Synthesis of β-Substituted γ-Aminobutyric Acid Derivatives through Enantioselective Photoredox Catalysis

Article abstract of DOI:10.1002/anie.201804040

β-Substituted chiral γ-aminobutyric acids feature important biological activities and are valuable intermediates for the synthesis of pharmaceuticals. Herein, an efficient catalytic enantioselective approach for the synthesis of β-substituted γ-aminobutyr

Full text of DOI:10.1002/anie.201804040

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Accepted Article
Title: Synthesis of beta-Substituted gamma-Aminobutyric Acid
Derivatives via Enantioselective Photoredox Catalysis
Authors: Jiajia Ma, Jiahui Lin, Lifang Zhao, Klaus Harms, Michael
Marsch, Xiulan Xie, and Eric Meggers
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201804040
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10.1002/anie.201804040
Angewandte Chemie International Edition
COMMUNICATION
Synthesis of -Substituted γ-Aminobutyric Acid Derivatives via
Enantioselective Photoredox Catalysis
Jiajia Ma, Jiahui Lin, Lifang Zhao, Klaus Harms, Michael Marsch, Xiulan Xie and Eric Meggers*
substituted GABA analogs, but substrates are limited to aromatic
tertiary amines and to cyclic enones.[17] Kang and coworkers
reported a single Rh-based Lewis acid catalyst to enable a
visible-light-induced asymmetric Giese-type reaction but with a
severe limitation to N-aryl tetrahydroisoquinolines as precursors
of the intermediate -aminoalkyl radicals.[18] Thus, despite this
noteworthy progress, the currently narrow substrate scope and
limited follow-up functional group interconversions render these
methods of low utility. Herein, we introduce a general and
practical photoredox-based catalytic asymmetric radical
conjugate addition to access a variety of -substituted GABA
analogs including previously unaccessible derivatives with -
fluorinated quaternary stereocenters, and provide applications
(Figure 2b).
Abstract: -Substituted chiral -aminobutyric acids feature important
biological activities and are valuable intermediates for the synthesis
of pharmaceuticals. Herein, an efficient catalytic enantioselective
approach for the synthesis of -substituted -aminobutyric acid
derivatives
through
visible-light-induced
photocatalyst-free
asymmetric radical conjugate additions is reported. Various -
substituted -aminobutyric acid analogs, including previously
unaccessible derivatives containing fluorinated quaternary
stereocenters, were obtained in good yields (4289%) and with
excellent enantioselectivities (9097% ee). Synthetically valuable
applications were demonstrated by providing straightforward
synthetic access to the pharmaceuticals or related bioactive
compounds (S)-pregabalin, (R)-baclofen, (R)-rolipram and (S)-
nebracetam.
-Aminobutyric acid (GABA) is
a
well-known inhibitory
neurotransmitter of the central nervous system (CNS).[1]
Structurally diverse chiral GABAs, especially those bearing
substituents at the -position are marketed as pharmaceuticals
for the treatment of diseases accompanied with GABA receptors,
such as (S)-pregabalin[2] and (R)-baclofen[3] (Figure 1a). These
chiral GABAs are also valuable feedstocks for synthesizing other
related drugs like arbaclofen placarbil[4] and (R)-rolipram[5]. Due
to their diverse and potent bioactivities, considerable efforts
have been devoted to the efficient catalytic asymmetric
synthesis of a wide spectrum of -substituted GABAs.[6] Typical
strategies rely on Michael additions of CH acidic carbonyl
compounds to nitroalkenes,[7] and nitroalkanes or cyanide to ,-
unsaturated carbonyl compounds (Figure 1b).[8] The asymmetric
hydrogenation of unsaturated nitriles has also been
demonstrated as an alternative approach.[9] However, these
methods require a separate reduction step under relatively harsh
conditions. Furthermore, only very few reports accomplish the
synthesis of derivatives bearing quaternary stereocenters at the
-position,[10] and fluorinated quaternary stereocenters which
might be of biological interest, remain unexplored.[11] Hence, the
development of new synthetic protocols to access non-racemic
-substituted GABAs in an economical fashion, including
previously unaccessible structural features, is of high interest.
Very recently, the visible-light-induced enantioselective
radical conjugate addition of -aminoalkyl radicals[12] to Michael
acceptors, classified as a Giese-type reaction,[13] has been
recognized as an interesting alternative avenue to -substituted
Figure 1. Representative bioactive -substituted GABAs, related derivatives
and their synthetic strategies.
Figure 2. Approaches to non-racemic γ-amino carbonyl derivatives via
asymmetric photoredox catalysis. Phth = phthalimide. PG = protecting group.
GABAs by using
a radical as a nucleophilic aminoalkyl
equivalent (Figure 1b).[14] However, current methods display
severe limitations to aryl substituted amines (Figure 2a). For
example, Yoon and coworkers employed aromatic tertiary -
silylalkyl amines as radical precursors under Ru-photoredox
conditions and combined it with a Sc-catalyzed enantioselective
All previous studies to access GABA derivatives through
catalytic enantioselective photoredox catalysis exploit the
oxidative generation of -aminoalkyl radicals from specific
tertiary aromatic amines, which can be traced back to the
requirement for their single electron oxidation under sufficiently
mild conditions. Realizing this limitation to generate -aminoalkyl
radicals under oxidative conditions, we turned our attention to
reductive methods and were inspired by studies using N-
(acyloxy)phthalimides[19,20] as radical precursors under reductive
photoredox conditions (Figure 3a). Specifically, we envisioned
that glycine derivatives 1, bearing an easily removable N-
protected group and an O-phthalimide ester group as the redox
handle, might constitute easily accessible and very general
precursors of a large variety of -aminoalkyl radicals.[21] These
radicals would then be interfaced with established chiral-at-
rhodium Lewis acid catalyzed radical conjugate addition to ,-
conjugate
addition.[15,16]
Melchiorre
reported
a
dual
photoredox/organo catalysis system as an approach to -
[*]
J. Ma, J. Lin, L. Zhao, Dr. K. Harms, M. Marsh, Dr. X. Xie, Prof. Dr.
E. Meggers
Fachbereich Chemie, Philipps-Universität Marburg, Hans-Meerwein-
Strasse 4, 35043 Marburg, Germany
E-mail: meggers@chemie.uni-marburg.de
Supporting information for this article can be found under: xxx
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10.1002/anie.201804040
Angewandte Chemie International Edition
COMMUNICATION
Table 1. Reaction development and control experiments.[a]
unsaturated N-acylpyrazoles 2 (intermediate Rh-I) to provide
intermediate Rh-II, which after reduction and protonation afford
the Rh-bound products (Rh-III).[22] Replacement of the product
by another substrate leads to a new catalytic cycle (Figure 3b).
Substrate 2
R1 R2
Me 3,5-di-Me (2a) fac-[Ir(ppy)3] 89 (3a)
Entry
PC
Yield [%][b] ee [%][c]
X
H
1
91
2
H
H
H
Me 3,5-di-Me (2a) none
Ph 3,5-di-Me (2b) none
86 (3a)
54 (3b)
84 (3c)
0 (3d)
94
3
90
4
Ph 3-Me (2c)
none
none
none
none
none
95
5
Me Ph 3-Me (2d)
n.a.
93
6[d]
7[e]
8[f]
F
Ph 3-Me (2e)
Ph 3-Me (2c)
Ph 3-Me (2c)
70 (3e)
0 (3c)
H
H
n.a.
93
Figure 3. Reaction design. PC = photocatalyst. PG = protecting group.
14 (3c)
We commenced our study by investigating the reaction of
N-(acyloxy)phthalimide 1a with ,-unsaturated N-acylpyrazole
2a under photoredox conditions (Table 1). Using the chiral-at-Rh
Lewis acid catalyst -RhS[23] combined with the photocatalyst
fac-[Ir(ppy)3] and Hantzsch ester (HE) as the reductant under
irradiation with a household CFL, the CC formation product 3a,
identified as a -methyl GABA analog, was isolated in 89% yield
and 91% ee (entry 1). Unexpectedly, in the absence of fac-
[Ir(ppy)3], 3a was obtained even with higher enantioselectivity
(94% ee) (entry 2). This indicates that the HE itself probably
serves as the photoexcited reducing agent and directly promotes
single electron reduction of the phthalimide.[24,25] Alternatively, a
photoexcited Rh complex first oxidizes the HE and then
transfers a single electron to a phthalimide substrate, thereby
serving as an electron shuttle. Overall, this protocol is very
attractive because only a single catalyst is required for this
catalytic asymmetric photoredox reaction.
We next investigated the tolerance of a phenyl (2b) instead
of a methyl group (2a) at the -position of ,-unsaturated N-
acylpyrazoles, which showed a more limited scope in our
previous reports.[20b,26] As a result, using N-acylpyrazole 2b as
substrate, the CC formation product 3b was formed with inferior
yield (54%) and decreased 90% ee (entry 3). However, we
found that a 3-Me-substituted pyrazole (2c) instead of a 3,5-di-
Me-substituted pyrazole moiety (2b) not only improved the yield
(84%) but also afforded a higher enantioselectivity (95% ee)
(entry 4).[27] A -disubstituted -methyl--phenyl alkene (2d) did
not provide any desired product under these optimized
conditions (entry 5). However, a -fluoro--phenyl substituted
,-unsaturated N-acylpyrazole 2e delivered 3e in 70% yield
and 93% ee, containing a fluorinated quaternary stereocenter,
which is a formidable challenge in the field of asymmetric
photocatalysis (entry 5).[28] Control experiments verified that
visible light (entry 7) was essential and air strongly diminished
the yield (entry 8).
[a] Conditions: 1a (0.30 mmol), 2a-e (0.20 mmol), -RhS (0.016 mmol),
and HE (0.40 mmol) in acetone (1.0 mL) at r.t. for 16 h under N2 and
irradiated with CFL (23 W) unless noted otherwise. [b] Isolated yield. [c]
Determined by HPLC analysis on chiral stationary phase. [d] -RhS
(0.016 mmol) and 2 mL of acetone were employed. [e] Conducted in the
dark. [f] Assembled under air, then sealed. r.t. = room temperature. n.a.
= not applicable. PC = photocatalyst.
The scope with respect to the synthesis of -alkyl and -
aryl substituted GABA analogs is outlined in Figure 4. ,-
Unsaturated N-acylpyrazoles display good tolerance with
respect to substituents at the -position, including various alkyl
groups (3g-i), an ethoxy group (3j), electron-rich phenyl moieties
(3k-l, 3u), as well as electron-deficient ones (3m-n).
Heteroaromatic rings, like an indolyl (3o) and a thienyl moiety
(3p) lead to satisfactory results. Furthermore, N-
(acyloxy)phthalimides with different N-protected amino moieties
could also enable this transformation smoothly by affording
products 3q-t with 55-87% yields and 91-96% ee. It is worth
noting that an estrone derived N-acylpyrazole (2q) provided the
corresponding GABA analog 3v with 85% yield and 92% de,
thereby demonstrating that our protocol was applicable for the
incorporation of bioactive motifs to the side chain of -
aminobutyric acid.
The scope with respect to the synthesis of -fluoro--aryl
GABA analogs is outlined in Figure 5. Accordingly, substituents
at different positions of the phenyl moiety show little influence on
the reaction outcome by providing 3w-y in 68-71% yields and
with 94-96% ee. Electron-donating groups (3z-3aa), a tBu group
(3ab), and a chlorine (3ac) were also accommodated. A
carbazole moiety was tolerated by affording the CC formation
product 3ad in 62% yield and 93% ee.
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10.1002/anie.201804040
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COMMUNICATION
available materials 10 and 12, respectively, and were then
subjected to the developed asymmetric radial conjugate addition
reaction, followed by a cyclization, thereby delivering Boc-(S)-
nebracetam (14) with 55% yield and 94% ee over the two steps.
Overall, the herein outlined synthetic applications clearly
demonstrate that our approach is very versatile for the synthesis
of structurally diverse enantioenriched -substituted -
aminobutyric acids and their derivatives.
Figure 4. Scope with respect to synthesis of -alkyl and -aryl substituted
GABA analogs. *-RhS was employed.
Figure 6. Synthetic applications. Conditions: (i) LiOH, THF/H2O; (ii) LiOH,
THF/H2O; (iii) D-Phenylglycine methyl ester hydrochloride, Et3N, HOBt; (iv)
NaBH4; (v) Pd/C, H2 (1 atm); (vi) LiCl, MeOH then TFA followed by Et3N; (vii)
N-Benzyloxycarbonyloxy succinimide; K2CO3; (viii) NHPI, DCC, DMAP; (ix)
Diethylphosphonoacetic acid, LHMDS; (x) 3,5-Dimethylpyrazole, T3P, Et3N; (xi)
-RhS, HE, 23 W CFL; (xii) Pd/C, H2 (1 atm).
In conclusion, we herein introduced a practical and
versatile synthetic access to the pharmaceutically important
class of -substituted GABA analogs. The methodology is based
on catalytic asymmetric photoredox catalysis using simple
glycine derivatives as the precursors for nucleophilic -
aminoalkyl radicals which are then engaged in highly
enantioselective Rh-catalyzed radical conjugate additions.
Furthermore, for the first time enantioselective radical conjugate
additions to -fluoro--aryl substituted ,-unsaturated enones
are reported which provides a potentially very valuable access to
GABA analogs with -fluorinated quaternary stereocenters.
Figure 5. Scope with respect to synthesis of -fluoro--aryl substituted GABA
analogs.
With a range of -substituted GABA analogs in hand, we
next evaluated the synthetic application of this protocol (Figure
6). The pyrazole moiety can be transformed into a broad range
of functionalities under mild conditions. Treating 3n with LiOH in
THF/H2O provided the corresponding N-protected -aminobutyric
acid Boc-(R)-baclofen (4) in 90% yield and complete retention of
the ee. Boc-(S)-pregabalin (5) was obtained by the same
method. Furthermore, compound 3v was converted to the
dipeptide 6 in 83% yield and as a single diastereomer by
reacting with D-phenylglycine methyl ester. A -amino alcohol (7)
and a -lactam (8) bearing fluorinated quaternary stereocenters
were obtained smoothly under mild transformation conditions.
Additionally, the GABA analog 3u was converted into the anti-
inflammatory drug (R)-rolipram (9) in 92% yield and with
unchanged ee. To further demonstrate the practicability of our
protocol, the synthetic route to Boc-(S)-nebracetam which is an
enantioenriched form of a N-protected nootropic drug,[29] is
shown in Figure 6b. Accordingly, the CC coupling partners 1e
and 2z were synthesized over two steps from commercially
Acknowledgements
We are grateful for funding from the Deutsche
Forschungsgemeinschaft (ME 1805/13-1).
Keywords: -aminobutyric acid • visible light • radical addition •
fluorinated quaternary stereocenter • asymmetric catalysis
[1] R. H. Purdy, A. L. Morrow, P. H. Moore, S. M. Paul, Proc. Nat. Acad. Sci.
1991, 88, 4553.
[2] R. B. Silverman, Angew. Chem. Int. Ed. 2008, 47, 3500; Angew. Chem.
2008, 120, 3552.
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COMMUNICATION
[3] N. G. Bowery, D. R. Hill, A. L. Hudson, A. Doble, D. N. Middlemiss, J. Shaw,
M. Turnbull, Nature 1980, 283, 92.
[16] For a report on using -silylalkyl amines to synthesize chiral ,-
substituted GABA analogs (58-72% ee) by a stoichiometric chiral template,
see: D. Lenhart, A. Bauer, A. Pöthig, T. Bach, Chem. Eur. J. 2016, 22,
6519.
[4] L. B. Gerson, F. J. Huff, A. Hila, W. K. Hirota, S. Reilley, A. Agrawal, R. Lal,
W. Luo, D. Castell, Am. J. Gastroenterology 2010, 105, 1266.
[5] G.-S. Lee, N. Subramanian, A. I. Kim, I. Aksentijevich, R. Goldbach-
Mansky, D. B. Sacks, R. N. Germain, D. L. Kastner, J. J. Chae, Nature
2012, 492, 123.
[17] a) J. J. Murphy, D. Bastida, S. Paria, M. Fagnoni, P. Melchiorre, Nature
2016, 532, 218. For another report by the same group containing two
examples with 71% and 75% ee, see: b) M. Silvi, C. Verrier, Y. P. Rey, L.
Buzzetti, P. Melchiorre, Nat. Chem. 2017, 9, 868.
[6] For a review, see a) M. Ordóñez, C. Cativiela, I. Romero-Estudillo,
Tetrahedron: Asymmetry 2016, 27, 999. For selected examples of
synthesis of diverse chiral GABAs, see: b) M. Wiesner, J. D. Revell, S.
Tonazzi, H. Wennemers, J. Am. Chem. Soc. 2008, 130, 5610; c) G. Yang,
C. Luo, X. Mu, T. Wang, X.-Y. Liu, Chem. Commun. 2012, 48, 5880; d) F.-
L. Wang, X.-Y. Dong, J.-S. Lin, Y. Zeng, G.-Y. Jiao, Q.-S. Gu, X.-Q. Guo,
C.-L. Ma, X.-Y. Liu, Chem 2017, 3, 979; e) J. E. Gómez, W. Guo, S. Gaspa,
A. W. Kleij, Angew. Chem. Int. Ed. 2017, 56, 15035; Angew. Chem. 2017,
129, 15231; f) X.-Y. Chen, J.-W. Xiong, Q. Liu, S. Li, H. Sheng, C. von
Essen, K. Rissanen, D. Enders, Angew. Chem. Int. Ed. 2018, 57, 300;
Angew. Chem. 2018, 130, 306; g) A. Guerrero-Corella, F. Esteban, M.
Iniesta, A. Martín-Somer, M. Parra, S. Díaz-Tendero, A. Fraile, J. Alemán,
Angew. Chem. Int. Ed. 2018, 57, 5350; Angew. Chem. 2018, 130, 5448.
[7] For selected examples, see: a) S. L. Poe, M. Kobašlija, D. T. McQuade, J.
Am. Chem. Soc. 2007, 129, 9216; b) D. A. Evans, S. Mito, D. Seidel, J. Am.
Chem. Soc. 2007, 129, 11583; c) Y. Hayashi, T. Itoh, M. Ohkubo, H.
Ishikawa, Angew. Chem. Int. Ed. 2008, 47, 4722; Angew. Chem. 2008,
120, 4800; d) P. García-García, A. Ladépêche, R. Halder, B. List, Angew.
Chem. Int. Ed. 2008, 47, 4719; Angew. Chem. 2008, 120, 4797.
[18] S.-X. Lin, G.-J. Sun, Q. Kang, Chem. Commun. 2017, 53, 7665.
[19] For selected examples using N-(acyloxy)phthalimides or N-
(oxaly)phthalimides as C-radical precursors under photoredox conditions,
see: a) K. Okada, K. Okamoto, M. Oda, J. Am. Chem. Soc. 1988, 110,
8736; b) K. Okada, K. Okamoto, N. Morita, K. Okubo, M. Oda, J. Am.
Chem. Soc. 1991, 113, 9401; c) G. L. Lackner, K. W. Quasdorf, L. E.
Overman, J. Am. Chem. Soc. 2013, 135, 15342; d) G. L. Lackner, K. W.
Quasdorf, G. Pratsch, L. E. Overman, J. Org. Chem. 2015, 80, 6012; e) L.
Candish, M. Teders, F. Glorius, J. Am. Chem. Soc. 2017, 139, 7440; f) A.
Fawcett, J. Pradeilles, Y. Wang, T. Mutsuga, E. L. Myers, V. K. Aggarwal,
Science 2017, 357, 283; g) Y. Zhao, J.-R. Chen, W.-J. Xiao, Org. Lett.
2018, 20, 224. For recent reviews, see: h) J. Xuan, Z.-G. Zhang, W.-J.
Xiao, Angew. Chem. Int. Ed. 2015, 54, 15632; Angew. Chem. 2015, 127,
15854;
i)
S.
Murarka,
Adv.
Synth.
Catal.
2018,
DOI:
10.1002/adsc.201701615.
[20] For selected examples on N-(alkoxy)phthalimides, see: a) J. Zhang, Y. Li,
F. Zhang, C. Hu, Y. Chen, Angew. Chem. Int. Ed. 2016, 55, 1872; Angew.
Chem. 2016, 128, 1904; b) C. Wang, K. Harms, E. Meggers, Angew.
Chem. Int. Ed. 2016, 55, 13495; Angew. Chem. 2016, 128, 13693.
[21] While our work was under review, Phipps and co-workers reported a
related access to -aminoalkyl radicals and applied it to an
enantioselective Minisci-type addition. See: R. S. J. Proctor, H. J. Davis, R.
J. Phipps, Science 2018, DOI: 10.1126/science.aar6376.
[8] For selected examples, see: a) G. M. Sammis, E. N. Jacobsen, J. Am.
Chem. Soc. 2003, 125, 4442; b) A. Baschieri, L. Bernardi, A. Ricci, S.
Suresh, M. F. A. Adamo, Angew. Chem. Int. Ed. 2009, 48, 9342; Angew.
Chem. 2009, 121, 9506; c) K. L. Jensen, P. H. Poulsen, B. S. Donslund, F.
Morana, K. A. Jørgensen, Org. Lett. 2012, 14, 1516; d) Q. Yao, Z. Wang, Y.
Zhang, X. Liu, L. Lin, X. Feng, J. Org. Chem. 2015, 80, 5704.
[22] L. Zhang, E. Meggers, Acc. Chem. Res. 2017, 50, 320.
[9] For selected examples, see: a) E. Brenna, M. Crotti, F. G. Gatti, D. Monti,
F. Parmeggiani, R. W. Powell, S. Santangelo, J. D. Stewart, Adv. Synth.
Catal. 2015, 357, 1849; b) X. Li, C. You, Y. Yang, Y. Yang, P. Li, G. Gu, L.
W. Chung, H. Lv, X. Zhang, Chem. Sci. 2018, 9, 1919.
[23] a) C. Wang, L.-A. Chen, H. Huo, X. Shen, K. Harms, L. Gong, E. Meggers,
Chem. Sci. 2015, 6, 1094; b) J. Ma, X. Shen, K. Harms, E. Meggers,
Dalton Trans. 2016, 45, 8320; c) J. Ma, X. Zhang, X. Huang, S. Luo, E.
Meggers, Nat. Protoc. 2018, 13, 605.
[10] Reports on catalytic asymmetric synthesis of GABAs bearing quaternary
stereocenters at -position: a) K. Akagawa, K. Kudo, Angew. Chem. Int.
Ed. 2012, 51, 12786; Angew. Chem. 2012, 124, 12958; b) R. Kastl, H.
Wennemers, Angew. Chem. Int. Ed. 2013, 52, 7228; Angew. Chem. 2013,
125, 7369; c) J. H. Sim, C. E. Song, Angew. Chem. Int. Ed. 2017, 56, 1835;
Angew. Chem. 2017, 129, 1861.
[24] For examples on photoinduced electron transfer (PET) by direct excitation
of Hantzsch ester with visible light, see: a) W. Chen, H. Tao, W. Huang, G.
Wang, S. Li, X. Cheng, G. Li, Chem. Eur. J. 2016, 22, 9546; b) X. Huang,
S. Luo, O. Burghaus, R. D. Webster, K. Harms, E. Meggers, Chem. Sci.
2017, 8, 7126. For the formation of electron-donor-acceptor (EDA)
complex between HE and N-(alkoxy)phthalimide, see: c) J. Zhang, Y. Li, R.
Xu, Y. Chen, Angew. Chem. Int. Ed. 2017, 56, 12619; Angew. Chem. 2017,
129, 12793.
[11] X. Yang, T. Wu, R. J. Phipps, F. D. Toste, Chem. Rev. 2015, 115, 826.
[12] For the production of -aminoalkyl radicals under photoredox conditions,
see: a) A. McNally, C. K. Prier, D. W. C. MacMillan, Science 2011, 334,
1114; b) Y. Miyake, K. Nakajima, Y. Nishibayashi, J. Am. Chem. Soc. 2012,
134, 3338; c) P. Kohls, D. Jadhav, G. Pandey, O. Reiser, Org. Lett. 2012,
14, 672; d) M. E. Khatib, R. A. M. Serafim, G. A. Molander, Angew. Chem.
Int. Ed. 2016, 55, 254; Angew. Chem. 2016, 128, 262; e) Y. Yin, Y. Dai, H.
Jia, J. Li, L. Bu, B. Qiao, X. Zhao, Z. Jiang, J. Am. Chem. Soc. 2018, DOI:
10.1021/jacs.8b01575. For reviews, see: f) J. W. Beatty, C. R. J.
Stephenson, Acc. Chem. Res. 2015, 48, 1474; g) K. Nakajima, Y. Miyake,
Y. Nishibayashi, Acc. Chem. Res. 2016, 49, 1946; h) J. K. Matsui, S. B.
Lang, D. R. Heitz, G. A. Molander, ACS Catal. 2017, 7, 2563.
[25] The formed HE radical cation then serves as the formal reductant and
proton source for converting intermediate Rh-II to Rh-III.
[26] H. Huo, K. Harms, E. Meggers, J. Am. Chem. Soc. 2016, 138, 6936.
[27] X. Huang, X. Li, X. Xie, K. Harms, R. Riedel, E. Meggers, Nat. Commun.
2017, 8, 2245.
[28] a) S. Cuadros, L. Dell'Amico, P. Melchiorre, Angew. Chem. Int. Ed. 2017,
56, 11875; Angew. Chem. 2017, 129, 12037. b) E. M. Dauncey, S. P.
Morcillo, J. J. Douglas, N. S. Sheikh, D. Leonori, Angew. Chem. Int. Ed.
2018, 57, 744; Angew. Chem. 2018, 130, 752.
[29] S. Shorvon, Lancet 2001, 358, 1885.
[13] B. Giese, Angew. Chem. Int. Ed. Engl. 1983, 22, 753; Angew. Chem.
1983, 95, 771.
[14] For selected examples on visible-light-activated synthesis of diverse
racemic GABAs, see: a) L. Chu, C. Ohta, Z. Zuo, D. W. C. MacMillan, J.
Am. Chem. Soc. 2014, 136, 10886; b) K. Miyazawa, T. Koike, M. Akita,
Adv. Synth. Catal. 2014, 356, 2749; c) L. Qi, Y. Chen, Angew. Chem. Int.
Ed. 2016, 55, 13312; Angew. Chem. 2016, 128, 13506; d) A. Millet, Q.
Lefebvre, M. Rueping, Chem. Eur. J. 2016, 22, 13464; e) J. Liu, J. Xie, C.
Zhu, Org. Chem. Front. 2017, 4, 2433. For a review, see: f) J. J. Douglas,
M. J. Sevrin, C. R. J. Stephenson, Org. Process Res. Dev. 2016, 20, 1134.
[15] L. R. Espelt, I. S. McPherson, E. M. Wiensch, T. P. Yoon, J. Am. Chem.
Soc. 2015, 137, 2452.
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10.1002/anie.201804040
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
J. Ma, J. Lin, L. Zhao, K. Harms, M.
Marsh, X. Xie, E. Meggers*
Page No. – Page No.
Synthesis of -Substituted γ-
Aminobutyric Acid Derivatives via
Enantioselective Photoredox
Catalysis
A practical protocol to enantioenriched -substituted -aminobutyric acid analogs,
particularly the previously inaccessible ones with fluorinated quaternary
stereocenters, was demonstrated via photoinduced catalytic asymmetric Giese-type
reaction.
This article is protected by copyright. All rights reserved.