Macrocyclic diarylheptanoids

Diarylheptanoids constitute a distinct group of natural plant metabolites characterized by two aromatic rings linked by a linear seven-carbon aliphatic chain. They may be divided into two subgroups, i.e. open chain and macrocyclic diarylheptanoids. In the latter the aromatic rings are connected to form a diarylether or a biaryl moiety. 

Macrocyclic diarylheptanoids can be derived from their open chain congeners by oxidative phenol coupling resulting in macrocyclic biaiyls or biaryl ethers. Usually they were named after the plant source and can be conveniently classified according to the plant families in which they occur. 

Compounds 80 and 93 were reisolated by Sawa and his cowoikers from C. cordata along with a new biaryl type macrocyclic diarylheptanoid (84) containing an unusual diol acetonide function. 

Macrocyclic diarylheptanoids can be derived from linear ones by oxidative cyclization. This is supported by the fact that in all of the biaryl type representatives the aryl-aryl bond is in meta position relative to both ends of the seven-carbon chain, while in those containing a diarylether bond a meta,para bridging can be identified. This substitution pattern corresponds to activation of the position ortho to the phenolic hydroxy group. Biosynthesis of cyclic diarylheptanoids was investigated by Inoue et al. (84). They fed [1- C] and... 

Inhibition of PG biosynthesis by open chain diarylheptanoids was first reported by Itokawa and his coworkers (26, 31). Their results were implemented by studies on additional compounds first by Flynn (88) and later by Kinchi et al. (85). The latter group extended the assay of inhibitor activity also to the 5-lipoxygenase enzyme system. Their results are summarized in Table 2. Among macrocyclic diarylheptanoids only for garuganins (88-95), isolated from Garuga pinnata was some antiinflammatory activity claimed, but no specific data were disclosed (57, 58). 

The closure of macrocyclic rings represents a special field of intramolecular aryl-aryl bond formation. Irradiation of an open-chain dibromide afforded myricanone (Scheme 48) [88], which represented the first synthesis of a macrocyclic diarylheptanoid [89]. 

It is worth noting that still no biological effects have been reported for the macrocyclic diarylheptanoids. 

From Alnus species i.e. varieties of alder, containing also a large variety of open chain diarylheptanoids (7-21), some biaryl type macrocyclic compounds have also been isolated. In Alnus japonica Steud. indigeneous in Japan Nomura et al. found four diphenols of this kind. The constitution of alnuson (80) and alnusoxide (81) was elucidated in 1975 (20), while alnusdiol (82) and its oxidation product, alnusonol (83) were characterized in 1981 (17). It was observed that 81 could only be isolated from the dried plant and may be therefore an artefact. Alnusdiol was optically active and therefore a trans-diol but its absolute configuration remained unknown. 

The total synthesis of the diarylheptanoid garugamblin 1 was achieved by M. Nogradi et al. using the modified Wurtz coupiing as the key macrocyclization step. The dibromide was treated with sodium metal at room temperature in the presence of TPE to afford the desired macrocycle in moderate yield. The N-0 bond of the isoxazole ring was cleaved under the reaction conditions. 

Scientific reports have appeared on 24 macrocyclic biarylheptanoids (60-83 Table 3), of which 17 are new natural products. A revised structure of porson (61) has been proposed [29]. Plants of the genera Betula (Betulaceae), Acer (Aceraceae) and Corylus (Betulaceae) are reported for the first time to contain Type III diarylheptanoids. Rhoiptelol A (79) is the first macrocyclic biarylheptanoid from the family Rhoipteleaceae. Compounds 65 and 66 were reported in 1991, unfortunately missed in the previous review (1), but arbitrarily included in die present compilation. 

Type I non-phenolic linear diarylheptanoids Type II phenolic linear diarylheptanoids Type III macrocyclic biarylheptanoids Type IV macrocyclic diaryl ether heptanoids Type V diarylheptanoids with cyclised C7-chain. 

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