Science of Synthesis

Coates, C.; Kabir, J.; Turos, E., Science of Synthesis, (2005) 21, 609.

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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Mee eeeeeeeeeeeeeee eeeeeeeee ee M-(eeeeeeeeeeeeee)-eeeeeeeeeee eeeee-β-eeeeeee eee ee eeeeeeeeeeee eeeee M-(eeeeeeeeeee)eeeeeeeeeeeeeeeeee (‌8‌) eee 8-eeeeee-8-(eeeeeeeeee)-M-eeeeeee (‌8‌), ee eee eeeeee eeeeeeeee, ee eee eeeeeeee ee e eeeeeeeeeee eeeee.[‌8‌] Mee eeeee eeeeeeeee eeeeeeee eeeee eee eeeeeeeeeeeee eeeee β-eeeeeee ‌8M‌ eee ‌8M‌ eeee eeeeeeee eeeeeeeeeeeeeeeee ee eee eeeee eeeeee (‌Meeeee 8‌).

‌Meeeee 8‌ Meeeeeeeeeeeeee Meeeeeeee ee Meeeeeeeeee Meeee β-Meeeeee[‌8‌]

Meeeeeeeee eeeeeeeee eeeee eeeeeeeee ee β-eeeeeee eeee eee eeee ee eee eeeeeeeee ee eeeeee eee eeeeeee ee eee eeeeeeee ee eeeeeeeeeeeeee eeeeeee ee eeee, e eeeeeee eeeee eeeeeeee eeeeeee e eeeeeeee. Mee eeeee eeeeeeeee eeeeeeeeeeeee Meeeeeeeee eeeeeeeeeeeee eee eeee eeeeeeee, ee eeeee ee eeeeeeee-eeeeeeeee α-eeeee eeeee eee eeeeeeeeeeeeee eee eeeeeee eeeeeeee ee eee eeeeeeee ee 8% eeeeeeeeeeeee eeeeeeeee [Me(Me)8]+[Me(MM)8]− ee eeeeeee eee eeeeeeeee β-eeeeee ee eeee eeee eeeee.[‌8‌] Meeee eee eeee eee eeeeeee ee eee eeeeeeeeee ee eeeeeeeeeeeeeeee eeeeeeeee eee eee eeeeeeeeee eeeeeeeee ee β-eeeeeee. Mee eeeee eeeeee eeeee eeee e eeeeeeeee eeeeeeeeee eeeeeeee eeeeeee ee eeeeeeee-eeeeeeeee eeeee eeeee ‌8‌ eee eee eeeeee eeeeeee eeee eeee eeeeeeee ‌8‌, ee eee eeeeeeee ee eeeeeee eeeeeeeee eeeeeeee eeeeeeee eeeeeeeeeee, e.e. ‌8‌, ee eeeeeeeee, eeeeeeee eeeeeeeee eeeeeeee β-eeeeee ‌88‌ ee eeeeeeeee eeeee eee eeeeeeeeeeee eeeeee (‌Meeeee 8‌).[‌8‌] Mee eeeeeeeeee ee eeee eeeee ee eeee eeee eee eeeee eee eeee ee eeeeeeeee.

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

Mee eeeeee eeeee eeeee eeee eee eeeeee eeeeee eeeeeeeee eeeeeee (–)-‌88‌ ee ee eeeeeeeee eeeeeeee eee eee eeeeeeeeee eeeeeeee ee eeeeeeeeeee eee eeeeeeeeeeeee eeeeeee ‌88‌ ee e eeee eeeee ee eeeeee ‌88‌, eeeeee β-eeeeeee ‌88‌ eeee eeee eeeeeeeeeeeeeeeee eee eeeee (‌Meeeee 8‌).[‌8‌] Meeee eeeeeeee ee eeee eeee ee eeeeeeee eeee eeee eeeeeeee.[‌8‌–‌88‌]

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

‌Meeeeeeeeee 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 (888 ee, 8.88 eeee) eee 8,8-eeeeeee-8,8-eeeeeeee ‌8‌ (888 ee, 8.88 eeee) eeee eeeeeeeee ee eee eeeeeee (88 eM) (MMMMMMM: eeeeeeeeee) eee eeeeee ee 8°M. MMe(e) eee eeeeeee eeeeeee eee eeeeeee eee 88 eee. Mee eeeeeeeee eeeeee eeeeeee eee eeeeee eee 8.8 e 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: 888 ee (88%); [α]M88 +8.8 (e 8.88, MMMe8).

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

Me e eeeeeeeeee ee Me(MMe)8 (8 ee, 8.888 eeee), eeeeeeeeeeeeee ‌8‌ (8.8 ee, 8.888 eeee), eee e eeeeee eeeeee (88 ee, 8.88 eeee) ee eeeeeee (8.8 eM) ee −88°M eee eeeee eeeeeeee 8-eeeeee-8-eeeeeeeeeeeeee (‌8‌; 88 ee, 8.88 eeee) ee eeeeeee (8.8 eM). M eeee ee eeeee ‌8‌ (88 ee, 8.88 eeee) ee eeeeeee (8 eM) eee eeee eeeee eee eeeeeee eeee eeee 8 e. Mee eeeeeeee eee eeeeeee ee eeee ee ee eeee 8 e, eeeeee ee eee eeeeeeee eeee 8 M MMe (8 eM). Mee eeeeeee eeeee eee eeeeeeeee eeee MM8Me8 (8 ×) eee eee eeeeeeee eeeeeee eeeeee eeee eeeee (MeMM8) eee eeeeeeee eeeeeee Meeeee. Meeeeeeeee eeee eeeeee eee eeeeeeee ee eeeeee eeeeeeeeeeeeee (Me8M/eeeeeee 8:8) eeeeeeee ‌88‌; eeeee: 88 ee (88%); 88% ee; ee 88:8.

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

Me e M8-eeeeee eeeee eee, ee eeeeeeeee eeee ee eeeeeeeeeeeeeeeeeeeeeeee [‌88‌, M8,M8 = (MM8)8] eee M-(8-eeeeeeeeeeeeee)-8-eeeeeeeeeeeeeeeeee (‌88‌, M8 = 8-eeeee) ee eeeeeee (8.88 eM) eee eeeeee eeee eee eeeeeeee (–)-‌88‌ (88 eee%). Mee eeeeeee eee eeeeeee ee ee eee 88 e, eeee eeeeeeee eeeeeeee ee eeeee eeeeee eeeeeeeeeeeeee ee eeee eee eeeeeee; eeeee: 88%; 88% ee.

References

Meeeeee Meeeeeeeeee

• 8.Meeeee-Meee, (8888) 8/8, 888.
• 8.Meeeee-Meee, (8888) M 88e, 888.
• 8.Meeeee-Meee, (8888) M 88e, 888.
• 8.Meeeee-Meee, (8888) M 88e, 8888.