Steric Effects in the Tuning of the Diastereoselectivity of the Intramolecular Free-Radical Cyclization to an Olefin As Exemplified through the Synthesis of a Carba-Pentofuranose Scaffold Mansoureh Karimiahmadabadi, Sayeh Erfan, Andras Fö ldesi, and Jyoti Chattopadhyaya* Program of Chemical Biology, Department of Cell and Molecular Biology, Biomedical Centre, Uppsala University, SE-75123 Uppsala, Sweden * S Supporting Information ABSTRACT: Two free-radical cyclization reactions with the radical at the chiral C4 of the pentose sugar and the intramolecularly C1-tethered olefin (on radical precursors 8 and 17) gave a new diastereospecific C4-C8 bond in dimethylbicyclo[2.2.1]heptane 9, whereas the new C4-C7 bond in 7-methyl-2-oxabicyclo[2.2.1]heptanes 18a/18b gave trans and cis diastereomers, in which the chirality of the C4 center is fully retained as that of the starting material. It has been shown how the chemical nature of the fused carba- pentofuranose scaffolds, dimethylbicyclo[2.2.1]heptane 9 vis-a- vis 7-methyl-2-oxabicyclo[2.2.1]heptanes 18a/18b (C7-Me in the former versus 2-O- in the latter), dictates the stereo- chemical outcome both at the Grignard reaction step as well as in the free-radical ring-closure reaction. The formation of pure 1,8-trans-bicyclo[2.2.1]heptane 9 from 8 suggests that the boat-like transition state is favored due to the absence of steric clash of the bulky 1(S)-O-p-methoxybenzyl (PMB) and 7(R)-Me substituents (both in the α-face) with that of the 8(R)-CH 2 • radical in the β-face. The conversion of 17 → 18a-7(S) and 18b-7(R) in 6:4 ratio shows that the participation of both the chair- and the boat-like transition states is likely. ■ INTRODUCTION Recently, we have shown that substitution of 2′-O- in LNA (locked nucleic acid: 2′-O,4′-C-methylenebicyclonucleoside) 1a,b by the 2′-CH(Me)- group, giving carbocyclic nucleosides (carba- LNA), 1c-i enhances the nucleolytic stability of the carba-LNA- modified oligo-DNA or RNA by ∼145 times. 1f These carba- LNA-modified small interfering RNAs (siRNA) have been found to be useful as potential therapeutic agents against HIV-1, 2,3 whereas the carba-LNA-modified antisense oligonucleotides are found to be active against allele-specific Huntington disease, 4 owing to improved target RNA affinity, single-mismatch discrimination, and nuclease stability. 1c-e On the other hand, the cyclopentane nucleoside derivative in which the furanose O4′-oxygen is replaced by methylene stabilizes the glycosidic bond and enhances the biological stability, 5,6 which in turn culminates into enhanced selectivity to different viral enzymes. 5e,f Thus, the locked North-type (N) methanocarba-adenosine analogues 6 showed favorable pharma- codynamic properties in binding assays to A1, A 2A , and A3 receptors compared to the S-locked analogue. 6 The syntheses of several carbocyclic nucleosides have been reported so far. 7a,b They used different (Grubb’s 7a and Schrock’s catalyst 8 ) metathesis approaches for closing the carba-ring to give functionalized cyclopentanol. Synthesis of annulated furanoses 9 was reported through the radical cyclization to the intra- molecularly tethered olefin (Table 1, compounds II, IV, VI, and VIII). 10 The radical was always generated at a nonchiral carbon center to avoid the generation of an intractable mixture of diastereomers owing to epimerization during the radical addition reaction. However, when the radical was generated at the nonchiral centers of the furanose ring (I → II), or at its side chain, a diastereomeric mixture of cis and trans isomers (III → IV and V → VI) 11 was obtained. When the radical was generated at a nonchiral carbon and had a constrained olefin in the proximity, which was part of a ring, it gave a diastereomerically pure isomer as shown by conversion of VII → VIII (74%) and IX → X (76%), 11 owing to steric reasons. A radical center generated at an achiral carbon added easily to a CN of an oximino ether (VII) to give 1-benzyloxyaminocy- clopentane (VIII) as a diastereomerically pure main product in 74% yield. All of these reactions, VII → VIII and IX → X, took place by 5-exo ring closure and gave one major isomer because of the steric effect imposed by the acetonide group on the α-face of the pentose sugar ring. However, the alkyl substitution at the radical center and ring strain have been shown to promote the radical 6-endo cyclization (XI → XII), thereby allowing syntheses of carba-pyranoses from a carbohydrate precursor. Similarly, a vinyl radical led to more 6-endo cyclization (XIII → XIV + XV, Received: May 9, 2012 Published: August 2, 2012 Article pubs.acs.org/joc © 2012 American Chemical Society 6855 dx.doi.org/10.1021/jo300936g | J. Org. Chem. 2012, 77, 6855-6872