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Palmerolide A: redux   

3 March 2008 6,365 views 10 Comments

Nicolaou, Chen, Guduru, Sun, and Banerji. ACIEE, 2007, EarlyView. DOI: 10.1002/anie.200702243 JACS, 2008, ASAP. DOI: 10.1021/ja710485n. Article PDF Supporting Information Group Website

You’d be forgiven for a feeling of déjà vu when looking at the post – yes, you have seen it before. Originally described in an Angewandte paper last year (which was discussed on this blog), Nicolaou and Chen achieved a smart, logical synthesis of the marine macrolide. The main problem was not the synthesis (which, at least from their description, was achieved without adversity), but the stereochemistry. The stereochemical relationship between the pair of distinct domains was unknown, so their approach was to dissect the molecule into bitesize chunks, which could be produced as pairs of enantiomers without difficulty. These fragments could then be assembled in a combinatorial manner to provide a range of macrocycles, one of which should match the natural product.

I discussed the synthesis of the fragments in the previous post, but missed out one rather nice reaction, using a piece of Brown’s chemistry to do a hydroxy-crotylation. Using a simple starting material, application of this one-pot reaction allowed construction of a complex chiral allylic diol with excellent control and a great yield. Great stuff!

The crux of this paper, however, was an analysis of the coupling stragety. With the four key fragments (2-4 as numbered in the paper) complete, they tried a variety of strategies to first build the acylic precursor, and then close the macrocycle. Somewhat unsurprisingly, they found that the two reactions most suited to cyclisation were RCM and Yamaguchi macrolactonisation. Perhaps more surprising was that they could do the RCM with the enamide sidechain inplace. The starting material for this cyclisation contains eight double-bonds, so there was every opportunity for havoc, but the reaction went in a rather pleasing 73% yield.

The overlap between last years Angewandte paper and this JACS troubles me a little; I can see that this paper goes further in it’s discussion of the strategic alternatives, but much of the first half of the paper is a repeat. But that shouldn’t distract from an excellent synthesis and a worthy analysis of strategy.

InChi Key Dump: HEOKDDVDVGNHMR-DAUCKHFQBA MLCUMJCCPMSERM-UHFFFAOYAZ PBDZPIOAJVSYJJ-CHWSQXEVBQ JLEWWMVEZDWKSF-OPNQXQEIBH JLEWWMVEZDWKSF-OPNQXQEIBH IULWLDNNGGDOLC-QEHWCHDUBC WHNPOQXWAMXPTA-UHFFFAOYAG

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10 Comments

  • antiaromatic says:

    Nice work, but certainly not as nice as Overman’s paper of that strychnos alkaloid. I guess it’s just Overman doing what Overman does best: alkaloids.

  • Tot. Syn. says:

    Overman paper next…

  • Potstirrer says:

    Going off topic here…I am reading a Corey total synthesis of fumagillin with Snider (Barry that is with an “i”) as coauthor[(JACS, 1972, 2549) DOI: 10.1021/ja00762a080]. Nice molecule, but something strange happens in one of their schemes. Compound 6 is the product of a Diels-Alder cycloaddition. They say they assign the relative stereochemistry of 6 based on the fact that it was converted, eventually, into the natural product. The relative stereochemistry they depict for 6 is what would be expected from an endo TS. No problem so far, except that this stereochemistry shouldn’t lead to the natural product. 6 is then converted into 9, where R1 is CH2OTMS and R2 is Br. TBAF desilylation (an early example of fluoride desilylation conditions) followed by NaOMe forms the spiro epoxide 11, the relative stereochemistry of which is ambiguous in their drawing, but should have the oxygen in a pseudoequatorial position. This is then converted to 13 where the spiro epoxide seems to have changed its relative configuration with the oxygen now residing pseudoaxial, the way it is found in the natural product. There is no doubt as to the structure of the natural product. I also believe that Barry made the damn molecule. I guess the best explanation is that they actually got the exo product in the Diels-Alder and just drew the structures incorrectly in the paper. I’d love to hear what those who have the time and inclination to check this out think. C’mon…it’s never a waste of your time to go and read an old Corey paper!

  • Potstirrer says:

    Ahem…I’m an idiot. I, as I should have suspected, was the one who was wrong. Stupid SN2 reaction! Still a good read though.

  • Diego says:

    Great synthesis, and great work with the molecule. I really like Nicolaou´s work.

  • ananymous says:

    Hi Potstirrer,

    while we are at it…. synthesis of Fuamgellin by Profs. Corey and Barry has been the benchmark for many syntheses that followed for that. Are you planning to make it in a better way? If you r a biologist, and looking for TNP-470 which is (thanks to Judah Folkman & co0 a potent anti-angiogenisis agent- just to let you that these are commercially available.

  • synthon says:

    Potstirrer…you should follow up now with Ovalicin (with Ditami) in JACSS (1986). It is interesting to read about the Corey modification of the Shapiro reaction in this paper as well. A methodology he didn’t publish a full account of until ~10 years later!

  • sundance kid says:

    Palm stereochem was reassigned by brabander (JACS 2007, 129, 6386-6387. DOI: 10.1021/ja0715142)

  • Guoho says:

    Recent synthesis of Palmerolide A by Chen (Chem Eur J.)is piece of crap because Nikolao is not there with Chen. I heard Chen kicked out Nikolao from Singapore lab.
    To compare, Formal synthesis of Palmerolide by P. Gowrisankar is much much better

    • Guoho says:

      Recent Palmerolide A (European Journal of Organic Chemistry ) synthesis by Chen is piece of crap as Nikolaou is not in the publication. I heard is result of Chen kicked out Nikolaou from the Singapore Group. He has to depend on the idea fromother..  Foraml synthesis of Palmerolide A  by P Gowrisankar is much much better