Parallel solid-phase synthesis and structural characterization of a library of highly substituted chiral 1,3-oxazolidines

The rapid parallel synthesis and characterization of diverse chirally defin ed 1,3-oxazolidines is reported, Three diversity elements were incorporated in a 6 x 4 x 4 block approach to generate a 96-member 1,3-oxazolidine libr ary. The synthetic route involved initial attachment of six nonracemic phen ylglycidols, (2S,3S)-1A-C and (2R,3R)-2A-C, to 2% cross-linked polystyrene resin via a chlorodiethylsilane linker (PS-DES), followed by regio; and ste reoselective oxirane ring opening with four primary amines (3a-d). The key condensation reaction between the resulting polymer-bound beta -amino alcoh ols and four aldehydes (4a-d) was found to occur optimally in warm benzene (60 degreesC) in the presence of anhydrous magnesium sulfate. Cleavage of t he oxazolidines from the resin support was achieved with TBAF to give the i ndividual members (2R,4R,5R)-5Aaa-Cdd and (2S,4S,5S)-6Aaa-Cdd in good to ex cellent yields (51-99%) based on mass recovery. Purities of all these crude products was generally >85% (as measured by LCMS). H-1 C-13 NMR, and 1D di fference nOe of the library members confirmed the structural and stersochem ical integrity of the substituents around the 1,3-oxazolidine core. The asy mmetric induction at C-2 (cis or trans to the C-4 substituent) ratio ranged from 4 to 1 to 49 to 1 across the library. This report highlights the vers atility of the 1,3-oxazolidine heterocycle as a scaffold for concise parall el library construction and opens the way for high-throughput screening of such compounds in the biological sphere.