Augustamines, synthesis

Augustamine, [109]. The stannylated inline 353 utilised in the synthesis of (-)-amabiline (346) also served as the advanced intermediate for the preparation (Scheme 65) of (-)-augustamine (493) [93,94]. Thus, treatment of the mixture of the lithium salts 355 and 356 with iodomethane furnished a 43 1 mixture of the two tertiaiy amines 494 and 495 respectively. The cij-diol, obtained on acid hydrolysis of the former was converted into the ortho ester 496, which on exposure to methanesulphonic acid underwent cyclisation via the carbenium ion 497 to (-)-augustamine (493) in 76% yield. 

Scheme 65. Synthesis of (-)-augustamine (continued next page).

In more recent times, 2-azaallyl anions have been much more conveniently generated by the transmetallation of 1-aminoalkylstannanes. Thus for the forward synthesis of (—)-augustamine, this would mean that the 2-azaallylstannane 5 would be the key intermediate needed. 

Pearson and Lovering have completed the first synthesis of the amaryllidaceae alkaloids (—)-amabiline 281 and ( —)-augustamine 280, from the common intermediate 279 using intramolecular [3+2] 2-azaallyl anion based methodology (Scheme 45). In the synthesis of 281 the intermediate is trapped by a Mannich type electrophilic aromatic substitution, while for 280, trimethyl orthoformate is used for electrophilic aromatic substitution-based cyclization. 

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