ORGANIC CHEMISTRY
Doubly stereoconvergent crystallization enabled by
asymmetric catalysis
Pedro de Jesús Cruz, William R. Cassels, Chun-Hsing Chen, Jeffrey S. Johnson*
Synthetic methods that enable simultaneous control over multiple stereogenic centers are desirable
for the efficient preparation of pharmaceutical compounds. Herein, we report the discovery and
development of a catalyst-mediated asymmetric Michael addition/crystallization–induced diastereomer
transformation of broad scope. The sequence controls three stereogenic centers, two of which are
stereochemically labile. The configurational instability of 1,3-dicarbonyls and nitroalkanes, typically
considered a liability in stereoselective synthesis, is productively leveraged by merging enantioselective
Brønsted base organocatalysis and thermodynamic stereocontrol using a single convergent
crystallization. The synthesis of usefulg-nitrob-keto amides containing three contiguous stereogenic
centers is thus achieved from Michael acceptors containing two prochiral centers.
T
he development of robust, stereoselec-
tive synthetic methods that achieve
precise control in the simultaneous con-
struction of multiple stereogenic centers
is crucial to accelerating the discovery
of the next generation of drugs ( 1 – 7 ). The
increase in the stereochemical complexity
of such compounds has inspired academic
and industrial chemists to invent modern
and more efficient methods to facilitate their
construction. Enantioselective catalysis is a
powerful and broadly applicable paradigm
that has been used extensively, and the avail-
ability of myriad mechanistic manifolds that
can be used in the construction of C–Cand
C–heteroatom bonds render this blueprint
especially attractive ( 8 ). With notable excep-
tions ( 9 ), the discovery of enantioselective
catalytic reactions tends to focus on how to
maximize stereoselectivity (transition state
focus), whereas issues around postreaction
processing and optimization of physical prop-
erties of the products (ground state focus),
considerations that are critical in fields such
as polymer chemistry or process chemistry,
tend to be neglected. An unfortunate by-
product of this bifurcation in focus is that
even for relatively efficient reactions, the prac-
ticing chemist is often faced with laborious
energy- and resource-intensive purifications
that limit applicability on larger scales ( 10 ).
This issue is aggravated when valuable matter
is lost as undesired stereoisomers.
To circumvent the inherent issues of ordi-
nary purification techniques (e.g., flash col-
umn chromatography, high-pressure liquid
chromatography, etc.), the crystallization or
precipitation of products from reaction mix-
tures substantially simplifies isolation while
decreasing the amount of waste generated,
time spent, and energy required ( 11 ). For re-
actions that generate stereoisomeric mixtures,
simple recrystallizations cannot overcome
the fact that valuable material will be lost
as undesired stereoisomers; however, for cases
in which equilibration between stereoisomers
is mechanistically feasible, convergence to a
single stereoisomer of the product can be
achieved by engineering crystallization-induced
diastereomer transformations (CIDTs). CIDTs
are highly desirable in synthetic chemistry and
industrial applications because they provide
a means to generate highly stereoenriched
products without requiring additional tedi-
ous purifications ( 12 , 13 ). CIDT selectivity is
governed by crystallization thermodynamics:
Diastereomers undergoing CIDT contain one
or more static asymmetric centers and at least
(and commonly) one labile element of chiral-
ity that is subjected to equilibration. Imple-
mentation of CIDT strategies into synthetic
routes reduces the effort required to access a
single stereoisomer of a complex molecule:
100% theoretical yield of a single stereoiso-
meric product can be obtained from an initial
mixture of interconverting epimers. CIDT re-
actions are usually applied to specific prob-
lems in industrial chemistry, they are difficult
to predict, and generalizable non-auxiliary–
based CIDT methods are currently underdevel-
oped ( 12 , 13 ). We were interested in testing the
notion that by leveraging epimerization to
achieve stereoconvergence in complex systems,
we could accrue unique advantages through
the merged application of asymmetric catalysis
and crystallization-driven selectivity.
The base-catalyzed Michael reaction between
two prochiral reaction partners was judged
to be an ideal test case to evaluate such a hy-
pothesis: Asymmetric variants comprise atom
economical skeletal assemblies in organic
synthesis and have been shown to proceed
efficiently with a variety of catalytic platforms
( 14 ). For the projected application, the obliga-
tory electron-withdrawing groups in the start-
ing materials that enable the polar C−Cbondconstruction should also engender multiple
acidic C−H sites in the product required to es-
tablish the requisite complex equilibria; how-
ever, a parallel consideration highlighted in
Fig. 1A is that the complexity of the system
rises geometrically as the number of configu-
rationally unstable asymmetric centers grows
(I.a ⇆ I.b ⇆ I.c ⇆ P). For this reason, an
enantioselective reaction in which a dual-role
catalyst both mediates the installation of a
keystone stereocenter and induces completely
convergent crystallization of a product with
two labile centers is unknown ( 15 – 17 ). Here,
we disclose such an advance, in which the
combination of bifunctional Brønsted base
asymmetric organocatalysis ( 18 ) with CIDT
principles enables the stereoconvergent syn-
theses ofg-nitrob-keto amides containing three
contiguous asymmetric centers from two prochi-
ral reaction partners through CIDT reactions
with considerable scope and downstream utility.
Foundational studies were initiated to assess
the viability of a stereoconvergent crystalliza-
tion using nitromethane (1a) as a pronucleo-
phileandtheprochiral Michael acceptor 2
(Fig. 1B). Under homogeneous conditions (see
the supplementary material for details), the
conjugate addition product was obtained in
high yields, although the stereochemistry of
theb-dicarbonyl stereogenic center was un-
controlled, as expected [85% yield, 1.1:1 dia-
stereomeric ratio (dr)]. The use of ethereal
solvents [e.g., diethyl ether, methyltert-butyl
ether (MTBE)] allowed for selective crystalli-
zation of a single diastereomer of the conjugate
addition adduct directly from the reaction
medium (see the supplementary materials
for solvent studies). Reaction concentrations
and temperatures were moreover optimized
to prevent the spontaneous precipitation of
starting material and isomerically impure
product (if the reaction was too concen-
trated) or loss of product in the filtrate (if the
reaction was too dilute). Concurrent with
the optimization of the reaction-based crys-
tallization protocol, we also examined the fea-
tures of the Brønsted base catalyst and their
effect on the stereoselectivities and efficiency
of the protocol (see the supplementary mate-
rials for catalyst optimization). We found that
the chiral Dixon iminophosphoraneA ( 18 )
successfully engaged in the proposed stereo-
convergent crystallization, givingb-keto amide
3a with excellent yields and enantioselectivity
and diastereoselectivity [yield 96%, enantio-
meric ratio (er) 94:6, dr >20:1] after a single
filtration of the reaction.
This stereoconvergent crystallization pro-
tocol could be successfully applied to a range
of substituted alkylidenes that were converted
into their corresponding crystalline nitro ke-
tone adducts in good to excellent yields and
stereoselectivities (Fig. 2). Nitro ketones con-
taining halogens (3b and 3k), alkyl (3c andRESEARCH
de Jesús Cruzet al., Science 376 , 1224–1230 (2022) 10 June 2022 1of7
Department of Chemistry, University of North Carolina at
Chapel Hill, Chapel Hill, NC 27599, USA.
*Corresponding author. Email: [email protected]