Asymmetric total synthesis of L-allo -1-deoxynojirimycin

Asymmetric total synthesis of L-allo -1-deoxynojirimycin (L-allo -DNJ) was achieved from cis - butene-1,4-diol by employing Sharpless asymmetric dihydroxylation, stereoselective flash dihydroxylation and ring enlargement

In literature, there are several protocols for the synthesis of L-allo-DNJ 4 [21][22][23][24][25][26][27][28][29][30] mostly based on carbohydrates or amino acids as chiral templates." Earlier, asymmetric syntheses of L-allo-DNJ 4 have been reported which was based on Sharpless asymmetric epoxidation, 31 Sharpless asymmetric dihydroxylation 32 and chemoenzymatic approach. 33Synthetic challenge in L-allo-DNJ 4 is the construction of piperidine moiety and installation of hydroxyl groups in a stereoselective manner.Due to its interesting biological activity and structural features, L-allo-DNJ 4 has attracted many organic chemists towards its synthesis.Herein, we describe an enantioselective synthesis of L-allo-DNJ 4 from commercially inexpensive and easily available starting material viz.cis-butene-1,4-diol.

Results and Discussion
According to the retrosynthetic plan (Scheme 1), lactam 6 can be generated from butenolide 7 via dihydroxylation, protection and deprotection sequence.Azidolactone 8 could be easily accessed from cis-butene-1,4-diol by employing OsO 4 as the catalyst in presence of chiral ligand (DHQD) 2 PHAL by following the procedure reported by us. 345][36][37][38] This group has also reported total synthesis D-allo-DNJ, L-talo-DNJ by chiron approach from L-tartaric acid. 35In continuation of our interest in synthesis of piperidine alkaloids, we then turned our attention towards the asymmetric synthesis of L-allo-DNJ 4 from cis-butene-1,4-diol (Scheme 3) employing isomerisation, 39 Claisen orthoester rearrangement, 40 Sharpless asymmetric dihydroxylation, [41][42][43] Scheme 2. Reagents and conditions: a) LDA, PhSeSePh, THF, -78 o C; b) Acetic acid, THF, H 2 O 2 , 10-20% yield. .stereoselective flash dihydroxylation and intra-molecular lactone ring opening reaction as the key steps.Azidolactone 8 is a versatile intermediate reported and exploited by our group.It was decided to utilise this azido lactone for the synthesis of L-allo-DNJ.So with this idea in mind, azidolactone was treated with LDA and diphenyl diselenide at -78 o C, furnished the phenyl αselenolacone 8a which on subsequent treatment with H 2 O 2 (Scheme 2) furnished the azido butenolide compound 8b in low yields Attempts to improve the yield of this conversion using varying amounts of LDA were unsuccessful.So an alternate reaction sequence strategy was employed wherein one pot azide reduction of 8 and in situ protection of amine was carried out using Pd(OH) 2 under hydrogen atmosphere in the presence of (Boc) 2 O, TEA to provide urethane 11 in 88% yield (Scheme 3).Carbamate 11 was treated with LDA (4 eq.) in THF at -78 o C followed by addition of diphenyldiselenide to furnish diastereomeric mixture of α-phenylseleno lactone 12 in 57% yield.We did not establish the stereochemistry of its diastereomers at this stage, as it was to be eliminated in the next step.The α-phenylseleno lactone 12 was subjected to elimination by using hydrogen peroxide in the presence of acetic acid in THF to afford butenolide 7 in 78% yield.Butenolide 7 was subjected to flash dihydroxylation 44 to provide diol 13 in 71% yield.We followed the same reaction sequence for the synthesis of racemic diol 13 and established the enantiomeric excess (ee>97%) and diastereomeric ratio (dr 95:5) by chiral HPLC.Literature survey for similar butenolide revealed that α-stereogenic centre directs the dihydroxylation reaction mediated by osmium tetraoxide 45 or KMnO 4 46 or RuCl 3 / NaIO 4 . 47To carry out other functional group transformations, diol 13 was protected as its acetonide by using DMP and cat.CSA in DCM to furnish acetonide 14 in 91% yield.Ring expansion of acetonide compound 14 was carried out out using TFA in DCM to provide the desired six membered lactam 6 in 53% yield.Lactam 6 was reduced by using BH 3 .DMS in THF to give corresponding amine, which without purification was protected using TEA, (Boc) 2 O and DMAP (cat.) in THF to afford urethane 15 in 58% (over two steps).The O-debenzylation of urethane compound 15 was carried out using Pd(OH) 2 as the catalyst under hydrogen atmosphere followed by acid treatment to provide hydrochloride salt of L-allo-DNJ 4. 48 In principle, one can easily synthesize D-isomer of L-allo-DNJ by switching catalyst from (DHQD) 2 PHAL to (DHQ) 2 PHAL and by following same protocol.

Conclusions
We have been able to develop a protocol for asymmetric total synthesis of L-allo-DNJ 4 (14 steps, 1.6% overall yield) from cis-butene-1,4-diol by employing Sharpless asymmetric dihydroxylation, stereoselective dihydroxylation and ring expansion as the key steps.

Experimental Section
General. 1   (20 mL) was added to the solution of LDA (prepared from diisopropyl amine (3.5 mL, 25 mmol), n-butyl lithium (15.7 mL, 25 mmol, 1.6 M in hexane) in dry THF (20 mL) at 0 o C under the nitrogen atmosphere at -78 o C.After 30 min, diphenyldiselenide (1.9 gm, 6.26 mmol) was added and the reaction mixture was stirred at -78 o C for 60 minutes.The reaction mixture was quenched with saturated solution of NH 4 Cl (50 mL) and extracted with ethyl acetate (3 × 30 mL).Drying over anhydrous sodium sulphate, filtering and evaporation of solvent furnished a residue which was purified by flash column chromatography (SiO 2 ) using 20 % ethyl acetate in pet.ether as an eluent to obtain αphenylseleno lactone 12 as white semisolid compound (1.2 gm, 55% bsmr).To a solution of α-phenylseleno lactone 12 (75 mg, 0.15 mmol) in THF (5 mL) containing CH 3 COOH (0.025 mL) cooled to 0 o C, was added 30% H 2 O 2 (0.035 mL).The reaction mixture was stirred for 30 minutes at 0 o C, then poured into cold saturated solution of sodium carbonate solution and extracted with ethyl acetate (2 × 20 mL).The combined organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to furnish a residue which was purified by column chromatography over flash silica gel, eluting with 20% ethyl acetate in pet.ether as the eluent to afford butenolide 7 (40 mg, 78%) as a white semisolid. [α]

tert-Butyl ((R)-2-(benzyloxy)-1-((3aR,4R,6aR)-2,2-dimethyl-6-oxotetrahydrofuro[3,4d][1,3]dioxol-4-yl)ethyl)carbamate (14).
To a solution of dihyroxy lactone 13 (0.2 gm, 0.54 mmol) in DCM was added p-TSA (cat) and 2,2-dimethoxypropane (0.28 mL, 2.7 mmol).After stirring under an atmosphere of nitrogen for 18 h at room temperature, the reaction mixture was concentrated under reduced pressure.Saturated solution of sodium carbonate was poured on residue and extracted with DCM (3 × 20 mL).The combined organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to furnish a residue which was purified by column chromatography over silica gel, eluting with 20% ethyl acetate in pet.ether as an eluent to afford compound 14 (0.2 gm, 91%) as a colorless syrup.[α]  (15).To a solution of lactam 6 (0.1 gm, 0.32 mmol) in anhydrous THF (5 mL) was added BH 3 .DMS (0.15 mL, 1.6 mmol) dropwise at 0 o C under the nitrogen atmosphere.The reaction mixture was allowed to stir at room temperature for 18 h, cooled to 0 o C and quenched by addition of ethanol (5 mL).Solvent was removed under reduced pressure and the crude semisolid residue was treated with additional ethanol (5 mL) and refluxed for 6 h.Solvent was removed under reduced pressure to furnish crude amine.To the solution of crude amine in THF was added TEA (0.07 mL) followed by addition of (Boc) 2 O (0.089 mL) and DMAP (cat.) and was stirred at room temperature for 24 h.The reaction mixture was extracted with ethyl acetate (3 × 20 mL), washed with water, brine and dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure.The residue was purified by silica gel chromatography using petroleum ether/ethyl acetate (7:3) as an eluent to afford colorless oily carbamate 15 (74 mg, 58% (over two steps)).[α] (2S,3S,4R,5R)-2-(hydroxymethyl)piperidine-3,4,5-triol hydrochloride (4).To a solution of urethane 15 (30 mg, 0.076 mmol) in MeOH (5 mL) was added Pd(OH) 2 under an atmosphere of hydrogen.The reaction mixture was allowed to stir for 6 h.After completion of reaction (monitored by TLC), the reaction mixture was filtered through a celite bed and was thoroughly washed with methanol (20 mL) for 3 times.Concentration of the reaction mixture under reduced pressure provided the diol.To the solution of diol in methanol (3 mL) was added conc.HCl (0.1 mL) at 0 o C. The reaction mixture was stirred for 3 h at room temperature.After completion of reaction, the volatiles were concentrated under reduced pressure.The semisolid mass was dried under high vacuum for 3 h (17.6 mg, 80% over two steps).