COMMUNICATION
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Antarafacial Mediation of Oxygen Delivery by a Phenylsulfinyl
Group in the Epoxidation of Proximal Double Bonds:
Intramolecular Trapping of an Early Pummerer Intermediate
with Stereoelectronic Control
Yandong Zhang,† Jun Hee Lee,† and Samuel J. Danishefsky*,†,‡
†Department of Chemistry, Columbia University, Havemeyer Hall, 3000 Broadway, New York, New York 10027, United States
‡Laboratory for Bioorganic Chemistry, Sloan-Kettering Institute for Cancer Research, 1275 York Avenue, New York, New York 10065,
United States
S Supporting Information
b
subjected to the action of TFAA in dichloromethane from 0 °C
ABSTRACT: Stereospecific intramolecular antarafacial
epoxidation of a double bond via an early Pummerer
reaction intermediate has been demonstrated. The inter-
mediate is presumably generated via trifluoroacetylation of a
sulfoxide precursor. Ionization of trifluoroacetate would
formally generate a dipositive “sulfenium” equivalent. This
species attacks an otherwise unactivated, proximal olefinic
linkage in an antiperiplanar fashion, with trifluoroacetate
serving as the nucleophile. Proposed mechanistic intermedi-
ates were characterized structurally (in several cases by
crystallographic means) and shown to serve as precursors
en route to the final antarafacial epoxides. The sense of the
cyclization seems to be driven by principles inherent in
Markovnikov's rule.
to room temperature over 1 h. The resultant product was treated
with aqueous sodium bicarbonate (in a two-phase setting).
Compound 4 was produced in 94% yield. In another experiment,
following the TFAA step but before the workup with aqueous
sodium bicarbonate, evaporation of the solvent gave rise to a
semisolid residue. However, exchange of trifluoroacetate by
tetrafluoroborate5 gave rise to a new salt that fortunately could
be coaxed into a state of crystallinity. X-ray analysis of this new
salt revealed it to be structure 9. As shown in Scheme 1, the
double bond had apparently been attacked in an electrophilic
sense by the TFAA-activated sulfoxide, giving rise to the bridged
sulfonium trifluoroacetate 8 and subsequently to the correspond-
ing sulfenium tetrafluoroborate 9. Moreover, the formal carbe-
nium-like entity at C8 in 7 had been discharged by trifluoro-
acetate. The precise timing of these steps with respect to level of
concertedness could not be established on the basis of our data
set. However, since the covalent trifluoroacetate in 9 is trans-
periplanar with respect to the “C-Sþ” bond, the two bond
formations (C7-Sþ and C8-O) may well correspond to orche-
strated trans-diaxial attacks upon the resident C7-C8 olefin in
precursor 5.
ecently, we described a simple two-step sequence for gen-
R
erating what we have termed “trans-Diels-Alder” (trans-
DA) motifs containing angular functionality.1 Of course, many
issues remain to be addressed before this capability can be fully
exploited. We have already come upon a remarkable observation
in the course of an attempted Pummerer rearrangement2 of
sulfoxide 2 (derived from the “trans-DA” product 1 in Scheme 1).
Treatment of 2 with trifluoroacetic anhydride (TFAA)3 led, not
unexpectedly, to the disappearance of the starting material.
However, subsequent treatment with aqueous sodium bicarbo-
nate failed to produce the anticipated aldehyde 3. Instead, a
compound in which the erstwhile angular sulfoxide function
in 2 had given way to a sulfide was obtained. Correspondingly,
the double bond had become an epoxide. It is clear that the
oxygen of the oxido linkage had not arisen by direct transfer
from the sulfoxide because the epoxide (see compound 4)4 had
emerged at the R-face of the double bond, i.e., anti to the
β-face phenylsulfinyl precursor. In this paper, we establish an
interesting mechanistic pathway to account for the formation of
4. Follow-up studies served to generalize the scope of this novel
intramolecular yet antarafacial sulfoxide-induced overall oxida-
tion of an otherwise unactivated double bond and to identify its
limitations.
Treatment of 9 with aqueous sodium bicarbonate indeed
afforded epoxide 4. In summary, then, the activated sulfonium
salt6 had attacked C7 of the double bond, giving rise to a stable
but unprecedented bicyclic [2.2.2] sulfonium-containing sub-
structure with neutralization by trifluoroacetate having occurred
at C8. Treatment of this salt with sodium bicarbonate apparently
accomplished deacylation of the covalent trifluoroacetate at C8,
leading to the formation of the oxido linkage with concurrent
release of the neutral thiophenyl function, as shown in 4.6-8
Of course, the dipositive “sulfenium” (early Pummerer9) species
formalized as 6, which arose from heterolysis of the presumed
trifluoroacetoxysulfenium species (of intermediate 5), could in
principle have attacked the proximal double bond at either C7 or
C8 (presteroid numbering), generating in either case tertiary carbe-
nium ion character at the alternate carbon. The fact that the reaction
produces apparently only the bicyclo [2.2.2] “sulfonium” substruc-
ture, as in 7, may reflect either kinetic or thermodynamic preferences
regarding the optimal size of the sulfonium-containing ring system
To initiate our study, we began by trying to understand the
2 f 4 conversion at a more rigorous level. Compound 2 was
Received: December 1, 2010
Published: December 23, 2010
r
2010 American Chemical Society
752
dx.doi.org/10.1021/ja1107707 J. Am. Chem. Soc. 2011, 133, 752–755
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