Copper Bis(oxazoline)-Catalyzed Enantioselective Alkynylation of Benzopyrylium Ions

Article abstract of DOI:10.1002/chem.201904822

The stereocontrolled construction of biologically relevant chromanones and tetrahydroxanthones has been achieved through the addition of alkynes to benzopyrylium trilfates under the influence of copper bis(oxazoline) catalysis. Excellent levels of enantiocontrol (63–98 % ee) are achieved in the addition of a variety of alkynes to an array of chromenones with a hydrogen in the 2-position. Promising levels of enantiocontrol (54–67 % ee) are achieved in the alkynylation of chromenones with esters in the 2-position, generating tertiary ether stereocenters resembling those frequently found in naturally occurring metabolites.

Full text of DOI:10.1002/chem.201904822

A Journal of
Accepted Article
Title: Copper Bis(oxazoline)-Catalyzed Enantioselective Alkynylation of
Benzopyrylium Ions
Authors: Yong Guan, Jonathan Attard, and Anita Elaine Mattson
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To be cited as: Chem. Eur. J. 10.1002/chem.201904822
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Copper Bis(oxazoline)-Catalyzed Enantioselective Alkynylation of
Benzopyrylium Ions
Yong Guan[a], Jonathan W. Attard[a], and Anita E. Mattson*[a]
Abstract: The stereocontrolled construction of biologically relevant
chromanones and tetrahydroxanthones has been achieved through
the addition of alkynes to benzopyrylium trilfates under the influence
of copper bis(oxazoline) catalysis. Excellent levels of enantiocontrol
(63-98% ee) are achieved in the addition of a variety of alkynes to an
array of chromenones with a hydrogen in the 2-position. Promising
levels of enantiocontrol (54-67% ee) are achieved in the alkynylation
of chromenones with esters in the 2-position, generating tertiary ether
stereocenters resembling those frequently found in naturally occurring
metabolites.
shown a racemic siloxyfuran addition to benzopyrylium triflates
followed by a sequence that includes a Birman resolution
Naturally occurring chromanones and tetrahydroxanthones
frequently possess attractive biological properties, including
anticancer, antibacterial, and antifungal activity (Figure 1).[1]
These molecules, existing in both monomeric and dimeric forms,
often present significant synthetic challenges. One aspect
contributing to their difficult synthesis is the 2-stereocenter (For
the purposes of this manuscript, a chromanone numbering
scheme has been adopted, Figure 1). Given the frequency with
which the 2-stereocenter emerges in several families of bioactive
chromenones and tetrahydroxanthones, there has been
significant interest in learning how to create this bond with high
levels of enantiocontrol.[2]
Scheme 1. Methods for synthesis of chromanones with a chiral tertiary ether
stereocenter.
can
be
a
productive
approach
to
synthesizing
tetrahydroxanthones with excellent levels of enantiomeric excess
(Scheme 1A).[3] Tietze uses an intramolecular Wacker reaction to
control the formation of the 2-stereocenter and several steps are
required to convert the alkene to the desired chromanone natural
product (Scheme 1B).[4] Despite the success of these tactics, a
direct and general method for the installation of the 2-stereocenter
remains a lucrative pursuit. Our group has been interested in
learning how to synthesize the 2-stereocenter of chromenones
with enantiocontrol. Our efforts initially focused on the addition of
silyl ketene acetals to benzopyrylium triflates, reactive species
generated in situ from chromenones and silyl triflates.[5] Initially
inspired by Porco’s success, we took advantage of silanediol
anion-binding catalysis to control, for the first time, addition
reactions of silyl ketene acetals to benzopyrylium triflates
affording 2-alkyl chromanones in up to 57% enantiomeric excess
(Scheme 1D).[6] We were delighted to see Mancheño and co-
workers further improved upon these findings, obtaining greater
than 90% enantiomeric excess under the influence of her
triazolium catalysts with select substrates.[7] Despite the promise
of anion-binding catalysis, the synthesis of tertiary ether 2-
Figure 1. Select bioactive chromanones and tetrahydroxanthones.
In the context of natural product synthesis, there are only a limited
number of strategies with demonstrated success. Porco has
[a]
Dr. Y. Guan, Mr. J. W. Attard, Prof. Dr. A. E. Mattson
Department of Chemistry and Biochemistry
Worcester Polytechnic Institute
100 Institute Road, Worcester, MA 01605
E-mail: aemattson@wi.edu
Supporting information for this article is given via a link at the end of
the document.
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chromanones in high enantiomeric excess directly from chromone
precursors remains a topic of great interest.
Our investigations were initiated with the addition of phenyl
acetylene to benzopyrylium triflate 2, generated in-situ from 1, in
the presence of a suitable copper source and ligand (Table 1).
During a systematic investigation of the reaction parameters it
was found that the nature of the copper source, bis(oxazoline)
ligand, and silyl triflate significantly affected the outcome of the
reaction with respect to both yield and enantioselectivity. Cu(OTf)2,
CuOTf, and CuBr gave rise to 4 with yields between 40-44% and
low enantiomeric excess (entries 1-3). CuI was identified as the
best reagent for this process, producing 4 with 69% yield and 95%
enantiomeric excess (entry 4). The screening of several
bis(oxazoline) ligands demonstrated the enantiomeric excess and
yield were readily influenced by the structure of the ligand. The
highest enantiomeric excess was realized with ligand 5a (R’=Bn,
95% ee, entry 4). Lower enantiomeric excesses were observed
with ligands 5b-c (R’ = Ph, i-Pr, t-Bu) but the yields were higher in
some cases (entries 4-7). Finally, the silyl triflate employed in the
reaction had a small influence on the yield and stereocontrol.
Specifically, t-butyldimethylsilyl triflate (TBSOTf) gave rise to the
best enantiomeric excess when compared to trimethylsilyl triflate
(TMSOTf) and triispropylsilyl triflate (TIPSOTf) (entries 4,8-9).
Considering the limitations of anion-binding catalysis (Table
1), we expanded our investigations to other catalytic platforms for
controlling addition reactions to chromone, such as alkynylation.[8]
We hypothesized that copper bis(oxazoline)[9] complexes would
influence the enantioselective addition of terminal acetylides onto
benzopyrylium triflates (Scheme 1E). This reasoning was inspired
by Watson’s work demonstrating that copper acetylides undergo
addition to in situ-generated oxocarbenium ions with high levels
of enantiomeric excess when a bis(oxazoline) ligand was
present.[10] While this manuscript was under preparation, Aponick
recently reported enantioselective alkynylation of chromones with
their StackPhos ligands (Scheme 1C).[11] Herein, we describe our
findings of copper bis(oxazoline) catalysis as an excellent
platform for the reaction of terminal alkynes and unhindered
benzopyrylium triflates (R=H) to generate desirable products with
excellent levels of enantiocontrol. This method represents a more
practical approach because it requires readily accessible
bis(oxazoline) ligands. Furthermore, we have found that copper
bis(oxazoline) catalysis provides promising levels of
enantiocontrol in the addition of terminal acetylides to substituted
benzopyrylium triflates (R = esters) to create chromanones with
highly substituted 2-stereocenters.
Table 2. Alkyne Substrate Scope
Table 1. Optimization
Entry[a]
Alkyne
R =
4
Yield[b]
(%)
ee
(%)
Entry[a]
Copper
Source
Ligand
R” =, R’ =
Silyl
Triflate
Yield[b]
(%)
ee
(%)
1
2
Ph
p-MeOPh
p-CF3Ph
p-tolyl
4a
4b
4c
4d
4e
4f
98
63
85
83
86
82
67
86
85
96
45
50
97
96
97
96
97
97
82
95
85
85
82
71
1
2
Cu(OTf)2
CuOTf
CuBr
CuI
Me, Bn (5a)
Me, Bn (5a)
Me, Bn (5a)
Me, Bn (5a)
Me, Ph (5b)
Me, i-Pr (5c)
Me, t-Bu (5d)
Me, Bn (5a)
Me, Bn (5a)
Me, Bn (5a)
Me, Bn (5a)
Me, Bn (5a)
TBSOTf
TBSOTf
TBSOTf
TBSOTf
TBSOTf
TBSOTf
TBSOTf
TMSOTf
TIPSOTf
TBSOTf
TBSOTf
TBSOTf
44
40
41
69
85
64
92
68
87
72
73
76
14
16
14
95
86
93
70
94
91
97
94
84
3
4
3
5
p-ClPh
4
6
m-tolyl
5
CuI
7
o-tolyl
4g
4h
4i
6
CuI
8[c]
9[d]
10[e]
11
12
TMS
7
CuI
CH2OBn
CH2CH2OBn
cyclopropyl
1-cyclohexenyl
8
CuI
4j
9
CuI
4k
4l
10
11
12
CuI[c]
CuI[d]
CuI[e]
[a] See Supporting Information for detailed procedures. [b] isolated yields. [c]
Ligand 5d was used. [d] Ligand 5e (R’ = Ph, R’’ = Bn) was used. [e] Ligand 5f
(R’ = 2-naphthyl, R’’ = Bn) was used. (S) enantiomer was obtained.
[a] See Supporting Information for detailed procedures. [b] NMR yields. [c]
Reaction conducted in a single flask with o-xylenes. [d] 5 mol % catalyst loading,
o-xylenes as solvent. [e] 1 mol % catalyst loading, o-xylenes as solvent.
The yield of the reaction was improved from 69% to 72% by
conducting the reaction in a single flask, the enantiomeric excess
remained excellent at 97% (entry 10). The reduction of the
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catalyst loading from 10 mol % to 5 mol % and 1 mol % resulted
in small losses in enantiomeric excess (entries 11-12).
enantiomeric excess. Donating substituents in the 7-position,
enabling formation of the desired products 4r-4s with excellent
enantiomeric excess but with reduced yield. 8-phenyl
Chromenone (1t), was also a competent reaction partner
affording 4t with 93% yield and 84% enantiomeric excess. The
naturally-inspired substitution pattern on chromenone 1u was
also easily incorporated into the reaction platform generating
product 4u in 75% yield and with 93% ee. Moderate enantiomeric
excess was obtained in the case of 3-(p-tolyl) chromone 1v, which
yielded 4v as a 2:1 mixture of diastereomers in 63% ee.
Having identified a promising set of reaction conditions for the
enantioselective alkynylation of chromenone 1, the scope of the
reaction with respect to chromenone and alkyne was tested. First,
the substituents on the alkyne were probed (Table 2). A variety of
aryl acetylides were found to operate well in the reaction
regardless of their substitution pattern. For instance, nearly
identical enantiomeric excesses were observed for phenyl
acetylene, p-methoxy phenyl acetylene, p-trifluoromethyl phenyl
acetylene, p-methyl phenyl acetylene, p-chloro phenyl aceytene,
and m-methyl phenyl acetylene (entries 1-6). The sterically
encumbered o-methyl phenyl acetylene gave rise to product 4e in
67% yield and 82% enantiomeric excess (entry 7). Alkynes
containing non-aryl substituents (R = TMS, alkyl, vinyl) were also
accommodated in the reaction (entries 8-12), although optimal
yields and stereocontrol was achieved with different
bis(oxazoline) ligands (entries 8-10). For example, trimethylsilyl
acetylene, a reaction partner of interest in the context of
tetrahydroxanthone synthesis, afforded product 4h in 86% yield
and 95% enantiomeric excess under the influence of
bis(oxazoline) 5d (entry 8). Synthetically relevant chromanone
products 4i and 4j were also produced in high yield and high
enantiomeric excess in the presence of ligands 5e and 5f,
respectively (entries 9 and 10).
The relevance of the methodology to natural product
construction was tested in the synthesis of chromanones 6-7 and
tetrahydroxanthone 9 (Scheme 3). The partial hydrogenation of
the alkyne in chromanone 4a was easily achieved with a
Pd/CaCO3, Pb catalyst system, 3,6-dithia-1,8-octanediol, and H2
to afford chromanone 6 in excellent yield with no loss in
enantiomeric excess (Scheme 2A). Under the influence of Pd,
CaCO3, Pb, and H2, the synthesis of 7 was affected in 84% yield
with no loss in enantiomeric excess. The application of the
methodology to the synthesis of tetrahydroxanthones is depicted
in Scheme 2B. Chromanone 4w is prepared in 77% yield and
excellent enantiomeric excess (92% ee) under the influence of
CuI and ligand 5d. Silyl group deprotection in the presence of
cesium fluoride (CsF), insertion of ethyldiazoacetate into the
terminal alkyne C-H bond,[12] and hydrogenation of the
intermediate allene gives rise to 8 in 40% yield and 90% ee over
three steps. Tetrahydroxanthone formation is achieved by a Lewis
acid promoted intramolecular Dieckmann cyclization to yield 9.[4b]
The final cyclization step does erode the enantiomeric excess
slightly and investigations are ongoing to overcome this issue.
Scheme 3. Demonstration of methodology in chromanone and
tetrahydroxanthone synthesis. See supporting information for detailed
procedures
Scheme 2. Chromenone Substrate Scope. See supporting information for
detailed procedures.
Chromones with substituents on the 5-, 6-, 7- and 8-positions
were generally well tolerated, yielding corresponding 2-
(phenylnyethynyl)chromanones in high enantiomeric excess.
(Scheme 2). Chromenones with a variety of substituents in the 6-
position (e.g., R = CF3, CH3, F, Cl, Br) performed well in the
reaction giving rise to products 4m-4q in excellent yield and
The high levels of enantiocontrol and extensive substrate
scope observed in the synthesis of 2-H chromanones 4a-4w
inspired us to stress the limits of the reaction system in the
synthesis of more highly substituted stereogenic centers.
Specifically, it was envisioned that chromenones containing
esters in the 2-position would render the methodology even more
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12 mol%), o-xylene (2 mL), i-Pr2NEt (52.3 μL, 0.3 mmol, 1.5 eq), and
phenyl acetylene (28.6 μL, 0.26 mmol, 1.3 eq) in that order at room
temperature. This mixture was allowed to stir for 30 minutes. The vial was
purged with dry N2 and then cooled to –78 ºC. TBSOTf (60 μL, 0.26 mmol,
1.3 eq) was added at –78 ºC, then the reaction was transferred to the lab
freezer at –28 ºC and allowed to react for 48h. The reaction was quenched
by the addition of 6N HCl (2 mL) and stirred for 2 hours. The reaction
mixture was extracted with EtOAc (3 x 2 mL), washed with saturated
NaHCO3 solution, dried over anhydrous NaSO4, and the solvent removed
under vacuum to obtain the crude product. The crude product was purified
by column chromatography on silica gel with Hexane:EtOAc (9:1) to afford
an off white solid (48.8 mg, 98% yield, 97 %ee).
valuable in the context of naturally occurring tetrahydroxanthone
synthesis by enabling the enantioselective construction of tertiary
ether stereocenters. The reaction was put to the test with the
addition of phenyl acetylene to chromone-2-carboxylate esters
(Table 3). We were delighted to find an initial enantiomeric excess
of 34% with the bis(oxazoline) ligand 5a containing a benzyl group
(R = Bn, entry 1). A quick screen of other readily available
bis(oxazoline) ligands resulted in the identification of t-Bu as the
best substituent identified to date with respect to both the yield
and enantiomeric excess (entry 3). Upon cooling the reaction from
0°C to –28°C a very encouraging 67% enantiomeric excess was
observed (entry 4). Ethyl, i-propyl, and t-butyl chromone-2-
carboxylate esters were also tolerated but with reduced
enantiomeric excess (entries 5-7).
Acknowledgements
Table 3. Tertiary ether stereocenter formation
The National Institutes of Health are gratefully acknowledged for
providing funds for our studies (5 R35 GM124804).
Keywords: Asymmetric Catalysis • Heterocycles • Synthetic
Methods • Natural Products • Synthetic Design
[1]
For recent reviews on dimeric chromanones and tetrahydroxanthones,
see: a) T. Wezeman, S. Brase, K. Masters Nat. Prod. Rep. 2015, 32, 6-
28; b) K. Masters, S. Brase, Chem. Rev. 2012, 112, 3717-3776. For
isolation and biological activities of gontyolides, see: H. Kikuchi, M. Isobe,
M. Sekiya, Y. Abe, T. Hoshikawa, K. Ueda, S. Kurata,Y. Katou, Y,
Oshima Org. Lett. 2011, 13, 4624-4627. For isolation and biological
activities of phomoxanthone A, see: a) M. Isaka, A. Jaturapat, K.
Rukserre, K. Damwisetkanjana, M. Tanticharoen, Y. Thebtaranonth J.
Nat. Prod. 2001, 64, 1015-1018; b) D. Ronsberg, A. Debbab, A. Mandi,
V. Vasylyeva, P. Bohler, B. Stork, L. Engelke, A. Hamcher, R. Sawadogo,
M. Diederich, V. Wray, W. Lin M. Kassack, C. Janiak, S. Scheu, S.
Wesselborg, T. Kurtan, A. Aly, P. Proksch J. Org. Chem. 2013, 78,
12409-12425. For isolation and biological activities of the blennolides,
see: W. Zhang, K. Krohn, Zia-Ullah, U. Florke, G. Pescitelli, L. Di Bari, S.
Antus, T. Kurtan, J. Rheinheimer, S. Draeger, B. Schulz Chem. Eur. J.
2008, 14, 4913-4923. For isolation and biological data on the
dicerandrols, see: M. M. Wagenaar and J. Clardy J. Nat. Prod. 2001, 64,
1006-1009.
Entry[a]
Ligand
R’ =
R =
Temp.
°C
Yield
(%)
ee
(%)
1[b]
2[b]
3[b]
4
Bn (5a)
Ph (5b)
Me
Me
Me
Me
Et
0
29
86
87
87
91
88
15
34
15
0
t-Bu (5d)
t-Bu (5d)
t-Bu (5d)
t-Bu (5d)
t-Bu (5d)
0
-38
-67
-65
-54
-60
–78 to – 28
–78 to – 28
–78 to – 28
–78 to – 28
5
5
i-Pr
t-Bu
7
[a] See Supporting Information for detailed procedures. [b] Conducted in a two-
step process in toluene, see procedure 1 in the supporting information for
details.
[2]
For a review, see: A. E. Nibbs.; K. A. Scheidt Eur. J. Org. Chem. 2012,
2012, 449−462. For select examples of enantioselective 2-
alkylchromanone synthesis, see: (a) A. V. Rao, A. S. Gaitonde, S. P.
Prakash, S. P. Rao Tetrahedron Lett. 1994, 35, 6347−6350. (b) M.
Kawasaki, H. Kakuda, M. Goto, S. Kawabata, T. Kometani Tetrahedron:
Asymmetry 2003, 14, 1529−1534; (c) M. M. Biddle, M. Lin, K. A. Scheidt
J. Am. Chem. Soc. 2007, 129, 3830−3831; (d) H. Boekl, R. Mackert, C.
Muramann, N. Schweickert US66646136B1, 2013; (e) A. O. Termath, H.
Sebode, W. Schlundt, R. T. Stemmler, T. Netscher, W. Bonrath, H.-G.
Schmalz Chem. - Eur. J. 2014, 20, 12051−12055; (f) M. K. Brown, S. J.
Degrado, A. H. Hoveyda Angew. Chem. Int. Ed. 2005, 44, 5306-5310;
(g) C. Vila, V. Hornillos, M. Fananas-Mastral, B. L. Feringa Chem.
Commun. 2013, 49, 5933-5935; (g) B. M. Trost, E. Gnanamani, C. A.
Kalnmals, C.-I. Hung, J. S. Tracy J. Am. Chem. Soc. 2019, 141, 1489-
1493.
In conclusion, copper bis(oxazoline) complexes have proven
to be easy to use, general catalyst systems for the synthesis of 2-
stereogenic centers found in biologically relevant chromanones.
Excellent levels of enantiocontrol can be achieved in the reaction
of a diverse array of chromenone and alkyne reaction partners,
generating desirable 2-ethynyl chromanone products in high yield.
The reaction system can also be extended to the synthesis of
more highly substituted 2-stereogenic centers that may have
direct applications in naturally occurring bioactive chromanone
and tetrahydroxanthone synthesis. Our current efforts, directed
toward the continued exploration of these reactions in the
synthesis of naturally occurring dimeric tetrahydroxanthones, will
be reported as soon as possible.
[3]
[4]
[5]
(a) T. Qin, T. Iwata, T. T. Ransom, J. A. Beutler, J. A. Porco J. Am. Chem.
Soc. 2015, 137, 15225-15233; (b) T. Qin, J. A. Porco Angew. Chem. Int.
Ed. 2014, 53, 3107-3110.
(a) L. F. Tietze, L. Ma, J. R. Reiner, S. Jackenkroll, S. Heidemann Chem.
Eur. J. 2013, 19, 8610-8614; (b) D. Ganapathy, J. R. Reiner, G. Valdomir,
S. Senthilkumar, L. F. Tietze Chem. Eur. J. 2017, 23, 2299-2302.
For select work on the generation and reactions of benzopyrylium triflates,
see: (a) H. Iwasaki, T. Kume, Y. Yamamoto, K. Akiba Tetrahedron Lett.
1987, 28, 6355-6358; (b) L. A. Stubbing, F. F. Li., D. P. Furkert, V. E.
Experimental Section
To an 8 mL screw top vial was added chromone (29.2 mg, 0.2 mmol, 1.0
eq), CuI (3.8 mg, 0.02 mmol, 10 mol%), (S)-Bn-BOX (8.8 mg, 0.024 mmol,
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Caprio, M. A. Brimble Tetrahedron 2012, 68, 6948-6956; (c) J. Liu, Z. Li,
P. Tong, Z. Xie, Y. Zhang, Y. Li J. Org. Chem. 2015, 80, 1632-1643.
[9]
For a review on chiral bis(oxazoline) ligands in asymmetric catalysis, see:
G. Desimoni, G. Faita, K. A. Jorgensen Chem. Rev. 2006, 106, 3561-
3651.
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[7]
[8]
A. M. Hardman-Baldwin, M. D. Visco, J. M. Wieting, C. Stern, S. Kondo,
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T. Fischer, J. Bamberger, M. Gomez-Martinez, D. Piekarski, O. G.
Mancheño Angew. Chem. Int. Ed. 2019, 58, 3217-3221.
(a) M. Eriksson, T. Iliefski, M. Nilsson, T. Olssen, J. Org. Chem. 1997,
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Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
Highly enantioenriched chromanones
are prepared by the copper
Yong Guan, Jonathan Attard, Anita E.
Mattson*
bis(oxazoline) catalysed addition of
terminal alkynes to benzopyrylium
ions, reactive heterocycles generated
in situ from chromenones. This
methodology can be an attractive key
step in the synthesis of biologically
relevant tetrahydroxanthones.
Page No. – Page No.
Copper Bis(oxazoline)-Catalyzed
Alkynylation of Benzopyrylium Ions
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