Asymmetric Organocatalyzed Reaction Sequence to Synthesize Chiral Bridged and Spiro-Bridged Benzofused Aminals via Divergent Pathways

Article abstract of DOI:10.1021/acs.orglett.9b01874

A highly efficient asymmetric organocatalysis-triggered reaction sequence is developed. 2-Hydroxy cinnamaldehydes and cyclic N-sulfonyl ketimines were both used as multisite substrates (more than two reactive sites) to access structurally diverse chiral b

Full text of DOI:10.1021/acs.orglett.9b01874

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Asymmetric Organocatalyzed Reaction Sequence To Synthesize
Chiral Bridged and Spiro-Bridged Benzofused Aminals via Divergent
Pathways
Ying-Han Chen,† Xue-Jiao Lv,† Zhi-Hao You,† and Yan-Kai Liu*,†,‡
†Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China,
Qingdao 266003, China
‡Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao
266003, China
S
* Supporting Information
ABSTRACT: A highly efficient asymmetric organocatalysis-
triggered reaction sequence is developed. 2-Hydroxy cinna-
maldehydes and cyclic N-sulfonyl ketimines were both used as
multisite substrates (more than two reactive sites) to access
structurally diverse chiral bridged and spiro-bridged benzo-
fused aminal derivatives, where an inseparable equilibrating
mixture of isomers can be regioselectively converted into
bridged benzofused aminals with different ring connectivities
via divergent pathways. Several stereoselective transformations
of the resulted bridged aminals are presented.
date, which thus remains an important but challenging task in
asymmetric synthesis.
he efficient construction of molecules of medicinal
Tinterest is an important area of drug discovery and has
thus attracted considerable attention from both synthetic and
medicinal chemists. The bridged aminal skeleton,1 especially
its benzofused form,2 can be found in numerous natural and
synthetic products, many of which have been reported to
exhibit intriguing biological activities (Scheme 1, top left);
however, despite their medicinal interest, to the best of our
knowledge all of the reported methodologies focused on only
their racemic synthesis,3 and the development of method-
ologies for the catalytic asymmetric construction of a chiral
bridged benzofused aminal skeleton has not been reported to
The cyclic N-sulfonyl ketimines, which can be easily
prepared from the commercially available saccharin, have
been well studied and applied in a variety of asymmetric
organocatalytic transformations as bifunctional substrates to
construct fused rather than bridged polycyclic compounds,4
and during the sequential reaction processes, the base-
catalyzed or spontaneous imine-enamine tautomerization
generated the key nitrogen nucleophile for the intramolecular
cyclization, leading to fused cyclic hemiaminal intermediates,
followed by reduction and oxidation, respectively, to give the
corresponding piperidine and 2-piperidinone scaffolds, which
are the key component of the bridged benzofused aminals A
and B (Scheme 1, top right).
Scheme 1. Different Bridged Aminal Scaffolds and Our
Previous Work
On the basis of structural analysis, both the benzofused
aminals A and B have in common a 2,4-disubstituted
chromane moiety in their bridged ring system. We recently
found that 2-hydroxy cinnamaldehydes have the unique
advantage of installing the 2,4-disubstituted chromane moiety
in a bridged ring system through a conjugate addition-triggered
reaction sequence (Scheme 1, bottom),5 where the acid-
promoted keto−enol tautomerization provides the required
oxygen nucleophile in the oxocarbenium-ion-induced acetal
formation process.
The control or switching of chemical equilibrium toward
diverse product formation has been a versatile tool for
Received: May 30, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01874
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
synthetic chemists.6 As shown in Scheme 2, we proposed that
the diphenylprolinol-silyl-ether-3-catalyzed conjugate addition
We initially attempted the reaction of cyclic N-sulfonyl
ketimine 4a with 2-hydroxy cinnamaldehyde 1a in the presence
of aminocatalyst 3 and in the absence of any additive (Scheme
3). To our surprise, the reaction proceeded smoothly in
Scheme 2. Design of Synthetic Strategies
Scheme 3. Divergent Reaction Pathways for the Reaction
Sequence of 1a and 4a
CH2Cl2 solvent at 25 °C but afforded an inseparable
equilibrating mixture of isomers, which could possibly be the
result of the above-mentioned two competitive reaction
pathways. Unexpectedly, we found that the oxidation of this
reaction mixture with pyridinium chlorochromate (PCC) in a
one-pot procedure provided the spiro-bridged benzofused
aminal 6a bearing a quaternary stereogenic center as the sole
product in good yield with excellent enantioselectivity as a
single diastereomer, and no isolable oxidation product 9a was
obtained. On the contrary, the dehydration of this mixture in
CH2Cl2 solvent at 25 °C catalyzed by the p-toluenesulfonic
acid (p-TsOH) resulted in two separable regioisomeric
products, the spiro-bridged aminal 7a and the bridged
polycyclic aminal 8a. Interestingly, 7a was found to be less
stable under such acidic conditions at 25 °C with increasing
reaction time and was gradually converted into 8a with
excellent regio- and stereocontrol.12
Next, we investigated the substrate scope with respect to 2-
hydroxy cinnamaldehydes for constructing the spiro-bridged
aminal 6 and the bridged polycyclic aminal 8 by reaction with
cyclic N-sulfonyl ketimine 4a via the conjugate addition−
oxidation sequence and the conjugate addition−dehydration
sequence, respectively. As shown in Scheme 4 (Cbz =
carboxybenzyl; Boc = tert-butoxycarbonyl), the 2-hydroxy
cinnamaldehydes having substituents at different positions of
the phenyl ring, regardless of their electronic properties,
of cyclic N-sulfonyl ketimine 4a to 2-hydroxy cinnamaldehyde
1a by asymmetric iminium catalysis would regioselectively
deliver two multifunctional intermediates I and II, which are at
the very least in equilibrium in the reaction mixture that might
introduce two competitive reaction pathways, path a and path
b, leading to structurally diverse heterocyclic compounds. In
path a, the ketimine with a sulfonyl group is expected to be
attacked first by the phenolic hydroxyl group to give the
spirocyclic four-substituted chroman-2-amine intermediate I,
followed by an intramolecular cyclization reaction delivering
hemiaminal product 5a, which could be converted into either
the spiro-bridged benzofused aminal 6a under oxidative
reaction conditions or the spiro-bridged benzofused aminal
7a through the acid-promoted dehydration. Whereas, in path
b, the formation of the four-substituted chroman-2-ol
intermediate II would be accomplished by the attack of the
phenolic hydroxyl group on the aldehyde group, and the acid-
promoted oxocarbenium ion-formation-induced cyclization
procedure would form the bridged polycyclic structure 8a.
Meanwhile, the oxidation of hemiacetal intermediate II would
enable the formation of the four-substituted chroman-2-one
product 9a. Accordingly, the key issue we hoped to address in
this study was the chemo- and regioselectivity of this
asymmetric organocatalyzed reaction sequence to furnish the
structurally diversified chiral bridged and spiro-bridged
benzofused aminal products.
Scheme 4. Substrate Scope of the Reaction of 1 and 4 To
Construct Spiro-Bridged Aminals 6 and Bridged Benzofused
Aminals 8
In our continuing effort on the construction of fused
polycyclic acetal7 and aminal8 compounds, herein we report a
highly regio- and stereoselective reaction sequence triggered by
the asymmetric organocatalytic conjugate addition of cyclic N-
sulfonyl ketimines to 2-hydroxy cinnamaldehydes, thus
providing structurally diversified bridged and spiro-bridged
benzofused aminal products.9 Although both cyclic N-sulfonyl
ketimines4 and 2-hydroxy cinnamaldehydes10 are very useful
synthons in asymmetric organocatalytic transformations, to the
best of our knowledge, they have been used for the first time as
multisite substrates (more than two reactive sites),11 which
showed unique advantages in the construction of chiral bridged
benzofused polycyclic ring system.
B
DOI: 10.1021/acs.orglett.9b01874
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
performed well in the designed two-step reaction sequence in
one pot, giving the corresponding spiro-bridged benzofused
aminal products 6a−g and bridged benzofused aminal
products 8a−f, respectively, in moderate to good yield with
high stereoselectivities. Notably, product 8g with a methyl
substituent could also be obtained with high levels of
stereocontrol. To our delight, N-Boc- and N-Cbz-protected
2-amino cinnamaldehyde are also suitable substrates, giving
bridged benzofused N,N-acetal products 8h and 8i in good
yield, albeit a slightly lower enantioselectivity was detected for
8i. Furthermore, reactions on a 1 mmol scale gave compounds
6a and 8a with similar results as the reactions carried out on a
0.1 mmol scale.
Scheme 6. Substrate Scope of the Reaction of 1a and 10 To
Construct Four-Substituted Chromane-2-ones 12 and
Bridged Benzofused Aminals 13
However, during the evaluation of the substrate scope of the
cyclic N-sulfonyl ketimines, we found that the steric hindrance
effect arising from the ring size of the cyclic N-sulfonyl
ketimines has critical effects on the reactivity of these
substrates (Scheme 5) because the reaction of the six-
Scheme 5. Different Behaviors of Six-Membered Cyclic N-
Sulfonyl Ketimine 10a
modification of the enamine moiety in the structure of 13
(Scheme 7; for a proposed mechanism, see Scheme S1).13 By
Scheme 7. Synthetic Transformations of 13 via Oxidative
Cleavage
membered cyclic N-sulfonyl ketimine 10a with 2-hydroxy
cinnamaldehyde 1a gave only the four-substituted chroman-2-
ol intermediate 11a, the structure of which was unequivocally
identified by nuclear magnetic resonance (NMR) spectrosco-
py, whereas the product derived from competitive path a (see
Scheme 2) was not detected under the same catalytic
conditions as those above. Subsequently, the obtained
hemiacetal product 11a can be readily oxidized in one pot,
resulting in four-substituted chromane-2-one 12a. Delightfully,
the bridged benzofused aminal 13a could be efficiently
accessed by a one-pot acid-catalyzed enamine-oxonium
cyclization procedure.
The substrate scope for the asymmetric conjugate-addition-
triggered reaction sequence of the six-membered cyclic N-
sulfonyl ketimines 10 to 2-hydroxy cinnamaldehyde 1a was
then investigated, and the results are summarized in Scheme 6.
When the R substituents on the aromatic rings of the six-
membered cyclic N-sulfonyl ketimines 10 were varied,
regardless of the positions and the electronic nature, good
yields and high stereoselectivities were achieved for four-
substituted chromane-2-one products 12a−f and the bridged
benzofused aminals 13a−e, respectively. When the phenyl ring
was replaced by a naphthalene group, similar good results were
obtained for product 12h. Notably, by changing the phenolic
oxygen atom in six-membered cyclic N-sulfonyl ketimine to a
nitrogen atom, the two sequential processes preceded
smoothly, leading to the desired products four-substituted
chromane-2-one product 12g and the bridged benzofused
aminal 13f, respectively, in good yield with high stereo-
selectivities.
treatment with m-chloroperbenzoic acid (m-CPBA), the
enamine moiety in 13a could undergo an epoxidation reaction,
followed by oxirane cleavage and double Baeyer−Villiger
oxidation, leading to 4-chromanol derivative 14a.14 It is
observed that the electronic effects of the substituents on the
aromatic ring of N-sulfonyl ketimine play a critical role in this
cascade transformation. An electron-withdrawing group, such
as the fluorine atom, on the benzene ring could effectively take
part in the reaction, providing 14c as the only product, whereas
upon introducing a methyl group instead of fluorine atom, the
normal aminal product 14d accompanied by the unexpected
bridged aminal 15d was obtained in a 2:1 ratio (based on the
isolated yield). Because of the electron-donating effect of the
methyl group, we proposed that there should be a Dakin-type
rearrangement after the epoxidation step to yield the
substituted phenol product. As expected, the stronger
electron-donating effect of the methoxy group on the ortho
and para positions resulted in the formation of the bridged
aminals 15b and 15e, respectively, as the sole products in 79
and 61% yield.
As illustrated in Scheme 8, the hydrogenation of 8a in the
presence of Pd/C as the catalyst resulted in the formation of
bridged aminal 16 with excellent diastereoselectivity. Addi-
tionally, the four-substituted chromane-2-one product 9a could
be readily obtained after the in situ hydrolysis of 6a under
acidic conditions (33% HBr in AcOH at reflux), which could
not be accessed through the oxidation of the reaction mixture
resulting from the conjugate addition of 1a and 4a.
To investigate the synthetic utility of these bridged
benzofused aminals, we focused our attention on the
C
DOI: 10.1021/acs.orglett.9b01874
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
evaluation of the obtained aminal products is now underway
and will be reported in due course.
Scheme 8. Preparation of Four-Substituted Chromane-2-
one 9a and Bridged Aminal 16
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01874.
Detailed optimization, complete experimental proce-
dures, spectroscopic data for all new compounds, X-ray
data, and proposed reaction mechanism for the
formation of compounds 14 and 15 (PDF)
Accession Codes
The structures and stereochemistries of 6a (CCDC
1915200), 8a (CCDC 1913911), 14d (CCDC 1913912),
and TBS-protected 17 (CCDC 1918877) were unambiguously
determined by single-crystal X-ray analysis (Figure 1; the H
CCDC 1913911−1913912, 1915200, and 1918877 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
■
Corresponding Author
*E-mail: liuyankai@ouc.edu.cn.
ORCID
Yan-Kai Liu: 0000-0002-6559-2348
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the NSFC-Shandong Joint Fund
for Marine Science Research Centers (no. U1606403), the
National Science and Technology Major Project for Significant
New Drugs Development (no. 2018ZX09735004), and the
Scientific and Technological Innovation Project Financially
Supported by Qingdao National Laboratory for Marine
Science and Technology (no. 2015ASKJ02-06).
Figure 1. X-ray structures of compounds 6a, 8a, 14d, and 17.
atoms are omitted for clarity; TBS = tert-butyldimethylsilyl;
DMAP = 4-dimethylaminopyridine). All other compound
structures were assigned by analogy assuming a uniform
reaction pathway. The relative stereochemistry of the novel
chiral center in product 16 was confirmed by nuclear
Overhauser effect (NOE) experiments (see the Supporting
Information).
REFERENCES
■
(1) (a) Hao, X.-J.; Node, M.; Taga, T.; Miwa, Y.; Zhou, J.; Chen, S.;
Fuji, K. The structures of four new diterpene alkaloids, spiramines A,
B, C, and D. Chem. Pharm. Bull. 1987, 35, 1670. (b) Awang, K.; Pais,
M.; Sevenet, T.; Schaller, H.; Nasir, A. M.; Hadi, A. H. A.
Eburnaminol and Larutensine, Alkaloids from Kopsia-Larutensis.
Phytochemistry 1991, 30, 3164. (c) Hao, X.-J.; Hong, X.; Yang, X.-S.;
Zhao, B.-T. Diterpene alkaloids from roots of Spiraea japonica.
Phytochemistry 1995, 38, 545. (d) Jossang, A.; El Bitar, H.; Pham, V.
C.; Sevenet, T. Daphcalycine, a novel heptacycle fused ring system
alkaloid from Daphniphyllum calycinum. J. Org. Chem. 2003, 68, 300.
(e) Shigemori, H.; Kagata, T.; Ishiyama, H.; Morah, F.; Ohsaki, A.;
Kobayashi, J. new monoterpene indole alkaloids from Nauclea
latifolia. Chem. Pharm. Bull. 2003, 51, 58. (f) Zhang, C.-R.; Liu, H.-
B.; Dong, S.-H.; Zhu, J.-Y.; Wu, Y.; Yue, J.-M. Calycinumines A and B,
two novel alkaloids from Daphniphyllum calycinum. Org. Lett. 2009,
11, 4692.
In summary, we have developed an asymmetric organo-
catalysis triggered reaction sequence of cyclic N-sulfonyl
ketimines to 2-hydroxy cinnamaldehydes, which provides an
efficient protocol for the enantioselective synthesis of
structurally diverse chiral bridged and spiro-bridged benzo-
fused aminal derivatives with high levels of regio- and
stereocontrol. It should be noted that the first conjugate
addition step of the developed reaction sequence afforded an
inseparable equilibrating mixture of isomers, which could be
converted into bridged aminal products with different ring
connectivities through divergent pathways. Additionally, the
steric hindrance effect arising from the ring size of the cyclic N-
sulfonyl ketimines has critical effects on the regioselectivity of
the sequential process because the cyclic N-sulfonyl ketimines
with different ring sizes provided different types of heterocyclic
products. Furthermore, several chemical transformations were
conducted to extend the structural complexity and diversity of
both the bridged and spiro-bridged aminals. The medicinal
(2) (a) Baldwin, J. J.; Claremon, D. A.; Lumma, P. K.; McClure, D.
E.; Rosenthal, S. A.; Winquist, R. J.; Faison, E. P.; Kaczorowski, G. J.;
Trumble, M. J.; Smith, G. M. Diethyl 3,6-dihydro-2,4-dimethyl-2,6-
methano-1,3-benzothiazocine-5,11-dicarboxylates as calcium entry
antagonists: new conformationally restrained analogs of Hantzsch
1,4-dihydropyridines related to nitrendipine as probes for receptor-
̈
site conformation. J. Med. Chem. 1987, 30, 690. (b) Jonsson, D.;
D
DOI: 10.1021/acs.orglett.9b01874
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
́
Erlandsson, M.; Unden, A. Solid-phase synthesis of oxygen-bridged
tetrahydropyridones. Tetrahedron Lett. 2001, 42, 6953. (c) Biała, J.;
Czarnocki, Z.; Maurin, J. K. Diastereoselective synthesis of lortal-
amine analogs. Tetrahedron: Asymmetry 2002, 13, 1021. (d) Lin, K.-S.;
Ding, Y.-S. Synthesis and C-11 labeling of three potent norepinephr-
ine transporter selective ligands ((R)-nisoxetine, lortalamine, and
oxaprotiline) for comparative PET studies in baboons. Bioorg. Med.
Chem. 2005, 13, 4658. (e) Deredas, D.; Albrecht, Ł.; Maniukiewicz,
(5) Lv, X.-J.; Chen, Y.-H.; Liu, Y.-K. Two competitive but switchable
organocatalytic cascade reaction pathways: the diversified synthesis of
chiral acetal-containing bridged cyclic compounds. Org. Lett. 2019,
21, 190.
(6) Thottiparambil, A.; Purushothaman, I.; De, S.; Parameswaran,
P.; Beegum, P. S.; Antharjanam, P. K. S.; Chakkumkumarath, L.
Differential reactivity of 3H-indole styrylcyanines: Intermolecular [4π
+ 2π] cycloaddition vs. proton-shift coupled six-electron electro-
cyclization. Tetrahedron 2018, 74, 2999.
́
W.; Wojciechowski, J.; Wolf, W. M.; Paluch, P.; Janecki, T.; Rozalski,
̇
M.; Krajewska, U.; Janecka, A.; Krawczyk, H. Three-component
reaction of 3-(diethoxyphosphoryl)coumarin, enolizable ketones and
primary amines: Simple, stereoselective synthesis of benzo[1,3]-
oxazocine skeletons. RSC Adv. 2013, 3, 6821.
(7) (a) Chen, Y.-H.; Sun, X.-L.; Guan, H.-S.; Liu, Y.-K. Diversity-
oriented one-pot synthesis to construct functionalized chroman-2-one
derivatives and other heterocyclic compounds. J. Org. Chem. 2017, 82,
4774. (b) Liu, C.; Liu, Y.-K. Asymmetric organocatalytic one-pot,
two-step sequential process to synthesize chiral acetal-containing
polycyclic derivatives from cyclic hemiacetals and enones. J. Org.
Chem. 2017, 82, 10450. (c) You, Z.-H.; Chen, Y.-H.; Wu, X.-N.; Liu,
Y.-K. Lactols in asymmetric sequential organo- and gold-catalysis:
synthesis of densely functionalized epimeric bicyclic O,O-acetals. Adv.
Synth. Catal. 2017, 359, 4260. (d) Pei, J. P.; Chen, Y. H.; Liu, Y. K.
Asymmetric organocatalytic sequential reaction of structurally
complex cyclic hemiacetals and functionalized nitro-olefins to
synthesize diverse heterocycles. Org. Lett. 2018, 20, 3609. (e) Wu,
X. N.; You, Z. H.; Liu, Y. K. Different hybridized oxygen atoms
controlled chemoselective formation of oxocarbenium ions: Synthesis
of chiral heterocyclic compounds. Org. Biomol. Chem. 2018, 16, 6507.
(8) (a) Chen, Y.-H.; Li, D.-H.; Liu, Y.-K. Diversified synthesis of
chiral chromane-containing polyheterocyclic compounds via asym-
metric organocatalytic cascade reactions. ACS Omega 2018, 3, 16615.
(b) Qiao, L.; Duan, Z.-W.; Wu, X.-N.; Li, D.-H.; Gu, Q.-Q.; Liu, Y.-K.
Organocatalytic diversity-oriented asymmetric synthesis of structurally
and stereochemically complex heterocycles. Org. Lett. 2018, 20, 1630.
(c) You, Z.-H.; Chen, Y.-H.; Tang, Y.; Liu, Y.-K. Organocatalytic
asymmetric synthesis of spiro-bridged and spiro-fused heterocyclic
compounds containing chromane, indole, and oxindole moieties. Org.
Lett. 2018, 20, 6682. (d) Xie, C.-C.; Tan, R.; Liu, Y.-K. Asymmetric
construction of polycyclic indole derivatives with different ring
connectivities by an organocatalysis triggered two-step sequence. Org.
Chem. Front. 2019, 6, 919.
̌
̌
(3) (a) Svetlík, J.; Goljer, I.; Turecek, F. Oxygen-bridged
tetrahydropyridines, hexahydropyridines, and dihydropyridones via a
Hantzsch-like synthesis with 4-(2-hydroxyphenyl)but-3-en-2-one. J.
Chem. Soc., Perkin Trans. 1 1990, 1, 1315. (b) Raev, L. D.; Frey, W.;
Ivanov, I. C. Coumarin-enaminoester adducts: structure corrections
(X-ray) and some novel transformations. Synthesis of annulated
tricyclic 2-pyridones. Synlett 2004, 2004, 1584. (c) Paira, R.; Mondal,
S.; Maity, A.; Sahu, K. B.; Naskar, S.; Saha, P.; Hazra, A.; Kundu, S.;
Banerjee, S.; Mondal, N. B. An easy access to diversely fused dioxa-2-
aza-tricyclo[n.3.1.02,n]tetra/pentadecanes under solvent-free condi-
̆
́
tion. Tetrahedron Lett. 2011, 52, 5516. (d) Svetlík, J.; Veizerova, L. A
different role of Meldrum’s acid in the Biginelli reaction. Helv. Chim.
Acta 2011, 94, 199. (e) Detistov, O. S.; Panda, S. S.; Steel, P. J.; Asiri,
A. M.; Hall, C. D.; Katritzky, A. R. Diastereoselective synthesis of
methanopyridoxazocinones. Synlett 2014, 25, 2654. (f) Rao, Y.; Liu,
M.; Wu, L.; Yin, G. Catalyst-free one-pot domino reactions for
selective synthesis of functionalized 2,8-oxazabicyclo[3.3.1]-nonanes
and 5H-indeno[1,2-b]pyridin-5-ones. RSC Adv. 2014, 4, 64551.
(g) Li, L.; Aibibula, P.; Jia, Q.; Jia, Y. Total syntheses of naucleamides
A−C and E, geissoschizine, geissoschizol, (E)-isositsirikine, and 16-
epi-(E)-isositsirikine. Org. Lett. 2017, 19, 2642. (h) Pramthaisong, C.;
Worayuthakarn, R.; Pharikronburee, V.; Duangthongyou, T.;
Rattanakam, R.; Ruchirawat, S.; Thasana, N. Base-mediated cascade
cyclization: stereoselective synthesis of benzooxazocinone. Org. Lett.
2018, 20, 4015.
(4) (a) Xiong, X.-F.; Zhang, H.; Peng, J.; Chen, Y.-C. Direct
asymmetric Michael addition of cyclic N-sulfonylimines to α,β-
unsaturated aldehydes. Chem. - Eur. J. 2011, 17, 2358. (b) An, Q.;
Shen, J.; Butt, N.; Liu, D.; Liu, Y.; Zhang, W. Asymmetric domino
reaction of cyclic N-sulfonylimines and simple aldehydes with trans-
perhydroindolic acid as an organocatalyst. Org. Lett. 2014, 16, 4496.
(c) Fei, J.; Qian, Q.; Sun, X.; Gu, X.; Zou, C.; Ye, J. Organocatalytic
enantioselective formal [4 + 2] cycloaddition of enones with cyclic N-
sulfonylimines and methylene chromene for chiral spirocyclic
compounds. Org. Lett. 2015, 17, 5296. (d) Zhang, S.; Li, L.; Hu,
Y.; Zha, Z.; Wang, Z.; Loh, T.-P. Bifunctional amino sulfonohydrazide
catalyzed direct asymmetric Mannich reaction of cyclic ketimines with
ketones: highly diastereo- and enantioselective construction of
quaternary carbon stereocenters. Org. Lett. 2015, 17, 1050. (e) An,
Q.; Li, J.; Shen, J.; Butt, N.; Liu, D.; Liu, Y.; Zhang, W. Asymmetric
tandem reactions of N-sulfonylimines and α,β-unsaturated aldehydes:
an alternative reaction pathway to that of using saturated aldehydes.
Chem. Commun. 2015, 51, 885. (f) Zhang, S.; Li, L.; Hu, Y.; Li, Y.;
Yang, Y.; Zha, Z.; Wang, Z. Highly enantioselective construction of
fluoroalkylated quaternary stereocenters via organocatalytic dehy-
drated Mannich reaction of unprotected hemiaminals with ketones.
Org. Lett. 2015, 17, 5036. (g) Yu, J.-S.; Zhou, J. A highly efficient
Mukaiyama-Mannich reaction of N-Boc isatin ketimines and other
active cyclic ketimines using difluoroenol silyl ethers catalyzed by
Ph3PAuOTf. Org. Biomol. Chem. 2015, 13, 10968. (h) Takizawa, S.;
Kishi, K.; Abozeid, M. A.; Murai, K.; Fujioka, H.; Sasai, H.
Enantioselective organocatalytic oxidation of ketimine. Org. Biomol.
Chem. 2016, 14, 761. (i) Zhang, S.; Li, L.; Xin, L.; Liu, W.; Xu, K.
Asymmetric aziridination of N-sulphonyl ketimines with unfunction-
alized ketones: a one-pot approach to multisubstituted fused
aziridines. J. Org. Chem. 2017, 82, 2399.
(9) For a review on the synthesis of spiro compounds, see: Xu, P.-
W.; Yu, J.-S.; Chen, C.; Cao, Z.-Y.; Zhou, F.; Zhou, J. Catalytic
enantioselective construction of spiro quaternary carbon stereo-
centers. ACS Catal. 2019, 9, 1820.
(10) (a) Ackrill, T. D.; Sparkes, H. A.; Willis, C. L. Synthesis of
diarylheptanoid scaffolds inspired by calyxins I and J. Org. Lett. 2015,
́
17, 3884. (b) Cabrera, S.; Reyes, E.; Aleman, J.; Milelli, A.;
Kobbelgaard, S.; Jørgensen, K. A. Organocatalytic asymmetric
synthesis of α,α-disubstituted α-amino acids and derivatives. J. Am.
Chem. Soc. 2008, 130, 12031. (c) Choi, K.-S.; Kim, S.-G. Asymmetric
organocatalytic Michael addition−cyclization cascade reaction of
nitroalkanes with o-hydroxycinnamaldehydes. Eur. J. Org. Chem. 2012,
́
2012, 1119. (d) Kim, Y. S.; Kim, S. M.; Wang, B.; Companyo, X.; Li,
̌
J.; Moyano, A.; Im, S.; Tosner, Z.; Yang, J. W.; Rios, R. Expanding the
scope of the organocatalytic addition of fluorobis(phenylsulfonyl)-
methane to enals: enantioselective cascade synthesis of fluoroindane
and fluorochromanol derivatives. Adv. Synth. Catal. 2014, 356, 437.
(e) Lee, Y.; Seo, S. W.; Kim, S.-G. Highly enantioselective conjugate
addition−cyclization cascade reaction of malonates with o-hydrox-
ycinnamaldehydes: asymmetric synthesis of 4-substituted chromanols.
Adv. Synth. Catal. 2011, 353, 2671. (f) Maity, R.; Pan, S. C.
Organocatalytic asymmetric Michael/hemiacetalization/acyl transfer
reaction of α-nitroketones with o-hydroxycinnamaldehydes: synthesis
of 2,4-disubstituted chromans. Org. Biomol. Chem. 2018, 16, 1598.
(g) Ramachary, D. B.; Shiva Prasad, M.; Vijaya Laxmi, S.;
Madhavachary, R. Asymmetric synthesis of drug-like spiro[chroman-
3,3′-indolin]-2’-ones through aminal-catalysis. Org. Biomol. Chem.
2014, 12, 574. (h) Zu, L.; Zhang, S.; Xie, H.; Wang, W. Catalytic
asymmetric oxa-Michael-Michael cascade for facile construction of
chiral chromans via an aminal intermediate. Org. Lett. 2009, 11, 1627.
E
DOI: 10.1021/acs.orglett.9b01874
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
́
(11) Cruz Cruz, D.; Mose, R.; Villegas Gomez, C.; Torbensen, S. V.;
Larsen, M. S.; Jørgensen, K. A. Organocatalytic cascade reactions:
towards the diversification of hydroisochromenes and chromenes
through two different activation modes. Chem. - Eur. J. 2014, 20,
11331.
(12) For a discussion of the formation of compound 8a, see the
Supporting Information.
(13) For a similar oxidative transformation of compound 8a, see the
Supporting Information.
(14) Hino, T.; Yamaguchi, H.; Matsuki, K.; Nakano, K.; Sodeoka,
M.; Nakagawa, M. Oxidation of 2,3-disubstituted indoles with m-
chloroperbenzoic acid. Formation of o-aminophenol derivatives and a
dimeric product. J. Chem. Soc., Perkin Trans. 1 1983, 1, 141.
F
DOI: 10.1021/acs.orglett.9b01874
Org. Lett. XXXX, XXX, XXX−XXX