A Practical Synthesis of Sugar-Derived Cyclic Nitrones: Powerful Synthons for the Synthesis of Iminosugars

Abstract

Sugar-derived cyclic nitrones were synthesized from the corresponding aldoses through an efficient and practical procedure involving a seven-step reaction sequence in good to excellent overall yield (10-42%). This synthetic strategy, requiring only inexpensive reagents, is easy to perform and hence suitable for large-scale preparations.

Key words

sugar-derived cyclic nitrones - synthesis - iminosugars - nitrones

References and Notes

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21

General methods for the synthesis of 5 and 10:
Method A: Compounds 1 and 6 were prepared from the corresponding aldoses (90 g 0.6 mol) in three steps according to the literature^²0 and were used directly in the next step without further purification. NH₂OMe˙HCl (55.12 g, 0.66 mol, 1.1 equiv) and Et₃N (91.9 mL, 0.66 mol, 1.1 equiv) were added to a solution of crude compound 1 or 6 (crude product prepared from 0.6 mol aldose) in anhydrous CH₂Cl₂ (300 mL). The reaction reached completion after vigorous stirring for about 12 h. The reaction mixture was then concentrated in vacuo and the resulting mixture was dissolved in EtOAc-H₂O. The organic phase was separated and the aqueous phase was extracted with EtOAc (3 × 150 mL). The combined organic phases were dried with anhydrous Na₂SO₄ and filtered, the filtrate was concentrated in vacuo to give the crude product 2 or 7, which was used directly in the next step of reaction without further purification. To an ice-cooled solution of 2 or 7 in Et₃N (91.9 mL, 0.66 mol, 1.1 equiv) and CH₂Cl₂ (300 mL), was added methanesulfonyl chloride (51.08 mL, 0.66 mol, 1.1 equiv) slowly, and the mixture was allowed to warm gradually to r.t. After 1 h, the reaction mixture was quenched by addition of H₂O (200 mL). The organic phase was separated and the aqueous phase was extracted with EtOAc (3 × 150 mL). The combined organic phases were dried over anhydrous MgSO₄. After filtration, the solvent was removed in vacuo to give crude product 3 or 8 as a yellow oil, which was used directly in the next step without further purification. To a well-stirred solution of 3 or 8 in THF (400 mL), p-TsOH (114 g, 0.6 mol) and aq HCHO (37%, 150 mL) were added subsequently. After stirring for 36 h, the reaction was neutralized with sat. aq NaHCO₃. EtOAc (600 mL) was added to the reaction mixture, the organic phase was separated and the aqueous phase was extracted with EtOAc (3 × 150 mL). The combined organic phases were dried with anhydrous Na₂SO₄. After filtration, the filtrate was concentrated in vacuo, the resulting crude product 4 or 9 was used directly in the next step of reaction without further purification. A solution of NH₂OH˙HCl (93.15 g, 1.35 mol) and NaHCO₃ (113.4 g, 1.35 mol) in H₂O (150 mL) was added to the solution of crude 4 or 9 in EtOH (600 mL) dropwise. The reaction mixture was stirred at r.t. for 12 h and then stirred at about 60 ˚C until TLC showed the reaction to have reached completion. The solvents were removed in vacuo and the residue was dissolved in EtOAc (300 mL) and H₂O (200 mL). The organic phase was separated and the aqueous phase was extracted with EtOAc (3 × 150 mL). The combined organic phases were dried with anhydrous Na₂SO₄. After filtration and concentration in vacuo, the resulting crude product was either recrystallized or purified by flash column chromatography (petroleum ether-EtOAc, 2:1→1:2). Method B: The same procedure as method A was used with purified compounds 1 and 6 as starting material. Compound 5a: 129.0 g (23% from 200 g d-arabinose); 79.4 g from 210.3 g 1a (38%). Yellow oil; [α] _d ^²0 -78 (c 1.08, CH₂Cl₂) {Lit^¹8d [α] _d ^²³ -75.9 (c 0.54, CH₂Cl₂)}. IR (thin film): 3030 (w), 2866 (m), 1582 (s), 1496 (w), 1454 (s), 1363 (m), 1095 (s), 737 (s), 697 (s) cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 7.27-7.14 (m, 15 H, Ph), 6.73 (s, 1 H, H-2), 4.67 (t, J = 2.1 Hz, 1 H, H-3), 4.58-4.38 (m, 6 H, PhCH ₂), 4.28 (dd, J = 7.6, 4.5 Hz, 1 H, H-4), 4.08-4.03 (m, 1 H, H-5), 3.90 (dd, J = 10.1, 4.3 Hz, 1 H, H-6), 3.73 (dd, J = 10.1, 1.6 Hz, 1 H, H-6). ^¹³C NMR (75 MHz, CDCl₃): δ = 138.0, 137.4, 137.3, 133.4 (C-2), 128.7, 128.6, 128.4, 128.2, 128.1, 128.0, 127.9, 127.6 (Ph), 83.2 (C-3), 80.6 (C-4), 74.2 (C-5), 73.6, 73.2, 72.5, 64.5 (C-6). Compound 10a: 88.2 g (42% from 75 g d-arabinose); 94 g from 181.6 g 6a (52%). Light-yellow oil; [α] _d ^²0 -44 (c 1.17, CHCl₃). IR (thin film): 2960 (s), 2925 (s), 2855 (s), 1597 (w), 1454 (m), 1260 (s), 1023 (s), 800 (s), 739 (m), 698 (m) cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 7.33-7.25 (m, 15 H, Ph), 7.01 (d, J = 2.9 Hz, 1 H, H-2), 4.94-4.58 (m, 6 H, PhCH₂), 4.31 (d, J = 3.6 Hz, 1 H, H-3), 4.06-3.82 (m, 4 H, H-6, H-4, H-5). ^¹³C NMR (75 MHz, CDCl₃): δ = 137.6, 137.3, 128.6, 133.4 (C-2), 128.6, 128.5, 128.2, 128.1, 128.0, 127.9, 127.8 (Ph), 74.6, 73.5, 72.9, 72.8, 72.1, 71.4 (C-3, C-4, C-5), 60.0 (C-6). TOF-HRMS (ESI+): m/z [M + H]⁺ calcd for C₂₆H₂₈NO₄: 418.2013; found: 418.2001.