An experimental and computational approach to defining structure/reactivity relationships for intramolecular addition reactions to bicyclic epoxonium ions

Article abstract of DOI:10.1021/ja0709674

In this manuscript we report that oxidative cleavage reactions can be used to form oxocarbenium ions that react with pendent epoxides to form bicyclic epoxonium ions as an entry to the formation of cyclic oligoether compounds. Bicyclic epoxonium ion structure was shown to have a dramatic impact on the ratio of exo- to endo-cyclization reactions, with bicyclo[4.1.0] intermediates showing a strong preference for endo-closures and bicyclo[3.1.0] intermediates showing a preference for exo-closures. Computational studies on the structures and energetics of the transition states using the B3LYP/6-31G(d) method provide substantial insight into the origins of this selectivity.

Full text of DOI:10.1021/ja0709674

Published on Web 06/05/2007
An Experimental and Computational Approach to Defining
Structure/Reactivity Relationships for Intramolecular Addition
Reactions to Bicyclic Epoxonium Ions
Shuangyi Wan,† Hakan Gunaydin,‡ K. N. Houk,*,‡ and Paul E. Floreancig*,†
Contribution from the Department of Chemistry and Biochemistry, UniVersity of California, Los
Angeles, California 90095, and Department of Chemistry, UniVersity of Pittsburgh,
Pittsburgh, PennsylVania 15260
Received February 20, 2007; E-mail: houk@chem.ucla.edu; florean@pitt.edu
Abstract: In this manuscript we report that oxidative cleavage reactions can be used to form oxocarbenium
ions that react with pendent epoxides to form bicyclic epoxonium ions as an entry to the formation of cyclic
oligoether compounds. Bicyclic epoxonium ion structure was shown to have a dramatic impact on the ratio
of exo- to endo-cyclization reactions, with bicyclo[4.1.0] intermediates showing a strong preference for
endo-closures and bicyclo[3.1.0] intermediates showing a preference for exo-closures. Computational studies
on the structures and energetics of the transition states using the B3LYP/6-31G(d) method provide
substantial insight into the origins of this selectivity.
Scheme 1. Exo- and endo-Cyclizations Using Alkene and Epoxide
Groups
Introduction
Cascade reactions, in which multiple bond-forming processes
occur in a single operation,1 have been shown to be effective
for executing rapid increases in molecular complexity, as
demonstrated by the biosyntheses of terpenes from polyolefins2
and cyclic ethers from polyepoxides.3 In these pathways strict
regiocontrol must be achieved in each cyclization step to form
products with high efficiency. Effective mimicry of these
processes in the absence of enzymatic mediation requires an
understanding of the inherent reactivity patterns of the relevant
intermediates in these transformations and of the manner in
which they can be manipulated. Of particular importance is
determining the structural features that promote exo- and endo-
cyclizations (Scheme 1).
Cyclic ether synthesis from polyepoxides has been demon-
strated under acidic,4 basic,5 and oxidative6 conditions. While
† University of Pittsburgh.
‡ University of California, Los Angeles.
(1) (a) Nicolaou, K. C.; Montagnon, T.; Snyder, S. A. Chem. Commun. 2003,
551. (b) Tietze, L. F. Chem. ReV. 1996, 96, 115.
(2) (a) Stork, G.; Burgstahler, A. W. J. Am. Chem. Soc. 1955, 77, 5068. (b)
Eschenmoser, A.; Ruzicka, L.; Jeger, O.; Arigoni, D. HelV. Chim. Acta
1955, 38, 1890.
(3) (a) Cane, D. E.; Celmer, W. D.; Westley, J. W. J. Am. Chem. Soc. 1983,
105, 3594. (b) Lee, M. S.; Qin, G.; Nakanishi, K.; Zagorski, M. G. J. Am.
Chem. Soc. 1989, 111, 6234. (c) Krishna Prasad, A. V.; Shimizu, Y. J.
Am. Chem. Soc. 1989, 111, 6476.
(4) (a) Still, W. C.; Romero, A. G. J. Am. Chem. Soc. 1986, 108, 2105. (b)
Schreiber, S. L.; Sammekia, T.; Hulin, B.; Schulte, G. J. Am. Chem. Soc.
1986, 108, 2106. (c) Xiong, Z.; Corey, E. J. J. Am. Chem. Soc. 2001, 122,
9328.
(5) (a) Nicolaou, K. C.; Claremon, D. A.; Barnette, W. E. J. Am. Chem. Soc.
1980, 108, 6611. (b) Dolle, R. E.; Nicolaou, K. C. J. Am. Chem. Soc. 1985,
107, 1691. (c) Hoye, T. R.; Suhadolnik, J. C. J. Am. Chem. Soc. 1985,
107, 5312. (d) Simpson, G. L.; Heffron, T. P.; Merino, E.; Jamison, T. F.
J. Am. Chem. Soc. 2006, 128, 1056.
exo-cyclizations are most commonly observed, recently several
reports have appeared in the literature that demonstrate favorable
endo-cyclizations leading to fused polyethers. In a series of
papers, McDonald and co-workers have convincingly proposed7
that bicyclic epoxonium ions, formed from nucleophilic attacks
of epoxides on Lewis acid activated epoxides, are key inter-
mediates in the formation of fused polycyclic ethers. In these
reactions endo-cyclizations were postulated to be favored due
to the ring strain accrued during bicyclic epoxonium formation
(6) (a) Alvarez, E.; D´ıaz, M. T.; Rodr´ıguez, M. L.; Mart´ın, J. D. Tetrahedron
Lett. 1990, 31, 1629. (b) Zakarian, A.; Batch, A.; Holton, R. A. J. Am.
Chem. Soc. 2003, 125, 7822. (c) Bravo, F.; McDonald, F. E.; Neiwert, W.
A.; Hardcastle, K. I. Org. Lett. 2004, 6, 4487.
(7) (a) Valentine, J. C.; McDonald, F. E. Synlett 2006, 1816. (b) McDonald,
F. E.; Bravo, F.; Wang, X.; Wei, X.; Toganoh, M.; Rodr´ıguez, J. R.; Do,
B.; Neiwert, W. A.; Hardcastle, K. I. J. Org. Chem. 2002, 67, 2515.
9
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J. AM. CHEM. SOC. 2007, 129, 7915-7923
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A R T I C L E S
Wan et al.
Figure 1. Cyclization substrates.
through exo-pathways. Holton proposed6b that endo-cyclizations
can be promoted through the use of a polar solvent to promote
the SN1-type transition state, in accord with computational
studies.8 We have undertaken a program in which cascade
cyclizations are initiated through intramolecular additions of
epoxides to oxidatively generated oxocarbenium ions9 to
determine whether other factors such as epoxonium ion structure
and Lewis acid selection could also impact the outcomes of
these processes. This activation protocol diminishes the potential
for product isomerizations that can complicate mechanistic
analyses of acid-mediated reactions,10 making it ideal for
studying the inherent reactivity patterns of epoxonium ions with
various structures.
Figure 2. Epoxonium ion substitution patterns to be compared in this study.
Scheme 2. Synthesis of Monoepoxide Substratesa
To elucidate the epoxonium ion structural features that impact
cyclization regiochemistry, we studied the effects of changing
the degree of substitution in the precursor epoxide (disubstituted
vs trisubstituted), the ring size of the epoxonium ion (bicyclo-
[4.1.0] ions vs bicyclo[3.1.0] ions), and the electrophilic alkyl
group that reacts with the epoxide to form the epoxonium ion
(oxocarbenium ion vs carbenium ion). In this manuscript we
show that each of these features can impact the partitioning of
the reaction through exo- or endo-pathways. Transition structure
energies of the exo- and endo-cyclizations were studied com-
putationally at the B3LYP/6-31G(d) level, providing insight into
the origins of the selectivity and a predictive model for the
design of future cascade reactions.
n
a Reagents and conditions: (a) Ph2CH2, BuLi, THF, 0 °C, 83% (n )
Results and Discussion
1), 70% (n ) 2). (b) NaH, DMF, 0 °C, then MeI, 97% (n ) 1), 95% (n )
2). (c) O3, CH2Cl2, -78 °C, then Ph3P, rt, 96% (n ) 1 or 2). (d)
(EtO)2P(O)CH2CO2Et, NaH, THF, 0 °C, 94% (n ) 1), 93% (n ) 2). (e)
DIBAL-H, THF, -78 °C. (f) m-CPBA, NaHCO3, CH2Cl2, 0 °C, 70% (n )
1), 91% (n ) 2), two steps. (g) Boc2O, N-methylimidazole, PhMe, 0 °C,
90% (n ) 1), 84% (n ) 2). (h) 2,2,6,6-Tetramethylpiperidine, nBuLi,
Et2AlCl, benzene, 0 °C, 90%. (i) (EtO)3CCH3, propionic acid, 145 °C, 96%.
(j) DIBAL-H, CH2Cl2, -78 °C. (k) Ph2CH2, nBuLi, THF, 0 °C, 70% (n )
1), 79% (n ) 2). (l) NaH, DMF, 0 °C, then MeI. (m) Bu4NF, THF, 100%
(n ) 1), 97% (n ) 2), two steps. (n) m-CPBA, NaHCO3, CH2Cl2, 0 °C,
95% (n ) 1), 99% (n ) 2). (o) Boc2O, N-methylimidazole, PhMe, 0 °C,
86% (n ) 1), 89% (n ) 2). (p) Ph3P+CH2OMeCl-, NaHMDS, THF, -78
°C, then Hg(OAc)2, THF, H2O, KI, 82%.
Substrate Design and Synthesis. We designed a set of mono-
and diepoxide cyclization substrates to determine the impact
of changing several epoxonium ion structural features on
cyclization regioselectivity (Figure 1). Monoepoxide substrates
1-4 were designed to probe the importance of bicyclic
epoxonium ion ring size ([3.1.0] vs [4.1.0]) and substitution
pattern (disubstituted vs trisubstituted) on cyclization efficiency
and product distribution when oxocarbenium ions are used as
activating groups (tethered Lewis acids). Diepoxide substrates
5-9 were designed to determine whether regioselectivity in the
terminal cyclization event is sensitive to the identity of the
cationic activating group, since the relevant epoxonium ions
are activated by unstabilized carbenium ions rather than
oxocarbenium ions. This study was also designed to determine
whether cyclization efficiency is affected by the relative
stereochemical orientations of the epoxide groups. Figure 2
illustrates the structural features of the intermediate epoxonium
ions that will be compared in this manuscript. The diphenyl-
methyl group was selected as the electroauxiliary11 because it
is more reactive than an unsubstituted benzyl group,12 as
required for cyclizations of weakly nucleophilic epoxycarbon-
ates, and because it is easily introduced through the addition of
Ph2CHLi (prepared from inexpensive diphenylmethane and
nBuLi) to aldehydes.
The monoepoxide substrates were synthesized according to
the straightforward sequences shown in Scheme 2. These
compounds were prepared as racemic mixtures, since our sole
objective was to determine the cyclization regiochemistry and
relative stereochemical orientations in the reaction products.
Disubstituted epoxides 1 and 2 were synthesized from unsatur-
(8) (a) Na, J.; Houk, K. N.; Shevlin, C. G.; Janda, K. D.; Lerner, R. A. J. Am.
Chem. Soc. 1993, 115, 8453. (b) Na, J.; Houk, K. N. J. Am. Chem. Soc.
1996, 118, 9204.
(9) (a) Kumar, V. S.; Aubele, D. L.; Floreancig, P. E. Org. Lett. 2002, 4, 2489.
(b) Kumar, V. S.; Wan, S.; Aubele, D. L.; Floreancig, P. E. Tetrahedron:
Asymmetry 2005, 16, 3570.
(10) (a) Nakata, T.; Schmid, G.; Vranesic, B.; Okigawa, M.; Smith-Palmer, T.;
Kishi, Y. J. Am. Chem. Soc. 1978, 100, 2933. (b) Hayashi, N.; Fujiwara,
K.; Murai, A. Tetrahedron 1997, 53, 12425.
(11) Yoshida, J.-i.; Nishikawa, K. J. Chem. Soc., Dalton Trans. 1998, 2589.
(12) (a) Seiders, J. R., II.; Wang, L.; Floreancig, P. E. J. Am. Chem. Soc. 2003,
125, 2406. (b) Wang, L.; Seiders, J. R., II; Floreancig, P. E. J. Am. Chem.
Soc. 2004, 126, 12596.
9
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Epoxonium Ion Cyclization Reactions
A R T I C L E S
Scheme 3. Synthesis of Diepoxide Cyclization Substrates 5-8a
n
a Reagents and conditions: (a) 2,2,6,6-Tetramethylpiperidine, BuLi, Et2AlCl, benzene, 0 °C, 92%. (b) (EtO)3CCH3, propionic acid, 145 °C, 94%. (c)
DIBAL-H, CH2Cl2, -78 °C, 92%. (d) Ph2CH2, nBuLi, THF, 0 °C, 80% (n ) 1), 80% (n ) 2). (e) NaH, DMF, 0 °C, then MeI. (f) Bu4NF, THF, 97% (n )
1), 98% (n ) 2), two steps. (g) Ph3P+CH2OMeCl-, NaHMDS, THF, -78 °C, then Hg(OAc)2, THF, H2O, KI, 91%. (h) Shi catalyst, KHSO5, (MeO)2CH2,
CH3CN, H2O, 0 °C, 88% (5), 91% (6), 64% (7). (i) Boc2O, N-methylimidazole, PhMe, 0 °C, 93% (5), 86% (6), 78% (7), 82% (8, two steps). (j) (+)-
t
Diisopropyl tartrate, BuOOH, Ti(OiPr)4, CH2Cl2, -25 °C, 96% (n ) 1), 97% (n ) 2).
Scheme 4. Convergent Synthesis of Epoxide 9a
n
a Reagents and conditions: (a) DIBAL-H, CH2Cl2, -78 °C. (b) Ph2CH2, BuLi, THF, 0 °C, 82% (two steps). (c) 1-Phenyl-1H-tetrazole-5-thiol, Ph3P,
DIAD, THF, 97%. (d) NaH, DMF, 0 °C, then MeI, 85%. (e) m-CPBA, NaHCO3, CH2Cl2, 0 °C, 95%. (f) KHMDS, DME, -78 °C, then 15, 63%. (g) Bu4NF,
THF, 95%. (h) Shi catalyst, KHSO5, (MeO)2CH2, CH3CN, H2O, -5 °C, 94%. (i) Boc2O, N-methylimidazole, PhMe, 83%.
ated aldehydes 10 and 11 by identical pathways that proceeded
through aldehydes 12 and 13. Alkenylation, reduction, epoxi-
dation, and carbonate formation13 provided the desired sub-
strates. The syntheses of trisubstituted epoxides 3 and 4
commenced by opening epoxide 1414 under Yamamoto’s
conditions15 and forming aldehyde 15 through a Claisen
rearrangement/reduction sequence. This aldehyde was either
taken directly to 3 or was homologated through methoxymeth-
ylenation and mercury-mediated enol ether hydrolysis.16 The
resulting homologated aldehyde was converted to 4 in an
identical manner to the conversion of 15 to 3.
The synthesis of diepoxide substrates 5-8 (Scheme 3)
parallels the synthesis of 3 and 4, with the exception that
asymmetric epoxidation reactions were employed to ensure high
diastereocontrol. Known epoxide 1617 was converted to aldehyde
17, which could either be transformed to 5 and 6 or homologated
and converted to 7 and 8. Substrates 5 and 7, with (2R, 3R, 6R,
7R) stereochemical orientations, were formed from a double
Shi epoxidation of dienes 18 and 19,18 while substrates 6 and
8, with (2S, 3S, 6R, 7R) stereochemical orientations, were
prepared through sequential Sharpless19 and Shi epoxidations.
Substrate 9 was prepared (Scheme 4) through a convergent
sequence that employed a Julia-Kocienski olefination20 between
sulfone 20 (five steps from valerolactone) and aldehyde 15. The
resulting alkene was converted to the desired product through
the sequence that was used for the preparation of 5 and 7.
Cyclization Reactions. The results of the oxidative cycliza-
tion reactions of monoepoxides 1-4 are shown in Table 1.
Essential components in these photochemical reactions (medium-
pressure mercury lamp, Pyrex filtration) were N-methylquino-
linium hexafluorophosphate (NMQPF6) as a catalytic oxidant,21
O2 (from air) as the terminal oxidant,22 and toluene as a
cosensitizer. Disubstituted epoxide 1 provided exo-product 21
as a mixture of anomers, as expected based on analogy to
previous studies.9 Cyclization of the homologated substrate 2
yielded a mixture of exo-product 22 and endo-product 23, with
the exo-pathway being slightly favored. The formation of 23
was quite interesting, since the difference between the reactions
of 1 and 2 is simply that the initial cyclization of 1 forms a
bicyclo[3.1.0] epoxonium ion and the cyclization of 2 proceeds
through a bicyclo[4.1.0] epoxonium ion. Endo-cyclizations into
bicyclo[4.1.0] epoxonium ions have also been observed by
McDonald and co-workers23 from Lewis acid mediated pro-
cesses in which epoxonium ions are formed by adding to
nonstabilized carbenium ions and are opened by epoxide
nucleophiles. Trisubstituted epoxide 3 also produced a complex
product mixture upon oxidation, with both exo- and endo-
cyclization products being formed. The stabilizing effect of the
methyl group on the cationic intermediate modestly impacted
the regioselectivity of the cyclization reaction but was insuf-
ficient to override the preference for the exo-pathway. Also of
note, the endo-cyclizations proceeded from both inversion and
retention of the epoxonium ion to form a mixture of trans- and
(13) Basel, Y.; Hassner, A. J. Org. Chem. 2000, 65, 6368.
(14) Maruoka, K.; Murase, N.; Bureau, R.; Ooi, T.; Yamamoto, H. Tetrahedron
1994, 50, 3663.
(15) Yasuda, A.; Tanaka, S.; Oshima, K.; Yamamoto, H.; Nozaki, H. J. Am.
Chem. Soc. 1974, 96, 6513.
(16) Ansell, M. F.; Caton, M. P. L.; Stuttle, K. A. J. J. Chem. Soc., Perkin
Trans 1 1984, 1069.
(17) Hamilton, J. G. C.; Hooper, A. M.; Ibbotson, H. C.; Kurosawa, S.; Mori,
K.; Muto, S.; Pickett, J. A. Chem. Commun. 1999, 2335.
(18) Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem. Soc.
1997, 119, 11224.
(19) Gao, Y.; Klunder, J. M.; Hanson, R. M.; Masamune, H.; Ko, S. Y.;
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765.
(20) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett 1998,
26.
(21) Kumar, V. S.; Floreancig, P. E. J. Am. Chem. Soc. 2001, 123, 2842.
(22) Kumar, V. S.; Aubele, D. L.; Floreancig, P. E. Org. Lett. 2001, 3, 4123.
(23) Valentine, J. C.; McDonald, F. E.; Neiwert, W. A.; Hardcastle, K. I. J.
Am. Chem. Soc. 2005, 127, 4586.
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A R T I C L E S
Wan et al.
Table 1. Cyclization Reactions of Monoepoxide Substrates
Table 2. Cyclization Reactions of Diepoxide Substrates
a Yields are reported for isolated materials unless otherwise stated. See
the Supporting Information for procedures. bYields are based on NMR
analyses of product mixtures.
cis-fused products. Homologous epoxide 4 proved to be the best
substrate for this study, yielding endo-product 27 in 73% yield.
Thus the combined impacts of the methyl substitution and the
bicyclo[4.1.0] intermediate lead to a complete reversal of the
exo-preference that was observed in the cyclization of 1.
The results of the cyclization reactions of the diepoxide
substrates generally followed those of the monoepoxide sub-
strates, though some subtle but noteworthy differences were
observed (Table 2). Diepoxides 5 and 6, in which the initial
cyclization reaction produces a bicyclo[3.1.0] epoxonium ion,
yield only the products of consecutive exo- (28 and 30) or
consecutive endo-cyclizations (29 and 31), with the all exo-
pathway being preferred. No products from an exo-cyclization
followed by an endo-cyclization or vice versa were isolated,
indicating that bicyclo[3.1.0] epoxonium ions that form from
the addition of epoxides to carbenium ions show a higher fidelity
toward opening through the exo-pathway than those that form
from the addition of epoxides to oxocarbenium ions. Syn-
products from the endo-cyclizations were not observed, indicat-
ing either that epoxides are superior nucleophiles to carbonates
or that carbonates react with epoxonium ions reversibly prior
to tert-butyl cation loss. Reactions of substrates 7 and 8, in which
the initial cyclizations produce bicyclo[4.1.0] epoxonium ions,
proceed exclusively through consecutive endo-pathways to
provide fused tricycles 32 and 33. The formation of 33 was
remarkably efficient considering the complexity of the product.
The higher yield for the cyclization of 8 relative to 7 presumably
reflects diminished steric interactions in the cyclization reactions.
As expected, when disubstituted epoxide 9 was used in the initial
cyclization the level of regioselectivity dropped, though all endo-
a Yields are reported for isolated materials unless otherwise stated. See
the Supporting Information for procedures. b See the Supporting Information
for isolation protocols.
Scheme 5. Lactone Formation from Acetals
product 34 was formed in a slight excess over all exo-product
35. Product regiochemical and stereochemical outcomes for the
cyclizations of 7 and 9 were confirmed by treating the acetals
with BF3‚OEt2 and m-CPBA, then adding Et3N (Scheme 5).24
The structures of the resulting lactones 36 and 37 were
unambiguously confirmed through crystallographic analysis.25
Computational Studies. The results of the cyclization
reactions demonstrate that the regiochemical outcomes of
(24) (a) Grieco, P. A.; Oguri, T.; Yokoyama, Y. Tetrahedron Lett. 1978, 19,
419. (b) Masaki, Y.; Nagata, K.; Kaji, K. Chem. Lett. 1983, 1835.
(25) CCDC620345 and CCDC620346 contain the supplementary crystallographic
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. Structures are included in the Supporting Information.
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Epoxonium Ion Cyclization Reactions
A R T I C L E S
Scheme 7. Model Reactions for Bicyclo[4.1.0] Epoxonium Ion
Scheme 6. Bimolecular Epoxonium Ion Opening
Opening
Figure 3. TS1 and TS2 for the addition of the dimethyl carbonate to the
1,2,2,3-tetramethyloxiranium ion. Relative energies are given in kcal/mol,
and the distances are given in Å.
Figure 4. 5-exo and 6-endo transition structures for the intramolecular
cyclization of the bicyclo[4.1.0] epoxonium ion. The energies are given in
kcal/mol, and the distances are given in Å.
intramolecular nucleophilic additions into bicyclic epoxonium
ions are highly structurally dependent. Activating epoxides
through coordinating to oxocarbenium ions rather than unsta-
bilized carbenium ions erodes the strong preference for the exo-
pathway in bicyclo[3.1.0] epoxonium ions. Trisubstituted ep-
oxide substrates show a higher preference for endo-cyclizations
relative to disubstituted epoxide substrates, as predicted by their
enhanced ability to stabilize positive charge, though the
magnitude of effect is small. Most notable, however, is the
dramatic impact of ring size on cyclization regioselectivity.
Bicyclo[3.1.0] epoxonium ions profoundly favor reaction through
the exo-pathway, while bicyclo[4.1.0] epoxonium ions favor the
endo-pathway. While the exo-cyclizations can be understood
based on analogies to Baldwin’s rules,26 the endo-cyclizations
are difficult to rationalize. This led us to initiate computational
studies using the B3LYP/6-31G(d) method27 to explore the
origin of the structural basis for our experimental observations.
The method applied here is known to overestimate the exo-
thermicity of the ring openings of the epoxonium ions by 2 to
3 kcal/mol when compared to more accurate CCSD(T) or
CBS-Q calculations, respectively.28 The calculations were
carried out by using the Gaussian0329 program. All of the
geometries were fully optimized, and ground state structures
were verified to have no imaginary frequencies. The transition
state geometries with one imaginary frequency were verified
to connect the desired reactants to the desired products via IRC
(intrinsic reaction coordinate) calculations.
Transition structures for the nucleophilic addition of dimethyl
carbonate to the 1,2,2,3-tetramethyloxiranium ion were com-
puted to reveal the geometry of the transition state in the absence
of geometrical constraints. The nucleophile, dimethyl carbonate,
can add to either the secondary or tertiary carbon of the
epoxonium ion in this model reaction. These two competing
pathways for the nucleophilic addition of the dimethyl carbonate
to the 1,2,2,3-tetramethyloxiranium ion are shown in
Scheme 6.
The transition structures (TSs) for the addition of dimethyl
carbonate to the 1,2,2,3-tetramethyloxiranium ion are shown in
Figure 3. TS1 in Figure 3 corresponds to nucleophilic addition
to the secondary carbon, and TS2 corresponds to the addition
to the tertiary carbon. The forming and breaking C-O distances
at the transition states for TS1 and TS2 vary between 2.0 and
2.2 Å, indicating that both reactions proceed through SN1-like
transition states. TS2 has longer C-O bond distances, with
greater SN1 character resulting from the formation of a partial
tertiary carbocation. The greater stabilization that arises from
the partial tertiary carbocation results in TS2 being lower in
energy than TS1 by 4.3 kcal/mol. The bond lengths in Figure
3 are taken as reference points, and the transition state structures
that are shown in subsequent studies with shorter bond lengths
than the ones given in Figure 3 can be considered to be
indicative of SN2-like transition structures.
Bicyclo[4.1.0] epoxonium ions preferentially undergo in-
tramolecular cyclization through the 6-endo cyclization pathway.
The intramolecular cyclization/epoxide opening of the bicyclo-
[4.1.0] epoxonium ion was mimicked with a model reaction
shown in Scheme 7. The difference between the model reaction
(26) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 738.
(27) (a) Becke, A. Phys. ReV. A 1988, 38, 3089. (b) Lee, C.; Yang, W.; Parr, R.
Phys. ReV. B 1988, 37, 785.
(28) (a) Carlier, P. R.; Deora, N.; Crawfold, T. D. J. Org. Chem. 2006, 71,
1592. (b) Zhao, Y.; Truhlar, D. G. J. Org. Chem. 2007, 72, 295.
(29) Frisch, M. J., et al. Gaussian 03, revision C.02; Gaussian, Inc.: Wallingford,
CT, 2004.
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A R T I C L E S
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Scheme 8. Model Reaction with Methoxy Group Incorporation
shown in Figure 4 for the reaction shown in Scheme 7.
TS3_endo is lower in energy than TS3_exo by 4.5 kcal/mol.
TS3_endo is an SN1-like TS with relatively longer forming
carbonyl oxygen-epoxide carbon and breaking epoxide
oxygen-epoxide carbon distances due to the formation of the
partial tertiary carbocation at the transition state. TS3_exo,
however, adapts a more SN2-like TS with shorter forming and
breaking bonds. The oxygen-carbon-oxygen bond angle in
TS3_exo is perturbed to a greater extent from the unconstrained
system (161.1° vs 147.4°) than TS3_endo (135.5° vs 143.3°).
The energy difference between TS3_exo and TS3_endo is
nearly identical to the energy difference in the unconstrained
model.
The effect of the anomeric alkoxy group on the reaction
energetics was explored with a second model reaction, as shown
in Scheme 8. In this model reaction, the methoxy group can be
either cis or trans to the epoxonium ring. The relative energies
of the both cis- and trans-methoxy isomers and the correspond-
ing TSs for the 5-exo and 6-endo modes of cyclization for both
isomers have been modeled.
The gas-phase transition structures for the 5-exo and 6-endo
modes are shown in Figure 5. The cis-methoxy epoxonium ion
is 0.3 kcal/mol more stable than the trans-methoxy epoxonium
ion for the bicyclo[4.1.0] epoxonium ion. The activation
enthalpy for the 6-endo cyclization mode for the cis-methoxy
isomer is 0.2 kcal/mol, whereas the activation enthalpy for
the trans-methoxy isomer for the same mode is 1.4 kcal/mol in
the gas phase. In general, methoxy group incorporation results
in negligible geometrical perturbations on the transition struc-
tures, though TS4_trans_endo shows slightly enhanced leaving
group departure and bond formation relative to TS3_endo. The
trans-methoxy isomer favors the 6-endo cyclization mode by
4.6 kcal/mol, and the cis-methoxy isomer favors the same mode
by 4.8 kcal/mol, also indicating that the impact of methoxy
group incorporation is negligible for bicyclo[4.1.0] epoxonium
ions.
To determine the extent to which the methyl group on the
epoxide promotes the 6-endo cyclization mode, as studied in
the conversion of 2 to 22 and 23 (Table 1) a third model reaction
was studied (Scheme 9). In this model reaction, the methyl group
on the epoxonium ion was replaced by a hydrogen atom to
equalize the capacity for carbocation stabilization for both 5-exo
and 6-endo cyclization transition structures.
The absence of the methyl group leads to significant
perturbations of the 6-endo-transition structures (Figure 6). The
oxygen-carbon-oxygen bond angle widens significantly. Greater
bond formation and less leaving group departure are observed,
indicating that the transition structures have increased SN2
character. The absence of the methyl group has a negligible
impact on the transition structures of the 5-exo-transition
structures. Calculations show that the 6-endo cyclization mode
is favored over the 5-exo cyclization mode by 1.4 kcal/mol for
both cis- and trans-methoxy isomers, presumably because strain
is released in the opening of the bicyclo[4.1.0] system while
the 5-exo TS retains the strain generated by the forming 1,3-
dioxolane ring. Although the experimental results show that the
reactions proceed through the exo- and endo-pathways to a
nearly identical extent, these results support the observation that
bicyclo[4.1.0] epoxonium ions are more highly disposed toward
the endo-pathway than bicyclo[3.1.0] epoxonium ions.
Figure 5. Transition structures for the 5-exo and 6-endo cyclization modes
of the bicyclo[4.1.0] epoxonium ion for the cis- and trans-methoxy isomers.
The energies are given in kcal/mol, and the distances are given in Å.
and the actual reaction (4 f 27, Table 1) is the replacement of
the anomeric methoxy group with a hydrogen atom and the tert-
butyl carbonate with a methyl carbonate. This model is also
relevant to the terminal ring forming events in the cyclizations
of 7 and 8 (Table 2).
The nucleophilic attack by the oxygen of the carbonyl group
to the epoxide carbon generates either five- or six-membered
cyclic carbonates. The transition structures for the 5-exo
(TS3_exo) and 6-endo (TS3_endo) modes of the attack are
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7920 J. AM. CHEM. SOC. VOL. 129, NO. 25, 2007

Epoxonium Ion Cyclization Reactions
A R T I C L E S
Scheme 10. Model Reaction for the Study of Bicyclo[3.1.0]
Scheme 9. Model Reaction for the Study of a
Methoxy-Substituted Bicyclo[4.1.0] Epoxonium Ion Derived from a
Disubstituted Epoxide
Epoxonium Ion Ring Opening
Figure 7. 5-exo and 6-endo transition structures for cyclizations of the
bicyclo[3.1.0] epoxonium ion.
nium ion with respect to bond formation, leaving group
departure, and the oxygen-carbon-oxygen bond angle.
TS6_endo, while showing a similar degree of bond formation
and leaving group departure relative to the transition structure
for the bicyclo[4.1.0] epoxonium ion, has a significantly
diminished oxygen-carbon-oxygen bond angle (123.6° vs
135.5°). This energetically costly perturbation results in the
5-exo cyclization mode being preferred over the 6-endo cy-
clization mode (TS6_endo) by 2.7 kcal/mol in the gas phase.
To elucidate the role of the methoxy group on the regio-
selectivity, relevant to the cyclization of 3 (Table 1), an
additional model reaction (Scheme 11) was studied in the
presence of the cis- and trans-methoxy group. For these
epoxonium ion structures, the trans-methoxy isomer is 1.0 kcal/
mol lower in energy than the substrate for the cis-methoxy
isomer because the lone pair of its epoxide oxygen is anti-
periplanar to the σ* orbital of the methoxy group.
For the cis-isomer, methoxy group incorporation led to
enhanced leaving group departure for the exo-transition structure
(TS7_cis_exo), but bond formation and the oxygen-carbon-
oxygen bond angle were essentially unchanged (Figure 8).
TS7_cis_endo, however, has enhanced bond formation and an
oxygen-carbon-oxygen bond angle that is close to those that
were observed for endo-cyclizations in reactions of bicyclo-
[4.1.0] epoxonium ions. For the trans-isomer, methoxy group
incorporationhadnoimpactontransitionstructureTS7_trans_exo.
The 6-endo transition structure (TS7_trans_endo), while geo-
metrically similar with respect to bond formation and leaving
group departure, has the expanded oxygen-carbon-oxygen
bond angle that was seen in TS7_cis_endo. Energetically
TS7_trans_endo is the lowest energy transition structure,
Figure 6. Transition structures for the 5-exo and 6-endo cyclization modes
of the bicyclo[4.1.0] epoxonium ion for the cis- and trans-methoxy isomers
in the absence of the methyl group. The energies are given in kcal/mol,
and the distances are given in Å.
Consistent with Baldwin’s rules, and as observed in the
terminal ring forming steps in the cyclizations of 7 and 8 (Table
2), intramolecular cyclization/epoxide ring openings of bicyclo-
[3.1.0] epoxonium ions preferentially produce 5-exo cyclization
products. This reaction was mimicked with the model reaction
shown in Scheme 10.
As shown in Figure 7, TS6_exo is nearly identical to the
corresponding transition structure for the bicyclo[4.1.0] epoxo-
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J. AM. CHEM. SOC. VOL. 129, NO. 25, 2007 7921

A R T I C L E S
Wan et al.
Scheme 11. Model Reaction for the Bicyclo[3.1.0] Epoxonium Ion
Ring Opening in the Presence of an Anomeric Methoxy Group
bicyclo[3.1.0] epoxonium ions form from the addition of
epoxides into oxocarbenium ions rather than nonstabilized
carbenium ions. This is also interesting in consideration of the
isolation of endo-product 25 as a single anomer in which the
methoxy group has an axial orientation. Of note, while anomeric
stabilization in the transition state accounts for the formation
of the endo-product for trisubstituted epoxide substrates, the
effect is not strong enough to promote endo-cyclization for
disubstituted epoxides such as 1.
Conclusions
We have conducted an extensive study of intramolecular
nucleophilic additions into bicyclic epoxonium ions to determine
the structural features that promote exo- and endo-selective
cyclization reactions. These results will serve as the basis for
designing cascade processes that lead to complex polycyclic
ethers. In particular the effects of the epoxide substitution
pattern, the structure of the carbocation that activates the
epoxide, and the ring size of the bicyclic epoxonium ion were
examined. We observed that ring size has a significant impact
on these processes, with endo-cyclizations being preferred for
bicyclo[4.1.0] epoxonium ions and exo-cyclizations being
preferred for bicyclo[3.1.0] epoxonium ions. This effect can be
attributed to the larger ring size accommodating a looser
transition state that has significant SN1 character, thereby
promoting the endo-process, regardless of solvent polarity. The
smaller ring size, however, distorts the endo-transition structure,
thereby increasing its energy to an extent that allows the exo-
process to become favorable. Thus the superior efficiency for
reactions that proceed through bicyclo[4.1.0] epoxonium ions
arises from the accessibility of the low energy endo-pathway
and not from the difficulty in forming bicyclo[3.1.0] epoxonium
ions.30 The substitution pattern of the epoxide also plays a
substantial role in determining the regiochemical outcome of
the reactions, with the endo-pathway being promoted for
cyclizations that result from tertiary leaving group displacement
due to the greater ability to stabilize the SN1-like transition state.
While the structure of the cationic activating group appears to
have little impact on the regioselectivity of reactions that proceed
through bicyclo[4.1.0] epoxonium ions, epoxide activation
through addition into unstabilized carbenium ions to form
bicyclo[3.1.0] epoxonium ions leads to a strong preference for
exo-cyclizations while activation by addition into oxocarbenium
ions leads to a diminished preference for the exo-pathway. This
was shown to result from an intriguing anomeric stabilization
that can develop in endo-cyclization transition states when the
alkoxy group has a pseudoaxial orientation. While the effect is
modest, this result provides evidence that bicyclic epoxonium
ion structure can potentially be modified to promote tetra-
hydropyran formation through endo-cyclizations, as will be
required to design cascade processes that form ladder polyether
structures. The results from these studies clearly demonstrate
that epoxonium ion structure is a significant determinant of
kinetic cyclization regioselectivity, and efforts to alter the
outcomes of these reactions must exploit thermodynamic
differences in product energy or employ reactions that proceed
through different mechanisms.
Figure 8. Transition structures for intramolecular cyclization/epoxide ring
opening of the bicyclo[3.1.0] epoxonium ion with methoxy group incorpora-
tion. The energies are given in kcal/mol, and the distances are given in Å.
presumably because this transition structure allows the electron-
withdrawing methoxy group to adopt an axial orientation with
respect to the forming pyran ring, thereby benefiting from a
developing anomeric effect. Transition structures for exo-
cyclizations were found to be slightly higher in energy, and
TS7_cis_endo, which does not benefit from developing ano-
meric stabilization, was the highest energy transition structure.
The fascinating role of the methoxy group in these reactions
explains the diminished selectivity for exo-cyclizations when
Acknowledgment. We thank the National Institutes of Health
(GM36700 to K.N.H. and GM62924 to P.E.F.) and the National
(30) For several reactions that proceed efficiently through bicyclo[3.1.0]
epoxonium ions, see ref 9.
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7922 J. AM. CHEM. SOC. VOL. 129, NO. 25, 2007

Epoxonium Ion Cyclization Reactions
A R T I C L E S
Science Foundation (CHE-0139851 to P.E.F.) for generous
support of this work. We thank Drs. Lijun Wang and Christopher
Lee for preliminary studies on this project and Dr. Steven Geib
(University of Pittsburgh) for crystal structure analysis.
products, crystallographic data for compounds 38 and 39,
absolute energies (in hartree) and optimized geometries (as
Cartesian coordinates) for all calculated transition structures,
and the full reference for Gaussian 03. This material is available
free of charge via the Internet at http://pubs.acs.org.
Supporting Information Available: Experimental procedures
for all cyclization reactions, spectral characterization of all new
JA0709674
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J. AM. CHEM. SOC. VOL. 129, NO. 25, 2007 7923