Irinotecan Curran

Curran et al. have developed an efficient access to 2 and its analogs,3 which provides the first direct synthesis of the prodrug irinotecan (1) without passing through the toxic molecule 3 as in prior studies.4 The latter is the active antitumor agent, which is formed in vivo by metabolism from 1. 

In the metalation reaction of pyridine 5 with fBuLi the methoxy Discussion 

This reaction type, known as directed ortho metalation reaction, requires strong bases, normally an alkyllithium reagent (most lithium dialkylamides are of insufficient kinetic basicity). Alkyllithium bases show high solubility in organic solvents due to association into aggregates of defined structure, typically as hexamers in hydrocarbon solvents e. g. hexane or tetramers-dimers in polar solvents e. g. THF (see Chapter 5). 

Addition of A/ -forrnyl-/V,/V,/V -trimethylethylenediamine to 21 yields a-amino alkoxide 22. A further directed ortho metalation takes place by coordination of nBuLi to the ethylenediamine moiety and subsequent deprotonation. As result intermediate 6 is formed. 

Lithiated pyridine 6 is trapped with iodine. Other iodonium sources are ICN, IC1, and M-iodosuccinimide (NIS see Chapter 16). Aqueous work-up destroys the deprotonated IV, O-acetal and provides aldehyde 7. 

The lithium of nBiiLi coordinates to the two nitrogen atoms of the ethylenediamine moiety. 

In the metalation reaction of pyridine 5 with tBuLi the methoxy substituent exhibits a directing effect. Solvated (tBuLi)4 aggregate 19 coordinates to the oxygen of the methoxy group to give 20. Successive deprotonation yields the ortljo-lithiated species 21, which is stabilized by 0-Li coordination. 

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