Cyclic 2-hydroxymethyl amines

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. 

Replacement of the diethylamino group by other secondary amines with an open chain or cyclic structures resulted in decrease in activity. However, introduction of secondary amino functions enhanced the activity the optimal activity was found in 2-[(isopropyl)aminomethyl]-6-methy -7-nitro-l,2,3,4-tetrahydroquinoline, called U.K, 3883 (13) [12,16], Exploiting the knowledge that hycanthone is the active metabolite of lucanthone, which may be prepared by microbial oxidation, the Pfizer scientists subjected 13 to microbiological oxidation in the presence of Aspergillus sderoticrutn and obtained the hydroxymethyl derivative of UK-3883, which was later known as UK-4271 or oxamniquine (14) [22,23], Oxamniquine proved to be a better... 

The only asymmetric synthesis of the Nuphar indolizidine to date is due to Barluenga and co-workers (615). Their route to the (5S,8 ,8aS)-( -) enantiomer of 944 commenced with cycloaddition between the proline-derived 2-amino-butadiene 957 and imine 958 (Scheme 125). Hydrolysis of the adduct 959 gave piperidinone 960 in 51% yield and an ee of better than 99%. Once the alcohol and amine groups had been mutually protected as the cyclic carbamate 961, defimctionalization of the ketone was accomplished via an enol triflate. Chain-extension of the deprotected piperidine 962 at the hydroxymethyl substituent afforded 963, which was cyclized to the bicyclic lactam 964 simply by heating in toluene. Reduction with lithium aluminum hydride completed the synthesis of ( - )-944 ([a]n -99°, c 1.3, CH2CI2). 

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