A versatile stereocontrolled synthesis of 2-deoxyiminosugarC-glycosides and their evaluation as glycosidase inhibitors

HAL Id: hal-03388809 https://hal.archives-ouvertes.fr/hal-03388809 Submitted on 21 Oct 2021 HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L’archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d’enseignement et de recherche français ou étrangers, des laboratoires publics ou privés. A versatile stereocontrolled synthesis of 2-deoxyiminosugar C -glycosides and their evaluation as glycosidase inhibitors Alexandre Lumbroso, Clément Berthonneau, Isabelle Beaudet, Jean-Paul Quintard, Aurélien Planchat, M. Isabel García-Moreno, Carmen Ortiz Mellet, Erwan Le Grognec To cite this version: Alexandre Lumbroso, Clément Berthonneau, Isabelle Beaudet, Jean-Paul Quintard, Aurélien Planchat, et al.. A versatile stereocontrolled synthesis of 2-deoxyiminosugar C -glycosides and their evaluation as glycosidase inhibitors. Organic & Biomolecular Chemistry, 2021, 19 (5), pp.1083-1099. �10.1039/d0ob02249g�. �hal-03388809� A Versatile Stereocontrolled Synthesis of 2-Deoxyiminosugar C-Glycosides and their Evaluation as Glycosidases Inhibitors Alexandre Lumbroso,a Clément Berthonneau,a Isabelle Beaudet,a Jean-Paul Quintard,a Aurélien Planchat,a M. Isabel García-Moreno,b Carmen Ortiz-Mellet,b Erwan Le Grogneca* a Université de Nantes, CNRS, CEISAM, UMR 6230, 44000 Nantes, France. e-mail: [email protected] b Department of Organic Chemistry, Faculty of Chemistry, University of Seville, c/ Professor García Gonzalez 1, 41012, Seville, Spain  Abstract A highly enantioselective synthesis of (R,S) or (S,S)-2,6-disubstituted dehydropiperidines has been previously achieved through Sn/Li transmetalation of the corresponding stannylated dehydropiperidines or of their precursors. Herein, we successively consider their Upjohn’s syn dihydroxylation and their anti dihydroxylation via an epoxidation reaction followed by epoxide opening reaction. The stereochemical course of these reactions was first reported including the use of appropriate protecting groups before considering the conversion of the obtained compounds into NH or NMe iminosugar hydrochlorides. A primary evaluation of the designed iminosugar C- glycosides as glycosidase inhibitors suggests candidates for the selective inhibition of -galactosidase, amyloglycosidase and naringinase. Beyond the reported results, the method constitutes a highly modulable route for the synthesis of well stereodefined iminosugar C- glycosides, an advantage which might be used for the design of iminosugars to enhance their biological properties. Keywords: Iminosugar C-glycosides, Stereoselective Synthesis, Dihydroxylation, Epoxidation, Inhibition of glycosidases, Piperidine, Tetrahydropyridine, Dehydropiperidine 1. Introduction Iminosugars are the most attractive class of glycomimetics for inhibiting glycosidases due to a structural resemblance with the sugar moiety of the natural substrates.1 The marketing of three iminosugar-based drugs for the treatment of type II diabete (Miglitol),2 Gaucher disease (Miglustat),3 or Fabry disease (Migalastat)4 demonstrates the role that iminosugars can play in the therapy of diseases associated with carbohydrates metabolism.1c, 5 A huge number of studies have been carried out to exploit the potential of iminosugars as antivirals6 or antidiabetic agents7 and to promote them in cancer therapy8 or for the treatment of lysosomal storage disorders.9 Therefore, numerous syntheses of iminosugars have been developed to improve the potency and selectivity of these inhibitors but also to better understand the structure-activity relationships.1c, 10The influence of ring size and rigidity have been studied through the synthesis of 4-membered,11 5-membered12 and 7-membered rings,13 through bicyclic locked deoxy-iminosugars,14 hydrazine type bicyclic iminosugars15, constrained fused bicyclic iminosugars16 or sp2-iminosugars.17 Many of the reported syntheses use carbohydrates as starting materials18 including stannylated ones19 but others start from simple organic molecules.20 The use of carbohydrates as starting materials allows an access to modified compounds of well-defined configuration while the use of simple organic starting materials offer the opportunity to insert a wide variety of substituents. Among the different classes of iminosugars, iminosugar C-glycosides display promising biological activities. They are supposed to allow an easier locking through a favorable conformation of the piperidine ring inducing a better ligand-enzyme interaction.21 While naturally occurring C- glycosides iminosugars have been isolated,22 versatile approaches to this type of compounds are required for the validation of these assessments.23 On our side, we have first developed a diastereoselective approach involving syn-allylstannation of N-acyliminium derivatives combined with a ring-closing metathesis and a dihydroxylation to obtain (±)-1-deoxy-6,8a-di-epi-castanospermine and (±)-1-deoxy-gulonojirimycine.24 However, an enantioselective version of this approach was shown to be hardly developed and we considered a second method based on the stannylated platform A derived from (S)-vinylglycinol (scheme 1).25 The 2,6-disubstituted dehydropiperidines B were obtained using two key reactions: 1) a Sn-Li transmetalation followed by an electrophilic trapping and 2) a ring-closing metathesis. The high stereoselectivity of the sequence was found to be governed by the chelation occurring between lithium and oxazolidinone carbonyl, revealing the importance of the relative order in which these two reactions are carried out and affording an opportunity for a selective preparation of (S,S)-trans dehydropiperidines B1 and (R,S)-cis dehydropiperidines B2.25b Herein, we report with further details the functionalization of these dehydropiperidines which constitutes the late stage of the stereocontrolled synthesis of iminosugar C-glycosides C1 and C2 which has been briefly reported.26 Furthermore, due to the high polarity of iminosugars, the removal of tetrabutyltin and other residual organotins can be easily achieved by biphasic partition or liquid chromatography,27 allowing preliminary biological assays of these iminosugar C- glycosides toward a set of glycosidases. Scheme 1. Syntheses of the two series of D-iminosugar C-glycosides 2. Synthesis of iminosugar C-glycoside analogs 2.1. Functionalization of intermediates B1 and B2 by syn-dihydroxylation The functionalization of intermediates B1 and B2 was first considered through an Upjohn’s dihydroxylation reaction achieved according to information reported in Table 1.28 A subsequent conversion into acetonides was carried out to facilitate further characterizations (except for 5 and 11). Accordingly, starting from dehydropiperidines B1, acetonides 1-6 were obtained in 55% to 94% yield as a mixture of two diastereomers which were fully characterized after separation by flash chromatography. Fortunately, suitable monocrystals for an X-ray diffraction analysis were obtained for the major diastereomer 2 resulting from the functionalization of B1-b, allowing its assignment as endo isomer. 26 On the basis of the similarity of their NMR data, the major diastereomers were always assigned to be endo in compounds 1 to 6 derived from B1 type dehydropiperidines (exo/endo = 24/76 to 9/91). When a similar procedure was applied to dehydropiperidines B2, acetonides 7-14 were obtained in good yields (62-89%) with a high preference for the exo isomers (91-98% when the side chain E contains an alcohol or an ester function (vide infra for the assignment of the exo configuration)). When E was an n-hexyl group, this exo preference (observed at the stage of the crude diol, without conversion into acetonide) appeared to be lower (exo/endo = 83/17). It is worth noting that the exo preference remained high (98%) when the product resulting from an acyl transfer reaction B2-d was considered for the dihydroxylation reaction.29  Table 1. Syn-Dihydroxylation of intermediates B1 and B2  [a] exo/endo ratio was determined by GC analyses on the crude product. [b] The absolute configuration of the endo compound was confirmed by X-ray analysis.26 [c] The exo isomer was not isolated after column chromatography. [d] exo/endo ratio was determined by 1H NMR analyses on the crude product. [e] Without step 2, the obtained diol was not modified into acetonide. [f] The minor compound was not observed in the 1H NMR spectrum. [g] The endo diol was not isolated after column chromatography. At this stage, the deprotection of compounds 9 and 10 was performed with trifluoroacetic acid (TFA) in water and furnished 15 and 16 in good yields (scheme 2). Fortunately, suitable monocrystals for an X-ray diffraction analysis were obtained for the major isomer of 16 allowing assignment of its exo configuration. This assignment has been a key-information for further assignment of an exo configuration for the major diastereomer of compound 10 and subsequently for the major diastereomer of compounds 7-14 on the basis of the analogies encountered in their NMR data. Accordingly the Upjohn’s dihydroxylation proceeded with a high exo-selectivity on intermediates B2. In addition, the X-ray analysis also corroborates the occurrence of the acyl transfer reaction during the synthesis of B2-d.29  N O O OH OH C5H11 OH 15 16 N O O OH C5H11 O O 9 90% 53% TFA TFA H2O, 25°C H2O, 25°C 16 NOH O O 10 O C5H11 O NOH OH OH O C5H11 O CCDC 2040539  Scheme 2. Deprotection of acetonides 9 and 10 at 25°C and ORTEP view of compound 16 The stereochemical trends of the Upjohn’s dihydroxylation reaction can be explained by considering the approach of osmium tetroxide on the exo or endo face of the cis and trans dehydropiperidines in their half chair conformation (Scheme 3).30 When the cis substrate is involved, the E group occupies a pseudo equatorial position which brings a steric hindrance on the endo face, inducing a prevalent reaction on the exo face. On the other hand, when the trans substrate is involved, the presence of the E group in a pseudo axial position strongly interferes with a reaction on the exo face, leading mainly to the reaction on the endo one. The higher preference for the exo approach starting from the cis dehydropiperidines B2 (exo/endo ~ 95/5) compared to the endo preference for trans dehydropiperidines B1 (exo/endo ~ 20/80) can be explained by a higher accessibility to the convex face (exo face) of these bicyclic molecules.  Scheme 3. Rationalization of the stereochemical trends for Upjohn’s dihydroxylation amyloglucosidase. The 4-epimer 2-DGUJ derivative 31 did not inhibit any of the enzymes tested in this work. However, 3-epimer 2-DNJ derivative 32 was a selective inhibitor of amyloglucosidase (Ki = 22.8 μM; Table 6). Altogether, the ensemble of results highlights the importance of developing methodologies compatible with structural diversity-oriented strategies allowing modification of the glycone and aglycone parts in glycomimetics to optimize the affinity and selectively towards glycosidase targets. This set of tests which has been done in a screening mode from available synthetic products suffers from a lack of continuum in the modifications of the structures in order to attempt further rationalization. However, just on the basis of the reported results, several facts can be noted: - No activity was observed on mannosidases regardless of the series and the nature of the aglycone, a result which is consistent with the non-hydroxylated C-2 position,12a - The presence or the absence of an hydroxyl group on the aglycon can strongly modify the selectivitities (Cf 25 versus 23 and 24 in the -series), - The spatial position of an aglyconic hydroxyl can strongly modify the selectivities (27 versus 28 in the -series), - While N-Me iminosugars appear generally to be less active in our tests, they are also able to exhibit simultaneously very high selectivity and efficiency on a single enzyme (Cf 34 against amyloglucosidase or 35 against naringinase). Table 5. Glycosidase inhibitory activities (Ki, M) of deoxy-α-D-C-glycoside 23-25 and N-methyl -DGJ C-glycoside 33. Values represent the mean ±SD (three independent determinations). Inhibition was competitive in all cases.a Enzymes 23 24 25 33  -galactosidase/ -glucosidase (bovine liver) 473 ± 23 652 ± 40 10 ± 2 475 ± 39  -glucosidase (almonds, pH 7.3) n.i. 46 ± 3 252 ± 20 n.i. -galactosidase (green coffee beans) 33 ± 3 36 ± 5 313 ± 28 223 ± 20 Amyloglucosidase ( A sp. ni g e r ) n.i. 153 ± 12 n.i. n.i. Naringinase (Penicilium decumbens) n.i. n.i. 115 ± 10 n.i. a No inhibition was observed for any compound at 1 mM concentration on baker yeast -glucosidase, E. coli -galactosidase, Jack bean -mannosidase, Helix pomatia -mannosidase, and pig kidney trehalase. Table 6. Glycosidase inhibitory activities (Ki, M) of deoxy-β-D C-glycosides 26-30, N-methyl -DAJ C-glycoside 34-35, 2-DGUJ C-glycoside 31 and 2-DNJ C-glycoside 32. Values represent the mean ± SD (three independent determinations). Inhibition was competitive in all cases.a Enzymes 26 27 28 29 30 34 35 31 32  -galactosidase/ -glucosidase (bovine liver) 301± 25 1.3 ± 0.1 42 ± 4 12.1 ± 1.3 58 ± 6 594 ± 50 195 ± 20 n.i n.i.  -glucosidase (almonds, pH 7.3) 693 ± 65 36 ± 4 11.4 ± 2 18 ± 2b 436 ± 41 537 ± 50 140 ± 11 n.i. n.i. Amyloglucosidase (Asp. niger) 116 ± 10 463 ± 40 169 ± 15 n.i. n.i. 1.4± 0.1 550 ± 45 n.i. 22.8 ± 1.9 Naringinase (Penicilium decumbens) 76 ± 5 131 ± 11 45 ± 3 50 ± 4 224 ± 20 67 ± 5 4.9 ± 0.5 n.i. 272 ± 25 a No inhibition was observed for any compound at 2 mM concentration on baker yeast -glucosidase, green coffe beans - galactosidase, E. coli -galactosidase, Jack bean -mannosidase, Helix pomatia -mannosidase, and pig kidney trehalase b Ki = 102 ± 10 M at pH 5.5.  4. Conclusion The chelative stabilization of lithium by the oxazolidinone carbonyl has allowed the use of an organometallic route to selectively obtain cis or trans 2,6-disubstituted dehydropiperidines, precursors of the β- or αseries of 2-deoxyiminosugar C-glycosides, respectively. Herein, we report the possible syn or anti dihydroxylation of the double bond to obtain selectively several configurations of 2-deoxy iminosugar C-glycosides. The screening of the inhibitory properties of the obtained NH- or NMe-iminosugar C-glycosides towards glycosidases has pointed out interesting features in terms of modulation of the activity by adjustment of the chemical structure of the aglycon. While non-conclusive, these results are promising, because taking advantage of the generality of our synthetic method, it is possible to modulate the configuration of the pseudo-anomeric centre, the nature of the aglycon moiety as well as the configuration of the iminosugar itself. Furthermore, by starting from 2-tributylstannyl-1,3-oxazolidinones derived from (R) vinylglycinol instead of (S) vinylglycinol, this same strategy could provide access to L iminosugar series. On the basis of these results, we can envisage numerous adjustments in order to optimize the inhibition properties both in terms of efficiency and selectivity and also to allow access to new structures able to help in the understanding of the inhibition process itself. 5. Experimental section General remarks for the following data: numbers, disconnected from the nomenclature, have been placed on the formula of the obtained compounds (given in supplementary information) in order to indicate the NMR assignments of protons and carbons. 5.1 General methods 1H and 13C NMR spectra were recorded on Bruker Avance 300 or Bruker ARX 400 instruments. Chemical shifts are given in ppm as  values related to tetramethylsilane (1H, 13C) and coupling constants are given in Hz. Mass spectra were obtained in EI (70 eV) and/or CI mode in direct introduction mode using a HP apparatus (Engine 5989A) or a DSQII (ThermoFisher Scientific). HRMS in ESI mode were recorded on a LTQ-Orbitrap (ThermoFisher Scientific) at Nantes- Atlantic National College of Veterinary Medicine, Food Science and Egineering (ONIRIS) or on a MicroTOFQII (ThermoFisher Scientific) at the University Claude Bernard Lyon 1. MALDI-TOF spectra were recorded on an Autoflex III apparatus (Bruker) in positive ionization mode and using DHB (dihydroxybenzoic acid) or DCTB (trans-2-[3-(4-tert-butyl-phenyl)-2-methyl-2- propenylidene]malononitrile) as matrix at the INRA of Nantes. IR spectra were recorded on a Bruker IFS Vector 22 apparatus. Optical rotations were measured on a Perkin-Elmer 341 apparatus and melting points were determined with a Tottoli SMP3 Stuart apparatus. CH2Cl2 was dried on CaH2 and distilled prior to use. Et2O and THF were distilled on sodium-benzophenone. EtOH was dried over magnesium methoxide and distilled before use. TLC analyses were carried out on silicacoated plates (Merck Kieselgel 60F254) as well as LC purifications (silica gel 60 Merck Geduran). GC analyses were performed on a capillary column optima 3 (long. 30 m, diameter 0.25 mm, stationary phase 0.25 µm) with the following parameters: flow = 1.3 mL/min of N2; injector = 200°C; detector = 300°C. HPLC analyses were performed on an Inertsil 5Si column (250 mm x 3 mm) using an UV detector (254 nm) and 95/5 mixture of hexanes and AcOEt (Flow = 0.5 mL/min). 5.2 General Procedure for Inhibition Assay Inhibition constant (Ki) values were determined by spectrophotometrically measuring the residual hydrolytic activities of the glycosidases against the respective o- (for β-galactosidase from E. coli) or p-nitrophenyl α- or β-D-glycopyranoside (for other glycosidases) in the presence of the iminosugars. Each assay was performed in phosphate buffer or phosphate-citrate buffer (for α- or β-mannosidase and amyloglucosidase) at the optimal pH for the enzymes. The reactions were initiated by addition of the enzyme to a solution of the substrate in the absence or presence of various inhibitor concentrations. The mixture was incubated for 10-30 min at 37 ºC or 55 ºC (for amyloglucosidase) and the reaction was quenched by addition of 1 M Na2CO3. Reaction times were appropriate to obtain 10–20% conversion of the substrate in order to achieve linear rates. The absorbance of the resulting mixture was determined at 405 nm. Approximate value of Ki was determined from the slope of Dixon plots using a fixed concentration of substrate (around the Km value for the different glycosidases) and various concentrations of inhibitor. Full Ki determinations and enzyme inhibition mode were determined from the slope of Lineweaver–Burk plots and double reciprocal analysis. Representative examples of Dixon and Lineweaver–Burk plots are shown in the Supplementary materials. 5.3 Preparation and Characterization of Compounds 5.3.1 Starting materials The stannylated dienyloxazolidinones A were obtained by ring opening of 2-tributylstannyl-1,3- oxazolidine derived from N-protected (S)-vinylglycinol by soft nucleophiles in the presence of Lewis acids according to our previously described procedure.36 The stereodefined platform B1 (trans isomer) was obtained through a sequence transmetalation (and electrophilic trapping) followed by a ring closing metathesis, while stereodefined platform B2 (cis isomer) was obtained through a reversed sequence (ring closing metathesis, then transmetalation and electrophilic trapping).25b Note that these syntheses have taken advantage of an improved preparation of N-Moc- (S)-vinylglycinol37 as well as of an improved cyclisation of the obtained tributylstannylated dienols into the corresponding oxazolidinones.25a 5.3.2 General procedure for the preparation of diols and acetonides To a solution of dehydropiperidine (0.2 mmol) in acetone (3 mL) and H2O (1 mL) were successively added NMO (135 mg, 1 mmol) and OsO4 (20 mg of a 2.5% solution in t-BuOH, 1 mol%) at room temperature. The reaction was monitored by TLC and after complete dihydroxylation of the C=C double bond into diol, saturated aqueous NaHCO3 solution was added. After further stirring for 1 h, the organic and aqueous phases were separated and the aqueous phase was extracted with AcOEt. The combined organic layers were dried (MgSO4), filtered and concentrated under reduced pressure. The crude product was used without further purification in the following procedure. Crude diol was dissolved in acetone (2 mL) and 2,2-dimethoxypropane (2 mL) before addition of camphor sulfonic acid (23 mg, 0.1 mmol) to the mixture and stirring at room temperature for 12 h. The reaction mixture was subsequently partitioned between AcOEt (5 mL) and water (5 mL) and the organic layer was separated, dried (MgSO4) and concentrated under reduced pressure. Purification was carried out by chromatography on silica gel using hexanes/AcOEt as eluent. 5.3.3 Characterization of the obtained acetonides Diastereomers 1-endo,1-exo, 2-endo, 2-exo, 7, 8, 33 and 34 have been previously prepared and fully characterized.26 Acetonide 3. By using the above general procedure and starting from B1-c (48 mg, 0.2 mmol) as starting material, 3-endo was isolated in 64% overall yield (Rf = 0.17, yellow oil, 40 mg) after purification on silica gel (eluent hexanes/AcOEt: 3/7). While observed in GC and NMR on the crude mixture, the exo-diastereomer was not isolated after liquid chromatography. (3aR,5S,9aR,9bS)-5-((S)-1-hydroxyhexyl)-2,2-dimethylhexahydro-7H-[1,3]dioxolo[4,5- c]oxazolo[3,4-a]pyridin-7-one, 3-endo. [αD= -25.4 (c 1.0, CHCl3); IR (neat): 3433, 2929, 2856, 1732, 1468, 1422, 1235, 1212, 1058, 1034, 1001 cm-1; 1H NMR (400 MHz, 300 K, CDCl3): 4.54 (bdt, 3JH3H2 = 3JH3H2’ = 2.7, 3JH3H4 = 7.8, 1H3), 4.42 (dd, 3JH6H5 = 2.3, 2JH6H6’ = -8.4, 1H6), 4.35 (t, 3JH6’H5 = 8.4, 2JH6’H6 = -8.4, 1H6’), 4.17 (dd, 3JH4H5 = 2.3, 3JH4H3 = 7.8, 1H4), 3.85 (m, 2H1,5), 3.60- 3.50 (m, 1H8), 2.1 (ddd, 3JH2H3 = 2.7, 3JH2H1 = 5.3, 2JH2H2’ = -15, 1H2), 1.7 (ddd, 3JH2’H3 = 2.7, 3JH2’H1 = 12.2, 2JH2’H2 = -15, 1H2’), 1.65-1.15 (m, 8H9,10,11,12), 1.40 (s, 3H15), 1.29 (s , 3H16), 0.87 (t, 3JH13H12 = 6.9, 3H13); 13C NMR (100 MHz, 300 K, CDCl3): 160.5 (C7), 109.2 (C14), 75.0 (C8), 73.6 (C4), 71.0 (C3), 64.2 (C6), 53.4 (C5), 51.4 (C1), 33.9 (C9), 31.9 (1C), 26.5 (C2), 26.1 (C15), 25.2 (1C), 24.0 (C16), 22.7 (1C), 14.1 (C13); HRMS (MALDI) calcd for C16H27NO5Na [M+Na]+: 336.1781, found: 336.1790; MS (EI): m/z (%) 313 (0.2, M+•), 298 (20), 214 (15), 213 (100), 212 (70), 198 (13), 154 (11), 112 (13), 69 (11), 55 (11), 44 (14), 43 (14), 41 (11), 28 (12). Meaningful signals for the isomer 3-exo in the crude product: 4.26 (dd, 3J = 2.5, 3J = 8.9, 1H), 1.86 (dt, 3J = 8, 2J = -15, 1H2) ppm. Acetonide 4. By using the above general procedure and starting from B1-d (48 mg, 0.2 mmol) as starting material, 4 was isolated in 55% overall yield (yellow oil, 34 mg) after purification on silica gel (eluent hexanes/AcOEt: 3/7). While observed in GC and NMR on the crude mixture, the exodiastereomer was not isolated after liquid chromatography. (3aR,5S,9aR,9bS)-5-((R)-1-hydroxyhexyl)-2,2-dimethylhexahydro-7H-[1,3]dioxolo[4,5- c]oxazolo[3,4-a]pyridin-7-one, 4-endo. [αD= -20.1 (c 1.0, CHCl3); IR (neat): 3568, 3445, 2930, 2857, 1732, 1433, 1383, 1247, 1211, 1034, 1001, 760 cm-1; 1H NMR (400 MHz, 300 K, CDCl3): 4.57 (bdt, 3J H3H2 = 3J H3H2’ = 2.6, 3J H3H4 = 7.9, 1H3), 4.45-4.33 (m, 2H6,6’), 4.18 (dd, 3J H4H5 = 2.3, 3J H4H3 = 7.9, 1H4), 3.93-3.85 (m, 2H5,8), 3.82 (ddt, 3J H1H8 = 4J H1-H9 = 2.1, 3J H1H2 = 5.0, 3J H1H2’ = 12.4, 1H1), 2.01 (ddd, 3J H2H3 = 2.6, 3J H2H1 = 5.0, 2JH2H2’ = -15.0, 1H2), 1.79 (ddt, 3J H2’H3 = 2.6, 3J H2’H1 = 12.4, 2J H2’H2 = -15.0, 1H2’), 1.65-1.47 (m, 1H9), 1.43 (s, 3H15), 1.29 (s, 3H16), 1.42-1.15 (m, 7H9’,10,11,12), 0.87 (t, 3J H13H12 = 6.9, 3H13); 13C NMR (100 MHz, 300K, CDCl3): 159.4 (C7), 109.2 (C14), 73.6 (C4), 73.1 (C8), 71.0 (C3), 64.1 (C6), 53.6 (C5), 51.7 (C1), 32.4 (1C), 32.0 (1C), 26.1 (1C15), 26.0 (C9), 24.1 (C16), 23.4 (C2), 22.7 (1C), 14.1 (C13); HRMS (MALDI): calcd for C16H27NO5Na [M+Na]+: 336.1781, found: 336.1792; MS (EI): m/z(%) 313 (0.2, M+•), 298 (18), 214 (15), 213 (100), 212 (77), 198 (13), 154 (12), 112 (13), 69 (11), 55 (10), 43 (13). Meaningful signals for isomer 4-exo in the crude product: 4.51 (bd, 3J = 8.4, 1H), 4.29 (dd, 3J = 2.7, 2J = -9.2, 1H6). Diol 5 (exo/endo). Diol 5 was obtained according to the general procedure, but without the step of diol protection as acetonide, using B1-e (56 mg, 0.2 mmol) as starting material. Accordingly, 5 was prepared in 72% yield (exo:endo = 9:91) after purification on silica gel (eluent: AcOEt). HRMS (MALDI): calcd for C16H29NO5Na [M+Na]+: 338.1943, found 338.1947. (5S,7S,8R,8aR)-7,8-dihydroxy-5-(5-hydroxynonan-5-yl)hexahydro-3H-oxazolo[3,4- a]pyridin-3-one, 5-exo.colourless oil (4 mg, 7%); Rf = 0.39; [αD= -15 (c 0.2, CHCl3); 1H NMR (400 MHz, 300 K, CDCl3): 4.42 (t, 3JH6H5 = 8.8, 2JH6H6’ = -8.8, 1H6), 4.35 (dd, 2JH6’H6 = -8.8, 3JH6’H5 = 2.4, 1H6’), 3.96 (bq, 3JH3H2 = 3JH3H2’ = 3JH3H4 ~ 3.4, 1H3), 3.92-3.88 (m, 1H1), 3.88 (bdd, 3JH5H6 = 8.8, 3JH5H6’ = 2.4, 1H5), 3.35-3.26 (m, 1H4), 2.65 (m, 1HOH), 2.35 (dt, 2JH2H2’ = -16.0, 3JH2H1 = 3JH2H3 = 3.4, 1H2), 1.98 (ddd, 2JH2’H2 = -16.0, 3JH2’H1 = 8.4, 3JH2’H3 = 3.4, 1H2’), 1.54-1.10 (m, 12H9,10,11), 0.96-0.88 (m, 6H12); 13C NMR (100 MHz, 300 K, CDCl3): 158.0 (C7), 78.1 (C8), 70.3 (C4), 66.0 (C3), 65.6 (C6), 53.0 and 52.6 (2C1,5), 36.4 (1C), 35.3 (1C), 29.6 (1C), 28.8 (C2), 25.8 (1C), 23.1 (2C), 14.0(C12), 13.9 (C12’). (5S,7R,8S,8aR)-7,8-dihydroxy-5-(5-hydroxynonan-5-yl)hexahydro-3H-oxazolo[3,4- a]pyridin-3-one, 5-endo. colourless oil (41 mg, 65%); Rf = 0.29; [αD= -2.2 (c 1, CHCl3); 1H NMR (400 MHz, 300 K, CDCl3): 4.41 (dd, 2JH6H6’ = -8.4, 3JH6H5 = 3.2, 1H6), 4.36-4.32 (m, 1H3, assigned by COSY experiment), 4.33 (t, 3JH6’H5 = 8.4, 2JH6’H6 = -8.4, 1H6’), 4.24 (ddd, 3JH5H6’ = 8.4, 3JH5H6 = 3.2, 3JH5H4 = 1.7, 1H5), 3.83 (d, 3JH1H2’ = 7.2, 1H1), 3.76 (bs, 1H4), 3.42 (bs, 1HOH), 3.06- 2.92 (m, 1HOH), 1.95 (dd, 2JH2H2’ = -13.2, 3JH2H3 = 4.8, 1H2), 1.84 (ddd, 2JH2’H2 = -13.2, 3JH2’H3 = 12.0, 3JH2’H1 = 7.2, 1H2’), 1.84-1.78 (m, 1HOH), 1.60-1.10 (m, 12H9,10,11), 0.93 (t, 3JH12H11 = 7.2, 3H12), 0.89 (t, 3JH12’H11 = 7.2, 3H12’); 13C NMR (CDCl3, 100 MHz, 300 K): 159.2 (C7), 79.1 (C8), 69.2 (C5), 66.7 (C3), 63.8 (C6), 55.7 (C4), 54.6 (C1), 36.6 (1C), 35.9 (1C), 26.0 (C2), 25.7(1C), 25.6 (1C), 23.4 (1C), 23.3 (1C), 14.2(C12), 14.1 (C12’). Acetonide 6 (exo/endo). By using the general procedure and starting from B1-f (45 mg, 0.2 mmol), 6 was prepared in 78% yield (exo:endo = 24:76) after purification on silica gel (eluent hexanes/AcOEt: 3/7). (3aS,5R,9aR,9bR)-5-hexyl-2,2-dimethylhexahydro-7H-[1,3]dioxolo[4,5-c]oxazolo[3,4- a]pyridin-7-one, 6-exo. colourless oil (11 mg, 19%); 1H NMR (300 MHz, 300 K, CDCl3): 4.46 (dd, 2JH6H6’ = -9.0, 3JH6H5 = 6.0, 1H6), 4.30 (ddd, 3JH3H2’ = 9.0, 3JH3H4 = 7.2, 3JH3H2 = 6.0, 1H3), 4.26 (dd, 2JH6H6’ = -9.0, 3JH6’H5 = 3.0, 1H6’), 4.02 (dd, 3JH4H5 = 9.0, 3JH3H4 = 7.2, 1H4), 3.69 (ddd, 3JH5H6’ = 3.0, 3JH5H6 = 6.0, 3JH5H4 = 9.0, 1H5), 3.62 (dq, 3JH1H2’ = 9.0, 3JH1H2 == 3JH1H8 = 3JH1H8’ = 6.0, 1H1), 2.19 (dt, 2JH2H2’ = -12.0, 3JH2H1 = 3JH2H3 = 6.0, 1H2), 1.68 (dt, 2JH2H2’ = -12.0, 3JH2’H1 = 3JH2’H3 = 9.0, 1H2’), 1.8-1.2 (m, 10H8 to 12), 1.47 (s, 3H15), 1.33 (s, 3H16), 0.87 (t, 3JH12H13 = 6.5, 3H13); 13C NMR (CDCl3, 75 MHz, 300 K): 157.5 (C7), 109.7 (C14), 75.5 (C4), 72.9 (C3), 66.9 (C6), 53.9 (C5), 48.8 (C1), 34.4 (1C), 31.8 (1C), 31.2 (C2), 29.2 (1C), 27.4 (C15), 25.4 (1C), 24.9 (C16), 22.7 (1C), 14.2 (C13). (3aR,5R,9aR,9bS)-5-hexyl-2,2-dimethylhexahydro-7H-[1,3]dioxolo[4,5-c]oxazolo[3,4- a]pyridin-7-one, 6-endo. colourless oil (35 mg, 59%); 1H NMR (300 MHz, 300 K, CDCl3): 4.50 (dt, 3JH3H2’ = 3JH3H2= 3.0, 3JH3H4 = 7.9, 1H3), 4.39 (dd, 2JH6H6’ = -8.5, 3JH6H5 = 2.5, 1H6), 4.3 (t, 2JH6H6’ = -8.5, 3JH6’H5 = 8.5, 1H6’), 4.17 (dd, 3JH4H5 = 2.5, 3JH3H4 = 7.9, 1H4), 3.82 (m, 1H1), 3.77 (dt, 3JH5H6’ = 8.5, 3JH5H6 = 3JH5H4 = 2.5, 1H5), 2.16 (ddd, 2JH2H2’ = -15.0, 3JH2H1 = 5.0, 3JH2H3 = 3.0, 1H2), 1.65-1.05 (m, 1H2’+ 10Haliph.), 1.43 (s, 3H15), 1.32 (s, 3H16), 0.86 (t, 3JH12H13 = 6.3, 3H13); 13C NMR (75 MHz, 300K, CDCl3): 158.7 (C7), 109.2 (C14), 73.7 (C4), 71.2 (C3), 63.6 (C6), 52.7 (C5), 46.8 (C1), 35.4 (1C), 31.9 (1C), 29.8 (1C), 29.5 (C2), 26.1 (C15), 24.9 (1C), 24.1 (C16), 22.7 (1C), 14.1 (C13). (3aS,5R,9aR,9bR)-5-((S)-1-hydroxyhexyl)-2,2-dimethylhexahydro-7H-[1,3]dioxolo[4,5- c]oxazolo[3,4-a]pyridin-7-one, 9. By using the general procedure and starting from B2-c (49 mg, 0.2 mmol), 9 was isolated in 71% overall yield (Rf = 0.75, yellow oil, 53 mg) after purification on silica gel using AcOEt as eluent. Note that only exo isomer was isolated after liquid chromatography while crude mixture exhibited a 91/9 exo/endo ratio. Isomer 9-exo, [αD= +36.5 (c 0.9; CHCl3); IR (neat): 3407, 2988, 2926, 2859, 1741, 1420, 1215, 1060, 768, 761 cm-1; 1H NMR (400 MHz, 300 K, CDCl3): 4.51 (m, 1H3), 4.50 (dd, 2JH6H6’ = -8.9, 3JH6H5 = 8.2, 1H6), 4.29 (m, 1H8), 4.17 (dd, 3JH6’H5 = 5.5, 2JH6H6’ = -8.9, 1H6’), 3.95 (dd, 3JH4H3 = 5.5, 3JH4H5 = 8.2, 1H4), 3.88 (d, 3JOH-H8 = 3.3, 1HOH), 3.67 (td, 3JH5H4 = 3JH5H6 = 8.2, 3JH5H6’ = 5.5, 1H5), 3.45 (ddd, 3JH1H8 = 1.6, 3JH1H2’ = 3.9, 3JH1H2 = 9.6, 1H1), 2.30 (ddd, 3JH2H3 = 4.6, 3JH2H1 = 9.6, 2JH2H2’ = -14.9, 1H2), 2.02 (td, 3JH2’H1 = 3JH2’H3 = 3.9, 2JH2H2’ = -14.9, 1H2’), 1.61-1.46 (m, 8H9 to 12), 1.48 (s, 3H15), 1.36 (s, 3H16), 0.88 (t, 3JH13H12 = 6.8, 3H13); 13C NMR (100 MHz, 300K, CDCl3): 156.9 (C7), 109.9 (C14), 75.9 (C4), 73.0 (C3), 69.1 (C8), 67.7 (C6), 58.4 (C5), 55.4 (C1), 33.6 (C9), 31.9 (1C), 28.1 (C16), 26.3 (1C), 25.9 (C16), 25.4 (C2), 22.7 (1C), 14.2 (C13); HRMS (MALDI): calcd for C16H27NO5Na [M+Na]+: 336.1781, found 336.1769; MS (CI, NH3): m/z 314 (M+H)+; MS (EI): m/z (%) 313 (0.1, M+•), 298 (13), 242 (4), 213 (100), 154 (10), 94 (16). Meaningful signal for isomer 9-endo in the crude product: 4.35 (m, 1H), 3.25 (dd, 3J = 4.0, 3J = 10.0, 1H). (3aR,4R,8R,8aR,9aS)-4-(hydroxymethyl)-2,2-dimethyl-8-pentylhexahydro-6H- [1,3]dioxolo[4,5-d]oxazolo[3,4-a]pyridin-6-one, 10 (isomer 10-exo). By using the general procedure and starting from B2-d (49 mg, 0.2 mmol), 10-exo was isolated in 76% overall yield (yellow oil, 48 mg) after purification on silica gel (eluent hexanes:AcOEt = 60:40). The endo isomer was not detected by 1H NMR on the crude. [αD= + 20.6 (c 1.0 ; CHCl3); IR (neat): 3431, 2931, 2858, 1732, 1422, 1382, 1260, 1212, 1163, 1047, 768 cm-1; 1H NMR (400 MHz, 300 K, CDCl3): 4.41-4.36 (m, 1H3), 4.16 (dd, 3JH4H3 = 5.6, 3JH4H5 = 7.3, 1H4), 4.09-4.02 (m, 2H6,8), 3.86 (dd, 3JH6’H5 = 5.3, 2JH6’H6 = -12.2, 1H6’), 3.56 (ddd, 3JH1H2 = 3.3, 3JH1H8 = 7.5, 3JH1H2’ = 11.8, 1H1), 3.34 (ddd, 3JH5H6 = 3.0, 3JH5H6’ = 5.3, 3JH5H4 = 7.3, 1H5), 2.17 (ddd, 3JH2H3 = 2.0, 3JH2H1 = 3.3, 2JH2H2’ = -14.4, 1H2), 1.79 (ddd, 3JH2’H3 = 3.9, 3JH2’H1 = 11.8, 2JH2’H2 = -14.4, 1H2’), 1.79-1.58 (m, 2H9), 1.55-1.15 (m, 6H10 to 12), 1.48 (s, 3H15), 1.34 (s, 3H16), 0.88 (t, 3JH12H13 = 7.0, 3H13); 13C NMR (100 MHz, 300 K, CDCl3): 156.8 (C7), 108.9 (C14), 81.2 (C8), 72.3 (C4), 71.8 (C3), 60.0 (C6), 57.9 (C5), 55.8 (C1), 34.0 (C9), 32.4 (C2), 31.5 (1C), 28.0 (C15), 25.6 (C16), 24.5 (1C), 22.5 (1C), 14.0 (C13); HRMS (MALDI): calcd for C16H27NO5Na [M+Na]+: 336.1781, found: 336.1775; MS (EI): m/z (%) 313 (9, M+•), 298 (11), 282 (100), 180 (40), 152 (8). Diol 11. Diol 11 was obtained according to the general procedure, but without the step of diol protection as acetonide, using B2-f (45 mg, 0.2 mmol) as starting material. Accordingly, 11 was isolated in 62% overall yield (Rf = 0.36, colourless oil, 48 mg) after purification on silica gel (eluent hexanes:AcOEt = 20:80). Once more, the minor endo-diastereomer (exo/endo = 83/17 in the crude product) was not isolated after chromatography. (5S,7S,8R,8aR)-5-hexyl-7,8-dihydroxyhexahydro-3H-oxazolo[3,4-a]pyridin-3-one, 11-exo. [αD= +16.1 (c 0.5, CHCl3); IR (neat): 3600-3100, 2985, 2934, 1734, 1651, 1455, 1381, 1248, 1218, 1041 cm-1; 1H NMR (400 MHz, 300 K, CDCl3): 4.31 (dd, 2JH6H6’ = -8.8, 3JH6H5 = 7.2, 1H6), 4.19 (dd, 2JH6’H6 = -8.8, 3JH6’H5 = 3.2, 1H6’), 4.15 (m, 1H3), 3.72 (ddd, 3JH5H4 = 10.0, 3JH5H6 = 7.2, 3JH5H6’ = 3.2, 1H5), 3.53 (dd, 3JH4H5 = 10, 3JH4H3 = 2.6, 1H3), 3.4 (m, 1H1), 2.36 (m, 1H8), 1.95 (ddd, 2JH2H2’ = -14.4, 3JH2H1 = 3.6, 3JH2H3 = 2.8, 1H2), 1.66 (ddd, 2JH2’H2 = -14.4, 3JH2’H1 = 12.0, 3JH2’H3 = 2.4, 1H2’), 1.68-1.58 (m, 1H8’), 1.40-1.23 (m, 8H9 to12), 0.88 (t, 3JH13H12= 7.2, 3H13); 13C NMR (100 MHz, 300 K, CDCl3): 156.3 (C7), 70.6 (C4), 68.5 (C3), 65.1 (C6), 57.4 (C5), 50.6 (C1), 37.1 (C2), 30.7 (C8), 31.9 (1C), 29.3 (1C), 27.1 (1C), 22.7 (1C), 14.2 (C13); HRMS (MALDI): calcd for C13H24NO4 [M+H]+: 258.1705, found: 258.1709; MS (CI, NH3): m/z 258.20 (M+H)+, 275.2 (M+NH4)+; MS (EI): m/z (%) 257 (4, M+•), 172 (100), 154 (10)3333, 91 (48), 82 (38), 67 (23), 55 (79), 41 (73). Meaningful signals for isomer 11-endo in the crude product: 4.10 (dd, 2JH6H6’ = -9, 3JH6H5 = 5.1, 1H6), 3.95 (dd, 2JH6H6’ = -9, 3JH6H5 = 4.7, 1H6’), 3.65 (m), 3.90 (dd, 3JH5H4 ~ 7, 3JH3H4 ~ 1, H4), 3.35 (m). Acetonide 12. By using the general procedure and starting from B2-g (49 mg, 0.2 mmol) as starting material, 12 was isolated in 83% overall yield (Rf = 0.43, colourless oil, 53 mg) after purification on silica gel (eluent:hexanes/AcOEt = 50/50). Once more, the minor diastereomer (about 4%) was not isolated after liquid chromatography. (3aS,5R,9aR,9bR)-5-((S)-hydroxy(phenyl)methyl)-2,2-dimethylhexahydro-7H- [1,3]dioxolo[4,5-c]oxazolo[3,4-a]pyridin-7-one, 12-exo. [αD= +37.1 (c 0.5, CHCl3); IR (neat): 3432, 2926, 1734, 1653, 1422, 1058 cm-1; 1H NMR (300 MHz, 300 K, CDCl3): 7.43-7.25 (m, 5HAr), 5.55 (d, 3JH8H1 = 1.9, 1H8), 4.60 (q, 3JH3H4 ~ 3JH3H2 ~ 3JH3H2‘ ~ 5.8, 1H3), 4.59 (dd, 2JH6’H6 = -8.7, 3JH6H5 = 8.1, 1H6), 4.20 (dd, 2JH6’H6 = -8.7, 3JH6’H5 = 6.9, 1H6’), 4.09 (dd, 3JH4H5 = 9.1, 3JH4H3 = 5.8, 1H4), 3.87-4.00 (bs, 1HOH), 3.77 (ddd, 3JH1H2 = 6.9, 3JH1H2‘ = 4.8, 3JH8H1 = 1.9, 1H1), 3.74 (ddd, 3JH5H4 = 9.1, 3J H5H6 = 8.1, 3JH5H6‘ = 6.9, 1H5), 2.24 (ddd, 2JH2H2’ = -15.0, 3JH1H2 = 6.9, 3JH3H2 = 5.8, 1H2), 1.74 (ddd, 2JH2’H2 = -15.0, 3JH3H2‘ = 5.8, 3JH1H2‘ = 4.8, 1H2’), 1.43 (s, 3H14), 1.33 (s, 3H15); 13C NMR (75 MHz, 300 K, CDCl3): 157.1 (C7), 140.4 (C9), 128.5 (2CAr), 127.6 (C12), 126.1 (2CAr), 109.7 (C13), 76.5 (C4), 72.6 (C3), 71.2 (C8), 68.0 (C6), 57.4 (C5), 56.4 (C1), 27.8 (C14), 25.4 (C15), 25.1 (C2); HRMS (MALDI): calcd for C17H21NO5Na [M+Na]+: 342.1317, found: 342.1307; MS (CI, NH3): m/z 320 (M+H)+, 337 (M+NH4)+; MS (EI): m/z (%) 262 (7), 213 (3), 212 (3), 175 (6), 173 (13), 172 (12), 141 (21), 115 (12), 107 (42), 105 (47), 91 (38), 79 (94), 77 (100), 68 (32), 55 (28), 43 (28). Meaningful signals for minor isomer 12 endo in the crude product: 5.70 (bs, 1H8), 4.60 (m, 1H), 3.98 (m, 2H), 1.59 (s, 3H), 1.36 (s, 3H). Acetonide 13. By applying the general procedure and using B2-h (49 mg, 0.2 mmol) as starting material, 13 was obtained in 86% overall yield (Rf = 0.28, colourless oil, 55 mg, exo/endo = 94/6). The purification on silica gel (eluent hexanes/AcOEt: 50/50) afforded the desired exo compound but the minor endo one was not isolated after flash chromatography. (3aS,5R,9aR,9bR)-5-((R)-hydroxy(phenyl)methyl)-2,2-dimethylhexahydro-7H- [1,3]dioxolo[4,5-c]oxazolo[3,4-a]pyridin-7-one, 13-exo. [αD= +12.1 (c 0.5, CHCl3) ; 1H NMR (300 MHz, 300 K, CDCl3): 7.50-7.25 (m, 5HAr), 5.04 (d, 3JH8H1 = 7.7, 1H8), 4.89 - 4.76 (bs, 1HOH), 4.54 (dd, 2JH6H6’ = -8.8, 3JH6H5 = 8.0, 1H6), 4.31 (dt, 3JH3H4 = 5.5, 3JH3H2’ = 3JH3H2 = 4.7, 1H3), 4.20 (dd, 2JH6’H6 = -8.8, 3JH6’H5 = 5.3, 1H6’), 3.95 (dd, 3JH4H5 = 8.7, 3JH4H3 = 5.5, 1H4), 3.84 (ddd, 3JH1H2 = 9.1, 3JH1H8 = 7.7, 3JH1H2’ = 3.9, 1H1), 3.68 (ddd, 3JH5H4 = 8.7, 3JH5H6 = 8.0, 3JH5H6’ = 5.3, 1H5), 2.01 (ddd, 2JH2H2’ = -15.0, 3JH2H1 = 9.1, 3JH2H3 = 4.7, 1H2), 1.79 (ddd, 2JH2’H2 = -15.0, 3JH2’H3 = 4.7, 3JH2’H1 = 3.9, 1H2’), 1.46 (s, 3H14), 1.31 (s, 3H15) ; 13C NMR (75 MHz, 300 K, CDCl3): 157.6 (C7), 140.7 (C9), 128.8 (2C10/11), 128.3 (C12), 126.8 (2C11/10), 110.1 (C13), 75.5 (C4), 74.7 (C8), 72.4 (C3), 68.2 (C6), 58.6 (C5), 56.9 (C1), 34.6 (C2), 29.2 (C14), 28.0 (C15) ; MS (CI, NH3): m/z 320 (M+H)+; MS (EI) m/z (%) 319 (14), 304 (20), 289 (23), 288 (91), 261 (23), 244 (93), 213 (26), 212 (20), 186 (66), 170 (25), 168 (100), 158 (26), 144 (27), 132 (45), 130 (57), 91 (87), 77 (35), 43 (49). Meaningful signals for minor isomer 13-endo in the crude product: 5.06 (d, 3J = 7.8, 1H8), 1.43 (s, 3H), 1.35 (s, 3H). Acetonide 14. By applying the general procedure and using from B2-i (49 mg, 0.2 mmol) as starting material, 14 was obtained in 89% overall yield (Rf = 0.32, colourless oil, 53 mg, exo/endo = 96/4).The purification on silica gel (eluent hexanes/AcOEt: 50/50) afforded the desired exo compound but the minor endo one was not isolated after chromatography. (3aS,5R,9aR,9bR)-5-((S)-1-hydroxy-3-methylbutyl)-2,2-dimethylhexahydro-7H- [1,3]dioxolo[4,5-c]oxazolo[3,4-a]pyridin-7-one, 14-exo. [αD= +26.9 (c 1, CHCl3); IR (neat): 3387, 2982, 2924, 2854, 1748, 1721, 1441, 1218, 1043 cm-1; 1H NMR (400 MHz, 300 K, CDCl3): 4.56-4.49 (m, 2H3,6), 4.40 (bd, 3JH8H9 = 9.6, 3JH8H9’ = 3.6, 3JH8H1 = 1.6, 1H8), 4.17 (dd, 2JH6’H6 = - 9.2, 3JH6’H5 = 5.2, 1H6’), 4.01 (dd, 3JH4H5 = 8.8, 3JH4H3 = 5.6, 1H4), 3.98-3.94 (m, 1HOH), 3.67 (dt, 3JH5H4 = 8.8, 3JH5H6 = 3JH5H6’ = 5.2, 1H5), 3.42 (ddd, 3JH1H2 = 9.6, 3JH1H2’ = 3.8, 3JH1H8 = 1.6, 1H1), 2.31 (ddd, 2JH2H2’ = -15.2, 3JH2H1 = 9.6, 3JH2H3 = 4.8, 1H2), 2.02 (dt, 2JH2’H2 = -15.2, 3JH2’H3 = 3JH2’H1 13C NMR (100 MHz, 300 K, CD3OD): 68.9 (C4), 66.7 (C3), 61.2 (C6), 58.4 (C5), 54.2 (C1), 33.5 (1C), 31.1 (1C), 30.9 (1C), 30.3 (C2), 28.1 (1C), 24.4 (1C), 15.2 (C12); HRMS (MALDI): m/z calcd for C12H26NO3 [M - Cl-]+: 232.1907, found: 232.1908; MS (CI, NH3): m/z 232 (M - Cl-)+. (2R,3R,4S,6R)-3,4-dihydroxy-6-(1-hydroxycyclohexyl)-2-(hydroxymethyl)piperidinium chloride, 26. By applying the procedure A to 7 (53 mg, 0.17 mmol), 26 was obtained in 81% yield (white solid, 39 mg); [αD= +23.7 (c 1.22, MeOH); IR (neat): 3424, 3265, 2930, 2852, 1638, 1545, 1069, 1047 cm-1; 1H NMR (300 MHz, 300 K, CD3OD): 4.12-4.06 (m, 1H3), 3.98 (dd, 2JH6H6’ = -12.0, 3JH6H5 = 3.0, 1H6), 3.86 (dd, 2JH6’H6 = -12.0, 3JH6’H5 = 6.0, 1H6‘), 3.71 (dd, 3JH4H5 = 12.0, 3JH4H3 = 3.0, 1H4), 3.48-3.35 (m, 2H1,5), 2.07 (dt, 2JH2H2’ = -12.0, 3JH2H1 = 3JH2H3 = 3.0, 1H2eq), 1.78 (bt, 3JH2’H1 = 12, 2JH2’H2 = -12.0, 3JH2’H3 ~ 1.0, 1H2’ax), 1.70-1.49 and 1.43-1.1 (m, 10H8,9,10); 13C NMR (75 MHz, 300 K, CD3OD): 71.5 (C7), 68.0 (C4), 67.1 (C3), 60.9 (C1), 59.1 (C6), 58.6 (C5), 35.5 (C8), 33.0 (C8’), 30.4 (C2), 26.4 (C10), 22.4 (C9), 22.1 (C9’); HRMS (MALDI): calcd for C12H24NO4 [M - Cl-]+: 246.1705, found: 246.1706; MS (CI, NH3): m/z 246 (M - Cl-)+. (2R,3R,4S,6R)-3,4-dihydroxy-6-((S)-1-hydroxyhexyl)-2-(hydroxymethyl)piperidinium chloride, 27. By applying the procedure A to 9 (53 mg, 0.17 mmol), 27 was obtained in 85% yield (white solid, 41 mg); [αD= +28.9 (c 0.425, MeOH); IR (neat): 3327, 2948, 2919, 2856, 1543, 1330, 1070, 1040 cm-1; 1H NMR (400 MHz, 300 K, CD3OD): 4.14 (m, 1H3), 4.00 (dd, 2JH6H6’ = - 12.0,3JH6H5 = 3.2, 1H6), 3.99-3.95 (m, 1H7), 3.88 (dd, 2JH6’H6 = -12.0, 3JH6’H5 = 6.2, 1H6’), 3.72 (dd, 3JH4H5 = 10.6, 3JH4H3 = 2.6, 1H4), 3.55-3.45 (m, 2H5,1), 2.00 (dt, 2JH2H2’ = -14.8, 3JH2H1 = 3JH2H3 = 3.5, 1H2eq), 1.92(ddd, 2JH2’H2 = -14.8, 3JH2’H1 = 12.1, 3JH2’H1 = 1.6, 1H2’ax), 1.6-1.3 (m, 8H8 to 11), 0.95 (d, 3JH11H12 = 6.8, 3H12); 13C NMR (100 MHz, 300 K, CD3OD): 71.3 (C7), 68.9 (C4), 67.8 (C3), 60.4 (C6), 58.9 (C1), 57.1 (C5), 35.3 (1C), 33.6 (1C), 29.0 (C2), 27.3 (1C), 24.4 (1C), 15.2 (C12); HRMS (MALDI): m/z calcd for C12H26NO4 [M - Cl-]+: 248.1856, found: 248.1866; MS (CI, NH3): m/z 248 (M - Cl-)+. (2R,3R,4S,6R)-3,4-dihydroxy-6-((R)-1-hydroxyhexyl)-2-(hydroxymethyl)piperidinium chloride, 28. By applying the procedure A to 10 (53 mg, 0.17 mmol), 28 was obtained in 91% yield (white solid, 44 mg); [αD= +12.4 (c 0.425, MeOH); IR (neat): 3396, 2956, 2932, 2859, 1629, 1429, 1072 cm-1; 1H NMR (400 MHz, 300 K, CD3OD): 4.11 (m, 1H3), 3.99 (dd, 2JH6H6’ = - 11.9, 3JH6H5 = 3.2, 1H6), 3.93 (dd, 2JH6’H6 = -11.9, 3JH6’H5 = 4.7, 1H6’), 3.79 (dd, 3JH4H5 = 10.7, 3JH4H3 = 2.6, 1H4), 3.67-3.60 (m, 1H7), 3.41-3.35 (m, 2H5,1), 2.07 (dt, 2JH2H2’ = -14.7, 3JH2H1 ≈ 3JH2H3 = 3.2, 1H2eq), 1.72 (ddd, 2JH2’H2 = -14.7, 3JH2’H1 = 12.5, 3JH2’H3 = 1.4, 1H2’ax), 1.65-1.3 (m, 8H8 to 11), 0.95 (d, 3JH11H12 = 6.8, 3H12); 13C NMR (100 MHz, 300 K, CD3OD): 72.6 (C7), 68.6 (C4), 67.9 (C3), 59.8 (C6), 58.4 (1C1/5), 58.1 (1C1/5), 35.5 (1C), 33.7 (1C), 33.3 (C2), 26.3 (1C), 24.5 (1C), 15.2 (C12); HRMS (MALDI): m/z calcd for C12H26NO4 [M - Cl-]+: 248.1856, found: 248.1861; MS (CI, NH3): m/z 248 (M - Cl-)+. (2R,3R,4S,6R)-3,4-dihydroxy-6-[(S)-1-hydroxy-3-methylbutyl)-2-(hydroxymethyl] piperidinium chloride, 30. By applying the procedure A to 14 (51 mg, 0.17 mml), 30 was obtained in 69% yield (white solid, 32 mg); [αD= +21.4 (c 0.5 , MeOH) ; 1H NMR (300 MHz, 300 K, CD3OD): 4.15-4.03 (m, 2H3,7), 3.98 (dd, 2JH6H6’ = -11.8, 3JH6H5 = 3.3, 1H6), 3.86 (dd, 2JH6’H6 = - 11.8, 3JH6’H5 = 6.0, 1H6’), 3.70 (dd, 3JH4H5 = 10.8, 3JH4H3 = 2.7, 1H4), 3.50-3.39 (m, 2H5,1), 1.98 (dt, 2JH2H2’ = -15.0, 3JH2H1 = 3JH2H3 = 3.3, 1H2eq), 1.89 (bt, 3JH2’H1 = 15.0, 2JH2’H2 = -15.0, 3JH2’H1 ~ 2.0, 1H2’ax), 1.78 (m, 1H9), 1.46 (ddd, 2JH8H8’ = -13.8, 3JH8H7/9 = 9.3, 3JH8H9/7 = 5.4, 1H8), 1.19 (ddd, 2JH8’H8 = -13.8, 3JH8’H7/9 = 8.7, 3JH8’H9/7 = 4.2, 1H8’), 0.96 (d, 3JH10H9 = 6.9, 3H10), 0.95 (d, 3JH11H9 = 6.9, 3H11); 13C NMR (75 MHz, 300 K, CD3OD): 68.4 (C7), 68.0 (C4), 67.1 (C3), 59.6 (C6), 58.1 (C1), 56.6 (C5), 43.4 (C8), 28.3 (C2), 25.5 (C9), 23.6 (C10), 22.3 (C11). HRMS (CI, NH3): m/z calcd for C11H24NO4 [M - Cl-]+: 234.1705, found: 234.1706; MS (CI, NH3): m/z 234 (M - Cl-)+. Procedure B An aqueous solution of NaOH (8 M, 0.6 mL) was added to a solution of protected piperidine (0.10 mmol) in MeOH (1.8 mL) before 24h stirring at 100°C. After cooling to room temperature and neutralization with a 6M HCl solution, the solvent was removed under reduced pressure and the crude product was dissolved in MeOH and filtered off through a pad of celite®. The solid residue was washed with MeOH (2 × 15 mL) and the combined filtrates were concentrated under reduced pressure. The crude product was then dissolved in MeOH (10 mL) and HCl (30%, 1.0 mL) and stirred 30 min at room temperature. The solvent was removed under reduced pressure to obtain the polyhydroxy-piperidinium chloride. (2R,3S,4R,6S)-3,4-dihydroxy-2-(hydroxymethyl)-6-(5-hydroxynonan-5-yl)piperidinium chloride, 24. By applying procedure B to 5 (54 mg, 0.17 mmol), 24 was obtained in 79% yield (white solid, 44 mg); [αD= +4.8 (c 1.2, MeOH); IR (neat): 3404, 2956, 2929, 2870, 1639, 1453, 1041 cm-1; 1H NMR (400 MHz, 300 K, CD3OD): 4.20 (dd, 2JH6H6’ = -12.0, 3JH6H5 = 10.4, 1H6), 4.11 (bq, 3JH3H4 ≈ 3JH3H2 ≈ 3JH3H2’ = 3.2, 1H3), 4.03 (dd, 3JH4H5 = 5.6, 3JH4H3 = 3.2, 1H4), 3.97 (dd, 2JH6’H6 = -12.0, 3JH6’H5 = 4.4, 1H6’), 3.70 (ddd, 3JH5H6 = 10.4, 3JH5H4 = 5.6, 3JH5H6’ = 4.4, 1H5), 3.53 (dd, 3JH1H2’ = 11.6, 3JH1H2 = 2.8, 1H1), 1.99 (ddd, 2JH2H2’ = -14.8, 3JH2H3 = 3.2, 3JH2H1 = 2.8, 1H2eq), 1.86 (ddd, 2JH2’H2 = -14.8, 3JH2’H1 = 11.6, 3JH2’H3 = 3.2, 1H2’ax), 1.60-1.20 (m, 12H8 to 10), 0.96 (t, 3JH11H10 = 6.8, 6H11); 13C NMR (100 MHz, 300 K, CD3OD): 74.0 (C7), 67.6 (C4), 67.4 (C3), 59.6 (C5), 57.3 (C6), 53.5 (C1), 36.3 (1C), 35.9 (1C), 30.0 (C2), 26.2(1C), 26.1 (1C), 24.2(1C), 24.1 (1C), 14.3 (2C11). HRMS (MALDI): calcd for C15H32NO4 [M - Cl-]+: 290.2331, found: 290.2325; MS (CI, NH3): m/z 290 (M - Cl-)+. (2R,3S,4S,6R)-3,4-dihydroxy-6-[(S)-1-hydroxy-3-methylbutyl]-2-(hydroxymethyl) piperidinium chloride, 31. By applying procedure B to 21 (51 mg, 0.17 mmol), 31 was obtained in 73% yield (white solid, 33 mg); [αD= -0.3 (c 0.57, MeOH); IR (neat): 3372, 1633, 1075 cm- 1; 1H NMR (400 MHz, 300 K, CD3OD): 4.04 (m, 3JH7H8’ = 8.8, 3JH7H8 = 5.2, 3JH7H1 = 2.7, 1H7), 3.98 (bq, 3JH3H4 ≈ 3JH3H2 ≈ 3JH3H2’ = 2.4, 1H3), 3.92-3.77 (m, 3H6,6’,4), 3.57 (bt, 3JH5H6 ≈ 3JH5H6’ = 6.4, 1H5), 3.39 (bdt, 3JH1H2 = -12.8, 3JH1H7 ≈ 3JH1H2’ = 2.7, 1H1), 2.20 (ddd, 2JH2H2’ = -14.2, 3JH2H1 = 12.8, 3JH2H3 = 2.4, 1H2), 1.83-1.70 (m, 1H9), 1.70 (dt, 2JH2’H2 = -14.2, 3JH2’H1 = 2.7, 3JH2’H3 = 2.4, 1H2’), 1.46 (ddd, 2JH8H8’ = -13.2, 3JH8H9= 9.2, 3JH8H7 = 5.2, 1H8), 1.18 (ddd, 2JH8’H8 = -13.2, 3JH8’H7 = 8.8, 3JH8’H9 = 4.0, 1H8’), 0.96 (d, 3JH10H9 = 6.8, 3H10), 0.94 (d, 3JH11H9 = 6.9, 3H11); 13C NMR (100 MHz, 300 K, CD3OD): 69.0 (C7), 66.9 (1C3/4), 66.8 (1C3/4), 60.6 (C6), 58.0 (C5), 57.4 (C1), 43.0 (C8), 25.5 (C9), 24.5 (C2), 23.6 (C10), 22.2 (C11); HRMS (MALDI): calcd for C11H24NO4 [M - Cl-]+: 234.1705; found 234.1707; MS (CI, NH3): m/z 234 (M - Cl-)+. (2R,3R,4R,6R)-3,4-dihydroxy-6-[(S)-1-hydroxy-3-methylbutyl]-2-(hydroxymethyl) piperidinium chloride, 32. By using the procedure B and starting from 22 (51 mg, 0.17 mmol) as starting material, 32 was prepared in 63% yield (white solid, 29 mg); [αD= -10 (c 0.22, MeOH); IR (neat): 3418, 1644, 1069 cm-1; 1H NMR (400 MHz, 300 K, CD3OD): 4.32 (dd, 3JH3H2’ = 6.0, 3JH3H4 = 3.6, 1H3), 4.19 (bdd, 3JH7H8 = 9.0, 3JH7H8’ = 5.0, 4JH7H2’ ≈ 0.7, 1H7), 3.80 (dd, 3JH6H5 = 5.6, 2JH6H6’= -11.8, 1H6), 3.77 (dd, 3JH1H2’ = 3.4, 3JH1H2 ≈ 0.7, 1H1), 3.71 (dd, 2JH6’H6 = -11.8, 3JH6’H5 = 10.0, 1H6’), 3.65 (dd, 3JH4H3 = 3.6, 3JH4H5 ≈ 2.7, 1H4), 3.32-3.22 (m, 1H5), 2.44 (dd, 2JH2H2’ = -13.6, 3JH1H2 ≈ 0.7, 1H2), 2.09 (m, 1H2’), 1.75 (m, 3JH9H8’ = 8.0, 3JH9H10 = 6.8, 3JH9H11 = 6.4, 3JH9H8 = 6.0, 1H9), 1.36 (ddd, 2JH8H8’ = -13.7, 3JH8H7 = 9.0, 3JH8H9 = 6.0, 1H8), 1.25 (ddd, 2JH8’H8 = -13.7, 3JH8’H9 = 8.0, 3JH8’H7 = 5.0, 1H8’), 0.95 (d, 3JH10H9 = 6.8, 3H10), 0.94 (d, 3JH11H9 = 6.4, 3H11); 13C NMR (100 MHz, 300 K, CD3OD): 80.1 (C7), 78.0 (C3), 68.2 (C4), 60.8 (C6), 60.5 (C5), 58.8 (C1), 44.5 (C8), 27.0 (C2), 25.8 (C9), 23.5 (C10), 22.2 (C11); HRMS (MALDI): calcd for C11H22NO3 [(M - Cl-)+- (H2O)]: 216.1600, found: 216.1601; MS (CI, NH3): m/z 216 [(M - Cl-)+- (H2O)]; Structural information: the adopted conformation is a distorted 4C1 chair due to hydrogen bondings. Procedure C (2R,3S,4R,6S)-3,4-dihydroxy-6-(1-hydroxycyclohexyl)-2-(hydroxymethyl)piperidinium chloride, 23. The protected piperidine 1 (8 mg, 0.026 mmol) was dissolved in MeOH (3 mL) containing 0.25 mL of HCl 30%, and stirred for 2 h at room temperature before removal of the solvents under vacuum. The crude product was dissolved in MeOH (1 mL) without further purification and submitted to basic treatment (aqueous solution of NaOH 8M, 0.31 mL) upon stirring at 100°C for 24 h. After removal of the solvent, the resulting colourless oil was dissolved in AcOEt (5 mL) and water was added (5 mL). The basic aqueous phase was extracted with AcOEt (5 × 5mL) and the combined organic fractions were dried (MgSO4) and concentrated under reduced pressure. Without further purification, the crude product was dissolved in 14.3 mL of a 10/1 mixture of MeOH and HCl 30% and stirred 2 h at room temperature. The solvent was removed under reduced pressure to obtain the polyhydroxy-piperidinium chloride 23 (6 mg; 85% yield); [αD= -0.6 (c 0.44, MeOH); 1H NMR (400 MHz, 300 K, CD3OD): 4.19 (dd, 2JH6H6’ = -12.0, 3JH6H5 = 10.0, 1H6), 4.10 (m, 1H3), 4.02 (dd, 3JH4H5 = 5.6, 3JH4H3 = 3.2, 1H4), 3.95 (dd, 2JH6’H6 = -12.0, 3JH6’H5 = 4.4, 1H6’), 3.68 (bddd, 3JH5H6 = 10.0, 3JH5H4 = 5.6, 3JH5H6’ = 4.4, 1H5), 3.39 (dd, 3JH1H2’ = 10.7, 3JH1H2 = 2.4, 1H1), 2.05 (dt, 2JH2H2’ = -14.4, 3JH2H3 = 3JH2H1= 2.4, 1H2eq), 1.85 (ddd, 2JH2’H2 = - 14.4, 3JH2’H1 = 10.7, 3JH2’H3 = 2.4, 1H2’ax), 1.75-1.20 (m, 10H8,9,10); 13C NMR (100 MHz, 300 K, CD3OD): 71.5 (C7), 67.7 (C4), 67.4 (C3), 59.5 (C5), 57.4 (C6), 55.9 (C1), 35.3 (C8), 33.3 (C8’), 29.8 (C2), 26.4 (C10), 22.4 (C9), 22.3 (C9’); HRMS (MALDI): calcd for C12H24NO4 [M – Cl-]+: 246.1705, found: 246.1695; MS (CI, NH3): m/z 246 M – Cl-)+. Procedure D (2R,3R,4S,6S)-6-hexyl-3,4-dihydroxy-2-(hydroxymethyl)piperidine, 29.An aqueous solution of NaOH (8 M, 0.31 mL) was added to a solution of piperidine 11 (7.5 mg, 0.029 mmol) in MeOH (1 mL) and the mixture was stirred at 100°C for 24 h. After removal of the solvent under reduced pressure, the resulting colourless oil was dissolved in AcOEt (4 mL) and water (4 mL) was added. The basic aqueous phase was extracted with AcOEt (5 × 5 mL) and the combined organic fractions were dried (MgSO4) and concentrated under reduced pressure to afford the polyhydroxy-piperidine 29 as a colourless oil (5 mg, 76% yield); [αD= +28.8 (c 0.37 , CHCl3); IR (neat): 3439, 2960, 2926, 2855, 1619, 1426, 1070 cm-1; 1H NMR (300 MHz, 300 K, CD3OD): 3.96 (bq, 3JH3H4 ≈ 3JH3H2 ≈ 3JH3H2’ = 2.8, 1H3), 3.89 (dd, 2JH6H6’ = -10.9, 3JH6H5 = 3.3, 1H6), 3.54 (dd, 2JH6’H6 = -10.9, 3JH6’H5 = 7.5, 1H6’), 3.33-3.28 (m, 1H4, masked by HCD2OD), 2.98-2.90 (m, superimposed with H5, 1H1), 2.97 (ddd, 3JH5H4 = 10.4, 3JH5H6’ = 7.5, 3JH5H6 = 3.3, 1H5), 1.91 (ddd, 2JH2H2’ = -13.9, 3JH2H1 = 3.6, 3JH2H3 = 2.8, 1H2), 1.50-1.20 (m, 11H2’,7 to 11), 0.91 (bt,3J2H11 = 6.5, 3H12); 13C NMR (100 MHz, 300 K, CD3OD): 71.6 (C4), 69.3 (C3), 63.9 (C6), 58.0 (C5), 50.6 (C1), 38.9 (C2), 36.8, 32.9, 30.5, 27.1, 23.6 (5Caliph.), 14.4 (C12); HRMS (MALDI): m/z calcd for C12H26NO3 [M+H+]: 232.1913, found: 232.1910; MS (CI, NH3): m/z 232(M+H+). 5.3.7.2 Reduction of the oxazolidinone function (2R,3R,4S,6R)-3,4-dihydroxy-6-[(S)-hydroxy(phenyl)methyl]-2-(hydroxymethyl)-1- methylpiperidinium chloride, 35. To a solution of protected piperidine 12 (17 mg, 0.055 mmol) in THF (5 mL) was added LiAlH4 (4 equiv., 92 L of a 2.4M solution in THF) at room temperature. After stirring for 4 hours at reflux, the mixture was cooled and H2O (500 L) was added dropwise. The crude product was filtrated through a pad of Celite®, washed with AcOEt and filtrated on alumina (eluent: methylene chloride/methanol: 9/1). The product was dissolved in a solution of MeOH/HCl(30%) (5:1, 5 mL) and stirred 3h at room temperature. The solvents were removed under reduced pressure to obtain compound 35 in 83% overall yield along the two steps (14 mg); [αD= +34 (c 0.4, CD3OD); IR (neat): 3440, 3357, 3318, 3254, 2925, 2904, 1622, 1063, 703 cm- 1; 1H NMR (400 MHz, 300 K, CD3OD): 7.45-7.35 and 7.32-7.26 (2m, 5H10,11,12), 5.47 (d, 3JH8H1 = 2.8, 1H8), 4.17-4.05 (m, 2H6/6’), 3.98-3.92 (m, 1H3), 3.79 (bdt, 3JH1H2 = 12.0, 3JH1H2’ ≈ 3JH1H8 = 2.8, 1H1), 3.73 (dd, 3JH4H5 = 11.0, 3JH4H3 = 2.8, 1H4), 3.38 (bd, 3JH5H4 = 11.0, 1H5), 3.25 (s, 3H7), 1.93 (ddd, 2JH2H2’= -14.6, 3JH2H1 = 12.0, 3JH2H3 = 1.6, 1H2), 1.45 (bdt, 2JH2’H2 = -14.6, 3JH2’H1 ≈ 3JH2’H3 = 2.8, 1H2’); 13C NMR (100 MHz, 300 K, CD3OD): 141.3 (C9), 129.6 (2C10/11), 128.9 (C12), 126.8 (2C10/11), 69.1 (C8), 67.3 (C4), 67.2 (C5), 66.4 (C3), 65.3 (C1), 56.7 (C6), 37.3 (C7), 28.6 (C2); HRMS (MALDI): calcd for C14H22NO4 (M – Cl-)+: 268.1549, found: 268.1549; MS (CI, NH3): m/z 268 (M – Cl-)+. Compounds 33 and 34 have been obtained previously according to the same procedure and have been fully characterized.26 NMR spectra and NOESY analysis of new compounds are given in supplementary information. CCDC 710420 and 2040539 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033. 6. Acknowledgments We are grateful to the « Institut de Chimie des Substances Naturelles » (ICSN, UPR CNRS 2301) for a PhD grant (AL), the Centre National de la Recherche Scientifique (CNRS), the Ministère de l’Enseignement Supérieur, de la Recherche et de l’Innovation (MESRI), to Loic Toupet (Institut de Physique, UMR CNRS 6521, Univ Rennes 1) for X-ray analysis of 18, to Julie Hémez and Laurence Arzel (CEISAM, UMR CNRS 6230) for HRMS analyses. 7. References 1. 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