La Marast synthesizer

In order to handle four reaetion vessels in parallel and to have a choice from four different washing solvents, the La Marast synthesizer is constructed with three four-port distribution Teflon valves (Fig. 3). Four reaction vessels are connected, via Teflon tubing, with the four ports of the V1 valve. The common port of the VI valve is conneeted to the common port of the four-port V2 valve. The port on the right-hand side is eonnected to the evacuated waste container. An empty syringe is attached to the upper port of the V2 valve. The lower port is left empty. The left-hand side port is eonneeted to the common port of the V3 valve. The four ports of the V3 valve are eonneeted to four reservoirs with solvents. All connections and wetted parts of valves are made of Teflon. The disposable reaction vessels are made of polypropylene. If dictated by a ehemi-cal protocol. Teflon reaction vessels could be used. 

The concept of liquid transfer is based on the same principle as that described for the La Marast synthesizer and uses an identical platform (Fig. 6). Obviously, having the same platform, a synthesizer can be used with a combination of the La Marast reaction vessels and Domino Blocks. 

In order to make washing resin beads very simple and to solve some of the inherent problems connected with the liquid transfer, we have developed and used two new concepts in our synthesizers. The liquid exchange in the La Marast and Domino Blocks is based on the evacuated reaction vessel concept (1). The Don Cucna synthesizer uses a suction principle for draining reaction vessels and a standard polypropylene 96-well plate as an integrated disposable reaction vessel (2). All synthesizers are commercially available (Torviq, Tucson, AZ, www.torviq.com). 

In addition to its very simple operation, the benefit of the La Marast (and also Domino Block) synthesizer is its complete enclosure. The contents of the reaction vessels need never be opened to the atmosphere, and, therefore, chemistry requiring an inert atmosphere can be performed. Dry solvent for the conditioning of resins or oxygen/moisture-sensitive reagents can be introduced directly from a septum-sealed container via a septum needle connected to any Solvent line. Alternatively, an enclosed syringe with the sensitive solution is coupled to the reagent port and the solution is introduced into reaction vessels. 

The principle of the split-split method is illustrated by an example of a three combinatorial step benzimidazole library that uses 24 amines, 12 o-fluoro-nitrobenzenes, and 48 acids, producing a library of 13,824 compounds (Scheme 1) (10), The first step can be performed in 24 La Marast reaction vessels, each containing 12 g of resin. For the second combinatorial step, resin from each La Marast reaction vessel is split into 24 syringes and the Domino Block synthesizer is used to handle the syringes. The last combinatorial step is performed in wells of 96-well plates, with the resin from each syringe being split into two rows (24 wells) of a plate. 

The La Marast and Domino Block synthesizers share the same principle and platform. As a result of this, Domino Blocks can he comhined with the La Marast reaction vessels on the same shaker, sharing the same valve system. Any port of the V1 valve can be connected either to a Domino Block or to a La Marast reaction vessel (compare Figs. 3 and 6). 

---