Approaches to Total Synthesis

The biomimetic approach to total synthesis draws inspiration from the enzyme-catalyzed conversion of squalene oxide (2) to lanosterol (3) (through polyolefinic cyclization and subsequent rearrangement), a biosynthetic precursor of cholesterol, and the related conversion of squalene oxide (2) to the plant triterpenoid dammaradienol (4) (see Scheme la).3 The dramatic productivity of these enzyme-mediated transformations is obvious in one impressive step, squalene oxide (2), a molecule harboring only a single asymmetric carbon atom, is converted into a stereochemically complex polycyclic framework in a manner that is stereospecific. In both cases, four carbocyclic rings are created at the expense of a single oxirane ring. 

However, if those natural products have been previously synthesised one may start from them, provided that it simplifies the synthesis, since repetitions and waste of time should be avoided. Moreover, once a key intermediate has been synthesised, but may also be obtained easily by degradation from some other product, including the same natural product that is being synthesised, the chemist should resort to such a source and use it to continue the synthesis. This approach to total synthesis is referred to as the relay approach. 

Approaches to Total Synthesis of Heterocyclic Steroidal Systems H. O. Huisman, Angew. Chem., Int. Ed. Engl., 1971,10, 450-459. 

The picrotoxane sesquiterpenes are a family of natural products from a poisonous berry Menispermum cocculus which were documented as early as the 1600s by Indian natives who used them to stun fish and kill body lice. Trost and coworkers reported an approach to total synthesis of this family based on Pd-catalyzed cycloisomerization [68, 69]. Several synthesis recipes were tested and it was found that a combination of dbpp with a ligand capable of internal proton delivery (dpba) gave the best result and provided a key intermediate 27 for total syntheses of corianin, picrotoxinin, picrotin, and picrotoxate (Scheme 10). 

Steroids, nonbiomimetic approach to total synthesis of 84MI29. Thia-analogues of gonasteroids, syntheses of 87MI62. 

Tadano, K, Isshiki, Y, Minami, M, Ogawa, S, Samarium(II) iodide-mediated reductive cyclization approach to total synthesis of the insect sex attractant (—)-anastrephin. Tetrahedron Lett, 33, 7899-7902, 1992. 

New approaches to total synthesis of manzamine A, ircinal A, and related alkaloids 99YGK1004. 

How might we obtain enantiomerically pure compounds Historically, the best answer to that question has been to isolate them from natural sources. Hence the dependence on natural product isolation for the production of enantiomerically pure pharmaceuticals. Derivatization of natural products or their use as synthetic starting materials has long been a useful tool in the hands of the synthetic chemist, but it has now been raised to an art form by practitioners of the Chiron approach to total synthesis, wherein complex molecules are dissected into chiral fragments that may be obtained from natural products [17-25]. 

Scheme (7). Lebrun et aL approach to total synthesis of racemic ty lophora alkaloids...

Throughout this book, functional group transforms for each new reaction were shown at the end of the discussion. In addition, disconnections for carbon-carbon bond-forming reactions have also been given. These transforms and disconnections form the basis of the modern approach to total synthesis. The simple strategies used for the problems in previous chapters may not work very well with complex molecules, and alternative strategies are required for their total synthesis. 

Nakagawa, M., Torisawa, Y Uchida, H, and Nishida, A, (1999) New approaches to total synthesis of manzamine A, ircinal A and related compounds. J. Synth. Org. Chem. Japan, 57,1004-1015,... 

Chao, W., Mahajan, Y.R., and Weinreb, S.M. (2006) An approach to total synthesis of the cylindridne B pyridoquinoline subclass of tricyclic marine asddian alkaloids. Tetrahedron Lett., 47, 3815-3818. 

Werner, KM., De los Santos, J.M., Weinreb, S.M., and Shang, M.Y. (1999) An intramolecular nitrone-olefin dipolar cydoaddition-based approach to total synthesis of the cylindridne and lepadiformine marine alkaloids./. Org. Chem., 64, 4865-4873. 

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