Late Stage Functionalisation
A late-stage functionalisation strategy was assessed for its ability to diversify OSM Series 4 compounds, exploring methods of C-H hydroxylation, fluorination and trifluoromethylation.
Methods of C-H substitution that occur through innate reactivity pathways were specifically explored, as it was hoped that such reactivity patterns would exhibit regionon-selectivity. Such non-selectivity would be advantageous for a drug development strategy, as it would allow the rapid synthesis of derivatives to be assessed for biological activity.
Further, innate methodologies such as hydrogen-atom transfer are biomimetic in their substitution pattern, reacting similarly to cytochrome P450 enzymes. This was hoped to confer enhanced metabolic stability to the derived molecules by substitution with a metabolically resistant atom (fluorine, deuterium, etc.).
Images and compound numbering are directly from thesis and so may not be in consecutive order
The late-stage installation of a hydroxyl group (-OH) into a drug-like molecule is a major area of research within the field of LSF. Hydroxylation can improve a lead compound's drug-like properties by increasing hydrophilicity, or by providing hydrogen bond donor and acceptor motifs to the molecule to better affect target-binding.
As a reactive polar protic group, hydroxyl typically requires protection when installed in earlier stages. Despite the obvious advantages of a late-stage method of C-H hydroxylation, there are still only a few methods able to perform such a transformation under mild conditions.
To produce a hydroxylated derivative of an active OSM Series 4 compound, we used two catalyst-based strategies, and two reagent-based strategies.
The two catalysts used have both previously demonstrated hydrogen substitution at unactivated aliphatic positions. The first catalyst, Fe(II)PDP (AKA Chen-White catalyst, 5) was chosen for its ability to hydroxylate unactivated sp3 C-H positions on complex molecules with high regioselectivity, while the second catalyst, Fe(II)TPA was chosen for its ability to functionalise simple substrates with low selectivity. The benzylic functionalised derivatives 40 and 41 were hypothesised to be the major products.
Using the iterative addition protocol (described in the original Chen-White paper) for both catalysts resulted in an intractable mixture that did not contain derivatised products. Starting material (58%) was reclaimed from the reaction using Fe(II)TPA as catalyst, while none reclaimed using Fe(II)PDP. Longer reaction times and slower oxidant addition times did not significantly affect the outcome.
With the failure of using catalytic methods to functionalise the substrate, we turned to a reagent-based method. Dimethyldioxirane (DMDO) (42) and methyl(trifluoromethyl)dioxirane (TFDO) (43) are three-membered ring peroxides, used as effective mild oxidising reagents with a wide variety of applications. TFDO is a similar oxidant to DMDO, but is more electrophilic due to the highly electron-withdrawing CF3 group, making it a useful alternative where DMDO fails. Rather than hydrogen-atom transfer, the mechanism of these reagents occurs through electrophilic oxygen atom transfer
Due to their sensitivity to heat and light, they are usually synthesised in low yield in a dilute solution with acetone/trifluoroacetone, by oxidation of acetone/trifluoroacetone with oxone (AKA potassium peroxymonosulfate). The volatile product is collected at -78 °C as a distillate via a cold finger condenser. Care must be taken to ensure glassware is free of any trace metal contaminants.
Attempts at using DMDO to afford a hydroxylated product of an OSM Series 4 compound were unsuccessful, with no conversion of starting material taking place. However, TFDO produced an oxidised derivative of 20 in low yield (44, 23%), with functionalisation occurring exclusively at the C8 position.
Unfortunately, this compound did not exhibit biological activity. Previous attempts at improving activity with hydroxylation at this position were also unsuccessful (MMV669025 and MMV675960).
Photochemical possibilities have been discussed in (Feb, May 2018)