the N-H of6aby LiHMDS with chelation of the
lithium counterion by the exocyclic isothiourea
nitrogen and the amide oxygen. In line with
experimental observations, density functional
theory (DFT) calculations on6aand the pro-
posed chelate structure ofLi-6apredict a
similar shift for both the isothiourea N–C–N
stretch (1591 cm–^1 to 1567 cm–^1 ,d=–24 cm–^1 )
and the amide C–O stretch (1648 cm–^1 to
1607 cm–^1 ,d=–41 cm–^1 ). An x-ray crystal struc-
ture analysis of methyl analogLi-6bprovided
additional experimental support for the che-
late model (Fig. 2B). ComplexLi-6bdisplayed
spectral characteristics similar to those of
Li-6abut proved more amenable to crystal-
lization; it also afforded similar but slightly
diminished enantioinduction in the rearrange-
ment of the model boronate3a(Fig.2C).Taken
together, these observations point to a cat-
alyst structure featuring a five-membered
lithium chelate with the cation located in a
highly dissymmetric pocket defined by the
4-chlorophenyl group, thetert-butyl group,
the isothiourea-boronate heterocycle, and the
3,5-bis(trifluoromethyl)phenyl group, the last
of which is rotated out of the plane of the het-
erocyclic core.
With the identification and structural char-
acterization ofLi-6aas a highly enantioselec-
tive catalyst, the scope of migrating groupsfor the catalytic rearrangement was explored
(Fig. 3A). Excellent levels of enantioselectivity
were achieved in rearrangements of boronates
accessed by addition of dichloromethyllithium
to readily available primary alkyl (5a–j) and
unhindered secondary alkyl (5k–m) pinacol
boronic ester derivatives bearing a variety of
substitution and branching patterns. Com-
pounds bearing mildly Lewis basic (5c,h,i)
or base-sensitive (5e,g) functionality under-
went the rearrangement effectively. Aryl or
alkenyl pinacol boronic esters, substrates bear-
ing more strongly Lewis basic substitution,
and tertiary alkylboronates either failed to
undergo rearrangement or did so with var-
iable levels of enantioselectivity (see supple-
mentary materials for additional information
and discussion regarding the substrate scope).
Compounds bearing isotopically labeled stereo-
centers could be readily generated by using
commercially available CD 2 Cl 2 (5f-d 1 ) and(^13) CH
2 Cl 2 (5b-
(^13) C).
As noted above, the products of rearrange-
ment of dichloromethyl boronates are bifunc-
tional building blocks that can be elaborated
sequentially and stereospecifically to a broad
array of stereodefined structural motifs (Fig.
3B). To illustrate the synthetic utility of the
enantioselective catalytic rearrangement reac-
tion in the preparation of such compounds, we
developed a two-step, telescoped procedure
entailing theLi-6a–catalyzed rearrangement
followed by a second, enantiospecific rear-
rangement to afford enantioenriched second-
ary boronic ester products directly. Grignard
reagents bearing various substitution patterns
were engaged in the second step to generate
boronic ester products bearing primary alkyl
(7a,g), secondary alkyl (7b,f,h), cyclic tertiary
alkyl (7c), aryl (7d), and alkenyl (7e,i) substi-
tution in good yields over two steps and with
complete enantiospecificity. Addition of het-
eroatomic nucleophiles to enantioenriched
chloride building block5bafforded the corre-
sponding ether (7j) and thioether (7k) products
with high levels of enantiospecificity. Similarly,
5b-^13 Cwas elaborated to thea-boryl amine
(7l)asthebasisforanefficientroutetoan
isotopically labeled analog of the proteasome
inhibitor drug bortezomib ( 29 ).
The purified secondary boronic ester pro-
ducts obtained as outlined above were further
elaborated to compounds bearing a diverse
array of trisubstituted stereocenters using
precedented carbon-boron bond transforma-
tions (Fig. 3C) ( 30 – 37 ). Boronic ester interme-
diates7f–hwere thus transformed directly
into products bearing a broad range of C–
C, C–N, and C–O bonds in high yields and
enantiospecificities (8a–e,h,i). Additionally,
allylboronic ester intermediates7eand7iwere
elaborated selectively at theg-position to afford
fully substituted products bearing ana-tertiary
amine (8f) and a quaternary stereocenter (8g),
756 5NOVEMBER2021•VOL 374 ISSUE 6568 science.orgSCIENCE
Fig. 4. Mechanistic analysis and computational study.(A) Gutmann-Beckett analysis ofLi-6ain
comparison to other Lewis acids. The analysis was performed by addition of a Lewis acid to a solution of
triethylphosphine oxide in diethyl ether using a solution of triphenylphosphine in C 6 D 6 in a sealed capillary
tube as an internal standard, with the acceptor number (AN) determined from the deshielding effect of
the additive on the^31 P NMR resonance. (B) DFT computational study of the putative enantiodetermining
major and minor transition states for the developed rearrangement reaction proceeding through a chloride-
abstraction mechanism. Calculations were carried out at the SMD(Et 2 O)-DLPNO-CCSD(T)/ma-def2-TZVP//
M06-2X/6-31G(d) level of theory, with explicit solvation of the lithium cations by dimethyl ether where
appropriate. See supplementary materials for computational details. *Literature values ( 40 ).
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