Macrolactamization 12-membered ring

Boger and co-workers performed a detailed study on the effect of substrate structural features on the 17-membered ring macrolactamization. It was found that the substituent at the remote C4 aryl position had a profound effect on the rate and yield of the cyclization. Substrates bearing either a free phenol or no substituent were found to cyclize more efficiently, whereas those bearing methyl or benzyl ethers cyclized considerably less efficiently (Table 1)J5 ... 

Macrolactamization has limitations. All macrolactamization methods studied to date are ineffective at forming 14-membered cycloisodityrosines of the type found in deoxy-bouvardin (2) and RA-VII (3).[1° In addition, macrolactamization was not successful at preparing 16-membered rings that are structurally similar to cycloisodityrosines, such as the type found in the vancomycin family of glycopeptide antibiotics.[11 12 ... 

Macrolactamization. Closure of the 23-membered ring is the most critical step for j > nthesis of (-)-madumycin II. Using the Bop-CF in the presence of i-Pr NEt provides i volution. Despite the modest yield (32%), the method is serviceable. 

In summary, the obvious difference between the two Nicolaou syntheses is the reversed order of the construction of the daunting macrocyclic domains of diazonamide A (47). The initial synthesis installed the macrolactam ring first, followed by photoinduced HBr eUmination for the heterocyclic 12-membered ring. The subsequent synthesis constiucted the heterocyclic core first, which featured a... 

Suzuki coupling and a heteropinacol coupling/oxitne-cleavage cascade reaction, followed by a similar macrolactamization for the remaining 12-membered ring. 

Scheme 18. Retrosynthesis for the construction of the 14-membered macrolactam ring oi Sch 38516 (fluvirucin Bj)... 

In contrast to his first synthesis vide supra), Nicolaou s second synthesis formed the left-side 12-membered in a late stage, through a macrolactamization process [40]. Retrosynthetic excision of the side chain and the chlorine atoms, and disconnection of the macrolactam, aminal, oxazole and bis-aryl ring system leads to fragments 76 and 77 (Scheme 12). 

Confalone demonstrated another route through a C-C bond-forming process to form the 19-membered ansa-ring. Closure of this ring was designed so that a dipolar cyclo-addition could be utilized between a simple terminal olefin and nitrile oxide (-C=N -> 0 ), which was provided from a nitroalkane precursor such as 8. A macrolactam ring was cyclized in the form of the isoxazoline product 9. The maytansine model 10 was obtained after reduction and hydrolysis into a P-oxyketone followed by cyclization of the carbamate ring. 

The macrolactamization strategy for the closure of the 14-membered D ring, previously developed from model structures, was applied to the dia-zatricychc acid 96 to afford tetracyclic lactam 97. Acid 96, which already incorporates the required functionalized 11-carbon chain at C-9, was prepared in four steps from the enantiopure alcohol 64 oxidation of the C-3... 

Scheme 21 Assembly of the 14-membered D ring of madangamine D by macrolactamization.

New 14-membered macrolactam antifungal antibiotics isolated from the broth of a new species of Actinomadura contain either mycosamine or its 4-epimer, 3-amino-3,6-dideoxy-L-talopyranose, attached to the macrolide ring. " ... 

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