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It has been a little over a year since the last synthesis-golf was posted. I have talked to orthocresol and would like to help revive the tag! A full FAQ post has been written on chemistry.meta.SE, explaining the premise of synthesis golf and the 'rules'. Please take a look at this before answering (if you haven't already).


Hyperielliptone HA is a phloroglucinol extracted by Wu et al1 in 2008. The compound is of particular interest because of its highly unique structure and demonstration of DNA oxidation inhibition.

Hyperielliptone HA

Rules:

  • Your synthesis must involve a method for the preparation of the phloroglucinol core.

  • Your synthesis must be stereoselective; however, the stereocenter attached to the phloroglucinol core can be racemic. Bonus points if you can develop a stereoselective synthesis for this moiety!

  • All reagents must be available from Sigma Aldrich.

  • If you do not have time to complete the entire synthesis but have a clever idea for a specific moiety, feel free to share your answer.


References

  1. Wu, C.; Yen, M.; Yang, S.; Lin, C. Phloroglucinols with Antioxidant Activity and Xanthonolignoids from the Heartwood of Hypericum geminiflorum. J. Nat. Prod. (2008) 71 (6), 1027-1031. DOI:10.1021/np8001145.
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  • $\begingroup$ HINT: This compound exist in two tautomeric forms. This might make conceptualizing this molecule a bit easier -- it's good to tackle a synthesis by looking at the molecule from multiple angles! $\endgroup$
    – Eli Jones
    May 18 '20 at 9:07
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    $\begingroup$ If you have not yet thought about it; maybe you would like to submit a synthesis. $\endgroup$ May 24 '20 at 9:19
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I'm sure there are a lot of issues with my attempt I haven't spotted (or maybe some of the ones I have are in fact lethal), but I saw the question and thought I'd give it a go.

Retro:

Went straight for the Diels-Alder with something resembling Danishefsky's diene. Disconnection to reveal the species I named A and B comes from a Baylis-Hillman reaction, which works reliably with α,β-unsaturated esters (unsure whether the attached enol-looking oxygen would have anything to say about this). Asymmetry in A is provided by a Sharpless epoxidation, and in B by a bit of a longshot centred on MacMillan imidazolidinones.

Forward synthesis:

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Notes:

TMS groups are used throughout but could always be beefed up to TBS as they're removed with TBAF at the end anyway.

I'd welcome suggestions of a better way of achieving step IIIa (formation of the enol-ether-like structure in A).

MacMillan catalyst sequence (steps VI to VII):

I'm aware that these catalysts (R = Bn, BnIndole etc.) are designed with one-pot systems using poor nucleophiles and electrophiles in mind, and hence expect this to be a bit of a stretch. I'm wondering if a more robust method might be to go with stoichiometric addition of the imidazolidinone before addition to THF containing the lithium alkyl cuprate shown to the left of step IV, rather than simultaneous addition of a Grignard and copper(I). The cyclisation seems like it would follow naturally and the correct stereochemistry would be provided by the imidazolidinone in accordance with MacMillan's models.

Not sure how big of a concern rearrangement during the Barton McCombie reduction step (IXa) is, but perhaps it would be better to conduct after the Diels-Alder; I don't know.

My hope is that the Diels-Alder step would get some stereocontrol from the 'B' section of the molecule folding down underneath the diene section, but expect this to be the sort of thing that has to be tried out in the lab.

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  • $\begingroup$ For now, I'll just comment on the preparation of A. Very interesting use of what I assume is double enolate in step II. I haven't seen this used before, but if you have any references, I'd love to read up on it. For step IIIa, I have a few concerns. The enolate will be a resonance hybrid of both of the carbonyl groups, but the majority of the enolate character will reside on the ketone (since ketone alpha protons are more acidic), making it relatively nucleophilic. Even if you did deprotonate the alcohol, I still don't think it would be able to attack the nucleophilic enolate form. $\endgroup$
    – Eli Jones
    Apr 8 at 22:20
  • $\begingroup$ For step IIIa, I thought about working the molecule up to its neutral form (you would need a less labile protecting group like TBDMS) and then adding a Lewis acid like Al3+. Since five-membered rings form faster than seven-membered ones, the OH should preferentially attack the ketone in the presence of the Lewis acid. As for the elimination, hopefully, the Lewis acid would be enough to make the -OH of the hemiacetal a good leaving group for an E1 elimination. As long as you use the same alcohol ROH, ester hydrolysis shouldn't be a problem. $\endgroup$
    – Eli Jones
    Apr 8 at 22:39
  • $\begingroup$ @EliJones On step II; as far as I'm aware it's fairly standard practice - if you've got Clayden 2nd ed. the method is covered briefly on page 601, but you can also find a fair amount about it by searching online for the acetoacetate dianion. Somewhat hilariously, I've just found this: books.google.co.uk/… which continues with a similar transform to my IIIa! $\endgroup$ Apr 9 at 13:45
  • $\begingroup$ My initial thoughts about IIIa were that simple dehydration under slightly acidic conditions would probably get the job done because the non-enol form would still exist in high enough equilibrium concentration. This seems to be exactly what they were going for in the case I just linked, but I was as dubious as you until now as I'd never seen this done before! $\endgroup$ Apr 9 at 13:50
  • $\begingroup$ Thanks for the reference! I also noticed a possible issue in step V. You may get polymerization and a mixture of products since the Wittig reagent might just keep reacting with the product, considering the carbonyl group gets more reactive with each Wittig addition. You could try protecting the Wittig reagent's formyl group first? $\endgroup$
    – Eli Jones
    Apr 9 at 20:05

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