Polymer-supported cyanoborohydride

The N-substituted aminoacids required could be prepared by microwave-assisted reductive amination of aminoacid methyl esters with aldehydes, and although in the Westman report soluble NaBH(OAc)3 was used to perform this step, other reports have shown how this transformation can be performed in using polymer-supported borohydrides (such as polymer-supported cyanoborohydride) under microwave irradiation [90]. An additional point of diversity could be inserted by use of a palladium-catalyzed reaction if suitably substituted aldehydes had been used. Again, these transformations might eventually be accomplished using supported palladium catalysts under microwave irradiation, as reported by several groups [91-93]. 

However, early attempts at synthesising compound arrays using polymer-supported reagents and automation proved to be problematic. Our group used an ACT 496 automated synthesiser to produce a 96-membered array of compounds in a single automated step. In this array, 12 aromatic aldehydes were reacted with eight aliphatic amines in the presence of polymer-supported cyanoborohydride to produce the corresponding secondary amines 33 (Scheme 11). 

Ley et al. have described the use of a combination of an oxidant, namely polymer-supported perruthenate 124, together with a reducing agent, namely polymer-supported cyanoborohydride 154. Readily available alcohols as primary feedstock were oxidized to intermediate 153 and further reacted with amines to afford more highly substituted amines, e.g., 155 (Scheme 29) [121]. 

Other analogs were also prepared from oxomaritidine by hydrogenation to give 24, which on reductive amination with polymer-supported cyanoborohydride afforded a small library of unnatural analogs based on the structure of 25. Obviously, many other derivatives would be possible given the efficiency of this route to the natural products, and clearly many of the intermediates, such as the spirodienone 23, could usefully be diverted to other combinatorial chemistry programs for further elaboration and decoration. 

The TOP sequence can also be carried out in the presence of a heterogeneous reductant to effect an oxidation-imination-reduc-tion process leading from activated alcohols to amines (eqs 86 and 87). Polymer-supported cyanoborohydride (PSCBH) or sodium borohydride can be used as the reductant. The use of an oxidant and reductant in the same one-pot procedure is noteworthy. 

Many borohydrides are highly unstable and have to be used as freshly prepared ethereal solutions. However there are instances where the polymer-supported versions are more stable e. g. an Amberlyst anion exchange resin supported borohydride and cyanoborohydride [61], polyvinylpyridine supported zinc borohydride [62] and the corresponding zirconium borohydride [63]. Such compounds, in their labeled forms, should turn out to be very useful. 

In a more recent study, polymer-bound borohydride was used for reductive ami-nation of tetrameric isoquinolines [116]. These tetrameric isoquinolines, serving as lead compounds in research to find antibacterial distamicyn A analogues, have been prepared from the corresponding isoquinoline, imidazole, and pyrrole building blocks by standard amide bond formation reactions. The final derivatization by reductive amination was efficiently accelerated by microwave irradiation in the presence of Merrifield resin-supported cyanoborohydride (Scheme 16.76). 

Polymer-supported sodium cyanoborohydride (PSCBH), now available commercially, has become more widely used. It is stable and effective even in the presence of oxidants, such as manganese dioxide, shown in this one pot oxidation-reduction amination protocol (eq 38). ... 

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