respectively. In this manner, readily available
aliphatic boronic esters could be converted
through a three-step sequence into a variety
of highly enantioenriched products bear-
ing stereocenters with diverse substitution
patterns.
The effectiveness of lithium-isothiourea-
boronateLi-6ain enantioselective 1,2-boronate
rearrangements raises intriguing questions
about the mode of catalysis and origin of
enantioinduction. Given the absence of any
potential H-bond donor groups on the cat-
alyst, the Lewis acidic lithium center repre-
sents the logical agent for chloride abstraction.
Quantification by Gutmann-Beckett analysis
( 38 – 40 ) revealed thatLi-6apossesses only
moderate Lewis acidity, similar to that of other
lithium salts and substantially lower than that
of traditional Lewis acid catalysts such as TiCl 4
(Fig. 4A). Notably, lithium boronateLi-9,
which was designed to serve as a substrate
mimic that cannot undergo rearrangement,
displayed a slightly higher acceptor number
than that obtained withLi-6a. Given the ob-
served levels of enantioselectivity under cata-
lytic conditions,Li-6amust be more reactive
than the lithium boronate substrate 3 itself in
promoting the rearrangement. Although these
observations do not rule outLi-6aacting
as a chiral Lewis acid, the similar degree of
Lewis acidity exhibited by lithium boronate
substrate mimicLi-9precludes Lewis acid-
ity alone as the only factor responsible for
rate acceleration in the catalyst-mediated
rearrangement.
Valuable insight into the basis for the high
reactivity ofLi-6ain mediating the boronate
rearrangement reaction was provided by DFT
computational studies. In the initial investiga-
tions, a substrate:catalyst stoichiometry of 1:1
in the enantiodetermining transition states
was assumed. The lowest-energy transition
state structures reveal networks of attractive
interactions involving the lithium ions and the
boronate moieties of both the substrate and the
catalyst. In the putative enantiodetermining
transition state leading to the major enanti-
omer in theLi-6a–catalyzed rearrangement
of isobutyl-substituted lithium boronate3b
(Fig. 4B), the anterior boronate oxygen and
a-boryl chloride ofLi-6achelate the lithium
ion of3b(depicted in blue in the graphic) while
the posterior boronate oxygen of substrate3b
is anchored by the lithium ion of the catalyst
(depicted in red). In this geometry, both lithium
ions are poised to promote abstraction of the
departing chloride (shown in green) by a
cooperative mechanism, with the Li–Cl bond
distances for the catalyst and substrate lith-
ium ions being 2.41 Å and 2.30 Å, respectively.
In contrast, in the lowest-energy transition
state structure leading to the minor product
enantiomer, the departing chloride resides
proximal to the substrate lithium (2.29 Å) but
distant from the catalyst lithium (4.81 Å); ad-
ditionally, the substrate and catalyst lithium
ions are both bound to the spectator chloride
of the substrate. The modestly lower level of
enantioselectivity observed in the rearrange-
ment mediated by catalyst analogLi-6b(Fig.
2C) is consistent with the proposed attractive
interaction between thea-boryl chloride of
Li-6aand the substrate lithium ion being
beneficial but not obligatory in the enantio-
determining event. Although a deeper anal-
ysis must await fuller characterization of the
aggregation state and relative stoichiome-
try of the product-determining transition
state, these results suggest a role for both
the catalyst and substrate lithium ions in pro-
moting chloride departure. Taken together,
the nuclear magnetic resonance (NMR) and
DFT studies are consistent with lithium-
isothiourea-boronate speciesLi-6apromot-
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dual–lithium-induced chloride abstraction,
aided by Lewis basic functionality on the
rigid catalyst scaffold that orients both the
catalyst and substrate lithium ions in a precise
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ACKNOWLEDGMENTS
We thank S.-L. Zheng (Harvard University) for determination of
x-ray crystal structures, and M. Levin and P. Vojáčková for
helpful discussions.Funding:NIH grant GM043214 (E.N.J.).
Author contributions:H.A.S. and E.N.J. conceived the work,
H.A.S. and J.Z.E. designed and conducted the experiments,
E.N.J. directed the research, and all authors wrote the
manuscript.Competing interests:The authors declare
no competing financial interests.Data and materials
availability:Crystallographic data for compounds 4 ,6a,6b,
Li-6b,6f,7l, and7vareavailablefreeofchargefromthe
Cambridge Crystallographic Data Centre under references
CCDC 2111740, CCDC 2111743, CCDC 2111741, CCDC 2111739,
CCDC 2111744, CCDC 2111742, and CCDC 2111745, respectively.
All other data are available in the main text or the
supplementary materials.SUPPLEMENTARY MATERIALS
science.org/doi/10.1126/science.abm0386
Materials and Methods
Supplementary Text
Figs. S1 to S20
Tables S1 to S25
References ( 41 Ð 69 )21 August 2020; accepted 29 September 2021
10.1126/science.abm0386SCIENCEscience.org 5 NOVEMBER 2021•VOL 374 ISSUE 6568 757
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