Staudinger synthesis

For the reaction that reduces azides to amines using phosphorus compounds, see Staudinger reaction.

The Staudinger synthesis, also called the Staudinger ketene-imine cycloaddition, is a chemical synthesis in which an imine 1 reacts with a ketene 2 through a non-photochemical 2+2 cycloaddition to produce a β-lactam 3.^[1] The reaction carries particular importance in the synthesis of β-lactam antibiotics.^[2] The Staudinger synthesis should not be confused with the Staudinger reaction, a phosphine or phosphite reaction used to reduce azides to amines.

Reviews on the mechanism, stereochemistry, and applications of the reaction have been published.^[3][4][5]

History

The reaction was discovered in 1907 by the German chemist Hermann Staudinger.^[6] The reaction did not attract interest until the 1940s, when the structure of penicillin was elucidated. The β-lactam moiety of the first synthetic penicillin was constructed using this cycloaddition,^[7] and it remains a valuable tool in synthetic organic chemistry.

Mechanism

The first step is a nucleophilic attack by the imine nitrogen on the carbonyl carbon to generate a zwitterionic intermediate. Electron-donating groups on the imine facilitate this step, while electron-withdrawing groups impede the attack.^[8] The second step is either an intramolecular nucleophilic ring closure or a conrotatory electrocyclic ring closure.^[9] The second step is different from typical electrocyclic ring closures as predicted by the Woodward–Hoffmann rules. Under photochemical and microwave conditions the intermediate's 4π-electron system cannot undergo a disrotatory ring closure to form the β-lactam, possibly because the two double bonds are not coplanar.^[10] Some products of the Staudinger synthesis differ from those predicted by the torquoelectronic model.^[11] In addition, the electronic structure of the transition state differs from that of other conrotary ring closures.^[11] There is evidence from computational studies on model systems that in the gas phase the mechanism is concerted.^[5]

Stereochemistry

The stereochemistry of the Staudinger synthesis can be difficult to predict because either step can be rate-determining.^[12] If the ring closure step is rate-determining, stereochemical predictions based on torquoselectivity are reliable.^[12] Other factors that affect the stereochemistry include the initial regiochemistry of the imine. Generally, (E)-imines form cis β-lactams while (Z)-imines form trans β-lactams.^[5] Other substituents affect the stereochemistry as well. Ketenes with strong electron-donating substituents mainly produce cis β-lactams, while ketenes with strong electron-withdrawing substituents generally produce trans β-lactams. The ketene substituent affects the transition state by either speeding up or slowing down the progress towards the β-lactam. A slower reaction allows for the isomerization of the imine, which generally results in a trans product.^[11]

Variations

Reviews on asymmetric induction of the Staudinger synthesis, including the use of organic and organometallic catalysts, have been published.^[1][5][13]

The imine can be replaced by adding olefin to produce a cyclobutanone, carbonyl to produce a β-lactone, or carbodiimides to produce 4-imino β-lactams.^[1] The Staudinger synthesis and variations are all ketene cycloadditions.

In 2014, Doyle and coworkers reported a one-pot, multicomponent Staudinger synthesis of β-lactams from azides and two diazo compounds. The reaction occurs by a rhodium acetate-catalyzed reaction between the aryldiazoacetate (red) and the organic azide (blue) to form an imine. A Wolff rearrangement of the diazoacetoacetate enone (black) forms a stable ketene, which reacts with the imine to form a stable β-lactam compound. The solvent used for this reaction is dichloromethane (DCM) and the solution needs to rest for 3 hours at room temperature. The yield of the reaction is about 99%.^[14]

The reaction with sulfenes instead of ketenes leading to β-sultams is called Sulfa-Staudinger cycloaddition. The following illustration shows an example of the Sulfa-Staudinger cycloaddition. Benzylidenemethylamine reacts with ethanesulfonyl chloride to a β-sultam. For this reaction was tetrahydrofuran (THF) used as a solvent and the solution needed to rest for 24 hours.^[15]