Catalyst-controlled doubly enantioconvergent coupling of racemic alkyl nucleophiles and electrophiles

Article abstract of DOI:10.1126/science.aaz3855

Stereochemical control in the construction of carbon-carbon bonds between an alkyl electrophile and an alkyl nucleophile is a persistent challenge in organic synthesis. Classical substitution reactions via SN1 and SN2 pathways are limited in their ability to generate carbon-carbon bonds (inadequate scope, due to side reactions such as rearrangements and eliminations) and to control stereochemistry when beginning with readily available racemic starting materials (racemic products). Here, we report a chiral nickel catalyst that couples racemic electrophiles (propargylic halides) with racemic nucleophiles (b-zincated amides) to form carbon-carbon bonds in doubly stereoconvergent processes, affording a single stereoisomer of the product from two stereochemical mixtures of reactants.

Full text of DOI:10.1126/science.aaz3855

RESEARCH
compatibility, the development of complemen-
tary approaches to the direct catalytic asym-
metric synthesis of amides that bear such b
stereocenters is a worthwhile objective.
ORGANIC CHEMISTRY
Catalyst-controlled doubly enantioconvergent
coupling of racemic alkyl nucleophiles
and electrophiles
In the initial phase of this program, we de-
termined that a chiral nickel/(pyridine-oxazoline)
catalyst can achieve enantioconvergent sub-
stitution reactions of achiral alkyl iodides by
racemic b-zincated amides with good enan-
tioselectivity and yield (Fig. 2). Thus, under
our optimized conditions, a b-zincated penta-
namide coupled with n-hexyl iodide in 90%
enantiomeric excess (ee) and 95% yield (entry 1).
The ee and yield values together establish that
the catalyst is providing enantioselectivity not
via a simple kinetic resolution of the racemic
nucleophile but instead by selective conversion
of both enantiomers of the nucleophile into a
single enantiomer of the product.
Haohua Huo, Bradley J. Gorsline, Gregory C. Fu*
Stereochemical control in the construction of carbon-carbon bonds between an alkyl electrophile and an
alkyl nucleophile is a persistent challenge in organic synthesis. Classical substitution reactions via
SN1 and SN2 pathways are limited in their ability to generate carbon-carbon bonds (inadequate scope,
due to side reactions such as rearrangements and eliminations) and to control stereochemistry when
beginning with readily available racemic starting materials (racemic products). Here, we report a chiral
nickel catalyst that couples racemic electrophiles (propargylic halides) with racemic nucleophiles
(b-zincated amides) to form carbon-carbon bonds in doubly stereoconvergent processes, affording a
single stereoisomer of the product from two stereochemical mixtures of reactants.
A wide array of primary alkyl iodides served
as suitable electrophiles in this nickel-catalyzed
enantioconvergent substitution reaction by a
racemic nucleophile (Fig. 2, entries 1 to 17). Sub-
stitution proceeded with good ee and yield with
electrophiles that varied in steric demand (en-
tries 1 to 4) and bore a broad range of functional
groups (entries 5 to 17: an olefin, a silyl ether, a
trifluoromethyl group, an acetal, an ester, a ke-
tone, a nitrile, an alkyl chloride, an alkyl bromide,
an imide, an amide, and a thiophene). Further-
more, through additive studies (see table S3),
we determined that groups such as an aldehyde,
an aryl bromide, an aryl chloride, a benzo-
furan, an epoxide, an indole, and a tertiary
amine are compatible with the method.
To achieve the challenging goal of catalyst-
controlled doubly enantioconvergent couplings
of racemic electrophiles with racemic nucleo-
philes (Fig. 1A, iii), it is necessary for secondary
electrophiles to undergo substitution by second-
ary nucleophiles; to date, examples of metal-
catalyzed secondary-secondary couplings are
still scarce (13, 14, 19–22), with the exception
of allylation reactions (23). When the condi-
tions developed for nickel-catalyzed enantio-
convergent substitution reactions of primary
alkyl iodides (conditions 1 in Fig. 2) were ap-
plied to cyclohexyl iodide, good enantioselec-
tivity but moderate yield were observed (93% ee,
49% yield at 52% conversion). Small modifi-
cations of the reaction conditions (conditions
2 in Fig. 2) led to improved yield with essen-
tially identical enantioselectivity (entry 18: 87%
yield, 92% ee). With this method, the chiral nickel/
(pyridine-oxazoline) catalyst achieved the enan-
tioconvergent substitution of a range of second-
ary alkyl iodides, including saturated oxygen
and nitrogen heterocycles, by the racemic
nucleophile with good ee and yield (entries
18 to 23).
ransition metal catalysts for the construc-
tion of aryl-aryl bonds have revolution-
ized organic synthesis (1, 2), particularly
in the pharmaceutical industry, where
these reactions have enabled the straight-
racemic partners is an especially challenging
goal (Fig. 1A, iii), efforts have until now fo-
cused on the two individual components of
this ultimate objective, specifically, enantio-
convergent substitution reactions of either
racemic electrophiles or racemic nucleophiles,
each with achiral reaction partners (Fig. 1A,
i and ii, respectively). To date, a range of ex-
amples of enantioconvergent substitutions of
racemic electrophiles have been described
(Fig. 1A, i) (6, 7), whereas in the case of alkyl-
alkyl couplings of racemic nucleophiles (Fig.
1A, ii), success has been restricted to a single
nucleophile, 2-zincated-N-Boc-pyrrolidine
(13–15).
Here, we describe progress in addressing
the two key stereochemical challenges re-
maining in such alkyl-alkyl bond formations
(Fig. 1A, ii and iii). First, we develop a catalyst
that effects enantioconvergent substitutions of
achiral alkyl electrophiles by a family of racemic
nucleophiles (Fig. 1B, i). Then, building on this
foundation, we establish that doubly enantio-
convergent substitution reactions of racemic
electrophiles by racemic nucleophiles can be
accomplished, whereby the chiral catalyst
achieves alkyl-alkyl bond formation while
simultaneously controlling the stereochemistry
at both termini of the newly formed bond
(Fig. 1B, ii).
The catalytic enantioselective synthesis of
carbonyl compounds that bear a b,b-dialkyl
stereocenter is a topic of substantial interest,
owing to the presence of such subunits in a
variety of bioactive molecules (e.g., valnocta-
mide) (16, 17). Unfortunately, one particularly
powerful strategy for the generation of such
targets, the conjugate addition of carbon
nucleophiles to a,b-unsaturated carbonyl
compounds, requires comparatively reactive
nucleophiles (Grignard reagents) in the case of
a,b-unsaturated amides, because of their rela-
tively low electrophilicity (18). Because Grignard
reagents have somewhat poor functional-group
T
forward diversification of lead structures and
thereby greatly facilitated drug development.
Nevertheless, there is growing recognition in
medicinal chemistry that, to improve the pros-
pect for clinical success, it may be advantageous
to incorporate more sp3-hybridized carbons
and more stereocenters into drug candidates
(3, 4). Furthermore, from a broader perspec-
tive, alkyl-alkyl bonds are even more perva-
sive in organic molecules than are aryl-aryl
bonds.
A particularly straightforward strategy for
the construction of alkyl-alkyl bonds is the
nucleophilic substitution reaction of an alkyl
electrophile with an alkyl nucleophile. Un-
fortunately, classical pathways for nucleophilic
substitution (SN1 and SN2 reactions) are ef-
fective for only a very small subset of the
possible electrophiles and nucleophiles, with
side reactions such as elimination (loss of H–X;
X, leaving group) or rearrangement often inter-
vening instead (5). Furthermore, products of
alkyl-alkyl coupling often bear a stereocenter
at one or both carbons of the new bond, where-
as uncatalyzed SN1 and SN2 reactions typi-
cally produce racemic products from racemic
reactants.
Recently, we and others have demonstrated
that transition metals, in particular earth-
abundant nickel, can catalyze nucleophilic
substitution reactions of alkyl electrophiles
and address key shortcomings (reactivity and
stereoselectivity) of classical SN1 and SN2 path-
ways for the construction of alkyl-alkyl bonds
(6–12). Because the simultaneous control of
two stereocenters in reactions between two
As described above, a single racemic alkyl
nucleophile (2-zincated N-Boc-pyrrolidine)
has previously been shown to engage in enan-
tioconvergent substitution reactions with alkyl
Division of Chemistry and Chemical Engineering, California
Institute of Technology, Pasadena, CA 91125, USA.
*Corresponding author. Email: gcfu@caltech.edu
Huo et al., Science 367, 559–564 (2020)
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Fig. 1. Alkyl-alkyl bond formation. (A) Catalyst-controlled stereoselectivity—previous work. (B) Catalyst-controlled stereoselectivity—this study. ee, enantiomeric
excess; M, metal; R, substituent; X, leaving group.
electrophiles (Fig. 1A, ii) (13, 14). In contrast, the
present method is effective for nucleophilic
substitutions by a family of racemic nucleo-
philes, with both primary and secondary alkyl
iodides as electrophiles (Fig. 2, entries 24 to
38). For example, the R3 substituent of the
nucleophile can vary in size or bear a func-
tional group, and good enantioselectivities
were consistently observed (entries 24 to 33).
Furthermore, the standard conditions can
be applied to a variety of amides, including
Weinreb amides (24) (entries 34 to 38).
Turning next to doubly enantioconvergent
alkyl-alkyl bond formation (Fig. 1A, iii), we
hypothesized that we might enhance the like-
lihood for success if we focused our efforts on
the use of electrophiles and nucleophiles that
have successfully participated in the indi-
vidual dimensions of this challenge (Fig. 1A,
i and ii). We therefore examined the cou-
pling of a racemic propargylic electrophile (25)
with a racemic b-zincated amide. Although
the nickel/(pyridine-oxazoline)–based condi-
tions that we developed to control one ste-
reocenter with a racemic b-zincated amide
(Fig. 2) could not be applied directly to the
doubly enantioconvergent substitution reac-
tion, we were able to achieve our goal with a
related nickel/(pyridine-oxazoline)–based
method (Fig. 3).
[Fig. 3, entry 1: 92% ee, 98:2 diastereomeric
ratio (dr), 74% yield]. Together, the values
for stereoselectivity and yield establish that
this substitution reaction is indeed a doubly
enantioconvergent process, whereby the cat-
alyst is transforming both enantiomers of the
two racemic starting materials into a partic-
ular stereoisomer of the desired product with
good stereoselectivity.
On a gram scale, the doubly enantioconver-
gent substitution reaction illustrated in entry
1 of Fig. 3 proceeded with essentially identical
stereoselectivity and yield as for a reaction con-
ducted on a 0.5-mmol scale. A higher turnover
number but a lower yield were observed when
half of the standard loading of the nickel cat-
alyst was used. The method was not highly
sensitive to traces of moisture or air—the ad-
dition of 0.1 equivalent of water or 0.5 ml of
air led to similar stereoselectivity and only a
modest drop in yield.
The scope of the method proved fairly broad
with respect to both the propargylic halide
and the b-zincated amide. In the case of the
propargylic halide, the R2 substituent could
vary in steric demand (Fig. 3, entries 1 to 4) and
bear functional groups such as an ether, an
acetal, an alkyne, an alkene, an ester, an alkyl
chloride, and a furan (entries 5 to 15). Further-
more, a variety of silicon substituents on the
alkyne were tolerated (entries 16 to 18).
functional groups (Fig. 3, entries 21 to 30).
Furthermore, different substituents on the
nitrogen of the amide [including a Weinreb
amide (24)] were tolerated (entries 19 and 20).
Although we have not yet carried out in-
depth mechanistic studies of this process, we
have determined that no EPR-active species
were observed during a reaction in progress,
which is consistent with our previous mech-
anistic investigations of nickel-catalyzed enan-
tioconvergent coupling reactions of racemic
electrophiles, wherein a diamagnetic organo-
nickel(II) complex was suggested to be the pri-
mary resting state of nickel during catalysis
(26, 27). Furthermore, when a coupling was
conducted in the presence of TEMPO (2,2,6,6-
tetramethyl-1-piperidinyloxy), adducts derived
from both the electrophile and the nucleophile
were observed, consistent with the generation
of organic radicals from each reaction partner
(Fig. 3, mechanistic data); the intermediacy
of organic radicals provides a pathway for
enantioconvergence of the two racemic reac-
tants. In order for the chiral nickel catalyst to
achieve good stereoselectivity in the case of
the nucleophile, it must distinguish between
two alkyl substituents (R3 and CH2CONR2 in
Fig. 3), which can be challenging in asymmetric
synthesis. We hypothesize that bidentate L2,
rather than a tridentate ligand [e.g., a pybox
(7)], is effective, because the lower coordina-
tion number of the ligand facilitates complex-
ation of the oxygen of the amide to nickel in the
stereochemistry-determining step, thereby en-
abling differentiation of the alkyl groups.
Under these conditions, the chiral nickel
catalyst coupled a 1.0:1.0 mixture of a racemic
electrophile and a racemic nucleophile to pro-
vide the substitution product with good enan-
tioselectivity, diastereoselectivity, and yield
Similarly, good stereoselectivity and yield
were observed with a variety of b-zincated
amides. For example, the b substituent (R3)
could range in size and include a variety of
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Fig. 2. Enantioconvergent substitution reactions of racemic nucleophiles. Couplings were generally conducted using 0.6 mmol of the electrophile. All data
represent the average of two experiments. The percent yield represents purified product. Bn, benzyl; Boc, tert-butoxycarbonyl; i-Bu, isobutyl; t-Bu, tert-butyl; Cy,
cyclohexyl; Et, ethyl; n-Hex, n-hexyl; Me, methyl; Ph, phenyl; i-Pr, isopropyl; n-Pr, n-propyl; TBS, tert-butyldimethylsilyl.
Huo et al., Science 367, 559–564 (2020)
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Fig. 3. Doubly enantioconvergent substitution reactions of racemic electrophiles by racemic nucleophiles. Couplings were generally conducted using
0.5 mmol of the electrophile. All data represent the average of two experiments. The percent yield represents purified product. dr, diastereomeric ratio; Ac, acetyl;
TIPS, triisopropylsilyl.
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ACKNOWLEDGMENTS
Fig. 4. Transformations into other useful families of enantioenriched compounds. The percent yield
represents purified product (average of two experiments). Tf, triflate; DTBMP, 2,6-di-t-butyl-4-methylpyridine;
AZT, azidothymidine; TC, thiophene-2-carboxylate; TMG, 1,1,3,3-tetramethylguanidine.
We thank S. H. Jungbauer, S. C. Virgil, L. M. Henling,
D. G. Vander Velde, H. Yin, D. J. Freas, W. Zhang, and Z. Yang
for assistance and discussions. Funding: Support has been
provided by the National Institutes of Health (National Institute
of General Medical Sciences, R37–GM62871). H.H. thanks the
Resnick Sustainability Institute at Caltech for fellowship
support. Author contributions: H.H. and B.J.G. performed
all experiments. H.H. and G.C.F. wrote the manuscript. All
authors contributed to the analysis and the interpretation of the
results. Competing interests: The authors declare no
competing interests. Data and materials availability: The
data that support the findings of this study are available in
the paper, in its supplementary materials (experimental
procedures and characterization data), and from the Cambridge
Crystallographic Data Centre (CCDC) (www.ccdc.cam.ac.uk/
structures; crystallographic data are available free of charge
under CCDC reference numbers 1935944 and 1935945).
The products of these enantioconvergent
couplings were readily converted into other
useful families of enantioenriched compounds
(Fig. 4). For example, N-aryl–N-alkylamides
could be directly transformed in good yield
without racemization into tertiary amines,
primary alcohols, and dialkylketones (28).
Furthermore, alkynes are highly versatile syn-
thetic handles that are suitable for elaboration
into a wide variety of useful functional groups
(29). Thus, the terminal alkyne (removal of
the silicon protecting group: tetra-n-buty-
lammonium fluoride, tetrahydrofuran, room
temperature; 91% yield) could be reduced to an
alkene or an alkane (Fig. 4, reactions a and b,
respectively); engaged in an azide cycload-
dition (reaction c) (30, 31) or a Sonogashira
reaction (reaction d); or converted into an amide
(reaction e) (32), an indole, or a benzofuran
(reaction f) (33).
Future studies will focus on expanding the
scope of these doubly enantioconvergent alkyl-
alkyl couplings to include a wide range of ac-
tivated and unactivated electrophiles, as well as
a broad array of conjugated and nonconjugated
nucleophiles. Success in these endeavors could
transform the enantioselective synthesis of or-
ganic compounds.
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SUPPLEMENTARY MATERIALS
science.sciencemag.org/content/367/6477/559/suppl/DC1
Materials and Methods
Supplementary Text
Figs. S1 and S2
Tables S1 to S5
Spectral Data
References (34–40)
4 September 2019; accepted 26 November 2019
10.1126/science.aaz3855
Huo et al., Science 367, 559–564 (2020)
31 January 2020
5 of 5

Catalyst-controlled doubly enantioconvergent coupling of racemic alkyl nucleophiles and
electrophiles
Haohua Huo, Bradley J. Gorsline and Gregory C. Fu
Science 367 (6477), 559-564.
DOI: 10.1126/science.aaz3855
Convergent coupling
Metal-catalyzed coupling of two flat aromatic rings is one of the most versatile and widely applied chemical
reactions. Efforts to extend this protocol to alkyl-alkyl coupling are complicated by the prospect of forming two different
three-dimensional configurations at each carbon center, corresponding to four possible products. Huo et al. now report
that a chiral nickel catalyst can convergently link two mirror-image pairs of alkyl reactants into just one product (see the
Perspective by Xu and Watson). The specific reaction couples propargylic halides to zinc-activated aliphatic amides.
Science, this issue p. 559; see also p. 509
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