Parallel Solid-Phase Synthesis and Structural Characterization of a Library of Highly Substituted Chiral 1,3-Oxazolidines

Abstract

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.

Five‐Membered Heterocycles: 1,3‐Azoles

“…For example, imidazolidine 262 is obtained by simply reacting at rt the aldehyde 260 with the vicinal Oxazolidines have also been obtained by these procedures [430], although an application to the production of a library of 96 oxazolidines through a parallel solidphase synthesis required MgSO 4 as dehydrating agent and a temperature of 60 C [431].…”

N-Alkylation Reactions and Indirect Formation of Amino Functionalities in Solid-Phase Synthesis

“…Ring-opening of epoxides with amines has been used only rarely on solid phase, but a few examples do exist. [211][212][213][214] Rossé et al prepared a 2,3-epoxypiperidine resin, which was treated with primary and secondary amines to give mixtures of stereoisomers of b-amino-g-hydroxypiperidines in good overall yields. 211 Epoxide opening was later applied in the preparation of large libraries of phenoxypropanolamines 113 (2,580 members) by Bryan et al, 212 and of 1,3-dioxanes 114 (18,000 members) by Schreiber and co-workers 213 (Figure 5).…”

“…Furthermore, Janda and co-workers applied diethylsilyl (DES) resin-bound epoxides in the preparation of a 96-member library of substituted 1,3-oxazolidines that were obtained in yields of 51-99%. 214 As mentioned in the introduction to Section 3, Michael addition has been adopted for loading of amines onto the REM linker. [215][216][217][218][219] The principle of this system is outlined in Scheme 22.…”

Oxazolidine Synthesis by Complementary Stereospecific and Stereoconvergent Methods

“…A combination of rhodium(biscyclooctadiene) triflate in dichloromethane as solvent was found to be optimal, generating oxazolidine 3c in 86% yield with 6:1 diastereoselectivity (entry 3). The more stable cis -oxazolidine was formed preferentially in favor of the trans diastereomer . The optimal conditions were observed to be general over a range of aryl imines.…”