A catalytic asymmetric reaction involving enolizable anhydrides

Article abstract of DOI:10.1021/ol300453s

In the presence of a highly efficient novel bifunctional organocatalyst at low loadings under mild conditions, enolizable homophthalic anhydrides can be added to a range of aromatic and aliphatic aldehydes to give dihydroisocoumarins, with excellent yields and diastereo-and enantiocontrol (up to 99% ee).

Full text of DOI:10.1021/ol300453s

ORGANIC
LETTERS
2012
Vol. 14, No. 7
1850–1853
A Catalytic Asymmetric Reaction
Involving Enolizable Anhydrides
Claudio Cornaggia, Francesco Manoni, Esther Torrente, Sean Tallon, and
Stephen J. Connon*
Centre for Synthesis and Chemical Biology, Trinity Biomedical Sciences Institute,
School of Chemistry, The University of Dublin, Trinity College, Dublin 2, Ireland
connons@tcd.ie
Received February 23, 2012
ABSTRACT
In the presence of a highly efficient novel bifunctional organocatalyst at low loadings under mild conditions, enolizable homophthalic anhydrides
can be added to a range of aromatic and aliphatic aldehydes to give dihydroisocoumarins, with excellent yields and diastereo- and enantiocontrol
(up to 99% ee).
Anhydrides have been used as electrophilic acyl transfer
agents1 for over a century.2 While their chemistry is almost
completely dominated by their electrophilicity, the parti-
cipation of enolizable anhydrides in aldol-like coupling
processes has been reported.3 In 1868, Perkin found that
aliphatic anhydrides can condense on heating with alde-
hydes in the presence of weak carboxylate bases to give
R,β-unsaturated acids.4 Much later, it was shown that
cyclic succinic and glutaric anhydrides 1can undergo formal
thermal cycloaddition with either aldehydes5 or imines6 to
form annulated products of general type 2 (Scheme 1A).3
Mechanistically, the two processes are distinct: it is
thought that reactions with imines involve the attack
of the imine on the anhydride to form an internal
acyl ammonium carboxylate ion, which undergoes rate-
limiting tautomerization to 3 followed by an endo-trig
cyclization to yield a lactam product.3 Aldehydes are not
nucleophilic enough to attack the anhydride, and thus
these reactions begin with enolization of the anhydride,
followed by nucleophilic attack on the aldehyde to gen-
erate alkoxide 4, which then lactonizes to form a dihydro-
isocoumarin unit in an intramolecular process.3
The imine-based methodology has received consider-
ably more attention than the lactone-forming variant,3
which most often employs homophthalic anhydride (i.e.,
5, R = H, Scheme 1B) and aromatic aldehyde (i.e., 6)
substrates and requires the use of stoichiometric loadings
of either a base7 or a Lewis acid.8 No catalytic, asymmetric
variants of either of these reactions have been reported,
despite both the obvious synthetic potential of these
products and the relevance of the bicyclic dihydroisocou-
marin structural unit in a broad spectrum of chiral natural
products possessing a remarkable range of (for example)
(7) (a) Bogdanov, M. G.; Palamareva, M. D. Tetrahedron 2004, 60,
2525. (b) Nozawa, K.; Yamada, M.; Tsuda, Y.; Kawai, K.-I.; Nakajima,
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1999, 55, 13735.
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Horne, W. S.; Day, B. W.; Floreancig, P. E. J. Am. Chem. Soc. 2011, 133,
16668. (b) Cichewicz, R. H.; Valeriote, F. A.; Crews, P. Org. Lett. 2004,
6, 1951. (c) Huang, Y. F.; Li, L.-H.; Tian, L.; Qiao, L.; Hua, H.-M.; Pei,
Y.-H. J. Antibiot. 2006, 59, 355.
(1) March, J. Advanced Organic Chemistry, 4th ed.; Wiley: New York,
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(3) Gonzalez-Lopez, M.; Shaw, J. T. Chem. Rev. 2009, 109, 164.
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r
10.1021/ol300453s
Published on Web 03/26/2012
2012 American Chemical Society

cytotoxic/antiproliferative,9 phytotoxic,10 antimicrobial,11
antifungal,12 antiulcer,13 antimalarial,14 anti-inflammatory,13
antioxidant,15 and antiallergic16 properties.
aldehyde through hydrogen bond donation/general acid
catalysis (Scheme 1C).
Our group (among others17,18) has recently been en-
gaged in the use of cinchona alkaloid-derived bifunctional
organocatalysts19c,d,20 topromotetheasymmetricaddition
of alcohol21 and thiol22 nucleophiles to cyclic anhydrides
and related electrophiles.23 These catalysts rely on the
confluence of relatively weak synergistic catalystꢀsubstrate
interactions (mostly the donation of hydrogen bonds to
the anhydride and general-base catalysis of the pronucleo-
phile addition).
Scheme 1. Annulations of Cyclic Anhydrides with Aldehydes/
Imines: Scope and Proposed Strategy
Since these catalysts are compatible with cyclic anhy-
dride substrates (hitherto only when the anhydrides are
being employed as electrophiles) and have been known (in
isolated cases) to activate aldehyde/ketone electrophiles,24
we proposed that, in the absence of a powerful pronucleo-
phile, these bifunctional catalysts could be employed to
bring about the activation of an enolizable anhydride as a
nucleophile (through catalysis of the equilibrium between
it and its enol form), while simultaneously activating the
To test this hypothesis, in preliminary experiments we
evaluated the addition of homophthalic anhydride (8) to
benzaldehyde (9) in THF at ambient temperature in the
presence of a wide range of chiral alkaloid-derived cata-
lysts 11 at 5 mol % loading. In the absence of catalyst, the
reaction proceeds very slowly, with moderate diastereoselec-
(10) Enomoto, M.; Kuwahara, S. Angew. Chem., Int. Ed. 2009, 121,
1144.
(11) (a) Bogdanov, M. G.; Kandinska, M. I.; Dimitrova, D. B.;
Gocheva, B. T.; Palamareva, M. D. Naturforsch. 2007, 62, 477. (b)
Tabopda, T. K.; Fotso, G. W.; Ngoupayo, J.; Mitaine-Offer, A.-C.;
Ngadjui, B. T.; Lacaille-Dubois, M.-A. Planta Med. 2009, 75, 1228.
(12) Hussain, H.; Akhtar, N.; Draeger, S.; Schulz, B.; Pescitelli, G.;
€
tivity in favor of trans-10 (Table 1, entry 1). Use of Hunig’s
base as a catalyst led to considerably faster reactions with no
improvement in diastereoselectivity (entry 2). The observed
catalysis of this reaction by a non-nucleophilic base lends
weight to the hypothesis that the enol of anhydride 8acts as a
nucleophilic species in the reaction. Quinine (11a), and its
O-benzoylated derivative 11b, promoted the reaction with
marginally higher diastereoselectivity. However, the product
enantiomeric excesses were inadequate (entries 3ꢀ4), as were
those obtained from reactions catalyzed by both the C-9
arylated alkaloids 11c and 11d (entries 5ꢀ6).22 The bifunc-
tional sulfonamide-substituted catalysts 11eꢀg, which have
proven highly efficacious in the catalysis of asymmetric
additions to anhydrides,18c,f,22b promoted the formation of
predominantly trans-10 in excellent yield, with poor to
moderate levels of ee (entries 7ꢀ9). The exchange of the
sulfonamide for urea and thiourea functionality18 (i.e.,
catalysts 11hꢀl) resulted in higher enantioselectivity, with
the thiourea-based catalyst 11l clearly superior to the others
(>75% ee for both the cis and trans diastereomers, with a
9-fold preference for the trans-stereoisomer, entries 10ꢀ14).
The recently developed alkaloid derivative 11m24b,c is a
relatively poor catalyst (entry 15). Recently, Rawal25 in-
troduced a class of squaramide-substituted catalyst as an
alternative to (thio)urea-based materials. Squaramide 11n
catalyzed the formation of trans-10 with good diastereos-
electivity and 90% ee (entry 16). The C2-symmetric analogue
11o, which is an excellent catalyst for azlactone alcoholysis,26
is unsuitable for use in this reaction (entry 17).
ꢀ
Salvadori, P.; Antus, S.; Kurtan, T.; Krohn, K. Eur. J. Org. Chem. 2009,
749.
(13) (a) Shimojima, Y.; Shirai, T.; Baba, T.; Hayashi, H. J. Med.
Chem. 1985, 28, 3. (b) McInerney, B. V.; Taylor, W. C.; Lacey, M. J.;
Akhurst, R. J.; Gregson, R. P. J. Nat. Prod. 1991, 54, 785.
(14) Kongsaeree, P.; Prabpai, S.; Sriubolmas, N.; Vongvein, C.;
Wiyakrutta, S. J. Nat. Prod. 2003, 66, 709.
(15) Nazir, N.; Koul, S.; Quirishi, M. A.; Najar, M. A.; Zargar, M. I.
Eur. J. Med. Chem. 2011, 46, 2415.
(16) Yoshikawa, M.; Uchida, E.; Chatan, N.; Kobayashi, H.;
Naitoh, Y.; Okuno, Y.; Matsuda, H.; Yamahara, J.; Murakami, N.
Chem. Pharm. Bull. 1992, 40, 3352.
(17) For seminal work on the highly enantioselective (modified)
cinchona-alkaloid-mediated desymmetrizations of meso-anhydrides
see: (a) Chen, Y.; Tian, S.-K.; Deng, L. J. Am. Chem. Soc. 2000, 122,
9542. (b) Bolm, C.; Gerlach, A.; Dinter, C. L. Synlett 1999, 195. (c)
Bolm, C.; Schiffers, I.; Dinter, C. L.; Gerlach, A. J. Org. Chem. 2000, 65,
6984.
(18) (a) Chen, Y.; McDaid, P.; Deng, L. Chem. Rev. 2003, 103, 2965.
(b) Atodiresei, I.; Schiffers, I.; Bolm, C. Chem. Rev. 2007, 107, 5683. (c)
Rodriguez-Docampo, Z.; Connon, S. J. ChemCatChem 2012, 4, 151. (d)
Honjo, T.; Sano, S.; Shiro, M.; Nagao, Y. Angew. Chem., Int. Ed. 2005,
44, 5838. (e) Rho, H. S.; Oh, S. H.; Lee, J. W.; Lee, J. Y.; Chin, J.; Song,
C. E. Chem. Commun. 2008, 1208. (f) Oh, S. H.; Rho, H. S.; Lee, J. W.;
Lee, J. E.; Youk, S. H.; Chin, J.; Song, C. E. Angew. Chem., Int. Ed. 2008,
47, 7872.
(19) (a) Li, B. -J.; Jiang, L.; Liu, M.; Chen, Y. -C.; Ding, L. -S.; Wu,
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Y. Synlett 2005, 603. (b) Vakulya, B.; Varga, S.; Csampai, A.; Soos, T.
Org. Lett. 2005, 7, 1967. (c) McCooey, S. H.; Connon, S. J. Angew.
Chem., Int. Ed. 2005, 44, 6367. (d) Ye, J.; Dixon, D. J.; Hynes, P. S.
Chem. Commun. 2005, 4481.
(20) Hiemstra, H.; Marcelli, T. Synthesis 2010, 1229.
(21) Peschiulli, A.; Gun’ko, Y.; Connon, S. J. J. Org. Chem. 2008, 73,
2454.
(22) (a) Peschiulli, A.; Quigley, C.; Tallon, S.; Gun’ko, Y.; Connon,
S. J. J. Org. Chem. 2008, 73, 6409. (b) Peschiulli, A.; Procuranti, B.; O’
Connor, C. J.; Connon, S. J. Nat. Chem. 2010, 2, 380.
(23) Quigley, C.; Rodriguez-Docampo, Z.; Connon, S. J. Chem.
Commun. 2012, 48, 1443.
(25) Malerich, J. P.; Hagihara, K.; Rawal, V. H. J. Am. Chem. Soc.
2008, 130, 14416.
(26) Lee, J. W.; Ryu, T. H.; Oh, J. S.; Bae, H. Y.; Jang, H. B.; Song,
(24) (a) Marcelli, T.; van der Haas, R. N. S.; van Maarseveen, J.;
Hiemstra, H. Angew. Chem., Int. Ed. 2006, 45, 929. (b) Palacio, C.;
Connon, S. J. Org. Lett. 2011, 13, 1298. (c) Palacio, C.; Connon, S. J.
Chem. Commun. 2012, 48, 2849.
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Org. Lett., Vol. 14, No. 7, 2012
1851

Table 1. Catalyst Evaluation and Optimization Studies
Table 2. Evaluation of Substrate Scope: Aldehyde Component
a Isolated yield of the trans-diastereomer after column chromato-
graphy. b Diastereomeric ratio (determined by 1H NMR spectroscopy).
c Determined by CSP-HPLC, see Supporting Information (SI). d Dia-
stereomers inseparable: combined isolated yield. e Ee of cis-isomer in
parentheses. f At ꢀ30 °C.
a Determined by 1H NMR spectroscopy using 4-iodoanisole
as an internal standard b Diastereomeric ratio (400 MHz 1H NMR
spectroscopy). c Determined by CSP-HPLC, see the SI. d Not
determined.
resulted in better yield as well as enantio- and diastereos-
electivity (entry 18). Further optimization (entries 19ꢀ27)
led to the identification of two sets of conditions for the
synthesis of trans-10 in g98% yield, g95:5 dr, and g96% ee
at a convenient loading, reaction concentration, and tem-
perature (entries 26 and 27).
With a synthetically useful protocol now in hand, our
attention turned to the important question of substrate
scope (Table 2). The methodology proved robust: when
reacted in a 1:1 ratio with anhydride 8, electron-deficient
Modification of 11n proved productive: upon installa-
27
tion of a phenyl substituent at C-20 (so that the steric
requirement of the quinoline ring is more appropriately
balanced around the C-40ꢀC-9 axis), catalyst performance
improved sharply. Use of the novel squaramide 11p
(27) Lee, A.; Michrowska, A.; Sulzer-Mosse, S.; List, B. Angew.
Chem., Int. Ed. 2011, 50, 1707.
1852
Org. Lett., Vol. 14, No. 7, 2012

(entries 1ꢀ4), electron-rich (entry 5), hindered (entry 6),
and heterocyclic aromatic (entries 7 and 8) aldehydes were
well tolerated by the catalyst at just 5 mol % loading.
Yields and enantiomeric excesses of the isolated trans-
diastereomers 12ꢀ19 (to facilitate isolation and separa-
tion of the diastereomers, the crude acids were esterified in
situ after reaction) were generally excellent (g92% yield
and g95% ee respectively). The deactivated p-anisalde-
hyde proved a greater challenge (entry 5), yet this could
still be obtained in good yield and >90% ee. Thiophene
carbaldehyde also proved a relatively recalcitrant sub-
strate, resulting in an 84% isolated yield (97% ee, entry
7) of 18. Aliphatic aldehydes also undergo the formal
cycloaddition; both straight-chain (entry 9) and more
hindered ‘branched’ aldehydes (entry 10) could be con-
verted to 20 and 21 respectively. While the dr is uniformly
excellent in the case of aromatic aldehydes, the use of
aliphatic aldehydes leads to elevated levels of the cis-
diastereomer. This is mitigated by the fact that the trans-
diastereomer is formed in both cases in near optical purity;
in addition, the ee of the formed cis-diastereomer is also
good to excellent.
Table 3. Substrate Scope: Homophthalic Anhydride
Component
a Isolated yield of the trans-diastereomer after column chromato-
graphy. b Diastereomeric ratio (determined by 400 MHz 1H NMR
spectroscopy). c Determined by CSP-HPLC, see the SI. d Yield
(determined by 1H NMR spectroscopy using an internal standard) of
the trans-diastereomer prior to esterification and chromatography in
parentheses.
Substitution at the aromatic ring is a feature of several
of the medicinally relevant bicyclic dihydroisocoumarin
compounds.9ꢀ16 Therefore, we considered it prudent to
evaluate the effect of the installation of electron-withdraw-
ing and -donating functionality on the homophthalic
anhydride pronucleophile (Table 3).
In summary, it has been demonstrated (for the first time
in an asymmetric catalysis context) that enolizable anhy-
drides can be coupled with aldehydes in the presence of a
chiral bifunctional organocatalyst to form lactone pro-
ducts. In a process reminiscent of the aldol reaction, it was
first demonstrated that homophthalic anhydride could
react with benzaldehyde in the presence of a catalytic
amine base. This allowed the catalysis of this reaction by
a novel bifunctional cinchona alkaloid to generate a
dihydroisocoumarin structure with the formation of two
new stereocenters in 98% yield, 97% ee, and 96:4 dr under
convenient conditions.28 The scope of the reaction is
robust; electron rich, electron-deficient, hindered, and
heterocyclic aromatic aldehydes, in addition to both
R-branched and unbranched aliphatic aldehydes are all
compatible. Substitution on the anhydride component is
also tolerated.
Deactivating nitro- (entry 1) and bromo- (entry 2)
functional groups can be used to form 22 and 23 respec-
tively in excellent dr and ee. While the yield of the crude
acids was excellent in both cases, isolation of these materi-
als is more difficult due toring opening of the lactones both
on esterification and during careful column chromatogra-
phy to separate the diastereomeric products. Nonetheless,
useful yields of pure trans-22 and 23 can be obtained. The
electron-donating methoxy group was also found to be
compatible (i.e., trans-24, entry 3). It is interesting to note
that the methoxy group would be expected a priori to
destabilize the enol tautomer of the anhydride substrate
(i.e., the putative nucleophile) and thus reduce its equilibrium
concentration, while simultaneously (mildly) activating
the nearest carbonyl moeity through an ꢀI effect (ꢀOMe
σm = 0.10). Thus the observation that the methoxy sub-
stituted anhydride reacts considerably more slowly than
either homophthalic anhydride itself (Tables 1ꢀ2) or the
nitro/bromo-substituted analogues (Table 3, entries 1ꢀ2)
would be consistent with the anhydride ketoꢀenol tauto-
meric equilibrium being a key factor influencing reaction
rate in the catalytic process.
Acknowledgment. Financial support from the Eur-
opean Research Council (ERC) is gratefully acknowledged
Supporting Information Available. Experimental pro-
cedures, 1H and 13C NMR spectra, characterization data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(28) Recently, after the preparation of this manuscript, an alternative
highly enantioselective organocatalytic methodology for the synthesis
of dihydroisocoumarins via the asymmetric bromolactonization of
styrene-type carboxylic acids has appeared: Chen, J.; Zhou, L.; Tan,
C. K.; Yeung, Y. -Y. J. Org. Chem. 2012, 77, 999.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 7, 2012
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