Macrocyclic skeleton

Phthalocyanines are commonly very stable compounds. Therefore, the macrocyclic structure of these compounds is maintained during most of the chemical reactions. If reaction conditions are harsh enough to break bonds ofthe macrocyclic skeleton, usually defined or undefined97-361 products of minor interest are obtained. Usually, however, reactions on phthalocyanines can be regarded as syntheses of other phthalocyanine compounds. 

Both of the tetraaza[3.3.3.3]paracyclophane (1) and tetraaza[n.l.n.l]paracyclo-phane (n = 6, 7, 8 cf. 2) rings have frequently been used as fundamental molecular skeletons for preparation of functionalized macrocyclic hosts [24-36]. Formation of three-dimensionally extended hydrophobic cavities was approached by introducing multiple hydrocarbon branches into the macrocyclic skeletons. Multiple hydrophobic chains thus placed in a macrocycle must be extended in the same direction and undergo mutual association to attain their optimal hydrophobic interactions in aqueous media due to thermodynamic reasons, while in nonaqueous media they presumably assume a free and separated configuration to minimize their mutual steric interactions. Consequently, such hydrophobic branches may provide a large hydrophobic cavity in aqueous media. 

In order to construct a hydrophobic three-dimensional cavity that is in-tramolecularly limited in space, we have prepared cage-type cyclophanes by linking macrocyclic rings. First we prepared a macropolycyclic host, which is constructed with two rigid macrocyclic skeletons of different size, tetraaza[3.3.3.3]paracyclophane as the larger one and tetraazacyclotetradecane as the smaller one, and four flexible hydrocarbon chains that connect the two macrocycles [40]. The flexibility of four hydrocarbon chains connecting the two macrocycles allows the induced-fit host-guest interaction in aqueous media. 

The incorporation of chiral units within the macrocyclic skeleton is an important route to the design of macrocyclic receptors capable of enantiomeric or chiral substrate recognition. In order to achieve this goal, the receptor must display a fine structure as a result of chiral barriers, which then allows diastereomeric receptor-substrate interactions, in addition to maintaining the desired cavity properties.18,30,51... 

Murakami and co-workers12) have carried out one of the most thorough investigations of multi-armed compounds with ion-terminated chains. In 1979 they reported the substrate-binding behavior of an azaparacyclophane (16) in which the hydro-phobic cavity was deepened by substitution of long ion-terminated chains on the macrocyclic skeleton. Salient properties of the cyclophane (16) include (1) The compound has a critical micelle concentration of 3.2 x 10 4 M. (2) (16) binds cationic and neutral dyes but not anionic ones. Thus, Rhodamine 6G and Quinaldine Red form 1 1 complexes with (16) having association constants of about 5 x 103 M 1. 

The steric repulsion energy between the methyl group and the macrocyclic skeleton (BDHC) is assumed to be negligible. 

Calixarene analogues having L-cysteine 52,105 (/ ,/ )-cystine 53/54,106 and other amino acid residues 55107 incorporated into one or two bridges of the macrocyclic skeleton have been synthesized by condensation of a bis(chloromethylated) dimer, trimer, or tetramer with the corresponding amino acid ester under basic conditions (Figure 10). 

The possible number of inherently chiral structures and conformers further increases if the calixarene contains both different phenolic units and different bridges in the macrocyclic skeleton. For example, two chiral monoethers 88a,b are available from dihomooxacalix[4]arenes (one -CH2-0-CH2- bridge instead of -CH2-).17188b is the preferred product of the mono-O-alkylation, since the negative charge of the respective phenoxide anion is better stabilized by intramolecular hydrogen bonds due to the smaller distance between the phenoxide anion and the hydroxy groups. Tetraketone derivatives (Y = CH,-C(0)-R) in the two possible partial cone conformations, have been prepared in moderate yields. 

It should be mentioned that conditions have been found recently to obtain C4-symmetrical tetraethers 115 directly from resorcinol monoethers by condensation with aldehydes. The regular incorporation in the macrocyclic skeleton was confirmed for one example by X-ray analysis.224 However, in contrast to Heaney s enantioselective synthesis, the racemic mixture of the two enantiomers is formed in this case. 

Another general method for the introduction of a nitrogen atom into a macrocyclic skeleton is via the Beckmann reaction. Rearrangement of cyclotridecanone oxime led to cyclic lactam, which was reduced to amine by lithium aluminium hydride (LAH). Further substitution yielded 14-membered mutuporamine <1999TL5401>. Dieckmann condensation was used for the preparation of 14-membered aza ketone 15 <1999JA2919>, but no experimental details were given. 

Characteristic to some important cembrane diterpenoids, such as isocembrene, cembrene, cembrene C, and sarcophytol A, is a 1,3-diene unit in the macrocyclic skeleton. In continuation of our ongoing project on the total synthesis of cembrane-type diterpenoids, we intended to explore a novel macrocyclization method to... 

Research in the laboratory of P. Magnus showed that the macrocyclic skeleton of diazonamide could be synthesized with the use of macroiactonization followed by a photo-Fries rearrangement. First, the aromatic carboxylic acid and the phenol were coupled with EDCI to form the macrolactone (phenolic ester), which was then exposed to light at high-dilution to cleanly afford the macrocyclic ortho-acylated phenol skeleton of diazonamide. 

A simple calixarene built up with four phenol units linked via methylene bridges is shown in Fig. 10 (substitution of the methylene junctions with S atoms gives rise to the class of thiocalixarenes). Cooperative networks of intramolecular hydrogen bonds (circular array of hydrogen bonds, observed also in cyclodextrins) play a capital role in the cavity shape as well as in the conformational features of the macrocyclic skeleton [291-293]. Encapsulation of other molecules in the cavity is also controlled by hydrogen bonds [294]. 

Synthesis of macrosphelides, natural potent cell-cell adhesion inhibitors having novel three ester linkages in their 16-membered macrocyclic skeleton 05H(65)1741, 05Y140. 

Fig. 3.24 Conformational changes in the porphyrin macrocyclic skeleton (for meso-substituted porphyrins only) on dication formation. The pyrrole subunits hinge about carbons 1, 4, 6, 9,11,14,16, and 19 (two up and two down) while the meso-aryl imits rotate more into the mean macrocyclic plane. [From E. Meyer and D.L. Cullen, in The Porphyrins, ed. D. Dolphin, Vol. 3, Academic Press, New York (1978), pp. 513-529.]...

Further, in continuation to the synthesis of chartellines, an approach was developed by Baran et al. to construct macrocyclic skeleton and 5-lactam functionality required for chartellines, securamines and securines [73],... 

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