Amide based construction/synthesis

The functionalisation also allows extending the complexity of intertwined molecular assemblies involving molecular catenanes, rotaxanes and knots. Elaborate interlocked assemblies constructed by means of metal-templation techniques and ji-ji-stacking preorganisation were reviewed [3, 11], Our last survey was devoted to the hydrogen bond templated synthesis of amide-based catenanes and rotaxanes [32], Since then a considerable advancement in elucidation of mechanisms of templation and derivatisation of the amide-based interlocked structures has been reached. Moreover, in 2000 we reported a one pot synthesis of amide-based knots such as 8 [21], which is so far the easiest preparation of molecular knots. In the following, specific possibilities of functionalisation of amide-based catenanes, rotaxanes and knots will be discussed. 

The hrst step in the preparation of the antidepressant maprotiline (33-5) takes advantage of the acidity of anthrone protons for incorporation of the side chain. Thus treatment of (30-1) with ethyl acrylate and a relatively mild base leads to the Michael adduct saponihcation of the ester group gives the corresponding acid (33-1). The ketone group is then reduced by means of zinc and ammonium hydroxide. Dehydration of the hrst-formed alcohol under acidic conditions leads to the formation of fully aromatic anthracene (33-2). Diels-Alder addition of ethylene under high pressure leads to the addition across the 9,10 positions and the formation of the central 2,2,2-bicyclooctyl moiety (33-3). The hnal steps involve the construction of the typical antidepressant side chain. The acid in (33-3) is thus converted to an acid chloride and that function reacted with methylamine to form the amide (33-4). Reduction to a secondary amine completes the synthesis of (33-5) [33]. 

The highest flexibility for a variation of the functional group and the chains X and Y (i.e. the size of the rim of the lamp shade) will be realiad when the synthesis of 3 is convergent and modular (Scheme 1). Amide bonds can easily be formed in macrocyclizations [13], therefore macrocyclic diamines 7 and diacyl dichlorides 8 had to be prepared. For the synthesis of macrocyclic diamines 7, also a large number of reactions are known. However, in this case a reduction of a macrocyclic diamide could not be achieved [11]. Therefore, another route was used the formation of macrocyclic diimines 6 (bis-Schiff bases) followed by NaBH4 reduction to the macrocyclic diamines 7. This approach has the advantage that for the construction of macrocyclic diimines 6, the metal ion template effect [14] may be exploited. 

An efficient synthesis of ( )-quebrachamine is based on the construction of a suitable precursor via ring cleavage of an a-diketone monothioketal (810) (80JCS(P1)457). This monothioketal, available from 4-ethoxycarbonylcyclohexanone ethylene ketal, was fragmented to the dithianyl half ester (811) with sodium hydride in the presence of water. Reaction of (811) with tryptamine and DCC provided an amide which was converted to the stereoisomeric lactams (812) on hydrolysis of the dithiane function. Reduction of either the a- or /3-ethyl isomer with lithium aluminum hydride followed by conversion of the derived amino alcohol to its mesylate produced the amorphous quaternary salt (813). On reduction with sodium in liquid ammonia, the isomeric salts provided ( )-quebrachamine (814 Scheme 190). 

Poss, M.A., and Reid, J.A., Synthesis of the hydroxyethylene dipeptide isostere, (2S,4S,5S)-5-amino-6-cyclohexy]-4-hydroxy-2-isopropyl hexanoic acid n-butyl amide. Tetrahedron Lett., 33, 1411, 1992. Handa, S., Pattenden, G., and Li, W.-S., A new approach to steroid ring construction based on a novel radical cascade sequence, J. Chem. Soc., Chem. Commun., 311, 1998. 

Gallc er and co-workers devised a formal enantioselective synthesis of ( — )-3 in wduch the stereogenic center at C-6 was derived fiom Cbz-protected (S)-2-amino-4-pentenoic acid (36) (44). Acylation of 3,3-dimethoxy-pyrrolidine (37) with this acid yielded amide 38, which was converted into aldehyde 39 by cleavage of the terminal alkene vnth osmium tetroxide and sodium periodate (Scheme 5). The indolizidine nucleus was constructed from 39 by a problematic intramolecular aldol condensation, which was eventually optimized by using 2,2,6,6-tetramethylpiperidine as base followed by adsorption onto, and elution from, silica gel (45). Diastereoselective reduction of the ketone group of the aldol product 40 was accomplished in better than 95% enantiomeric excess (ee) with the Corey... 

---