Synthesis, automated

Scheme 1. Automated Synthesis of Oligonucleotides. Synthetic Cycle for the Phosphoroamidite Method.

Robert Bruce Merrifield (1921-2006) was born in Fori Worth, Texas, anti received his Ph.D. at the University oi California, Los Angeles, in 1949. He then joined the faculty at the Rockefeller Institute, where he remained until his death. In 1984, he was awarded the Nobel Prize in chemistry for his development of methods for the automated synthesis of peptides. 

Hoogenboom, R., Meier, M.A.R. and Schubert, U.S. (2003) Combinatorial methods, automated synthesis and high-throughput screening in polymer research past and present. Macro-mol. Rapid Commun., 24, 16. 

Furthermore, iterative approaches are useful methods to construct polyhydroxy chains with 1,2- or 1,3-diol units of any length as chiral precursors for the synthesis of complex natural products [57] because automated synthesis becomes feasible. A preparation of trans-fused polytetrahydropyranes as structural unit for polycyclic ether biotoxines by repeated reaction sequences was recently named reiterative synthesis [58]. 

Jacobsen proposed a related heterogeneous catalyst in which the complex is bound via an ester linkage to commercial hydroxymethylpolystyrene beads. Such catalysts are of value not only in large-scale processes, but also in the combinatorial automated synthesis of libraries of new compounds.180... 

A multipurpose mesofluidic flow reactor was developed for the automated synthesis of libraries of 4,5-disubstituted oxazoles. The process was based on the known reaction of alkylisocyanoacetates and acylchlorides <06OL5231>. 

G. Pourceau, A. Meyer, J.-J. Vasseur, and F. Morvan, Combinatorial and automated synthesis of phosphodiester galactosyl cluster on solid support by click chemistry assisted by microwaves, J. Org. Chem., 73 (2008) 6014—6017. 

F. Morvan, A. Meyer, A. Jochum, C. Sabin, Y. Chevolot, A. Imberty, J.-P. Praly, J.-J. Vasseur, E. Souteyrand, and S. Vidal, Fucosylated pentaerythrityl phosphodiester oligomers (PePOs) Automated synthesis of DNA-based glycoclusters and binding to Pseudomonas aeruginosa lectin (PA-IIL), Biocon-jug. Chem., 18 (2007) 1637-1643. 

Polymer-bound 1-hydroxybenzotriazole 1008 reacts with carboxylic acids in the presence of 1,3-diisopropylcarbo-diimide (1,3-DIC) and DMAP to produce esters 1009. Treated with hydroxylamine, esters 1009 are converted to hydroxamic acids 1010 (Scheme 167) <20030BC850>. Starting 1-hydroxybenzotriazole 1008 is recycled in the process and can be used for other syntheses. This method is well suited for automated synthesis of a library of hydroxamic acids. In similar applications of polymer-supported 1-hydroxybenzotriazole 1008, a wide variety of amides is synthesized <1997JOC2594, 2002JC0576>. 

Solid-supported technologies are already well established methods in medicinal chemistry and automated synthesis. Over the last couple of years new trends have evolved in this field which are of utmost importance as they have the potential to revolutionize the way chemical synthesis especially for library production is performed. Microchip-based synthesis technologies and multistep sequences with solid-supported catalysts or reagents in flow-through systems are only two spectacular examples. A new approach is the use of solid-supported systems for the scale-up of chemical reactions thereby enabling the rapid and smooth transition from discovery to development units. 

Adaptation of complete unit operation for automated synthesis required... 

Figure 11.27 Automated synthesis station (A) and top view of a 49-fold parallel reactor (B).

RB Merrifield, JM Stewart, N Jemberg. Instrument for automated synthesis of peptides. Anal Chem 38, 1905, 1966. 

JK Chang, M Shimuzu, S-S Wang. Fully automated synthesis of fully protected peptide hydrazides on recycling hydroxymethyl resin. J Org Chem 41, 3255, 1976. 

Cubic Phase of Boron Nitride c-BN. The cubic phase of boron nitride (c-BN) is one of the hardest materials, second only to diamond and with similar crystal structure. It is the first example of a new material theoretically predicted and then synthesized in laboratory. From automated synthesis a microcrystalline phase of cubic boron nitride is recovered at ambient conditions in a metastable state, providing the basic material for a wide range of cutting and grinding applications. Synthetic polycrystalline diamonds and nitrides are principally used as abrasives but in spite of the greater hardness of diamond, its employment as a superabrasive is limited by a relatively low chemical and thermal stability. Cubic boron nitride, on the contrary, has only half the hardness of diamond but an extremely high thermal stability and inertness. 

Peptides have many desirable properties as components of synthetic vectors. Peptide synthetic chemistry is well established, with the convenience of automated synthesis resulting in a well-defined, high-purity product of low toxicity and immunogenicity for in vivo use. Furthermore, even short peptides of 7 to 30 amino acids can accommodate enormous structural diversity, functionality, and combinations of properties. 

Size exclusion chromatography (SEC), also known as gel permeation chromatography (GPC), was used for the separation and fractionation of macromolecules on an analytical and preparative scale [17]. The separation occurs predominantly by the hydrodynamic volume of the macromolecules in solution, however, in some cases the polarity of the molecules can also influence the retention times. Like HPLC, the SEC technique is generally very reproducible with regard to its elution times (typically < 1 h) and hence can be used for automated synthesis. But because the cost for an automated SEC system is high, it must be considered as a serial separation technique. In addition, larger scale separations > 100 mg, usually require repetitive injection of small aliquots. 

An approach we term Virtual Screening of Virtual Libraries (VSVL) is intended to take advantage of our in-house automated synthesis capabilities. This involves the creation of large 3-D databases of virtual libraries using the Catalyst system [20]. Catalyst uses a prestored set of conformations for each molecule, so while construction of the... 

An important application of these precursors is the asymmetric synthesis of aminoacids, the key step being an enantioselective benzylation using a chiral auxiliary (route A, Scheme 25) [155] or a chiral phase transfer catalyst (PTC) [156] (route B, Scheme 25). This latter approach avoiding the use of dry reagents is particularly adapted to automated synthesis and enables the production of more than 7.4 GBq (200 mCi) of [6- F]fluoro-L-DOPA from 55.5 GBq (1.5 Ci) of starting [ F] fluoride [157]. 

This strategy using rapid automated synthesis of libraries of peptides and fluorescent screening of reactivity has allowed Miller to identify specific peptide-catalysts for specific applications such as the KR of an intermediate en route to an aziridomi-tosane [165,169], the KR of certain fert-alcohols [166], the regioselective acylation of carbohydrates [168], and finally the KR of AT-acylated fert-amino alcohols with s values from 19 to >50 (Scheme 21) [166],... 

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