The asymmetric synthesis of amines via nickel-catalyzed enantioconvergent substitution reactions

Article abstract of DOI:10.1021/jacs.0c13034

Chiral dialkyl carbinamines are important in fields such as organic chemistry, pharmaceutical chemistry, and biochemistry, serving for example as bioactive molecules, chiral ligands, and chiral catalysts. Unfortunately, most catalytic asymmetric methods for synthesizing dialkyl carbinamines do not provide general access to amines wherein the two alkyl groups are of similar size (e.g., CH₂R versus CH₂R¹). Herein, we report two mild methods for the catalytic enantioconvergent synthesis of protected dialkyl carbinamines, both of which use a chiral nickel catalyst to couple an alkylzinc reagent (1.1-1.2 equiv) with a racemic partner, specifically, an α-phthalimido alkyl chloride or an N-hydroxyphthalimide (NHP) ester of a protected α-amino acid. The methods are versatile, providing dialkyl carbinamine derivatives that bear an array of functional groups. For couplings of NHP esters, we further describe a one-pot variant wherein the NHP ester is generated in situ, allowing the generation of enantioenriched protected dialkyl carbinamines in one step from commercially available amino acid derivatives; we demonstrate the utility of this method by applying it to the efficient catalytic enantioselective synthesis of a range of interesting target molecules.

Full text of DOI:10.1021/jacs.0c13034

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The Asymmetric Synthesis of Amines via Nickel-Catalyzed
Enantioconvergent Substitution Reactions
Ze-Peng Yang,† Dylan J. Freas,† and Gregory C. Fu*
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ABSTRACT: Chiral dialkyl carbinamines are important in fields
such as organic chemistry, pharmaceutical chemistry, and bio-
chemistry, serving for example as bioactive molecules, chiral ligands,
and chiral catalysts. Unfortunately, most catalytic asymmetric
methods for synthesizing dialkyl carbinamines do not provide
general access to amines wherein the two alkyl groups are of similar
size (e.g., CH2R versus CH2R1). Herein, we report two mild methods
for the catalytic enantioconvergent synthesis of protected dialkyl
carbinamines, both of which use a chiral nickel catalyst to couple an
alkylzinc reagent (1.1−1.2 equiv) with a racemic partner, specifically,
an α-phthalimido alkyl chloride or an N-hydroxyphthalimide (NHP)
ester of a protected α-amino acid. The methods are versatile,
providing dialkyl carbinamine derivatives that bear an array of
functional groups. For couplings of NHP esters, we further describe a one-pot variant wherein the NHP ester is generated in situ,
allowing the generation of enantioenriched protected dialkyl carbinamines in one step from commercially available amino acid
derivatives; we demonstrate the utility of this method by applying it to the efficient catalytic enantioselective synthesis of a range of
interesting target molecules.
likely to provide a general solution to the asymmetric synthesis
of dialkyl carbinamines, e.g., for those bearing similar alkyl
groups (e.g., CH2R versus CH2R1).
INTRODUCTION
■
Because a chiral dialkyl carbinamine subunit is found in a wide
array of bioactive molecules (e.g., Figure 1A), the development
of efficient methods for its synthesis, particularly catalytic and
enantioselective processes, is an important objective in synthetic
organic chemistry.1 A variety of approaches have been described
to date, each of which has limitations,2 including the addition of
alkyl nucleophiles to imines of aliphatic aldehydes (limited
scope with respect to the nucleophile),3 the reduction/
hydrogenation of imines of unsymmetrical dialkylketones
(modest enantioselectivity when the alkyl groups are similar)
and enamines,4−6 and the hydroamination of olefins (modest
regioselectivity for many internal olefins).7−9 After our study
was completed, several groups independently demonstrated that
nickel-catalyzed asymmetric reductive couplings of olefins and
alkyl halides10 can provide access to protected dialkyl carbin-
amines.11−14
With regard to retrosynthetic analysis, the nucleophilic
substitution of an alkyl electrophile represents a straightforward
approach to the synthesis of dialkyl carbinamines (top of Figure
1B). Although substitution by a nitrogen or by a carbon
nucleophile could in principle afford the target molecules, in
order to achieve high enantioselectivity, the use of a nitrogen
nucleophile would require the effective differentiation between
two alkyl groups, whereas the use of a carbon nucleophile would
require the effective differentiation between an alkyl group and a
nitrogen substituent. We viewed the latter approach to be more
Recently, transition metals have been shown to catalyze an
array of enantioconvergent couplings of racemic alkyl electro-
philes with alkyl nucleophiles.15−18 However, there have been
no reports of such metal-catalyzed substitution reactions in the
case of electrophiles that bear a nitrogen substituent geminal to
the leaving group, as required for the strategy for the asymmetric
synthesis of dialkyl carbinamines illustrated at the top of Figure
1B. Herein, we describe two complementary approaches to such
enantioconvergent substitutions, specifically, nickel-catalyzed
couplings of alkylzinc reagents with α-phthalimido alkyl
chlorides (Method 1) and with N-hydroxyphthalimide (NHP)
esters of α-amino acids (Method 2).
RESULTS AND DISCUSSION
■
Couplings of α-Phthalimido Alkyl Chlorides: Scope.
The phthalimide functional group is a well-established protected
Received: December 16, 2020
Published: February 10, 2021
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unactivated primary alkyl halide (fluoride, chloride, and
bromide), indazole, and activated heteroaryl chloride (products
5−14). In the case of an electrophile that bears a remote
stereocenter, the stereochemistry of the catalyst, rather than that
of the substrate, controls the stereochemistry of the product
(products 15 and 16). On a gram scale (1.40 g of product), the
coupling to generate product 2 proceeds in similar yield and ee
(93% yield, 92% ee) as for a reaction conducted on a 0.6 mmol
scale (94% yield, 92% ee).
The scope of this enantioconvergent alkyl−alkyl coupling is
also broad with respect to the nucleophile, leading to an array of
protected dialkyl carbinamines with good yield and ee. For
example, the R (blue) substituent can range in size from n-hexyl
to isobutyl (Figure 2B.2, products 17−19; however, the use of a
secondary alkylzinc reagent results in a low yield of the coupling
product), and a variety of functional groups can be present
(entries 20−35; for additional studies of the functional-group
compatibility of the method, see the Supporting Information).
Couplings of α-Phthalimido Alkyl Chlorides: Mecha-
nistic Observations. We have previously reported that two
distinct nickel-catalyzed enantioconvergent couplings (Negishi
reactions of propargylic halides and Kumada reactions of α-
haloketones) appear to proceed through a common pathway
(Figure 3A), wherein the predominant resting state of the
catalyst is an organonickel(II) complex (A).21,22 For the
couplings of α-phthalimido alkyl chlorides with alkylzinc
reagents described herein, our mechanistic observations are
again consistent with this pathway.
For example, quantitative EPR analysis indicates that odd-
electron nickel intermediates (e.g., NiI or NiIII) do not
accumulate to a significant extent during the reaction (<2% of
the total nickel present). Furthermore, ESI−MS analysis of a
coupling (Figure 2A) at partial conversion reveals masses
consistent with A1 and A2 (Figure 3B). Finally, when the same
coupling is conducted in the presence of TEMPO, a TEMPO
adduct of the electrophile can be isolated (Figure 3C),
consistent with the generation of an organic radical from the
alkyl chloride.
Couplings of NHP Esters of α-Amino Acids: Scope.
Redox-active esters (e.g., NHP esters) serve as useful partners in
a variety of metal-catalyzed carbon−carbon bond-forming
reactions.23−27 The use of NHP esters derived from readily
available α-amino acids28−32 could provide a complementary
strategy to the use of α-amino halides, many of which are
relatively unstable, to generate an organic radical (Figure 3A) en
route to enantioenriched dialkyl carbinamines.
After an extensive survey of reaction parameters, we
determined that the desired decarboxylative coupling of a
racemic NHP ester with an alkylzinc reagent can be achieved in
the presence of a chiral nickel/diamine catalyst, providing the N-
protected dialkyl carbinamine in good yield and ee (Figure 4A,
entry 1; 79% yield, 91% ee). It is worth noting that only 1.2 equiv
of the nucleophile is used, despite the presence of a potentially
labile N−H proton; in contrast, most previous metal-catalyzed
couplings of NHP esters have employed at least 2 equiv of the
organometallic nucleophile, even in the absence of an acidic
proton.23,24
Essentially no carbon−carbon bond formation is observed in
the absence of NiBr2·glyme (Figure 4A, entry 2), and the
coupling proceeds in significantly lower yield and/or ee when
chiral diamine L2, LiCl,33,34 TMSCl,35,36 or DMAP37 is omitted
(entries 3−6). The use of half of the standard catalyst loading
results in a small loss in efficiency (entry 7; 65% yield, 88% ee).
Figure 1. Dialkyl carbinamines. (A) Examples of compounds that
include a chiral dialkyl carbinamine subunit. (B) This study: Nickel-
catalyzed enantioconvergent substitution reactions of alkyl electro-
philes to generate protected dialkyl carbinamines.
form of a primary amine.19 We have determined that a chiral
nickel/pybox catalyst can achieve the coupling of an alkylzinc
reagent (1.1 equiv) with a racemic α-phthalimido alkyl chloride
to afford a protected dialkyl carbinamine in good yield and
enantioselectivity (Figure 2A, entry 1: 90% yield, 92% ee).
Essentially no alkyl−alkyl bond formation is observed in the
absence of NiBr2·glyme or of the pybox ligand (entries 2 and 3),
whereas a slightly diminished yield (but good ee) is obtained
when half of the standard catalyst loading is used (entry 4). The
presence of water or of air impedes carbon−carbon bond
formation, while the enantioselectivity is not affected (entries 5
and 620) (for the impact of other reaction parameters, see
Section VI of the Supporting Information).
As illustrated in Figure 2B.1, the scope of this method for the
catalytic enantioconvergent synthesis of protected dialkyl
carbinamines is fairly broad with respect to the electrophile.
For example, good yields and ee’s are observed when alkyl
substituent R (red) varies in size from methyl to isobutyl
(products 1−4), although a poor yield is observed if it is a bulky
isopropyl group. A variety of functional groups are compatible
with the method, including an aryl iodide, ester, carbonate,
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Figure 2. Enantioconvergent substitution reactions of alkyl chlorides to generate phthalimide-protected dialkyl carbinamines. (A) Effect of reaction
parameters. (B) Scope. All data are the average of two experiments run on a 0.6 mmol scale (unless otherwise noted), and all yields are of purified
products. aThe reaction was conducted at r.t.
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process without isolation of the NHP ester,43 thereby providing
the desired products in one step from commercially available
protected α-amino acids (Figure 5A). The yields for the one-pot
procedure are similar to or modestly lower than those for the
corresponding couplings of purified NHP esters, and the
enantioselectivities are essentially identical. The success of this
process is a testament to the robustness of the method:
impurities and side products from the DIC coupling, including
N,N′-diisopropylurea, neither poison the catalyst nor consume
the alkylzinc reagent via protonation, enabling the reaction to
proceed with only 1.2 equiv of the nucleophile.44
Couplings of NHP Esters of α-Amino Acids: Applica-
tions. We have applied our catalytic asymmetric synthesis of
protected dialkyl carbinamines to a variety of target molecules,
starting from commercially available α-amino acid derivatives
(Figure 5B). For example, urea 74, an analogue of an inhibitor of
protein kinases 1 and 2,45 can be synthesized in two steps and
40% overall yield from N-Boc-alanine, via a one-pot coupling,
followed by conversion of the carbamate to the urea.
Furthermore, Fmoc-protected aminoalcohol 75, an intermedi-
ate in the synthesis of a constrained peptidomimetic (prior
route: eight steps),46 can be produced in two steps from N-
Fmoc-phenylalanine using our method; although the nickel-
catalyzed coupling itself proceeds with moderate enantioselec-
tivity (81% ee), Fmoc-protected aminoalcohol 75 can readily be
recrystallized to >99% ee. Pyrrolidine 76, which has previously
been generated in four steps from N-Cbz-proline en route to a
hydrazone-based chiral auxiliary,47 can be synthesized in one pot
and 72% yield from N-Boc-proline via our approach. Finally,
pyrrolidine 78, which has been employed as an intermediate in a
study of serotonin inhibitors, can be formed in 50% overall yield
in three, rather than eight, steps, via a nickel-catalyzed
coupling.48
Figure 3. Nickel-catalyzed enantioconvergent substitution reactions:
Mechanism. (A) Outline of a possible pathway. (B) ESI−MS data for
the coupling illustrated in Figure 2A. (C) TEMPO adduct of the
electrophile (Figure 2A). X = halide (an inner- or an outer-sphere
ligand).
Couplings of NHP Esters of α-Amino Acids: Mecha-
nistic Observations. Our working hypothesis is that these
nickel-catalyzed enantioconvergent couplings of NHP esters
may be following a pathway analogous to that outlined in Figure
3A for couplings of alkyl halides, wherein the same radical R·
may be generated by the decarboxylative reduction of the NHP
ester by LXNiI.23,49 As in the case of couplings of α-phthalimido
alkyl chlorides (see above), the EPR spectrum of the nickel-
catalyzed reaction of the NHP ester illustrated in Figure 4A
indicates that odd-electron nickel intermediates do not
accumulate to a significant extent during the coupling (<2% of
the total nickel present). Furthermore, C−C bond formation is
inhibited by the presence of TEMPO.50
We have examined whether the chiral nickel catalyst achieves
any kinetic resolution in the enantioconvergent coupling of a
racemic NHP ester. Although this issue has been explored in the
case of alkyl halides,51,52 we are not aware of corresponding
investigations in the case of NHP esters. When the coupling of a
racemic NHP ester is stopped at partial conversion, the
unreacted NHP ester is still racemic (<1% ee; Figure 5C,
experiment 1). Taken together with our observation that the
enantioenriched NHP ester does not racemize under the
reaction conditions (experiment 2), these data indicate that the
chiral nickel catalyst is reacting at essentially identical rates with
each enantiomer of the NHP ester (no kinetic resolution).
From a practical point of view, it is noteworthy that this
enantioconvergent coupling is not highly water- or air-sensitive:
the addition of 0.05 equiv of water or of 1 mL of air to the
reaction vessel has only a minor deleterious effect (entries 8 and
9) (for the impact of other reaction parameters, see Section VI of
the Supporting Information).
A variety of NHP esters serve as suitable coupling partners in
these nickel-catalyzed enantioconvergent couplings to generate
protected dialkyl carbinamines (Figure 4B.1 and B.2). The alkyl
group R (red) can vary in steric demand from Me to i-Pr
(products 36−40), and it can bear a range of functional groups,
including a thioether, an indole, and a thiophene (products 41−
48). The method can be applied to glutamic acid and proline
derivatives, thereby affording enantioenriched protected γ-
amino acids38,39 and 2-alkylpyrrolidines40,41 in good ee from
readily available starting materials (products 47 and 48). Not
only Boc-protected, but also Fmoc- and Cbz-protected, amines
are useful reaction partners (products 49 and 50). The coupling
products are generally crystalline, allowing ready enhancement
of stereochemical purity (e.g., products 51 and 69).
The scope of this method is also broad with respect to the
nucleophile (Figure 4B.3). Unbranched and branched primary
(but not secondary) alkylzinc reagents serve as suitable
nucleophiles (products 51−54), as do a variety of functionalized
alkylzincs (products 55−72;42 see the Supporting Information
for additional functional-group compatibility studies).
CONCLUSIONS
■
We have developed two versatile methods for the catalytic
asymmetric synthesis of dialkyl carbinamines, an important
family of molecules in chemistry and biology, through the use of
This approach to the catalytic asymmetric synthesis of
protected dialkyl carbinamines can be achieved in a one-pot
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Figure 4. Enantioconvergent synthesis of protected dialkyl carbinamines from racemic NHP esters. (A) Effect of reaction parameters. (B) Scope. All
data are the average of two experiments run on a 0.6 mmol scale, and all yields are of purified products. a10 mol % NiBr2·glyme, 12 mol % L2, and 5.0
equiv of LiCl were used (no DMAP or TMSCl). bThe product was recrystallized to >99% ee or >99.5:0.5 d.r.
chiral catalysts based on nickel, an earth-abundant metal. With
enantioconvergent couplings can be achieved under mild
an alkylzinc reagent (1.1−1.2 equiv) as the nucleophile,
conditions with either an α-phthalimido alkyl chloride or an
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Figure 5. Asymmetric synthesis of protected dialkyl carbinamines via substitution reactions of NHP esters. (A) One-pot procedure. The values in
parentheses are the data for the corresponding couplings of purified NHP esters (see Figure 4B). (B) Applications. (C) Study of kinetic resolution.
NHP ester of a protected α-amino acid; both methods display a
broad scope and good functional-group tolerance. The NHP
esters can be generated in situ from commercially available α-
amino acid derivatives and coupled directly, resulting in a
straightforward one-pot catalytic enantioselective synthesis of a
variety of interesting target molecules.
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ASSOCIATED CONTENT
REFERENCES
■
■
sı
(1) For an overview, see: Nugent, T. C. Chiral Amine Synthesis:
Methods, Developments and Applications; Wiley-VCH: Weinheim, 2010.
(2) For leading references, see: Yin, Q.; Shi, Y.; Wang, J.; Zhang, X.
Direct catalytic asymmetric synthesis of α-chiral primary amines. Chem.
Soc. Rev. 2020, 49, 6141−6153.
(3) For a review, see: Lindsay, V. N. G.; Charette, A. B. Nucleophilic
Addition of Nonstabilized Carbanions to Imines and Imine Derivatives.
In Comprehensive Organic Synthesis, 2nd ed., Vol. 1, Elsevier:
Amsterdam, Netherlands, 2014; pp 365−394.
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c13034.
Experimental details: general information, preparation of
chiral ligands, preparation of electrophiles, preparation of
nucleophiles, procedures for catalytic enantioconvergent
cross-couplings, effect of reaction parameters, studies of
functional-group compatibility, procedures for one-pot
reactions, applications of the methods, mechanistic
experiments, assignments of absolute configuration,
NMR spectra, and data on determination of stereo-
selectivity (PDF)
(4) For overviews, see: Ponra, S.; Boudet, B.; Phansavath, P.;
Ratovelomanana-Vidal, V. Recent Developments in Transition-Metal-
Catalyzed Asymmetric Hydrogenation of Enamides. Synthesis 2021, 53,
193−214.
(5) Wang, C.; Xiao, J. Asymmetric Reductive Amination. Top. Curr.
Chem. 2013, 343, 261−282.
Accession Codes
(6) Xie, J.-H.; Zhu, S.-F.; Zhou, Q.-L. Transition Metal-Catalyzed
Enantioselective Hydrogenation of Enamines and Imines. Chem. Rev.
2011, 111, 1713−1760.
CCDC 2057330 and 2057338 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
(7) Michon, C.; Abadie, M.-A.; Medina, F.; Agbossou-Niedercorn, F.
Recent metal-catalysed asymmetric hydroaminations of alkenes. J.
Organomet. Chem. 2017, 847, 13−27.
(8) Reznichenko, A. L.; Nawara-Hultzsch, A. J.; Hultzsch, K. C.
Asymmetric Hydroamination. Top. Curr. Chem. 2013, 343, 191−260.
(9) Xi, Y.; Ma, S.; Hartwig, J. F. Catalytic asymmetric addition of an
amine N−H bond across internal alkenes. Nature 2020, 588, 254−260.
(10) Wang, Z.; Yin, H.; Fu, G. C. Catalytic Enantioconvergent
Coupling of Secondary and Tertiary Electrophiles with Olefins. Nature
2018, 563, 379−383.
AUTHOR INFORMATION
■
Corresponding Author
Gregory C. Fu − Division of Chemistry and Chemical
Engineering, California Institute of Technology, Pasadena,
California 91125, United States; orcid.org/0000-0002-
0927-680X; Email: gcfu@caltech.edu
(11) Qian, D.; Bera, S.; Hu, X. Chiral Alkyl Amine Synthesis via
Catalytic Enantioselective Hydroalkylation of Enamides. J. Am. Chem.
Soc. [Online early access]. DOI: 10.1021/jacs.0c11630 Published
Online: Jan 22, 2021. https://pubs.acs.org/doi/10.1021/jacs.0c11630
(12) Wang, J.-W.; Li, Y.; Nie, W.; Chang, Z.; Yu, Z.-A.; Zhao, Y.-F.; Lu,
X.; Fu, Y. Catalytic asymmetric reductive alkylation of enamines to
chiral aliphatic amines. ChemRxiv, 2020. https://chemrxiv.org/
articles/preprint/Catalytic_Asymmetric_Reductive_Alkylation_of_
Enamines_to_Chiral_Aliphatic_Amines/13102307.
Authors
Ze-Peng Yang − Division of Chemistry and Chemical
Engineering, California Institute of Technology, Pasadena,
California 91125, United States; orcid.org/0000-0003-
0248-1963
(13) Wang, S.; Zhang, T.-Y.; Zhang, J.-X.; Meng, H.; Chen, B.-H.; Shu,
W. Enantioselective Access to Dialkyl Amines and Alcohols via Ni-
Catalyzed Reductive Hydroalkylations. ChemRxiv, 2020. https://
chemrxiv.org/articles/preprint/Enantioselective_Access_to_Dialkyl_
Amines_and_Alcohols_via_Ni-Catalyzed_Reductive_
Hydroalkylations/13284416 (limited to methyl alkyl carbinamines).
(14) See also: Schmidt, J.; Choi, J.; Liu, A. T.; Slusarczyk, M.; Fu, G. C.
A General, Modular Method for the Catalytic Asymmetric Synthesis of
Alkylboronate Esters. Science 2016, 354, 1265−1269.
Dylan J. Freas − Division of Chemistry and Chemical
Engineering, California Institute of Technology, Pasadena,
California 91125, United States; orcid.org/0000-0003-
0611-7907
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c13034
Author Contributions
(15) Choi, J.; Fu, G. C. Transition metal-catalyzed alkyl−alkyl bond
formation: Another dimension in cross-coupling chemistry. Science
2017, 356, eaaf7230.
†Z.-P.Y. and D.J.F. contributed equally.
Notes
(16) Fu, G. C. Transition-Metal Catalysis of Nucleophilic Substitution
Reactions: A Radical Alternative to SN1 and SN2 Processes. ACS Cent.
Sci. 2017, 3, 692−700.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(17) Kaga, A.; Chiba, S. Engaging Radicals in Transition Metal-
Catalyzed Cross-Coupling with Alkyl Electrophiles: Recent Advances.
ACS Catal. 2017, 7, 4697−4706.
Support has been provided by the National Institutes of Health
(National Institute of General Medical Sciences; grant R01-
GM062871), the National Science Foundation Graduate
Research Fellowship Program (grant DGE-1745301 to D. J.
F.), and the Dow Next-Generation Educator Fund (grant to
Caltech). We thank Dr. Haohua Huo for important early
contributions to this project, and we thank Nicholas J. Fastuca,
Lawrence M. Henling and Dr. Michael K. Takase (Caltech X-
Ray Crystallography Facility), Dr. Paul H. Oyala (Caltech EPR
Facility), Dr. Felix Schneck, Xiaoyu Tong, Dr. David G.
VanderVelde (Caltech NMR Facility), Dr. Scott C. Virgil
(Caltech Center for Catalysis and Chemical Synthesis), and
Wanji Zhang for assistance and helpful discussions.
(18) Iwasaki, T.; Kambe, N. Ni-Catalyzed C−C Couplings Using
Alkyl Electrophiles. Top. Curr. Chem. 2016, 374, 66.
(19) For example, see: Ahmad, N. M. Gabriel synthesis. In Name
Reactions for Functional Group Transformations; Li, J. J., Corey, E. J.,
Eds.; John Wiley & Sons: Hoboken, NJ, 2007; pp 438−450.
(20) When the reaction time was increased for entry 6, the yield
increased to 77% (91% ee).
(21) Schley, N. D.; Fu, G. C. Nickel-Catalyzed Negishi Arylations of
Propargylic Bromides: A Mechanistic Investigation. J. Am. Chem. Soc.
2014, 136, 16588−16593.
(22) Yin, H.; Fu, G. C. Mechanistic Investigation of Enantioconver-
gent Kumada Reactions of Racemic α-Bromoketones Catalyzed by a
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Nickel/Bis(oxazoline) Complex. J. Am. Chem. Soc. 2019, 141, 15433−
15440.
esters that are generated in situ (in the presence of DIC and DMAP;
Figure 5A). If a hindered pyridine (2,6-dimethylpyridine) is employed
instead of DMAP, no enhancement in enantioselectivity is observed.
For a previous example of improved enantioselectivity in the presence
of pyridine itself, see: Zhao, D.; Mao, L.; Yang, D.; Wang, R. Zinc-
Mediated Asymmetric Additions of Dialkylphosphine Oxides to α,β-
Unsaturated Ketones and N-Sulfinylimines. J. Org. Chem. 2010, 75,
6756−6763.
(23) For an example of the use of redox-active esters in nickel-
catalyzed cross-couplings, see: Cornella, J.; Edwards, J. T.; Qin, T.;
Kawamura, S.; Wang, J.; Pan, C.-M.; Gianatassio, R.; Schmidt, M.;
Eastgate, M. D.; Baran, P. S. Practical Ni-Catalyzed Aryl−Alkyl Cross-
Coupling of Secondary Redox-Active Esters. J. Am. Chem. Soc. 2016,
138, 2174−2177.
(24) For an overview of the use of redox-active esters in coupling
reactions, see: Murarka, S. N-(Acyloxy)phthalimides as Redox-Active
Esters in Cross-Coupling Reactions. Adv. Synth. Catal. 2018, 360,
1735−1753.
(25) For reports of metal-catalyzed enantioconvergent coupling
reactions of redox-active esters, see: reductive cross-coupling: Suzuki,
N.; Hofstra, J. L.; Poremba, K. E.; Reisman, S. E. Nickel-Catalyzed
Enantioselective Cross-Coupling of N-Hydroxyphthalimide Esters with
Vinyl Bromides. Org. Lett. 2017, 19, 2150−2153.
(26) Wang, D.; Zhu, N.; Chen, P.; Lin, Z.; Liu, G. Enantioselective
Decarboxylative Cyanation Employing Cooperative Photoredox
Catalysis and Copper Catalysis. J. Am. Chem. Soc. 2017, 139, 15632−
15635.
(38) For an overview and leading references, see: Ordónez, M.;
̃
Cativiela, C.; Romero-Estudillo, I. An update on the stereoselective
synthesis of γ-amino acids. Tetrahedron: Asymmetry 2016, 27, 999−
1055.
(39) Al-Majed, A. Vigabatrin. In Profiles of Drug Substances, Excipients,
and Related Methodology, Vol. 35; Brittain, H. G., Ed.; Elsevier:
Amsterdam, Netherlands, 2010; pp 309−345.
(40) For overviews and leading references, see: Vega-Penaloza, A.;
̃
Paria, S.; Bonchio, M.; Dell’Amico, L.; Companyó, X. Profiling the
Privileges of Pyrrolidine-Based Catalysts in Asymmetric Synthesis:
From Polar to Light-Driven Radical Chemistry. ACS Catal. 2019, 9,
6058−6072.
(41) Bhat, C.; Tilve, S. G. Recent advances in the synthesis of naturally
occurring pyrrolidines, pyrrolizidines and indolizidine alkaloids using
proline as a unique chiral synthon. RSC Adv. 2014, 4, 5405−5452.
(42) The lower stereoselectivity for products 69 and 70 may be due to
an interaction of the carbonyl oxygen of the ester with the chiral nickel
catalyst (six-membered chelate) in the stereochemistry-determining
step of the reaction.
(43) For a prior example of one-pot couplings of NHP esters that are
generated in situ, see: Edwards, J. T.; Merchant, R. R.; McClymont, K.
S.; Knouse, K. W.; Qin, T.; Malins, L. R.; Vokits, B.; Shaw, S. A.; Bao,
D.-H.; Wei, F.-L.; Zhou, T.; Eastgate, M. D.; Baran, P. S.
Decarboxylative alkenylation. Nature 2017, 545, 213−219 (In this
study, the standard coupling conditions employ 2.0 equiv of the
nucleophile, whereas the one-pot procedure employs 3.0 equiv of the
nucleophile, “due to the acidic protons of the DIC urea byproduct”).
(44) Prior couplings of NHP esters that are generated in situ have
nearly always employed a significant excess of the nucleophile (at least 2
equiv). For example, see ref 43.
(45) Lackey, K.; Schnellmann, R.; Goodwin, A. J. Treatment of
Septicemia and ARDS with ERK Inhibitors. PCT Int. Appl. WO
2017180817 A1, 2017.
(46) Nasopoulou, M.; Georgiadis, D.; Matziari, M.; Dive, V.; Yiotakis,
A. A Versatile Annulation Protocol toward Novel Constrained
Phosphinic Peptidomimetics. J. Org. Chem. 2007, 72, 7222−7228.
(47) Denmark, S. E.; Edwards, J. P.; Weber, T.; Piotrowski, D. W.
Organocerium additions to proline-derived hydrazones: synthesis of
enantiomerically enriched amines. Tetrahedron: Asymmetry 2010, 21,
1278−1302.
(27) Xia, H.-D.; Li, Z.-L.; Gu, Q.-S.; Dong, X.-Y.; Fang, J.-H.; Du, X.-
Y.; Wang, L.-L.; Liu, X.-Y. Photoinduced Copper-Catalyzed Asym-
metric Decarboxylative Alkynylation with Terminal Alkynes. Angew.
Chem., Int. Ed. 2020, 59, 16926−16932.
(28) For examples of metal-catalyzed coupling reactions of redox-
active esters of α-amino acids with organometallic nucleophiles (none
are enantioselective), see: Qin, T.; Cornella, J.; Li, C.; Malins, L. R.;
Edwards, J. T.; Kawamura, S.; Maxwell, B. D.; Eastgate, M. D.; Baran, P.
S. A general alkyl-alkyl cross-coupling enabled by redox-active esters
and alkylzinc reagents. Science 2016, 352, 801−805 (1 example).
(29) Toriyama, F.; Cornella, J.; Wimmer, L.; Chen, T.-G.; Dixon, D.
D.; Creech, G.; Baran, P. S. Redox-Active Esters in Fe-Catalyzed C−C
Coupling. J. Am. Chem. Soc. 2016, 138, 11132−11135 (3 examples).
(30) Liu, X.-G.; Zhou, C.-J.; Lin, E.; Han, X.-L.; Zhang, S.-S.; Li, Q.;
Wang, H. Decarboxylative Negishi Coupling of Redox-Active Aliphatic
Esters by Cobalt Catalysis. Angew. Chem., Int. Ed. 2018, 57, 13096−
13100 (4 examples).
(31) Wang, Z.-Z.; Wang, G.-Z.; Zhao, B.; Shang, R.; Fu, Y. Cobalt-
Catalyzed Decarboxylative Methylation and Ethylation of Aliphatic N-
(Acyloxy)phthalimides with Organoaluminum Reagents. Synlett 2020,
31, 1221−1225 (1 example).
(32) For a nickel-catalyzed enantioselective decarboxylative coupling
of an α-amino acid with an aryl halide, see: Zuo, Z.; Cong, H.; Li, W.;
Choi, J.; Fu, G. C.; MacMillan, D. W. C. Enantioselective
Decarboxylative Arylation of α-Amino Acids via the Merger of
Photoredox and Nickel Catalysis. J. Am. Chem. Soc. 2016, 138,
1832−1835.
(33) For an early report of the beneficial effect of a halide salt on an
enantioconvergent coupling reaction, see: Son, S.; Fu, G. C. Nickel-
Catalyzed Asymmetric Negishi Cross-Couplings of Secondary Allylic
Chlorides with Alkylzincs. J. Am. Chem. Soc. 2008, 130, 2756−2757.
(34) For a recent discussion of salt effects in Negishi reactions, see:
Eckert, P.; Sharif, S.; Organ, M. G. Salt to Taste: The Critical Roles
Played by Inorganic Salts in Organozinc Formation and in the Negishi
Reaction. Angew. Chem., Int. Ed. 2020. DOI: 10.1002/anie.202010917.
(35) The beneficial effect of TMSCl may arise from the removal of N-
zincated phthalimide that is formed during the coupling process. Under
our standard conditions, we have identified resonances in the 1H and
29Si NMR spectra that match independently synthesized N-
trimethylsilylphthalimide.
(36) TMSBr has previously been shown to be beneficial in an
enantioselective cross-electrophile coupling: Suzuki, N.; Hofstra, J. L.;
Poremba, K. E.; Reisman, S. E. Nickel-Catalyzed Enantioselective
Cross-Coupling of N-Hydroxyphthalimide Esters with Vinyl Bromides.
Org. Lett. 2017, 19, 2150−2153 (The authors note that TMSCl was less
effective and that the role of TMSBr is “unclear”).
(48) Tanaka, N.; Goto, R.; Hayakawa, M.; Sugidachi, A.; Ogawa, T.;
Asai, F.; Fujimoto, K. [2-(ω-Phenylalkyl)phenoxy]alkylamines II:
Synthesis and Selective Serotonin-2 Receptor Binding. Chem. Pharm.
Bull. 2000, 48, 245−255.
(49) Oelke, A. J.; Sun, J.; Fu, G. C. Nickel-Catalyzed Enantioselective
Cross-Couplings of Racemic Secondary Electrophiles That Bear an
Oxygen Leaving Group. J. Am. Chem. Soc. 2012, 134, 2966−2969.
(50) Although we have not been able to isolate the TEMPO adduct of
the postulated organic radical, perhaps due to its lability, we have
confirmed its presence through high-resolution mass spectrometry.
(51) For an example wherein kinetic resolution is observed, see:
Lundin, P. M.; Fu, G. C. Asymmetric Suzuki Cross-Couplings of
Activated Secondary Alkyl Electrophiles: Arylations of Racemic α-
Chloroamides. J. Am. Chem. Soc. 2010, 132, 11027−11029.
(52) For an example wherein kinetic resolution is not observed, see:
Fischer, C.; Fu, G. C. Asymmetric Nickel-Catalyzed Negishi Cross-
Couplings of Secondary α-Bromo Amides with Organozinc Reagents. J.
Am. Chem. Soc. 2005, 127, 4594−4595.
(37) Our discovery of the beneficial effect of DMAP arose from our
investigation of a one-pot coupling procedure through the use of NHP
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