A PROCESS FOR SYNTHESIS OF PIPERIDINE ALKALOIDS

Abstract

The present invention discloses a process for synthesis of piperidine alkaloids selected from fagomine, 4-epi-fagomine and nojirimycin from tri-O-benzyl-D-glucal or tri-O-benzyl-D-galactal.

Claims

1. A process for the preparation of piperidine alkaloids, the process comprising: a) dissolving gluconolactone compound (1) in methanolic ammonia solution followed by stirring at room temperature in the range of 20 to 35° C. for 1 to 1.5 h to afford 5-δ-hydroxy amide (2); ##STR00011## b) stirring a solution of compound 2 as obtained in step (a) in DMSO and Ac.sub.2O at room temperature in the range of 20 to 35° C. for period in the range of 22 to 23 h followed by addition of water to afford δ-keto amide (3); ##STR00012## c) adding formic acid and sodium cyanoborohydride to a solution of compound 3 as obtained in step (b) in acetonitrile followed by refluxing at temperature in the range of 80 to 85° C. for period in the range of 4 to 4.5 h to afford glycolactam compound (5); ##STR00013## d) adding lithium aluminium hydride to a solution of compound 5 as obtained in step (c) in tetrahydrofuran followed by stirring the reaction mixture for period in the range of 3.5 to 4 h at temperature in the range of 65 to 70° C. and purification to afford protected piperidine compound (6); ##STR00014## e) adding palladium on active charcoal to a solution of piperidine compound 6 as obtained in step (d) in acetic acid followed by stirring the mixture for overnight for period in the range of 10 to 12 hr at room temperature in the range of 20 to 35° C. under hydrogen atmosphere to afford piperidine alkaloids (7); ##STR00015## f) adding Et.sub.3N to a solution of glycolactam (5) as obtained in step (c) in dichloromethane followed by cooling to 0° C. and further adding Boc.sub.2O, DMAP followed by stirring at temperature in the range of 20 to 25° C. for period in the range of 8 to 9 h to afford N-Boc protected lactam (8); ##STR00016## g) dissolving N-Boc protected lactam (8a) of step (d) in toluene and cooling to −76° C. under inert atmosphere and adding superhydride and ammonium chloride solution at −76° C. followed by stirring the reaction mixture for period in the range of 9 to 10 h at room temperature to afford lactamol compound 9a; ##STR00017## h) stirring a mixture of compound of step (e) and HCl in methanol at 70° C. for 5 h followed by basifying the reaction mixture to afford 3-deoxynojirimycin (10a); ##STR00018## i) dissolving N-Boc protected lactam (8a) of step (d) in dry toluene and cooled at −76° C. under inert atmosphere and adding superhydride with stirring followed by addition of TFAA, DIPEA, catalytic amount of DMAP and purification to afford Boc-iminoglycal (11a/11b); and j) adding Boc-iminoglycal (11a) to a solution of (DHQ).sub.2AQN, K.sub.3Fe(CN).sub.6, K.sub.2CO.sub.3, K.sub.2OsO.sub.2(OH).sub.4 and CH.sub.3SO.sub.2NH.sub.2 in tert-butyl alcohol and water cooled at 0° C. followed by stirring the mixture at 0° C. for 60 to 66 h to afford iminoglycal compound (12a).

2. The process as claimed in claim 1, wherein the piperidine alkaloids are (+)-fagomine (7a), 4-epi-fagomine(7b), 3-deoxynojirimycin (10a), Boc-iminoglycal (11a/11b), iminoglycal compound (12a) and iminoglycal compound (13a).

3. The process as claimed in claim 1, wherein the steps (a), (b) and (d) are carried out under nitrogen atmosphere.

4. The process as claimed in claim 1, wherein the Boc-iminoglycal is tert-butyl (2R,3R)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-3,4-dihydropyridine-1(2H)-carboxylate (11a), tert-butyl (2R,3S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-3,4-dihydropyridine-1(2H)-carboxylate(11b).

5. The process as claimed in claim 1, wherein the iminoglycal compound is tert-Butyl (2R,3R,5R,6R)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5,6-dihydroxy-piperidine-1-carboxylate (12a) or tert-Butyl (2R,3R,5S,6S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5,6-dihydroxypiperidine-1-carboxylate (13a).

6. The process as claimed in claim 1, wherein said process may also comprise adding Boc-iminoglycal (11a) to a solution of (DHQD).sub.2AQN, K.sub.3Fe(CN).sub.6, K.sub.2CO.sub.3, K.sub.2OsO.sub.2(OH).sub.4 and CH.sub.3SO.sub.2NH.sub.2 in tert-butyl alcohol and water cooled at 0° C. followed by stirring the mixture at 0° C. for 60 to 66 h to afford iminoglycal compound (13a).

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Scheme 1 represents processes for the synthesis of (+)-fagomine and 4-epi-fagomine.

[0014] Scheme 2 represents process for the synthesis of 3-deoxynojirimycin.

[0015] Scheme 3 represents process for the synthesis of piperidine alkaloids (imino glycals).

SUMMARY OF THE INVENTION

[0016] Accordingly, present invention provides a process for the preparation of piperidine alkaloids comprising the steps of: [0017] a) dissolving gluconolactone compound (1) in methanolic ammonia solution followed by stirring at room temperature in the range of 20 to 35° C. for 1 to 1.5 h to afford 5-δ-hydroxy amide (2);

##STR00003## [0018] b) stirring a solution of compound 2 as obtained in step (a) in DMSO and Ac.sub.2O at room temperature in the range of 20 to 35° C. for period in the range of 22 to 23 h followed by addition of water to afford δ-keto amide (3);

##STR00004## [0019] c) adding formic acid and sodium cyanoborohydride to a solution of compound 3 as obtained in step (b) in acetonitrile followed by refluxing at temperature in the range of 80 to 85° C. for period in the range of 4 to 4.5 h to afford glycolactam compound (5);

##STR00005## [0020] d) adding lithium aluminium hydride to a solution of compound 5 as obtained in step (c) in tetrahydrofuran followed by stirring the reaction mixture for period in the range of 3.5 to 4 h at temperature in the range of 65 to 70° C. and purification to afford protected piperidine compound (6);

##STR00006## [0021] e) adding palladium on active charcoal to a solution of piperidine compound 6 as obtained in step (d) in acetic acid followed by stirring the mixture for overnight for period in the range of 10 to 12 hr at room temperature in the range of 20 to 35° C. under hydrogen atmosphere to afford piperidine alkaloids (7);

##STR00007## [0022] f) adding Et.sub.3N to a solution of glycolactam (5) as obtained in step (c) in dichloromethane followed by cooling to 0° C. and further adding Boc.sub.2O, DMAP followed by stirring at temperature in the range of 20 to 25° C. for period in the range of 8 to 9 h to afford N-Boc protected lactam (8);

##STR00008## [0023] g) dissolving N-Boc protected lactam (8a) of step (d) in toluene and cooling to −76° C. under inert atmosphere and adding superhydride and ammonium chloride solution at −76° C. followed by stirring the reaction mixture for period in the range of 9 to 10 h at room temperature to afford lactamol compound 9a;

##STR00009## [0024] h) stirring a mixture of compound of step (e) and HCl in methanol at 70° C. for 5 h followed by basifying the reaction mixture to afford 3-deoxynojirimycin (10a).

##STR00010## [0025] i) dissolving N-Boc protected lactam (8a) of step (d) in dry toluene and cooled at −76° C. under inert atmosphere and adding superhydride with stirring followed by addition of TFAA, DIPEA, catalytic amount of DMAP and purification to afford Boc-iminoglycal (11a/11b); [0026] j) adding Boc-iminoglycal (11a) to a solution of (DHQ).sub.2AQN, K.sub.3Fe(CN).sub.6, K.sub.2CO.sub.3, K.sub.2OsO.sub.2(OH).sub.4 and CH.sub.3SO.sub.2NH.sub.2 in tert-butyl alcohol and water cooled at 0° C. followed by stirring the mixture at 0° C. for 60 to 66 h to afford iminoglycal compound (12a); [0027] k) The process as claimed in any of the preceding claims, wherein said process may also comprises adding Boc-iminoglycal (11a) to a solution of (DHQD).sub.2AQN, K.sub.3Fe(CN).sub.6, K.sub.2CO.sub.3, K.sub.2OsO.sub.2(OH).sub.4 and CH.sub.3SO.sub.2NH.sub.2 in tert-butyl alcohol and water cooled at 0° C. followed by stirring the mixture at 0° C. for 60 to 66 h to afford iminoglycal compound (13a).

[0028] In an embodiment of the present invention, the piperidine alkaloids are (+)-fagominc (7a), 4-epi-fagomine(7b), 3-deoxynojirimycin (10a).

[0029] In another embodiment of the present invention, the steps (a), (b) and (d) are carried out under nitrogen atmosphere.

[0030] In yet another embodiment of the present invention, the process may also comprises dissolving N-Boc protected lactam (8a) of step (d) in dry toluene and cooled at −76° C. under inert atmosphere and adding superhydride with stirring followed by addition of TFAA, DIPEA, catalytic amount of DMAP and purification to afford Boc-iminoglycal (11a/11b).

[0031] In yet another embodiment of the present invention, the Boc-iminoglycal is tert-butyl (2R,3R)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-3,4-dihydropyridine-1(2H)-carboxylate (11a), tert-butyl (2R,3S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-3,4-dihydropyridine-1(2H)-carboxylate(11b).

[0032] In yet another embodiment of the present invention, said process may also comprise adding Boc-iminoglycal (11a/11b) to a solution of (DHQ).sub.2AQN, K.sub.3Fe(CN).sub.6, K.sub.2CO.sub.3, K.sub.2OsO.sub.2(OH).sub.4 and CH.sub.3SO.sub.2NH.sub.2 in tert-butyl alcohol and water cooled at 0° C. followed by stirring the mixture at 0° C. for 60 to 66 h to afford iminoglycal compound (12).

[0033] In yet another embodiment of the present invention, said process may also comprises adding Boc-iminoglycal (11a) to a solution of (DHQD).sub.2AQN, K.sub.3Fe(CN).sub.6, K.sub.2CO.sub.3, K.sub.2OsO.sub.2(OH).sub.4 and CH.sub.3SO.sub.2NH.sub.2 in tert-butyl alcohol and water cooled at 0° C. followed by stirring the mixture at 0° C. for 60 to 66 h to afford iminoglycal compound (13a).

[0034] In yet another embodiment of the present invention, the iminoglycal compound is tert-Butyl (2R,3R,5R,6R)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5,6-dihydroxy-piperidine-1-carboxylate (12a) or tert-Butyl (2R,3R,5S,6S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5,6-dihydroxypiperidine-1-carboxylate (13a).

DETAILED DESCRIPTION OF THE INVENTION

[0035] Present invention provides a process for the synthesis of piperidine alkaloids starting from glucal or galactal.

[0036] In an aspect, the present invention provides a process for the synthesis of (+)-fagomine and 4-epi-fagomine starting from glucal or galactal.

[0037] In another aspect, the present invention provides a process for the synthesis of 3-deoxynojirimycin starting from glucal or galactal.

[0038] The present invention provides a process for the synthesis of piperidine alkaloids selected from (+)-fagomine and 4-epi-fagomine in 14% and 6% overall yields and the said process comprising the steps of: [0039] a) dissolving gluconolactone compound (1a/1b) in methanolic ammonia solution followed by stirring at room temperature in the range of 20 to 35° C. for 6 h under nitrogen atmosphere to afford δ-hydroxy amide (2a/2b); [0040] b) stirring a solution of compound of step (a) in DMSO and Ac.sub.2O at room temperature in the range of 20 to 35° C. for 23 h under nitrogen atmosphere followed by addition of water to obtain a yellow oil precipitate of δ-keto amide (3a/3b); [0041] c) adding formic acid and sodium cyanoborohydride to a solution of compound of step (b) in acetonitrile followed by refluxing the reaction mixture at 85° C. for 4.5 h to afford glycolactam compound (5a/5b); [0042] d) adding lithium aluminium hydride to a solution of compound of step (c) in tetrahydrofuran followed by stirring the reaction mixture for 4 h at 70° C. under nitrogen atmosphere and purification to afford protected piperidine compound (6a/6b) as a yellow syrup; [0043] e) adding 10% palladium on active charcoal to a solution of compound of step (d) in acetic acid followed by stirring the mixture for overnight at room temperature under hydrogen atmosphere to afford piperidine alkaloids selected from (+)-fagomine (7a) and 4-epi-fagomine (7b).

[0044] The compounds formed in step (a) are (3R,4R)-3,4,6-Tris(benzyloxy)-5-hydroxyhexanamide(2a) and (3R,4S)-3,4,6-tris(benzyloxy)-5-hydroxyhexanamide (2b).

[0045] The compounds formed in step (b) are (3R,4S)-3,4,6-Tris(benzyloxy)-5-oxohexanamide(3a) and (3R,4R)-3,4,6-Tris(benzyloxy)-5-oxohexanamide(3b).

[0046] The glycolactam compounds formed in step (c) are (5R,6R)-4,5-Bis(benzyloxy)-6-(benzyloxymethyl)piperidin-2-one (5a),(5S,6R)-4,5-Bis(benzyloxy)-6-(benzyloxymethyl) piperidin-2-one(5b).

[0047] The compounds formed in step (d) are (2R,3R,4R)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)piperidine(6a), (2R,3S,4R)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl) piperidine(6b).

[0048] The present invention provides a process for the synthesis of 3-deoxynojirimycin (10a) starting from glucal or galactal and the said process comprising the steps of: [0049] a) dissolving gluconolactone compound (1a/1b) in methanolic ammonia solution followed by stirring at room temperature in the range of 20 to 35° C. for 1.5 h under nitrogen atmosphere to afford δ-hydroxy amide (2a/2b); [0050] b) stirring a solution of compound of step (a) in DMSO and Ac.sub.2O at room temperature in the range of 20 to 35° C. for 23 h under nitrogen atmosphere followed by addition of water to obtain a yellow oil precipitate of δ-keto amide (3a/3b); [0051] c) adding formic acid and sodium cyanoborohydride to a solution of compound of step (b) in acetonitrile followed by refluxing the reaction mixture at 85° C. for 4.5 h to afford glycolactam compound (5a/5b); [0052] d) adding Et3N to a solution of glycolactam (5a/5b) of step (c) in dichloromethane followed by cooling to 0° C. and further adding Boc2O, DMAP followed by stirring at 25° C. for 9 h to afford N-Boc protected lactam (8a/8b); [0053] e) dissolving N-Boc protected lactam (8a/8b) of step (d) in toluene and cooling to −76° C. under inert atmosphere and adding superhydride and ammonium chloride solution at −76° C. followed by stirring the reaction mixture for 10 h at room temperature to afford lactamol (9a); [0054] f) stirring a mixture of compound of step (e) and HCL in methanol at 70° C. for 5 h followed by basifying the reaction mixture to afford 3-deoxyNojirimycin (10).

[0055] The N-Boc protected lactam compound formed in step (d) are Tert-butyl (2R,3R,4S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-6-oxopiperidine-1-carboxylate(8a), Tert-butyl (2R,3S,4S)-3,4-Bis(benzyloxy)-2-((benzyloxy)methyl)-6-oxopiperidine-1-carboxylate(8b).

[0056] The carboxylate compound formed in step (e) is tert-butyl (2R,3R)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-6-hydroxypiperidine-1-carboxylate(9a).

[0057] The present invention provides a process for the synthesis of piperidine alkaloids (imino glycals) comprising the steps of: [0058] a) dissolving gluconolactone compound (1a/1b) in methanolic ammonia solution followed by stirring at room temperature for 1.5 h under nitrogen atmosphere to afford δ-hydroxy amide (2a/2b); [0059] b) stirring a solution of compound of step (a) in DMSO and Ac.sub.2O at room temperature for 23 h under nitrogen atmosphere followed by addition of water to obtain a yellow oil precipitate of 8-keto amide (3a/3b); [0060] c) adding formic acid and sodium cyanoborohydride to a solution of compound of step (b) in acetonitrile followed by refluxing the reaction mixture for 4.5 h to afford glycolactam compound (5a/5b); [0061] d) adding Et.sub.3N to a solution of glycolactam (5a/5b) of step (c) in dichloromethane followed by cooling to 0° C. and further adding Boc.sub.2O, DMAP followed by stirring at 25° C. for 9 h to afford N-Boc protected lactam (8a/8b); [0062] e) dissolving N-Boc protected lactam (8a/8b) of step (d) in dry toluene and cooling under inert atmosphere, and adding superhydride with stirring followed by addition of TFAA, DIPEA, catalytic amount of DMAP and purification to afford Boc-iminoglycal (11a/11b). [0063] f) adding Boc-iminoglycal (11a) to a solution of (DHQ).sub.2AQN, K.sub.3Fe(CN).sub.6, K.sub.2CO.sub.3, K.sub.2OsO.sub.2(OH).sub.4 and CH.sub.3SO.sub.2NH.sub.2 in tert-butyl alcohol and water cooled at 0° C. followed by stirring the mixture at 0° C. for 60 to 66 h to afford iminoglycal compound (12a). [0064] g) adding Boc-iminoglycal (11a) to a solution of (DHQD).sub.2AQN, K.sub.3Fe(CN).sub.6, K.sub.2CO.sub.3, K.sub.2OsO.sub.2(OH).sub.4 and CH.sub.3SO.sub.2NH.sub.2 in tert-butyl alcohol and water cooled at 0° C. followed by stirring the mixture at 0° C. for 60 to 66 h to afford iminoglycal compound (13a).

[0065] The Boc-iminoglycal formed in step (e) is tert-butyl (2R,3R)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-3,4-dihydropyridine-1(2H)-carboxylate (11a), Tert-butyl (2R,3S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-3,4-dihydropyridine-1(2H)-carboxylate(11b).

[0066] The iminoglycal compound is tert-Butyl (2R,3R,5R,6R)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5,6-dihydroxypiperidine-1-carboxylate (12a) or tert-Butyl (2R,3R,5S,6S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5,6-dihydroxypiperidine-1-carboxylate(13a).

EXAMPLES

[0067] Following examples are given by way of illustration and therefore should not be construed to limit the scope of the invention.

Example 1

Preparation of (+)-fagomine and 4-epi-fagomine

Example 1 (A)

Preparation of (3R,4R)-3,4,6-Tris(benzyloxy)-5-hydroxyhexanamide (2a)

[0068] Gluconolactone 1a (1.393 g, 2.32 mmol) was dissolved in methanolic ammonia soln. (7N, 22 mL) and was stirred at room temperature 25° C. for 6 h. After completion of the reaction (TLC), reaction mixture was concentrated in vacuo followed by purification by SiO.sub.2 column chromatography (EtOAc-petroleum ether, 6:4) to afford 2a (859 mg, 82%) as colorless solid; mp 74-76° C.

[0069] R.sub.f 0.26 (EtOAc-petroleum ether, 1:1); [α].sup.20.sub.D+14.27 (c 1.43, CHCl.sub.3); IR (CHCl.sub.3): ν.sub.max 3374, 3201, 3012, 2869, 1673, 1615, 1404, 1216, 1072, 1028, 908, 747, 698, 667 cm.sup.−1; .sup.1H NMR (200 MHz, CDCl.sub.3, assignment by COSY, FISQC and HMBC experiments): δ.sub.H 7.33-7.24 (m, 15H, ArH), 5.76 (bs, 1H, NH), 5.45 (bd, 1H, NH), 4.61-4.47 (m, 6H, Ph-CH.sub.2), 4.31-4.23 (m, 1H, H-3), 3.99-3.92 (m, 1H, H-5), 3.67-3.62 (m, 3H, H-4, H-6), 3.14 (bs, 1H, OH), 2.52-2.57 (m, 2H, H-2); δ.sub.C (100 MHz. CDCl.sub.3) 173.5 (q, C-1) 138.0, 137.8, 137.6 (q, Ar), 128.5, 128.4, 128.3, 128.0, 127.8 (s, Ar), 78.2 (s, C-4), 76.6 (s, C-3), 73.5 (d, —OCH.sub.2Ph), 73.4 (d, 2C, C-6, —OCH.sub.2Ph), 71.2 (d, —OCH.sub.2Ph), 70.8 (s, C-5), 37.3 (d, C-2); ESI-MS: m/z 450.2240 (M+H).sup.+; HRMS: m/z calcd for C.sub.27H.sub.31NO.sub.5 449.22022, found 449.20571.

Example 1 (B)

Preparation of (3R,4S)-3,4,6-tris(benzyloxy)-5-hydroxyhexanamide(2b)

[0070] Galactonolactone 1b (2.0 g, 4.65 mmol) was dissolved in methanolic ammonia soln. (7N, 25 mL) and stirred at room temperature 27° C. for 11 h under nitrogen atmosphere. After completion of the reaction (TLC), reaction mixture was concentrated in vacuo to furnish a crude which was purified by SiO.sub.2 column chromatography (EtOAc-petroleum ether, 1:1) to afford 2b (1.997 g, 96%) as yellowish gum.

[0071] R.sub.f 0.19 (EtOAc-petroleum ether, 1:1); [α].sup.20.sub.D+2.92 (c 1.2, CHCl.sub.3); IR (CHCl.sub.3): ν.sub.max 3660, 3372, 3019, 2872, 1736, 1454, 1216, 1101, 1064, 908, 755, 698, 668 cm.sup.−1; .sup.1H NMR (200 MHz, CDCl.sub.3, assignment by COSY, HSQC and HMBC experiments, D.sub.2O exchange): δ.sub.H 7.33-7.25 (m, 15H, ArH), 6.00 (bs, 1H, NH), 5.51 (bs, 1H, NH), 4.79-4.48 (m, 6H, PhCH.sub.2), 4.18-4.10 (m, 1H, H-3), 3.95 (bs, 1H, H-4), 3.76-3.72 (m, 1H, H-5), 3.60-3.44 (m, 2H, H-6), 2.83 (bs, 1H, OH), 2.68-2.47 (m, 2H, H-2); .sup.13C NMR (50 MHz, CDCl.sub.3): δ.sub.C 173.6 (q, C-1), 137.8, 137.7 (q, Ar), 128.6, 128.5, 128.1, 128.0, 127.9 (s, Ar), 78.8 (s, C-4), 77.3 (s, C-3), 74.1, 73.5, 73.0, 71.1 (d, PhCH.sub.2, C-6), 69.9 (s, C-5), 37.7 (d, C-2); ESI-MS: m/z 450.4348 (M+H).sup.+, 472.4115 (M+Na).sup.+, 487.5341 (M+K).sup.+; HRMS: m/z calcd for C.sub.27H.sub.31NO.sub.5 449.22022, found 449.20571.

Example 1 (C)

Preparation of (3R,4S)-3,4,6-Tris(benzyloxy)-5-oxohexanamide (3a)

[0072] A solution of 2a (1.105 g, 2.5 mmol) in DMSO (11 mL) and Ac.sub.2O (6.7 mL) was stirred under nitrogen atmosphere for 23 h. Water (50 mL) was added and the mixture was stirred for another 15 minutes during which a yellow oil precipitated. The water layer was then removed and the residue was washed with water (3×50 mL). The residue was dissolved in DCM (25 mL) and extracted with brine (2×50 mL). The organic layers were dried (anhyd. Na.sub.2SO.sub.4) and concentrated in vacuo to afford crude 3a (59%). The crude obtained was used as such for the next step.

Example 1 (D)

Preparation of (3R,4R)-3,4,6-Tris(benzyloxy)-5-oxohexanamide(3b)

[0073] A solution of 2b (1.105 g, 2.5 mmol) in DMSO (11 mL) and Ac.sub.2O (6.7 mL) was stirred under nitrogen atmosphere for 26 hours at room temperature 22° C. H.sub.2O (50 mL) was added and the reaction mixture was stirred for another 15 minutes during which a yellow oil precipitated. The water layer was then removed and the residue was washed with water (3×50 mL). The residue was dissolved in DCM (25 mL) and extracted with brine (2×50 mL). The organic fractions were dried (anhyd. Na.sub.2SO.sub.4) and concentrated in vacuo to afford crude 3b (24%). The crude obtained was used as such for the next step.

Example 1 (E)

Preparation of (5R,6R)-4,5-Bis(benzyloxy)-6-(benzyloxymethyl)piperidin-2-one(5a)

[0074] Compound 3a (582 mg, 1.302 mmol) was dissolved in MeCN (20 mL) and HCOOH (3.8 mL) was added to the reaction mixture followed by NaCNBH.sub.3 (177 mg, 2 eqs.) and the reaction mixture was refluxed at 85° C. for 4.5 h. The reaction mixture was then cooled in an ice-bath and was quenched by adding aq. HCl solution (0.1 N, 30 mL). After stirring for another 15 minutes, EtOAc (50 mL) and then saturated aq. NaHCO.sub.3 solutions (50 mL) were added to it. The water layer was separated and extracted with EtOAc (2×25 mL), the combined organic fractions were pooled and then washed with brine (1×30 mL) and dried (anhyd. Na.sub.2SO.sub.4). After concentration in vacuo, the resulting crude was purified by SiO.sub.2 column chromatography (EtOAc-petroleum ether, 4:6) to afford a white solid which on crystallization (EtOAc-petroleum ether) furnished 5a as colorless needles. (329 mg, 59%); mp 73-75° C.; R.sub.f0.32 (EtOAc-petroleum ether, 1:1); [α].sup.20.sub.D+16.78 (c 1.02, CHCl.sub.3); IR (CHCl.sub.3): ν.sub.max 3396, 3019, 2868, 1666, 1455, 1215, 1100, 755, 699, 669 cm.sup.−1; .sup.1H NMR (200 MHz, CDCl.sub.3): δ.sub.H 7.39-7.21 (m, 15H, ArH), 6.16 (bs, 1H, NH), 4.84-4.46 (m, 6H, PhCH.sub.2), 3.94-3.84 (m, 1H, H-6), 3.69-3.49 (m, 3H, H-6, H-3, H-4), 3.41-3.32 (m, 1H, H-5), 2.86-2.42 (m, 2H, H-2); .sup.13C NMR (50 MHz, CDCl.sub.3): δ.sub.C 169.6 (q, C-1, C═O), 137.7, 137.6, 137.4 (q, Ar), 128.5, 128.1, 127.9, 127.7, 127.6 (s, CH, Ar), 75.8 (s, C-4), 75.6 (s, C-3), 73.7, 73.4, 71.7 (d, —CH.sub.2Ph), 71.0 (d, C-6), 54.8 (s, C-5), 35.2 (d, C-2); ESI-MS: m/z 432.7864 (M+H).sup.+, 454.5697 (M+Na).sup.+, 470.7429 (M+K).sup.+; HRMS:m/z calcd for C.sub.27H.sub.30NO.sub.4432.2166, found 432.2169.

Example 1 (F)

Preparation of (5S,6R)-4,5-Bis(benzyloxy)-6-(benzyloxymethyl)piperidin-2-one (5b)

[0075] Compound 3b (437 mg, 1 mmol) was dissolved in a mixture of MeCN (15 mL) and HCOOH (3.0 mL). To this mixture, NaCNBH.sub.3 (133 mg, 2 eqs.) was added and the reaction mixture was refluxed at 85° C. for 4.5 h. The reaction mixture was then cooled in an ice-bath and the reaction was quenched by adding aq. HCl solution (0.1 N, 30 mL). After stirring for another 15 minutes, EtOAc (50 mL) and then saturated aq. NaHCO.sub.3 solutions (50 mL) were added to it. The water layer was separated and extracted with EtOAc (2×25 mL), the combined organic fractions were pooled and then washed with brine (1×30 mL) and dried (anhyd. Na.sub.2SO.sub.4). After concentration in vacuo, the resulting crude was purified by SiO.sub.2 column chromatography (EtOAc-petroleum ether, 4:6) to afford a colorless semi-solid 5b (250 mg 59%).

[0076] R.sub.f 0.21 (EtOAc-petroleum ether); [α].sup.20.sub.D+29.43 (c 1.1, CHCl.sub.3); IR (CHCl.sub.3): ν.sub.max 3395, 3017, 2926, 1663, 1454, 1216, 1114, 756, 698, 668 cm.sup.−1; .sup.1H NMR (200 MHz, CDCl.sub.3): δ.sub.H 7.40-7.25 (m, 15H, ArH), 6.06 (bs, 1H, NH) 4.97-4.39 (m, 6H, PhCH.sub.2), 4.00 (bs, 1H, H-4), 3.89-3.79 (ddd, 1H, J=10.6, 6.3, 1.6 Hz, H-5), 3.59-3.48 (m, 3H, H-6, H-3), 2.91-2.63 (m, 2H, H-2); .sup.13C NMR (50 MHz, CDCl.sub.3): δ.sub.C 170.2 (q, C-1), 138.1, 137.7, 137.4 (q, Ar), 128.6, 128.6, 128.4, 128.0, 128.0, 127.9, 127.8, 127.5 (d, Ar), 75.6 (s, C-4), 73.9, 73.6, 71.7 (s, C-3), 70.9, 70.6 (d, PhCH.sub.2, C-6), 54.9 (s, C-5), 33.7 (d, C-2); ESI-MS: m/z 432.3909 (M+H).sup.+, 454.3993 (M+Na).sup.+, 470.3436 (M+K).sup.+; HRMS: m/z calcd for C.sub.27H.sub.29NO.sub.4 432.2169, found 432.2170.

Example 1 (G)

Preparation of (2R,3R,4R)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)piperidine(6a)

[0077] To a solution of 5a (256 mg, 0.594 mmol) in THF (15 mL), LAH (68 mg, 3 eqs.) was added. The reaction mixture was stirred for 4 h at 70° C. under nitrogen atmosphere. The mixture was then brought to room temperature 30° C. and poured into a mixture of diethyl ether and ice water (1:1, 100 mL). After stirring for 15 minutes, 0.5 M aq. NaOH (75 mL) was added and the mixture was stirred for another 10 minutes. The water layer was then separated and extracted with diethyl ether (3×50 mL), the organic fractions were pooled, washed with brine and finally dried (anhyd. Na.sub.2SO.sub.4) and concentrated in vacuo. The crude product was purified by SiO.sub.2 column chromatography (EtOAc-petroleum ether, 1:1) to afford 6a (120 mg, 49%) as a yellow syrup;

[0078] R.sub.f 0.12 (EtOAc-petroleum ether, 1:1); [α].sup.20.sub.D+21.76 (c 1.1, CHCl.sub.3); IR (CHCl.sub.3): ν.sub.max 3151, 3017, 2922, 1398, 1220, 1099, 772, 669, 615 cm.sup.−1; .sup.1H NMR (200 MHz, CDCl.sub.3): δ.sub.H 7.38-7.21 (m, 15H, ArH), 4.98-4.47 (m, 6H, PhCH.sub.2), 3.76-3.73 (dd, 1H, J 2.5, 9.0 Hz, H-6.sub.a), 3.62-3.52 (m, 2H, H-6.sub.b, H-3), 3.39-3.34 (t, 1H, J=9.0 Hz, H-4), 3.10-3.05 (ddd, 1H, J=1.8, 2.3, 12.6 Hz, H-1.sub.a), 2.76-2.71 (m, 1H, H-5), 2.62-2.56 (dt, 1H, J=12.6, 2.3 Hz, H-1.sub.b), 2.34 (bs, 1H, NH), 2.20-2.14 (m, 1H, H-2.sub.a), 1.57-1.50 (m, 1H, H-2.sub.b); .sup.13C NMR (50 MHz, CDCl.sub.3): δ.sub.C 138.8, 138.7, 138.2 (q, Ar), 128.4, 128.4, 128.4, 128.1, 127.9, 127.7, 127.7, 127.6, 127.6 (s, Ar), 82.5 (s, C-3), 80.8 (s, C-4), 75.2, 73.4, 71.5 (d, PhCH.sub.2), 70.7 (d, C-6), 60.1 (s, C-5), 43.6 (d, C-1), 32.1 (d, C-2); ESI-MS: m/z 418.4191 (M+H).sup.+; HRMS: m/z calcd for C.sub.27H.sub.31NO.sub.3 418.2377, found 418.2378.

Example 1 (H)

Preparation of (2R,3S,4R)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)piperidine (6b)

[0079] To a solution of 5b (242 mg, 0.58 mmol) in THF (15 mL), LAH (65 mg, 3 eqs.) was added. The reaction mixture was stirred for 2 h at 70° C. under nitrogen atmosphere. The reaction mixture was then brought to room temperature 25° C. and poured into a mixture of diethyl ether and ice water (1:1, 100 mL). After stirring for 15 minutes, aq. NaOH (0.5 M, 75 mL) was added and the reaction mixture was stirred for another 10 minutes. The water layer was then separated and extracted with diethyl ether (3×50 mL), the organic fractions were pooled and washed with brine (1×30 mL) and dried (anhyd. Na.sub.2SO.sub.4). After concentration in vacuo, the reaction mixture was purified by SiO.sub.2 column chromatography (EtOAc-petroleum ether, 1:1) to afford 6b (95 mg, 41%) as a yellow syrup;

[0080] R.sub.f0.12 (EtOAc-petroleum ether); [α].sup.20.sub.D−4.07 (c 1.0, CHCl.sub.3); IR (CHCl.sub.3): ν.sub.max 3302, 3089, 3066, 3019, 2929, 1455, 1365, 1216, 1088, 751, 699, 669 cm.sup.−1; .sup.1H NMR (400 MHz, CDCl.sub.3): δ.sub.H 7.40-7.28 (m, 15H, ArH), 5.01-4.46 (m, 6H, PhCH.sub.2), 3.98 (bs, 11-1, H-4), 3.59-3.55 (m, 1H, H-6.sub.a), 3.53-3.49 (m, 1H, H-3), 3.48-3.44 (t, 1H, J=8.5, 7.8 Hz, H-6.sub.b), 3.32 (1H, bs, NH), 3.17-3.13 (dd, 1H, J=13.3, 2.0 Hz, H-1.sub.a), 2.85-2.81 (t, 1H, J=6.8 Hz, H-5), 2.66-2.58 (dt, 1H, J=12.8, 3.0, 3.0, 2.8 Hz, H-1.sub.b), 2.05-1.94 (m, 1H, H-2.sub.a), 1.86-1.83 (dd, 1H, J=12.4, 2.2 Hz, H-2.sub.b); .sup.13C NMR (100 MHz, CDCl.sub.3): δ.sub.C 139.1, 138.7, 138.1 (q, Ar), 128.5, 128.2, 128.0, 127.6, 127.3 (s, Ar), 79.7 (s, C-3), 74.1, 73.5, 70.1 (d, PhCH.sub.2), 73.3 (s, C-4), 70.4 (d, C-6), 58.8 (s, C-5), 44.2 (d, C-1), 27.7 (d, C-2); ESI-MS: m/z 418.0585 (M+H).sup.+; HRMS: m/z calcd for C.sub.27H.sub.32NO.sub.3 418.2377, found 418.2377.

Example 1 (I)

Preparation of (+)-Fagomine (7a)

[0081] To a solution of 6a (100 mg, 0.24 mmol) in AcOH (2.5 ml) was added 10% palladium on active charcoal (10 mg) at room temperature 27° C. and the mixture stirred overnight for 12 h under hydrogen gas. The reaction mixture was filtered through a celite pad and washed with MeOH (50 mL), the filtrate was concentrated in vacuo. The residue was dissolved in water (5 mL) and the solution was stirred at room temperature 25° C. with Amberlite IR-120 (H.sup.+) for 3 h. The suspension was eluted with water and then 0.5 M NH.sub.4Cl to furnish pure (+)-fagomine (7a) (31 mg, 87%), which was identified on the basis of comparison with reported spectral data.

Example 1 (J)

Preparation of 4-epi-Fagominc (7b)

[0082] Similarly, 7b (30 mg, 86%) was obtained from 6b (100 mg, 0.24 mmol) by following the above-mentioned procedure.

Example 2

Preparation of 3-deoxynojirimycin (10)

Example 2 (A)

Preparation of Tert-butyl (2R,3R,4S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-6-oxopiperidine-1-carboxylate (8a)

[0083] Glycolactam 5a (150 mg, 0.35 mmol) was dissolved in DCM (10 mL), Et.sub.3N (48.8 μL, 0.35 mmol) was added and cooled to 0° C., Boc.sub.2O (152 mg, 0.70 mmol) was then added followed by DMAP (43 mg, 0.35 mmol) and stirred at 25° C. for 9 h. The reaction mixture was evaporated to dryness and subjected to SiO.sub.2 column chromatography (EtOAC-Et.sub.3N-petroleum ether, 5:2:93) to afford 8a (175 mg, 82%) as an oily syrup;

[0084] R.sub.f 0.76 (EtOAc-petroleum ether, 1:1); [α].sup.25.sub.D−49.53 (c 1.12, CHCl.sub.3); IR (CHCl.sub.3): ν.sub.max 3021, 2978, 2402, 2360, 1767, 1718, 1511, 1220, 1034, 789, 734, 670 cm.sup.−1; .sup.1H NMR (200 MHz, CDCl.sub.3): δ.sub.H 7.33-7.25 (m, 15H, ArH), 4.76-4.45 (m, 7H), 4.05-4.01 (dd, 1H, J=5.9, 2.4 Hz, 1H), 3.91-3.81 (m, 1H), 3.71-3.63 (m, 1H), 3.55-3.48 (m, 1H), 2.92-2.81 (dd, 1H, J=16.8, 5.1 Hz), 2.70-2.57 (dd, 1H, J=16.8, 8.7 Hz), 1.48 (s, 9H); .sup.13C NMR (50 MHz, CDCl.sub.3): δ.sub.C 169.6, 152.2, 137.8, 128.5, 128.0, 127.9, 127.8, 127.6, 83.4, 75.5, 73.2, 72.3, 71.6, 70.4, 59.0, 37.6, 28.0; ESI-MS: m/z 554.23 (M+Na).sup.+; HRMS: m/z calcd for C.sub.32H.sub.37NO.sub.6Na, 554.2513 (M+Na).sup.+, found 554.2513.

Example 2 (13)

Preparation of Tert-butyl (2R,3S,4S)-3,4-Bis(benzyloxy)-2-((benzyloxy)methyl)-6-oxopiperidine-1-carboxylate (8b)

[0085] Similarly 8b was obtained from 5b by following above-mentioned procedure. The crude reaction mixture was purified by SiO.sub.2 column chromatography (EtOAC-Et.sub.3N-petroleum ether, 5:2:93) to afford 8b as an oily syrup (143 mg, 79%);

[0086] R.sub.f 0.57 (EtOAc-petroleum ether, 1:1); [α].sup.25.sub.D+1.16 (c 1.14, CHCl.sub.3); IR (CHCl.sub.3): ν.sub.max 3014, 2362, 1741, 1707, 1657, 1516, 1265, 1033, 812, 759, 674 cm.sup.−1; .sup.1H NMR (200 MHz, CDCl.sub.3): δ.sub.H 7.34-7.24 (m, 15H), 4.86-4.46 (m, 6H), 4.40-4.30 (m, 1H), 4.16-4.13 (m, 1H), 3.92-3.85 (m, 2H), 3.77-3.69 (m, 1H), 3.02-2.89 (dd, 1H, J=17.2, 9.2 Hz), 2.77-2.66 (dd, 1H, J=17.2, 5.7 Hz), 1.45 (s, 9H); .sup.13C NMR (50 MHz, CDCl.sub.3): δ.sub.C 168.6, 152.5, 138.1, 138.0, 137.8, 128.5, 128.4, 128.0, 127.7, 127.5, 83.7, 73.7, 73.5, 73.3, 73.1, 71.4, 68.9, 57.1, 37.0, 27.8; ESI-MS: m/z 554.27 (M+Na).sup.+; HRMS: m/z calcd for C.sub.32H.sub.37NO.sub.6Na, 554.2513 (M+Na).sup.+, found 554.2521.

Example 2 (C)

Preparation of Tert-butyl (2R,3R)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-6-hydroxypiperidine-1-carboxylate (9a)

[0087] N-Boc protected lactam 8a (100 mg, 0.188 mmol) was dissolved in dry toluene (5.0 mL) and cooled to −76° C. under inert atmosphere, and superhydride (1.0 M in THF) (0.21 mL, 1.12 eq) was added slowly drop wise over a period of 10 min, and stirred at −76° C. for 1 h. Saturated NH.sub.4Cl soln (4.0 mL) was added and stirred further for 1.5 h at −76° C., and then temp was raised to room temperature 35° C. and stirred at room temperature 35° C. for 10 h. Reaction mixture was then treated with 10% Na.sub.2CO.sub.3 soln (4.0 mL) and DCM (10 mL) was added to the reaction mixture. The organic layer was separated, and the aq. layer was extracted with DCM (3×5 mL). All the organic layers were pooled together, dried (anhyd. Na.sub.2SO.sub.4), concentrated in vacuo and finally purified by SiO.sub.2 column chromatography (EtOAC-Et.sub.3N-petroleum ether, 5:1:44) to afford 9a as a viscous oil (94 mg, 94%);

[0088] R.sub.f 0.38 (EtOAc-petroleum ether, 3:7); [α].sup.25.sub.D−47.44 (c 1.21, CHCl.sub.3); IR (CHCl.sub.3): ν.sub.max 3741, 3019, 2362, 2334, 1692, 1531, 1216, 757, 695, 672 cm.sup.−1; .sup.1H NMR (200 MHz, CDCl.sub.3): δ.sub.H 7.30-7.25 (m, 15H), 5.64 (brs, 1H), 4.71-4.48 (m, 6H), 4.05-4.01 (m, 2H), 3.85-3.68 (m, 2H), 3.62-3.50 (m, 1H), 2.26-2.15 (m, 1H), 2.04-1.90 (m, 1H), 1.69 (brs, 1H), 1.46 (s, 9H); .sup.13C NMR (50 MHz, CDCl.sub.3): δ.sub.C 156.7, 138.2, 138.1, 137.5, 128.5, 128.4, 128.0, 127.7, 127.7, 127.5, 80.8, 77.3, 74.8, 73.2, 72.9, 71.7, 71.5, 30.9, 28.4; ESI-MS: m/z 556.27 (M+Na).sup.+; HRMS: m/z calcd for C.sub.32H.sub.39NO.sub.6Na, 556.2670, found 556.2670.

Example 2 (D)

Preparation of 3-DeoxyNojirimycin (10)

[0089] A mixture of 9a (100 mg, 0.19 mmol) and 10% aq. HCL (5 mL) in MeOH (5.0 ml) was stirred at 70° C. for 5 h. The reaction mixture was basified with 2M NaOH at 0° C. The resulting mixture was extracted with DCM (3×10 mL). The combined organic layers were pooled and dried (anhyd. Na.sub.2SO.sub.4) and concentrated in vacuo. The residue was dissolved in AcOH (2.5 ml) and 10% palladium on active charcoal (10 mg) was added at room temperature 25° C. and the mixture stirred overnight for 12 h under hydrogen gas. The reaction mixture was filtered through a celite pad and washed with MeOH (50 mL), the filtrate was concentrated in vacuo. The residue was dissolved in water (0.5 mL) and the solution was stirred at room temperature 25° C. with Amberlite IR-120 (H.sup.+) for 3 h. The suspension was eluted with water and then 0.5 M NH.sub.4Cl to furnish pure 3-deoxyNojirimycin (10) (17 mg, 56%).

Example 3 (A)

Preparation of Tert-butyl (2R,3R)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-3,4-dihydropyridine-1(2H)-carboxylate(11a)

[0090] N-Boc protected lactam 8a (136 mg, 0.26 mmol) was dissolved in dry toluene (3 mL) and cooled to −70° C. under inert atmosphere, and superhydride (1.0 M in THF) was added slowly drop wise over a period of 10 min, and stirred at −70° C. for 30 min. TFAA (0.31 mL, 2.2 mmol) was added followed by addition of DIPEA (1.5 mmol) and catalytic amount of DMAP. Temperature is then raised from −70° C. to room temperature 30° C. in 8 h and stirred further for 3 h at 25° C. Water was added (10 mL), organic layer was separated, washed with water (2×10 mL), dried (anhyd. Na.sub.2SO.sub.4), concentrated in vacuo and purified by SiO.sub.2 column chromatography (EtOAC-Et.sub.3N-petroleum ether, 3:2:95) to afford 11a as a viscous oil (119 mg, 90%);

[0091] R.sub.f 0.57 (EtOAc-petroleum ether, 1:1); [α].sup.25.sub.D−97.97 (c 1.10, CHCl.sub.3); IR (CHCl.sub.3): ν.sub.max 3739, 3426, 2362, 2334, 1645, 1547, 1365, 924, 800, 699 cm.sup.−1; .sup.1H NMR (500 MHz, CDCl.sub.3): δ.sub.H 7.35-7.24 (m, 15H), 7.11-6.93 (m, 1H), 5.10-4.90 (m, 1H), 4.74-4.56 (m, 3H), 4.52-4.39 (m, 4H), 4.19-4.13 (m, 1H), 3.86-3.57 (m, 3H), 1.54-1.49 (m, 9H); .sup.13C NMR (125 MHz, CDCl.sub.3, mixture of isomers): δ.sub.C 152.3, 138.8, 138.6, 138.3, 138.0, 128.6, 128.5, 128.4, 128.2, 127.7, 127.4, 127.3, 126.9, 126.6, 101.5, 81.5, 81.4, 77.9, 77.8, 75.6, 75.1, 73.1, 72.9, 72.9, 72.8, 72.7, 71.9, 71.5, 71.2, 71.1, 70.9, 70.7, 70.4, 70.2, 68.4, 66.9, 66.8, 66.5, 66.0, 53.3, 52.7, 50.8, 28.2, 28.1, 27.9; ESI-MS: m/z 538.27 (M+Na).sup.+; HRMS: m/z calcd for C.sub.32H.sub.37NO.sub.5Na, 538.2564, found 538.2564.

Example 3 (B)

Preparation of Tert-butyl (2R,3S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-3,4-dihydropyridine-1(2H)-carboxylate(11b)

[0092] Similarly 11b was obtained from 8b (283 mg, 0.533 mmol) by following the same procedure described above as a pale yellow viscous oil (238 mg, 87%) after purification by SiO.sub.2 column chromatography (EtOAC-Et.sub.3N-petroleum ether, 3:2:95);

[0093] R.sub.f 0.57 (EtOAc-petroleum ether, 1:1); [α].sup.25.sub.D-56.21 (c 1.13, CHCl.sub.3); IR (CHCl.sub.3): ν.sub.max 3740, 3620, 2362, 2334, 1647, 1547, 1367, 921, 821, 678 cm.sup.−1; .sup.1H NMR (200 MHz, CDCl.sub.3): δ.sub.H 8.29 (m, 1H), 7.35-7.22 (m, 15H), 4.89-4.77 (m, 2H), 4.70-4.61 (m, 3H), 4.52-4.29 (m, 2H), 3.99-3.95 (m, 2H), 3.85-3.73 (m, 1H), 3.64-3.44 (m, 1H), 1.48-1.46 (m, 9H); .sup.13C NMR (50 MHz, CDCl.sub.3): δ.sub.C 150.9, 138.8, 138.3, 137.5, 128.6, 128.5, 128.2, 128.1, 128.1, 127.7, 127.7, 127.6, 127.5, 127.4, 110.5, 75.6, 75.1, 72.9, 71.6, 68.5, 67.7, 63.8, 62.8, 58.0, 27.7; ESI-MS: m/z 538.08 (M+Na).sup.+; HRMS: m/z calcd for C.sub.32H.sub.37NO.sub.5Na, 538.2564, found 538.2565.

Example 4

tert-Butyl (2R,3R,5S,6S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5,6-dihydroxypiperidine-1-carboxylate (12a)

[0094] (DHQD).sub.2AQN (4.16 mg, 0.00485 mmol, 5 mol %), K.sub.3Fe(CN).sub.6 (96 mg, 0.291 mmol, 3 eq), K.sub.2CO.sub.3 (93.7 mg, 0.679 mmol, 70 eq), and K.sub.2OsO.sub.2(OH).sub.4 (2 mg, 0.00543 mmol, 5.59 mol %) were dissolved in tert-butyl alcohol and water (5 ml each) at room temperature 25° C. CH.sub.3SO.sub.2NH.sub.2 (18.43 mg, 0.194 mmol, 2.0 eq) was added. The solution was cooled to 0° C. and Boc-iminoglycal 11a was added (50 mg, 0.097 mmol). The mixture was stirred at 0° C. for 60 h. In the work up Na.sub.2SO.sub.3 (200 mg) was slowly added and the suspension was warmed to room temperature 25° C. with vigorous stirring. Ethyl acetate was added and the aq. layer was further extracted with EtOAc (2×5 ml), the combined organic layers were washed with 2M NaOH (20 ml). The combined organic layers were dried over Na.sub.2SO.sub.4 and concentrated in vacuo, which on preparative TLC separation (20% EtOAc-Pet ether) furnished 12a (38 mg, 30%), R.sub.f 0.23 (EtOAc-petroleum ether, 7:3); [α].sup.2′.sub.D−18.79 (c 1.15%, CHCl.sub.3); ν.sub.max (CHCl.sub.3)/cm.sup.−1, 667; δ.sub.H (200 MHz, CDCl.sub.3) 7.39-7.24 (m, 15H), 5.69-5.56 (m, 1H), 4.69-4.48 (m, 6H), 4.19-4.08 (m, 1H), 3.99-3.93 (m, 1H), 3.87-3.85 (m, 2H), 3.78-3.69 (m, 1H), 3.63-3.55 (m, 1H), 2.74 (brs, 1H), 1.79 (brs, 1H), 1.53-1.47 (m, 9H); δ.sub.C (50 MHz, CDCl.sub.3) 155.4, 138.2, 138.0, 137.7, 128.7, 128.6, 128.5, 128.4, 128.4, 128.3, 128.2, 128.1, 128.0, 128.0, 127.9, 127.7, 127.6, 81.7, 78.3, 77.2, 77.0, 73.1, 71.5, 70.0, 65.6, 28.3; ESI-MS: m/z 572.27 (M+Na).sup.+; HRMS: m/z calcd for C.sub.32H.sub.39NO.sub.7Na.sup.+ 572.2619, found 572.2621.

Example 5

Tert-Butyl (2R,3R,5R,6R)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5,6-dihydroxypiperidine-1-carboxylate (13a)

[0095] (DHQ).sub.2AQN (5.0 mg, 0.0058 mmol, 5 mol %), K.sub.3Fe(CN).sub.6 (118 mg, 0.358 mmol, 3 eq), K.sub.2CO.sub.3 (114 mg, 0.826 mmol, 70 eq), and K.sub.2OsO.sub.2(OH).sub.4 (2.5 mg, 0.0068 mmol, 5.59 mol %) were dissolved in tert-butyl alcohol and water (6 ml each) at room temperature 30° C. CH.sub.3SO.sub.2NH.sub.2 (23 mg, 0.242 mmol, 2.0 eq) was added. The solution was cooled to 0° C. and Boc-iminoglycal 11a was added (61 mg, 0.118 mmol). The mixture was stirred at 0° C. for 66 h. In the work up, Na.sub.2SO.sub.3 (200 mg) was slowly added and the suspension was warmed to room temperature 30° C. with vigorous stirring. EtOAc was added and the aq layer was further extracted with ethyl acetate (2×5 ml), the combined organic layers were washed with 2M NaOH (20 ml). The combined org layers were dried over Na.sub.2SO.sub.4 and concentrated in vacuo, which on preparative TLC separation (EtOAc-petroleum ether, 7:3) furnished 13a (20 mg, 71%), R.sub.f 0.21 (EtOAc-petroleum ether, 7:3); [α].sup.25.sub.D−13.33 (c 1.1%, CHCl.sub.3); ν.sub.max (CHCl.sub.3)/cm.sup.−1 3443, 3064, 2927, 2859, 2362, 2334, 1690, 1499, 1368, 1086, 757, 699, 669; δ.sub.H (200 MHz, CDCl.sub.3) 7.35-7.26 (m, 15H), 5.65-5.52 (m, 1H), 4.70-4.41 (m, 6H), 4.24-4.04 (m, 1H), 3.95-3.89 (m, 1H), 3.85-3.80 (m, 1H), 3.75-3.63 (m, 2H), 3.58-3.45 (m, 1H), 2.68 (brs, 1H), 1.68 (brs, 1H), 1.48-1.40 (m, 9H); δ.sub.C (50 MHz, CDCl.sub.3) 154.1, 138.1, 137.5, 137.4, 128.7, 128.6, 128.5, 128.5, 128.3, 128.3, 128.2, 128.1, 128.0, 127.9, 127.8, 127.6, 81.7, 81.4, 78.6, 77.3, 75.3, 73.4, 72.5, 64.2, 61.4, 28.4; ESI-MS: m/z 572.26 (M+Na).sup.+; HRMS: m/z calcd for C.sub.32H.sub.39NO.sub.7Na.sup.+572.2619, found 572.2619.

Advantages of Invention

[0096] Novel route of synthesis of alkaloids [0097] Provides reasonable good yields [0098] Piperidine alkaloids are not known to be synthesized from gluconolactone [0099] Other methods of synthesis are known, but this process is shorter, enantiomeric tuning is possible depending on starting enantiomer used.