(-)-Serotobenine

(-)-Serotobenine

Key Step:

11

Koizumi, Kobayashi, Wakimoto, Furuta, Fukuyama and Kan

Link: http://pubs.acs.org/doi/abs/10.1021/ja807676v

This paper was published a month ago and catched my eye because of the sweet intramolecular, auxiliary controlled C-H-insertion. In the paper itself nothing is said about biology except it’s isolation back in 1985. The structure is dominated by the eight-membered lactam fused with an indole and a dihydrofuran unit. Serotobenine was isolated as a racemic mixture which was reduced to a ring opening/closing reaction through a quinonemethide-like intermediate.

Now some chemistry. The indole was built up in four steps with an overall yield of 75% from 3-methyl-4-nitrophenole. Allylation followed by indole formation using the Leimgruber-Batcho-protocol and Clemmensen reduction resulted in the formation of the indole subunit.

Indole formation:

21

After several manipulations the key step was introduced by an EDCI mediated coupling with piperidinyl mandelate followed by diazotransfer to the lactone. Rhodium catalysed carbenoid formation resulted in the C-H-insertion with great control of diastereoselectivity. They said that the “asymmetric induction was strongly depended on the auxiliary used rather than the catalyst”.

3

The introduction of the eight-membered ring proved to be more difficult.

They first brominated and coupled with an allyl-stannane. The alkene was dihydroxylated, cleaved and reduced. The resulting alcohol was mesylated and after azide formation a consequent Staudinger reaction resulted in the lactam formation.

4

Because the natural product was only found in racemic form they tried to racemize the pure product which was impossible under both acidic or basic conditions. Racemization occurred using the Ts-protected indole and Cs2CO3 due to the promoted leaving ability of the 5-hydroxyindole.

So that’s my first shot. No “new” chemistry or surprising reactions but all in all an interesting target. Next time I will get into more detail and improve my style (tipps?) but I wanted to get this thing online and test this blogging system.

Merry Xmas

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