Total Synthesis Blog

Today, some target which seems to be quite easy to synthesise – (-)-Andrachcinidine:

That 2,6-disubstituted piperidine-derived alkaloid was isolated from plant Andrachne aspera (picture taken from http://www.teline.fr/:

Yes… target seems to be easy to synthesise, but its synthesis is quite complicated. Retrosynthesis of (-)-andrachcinidine is shown below:

As you can see intramolecular Sn2 cyclization and olefin-cross metathesis are key reactions for this synthesis.

Let’s see synthesis of compound 3:

First step leading form 5 to 7 is epoxide ring opening by hydride anion form Red-Al. Alkoxide anion is generated in such way which in turn reacts with benzaldehyde acetal – giving another acetal. That one is reduced to corresponding ether 7 by LiAlH4-AlCl3. Next, 7 is oxidised under Swern condition and formed aldehyde is stereoselectively allylated.

Also synthesis of 4 is drawn below:

Here, we have Wittig olefination of Garner’s aldehyde 6 and followed hydroboration which gives 8. Next, 8 is TBDPS-protected and then ring opening occurs in presence of copper chloride hydrate. Then, Swern oxidation and Wittig olefination of 9 are undergone to form 4.

Having synthesised 3 and 4 olefin cross-metathesis could be done.

There were a few transformations after metathesis to get final product…

For more information see:

P. R. Krishna, G. Dayaker, Tetrahedron Lett., 2007, 48, 7279.