Simple synthesis of enantiomers of 6-hydroxyalkan-4-olides by stereoselective hydrogenation of methyl 4,6-dioxoalkanoates

Article abstract of DOI:10.1039/a902022e

A simple method for the synthesis of (S,S)- or (R,R)-6-hydroxyalkan-4-olides, components of the pheromonal secretion of the butterfly Idea leuconoe, in high ee by enantioselective hydrogenation of 4,6-diketo esters with a commercial available Ru-BINAP catalyst is described.

Full text of DOI:10.1039/a902022e

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Simple synthesis of enantiomers of 6-hydroxyalkan-4-olides by stereoselective
hydrogenation of methyl 4,6-dioxoalkanoates
Stefan Schulz
Institut fu¨r Organische Chemie, TU Braunschweig, Hagenring 30 D-38106 Braunschweig, Germany.
E-mail: stefan.schulz@tu-bs.de
Received (in Liverpool, UK) 10th March 1999, Accepted 14th May 1999
A simple method for the synthesis of (S,S)- or (R,R)-
6-hydroxyalkan-4-olides, components of the pheromonal
secretion of the butterfly Idea leuconoe, in high ee by
enantioselective hydrogenation of 4,6-diketo esters with a
commercial available Ru–BINAP catalyst is described.
and 99%, while the ee of the major enantiomer varied between
93 and 95%. The ee of the minor diastereomer could only be
estimated to be between 0 and 20% because of the small amount
isolated. Several lactones with chain lengths between C10 and
C13 have been prepared with similar results by this method.
Finally, a chemical correlation was needed to see whether the
stereochemical outcome of the reaction was as expected.
Therefore, our synthesis of rac-6-hydroxydodecan-4-olide1 was
modified to obtain compounds with defined stereochemistry.
Allylation of methyl 4-oxobutanoate with allyl(diisopinocam-
pheyl)borane derived from (2)-a-pinene furnished (S)-hept-
6-en-4-olide.12 After ozonolysis, the labile and slowly epimeris-
ing aldehyde (S)-6-oxohexan-4-olide was alkylated with
hexylmagnesium bromide, yielding a diastereomeric mixture of
the hydroxy lactones, enriched in the (4S)-enantiomers. In a
second experiment, rac-6-oxohexan-4-olide was alkylated
using dihexylzinc in the presence of (1R,2R)-1,2-bis(tri-
fluoromethylsulfonylamino)cyclohexane to yield a mixture
enriched in the (6S)-enantiomers.13 Gas chromatographic
analysis of these mixtures and the racemate allowed unambigu-
ous assignment of the (4S,6S)-configuration in the hydro-
During our studies on the pheromone system of males of the
large danaine butterfly Idea leuconoe1,2 we identified the
previously unknown 6-hydroxyalkan-4-olides with chain-
lengths between 10 and 13 carbon atoms. They seem to act
synergistically with the other pheromone components and are
probably involved in male–male interactions.2 Therefore a
synthesis of the pure enantiomers was needed to elucidate their
absolute configuration and further investigate their ecological
role.
High ee and dr of diols have been observed in Ru–BINAP
catalyzed stereoselective hydrogenations of b-diketones.3,4 We
reasoned that 4,6-diketo esters might also be good substrates for
such hydrogenations. Experiments with 3,5-diketo esters
showed poor selectivity using the employed catalyst [NH2Et2]+-
[{RuCl(BINAP)}2(m-Cl)3]2 between the diketo and the b-keto
ester functionalities,5 coupled with moderate enantioselectivity.
In addition, the results could be interpreted as a preferred
ligation of the ester group over the keto group.5,6 On the other
hand, small structural differences of the end groups are
recognized by the catalyst, so that products with high dr and ee
can be obtained, as has been shown by the hydrogenation of
hexane-2,4-dione.4 Therefore, the preferred reduction of the
4,6-diketo system in the presence of an ester group seemed to be
possible. To the best of our knowledge, the only stable and
commercially available chiral Ru–BINAP catalysts are
[RuCl((R)-BINAP)(p-cymene)]Cl [(R)-6] and its (S)-enantio-
mer (Fluka). These catalysts have been regarded as ineffective
below 60 °C in catalytic hydrogenations of dicarbonyl com-
pounds.6,7 Nevertheless, their application in the hydrogenation
of allylic alcohols8 and experience from our laboratories9
showed that they can be effective catalysts in the reduction of b-
keto esters at 80 °C and 40 bar hydrogen pressure, the upper
limits of the equipment available to us. For example, hydro-
genation of methyl 3-oxononanoate in the presence of (S)-6
yielded methyl (S)-3-hydroxynonanoate in quantitative yield
and 97.4% ee.
The major lactone in the secretion of Idea leuconoe is
6-hydroxyundecan-4-olide 8. The 4,6-diketo ester required for
its synthesis can be easily prepared starting from hexanal 1.
Reaction with ethyl diazoacetate yielded ethyl 3-oxooctanoate
2,10 which was acylated with 3-methoxycarbonylpropionyl
chloride 3 (Scheme 1). Krapcho de-ethoxycarbonylation11 of
the product 4 then lead to the required precursor, methyl
4,6-dioxoundecanoate 5. Hydrogenation at 40 bar H2 and 80 °C
in the presence of (S)-6 for two days yielded a mixture of (S,S)-8
and methyl (S,S)-4,6-dihydroxyundecanote 7,† verified by
chemical correlation as described below. The ester 7 could be
smoothly transformed into (S,S)-8 by column chromatography
over silica, and subsequent treatment of the product with old
CHCl3 or TsOH. The dr and ee were determined by GC on a
chiral phase (Lipodex E), which allowed separation of all
enantiomers. The dr varied in different experiments between 95
Scheme 1
Chem. Commun., 1999, 1239–1240
1239

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H-11, J 6.9), 1.25–1.52 (m, 8H, H-7–H-10), 1.68 (ddd, 1H, H5, J4,5 3.3, J5,6
9.8, J5,5A 14.5), 1.80 (ddd, 1H, H-5A, J5A,6 2.6 J4,5A 9.5), 1.90 (ddt, 1H, H-3,
J3,4 8.5, J2,3 9.5, J3,3A 12.5), 2.38 (m, 1H, H-3A, J3A,4 6.5), 2.55 (m, 2H, H-2),
3.89 (m, 1H, H-6), 4.80 (dddd, 1H, H-4); dC(100 MHz, CDCl3) 13.98 (C-
11), 22.58 (C-9), 25.14 (C-8), 28.52 (C-3), 28.86 (C-2), 31.70 (C-10), 38.02
(C-7), 43.16 (C-5), 68.54 (C-6), 78.10 (C-4), 177.09 (C-1).
genation products obtained with (S)-6. The result is in accord
with the enantioselective hydrogenations of b-diketones with
Ru-BINAP catalysts described in the literature.3,4 Obviously the
alkyl and ester groups are clearly differentiated by the
catalyst.
Work is in progress to expand the described methodology to
other compounds and optimize it by using other catalysts. This
method bears considerable potential for the synthesis of
building blocks, because of the two stereocenters and three
differentiated carbon atoms in an alkyl chain.
1 S. Schulz and R. Nishida, Bioorg. Med. Chem., 1996, 4, 341.
2 R. Nishida, S. Schulz, C. H. Kim, H. Fukami, Y. Kuwahara, K. Honda
and N. Hayashi, J. Chem. Ecol., 1996, 22, 949.
3 M. Kitamura, T. Ohkuma, S. Inoue, N. Sayo, H. Komobayashi, S.
Akutagawa, T. Ohta, H. Takaya and R. Noyori, J. Am. Chem. Soc., 1988,
110, 629.
I thank W. Luttmer for technical assistance. Financial support
from the Deutsche Forschungsgemeinschaft is gratefully ac-
knowledged.
4 H. Kawano, Y. Ishii, M. Saburi and Y. Uchida, J. Chem. Soc., Chem.
Commun., 1988, 35, 87.
5 L. Shao, H. Kawano, M. Saburi and Y. Uchida, Tetrahedron, 1993, 49,
1997.
6 D. J. Ager and S. A. Laneman, Tetrahedron: Asymmetry, 1997, 8,
3327.
7 K. Mashima, K. Kusano, M. Sato, Y. Matsumura, K. Nozaki, H.
Komobayashi, N. Sayo, Y. Hori, T. Ishizaki, S. Akutagawa, H. O. T.
Takaya and R. Noyori, J. Org. Chem., 1994, 59, 3064.
8 T. Eguchi, K. Arakawa, T. Terachi and K. Kakinuma, J. Org. Chem.,
1997, 62, 1924.
9 A. Hefetz, T. Taghizadeh and W. Francke, Z. Naturforsch., 1996, 51c,
409.
10 C. R. Holmquist and E. J. Roskamp, J. Org. Chem., 1989, 54, 3258.
11 A. P. Krapcho, Synthesis, 1982, 893.
12 U. S. Racherla and H. C. Brown, J. Org. Chem., 1991, 56, 401.
13 M. J. Rozema, A. Sidduri and P. Knochel, J. Org. Chem., 1992, 57,
1956.
Notes and references
† Synthesis of (4S,6S)-6-hydroxyundecan-4-olide: A stainless steel auto-
clave lined with Teflon and equipped with a stirring bar was charged with
200 mg of methyl 4,6-dioxoundecanoate and 5 ml of absolute MeOH. The
solution was freed from air by repeatedly applying and releasing nitrogen
pressure.
Approximately 10 mg of the catalyst (S)-6 was added maintaining a
steady flow of nitrogen to minimize contact with air. Then the autoclave was
closed, a pressure of 40 atm applied, and finally heated to 80 °C for two
days. When all educt was consumed (TLC control), the autoclave was
cooled, the solvent removed, the product taken up in Et2O and finally
filtered over Celite. TLC control showed two spots, corresponding to 8 and
7, which could be separated at this point by chromatography, if desired.
Treatment of the crude mixture with a small amount of TsOH in CH2Cl2
transformed 7 into 8. The product was then purified by chromatography
over silica after removal of TsOH with saturated NaHCO3 solution. Yield:
160 mg (91%); [a]2D2 +64.4 (c 1.30, Et2O); dH(500 MHz, CDCl3) 0.89 (t, 3H,
Communication 9/02022E
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Chem. Commun., 1999, 1239–1240