Palladium-Catalyzed Allylic Alkylation
COMMUNICATION
As such, we examined the influence of alternate N-substitu-
ents in the context of the allylic alkylation with imides.
Gratifyingly, we identified N-benzyloxy imides as excel-
lent substrates for this methodology, generating imides 7d
and e in yields and enantioselectivities comparable to their
N-benzoyl counterparts. In conjunction with the results ob-
tained for substituted N-acyl lactams 5g–j, we reason that
the nature of the a’-substituent leads to the observed en-
hancements in enantioselectivity, though enolate electronics
have been shown to dramatically affect the reaction rate.
To examine the relative influence of the steric and stereo-
electronic effects associated with the a’-group, we prepared
enones 9b and c and diosphenol ethers 18a and b and sub-
jected these substrates to the standard conditions employed
in the alkylation of lactams and imides (Scheme 4). Enones
In summary, we have designed and evaluated a number of
novel substrates to probe the influence of enolate electron-
ics and the role of a’-functionality on selectivity in the palla-
dium-catalyzed decarboxylative allylic alkylation. Based on
these results, we reason that the high enantioselectivities ob-
served with lactams and imides are a consequence of both
electronic and steric effects associated with a’-substituents,
and that enolate electronics alone contribute relatively little
to the stereochemical outcome of the reaction. Both experi-
mental and theoretical investigations are currently underway
in our group to determine the nature and origin of the
effect of a’-substitution on this transformation and to use
this insight to improve and expand our methods.
Acknowledgements
The authors thank NIH-NIGMS (R01 M080269-01), Roche, Abbott Lab-
oratories, Amgen, Boehringer Ingelheim, the Gordon and Betty Moore
Foundation, and Caltech for awards and financial support. D.C.D. thanks
the National Science Foundation for financial support (Predoctoral Re-
search Fellowship, No. DGE-1144469). W.-B.L. thanks the Shanghai Insti-
tute of Organic Chemistry for financial support (SIOC Postdoctoral Fel-
lowship). A.N.M. is grateful for a fellowship by the Deutsche Akademie
der Naturforscher Leopoldina. Profs. Sarah Reisman and Theodor
Agapie are acknowledged for helpful discussions and suggestions. Dr.
David VanderVelde and Dr. Scott Ross are acknowledged for NMR as-
sistance. Dr. Mona Shahgoli and Naseem Torian are acknowledged for
High-Resolution Mass Spectrometry assistance.
Keywords: allylation · asymmetric catalysis · heterocyclic
compounds · high-throughput screening · palladium
[1] For review of approaches for the asymmetric construction of all-
carbon quaternary stereocenters, see: a) J. Christoffers, A. Baro,
Scheme 4. Allylic alkylation of a’-functionalized enones.
[2] For examples of other efforts in the enantioselective allylic alkyla-
tion of enolates catalyzed by palladium, see: a) B. M. Trost, J. Xu, T.
Schmidt, J. Am. Chem. Soc. 2009, 131, 18343–18357; b) B. M. Trost,
B. Schꢁffner, M. Osipov, D. A. A. Wilton, Angew. Chem. 2011, 123,
3610–3613; Angew. Chem. Int. Ed. 2011, 50, 3548–3551; c) M. Na-
kamura, A. Hajra, K. Endo, E. Nakamura, Angew. Chem. 2005, 117,
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[3] For reviews on palladium-catalyzed allylic alkylation, see: a) J. A.
[4] For references on the development of oxazoline ligands, see: a) P.
Schnider, G. Koch, R. Prꢃtꢄt, G. Wang, F. M. Bohnen, C. Krꢅger, A.
13b and c are formed in low enantioselectivity. By contrast,
benzyl diosphenol ether 19a, which differs from 13c only in
the substitution of oxygen for a methylene group, is generat-
ed in 92% yield and 94% ee. This suggests that purely steric
or p-stacking interactions are not the sole contributing fac-
tors to enantioselectivity. Rather, electronic effects of the
a’-substituent exert an important influence on the stereose-
lectivity of the reaction. However, a certain amount of steric
bulk appears to be critical in obtaining high enantioselectivi-
ty, as methyl diosphenol ether 19b is produced in 85% ee.
In comparison, analogous enone 9a, which bears no a’-func-
tionality, proceeds under the same conditions to afford
enone 13a in 88% ee,[19] with vinylogous amides and esters
also in the 80–90% ee range (vide supra). Overall, our stud-
ies on the role of the a’-substituent have culminated in the
discovery of substrate 18a, which proceeds with the greatest
enantioselectivity observed in a PdACTHNUTRGNEUNG(PHOX) catalyst system
for a carbocyclic substrate bearing an a-methyl group and
unsubstituted allyl moiety.
Chem. Eur. J. 2013, 19, 4414 – 4418
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