Regio- and Enantioselective Synthesis of Novel Functionalized Pyrano­pyrrolidines by 1,3-Dipolar Cycloaddition of Carbohydrates

Abstract

A new methodology is described for the rapid enantiomeric synthesis of a novel series of pyranopyrrolidines from readily available and inexpensive carbohydrate compounds. The major feature of the method is a highly selective [3+2] cycloaddition reaction of different azomethine ylides with a chiral carbohydrate-derived enone. The reaction proved to be extremely regio- and stereoselective, giving rise to single enantiomeric compounds in all cases. Moreover, the method is totally atom-efficient and amenable to diversity, since structural diversity of the new compounds is dictated by the choice of the starting materials employed.

Key words

cycloaddition - carbohydrates - azomethine ylides - pyranopyrrolidines - asymmetric synthesis

References

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12

All compounds were purified by the appropriate techniques and fully characterized by spectroscopic means.
Typical Experimental Procedure - Synthesis of Methyl-(1 S ,3 R ,3a R ,7a S )-4-ethoxy-6-hydroxymethyl-7-oxo-1-phenyl-octahydro-pyrano[3,4- c ]pyrrole-3-carboxylate ( 9a).
To a solution of methyl-N-benzylideneglycinate (7a, 0.23 g, 1.3 mmol, 1.5 equiv) in 20 mL of dry MeCN in a two-necked, round-bottomed flask equipped with a magnetic stirring bar and a reflux condenser were added enone 5 (0.15 g, 0.9 mmol), AgOAc (0.18 g, 1.05 mmol, 1.2 equiv), and 0.16 mL of DBU (1.05 mmol, 1.2 equiv). The mixture was stirred at r.t. during 4 h in absence of light (flask covered in aluminium foil). After filtration on celite and evaporation of the solvent under reduced pressure, the resulting brown oil was dissolved in 15 mL of CH₂Cl₂ and washed with 20 mL of NH₄Cl solution. The organic layer was then dried over MgSO₄, and the solvent was removed under reduced pressure. The resulting oil was purified by flash chromatography on silica gel (EtOAc-pentane 70:30, R _f = 0.30) to provide 9a in 60% yield as a viscous colorless oil. ¹H NMR and ¹³C NMR spectroscopy revealed two conformers.
Major conformer: ¹H NMR (300 MHz, CDCl₃): δ = 1.21 (t, J = 7.1 Hz, 3 H, ethyl-CH₃), 2.86 (dd, J _3a,7a = 9.4 Hz, J _3a,3 = 9.0 Hz, 1 H, H-3a), 3.07 (dd, J _7a,3a = 9.4 Hz, J _7a,1 = 5.7 Hz, 1 H, H-7a), 3.51-3.98 (m, 5 H, H-5, CH₂-O and ethyl-CH₂), 3.77 (s, 3 H, ester-CH₃), 4.04 (d, J _3,3a = 9.0 Hz, 1 H, H-3), 4.69 (d, J _1,7a = 5.7 Hz, 1 H, H-1), 5.12 (br s, 1 H, H-4α), 7.25-7.46 (m, 5 H, H-arom.) ppm. ¹³C NMR (CDCl₃): δ = 14.7 (ethyl-CH₃), 48.3 (C-3a), 52.5 (ester-CH₃), 55.7 (C-7a), 62.1 (ethyl-CH₂), 62.7 (C-3), 63.0 (C-1), 63.8 (CH₂-O), 76.8 (C-6), 97.0 (C-4), 124.9-139.3 (C-Ar), 172.8 (ester C=O), 207.4 (C-7) ppm. IR = 3362 (OH), 3059 (arom. C-H), 2972, 2929, 2905 (CH_n), 1736 (C=O ester), 1715 (C=O ketone), 1606 (arom. C=C), 1180, 1132, 1063 (C-O), 736 (arom. C-H), 702 (arom. C-H) cm^-1.
Minor conformer: ¹H NMR (300MHz, CDCl₃): δ = 1.17 (t, J = 7.1 Hz, 3 H, ethyl-CH₃), 3.12-3.15 (m, 1 H, H-3a, 3.25 (dd, J _7a,3a = 7.7 Hz, J _7a,1 = 7.2 Hz, 1 H, H-7a), 3.51-3.98 (m, 5 H, H-5, CH₂-O and ethyl-CH₂), 3.86 (s, 3 H, ester-CH₃), 4.19 (d, J _3,3a = 9.4 Hz, 1 H, H-3), 4.41 (d, J _1,7a = 7.2 Hz, 1 H, H-1), 5.12 (br s, 1 H, H-4α), 7.25-7.46 (m, 5 H, H-arom.) ppm. ¹³C NMR (CDCl₃): δ = 14.2 (ethyl-CH₃), 45.9 (C-3a), 52.3 (ester-CH₃), 52.4 (C-7a), 60.9 (C-1), 62.0 (ethyl-CH₂), 63.7 (CH₂-O), 65.9 (C-3), 75.5 (C-6), 96.1 (C-4), 124.9-139.3 (C-Ar), 172.2 (ester C=O), 207.4 (C-7).