Piperidine 2 -benzyl ester

Once it is part of a cyclic dipeptide, the prolyl residue becomes susceptible to enantiomerization by base (see Section 7.22). The implication of the tendency of dipeptide esters to form piperazine-2,5-diones is that their amino groups cannot be left unprotonated for any length of time. The problem arises during neutralization after acidolysis of a Boc-dipeptide ester and after removal of an Fmoc group from an Fmoc-dipeptide ester by piperidine or other secondary amine. The problem is so severe with proline that a synthesis involving deprotection of Fmoc-Lys(Z)-Pro-OBzl produced only the cyclic dipeptide and no linear tripeptide. The problem surfaces in solid-phase synthesis after incorporation of the second residue of a chain that is bound to the support by a benzyl-ester type linkage. There is also the added difficulty that hydroxymethyl groups are liberated, and they can be the source of other side reactions. 

In a three-component synthesis the amide (86-1) obtained from the ester (85-5) and benzyl isocyanide is reacted with the piperdone (86-2). The product from this transform consists of the addition product (86-3) where amide nitrogen in (86-1) as well as the carbon from the isocyanide have added to the carbonyl group on the piperidine. Treatment of the adduct (86-3) with a strong acid hydrolyzes the urethane function on the fert-butyloxycarbonic protecting group, leaving behind the primary... 

The esterification of l-benzyM-(phenylamino) piperidine-4-carboxylic acid with ethanol and H2SO4 gives the corresponding ethyl ester, which is reduced with LiAIH2(0CH2CH20CH3)2 in benzene affording 1-benzyl-4-(phenylamino)piperidine-4-methanol. The methylation of this compound with methyl iodide and NaH in HMPA yields 1 -benzyl-4-methoxymethyl-4-(phenylamino)-... 

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