Two- and Three-Component Hantzsch Reaction Using C-Glycosylated Reagents. Approach to the Asymmetric Synthesis of 1,4-Diyhydropyridines

 

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Abstract

Two- and three-component Hantzsch-type cyclocondensation reactions were carried out under thermal conditions using C-glycosylated reagents, namely sugar aldehydes, ketoesters, and enamines. Two different series of 1,4-dihydropyridines bearing C-glycosyl moieties at C4 and C6 were obtained in good to excellent overall yields (61-90%). The asymmetric induction due to carbohydrate residues was also investigated.

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Enamine 3a was obtained as single geometric isomer while 3b appeared to be ˜1:1 mixture of E and Z isomers. Specific rotation values are reported. Ribo series: 3a: [α]^{2 0} _D +19 (c 1.1, CHCl₃). 6a: [α]^{2 0} _D +39 (c 0.9, CHCl₃). 7a: [α]^{2 0} _D +4 (c 1.0, MeOH). 9a(major): [α]^{2 0} _D +103 (c 1.5, CHCl₃).
9a (minor): [α]^{2 0} _D +136 (c 0.8, CHCl₃). 10a (major): [α]^{2 0} _D = +11 (c 1.7, MeOH). 10a(minor): [α]^{2 0} _D = +84 (c 1.0, MeOH). Galacto series: 6b: [α]^{2 0} _D +72 (c 1.4, CHCl₃). 7b: [α]^{2 0} _D -26 (c 0.8, MeOH). 9b(major): [α]^{2 0} _D +33 (c 1.1, CHCl₃).

Aminomethylated polystyrene (AM-resin) was purchased from Novabiochem.

General experimental procedure for the two-component Hantzsch reaction leading to 6-C-glycosyl 4-phenyl DHP’s: A mixture of enamine 3a (258 mg, 0.5 mmol), enone 11 (545 mg, 2.5 mmol), activated 4-Å molecular sieves (200 mg), and anhyd DMF (2 mL) was stirred at 150 °C for 48 h, then cooled to r.t., filtered through a pad of Celite, and concentrated. The residue was diluted with CH₂Cl₂ (5 mL) and treated with aminomethylated polystyrene [18] (1.0 g, 2.5 mmol of ˜2.5 mmol/g resin). The suspension was stirred for an additional 2 h then the resin was filtered off and washed thoroughly with CH₂Cl₂. The combined filtrates were concentrated and eluted from a column of silica gel with cyclohexane-EtOAc, 9:1 to give first major-9a (154 mmol, 43%). Eluted second was minor-9a (102 mg, 28%). A vigorously stirred mixture of major-9a (154 mg, 0.21 mmol), 20% Pd(OH)₂ on activated carbon (80 mg), AcOEt (2 mL) and EtOH (2 mL) was degassed under vacuum and saturated with H₂ (by a H₂-filled balloon) three times. The suspension was stirred at room temperature for 2 h under a slightly pressure of H₂(balloon), then filtered through a pad of Celite and concentrated to afford major-10a (91 mg, 95%) as a white amorphous solid. ¹H NMR (CD₃OD): δ = 9.15 (s, 1 H, NH), 7.35-7.05 (m, 5 H, Ph), 5.51 (d, 1 H, J _1",2" = 0.5 Hz, H-1"), 4.95 (s, 1 H, H-4), 4.20-3.90 (m, 8 H, 2 OCH ₂CH₃, H-2", H-3", H-4", H-5"a), 3.84 (d, 1 H, J _5"a,5"b = 12.0 Hz, H-5"b), 2.30 (s, 3 H, CH₃), 1.24 (t, 3 H, J = 7.0 Hz, OCH₂CH ₃), 1.23 (t, 3 H, J = 7.0 Hz, OCH₂CH ₃). ¹³C NMR (CD₃OD) selected data: δ = 168.4, 167. 6, 148.5, 148.0, 145.6, 103.6, 101.5, 82.0, 78.4, 65.4, 59.9, 59.1, 39.7, 17.2, 13.4. MALDI-TOF MS: 448.2 (M⁺+H), 470.5 (M⁺+Na). Anal. Calcd for C₂₃H₂₉NO₈: C, 61.73; H, 6.53; N, 3.13. Found: C, 61.78; H, 6.55; N, 3.18.

The 1,2-elimination of BnOH occurred in the galactosyl moiety of 9b to give the corresponding 1,2-dihydro-derivative as a main product in 60% yield.