Silanediol-Catalyzed Chromenone Functionalization

Article abstract of DOI:10.1021/acs.orglett.6b01783

Promising levels of enantiocontrol are observed in the silanediol-catalyzed addition of silyl ketene acetals to benzopyrylium triflates. This rare example of enantioselective, intermolecular chromenone functionalization with carbonyl-containing nucleophiles has potential applications in the synthesis of bioactive chromanones and tetrahydroxanthones.

Full text of DOI:10.1021/acs.orglett.6b01783

Letter
pubs.acs.org/OrgLett
Silanediol-Catalyzed Chromenone Functionalization
Andrea M. Hardman-Baldwin,† Michael D. Visco,† Joshua M. Wieting,‡ Charlotte Stern,§
Shin-ichi Kondo,∥ and Anita E. Mattson*
Department of Chemistry and Biochemistry, The Ohio State University, 100 West 18th Avenue, Columbus, Ohio 43210, United
States
S
* Supporting Information
ABSTRACT: Promising levels of enantiocontrol are observed
in the silanediol-catalyzed addition of silyl ketene acetals to
benzopyrylium triflates. This rare example of enantioselective,
intermolecular chromenone functionalization with carbonyl-
containing nucleophiles has potential applications in the
synthesis of bioactive chromanones and tetrahydroxanthones.
methods are not directly applicable to many families of
bioactive chromanones, such as the gonytolides and blenno-
lides.5 Herein, we describe the first catalytic strategy for
enantioselective intermolecular functionalization of chrome-
nones with carbonyl-containing nucleophiles.
Our inspiration for these studies originated from data
reported by Akiba and co-workers that demonstrated the
racemic addition of silyl ketene acetals, allyl silanes, and dienes
to benzopyrylium triflates 2, reactive species generated from the
exposure of chromen-4-ones (1) to silyl triflates.6 Our studies
were further encouraged by the Porco group’s recent
application of racemic additions of siloxyfurans to 4-
siloxybenzopyrylium ions in the syntheses of complex
chromanone natural products.7 Enticed by the synthetic utility
of these racemic additions, we set out to develop the first
enantiocontrolled functionalization of 4-siloxybenzopyrylium
ions.
lthough a small array of strategies to construct chiral 2-
1
Aalkylchroman-4-ones has been explored and reported, a
general catalytic, enantioselective method to access these
important bioactive heterocycles in enantiopure form remains
elusive.2 To this end, in 2005, Hoveyda reported a copper−
peptide complex for catalytic enantioselective addition of
dialkylzincs to chromone (Scheme 1).3 More recently, Feringa
and co-workers found that Grignard reagents undergo
enantioselective additions to chromone in the presence of a
copper catalyst and Josiphos-based ligands.4 While high
yielding and highly stereoselective, both of these strategies
only enable the addition of simple aliphatic groups: these
Scheme 1. Enantioselective Strategies toward 2-
Alkylchromanones
In connection with our ongoing research program dedicated
toward metal-free, noncovalent catalyst design, we became
interested in exploring the anion-binding ability of silanediols in
the context of enantioselective 2-alkylchroman-4-one con-
struction (Scheme 2).8−10 We envisioned capturing 4-
siloxybenzopyrylium triflates (2) with a silanediol catalyst
resulting from the in situ generation of a chiral ion pair. It was
reasoned that our arene-rich silanediols would offer a chiral
pocket uniquely suited to stabilize a network of noncovalent
interactions (e.g., hydrogen bonding, π−π, π−cation) in a
transition state that would ultimately enable the facially biased
addition of nucleophiles to the reactive benzopyrylium ion.
Our studies began by probing the influence of silanediol
structure on enantioselectivity in the addition of silyl ketene
Received: June 19, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01783
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Strategy for Silanediol-Catalyzed Enantioselective
Benzopyrylium Ion Functionalization
Scheme 4. Silanediol−Triflate Association Measured by
Fluorescence Spectroscopy
acetal 3 to siloxybenzopyrylium triflates (Scheme 3). Prior
success with BINOL-based silanediols 5a and 5b in the addition
Scheme 3. Some Effects of Silanediol Structure on Yield and
Enantiocontrol
constant of 2.31 0.52 × 103 M−1 was obtained for 5a and
triflate.11
Concomitant with our BINOL−silanediol catalyst design
program emerged the development of both acyclic (5c) and
cyclic (5d) VANOL-based silanediols. We were especially
excited by the prospect of incorporating VANOL into our
silanediol scaffolds as it is able to reach unique chemical space
and can offer improved selectivity over BINOL-based catalysts
and ligands.12 The synthetic accessibility of VANOL-based
silanediols had not been reported prior to our investigations, so
we dedicated a significant amount of effort to establishing
routes to these interesting structures (Scheme 5). Acyclic
Scheme 5. VANOL−Silanediol Syntheses
of silyl ketene acetals to isoquinolinium ions prompted us to
explore these catalysts in the synthesis of 4.9b The ability of our
BINOL-based silanediols to enable and influence the
enantioselective addition of silyl ketene acetals to benzopyry-
lium triflates was almost immediately evident; the unsubstituted
cyclic silanediol 5a gave a 24% ee but low yield (25%). Our
initial catalyst screen demonstrated the dramatic effect of
silanediol structure on enantiocontrol. For example, 4,4′,6,6′-
tetraphenyl-substituted 5b only provided an 8% ee. The nature
of the silyl group of the silyl triflate and silyl ketene acetal (3)
had a fairly substantial influence on the enantioselectivity: the
tert-butyldimethylsilyl group was more effective with regard to
stereocontrol but lower yielding than the triisopropylsilyl
group, possibly due to undesired silylation of the catalyst.
The promising levels of enantiocontrol observed with
BINOL-based silanediol 5a in the addition of 3 to proposed
benzopyrilium triflate 2 prompted us to briefly explore the
plausible triflate−silanediol 5a binding by fluorescence spec-
troscopy (Scheme 4). Experimentally, changes observed in the
fluorescence spectra were measured as aliquots of tetrabuty-
lammonium triflate were titrated into a solution of silanediol in
CHCl3. From the average of four experiments, an association
VANOL−silanediol 5c was prepared by first monotriflating 6
and then reducing and triflating the remaining hydroxyl group
to reach 7.13 The Kumada cross coupling of 7 with
methylmagnesium bromide followed by radical bromination
gave rise to 8.14 Introduction of the silyl group was achieved in
excellent yield upon treatment of 8 under recently developed
Barbier-type reaction conditions for this C−Si bond
formation.15 The intermediate silane was subjected to hydro-
lytic oxidation with Pd/C as a catalyst to generate 5c.
B
DOI: 10.1021/acs.orglett.6b01783
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Cyclic VANOL silanediol 5d presented a greater synthetic
challenge than 5c because the introduction of the two methyl
groups is difficult, presumably because the 2,2′ positions of
VANOL are so sterically encumbered and had not been
previously reported. A significant amount of experimentation
enabled the identification of NiCl2(PCy3)2 as a unique catalyst
able to effect the desired double Kumada cross coupling on 9 to
access 10. Subsequent lithiation of 10 followed by silacycliza-
tion with tetramethoxysilane followed by hydrolysis afforded
desired silanediol 5d.
To our delight, VANOL-based silanediols 5c and 5d did offer
us improvements in stereocontrol and/or yield when compared
to the BINOL-based scaffolds (Scheme 3). For instance, acyclic
VANOL−silanediol 5c provided a 24% enantiomeric excess of
4 in excellent yield (91%). The best stereocontrol in Scheme 3
was observed with cyclic VANOL−silanediol 5d: 50%
enantiomeric excess was realized for the functionalized
chromanone 4 after 4 h at −78 °C. Unfortunately, the best
enantioselective reaction conditions in Scheme 3 gave rise to
just 35% yield of product.
groups. For example, chromenones substituted with chloro
and bromo in the 6-position gave rise to 4b and 4c in high yield
with 41% and 45% ee, respectively, with shorter reaction times.
The highest enantiocontrols observed in this system were with
3,5-bistrifluoromethylphenyl and nitro in the 6-position: 56%
and 49% enantiomeric excesses were observed in the formation
of 4d and 4e. In comparison, the electron-donating methyl
group in the 6-position gave rise to 4g with 16% ee. Electron-
withdrawing groups installed in the 7- and 8-positions also gave
rise to high yields (i.e., 4h and 4i) and promising levels of
enantiocontrol of the desired alkylated chromanones.
The absolute stereochemistry of the newly formed stereo-
genic center at the 2-position of chromanone products 4 was
studied by X-ray crystallography (Scheme 7). Compound 4c
Scheme 7. Evidence for the Absolute Configuration of 4c
a
Including an ORTEP Representation of 11a
Our efforts to find both high yielding and stereoselective
reaction conditions for the functionalization of chromenones
continued with the investigation of 3,3′-substituted BINOL-
based silanediol 5e (Scheme 6).16 We hypothesized that
Scheme 6. Effect of 3,3′-Substituted BINOL-Based
Silanediol on Alkylation Reactions of Various Chromenones
a
The anisotropic displacement parameters are drawn at the 50%
probability level.
was converted to iminochromanone 11 by condensation with
(R)-2-methylpropane-2-sulfinamide.19 The two diastereomers
of 11, 11a, and 11b were then separable by crystallization from
dichloromethane and hexanes. The X-ray quality crystals
obtained for 11a allowed for its solid-state structure
determination and revealed its absolute stereochemistry. The
deprotection of 11a gave rise to 4c. HPLC analyses of 11a and
4c suggest that the absolute configuration of the major
enantiomer of the newly formed stereocenter in 4 is S.
The promising levels of enantiocontrol observed in the
silanediol-catalyzed reaction of 1 and 3 become synthetically
useful when coupled with recrystallization (Scheme 8). For
example, on scale up, 4c can be isolated and further purified by
a
2 formed with 1.1 equiv of silyl triflate and 0.3 equiv of 2,6-di-tert-
butyl-4-methylpyridine in 0.5 M toluene at 60 °C for 1 h. See the
Supporting Information for details. Yields based on unreacted starting
b
Scheme 8. Synthetically Useful Enantiomeric Excess of 4
Observed upon Recrystallization
material.
increased bulk surrounding the silanediol functionality would
prevent undesired silylation events. Indeed, the unique chiral
pocket offered by catalyst 5e effects a high-yielding reaction of
the silyl ketene acetal and chromenone with moderate levels of
enantiocontrol (4a: 76% yield and 39% ee).17,18 The structure
of the chromenone was found to have a dramatic effect on the
reaction outcome. In general, chromenones substituted with
electron-withdrawing groups were higher yielding and more
selective than chromenones possessing electron-donating
C
DOI: 10.1021/acs.orglett.6b01783
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(3) Brown, M. K.; Degrado, S. J.; Hoveyda, A. H. Angew. Chem., Int.
Ed. 2005, 44, 5306−5310.
recrystallization from 2-propanol and hexanes. Upon recrystal-
lization, the enantiomeric excess of 4c is improved to 74% ee.
In summary, the first demonstration of the enantioselective
intermolecular functionalization of 4-siloxybenzopyrylium ions
is reported. BINOL− and VANOL−silanediols have been
identified as anion-binding catalysts able to offer promising
levels of stereocontrol in the addition of silyl ketene acetals to
benzopyrylium ions. The data suggest that both the silanediol
scaffold and chromenone structure can significantly influence
the reaction outcome. The advancement of BINOL− and
VANOL−silanediol analogues to achieve excellent levels of
stereocontrol in the enantioselective alkylation of benzopyry-
lium ions is a topic of current interest in our laboratories, and
we are looking forward to reporting our progress.
(4) Vila, C.; Hornillos, V.; Fananas
́
-Mastral, M.; Feringa, B. L. Chem.
̃
Commun. 2013, 49, 5933−5935.
(5) For isolation reports of gonytolides and blennolides, see:
(a) Kikuchi, H.; Isobe, M.; Sekiya, M.; Abe, Y.; Hoshikawa, T.; Ueda,
K.; Kurata, S.; Katou, Y.; Oshima, Y. Org. Lett. 2011, 13, 4624−2627.
(b) Zhang, W.; Krohn, K.; Zia-Ullah; Florke, U.; Pescitelli, G.; Di Bari,
̈
́
L.; Antus, S.; Kurtan, T.; Rheinheimer, J.; Draeger, S.; Schulz, B. Chem.
- Eur. J. 2008, 14, 4913−4923.
(6) (a) Iwasaki, H.; Kume, T.; Yamamoto, Y.; Akiba, K. Tetrahedron
Lett. 1987, 28, 6355−6358. (b) Stubbing, L. A.; Li, F. F.; Furkert, D.
P.; Caprio, V. E.; Brimble, M. A. Tetrahedron 2012, 68, 6948−6956.
(c) Liu, J.; Li, Z.; Tong, P.; Xie, Z.; Zhang, Y.; Li, Y. J. Org. Chem.
2015, 80, 1632−1643.
(7) (a) Qin, T.; Johnson, R. P.; Porco, J. A. J. Am. Chem. Soc. 2011,
133, 1714−1717. (b) Qin, T.; Skraba-Joiner, S. L.; Khalil, Z. G.;
Johnson, R. P.; Capon, R. J.; Porco, J. A. Nat. Chem. 2015, 7, 234−240.
(c) Qin, T.; Porco, J. A. Angew. Chem., Int. Ed. 2014, 53, 3107−3110.
(8) For recent reviews on anion-binding catalysis, see: (a) Busschaert,
N.; Caltagirone, C.; Van Rossom, W.; Gale, P. A. Chem. Rev. 2015,
115, 8038−8155. (b) Brak, K.; Jacobsen, E. N. Angew. Chem., Int. Ed.
2013, 52, 534−561. For recent examples of reactions likely
proceeding through anion inding, see: (c) Zurro, M.; Asmus, S.;
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.6b01783.
General methods and selected HPLC and NMR spectra
(PDF)
Crystallographic data (PDF)
Bamberger, J.; Beckendorf, S.; García Mancheno, O. Chem. - Eur. J.
̃
2016, 22, 3785−3793. (d) García Mancheno, O.; Asmus, S.; Zurro,
̃
M.; Fischer, T. Angew. Chem., Int. Ed. 2015, 54, 8823−8827. (e) Mittal,
N.; Lippert, K. M.; De, C. K.; Klauber, E. G.; Emge, T. J.; Schreiner, P.
R.; Seidel, D. J. Am. Chem. Soc. 2015, 137, 5748−5758. (f) Witten, M.
R.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2014, 53, 5912−5916.
(9) (a) Schafer, A. G.; Wieting, J. M.; Fisher, T. J.; Mattson, A. E.
Angew. Chem., Int. Ed. 2013, 52, 11321−11324. (b) Wieting, J. M.;
Fisher, T. J.; Schafer, A. G.; Visco, M. D.; Gallucci, J. C.; Mattson, A. E.
Eur. J. Org. Chem. 2015, 2015, 525−533. (c) Schafer, A. G.; Wieting, J.
M.; Mattson, A. E. Org. Lett. 2011, 13, 5228−5231.
(10) For an early report on silanediol anion inding,see: Kondo, S.;
Harada, T.; Tanaka, R.; Unno, M. Org. Lett. 2006, 8, 4621−4624.
(11) See the Supporting Information for detailed procedures
describing the determination of the association constant of 5a and
triflate.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: mattson@chemistry.ohio-state.edu.
Present Addresses
‡(J.M.W.) Vanderbilt Center for Neuroscience Drug Discovery,
393 Nichol Mill Lane, Suite 1000 Franklin, TN 37067.
§(C.S.) Northwestern University, 2145 Sheridan Road,
Evanston, IL 60208.
∥(S.-i.K.) Yamagata University, 1-4-12 Kojirakawa-machi,
Yamagata 990-8560, Japan.
(12) For examples of VANOL offering improvements over BINOL in
catalytic reactions, see: (a) Antilla, J. C.; Wulff, W. D. Angew. Chem.,
Int. Ed. 2000, 39, 4518−4521. (b) Lou, S.; Schaus, S. E. J. Am. Chem.
Soc. 2008, 130 (22), 6922−6923. (c) Desai, A. A.; Wulff, W. D. J. Am.
Chem. Soc. 2010, 132, 13100−13103. (d) Blay, G.; Cardona, L.; Pedro,
J. R.; Sanz-Marco, A. Chem. - Eur. J. 2012, 18, 12966−12969.
(e) Zhang, X.; Staples, R. J.; Rheingold, A. L.; Wulff, W. D. J. Am.
Chem. Soc. 2014, 136, 13971−13974. (f) Li, X.; Han, J.; Jones, A. X.;
Lei, X. J. Org. Chem. 2016, 81, 458−468.
Author Contributions
†A.M.H.-B. and M.D.V. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Science Foundation (Award No.
1362030) and the Ohio State University for supporting these
investigations.
(13) Mori, A.; Mizusaki, T.; Ikawa, T.; Maegawa, T.; Monguchi, Y.;
Sajiki, H. Tetrahedron 2007, 63, 1270−1280.
(14) Han, Y.-Y.; Wu, Z.-J.; Chen, W.-B.; Du, X.-L.; Zhang, X.-M.;
Yuan, W.-C. Org. Lett. 2011, 13, 5064−5067.
(15) Visco, M. D.; Wieting, J. M.; Mattson, A. E. Org. Lett. 2016, 18,
2883−2885.
(16) See the Supporting Information for the preparation of 5e.
(17) Optimization screens including solvent, temperature, silylating
reagent, nucleophile, etc. provided no improvements in ee. In the
absence of catalyst, 13% yield of the product is observed.
(18) 5e provided 30% yield and 29% ee with tert-butyldimethylsilyl
reagents with minimal silylation of the catalyst. 5e and 5e-SiR3 can be
recovered via chromatography.
REFERENCES
■
(1) For recent reviews containing numerous examples of bioactive
targets with chromanone cores, see: (a) Rateb, M. E.; Ebel, R. Nat.
Prod. Rep. 2011, 28, 290−344. (b) Masters, K. S.; Brase, S. Chem. Rev.
̈
2012, 112, 3717−3776. (c) Wezeman, T.; Brase, S.; Masters, K. S. Nat.
̈
Prod. Rep. 2015, 32, 6−28.
(2) For a review, see: Nibbs, A. E.; Scheidt, K. A. Eur. J. Org. Chem.
2012, 2012, 449−462. For select examples of enantioselective 2-
alkylchromanone synthesis, see: (a) Rao, A. V. R.; Gaitonde, A. S.;
Prakash, S. P.; Rao, S. P. Tetrahedron Lett. 1994, 35, 6347−6350.
(b) Kawasaki, M.; Kakuda, H.; Goto, M.; Kawabata, S.; Kometani, T.
Tetrahedron: Asymmetry 2003, 14, 1529−1534. (c) Biddle, M. M.; Lin,
M.; Scheidt, K. A. J. Am. Chem. Soc. 2007, 129, 3830−3831. (d) Boekl,
H.; Mackert, R.; Muramann, C.; Schweickert, N. US66646136B1,2013.
(e) Termath, A. O.; Sebode, H.; Schlundt, W.; Stemmler, R. T.;
Netscher, T.; Bonrath, W.; Schmalz, H.-G. Chem. - Eur. J. 2014, 20,
12051−12055.
(19) Sirvent, J. A.; Foubelo, F.; Yus, M. Chem. Commun. 2012, 48,
2543−2545.
D
DOI: 10.1021/acs.orglett.6b01783
Org. Lett. XXXX, XXX, XXX−XXX