Enantioselective synthesis of the carbocyclic nucleoside (−)-abacavir

Abstract

An enantiopure β-lactam with a suitably disposed electron withdrawing group on nitrogen, participated in a π-allylpalladium mediated reaction with 2,6-dichloropurine tetrabutylammonium salt to afford an advanced cis-1,4-substituted cyclopentenoid with both high regio- and stereoselectivity. This advanced intermediate was successfully manipulated to the total synthesis of (-)-Abacavir.

Biocatalytic approaches applied to the synthesis of nucleoside prodrugs

“…Finally, CBV-MP is anabolised to CBV-TP, a potent inhibitor of HIV-RT that acts both as a competitive inhibitor of dGTP for DNA incorporation and as a DNA chain terminator (Faletto et al, 1997;Stankova et al, 2012). Boyle et al (2012) reported the synthesis of ABC from the β-lactame (2) obtained by [2 + 2] cycloaddition of chlorosulphonyl isocyanate with cyclopentadiene (Scheme 5b) and subsequent Lipolase (a soluble preparation of Thermonyces lanuginosus lipase, produced by submerged fermentation of a genetically modified Aspergillus oryzae microorganism) catalysed kinetic resolution. Tardibono et al (2011) developed a new synthetic route from an acylnitroso-derived hetero Diels-Alder cycloadduct (3), which after reduction conducted to the synthesis of racemic aminocyclopentenol (4).…”

Biocatalytic routes to anti-viral agents and their synthetic intermediates

“…This allowed for palladiumcatalysed nucleobase (60) coupling after tosylation, leading up to the synthesis of abacavir. 126 Although much of the research described above has been conducted at laboratory scale, protease-catalysed Vince-lactam ring-opening is nowadays performed on industrial scale, too.…”

Enantioselective and Regiodivergent Addition of Purines to Terminal Allenes: Synthesis of Abacavir

“…At this stage, NOESY experiments confirmed the relative configuration of the syn ‐ and anti ‐stereoisomers. The final introduction of the guanidine function in 2‐position followed literature‐known steps consisting of S N Ar with PMB amine under harsh conditions followed by cleavage of the PMB group in refluxing TFA . Under these conditions the silyl ether protecting group was simultaneously cleaved making an additional deprotection step unnecessary.…”