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Synlett 2010(3): 488-492  
DOI: 10.1055/s-0029-1219189
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

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

Wu-Bao Wanga,b, Mu-Hua Huanga, Yi-Xian Lia,b, Pei-Xin Ruia, Xiang-Guo Hua,b, Wei Zhanga,b, Jia-Kun Sua,b, Zhao-Lan Zhanga,b, Jian-She Zhua,b, Wei-Hua Xua, Xian-Qing Xiea, Yue-Mei Jia*a, Chu-Yi Yu*a
a Beijing National Laboratory for Molecular Science (BNLMS), CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, P. R. of China
Fax: +86(10)82616433; e-Mail: yucy@iccas.ac.cn;
b Graduate University of The Chinese Academy of Sciences, Beijing 100049, P. R. of China
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Publication History

Received 28 October 2009
Publication Date:
11 January 2010 (online)

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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

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 literature²0 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) {Lit¹8d [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.