Lactam

A lactam is a cyclic amide, formally derived from an amino alkanoic acid. The term is a portmanteau of the words lactone + amide.

From left to right, general structures of a β-lactam, a γ-lactam, a δ-lactam, and an ε-lactam. The specific structures are β-propiolactam, γ-butyrolactam, δ-valerolactam, and ε-caprolactam.

Nomenclature

Greek prefixes in alphabetical order indicate ring size:

This ring-size nomenclature stems from the fact that a hydrolyzed α-Lactam leads to an α-amino acid and a β-Lactam to a β-amino acid, etc.

Synthesis

General synthetic methods exist for the organic synthesis of lactams.

Beckmann rearrangement

Lactams form by the acid-catalyzed rearrangement of oximes in the Beckmann rearrangement.

Schmidt reaction

Lactams form from cyclic ketones and hydrazoic acid in the Schmidt reaction.

Cyclization of amino acids

Lactams can be formed from cyclisation of amino acids via the coupling between an amine and a carboxylic acid within the same molecule. Lactamization is most efficient in this way if the product is a γ-lactam. For example, Fmoc-Dab(Mtt)-OH, although its side-chain amine is sterically protected by extremely bulky 4-Methyltrityl (Mtt) group, the amine can still intramolecularly couple with the carboxylic acid to form a γ-lactam. This reaction almost finished within 5 minutes with many coupling reagents (e.g. HATU and PyAOP).[1]

Intramolecular nucleophilic substitution

Lactams form from intramolecular attack of linear acyl derivatives from the nucleophilic abstraction reaction.

Iodolactamization

An iminium ion reacts with a halonium ion formed in situ by reaction of an alkene with iodine.[2]

Iodolactamization reaction

Kinugasa reaction

Lactams form by copper-catalyzed 1,3-dipolar cycloaddition of alkynes and nitrones in the Kinugasa reaction

Diels-Alder reaction

Diels-Alder reaction between cyclopentadiene and chlorosulfonyl isocyanate (CSI) can be utilized to obtain both β- as well as γ-lactam. At lower temp (−78 °C), β-lactam is the preferred product. At optimum temperatures, a highly useful γ-lactam known as Vince Lactam[3] is obtained.[4]

Preparation of VL and beta lactam

Tautomerization to lactims

A lactim is a cyclic carboximidic acid compound characterized by an endocyclic carbon-nitrogen double bond. They are formed when lactams undergo tautomerization.

Reactions

See also

References
  1. Lam, Pak-Lun; Wu, Yue; Wong, Ka-Leung (30 March 2022). "Incorporation of Fmoc-Dab(Mtt)-OH during solid-phase peptide synthesis: a word of caution". Organic & Biomolecular Chemistry. 20 (13): 2601–2604. doi:10.1039/D2OB00070A. ISSN 1477-0539.
  2. Spencer Knapp, Frank S. Gibson Organic Syntheses, Coll. Vol. 9, p.516 (1998); Vol. 70, p.101 (1992) Online article
  3. Singh, R.; Vince, R. Chem. Rev. 2012, 112 (8), pp 4642–4686."2-Azabicyclo[2.2.1]hept-5-en-3-one: Chemical Profile of a Versatile Synthetic Building Block and its Impact on the Development of Therapeutics"
  4. Pham, P.-T.; Vince, R. Phosphorus, Sulphur and Silicon 2007, 779-791.
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