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당분해저해활성을 갖는 피롤리딘 알카로이드의 입체선택적인 합성

Stereodivergent Synthesis of Glycosidase Inhibitory Pyrrolidine Alkaloids,

류영배 (Ryu, Young Bae, 경상대학교 대학원)

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초록/요약moremore
Hydroxy substituted pyrrolidines have recently attracted much attention because of their antidiabetic properties and the significant of such inhibition to both viral expression and tumor growth. Consequently, the developments of general and selective methods for the synthesis of substituted pyrrolid...
Hydroxy substituted pyrrolidines have recently attracted much attention because of their antidiabetic properties and the significant of such inhibition to both viral expression and tumor growth. Consequently, the developments of general and selective methods for the synthesis of substituted pyrrolidine is an active field of research. This study developed the new approach to five-membered azasugar, 1,4-dideoxy-1,4-imino-D-arabinitol (1) and 1,4-dideoxy-1,4-D-ribitol (2), from D-glucono-δ-lactone. The new approach involved an 5-endo-trig-cycl ization and a stereodivergent hydroxylation using Woodward-Prevost transformation. Both synthesized azasugars 1,4-dideoxy-1,4-imino-D-arabini tol (1) and 1,4-dideoxy-1,4-imino-D-ribitol (2) were examined a glycosidase inhibitory activity. The results were summarized as follows. -The requisitic substrate 8 was prepared through selective protection of diisopropylidene groups and perfect SN2 azidation step. Resioselective hydrolysis of diisopropylidene 10 and simple C-C bond cleavage gave compound 12. - Further transformations by efficient eliminative cleavage of the ketal by n-butyl lithium gave allyl alcohol 15 which is the valuable chiral synthon for 5-endo-trig-cyclization step. - The developed synthon 16 was treated with I2 under biphasic conditions (eq. NaHCO3-THF-Et2O = 2:1:1) at room temperature to give all trans pyrrolidine 17 as the sole product in high yield via 5-exo-trig- cyclization. - Key intermediate 17 with a trans relationship between iodine and acetoxy groups allowed to set up for Woodward-Prevost transformations, which proceed by neighboring group participation of the acetate. Treatment of wet AgBF4 (Woodward condition) to 17 and the following simple deacetylation with LAH gave 3,4-cis pyrrolidine 21. On the other hand, treatment of 17 with dried AgOAc (Prevost condition) and the following deacetylation with LAH gave 3,4-trans pyrrolidine 19 in high yield stereodivergently. Target compounds 1 and 2 were prepared easily through the hydrogenation of 17 and 19 with H2/Pd. - Target compounds 1 and 2 showed a strong glucosidase inhibitory activity with IC50 = 0.4 mM and IC50 = 0.9 mM, respectively. - In the type of inhibition through Lineweaver-Burk plot, both target compounds 1 and 2 showed competitive model against a-glucosidase.
목차moremore
Ⅰ. Abstract 1
Ⅱ. 서 론 3
Ⅲ. 결 과 및 고 찰 10
...
Ⅰ. Abstract 1
Ⅱ. 서 론 3
Ⅲ. 결 과 및 고 찰 10
1. 역합성경로 10
2. 1,4-dideoxy-1,4-imino-D-arabinitol (1) 11
3. 1,4-dideoxy-1,4-imino-D-ribitol (2) 15
4. 당분해효소저해활성 17
Ⅳ. 실 험 재 료 및 방 법 20
1. 실험재료 및 사용 기기 20
2. Methyl 3,4;5,6-di-O-isopropylidine-D-gluconate (4) 합성 21
3. Methyl 2-[(9-phenyl-fluoren-9-yl)amino]-2-deoxy-3,4;5,6-di-O-isopropylidine-D-mannoante (8) 합성 23
4. 3,4-O-isopropylidine-6-O-benzyl-5-[(9-phenyl-fluoren-9-yl)amino]-1,2,3,4,6-pentatetraol (11) 합성 26
5. 5-O-benzyl-4-[(9-phenyl-fluoren-9-yl)amino]-3,5-pentadiol-1-en (15) 합성 29
6. 1-O-benzyl-3-O-acetyl-4-iodo-N-(9-phenyl-fluoren-9-yl)-(2R,3R,4S)-pyrrolidine (17)의 합성 30
7. 1,4-Dideoxy-1,4-imino-D-arabinitol (1) 합성 33
8. 1,4-Dideoxy-1,4-imino-D-ribitol (2) 합성 34
9. 당분해효소저해 검증 36
Ⅵ. 요 약 37
Ⅶ. 참 고 문 헌 39
Ⅷ. 별 첨 43