FIELD OF THE INVENTION

The present invention relates to novel diol derivatives and a chiral pool process for their synthesis from D glucose thereof. Further, the present invention relates to a process for the synthesis of (2R, 3S)-3-hydroxypipecolic acid from D-glucose using chiral pool approach, wherein the D-glucose used is in enantiomerically pure form. BACKGROUND AND PRIOR ART OF THE INVENTION

The 3-hydroxy pipecolic acid is a non proteinogenic cyclic a-amino acid. It is used in the preparation of conformationally restricted peptides and ligands binding studies. It is a constituent of many natural as well as synthetic biologically active compounds. The biological activities of piperidines vary with the position and nature of substituent on the ring. Both cis as well as trans isomers are structural units found in diverse natural products. The hydroxy pipecolic acid framework is target of several synthetic efforts. Synthetic chemists are interested in this structural motif because of its presence in compounds with diverse biological activities. They are of pivotal importance to medicinal chemistry and organic synthesis.

In view of their great significance, a number of synthetic strategies have been devoted to the stereoselective synthesis of these chiral piperidines. These syntheses utilized both chiral pool and asymmetric routes. In chiral pool approaches, carbohydrates and non-carbohydrate sources are used for their syntheses. Carbohydrates are ideally suited to the preparation of single isomer of piperidines.

US 6528538 B l discloses compounds having the following general formula for the treatment of dyslipidemia, atherosclerosis and diabetes;

where X, Y=CH ₂ , O, S, Ra (Ra=H, alkyl, aryl, etc.); R=H, alkyl, cycloalkyl, etc.;R =H, alkyl, hydroxyalkyl,— (CH ₂ ) _t -COORc where t=0-6 & Rc represents H or alkyl group, etc.; R ₂ & R ₃ =H, alkyl, cycloalkyl, (C ₆ -Cio)aryl, (C ₆ -Cio)aryl(Ci-C7)alkyl, 3-10 membered optionally substituted heterocyclic group etc.; or R ₂ & R ₃ optionally form a chain— (CH2) _r i(rl=2-5), etc.; R ₄ -R7=H, alkyl, (un)substituted aryl, etc. It further relates to method for the synthesis of racemic compounds which is not useful in the synthesis of diols and pipecolic acids.

US 5594153 A discloses a process for the preparation of 1,3-dioxane derivatives useful in the preparation of HMG-CoA reductase inhibiting compounds. The 1,3 dioxane derivatives does not lead to diols but it gives acyclic hydroxyl compounds.

US 5,103,024 discloses a process which starts with (4R-cis)-l,l-dimethylethyl 6- hydroxymethyl-2,2-dimethyl-l,3-dioxane-4-acetate and derives the desired substance therefrom by two steps, namely conversion to an arylsulfonate and cyanation. However, the starting material disclosed therein is expensive and a multistep synthetic process is required for the preparation of the startin material itself from commercially available materials.

CH ₃

X

Article titled "Chiron Approach to the Synthesis of (25, 3 ?)-3-Hydroxypipecolic Acid and (2R, 3 ?)-3-Hydroxy-2-hydroxymethylpiperidine from D-Glucose" by Dilip D. Dhavale et al. in J. Org. Chem., 2008, 73 (9), pp 3619-3622 reports the first chiron approach from d- glucose for the total synthesis of (25, 3 ?)-3-hydroxypipecolic acid. This is a long synthetic route which involves azide chemistry wherein scalability is an issue, reaction conditions are sensitive and not practical on higher scale.

Article titled, "A regioselective reductive cleavage of benzylidene acetal: Stereoselective synthesis of N-Boc-protected cis-(2R,3S)-3-hydroxypipecolic acid" by Kumar, Ponminor Senthil; Baskaran, Sundarababu in Tetrahedron Letters (2009), 50(26), 3489-3492 reports a stereoselective synthesis of N-Boc-protected cis-(2R,3S)-3-hydroxypipecolic acid, starting from D-glucose. The key step in the overall synthesis is a highly regioselective reductive cleavage of benzylidene acetal leading to (2R,3S)-l-tert.-butoxycarbonyl-3- benzyloxypiperidine-2-methanol. This process involves the use of azide chemistry, hazardous and sensitive reagents like Lithium aluminium hydride, silyl hydride, diphenyl phosphoryl azide which makes it less preferable for scale up. Further, 13 steps are required to achieve final target compound with low overall yield.

Article titled "An efficient stereoselective and stereodivergent synthesis of (2R,3R)- and (2 ?,35)-3-hydroxypipecolic acids" by Jourdant et al. in Tetrahedron Letters, 2000, 41 (36), pp 7033-7036 reports a synthetic route to both cis and trans isomers 15 and 13 linear steps respectively from L-serine.

Article titled, "A convenient formal synthesis of (25,35)-3-hydroxy pipecolic acid" by Subhash P. Chavan in Tetrahedron: Asymmetry Volume 22, Issue 5, 2011, 587-590 reports a convenient synthesis of (25,35)-3-hydroxy pipecolic acid starting from inexpensive and easily available l-(+)-tartaric acid.

Article titled, "Stereoselective Syntheses of 1-Pipecolic Acid and (25,35)-3-Hydroxypipecolic Acid from a Chiral N-Imino-2-phenyl-l,2-dihydropyridine Intermediate" by Alexandre Lemire and Andre B. Charette in J. Org. Chem., 2010, 75 (6), pp 2077-2080 reports a. stereoselective synthesis of 1-pipecolic acid and (25,35)-3-hydroxypipecolic acid were achieved from a chiral N-imino-2-phenyl-l,2-dihydropyridine intermediate. The 3-hydroxy substituent of the latter amino acid was introduced by hetero-Diels- Alder reaction of singlet oxygen with the 1,2-dihydropyridine.

Article titled, "5,5-Bis(hydroxymethyl)-2-phenyl-l,3-dioxane" in Acta Cryst. (2008). E64, ol536 by Y.-M. Luo, X.-M. Liu, X.-Y. Yuan, M. Zhang and S. W. Ng reports the title compound, Ci ₂ Hi ₆ 0 ₄ , wherein the 1,3-dioxane ring adopts a chair conformation; the 2-phenyl substitutent occupies an equatorial position. Adjacent molecules are linked by 0-H, , _e O hydrogen bonds into a chain.

Article titled,"m-Dioxanes and Other Cyclic Acetals" by CHRISTIAN S. RONDESTVEDT Jr. in . Org. Chem., 1961, 26 (7), pp 2247-2253 reports an extensive series of substituted m- Dioxanes.

WO 2006030892 Al discloses a process for the production of NS-220 which is suitable for mass production on an industrial scale. The invention is constituted of (1) a process for the production of methyl cis-5-(4-chlorobutyl) -2-methyl-l,3-dioxane-2-carboxylate, characterized by hydrolyzing a cis/trans isomer mixture of methyl 5-(4- chlorobutyl)-2- methyl-l,3-dioxane-2-carboxylate in the presence of a base; (2) a process for the production of 4-methyl-N-(2-oxopropyl)benzamide, characterized by oxidizing 4-methyl-N-(2- hydroxypropyl)benzamide with 2,2,6, 6-tetra- methyl- 1-piperidinyloxyl radicals and sodium hypochlorite; and so on.

In literature there are number of syntheses reported. These synthesis have various drawbacks such as use of costly harmful metals, expensive starting material, lengthy synthetic routes which reduces over all yield of 3-hydroxy pipecolic acid.

Therefore there is need to develop a process for the synthesis of 3-hydroxy pipecolic acid which is short, efficient, scalable and with minimum purifications required, which successfully over coming these drawbacks. OBJECTIVE OF THE INVENTION

The main object of present invention is to provide novel diol derivatives and a chiral pool process for their synthesis from D glucose thereof.

Another object of the present invention relates to a process for the synthesis of (2R, 3S)-3- hydroxypipecolic acid from D-glucose using chiral pool approach, wherein the D-glucose used is in enantiomerically pure form. SUMMARY OF THE INVENTION

Accordingly, the present invention provides novel diol derivatives and a chiral pool process for their synthesis from D glucose thereof.

Further, the present invention provides a process for the synthesis of (2R, 3S)-3- hydroxypipecolic acid from D-glucose using chiral pool approach.

In an aspect of present invention is to provides a simple reaction sequences, azide free, improved process for the synthesis of (2R, 3S)-3-hydroxypipecolic acid from D-glucose with over all yield in the range of 20-26 %. DETAILED DESCRIPTION OF THE INVENTION

The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.

In an embodiment, the present invention provide novel diol derivatives of general formula I,

R ₂ = OH, I I . N i l . I I

R ₃ = I I . OH, I I . N i l ,

R , =R , = -CH ₂ CH ₂ CH ₂ NR ₄

R ,= CH ₂ Ph, A l ly l , I I . Hoc. CBz, COO Me

Formula I

In another embodiment, the present invention provides chiral pool process for the synthesis of the compound of formula I from D glucose.

In yet another embodiment, the present invention provide a process for the synthesis of (2R, 35)-3-hydroxypipecolic acid from D-glucose using chiral pool approach, wherein the D- glucose used is in enantiomerically pure form. The D-glucose compound as used herein for the synthesis of (2R, 35)-3-hydroxypipecolic acid is prepared by below scheme 1 :

D glucose 4

Scheme: 1

In a preferred embodiment, the present invention provides a process for synthesis of (2R, 35)- 3-hydroxypipecolic acid from D-glucose, wherein said process comprises the following steps: a) Reacting D-glucose with paraldehyde to give mono acetal protected (17?)-(-)-4,6-0- ethylidene-D-glucose;

b) Compound from step (a) is then subjected for cleavage with NaI0 ₄ to give (-)-2,4-0- ethylidene-D-erythrose;

c) Stirring the compound of step (b) at room temperature with Ph ₃ PCHCOOEt in presence of toluene to give a, ^-unsaturated hydroxy ester;

d) Reduction of a, ^-unsaturated hydroxy ester by treatment with LiBr or LiCl and NaBH ₄ in THF: Water (1: 1) at ambient temperature to give allyl alcohol;

e) Hydrogenation of allyl alcohol of step (d) with Pd/C in methanol in hydrogen atmosphere to give the saturated compound 1,5 diol;

f) Reacting the compound of step (e) with methanesulphonyl chloride and triethyl amine to give obtain dimesylate compound;

g) Cyclization of compound of step (f) is carried out by heating dimesylate compound in neat benzyl amine to give cyclized product;

h) Hydrogenation of compound of step (g) in the presence of Boc anhydride and Pd/C to give N-debenzylation-N-Boc formation;

i) The N-boc piperidine from step (h) deprotected with PTSA in methanol and purified by recrystalization to get the target intermediate cis piperidine 2,6-diol in quantitative yield; j) Adding t-BuMe ₂ SiCl and imidazole to a solution of compound of step (i) in DMF followed by stirring at 40°C for 12 h to obtain (2R,3R)-tert-Butyl 3-(tert- butyldimethylsilyloxy)-2- ((tert-butyldimethylsilyloxy)methyl)piperidine- 1 - carboxylate;

k) Treating compound of step (j) with acetic acid to afford the selectively deprotected free primary alcohol;

1) Adding solution mixture of NaI0 ₄ in CH ₃ CN/CC1 ₄ /H ₂ 0 and RuCl ₃ .H ₂ 0 to a solution of compound of step (k) in CH ₃ CN followed by stirring at room temperature for 30 min to obtain (2S,3R)-N-tert-Butoxycarbonyl-3-hydroxypipecolic Acid; m) Heating the compound of step (1) in HC1 at 70 °C for 2 h to obtain (2S,3R)-3-

Hydroxypipecolic Acid Hydrochloride.

The above process for the synthesis of (2R, 35)-3-hydroxypipecolic acid compound of formula 12 is shown below in scheme 2.

11 12

Scheme 2

Scheme2. Reagents and conditions a) Ref.

¹ ; b) NaI0 ₄ , Water, 3 h, 97%; c) Ph ₃ PCHCOOEt DCM, rt, 6 h, 87%; d) i) NaBH ₄ , LiCl, THF:water (1: 1), 12 h, ii) H ₂ , Pd/C, MeOH, 60 psi, 3 h, 96%; e) MsClJEA, DCM, 0 °C, 30 min; f) BnNH ₂ , heat, 2 h, 90%; g) H ₂ , Pd/C, Boc ₂ 0, MeOH, 60 Psi, 6 h; h) PTSA, MeOH, 3 h, rt, 91%; i) TBSC1, TEA, DMAP, DCM, 12 h, 86%; j) AcOH:H ₂ 0:THF, 94%; k) RuCl ₃ (Cat.), NaI0 ₄ , MeCN:CCl ₄ :H20; 1) 6N HC1, 70 °C, 2 h.

The intermediate cis piperidine 2,6-diol used for the synthesis of (2R, 3S)-3- hydroxypipecolic acid is also prepared by using one pot synthesis from N-benzylated compound by carrying hydrogenation reaction in presence of dil.HCl followed by addition of boc anhydride to get this intermediate in good yields.

The process for synthesis of intermediate cis piperidine 2,6 diol compound of formula 1 is as shown in scheme

Scheme: 3

The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention. EXAMPLES

Example 1:

Synthesis intermediate diol (1):

Synthesis of (2R, 35)-3-hydroxypipecolic acid began with mono acetal protection of glucose to obtain (17?)-(-)-4, 6-O-ethylidene-D-glucose in 65% yield which was then subjected for cleavage with NaI0 ₄ to afford ( ^_ )-2, 4-O-ethylidene-D-erythrose in almost quantitative yield. The two-carbon Wittig homologation of (-)-2,4-0-ethylidene-D-erythrose with Ph ₃ PCHCOOEt by stirring in DCM afforded a, ?-unsaturated hydroxy ester in 7:3 trans/ cis ratio in good yield. Reduction of a, ^-unsaturated hydroxy ester by treatment with LiBr or LiCl and NaBH ₄ in THF: Water (1: 1) at ambient temperature. Allyl alcohol formed during reduction was hydrogenated with Pd/C in methanol in hydrogen atmosphere which give the saturated compound 1,5 diol in 96% yield. This 1, 5 diol compound is subjected for mesylation by treating it with methanesulphonyl chloride and triethyl amine in DCM at 0 °C for 0.5 h to obtain dimesylate compound. This mesylate derivative is used for further cycloamination without purification. Cyclization was carried out by heating dimesylate compound in neat benzyl amine at 90 °C for 2 h to afford cyclized product in 90% yield. This cyclized benzylated piperidine was hydrogenated with Pd/C in methanol at 60 psi and concomitant boc protection which led to one-pot N-debenzylation-N-Boc formation. The N- boc piperidine was obtained in almost quantitative yield which is deprotected with PTSA in methanol and purified by recrystalization to get the target intermediate in quantitative yield. Example 2:

Ethyl (E)-3-((2R,45,5R)-5-hydroxy-2-methyl-l,3-dioxan-4-yl)acrylat e (6):

The crude aldehyde 3 (1.12 g, 7.87 mmol) was dissolved in DCM (100 mL) and to this solution Ph ₃ PCHC0 ₂ Et (3 g, 8.66 mmol) was added. The reaction mixture was stirred at room temperature for 4 h. Completion of reaction was monitored on TLC. After completion of reaction, solvent was removed under reduced pressure and the crude product was purified using silica gel coloumn chromatography to furnish the a, ?-unsaturated ester 6 (1.7 g, 87% ) as a colorless solid. Rf (ethyl acetate: pet. ether/2:3): 0.3

Yield: 87%

Molecular formula: CioHi ₆ Os;

Molecular weight: 216.2310

IR: 3453, 2988, 2932, 1718, 1662, 1447 cm ^"1

Optical rotation: [a] ^ : -41.45 ( c = 0.5, chloroform)

1H NMR (400 MHz, CDC1 ₃ +CC1 ₄ ): δ 1.31 (t, / = 7.2 Hz, 3 H), 1.36 (d, = 5.0 Hz, 3 H), 2.68 (br. s., 1 H), 3.44 (q, = 10.5 Hz, 1 H), 3.48 - 3.55 (m, 1 H), 3.98 (ddd, = 9.0, 4.6, 1.5 Hz, 1 H), 4.13 (dd, = 10.4, 4.6 Hz, 1 H), 4.21 (q, = 7.2 Hz, 2 H), 4.73 (q, = 5.0 Hz, 1 H), 6.14 (dd, = 15.8, 1.6 Hz, 1 H), 7.08 (dd, = 15.8, 4.5 Hz, 1 H).

¹³ C NMR (100 MHz, CDCI ₃ +CCI ₄ ): δ 14.29, 20.45, 60.62, 65.23, 70.71, 80.04, 98.78, 122.19, 143.68, 166.50.

HRMS: calcd for Ci ₀ Hi ₆ O ₅ Na 239.0895 found 239.0890 [M+Na] ⁺ .

(2R,45,5R)-4-(3-hydroxypropyl)-2-methyl-l,3-dioxan-5-ol (2):

addition by saturated NH ₄ C1 solution at 0 °C and again stirred for 10 min. Evaporation of the solvent furnished a residue which was extracted with ethyl acetate (3x8 mL). The combined organic layer was washed with brine (7 mL) and dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated under reduced pressure. The crude residue was dissolved in methanol. To this solution catalytic Pd/C was added. This reaction mixture was stirred under hydrogen gas pressure. After 3 h, catalyst was filtered off. Methanol was eavaporated under reduced pressure. The residue was purified by a silica gel column chromatography using ethyl acetate/hexane (1: 1) as eluent furnished the reduced 1,5-diol compound 2 (790 mg, 97%) as a colorless liquid. Rf (ethyl acetate: pet. ether/3 :2): 0.2.

Molecular formula: Formula: C ₈ Hi ₆ 0 ₄

Molecular Weight: 176.21

Yield: 94%.

Optical rotation: [a]^ : -45.45 (c = 1.02, chloroform).

IR (CHC1 ₃ ): 3390, 2992; 1652 cm ^"1 .

1H NMR (400 MHz, CDC1 ₃ ): δ 1.30 (d, J = 5.0 Hz, 3 H), 1.47 - 1.68 (m, 2 H), 1.69 - 1.83 (m, 1 H), 1.89 - 2.06 (m, 1 H), 3.26 - 3.48 (m, 3 H), 3.57 - 3.76 (m, 3 H), 4.05 (dd, J = 10.5, 5.0 Hz, 1 H), 4.29 (br. s., 1 H), 4.65 (q, = 5.0 Hz, 1 H).

¹³ C NMR (100 MHz, CDC1 ₃ ): δ 20.39, 27.70, 28.03, 62.18, 65.12, 70.71, 81.15, 98.88.

HRMS: calcd for C ₈ Hi ₆ 0 ₄ Na: 199.0946; found 199.0942 [M+Na] ⁺ .

(2R,4a5,8a5)-5-Benzyl-2-methylhexahydro-4H-[l,3]dioxino[5,4- b]pyridine(7)

A solution of 1,5-diol 2 (400 mg, 2.27 mmol) in dry CH ₂ C1 ₂ (5 mL), and

Et ₃ N (1.37g, 13.63 mmol) was cooled to 0 °C. Subsequently mesyl chloride (780 mg, 6.81 mmol) was added and the mixture was stirred for 30 min at the same temperature. Progress of reaction was monitored by TLC. After completion of the reaction, it was quenched by addition of 5 mL of aqueous solution of NaHC0 ₃ and the organic layer was washed with water (2 x 5 mL), followed by brine (5 mL). The organic layer was dried over NaS0 ₄ , filtered and concentrated in vacuo. The residue of dimesylate was used as such for further reaction witout purification.

The dimesylate (300 mg, 0.617 mmol) was dissolved in benzylamine (5 mL) and stirred at 90 °C for 2 h. After completion of reaction (monitored by TLC), 10 mL of IN HC1 was added and extracted with DCM (3 x 10 mL). The organic layer was washed with saturated aqueous NaHC0 ₃ (15 mL) and brine (10 mL), dried over NaS0 ₄ , concentrated in vacuo and the crude product purified by silica gel column chromatography (Hexane-EtOAc = 9: 1) to yield 7 (215 mg, 90%) as a colorless oil. 7 (ethyl acetate: pet. ether/2:3): 0.5.

Chemical Formula: C15H21NO2

Molecular Weight: 247.33

Yield: 90%. Optical rotation: [a] ^ : -37 (c=1.036, chloroform)

1H NMR (200 MHz, CDC1 ₃ +CC1 ₄ ): δ 1.40 - 1.44 (m, 3 H), 1.88 - 2.23 (m, 6 H), 2.95 (dd, J = 10.6, 2.1 Hz, 1 H), 3.59 (d, J = 14.1 Hz, 1 H), 3.68 (dd, = 12.8, 2.3 Hz, 1 H), 3.79 - 3.90 (m, 1 H), 4.05 (d, J = 14.1 Hz, 1 H), 4.58 (dt, = 12.8, 0.7 Hz, 1 H), 4.80 (q, J = 5.1 Hz, 1 H), 7.15 - 7.44 (m, 5 H).

¹³ C NMR (50 MHz, CDCI ₃ +CCI ₄ ): δ 19.66, 20.91, 29.93, 51.84, 56.20, 57.05, 67.25, 73.44, 99.41, 126.96, 127.99, 129.30, 136.65.

HRMS: calcd for C ₁₅ H ₂₂ NO ₂ : 248.1651 ; found: 248.1645 [M+Na] ⁺ .

tert-Butyl(2/f,4a5,8a5)-2-methylhexahydro-5H-[l,3]dioxino [5,4-b]pyridine-5- carboxylate (8):

To the solution of N-benzyl piperidine 7 (0.250 g, 0.546 mmol) in methanol (20 mL, 9: 1) was added boc anhydride (0.17 g, 0.65 mmol) and catalytic Pd/C. The reaction mixture was stirred under hydrogen gas atmoshphere at

60 psi pressure for 8 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered on celite. The solvent was removed under reduced pressure to afford crude N-boc protected compound 8. The residue was purified by flash silica gel column chromatography in 10% ethyl acetate in pet. ether to give compound 8 (0.118 g, 94%) as colorless thick syrup. 7 (ethyl acetate: pet. ether/l :3): 0.5.

Molecular formula: Ci ₃ H ₂₃ N0 ₄ Molecular weight: 257.32

Yield: 94%.

25

Optical rotation: [a] ^ : -32 ( c = 1.05, chloroform) IR (CHCI ₃ ): 2979, 1671, 757 cm ^"1 .

1H NMR (500 MHz, CDCI ₃ +CCI ₄ ): δ 1.31 (d, J = 4.9 Hz, 3 H), 1.44 (s, 9 H), 1.51 - 2.08 (m, 4 H), 3.36 (br. s., 1 H), 3.48 (td, = 12.5, 6.1 Hz, 1 H), 3.72 (dd, = 12.4, 2.3 Hz, 1 H), 3.94 (dd, = 13.1, 7.9 Hz, 1 H), 4.01 (q, = 3.4 Hz, 1 H), 4.25 (d, = 12.2 Hz, 1 H), 4.67 (q, = 5.0 Hz, 1 H).

¹³ C NMR (125 MHz, CDCI ₃ +CCI ₄ ): δ 18.75, 21.35, 24.17, 28.52, 38.10, 49.12, 70.50, 71.13, 79.37, 79.40, 98.36, 154.93. HRMS: calcd for Ci ₃ H ₂₃ N0 ₄ Na: 280.1519; found: 280.1525 [M+Na] ⁺ . tert-butyl (2S,3S)-3-hydroxy-2-(hydroxymethyl)piperidine-l-carboxylate( l)

To a solution of ieri-butyl (2 ?,4aS,8aS)-2-methylhexahydro-5H- [l,3]dioxino[5,4-b]pyridine-5-carboxylate 8 (1.7 g, 6.88 mmol) in MeOH (20 mL) was added p-TSA (130 mg, 0.69 mmol) at 0 °C and the mixture stirred for 2 h at room temperature. After completion of the reaction (monitored by TLC), the reaction mixture was neutralized with NaHC0 ₃ and the organic layer and aqueous layers were separated. Aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated to dryness under reduced pressure. Purification by column chromatography using petroleum ether: ethyl acetate (1: 1) as eluent afforded 1.55 g compound as a white solid in 96% yield. Purification can also be carried out by recrystalizing the compound 1 from pet ether by dissolving in it by addition of minimum amount of ethyl actetate. Rf (ethyl acetate: Pet. ether/2:3): 0.4.

Molecular formula: CnH ₂ iN0 ₄ Molecular weight: 231.29 Yield: 96%.

MP: 115-117 °C Lit. 114-116 °C

Optical rotation: [<x]¾ : +24.2 (c: 1, MeOH); Lit. ³⁷ [<x]¾ : (c: 1.03, MeOH), [<x]¾ : +33.6 (c = 1.04, CHC1 ₃ ); Lit. [<x]¾ : +23.4 (c = 1, CHC1 ₃ ) IR (CHC1 ₃ ): I : 3407, 2935, 1668, 1423 cm ^"1

1H NMR (400 MHz, CDCI ₃ +CCI ₄ ): δ 1.45 (s, 10 H), 1.55 - 1.77 (m, 2 H), 1.85 (d, 7 = 12.3 Hz, 1 H), 2.82 (br. s., 1 H), 3.36 (br. s, 2 H), 3.73 (dd, 7 = 11.2, 6.9 Hz, 1 H), 3.79 (br. s., 1 H), 3.87 - 3.96 (m, 1 H), 4.10 (dd, 7 = 11.2, 6.5 Hz, 1 H), 4.42 (q, 7 = 6.1 Hz, 1 H).

¹³ C NMR (100 MHz, CDCI ₃ +CCI ₄ ): δ 23.80, 28.34, 28.45, 39.76, 56.08, 59.26, 69.39, 80.26, 155.62.

HRMS: calcd for CnH ₂ iN0 ₄ Na: 254.1368; found:254.1363 [M+Na] ⁺ .

(25,35)-tert-Butyl3-((tert-butyldimethylsilyl)oxy)-2-(((t ert-butyldimethylsilyl)oxy) methyl)piperidine- 1 -carboxylate (9) ¹⁵ To the solution of diol 1 (40 mg, 0.173 mmol ) in DCM (1 mL) TBDMSC1 (79 mg, 0.52 mmol), imidazole (71 mg, 0.10 mmol) and DMAP (0.0173 mmol) was added under nitrogen. The mixture was stirred at room temperature for 12 h and diluted with DCM (3.0 mL). An aqueous solution saturated of NaHC0 ₃ (3.0 mL) was added and the product was extracted four times with DCM (3 mL). The organic layer was, dried over NaS0 ₄ , filtered and concentrated in vacuo and the crude product purified by silica gel column chromatography (Hexane-EtOAc = 9: 1) to yield 9 (69 mg, 86%) as a colorless oil. 7 (ethyl acetate: Pet. ether/l:8): 0.3.

Molecular formula: C ₂₃ H ₄₉ N0 ₄ Si ₂ Molecular weight: 459.81

Yield: 86%

Optical rotation: +14 (c 0.5, CHC1 ₃ ); ent-l: Lit. ¹⁵ -13:6 (c 0.5, CHC1 ₃ ); IR (CDC1 ₃ ): 2930, 1693, 756 cm ^"1 .

1H NMR (400 MHz, CDCI ₃ ): δ 0.02 - 0.17 (m, 12 H), 0.79 - 1.00 (m, 18 H), 1.46 (s, 9 H), 1.53 - 1.86 (m, 4 H), 2.71 - 3.06 (m, 1 H), 3.58 - 4.09 (m, 4 H), 4.19 - 4.46 (m, 1 H).

¹³ C NMR (100 MHz, CDC1 ₃ ): δ -5.4, -5.4, -5.0, -4.8, 18.1, 18.2, 24.2, 25.8, 25.9, 28.4, 29.6, 29.7, 37.3, 39.2, 55.8, 57.8, 58.1, 69.6, 79.1, 155.2.

Example 3:

Synthesis of (25,3/?)-N-tert-Butoxycarbonyl-3-hydroxypipecolic Acid (11):

To a suspension of NaI0 ₄ (235 mg, 1.1 mmol) in (4.8 mL; 1: 1: 10) was added RuCl ₃ ,H ₂ 0 (11.4 mg, 0.055 mmol) in small portions, and the mixture was stirred at room temperature for 45 min. The resulting solution was added to the alcohol 10 (191 mg, 0.55 mmol) dissolved in CH ₃ CN (3 mL), followed by the addition of a second portion of NaI0 ₄ (118 mg, 0.55 mmol). The resulting mixture was stirred at room temperature for 30 min and filtered through Celite, and the Celite layer was washed thoroughly with EtOAc. The combined filtrate was dried over Na ₂ S0 ₄ and concentrated. The crude product thus obtained was purified by flash column chromatography (MeOH/CHCl ₃ ) 5:95 to 20:80) to yield the pure acid 11 (97 mg, 72%) as a semisolid.

Example 4:

Synthesis of (25, 3/?)-3-Hydroxypipecolic acid hydrochloride (12): The Boc-protected acid 11 (78 mg, 0.32 mmol) was taken in 6 N HCl (10 mL) and heated at 70 °C for 2 h. The reaction mixture was cooled to room temperature and extracted once with CH ₂ CI ₂ (10 mL) to remove any organic soluble impurities. Concentration of the aqueous layer under high vacuum followed by overnight drying under high vacuum afforded the product 12 as a light yellow solid (57 mg, quantitative).

Example 5:

Synthesis of cis piperidine 2,6 diol (1):

The intermediate cis piperidine 2, 6-diol compound of formula 1 is prepared by one pot synthesis from N-benzylated compound by carrying hydrogenation reaction in presence of dil.HCl followed by addition of boc anh dride to get this intermediate in ood yields. Then (Boc)2°

To the solution of N-benzyl piperidine 7 (0.250 g, 0.546 mmol) in methanol - dil. HCl (20 mL, 9: 1), was added catalytic Pd/C and the reaction mixture was stirred under hydrogen gas atmoshphere at 60 psi pressure for 4 h. After completion of the reaction (monitored by TLC), the boc anhydride (0.17 g, 0.65 mmol) was added to this reaction mixture and stirred further for 2 h. The reaction mixture was filtered on celite. The solvent was removed under reduced pressure to afford crude N-boc protected compound 8. The product was purified by recrystalization. ADVANTAGES OF THE PRESENT INVENTION

Simple reaction sequence which is good for industrial production.

1) Azide-free reaction makes the process cheaper.

2) Improved over all yield good for large scale synthesis.

3) Easily available cheap staring material decreases the cost.