Total syntheses of D-allo-1-deoxynojirimycin and L-talo-1-deoxynojirimycin via reductive cyclization

Abstract

Synthesis of a polyhydroxypiperidine framework for L-talo-1-deoxynojirimycin and D-allo-1-deoxynojirimycin was achieved from L-tartaric acid by employing flash dihydroxylation and reductive lactamisation as the key steps.

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Azasugars or iminosugars have significant biological activities and they act as glycosidase inhibitors and are extensively used for the treatment of AIDS, cancer, diabetes and viral infections.¹ The configuration of hydroxyl groups on the piperidine ring has been shown to have different and profound biological activities. Recently, derivatives of 1-deoxynojirimycin (1-DNJ) 1 such as miglitol 2 (ref. 2) and N-butyl-1-deoxynojirimycin 3 (ref. 2) (Fig. 1) have also attracted great deal of attention due to their promising biological activities. Miglitol 2 is approved for non-insulin dependent diabetes treatment and N-butyl-1-deoxynojirimycin 3 for Gauchers disease.^2d However, very less attention has been paid towards the syntheses of other isomers of 1-DNJ 1 such as L-talo-1-deoxynojirimycin (L-talo-1-DNJ)³ and D-allo-1-deoxynojirimycin (D-allo-1-DNJ).⁴

Fig. 1 1-Deoxynojirimycin and its analogs.

Hashimoto et al. had first reported the synthesis of L-1-deoxytalonojirimycin (L-talo-1-DNJ) 4 (Fig. 1) which was shown to be a potent inhibitor of α-glycosidase and α-L-fucosidase.^3a There are very few reports on synthesis of L-talo-1-DNJ 4.⁵ Recently, it has been shown that L isomers of azasugars also possess remarkable activity as glycosidase inhibitor.⁶ Previously, we reported the synthesis of piperidine alkaloids, which are important structural constituents of many alkaloids having potential biological activity by chiral pool⁷ and non chiral pool strategies.⁸

In continuation of our interest in the synthesis of piperidine alkaloids, we undertook the syntheses of D-allo-1-deoxynojirimycin 5 and L-talo-1-DNJ 4 by a chiral pool strategy using L-tartaric acid as the renewable starting material. For the L-talo-1-DNJ 4 and D-allo-1-DNJ 5 syntheses, the main synthetic challenge is the construction of piperidine moiety and installation of hydroxy groups in a stereoselective manner.

1. Results and discussion

According to our retrosynthetic plan (Scheme 1), 4 and 5 can be easily derived from lactams 6 and 7 respectively. Lactams 6 and 7 can be easily generated from hydroxy lactone 8 via a reductive cyclization. Hydroxy lactone 8 in turn can be readily accessed from L-tartaric acid 9.

Scheme 1 Retrosynthetic analysis of D-allo-1-DNJ and L-talo-1-DNJ.

The synthesis began from commercially available starting material viz. L-tartaric acid (Scheme 2). The symmetric diol 10 was obtained by following a known literature procedure.⁹ The C₂ symmetric diol 10 was selectively protected by using NaH, BnBr in presence of TBAB as the catalyst to furnish mono benzylated ether 11 in 75% yield. Primary hydroxy of compound.

Scheme 2 Reagents and conditions: (a) ref. 8; (b) BnBr, TBAB, NaH, THF, 0 °C to r.t., 3 h, 75%; (c) oxalyl chloride, DMSO, DCM, −78 °C, TEA, 30 min; (d) Ph₃PCHCOOEt, MeOH, −50 °C to r.t., overnight, 70%; (e) conc. HCl (cat.), MeOH, 0 °C to r.t., overnight, 70%; (f) RuCl₃, NaIO₄, EtOAc–H₂O–MeCN (1 : 1 : 1), 0 °C, 3 min, 53%; (g) DMP, CSA, DCM, r.t., overnight, 90%; (h) MsCl, TEA, DMAP (cat.), DCM, 0 °C, 1 h, 91%; (i) NaN₃, DMF, 90 °C, 18 h, 87%; (j) Pd(OH)₂, H₂, MeOH, r.t., 1 h, 90%; (k) BH₃·DMS, THF, 0 °C to r.t., overnight; (l) (Boc)₂O, TEA, DMAP (cat), THF, r.t., overnight, 58% (over two steps); (m) Pd(OH)₂, H₂, MeOH, r.t., 6 h, 90%; (n) conc. HCl, MeOH, r.t., 3 h, (quantitative).

11 was oxidized under Swern reaction conditions to provide corresponding aldehyde which without purification was subjected for two-carbon homologation in MeOH at −50 °C to room temperature to afford α,β-unsaturated ester 12 in 70% yield (E/Z = 1/9). The unsaturated ester 12 was treated with conc. HCl (cat.) in MeOH to furnish butenolide 13. Butenolide 13 was subjected to flash dihydroxylation conditions¹⁰ by using RuCl₃, NaIO₄ in EtOAc–H₂O–MeCN (1 : 1 : 1) at 0 °C to give triol 14 in 53% yield. Vicinal dihydroxyl groups in compound 14 were protected using DMP, CSA (cat.) to afford acetonide 8 in 90% yield. Spectroscopic data of 8 was in good agreement with reported one.^11a,b We did not observe the formation of other diastereomers which we confirmed from spectral analysis (¹H and ¹³C NMR spectra). Hydroxy lactone 8 was converted into corresponding mesylate 15 in 91% yields by using triethyl amine and mesyl chloride. The resultant mesylate 15 was treated with NaN₃ in DMF at 80 °C to afford azidolactone 16 in 88% yield. Reductive cyclisation of azidolactone 16 using Pd(OH)₂ under H₂ atmosphere at 10 psi in methanol furnished the desired six membered lactam 7 in 90% yield. Lactam 7 was reduced to corresponding amine using BH₃·DMS in THF to afford amine 17. To carry out other functional group transformations, amine was protected as its urethane derivative 18. Thus, without purification amine 17 was treated with (Boc)₂O, triethyl amine and DMAP (cat.) in THF to afford carbamate 18 in 58% yield (over two steps).

Hydrogenolysis of 18 was carried out using Pd(OH)₂ under hydrogen atmosphere to provide diol 19. The global deprotection of 19 with concentrated HCl in methanol afforded the hydrochloride salt of D-allo-1-DNJ 5. Spectroscopic data of 5 was in good agreement with the reported one.¹²

After successful synthesis of D-allo-1-DNJ 5, our attention was shifted towards the synthesis of other isomer of 1-DNJ. Taking advantage of structural features of hydroxy lactone 8, L-talo-1-DNJ 4 (Scheme 3) was synthesized by employing double inversion strategy. The hydroxy lactone 8 was subjected to iodination by using PPh₃, imidazole and iodine to afford iodolactone 20 in 75% yield (HPLC purity >87%). Iodolactone 20 was treated with NaN₃ in DMF at 80 °C to give pure azidolactone 21 in 60% yield. Following the same reaction sequence strategy, as described for D-allo-1-DNJ 5 synthesis, reductive cyclisation of 21 was carried out using Pd(OH)₂ under hydrogen atmosphere to furnish the desired six membered lactam 6 in 88% yield. Lactam 6 was reduced to corresponding amine 22 using BH₃·DMS which without purification was treated with (Boc)₂O to afford its carbamate 23 in 50% yield (over two steps). O-Debenzylation followed by acetonide and urethane deprotection of 23 afforded the L-talo-1-DNJ 4. Spectroscopic data of 4 was in good agreement with the reported one.^4c

Scheme 3 Reagents and conditions: (a) PPh₃, imidazole, iodine, toluene, 110 °C, 75%; (b) NaN₃, DMF, 80 °C, 60%; (c) Pd(OH)₂, H₂, MeOH, r.t., 88%; (d) BH₃·DMS, THF 0 °C to r.t., overnight; (e) (Boc)₂O, TEA, DMAP (cat.), THF, r.t., overnight, 50% (over two steps); (f) (i) Pd(OH)₂, H₂, MeOH, r.t., 6 h; (ii) conc. HCl, MeOH, r.t., 3 h, 72% (over two steps).

2. Conclusions and summary

In conclusion, we have accomplished the total syntheses of D-allo-1-DNJ 5 and L-talo-1-DNJ 4 by employing flash dihydroxylation and reductive lactamisation as key steps from readily available L-tartaric acid.

3. Experimental section

3.1. General

Melting points are recorded using Buchi B-540 or M-560 melting point apparatus in capillary tubes and are uncorrected and the temperatures are in centigrade scale. IR spectra were recorded on a Perkin-Elmer Infrared Spectrophotometer Model 68B or on a Perkin-Elmer 1615 FT Infrared spectrophotometer. ¹H (200 and 400 MHz) and ¹³C (50 and 100 MHz) NMR spectra were recorded on Bruker and Bruker Advance 400 spectrometers. The chemical shifts (δ ppm) and coupling constants (Hz) are reported in the standard fashion with reference to chloroform, δ 7.27 (for ¹H) or the central line (77.0 ppm) of CDCl₃ (for ¹³C). In the ¹³C NMR spectra, the nature of the carbons (C, CH, CH₂ or CH₃) was determined by recording the DEPT-135 spectra. The reaction progress was monitored by the TLC analysis using thin layer plates precoated with silica gel 60 F254 (Merck) and visualized by fluorescence quenching or iodine or by charring after treatment with p-anisaldehyde. Merck's flash silica gel (300–400 mesh) was used for column chromatography. All small scale dry reactions were carried out using standard syringe-septum technique. Low temperature reactions were carried out using a bath made of sodium chloride and ice. Dry THF was obtained by distillation over sodium/benzophenone ketyl. Dry DCM was prepared by distillation over phosphorous pentoxide or calcium hydride. All other reagents and solvents were used as received from the manufacturer, unless otherwise specified. All air and water sensitive reactions were performed in flasks flame dried under positive flow of argon and conducted under an argon atmosphere.

3.1.1. (4S,5S)-5-((Benzyloxy)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl-methanol (11). To a well stirred solution of symmetric diol 10 (3 g, 18.49 mmol) in anhydrous THF (50 mL), was added NaH (60% in oil suspension) (0.88 g, 22.19 mmol) portion wise at 0 °C over 30 min under nitrogen atmosphere. The reaction mixture was allowed to stir for 30 min at 0 °C and benzyl bromide (2.4 mL, 20.33 mmol) was added dropwise over 10 min followed by addition of TBAB (cat.). The reaction mixture was allowed to stir at 0 °C and allowed to warm to room temperature and stirred overnight. After completion of reaction, the saturated aq. solution of ammonium chloride was added to the reaction mixture and extracted with ethyl acetate (2 × 60 mL). The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to provide crude monobenzylated compound. The residue was purified by flash silica gel column chromatography using light petroleum ether–EtOAc (7 : 3) as an eluent to afford 11 (3.4 g, 75%) as a colorless syrup. R_f (30% EtOAc–petroleum ether) 0.4; [α]²⁵_D = +7.7 (c 2.58, CHCl₃); ¹H NMR (200 MHz, CDCl₃ + CCl₄): δ 1.41 (s, 6H), 2.17–2.28 (m, 1H), 3.50–3.58 (m, 1H), 3.62–3.82 (m, 3H), 3.88–3.97 (m, 1H), 4.02–4.09 (m, 1H), 4.58 (s, 2H), 7.25–7.38 (m, 5H); ¹³C NMR (50 MHz, CDCl₃ + CCl₄): δ 26.9, 62.3, 70.3, 73.6, 76.5, 79.6, 109.2, 127.7, 127.8, 128.4, 137.5.

3.1.2. (Z)-Ethyl 3-((4S,5S)-5-((benzyloxy)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)acrylate (12). To a solution of (COCl)₂ (2.1 mL, 23.78 mmol) in CH₂Cl₂ (30 mL) was added DMSO (3.37 mL, 47.56 mmol) at −78 °C, and the mixture was stirred for 10 min. A solution of alcohol 11 (3 g, 11.89 mmol) in CH₂Cl₂ (20 mL) was added to the resulting mixture and stirring was continued for another 15 min at −78 °C Then, TEA (6.6 mL, 47.56 mmol) was added at −78 °C and the reaction mixture was warmed to 0 °C and stirred for 20 min. Water (20 mL) was added and the reaction mixture was extracted with CH₂Cl₂ (2 × 60 mL), dried over anhydrous Na₂SO₄, filtered and the solvent evaporated under reduced pressure to provide the crude aldehyde, which was used as such in the next step. To a solution of above aldehyde in methanol, PPh₃CHCOOEt (6.2 g, 17.83 mmol) was added at −50 °C. Then, the reaction mixture was stirred overnight at room temperature. After completion of reaction, the reaction mass was adsorbed on silica gel and eluted with ethyl acetate–pet. ether (1 : 9) to afford unsaturated ester 12 as a colorless liquid (2.66 g, 70%). R_f (10% EtOAc–petroleum ether) 0.5; E/Z: 1 : 9; IR (CHCl₃, cm⁻¹): 1719, 1658, 1380, 1371, 1195, 1079; for major cis isomer ¹H NMR (200 MHz, CDCl₃ + CCl₄): δ 1.25 (t, J = 7 Hz, 3H), 1.45 (s, 6H), 3.61–3.71 (m, 2H), 3.90–3.99 (m, 1H), 4.12 (q, J = 7 Hz, 2H), 4.53 (d, J = 12 Hz, 1H), 4.63 (d, J = 12 Hz, 1H), 5.37 (t, J = 8.2 Hz, 1H), 5.91 (d, J = 12 Hz, 1H), 6.12–6.23 (m, 1H), 7.23–7.39 (m, 5H); For major cis isomer ¹³C NMR (50 MHz, CDCl₃ + CCl₄): δ 14.2, 27.1, 60.3, 70.5, 73.4, 73.7, 80.4, 110.2, 122.7, 127.4, 127.6, 128.2, 138.1, 145.7, 165.2; ESIMS (m/z): 346.37 (M + Na)⁺.

3.1.3. (S)-5-((S)-2-(Benzyloxy)-1-hydroxyethyl)furan-2(5H)-one (13). To a solution of unsaturated ester 12 (2 g, 6.24 mmol) in (20 mL) methanol was added conc. HCl (0.1 mL) at 0 °C. The reaction mixture was stirred at room temperature for 6 h. The solvent was removed under reduced pressure and the residue was neutralized with sodium carbonate and extracted with DCM (3 × 60 mL). The combined organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to provide crude residue. Te residue was purified by flash silica gel chromatography using pet ether–ethyl acetate (6 : 4) as eluent to afford butenolide 13 as a white solid compound (1.02 g, 70%). R_f (60% EtOAc–pet ether) 0.4; [α]²⁵_D: −72.72 (c 0.55, CHCl₃); lit.¹⁰ [α]²⁵_D: −73 (c 1, CHCl₃); M.P: 78–80 °C; IR (CHCl₃, cm⁻¹): 3448, 1749, 1637, 1164, 1094; ¹H NMR (200 MHz, CDCl₃ + CCl₄): δ 2.41 (bs, 1H), 3.54–3.69 (m, 2H), 3.98–4.05 (m, 1H), 4.53 (d, J = 12 Hz, 1H), 4.60 (d, J = 12 Hz, 1H), 5.17 (dt, J = 4, 2 Hz, 1H), 6.15 (dd, J = 5.6, 2 Hz, 1H), 7.30–7.41 (m, 5H), 7.48 (dd, J = 5.6, 2 Hz, 1H); ¹³C NMR (50 MHz, CDCl₃+ CCl₄): δ 70.0, 70.2, 73.6, 83.7, 122.2, 127.9, 128.0, 128.5, 137.3, 153.8, 172.9; ESIMS (m/z): 256.95 (M + Na)⁺.

3.1.4. (3R,4S,5R)-5-((S)-2-(Benzyloxy)-1-hydroxyethyl)-3,4-dihydroxydihydrofuran-2(3H)-one (14). To a vigorously stirred solution of butenolide 13 (0.700 g, 2.98 mmol) in CH₃CN–EtOAc (3 mL each) at 0 °C, was added a solution of RuCl₃·3H₂O (43 mg, 0.21 mmol) and NaIO₄ (0.95 g, 4.47 mmol) in distilled water (3 mL). The reaction mixture was stirred for 3 min after which saturated solution of Na₂S₂O₃ was added. Reaction mixture was extracted with ethyl acetate (3 × 50 mL) and dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to give crude triol. Residue was purified by flash silica gel chromatography using pet ether–ethyl acetate (1 : 9) as eluent to afford triol 14 as thick yellow syrup (0.42 g, 53%). R_f (100% EtOAc) 0.2; [α]²⁵_D: +41 (c 1, MeOH); IR (CHCl₃, cm⁻¹): 3393, 1765, 1142, 1094; ¹H NMR (200 MHz, CD₃OD): δ 3.47 (dd, J = 6.6, 2.6 Hz, 2H), 3.92 (dt, J = 6.6, 1.6 Hz, 1H), 4.27 (d, J = 5.6 Hz, 1H), 4.42 (d, J = 1.6 Hz, 1H), 4.50 (s, 2H), 4.58 (d, J = 5.6 Hz, 1H), 7.24–7.30 (m, 5H); ¹³C NMR (125 MHz, CD₃OD): δ 70.3, 70.7, 71.7, 72.0, 74.6, 86.9, 128.9, 129.0, 129.5, 139.6, 178.9; ESIMS (m/z): 291 (M + Na)⁺.

3.1.5. (3aR,6R,6aR)-6-((S)-2-(Benzyloxy)-1-hydroxyethyl)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-4(3aH)-one (8). To a well stirred solution of triol 14 (0.300 g, 1.11 mmol) in DCM (10 mL) was added CSA (cat.) and 2,2-dimethoxypropane (1.36 mL, 11.1 mmol) and stirred under an atmosphere of nitrogen for 18 h at room temperature. The reaction mixture was poured into cold saturated sodium carbonate solution and extracted with DCM (2 × 30 mL). Organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to furnish a residue which was purified by column chromatography over silica gel, eluting with 30% ethyl acetate in pet. ether as an eluent to afford 8 (0.31 g, 90%) as white crystals. R_f (40% EtOAc–petroleum ether) 0.4; M.P: 82 °C; [α]²⁵_D: −12.7 (c 1, CHCl₃); IR (CHCl₃, cm⁻¹): 3445, 1783, 1646, 1216, 1153, 1083, 729, 695; ¹H NMR (500 MHz, CDCl₃ + CCl₄): δ 1.38 (s, 3H), 1.46 (s, 3H), 2.51 (bs, 1H), 3.58 (t, J = 9.5 Hz, 1H), 3.61 (dd, J = 9.5, 4.5 Hz, 1H), 3.99–4.06 (m, 1H), 4.53 (s, 1H), 4.55–4.59 (m, 2H), 4.78 (d, J = 5.5 Hz, 1H), 4.83 (d, J = 5.5 Hz, 1H), 7.31–7.38 (m, 5H); ¹³C NMR (125 MHz, CDCl₃): δ 25.6, 26.7, 70.1, 70.3, 73.7, 75.1, 78.8, 81.2, 113.2, 127.9, 128.1, 128.6, 137.2, 174.5; ESIMS (m/z): 331.05 (M + Na)⁺.

3.1.6. (S)-2-(Benzyloxy)-1-((3aR,4S,6aR)-2,2-dimethyl-6-oxotetrahydrofuro[3,4-d][1,3]dioxol-4-yl)ethyl methanesulfonate (15). To a stirred solution of hydroxy lactone 8 (0.3 g, 0.97 mmol) in dry DCM (5 mL) was added Et₃N (0.27 mL, 1.94 mmol) at 0 °C, followed by dropwise addition of mesyl chloride (0.103 mL, 1.26 mmol) and finally DMAP (cat.) was added. The reaction mixture was stirred at 0 °C for 1 h under nitrogen atmosphere. After completion of reaction, the reaction mixture was diluted with dichloromethane (40 mL) and washed with saturated solution of sodium bicarbonate (20 mL) and water (20 mL). The organic layer was separated, dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography in 40% ethyl acetate in pet. ether to afford mesylate compound 15 as a colorless syrup (0.34 g, 91%). R_f (40% EtOAc–petroleum ether) 0.5; [α]²⁵_D: −31.81 (c 4.4, CHCl₃); IR (CHCl₃ cm⁻¹): 1797, 1366, 1176, 1092, 737, 699; ¹H NMR (200 MHz, CDCl₃ + CCl₄): δ 1.38 (s, 3H), 1.45 (s, 3H), 3.07 (s, 3H), 3.71 (dd, J = 10, 4 Hz, 1H), 3.79–3.88 (m, 1H), 4.56 (s, 2H), 4.71 (d, J = 1.2 Hz, 1H), 4.87 (dd, J = 9.5, 5.7 Hz, 2H), 5.06 (ddd, J = 8, 4, 2 Hz, 1H), 7.28–7.41 (m, 5H); ¹³CNMR (100 MHz, CDCl₃): δ 25.7, 26.8, 39.1, 68.7, 73.8, 74.5, 78.1, 79.4, 80.4, 113.6, 128.0, 128.4, 128.7, 136.6, 172.9.

3.1.7. (3aR,6R,6aR)-6-((R)-1-Azido-2-(benzyloxy)ethyl)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-4(3aH)-one (16). To a solution of O-mesyl derivative 15 (200 mg, 0.51 mmol) in anhydrous DMF (5 mL) was added sodium azide (67 mg, 1.02 mmol) under nitrogen atmosphere. The reaction mixture was stirred at 80 °C for 16 h. After completion of the reaction (monitored by TLC), it was cooled to room temperature, diluted with water and extracted with ethyl acetate (3 × 20 mL). The combined organic extracts were washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography using ethyl acetate–light petroleum ether (1 : 9) as an eluent to afford 16 (150 mg, 87%) as a colorless syrup. R_f (15% EtOAc–pet. ether) 0.6; [α]²⁵_D: −60 (c 1, CHCl₃), lit.¹⁰ [α]²⁵_D: −61 (c 1, CHCl₃); IR (CHCl₃, cm⁻¹): 2110, 1793, 1215; ¹H NMR (400 MHz, CDCl₃ + CCl₄): δ 1.36 (s, 3H), 1.46 (s, 3H), 3.68–3.74 (m, 2H), 3.89–3.98 (m, 1H), 4.56–4.63 (m, 3H), 4.65 (d, J = 6Hz, 1H), 4.74 (d, J = 6Hz, 1H), 7.32–7.39 (m, 5H); ¹³C NMR (100 MHz, CDCl₃ + CCl₄): δ 25.5, 26.7, 62.2, 68.6, 73.8, 75.0, 76.5, 81.5, 113.6, 127.7, 128.2, 128.7, 136.8, 173.0; ESIMS (m/z): 356.08 (M + Na)⁺; HRMS calculated for [C₁₆H₁₉N₃O₅ + Na]⁺: 356.1217; found: 356.1224.

3.1.8. (3aR,6R,7R,7aR)-6-((Benzyloxy)methyl)-7-hydroxy-2,2-dimethyltetrahydro-[1,3]dioxolo[4,5-c]pyridin-4(3aH)-one (7). A mixture azido lactone 16 (100 mg, 0.300 mmol) and 10% Pd/C in methanol (3 mL) was stirred under the hydrogen atmosphere at 10 psi at room temperature (25 °C) for 1 h. The reaction mixture was filtered through celite and the celite layer was washed thoroughly with methanol (20 mL × 3) and concentrated under reduced pressure. The residue thus obtained was purified by flash silica gel chromatography using pet. ether–ethyl acetate (2 : 8) as an eluent to furnish 7 as a white semisolid (82 mg, 90%). R_f (100% EtOAc) 0.5; [α]²⁵_D: +19 (c 1.2, CHCl₃); IR (CHCl₃, cm⁻¹): 3395, 1676, 1196; ¹H NMR (200 MHz, CDCl₃ + CCl₄): δ 1.40 (s, 3H), 1.50 (s, 3H), 2.50 (bs, 1H), 3.48–3.56 (m, 1H), 3.70–3.82 (bs, 3H), 4.46 (d, J = 6.5 Hz, 1H), 4.58–4.59 (m, 3H), 6.21 (bs, 1H), 7.28–7.38 (m, 5H); ¹³C NMR (125 MHz, CDCl₃ + CCl₄): δ 24.8, 26.5, 52.3, 67.7, 69.9, 73.7, 73.9, 74.9, 110.9, 127.8, 128.1, 128.6, 137.2, 168.2; ESIMS (m/z): 330.2 (M + Na)⁺; HRMS calculated for [C₁₆H₂₁NO₅ + Na]⁺: 330.1312; found: 330.1322.

3.1.9. (3aS,6R,7R,7aR)-tert-Butyl 6-((benzyloxy) methyl)-7-hydroxy-2,2-dimethyltetrahydro-[1,3]dioxolo[4,5-c]pyridine-5(6H)-carboxylate (18). To a solution of lactam 7 (0.1 g, 0.32 mmol) in anhydrous THF (5 mL) was added BH₃·DMS (0.15 mL, 1.6 mmol) dropwise at 0 °C under the nitrogen atmosphere. The reaction mixture was allowed to stir at room temperature for 18 h. The reaction mixture was cooled to 0 °C and quenched by addition of ethanol (5 mL). Solvent was removed under reduced pressure and the crude semisolid residue was treated with additional ethanol (5 mL) and refluxed for 4 h. Solvent was removed under reduced pressure to furnish crude amine 17. To the solution of crude amine 17 in THF (5 mL) was added TEA (0.07 mL) followed by addition of (Boc)₂O (0.089 mL) and DMAP (cat.) and was stirred at room temperature for 24 h. The reaction mixture was extracted with ethyl acetate (3 × 20 mL), washed with water, brine and dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using petroleum ether–ethyl acetate (7 : 3) as an eluent to afford colorless oily carbamate 18 (74 mg, 58% (over two steps). R_f (40% EtOAc–petroleum ether) 0.4; [α]²⁵_D: −71.6 (c 0.53, CHCl₃); IR (CHCl₃, cm⁻¹): 3445, 1698, 1682, 1455, 1416, 1161; ¹H NMR (200 MHz, CDCl₃ + CCl₄): δ 1.34 (s, 3H), 1.42 (s, 9H), 1.46 (s, 3H), 2.82 (m, 1H), 3.56–3.74 (m, 1H), 3.78–4.18 (m, 4H), 4.29 (m, 1H), 4.44–4.63 (m, 3H), 7.21–7.37 (m, 5H); ¹³C NMR (50 MHz, CDCl₃ + CCl₄): δ 24.4, 26.2, 28.4, 41.9, 43.3, 53.3, 53.8, 67.3, 67.8, 69.7, 70.2, 73.4, 73.7, 74.2, 79.7, 109.4, 127.4, 127.7, 128.4, 138.2, 154.9; ESIMS (m/z): 416.51 (M + Na)⁺; HRMS calculated for [C₂₁H₃₁NO₆ + Na]⁺ 416.2044; found: 416.2060.

3.1.10. (3aS,6R,7R,7aR)-tert-Butyl 7-hydroxy-6-(hydroxymethyl)-2,2-dimethyltetrahydro-[1,3]dioxolo[4,5-c]pyridine-5(6H)-carboxylate (19). Urethane 18 (0.03 g, 0.076 mmol) in methanol was subjected to hydrogenation in presence of 10% Pd/(OH)₂ at room temperature (25 °C) at 70 psi for 3 h. The reaction mixture was filtered through celite, celite was washed thoroughly with methanol and concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography using ethyl acetate–pet. ether (9 : 1) as an eluent to furnish diol 19 (20.8 mg, 90%). R_f (80% EtOAc–petroleum ether) 0.4; [α]²⁵_D: −47.14 (c 1.4, CHCl₃); IR (CHCl₃, cm⁻¹): 3437, 1667, 1417, 1161; ¹H NMR (500 MHz, CDCl₃): δ 1.34 (s, 3H), 1.42 (s, 3H), 1.47 (s, 9H), 2.83 (bs, 1H), 3.09 (bs, 1H), 3.73–3.95 (m, 4H), 3.95–4.01 (m, 1H), 4.30 (bs, 1H), 4.50 (bs, 1H); ¹³C NMR (125 MHz, CDCl₃ + CCl₄): δ 24.3, 26.2, 28.4, 42.1, 42.9, 55.3, 62.9, 63.6, 66.9, 67.3, 73.5, 73.6, 74.2, 74.4, 80.4, 109.6; ESIMS (m/z): 326.4 (M + Na)⁺; HRMS calculated for [C₁₄H₂₅NO₆ + Na]⁺: 326.1574; found: 326.1583.

3.1.11. (2R,3R,4S,5S)-2-(Hydroxymethyl) piperidine-3,4,5-triol hydrochloride (5). To a solution of diol 19 (20 mg, 0.065 mmol) in methanol (3 mL) was added conc. HCl (0.1 mL) at 0 °C. The reaction mixture was stirred for 3 h at room temperature. After completion of reaction, the reaction mixture was concentrated under reduced pressure. The semisolid mass 5 was dried under vacuum for 3 h to get 5 as a slightly brownish semisolid mass (13.0 mg, 99%). [α]²⁵_D: +33.7 (c 1, MeOH); ¹H NMR (400 MHz, D₂O): δ 4.20 (s, 1H), 4.02 (ddd, J = 11.7, 5.0, 2.5 Hz, 1H), 3.96 (dd, J = 12.8, 3.1 Hz, 1H), 3.91–3.84 (m, 2H), 3.36 (ddd, J = 10.7, 5.1, 3.2 Hz, 1H), 3.29 (dd, J = 12.1, 5.0 Hz, 1H), 3.15 (t, J = 11.9 Hz, 1H); ¹³C NMR (100 MHz, D₂O): δ 41.4, 54.6, 57.5, 64.4, 65.2, 69.8; ESIMS (m/z): 164.08.

3.1.12. (3aR,6S,6aS)-6-((R)-2-(Benzyloxy)-1-iodoethyl)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-4(3aH)-one (20). A mixture of 8 (500 mg, 1.62 mmol), PPh₃ (1.4 g, 5.34 mmol), imidazole (0.35 g, 5.18 mmol) and iodine (0.902 g, 3.56 mmol) in anhydrous toluene (20 mL) was refluxed under nitrogen atmosphere for 30 min. After completion of reaction (monitored by TLC), the reaction mixture was cooled to room temperature and diluted with saturated solution of Na₂S₂O₃. The reaction mixture was extracted with ethyl acetate (2 × 50 mL). The organic layer was separated and dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to provide crude iodo lactone. The residue was purified by flash column chromatography using pet ether–ethyl acetate as eluent to afford olefin 20 as a colorless liquid (0.508 g, 75%, HPLC purity 88%). R_f (15% EtOAc–petroleum ether) 0.6; [α]²⁵_D: −16.8 (c 1, CHCl₃); IR (CHCl₃, cm⁻¹): 1790, 1628, 1153, 1076; GCMS: 418; ¹H NMR (400 MHz, CDCl₃ + CCl₄): δ 1.39 (s, 3H), 1.48 (s, 3H), 3.77–3.88 (m, 2H), 4.35–4.39 (m, 1H), 4.55–4.62 (m, 2H), 4.72–4.77 (m, 2H), 4.87 (d, J = 6 Hz, 1H), 7.31–7.39 (m, 5H); ¹³C NMR (50 MHz, CDCl₃ + CCl₄): δ 25.3, 26.4, 28.6, 71.2, 73.3, 75.2, 79.5, 84.2, 113.8, 127.7, 128.1, 128.5, 136.8, 172.8.

3.1.13. (3aR,6R,6aR)-6-((S)-1-Azido-2-(benzyloxy)ethyl)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-4(3aH)-one (21). To a solution of iodo-lactone 20 (100 mg, 0.239 mmol) in anhydrous DMF (3 mL), was added NaN₃ (31 mg, 0.47 mmol) under nitrogen atmosphere. The reaction mixture was stirred at 80 °C for 12 h. After completion of the reaction (monitored by TLC), it was cooled to room temperature, diluted with water and extracted with ethyl acetate (3 × 20 mL). The combined organic extracts were washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography using ethyl acetate–light petroleum ether (1 : 9) as an eluent to afford 21 (47.8 mg, 60%) as a colorless oil. R_f (15% EtOAc–petroleum ether) 0.6; [α]²⁵_D: +19 (c 0.63, CHCl₃); IR (CHCl₃, cm⁻¹): 2114, 1790, 1087; ¹H NMR (200 MHz, CDCl₃): δ 1.38 (s, 3H), 1.46 (s, 3H), 3.72–3.80 (m, 2H), 3.89–3.97 (m, 1H), 4.52–4.59 (m, 3H), 4.67 (d, J = 5.8 Hz, 1H), 4.82 (d, J = 5.8 Hz, 1H), 7.29–7.41 (m, 5H); ¹³C NMR (50 MHz, CDCl₃ + CCl₄): δ 25.5, 26.7, 61.5, 69.4, 73.8, 74.7, 78.5, 80.3, 113.5, 127.8, 128.1, 128.6, 136.9, 173.1; ESIMS (m/z): 356 (M + Na)⁺; HRMS calculated for [C₁₆H₁₉N₃O₅ + Na]⁺: 356.1217; found: 356.1224.

3.1.14. (3aR,6S,7R,7aR)-6-((Benzyloxy)methyl)-7-hydroxy-2,2-dimethyltetrahydro-[1,3] dioxolo[4,5-c]pyridin-4(3aH)-one (6). Azido lactone 21 (50 mg, 0.15 mmol) in methanol (2 mL) was stirred with 10% Pd(OH)₂ under the hydrogen atmosphere at 10 psi at room temperature (25 °C) for 1 h. The reaction mixture was filtered through celite and the celite layer was washed thoroughly with methanol (3 × 20 mL) and concentrated under reduced pressure. The residue thus obtained was purified by flash silica gel chromatography using pet ether–ethyl acetate (2 : 8) as an eluent to furnish lactum 6 as a colorless liquid (40 mg, 88%). R_f (100% EtOAc) 0.4; [α]²⁵_D: −4 (c 1.5, CHCl₃); IR (CHCl₃, cm⁻¹): 3444, 1671, 1089; ¹H NMR (500 MHz, CDCl₃): δ 1.43 (s, 3H), 1.56 (s, 3H), 2.50 (bs, 1H), 3.60 (dd, J = 9, 4.2 Hz, 1H), 3.70 (dd, J = 9, 4.2 Hz, 1H), 3.75 (d, J = 9 Hz, 1H), 4.01 (d, J = 3 Hz, 1H), 4.43 (dd, J = 8, 3 Hz, 1H), 4.52–4.59 (m, 3H), 6.08 (bs, 1H), 7.31–7.37 (m, 5H); ¹³C NMR (125 MHz, CDCl₃ + CCl₄): δ 23.9, 25.9, 52.4, 63.6, 69.7, 72.1, 73.6, 74.8, 110.5, 127.8, 128.1, 128.6, 137.2, 168.9; ESIMS (m/z): 330.22 (M + Na)⁺; HRMS calculated for [C₁₆H₂₁NO₅ + Na]⁺: 330.1312; found: 330.1322.

3.1.15. (3aS,6S,7R,7aR)-tert-Butyl 6((benzyloxy) methyl)-7-hydroxy-2,2-dimethyltetrahydro-[1,3] dioxolo[4,5-c]pyridine-5(6H)-carboxylate (23). To a solution of lactam 6 (0.15 g, 0.48 mmol) in anhydrous THF (7 mL) was added BH₃·DMS (0.23 mL, 2.4 mmol) dropwise at 0 °C under the nitrogen atmosphere. The reaction mixture was allowed to stir at room temperature for 18 h. The reaction mixture was then cooled to 0 °C and quenched by ethanol (10 mL). Solvent was removed under reduced pressure and the crude semisolid residue was treated with additional ethanol (10 mL) and refluxed for 4 h. Solvent was removed under reduced pressure to furnish crude amine 22. To the solution of crude amine 22 in THF (5 mL) was added TEA (0.14 mL) followed by addition of (Boc)₂O (0.16 mL) and DMAP (cat.) and was stirred at room temperature for 24 h. The reaction mixture was extracted with ethyl acetate (3 × 20 mL), washed with water, brine and dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using petroleum ether–ethyl acetate (7 : 3) as an eluent to afford 23 as a white semisolid (95 mg, 50% over two steps). R_f (40% EtOAc–petroleum ether) 0.4; [α]²⁵_D: +44.4 (c 1.5, CHCl₃); ¹H NMR (400 MHz, CDCl₃): δ 1.37 (s, 3H), 1.41 (s, 4H), 1.45 (s, 5H), 1.51 (s, 3H), 2.70 (bd, 1H), 3.14 (bs, 1H) 3.66–3.99 (m, 3H), 4.13 (bs, 2H), 4.30 (bs, 2H), 4.51–4.64 (m, 2H), 7.28–7.34 (m, 5H);¹³C NMR (125 MHz, CDCl₃ + CCl₄): δ 26.5, 27.7, 28.4, 40.9, 42.3, 52.3, 53.0, 65.6, 66.7, 66.8, 71.3, 71.5, 73.3, 74.8, 80.3, 109.6, 127.7, 128.4, 138.2, 154.7; ESIMS (m/z): 416.51 (M + Na)⁺; HRMS calculated for [C₂₁H₃₁NO₆ + Na]⁺: 416.2044; found: 416.2065.

3.1.16. (2S,3R,4S,5S)-2-(Hydroxymethyl) piperidine-3,4,5-triol hydrochloride (4). To a solution of urethane 23 (30 mg, 0.076 mmol) in MeOH (5 mL) was added Pd(OH)₂ under the atmosphere of hydrogen. The reaction mixture was allowed to stir for 6 h. After completion of reaction (monitored by TLC), the reaction mixture was filtered through a celite bed and bed thoroughly washed with methanol for (3 × 30 mL). The reaction mixture was concentrated under reduced pressure to provide the diol. To a solution of diol in methanol (3 mL) was added conc. HCl (0.05 mL) at 0 °C. The reaction mixture was stirred for 3 h at room temperature. After completion of reaction, the reaction mixture was concentrated under reduced pressure. The semisolid mass 4 was dried under vacuum for 3 h to get 4 as slightly brownish semisolid (11 mg, 72% over two steps). [α]²⁵_D: +20.2 (c 1, MeOH); ¹H NMR 400 MHz, D₂O): δ 3.21–3.32 (m, 1H), 3.39 (t, J = 6.7 Hz, 1H), 3.51 (dt, J = 13.8, 2.2 Hz, 1H), 3.81–3.95 (m, 3H), 4.14 (bs, 1H), 4.23 (bs, 1H); ¹³C NMR (100 MHz, D₂O): δ 50.4, 61.2, 62.3, 68.7, 69.2, 69.7 ESIMS (m/z): 164.08.

Acknowledgements

N.B.D. and K.P.P. thank CSIR, New Delhi, India, for fellowship, Dr H. B. Borate for hekpful discussion, Mrs Kunte for HPLC and Mrs Shanthakumari for HRMS facility. The authors thank CSIR, New Delhi for financial support as part of XII Five Year Plan programme under title ACT (CSC-0301).

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4ra06884j

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