Catalytic enantioselective radical coupling of activated ketones with: N -aryl glycines

Article abstract of DOI:10.1039/c8sc02948b

Asymmetric H-bonding catalysis as a viable strategy for enantioselective radical coupling of ketones is demonstrated. With a visible-light-mediated dual catalytic system involving a dicyanopyrazine-derived chromophore (DPZ) photosensitizer and a chiral phosphoric acid (CPA), N-aryl glycines with a variety of 1,2-diketones and isatins underwent a redox-neutral radical coupling process and furnished two series of valuable chiral 1,2-amino tertiary alcohols in high yields with good to excellent enantioselectivities (up to 97% ee). In this catalysis platform, the formation of neutral radical intermediates between ketyl and H-bonding catalyst CPA is responsible for presenting stereocontrolling factors. Its success in this work should provide inspiration for expansion to other readily accessible ketones to react with various radical species, thus leading to a productive approach to access chiral tertiary alcohol derivatives.

Full text of DOI:10.1039/c8sc02948b

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Catalytic Enantioselective Radical Coupling of Activated Ketones
with N-Aryl Glycines
Yang Liu,a,† Xiangyuan Liu,a,† Jiangtao Li,a Xiaowei Zhao,a Baokun Qiao,a and Zhiyong Jianga,b
Received 00th January 20xx,
Accepted 00th January 20xx
*
Asymmetric H-bonding catalysis as a viable strategy for enantioselective radical coupling of ketones is demonstrated. With
a visible-light-mediated dual catalytic system involving a dicyanopyrazine-derived chromophore (DPZ) photosensitizer and
a chiral phosphoric acid (CPA), N-aryl glycines with a variety of 1,2-diketones and isatins underwent a redox-neutral radical
coupling process and furnished two series of valuable chiral 1,2-amino tertiary alcohols in high yields with good to
excellent enantioselectivities (up to 97% ee). In this catalysis platform, the formation of neutral radical intermediates
between ketyl and H-bonding catalyst CPA is responsible for presenting stereocontrolling factors. Its success in this work
should provide inspiration for expansion to other readily accessible ketones to react with various radical species, thus
leading to a productive approach to access chiral tertiary alcohol derivatives.
DOI: 10.1039/x0xx00000x
www.rsc.org/
photosensitizer and an ionic Brønsted acid led to chiral 1,2-
diamine derivatives featuring a tertiary carbon stereocenter.
Almost at the same time, the Meggers group described an
Introduction
The radical coupling reaction,1 wherein the nearly zero
activation energy2 of connecting two distinct odd-electron
partners enables a strong tendency to generate a new
chemical bond, often furnishes an efficient and direct synthetic
pathway to molecules with high functional group tolerance.
Therefore, the development of compatible strategies to
produce two types of radical species and facilitate the coupling
reaction has attracted much attention from chemists over the
last few decades.1-3 In 2011, the MacMillan group made a
significant breakthrough4 in which such a transformation was
realized via visible-light-driven photoredox catalysis.5 This
convenient and sustainable platform promptly inspired a
number of elegant efforts focusing on radical coupling.6
However, the enantioselective manifold still remains
underdeveloped given that few examples have been
established.7 This lack of development is mainly due to the
high reactivity that results in an elusive precise absolute
stereocontrol of the reaction. In 2015, Ooi and co-workers7a
reported the first example with excellent enantioselectivity,
wherein asymmetric α-coupling of N-arylaminomethanes with
aldimines through cooperative catalysis7-10 of an Ir-centered
asymmetric radical coupling of tertiary amines with 2-
trifluoroacetyl imidazoles catalyzed by chiral iridium
a
complex.7b They also developed a cooperative Ru-centered
photosensitizer and Rh-based chiral Lewis acid catalysis for the
cross−coupling of 2-acyl imidazoles with α-silylamines.7d In
their elegant works, the α-aminoalkyl moieties were
successfully introduced onto the more challenging quaternary
carbon stereogenic center. Inarguably, the judicious use of
imidazole as the substituent of ketones is crucial for the
enantioselectivity, as its N atom was shown to enhance the
ability of stereocontrol by interacting with the chiral Lewis acid.
Although the groups of Xiao,6f Shah6g and Yang6h have
demonstrated the viability of radical coupling of various readily
accessible ketones with different substrates in a racemic
manner, an enantioselective variety still constitutes
formidable challenge.
a
In the putative reaction mechanism of the radical-coupling
transformations, ketones always experience a single-electron
reduction to generate the corresponding ketyl variants.6,7 In
2013, the Knowles group9f revealed the strong basicity of
ketyls and their capability of forming neutral ketyl radicals with
a
chiral Brønsted acid which could provide efficient
enantioselective control for the coupling reaction with
hydrazones. This prominent H-bonding catalytic strategy
recently inspired us to accomplish a highly enantioselective
photoreduction of 1,2-diketones.10c Accordingly, we
speculated that such an approach would offer the possibility to
address the desired radical coupling of undecorated ketones. If
so, it should be a promising and general strategy as it would
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visible-light-activated DPZ, i.e. *DPZ (Et(S*/S•−) = +0.91 V vs in
CH2Cl2).7g,10d-e More importantly, the formed α-amino radicals
contain
a H-bonding donor (N−H) which will be more
nucleophilic via a possible interaction with the H-bonding
acceptor (X = N, O et. al) of chiral bifunctional catalyst thus
facilitating coupling with the electrophilic α-ketone
radicals.9s,13 Of note, the use of tertiary amines was susceptible
to reduce 1,2-diketones to α-hydroxy ketones under
photoredox catalysis.10c,14
Table 1 Optimization of the reaction conditionsa
Scheme 1 Outline of this work.
allow diverse radical species to connect with ketones, thus
opening a fruitful avenue for the synthesis of the important
chiral tertiary alcohols. Here, we report the development of a
redox-neutral, enantioselective, radical coupling of N-aryl
glycines with activated ketones, including acyclic 1,2-diketones
Entry
1
Variation from standard conditions
0.5 mol% DPZ in CH2Cl2 at 25 oC and
Yield (%)b
62
Ee (%)c
N.A.
without C1 and any additives, 12 h
and cyclic isatins (Scheme 1). The association of
dicyanopyrazine-derived chromophore (DPZ) as the
photoredox catalyst and 1,1’-spirobiindane-7,7’-diol
a
2
None
78
74
73
58
69
76
75
76
35
0d
93
a
3
C2 instead of C1
C3 instead of C1
Ru(bpy)3Cl2•6H2O instead of DPZ
Rose Bengal instead of DPZ
No TBPB
76
(SPINOL)-based chiral phosphoric acid (CPA) as the H-bonding
catalyst was demonstrated as being a workable catalytic
system. Two series of chiral 1,2-amino tertiary alcohols that
are significant structural scaffolds in synthetic and medicinal
chemistry11 were prepared in high yields with good to
excellent enantioselectivities.
4
67
5
89
6
91
7
89
8
No Na2S2O4
90
Results and Discussion
9
No 5Å MS
90
10
11
12
13
No DPZ
88
No light
N.A.
N.A.
N.A.
Under air
0e
No C1
53
a Reaction conditions: 1a (0.075 mmol), 2a (0.05 mmol), degassed CPME (1.0 mL),
10 oC, irradiation with blue LED (3 W, 450 nm), 36 h. b Yield of isolated product. c
d
Determined by HPLC analysis on a chiral stationary phase. No reaction was
Scheme 2 Design plan based on mechanistic considerations.
e
detected.
1a was consumed, but no 3a was achieved. TBPB
=
tetra-n-
butylphosphonium bromide. CPME
available.
=
cyclopentyl methyl ether. N.A. not
=
At the onset of our study, we sought to explore the coupling of
ketyls derived from 1,2-diketones with α-amino radicals to
provide the valuable enantioenriched 1,2-amino tertiary
alcohols,11a for which no catalytic asymmetric synthesis has yet
been developed. Our developed metal-free DPZ7g,10 was
To this end, we began the investigation with N-phenyl
glycine 1a and benzil 2a in the presence of DPZ as the
photoredox catalyst (Table 1).10c-e The initial investigation
showed that the transformation furnished racemic product 3a
in 62% yield after 12 h when only using 0.5 mol% DPZ at 25 oC,
indicating the feasibility of the reaction and the high reactivity
(entry 1). Upon examining a range of chiral H-bonding catalysts
and the reaction parameters (see Table S1 in the Supporting
Information [SI]), we observed that the reaction conducted in
CPME at 10 oC for 36 h in the presence of 1.5 mol% DPZ and 10
mol% chiral SPINOL-CPA15 C1 and with the combination of 30
mol% TBPB, 0.5 equiv. Na2S2O4 and 25 mg 5 Å MS as additives
affords desired chiral product 3a in 78% yield with 93% ee
selected as the photosensitizer since 1,2-diketones (e.g. benzil,
red
E
= −1.169 V and −1.251 V vs saturated calomel electrode
1/2
(SCE) in CH3CN)10c could be directly reduced by DPZ•− (E
=
red
1/2
−
1.45 V vs SCE in CH2Cl2) when the transformation experiences
a reductive quenching cycle (Scheme 2). Furthermore, we
intent to use N-aryl glycines (e.g. N-phenyl glycine, carboxylate
ion, Ep = +0.52 [for the N moiety] and +1.09 V [for the COO−
moiety] vs Ag/AgCl in CH3CN) as the precursors of α-amino
radicals given the prominent ability to generate the radical
species12 via single-electron oxidative decarboxylation by the
2 | J. Name., 2012, 00, 1-3
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achieved in 87% yield with 93% ee after 48 h (footnote a). With
(entry 2). Other SPINOL-CPAs (e.g., C2 and C3) with distinct
substituents at the 6,6’-positions presented 3a with lower ee
respect to symmetric 1,2-diketones, the reaction tolerated a wide
values (entries 3−4). [Ru(bpy)3]Cl2 and Rose Bengal as plausible range of aryl substituents regardless of their electronic properties
photoredox catalysts were evaluated (entries 5−6), but both
the yield and enantioselectivity were decreased. Each of the
three additives, which could regulate the strength of H-
bonding interaction by exploiting the salt effect (i.e. TBPB10d
and Na2S2O4) or diminishing moisture of the reaction system
(i.e. molecular sieves7g), was found to slightly affect the
enantioselectivity to the same degree (entries 7−9). The results
reveal that all of the additives jointly exerted a positive
influence on the stereocontrol of C1. The control experiments
confirmed that DPZ, visible light, and an oxygen-free
environment are indispensable for the transformation to occur
(entries 10−12). Note that the reaction performed under the
standard conditions but in the absence of catalyst C1 still
produced rac-3a in 53% yield (entry 13), suggesting the
existence of a considerable competitive achiral background
reaction.
and substitution patterns, and corresponding products 3h-q were
obtained in 61 to 89% yields with 84 to 97% ees. Based on the
persistent radical effect,13 the slightly lower enantioselectivity for
1,2-diketones (3h-j) with electron-withdrawing substituents is likely
due to the stronger racemic background reaction, as the higher
stability of these ketyl intermediates would facilitate a coupling
with the unstable α-amino radical. For 3-methyl-1-phenyl-1,2-
butanedione as a representative of unsymmetrical 1,2-diketones,
product 3r was obtained in only 34% ee. However, the modified
reaction conditions, that are C2 as chiral catalyst and 4 Å MS as an
additive in CPME at −5 oC, could furnish 3r in 78% ee. The
stereochemistry of these adducts was assigned based on the
structure of 3q, as solved by single crystal X-ray diffraction.16
NHAr
O
DPZ (1.0 mol%)
OH
O
C3
(20 mol%)
H
+
O
THF, 10 o
C
N
O
Ar
OH
N
Boc
R
N
3 W blue LED
36 h
DPZ (1.5 mol%)
R
Boc
5
C1
(10 mol%)
1h
: Ar = 2-Me-4-MeOPh
4
O
O
O
TBPB (30 mol%)
H
R
+
NHAr
OH
NHAr
OH
NHAr
NHAr
OH
ArHN
R
N
Ar'
Na2S2O4 (0.5 equiv.)
5 Å MS (50 mg)
Ar
OH
Cl
Br
Ar'
O
OH
OH
F
1
CPME, 10 o
C
2
3
O
O
O
N
O
3 W blue LED
36 h
N
N
N
Boc
Boc
Boc
Boc
a
3a
: Ar = Ph, 85% yield, 93% ee
5a
5b
5c
: 77% yield
85% ee
5d
O
: 91% yield
91% ee
: 80% yield
85% ee
: 88% yield
92% ee
3e: Ar = 4-MePh, 85% yield, 91% ee
3b
: Ar = 4-ClPh, 83% yield, 90% ee
3f
: Ar = 3-MePh, 78% yield, 90% ee
ArHN
PhHN
Ph
3c: Ar = 4-BrPh, 85% yield, 91% ee
3g: Ar = 4-MeOPh, 85% yield, 92% ee
Ph
NHAr
NHAr
OH
NHAr
OH
NHAr
OH
O
3d
: Ar = 3-ClPh, 89% yield, 90% ee
OH
OH
Cl
Br
Me
MeO
O
O
O
O
O
O
O
PhHN
Cl
PhHN
PhHN
Me
N
N
N
N
OH
Boc
Boc
Boc
Boc
OH
OH
OH
F
Cl
Br
Me
5e: 88% yield
90% ee
5f: 88% yield
94% ee
5g: 91% yield
90% ee
5h: 90% yield
85% ee
3h: 69% yield
3i: 72% yield
84% ee
3j: 76% yield
3k: 81% yield
F
88% ee
Br
86% ee
93% ee
NHAr
OH
NHAr
NHAr
NHAr
O
O
O
OH
O
OH
O
OH
O
O
PhHN
PhHN
tBu
PhHN
MeO
Me
O
N
Boc
PhHN
OH
OH
OH
N
N
N
F
Cl
Br
OMe
iPr
tBu
OH
Boc
Boc
Boc
Cl
Me
5i
5j
5k
5l
: 74% yield
93% ee
: 76% yield
93% ee
: 78% yield
90% ee
: 73% yield
94% ee
3l: 83% yield
3m: 85% yield
3n: 81% yield
3o: 83% yield
iPr
91% ee
90% ee
93% ee
88% ee
O
O
Scheme 4 Reactions of N-aryl glycine with isatins. +Reaction conditions: 1h (0.15
mmol),
4 (0.1 mmol), DPZ (1.0 mol%), C1 (20 mol%), degassed THF (2.0 mL), 10
PhHN
O
ArHN
oC, irradiation with blue LED (3 W, 450 nm), 36 h. The yield amount was isolated
by flash column chromatography on a silica gel. Ee was determined by HPLC
analysis on a chiral stationary phase.
OH
OH
PhHN
OMe
Ph
OH
3q: Ar = 4-BrPh
89% yield
3p
3r
: 61% yieldMeO
91% ee
: 65% yield
78% eec
97% eeb
The promising results inspired us to further evaluate this catalytic
Scheme 3 Reactions of N-aryl glycines with 1,2-diketones. Reaction conditions:
1
(0.15 mmol),
2 (0.1 mmol), DPZ (1.5 mol%), C1 (10 mol%), TBPB (30 mol%), strategy for isatins, a representative cyclic ketone, to first construct
Na2S2O4 (0.5 equiv.), 5 Å MS (50 mg), degassed CPME (2.0 mL), 10 oC, irradiation
with blue LED (3 W, 450 nm), 36 h. The yield amount was isolated by flash
column chromatography on a silica gel. Ee was determined by HPLC analysis on a
the
important
chiral
3-hydroxy-3-aminoalkylindolin-2-one
derivatives in a direct manner.11b-g As depicted in Scheme 4, under
the same catalysis platform but with modified reaction conditions
(1.0 mol% DPZ, 20 mol% SPINOL-CPA C3 in THF at 10 oC), the
transformations of N-aryl glycine 1h with N-Boc-substituted isatins
4 were complete within 36 h, providing the desired adducts 5a-l
with diverse substituents on the aromatic ring of the isatins in 73 to
91% yields with 85 to 94% ees. It was observed that the substituent
group at the 4-position (e.g., 5b-c) presented a slightly decreased
enantioselectivity, probably owing to the steric hindrance.
chiral stationary phase. a On a 1.0 mmol scale, 48 h, yield of 3a = 87%, ee of 3a
=
93%. b The ee value was obtained after a single recrystallization. Initial data: 85%
c
ee. Reaction conditions:
mol%), 4 Å MS (50 mg), degassed CPME (2.0 mL),
previous reaction conditions, ee = 34%.
1
(0.15 mmol),
2
(0.1 mmol), DPZ (1.5 mol%), C2 (10
−
5
oC, 36 h. When under the
With the optimal reaction conditions in hand, the scope of this H-
bonding catalysis-enabled asymmetric radical coupling strategy was
examined (Scheme 3). The reactions of 2a with a variety of N-aryl
glycines 1 furnished adducts 3a-g in 78 to 89% yields with 90 to 93%
ees within 36 h. Electron-deficient or electron-donating
substituents at the para- and meta-positions of the aryl ring
presented similar reactivities and enantioselectivities. An attempt
of performing the reaction of 1a with 2a in a 1.0 mmol scale
presented a similar reactivity and enantioselectivity as 3a was
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13, Table 1). According to the persistent radical effect,13 the results
suggest the existence of an interaction between N−H of 1a as a H-
bonding donor and P=O of the chiral CPA as a H-bonding acceptor,
thus increasing the nucleophilicity of the α-amino radicals. In this
context, the chiral CPA should serve as a bifunctional catalyst to
activate the reaction and provide stereocontrol for the new C−C
bond formation,9s for which a ternary transition state as shown in
Scheme 2 is plausible.
Scheme 5 Synthetic applications. (a) TCCA (0.5 equiv.), H2SO4 (1 M, aq., 2.0
equiv.), CH3CN/H2O = 1:1, 16 h. (b) HCHO (2.0 equiv.), OHC-CHO (2.0 equiv.),
NH4OAc (2.0 equiv), MeOH, 80 oC, 5 h, 65% yield, 92% ee. (c) (Boc)2O (1.1 equiv.),
DMAP (0.2 equiv.), DCM, 0 oC, 0.5 h, 98% yield, 91% ee. (d) TCCA (0.5 equiv.),
H2SO4 (1 M, aq., 2.0 equiv.), CH3CN/H2O = 1:1, 16 h. (e) TsCl (2.0 equiv.), Et3N (2.0
Conclusions
equiv.), EtOAc, 0 oC to r.t., 5 h, 72% yield in two steps, 91% ee. PMP = para
-
In summary, we developed an enantioselective radical
coupling of N-aryl glycines with diverse activated ketones,
including acyclic 1,2-diketones and cyclic isatins, via visible-
light-driven cooperative photoredox and chiral H-bonding
catalysis. A range of significant enantioenriched 1,2-amino
alcohols that feature an oxo-hetero-quaternary carbon
stereocenter were obtained in high yields and ees. This work
robustly demonstrates the viability of H-bonding catalysis for
the highly reactive radical−coupling of ketones by directly
providing a stereocontrolled environment for ketones. We
methoxyphenyl; TCCA =
dicarbonate; Boc = tert-butyl carbonate; DMAP = 4-dimethylaminopyridine; TsCl
-toluenesulfonyl chloride; Ts = tosyl.
N,N’,N’’-trichloroisocyanuric acid; (Boc)2O = di-tert-butyl
=
p
The two series of enantiomerically enriched 1,2-amino-alcohols
featuring oxo-hetero-quaternary carbon stereocenters are direct
precursors to many bioactive natural and non-natural compounds
(Scheme 1). For example, the treatment of adduct 3g derived from
1,2-diketone using TCCA readily cleaved the PMP N-protective
group (Scheme 5). The resultant amine 6 was then transformed to
chiral 1,2-imidazolyl tertiary alcohol 7 that posseses oral antifungal believe that this dual catalytic system can serve as a powerful
activity11a in 65% yield over two steps with 92% ee. The
tool to address a variety of radical coupling reactions of
diverse ketones through flexibly selecting
a photoredox
transformation of adducts from isatins was also carried out. The
Boc-protected product 8 was rapidly obtained in 98% yield by
treating 5a with (Boc)2O and DMAP. The replacement of 2-methyl-
4-methoxyphenyl with Ts as the N-protective group was performed
through a sequetial process involving the use of TCCA for the
deprotection and TsCl for the protection, furnishing product 9 in 72%
yield and without diminishing the ee. The results clearly indicate
that chiral products 5 are excellent synthetic intermediates for
conveniently synthesizing the biologically important 3-hydroxy-3-
aminoalkylindolin-2-one variants as shown in Scheme 1.11b-g
catalyst and a H-bonding catalyst, thus providing a direct and
productive approach to access various chiral tertiary alcohols.
We also anticipate that this work will inspire the pursuit of
novel enantioselective radical coupling for other oxidative
substrates with feasible H-bonding acceptor moieties.
Acknowledgements
Grants from the NSFC (21672052) and Provincial Innovation
Scientists and Technicians Troop Construction Projects are
gratefully acknowledged. We also appreciate Mr. Yangyang Shen
(ICIQ) for the constructive discussions.
Notes and references
Scheme 6 Transformation of 10 and 2a
.
1
Radicals in Organic Synthesis (Eds.: P. Renaud, M. P. Sibi),
Wiley-VCH, Weinheim, 2001.
Based on the previous examples10,12 and the product structure,
the reaction between N-aryl glycines and ketones that underwent a
single electron transfer (SET) redox radical coupling process to form
the products is reasonable. The Stern-Volmer experiments17
confirmed that the catalytic cycle was triggered from the reductive
quenching of *DPZ (Scheme 2). To better understand the role of the
chiral CPA in asymmetric induction, the transformation of N-phenyl-
N-methyl glycine 10 with benzil 2a under the standard reaction
conditions as shown in Table 1 was carried out, and adduct 11 was
obtained in 35% yield with 15% ee (Scheme 6). The lower yield than
that achieved with the transformation of N-phenyl glycine 1a (entry
2, Table 1) was due to the deteriorated chemoselectivity, as the
reduced product of 2a, i.e., benzoin, was obtained in a considerable
amount. Note that in the absence of catalyst C1, 3a was also
produced in a decreased yield in the reaction of 1a with 2a (entry
2
H. Togo in Advanced Free Radical Reactions for Organic
Synthesis, Elsevier Science: Amsterdam, 2004; p 39.
(a) H. Fischer, Chem. Rev. 2001, 101, 3581; (b) H. Yi, G. Zhuang,
H. Wang, Z. Huang, J. Wang, A. K. Singh, A. Lei, Chem. Rev.
2017, 117, 9016.
3
4
5
M. Andrew, C. K. Prier, D. W. C. MacMillan, Science 2011, 334,
1114.
For selected reviews, see: (a) C. K. Prier, D. A. Rankic, D. W. C.
MacMillan, Chem. Rev. 2013, 113, 5322; (b) D. M. Schultz, T. P.
Yoon, Science 2014, 343, 985; (c) J. W. Beatty, C. R. J.
Stephenson, Acc. Chem. Res. 2015, 48, 1474; (d) M. H. Shaw, J.
Twilton, D. W. C. MacMillan, J. Org. Chem. 2016, 81, 6898; (e)
N. A. Romero, D. A. Nicewicz, Chem. Rev. 2016, 116, 10075; (f)
J. Twilton, C. C. Le, P. Zhang, M. H. Shaw, R. W. Evans, D. W. C.
MacMillan, Nat. Rev. Chem. 2017, 1, 0052.
6
For a selected review, see: (a) J. Xie, H. Jin, A. S. K. Hashmi,
Chem. Soc. Rev. 2017, 46, 5193; For selected examples, see: (b)
4 | J. Name., 2012, 00, 1-3
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E. Fava, A. Millet, M. Nakajima, S. Loescher, M. Rueping,
Angew. Chem. Int. Ed. 2016, 55, 6776; (c) W.-P. Li, Y.-Q. Yuan,
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DOI: 10.1039/C8SC02948B