Asymmetric Synthesis of (+)-Polyanthellin A

Asymmetric Synthesis of (+)-Polyanthellin A

Matthew J. Campbell and Jeffrey S. Johnson

DOI: http://dx.doi.org/10.1021/ja904136q

Hell yeah, back from the grave…

It took some time but now it’s finished: this time featuring a very cool asymmetric synthesis of the natural product Polyanthellin A. I do remember an extremely effective synthesis from Overman in this class of natural products a few years ago employing his oxy-Cope/Mannich-tandem reaction. In this paper the attention is less methodical nature and more focussed on the target itself.

Whatsoever let’s get started:

If you’re interested in the biology of this little metabolite take a look in the original report in Natural Products (ref. 7)…

First the retro:

polyanthellin A_160909

The key step in this synthesis features an asymmetric formal [3+2] cycloaddition starting from the 2 fragments which I will call from now on the red and the blue one.

This paper is full of interesting chemistry, too much for this little review, so I will focus only on the key aspects. If you’re interested we can discuss the reactions I did not picture in full detail later in the comments.

The blue fragment was synthesised starting from commercially available methallyl alcohol:

Scheme 1

scheme_1_160909

Sharpless asymmetric epoxidation creates the only stereocenters in this fragment, followed by an epoxide opening from a copper catalysed allylation. Chemoselective tosylation, Kolbe-Schmitt-nitrile synthesis, TMS protection and DIBAL-H reduction furnished the blue fragment in an overall acceptable yield (the solvent is choice is odd, I would have taken THF)…

Synthesis of the red one needed some more attention but in the end makes use of a bunch of quite efficient stereoselective methods. And here it comes:

Scheme 2

scheme_2_160909

First a more or less standard Michael addition catalysed by Prolinol-derivative (1) and catechol ester (2) to give the 1,5-diketone in high yield. A Wittig reaction with titanated allyldiphosphine yields the required Z-allyl side chain which was followed by methylcarboxylation using Mander’s reagent furnishing the functionalized malonester. Diazotransfer and subsequent carbene inserton catalysed by (3) into the nearer double bond gives in the end the red fragment ready for the formal [3+2] cycloaddition.

Now the key step: After an extensive screening of catalysts the authors found this bulky aluminium based Lewis-acid catalyst giving the best results. The complete scheme looks like this:

Scheme 3

scheme_3_160909

However they needed 3eq of the blue fragment but this gives them the core structure in a very good yield and stereoselectivity. A metathesis employing Grubbs II closes the ring ensued by Krapcho decarboxylation, a sequence of hydroboration/TPAP oxidation and another Wittig reaction completes this scheme.

Because there are no mechanisms in this paper I created this one for the [3+2] cycloaddition:

mechanism_160909

First a Lewis-acid catalysed cyclopropane opening gives the stabilised allyl cation and the enol ester which in turn attacks the carbonyl in an aldol fashion followed by ring closure from the enolate oxygen. Or a more concerted cyclization?

Ok, nevertheless only a few more steps to go:

Scheme 4

scheme_4_160909

Simple iodo etherification, oxymercuration and global reduction yields the naked Polyanthellin which was acetylated to give the desired product.

To my surprise the JACS paper is only 2 pages long… I would have expected the paper to be at least 4 to 6 pages long to show how they employed the specific methods cause some of them a really rare. That’s why I prefer the Angewandte papers: they feature almost the complete synthesis in detail, which is not always useful but gives you a better insight into the planning and realization of such a complex synthesis.

Ok, that’s it from my site, any comments?

___________________________________________________________________________________________

To the selectivity in the iodoetherfication:

I made this nice little 3D model with ChemDraw which might explain the differentiation. The cyclohexane-methylen group is blocked from equatorial attack by the hydroxy functionality cause the cyclononane ring forms a twist boat whereas axial attack is blocked as usual by  1,3 axial strain.  Or the access to the other methylen group is much easier as we’re dealing with a more convex shape of the molecul in this area. Here is what I mean: the green ring marking the blocked methylen-group, the red ring marking the attacked one:

iodoetherfication

But yeah, cool selectivity!! 🙂

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5 Responses

  1. I guess they will report more details in a follow up full paper 🙂

  2. yeah, hopefully! but why didn’t they take some time and publish a full blown paper a month later? nevertheless cool stuff 😉

  3. cool, thank you, I like mechanistic part.

  4. Nice selectivity in iodo etherification step 😉

  5. The mechanism for this type of cyclopropane/aldehyde annulation was previously discussed in detail: http://pubs.acs.org/doi/abs/10.1021/ja8015928

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