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Resveratrol-Based Natural Products   

30 September 2007 15,913 views 25 Comments

InChI=1/C14H12O3/c15-12-5-3-10(4-6-12)1-2-11-7-13(16)9-14(17)8-11/h1-9,15-17H/b2-1+

Snyder, Zografos and Lin. ACIEE, 2007, EarlyView. DOI: 10.1002/anie.200703333. Article PDF Supporting Information Group Website
This must be the simplest looking natural product I’ve drawn (since phenol, at least). However, it isn’t actually the goal of this work – rather, the goal is an array of targets based on resveratrol. If you are thinking that you might have read about resveratrol before – congratulate yourselves on reading the labels on red wine bottles thoroughly. Yep, it’s in red wine, and is known to combat inflammation, heart disease, aging, and cancer. Impressive. Snyder also mentions it may be responsible for the ” French paradox“… interesting!!!

With this impressive biological profile, Snyder proposes that the oligomers of resveratrol may be even more potent, and are therefore worth investigating. Rather than just making one or two, he make a whole load from common precursors. The first of building-block is made simply from an aldol condensation to give the biaryl alcohol shown below. Treatment of the alcohol with acid (either TFA or TsOH) promotes cation formation, and trapping in a 5-endo-trig manner to give the cyclopentane.
InChI=1/C26H28O6/c1-28-20-10-7-17(8-11-20)6-9-18-12-23(31-4)16-24(32-5)25(18)26(27)19-13-21(29-2)15-22(14-19)30-3/h6-16,26-27H,1-5H3/b9-6+

When TFA was used, the trifluroacetate anion trapped the resulting cation to give the trifluroacetate product. This was saponified in situ and after oxidation and deprotection gave paucilfloral F. However, using an acid with a non-nucleophillic conjugate base (TsOH in this case) allowed intermolecular trapping with p-methoxy-α-toluenethiol to give the sulfide. This was oxidised to the sulfone, and treated with base to induce a Ramberg–Bäcklund reaction. This rearrangement extruded the SO2 moiety and gave the alkene product, which after deprotection left ampelopsin D.

InChI=1/C21H16O6/c22-12-3-1-10(2-4-12)19-18(11-5-13(23)7-14(24)6-11)20-16(21(19)27)8-15(25)9-17(20)26/h1-9,18-19,22-26H/t18-,19-/m1/s1

Not quite done with this skeleton – treatment of ampelopsin D with a touch of acidic methanol promoted rearrangement to isoampelopsin D. Nice!

rInChI=1/C28H21O6/c29-18-5-1-15(2-6-18)9-23-24-13-22(33)14-25(34)28(24)27(17-10-20(31)12-21(32)11-17)26(23)16-3-7-19(30)8-4-16/h1-14,26-27,30-34H/b23-9-/t26-,27+/m0/s1 InChI=1/C28H22O6/c29-18-5-1-15(2-6-18)9-23-24-13-22(33)14-25(34)28(24)27(17-10-20(31)12-21(32)11-17)26(23)16-3-7-19(30)8-4-16/h1-8,10-14,27,29-34H,9H2/t27-/m1/s1

Use of the same approach with a different building-block (which is structurally very similar – I’ve shown the similarity by indicating the previous building-block functionality in grey) worked just as well. TsOH, sulfide trapping and Ramberg–Bäcklund rearrangement led eventually to quadrangularin A (a great name!). TFA, oxidation and deprotection gave isopaucifloral F. If it works…
InChI=1/C26H28O6/c1-28-20-10-8-18(9-11-20)26(27)25-19(14-23(31-4)16-24(25)32-5)7-6-17-12-21(29-2)15-22(13-17)30-3/h6-16,26-27H,1-5H3/b7-6+ InChI=1/C28H22O6/c29-18-5-1-15(2-6-18)9-23-24-13-22(33)14-25(34)28(24)27(16-3-7-19(30)8-4-16)26(23)17-10-20(31)12-21(32)11-17/h1-14,26-27,29-34H/b23-9-/t26-,27+/m1/s1 InChI=1/C21H16O6/c22-12-3-1-10(2-4-12)18-19(11-5-13(23)7-14(24)6-11)21(27)16-8-15(25)9-17(26)20(16)18/h1-9,18-19,22-26H/t18-,19-/m0/s1

Next, Snyder looked at the fused bis-cylopentane natural products. Taking permethylated quadrangularin A, they brominated with molecular bromine to resulted in stepwise bromination, terminating with the tribromo intermediate shown below. The oxonium ion then rearranged via a Friedel-Crafts type reaction to give the required 5,5-fused skeleton. Reductive dehalogenation and deprotection then gave pallidol. However, you’re probably wondering why bromination was required? Snyder answers this by suggesting that their bulk controls the stereoselectivity of the cyclisation.
InChI=1/C34H34O6/c1-35-24-11-7-21(8-12-24)15-29-30-19-28(39-5)20-31(40-6)34(30)33(22-9-13-25(36-2)14-10-22)32(29)23-16-26(37-3)18-27(17-23)38-4/h7-20,32-33H,1-6H3/b29-15-/t32-,33+/m1/s1  InChI=1/C28H22O6/c29-15-5-1-13(2-6-15)23-25-19(9-17(31)11-21(25)33)28-24(14-3-7-16(30)8-4-14)26-20(27(23)28)10-18(32)12-22(26)34/h1-12,23-24,27-34H/t23-,24-,27+,28+/m1/s1

I’ve thought about this reaction for, oh, about 5 minutes, and I think it must be an equilibrium process. The product must actually be another oxonium ion, which I think could perform a ring opening back to the starting material. This equibrilation must allow the thermodynamically preferred cis-ring juction to dominate. Thoughts?

With a further series of resveratrol based natural products to consider, they sucessfully applied the same chemistry to a further substrate, again cyclising with bromination to give a [3.2.1] bicyclic ring system. This time the extraneous halogens were removed with a radical reduction, which after deprotection gave ampelopsin F.

InChI=1/C34H34O6/c1-35-24-11-7-21(8-12-24)15-29-30-19-28(39-5)20-31(40-6)34(30)33(23-16-26(37-3)18-27(17-23)38-4)32(29)22-9-13-25(36-2)14-10-22/h7-20,32-33H,1-6H3/b29-15-/t32-,33+/m0/s1<br /> InChI=1/C28H22O6/c29-15-5-1-13(2-6-15)23-25-19(9-17(31)11-21(25)33)28-24(14-3-7-16(30)8-4-14)27(23)20-10-18(32)12-22(34)26(20)28/h1-12,23-24,27-34H/t23-,24?,27?,28?/m1/s1

Switching substrate, the same trick gave them a seven member ring. However, this time they didn’t quite make it to a natural product. Ampelopsin F required the remaining bromide to be switched for a hydroxyl (with retention…), but they were more interesting in making the more complex dimer, Hopeaphenol. Treatment of the bromide with silver acetate promoted elimination to give the stabilised cation, which the neigbouring methoxylphenol trapped to give a cyclopropane with the methyl oxonium ion. This then quenched by opening of the cyclopropane to give the actate. This was then saponified and oxidised to the ketone, which they hope to use for future syntheses.

InChI=1/C26H26O6/c1-28-20-10-7-17(8-11-20)6-9-18-12-23(31-4)16-24(32-5)25(18)26(27)19-13-21(29-2)15-22(14-19)30-3/h6-16H,1-5H3/b9-6+<br /> InChI=1/C25H23BrO5/c1-28-15-10-8-14(9-11-15)21-22-17(6-5-7-19(22)30-3)25(27)23-18(24(21)26)12-16(29-2)13-20(23)31-4/h5-13,21,24H,1-4H3/t21-,24-/m1/s1<br /> InChI=1/C25H22O6/c1-28-15-10-8-14(9-11-15)21-18-12-16(29-2)13-20(31-4)23(18)24(26)17-6-5-7-19(30-3)22(17)25(21)27/h5-13,21H,1-4H3/t21-/m0/s1InChI=1/C21H16O6/c22-11-6-4-10(5-7-11)17-18-13(2-1-3-15(18)24)20(26)19-14(21(17)27)8-12(23)9-16(19)25/h1-9,17,21-25,27H/t17-,21-/m1/s1

This was cetainly a tour d’force, especially for Snyders first paper. However, the end of the paper felt a little ragged, in that we were left with an amazingly intricate and impressive jigsaw, short a few pieces. That’s not to detract from what is an awesome acheivement that certainly puts his creativity and ability on the map.

InChiKey data: LUKBXSAWLPMMSZ-OWOJBTEDBU YIWJSAJNDWAXJQ-RMKNXTFCBN BADTYSQKXNDGFG-RTBURBONBV MULNNXIKUFWKKA-PHPWSYFYBR HRIJITRLXFENGP-HHHXNRCGBO ATWAIDOMHGTSBV-VOTSOKGWBC BIQMSWPBPAKGSE-PBSLAQMIBZ RXCCNNFHGNTSJG-OALUTQOABT NWLQBPMURULYRR-ZAGIXMNSBZ YNVJOQCPHWKWSO-ZBVBGGFBBR MHVFJYHYSRCUCA-ODKXTJGPBB LJHNYAXAPRDORG-JBNIXYIJBK CWPRGWDYYFHMAY-RMKNXTFCBU LVKOEOOKFDPAGT-ZJSXRUAMBK LNSSTDGEKUTCKJ-NRFANRHFBT ZLNNTCYOPQRXDY-DYESRHJHBQ

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25 Comments

  • tom says:

    That is a damn nice supporting information section! Nice touch on linking the paper and supp. info.

  • Spiro says:

    Correct me if I am wrong, but this article is Snyder’s first one as a PI. Impressive start!

  • synthon says:

    Someone want to explain to me what the oxidant is that allows one to perform a double electrophilic aromatic bromination when using only 1 equiv molecular bromine?

  • Spiro says:

    #3 : I was about to answer you that the yields were based on recovered starting materials.

    But looking at the supporting information, what a surprise!!
    Excerpt : “A solution of Br2 (8.60 µL, 0.167 mmol, 2.0 equiv) in CH2Cl2 (0.1
    mL) was added dropwise to a solution of permethylated quadrangularin A (23, 0.045 g, 0.083
    mmol, 1.0 equiv) in CH2Cl2 (4.5 mL) at –78 ºC. […] to give trihalogenated adduct 27 (0.052 g, 81%) as a pale yellow oil.”

    Here we have a triple bromination with a maximum possible yield of 66.66666666666666%. And the authors get an indecent 81%!

    BUSTED!

  • Barney says:

    The bromination may not be purely by electrophilic means; perhaps it is a radical reaction. As such, the yield reported could be correct; why would these researchers have any reason to lie. This is such a complex reaction it is likely to require additional exploration. In any event, what is accomplished is incredibly impressive.

  • Spiro says:

    #5 : the conditions they use are not typical for radicalar reactions. And if the reaction was radicalar, the selectivity would not match.

  • Paul says:

    French are a paradox themselves :)

  • chemfanatic says:

    Impressive work! They comment about the bromination and they say that it is under further exploration. In my opinion I believe that it is a partial radical procedure..Anyway I am pretty sure that we are going to see more on this topic!
    Did you also notice that the first author is the same guy as in Baran’s first publication? Well done for a postdoc finishing sceptrin, ageliferin, axinellamine core and also this work.From a simple google search I found that he also did the core structure for abyssomicin!!! Pretty impressive isn’t it and if you consider that he is greek then I can tell that KC did I nice job for the selection of this guy..Probably we are going to see more good work from him soon as he has already an academic job..

  • milkshake says:

    I think it is an version of an intramolecular Friedel-Craft alkylation with a stabilized benzylic cation, enabled by proximity and brought about by catching Br(+) to p-methoxystyrene. One possible role Br can play is electronic – if they tried to bring about the cyclization with acidm maybe all they got was tar. Partial bromination will reduce the number of reactive aryl positions.

    Regarding the yields and trihalogenated product with just 2 equivs of Br2. If they used 8.6uL of Br2, that is pretty damn hard to measure precisely (unless they used a diluted stock solution) so maybe they added 11uL instead. I am always little suspicious about yields of experiments done on 10 mg scale – you weight out the flask weight difference and it matters how well you dry your product from EtOAc or if you got some silica particles in it…

  • gilgerto says:

    If I am right, the 5,5 cis ring junction is already set from previous bromination and has nthing to see with the cyclisation itself. I am also amazed regarding the formation of a tribrominated product using 2 eq of electrophilic bromine. So amazed that I wont say anything about it…

  • S says:

    Change of topic for just a comment. I bet you guys have already checked out Dylan Stiles’ new blog.If you haven’t, http://dylanstiles.com/
    -S

  • jimbo says:

    chemfanatic: one should ask why Dr. Zografos is doing another post-doc at all, following his stellar work in Baran’s group.

  • Joe says:

    Sorry for the attempt to high-jack the discussion:

    TO MILKSHAKE: Could you post the CAS-nr. Herrmann’s catalyst?

  • chemfanatic says:

    jimbo: politics I guess! Do you have a better explanation?

  • Apropos says:

    I have talked to him before when visiting the Snyder lab. He is looking to go back to Greece to take a faculty position there. However, there are so few positions available that it is nearly impossible to get a job.

  • milkshake says:

    Joe: Strem Catalog No. 20 page 174 Catalog # 46-0290, CAS# 172418-32-5

    I think Aldrich is selling it too

  • races says:

    Just finished reading Snyder paper. Its really nice to see a young faculty going for some awesome total synthesis instead of cooking up tables of useless reactions to be published in JACS/Org. lett. I learned a lot from this paper.

    If you look at the previous syntheses of some of these molecules they are really horrible. snyder has made a solid contribution with this. I wish I could postdoc in his group.

  • about the post-doc says:

    Supposedly K.C. has been holding the promise of a faculty position in Greece over this guy in order to have him slave it out for his chosen ones…

  • PMP says:

    Beautiful paper. Just one small simple question: why would Scott Snyder call the first reaction (the union of an lithiated aromatic ring with an aromatic aldehyde) an ALDOL reaction? (And why did Tot. Syn. fall into the same trap? Tsk, tsk…)

  • star says:

    hi,

    i am little bit depressed cos that you havet added to this site other site links such as pipeline etc. as you did in old site. please can you add those links to this site on right side!
    star

  • Tot. Syn. says:

    Umm… they are there. Just down a bit. Below the calender. Also, sorry for the lack of updates, I’ll try to blog today…

  • DrBaritone says:

    Nice paper, great site, glad to hear you’re writing up.

    Keep it up.

    Stuart

  • S says:

    So, wrt the Zografos story, there is a snippet in Snyder’s website. Apparently,as of Aug ’07, he is an assistant professor in the University of Thessaloniki.

  • Trevorz says:

    Finally the media caught up the scientific studies of a drink I have been using for more than 7 years, if I am aloud to say the name it is symmetry direct genesis one of the highest standardized Resveratrol non-alcoholic drink. You can understand my excitement when I saw the media started to report their Resveratrol findings. Let’s hope more Doctors start looking in this direction. By the way I look and feel a lot younger than 47 and I intend to keep it that way. Note we will hear a lot more about the combination of Two Miracle Molecules: Ellagic Acid and Resveratrol.

  • resveratrol says:

    I still like to get my Resveratrol the natural way with a glass of red wine or by eating some grapes. However, the pharmaceutical industry always likes to get their hands on something for the big cash cow it can become. I think it’s all a false hope though that the pharmaceutical companies can latch onto something “chemical” to slow down the aging process. However, they’ll have a very strong advertising campaign with some great looking “50-something models” and they will probably profit anyway. I still like my red wine though – it’s so much more civilized than popping some pill.