Synthesis of dihydro-2 H -pyran-3(4 H )-one

A practical synthetic procedure for the synthesis of dihydro-2 H -pyran-3(4 H )-one is reported. The method commenced from the readily available  -ketoglutaric acid and allowed preparation of the title compound in four steps in 31% overall yield.


Introduction
A careful choice of the chemotype used as the starting point of drug discovery seems to gain momentum in recent medicinal chemistry studies.[5]7 In particular, it was shown by Fecher and Schmidt 5 that current combinatorial collections suffer from a low ratio of oxygen atoms to all heavy atoms compared with both drugs and natural compounds.In this view, saturated conformationally restricted oxygen-enriched building blocks of low molecular weight and lipophilicity are of particular interest.
Implementation of these ideas leads to saturated oxygen heterocycles such as tetrahydropyran as key structural motifs.Dihydro-2H-pyran-3(4H)-one (1) is an appropriate example which has already proven its utility as a building block in the synthesis of α-amino acids, 8 histamine H3 receptor antagonists, 9 modulators of the AMPA receptor, 10 thrombin inhibitors, 11 and 5lipoxygenase inhibitors. 12o date, most of the approaches to the synthesis of 1 reported in the literature have relied on the functionalization of the double bond in dihydropyran (2) (Figure 1). 13Their major drawback was moderate regioselectivity which led to low yields and problems with purification of the product.Another method which also suffered from low yield and tedious purification of the product commenced from the alkyne 3.

Results and Discussion
In this work we describe a different reaction sequence which starts from the readily available α-ketoglutaric (4) (Scheme 1).In the first step, compound 4 is transformed into the ketal ester 5 in 90% yield by the action of trimethyl orthoformate and sulfuric acid in absolute methanol.The compound 5 was reduced with LiAlH4 to give the diol 6 in 74% yield.The pyran ring was then closed by mesylation of the dianion obtained from 6 to give the tetrahydropyran derivative 7 (47%).Acidic hydrolysis of 7 led to the formation of dihydro-2H-pyran-3(4H)-one (1) in 99% yield.The overall reaction sequence included four steps and gave the target compound in 31% yield starting from 4. It should be noted that only distillation was used for the purification of the products in all the steps.Hence the method reported herein is suitable for the multigram preparation of 1.

Experimental Section
General.The solvents were purified according to standard procedures.All starting materials were purchased from Acros, Merck and Fluka.Analytical TLC was performed using Polychrom SI F254 plates. 1 H and 13 C NMR spectra were recorded on a Bruker 170 Avance 500 spectrometer (at 499.9 MHz for protons and 124.9 MHz for carbon-13).Chemical shifts are reported in ppm downfield from TMS ( 1 H, 13 C) as an internal standard.Elemental analyses were performed at the Laboratory of Organic Analysis, Department of Chemistry, Kyiv National Taras Shevchenko University.Mass spectra were recorded on an Agilent 5890 Series II 5972 GCMS instrument (electron impact ionization (EI)).Dimethyl 2,2-dimethoxypentanedioate (5).The procedure for the preparation of 5 is updated from the literature data. 15  (6).To a suspension of LiAlH4 (73 g) in dry THF (1.4 L), a solution of 5 (205 g, 0.93 mol) in dry THF (450 mL) was added dropwise with effective stirring.The reaction mixture was refluxed for additional 2 h, and then cooled.10% aq KOH (90 mL) was added dropwise upon effective stirring, followed by water (140 mL).The mixture was refluxed for 0.5 h, then cooled and filtered.The precipitate was washed thoroughly with hot THF (1 L).The combined filtrates were evaporated in vacuo.The residue was dissolved in dichloromethane, dried over Na2SO4 and evaporated again.The crude product was distilled in vacuo.Yield 114 g (74%).Colourless oil.Bp 115-117 C / 1 mmHg.

Figure 1 .
Figure 1.Synthetic precursors of 1 reported in the literature.