Staudinger synthesis

Source: Wikipedia, the free encyclopedia.
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

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

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

(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

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]

References

  1. ^
    ISBN 9780470872208. {{cite book}}: |first= has generic name (help)CS1 maint: multiple names: authors list (link
    )
  2. PMID 18022986
    .
  3. ^ Fu, N.; Tidwell, T. T. "Preparation of β-lactams by [2+2] cycloaddition of ketenes and imines" Tetrahedron 2008, 64, 10465-10496. ([1])
  4. ISBN 978-0471187998
    .
  5. ^
    PMID 18662024
    .
  6. doi:10.1002/jlac.19073560106
    .
  7. doi:10.1021/ja01164a534.{{cite journal}}: CS1 maint: multiple names: authors list (link
    )
  8. ISBN 9780470872208. {{cite book}}: |first= has generic name (help)CS1 maint: multiple names: authors list (link
    )
  9. S2CID 37085450
    .
  10. PMID 15624943
    .
  11. ^
    PMID 16669675
    .
  12. ^
    PMID 19132931
    .
  13. doi:10.1002/(SICI)1099-0690(199912)1999:12<3223::AID-EJOC3223>3.0.CO;2-1
    .
  14. PMID 24423056
    .
  15. PMID 25756543
    .
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