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Reactions of four-membered heterocycles also show the influence of ring strain.
Some examples are given in the following diagram. Acid-catalysis is a common
feature of many ring-opening reactions. In
the thietane reaction, the sulfur undergoes electrophilic chlorination to
form a chlorosulfonium intermediate followed by a ring-opening chloride ion
substitution. Strong nucleophiles will also open the strained ether. Cleavage reactions of β-lactones may take place either by
acid-catalyzed acyl exchange, or by alkyl-O rupture by nucleophiles. Example 5 is an interesting case of intramolecular rearrangement to an
ortho-ester. Finally, the β-lactam cleavage of penicillin G (reaction 6)
testifies to the enhanced acylating reactivity of this fused ring system. Most
amides are extremely unreactive acylation
reagents, thanks to stabilization by p-π
resonance. Such electron pair delocalization is diminished in the
penicillins, leaving the nitrogen with a pyramidal configuration and the
carbonyl function more reactive toward nucleophiles.
(http://www.cem.msu.edu/) A set of ten azetidinic amino acids, that can be envisioned as C-4 alkyl
substituted analogues of trans-2-carboxyazetidine-3-acetic acid (t-CAA) and/or
conformationally constrained analogues of (R)- or (S)-glutamic acid (Glu) have
been synthesized in a diastereo- and enantiomerically pure form from b-amino
alcohols through a straightforward five step sequence. The key step of this
synthesis is an original anionic 4-exo-tet ring closure that forms the azetidine
ring upon an intramolecular Michael addition. This reaction was proven to be
reversible and to lead to a thermodynamic distribution of two diastereoisomers
that were easily separated and converted in two steps into azetidinic amino
acids. Azetidines 35–44 were characterized in binding studies on native ionotropic
Glu receptors and in functional assays at cloned metabotropic receptors mGluR1,
2 and 4, representing group I, II and III mGlu receptors, respectively. (http://www.rsc.org/delivery/)
Azetidine, (oxetane, or thietane) is a heterocyclic
compound of 4-membered ring with nitrogen as its heteroatom
replacing a carbon at one position.
It is a
cyclic amine
containing three carbon atoms and one nitrogen atom. It is a clear liquid
(boiling point 61 - 62 C) with an unpleasant ammonia-like odor. It is found in many pharmaceutical drugs such as Carmantadine, Fluzinamide, Mugineic acid, Azetomycins, Tazadolene, Cefsulodin monobactam,
Dezinamide and Imipenem. Azetidine-2-carboxylic acid (abbreviated Aze) is a homologue of proline, an 4-membered ring structure
alpha-amino acid. It is a toxic non-protein amino acid that is misincorporated into protein in place of
proline; induces nonfunctional heat-shock proteins; inhibits acquired
thermotolerance. Cyclic amine
analogues are aziridine (3-member ring),
pyrrolidine (5-member ring) and
piperidine (6-member ring). And Aromatic analogs are pyrrole
( 5-member ring with
two solid bonds), pyrroline (5-member ring with one
solid bond) and Azepine ( 7-member ring with
three solid bonds).
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