Late-stage functionalization (LSF) is a desired, chemical or biochemical,
chemoselectivetransformation on a complex molecule to provide at least one analog in sufficient quantity and purity for a given purpose without needing the addition of a
functional group that exclusively serves to enable said transformation.[1]
Molecular complexity is an
intrinsic property of each molecule and frequently determines the synthetic effort to make it.[2][3] LSF can significantly diminish this synthetic effort, and thus enables access to molecules, which would otherwise not be available or too difficult to access. The requirements for LSF can be met by both
C–H functionalization reactions and functional group manipulations.[1] LSF reactions are particularly relevant and often used in the fields of
drug discovery and
materials chemistry,[4][5][6] although no LSF has been implemented in a commercial process.
Chemoselectivity
Example for the distinction between LSF and a functional group tolerant reaction.[7]
All LSF reactions are
chemoselective but not every chemoselective reaction fulfills the requirements of the definition for LSF.[1] High
chemoselectivity is required for a useful LSF with a predictable reaction outcome because complex molecules typically feature several distinct
functional groups that need to be tolerated. In this sense, chemoselectivity is sometimes referred to as functional group tolerance. Furthermore, high chemoselectivity avoids often undesired over-functionalization of the valuable substrate, which is used as a limiting reagent in LSF reactions.[1]
Every
C–H bond functionalization on a complex molecule classifies as LSF, except when a directing or activating group must be installed in a previous step of the synthesis to accomplish the transformation. For functional group manipulations, the distinction between LSF and functional-group-tolerant reactions is more subtle. For example, peptide
bioconjugation reactions make use of the native functionality in
amino acid side chains, and thus classify as LSF. In contrast,
bioorthogonal1,3-dipolar cycloadditions (see also
copper-free click chemistry and
Huisgen cycloaddition) generally require prior introduction of azide or cycloalkyne functionalities to biomolecules. Hence, such transformations do not classify as LSF despite their excellent functional group tolerance.[1][7][8]
Site-selectivity
Example for a site-unselective LSF reaction for structural diversification.[9]
Site-selectivity, also positional or
regioselectivity, is generally desired but no requirement for LSF reactions because site-unselective LSF reactions can also be useful for special purposes. For example, site-unselective late-stage
C–H functionalization reactions can provide quick access to several constitutional isomers of complex molecules relevant for biological testing in
drug discovery.[1][4][5][9] Site-selective reactions to access each possible
constitutional isomer independently are scarce but highly desirable because cumbersome purification procedures are avoided, and other isomers are not produced as waste. Some LSF reactions provide one constitutional isomer in high selectivity based on innate substrate selectivity for a given reaction or based on
catalyst control. The discovery of site-selective LSF reactions constitutes an important research objective in the field of
synthetic methodology development.[1][10][11][12]
Example for a site-selective LSF reaction, in which the reagent discriminates between two innately reactive aromatic C–H bonds.[10]Example for an enzyme catalyzed LSF C–H oxygenation, in which site-selectivity is controlled by the enzyme catalyst.[11]