Enantioselective Construction of Octahydroquinolines via Trienamine-Mediated Diels-Alder Reactions

Article abstract of DOI:10.1021/acs.orglett.9b00932

A trienamine-mediated asymmetric Diels-Alder reaction using a 5-nitro-2,3-dihydro-4-pyridone derivative as a dienophile in the presence of a secondary amine organocatalyst derived from cis-hydroxyproline was discovered. The reaction provides optically act

Full text of DOI:10.1021/acs.orglett.9b00932

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Enantioselective Construction of Octahydroquinolines via
Trienamine-Mediated Diels−Alder Reactions
Taichi Inoshita,† Kei Goshi,† Yuka Morinaga,† Yuhei Umeda,† and Hayato Ishikawa*,†,‡
†Department of Chemistry, Graduate School of Science and Technology, Kumamoto University, 2-39-1, Kurokami, Chuo-ku,
Kumamoto 860-8555, Japan
‡Faculty of Advanced Science and Technology, Kumamoto University, 2-39-1, Kurokami, Chuo-ku, Kumamoto 860-8555, Japan
S
* Supporting Information
ABSTRACT: A trienamine-mediated asymmetric Diels−
Alder reaction using a 5-nitro-2,3-dihydro-4-pyridone deriva-
tive as a dienophile in the presence of a secondary amine
organocatalyst derived from cis-hydroxyproline was discov-
ered. The reaction provides optically active octahydroquino-
lines through an endo-selective [4 + 2] cyclization pathway.
The following stereoselective denitration, isomerization, and/
or hydrogenation generated divergent stereoisomers of decahydroquinolines, which are useful synthons for the total synthesis of
Lycopodium alkaloids.
ecahydroquinoline scaffolds are present in a wide range
Dof natural products, and they are important pharmaco-
logically active structural units. In particular, Lycopodium
alkaloids, which are composed of complex ring structures and
present interesting biological activities, possess a multiply
substituted decahydroquinoline moiety (Figure 1a).1 These
alkaloids contain not only cis- or trans-fused decahydroquino-
lines but also several diastereomers at the C8 methyl group and
C10 alkyl group. Thus, the enantioselective synthesis of various
stereoisomers of decahydroquinolines is an important issue in
current natural product chemistry. Indeed, several synthetic
protocols to access optically active decahydroquinolines have
been reported.2 Since the advent of the 21st century, interest in
organocatalyzed asymmetric reactions has grown rapidly.3
Figure 1. (a) Alkaloids containing decahydroquinoline scaffolds
Asymmetric Diels−Alder reactions are commonly used
isolated from Lycopodium plants. (b) Enantioselective approach to a
methods that involve the application of organocatalysts to
construct multiply substituted ring systems. In 2011, Jørgensen
multiply substituted decahydroquinoline scaffold.
and Chen reported an enantioselective Diels−Alder reaction
that proceeded via a trienamine intermediate with a secondary
amine organocatalyst.4 Since their findings, several trienamine-
mediated Diels−Alder reactions including hetero-Diels−Alder
reactions have been reported.5 In this context, we envisaged
that 2,3-dihydro-4-pyridones may be suitable dienophiles
against activated chiral trienamines derived from a secondary
amine organocatalyst and α,β,γ,δ-unsaturated aldehydes to
provide chiral multiply substituted octahydroquinolines in one
step (Figure 1b). In 2002, the Diels−Alder approach to
construct octahydroquinolines using 5-ethoxycarbonyl-2,3-
dihydro-4-pyridone 1 in the presence of Danishefsky’s diene
was reported by the group of Dhimane et al.6 These methods
were carried out under Lewis acid conditions or at elevated
temperatures to provide achiral octahydroquinolines. To our
knowledge, this is the only example of 2,3-dihydro-4-pyridones
functioning as a dienophile.
Herein, we disclose secondary amine catalyzed enantio- and
diastereoselective Diels−Alder reactions using 5-nitro-2,3-
dihydro-4-pyridone as a dienophile in the presence of
α,β,γ,δ-unsaturated aldehydes to provide octahydroquinolines.
In addition, a wide variety of α,β,γ,δ-unsaturated aldehyde
substrates and derivatization to decahydroquinolines are
described together with an application of the method toward
the total synthesis of Lycopodium alkaloids.
Initially, 5-ethoxycarbonyl-2,3-dihydro-4-pyridone derivative
1, which was reported as a dienophile in the Diels−Alder
reaction by Dhimane et al., was employed as a substrate in the
presence of methylhexadienal 2 and a catalytic amount of
diphenylprolinol silyl ether A, which is known as the Hayashi−
Received: March 15, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00932
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Jørgensen catalyst (eq 1). The reaction was attempted under
various conditions, but no target compound was obtained.
NMR spectroscopic studies showed that dihydropyridone 1
did not react and that only aldehyde 2 decomposed by a self-
condensation reaction over time. Thus, it was suggested that
the ethoxycarbonyl group on the dihydropyridone was not
sufficiently electron-withdrawing to promote the desired
Diels−Alder reaction. Thus, a suitable dienophile with a
lower LUMO energy was required.
Table 1. Optimization of Diels−Alder Reaction Using 2,3-
a
Dihydro-4-pyridone
Considering alternative dienophile candidates, 5-nitro-2,3-
dihydropyridone derivative 3 was designed and synthesized.
Dihydropyridone 3 was prepared from commercially available
N-Boc-β-alanine in 58% yield as stable yellow crystals through
the application of two, one-pot operations (see details in the
Supporting Information). Thus, when the reaction was
performed with 5-nitro-2,3-dihydropyridone derivative 3 and
2.0 equiv of aldehyde 2 in the presence of 20 mol % catalyst A
in toluene for 9 h at ambient temperature, the desired Diels−
Alder product was obtained as a mixture of two diastereomers.
The obtained aldehyde was unstable on silica gel, and therefore
the crude mixture was treated with ethylene glycol in the
presence of 1 equiv of p-TsOH to provide acetal compounds 4
and 5 in 68% yield (two steps, dr = 1.4:1; isolatable major
isomer 4 in 40% yield, minor isomer 5 in 28% yield; Table 1,
entry 1). The enantiomeric excesses of compounds 4 and 5
were 83% and 40% ee, respectively. The structure of 4,
including relative and absolute stereochemistries, was
determined by X-ray analysis (Figure S1). We recognized
that the major isomer 4 was produced via an endo-cyclization
pathway. However, after recrystallization of compound 5,
crystals were obtained as a racemic mixture. The relative
stereochemistry of 5 was determined by X-ray crystallographic
analysis, although the absolute stereochemistry was not clear
(Figure S1). In addition, it is apparent that the minor product
was produced through an exo-cyclization pathway.
For optimization of the yield and enantioselectivity, a
number of catalysts were screened. When diphenylprolinol
diphenylmethylsilyl ether (B)7 was employed in the reaction, a
significant improvement in the yield was observed (85%; Table
1, entry 2; see also solvent screening in Table S1). With
satisfactory yields for the two-step protocol in hand, we
focused on improving the enantioselectivity to over 90% ee.
Then, 4-siloxycatalyst C8 which was prepared from trans-
hydroxy proline was employed. As a result, the enantiomeric
excess was slightly improved to 90% ee (Table 1, entry 3).
Next, cis-hydroxy proline derivative D was designed and
synthesized, because the steric bulk of the cis-4-siloxy group on
the proline core was expected to favor one orientation of the
diphenylmethylsilyl group (see details in the Supporting
Information for the synthesis of D). As expected, when
catalyst D was employed in the Diels−Alder reaction, the
enantiomeric excess was improved to 96% ee (Table 1, entry
4). In addition, the diastereomeric ratio was slightly improved
to 2.4:1. On the other hand, diarylprolinol silyl ether catalyst E
was not suitable for the reaction (Table 1, entry 5) because,
although both diastereomeric ratio and enantiomeric excess
cat. amount
[mol %]
equiv of
time
[h]
yield ee of 4
b
entry cat.
PhCO2H
dr
[%]
[%]
1
2
3
4
5
6
7
8
A
B
C
D
E
D
D
D
20
20
20
20
20
20
5
−
−
−
−
9
1.4:1
1.6:1
1.8:1
2.4:1
4.0:1
4.6:1
4.3:1
4.4:1
68
85
80
86
<10
96
80
88
83
87
90
96
95
96
96
96
6.5
6.5
6
120
2.5
15
15
−
1.0
1.0
0.75
c
5
a
Reaction conditions: 3 (0.1 mmol), 2 (0.2 mmol), and catalyst A−E
(0.02 or 0.005 mmol) in the presence of benzoic acid in toluene (0.25
mL) was stirred at 23 °C. Ethylene glycol (1.5 mmol) and p-TsOH·
H2O (0.1 mmol) were added to the crude mixture at 0 °C. See details
b
in the Supporting Information. The diastereomeric ratio was
c
1
determined by H NMR analysis of the crude mixture. 1 g of 3
was employed. See details in the Supporting Information.
were excellent, the reaction rate was too slow and the yield was
under 10% after 5 days of stirring.
After optimization of the reaction with respect to yield and
enantioselectivity, we then focused on reducing the catalyst
loading while maintaining an acceptable reaction time. Thus, a
number of acid additives were screened in an attempt to
accelerate the reaction (Table 1 and Table S2). When 1 equiv
of benzoic acid was added to the reaction mixture, the reaction
time decreased to 2.5 h (Table 1, entry 6). Fortunately, the
addition of benzoic acid had a positive effect, not only on the
reaction rate but also on both the yield and diastereoselectivity.
Thus, the yield was improved to almost quantitative and the
diastereomeric ratio reached 4.6:1. We then attempted to
reduce the catalyst loading. When the reaction was carried out
with 5 mol % catalyst under the above conditions, the reaction
reached completion in 15 h (80% yield, 94% ee; Table 1, entry
7). Given that the chemical yield was slightly decreased, the
amount of benzoic acid was reinvestigated. As a result, the use
of 75 mol % benzoic acid led to an excellent result (dr = 4.4:1,
88% yield, 96% ee; Table 1, entry 8; major compound 4 was
isolated in 72% in gram-scale quantities; see details in
Supporting Information).
Having established fully optimized conditions, the substrate
scope of the reaction with respect to the aldehyde was
examined (Figure 2). Simple hexadienal could be employed as
B
DOI: 10.1021/acs.orglett.9b00932
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
Scheme 1. Derivatization of Cycloadduct 4 toward Total
Synthesis of Lycopodium Alkaloids
examined (Scheme 1a). Thus, when cycloadduct 4 was treated
with catalytic 2,2′-azobisisobutyronitrile (AIBN) and 1 equiv
of n-Bu3SnH,9 cis-fused octahydroquinoline 15 was obtained
predominantly as the kinetic product (quant, dr = 3:1). The
cis-fused product 15 could be isomerized to thermodynami-
cally stable 16 by treatment with DBU in MeOH. Thus, after
addition of DBU to a diastereomer mixture of 15 and 16, the
diastereomeric ratio was shifted to 1:5 without loss of any
material. Next, diastereoselective hydrogenation of isolated cis-
fused octahydroquinoline 15 was carried out (Scheme 1b).
The concave-face-selective hydrogenation of 15 was accom-
plished by treatment with 5 mol % of Crabtree’s catalyst under
a hydrogen atmosphere to provide 17 in excellent yield (91%).
The stereochemistry of decahydroquinoline (DHQ) 17
corresponded to that of dihydrolycolucine (Figure 1a). The
trans-fused octahydroquinoline 16 was submitted to hydro-
genation reaction conditions with Pd−C to give 18, containing
an axial methyl group on C8, in excellent yield (82%);
hydrogenation proceeded at the equatorial site (Scheme 1c).
The relative stereochemistry of 18 matched that of the DHQ
ring of huperzine N. On the other hand, a senepodine F-type
dihydroquinoline ring 19 was obtained through thermody-
namic hydrogenation using Mn(dpm)3 and PhSiH3 in the
presence of TBHP10 with trans-fused octahydroquinoline 16 as
a substrate (Scheme 1c, 64%). The stereochemistries of the
obtained decahydroquinolines (17−19) were determined by
differential NOE experiments.
Figure 2. Substrate scope.
a diene to provide 6 in good yield and with excellent
enantioselectivity (dr = 3.0:1, 62% yield, 97% ee). In addition,
several aromatic groups were inserted at the C8 position of
octahydroquinolines. Thus, C8-phenyl- and naphthyl-substi-
tuted octahydroquinolines (7, 8) were obtained with high
diastereo- and enantioselectivity in good yield [7: dr = 10:1,
74% yield, 95% ee (Diels−Alder reaction was performed at 0
°C); 8: dr = 7.8:1, 73% yield, 95% ee]. Substrates with an
electron-withdrawing group on the phenyl, such as p-nitro, p-
bromo, and 3,5-bis(trifluoromethyl)phenyl groups, promoted
the Diels−Alder reaction; compounds 9−11 were obtained in
satisfactory yield with excellent stereoselectivity (9: dr = 10:1,
71% yield, 97% ee; 10: dr = 4.6:1, 84% yield, 95% ee; 11: dr =
4.5:1, 68% yield, 91% ee). Furthermore, compound 12, with a
3,5-dimethoxyphenyl group as an electron-rich aromatic group
at the C8 position, was efficiently obtained under the
optimized reaction conditions (dr = 5:1, 78% yield, 94% ee).
The presence of a sterically bulky substituent led to a slight
decrease in both the chemical yield and diastereoselectivity,
although the enantiomeric excess was excellent. Thus,
compound 13, which has a tert-butyl group at the C8 position,
was isolated in moderate yield and diastereomeric ratio (dr =
2.8:1, 52% yield, 92% ee). Finally, the preparation of product
14, which was substituted with methyl groups at the C8 and
C9 positions, was achieved (dr = 3.5:1, 71% yield, 90% ee).
Next, cycloadduct 4 was transformed into decahydroquino-
line toward the total synthesis of Lycopodium alkaloids
(Scheme 1). To construct the cis- and trans-decahydroquino-
line scaffold, diastereoselective removal of the nitro group was
In conclusion, we have developed trienamine-mediated
asymmetric Diels−Alder reactions using 5-nitro-2,3-dihydro-
4-pyridones as a dienophile. It is the first example in which 2,3-
dihydro-4-pyridone was employed in an asymmetric Diels−
Alder reaction. The C5-nitro group was required to decrease
the LUMO level of the dienophile. In addition, our designed
secondary amine organocatalyst, which was derived from cis-
C
DOI: 10.1021/acs.orglett.9b00932
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
(c) Amat, M.; Fabregat, R.; Griera, R.; Bosch, J. J. Org. Chem. 2009,
74, 1794−1797. (d) Evans, C. G.; Gestwicki, J. E. Org. Lett. 2009, 11,
2957−2959. (e) Tanaka, T.; Kogure, N.; Kitajima, M.; Takayama, H.
J. Org. Chem. 2009, 74, 8675−8680. (f) Rai, A.; Singh, A. K.; Singh,
P.; Yadav, D. S. Tetrahedron Lett. 2011, 52, 1354−1358. (g) Bradshaw,
B.; Luque-Corredera, C.; Bonjoch, J. Org. Lett. 2013, 15, 326−329.
(h) Bradshaw, B.; Luque-Corredera, C.; Saborit, G.; Cativiela, C.;
Dorel, R.; Bo, C.; Bonjoch, J. Chem. - Eur. J. 2013, 19, 13881−13892.
(i) Bradshaw, B.; Luque-Corredera, C.; Bonjoch, J. Chem. Commun.
2014, 50, 7099−7102. (j) Amat, M.; Pinto, A.; Griera, R.; Bosch, J.
hydroxyproline, provided an excellent yield and enantioselec-
tivity. Furthermore, several C8- and C9-substituted octahy-
droquinolines were prepared using our methodology. The
subsequent stereoselective denitration, isomerization, and/or
hydrogenation of multiply substituted octahydroquinolines
generated divergent stereoisomers of decahydroquinolines,
which are useful synthons for the total synthesis of Lycopodium
alkaloids. Further synthetic studies of Lycopodium alkaloids are
in progress in our group.
̀
Chem. - Eur. J. 2015, 21, 12804−12808. (k) Pinto, A.; Picciche, M.;
ASSOCIATED CONTENT
* Supporting Information
Griera, R.; Molins, E.; Bosch, J.; Amat, M. J. Org. Chem. 2018, 83,
8364−8375.
(3) For general reviews on asymmetric organocatalysis, see:
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00932.
̈
(a) Berkessel, A.; Groger, H. Asymmetric Organocatalysis; Wiley-
̈
VCH: Weinheim, 2005. (b) Erkkila, A.; Majander, I.; Pihko, P. M.
Chem. Rev. 2007, 107, 5416−5470. (c) Mukherjee, S.; Yang, J. W.;
Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471−5569. (d) Dalko,
P. I. Enantioselective Organocatalysis; Wiley-VCH: Weinheim, 2007.
(e) Gaunt, M. J.; Johansson, C. C. C.; McNally, A.; Vo, N. T. Drug
Discovery Today 2007, 12, 8−27. (f) Dondoni, A.; Massi, A. Angew.
Chem., Int. Ed. 2008, 47, 4638−4660. (g) Melchiorre, P.; Marigo, M.;
Carlone, A.; Bartoli, G. Angew. Chem., Int. Ed. 2008, 47, 6138−6171.
(h) Mielgo, A.; Palomo, C. Chem. - Asian J. 2008, 3, 922−948.
(i) Maruoka, K. Asymmetric Phase Transfer Catalysis; Wiley-VCH:
Weinheim, 2008. (j) Bertelsen, S.; Jørgensen, K. A. Chem. Soc. Rev.
2009, 38, 2178−2189. (k) Shoji, M.; Hayashi, Y. In Modern Tools for
the Synthesis of Complex Bioactive Molecules; Cossy, J., Arseniyadis, S.,
Eds.; Wiley: Hoboken, NJ, 2012; pp 189−212. (l) Christmann, M.;
Figure S1, Tables S1 and S2, and experimental details
and characterization data for all new compounds (PDF)
Accession Codes
CCDC 1903409 and 1903439 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
̈
Brase, S. Asymmetric Synthesis II: More Methods and Applications;
■
Wiley: 2013. (m) Gotoh, H.; Hayashi, Y. In Sustainable Catalysis;
Dunn, P. J., Hii, K. K., Krische, M. J., Williams, M. T., Eds.; John
Wiley & Sons Inc: NJ, 2013; pp 287−316. (n) Mase, N.; Hayashi, Y.
In Comprehensive Organic Synthesis, 2nd ed.; Knochel, P., Molander,
G. A., Mikami, K., Eds.; Elsevier: Amsterdam, 2014; pp 273−339.
(o) Sun, B.-F. Tetrahedron Lett. 2015, 56, 2133−2140. (p) Ishikawa,
H.; Shiomi, S. Org. Biomol. Chem. 2016, 14, 409−424. (q) Ishikawa,
Corresponding Author
*E-mail: h_ishikawa@kumamoto-u.ac.jp.
ORCID
Hayato Ishikawa: 0000-0002-3884-2583
Notes
̈
H.; Shiomi, S. In The Alkaloids; Knolker, H.-J., Ed.; Elsevier: 2018;
Vol. 79, pp 1−70.
The authors declare no competing financial interest.
(4) (a) Jia, Z.-J.; Jiang, H.; Li, J.-L.; Gschwend, B.; Li, Q.-Z.; Yin, X.;
Grouleff, J.; Chen, Y.-C.; Jørgensen, K. A. J. Am. Chem. Soc. 2011, 133,
5053−5061. (b) Jia, Z.-J.; Zhou, Q.; Zhou, Q.-Q.; Chen, P.-Q.; Chen,
Y.-C. Angew. Chem., Int. Ed. 2011, 50, 8638−8641.
ACKNOWLEDGMENTS
■
We gratefully acknowledge financial support through a Grant-
in-Aid for Scientific Research (B) (17H03059) from JSPS and
the Naito Foundation. We also wish to thank Prof. Hyuma
Masu (Chiba University) and Prof. Noriyuki Kogure (Chiba
University) for help in single crystal X-ray diffraction analysis.
(5) For reviews on trienamine-mediated reactions, see: (a) Kumar,
I.; Ramaraju, P.; Mir, N. A. Org. Biomol. Chem. 2013, 11, 709−716.
(b) Halskov, K. S.; Donslund, B. S.; Paz, B. M.; Jørgensen, K. A. Acc.
Chem. Res. 2016, 49, 974−986. For examples of aminocatalytic
reactions via trienamine or related intermediates, see: (c) Liu, Y.;
Nappi, M.; Arceo, E.; Vera, S.; Melchiorre, P. J. Am. Chem. Soc. 2011,
133, 15212−15218. (d) Xiong, X.-F.; Zhou, Q.; Gu, J.; Dong, L.; Liu,
T.-Y.; Chen, Y.-C. Angew. Chem., Int. Ed. 2012, 51, 4401−4404.
(e) Liu, Y.; Nappi, M.; Escudero-Adan, E. C.; Melchiorre, P. Org. Lett.
2012, 14, 1310−1313. (f) Halskov, K. S.; Johansen, T. K.; Davis, R.
L.; Steurer, M.; Jensen, F.; Jørgensen, K. A. J. Am. Chem. Soc. 2012,
134, 12943−12946. (g) Albrecht, Ł.; Acosta, F. C.; Fraile, A.;
Albrecht, A.; Christensen, J.; Jørgensen, K. A. Angew. Chem., Int. Ed.
2012, 51, 9088−9092. (h) Jiang, H.; Rodriguez-Escrich, C.; Johansen,
T. K.; Davis, R. L.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2012, 51,
10271−10274. (i) Jiang, H.; Cruz, D. C.; Li, Y.; Lauridsen, V. H.;
Jørgensen, K. A. J. Am. Chem. Soc. 2013, 135, 5200−5207. (j) Ma, C.;
Jia, Z.-J.; Liu, J.-X.; Zhou, Q.-Q.; Dong, L.; Chen, Y.-C. Angew. Chem.,
Int. Ed. 2013, 52, 948−951. (k) Dieckmann, A.; Breugst, M.; Houk, K.
REFERENCES
■
(1) For isolation of dihydrolycolucine, see: (a) Ayer, W. A.; Browne,
L. M.; Nakahara, Y.; Tori, M.; Delbaere, L. T. Can. J. Chem. 1979, 57,
1105−1107. (b) Tori, M.; Shimoji, T.; Shimura, E.; Takaoka, S.;
Nakashima, K.; Sono, M.; Ayer, W. A. Phytochemistry 2000, 53, 503−
509. For isolation and structure determination of huperzine N, see:
(c) Gao, W. Y.; Li, Y. M.; Jiang, S. H.; Zhu, D. Y. Helv. Chim. Acta
2008, 91, 1031−1035. (d) Saborit, G. V.; Bosch, C.; Parella, T.;
Bradshaw, B.; Bonjoch, J. J. Org. Chem. 2016, 81, 2629−2634. For
isolation of senepodine F, see: (e) Hirasawa, Y.; Morita, H.;
Kobayashi, J. Heterocycles 2004, 64, 515−521. For recent reviews,
see: (f) Ayer, W. A.; Trifonov, L. S. In The Alkaloids; Cordell, G. A.,
Brossi, A., Eds.; Academic Press: New York, 1994; Vol. 45, pp 233−
266. (g) Ma, X.; Gang, D. R. Nat. Prod. Rep. 2004, 21, 752−772.
(h) Kobayashi, J.; Morita, H. In The Alkaloids; Cordell, G. A., Ed.;
Academic Press: New York, 2005; Vol. 61, pp 1−57. (i) Hirasawa, Y.;
Kobayashi, J.; Morita, H. Heterocycles 2009, 77, 679−729.
(j) Siengalewicz, P.; Mulzer, J.; Rinner, U. In The Alkaloids;
́
N. J. Am. Chem. Soc. 2013, 135, 3237−3242. (l) Albrecht, Ł.; Gomez,
C. V.; Jacobsen, C. B.; Jørgensen, K. A. Org. Lett. 2013, 15, 3010−
3013. (m) Prieto, L.; Talavera, G.; Uria, U.; Reyes, E.; Vicario, J. L.;
́
̈
Carrillo, L. Chem. - Eur. J. 2014, 20, 2145−2148. (n) Li, Y.; Lopez-
Knolker, H.-J., Ed.; Elsevier: 2013; Vol. 72, pp 1−152.
Delgado, F. J.; Jørgensen, D. K. B.; Nielsen, R. P.; Jiang, H.;
Jørgensen, K. A. Chem. Commun. 2014, 50, 15689−15691. (o) Zhou,
Q.-Q.; Xiao, Y. C.; Yuan, X.; Chen, Y. C. Asian J. Org. Chem. 2014, 3,
(2) (a) Galbo, F. L.; Occhiato, E. G.; Guarna, A.; Faggi, C. J. Org.
Chem. 2003, 68, 6360−6368. (b) Amat, M.; Griera, R.; Fabregat, R.;
Molins, E.; Bosch, J. Angew. Chem., Int. Ed. 2008, 47, 3348−3351.
D
DOI: 10.1021/acs.orglett.9b00932
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
545−549. (p) Su, Z.; Kim, C. K. Org. Biomol. Chem. 2015, 13, 6313−
́
6324. (q) Roca-Lopez, D.; Uria, U.; Reyes, E.; Carrillo, L.; Jørgensen,
K. A.; Vicario, J. L.; Merino, P. Chem. - Eur. J. 2016, 22, 884−889.
́
(r) Skrzynska, A.; Przydacz, A.; Albrecht, Ł. Org. Lett. 2015, 17,
5682−5685. (s) Gu, J.; Xiao, B.-X.; Chen, Y.-R.; Du, W.; Chen, Y.-C.
Adv. Synth. Catal. 2016, 358, 296−302. (t) Li, Y.; Tur, F.; Nielsen, R.
P.; Jiang, H.; Jensen, F.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2016,
́
55, 1020−1024. (u) Albrecht, A.; Skrzynska, A.; Pietrzak, A.;
Bojanowski, J.; Albrecht, Ł. Asian J. Org. Chem. 2016, 5, 1115−
1119. (v) Donslund, B. S.; Nielsen, R. P.; Mønsted, S. M. N.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 2016, 55, 11124−11128.
(w) Chintalapudi, V.; Galvin, E. A.; Greenaway, R. L.; Anderson, E. A.
Chem. Commun. 2016, 52, 693−696. (x) Yuan, X.; Zhang, S.-J.; Du,
W.; Chen, Y.-C. Chem. - Eur. J. 2016, 22, 11048−11052. (y) Li, Y.;
Barløse, C.; Jørgensen, J.; Carlsen, B. D.; Jørgensen, K. A. Chem. - Eur.
J. 2017, 23, 38−41. (z) Xiao, B.-X.; Du, W.; Chen, Y.-C. Adv. Synth.
Catal. 2017, 359, 1018−1027. (aa) He, X.-L.; Zhao, H.-R.; Duan, C.-
Q.; Du, W.; Chen, Y. C. Org. Lett. 2018, 20, 804−807.
́
(6) Dhimane, H.; Meunier, S.; Vanucci-Bacque, C.; Lhommet, G.
Tetrahedron Lett. 2002, 43, 1645−1648.
̌
(7) Groselj, U.; Seebach, D.; Badine, D. M.; Schweizer, W. B.; Beck,
A. K.; Krossing, I.; Klose, P.; Hayashi, Y.; Uchimaru, T. Helv. Chim.
Acta 2009, 92, 1225−1259.
(8) Caruana, L.; Kniep, F.; Johansen, T. K.; Poulsen, P. H.;
Jørgensen, K. A. J. Am. Chem. Soc. 2014, 136, 15929−15932.
(9) Kim, W. H.; Lee, J. H.; Danishefsky, S. J. J. Am. Chem. Soc. 2009,
131, 12576−12578.
(10) (a) Crossley, S. W. M.; Obradors, C.; Martinez, R. M.; Shenvi,
R. A. Chem. Rev. 2016, 116, 8912−9000. (b) Iwasaki, K.; Wan, K. K.;
Oppedisano, A.; Crossley, S. W. M.; Shenvi, R. A. J. Am. Chem. Soc.
2014, 136, 1300−1303.
E
DOI: 10.1021/acs.orglett.9b00932
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