Bifunctional Phosphonium Salt Directed Enantioselective Formal [4 + 1] Annulation of Hydroxyl-Substituted para-Quinone Methides with α-Halogenated Ketones

Article abstract of DOI:10.1021/acs.orglett.9b02560

A highly diastereo- and enantioselective [4 + 1] cycloaddition of para-quinone methides to α-halogenated ketones was realized by bifunctional phosphonium salt catalysis, furnishing functionalized 2,3-dihydrobenzofurans in high yields and excellent stereoselectivities (>20:1 dr and up to >99.9% ee). Mechanistic observations suggested that the reaction underwent a cascade intermolecular substitution/intramolecular 1,6-addition process. DFT calculations revealed the presence of multiple H-bonding interactions between the catalyst and the enolate intermediate in the stereodetermining transition states.

Full text of DOI:10.1021/acs.orglett.9b02560

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Bifunctional Phosphonium Salt Directed Enantioselective Formal [4
+ 1] Annulation of Hydroxyl-Substituted para-Quinone Methides
with α‑Halogenated Ketones
Jian-Ping Tan,†,# Peiyuan Yu,‡,# Jia-Hong Wu,† Yuan Chen,† Jianke Pan,† Chunhui Jiang,†,§
Xiaoyu Ren,† Hong-Su Zhang,† and Tianli Wang*,†
†Key Laboratory of Green Chemistry & Technology of Ministry of Education, College of Chemistry, Sichuan University, Chengdu
610064, P. R. China
‡Department of Chemistry and Shenzhen Grubbs Institute, Southern University of Science and Technology, Shenzhen, China
§School of Environmental and Chemical Engineering, Jiangsu University of Science and Technology, 2 Mengxi Road, Zhenjiang
212003, P. R. China
S
* Supporting Information
ABSTRACT: A highly diastereo- and enantioselective [4 + 1] cycloaddition of para-quinone methides to α-halogenated
ketones was realized by bifunctional phosphonium salt catalysis, furnishing functionalized 2,3-dihydrobenzofurans in high yields
and excellent stereoselectivities (>20:1 dr and up to >99.9% ee). Mechanistic observations suggested that the reaction
underwent a cascade intermolecular substitution/intramolecular 1,6-addition process. DFT calculations revealed the presence of
multiple H-bonding interactions between the catalyst and the enolate intermediate in the stereodetermining transition states.
enzo-fused O-heterocyclic skeletons, especially 2,3-dihy-
drobenzofuran-containing structures, are prominent build-
straightforward synthetic methods for producing such ring
systems.3−8 Accordingly, the hydroxyphenyl-substituted para-
quinone methides (p-QMs) emerged as a potential class of
versatile C4-synthons for formal [4 + 1] annulation reactions to
access the 2,3-dihydrobenzofuran skeletons, due to their
intrinsic reactivity of aromatization as well as the nucleophilicity
of their phenolic sites.4 Recently, the research groups of Enders,5
Yuan,6 and Yao7 pioneered to report their utilization of the
hydroxyl-containing p-QMs for racemic [4 + 1] cycloadditions
with sulfonium and/or ammonium ylides, particularly providing
trans-2,3-dihydrobenzofurans with high yields and good
diastereoselectivities.8 However, despite these impressive
advances, a highly catalytic asymmetric variant of a formal [4
+ 1] synthetic strategy using such p-QMs as C4-synthons still
constitutes a daunting challenge. It may be due to the fact that
the distance and space position between the carbonyl group and
acceptor−donor reactive sites (CC bond and phenol group)
are not favorable for stereocontrol. To the best of our
knowledge, no practical and efficient catalytic system to realize
B
ing blocks not only in many biologically active natural products
but also in numerous medicinally important agents (Scheme 1).1
Scheme 1. Bioactive and Natural Compounds Containing
2,3-Dihydrobenzofuran Skeletons
The broad spectra of their applications make such chiral
structural motifs attractive synthetic targets, and many efforts
have been devoted to construct such significant architectures
over the past decade.2−4 Among several synthetic methods, the
[4 + 1] annulation reaction, which uses a suitable C1-synthon
and an acceptor−donor containing C4-synthon as building
blocks, is considered to be one of the most efficient and
Received: July 23, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02560
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
this objective has been reported to date. Thus, it is highly
desirable to develop an efficient catalytic system to fill this void.
In this study, we aim to exploit a highly efficient and easily
accessible catalytic system to solve the principal stereoinduction
problem, and thus offer an alternative approach to access chiral
2,3-dihydrobenzofuran compounds. Over the past decades,
peptide-based catalysis, which was particularly influenced by
enzymology, has been diffusely investigated as a versatile tool for
the asymmetric synthesis of structurally divergent chiral
molecules; numerous privileged chiral catalysts/ligands con-
taining peptide active sites have been accordingly developed by
chemists.9−11 For instance, peptide-based phosphine catalysis
has already been well established and widely applied in
asymmetric synthesis in the past years.12 However, despite the
past decade of great progress in enantioselective phosphonium
salt catalysis,13−15 analogous P-based phosphonium salt
catalysts by taking peptide residues as secondary active sites
are very limited. Recently, Zhao and co-workers pioneered the
development of bifunctional phosphonium salt catalysts derived
from amino acids16a,b and further demonstrated their effective-
ness in a number of catalytic reactions.16 Very recently, we
developed an L-threonine-derived bifunctional phosphonium
salt catalyst for the highly enantioselective synthesis of
tetrasubstituted aziridines.17a It should be noted that such an
amino acid derived phosphonium salt possesses remarkably high
tunability, and further, this catalyst with an ion-pairing moiety
and peptide backbone that captures essential features of
enzymatic active sites with hydrogen-donating characteristics
becomes a multifunctional phase-transfer catalyst, which can be
advantageous for asymmetric induction.18 Inspired by these
advancements, we envisioned that such a powerful dipeptide-
based phosphonium salt catalyst may bridge the gap in realizing
the stereoinduction and thus direct the guidance of bifunctional
hydroxyl-containing p-QMs to a catalytic asymmetric formal [4
+ 1] process, which represents a complementary strategy for
accessing biologically significant chiral 2,3-dihydrobenzofurans
(Figure 1). Herein, we describe the first highly catalytic
Table 1. Reaction Optimization
b
c
entry
cat.
solvent
base
yield (%)
er
1
2
3
4
5
6
7
8
none
P0
A
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
PE
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
21
62
92
93
86
88
90
94
96
93
−
−
52:48
57:43
58:42
60:40
62:38
61:39
77:23
99:1
B
C1
C2
D1
D2
D3
D3
9
10
de f
, ,
a
Reactions were performed with 1a (0.10 mmol), 2a (0.12 mmol),
base (0.40 mmol), and the catalyst (0.02 mmol) in the solvent (1.0
mL) at room temperature. Isolated yields. Enantiomeric ratio (er)
b
c
d
determined by chiral HPLC. Reaction run at −20 °C for 48 h.
e
f
Cs2CO3 (2.0 equiv). Reaction run at 10 mol % catalyst for 72 h. P0
= Ph2Me2P+·I−, and PE = petroleum ether (bp 60−90 °C).
virtually unexplored. According to our previous studies,17a we
preferred to select a dipeptide as the basic chiral backbone for
our catalyst preparation and further optimization. To our
delight, all the bifunctional phosphonium salts examined were
effective in promoting this reaction (Table 1, entries 3−9).19
Generally, dipeptide-based phosphonium salts were better than
monopeptide-based ones (see Table S1 for details). While the L-
Val-derived dipeptide phosphonium salt induced relatively low
enantioselectivity (entries 3 and 4), the L-Thr-derived
phosphonium salts were found to be more favorable in
stereoinduction (entries 5−9), and the O-TBDPS-protected L-
Thr-D-tert-Leu-derived phosphonium salt D3 was found to be
the best, providing the annulation product in 96% yield with
77:23 er at room temperature (entry 9). To improve the
enantioselectivity of this transformation, we further screened the
following reaction conditions: base (Table S2), solvent (Table
S3), and others (Table S4). Notably, it was found that nonpolar
solvents might be favorable to improve the enantioselectiv-
ities.19 When the model reaction was performed at −20 °C with
10 mol % of catalyst D3 and 2.0 equiv of Cs2CO3 in petroleum
ether, the cyclization product was obtained in 93% yield with
99:1 er (entry 10).
Figure 1. Asymmetric construction of 2,3-dihydrobenzofurans via
bifunctional phosphonium salt-catalyzed formal [4 + 1] annulation.
enantioselective [4 + 1] annulation between hydroxyl-
containing p-QMs and α-halogenated ketones by dipeptide-
derived phosphonium salt catalysis, providing an efficient and
complementary way to functionalized 2,3-dihydrobenzofuran
derivatives. Moreover, the critical importance of the peptide
residue on the catalyst backbone in dictating the stereochemical
outcome was elucidated through DFT calculations.
We initially evaluated the feasibility of the annulation between
hydroxyl-substituted p-QM 1a and α-bromo acetophenone 2a in
the presence of cesium carbonate or/and monofunctional
phosphonium salt (P0). Unfortunately, the desired products
were obtained in very low yields even after 12 h (Table 1, entries
1 and 2). These preliminary results inspired us to search for a
more efficient catalytic system for realizing this reaction in an
asymmetric manner. It should be noted that employment of α-
halogenated ketones in such formal [4 + 1] cyclization is
With the identified optimized conditions (Table 1, entry 10),
the scope of p-QMs was investigated with 2a as the cyclization
partner (Scheme 2). The substituents on the phenol ring of p-
QMs were first investigated. Generally, both electron-donating
groups including methyl and methoxyl and electron-with-
drawing groups including fluoro, chloro, and bromo at the 4,
5, or 6-position of the phenol ring were perfectly compatible
B
DOI: 10.1021/acs.orglett.9b02560
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Organic Letters
Letter
a
a
Scheme 2. Substrate Scope of p-QMs
Scheme 3. Substrate Scope of α-Halogenated Ketones
a
Reactions were performed with 1 (0.10 mmol), 2a (0.12 mmol),
Cs2CO3 (0.20 mmol), and the catalyst D3 (0.01 mmol) in PE (1.0
mL) at −20 °C for 72 h. Isolated yields provided; er determined by
b
chiral HPLC. PE = petroleum ether (bp 60−90 °C). The α-
chloroketone 2a′ was used as reaction partner. See SI for more details.
a
Reactions were performed with 1a (0.10 mmol), 2 (0.12 mmol),
Cs2CO3 (0.20 mmol), and the catalyst D3 (0.01 mmol) in PE (1.0
mL) at −20 °C for 72 h. Isolated yields provided; er determined by
with the reaction conditions, and the corresponding products
3a−l were obtained in high yields (84−96%) with excellent
diastereo- and enantioselectivities (>20:1 dr, 91:9−99:1 er).
Substrates bearing substitutents at the 3-position on the phenol
ring slightly lowered the enantioselectivities of the reaction (3m
and 3n). Notably, naphthol-containing p-QM proved to be an
excellent substrate and gave the annulation product 3o with
exceptionally high ee (>99.9%). The absolute configurations of
the annulation products were assigned based on the X-ray crystal
structural analysis of 3a (CCDC1864020).
The above optimal conditions were readily extended to
reactions utilizing α-halogenated ketones as substrates (Scheme
3). First, different substituents on the aromatic ring of α-bromo
ketones were investigated. Both the electronic properties and
the positions of the substituents on the aromatic ring did not
observably influence the isolated yield and stereoselectivity of
the annulation reaction (Scheme 3, 4a−p). Then, the thienyl
and naphthyl substituted α-bromoketones were tested and
found to be excellent substrates (4q and 4r). It is worth noting
that the reaction conditions were also suitable for the cyclic α-
halogenated ketones, which afforded the cyclization products
with a quaternary stereogenic center in good yields and excellent
er values (4s and 4t). Remarkably, the aliphatic α-bromoketone
was also well tolerated under the catalytic system and provided
the desired product 4u with excellent enantioselectivity (97:3
er). Moreover, the large-scale reaction between p-QM 1a (2.0
mmol) and α-bromoacetophenone 2a was performed under the
optimal reaction conditions, and the corresponding product 3a
was obtained in 83% yield without any loss of stereoselectivities
(Scheme S6); further, the optically enriched product 3a could be
b
chiral HPLC. PE = petroleum ether (bp 60−90 °C). The
corresponding α-chloroketone 2′ was used as a cyclization partner.
See SI for more details.
readily derived into 3′-hydroxyl substituted chiral compound 5a
in 91% yield via a reduction step. Alternatively, the bulky
substituent tert-butyl group could be removed easily, thus
affording 5b in 78% yield promoted by AlCl3 (Scheme S7).19
Subsequently, we carried out further experiments to better
understand the reaction pathway (see Scheme S8 in SI for more
details). As shown in Scheme 4, the p-QMs without a free
hydroxyl group at the aromatic ring were examined in their
reactions with α-bromoketone 2c, and no reaction took place
(eq 1). When the annulation reaction between 1a and 2c was
suspended after 24 h, the intermediate 8 generated from
intermolecular substitution was successfully isolated in 41%
yield, and some of the desired product 4c was also observed with
unchanged stereoselectivities; further, only the cyclization
product 4c was obtained upon a prolonged reaction time (eq
2). Moreover, we synthesized this intermediate 8 and tested its
intramolecular 1,6-addition under the identical reaction
conditions, and the sole product 4c was obtained with similar
enantioselectivity to that of the cyclization reaction (eq 3). On
the basis of these results, a cascade pathway including
intermolecular nucleophilic substitution and subsequent intra-
molecular 1,6-addition might be very likely for our catalytic
system (Figure S10).
In addition, DFT calculations (see SI for computational
details), which mainly focused on the step of intramolecular 1,6-
C
DOI: 10.1021/acs.orglett.9b02560
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Organic Letters
Letter
interactions between the enolate oxygen and the peptide
catalyst. One additional hydrogen bond is also present in the
catalyst itself (Figure 2b, 2.13 Å), as well as in the TSs (2.14 and
2.16 Å, respectively). This intramolecular hydrogen bond leads
to a ten-membered ring (excluding hydrogen) conformation of
the catalyst. The three axial hydrogen atoms that bear
considerable positive charges (Figure 2b, computed charges
shown in blue) are able to interact strongly with the enolate
oxygen in the TS. The computed electrostatic potential (ESP)
map (Figure 2b, right) also demonstrates that these hydrogen
atoms on the catalyst form an electropositive region (blue color
in the center of the ESP map), which enables the strong
interactions between the phosphonium cation and the enolate.
Moreover, some other TSs were also located, but are much
higher in energy (Figure S8). To validate our TS model from
DFT computations, we further prepared both substituted-
benzyl-assisted phosphonium salts (D1-a and D1-b) and
methylated catalysts (D3-a and D3-b). When these phospho-
nium salts were used as the catalyst, respectively, the reaction
became much slower, and the enantioselectivities decreased
dramatically (Table S6),19 which also suggested that the
enantioselectivity originates from the multiple hydrogen-
bonding interactions between the dipeptide-based phospho-
nium catalyst and the key enolate intermediate of the reaction.
In conclusion, we have disclosed the first catalytic
enantioselective formal [4 + 1] annulation reaction between
hydroxyl-substituted p-QMs and α-halogenated ketones by a
dipeptide-based bifunctional phosphonium salt catalyst. This
method represented a novel and complementary approach for
the preparation of optically active 2,3-dihydrobenzofuran
derivatives in excellent diastereo- and enantioselectivities.20
Mechanistic study of the reaction intermediate and control
experiments indicated that the annulation reaction underwent a
cascade pathway including intermolecular nucleophilic sub-
stitution and subsequent intramolecular 1,6-addition. Moreover,
DFT calculations suggested that the enantioselectivity originates
from a triad of hydrogen-bonding interactions in the L-Thr-
derived dipeptide catalytic system. Further mechanistic studies
and applications of this privileged peptide-phosphonium salt to
other challenging organic syntheses are underway.
Scheme 4. Preliminary Mechanistic Studies
addition, were performed to probe the origin of the observed
stereoinduction. The enolate formed by deprotonation of
intermediate 8 was found to be unstable in the absence of a
counterion (Figure S5). Thus, the phosphonium catalyst is likely
to play a role in stabilizing the enolate, in addition to controlling
the enantioselectivity. In the presence of the phosphonium
cation, the enantio-determining transition states (TSs) could be
located (Figure 2a). TS-(S,S), which leads to the major
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b02560.
Experimental procedures and compound characterization
data (PDF)
Accession Codes
CCDC 1864020 contains 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.
Figure 2. DFT calculations: (a) DFT-optimized transition states that
lead to the major (left) and minor (right) enantiomers, respectively. (b)
Conformation of the catalyst (phosphonium cation) that features one
intramolecular C−H···O hydrogen bond and three axial H atoms with
computed charges shown in blue (left) and its ESP map (right).
Distances are in Å.
AUTHOR INFORMATION
enantiomer, is slightly more stable than TS-(R,R) by 0.5 kcal/
mol, in agreement with the moderate enantioselectivity (54 ee
%) observed at room temperature. Calculations using three
different density functionals have been performed to make sure
this small difference in energy is consistent (Figure S7). The
DFT-optimized TSs featured multiple strong hydrogen-bonding
■
Corresponding Author
*E-mail: wangtl@scu.edu.cn.
ORCID
Peiyuan Yu: 0000-0002-4367-6866
D
DOI: 10.1021/acs.orglett.9b02560
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(11) For impressive work of Kudo, see: Akagawa, K.; Kudo, K. Acc.
Chem. Res. 2017, 50, 2429 and references therein .
Tianli Wang: 0000-0002-8431-9048
Author Contributions
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#J.-P.T. and P.Y. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
T.W. particularly thanks Prof. Yixin Lu (National University of
Singapore) for valuable help and suggestions. Financial support
was provided by the National Natural Science Foundation of
China (21702139), the “1000-Youth Talents Program”
(YJ201702), and the Fundamental Research Funds for the
Central Universities. We also acknowledge the comprehensive
training platform of the Specialized Laboratory in the College of
Chemistry at Sichuan University and the Analytical & Testing
Center of Sichuan University for compound testing.
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(19) See the Supporting Information (SI) for more details.
(20) During our preparation of this manuscript, a single isolated
example of a phosphine-catalyzed [4 + 1] cyclization of ortho-
hydroxypara-quinone methides with allenoates was reported, which
proceeded with moderate yields (59−89%) and enantioselectivities
́
̌
̌
(0−88% ee); see: Zielke, K.; Kovac, O.; Winter, M.; Pospísil, J.; Waser,
M. Chem. - Eur. J. 2019, 25, 8163.
(10) For impressive work of Wennemers, see: Wennemers, H. Chem.
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E
DOI: 10.1021/acs.orglett.9b02560
Org. Lett. XXXX, XXX, XXX−XXX