- Email: [email protected]
Streamlining Synthesis
POTENTIAL ENERGY
Streamlining Synthesis Stacy C. Fosu1,*
Stacy Fosu received her BS degree in chemistry from the University of Illinois at Urbana-Champaign in 2011. Working with Prof. Timothy Lash, she then went on to complete her MS degree from Illinois State University, where she developed syntheses of novel carbaporphyrinoid systems. She then joined The Ohio State University to pursue her PhD. She is currently a Howard Hughes Medical Institute Gilliam Fellow working with Prof. David Nagib to develop C–H functionalization methodologies toward medicinal applications. On my first day of grad school, I heard this great advice: ‘‘Every student starts graduate school the same way, but not everyone ends the same. Make yourself stand out for the better at the end.’’ During my first year, experiments obviously did not always work as planned. However, continually pushing myself and trying new, sometimes intimidating things in graduate school has improved me—as a chemist and as a person. As a member of the first
class of graduate students in the Nagib lab, I was privileged to see something start from nothing and grow into something even beyond my imagination. This was possible through the collaborative and supportive network my labmates and I built with each other. When we started our lab, we had the desire to create methods that could potentially be applied to solve big problems—in biology, medicine, and synthesis. In drug development, medicinal chemists spend ample time synthesizing various analogs of potential drug candidates to enhance desired efficacy. These multi-step synthetic sequences can create a bottleneck in the discovery process. Most organic transformations rely on interconversion of pre-installed reactive functional groups, although C–H bonds are abundant in organic molecules. However, with the development of C–H functionalization, an otherwise inert C–H bond can be transformed into a C–X bond (where X is a useful non-H atom or group) in one simple step, eliminating the need for pre-functionalization and thereby streamlining organic synthesis. To this end, our lab develops mild, radicalmediated C–H functionalization protocols for post-synthetic modification of complex molecules and construction of molecular cores often found in medicines. Aryl C–H In this issue of Chem,1 using simple, bench-stable reagents, my colleagues and I developed a mild protocol to efficiently halogenate and oxygenate a variety of arene and heteroarene motifs (Figure 1A). Our inspiration for this method stemmed from the unique reactivity of hypervalent iodine reagents. We envisioned that this oxidant could be activated to serve as a mediator to replace C–H bonds with valuable C–X and C–O bonds.
Using commercial PhI(OAc)2 and aqueous HCl or acyl chlorides, we developed an efficient chlorination method for arenes and heteroarenes. Chlorine is an important motif in medicines and provides a synthetic handle for further functional-group manipulation. We also expanded our C–H functionalization strategy to include bromination and oxygenation by using other Brønsted acids. Employing this simple strategy, we were able to quickly derivatize several drug and natural-product analogs. C–H Amination In addition to sp2 C–H functionalization, we were also interested in modifying sp3 C–H bonds. We were inspired by the d-selective amination of sp3 C–H bonds in the Hofmann-Lo¨ffler-Freytag (HLF) reaction (Figure 1B). Under traditional HLF conditions, pre-formed haloamines and refluxing strong acid are necessary to mediate this amination. As a result of these harsh conditions, efficient amination of unbiased secondary C–H bonds has remained an unmet challenge for the HLF mechanism. Once again, our solution to this dilemma was stimulated by iodine reagents. We proposed that if we were able to oxidize iodide to make iodine in situ and trap it as I3 , this would reduce the concentration of iodine in the reaction, which is prone to decomposition but still needed to form the active oxidant. This triiodidemediated approach would allow for a lower concentration of oxidant to curtail the production of side products. We found that through the combination of NaI and PhI(OAc)2, we were in fact able to generate a triiodide species. In turn, this enabled the selective formation of highly functionalized pyrrolidines. This method proved to be a mild alternative for the generation of
Chem 5, 251–253, February 14, 2019
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Figure 1. Strategies for Functionalization (Hetero)arenes (A), amines (B), allylic alcohols (C), and aldehydes (D).
N-centered radicals for selective C–H amination protocols.2 Radical Difunctionalization Building on the strategy of using N-centered radicals to achieve radicalmediated amination, we developed a difunctionalization protocol by using imidate radicals. This method enabled the selective amino-functionalization of allylic alcohols3 (Figure 1C). When allylic alcohols are added into nitriles to form imidates, they readily undergo the Overman rearrangement to produce allylic amines. We envisioned that we could bypass this well-known 2e pathway with a 1e mechanism. Initial reduction of the N–O bond of an oxime imidate under photocatalytic conditions produced an imidate radical, which selectively underwent 5-exo-trig cyclization. The subsequently generated alkyl radical was then capped with a H atom and after hydrolysis afforded 1,2-amino alcohols.
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Expanding upon this reactivity, we showed that the alkyl radical intermediate could be terminated with various C radical traps to afford amino-alkylation and amino-arylation products. Ketyl Radicals We have also demonstrated how ketyl radicals can be utilized for achieving difunctionalization through a 1e pathway (Figure 1D). These reactive intermediates reverse the polarity of carbonyls to construct valuable motifs through C–C bond formation. We found that simple aliphatic aldehydes can be transformed to the corresponding a-oxy iodides in one step with acetyl iodide. This lowers the reduction potential of the aldehydes by >1,200 mV, allowing milder reductants to form ketyl radicals. Under blue LED irradiation, the photocatalyst, Mn2(CO)10, is homolytically cleaved to reveal a 17 e Mn species, which can reduce the a-oxy iodide to
the corresponding ketyl radical. After the ketyl radical is added to the appropriate p- electrophile, Mn–I subsequently oxidizes the resulting vinyl radical to produce the vinyl iodide product via an atom-transfer radical addition. With these mild atom-transfer conditions, we were able to achieve carbonyl-alkyne couplings for a variety of carbonyls and p-electrophiles in a redox-neutral fashion.4 All these strategies take simple starting materials and transform them into more valuable motifs. In graduate school, I have also been transformed into a stronger person through all the obstacles I have encountered along the way. In the weeds of grad school, it can be difficult to see the finish line, and sometimes quitting might seem appealing. Yet, my resilience stems from the following desire: I want to be remembered for the positive impact that I have made. As I begin a new chapter after graduate school with my new career, I will
always remember that it doesn’t matter how I start. It matters how I finish. 1. Fosu, S.C., Hambira, C.M., Chen, A.D., Fuchs, J.R., and Nagib, D.A. (2019). Site-selective C–H functionalization of (hetero)arenes via transient, non-symmetric iodanes. Chem 5, this issue, 417–428.
2. Wappes, E.A., Fosu, S.C., Chopko, T.C., and Nagib, D.A. (2016). Triiodide-mediated damination of secondary C–H bonds. Angew. Chem. Int. Ed. 55, 9974–9978.
4. Wang, L., Lear, J.M., Rafferty, S.M., Fosu, S.C., and Nagib, D.A. (2018). Ketyl radical reactivity via atom transfer catalysis. Science 362, 225–229. 1Department
3. Nakafuku, K.M., Fosu, S.C., and Nagib, D.A. (2018). Catalytic alkene difunctionalization via imidate radicals. J. Am. Chem. Soc. 140, 11202–11205.
of Chemistry and Biochemistry, The Ohio State University, Columbus, OH 43210, USA *Correspondence: [email protected] https://doi.org/10.1016/j.chempr.2019.01.008
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Streamlining Synthesis Stacy C. Fosu1,*
Stacy Fosu received her BS degree in chemistry from the University of Illinois at Urbana-Champaign in 2011. Working with Prof. Timothy Lash, she then went on to complete her MS degree from Illinois State University, where she developed syntheses of novel carbaporphyrinoid systems. She then joined The Ohio State University to pursue her PhD. She is currently a Howard Hughes Medical Institute Gilliam Fellow working with Prof. David Nagib to develop C–H functionalization methodologies toward medicinal applications. On my first day of grad school, I heard this great advice: ‘‘Every student starts graduate school the same way, but not everyone ends the same. Make yourself stand out for the better at the end.’’ During my first year, experiments obviously did not always work as planned. However, continually pushing myself and trying new, sometimes intimidating things in graduate school has improved me—as a chemist and as a person. As a member of the first
class of graduate students in the Nagib lab, I was privileged to see something start from nothing and grow into something even beyond my imagination. This was possible through the collaborative and supportive network my labmates and I built with each other. When we started our lab, we had the desire to create methods that could potentially be applied to solve big problems—in biology, medicine, and synthesis. In drug development, medicinal chemists spend ample time synthesizing various analogs of potential drug candidates to enhance desired efficacy. These multi-step synthetic sequences can create a bottleneck in the discovery process. Most organic transformations rely on interconversion of pre-installed reactive functional groups, although C–H bonds are abundant in organic molecules. However, with the development of C–H functionalization, an otherwise inert C–H bond can be transformed into a C–X bond (where X is a useful non-H atom or group) in one simple step, eliminating the need for pre-functionalization and thereby streamlining organic synthesis. To this end, our lab develops mild, radicalmediated C–H functionalization protocols for post-synthetic modification of complex molecules and construction of molecular cores often found in medicines. Aryl C–H In this issue of Chem,1 using simple, bench-stable reagents, my colleagues and I developed a mild protocol to efficiently halogenate and oxygenate a variety of arene and heteroarene motifs (Figure 1A). Our inspiration for this method stemmed from the unique reactivity of hypervalent iodine reagents. We envisioned that this oxidant could be activated to serve as a mediator to replace C–H bonds with valuable C–X and C–O bonds.
Using commercial PhI(OAc)2 and aqueous HCl or acyl chlorides, we developed an efficient chlorination method for arenes and heteroarenes. Chlorine is an important motif in medicines and provides a synthetic handle for further functional-group manipulation. We also expanded our C–H functionalization strategy to include bromination and oxygenation by using other Brønsted acids. Employing this simple strategy, we were able to quickly derivatize several drug and natural-product analogs. C–H Amination In addition to sp2 C–H functionalization, we were also interested in modifying sp3 C–H bonds. We were inspired by the d-selective amination of sp3 C–H bonds in the Hofmann-Lo¨ffler-Freytag (HLF) reaction (Figure 1B). Under traditional HLF conditions, pre-formed haloamines and refluxing strong acid are necessary to mediate this amination. As a result of these harsh conditions, efficient amination of unbiased secondary C–H bonds has remained an unmet challenge for the HLF mechanism. Once again, our solution to this dilemma was stimulated by iodine reagents. We proposed that if we were able to oxidize iodide to make iodine in situ and trap it as I3 , this would reduce the concentration of iodine in the reaction, which is prone to decomposition but still needed to form the active oxidant. This triiodidemediated approach would allow for a lower concentration of oxidant to curtail the production of side products. We found that through the combination of NaI and PhI(OAc)2, we were in fact able to generate a triiodide species. In turn, this enabled the selective formation of highly functionalized pyrrolidines. This method proved to be a mild alternative for the generation of
Chem 5, 251–253, February 14, 2019
251
Figure 1. Strategies for Functionalization (Hetero)arenes (A), amines (B), allylic alcohols (C), and aldehydes (D).
N-centered radicals for selective C–H amination protocols.2 Radical Difunctionalization Building on the strategy of using N-centered radicals to achieve radicalmediated amination, we developed a difunctionalization protocol by using imidate radicals. This method enabled the selective amino-functionalization of allylic alcohols3 (Figure 1C). When allylic alcohols are added into nitriles to form imidates, they readily undergo the Overman rearrangement to produce allylic amines. We envisioned that we could bypass this well-known 2e pathway with a 1e mechanism. Initial reduction of the N–O bond of an oxime imidate under photocatalytic conditions produced an imidate radical, which selectively underwent 5-exo-trig cyclization. The subsequently generated alkyl radical was then capped with a H atom and after hydrolysis afforded 1,2-amino alcohols.
252
Chem 5, 251–253, February 14, 2019
Expanding upon this reactivity, we showed that the alkyl radical intermediate could be terminated with various C radical traps to afford amino-alkylation and amino-arylation products. Ketyl Radicals We have also demonstrated how ketyl radicals can be utilized for achieving difunctionalization through a 1e pathway (Figure 1D). These reactive intermediates reverse the polarity of carbonyls to construct valuable motifs through C–C bond formation. We found that simple aliphatic aldehydes can be transformed to the corresponding a-oxy iodides in one step with acetyl iodide. This lowers the reduction potential of the aldehydes by >1,200 mV, allowing milder reductants to form ketyl radicals. Under blue LED irradiation, the photocatalyst, Mn2(CO)10, is homolytically cleaved to reveal a 17 e Mn species, which can reduce the a-oxy iodide to
the corresponding ketyl radical. After the ketyl radical is added to the appropriate p- electrophile, Mn–I subsequently oxidizes the resulting vinyl radical to produce the vinyl iodide product via an atom-transfer radical addition. With these mild atom-transfer conditions, we were able to achieve carbonyl-alkyne couplings for a variety of carbonyls and p-electrophiles in a redox-neutral fashion.4 All these strategies take simple starting materials and transform them into more valuable motifs. In graduate school, I have also been transformed into a stronger person through all the obstacles I have encountered along the way. In the weeds of grad school, it can be difficult to see the finish line, and sometimes quitting might seem appealing. Yet, my resilience stems from the following desire: I want to be remembered for the positive impact that I have made. As I begin a new chapter after graduate school with my new career, I will
always remember that it doesn’t matter how I start. It matters how I finish. 1. Fosu, S.C., Hambira, C.M., Chen, A.D., Fuchs, J.R., and Nagib, D.A. (2019). Site-selective C–H functionalization of (hetero)arenes via transient, non-symmetric iodanes. Chem 5, this issue, 417–428.
2. Wappes, E.A., Fosu, S.C., Chopko, T.C., and Nagib, D.A. (2016). Triiodide-mediated damination of secondary C–H bonds. Angew. Chem. Int. Ed. 55, 9974–9978.
4. Wang, L., Lear, J.M., Rafferty, S.M., Fosu, S.C., and Nagib, D.A. (2018). Ketyl radical reactivity via atom transfer catalysis. Science 362, 225–229. 1Department
3. Nakafuku, K.M., Fosu, S.C., and Nagib, D.A. (2018). Catalytic alkene difunctionalization via imidate radicals. J. Am. Chem. Soc. 140, 11202–11205.
of Chemistry and Biochemistry, The Ohio State University, Columbus, OH 43210, USA *Correspondence: [email protected] https://doi.org/10.1016/j.chempr.2019.01.008
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