Syntheses of Carbocyclic Nucleosides and Relevant Biomolecules: Palladium(0)/Indium iodide-mediated Allylations and Ti(III)-promoted N-O Bond Reductions

New synthetic methodologies, Ti(III)-promoted N-O bond reductions and Pd(0)/InI-mediated allylations, are developed with acylnitroso-derived hetero-Diels-Alder adducts to provide relevant syn-1,4-disubstituted cyclopentene intermediates. The carbocyclic scaffolds are further functionalized to afford biologically significant molecules, including carbocyclic uracil polyoxin C analogs, carbocyclic aminonucleosides and (-)-epi-4'-carbocyclic puromycin.

Chapter two explores Pd(0)/InI-mediated allylations with acylnitroso-derived hetero-Diels-Alder adducts in the presence of diverse electrophiles. Eschenmoser's salt, 4-acetoxy-2-azetidinone, and formaldehyde (formed in situ from Eschenmoser's salt) serve as appropriate electrophiles for the indium(III)-mediated allylic additions. The resultant functionalized cyclopentenes are key intermediates in the syntheses of biologically significant molecules.

In chapter three, titanocene monochloride (Cp₂TiCl) is described as an alternative source of Ti(III) for the selective reductions of the N-O bonds of acylnitroso-derived hetero-Diels-Alder adducts, N-hydroxy carbamates and hydroxamic acids under mild conditions. Additionally, N-O bonds may be reduced with catalytic amounts of Cp₂TiCl.

The synthesis of carbocyclic polyoxin C analogs is discussed in chapter four. A ̢-lactam-derived carbocyclic scaffold is used as a key intermediate in the preparation of unprecedented carbocyclic nucleosides. An N-methylthio protecting group is required for the key transformation to the uracil moiety.

In chapter five, hydroxymethyl(cyclopentenyl) derivatives are used as intermediates in the syntheses of carbocyclic aminonucleosides and (-)-epi-4'-carbocyclic puromycin. The cis-2',3'-aminoalcohol moiety is installed by employing an osmium-catalyzed tethered aminohydroxylation reaction to afford functionalized carbocyclic substrates with complete regio- and diastereocontrol.

In conclusion, acylnitroso-derived hetero-Diels-Alder adducts are versatile substrates that may be elaborated to provide functionalized cyclopentene scaffolds. These carbocyclic platforms serve as key intermediates in the syntheses of biologically relevant molecules.