Efficient Route to (2R)-6-Hydroxy-2-methyl- dihydropyridin-3-ones, Key Intermediates for Piperidine Alkaloids Syntheses

The efficient synthesis of (2R,6S)-6-hydroxy-2-methyl-1-tosyl-1,2-dihydropyridin-3(6H)-one 5 in five steps and 30 % overall yield is reported. This dihydropyridone constitutes versatile chiral building block repetitively used in the synthesis of various piperidine alkaloids and may serve as key template for the construction of synthetic libraries of bioactive derivatives and analogues of the piperidine alkaloids.


Introduction
Multifunctionalized piperidine alkaloids (including azasugars) constitute a distinct class of natural compounds widely found in living systems [1] that exhibit a wide range of biological activities, as a result of their ability to mimic carbohydrate substrates in a plethora of enzymatic processes [2,3]. These activities include glycosidase inhibition [4], tumour growth inhibition [5] and anti-HIV behaviour[6], making those particularly attractive synthetic targets.
Thus, an intense research effort has been devoted for the development of methodologies and synthetic strategies for the efficient approach of these compounds and their derivatives [7][8][9][10]. Among the various synthetic routes developed for their efficient access, the use of dihydropyridones as advanced intermediates −prior to their conversion to piperidines− constitutes a well reviewed important synthetic strategy [11,12] that has been a long term objective of our research group [12 and references therein]. In this respect, a series of synthetic methods including the microwave-assisted synthesis, regioselective nucleophilic addition to pyridinium salts, incorporation of boronate esters to dihydropyridones, have been reported during the last 5 years as concise routes for the preparation of dihydropyridone derivatives [13][14][15].

Chemistry
Our synthetic route substrate is the commercially available molecule of 3,4-di-O-acetyl-6-deoxy-L-glucal, which in acidic environment (0.002 M H 2 SO 4 solution) by reaction with HgSO 4 was efficiently converted to the optically active furfural 2, in accordance to a previously reported method [17]. The displacement of the secondary hydroxy group with the azide moiety, with the simultaneous inversion of its configuration, was performed in high enantiomeric excess (>98%) by treating the compound 2 with DBU in toluene and DPPA. The enantiomeric excess of azide 3 was determined after the hydrogenation of the molecule for 50 min over 10% Pd/C catalyst and 1 bar pressure [18]. The mixture was filtered over Celite® and the resulting amine was in situ derivatized with (−)-menthyl chloroformate, in the presence of  On the other hand, the hydrogenation of 3 over Pd/C and subsequent in situ tosylation of the resulting amine afforded the (R)-N-furfurylsulfonamide 4. Finally, the oxidative cyclization of compound 4, using a modified version of the standard aza-Achmatowich rearrangement conditions, provided the target dihydropyridone 5.
The diastereomeric purity of the product was revealed by 1 H-NMR and HPLC, since the presence of the other diastereoisomer was not detected, while the stereochemistry of the newly formed stereocenter was determined by 2D-NOESY spectroscopic analysis (the absolute configuration of C-2 derived from the starting material). Thus, the clear strong cross peak observed between the protons on C-2 and C-6 confirms their cis pseudo-diaxial conformation ( Figure  2).

Experimental Part
Air-and /or moisture sensitive reactions were carried out under argon atmosphere in flame-dried glassware. Solvents were distilled from the appropriate drying agents prior to use. All starting materials were purchased from Aldrich (analytical reagent grades) and used without further purification.
(R) -N-(1-(furan-2-yl)ethyl)-4-methylbenzenesulfonami de, 4: 60 mg (0.44 mmol) of (R)-2-(1-azidoethyl)furan 3 in 10 mL EtOAc were hydrogenated at atmospheric pressure using as catalyst 10% w/w Pd/C (0.04 g). After 1.5 h of stirring the reaction was completed and the solution was filtered through celite. The filtrate was dried over MgSO 4 and concentrated under reduced pressure to provide an oily residue. Then, 3 mL CH 2 Cl 2 and 0.12 mL Et 3 N (0.9 mmol) were added, cooled to 0 ° C and 0.07 g (0.49 mmol) of benzoyl-chloride were added gradually under stirring. After completion of the addition, the reaction temperature was maintained at 0 ° C for 10 min and then allowed to proceed the room temperature and stirred for additional 3 h. Then, the reaction mixture was quenched with saturated solution of NaHCO 3 and brine was added. The organic phase was separated, dried over MgSO 4 and concentrated under reduced pressure. The resulting yellow solid was flash chromatographed using as eluent hexane/EtOAc 8.5:1.5, providing 77 mg of sulphonamide 4 (yield, 67%), which recrystallizes as white crystals from Et 2 O/hexane. 1

Conclusions
The commercially available L-glucal substrate provided efficiently the molecule of dihydropyridin-3(6H)-one in five steps and satisfactory overall yield (30.3%). This compound can serve as crucial key intermediate for the efficient syntheses of various bioactive natural piperidine alkaloids.