This result represents a rare example of an
efficient noncascade Michael addition reac-
tion between prochiral nucleophilic and elec-
trophilic reaction partners in which the latter
is prochiral at both alkene carbon atoms ( 14 ).
Like the single CIDT reaction, this protocol
is applicable to a wide range of substrates
(Fig. 3). A variety of aryl alkylidenes delivered
nitroalkanes containing halogens (4b to 4d),
and electron-withdrawing (4e to 4g) func-
tional groups. Heterocyclic alkylidenes were
tolerated (4h to 4k), and substrates includ-
ing N-methyl pyrrole (4h), and furan-2-yl (4i),
furan-3-yl (4j), and Boc-protected indol-3-yl
(4k) were suitable substrates for this trans-
formation. Other prochiral nitroalkanes weretolerated in the doubly stereoconvergent crys-
tallization manifold and deliveredb-keto amides
containing other alkyl (4l), alcohol (4m), ester
(4n), and aryl (4o) functional groups in mod-
erate to good yields and stereoselectivities. A
variety of aryl ketone substrates bearing halo-
gens (4p), electron-withdrawing substitutents
(4q), and alkyl substituents (4r)werealsoviable
substrates for this transformation. Ethyl ketone
substrate delivered the desired nitroalkane in
excellent yield but lowstereoselectivities (4s).
Finally, a variety of amides were suitable sub-
strates for this transformation, and nitroalkane
adducts containing piperidine amide (4t), syn-
thetically useful Weinreb amide (4u), and
dicyclohexyl amide (4v) delivered the desired
conjugate addition products in good to excel-
lent yield and stereoselectivities.
Asinthenitromethaneadditions,x-raycrys-
tallography was indispensable in assessing
the stereochemical outcomes of the high-order
CIDTs. Effective regulation of the static asym-
metricb-center was again enabled by the Dixon
iminophosphorane catalyst. Theg-stereocenter
was conserved in the six of the seven analyzed
products, with the (S)-configuration regularly
observed at the nitronate center; the outlier
(g-(R) configuration) was nitroalkane4v.A
comparison of amides4g and 4v revealed
inverted configurations at both labile centers
intheproducts,triggeredonlybychanging
the amide identity (morpholine amide versus
dicyclohexyl amide). Dichotomous stereochem-
ical behavior at thea-center was observed in
CIDT reactions giving Michael adducts with
electron-poor (4e to 4g) and electron-neutral
or -rich aromatic groups (4d, 4i,and4m). The
assignments for those products not yet studied
by x-ray diffraction must be construed as ten-
tative at this point, but the ability to fully in-
vert the obtained major diastereomer in certain
cases is exciting, and future work will be directed
at understanding and exploiting the structural
factors that favor isomer-selective crystallization.
To gain further insight into the proposed
doubly stereoconvergent crystallization pro-
cess, a series of mechanistic experiments was
performed (Fig. 4). To understand the stereo-
lability ofCaandCginthepresenceofachiral
Brønsted base, deuterium/hydrogen exchange
studies using isotopically labeled, diastereo-
merically pure (dr >20:1) nitroalkane4b-d 2
were performed. Using CH 3 OH [20 equiva-
lents (equiv)] as the protic additive, >95% H
incorporation and stereochemical scrambling
at CaandCgwere observed in the presence of
the iminophosphoraneA, indicating that both
centers are susceptible to epimerization by the
catalyst under the reaction conditions (Fig. 4A).
We then turned our attention to understanding
the rates of epimerization and the efficiency of
the crystallization (Fig. 4B). An identical set of
parallel reactions were performed simulta-
neously and quenched at different time pointsde Jesús Cruzet al., Science 376 , 1224–1230 (2022) 10 June 2022 5of7
Fig. 4. Mechanistic insights into the origin of stereoselectivity.(A) Deuterium/hydrogen exchange
studies were performed to establish that the catalyst can epimerize both labile stereocenters. (B) An initial
diastereomeric mixture converges to a major diastereomer through crystallization-driven stereoconvergence.
(C) Epimerization through retro-Michael addition is mechanistically possible but not operative.
RESEARCH | REPORT