Formal Syntheses of (+/-)-Stemonamine and (+/-)-Cephalotaxine

Formal Syntheses of (+/-)-Stemonamine and (+/-)-Cephalotaxine

Yu-Ming Zhao, Peiming Gu, Hai-Jun Zhang, Qing-Wei Zhang, Chun-An Fan, Yong-Qiang Tu and Fu-Min Zhang

DOI: http://dx.doi.org/10.1021/jo900113s

The 2003 synthesis of Cephalotaxine: http://dx.doi.org/10.1021/ol035098b

The 2008 synthesis of Stemonamine: http://dx.doi.org/10.1021/ol800433r

In this post I want to present to you a publication dealing with two polycyclic alkaloids with obviously different structures but synthesized using the same methodology.

Both syntheses were published earlier by the same group, in 2003 and 2008 respectively, and were reinvestigated in relation to their tandem semipinacol/Schmidt methodology developed during the synthesis of Stemonamine.

In this short review I will consider the above mentioned paper and the two old ones to give an overview of this interesting methodology.

Their key step is summed up below and could be used for other members of these classes of natural products:

Scheme 1

300309_1

The two key intermediates were synthesized as follows.

First the synthesis of the key intermediate of (+/-)-Stemonamine:

Scheme 2

300309_21

This one is found the paper from 2008. They started with the known cyclohexenone-azide, react it with the allyl-magnesium Grignard which after epoxidation and TMS-protection yields the expected key intermediate. Exposure to an excess of TiCl4 in DCM gives in good yield the rearranged alcohol.

Next oxidation, ozonolysis and subsequent Dieckmann condensation yields the tricyclic cyclopentanone which in turn was reacted with Mander’s reagent and oxidised using a mixture of CeCl3 in IPA under an oxygen atmosphere to give the ester as a racemic mixture which was purified by resolution.

Scheme 3

300309_3

The mechanism of the TiCl4 mediated Schmidt reaction looks like this:

Scheme 4

300309_mechanism_1

First the TiCl4 opens the epoxide which leads to an allylic semipinacol rearrangement to give the decahydrochinoline intermediate. This loses nitrogen (Schmidt reaction) and rearranges again (pinacol-rearrangement) to give the key intermediate used above for further reactions. The rest of the synthesis can be summed up to ester formation, another Dieckmann condensation (they do like this reaction) and amide oxygen removal by Lawesson reaction/Raney Ni to give(+/-)-Stemonanime.

(+/-)-Cephalotaxine on the other hand was first synthesis by this group in 2003 but, as mentioned, reinvestigated to use their methodology on this target again.

Scheme 5

300309_4

They started with the known aryl bromide doing a Suzuki coupling. Another allyl-Grignard was used, followed by azidonation, epoxidation and TMS-protection to give the protected aryl azide. Here for the first time in this synthesis TiCl4 was used to do the semipinacol-rearrangement and after DMP-oxidation giving the aryl dione. This was their second key intermediate which was again reacted with TiCl4 under the same conditions to give the next rearranged product:

Scheme 6

300309_mechanism_2

The rest of the synthesis can be viewed in the original paper. In the synthesis of Stemonanime they did the two TiCl4 mediated reaction as one, I’m wondering of this could be done here, too?

What caught my eye this time was their use of the same methodology on two really different looking targets. Currently they are working on an asymmetric version of that reaction because unfortunately they had to use in both syntheses resolution to purify their intermediates which is not acceptable in such a late stage of a synthesis.

I’m really looking forward to see their asymmetric one.

Oh, and I forgot to mention the biology: Both alkaloids are used in classical Chinese and Japanese medicine to treat respiratory diseases and were used as insecticides. In addition some derivatives were found to be highly effective for the treatment of acute human leukaemia and are currently tested.

So hopefully you found these syntheses as interesting as I did and feel free to comment. I’m really interested in discussing stuff maybe I should promote this blog more… If you want to link this page, feel free.

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3 Responses

  1. sir, the two synthesis (The 2003 synthesis of Cephalotaxine: http://dx.doi.org/10.1021/ol035098b and The 2008 synthesis of Stemonamine: http://dx.doi.org/10.1021/ol800433r) are from the same university, but different groups.

  2. okay… i thought because they cited each other the papers were published by the same group…
    i will fix it the next days…
    thank you for your comment. i thought no one read my reviews 🙂

  3. I’m reading all of your reviews 😉 but there’s no need for me, to tell you about it, not here, so keep on writing !

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