Enantioconvergent cross-couplings of racemic alkylmetal reagents with unactivated secondary alkyl electrophiles: Catalytic asymmetric Negishi α-alkylations of N-Boc-pyrrolidine

Article abstract of DOI:10.1021/ja4054114

Although enantioconvergent alkyl-alkyl couplings of racemic electrophiles have been developed, there have been no reports of the corresponding reactions of racemic nucleophiles. Herein we describe Negishi cross-couplings of racemic α-zincated N-Boc-pyrrolidine with unactivated secondary halides, thus providing a one-pot, catalytic asymmetric method for the synthesis of a range of 2-alkylpyrrolidines (an important family of target molecules) from N-Boc-pyrrolidine, a commercially available precursor. Preliminary mechanistic studies indicated that two of the most straightforward mechanisms for enantioconvergence (dynamic kinetic resolution of the organometallic coupling partner and a simple β-hydride elimination/β-migratory insertion pathway) are unlikely to be operative.

Full text of DOI:10.1021/ja4054114

Communication
pubs.acs.org/JACS
Enantioconvergent Cross-Couplings of Racemic Alkylmetal Reagents
with Unactivated Secondary Alkyl Electrophiles: Catalytic
Asymmetric Negishi α‑Alkylations of N‑Boc-pyrrolidine
Christopher J. Cordier,†,‡ Rylan J. Lundgren,† and Gregory C. Fu†,‡,*
†Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, United States
‡Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
S
* Supporting Information
effective chiral organocatalysts and ligands in asymmetric
catalysis.11 Because of this wide-ranging significance, the
development of efficient methods for the enantioselective
synthesis of 2-alkylpyrrolidines has been the target of substantial
effort, and a broad array of approaches have been described,
ranging from chiral-pool strategies to asymmetric synthesis.12,13
The catalytic enantioselective 2-alkylation of pyrrolidine (or a
readily available protected derivative) via deprotonation/electro-
phile-trapping represents an attractive, direct approach to the
asymmetric synthesis of 2-alkylpyrrolidines (eq 3); to the best of
ABSTRACT: Although enantioconvergent alkyl−alkyl
couplings of racemic electrophiles have been developed,
there have been no reports of the corresponding reactions
of racemic nucleophiles. Herein we describe Negishi cross-
couplings of racemic α-zincated N-Boc-pyrrolidine with
unactivated secondary halides, thus providing a one-pot,
catalytic asymmetric method for the synthesis of a range of
2-alkylpyrrolidines (an important family of target mole-
cules) from N-Boc-pyrrolidine, a commercially available
precursor. Preliminary mechanistic studies indicated that
two of the most straightforward mechanisms for
enantioconvergence (dynamic kinetic resolution of the
organometallic coupling partner and a simple β-hydride
elimination/β-migratory insertion pathway) are unlikely to
be operative.
our knowledge, such a process has not been reported to date. On
the other hand, pioneering studies by Beak established that
deprotonation of N-Boc-pyrrolidine in the presence of a
stoichiometric quantity of (−)-sparteine14 followed by trapping
with any of a wide range of electrophiles (e.g., n-Bu3SnCl,
Me3SiCl, benzophenone, CO2) can furnish 2-substituted
pyrrolidines with high enantioselectivity; among unactivated
alkyl electrophiles, only dimethyl sulfate and methyl iodide have
been shown to serve as suitable coupling partners.15 Building on
these key observations, O’Brien developed a method that
employs a substoichiometric quantity (20 mol %) of a chiral
amine and provides 2-functionalized (although not 2-alkyl) N-
Boc-pyrrolidines with up to 88% ee.16
In view of the potential utility of the transformation outlined in
eq 3, we pursued the development of the first enantioconvergent
alkyl−alkyl cross-coupling wherein a racemic alkyl nucleophile is
employed as a reaction partner. In particular, we found that, in
the presence of a chiral Ni catalyst, racemic α-zincated N-Boc-
pyrrolidine (prepared in situ from commercially available N-Boc-
pyrrolidine) can be coupled with unactivated alkyl electrophiles
to generate 2-alkylpyrrolidines with good ee (eq 4).17
ecently we have been pursuing the development of an array
1−3
Rof metal-catalyzed alkyl−alkyl cross-coupling processes.
As part of this program, we have described several Ni-catalyzed
methods for the enantioconvergent coupling of achiral alkylmetal
reagents with racemic secondary alkyl electrophiles (eq 1).4,5
The reversed-polarity process, wherein a racemic alkyl
nucleophile is coupled with an alkyl electrophile (eq 2), has
remained an unsolved challenge. However, Kumada has
described a Ni-catalyzed enantioconvergent coupling of a
racemic benzylic Grignard reagent (PhCHMeMgCl) with an
alkenyl halide (bromoethylene) to generate an enantioenriched
allylbenzene.6,7
Pyrrolidines bearing an alkyl substituent at the 2-position are
important across many areas of chemistry and biology. For
example, they are present as subunits in bioactive natural8 and
non-natural9 products, function as versatile intermediates in the
synthesis of other useful classes of compounds,10 and serve as
Initially, in view of recent reports by Campos of stoichiometric
asymmetric α-lithiation/transmetalation/Pd-catalyzed Negishi
arylation of N-Boc-pyrrolidine,18 we examined the cross-
coupling of enantioenriched α-zincated N-Boc-pyrrolidine
(>90% ee)19 with n-hexyl iodide and cyclohexyl iodide in the
presence of an achiral Ni−1,2-diamine catalyst (eq 5). In both
Received: May 30, 2013
Published: July 19, 2013
© 2013 American Chemical Society
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Boc-pyrrolidine was not a suitable coupling partner (entry 4).
Under the same conditions, related C2-symmetric 1,2-diamines
furnished somewhat lower ee and yield (entries 5 and 6). Using
less catalyst (entry 7) or another Ni source (entries 8 and 9) led
to comparable ee but reduced yield. Our observation that 2-
cyclohexyl-N-Boc-pyrrolidine formed in 74% yield with 90% ee in the
presence of 0.5 equiv of the diorganozinc reagent (entry 10) provides
strong evidence that the cross-coupling is an enantioconvergent
process, not a simple kinetic resolution.
The catalytic asymmetric synthesis of an array of 2-
alkylpyrrolidines can be achieved via the coupling of a single
precursor (N-Boc-pyrrolidine) with a variety of readily available,
unactivated alkyl iodides (Table 2).23 Three parent cycloalkyl
Table 2. Enantioconvergent Negishi Reactions of Racemic α-
a
Zincated N-Boc-pyrrolidine with Unactivated Alkyl Iodides
cases, the alkyl−alkyl coupling product was formed with low ee
(<15% ee).20 Because the organozinc reagent is configurationally
stable at room temperature, these observations suggest that
stereochemical scrambling occurs during the Ni-catalyzed cross-
coupling process.
Because the use of an achiral catalyst for the cross-coupling of a
highly enantioenriched nucleophile provided almost racemic
product, we decided to examine the stereochemically converse
transformation: the use of a chiral catalyst for the cross-coupling
of a racemic nucleophile to generate enantioenriched product. In
view of the paucity of asymmetric metal-catalyzed alkyl−alkyl
couplings of secondary nucleophiles with secondary electro-
philes,21 we chose to employ cyclohexyl iodide as the
electrophilic coupling partner. Investigation of a range of
parameters showed that the desired enantioconvergent coupling
of racemic α-zincated N-Boc-pyrrolidine with cyclohexyl iodide
can be achieved using a combination of NiCl2·glyme and chiral
1,2-diamine ligand 122 in good yield (86%) with high ee (93% ee)
at room temperature (Table 1, entry 1). In the absence of either
NiCl2·glyme or 1, essentially no alkyl−alkyl cross-coupling
product was observed (entries 2 and 3); similarly, α-lithiated N-
a
For the reaction conditions, see eq 4. All data are averages of two
b
experiments. Yields of purified products (reaction scale: 1.0 mmol of
the electrophile).
iodides underwent enantioconvergent alkyl−alkyl cross-coupling
with racemic α-zincated N-Boc-pyrrolidine with good enantio-
selectivity (entries 1−3); the process could be conducted on a
gram scale with comparable efficiency [performing entry 1 on a
6.0 mmol scale gave 1.12 g of product (74% yield) with 94% ee].
Heterocyclic electrophiles coupled with high ee (entries 4−6), as
did an acyclic secondary alkyl iodide (entry 7). In contrast,
moderate ee was observed for the asymmetric Negishi reaction of
a primary alkyl iodide (entry 8).
This method thus complements other catalytic enantioselec-
tive approaches to the synthesis of 2-alkylpyrrolidines, which are
typically only effective for the incorporation of a primary alkyl
group.24 Pyrrolidines bearing a secondary alkyl substituent at the
2-position are found in a wide variety of compounds, including an
array of pyrrolizidine (e.g., heliotridane), indolizidine (e.g.,
tashiromine, grandisine A25), and crambescidin26 alkaloids.
Alkyl bromides can also be employed as electrophiles in these
Ni-catalyzed enantioconvergent cross-couplings of a racemic
nucleophile (Table 3).27 Under the same conditions as for
iodides (except for the temperature, in a few cases), alkyl−alkyl
bond formation between α-zincated N-Boc-pyrrolidine and a
range of cyclic and acyclic unactivated secondary alkyl bromides
proceeded with good ee’s but generally modest yields (entries 1−
4). As in the case of a primary alkyl iodide, a primary bromide
cross-coupled with lower ee (entry 5).
Table 1. Enantioconvergent Cross-Coupling of a Racemic
a
Nucleophile: Effect of the Reaction Parameters
We next focused on gaining insight into the origin of the
stereoconvergence in these asymmetric Negishi reactions of α-
zincated N-Boc-pyrrolidine.28 In Kumada’s earlier study of the
enantioselective cross-coupling of racemic PhCHMeMgCl with
bromoethylene to form an allylbenzene, it was postulated that
stereoconvergence arose from a dynamic kinetic resolution of a
a
b
All data are averages of two experiments. Determined by GC
analysis vs a calibrated internal standard.
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Table 3. Enantioconvergent Negishi Reactions of Racemic α-
Zincated N-Boc-pyrrolidine with Unactivated Alkyl
a
Bromides
Figure 2. A hypothetical pathway for stereomutation of an α-metalated
N-Boc-pyrrolidine: β-hydride elimination and β-migratory insertion
without olefin dissociation.
pyrrolidine (eq 6). Essentially no deuterium incorporation
(<5%) α to nitrogen in the cross-coupling product was observed,
a
For the reaction conditions, see eq 4. All data are averages of two
b
c
experiments. Yields of purified products. Reaction temperature: 35
°C.
rapidly racemizing benzylic nucleophile by the chiral Ni catalyst.6
In contrast, our nucleophile, α-zincated N-Boc-pyrrolidine, is
configurationally stable under our reaction conditions in the
absence of Ni. Thus, an enantioenriched organozinc reagent was
prepared from the corresponding stannane through Sn−Li
exchange followed by transmetalation to zinc (Figure 1).29 When
indicating that the β-hydride elimination/β-migratory insertion
pathway for stereomutation depicted in Figure 2 is not the
mechanism by which stereoconvergence is achieved.30
In summary, we have developed the first enantioconvergent
alkyl−alkyl cross-coupling of a racemic nucleophile, specifically,
the asymmetric Negishi reaction of α-zincated N-Boc-pyrrolidine
with unactivated secondary iodides and bromides, providing a
one-pot route to an array of 2-alkylpyrrolidines from a single,
readily available precursor (N-Boc-pyrrolidine). Because the
highest enantioselectivity was obtained for the incorporation of
secondary alkyl substituents, this method complements existing
catalytic asymmetric approaches to the synthesis of 2-
alkylpyrrolidines, which are generally most effective for primary
alkyl groups. The pathway for stereoconvergence in the present
method does not involve a dynamic kinetic resolution of the
organometallic coupling partner, in contrast to a previous report
of an enantioconvergent alkyl−alkenyl cross-coupling. Further-
more, a deuterium-labeling study ruled out stereomutation via a
simple β-hydride elimination/β-migratory insertion pathway
that we had observed in another Ni-catalyzed alkyl−alkyl
coupling. Additional investigations to elucidate the mechanism
of this unusual enantioconvergent cross-coupling and to expand
the range of racemic nucleophiles that can be employed in such
alkyl−alkyl coupling processes are underway.
Figure 1. The product stereochemistry is controlled predominantly by
the stereochemistry of the chiral Ni catalyst, not that of the nucleophile,
in a Negishi reaction of α-zincated N-Boc-pyrrolidine.
this nucleophile was cross-coupled with bromobenzene under
the Campos conditions,18 (R)-2-phenyl-N-Boc-pyrrolidine was
generated in 95% yield with 90% ee, thereby establishing the
stereochemical integrity of the organozinc reagent. When this
enantioenriched nucleophile was reacted with cyclohexyl iodide
under our standard conditions using either (R,R)- or (S,S)-1, the
stereochemistry of the cross-coupling product was dependent
primarily on the stereochemistry of the ligand rather than of the
organozinc nucleophile.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
A possible mechanism for enantioconvergence in the Ni-
catalyzed asymmetric Negishi reactions described herein is a
series of β-hydride eliminations/β-migratory insertions of an
organonickel intermediate, without dissociation of the olefin
from Ni (Figure 2). We have in fact observed such an
isomerization process in an enantioselective Negishi cross-
coupling of a racemic electrophile with an achiral cyclopentylzinc
reagent.21
AUTHOR INFORMATION
Corresponding Author
gcfu@caltech.edu
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the NIH NIGMS (R01-GM62871) for support and
Dr. Scott C. Virgil (Caltech Center for Catalysis and Chemical
■
To assess the viability of the pathway outlined in Figure 2, we
investigated the Negishi reaction of a deuterium-labeled N-Boc-
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Stereochem. 2010, 26, 93. (d) Mitchell, E. A.; Peschiulli, A.; Lefevre, N.;
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alkylpyrrolidines, see: (a) Hennessy, E. T.; Betley, T. A. Science 2013,
Synthesis) and Dr. David G. VanderVelde (Caltech NMR
facility) for assistance.
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