Exploring the Solid-Phase Synthesis of 3,4-Disubstituted β-Lactams:  Scope and Limitations

Abstract

This work describes a comprehensive study on the solid-phase synthesis of 3,4-disubstituted beta-lactams. In situ generated ketenes react with immobilized aldimines under mild conditions to generate libraries of beta-lactams in good to very good overall isolated yields. Different commercially available solid supports were studied, with the cost-effective Wang resin proving to be the most effective. The utility of the protocol was also demonstrated by the highly efficient asymmetric versions when homochiral ketenes or homochiral aldimines were used. A practical technique for the preparation of manual solid-phase parallel libraries of biologically interesting beta-lactam compounds, using Mukaiyama's salt as dehydrating agent, is also presented. Reactions were easily monitored by FT-IR and gel-phase 13C NMR using conventional equipment.

Molecular Diversity by Olefin Cross-Metathesis on Solid Support. Generation of Libraries of Biologically Promising β-Lactam Derivatives

“…For the solid-phase version of the classical Staudinger reaction between imines and ketenes [ 43 , 44 , 45 ], we first developed the synthesis of a set of immobilized imines 5a – d by treatment of the aldehyde with different amines 4a – d in refluxing benzene using a Dean–Stark trap ( Scheme 4 ).…”

Stereoselective Synthesis of (+)‐Goniodiol, (+)‐Goniotriol, (–)‐Goniofupyrone, and (+)‐Altholactone Using a Catalytic Asymmetric Hetero‐Diels–Alder/Allylboration Approach

“…Synthesis of the key building block 8 required the preparation of the ( R )‐( tert ‐butyldiphenylsilyloxy)phenylacetaldehyde ( 6 ) in three steps from ( R )‐mandelic acid 17. After an esterification reaction followed by the protection of the hydroxy group with tert ‐butyldiphenylsilyl chloride, the resulting methyl mandelate was efficiently reduced with i Bu 2 AlH at –78 °C to give expected aldehyde 6 in 77 % overall yield (Scheme ).…”

Recent Approaches Toward Solid Phase Synthesis of β-Lactams

“…Solid-phase synthesis of 3,4-disubstituted b-lactams was accomplished [104] via reaction of in situ generated ketenes with immobilized aldimines under mild conditions. Initially Fmoc-protected Wang resin strategy was followed (Scheme 15) and the [2+2] cycloaddition was performed by adding phenoxylacetyl chloride (49, R 1 = phenoxy) and triethylamine in excess to a suspension of 48 in dichloromethane.…”