Home » Still In The RBF

Total Syntheses of Amphidinolide X and Y   

24 June 2006 7,130 views 5 Comments

Amphidinolide_X_Y_2.jpg

Fürstner, Kattnig, and Lepage. JACS, 2006, ASAP. DOI: 10.1021/ja061918e.

Another pair of amphidinolides in the bag, Furstner et al. have completed the synthesis of X (the only member of the series with an even-numbered macrocycle) and Y using a powerful iron catalysed process. Both products (as with most of the family) are cytotoxic, and contain the heavily functionalised THF moiety. This allowed the group to create an intermediate common to both campaigns, starting from a simple epoxide produced from an SAE.

Amphidinolide_X_Y.jpg
Treatment of this with n-propyl grignard and catalytic quantities of the iron catalyst generated the allene in a 8:1 dr (this system has been used by the group in other work; see: DOI: 10.1246/cl.2005.624, DOI: 10.1021/ja027190t, DOI: 10.1002/anie.200460504, plus further examples cited in the paper). The allene was then cyclised with silver nitrate and calcium carbonate, returning the DHP, which was augmented to the desired THF via bromoesterification.

This portion of the natural product was coupled using an alkyl-suzuki reaction to the rest of the molecule in both cases, along with macrolactonisation to furnish the major ring system. In amphidinolide Y, a boron aldol was used to create the 1,4 anti relationship between a pair of hydroxyls in the C1 – C12 fragment, in a 4:1 dr. Inseparable at this point, they carried the mixture through to a diastereoselective methyl grignard addition.

Amphidinolide_X_Y_3.jpg

The desired aldol product reacted diastereoselectively with the grignard following the 1,2-anti chelate-cram model, whereas the undesired aldol product reacted with far less control. This section of the synthesis is quite intriguing, and is discussed in far more detail in the paper, which is a truly excellent read.

1 Star2 Stars3 Stars4 Stars5 Stars (No Ratings Yet)
Loading ... Loading ...

5 Comments

  • rb says:

    furstner is a pimp. sweet mustache too.

  • Concerned says:

    Did anyone notice that sweet synthesis of Nominine by D. Gin in JACS ASAP about a week ago?

  • rb says:

    concerned: saw it, very impressive. The previous synthesis was 40 steps, gin’s was 15!

  • Dennis says:

    anyone else have issue with his use of “match” and “mismatch”. A semantic issue but led to some confusion for me at first. I know what he means but this is not the intended usage as discussed by Masamune (ACIEE, 1985, 24, 1-76).

    The Gin synthesis is really nice.

  • [...] not actually covered that many, but X & Y (as well as being an affront to my ears) were blogged in 2006, where the focus was on the THF synthesis.  This is the case again with Eun Lee’s synthesis, [...]