Asymmetric synthesis via stereospecific C-N and C-O bond activation of alkyl amine and alcohol derivatives

Article abstract of DOI:10.1039/C8CC07093H

This perspective showcases our development of benzylic and allylic amine and alcohol derivatives as electrophiles for stereospecific, nickel-catalyzed cross-coupling reactions, as well as the prior art that inspired our efforts. The success of our effort

Full text of DOI:10.1039/C8CC07093H

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
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Asymmetric Synthesis via Stereospecific C–N and C–O Bond
Activation of Alkyl Amine and Alcohol Derivatives
Sarah M. Pounda and Mary P. Watson*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
This perspective showcases our development of benzylic and allylic amine and alcohol derivatives as electrophiles for
stereospecific, nickel-catalyzed cross-coupling reactions, as well as the prior art that inspired our efforts. The success of
our effort has relied on the use of benzyl ammonium triflates as electrophiles for cross-couplings via C–N bond activation
and benzylic and allylic carboxylates for cross-couplings via C–O bond activation. Our work, along with others’ exciting
discoveries, has demonstrated the potential of stereospecific, nickel-catalyzed cross-couplings of alkyl electrophiles in
asymmetric synthesis, and enables efficient generation of both tertiary and quaternary stereocenters.
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1. Introduction
Transition metal-catalyzed cross-couplings have revolutionized
organic chemistry, allowing creative and nonobvious
disconnections in organic synthesis. Compared to cross-
couplings of sp2-hybridized carbons,1 cross-couplings of sp3-
hybridized carbons are much less developed due to
challenging oxidative addition and reductive elimination steps,
along with competitive side reactions.2 However, cross-
couplings of sp3-hybridized carbons are gaining increased
attention.3
In particular, the use of alkyl reagents in transition metal-
catalyzed cross-coupling reactions provides opportunities for
the incorporation of stereochemical information. As
complementary
approaches,
enantioselective
and
stereospecific cross-couplings offer distinct advantages
(Scheme 1a).4 Enantioselective cross-couplings rely on catalyst-
controlled asymmetric induction and allow for the first
installation of stereochemistry in a molecule. Stereospecific
reactions are substrate-controlled with respect to product
stereochemistry, and conserve stereochemical information
while building complexity. Because a stereocenter has been
set previously, stereospecific cross-couplings do not require
steric or electronic differentiation to afford high
enantiospecificity (es).5 This makes stereospecific cross-
couplings particularly useful for late-stage synthesis and for
generating stereocenters where enantioselective catalysis
fails.
When forming C(sp3)–C(sp2) bonds, either the electrophile
or nucleophile can be enantioenriched. A number of methods
have been developed for the use of secondary and tertiary
alkylmetal reagents in stereospecific reactions (Scheme 1b),
which have been recently reviewed.6 This perspective will
focus instead on our use of enantioenriched electrophiles in
stereospecific transition metal-catalyzed cross-coupling
reactions, as well as precedent that inspired our work and
related concurrent examples (Scheme 1c).
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Although the SN2 reaction is of historical and pedagogical
importance, the stereospecific reaction of secondary
a
electrophile to generate a tertiary carbon stereocenter is an
atypical disconnection. Elimination (E2) competes with
stereospecific substitution. This challenge is even more
pronounced for the preparation of all-carbon quaternary
stereocenters from tertiary electrophiles.7 By offering an
alternative mechanism, transition metal catalysis offers an
opportunity to expand the utility of stereospecific
substitutions to secondary and tertiary enantioenriched
electrophiles, while also enabling the use of mild and
functional group-tolerant nucleophilic partners. Palladium-
catalyzed cross-couplings of alkyl halides are typically
stereospecific and proceed with inversion at the stereogenic
center.8 However, as the steric hindrance of the electrophile
increases, the energy barrier for oxidative addition increases,
making palladium-catalyzed cross-couplings of secondary and
tertiary halides more challenging.9 On the other hand, first-
row transition metal complexes are highly reactive toward
oxidative addition and slow to undergo β-hydride
elimination,4c,9 which makes them ideal catalysts for cross-
coupling reactions involving alkyl electrophiles. However,
oxidative addition of nickel complexes with alkyl halides
typically proceeds through radical intermediates, resulting in
stereoablative reactions.10
report in 1995, Trost and coworkers reported a nickel-
catalyzed cross-coupling of tertiary allylic amines with boronic
acids wherein the boronic acid served as both the nucleophile
and a Lewis acid activating group for the amine.15 Tian and
coworkers utilized this strategy for the activation of allylic
amines in palladium-catalyzed cross-couplings with boronic
acids16 and substitutions with other nucleophiles.17
Subsequently, Tian and coworkers proposed that the
presence of a sulfonyl group would activate allylic amines
toward C(sp3)–N bond cleavage.18 Reaction of enantioenriched
Instead, non-traditional electrophiles—namely, amine and
alcohol derivatives—provide a complementary alternative to
alkyl halides and an entry into stereospecific reactions to
afford tertiary and quaternary stereocenters. Amines and
alcohols are generally air- and moisture-stable and have low
toxicity. Additionally, although few methods exist for the
preparation of enantiomerically enriched alkyl halides, amines
and alcohols are readily available in high enantiopurity.3a
Furthermore, amine and alcohol derivatives can engage in
polar, two-electron oxidative addition with low-valent nickel
complexes, thereby enabling stereospecific transformations.11
With this review, we aim to showcase the work that we and
others have conducted to expand the synthetic utility of
enantioenriched amine- and alcohol-based electrophiles in
transition metal-catalyzed cross-coupling reactions to prepare
tertiary and quaternary stereocenters.
allylic sulfonamide
1
with catalytic copper(I) iodide and
as a single regioisomer
phenylmagnesium bromide afforded
2
in 84% yield (Scheme 2a). This transformation proceeded with
complete inversion of configuration at the allylic stereocenter.
In applying this strategy to benzylic amines, a second tosyl
group was necessary to activate the more stubborn benzylic C–
N bond. Arylation of enantioenriched benzylic sulfonimide
with 4-methoxyphenylmagnesium bromide also proceeded
with inversion of configuration to afford diarylethane
3
4
(Scheme 2b), albeit in modest stereochemical fidelity. This
pivotal work demonstrated that a benzylic C–N bond could
indeed be converted to a C–C bond stereospecifically, but that
considerable activation of the nitrogen was necessary.
2.2 Secondary and Tertiary Aziridines
At the time we began our work, aziridines were the only other
electrophiles that had been demonstrated in cross-couplings
via C–N bond activation. Like allylic and benzylic amines,
aziridines are versatile synthetic intermediates, especially for
the preparation of valuable β-substituted amines. Like
epoxides, aziridines experience significant ring strain (26–27
kcal/mol),19 which renders them susceptible to nucleophilic
ring-opening. Transition metal catalysis offers an alternative to
classic aziridine alkylation and arylation, which require strong
nucleophiles and often afford poor regioselectivity.20 However,
the development of transition metal-catalyzed cross-coupling
reactions of aziridines faces challenging oxidative addition and
competitive β-hydride elimination.21 In seminal reports,
2. C(sp3)–N Bond Activation of Amine Derivatives
2.1 Secondary Allylic and Benzylic Amines
The carbon–nitrogen (C–N) bond is ubiquitous, present in
many organic and biological molecules.12 Although C–N bonds
are typically considered inert due to high bond dissociation
energies and poor leaving group ability,13 significant attention
has been given to the activation and use of C(sp2)–N bonds in
transition metal-catalyzed cross-coupling reactions.14 In
contrast, the use of alkyl amines as electrophiles in cross-
coupling reactions has been much less examined, and much of
this focus has been on allylic amine substrates. In a seminal
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Hillhouse22 and Wolfe23 demonstrated that aliphatic N-sulfonyl when enantiopure aziridine
ARTICLE
5
was subjected to the cross-
aziridines undergo oxidative addition with stoichiometric coupling conditions, amine
7
was generated in only 11% ee.
was unchanged. The
nickel or palladium species to form isolable The enantiomeric excess of recovered
5
azametallocyclobutanes, wherein the metal has inserted into authors thus proposed that oxidative addition is irreversible
the less hindered C–N bond. Alper and coworkers also with a subsequent stereoablative step.
demonstrated that carbonyl insertion could outcompete β-
Expanding on these studies, Doyle and Huang then
hydride elimination in rhodium-catalyzed reactions of styrenyl reported a nickel-catalyzed Negishi cross-coupling of 1,1-
aziridines to form β-lactams with high regioselectivity for disubstituted
aziridines,
affording
β-substituted
insertion into the benzylic C–N bond.24
phenethylamines.27 The electron-deficient olefin ligand Fro-DO
was crucial in achieving C–C bond formation over β-hydride
elimination. To test the stereospecificity of the cross-coupling
reaction, the authors subjected enantioenriched aziridine
the reaction conditions with n-butylzinc bromide (Scheme 3b).
However, product was obtained in only 20% ee. Although
8 to
9
this was the first example of a transition metal-catalyzed cross-
coupling of a benzylic electrophile forming an all-carbon
quaternary stereocenter with any stereospecificity, the low
stereochemical fidelity indicated that a stereoablative or
epimerization step was competitive with the stereospecific
pathway. Recovered
8 was enantiopure, which is consistent
with the transformation proceeding through an irreversible
oxidative addition, at or after which a stereoablative step
occurs. The authors proposed that the most likely mechanism
for oxidative addition is single-electron transfer (SET) from a
nickel(I) species to generate a stabilized benzylic radical
intermediate. They also proposed that by using a chiral ligand,
this cross-coupling could be stereoconvergent. Indeed, when
racemic aziridine 10 was subjected to the reaction conditions
with chiral electron-deficient olefin ligand 11, β-substituted
phenethylamine 12 was formed in 73% yield and 27% ee
(Scheme 3c). Notably, this result is the first example of a
stereoselective cross-coupling with
a tertiary, non-allylic
electrophile. Based on this result, Doyle and coworkers
developed an enantioselective nickel-catalyzed reductive
cross-coupling of styrenyl aziridines and aryl iodides, which
proceeds with good yields and enantioselectivities.28
Building on this precedent, Doyle and Huang reported the
first catalytic activation of an aziridine C(sp3)–N bond in a
cross-coupling reaction.25 Under nickel catalysis, styrene-
derived N-tosyl aziridines underwent a Negishi cross-coupling
In a complementary example, Minakata and coworkers
demonstrated a stereospecific, palladium-catalyzed Suzuki–
Miyaura cross-coupling of styrenyl aziridines and aryl boronic
acids.29 N-heterocyclic carbene (NHC) ligands efficiently
promoted the cross-coupling while suppressing β-hydride
with alkylzinc reagents. Use of dimethylfumarate
6 (Scheme
3a) as ligand was essential; this electron-deficient olefin is
proposed to accelerate the challenging reductive elimination.26
elimination. Reaction of enantioenriched aziridine
5 with p-
tolylboronic acid afforded β-substituted amine 15 in 74% yield
The reaction went with complete regioselectivity for cleavage and complete stereochemical fidelity (Scheme 4). The cross-
of the benzylic C–N bond. With respect to stereospecificity, coupling proceeded with inversion of configuration, consistent
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with oxidative addition occurring via an SN2- or SN2’-type yield via methylation of the corresponding chiral tertiary
mechanism to give intermediates 13 or 14 amines and did not require chromatographic purification.
Three transition metal-catalyzed cross-coupling reactions The combination of Ni(cod)2 and monodentate
.
a
of unactivated aliphatic N-sulfonyl aziridines have also been phosphine, P(o-Tol)3, proved optimal for catalyzing the cross-
reported. Doyle30 and Jamison31 reported nickel-catalyzed coupling, affording enantioenriched diarylmethanes in good
Negishi cross-couplings employing aryl- and alkylzinc reagents, yields, high stereochemical fidelity, and inversion of
respectively. Michael also reported a palladium-catalyzed configuration at the benzylic stereocenter (Scheme 6). The
Suzuki–Miyaura cross-coupling of alkyl aziridines and weakly coordinating triflate counterion gave the best
arylboronic acids.32 Unlike the cross-coupling reactions of reactivity. We hypothesize that this may be due to more facile
benzylic aziridines, these cross-couplings of unactivated alkyl coordination of the boronate to a more electrophilic Ni(II)
aziridines displayed complete regioselectivity for oxidative intermediate. Either K3PO4 or CsF could serve as the base;
addition into the least substituted C(sp3)–N bond to afford however, if base-sensitive functional groups were present, the
linear products.
use of CsF proved advantageous. The mild conditions tolerated
2.3 Secondary Benzylic Ammonium Salts
The work by Tian, Doyle, Minakata, and others impressively
demonstrates the potential of using benzylic amine derivatives
and azirdines as substrates for stereospecific cross-couplings
to yield highly enantioenriched diarylalkanes. This prior art
also taught us that both the nitrogen activating group and the
catalyst components would be crucial in achieving high
stereochemical fidelity in such cross-couplings. We needed to
identify a nitrogen leaving group and conditions that would
not lead to radical intermediates, epimerization, or β-hydride
elimination. We proposed that the C(sp3)–N bond of benzyl
amines, when activated as an ammonium salt, would undergo
nickel-catalyzed cross-coupling reactions in a stereospecific
fashion. Cross-coupling reactions of aryl ammonium salts were
known,33 and the trimethylammonium group was unlikely to
undergo SET to form alkyl radical intermediates due to the lack
of an available π* orbital. However, although allylic and
benzylic ammonium salts had been utilized as electrophiles in
reactions with organometallic nucleophiles,34 their use in
transition metal-catalyzed cross-coupling reactions was limited
to a single example. Csákÿ and coworkers demonstrated the
a wide range of functional groups, including ether 20, alkene
21, ester 22, and nitrile 23, highlighting the advantage of an
arylboronic acid over a Grignard partner. In addition to
arylboronic acids, a vinylboronic acid underwent the cross-
coupling to give 24 in 96% yield and >99% es. To expand the
ammonium triflate scope beyond those with napthyl
rhodium-catalyzed
cross-coupling
of
gramine-derived
ammonium iodide 16 with phenylboronic acid, affording 3-
benzylindole 17 in 85% yield (Scheme 5).35 Notably, this
gramine-derived substrate benefits from weakening of the C–
N bond by the indole, and no other benzylic ammonium salts
were included.
Our goal was to develop a general method for the
stereospecific cross-coupling of benzylic electrophiles and
functional group-tolerant coupling partners.36 Although great
progress had been made with Grignard18,37–39 and organozinc
coupling partners,8c,40–41 no enantioselective cross-couplings of
benzylic electrophiles were known with arylboronic reagents
at the time we began our work, and there was only a single
stereospecific example of
a
benzylic
α-cyanohydrin
mesylate.8b Highly enantioenriched benzylic amines are ideal
electrophile precursors, because they are readily prepared, are
stable to long-term storage, and offer a functional group
handle orthogonal to halides and ethers.12,42 Enantioenriched
ammonium triflates 18 were readily prepared in quantitative
substitution—a common limitation in stereospecific cross-
couplings37–40,43–44—higher catalyst loadings and a change of
t
ligand to Bu-XantPhos were required. Using these modified
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conditions, diarylethanes 25 and 26 were obtained with excellent boronic acids underwent the cross-coupling to afford products 30
stereochemical fidelity albeit lower yields. Additionally, these and 31 in good yields and excellent stereochemical fidelity. Finally,
conditions allowed selective C–N bond activation in the presence of although the stereochemical fidelity was slightly diminished, non-
ethers, highlighting the orthogonal functionality of ammonium naphthyl-substituted ammonium triflates underwent the reaction
salts.
with moderate to good yields. Electron-poor substrates were most
efficient (32), but the cross-coupling also afforded p-
methoxyphenyl-substituted 33 in 53% yield.
Expanding the utility of benzylic ammonium salts in cross-
coupling reactions, we also developed a stereospecific, nickel-
catalyzed Miyaura borylation.46 As the first example of a cross-
coupling utilizing
a benzylic electrophile to afford highly
enantioenriched organoboranes, this provides a complementary
method to previous methods for the asymmetric synthesis of
benzylic boronate esters.47 Reaction of ammonium triflates 34 with
B2pin2, Ni(cod)2, and PPh3 afforded enantioenriched benzylic
pinacol boronates in good yields and stereochemical fidelity
(Scheme 8a). Heteroaryl substitution was well tolerated, affording
benzofuran 35 in 64% yield. Increased substitution adjacent to the
benzylic stereogenic center was also tolerated, with 36 forming in
50% yield. Notably, products with such branched substituents are
not accessible under asymmetric hydroboration conditions.48 Other
diboranes also successfully underwent the cross-coupling reaction
to afford boronate esters (37). With the more electron-donating
PPh2Cy and increased reaction temperature, benzylic ammonium
triflates without naphthyl substitution engaged in the cross-
coupling (Scheme 8b). Enantioenriched boronate products 39, 40,
and 41 were obtained in good yields and stereospecificities.
In 2014, we reported improved conditions for the
stereospecific cross-coupling of secondary benzylic ammonium
salts.45 By conducting the cross-coupling of ammonium triflates 27
and arylboronic acids in the presence of Ni(cod)2 without
exogenous ligand, diarylalkanes were obtained in higher yields than
under our first-generation conditions (Scheme 7). As before, the
reaction proceeds with inversion at the benzylic stereocenter with
high levels of stereochemical fidelity. Under our original conditions,
heteroaromatic boronic acids gave only modest yields and
enantiospecificities. Under the “phosphine-less” reaction
conditions, heteroaromatic groups were well tolerated, including
In analogy to stereospecific cross-couplings of benzylic ethers,
we hypothesize that the stereospecific cross-couplings of benzylic
ammonium salts 42 proceed via oxidative addition of an electron-
rich Ni(0) complex into the C–N bond, generating either η1- or η3-
bound nickel(II) intermediate 43 or 44 (Scheme 9a).49
Transmetalation with the activated boronate to form intermediate
45 (or its η3 analogue) and subsequent reductive elimination then
delivers cross-coupled product 46. Consistent with oxidative
addition into the C–N bond, benzylnickel(II) triflate 48 was
produced in 51% isolated yield upon reaction of ammonium triflate
benzofuran 28. These conditions also tolerated bulky groups at R, with stoichiometric Ni(cod)2 and PPh2Cy. The structure of 48 was
including isopropyl (29). In addition to aryl boronic acids, vinyl confirmed by X-ray crystallography (Scheme 9b), and 48 proved
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reactive as a substrate and catalytically competent in the Suzuki– aromaticity of a phenyl substituent in this step. An analogous
Miyaura arylation. Because retention of configuration during mechanism had been previously proposed by Jarvo for her
transmetalation and reductive elimination is precedented for alkyl stereospecific cross-couplings of benzylic ethers.43 To test this
metal species,50 we propose that inversion of configuration occurs hypothesis, we compared the borylation of ammonium triflates 49
during oxidative addition of the nickel catalyst into the benzylic C–N and 52 (Scheme 9c). For ammonium triflate 49, if the methoxy
bond. Additionally, because the cross-couplings afford higher yields group sterically blocks addition at C1, SN2’-type attack of nickel at
for substrates with naphthyl substituents instead of phenyl C3 would result in complete loss of aromaticity. Indeed, no desired
substituents, we propose that oxidative addition likely occurs via an product 50 was observed. However, SN2’-type attack on ammonium
SN2’-type mechanism (TS-1). Partially breaking the aromaticity of triflate 52 maintains some aromaticity in intermediate 53, resulting
the naphthyl group is far less endothermic than fully breaking the in product 54 in 49% yield.
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3. C(sp3)–O Bond Activation of Benzylic Alcohol
Derivatives
Excitingly, our efforts seem to have reinvigorated interest in
utilizing ammonium salts as electrophiles in transition metal-
catalyzed cross-coupling reactions, including the development of 3.1 Secondary Benzylic Ethers
nickel-catalyzed carboxylation51 and reduction52 of benzylic
Alcohols are readily available substrates, making them ideal
candidates to participate as electrophiles in cross-coupling
reactions. Indeed, nickel-catalyzed C(sp2)–O bond activation of
phenols, enols, and their derivatives is well developed.58
However, productive activation of C(sp3)–O bonds is more
challenging; they undergo slow oxidative addition due to their
high bond dissociation energies.59 Overcoming this barrier, Shi
and coworkers reported the first nickel-catalyzed C(sp3)–O
bond activation of benzylic ethers.60 Reaction of ether 57 with
methylmagnesium bromide under nickel catalysis afforded
product 58 quantitatively (Scheme 11). Complete selectivity
for the benzylic ether over an aryl ether was observed.
ammonium
triflates.
Additionally,
non-metal-catalyzed
stereospecific reactions of benzylic ammonium triflates have been
reported subsequent to our work.53 Further, Tortosa and coworkers
have demonstrated that copper catalysts can also be used,
specifically in their stereospecific arylation of propargylic
ammonium salts.54 Reaction of enantioenriched propargylic
ammonium triflate 55 with aryl Grignard reagent affords 56 in 98%
yield (Scheme 10). The reaction proceeds with α-regioselectivity
and inversion of configuration in excellent stereochemical fidelity. A
subsequent report from this group has also utilized enantioenriched
propargylic ammonium triflates to generate allenes in high ee’s.55
Additionally, the use of benzylic ammonium salts in cross-coupling
reactions has led to the development of alternative activating
groups for amines, including pyridinium salts, reported by us56 and
others.57 Overall, we are excited to have identified a novel mode of
C(sp3)–N bond activation, which allows for the stereospecific
formation of new C–C bonds.
In 2011, Jarvo and coworkers reported the first
stereospecific, nickel-catalyzed cross-coupling of secondary
benzylic ethers.39 Reaction of enantioenriched ether 59 with
methylmagnesium iodide afforded 60 in 72% yield (Scheme
12a). Optimization of the ligand was key to promoting the
desired reactivity by accelerating oxidative addition and
minimizing β-hydride elimination. This cross-coupling
proceeded with excellent stereochemical fidelity for inversion
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at the benzylic stereocenter. The authors demonstrated the also demonstrated this C(sp3)–O bond activation and ring-
utility of this method by synthesizing a diarylethane with opening strategy in a stereospecific, nickel-catalyzed cross-
potent tubulin polymerization inhibition activity. They electrophile reductive coupling to efficiently synthesize
subsequently utilized enantioenriched secondary methyl cyclopropanes from tetrahydropyrans.66 Overall, the work by
ethers as electrophiles in additional stereospecific, nickel- Jarvo and coworkers demonstrated that nickel-catalyzed cross-
catalyzed cross-couplings, including a Kumada cross-coupling couplings of enantioenriched benzylic ethers with Grignard
with alkyl Grignard reagents61 and an intramolecular Heck and organozinc reagents occur with excellent levels of
reaction.62
By changing the alcohol activating group from a methyl the power of stereospecific cross-couplings of readily available
ether to 2-methoxyethyl ether, Jarvo and coworkers enantioenriched electrophiles, and inspired much of our effort
stereochemical fidelity. Their seminal reports certainly showed
a
expanded the stereospecific, nickel-catalyzed methylation with benzylic ammonium triflates, as well as benzylic pivalates
scope to secondary dibenzylic ethers without naphthyl as discussed below.
substituents.37 Under nickel catalysis, cross-coupling of
enantioenriched dibenzylic ether 61 and methylmagnesium
iodide afforded diarylethane 63 in 65% yield and 98% es
(Scheme 12b). The authors proposed that the traceless
directing group accelerates oxidative addition by forming five-
membered chelate 62 with magnesium salts,10h,44b,63 thereby
allowing the use of less reactive electrophiles. In subsequent
publications, Jarvo and coworkers used this traceless directing
group for stereospecific, nickel-catalyzed cross-coupling
reactions of secondary benzylic ethers with aryl Grignard
reagents to afford enantioenriched triarylmethanes.38,64
Additionally, they utilized a similar directing group for the
stereospecific, nickel-catalyzed Negishi cross-coupling of
secondary benzylic esters with dimethylzinc.40
3.2 Secondary Benzylic Carboxylates and Carbamates
In the stereospecific cross-couplings discussed above, Grignard
reagents were used as the nucleophilic coupling partners.
Although Grignard reagents are less expensive than their
boronic acid counterparts, we imagined that the convenience
and functional group tolerance offered by using an
organoboron reagent would often be an attractive alternative.
Based on our previous success with the activation of the
C(sp2)–O bond of aryl pivalates,67 we focused our attention on
developing a stereospecific, nickel-catalyzed Suzuki–Miyaura
cross-coupling of benzylic pivalates.689 Predicting that
boronate coordination to an electrophilic Ni(II) intermediate
may be a key step in transmetallation,69 we hypothesized that
the nickel(II) pivalate may be able to undergo transmetalation
with an aryl boronate due to the weaker coordination of the
pivalate versus the alkoxides generated with benzylic ether
substrates. The weaker C–O bond may also lead to a higher
concentration of the oxidative addition intermediate, further
facilitating a more difficult transformation. Enantioenriched
secondary pivalates were prepared via Corey–Bakshi–Shibata
(CBS) reduction of the corresponding ketones, followed by
acylation.70 In the presence of Ni(cod)2 and electron-rich
Benzylic tetrahydropyrans, tetrahydrofurans, and lactones
also undergo ring-opening under similar nickel-catalyzed
methylation conditions.65 When multiple stereogenic centers
are present, the ring opening occurs with inversion at the
benzylic stereogenic center without affecting or being affected
by the other stereogenic centers. Reaction of cis-64 afforded
syn-65 in 93% yield and excellent diastereoselectivity (Scheme
12c). When the trans diastereomer was used, anti product was
obtained in the same yield and diastereoselectivity. Jarvo has
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PCy2Ph, cross-coupling of enantioenriched pivalate 66 and that water had a detrimental effect on the reaction. Notably,
phenylboronic acid afforded diarylethane (R)-67 in 93% yield aryl chloride is tolerated (73), providing a functional group
and 54% es with retention of configuration (Scheme 13a). In handle for further cross-coupling reactions. Steric hindrance
contrast, conditions without exogenous ligand afforded (S)-67 was also well tolerated, as evidenced by the i-Pr group in 72
.
in improved yield and stereochemical fidelity with inversion of Electron-poor (74) and -rich (75) heteroaryl-substituted
configuration. Stereoretention had not been previously pivalates underwent the cross-coupling, although the yield was
reported in any stereospecific cross-coupling of a benzylic diminished for 75. Additionally, biphenyl-substituted pivalate
electrophile, and we were intrigued by this result.
underwent the reaction to afford 76 in good stereochemical
In analogy to our benzylic ammonium triflates (see fidelity, albeit diminished yield.
Scheme 9 above), we hypothesized that the stereochemical
Concurrent with our report of this work, Jarvo and
outcome is dictated by the oxidative addition step. To confirm coworkers reported a stereospecific, nickel-catalyzed Suzuki–
that the overall stereoretention was indeed due to the Miyaura cross-coupling of dibenzylic carbamates 77a (Scheme
oxidative addition step, we wanted to isolate the oxidative 14).43 Excitingly, they also observed that the ligand determined
addition from the subsequent transmetallation and reductive whether the cross-coupling proceeds with retention or
elimination. Inspired by a similar experiment by Fu,50b we inversion of configuration. Furthermore, they were able to
subjected deuterated pivalate 68 to stoichiometric Ni(cod)2 optimize conditions to achieve excellent stereochemical
fidelity in both pathways. The ability to access both product
enantiomers in high ee from a single enantiomer of starting
material overcomes the common limitation of stereospecific
reactions. This work, along with stereochemical flips observed
in allylic substrates, set the stage for advancing the field’s
understanding of what reaction parameters can be used for
stereodivergency in stereospecific cross-coupling reactions.
Towards this goal of mechanistic understanding,
subsequent computations by Jarvo, Houk, and Hong studied
and PCy3, and allowed
β-hydride elimination to take place.
Alkene 69 was the major product with alkene 70 as a minor
byproduct (Scheme 13b). Formation of alkene 69 is consistent
with β-hydride elimination (via synperiplanar C–Ni and C–D
bonds) of the intermediate resulting from stereoretentive
oxidative addition. This suggested that oxidative addition in
the presence of phosphine ligand proceeds via a distinct
mechanism from the precedented SN2’-type oxidative addition
of nickel complexes into ammonium salts and ether
electrophiles. Without phosphine ligand, oxidative addition
likely follows the SN2’-type mechanism, consistent with the
observed inversion of configuration at the benzylic
stereocenter.
the transformation of pivalate 77b to form 78
. Their
calculations suggest that with phosphine ligand PCy3, there is a
preference for oxidative addition via cyclic transition state TS-
, resulting in retention of stereochemistry.71 When using N-
2
heterocyclic carbene (NHC) ligand SIMes, there is a preference
for oxidative addition by SN2’ back-side attack through an open
Under the “phosphine-less” conditions, reaction of
enantioenriched 71 with arylboroxine had good functional
group tolerance (Scheme 13c). The use of boroxine resulted in transition state (TS-3), leading to inversion of configuration.
better yields and higher levels of chirality transfer, indicating They propose that the major factor contributing to this change
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in mechanism is the difference in energy caused by bending achiral ketone precursors. Notably, the only examples of
the C1–Ni–ligand angle to accommodate the formation of the metal-catalyzed cross-couplings of alkyl electrophiles to give
Ni–O bond in TS-2. For PCy3, the nickel–ligand interaction quaternary centers in high enantioenrichment utilized allylic
involves mainly σ-donation, so there is less of an energy substrates;81 no tertiary benzylic electrophiles had yet been
penalty for C1–Ni–ligand angle distortion than when using demonstrated.
SIMes, which has a more rigid nickel–ligand bond due to
additional d–p back-donation.
Capitalizing on this idea, we developed a stereospecific,
nickel-catalyzed arylation of tertiary benzylic acetates with
Functional group tolerance was good for both reaction
conditions, including reaction of heteroaryl boronic esters 79
and 80. Although naphthyl substitution was not required, this
report is limited to dibenzylic carbamates. This requirement
results from coordination of the nickel to the aryl group prior
to oxidative addition, which is consistent with both computed
mechanistic pathways and is similar to the previously
proposed SN2’-type mechanism. Jarvo and coworkers later
used this method to synthesize enantioenriched diarylalkanes
and trialkylmethanes.72
The use of enantioenriched alcohol derivatives has
continued to gain increasing attention in transition metal
catalysis. Benzylic pivalates have been used in subsequent
reports of nickel-catalyzed reactions, including a Suzuki–
Miyaura cross-coupling to form triarylmethanes73
a
stereospecific intramolecular cross-electrophile coupling,74
and a stereospecific Miyaura borylation.75 C(sp3)–O activating
groups now include 2-pyridyl etherates76 and vinyl
boronate esters.82 Enantioenriched tertiary alcohols were
readily prepared via Walsh’s enantioselective addition of
organozinc reagents to acetophenones.83 Although pivalates
could not be easily prepared likely due to steric congestion of
the tertiary alcohol, acetates 82 were readily accessible and
proved to be excellent substrates (Scheme 15).
dioxanones.77 In
a related reaction, Tunge and Mendis
reported a stereospecific, palladium-catalyzed decarboxylative
alkynylation of diarylcarbonates.78 Additionally, Tang and
coworkers demonstrated a transition metal-free stereospecific
addition of vinyl boronic acids to enantioenriched benzylic
mesylates.79 Palladium-catalyzed dynamic kinetic resolution of
dibenzylic carboxylates has also been recently reported.80 By
activating widely available enantioenriched alcohols as
The success of this reaction relied upon significant
optimization of the catalyst system. The reaction conditions
optimized for the cross-coupling of secondary benzylic
pivalates afforded high yield of cross-coupled product but with
carboxylates
and
carbamates, cross-couplings
with
organoboranes have been enabled, greatly increasing the
functional group tolerance and convenience of these
stereospecific reactions.
low stereochemical fidelity. Addition of
a monodentate
phosphine ligand improved stereochemical fidelity, but also
led to elimination byproducts. Hypothesizing that these were
due to competitive β-hydride elimination, we investigated
bidentate ligands, including those with hemilabile arms. By
switching to a Buchwald ligand, CyJohnPhos, elimination
products were reduced and the enantiospecificity was much
3.3 Tertiary Benzylic Carboxylates
Based on the proposed SN2’ oxidative addition and the high
degree of steric hindrance tolerated in the stereospecific
cross-coupling reactions of secondary benzylic carboxylates,
we envisioned that a stereospecific, nickel-catalyzed cross-
coupling of tertiary benzylic electrophiles may be possible. If
the nickel catalyst was adding in an SN2’ fashion, increased
steric hindrance at the benzylic position should be tolerated.
This reaction would allow access to benzylic, all-carbon
quaternary stereocenters in high enantiopurity. By using a
stereospecific cross-coupling to accomplish this challenging
transformation, there would be no need to differentiate
similar alkyl groups with a chiral catalyst. Thus, when coupled
with enantioselective ketone alkylation, we believed that this
method would offer a powerful asymmetric synthesis of
benzylic quaternary stereocenters from readily available,
improved,
affording
products
with
retention
of
stereochemistry.
A wide range of functional groups were well tolerated,
including chloride 83. An example of heteroaryl substitution
was also demonstrated, affording 84 in 79% yield. As with the
cross-coupling of secondary alcohol and amine derivatives,
either an aryl substituent with an extended π-system or diaryl
substitution (85) was required on the electrophile. Despite this
limitation, this reaction was the first example of a transition
metal-catalyzed cross-coupling of
a
benzylic tertiary
electrophile to give products in high enantiomeric excess, and
overcame traditional limitations in utilizing tertiary
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electrophiles in substitution reactions. It highlights the allylic electrophile to deliver
ARTICLE
a
highly enantioenriched
advantage of combining a stereospecific cross-coupling with product.89 Pivalates were readily prepared in high
known catalytic asymmetric reactions, and offers a highly enantiomeric excess via CBS reduction and pivalation.70
efficient strategy for asymmetric synthesis of diaryl and triaryl
alkanes with quaternary stereocenters.
4. C(sp3)–O Bond Activation of Allylic Alcohol
Derivatives
4.1 Secondary Allylic Alcohol Derivatives
Stereospecific arylation of readily accessible 1,3-disubstituted
secondary allylic electrophiles enables facile construction of
enantioenriched products equipped with vinyl-substituted
benzylic carbon stereocenters. Kobayashi was the first to
report a stereospecific, nickel-catalyzed Suzuki–Miyaura cross-
coupling of an allylic alcohol derivative.84 Cyclic allylic acetate
86 underwent cross-coupling with phenylzinc borate reagent
to afford product 87 with inversion of configuration (Scheme
16a). Sawamura and coworkers then developed stereospecific,
palladium- and copper-catalyzed Suzuki–Miyaura cross-
coupling reactions of allylic esters and phosphates (Scheme
16b).85 These γ-selective reactions afforded products with
retention of stereochemistry
Bäckvall88 developed stereospecific cross-coupling reactions of
allylic electrophiles that proceed with -selectivity 90).
(
89). Zhang,86 Tian,87 and
α
(
However, no stereospecific, nickel-catalyzed cross-couplings of
acyclic allylic electrophiles and arylboron reagents to deliver
highly enantioenriched products had been reported.
Reaction of pivalates 91 and arylboroxines with Ni(cod)2 and
BnPPh2 afforded products with excellent yields,
regioselectivities, and enantiospecificities (Scheme 17a). This
method is mild and tolerates a wide scope of functional groups
including heteroaryl substitution. Halides were well tolerated
on the allylic pivalate (93) and arylboroxine (94), highlighting
the orthogonality of the reaction to this group. Additionally,
the cross-coupling had a high tolerance for steric hindrance at
the benzylic position (95). We proposed that the reaction
proceeds through a π-allylnickel intermediate with selectivity
for forming the conjugated alkene in the product. Consistent
with the intermediacy of a π-allylnickel complex, the reaction
of alkene regioisomer 96 resulted in product 97 (Scheme 17b).
Based on our studies of stereospecific, nickel-catalyzed
cross-couplings of benzylic carboxylates and arylboronates, we
envisioned that nickel-based catalysts may also serve as
efficient, nonprecious metal catalysts for highly stereospecific
and regioselective cross-couplings of 1,3-disubstituted allylic
pivalates and arylboronates. In 2014, we reported the first
stereospecific, nickel-catalyzed cross-coupling of an acyclic
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We also recognized that allylic boronates are useful occurs via closed transition state TS-4. Nickel adds to the re
intermediates in organic synthesis.90 In 2005, Ito, Kawakami, face of the alkene, thereby allowing R1 and R2 to be
and Sawamura reported a stereospecific, copper-catalyzed pseudoequatorial,
which
leads
to
retention
of
borylation of allylic carbonates to deliver highly stereochemistry. More strongly coordinating carboxylates lead
enantioenriched γ-alkyl allylic boronates.91 However, no to higher stereochemical fidelity, consistent with carboxylate
stereospecific, transition metal-catalyzed borylation for the coordination to the nickel catalyst.
When conducted in more polar solvents, oxidative
addition via an open transition state to give a charge-
separated intermediate is competitive. Acetonitrile also
appears to act as a ligand, coordinating nickel and prohibiting
coordination of the pivalate. Favored transition state TS-5
minimizes A1,3-strain, affording inversion of configuration.
preparation of γ-aryl α-chiral allylic boronates had been
reported. We envisioned that a stereospecific, nickel-catalyzed
Miyaura borylation of γ-aryl allylic pivalates would deliver
highly enantioenriched γ-aryl
α
-stereogenic boronates.92 The
optimal conditions for our stereospecific allylic arylation gave
high yields and stereochemical fidelity for the Miyaura
borylation, affording product (S)-101 with inversion of
stereochemistry (Scheme 18). However, when toluene was
used as the solvent, product (R)-101 formed with retention of
configuration. Further optimization of ligand and other
conditions led to high stereochemical fidelity and
regioselectivity under these stereoretentive conditions.
Notably, this was the first example of solvent as the
predominant factor in a stereochemical flip.93
Heteroaryl groups could be incorporated (102). Tether
length of pendant olefins affected the stereochemical fidelity
of the cross-coupling (103, 104), potentially indicating a
change in mechanism or epimerization pathway. In addition to
aryl allylic boronates, γ-alkyl allylic boronate 105 was formed
in high yield, regioselectivity, and enantiospecificity. Diborane
coupling partners other than B2pin2 could be used; for
example, boronate 106 was produced in 90% yield and 91% es.
Based on a series of mechanistic studies, we proposed
that when the cross-coupling is run in nonpolar solvents, the
pivalate leaving group directs the nickel. Oxidative addition
Under the conditions optimized for stereoretention, p-
substituted benzonitriles were added. There was excellent
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correlation between the electron-donating ability of the added
nitrile and the stereospecificity, with more electron-poor
of pivalate. Heteroaryl-substituted boroxines were well
tolerated, affording products 112 and 113 in good yields. Steric
benzonitriles leading to higher stereochemical fidelity under hindrance at the stereogenic center was also well tolerated,
affording 114 in 84% yield. As expected in MeCN solvent, the
reaction proceeds with inversion of configuration. Additionally,
the geometry of the starting alkene affects the
stereochemistry. The allylic pivalate synthesized from nerol
gives the opposite absolute configuration of product 115 as
the allylic pivalate synthesized from geraniol (116).
the retention conditions. This mechanistic insight offers
exciting new options for stereodivergent synthesis and adds
solvent as an additional parameter to accomplish
stereochemical flips.
4.2 Tertiary Allylic Alcohol Derivatives
We propose that oxidative addition proceeds through
open transition state TS-6, where the nickel adds to the
opposite face of the allylic system as the pivalate leaving
group. This conformation minimizes any developing A1,3
interactions. Acetonitrile may favor this open transition state
by coordinating with the nickel catalyst and blocking
coordination with the pivalate. Transmetalation and reductive
elimination then deliver the product where the alkene is
conjugated with the adjacent aryl group. This reaction offers
an entry into the preparation of all-carbon quaternary
stereocenters adjacent to internal alkenes in high
regioselectivity and enantiospecificity.
With our success in setting benzylic quaternary centers and
allylic substitution, we targeted quaternary center formation
via allylic arylation. In particular, we were excited to form
products with the additional vinyl handle for further
elaboration. The use of allylic halides and phosphate esters in
enantioselective cross-coupling reactions to afford molecules
containing all-carbon quaternary stereocenters with terminal
alkenes is well developed (Scheme 19a).81f,94 However, the
preparation of enantioenriched products with all-carbon
quaternary stereocenters and internal alkenes using
enantioenriched allylic electrophiles was limited to reactions
using stoichiometric copper (Scheme 19b).81e,95 In an
umpolung approach, Morken and coworkers developed a
stereospecific, palladium-catalyzed cross-coupling of allylic
boronate esters with aryl halides.96
5. Conclusions and Outlook
Inspired by the prior art from a range of groups, we have
developed a series of stereospecific cross-couplings of benzylic
and allylic amine and alcohol derivatives. The success of this
effort has relied on the design of benzylic ammonium triflates
as substrates for cross-couplings via C–N bond activation, and
the development of benzylic and allylic carboxylates for cross-
couplings via C–O bond activation. Our efforts, along with
others’ exciting discoveries, have demonstrated that
stereospecific, transition metal-catalyzed cross-coupling
reactions using enantioenriched electrophiles are useful in
asymmetric synthesis, particularly when combined with highly
As we considered an efficient and convenient approach to
the synthesis of quaternary stereocenters substituted with
internal alkenes, we were inspired to develop a stereospecific,
nickel-catalyzed Suzuki–Miyaura cross-coupling of allylic
pivalates and arylboronates (Scheme 20).97 The secondary
pivalates 111 were readily prepared in highly enantioenriched
form using
a
CBS reduction.98 Although electron-rich
phosphine dppf gave high stereochemical fidelity, it afforded
low yield, which we hypothesized was due to decomposition of
starting material from redox activity with the ferrocene.
Changing the ligand to BISBI, which has a wide bite angle and a
semi-rigid backbone,99 afforded products in high yield and efficient
asymmetric
reactions
to
generate
the
stereochemical fidelity. The use of aryl boronic acid in place of enantioenriched intermediates. We have also begun to
arylboroxine resulted in lower yields with significant hydrolysis uncover detailed understanding of how to manipulate catalyst
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stereodivergency in these stereospecific reactions. Despite the
clear potential of these reactions in asymmetric synthesis,
challenges remain. The scope of benzylic ammonium salts and
carboxylates remains limited by the need for polycyclic aryl
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Ph
Cl
Bpin
Me
Me
O
O
OTf
H
Me3N
Me
Et
Bpin
Me
Ph
R1
MeO
Ar
R
Me
N
Np
Me
Et
Ni
O
Stereospecific
O
R2
R1
Cross-Couplings
Me
tBu
Me
N
Ar
O
OMe
Ph
Me
• Substrates readily available in high ee
• Mild reaction conditions
Me
Me
• High stereochemical fidelity
Ph
• Diaryl and triaryl products
• Tertiary and quaternary stereocenters
Stereospecific, nickel-catalyzed cross-couplings of alkyl ammonium salts and
carboxylates enable preparation of highly enantioenriched products with tertiary and
quaternary stereocenters.