Carbene-Catalyzed Dynamic Kinetic Resolution of Carboxylic Esters

Article abstract of DOI:10.1021/jacs.6b00406

Carbene-catalyzed reaction of carboxylic esters has the potential to offer effective synthetic solutions that cannot be readily achieved by using the more conventional aldehyde-Type substrates. Here we report the first carbene-catalyzed dynamic kinetic resolution of α,α-disubstituted carboxylic esters with up to 99:1 er and 99% yield. The present study clearly illustrates the unique power of carbene-catalyzed reactions of readily available and easy to handle carboxylic esters.

Full text of DOI:10.1021/jacs.6b00406

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Communication
Carbene-Catalyzed Dynamic Kinetic Resolution of Carboxylic Esters
Xingkuan Chen, Jacqueline Zi Mei Fong, Jianfeng Xu, Chengli Mou,
Yunpeng Lu, Song Yang, Bao-An Song, and Yonggui Robin Chi
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b00406 • Publication Date (Web): 24 May 2016
Downloaded from http://pubs.acs.org on May 25, 2016
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Xingkuan Chen,† Jacqueline Zi Mei Fong,† Jianfeng Xu,† Chengli Mou,‡ Yunpeng Lu,† Song Yang,‡
Bao-An Song,‡ and Yonggui Robin Chi*,†,‡
†Division of Chemistry & Biological Chemistry, School of Physical & Mathematical Sciences, Nanyang Technological Uni-
versity, Singapore 637371, Singapore
‡Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Key Laboratory of Green Pesticide and Ag-
ricultural Bioengineering, Ministry of Education, Guizhou University, Huaxi District, Guiyang 550025, China.
Supporting Information Placeholder
ABSTRACT: Carbene-catalyzed reaction of carboxylic esters
has the potential to offer effective synthetic solutions that cannot
be readily achieved by using the more conventional aldehyde-type
substrates. Here we report the first carbene-catalyzed dynamic
kinetic resolution of α,α-disubstituted carboxylic esters with up to
99:1 er and 99% yield. The present study clearly illustrates the
unique power of carbene-catalyzed reactions of readily available
and easy to handle carboxylic esters.
Carboxylic acids and the related carbonyl compounds bearing two
or more substituents at the α-carbons are important functional
molecules. For example, ibuprofen and ketoprofen, derivatives of
propionic acid bearing a stereogenic α-carbon center, are widely
used as non-steroidal anti-inflammatory drugs1 (Figure 1a). Thus,
Figure 1. Enantiomerically enriched α,α-disubstituted carboxylic
acids/esters and our synthetic strategy
the synthesis and transformation of such α,α-disubstituted carbon-
yl compounds is of profound importance. N-Heterocyclic carbene
(abbreviated as NHC or carbene in this article) organic catalysts
have been successfully used to activate aldehydes and α,β-
unsaturated aldehydes (enals) for a diverse set of asymmetric
reactions.2 However, when an additional alkyl or aryl substituent
is placed at the α-carbon of the aldehydes or enals, the reaction
efficiency is dramatically reduced.3a This restriction on the
enal/aldehyde α-carbon substitutents has limited the application of
carbene catalysis to prepare some of the most important molecules
such as bioactive α,α-disubstituted carboxylic acids. It remains
underdeveloped at this point in using carbene-catalyzed aldehyde
reactions to prepare α,α-disubstituted carboxylic acids asymmetri-
cally.3,4 On the other hand, researches have focused on the more
reactive ketene substrates via organic catalysis to prepare enanti-
omerically enriched α,α-disubstituted carboxylic esters/acids. Fu
has pioneered asymmetric protonation reactions by using planar-
chiral DMAP type organic catalysts with excellent enantioselec-
tivities;5 Smith and Ye have pioneered the asymmetric protona-
tion reactions of ketenes to give α,α-disubstituted carboxylic ester
products with moderate to good enantioselectivities.6 The instabil-
ity of ketene substrates and the challenges in selective
asymmetric protonation have limited the wide applications of
these otherwise elegant approaches using ketene substrates.
Our laboratory is interested in using carbene catalysts to acti-
vate readily available and stable carboxylic esters for effective
transformations.7 In particular, the use of carboxylic esters as
substrates can induce useful transformations that cannot be easily
achieved by using the related aldehyde and enal substrates, as
demonstrated by Lupton8 and our laboratories.7 Here we report
the first carbene-catalyzed reaction to effectively prepare enanti-
omerically enriched α,α-disubstituted carboxylic esters via a
dynamic kinetic resolution process (Figure 1b). Our reaction starts
with racemic carboxylic ester substrates and gives transesterified
products with excellent er (up to 99:1) and yield (up to 99%).
There are no previous reports for the preparation of such chiral
product by using the related enal or aldehyde substrates under
(oxidative) carbene catalysis.
Notably, carbene organic catalysts have been previously used
in two types of kinetic resolution. Firstly, kinetic resolution of
racemic alcohols and related binols with up to 50% yields have
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been reported by Suzuki,9a Maruoka,9b Studer,9c Yamada9d and
a
Table 2. Scope of Reactions
Zhao.9e, f Additionally, (dynamic) kinetic resolution of ketones or
imines (bearing a chiral center) via NHC-bound Breslow interme-
diates10 or dienolate intermediates have been reported by Scheidt,
Johnson, Wang, and our own laboratory.11
Key results of initial reaction optimization using ester 1a as the
model substrate are summarized in Table 1. Alcohol 2 was found
to be optimal after screening (e.g., the use of methanol, benzyl
alcohol led to product with less than 69:31 er under various condi-
tions, see SI). We were pleased to first find that the background
ester exchange reaction (in the absence of carbene catalyst) was
minimal (< 5% conversion after 24 hours, entry 1), but also that
the addition of achiral triazolium NHC pre-catalyst A, first report-
ed by Rovis,12a led to 3a with quantitative yield (entry 2). Having
thus proven the efficiency of the carbene-catalyzed ester exchange
reaction in our system, we next moved to screening chiral carbene
catalysts. Amino alcohol-derived chiral NHC pre-catalyst B, first
reported by Leeper,12b could mediate this reaction to give 3a with
excellent yield and encouraging er of 67:33 (entry 3). Solvent was
found to affect both yields and er values (entry 4, and see SI), the
best of which were obtained with CHCl3 (99% yield, 80:20 er,
entry 5). Additional studies found that the use of N-Mes substitut-
ed triazolium catalysts offered product 3a with higher er values
(e.g., compared entry 6 with 5, 8 with 7). We finally discovered
that the use of pre-catalyst E, first explored by Bode,12c gave 3a
with optimal 96% isolated yield and acceptable (96:4) er (entry 8).
Catalyst F could mediate this reaction to give 3a with 70% yield
and 91:9 er (entry 9).
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a
Table 1. Condition Optimization
a Reaction conditions: 1 (0.1 mmol), 2 (0.2 mmol), CHCl3 (1 mL). b 40 oC.
c 1 (0.21 mmol), 2 (0.1 mmol), 40 oC. d 20 mol% NHC D.
ester substrates were all tolerated (product 3a-g). The phenyl sub-
stituent of substrate 1a could be replaced with 1-naphthyl and
heteroaryl substituent without obviously affecting the reaction
yields and er values (3h-j). In the cases where the reaction was
slow at rt (3e, 3g, 3j, 3l-3p), the reaction mixture was heated to 40
oC and acceptable er values were still achieved. Diester (3k) could
be resolved as well with excellent dr and er. When the α-methyl
unit of 1a was replaced with an ethyl substituent (3l), a decreased
er (85:15 er) was observed under the standard condition. The drop
in er could be solved by using a different alcohol reacting partner
(e.g., (α-Np)2CHOH, gave 3m with 92:8 er). The methyl group in
1a could also be replaced by a benzyl substituent (3n) negligible
change on reaction outcomes. When a cyanomethyl substituted
ester was used under the standard condition, the corresponding
transesterification product (3o) was obtained in quantitative yield
but with close to 50:50 er. We then found that by using 0.5 equiv.
of the alcohol substrate (to achieve kinetic resolution; rather than
dynamic kinetic resolution in this case), the corresponding ester
product 3o could be obtained with 90:10 er and 91% yield (based
on alcohol substrate, or 43% yield based on ester substrate). A
TBS-protected hydroxylmethyl unit (3p) could also be used to
replace the methyl group of substrate 1a, here the use of less
bulky N-phenyl substituted catalyst D gave better results. The
products from our reactions and their closely related derivatives
entry NHC solvent
yield (%)b
<5
erc
--
1
2
3
4
THF
THF
THF
--
A
B
B
99
--
99
67:33
solvents
(see SI)
45-99
62:38 to
75:25
5
6
7
8
9
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
99
80:20
88:12
85:15
96:4
B
C
D
E
F
80
99
99(96)
70
91:9
a Reaction conditions: 1a (0.1 mmol), 2 (0.2 mmol), solvent (1 mL), rt, 24 h.
bYield determined by NMR analysis with an internal standard. Isolated yield
in parentheses based on 1a. cEnantiomeric ratio of 3a, determined via chiral
phase HPLC analysis. Mes = 2,4,6-Trimethylphenyl.
With an acceptable reaction condition in hand (Table 1, entry 8),
we next examined the scope of the esters (Table 2). Different
substituents and substitution patterns on the α-phenyl ring of the
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(a) proposed reaction pathway of catalytic Dynamic Kinetic Resolution (DKR)
are useful functional molecules. For example, product 3o could be
readily converted to β2-amino acid,13a and TBS-protected hydrox-
ylmethyl product (3p) could be converted to natural products such
as chiral tropic acid and its analogues.13b
CH3
alcohol 2
NHC+
Ph
NHC
NHC-E
step 1
(R)-I
O
step 2
Fast
CH3
base
Optically enriched α-aryl propionic acid and their derivatives
are bioactive molecules and medicines.1, 14 Our method offers
very effective access to many of these medicines and their deriva-
tives, as illustrated in Table 3. Our method is also amenable for
scale-up synthesis, as illustrated by a gram scale preparation of
naproxen ester (3v, 1.1g). The ester group of our product (e.g., 3v)
can be easily removed by using well-established method.
CH3
CO2Ar
(±)-1a
racemic
OCHPh2
Ph
O
Ph
96:4 er
(R)-3a
O
similar
rate
H3C
NHC+
Ph II
CH3
substrate
OCHPh2
base
Ph
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Slow
step 1'
(S)-3a
O
step 2'
CH3
NHC-E
NHC+
Ph
NHC
alcohol 2
a
(S)-I
O
Table 3. Medicinal Molecules Prepared Using Our Method
(b) NHC catalyst is necessary for the isomerization of ester substrate 1
CH3
CH3
OAr
OAr
w/o NHC (E)
with or w/o alcohol 2
O
O
MeO
150 mol% Cs2CO3
CHCl3, 4Å MS, RT
24h
MeO
1v recovered in > 98% yield; 99:1 er
(S)-1v, >99:1 er
no racemization
CH3
OAr
CH3
OAr
20 mol% NHC (E)
w/o alcohol 2,
150 mol% Cs2CO3
CHCl3, 4Å MS, RT
24h
O
O
MeO
MeO
1v recovered in 60%yield, 62:38 er
(R)-1v, >99:1 er
racemized
(c) The use of (R) or (S)-isomer of ester substrate led to same enantioselectivity
CH3
CH3
20 mol% NHC E
200 mol% alcohol 2
150 mol% Cs2CO3
CHCl3, 4Å MS
OCHPh2
CO2Ar
O
(R)-3v
MeO
MeO
rxn #1: (R)-1v; 92% yield, 97:3 er, (R)-3v
rxn #2: (S)-1v; 90% yield, 97:3 er, (R)-3v [same enantiomer as using (R)-1v]
(d) Ester (R)-1v with alcohol 2 reacts faster than the corresponding enantiomer (S)-1v
OH
CH3
CH3
freel NHC E
(1.0 eq)
CH3
OCHPh2
Ph
Ph
OAr
Ar'
(R)
NHC+
Ar'
(2.0 eq)
(R)
Ar' (R)
O
CDCl3, 1h
step 1
a Reaction conditions: 1 (0.1 mmol), 2 (0.2 mmol), NHC E (0.02 mmol),
CHCl3 (1 mL). 24 h.
24 h
step 2
O
> 90% conv. of 1v
O
~50%
(R)-1v, >99:1 er
(99:1 er)
(R)-I'
OH
CH3
CH3
OAr
free NHC E
(1.0 eq)
CH3
OCHPh2
Ph
Ph
A postulated reaction pathway is briefly illustrated in Scheme
1a. The addition of chiral carbene catalyst E to racemic ester sub-
strate 1a gives diastereomeric intermediate (R)-I and (S)-I. Inter-
mediate (R)-I preferentially reacts with alcohol substrate 2 to give
3a with high enantiomeric ratio. To further understand the mech-
anism, we performed the reaction by using enantiomerically pure
(S)-1v as the substrate in the absence of carbene catalyst (Scheme
1b). Neither background transesterification reaction nor racemiza-
tion of (S)-1v was observed. In contrast, when enantiomerically
pure (R)-1v was mixed with carbene E, the recovered 1v was
partially racemized. Thus the carbene catalyst is required for the
racemization of the ester substrate (isomerization between (R)-I
and (S)-I) and the transesterification reaction (1v to 3v). In addi-
tion, the use of either (R) or (S)-enantiomer of the ester substrate
under our catalytic conditions gave the transesterification product
with the same enanioselectivities and similar yields (Scheme 1c).
When pre-formed free NHC catalyst was used in the absence of
additional base, racemization of the ester substrate was not ob-
served (Scheme 1d), suggesting that both NHC and base were
required for the isomerization of the ester substrate. It was also
found that the addition of (pre-formed) NHC catalysts to either
enantiomer of the ester substrate 1v had similar reaction rate
(Scheme 1d, “step1” and “step1') in forming the acylazolium ester
intermediate (R)-I' and (S)-I' (approximately 50% conversion in
Ar'
NHC+
(S)
(2.0 eq)
24 h
step 2'
Ar'
(S)
Ar'
(S)
O
CDCl3, 1h
step 1'
O
O
~50%
< 5% conv. of 1v
(S)-1v, >99:1 er
(S)-I'
pre-formed free NHC was prepared by mixing NaH with azolium salt; No additional
base (such as Cs2CO3 used in standardard condition) was added
(e) Activation energy for the addition of alcohol 2 to azolium ester intermediates (see SI)
O2N
O2N
H
O
O
N
H
N
Me
Me
O
O
N
N
VS
N
H
N
Me
Me
H
(R)
(R)
Ph
Ph
Me
Ph
Me
Me
O
O
(R)
Me
(S) Ph
VS
transition state (TS-R): Erel = 0 kcal/mol
transition state (TS-S): Erel = 5.02 kcal/mol
Scheme 1. Proposed Pathway and Mechanistic Studies.
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2014, 510, 485. (j) Flanigan, D. M.; Romanov-Michailidis, F.;
White, N. A.; Rovis, T. Chem. Rev. 2015, 115, 9307.
both cases after 1h). In the subsequent addition of alcohol 2 to the
azolium ester intermediates, the intermediate (R)-I' reacted much
faster than (S)-I' (Scheme 1d, “step 2” and “step 2'). These studies
(Scheme 1d) suggest that the final step of ester formation is the
asymmetric step, and the overall process is a dynamic kinetic
resolution. The key step of alcohol addition to the acylazolium
ester intermediate was also evaluated via DFT calculation
(Scheme 1e). The calculation revealed that the energy of the addi-
tion of alcohol 2 to intermediate (S)-I is 5.02 kcal/mol higher
than that of alcohol 2 adding to the intermediate (R)-I, which is in
consistence with our experimental observations.
(3) (a) Sohn, S.; Bode, J. W. Org. Lett. 2005, 7, 3873. (b) Chan, A.;
Scheidt, K. A. Org. Lett. 2005, 7, 905. (c) Burstein, C.; Tschan, S.;
Xie, X.; Glorius, F. Synthesis 2006, 14, 2418. (d) Maki, B. E.;
Scheidt, K. A. Org. Lett. 2008, 10, 4331. (d) Yatham, V. R.; Harny-
ing, W.; Kootz, D.; Neudörfl, J.-M.; Schlörer, N.; Berkesel, A. J.
Am. Chem. Soc., 2016, 138, 2670.
(4) Alpha-halogenated aldehyde could be transformed to enantiomeri-
cally enriched carboxylic acid/esters, as pioneered by Rovis, see: (a)
Reynolds, N. T.; Rovis, T. J. Am. Chem. Soc., 2005, 127, 16406; (b)
Vora, H. U.; Rovis, T. J. Am. Chem. Soc., 2010, 132 , 2860.; Enan-
tiomerically enriched β,β-disubstituted carboxylic acid/esters could
be achieved via NHC-catalyzed β-protonation, see: (c) Wang, M. H.;
Cohen, D. T.; Schwamb, C. B.; Mishra, R. K.; Scheidt, K. A. J. Am.
Chem. Soc., 2015, 137 , 5891.
(5) (a) Hodous, B. L.; Ruble, J. C.; Fu, G. C. J. Am. Chem. Soc. 1999,
121, 2637. Also see review: (b) Fu, G. C. Acc. Chem. Res. 2000, 33,
412.
(6) (a) Wang, X.-N.; Lv, H.; Huang, X.-L.; Ye, S. Org. Biomol. Chem.,
2009, 7, 346. (b) Concellón, C.; Duguet, N.; Smith, A. D. Adv.
Synth. Catal. 2009, 351, 3001.
(7) (a) Hao, L.; Du, Y.; Lv, H.; Chen, X.; Jiang, H.; Shao, Y.; Chi, Y.
R. Org. Lett. 2012, 14, 2154. (b) Chen, S.; Hao, L.; Zhang, Y.; Ti-
wari, B.; Chi, Y. R. Org. Lett. 2013, 15, 5822. (c) Hao, L.; Chen,
S.; Xu, J.; Tiwari, B.; Fu, Z.; Li, T.; Lim, J.; Chi, Y. R. Org. Lett.
2013, 15, 4956. (d) Fu, Z.; Xu, J.; Zhu, T.; Leong, W. W. Y.; Chi,
Y. R. Nat. Chem. 2013, 5, 835. (e) Cheng, J.; Huang, Z.; Chi, Y. R.
Angew. Chem., Int. Ed. 2013, 52, 8592. (f) Xu, J.; Jin, Z.; Chi, Y. R.
Org. Lett. 2013, 15, 5028. (g) Fu, Z.; Jiang, K.; Zhu, T.; Torres, J.;
Chi, Y. R. Angew. Chem.; Int. Ed. 2014, 53, 6506. (h) Hao, L.;
Chen, X.; Chen, S.; Jiang, K.; Torres, J.; Chi, Y. R. Org. Chem.
Front. 2014, 1, 148. (i) Jin, Z.; Chen, S. J.; Wang, Y.; Zheng, P.;
Yang, S.; Chi, Y. R. Angew. Chem.; Int. Ed. 2014, 53, 13506.
(8) (a) Ryan, S. J.; Candish, L.; Lupton, D. W. J. Am. Chem. Soc. 2009,
131, 14176. (b) Candish, L.; Lupton, D. W. Org. Biomol.
Chem. 2011, 9, 8182. (c) Candish, L.; Lupton, D. W. Chem. Sci.
2012, 3, 380. (d) Candish, L.; Levens, A.; Lupton, D. W.; J. Am.
Chem. Soc. 2014, 136, 14397. (e) Candish, L.; Levens, A.; Lupton,
D. W. Chem. Sci. 2015, 6, 2366. (f) Levens, A.; Zhang, C.; Candish,
L.; Forsyth, C. M.; Lupton, D. W. Org. Lett. 2015, 17, 5332.
(9) For NHC-catalyzed kinetic resolution of secondary alcohols, see: (a)
Suzuki, Y.; Yamauchi, K.; Muramatsu, K.; Sato, M. Chem. Com-
mun., 2004, 2770. (b) Kano, T.; Sasaki, K.; Maruoka, K. Org. Lett.
2005, 7, 1347. (c) DeꢀSarkar, S.; Biswas, A.; Song, C. H.; Studer, A.
Synthesis 2011, 1974. (d) Kuwano, S.; Harada, S.; Kang, B.; Oriez,
R.; Yamaoka, Y.; Takasu, K.; Yamada, K.-i. J. Am. Chem. Soc.
2013, 135, 11485. (e) Lu, S.; Poh, S. B.; Siau, W.-Y.; Zhao, Y. An-
gew. Chem., Int. Ed. 2013, 52, 1731. (f) Lu, S.; Poh, S. B.; Zhao, Y.
Angew. Chem., Int. Ed. 2014, 53, 11041. For NHC-catalyzed kinet-
ic resolution with other substrates, see: (g) Li, G.-Q.; Li, Y.; Dai,
L.-X.; You, S.-L. Adv. Synth. Catal. 2008, 350, 1258. (h) Binanzer,
M.; Hsieh, S.-Y.; Bode, J. W. J. Am. Chem. Soc. 2011, 133, 19698.
(10) (a) Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719. (b) DiRocco, D.
A.; Oberg, K. M.; Rovis, T. J. Am. Chem. Soc. 2012, 134, 6143. (c)
Maji, B.; Mayr, H. Angew. Chem.; Int. Ed. 2012, 51, 10408. (d)
Berkessel, A.; Elfert, S.; Yatham, V. R.; Neudörfl, J.-M.; Schlörer,
N. E.; Teles, J. H. Angew. Chem., Int. Ed. 2012, 51, 12370.
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In summary, we have developed a carbene-catalyzed reaction
of esters that offers useful synthetic solutions which are not readi-
ly accessible from the conventional reactions based on aldehyde
substrates. Our approach, through dynamic kinetic resolution of
carboxylic esters, allows for effective access to the broadly useful
α,α-disubstituted carboxylic esters with up to 99:1 er and 99%
yield. The present study clearly illustrates the unique power of
carbene-catalyzed activation and reaction of carboxylic esters, and
shall encourage further development of new activation modes.
ASSOCIATED CONTENT
Supporting Information
Experimental procedures and spectral data for all new com-
pounds. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: robinchi@ntu.edu.sg.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We acknowledge financial support by the Singapore National
Research Foundation, GlaxoSmithKline, the Ministry of Educa-
tion of Singapore, Nanyang Technological University, China’s
National Key program for Basic Research (No. 2010CB 126105),
Thousand Talent Plan, NSF of China (No. 21132003; No.
21472028), Guizhou Province Returned Oversea Student Science
and Technology Activity Program, Science and Technology De-
partment of Guizhou Province, and Guizhou University.
REFERENCES
(1) (a) Harrison, I. T.; Lewis, B.; Nelson, P.; Rooks, W.; Roszkowski,
A.; Tomolonis, A.; Fried, J. H. J. Med. Chem. 1970, 13, 203. (b)
Shen, T. Y. Angew. Chem., Int. Ed. 1972, 11, 460. (c) Lednicer, D.;
Mitscher, L. A. The Organic Chemistry of Drug Synthesis, Wiley,
New York, 1977,vol. 1.
(2) For selected recent reviews on NHC catalysis, see: (a) Zeitler, K.
Angew. Chem., Int. Ed. 2005, 44, 7506. (b) Enders, D., Niemeier,
O.; Henseler, A. Chem. Rev. 2007, 107, 5606; (c) Nair, V.; Menon,
R. S.; Biju, A. T.; Sinu, C. R.; Paul, R. R.; Jose, A.; Sreekumar, V.
Chem. Soc. Rev. 2011, 40, 5336. (d) Douglas, J.; Churchill, G.;
Smith, A. D. Synthesis 2012, 44, 2295. (e) Cohen, D. T.; Scheidt, K.
A. Chem. Sci. 2012, 3, 53. (f) Ryan, S. J.; Candish, L.; Lupton, D.
W. Chem. Soc. Rev. 2013, 42, 4906. (g) De Sarkar, S.; Biswas, A.;
Samanta, R. C.; Studer, A. Chem. Eur. J. 2013, 19, 4664. (h) Ma-
hatthananchai, J.; Bode, J. W. Acc. Chem. Res. 2014, 47, 696. (i)
Hopkinson, M. N.; Richter, C.; Schedler, M.; Glorius, F. Nature
(11) (a) Cohen, D. T.; Eichman, C. C.; Phillips, E. M.; Zarefsky, E. R.;
Scheidt, K. A. Angew. Chem., Int. Ed. 2012, 51, 7309. For full arti-
cle, see: (b) Johnston, R. C.; Cohen, D. T.; Eichman, C. C.; Scheidt,
K. A.; Cheong, P. H.-Y. Chem. Sci. 2014, 5, 1974. (c) Goodman, C.
G.; Johnson, J. S. J. Am. Chem. Soc. 2014, 136, 14698. (d) Wang,
M.; Huang, Z.; Xu, J.; Chi, Y. R. J. Am. Chem. Soc. 2014, 136,
1214. (e) Wu, Z.; Li, F.; Wang, J. Angew. Chem., Int. Ed. 2015, 54,
1629. (f) Goodman, C. G.; Walker, M. M.; Johnson, J. S. J. Am.
Chem. Soc., 2015, 137 , 122. (g) Zhao, C.-G.; Li, F.-Y.; Wang, J.
Angew. Chem., Int., Ed. 2016, 55, 1820
(12) (a) Reynolds, N. T.; Read de Alaniz, J.; Rovis, T. J. Am. Chem.
Soc. 2004, 126, 9518. (b) Knight, R. L.; Leeper, F. J. J. Chem. Soc.
Perkin Trans. 1 1998, 1891. (c) Chiang, P.-C.; Rommel, M.; Bode,
J. W. J. Am. Chem. Soc. 2009, 131, 8714.
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(13) (a) Camps, P.; Muñoz-Torrero, D.; Sánchez, L. Tetrahedron
Asymmetry 2004, 15, 311. (b) Klomp, D.; Peters, J. A.; Hanefeld, U.
Tetrahedron Asymmetry 2005, 16, 3892.
(14) (a) Chiu, C. T.; Wang, Z.; Hunsberger, J. G.; Chuang, D.-M.
Pharmacological Reviews, 2013, 65, 105. (b) Lapinsky, D. J.;
Velagaleti, R.; Yarravarapu, N.; Liu, Y.; Huang, Y.; Surratt, C. K.;
Lever, J. R.; Foster, J. D.; Acharya, R.; Vaughan, R. A.; Deutsch, H.
M. Bioorg. & Med. Chem. 2011, 19, 504. (c) Lednicer, D.; Mitscher,
L. A. The Organic Chemistry of Drug Synthesis, Wiley, New York,
1977,vol. 1.
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