for stereoinduction in the cycloaddition reaction
was probed computationally using DFT with 5f
as the squaramide catalyst. Consistent with previous studies on (4+3) cycloadditions of furan and
alkoxy silyloxyallyl cations (31, 32), the calculations converge on a stepwise mechanism involving initial nucleophilic attack by furan at the
vinyl terminus of the oxyallyl cation followed by
ring closure (fig. S22). The structures corresponding to the lowest-energy transition states for the
first, enantioselectivity-determining C–C bond-forming step en route to the major and minor
enantiomers of product are presented in Fig. 4,
B and C, respectively. Single-point calculations
at the M062X/6-31+G(d,p) level of theory reproduce both the sense and magnitude (DDE‡calc =
1.28 kcal/mol) of enantioinduction determined
experimentally. Both transition states display a
network of hydrogen-bonding interactions between the oxyallyl fragment and the triflate counterion, as well as between furan and the amide
backbone of the catalyst. However, the positioning of the furan nucleophile in proximity to the
aromatic substituent of the catalyst in the major
transition state suggests a stabilizing interaction
between the furan and the catalyst. Such an interaction is absent in the minor one and may thus
be a key factor responsible for enantioselectivity
The interaction between simple silyl triflates
and squaramide H-bond donors produces a highly reactive Lewis acid complex capable of activating acetals to produce chiral catalyst-associated
oxocarbenium ion intermediates. Enantioselectivity in reactions of these intermediates can be
achieved through the interplay of noncovalent
interactions between the H-bond donor catalyst
and both components of the ion pair. Enhancement of the intrinsic reactivity of Lewis acids
represents a potentially powerful strategy for the
development of asymmetric reactions proceeding through high-energy cationic intermediates.
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We gratefully acknowledge financial support from NIH (grant
GM043214 to E.N.J. and a postdoctoral fellowship to A.M.H.)
and NSF (predoctoral fellowship to S.M.B.) and helpful
discussions with M. Harmata (University of Missouri).
Crystallographic data for compounds 9b and S9e are available
free of charge from the Cambridge Crystallographic Data
Centre under references CCDC 1578582 and CCDC 1578581,
respectively. Additional optimization and mechanistic data are
provided in the supplementary materials.
Materials and Methods
Figs. S1 to S23
Tables S1 to S9
7 August 2017; accepted 12 October 2017
764 10 NOVEMBER 2017 • VOL 358 ISSUE 6364 sciencemag.org SCIENCE
Fig. 4. Proposed mechanism. (A) Proposed catalytic cycle for the enantioselective, catalytic (4+3)
reactions with 5•R3SiOTf acting as an enhanced Lewis acid. (B) Lowest-energy transition structure
for the first, selectivity-determining C–C bond-forming step in the addition of furan to an oxyallyl
cation intermediate, leading to the experimentally observed major enantiomer. (C) Corresponding
transition structure leading to the minor enantiomer. Structures were calculated at the B3LYP/6-31G(d)
level of theory, with uncorrected electronic energies at the M062x/6-31+G(d,p) level.