Furka split synthesis

Combinatorial synthesis on solid supports is usually carried out by using either the parallel synthesis (see section 6.2.1) or the Furka split and mix procedures (see section 6.2.2). The precise method and approach adopted when using these methods will depend on the nature of the combinatorial library being produced and also the objectives of the investigating team. However, in all cases it is necessary to determine the structures of the components of the library by either keeping a detailed record of the steps involved in the synthesis or giving beads a label that can be decoded to give the structure of the compound attached to that bead (see section 6.3). The method adopted to identify the components of the library will depend on the nature of the synthesis. 

It has been shown by Furka and his colleagues [27] that, in split synthesis, encoding becomes unnecessary if the spatial relation to each other of the... 

Split synthesis or one bead one compound was first described by Furka... 

What is clear is that all of these early combinatorial experiments had their basis in the solid-phase peptide synthesis developed in 1964 by Bruce Merrifield (see chapter 7). The Furka split-mix technique is outlined in the figure on page 337. For the sake of brevity, only 3 different components (X, Y, and Z) are depicted and only trimers (3 steps) are depicted so that the library has 3 entries (combinations). In practice, Furka was initially interested in peptide synthesis. If all 20 common amino acids are employed to make a library of pentapeptides, then the number of entries is 20 or 3.2 million. For a decapeptide, the library would have 1.02 x 10 entries. The use of solid-phase beads serves two purposes ... 

The mix-and-split method was a combinatorial synthesis pioneered by Furka in 1988. The method is illustrated in figure 7.4 with three reaction vessels, each of which contains large quantities of small resin beads. The first vessel is treated with amino acid A to start a peptide, the second vessel with B, and the third vessel with C. Then the beads from the three vessels are mixed together and divided equally into three vessels. In the second generation of processing, the first vessel is treated with amino acid D, the second vessel with E, and the third vessel with F. Now we have a library... 

The concept of reducing the number of reaction vessels and exponentially increasing the number of synthesized compounds was brought to a next level of simplicity by the split-and-pool method of Furka et al.5 The split-and-pool method was independently applied by Lam et al.6 in a one-bead-one-compound concept for the combinatorial synthesis of large compound arrays (libraries) and by Houghten et al.7 for the iterative libraries. Now several millions peptides could be synthesized in a few days. In Furka s method the resin beads receiving the same amino acid were contained in one reaction vessel—identical to Frank s method—however, the beads were pooled and then split randomly before each combinatorial step. Thus the method is referred to as the random split-and-pool method to differentiate it from Frank s method in which each solid-phase particle was directed into a particular reaction vessel (the directed split-and-pool method). 

An alternative method for tracking the chemical history is encoding by spatial address. The identity of each entity is defined by its spatial address. A one-dimensional directed split-and-pool procedure, referred to as necklace coding, has been developed for synthesis carried out on SynPhase Crowns and Lanterns.13 Individual supports are strung on a Teflon thread and the position of a particle on the thread (necklace) encoded the previous chemical history (Fig. 1). A similar concept was later reported by Furka and co-workers14,15 Two-and three-dimensional encoding of the directed split-and-pool synthesis platform has been patented by Selectide Corp.16... 

Outline the parallel synthesis technique for carrying out a combinatorial synthesis. How does this method differ from Furka s mix and split method ... 

Outline a design for a combinatorial synthesis for the formation of a combinatorial library of nine compounds with the general formula B using the Furka mix and split method. Outline any essential practical details. Details of the chemistry of peptide link formation are not required it is sufficient to say that it is formed. 

Outline the range of encoding methods used to deduce the structures of compounds produced in a Furka mix and split combinatorial synthesis. 

If solid phase is selected, use parallel synthesis or Furka s mix and split ... 

A Furka, JW Christensen, E Healy, HR Tanner, H Saneii. The string synthesis. A spatially addressable split procedure. J. Comb. Chem. 2 220-223, 2000. 

Furka and co-workers pioneered the split-pool synthesis method [19-22] for the synthesis of large peptide libraries in 1988 this approach is termed divide, couple, and recombine synthesis by other workers [44-47]. 

In 1985, Houghten [11] used this method in his tea bag approach described in section 3.4.4.2 of this chapter. As an elemental synthesis unit, instead of individual resin beads, he used small batches of resin packed into a polypropylene mesh. Furka [12,13] described the split/pool methodology for the synthesis of peptides. The peptides were cleaved and analyzed as mixtures and separated by HPLC as a rapid method for multiple peptide synthesis. In his work, Furka did not suggest explicitly to cleave individual compounds from individual beads. This seemingly obvious idea was recognized by Lam [14,15]. Split/pool synthesis was further developed and widely used by many others working in-the field of combinatorial chemistry [16]. The new Journal of Combinatorial Chemistry published a very interesting historical perspective on the major events in this field [17],... 

Recent reviews discuss the latest developments in DOS, which provide various examples leading to natural-like compound libraries (Cordier et al., 2008 Marcaurelle and Johannes, 2008). The split-mix solid-phase synthesis technology developed by Furka (Furka et al., 1991) is particularly useful for library generation using fhe DOS strategy leading to over a million members of libraries as mixtures. 

Synthesis of combinatorial arrays of compounds can, in principle, be performed three different ways. The Split and Mix (split and pool/recombine) concept introduced by Furka (4-6) is the most efficient method for preparation of sizable libraries (tens of thousands of compounds). However, the technique requires tracking of the chemical history of the resin beads and limits the quantity of synthesized material to the loading per solid phase unit (one unit can be represented by one particle, bead, lantern, etc., or one container, T-bag, Kan, etc.). Parallel synthesis, on the other hand, can supply any quantity per compound, but it requires handling large numbers of reaction vessels at one time. 

---