Journal of the American Chemical Society
Communication
Stereogenicity at iridium is also a critical determinant of
enantioselectivity. Because of trans-effects (vide supra), the
“proximal” isomers of C and D are the most reactive among all
16 stereoisomers. The four most favorable pathways involve
D_exo_proximal (TS-1) and C_endo_proximal (TS-7), which
give (S)-product, and D_endo_proximal (TS-6) and C_exo_
proximal (TS-5), which give (R)-product. Optimized struc-
tures of these branch-selective transition states are shown in
Figure 5. The two transition states leading to the (R)-product,
TS-5 and TS-6, are destabilized because the allyl C2−H
moiety in TS-5 and the C3−methyl in TS-6 clash with a P-
tolyl group of (S)-tol-BINAP. Thus, TS-5 and TS-6 are 1.6
and 1.8 kcal/mol less stable than the lowest-energy transition
state, TS-1, that gives the (S)-product. In TS-1, the steric
repulsions between tol-BINAP and the allyl group are absent.
Our calculations are consistent with the experimentally
observed enantioselectivity for the (S)-product.
Michael J. Krische − Department of Chemistry, University of
Texas at Austin, Austin, Texas 78712, United States;
Authors
Woo-Ok Jung − Department of Chemistry, University of
Texas at Austin, Austin, Texas 78712, United States
Binh Khanh Mai − Department of Chemistry, University of
Pittsburgh, Pittsburgh, Pennsylvania 15260, United States;
Brian J. Spinello − Department of Chemistry, University of
Texas at Austin, Austin, Texas 78712, United States
Zachary J. Dubey − Department of Chemistry, University of
Texas at Austin, Austin, Texas 78712, United States
Seung Wook Kim − Department of Chemistry, University of
Texas at Austin, Austin, Texas 78712, United States
In summary, we report iridium-catalyzed allylic alkylations of
nitronate nucleophiles. This method, which employs an air-
and water-stable π-allyliridium C,O-benzoate catalyst modified
by tol-BINAP, enables highly regio- and enantioselective
substitution of racemic branched alkyl-substituted allylic
acetates by α,α-disubstituted nitronates and, hence, entry to
β-stereogenic α-quaternary primary amines. As revealed by
DFT calculations, early transition states that render the
reaction less sensitive to steric effects and distinct trans-effects
of diastereomeric chiral-at-iridium π-allyl complexes facilitate
formation of congested tertiary−quaternary C−C bonds.
Related asymmetric allylic alkylations of nonstabilized
carbanions are currently underway.23
Complete contact information is available at:
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The Robert A. Welch Foundation (F-0038) and the NIH-
NIGMS (RO1-GM069445, 1 S10 OD021508-01, R35
GM128779) are acknowledged. We thank Mr. Weijia Shen
and Ms. Sakiho Sumikura for skillful technical assistance.
Genentech is acknowledged for summer predoctoral internship
support (W.-O.J., B.J.S., and S.W.K.). DFT calculations were
carried out at the Center for Research Computing at the
University of Pittsburgh, the Extreme Science and Engineering
Discovery Environment (XSEDE), and the TACC Frontera
Supercomputer supported by the National Science Foundation
Grant Number ACI-1548562. We thank Dr. Michael Ruf of
Bruker AXS for acquisition of crystallographic data.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
■
sı
Experimental procedures; spectroscopic and chromato-
graphic data for all new compounds (1H NMR, 13C
NMR, IR, and HRMS), including HPLC traces for
racemic and enantiomerically enriched compounds;
computational details; single-crystal X-ray diffraction
data for compound 4l (PDF)
REFERENCES
■
(1) It was estimated in 2014 that chiral amines constitute roughly
40% of new FDA-approved small-molecule drugs: Jarvis, L. M. Chem.
Eng. News 2014, 94, 12−17.
(2) For selected reviews on the synthesis of chiral amines, see:
3740. (d) Chiral Amine Synthesis: Methods, Developments and
Applications; Nugent, T. C., Ed.; Wiley-VCH, 2010. (e) Nugent, T.
Reduction. Adv. Synth. Catal. 2010, 352, 753−819. (f) Stereoselective
Formation of Amines; Li, W., Zhang, X., Eds.; Topics in Current
Chemistry; Springer, 2014; Vol. 343. (g) Mailyan, A. K.; Eickhoff, J.
(h) Abdine, R. A. A.; Hedouin, G.; Colobert, F.; Wencel-Delord, J.
Catal. 2021, 11, 215−247.
Accession Codes
CCDC 2081056 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
Craig E. Stivala − Discovery Chemistry, Genentech, Inc., South
San Francisco, California 94080, United States;
Jason R. Zbieg − Discovery Chemistry, Genentech, Inc., South
San Francisco, California 94080, United States;
Peng Liu − Department of Chemistry, University of Pittsburgh,
Pittsburgh, Pennsylvania 15260, United States; orcid.org/
(3) For chiral β-stereogenic amines via catalytic enantioselective
hydrogenation of enamines derivatives (including dehydro-β-amino
acid derivatives), see: (a) Elaridi, J.; Thaqi, A.; Prosser, A.; Jackson,
9347
J. Am. Chem. Soc. 2021, 143, 9343−9349