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Paper 3 Org. Biomol. Chem., 2012, 10, 4381–4389
Synthesis of novel enantiomerically pure tetra-carbohydrazide cyclophane
macrocycles
Hany F. Nour, Nadim Hourani and Nikolai Kuhnert*
Reproduced by permission of The Royal Society of Chemistry
http://pubs.rsc.org/en/content/articlelanding/2012/OB/C2OB25171J
Objectives of the work
Trianglimines were synthesized in high purity; however the yields of the macrocycles were low. In
addition, the regioisomeric macrocycles equilibrated with one another in the NMR tube during measurements.
Equilibration of the regioisomers was only observed in case where CDCL 3 was the deuterated
solvent used. It was accordingly necessary to improve the yields of trianglimines by avoiding formation
of the regioisomers. All attempts to synthesize symmetrically functionalized dialdehyde building blocks
did not succeed. Replacing the diaminocyclohexane unit in trianglimine was an objective towards the
synthesis of symmetrical macrocycles. The ring which replaces diaminocyclohexane should be chiral and
should possess the attractive conformational bias feature of diaminocyclohexane. Also, it should be easily
loaded with different functionalities. A ring with all these features can be obtained by protecting
ketones with the vicinal hydroxyl groups of commercially available (+)-diethyl L-tartrate or (−)-diethyl D-
tartrate. Molecular modeling at the MM+ level showed that dihydrazides obtained by this approach can
undergo macrocyclization reactions. The new dihydrazides reacted with aromatic dialdehydes in
[2+2]˗cyclocondensation reactions to form a novel class of chiral non˗racemic macrocycles which were
named tetra˗carbohydrazide cyclophanes.
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