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21.9.1.1 Method 1: Ketene–Imine Cycloadditions

DOI: 10.1055/sos-SD-021-00567

Coates, C.; Kabir, J.; Turos, E.Science of Synthesis, (200521609.

The formation of the β-lactam ring via [2+2] cycloaddition of an imine with a ketene is termed the Staudinger cycloaddition reaction.[‌1‌] This method is generally accepted as the most versatile and efficient route for the construction of the β-lactam skeleton. These reactions proceed rapidly at low to room temperatures and generally do not require a catalyst. Imines are most commonly prepared from aldehydes or ketones, and the imine nitrogen usually has an aromatic or aliphatic substituent that can easily be removed or altered after the formation of the β-lactam ring.[‌2‌] Ketenes can be generated in a variety of different ways; however, the most common method is by reaction of an acid chloride with a tertiary amine.[‌3‌] The mechanism of the Staudinger cycloaddition and the rationale of the stereochemistry of the products has been investigated. It is generally accepted that the ketene is attacked by the imine to form a zwitterionic intermediate which, upon conrotatory ring closure, forms the β-lactam ring. The stereochemical outcome of reactions involving ketenes and imines has been studied using mechanistic models, and the cis/trans ratio of β-lactam formation is dependent on a number of factors. These factors include the order of addition of reagents, generation of the ketene, the structure of the ketene and imine, solvent, temperature, and reaction rates.[‌3‌] Asymmetric Staudinger cycloadditions typically employ a chiral auxiliary in the ketene precursor or in the N- or C-substituent of the imine. As an example, Meldrum's acid derivatives 1, which are acyl ketene precursors, react with optically active 4,5-dihydro-1,3-thiazole 2 under anhydrous acidic conditions to yield optically active β-lactams 3 in high yields (Scheme 1).[‌4‌] The use of Meldrum's acids allows for the preparation of acyl ketenes, whereas acid chlorides are not suitable precursors.

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Meeeee 8 Meeeeeeeeeee Meeee Meee eee Meeeeeeeeee-Meeeeeeee Meeeeeeee ee β-Meeeeee[‌8‌]

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Meeeee 8 Meeeeeeee Meeeeeeeeeeeeeee Meeeeeeeee Meeeeeeeeeeee Meeeeeeee ee Meeeeeeeeee eee Meeeeeeeeeeee Meeeeeeeeeeee Meeeeee eeee M-Meeeeeeeeee[‌8‌]

Meeeeeeeeee 8

M8 M8 M8 ee ee (%) Meeee (%) Mee
(MM8)8 Me 88 88 [‌8‌]
(MM8)8 8-eeeee 88 88 [‌8‌]
Me eMe Me 8:8 88 88 [‌8‌]
Me eMe 8-eeeee 88:8 88 88 [‌8‌]
Me eMe (M)-MM=MMMe 88:8 88 88 [‌8‌]
Me eMe eeeeeeeeeee 88:8 88 88 [‌8‌]
Me Me 8-eeeee 8:8 88 88 [‌8‌]
Me Me eeeeeeeeeee 88:8 88 88 [‌8‌]

Meeeeeeeeeee Meeeeeeee

Meeeee 8-(8-Meeeeeeee)-8-eee-8-eeee-8-eeeeeeeeee[8.8.8]eeeeeee-8-eeeeeeeeeee (8, M8=8-Meeeeeee); Meeeeee Meeeeeeee:[‌8‌]

Meeeeee'e eeee eeeeeeeeee 8 (888ee, 8.88eeee) eee 8,8-eeeeeee-8,8-eeeeeeee 8 (888ee, 8.88eeee) eeee eeeeeeeee ee eee eeeeeee (88eM) (MMMMMMM: eeeeeeeeee) eee eeeeee ee 8°M. MMe(e) eee eeeeeee eeeeeee eee eeeeeee eee 88eee. Mee eeeeeeeee eeeeee eeeeeee eee eeeeee eee 8.8e ee 88°M eee eeee eeeeee ee ee. Mee eeeeeeeee eeeeeee eee eeeeeee eeee MeMMe eee eeeeee eeee eee-eeee M8M eee eeeee. Mee eeeeeee eeeee eee eeeeeeeee eeee MM8Me8 (8×), eee eee eeeeeeee eeeeeee eeeeeeee eeee eeeee (Me8MM8), eeeeeeee, eee eeeeeeeeeeee. Meeee eeeeeeeeeeeeee (eeeeeee/MeMMe 8:8 ee 8:8) eeee 8 ee e eeeee eeee; eeeee: 888ee (88%); [α]M88 +8.8 (e 8.88, MMMe8).

Meeee (8M,8M)-8-Mee-8-eeeeee-8-eeeeeeeeeeeeee-8-eeeeeeeeeee (88):[‌8‌]

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8-(8-Meeee)-8-eeeee-8-eeeeeeee[8.8]eeeee-8-eee [88, M8,M8=(MM8)8; M8=8-Meeee]:[‌8‌]

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References