Enantioselective Synthesis of Pyroglutamic Acid Esters from Glycinate via Carbonyl Catalysis

Article abstract of DOI:10.1002/anie.202017306

Direct α-functionalization of NH₂-free glycinates with relatively weak electrophiles such as α,β-unsaturated esters still remains a big challenge in organic synthesis. With chiral pyridoxal 5 d as a carbonyl catalyst, direct asymmetric conjugated addition at the α-C of glycinate 1 a with α,β-unsaturated esters 2 has been successfully realized, to produce various chiral pyroglutamic acid esters 4 in 14–96 % yields with 81–97 % ee's after in situ lactamization. The trans and cis diastereomers can be obtained at the same time by chromatography and both of them can be easily converted into chiral 4-substituted pyrrolidin-2-ones such as Alzheimer's drug Rolipram (11) with the same absolute configuration via tert-butyl group removal and subsequent Barton decarboxylation.

Full text of DOI:10.1002/anie.202017306

Angewandte
Communications
Chemie
How to cite: Angew. Chem. Int. Ed. 2021, 60, 10588–10592
International Edition:
German Edition:
doi.org/10.1002/anie.202017306
doi.org/10.1002/ange.202017306
Asymmetric Catalysis
Enantioselective Synthesis of Pyroglutamic Acid Esters from Glycinate
via Carbonyl Catalysis
Jiguo Ma, Qinghai Zhou, Guanshui Song, Yongchang Song, Guoqing Zhao, Kuiling Ding, and
Baoguo Zhao*
Abstract: Direct a-functionalization of NH2-free glycinates
with relatively weak electrophiles such as a,b-unsaturated
esters still remains a big challenge in organic synthesis. With
chiral pyridoxal 5d as a carbonyl catalyst, direct asymmetric
conjugated addition at the a-C of glycinate 1a with a,b-
unsaturated esters 2 has been successfully realized, to produce
various chiral pyroglutamic acid esters 4 in 14–96% yields with
81–97% eeꢀs after in situ lactamization. The trans and cis
diastereomers can be obtained at the same time by chromatog-
raphy and both of them can be easily converted into chiral 4-
substituted pyrrolidin-2-ones such as Alzheimerꢀs drug Roli-
pram (11) with the same absolute configuration via tert-butyl
group removal and subsequent Barton decarboxylation.
C
hiral pyroglutamic acids and their derivatives are a type of
important compounds with high bioactivities.[1,2] The pyro-
glutamic acid moieties are present in many natural products[1]
and medicinal molecules.[2] Besides, pyroglutamic acids have
also been used as versatile synthons to make various N-
containing compounds.[3] Thus the synthesis of pyroglutamic
acid derivatives is highly desirable and it has already attracted
much attention. Conjugated addition at the a-C of glycinates
with a,b-unsaturated esters followed by lactamization is
a highly straightforward strategy to access pyroglutamic acid
derivatives (Figure 1). However, NH2 protecting group
manipulation is usually needed before and after the a-C
conjugated addition since the reaction can be easily inter-
rupted by the nucleophilic NH2 group. For example, Vialle-
font, Kanemasa, Kobayashi, and other groups found that
glycinate imines could undergo conjugated addition to a,b-
unsaturated esters, followed by deprotection of the carbonyl
protecting groups and subsequent in situ lactamization, to
afford various pyroglutamic acid esters (Figure 1a).[4,5] Solo-
shonok and Hruby utilized NiII complexes of glycine Schiff
bases as a-C nucleophiles to react with a,b-unsaturated
Figure 1. Strategies for the synthesis of pyroglutamic acids and esters
from glycine derivatives.
amides to make substituted pyroglutamic acids in three steps
with excellent diastereoselecivity (Figure 1b).[6] Direct reac-
tion of glycinates with a,b-unsaturated esters to synthesize
pyroglutamic acid derivatives without protecting group
manipulation is highly attractive but it still remains a big
challenge in organic synthesis. Carbonyl catalysis uses an
[*] J. Ma, Q. Zhou, G. Song, Y. Song, G. Zhao, B. Zhao
The Education Ministry Key Lab of Resource Chemistry and Shanghai
Key Laboratory of Rare Earth Functional Materials, College of
Chemistry and Materials Science, Shanghai Normal University
Shanghai 200234 (China)
appropriate aldehyde or ketone as the catalyst to activate the
[7–9]
À
a C H of primary amines for direct a functionalization,
which theoretically provides an opportunity for asymmetric
conjugated addition at the a-C of glycinate 1a with a,b-
unsaturated esters 2 without pre-protection of the NH2 group,
to produce the desired chiral pyroglutamic acid esters 4 after
in situ lactamization (Figure 1c). Herein, we report our
studies on the project.
E-mail: zhaobg2006@shnu.edu.cn
J. Ma, K. Ding
State Key Laboratory of Organometallic Chemistry, Center for
Excellence in Molecular Synthesis, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences
The studies started with the investigation of the reaction
of tert-butyl glycinate (1a) with a,b-unsaturated ester 2a
(Table 1). In the presence of 10 mol% of chiral pyridoxal[8,10]
5b as the carbonyl catalyst (Scheme 1), the reaction did occur
345 Lingling Road, Shanghai 200032 (China)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202017306.
10588
ꢀ 2021 Wiley-VCH GmbH
Angew. Chem. Int. Ed. 2021, 60, 10588 –10592

Angewandte
Communications
Chemie
Table 1: Optimization for the synthesis of chiral pyroglutamic acid esters 4.[a]
and displayed good catalytic activity and excellent
selectivity in biomimetic Mannich reaction of glyci-
nate (Table 1, entry 2).[8] This is probably because the
too stable a-amino carbanion intermediate pro-
moted by 5a during the catalysis is not nucleophilic
enough for the 1,4-conjugated addition to 2a.
Replacement of the primary amide side chain of
the catalyst 5b with a secondary amide (5c) led to an
obvious improvement in reaction yield (Table 1,
entry 4 vs. 3). Further catalyst screening showed
that chiral pyridoxal 5d was the best choice among
the catalysts 5a–k examined in terms of activity and
enantioselectivity (Table 1, entries 5 and 8 vs. 2–4, 6–
7 and 9–13). Further condition investigations indi-
cated that acetonitrile was the best solvent (Table 1,
entry 8 vs. 5 and 14–15) and DBU was the base of
choice (Table 1, entry 8 vs. 19–21). Lewis acid was
a necessary additive (Table 1, entry 8 vs. 16) and
LiOTf was the most active for the reaction (Table 1,
entry 8 vs. 17–18). Interestingly, temperature influ-
enced the activity of the reaction, but displayed little
impact on the enantioselectivity of the products 4a
(Table 1, entry 8 vs. 22 and 23). The reaction was
chosen to carry out at 408C.
Under the optimal conditions, the substrate
scope was then investigated for the pyridoxal-cata-
lyzed direct synthesis of chiral pyroglutamic acid
esters 4 (Table 2). Phenyl (for 4b) and various
substituted phenyl (for 4a and 4c–m) a,b-unsatu-
rated esters all smoothly underwent asymmetric 1,4-
conjugated addition and subsequent lactamization to
give chiral pyroglutamic acid esters 4a–m in good
yields with low diastereoselectivities but high enan-
tioselectivities for both of the trans- and cis-diaste-
reomers. The 2-substituted substrates such as methyl
Entry Cat.
Conditions
Yield [%][b] trans:cis[c] ee [%][d]
1
–
LiOTf, DBU, THF, 408C
LiOTf, DBU, THF, 408C
LiOTf, DBU, THF, 408C
LiOTf, DBU, THF, 408C
LiOTf, DBU, THF, 408C
LiOTf, DBU, THF, 408C
LiOTf, DBU, THF, 408C
LiOTf, DBU, CH3CN, 408C
LiOTf, DBU, CH3CN, 408C
LiOTf, DBU, CH3CN, 408C
LiOTf, DBU, CH3CN, 408C
LiOTf, DBU, CH3CN, 408C
LiOTf, DBU, CH3CN, 408C
LiOTf, DBU, CHCl3, 408C
LiOTf, DBU, DMF, 408C
DBU, CH3CN, 408C
0
0
–
–
–
–
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
5a
5b
5c
5d
5 f
5g
5d
5e
5h
5i
47
77
85
60
88
90
58
70
89
71
46
60
26
0
1.2:1
1:1
À75/À82
77/87
82/85
74/85
80/84
86/91
84/89
86/89
À87/À90
35/41
21/À15
82/85
87/91
–
1.5:1
1.1:1
1.1:1
1.1:1
1.1:1
1.2:1
1.1:1
1.2:1
1.3:1
1.2:1
1.2:1
–
5j
5k
5d
5d
5d
5d
5d
5d
5d
5d
5d
Zn(OTf)2, DBU, CH3CN, 408C
LiBF4, DBU, CH3CN, 408C
LiOTf, CH3CN, 408C
LiOTf, Et3N, CH3CN, 408C
LiOTf, LiOH, CH3CN, 408C
LiOTf, DBU, CH3CN, 208C
0
–
–
59
0
1:1
–
86/92
–
0
–
–
trace
39
71
58
47
–
1:1
1.4:1
1.2:1
1.1:1
–
85/91
87/91
86/92
86/92
5d LiOTf, DBU, CH3CN, 508C, 48 h
5d LiOTf, DBU, CH3CN, 508C, 30 h
5d LiOTf, DBU, CH3CN, 508C, 15 h
[a] All reactions were carried out with glycinate 1a (0.15 mmol), 2a (0.10 mmol), 5
(0.010 mmol), LiOTf (0.040 mmol) and DBU (0.10 mmol) in solvent (0.30 mL) at
408C for 48 h unless otherwise stated. [b] Isolated yields based on 2a. [c] The trans/
cis ratios were determined by HPLC analysis. [d] The ee values were determined by
chiral HPLC analysis.
(E)-3-(2-fluorophenyl)acrylate (for 4k) and methyl (E)-3-(2-
bromophenyl)acrylate (for 4l) gave somewhat lower reaction
yields likely due to steric hindrance. The electronic property
of the substituted phenyl groups seemed to have little
influence on the enantioselectivity. Naphthyl (for 4n) and
heteroaromatic (for 4o–r) a,b-unsaturated esters both were
effective substrates for the transformation, providing the
corresponding chiral pyroglutamic acid esters 4n–r in 43–
96% yields with similar selectivities. Alkynyl and alkyl a,b-
unsaturated esters underwent the transformation to produce
chiral pyroglutamic acid esters 4s and 4t in 45% and 52%
yields, respectively. Disubstituted a,b-unsaturated ester
methyl (E)-2-methyl-3-phenylacrylate was less reactive for
the reaction likely due to steric hindrance, to give a pair of
diastereomers 4u with the 3-phenyl and 4-methyl groups on
the same side of the pyrrolidinone ring in a 14% yield with
excellent enantioselectivities. The trans/cis configurations of
Scheme 1. Chiral pyridoxals 5a–k examined.
as expected, producing the desired chiral pyroglutamic acid
ester 4a in a 47% yield with moderate enantioselectivities for
both of the diastereomers (Table 1, entry 3). Although the
diastereoselectivity was very low (trans/cis 1.2:1), fortunately
the big polarity difference between the two diastereomers
makes it easy to get them separated by column chromatog-
raphy. The pyridoxal catalyst is crucial for the reaction. No
desired addition products were observed in the absence of
pyridoxals 5 (Table 1, entry 1). To our surprise, N-methyl
chiral pyridoxal 5a was totally ineffective for the reaction
although it has very strong electron-withdrawing capability
1
the products 4a–u were determined by H-1H NOESY (see
Supporting Information). The absolute configurations for
trans-4a and cis-4p were, respectively assigned as (2R,3S) and
(2S,3S) based on X-ray analysis (Figure 2).[11]
While a precise mechanism awaits further studies, a plau-
sible pathway has been proposed for the reaction (Sche-
me 2a). Chiral pyridoxal 5d condenses with glycinate 1a to
Angew. Chem. Int. Ed. 2021, 60, 10588 –10592
ꢀ 2021 Wiley-VCH GmbH
www.angewandte.org 10589

Angewandte
Communications
Chemie
Table 2: Substrate scope investigation.[a]
Figure 2. The X-ray structures of trans-4a-amide and cis-4p.
[a] The reactions were carried out with glycinate 1a (0.45 mmol), 2
(0.30 mmol), (S)-5d (0.030 mmol), LiOTf (0.12 mmol), DBU
(0.30 mmol) in CH3CN (0.90 mL) at 408C for 48 h unless otherwise
stated. Reaction time was 96 h for 4t. Isolated yields based on 2. The
trans/cis ratios of 4a–t and the dr value of 4u were determined by
1H NMR analysis of the crude reaction mixtures. The ee values were
determined by chiral HPLC analysis. The absolute configurations of
trans-4a and cis-4p were, respectively determined as (2R,3S) and (2S,3S)
based on X-ray analysis.[11] The absolute configurations for trans-isomers
of products 4b–s were proposed as (2R,3S), cis-isomers of 4a–o and 4q–
s as (2S,3S), trans-4t as (2R,3R), and cis-4t as (2S,3R) by analogy.
Scheme 2. a) Proposed reaction mechanism. b) Computationally-opti-
mized transition state.
out for the key step, that is, asymmetric addition of carbon
anion 7 to a,b-unsaturated ester 2 (see SI). As shown in the
optimized transition state 8 (Scheme 2b), LiOTf coordinates
with both compound 2 and anion 7, which not only improves
the electrophilicity of the a,b-unsaturated ester but also
brings the two reactants together with a specific spatial
arrangement, accelerating the conjugated addition. This was
supported by the fact that no desired product 4 was obtained
without the Lewis acid additive (Table 1, entry 16 vs. 8 and
18). The N,N-propyl groups of the amide locate above the
pyridine ring of 5d, serving as a rigid and bulky group to block
the up side of the pyridine ring. The a,b-unsaturated ester 2
approaches the enolate anion from the below of the pyridine
form Schiff base 6, which is deprotonated[12] at the a position
of the ester by the base DBU to generate delocalized carbon
anion 7.[13] The intermediate 7 undergoes asymmetric 1,4-
conjugated addition to a,b-unsaturated ester 2 and subse-
quent hydrolysis to produce g-amino ester 3 and regenerate
the pyridoxal catalyst 5d. Compound 3 is in situ converted
into pyroglutamic acid ester 4 through intramolecular cycli-
zation.
In order to understand the role of LiOTf and the origin of
the chiral induction, computational studies has been carried
10590 www.angewandte.org
ꢀ 2021 Wiley-VCH GmbH
Angew. Chem. Int. Ed. 2021, 60, 10588 –10592

Angewandte
Communications
Chemie
ring, away from the amide side chain, resulting in the
formation of chiral product 4 with (2R,3S) configuration (if
the R in 4 is an aryl group) from (S)-5d. Pyridoxal 5j bearing
an ester side chain showed good catalytic activity but much
lower enantioselectivity as compared to 5d (Table 1, entry 12
vs. 8), although the ester group has similar ability to
coordinate with LiOTf as the amide of 5d, indicating the
amide doesnꢀt coordinate with LiOTf but provides steric
shielding for enantioselective control during catalysis.
Low trans/cis ratios were obtained for pyroglutamic acid
esters 4a–t in the reaction likely due to the epimerization
between the trans- and cis-isomers under the basic reaction
conditions (Table 2). As expected, control experiments
revealed that the two isomers trans-4a and cis-4a indeed
can be interconverted into each other under the standard
reaction conditions (Scheme 3a, entries 1–4). The epimeriza-
Scheme 4. Synthetic transformations.
As demonstrated in Scheme 4a, treatment of the pyro-
glutamic acid ester trans-4a with 2 M HCl may remove the
tert-butyl group to afford the corresponding pyroglutamic
acid trans-10a in 99% yield without any loss of enantiose-
lectivity. Although a mixture of trans and cis pyroglutamic
acid esters 4 were formed in the reaction (Table 2), both of
them can be readily converted into bioactive 4-substituted
pyrrolidin-2-ones with the same absolute configuration via
tert-butyl group removal and subsequent Barton decarbox-
ylation.[14] For example, Alzheimerꢀs drug (S)-Rolipram[15]
(11) can be synthesized with high enantiopurity from
a mixture of trans-4m and cis-4m via the reaction sequence
(Scheme 4b).
In summary, we have successfully realized direct asym-
metric a-functionalization of NH2-unprotected glycinate with
relatively weak electrophile a,b-unsaturated esters by using
carbonyl catalysis strategy. In the presence of chiral pyridoxal
catalyst 5d, asymmetric 1,4-conjugated addition of glycinate
1a at the a-position to a,b-unsaturated esters 2 and sub-
sequent in situ lactamization formed chiral pyroglutamic acid
esters 4 in 14–96% yields with 81–97% enantioselectivities,
providing an interesting and highly efficient way to make
chemically and biologically significant pyroglutamic acid
compounds. This work has also displayed the magic catalytic
power of pyridoxal structure in asymmetric catalysis.[16]
Acknowledgements
Scheme 3. a) Epimerization investigation. b) Reaction of alaninate 1b
with 2a.
We are grateful for the generous financial support from the
National Natural Science Foundation of China (21672148,
21871181), CAS (QYZDY-SSW-SLH012, XDB20000000),
the Shanghai Municipal Education Commission (2019-01-
07-00-02-E00029), and the Shanghai Engineering Research
Center of Green Energy Chemical Engineering.
tion also occurred when only in presence of the base DBU.
And similar trans/cis ratios (3.0:1 vs. 2.4:1) were obtained in
the experiments started from either trans-4a or cis-4a after
extended reaction time (144 h) (Scheme 3a, entries 5–10).
The epimerization during the reaction likely was faster than
the pyridoxal-catalyzed conjugated addition, which was
supported by the fact that the reactions carried out for
different times gave different yields but with similar trans/cis
ratios and ee values (Table 1, entries 23–25). For tert-butyl
alaninate (1b) with a a-substituent, the corresponding 2-
methyl pyroglutamic acid esters 4v were obtained in a lower
yield (10%) albeit with an obviously higher trans/cis selec-
tivity (4.1:1) (Scheme 3b),[11] further supporting the proposed
transition state for the asymmetric 1,4-addition step
(Scheme 2).
Conflict of interest
The authors declare no conflict of interest.
Keywords: asymmetric Michael addition · carbonyl catalysis ·
chiral pyridoxal · vitamin B6 · a-functionalization of amines
Angew. Chem. Int. Ed. 2021, 60, 10588 –10592
ꢀ 2021 Wiley-VCH GmbH
www.angewandte.org 10591

Angewandte
Communications
Chemie
750; c) V. A. Soloshonok, C. Cai, V. J. Hruby, Tetrahedron Lett.
2000, 41, 135 – 139; d) V. A. Soloshonok, C. Cai, V. J. Hruby,
L. V. Meervelt, T. Yamazaki, J. Org. Chem. 2000, 65, 6688 – 6696;
e) C. Cai, V. A. Soloshonok, V. J. Hruby, J. Org. Chem. 2001, 66,
1339 – 1350; f) V. A. Soloshonok, H. Ueki, R. Tiwari, C. Cai, V. J.
Hruby, J. Org. Chem. 2004, 69, 4984 – 4990; g) V. A. Soloshonok,
C. Cai, T. Yamada, H. Ueki, Y. Ohfune, V. J. Hruby, J. Am.
Chem. Soc. 2005, 127, 15296 – 15303; h) T. Yamada, K. Sakagu-
chi, T. Shinada, Y. Ohfune, V. A. Soloshonok, Tetrahedron:
Asymmetry 2008, 19, 2789 – 2795; i) M. Bergagnini, K. Fukushi, J.
Han, N. Shibata, C. Roussel, T. K. Ellis, J. L. AceÇa, V. A.
Soloshonok, Org. Biomol. Chem. 2014, 12, 1278 – 1291.
[7] a) S. Li, X.-Y. Chen, D. Enders, Chem 2018, 4, 2026 – 2028; b) Q.
Wang, Q. Gu, S.-L. You, Angew. Chem. Int. Ed. 2019, 58, 6818 –
6825; Angew. Chem. 2019, 131, 6890 – 6897; c) L.-Z. Gong, Sci.
China Chem. 2019, 62, 3 – 4.
[8] a) J. Chen, X. Gong, J. Li, Y. Li, J. Ma, C. Hou, G. Zhao, W. Yuan,
B. Zhao, Science 2018, 360, 1438 – 1442; b) J. Chen, Y. E. Liu, X.
Gong, L. Shi, B. Zhao, Chin. J. Chem. 2019, 37, 103 – 112.
[9] a) B. Xu, L.-L. Shi, Y.-Z. Zhang, Z.-J. Wu, L.-N. Fu, C.-Q. Luo,
L.-X. Zhang, Y.-G. Peng, Q.-X. Guo, Chem. Sci. 2014, 5, 1988 –
1991; b) W. Wen, L. Chen, M.-J. Luo, Y. Zhang, Y.-C. Chen, Q.
Ouyang, Q.-X. Guo, J. Am. Chem. Soc. 2018, 140, 9774 – 9780;
c) L. Chen, M.-J. Luo, F. Zhu, W. Wen, Q.-X. Guo, J. Am. Chem.
Soc. 2019, 141, 5159 – 5163.
[1] a) J. Deng, B. Zhu, Z. Lu, H. Yu, A. Li, J. Am. Chem. Soc. 2012,
134, 920 – 923; b) M. Kikuchi, H. Konno, Org. Lett. 2014, 16,
4324 – 4327; c) S. Chu, S. Liu, W. Duan, Y. Cheng, X. Jiang, C.
Zhu, K. Tang, R. Wang, L. Xu, X. Wang, X. Yu, K. Wu, Y. Wang,
M. Wang, H. Huang, J. Zhang, Pharmacol. Ther. 2016, 162, 179 –
187; d) W. Fenical, P. R. Jensen, M. A. Palladino, K. S. Lam,
G. K. Lloyd, B. C. Potts, Bioorg. Med. Chem. 2009, 17, 2175 –
2180; e) I. Speciale, F. Di Lorenzo, V. Gargiulo, G. Erbs, M.-A.
Newman, A. Molinaro, C. De Castro, Angew. Chem. Int. Ed.
2020, 59, 6368 – 6374; Angew. Chem. 2020, 132, 6430 – 6436.
[2] a) H. Mandal, P. K. Ghosh, N. M. Biswas, J. Endocrinol. 1990,
126, 431 – 435; b) D. Gunn, C. Akuche, J. Baryza, M.-L. Blue, C.
Brennan, A.-M. Campbell, S. Choi, J. Cook, P. Conrad, B. Dixon,
J. Dumas, P. Ehrlich, T. Gane, T. Joe, J. Johnson, J. Jordan, R.
Kramss, P. Liu, J. Levy, D. Lowe, I. McAlexander, R. Natero,
A. M. Redman, W. Scott, T. Seng, R. Sibley, M. Wang, Y. Wang,
J. Wood, Z. Zhang, Bioorg. Med. Chem. Lett. 2005, 15, 3053 –
3057; c) S. Hanessian, H. Yun, Y. Hou, G. Yang, M. Bayrakdar-
ian, E. Therrien, N. Moitessier, S. Roggo, S. Veenstra, M.
Tintelnot-Blomley, J.-M. Rondeau, C. Ostermeier, A. Strauss, P.
Ramage, P. Paganetti, U. Neumann, C. Betschart, J. Med. Chem.
2005, 48, 5175 – 5190; d) S. Hanessian, H. Yun, Y. Hou, M.
Tintelnot-Blomley, J. Org. Chem. 2005, 70, 6746 – 6756; e) J.-F.
Hu, S.-F. Chu, N. Ning, Y.-H. Yuan, W. Xue, N.-H. Chen, J.-T.
Zhang, Neurosci. Lett. 2010, 483, 78 – 82; f) S. Hong, M. Jung, Y.
Park, M. W. Ha, C. Park, M. Lee, H.-g. Park, Chem. Eur. J. 2013,
19, 9599 – 9605; g) T. Mukaiyama, K. Ogata, I. Sato, Y. Hayashi,
Chem. Eur. J. 2014, 20, 13583 – 13588; h) S. W. Wright, B. Li, Z.
Peng, L. Wei, E. McInturff, D. Place, D. B. Damon, R. A. Singer,
Org. Process Res. Dev. 2018, 22, 1835 – 1845.
[10] a) L. Shi, C. Tao, Q. Yang, Y. E. Liu, J. Chen, J. Chen, J. Tian, F.
Liu, B. Li, Y. Du, B. Zhao, Org. Lett. 2015, 17, 5784 – 5787;
b) Y. E. Liu, Z. Lu, B. Li, J. Tian, F. Liu, J. Zhao, C. Hou, Y. Li, L.
Niu, B. Zhao, J. Am. Chem. Soc. 2016, 138, 10730 – 10733; c) X.
Lan, C. Tao, X. Liu, A. Zhang, B. Zhao, Org. Lett. 2016, 18,
3658 – 3661.
[3] a) C. Nꢁjera, M. Yus, Tetrahedron: Asymmetry 1999, 10, 2245 –
2303; b) S. K. Panday, J. Prasad, D. K. Dikshit, Tetrahedron:
Asymmetry 2009, 20, 1581 – 1632.
[11] Deposition Numbers 2020782 (for cis-4p), 2020783 (for trans-4a-
amide), and 2042121 (for trans-4v) contain the supplementary
crystallographic data for this paper. These data are provided free
of charge by the joint Cambridge Crystallographic Data Centre
and Fachinformationszentrum Karlsruhe Access Structures
service www.ccdc.cam.ac.uk/structures.
[12] a) K. Toth, J. P. Richard, J. Am. Chem. Soc. 2007, 129, 3013 –
3021; b) J. Crugeiras, A. Rios, E. Riveiros, T. L. Amyes, J. P.
Richard, J. Am. Chem. Soc. 2008, 130, 2041 – 2050; c) J.
Crugeiras, A. Rios, E. Riveiros, J. P. Richard, J. Am. Chem.
Soc. 2011, 133, 3173 – 3183.
[13] a) S. Tang, X. Zhang, J. Sun, D. Niu, J. J. Chruma, Chem. Rev.
2018, 118, 10393 – 10457; b) W.-W. Chen, B. Zhao, Synlett 2020,
31, 1543 – 1550.
[14] a) A. Diaz, J. G. Siro, J. L. Garcꢂa-Navꢂo, J. J. Vaquero, J.
Alvarez-Builla, Synthesis 1997, 559 – 562; b) M.-Y. Chang, P.-P.
Sun, S.-T. Chen, N.-C. Chang, Tetrahedron Lett. 2003, 44, 5271 –
5273.
[15] a) N. Sommer, P.-A. Lçschmann, G. H. Northoff, M. Weller, A.
Steinbrecher, J. P. Steinbach, R. Lichtenfels, R. Meyermann, A.
Riethmꢃller, A. Fontana, J. Dichgans, R. Martin, Nat. Med. 1995,
1, 244 – 248; b) S. J. Kanes, J. Tokarczyk, S. J. Siegel, W. Bilker, T.
Abel, M. P. Kelly, Neuroscience 2007, 144, 239 – 246.
[16] a) M. D. Toney, Arch. Biochem. Biophys. 2005, 433, 279 – 287;
b) R. Breslow, Acc. Chem. Res. 1995, 28, 146 – 153; c) Y.
Murakami, J.-i. Kikuchi, Y. Hisaeda, O. Hayashida, Chem. Rev.
1996, 96, 721 – 758; d) Y. Xie, H. Pan, M. Liu, X. Xiao, Y. Shi,
Chem. Soc. Rev. 2015, 44, 1740 – 1748.
[4] a) A. El Achqar, M. Boumzebra, M.-L. Roumestant, P. Vialle-
font, Tetrahedron 1988, 44, 5319 – 5332; b) S. Kanemasa, A.
Tatsukawa, E. Wada, O. Tsuge, Chem. Lett. 1989, 18, 1301 – 1304;
c) C. Alvarez-Ibarra, A. G. Csakye, M. Maroto, M. L. Quiroga, J.
Org. Chem. 1995, 60, 6700 – 6705; d) P. Elsner, L. Bernardi, G. D.
Salla, J. Overgaard, K. A. Jørgensen, J. Am. Chem. Soc. 2008,
130, 4897 – 4905; e) T. Tsubogo, S. Saito, K. Seki, Y. Yamashita,
S. Kobayashi, J. Am. Chem. Soc. 2008, 130, 13321 – 13332; f) H.-
L. Teng, F.-L. Luo, H.-Y. Tao, C.-J. Wang, Org. Lett. 2011, 13,
5600 – 5603; g) J. Hernꢁndez-Toribio, R. G. Arrayꢁs, J. C. Carre-
tero, Chem. Eur. J. 2011, 17, 6334 – 6337; h) Y.-F. Liang, C.-C.
Chung, D.-J. Liao, W.-J. Lee, Y.-W. Tu, B.-J. Uang, J. Org. Chem.
2018, 83, 10564 – 10572; i) T. M. Khopade, P. K. Warghude, A. D.
Sonawane, R. G. Bhat, Org. Biomol. Chem. 2019, 17, 561 – 566.
[5] a) S. Saito, T. Tsubogo, S. Kobayashi, J. Am. Chem. Soc. 2007,
129, 5364 – 5365; b) M. Strohmeier, K. Leach, M. A. Zajac,
Angew. Chem. Int. Ed. 2011, 50, 12335 – 12338; Angew. Chem.
2011, 123, 12543 – 12546; c) T. Ma, X. Fu, C. W. Kee, L. Zong, Y.
Pan, K.-W. Huang, C.-H. Tan, J. Am. Chem. Soc. 2011, 133,
2828 – 2831; d) Z.-Y. Xue, Q.-H. Li, H.-Y. Tao, C.-J. Wang, J. Am.
Chem. Soc. 2011, 133, 11757 – 11765; e) H. Y. Kim, J.-Y. Li, S.
Kim, K. Oh, J. Am. Chem. Soc. 2011, 133, 20750 – 20753; f) Y.-H.
Shi, Z. Wang, B. Hu, M. Wang, J. S. Fossey, W.-P. Deng, Org. Lett.
2011, 13, 6010 – 6013; g) J. S. Bandar, T. H. Lambert, J. Am.
Chem. Soc. 2012, 134, 5552 – 5555; h) J. Nie, M.-Q. Hua, H.-Y.
Xiong, Y. Zheng, J.-A. Ma, J. Org. Chem. 2012, 77, 4209 – 4216;
i) K. Imae, T. Konno, K. Ogata, S.-i. Fukuzawa, Org. Lett. 2012,
14, 4410 – 4413.
Manuscript received: December 30, 2020
Revised manuscript received: January 28, 2021
Accepted manuscript online: February 8, 2021
Version of record online: March 30, 2021
[6] a) V. A. Soloshonok, C. Cai, V. J. Hruby, Angew. Chem. Int. Ed.
2000, 39, 2172 – 2175; Angew. Chem. 2000, 112, 2256 – 2259;
b) V. A. Soloshonok, C. Cai, V. J. Hruby, Org. Lett. 2000, 2, 747 –
10592 www.angewandte.org
ꢀ 2021 Wiley-VCH GmbH
Angew. Chem. Int. Ed. 2021, 60, 10588 –10592