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26 February 2008 15,296 views 48 Comments

Smith, Basu and Bosanac. JACS, 129, 14872 – 14874. DOI: 10.1021/ja077569l. Article PDF Supporting Information Group Website

I felt like suggesting I was bullied into posting an entry on this synthesis, but the truth is that 1) it’s an awesome piece of work, and 2) I did ask for suggestions… So feeling suitably deferential, let’s look at the biological activity. Nothing particularly special in terms of the effect (cytotoxicity against the human cell lines P388 and lymphoid leukemia), but the numbers are fairly small: IC50 0.09 and 0.037 μg/mL. However, if we’re fair – it’s that amazing 11,6,6,5- ring system that’s the real pull! Retro time…

So the larger ring was to be completed by RCM, reducing out the extraneous unsaturation, and the smallest ring by an enolate-type addition into a carbonate. This brings us back to a complex pair of linked six-member rings, which they intended to join using a (relatively) simple acetal formation, followed by Petasis-Ferrier rearrangement… ambitious! The linear fragment is a standard polyketide type of thing, and the heavily substituted cyclohexane resulted from a Rawal Diels-Alder… lets start from there:

After the DA, and a few functional group transformations, they were set for a short series of sweet reactions. First, a catalytic carbonylation, and then diastereoselective allylation -nice result. They then transformed the enol ether into a dimethyl acetal by treating with mCPBA in methanol, delivering the oxidant diastereoselectively, and providing the required tertiary alcohol. After a few more functional group transformations (required for optimal results in the next few steps), they were set for the unification of the two fragments.

First-up – formation of the acetal/lactone thing (apparently a “dioxanone”), methylenation of the carbonyl group and then that awesome rearrangement. The yield might not be stunning, but the result is really nice! Then time for a bit of carbonyl-chemistry; deprotonation of the free alcohol and enolate formation, followed by trapping of both with methyl chloroformate gave a pair of carbonates. Explaining what happens next is a task I’ll just quote: “biscarbonate… was subjected to chemoselective methanolysis to form an intermediate sodium enolate, derived from the enol carbonate, which in turn undergoes cyclization with the tertiary carbonate to furnish lactone”. Nice stuff… With the 1,3-dicarbonyl in place, methylation was easy, and also stereoselective.

With a bit of metathesis action and reduction of the alkene, the macrocycle was complete, leaving them with only a few function group transformations to complete the molecule. However, these steps seemed to trouble the group – the planed selenoxide eliminations were tricky, as they couldn’t form both the enolates required to trap PhSeCl. They overcame this by performing one elimination as usual, and the other by first completing a Grieco-Nishizawa elimination, and then oxidising the product (over a few steps) to the desired unsaturated acid.

Again, this synthesis is an awesome read, and full of interesting chemistry. Thanks for the tip, folks…

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  • Madforit says:

    Great Paper!!Tot Syn.the link to the Pdf lead to Fluostatina C.

  • Dr. Bloomquist says:

    How about Palmerolide A?

  • PENN CHEM says:

    To give some background, the molecule was proposed by a Post-Doc as part of his funding (Bosanac). In 2 yrs he was able to complete 95% of the molecule except for that last elimination. He left and another post-doc came in and had to start from scratch bringing up material. He too was temporarily stuck at the end and tried everything, ultimately the final idea came from a poster at a conference and voila, synthesis complete. It’s funny how serendipity works sometime. Thanks for the post!

  • rosko says:

    Is that reagent over the first arrow really the methyl ketone, or is it a methyl ester? If it really is the ketone, that’s an interesting ester formation reaction.

  • rosko says:

    Sorry, I meant the first step in the unification, not in the synthesis of the first fragment. I just realized I should have been clearer.

  • Tot. Syn. says:

    Sorry Rosko – that should be a free acid, not a methyl ketone… I’ll fix it later today.

  • Unsatisfied says:

    Seems like Sorensen’s DA approach to the structurally similar abyssomycins could provide a tidier synthesis in fewer steps. Wonder if he’s working on it.

    This seems like another Petasis-Ferrier forced-fit: does it really simplify the synthesis? Will this really allow access to pharmacologically-useful quantities of material? If synthesis is going to take that next step into the 21st century, we’ve got to do better than this…

  • SI Rant says:

    I was recently working on a hydroformylation reaction similar to the one done on vinyl triflate (-)16 but had trouble with direct reduction to the unsubstituted alkene and had to resort to slow addition of Bu3SnH. I checked the SI for this paper to see what they did and what do you know, it wasn’t there! Check out the scheme for the first entry, that would be an interesting transformation. Not to mention the fact that the first 13 steps aren’t in the SI either. If you’re going to spend years on a synthesis, what’s a few weeks writing up proper SI?

  • Newbie says:

    Hi fellow total synthesis friends, I am just a new graduate who completed my Bsc degree. I am often amazed by way total synthesis chemists are able to do the retrosynthetic analysis. I am very curious on how I can find out more about all you all can retro the synthetic schemes and the amazing variety of reactions pple do. Pls enlighten me with pointers and advise from which I can learn from. Is there any gd books I can start reading on? The classics in total synthesis is quite difficult to read for a fresh man like me. Any help? Thks.

  • Tot. Syn. says:

    I guess as a starting point for total synthesis, there isn’t much better than the Classics books, so they’re probably worth the effort. For reactions, the best book in my opinion is “Strategic Applications of Named Reactions in Organic Synthesis” by Kurti and Czako, which shows neat examples of the use of each reaction, and is well referenced.

    Also, for a more in-depth explanation of the chemistry in use, and also in retrosynthesis, Stuart Warren’s books are invaluable. “Organic Chemistry” by Clayden, Warren, Greeves, and Wothers got me through my MChem, “Organic Synthesis: The Disconnection Approach” taught me retrosynthesis and “Organic Synthesis: Strategy and Control” by Wyatt and Warren is his latest text – ideal for post-graduate chemists.

  • Spiro says:

    I totally concur with Tot. Syn. Warren’s books are priceless if you want to master organic chemistry. It is really too bad that they are little known out of the UK. You may have trouble finding his latest one in a US library.
    Nicolaou’s books are entertaining, but you won’t improve your chemistry as much as by reading Kurti and Czako’s masterpiece.
    If you like the question-and-answer format, take a look at the Organic Synthesis Workbooks edited by Wiley.
    As for retrosynthesis, Warren’s “Disconnection Approach” is a must-read, but it is only introductory. Don’t try Corey’s “Logic of Total Synthesis”, it is not a book about what it says it is, but a comprehensive review of Corey’s syntheses.

    And thanks Tot. Syn. for showing me that there is a new “Warren” out there. I have to go to the library ASAP!

  • Madforit says:

    Hey guys what do you think about Tietze’s Domino Reaction?i think is really interesting..
    I totally agree with you,Clayden Warren and Kurti’s book are great piece of work!!

  • antiaromatic says:

    One quick comment regarding learning retro. As much as the different books are helpful (I do own most of the ones thus far mentioned), one of the best things you can do is just read a bunch of syntheses from journals. There’s really no substitute for seeing many many patterns and learning to recognize them.

  • In response to “Unsatisfied”:

    Son, we live in a world that needs natural products for medicinal purposes. And those natural products have to be synthesized by scientists with the right graduate students and postdocs. Who’s gonna do it? You? KC Nicolaou? Sam Danishefsky? Erik Sorenson?! Synthetic chemists have a greater responsibility than you can possibly fathom. You weep for seemingly inefficient reactions like the Petasis-Ferrier rearrangement and you curse Amos B. Smith, III. You have that luxury.

    You have the luxury of not knowing what I know: That the use of the Petasis-Ferrier rearrangement, while tragic, probably saved lives. And this total synthesis of okilactomycin, while grotesque and incomprehensible to you, will likely save lives. You don’t want the truth. Because deep down, in places you don’t talk about at parties, you want Amos in that lab. You need him in that lab.

    He uses words like gram-scale, linchpin, dithiane… he uses these words as the backbone to a life spent building something. You use them as a punchline. I have neither the time nor the inclination to explain myself to someone who rises and sleeps under the blanket of the innovative synthetic technologies Amos provides, then questions the manner in which he provides them. I’d prefer you just said thank you and went on your way. Otherwise, I suggest you pick up a suitable aldehyde, a proline-based catalyst, and a couple gas tight syringes and run a MacMillian aldol reaction. Either way, I don’t give a damn what you think is going to bring organic synthesis into the 21st century. Amos is already well on his way to bringing it into the 22nd century and beyond.

  • GYA says:

    I love the rant. Not an Amos fan, but love the response to “unsatisfied” keep it up!

  • TWYI says:

    Erik Sorensen got an extra exclamation mark.

  • SAC says:

    Dear SI Rant,

    Chemistry has been around long before your genius stepped on the scene. If you would have read a few papers on carbonylations you would know that you add the tin hydride dropwise slowly over time to avoid the direct reduction. Therefore you could have done the reaction right the first time around. Also, if you read the paper you would see there is a reference for the carbonylation reaction. IF you would look that reference up you would see that in the original protocol by Stille they add the tin hydride over 2.5 to 3.5 h.

    So in your words of wisdom,

    Why spend a week reinventing the wheel, when you could have spent 30 min looking up a reference and doing right the first time?

  • Jonny says:

    I don’t mean to criticize but your disconnection in the Rawal D-A is in the wrong location.

  • Quite Quite Satisfied says:

    In Response to Quite Satisfied’s Response To Unsatisfied:

    I would like to say that I was very pleased to see someone write back and stick it to Unsatisfied. Bravo Quite Satisfied, Bravo!

    Now I will admit that when I saw this paper and noticed it came from the Amos B. Smith III (creater of the Smith-Tietze multicomponent dithiane linchpin coupling ….) and noticed the Pyran ring system, I thought to myself “here comes another Petasis-Ferrier”. And what do you know, there it was. Funny thing about it is that though the synthesis was built to incorporate the P-F, I would not really consider this a “forced-fit”. This turns out to actually be an excellent example of how powerful a reaction this really can be and is probably the most elaborate P-F to date out of the Amos B. Smith III labs! Sure you could piece that ring together a number of other ways, but would it really be that much more efficient a synthesis??? The problems really didn’t occur until the authors actually tried to do a rather impressive, IMHO, double selenoxide addition and came to realize just how difficult the second deprotonation was. Had this reaction worked, it would have provided another creative piece of this synthesis and yielded the final product more efficiently.

    Now at this point the authors had to make some difficult decisions: do they abandon the use of the P-F all together and go about this another way? (I think not!), do they go back to the beginning and incorporate a different coupling piece in the P-F and basically start another synthesis? (probably not a good idea either) or do they simply find alternative means to utilize the material they currently have on hand in order to finish their ultimate goal: Okilactomycin!!! Obviously they made a choice any post-doc wanting to get on with their life would make and used what material they had to push forward. I say kudos to them for finishing this molecule and proving once again just how far Amos B. Smith III is willing to go to ensure the future of organic synthesis.

    Another point worth making is that to point out the “forced-fit” of the P-F here and act as if Amos B. Smith III is the only one who “force-fits” anything, is absolutely ridiculous!!!!! His group is not the first to design a synthesis around reactions discovered in his lab, nor will they be the last! Lets be honest, unsatisfied has issues with Amos B. Smith III and not with the synthesis of this molecule. I say excellent work and can’t wait to see more from the labs (gram scale of spongistatin anyone???? )

  • Tot. Syn. says:

    Whoops… I’ll fix that later.

    I’m currently reading the Nicolaou and Overman papers in JACS – I’ll have posts early next week. And as for this synthesis – I think it’s one of the best so far this year…

  • SI Rant says:

    Dear SAC,

    While I appreciate the gesture, I must decline your compliment as you hardly know me.

    But just as I have to assume 13 reactions in this article were run under exactly the same conditions as the referenced articles, your lack of response to the crux of my rant forces me to assume you agree with my annoyance of incomplete SI.

    This is a fantastic article with some very impressive work. I just wish the authors were also proud of it enough to include the details of everything they did.

    Raise your hand if you’ve ever found the “perfect” reaction or intermediate in an article only to find it’s missing in the SI.
    *raises hand*

  • ha ha says:

    Quite Satisfied: Perfect. But you missed the opportunity for a great “You want natural products? You CAN’T HANDLE natural products!” line.

  • SAC says:

    SI Rant,


    I think the authors should have put in experimentals for all new compounds. Especially since there is no restriction on space.

  • NEwbie says:

    Dear All,

    I wld like to thank “Mr total synthesis”, “antiaromatic” and “spiro” for their invaluable advices. I am working in a company now doing methology studies which I feel is quite monotonous. I cant get to explore other kinds of fasinating reactions I see in the total synthesis papers. My future plans is to get into a total synthesis grp and be realli engage in this field. Do any one know which is a good total synthesis grp US/ Uk to work for? Is it really true that in a BIG grp, the “swim or Sink” theory applies? DO smaller grps grad students engage more with their advisor and hence recieve better training? Pls advise. Thks in advance.

  • TheEdge says:

    For all of the sake of the foreigners (and quite quite satisfied), I feel I need to post a link to this:


    Unfortunately, the sound is out of sync, but I think some of the earlier comments will make more sense.

  • GYA says:

    I actually do think the potential to get more out of the advisor is greater in a smaller lab based on firsthand experience.

  • GYA says:

    I didn’t get as much out of this work as others. The approach is pretty straightforward and lacks a degree of novelty. The execution is no doubt challenging, but I’m not sure what it teaches the community aside from how to make this particular molecule.

  • TheEdge says:

    Sorry, Paul. I just realized that I’m the foreigner here. I apologize for my US-centric world view.

  • clueless says:

    I wish I understood the purpose of quite satisfied’s comment.

    “Otherwise, I suggest you pick up a suitable aldehyde, a proline-based catalyst, and a couple gas tight syringes and run a MacMillian aldol reaction. “

  • Paul…is there a reason you’ve stopped including InChIs on the pages or under the graphics?

  • Quite Satisfied says:

    clueless, maybe if you weren’t “clueless” you would understand.

    I have neither the time nor the inclination to explain myself to someone who rises and sleeps under the blanket of the innovative synthetic technologies scientists like Dave Macmillian provide, then questions the manner in which he provides them. I’d prefer you just said thank you and went on your way.

  • antiaromatic says:

    Going back to the big group/little group question, I certainly agree (also from first hand experience) that the smaller groups tend to learn more from those around them. That’s not to say that you can’t do well in a big group and have a lot of involvement from your advisor, but in larger groups, the majority of the learning comes from either yourself or postdocs. This isn’t always a bad thing as postdocs often times are excellent resources, especially if the advisor hasn’t actually worked in a lab in many years.

  • Newbie says:

    Thks for the advise again “GYA” and “antiaromatic”. Do you all have any experience/ heard gd comments abt any total synthesis grps out there? I heard Steve Ley’s grp is not bad. But I checked out his website and its like a gigantic grp. Also, I thought its was Ben List who popularised the proline aldol reaction when he did his work at Scripps with Carlos F III. David improvised the cat and used it in diels alder reactions? Correct me if i am wrong.

  • Jim says:

    When looking for a PhD place, I’d say that the focus should be on the project, not the personalities. If the project dosen’t interest/excite you then it dosen’t matter how good the group is – you’ll learn nothing.

    This is obviously tempered by the fact that I wouldn’t pick a project with someone I detested; no matter how interesting. But then, I detest very few people.

  • GYA says:

    MacMillan is the pioneer of the proline revolution. NO DOUBT. The other guys entered the game after he got the ball rolling and in many cases he was quicker to every discovery than the rest (they usually followed shortly after he published). List no doubt has done great work in the area, but after MacMillan got things going.

    Consider YOUNG total synthesis groups. Ley’s group is huge because he’s older and established. Young groups include Baran, DuBois, Gin, Movassaghi, Sorensen, Stoltz, among others (tenured but still young). There are even younger labs that would be even better from a learning standpoint (more direct interaction with and learning from the advisor), but you need to look harder to find what you’re looking for there. Speak to faculty members to get advice on pre-tenure guys and visit the schools to get to know there expectations and personalities.

  • synthon says:

    GYA…please don’t make MacMillan’s head any bigger than it already is.

  • GYA says:

    Its a fact, and others already have taken care of that.

  • synthon says:

    GYA…you know its all good with me, I just think List might disagree. With respect to the imidazolidinone catalyts, you will surely get no argument with me…some of the most beautiful transformations I have seen in modern catalysis. Although Enders deserves significant props as well. I guess I just have read and heard too many stories to feel that strongly about MacMillan. The SOMO dispute with Sibi being the most recent.

    Back to the choice of research group…the list GYA provides is a good start. There are an absolute TON of good groups with advisors that started in the last 15-20 years. Most groups are methodology-based with total synthesis application…although that trend is shifting to the later with the more recent generation of faculty. I clearly remember picking my advisor after reading a total synthesis paper that completely blew me away. Don’t forget to look nationally as well as abroad.

  • Big_C says:

    Tot. Syn.-

    The recent JACS-ASAP of ( )pinnatoxin A might be of interest. Quite an impressive approach to such a heavily-studied molecule.


    That’s one beefy Ireland-Claisen…

  • antiaromatic says:

    Definite props for the pinnatoxin synthesis. Good to see people using rearrangements to access cyclohexenes as opposed to DA.

  • Tot. Syn. says:


    Hope to fill in the blanks fairly soon… just haven’t had time, and I’ve been considering a fairly major infrastructure change at totsyn.com. This theme was supposed to be flexible and easy to work with, but it’s turned out to be a bastard, and the PHP code that it uses isn’t commented well. We’ll see what happens with the theme, but I’ll put the InChis in soon.

  • clueless says:


    Quick question about your statement:

    “The SOMO dispute with Sibi being the most recent.”

    I had not heard about this, was this dispute over who claimed credit for this discovery or a mechanistic disagreement?

  • milkshake says:

    I knew MacMillan when he was a postdoc – and back then he was a thoroughly decent guy – and fairly modest. He would even discuss his research proposals (that he was gonna do as asistant prof) with lowly junior students. People do get changed by success but it would surprise me if he turned unpleasant.

  • synthon says:

    Clueless, others…I do not know Dave at all and anything I have heard is all hearsay and is by no means worth repeating here. I personally think his work is quite spectacular and would love to meet him someday and talk shop.

  • Hap says:

    I concur with MS – he seemed like a nice guy as a postdoc. I don’t think he’s the only one to play in the organocatalyst field, though he’s done neat stuff with it(the proline-catalyzed aldol was like thirty years old when he started) – List and maybe Corey (with the oxazoborolidine triflate-catalyzed reactions).

    There seem like a lot of good groups in synthesis to work for, but I don’t know too many professors (or what they’re like in RL).

  • Unsatisfied says:

    Blimey. Quite a response. Wasn’t expecting that.

    Two items in reply:

    1) The lady doth protest too much.

    2) Satisfaction breeds mediocrity.

  • Frankenballs says:

    PENN CHEM, What do ya mean, “It’s funny how serendipity works sometime?” Let me understand this cause, I don’t know maybe it’s me, I’m a little fucked up maybe, but I’m funny how? I mean, Amos is funny like he’s a clown? He amuses you? He makes you laugh… He’s here to fuckin’ amuse you? What do you mean funny, funny how? How is it funny? How he publishes the synthesis? No, no, I don’t know… you said it. How the fuck do I know? You said it’s funny. How the fuck is Amos funny, what the fuck is so funny about Amos? sphincter!