A Practical Asymmetric Synthesis of the Antiviral Agent Lobucavir, BMS-180194

Abstract

A practical synthesis of the antiviral agent lobucavir, [1R-(1r,2β,3r)]-2-amino-9-[2,3-bis(hydroxymethyl)cyclobutyl]-6Hpurin-6-one (BMS-180194), is described. The key chiral intermediate, [1S-(1r,2β,3r)]-3-hydroxy-1,2-cyclobutanedimethanol, dibenzoate ester, was made by an asymmetric [2 + 2] cycloaddition of dimenthyl fumarate with ketene dimethyl acetal followed by sequential diester reduction, benzoylation, deketalization, and stereoselective ketone reduction. Regioselective N9-alkylation of the tetra-n-butylammonium salt of 2-amino-6-iodopurine with the derived cyclobutyltriflate furnished the purinecyclobutyl dibenzoate. Methanolysis followed by acid hydrolysis produced lobucavir in a 35% overall yield with an ee > 99%.

Synthesis and Evaluation of Novel Carbocyclic Oxetanocin A (COA-Cl) Derivatives as Potential Tube Formation Agents

“…Chemistry The COA-Cl analogs 2a-d shown in Chart 1 were prepared using known cyclobutyl alcohols (3a, 19) b, 20) c, 21,22) d, 21,23) ) as starting materials in two steps reactions, according to a modified method from a previous report. 24) Secondary alcohols 3a-d were treated with 2,6-dichloropurine and underwent the Mitsunobu reaction 25) in the presence of PPh 3 and DIAD to yield 9-cyclobutyl-2,6-dichloropurine congeners, 4a-d, in 37-84% yields, which were treated with methanolic ammonia to give the desired products 2a-d in 68-87% yields.…”

“…4) and comparison with previous litera- ture. [20][21][22][23] For compound 4b, the NOESY correlations between H-1′ and H-4′b, between H-4′a and H-3′, and between H-2′ and H-3′, and the absence of NOESY correlations between H-1′ and H-2′, suggested the 1′,2′-trans-2′,3′-cis congener (4b). Similarly, for compounds 4c and d, the NOESY correlations between H-1′ and H-3′ indicated the 1′,3′-cis analog (4c), whereas the absence of NOESY correlations between H-1′ and H-3′ indicated the 1′,3′-trans derivative (4d).…”

Chiral Synthesis of Carbocyclic Nucleoside Analogs from Noncarbohydrate Precursors

“…The resulting chiral cyclobutanone 123 was deoxygenated by treatment with samarium iodide. In a more convenient approach to the large-scale synthesis of lobucavir, enantioselective [2+2] cycloaddition was obtained by using the relatively inexpensive dimenthyl fumarate 132 (Scheme 18) [63,64]. (Scheme 17) [61,62].…”

“…The reductive cleavage of the ethoxy group proceeded via an enolate, which allowed epimerization of the benzyloxymethyl group to the thermodynamically more stable trans-cyclobutanone 124. Optimized coupling conditions involved activation of 137 as triflate 138 and condensation with 2-amino-6-iodopurine [64,65]. Olefination of ketone 124 and oxidative hydroboration of the resulting alkene 125 proceeded in non-stereoselective fashion to give the mixture of isomers 126.…”

Tandem catalysis for asymmetric coupling of ethylene and enynes to functionalized cyclobutanes

“…1 A ). ( 13-19 ) The chiral all-carbon quaternary centers present in many of these molecules often prove challenging to install efficiently. ( 20 ) Cyclobutane derivatives have also found broad use as intermediates for the synthesis of more advanced target structures such as stereo-defined 1,3-dienes, cyclopentanes and ligands for catalytic applications.…”