Anti-selective epoxidation of methyl α-methylene-β-tert- butyldimethylsilyloxycarboxylate esters. evidence for stereospecific oxygen atom transfer in a nucleophilic epoxidation Process

Article abstract of DOI:10.1021/ol900665a

Methyl r-methylene-β-tert-butyldimethylsilyloxycarboxylate esters are found to undergo diastereoselective epoxidation in the presence of potassium tert-butoxide-tert-butyl hydroperoxide to form anti products. In an effort to better understand mechanistic

Full text of DOI:10.1021/ol900665a

ORGANIC
LETTERS
2009
Vol. 11, No. 11
2437-2440
Anti-Selective Epoxidation of Methyl
r-Methylene-ꢀ-tert-butyldimethyl-
silyloxycarboxylate Esters. Evidence for
Stereospecific Oxygen Atom Transfer in
a Nucleophilic Epoxidation Process
ˇ
Jakub Svenda and Andrew G. Myers*
Department of Chemistry and Chemical Biology, HarVard UniVersity,
Cambridge, Massachusetts 02138
myers@chemistry.harVard.edu
Received March 31, 2009
ABSTRACT
Methyl r-methylene-ꢀ-tert-butyldimethylsilyloxycarboxylate esters are found to undergo diastereoselective epoxidation in the presence of
potassium tert-butoxide-tert-butyl hydroperoxide to form anti products. In an effort to better understand mechanistic details of the transformation
and the basis of diastereoselectivities observed, we studied the epoxidation of substrates with r-methylene groups containing (trans) deuterium
labels and discovered that oxygen-atom transfer proceeds with g95% stereospecificity in all cases examined. These and other experiments
suggest that the mechanism of epoxidation is not distinguishable from a concerted process.
In the context of a problem in target-directed, complex
synthesis, we were led to explore the epoxidation of methyl
R-methylene-ꢀ-hydroxycarboxylate esters and their hydroxyl-
protected derivatives and report here that the corresponding
tert-butyldimethylsilyl ethers undergo efficient, anti-selective
epoxidation with potassium tert-butylperoxide in tetra-
hydrofuran (THF). While syn-selective epoxidations of R-
methylene-ꢀ-hydroxycarboxylate esters have been reported,1
a method for anti-selective epoxidation of this substrate class
had not been described previously.
Summarized in Figure 1 are results of epoxidations of
nine methyl R-methylene-ꢀ-tert-butyldimethylsilyloxy-
carboxylate esters bearing different ꢀ-alkyl substituents.
All transformations employed stoichiometric amounts of
tert-butyl hydroperoxide and catalytic quantities of potas-
sium tert-butoxide (0.1-0.3 equiv) in THF at 0 °C.2
Substrates with dimethoxymethyl, benzyloxymethyl, or
unsaturated ꢀ-substituents reacted relatively rapidly, while
those with cyclohexyl, ethyl, or 2-benzyloxyethyl ꢀ-sub-
stituents reacted more slowly and required distributed
addition of as much as 0.3 equiv of potassium tert-
butoxide to achieve complete conversion. All reactions
were complete within 12 h at 0 °C, provided that care
was taken to thoroughly dry all substrates, reagents, and
solvents (see the Supporting Information). As summarized
in Figure 1, anti products were formed selectively in all
cases. Substrates with unsaturated ꢀ-substituents were
(2) To the best of our knowledge, these conditions were first reported
in the following works: (a) Warrener, R. N.; Butler, D. N.; Margetic, D.;
Pfeffer, F. M.; Russell, R. A. Tetrahedron Lett. 2000, 41, 4671–4675. (b)
Pfeffer, F. M.; Russell, R. A. J. Chem. Soc., Perkin Trans. 1 2002, 2680–
2685. Although we have successfully used anhydrous solid potassium tert-
butoxide in several experiments, for convenience we typically employ a
1.0 M stock solution of base in THF, prepared from the anhydrous solid
(see the Supporting Information).
(1) (a) Bailey, M.; Marko´, I. E.; Ollis, W. D.; Rasmussen, P. R.
Tetrahedron Lett. 1990, 31, 4509–4512. (b) Bailey, M.; Staton, I.; Ashton,
P. R.; Marko´, I. E.; Ollis, W. D. Tetrahedron: Asymmetry 1991, 2, 495–
509.
10.1021/ol900665a CCC: $40.75
Published on Web 04/27/2009
 2009 American Chemical Society

for epoxidations in the literature. Alkene epoxidations with
electrophilic reagents such as m-chloroperoxybenzoic acid
(m-CPBA) or dimethyldioxirane are prototypically stereo-
specific, largely concerted processes.4 In contrast, epoxi-
dations of electrophilic alkenes with alkaline hydrogen
peroxide are established to be non-stereospecific in many
instances. For example, in a careful analysis of the
epoxidations of (E)- and (Z)-3-methylpent-3-en-2-one with
alkaline hydrogen peroxide in methanol, House and Ro
showed that both substrates afforded the same (trans)
epoxide.5 They argued that rotation about the CR-Cꢀ σ
bond of a ꢀ-hydroperoxy enolate intermediate (and
stereochemical scrambling) was rapid relative to cleavage
of the peroxyl O-O bond to form the oxirane ring. This
analysis was consistent with a number of earlier observa-
tions by others concerning related processes,6 and has
since been reinforced by studies of the peroxidation of
different R,ꢀ-unsaturated carbonyl compounds with alka-
line hydrogen peroxide in both protic and aprotic media.7
Clearly, a rationalization of the stereochemical outcomes
of the transformations of Figure 1 could be framed quite
differently for stepwise and concerted processes.
Figure 1. Anti-selective epoxidation of methyl R-methylene-ꢀ-tert-
butyldimethylsilyloxycarboxylate esters with potassium tert-
butoxide-tert-butyl hydroperoxide in THF at 0 °C. Key: (a) isolated
yield of the pure anti diastereomer; (b) isolated yield of the anti
and syn diastereomers combined.
To differentiate these mechanistic possibilities, we pre-
pared methyl R-methylene-ꢀ-tert-butyldimethylsilyloxycar-
boxylate ester substrates with trans deuterium labels by the
sequence shown in Scheme 1. In order to maximize the
epoxidized with somewhat lower selectivities, which
evidence suggests may be due in part to a stereoelectronic
effect (vide infra).
Scheme 1. Preparation of Substrates with Trans Deuterium Labels
In an important early finding, Tanaka et al. showed that
1,2-disubstituted allylic alcohols undergo syn-selective epoxid-
ation in the presence of vanadium acetylacetonate and tert-
butyl hydroperoxide.3 Later, Baylis-Hillman products were
shown to undergo syn-selective epoxidation with both
vanadium- and titanium-based reagents.1 We used the latter
method to obtain authentic samples of the syn diastereomers
for two of the examples of Figure 1, with the results shown
in eqs 1 and 2 below.
Interestingly, but not unexpectedly, the rates of epoxidations
mediated by potassium tert-butoxide and titanium tetraiso-
propoxide varied inversely with substrates bearing electron-
donating and electron-withdrawing ꢀ-substituents. Substrates
in Figure 1 with more electron-withdrawing ꢀ-substituents
reacted more rapidly in the base-catalyzed epoxidations.
In attempting to rationalize the stereochemical outcomes
of the epoxidations of Figure 1, we began by considering
the classical extremes of mechanism previously discussed
(3) Tanaka, S.; Yamamoto, H.; Nozaki, H.; Sharpless, K. B.; Michaelson,
R. C.; Cutting, J. D. J. Am. Chem. Soc. 1974, 96, 5254–5255.
(4) m-CPBA: Singleton, D. A.; Merrigan, S. R.; Liu, J.; Houk, K. N.
J. Am. Chem. Soc. 1997, 119, 3385–3386, and references therein. Dimeth-
yldioxirane: (a) Adam, W.; Curci, R.; Edwards, J. O. Acc. Chem. Res. 1989,
22, 205–211. (b) Schneebeli, S. T.; Hall, M. L.; Breslow, R.; Friesner, R.
J. Am. Chem. Soc. 2009, 131, 3965–3973, and references therein.
(5) House, H. O.; Ro, R. S. J. Am. Chem. Soc. 1958, 80, 2428–2433.
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Org. Lett., Vol. 11, No. 11, 2009

deuterium content of the final product, the isotopic label was
introduced in the first step of the sequence by base-catalyzed
H/D exchange of the alkynyl hydrogen of methyl propiolate
(two iterations).8 Then, by employing the Pare´ modification
of the Kishi iodoallenolate aldol reaction,9 the labeled
precursor was coupled with cyclohexanecarboxaldehyde and,
separately, with benzaldehyde, 4-methoxybenzaldehyde, and
4-cyanobenzaldehyde (Scheme 1). tert-Butyldimethylsilyla-
tion of the aldol products, followed by sequential stereospe-
cific metal-halogen exchange and stereospecific protonation
with acetic acid, then provided the deuterium-labeled sub-
strates for epoxidation. In practice, metal-halogen exchange
was best accomplished with isopropylmagnesium chloride10
(THF, -78 °C, 10 min); exchange with n-butyllithium (THF,
-100 °C, 2 min) was less efficient.11 1H NMR analysis of
the products of this reaction sequence (13-16) showed that
the deuterium content at the labeled position was g90% and
that the labeled compounds were g95% trans.12
We first studied the epoxidation of the deuterium-labeled
ꢀ-cyclohexyl substrate (13), under the conditions detailed
above, and found that a g18:1 mixture of anti and syn
epoxides was formed, as had been observed with the
unlabeled substrate (Figure 1). The pure (deuterium-labeled)
anti epoxide (17, Figure 2) was obtained in 78% isolated
yield after column chromatography. 1H NMR analysis of this
product revealed that epoxidation had proceeded with g95%
stereospecificity, with retention of trans stereochemistry
(Figure 2). Aliquots from a separate but identical experiment
removed at points of 50, 60, and 70% conversion and
analyzed by 1H NMR showed that unreacted substrate
retained g95% stereochemical purity. The lack of stereo-
chemical scrambling makes clear that, in contrast to the
findings of House and Ro, the mechanism of epoxidation in
the present case (involving different substrates and different
reagents) cannot involve a freely rotating ꢀ-tert-butylperoxy
enolate intermediate.13 If such an intermediate is formed,
then the rate of peroxyl O-O bond cleavage must be quite
rapid relative to rotation about the CR-Cꢀ σ bond. The data
are also consistent with concerted mechanisms of oxygen-
atom transfer. To learn if similar conclusions extended to
the least anti-selective transformation of Figure 1 (the
ꢀ-phenyl-substituted substrate, which had afforded a 2:1
mixture of diastereomers favoring the anti isomer 6) we
examined the epoxidation of the trans deuterium-labeled
substrate 14, with the results summarized in eq 3 of Figure
2. Also presented in Figure 2, in descending order of anti
selectivity, are results of epoxidations of the ꢀ-4-methoxy-
phenyl- and ꢀ-4-cyanophenyl-substituted, deuterium-labeled
substrates 15 and 16 (depicted at the bottom of Scheme 1).
All three deuterium-labeled ꢀ-aryl substrates were found to
undergo epoxidation with g95% stereospecificity in both anti
and syn manifolds. The variation of anti-syn ratios among
the three ꢀ-aryl substrates reveals an interesting stereoelec-
tronic effect. The rates of epoxidations with the three ꢀ-aryl
substrates also varied, with 4-cyanophenyl > phenyl >
4-methoxyphenyl (see the Supporting Information).
(6) (a) Bunton, C. A.; Minkoff, G. J. J. Chem. Soc. 1949, 665–670. (b)
Wasserman, H. H.; Aubrey, N. E.; Zimmerman, H. E. J. Am. Chem. Soc.
1953, 75, 96–98. (c) Black, W. B.; Lutz, R. E. J. Am. Chem. Soc. 1953, 75,
5990–5997.
(7) (a) Zimmerman, H. E.; Singer, L.; Thyagarajan, B. S. J. Am. Chem.
Soc. 1959, 81, 108–116, and references therein. (b) Kelly, D. R.; Caroff,
E.; Flood, R. W.; Heal, W.; Roberts, S. M. Chem. Commun. 2004, 2016–
2017.
(8) (a) Labuschange, A. J. H.; Schneider, D. F. Tetrahedron Lett. 1983,
24, 743–744. (b) Schwier, T.; Gevorgyan, V. Org. Lett. 2005, 7, 5191–
5194.
(9) (a) Taniguchi, M.; Hino, T.; Kishi, Y. Tetrahedron Lett. 1986, 27,
4767–4770. (b) Wei, H. X.; Hu, J.; Jasoni, R. L.; Li, G.; Pare´, P. W. HelV.
Chim. Acta 2004, 87, 2359–2363.
(10) Rottla¨nder, M.; Boymond, L.; Cahiez, G.; Knochel, P. J. Org. Chem.
1999, 64, 1080–1081.
(11) Metal-halogen exchange using i-PrMgCl and n-BuLi provided the
following isolated yields of labeled substrates (respectively): 13 (88% and
85%), 14 (77% and 52%), 15 (87% and 45%), and 16 (91% and 18%).
(12) In the course of developing a synthetic route to the deuterium-
labeled substrates, we made the following observation: treatment of
3-deuteriopropiolate with diisobutylaluminum hydride-N-methylmorpho-
line-N-oxide complex (Ramachandran, P. V.; Reddy, M. V.; Rudd, M. T.
Chem. Commun. 1999, 1979-1980) followed by addition of benzaldehyde
afforded a 1:1 mixture of stereoisomeric (E)- and (Z)-alkenes. This
stereochemical outcome is consistent with the intermediacy of an aluminum
allenolate, as previously discussed by Tsuda et al. (Tsuda, T.; Yoshida, T.;
Saegusa, T. J. Org. Chem. 1988, 53, 1037–1040).
Figure 2. Stereospecific epoxidations of trans deuterium-labeled
substrates. Key: (a) isolated yield of the pure anti diastereomer;
(b) isolated yield of the anti and syn diastereomers combined.
To further explore the mechanism of epoxidation, we
conducted a competition experiment wherein a ∼1:1 mixture
of the deuteriated substrate 13 and its nonlabeled counterpart
was subjected to standard conditions of epoxidation, with
quenching of the reaction at ∼80% conversion. By integra-
1
tion of the R-methylene resonances in H NMR spectra of
Org. Lett., Vol. 11, No. 11, 2009
2439

the recovered, unreacted starting materials we determined
that there was a significant inverse secondary deuterium
isotope effect (kH/kD ) 0.95) upon substitution of the exo-
carbon atom of the R-methylene group (Figure 3), suggesting
that this carbon is rehybridized in the transition state.
Finally, we employed the Singleton method14 to measure
the 12C/13C isotope effects at C2 and C3 during epoxidation
in the specific case of the ꢀ-cyclohexyl-substituted substrate,
with the results summarized in Figure 3. A large isotope
effect was observed at C3 (∼1.032) and a smaller but
significant isotope effect observed at C2 (∼1.009). A
strikingly similar data set was reported by Singleton et al.
in their recent study of the mechanism of epoxidation of
2-cyclohexenone with tert-butyl hydroperoxide and 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) in 1,2-dichloro-
ethane.15 There, as here, the kinetic isotope effects provide
evidence for an asynchronous transition state with substantial
rehybridization of the ꢀ-olefinic carbon atom. Stepwise
mechanisms involving rate-limiting oxirane formation within
a ꢀ-peroxy enolate intermediate are not supported, while
concerted mechanisms cannot be ruled out.
The experimental results presented herein make evident
that the basis of anti selectivity in epoxidations of methyl
R-methylene-ꢀ-tert-butyldimethylsilyloxycarboxylate esters
arises from a face-selective attack of the tert-butylperoxide
reagent upon the substrate. We have evidence that stereo-
electronic factors play a role in determining the diastereo-
facial preference, at least within one substrate subset (the
ꢀ-aryl series). Ground-state conformational analyses of the
methyl R-methylene-ꢀ-tert-butyldimethylsilyloxycarboxylate
ester substrates studied herein reveal a large number of
closely spaced, quite different rotameric forms within 3.0
kcal/mol of the global energy minimum and do not suggest
Figure 3. Measured isotope effects for epoxidation of the ꢀ-
cyclohexyl-substituted substrate depicted.
that a clear basis for the facial selectivity of reagent addition
can be gained by consideration of the substrate alone.16 High-
level computational modeling of transition-states is clearly
necessary, but beyond the scope of the present study.
Regardless of its theoretical underpinnings, the anti-selective
epoxidation process we describe provides unique access to
highly functionalized, stereochemically complex structures
and in this regard is likely to be quite useful. Our under-
standing of the mechanism of this nucleophilic epoxidation
process, while incomplete, is informed by the self-consistent
series of experiments presented herein, which leads to a view
of the reaction that is not distinguishable from a concerted,
albeit asynchronous process.
Acknowledgment. Financial support from the National
Institutes of Health (Grant No. CA047148) is gratefully
ˇ
acknowledged. J.S. acknowledges Dr. Alfred Bader for his
creation and generous financial support of the Alfred Bader
Fellowship Program in Chemistry at Harvard University. We
thank Professors David Evans and Eric Jacobsen of Harvard
University for helpful discussions. We also thank Dr. Shaw
Huang for assistance with NMR analyses.
(13) Meth-Cohn et al. have reported examples of both stereospecific
and non-stereospecific epoxidations with lithium tert-butylperoxide in THF
((a) Clark, C.; Hermans, P.; Meth-Cohn, O.; Moore, C.; Taljaard, H. C.;
van Vuuren, G. J. Chem. Soc., Chem. Commun. 1986, 1378–1380. (b) Meth-
Cohn, O.; Moore, C.; Taljaard, H. C. J. Chem. Soc., Perkin Trans. 1, 1988
2663-2674).For example, these authors found that epoxidation of phenyl
(Z)-2-phenylethenylsulfone proceeded with retention of stereochemistry,
providing the corresponding cis epoxide in 90% yield, while epoxidation
of di-tert-butyl maleate (cis) proceeded with inversion of stereochemistry,
providing the trans epoxide in 60% yield. We have examined the
epoxidation of the latter substrate under the optimized conditions
described above and found that the cis epoxide was formed with g95%
stereospecificity in 80% yield after column chromatography (see the
Supporting Information).
Supporting Information Available: Detailed experimen-
tal procedures, characterization data for all new compounds,
and procedures for determination of isotope effects. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL900665A
(16) For discussions of the diastereoselectivities of dihydroxylations of
closely related substrates, see: (a) Evans, D. A.; Kaldor, S. W. J. Org. Chem.
1990, 55, 1698–1700. (b) Marko´, I. E.; Giles, P. R.; Janousek, Z.; Hindley,
N. J.; Declercq, J. P.; Tinant, B.; Feneau-Dupont, J.; Svendsen, J. S. Recl.
TraV. Chim. Pays-Bas 1995, 114, 239–241.
(14) Singleton, D. A.; Thomas, A. A. J. Am. Chem. Soc. 1995, 117,
9357–9358.
(15) Christian, C. F.; Takeya, T; Szymanski, M. J.; Singleton, D. A. J.
Org. Chem. 2007, 72, 6183–6189.
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