Catalytic asymmetric alkylation of substituted isoflavanones

Article abstract of DOI:10.1021/ol901676f

The asymmetric alkylation of isoflavanones (3-aryl-chroman-4-ones) and protected 3-phenyl-2,3-dihydroquinolin-4(1H)-ones catalyzed by a novel cinchonidine-derived phase transfer catalyst E is reported. This functionalization occurs at the unactivated C3 methine to afford novel products that can easily be functionalized to generate more complex fused ring systems. The process accommodates a variety of isoflavanones and activated electrophiles and installs a stereogenic quaternary center in high yield and with good-to-excellent selectivity. Isoflavanones are a privileged class of natural products with a broad spectrum of biological activities including insecticidal, antimicrobial, antibacterial, estrogenic, antitumor, and anti-HIV activity. ¹ Isoflavanones are also precursors for more complex natural products such as pterocarpans and rotenones.¹ Given their therapeutic promise, selective strategies to access new classes of isoflavanones and related structures has high value.² The functionalization of the C3 position could promote beneficial interactions with biological targets of interest. Specifically, an alkylation at C3 can rapidly access new members of the general class of biologically active homoisoflavanones.³

Full text of DOI:10.1021/ol901676f

ORGANIC
LETTERS
2009
Vol. 11, No. 17
4010-4013
Catalytic Asymmetric Alkylation of
Substituted Isoflavanones
Antoinette E. Nibbs, Amanda-Lauren Baize, Rachel M. Herter, and Karl A. Scheidt*
Department of Chemistry, Center for Molecular InnoVation and Drug DiscoVery,
Northwestern UniVersity, 2145 Sheridan Road, EVanston, Illinois 60208
scheidt@northwestern.edu
Received July 22, 2009
ABSTRACT
The asymmetric alkylation of isoflavanones (3-aryl-chroman-4-ones) and protected 3-phenyl-2,3-dihydroquinolin-4(1H)-ones catalyzed by a
novel cinchonidine-derived phase transfer catalyst E is reported. This functionalization occurs at the unactivated C3 methine to afford novel
products that can easily be functionalized to generate more complex fused ring systems. The process accommodates a variety of isoflavanones
and activated electrophiles and installs a stereogenic quaternary center in high yield and with good-to-excellent selectivity. Isoflavanones are
a privileged class of natural products with a broad spectrum of biological activities including insecticidal, antimicrobial, antibacterial, estrogenic,
antitumor, and anti-HIV activity.1 Isoflavanones are also precursors for more complex natural products such as pterocarpans and rotenones.1
Given their therapeutic promise, selective strategies to access new classes of isoflavanones and related structures has high value.2 The
functionalization of the C3 position could promote beneficial interactions with biological targets of interest. Specifically, an alkylation at C3
can rapidly access new members of the general class of biologically active homoisoflavanones.3
The installation of stereodefined quaternary centers4 in aryl-
substituted indanones has been reported5 but the correspond-
ing methodology for the related isoflavanones has not been
developed to the same extent. The larger core structure of
isoflavanones (six carbons versus five for indanones) and
potential scission of the C-O bond via elimination under
basic conditions make modifications at C3 with established
approaches a challenging endeavor. The palladium-catalyzed
asymmetric alkylations of enol carbonates developed inde-
pendently by Stoltz and Trost is restricted to allyl electro-
philes and related structures by virtue of the reaction
mechanism.6 Alkylations of aryl ketones with a strongly
electron-withdrawing group (F, CO2R, CN) in the R-position
(1) (a) Harborne, J. B., Baxter, H., Eds. The Handbook of Natural
FlaVonoids, Volumes 1 and 2; Wiley: Chichester, U.K., 1999. (b) Andersen,
O. M., Markham, K. R., Eds. FlaVanoids: Chemistry, Biochemistry and
Applications; CRC Press: Boca Raton, FL, 2006.
(2) (a) Skouta, R.; Li, C. J. Angew. Chem., Int. Ed. 2007, 46, 1117–
1119. (b) Skouta, R.; Li, C. J. Synlett 2007, 1759–1762. (c) Rahman, M. M.;
Gibbons, S.; Gray, A. I. Phytochemistry 2007, 68, 1692–1697. (d)
Rukachaisirikul, T.; Innok, P.; Suksamram, A. J. Nat. Prod. 2008, 71, 156–
158.
(3) (a) Heller, W.; Tamm, C. Fortschr. Chem. Org. Naturst. 1981, 40,
105–152. (b) Heller, W.; Tamm, C. Fortschr. Chem. Org. Naturst. 1981,
40, 128–145. (c) Adinolfi, M.; Barone, G.; Belardini, M.; Lanzetta, R.;
Laonigro, G.; Parrilli, M. Phytochemistry 1985, 24, 2423–2426.
(4) For reviews, see: (a) Corey, E. J.; Guzman-Perez, A. Angew. Chem.,
Int. Ed. 1998, 37, 388–401. (b) Douglas, C. J.; Overman, L. E. Proc. Nat.
Acad. Sci. U.S.A. 2004, 101, 5363–5367. (c) Trost, B. M.; Jiang, C. H.
Synthesis 2006, 369–396. (d) Cozzi, P. G.; Hilgraf, R.; Zimmermann, N.
Eur. J. Org. Chem. 2007, 596, 9–5994.
(5) (a) Dolling, U. H.; Davis, P.; Grabowski, E. J. J. J. Am. Chem. Soc.
1984, 106, 446–447. (b) Hughes, D. L.; Dolling, U. H.; Ryan, K. M.;
Schoenewaldt, E. F.; Grabowski, E. J. J. J. Org. Chem. 1987, 52, 4745–
4752. (c) Ducry, L.; Diederich, F. HelV. Chim. Acta 1999, 82, 981–1004.
For recent reviews on chiral PTC, see: (d) Hashimoto, T.; Maruoka, K.
Chem. ReV. 2007, 107, 5656–5682. (e) Ooi, T.; Maruoka, K. Angew. Chem.,
Int. Ed. 2007, 46, 4222–4266.
10.1021/ol901676f CCC: $40.75
Published on Web 08/07/2009
 2009 American Chemical Society

have recently been reported separately by Deng, Dixon and
Jorgensen using phase transfer catalysis (PTC).7 Transition
metal-catalyzed enantioselective R-arylations of tetralones
and indanones have also been reported, but surprisingly, these
reactions have focused predominately on R-methyl substi-
tuted substrates.8 To date, a general solution to produce C3-
substituted isoflavanones efficiently with high enantiomeric
excess for the newly formed quaternary stereogenic center
has not emerged. We report herein the direct asymmetric
alkylation of isoflavanones (1, Y ) O) and protected
3-phenyl-2,3-dihydroquinolinones (1, Y ) NP) catalyzed by
a new cinchonidine-derived quaternary ammonium salt to
afford alkylated heterocycles (2, Figure 1).
Table 1. Optimization of Allylation Conditions
Figure 1. Phase transfer alkylation of unactivated benzocyclic
ketones (this work).
Our studies began by treating isoflavanone (1a) with allyl
bromide and surveying various cinchonidine-derived qua-
ternary ammonium salts and reaction conditions (Table 1).
Initial problems of low conversion were circumvented by
using excess base and alkyl halide to consume 1a, which
allowed us to focus our attention on obtaining optimal
selectivities. Employing catalyst A and 50% aqueous KOH
as the base at ambient temperature provided encouraging
results (15% ee, entry 1). Cooling the reaction to 0 °C
resulted in a minor increase in enantioselectivity (21% ee,
entry 2). Vigorous stirring of the reaction increased the
reaction rate, as did increasing the catalyst loading from 5
to 10 mol %, but neither modification dramatically improved
the stereoselectivity of the reaction.
We hypothesized that a larger nitrogen substituent ap-
pended to the quinuclidine core might improve the stereo-
selectivity, which led us to employ well-known phase-transfer
catalyst B.9 This modulation and changing the base from
aqueous KOH to solid CsOH·H2O provided a moderate
increase in enantiomeric excess (entry 3), which improved
a Determined by HPLC Chiracel OD-H. b % ee after recrystallization.
slightly when the reaction temperature was lowered (-40
°C, entry 4). Further cooling to -78 °C (entry 5) resulted in
a longer reaction time and comparable selectivity, so we
continued our optimization studies at -40 °C. While we were
pleased with the slight increase in selectivity observed when
employing a cosolvent (entry 6), we remained dissatisfied
with the level of asymmetric induction, so we investigated
other catalysts. The previously reported catalyst C10 with
toluene as the solvent afforded 2a with 76% ee (entry 7),
and 78% ee with 9:1 PhMe/CH2Cl2 as the solvent (entry 8).11
The success of this catalyst indicates that the bulk of the
substituent appended to the quinuclidine nitrogen atom is
crucial for significant asymmetric induction.
The 3,5-diphenyl benzyl-ammonium catalyst D afforded
2a with the same selectivity (entry 9) as observed catalyst
B (44% ee, entry 4). After an extensive survey, the new
catalyst with the specific 2,5-biaryl substitution pattern (E)
afforded the C3-allylated isoflavanone 2a with 83% ee (entry
10). The optical purity could be improved to 97% ee with a
single recrystallization. While the lack of covalent bonding
with PTC makes providing a model for stereoinduction with
E difficult, it is clear that the placement of phenyl rings in
the 2 and 5 positions on the benzyl fragment allows for the
formation of the contact ion pair necessary for high levels
of stereoinduction. Single crystal X-ray diffraction analysis
(6) (a) Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2004, 126,
15044–15045. (b) Trost, B. M.; Xu, J. Y. J. Am. Chem. Soc. 2005, 127,
2846–2847. (c) Mohr, J. T.; Behenna, D. C.; Harned, A. M.; Stoltz, B. M.
Angew. Chem., Int. Ed. 2005, 44, 6924–6927.
(7) (a) Arai, S.; Oku, M.; Ishida, T.; Shioiri, T. Tetrahedron Lett. 1999,
40, 6785–6789. (b) Wang, B. M.; Wu, F. H.; Wang, Y.; Liu, X. F.; Deng,
L. J. Am. Chem. Soc. 2007, 129, 768–769. (c) Rigby, C. L.; Dixon, D. J.
Chem. Commun. 2008, 3798–3800. (d) Moss, T. A.; Fenwick, D. R.; Dixon,
D. J. J. Am. Chem. Soc. 2008, 130, 10076–10077. (e) Paixao, M. W.;
Nielsen, M.; Jacobsen, C. B.; Jorgensen, K. A. Org. Biomol. Chem. 2008,
6, 3467–3470.
(8) (a) Ahman, J.; Wolfe, J. P.; Troutman, M. V.; Palucki, M.; Buchwald,
S. L. J. Am. Chem. Soc. 1998, 120, 1918–1919. (b) Hamada, T.; Chieffi,
A.; Ahman, J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 1261–1268.
(c) Chen, G. S.; Kwong, F. Y.; Chan, H. O.; Yu, W. Y.; Chan, A. S. C.
Chem. Commun. 2006, 1413–1415. (d) Liao, X. B.; Weng, Z. Q.; Hartwig,
J. F. J. Am. Chem. Soc. 2008, 130, 195–200.
Org. Lett., Vol. 11, No. 17, 2009
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of salt 3, derived from isoflavanone 2a, allowed for the
assignment of the absolute stereochemical configuration (and
other products, by analogy) as the R enantiomer.
Table 2. Reaction Scopea
Figure 2. ORTEP of Isoflavanone 3.
We next examined the scope of this reaction with regard
to alkyl halides (Table 2). Alkylation of isoflavanone with a
variety of alkyl halides gave products in good yields and
with high to excellent enantioselectivities (entries 1-7).
While alkylation with methallyl, and crotyl bromide gave
products with 82-86% ee (entries 1-2), alkylation with
cinnamyl chloride gave a selectivity of 92% ee (entry 3).
Alkylations employing substituted benzyl halides typically
necessitated longer reaction times, but also generally afforded
products with higher selectivities (entries 5-6) as compared
to the allylation processes. The reaction with TMS-propargyl
bromide provided the desired product in good yield with 76%
ee (entry 7).
The reaction tolerates electron-withdrawing aromatic
substitution on the pendant C3 aryl ring with moderate-to-
excellent levels of enantioselectivity. Alkylation of the
2-naphthyl analog of isoflavanone (entries 8-9) gave
products with selectivities comparable to those of the
alkylations of isoflavanone. Substrates with C3 aryl rings
possessing carbon-based ortho substituents resulted only
O-alkylation, but alkylation of 2′-fluoroisoflavanone (entry
10) resulted in only C alkylation, albeit with 80% ee. We
were pleased to find that employing 4′-chloroisoflavanone
afforded products with high levels of enantioselectivity
(entries 12-13). However, electron-donating substituents on
the C3 aryl ring (entry 11) consistently afforded products
with lower selectivities. Electron-donating groups at the C7
position also afforded products with lower selectivities (<60%
ee, not shown), but interestingly, C7 electron-withdrawing
groups (entry 14) did not dramatically increase or decrease
selectivity.
In our investigations of the nucleophile scope of this
reaction, we tested different benzocyclic ketones, modifying
the ring size and also the substitution of Y. Alkylation of
tetralones (Y ) CH2) proved to be surprisingly difficult; the
reactions rarely went to completion, even over a period of
seven days, and the selectivity was surprisingly low (<50%
ee). While the alkylations of 2-phenyl 1-indanone resulted
in complete conversion to the desired products, selectivities
comparable to those of tetralones were observed. We
hypothesize that the planarity of the enolate is crucial for
formation of a tight, contact ion pair with the cinchonidine-
derived catalyst.7a This optimal planarity is achieved with
a General conditions: ketone 1 (1 equiv), R2X (1.5 equiv), catalyst E,
CsOH·H2O, 9:1 PhMe/CH2Cl2 (0.1 M), -40 °C. b Enantiomeric excess
determined by HPLC Chiralcel O-DH, AD-H, or Whelk-O1. c Isolated
yields.
the flavanones but not with tetralones or indanones.12 To
test our hypothesis, we subjected various protected 3-phenyl-
2,3-dihydroquinolin-4(1H)-ones (1, Y ) NP) to the reaction
conditions above. We were pleased to find that employing
the N-Alloc quinolone gave products between 86 and 91%
ee (entries 15-17). These molecules are of particular interest
to us given their limited biological and synthetic studies.13
(9) (a) Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc. 1997, 119,
12414–12415. (b) Lygo, B.; Wainwright, P. G. Tetrahedron Lett. 1997,
38, 8595–8598.
(10) Park, E. J.; Kim, M. H.; Kim, D. Y. J. Org. Chem. 2004, 69, 6897–
6899.
(11) Using polar aprotic solvents as the sole solvent for the reaction
(not shown) resulted in significantly lower selectivities.
(12) The impact of these subtle structural changes is under investiga-
tion.
(13) (a) Daruwala, A. B.; Gearien, J. E.; Dunn, W. J.; Benoit, P. S.;
Bauer, L. J. Med. Chem. 1974, 17, 819–824. (b) See ref 2b.
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Org. Lett., Vol. 11, No. 17, 2009

of alkenes with >20:1 cis relative stereochemistry at the ring
fusion. A subsequent reduction (Pd/C, hydrogen) approaches
from the convex face of the tricyclic system and generates
cyclopentane 7 in excellent yield.
Scheme 1. Functionalization of Isoflavanone 2b
Driven by the potential utility of optically active C3-
substituted isoflavanones, we have developed the first enan-
tioselective alkylation of these heterocycles (1, Y ) O) and
related nitrogen analogs (1, Y ) NAlloc) employing a new
cinchonidine-derived phase transfer catalyst E. The process
accommodates a variety of isoflavanones and activated
electrophiles and installs a stereogenic quaternary center in
high yield and with good to excellent levels of enantiose-
lectivity. This mild alkylation adds isoflavanones to the
general compound classes for successful and useful enanti-
oselective PTC and affords products from simple starting
materials that can be easily transformed into novel hetero-
cycles. Further reaction development with this new PTC
catalyst and the application of the polycyclic products are
ongoing in our laboratory.
Acknowledgment. Support for this work was provided
by the NIH (NCI CA126827), the American Cancer Society
(Research Scholar Award), the H Foundation, GlaxoSmith-
Kline, AstraZeneca and the Sloan Foundation. A.E.N. thanks
the NIH for a predoctoral fellowship (F31CA13132617) and
is a 2009 Malkin Scholar. R.M.H. and A.B. thank NU for
Summer Research Grants. We thank John M. Roberts (NU)
for assistance with X-ray crystallography.
With an efficient pathway to access alkylated isoflavanones
and aza-isoflavanones, we have started to explore the
synthetic utility of these compounds (Scheme 1). An ozo-
nolysis/aldol condensation sequence from 2b delivers enones
such as 5 with high optical purity.14 Alternatively, the
exposure of ketone 2b to reducing conditions followed by
strong acid facilitates a Prins cyclization to afford a mixture
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(14) For the 2-methyltetralone analog of 5, see: Clift, M. D.; Taylor,
C. N.; Thomson, R. J. Org. Lett. 2007, 9, 4667–4669.
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