Claims:We Claim:
1. An improved process for the preparation of optically pure (S)-(-)-Garner aldehyde of formula (1),

Formula (1)
comprising the steps of:
i) reacting L-Serine of formula (3)

Formula (3)
with methanol in the presence of acid reagent to get L-Serine methyl ester hydrochloride of formula (11),

Formula (11)
ii) protecting L-Serine methyl ester hydrochloride of formula (11) with Boc anhydride in the presence of a base in a suitable solvent medium to get Boc-L-Serine methyl ester formula (5),

Formula (5)
iii) condensation of Boc-L-Serine methyl ester formula (5) with 2,2-dimethoxypropane in the presence of Lewis acid catalyst in a suitable solvent medium to afford acetonide of formula (6),

Formula (6)
iv) reduction of ester functionality of acetonide (6) with reducing agent in a suitable solvent medium to afford alcohol of formula (10),

Formula (10)
v) oxidation of alcohol of formula (10) under Swern-oxidation conditions to get (S)-(-)-Garner aldehyde of formula (1)

Formula (1)

vi) purifying the (S)-(-)-Garner aldehyde of formula (1) via sodium bisulphite adduct formation.

2. The process as claimed in claim 1, wherein step (i) the acid reagent employed is selected from sulphuric acid, thionyl chloride, Oxalyl chloride, pivaloyl chloride, hydrochloric acid or acetyl chloride.

3. The process as claimed in claim 1, wherein step (ii) the base used is selected from triethylamine, diisopropylethylamine, N-Methylmorpholine, DBU, pyridine, potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate.

4. The process as claimed in claim 1, wherein step (ii) the solvent used for the protection of L-Serine methyl ester hydrochloride of formula (10) with Boc anhydride is selected form acetonitrile, tetrahydrofuran, toluene, diisopropylether, dichloromethane, ethylacetate, 1,4-dioxane, t-butanol, n-propanol, 2-propanol.

5. The process as claimed in claim 1, wherein step (iii) the catalyst used is selected from titanium tetrachloride, Boron trifluoride etherate, Tin (IV)chloride, Aluminum chloride, Iron (III) chloride, zinc chloride, zirconium tetra chloride.
6. The process as claimed in claim 1, wherein step (iii) the solvent used is selected from ethyl acetate, butyl acetate, acetone, toluene, cyclohexane, acetonitrile.

7. The process as claimed in claim 1, wherein step (iv) reducing agent is selected from zinc borohydride, calcium borohydride, magnesium borohydride, barium borohydride generated in-situ by the reaction of zinc chloride with sodium borohydride, calcium chloride with sodium borohydride or barium chloride with sodium borohydride or magnesium chloride with sodium borohydride.

8. The process as claimed in claim 1, wherein step (iv) the solvent used is selected from tetrahydrofuran, 1,4-dioxane, 2-methyl tetrahydrofuran, cyclopentylmethyl ether, n-butyl ether, diethyl ether.

9. The process as claimed in claim 1, wherein step (vi) the obtained crude (S)-(-)-Garner aldehyde of formula (1) is purified via bisulfite adduct formation by reacting crude (S)-(-)-Garner aldehyde of formula (1) with aqueous sodium bisulfite solution.

10. The process as claimed in claims 1-9, wherein, the purity and enantiomeric purity of (S)-(-)-Garner aldehyde of formula (1), is more than 99.0% by GC.
, Description:FIELD OF THE INVENTION:
The present invention relates to an improved process for the preparation of optically pure form of (S)-(-)-Garner aldehyde, chemically known as 1,1-dimethylethyl-2,2-dimethyl-4-(S)-formyloxazolidine-3-carboxylate of formula (1). It is one of the key chiral building block used in the synthesis of Trabectedin of formula (2) by employing commercially viable process.

PRODUCT SUMMARY:
Phillip Garner was the first to report a synthesis for (S)-1, 1-dimethylethyl 4-formyl-2,2-dimethyloxazolidine-3-carboxylate today widely known as (S)-(-)-Garner aldehyde (1). This configurationally stable aldehyde has shown its significance as a chiral building block in the synthesis of various natural products as well as their synthetic intermediates. It is one of the most cited chiral building blocks in recent times and has been reported to be used in over 600 publications.
As part of the synthesis of Ecteinascidin 743 (Trabectedin) or ET-743 (2), an anti-tumor drug, considerable amounts of (S)-(-)-Garner aldehyde (1) is required.
The synthesis of (S)-(-)-Garner aldehyde (1) is first published in J. Org. Chem., 1987, 52, 2361-2364 by Phillip Garner. The synthesis is started with protection of L-serine (3) amine with Boc anhydride followed by converting corresponding carboxylic acid (4) to its methyl ester (5) using diazomethane with 80-90% overall yield. The methyl ester (5) is then condensed with 2, 2-dimethoxypropane in the presence of p-TsOH at reflux temperature in benzene to give the oxazolidine ester (6) with 70% yield which is then reduced to afford (S)-(-)-Garner aldehyde (1) using DIBAL-H in toluene at -78° C. The reported yield is 76% yield (Scheme 1). The enantiomeric excess of the Garner aldehyde (1) is determined by reducing it with sodium borohydride in IPA-THF medium with 71% yield and the resulting alcohol is converted to Mosher’s esters by reacting with Mosher’s acids of both isomers in the presence of dicyclohexyl carbodiimide and DMAP as catalyst. Later the resulting esters were analyzed for enantiomeric purity by HPLC. The reported enantiomeric excess is ~98%. Similar approaches with slight modification in reduction of ester and oxidation of alcohol is reported in Synthesis, 2010, 18, 3063-3066; Synthesis, 1994, 1, 31-33; Chinese J. Chem., 2009, 27(11), 2296-2299; Chem. Lett., 1987, 1, 2085-2088; Tet. Lett., 1988, 29(25), 3037-3040; Tet. Lett., 1990, 31(1), 21-22; Org. Synth., 1992, 70, 18-28; Tet. Lett., 1995, 36(31), 5619-5622; J. Org. Chem., 2003, 68(2), 355-359 & Synlett, 2006, 3, 435-439 & Nat. Prod. Lett., 1993, 1(4), 239-242.
Scheme-1
In another process (scheme-2) published in Chem. Commun., 1988, 1, 10-12, Boc protected L-serine (4) is condensed with 2,2-dimethoxypropane in the presence of catalytic amount of p-toluene sulfonic acid in DMF at 100° C followed by methylation of acid with diazomethane and reduction of ester with DIBAL-H in toluene at -70° C to get (S)-(-)-Garner aldehyde of formula (1).

Scheme-2
Processes described in Scheme-1 & 2 are not viable for commercial production as the process requires toxic and explosive reagent like diazomethane, pyrophoric DIBAL-H reagent and carcinogenic solvent like benzene.
In another methodology published in Helv. Chim. Acta., 1992, 75(3), 865-882, N-Boc-L-serine (4) is reacted first with pivaloyl chloride followed by condensation of ester with N, O-dimethylhydroxylamine hydrochloride in the presence of N-methylmorpholine to get Weinreb amide (8). Later Weinreb amide is condensed with 2,2-dimethoxypropane in the presence of pyridinium p-toluene sulfonate to get amide (9). The amide is then reduced with lithium aluminum hydride in ether at 0° C to get (S)-(-)-Garner aldehyde of formula (1) (scheme-3).
Scheme-3
Process described in Scheme-3 is not viable for commercial production, as the process is associated with disadvantages like usage of moisture sensitive reagent like pyridinium p-toluene sulfonate (PPTS) and pyrophoric reagent like Lithium aluminium hydride.
In Synth. Commun., 1994, 24(15), 2147-2152, oxazolidine ester (6) is reduced first with lithium borohydride to corresponding alcohol (10) followed by oxidation of alcohol under Swern oxidation conditions to get (S)-(-)-Garner aldehyde (1) with 77% yield (scheme-4). Similar processes with slight modifications are reported in J. Org. Chem., 1995, 60, 798-806 & Synthesis, 1997, 5, 527-529.

Scheme-4
Process described in Scheme-4 is not viable for commercial production as process involves usage of expensive and unstable reagent like lithium Borohydride for reduction of ester (6) to alcohol (10).
In another approach published in Org. Synthesis, 2000, 77, 64 as depicted in scheme-5, L-serine (3) is esterified with methanol in the presence of acetyl chloride and the resulting methyl ester hydrochloride (11) (98-99% yield) is protected with Boc anhydride followed by condensation with 2,2-dimethoxypropane to get oxazolidine ester (6) with 88-91% yield. Later the ester (6) is reduced with lithium aluminum hydride with 93-96% yield followed by oxidation of alcohol (10) using Swern oxidation conditions (DMSO, oxalyl chloride, DIPEA, -78° C) to get (S)-(-)-Garner aldehyde (1) with 99% yield. The enantiomeric excess is reported to be 96-98%. Similar procedure is disclosed in WO2002009752; J. Org. Chem., 2004, 69(16), 5314-5321; WO2004010949.
Scheme-5
Process described in Scheme-5 is not suitable for commercial production as the process requires pyrophoric reagent like Lithium aluminium hydride.
In another approach published in Tet. Asymm. 2012, 23(8), 602-604, L-serine (3) is reported to be first protected with Boc anhydride and the protected acid is condensed with 2,2-dimethoxypropane followed by converting acid to pivaloyl ester using pivaloyl chloride. The ester is reacted further with ethane thiol in the presence of triethylamine to get thio ester (12). Later the thioester is reduced using triethyl silyl hydride and palladium on carbon to afford (S)-(-)-Garner aldehyde (1) with ~95% enantiomeric excess (scheme-6).

Scheme 6

Process described in Scheme-6 is not suitable for commercial production as it requires hazardous reagent like ethanethiol and expensive reagents like palladium on carbon.
However, in spite of having the choice of variety of methods for preparation of (S)-(-)-Garner aldehyde of formula (1), there is still a need to develop commercially viable process for large scale operations since, in general, the processes reported for preparation of (S)-(-)-Garner aldehyde of formula (1) have the following disadvantages:
1. Prior art processes requires toxic and pyrophoric reagents like diazomethane and ethane thiol, pyrophoric reagents like DIBAL-H reagent, Lithium aluminum hydride or palladium on carbon, moisture sensitive reagents like pyridinium p-toluene sulfonate and expensive and unstable reagent like lithium borohydride.
2. Prior art process does not teaches about purification of (S)-(-)-Garner aldehyde of formula (1).

SUMMARY OF THE PRESENT INVENTION:
Keeping in view of the disadvantages associated with the prior art processes disclosed in the literature for the preparation of (S)-(-)-Garner aldehyde of formula (1), we aimed to develop simple and economically viable process for commercial production of (S)-(-)-Garner aldehyde of formula (1).
Accordingly, the main objective of the present invention is to provide an improved process for the preparation of (S)-(-)-Garner aldehyde of formula (1), which comprises simple, safe, economical, and commercially viable process which circumvents the above mentioned disadvantages.
Accordingly, still another objective of the present invention is to provide an improved process for the preparation of (S)-(-)-Garner aldehyde of formula (1), by avoiding toxic and explosive reagent like diazomethane and ethane thiol, pyrophoric reagents like DIBAL-H reagent, palladium on carbon or Lithium aluminum hydride, moisture sensitive reagents like pyridinium p-toluene sulfonate and expensive and unstable reagent like lithium borohydride and.
Accordingly, another aspect of the present invention is to provide simple purification method for the purification of (S)-(-)-Garner aldehyde of formula (1) by reacting with sodium bisulfite in aqueous medium.
Accordingly, yet another objective of the present invention is to provide an improved process for the preparation of (S)-(-)-Garner aldehyde of formula (1), which produces relatively pure (S)-(-)-Garner aldehyde of formula (1) having more than 99.5% GC purity with more than 99.0% enantiomeric excess. The present invention is depicted in scheme-7.

Scheme-7
DETAILED DESCRIPTION OF THE INVENTION:
According to the present invention, in stage (i), L-serine of formula (3), is converted to corresponding methyl ester hydrochloride of formula (11) using methanol in the presence of acid reagent. Later, in stage (ii), methyl ester hydrochloride of formula (11) is reacted with Boc anhydride in the presence of base to afford Boc protected L-serine methyl ester of formula (5). In stage (iii), Boc protected L-serine methyl ester of formula (5) is condensed with 2,2-dimethoxypropane in the presence of Lewis acid catalyst to afford acetonide derivative of formula (6). Thereafter, in stage (iv), acetonide derivative of formula (6) is reduced to corresponding alcohol of formula (10). In the final stage (v), alcohol of formula (10) is finally oxidized under Swern-oxidation reaction conditions followed by purification via bisulphite adduct to afford (S)-(-)-Garner aldehyde of formula (1).
Accordingly, the present invention provides an improved process for the preparation of optically pure (S)-(-)-Garner aldehyde of formula (1),

Formula (1)
which comprises:-
i) reaction of L-Serine of formula (3)

Formula (3)
with methanol in the presence of acid reagent to get L-Serine methyl ester hydrochloride of formula (11)

Formula (11)
ii) protection of L-Serine methyl ester hydrochloride of formula (11) with Boc anhydride in the presence of an acid catalyst in a suitable solvent medium to get Boc-L-Serine methyl ester of formula (5)

Formula (5)
iii) reaction of Boc-L-Serine methyl ester of formula (5) with 2,2-dimethoxypropane in the presence of Lewis acid catalyst in a suitable solvent medium to afford acetonide of formula (6)

Formula (6)
iv) reduction of ester functionality of acetonide (6) with reducing agent in a suitable solvent medium to afford alcohol of formula (10)

Formula (10)
v) oxidation of alcohol of formula (10) under Swern-oxidation conditions followed by purification via sodium bisulphite adduct formation to afford (S)-(-)-Garner aldehyde of formula (1)

Formula (1)
Accordingly, in a preferred embodiment of the present invention:-
In stage (i) of the present invention, wherein the solvent used for esterification of L-serine of formula (3) is methanol.
In stage (i) of the present invention, wherein the volume of methanol is selected from 10-30 volumes against L-serine of formula (3).
In stage (i) of the present invention, wherein acid reagent employed is selected from sulphuric acid, thionyl chloride, Oxalyl chloride, pivaloyl chloride, hydrochloric acid or acetyl chloride, preferably, thionyl chloride.
In stage (i) of the present invention, wherein the temperature at which acid reagent is added to the reaction mixture is between -10 to 15°C preferably 0-5°C.
In stage (i) of the present invention, wherein temperature at which reaction is maintained is in between -10 to 65°C preferably between 20-35°C.
In stage (i) of the present invention, wherein the time required for completion of the reaction is in between 12-48h.
In stage (i) of the present invention, wherein, after completion of reaction, the methanol is distilled out completely under vacuum and L-Serine methyl ester hydrochloride of formula-(11) is isolated from organic solvent selected from ethyl acetate, toluene, cyclohexane or any other suitable organic solvent preferably ethyl acetate.
In stage (i) of the present invention, wherein L-Serine methyl ester hydrochloride of formula (11) is dried at temperature between 50-70°C preferably between 55-60°C.
In stage (ii) of the present invention, wherein Boc anhydride is used for the protection of L-serine methyl ester hydrochloride of formula (11).
In stage (ii) of the present invention, wherein the solvent used for the protection of L-Serine methyl ester hydrochloride of formula (11) with Boc anhydride is selected form acetonitrile, tetrahydrofuran, toluene, diisopropylether, dichloromethane, ethylacetate, 1,4-dioxane, t-butanol, n-propanol, 2-propanol, or any other organic solvent preferably tetrahydrofuran.
In stage (ii) of the present invention, wherein the volume of tetrahydrofuran is selected from 5-30 volumes against L-serine methyl ester hydrochloride of formula (11).
In stage (ii) of the present invention, wherein the base used for the protection of L-Serine methyl ester hydrochloride of formula (11) with Boc anhydride is selected from triethylamine, diisopropylethylamine, N-Methylmorpholine, DBU, pyridine, potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate or any other suitable base preferably triethylamine.
In stage (ii) of the present invention, wherein the temperature at which base is added to the reaction mixture is between -10 to 15°C preferably 0-5°C.
In stage (ii) of the present invention, wherein the temperature at which Boc anhydride is added to the reaction mixture is between -10 to 15°C preferably 0-5°C.
In stage (ii) of the present invention, wherein temperature at which reaction mass is maintained is in between -10 to 65°C preferably between 20-35°C.
In stage (ii) of the present invention, wherein the time required for completion of the reaction is in between 4-36h.
In stage (iii) of the present invention, wherein 2,2-dimethoxypropane is used for the protection of Boc-L-serine methyl ester of formula (5).
In stage (iii) of the present invention, wherein the solvent used for the protection of Boc-L-Serine methyl ester of formula (5) with 2,2-dimethoxypropane is selected from ethyl acetate, butyl acetate, acetone, toluene, cyclohexane, acetonitrile, or any other organic solvent or solvent mixture preferably acetone.
In stage (iii) of the present invention, wherein the volume of solvent is selected from 5-30 volumes against Boc L-serine methyl ester of formula (5).
In stage (iii) of the present invention, wherein the catalyst used for the protection of Boc L-Serine methyl ester of formula (5) with 2,2-dimethoxypropane is selected from titanium tetrachloride, Boron trifluoride etherate, Tin (IV)chloride, Aluminum chloride, Iron (III) chloride, zinc chloride, zirconium tetra chloride, or any other suitable Lewis acid catalyst.
In stage (iii) of the present invention, wherein the percentage of Lewis acid catalyst is used in the reaction is in the range of 0.5 to 10%.
In stage (iii) of the present invention, wherein temperature at which reaction mass is maintained is in between 10 to 45°C.
In stage (iii) of the present invention, wherein the time required for completion of the reaction is in between 1-6h.
In stage (iii) of the present invention, wherein the compound of formula (6) is optionally purified by distillation under vacuum.
In stage (iv) of the present invention, wherein the reducing agent for the reduction of ester functionality of compound of formula (6) is selected from zinc borohydride, calcium borohydride, magnesium borohydride, barium borohydride generated in-situ by the reaction of sodium borohydride with zinc chloride, calcium chloride, barium chloride or magnesium chloride.
In stage (iv) of the present invention, wherein the solvent used for the reduction of methyl ester of formula (6) is selected from tetrahydrofuran, 1,4-dioxane, 2-methyl tetrahydrofuran, cyclopentylmethyl ether, n-butyl ether, diethyl ether or any other organic solvent or solvent mixture.
In stage (iv) of the present invention, wherein the volume of solvent is selected from 5-30 volumes against methyl ester of formula (6).
In stage (iv) of the present invention, wherein temperature at which reaction mass is maintained is in between 10 to 45°C.
In stage (iv) of the present invention, wherein the time required for completion of the reaction is in between 1-6h.
In stage (iv) of the present invention, wherein the compound of formula (10) is optionally purified by distillation under vacuum.
In stage (v) of the present invention, wherein the compound of formula (10) is oxidized in the presence of base using oxidizing reagent such as DMSO-oxalylchloride complex, DMSO-thionyl chloride, DMSO-pivaloyl chloride, DMSO-acetic anhydride complex, DMSO-DCC complex, DMSO-Trifluroacetic anhydride complex, DMSO-Pyridinium sulfonate complex, Dess Martin periodinane reagent or any other suitable oxidizing agent.
In stage (v) of the present invention, wherein the base is selected from diisopropylethylamine, triethylamine, DBU, DMAP, or any other suitable base.
In stage (v) of the present invention, wherein the solvent used for the oxidation of compound of formula (10) is selected from dichloromethane, chloroform or any other organic solvent or solvent mixture.
In stage (v) of the present invention, the volume of solvent is selected from 5-20 volumes against alcohol of formula (10).
In stage (v) of the present invention, temperature at which reaction mass is maintained is in between -80 to -35°C.
In stage (v) of the present invention, the time required for completion of the reaction is in between 1-5h.
In stage (v) of the present invention, wherein, after completion of reaction, the reaction mass is quenched with dilute acid such as dilute hydrochloride acid.
In stage (v) of the present invention, wherein, the organic layer is separated, and washed with aqueous buffer solution followed by water.
In stage (v) of the present invention, wherein, the crude (S)-(-)-Garner aldehyde of formula (1) is purified via bisulfite adduct formation by reacting crude (S)-(-)-Garner aldehyde of formula (1) with aqueous sodium bisulfite solution.
In stage (v) of the present invention, wherein, aqueous sodium bisulfite adduct solution is purified by washing with ether solvent such as diisopropyl ether, diethyl ether, 2-methyl tetrahydrofuran, cyclopentylmethyl ether or any other suitable organic solvent.
In stage (v) of the present invention, wherein, pure (S)-(-)-Garner aldehyde of formula (1) is regenerated from aqueous sodium bisulfite adduct by treating with aqueous carbonate solution, such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate.
In stage (v) of the present invention, wherein, pure (S)-(-)-Garner aldehyde of formula (1) is extracted with organic solvent such as dichloromethane, chloroform, ethylacetate, toluene, 2-methyl tetrahydrofuran, diisopropylether, cyclopentylmethyl ether or any other suitable solvent or solvent mixture.
In stage (v) of the present invention, wherein, the organic layer is washed successively with water, aqueous acetic acid and water.
In stage (v) of the present invention, wherein, the purity and enantiomeric purity of (S)-(-)-Garner aldehyde of formula (1), is more than 99.0% by GC.

Advantages of the present process:
• Present process does not require toxic and explosive reagents like diazomethane and ethane thiol, pyrophoric reagents like DIBAL-H, palladium on carbon or Lithium aluminum hydride, moisture sensitive reagents like pyridinium p-toluene sulfonate, expensive and unstable reagent like lithium borohydride, hazardous reagent like ethanethiol and carcinogenic solvent like benzene.
• Present process discloses reduction of 3-(1,1-Dimethylethyl)-4-methyl-(S)-2,2-dimethyloxazolidine-3,4-dicarboxylate of formula (6) with zinc borohydride, calcium borohydride, magnesium borohydride, barium borohydride generated in-situ by the reaction of sodium borohydride with zinc chloride, calcium chloride, barium chloride or magnesium chloride.
• Present process produces optically pure (S)-(-)-Garner aldehyde of formula (1) via sodium bisulfite adduct formation.
• Present process is cost effective and feasible on large scale production.
• Raw materials used in the process are commercially available and easy to handle on commercial scale.

The following examples are provided for illustration purpose only and are not intended to limit the scope of invention.

Example-1:
Stage-1: Preparation of L-Serine methyl ester Hydrochloride (11)
Thionyl chloride (1.698 Kg) was added drop wise into a cooled mixture of L-Serine (3; 300g) suspended methanol (6.0L) under stirring at 0-5°C and further maintained for about 24h at ambient temperature. After maintenance, methanol was distilled off completely under vacuum. The resulting product was isolated from ethylacetate and dried at 55-60°C under vacuum to afford L-Serine methyl ester Hydrochloride (11) as crystalline solid.
Yield: 430.1g (96.8% by theory); Optical rotation: (+)12.2° (c=2, MeOH at 25° C): Purity: >98% by TLC.

Stage-2: Preparation of N-[(1,1-Dimethylethoxy)carbonyl]-L-serine methyl ester (5)
Triethylamine (420g) and Ditertiarybutyl dicarbonate (430g) were successively added into reaction flask containing chilled mixture of L-Serine methyl ester Hydrochloride (11; 300g) in Tetrahydrofuran (3.0L) at 0-5°C. After addition, the reaction mixture was stirred for about 24h at room temperature and distilled off the solvent completely under vacuum. The resulting residue was stirred with ~8% aqueous sodium bicarbonate solution and extracted the product with diisopropylether. The organic layer was dried and the solvent distilled off completely under vacuum to afford 388g (91.7% by theory) of N-[(1,1-Dimethylethoxy)carbonyl]-L-serine methyl ester (5) as thick oily syrup.
Purity: 95.8% (by GC). Optical rotation: (-)18.0° (c=5, MeOH at 25° C).

Stage-3: Preparation of 3-(1,1-Dimethylethyl)-4-methyl-(S)-2,2-dimethyloxazolidine-3,4-dicarboxylate (6)
2,2-dimethoxypropane (47.5g) and Boron trifluoride etherate (1.0g) were successively added into a stirred solution of N-[(1,1-Dimethylethoxy)carbonyl]-L-serine methyl ester (5; 25g) in dissolved acetone (125 mL) at 25-30°C and maintained for ~6h. After maintenance, triethylamine (2.3mL) was added under stirring and the solvent was distilled out completely under vacuum. The resulting oily residue was treated with ~8% aq. Sodium bicarbonate solution and the product was extracted with cyclohexane. The organic layer was washed with water, dried and the solvent was distilled off completely under vacuum to afford 24.5g (83.0% by theory) of 3-(1,1-Dimethylethyl)-4-methyl-(S)-2,2-dimethyloxazolidine-3,4-dicarboxylate (6) as oily syrup. The oily syrup was utilized in the next stage without further purification.
Purity: 94.4% (by GC); Optical rotation: (-)50.5° (c=1 CHCl3 at 25° C).

Stage-4: Preparation of N-[(1,1-Dimethylethoxy)carbonyl]-N,O-isopropylidene-L-Serinol (10)
Sodium borohydride (14.5g) was added lot wise into a reaction flask containing zinc chloride (26.5g) in tetrahydrofuran (800 mL) under nitrogen atmosphere at 25-30°C and maintained the heterogeneous reaction mass for ~2h. After maintenance, a solution of 3-(1,1-Dimethylethyl)-4-methyl-(S)-2,2-dimethyloxazolidine-3,4-dicarboxylate (6; 100g) in tetrahydrofuran (100 mL) was added and heated to 65-70°C. After completion of reaction, the reaction mixture was cooled to 0-5°C and quenched with ice water. Thereafter, the inorganic salts were filtered and the product was extracted with diisopropylether. The organic layer was dried and the solvent was distilled off completely under vacuum to afford 70.0g (78.5%) of N-[(1,1-Dimethylethoxy)carbonyl]-N,O-isopropylidene-L-Serinol (10).
Purity by GC: 96.4 %, Optical rotation: (-)24.1°(c=1.5 CHCl3 at 25° C).

Stage-5: Preparation of (S)-(-)-Garner aldehyde (1)
Into a reaction flask, a solution of Dimethylsulfoxide (101.4g) in methylene chloride (100 mL) was added to a solution of oxalyl chloride (82.4g) in methylene chloride (500 mL) under nitrogen atmosphere at ~ -75°C. Thereafter, a solution of N-[(1,1-Dimethylethoxy)carbonyl]-N,O-isopropylidene-L-Serinol (10; 100g) in methylene chloride (100 mL) followed by N,N-diisopropyl ethyl amine (335.3g) were successively added to the above chilled reaction mixture at - 65°C to -40°C and maintained for ~2h at -45°C. After completion of reaction, the reaction mixture was quenched by the addition of aqueous HCl and the organic layer was washed with aqueous sodium dihydrogen phosphate buffer solution. The organic layer was separated, washed with water, and solvent was distilled off completely under vacuum.
(S)-(-)-Garner aldehyde oily residue: ~120g

Step-6: Purification of (S)-(-)-Garner aldehyde (1)
Into a reaction flask, an aqueous solution of sodium bisulfite (78g) in DM water (200 mL) was added to above oily residue (~120g) and stirred for ~2h at 25-30°C. Thereafter, the aqueous solution was washed with diisopropylether and the aqueous solution was clarified with activated carbon and basified the filtrate with ~10% aqueous sodium carbonate. The product was extracted with methylene chloride and washed with ~1% aqueous acetic acid followed by DM water. The organic layer was dried, and concentrated under vacuum to afford 74.1g (73.9% by theory) of pure (S)-(-)-Garner aldehyde (1) as pale yellow oil.
GC purity: 99.35%; Chiral purity: >99.7%; Optical Rotation: (-) 94.2° (c=0.78, CHCl3, 25°C).