Domino block synthesizer

Ten reaction vessels are charged with 96 Lanterns each and the first combinatorial synthetic step is performed. A suitable reaction vessel is a 50-ml syringe and the synthesis can be performed on the Domino Block synthesizer (Torviq, Tucson, AZ). At this point, all the Lanterns in a reaction vessel are identical. There is no need to distinguish among Lanterns in one reaction vessel. 

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). 

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). 

Shaker platform Fig. 6. A synthesizer with four Domino Blocks. 

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. 

Another elimination triggered tetrafold anionic domino process has been reported by Risch and coworkers [301]. These authors synthesized polycyclic bipyridine scaffolds as 2-585 (Scheme 2.132) which are potentially useful as ligands for host-guest systems or interesting building blocks for supramolecular applications [302]. The process combines an amine elimination from 2-584 and a Michael addi-... 

Efficient and elegant syntheses of complex organic molecules with multiple stereogenic centers continue to be important in both academic and industrial laboratories (Nicolaou et al. 2003, 2006). In particular, catalytic asymmetric multicomponent domino reactions, used in the course total syntheses of natural products and synthetic building blocks, are highly desirable (Nicolaou et al. 2003, 2006 Tietze and Beifuss 1993 Tietze 1996 Tietze and Haunert 2000 Wasilke et al. 2005 Ramon and Yus 2005 Guo and Ma 2006 Pellissier 2006 Pellisier 2006 Tietze... 

In the build-couple-pair approach to library synthesis, the building blocks are first synthesized from commercial material (build phase), which are then coupled to form a substrate (couple phase) that can further react under certain conditions and pair itself intramolecularly to form the cyclic products depicting the scaffold framework [24]. It is in the last two steps that the domino reaction can intervene to yield a more complex scaffold and with higher ring diversity. 

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