between the nucleophile and the electro-
phile was required to control the stereochemical outcome.
The trapping of transposing alcohols with chiral electrophiles,
however, offers significant advantages for the preparation of
enantiomerically pure materials through this sequence. The
use of epoxides in these reactions is particularly attractive
because of their versatile reactivity patterns, whereby they
[*] Y. Xie, Prof. P. E. Floreancig
Department of Chemistry, University of Pittsburgh
Pittsburgh, PA 15260 (USA)
E-mail: florean@pitt.edu
[**] This work was supported by grants from the National Institutes of
Health (P50-GM06082) and the National Science Foundation (CHE-
1151979). We thank Dr. Steve Geib for crystallographic analyses,
and Dr. Damodaran Krishnan and Sage Bowser for assistance with
NMR experiments.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201208132.
Scheme 2. Epoxides as trapping agents in alcohol transposition reac-
tions.
Angew. Chem. Int. Ed. 2013, 52, 625 –628
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
625

.
Angewandte
Communications
secondary alcohol 4 proved to be more complex. After 45 min
the reaction produced a mixture of oxepanes 5 and 6 in
a nearly 1:1 ratio. Prolonged exposure in the presence of
higher catalyst loading (15 mol%) resulted in the formation
of tetrahydropyrans 7 and 8, again in a nearly 1:1 ratio.
Resubjecting 5 to the reaction conditions predominantly
provides 7 and resubjecting 6 to the reaction conditions
predominantly provides 8, and 7 and 8 interconvert extremely
slowly when resubjected to Re2O7.
These studies showed that primary and secondary allylic
alcohols react through divergent pathways in these processes
(Scheme 3). Primary allylic alcohol 1 undergoes transposition
to form a mixture of diastereomeric secondary alcohols 9. The
Scheme 4. Stereochemical isomerization.
merization. An analogous terminal alkene showed very little
isomerization (not shown), thus confirming the importance of
cation stabilization in stereochemical equilibration. These
studies indicated that these processes could provide stereo-
chemically pure products if the hydroxy group that results
from epoxide opening is used as a nucleophile in a cascade
process.
The initial set of cascade reactions proceeded through the
incorporation of an electrophile or proelectrophile at the
substrate terminus to trap the hydroxy group following
epoxide opening (Scheme 5). Treatment of epoxy ester 14
with Re2O7 provided lactone 15 as a single stereoisomer in
Scheme 3. Mechanistic details.
Re2O7 or the HOReO3 that forms upon reaction with the
hydroxy group, activates the epoxide group toward nucleo-
philic attack, thus providing the tetrahydropyran products.
Secondary alcohol 4, however, reacts with Re2O7 to form allyl
cation 10 as the result of stabilization by the additional alkyl
group. The epoxide then adds to the cation to form
epoxonium ion 11, which reacts with the perrhenate through
a kinetically preferred[10e] endo pathway to give an oxepanyl
perrhenate ester that decomposes to yield the observed
oxepanyl alcohols 5 and 6 as the initial products. Crystallo-
graphic[13] and Mosher ester[14] analyses of the products from
enantiomerically enriched substrates provided evidence for
this pathway by showing that the absolute stereochemistry at
the distal carbon of the epoxide (with respect to the allylic
alcohol) was retained, whereas the absolute stereochemistry
at the proximal carbon was inverted. Re2O7-mediated ioniza-
tion of the oxepanes yields allyl cations 12, which react with
the free hydroxy groups, predominantly with stereochemical
retention, to yield the tetrahydropyrans 7 and 8, as thermo-
dynamic products; these tetrahydropyrans appear to be inert
toward further ionization. Racemization in these processes is
minimal, thus indicating that allylic ethers undergo ionization
at a faster rate than the aliphatic ethers.
Scheme 5. Cascade reactions. Bn=benzyl.
71% yield, although the removal of MeOH proved to be
essential for equilibration. Acetal 16 was prepared to study
the viability of using the Lewis acidity of the rhenium oxide to
promote the formation of an oxocarbenium ion[5b–c,15] as
a trapping group. Treatment of 16 with Re2O7 at room
temperature led to decomposition, whereas treatment at
a lower reaction temperature provided a low yield of 17.
Switching to the more soluble catalyst Ph3SiOReO3,[16]
however, allowed the initial phase of the reaction to be
conducted at À258C. After the reaction mixture was warmed
to room temperature to effect the stereochemical equilibra-
tion, 17 was isolated as a single stereoisomer with respect to
the tetrahydropyran and as a 5:2 mixture at the anomeric site.
This improved efficiency could be attributed to the absence of
HOReO3 formation when Ph3SiOReO3 is used as the catalyst.
Shorter reaction times resulted in the observation of more
stereoisomeric products, thus confirming that equilibration
occurs after the initial cyclization. Cascade reactions with
enone electrophiles provided tetrahydropyranyl ketones, as
shown through the conversion of 18 into 19. This reaction
provided a bis(tetrahydropyran) within 12 h, but required
3.5 days at room temperature to provide the product as
a single stereoisomer. The reaction with an enone electrophile
is significant in that it demonstrates bidirectional stereo-
genesis, in which the introduction of new stereogeneic centers
from distal prochiral units are directed by the stereogenic
The slow isomerization of 8, in contrast to the isomer-
izations of 5 and 6, led us to speculate that the exocyclic
hydroxyalkyl group suppresses allyl cation formation. This
hypothesis was tested (Scheme 4) by preparing methyl ether
13 as a 1:1 mixture of stereoisomers. Upon treatment of this
mixture with Re2O7 for 5 h at room temperature, the
cis isomer was obtained nearly exclusively, thereby confirm-
ing that hydrogen bonding suppresses ionization-based iso-
626
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 625 –628

Angewandte
Chemie
centers in the epoxide group. Notably, this transformation
also proceeds with perfect atom economy.[17]
an allylic cation intermediate. Success was achieved, however,
by using Ph3SiOReO3 and conducting the initial phases of the
reaction at À788C followed by slow and controlled warming.
This protocol resulted in the conversion of 25 into 26 in 71%
yield. A minor amount (4%) of a diastereomer was isolated,
but the overall yield of 26 was compromised when the
reaction was run to complete equilibration.
Lower homologues are also suitable substrates for the
process, although product stereocontrol is lost in these
transformations owing to the greater conformational freedom
for tetrahydrofurans in comparison to tetrahydropyrans.
Treatment of 27 with Re2O7 provided a 1:1 mixture of
spirocycles 28 and 29 in 94% overall yield after 3 h. Although
thermodynamic control fails to deliver a major product,
either isomer is available in useful quantities through
a simple recycling protocol. Thus, 28 can be obtained in
69% yield by resubjecting 29 to the reaction conditions
and in 78% yield after two recyclings. Alternatively 29
can be isolated in 66% yield after subjecting 28 to one
recycling and in 75% yield after two recyclings.
The use of ketones as stereochemical conduits provides an
alternate strategy to chirality transfer from the epoxide
groups to remote sites. This approach uses a ketone group as
a nucleophile to open the epoxide, thereby generating a chiral
oxocarbenium ion[18] that acts as an electrophilic trap for the
transposing alcohol. Therefore, the reaction proceeds through
acetal ionization and allylic alcohol transposition rather than
allylic ether ionization, thus facilitating the transfer of
stereochemical information to products that contain terminal
alkenes. This feature is demonstrated (Scheme 6) by the
reaction of 20 with Re2O7, which proceeds within 20 h at room
The use of ketones as stereochemical conduits can be
combined with the inclusion of enones as terminal
electrophiles to provide an impressive increase in molec-
ular complexity through bidirectional stereogenesis. This
is demonstrated (Scheme 7) by the conversion of 30 into
31. This atom-economical transformation, in which
a compound with one ring and two stereogenic centers
is converted into a structure with three rings and five
stereogenic centers, proceeded in 8 h at room temper-
ature to form the product with complete stereocontrol in
84% yield.
The difficulty associated with the addition of small
quantities of Re2O7 with precision led us to explore
alternative reagent preparations. We discovered that
a supported catalyst can be prepared through a conven-
ient protocol in which a slurry of Re2O7 and silica gel in
Et2O is stirred for several hours followed by drying under
vacuum.[19] We prepared a 10% (w/w) mixture of Re2O7
on SiO2 through this protocol and showed that it is
a competent catalyst for the transformations that we have
previously developed. Yields and reaction times were
similar when the immobilized and free catalysts were
employed, with the conversion of 20 into 21 proceeding in
93% yield after 12 h and the conversion of 30 into 31
proceeding in 76% yield after 24 h, for the immobilized
catalyst. Notably, the immobilized catalyst could be used for
the conversion of 16 into 17 in 60% yield, thus indicating that
this easily accessed material could be an alternative to the
much more expensive Ph3SiOReO3. The free-flowing immo-
bilized catalyst is easily weighed, even in humid environ-
ments, which cause Re2O7 to liquefy. Reactions with the
immobilized catalyst do not require the induction periods that
Scheme 6. Ketones as stereochemical conduits.
temperature to form spiroacetal 21 as a single stereoisomer in
93% yield. A plausible mechanism for this transformation
proceeds through the Lewis acid mediated opening of the
epoxide by the oxygen atom of the ketone to yield oxocarbe-
nium ion 22. The allylic alcohol reversibly transposes to form
a mixture of secondary alcohols (23) that add to the
oxocarbenium ion to form 21 and 24. The thermodynamically
less-stable 24 can revert into a single diastereomer of 23,
which undergoes stereochemical ꢀeditingꢁ through allylic
alcohol transposition. Eventually this process leads to the
thermodynamically preferred spiroacetal 21 as the sole
product of this transformation. An alternative mechanism in
which the transposing alcohols add to the ketone to form
a mixture of hemiacetals that add to the epoxide to form 21
and 24 can also be envisioned. Secondary alcohol substrates
decomposed under these reaction conditions, presumably
owing to the myriad pathways that are possible upon forming
Scheme 7. Bidirectional stereogenesis with a ketone conduit.
Angew. Chem. Int. Ed. 2013, 52, 625 –628
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
627

.
Angewandte
Communications
Herrmann, T. Saito, C. E. Stivala, J. Tom, A. Zakarian, J. Am.
Chem. Soc. 2010, 132, 5962; c) Y. Xie, P. E. Floreancig, Chem.
Sci. 2011, 2, 2423.
are often observed for the free catalyst because of superior
dispersion. The catalyst could be recovered by filtration but
this recovered reagent showed diminished activity, thus
indicating that partial catalyst leaching occurs during the
reaction. Thus this preparation primarily serves to facilitate
the transformations from an operational perspective, partic-
ularly for reactions that utilize high-molecular-weight sub-
strates.
[7] a) B. M. Trost, F. D. Toste, J. Am. Chem. Soc. 2000, 122, 11262;
b) J. M. Hutchison, H. A. Lindsay, S. S. Dormi, G. D. Jones,
D. A. Vivic, M. C. McIntosh, Org. Lett. 2006, 8, 3663; c) S. Y.
Yun, E. C. Hansen, I. Volchkov, W. Y. Lo, D. Lee, Angew. Chem.
2010, 122, 4357; Angew. Chem. Int. Ed. 2010, 49, 4261; d) B. M.
Trost, D. Amans, W. M. Seganish, C. K. Chung, Chem. Eur. J.
2012, 18, 2961.
We have demonstrated that epoxide cascade reactions can
be initiated by rhenium oxide mediated allylic alcohol
transposition reactions. These transformations are possible
because rhenium oxide has dual roles as a transposition
catalyst and as an acid that enhances the electrophilicity of
the epoxide group and promotes product ionization, thereby
allowing thermodynamically controlled stereochemical equi-
libration. The syntheses rely on the functionalization of
prochiral carbons rather than the generation of stereochem-
ically defined nucleophiles for epoxide opening. Reactions
proceed either by direct addition of the transposing alcohol to
the activated epoxide or by using ketones as conduits that
relay the stereochemical information from the epoxide to
distal regions of the molecule. Maximal increases in molecular
complexity are observed when an electrophile is present to
trap the hydroxy group that is liberated upon epoxide
opening. Enones can be used in this capacity to provide
atom-economical transformations that exhibit bidirectional
stereogenesis, in which the stereogenic centers in the epoxide
guide the formation of stereocenters on opposite ends of the
structure.
[8] S. Bellemin-Laponnaz, J. P. LeNy, A. Dedieu, Chem. Eur. J.
1999, 5, 57.
[9] For recent examples, see: a) G. L. Simpson, T. P. Heffron, E.
Merino, T. F. Jamison, J. Am. Chem. Soc. 2006, 128, 1056; b) J. A.
Marshall, A. M. Mikowski, Org. Lett. 2006, 8, 4375; c) Y.
Morimoto, T. Okita, M. Takaishi, T. Tanaka, Angew. Chem.
2007, 119, 1150; Angew. Chem. Int. Ed. 2007, 46, 1132; d) I.
Vilotijevic, T. F. Jamison, Science 2007, 317, 1189; e) Y. Mor-
imoto, H. Yata, Y. Nishikawa, Angew. Chem. 2007, 119, 6601;
Angew. Chem. Int. Ed. 2007, 46, 6481; f) J. A. Marshall, R. K.
Hann, J. Org. Chem. 2008, 73, 6753; g) Z. Xiong, R. Busch, E. J.
Corey, Org. Lett. 2010, 12, 1512; h) C. J. Morten, J. A. Byers, T. F.
Jamison, J. Am. Chem. Soc. 2011, 133, 1902.
[10] a) N. Hayashi, K. Fujiwara, A. Murai, Tetrahedron 1997, 53,
12425; b) A. Zakarian, A. Batch, R. A. Holton, J. Am. Chem.
Soc. 2003, 125, 7822; c) J. C. Valentine, F. E. McDonald, W. A.
Neiwert, K. I. Hardcastle, J. Am. Chem. Soc. 2005, 127, 4586;
d) R. Tong, J. C. Valentine, F. E. McDonald, R. Cao, X. Fang,
K. I. Hardcastle, J. Am. Chem. Soc. 2007, 129, 1050; e) S. Wan,
H. Gunaydin, K. N. Houk, P. E. Floreancig, J. Am. Chem. Soc.
2007, 129, 7915; f) J. Tanuwidjaja, S.-S. Ng, T. F. Jamison, J. Am.
Chem. Soc. 2009, 131, 12084; g) D. J. Clausen, S. Wan, P. E.
Floreancig, Angew. Chem. 2011, 123, 5284; Angew. Chem. Int.
Ed. 2011, 50, 5178.
[11] For representative examples, see: a) T. Katsuki, K. B. Sharpless,
J. Am. Chem. Soc. 1980, 102, 5974; b) Z.-X. Wang, Y. Tu, M.
Frohn, J.-R. Zhang, Y. Shi, J. Am. Chem. Soc. 1997, 119, 11224;
c) S. E. Schaus, B. D. Brandes, J. F. Larrow, M. Tokunga, K. B.
Hansen, A. E. Gould, M. E. Furrow, E. N. Jacobsen, J. Am.
Chem. Soc. 2002, 124, 1307; d) H. Kakei, R. Tsuji, T. Ohshima,
M. Shibasaki, J. Am. Chem. Soc. 2005, 127, 8962; e) X. Wang, B.
List, Angew. Chem. 2008, 120, 1135; Angew. Chem. Int. Ed. 2008,
47, 1119; f) Z. Li, H. Yamamoto, J. Am. Chem. Soc. 2010, 132,
7878.
[12] For reviews, see: a) I. Vilotijevic, T. F. Jamison, Angew. Chem.
2009, 121, 5352; Angew. Chem. Int. Ed. 2009, 48, 5250; b) I.
Vilotijevic, T. F. Jamison, Mar. Drugs 2010, 8, 763.
[13] Please see the Supporting Information. CCDC 903395 (2),
903396 (6), and 903397 (19) contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Received: October 9, 2012
Published online: November 22, 2012
Keywords: cascade reactions · isomerization ·
.
oxygen heterocycles · rearrangement · stereoselectivity
[1] a) E. A. Anderson, Org. Biomol. Chem. 2011, 9, 3997; b) C.
Grondal, M. Jeanty, D. Enders, Nat. Chem. 2010, 2, 167; c) K. C.
Nicolaou, J. S. Chen, Chem. Soc. Rev. 2009, 38, 2993; d) K. C.
Nicolaou, D. J. Edmonds, P. G. Bulger, Angew. Chem. 2006, 118,
7292; Angew. Chem. Int. Ed. 2006, 45, 7134; e) L. F. Tietze,
Chem. Rev. 1996, 96, 115.
[2] J. B. Hendrickson, J. Am. Chem. Soc. 1975, 97, 5784.
[3] a) P. A. Wender, B. L. Miller, Nature 2009, 460, 197; b) P. A.
Wender, B. L. Miller, in Connectivity Analysis and Multibond-
forming Processes in Organic Synthesis: Theory and Applica-
tions (Ed.: T. Hudlicky), JAI, Greenwich, 1993, pp. 27 – 66.
[4] For a review of rhenium oxide mediated transformations, see:
a) S. Bellemin-Laponnaz, ChemCatChem 2009, 1, 357; for
examples of allylic alcohol transposition, see: b) K. Narasaka,
H. Kusama, Y. Hiyashi, Tetrahedron 1992, 48, 2059; c) S.
Bellemin-Laponnaz, H. Gisie, J. P. LeNy, J. A. Osborn, Angew.
Chem. 1997, 109, 1011; Angew. Chem. Int. Ed. Engl. 1997, 36,
976.
[14] a) J. A. Dale, D. L. Dull, H. S. Mosher, J. Org. Chem. 1969, 34,
2543; b) I. Ohtani, T. Kusumi, Y. Kashman, H. Kakisawa, J. Am.
Chem. Soc. 1991, 113, 4092.
[15] K. Tadpetch, S. D. Rychnovsky, Org. Lett. 2008, 10, 4839.
[16] T. Schoop, H. W. Roesky, M. Noltemeyer, H.-G. Schmidt,
Organometallics 1993, 12, 571.
[17] B. M. Trost, Angew. Chem. 1995, 107, 285; Angew. Chem. Int. Ed.
Engl. 1995, 34, 259.
[18] a) R. L. Mulholland, Jr., A. R. Chamberlin, J. Org. Chem. 1988,
53, 1082; b) C. H. Fotsch, A. R. Chamberlin, J. Org. Chem. 1991,
56, 4141; c) S. D. Rychnovsky, V. H. Dahanukar, Tetrahedron
Lett. 1996, 37, 339.
[5] a) C. Morrill, R. H. Grubbs, J. Am. Chem. Soc. 2005, 127, 2842;
b) C. Morrill, G. L. Beutner, R. H. Grubbs, J. Org. Chem. 2006,
71, 7813; c) E. C. Hansen, D. Lee, J. Am. Chem. Soc. 2006, 128,
8142.
[19] For a more rigorous preparation of Re2O7·SiO2, see: S. L. Scott,
J.-M. Basset, J. Am. Chem. Soc. 1994, 116, 12069.
[6] a) H. H. Jung, J. R. SeidersII, P. E. Floreancig, Angew. Chem.
2007, 119, 8616; Angew. Chem. Int. Ed. 2007, 46, 8464; b) A. T.
628
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 625 –628