Enantioselective Synthesis Enabled by Visible Light Photocatalysis

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Page 1 of 83 Organic & Biomolecular Chemistry
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Enantioselective Synthesis Enabled by Visible Light Photocatalysis

DOI: 10.1039/D0OB00759E
Organic & Biomolecular Chemistry Accepted Manuscript

Bor-Cherng Hong
Department of Chemistry and Biochemistry, National Chung Cheng University, Chia-Yi, 621,
Taiwan, R.O.C.
chebch@ccu.edu.tw
Published on 21 May 2020. Downloaded by Uppsala University on 5/21/2020 5:45:44 PM.
Abstract:
Enantioselective photoreaction has been a synthetic challenge for decades. With the continuous
development of modern visible light photocatalysis and asymmetric catalysis, remarkable advances
have been achieved through the synergistic action of these catalytic reactions, allowing the
construction of various enantiomerically enriched molecules that were once inaccessible using
photocatalytic reactions. This review presents some of the contemporary developments in
enantioselective visible-light photocatalysis reactions, covering the period from 2008 to March 2020,
with the contents classified by catalysis type.
Contents:
1. Introduction
2. Chiral enamine/iminium catalysis with/without photocatalyst
3. Chiral Lewis acid catalysis with photocatalyst
4. Chiral Lewis base catalysis with photocatalyst
5. Phase transfer catalysis with photocatalyst
6. Chiral Brønsted acid catalysis with photocatalyst
7. Chiral photocatalysts
8. Chiral anion binding catalysis with photocatalyst
9. Metal catalysis
10. N-Heterocyclic carbene catalysis with photocatalyst
11. Enzyme catalysis with/without photocatalyst
12. Miscellaneous
13. Conclusions
1. Introduction
Visible light-catalyzed reactions have received much attention in modern chemistry since the
turn of the 21st century. Many visible light photocatalysis techniques are convenient and efficient
synthetic methods for selectively creating chemical bonds and producing multiple stereocenters.
Organic & Biomolecular Chemistry Page 2 of 83
More than a thousand publications have documented photocatalytic organic reactions driven byOnline
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DOI: 10.1039/D0OB00759E
visible light, some of which have been summarized in various review papers. Among these
photocatalytic reactions, over 200 papers have described enantioselective reactions, showing an

increasing trend in recent years. In particular, the recent development of electron donor–acceptor
complexes for enantioselective photocatalyst-free reactions has further expanded this field.1
However, fewer reviews have covered enantioselective examples of visible light photocatalysis, with
most concentrating on particular topics and niche areas,2 while several mini-reviews on
enantioselective visible light photocatalysis have focused on specific topics, including chiral
phosphoric acids,3 chiral Lewis acid catalysis,4 enantioselective [2+2] cycloadditions,5 chiral metal
photocatalysts comprising octahedral RuII and IrIII complexes,6 the activation of α,β-unsaturated
carbonyl compounds,7 enantioselective catalysis,8 iminium and enamine catalysis,9

biscyclometalated rhodium complexes,10 deracemization,11 and enzymes in biocatalysis.12
The vigorous development of visible light photocatalytic technology will undoubtedly continue
for decades. Therefore, to obtain a practical perspective on enantioselective visible light
photocatalysis, an update and broad overview of different aspects of this research area is needed to
establish the more effective synthetic methods. Accordingly, this review article summarizes some of
the progress on this theme between 2008 and March 2020. The content is categorized according to
the type of catalysis with or without photocatalyst, including chiral enamines/imine catalysis, chiral
Lewis acid catalysis, chiral Lewis base catalysis, phase-transfer catalysis, chiral Bronsted acid
catalysis, chiral anion binding catalysis, metal catalysis, N-heterocyclic carbene catalysis, enzyme
catalysis, and chiral photocatalysis, and a few other uncommon reaction types.
2. Chiral enamine/iminium catalysis with/without photocatalysts

In 2008, Macmillan and coworkers reported the first example of combining photoredox catalyst
Ru(bpy)3Cl2 with an imidazolidinone organocatalyst in the direct enantioselective α-alkylation of
aliphatic aldehydes with racemic α-bromocarbonyl compounds (Scheme 1).13 Subsequently, this
synthetic method was applied to the enantioselective α-trifluoromethylation of aldehydes (Scheme
1).14 More recently, this strategy was applied to the direct enantioselective α-amination of aldehydes
using a photonic excitable amine reagent (Scheme 1).15 Under light irradiation, the amine reagent
extrudes the photolabile dinitrophenylsulfonyloxy (ODNs) leaving group and provides the
electrophilic N-centered radical, which then couples with the enamine (derived from condensation of
the imidazolidinone catalyst and starting aldehyde) to obtain the α-amination product.
2008 MacMillan O View Article Online

N R2
DOI: 10.1039/D0OB00759E
• HOTf O
t
N Bu 4
R2 H R3

O H (20 mmol %)
R1 + R1 3
H Br R3 Ru(bpy)3Cl2 (0.5 mmol %)
2,6-lutidine, DMF, rt, 15-W CFL 63–93% yield
1 2
up to 99% ee
R1 = nhex, EtCH=CH(CH2)3, Bn, chex, 4-piperidinyl,1-adamantyl,
R2 = CO2Et, H; R3 = CO2Et, Bz, CO2CH2CF3
2009 MacMillan
O
N
• TFA O F F
t
N Bu 4
O H (20 mmol %) H R2
F F
R1 + R1 7
H I R2 Ir(ppy)2(dtb-bpy)•PF6 (0.5 mol %)
61–86% yield
5 6 2,6-lutidine, DMF, –20 °C
up to 99% ee
26-W CFL
R1 = nhex, (CH2)3CO2Et, (CH2)3OBn, (CH2)3NPhth, Bn, MeOC6H4, MeCHPh, 1-adamantyl

R2 = CF3, C6F5, Br, CO2Et, F
2013 MacMillan O
N R3
R3 O O • HOTf O
NO2 Et
O N
N S N (30 mmol %) H R2
R1 + R2 O 11 H
H R1
2,6-lutidine, DMSO–CH3CN, 15 °C 10
8 9 NO2
26-W CFL 67–79% yield
up to 94% ee
R1 = nhex, iPr, Bn, (CH2)3CO2Et, (CH2)3OBn, (CH2)3NPhth, 4-MeOC6H4, chexCH2, allyl
R2 = CO2Me, Cbz, Boc, Alloc, Fmoc; R3 = Me, nBu, Ph(CH2)3, MOM
Scheme 1 Enantioselective -alkylation or -amination of aldehydes.
In 2010, Macmillan et al. developed the enantioselective -benzylation of aliphatic aldehydes

12 with benzyl bromides 13 by the synergistic action of photoredox catalysis and organocatalysis.
Combining the Macmillan imidazolidinone organocatalyst and photoredox catalyst fac-Ir(ppy)3 under
household compact fluorescent light irradiation provided -alkylation products with a homobenzylic
stereocenter in good yields (68%–93%) and good enantioselectivities (82%–97% ee) (Scheme 2).16
In their study, benzylic bromide 13 reacted with fac-Ir(ppy)3* via single-electron transfer (SET) to
generate benzylic radical 15. Concomitantly, exposure of aldehyde 1 to organocatalyst 4 provided
chiral enamine 16, which then reacted with radical 15 through Si-face addition to afford radical 17.
Subsequent oxidation of 17 by fac-Ir(ppy)3+ followed by hydrolysis to give -alkylation product 14
completed the photoredox catalysis and organocatalysis cycles.
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DOI: 10.1039/D0OB00759E
O N
O
HOTf
N

O Bn 4 (20 mole %) H Ar
H
R + Ar Br
H R
fac-IrIII(ppy)3 (0.5 mol %), CFL 14
12 13 2,6-lutidine (2 equiv), DMSO, rt
68-93% yield
82-97% ee
R = n-hexyl, Bn, BnO(CH2)3, cyclohexyl, PhthNCH2
Ar = benzyl, 2,4-(NO2)2C6H3, 4-pyridinyl, quinolinyl, pyrazinyl, triazinyl, 1H-benzo[d]imidazolyl
Me
15 O
Ar Br reduction Ar Me N O
H R
13 + e- CH2 H
N 12
16
R
O
fac-IrIII(ppy)3* fac-IrIV(ppy)3+ N
O N
photoredox Bn N organocatalysis
catalysis
Bn N
Ar H 4
CFL e- 17
R O
oxidation N
fac-IrIII(ppy)3 Bn N O
Ar Ar H
18
R R 14
Scheme 2 Enantioselective α-benzylation of aldehydes.
Later, Zeitler and coworkers reported an enantioselective -alkylation of aliphatic aldehydes

with diethyl 2-bromomalonate, 2-bromo-1-(4-nitrophenyl)ethan-1-one, or 1-iodononafluorobutane
via enamine–iminium organocatalysis and organophotocatalysis with eosin Y and green-light
irradiation (Scheme 3).17 This process provides a new approach to the -alkylation of aliphatic
aldehydes beyond the scope of benzylic halides. The mechanism was proposed, as depicted in Scheme
3. After irradiating with green light, excited photoredox catalyst 1eosin Y* transitioned to its more
stable triplet state (3eosin Y*) through intersystem crossing (ISC) process. The authors assumed that
eosin Y served as a reducing agent, which depended on sacrificial oxidation of a catalytic amount of
the enamine as the initial electron supply, to afford alkyl radical 22 through single electron transfer
with alkyl halide 20. Subsequent addition of alkyl radical 22 to enamine 23, obtained from the
organocatalysis system, provided radical 24. Oxidation of radical 24 by reductive quenching of 3eosin
Y* gave iminium 25, which was hydrolyzed to afford product 21, and generated catalyst 4 to complete
the organocatalytic cycle. Subsequently, Zeitler et al. applied microflow technology to synergistic
organocatalysis and visible-light photoredox catalysis, which accelerated the reaction rate of
enantioselective alkylation of fatty aldehydes by more than one order of magnitude.18 For example,
one of the reactions required 18 h to reach completion under traditional batch irradiation, but only 45
min under microreactor irradiation. Further extensive study on related methods has been reported byOnline
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DOI: 10.1039/D0OB00759E
the same group.19 More recently, Melchiorre extended the enantioselective alkylation of aldehydes
to alkyl chloride using a dithiocarbamate anion catalysis strategy (Scheme 4).20 Alkyl chloride is

activated by an SN2 pathway using the chromophoric unit of nucleophilic dithiocarbamate. The
resulting photon-absorbing intermediate provides alkyl radicals through visible-light-induced
homolytic cleavage, and undergoes a C–C bond-forming reaction using the asymmetric amino
catalyst. Furthermore, recyclable visible-light photocatalysis of the enantioselective -alkylation of
aldehydes with alkyl bromides has been reported by Li, Zhang, and coworkers by merging the
Macmillan catalyst and porous Ru(bpy)32+-linked polymers.21 Additionally, the enantioselective -
alkylation of aldehydes with alkyl bromides using covalent organic frameworks (COFs) as
heterogeneous photocatalysts, the Macmillan imidazolidinone organocatalyst, and 2,6-lutidine in

DMF under LED irradiation at 440 nm has been reported by Cui.22
O N
t HOTf
Bu O
N (20 mol %) R2
H 4
O H
+ R2 X Br Br lutidine (2 equiv)
H R1
HO O O DMF, rt 21
20
19 R1 green LED 56-85% yield
( = 530 nm) 86-96% ee
R1 = n-hexyl, PhCH2 Br Br
X = Br, I HO2C
eosin Y
(2.5 mol %)
examples of halides:
NO2
CO2Et
Br CO2Et Br I(CF2)3CF3
O
O R2 R2 X
N O
22 20
t
Bu reduction
N N
23 N
O H H t
24 Bu
eosin Y eosin Y
H R1 R2
R1
R1 O
19
organocatalysis oxidation photoredox Green
N catalysis light
HN 4 O
t
Bu 3 1
O N eosin Y* eosin Y*
R2 N
H
H t
Bu
R1 21 ISC
R1 R2 25
Scheme 3 Enantioselective -akylation of aldehydes.

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29 (20 mol %)
OHC R2 DOI: 10.1039/D0OB00759E
30 (20 mol %)
OHC R1 + R2 Cl
2,6-lutidine (1.2 equiv) R1

26 27 CH3CN, 25 °C
blue LEDs, 24 h 29
R1 = nBu, Bn 57-77% yield
R2 = CH2C(O)Ph, CH2CN, CH(CO2Et)2 74-90% ee
Ar Br
N Ar
H OTMS N
29 30 SK
Ar = 3,5-(CF3)2C6H3 S
Scheme 4 Enantioselective -alkylation of aldehydes with alkyl chlorides.
In contrast, an enantioselective domino Michael addition/oxyamination of ,-unsaturated

aldehydes through iminium catalysis and photoinduced singly occupied molecular orbital (photo-
SOMO) catalysis was reported by Jang and coworkers (Scheme 5).23 The reaction introduced an
efficient photosensitizer, di-tetrabutylammonium cis-bis(isothiocyanato)bis(2,2′-bipyridyl-4,4′
dicarboxylato)ruthenium(II) (N719 dye), and the Jørgensen–Hayashi catalyst to enals, affording -
alkyl--oxyamination products in good yields (53%–80%) and good enantioselectivities (90%–99%
ee).
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DOI: 10.1039/D0OB00759E
Ph CO2TBA
Ph EtO2C CO2Et
N
34

H OTMS OHC HO2C
EtO2C (20 mol %) R N
OHC
R + O N NCS
EtO2C N719 (0.04 mol %), TiO2 N Ru
31 adamantanecarboxylic acid N NCS
32 (30 mol %)
(3 equiv) TEMPO (2 equiv), CH3CN, rt N
33 HO2C
8 W cool whilte fluorescent
53-80%yield
R = Ph, C6H4OMe, C6H4Me, C6H4NO2, C6H4Cl, 90-99% ee N719
C6H4Br, 2-naphthyl, 2-thiophenyl CO2TBA
TBA = tetrabutylammonium
CFL
EtO2C CO2Et
N719 32
Ru(II) Ru(II)*
photoredox N Ph
catalysis
Ph
e- N
OTMS
- e- EtO C
2 H 2O
TEMPO Ru(I) R
or O2 CO2Et 36 35
SOMO R
OHC
R
= CPh2OTMS R Ph 31
organocatalysis
37 Ph
N
N CO2Et H EtO2C CO2Et
OTMS
EtO2C
OHC
R
O N
N O
TEMPO 33 N
38
EtO2C H 2O
TEMPO
R
CO2Et
Scheme 5 Domino Michael addition/oxyamination
In 2013, Melchiorre et al. reported applying photoactivated chiral electron donor–acceptor

(EDA) complexes to the alkylation of aldehydes with alkyl bromides (Scheme 6).24 This chiral
catalyst does not contain any photosensitive groups, but instead directs photochemical activation of
substances by evoking the transient formation of chiral EDA complexes to establish a stereoselective
process.
View Article Online
42 (20 mol %) O H DOI: 10.1039/D0OB00759E

O O
2,6-lutidine (1 equiv) O Ar
R1 Br H
H + R2 MeOtBu, rt, 23 W CFL R1 R2 N Ar

39 40 41 H H
OTMS
70-96% yield 42
up to 94% ee Ar = 3,5-(CF3)2C6H3
O NO2
O NO2 42 (20 mol %)
2,6-lutidine (1 equiv) H
R1 Br
H
+ t
MeO Bu, rt, 23 W CFL
R1
NO2
39 NO2 44
43
73-92% yield
90-93% ee
R1 = iPr, Me(CH2)5, cyclohexyl, TIPSO(CH2)3
R2 = Ph, 4-Ph-C6H4, 4-NO2C6H4, 2-NO2C6H4, 2-BrC6H4, 2-thiophenyl, 2-naphthyl
NO2
Br
= CPh2OTMS
N NO2 43
colorless
45
O
R1 R1
H
39 colorless N
H Br
46 R1
H N
H H yellow-orange EDA complex
O 42
R1
e
SET
NO2
O2N 44
N N Br
48 R1 47 R1
chiral radical ion pair
Br
Scheme 6 Enantioselective photocatalytic alkylation of aldehydes with alkyl bromides.
Palomares, Pericàs, and coworkers introduced nontoxic and inexpensive semiconductor Bi2O3
as photocatalyst and a second-generation Macmillan catalyst for the enantioselective -alkylation of
hydrocinnamaldehyde with diethyl bromomalonate (Scheme 7).25 The strategy was accomplished by
combining bismuth-based semiconductors (such as Bi2O3 and Bi2S3) as low-band-gap photocatalysts
with Macmillan’s imidazolidinone as the chiral catalyst under sunlight or white light from a regular
fluorescent bulb. The semiconductor catalysis mechanistic cycle was presented by the authors, as
shown in Scheme 7. The reaction cycle is initiated by the promotion of electrons from the valence
band (VB) to the conduction band (CB) by light irradiation, followed by single electron transfer
reduction of halide 50 to generate alkyl radical 52, which then underwent addition to enantiopure
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DOI: 10.1039/D0OB00759E
enamine 53 to afford radical 54. Finally, oxidation to an iminium species by transfer of an electron
to the semiconductor afforded product 3, completing the semiconductor catalysis cycle. The EDA

complex catalysis cycle was also found to be involved, but with a lower reaction rate than the
semiconductor catalysis cycle. As bismuth semiconductors are low-cost and nontoxic, while sunlight
is a low-cost and renewable energy source, this enantioselective photocatalysis process is
environmentally friendly and sustainable.
Melchiorre et al. has also applied the EDA complex strategy to the intermolecular
enantioselective -alkylation of cyclic ketones and alkyl bromides, using catalytic quantities of a
quinidine-derived primary amine (20 mol%) and TFA (40 mol%) in toluene under CFL irradiation
(23 W) to afford -alkylated products with high diastereoselectivity and enantioselectivity (Scheme
8).26 Subsequently, this strategy was also successfully employed in enantioselective - and -
alkylations of enals and aldehydes, respectively, with bromomalonates, using the Jørgensen–Hayashi
aminocatalyst under CFL irradiation condition. The key element of this process is the use of derived
chiral enamines as photosensitizers to trigger the asymmetric radical chain reactions (Scheme 8).27
The same group has since reported a more detailed mechanism for this photochemical
enantioselective -alkylation of aldehydes with electron-deficient alkyl halides.28 This reaction
could proceed via the EDA complex, as well as through direct photoactivation of the chiral enamine
to attain an electronically excited state that acts as a photoinitiator in the subsequent radical reaction.
Alternatively, similar -alkylations of aldehydes with -bromoesters (or -bromoketones) using the
Macmillan catalyst and [Fe(bpy)3]Br2 as photocatalyst under visible-light irradiation have been
reported by Ceroni, Cozzi, and coworkers (Scheme 8).29 This study demonstrated that [Fe(bpy)3]Br2
can adequately substitute for [Ru(bpy)3]2+ or other photosensitizers in enantioselective visible-light
catalysis reactions.
10
View Article Online

O N DOI: 10.1039/D0OB00759E
t
Bu • HCl R3
R3 N OHC
H 4 (20 mol %)

R1 CHO R2
+ R2 Br Bi2O3 powder or Bi2S3 nanoparticles R1
(ca. 20 mol %), 2,6-lutidine, DMF, rt 51
49 50 23 W CFL 57-91% yield
82-98% ee
R1 = (CH2)6Me, (CH2)2Ph, cyclohexyl-CH2, (CH2)4CH=CHEt,
R2 = CO2Et, CO2Me, H; R3 = CO2Et, CO2Me, C(O)Ph, C(O)C6H4OMe
t N O
Bu
R2 X
R1
N radical ion pair

O t O
N X Bu 57
t
Bu N
N
EWG R2 X
R1 EDA O
R1  to  EDA cycle
56 complex N
N
H t
Bu
R1 R2 58
R1 CHO
49
O
t N O R2
Bu H
R2 52
N R1 51
O
53
reduction
R1 N
R2 X
N
H t 50
Bu
R1 R2
cat. 4
semiconductor 54
O cycle
oxidation e- CB
R2
H
O light
R1
51 N h+ VB
N
H t
Bu
R1 R2 55
Scheme 7 Enantioselective -alkylation of aldehydes using the Macmillan catalyst and semiconductors.
11
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2014 Melchiorre
DOI: 10.1039/D0OB00759E
O O NH2
O 62 (20 mol %)
TFA (40 mol %) O
N

Br
+ R1 NaOAc, tolutene n R1 N
n 60 0 °C, 23 W CFL 62
61
59 38–94% yield OMe
up to 95% ee
O NO2 62 (20 mol %) R2
O
TFA (40 mol %)
Br
n
+ NaOAc, tolutene
R2 0 °C, 23 W CFL n
63 NO2
59 64
R1 = Ph, 4-Ph-C6H4, 4-NO2C6H4, 2-NO2C6H4, 2-BrC6H4, 2-thiophenyl, 2-naphthyl
R2 = NO2, CN
2015 Melchiorre
R2 Ar
CHO R2 29 (20 mol %) R3
2,6-lutidine (1 equiv) CHO N Ar
R3
+ EtO2C H OTMS
R1 Br CO2Et MeOtBu, rt, 23 W CFL 29
65 66 R1
67 Ar = 3,5-(CF3)2C6H3
R1 = Me, Me(CH2)4, TIPSO(CH2)2, MeCH2CH=CH(CH2)2
R2 = Me, Bn, CO2Et, HO(CH2)5; R3 = H, CO2Et
2015 Cozzi and Ceroni O N

t HOTf
Bu
R2
O N
H 4 (20 mol %)
Br OHC R3
OHC R1
+ R3
R2 [Fe(bpy)3]Br2 (2.5 mol %) R1 O
68 2,6-lutidine (2 equiv)
69 70
DMF, rt, 23 W CFL
40–83% yield
R1 = Ph, Me(CH2)4, cyclohexyl, EtCH=CH(CH2)3, 4-piperidinyl up to 97% ee
R2 = H, Ph, CO2Et, HO(CH2)5; R3 = CO2Et, 4-NO2C6H4,
Scheme 8 Enantioselective -alkylation of aldehydes.
In 2013, MacMillan et. al. reported a β-arylation of cyclohexanone with terephthalonitrile and
the photocatalyst Ir(ppy)3 and a cinchona-derived organocatalyst, Scheme 9.30
CN O
O Ir(ppy)3 (1 mol %) H N
74 (20 mol %)
+
DABCO, HOAc, DMPU NH2
H2O, rt, CFL N
CN
71 82% yield; 50% ee 73 CN 74
72
Scheme 9 Enantioselective -arylation of cyclohexanone.
In 2014, Luo and coworkers reported an enantioselective photocatalytic -alkylation of -

ketocarbonyls with -bromocarbonyls using a primary amine catalyst (Scheme 10).31 The author
believed that the reaction proceeded through direct photoredox catalysis of the alkyl bromide, with
the EDA reaction pathway also making a minor contribution. Phenacyl radicals are generated by both
photocatalytic pathways, followed by an additional reaction. Later, the same group reported the
12
feasibility of enantioselective reactions without any external photosensitizer.32 View Article Online
DOI: 10.1039/D0OB00759E
t
H
Bu Et O
O O N 78
O

O NH2 Et OTf (20 mol %) R1
R1 R3 + Br
R4 R2 O R4
R2 Ru(bpy)3Cl2•6H2O (1 mol %)
76 NaHCO3 (1.0 equiv), CH3CN R3
75 77
rt, 33-W CFL
cyclic or acyclic 30-96% yield
up to 99% ee
acyclic: R1 = Me; R2 = Me, nPr, Bn, CH2COPh, CH2COPh-4-OMe
cyclic: R1–R2 = (CH2)3, (CH2)4, (CH2)5
R3 = OEt, OBn, OtBu, iBu, Et,
R4 = Ph, 4-PhC6H4, 4-CF3C6H4, 4-NO2C6H4, OBn,
R6
O O H
t
Bu Et O
R5 O N 78 OH
N Br
H + NH2 Et OTf (20 mol %)
n N
n R5
79 80 Ru(bpy)3Cl2•6H2O (1 mol %)
O
R6 NaHCO3 (1.0 equiv), CH3CN 81
n = 1, 2, 3 rt, 33-W CFL 55-90% yield
up to >99% ee
R5 = Ph, Bn, 3,4-Cl2C6H3, 4-MeC6H4, 4-MeOC6H4
R6 = H, Me, Br, Ph
Scheme 10 Enantioselective ‑alkylation of -ketocarbonyls.
Pericàs and coworkers developed an enantioselective cross-dehydrogenative coupling of

xanthenes with aliphatic aldehydes using visible-light photocatalysis and amino organocatalysis
(Scheme 11).33 The mechanism for the synergistic catalytic enantioselective cross-coupling of two
C(sp3)–H bonds has been studied using computational calculations and experimental evidence to
explain the origin of the enantioselectivity observed.
(1) Ru(bpy)3(PF6)2 (2 mol %)
Ar
Ar 29 (10 mol %) R3 CHO
R1 R2 + R3 CHO N Ar = 3,5-(CF3)2C6H3
X H OTMS
83
82 CH2Cl2, white LED, 35 °C R1 R2
X = O, S X
(2) NaBH4, MeOH, rt
84
R1, R2 = H, Me, MeO, di-Me, di-MeO, Et2N, Br, F up to 89% yield
R3 = Me, Et, nPr, iPr, nPent, BnO, BnO(CH2)2, BnO(CH2)3, PhCH2, 4-FPhCH2 up to 99% ee
Scheme 11 Enantioselective photoredox cross-dehydrogenative coupling.
In 2017, Luo et al. reported the enantioselective -alkylation of -ketocarbonyl compounds with
propiolic acids using photocatalytic decarboxylation and chiral aminocatalysis (Scheme 12).34 The
reactions afforded the expected -alkynylation product 87 and -alkylation adducts 88 as side
products. As shown in Scheme 12, a rational mechanism was proposed for this photoreaction,
showing that the addition of -imino radicals proceeded in a characteristic amino-catalyzed manner.
13
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t
Bu 78 DOI: 10.1039/D0OB00759E
NEt2
CO2H
NH2 TfOH R4
O O O R2
(20 mole %) O R2
R4

R1 R3 + R1
R2
O R1 +
O
R4 R3 O 87 R3 O
O 88
85 I 18-35% yield
17-57% yield
86 OH up to 99% ee up to 92% ee
(1.5 equiv)
Ru(bpy)3Cl2 6H2O (1 mol %)
R1 = Me; R2 = Me, CH2Cl2, rt, Ar, blue LED
R1 = R2 = -(CH2)3-, -(CH2)4-
R3 = OMe, OEt, Me, Et, iPr, nBu, iBu, tBu, Bn, allyl, cinnamyl,
R4 = Me, F, Cl, Br, OMe, n-pentyl,
t
Bu 85
87
NHEt2
NH2
CO2
O
t
Bu I
NHEt2
O
H
N O I
t
Bu O
NHEt2 RuIII
R1 R3 SET BI
N R2 Ph R2
asymmeric
R1 aminocatalysis
SET photocatalysis
R3 O
RuII*
t
Bu
NHEt2
H blue LEDs
N O RuII
t
Bu
NHEt2 O R2
R1 R3
Ph
N O -H+ R2 R1
O
R1 R3 R3 O
R2 88
O O
O O O O
O
I I
I O I O I O
OH OH -CO2
O 86 O O
Ph -H2O hydration Ph Ph
O HO2C
Scheme 12 Enantioselective alkylation of -ketocarbonyls with propiolic acids.
In 2017, Melchiorre et al. reported an enantioselective -alkylation of enals with alkyl silanes
enabled by visible-light excitation of chiral iminium ions (Scheme 13).35 The enantioselectivity and
yield of the reaction were directly proportional to the amine catalyst oxidation potential (92–94), with
94 having the greatest oxidation potential owing to the introduction of gem-difluoride atoms on the
pyrrolidine ring and the bulky perfluoro-isopropyl substituents on the phenyl groups.
14
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F
O F DOI: 10.1039/D0OB00759E
O 92 (20 mol %) Ar
TFA (40 mol %) H
R TMS N Ar
H
+

CH3CN, rt R H OTDS
Ar
single high-power LED 92
89 Ar 90 (max = 420 nm) 91
Ar = 3,5-(C(CF3)2F)2C6H3
up tp 93% yield
TDS = thexyldimethylsilyl
up to 94% ee
Ar = Ph, 1-MePh, 4-FPh, 4-ClPh, 4-BrPh, 4-MeOPh, 4-CF3Ph, 2-ClPh, 3-BrPh, 3-MeOPh, 3,5-tBu2Ph
R = Ph, 4-MePh, 2-MePh, 2,4,6-Me3Ph, 4- MeOPh, 4-FPh, 4-BrPh, 2-naphthyl, 3-benzo[b]thiophenyl
PhS, N(Boc)Ph, N-carbazolyl, N-tosyl-3-indolyl
X
X
Ar 93 X = H, Ar = 3,5-(CF3)2C6H3 Eox (93 /93 = +1.57 V, Ag/Ag+ in CH3CN)
94 X = F, Ar = 3,5-(CF3)2C6H3 Eox (94 /94 = +2.20 V, Ag/Ag+ in CH3CN)
N Ar 92 X = F, Ar = 3,5-(C(CF3)2F)2C6H3 Eox (92 /92 = +2.40 V, Ag/Ag+ in CH3CN)

H OTDS
O N Ph TMS 96
t
Bu
Ph N
H 95 Eox (96 /96 = +1.74 V, Ag/Ag+ in CH3CN)
Eox (95 /95 = +1.80 V, Ag/Ag+ in CH3CN)
F = C(3,5-(C(CF3)2F)2C6H3)2OTDS
F
H 2O
89a
N
TFA LED
O
H TFA
H F
Ph
Ph F *
Ph 92 colored
91a
N
H TFA
H 2O
F Ph
H F excited
Ph N as a strong oxidant
Ph F Ph TMS
F
SET 90a
N
H Ph TMS
Ph solvent
PhCH2 solvent–TMS TFA
Scheme 13 Photochemical enantioselective -alkylation of enals with alkylsilanes.
In 2018, Melchiorre et al. reported the enantioselective photocatalytic conjugated alkylation of

enals using alkyl dihydropyridine as a radical precursor (Scheme 14).36 This reaction was dependent
on violet LED and the excitation of chiral imine ions, which made them strong oxidants to produce
alkyl radicals from 4-alkyl-1,4-dihydropyridine and activate the enantioselective radical conjugate
addition pathway of the ,-unsaturated aldehyde.
15
Ar View Article Online

CHO DOI: 10.1039/D0OB00759E
O F
97 92 (20 mol %) F
+ H Ar
TFA (80 mol %)

R N Ar
CH3CN–perfluorohexane H
EtO2C CO2Et R Ar OTDS
(4:1), –10 °C
LED (max = 420 nm) 99 92
N Ar = 3,5-(C(CF3)2F)2C6H3
up tp 83% yield
H 98 TDS = thexyldimethylsilyl
up to 94% ee
Ar = Ph, 2-MePh, 4-MePh, 4-MeOPh, 4-FPh, 4-ClPh, 4-BrPh, 2-ClPh

R = iPr, tBu, sBu, 3-pentyl, Cyp, Cy, cyclobutyl, tetrahydro-2H-pyran-4-yl , N-Boc-piperidin-4-yl,
pent-1-en-4-yl, 2-methylhept-2-en-6-yl
Ph OHC
CHO F
F
+ 97a 94 (20 mol %)
O O Ar
TFA (80 mol %) Ph
DHP N Ar
CH2Cl2, –10 °C, 20 h O H OTDS
O O
O LED (max = 420 nm) O 94
O Ar = 3,5-(CF3)2C6H3
O
99a TDS = thexyldimethylsilyl
O
98a
Scheme 14 Enantioselective conjugate alkylation of enals with alkyl dihydropyridines.
In 2017, MacMillan et al. developed an enantioselective photocatalytic -alkylation of

aldehydes with olefins (Scheme 15).37 The intra- and intermolecular variants of these reactions were
feasible via hydrogen atom transfer (HAT) catalysis, single-electron transfer (SET), and electron
borrowing through photoredox catalysis, in addition to enamine–iminium catalysis.
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DOI: 10.1039/D0OB00759E
O H 102 (20 mol %) R2 H O
R2 Me
103 (3 mol %) O N
R3 104 (20 mol %) R1 t

R1 t Bu
R3 Bu
N 1-naph N
DMSO–NMA X n
X n LEDs N H
101 Ir F 102
100 F
dr up to >20:1 60-91% yield N
n = 0, 1, 2 i
Pr
up to 95% ee t N
Bu
i
Pr SH
Me
103 PF6
i
Ir(Fmppy)2(dtbbpy)PF6 104 Pr
R1 = R2 = Me, -(CH2)3-, H
R1 = H and R2= Me, (CH2)2TMS, prenyl, 1,3-diphenyl-1H-pyrazol-4-yl
R3 = H, Me
X = NTs, NBoc, CH2, C(CO2tBu)2, O
OHC R 108 (20 mol %) CHO Ar

109 (1 mol %) R Me
105 110 (10 mol %) N Ar
+ DME, 10 °C
107 t
Bu
N
H OTMS
LEDs 108
Ar Ar N
Me Ar = 3,5-(C(CF3)2F)2C6H3
Ir
106 56-92% yield Me
N
up to 93% ee t
Bu
t N
Bu
t
Bu SH
Me
PF6
109 t
Bu
Ir(dmppy)2(dtbbpy)PF6 110
R = Me, nHex, iPr, (CH2)4Cl, (CH2)3CO2Et, CH2NHCbz

Ar = Ph, 4- MeOPh, 4-FPh, 4CF3Ph, 3-pyridinyl, 1-benzyl-1H-pyrrol-3-yl, 2,3-dihydro-1H-inden-2-yl
107 105
= C(3,5-(C(CF3)2F)2C6H3)2OTMS
H 2O N H 2O
H
N
N
Ar H *IrIII
H oxidant
R
R
SET Photoredox IrIII

catalysis
HAT
IrII
N
reductant e
N
Ar H
H ArS
R
R
Ar HAT
catalysis ArS
106
H
H 2O
ArSH
110
Scheme 15 Enantioselective photocatalytic -alkylation of aldehydes.

17
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DOI: 10.1039/D0OB00759E
In 2018, Bach et al. showed that eniminium ions prepared from the corresponding enals could
be promoted by visible-light-induced energy transfer to their respective triplet states.38 The

intermolecular [2+2] photocycloaddition of eniminium ion 111 with 2,3-dimethylbutadiene using
Ru(bpy)3(PF6)2 (2.5 mol%) as photocatalyst at 40 °C under visible-light irradiation for 3.5 h afforded
the adduct in 78% yield with 88% ee (Scheme 16). Later, Bach and coworkers reported a visible-
light-enabled ( = 457 nm) chiral oxazaborolidine-catalyzed ortho photocycloaddition of
phenanthrene-9-carboxaldehydes and alkenes (Scheme 17).39 The authors observed that coordination
of the chiral Lewis acid with the aldehyde caused a bathochromic shift in the original n* absorption,
which enabled the reaction to be activated by visible-light irradiation.
Ar
(1) Ru(bpy)3(PF6)2 (2.5 mol %) OHC
N Ar
light, (max = 420 nm)
OTDS
H + (2) aq. NaOH Ph
BF4
Ph 111 112 113
TDS = thexyldimethylsilyl 78% yield; dr = 94:6
88% ee
Ar = 3,5-(CF3)2C6H3
Scheme 16 Enantioselective photocatalytic [2+2] cycloaddition.
OHC Ar1 Ar
117 (20 mol %) 1
–78 °C, CH2Cl2 OHC H

+ O
visible light N B
R1 R2 ( = 457 nm)
Br3Al Ar2
24 h R1 R2
114 115
116 117
R1 = H, 2-Me, 2-Cl, 3-F, 3-Me Ar1 = 3,5-dimethylphenyl
66-93% yield
R2 = H, 5-Me, 6-CF3, 6-F Ar2 = 2,6-dimethylphenyl
up tp 96% ee
Scheme 17 Photocycloaddition of phenanthrene-9-carboxaldehydes and olefins.
In 2018, Melchiorre reported a visible-light photocatalysis strategy for the intramolecular EDA
complex, applying this method to enantioselective radical conjugate additions of enones (Scheme
18)40 Key to this method was a chiral carbazole catalyst that contained no photosensitive unit, but
was able to induce the transient formation of an intramolecular EDA complex that absorbed visible
light and guided the enantioselective reaction of the photochemically formed radicals.
18
View Article Online
R4 O CF3
DOI: 10.1039/D0OB00759E
O R3 121 (20 mol %) t
high-power single LED N Bu
R1
+ ( = 420 nm) n

R2
n R1 N salicyclic acid (40 mol %) R4
H2O (2 equiv) R2 N 121
118 119 SiMe2Ph R3
CH3CN, 35 °C, 48 h
n = 1-3
120 NH2
R1 = Me, Et, Bn, cyclopropyl 44-95 % yield
up to 95% ee t
R2 = H, Me, OMe, Ph, 4-MePh, 4-ClPh, 2-furyl, 2-thienyl Bu
R3 = H, Et, F; R4 = H, Me
CF3
R3 O
O
R4 121 (20 mol %) R1

R2 high-power single LED N
R2
+ R1
( = 420 nm)
n
n N benzoic acid (40 mol %)
H2O (2 equiv) R3
122 123 SiMe2Ph CH3CN, 35 °C, 48 h R4
n = 1-2 124
R1 = Me, Et; R2 = H, Cl; R3 = H, Cl, F, MeO 57-82 % yield
up to 93% ee
Scheme 18 Enantioselective radical conjugate additions of enones.
In 2018, Melchiorre et al. reported a visible-light-induced enantioselective radical cyclization–

addition cascade of alkenoic acids and ,-unsaturated aldehydes by activating unfunctionalized
alkenes with a photoactivated chiral iminium ion (Scheme 19).41 This method is a further example
of visible light photocatalysis without a photocatalyst.
19
92 (20 mol %) R2 R2 View Article Online

F DOI: 10.1039/D0OB00759E
R3 TFA (60 mol %) OHC F
HexF /CH3CN (1:1) Ar
OHC CO2H O
R1 + R3 30 °C, 16 h R1 O N Ar

R2 R2 High power single LED H OTDS
125 126 (420 nm) R3 R3 127
92
up to 77% yield Ar = 3,5-(C(CF3)2F)2C6H3
up to 95% ee TDS = thexyldimethylsilyl
R1 = Ph, 4-FPh, 4-ClPh, 4-MePh, 3-ClPh, 3-MePh, 2-ClPh, 4-TMSPh, 4-BpinPh
R2 = Me, (CH2)5; R3 = Me, H, Ph, Et, (CH2)5
F = C(3,5-(C(CF3)2F)2C6H3)2OTDS
F
H 2O
125a LED
N
TFA 420 nm
OHC H TFA
O
F
Ph O Ph F *
92 colored
127a
N
H TFA
H 2O
Ph
F excited
F as a strong oxidant
Ph N
F
F 126a
SET
O N
O H
HO2C
Ph
O O
Scheme 19 Enantioselective radical addition and cyclization cascade.
In 2019, Pedro, Vila, and coworkers reported an enantioselective Mannich reaction of 3,4-
dihydroquinoxalin-2-one derivatives with ketones by merging visible-light organophotocatalysis
(eosin Y) with asymmetric aminocatalysis ((S)-proline), achieving good yields and excellent
enantioselectivities (up to 99% ee) for the chiral quinoxaline products (Scheme 20).42 Furthermore,
the reaction was feasible at a 5-mmol scale under sunlight irradiation.
O R3
H eosin Y (2 mol %)
N H
(S)-Proline (20 mol %) N
R1 R4
+ R3 R4
DMF, rt R1
O
N O blue LEDs N O
R2 129 R2
128
130
R1 = Me, MeO, CF3, F, CO2H, Cl,
R2 = H, Me, Bn, allyl, CH2CO2Me 55-94% yield
R3 = H, OH 75-99% ee
R3 = R4 = (CH2)3, (CH2)2
R4 = H, Me, iPr, noctyl, di-MeO
Scheme 20 Enantioselective Mannich reaction.

20
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DOI: 10.1039/D0OB00759E
He, Guan, and coworkers reported a photocatalytic oxidative dearomatization of 2-arylindoles
and enantioselective Mannich reaction with ketones through amino catalysis (using L-proline and D-

proline, respectively) to give C2-quaternary indolin-3-ones (Scheme 21).43
O R3
O Ru(bpy)3Cl2•6H2O O
(S)
R2 L-Pro, EtOH R4
R1 + R3 R1 (S) R2
N R4 2,6-lutidine, O2 N
H 9 W blue LEDs H
131 132 133
R1 = H, F, Cl, Br, Me, MeO
up to >20:1 dr 55-86 % yield

R2 = H, F, Cl, Br, Me, CO2Me, MeO, Me 95-99% ee
R3 = H, Me; R4 = H, Me, Bn, nC8H17
R3 = R4 = (CH2)4, (CH2)3
Scheme 21 Photocatalyzed oxidative dearomatization and enantioselective Mannich reaction.
Recently, Melchiorre et al. accomplished a photocatalytic and enantioselective reaction of in-

situ-generated chiral and colored iminium ions of ,-unsaturated aldehydes with allenic acids via
single-electron oxidation, which involved a cascade addition and cyclization process, affording
polysubstituted bicyclic lactones (Scheme 22).44
O
R1 92 (20 mol %) O F
R2 R2 H R2 F
high power LED(420 nm)
Ar R1 C R2 Ar
CH2OH CO2H Zn(OTf)2 (25 mol %) H Ar
N
134
+ H CH3CN, 35 °C, 18-72 h Ar O H OTDS 92
135 R1 R1
136 Ar = 3,5-(C(CF3)2F)2C6H3
Ar = Ph, 4-ClPh, 4-MePh, 3-MeOPh
R1 = Me, Et, (CH2)5, (CH2)11 42-56% yield TDS = thexyldimethylsilyl
R2 = Me, Et, (CH2)5, 57-74% ee
Scheme 22 Enantioselective cyclization of enals with allenic acids.
An enantioselective -alkylation of ketones using a cinchona-based primary amine catalyst and

alkyl radicals, generated in situ from alkyl chloride and dithiocarbamate anion catalyst A under blue-
light irradiation, has been reported by Melchiorre and coworkers (Scheme 23).45
Br
O 30 (20 mol %) R O
140 (20 mol %)
Cl R N
+ NaOAc (2 equiv) 30 SK
X n 138 toluene, 10 °C n S
137 blue LEDs, 24 h 139 OMe Et
n = 1, 2 up to 87% yield
up to 95% ee NH2
X = CH2, MeCH, tBuCH, PhCH, C(OCH2CH2)2, BocN N
R =CN, 2,4-(NO2)2Ph, PhC(O) •2TFA
N
140
Scheme 23 Enantioselective α-alkylation of ketones with alkyl chloride

21
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3. Chiral Lewis acid catalysis with photocatalyst

In 2014, Yoon et al. reported an enantioselective catalytic [2+2] photocycloaddition of ,-
unsaturated ketones using a dual-catalysis approach comprising a photocatalyst and chiral Lewis acid
catalyst (Scheme 24).46 This strategy addressed the long-standing problem of how to suppress the
racemic background [2+2] reaction under regular photocatalytic reactions. However, as shown at the
bottom of Scheme 24, under visible-light conditions, the uncatalyzed racemic background
cycloaddition was unable to proceed, reducing the effect on the net enantiomeric excess of the product.
Inspired by the pioneering study of Bach,47 Yoon observed that complexing the Lewis acid with
enones resulted in a bathochromic shift that provided longer-wavelength absorption, allowing the
[2+2] reaction to be activated under visible-light irradiation. Furthermore, introducing an H-bonded
substrate into the reactants produced a similar effect and enantioselectivity. Consequently, the [2+2]
cycloaddition of enones was achieved using photocatalyst Ru(bpy)3Cl2, Lewis acid Eu(OTf)3, and
chiral Schiff base ligand 144 to give cyclobutane adduct 143 in 34%–71% yield and 86%–93% ee.
Furthermore, different diastereoselective cyclobutane adducts were obtained by the alteration of the
chiral Lewis acid structure resulting from the reduction of chiral Schiff base ligand 144 to 146
(Scheme 24). Subsequently, Yoon applied a similar methodology to the enantioselective [2+2]
cycloaddition of 2′-hydroxychalcone and dienes using chiral Lewis acid-catalyzed photoexcitation
energy transfer (Scheme 25).48 Chiral Lewis acid coordination of the chalcone substrate significantly
reduced its triplet energy, allowing cycloaddition reactions to be performed with enantioselectivity.
Recently, Yoon used this approach in crossed enantioselective photocatalytic cycloadditions of 2’-
hydroxychalcone and styrene (Scheme 26).49 As expected, Lewis acid coordination of 2′-
hydroxychalcone 152a (ET = 54 kcal/mol) dramatically decreased the energy of Lewis-acid-bound
compound 157 (ET = 32 kcal/mol), allowing triplet energy transfer from 3Ru*(bpy)32+ (ET = 45
kcal/mol) and affording an enantioselective cycloaddition process. More recently, merging Lewis
acid catalysis and photocatalysis for enantioselective [2+2] cycloaddition has been extended to the
reactions of regular cinnamate esters with styrenes (Scheme 27).50
22
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DOI: 10.1039/D0OB00759E
N
N
O O O O
OH

HN
R1 O O n R2 R3
144 (20 mol %) Bu
+ R3
141 R2 142 Ru(bpy)3Cl2 (5 mole %)
R1 143
5 equiv Eu(OTf)3 (10 mol %)
i-Pr2NEt (2 equiv), CH3CN 34-71 % yield
R1 = Me, Et, i-Pr, CH2OBn
23 W compact fluorescent light 2.5-7 : 1 dr
R2 = Ph, C6H4Cl, C6H4Br, C6H4OMe,
C6H4F, 2-naphthyl, 2-furanyl 86-93 % ee
R3 = Me, Et
N
N
H
O O O O
R1 O O OH HN
+ R
146 (20 mol %) n
Bu R2 R3
141 R2 142 3
5 equiv Ru(bpy)3Cl2 (5 mole %)
Eu(OTf)3 (10 mol %) R1 145
R1 = Me, i-Pr, CH2OBn
R2 = Ph, C6H4Cl, C6H4Br, C6H4OMe, i-Pr2NEt (2 equiv), CH3CN 49-80 % yield
C6H4F, 2-naphthyl, 2-furanyl 23 W compact fluorescent light 1.5-4.5 : 1 dr
R3 = Me, Et, i-Bu 84-95 % ee
CFL
MLn* Ru(bpy)32+ Ru(bpy)32+*

O
141 photoredox i
R2 Pr
catalysis
N
Lewis acid R1 + e- Et i
Pr
- e-
catalysis
MLn* i
Pr
O Ru(bpy)3+
O N
i
Et Pr
R3 + R2 147
142 R1
MLn* [2 + 2]
– e-
direct photocycloaddition
O O O O
R2 R3 [2 + 2] R2 R3
+
CFL
R1 141 R1 142
143 or 145
Scheme 24 Enantioselective photocatalyzed [2 + 2] cycloaddition.

OH O
OH O Ru(bbp)3(PF6)2 (2.5 mol %)
(S,S)-tBu-PyBox (15 mol %)
Sc(OTf)3 (10 mol %) R1
R1 R2 + i
PrOAc–CH3CN v/v = 3:1
148 23W CFL, 20h
149 150 R2
R1 = H, Me, Cl
R2 = H, Br, Cl, OMe dr 2-4:1 66–84% yield
up to 98% ee
O O
N
N N
t t
Bu 151 Bu
(S,S)-tBu-PyBox
Scheme 25. Enantioselective catalytic [2 +2] cycloadditions.

23
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OH O DOI: 10.1039/D0OB00759E
t
OH O R2 (S,S)- BuPyBox (15 mol %)
Sc(OTf)3 (10 mol %)
R1 Ar2
Ar1 + Ar2 Ru(bpy)3(PF6)2 (2.5 mol %)

R1 i Ar1 R2
153 PrOH–CH3CN (3:1)
152 (10 equiv) 23W CFL, rt 154
up to 97% yield
up to >99% ee
R1 = F, Cl, Me, MeO; R2 = H, Me
Ar1 = Ph, 2-FPh, 2-ClPh, 2-CF3Ph, 2-MeOPh, 4-BrPh, 4-CF3Ph, 4-MeOPh, 3,5-(MeO)2Ph, 3-furanyl
Ar2 = Ph, 2-MePh, 2-ClPh, 4-MePh, 4-ClPh, 4-BrPh, 4-CF3Ph, 4-CO2MePh, 4-B(pin)Ph, 4-tBuOPh,
3-ClPh, 3-MeOPh, 3,5-(MeO)2Ph, SPh
OH O O
OMe OMe
MeO
O O
N
N N Br
O O OMe
t
Bu 151 t
Bu OMe OMe
(S,S)-tBuPyBox O OMe O OMe
155 156
80% yield, dr: 3:1; 94% ee a norlignan cyclobutane
natural product
OH O
OH O
Ph
152a
Ph (ET = 54 kcal/mol)
Ph (S,S)-tBuPyBox
154a
Sc
O O
Sc asymmetric Ph
O O catalysis 157
(ET = 32 kcal/mol)
Ph
Ph 3
Ru*(bpy)32+
159 (ET = 45 kcal/mol)
Sc
O O
photoredox
catalysis ISC
Ph
Ph Ru(bpy)32+ 1
158 Ru*(bpy)32+
153a (ET = 32 kcal/mol)
CFL
Scheme 26 Enantioselective photoredox cross-cycloaddition.

24
O View Article Online

DOI: 10.1039/D0OB00759E
O 163 (25 mol %)
RO
[Ir(Fppy)2(dtbbpy)](PF6) (1 mol %)
RO Ar1 + Ar2

Ar2
161 CH2Cl2 Ar1
160 (5 equiv) blue LED, –25 °C, 24h 162
dr up to >20:1 67-97% yield
i
R = Me, Et, Pr, Bn up to 99% ee
Ar1 = Ph, 4-MeOPh, 3-BrPh, 2-MePh, 2-thienyl
Ar2 = Ph, 4-MePh, 3-MeOPh, 3-FPh, 4-CF3Ph, 4-ClPh, 2-ClPh, 4-PinBPh
PF6
t
Bu
N
H
N
F IrIII
F O
N B NTf2
N
N H F
t
Bu F
[Ir(Fppy)2(dtbpy)]PF6 F
163
Scheme 27. Enantioselective catalytic [2+2] cycloadditions of cinnamate esters and styrenes.
Yoon et al. reported the enantioselective conjugate addition of -amino radical 167, generated
in situ from silylmethyl aniline 164, to crotonyl oxazolidinone 165 using synergistic Lewis acid
catalysis and photocatalysis (Scheme 28).51 The process provided Michael adduct 166 in good
yields (60%–96 %) with high enantioselectivities (85%–96% ee). A rational mechanism was
proposed by the authors. Initial photoredox catalysis of the -silylamine 167 affording -amino
radical 165. Concomitantly, chiral Lewis acid (pybox)Sc(OTf)3 catalyzed the conjugate addition of
167 to 165 and controlled the stereochemistry by activating the N-acyl pyrazolinone amide group in
165.
25
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R1 O Ru(bpy)3Cl2 (2 mol %), DOI: 10.1039/D0OB00759E
Sc(OTf)3 (15 mol %), (S,S)-151 (20 mol %) R1 R3 O
N TMS R3 R4 Bu4N+Cl (30 mol %)
R2 + N
R2 R4

164 165 (2 equiv) degassed MeCN, 23 W CFL
166
R1 = Me, Ph, Bn, Boc
60-96% yield
R2 = Ph, 4-FC6H4, 2-FC6H4, 4-ClC6H4, 4-BrC6H4, 4-MeC6H4, 4-MeOC6H4, 3-MeOC6H4,
85-96% ee
Pr, iPr, BnOCH2, tBu, 3-furanyl
R3 = Me,
R4 = O O
O O
N N
N O
N N N
Et i
Bu (S,S)-151 i
Bu
CFL
ScLn*
Ru(bpy)32+ Ru(bpy)32+*
+ TMS+ R1 R3 O
photoredox
N R1
R2 R4 catalysis
N TMS
170 R2
+ e- - e-
R1 R3 OTMS 164
N R1
R2 R4 Ru(bpy)3+
N TMS
171 ScLn* R2
R1 R3 O
H+ N TMS+
5 R2 R4
7 169 R1
166 164
N
R2
Lewis acid
catalysis 167
ScLn*
O O
ScLn*
168
R3 R4 chiral Lewis acid R4
activation
165 R3
Scheme 28 Enantioselective -amino radical addition.
In 2018, Zheng and coworkers reported an enantioselective reductive alkylation of nitrones to

aromatic aldehydes using the synergistic action of photocatalysis and Lewis acid catalysis to prepare
vicinal amino alcohols (Scheme 29).52 The chiral Lewis acid was an essential template for
assembling the two intermediates in this reaction, and activated the asymmetric radical coupling
reaction.
26
View Article Online

i
Pr DOI: 10.1039/D0OB00759E
Ru(bpy)3(PF6)2 (2.0 mol %) OH
O O Sc(OTf)3 (15 mol %) R3 i
Pr
N R3 175 (18 mol %) R2
+ O

R1 H i
TEEDA (4.0 equiv) N NH Pr
R2 R1 OH
CH2Cl2, 0 °C R4
173 R4 O
65 W CFL, 48 h 174 N
172
up to 99% yield
R1 = Bn, Me, iPr; R2 = iPr, nPr, Me, cHex, tBu; R3 = H up to 99% ee
or 175
R2 = R3 =Me, (CH2)4, (CH2)5
R1 = R2 = (CH2)3, (CH2)4, CH2CH2CMe2 N O
R4 = H, F, MeS, MeO, Br, NHAc
i
NH Pr
O
i
CFL Pr
i
Pr H OH
i
Pr
H OH i
Pr H O
N
Ph Ru(bpy)32+ Ru(bpy)32+*
Bn 174a H
N
O [Sc] *
Ph photoredox i
Pr
Bn catalysis
N
Et i
- e- Pr
+H + e-
172a i
Pr
+ Ru(bpy)3+
173a N
Et i
Pr
Lewis acid
catalysis
i
Pr H H i
PrH O
O
H
N
O [Sc] *
H
N
O [Sc] *
Ph
Ph Bn
Bn
i +H
Pr i H
Pr O
N
i
Pr i
Pr H
N
O *
[Sc]
N Ph
Et i
Pr Bn
Scheme 29 Enantioselective -amino radical addition.
In 2019, Xu et al. reported an enantioselective alkylation of 2-acyl imidazole with

bromodifluoroacetamide under the synergistic action of photocatalysis and chiral Lewis acid catalysis,
providing chiral -keto amides bearing a geminal difluoro group (Scheme 30).53 Catalyst –179 was
used as a chiral Lewis acid here, rather than as a conventional chiral photocatalyst.
Me
Ir(ppy)2(dtbbpy)PF6 Ar
O (1 mol %) N O
O t
Bu
N Ar -179 (4 mol %) R S
Br R N N
N PF6
Me
N + F F R
DIPEA (2.0 equiv) O F F R N C
Me CH2Cl2, rt N
23W CFL, N2 178 71-96% yield Rh
176 177 up to >99% ee N
N C
Me
Ar = Ph, 4-FPh, 4-ClPh, 4-BrPh, 4-CF3Ph, 4-MePh, 4-tBuPh, 4-MeOPh,
4-EtOPh, 4-PhPh, 4-MeSPh, 3-ClPh, 3-MePh, 2-MePh, 3,4-di-MeOPh, S t
Bu
3,4,5-tri-MeOPh, 3-EtO-4-EtC(O)OPh, 3-thienyl, 2,3-dihydrobenzofuran-5-yl chloride
R = (CH2)2, (CH2)3, (CH2)4, (CH2)2O(CH2)2, (CH2)2S(CH2)2, (CH2)2NPh(CH2)2, -179
(CH2)2NBoc(CH2)2
Scheme 30 Enantioselective alkylation of 2-acyl imidazole.
In 2019, Jiang et al. reported enantioselective coupling reactions of toluene with N-tosyl isatins
27
using a La(OTf)3/pybox catalyst (pybox comprises a chiral 3-hydroxy-3-benzyl-substituted 2-Online

View Article
DOI: 10.1039/D0OB00759E
oxindoles) under blue LED irradiation (Scheme 31).54 Furthermore, the enantioselective coupling
reaction of toluene and acenaphthoquinone was achieved using a chiral phosphoric acid (CPA)

catalyst under visible light irradiation. Notably, PhCl was the best solvent for this reaction, with other
solvents, including CH2Cl2, CMPE, MTBE, DME, THF, EtOAc, tBuPh, and BrPh, failing to afford
the product or resulting in very low product yields.
Ar R1 NMe2
O La(OTf)3 (20 mol %) HO
R1 183 (22 mol %) R2
X O + R2 Ar
O
N 4 Å MS, argon N O O
N
PhCl, 25 °C
Ts 181 X Ts N N
3 W blue LED, 48-60 h 182
180
63-94 % yield Et 183 Et
X = H, F, Cl, Br, Me Me Me
t
up ro 98% ee
Ar = Ph, 4-MePh, 4-FPh, 4-ClPh, 4-BrPh, 4- BuPh, 4-PhPh,
4-MeOPh, 4-EtPh, 3-MePh, 2-MePh, 2-MeOPh, 3,5-Me2Ph, Ph
2,4,5-Me3Ph, 2,3,4,5,6-Me5Ph, 3-tBu,5-MePh, 5-methylfuran-2-yl,
5-methylthiophene-2-yl
R1 = H, and R2 = Me, Et, Bn, Ph; or R1 = R2 = Me
Ph
O O
O O 187 (20 mol %) O HO R
P
183 (22 mol %) OH
O
+ R–H
4 Å MS, argon
Ph
185 PhCl, –5 °C
3 W blue LED, 60 h
184 186
187
40-76 % yield Ph
R: Bn, 4-PhCH2, 4-MePhCH2, 3-MeOPhCH2, PhMe2C up ro 90% ee
9H-fluoren-9-yl
Scheme 31 Enantioselective coupling of toluene with N-tosyl isatins or acenaphthoquinone.
4. Chiral Lewis base catalysis with photocatalyst

Smith et al. reported a sequential and stepwise enantioselective alkylation of 4-nitrophenyl esters
to 2-phenyl-1,2,3,4-tetrahydroisoquinoline using Ru(bpy)3Cl2 as the photocatalyst and isothiourea
tetramisole as the Lewis base catalyst (Scheme 32).55 The ester product was converted to the
corresponding amide by treating with benzylamine. The reaction with 4-
nitrophenoxytetrabutylammonium (TBAPNP) added resulted in an increased yield, which mighty be
due to the combined effect of increased reaction mixture polarity and the promotion of catalyst
turnover by 4-nitrophenoxylate.
28
View Article Online

(1) Ru(bpy)3Cl2 (0.5 mol %) DOI: 10.1039/D0OB00759E
CBrCl3 (1.5 equiv) H
CH3CN, blue LED, 2 h NPh N+
NPh NR2R3 O

(2) O R1
189
188 H - N+
R1 (1.5 equiv) O 191 O
OPNP
51-86 % yield
PNP = p-nitrophenyl dr ~75:25 TBAPNP O-
up to 88% ee
190•HCl (5 mol %), TBAPNP (1 equiv) N
Ph
i
Pr2NEt (1.5 equiv), THF, –10 °C, 24-36 h N S
(3) R2R3NH (5 equiv), –10 °C, 24 h 190
R1 = 4-MePh, 2-MePh, 4-CF3Ph, 4-BrPh, 4-PhPh, 4-MeOPh, 3-MeOPh, 3-thienyl, 2-naphthyl,

1-naphthyl, MeCH=CH, iPrCH=CH
R2 = Bn and R3 = H
R2 = R3 = 1-pyrrolidinyl, 4-morpholinyl, 1-Boc-piperazin-4-yl chloride
BrCCl3
2+
Ru(bpy)3
blue LED
CCl3 + Br
photoredox
Ru(bpy)32+* catalysis Ru(bpy)3+ HCCl3
Br
N – e- N –H N
Ph amine oxidation Ph Ph
188 191 192
O
S
R
base–H N
N
Ph
base
O H
S NPh
R Ph
N
N N
OAc N
Ph R
H S
O
N BnNH2
Ph
189 N S
190 191
Scheme 32 Enantioselective addition using isothiourea catalyst.
5. Phase transfer catalysis with photocatalyst

Melchiorre and coworkers developed an enantioselective perfluoroalkylation of cyclic
‑ketoesters using a chiral phase transfer catalyst with the in-situ-generated electron donor–acceptor
complex (EDA complex) strategy (Scheme 33).56 The yellow-colored EDA complex was initially
produced after the aggregation of chiral enolate 193 with R3I (a perfluoralkyl iodide). Promoted by
white LED light irradiation, the electron-deficient R3 radical was formed via single-electron transfer
29
and reductive cleavage of the C–I bond. Subsequently, the R3 radical reacted with the chiral PTCOnline
View Article
DOI: 10.1039/D0OB00759E
196–enolate 193 complex to give radical adduct 195a, which was trapped by R3I to afford iodide
195b and regenerate the R3 radical. Iodide 195b then released an iodide anion, affording product 195.

O 196+Br- (20 mole %), O
Cs2CO3 (2 equiv) R3
R1 CO2R2 + R3 I
C6H5Cl–C8F18 (2:1)
R1
CO2R2
194 rt, white LEDs, 64 h
193 195
R1 = F, Cl, Br, CF3, Me, MeO 38-71% yield
R2 = Me, tBu 78-96% ee
R3 = CF3, C4F9, C6F13, C8F17, C10F21
R3 I
194
Cs2CO3 chiral PTC R3 I Aceptor
196 O  to 
196+Br-
CO2R2
F3C Donor
OH
EDA catalysis
N O
colored EDA complex
N F
R1 CO2R2
Br
F light
193
196+Br- (a chral PTC) F
chiral PTC
196 O R3 +I
CH2O2R2
Cs2CO3
196+193–
196+X– R3
chiral PTC
O 196 O
R3
R1 CO2R2
CO2R2
PTC asymmetric
195 catalysis 196+193–
196
I O
R3
CO2R2
195b
O
R3
R3 CO2R2
195a
R3 I
194
Scheme 33 Enantioselective perfluoroalkylation of cyclic -ketoesters.
6. Chiral Brønsted acid catalysis with photocatalyst
The first procedure combining visible-light photocatalysis with chiral Brønsted acid catalysis
was developed by Knowles et al. in 2013 for an enantioselective aza-pinacol cyclization (Scheme
34).57 This enantioselective intramolecular reductive coupling of ketones and hydrazones was
achieved via a ketyl radical intermediate, which was enabled by a concerted proton-coupled electron
transfer (PCET) process. The operation was promoted by both photocatalyst Ir(ppy)2(dtbpy)PF6 and
30
CPA catalyst (R,R)-199. The synergistic action of the two catalysts is depicted in Scheme 34. Initial
View Article Online
DOI: 10.1039/D0OB00759E
excitation of the iridium photocatalyst followed by reduction of the Hantzsch ester (HE, diethyl 1,4-
dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate, 200)58 provides IrII(ppy)2(dtbpy) as a strong

reducing agent for the subsequent PCET-mediated ketone reduction, affording ketyl intermediate 203.
The intramolecular C–C bond coupling reaction of 203 produces 204, followed by H-atom transfer
from HE to give product 198 and HE radical 201, which is then oxidized by IrIII(ppy)2(dtbpy)* to
yield acidic pyridinium ion 202. Phosphate anion 205 can be protonated by ion 202 to regenerate
CPA 199 and complete the acid catalysis cycle. This synthetic methodology provided a new pathway
for catalytic enantioselective radical reactions.
Ir(ppy)2(dtbby)PF6 (2 mol %) SiPh3

(R,R)-199 (10 mol %) NHR2
O HE (1.5 equiv), dioxane R1 O O
R2 blue LEDs, rt
R1 n N HO P
n O OH
197 n = 1, 2
198
SiPh3
R1 = Ph, C6H4OMe, C6H4CF3, C6H4Me, 45-96% yield
2-benzofuranyl, 2-naphthyl, 2-thiophenyl, 77-95% ee (R,R)-199
H
EtO2C CO2Et EtO2C CO2Et
EtO2C CO2Et
Me N Me Me N Me
O H 202 H
P
O * 201 Me N
H
Me
O O oxidation
H O O e- or 200
204 O H O
P *
O oxidation
O
R1 e-
N R1 II EtO2C CO2Et
Ir (ppy)2(dtbpy)
R2 N 203
H R2
H Me N Me
200 H
+H Acid
201 reduction photoredox
catalysis + e- IrIII(ppy)2(dtbpy)*
catalysis
OH
HO PCET
R1
P
O *
NHR2
O O Blue LED
H 198 O O
205
HO
P * IrIII(ppy)2(dtbpy)
O O
202
EtO2C CO2Et 199 R1
N
R2 197
Me N Me H
206
Scheme 34 Enantioselective aza-pinacol cyclization.
Ooi et al. reported an enantioselective -coupling of N-arylaminomethanes with N-sulfonyl

aldimines through the cooperation of a photocatalyst and ionic Brønsted acid catalyst under 15-W
white LED irradiation (Scheme 35).59 The process was achieved using P-spirocyclic
arylaminophosphonium barfate (210•BARF, BARF = [3,5-(CF3)2C6H3]4B) as the chiral ionic
Brønsted acid catalyst and an Ir(III) species as the photoredox catalyst via synergistic catalysis. Initial
reductive quenching of the excited [*IrIII]+BARF species by amine 207 affords the corresponding
amine radical cation with negatively charged counterion BArF (213•BARF) and a neutral Ir(II)
complex. The resulting Ir(II) complex reduces imine 208 via single electron transfer to give radical
anion 212, which then pairs with Ir(III)+ to form complex 212•Ir(III)+. After prompt ion exchange
with 210•BARF, complex 212•Ir(III)+ forms chiral ion pair 210•212 and regenerates the photocatalyst
31
(211•BARF) to complete the photocatalysis cycle. Meanwhile, aminomethyl radical 214, generated View Article Online
DOI: 10.1039/D0OB00759E
by the deprotonation of radical cation 213•BARF with base, reacts with imine radical anion complex
210•212 under asymmetric induction by the chiral P-spirocyclic Brønsted acid to give product 209

and regenerate chiral acid 210 for continuation of the ionic Brønsted acid catalysis cycle.
Ms 210•BARF (4 mol %) R1 Ms
R1 HN
N 211•BARF (1 mol %)
N Me + N
H R3 visible light, toluene, rt R2 R3
R2
209
207 208
63-90% yield; 85-97% ee
R1, R2 = Ph, Ph; 2-naphthyl, Ph; 3-MeC6H4, Ph; 4-BrC6H4, 4-BrC6H4; iPr, Ph; nHex, Ph
R3 = Ph, 4-MeC6H4, 4-FC6H4, 4-ClC6H4, 4-MeSC6H4, 3-MeC6H4, 3-MeOC6H4, 2-MeC6H4,
2-napthyl, 3-thiophenyl,
Ph CF3
Me F3C CF3
N F3C CF3
H H N
N N
P Ir B
N N N
H H
N F3C CF3
Me
F3C CF3
Ph CF3 211
Ir(ppy)2(Me2phen) BARF
210
Ms R1
N [IrII]
211 N Me
H R3 R2
207
208
Ms photoredox
N catalysis [*IrIII]+BARF-
[IrIII]+
H R3 R1
white
IrIII•212 LED N Me
III + - R2 213•BARF
[Ir ] BARF
(211•BARF)
B
B•HBARF
NH
*
Ms
HN P NH N R1
210•BARF NH H R3 N CH2
* 210•212 R2
214
IBA
catalysis
R1 HN Ms
B: base, e.g. 207, 212, BARF-, etc 209
N
IBA: ionic Brønsted acid R2 R3
Scheme 35.Enantioselective -coupling of N-arylaminomethanes with imines.
An intramolecular hydroetherification of alkyl pent-4-enol with poor to moderate

enantioselectivity enabled by blue LED irradiation and a chiral ion pair acridinium photocatalyst was
reported by Luo et al., which afforded tetrahydrofuran (Scheme 36).60 In this study, the ion pair
32
catalyst demonstrated higher activity compared with its parent catalyst, 2 (Fukuzumi catalyst).
View Article Online
DOI: 10.1039/D0OB00759E
Cl

MesAcr+217– (5 mol %) Mes
R1 R1 R2 R2
PhCH(CN)2 (100 mol %) R1 O
O O
HO R2 CH2Cl2, –25 °C R1 R2 P
blue LEDs N O O
215 216
Me
50-88% yield
2-64% ee MesAcr+ 217–
R1 = Ph, 4-ClPh, 2-MePh, 3-MePh, 4-MePh Cl
R2 = Me, -(CH2)4-, -(CH2)5-, -(CH2)6-, 4-ClPh, 4-FPh, 4-MeOPh
Scheme 36 Enantioselective intramolecular hydroetherification.

Jiang et al. reported an enantioselective substitution reaction of alkyl halides and -amino
radicals derived from N-aryl amino acids via photoredox catalysis (Scheme 37).61 Photosensitizer
dicyanopyrazine-derived chromophore (DPZ) 221 was used as the photoredox catalysis to generate
achiral alkyl radicals from racemic -bromoketone and N-phenyl glycines, and CPA catalyst SPINOL
222 was applied to control the stereoselectivity of the free radical coupling reaction between both
alkyl radicals.
DPZ (0.5 mol %)

O R3 222 (10 mol %) R3 NC N OMe
O S
Br Ar NaHCO3 (3.0 equiv)
R1 + HO2C N R1 NHAr S
H 3Å MS, DME NC N OMe
R2 R2
0 °C, 60 h
218 219 3 W blue LEDs 220
DPZ (221)
46-86 %yield
up to 96% ee t
Bu
R1 = Ph, 4-ClPh, 4-MePh, 4-MePh, 4-MeOPh, 4-OHPh, 4-BrPh, 3-ClPh, 3-MePh,
3-MeOPh, Me, tBu, 2-thienyl t
Bu
R2 = Me, Et, Bn, 2-MePhCH2, 3-MeOPhCH2, 4-ClPhCH2, 4-MeOPHCH2,
R3 = H, Me ; Ar = Ph, 4-ClPh, 4-MePh, 4-MeOPh, 3-ClPh, 3-MePh
O O
P OH
DPZ*
t
O Bu
LED
219
t
222 Bu
DPZ photocatalysis
R3
Ar
N
H
DPZ
218
O O R3
222
R1 R1 NHAr
R2 enantioselective acid catalysis
R2 220
Scheme 37 Enantioselective C(sp3)–C(sp3) coupling reaction.
Jiang et al. reported an enantioselective decarboxylative -aminoalkylation of -amino acid-

33
derived redox-active esters (RAEs) to give isoquinolines using a SPINOL-CPA 226 andOnline
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DOI: 10.1039/D0OB00759E
photosensitizer DPZ 221 under blue LED irradiation. This reaction was used to prepare a series of -
isoquinoline-substituted amines in good yields with enantioselectivity up to 93% ee (Scheme 38).62

The same group also reported an enantioselective semipinacol rearrangement and aerobic oxidation
of 2-aryl-3-alkyl indoles, affording chiral 2,2-disubstituted indolin-3-ones, through synergistic
operation of SIINOL-CPA catalysis and visible-light photocatalysis (Scheme 39).63
O O R2 R1
DPZ (1 mol %) N
226 (15 mol %)
R1
N + N O HN CO2Et
R2
4 Å MS, DME, –10 °C CO2Et
N
223 O 3W blue LEDs, 60 h H O

224 225 O
P
R1 = H, Cl, Br, OMe 77-95% yield O OH
R2 = Ph, 4-FPh, 4-MePh, 4-iPrPh, 4-MeOPh, 4-AcOPh, 3-FPh, up to 93% ee 226
3-ClPh, 3-BrPh, 2-FPh, 2-MePh, 2-BrPh, iPr, iBu, Me, Bn,3-indolyl methyl
NC N OMe
S
S
NC N OMe
DPZ (221)
Scheme 38 Enantioselective decarboxylative -aminoalkylation.
NC N OMe
S
R3
O S
NC N OMe
DPZ (0.5 mol %)
229 (10 mol %) R1 R3
R1 R2 DPZ (221)
4 Å MS, tBuPh, 8 °C, air N R2
N H
H 3 W blue LED, 40 h
228 Ar
227
64-90% yields
up to 94% ee O O
R1 = H, Me, F P
R2 = Ph, 4-FPh, 4-ClPh, 4-iPrPh, 4-tBuPh, 3-MePh OH
O
R3 = Ph, 4-FPh, 3-FPh, 4-ClPh, 3-ClPh, 2-ClPh, 3-BrPh, 4-MePh, 3-MePh, 229
4-iPrPh, 4-tBuPh, 4-MeOPh, 3-MeOPh, 2-naphthyl, 2-thienyl, Cy,
Ar Ar = 4-pyrenyl
Scheme 39 Enantioselective semipinacol rearrangement and aerobic oxidation.
In 2018, Xia et al. reported the enantioselective cyclization of tryptamines with TEMPO under
visible-light irradiation (Scheme 40).64 Nitroxide TEMPO converted the indole to its free radical
through visible-light enabled hydrogen atom transfer (HAT) and NH activation, followed by imine
radical cyclization catalyzed by a CPA. Subsequent reaction with another TEMPO molecule afforded
octahydropyrrolo[2,3-b]pyrroles in high yields with high enantioselectivities. The total synthesis of
natural product ()-verrupyrroloindoline was achieved in five steps from Cbz-tryptamine using this
synthetic method.
34
View Article Online
NHR2 233 (10 mol %), DMAP (1.5 equiv)

i
Pr DOI: 10.1039/D0OB00759E
i
Pr
CyNCO (1.0 equiv), toluene, –15 °C N
N blue LEDs (max = 455 nm) O
R1 R3 +

i
N O N Pr
H R1 O O
R2 P
231 (TEMPO) N R3
230 H OH
O i
(2.5 equiv) 232 Pr
R1 = Me, F, Cl, Br, OMe; R2 = Ac, CO2Me, Fmoc, Cbz, Alloc, Boc 63-94 % yield
R3 = H, Me up ro 98% ee
i i
233 Pr Pr
NHR2 O
N C
233 N
OH
R1 R3 cyclohexyl isocyanate
N 234 (CyNCO)
N
blue LEDs R2
O
N
231 NHR2 H
R1 R3 O
R1 R3 N
N P O
H H O *
O
230
233
N N
O O
N
R1 R2
N R3 232
H
Scheme 40 Enantioselective photocyclization.
In 2018, Jiang et al. reported an enantioselective decarboxylation and radical coupling reaction
of N-aryl glycines to give 1,2-diketones using CPA SPINOL and a photosensitizer DPZ under blue
LED irradiation (Scheme 41).65 N-arylglycine produced an -amino intermediate through a single-
electron oxidative decarboxylation reaction under photoredox catalysis, then underwent a coupling
reaction with an electrophilic -keto radical that was stereocontrolled by H-bonding with the CPA.
Similarly, the CPA SPINOL and DPZ method has been applied to the conjugate addition and
enantioselective protonation of N-aryl glycines to SPINOL -branched 2-vinylazaarenes for the
synthesis of 3-(2-pyridine/quinoline)-3-substituted amines (Scheme 42).66 In addition, cooperative
Brønsted acid catalysis and visible-light photocatalysis using a combination of photosensitizer DPZ
and CPA SPINOL has been applied in the enantioselective -deuteration of prochiral azaarene-
substituted ketones or racemic -chloroazaarenes with D2O as the deuterium source (Scheme 43)67
Similarly, reactions of azaarene-substituted ketones in the absence of D2O afforded the corresponding
chiral alcohols with good enantioselectivities.68 Furthermore, the strategy combining photosensitizer
DPZ with a chiral H-bonding catalyst (L-tert-leucine-based squaramide amine 255) has been used for
the enantioselective -dehalogenative protonation of chiral cyclic and acyclic ketones under visible-
light photocatalysis, with 2,3-dimethyl-1,2,3,4-tetrahydroquinoxaline (256) as the terminal reductant
(Scheme 44).69
35
238 (10 mol %) O

View Article Online
R3 DPZ (1.5 mol %) R1 DOI: 10.1039/D0OB00759E
H OMe
N CO2H O (nBu)4PBr (30 mol %) NC N
N R2 S
R1 H
+ R2 Na2S2O4 (0.5 equiv) HO
NC N
S

cyclopentyl methyl ether OMe
O 237
235 3 W blue LED R3
236 5Å MS, 10 °C, 36 h yield up to 89% DPZ (221)
up to 97% ee
Ar
R5
O O
H O 239 (20 mol %) HO P
N CO2H N OH
DPZ (1.0 mol %) H O
R4 R5 O
+ N THF, 10 °C
R4 O
SPINOL-CPA
N Ar
235 3 W blue LED, 36 h
Boc Boc 241 238: Ar = 2,6-Me2-4-tBuC6H2
240
yield up to 91% 239: Ar = 3,5-tBu2-4-MeOC6H2
up to 94% ee
R1 = PH, Cl, Br, Me, MeO

R2 =Ph, iPr, 4-FPh, 4-ClPh, 4-BrPh, 4-tBuPh, 4-MePh, 3-MePh, 4-MeOPh, Naph
R3 = H, F, Cl, Br, tBu, Me, MeO
R4 = 2-Me-4-MeOPh; R5 = H, F, Cl, Br, Me, MeO
DPZ*
235
LED
H
N CO2H
Ph
DPZ photocatalysis
–H+
–CO2
H
N
Ph CH2
DPZ
236
O O
238 Ph
Ph N
R2 R2
enantioselective H-bonding H
O catalysis HO Ph
237
Scheme 41 Enantioselective radical coupling reaction.

R2 R2
H 245 (15 mol %) R3
N CO2H DPZ (0.2 mol %) NC N OMe
N S
R1 R3
+ N LiPF6 (40 mol %) R1 H
N S
THF, –35 °C 244 NC N OMe
242
243 3 W blue LED, 48-72 h yield up to 94%
up to 95% ee DPZ (221)
Ar
R2 R2
H 246 (15 mol %)
N CO2H N DPZ (0.2 mol %) N O O
R1 N P
+ LiPF6 (40 mol %) R1 H
O OH
242 THF, –35 °C 248
247 3 W blue LED, 48-72 h yield up to 85% Ar
up to >99% ee
SPINOL-CPA
R1 = H, F, Cl, Br, Me, CF3, MeO; R3 = H, Br, Me, MeO 245: Ar = 2-CF3Ph
R2 = Ph, 4-CNPh, 4-CF3Ph, 4-FPh, 4-ClPh, 4-BrPh, 4-MePh, 4-PhPh, 4-MeOPh, 3-FPh, 3-MePh, 246: Ar = 2-naphthyl
2-MePh, 2-napthyl, 1-naphthyl, 5-benzofuranyl, Me
Scheme 42 Conjugate addition and enantioselective protonation.

36
View Article Online

222 (20 mol %) DOI: 10.1039/D0OB00759E
DPZ (1 mol %) NC N OMe
R1 D S
R1 Cl 200 (1.5 equiv) R2
R2 N
N S

D2O (150 equiv) NC N OMe
R3 NaHCO3 (1.0 equiv) R3
249 250
mesiylene, 25 °C 58-89% yield
(racemate) DPZ (221)
3 W blue LED up to 95% ee
Ar
245 (10 mol %)
O O EtO2C CO2Et
DPZ (0.5 mol %) D
R4 200 (1.5 equiv) R4 R5 P
R5 N O OH
N Me N Me
D2O (200 equiv) H
252 OH
251 O NaCl (0.2 equiv), –5 °C
Ar 200
(racemate) cyclopentyl methyl ether 65-99% yield
SPINOL-CPA
3 W blue LED, 14 h up to 99% ee

222: Ar = 2-tBuPh
245: Ar = 2-CF3Ph
R1 = H, Me, Br, MeO
R2 = Ph, 4-CF3Ph, 4-FPh, 4-MePh, 3-MePh, 3-ClPh, 3-MeOPh, 2-MePh, 4-MePh, 4-tBuPh, 4-PhPh, 4-vinylPh
1-naphthyl, 9-phenanthrenyl
R3 = iPr, Me, Et, Bn, allyl, (CH2)3C=CH2, 3-pentanyl, cyclopentyl, Cy, tetrahydro-2H-pyran-4-yl chloride, cycloheptanyl
R4 = H, F, Me; R5 = Ph, 4-CF3Ph, 4-FPh, 4-MePh, 4-BrPh, 3-MePh, 2-MePh, 2-thenyl, 2-furanyl, 2-naphthyl, (CH2)2CH=CH2, Me
Scheme 43 Enantioselective reductive deuteration and dehalogenative deuteration.

O O
DPZ (0.5 mol %) t
O Br Bu
O 255 (5 mol %) F
F N N
256 (0.6 equiv)
Cl R H H H
R Br N
n Na2CO3 (2.5 equiv) X n
X H2O (1.0 equiv) 255
DCE, 5 °C, 3 W blue LEDs 254
253 H
55-96% yield N
X = C, O, S up to >99% ee
n = 0, 1, 2 256
R = H, F, Cl, Br, Me, OMe, OTs, OAllyl, OH, OMs, OTBS N
H
DPZ* 256 H
LED N
+ H+
SET
N
photocatalysis H
DPZ
N
O O
SET N
t DPZ
Br Bu
N N
H H
Br O O
O +e O
F
F Br
t
Bu + H+
enantioselective H
Cl N N
protonation
H H
Br
O 254
acid catalysis F
Scheme 44 Enantioselective dehalogenative protonation of ketones.
In 2018, Phipps et al. report an enantioselective Minisci-type addition of N-acyl -amino alkyl
radicals, generated in situ from the corresponding amino acid derivatives, to pyridines and quinolines
by merging photocatalysis with Brønsted acid catalysis (Scheme 45).70 This method has
37
demonstrated the highly regio- and stereoselective late-stage functionalization of twoOnline

View Article
DOI: 10.1039/D0OB00759E
pharmaceuticals, namely, metyrapone, for the diagnosis of adrenal insufficiency, and etofibrate, a
fibrate.

O O R2 NHAc
(Ir(dF(CF3)ppy)2(dtbpy)]PF6 (1 mol %)
N
(R)-TRIP or (R)-TCYP (5 mol %) N
+ N O NHAc
1,4-dioxane
R2
R1 blue LEDs, 14 h
O 258 R1
257
259
R1 = Me, MeO, Ph, F, Cl, CO2Me, EtC=O, CN, CF3, 4-BrPhO
R2 = Bn, Me, iPr, sBu, (CH2)2Ph, (CH2)4NHBoc, (CH2)2CO2tBu, (CH2)2SMe, 4-I-PhCH2, up to 98% yield
4-AcOPhCH2, (1H-indol-3-yl)methanyl up to 97% ee
R R
CF3 PF6
F
t
Bu
N
N R O
O
F Ir III P
F O
N R OH
N
t
Bu
F
CF3 R R
i
260, (R)-TRIP: R = Pr
[Ir(dF(CF3)ppy)2(dtbpy)]PF6
261, (R)-TCYP: R = Cy
Scheme 45 Enantioselective Minisci-type addition.
In 2019, Jiang et al. reported an enantioselective addition of alkyl or ketyl radicals to

vinylpyridines by merging asymmetric Brønsted acid catalysis with photoredox catalysis under
visible light irradiation to afford chiral -phenyl and aminopropylpyridines (Scheme 46).71 The chiral
Brønsted acid catalyst (SPINOL-CPA) activated pyridine and C=X, and controlled the
enantioselectivity. A series of -aminoalkyl and ketyl radicals generated in situ from the
corresponding ketones, aldehydes, and imines underwent conjugation addition to vinylpyridine with
good enantioselectivities.
38
DPZ 221 (0.5 mol %) R1 View Article Online

R1 DOI: 10.1039/D0OB00759E
SPINOL-CPA 233 (8 mol %)
X
+ Hantzch ester 265 (1.5-2.0 equiv)
N
Ar
N Ar R2 3 Å MS, CH3Cl, or CH3Cl–C6F5H (4:1),

262 –5 °C,3W blue LEDs 264 R2 X
263
or or
DPZ 221 (0.5 mol %)
X N
SPINOL-CPA 268 (20 mol %)
N + Ar
Ar R2 Hantzch ester 200 (2.5 equiv)
263 toluene, –5 °C or –50 °C 267 R2 X
266
3W blue LEDs
up to 99% yield
X = O, N(4-EtOPh) up to >99% ee
R1 = H, Me, MeO; R2 = H, Me, Et, FCH2
Ar = Ph, 4-FPh, 4-ClPh, 4-BrPh, 4-CF4Ph, 4-MePh, 4-MeOPh, 4-CO2EtPh,
3-CF3Ph, 4-FPh, 3-FPh, 3-BrPh, 3-BrPh, 3-MePh, 3-MeOPh, 3-CNPh,

2-BrPh, 2-thienyl, 2-furanyl, cinnamyl
Ar1
O RO2C CO2R
OMe O
NC N
S P OH
S O Me N Me
NC N H
OMe
Ar1 265 R = tBu
200 R = Et
DPZ (221) SPINOL-CPA
233 Ar1 = 2,4,6-iPr3C6H2
268 Ar1 = 9-anthryl
Scheme 46 Enantioselective addition of radicals to vinylpyridine.
Wang, Yang, and coworkers reported the enantioselective reaction of 2-aminochalcone with
catalytic CPA under blue LED irradiation to afford tetrahydroquinolines (Scheme 47).72 In the
absence of photocatalyst, the process underwent a relay visible-light-enabled cyclization and chiral
Brønsted acid-catalyzed hydrogenation reaction.
O 271 (2 mol %) Ar
200 (3.0 equiv) R1
R2
N R2 O O
R1 EtOAc, rt P
H O OH
NH2 5W blue LEDs
269 270
R1 = H, Cl, Br, Ph 51-96% yield Ar 271
R2 = Ph, 4-MePh, 3-MePh, 2-MePh, 4-MeOPh, up to >99% ee
3-MeOPh, 4-PhPh, 4-FPh, 4-ClPh, 4-BrPh, Ar = 9-(10-phenyl)-anthryl
4-CF3Ph, 1-napthyl, 2-napthyl, 2-thienyl,
2-furyl, Me, Ph(CH2)2 EtO2C CO2Et
blue
Me N Me
LEDs H
200
cat. 271
R1
can be done
N R2 in the absence of light
Scheme 47. Enantioselective coupling of tetrahydroisoquinolines and alkynes.
Knowles et al. reported an intramolecular enantioselective hydroamination of alkenes with

39
sulfonamides using a CPA and photocatalyst [Ir(dF(CF3)ppy)2(5,5’-dCF3bpy)]PF6 via N-centered View Article Online
DOI: 10.1039/D0OB00759E
radicals, formed in-situ from the proton-coupled electron transfer (PCET) activation of sulfonamide
N–H bonds (Scheme 48).73 Subsequent induction of the sulfonamidyl radicals by the CPA resulted

in enantioselective C–N bond construction.
[Ir(dF(CF3)ppy)2(5,5'-CF3bpy)]PF6 R2 R2
R2 O O (2 mol %), 274 (2.5 mol %)
R1 O
S thiol 275 (30 mol %) O
R3 N S N
H CF3Ph, –20 °C, 72 h
272 blue LEDs R1
273
R1 = H, MeO, Me, Cl, Br, CN, CF3, etc.
up to 98%yield
R2 = R3 = Me, (CH2)5, (CH2)3, (CH2)2NBoc(CH2),
up to 96% ee
R2 = H, R3 = Me, tBu
Ph
N N
n
Oct N i
Pr
SH
O O Ph
P NBu4 i i
Pr Pr
O O Ph
n
275
Oct N
N N
274
Ph
Scheme 48. Enantioselective intramolecular hydroamination of alkenes.
7. Chiral photocatalysts
Chiral-only-at-metal asymmetric catalysts, including ruthenium or iridium complexes, can be

activated by visible light, allowing visible light to affect asymmetric catalysis.74 In 2014, Meggers et
al. reported a new strategy using chiral iridium photocatalyst –279 for enantioselective photoredox
catalysis (Scheme 49).75 The chiral metal center in the photocatalyst served as the sole source of
chirality, as well as providing catalytic Lewis acid activity. A conceivable mechanism for photoredox
catalysis combined with asymmetric catalysis was proposed, as shown in Scheme 49. Initial bidentate
coordination of 2-acyl imidazole 276 with catalyst –279 and subsequent deprotonation formed
iridium (III) enolate complex 281. Next, the enantioselective addition of alkyl radical 282, generated
from photoredox catalysis of alkylbromide 277, generated radical 283. Single-electron oxidation of
ketyl radical 283 to give the iridium-coordinated keto intermediate 284 by photocatalyst iridium (IV)
regenerated the photocatalyst PS [IrIII]. After exchange with starting substrate 276, product 278 was
released from complex 284, and a new asymmetric catalytic cycle proceeded. The structure of IrIII
enolate complex 281, which is the key intermediate between the asymmetric catalysis and
photocatalysis cycles, was confirmed by X-ray crystal analysis. The synthetic strategy of integrating
the asymmetric and photoredox catalytic cycles in a single photocatalyst provided a new approach to
enantioselective visible-light-induced photocatalysis. The same group later applied these catalysts to
40
the reactions of N,N-diaryl-N-(trimethylsilyl) methylamines and 2-acyl-1-phenylimidazoles under airOnline

View Article
DOI: 10.1039/D0OB00759E
and household-lamp irradiation to provide oxidative coupling products in good yields (61%–93%)
with high enantioselectivities (90%–98% ee) (Scheme 50).76 This catalyst had three unique functions,

namely, as an active Lewis acid, a photoredox sensitizer, and as the sole source of chirality.
This chiral photocatalyst and strategy has since been successfully applied to the enantioselective
trichloromethylation of 2-acyl imidazoles and 2-acylpyridines with excellent enantioselectivities of
up to >99% ee (Scheme 50).77
O O
N R2 N
Br R3 –279 (2 mol %) R3
N + Na2HPO4 (1.1 equiv), 40 °C N R2
R1 276 277 R1
14W white light energy-saving lamp 278
R1 = Me, iPr t
R2 = Me, Et, Ph, C6H4Me, C6H4OMe, C6H4Cl, 2-naphthyl, 3-thiophenyl Bu
S
R3 =
X N Me PF6
F O C
N
Ir –279
Y N
NO2 NO2 N C
Me
X = CN, NO2, CO2Et Y = NO2, Cl, Br S t
Bu
[IrIII]
[IrIII] CH2R3
N O
N O 282
N Br R3
R2
N R2
R1 PS [Ir ]IV +e 277
R1 281 R3
H+ 283
[IrIII]
N O 280 asymmetric
analysis
e
photocatalysis PS [IrIII]*
N R2
R1
[IrIII]
O
–279 N O PS [IrIII]
N R2
N R2 [IrIII]
N III
R1 276 R1 PS [Ir ] = –279 N O
O R3 or
284 N R2
N
R3 R1
N R2
R1 279
Scheme 49 Enantioselective -alkylation of 2-acyl imidazoles.

41
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O DOI: 10.1039/D0OB00759E
O t
R4 Bu PF6
N O
N R2 R4 -288 (2 mol %) N
Me3Si N Me
+

H2Cl2, rt, air N R2 R3 N C
N R3 12-W CFL R1 N
R1 287 Ir
285 286
61-93 % yield N
N C
up to 98% ee Me
i
R1 = Ph, Me, Pr,
R2 = Ph, 2-MeC6H4, 3-MeC6H4, 4-MeOC6H4, 4-ClC6H4,3-thiophenyl, Me, Et O t
Bu
R3 = Ph, 4-MeOC6H4, 4-MeC6H4, 2-naphthyl; R4 = Ph, 4-MeC6H4
O -288
O
-279 (2-4 mol %) N R
N R
+ BrCCl3
NaHCO3, MeOH–THF N CCl3 S
t
Bu PF6
N
Ph 290 rt, 20-W CFL R1 291

289 N Me
62-96 % yield C
N
up to >99.9% ee Ir
N
R = Ph, 2-MeC6H4, 3-MeC6H4,4-MeOC6H4,4-ClC6H4, 2-ClC6H4, 2-naphthyl, C
N Me
3-thiophenyl, Me, Et, nPent
O S t
Bu
O
N R2
N R2 -279 (2-4 mol %)
+ BrCCl3
2,6-lutidine CCl3
-279
293 MeOH–CH3CN R1
R1 292 294
40 °C, 20-W CFL
65-91 % yield
R1 = H, Me, Cl, Br, Ph, nPr; R2 = Me, Ph up to 99.6% ee
Scheme 50 Enantioselective coupling reactions.
Meggers, Gong, and coworkers later applied a similar chiral rhodium (III) photoredox catalyst
in the aerobic enantioselective visible-light-driven dehydrogenative cross-coupling of 2-acyl
imidazole 295 with arylamine 296, providing dual functions as a Lewis acid and visible-light
photocatalyst (Scheme 51).78 In most cases, the reaction yields were >70% with >90 % ee, with a
few examples of 99% ee. A proposed mechanism was provided by the authors in which the enolate
rhodium complex approached the iminium species, generated in situ from the photosensitized
oxidation or autoxidation of amine 296, from the Re face. Furthermore, the chiral photocatalyst has
been applied to the visible-light-activated enantioselective addition of alkyl radicals to ,-
unsaturated acyl imidazole (Scheme 52).79
42
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O R3 O R5 DOI: 10.1039/D0OB00759E
-288 (2-5 mol %)
R2 N R3
R1 R1 N
+ R5 R4 air, 24 W blue LED

295 R2 R4
296 297
35-85% yield; 79-99% ee
R 1: N N For R5 = CO2tBu, dr: 5:1 - 12:1
N most cases: >70% yield; >90% ee

N
i
R R = Ph, H, i-Pr Pr
R2 = Ph, 4-MeOC6H4, 4-BrC6H4, 3-thiophenyl, 2-naphthyl

R3 = Me, Ph, p-Tol, o-Tol, 3,5-Me2C6H3, 4-MeOC6H4, 4-Cl, C6H4
R4 = H, Me, Et, iPr

R5 = CO2tBu, H
Best condition for R5 = CO2tBu: -288 (2.0 mole %), TFA (2.0 mole %), O2,
NMP, 40 °C
O
Si R5
N
N R R3
N N
Ir
O R2 R4
N
O
Scheme 51 Enantioselective domino photo-oxidation/Mannich reaction.

R3
O
O
-179 (4 mol %) N
N - +
R2
R2 + R3 BF3 K seseitizer 301 (2 mol %), rt N
N acetone-H2O, blue LEDs, 4-24 h R1 300
R1 298 299
40-97 % yield
R1 = Ph, Me, iPr, up to 99% ee
R2 = Me, Et, nPr, iPr, CH2OBn, Ph, 2-BrC6H4, 4-FC6H4, 4-MeOC6H4
R3 = 4-MeOC6H4CH2, 4-MeC6H4CH2, 4-ClC6H4CH2, tBuOCH2, MeOCH2,
4-MeOC6H4CH2OCH2, TMSCH2OCH2, iPr, tBu, cyclpentyl, cyclohexyl,
t
Bu PF6
S
N Me
C
N
Rh
N
N C
Me
N
S t
Bu ClO4
301
-179
Scheme 52 Enantioselective addition of alkyl or aminyl radicals to alkenes.
43
Meggers et al. reported an enantioselective synthesis of 1,2-amino alcohols from tertiaryView

amines
Article Online
DOI: 10.1039/D0OB00759E
and trifluoromethyl ketones using a chiral iridium complex as a dual Lewis acid/photoredox catalyst
(Scheme 53a).80 This visible-light-driven process incorporated single-electron transfer between a

donor substrate and catalyst-activated acceptor substance with a stereocontrolled radical–radical
cross-coupling, affording excellent enantioselectivity of up to 99% ee. This protocol was also
implemented in the coupling reaction of -silylamines with 2-acyl imidazoles, followed by
desilylation, to prepare 1,2-amino-alcohols in 69%–88% yields with high enantioselectivity (up to
99% ee) (Scheme 53b).81 Furthermore, these catalysts have also been applied to the enantioselective
radical amination of 2-acyl imidazoles using 2,4-dinitrophenylsulfonyloxy carbamates82 (Scheme
53c) and the radical perfluoroalkylation of 2-acyl imidazoles using perfluorobenzyl iodide and
perfluoroalkyl iodides (Scheme 53d).83 Additionally, the enantioselective -fluorination of 2-acyl

imidazoles using this iridium catalyst was reported by Xu et al. (Scheme 53e).84 However, these
reactions did not indicate whether the compounds were obtained by visible-light irradiation, or
whether they could still be obtained in the dark. However, according to the literature, these reactions
are likely promoted by indoor compact fluorescent or LED lighting. Furthermore, Kang et al. reported
an enantioselective conjugate addition of ,-unsaturated 2-acyl imidazole with
tetrahydroisoquinolines, activated by visible-light irradiation and chiral rhodium catalyst -320
(Scheme 53f).85
44
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DOI: 10.1039/D0OB00759E
R1
(a) t
R1 Bu PF6
S

-279 Me
O N C
(3 mol %) HO CF3 N
N Ir
CF3 + CHCl3 N N
N
N N C
Me CFL or N Me
Ph N
blue LEDs Ph R2
R2 304 S t
Bu
302 303
60-82% yield -279
R1 = H, Me, tBu, Cl; R2 = H, Me, OMe, tBu, Cl up to 99% ee
(b)
(1) -179 (4 mol %) R1 t
Bu PF6
O HO R2 S
R3 Ru(bpy)3(PF6)2 (1 mol %)
N N N Me
R2 CH3CN–DMAC, CFL R2 N C
+ TMS N
N R4 N N
(2) TBAF 307 Rh
R1 R1
306 N
305 69-88% yield N C
Me
up to 99% ee
R1 = Me, Ph, o-Tol, (2-Ph)Ph S t
Bu
R2 = Me, Et, Ph, Tol, 2-MePh, 4-ClPh, 4-AcOPh, 4-CO2MePh, 4-MeOPh, AcOPh, 4-PhPh -179
R3 = Me, Bn, tol, 4-tBuPh; R4 = tol, 4-tBuPh, 3-ClPh
(c)
O R3
O O Me -311 O PF6 t
Bu
N R2 S N (2 mol %) N O
N
+ O CO2Me CO2Me Me N
N 2,6-lutidine, rt N C
R2 N
R1 O2N NO2 309 CH3CN–DMSO, R1 310 Rh
308 blue LEDs N
52-99% yield C N
Me
up to 98% ee
R1 = Ph, o-Tol, iPr t O
R2 = Ph, 4-FPh, 4-ClPh, 3-ClPh, 2-ClPh, 4-BrPh, 4-MePh, 4-MeOPh, 2-naphthyl Bu
-311
R3 = Me, nBu, iBu
(d)
O t PF6
O Bu
R3 S
-279 N
N R2 (2-4 mol %) Me
N
+ R3 I N R2 314 N
C
N NaHCO3, MeOH–THF R1 Ir
R1 312 313 rt, 21-W CFL N
24-93% yield N C
absolute config. vary Me
up to >99.5% ee
R1 = Ph, o-Tol S t
R2 = Me, Et, nBu, Ph, 4-MeOPh, 4-MeOPhO, 4-ClPh, 2-ClPh Bu
-279
R3 = CF3, C3F7, C4F9, C6F13, C8F17, C10F21, C6F5CF2
(e)
O
O PF6 t
Bu
N R2 S
N R2 -279 (4 mol)
N Me N
F C
N selectfluor (1.2 equiv) R1 316 N
R1 315 MeOH, rt Ir
60-97% yield N
up to 99% ee C N
Me
R1 = Me, iPr, Ph
R2 = Ph, 4-PhPh, 4-ClPh, 4-FPh, 4-MeOPh, 2-ClPh, 2-MePh, 3-MePh, 3,4-diMeOPh, t
Bu S
2-naphthyl, Me, Et, nBu, nPent -279
(f) O R1 R3
O
-320 N N t PF6
N Ar Bu
R1 (2 mol %) O
R2
N N
N + R3 CH2Cl2, rt R1 N C
Me
i
Pr blue LEDs R2 N
318 319 Rh
317 N
54-96% yield N C
Me
90-99% ee
Ar O t
Bu
R1 = Ph, 4-MePh, 4-ClPh, 4-BrPh, 4-NO2Ph, 4-CF3Ph, 3-MeOPh, 2-MePh, 2-furyl,
2-thienyl, 1-naphthyl, 2-naphthyl, Me, CO2Et
Ar = 3,5-(CF3)2C6H3 -320
R2 = 6-Cl, 6,7-(MeO)2; R3 = Ph, 4-MePh, 4-BrPh, 3-BrPh, 4-CO2Me, 2-MeOPh
Scheme 53 Coupling reactions of 2-acyl imidazoles with different substrates.

45
Meggers et al. subsequently reported a proton-coupled electron transfer (PCET)86 strategy forOnline
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DOI: 10.1039/D0OB00759E
the photocatalytic enantioselective -amination of ,-unsaturated 2-acyl imidazole with N-phenyl
carbamic acid methyl ester using a combination of a weak phosphate base (tetrabutylammonium

diphenyl phosphate), iridium photocatalyst, and chiral rhodium Lewis acid -311 (Scheme 54).87
This process relied on a visible-light-induced and phosphate-facilitated single-electron transfer from
the NH group to a nitrogen-centered free radical, and the reaction of a nitrogen nucleophile with a
catalyst-bound substituted olefin, accompanied by a highly enantioselective radical–radical cross-
coupling, driven by a chiral rhodium–enolate radical intermediate. Meggers and coworkers reported
a visible-light-activated enantioselective reaction of ,-unsaturated N-acylpyrazole with allyl
sulfone using chiral rhodium catalyst -311, which provided the radical allylation product and
sulfonyl radical addition product in one process (Scheme 55).88 This method used the Hantzsch ester
328 and bidentate coordination of N-acylpyrazole with rhodium catalyst -311 under visible-light
irradiation to generate a radical species that reacted with allyl sulfone 325 and delivered the sulfonyl
radical and an enolate intermediate. The enolate afforded product 326 after protonation, with
regeneration of catalyst -311. Concurrently, in a sequence involving a stereodirected radical addition,
hydrogen atom transfer, and ligand exchange, the sulfonyl radical reacted with the rhodium-
coordinated N-acylpyrazole to form sulfonation product 327. In contrast, in the absence of LED
irradiation, Kang and coworkers have reported that the conjugate addition of N-protected
hydroxylamines to ,-unsaturated 2-acylimidazoles can be catalyzed by these types of chiral Rh
(III) catalysts to afford the adducts in good yields with good enantioselectivities.89 Furthermore,
Kang et al. also reported that, without intentional light irradiation, these types of chiral Rh(III)
complex can catalyze the decarboxylative conjugate addition of -keto acids to ,-unsaturated 2-
acyl pyridines or imidazoles with catalytic loadings as low as 0.05 mol%, providing the products in
excellent yields (94%–98%) with high enantioselectivities (88%–96%).90 More recently, Meggers et
al. reported an enantioselective -alkylation of ,-unsaturated 2-acyl imidazoles using a series of
Hantzsch esters as alkyl radical sources under the typical conditions (Scheme 56).91
O
PF6 t
Bu
R3 O
O -311 (5 mol %) O N OR2
O [Ir(dF(CF3)ppy)2(5,5'-dCF3bpy)]PF6 Me
N N C N
R1 R3 (2 mol %), Ph2PO4-Bu4N+ (20 mol %) R1
N OR2 N
N + H
CH2Cl2, blue LEDs, rt
N
N
Rh
Ph 321 322 Ph 323 C
Me N
up to 97% yield
R1 = Ph, 4-CF3Ph, 4-ClPh, 4-BrPh, 4-FPh, 4-MeOPh, 4-MePh, 3-MePh up to >99% ee t
Bu O
R2 = Me, Et, iPr, tBu, iBu, Bn, (CH2)2Ph, Ph -311
R3 = Ph, 4-ClPh, 4-Br, 4-MePh, 3-Me, 2-Me
Scheme 54 Enantioselective catalysis of 2-acyl imidazoles with carbamates.

46
EtO2C CO2Et View Article Online

328 O SODOI:
2Ar 10.1039/D0OB00759E
O O R2
R2 Et N Et (1.5 equiv) N
N H N R1
R1 R1
N SO2Ar -311 (8 mol %) N
+ N + 327

326
1,4-dioxane, N2, white LEDs, rt
324 325 up to 92% yield
(2 equiv) (1 equiv) up to 85 % yield up to 89% ee
up to 97% ee
R1 = Me, Et, nPr, (CH2)2CH=CH2; R2 = CN, CO2Et, etc.
Ar = Ph, 4-MePh, 4-BrPh, 4-CF3Ph, 4-MeOPh, 2-MePh, 2,4,6-Me3Ph, 2-naphthyl, 1-naphthyl
N
DMP =
N
SO2Ar
ArSO2
[Rh] O R2
*
DMP R1 [Rh] O R2
R2
*
SO2Ar DMP R1
EtO2C CO2Et
325
Et N Et
[Rh] O H 328
DMP R1
EtO2C CO2Et
O R2
+ *
Et N Et DMP R1
SET
328 326
-311
photocatalysis
+ O
[Rh]
1
328 DMP R1
ArSO2
O SO2Ar
DMP * R1
327 + SO2Ar
[Rh] O
DMP * R1
EtO2C CO2Et
O + SO2Ar
[Rh] O Et N Et
DMP R1
324
DMP * R1
EtO2C CO2Et
Et N Et
Scheme 55 Visible-light-activated enantioselective radical allylation and sulfonylation.
t PF6
R2 Bu
O R2 S
t
O
N BuO2C CO2tBu N Me
R1 -179 (4 mol %) N C
R1 N
N + N CH2Cl2, 21W CFL N Rh
Ph N
H 13-18 h Ph 331 C
329 N Me
330
up to 96 %yield S t
R1 = Me, Ph, 4-MeOPh, 4-FPh, 2-BrPh, 4-Br-2-AcOPh, nPr, iPr, up to 98% ee Bu
R2 = Ph, 4-MeOPh, 4-FPh, 2-BrPh, 2-thienyl, BnO, BocNH, iPr -179
Scheme 56 Enantioselective -alkylation of 2‑acyl imidazoles using Hantzsch esters.

47
Meggers, Wiest, and coworkers employed chiral photocatalyst -RhS2 in DOI: a visible-light-
View Article Online
10.1039/D0OB00759E
induced enantioselective -alkylation of 2-acyl imidazoles and 2-acylpyridines with -ketoesters
(Scheme 57).92 Based on the results of experimental studies and theoretical calculations, the authors

presented a mechanism in which a photoactivated Rh-enolate, after light excitation, transfers a single
electron to the -ketoester, followed by -proton transfer, and a subsequent stereodirected carbon
radical–radical coupling reaction.
t
O R1 Bu Ph
O -336 (4 mol %) O O S
PF6
N R2 DABCO (20 mol %) Me
R1 OR3 X OR3 C N
N
+ acetone, blue LEDs, rt N
O R2 OH Rh
332
Ph 334 335 N
C N
or X = 2-imidazole or 2-pyridine Me
O up to 97% yield t S Ph
up to >99% ee Bu
N
R1 -336
333
R1 = Ph, 4-MePh, 4-tBuPh, 4-MeOPh, 4-TBSOPh, 4-HOPh, 4-MeSPh, 4-CF3Ph, 3-BrPh, 3-indole-Boc
R2 = Ph, 4-MePh, 3-MePh, 4-FPh, 3-MeOPh; R3 = Cy, damantyl
O
N [Rh]+ O
R1 cat. [Rh]+
N
332 R1 –H+
[Rh]+ O
O R1 O N R1
X OR3
R2 OH
*
335 [Rh] O H
N
 R1
[Rh] O R1 O SET
N
OR3
R2 OH O
OH R2
R 3O
R 3O
R2 334 O
O
+H+
–H+
transfer
[Rh] O R1 O [Rh] O
N N
OR3 R1
R2 OH
Scheme 57 Enantioselective -alkylation of 2-acylimidazoles and 2-acylpyridines with -ketoesters.
Furthermore, in 2015, Meggers et al. reported the enantioselective conjugate addition of aryl
groups to 2-acyl imidazole derivatives using iridium catalysts bearing octahedral chiral ligands for
chiral Lewis acids catalysis in the absence of light irradiation.93 Later, the authors also applied this
catalyst to enantioselective hydrogenation and sequential photocatalytic radical
trifluoromethylation/cyclization (or atom transfer radical addition) reactions using the iridium
48
catalyst (Scheme 58).94 Recently, this process has been improved to a one-pot operation View
in other
Article Online
DOI: 10.1039/D0OB00759E
related reactions (Scheme 59).95

(1) -279 (2 mol %) OH
O dmp (40 mol %) t
Bu PF6
H2 (50 bar), THF, rt S
R
N Me
R (2) 339 (1.5 equiv) C
NaHCO3 (2.0 equiv)
N
337 338 CF3 Ir
MeOH, 7 °C N
R = 4-Ph, 4-OMe, 4-CF3 24 W blue LEDs 54-76% yield N C
Me
dr 1:1; 94-96% ee
S t
Bu
(1) -279 (2 mol %) HO
O
R3 dmp (40 mol %) R3 -279

H2 (50 bar), THF, rt
R1 CF3 O
R1 (2) 2 (1.5 equiv)
N N
2,6-lutidine (2.0 equiv)
R2 O
R2 CH3CN, rt 341 I N NH
340 24 W blue LEDs
52-72% yield CF3 dmp
R1 = H, Br, R2 = Boc, CO2Me; R3 = Me, nPr 93-99% ee
339
(1) -279 (2 mol %) OH CCl3

O dmp (40 mol %)
H2 (50 bar), THF, rt R
Br
R (2) BrCCl3 (2.0 equiv) 343
342 NaHCO3 (2.0 equiv) 70-90% yield
MeOH, 7 °C dr 1:1; 97-99 % ee
R = 4-Ph, 4-OMe, 4-CF3 24 W blue LEDs
Scheme 58 Sequential hydrogenation–trifluoromethylation.

49
View Article Online

(1) -279 (2 mol %) DOI: 10.1039/D0OB00759E
dmp (40 mol %)
O OMe CH3CN, rt OH

21 W blue LEDs
R
Br + OTBS R CO2Me
(2) HCO2NH4
344 345 THF–H2O (1:1), 40 °C 346
71-85% yield
R = 4-BrPh, 4-ClPh, 3-NO2Ph
93-95 % ee
(1) -279 (2 mol %)
dmp (40 mol %)
O
2,6-lutidine, CH3CN, rt OH
R1
21 W blue LEDs
+ O R1
CF3
OTBS I (2) HCO2NH4
349
THF–H2O (1:1), 60 °C
347 348 CF3
76-81% yield
R1 = 4-PhPh, 4-MeOPh, 4-BrPh, 3-benzofuranyl 91-94 % ee
OH
(1) -279 (2 mol %)
dmp (40 mol %) R
O TFA (1.0 equiv)
N
CH3CN, rt
R2 + 6 W blue LEDs
Me
N 352
350 Me 351 (2) HCO2NH4
THF–H2O (1:1), 40 °C 71-79 % yield
R2 = Ph, 4-ClPh, 4-ClPh 98-99 % ee
(1) -279 (4 mol %) Br

O O O
R3 Na2HPO4 (1.1 equiv)
N THF–MeOH (1:1), 40 °C N
N + Br
21 W blue LEDs, 24 h
N R3 OH
Me Br Me
(2) HCO2NH4 (9 equiv) 355
353 354 dmp (80 mol %) 80%yield; dr 4.5:1
R3 = 2-MePh THF–H2O (1:1), 60 °C, 5 h 96% ee
Scheme 59 Sequential photoredox and hydrogenation transfer reactions.
Megger et al. reported an enantioselective intermolecular [2+2] photocycloaddition of 2-acyl

imidazoles with alkenes by direct visible-light excitation of the Lewis acid catalyst/substrate complex
(Scheme 60).96 This process provided cyclobutanes with high yields, diastereoselectivity, and
enantioselectivity.
50
View Article Online

DOI: 10.1039/D0OB00759E
O R2 PF6 t
Bu
O R3 R5 -179 S
R1

(2-4 mol %) R3 Me
R1 R2
+ R4 C N
acetone, rt R5 N
356 357 blue LEDs Rh
358 R4 N
C N
up to 99% yield Me
N N N dr up to >20:1
R1 = Me t
Bu S
up to 99% ee
N N
Ph Me -179
R2 = Ph, 4-FPh, 4-CF3Ph, 4-ClPh, 4-BrPh, 4-MePh, 4-MeOPh, 3-BrPh, 2-BrPh, 3,5-(CF3)2Ph,
2-furanyl, 3-furanyl, cinnamyl,
R3 = H, Me; R4 = n-BuO, Ph, 2-thienyl, ; R5 = H, Me
[Rh]+ O R3
358
N
R2 blue LEDs
356
[Rh]+ O R3 *
N
R2
[Rh]+ O
R2
N excited siglet
R3
R5
ISC
R4
cyclization
[Rh]+ O R3 *
N
R2
ISC
[Rh]+ O R3 excited triplet
N
R2
R5 357
R4
Scheme 60 Enantioselective [2+2] cycloaddition.
In 2014, Bach and coworkers introduced chiral thioxanthone 361 as an organic photocatalyst
under visible-light irradiation for the enantioselective intramolecular [2+2] photocycloaddition of 359,
affording corresponding cyclobutane adduct 360 (Scheme 61). At a higher concentration of 2.5 nM,
the photoreaction of 359a gave 360a in 86% yield with 92% ee, while at a dilute concentration of
360a (1.0 mM), a 99% yield and slightly lower enantioselectivity (89% ee) were observed.97 A series
of quinolones, 359, were screened with catalyst 361 under the optimal reaction conditions, affording
promising results of 79%–95% yields with 87%–94% ee (Scheme 61).
51
View Article Online

O DOI: 10.1039/D0OB00759E
N

O S H
NH
361
O (10 mol %)
H
N O PhCF3, – 25 °C, visible light N O
H H
2.5 nM (359a), 30 min, 86% yield, 92% ee
359a 1.0 nM (359a), 30 min, 99% yield, 89% ee 360a
R1
X R2
X = O, NTs, C 79-95 % yield
R2
R1 = H, Me 87-94% ee
H R2 = H, Me
N O
H 360
N
O
N
O *
O S O
visible light S
N H O R N H O R
O H N O H N
361*•359a
361•359a R = (CH2)3CH=CH2
360a triplet-energy
transfer
359a
O
O N
N
O S
O S
N H O
N H O
*
O H N
O H N
361•359a*
361•360a
Scheme 61 Enantioselective intramolecular [2+2] photocycloaddition.
Later, Bach et al. applied the yellow chiral thioxanthone catalyst to intermolecular [2+2]
photocycloadditions of 2(1H)-quinolones to electron-deficient olefins, such as acrylates, to afford
products with good regio-, diastereo-, and enantioselectivities (Scheme 62).98 The products were
found to be head-to-tail (HT) adducts with the electron-withdrawing substituent at the exo-position.
The reactions proceeded under a Rayonet RPR-4190A light source (maximum wavelength, 419 nm)
in Rayonet-type photochemical reactors. As shown in Scheme 62, two-point hydrogen bonding
between the catalyst and quinolone was crucial for reaction success, providing adequate triplet energy
transfer and high enantioface differentiation. Furthermore, the cycloaddition process was also feasible
52
under solar radiation. Alternatively, this strategy was applied to the enantioselective photocatalysis
View Article Online
DOI: 10.1039/D0OB00759E
of the intermolecular [2+2] cycloaddition between acetylenedicarboxylates and 2-pyridones under
near-UV irradiation with fluorescence lamps (max = 366 nm) (Scheme 63).99

O
N R3
Y R2
R1
R3 O R1
S R2
R2 NH
X + Y 361 X H
N O R2 (10 mol %) N O
H O H
362 363 364
PhCF3, – 25 °C
R1 = H, C5H11 violet light ( = 419 nm) 47-94% yield
R2 = H, Me X = H, Me, Br 80-95% ee
R3 = H, Me Y = CO2Me, CO2Et, CO2Bn, COMe, COEt, CHO
N
O *
O S
violet light
N H O R1
O H N 362•361*
O
N
O S
N H O 362*•361
R1 O
O H N N
362•361 O S
photocatalysis
N H O R1
R2
R2
R3 O H N *
H
O Y
O
R1
HN N R3
R2
O S
362 Y
R2 H R R2
364 N H O 1
Y
363
O H N
R3
R2
365•361
Scheme 62 Enantioselective intermolecular [2 + 2] photocycloaddition.

O
N
O H
O R 3O 2C R2
R2 CO2R3
NH
369
+ (10 mol %) R 3O 2C N O
R1 N O O R1 H
H CO2R3
366 Hexafluoro-m-xylene/trifluorotoluene = 2:1 368
367 – 65 °C, near UV light ( = 366 nm), 4 h 40-88% yield
59-92% ee
R1 = H, Me; R2 = H, Me; R3 = Me, Et, iPr, tBu
Scheme 63 Enantioselective [2+2] cycloaddition of acetylenedicarboxylates and 2-pyridones.
Sibi, Sivaguru, and coworkers reported an asymmetric intramolecular [2+2] photocycloaddition

of coumarin with atropisomeric thiourea catalysts (Scheme 64).100 The reactions provided the
corresponding cycloadduct at a low catalyst loading with high conversion and good enantioselectivity
53
(77%–96% ee). The binaphthyl-based thiourea exhibited lower excited-state energies than theView starting
Article Online
DOI: 10.1039/D0OB00759E
coumarin substrate. In this reaction, the observation and manipulation of excited-state reactivity has
been accomplished by creating dynamic and static complexes (exciplex formation).

H
R1 (S)-372 (1-10 mole %) R1

H
toluene/m-xylene (1:1), –78 °C R2 O O
R2 O O
370 371
coversion up to 100%,
R1 = H, Me, F, OMe; R2 = H, Me, F
isolted yield 77%
77-96% ee
R3
S
Ar
N N
H H
OR4
R3 (S)-372
R3 = H, CF3; R4 = H, Me; Ar = 3 5-(CF3)2C6H3, C6F5
Scheme 64. Enantioselective intramolecular [2+2] photocycloaddition of coumarin.
Yoon and coworkers reported an enantioselective intramolecular [2+2] cycloaddition using an

effective chiral photocatalyst ()-[Ir(tF(CF3)ppy)2(pypz)][BArF] under visible light irradiation
(Scheme 65). This process directed the quinolones using a series of hydrogen-bonding and –
interactions.101
R4 R3
R2 R4
R3 H
O R2 375•BARF (1 mol %)
R1 O
R1 CH2Cl2/pentane (1:1) N O
N O –78 °C, blue LED, 24 h H
H
373 374
up to >98% yield
R1 = F, Cl, Br, I, CF3, Me, MeO
up to 91% ee
R2 = H, Me, R3 = H, Me, Et; R4 = H, Me
CF3
F F3C CF3
N
F3C CF3
F N
F
Ir B
F
F N
HN F3C CF3
N
F F3C CF3
375 CF3 BARF
Scheme 65 Enantioselective [2 + 2] photocycloaddition.

54
Nicewicz et al. reported a moderate enantioselective radical cation Diels–Alder reaction Viewunder
Article Online
DOI: 10.1039/D0OB00759E
visible-light photocatalysis using photosensitizer 1c, comprising an oxidizing pyrilium salt, that
contains a chiral N-triflyl phosphoramide anion (Scheme 66).102 Unfortunately, some of the

examples afforded low yields and enantioselectivities.
H
R R OMe
X SiPh3
378 (3.5 mol %) X
LEDs (470 nm) O 378
H O
toluene, –20 °C, 72 h P
O NTf
OMe
SiPh3 O
377 OMe
376
up to 72% yield MeO OMe

X = O, NTs; R = iPr, Cy, Bn, Me up to 50% ee
R 378 (3.5 mol %) H

H
+ LEDs (470 nm)
MeO 381
toluene, 60 °C
379 380 38-85% yield; dr 8-10:1; 32-36% ee
R = Me, Et OMe
Scheme 66 Enantioselective cation radical Diels–Alder reaction.
Meng et al. reported the enantioselective aerobic oxidation of -ketoesters, -ketoamides, and
1,3-diketones using a phase transfer catalyst containing a photosensitizer grafted to a cinchona
derivative (Scheme 67).103 Under white LED irradiation and air, the photocatalytic reactions resulted
in the corresponding -hydroxylation of -ketoesters in yields of up to 97% and enantioselectivities
of up to 86% ee. Subsequently, the enantioselective aerobic -hydroxylation of -dicarbonyl
compounds has been improved using cinchona-based phase-transfer catalysts and can be performed
in semi-flow photoredox processes.104
Ph
Ph NH
N
O O N
O OH O
384 (5 mol %) HN
R1 R1
Cs2CO3 (2 equiv)
n R2 toluene, rt, air n R2 Ph
382 25W white LEDs
383
n = 1, 2 N
Br
R1 = H, Cl, F, Br, Me, MeO,
R2 = adamantan-1-ol, Et3CO, tBuO, MeO, 4-methylpiperidin-1-ol, 384
NMePh, NHPh Br Br
CF3
Scheme 67 Enantioselective aerobic oxidation of -keto carbonyl compounds.
In 2018, Meggers et al. reported visible-light induced photocatalytic and enantioselective radical
conjugate additions of -aminoalkyl radicals, generated in situ from the precursor of glycine
derivatives, to ,-unsaturated N-acylpyrazoles for the synthesis of -substituted -aminobutyric acid
derivatives (Scheme 68).105 Some of the reaction products were converted to related bioactive
55
compounds or pharmaceuticals, such as (S)-nebracetam, (R)-baclofen, (S)-pregabalin, and (R)-Online

View Article
DOI: 10.1039/D0OB00759E
rolipram.

O
EtO2C CO2Et
R1 R3
t
Bu
385 N S
R2 R3 PF6
+ H O
Me
(2.0 equiv) N N C
O R1 R4 N
O
R3 -179 (8 mol %) Rh
acetone, rt 387 N
N N N C
O R4 23 W CFL 42-89 % yield Me
O up to 97% ee S
386 t
Bu
N N
N N -179
R1 =
t
R2 = Ph, Bn, Me, iBu, nPr, npentel, OEt, 2-thienyl, CH2iPr Bu Ph
PF6 S
R3 = H, Me, Ph, Bn; R4 = Boc, Fmoc, Cbz
Me N
C
O F N
EtO2C CO2Et Rh
N N
N R5 C
O R5 F Me Me N
388 N N
N S
+ H N Boc t
Bu Ph
(2.0 equiv)
O 390 -336
O Me -179 (8 mol %)
N N acetone, rt 53-80 % yield
O Boc 23 W CFL up to 96% ee
O 389
R5 = Ph, 4-MePh, 3-MePh, 2-MePh, 4-MeOPh, 4-MeSPh, 4-tBuPh, 4-ClPh
Scheme 68 Enantioselective aerobic oxidation of -keto carbonyl compounds.
Some chiral copper (II) bisoxazoline complexes (CuII-BOX) have been reported by Gong et al.
to possess absorptions in the region of 400–550 nm, owing to metal–ligand charge transfer, which is
an essential characteristic required for visible-light photoredox catalysis. The catalysts were applied
by the group in the enantioselective alkylation of imines with a series of benzyl trifluoroborates under
visible-light irradiation (Scheme 69).106
56
R2 View Article Online

R2
BF3K Cu(BF4)2•H2O (10 mol %) DOI: 10.1039/D0OB00759E
R3
R1 N 394 (11 mol %)
S
+ R3 CHCl3, argon, –20 °C
R1 NH
S
O O 24 W blue LEDs

391 O O 393
392
R1 = H, MeO, CF3O, CF3, Cl, Me ; R2 = CO2Me, CO2iPr, CO2Et, CO2Bn, 69-88 % yield
R3 = H, F, Cl, Br, CF3, MeO, Ph, CO2Me up to 98% ee
NBoc BF3K BocHN

Cu(BF4)2•H2O (10 mol %) CO2Me
R4 398 (11 mol %) R4 O
O
N + CHCl3, argon, –20 °C N
CO2Me 24 W blue LEDs R5
395 R5 396 397
R4 = H, F, Cl, Br, MeO 84-99 % yield
R5 = Bn, Me up to 94% ee
Bn Bn
O O
N N
O O
N N
398
394
Scheme 69 Enantioselective alkylation of imines by benzyl trifluoroborates.
In 2018, Meggers et al. reported an enantioselective [3+2] cycloaddition of cyclopropanes to

alkynes or alkenes via visible-light photoredox catalysis using a rhodium-based chiral photocatalyst
(Scheme 70).107 The reactions gave high product yields with excellent enantioselectivities. The
cycloaddition reaction mechanism has been proposed to proceed through direct photoexcitation of
the single-electron transfer reduction of the catalyst–substrate complex, followed by radical ring-
opening of cyclopropane and subsequent cycloaddition of an alkyne or olefin.
O R3
O R1 R4
R2 R3 -179 (2-4 mmol %) N
N DIPEA (50-200 mol %)
N
+ R4 acetone, N2 N PF6 t
Bu
Ph R2 S Ph
Ph blue LEDs, rt R1
400 401
399 Me N
up to 99% yield C
up to 99% ee N
Rh
O R6 N
C N
O R5
R5 -179 (2-4 mmol %) N
Me
N R6 DIPEA (50-200 mol %) S
t
Bu Ph
+ acetone, N2 N
N
Mes blue LEDs, rt
Mes
R5
R5 -336
403
402 404
up to 99% yield
up to 99% ee
R1 = R2 = Me, (CH2)4, (CH2)3, or R1 = Ph, R2 = Me, etc
R3 = CO2Me, COPh, P(O)(OEt)2, SO2Ph, Ph, 4-MeOPh, 4-FPh, 4-BrPh, 4-CNPh, pyridin-2-yl, 4-CO2MePh, CN
R4 = H, Me; R5 = Me, (CH2)3; R6 = 4-MeOPh, 3,5-di-CF3Ph, 4-BrPh, 4-MePh, 3-MePh, 2-MePh, 3-thienyl
Scheme 70 Enantioselective [3+2] cycloadditions of cyclopropanes.
8. Chiral anion binding catalysis with photocatalyst
In 2014, Stephenson et al. introduced a strategy of merging asymmetric anion-binding catalysis

57
with photoredox catalysis for an enantioselective alkylation of N-aryltetrahydroisoquinolines View

405Article
andOnline
DOI: 10.1039/D0OB00759E
silyl ketene acetal 406 using photoredox catalyst Ru(bpy)3Cl2 and asymmetric catalysis 408, affording
-amino esters 407 in good yields and enantioselectivities (Scheme 71).108 The process was achieved

as follows. A solution of tetrahydroisoquinoline 405a, photocatalyst, and CCl4 in CH3CN was
irradiated with blue light for 16 h, followed by concentration to give crude iminium product 410.
Crude compound 410 was then reacted with silyl ketene acetal 406 and asymmetric catalyst 408 in
methyl tert-butyl ether (MTBE) at 60 °C for 16 h. As shown in Scheme 71, the process achieved
photoredox catalysis of amine oxidation and subsequent chiral anion-binding catalysis109 of the
imine to give the desired product. Applying the dual function of oxidative photoredox activation and
asymmetric anion binding catalysis in this asymmetric synthesis process provided a distinct strategy
for enantioselective photocatalysis. Furthermore, N-dearylation of product 408 was achieved by

reacting with [Fe(bpy)3](PF6)2 and CAN to give secondary amine 409, which was smoothly converted
to 410 using acetyl chloride and pyridine. This conversion expanded the examples of aryl-substituted
derivatives to other functionalities and demonstrates the synthetic utility of chiral
tetrahydroisoquinolines.
(1) Ru(bpy)3Cl2 (1 mol %)
OTBS CCl4 (4 equiv), CH3CN, blue LED, 16 h R
R
N
+ N
Ar OMe (2) CF3 Ar
405 406 t
Bu S 407 CO2Me
(2.0 equiv)
N
R = H, Cl, OMe N N CF3
S H H
Ar = Ph, MeOC6H4, BrC6H4, O
ClC6H4, (MeO)2C6H3
408 (20 mol %), MTBE, 16 h, -60 oC
OMe CAN, CH3CN, H2O OMe

N [Fe(bpy)3](PF6)2 N AcCl, pyridine N
87% O
MeO2C MeO2C MeO2C
408 409 410
CCl4 OTBS
Ru(bpy)32+ N OMe
Ar
blue LED 406
CCl3 + Cl 407a
CO2Me
photoredox
Ru(bpy)3 2+
* catalysis Ru(bpy)3+ HCCl3 cat. 408
anion-binding
asymmetric
catalysis
N – e- N –H N
Ph amine oxidation Ph Ph
409 N
405a 410 Ph
lower pKa, lower BDE Cl
– e- 413
–H H H
F 3C N N
CCl4 R*
N N S
Ph Ph
411 412 Cl CF3
Scheme 71 Merging photocatalysis and anion-binding asymmetric catalysis.
9. Metal catalysis
58
In 2014, Molander and coworkers developed an enantioselective photoredox cross-coupling View Article Online
DOI: 10.1039/D0OB00759E
reaction of racemic trifluoroborate with methyl 3-bromobenzoate to afford a 1,1-diarylethane product
in 52% yield with 50% ee (Scheme 72).110 Furthermore, a single-electron mechanism for

transmetalation in the photoredox/nickel cross-coupling with organoboron was proposed by the
authors, as shown in Scheme 72. A detailed mechanistic investigation of the reaction by density
functional theory was reported later, with the dynamic kinetic resolution (DKR) of Ni-catalyzed111
cross-couplings presented.112 More recently, the Macmillan group reported an enantioselective Csp3–
Csp2 cross-coupling of aryl halides and -amino acids through the synergistic action of photoredox
and nickel catalysts, affording to the chiral benzylic amines with high enantioselectivities (Scheme
73).113
Ir[dFCF3ppy]2(bpy)PF6 (2 mol %)
417 (3 mol %) Me
Me Br CO2Me Ni(COD)2 (3 mol %) CO2Me
+ Ph
Ph BF3K 2,6-lutidine
THF–MeOH, blue LED, 24 h
414 415 416
racemic Bn N N Bn
52% yield; 50% ee
O O 417
Scheme 72 Enantioselective cross-coupling reaction.

[Ir[dF(CF3)ppy]2(dtbbpy)]PF6 (2 mol %) CN
X NiCl2•glyme (2 mol %) X
CO2H Y 421 (2.2 mol %), TBAI Y O O
R1 R2
+
NHBoc Br 4-BrPhCN R1 NH N
Cs2CO3, DME–toluene R2
418 419 rt, blue LED NHBoc
420
R1 = iPr, nPr, OBn, CO2Me, CH2CO2Me, (CH2)3NHCbz, (CH2)2Cl, yield up to 84% 421
Ph, 4-BocOPh, 3-indolyl, 2-thienyl up to 93% ee
X = CH, N; Y = CCN, CAc, CH, N
R2 = H, F, CO2Me, CF3, F
Scheme 73 Enantioselective carboxylative alkylation.
Li and coworkers reported an enantioselective cross-dehydrogenative-coupling of

tetrahydroisoquinolines and terminal alkynes under visible-light irradiation. The process was
accomplished by combining chiral copper catalysis and photocatalysis (Scheme 74).114 The reactions
were conducted under 26-W household compact florescence light with CuBr (10 mmol%), ligand 4
(15 mmol%), Ir(ppy)2(dtbbpy)PF6 (1 mmol %), and benzoyl peroxide (or under O2), in CH3CN–HF
(1:1) at 20 °C for 2 days. This methodology demonstrated the synergistic cooperation of photoredox
catalysis. Unfortunately, a rational mechanism accounting for enantioselective induction in the
copper catalysis cycle has yet to be proposed, and the absolute configurations of the adducts have not
been determined.
59
Ir(ppy)2(dtbbpy)PF6 View Article Online

DOI: 10.1039/D0OB00759E
(1 mmol %) R1
R1
N
+ H R2
* N
Ar CuBr (10 mmol %) Ar
423 425 (15 mmol %)

422 (BzO)2 (1.2 equiv) or O2
CH3CN–THF (1:1)
CFL, –20 °C 424 R2
N
30-90 % yield
PPh2 60-97% ee
425
Scheme 74. Enantioselective coupling of tetrahydroisoquinolines and alkynes.

Xiao and coworkers reported an enantioselective photocatalytic oxidation of dihydro-1H-

indene-type -ketoesters with oxygen through complexation of a linker of the chiral bisoxazoline
(boxes) ligand with photosensitizer thioxanthen-9-one and catalytic Ni(acac)2, producing the
corresponding -hydroxy products in yields of up to 97% with up to 95% ee (Scheme 75).115
Furthermore, the reactions were conducted under irradiation by the 3W violet LEDs with a
wavenumber of around 390–410 nm. Furthermore, the reaction was not only limited to benzene
examples but also applied to some examples of pyridine and thiophene systems.
O 428 (10 mol %) O

Ni(acac)2 (10 mol %) OH O
R1 CO2R2 S
R1 CO2R2
toluene, –15 °C, O2 O
n 3W violet LEDs n
O O
426 427
Ph Ph
n = 1, 2, 3 N N 428
R1 = Me, MeO, F, Cl, Br, TBSO, MeCCH2O, allyl Ph Ph
R2 = adamantanyl, tBu,
Scheme 75 Enantioselective photocatalytic aerobic oxidation.
Xiao et al. later reported the enantioselective perfluoroalkylation and difluoroalkylation

reactions of -ketoesters by combining photoredox, chiral Lewis acid, and nickel catalysis cascades
(Scheme 76).116
Ir[dF(CF3)ppy]2(dtbbpy)PF6 O
O (3 mol %), NiBr2•glyme O O
432 (20 mol %) CO2Ad
F F
R1
R1 CO2Ad + I R2 NaHCO3 (2.0 equiv) CF2R2
Bn
N N
Bn
n
n DME, degas, rt 432
430 7 W blue LEDs, 30 h 431
429
n = 1, 2 40-67% yield
R1 = H, Me, MeO, F, Cl, Br, OTf up to 90% ee
R2 = CO2Et, C2F5, C3F7; Ad = 1-adamantanyl
Scheme 76 Enantioselective photocatalytic aerobic oxidation.
Liu, Lin, and coworkers reported an enantioselective decarboxylative radical cyanation reaction
of N-hydroxy-phthalimide (NHP) esters to afford the corresponding chiral alkyl nitriles through
synergistic action of photocatalysis and asymmetric copper catalysis (Scheme 77).117
60
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DOI: 10.1039/D0OB00759E
R2
R2 Ir(ppy)3 (0.5 mol %)
O O O

O CuBr (1 mol %) CN
N 435 (1.2 mol %) R1 N N
R1
O 434
O TMSCN (1.1 equiv)
DMF/p-xylene (4:6) 59-98 % yield 435
433 (racemic) Ar, blue LEDs up to 99% ee
R1 = Me, Cl, Br, tBu, MeO, and other aromatic system, e.g. 1-naphthyl, 3-pyridinyl, benzo[b]thiophenyl, etc
R2 = Me, Et, iPr, Cy, allyl, (CH2)3OMe, CH2CO2Et
434 blue LEDs

435-CuICN
IrIII
asymmeric IrIII *
SET photocatalysis
coppercatalysis
435-CuII(CN)2
435-CuIICN
IrII SET
R2 R2 O 433
O + N
-CO2
O
O
Scheme 77 Enantioselective decarboxylative cyanation reaction.
In 2017, Lu, Xiao, and coworkers reported a sequential enantioselective Pd-catalyzed

photoactivated [4+2] cycloaddition of vinyl benzoxazinanones and -diazoketones (Scheme 78).118
Visible-light activation of -diazoketones facilitates Wolff rearrangement, providing an intermediate
ketene for the subsequent Pd-catalyzed enantioselective [4+2] annulation.
61
View Article Online
R1 Br DOI: 10.1039/D0OB00759E
N2 Pd2(Dba)3-CHCl3 (5 mol %) R1 R2
O R2 439 (11 mol %), CH2Cl2, rt
+ R3 R3

6W blue LEDs
N O O N O
Ts Ts Ph
437 438 S
436
439
(racemic) dr up to >95:5 75-99% yield
up to 96% ee Ph NBn
R1 = Me, Br, Cl, F, CF3, MeO
(PhO)2P
R2 = Ph, iPr, tBu, cyclopropyl; R3 = Me, iPr, Bn, (CH2)2CH=CH2, (CH2)3OBn, H
blue LEDs O
[Pd]*
437 C
Wolff O asymmetric
rearrangement allylic alkylation
R3 R2 R2
N
Ts
R3 [Pd]*
R2
[Pd]*
R3
N O
NTs Ts
ligand
[Pd]* exchange
436
O
N O
Ts 438
Scheme 78 Enantioselective Pd-catalyzed photoactivated [4+2] cycloaddition.
Xiao et al. reported dual nickel catalysis and visible-light photoredox catalysis in desymmetric
C–O coupling reactions of 2-(2-halophenoxy)-propane-1,3-diols for the enantioselective synthesis of
1,4-benzodioxanes (Scheme 79).119 This process was realized by deploying an axially chiral 2,2’-
bipyridine ligand L3 and photocatalyst Ir(dFCF3ppy)2(dtbbpy)PF6.
CF3
F
t
Bu
Ir(dFCF3ppy)2(dtbbpy)PF6 (3 mol %) N
R2 R2
O NiCl2•glyme (5 mol %) N
OH O N F
442 (5 mol %), K2CO3 OH O Ir
R1 R1 F PF6
I OH quinuclidine (20 mol %) O
O N N
THF, 30W blue LEDs N
440 441 t
Bu
t 442 F
R1 = H, Et, Bn, Bu, Cy, F, iPr, Cl, F, Me, PhMe2C, 65-84% yield CF3
R2 = H, Me up to 76% ee
Ir(dFCF3ppy)2(dtbbpy)PF6
Scheme 79 Enantioselective synthesis of 1,4-benzodioxanes.
Mei, Han, and coworkers reported an enantioselective radical cyanoalkylation of styrenes by

incorporating copper catalysis and photoredox catalysis (Scheme 80).120 Alkyl N-
hydroxyphthalimide esters are introduced as alkylation reagents, and the chiral Box/Cu(II) catalyst is
62
responsible for enantioselectivity. View Article Online

DOI: 10.1039/D0OB00759E
O
O Ir(ppy)3 (0.5 mol %)

CN
CuBr (1.0 mol %) O O
N R2
R1 R2 O 446 (1.2 mol %)
+ 444 R1 N N
O
+ bNMP–ClPh, rt 445
443 blue LEDs, 24 h 446
TMSCN up to 85% yield
up to 94 % ee
R1 = H, F, Cl, Br, CF3, Me, tBu
R2 = Me, Et, nPr, iPr, tBu, cyclobutyl, cyclopentyl, Ph(CH2)2, 4-MePh(CH2)2,
Scheme 80 Photocatalytic cyanoalkylation of styrenes.

In 2018, Feng et al. applied a visible-light excitable alkenoylpyridine-bound N,N’-dioxide–TbIII

complex to the enantioselective [2+2] photocycloaddition reactions of enones with dienes (Scheme
81).121 Furthermore, the combination of photocatalyst [Ru(bpy)3]Cl2 with a chiral N,N’-dioxide–ScIII
complex for the enantioselective photocycloaddition reactions of 2’-hydroxychalcones using alkenes
has been established. Both methods provide the corresponding cyclobutanes with good yields and
enantioselectivities.
Sc(OTf)3/ 450 OH O
OH O (1:1, 10 mol %)
R2
[Ru(bpy)3]Cl2 R1
(5 mol %), iPrCN O N N
R1 + i
Pr
O
i
Pr
N H O O
447
5 Å MS, rt H N
448 23W CFL R2
449 i i
R1 = H, Me, F, Cl, Br Pr 450 Pr
R2 = H, Me, F, Cl, Br, CF3 dr up to 6:1 up to 99% yield
up to 92% ee
O
O Tb(OTf)3/453 N
R2
N (1:1, 10 mol %) R1 O N 2 N O
i i
+ Pr Pr
R1 N H O O
H N
i
PrCN, 5 Å MS, rt
451 23W CFL
448 i i
452 R2 Pr 453 Pr
R1 = H, Me, F
R2 = H, Me, F, Cl, Br, CF3 dr up to >19:1 up to 75% yield
up to 96% ee
Scheme 81 Enantioselective [2+2] photocycloaddition.
In 2018, Gong et al. reported an enantioselective conjugate addition of ,-unsaturated amide

derivatives and -silylamines using a NiII–DBFOX photoredox catalyst under blue LED irradiation
(Scheme 82).122 The chiral catalyst participated in the photoredox processes to initiate single-electron
transfer, while providing a coherent chiral setting for the subsequent free radical reaction.
R1 R2
O R2 Ni(ClO4)2•6H2O O
TMS (10 mol %) N
N 457 (12 mol %) N
R1
R3 N O
N + THF, Ar, 25 °C
456 O O
454 24W blue LEDs R3 N N
8-16 h yield up to 85%
455 up to 96% ee 457
Ph Ph
n c n
R1 = Me, Et, Pr, Hex, Bu, OEt, CF3, CO2Me, Ph, 4-MePh, 4-MeOPh, 4-FPh, 3-furanyl
R2 = Me, Et, iPr, Ph; R3 = H, Me, Br, F, OMe,
63
Scheme 82 Enantioselective radical addition. View Article Online

DOI: 10.1039/D0OB00759E
In 2018, Yu et al. reported an enantioselective allylic alkylation of allyl acetates with 4‑alkyl-

1,4-dihydropyridines by combining photoredox catalysis and palladium catalysis (Scheme 83).123
The alkyl radicals were generated from 4-alkyl-1,4-dihydropyridine under visible light redox
conditions and underwent a free radical coupling reaction with a -allyl palladium complex to
perform an asymmetric Pd-catalyzed allyl alkylation.
R3
R4
R2 R4 Ir(ppy)2(dtbbpy)PF6 (2 mmol) R3
OAc Pd2(dba)3 (2.5 mol %)
R1 EtO2C CO2Et 461 (6 mmol) R2
+ K3CO3, CH3CN, N2
blue LEDs, 12 h R1
N 460
H
458
459
44-84 % yield
R1 = H, OMe, Me, F, Cl, CF3, CO2Me, NHAc, 2-naphthyl, 2-thieny, 2-furanyl, up to 96% ee
R2 = Ph, 4-MeOPh, 4-MePh, 4-ClPh, 3-MeOPh, 3-MePh, 3-ClPh, 2-MeOPh,
2-MePh, 2-FPh, 2-ClPh, 2-thienyl, BnO, BocNH
R3 = H, Me, Ph; R4 = H, Me
OMe
t PF6
Bu
N
MeO PAr2
N
MeO PAr2
Ir
N
t N
Bu OMe 461
Ar = 4-OMe-3,5-tBu2-C6H2
Ir(ppy)2(dtbbpy)PF6 (R)-GARPHOS
Scheme 83 Enantioselective allylic alkylation.
In 2019, Cabrera, Alemán, and coworkers reported an enantioselective [3+2] cycloaddition of

,-unsaturated N-acyl oxazolidinones to silyl-indole derivatives using a dual catalytic system of
Lewis acid catalysis and visible-light photoredox catalysis, affording pyrrolo[1,2-a]indoles (Scheme
84).124 Chiral ligand (R,R)-iPr-PyBOX, which gave a moderate ee, was found to be the best candidate
for this enantioselective reaction.
64
Yb(OTf)3 (15 mol %) R1 View Article Online

R1 O O O DOI: 10.1039/D0OB00759E
466 (20 mol %)
R3 N 465 (2 mol %) R2 X
R2 + N

N N CNCH2CO2Et (2 equiv)
Bn CH3CN, rt, N2 R3
TMS 464
462 463 white LED, 18 h
up to 80 % yield
R1 = Me, CO2Me; R2 = H, Br; R3 = Me, iPr up to >95:5 dr
40-70% ee
F3C
F i
t
Pr
Bu O
N PF6 N
N
F
Ir
F 466 N
N
N
t
Bu N
O
F i
Pr
F3C
465
Scheme 84 Enantioselective [3+2] annulation.
Wang, Xu, and coworkers reported a chiral Cu-catalyst-induced enantioselective

cyanofluoroalkylation of styrenes under violet LED irradiation (Scheme 85).125 For the
enantioselective formation of C–CN bonds, the chiral Cu catalyst served as both the visible-light
photoredox catalyst and electron transfer catalyst.
R1
R1 CuI (10 mol %), 435 (12 mol %)
467 O O
N,N-dimethylbenzylamine (1.5-3.0 equiv)
H2O (2.0 equiv), CH3CN N N
+ 24 W violet LED (390–410 nm)
R2
CN
R 2I + TMSCN 470
435
468 469 up to 93% yield
up to 96% ee
R1 = H, Me, MeO, F, tBu, AcO, MeS, CH2OH, CH2OCH2OMe, Ph, etc
R2 = C4F9, CF3, CF2CO2Et
Scheme 85 Enantioselective cyanofluoroalkylation of styrenes.
In 2019, Mitsunuma, Kanai, and coworkers reported an enantioselective allylation of aldehydes

with cooperative chiral chromium complex catalysis and organophotoredox catalysis using an
acridinium catalyst (Scheme 86).126 The chiral chromium hybrid complex not only served as chiral
allylchromium nucleophiles for enantioselective allylation of aldehydes, but the chromium(III)
complex intermediate also served as a reductant for the electron-transfer reduction of photocatalyst
radicals to regenerate the acridinium catalyst and complete the catalytic cycle. Furthermore, the
addition of magnesium salt, such as Mg(ClO4)2, significantly increased both the enantioselectivity
and reactivity. Additionally, the enantioselective allylation of 4-fluorobenzaldehyde with 4-allyl-1,2-
dimethoxybenzene with photocatalyst [Ir(dFCF3ppy)(dtbbpy)PF6] (2 mol%), Cr2Cl (10 mol%), and
pyridine (20 mol%) in DMF for blue light irradiation has been reported by Glorius et al.127
65
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R4 CrCl2/435 (2.5-20 mol %) R4 OH O O
O 474 or 475 (0.5-5 mol) R2
+ R2 R1 N N
R1 Mg(ClO4)2 or MgPhPO3

H
R3 R5 472 (20-100 mol %) R5 R3
471 473
CH2Cl2, rt, 12-48 h 435
38 W LED (430 nm) up to 97% yield
85-99 % ee R
R1 = Ph, 4-ClPh, 4-BrPh, 4-IPh, 3-AcPh, 4-CO2MePh, 4-CF3Ph, 3-MePh,

2-MePh, 3-MeOPh, 2-furanyl, Cy, Ph(CH2)2, nPent, Me2CHCH2
Me Me
List of compound 472:
N
Me
ArAcr ClO4
Ar = Acr = 10-methylacridinium 474 R = H; 475 R = Me

or
N
Me
Ar Acr •X
472a
LED
ArAcr
ArAcr •X
X
* OH
N N R1
– H+ CrIII
473a
* X X X
N N
CrII
+ H+
X X
*
* N N
CrIII
N N
O X X
ArAcr •X CrIII
X X R1
R1 H 471
Scheme 86 Enantioselective allylation of aldehydes.
Xiao et al. reported enantioselective radical conjugated addition (photo-Giese reactions) of

enones using alkyl Hantzsch esters with photocatalyst Mes-AcrClO4 (9-mesityl-10-methylacridinium
perchlorate) and a chiral cobalt (II) catalyst, formed in situ from the addition of CoCl2•6H2O and
chiral N4-ligand 479 under blue LED irradiation (Scheme 87).128 Notably, for the reaction with acyl
Hantzsch esters, the reactions proceeded in the absence of a photoredox catalyst.
66
CoCl2•6H2O (8 mol %) R1
View Article Online
O R2 479 (9.6 mol %) O DOI: 10.1039/D0OB00759E
N EtO2C CO2Et AgOTf (16 mol %) N
R1 R2
N + Mes-AcrClO4 (2 mol %) N

Ph N CH3CN, rt, 20-48 h Ph
H 478
3W blue LEDs
476 477 49-90% yield
up to 91% ee
R1 = Me, Et, nPr, iPr, Ph, 4-BrPh, 4-MePh, 2-BrPh, 4-FPh, 2-thienyl, 3-thienyl, nPent, Ph(CH2)2,
R2 = Bn, 4-BrPhCH2, 4-ClPhCH2, 4-MePhCH2, 4-MeOPhCH2, 2-MeOPhCH2, 3-MeOPhCH2,
3,4-diMeO2PhCH2, 2-nathylCH2, 2-thienylCH2, cyclopentyl, cyclohexyl,
tetrahydro-2H-pyranyl, N-Boc-4-piperidinyl, NBocCH2,
O R4 R3
O CoCl2•6H2O (8 mol %) O
N EtO2C CO2Et 479 (9.6 mol %) N O
R3 AgOTf (16 mol %)
N + N
N R4
Ph CH3CN, rt, 2-12 h Ph 482
H
480 3W blue LEDs
481 47 to >99% yield
up to 94% ee
R1 = Me, Ph, 4-BrPh, 4-FPh, 4-MePh, 2-BrPh, 2-thienyl, nPr, nhexyl, chexyl, iPr
R4 = Ph, 4-FPh, 4-MePh, 4-MeOPh, 3-MePh, 2-MePh, 2-naphthyl, 2-thienyl, cyclohexyl, 1-adamantyl
Ph Ph
N N Et Cl
N
Et Et Ar
N N N
N N Me
Cl N Ph
Co
H 2O N Ph
Me
N
i i N
i
Pr Pr iPr Pr Ar
N ClO4
Et
i i -Co•479 Mes-AcrClO4
Pr Pr
479 Ar = 2,4,6-iPr3C6H2
Scheme 87 Enantioselective photo-Giese reactions.
In 2019, Gong et al. reported an enantioselective -aminoalkylation of oxazolidin-2-one-derived

imine with -silylarylamine using asymmetric copper catalysis under blue LED irradiation (Scheme
88).129 In the presence of photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2 mol%), the reaction yield was
higher, but the reaction was feasible without a photocatalyst under visible-light irradiation. Individual
chiral ligand L7 and oxazolidin-2-one-derived imine were found to have no significant absorption in
the visible region, but their reduced state [L7-CuI-imine] had an obviously enhanced absorption.
Therefore, the copper (I) substance generated in situ from the reaction process can be concluded to
be used as a photosensitizer in the reaction.
O O
O R2 O
R1 Cu(OTf)2 (10 mol %)
N TMS N 486 (11 mol %) N
N NH R2
+ –40 °C, THF, argon N
R1
Ar H 24W blue LEDs, 40 h Ar O O
484
483 485 N N
with or without Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2 mol %)
55-82% Ph Ph
486
up to 98% ee
Ar = Ph, 2-MePh, 3-MePh, 4-MePh, 2-MeOPh, 2-PhPh, 2-FPh, 2-ClPh, 2-BrPh, 2-naphthyl
R1 = H, Br, Me, Cl, F; R2 = Me, iPr, H, Ph, Et
Scheme 88 Enantioselective -aminoalkylation of imines.

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Glorius et al. reported a three-component enantioselective dialkylation of butadiene with
aldehydes and Hantzsch esters by chromium catalysis (with a chromium–bisoxazoline complex) and

visible-light photocatalysis (organic dye 4CzIPN) (Scheme 89).130
491 (2 mol %) OH
R2 R3
O 435 (10 mol %) R3
EtO2C CO2Et CrCl2 (10 mol %) R1
R1 H + +
THF, rt, 24 h
R2 N
487 488 34W blue LEDs
H 490
R1 = Ph(CH2)2, Et2CH 489 57-80% yield
R2 = H, Me 84-96% ee
R3 = iPr, iBu, Et2CHCH2, CyCH2
N O O
NC CN
N N
N N
435
N
491
4CzIPN
Scheme 89 Enantioselective dialkylation of butadiene.
Zhang et al. reported a photo-driven enantioselective dual arylation/alkylation and alkynylation

of styrenes, catalyzed by chiral copper (I) complex tBu-BOPA (Scheme 90).131 Presumably, the
BOPA-Cu (I) complex aggregated with alkynes, serving as a photo-reducing agent and enantiomeric
induction source. Expanding the scope of the phenyl group in styrene to other heteroaryl groups, such
as thiophene, is feasible in this three-component coupling reaction.
R1
CuI (10 mol %)
R1 R2
496 (20 mol %)
K3PO4 (3 equiv)
+ R2 H + R3 I
CH3CN, 0 °C or rt
(R)
492 493 494 40 W blue LEDs R3

495
42-87% yield
R1 = H, F, Cl, Br, CH3, tBu, MeO, CF3, Ph up to 98% ee
R2 = SiiPr3, SiMe3, SiEt3, (CH2)3CH3, (CH2)3Ph,
t
Bu, iPr, sBu, cyclopropyl, 3-pyridinyl, 2-thienyl, N
H
3-methylphenyl, 2-chlorophenyl, 4-methoxyphenyl O O
N N
R3 = CH2CHF2, CH2CF2CF2H, CH2CF2CF3, iPr, Ph,
4-tBuPh, 4-MeOPh, 4-BrPh, 4-PhPh, 2-thienyl, t t
Bu Bu
CH2F, nBu, 1-naphthyl, 3-pyridinyl
tBu-BOPA
(496)
Scheme 90 nantioselective dual alkylation and alkynylation.
Wang et al. reported an enantioselective acyl-carbamoylation of alkenes bound to aryl carbamic

chlorides with aldehydes by combining nickel catalysis (using a chiral Ni-PHOX complex) with
photocatalysis (using an advantageous hydrogen-atom transfer photocatalyst, tetrabutylammonium
68
decatungstate) to give a series of oxindoles bearing a quaternary stereogenic center (Scheme View
91). 132Online
Article
DOI: 10.1039/D0OB00759E
R2 TBADT (5 mol %) R2 O
O
t
O Ni(OTf)2 (10 mol %) Bu

500 (12 mol %) R4 N
R1 R1 O
R3 + H
K3PO4 (1.1 equiv) N
N PPh2
R4 CH3CN, 9h R3 500
497 O Cl 498 blue LED (390 nm) 499
up to 96% yield Tetrabutylammonium
R1 = H, , MeO, BnO, Me, Cl, CF3; R2 = Me, Et, nPr, iPr, cHex, up to 96% ee decatungstate (TBADT)
R3 = Me, Bn, nPent, PMB
R4 = nBu, iPr, tBu, Bn, BzO(CH2)2, TBDPS(CH2)2, BocNHCH2,
PhC(O), 4-MePhC(O), 4-tBuPhC(O), 4-FPhC(O), 3-MePhC(O),
2-MePhC(O), 3,4-(MeO)2PhC(O),
Scheme 91 Enantioselective dual alkylation and alkynylation.
10. N-Heterocyclic carbene catalysis with photocatalyst

Rovis et al. developed an -acylation of tertiary amines with aldehydes by merging photoredox
catalysis with chiral N-heterocyclic carbene catalysis (Scheme 92).133 The iminium ion was formed
by visible-light photoredox catalysis of tertiary amine 1. Accordingly, the acyl anion equivalent was
derived from aldehyde 2 using an N-heterocyclic carbene (NHC) catalyst, followed by nucleophilic
addition to the subsequently formed iminium ion, affording asymmetric -acylated amine 3.
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O DOI: 10.1039/D0OB00759E
Ru(bpy)3Cl2 (1 mol %) R1
O N
m-dinitrobenzene Ar N Br
R1 504 (10 mol %), CH2Cl2 N
N + R2 H R2 O
N
Ar blue light (~450 nm)

501 502 503 Br
504 Br
51–94% yield
up to 92 ee
R1 = H, 6,7-MeO; Ar = Ph, 4-MeC6H4, 4-Br, C6H4, 4-MeOC6H4, 4-CF3C6H4
R2 = Me, Et, nPr, iPr, cyclopropyl, MeS(CH2)2, Ph(CH2)2 CH2=CH(CH2)2,
PhthN(CH2)3, AcO(CH2)3
NO2
Ox e.g.
Ru(bpy)32+
blue light
NO2
Ox
photoredox
Ru(bpy)32+* catalysis Ru(bpy)3+
PC
N N N
Ph Ph – e- Ph
501
iminium ion
–H
–H
– e-
N N
Ph Ph
503
O
N Br
N
N
HO Br Br
R2 O
N Br
O NHC O N N
asymmetric Br
R2 R2 H HO Br
NHC catalysis
acyl anion 502 R2
O N
Ar
N Br
N
N
Br
504 Br
N
Ar
R2 O 503
Scheme 92 -Acylation of N-phenyltetrahydroisoquinoline.
An unprecedented N-heterocyclic carbene-catalyzed - and -alkylation using alkyl radicals

under visible-light irradiation, but affording low enantioselective, was reported by Gao, Ye, and
coworkers (Scheme 93).134
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N N
N

OCO2Me CN
BF4 Mes
O 508 (20 mol %)
Ph + I CN Ph
O
H Ru(bpy)3(PF6)2 (2 mol %)
*
505 506 H
CaOAc (2.0 equiv) 507
MeOH (5.0 equiv) 57% yield
DCE, 25 °C, 32 W CFL 29% ee
N N
N CO2Et
OCO2Me CO2Et BF4 Mes Bn CO2Et
O Br CO2Et 508 (20 mol %)

+ O
H Bn 510 Ru(bpy)3(PF6)2 (2 mol %) *
509 CaOAc (2.0 equiv) H
511
MeOH (5.0 equiv)
51% yield
DCE, 25 °C, 32 W CFL
12% ee
Scheme 93 Enantioselective - and -alkylation.
11. Enzyme catalysis with photocatalyst
Visible-light photobiocatalysis is a new method that attempts to combine the characteristics of

enzymatic catalysis and photocatalysis. The photobiocatalytic method has two approaches, namely,
the use of an external photocatalyst, or that in which no additional photocatalyst is necessary. A brief
review of recent advances in the synthesis of volatile sulfur compounds via photobiocatalytic
cascades has been reported.135
In 2016, Hyster et al. demonstrated the first enantioselective example of the synergistic action
of photocatalysis and biocatalytic techniques (Scheme 94).136 This strategy modified the enzyme
catalytic activity by applying the photo-excited state of its nicotinamide cofactors. For example,
NADPH (the reduced form of nicotinamide adenine dinucleotide phosphate) is both a source of
hydrogen atoms and a photoreductive agent, while under visible-light irradiation, the ketoreductase
is converted from carbonyl reductase into a radical species initiator and a chiral source of hydrogen
atoms. Later, the same group also extended the strategy of applying the photoexcitation of an EDA
complex of an enzyme and substrate to directly promote electron transfer in several enantioselective
reactions. Examples include the enantioselective deacetoxylation of -acetoxytetralone,
photoenzymatic catalytic ketone reduction, enantioselective radical cyclization of -chloroacetamide
to afford lactam by the photoexcitation of flavoenzymes ('ene'-reductase), and enantioselective
photoexcited radical cyclization of -haloamides to provide oxindoles using flavin-dependent ‘ene’-
reductases (Scheme 95.).137
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O RasADH (1 mol %) O LKADH (0.25 mol %) O View Article Online

NADP+ (1 mole %) Br DOI: 10.1039/D0OB00759E
R R NADP+ (0.45 mole %) R
O O O
GDH-105, glucose (200 mM) kPi (pH = 6.5, 1 mM MgCl)
n TRIS (pH = 7.0, 10 mM CaCl) n n
iPrOH–DMSO (460 nm, rt, 12 h)

(R)-513 glycerol–DMSO (460 nm, rt, 12 h) 512 (S)-513
n = 1, 2; R = Ph, 4-FC6H3, 4-ClC6H3, 4-BrC6H3, 4-CF3C6H3, PhCH2 up to 92%yield; 96% ee
O H H O
O R NH2
photo
N irradiation
(S)-513
R NADPH
cofactor oz
E 1/2 = 0.57 V vs SCE
regeneration H H O *
NH2
O O
H N
R NH2 R
O
N NADPH*
oz
R E 1/2* = –2.60 V vs SCE
NADP+ O
Br
O R
asymmetric
H atom 512
transfer
H H O O H H O
O
Br
R NH2 R NH2
O O
N N
R R
mesolytic
cleavage
Br
Scheme 94. Enantioselective photoexcited dehalogenation.

72
2018 Hyster View Article Online

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O NtDBR (1.0 mol %) O
R Rb (0.5 mol %), GDH-105
OAc R

X NADP+ (1 mol %), glucose X
514 KPi (100 mM, pH 8.0)
10% glycerol, 530 nm LEDs 515
racemate
38–85%yield
R = Me, Pr, allyl, iPr, Bn; X = H, OMe, Cl, Br up to 94% ee
2019 Hyster
O MorB (1.0 mol %) OH
Ru(bpy)3Cl2 (1.0 mol %)
R R
X X
NAD(P)+ (2.0 mol %)
516
GDH-105, glucose 517

achiral 460 nm LEDs, 24 h
15 to >99%yield
up to 76% ee
R = Me, Pr, allyl, nC5H11, 2-thiophenyl; X = H, OMe, Cl
2019 Hyster
O O
Cl 'ene'-reductase (0.5mol %)
N NADP+ (1.0 mol %) N
518 n n
GDH-105, glucose R1
KPi (100 mM, pH 8.0) R2
R1 R2 497 nm cyan LEDs, 36 h 519
achiral 44-99%yield
R1 = Me, Et, Ph, benzyl, cyclohexyl, vinyl up to >99% ee
R2 = H, Me, Et
2020 Hyster
N O OPR1 (0.5 mol %) N

tricine buffer (pH 8.0, 100 nM) X O
X
i
R1 Cl PrOH (10% v/v), 4 °C
R2 497 nm cyan LED, 24 h. R1 R2
520 521
racemate 39–96%
up to 96% ee
R1 = CO2Me, CO2Et, CO2nPr; R2 = Me, Et, nPr, nBu, iPr, allyl
X = Me, Et, Br. Cl, OMe
Scheme 95. Examples of the combination of enzymes with photocatalysis.
The photosensitized activation of redox enzymes is of interest in promoting electron transfer,

particularly in the context of sustainable and green chemistry using clean light energy. A solar-light-
driven enantioselective ketone reduction through domino photocatalytic–biocatalytic reactions was
reported by Baeg et al. (Scheme 96a).138 The enantioselective reduction of some ketones was
achieved under visible light using an orchestration system comprising a chemically converted
graphene-based photocatalyst (CCG-BODIPY) 524, an electron donor (triethanolamine), an electron
mediator precursor ([Cp*Rh(bpy)Cl]Cl), an electron donor (TEOA), nicotinamide nucleotide
coenzyme (NADP+), and an alcohol dehydrogenase (LKADH, known as a NADPH dependent). This
process imitates the mechanism in which chlorophyll absorbs and converts solar energy in plants.
In contrast, Hollmann et al. reported an enantioselective photobiocatalytic alcohol oxidation and
lactonization of meso-3-methyl-1,5-pentanediol to give (S)-4-methyltetrahydro-2H-pyran-2-one
using NAD+ (>98% ee), which was aerobically regenerated by a flavin photocatalyst (FMN) and blue-
73
light irradiation from horse liver alcohol dehydrogenase (HLADH) (Scheme 96b).139 Hollmann, Park,
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DOI: 10.1039/D0OB00759E
and coworkers also reported that 2-methylcyclohexenone was hydrogenated to 2-
methylcyclohexanone with high enantioselectivity (>99% ee) under irradiation using photosensitizer

Rose bengal with white LED lamps, and that Flavin-containing enzymes were obtained from the old
yellow enzyme family (OYEs) (Scheme 96c).140
(a) graphene-based photocatalyst
(CCG-BODIPY) 524 OH
O [Cp*Rh(bpy)Cl]Cl
R2 R1 R2 R1
NADP+, LKADH, visible light, rt
522 523
GC-yield: 58-74%
R1 = CH3, CF3; R2 = Ph,
ee: 95 to >99.9%
O S
N O
(b) O
HLADH O
HO OH
NAD+ NADH
> 98% ee
H2O2 h
FMN
O2
(c) O
white
LED RB* FMNox
RB
TsOYE
O
donorox
RB FMNred
donor
>99% ee
donor: triethanolamine (TEOA)
TsOYE: flavin-containing OYE homologue from Thermus scotoductus
Scheme 96 Photobiocatalytic oxidation and reduction reactions.
In 2018, Zhou et al. reported an application of redox catalysis and enzyme catalysis to the
dynamic kinetic resolution (DKR) of amines (Scheme 97).141 The racemization of various primary
amines has been achieved through photoredox-induced hydrogen atom transfer (HAT) and enzyme
catalysis.
Ir(ppy)2(dtb-bpy)PF6 (2 mol %) O
n
OctSH (50 mol %), Novozym 435
R NH2 MeO(CH2)2CO2Me (2-7 equiv) R N OMe
H 526
525 CH3CN, 38 °C
racemate 4 Å MS, 32 W white LED, 2d up to 95% yield
99% ee
R = Ph(CH2)2, 4-MePh(CH2)2, 2-MePh(CH2)2, 3-MePh(CH2)2,
4-EtPh(CH2)2, 4-MeOPh(CH2)2, 2,4-diMePh(CH2)2,
3,5-diMePh(CH2)2 PhCH2, 4-MePhCH2, 4-FMPhCH2, 4-ClPhCH2,
i
Pr, nPent, Me2CH(CH2)3, nHex, Cy
Scheme 97. Dynamic kinetic resolution of amines by the combination of enzyme and photoredox catalysis.
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In 2018, Ward et al. reported an enantioselective synthesis of cyclic amines by incorporating
photoredox catalyst Na3Ir(sppy)3 under visible light irradiation to generate an -amino alkyl radical

under hydrogen atom transfer (HAT) from ascorbic acid, as well as enzymatic catalytic oxidation of
one cyclic amine enantiomer back to the starting imine by enzyme monoamine oxidase (MAO-N-9)
(Scheme 98).142
MAO-N-9
H
Na3Ir(sppy)3 (1 mol %)
ascorbic Acid (0.2 M) N R NaO3S SO3Na
R H N
N phosphate buffer solution
(pH 8.0), air, 30 h 528
527 yield >95% Ir

405 or 450 nm LED (3 W)
up to >99% ee N N
R = nBu, Bn, cHex,
529
Na3Ir(sppy)3 Na3Ir(sppy)3 SO3Na
N R
photoredox H
catalysis
Ascorbic SET
Ascorbic acid acid
N R
H
527
N R
MAO-N-9 H
enzymatic
catalysis O2
H2O2
Scheme 98. Reduction of imines by the combination of enzyme and photoredox catalysis.
Park et al. reported an enantioselective hydrogenation of 2-methylcyclohex-2-en-1-one to give

(R)-2-methylcyclohexan-1-one by employing photosensitizer rose bengal and an ene-reductase from
Thermus scotoductus SA-01 (TsOYE), as well as triethanolamine (TEOA) as an electron donor under
irradiation with white LED (Scheme 99).143
O old yellow enzyme O
>99% ee
Rose bengal max. conversion: 70.4%
triethanolamine turnover frequency: 1.54/min
white LED turnover number: 300.2
530 531
Scheme 99. Enantioselective hydrogenation.
Guan, He, and coworkers reported an enantioselective concomitant oxidation and alkylation of
2-arylindoles by combining photocatalysis (with Ru(bpy)3Cl2•H2O) and enzyme catalysis (with
wheat germ lipase, WGL) under white compact fluorescent lamp irradiation, providing chiral 2,2-
disubstituted indol-3-ones (Scheme 100).144
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O R
DOI: 10.1039/D0OB00759E
R2 O Ru(bpy)3Cl2•6 H2O 2
R1 (2 mmol)
N
+ R1
R4

H WGL (0.16 mol %) N
R3 R4 H
532 DMF, O2, rt, 32 W CFL
533 534 O
R3
R1 = H, F, Br, MeO, Me, O
R2 27-70% yield
R2 = H, CF3, F, Cl, Br, Me, MeO 32-86% ee
R3 = H and R4 = H, Me, Ac R1
R3 = R4 = (CH2)3 N
535
Scheme 100. Enantioselective concomitant oxidation and alkylation.

In 2018, Höhne, Schmidt, and coworkers reported an enantioselective C–H bond

functionalization by merging the organo photoredox catalysis and enzyme catalysis (Scheme 101).145
In their study, alkanes were oxidized to aldehydes and ketones by photocatalyst anthraquinone sulfate
(SAS) under an oxygen balloon atmosphere and irradiated by a household 200-W white light bulb at
30 °C. After complete photooxidation, enzymes and appropriate reagents were added to the reaction
mixtures for one-pot operation. A series of chiral amines, hydroxynitriles, -chiral ketones, and
acyloins with up to 99% ee were prepared from the corresponding alkanes using this protocol.
OH
CN
*
X 538
X = H, Cl, MeO
or
O Y
SAS (1.0 mM)
R1 R2 enzymes
CH3CN–H2O R1 R2 * 539
536 various reagents
two-phase system
537 e.g. NaCN, IPA, O2,
200W white light bulb Y = NH2, OH
NADH, etc.
O or
SO3Na O
541 X = H, Cl, MeO

OH
O Y = NH2, OH
sodium anthraquinone sulfonate 540
(SAS) up to 99% conversion
up to 99% ee
Scheme 101 Enantioselective C–H bond functionalization.
Recently, Hyster et al. reported an enantioselective reduction of vinyl pyridines to alkanyl

pyridines by the synergistic action of flavin-dependent ‘ene’-reductases from N. punctiforme
(NostocER) and photocatalyst Ru(bpy)3Cl2 under irradiation by blue LEDs (Scheme 102).146
76
R1 NostocER (1.0 mol %) R1

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DOI: 10.1039/D0OB00759E
Ru(bpy)3Cl2 (0.5 mol %)
NaDP+ (1.0 mol %)

N GDH-105, glucose (2 equiv) N
R2 R2
tricine (100 mM, PH = 9)
i 543
542 PrOH (5% v/v), 4 °C, 48 h
2,3,4-substituted blue LEDs up to 87% yield
up to 98% ee
R1 = H, OMe
R2 = Ph, 4-MePh, 4-FPh, 4-ClPh, 4-CF3Ph, 4-MeOPh, 3-MePh,
3-MeOPh, 3-CF3Ph, 2-MePh, 3-furanyl, 3-thiophenyl,
benzo[d][1,3]dioxole-5-yl, Ph(CH2)2, Bn, CH2OH
Scheme 102 Hydrogenation by the combination of enzyme and photoredox catalysis
12. Miscellaneous
Photocatalysis with Brønsted base
Jiang and coworkers reported the first enantioselective visible-light photocatalytic reduction of
-ketoketimines and 1,2-diketones to the corresponding chiral -amino ketones and -hydroxy
ketones using photoredox catalyst DPZ (221), a chiral organic catalyst, and reductant 2-naphthyl
tetrahydroisoquinolines (THIQ-2) (Scheme 103).147 Notably, the same 1,2-diketone photoreaction
was also feasible in the absence of photosensitizer DPZ. A visible-light-promoted SET reduction of
1,2-diketones with THIQ-2 was initiated by the photochemically active EDA complex of THIQ-2
and 1,2-diketone. Enantioselective protonation was realized using chiral Brønsted base or Brønsted
acid. The authors proposed the detailed mechanisms with and without sensitizer DPZ, and the lack-
of-sensitizer mechanism was simplified, as outlined in Scheme 103.
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OMe View Article Online

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Br OMe NC N OMe
DPZ (1 mol %) S
546 (10 mol %) Br
N THIQ-2 (2.0 equiv) S

NC N OMe
R2 HN H
3 Å MS, 2-bromoanisole
R1 R2 DPZ (221)
0 °C, 3W blue LEDs, 72 h
O R1
544 545 O
68-95% yield
N
85-90% ee
R1 = R2 = Ph, 4-FPh, 4-MePh, 4-nBuPh, 4-iPrPh, 4-MeOPh, 3-MePh, THIQ-2
3,5-Me2Ph, 2-naphthyl
DPZ (1 mol %), 549 (10 mol %)

O THIQ-2 (2.0 equiv) HO H N O CF3
R2 NaBARF (10 mol %) R2 HN
R1 R1
PhCl, 0 °C HN
O O
3W blue LEDs, 24 h 548 546
547 60-99% yield CF3
80-92% ee
Ph Ph
R1 = R2 = Ph, 4-FPh, 4-CF3Ph, 4-ClPh, 4-BrPh, 4-MePh, 4-nBuPh,
4-tBuPh, 4-MeOPh, 3-MePh, 3-MeOPh, 3,5-Me2Ph, 2-naphthyl, 2-thienyl N N
N N
N H H N
BF4 BF4
N 549
blue LED
O
THIQ-2
THIQ-2 R2
R1 +
O 547
color EDA complex
O
R2 HO H
R1 C3
R2
O R1
549 O 548
THIQ-2•HBF4 THIQ-2•HBF4
BF4
Ph Ph
N N BF4 THIQ-2
N N Ph Ph
N N N N
H H N N
N N
O H H
R2
R1 O
O SET R2
R1
O
THIQ-2 THIQ-2
Scheme 103 Enantioselective visible-light photocatalytic reduction of -ketoketimines and 1,2-diketones.
Photocatalysis with chiral media

The formerly elusive enantioselective [2+2] photocycloaddition of 1-bromoacenaphthylene has
been achieved by Su et al. using the strategy of cage-confined catalysis under blue LED irradiation,
max = 450 nm, (Scheme 104).148 The supramolecular photoactive catalyst was established based on
the chiral Δ/Λ-[Pd6(RuL3)8]28+ metal-organic cage (Δ/Λ-MOC-16).
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Br Br Br View Article Online

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10% -MOC-16 10% -MOC-16

blue LED, 2 h blue LED, 2 h Br Br
550 551
90% conversion, 88% ee 92% conversion, 86% ee
2+ 2+
N
N
HN
N
N
NH
N
N
H N N N
N N N N Ru
Ru
N N N N
N N N H N
N
NH
N
N
HN
-552 -552
N
N Pd(BF4)2
Pd(BF4)2
-MOC-16 -MOC-16
Scheme 104 Eantioselective [2+2]cycloaddition with metal-organic cage-confine supramolecular catalysis
13. Conclusion
Photoreaction, especially enabled by UV irradiation, has been a compelling subject in organic

chemistry for more than a century. It was not until almost half a century ago, however, that chemists
began to overcome the complicated stereoselectivity of photochemical reactions and succeed in the
effective synthesis of elaborate organic molecules with multiple stereocenters. The difficulties with
this enantioselective photoreaction stem from a limited understanding of the higher energy excited
states of UV-irradiated substrates and the scarcity of effective enantioselective catalysis. With the
most recent progress in asymmetric catalysis and the emergence of visible-light photocatalysis, a
number of new methods have arisen to fill the gaps in this field. The enantioselective synthesis
enabled by visible-light photocatalysis clearly has been advancing significantly over the last decade
or so. In this review, we have summarized a great deal of this substantial progress.
Despite these rapid advances, some challenges remain to be tackled, and certain objectives can
be anticipated and accomplished, as follows. First is the development of more effective catalysts with
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DOI: 10.1039/D0OB00759E
of visible-light photocatalysis reactions. With the discovery of new photocatalysts and an improved
understanding of photocatalytic mechanisms, a second objective is the development of more

advanced methods that further enrich the field. As a third objective, future strategies in this field could
involve the cascade reaction or one-pot operation of multiple bonds and chiral centers with
enantioselectivity by visible-light photocatalysis. New multicomponent visible-light photocatalysis
for enantioselective reactions should be a fourth objective. A fifth aim should be a better
understanding of the photophysical properties of reactants, such as transient electron donor–acceptor
complexes, as a step toward discovering more photocatalyst-free enantioselective photocatalysis
reactions. Finally, with the development of more effective asymmetric catalysis that is
environmentally friendly and convenient to operate, or of a continuous flow process, further

innovations can become possible that integrate this technology with visible-light photocatalytic
reactions.
In short, enantioselective photocatalysis will undoubtedly continue to expand and thrive in
decades to come while offering benefits for advanced synthetic chemistry.
Abbreviation list
CFL compact fluorescent light

CAN cerium ammonium nitrate
CPA chiral phosphoric acid
DIPEA diisopropylethylamine
DPZ A chromophore (DPZ) photosensitizer derived from dicyanopyrazine.
Usually refers to 5,6-bis (5-methoxythien-2-yl) pyrazine-2,3-dicarbonitrile.
EDA electron donor-acceptor complex
HAT hydrogen atom transfer
HE Hantzsch ester. It refers to a series of dialkyl 1,4-dihydro-2,6-dialkyl-3,5-
pyridinedicarboxylate. Unless otherwise indicated with different substitutes or
esters, it refers to diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate.
ISC intersystem crossing
LED light emitting diode
MTBE methyl tert-butyl ether
NHC N-Heterocyclic carbenes
NMA N-methyl acetamide
PC photocatalysis
SET single electron transfer
SOMO singly occupied molecular orbital
SPINOL Refers to a series of axially chiral 1,1′-spirobiindane-7,7′-diols
SPINOL-CPA SPINOL-derived chiral phosphoric acids
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DOI: 10.1039/D0OB00759E

Conflicts of interest
There are no conflicts to declare.
Acknowledgments
Financial support from the Ministry of Science and Technology (MOST, Taiwan), is gratefully
acknowledged. We thank Simon Partridge, Ph.D., from Edanz Group for editing the English text of
a draft of this manuscript.
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