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Callipeltoside C   

6 April 2008 12,624 views 26 Comments

MacMillan, Carpenter, Northrup, Chung, Wiener and Kim, ACIEE, 2008, EarlyView. DOI: 10.1002/anie.200800086. Article PDF Supporting Information Group Website

Macrolide time again, and as this is David MacMillan, proline time too. The callipeltoside family of natural products has been reasonably popular, with syntheses from the usual suspects: Trost, Evans, Paterson, and Panek. However, all of those syntheses were of callipeltoside A, so this synthesis marks the first of callipeltoside C, including a reassignment of stereochemistry (the sugar fragment needed all is stereocenters inverted). Retro:

So far reasonably predictable/sensible disconnection – and you’ll note no organocatalysis so far. It’s also worth pointing out here that the dieneyne fragment was made using the route developed by Evans. However the fragment synthesis is where MacMillan’s favourite amino acid come in, with several proline catalysed aldol condensations.

The first of those is in the construction of the THP, in which a nice little matched-organocatalytic aldol with a derivative of the ever-popular Roche ester. However, what I liked most was their use of a Semmelhack reaction to close the THP and leave a methyl ester as a useful functional handle. (For those of you who aren’t aware of this reaction – and it’s absent for several named reaction books – MacMillan references two papers. The original paper is here; Marshall’s improved conditions for acetylinic systems are here.) In their hands this went with great diastereomeric control, and left a heavily functionalised THP after only two steps. Now that’s smart work!

The next aldol to look at is of the prodigious direct aldehyde-aldehyde variety. A spot of L-proline this time results in a great e.e. and decent yield of the semi-protected triol. Next, a bit of silyl enol-ether completes the hexose framework and leaves a differentially protected sugar (if you accept that the two TIPS protected hydroxyls will react differently). Of course, we read all about this sugar synthesis in Science a few years back.

It took them a few more steps to complete the sugar synthesis (for the second time – as I mentioned above the originally proposed stereochemical configuration of the sugar was incorrect), and a bit of Tietze chemistry allowed them to bolt this onto the aglycon.

As with many syntheses, the last step was deprotection of the silyl groups – but not with TBAF or HF.amine here. Nope, MacMillan uses tris(dimethylamino)sulfonium difluorotrimethylsilicate (or TASF to it’s friends) – useful if there’s any water sensitivity as the reagent is completely anhydrous.

An interesting synthesis, showcasing much of MacMillan’s work – and notably only using unmolested proline as the catalyst.

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  • milkshake says:

    There is a cheap alternative of TASF actually:When you mix anhydrous Bu4NCN with 0.2 equvs of C6F6 in THF you get perfectly anhydrous TBAF solution that is also stable at RT (the sideproduct is hexacyanobenzene)

  • proline expert says:

    congrats to barbas and list on this force fit. not sure how it improves much on 2001 paterson synthesis, since paterson doesnt base overall yield on recycled material – read SI carefully.

  • TWYI says:

    Is the Barbas and List line another hilarious ‘who invented organocatalysis’ quip?

  • Big_C says:

    I’m partial to Panek’s take, chock full of his nice [4+2] pyran-annulation methodology.

    Also, he happens to be a former professor of mine…

  • twyi – no, they just re-popularized intermolecular hajos-parrish reactions.

  • milkshake says:

    I thought Cordova deserves all the credit…

  • ZZZZZ says:


    …lol at the Cordova comment…


  • milkshake says:

    Semmelhack sounds like a health condition that one can pass on his girlfriend – small wonder people are slow to adopt it as a name reaction. Anyway – please can you fix the reference to the Marshall’s paper? – it has two “html//” in the link

  • Tot. Syn. says:

    Fixed. Thanks for that, Milkshake.

  • ... says:

    I fail to see how MacMillan’s chemistry is simply a repeat of the Hajos-Parish. It seems to me that using an aldehyde as nucleophile in a direct aldol took some development. Even though the concept of using proline was well established decades earlier, nobody was using it for substrates that strayed far from what Hajos-Parish originally reported until Barbas, List and MacMillan reinvestigated it. There’s no shortage of repetition, salesmanship, and overly thorough scope tables in the recent literature, but I feel MacMillan (and LIst and Barbas) have made some important contributions to aldol chemistry.

  • TheEdge says:

    “proline expert”-Mac’s overall yield is still better than the overall yield of the Paterson and Evans syntheses, even without the recycled yield included (which only bought them like 25% anyway). The improvement mostly comes from 2 things: the MacMillan synthesis is slightly more convergent than the other two because of where he couples, and the proline aldol/Semmelhack sequence avoided some of the protecting group manipulation present in the other syntheses. If there’s ever going to be a “protecting group free” synthesis of a polyketide, it’s going to be of Calli. I think a well thought out prep that used the sugar as a “pg” could probably do it.

  • gilgerto says:

    Anybody know why MacMillan is publishing only a few papers per year, even with a group of more than 25 researchers? I heard that he keeps papers which are’nt JACS – ACIEE publisheable…

  • Big_C says:

    “I heard that he keeps papers which are’nt JACS – ACIEE publisheable…”

    This is fairly common in my experience. Esp. among the younger crowd.

  • gilgerto says:

    Big_C: I’m not quite sure to understand why a young researcher would do that. Of course, you can think about names like Toste, Baran, Fu and Macmillan just to name a few who seem to publish only in JACS-ACIE, and I believe quality is better than quantity, but I would’nt want to be a Ph.D. student in Macmillan lab applying for post-doc followship with zero publication just because my supervisor held three org.lett. I could have published. ..

  • Mouse says:

    “I heard that he keeps papers which are’nt JACS – ACIEE publisheable…”

    He typically doesn’t let students work on projects that wouldn’t wind up in JACS or ACIEE should they go as planned. There simply aren’t a lot of completed projects waiting for OL (only junk that didn’t quite work as planned and may never be published outside of a thesis). The size of the research group reflects the difficulty of the projects and speculative nature of programs that would wind up in JACS if they worked.

  • Big_C says:

    “I wouldn’t want to be a Ph.D. student in Macmillan lab applying for post-doc fellowship with zero publications just because my supervisor held three org.lett’s I could have published…”

    To me, this is a good reason NOT to join some of these young, up-and-coming groups for a PhD.

    With guys like Mo Movassaghi, Dean Toste, Phil Baran, Justin Du Bois etc… your work will not see a journal unless it is of JACS/ACIE quality. So you’re at the exclusive mercy of the project assigned to you.

    And lets face it, there aren’t many PI’s of interest who assign “projects that wouldn’t wind up in JACS or ACIEE should they go as planned.” The question is of disclosure, and when the PI is comfortable sending a communication as opposed to waiting for the “big” result, which in some cases can turn out to be quite a long wait…

  • Mouse says:

    “With guys like Mo Movassaghi, Dean Toste, Phil Baran, Justin Du Bois etc… your work will not see a journal unless it is of JACS/ACIE quality. So you’re at the exclusive mercy of the project assigned to you.”

    I’ve been doing on-campus recruiting for a big pharma for a few years now and it seems to me the best candidates have always been able to turn a dog of a project into gold by making it their own. I’ve seen students from those groups and MacMillan’s and it seems that what separates the good from the excellent student is the ability to turn adversity into advantage. Frankly, guys from those groups don’t have to worry too much about getting jobs or post docs.

  • TWYI says:

    LOL @ only the junk goes into Org Lett :roll:

  • Zoltan says:

    Well before MacMillan published ‘his’ aldehyde cross aldol, Barbas had already published the aldehyde cross aldol (not efficient) as well as efficient aldehyde based Michael and Mannich reactions. MacMillan ‘tends’ to forget those citations but certainly has no claim developing the concept.

  • milkshake says:

    life’s full of adversities.

    In the end we all end up defeated by it, 98%+ ee reactions credited to our name notwithstanding.

  • Eraser says:

    As pointed out by Berkessel (Author of Asymmetric Organocatalysis, Wiley-VCH, Weinheim (2005)). None of this is new. I recently saw him give a talk, at the end of which he showed us the cover of a 1955 second edition (the first was from 1936 but impossible to find). Detailing a lot of what today is known as organocatalysis. According to him they didn’t check e.e. back then, but the chemistry was already being studied. Not to mention later work by Hans Wynberg (quinine) and of course the work by Hajos, Parrish, Eder, Sauer and Wiechert in the 70ties.

  • milked says:

    At least MacMillan made a real go at this synthesis and it truly deserved publication. I wouldn’t say that about List’s Mannich paper in nature. That paper is virtually republishing. How does a weekend’s work end up in Nature? 5 bucks to CC if he can pull that off!

  • JJ says:

    There are so many lies, mistakes and vague spectrum in this publication, I just can not believe how they proof-read papers in all journals!!

  • Tot. Syn. says:

    Read the AUP people, or comments get deleted…

  • Caustic says:

    Of course MacMillan did a great job, if you closely this paper the first step, a proline catalyzed aldol condensations (outlined by Tot.Syn. with 48% yield), seems to work “nicely” in moderate yield as I have written 48% (75% brsm) and in good diastereoselectivity 12:1, but MacMillan “forgot” to write something about the time reaction, if you read the supp.inf. you can see that the introduction of propionaldehyde takes 100h.
    Why a so long time reaction to have “only” 48% yield? is this reaction really optimized?

  • Found today (12.01.08) a remark by Zoltan. Let me stress, it was not I who made the “Zoltan comment”. I have the highest respect towards Carlos F. Barbas III. as well as David C. MacMillan who have developed the original studies of myself and David R. Parrish <a href=”’J.Org.Chem.,1974 , 39, 1615-1621”’. Zoltan G. Hajos