Catalytic, enantioselective [4 + 2]-cycloadditions of ketene enolates and o-quinones: Efficient entry to chiral, α-oxygenated carboxylic acid derivatives

Article abstract of DOI:10.1021/ja058077g

We report catalytic, enantioselective [4 + 2]-cycloadditions of o-quinones with ketene enolates (derived from readily available acid chlorides) using cinchona alkaloid derivatives as catalysts to produce products in high enantiomeric excess (ee) and good

Full text of DOI:10.1021/ja058077g

Published on Web 01/21/2006
Catalytic, Enantioselective [4 + 2]-Cycloadditions of Ketene Enolates and
o-Quinones: Efficient Entry to Chiral, r-Oxygenated Carboxylic Acid
Derivatives
Tefsit Bekele, Meha H. Shah, Jamison Wolfer, Ciby J. Abraham, Anthony Weatherwax, and
Thomas Lectka*
Department of Chemistry, New Chemistry Building, Johns Hopkins UniVersity,
3400 North Charles Street, Baltimore, Maryland, 21218
Received December 8, 2005; E-mail: lectka@jhu.edu
Chart 1. o-Quinones Screened
The use of chiral, catalytically derived zwitterionic “ketene”
enolates has brought forth powerful methodology for the synthesis
of a diverse variety of optically enriched products. Chiral ketene
enolate intermediates are well-known for undergoing highly enantio-
selective [2 + 2]-cycloadditions with both aldehydes and imines
to produce â-lactones and â-lactams, respectively.1 However, cases
in which ketene enolates engage in formal [4 + 2]-cycloaddition
reactions are almost unknown. The products of these [4 + 2]
reactions would be useful in their own right, while significantly
expanding the synthetic utility of ketene enolate reactions in general.
Accordingly, we report catalytic, enantioselective [4 + 2]-cycload-
ditions of o-quinones with chiral ketene enolates that are derived
from readily available acid chlorides and a cinchona alkaloid-based
catalyst. Additionally, the chiral cycloadducts can be derivatized
to provide a flexible synthesis of R-oxygenated carboxylic acid
derivatives (Scheme 1).2
The reasons for the absence of the [4 + 2]-manifold in ketene
enolate-based reactions may be due to a number of factors, including
a kinetic preference for the creation of four-membered rings and
the relative unreactivity of the enolates themselves toward various
heterodienes. A strategy to overcome these obstacles would be to
employ more energetic substrates such as o-quinones to achieve
the desired higher-order asymmetric cycloadditions.3 The driving
force for these reactions would be, in large part, the restoration of
aromaticity to the products.
would also be activated esters6), and CAN “deprotection” would
then unmask the R-hydroxylated product (Scheme 1).
Our initial screen employed o-quinones 1a-1d (Chart 1) and
butyryl chloride (2a, R ) Et) as the reactants. Triethylamine (1.1
equiv.) served as both the dehydrohalogenating agent and the
catalyst. We initially employed o-chloranil 1a, but to our disap-
pointment, no desired product was obtained in THF or toluene even
at room temperature.7 However, when we employed our chiral
“shuttle base” system (10 mol % benzoylquinidine (“BQd”, 3), 1.0
equiv Proton Sponge in toluene at -78 °C), surprisingly, after 4 h
reaction time, we isolated the desired product in 40% yield and
93% enantiomeric excess (ee) (eq 1). The very dark color of the
The chemistry of o-quinones has been extensively outlined.4 In
some cases o-quinones are commercially available, such as o-
chloranil 1a,5 and 9,10-phenanthrenequinone 1c (Chart 1). We
envisioned the standard transformation of an acid chloride into a
chiral ketene enolate (10 mol % of a cinchona alkaloid derivative,
stoichiometric base, toluene or THF solvent, low temperature) that
then reacts with the o-quinone to produce a chiral adduct. Follow-
up reactions with nucleophiles should occur smoothly (the products
reaction was a cause for concernsprecedent suggests that a charge-
transfer complex between o-chloranil and Proton Sponge may be
reducing the yield.8 By replacing Proton Sponge with Hu¨nig’s base
in THF at -78 °C, the yield and the ee rose significantly (to 91%
and 99% respectively, 4a, Table 1).
Scheme 1. Synthesis of Cycloadducts and Carboxylic Acid
Derivatives
Thenceforth, we employed these conditions with all substrates.
We also screened o-bromanil (1b), which was found to form product
in high ee (95%), and 90% yield (4g, Chart 2).9 9,10-Phenanthrene-
quinone (1c) was screened using similar conditions; its reactivity
proved to be much lower than that of o-chloranil. However, when
the reaction temperature was raised to 0 °C, reaction occurred
sluggishly to afford product. On the other hand, 4,5-dimethoxy-o-
quinone 1d failed to provide appreciable product under any
conditions.
Given the superiority of o-chloranil (1a) in our screen, we
decided to investigate its reaction with a variety of acid chlorides.
For example, the aliphatic 3-methylbutyryl chloride (2b, Table 1)
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10.1021/ja058077g CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Synthesis of o-Chloranil-Derived Cycloadducts
genation reactions.5a Several other cycloadducts (4a-4d) were
likewise converted to optically active R-hydroxyesters (Chart 3).
Chart 3. Conversion of Cycloadducts to R-Hydroxyesters
In each case, the alcoholysis/oxidation sequence proceeds in high
yield, under mild conditions, and with full preservation of optical
activity, comparing favorably with other methods for the synthesis
of chiral R-hydroxyesters.
In future work, we intend to expand the scope of the o-quinone
[4 + 2] reaction and investigate other o-quinone derivatives as well.
Acknowledgment. T.L. thanks the NIH (GM064559), the Sloan
and Dreyfus Foundations, and Merck & Co. for support.
Note Added after ASAP Publication. After this paper was
published ASAP on January 21, 2006, changes were made in the
Table 1 footnote. The corrected version was published January 26,
2006.
Supporting Information Available: General procedures for the
catalytic synthesis of the cycloadducts and compound characterization.
This information is available free of charge via the Internet at http://
pubs.acs.org.
References
(1) A few precedents for enantioselective â-lactone formation: (a) Wynberg,
H.; Staring, E. G. J. J. Am. Chem. Soc. 1982, 104, 166-168. (b) Calter,
M. A. J. Org. Chem. 1996, 61, 8006-8007. (c) Nelson, S. G.; Peelen, T.
J.; Wan, Z. J. Am. Chem. Soc. 1999, 121, 9742-9743. (d) Cortez, G. S.;
Tennyson, R. L.; Romo, D. J. Am. Chem. Soc. 2001, 123, 7945-7946.
For â-lactam formation: (e) Taggi, A. E.; Hafez, A. M.; Wack, H.; Young,
B.; Drury, W. J., III; Lectka, T. J. Am. Chem. Soc. 2000, 122, 7831-7832.
(f) Hodous, B. L.; Fu, G. C. J. Am. Chem. Soc. 2002, 124, 1578-1579.
(2) Notable examples of asymmetric synthesis of R-hydroxy carbonyl
compounds: (a) Mikami, M.; Terada, M.; Nakai, T. J. Am. Chem. Soc.
1989, 111, 1940-1941. (b) Adam, W.; Fell, R. T.; Saha-Mo¨ller, C. R.;
Zhao, C.-G. Tetrahedron: Asymmetry 1998, 9, 397-401. (c) Caputo, R.;
Cecere, G.; Guaragna, A.; Palumbo, G.; Pedatella, S. Eur. J. Org. Chem.
2002, 3050-3054. (d) Momiyama, N.; Yamamoto, H. J. Am. Chem. Soc.
2005, 127, 1080-1081.
a Reactions run with 10 mol % catalyst, 0.55 mmol Hunig’s base, 0.55
mmol acid halide, and 0.55 mmol 1a at -78 °C with slow addition of the
acid halide over 5 h employed for R-aryl acid halides (2c, e, f). Yields
given are for isolated products.
Chart 2. Various Chiral o-Quinone Adducts
(3) Whereas o-quinones have not been exploited in asymmetric catalysis,
p-quinones are known as Diels-Alder dienophiles in enantioselective
reactions: (a) Evans, D. A.; Wu, J. J. Am. Chem. Soc. 2003, 125, 10162-
10163. (b) Ryu, D. H.; Zhou, G.; Corey, E. J. J. Am. Chem. Soc. 2004,
126, 4800-4802. (c) Jarvo, E. R.; Lawrence, B. M.; Jacobsen, E. N.
Angew. Chem., Int. Ed. 2005, 44, 6043-6046.
(4) (a) Patai, S., Ed. The Chemistry of the Quinonoid Compounds; John Wiley
& Sons: New York, 1974; Vol. 1-4. For a recent review, see: (b)
Kharisov, B. I.; Mendez-Rojas, M. A.; Garnovskii, A. D.; Ivakhnenko,
E. P.; Ortiz-Mendez, U. J. Coord. Chem. 2002, 55, 745-770.
(5) o-Chloranil bears an intriguing resemblance to perchlorocyclohexa-2,4-
dien-1-one, a very successful substrate for the highly enantioselective
ketene-derived R-chlorination of acid halides, see: (a) France, S.; Wack,
H.; Taggi, A. E.; Hafez, A. M.; Wagerle, T. R.; Shah, M. H.; Dusich, C.
L.; Lectka, T. J. Am. Chem. Soc. 2004, 126, 4245-4255. (b) France, S.;
Weatherwax, A.; Lectka, T. Eur. J. Org. Chem. 2005, 475-479.
(6) (a) Friedrichsen, W.; Schroeer, W. D.; Schwarz, I.; Boettcher, A. Z.
Naturforsch., B: Chem. Sci. 1981, 36, 609-621. (b) Friedrichsen, W.;
Schmidt, R.; Van Hummel, G. J.; Van den Ham, D. M. W. Liebigs Ann.
Chem. 1981, 3, 521-531.
afforded product 4b in 75% yield and 93% ee (entry 2). An aromatic
substrate, phenylacetyl chloride (2c), afforded product 4c in 90%
ee and also in excellent yield (90%, entry 3). Dihydrocinnamoyl
chloride (2d) performed similarly, affording product 4d in high ee
(99%). Additionally, other R-arylacetyl chlorides proved to be excel-
lent substrates. For example, (p-methoxyphenyl)acetyl chloride (2e)
generated product in very high (99%) ee (entry 5). Using BQd as
catalyst, the (R)-enantiomers were formed preferentially.10 The (S)-
enantiomers are made using benzoylquinine (BQ) as catalyst instead.
The o-chloranil-derived cycloadducts can be derivatized to chiral,
R-oxygenated carboxylic acid derivatives. For example, methano-
lysis of 4c followed by CAN oxidation affords (+)-methylmandelate
8c in excellent (95%) yield (90% ee). This result confirmed the
sense of induction in our products, which is consistent with the
stereochemical model we devised for related â-lactam and halo-
(7) Under these conditions, undesired ketene dimers are usually isolated.
(8) Bhattacharya, S.; Banerjee, M.; Mukherjee, A. K. Spectrochim. Acta, Part
A 2001, 57, 2409-2416.
(9) o-Bromanil was added slowly to the reaction mixture over 6 h.
(10) Absolute configurations of the products were determined by conversion
to the corresponding R-hydroxyesters of known configuration through
sequential methanolysis/CAN oxidation. See Supporting Information for
details.
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