Preparation of Novel 4′-Spirocyclopropyl Nucleoside Analogues

Abstract

The stereoselective preparation of a novel 4’-spirocyclopropyl nucleoside analogue has been described using a semi-benzilic Favorskii rearrangement of a 4’-(2-chloro-3-oxocyclobutyl)spirofuranose as a key step. We demonstrated that the latter chiral spirocyclic intermediates, readily obtained on multigram scale from chiral pool starting materials, are highly suitable precursors to obtain full stereoselectivity in the reduction-ring contraction sequence. The downstream nucleobase introduction via Vorbrüggen glycosylation successfully resulted in the formation of the corresponding novel 4’-spirocyclic nucleoside analogue in a stereospecific manner.

Regio- and Stereoselective Synthesis of C-4′ Spirocyclobutyl Ribofuranose Scaffolds and Their Use as Biologically Active Nucleoside Analogues

“…Indeed, the previously reported completely stereoselective and scalable transformation toward cycloadduct 8 already provides the required functionalization at the β face, in the form of a geminal dichloride. Hydride reduction of the dichlorocyclobutanone 8 afforded the cyclobutanol 10 as a single isomer . The latter was efficiently converted to chlorocyclobutene 11 via triflation of the alcohol and subsequent reductive elimination induced by zinc and acetic acid.…”

“…7,8 Conformational restriction by installing a small cyclic bridge across the C-4′,C-5′ nucleosidic bond, as present in compounds of type 6, not only could increase the structural rigidity by lowering the side chain mobility but would also remove the potential hydrolytic liability of enol ethers as found in dehydrosinefungin 4. Apart from one recent example using a C-4′,C-5′-cyclopropane restriction, 9 no spirocyclobutyl analogues have been described, apart from our previous work on 1,3-substituted analogues 5. 10 Adenosine analogues of type 6 represent highly attractive examples of an as yet undescribed class of constrained nucleoside mimics.…”

“…Hydride reduction of the dichlorocyclobutanone 8 afforded the cyclobutanol 10 as a single isomer. 9 The latter was efficiently converted to chlorocyclobutene 11 via triflation of the alcohol and subsequent reductive elimination induced by zinc and acetic acid. Subsequently, chloroepoxide 12 was obtained by treatment of 11 with m-CPBA and was further reduced with LiBH 4 to afford the envisaged cyclobutanols 13 as a 1:1.2 mixture of stereoisomers.…”

Stereodivergent Synthesis of Biologically Active Spironucleoside Scaffolds via Catalytic Cyclopropanation of 4-exo-Methylene Furanosides

“…While several synthetic methods exist to access 4-spirocyclopropyl ester pyranose scaffolds, the approaches for the corresponding spirocyclic furanoses are quite limited (Scheme ). − Cyclopropanation of 4- exo -methylene furanosides is the most direct strategy to achieve the attractive spirofuranose scaffold. The first such approach was developed on the 4- exo -methylene furanoside 1 by Werz and co-workers, using copper-catalyzed carbene generation from ethyl diazoacetate (Scheme , eq 1) .…”

“…Spurred by the success of the stereoselective cyclobutanone spiro-annulation developed earlier for spironucleosides (cf. Scheme , eq 3 and 4), , we set out to find a more direct selective cyclopropanation approach. In fact, several asymmetric catalytic cyclopropanation methodologies have been reported, but these have been limited to much more generic substrates than 4- exo -methylene furanosides.…”