Enantioselective enol lactone synthesis under double catalytic conditions

Article abstract of DOI:10.1021/ol047872g

(Chemical Equation Presented) The reaction of dimedone with 1-(2-alkenoyl)-4-bromo-3,5-dimethylpyrazoles in THF, catalyzed by catalytic amounts of both DBFOX/Ph-nickel-(II) perchlorate trihydrate and 2,2,6,6-tetramethylpiperidine, in the presence of acetic anhydride in THF produces the corresponding enol lactones in high enantioselectivities through enantioselective Michael additions followed by cyclization with removal of the pyrazole auxiliary. Other related nucleophile precursors can be successfully applied in the enantioselective enol lactone synthesis under the double catalytic conditions.

Full text of DOI:10.1021/ol047872g

ORGANIC
LETTERS
2005
Vol. 7, No. 6
979-981
Enantioselective Enol Lactone Synthesis
under Double Catalytic Conditions
Kennosuke Itoh,† Masayuki Hasegawa,† Junji Tanaka, and Shuji Kanemasa*
Institute for Materials Chemistry and Engineering, CREST of JST (Japan Science and
Technology Agency), Kyushu UniVersity, 6-1 Kasugakoen, Kasuga 816-8580, Japan,
and Department of Molecular and Material Sciences, Graduate School of Engineering
Sciences, Kyushu UniVersity, 6-1 Kasugakoen, Kasuga 816-8580, Japan
kanemasa@cm.kyushu-u.ac.jp
Received October 14, 2004 (Revised Manuscript Received February 11, 2005)
ABSTRACT
The reaction of dimedone with 1-(2-alkenoyl)-4-bromo-3,5-dimethylpyrazoles in THF, catalyzed by catalytic amounts of both DBFOX/Ph-nickel-
(II) perchlorate trihydrate and 2,2,6,6-tetramethylpiperidine, in the presence of acetic anhydride in THF produces the corresponding enol lactones
in high enantioselectivities through enantioselective Michael additions followed by cyclization with removal of the pyrazole auxiliary. Other
related nucleophile precursors can be successfully applied in the enantioselective enol lactone synthesis under the double catalytic conditions.
We have recently developed a new enantioselective Michael
addition of nitromethane1 or malononitrile2 to R,â-unsaturated
carbonyl compounds such as 3-(2-alkenoyl)-2-oxazolidinones
and 1-(2-alkenoyl)-3,5-dimethylpyrazoles where the reaction
was highly activated under the so-called double catalytic
conditions using catalytic amounts of both amine and chiral
Lewis acid. For example, the reaction of malononitrile with
4-bromo-1-crotonoyl-3,5-dimethyl-pyrazole was successfully
performed in the presence of 10 mol % each of 2,2,6,6-
tetramethylpiperidine (TMP) and the R,R-DBFOX/Ph com-
plex of nickel(II) perchlorate hexahydrate, affording 4-bromo-
1-(4,4-dicyano-3-methyl-butanoyl)-3,5-dimethylpyrazole as
Michael adduct in a high yield and high enantioselectivity.2
However, a catalyzed enantioselective version of this new
reaction is so far unknown.
Some of the enol lactone family including coumarins,
flavonoids, and neoflavonoids are known to show potent
biological activity.4-6 However, only limited numbers of
effective synthetic methodologies are available for the
synthesis of enol lactone derivatives.6a-c,7 Our catalytic
When cyclic â-diketones or â-keto lactones are employed
as nucleophile precursors in the reactions with 1-(2-alkenoyl)-
4-bromo-3,5-dimethylpyrazoles under the double catalytic
conditions using catalytic amounts of both nickel(II) per-
chlorate hexahydrate and TMP, the products obtained were
not the corresponding Michael adducts but the enol lactones.3
(4) Seo, E. K.; Wani, M. C.; Wall, M. E.; Navarro, H.; Mukherjee, R.;
Farnsworth, N. R.; Kinghorn, A. D. Phytochemistry. 2000, 55, 35-42.
(5) (a) Zhao, H.; Neamati, N.; Hong, H.; Mazumder, A.; Wang, S.;
Sunder, S.; Milne, G. W. A.; Pommer, Y.; Burke, T. R., Jr. J. Med. Chem.
1997, 40, 242-249. (b) Wang, S.; Milne, G. W. A.; Yan, X.; Posey, I. J.;
Nicklaus, M. C.; Graham, L.; Rice, W. G. J. Med. Chem. 1996, 39, 2047-
2054. (c) Mazumder, A.; Wang, S.; Neamati, N.; Nicklaus, M.; Sunder, S.;
Chen, J.; Milne, G. W. A.; Rice, W. G.; Burke, T. R., Jr.; Pommier, Y. J.
Med. Chem. 1996, 39, 2472-2481.
† Department of Molecular and Material Sciences.
(1) Itoh, K.; Kanemasa, S. J. Am. Chem. Soc. 2002, 124, 13394-13395.
(2) Itoh, K.; Oderaotoshi, Y.; Kanemasa, S. Tetrahedron: Asymmetry
2003, 14, 635-639.
(3) Itoh, K.; Kanemasa, S. Tetrahedron Lett. 2003, 44, 1799-1802.
10.1021/ol047872g CCC: $30.25
© 2005 American Chemical Society
Published on Web 02/22/2005

reaction described above3 is a rare successful example that
can be performed at room temperature, giving quantitative
yields of enol lactones.
In this communication, we present the highly efficient
catalyzed enantioselective enol lactone synthesis through the
Michael addition/lactonization sequence under double cata-
lytic conditions.
was much faster in THF than in dichloromethane, and a
higher enantioselectivity was observed. Although the pyra-
zole acceptor 4 as one of the substrates was rapidly consumed
in a few hours at room temperature in the reaction in THF,
the yield of enol lactone 3a was disappointingly low (38%,
Scheme 2). The side product was 6, which was proposed to
Under the reaction conditions using TMP and the enan-
tiopure complex catalyst derived from the R,R-DBFOX/Ph
ligand and nickel(II) perchlorate hexahydrate (10 mol %
each),8 the reaction of 5,5-dimethyl-1,3-cyclohexanedione (1,
named dimedone) with 3-crotonoyl-2-oxazolidinone (2), in
THF at room temperature for 48 h, produced 4,7,7-trimethyl-
3,4,5,6,7,8-hexahydrobenzopyran-2(H),5-dione (3a) as enol
lactone in 78% yield with the enantioselectivity of 63% ee
(Scheme 1). The reaction mechanism proposed involves the
Scheme 2. Solvent and Additive Effect in the Enol Lactone
Formation
Scheme 1. Nickel(II)-Catalyzed Enantioselective Enol Lactone
Formation
form through conjugate addition of the 3,5-dimethylpyrazole
removed in the lactonization step.3
Use of acetic anhydride was highly effective to prevent
formation of the undesired 6, through the acetylation trapping
of the liberated pyrazole giving 1-acetyl-3,5-dimethylpyrazole
(5).9,10 Thus, the reaction in THF was complete in 12 h in
the presence of acetic anhydride (1.1 equiv) to give enol
lactone 3a with the improved yield of 99% and enantiose-
lectivity of 96% ee.10 However, the reaction in dichlo-
romethane was very slow, even in the presence of acetic
anhydride, indicating that THF is the solvent of choice.
After efforts for the optimization of reaction conditions,
we have found that use of 4-bromo-3,5-dimethylpyrazole
chelating auxiliary gives better results (Scheme 3). Thus,
initial formation of the Michael adduct anion A, the
subsequent intramolecular protonation of A generating enol
B, and the final step of cyclization of B with the removal of
2-oxazolidinone auxiliary giving enol lactone 3a.3 Although
lactonization of the enol B derived from the 2-oxazolidinone
substrate 2 is generally not an easy process, the nickel(II)
catalysis in the above reaction activates the imide carbonyl
group of B and at the same time the leaving ability of
2-oxazolidinone auxiliary is enhanced.
Scheme 3. Nickel(II)-Catalyzed Enantioselective Synthesis of
a Variety of Enol Lactones
When 3-crotonoyl-2-oxazolidinone (2) was replaced with
1-crotonoyl-3,5-dimethylpyrazole (4), not only the reactivity
but also the selectivity was found to depend sharply upon
the nature of reaction solvent. The reaction of dimedone (1)
(6) (a) Lee, Y. J.; Tseng, T. H.; Lee, Y. J. Synthesis 2001, 2247-2254.
(b) Speranza, G.; Morelli, C. F.; Manitto, P. Synthesis 2000, 123-126. (c)
Hoz, A. D. L.; Moreno, A.; Va´zquez, E. Synlett 1999, 5, 608-610. (d)
Speranza, G.; Di Meo, A.; Zanzola, S.; Fontana, G.; Manitto, P. Synthesis
1997, 931-936.
(7) (a) Shen, H. C.; Wang, J,; Cole, K. P.; McLaughlin, M. J.; Morgan,
C. D.: Douglas, C. J.; Hsung, R. P.; Coverdale, H. A.; Gerasyuto, A. I.;
Hahn, J. M.; Liu, J.; Sklenicka, H. M.; Wei, L.-L.; Zehnder, L. R.; Zificsak,
C. A. J. Org. Chem. 2003, 68, 1729-1735. (b) Zehnder, L. R.; Dahl, J.
W.; Hsung, R. P. Tetrahedron Lett. 2000, 41, 1901-1905.
(8) The double catalytic conditions using 10 mol % each of TMP and
the R,R-DBFOX/Ph complex of nickel(II) perchlorate hexahydrate is called
“the standard double-catalytic conditions” in the present communication.
980
Org. Lett., Vol. 7, No. 6, 2005

reactions of dimedone 1 (2 equiv) with 1-(2-alkenoyl)-4-
bromo-3,5-dimethylpyrazoles 7a and 7c-k having a variety
of â-substituents and 1-crotonoyl-4-iodo-3,5-dimethyl-pyra-
zole (7b), in THF at room temperature under the standard
double catalytic conditions in the presence of 2 equiv of
acetic anhydride, gave 7,7-dimethyl-3,4,5,6,7,8-hexahy-
drobenzopyran-2(H),5-diones 3a-j in high yields and excel-
lent enantioselectivities as shown in Scheme 3.
Scheme 4. Catalytic Efficiency
The absolute configuration of enol lactones 3a-j was
determined as shown in Scheme 3 on the basis of the X-ray
confirmed structure of 4-(R)-(p-bromophenyl)-7,7-dimethyl-
3,4,5,6,7,8-hexahydrobenzopyran-2(H),5-dione (3j), which
was derived from the reaction of 1 with 4-bromo-1-(p-
bromocinnamoyl)-3,5-dimethylpyrazole (7k) under the double
catalytic conditions using the aqua complex of R,R-DBFOX/
Ph ligand. This indicates that the re face at the â-position of
7k has been involved in the step of enantioselective Michael
addition reaction. A possible transition structure for the
highly enantioselective enol lactone formation reaction in
the presence of the R,R-DBFOX/Ph complex catalyst is given
in Figure 1.
10, enol lactones 12 and 13 derived from the ketone enols
were produced selectively rather than those from the corre-
sponding ester enols. Their structures were determined on
the basis of the X-ray-based structure of 13d produced from
the reaction of 10 with 7l.3
Scheme 5. Reactions of â-Hydroxy Lactones
Figure 1. Suggested transition model to rationalize the stereose-
lectivity observed in the R,R-DBFOX/Ph complex catalyzed reac-
tion.
In conclusion, the first example has been achieved for
highly enantioselective enol lactone synthesis through the
reaction of a variety of nucleophile precursors, under double-
catalytic conditions. The catalytic loadings can be minimized
to 2 mol % and the highest enantioselectivity attained is 99%
ee. The scope of reactions with other cyclic 1,3-dicarbonyl
compounds is under investigation and will be detailed soon
in a full paper.
The loading of catalysts can be reduced to 2%. Reaction
time to completion under these conditions increases to 2 days,
but product 3a is formed quantitatively with an enantiomeric
excess that is only slightly lower than those from reactions
with 5% or 10% catalysts (Scheme 4).
3-Hydroxyperinaphthenone (8), 4-hydroxy-6-methyl-2-
pyrone (9), and 4-hydroxycoumarin (10) can be applied as
well in the reactions to pyrazole acceptors 7, under the
standard double-catalyzed conditions, to give the correspond-
ing enol lactones 11a,b, 12a-c, and 13a-e, respectively,
in high to excellent enantioselectivities (Scheme 5). Although
two cyclization modes are possible in the reactions of 9 and
Acknowledgment. Financial supports from the Grant-
in-Aid for Scientific Researches on Scientific Research (B)
15350059 and on Exploratory Research 16655038 from the
Ministry of Education, Culture, Sports, Science and Technol-
ogy of Japan are acknowledged.
Supporting Information Available: Experimental pro-
cedure, spectral data of all new compounds, and X-ray
crystallographic data of 3j in CIF format. This material is
available free of charge via the Internet at http://pubs.acs.org.
(9) The reaction of 3,5-dimethylpyrazole with acetic anhydride (1.1 equiv)
in THF is finished in 5 min at 0 °C producing 5 in 91% yield.
(10) Di-tert-butyl dicarbonate (65%, 91% ee), dimethyl pyrocarbonate
(88%, 86% ee), and diethyl carbonate (63%, 75% ee) were also effective.
However, trifluoroacetic anhydride did not work well.
OL047872G
Org. Lett., Vol. 7, No. 6, 2005
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