A systematic study of functionalized oxiranes as initiating groups for cationic polycyclization reactions

Article abstract of DOI:10.1021/jacs.5b03229

Three different methods have been developed that effectively utilize chiral oxiranes derived from Katsuki-Sharpless epoxidation of allylic alcohols as initiating groups for cationic cyclization of unsaturated substrates to form chiral polycycles. This type of transformation has previously been problematic. These employ either epoxy-methoximes, vinyl-substituted oxiranes, or hydroxymethyl oxiranes. All three approaches are described in detail. In addition, this research has led to possible explanations for previously encountered difficulties in this area and provided two new insights into the Lewis acid activation of oxiranes. The methodology described herein constitutes a valuable link between two powerful synthetic constructions, enantioselective Katsuki-Sharpless epoxidation and cationic polycyclization reactions.

Full text of DOI:10.1021/jacs.5b03229

Article
pubs.acs.org/JACS
A Systematic Study of Functionalized Oxiranes as Initiating Groups
for Cationic Polycyclization Reactions
Goreti Rajendar and E. J. Corey*
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, United States
S
* Supporting Information
ABSTRACT: Three different methods have been developed
that effectively utilize chiral oxiranes derived from Katsuki−
Sharpless epoxidation of allylic alcohols as initiating groups for
cationic cyclization of unsaturated substrates to form chiral
polycycles. This type of transformation has previously been
problematic. These employ either epoxy-methoximes, vinyl-
substituted oxiranes, or hydroxymethyl oxiranes. All three
approaches are described in detail. In addition, this research
has led to possible explanations for previously encountered
difficulties in this area and provided two new insights into the
Lewis acid activation of oxiranes. The methodology described herein constitutes a valuable link between two powerful synthetic
constructions, enantioselective Katsuki−Sharpless epoxidation and cationic polycyclization reactions.
complex step to lanosterol (3). From lanosterol, a total of 18
enzymes and 19 steps are required to generate cholesterol (4)
(Scheme 1).2 Previously, it had been known from the work of
Bloch et al. that squalene is the precursor of lanosterol and
cholesterol, but only in the presence of molecular O2.3 The
biosynthetic power of the step 2 → 3 is so large that it has
prevailed in nature even though many steps (ca. 19) are
required to make cholesterol (4) from 3. Since these early
investigations on sterol and triterpene biosynthesis, there have
been numerous studies on the synthetic application of epoxide-
initiated cyclization reactions to the construction of polycyclic
structures.4 The power of such cationic polycyclizations has
been repeatedly demonstrated by the realization of effective
synthetic pathways to many natural products including
pyripyropene E,5 adociasulfate,6 aphidicholin,7 lanosterol,8
many triterpenes in the β-amyrin family,9,10 onocerin,11
serratenediol,12 germanicol,13a lupeol,13b hongoquercin B,14
kaurene diterpenoids,15 and limonoids.16
INTRODUCTION
■
This paper describes research on the fundamental under-
standing and application of epoxide-initiated cationic π-
cyclization reactions, one of the most powerful constructions
in both biosynthesis and chemical synthesis. It is the key step in
the construction of squalene to lanosterol, as outlined in
Scheme 1. Russey in our group1 first showed that the initial
step in the biosynthetic sequence is the oxidation of squalene
(1) to (S)-2,3-oxidosqualene (2). The epoxide (2) is then
transformed enzymatically and without O2 in a single, but very
Scheme 1. Bioconversion of Squalene to Cholesterol
Despite these advances and the gradually increasing under-
standing of the biosynthetic process, there is still a large gap
between the results in synthetic practice and the awesome
efficiency, brevity, and stereocontrol shown in enzyme-
catalyzed polycyclization reactions. The reason for this gap
can be appreciated when the following properties of cyclase
enzymes are considered: (1) the availability of an extensive
binding pocket which imposes on the substrate a three-
dimensional coiling in which the specific π-face of each
participating C−C double bond is controlled and all
intermediate carbocations are protected from nucleophilic
attack by the protein itself or the aqueous environment; (2)
Received: April 2, 2015
© XXXX American Chemical Society
A
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proximity of an initiating proton donor (generally aspartic acid)
in the enzyme to the oxirane function of the bound substrate;
(3) ability of the enzyme to utilize the exothermicity of
cyclization (ca. 20 kcal/mol for each ring formed) to access a
higher energy conformation which continues to hold the
reactive intermediates that are generated during cyclization and
protect them from diversion to other pathways;17 (4) a
precisely positioned proton acceptor that controls the reaction
product by accepting a proton from the last cationic
intermediate, and only that proton, while also not attacking
other cationic intermediates. In addition, because of conforma-
tional changes of cyclase enzymes during the course of a
biosynthetic conversion, it is likely that dynamic protein−
substrate interactions play an important role in guiding
rearrangements of carbon and hydrogen toward the formation
of a specific biochemical target molecule. At the same time, the
enzyme group that accepts a proton in the final product
determining step is held at bay until the crucial final
intermediate is formed.
most of the reported cases5,6,20 with substrates of type 7 have
fallen in the range of only 23−52%. These mediocre results also
seem at odds with the expectation that epoxide activation might
be facilitated by chelation of Lewis acid.
We are aware of two special cases in which of higher yields
have been obtained. In the synthesis of neotripterifordin
reported earlier from our laboratories,21 the cyclization of 8 to
9 was accomplished in 86% yield (Scheme 2). In the other case,
Scheme 2. Best Previously Reported Cyclizations
In contrast to such sophisticated enzyme control, current
laboratory cyclizations are rudimentary and depend on the use
of (1) Lewis acidic catalysis (or in some cases a protic acid)
which selectively activate the oxirane function and (2) a non-
nucleophilic and noncoordinating moderately polar medium
(e.g., CH2Cl2) which can solvate, but not trap the various
cationic intermediates. Given the enormous difference in
sophistication of biochemical and chemical catalysis and the
complexity of cationic polycyclization reactions, it is obvious
that there is much room for improvement in the synthetic
chemical methodology. This includes the initiating subunit in
the substrate, the catalytic Lewis acid, the control of substrate
conformation (e.g., restricting conformation so as to favor a
particular product), deactivating potentially interfering groups,
and controlling the termination process. We discuss herein
specifically a systematic study of various kinds of oxirane-based
initiating structures and the use of our findings both to assist in
synthetic applications and to understand the electronic factors
which influence the course of cyclization. This is just an early
step in the important but lengthy journey that lies ahead, surely
one of the great unmet challenges in synthetic chemistry.
the yield in the conversion of ( )-10 to ( )-11 could be
improved from 23 to 35% (as originally reported20a) to 72%
but only under special conditions and after extensive
optimization.
RESULTS AND DISCUSSION
■
Most of the examples of epoxide-initiated cyclization in the
successful multistep syntheses that are cited above4b are of the
type 5 → 6 with respect to the initiating step (LA = Lewis
acid). This closure of the initial ring can sometimes be
concerted with C−O cleavage and thus efficient.18 The epoxide
initiated approach starting from 5 is convenient for syntheses of
natural products having unfunctionalized A-ring methyl groups
because of the synthetic accessibility of the required chiral
oxirane 5 via enantioselective, position-selective dihydroxyla-
tion using a mechanistically designed chiral catalyst that binds
OsO4 and the polyunsaturated substrate.19 In addition, the
Katsuki−Sharpless catalytic epoxidation of allylic alcohols can
be applied to the synthesis of substrates for epoxide-initiated
cationic polycyclization processes. Indeed, extensive literature is
available describing this approach,5,6,20 which is especially
appropriate when one of the gem-dimethyl groups of 6 is
functionalized. In principle, the combination of the practicality
of the Katsuki−Sharpless epoxidation with the power of
epoxide-initiated cationic polycyclization, would seem to be
an optimal strategy. In actual practice, this approach has been
disappointing since the realized yields of cyclization product in
Our studies were motivated by the unexpected problems
encountered previously with substrates derived from Katsuki−
Sharpless epoxy alcohols and their derivatives. We chose
specifically to study the bis-cyclization of the test series of
compounds 15−17 which are readily synthesized by the route
outlined in Scheme 3. The investigations of these three
substrates turned out to be quite revealing and to provide
valuable insights on the fine details of the epoxide-initiated
cyclization, and some causes of the disappointing results of
previous synthetic studies.5,6,20 The epoxy ester 17 turned out
to be surprisingly unreactive in Lewis acid induced cationic
cyclization, despite the possibility that it can be a bidentate
ligand for catalysts like SnCl4 (generally an effective epoxide
activating reagent). One possible stereorepresentation of such a
complex is shown in expression 18. Ester 17 was completely
unchanged when exposed to 1.5 equiv of SnCl4 in CH2Cl2
solution over the range −78 to −20 °C after 12 h. Even the
potent Lewis acid TiCl4 at −20 °C for 6 h left the epoxy ester
largely unchanged (80% recovery with the remainder being a
complex mixture that contained none of the desired tricyclic
product). It should be noted that the unfunctionalized substrate
B
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accelerate cationic cyclization. Indeed, that turned out to be
the case. Thus, exposure of the methoxime 20 to SnCl4 in
CH2Cl2 at −45 °C led to clean formation of the desired
tricyclic product 21 in 95% isolated yield (Scheme 4). Several
other transformations of this type are summarized in Table 1.
Scheme 3. Synthesis of Test Substrates
Scheme 4. Cyclization of Epoxy Methoxime 20
It is evident from the good results shown in Table 1 that α-
methoxime oxirane substrates are satisfactory initiating subunits
for cationic polycyclization reactions to form A-ring doubly
functionalized products. The product β-hydroxy methoximes
can be cleaved to the corresponding aldehydes under mild
conditions (CH2O, aq. acetone, Amberlyst 15 sulfonic acid
resin at room temperature) in high yield. There are, however,
limitations in the structure of the α-methoxime oxirane
substrate that arise when the Lewis acid can interact with
groups elsewhere in the molecule. For example, in the case of
substrate 22, the yield of tricyclic product 23 is only 50%
(SnCl4, CH2Cl2 at −45 °C for 6 h) because of a side reaction
which produces along with 23 a mixture of isomers
chlorohydrins (40%) by simple oxirane cleavage without
cyclization.
The simplest explanation of this observation may be the co-
occurrence of Lewis acid coordination with the aromatic
subunit which inhibits the cyclization. The same effect may
operate in the last example 30 in Table 1 for which the yield is
also lowered. If such competitive coordination (either to a
methoxy group or the benzenoid π-electron system in 22) does
indeed compete with oxirane activation, it would cast some
doubt on a bidentate interaction between SnCl4, the oxirane
oxygen, and the methoxime function. To follow up on this, we
studied the cyclization of 22 using BF3·Et2O in CH2Cl2 at −78
°C for 1 h. The cyclization is not only faster than that with
SnCl4 but also substantially more efficient, since it afforded 23
in 81% isolated yield (Scheme 5). Since BF3 has only one
vacant orbital for coordination and is unlikely to complex with
22 in a bidentate way, so this result provides compelling
evidence that the transformation 22 → 23 is initiated by
complexation of BF3 at the oxiranyl oxygen and does not
involve chelation of the methoxime.
corresponding to 17 (CH3 instead of COOCH3) undergoes
rapid conversion to tricyclic product (19 with CH3 instead of
COOCH3) under these conditions.
We have also performed similar experiments with SnCl4 and
the epoxy aldehyde 16 (Scheme 3). Again, there was no
reaction at −78 °C in CH2Cl2, with no sign of tricyclic product
(the aldehyde corresponding to the ester 19). At −20 °C for 12
h in CH2Cl2, about 20% of unreacted aldehyde 16 was
recovered along with a complex mixture of mainly uncyclized
materials and none of the desired 6,6,6-tricycle. These results
with the epoxy aldehyde 16 and the corresponding epoxy ester
17 indicate that chelate complexes such as 18 do not facilitate
cyclization and, if anything, prevent it from occurring. Such a
result would be understandable if coordination of Lewis acid to
the carbonyl function makes it so electron deficient that
heterolysis of the oxirane α-C−O bond is inhibited. Such an
inhibiting effect seems to operate quite generally in series of the
other results reported below. In addition, the reluctance of
aldehyde 16 and ester 17 call in to question a chelation
pathway even with SnCl4 which readily chelates via six-
membered cycle.
The reluctance of the epoxy ester 17 and the epoxy aldehyde
16 to undergo cyclization with bis-coordinating Lewis acids
such as SnCl4 and the observation that the cyclization of
methoxime 20 appears to occur by monodentate interaction of
Lewis acid with the oxirane oxygen rather than by a bidentate
pathway could be consequences of the electronic effects
described above. For instance, bidentate complexation as
shown above in 18 would impede α-C−O heterolysis of the
oxirane by destabilizing the incipient carbocation because of
electron transfer from carbonyl to SnCl4. This same type of
inductive effect can explain selectivity in many nucleophilic C−
O cleavage reactions of epoxy carbinols by external
nucleophiles using a coordinating metal, an example of which
We attempted to counter the problems of Lewis acid
activation of α-functionalized oxiranes by turning to the
methoxime 20 corresponding to the test aldehyde 16. This
line of research was motivated by the idea that the electron
donating methoxy group in 20 would significantly favor the
heterolytic fission of the oxirane α-C-O bond and thus
C
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Table 1. Lewis Acid Catalyzed Cationic Cyclization of Epoxy
Methoximes
Scheme 6. Metal-Catalyzed Selective Oxirane Cleavage
Density functional theory calculations indicate that BF3
coordinates with ethylene oxide out of plane, as though the
lone pairs on oxygen are in sp3-hybridized orbitals.24 With
substrates such as 22, there can be two diastereomeric
complexes of this sp3-hybridization type, as shown in Figure
1a. These are arbitrarily designated as α- and β- complexes. It is
Figure 1. (a) α- and β-Oriented oxirane BF3 complexes; (b) partially
cyclized β-complex.
not unreasonable to argue that the rates of concerted oxirane
cleavage-cyclization would be different for these α- and β-
complexes and, more specifically, that the β-complex might
react faster because C−C bond formation involves less charge
separation than for the α-diastereomer (Figure 1b). Thus, it
possible that this is another factor that can favor the
monodentate cyclization pathway over the bidentate mode
with Lewis acids such as SnCl4. This represents yet another
kind of stereoelectronic/electrostatic effect.25,26
a
b
Reaction carried out with SnCl4 in CH2Cl2 at −45 °C. Reaction
c
carried out with BF3·OEt2 in CH2Cl2 at −78 °C. Yield is similar to
that of both Lewis acids SnCl4 and BF3·OEt2.
Another aspect of epoxide-initiated cyclization reactions that
we have studied involved the use of vinyl oxiranes such as 32
which are readily accessed from the corresponding aldehydes,
16 in the case of 32. It was expected from the above-described
results that vinyl substitution would facilitate Lewis-acid
activation of the epoxide function and beneficial in cyclization
reactions relative to CH3 or H in the corresponding position,
that surmise was verified by the experimental finding that 32
was smoothly and rapidly converted to the 6,6,6-tricyclic
product 33 at −78 °C in CH2Cl2 with MeAlCl2, SnCl4, TiCl4,
or i-PrOTiCl3 (see Scheme 7). Even the quite mild Lewis acid
InBr3 transformed 32 efficiently and rapidly to 33 in CH2Cl2 at
−10 °C. It is clear that π-electron donation from the vinyl
substituent is significantly beneficial to both the rate and
efficiency of epoxide-initiated cationic cyclization of substrates
such as 32. This conclusion is further supported by results with
six other examples which are summarized in Table 2.
Scheme 5. Cyclization of Epoxy Methoxime 22
is shown in Scheme 6.22,23 In general, oxirane cleavage occurs
selectively at C(β) in α,β-epoxy carbinol, α,β-epoxy acid, and
α,β-epoxy ester systems.22,23
D
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Scheme 7. Cyclization Results for Vinyl Epoxide 32
Table 2. Vinyl Substitution Alpha to Oxirane Facilitates
Cyclization and Improves Generality (CH2Cl2, SnCl4, −78
°C)
The high efficiency of the cyclization 8 to 9,21 a key step in
the total synthesis of neotripterifordin, can now be understood
as due to π-electron donation from the vinyl group in 8 which
assists in the closure of the first ring due to stabilization of the
resulting carbocation.
The cyclization of 38 to 39 is especially noteworthy since the
corresponding reaction of the analogous substrate with CH3
replacing vinyl is both slow and low yielding. Evidence has been
obtained from the study of alkyl-substituted vinyl groups that
the vinyl group itself provides the optimum level of π-electron
donation. The results with three substrates with terminal alkyl
substituents attached to vinyl are shown in Table 3. The data
on the cyclization 46 to 47 suggest that the degree of activation
of the epoxide by the more strongly π-electron donating
isobutenyl group may be beyond the optimum degree. In
summary, the simple vinyl substituent leads to the most
efficient cationic cyclization reactions. The vinyl substituent in
the products is readily oxidized with CC cleavage to form
corresponding β-hydroxy aldehydes, useful intermediates for
further functional group transformations.
The synthesis of E-substrate 50 was carried out by a simply
but very beneficial modification of the Julia−Kocienski method
which provides superior E/Z selectivity over published
procedures, as shown. Our improved method utilizes the
soluble quaternary ammonium salt n-hex4N+Br− to improve
both yield and E/Z ratio (72%, 5:1 without n-hex4N+Br−).27
Because of the need for better E-selective olefin synthesis, we
include here a representative procedure.28
competing Lewis acid binding to other sites in the molecule.
The early results were informative, but not especially useful.
For example, reaction of 15 with 1 equiv of Me3Al, i-Bu2AlH,
or Et2Zn in CH2Cl2 afforded the corresponding alkoxides of 15
(ROAlMe2, ROAli-Bu2, and ROZnEt, respectively). However,
these metallic derivatives were incapable of activating the epoxide
for cyclization in CH2Cl2 even at 23 °C. Further activation of
ROAlMe2 by treatment with Br2 (to form ROAlMeBr) also did
not lead to cyclization. The failure of these internally bound
Lewis acidic centers in proximity to the oxiranyl oxygen to
initiate cyclization is consistent with the stereoelectronic effect
posited above.
The α-hydroxymethyl epoxide 15 was also studied as a
reactant for cationic cyclization under a variety of conditions.
One motivation for this part of our systematic investigation
came from the possibility that the initiating Lewis acid might be
covalently attached to the hydroxyl oxygen of 15 so as to
internally direct activation to the oxirane C−O bond without
Fortunately, stronger activation by converting 15 to 53 did
lead to cyclization, as shown in Scheme 8. The cyclization of 52
E
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Table 3. Cyclization Results with Substituted Vinyl
Scheme 8. Cyclization of Epoxy Alcohols
Activating Groups (CH2Cl2, SnCl4, −78 °C)
was very slow at lower temperatures and required 14 h even at
−30 °C. The structure of 54 was confirmed by single crystal X-
ray diffraction analysis on the 4-bromobenzal acetal. The
procedure with the alkoxy-SnCl3 complex for the epoxide
activation was equally effective for the three substrates shown in
Scheme 8. The yields for formation of 54, 56, 58, and 60 are
lowered because in each case considerable starting material was
recovered (possibly due to HCl formed in the cyclization). In
these cases, it would seem that cyclization be induced by (the
normally less activating) coordination between the SnCl3 group
and the oxygen lone pair in the α-oriented sp3-orbital at the
higher temperatures. A last example shown in Scheme 9 for the
cyclization of 61 to 62. This reaction was exceptionally rapid
and efficient (94% yield after 1 h at −78 °C in CH2Cl2). The
structure of the product was proven by single-crystal X-ray
diffraction analysis of acetonide 63. This last example also
illustrates the ease of accessing A-ring trifunctionalyzed
products. Further, it demonstrates that having simultaneously
both a covalently attached Lewis acid and a vinyl activating
group facilitates fission of the oxirane C−O bond. The results
in Schemes 8 and 9 indicate that even though the geometry is
not ideal for intramolecular metal-accelerated oxirane C−O
cleavage, that factor is outweighed by the high Lewis acidity and
proximity of the ROSnCl3 group and also the presence of the
activating vinyl group in the case of 61. The use of MeAlCl2,
TiCl4, or SnBr4 in this type of process from the intermediate
sodium alkoxide 52 did not lead to useful yields of the desired
tricyclic product 54.
Scheme 9. Cyclization of Epoxy Alcohol 61
powerful constructions, specifically the possibility of taking
advantage of functionalized substrates for chelation between a
catalytic Lewis acid, the epoxide oxygen and the functionalized
substituent attached the oxirane ring could not be realized in
practice.5,6,20 Indeed our results with the test aldehyde 16 and
ester 17 clearly shown that such chelation, if it occurs with
these substrates, does not meaningfully accelerate cyclization.
As pointed out above, one factor in the absence of chelate
activation could be the inductive effect of a Lewis-acid-
CONCLUSION
■
The full potential for application of Katsuki−Sharpless
oxidation in combination with epoxide-initiated cationic
cyclization process has hitherto been unrealized. What would
seem to be an inherent advantage of this tactical combination of
F
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(6) Bogenstatter, M.; Limberg, A.; Overmann, L. E.; Tomasi, A. L. J.
Am. Chem. Soc. 1999, 121, 12206−12207.
coordinated carbonyl (formyl in 16 and methoxy carbonyl in
17) to destabilize heterolysis of an oxirane α-C−O bond.
The systematic studies that are described above have revealed
three approaches which are highly effective for cationic
cyclization process based on Katsuki−Sharpless-derived epox-
ides. First, the use of methoximes of aldehyde such as 16 leads
to efficient cyclization reactions by way of a nonchelated
complex of Lewis acid with the epoxide oxygen. These
reactions (see Table 1) are clearly accelerated by the
electron-donating properties of the methoxime group which
favor Lewis-acid-induced oxiranyl C−O cleavage. A second, and
related, method involves activation of the oxirane C−O group
by attachment of vinyl substituent, such as in substrate 32, or
those listed in Table 2. Lastly, covalent attachment of a strong
Lewis acid directly to oxygen of an α-hydroxymethyl oxirane
can induce cyclization through an intramolecular mode of
action. In this case, however, oxirane activation is unusually
weak and only observed with quite strong Lewis acidic metals.
Our work has led to the identification of two factors which
may play critical role in the Lewis-acid-induced cyclization of α-
functionalized epoxides, one an inductive effect which results
from chelation and the other a kind of stereoelectronic/
electrostatic effect.
(7) Tanis, S. P.; Chaung, Y. H.; Head, D. B. J. Org. Chem. 1988, 53,
4929−4938.
(8) Corey, E. J.; Lee, J.; Liu, D. R. Tetrahedron Lett. 1994, 35, 9149−
9152.
(9) Corey, E. J.; Lee, J. J. Am. Chem. Soc. 1993, 115, 8873−8874.
(10) Haung, A. X.; Xiong, Z.; Corey, E. J. J. Am. Chem. Soc. 1999,
121, 9999−10003.
(11) Mi, Y.; Schreiber, J. V.; Corey, E. J. J. Am. Chem. Soc. 2002, 124,
11290−11291.
(12) Zhang, J.; Corey, E. J. Org. Lett. 2001, 3, 3215−3216.
(13) (a) Surendra, K.; Corey, E. J. J. Am. Chem. Soc. 2008, 130,
8865−8869. (b) Surendra, K.; Corey, E. J. J. Am. Chem. Soc. 2009, 131,
13928−13929.
(14) Barrett, T. N.; Barrett, A. G. M. J. Am. Chem. Soc. 2014, 136,
17013−17015.
(15) Cherney, E. C.; Green, J. C.; Baran, P. S. Angew. Chem., Int. Ed.
2013, 52, 9019−9022.
(16) Behenna, D. C.; Corey, E. J. J. Am. Chem. Soc. 2008, 130, 6720−
6721.
(17) Kurti, L.; Chein, R. J.; Corey, E. J. J. Am. Chem. Soc. 2008, 130,
9031−9036.
(18) Corey, E. J.; Staas, D. D. J. Am. Chem. Soc. 1998, 120, 3526−
3527.
(19) (a) Corey, E. J.; Zhang, J. Org. Lett. 2011, 3, 3211−3214.
(b) Corey, E. J.; Noe, M. C.; Lin, S. Tetrahedron Lett. 1995, 36, 8741−
8744. (c) Corey, E. J.; Noe, M. C. J. Am. Chem. Soc. 1996, 118, 319−
329.
The knowledge gained from the work described herein can
guide additional research on the application of epoxide induced
cationic cyclization reactions to synthesis, which remains a
major challenge.
(20) (a) Tanis, S. P.; Chuang, Y. H.; Head, D. B. Tetrahedron Lett.
1985, 26, 6147−6150. (b) Clark, J. S.; Myatt, J.; Wilson, C.; Roberts,
L.; Walsh, N. Chem. Comm 2003, 1546−1547. (c) Rosen, B. R.;
ASSOCIATED CONTENT
■
̀
Werner, E. W.; OBrien, A. G.; Baran, P. S. J. Am. Chem. Soc. 2014, 136,
S
* Supporting Information
5571−5574.
Experimental procedures and characterization data for all
reactions and products including copies of H and 13C NMR
1
(21) Corey, E. J.; Liu, K. J. Am. Chem. Soc. 1997, 119, 9929−9930.
(22) (a) Caron, M.; Carlier, P. R.; Sharpless, K. B. J. Org. Chem.
1988, 53, 5185−5187. (b) Chong, J. M.; Sharpless, K. B. Tetrahedron.
Lett. 1985, 26, 4683−4686. (c) Chong, J. M.; Sharpless, K. B. J. Org.
Chem. 1985, 50, 1560−1563. (d) Saito, S.; Takahashi, N.; Ishikava, T.;
Moriwake, T. Tetrahedron. Lett. 1991, 32, 667−670.
spectra. This material is available free of charge via the Internet
at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*corey@chemistry.harvard.edu
■
(23) (a) Roush, W. R.; Adam, M. A.; Peseckis, S. M. Tetrahedron.
Lett. 1983, 24, 1377−1380. (b) Finan, J. M.; Kishi, Y. Tetrahedron. Lett.
1982, 23, 2719−2722.
(24) (a) Fraile, J. M.; Mayoral, J. A.; Salvatella, L. J. Org. Chem. 2014,
79, 5993−5999. (b) Seanz, P.; Cachau, R. E.; Seoane, G.; Kieninger,
M.; Ventura, O. N. J. Phys. Chem. A 2006, 110, 11734−11751.
(25) (a) Corey, E. J. Experientia 1953, 9, 329−336. (b) Corey, E. J.;
Sneen, R. A. J. Am. Chem. Soc. 1956, 78, 6269−6278.
(26) Kirby, A. J. Stereoelectronic effect; Oxford University Press: New
York, 1996.
(27) (a) Blackemore, P. R.; Cole, W. J.; Kociensky, J. P.; Morley, A.
Synlett 1998, 26−28. (b) DiBlasi, C. M.; Macks, D. E.; Tan, D. S. Org.
Lett. 2005, 7, 1777−1780.
(28) To a stirred solution of tetrazole sulfone (0.494 g, 1.86 mmol)
and tetrahexylammonium bromide (0.905 g, 2.32 mmol) in
dimethoxyethane (15 mL) was added a solution of aldehyde 16 (0.3
g, 1.16 mmol) in dimethoxyethane (5 mL). The reaction mixture was
cooled to −78 °C, and treated with KHMDS (4.2 mL, 0.5 M)
dropwise over 4 h using a syringe pump. After the addition was
completed, the reaction mixture was stirred at −78 °C for 30 min and
then warmed to 23 °C and stirred for 2 h. The reaction was followed
by TLC analysis (triethylamine treated TLC plate). The resulting
mixture was treated with water (5 mL) and then ether (10 mL). The
organic layer was separated, and the aqueous layer was extracted with
ether (2 × 10 mL). The combined organic extract was washed with
water and brine, dried over Na2SO4, and concentrated under vacuum.
The crude product was purified by column chromatography
(triethylamine treated silica gel, 0.5% ethyl acetate in hexane basified
with a drop of triethylamine) to give the epoxy olefin 50 (0.304 g,
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. S.-L. Zeng of Harvard University for the X-ray
crystallographic analysis. Financial support of Pfizer Inc.,
Bristol-Myers Squibb and Gilead Sciences is gratefully acknowl-
edged.
REFERENCES
■
(1) (a) Corey, E. J.; Russey, W. E.; Ortiz de Montellano, P. R. J. Am.
Chem. Soc. 1966, 88, 4750−4751. (b) Corey, E. J.; Russey, W. E. J. Am.
Chem. Soc. 1966, 88, 4751−4752. (c) Russey, W. E. Ph.D. Thesis,
Harvard University, 1966.
(2) For a broad review, see Schulz, G. E.; Corey, E. J.; Liu, D. R.
Angew. Chem., Int. Ed. 2000, 39, 2812−2833.
(3) See Maudgal, R. K.; Tchen, T. T.; Bloch, K. J. Am. Chem. Soc.
1958, 80, 2589−2590.
(4) For reviews, see (a) Yoder, R. A.; Johnston, J. N. Chem. Rev.
2005, 105, 4730−4756. (b) Corey, E. J.; Kurti, L. Enantioselective
Chemical Synthesis; Elsevier Publishers: Amsterdam, 2010; pp 281−
307. (c) Pronin, S. V.; Shenvi, R. A. Nat. Chem. 2012, 4, 915−920.
(d) Taylor, S. K. Org. Prep. Proced. Int. 1992, 24, 245−284.
(5) Aggarwal, V. K.; Bethel, P. A.; Giles, R. Chem. Commun. 1999,
325−326.
G
DOI: 10.1021/jacs.5b03229
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
88%) as a colorless liquid. E/Z = 25:1 (by NMR analysis); Rf = 0.85
23
1
(in 10% ethyl acetate in hexane); [α]D +4.2 (c 1.0, CHCl3); H
NMR (500 MHz, CDCl3) δ 7.27 (t, J = 5.0 Hz, 2H), 7.18 (d, J = 6.5
Hz, 3H), 5.71 (dd, J = 6.0, 16.0 Hz, 1H), 5.25−5.19 (m, 2H), 2.76 (t, J
= 6.5 Hz, 1H), 2.64 (t, 6.0 Hz, 2H), 2.33−2.28 (m, 3H), 2.19−2.07
(m, 2H), 1.72−1.63 (m, 2H), 1.57 (s, 3H), 1.36 (s, 3H), 1.00 (s, 3H),
0.98 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 142.2, 139.4, 134.8,
129.8, 128.4, 128.2, 125.6, 124.3, 65.1, 59.4, 36.2, 36.0, 30.8, 29.9, 27.3,
22.2, 22.2, 15.9, 15.6; HRMS (ESI) calcd for C21H31O [M + H]+
299.2375, found 299.2369.
H
DOI: 10.1021/jacs.5b03229
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX