A Facile Enantioselective Alkynylation of Chromones

Article abstract of DOI:10.1002/anie.201902405

The first catalytic enantioselective alkynylation of chromones is reported. In this process, chromones are silylated to form silyloxybenzopyrylium ions that lead to silyl enol ethers after Cu-catalyzed alkyne addition using StackPhos as a ligand. The outcome of the reaction is impacted by distal ligand substituents with differing electronic character and it was found that successful reactions could be achieved with different ligand congeners by using different solvents. This sequence enables access to different products by protonation or further functionalization, thus increasing complexity in a divergent manner. The transformation is high yielding over a broad scope to provide a variety of useful chromanones in high enantioselectivity.

Full text of DOI:10.1002/anie.201902405

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Accepted Article
Title: A Facile Enantioselective Alkynylation of Chromones
Authors: Lindsey G. DeRatt, Mukesh Pappoppula, and Aaron Aponick
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201902405
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10.1002/anie.201902405
Angewandte Chemie International Edition
COMMUNICATION
A Facile Enantioselective Alkynylation of Chromones
Lindsey G. DeRatt, Mukesh Pappoppula, and Aaron Aponick*[a]
Abstract: The first catalytic enantioselective alkynylation of
chromones is reported. In this process, chromones are silylated to
form silyloxybenzopyrylium ions that lead to silyl enol ethers after
Cu-catalyzed alkyne addition using StackPhos as ligand. The
outcome of the reaction is impacted by distal ligand substituents with
differing electronic character and it was found that successful
reactions could be achieved with different ligand congeners by using
different solvents. This sequence enables access to different
products by protonation or further functionalization, thus increasing
induce a selective reaction and that non-covalent interactions
could possibly play role (Scheme 1). Successful
implementation of this strategy would provide useful
alternative to the anion binding strategy and we set our sights on
chromone alkynylation.[11]
a
a
State-of-the-art For Catalytic Addition to Oxonium Ions
Nuc, C or
H-Bond
Heteroatom
Donor
X
Catalyst
O
3
Nuc
O
+
-
O
1
H
H
A
A
complexity in
yielding over
a
divergent manner. The transformation is high
broad scope to provide variety of useful
2a
X
a
a
Chiral
Scaffold
chromanones in high enantioselectivity.
Mattson's Chromenone Functionalization
OSiR3
O
OTMS
O
Enantioselective catalysis is one of the principal strategies for
the introduction of chirality to molecules used in disciplines
throughout the molecular sciences,[1] driving the development of
Me
OMe
TMSOTf
Me
CO2Me
Me Me
Silyl Diol
Catalyst
O
5
O
+
O
4
new catalysts and ligands.[2]
structures display applicability
Although certain privileged
across range of
H
H
A
-
2b
TfO
Up to 56% ee
a
A
transformations,[3] the discovery of new types of catalysts and
ligands is crucial. Small molecule H-bond donor catalysts have
now found success in many different types of transformations
and one challenging area that has successfully been addressed
is the enantioselective addition to oxonium ions whereby H-bond
donor catalysts participate in anion binding (Scheme 1).[4] In
these reactions, an oxonium ion is often formed by catalyst
promoted ionization forming a chiral ion pair 2a.[5] Many elegant
examples demonstrate the applicability of this strategy, resulting
in the enantioselective preparation of a variety of different bond
motifs.[6] Alternatively, the oxonium can be formed by other
means and Mattson showed that 2b could be formed by
silylation of 4.[7] This work demonstrated the first
enantiocontrolled addition to 4-silyloxybenzopyrylium triflates
and employed silyldiol catalysts reaching 56% ee. Metal-
catalyzed enantioselective addition to oxonium ions is much less
common, despite the fact that more basic nucleophiles could be
compatible.[8] Watson has reported on the addition to cyclic
oxocarbeniums formed by ionization of substrates 1.[9] Using
BOX ligands, they report significant differences between related
substrates and the identification of alternative ligand congeners
was unsuccessful, necessitating specific substrate types.[9c]
We have recently been exploring the application of stabilizing,
non-covalent interactions within imidazole-based biaryls[10] and
wondered if our Stack-ligand platform might provide a useful
scaffold for addition to oxonium ions. Since oxocarbenium
electrophiles have no lone pairs available to engage the catalyst
via Lewis acid/base interactions, we were intrigued by the
possibility that our arene-rich ligand framework might be able to
Chiral
Silyl Diol
This Work
O
OTMS
TMSO
O
X
L
TMSOTf
Base
+
O
O
L
-
7
4
+
6
R
M
R
functionalization?
Chromanones
Scheme 1. Enantioselective Chromone Alkynylation.
Chromanones constitute an important core that is shared by
many biologically active natural products.[12] Diverse bioactivity
includes antitumor,[12c] antimicrobial,[12d] and antibacterial
activities,[12e] among others. This core has also been
incorporated into synthetic analogues such as Krische’s
chromanone-based bryostatin analogues.[12f] Notably the 2-
position is generally substituted and, as such, enantioselective
methods have been developed to access this motif.[13] Despite
this importance, catalytic enantioselective methods are limited,
perhaps because there are issues that may be problematic.
Notably, under basic conditions, the reversible elimination of
phenoxide can result in racemization.[13a] The addition of
aliphatic
groups
has
been
reported
using
basic
organometallics,[14] but these groups do not broadly map onto
bioactive compounds.[7] In this regard, the direct addition of
alkynes is desirable because they are readily available and
diverse synthons. This new method would also be advantageous
because the silyl enol ether 7, could potentially be protonated or
further elaborated to increase the molecular complexity. Herein,
we report our results in this area.
[a]
Lindsey G. DeRatt, Mukesh Pappoppula, and Prof. Aaron Aponick*
Florida Center for Heterocyclic Compounds & Department of
Chemistry
With the goal of developing an enantioselective chromone
alkynylation, we set out to explore the proposed transformation
using our Stack-ligands. These ligands were designed to have a
stabilizing intramolecular catalyst-catalyst interaction between
the naphthyl and C6F5-groups,[10a,f] and the groups on the
University of Florida
P.O. Box 117200
Gainesville, FL 32607, USA
E-mail: aponick@chem.ufl.edu
backbone were originally incorporated to establish
pocket with quadrants of differing steric demand.[10b] The
a chiral
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201902405
Angewandte Chemie International Edition
COMMUNICATION
Table 1. Optimization Studies.
backbone aryl groups can be modified to include electron
withdrawing/donating substituents[10f] and we sought to
determine if these modifications could impact the reaction,
possibly by intermolecular p-p[15] or p-cation[16] interactions.
Although the phosphine’s aryl groups are also positioned in
proximity, and P-aryl-substrate interactions are known,[17] the
backbone aryls are unique to this imidazole P,N-ligand class and
offer tunability without directly impacting the nature of the metal-
ligand bond as does phosphine modification.
StackPhos
Ligands:
5.0 mol % CuI
O
R
R
O
O
5.5 mol % Ligand
Ph (1.3 equiv)
L1, R = Ph
N
N
F5
L2, R = 4-MeOPh
L3, R = 4-F-Ph
L4, R = C6H11
L5, R = Me
i-Pr2NEt (1.6 equiv)
TMSOTf (1.3 equiv)
PPh2
O
Ph
8a
4a
tol, -78 to -20 °C, 18 h;
then 3 N HCl, rt, 2 h
yield
(%)
ee
(%)
entry
ligand
deviation
R
R
1
2
--
no ligand
rac-ligand
none
73
91
89
79
85
71
65
74
89
76
92
--
rac-StackPhos, rac-L1
(S)-StackPhos, L1
--
Metal/
Substrate
Binding
Area
• R groups distal to binding site
with minimal steric impact
• Electronic changes insulated
from basic/chelating nitrogen
N
N
3
94
85
94
90
56
55
88
79
45
PPh2
F5
4
(S)-p-OMe-StackPhos, L2
(S)-p-F-Ph-StackPhos, L3
none
5
none
The study commenced with optimization experiments (see
Supporting Information) and the reaction parameters shown in
Table 1 were established. Under these conditions, the reaction
proceeded without exogenous ligand to provide the chromanone
8a in 73% yield (entry 1) and it was encouraging to find that the
yield was improved by addition of rac-StackPhos (entry 2). The
reaction was then tested with a variety of chiral ligands to probe
how distal changes would impact the selectivity. Using (S)-
StackPhos L1, with unsubstituted phenyl groups on the
backbone, the product was isolated 89% yield and the selectivity
was excellent (94% ee, entry 3). Interestingly, increasing the
electron density on the backbone aryls by incorporation of
methoxy groups in L2 yielded a reduction in both reactivity and
selectivity (79% yield, 85% ee, entry 4). Inclusion of 4-
fluorophenyl groups in ligand L3 restored the ee to 94% and 8a
was isolated in 85% yield (entry 5). Surprisingly, these
reactivity/selectivity results are opposite to what might be
predicted considering catalyst-benzopyrylium interactions.[18]
Although the substituents on the backbone aromatic are not able
to directly donate to the basic imidazole nitrogen through
resonance, these changes may also be due to inductive
effects;[19] however, both methoxy and fluoro are inductive
withdrawing groups and would likely show a similar trend. Our
original hypothesis neglected solvent,[15,16] and the fact that
toluene emerged as the solvent of choice in our initial
optimization was somewhat surprising. Using benzene instead
of toluene with the methoxy ligand L2, the selectivity increased
to 90% ee, while non-aromatic solvents gave dramatically
decreased yield and selectivity (entries 6-8). Furthermore, using
benzene as solvent with L1, the selectivity was reduced (entry 9
vs 3). These results suggest that the aromatic solvent molecules
play an important role, perhaps by mediating interactions with
the cationic intermediate. This is further supported by the
necessity for aromatic groups on the backbone. With either
cyclohexyl- or methyl ligands L4/L5, the selectivity decreased
substantially (entries 10, 11). Although the exact nature of the
interactions required for high selectivity are unclear at the
moment, the evidence points to the mitigating factors being
largely electronic and are suggestive of solvent mediated arene-
arene/ arene-cation interactions.
6[a]
7
(S)-p-OMe-Ph-StackPhos, L2
(S)-p-OMe-Ph-StackPhos, L2
PhH as solvent
THF as solvent
8
(S)-p-OMe-Ph-StackPhos, L2 CH2Cl2 as solvent
9[a]
10
11
(S)-StackPhos, L1
(S)-Cy-StackPhos, L4
(S)-Me-StackPhos, L5
PhH as solvent
none
none
[a] Reaction temperature = -78 °C to 0 °C, 18 h.
Irrespective of the mechanistic underpinnings, the reaction
worked quite well. The conditions in Table 1, entry 3 were
deemed optimal and the scope of the reaction was explored. As
seen in Table 2, it was found that the transformation tolerates a
variety of alkynes. In addition to phenylacetylene, both electron
withdrawing and donating groups on aromatic alkynes produced
8b and 8c in high ee (94% and 89% ee, Table 2, entries 2-3).
The reaction also tolerated substitution in the ortho and meta
positions (entries 4-5) as well as heteroaromatics (entry 6).
Protected propargyl alcohol and amine worked well under the
reaction conditions forming the products 8g and 8h in 95% and
90% ee (entries 7-8). The reaction proceeded smoothly using
TMS acetylene, giving the alkynylated product 8i in 73% yield
and 95% ee (entry 9), which is important for terminal alkyne
synthesis. It was also demonstrated that enynes and aliphatic
alkynes were functional under the reaction conditions (entries
10-13). Finally, the presence of additional stereocenters did not
affect the reaction and 8n was formed in 92% ee vide infra.
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10.1002/anie.201902405
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COMMUNICATION
Table 2. Alkyne Scope Studies.
Oxygenation at the 8-position afforded the product 8p in 91% ee
(entry 2). Interestingly, both 6-fluoro and 6-acetoxyl substituents
were tolerated under the reaction conditions (entries 5,3). We
were also encouraged to find that the reaction functions on
substrates bearing a substituent at the 3-postion, allowing for the
incorporation of an additional stereocenter on the nucleus. As
observed in entries 6 and 7, the 3-substituted products 8t and
8u were isolated in good yield and diastereoselectivity favoring
the 2,3-cis products in high optical purity. Compounds with this
relative stereochemistry are likely the kinetic products derived
from silyl enol ether protonation.
5.0 mol % CuI
O
O
O
5.5 mol % (S)-StackPhos
Alkyne (1.3 equiv)
i-Pr2NEt (1.6 equiv)
TMSOTf (1.3 equiv)
O
8a-n
R
4a
tol, -78 to -20 °C;
then 3 N HCl, rt, 2 h
entry
1
product
entry
8[a]
product
O
O
O
O
Bn
N
Ph
8a, 89%
Bn
8h, 63%
94% ee
90% ee
Table 3. Studies on Chromone Scope.
O
O
5.0 mol % CuI
5.5 mol % (S)-StackPhos
Ph (1.3 equiv)
O
O
R2
R2
2
3
9[a]
O
O
R1
R1
TMS
8i, 73%
95% ee
8b, 73%
94% ee
i-Pr2NEt (1.6 equiv)
TMSOTf (1.3 equiv)
tol, -78 to -20 °C, 18-24 h;
then 3 N HCl, rt, 2 h
O
O
NO2
8o-u
Ph
4b-h
O
O
entry
1
product
entry
4
product
10
O
O
O
O
O
O
8j, 44%
82% ee
8c, 70%
89% ee
O
O
MeO
O
Br
O
8o, 78%
94% ee
8r, 52%
94% ee
Ph
Ph
O
4
5
6
11
12[b]
13
O
O
O
Br
8k, 89%
90% ee
F
8d, 89%
93% ee
Cl
Cl
2
3
5
O
O
O
O
8s, 84%
89% ee
OMe
8p 81%
91% ee
Ph
Ph
Me
O
O
O
R
8l, 69%
90% ee
5
8e, 94%
89% ee
O
AcO
O
O
O
O
Ph
O
R = Ph, 8t, 78%
dr 10:1; 95% ee
8q, 83%
87% ee
Ph
6
7
O
S
8m, 71%
87% ee
Br
8f, 78%
93% ee
R = Me, 8u 81%
dr 10:1; 95% ee
O
O
7
14[c,d]
O
O
OBn
OH
OH
With a broad substrate scope established, it was necessary to
determine the absolute configuration of the products. To this
end, 8a, formed using the (S)-L1, was transformed into the
natural product flindersiachromanone 9b,[20] which has been
selectively prepared as both enantiomers by chemical
synthesis.[13b,21] Comparison of the sign of the optical rotation of
both intermediate 9a and the natural product 9b revealed the
stereochemistry to be (S), as shown in Scheme 2, and the
alkyne products 8 were assigned as shown by analogy.
8n, 55%
dr 1:1
92% ee
8g, 85%
95% ee
[a] Reaction temperature = -78 °C to -10 °C; [b] The enyne starting
material and the product 8l were both used and isolated in a (5:1) E:Z ratio;
[c] The alkyne bis-acetate was used as starting material and immediately
deprotected to form the diol 8n. Yield is reported over
Enantioselectivity determined after Au-catalyzed cyclization to form the
furan (Scheme 3).
2 steps; [d]
O
O
H2, Pd/C
IBX21a
MeOH
The scope of the chromones was also explored (Table 3).
The reaction proceeded smoothly with incorporation of an
electron donating methoxy group in the 7-position, which is seen
in numerous natural products, to give the product 8o in 78%
yield and 94% ee (Table 3, entry 1). Alkynylation of 7-
bromochromone also worked well under the reaction conditions
(entry 4), which could allow for further functionalization of the
DMSO
50%
O
O
rt, 24h, 80%
Ph
O
9a
9b
Ph
Ph
8a
[α]23 = -63.9
(c 1.2 CH3OH)
[α]23 = -103.2
(c 1.0 CHCl3)
Scheme 2. Determination of Absolute Configuration
chromone
skeleton
through
cross-coupling
reactions.
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10.1002/anie.201902405
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COMMUNICATION
Intercepting the Silyl Enol Ether
To be synthetically useful, the reaction would need to function
on scale, preferably with a reduced catalyst loading, and this
was briefly explored. It was found that the loading could be
reduced to 1 mol % at 0.2 M in toluene with minimal impact to
yield and ee. As seen in equation 1, with (R)-StackPhos as
ligand, ent-8a was obtained in 90% ee on gram scale. Judging
from this result, the reaction scale could likely be further
increased without detrimental effects.
O
OH
DMDO (3.0 equiv)
-78 °C, 1 h
O
10
Ph
OTMS
dr >20:1
68%, 93% ee
O
O
OH
R
H
7
O
1.0 mol % CuI
1.1 mol % (R)-StackPhos
Ph
O
PhCHO
BF3•OEt2
-78 °C, 1 h
O
Ph (1.3 equiv)
(1)
11
dr >20:1
74%, 94% ee
TMS
i-Pr2NEt (1.6 equiv)
TMSOTf (1.3 equiv)
tol, -78 to -20 °C, 36 h;
then 3 N HCl, rt, 2 h
O
O
Ph
ent-8a
88%, 90% ee
[gram scale]
4a
5 mmol
Heterocycle Synthesis
O
O
It was envisioned that this methodology could provide access
to a variety of useful compounds in high enantioselectivity. To
explore this, we looked at intercepting the ostensibly formed silyl
enol ether 7. In this context, instead of treating the reaction
mixture with HCl after alkyne addition, it was cooled to -78 °C
and 3 equivalents of dimethyldioxirane were added directly to
the reaction vessel to effect Rubottom oxidation.[22] Under these
conditions, the corresponding α-hydroxyketone 10 was isolated
as a single diastereomer in 68% overall yield (Scheme 3).
Additionally, it was found that the silyl enol ether could engage in
reactions with other electrophiles such as aldehydes to give the
aldol product 11, also as a single diastereomer. It should be
noted that both of these transformations proceeded with the
same level of enantioselectivity that was observed for
chromanones (93-94% ee) and that the 2,3-trans diastereomers
were the major products. This stereoselectivity is
complementary to the cis diastereomers obtained by protonation
8t/u (Table 3). We also envisioned that the alkyne could be
further transformed into useful moieties. One such example is
included in Scheme 3 using the chromanone 8n as a starting
material. Under Au-catalysis conditions,[23] the propargyl diol
moiety was transformed in a straightforward manner to produce
the furan 12 in 92% ee. Finally, we were also able to convert the
chromanone 8a to the dihydrobenzofuran 13 in 70% yield,[24]
also maintaining the same ee.
AuCl (10 mol %)
THF, rt, 1 h
O
O
12
OH
O
8n, 92% ee
92%, 92% ee
OH
Stereospecific Ring Contraction
CO2Et
O
PIFA
Ph
HCO2H, H2SO4
CH(OEt)3,
0 °C, 0.5 h
O
O
13
94% ee
Ph
8a
dr >20:1
70%, 94% ee
Scheme 3. Synthetic utility of the products.
Acknowledgements
The authors thank the University of Florida and The National
Science Foundation (CHE-1362498) for their generous support
of our programs. Mass spectrometry instrumentation was
supported by a grant from the National Institutes of Health (S10
OD021758-01A1).
Keywords: Chromanone • Enantioselective Catalysis • Non-
In summary, we have developed the first catalytic
enantioselective alkynylation of silyloxybenzopyrylium ions. The
reaction is effective over a broad substrate scope and the
products can be efficiently transformed in a variety of ways. The
success of the reaction with respect to both chemical yield and
selectivity is influenced by ligand substituents and, although the
parent StackPhos ligand was used here, the conditions can be
modulated to provide good results with different ligand
congeners by solvent choice. Our current interpretation of these
data is that the effects are mostly electronic in nature and may
impact the reaction via non-covalent interactions; however,
further studies to elucidate the nature of the catalyst-substrate
interactions are necessary and are underway. Moreover, we are
currently developing new reactions taking advantage of this
concept and this work will be reported in due course.
Covalent Interactions • Cu-catalysis • StackPhos • Alkynylation
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COMMUNICATION
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This article is protected by copyright. All rights reserved.

10.1002/anie.201902405
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Lindsey G. DeRatt, Mukesh
Pappoppula, and Aaron Aponick*
5.0 mol % CuI
O
OTMS
O
O
5.5 mol % (S)-StackPhos
Alkyne (1.3 equiv)
R1
R1
R1
i-Pr2NEt (1.6 equiv)
TMSOTf (1.3 equiv)
O
Page No. – Page No.
O
R2
R2
up to 95% ee
A Facile Enantioselective
Alkynylation of Chromones
The first catalytic enantioselective alkylation of chromones is reported. The
reaction, which is both high yielding and highly enantioselectivity over a broad
range of substrates, utilizes StackPhos as ligand and proceeds through an
intermediate oxonium ion generated in situ. The direct product is a silyl enol ether
which can either be protonated or treated with additional electrophilic reagents to
build further complexity.
This article is protected by copyright. All rights reserved.