RESEARCH
| REPORTS
stereocenters. However, trisubstituted cin-
namamide derivatives undergo selective an-
chimeric assistance by the amide group en
route to 1,2-difluorination products (i.e., 2s)
tures in the hypervalent iodine-catalyzed reac-
tion, and we sought to evaluate this possibility
by tuning the p-donating ability of the catalysts.
The incorporation of more electron-rich or
polarizable aromatic substituents into the cat-
alyst was not a viable approach because these
groups are incompatible with the strongly oxi-
dizing reaction medium. However, the more
electron-deficient 3,4,5-trifluorophenyl analog
1d (Fig. 4B) could be evaluated and was found
to be markedly less enantioselective than 1b,
as expected if cation-p interactions play a pro-
ductive role in modulating stereocontrol (41).
Eyring analysis in the 23° to –45°C temperature
range of catalysts 1b, 1c, and 1d for reaction
of substrate 4a was performed in order to
glean additional insight into the basis for
enantioinduction (Fig. 4B). For each catalyst,
enantioselectivity was found to be enthalpical-
ly controlled, with a relatively small entropic
compensation. The significant difference in the
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1
1
1
(
(
33). According to the mechanism outlined in
3
Fig. 1E, decomposition of intermediate II via
the phenonium ion rearrangement should be
favored by the use of cinnamate derivatives
bearing less nucleophilic carbonyl groups. In-
deed, trisubstituted methyl cinnamate deriva-
tives were found to be excellent substrates for
enantioselective oxidative rearrangement cata-
lyzed by 1b (Fig. 3). As illustrated with 4a,
comparable results were obtained on both
20. M. G. B. Drew, J. Mann, B. Pietrzak, J. Chem. Soc.
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(
2
2
2
1
-mmol and gram scale in good yields. Although
electron-rich arenes such as phenols are incom-
patible with the oxidative hypervalent iodine
conditions due to dearomatization pathways (40),
suitably protected derivatives such as the acetate
(
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2
2
2
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4g were found to undergo the desired difluori-
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nation to produce 5g in high enantioselectivity
and yield. The a-alkyl substituent of the cinna-
mate ester could also be varied without detri-
mental effect on reaction outcome (5j to 5l),
further underlining the utility of this rearrange-
ment approach for the synthesis of sterically
congested stereocenters. Low reactivity was
observed in the difluorinative rearrangement of
(
1966).
‡
differential enthalpy of activation (DDH ) be-
9. T. B. Patrick, J. J. Scheibel, W. E. Hall, Y. H. Lee, J. Org. Chem.
45, 4492–4494 (1980).
tween 1b and 1c is difficult to ascribe to steric
effects alone, and it suggests instead a selective
stabilizing interaction with 1b in the transition
state leading to the major enantiomer (42). To
the extent that it exists, this stabilization is lost
with weaker p-donating catalyst 1d, as reflected
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7
3
3
5
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‡
3-chloropropyl–substituted 4m, suggesting that
in a DDH value more similar to that of 1c.
33. S. M. Banik, J. W. Medley, E. N. Jacobsen, J. Am. Chem. Soc.
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1
relatively long-range inductive effects can influ-
ence the susceptibility of the alkene to the oxi-
dation reaction. This deactivating effect is offset,
however, by introduction of an electron-donating
group on the aromatic ring of the substrate as
in 4n.
The products of this asymmetric reaction can
be elaborated through a variety of synthetic
manipulations without compromise of enantio-
meric integrity (Fig. 3B). Cinnamamide-derived
This analysis is consistent with a more electron-
donating p surface contributing to the high
enantioselectivity in the 1,1-difluorination reac-
tion, and it raises the intriguing possibility that
cation-p interactions might be used to modulate
enantioselectivity in other hypervalent iodine-
mediated alkene oxidations.
3
3
(
2
36. M. Uyanik, T. Yasui, K. Ishihara, Angew. Chem. Int. Ed. 52,
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3
3
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malonate derivatives bearing difluoromethylated
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in enantioselectivity is observed in difluorina-
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benzylic (i.e., 1a and 1b) versus aliphatic sub-
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ACKNOWLEDGMENTS
5.
Complete experimental and characterization data
are provided in the supplementary materials. This
work was supported by NIH (GM043214), by an
NSF predoctoral fellowship to S.M.B., and by an NIH
postdoctoral fellowship to J.W.M. We thank
S.-L. Zheng (Harvard) for determination of the x-ray
crystal structures of 3h and 10. Metrical parameters
are available free of charge from the Cambridge
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SUPPLEMENTARY MATERIALS
www.sciencemag.org/content/353/6294/51/suppl/DC1
Materials and Methods
Figs. S1 to S4
Schemes S1 and S2
Tables S1 to S7
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