N-Heterocyclic Carbene-Catalyzed Enantioselective Intramolecular Annulations to Construct Benzo-Fused Pyranones with Quaternary Stereocenter

Article abstract of DOI:10.1002/adsc.202000550

A highly enantioselective intramolecular NHC-catalyzed approach for the synthesis of benzo-fused pyranones bearing quaternary stereocenter is described. The developed methodology is based on annulation reaction between acyl anion intermediates and β,β-disubstituted Michael acceptors. The reaction offers streamlined and effective access to target products in a highly stereoselective manner. (Figure presented.).

Full text of DOI:10.1002/adsc.202000550

Title: N-Heterocyclic Carbene-Catalyzed Enantioselective
Intramolecular Annulations to Construct Benzo-Fused Pyranones
with Quaternary Stereocenter
Authors: Krzysztof Dzieszkowski and Zbigniew Rafiński
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.202000550
Link to VoR: https://doi.org/10.1002/adsc.202000550

10.1002/adsc.202000550
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.202
N-Heterocyclic Carbene-Catalyzed Enantioselective
Intramolecular Annulations to Construct Benzo-Fused
Pyranones with Quaternary Stereocenter
Krzysztof Dzieszkowski and Zbigniew Rafiński*
Faculty of Chemistry, Nicolaus Copernicus University in Torun, 7 Gagarin Street, 87-100 Torun, Poland,
payudo@umk.pl
Dedication to Professor Grzegorz Mlostoń on the Occasion of his 70th Birthday.
Received:
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract. A highly enantioselective intramolecular NHC-
catalyzed approach for the synthesis of benzo-fused
pyranones bearing quaternary stereocenter is described. The
developed methodology is based on annulation reaction
between acyl anion intermediates and β,β-disubstituted
Michael acceptors. The reaction offers streamlined and
effective
access
to
target
products
in
a highly stereoselective manner.
Keywords: Organocatalysis, Umpolung, N-heterocyclic
carbene, Stetter reaction
The stereocontrolled synthesis of specific structural
motifs possessing at least one quaternary stereocenters
is of the key challenges in the contemporary organic
chemistry.[1–3] One of the difficulties in constructing
quaternary carbons is their congested nature, wherein
the creation of such centers is complicated by steric
repulsion between the carbon substituents. Despite
remarkable advances, such catalytic enantioselective
creation of quaternary carbon stereocenters is still
rather limited for this task.[4–6] Among biologically
relevant molecules bearing such stereocenters, benzo-
fused ketones such as chromanones and their tetralone
derivatives appear in a variety of many bioactive
natural products (with selected examples in Figure 1
and have found interesting applications as building
blocks and reagents in organic synthesis.[7–10]
Figure 1. Natural products and bioactive molecules
containing six-membered benzo-fused ketones.
For instance, garcibracteatone is a polycyclic
polyprenylated acylphloroglucinol (PPAP) natural
product, most structurally complex PPAP with
a highly compact polycyclic ring system containing
seven stereocenters, five of which are quaternary.[11]
Additionally, homoisoflavonoids derived from
scillascillin have been intensively investigated in the
study for antiangiogenic activity.[12] The importance of
benzo-fused cyclohexanones can be further
exemplified by the natural occurring nideome which
possess additionally spiro[4.5]decane carbon
framework and also on other structurally important
motif such as nafenodone as the antidepressant
drug.[13,14] In recent years N-heterocyclic carbene
catalysis has emerged as an attractive and ideal
strategy to synthesize complex heterocyclic molecules
via umpolung reactivity.[15–29] Among various
asymmetric catalytic strategies for the stereoselective
construction and selective functionalization of the six-
membered motifs, the Stetter reaction proved to be one
1
This article is protected by copyright. All rights reserved.

10.1002/adsc.202000550
Advanced Synthesis & Catalysis
of the universal and fundamental tool of the
N-heterocyclic carbene (NHC) catalysis[30–36] After
Ciganek initial contribution on intramolecular NHC-
catalyzed synthesis of chromanones, during next years
many highly enantioselective approaches have been
developed (Scheme 1, eq a).[30,37–40] In the later stage,
Rovis and coworkers disclosed
enantioselective and diastereoselective Stetter reaction
of salicylaldehyde-derived bearing a tethered
a
highly
α,β-disubstituted Michael acceptors (eq b).[31] This
transformation allowed to obtain chromanones with
two tertiary stereogenic centers. More recently, Zhou
group reported a selective approach to enantioenriched
chromanones utilizing NHC-catalyzed intramolecular
SN2' nucleophilic substitution reaction (eq c).[41]
Furthermore, Glorius demonstrated another way
which offers access to chromanones bearing
quaternary stereocenter though intramolecular
hydroacylation of electron-neutral olefins (eq d).[42]
However, it must be strongly emphasized, that this
methodology is limited to the O-styryl moiety and as a
result, only chromanones containing methyl-aryl
substituents at the quaternary stereocenter are formed.
The use of β,β-disubstituted Michael acceptors in the
synthesis of five-membered rings containing fully
substituted stereocenters is well known for a wide
range of olefin activating groups.[43–45] Nevertheless,
annulation to the six-membered rings via
intramolecular Stetter reaction certain challenges
related to the reactivity of these substrates had to be
addressed. First, replacing the hydrogen atom in the β-
position with an alkyl substituent generates additional
spatial crowding, thereby reducing the acceptor’s
reactivity to a nucleophilic attack. Secondly, in
contrast to synthesis of five-membered analogues, the
heteroatom is directly bound in the β-position, thereby
increasing the electrophilicity and reactivity of the
double bond. It is not possible in the case of six-
membered systems, β,β-disubstituted Michael
acceptors, in particular ester derivatives, is not
sufficiently activated under the conditions of the
Stetter reaction. The absence of a heteroatom directly
bond in the β-position results in a drastic reduction in
reactivity. To the best of our knowledge, only one case
of enantioselective approach to six-membered ring
using ester β,β-disubstituted Michael acceptor is
known in literature.[46]
Scheme
1.
NHC-Catalyzed
intramolecular
Stetter/substitution/hydroacylation reactions.
We envisioned that through the appropriate
substrate construction, a proper choice of the NHC
catalyst should enhance such a reactivity pattern
ensuring a selectivity at the same time, thereby,
enabling the reaction to proceed via a desired
annulation (eq e). The catalytic, enantioselective
formation of quaternary stereocenters has received
a considerable amount of attention recently, yet
remains a very challenging endeavor in organic
synthesis. Herein, we report our studies on this novel
approach for the synthesis of optically active
chromanone
derivatives
bearing
quaternary
stereogenic center employing NHC chemistry. The
developed strategy utilized β,β-disubstituted Michael
acceptors as electron-deficient olefins.
The present studies were initiated by treating
salicylaldehyde-derived β-methylacrylate 1a with
various optically pure N-substituted triazolium salts
using different bases and solvents (Table 1). When
pinene-derived triazolium salt
A
with an
pentafluorophenyl group was chosen as a precatalyst
with DIPEA in toluene, a pyranone skeleton with
all-carbon quaternary stereocenter was constructed
with great enantioselectivity (98% ee) and yield of
92%. Chiral catalyst B1, which bears a camphor
skeleton as the stereo-inducing unit, gave also almost
full conversion to the product with the same level of
2
This article is protected by copyright. All rights reserved.

10.1002/adsc.202000550
Advanced Synthesis & Catalysis
enantioselectivity but as a opposite enantiomer.
Replacing the N-C6F5 substituent of the NHC catalyst
B1 with 2,4,6-trichlorophenyl unit B2 and
tetraphenylborate anion as a counterion did not lead to
the desired product. Similar effect was observed for
Table 1. Optimization of the Reaction Conditions.
the
NHC-precatalyst
E
with
the
same
tetraphenylborate counterion. Probably, the more
sterically demanding BPh4 counterion effectively
prevents the attack of generated in situ acyl anion to
the disubstituted Michael acceptor. Interestingly,
catalyst C which possess switched amino and alcohol
position and endo,endo-relation to the gem-dimethyl
bridge exhibit quite high selectivity for the reaction
albeit very low activity was observed (Table 1, entry
4). Most likely, the reason for such a low conversion
is spatial congestion additionally enhanced by the
methyl group located near the carbene center and
decrease reactivity in the annulation process.
Spirocyclic-derived NHC precatalyst D could also
afford the desired benzannulated product with high
yield but a reduced enantioselectivity of 40% ee.
Aminoindanol-derived NHC precatalysts bearing
N-Ph (F1) and N-Mes (F2) groups were not effective
for this process, while the one bearing N-C6F5 (F3)
group showed superior effectiveness provided the
chromanone 2a in an excellent yield and exceptional
enantioselectivity 99.8% ee. Subsequent base
screening (Table 1, entries 10-16) revealed, that
different organic bases, even extremely strong ones
such as BEMP or P2-Et could give the products with
high yields and without erosion of stereoselectivity,
remaining at <99%. Additional screening of the
reaction solvents did not show further improvements
in the reaction outcomes (Table 1, entries 16-20).
Finally, identification of diisopropylethylamine and
toluene as the best-suited reaction conditions were
indicated in terms of enantioselectivity for the
developed annulation.
yield
ee
entry preNHC
Base
Solvent
(%)b) (%)c)
1
2
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DCyEA
BEMP
toluene
toluene
toluene
92
94
---
98
98d)
---
A
B1
B2
C
3
4
toluene 10e)
81
5
toluene
toluene
toluene
toluene
toluene
toluene
toluene
98
---
---
---
99
97
98
96
97
85
88
89
97
99
97
95
41
D
6
---
E
7
---
F1
F2
F3
F3
F3
F3
F3
F3
F3
F3
F3
F3
F3
F3
8
---
9
99.8
99.6
99.6
99.6
99.0
98.2
98.0
99.1
99.6
99.4
99.4
99.5
10
11
12
13
14
15
16
17
18
19
20
Pempidine toluene
NMM
DBU
toluene
toluene
toluene
toluene
DCM
DABCO
P2-Et
DIPEA
DIPEA
DIPEA
DIPEA
THF
Et2O
MTBE
a)
Unless otherwise specified, the reaction was performed on a
0.1 mmol scale 1a in solvent (2.0 mL) at room temperature.
b) Yields of isolated products. c) ee values determined by HPLC on
d)
Phenomenex Lux Cellulose-1 column (see the SI). Opposite
enantiomer. e) Reaction was performed for 48 h. Abbreviations:
BEMP: 2-tert-Butylimino-2-diethylamino-1,3-dimethylperhydro-
1,3,2-diazaphosphorine; Phosphazene base P2-Et: 1-Ethyl-
2,2,4,4,4-pentakis(dimethylamino)-2λ5,4λ5-
catenadi(phosphazene); DCyEA: Dicyclohexylethylamine.
Furthermore, the scope of this annulation using
a wide range of substrates with different substitution
patterns of the aromatic ring was examined. As shown
in Table 2, a broad spectrum of salicylaldehyde-
derived β-methylacrylates were explored and
produced chromanone products in very high yield and
3
This article is protected by copyright. All rights reserved.

10.1002/adsc.202000550
Advanced Synthesis & Catalysis
with excellent enantioselectivities. Initially the
influence of the electron properties and position of
substituents on the aromatic ring was investigated. The
use of substrates with electron-withdrawing
substituents at 5-position showed exceptional
reactivity (2b,c,e,f). Surprisingly, 5-iodo derivative 2h,
was also tolerated affording the product with slightly
lower yield, albeit without any loss of
enantioselectivity. The use of 5-methoxy or 5-methyl
groups as a electron-donating substituents leads to
products 2d,g in excellent yields and remarkably high
enantioselectivities (99.4-99.8% ee). A similar trend
was observed when the electron-donating methyl 2i
and methoxy 2j groups were introduced in the 4-
position of the aromatic ring giving the products
almost quantitively with excellent optical purity (99.8-
99.9% ee). The cyclization proceeded consistently for
4-substituted substrates carrying an electron-
withdrawing groups on the aromatic ring (2k, 2l).
Notably, the reaction was found to tolerate
diethylamino 2m as a strong activation group having
a tendency to increase of an undesired aldol-
elimination side reaction, providing the product with
Table 2. Substrate Scope for the Synthesis of Chromanones
with Quaternary Stereocentera).
96%
yield
and
with
slightly
decreased
enantioselectivity (93% ee). Furthermore, we also
examined the effect of substitution at 6-position on the
reactivity and selectivity of the annulation process due
to the close proximity of activating and deactivating
groups in ortho-orientation. To our great delight, both
electron-withdrawing (2n-p) and electron-donating
(2q) substituents were well-tolerated to obtain the
chromanones in good to excellent yields and level of
enantioselectivity in all of the cases. In addition,
2-fluoro salicylaldehyde-derived was also investigated
in the reaction, thereby affording the desired
quaternary chromanone 2r with comparable result.
Next, we were pleased to find that the disubstituted
and trisubstituted substrates with different substitution
patterns of the aromatic ring undergoes the reaction
smoothly
and
generate
the
corresponding
chromanones (2s-v). Finally, naphtaldehyde-derived
methylacrylate 1w also readily cyclized to the target
tricyclic naphthoannulated pyranone 2w in high
stereoselective fashion, however, with lower yield.
The results show, the reaction proved unbiased
towards the position of the substituents on the aromatic
ring afforded the desired products with excellent
stereocontrol. The absolute configuration of benzo-
fused pyranones was assigned based on the assumption
that the bias of the aminoindanol-NHC catalyst is
identical for five-membered analogous, the absolute
stereochemistry observed for six-membered skeletons
would be consistent with those substrates reacting
preffentially in S-configuration.[42],[46] Taking into
account such high values of enantiomeric excesses
generally obtained in the present study, it is reasonable
to assume that all the benzannulated pyranones 2a–2zz
are formed with the same absolute configuration.
a
Unless otherwise specified, the reaction was performed
on a 0.1 mmol scale in solvent (1.0 mL) at room temperature
for 20 h. Yields of isolated products. Ee values determined by
HPLC on Phenomenex Lux Cellulose-1 column (see the SI).
To further demonstrate the generality of this
annulation, we also examined the use of various
β,β-disubstituted Michael acceptors with different
lengths alkyl chain substituent (Table 3). Delightfully,
the extension of alkyl chain was well-tolerated without
a significant influence on the outcome in terms of
stereochemical efficiency. Nevertheless, as a results
an increase in the alkyl chain length from the butyl
substituent a significant decrease in chemical yield as
demonstrated in the synthesis of 2z (63%, 99.7% ee)
and 2zz (17%, 97.9% ee). Furthermore, we also
decided to investigate sterically more hindered
substituent in the β-position of the Michael acceptor
4
This article is protected by copyright. All rights reserved.

10.1002/adsc.202000550
Advanced Synthesis & Catalysis
introduce the phenyl group instead of methyl
substituent. However, using different reaction
conditions (elevated temperature, microwaves) failed
to obtain the desired product and only the starting
material was recovered.
[1]
[2]
J. P. Das, I. Marek, Chemical Communications
2011, 47, 4593–4623.
J. G. De Vries, in Quaternary Stereocenters:
Challenges and Solutions for Organic Synthesis,
2006.
[3]
[4]
X. P. Zeng, Z. Y. Cao, Y. H. Wang, F. Zhou, J.
Zhou, Chemical Reviews 2016, 116, 7330–7396.
C. J. Douglas, L. E. Overmant, Proceedings of the
National Academy of Sciences of the United States
of America 2004, 101, 5363–5367.
Table 3. Scope of β-alkyl-β-substituted Michael acceptorsa).
[5]
[6]
B. M. Trost, C. Jiang, Synthesis 2006, 369–396.
K. W. Quasdorf, L. E. Overman, Nature 2014, 516,
181–191.
[7]
Ø. M. Andersen, K. R. Markham, Flavonoids:
Chemistry, Biochemistry and Applications, 2005.
J. B. Harborne, The Flavonoids: Advances in
Research since 1986, 2017.
[8]
[9]
C. A. Williams, R. J. Grayer, Natural Product
Reports 2004, DOI 10.1039/b311404j.
S. Emami, Z. Ghanbarimasir, European Journal of
Medicinal Chemistry 2015, 93, 539–563.
H. P. Pepper, S. J. Tulip, Y. Nakano, J. H. George,
Journal of Organic Chemistry 2014, 79, 2564–
2573.
[10]
[11]
a) Unless otherwise specified, the reaction was performed on
a 0.1 mmol scale in solvent (1.0 mL) at room temperature for
20 h. Yields of isolated products. Ee values determined by
HPLC on Phenomenex Lux Cellulose-1 column (see the SI).
[12]
S. Schwikkard, H. Whitmore, K. Sishtla, R. S.
Sulaiman, T. Shetty, H. D. Basavarajappa, C.
Waller, A. Alqahtani, L. Frankemoelle, A.
Chapman, N. Crouch, W. Wetschnig, W. Knirsch,
J. Andriantiana, E. Mas-Claret, M. K. Langat, D.
Mulholland, T. W. Corson, Journal of Natural
Products 2019, 82, 1227–1239.
D. S. Hsu, C. Y. Liou, Organic and Biomolecular
Chemistry 2018, 16, 4990–4995.
F. Pérez-Vizcaino, R. Carrón, E. Delpón, J.
Tamargo, European Journal of Pharmacology
1991, 199, 43–50.
D. Enders, O. Niemeier, A. Henseler, Chemical
Reviews 2007, 107, 5606–5655.
N. Marion, S. Díez-González, S. P. Nolan,
Angewandte Chemie - International Edition 2007,
46, 2988–3000.
S. Mondal, S. R. Yetra, S. Mukherjee, A. T. Biju,
Accounts of Chemical Research 2019, 52, 425–
436.
In summary, we have developed a highly
asymmetric and new NHC-catalyzed annulation with
the use of ester β,β-disubstituted Michael acceptors for
efficient synthesis of chromanone derivatives bearing
quaternary stereogenic center. A broad scope of
substates worked well in this transformation affording
the products with high yields and with exceptional
enantioselectivities through simple operation.
Application of long chain alkyl substituents in Michael
acceptors is also possible giving the products without
any loss of enantiocontrol. The robustness screen
showed a very high tolerance of this reaction to a
diverse range of functional groups. These results
should be helpful to develop related transformations.
[13]
[14]
[15]
[16]
[17]
[18]
[19]
[20]
[21]
R. S. Menon, A. T. Biju, V. Nair, Beilstein Journal
of Organic Chemistry 2016, 12, 444–461.
K. Dzieszkowski, Z. Rafiński, Catalysts 2018, 8,
549.
D. S. Hsu, C. Y. Cheng, Journal of Organic
Chemistry 2019, DOI 10.1021/acs.joc.9b01403.
M. Zhao, Y. T. Zhang, J. Chen, L. Zhou, Asian
Journal of Organic Chemistry 2018, DOI
10.1002/ajoc.201700538.
A. T. Biju, N. Kuhl, F. Glorius, Accounts of
Chemical Research 2011, 44, 1182–1195.
X. Bugaut, F. Glorius, Chemical Society Reviews
2012, 41, 3511–3522.
S. J. Ryan, L. Candish, D. W. Lupton, Chemical
Society Reviews 2013, 42, 4906–4917.
D. M. Flanigan, F. Romanov-Michailidis, N. A.
Experimental Section
Diisopropylethylamine (1 eq) was added to the suspension
of precatalyst (20 mol%, 0.02 M) in toluene. The obtained
mixture was stirred at room temperature for 10 min. Then
the substrate was added and stirring was continued for 20 h.
The solvent was evaporated and the residue was diluted with
diethyl ether. The obtained suspension was filtered via
a syringe filter and the solvent was evaporated.
Acknowledgements
[22]
[23]
[24]
[25]
We
thank
the
National
Science
Center
UMO-2016/22/E/ST5/00469 for financial support.
References
5
This article is protected by copyright. All rights reserved.

10.1002/adsc.202000550
Advanced Synthesis & Catalysis
White, T. Rovis, Chemical Reviews 2015, 115,
Hamada, Synlett 2005, 155–157.
9307–9387.
[37]
[38]
E. Ciganek, Synthesis 1995, 1311–1314.
M. S. Kerr, J. R. De Alaniz, T. Rovis, Journal of
the American Chemical Society 2002, 124, 10298–
10299.
S. C. Cullen, T. Rovis, Organic Letters 2008, 10,
3141–3144.
[26]
[27]
M. N. Hopkinson, C. Richter, M. Schedler, F.
Glorius, Nature 2014, 510, 485–496.
J. Izquierdo, G. E. Hutson, D. T. Cohen, K. A.
Scheidt, Angewandte Chemie - International
Edition 2012, 51, 11686–11698.
K. J. R. Murauski, A. A. Jaworski, K. A. Scheidt,
Chemical Society Reviews 2018, 47, 1773–1782.
S. R. Yetra, A. Patra, A. T. Biju, Synthesis
(Germany) 2015, 47, 1357–1378.
[39]
[40]
[41]
[42]
[28]
[29]
[30]
Z. Rafiński, A. Kozakiewicz, K. Rafińska, ACS
Catalysis 2014, 4, 1404–1408.
M. Zhao, J. Chen, H. Yang, L. Zhou, Chemistry - A
European Journal 2017, 23, 2783–2787.
I. Piel, M. Steinmetz, K. Hirano, R. Fröhlich, S.
Grimme, F. Glorius, Angewandte Chemie -
International Edition 2011, 50, 4983–4987.
M. S. Kerr, T. Rovis, Journal of the American
Chemical Society 2004, 126, 8876–8877.
C. M. Filloux, S. P. Lathrop, T. Rovis,
Proceedings of the National Academy of Sciences
of the United States of America 2010, 107, 20666–
20671.
J. R. De Alaniz, M. S. Kerr, J. L. Moore, T. Rovis,
Journal of Organic Chemistry 2008, 73, 2033–
2040.
[31]
[32]
J. R. De Alaniz, T. Rovis, Journal of the American
Chemical Society 2005, 127, 6284–6289.
M. Zhao, J. L. Liu, H. F. Liu, J. Chen, L. Zhou,
Organic Letters 2018, 20, 2676–2679.
Z. Rafiński, ChemCatChem 2016, 8, 2599–2603.
B. Wang, L. Huang, Y. Hou, S. Lan, J. Cheng,
Organic Letters 2018, 20, 6012–6016.
Z. Rafiński, M. P. Krzemiński, Catalysts 2019, 9,
117.
[43]
[44]
[33]
[34]
[45]
[46]
Z. Rafiński, Catalysts 2019, 9, 192.
J. L. Moore, M. S. Kerr, T. Rovis, Tetrahedron
2006, 62, 11477–11482.
[35]
[36]
T. Nakamura, O. Hara, T. Tamura, K. Makino, Y.
6
This article is protected by copyright. All rights reserved.

10.1002/adsc.202000550
Advanced Synthesis & Catalysis
COMMUNICATION
Highly Enantioselective, NHC-Catalyzed
Intramolecular Annulations to Construct Benzo-
Fused Pyranones with All-Carbon Quaternary
Stereocenter
Adv. Synth. Catal. Year, Volume, Page – Page
Krzysztof Dzieszkowski, Zbigniew Rafiński*
7
This article is protected by copyright. All rights reserved.