Control of Vicinal Stereocenters through Nickel-Catalyzed Alkyl–Alkyl Cross-Coupling

Article abstract of DOI:10.1002/anie.201702402

Vicinal stereocenters are found in many natural and unnatural compounds. Although metal-catalyzed cross-coupling reactions of unactivated alkyl electrophiles are emerging as a powerful tool in organic synthesis, there have been virtually no reports of processes that generate, much less control, vicinal stereocenters. In this investigation, we establish that a chiral nickel catalyst can mediate doubly stereoconvergent alkyl–alkyl cross-coupling, specifically, reactions of a racemic pyrrolidine-derived nucleophile with cyclic alkyl halides (as mixtures of stereoisomers) to produce vicinal stereocenters with very good stereoselectivity.

Full text of DOI:10.1002/anie.201702402

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201702402
German Edition: DOI: 10.1002/ange.201702402
Asymmetric Synthesis
Hot Paper
Control of Vicinal Stereocenters through Nickel-Catalyzed Alkyl–
Alkyl Cross-Coupling
Xin Mu, Yu Shibata, Yusuke Makida, and Gregory C. Fu*
Abstract: Vicinal stereocenters are found in many natural and
unnatural compounds. Although metal-catalyzed cross-cou-
pling reactions of unactivated alkyl electrophiles are emerging
as a powerful tool in organic synthesis, there have been
virtually no reports of processes that generate, much less
control, vicinal stereocenters. In this investigation, we establish
that a chiral nickel catalyst can mediate doubly stereoconver-
gent alkyl–alkyl cross-coupling, specifically, reactions of
a racemic pyrrolidine-derived nucleophile with cyclic alkyl
halides (as mixtures of stereoisomers) to produce vicinal
stereocenters with very good stereoselectivity.
cross-coupling have been described that control the stereo-
chemistry at one, but not both, of the carbon atoms of the new
carbon–carbon bond (top of Figure 1).[1–3] In contrast, there
are no examples of effective control of vicinal stereocenters in
cross-coupling reactions of unactivated secondary electro-
philes, owing to the difficulty of achieving bond formation,[4]
much less stereoselectivity (maximum d.r. < 1.5:1).[4d]
Because pyrrolidine subunits are present in many natural
and non-natural compounds,[5] a variety of methods for the
asymmetric synthesis of chiral pyrrolidines have been de-
scribed, including catalytic enantioselective processes.[6] For
example, we have recently reported a nickel-catalyzed
enantioconvergent cross-coupling of racemic[7] a-zincated
N-Boc-pyrrolidine with an array of achiral secondary alkyl
electrophiles [Eq. (1)].[2]
T
he transition-metal-catalyzed cross-coupling of an alkyl
nucleophile with an unactivated alkyl electrophile to generate
an alkyl–alkyl bond is emerging as a powerful tool for the
synthesis of organic molecules.[1] For many such processes, the
challenge is two-fold: constructing the desired carbon–carbon
bond and controlling the stereochemistry at one or both
carbon atoms. Stereoconvergent reactions, wherein a catalyst
converts a mixture of stereoisomeric substrates into a partic-
ular stereoisomer of the product, are attractive because such
substrate mixtures are readily available (Figure 1). A number
of methods for stereoconvergent metal-catalyzed alkyl–alkyl
We decided to pursue the possibility that this method
could provide control of vicinal stereocenters in alkyl–alkyl
coupling. Specifically, we examined the cross-coupling of 2-
zincated N-Boc-pyrrolidine with a 4-substituted cyclohexyl
halide[8] (entry 1 of Table 1). Under our previously reported
conditions,[2] we generated the coupling product with very
good stereoselectivity (92% ee, 91:9 d.r.). Through the use of
a different nickel source (Ni(acac)2), we were able to obtain
similar results while employing a smaller excess of the
nucleophile (0.6 instead of 0.75 equiv of ZnR2).[9] The ee
and d.r. of the cross-coupling product remain constant
throughout the course of the reaction.
This method produces good control of vicinal stereocen-
ters[10] in alkyl–alkyl cross-coupling reactions of an array of
achiral cyclohexyl and tetrahydropyranyl iodides (Table 1).
For example, Negishi reactions of 4-monosubstituted cou-
pling partners proceed with very good ee and diastereoselec-
tivity with a sterically and electronically diverse set of
substituents (Me, Et, t-Bu, CF3, and Ph; Table 1, entries 1–
5); except in the case of the methyl-substituted electrophile,
essentially only one diastereomer is observed (> 99:1).
Furthermore, the alkyl–alkyl cross-coupling of a 4,4-disub-
stituted cyclohexyl iodide occurs with good stereoselectivity
Figure 1. Stereoconvergent metal-catalyzed alkyl–alkyl cross-coupling.
[*] X. Mu, Y. Shibata, Y. Makida, Prof. G. C. Fu
Division of Chemistry and Chemical Engineering
California Institute of Technology, Pasadena, CA 91125 (USA)
E-mail: gcfu@caltech.edu
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201702402.
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Table 1: Control of vicinal stereocenters: alkyl–alkyl cross-coupling of
partial conversion, we determined that the electrophile
undergoes isomerization during the reaction [Eq. (2) and
Eq. (3)]; in each case, the cross-coupling product is generated
in 92% ee and with > 99:1 d.r.). Possible mechanisms for this
isomerization include halogen exchange through an SN2
reaction (e.g., by zinc iodide that is generated during the
cross-coupling) and reversible transfer of IC from the alkyl
iodide to the nickel catalyst. Because the two isomers of the
electrophile do not interconvert in the presence of an iodide
source (1 equiv ZnI2 or TBAI; THF/Et2O, RT, 48 h), we favor
reversible iodine transfer between the alkyl radical and nickel
as the more likely pathway.[14] Because the d.r. values of the
alkyl iodides at partial conversion are different in [Eq. (2)]
versus [Eq. (3)], this reversible iodine transfer appears not to
occur rapidly relative to the cross-coupling.
achiral electrophiles.[a]
[a] All values are the average of two experiments. [b] Determined through
GC, HPLC, and/or SFC analysis. [c] Yield of purified product.
(entry 6). Finally, excellent control of the vicinal stereocenters
is observed in Negishi reactions of 3,5-disubstituted electro-
philes, including an oxygen heterocycle (entries 7 and 8).
Because high stereoselectivity and high yield can be
obtained in the cross-coupling of a racemic nucleophile (i.e.,
prepared from racemic 2-lithio-N-Boc-pyrroline) with an
electrophile that is an approximately 2:1 mixture of stereo-
isomers (entries 4 and 7 of Table 1), these Negishi reactions
are doubly stereoconvergent (bottom of Figure 1). In the case
of the stereogenic center on the pyrrolidine ring, the absolute
stereochemistry is controlled by the chiral catalyst.[2] The
stereochemistry at the other carbon atom of the new carbon–
carbon bond is dependent upon the structure of the electro-
phile. We hypothesize that the nickel catalyst abstracts iodine
from the electrophile,[11] which generates the same alkyl
radical from either diastereomer of the alkyl iodide. In all
cases in Table 1, the major stereoisomer of the product bears
the new alkyl substituent in the thermodynamically favored
equatorial position on the six-membered ring; this may be due
to a kinetic preference during the reaction of the alkyl radical
with nickel to form a nickel–carbon bond,[12] or to reversible
nickel–carbon bond formation and stereochemistry-deter-
mining reductive elimination.[13]
Not only achiral, but also chiral electrophiles serve as
suitable substrates for this nickel-catalyzed stereoselective
alkyl–alkyl cross-coupling, generating vicinal stereocenters
with good selectivity (Table 2).[15] A 3-substituted carbocyclic
or heterocyclic alkyl iodide reacts with high stereoselectivity
to form the cis-1,3-disubstituted product (entries 1–3). Fur-
thermore, coupling of a 3,3-disubstituted electrophile pro-
ceeds with good stereoselectivity (entry 4). Finally, bicyclic
and polycyclic secondary alkyl iodides can be employed as
cross-coupling partners (entries 5 and 6).
When the (R,R) rather than the (S,S) enantiomer of ligand
1 is used, similar stereoselectivity is generally observed, with
the major products differing only in the stereochemistry at the
position a to nitrogen (Table 1). This is consistent with control
of that stereocenter by the chiral catalyst and control of the
second stereocenter by the substrate.
In summary, alkyl–alkyl cross-coupling reactions have
now been expanded to include an array of processes wherein
vicinal stereocenters, rather than a single stereocenter, are
controlled with high selectivity. In particular, a nickel/diamine
By conducting the asymmetric cross-coupling with a single
diastereomer of the alkyl iodide and stopping the reaction at
2
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Table 2: Control of vicinal stereocenters: alkyl–alkyl cross-coupling of
(fellowship to X.M.), and the Japan Society for the Promotion
chiral electrophiles.[a]
of Science (fellowship to Y.M.). We thank Jun Myun Ahn (x-
ray crystallography), Lawrence M. Henling (Caltech X-Ray
Crystallography Facility), Dr. Nathan Schley (x-ray crystal-
lography), Samantha E. Shockley (Stoltz lab), Dr. Scott C.
Virgil (Caltech Center for Catalysis and Chemical Synthesis),
Dr. David G. VanderVelde (Caltech NMR facility), and Dr.
Haolin Yin for assistance.
Conflict of interest
The authors declare no conflict of interest.
Keywords: alkylation · asymmetric synthesis · cross-coupling ·
nickel · zinc
[1] J. Choi, G. C. Fu, Science accepted for publication.
[2] Use of a racemic nucleophile: C. J. Cordier, R. J. Lundgren,
G. C. Fu, J. Am. Chem. Soc. 2013, 135, 10946 – 10949. We
speculate that enantioconvergence is achieved through rever-
sible homolysis of the nickel-pyrrolidinyl bond.
[3] Use of a racemic electrophile: a) B. Saito, G. C. Fu, J. Am. Chem.
Soc. 2008, 130, 6694 – 6695; b) J. Schmidt, J. Choi, A. T. Liu, M.
Slusarczyk, G. C. Fu, Science 2016, 354, 1265 – 1269.
[4] a) E. Hohn, J. Pietruszka, Adv. Synth. Catal. 2004, 346, 863 – 866
(one example: cyclopropylboron reagent with cyclopropyl
electrophile); b) P. Ren, O. Vechorkin, K. von Allmen, R.
Scopelliti, X. Hu, J. Am. Chem. Soc. 2011, 133, 7084 – 7095
(one example: 7% yield); c) S. L. Zultanski, G. C. Fu, J. Am.
Chem. Soc. 2011, 133, 15362 – 15364 (one example: cyclopropyl-
boron reagent); d) C.-T. Yang, Z.-Q. Zhang, J. Liang, J.-H. Liu,
X.-Y. Lu, H.-H. Chen, L. Liu, J. Am. Chem. Soc. 2012, 134,
11124 – 11127 (Grignard reagents as nucleophiles); e) Ref. [2]
(nucleophile: a-zincated N-Boc-pyrrolidine).
[5] Examples and leading references: a) Table 6 in: S. D. Roughley,
A. M. Jordan, J. Med. Chem. 2011, 54, 3451 – 3479; b) J. P.
Michael, Nat. Prod. Rep. 2008, 25, 139 – 165; c) J. P. Michael,
Alkaloids 2001, 55, 91 – 258; d) A. F. M. Rizk, Naturally Occur-
ring Pyrrolizidine Alkaloids, CRC Press, Boca Raton, 1991.
[6] For example: a) A. R. Brown, C. Uyeda, C. A. Brotherton, E. N.
Jacobsen, J. Am. Chem. Soc. 2013, 135, 6747 – 6749; b) B. M.
Trost, T. M. Lam, M. A. Herbage, J. Am. Chem. Soc. 2013, 135,
2459 – 2461.
[7] The organozinc reagent is prepared through lithiation with s-
BuLi (no chiral additive) to generate a racemic organolithium
reagent (RLi). Reaction with ZnI2 affords a diorganozinc
reagent (ZnR2) that may bear homochiral or heterochiral
substituents (R).
[8] Systematic studies of the use of an achiral catalyst to achieve
diastereoselective cross-coupling of primary alkyl nucleophiles
with cyclic alkyl electrophiles: a) P. M. Perez Garcia, T.
Di Franco, A. Orsino, P. Ren, X. Hu, Org. Lett. 2012, 14,
4286 – 4289; b) H. Gong, R. Sinisi, M. R. Gagnꢀ, J. Am. Chem.
Soc. 2007, 129, 1908 – 1909.
[a] The electrophilic coupling partners were applied at ꢀ99% ee, except
for entry 4, where the coupling partner was present at 94% ee.
[b] Determined through HPLC analysis; ratio (major stereoisomer):(sum
of all other stereoisomers). [c] The values in parentheses are the data for
(R,R)-1. [d] Yield of purified product.
catalyst mediates doubly stereoconvergent Negishi coupling
of an alkylzinc reagent with an alkyl halide. With respect to
the new carbon–carbon bond, the chiral catalyst controls the
stereochemistry of the carbon that originates from the
nucleophile, and the substrate controls the stereochemistry
of the carbon that originates from the electrophile. Given the
frequency with which vicinal stereocenters are encountered in
organic molecules, we anticipate that the development of
methods that achieve doubly stereoconvergent alkyl–alkyl
bond formation will emerge as a highly active area of research
in the coming years.
[9] Use of a lower catalyst loading (10% Ni(acac)2/12% (S,S)-1) led
to formation of the product in 92% ee, 93:7 d.r., and 85% yield.
[10] According to the IUPAC Compendium of Chemical Terminol-
ogy (https://goldbook.iupac.org/S05980.html; accessed 21 Feb-
ruary 2017), a stereogenic center is a “grouping of atoms
consisting of a central atom and distinguishable ligands, such that
Acknowledgements
Support has been provided by the National Institutes of
Health (National Institute of General Medical Sciences: R01-
GM62871), the Shanghai Institute of Organic Chemistry
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the interchange of any two of the substituents leads to
a stereoisomer.”
J. C. Tellis, D. N. Primer, G. A. Molander, M. C. Kozlowski, J.
Am. Chem. Soc. 2015, 137, 4896 – 4899.
[11] a) J. Zhou, G. C. Fu, J. Am. Chem. Soc. 2004, 126, 1340 – 1341;
b) T. J. Anderson, G. D. Jones, D. A. Vicic, J. Am. Chem. Soc.
2004, 126, 8100 – 8101; c) N. D. Schley, G. C. Fu, J. Am. Chem.
Soc. 2014, 136, 16588 – 16593.
[14] Examples of previous studies of the reversibility of halogen-
atom transfer in nickel-catalyzed cross-coupling of unactivated
alkyl halides: a) Ref. [4c] (Suzuki coupling; irreversible);
b) Ref. [8a] (Kumada coupling; reversible).
[12] Capture of the 4-t-butylcyclohexyl radical often proceeds with
poor to moderate stereoselectivity. For example: a) W. Damm,
B. Giese, J. Hartung, T. Hasskerl, K. N. Houk, O. Hꢁter, H.
Zipse, J. Am. Chem. Soc. 1992, 114, 4067 – 4079; b) J. O. Osby,
S. W. Heinzman, B. Ganem, J. Am. Chem. Soc. 1986, 108, 67 – 72.
[13] For example: a) X. Lin, J. Sun, Y. Xi, D. Lin, Organometallics
2011, 30, 3284 – 3292; b) R. Fu, Ph.D. Thesis, California Institute
of Technology, Pasadena, CA, 2014, chap. 5; c) O. Gutierrez,
[15] In preliminary studies under our standard conditions, very
modest stereoselectivity was observed in cross-coupling of
secondary alkyl electrophiles that are conformationally flexible.
Manuscript received: March 6, 2017
Final Article published: && &&, &&&&
4
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Communications
Asymmetric Synthesis
X. Mu, Y. Shibata, Y. Makida,
G. C. Fu*
&&&& — &&&&
Control of Vicinal Stereocenters through
Nickel-Catalyzed Alkyl–Alkyl Cross-
Coupling
Side by side: A chiral nickel catalyst was
found to mediate doubly stereoconver-
gent alkyl–alkyl cross-coupling, specifi-
cally, reactions of a racemic pyrrolidine-
derived nucleophile with cyclic alkyl hal-
ides (as mixtures of stereoisomers) to
produce vicinal stereocenters with very
good stereoselectivity.
Angew. Chem. Int. Ed. 2017, 56, 1 – 5
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!