View source for Late-stage functionalization

'''Late-stage functionalization''' (LSF) is a desired, chemical or biochemical, [[Chemoselectivity|chemoselective]] [[Chemical reaction|transformation]] 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.<ref name=":0">{{Cite journal|last1=Börgel|first1=Jonas|last2=Ritter|first2=Tobias|date=2020-08-06|title=Late-Stage Functionalization|journal=Chem|language=English|volume=6|issue=8|pages=1877–1887|doi=10.1016/j.chempr.2020.07.007|issn=2451-9294|doi-access=free}}</ref>

Molecular complexity is an [[intrinsic property]] of each molecule and frequently determines the synthetic effort to make it.<ref>{{Cite journal|last1=von Korff|first1=Modest|last2=Sander|first2=Thomas|date=2019-01-30|title=Molecular Complexity Calculated by Fractal Dimension|journal=Scientific Reports|language=en|volume=9|issue=1|pages=967|doi=10.1038/s41598-018-37253-8|pmid=30700728|pmc=6353876|bibcode=2019NatSR...9..967V|issn=2045-2322}}</ref><ref>{{Cite journal|last1=Corey|first1=E. J.|last2=Wipke|first2=W. Todd|date=1969-10-10|title=Computer-Assisted Design of Complex Organic Syntheses|url=https://www.science.org/doi/10.1126/science.166.3902.178|journal=Science|language=en|volume=166|issue=3902|pages=178–192|doi=10.1126/science.166.3902.178|issn=0036-8075|pmid=17731475|bibcode=1969Sci...166..178C}}</ref> 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|C–H functionalization]] reactions and functional group manipulations.<ref name=":0" /> LSF reactions are particularly relevant and often used in the fields of [[drug discovery]] and [[Materials Chemistry|materials chemistry]],<ref name=":1">{{Cite journal|last1=Cernak|first1=Tim|last2=Dykstra|first2=Kevin D.|last3=Tyagarajan|first3=Sriram|last4=Vachal|first4=Petr|last5=Krska|first5=Shane W.|date=2016-02-01|title=The medicinal chemist's toolbox for late stage functionalization of drug-like molecules|url=https://pubs.rsc.org/en/content/articlelanding/2016/cs/c5cs00628g|journal=Chemical Society Reviews|language=en|volume=45|issue=3|pages=546–576|doi=10.1039/C5CS00628G|pmid=26507237|issn=1460-4744}}</ref><ref name=":2">{{Cite journal|last1=Moir|first1=Michael|last2=Danon|first2=Jonathan J.|last3=Reekie|first3=Tristan A.|last4=Kassiou|first4=Michael|date=2019-11-02|title=An overview of late-stage functionalization in today's drug discovery|url=https://doi.org/10.1080/17460441.2019.1653850|journal=Expert Opinion on Drug Discovery|volume=14|issue=11|pages=1137–1149|doi=10.1080/17460441.2019.1653850|issn=1746-0441|pmid=31411499|hdl=1885/213256|s2cid=199572352|hdl-access=free}}</ref><ref>{{Cite journal|last1=Wencel-Delord|first1=Joanna|last2=Glorius|first2=Frank|date=2013-04-23|title=C–H bond activation enables the rapid construction and late-stage diversification of functional molecules|url=https://www.nature.com/articles/nchem.1607|journal=Nature Chemistry|language=en|volume=5|issue=5|pages=369–375|doi=10.1038/nchem.1607|pmid=23609086|bibcode=2013NatCh...5..369W|issn=1755-4349}}</ref> although no LSF has been implemented in a commercial process.

== Chemoselectivity ==
[[File:Distinction LSF and chemoselective reaction.tif|thumb|500x500px|Example for the distinction between LSF and a functional group tolerant reaction.<ref name=":3">{{Cite journal|last1=Lin|first1=Shixian|last2=Yang|first2=Xiaoyu|last3=Jia|first3=Shang|last4=Weeks|first4=Amy M.|last5=Hornsby|first5=Michael|last6=Lee|first6=Peter S.|last7=Nichiporuk|first7=Rita V.|last8=Iavarone|first8=Anthony T.|last9=Wells|first9=James A.|last10=Toste|first10=F. Dean|last11=Chang|first11=Christopher J.|date=2017-02-10|title=Redox-based reagents for chemoselective methionine bioconjugation|journal=Science|language=en|volume=355|issue=6325|pages=597–602|doi=10.1126/science.aal3316|issn=0036-8075|pmid=28183972|pmc=5827972|bibcode=2017Sci...355..597L|osti=1465412}}</ref>]]
All LSF reactions are [[Chemoselectivity|chemoselective]] but not every chemoselective reaction fulfills the requirements of the definition for LSF.<ref name=":0" /> High [[chemoselectivity]] is required for a useful LSF with a predictable reaction outcome because complex molecules typically feature several distinct [[Functional group|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.<ref name=":0" />

Every [[C-H functionalization|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, [[Bioorthogonal chemistry|bioorthogonal]] [[1,3-Dipolar cycloaddition|1,3-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.<ref name=":0" /><ref name=":3" /><ref>{{Cite journal|last1=Jewett|first1=John C.|last2=Bertozzi|first2=Carolyn R.|date=2010-03-22|title=Cu-free click cycloaddition reactions in chemical biology|journal=Chemical Society Reviews|language=en|volume=39|issue=4|pages=1272–1279|doi=10.1039/B901970G|pmid=20349533|pmc=2865253|issn=1460-4744}}</ref>

== Site-selectivity ==
[[File:Example for a site-unselective LSF.tif|thumb|500x500px|Example for a site-unselective LSF reaction for structural diversification.<ref name=":4" />]]
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|C–H functionalization]] reactions can provide quick access to several constitutional isomers of complex molecules relevant for biological testing in [[drug discovery]].<ref name=":0" /><ref name=":1" /><ref name=":2" /><ref name=":4">{{Cite journal|last1=Nagib|first1=David A.|last2=MacMillan|first2=David W. C.|date=2011-12-08|title=Trifluoromethylation of arenes and heteroarenes by means of photoredox catalysis|journal=Nature|language=en|volume=480|issue=7376|pages=224–228|doi=10.1038/nature10647|pmid=22158245|pmc=3310175|bibcode=2011Natur.480..224N|issn=1476-4687}}</ref> 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 [[Catalysis|catalyst]] control. The discovery of site-selective LSF reactions constitutes an important research objective in the field of [[Chemical synthesis|synthetic]] methodology development.<ref name=":0" /><ref name=":5">{{Cite journal|last1=Berger|first1=Florian|last2=Plutschack|first2=Matthew B.|last3=Riegger|first3=Julian|last4=Yu|first4=Wanwan|last5=Speicher|first5=Samira|last6=Ho|first6=Matthew|last7=Frank|first7=Nils|last8=Ritter|first8=Tobias|date=2019-03-13|title=Site-selective and versatile aromatic C−H functionalization by thianthrenation|url=https://www.nature.com/articles/s41586-019-0982-0|journal=Nature|language=en|volume=567|issue=7747|pages=223–228|doi=10.1038/s41586-019-0982-0|pmid=30867606|bibcode=2019Natur.567..223B|s2cid=76660453|issn=1476-4687}}</ref><ref name=":6">{{Cite journal|last1=Zhang|first1=Kaidong|last2=Shafer|first2=Brian M.|last3=Demars|first3=Matthew D.|last4=Stern|first4=Harry A.|last5=Fasan|first5=Rudi|date=2012-11-14|title=Controlled Oxidation of Remote sp3 C–H Bonds in Artemisinin via P450 Catalysts with Fine-Tuned Regio- and Stereoselectivity|url=https://doi.org/10.1021/ja3073462|journal=Journal of the American Chemical Society|volume=134|issue=45|pages=18695–18704|doi=10.1021/ja3073462|issn=0002-7863|pmc=3498520|pmid=23121379}}</ref><ref name=":7">{{Cite journal|last1=Lasso|first1=Juan D.|last2=Castillo-Pazos|first2=Durbis J.|last3=Li|first3=Chao-Jun|date=2021-10-04|title=Green chemistry meets medicinal chemistry: a perspective on modern metal-free late-stage functionalization reactions|url=https://pubs.rsc.org/en/content/articlelanding/2021/cs/d1cs00380a|journal=Chemical Society Reviews|language=en|volume=50|issue=19|pages=10955–10982|doi=10.1039/D1CS00380A|pmid=34382989 |s2cid=236988469 |issn=1460-4744}}</ref>
[[File:Wiki-III-selective LSF innate.tif|thumb|500x500px|Example for a site-selective LSF reaction, in which the reagent discriminates between two innately reactive aromatic C–H bonds.<ref name=":5" />]]
[[File:Site-selective LSF enzyme catalyst control.tif|thumb|500x500px|Example for an enzyme catalyzed LSF C–H oxygenation, in which site-selectivity is controlled by the enzyme catalyst.<ref name=":6" />]]
== References ==
{{reflist}}
[[Category:Molecules]]
[[Category:Transformation (function)]]