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Oct 20

Macrolactonisation

by Quintus | Categories: chemical education, synthetic chemistry | (16890 Views)

Macrolactonization: Now here is a word to strike fear into the heart of any synthetic organic chemist. It’s usually the last step, or one of the last steps in a long complicated natural product synthesis. Not much material left to experiment with so each crumb of unreacted starting material, usually the seco-acid has to be recovered. So which method do you choose? Off to the library may no longer be required, as recently Campagne etal have kindly updated their comprehensive review on the subject1 containing 860 references and covering the literature in the review up to 2011.

Upon reading this I was astounded with the number of methods, obviously I was acquainted with some of them, even done a few in the lab, but the scope here is tremendous. There are some 26 or so methods discussed in this review. Which begs the question: Which one do you choose? Stick with the older well-documented ones or go for a newer method? Well it obviously depends upon your molecule and its functionality. I will just pick out some of the reactions discussed, mainly those I am not so well acquainted with and hope that you will find something useful for your own synthesis.

Let’s begin by looking at macrolactonizations by the Boeckman method. This is based on the known formation of ketenes by thermolysis of dioxolenones2. The conditions are mild and hydroxy or amino groups can trap the ketene. Here is the general idea:

Boeckman3 applied it in the following step note the high dilution.

A testimony to the power of this approach is the next example described by Hoye etal4 demonstrating impressive  impressive regioselectivity.

Moslin5a-d described an elegant approach, in his synthesis of (+)-acutiphycin, which employed a retro-ene reaction of an alkynyl ether to produce the ketene.

 

The Yamaguchi method6 remains one of the most popular procedures for macrolactonization. According to the reviewers more that 340 papers have been published using this method. This, of course, uses the Yamaguchi reagent; 2,4,6-trichlorobenzoyl chloride in the presence of triethylamine to form the mixed anhydride, the triethylamine hydrochloride is filtered and the solution concentrated. After dilution the mixed anhydride solution is added to a very dilute hot (80°C) solution of 2 – 5 equivalents of DMAP. This method is usually excellent for large ring lactones the efficiency falling off as the ring size diminishes. A disadvantage of the method is the use of high temperatures and DMAP conditions that can lead to isomerization and epimerization. As is usually the case with such methods there have been many variations described and the reader is referred to reference 1 for more information.

The Mitsunobu reaction7 a-c has also successfully found it’s way into this chemistry and the success is nicely demonstrated by the formation of the strained 9-membered lactone moiety of griseoviridin8.

Normally high dilution is required for these reactions. Recently a method appeared which does not require high dilution. It was described by White and co-workers9 and relies on some catalytic palladium chemistry (if you call 30 mol% catalytic) and proceeds via an intramolecular allylic oxidation. This has been used for the synthesis of lactones of ring sizes between 14 and 19. The example shown here is part of a deoxyerythronolide B synthesis and proceeds in reasonable yield without the high dilution requirement. However, in order to obtain the 56% yield quoted the starting materials must be re-cycled.

So there it is another very useful review article on a challenging topic. The list of contents is mind-boggling never mind the content itself. If you are in the macrolactonization business I can recommend this tome to you it may just help solve that knotty problem you’ve been having for the last six months.

References:

  1.  Parenty, A., Moreau, X. and Campagne, J. M., Chemical Reviews, 2012, Articles ASAP, DOI: 10.1021/cr300129n, 24/9/2012.
  2.  Hyatt, J. A.; Feldman, P. L.; Clemens, R. J. J. Org. Chem. 1984, 49, 5105.
  3.  Boeckman, R. K., Jr.; Pruitt, J. R. J. Am. Chem. Soc. 1989, 111, 8286.
  4.  Hoye, T. R.;  Danielson, M. E.;  May, A. E.;  Zhao, H.  Angew. Chem., Int. Ed. Engl. 2008, 47, 9743.
  5. a Liang, L.; Ramaseshan, M.; MaGee, D. I.  Tetrahedron 1993, 49, 2159. b Magriotis, P. A.; Vourloumis, D.; Scott, M. E.; Tarli, A. Tetrahedron Lett. 1993, 34, 2071. c Moslin, R. M.; Jamison, T. F. , J. Am. Chem. Soc. 2006, 128, 15106.d Moslin, R. M.; Jamison, T. F.,  J. Org. Chem. 2007, 72, 9736.
  6. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn. 1979, 52, 1989.
  7. a Kurihara, T.; Nakajima, Y.; Mitsunobu, O. Tetrahedron Lett. 1976, 2455.  b Mitsunobu, O. Synthesis 1981, 1.
(734) Hughes, D. L. Org. React. 1992, 42, 335. c Swamy, K. C. K.; Kumar, N. N. B.; Balaraman, E.; Kumar, K. V. P. P. Chem. Rev. 2009, 109, 2551.
  8. Kuligowski, C.; Bezzenine-Lafollee, S.; Chaume, G.; Mahuteau, J.; Barriere, J.-C.; Bacque, E.;  Pancrazi, A.; Ardisson, J. J. Org. Chem. 2002, 67, 4565.
  9. Fraunhoffer, K. J.; Prabagaran, N.; Sirois, L. E.; White, M. C. J. Am. Chem. Soc. 2006, 128, 9032.

1 comment

  1. milkshake

    There are two scale-up friendly approaches for emulating high dilution conditions on large scale with manageable volumes (provided that the cyclic product is stable and does not interfere): 1) Slow syringe pumping the reactants into the reaction mixture 2) use of polymer-supported reactants or reagents

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