WO2015170339A1

WO2015170339A1 - A process for synthesis of piperidine alkaloids

Info

Publication number: WO2015170339A1
Application number: PCT/IN2015/000196
Authority: WO
Inventors: Asish Kumar Bhattacharya; Hemender Rami CHAND
Original assignee: Council of Scientific and Industrial Research CSIR
Current assignee: Council of Scientific and Industrial Research CSIR
Priority date: 2014-05-09
Filing date: 2015-05-05
Publication date: 2015-11-12
Anticipated expiration: 2016-11-09
Also published as: US9834515B2; US20170267636A1

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.

Description

A PROCESS FOR SYNTHESIS OF PIPERIDINE ALKALOIDS

FIELD OF THE INVENTION

|0001} The present invention relates to a process for synthesis of piperidine alkaloids. Particularly, present invention relates to a process for synthesis of piperidine alkaloids selected from fagomine, 4-e/?/-fagomine and nojirimycin.

BACKGROUND AND PRIOR ART OF THE INVENTION

[0002] Polyhydroxylated piperidines and their synthetic analogues have attracted a great deal of attention in recent years due to their ability to mimic sugars, and competitively and selectively inhibit glycosidases and glycosyltransferases, the carbohydrate processing enzymes. These attributes make hydroxylated piperidines (azasugars) likely therapeutic agents for the treatment of diseases related to metabolic disorders involving carbohydrates such as diabetes, cancer, AIDS, and viral infections, where glycoprotein processing is crucial. Recently three fagomine and some of its isomers were found from Xanthocercis zambesiaca occurring in southern Africa in dry forest. Among them, fagomine and 3-e ?/-fagomine have been shown to have activity against mammalian a- glucosidase and β-galactosidase. More recently fagomine was found to have a potent antihyperglycaemic effect in streptozocin-induced diabetic mice and a potentiation of glucose-induced insulin secretion.

Nojirimycin Adenophorine 5-Deoxyadenophorine β-1-C-butyl-deoxy- galactonojirimycin

-tr y roxyp per ne

Figure 1. Some glycosidase or galactosidase inhibitors belonging to piperidine class of alkaloid. [0003] Glycals, carbohydrates incorporating a double bond between C- l and C-2, have emerged as powerful building blocks in synthetic chemistry especially in the context of oligosaccharide assembly. In light of this fact, it is perhaps surprising that the synthesis and chemistry of imino glycals, glycals in which the ring oxygen atom is replaced by nitrogen, has not been explored in a systematic fashion. Such compounds should participate in a diverse range of reactions (e.g. addition and cycloadditions reactions, metal catalyzed cross-couplings), and thus provide access to many potentially useful classes of imino sugars which are of interest because of their ability to influence a variety of biological processes by the inhibition of the glycosidase enzymes. Furthermore, imino glycals might serve as precursors to various glycosyl donors which could be used to make oligosaccharides incorporating nitrogen atoms, another area of current interest.

[0004] Article titled "Stereoselective synthesis and biological evaluation of D-fagomine, D-3-epi-fagomine and D-3,4-epi-fagomine analogs from D-glyceraldehyde acetonide as a common building block" by JA Diez et al. Published in Org Biomol Chem., 2012; 10(46), pp 9278-86 reports synthesis involves diastereoselective anti-vinylation of its homoallylimine, ring-closing metathesis, and stereoselective epoxidation followed by regioselective ring-opening or stereoselective dihydroxylation.

[0005] Article titled "Efficient and stereodivergent syntheses of D- and L-fagomines and their analogues" by N Kumari et al. published in European Journal of Organic Chemistry, 2009, 2009 ( 1 ), pp 160-169 reports the synthesis of d- and l-fagomines 1 , 4, 5 and 6 and their isomers from starting d-glycals. The syntheses involve elaboration of common amino alcohol precursors obtained from 2-deoxy- l -amino sugar derivatives. The key steps in the synthesis are intramolecular reductive amination and intramolecular N-heterocyclization.

[0006] Article titled "A divergent synthesis of 4-epi-fagomine, 3, 4-dihydroxypipecolic acid, and a dihydroxyindolizidine and their beta-galactosidase inhibitory and immunomodulatory activities" by KS Kumar et al. published in J Org Chem., 2013, 78(15), pp 7406- 13 reports a divergent asymmetric synthesis of the iminosugars starting from a chiral homoallyl alcohol as the versatile intermediate. The homoallyl alcohol is prepared by a highly diastereoselective Barbier reaction on a D-glucose-derived aldehyde. The protection of hydroxyl function followed by reductive ozonolysts of the olefin and a subsequent one-pot three-step protocol involving a Staudinger reaction, reductive animation, and benzyloxy carbonyl protection yielded an important bicyclic furanopiperidine derivative.

[0007] Article titled "A synthesis of 2-epi-fagomine using gold (l)-catalyzed allene cyclisation" by Bates et al. published in a synthesis of 2-epi-fagomine via a highly stereoselective gold(I)-catalyzed allene cyclisation . A highly stereoselective Au(I)- catalyzed cyclization of allene (IV) is the key step in the synthesis of 2-epi-fagomine (VI).

[0008] Article titled "General synthesis and biological evaluation of alpha- 1 -C- substituted derivatives of fagomine (2-deoxynojirimycin-alpha-C-glycosides)" by JY Goujon et al. published in Bioorg Med Chem., 2005, 13(6), pp 2313-24 reports a general synthesis of alpha- 1 -C-substituted derivatives of fagomine (2-deoxynojirimycin-alpha-C- glycosides) by ring-opening reactions of an aziridine with various heteroatomic nucleophiles, including thiol, amine, alcohol, carboxylate and phosphate. This nine-step reaction sequence proceeded in an overall yield of 14-28% from tri-O-benzyl-D-glucal.

[0009] Article titled "Chemistry of imino glycals: preparation and application to the synthesis of (+)-fagomine" by J Desire et al. published in Synlett, 2001 , 2001 (8), 1329- 1331 reports the synthesis of imino glucal from tri-O-benzyl-D-glucal in 8 steps. This novel imino sugar building block is further converted into (+)-fagomine by a two-step hydrogenation sequence.

[0010] The prior art processes had many drawbacks such as poor yield and longer reaction sequence. Therefore there is need in the art to develop a shorter process for the preparation of piperidine alkaloids selected from (+)-fagomine, 4-e/>/-fagomine and nojirimycin with better yield.

OBJECTIVE OF INVENTION

[0011] The main objective of the present invention is to provide a process for the synthesis of piperidine alkaloids from glucal or galactal.

[0012] Another objective of the present invention is to provide a process for the synthesis of (+)-fagomine, 4-e ? -fagomine and 3-deoxynoj irimycin from glucal or galactal.

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:

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 fford 5-5-hydroxy amide 2);

1a R₁=R₂=H, R₃= OBn, R₄= H 2a R₁=R₂=H, R₃= OBn, R₄= H

1 b R₁=R₂=H, R₃= H, R₄= OBn 2b R₁=R₂=H, R₃= H, R₄= OBn

stirring a solution of compound 2 as obtained in step (a) in DMSO and Ac₂0 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);

3a R₁=R₂=H, R₃= OBn, R₄= H

3b R₁=R₂=H, R₃= H, R₄= OBn

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);

5a R₁ =R₂=H, R₃= OBn, R₄= H

5b R₁ =R₂=H, R₃= H, R₄= OBn

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 4h at temperature in the range of 65 to 70°C and purification to afford protected piperidine compound (6);

6a R₁ =R₂=H, R₃= OBn, R₄= H

6b R₁=R₂=H, R₃= H, R₄= OBn

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);

7a R₁=R₂=H, R₃= OH, R₄= H, (+)-Fagomine

7b R₁ =R₂=R₃= H, R₄= OH, 4-ep/^'-Fagomine

adding Et₃N to a solution of glycolactam (5) as obtained in step (c) in dichloromethane followed by cooling to 0°C and further adding Boc₂0, DMAP followed by stirring at temperature in the range of 20 to 25°C for

8 peri in the range of 8 to 9 h to afford N-Boc protected lactam (8);

8a R₁ =R₂=H, R₃= OBn, R₄= H

8b R₁=R₂=H, R₃= H, R₄= OBn

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 ran e of 9 to 10 h at room temperature to afford lactamol compound 9a;

9a R₁=R₂=H, R₃= OBn, R₄= H

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

( 10a).

10a R-,=R₂=H, R₃= OH, R₄= H

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 DMA P and purification to afford Boc-iminoglycal ( l l a/1 l b);

adding Boc-iminoglycal ( 1 1 a) to a solution of (DHQ)₂AQN, ₃Fe(CN)₆, K₂C0₃, K₂Os0₂(OH)₄ and CH₃S0₂NH₂ in r/-butyl alcohol and water cooled at 0°C fol lowed by stirring the mixture at 0°C for 60 to 66 h to afford iminoglycal compound ( 12a); k) The process as claimed in any of the preceding claims, wherein said process may also comprises adding Boc-iminoglycal ( 1 1 a) to a solution of (DHQD)₂AQN, K₃Fe(CN)₆, ₂C0₃, K₂Os0₂(OH)₄ and CH₃S0₂NH₂ 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 iminogiycal compound( 13a).

[0017] In an embodiment of the present invention, the piperidine alkaloids are (+)- fagominc (7a), 4-e/?/-fagomine(7b), 3-deoxynojirimycin ( 10a).

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

[0018] 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 ( 1 l a/ 1 l b).

[0019] 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- l (2H)- carboxylate ( 1 1 a), tert-butyl (2R,3S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-3,4- dihydropyridine- 1 (2H)-carboxylate( 1 1 b).

[0020] In yet another embodiment of the present invention, said process may also comprise adding Boc-iminoglycal (1 l a/1 l b) to a solution of (DHQ)₂AQN, K₃Fe(CN)₆, 2C0₃, K₂Os0₂(OH)₄ and CH₃S0₂NH₂ in tert-buly\ alcohol and water cooled at 0°C followed by stirring the mixture at 0°C for 60 to 66 h to afford iminogiycal compound ( 12).

[0021] In yet another embodiment of the present invention, said process may also comprises adding Boc-iminoglycal ( 1 1 a) to a solution of (DHQD)₂AQN, K₃Fe(CN)₆, 2C0₃, ₂Os0₂(OH)₄ and CH₃S0₂NH₂ in /eri-butyl alcohol and water cooled at 0°C followed by stirring the mixture at 0°C for 60 to 66 h to afford iminogiycal compound( 13a).

[0022] In yet another embodiment of the present invention, the iminogiycal compound is /i_?r/-Butyl (2R, J/?,J7?, (5 ?)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5,6-dihydroxy- piperidine- 1 -carboxy late ( 12a) or /<?r/-Butyl (2 ?,3/?,55,65 -3,4-bis(benzyloxy)-2- ((benzyloxy)methyl)-5,6-dihydroxypiperidine- l -carboxylate ( 1 3a).

DETAILED DESCRIPTION OF THE INVENTION

[0023] Present invention provides a process for the synthesis of piperidine alkaloids starting from glucal or galactal.

[0024] In an aspect, the present invention provides a process for the synthesis of (+)- fagomine and 4-e/?/-fagomine starting from glucal or galactal.

[0025] In another aspect, the present invention provides a process for the synthesis of 3- deoxynojirimycin starting from glucal or galactal.

[0026] The present invention provides a process for the synthesis of piperidine alkaloids selected from (+)-fagomine and 4-e^ -fagomine in 14% and 6% overall yields and the said process comprising the steps of:

a) dissolving gluconolactone compound(l a/l b) in methanolic ammonia solution followed by stirring at room temperature in the range of 20 to 35°C for 6h under nitrogen atmosphere to afford δ-hydroxy amide (2a/2b);

b) stirring a solution of compound of step (a) in DMSO and Ac₂0 at room temperature in the range of 20 to 35°C for 23h under nitrogen atmosphere followed by addition of water to obtain a yellow oil precipitate of δ-keto amide (3a/3b);

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);

d) adding lithium aluminium hydride to a solution of compound of step (c) in tetrahydrofuran followed by stirring the reaction mixture for 4h at 70 °C under nitrogen atmosphere and purification to afford protected piperidine compound (6a/6b) as a yellow syrup;

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-e -fagomine (7b). [0027] 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).

[0028] The compounds formed in step (b) are (3 ?,4S)-3,4,6-Tris(benzyloxy)-5- oxohexanamide(3a) and (3R,4R)-3,4,6-Tris(benzyloxy)-5-oxohexanamide(3b).

[0029] 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).

[0030] 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).

[0031] 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:

a) dissolving gluconolactone compound ( l a/l b) in methanolic ammonia solution followed by stirring at room temperature in the range of 20 to 35°C for 1.5h under nitrogen atmosphere to afford δ-hydroxy amide (2a/2b);

b) stirring a solution of compound of step (a) in DMSO and Ac₂0 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);

adding Et3N to a solution of glycolactam (5a/5b) of step (c) in dichloromethane followed by cooling to 0°C and further adding Boc20, DMAP followed by stirring at 25°C for 9 h to afford N-Boc protected lactam

(8a/8b);

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): f) stirring a mixture of compound of step (e) and HCL in methanol at 70°C for 5h followed by basifying the reaction mixture to afford 3-deoxyNoj irimycin ( 10).

[0032] 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- l - carboxylate(8a), 7er/-butyl (2R,3S,4S)-3,4-Bis(benzyloxy)-2-((benzyloxy)methyl)-6- oxopiperidine- 1 -carboxylate(8b).

[0033] The carboxylate compound formed in step (e) is tert-butyl (2R,3R)-3,4- bis(benzyloxy)-2-((benzyloxy)methyl)-6-hydroxypiperidine- l -carboxylate(9a).

[0034] The present invention provides a process for the synthesis of piperidine alkaloids (imino giycals) comprising the steps of:

a) dissolving gluconolactone compound (la/l b) in methanolic ammonia solution followed by stirring at room temperature for 1.5h under nitrogen atmosphere to afford δ-hydroxy amide (2a/2b);

b) stirring a solution of compound of step (a) in DMSO and Ac₂0 at room temperature for 23 h under nitrogen atmosphere followed by addition of water to obtain a yellow oil precipitate of δ-keto amide (3a/3b); 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);

d) adding Et₃N to a solution of glycolactam (5a/5b) of step (c) in dichloromethane followed by cooling to 0°C and further adding Boc₂0, DMAP followed by stirring at 25°C for 9 h to afford N-Boc protected lactam (8a/8b);

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 ( 1 l a/1 l b).

adding Boc-iminoglycai ( 1 1 a) to a solution of (DHQ)₂AQN, ₃Fe(CN)₆, 2C0₃, ₂Os0₂(OH)₄ and CH₃S0₂NH₂ in /er/-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).

g) adding Boc-iminoglycal ( 1 l a) to a solution of (DHQD)₂AQN, K₃Fe(CN)₆, K₂C0₃, K₂Os0₂(OH)₄ and CH₃S0₂NH₂ in /er/-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).

[0035] The Boc-iminoglycal formed in step (e) is tert-butyl (2R,3R)-3,4-bis(benzyIoxy)- 2-((benzyloxy)methyl)-3,4-dihydropyridine- l (2H)-carboxylate ( 1 1 a), Tert-butyl (2R,3S)- 3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-3,4-dihydropyridine- l (2H)-carboxylate( l l b).

[0036] The iminoglycal compound is ter/-Butyl (2R,3R,5R,

((benzyloxy)methyl)-5,6-dihydroxypiperidine- l -carboxylate ( 12a) or ter/-Butyl (2R, 3R,5S, (5S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5, 6-dihydroxypiperidine- 1 - carboxy!ate( 13a).

Examples

[0037] 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-£/? -fagomine

Example 1 (A)

[0038] Preparation of (3R,4R)-3,4,6-Tris(benzyloxy)-5-hydroxyhexanamide (2a)

Gluconolactone la ( 1 .393 g, 2.32 mmol) was dissolved in methanolic ammonia soln. (7N, 22 mL) and was stirred at room temperature 25°C for 6h. After completion of the reaction (TLC), reaction mixture was concentrated in vacuo followed by purification by Si0₂ column chromatography (EtOAc-petroleum ether, 6:4) to afford 2a (859 mg, 82%) as colorless solid; mp 74-76°C.

Rf 0.26 (EtOAc-petroleum ether, 1 : 1 ); [a]²⁰ _u + 14.27 (c 1 .43, CHCI₃); IR (CHC1₃): i>_max 3374, 3201 , 3012, 2869, 1673, 1615, 1404, 1216, 1072, 1028, 908, 747, 698, 667 cm^{" 1} ; Ή NMR (200 MHz, CDC1₃, assignment by COSY, HSQC and HMBC experiments): δ_Η 7.33-7.24 (m, 15H, ArH), 5.76 (bs, 1 Η, NH), 5.45 (bd, 1 Η, NH), 4.61 -4.47 (m, 6Η, Ph- CH₂), 4.3 1 -4.23 (m, 1 Η, Η-3), 3.99-3.92 (m, 1 Η, Η-5), 3.67-3.62 (m, 3Η, Η-4, Η-6), 3.14 (bs, 1 Η, OH), 2.52-2.57 (m, 2Η, H-2); δ_Γ ( 100 MHz, CDCI3) 1 73.5 (q, C- l ) 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, -OCH₂Ph), 73.4 (d, 2C, C-6,-OCH₂Ph), 71 .2 (d, -OCH₂Ph), 70.8 (s, C-5), 37.3 (d, C-2); ES1-MS: m/z 450.2240 (M+H)⁺; HRMS: m/z calcd for C₂₇H₃ i 0₅ 449.22022, found 449.20571.

Example 1 (B)

[0039] Preparation of (3/?,45)-3,4,6-tris(benzyloxy)-5-hydroxyhexanamide(2b)

Galactonolactone lb (2.0 g, 4.65 mmol) was dissolved in methanolic ammonia soln. (7N, 25 mL) and stirred at room temperature 27°C for 1 l h under nitrogen atmosphere. After completion of the reaction (TLC), reaction mixture was concentrated in vacuo to furnish a crude which was purified by Si0₂ column chromatography (EtOAc-petroleum ether, 1 : 1 ) to afford 2b ( 1 .997 g, 96%) as yellowish gum.

R{ 0.19 (EtOAc-petroleum ether, 1 : 1 ); [ ]²⁰ _D+2.92 (c 1 .2, CHC1₃); IR (CHCI₃): ½_ax 3660, 3372,3019, 2872, 1736, 1454, 1216, 1 101 , 1064, 908, 755, 698, 668 cm^"1 ; Ή NMR (200 MHz, CDC1₃, assignment by COSY, HSQC and HMBC experiments, D₂0 exchange): δ_Η 7.33-7.25 (m, 15H, ArH), 6.00 (bs, 1 H, NH), 5.51 (bs, 1Η, NH), 4.79-4.48 (m, 6Η, PhCH₂), 4.18-4.10 (m, 1 Η, Η-3), 3.95 (bs, 1 Η, Η-4), 3.76-3.72 (m, 1 Η, Η-5), 3.60-3.44 (m, 2Η, Η-6), 2.83 (bs, 1 Η, OH), 2.68-2.47 (m, 2Η, H-2); ¹³C NMR (50 MHz, CDC1₃):6_C 1 73.6 (q, C- l ), 137.8, 1 37.7 (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, PhCH₂, C-6), 69.9 (s, C-5), 37.7 (d, C-2); ESI- MS: m/z 450.4348 (M+H)⁺, 472.41 1 5 (M+Na)⁺, 487.5341 (M+ )⁺; HRMS: m/z calcd for C₂₇H₃,N0₅449.22022, found 449.20571 .

Example 1 (C)

[0040] Preparation of (3A,4S)-3,4,6-Tris(benzyIoxy)-5-oxohexanamide (3a)

A solution of 2a (1 .105 g, 2.5 mmol) in DMSO ( 1 1 mL) and Ac₂0 (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 (3x 50 mL). The residue was dissolved in DCM (25 mL) and extracted with brine (2x50 mL). The organic layers were dried (anhyd. Na₂S0₄) and concentrated in vacuo to afford crude 3a (59%). The crude obtained was used as such for the next step.

Example 1 (D) [0041] Preparation of (3/?,4/?)-3,4,6-Tris(benzyloxy)-5-oxohexanamide(3b)

A solution of 2b ( 1.105 g, 2.5 mmol) in DMSO ( 1 1 mL) and Ac₂0 (6.7 mL) was stirred under nitrogen atmosphere for 26 hours at room temperature 22°C. H₂0 (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 (3x 50 mL). The residue was dissolved in DCM (25 mL) and extracted with brine (2x 50 mL). The organic fractions were dried (anhyd. Na₂S0₄) and concentrated in vacuo to afford crude 3b (24%). The crude obtained was used as such for the next step.

Example 1 (E)

[0042] Preparation of (5R,6R)-4,5-Bis(benzyloxy)-6-(benzyloxymethyl)piperidin-2- one(5a)

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 NaCNBH₃ ( 1 77 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. HC1 solution (0.1 N, 30 mL). After stirring for another 15 minutes, EtOAc (50 mL) and then saturated aq. NaHC0₃ solutions (50 mL) were added to it. The water layer was separated and extracted with EtOAc (2 x 25 mL), the combined organic fractions were pooled and then washed with brine ( 1 x 30 mL) and dried (anhyd. Na₂S0₄). After concentration in vacuo, the resulting crude was purified by Si0₂column 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/0.32 (EtOAc-petroleum ether, 1 : 1 ); [ ]²⁰ _D+16.78 (el .02, CHCI3); 1R (CHCI3): D_max 3396, 3019, 2868, 1666, 1455, 1215, 1 100, 755, 699, 669 cm ¹ ; Ή NMR (200 MHz, CDC1₃):6_H 7.39-7.21 (m, 15H, ArH), 6.16 (bs, 1 Η, NH), 4.84-4.46 (m, 6Η, PhCH₂), 3.94-3.84 (m, 1Η, Η-6), 3.69-3.49 (m, 3Η, Η-6, Η-3, Η-4), 3.41 -3.32 (m, 1 Η, Η-5), 2.86-2.42 (m, 2Η, H-2); ¹³C NMR (50 MHz, CDC1₃):5_C 169.6 (q, C- l , C=0), 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, -CH₂Ph), 71 .0 (d, C-6), 54.8 (s, C-5), 35.2 (d, C- 2); ESI-MS : m/z 432.7864 (M+H)⁺, 454.5697 (M+Na)⁺, 470.7429 (M+ )⁺; HR S:m/z calcd for C₂₇H₃oN0₄432.2166, found 432.2169.

Example 1 (F) [0043] Preparation of (5S,6/f)-4,5-Bis(benzyIoxy)-6-(benzyloxymethyl)piperidin-2- one (5b)

Compound 3b (437 mg, 1 mmol) was dissolved in a mixture of MeCN ( 15 mL) and HCOOH (3.0 mL). To this mixture, NaCNBH₃ ( 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. HC1 solution (0.1 N, 30 mL). After stirring for another 15 minutes, EtOAc (50 mL) and then saturated aq. NaHC0₃ solutions (50 mL) were added to it. The water layer was separated and extracted with EtOAc (2 x 25 mL), the combined organic fractions were pooled and then washed with brine ( 1 x 30 mL) and dried (anhyd. Na₂S0₄). After concentration in vacuo, the resulting crude was purified by Si0₂column chromatography (EtOAc-petroleum ether, 4:6) to afford a colorless semi-solid 5b (250 mg 59%).

R_f 0.21 (EtOAc-petroleum ether); [a]²⁰ _D +29.43 (cl . l , CHC1₃); IR (CHC1₃): o>_max 3395, 3017, 2926, 1663, 1454, 1216, 1 1 14, 756, 698, 668 cm^"1 ; Ή NMR (200 MHz, CDCi₃): δ_Η 7.40-7.25 (m, 15H, ArH), 6.06 (bs, 1H, NH) 4.97-4.39 (m, 6H, PhCH₂), 4.00 (bs, 1 Η, Η-4), 3.89-3.79 (ddd, 1 H, 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); ¹³C NMR (50 MHz, CDCI₃):5_C 170.2 (q, C-l ), 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, PhCH₂, C-6), 54.9 (s, C-5), 33.7 (d, C-2); ES1-MS: m/z 432.3909 (M+H)⁺, 454.3993 (M+Na)⁺, 470.3436 (M+ )⁺; HRMS: m/z calcd for C₂₇H₂₉N0₄432.2169, found 432.2170.

Example 1 (G)

[0044] Preparation of (2fl,3i?,4/i)-3,4-Bis(benzyloxy)-2-

(benzyloxymethyl)piperidine(6a)

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 4h 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 1 0 minutes. The water layer was then separated and extracted with diethyl ether (3 x 50 mL), the organic fractions were pooled, washed with brine and finally dried (anhyd. Na₂S0₄) and concentrated in vacuo. The crude product was purified by SiC^column chromatography (EtOAc-petroleum ether, I : I) to afford 6a (120 mg, 49%) as a yeliow syrup;

R( 0.12(EtOAc-petroleum ether, 1:1); [a]²⁰ _D +21.76 (c 1.1, CHC1₃); 1R (CHCI₃):i 3151, 3017, 2922, 1398, 1220, 1099, 772, 669, 615cm-'; Ή NMR (200 MHz, CDC1₃):5„7.38-7.21 (m, 15H, ArH), 4.98-4.47 (m, 6Η, PhCH₂), 3.76-3.73 (dd, 1Η, J = 2.5, 9.0 Hz, H-6_a), 3.62-3.52 (m, 2H, H-6_b, H-3), 3.39-3.34 (t, 1H, J= 9.0 Hz, H-4), 3.10- 3.05 (ddd, 1I1,J= 1.8,2.3, 12.6 Hz, H-l_a), 2.76-2.71 (m, 1H, H-5), 2.62-2.56 (dt, 1H,J = 12.6, 2.3 Hz, H-l_b), 2.34 (bs, 1H, NH), 2.20-2.14 (m, 1H, H-2_a), 1.57-1.50 (m, 1H, H-2_b); ^,3C NMR (50 MHz, CDC1₃): 5_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, PhCH₂), 70.7 (d, C-6), 60.1 (s, C-5), 43.6 (d, C-l), 32.1 (d, C-2); ES1-MS: m/z 418.4191 (M+H)⁺; HRMS: m/z ca!cd for C₂₇H₃iN0₃418.2377, found 418.2378.

Example 1 (H)

[0045] Preparation of (2/f,354/i)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)piperidine (6b)

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 2h 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 x 50 mL), the organic fractions were pooled and washed with brine (1 x 30 mL) and dried (anhyd. Na₂S0₄). After concentration in vacuo, the reaction mixture was purified by Si0₂column chromatography (EtO Ac-petroleum ether, 1:1) to afford 6b (95 mg, 41%) as a yellow syrup;

Rf.\2 (EtOAc-petroleum ether); [a °_D -4.07 (c 1.0, CHC1₃); IR (CHC1₃): O_max 3302, 3089, 3066, 3019, 2929, 1455, 1365, 1216, 1088, 751, 699, 669 cm^"'; Ή NMR (400 MHz, CDC1₃): δ_Η 7.40-7.28 (m, 15H, ArH), 5.01-4.46 (m, 6Η, PhCH₂), 3.98 (bs, 1Η, Η- 4), 3.59-3.55 (m,lH, H-6_a), 3.53-3.49 (m,lH, H-3), 3.48-3.44 (t, 1H,J= 8.5, 7.8 Hz, H- 6_b), 3.32 (1H, bs, NH), 3.17-3.13 (dd, 1H,J= 13.3, 2.0 Hz, H-l_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-l_b), 2.05-1.94 (m, 1H, H-2_a), 1 .86- 1.83 (dd, 1 H, J = 12.4, 2.2 Hz, H-2_h); ^{1 3}C NMR ( 100 MHz, CDC1₃): 5_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, PhCH₂), 73.3 (s, C-4), 70.4 (d, C-6), 58.8 (s, C-5), 44.2 (d, C- l ), 27.7 (d, C-2); ESI-MS: m/z 418.0585 (M+H)⁺; HRMS: m/z calcd for C27I I32NO3 418.2377, found 41 8.2377. Example 1 (I)

[0046] Preparation of (+)-Fagomine (7a)

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 12h 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⁺) for 3h. The suspension was eluted with water and then 0.5 M NH4CI to furnish pure (+)-fagomine (7a) (3 1 mg, 87%), which was identified on the basis of comparison with reported spectral data.

Example 1 (J)

[0047] Preparation of 4-epi-Fagominc (7b)

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)

[0048] Preparation of Tert-buty\ (2R,3R,4S)-3,4-bis(benzyloxy)-2-

((benzyIoxy)methyl)-6-oxopiperidine-l-carboxylate (8a)

Glycolactam 5a ( 150 mg, 0.35 mmol) was dissolved in DCM (10 mL), Et₃N (48.8 μί, 0.35 mmol) was added and cooled to 0°C, Boc₂0 ( 152 mg, 0.70 mmol) was then added followed by DMAP (43 mg, 0.35 mmol) and stirred at 25°C for 9h. The reaction mixture was evaporated to dryness and subjected to Si0₂ column chromatography (EtOAC-Et₃N- petroleum ether, 5:2:93) to afford 8a ( 175 mg, 82%) as an oily syrup;

R_{ 0.76 (EtOAc-petroleum ether, 1 : 1 ); [a]²⁵ _D -49.53 (c 1 .12, CHCI3); 1R (CHCI3): D_max 3021 , 2978, 2402, 2360, 1767, 1 71 8, 1 5 1 1 , 1 220, 1034, 789, 734, 670 cm^{" 1} ; Ή NMR (200 MHz, CDCI3): δ_Η 7.33-7.25 (m, 1 5H, ArH), 4.76-4.45 (m, 7H), 4.05-4.01 (dd, 1 H, = 5.9, 2.4Hz, 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); ⁱ³C NMR (50 MHz, CDCI,): 5c 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)⁺; HRMS: m/z calcd for C₃₂H₃₇N0₆Na 554.2513 (M+Na)⁺, found 554.2513.

Example 2 (B)

[0049] Preparation of Tert-bu \ (2 ,jS, S 3,4-Bis(benzyloxy)-2-

((benzyIoxy)methyl)-6-oxopiperidine-l-carboxylate (8b)

Similarly 8b was obtained from 5b by following above-mentioned procedure. The crude reaction mixture was purified by Si0₂ column chromatography (EtOAC-Et₃N-petroleum ether, 5:2:93) to afford 8b as an oily syrup (143 mg, 79%);

R_f 0.57 (EtOAc-petroleum ether, 1:1); [a]²⁵ _D +1.16 (c 1.14, CHC1₃); IR (CHC1₃): υ_1(13Χ 3014, 2362, 1741, 1707, 1657, 1516, 1265, 1033, 812, 759, 674 cm^"1; Ή NMR (200 MHz, CDCI₃): δ_Η 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,lH), 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); ^l3C NMR (50 MHz, CDC1₃): 5_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)⁺; HRMS: m/z calcd for C₃₂H₃₇N0₆Na 554.2513 (M+Na)⁺, found 554.2521.

Example 2 (C)

[0050] Preparation of 7er/-butyl (2R,5/?)-3,4-bis(benzyIoxy)-2-((benzyloxy)methyl)- 6-hydroxypiperidine-l-carboxylate (9a)

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 NH₄C1 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% Na₂C0₃Soln (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 x 5 mL). All the organic layers were pooled together, dried (anhyd. Na₂S0₄), concentrated in vacuo and finally purified by Si0₂column chromatography (EtOAC-El₃N-petroleum ether, 5 : 1 :44) to afford 9a as a viscous oil (94 mg, 94%);

R_t 0.38 (EtOAc-petroleum ether, 3 :7); [a]²⁵ _D -47.44 (c l .21 , CHC1₃); 1R (CHC1₃): u_max 3741 , 3019, 2362, 2334, 1692, 153 1 , 12 16, 757, 695, 672 cm^"1; ^JH NMR (200 MHz, CDC1₃): 8_H 7.30-7.25 (m, 15H), 5.64 (brs, 1 H), 4.71 -4.48 (m, 6H), 4.05-4.01 (m, 2H), 3.85-3.68 (m, 211), 3.62-3.50 (m, 1 H), 2.26-2.15 (m, 1 H), 2.04- 1 .90 (m, 1 H), 1.69 (brs, 1 H), 1 .46 (s, 9H); ¹³C NMR (50 MHz, CDC1₃): 6_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)⁺; HRMS: m/z calcd for C₃₂H₃₉N0₆Na 556.2670, found 556.2670.

Example 2 (D)

[0051] Preparation of 3-DeoxyNojirimycin (10)

A mixture of 9a ( 1 00 mg, 0. 1 9 mmol) and 10% aq. HCL (5 mL) in MeOH (5.0 ml) was stirred at 70 °C for 5h. The reaction mixture was basified with 2M NaOH at 0 °C. The resulting mixture was extracted with DCM (3 x 10 mL). The combined organic layers were pooled and dried (anhyd. Na₂S0₄) 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 12h 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⁺) for 3h. The suspension was eluted with water and then 0.5 M NH₄C1 to furnish pure 3- deoxyNojirimycin (10) ( 1 7 mg, 56%).

Example 3 (A)

[0052] Preparation of 7er/-butyl (2R,3/?)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)- 3,4-dihydropyridine-l(2H)-carboxyIate(l la)

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 1 0 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 8h and stirred further for 3h at 25°C. Water was added (10 mL), organic layer was separated, washed with water (2x 10 mL), dried (anhyd. Na₂S0₄), concentrated in vacuo and purified by Si0₂ column chromatography (EtOAC-Et₃N-petroleum ether, 3:2:95) to afford 11a as a viscous oil (119 mg, 90%);

R_f 0.57 (EtOAc-petroleum ether, 1:1); [oc]²⁵ _D -97.97 (cl.10, CHC1₃); IR (CHC1₃): i>_max

3739, 3426, 2362, 2334, 1645, 1547, 1365, 924, 800, 699 cm^-1; ^]H NMR (500 MHz, CDC1₃): δ_Η 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); ¹³C NMR (125 MHz, CDCI3, mixture of isomers): 5_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)⁺; HRMS: m/z calcd for C₃₂H₃₇N0₅Na 538.2564, found 538.2564.

Example 3 (B)

[0053] Preparation of Tert-but l (2R,5S 3,4-bis(benzyloxy)-2-((benzyloxy)methyl)- 3,4-dihydropyridine-l(2H)-carboxylate(llb)

Similarly lib 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 Si0₂ column chromatography (EtOAC-Et₃N-petroleum ether, 3:2:95);

?, 0.57 (EtOAc-petroleum ether, 1:1); [a]²⁵ _D -56.21 (c 1.13, CHC1₃); IR (CHC1₃): v_max

3740, 3620, 2362, 2334, 1647, 1547, 1367, 921, 821, 678 cm^"1; Ή NMR (200 MHz, CDCI₃): δ_Η 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); ¹³C NMR (50 MHz, CDC1₃): 5_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)⁺; HRMS: m/z calcd for C₃₂H₃₇N0₅Na 538.2564, found 538.2565.

Example 4

[0054] tert-Butyl (2_JR,Ji?,5S,6-S -3,4-bis(benzyloxy)-2-((benzyloxy)met yl)-5,6- dihydroxypiperidine-l-carboxylate (12a) (DHQD)₂AQN (4.16 mg, 0.00485 mmol, 5 mol% ), K₃Fe(CN)₆ (96 mg, 0.291 mmol, 3 eq), ₂C0₃ (93.7 mg, 0.679 mmol, 70 eq), and ₂0s0₂(0H)₄ (2 mg, 0.00543 mmol, 5.59 mol%) were dissolved in /<?r/-butyi alcohol and water (5 ml each) at room temperature 25°C. CH₃S0₂NH₂ ( 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 Na₂S0₃ (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 (2x5 ml), the combined organic layers were washed with 2M NaOH (20 ml). The combined organic layers were dried over Na₂S04 and concentrated in vacuo, which on preparative TLC separation (20% EtOAc-Pet ether) furnished 12a (38 mg, 30%), R_{ 0.23 (EtOAc-petroleum ether, 7:3); [a]²⁵ _D - 1 8.79 (c 1. 15% , CHC1₃); v_mm (CHCl₃)/cm^"' , 667; δ_Η (200 MHz, CDC1₃) 7.39-7.24 (m, 15H), 5.69-5.56 (m, 1 H), 4.69-4.48 (m, 6H), 4. 19-4.08 (m, 1H), 3.99-3.93 (m, 1 H), 3.87-3.85 (m, 2H), 3.78-3.69 (m, 1 H), 3.63-3.55 (m, 1 H), 2.74 (brs, 1 H), 1.79 (brs, 1 H), 1.53- 1.47 (m, 9H); 6_C (50 MHz, CDC1₃) 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)⁺; HRMS: m/z calcd for C₃₂H₃₉N0₇Na⁺ 572.2619, found 572.2621. Example 5

[0055] 7er/-Butyl (2R,J^5/i,6 )-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5,6- dihydroxypiperidine-l-carboxylate (13a)

(DHQ)₂AQN (5.0 mg, 0.0058 mmol, 5 mol%), ₃Fe(CN)₆ ( 1 18 mg, 0.358 mmol, 3 eq), 2C0₃ ( 1 14 mg, 0.826 mmol, 70 eq), and K₂Os0₂(OH)₄ (2.5 mg, 0.0068 mmol, 5.59 mol%) were dissolved in ier/-butyl alcohol and water (6 ml each) at room temperature 30°C. CH₃S0₂NH₂ (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. 1 18 mmol). The mixture was stirred at 0°C for 66 h. In the work up, Na₂S0₃ (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 (2x5 ml), the combined organic layers were washed with 2M NaOH (20 ml). The combined org layers were dried over Na₂S0₄ and concentrated in vacuo, which on preparative TLC separation (EtOAc-petroleum ether, 7:3) furnished 13a (20 mg, 71 %), R_{ 0.21 (EtOAc-petroleum ether, 7:3); [a]²⁵ _D - 13.33 (c 1 .1 %, CHC1₃); i (CHCl₃)/cm^"' 3443, 3064, 2927, 2859, 2362, 2334, 1690, 1499, 1368, 1086, 757, 699, 669; δ_Η (200 MHz, CDC1₃) 7.35-7.26 (m, 15H), 5.65-5.52 (m, 1H), 4.70-4.41 (m, 6H), 4.24-4.04 (m, 1 H), 3.95-3.89 (m, 1 H), 3.85-3.80 (m, 1 H), 3.75-3.63 (m, 2H), 3.58-3.45 (m, 1 H), 2.68 (brs, 1 H), 1 .68 (brs, 1 H), 1 .48-1 .40 (m, 9H); 5_C (50 MHz, CDCI₃) 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)⁺; HRMS: m/z calcd for C₃₂H₃₉N0₇Na⁺ 572.2619, found 572.2619.

[0056] ADVANTAGES OF INVENTION

• Novel route of synthesis of alkaloids

• Provides reasonable good yields

• Piperidine alkaloids are not known to be synthesized from gluconolactone

• Other methods of synthesis are known, but this process is shorter, enanti

tuning is possible depending on starting enantiomer used.

Claims

WE CLAIM

1 . A process for the preparation of piperidine alkaloids comprising the steps of: 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 5-5-hydroxy amide (2);

1a R₁ =R₂=H , R₃= OBn, R₄= H 2a R₁=R₂=H, R₃= OBn, R₄= H

1 b R₁ =R₂=H, R₃= H, R₄= OBn 2b R^R^H, R₃= H, R₄= OBn

b) stirring a solution of compound 2 as obtained in step (a) in DMSO and Ac₂0 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);

3a R₁ =R₂=H, R₃= OBn, R₄= H

3b R₁ =R₂=H, R₃= H, R₄= OBn

c) adding formic acid and sodium cyanoborohydride to a solution of compound 3 as obtained in step (b) in acetonitri le 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);

5a R! =R₂=H, R₃= OBn, R₄= H

5b R₁ =R₂=H , R₃= H, R₄= OBn

d) adding l ith ium alum inium hydride to a sol ution 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 4h at temperature in the range of 65 to 70°C and purification to afford rotected piperidine compound (6);

6a R₁ =R₂=H, R₃= OBn, R₄= H

6b R₁ =R₂=H, R₃= H, R₄= OBn

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);

7a R₁ =R₂=H, R₃= OH, R₄= H, (+)-Fagomine

7b R₁ =R₂=R₃= H, R₄= OH, 4-ep/-Fagomine

adding Et₃N to a solution of giycolactam (5) as obtained in step (c) in dichloromethane followed by cooling to 0°C and further adding Boc₂0, 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 TM-Boc protected lactam (8);

8a R₁ =R₂=H, R₃= OBn, R₄= H

8b R₁ =R₂=H, R₃= H, R₄= OBn

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;

9a R₁ =R₂=H, R₃= OBn , R₄= H

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

10a R₁ =R₂=H , R₃= OH , R₄= H

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 (1 l a/1 l b);

j) adding Boc-iminoglycal ( 1 1 a) to a solution of (DHQ)₂AQN, K₃Fe(CN)₆, K₂C0₃, ₂Os0₂(OH)₄ and CH₃S0₂NH₂ in fert-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);

k) The process as claimed in any of the preceding claims, wherein said process may also comprises adding Boc-iminoglycal ( 1 1 a) to a solution of (DHQD)₂AQN, ₃Fe(CN)₆, ₂C0₃, ₂Os0₂(OH)₄ and CH₃S0₂NH₂ 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).

2. The process as claimed in claim 1 , wherein the piperidine alkaloids are (·+)- fagomine (7a), 4-<? /-fagomine(7b), 3-deoxynojirimycin ( 10a), Boc-iminoglycal ( 1 l a/1 l b), 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- l (2H)- carboxylate ( 1 1 a), tert-butyl (2R,3S)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)- 3,4-dihydropyridine- 1 (2H)-carboxylate( l i b).

5. The process as claimed in claim 9, wherein the iminoglycal compound is tert- Butyl (2/?,ii?,Ji?,(5 ?)-3,4-bis(benzyloxy)-2-((benzyloxy)methyl)-5,6-dihydroxy- piperidine- l-carboxylate (12a) or fer/-Butyl (2R,3R,5S, 6S)-3,4-b\s(benzy\oxy)-2- ((benzyloxy)methyl)-5,6-dihydroxypiperidine- 1 -carboxylate ( 13a).