Highly Concise Synthesis of 3'-"Up"-ethynyl-5'-methylbicyclo-[3.1.0]-hexyl Purine and Pyrimidine Nucleoside Derivatives Using Rhodium(II) Carbenoid Cycloaddition and Highly Diastereoselective Grignard Reaction |
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| Authors: | YANG Zunhua KIM Kyung Ran PARK Ah-Young LEE Hyung-Rock KANG Jin-Ah KIM Won Hee CHUN Pusoon GONG Ping LEE Boeun JEONG Lak Shin MOON Hyung Ryong |
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| Institution: | 1. School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China;2. Laboratory of Medicinal Chemistry, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan 609‐735, Korea;3. College of Pharmacy, Seoul National University, Seoul 151‐742, Korea;4. Laboratory of Medicinal Chemistry, College of Pharmacy, Ewha Womans University, Seoul 120‐750, Korea;5. Tel.: 0082‐51‐510‐2815;6. Fax: 0082‐51‐513‐6754 |
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| Abstract: | Synthesis of north‐5'‐methylbicyclo3.1.0]hexyl purine and pyrimidine nucleosides with an ethynyl group at C‐3' position has been successfully accomplished by a facile method. Methylbicyclo3.1.0]hexanone (±)‐ 5 having three contiguous chiral centers was remarkably simply constructed only by four steps containing a carbenoid insertion reaction in the presence of rhodium(II) acetate dimer and CuSO4, giving a correct relative stereochemistry of the generated three chiral centers. Upon Grignard reaction of (±)‐ 5 with ethynylmagnesium bromide, exclusive diastereoselectivity was observed. Condensation of glycosyl donor (±)‐ 9 with purine nucleobase afforded only the desired N9‐alkylated nucleoside, while condensation with pyrimidine, N3‐benzoylated uracil gave the desired N1‐alkylated nucleoside (±)‐ 13 with the undesired O2‐alkylated nucleoside (±)‐ 14 . Probably, (±)‐ 14 would be formed due to steric hindrance caused upon approaching for N1‐alkylation. |
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| Keywords: | cycloaddition diastereoselective bicyclo[3 1 0]hexanone north conformation steric hindrance |
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