Macrocycles high dilution conditions

Macrocycles are often not easy to form, especially when they include many substituents. The applied procedure to synthesize macrolactones was introduced by Yamaguchi and co-workers and has since been used extensively.21 First the acid is transformed into the mixed anhydride 26. Refluxing the anhydride in toluene will yield the desired macrocycle. The attack of the alcohol at the trichlorobenzoic acid carbonyl moiety is not favored because of steric hindrance by the chlorine substituents ortho to the acid. Therefore the ring is closed selectively. Usually in macrocyclizations high dilution conditions are applied, too, in order to avoid intermolecular reactions. 

The intramolecular version for synthesizing cyclic and polycyclic compounds offers a powerful synthetic method for naturally occurring macrocyclic and polycyclic compounds, and novel total syntheses of many naturally occurring complex molecules have been achieved by synthetic designs based on this methodology. Cyclization by the coupling of an enone and alkenyl iodide has been applied to the synthesis of a model compound of l6-membered car-bomycin B 162 in 55% yield. A stoichiometric amount of the catalyst was used because the reaction was carried out under high dilution conditions[132]. 

Shortly after their first report of all-oxygen bridged cryptands, Dietrich, Lehn and Sauvage reported incorporation of sulfur in the strands. The experimental methods used were essentially similar to those applied in the syntheses of the parent cryptands. As in previous cases, a diacyl chloride was condensed with a diamine under high dilution conditions. In this case, however, the diamine contained sulfur atoms rather than oxygen. The synthesis of compound 5 was accomplished in two stages as illustrated below in Eq. (8.3). The first cyclization step affords the macrocyclic amine in 55% yield. The macrobicyclic product (5) is formed in 25% yield from the monocyclic diamine and the acid chloride. 

Additions of carbon nucleophiles to vinylepoxides are well documented and can be accomplished by several different techniques. Palladium-catalyzed allylic alkylation of these substrates with soft carbon nucleophiles (pKa 10-20) proceeds under neutral conditions and with excellent regioselectivities [103, 104]. The sul-fone 51, for example, was cyclized through the use of catalytic amounts of Pd(PPh3)4 and bis(diphenylphosphino)ethane (dppe) under high-dilution conditions to give macrocycle 52, an intermediate in a total synthesis of the antitumor agent roseophilin, in excellent yield (Scheme 9.26) [115, 116]. 

When disodium (Z)-l,2-dicyanoethene-l,2-dithiolate and 1,3-dibromopropane are cyclized under high dilution conditions, the desired 14-membered macrocyclic tetrathioether was isolated <96LA1005>. 

Condensation of dicesium 2-thioxo-l,3-dithiole-4,5-diselenolate with fo/s-alkylating polythioethers under high dilution conditions afforded the TTF-containing macrocycles possessing soft donor sites and 12-, 15-, and 18-membered rings <%JCS(P1)1995>. 

Synthesis of TTF-phenanthroline macrocycles (e.g., 13) were accomplished in a simple multi-step sequence the macrocyclization procedure was from the 2,9-di(p-hydroxyphenyl)-1,10-phenanthroline with TTF-diiodide under high dilution conditions in the presence of CS2CO3 <00CC215>. 

As recently demonstrated by Furstner and Langemann, higher yields of the disubstituted olefin 83 can be obtained under high dilution conditions using la as the catalyst. Our experiments clearly illustrate that synthesis of trisubstituted macrocyclic alkenes is more complicated than that of their disubstituted analogues. See Furstner A, Langemann K (1996) J Org Chem 61 3942... 

The chiral dimethyl derivatives RR)-M and (SS)-84 of tetraethylene glycol have been employed (126) in the preparation of chiral macrocyclic polyether diesters such as (JU )-85 and (SS)S6. The reactions of the chiral diols with the appropriate diacid chlorides generally proceed (Scheme S) in good yield in warm benzene under high dilution conditions. 

The effident synthesis of macrocycles generally requires the use of high dilution conditions in order to depress the formation of oligomers and polymers with respect to the monomer ( High Dilution Principle ) (52, 53). 

SCHEME 7 The MACROCYCLIZATION OF PRECURSOR 14 WITH ISOPHTHALIC ACID D1CHLOR1DE UNDER HIGH DILUTION CONDITIONS YIELDS A TETRALACTAM MACROCYCLE 13, THE CATENANE 15, AND A LARGER OCTALACTAM MACROCYCLE 16. 

Dienes are cyclized by intramolecular metathesis. In particular, cyclic alkenes 43 and ethylene are formed by the ring-closing metathesis of the a,co-diene 46. This is the reverse reaction of ethenolysis. Alkene metathesis is reversible, and usually an equilibrium mixture of alkenes is formed. However, the metathesis of a,co-dienes 46 generates ethylene as one product, which can be removed easily from reaction mixtures to afford cyclic compounds 43 nearly quantitatively. This is a most useful reaction, because from not only five to eight membered rings, but also macrocycles can be prepared by RCM under high-dilution conditions. However, it should be noted that RCM is an intramolecular reaction and competitive with acyclic diene metathesis polymerization (ADMET), which is intermolecular to form the polymer 47. In addition, the polymer 47 may be formed by ROMP of the cyclic compounds 43. 

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