Ether bond formation

Ether bond formation via reduction of the oxonium species with Et3SiH. 

Ether bond formation with chiral imidate 67. 

Ether Bond Formation with Chiral Imidate 67... 

Ether Bond Formation with Conversion to Carboxylate... 

The introduction and cleavage of the trityl ether proceeds through a very well-stabilised triphenylmethyl carbocation. In the case of trityl ether bond formation, the reaction is performed under anhydrous conditions and the carbocation, which is formed by an SN1 mechanism, reacts with an alcohol. In the case of cleavage, the triphenylmethyl carbocation ion is formed by treatment with acid, which is then trapped by water or a nucleophilic solvent to give trityl alcohol or other derivatives, respectively. Trityl ethers have also been used to protect thiols. 

Scheme 7 Two possible mechanisms of thio-ether bond formation based on either (a) Cu(II) and a tyrosyl radical or (b) Cu(l) and a thiyl radical ((a) S.J. Firbank, M.S. Rogers, C.M. Wilmot, D.M. Dooley, M.A. Halcrow, P.F. Knowles, M.J. McPherson, and S.E. Phillips. Proc. Natl. Acad. Sci. USA, 2001, 98, 12932. 2001 National Academy of Sciences, USA and (b) Ref. 61. Reproduced by permission of The American Society for Biochemistry Molecular Biology)...

Fig. 4. Ether phospholipid synthesis from dihydroxyacetone-phosphate. (A) Dihydroxyacetone-P acyl transferase (DHAPAT). The first step of ether phospholipid synthesis is catalyzed by peroxisomal DHAPAT. This enzyme is a required component of complex ether lipid biosynthesis and its role cannot be assumed by a cytosolic enzyme that also forms acyldihydroxyacetone-P. (B) Ether bond formation by alkyl-DHAP synthase. The reaction that forms the 0-alkyl bond is catalyzed by alkyl-DHAP synthase and is thought to proceed via a ping-pong mechanism. Upon binding of acyl-DHAP to the enzyme alkyl-DHAP synthase, the pro-f hydrogen at carbon atom 1 is exchanged by enolization of the ketone, followed by release of the acyl moiety to form an activated enzyme-DHAP complex. The carbon atom at the 1-position of DHAP in the enzyme complex is thought to carry a positive charge that may be stabilized by an essential sulfhydryl group of the enzyme thus, the incoming alkox-ide ion reacts with carbon atom 1 to form the ether bond of alkyl-DHAP. It has been proposed that a nucleophilic cofactor at the active site covalently binds the DHAP portion of the substrate.

It is a reasonable assumption that macrocyclic bis(bibenzyls) such as the marchantins arise by oxidative C-C or ether bond formation from acyclic precursors already containing all four aromatic rings (e.g. perrotetin E). The ether linkage between the second and third rings is probably also established by phenol oxidation. Gnetifolin, though phytochemically unrelated, is structurally rather similar to bis(bibenzyls) (Scheme 20). 

In some cases, ethers are also formed (Equation 8.39) and elimination of water in that reaction may precede carbon-oxygen (ether) bond formation. 

In the succeeding steps, we first encotmter ether bond formation between 12 and 13, at step V, which proceeds with inversion of the configuration at the stereogenic centre in the chiral building block 13. Anomalous lactone ring opening in 14, step vi, is a key step in the whole process and will be discussed in more detail. Hydrogenolysis of iodine in 15 leads to the (S)-2-hydroxybutanoate unit in the final product, 1. 

In the final steps of the synthetic pathway, Williamson-type ether bond formation, with inversion of configuration at the stereogenic centre, followed by hydrolysis of the ester group, completed the large-scale production of ( )-l (Scheme 3.9) [38]. 

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