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5 March 2008 11,879 views 22 Comments

Overman, Dounay, Humphreys and Wrobleski. JACS, 2008, ASAP. DOI: 10.1021/ja800163v. Article PDF Supporting Information Group Website

A far smaller target than the last we examined, but that’s still a very interesting architecture. Although the biological activity of this beast isn’t mentioned, similar natural products are found in traditional medicines, so perhaps it’ll do something interesting if you eat it. Their retrosynthesis is fairly ambitious, with a plan to use palladium couplings to complete two of the rings, and to do these reactions as part of a pair of tandem reactions.

The interesting chemistry kicks-off pretty early, with their asymmetric Heck coupling of the aryl triflate onto the cyclohexadiene. The reaction performed reasonably under thermal conditions, but improved considerably in the microwave, allowing lowering of the catalyst loading and vastly truncated reaction times. After this success, they dumped some TFA into the mix, and got their desired iminium-ion cyclization, completing both five-member rings in excellent yield and control.

A substrate-controlled epoxidation, followed by PhSeNa opening/elimination gave them the allylic alcohol they wanted and appendage of a vinyl iodide left them with the substrate for a palladium-cascade. They hoped that the palladium would oxidatively insert into the vinyl iodide, add to the cyclohexene in a Heck manner to form a new carbon-palladium bond. This would then be trapped by carbon monoxide, completin the carbon skeleton of the natural product. However, the actual product from this reaction was quite surprising – a third five-member ring. As they write, it would be tempting to suggest that an alkenylpalladium species had inserted into the allylic C-H bond – but they postulate a far more reasonable mechanism in which the somewhat tetchy aminal moiety cleaves, rearranges the cyclohexene via an iminium ion and then performs a more traditional 5-exo-trig Heck cyclisation. Dissapointing for them, but interesting none-the-less…

A revised strategy allowed them to complete the molecule, but they didn’t quite get to have their cake and eat it – that tandem palladium chemistry wouldn’t go. Instead as stepwise approach prevailed, starting with a palladium-catalysed intramolecular enolate/vinyl iodide coupling. The cyclohexanone product was then converted to a triflate, and a bit more palladium allowed introduction of carbon-monoxide and trapping with methanol to give the unsaturated ester.

This is an awesome read – lots of detail for each transformation, and a logical discussion of the problems they encountered.

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  • antiaromatic says:

    One thing you’ve gotta give Overman a lot of credit for is taking the effort to explain what didn’t work. Another great example of this is his paper on Sarain A. Of course no one’s syntheses go as planned, but at least Overman lets you know why it didn’t. Awesome job.

  • ... says:


    If you like informative discussions of failures, I suggest you check out Ireland’s full papers on FK-506.

  • HB says:

    I recall seeing this Heck methodology applied in Tetrahedron (also by Overman) a few months back…

    Does anyone know who was first to trot out such Aryl-disubstituted sp2 Heck reactions?

  • ZAL says:

    I agree that the Sarain A paper was great – and I’m printing this one right now!
    Thx for another precious reading suggestion!

  • Newbie says:

    Hi guys, I was surfing the net looking for all the great synthetic synthesis chemist and I came across professor called Scott Synder in Columbia. Any ideas about his work? BTW how come all the total synthesis profs always put their name as the first author? Do they have an ego problem? Or they believe the synthesis idea belongs to them so rightfully they shld be the first author even though their grad students were actaully the ones doin the work. Any comments?

  • Tot. Syn. says:

    Snyder’s work is nice, but he’s only been a PI for a short time. His synthesis of some Resveratrol based natural products (covered here: http://totallysynthetic.com/blog/?p=785) is really smart, but there’s not a lot else to go on. The author name order debate has been going on since people were writing on marble with chisels. There is no (repeat NO) consensus as to whether the PI’s name is first or last. Paul Bracher at the sorely missed ChemBark wrote a great piece on this last year (http://blog.chembark.com/2007/03/29/standardizing-author-order/). I standardise the order here just to make is convenient for me.

  • cjdquest says:

    Newbie – you might have noticed Overman (who’s synthesis is featured in this post) lists all authors alphabetically. Tot. Syn., as he notes above, standardized the author listing, with the PI first. in the actual paper, Overman’s name appears between Humphreys and Wrobleski.

  • antiaromatic says:

    The basic idea I think most people have who put their name first is that many times, they ACTUALLY WRITE the paper. If you look at author guidelines for ACS, the perosn who writes the paper is the FIRST author. But also, they do it because it gives a person skimming the TOC the ability to quickly see their name if they want to check out their work.

    In Snyder’s case, he’s doing some awesome work. I’ve had some discussions with him recently and it seems there are a few more installments along the way. From what I’ve heard, his group has finished another 6 molecules.

  • Newbie says:

    wooah. I wld like to thank paul (for pointing out his previous post), cidquest and antiaromatic for sharing their point of view and prompt response. However, its just a trend I observe that PARTICULARLY for the total synthesis grps (as compared to catalysis grps), the PI name is prominently infront. I am not implying that is wrong but its just a trend I observe. Maybe its a kind of inherited “culture” from KC?
    -Mr Antiaromatic: You seem to know Prof Synder personally. Wooah another 6 molecules! Incrediable! Is he a gd mentor? He seems to be a friendly and approachable guy from the pics i see in his website. I wld refer a teacher who comes in the lab and imparts “hands-on” techniques rather than sit in the office and give ideas. Always at times, its is the “hands” that fail when it comes to synthesis and not the science. Comments?

  • ZZZZZ says:


    …Snyder is a great guy. Very nice and down to earth: you will not find a more humble, smart chemist out there. You couldn’t ask for a better mentor or person to be associated with. He is the next star in our field…


  • lemi says:

    No Offence, but are you pretty sure this guy deserve such high praises? for me,i know nothing about him, so i have some doubts. after all, he still didn’t have much work published yet, although i admit his Angewandte paper about Resveratrol-based natural products is awesome, we shall go and see…

  • antiaromatic says:

    I know some of the grad students in his group, and they all seem extremely happy. He must be doing something right!

  • Larval Chemist says:

    I met Snyder recently at a visitation weekend and the praise is certainly grounded in fact. He’s an immensely approachable and friendly individual. He has some absolutely stunning ideas and both with his chemistry and with his mentoring. I must say, he is a very very tempting choice for mentor. His grad students are all very happy and he offers a good deal of hands on learning. Apparently, he likes to be with you at the NMR for your first few weeks and whenever you complete a molecule. They’ve also got a hood set up for him so that he can run TLCs. He’s also got quite the memory for the literature and application details. Really impressive.

  • milkshake says:

    For my MS thesis work in Prague in early 90s (on tot synthesis of alkylphospholipids) I ripped off the Snyders methodology for glycidol sulfonate ester ring opening with long-chain alcohols, catalysed with BF3.Et2O. It worked great.

  • TWYI says:

    When Snyder was still in High school?

    Sure you have the right guy here?!

  • Big_C says:

    To be fair, even the nastiest of PIs will be cordial and humble in person or at conferences. KC himself is quite the gentleman, but he’ll still call you into the lab at 3 AM to run a prep-TLC on your natural product…

    Talking to his grad students/group alumni will be your best bet in learning about his mentoring ability.

  • Larval Chemist says:

    I extensively talked to his grad students to be sure. No complaints as far as I could tell. Whether that was free will or drug induced I don’t know. But I’m sure I’ll find out…

  • Newbie says:

    yea, I guess theres no such thing as the best PI in the world. The grad students themselves must be doin their part. Its a symbiotic relationship. Talking about conferences, anyone is attending the spring ACS meeting? I am going for the organic divsion one in fall. Maybe we can meet up and have a chat! haha

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