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

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 stereochemical 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.

Distal Two-Bond versus Three-Bond Electronegative Oxo-Substituent Effect Controls the Kinetics and Thermodynamics of the Conversion of a C-Nitroso Function to the Corresponding Oxime in the Conformationally Locked Pentofuranose (Bicyclo[2.2.1]heptane) System

“…The synthesis of oxime 17 started from the known tetrahydrofuran derivative 11 (Scheme ) . Compound 11 was treated with OsO 4 in H 2 O, N -methylmorpholine- N -oxide (NMO), and NaIO 4 in a one-pot reaction to obtain aldehyde 12 without purification.…”

“…This mixture was subjected to free-radical cyclization, which was carried out under N 2 in anhydrous toluene with Bu 3 SnH under reflux, adding azobis­(isobutyronitrile) (AIBN) as an initiator in a dropwise manner; this resulted in the formation of compound 15 in 65% yield. The hexenyl radical cyclization of compounds E - 14 and Z - 14 at C4 proceeded in the 5- exo cyclization mode to give only one [2.2.1]-fused product, H1,H8- trans -fused product 15 with the (8 S ) configuration. Detailed NMR analysis of 15 confirmed that the diastereotopically pure product 15 exclusively has α-8-NHOBn (C8- S ) and β-1-OPMB (C1- R ) configurations.…”

“…The same route ( 1 → 2a → 3a → 4a → 5a → 6a ) was not general for the construction of fused carbabicycles lacking C7′ and C8′ substituents by replacing O4′ with an 8′-CH 2 . Hence, we became interested in exploring the free-radical cyclization of a vicinal C4′ -alkyloximino group in a C1 -methyl glycoside, as in compound 2b ( 1 → 2b → 3b → 4b → 5b → 6b ; Scheme ). If successful, this strategy would permit the construction of [2.2.1] carba systems on both the α and β faces of the sugar ring.…”

“…We recently completed the synthesis of the conformationally locked bicycloheptane derivatives 21 and 25 (Figure ) in order to transform them into the corresponding β- d -carbocyclic nucleosides for incorporation into oligo-DNA or -RNA to study their biochemical properties as antisense agents − and small interfering RNAs in order to control RNA translation to proteins. The availability of carbocyclic-modified nucleosides without any substitution, such as 19 obtained using 8-desmethylheptane system 22 (Figure ), is also important to modify DNA and RNA duplexes at different positions with hydrophobic groups.…”

“…In our previous studies, we were able to perform a radical ring closure to form bicyclo[2.2.1]­heptane 21 ( 20 → 21 ; Figure ), which allowed us to perform a nucleobase coupling without any difficulty to give compound 23 . The main problem of this coupling reaction was that the S and R diastereomers arising from the methyl group at C8′ were inseparable and therefore could not be used for the synthesis of diastereomerically pure modified oligo-DNA and -RNA for further studies.…”