Historical Synthesis of Macrocycles

The first syntheses [172] of macrocyclic scented compound were based on the Piria cyclisation (Raffaele Michele Rocco Piria (1814-1865), Italian chemist) of terminally functionalised aliphatic precursors. Thus, pyrolysis of the thorium salt of thapsic acid (Fig. 3.42) and purification via the semicarbazone gave exaltone in a yield of 5.5 % (Ruzicka cyclisation). The mechanism ofthis reactionhas not been finally established, although it is accepted that free radicals are involved in the cyclisation. [173] Oxidation using Caro s acid then gives exaltolide in 47 % yield. 

The intramolecular Thorpe-Ziegler reaction of hexadecadinitrile with lithium l -ethylanHide according to the Ruggli-Ziegler dilution principle provided a technical advancement. At a concentration of 0.067 mole/1 the yield ranged around 60-70%. 

The technical breakthrough was however only attained with the StoU-Hansley-Prelog procedure for the synthesis of exaltone. By reaction with sodium, dimethyl hexadecanedioate was converted into the acyloin, [174] the reduction of which with zinc and hydrochloric acid (Qemmensen reduction) gave exaltone. On the other hand, dehydration of the acyloin over hot aluminium oxide gave exaltenone, which could be converted by a copper(I)-catalysed reaction with methylmagnesium bromide into (+/-)-muscone. 

42 Thapsic acid (hexadecanedioic acid) may be isolated from the dried roots of Thapsia garganica, a Mediterranean, umbelliferous plant, which was known already In ancient times to be poisonous (due to thapsigargin and other components). In Arabian caravans it was called deadly carrot, because camels would eat it and die quickly 

---