Catalyst-controlled asymmetric substitution reactions by
racemic nucleophiles: From singly to doubly enantioconvergent
processes
Haohua Huo
,
Bradley J. Gorsline
,
Gregory C. Fu
*
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena,
CA 91125, USA
Abstract
The construction of carbon–carbon bonds and the control of product stereochemistry are two of
the most important challenges in organic synthesis. The substitution reaction of an alkyl
electrophile by an alkyl nucleophile is a potentially powerful, convergent strategy for organic
synthesis; however, in practice, classical mechanisms for substitution reactions (S
N
1 and S
N
2
pathways) are limited in their ability to generate carbon–carbon bonds and to control product
stereochemistry when beginning with readily available racemic starting materials. We have
developed a chiral nickel catalyst that couples, for the first time, racemic electrophiles with
racemic nucleophiles to form carbon–carbon bonds in doubly stereoconvergent processes (i.e.,
affording a single stereoisomer of the product from two stereochemical mixtures of starting
materials).
One Sentence Summary:
The nickel-catalyzed coupling of two racemic partners to form a new carbon–carbon bond as a
single stereoisomer is described.
The development of effective methods for the synthesis of carbon–carbon bonds is a central
challenge in organic chemistry. Transition-metal catalysts for the construction of aryl–aryl
bonds have revolutionized organic synthesis (
1
,
2
), particularly in the pharmaceutical
industry, where they have enabled the straightforward diversification of lead structures and
thereby greatly facilitated drug development. Nevertheless, there is a growing recognition in
medicinal chemistry that, to improve the prospect for clinical success, it may be
advantageous to incorporate more sp
3
-hybridized carbons and more stereocenters into drug
candidates (
3
,
4
); furthermore, from a broader perspective, alkyl–alkyl bonds are even more
pervasive in organic molecules than are aryl–aryl bonds. In this report, we describe a new
*
Correspondence to: gcfu@caltech.edu.
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 within the paper, its Supplementary
Materials (experimental procedures and characterization data) and from the Cambridge Crystallographic Data Centre (
https://
www.ccdc.cam.ac.uk/structures
; crystallographic data are available free of charge under CCDC reference numbers 1935944 and
1935945).
HHS Public Access
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Published in final edited form as:
Science
. 2020 January 31; 367(6477): 559–564. doi:10.1126/science.aaz3855.
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dimension in metal-catalyzed nucleophilic substitution reactions, wherein a nickel catalyst
not only forges an alkyl–alkyl bond, but also controls the stereochemistry at both carbons of
the new bond, beginning with a 1:1 mixture of a racemic electrophile and a racemic
nucleophile, in a doubly enantioconvergent process.
A particularly straightforward strategy for the construction of alkyl–alkyl bonds is the
nucleophilic substitution of an alkyl electrophile by an alkyl nucleophile; if this approach
were entirely general, synthetic organic chemistry would be greatly simplified (e.g., Figure
1A). Unfortunately, classical pathways for nucleophilic substitution (S
N
1 and S
N
2 reactions)
are effective for only a very small subset of the possible electrophiles and nucleophiles, with
side reactions such as elimination (loss of H–X) often intervening instead (
5
).
When constructing alkyl–alkyl bonds via nucleophilic substitution, in addition to the
challenge of reactivity, in many instances there is also the challenge of stereoselectivity,
since the product can bear a stereocenter at one or both carbons of the new bond (e.g., Figure
1B). Again, uncatalyzed S
N
1 and S
N
2 reactions are not able to properly address this
challenge, as readily available racemic starting materials lead to racemic products.
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 of classical S
N
1 and S
N
2 pathways for the construction of alkyl–
alkyl bonds, both in terms of reactivity and stereoselectivity (
6
,
7
,
8
,
9
,
10
,
11
). Because the
simultaneous control of two stereocenters, beginning with two racemic partners, is an
especially challenging goal (Figure 1B–3), efforts to date have focused on the two individual
components of this ultimate objective, specifically, enantioconvergent substitution reactions
of racemic electrophiles and of racemic nucleophiles, each with achiral reaction partners
(Figure 1B–1 and Figure 1B–2, respectively). To date, a number of examples of
enantioconvergent substitutions of racemic electrophiles have been described (Figure 1B–1)
(
6
,
7
), whereas, in the case of racemic nucleophiles (Figure 1B–2), success has been
restricted to a single nucleophile, 2-zincated-
N
-Boc-pyrrolidine (
12
,
13
).
In this report, we describe progress in addressing both of the key remaining stereochemical
challenges (Figure 1B–2 and Figure 1B–3). First, we develop a catalyst that effects the
enantioconvergent substitution of alkyl electrophiles by a
family of racemic nucleophiles
(Figure 1C–1). Then, building on this foundation, we establish that
doubly
enantioconvergent substitution reactions of racemic electrophiles by racemic nucleophiles
can be accomplished wherein the chiral catalyst achieves alkyl–alkyl bond formation while
simultaneously controlling the stereochemistry at both termini of the newly formed bond
(Figure 1C–2).
The catalytic enantioselective synthesis of carbonyl compounds that bear a
β
,
β
-dialkyl
stereocenter is a topic of substantial interest, due to the presence of such subunits in a variety
of bioactive molecules (e.g., valnoctamide (
14
)) (
15
). Unfortunately, one particularly
powerful strategy for the generation of such targets, the conjugate addition of carbon
nucleophiles to
α
,
β
-unsaturated carbonyl compounds, requires relatively reactive
nucleophiles (Grignard reagents) in the case of
α
,
β
-unsaturated amides, due to their
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relatively low electrophilicity (
16
). Because Grignard reagents have comparatively poor
functional-group compatibility, the development of complementary approaches to the
catalytic asymmetric synthesis of amides that bear such
β
stereocenters is an important
objective.
In the initial phase of this program, we determined that a chiral nickel/(pyridine–oxazoline)
catalyst can achieve enantioconvergent substitution reactions of achiral alkyl iodides by
racemic
β
-zincated amides with good enantioselectivity and yield (Figure 2). Thus, under
our optimized conditions, a
β
-zincated pentanamide couples with
n
-hexyl iodide with 90%
ee and 95% yield (entry 1; 1.1 equiv of R–ZnBr: 88% ee, 85% yield). The high ee and high
yield, taken together, establish that the catalyst is providing enantioselectivity not via a
simple kinetic resolution of the racemic nucleophile, but that instead
both enantiomers of the
nucleophile are being converted to the product with good ee.
A wide array of primary alkyl iodides serve as suitable electrophiles in nickel-catalyzed
enantioconvergent substitution reactions by the racemic nucleophile (Figure 2, entries 1–17).
Substitution proceeds with good ee and yield with electrophiles that vary in steric demand
(entries 1–4) and that bear a broad range of functional groups (entries 5–17: an olefin, a silyl
ether, a trifluoromethyl group, an acetal, an ester, a ketone, a nitrile, an alkyl chloride, an
alkyl bromide, an imide, an amide, and a thiophene). Furthermore, through additive studies
(see the Supplementary Materials), we have determined that groups such as an aldehyde, an
aryl bromide, an aryl chloride, a benzofuran, 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 nucleophiles (Figure 1B–3), it is necessary that
secondary electrophiles undergo substitution by secondary nucleophiles; to date, examples
of metal-catalyzed secondary–secondary couplings are still quite scarce (
12
,
13
,
17
,
18
,
19
,
20
), with the exception of allylation reactions (
21
). When the conditions developed for
nickel-catalyzed enantioconvergent substitution reactions of primary alkyl iodides
(Conditions 1 in Figure 2) were applied to cyclohexyl iodide, good enantioselectivity but
moderate yield were observed (93% ee, 49% yield at 52% conversion). Small modifications
of the reaction conditions (Conditions 2 in Figure 2) led to improved yield with essentially
identical enantioselectivity (entry 18: 87% yield, 92% ee). With this method, the chiral
nickel/(pyridine–oxazoline) catalyst can achieve the enantioconvergent substitution of an
array of secondary alkyl iodides, including saturated oxygen and nitrogen heterocycles, by
the racemic nucleophile with good ee and yield (entries 18–23).
As described above, a single racemic nucleophile (2-zincated
N
-Boc-pyrrolidine) has been
shown to date to engage in enantioconvergent substitution reactions of alkyl nucleophiles
with alkyl electrophiles (Figure 1B–2) (
12
,
13
). In contrast, the present method is effective
for nucleophilic substitutions by a family of racemic nucleophiles, with both primary and
secondary alkyl iodides as electrophiles (Figure 2, entries 24–38). For example, the R
3
substituent of the nucleophile can vary in size or bear a functional group, and good
enantioselectivities are consistently observed (entries 24–33). Furthermore, the standard
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conditions can be applied to a variety of amides, including Weinreb amides (
22
) (entries 34–
38).
Clearly, the difficulty in developing an effective catalyst increases quite considerably as the
challenge progresses from: (1) simple (non-asymmetric) alkyl–alkyl bond formation (e.g.,
Figure 1A)
→
(2) bond formation plus control of stereochemistry at
one terminus of the new
carbon–carbon bond (Figure 1B–1 or Figure 1B–2)
→
(3) bond formation plus control of
stereochemistry at
both termini of the new carbon–carbon bond (Figure 1B–3). We
hypothesized that we might enhance the likelihood of accomplishing
doubly
enantioconvergent alkyl–alkyl bond formation (Figure 1B–3) if we focused our effort on the
use of electrophiles and nucleophiles that have successfully participated in the individual
dimensions of this challenge (Figure 1B–1 and 1B–2). We therefore examined the coupling
of a racemic propargylic electrophile (
23
) with a racemic
β
-zincated amide (this study).
Although the nickel/(pyridine–oxazoline)-based conditions that we developed to control
one
stereocenter with a racemic
β
-zincated amide (Figure 2) could not be applied directly to a
doubly enantioconvergent substitution reaction, we were able to achieve our goal with a
related nickel/(pyridine–oxazoline)-based method (Figure 3).
Under these conditions, the chiral nickel catalyst couples a 1.0:1.0 mixture of a racemic
electrophile and a racemic nucleophile to provide the substitution product with good
enantioselectivity, diastereoselectivity, and yield (Figure 3, entry 1: 92% ee, 98:2 dr, 74%
yield). Together, the values for stereoselectivity and yield establish that this substitution
reaction is indeed a doubly enantioconvergent process, wherein the catalyst is transforming
both enantiomers of the two racemic starting materials into a particular stereoisomer of the
desired product with good stereoselectivity.
A few practical points are worthy of note. On a gram scale, the doubly enantioconvergent
substitution reaction illustrated in entry 1 of Figure 3 proceeds with essentially identical
stereoselectivity and yield as does a reaction conducted on a 0.5-mmol scale. A higher
turnover number, although a lower yield, is observed when half of the standard loading of
the nickel catalyst is used. Finally, the method is not highly sensitive to traces of moisture or
air–the addition of 0.1 equiv of water or 0.5 mL of air leads to similar stereoselectivity and
only a modest drop in yield.
The scope of the method is fairly broad with respect to both the propargylic halide and the
β
-zincated amide. In the case of the propargylic halide, the R
2
substituent can vary in steric
demand (entries 1–4), and it can bear functional groups such as an ether, an acetal, an
alkyne, an alkene, an ester, an alkyl chloride, and a furan (entries 5–15). Furthermore, a
variety of silicon substituents on the alkyne are tolerated (entries 16–18).
Similarly, good stereoselectivity and yield are observed with a variety of
β
-zincated amides.
For example, the
β
substituent (R
3
) can range in size and can include a variety of functional
groups (Figure 3, entries 21–30). Furthermore, different substituents on the nitrogen of the
amide (including a Weinreb amide (
22
)) are tolerated (entries 19 and 20).
The products of these enantioconvergent couplings are readily converted into other useful
families of enantioenriched compounds (Figure 4). For example,
N
-aryl–
N
-alkylamides can
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be directly transformed in good yield without racemization into tertiary amines, primary
alcohols, and dialkylketones (
24
). Furthermore, alkynes are highly versatile synthetic
handles that are suitable for elaboration into a wide variety of useful functional groups (
25
).
Thus, the terminal alkyne (removal of the silicon protecting group: TBAF, THF, r.t.; 91%
yield) can be reduced to an alkene or an alkane (reactions
a
and
b
, respectively), engaged in
an azide cycloaddition (reaction
c
) (
26
,
27
) or a Sonagashira reaction (reaction
d
), or
converted into an amide (reaction
e
) (
28
), an indole, or a benzofuran (reaction
f
) (
29
).
In summary, we have described new dimensions for metal-catalyzed enantioconvergent
nucleophilic substitution reactions. In initial work, we have established that a family of
racemic secondary nucleophiles can couple with achiral electrophiles to form alkyl–alkyl
bonds with good enantioselectivity and yield (Figure 1C–1). Building upon this
development, we have also achieved
doubly enantioconvergent substitutions of racemic
secondary electrophiles by racemic secondary nucleophiles, thereby controlling vicinal
stereochemistry at both termini of the new carbon–carbon bond (Figure 1C–2). This study
thus demonstrates the viability of a retrosynthetic disconnection that has substantial strategic
potential in asymmetric synthesis.
Supplementary Material
Refer to Web version on PubMed Central for supplementary material.
ACKNOWLEDGMENTS:
We thank Dr. Stefan H. Jungbauer, Dr. Scott C. Virgil, Lawrence M. Henling, Dr. David G. Vander Velde, Dr.
Haolin Yin, Dylan J. Freas, and Wanji Zhang for assistance and discussions.
Funding:
Support has been provided by the National Institutes of Health (National Institute of General Medical
Sciences, R01–GM62871). H. H. thanks the Resnick Sustainability Institute at Caltech for fellowship support.
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Fig. 1. Alkyl–alkyl bond formation.
(
A
) A potentially powerful retrosynthetic disconnection. (
B
) Catalyst-controlled
stereoselectivity: Previous work. (
C
) Catalyst-controlled stereoselectivity: This study. ee =
enantiomeric excess, M = metal, R = substituent, X = leaving group.
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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.].
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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,
diastereomer ratio.
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Fig. 4. Transformations into other useful families of enantioenriched compounds
[All data represent the average of two experiments. The percent yield represents purified
product.].
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