Macrocyclic skeleton, macrocyclization method

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... 

The chiral organocopper compound (186) adds diastereoselectively to 2-methyl-2-cyclopentenone, allowing the preparation of optically active steroid CD-ring building blocks (Scheme 68).202-204 A related method was applied to a synthesis of the steroid skeleton via an intramolecular (transannular) Diels-Alder reaction of a macrocyclic precursor.203 Chiral acetone anion equivalents based on copper azaeno-lates derived from acetone imines were shown to add to cyclic enones with good selectivity (60-80% ee, after hydrolysis).206-208 Even better ee values are obtained with the mixed zincate prepared from (187) and dimethylzinc (Scheme 69). Other highly diastereoselective but synthetically less important 1,4-additions of chiral cuprates to prochiral enones were reported.209-210... 

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. 

In general, yields decrease in cesium assisted cyclizations changing to smaller ring sizes (7a) or by introduction of hetero atoms into the ring skeleton. The cesium method is also well suited for the preparation of cyclophane compounds like the 23-membered macrocycle 9 or the tetraoxa cycle 10, which were obtained in 60 and 46% yields respectively, starting with the ditosylates [19]. 

Macrolides and Related Compounds.- The total synthesis of amphoteronolide B (166) and amphotericin B (167) has been reported in a series of papers by Nicolaou s group.The method uses the phosphonate-based olefination of (164) with (165) to form the basic carbon skeleton which is cyclised by an intramolecular phosphonate-based olefination. A Wittig reaction of the ylide (168) is a key step in the synthesis of the cytotoxic macrocycle riccardin C (169). 

There are a number of methods for the synthesis of quinoxaline macrocycles that have been successfully implemented for constructing quinoxahnoporphyrins, quinoxalinoporphyrazines, quinoxalinocrown ethers, quinoxalinocavitands, quinoxalinohemispherands, and hybrid macrocycles. In these macrocyclic systems, quinoxaline moiety(ies) were attached to the macrocyclic skeleton by the atoms N(l) and C(3), N(l) and N(4), C(2) and C(3), C(2) and C(8), C(6) and C(7). In these cases, macrocyclic systems in which the quinoxaline moiety is fixed in a macrocyclic skeleton by atoms of C(2) and C(3) are represented best of all. Considerably less attention is paid to their 6, 7 analogs, and all the others are represented in single works. 

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