Iterative synthesis

The repeated succession of similar reaction sequences for the stepwise synthesis of molecules which consist of repeated building blocks has been termed in literature as repetitive or iterative synthesis. To a molecule with a defined framework having one or more functional groups A (Fig. 1) an identical molecule unit is attached (Iter. 1). Subsequently the functional groups are then reobtained (Iter. 2) so that the reaction sequences can be repeated over and over with the molecule growing by one unit in each reaction cycle (Iter. 1 + 2). This growth... 

Fig. 1. Principle of iterative synthesis. In the first reaction step (Iter. 1) a monomeric unit, which may possess another functional group, is attached to the starting material. In the second step of the reaction sequence (Iter. 2) the functional group A is reobtained, so that Iter. 1 and 2 can be repeated...

In supramolecular chemistry [31] iterative synthesis is frequently used for the construction of ribbon and belt shaped molecules [32]. The repeated Diels-Alder reaction is suitable for the preparation of beltenes, collarenes and cycla-cenes containing partially or fully unsaturated annelated six-membered rings. They are potential molecular receptors for appropriate substrates. Stoddart et al. synthesized the cyclacene 18 by Diels-Alder cyclization of the bisdiene 15 and the bisdienophil 16 [33] (Fig. 10). 

The iterative synthesis of bi- and tercyclohexyl derivatives as liquid crystals shows that this method is widely applicable in various fields of chemistry... 

There are surely many more examples in preparative organic chemistry that follow the iterative synthesis principle for successive construction of larger molecules [62]. Yet the few examples described here illustrate its versatile applications. 

C. D. Heidecke and T. K. Lindhorst, Iterative synthesis of spacered glycodendrons as oligomannoside mimetics and evaluation of their antiadhesive properties, Chem. Eur. J., 13 (2007) 9056-9067. 

N. Feuerbacher, E Vogtle, Iterative Synthesis in Organic Chemistry , Top. Curr. Chern, Vol. 197 Dendrimers (Ed. F. Vogtle), Springer-Verlag, Berlin, Heidelberg 1998,1-18. 

Fig. 20 Iterative synthesis of pseudoloigosaccharides using 6-desoxy-6-methoxyamino-a-D-glucopyranose.

Its design versatility, as generic dendrons may be prepared to be used later as building blocks in conjunction with other reactive molecules, or coupled to a multifunctional core to afford functional dendrimers, dendritic-linear hybrids, dendronized polymers, etc. This may be a particularly significant advantage if the coupled reactive or core molecule is itself sensitive to the reaction conditions used in the multiple steps of the iterative synthesis of a dendrimer. 

This methodology has been used for an iterative synthesis of the tricyclopenta-noid hirsulene (6), as outlined in equation (II).2 Two steps in the synthesis involve conversion of an -chloro ketone to an alkcne. This reaction was accomplished by reduction to a chlorohydrin followed by treatment with chromium(ll) perchlorate.1... 

This method has been successfully extended to the iterative synthesis of oligosaccharides. The disaccharides, derived from selective activations of unprotected MOP donors and partially esterified MOP acceptors, can be converted into reactive donors simply by deacylation. The newly generated unprotected MOP disaccharide donor can be subjected to another cycle of glycosylation by repeating the same process. Schemes 7 and 8 illustrate... 

Boron trifluoride, zinc bromide, and tin tetrachloride led to non-chelation-controlled antt -adducts 3, whereas the use of titanium tetrachloride and magnesium bromide resulted in chelation-controlled syn-adducts 2. Both adducts can be used as starting compounds for the iterative synthesis of amino sugars. 

Tandem RCM/allylstannane-aldehyde cyclizations are successfully used for the iterative synthesis of /ra/w-fused oxepane systems, particularly, three tricycles modeling different fragments in brevetoxins and ciguatoxins <2000S883>. Grubbs catalyst <1996JA100> was used on RCM step of the tandem while the procedure similar to that proposed by Yamamoto et al. <1991TL7069> was applied on the second step. 

Accessible by several-step to many-step (iterative) synthesis... 

D.M., Beck, P.A. and Strongin, R.M. (2000) Convenient iterative synthesis of an octameric tetracarboxylate-functionalized oligophenylene rod with divergent end groups. Organic Letters, 2, 3201 1. 

Fig. 15.15 Iterative synthesis and asymmetric synthesis of carbon-sulfur [7]helicene 40.

Scheme 4.47. Iterative synthesis of dendrimers using tetrahedral alkyl ammonium moieties as branching centers.

A representative selection of [2]catenanes synthesized by this route is given in Table 10.1[14b, 15a, 16]. It is remarkable to note that the first [2]catenane synthesized (entry 2, Table 10.1) could be isolated in 74% yield [14,16], The final entry in the table is an example of an expanded version of the tetracationic macrocycle which incorporates a biphenylene spacer between the paraquat residues and can accommodate two n-stacked aryl rings within its cavity. The reaction results in the isolation of the [3]catenane product in 25% yield with very little (2%) [2]catenane isolated [16p]. A spectacular demonstration of the power of this approach by Stoddart and coworkers was the iterative synthesis of a [5] catenane which the authors dubbed Olympiadane after its resemblance to the Olympic rings [17]. 

Many successful experimental results show that a previously unthinkable task can be accomplished by iterative synthesis and screening of partial libraries. Even the need of iterative synthesis and screening can be eliminated by properly designed and pre-prepared sets of partial libraries (see below). 

The traditional approach to drug discovery involves an iterative synthesis and test cycle in which a medicinal chemist synthesises a compound, tests it for activity and then uses the results to suggest a new compound for synthesis, in the... 

Direct structure determination methods, where positives are characterized directly via off-bead or on-bead identification of their chemical structure, will be described in detail in this section. Indirect methods that determine the structure of positives from the library architecture will be covered later they use either deconvolutive methods (Section 7.3), where the iterative synthesis of library pools with decreasing complexity via sequential determination of the best monomers leads to the identification of a positive structure, or encoding methods (Section 7.4), where, during the library synthesis, the structure of each component is coupled to a tag that can be read from a single bead after the library screening. 

While the structure determination methods seen in the previous section are based on the analytical identification of the positive library individuals, other methods exist to perform the so-called deconvolution of the library complexity and allow the eventual identification of one or more positives from the library without determining their structure by analytical methods. The most common approach is based on iterative synthesis cycles of less complex pools deriving from the original active pool(s) until single compounds are prepared and tested iterative deconvolution) (3). 

Mori, Y, Takase, T, and Noyori, R. 2003. Iterative synthesis of the ABCDEF-ring system of yessotoxin and adriatoxin. 

The availability of benzocyclobutenes from cocycloadditions of 1,5-hexadiynes and hindered alkynes has been elaborated into an iterative synthesis of a variety of novel polycyclic biphenylene derivatives. 

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