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Angewandte
Communications
Synthetic Methods
Hot Paper
Enantioselective a-Alkylation of Aldehydes by Photoredox
Organocatalysis: Rapid Access to Pharmacophore Fragments from b-
Cyanoaldehydes**
Eric R. Welin, Alexander A. Warkentin, Jay C. Conrad, and David W. C. MacMillan*
Abstract: The combination of photoredox catalysis and
enamine catalysis has enabled the development of an enantio-
selective a-cyanoalkylation of aldehydes. This synergistic
catalysis protocol allows for the coupling of two highly
versatile yet orthogonal functionalities, allowing rapid diversi-
fication of the oxonitrile products to a wide array of
medicinally relevant derivatives and heterocycles. This meth-
odology has also been applied to the total synthesis of the
lignan natural product (À)-bursehernin.
Recently, we questioned whether this dual photoredox-
organocatalysis platform could be translated to the asym-
metric catalytic alkylation of aldehydes using a-bromo
cyanoalkyls, a protocol that would generate b-cyanoalde-
hydes in one step. As a critical design element, we recognized
that a-bromo cyanoalkylating reagents would not be suitable
electrophiles for most catalytic enolate addition pathways;
however, the corresponding open-shell radicals, derived by
one-electron reduction of a-bromonitriles, should readily
undergo coupling with transiently generated chiral enamines.
In addition, the nitrile functional group offers rapid access to
a large array of carbonyl, amine, or imidate motifs,[10] and as
such, b-cyanoaldehydes can be readily translated to lactones,
pyrrolidines, lactams, and cyanoalcohols—pharmacophore
fragments that are ubiquitous in medicinal chemistry.[11]
Herein we report the first enantioselective a-cyanoalkylation
of aldehydes via the synergistic combination of photoredox
and organocatalysis (Figure 1).[12] Furthermore, we demon-
T
he enantioselective a-alkylation of carbonyl compounds
with sp3-hybridized halide-bearing electrophiles has long
been considered an elusive goal for practitioners of asym-
metric catalysis.[1] Indeed, the most commonly employed
strategy to achieve the stereoselective construction of a-alkyl
carbonyls involves the coupling of auxiliary-based metal
enolates with halo or tosyloxy alkanes.[2,3] A critical issue for
the development of catalytic variants of this venerable
reaction has been the insufficient electrophilicity of alkyl
halides towards silyl or alkyl enol ether p-nucleophiles
(enolate equivalents that are broadly employed in asymmetric
catalysis). This limitation has mandated the use of lithium-,
sodium-, or cesium-derived enolates for auxiliary controlled
carbonyl a-functionalization at higher carbonyl oxidation
states. Recently, however, the application of secondary amine
organocatalysts has overcome several of these constraints by
the direct use of aldehydes or ketones in a variety of chiral
enamine a-functionalization reactions.[4] As one example, our
laboratory disclosed the synergistic merger of enamine
catalysis with visible-light photoredox catalysis, wherein
a ruthenium photocatalyst is used to generate highly electro-
philic alkyl radicals derived from simple a-bromoesters and
ketones.[5] Since that time, the field of photoredox catalysis as
applied to organic synthesis has received considerable
attention[6] and we have disclosed its successful application
to the enantioselective a-trifluoromethylation,[7] a-benzyla-
tion,[8] and a-amination[9] of aldehydes.
[*] E. R. Welin, Dr. A. A. Warkentin, Dr. J. C. Conrad,
Prof. Dr. D. W. C. MacMillan
Merck Center for Catalysis at Princeton University
Washington Road, Princeton, NJ 08544-1009 (USA)
E-mail: dmacmill@princeton.edu
Figure 1. Photoredox organocatalysis a-cyanoalkylation of aldehydes.
[**] The authors are grateful for financial support provided by the NIH
General Medical Sciences Grant NIHGMS (grant number R01
GM093213-01) and kind gifts from Merck, AbbVie, and Bristol
Myers Squibb.
strate the application of this new dual catalysis platform to the
rapid and stereoselective construction of cyclic and acyclic
motifs of broad value to the chemistry of drug discovery.
We envisioned that our cyanoalkylation dual catalysis
mechanism would proceed as depicted in Scheme 1. Single-
Supporting information for this article is available on the WWW
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ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 9668 –9672