One‐Pot Synthesis of Azanucleosides from Proline Derivatives – Stereoselectivity in Sequential Processes

Abstract

reaction. The stereoselectivity of the reaction is influenced by the nucleophilicity of the approaching base and by the substitution pattern of proline derivative. -(BOTO*, A.; HERNANDEZ, D.; HERNANDEZ, R.; Eur.

One‐Pot Conversion of Proline Derivatives into Iodinated Iminosugar‐Based Nucleosides, Useful Precursors of Highly Functionalized Nucleoside Analogues

“…In a similar manner, the reaction with trimethylsilyl‐benzyloxypurine gave the non‐iodinated derivative (±)‐ 21 (10 %)6 and the desired β‐iodo‐nucleoside analogue (±)‐ 22 (40 %).…”

“…In contrast, addition of the nucleophile from the outer face of intermediates 31 and 32 is disfavored: in this case the initially‐formed trans product presents strong eclipsing interactions between the substituents at C‐2 and C‐3 6,20. Due to this effect, the all‐ cis pyrrolidine 34 is formed in spite of the steric hindrance posed by the iodo group once the initially‐formed trans product equilibrates to its other conformations.…”

“…In the case of the chloropurine derivatives, the non‐halogenated product (±)‐ 19 (11 %)6 and the desired 2,3‐ trans ‐3‐iodo‐nucleoside analogue (±)‐ 20 (47 %) were readily separated. The chloro group in 6‐chloropurine can be replaced by other groups (amino, aryl, or alkyl, etc) using sp n –sp n couplings, radical reactions, etc.,15 which allows the formation of libraries of nucleoside derivatives.…”

“…6‐(Benzyloxy)‐9‐[ N ‐(methoxycarbonyl)‐2‐pyrrolidinyl]purine (±)‐21 and 6‐(Benzyloxy)‐9‐[(2 R *,3 S *)‐3‐iodo‐ N ‐(methoxycarbonyl)‐2‐pyrrolidinyl]purine (±)‐22: Obtained from proline methyl carbamate ( 10 ) and (trimethylsilyl)(benzyloxy)purine according to Method C. The reaction mixture was purified by chromatography (hexanes/EtOAc, 7:3 then 1:1), giving the non‐halogenated product (±)‐ 21 (7 mg, 10 %)6 and the iodinated compound (±)‐ 22 (38 mg, 40 %).…”

“…In a previous work, we reported the tandem radical decarboxylation–oxidation of proline derivatives 5a and 5b (Scheme ) to give the acyliminium ion 6 , which was trapped by nitrogen bases to afford the nucleoside analogues 7 6. The one‐pot process took place in high yields under very mild conditions.…”