Synthesis of (r)-dihydropyridones as Key Intermediates for an Efficient Access to Piperidine Alkaloids

The efficient transformation of D-glucal to (2R)-hydroxymethyldihydro-pyridinone 5 in seven steps and 35 % overall yield is reported. Dihydropyridone 5 constitutes a versatile chiral building block for the synthesis of various piperidine alkaloids. In this regard, 5 was converted to piperidinol 13 and piperidinone 15, that may be further elaborated for the syntheses of (+)-desoxoprosophylline (1) and deoxymannojirimycin (3) or D-mannolactam (4), respectively.


Ts
As a result intense research efforts have been devoted to the development of methodologies and synthetic strategies for the efficient preparation of these compounds and derivatives.Most of these methods utilize sugars or amino acids as their chiral pool synthons [13][14][15][16][17][18][19] and suffer from a lack of selectivity and applicability to diverse compounds.On the other hand, the optically active 1,6-dihydro-2H-pyridin-3-ones represent flexible building blocks for the efficient access to diverse multifunctionalized bioactive indolizines, quinolizidines and piperidine alkaloids [20].Recently, we reported the preparation of (2S)-hydroxymethyldihydropyridinone, [21] a chiral key intermediate for the synthesis of various piperidine alkaloids such as (-)-desoxoprosophylline, allonojirimycin and indolizidine alkaloids (e.g.swainsonine).The common structural feature of all the aforementioned molecules is the (S)-configuration at C-2. Herein we present an efficient and highly enantioselective route to its (R)−enantiomer 5 starting from the commercially available D-glucal.This molecule represents a key intermediate for the synthesis of broad variety natural and unnatural piperidine alkaloids and/or iminosugars displaying an (R)-configuration at C-2.

Results and Discussion
The key step for the implementation of the proposed synthetic sequence is the synthesis of chiral (R)-N-[2-(tert-butyldiphenylsilyloxy)-1-furan-2-yl-ethyl]-4-methylbenzenesulfonamide (10), since all final products retain that stereochemistry.Commercially available D-glucal was used as strarting material for the synthesis of this intermediate.More specifically, D-glucal was reacted with HgSO 4 (as a solution in 0.002 M H 2 SO 4 ) and subsequently its primary hydroxy group was protected with TBDPSCl to provide the 2-furyl glycol (+)−6, according to a literature procedure reported by Hauser et al. (Scheme 1) [22].
The stereochemistry of compound 6 was efficiently inverted using the Mitsunobu protocol (DEAD, Ph 3 P, benzoic acid) affording the (S)-ethyl-2-(tert-butyldiphenylsilanyloxy)-1-furan-2-yl-benzoate 7, which was further saponified to afford (S)-1-furan-2-yl-ethanol 8.The displacement of the secondary hydroxy group with azide with inversion of configuration was performed in high enantiomeric excess (>98%) on treating 8 with DBU in toluene and DPPA.The enantiomeric excess was determined by hydrogenating compound 9 over 10% Pd/C (4 mg) under 1 bar pressure for 40 min [23].The mixture was filtered over Celite ® and the amine was then derivatized by adding Et 3 N and (−)-menthyl chloroformate.The ratio of enantiomers was determined by reversed-phase HPLC [Kromasil 100- 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 at C-2 derives from the starting material).Thus, the clear strong cross peak observed between the protons on C-2 and C-6 is indicative of their cis pseudo-diaxial conformation (Figure 2).Furthermore, the observed NOE between the aromatic protons of the tosyl group and the protons of tert-butyldiphenylsilanyloxymethyl group confirmed this configuration.Finally, the observed optical rotation value for  This intermediate may be incorporated into the stereoselective synthesis of (+)-desoxoprosophylline (1), according to already published synthetic routes [1,24].

Conclusions
In summary, we have demonstrated a concise synthetic route to (2R)-hydroxymethyldihydropyridone 5, a chiral key intermediate useful in the synthesis of a variety of naturally occurring bioactive piperidine alkaloids, such as (+)-desoxoprosophylline, deoxymannojirimycin and D-mannolactam.

General
Air-and /or moisture sensitive reactions were carried out under an argon atmosphere in flamedried 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 +28.7, c 2.03, MeOH) was prepared according to a literature procedure [22].All reactions were monitored by thin-layer chromatography using TLC sheets coated with silica gel 60 F 254 (Merck); spots were visualized with UV light or/and an alcohol solution of anisaldehyde.Products were purified by flash chromatography on Merck silica gel 60 (230-400 mesh ASTM).Melting points (uncorrected): Büchi melting point apparatus.FT-IR: Nicolet Magna 750, series II.Samples were recorded as KBr pellets, unless otherwise stated.Optical rotations were measured with a Perkin-Elmer-241 polarimeter. 1 H-NMR spectra were recorded on a Bruker DRX-400 (400 MHz) spectrometer, in CDCl 3 .Chemical shifts are referenced to internal TMS.Coupling constants (J) are expressed in Hz.HPLC: Hewlett Packard 1100 series instrument with a variable wavelength UV detector and coupled to HP Chem-Station utilizing the manufacturer's 5.01 software package.