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Salinosporamide A (NPI-0052)   

21 May 2007 9,387 views 23 Comments


Macherla, Manam, McArthur and Potts. Org, 2007, ASAP. DOI: 10.1021/ol0706051 .

This target has certainly seen it’s share of interest, and you certainly know it’s an interesting target if industry decide to make it! Indeed, this paper is by some folks at Nereus Pharmaceuticals, San Diego, who were clearly interested in its 20S proteasome busting activity (read inhibition). Although there have been several syntheses of Salinosporamide A, the group state that they needed a route suitable for analogue generation – apparently that beta-lactone is a bit of a bugger.


The reactions of interest to me kick-off very early, with an interesting “auxiluary” directed aldol, closing the beta-keto oxazolidinone to give a lactam. The mechanism for this aldol condensation is thought to be through the “self-regeneration of stereocenters (SRS) principle” developed by (the living-legend that is) Seebach, seen in this paper. This paper’s worth a thorough read!

Interestingly, the only chromatography in the entire synthesis is purification of that starting material. The allyl substituent was then oxidised with Upjohn conditions, and the diol cleaved to generate the lactol – nice work to make a complex 5,5,5- unit so quickly. At this point, the route to the target is relatively transparent, and is nicely achieved; however, they state the route is amenable to scale up, but I’m less convinced… Perhaps my some of our industrial readers could give their opinion. My major issue is the multitude of oxidation and reduction steps…

Also worth a mention: chlorination of a primary alcohol using Ph3PCl2. How stable is that reagent?

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  • Lurker says:

    If I remember correctly, Ph3PCl2 and Ph3PBr2 are both easily prepared from triphenylphosphine and the corresponding halogen. I think it’s a pretty stable substance. I’ve never used it myself, but I don’t think it’s unstable or particularly hard to make…

  • Tot. Syn. says:

    Fair enough, always worth learning something new. I guess it’s not really that different to converting an alcohol to a bromide with PPh3 and Br2.

  • TWYI says:

    Cannot get the paper, is it mate in situ? Did something similar with PPh3 and hexachloroethane giving the species in question..

  • provocateur says:

    yes…but that system is used for making oxazoles …

  • jimbo says:

    Didn’t that company get founded around that molecule (and related natural products)? I’ve seen Fenical speak about it, and I swear he said something along these lines. Or maybe he just licensed it.

    That lecture is fascinating… I never thought a speech about natural product isolation could be that interesting. If you overgrow the bugs that make salinosporamide, it gets absorbed and Sporalides A and B are produced. Crazy shit.

  • jimbo says:

    re: scale-up — you’d be surprised what you can do on a big scale, especially if you can avoid columns.

    If the compound is potent enough, you can probably get through phase I with a few hundred grams, which isn’t that hard for a decent process group to do. Without having seen the biological data for the compound, they’ll most likely have to do some analoging to make something which is more drug-like. That primary chloride may need to go away… alkyl halides raise eye-brows at the FDA (and thus most med-chem departments).

  • aa says:

    i made a small batch of PPh3Br2 a few years ago and kept it in a vial on my bench. i’m pretty sure its still perfectly useable… i swear i’ll get around to that bromination this week boss…

  • Handles says:

    I bought triphenylphosphine dibromide as a white powder from Aldrich once, but it worked better when I made it myself in situ. The chloride seems to be available too:
    378755-25G AUD55.00

    Regarding alkyl halides and the FDA: check out the structure of sucralose (Splenda) on Wikipedia.

  • milkshake says:

    I worked with massive amounts of PPh3Br2 (PPh3, Br2, acetonitrile, add Br2 with cooling on ice until orange, then evaporate). If you melt BINOL with the neat reagent, you get 2,2′-di-Br-binaphtyl. You add Celite, let solidify, break the flask with hammer, peal off the glass, break the formed ball into chunks of smoky corrosive hygroscopic asphalt, extract this tar it in Soxhlet, column, re-crystallize. Charming procedure – the authors should be lined against the wall.

    As previous commenters have said, they needed analoging and efficient route to a common intermediate. (The chlorine in the molecule has to stay, that’s what makes it super-potent proteasome inhibitor.) Most of all they need a proprietary analogue because obviously they cannot get a composition-of-matter patent on a natural substance.

    200g of a compound is probably enough to get them through a pilot clinical trials phase I + IIa. If they need to go further they will have a number of difficult process problems to work out, things like Dess-Martin are a not pleasant on a plant scale. Silica and non-recyclable solvents are expensive but can be justified if the compounds are super-active and only few kg is needed. (There were companies that did total synthesis of prostaglandin analogues on 10kg scale; I think it is a comparable level of complexity).

  • kiwi says:

    the complex Ph3P-Br2 crashes out of cold DCM (from memory), you can filter it off. easy as pie

  • philip says:

    I haven’t looked up the article yet, but that first step that you show is quite surprising to me. The ester anion has to be ten or so pK units above the b-keto amide. It seems like a low probability reaction. I certainly wouldn’t have planned it. Is there literature precedent?

  • TheEdge says:

    Re: #11 A1,3 strain will increase the pKa of the b-ketoamide dramatically. It’s the same reason Evans’ beta-ketoimide is stable.

  • jimbo says:

    re: chloroalkyl — good points

    Are these compounds selective at all, or are they just cytotoxic? Maybe not so bad because it’s not directly messing with DNA or cell replication, so they shouldn’t be carcinogenic like most cytotoxic chemo treatments.

    “Most of all they need a proprietary analogue because obviously they cannot get a composition-of-matter patent on a natural substance. ”

    Is that true? So companies producing antibiotics don’t get patent protection? That hardly seems fair…

  • milkshake says:

    you can get a patent for the (non-obvious) use of a natural compound or for a method of its manufacturing.

    Composition-of-matter patents (i.e. patenting a structure) provide of course a much more solid protection.

  • WillisWill says:

    You can absolutely patent naturally occuring compounds as long as your patent covers the purified form, i.e., something that could be used in preparing a pharmaceutical…as long as the isolation of the natural product is itself not “obvious.” By Jimbo’s 1st comment that would seem to be the case

    At least that’s the law in the US, I don’t know the standard in the UK or elsewhere

  • cryo says:

    you are right

  • cryo says:

    And thanks for blocking me Paul.

  • Ron says:

    This synthesis is supposed to have no columns after the indicated reaction? The supporting information seems to certainly have plenty of them – am I missing something here?

  • jimbo says:

    I haven’t read the paper, but in my own work, I’ve done columns just to prepare analytical samples in steps that I normally carry crude.

  • milkshake says:

    I looked up some procedures in the supplementary material and it occured to me that it is indeed a scale-up, but using the unoptimized first generation approach, pushing the gram quantities of material through as fast as possible regardless of the cost of the chemicals. This could be quite typical for a startup pharma company in a hurry.

  • vikrant says:

    Its kinda amazing that the mention of Fenical and his group is missing from the paper. Corey according to me has a better approach to make the smae molecule.

  • rb says:

    fenical started the company that the work was done at…

  • raj says:

    Ph3PCl2 is stable reagent and commercially available, but this synthesis is not good synthesis. Several better syntheses are available in literature