A

Neocarzinostatin 4.45

Neocarzinostatin 4.45

FIGURE 4.31 Activation of enediynes through a thiol addition (A) or an intramolecular addition (B).

FIGURE 4.31 Activation of enediynes through a thiol addition (A) or an intramolecular addition (B).

FIGURE 4.32 Generation of radicals from calicheamicins and esperamicins.

In the case of dynemicin A, its rigid structure keeps the alkynes separate, preventing the Bergmann cyclization. The anthraquinone part intercalates into the minor groove, and subsequent activation may involve nucleophilic attack by a thiol or a reductive mechanism mediated by NADPH. In the first case, epoxide opening gives the highly electrophilic quinonimine methide 4.52. Addition of a thiol gives 4.53, the precursor of biradical 4.54 through a Bergmann reaction (Fig. 4.33).

In the NAD-mediated mechanism, formation of hydroquinone 4.55 is followed by epoxide ring opening with formation of an extended quinone methide 4.56. This intermediate can behave both as a nucleophile (Fig. 4.34A) and as an electro-phile (Fig. 4.34B).86 In the first case, protonation leads to 4.57 and in the second

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