Macrocycle synthesis high pressure

The synthesis of the macrocycles 43 (Scheme 9) is an example of repetitive, highly stereoselective Diels-Alder reaction between bis-dienes 41 and bis-dienophiles 42, containing all oxo or methano bridges syn to one another. The consecutive inter- and intramolecular Diels-Alder reactions only succeed at high pressure. Obviously, both reactions are accelerated by pressure. The macrocycles are of interest in supramolecular chemistry (host-guest chemistry) because of their well-defined cavities with different sizes depending on the arene spacer-units. 

The Diels-Alder reaction is an important and widely used reaction in organic synthesis (Sauer and Sustmann, 1980), and in the chemical industry (Griffiths and Previdoli, 1993). Rate enhancement of this reaction has been achieved by the use of solvents such as water, surfactants, very high pressure, lithium amides, alkylammonium nitrate salts, and macrocyclic hosts (Sherman et ak, 1998). Diels-Alder reactions can be ran in neutral ionic liquids (such as 1-butyl-3-methylimidazolium trifluoromethanesulfo-nate, l-butyl-3-methylimidazolium hexafluorophophate, l-butyl-3-methylimidazolium tetrafluoroborate, and l-butyl-3-methylimidazolium lactate). Rate enhancements and selectivities are similar to those of reactions performed in lithium perchlorate-diethyl ether mixtures. 

The total synthesis of the potent anticancer macrocyclic natural product lasiodiplodin was achieved in the laboratory of A. Furstner. The key macrocyclization step was carried out by the alkene metathesis of a styrene derivative, which was prepared in excellent yield via an intermolecular Heck reaction between an aryl triflate and high-pressure ethylene gas. 

A general procedure for the synthesis of cryptands from the corresponding diazacoronand by means of a high-pressure double amidation using diverse dicarboxylic acids has appeared and should prove to be quite useful <04S369>. The attachment of functionality onto a macrocyclic... 

Fig. 18 High-pressure synthesis (a) of cryptands and (b) of chiral macrocyclic tetraamides.

Stoddart and cowotkers have extensively exploited the principle of repetitive arene and bis-arene cycloaddition to furans for the design and synthesis of novel macropolycyclic stractures [22,23]. For example, bis-dienophile 21 obtained from ortho-xylene 20 with butyllithium followed by trapping of the resulting bis-arene equivalent 22 with 2 equiv of furan represents a suitable building block for the construction of the macropolycylic belt-like molecule 23. Diels-Alder reaction of 21 with an appropriate bis-diene under alternate thermal and high-pressure conditions afforded macrocycle 23 in good yield, together with an acyclic isomer (Scheme 13.8) [22,23]. 

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