Chemoselective reduction of unsaturated γ - and δ-lactones by sodium borohydride in the presence of triethylamine in THF

α,β-Unsaturated γ-and δ-lactones were selectivity reduced to the corresponding saturated lactones and oxospiro systems respectively using sodium borohydride in the presence of triethylamine in THF, in excellent yields


Introduction
It is well known, that many saturated lactones are displaying interesting biological activities and can be used in many various areas, especially, in medicine, pharmacology, perfume making, pesticides etc. Artemisinin and Santonin, endowed with valuable biological activity, are compounds containing saturated γand δ-lactone rings. 1,2Many compounds, such as pilocarpine, a cholinergic drug, are also derivatives of γ-butanolides.Subsequent investigations, in the area of the synthesis of new derivatives of saturated γ-lactones are of great interest and can have a valuable potential for new biologically active compounds. 3herefore, reduction of functionalized unsaturated lactones can be useful method for synthesizing functionalized saturated lactones, which would be otherwise difficult -if not impossible-to obtain. 4There are known methods for synthesizing γ-butanolide, based on various organic oxides, 4 but unfortunately these reagents are not readily available.
Synthesis of functionalized unsaturated γ-lactones from 2,3-substitued α-hydroxy ketones and compounds with active methylene group is well documented and can easily be extended to the synthesis of unsaturated γ-lactones through double bond reduction with various reagents. 5atalytic hydrogenation is not always possible to apply because of unavailability of necessary catalysts and hydrogen hazards. 6On the other hand, the reduction of butenolides by complex metal hydrides (LiAlH4, NaBH4) opens the lactone rings for production of the corresponding glycols. 7,8he report by Reddy et al. 9 who described the reduction of α-arylidene-γ-phenyl-,γbutenolides to the respective γ-butyrolactones in methyl alcohol with sodium borohydride in the presence of triethylamine, was for us very interesting.
Following the described method by Reddy using some unsaturated γ-and δ-lactones, in which C=C double bond of lactone ring is conjugated with present active functional groups (CN, CO2Et, COCH3, COOH, etc.), we tested NaBH4 in the presence of triethylamine in THF, to reduce the C=C double bond of the ring in the mentioned lactones to obtain saturated derivatives of these compounds.

Results and Discussion
Metal hydrides are valuable reagents in modern organic chemistry.The most frequently used hydride is the NaBH4 reagent.It is a mild, and inexpensive reagent used in a wide range of reduction processes.The reactivity and selectivity of NaBH4 can be enhanced by carrying out the reaction in the presence of certain additives. 10Reduction of unsaturated γ-and δ-lactones 1a-d by NaBH4 and Et3N in THF at room temperature results in the production of the corresponding saturated lactones 2a-d in high to excellent yields (Scheme 1).
Under similar conditions, the unsaturated oxospiro compounds 3a, 3b also formed related saturated oxospiro systems in excellent yields (Scheme 2).
The delocalization of the π-electrons of the ethylenic linkage, which occurs through conjugation of the carbon-carbon double bond with the ester, nitrile, phenyl, and/or amide groups present in various substrates, resulted in the creation of an electrophilic center which was capable of being attacked by a nucleophile, in this case the borohydride anion.
The exact mechanism for this reduction reaction is unclear.The presence of triethylamine is essential to modify the reactivity of NaBH4 and achieve the required selectivity.A proposed mechanism for this reaction is outlined in Scheme 3 based on previous reports. 11

Scheme 3
The structures of compounds 2a-2d and 4a, 4b were deduced from their IR, 1 H NMR and, 13 C NMR spectroscopy.The mass spectra of these compounds displayed molecular ion peaks at appropriate m/z values, except for 2b.In the mass spectrum of 2b, the mass number is the largest ion with m/z 138, which likely corresponds to the fragment M + -CH3.Given the data 1 H and, 13 C NMR, this compound is a pure substance and corresponds to the structure attributed to it.
The IR spectrum of each isolated product exhibited the sharp absorption band of lactone carbonyl group at about 1740-1780 cm −1 and the absorption band for C = C double bond of lactone ring at 1660 cm -1 was not observed.The structures of all new compounds 2a-d and 4a-b were established by, 1 H NMR spectroscopy.In the, 1 H NMR spectrum of the products, a particular characteristic of the spectra is that the methyl protons at C4 are displaying a doublet at about δ = 1.07-1.20 ppm with 3 JHH = 7.0 Hz.CH proton at C3 for the compound 2b displayed a doublet at δ = 4.37 ppm with 3 JHH = 12.8 Hz and CH proton at C4 showed an AB3X system (δA = 2.68, JAB = 7.0 Hz, JAX = 12.8 Hz).It was in agreement with the anti addition of hydrogens to the double bond of 1b. 12 The methyl groups at C5 for 2b are diastereotopic and exhibit two signals at 1.27 and 1.46 ppm.The, 13 C NMR spectrum of 2b displayed eight distinct resonances in agreement with the 3-cyano-4,5,5-trimethyl-tetrahydrofuranone structure.Partial assignments of these resonances are given in the experimental section.
The 1 H and, 13 C NMR spectra of other products are similar to those of 2b, except for the functional moieties, which exhibited characteristic resonances with appropriate chemical shifts.The anti addition of hydride to the double bond was also observed in, 1 H NMR spectra of other products (see Experimental Section).

Conclusions
In conclusion, we have demonstrated that sodium borohydride in the presence of triethylamine is an effective reagent for chemoselective reduction of unsaturated γ-and δ-lactones 1a-d and also the unsaturated oxospiro compounds 3a-b, which provides a number of interesting and novel 3functionalized tetrahydrofuranones, that could be of value in a biological sense.These reactions are extremely clean with little by-product formation.Functional groups and lactone rings can all be reduced, but in these cases only conjugated carbon-carbon double bond with carbonyl was reduced efficiently.

Experimental Section
General.Melting points were measured with an Electrothermal 9100 apparatus.IR spectra were obtained on a Specord-751R IR spectrophotometer.NMR spectra were measured with a Varian Mercury-300 VX instrument (300.1 MHz for. 1 H and 75.5 MHz for. 13C) with CDCl3 as solvent.Chemical shifts are given in ppm (δ) relative to internal TMS, and coupling constant (J) are reported in Hertz (Hz).Mass spectra were recorded on a MX-1321A mass spectrometer operating at an ionization potential of 70 eV.Lactones were prepared by known methods. 5Other reagents were obtained from Fluka (Buchs, Switzerland) and were used without further purification.