Asymmetric cycloadditions of o-quinone methides employing chiral ammonium fluoride precatalysts

Article abstract of DOI:10.1021/ol802029e

(Chemical Equation Presented) The catalytic, enantioselective, [4+2] cycloaddition reaction of ortho-quinone methides with silyl ketene acetals is described. This mechanistically interesting reaction, initiated by a chiral cinchona alkaloid-derived ammonium fluoride "precatalyst" complex, affords a variety of alkyl- and aryl-substituted 3,4-dihydrocoumarin products in excellent yield and with good enantioselectivity.

Full text of DOI:10.1021/ol802029e

ORGANIC
LETTERS
2008
Vol. 10, No. 21
4951-4953
Asymmetric Cycloadditions of
o-Quinone Methides Employing Chiral
Ammonium Fluoride Precatalysts
Ethan Alden-Danforth, Michael T. Scerba, and Thomas Lectka*
Department of Chemistry, Johns Hopkins UniVersity, 3400 North Charles Street,
Baltimore, Maryland 21218
lectka@jhu.edu
Received August 29, 2008
ABSTRACT
The catalytic, enantioselective, [4 + 2] cycloaddition reaction of ortho-quinone methides with silyl ketene acetals is described. This mechanistically
interesting reaction, initiated by a chiral cinchona alkaloid-derived ammonium fluoride “precatalyst” complex, affords a variety of alkyl- and
aryl-substituted 3,4-dihydrocoumarin products in excellent yield and with good enantioselectivity.
o-Quinone methides (o-QMs) are a valuable class of
compounds with an illustrious chemical history.1 QMs serve
as important intermediates in a variety of biological
pathways,1a,2 and their reactions generate products of broad
synthetic utility.1a Yet surprisingly, catalytic, asymmetric
cycloadditions of o-quinone methides are virtually absent
from the literature. Typically, o-QMs are generated under
Lewis acidic,1a,3 thermal,1a,4 or photochemical conditions1a,5
and are used/trapped in situ. As a result, polymerization is a
common problem, as is generation of a significant quantity
of the desired compound at any given time. o-QMs that are
isolable and whose reactivity is controllable would be ideal;
their utilization in asymmetric cycloaddition reactions would
provide access to a basic scaffold on which many therapeutic
agents are based. For example, molecules containing the
coumarin and dihydrocoumarin skeleton are prevalent in
nature.6 Derivatives of these compounds have been shown
to exhibit a variety of pharmacological properties, including
antiherpetic activity,7a inhibition of protein kinases7b and
aldose reductase,7c activity against several cancer lines,7d-f
and selective inhibition of HIV-1 reverse transcriptase.7g
Drawing from our successes with catalytic [4 + 2] cycload-
ditions,8 we sought to extend the scope of these highly
enantioselective ketene enolate reactions to those of o-
quinone methides, using cinchona alkaloid-derived precata-
(1) (a) Van De Water, R. W.; Pettus, T. R. R. Tetrahedron 2002, 58,
5367–5405. (b) Jurd, L. Tetrahedron 1977, 33, 163–168. (c) Jurd, L.;
Roitman, J. N. Tetrahedron 1978, 34, 57–62. (d) Jurd, L. Aust. J. Chem.
1978, 31, 347–352.
(2) (a) Peter, M. G. Angew. Chem., Int. Ed. Engl. 1989, 28, 555–570.
(b) Wang, Q. P.; Dechert, U.; Jirik, F.; Withers, S. G. Biochem. Biophys.
Res. Commun. 1994, 200, 577–583. (c) Buchan, G.; Turner, A. B. J. Chem.
(6) Murray, R. D. H.; Mendez, J.; Brown, S. A. The Natural Coumarins:
Occurrence, Chemistry, and Biochemistry; Wiley: New York, 1982. (b)
O’Kennedy, R.; Thornes, R. D. Coumarins: Biology, Applications, and Mode
of Action, 1st ed.; Wiley: Chichester, UK, 1997.
Soc., Perkin Trans. 1 1979, 1326–1332
.
(3) Chiba, K.; Hirano, T.; Kitano, Y.; Tada, M. Chem. Commun. 1999,
(7) (a) Takechi, M.; Tanaka, Y.; Takehara, M.; Nonaka, G.; Nishioka,
I. Phytochemistry 1985, 24, 2245–2250. (b) Hsu, F.-L.; Nonaka, G.-I.;
Nishioka, I. Chem. Pharm. Bull. 1985, 33, 3142–3152. (c) Iinuma, M.;
Tanaka, T.; Mizuno, M.; Katsuzaki, T.; Ogawa, H. Chem. Pharm. Bull.
1989, 37, 1813–1815. (d) Jurd, L. J. Heterocycl. Chem. 1996, 33, 1227–
1232. (e) Jurd, L. J. Heterocycl. Chem 1988, 25, 89–96. (f) Jurd, L.
J. Heterocycl. Chem. 1997, 34, 601–604. (g) Tillekeratne, L. M. V.; Sherette,
A.; Grossman, P.; Hupe, L.; Hupe, D.; Hudson, R. A. Bioorg. Med. Chem.
Lett. 2001, 11, 2763–2767.
691–692
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(4) (a) Arduini, A.; Bosi, A.; Pochini, A.; Ungaro, R. Tetrahedron 1985,
41, 3095–3103. (b) Chambers, J. D.; Crawford, J.; Williams, H. W. R.;
Dufresne, C.; Scheigetz, J.; Bernstein, M. A.; Lau, C. K Can. J. Chem.
1992, 70, 1717–1732
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10.1021/ol802029e CCC: $40.75
Published on Web 10/14/2008
2008 American Chemical Society

lysts.9 Chiral ammonium halide catalysis is well docu-
mented,10 and it has found ubiquitous application of late.
However, fluoride ion catalysis remains relatively underuti-
lized.11 In this letter, we disclose the first example of a
cycloaddition with o-quinone methides using silyl ketene
acetals12 and chiral ammonium fluoride precatalysts.13 This
methodology allows the production of 3,4-dihydrocoumarin
derivatives in excellent yield with up to 90% ee and up to
15.4:1 dr.
-78 °C (Scheme 1, B). We saw full consumption of the
o-QM after only 1 h, to form the desired [4 + 2] cycloadduct
in excellent yield after workup. To probe the potential
enantioselectivity of the reaction, a number of chiral am-
monium fluoride precatalysts were tested. The most suc-
cessful precatalyst, N-(3-nitrobenzyl)quinidinium fluoride
(Figure 1), when combined with ketene acetal (2), afforded
The electron-rich o-quinone methide (1), first synthesized
by Jurd in 1977, was chosen as a test substrate. This
compound stood out as an excellent candidate because of
its facile preparation and isolability. The o-QM (1) is easily
synthesized in two steps from sesamol and 4-methoxybenzyl
alcohol under mild Friedel-Crafts conditions, followed by
Ag2O oxidation. Initially, we treated the o-QM (1) with
butyryl chloride, thermodynamic Hu¨nig’s base, and kinetic
base/chiral catalyst benzoylquinidine (BQd) (Scheme 1, A).
Figure 1
precatalyst.
. Chiral cinchona alkaloid-derived ammonium fluoride
Scheme 1. o-Quinone Methide Test Reactions
cycloaddition products with 80% ee. We determined that the
precatalyst’s effect on the enantioselectivity of the reaction
was not dictated by steric bulk but rather by electronic
effects.15
Various precatalyst optimization experiments led us to the
strongly withdrawing nitro group, which afforded the best
results. The substitution pattern of the nitro group also proved
to be important, with the 4-nitro versus 3-nitro precatalysts
giving a difference of 10% ee (70 versus 80%, respectively).
In addition, we found that the hydroxyl group of the cinchona
alkaloid moiety was critical to high optical induction. In all
cases, O-alkylated and acylated precatalysts gave lower % ee
than their respective precatalysts bearing a free -OH. The
necessity for a hydrogen bond donation source led us to explore
chiral H-bond donors as additives in the reaction. An assortment
of chiral additives was screened, and we found that 10 mol %
of the bis(diphenylphosphoryl)pyrrolidine16 (Figure 2, right),
To our dismay, these conditions that worked beautifully in
previous systems8a produced no product in the reaction. We
reasoned that the high electron density of the o-QM was
incompatible with the mildly nucleophilic, zwitterionic ketene
enolate. Instead, we drew on silyl ketene acetal (2) as our
ketene enolate precursor.
This substrate was then combined with the o-QM and
catalytic tetrabutylammonium fluoride (TBAF) in THF14 at
(8) (a) Bekele, T.; Shah, M.; Wolfer, J.; Abraham, C. J.; Weatherwax,
A.; Lectka, T. J. Am. Chem. Soc. 2006, 128, 1810–1811. (b) Wolfer, J.;
Bekele, T.; Abraham, C. J.; Dogo-Isonagie, C.; Lectka, T. Angew. Chem.,
Int. Ed. 2006, 45, 7398–7400. (c) Abraham, C. J.; Paull, D. H.; Scerba,
M. T.; Grebinski, J. W.; Lectka, T. J. Am. Chem. Soc. 2006, 128, 13370–
13371.
(9) The term “precatalyst” signifies that the fluoride ion is sacrificed to
initiate the reaction. Thus, the ammonium ion of the catalyst presumably
forms ion pairs with the various anionic species throughout the course of
the reaction.
(10) (a) Ooi, T.; Maruoka, K. Angew. Chem., Int. Ed. 2007, 46, 4222–
4266. (b) Hashimoto, T.; Maruoka, K. Chem. ReV. 2007, 107, 5656–5682.
(11) Kruger, J.; Carreira, E. M. J. Am. Chem. Soc. 1998, 120, 837–838.
(12) Kobayashi, S.; Sano, T.; Mukaiyama, T. Chem. Lett. 1989, 1319–
1322.
Figure 2. Chiral additive (N-Boc-protected and free -NH).
(13) (a) Colonna, S.; Hiemstra, H.; Wynberg, H. J. Chem. Soc., Chem.
Commun. 1978, 238–239. (b) Ando, A.; Miura, T.; Tatematsu, T.; Shiori,
T. Tetrahedron Lett. 1993, 34, 1507–1510. (c) Drew, M. D.; Lawrence,
N. J. Tetrahedron Lett. 1997, 38, 5857–5860.
in conjunction with 4-nitrobenzylquinidinium fluoride precata-
lyst, o-QM (1), and ketene acetal (2) in THF at -78 °C,
increased the % ee from 70 to 80 (Figure 2). Unfortunately, no
such increase in % ee was afforded when combined with the
N-3-nitrobenzyl precatalyst.
(14) THF proved to be the superior solvent in the reaction, affording
products with higher yields and selectivities than toluene, diethyl ether and
CH2Cl2.
(15) N-Benzylquinidinium fluoride and N-(9-anthracenylmethyl)quini-
dinium fluoride precatalysts afforded products with similar enantioselec-
tivities (50% ee).
4952
Org. Lett., Vol. 10, No. 21, 2008

Scheme 2. Proposed Mechanism of Our Enantioselective, Chiral Ammonium Fluoride Initiated [4 + 2] Cycloaddition Reaction
With optimized conditions in hand, we illustrated the versatil-
ity of the methodology by screening a selection of ketene acetals
(Table 1). As illustrated by the diverse array of products
afford cycloadducts with equal and opposite selectivity. Of note,
by replacing the 2-naphthyl group of the ketene acetal with a
phenyl group, the ee decreased about 5% for each ketene acetal
tested. It is also interesting to mention that, by replacing the
2-naphthyl group of the ketene acetal with a methyl group, the
reaction afforded only alkylated product (5, after hydrolytic
workup). In this case, by halting lactonization (4f6) and the
release of the aryloxide to perpetuate the catalytic cycle, an
autocatalytic mechanism is implied. These data have led us to
propose a mechanism for the reaction, which is initiated by
fluoride ion desilylation of the ketene acetal (2), forming chiral
ion-paired ketene enolate (3). The ketene enolate then regiose-
lectively alkylates the o-QM at the methide carbon, with
restoration of aromaticity acting as the driving force. At this
point, two operative pathways are envisioned. Lactonization
forms the desired cycloadduct (6) and releases 2-naphthoxide,
which then replaces the catalyst counterion and, eventually,
desilylates the next molecule of ketene acetal (2). Alternatively,
the phenoxide of the alkylated product (4) can desilylate the
ketene acetal (2), forming O-silylated, alkylated product (5) and
ketene enolate (3). After full consumption of the o-quinone
methide, a sodium fluoride wash in the workup ensures
complete conversion to the lactone product (6).
Table 1. Catalytic, Asymmetric [4 + 2] Cycloadditions of
o-Quinone Methides with Silyl Ketene Acetalsa
In conclusion, we have demonstrated an effective entry into
catalytic, asymmetric o-quinone methide cycloaddition chem-
istry. The [4 + 2] cycloadducts were formed in excellent yield
and with very good enantioselectivity. This system provides
access to products having potentially broad therapeutic applica-
tion. Efforts to expand the scope of the system by introducing
additional o-quinone methide cores are forthcoming.
Acknowledgment. T.L. thanks the NIH (Grant GM064559)
a Reaction conditions: N-(3-nitrobenzyl)quinidinium fluoride (0.l equiv),
o-QM (1.0 equiv), ketene acetal (1.1 equiv) in THF at -78 °C for 1-2 h.
b The % ee after single recrystalization. c Yield of analytically pure product.
d Determined by NMR prior to purification.
for support.
Supporting Information Available: General experimental
procedures and compound characterization. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL802029E
produced, the system is tolerant of both aliphatic and aryl
substituents and those with sterically hindered, small, or heavy-
atom groups. The use of quinidine-derived precatalyst produces
products with the 7S,8R absolute configuration as the predomi-
nant enantiomer,17 and the analogous quinine-based precatalysts
(16) The bis(diphenylphosphoryl)pyrrolidine is synthesized in six steps
from trans-4-hydroxy-L-proline. See: Ojima, I.; Kogure, T.; Yoda, N. J.
Org. Chem. 1980, 45, 4728–4739.
(17) Absolute stereochemical configuration of the product was deter-
mined by X-ray crystallography.
Org. Lett., Vol. 10, No. 21, 2008
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