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 defined 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 library. The synthetic route involved initial attachment of six nonracemic phenylglycidols, (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 stereoselective oxirane ring opening with four primary amines (3a-d). The key condensation reaction between the resulting polymer-bound beta-amino alcohols and four aldehydes (4a-d) was found to occur optimally in warm benzene (60 degrees C) in the presence of anhydrous magnesium sulfate. Cleavage of the oxazolidines from the resin support was achieved with TBAF to give the individual members (2R,4R,5R)-5Aaa-Cdd and (2S,4S,5S)-6Aaa-Cdd in good to excellent yields (51-99%) based on mass recovery. Purities of all these crude products was generally >85% (as measured by LCMS). 1H, 13C NMR, and 1D difference nOe of the library members confirmed the structural and stereochemical integrity of the substituents around the 1,3-oxazolidine core. The asymmetric induction at C-2 (cis or trans to the C-4 substituent) ratio ranged from 4 to I to 49 to 1 across the library. This report highlights the versatility of the 1,3-oxazolidine heterocycle as a scaffold for concise parallel library construction and opens the way for high-throughput screening of such compounds in the biological sphere.
Tremblay
M R
MR
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
Wentworth
P
P
Lee
G E
GE
Janda
K D
KD
D002853:Chromatography, Liquid; D020650:Combinatorial Chemistry Techniques; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D015394:Molecular Structure; D010080:Oxazoles / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism
D010080:Oxazoles