Home » Still In The RBF

Sporolide B   

28 February 2009 17,257 views 21 Comments

sporolide-b

Nicolaou, Tang, Wang. ACIEE, 2009, EarlyView. DOI: 10.1002/anie.200900264. Article PDF Supporting Information Group Website

The second of two papers published (almost) in succession in Angewandte from the KCN labs (also check out some more methodology in JACS – nice to see more methods from his group), sporolide B is the more challenging target, but devoid of any biological activity.  Nicolaou justifies his synthesis by discussing the biosynthetic origins of the sporolides, which are potentially products of enediyne cyclisation.  Convinced?  Perhaps…

Anyway, the structure is certainly interesting, being one of relatively few natural products that needs to be drawn in 3D, as a 2D rendition would be a tough -draw.  Perhaps the most interesting feature is the 1,4-dioxane-style bridging ring, which would be a tough disconnection in anyone’s book.  The other intriguing disconnection is about the chloro-benzene ring, where KCN hoped to utilise a [2+2+2] cyclisation:

sporolide-b_1

Those of you who have already seen the abstract for this paper will have noticed that crayon-o-vision is again reprised, but rather than yet again getting upset about it, I’ve decided to provide my own attempt at it. (Some readers apparently like it!)

sporolide-b_1b

Those will (potentially) be my last words on this subject, so let move promptly on to the chemistry.  First up is construction of an intermediate distinctly reminiscent of the enediyne natural products mentioned earlier.  To get to this point, the group already had 13 steps jotted-down in the lab-book, starting from a chiral cyclopentenone originally developed by Carl Johnson.  The more interesting steps included an early palladium mediated carbonylation and later an exceptionally high-yielding Sonogashira coupling using only 2% palladium.  The then used a rather nice bit of anion formation to install the chloroacetylene, in which pre-treatment of cis-dichloro ethylene with methyl lithium resulted in a pot of lithiochloroacetylene.  Addition of the aldehyde resulted in a impressively clean reaction, almost completing the substrate for the [2+2+2].

sporolide-b_2

The other partner was produced in a less ‘steppy’ manner, installing the asymmetry using a Sharpless dihydroxylation, and using the Yadav procedure to make the the chiral propargyl alcohol.  Towards the end, though, I liked the usage of some old-school chemistry to provide an ortho-ester from the acetal protected catechol.  The plumbic acetate is a reagent that always grabs my attention, as it featured on the retrosynthetic scheme in my PhD grant proposal.  However, I didn’t quite get to the that point of my total synthesis, which tends to stick in my throat.  In this case, I don’t quite get the point of the reaction – why do they need to do this chemistry at all?  The whole group is removed after the [2+2+2], sits remote from the site of reaction, and surely the orthoester is less stable than the acetal…?

sporolide-b_3

And now to that [2+2+2], and a regioselectivity issue, as there are two ways for the propargyl alcohol partner to approach the diyne.  Nicolaou suggests that the perfect selectivity acheived results from steric (the chlorine atom) and chelation (the propargyl alcohol) control, exemplified in the scheme shown below (which I’ve cribbed directly from the paper).  Damn nice preparation of a tetra-substituted benzene – something I’m appreciating more often now I’m med-chemming.

sporolide-b_5

A bit of protecting group shennanigans, and it’s on to the macrocyclisation, using an approach gratifyingly different to the usual RCM or lactonisation events usually seen.  To install the pyan-style bridge in a [4+2], they needed an equivalent of a diene – in this case, an ortho quinone, provided by silver-oxide oxidation of the diol.  Then, in a remarkable feat of molecular flexibility, thermolysis of the intermediate led to a reasonable yield of the desired macrocycle (with a fair chunk of recovered starting material).  The selectivity of this cycloaddition is remarkable – sure, the top face of the ‘dienophile’ is restricted by the bulk of the fused cyclpenadiol, but either face of the ortho-quinone should be accessible.  Nicolaou describes as much, and admits that the group is none-the-wiser; must have been a damned good day in the lab, though!

sporolide-b_4

The last reaction worth discussing is the delivery of oxygenation to the dioxane to give the ketal.  This was neatly done with a bit of hypervalent iodine, using a ten-fold excess of PMB-alcohol.  Delivery to the desired ether is presumably controlled by the para-phenol, and leaves only a few more steps to complete the synthesis; vis oxidation/reduction to correction the erroneous configuration of the cyclopentadiol, a round of deprotections and finally a selective epoxidation of the cyclohexadienone.  This final reaction was done using a combiation of reagents that I hadn’t come across before – t-BuOOH /DBU; unfortunately there’s no discussion of why these conditions were chosen.

sporolide-b_6

Mmm – another tasty synthesis from the Nicolaou labs.  The man takes a lot of flak for this modus operandi, but I personally love this type of synthesis – small(ish), interesting molecules crafted by single-digit teams.  However, this view has to be tempered by his ongoing conquest of maitotoxin – not a synthesis I feel is particularly necessary…

1 Star2 Stars3 Stars4 Stars5 Stars (23 votes, average: 3.91 out of 5)
Loading ... Loading ...

21 Comments

  • Dr. ICE says:

    The [2+2+2] is pretty impressive and I think this is a good structure for method development. But since this Sporolide doesnt have biological activity its more of a shag than something real.

  • stone says:

    To Answer to questions:

    In this case, I don’t quite get the point of the reaction – why do they need to do this chemistry at all? The whole group is removed after the [2+2+2], sits remote from the site of reaction, and surely the orthoester is less stable than the acetal…?

    Answer:

    The substrate had to be converted to the orthoester for facile deprotection downstream, which will yield the catechol species.

  • Hap says:

    That’s impressive – that’s a really ugly structure to have made. It’s a neat structure, and the chemistry doesn’t seem pedestrian.

    You could probably draw the 6.5.5 flat, draw the other benzene ring below with just enough room for the methyl group. I don’t know how the bonds fusing the 6.5.5 to the benzene will look, but the linker will probably be OK but distorted or with long bonds. I’ll have to see if I can draw it.

    Someone still needs to take away Prof. Nicolaou’s crayons, though.

  • Atticus says:

    Nice mock-up of KCN’s coloring in, Paul, although for the full effect I think you’d need to give the entire macrocycle it’s own coloring-in job, maybe yellow or green for the two color effect.

    On a more serious note, I’ve never seen ortho-quinones do Diels-Alders at the oxygens–only at the carbons–pretty neat! I haven’t made a model or anything, but my guess would be that the o-quinone just can’t reach over far enough to react at the carbons in this case. As for stereoselectivity, the o-quinone is quite electronically asymmetric, so maybe that plays a role.

  • CS says:

    Genomic sequencing of the producing strain has established the sporolide are indeed enediyne cyclization products.

    See: Ryan P. McGlinchey, Markus Nett, and Bradley S. Moore J. Am. Chem. Soc., 2008, 130 (8), pp 2406–2407

  • stone says:

    Synthesis of the Sporolide Ring Framework through a Cascade Sequence Involving an Intramolecular [4+2] Cycloaddition Reaction of an o-Quinone

    K. C. Nicolaou, Jianhua Wang , Yefeng Tang

    Angew. Chem. Int. Ed. 2008, 47, 1432-1435.

  • WestCoast85 says:

    I don’t have the paper under my eyes but in the second scheme, during the first [2+2], do you know why the TMS group is cleaved ?

  • WestCoast85 says:

    I’ve read the paper and there is a mistake in your second scheme Tot. Synt. Indeed, the TMS group is cleaved before to do the [2+2+2].

    Regards

  • InfMP says:

    tBuOOH/DBU is a good system for epoxidation of alp/beta unsat. Not sure who invented it, but imagine deprotonation followed by attack of the peroxoanion 1,4 and then enolate displaces tbu-alcohol.

    it is in baran’s and nicolaou/chen’s cortistatin A syntheses.

  • Dr. J says:

    Any ideas on why the epoxidation is selective for that particular olefin?

    • Nonmetal Alchemist says:

      Nucleophilic epoxidation conditions (t-BuOOH/DBU) would select the electron-poor alkene (enone side), whereas elecrophilic epoxidation (e.g., w/ MCPBA) would select the electron-rich alkene (vinylogous ester side). Then again, this is all 20/20 hindsight handwaving.

  • Bery says:

    “…The plumbic acetate is a reagent that always grabs my attention, as it featured on the retrosynthetic scheme…”

    You mention plumbic acetate but have palladium in the picture. Is this a mistake or did I miss something?

  • chinstrap says:

    @ tot. syn.

    No offense, but the comment section has been lacking a little in recent weeks. Don’t misunderstand me as meaning the quality of the blog has fallen off. Just not a lot of activity. Maybe a pot-shot at a popular researcher, such as “baran is an overated chemist and wears pink polka dotted underwear while doing chromatography columns…”, will get the juices flowing in the typing fingures of your readers and promote some backlash.

    Worth a shot

    • Tot. Syn. says:

      I rather think that informed and content silence is more useful than hysterical ranting… The number of daily page-views is pretty-much constant over the last 12 months, increasing slightly in the past two months, so it’s probably just less-provocative papers than in other months. Just hang on for maitotoxin – bound to get a heated debate with that one!

  • John Wood says:

    i suppose Dubois is not leaving Stanford? anyone hear any more on that?

  • ... says:

    I heard Caltech made an offer and he turned it down.

  • sugar says:

    re: crayons
    Your crayon-style picture does look good; but just imagine how much crayoning there is to be done, once KCN finishes maitotoxin!

  • Hankui Wu says:

    I Like this blog,I woud like to enjoy the art of synthesis !!

  • Laura says:

    I know I am a bit late… I am confused how Nicolaou can continue to use Ken Shea’s type II intramolecular Diels–Alder methodology without even a site. He did the same thing for CP-263,114 and CP-225,917 molecules. Not cool.