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Solid-phase organik syntheses - Burdges K.

Burdges K. Solid-phase organik syntheses - John Wiley & Sons, 2000. - 283 p.
ISBN 0-471-22824-9
Download (direct link): phaseorganicsynthesis2000.pdf
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This section outlines useful strategies for preparing aldehydes and hydroxamic acids that were developed on SynPhase crowns.
6.3.1. Linkers to Generate Aldehydes
Recently, we developed a simple and efficient aldehyde linker using crowns as the solid support.24 It consists of the amino acid threonine coupled to the crown via the carboxyl group, leaving the nucleophilic amino and alcohol functional groups free for oxazolidine formation with an aldehyde (Scheme 10). To investigate this attachment method, threonine was added to the Sasrin linker25 and a range of condensation conditions were then investigated. Benzaldehyde was used for the initial studies. The product formed was treated with 1% TFA-DCM, conditions that cleaved the Sasrin linker, but not the oxazolidine aldehyde linker. Variables included solvent (MeOH or DMF), additive (1% EtNPr2 or 1% AcOH), temperature (25 or 60C), time (2 or 18 h), and aldehyde concentration (0.1 M or 2 M). Product purities were assessed using analytical reverse-phase HPLC and ESMS.
Superior attachment conditions were identified as 0.1 M aldehyde in methanol with 1% NPr2Et for 2 h at 60C; these gave >90% incorporation. Additional experiments showed that the N'Pr2Et additive was not required.
The first conditions investigated for cleavage of the oxazolidine ring were 95% TFA-H20. These gave, at best, only 10% cleavage. Consideration of the cleavage mechanism suggested that increasing the water concentration and temperature might assist the reaction. Efficient cleavage was ultimately
Scheme 10.
achieved using 5% Ac0H-H20 at 60C for 30 min. Other mild aqueous acids, such as 0.1% TFA in 60% acetonitrile-water, also proved effective; this cleavage solution is more suitable when hydrophobic target compounds are being cleaved. Dependence on water concentration has proven advantageous because TFA labile protecting groups can be removed using 100% TFA prior to cleavage with mild aqueous acids at 60C. The linker is now routinely used for the synthesis of aldehydes, specifically libraries of potential protease inhibitors.
6.3.2. Linkers to Generate Hydroxamic Acids
Hydroxamic acids are key functional groups in some matrix metallopro-teinase (MMP) inhibitors. This observation has motivated several groups to develop linkers that give hydroxamic acids on cleavage.26-29 Prior to these publications, we had developed a route to hydroxamic acids based on the trityl linker.30 yV-hydroxyphthalamide was attached to the trityl linker on SynPhase crowns (Scheme 11). The phthalamide-protecting group was cleaved using hydrazine hydrate in DMSO and a carboxylic acid coupled to the hydroxylamine on the solid phase using DIC/HOBt to form the
(i) modify R

Scheme 11.
hydroxamate. On completion of the synthesis, cleavage was performed using 1% TFA-DCM for 30 min. Exclusion of water from the cleavage mixture is critical; use of 95%TFA-H20 causes significant hydrolysis of the hydroxamic acid to the corresponding carboxylic acid. We have found this linker to be very clean and efficient, with the steric bulk of the trityl group hindering unwanted side reactions by the nucleophilic hydroxamate nitrogen.
One-compound-per-well strategies for parallel syntheses require multiple additions. A library of 500 compounds prepared in 500 wells in three steps and using 5 x 10 x 10 reagents requires 1500 additions. Conversely, strategies featuring only one vial per reagent require far fewer additions. In that case, when, for example, 10 reagents are used in a particular step, only 10 vials per addition would be required. For 500 compounds made in three steps from 5 x 10 x 10 reagents, only 25 additions would be necessary.
Tagging the individual SynPhase crowns facilitates dramatic reduction in workload as outlined above. Unique tags identify the reaction history of the crown, instead of the grid position in the 8 x 12 array (Multipin) method. Coloring (in the stems and on attached tags) has been used in our laboratory as a tagging method for preparation of libraries of 800 compounds. This approach, however, does have limitations. Colors that can be used and easily distinguished are limited in number, and this form of coding is unsuitable when there is a need to unambiguously identify individual crowns in a mixed batch.
Radiofrequency tags3132 (i.e., transponders) facilitate manipulation of much larger and/or more complex libraries than color coding does. In this approach, read-only transponders are encapsulated in the removable polypropylene stem (called a TranStem; Figure 6.3) that clips into the crown. The transponders used in our system are manufactured by Baumer, who claim to be able to produce 264 unique codes. Consequently, TranStems uniquely identify each crown used in the synthesis. In practice, the TranStem with crown attached is passed in front of a radiofrequency reader (viz. antenna) to computer register the transponder code. A software package called TranSort manages the entire synthesis. For example, TranSort, which has a multimedia function, instructs the chemist both visually and verbally
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