3d), and electron-withdrawing (3e to 3h)
groups at various positions were obtained in
good to excellent yields and stereoselectivities
starting from unsymmetricalarylalkylidenes.
A product containing synthetically useful bo-
ronic ester3i was synthesized in moderate
yields and excellent stereoselectivities after
the stereoconvergent crystallization proce-
dure.p-Dimethylamine–and naphth-2-yl–
derived alkylidenes successfully engaged in
this reaction delivering nitroalkanes3j and3l
in good yields and stereoselectivities. A variety
of heteroaryl products, including furan-3-yl
(3m), thien-2-yl (3n), N-methyl pyrrol-2-yl (3o),
pyrid-2-yl (3p), and Boc-protected indol-3-yl
(3q), were obtained in equally efficient and
enantioselective reactions. Several ketone and
amidesubstratesweretestedinthisreaction
(Fig. 3). Aryl ketone products containing halo-
gens (3r), alkyl (3s), and electron-donating
groups (3t) were obtained in good to excellent
yields and enantioselectivities. Alkyl ketone
substrates were tolerated under the reaction
conditions, although nitroalkane (3u)was
obtained at a low enantiomeric ratio. A variety
of amides were suitable substrates for this
protocol. Piperidine and synthetically useful
Weinreb ( 19 ) amide substrates engaged in
fully enantio- and diastereoselective stereocon-
vergent crystallization to deliver the corre-
sponding nitroalkanes (3v and3w) in good
yields. Last, diisopropyl amide alkylidenes
delivered the corresponding nitroalkanes with
excellent efficiency (3x to 3z). In some in-
stances (3y and 3z), the diisopropyl amide
outperformed the morpholine amide (3f and
3k), and improvements in the enantio- and
diastereoselectivity were observed (see below).
These preliminary results suggest that the
identity of the acyl group could be tuned to
improve the efficiency of the crystallization
and can be a point of diversification when op-
timizing related CIDT reactions.
Extensive x-ray diffraction studies were un-
dertaken to evaluate product stereochemistry.
As predicted based on a paradigm involving
kinetic (catalyst) control of the static asym-
metric center, x-ray analysis showed that the
b-configuration is rigorously conserved for the
Michael addition products3a, 3f, 3h, 3i, 3j,
3n, 3t,and3x. The fluxional nature of the
a-stereocenter could in principle lead to differ-
ent results across the series based on solubil-
ity properties, but the outcomes here wereconsistent as well: The (S)-configuration
was observed at theb-keto amide methine
in the crystallized products.
Having established a method to control the
a-stereogenic center through thermodynamically
driven stereoconvergence, attention was then
directed to expanding this platform to the use
of prochiral nucleophiles. We began our studies
with the reaction ofp-trifluoromethylphenyl
alkylidene using nitroethane as the prochiral
nucleophile. Under identical conditions (see
the supplementary materials), nitroalkane
product4e crystallized from solution and
was obtained in 95% yield, 95:5 er, and 6:1 dr
after a single filtration. In situ monitoring
revealed that the Michael addition was rela-
tively fast, whereas diastereomerization and
crystallization were slower. Accordingly, in-
creasing the catalyst loading to 20 mol % and
changing the solvent to 2-methyltetrahydrofuran
improved the overall efficiency of the CIDT
(see the supplementary materials for addi-
tional details), presumably due to accelerated
interconversion of the diastereomeric mixture.
Under the optimized conditions, the desired
conjugate addition product was obtained in
excellent yield and stereoselectivity (Fig. 3).de Jesús Cruzet al., Science 376 , 1224–1230 (2022) 10 June 2022 2of7
Fig. 1. Proposed mechanism and preliminary studies.(A) Combination of Brønsted base enantioselective catalysis and crystallization-induced diastereomer
transformations for stereoconvergent reactions. (B) Successful combination of asymmetric organocatalysis and CIDT to realize thermodynamically driven
stereoconvergence.
RESEARCH | REPORT