Assembly line for biomolecules
The natural way of synthesis of complex molecules inspired a broad variety of iterative methods for an efficient creation of biomolecules. The EU-funded ALCAMS (Application of assembly line synthesis to the construction of biologically active molecules) project applied new methodology to the synthesis of functional complex biological molecules. ALCAMS’ unique methodology involves the reaction between a lithiated carbamate and a boronic ester to form the homologated product. This reaction can be done in an iterative manner without purification between steps. This allows the creation of complex molecules with complete control of both relative and absolute stereochemistry. The main novel idea was to use α-silyl carbenoids as masked-oxygen building blocks together with chiral lithiated benzoate esters in the iterative homologation process of boronic esters. This approach allows incorporating multiple silyl groups and methyl side-groups into carbon chains with full stereocontrol. Finally, carbon-silicon bonds can be oxidised stereospecifically, leading to the formation of the desired polypropionate core. This iterative method is dominated by reagent control, thereby enabling synthesis of different isomers with excellent levels of diastereoselectivity. After extensive investigation, scientists successfully developed new chiral silicon-containing building blocks to provide masked-oxygen functionality. Initially, generation of such intermediates in the presence of stoichiometric amounts of external chiral ligands led to the product’s formation with no selectivity under the lithiation-borylation reaction. However, the problem was solved by incorporating a chiral auxiliary side-arm into silyl moiety of the carbenoid precursor. Using the created carbenoid building blocks, researchers demonstrated their utility in the assembly-line synthesis of polypropionates. They found that the chiral auxiliary side-arms in the homologated product 19 could be removed under visible light photoredox conditions, yielding the methoxysilane 20. Finally, the methoxysilane intermediate 20 was subjected to two consecutive homologation sequences to provide the desired product 21 with high stereocontrol. In conclusion, ALCAMS developed a highly effective assembly-line synthesis protocol. An optimised protocol had to be developed for iterative homologation to ensure high fidelity and further application of this approach for the synthesis of polypropionate natural products.
Keywords
Biomolecules, complex molecules, ALCAMS, lithiated carbamate, boronic ester
