Spin-Center Shift-Enabled Direct Enantioselective α-Benzylation of Aldehydes with Alcohols

Article abstract of DOI:10.1021/jacs.7b12768

Nature routinely engages alcohols as leaving groups, as DNA biosynthesis relies on the removal of water from ribonucleoside diphosphates by a radical-mediated "spin-center shift" (SCS) mechanism. Alcohols, however, remain underused as alkylating agents in synthetic chemistry due to their low reactivity in two-electron pathways. We report herein an enantioselective α-benzylation of aldehydes using alcohols as alkylating agents based on the mechanistic principle of spin-center shift. This strategy harnesses the dual activation modes of photoredox and organocatalysis, engaging the alcohol by SCS and capturing the resulting benzylic radical with a catalytically generated enamine. Mechanistic studies provide evidence for SCS as a key elementary step, identify the origins of competing reactions, and enable improvements in chemoselectivity by rational photocatalyst design.

Full text of DOI:10.1021/jacs.7b12768

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Article
Spin-Center Shift-Enabled Direct Enantioselective
a-Benzylation of Aldehydes with Alcohols
Eric D Nacsa, and David W. C. MacMillan
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b12768 • Publication Date (Web): 05 Feb 2018
Downloaded from http://pubs.acs.org on February 5, 2018
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Spin-Center Shift-Enabled Direct Enantioselective -Benzylation of
Aldehydes with Alcohols
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Eric D. Nacsa and David W. C. MacMillan
Merck Center for Catalysis at Princeton University Washington Road, Princeton, NJ 08544, USA.
ABSTRACT: Nature routinely engages alcohols as leaving groups, as DNA biosynthesis relies on the removal of water
from ribonucleoside diphosphates by a radical-mediated ‘spin-center shift’ (SCS) mechanism. Alcohols, however, remain
underused as alkylating agents in synthetic chemistry due to their low reactivity in two-electron pathways. We report
herein an enantioselective a-benzylation of aldehydes using alcohols as alkylating agents based on the mechanistic prin-
ciple of spin-center shift. This strategy harnesses the dual activation modes of photoredox and organocatalysis, engaging
the alcohol by SCS and capturing the resulting benzylic radical with a catalytically-generated enamine. Mechanistic stud-
ies provide evidence for SCS as a key elementary step, identify the origins of competing reactions, and enable improve-
ments in chemoselectivity by rational photocatalyst design.
a.
INTRODUCTION
Spin-center shift: an essential biochemical mechanism
In DNA biosynthesis, deoxyribonucleoside diphosphate
building blocks are procured from their corresponding
PPO
PPO
R
R
O
O
RNR
class I
ribonucleosides by the action of ribonucleotide reductase
(RNR) enzymes.1 The step in this deoxygenation occurs
via a (3¢,2¢)-spin-center shift (SCS) event, which induces a
b-C–O-scission and the net loss of water (Figure 1a).2 De-
spite this well-established open-shell mechanism that
engages alcohols as leaving groups, alcohols remain un-
derexploited as alkylating agents due to the substantial
barrier to the displacement of the hydroxyl group by two-
electron pathways.3 Nonetheless, the direct use of alco-
hols as electrophiles remains an important goal in syn-
thetic organic chemistry due to their low genotoxicity,
robustness, and ubiquity in naturally-occurring mole-
cules.4
HO
O
OH
SCS
ribose motif
deoxyribose motif
–H2O
b.
Design plan for enantioselective !-benzylation with alcohols
O
O
Ir
En
HO
H
H
N
Me
N
Me
enantioenriched
!-benzyl aldehyde
aldehyde
alcohol
–H2O
ꢀ
ꢀ
Non-traditional alkylating agent
Key synthon for
natural products &
pharmaceuticals
ꢀ
Native handle, stable, non-genotoxic
Inspired by nature’s spin-center shift process, our group
recently reported the alkylation of heteroarenes with al-
cohols as latent alkylating agents, relying on dual photo-
redox and hydrogen atom transfer catalysis.5 Given that
photoredox catalysis provides (1) mild access to open-
shell radical intermediates and (2) a general platform to
perform concurrent oxidation and reduction steps in the
same vessel,6 we hypothesized that this activation mode,
in concert with organocatalysis, could enable a direct,
enantioselective a-benzylation of aldehydes with hetero-
benzylic alcohols as electrophiles by exploiting SCS (Fig-
ure 1b).
Pioneering work by Evans,7 Oppolzer,8 Seebach,9 and
Myers10 has long established that the stereoselective a-
benzylation of carbonyls can be readily accomplished
using chiral auxiliaries. Surprisingly, however, catalytic
enantioselective variants of this important transformation
Photoredox-enabled
spin-center shift
En
SET
HO
SCS
NH
NH
electron-rich
radical
electrophilic
radical
+
–H2O
Figure 1. Spin-center shift (SCS) as a conceptual basis for the
enantioselective a-benzylation of aldehydes with alcohols.
(a) SCS in DNA biosynthesis. (b) Advantages of alcohols as
alkylating agents, and a possible mechanism in which ben-
zylic alcohols may be engaged by SCS.
have been slower to develop, with the most notable ex-
amples being the phase transfer benzylation of glycine
imines,11 chiral triamine ligation of ketone-derived lithium
enolates,12 and Cr(salen) activation of preformed tin eno-
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Page 2 of 11
lates.13 More recently, photoredox organocatalysis has
Scheme 1. Proposed mechanism for the enantioselec-
1
2
3
4
5
6
7
8
emerged as a platform for the enantioselective construc-
tion of a-alkylated carbonyl motifs,14 including the a-
benzylation of aldehydes using electron-deficient benzylic
bromide.14b
a
tive -benzylation of aldehydes with alcohols.
O
O
Me
H
N
Me
Me
R
7
Bn
N
A common feature of both catalytic and auxiliary-based
strategies is the reliance on benzylic halide electrophiles
or their equivalents (e.g., tosylates). Indeed, alkyl (pseu-
do)halides are archetypal alkylating agents due to the
excellent leaving group ability of bromide, iodide, and
sulfonate ions. This reactivity, however, also confers un-
desirable properties such as genotoxicity and light-
sensitivity, necessitating care in handling and storing the-
se reagents. Furthermore, alkyl halides are frequently ob-
tained by treatment of the corresponding alcohols with a
stoichiometric activating agent,15 highlighting the appeal
of engaging alcohols directly. In the context of asymmet-
ric a-alkylation, the use of alcohols has been restricted to
specialized cases where heterolytic C–O cleavage gener-
ates highly stabilized cations.16 In this article, we report
the design and application of an enantioselective a-
benzylation of aldehydes with heterobenzylic alcohols as
well as mechanistic studies that support the proposed SCS
pathway, elucidate the major undesired reaction path-
ways, and enable improvements in chemoselectivity by
photocatalyst modification.
aldehyde
Si-face
open
9
DFT-9
R
enamine
O
Me
N
9
Me
Me
NH
+
Bn
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N
H
Organocatalytic
Cycle
6
radical
8
organocatalyst
O
Me
O
Me
N
N
Me
Me
Me
Me
+
N
Bn
Bn
N
Ar
11
Ar
SET
R
R
10
NH
6
IrIV (5)
+
O
IrIII (1)
oxidant
H
Photoredox
Catalytic
Cycle
SCS
–H2O
NH
R
N
12
α-benzyl aldehyde
HO
+
SET
H
4
*IrIII (2)
visible light
HO
reductant
3
N
DESIGN PLAN
alcohol
Our design for the enantioselective a-benzylation of alde-
hydes with alcohols is outlined in Figure 1b. Single-electron
reduction of a benzylic alcohol by a photoredox catalyst
would initially give rise to an electron-rich radical. This in-
termediate would be poised to undergo SCS, whereby ben-
zylic C–O bond cleavage and proton transfer would expel a
molecule of water and reveal an electrophilic benzylic radi-
cal. This electron-deficient species would then react with a
catalytically-generated enamine, forming the desired C–C
bond stereoselectively and ultimately leading to the enanti-
oenriched a-benzyl aldehyde.
regenerate ground state IrIII photocatalyst 1 and iminium
ion 11. Finally, hydrolysis of the latter species would liber-
ate enantioenriched a-benzyl aldehyde 12 and organocat-
alyst 8.
RESULTS
We first tested this hypothesis by subjecting hydrocin-
namaldehyde (13) and alcohol 3, as its trifluoroacetic acid
salt, to the reaction conditions which proved optimal in
the enantioselective a-benzylation of aldehydes using
benzylic bromides14b (20 mol% 14 as the organocatalyst,
0.5 mol% Ir(ppy)3 (15) as the photocatalyst, and 3 equiv
lutidine in DMSO at r.t.) under blue light irradiation (Ta-
ble 1, entry 1). While none of the desired product was ob-
tained, omitting the lutidine base (entry 2) gave rise to
the desired a-benzyl aldehyde 16 in promising yield (37%)
and enantioselectivity (62% ee). We postulate that a more
acidic medium is necessary to facilitate both the reduc-
tion of alcohol 3 via protonation and ultimately the re-
quired spin-center shift event. Optimization of the reac-
tion conditions (see SI, Tables S1–S6) revealed that em-
ploying a substoichiometric amount of lutidine (25 mol%)
and HBr as the acid, two-fold dilution of the mixture, the
addition of water (30 equiv), and cooling the mixture to 0
°C provided 16 in 48% yield and much improved 90% ee
(entry 3). The modest efficiency was due primarily to the
net reduction of alcohol 3 to 4-methylpyridine, rather
than low consumption of 3, so we surmised that a less
reducing photocatalyst such as fluorinated IrIII complex
1719 would minimize the production of the reduction by-
A detailed mechanistic description of the proposed trans-
formation is shown in Scheme 1. Excitation of an IrIII catalyst
*
(1) with blue light would first generate a long-lived IrIII ex-
cited state (2) (t = 1.90 µs for Ir(ppy)3).17 This highly reducing
species (E1/2red[IrIV/*III] = –1.81 V vs. saturated calomel elec-
trode (SCE) in CH3CN for Ir(ppy)3) should reduce a proto-
nated
heterobenzylic
alcohol
such
as
4-
(hydroxymethyl)pyridine (3, Ered = –1.29 V vs. SCE in CH3CN
for 3•HBr) to furnish electron-rich radical 4 and IrIV interme-
diate 5. Radical 4 would then undergo the key spin-center
shift event to unveil electrophilic radical 6 and extrude a
molecule of water after proton transfer. Within the same
time frame, aldehyde 7 and an organocatalyst (8) would con-
dense to form chiral enamine 9. The depicted DFT structure
of 9 (with propionaldehyde as the aldehyde) illustrates that
the benzyl substituent of the organocatalyst shields the Re-
face of the enamine, leaving the Si-face exposed for reaction
with electrophilic radical 6. The resulting a-amino radical 10
(E1/2ox = –1.12 to –0.92 V vs. SCE in CH3CN for simple a-amino
radicals)18 would be readily oxidized by the IrIV intermediate
3 (E1/2red[IrIV/III] = +0.77 V vs. SCE in CH3CN for Ir(ppy)3) to
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a
-
go efficient and highly enantioselective benzylation with
4-(hydroxymethyl)pyridine (3). Hydrocinnamaldehyde
was alkylated to give 16 in 84% isolated yield and 98% ee,
consistent with smaller scale optimization studies. A di-
methoxy-substituted analogue (20) was also obtained in
excellent efficiency and selectivity (86% yield, 98% ee). b-
branched aldehydes are competent substrates, with cy-
clohexyl and piperidinyl products 21 and 22 obtained in
good yields (86% and 80%, respectively) and enantiose-
lectivities (96% ee and 94% ee, respectively). Simple alka-
nals such as octanal and propionaldehyde also reacted
cleanly to give 23 (90% yield, 96% ee) and 24 (93% yield,
96% ee). Finally, unsaturation is tolerated, as shown by
the production of alkene 25 (85% yield, 4.5:1 Z/E, 95% ee)
and alkyne 26 (89% yield, 97% ee).
Table 1. Optimization of the enantioselective
benzylation of aldehydes with alcohols.a
1
2
3
4
5
6
7
8
Ir
En
O
O
HO
H
H
N
lutidine, H2O (30 equiv)
DMSO (0.25 M)
0 °C, 3 h
Bn
Bn
16
!-benzyl aldehyde
N
•HBr
3
13
aldehyde
alcohol
entry
lutidine
conditions
catalysts
yield
ee
9
1b
2b
3
no H2O, 0.5 M, r.t.
no H2O, 0.5 M, r.t.
as shown
14 + 15
14 + 15
14 + 15
14 + 17
14 + 18
14 + 18
19 + 18
8 + 18
300 mol%
0 mol%
0%
37%
48%
18%
78%
90%
6%
n.d.
62%
90%
n.d.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
25 mol%
25 mol%
25 mol%
50 mol%
50 mol%
50 mol%
4
as shown
5
as shown
92%
92%
n.d.
6c
7c
8 c
DMA solvent
DMA solvent
DMA solvent, 6 h
With respect to the heterobenzylic alcohol, a variety of
substituted pyridines are competent in the reaction with
hydrocinnamaldehyde. Methyl substitution at the 2-
position or disubstitution at the 2- and 6-positions were
well-tolerated, as were 2-phenyl or protected 2-amino
substituents (27–30, 72–82% yield, 97–98% ee). The 3-
position can also be substituted, with methyl-, methoxy-,
fluoro-, and chloro-containing products 31–34 obtained in
good yields (69–78%) and excellent enantioselectivities
(94–98% ee). Quinolines are also capable of inducing the
requisite spin-center shift, and a variety of substitution
patterns about this aromatic motif are accommodated in
the a-benzylation of hydrocinnamaldehyde. Specifically,
4-(hydroxymethyl)quinoline served as a competent alkyl-
ating agent, furnishing product 35 in 83% yield and 96%
ee. The 2-methyl analogue (36) was also cleanly isolated
(75% yield, 98% ee). Alcohols bearing substituents at the
6-position of the quinoline system can be employed, and
gave rise to products 37–39 containing fluoro, bromo, and
protected oxygen functionalities in synthetically useful
yields (60–70%) without compromising enantioselectivity
(97–99% ee). Finally, 7-chloroquinoline 40 was also iso-
lated in 76% yield and 99% ee.
88%
98%
(20 mol%)
Me
En
O
Me
O
O
Me
N
N
N
Me
Me
Me
Me
t-Bu
N
N
H
N
H
H
Ph
Ph
14
19
8
(0.5 mol%)
Ir
F
F
t-Bu
N
Ir
N
N
Ir
F
t-Bu
F
Ir
N
N
N
N
N
N
15
17
18
F
t-Bu
F
a
Alcohol 3 (0.1 mmol), aldehyde 13 (1.5 equiv), lutidine, wa-
ter, organocatalyst, and photocatalyst were irradiated in the
indicated solvent with a 34 W blue LED lamp. Yields were
determined by 1H NMR. Enantioselectivities were deter-
mined by chiral HPLC analysis following reduction of the
b
crude aldehyde to the corresponding alcohol. Trifluoroace-
Products obtained by this enantioselective a-
benzylation possess enantioenriched homobenzylic stere-
ocenters and a versatile aldehyde functional handle, and
thus may serve as important synthons for the preparation
of bioactive molecules. To demonstrate the utility of this
protocol, we sought to prepare the stereoselective ligand
of translocator protein (18 kDa), PK–14067 (44, Figure 2).20
To this end, propionaldehyde (41) was alkylated directly
by alcohol 42. The crude aldehyde (not shown) was oxi-
dized to the corresponding carboxylic acid, and subse-
quent HATU-mediated coupling with diethylamine pro-
vided amide 43 in 79% yield and 95% ee over 3 steps. Fi-
nally, the phenyl substituent was installed in modest effi-
ciency via a Minisci-type arylation21 to afford the target
(44) in 52% yield and without erosion of enantiopurity. It
is noteworthy that this synthesis corroborates the as-
signed (R)-configuration of the active isomer. Previous
studies of PK–14067 had obtained this compound by ra-
cemic synthesis, followed by resolution, and assigned the
configuration of the bioactive enantiomer by comparison
of its experimental VCD spectrum to the simulated spec-
tic acid salt of the alcohol instead of the HBr salt. c Aldehyde
13 (2.0 equiv).
product. We were surprised, however, to observe a dimin-
ished 18% yield (entry 4). Instead, the more reducing pho-
tocatalyst 1817 improved efficiency without compromising
enantioselectivity (entry 5, 78% yield, 92% ee, see later
text for a detailed discussion). Further modification of
stoichiometries and conducting the reaction in N,N-
dimethylacetamide (DMA) gave optimal efficiency (90%
yield, entry 6). Finally, while the sterically demanding
tert-butyl organocatalyst 19 was unproductive (entry 7),
catalyst 8, featuring a fully substituted aminal, provided
16 in 88% yield and 98% ee after 6 h (entry 8). Further
photocatalyst modifications could improve chemoselec-
tivity and thus yield (see Figure 3), but 18 proved optimal
when considering alcohol conversion and synthetic acces-
sibility (see the SI).
With this optimized set of conditions, we evaluated the
scope of the enantioselective a-benzylation of aldehydes
with alcohols (Table 2). First, a range of aldehydes under-
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Journal of the American Chemical Society
Table 2. Scope of the enantioselective
-benzylation of aldehydes with alcohols.a
Page 4 of 11
a
1
2
3
4
5
6
7
8
9
Catalyst combination
t-Bu
N
Ir
Ir En
O
O
O
Me
HO
N
X
t-Bu
H
H
Me
Me
N
En
Ir
lutidine (50 mol%)
H2O (30 equiv)
X
N
N
R
R
N
N
H
•HBr
(20 mol%)
(0.5 mol%)
Ph
DMA (0.25 M), 0 °C
!-benzyl aldehyde
aldehyde
alcohol
8
t-Bu
18
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Aldehyde Scope
O
O
O
O
H
H
H
H
16
20
21
22
84% yield
98% ee
86% yieldb
98% ee
86% yieldc
96% ee
80% yieldc
94% ee
N
N
N
N
MeO
N
Boc
OMe
O
O
O
O
H
H
H
23
24
25
26
93% yieldd
96% ee
90% yield
96% ee
85% yielde
95% ee
89% yield
97% ee
Me
H
N
N
N
Me
N
2
3
Me
Me
Alcohol Scope
O
O
O
O
Me
Me
H
H
27
28
35
36
H
H
Bn
N
Bn
N
82% yield
98% ee
73% yield
98% ee
83% yieldb
96% ee
75% yield
98% ee
Bn
N
Bn
N
Me
Me
O
O
NHAc
H
H
29
30
F
Br
N
Bn
N
Bn
N
74% yield
97% ee
72% yield
98% ee
O
O
H
H
37
38
Bn
N
Bn
63% yield
97% ee
60% yield
99% ee
O
Me
O
OMe
N
Me
Me
H
H
31
32
75% yield
98% ee
71% yield
98% ee
Bn
N
Bn
OMs
Cl
O
O
O
F
O
Cl
H
H
H
H
33
34
39
40
78% yieldc
96% ee
69% yieldc
94% ee
70% yield
98% ee
76% yield
99% ee
Bn
N
Bn
N
Bn
N
Bn
N
Me
Me
a Alcohol (0.5 mmol), aldehyde (2.0 equiv), lutidine (50 mol%), water (30 equiv), organocatalyst 8 (20 mol%), and photocata-
lyst 18 (0.5 mol%) were irradiated in DMA with a 34 W blue LED lamp at 0 °C. Isolated yields are reported. Enantioselectivities
were determined by chiral HPLC analysis following reduction of the crude aldehydes to the corresponding alcohols. b Character-
ized as the corresponding alcohol. c Aldehyde (5.0 equiv). d Yield determined by 1H NMR. e From the Z-starting material, 25 was
obtained as a 4.5:1 mixture of Z and E isomers; chiral HPLC analysis was performed following reduction of the crude aldehyde to
the corresponding alcohol and subsequent hydrogenation of the alkene.
trum of both enantiomers.22 The known stereochemical
value for the active enantiomer (99% ee, [a]D = –90°, c =
2.86, EtOH).22
course of our a-benzylation (see the SI for a discussion)
reliably delivered (R)-44, the optical rotation of which
Finally, we sought further to broaden the utility of this
(95% ee, [a]D = –88°, c = 1.0, EtOH) matched the reported
spin-center shift paradigm for the enantioselective a-
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Journal of the American Chemical Society
ties (46–48, 73–80% yield, 87–93% ee).
1.
Ir
En
O
O
1
2
3
4
5
6
7
8
Notably, these preliminary results demonstrate that an
additional class of non-traditional alkylating agents, a-
acetoxyketones, can be activated to this end by spin-
center shift. While acetates are activated leaving groups
compared to alcohols (see Table 4 and the associated dis-
cussion), they are seldom employed directly in alkylation
reactions, as they are still significantly less reactive than
typical alkylating agents such as alkyl bromides or io-
dides. Furthermore, like alcohols, they are less genotoxic
and more stable than conventional electrophiles.
HO
H
Et2N
2. NaClO2, NaH2PO4
3. Et2NH, HATU
N
Me
Me
43
N
•HBr
41
42
79% yield (3 steps)
95% ee
O
PK–14067
Et2N
Me
PhB(OH)2
Stereoselective ligand for
translocator protein (18 kDa)
N
ꢀ
TFA, K2S2O8
9
44
52% yield
95% ee
AgNO3 (20 mol%)
Confirms (R)-configuration of
active enantiomer
ꢀ
10
11
12
MECHANISTIC STUDIES
Figure 2. Enantioselective synthesis of stereoselective trans-
locator protein (18 kDa) ligand PK–14067. The enantioselec-
tive a-benzylation procedure was conducted using alcohol 42
(2.0 mmol) and aldehyde 41 (5.0 equiv) under conditions
listed in Table 2 for 42 h.
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Further investigations were performed to gain a greater
mechanistic understanding of the enantioselective a-
benzylation of aldehydes with alcohols. Specifically, we
sought to determine whether spin-center shift occurs as
hypothesized, to elucidate the origin of the major by-
product (i.e., the formation of 4-methylpyridine (49) from
4-(hydroxymethyl)pyridine (3)) that initially complicated
the optimization of this reaction, and to test the possibil-
ity of a radical chain mechanism. Thus, three investiga-
tions were performed: (1) an examination of how modifi-
cations to the leaving group in the electrophile impact
reactivity and selectivity, (2) a photocatalyst structure-
activity relationship (SAR) study, and (3) quantum yield
measurements.
alkylation of aldehydes with unconventional electrophiles
as latent alkylating agents. Beyond the heterobenzylic
alcohols described above, work by Stephenson23 suggested
that alcohols such as a-hydroxyketones, or their deriva-
tives, may also be viable electrophiles in this alkylation
manifold. While initial experiments demonstrated that
free alcohols of this type are not competent alkylating
agents, the corresponding acetates show excellent reactiv-
ity (Table 3). Therefore, under slightly modified condi-
tions,
octanal
(45)
was
alkylated
with
a-
To begin, we investigated the impact of the leaving
group X on reaction efficiency and chemoselectivity (Ta-
ble 4). Thus, we prepared a series of (4-pyridyl)methyl
electrophiles and subjected them to the standard reaction
conditions with hydrocinnamaldehyde (13). First, several
functional groups aside from alcohols can serve as leaving
groups in this transformation. These electrophiles (ace-
tate, trialkylammonium, alkyl ether, and silyl ether) all
give rise to a-benzyl aldehyde 16 in respectable to excel-
lent yields (61–90%) and with uniformly high enantiose-
lectivity (97% ee). Further functional groups that do not
generally confer alkylating ability can therefore be em-
ployed in the outlined enantioselective a-benzylation of
aldehydes.
acetoxyacetophenone, as well as the 3,4-(methylenedioxy)
and 4-fluoro analogues, to procure the corresponding a-
alkyl aldehydes in good yields and high enantioselectivi-
Table 3. Spin-center shift-enabled enantioselective -
a
alkylation of aldehydes with
a
-acetoxyketones.a
Acetates
O
Additional class of non-traditional
alkylating agent engaged by SCS
ꢀ
ꢀ
AcO
Ar
Stable, non-genotoxic electrophile
!-acetoxyketone
We then sought to account for the different reactivities
observed among these electrophiles in order to evaluate
our proposal that this reaction proceeds via SCS (Table 4,
entries are sorted by decreasing yield and chemoselectivi-
ty, the latter parameter being the ratio between yields of
desired product 16 and byproduct 49). Therefore, we
measured their reduction potentials (Ered) and Stern-
Volmer quenching constants (KSV) with photocatalyst 18,
which, in this context, quantifies the relative rates at
which the electrophile substrates receive an electron from
the excited state of 18.
Ir
En
O
O
Ar
Ar
AcO
H
H
lutidine (50 mol%)
lutidine•HOTf (20 mol%)
DMA (0.25 M), 0 °C
O
n-hex
45
n-hex
O
!-alkyl aldehyde
aldehyde
acetate
F
O
O
O
O
O
H
H
H
n-hex
O
n-hex
47
O
n-hex
48
O
78% yield
93% ee
73% yield
92% ee
80% yield
87% ee
46
Notably, the reduction potentials of the electrophiles
(entries 1–5, Ered = –1.19 to –1.30 V vs. SCE in CH3CN) are
nearly identical both to each other and to that of pyri-
dine•HBr (entry 6, Ered = –1.30 V vs. SCE in CH3CN). Such
similar potentials suggest that the LUMOs of these com-
pounds all reside primarily on their common structural
a
Acetate (0.5 mmol), aldehyde (2.0 equiv), lutidine (50
mol%), lutidine•HOTf (20 mol%), organocatalyst 8 (20
mol%), and photocatalyst 18 (0.5 mol%) were irradiated in
DMA with a 34 W blue LED lamp at 0 °C. Isolated yields; ee
was determined by chiral HPLC analysis.
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Table 4. Leaving group scope in the enantioselective
spin-center shift-enabled -benzylation of aldehydes
and its impact on reactivity.a
the leaving groups (X–) with reaction rates and yields in
1
2
3
4
5
6
7
8
a
Table 4 suggests that the electrophiles sort into two clas-
ses. First, the more reactive electrophiles possess weakly
basic leaving groups (entry 1, X = OAc, and entry 2, X =
NMe3+). The protonation states of these leaving groups
following simple heterolytic C–X scission (anionic car-
boxylate and neutral trialkylamine, respectively) should
be stable in the pyridine/pyridinium reaction buffer. For
these electrophiles, therefore, SCS directly follows single-
electron reduction of the pyridinium moiety. In contrast,
the less reactive electrophiles possess strongly basic leav-
ing groups (entries 3–5, X = OH, OMe, OTBDPS), the cor-
responding anions of which should be unstable in the
reaction medium. These leaving groups must be activated
by protonation or hydrogen-bonding before C–X cleav-
age, and this additional barrier slows the a-benzylation
reaction. This clear dependence of reactivity on leaving
group acidity suggests that the rate of C–X bond-breaking
contributes to the overall rate of reaction. A discussion of
reactivity trends within the two classes of electrophiles is
provided in the SI.
Leaving Group Evaluation
O
H
13
O
Ir
En
Bn
H
H
Bn
N
N
X
lutidine (50 mol%)
H2O (30 equiv)
N
16, 97% ee
!-benzyl aldehyde
49
byproduct
•HBr
electrophile
9
DMA (0.25 M), 0 °C
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ꢀ
ꢀ
Probe for SCS mechanism
Many leaving groups viable
entry
Ered (V)
K
SV (mM–1
)
yield (2 h)
yield [time] 16:49
X
pKa (XH)
1
2
3
4
5
–1.19
an.d.b
–1.29
–1.29
–1.30
0.84
0.13
1.05
1.15
0.82
75%
67%
39%
29%
20%
4.76
9.80
15.7
15.2
90% [3 h]
86% [5 h]
85% [5 h]
71% [24 h]
61% [48 h]
18
14
OAc
NMe3+ Br–
OH
7.7
5.1
3.1
OMe
~
< 13.6
OTBDPS
–
data for pyridine•HBr
6
–1.30
1.30
On balance, the data in Table 4 suggest that a rapid SET
from the excited state photocatalyst to the electrophile
initiates the reaction, followed by slow C–X cleavage
(SCS). This step impacts the rate of a-benzylation and is
the rate-determining step (RDS) in the linear reaction
between the electrophile and the enamine. While these
experiments do not assess the kinetics of C–C bond-
formation, as they all involve a common electrophilic rad-
ical and enamine that would participate in this step, (a)
an examination of reactivities among the different alcohol
electrophiles employed in Table 2 is consistent with SCS
being slower than C–C bond-formation, and (b) initial
rate studies suggest that the enamine is not involved the
RDS of its photoredox-mediated alkylation by the elec-
trophile (see the SI). Higher loadings of either aldehyde
or organocatalyst lead to increased rates beyond this ini-
tial period, however, as the organocatalytic cycle must
turn over to provide further enamine and preliminary
experiments suggest that iminium ion hydrolysis is turn-
over-limiting (also see the SI). Chemoselectivity between
desired product 16 and byproduct 49 (Table 4, final col-
umn) is addressed in the following discussion of Figure 3.
a
Alcohol 3 (0.25 mmol), aldehyde 13 (2.0 equiv), lutidine
(50 mol%), water (30 equiv), organocatalyst 8 (20 mol%), and
photocatalyst 18 (0.5 mol%) were irradiated in DMA with a
34 W blue LED lamp. Yields of 16 and 49 were determined by
1H NMR. Enantioselectivities were determined by chiral
HPLC analysis following reduction of the crude aldehyde to
the corresponding alcohol. Acidity data in water from Refer-
b
ence 24. See SI for full experimental details. Low solubility
prevented electrochemical measurements in aprotic solvents.
feature, the protonated heteroaromatic system. If the
leaving groups made a significant contribution to the
LUMOs, we would expect a wider range of Ered values,
given the appreciable stereoelectronic differences be-
tween these functionalities. As such, the photoredox acti-
vation of these electrophiles likely proceeds via initial SET
to the aromatic core, followed by SCS, as proposed in Fig-
ure 1 and Scheme 1. For comparison, a conventional elec-
trophile for this reaction, 4-(bromomethyl)pyridine (50,
see Figure 4),14b is much more easily reduced (Ered = –0.88
V vs. SCE in CH3CN for the HBr salt). We propose, there-
fore, that 50 is engaged by a photoredox catalyst for a-
benzylation via direct SET to the C–Br s* orbital, rather
than by SCS.
Next, we conducted a photocatalyst SAR study. We sys-
tematically prepared a series of tert-butyl- and methoxy-
substituted derivatives of Ir(ppy)3 and measured their
photophysical and electrochemical properties (Figure 3a,
also see SI, Figures S3–S35). We then evaluated their per-
formance in the a-benzylation of hydrocinnamaldehyde
(13) with 4-(hydroxymethyl)pyridine (3) and focused on
the selectivity between the yields of desired a-benzyl al-
dehyde 16 and undesired 4-methylpyridine (49).
The KSV data, in comparison, exhibit appreciable varia-
bility among the electrophiles, although no clear relation-
ship is evident between these values and reactivity. Since
KSV directly reflects the relative rates of SET between the
excited state photocatalyst and the electrophiles, we con-
clude that this SET is likely rapid, and a subsequent event,
such as SCS, dictates reactivity. The measurement of non-
zero KSV values also confirms that the excited state photo-
catalyst is quenched by these electrophiles, consistent
with our proposal that the reaction is initiated by SET
from the excited photocatalyst to the electrophile.
Figure 3a tabulates these results, which are sorted from
least selective to most selective (final column). Prelimi-
nary examinations of two potentially important properties
of these photocatalysts, their excited state lifetimes17 and
Stern-Volmer
quenching
rates
with
4-
The observed reactivity trends are best explained by the
acid-base properties of the leaving groups. A comparison
of the literature pKa values for the parent acids (XH) of
(hydroxymethyl)pyridine (3) (see SI, Figure S53), showed
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Journal of the American Chemical Society
a.
negligible differences. Instead, their electrochemical po-
Photocatalyst Structure-Activity Relationship
R2
tentials (E1/2red) seemed to play a primary role in deter-
mining selectivity. Since there are four such values to
consider (ground state oxidation by IrIV, ground state re-
duction by IrII, and excited state oxidation or reduction by
*IrIII), we plotted the observed chemoselectivity as a func-
1
2
3
4
5
6
7
8
R1
R4
R3
R3
N
Ir
What property governs
chemoselectivity?
R4
R1
Ir
red
N
N
tion of each E1/2 series, as shown in Figure 3b. The
R2
strongest correlation (r2 = 0.93) was found between selec-
tivity and E1/2red[IrIV/III], the oxidizing power of the IrIV
ground state, with lower oxidation potentials leading to
higher selectivity. A modest correlation was also found
between selectivity and E1/2red[Ir*III/II], the oxidizing ability
R2
R1
R4
R3
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
O
O
Ir
En
*
of the IrIII excited state (r2 = 0.76). We postulate that this
H
13
H
H
Bn
lutidine (50 mol%)
H2O (30 equiv)
DMA (0.25 M)
0 °C, 6 h
Bn
N
correlation is incidental, however, as the lower oxidation
N
*
potentials of IrIII excited states compared to IrIV ground
HO
16
!-benzyl aldehyde
49
3
N
byproduct
states suggest that the former species are not responsible
for the oxidation leading to 49 (see below). The remaining
potentials, E1/2red[IrIV/*III] and E1/2red[IrIII/II], clearly do not
explain the observed trends in chemoselectivity (r2 = 0.33
and 0.24, respectively).
•HBr
E1/2red vs. SCE (V)
yield selectivity
entry
Ir
IrIV/III a IrIV/*III a IrIII/II b Ir*III/II b
(16)
(16:49)
R1 = t-Bu
Ir(ppy)3
1
+0.68
+0.69
+0.70
+0.64
+0.59
+0.60
+0.60
+0.53
+0.34
–1.89
–1.88
–1.95
–1.94
–2.00
–1.96
–1.92
–1.87
–2.07
–2.30
–2.23
–2.34
n.d.
+0.28
+0.35
+0.30
n.d.
53%
53%
71%
51%
70%
87%
90%
91%
92%
1.6
1.7
3.4
4.3
4.4
10
2
From the preceding studies, a detailed mechanistic un-
derstanding of chemoselectivity emerges, which is out-
lined in Scheme 2. The electrophile starting material is
R4 = MeO
R2 = t-Bu
R2 = MeO
3
4a
5a
6
*
first reduced by the excited state IrIII photocatalyst to
n.d.
n.d.
give radical 51 and an IrIV species. At this stage, the rela-
tive reactivities of radical 51, enamine 9, and the IrIV in-
termediate dictate the final chemoselectivity. Desired a-
benzyl aldehyde 12 is formed (Scheme 2, top) when spin-
center shift occurs to give electrophilic radical 6, which
alkylates enamine 9. The resulting a-amino radical 10 is
oxidized by the IrIV species to produce iminium ion 11 (see
Scheme 1), which is hydrolyzed to deliver 12. Major by-
product 49 arises (Scheme 2, bottom) when the IrIV spe-
cies oxidizes enamine 9 directly. This SET presumably
leads to radical 52, which formally reduces electrophilic
radical 6, likely with the assistance of the photocatalyst.
The resulting byproducts are thus the previously dis-
cussed 49, from net alcohol reduction, and oxidized or-
ganocatalyst 53,25 which we have also isolated from sever-
al reaction mixtures.26
R
4 = t-Bu
–2.33
–2.26
–2.21
n.d.
+0.23
+0.26
+0.19
n.d.
R3 = t-Bu
7
13
R3 = MeO
8
23
R2, R3 = MeO,
R4 = Me
9a
46
b.
Plots of Selectivity vs. Electrochemical Potentials
50
50
r2 = 0.93
good correlation
r2 = 0.33
poor correlation
40
30
20
10
0
40
30
20
10
0
0.30
0.40
0.50
0.60
0.70
-2.10
-2.05
-2.00
-1.95
-1.90
-1.85
E1/2red[IrIV/III] (V vs. SCE)
E1/2red[IrIV/*III] (V vs. SCE)
This description accounts for the chemoselectivity
trends outlined in Table 4 and Figure 3 in terms of two
competing pathways for the IrIV intermediate. Desired a-
benzyl aldehyde 12 is obtained when the IrIV species oxi-
25
20
15
10
5
25
20
15
10
5
r2 = 0.24
poor correlation
r2 = 0.76
modest correlation
ox
dizes the strongly reducing a-amino radical 10 (E1/2 = –
0.92 to –1.12 V vs. SCE in CH3CN for simple a-amino radi-
cals),18 an SET which should be rapid and irreversible for
all photocatalysts employed in this investigation
(E1/2red[IrIV/III] = +0.34 V to +0.70 V vs. SCE in CH2Cl2, see
Figure 3). Conversely, undesired byproducts 49 and 53
form when the IrIV species oxidizes enamine 9 (Eox = +0.84
vs. SCE in CH3CN for R = n-hex). This SET is feasible, al-
beit endergonic, for all the above-listed IrIV oxidation po-
tentials (see above for data in CH2Cl2; for photocatalysts
soluble in CH3CN, E1/2red[IrIV/III] ≤ +0.77 V vs. SCE in this
solvent, see SI). Furthermore, appreciable concentrations
of enamine 9 are present throughout the reaction, where-
as radical 10, which must be oxidized to obtain the de-
sired product, should only be present in trace amounts.
0
-2.35
0
-2.30
-2.25
-2.20
0.15
0.20
0.25
0.30
0.35
E1/2red[IrIII/II] (V vs. SCE)
E1/2red[Ir*III/II] (V vs. SCE)
Figure 3. Impact of photocatalyst structure on chemoselec-
tivity in the a-benzylation of aldehydes with alcohols. (a)
Alcohol 3 (0.25 mmol), aldehyde 13 (2.0 equiv), lutidine (50
mol%), water (30 equiv), organocatalyst (±)-8 (20 mol%), and
photocatalyst 18 (0.5 mol%) were irradiated in DMA with a
34 W blue LED lamp. Yields of 16 and 49 were determined by
1H NMR. (b) Plots of selectivity vs. each electrochemical po-
tential. a Measured in CH3CN. b Measured in CH2Cl2.
51
52
53
54
55
56
57
58
59
60
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a
-benzylation of
Scheme 2. Mechanistic description of chemoselectivity in the enantioselective SCS-enabled
aldehydes.
1
2
3
Starting Materials
Initial Intermediates
Desired Path: SCS & Enamine Alkylation
Desired Product
4
5
6
7
8
9
O
Me
O
N
X
X
10
*IrIII
IrIV
Me
Me
En
SCS
N
HN
radical
51
H
Bn
SET
SET
N
•HBr
HN
12
6
radical
+
R
N
electrophile
Eox = –0.92 V
to –1.12 V
radical
Ar
+
α-benzyl aldehyde
R
+
O
Me
Improved Selectivity
N
Byproducts
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
radical
O
Me
Me
Me
O
N
6
Rapid SCS (acidity
ꢀ
of X )
Bn
N
Me
Me
52
O
Me
H
IrIV
Bn
N
En
N
H
+
SET
Me
Me
9
R
SET
Less oxidizing IrIV
(Ered ≤ +0.77 V studied)
7
N
49
ꢀ
R
enamine
+
Bn
N
–H
aldehyde
R
E
ox = +0.84 V (R = n-hex)
53
Undesired Path: Enamine Oxidation
With respect to the electrophile, the least basic leaving
groups give the highest chemoselectivities (see Table 4)
due to the corresponding acceleration of the SCS step.
While SCS must occur to form both desired a-benzyl al-
dehyde 12 and byproduct 49, the rate of this elementary
step has a different impact on the pathways leading to
each product. In the limiting case when SCS is fast, a-
amino radical 10 forms rapidly, and this strong reductant
reacts preferentially with the IrIV intermediate to close the
photocatalytic cycle and generate desired product 12.
Conversely, when SCS is slow, 10 is unavailable to reduce
the IrIV species. Instead, enamine 9 can be oxidized by the
IrIV intermediate, giving 52 (or a related species) after pro-
ton transfer. Radicals such as 52 should be modest reduc-
ing agents, and upon the eventual formation of electro-
philic radical 6, its formal reduction by 52 (likely mediat-
ed by a photocatalyst) competes with C–C bond for-
mation, ultimately producing 49 and 53.
oxidation potentials. Lower IrIV potentials render unde-
sired enamine oxidation increasingly endergonic, while
oxidation of the strongly reducing radical 10 remains
highly exergonic and ensures that the desired product can
still be accessed without complication. Indeed, as shown
in Figure 3, chemoselectivity rises from modest levels
when using photocatalysts with the most oxidizing IrIV
states (entries 1–3, 16:49 = 1.6:1–3.4:1 for E1/2red[IrIV/III] =
+0.68 to +0.70 V vs. SCE in CH2Cl2) to excellent when
using the least oxidizing derivative, which we designed
explicitly for this purpose (entry 9, 16:49 = 46:1 for
E1/2red[IrIV/III] = +0.34 V vs. SCE in CH2Cl2).
Finally, we questioned whether a radical chain propaga-
tion mechanism could be occurring in this transfor-
mation, as work by Yoon et al. has demonstrated that
such pathways operate in a range of photoredox-catalyzed
transformations27 including the enantioselective a-
alkylation of aldehydes with alkyl bromides.14a With the
present alcohol electrophiles, however, we hypothesized
that the relatively difficult reduction of the model sub-
strate 3 (Ered = –1.29 V vs. SCE in CH3CN for the HBr salt)
would prohibit its reduction by any organic intermediates
formed during the reaction (the most likely candidate
would be a-amino radical 10, depicted in Scheme 1 and 2,
but literature data suggest that the potentials of simple
With respect to the photocatalyst, selectivity for desired
product 12 increases straightforwardly with decreasing IrIV
Quantum Yield Measurement
" = 0.071
ox
HO
analogues, E1/2 = –0.92 to –1.12 V vs. SCE in CH3CN, are
alcohol
(39% yield, 24 h)
3
still insufficiently reducing).18 As shown in Figure 4, the
quantum yield for the reaction of alcohol 3 with hydro-
cinnamaldehyde (13) is 0.071. While this observation does
not rule out propagation events conclusively, the relative-
ly low value is consistent with our mechanistic hypothesis
that each photon absorbed by the photocatalyst should
lead, at most, to a single product molecule. In contrast,
we surmised that the formation of reducing intermediates
such as 10 would enable radical chain propagation events
when a more easily-reduced electrophile, such as the cor-
responding benzylic bromide (50), is employed (Ered = –
0.88 V vs. SCE in CH3CN for the HBr salt). Indeed, for the
a-benzylation of hydrocinnamaldehyde (13) with 50, un-
der the optimal conditions for benzylic bromide electro-
philes reported in 2010, we measured a quantum yield of
12.6. In this reaction, therefore, the photocatalyst serves
this work
N
•HBr
chain unlikely
O
O
Ir
En
H
H
Bn
Bn
16
N
402 nm LEDs
1.3 #E·cm–2·s–1
13
aldehyde
!-benzyl aldehyde
" = 12.6
Br
•HBr
bromide
MacMillan
(2010)
50
(26% yield, 10 min)
chain dominant
N
Figure 4. Quantum yield determination for the enantioselec-
tive a-benzylation of aldehydes with alcohols and bromides.
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Journal of the American Chemical Society
primarily as an initiator for a self-propagating chain re-
sponsible for the majority of product formation.
1
2
3
CONCLUSIONS
4
5
6
7
8
9
5.
Jin, J.; MacMillan, D. W. C. Alcohols as alkylating
We have developed a strategy based on spin-center
shift that enables the enantioselective a-benzylation of
aldehydes with electron-deficient heterobenzylic alcohols.
To our knowledge, this work represents the first example
of a direct enantioselective a-alkylation of carbonyl com-
pounds with alcohols where the electrophile does not
contain specialized cation-stabilizing features to promote
SN1-type activation. Additional non-traditional leaving
groups, such as acetates and ethers, are also competent in
this reaction, and a-acetoxyketone electrophiles can be
employed to access a further aldehyde a-alkylation motif
via SCS. Mechanistic studies are consistent with spin-
center shift as a key elementary step and elucidate the
impact of electrophile and photocatalyst structures on
reactivity. Finally, enamine oxidation was identified as the
origin of the major side reaction, enabling optimal yields
to be obtained by rational photocatalyst design.
agents in heteroarene C–H functionalization. Nature 2015, 525,
87.
6.
(a) Narayanam, J. M. R.; Stephenson, C. R. J. Visible
light photoredox catalysis: applications in organic synthesis.
Chem. Soc. Rev. 2011, 40, 102. (b) Xuan, J.; Xiao, W. J. Visible-
light photoredox catalysis. Angew. Chem. Int. Ed. 2012, 51, 6828.
(c) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Visible light
photoredox catalysis with transition metal complexes: Applica-
tions in organic synthesis. Chem. Rev. 2013, 113, 5322. (d) Schultz,
D. M.; Yoon, T. P. Solar Synthesis: Prospects in Visible Light
Photocatalysis. Science 2014, 343, 1239176. (e) Skubi, K. L.; Blum,
T. R.; Yoon, T. P. Dual Catalysis Strategies in Photochemical
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ASSOCIATED CONTENT
Supporting Information
kylation of N-acylsultams: A general route to enantiomerically
pure, crystalline C(α,α)-disubstituted carboxylic acid derivatives.
Tetrahedron Lett. 1989, 30, 5603.
The Supporting Information is available free of charge on the
ACS Publications website.
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Hydroxybernsteinsäure-Derivaten aus Äpfelsäureester. Helv.
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of pseudoephedrine as a practical chiral auxiliary for asymmetric
synthesis. J. Am. Chem. Soc. 1994, 116, 9361.
Experimental procedures and compound characterization
data (PDF).
Myers, A. G.; Yang, B. H.; Chen, H.; Gleason, J. L. Use
11.
Maruoka, K.; Ooi, T. Enantioselective Amino Acid Syn-
AUTHOR INFORMATION
thesis by Chiral Phase-Transfer Catalysis. Chem. Rev. 2003, 103,
3013.
12.
ga, K. Catalytic Asymmetric Benzylation of Achiral Lithium Eno-
lates Using a Chiral Ligand for Lithium in the Presence of an
Achiral Ligand. J. Am. Chem. Soc. 1994, 116, 8829.
Corresponding Author
Imai, M.; Hagihara, A.; Kawasaki, H.; Manabe, K.; Ko-
*dmacmill@princeton.edu
ACKNOWLEDGMENT
13.
Doyle, A. G.; Jacobsen, E. N. Enantioselective Alkyla-
tions of Tributyltin Enolates Catalyzed by Cr(salen)Cl: Access to
Enantiomerically Enriched All-Carbon Quaternary Centers. J.
Am. Chem. Soc. 2005, 127, 62.
Financial support provided by the NIHGMS (R01 GM-103558-
05) and kind gifts from Merck, Abbvie, BMS, and Janssen.
E.D.N. acknowledges the NIH for a postdoctoral fellowship
(F32 GM119362-01A1).
14.
(a) Nicewicz, D. A.; MacMillan, D. W. C. Merging pho-
toredox catalysis with organocatalysis: the direct asymmetric
alkylation of aldehydes. Science 2008, 322, 77. (b) Shih, H.-W.;
Vander Wal, M. N.; Grange, R. L.; MacMillan, D. W. C. Enanti-
oselective α-benzylation of aldehydes via photoredox organoca-
talysis. J. Am. Chem. Soc. 2010, 132, 13600. (c) Zhu, Y.; Zhang, L.;
Luo, S. Asymmetric α-Photoalkylation of β-Ketocarbonyls by
Primary Amine Catalysis: Facile Access to Acyclic All-Carbon
Quaternary Stereocenters. J. Am. Chem. Soc. 2014, 136, 14642. (d)
Welin, E. R.; Warkentin, A. A.; Conrad, J. C.; MacMillan, D. W.
C. Enantioselective α-Alkylation of Aldehydes by Photoredox
Organocatalysis: Rapid Access to Pharmacophore Fragments
from β-Cyanoaldehydes. Angew. Chem. Int. Ed. 2015, 54, 9668.
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vent by 6 does not occur, as no D-incorporation in 49 is ob-
served when conducting the reaction in d7-DMF.
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1
2
O
O
3
4
5
OH
Ir En
H
H
N
Bn
aldehyde
Bn
N
–H2O
alcohol
84% yield, 98% ee
6
7
Photoredox enabled
spin-center shift
+
SET
H
SET
O
Me
8
9
N
Me
Me
OH
Bn
N
HN
SCS
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HN
+
Me
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