Hydroxy hindered, acylation

Although N -benzylated amino acids or peptides are known to be sterically hindered with respect to anninoacylation, acylation of A -(2-hydroxybenzyl) (Hbz) amino acid derivatives proceeds surprisingly well.P As shown in Scheme 1, the initial step in aminoacylation of A -Hbz-derivatized amino acid residues (Y = H) is esterification of the hydroxy group, which is followed by intramolecular, base-catalyzed O N acyl migration to produce the peptide bond.P l... 

Threonine contains a sterically hindered and therefore less reactive hydroxy group. The O-acylation of unprotected threonine during coupling reactions is therefore less problematic, but can nevertheless occur. Noncoded hydroxy amino acids containing a secondary hydroxy group have a reactivity similar to threonine. These hydroxy amino adds contain an additional asymmetric center at the (3-carbon atom. In the case of reactions on the secondary hydroxy group, this center is accessible to racemization, e.g. threonine can be converted into allo-threonine. 

A serious obstacle to the use of the Julia alkenation for the synthesis of trisubstituted alkenes is illustrated in Scheme 31. Addition of cyclohexanone to the lithiated sulfone (86) gave intermediate (87), which could not be acylated under the reaction conditions because of the sterically hindered tertiary alk-oxide. Owing to an unfavorable equilibrium, (87) reverted back to starting materials. However, by reversing the functionality of the fragments a stable adduct (88) was formed in which the less hindered secondary alkoxide was acylated and the resultant -benzoyloxy sulfone (89) reductively eliminated to the alkene (90) in 54% overall yield. Trisubstimted alkenes have been generated by reductive elimination of 3-hydroxy sulfones ° but, in general, retroaldol reactions compete. 

Few examples exist in the literature concerning the stereoselective addition of acyl radicals to a radical acceptor in an acyclic manner. Equation (13.1) shows the efficient 1,2-asymmetric induction in the addition of aliphatic or aromatic acyl radicals to chiral acyclic alkenes 1 [7]. The corresponding a-hydroxy ketones 3 were produced with high syn selectivity (Table 13-1). This acyl radical addition is very exothermic, and it is hypothesized that Hammond s postulate can be invoked to predict a transition state that is very close in energy to the starting alkene 1. The X-ray structure of 1 was then used to rationalize the stereochemical outcome of this radical addition by determination of the least sterically hindered path for the approaching radical. 

Sodium borohydride treatment of reduction product 2 gives reduction product 3 (80), a di-indoline, which shows no carbonyl absorption in its i.r. spectrum. The product gives only a mono-N-acetyl derivative (81). The secondary hydroxy-group must be sterically hindered after acylation of the neighbouring nitrogen has taken place. J... 

Enol esters are another type of acylating agent. The acetate of the enol form of acetone, isopropenyl acetate, is the most commonly used example. In the presence of an acid catalyst, they act as acylating agents and are reactive toward weak nucleophiles such as hindered hydroxy groups. 

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