Regio - and stereoselective synthesis of the iminosugars – 4-substituted 1-benzylpiperidine-3,5-diols

We report a new approach to preparing iminosugars – 4-substituted 1-benzylpiperidin-3,5-diols by reaction of 1-benzyl-4,5-epoxypiperidine-3-ols in the presence of lithium perchlorate. This regio-and stereoselective synthesis proceeds via successive nucleophilic cleavage of 1-benzyl-4,5-epoxypiperidin-3-ols by benzylamine, thiophenol and diallylamine. Initial 1-benzyl-4,5-epoxypiperidin-3-ols were obtained by oxidation of trifluoroacetates of 1-benzyl-1,2,3,6-tetrahydropyridin-3-ols


Introduction
2][3] A new interesting research area has recently emerged regarding polyhydroxylated piperidines as enzymatic inhibitors particularly for glycosidases, sialidases or neuraminidases. 1,2Iminosugars are potentially useful for the therapy of the metabolic disorders such as diabetes, viral and bacterial infections, tumors, lysosomal storage diseases. 3,4For instance, the alkaloid nojirimycin 1 is a strong inhibitor of α-and β-glucosidases involved in the metabolism of carbohydrates.Some derivatives of polyhydroxylated piperidines 1-6, for example 1deoxynojirimycin 2 are used for the treatment of Alzheimer's disease 5 and Farby disease.It has been found [7][8][9][10] that introduction of an amino group into the structure of iminosugars (compounds 3,5,6) leads to a change of their activity towards enzyme targets.For example, 4-acetamido-3,5dihydroxypiperidine 3 inhibits sialidase -a virus neuroaminidases incorporated in the membranes of certain viruses.Galactoisofagomine 4 is an inhibitor of β-galactosidase, while its counterpart 3-azaanalog 5 with the same configuration of stereocentres selectively inhibits β-glucosidase. 7,8Stereochemical analogue of galactoisofagomine 3-acetaminopiperidine 6 selectively inhibits β-N-acetylglucosaminidase and is not active towards other types of glycosidases. 9,10High therapeutic potential of iminosugars, in particular analogues 1-6, stimulated intensive structural and stereochemical studies of new iminosugars.5][16] There is a limited number of approaches suitable for the preparation of 3,4,5-trisubstituted and 2,3,4,5-tetrasubstituted piperidines. 15,16For this reason, the development of convenient and effective ways of synthesis of polysubstituted piperidines would significantly increase chance of finding new selective inhibitors.
We have previously developed a regio-and stereospecific synthesis of racemic and enantiopure trans-4amino-1-benzylpiperidin-3-ols 17,18 via nucleophilic ring opening of epoxide 7a under mild conditions with high yields in the presence of Lewis acid (lithium perchlorate, 1 equivalent).0][21][22][23] Such coordination activates the epoxide ring for the nucleophilic attack and shifts the conformational equilibrium (originally in favor the anti-conformer A by ~1.6 kcal/mol 17 ) entirely towards the lithium complex of syn-conformer B, producing only 4-substituted regioisomer upon the epoxide cleavage.

anti-conformer A syn-conformer B 7a
] The present work proceeds the stereochemical investigations of nucleophilic ring opening of epoxypiperidines 7a-c.Targeted 4-substituted 1-benzylpiperidine-3,5-diols 10а-e which are stereochemical analogues of iminosugars 1-6, were prepared according to Scheme 2. The initial 1-benzyl-4,5-epoxypiperidine-3-ols 9a-c were produced by oxidation of trifluoroacetates of 1-benzyl-1,2,3,6-tetrahydropyridine-3-ols 8а-с with trifluoroperacetic acid (5 equivalents) at 0° C in anhydrous CH 2 Cl 2 . 17 The key allyl alcohols 8a-c were produced by rearrangement of 1-benzyl-3,4-epoxy piperidines 7а-c under the influence of lithium diisopropylamide in THF at -70 o C under argon atmosphere. 18Epoxidation of the allyl alcohol 8a generates a single compound with a mass molecular ion (m/z 205) corresponding to the epoxy alcohol 9a, which was isolated by column chromatography on silica gel with 63% yield.The epoxy alcohols 9b,c were produced with the 58-65% yields under similar conditions.Formation of the epoxy alcohols 9a-c was confirmed by the presence of a signal at 50-60 ppm and at 65 ppm in 13 C NMR spectra, which are typical for ARKAT USA, Inc C-4/C-5 atoms of 1-benzyl-4,5-epoxy piperidines 26 and the C-3 hydroxyl group, respectively.The pseudo equatorial direction of the 3-hydroxy group was determined based on the large vicinal coupling constant 3 J 2a,3a (7-8 Hz) of the axial protons connected to the C-2 and C-3 stereocenters of the piperidine core.Basing on NMR 1 H and 13 C spectral data, it was found that the epoxidation proceeds as a syn process and leads to the formation of epoxides 9a-c with cis orientation of epoxy and the 3-hydroxy groups.We assume that high syn stereoselectivity of the epoxidation of allyl alcohols 8a-c is connected with the assistance of 3-hydroxyl group due to formation of the intermediates I or II, stabilized by hydrogen bonds, including the nitrogen atom of the piperidine cycle.Apparently, the peculiarities of a Lewis acid coordinating with epoxide must play a significant role in the relative stability and structure of the reaction intermediates.Consequently, syn-epoxidation of allyl alcohols 8a-c leads to the formation of the epoxy alcohols 9a-c of preferably in anti-conformation half chair with pseudo equatorial 3-hydroxyl group.(Figure 2).Previously synstereoselectivity has been observed upon epoxidation of N-ethoxycarbonyl-3-hydroxy-1,2,3,6tetrahydropyridine with a free 3-hydroxy group.][29] Next, we carried out stereoselective synthesis of targeted 4-substituted 1-benzylpiperidine-3,5-diols 10а-e via nucleophilic cleavage of the epoxy alcohols 9a-c with benzylamine, thiophenol and diallylamine.Reactions were performed in anhydrous CH 3 CN at room temperature in the presence of lithium perchlorate (two equivalents) with good yields.According to 1 H NMR and chromatographic monitoring, the ring opening of epoxy alcohols 9a-c with benzylamine and thiophenol afforded single regio-and stereoisomer 4-substituted (3R,4r,5S)-1-benzylpiperidines 10a,b,e and racemic 1-benzyl-2-methyl-4-benzylaminopiperidine-3,5-diols 10c,d which were isolated with 55-71% yields.Under the same experimental conditions, the opening of epoxy alcohol 9a with diallylamine afforded a mixture of 10e and 10f in a ratio of 4:1, according to 1 H NMR spectra of the reaction mixture.These compounds were easily separated by column chromatography and were isolated ARKAT USA, Inc in 64 and 12% yield, respectively.Also the (3R,4r,5S)-4-aminopiperidine-3,5-diol 11 was obtained by removing of both benzyl groups from the compound 10a through hydrogenolysis above Pd/C10% in CH 3 OH with 82% yield.
It should be emphasized that according to the rule of Fuerst-Plattner 30 , the nucleophilic opening of the epoxy alcohols 9a-c must pass "trans-diaxially", preferably by the C-5 position of the anti-conformer C, with the formation of 5-substituted 1-benzylpiperidine-3,4-diols of the "10f" type.However, our stereochemical study indicated the preservation of the dominant regio-and stereoselective ring opening of epoxyalcohols 9a-c at the C-4 position of the piperidine core with the formation of 4-substituted 1-benzylpiperidine-3,5-diols 10a-e.The observed highly regioselective opening at the C4 position of the piperidine core сan be explained by the participation of a more preferred syn-complex D, which is activated by a bidentate coordination of the lithium cation to the nitrogen atom of the piperidine core and the oxygen atoms of the 4,5-epoxy and 3-hydroxy groups.

Experimental Section
General.The NMR spectra were recorded on Varian VXR-400 and Brucker DRX-500 spectrometers using CDCl 3 , CD 3 OD and DMSO-d 6 as solvents.Chemical shifts are given in δ (ppm) relative to TMS as internal standard.Elemental analysis was performed with a Perkin-Elmer 2400 CHNS elemental analyzer.GC-MS analysis was performed on spectrometer HP5989x-G and Finnigan SSQ7000, ionizing electrons energy 70 eV, capillary column DB5 30 m.The structures of 10a, 10e and 11 were confirmed with Orbitrap Elite mass-spectrometer (Thermo Fisher Scientific, USA) with an electrospray ionization (ESI) source.Formic acid (Sigma Aldrich, St. Louis, Missouri, USA) was added to the methanol solutions of all samples for the analysis in positive mode.The system was controlled by the Xcalibur software, which was also used for data collection and data processing.The methanol solution of each compound was introduced through syringe pump directly into the ion source at 5 l/min.Sheath gas flow rate was from 10 to 25 arbitrary units, auxiliary and sweep gas flow rate was set to zero.Capillary temperature was set to 275 o C and spray voltage to 3.5 kV.Accurate mass measurements were carried out in Orbitrap analyzer with 480000 resolving power.Elemental composition of each fragment ion was calculated within 5 ppm mass accuracy.MS/MS experiments were carried out using both collision induced dissociation (CID) fragmentation triggering techniques at 20 arbitrary units.Nitrogen was used as collision gas.

Figure 3 .
Figure 3. Plausible structures of intermediates I and II.

Scheme 3 .
Scheme 3. Plausible mechanism of the nucleophilic opening of the epoxy alcohols 9 a-c.