NaTuRe CHeMiSTRy
Articles
2. Cernak, T., Dykstra, K. D., Tyagarajan, S., Vachal, P. & Krska, S. W. Te
medicinal chemist’s toolbox for late stage functionalization of drug-like
molecules. Chem. Soc. Rev. 45, 546–576 (2016).
small-molecule therapeutics will be empowered with 1 to rapidly
diversify aromatic drugs and natural products and quickly iden-
tify their metabolites. Future studies will probe the mechanism
that biases the relatively simple Mn(CF3–PDP) 1 catalyst system
towards methylene C–H oxidation and impedes non-productive
aromatic oxidation.
3. McMurray, L., O’Hara, F. & Gaunt, M. J. Recent developments in natural
product synthesis using metal-catalysed C–H bond functionalisation. Chem.
Soc. Rev. 40, 1885–1898 (2011).
4. Ford, M. C. & Ho, P. S. Computational tools to model halogen bonds in
medicinal chemistry. J. Med. Chem. 59, 1655–1670 (2016).
5. Ortiz de Montellano, P. R. (ed.) Cytochrome P450: Structure, Mechanism, and
Biochemistry (Springer, Berlin, 2015).
Methods
Method A: single catalyst addition protocol. A 40ml vial was charged with
substrate (0.3mmol, 1.0equiv.), Mn(CF3–PDP) 1 (0.03mmol, 10mol%),
ClCH2CO2H (425mg, 4.5mmol, 15.0equiv.) and a stir bar. Acetonitrile (MeCN,
0.6ml, 0.50M) was added along the wall to ensure all compounds were washed
beneath the solvent level and the vial was sealed with a screw cap ftted with a
polytetrafuoroethylene (PTFE)/silicone septum. Te vial was cooled to 0°C with
an ice/water bath. A separate solution of H2O2 ((204mg, 3.0mmol, 10.0equiv.),
50% (wt) in H2O, purchased from Sigma-Aldrich) in MeCN (3.75ml) was loaded
into a 10ml syringe ftted with a 25G needle and added dropwise to the stirring
reaction over 3h via a syringe pump (1.25mlh−1 addition rate) while maintaining
the reaction vial at 0°C. On completion, the reaction mixture was concentrated to
a minimum amount of solvent. Te residue was dissolved in ~20ml
dichloromethane (DCM) and washed with 9ml sat. NaHCO3 solution (caution:
CO2 released) to remove ClCH2CO2H. Te aqueous layer was extracted with
~15ml DCM twice and the combined organic layer was dried with Na2SO4.
Te fltrate was concentrated and purifed by fash chromatography on silica gel.
6. Mack, J. B. C., Gipson, J. D., Du Bois, J. & Sigman, M. S. Ruthenium-
catalyzed C–H hydroxylation in aqueous acid enables selective
functionalization of amine derivatives. J. Am. Chem. Soc. 139,
9503–9506 (2017).
7. Ottenbacher, R. V., Samsonenko, D. G., Talsi, E. P. & Bryliakov, K. P. Highly
efcient, regioselective, and stereospecifc oxidation of aliphatic C–H groups
with H2O2, catalyzed by aminopyridine manganese complexes. Org. Lett. 14,
4310–4313 (2012).
8. Adams, A. M., Du Bois, J. & Malik, H. A. Comparative study of the
limitations and challenges in atom-transfer C–H oxidations. Org. Lett. 17,
6066–6069 (2015).
9. Chen, M. S. & White, M. C. A predictably selective aliphatic C–H oxidation
reaction for complex molecule synthesis. Science 318, 783–787 (2007).
10. Chen, M. S. & White, M. C. Combined efects on selectivity in Fe-catalyzed
methylene oxidation. Science 327, 566–571 (2010).
11. Gormisky, P. E. & White, M. C. Catalyst-controlled aliphatic C–H
oxidations with a predictive model for site-selectivity. J. Am. Chem. Soc. 135,
14052–14055 (2013).
12. White, M. C. Adding aliphatic C–H bond oxidations to synthesis. Science
335, 807–809 (2012).
Method B: iterative catalyst addition protocol. A 40ml vial was charged
with substrate (0.3mmol, 1.0equiv.), Mn(CF3–PDP) 1 (0.015mmol, 5mol%),
ClCH2CO2H (425mg, 4.5mmol, 15.0equiv.) and a stir bar. MeCN (0.6ml, 0.50M)
was added along the wall to ensure all compounds were washed beneath the solvent
level and the vial was sealed with a screw cap fitted with a PTFE/silicone septum.
The vial was cooled to −36°C with a 1,2-dichloroethane/dry ice bath or to 0°C
with an ice/water bath. A separate solution of H2O2 (204mg, 3.0mmol, 10.0equiv.;
50% (wt) in H2O, purchased from Sigma-Aldrich) in MeCN (3.75ml) was loaded
into a 10ml syringe fitted with a 25G needle and added dropwise to the stirring
reaction over 3h via a syringe pump (1.25mlh−1 addition rate) while maintained
at the initial temperature set for the reaction (–36 °C or 0 °C). The initial time was
recorded as the time the first drop of H2O2 solution was added into the reaction.
One hour after the initial time, another batch of catalyst (0.015mmol, 5mol%)
was dissolved with 0.1ml MeCN in a 0.5-dram vial and added dropwise into the
reaction via syringe followed directly by another 0.1ml MeCN (used to rinse the
vial). The addition of 5mol% catalyst was repeated 2h after the initial time using
the same procedure. A total of 15mol% of catalyst was used in this protocol. On
completion, the reaction was worked up and purified as described in method A.
13. White, M. C. & Zhao, J. Aliphatic C–H oxidations for late-stage
functionalization. J. Am. Chem. Soc. 140, 13988–14009 (2018).
14. Paradine, S. M. et al. A manganese catalyst for highly reactive yet
chemoselective intramolecular C(sp3) –H amination. Nat. Chem. 7,
987–994 (2015).
15. Padwa, A. et al. Ligand efects on dirhodium(ii) carbene reactivities.
Highly efective switching between competitive carbenoid transformations.
J. Am. Chem. Soc. 115, 8669–8680 (1993).
16. Quinn, R. K. et al. Site-selective aliphatic C–H chlorination using N-
chloroamides enables a synthesis of chlorolissoclimide. J. Am. Chem. Soc.
138, 696–702 (2016).
17. Asensio, G., Castellano, G., Mello, R. & González Núñez, M. E.
Oxyfunctionalization of aliphatic esters by methyl(trifuoromethyl)dioxirane.
J. Org. Chem. 61, 5564–5566 (1996).
18. Kawamata, Y. et al. Scalable, electrochemical oxidation of unactivated C–H
bonds. J. Am. Chem. Soc. 139, 7448–7451 (2017).
Method C: slow catalyst addition protocol. A 40ml vial was charged with
substrate (0.3mmol, 1.0equiv.), ClCH2CO2H (425mg, 4.5mmol, 15.0equiv.)
and a stir bar. MeCN (0.6ml, 0.50M) was added along the wall to ensure all
compounds were washed beneath the solvent level and the vial was sealed with
a screw cap fitted with a PTFE/silicone septum. The vial was cooled to −36°C
with a 1,2-dichloroethane/dry ice bath or to 0°C with an ice/water bath. A 1.0ml
syringe was filled with a solution of Mn(CF3–PDP) 1 (0.03mmol, 10mol%) in
MeCN (0.375ml, 0.083M). A few drops of this solution were added to the reaction.
A 10ml syringe was filled with a solution of H2O2 (204mg, 3.0mmol, 10.0equiv.;
50% wt in H2O, purchased from Sigma-Aldrich) in MeCN (3.75ml, 0.8M). Both
syringes were fitted with 25G needles and loaded onto a syringe pump, providing
a slow simultaneous addition of catalyst and oxidant solutions over 3h while
maintaining the initial temperature set for the reaction (–36 °C or 0 °C) (1.25mlh−1
addition rate for the H2O2 syringe; 0.125mlh−1 for the catalyst syringe). On
completion, the reaction was worked up and purified as described in method A.
Synthetic procedures for Mn(CF3–PDP) 1 and for all substrates in the
19. Yosca, T. H. et al. Iron(iv)hydroxide pKa and the role of thiolate ligation in
C–H bond activation by cytochrome P450. Science 342, 825–829 (2013).
20. Gurof, G. et al. Hydroxylation-induced migration. Te NIH shif: recent
experiments reveal an unexpected and general result of enzymatic
hydroxylation of aromatic compounds. Science 157, 1524–1530 (1967).
21. Jeon, S. & Bruice, T. C. Redox chemistry of water-soluble iron, manganese,
and chromium metalloporphyrins and acid–base behavior of their lyate axial
ligands in aqueous solution: infuence of electronic efects. Inorg. Chem. 31,
4843–4848 (1992).
22. Chen, J. et al. Tuning the reactivity of mononuclear nonheme manganese(iv)-
oxo complexes by trific acid. Chem. Sci. 6, 3624–3632 (2015).
23. White, M. C., Doyle, A. G. & Jacobsen, E. N. A synthetically useful,
self-assembling MMO mimic system for catalytic alkene epoxidation with
aqueous H2O2. J. Am. Chem. Soc. 123, 7194–7195 (2001).
24. Bigi, M. A., Reed, S. A. & White, M. C. Directed metal (oxo) aliphatic
C–H hydroxylations: overriding substrate bias. J. Am. Chem. Soc. 134,
9721–9726 (2012).
manuscript are provided in Supplementary Sections II–IX.
25. Miao, C. et al. Proton-promoted and anion-enhanced epoxidation of
olefns by hydrogen peroxide in the presence of nonheme manganese
catalysts. J. Am. Chem. Soc. 138, 936–943 (2016).
Data availability
Crystallographic data for the structures reported in this Article have been
deposited at the Cambridge Crystallographic Data Centre (CCDC) under
deposition nos. CCDC 1869257 for (S,S)-5, CCDC 1869258 for 73, CCDC 1869259
Information, or from the corresponding author upon reasonable request.
26. Mas-Ballesté, R. & Que, L.Jr. Iron-catalyzed olefn epoxidation in the
presence of acetic acid: insights into the nature of the metal-based oxidant.
J. Am. Chem. Soc. 129, 15964–15972 (2007).
27. Marson, C. M. New and unusual scafolds in medicinal chemistry.
Chem. Soc. Rev. 40, 5514–5533 (2011).
28. Howell, J. M., Feng, K., Clark, J. R., Trzepkowski, L. J. & White, M. C.
Remote oxidation of aliphatic C–H bonds in nitrogen-containing molecules.
J. Am. Chem. Soc. 137, 14590–14593 (2015).
Received: 25 August 2018; Accepted: 18 October 2018;
Published: xx xx xxxx
29. Osberger, T. J., Rogness, D. C., Kohrt, J. T., Stepan, A. F. & White, M. C.
Oxidative diversifcation of amino acids and peptides by small-molecule iron
catalysis. Nature 537, 214–219 (2016).
References
30. Rennhack, A. et al. Synthesis of a potent photoreactive acidic gamma-
secretase modulator for target identifcation in cells. Bioorg. Med. Chem. 20,
6523–6532 (2012).
1. Blakemore, D. C. et al. Organic synthesis provides opportunities to transform
drug discovery. Nat. Chem. 10, 383–394 (2018).