Synthesis of ( ± )-mevalonic acid lactone via a meso-dialdehyde : a model for desymmetrization

Two procedures are described for the preparation of the racemic mevalonic lactone (±)-2, via a meso-dialdehyde 8. The preparation of compound 8 in seven steps from cyclopentadiene is also described. This procedure intends to be model for a desymmetrization study of dialdehyde 8, leading to optically active (–) (R)and (+) (S)mevalonolactone, 2.


Introduction
Mevalonic acid, which exists in an equilibrium between its open (-)-(R)-1 and cyclic form (mevalonolactone, (-)-(R)-2), is a key intermediate in cellular biochemistry. 1It is a precursor for a number of biologically important lipids, including cholesterol, steroid hormones, bile acids, ubiquinone and dolichols.In addition, mevalonate-derived isoprenoids are intermediates in the biosynthesis of isoprenylated tRNAs, prenylated proteins involved in cell signaling and growth, and heme a, a prosthetic group of cytochrome oxidase.It is also the biogenetic precursor of most terpenoids, steroids, carotenoids and isoprenoids 2 and has therefore been a synthetic target of considerable interest.
Mevalonolactone (-)-(R)-2 was first discovered and synthesized via resolution by Folkers and co-workers. 3Since then a number of asymmetric syntheses of this molecule have been published, the most popular of which involves the Sharpless epoxidation of a suitable allylic alcohol. 4The chiral pool materials such as linalool, 5 quinic acid, 6 2-methyl-2-hydroxy-γbutyrolactone, 7 a chiral equivalent of cyclohexa-2,5-dienone, 8 and the chiral template 1,2:5,6-di-O-isopropylidene-α-D-glucofuran-3-ulose 9 were reported as sources for the preparation of mevalonolactone.Other interesting synthetic methodologies involve the use of chiral sulfoxides, 10 1,3-oxathianes, 11 and axially dissymmetric binaphthyldiamines. 12In addition, several enzymatic syntheses starting from achiral precursors have been described in the literature. 13However, many of these methods suffer either from poor enantiomeric purity or low chemical yield, 10,12 and therefore there is room for new approaches.

Scheme 1
Desymmetrization is proving to be a powerful synthetic tool, 14 and dialdehydes have been the focus of a number of studies. 15With this methodology, instead of incorporating the chirality from the very beginning of the synthesis, a certain level of elaboration can be incorporated into the mesomolecule prior to the enantioselective desymmetrization step.We present here a model study of the synthesis of racemic mevalonic acid lactone (±)-2, which can be applied to a enantioselective synthesis of (-)-(R)-and (+)-(S)-mevalonolactone, 2, as we have shown recently in the synthesis of (+)-(S)-and (-)-(R)-nor-methyl mevaldate derivatives. 16

Results and Discussion
Although several approaches to analogues of the dialdehyde 8 have been reported, 17 we found it to be conveniently prepared through a seven-step sequence from cyclopentadiene.The alcohol 5 was obtained from cyclopentadiene via epoxide 3, following the procedure of Crandall. 18earrangement of 3 to cyclopent-3-enone, 4, catalyzed by Pd(Ph 3 ) 4 , 19 and treatment with MeMgCl led to the alcohol 5 in 18% overall yield.The alcohol 5 was protected as its tbutyldimethylsilyl ether 6 in 95% yield (TBDMSOTf-DIPEA, CH 2 Cl 2 , -78 o C), identified by the disappearance of the hydroxyl absorption in the infrared spectrum and the replacement of the apparent singlet in the 1 H-NMR, corresponding to the methylene groups of the unprotected alcohol 5 at δ 2.44 ppm, with two 2H doublets (δ 2.43 and δ 2.25, J 15 Hz) in 6.The protected alcohol 6 was transformed into a 5:1 mixture of diastereoisomeric diols 7 by the method of Matteson, employing catalytic osmium tetroxide in t-butanol at reflux with trimethylamine-Noxide as the reoxidant. 20Cleavage of 7 with sodium periodate in 8:2 dioxane-water, followed by exhaustive extraction with ethyl acetate furnished diol 8, which forms the cyclic hydrate 9 on standing.It is possible to transform the hydrate back to the dialdehyde by treating with powdered 4Å molecular sieves in refluxing THF for 2 hours.
Once the meso-dialdehyde 8 was obtained, we aimed at a preparation of mevalonic lactone (±)-2 which would be used for enantioselective differentiation of the aldehyde groups in compound 8.In order to do this, two different approaches to the mevalonic lactone were examined.In the first, a direct reduction of either of the prochiral aldehyde groups, followed by attack on the remaining carbonyl would lead to a ring closure.A final oxidation of the resulting alcohol, and deprotection of the silyl group would complete the synthesis of the racemic lactone (±)-2.
Treatment of the dialdehyde 8 with 1.5 equivalents of NaBH 4 in dry methanol at -30 o C afforded the lactol 10.As a model, 2-hydroxytetrahydropyran, 11, was prepared as reported by Schniepp et al. in 40% yield (Scheme 3). 21The 1 H-NMR spectra of lactols 10 and 11 were then compared, to support the production of the lactol 10.In the 1 H-NMR spectrum of 2hydroxytetrahydropyran, 11, a broad singlet at δ 4.90 ppm corresponding to the anomeric proton was matched by a broad singlet at δ 4.98 ppm in the spectrum of lactol 10.The protons of the methylene group adjacent to the lactol oxygen are diastereotopic, appearing as two separate multiplets at δ  4.03-4.00and δ  3.55-3.47 in the hydroxytetrahydropyran 11 spectrum and at δ 3.72-3.65and δ 3.55-3.42 in the lactol 10 spectrum.The remaining methylene groups were observed in the δ 1.00-2.00region.The presence of lactol 10 was further indicated by the observation of a molecular ion of m/z 229 corresponding to the loss of water in the mass spectrum.The crude lactol 10 was subsequently oxidized with a suspension of PCC and 4Å molecular sieves at room temperature over 24 hours to furnish the lactone 12, in 43% yield over 2 steps, after chromatographic purification (Scheme 3).The lactone was characterized by two distinctive multiplets at δ 4.51-4.41and δ 4.26-4.18,corresponding to the diastereotopic protons of the methylene group adjacent to the lactone oxygen, in the 1 H-NMR spectrum, and the strong lactone carbonyl absorption at 1743 cm -1 in the infrared spectrum.Finally, treatment of the protected lactone 12 with HCl (10%, aqueous) in THF for 48 h afforded racemic mevalonic lactone (±)-2 in 29% yield.The second alternative approach would aim to differentiate between the two prochiral aldehyde groups, by using an appropriate alcohol which would act as a chiral auxiliary in the stereo-differentiating process.Treatment of the adduct with an alkoxide would open the lactone, with the recovery of the chiral auxiliary.Reduction of the aldehyde, re-lactonization, and deprotection of the silyl group would yield the mevalonic acid lactone (±)-2.This approach has been put in practice in the synthesis, recently described by our group, of (+)-(S)-and (-)-(R)nor-methyl mevaldate derivatives. 16To this end, the dialdehyde 8 was treated with 1 equiv. of EtOH in THF and heated at reflux for 24 h.The crude reaction material obtained from this reaction was immediately oxidized with a suspension of PCC and 4Å molecular sieves at room temperature over 24 h, to furnish 14 in 44% yield over 2 steps, after chromatographic purification.Treatment of the compound 14 with sodium ethoxide in Et 2 O at 0 o C yielded 15, which possesses a resonance in its 1 H-NMR spectrum at δ 9.75 (t, 1H, J 2.6 Hz), characteristic of an aldehyde adjacent to a methylene group.The next stage involved ring closure to provide the protected lactone 12.Even though a two-step procedure was expected to be required, treatment of 15 with 2 equivalents of NaBH 4 in EtOH at -30 o C, afforded directly the protected racemic lactone 12 in 44% yield.Finally, racemic mevalonolactone (±)-2 was obtained from 12 by the procedure described previously.In conclusion, two procedures have been described for the preparation of the racemic mevalonic lactone (±)-2, vía a meso-dialdehyde 8.The preparation of compound 8, in seven steps, from cyclopentadiene is also described.This procedure is intended to be model for a desymmetrization study of dialdehyde 8, leading to optically active (-)-(R) and (+)-(S) mevalonolactone, 2.

Experimental Section
General Procedures.Spectroscopic data were recorded with the following instruments: Perkin Elmer Paragon FT-IR or Perkin Elmer 1720-X spectrophotometers (IR); Bruker WM 250, Bruker DPX250 (NMR: 1 H at 250 MHz, 13 C at 62.5 MHz) and Jeol EX 400 (NMR: 1 H at 400 MHz, 13 C at 100 MHz).The assignment of 1 H and 13 C NMR signals is based on two-dimensional NMR techniques.Signal positions are recorded in δ, with the abbreviations s, d, t, q, dd, ddd, dt, dq, br, and m, representing singlet, doublet, triplet, quartet, double doublet, double double doublet, double triplet, double quartet, broad and multiplet, respectively.Mass spectra (m/z) and accurate mass data (HRMS) were recorded on a Fisons VG Autospec mass spectrometer.Spectra were obtained using chemical ionization or electron impact methods as stated.Microanalyses were carried out by Medac Ltd. at Brunel University (UK).Melting points (m.p.) were determined with a Kofler hot stage microscope (Reichert) and are uncorrected.Flash column chromatography was performed according to the method by Still et al. with Silica gel 60 (Merck 9385) using a head pressure by means of head bellows. 22T.L.C. analyses were carried out using 0.25 mm silica gel precoated aluminum-or glass-backed plates with fluorescent indicator, UV 254 .Spots were visualized by quenching of UV fluorescence, by staining with a potassium permanganate solution, by staining with a vanillin solution, or by staining with a molybdate solution.Reagents and solvents obtained from Aldrich, Avocado, BDH, Fisher, Fluka, and Lancaster chemical suppliers were used directly as supplied or following purification according to procedures described by Perrin and Armarego. 23Diethyl ether and tetrahydrofuran were distilled over sodium-benzophenone ketyl radical, and dichloromethane was distilled by refluxing over calcium hydride.Methanol and ethanol were distilled from calcium chloride and stored over 4Å molecular sieves.Diisopropylethylamine was distilled and stored over potassium hydroxide pellets.Light petroleum refers to the fraction in the boiling point range of 30-40 o C, which was fractionally distilled through a Vigreux column prior to use.