Synthetic applications involving the heterocycloreversion of 2-azanorbomenes

In addition to utilizing the heterocycloreversion of 2-azanorbomenes as an aqueous deprotection protocol for primary amines, where the formation of the transient iminium ion is incidental, 2-azanorbomene derivatives can also serve as precursors to iminium ions with the intention of synthetically exploiting these unstable intermediates. Such heterocycloreversion applications do not involve the use of aqueous media to avoid undesired hydrolysis of the newly generated iminium ion. The next few examples illustrate the use of 2-azanorbomenes as iminium-ion synthons unmasked by the reverse Diels-Alder process (see section 2.4.1). 

The first synthetic application of this type features a novel method for the iV-methylation of amino acid and polypeptide derivatives [36]. This methodology involves trapping of the incipient iminium ions, formed from facile heterocycloreversion of iV-substituted 2-azanorbomenes, with triethyl-silane/trifluoroacetic acid. For example, treatment of a 0.1 M solution of the 2-azanorbomene derived from L-phenylalanyl-L-leucine methyl ester (105) in chloroform/trifluoroacetic acid (1/1) with 3.0equiv of triethylsilane provides after 20 h at room temperature an 84% yield of /V-methyl-L-phenylalanyl-L-leucine methyl ester, 107  

The process lacks any detectable racemization. Even racemization-prone phenylglycine can be monomethylated by this protocol without detectable epimerization. 

This two-step methylation sequence, involving 2-azanorbornene synthesis and retro Diels-Alder initiated iminium-ion reduction, is applicable to a variety of amino acid derivatives. The protocol is compatible with unprotected phenols and hydroxyl groups. The 2-azanorbornenes derived from the methyl esters of unprotected L-tyrosine and L-serine both undergo the N- 

Another application of the A-methylation sequence was disclosed in the synthesis of physostigmine [37]. The methodology features a unique protocol for the aminoethylation or the A-methyl aminoethylation of carbonyl compounds with a novel spiroaziridinium salt, 2-azanorbornene-2-spiro-l -aziridinium triflate (109). The spiroaziridinium salt, 109, is prepared in a two-step process  

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