Enantiomerically Pure trans-β-Lactams from α-Amino Acids via Compact Fluorescent Light (CFL) Continuous-Flow Photolysis

Abstract

Photolysis of α-diazo N-methoxy-N-methyl (Weinreb) β-ketoamides derived from enantiomerically pure (EP) α-amino acids affords the corresponding EP β-lactam via an intramolecular Wolff rearrangement. Photochemistry is promoted with either standard UV irradiation or through the use of a 100W compact fluorescent light (CFL); the latter affords a safe and environmentally friendly alternative to standard photolysis conditions. A continuous-flow photochemical reactor, made from inexpensive laboratory equipment, expedites reaction times and is amenable to scale-up. Diastereoselectivity (cis or trans) of the product β-lactams has been shown to vary from modest to nearly complete. An extremely facile, atom-economical method for the epimerization of the product mixture to the trans isomer, generally highly crystalline, has been developed. Evidence is presented for C-3 epimerization of Weinreb amide structures via a non-basic, purely thermal route. Subsequent transformations of both the Weinreb amide at C-3 (β-lactam numbering) and amino acid side chain at C-4 are well tolerated, allowing for a versatile approach to diverse β-lactam structures. The technology is showcased in the synthesis of a common intermediate used toward several carbapenem-derived structures starting from unfunctionalized aspartic acid.

Modern Organic Synthesis with α-Diazocarbonyl Compounds

“…98 Although light-promoted decomposition of diazocarbonyls is usually accomplished using a medium-pressure mercury vapor lamp, there are reports that a 100 W compact fluorescent light source, operating in a continuous-flow reactor, can also be effective. 99 Apart from photolysis, silver ion catalysis remains a popular choice for effecting Wolff rearrangement of diazoketones; the combination of silver benzoate and triethylamine has been used successfully for more than 50 years. The addition of silica gel to catalytic amounts of silver trifluoroacetate has been used by Podlech to prepare β-amino acids very efficiently.…”

Micro reactor and flow chemistry for industrial applications in drug discovery and development

“…The simple continuous fl ow photochemical reactor was constructed from common laboratory equipment and consisted of the requisite tubing and a medium-pressure liquid chromatography pump in addition to standard fl asks to improve upon processing capabilities. Thus, this different route to obtain β -lactam structures showed interesting results in both CFL and MVL continuous fl ow reactors [48] .…”

“…The natural product Thienamycin and monocyclic β -lactam compounds exemplifi ed by Aztreonam are carbapenem structures which possess trans stereochemistry at the two chiral centers of the azetidinone ring (Figure 3 ). When suitably functionalized, the β -lactam ring in enantiomerically pure (EP) form represents the core of a vast array of antibiotics, some of which are used to treat drug-resistant bacterial strains [48] . A new strategy was developed to obtain this strained four-membered ring system which regarded versatility, economy, safety and simplicity issues.…”

Integrated Micro‐Flow Synthesis Based on Photochemical Wolff Rearrangement

“…[39] They conducted the photochemical Wolff rearrangement of α-diazo--ketoamide 7 and the subsequent lactamization of 8 (generated in situ) to afford -lactam 9 (Scheme 2).…”