Formyl protective group

A class of enzymes that was made accessible only recently is the peptide de-formylases. It was demonstrated that peptide deformylase can be used for kinetic resolutions, but they can also be employed to cleave off formyl protection groups [99]. Due to the stereoselectivity of the enzyme the enantiopurity of the product is also improved during the deprotection (Scheme 6.31). 

Scheme 6.31 Removal of a formyl protection group with a peptide deformylase.

Ser, Thr, and Trp were left unprotected for short sequences (i.e., 5 to 6 amino acids in length). Initially we used benzyl-protecting groups for the alcohols, but resulting from incomplete deprotection for some libraries, we left the side-chain unprotected. For Trp, alkylations during activation/ deprotection step was sometimes observed. As such we sometimes include the formyl protecting group on the indole for difficult sequences. 

The N -formyl protecting group is easily introduced it is very stable to acidic reagents, even pure hydrofluoric acid it is cleaved by strong acid-soft nucleophile cocktails (such as HF/ thiols), and by nucleophiles in basic conditions (hydrazine, alkali, piperidine in It... 

Kiedrowski and Ddrwald (1988) have reported a different strategy for preparation of polytrimethyleneamines. In their process, l-bromo-3-chloro-propane was used to extend the chain by trimethylene units. In the example shown below, A -formyl-yV -tosyl-l,4-butanediamine was extended by a multistep process utilizing both tosyl and formyl protecting groups. 

Fluoromacrocycles, 141 A-Formyl-A -tosyl-1,4-butanediamine. 55 A-Formyl protecting groups, 54, 55 Functionalized aza-crown macrocycles. 34. 148-151, 153, 180,181, 246, 250, 252. 

Since (A) does not contain any other functional group in addition to the formyl group, one may predict that suitable reaction conditions could be found for all conversions into (A). Many other alternative target molecules can, of course, be formulated. The reduction of (H), for example, may require introduction of a protecting group, e.g. acetal formation. The industrial synthesis of (A) is based upon the oxidation of (E) since 3-methylbutanol (isoamyl alcohol) is a cheap distillation product from alcoholic fermentation ( fusel oils ). The second step of our simple antithetic analysis — systematic disconnection — will now be exemplified with all target molecules of the scheme above. For the sake of brevity we shall omit the syn-thons and indicate only the reagents and reaction conditions. 

The oxazolidine system proved a good protecting group with which to mask the ethanolamine moiety in the a-formylation and a-benzoylation of 558, and it could also be used as an aldehyde donor in the rearrangement, based on the ring-chain tautomeric character of 559, under acidic conditions to yield 3-(2-hydroxyethyl)-substituted 1,3-oxazin-4-ones 560 (Scheme 106) <1996JOC3358>. 

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