Enantioselective α-Alkylation of Aldehydes by Photoredox Organocatalysis: Rapid Access to Pharmacophore Fragments from β-Cyanoaldehydes

Article abstract of DOI:10.1002/anie.201503789

The combination of photoredox catalysis and enamine catalysis has enabled the development of an enantioselective α-cyanoalkylation of aldehydes. This synergistic catalysis protocol allows for the coupling of two highly versatile yet orthogonal functionalities, allowing rapid diversification of the oxonitrile products to a wide array of medicinally relevant derivatives and heterocycles. This methodology has also been applied to the total synthesis of the lignan natural product (-)-bursehernin. A combination of photoredox catalysis and enamine catalysis has enabled the development of an enantioselective cyanoalkylation of aldehydes. This synergistic catalysis protocol makes possible the coupling of two highly versatile yet orthogonal functionalities.

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International Edition: DOI: 10.1002/anie.201503789
German Edition: DOI: 10.1002/ange.201503789
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.
Homepage: http://www.princeeton.edu/chemistry/macmillan/
[**] 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
under http://dx.doi.org/10.1002/anie.201503789.
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Table 1: Optimization of the photoredox organocatalytic addition.
Entry Solvent
Concentration [m] Catalyst Yield [%] ee [%][a]
1
2
3
4
5
6
7
8
9
DMF
CH3CN
CH3NO2 0.5
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
0.5
0.5
4
4
4
4
8
8
4
4
4
72
62
28
84
85
90
93
92
94
95
95
95
95
95
95
0.5
0.5
4
4
4
95[b]
90[c]
74[d]
4
[a] Yield and enantiomeric excess determined by chiral GLC analysis of
the aldehyde product using p-methoxyphenylacetone as internal stan-
dard. Reactions were performed with five equivalents of octanal unless
otherwise noted. [b] Yield of isolated product. [c] Three equivalents of
octanal. [d] One equivalent of octanal.
Scheme 1. Catalytic cycle for aldehyde a-cyanoalkylation.
(Table 1, entry 1, 93% ee). Evaluation of a variety of high-
dielectric solvents identified dimethyl sulfoxide (DMSO) as
the optimal medium, while increasing the reaction concen-
tration provided excellent levels of both yield and enantio-
selectivity (entry 7, 95% yield, 95% ee). Notably, high-
throughput analysis of a 96-member organocatalyst library
identified the novel tert-butyl-furyl substituted imidazolidi-
none 8 as a viable alternative to catalyst 4 (entry 6, 90% yield,
95% ee). Finally, reducing the aldehyde stoichiometry to 1–3
equivalents could be tolerated without significant impact on
yield or enantiocontrol (entries 8–9, 74–90% yield, 95% ee).
Using the optimal conditions identified in Table 1, we
have demonstrated that our alkylcyanation reaction is quite
general in scope with respect to the aldehyde component
(Table 2). For example, aldehydes bearing aryl rings and
significant steric bulk were well tolerated (11–16, 18, 79–97%
yield, 92–96% ee). Interestingly, intramolecular radical cyc-
lization was not observed when aldehydes bearing pendent p-
bonds were used (10 and 17, 68–90% yield, 91–95% ee).
Finally, p-methoxyphenylacetaldehyde represents an intrigu-
ing addition to the scope of aldehydes in the transformation,
as the alkylcyano product contains a tertiary a-formyl
benzylic stereocenter, a motif typically prone to facile
racemization (18, 80% yield, 90% ee).
electron reduction of the bromonitrile species by the strongly
+
reducing Ru(bpy)3 ion 1[13] (E1/2II/I = À1.33 V vs. SCE in
+ [14]
CH3CN for Ru(bpy) ;
E
1/2
red = À0.69 V vs. SCE in DMF for
bromoacetonitrile[15]) should provide the cyanoalkyl radical 3
and bromide ion after fragmentation. Simultaneously, the
organocatalytic cycle would initiate by condensation of amine
catalyst 4 with an aldehyde to generate a chiral enamine.
Computational studies reveal that the lowest-energy confor-
mation of the enamine DFT-5 is found to position the p-
=
nucleophilic C C system distal to the large tert-butyl group on
the imidazolidinone catalyst framework. Effective shielding
of the Re face of the enamine by the pendent methyl group of
the organocatalyst requires coupling to the electron-deficient
radical 3 via the enamine Si face, thereby generating a-amino
radical 6, which is poised to re-engage the photoredox
2+
catalytic cycle. Photoexcitation of Ru(bpy)3 generates the
oxidizing species 2 (E1/2*
II/I =+ 0.77 V vs. SCE in CH3CN),[14]
which is well suited to perform a single-electron oxidation of
a-amino radical 6 (E1/2red = À0.92 to À1.12 V vs. SCE)[16]
thereby delivering iminium ion 7; hydrolysis thereafter
provides the a-cyanoalkylated aldehyde product while regen-
erating amine 4, thus completing the organocatalytic cycle.
We chose to initiate our a-cyanoalkylation studies by
exposing octanal, a-bromoacetonitrile, Ru(bpy)3Cl2, and
imidazolidinone catalyst 4 to a 26 W CFL light source.[6] To
our great delight, the desired asymmetric bond formation was
realized in 72% yield and with excellent enantioselectivity
We next investigated the scope of the a-bromonitrile
alkylating component in this new dual catalysis bond-forming
reaction. While bromoacetonitrile is an ideal coupling
partner, we were also delighted to find that bromocyano
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Table 2: Enantioselective a-cyanoakylation: aldehyde scope.
Table 3: Evaluation of the cyanobromide coupling partner.
<
Product yield [%], (ee [%])[a]
Product yield [%], (ee [%])[a]
Product yield [%], (ee [%])[a]
Product yield [%], (ee [%])[a]
[a] Yield of isolated product. Diastereomeric ratios (dr) 1–3:1, deter-
mined by 1H NMR analysis, see the Supporting Information. Products
were isolated as the aldehyde and further derivatized to determine
enantiomeric excess (see the Supporting Information). [b] Catalyst
added as the solid free amine; 20 mol% 2,6-lutidinium triflate was added
as a source of the acid co-catalyst.
yls were employed.[17] Notably, fully substituted bromonitriles
coupled efficiently, generating all-carbon quaternary stereo-
centers with excellent enantiocontrol albeit with modest
diastereoselectivity (25 and 26, > 93% ee).
[a] Yield of isolated aldehyde product. Enantiomeric excess determined
by chiral GLC, HPLC, or SFC analysis on the aldehyde or the
corresponding alcohol (see the Supporting Information). [b] Reaction
performed at À208C. Product isolated as the corresponding alcohol after
NaBH4 reduction of the crude reaction mixture.
Having examined the scope of both reaction partners, we
next explored the breadth of pharmacophore fragments that
could be accessed readily using these enantioenriched cyano-
aldehyde building blocks. As illustrated in Scheme 2, alcohols,
ethers, lactones, aldehydes, ketones, amides, amines, and
lactams could be constructed in a straightforward manner in
under three steps.[18] Intriguingly, we found that the nitrile
could be hydrogenated under Raney Nickel conditions and
achieve in situ cyclization of the amine on the pendent
aldehyde moiety; further reduction of the resulting iminium
ion generates (R)-3-benzylpyrrolidine (35) in a single step in
systems bearing diverse substitution patterns couple in high
efficiency and excellent enantioselectivity (Table 3, 73–88%
yield, 93–98% ee). It should be noted that imidazolidinone 8
was the preferred amine catalyst when substituted cyanoalk-
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Scheme 3. Total synthesis of (À)-bursehernin. LDA=lithium diisopro-
pylamide, HMPA=hexamethylphosphoramide.
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Scheme 2. Elaboration of cyanoalkylation products to useful motifs.
Conditions: a) NaBH4, MeOH, CH2Cl2, 84%, 93% ee. b) MeOH, conc.
HCl, 1008C, 88%, 93% ee. c) NaH, BnBr, DMF, 85%, 93% ee.
d) DIBAL-H, Et2O, 83%, 93% ee. e) Mg, I2, PhBr, Et2O, then THF, 1m
HCl, 88%, 92% ee. f) NaClO2, NaH2PO4, THF, tBuOH, 2-methyl-2-
butene, H2O, product not isolated. g) BnNH2, HOBt·H2O, NMM,
EDCI·HCl, THF, 48%, 93% ee for two steps. h) BnNH2, NaBH(OAc)3,
DCE, 77%, 93% ee. i) 1 mol% Parkins’ catalyst, diglyme, 1608C, 93%,
93% ee. j) p-TsOH·H2O, Raney Nickel 2400, H2, EtOH, 81%, 93% ee.
Bn=benzyl, DMF=dimethylformamide, DIBAL-H=diisobutylalumi-
num hydride, THF=tetrahydrofuran, HOBt=1-hydroxybenzotriazole,
EDCI=1-ethyl-3-(3’-dimethylaminopropyl)carbodiimide, OAc=acetate,
and DCE=1,2-dichloroethane.
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(< 1%) was observed in any of these synthetic elaboration
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Finally, to demonstrate the utility of our novel alkylcya-
nation technology, we undertook a short synthesis of (À)-
bursehernin (37), a lignan natural product of proven biolog-
ical activity (Scheme 3).[20] Employing our standard photo-
redox-amine catalysis protocol, exposure to sodium borohy-
dride and cyclization under basic conditions provided the
lactone 36. The four-step synthesis of (À)-bursehernin was
then completed via a highly selective a-alkylation using 3,4-
dimethoxybenzyl bromide, generating the natural product in
80% yield overall from bromoacetonitrile.
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Keywords: aldehydes · alkylation · organocatalysis ·
photoredox catalysis · total synthesis
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Received: April 25, 2015
Published online: June 30, 2015
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