Synthesis of 7-functionalized γ-lactones from furfural

Journal of the National Science Foundation of Sri Lanka 36 (3) September 2008 Abstract: Condensation of the methyl ketones, 2-propanone, 2-butanone, 2-pentanone, 2-hexanone and 2-heptanone with furfural under alkaline conditions yielded the corresponding furfurylidene ketones arising from condensation at the methyl group. Hydrolytic ring cleavage of the furfurylidene ketones under acidic conditions yielded the corresponding 4,7-dioxocarboxylic acids. Borohydride reduction of these acids followed by acidification yielded the corresponding 7-hydroxy-γ-lactones. The 7-hydroxy group could be oxidized to a keto group or acetylated easily. The 7-hydroxy-, 7-oxoand 7-acetoxy-γ-lactones synthesized are not natural compounds, and are being reported for the first time. Their structures were established by Infra Red (IR), 1H and 13C Nuclear Magnetic Resonance (NMR), 2D NMR (COSY and HETCOR) spectroscopy and Gas Chromatography-Mass Spectrometry (GC-MS).


IntroductIon
Furfural is a readily available, versatile and cheap material which can be generated from a variety of waste agricultural biomass such as rice hull and bagasse 1 .
Gamma lactones are widely distributed in nature.They are an important class of compounds found in both natural and synthetic flavours and fragrances 2,3 .They have been also reported to exhibit biological activities such as cytotoxicity, pheromone activity and anti-feedant activity.The biological activity, as well as the flavour and fragrance of the individual gamma lactones vary with the structural features associated with side chain attached to the 4-position of the butyrolactone nucleus, such as chain length, chain branching, unsaturation, substitution and stereochemistry 4 .Thus, synthetic methods for functionalizing the side chain and for further manipulation of the functionality will be useful in generating new potentially bioactive compounds.
We report here a convenient synthesis of 7-functionalized γ-lactones, using furfural as a common precursor.These compounds have been neither reported from nature, nor synthesized earlier.Preparation of furfurylideneketones: A mixture of furfural (1.27 mol), water (1 L) and the methyl ketone 1a, 1b, 1c, 1d or 1e (2.87 mol) was cooled to 10 o C. A solution of 33% aqueous sodium hydroxide (25 mL) was added slowly while stirring.Stirring was continued for 4 h without external cooling and the reaction mixture was acidified with 20% sulphuric acid.The liquid separated out into two layers on standing.The organic layer was purified by column (silica) chromatography, using a gradient elution with hexane-dichloromethanemethanol.
Although the conversion of furfurylidene ketones to 4,7dioxocarboxylic acids by aqueous acids has been known for over a century, there have been no reports on the mechanism of the reaction.A mechanism for the reaction has been proposed involving the initial protonation of the carbonyl oxygen and nucleophilic attack by a water molecule at the C-1 position of the furan ring 6 .
Thereduction of 4,7-dioxocarboxylic acids by the Clemmenson reagent to gamma lactones bearing saturated alkyl chains in the 4-position has been reported earlier 9 (Scheme I).In the Clemmenson reduction a carbonyl group is reduced to a methylene group via a hydroxy group.In the reported reaction, the carbonyl group at the 7-position is reduced to a methylene group while the intermediate hydroxy group at the 4-position is not subjected to further reduction as it undergoes an intramolecular reaction with the carboxylic acid group and cyclizes to a lactone under the acidic reaction conditions.
Our synthetic strategy was to use a reagent with a lower reducing potential to retain the intermediate hydroxy group at the 7-position in the product.Thus, the reduction of the 4,7-dioxocarboxylic acids (3a-3e) with sodium borohydride followed by acidification gave 7-hydroxy-γ-lactones (4a-4e) (Scheme II).The hydroxy lactones were extracted in to dichloromethane, after acidification of the reaction mixture with 1 M HCl.All the 4,7-dioxocarboxylic acids gave moderate to high yields (33%-75%) of the corresponding 7-hydroxy-γ-lactone with this procedure except 3a (~20%).However, the yield of the product 4a could be increased (48%) by strongly acidifying the reaction mixture with 10 M HCl and heating at 60 o C for 2 h prior to the extraction into the organic layer.There was no corresponding increase in the yield observed when the reaction mixtures from the other 4,7-dioxocarboxylic acids were treated similarly.It would appear that the 4,7-dihydroxy acid from 3a requires a lower pH than the other 4,7-dihydroxy acids, for total conversion to the corresponding 7-hydroxy-γlactone.
The 7-hydroxy group provides a convenient handle for manipulation of the side chain functionality (Scheme I1).Thus, the 7-hydroxy group was easily acetylated to obtain the 7-acetoxy-γ-lactones (5a -5e) or oxidized to a keto group to obtain the corresponding 7-oxo-γ-lactones (6a -6e).For both transformations only mild conditions were used, so as to avoid reactions at the gamma lactone ring.
Scheme I: Synthesis of gamma lactones with saturated alkyl chains