Nine-membered enediyne

Figure 11.2 Biosynthesis of the nine-membered enediynes. Members of this family share a common biosynthetic pathway for the enediyne core intermediate. Domains are shown in circles with abbreviations (KS, ketosynthase AT, acyltransferase KR, ketoreductase DH, dehydratase TE, thioesterase ACP, acyl carrier protein PPT, phosphopantetheine transferase)...

Nozaki reaction (12, 137 14, 96 15, 95). An intramolecular version of this reaction can effect cyclization even to a strained nine-membered ring. Thus 1 on treatment with CrCl2 at a low temperature cyclizes mainly to 2, a mixture of epimers in which a cyclononadiyne ring is fused to a cyclopentene ring. After acetylation of the secondary hydroxyl group, the mixture is dehydrated to 3, with a nine-membered enediyne ring. 

N1999-A2 is a highly strained nine-membered enediyne with potent antitumour activity. Its synthesis is a formidable challenge owing to its instability. The Hira-ma group20 accomplished a synthesis of N1999-A2 in which a chloroacetate underwent ethanolysis without loss of the labile phenolic TES ether provided the temperature was maintained below -5 [Scheme 4.345]. 

Total synthesis and absolute stereochemistry of the DNA-cleaving nine-membered enediyne antibiotic N1999-A2 04YGK184. 

In the attempt to unravel the biosynthetic origin of sporolides, and considering that these compounds are composed of a chlorinated cyclopenta[a]indene ring and a cyclohexenone moiety, it was hypothesized that the former fragment could be nonenzymatically derived from an unstable nine-membered enediyne precursor by the nucleophilic addition of chloride. Support to this suggestion came from sequence analysis of S. tropica CNB-440 genome, which led to the identification of two biosynthetic loci encoding enediyne PKSs. Analysis of the respective... 

The stractural and functional relatedness of SgcE and CalES suggested a common polyketide pathway for the biosynthesis of both nine and ten-membered enediynes, despite the fact that their incorporation patterns by Relabeled acetate feeding experiments were distinct. The two carbons that make up each triple bond of neocarzinostatin and C-1027 (both nine-membered enediynes) are derived from intact acetate units, whereas those of cahcheamicin are known to be derived from adjacent acetate units. Like SgcE, the CalES PKS could be envisioned to produce a nascent polyunsaturated intermediate from... 

Figure 5. Final domain assignments of nine-membered enediyne PKSEs from C-1027producer S. globisporus and the NCSproducer S. carzinostaticus. Active site serines within ACP domains arephosphopantetheinylated by PPTdomain (in cis) followed by production of the polyene precursor to the enediyne core. R, 3, 5 -adenosine diphosphate.

The nine-membered enediynes, in contrast to all other enediynes, are capable of cutting a single- and a double-stranded DNA by the same... 

Figure 3.1 Nine-membered enediyne chromophores whose structures have been elucidated neocarzinostatin (3.405), kedarcidin (3.406), C-1027 (3.407), maduropeptin (3.408), and N1999A2 (3.409).

The nine-membered enediyne chromophores require activation. Most biological pathways of activation involve the collapse of diradicals that are generated from thiol groups, although other chemical routes, as well as photochemical activation, are able to initiate the electronic rearrangement of the chromophore. It is noted that C-1027 is the most labile of the explored free enediyne chromophores of the nine-membered subfamily. 

Usuki, T.jMita, T., Lear, M.J.,etal. (2004) Spin trapping of C-labeledp-benzynes generated by Masamune-Bergman cyclization of bicyclic nine-membered enediynes. Angewandte Chemie International Edition, 43(39), 5249-5253. 

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