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Recent applications of CH functionalization in complex molecule synthesis
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Current Opinion in
Green and Sustainable Chemistry
Recent applications of CeH functionalization in complex molecule synthesis Kaiqi Chen and Xiaoguang Lei We have witnessed the striking advancement of CeH functionalization in organic synthesis over the past decade. This short review spotlights the very recent applications of CeH functionalization in natural product synthesis and drug synthesis. Some representative examples of natural product total synthesis facilitated by CeH functionalization are classified by CeO, CeC, CeN or C–X bond formation. Three different total syntheses are highlighted in details, in which iterative CeH functionalization strategy is involved. Another example of Merck’s synthesis of anacetrapib is also discussed to briefly demonstrate the broad application of CeH functionalization strategy in process chemistry of pharmaceutical industry. Addresses Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Department of Chemical Biology, College of Chemistry and Molecular Engineering, Synthetic and Functional Biomolecules Center, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China Corresponding author: Lei, Xiaoguang ([email protected])
Current Opinion in Green and Sustainable Chemistry 2018, 11:9–14 This review comes from a themed issue on Pharmaceuticals Edited by Fabrice Gallou and Kian Tan Available online 31 January 2018 https://doi.org/10.1016/j.cogsc.2018.01.001 2452-2236/© 2018 Elsevier B.V. All rights reserved.
Introduction We have witnessed the striking advancement of CeH functionalization in organic synthesis over the past decade [1,2]. The continuous development of new CeH functionalization methodologies allows us to achieve more efficient synthesis and modification of complex molecules. CeH functionalization has been increasingly used in the synthesis of both natural product and drug molecule. To construct the CeC or CeX bond, we need to transfer reactive functional groups to what we want in traditional methods. There is a potentially significant advantage to employing CeH functionalization over the conventional methods considering atom, redox and step economy. In addition, CeH functionalization is normally catalyzed by a transition metal, which has great potential in large-scale industrial production (Figure 1). www.sciencedirect.com
Applications of CeH functionalization in nature product total synthesis We have selected a few representative examples of natural product total synthesis facilitated by CeH functionalization which have been published in recent years (within 5 years). We sincerely apologize that due to the limited space we could not include all excellent works in the field. These examples are classified by CeO, CeC, CeN or CeX bond formation.
Constructing CeO bond via CeH functionalization Constructing CeO bond through CeH functionalization has been used in total synthesis widely [3e7]. In 2016, Baran group reported a nineteen-step total synthesis of (þ)-phorobol (Scheme 1a) [13]. In this approach, a CeH oxidation strategy was used to increase the oxidative state. The TMS-protected alcohol 1 was oxidized to compound 2 by TFDO. This method activated inert methylene to a hydroxyl group, which demonstrated the atom economy and redox economy of CeH functionalization. In the same year, Baran group also reported that the carbonyl or hydroxyl groups on the non-activated methylene and methyne groups could be obtained in a moderate to good yield by electrochemical oxidation (Scheme 1b) [14]. Respectively, silicon, free hydroxyl, amine, amide, lactone and other groups were tolerable during this process. (þ)-2-oxo-yahazunone was efficiently prepared from 50 g of compound 4, which proved the utility of this methodology.
Constructing CeC bond via CeH functionalization CeC bond formation enabled by CeH functionalization has been increasingly applied in natural product synthesis over the past decade [8e12]. In 2016, Zhang et al. disclosed a Rh-Catalyzed C(sp3)eH insertion strategy for the total synthesis of aplydactone (Scheme 1c) which is a successful example of late stage CeH functionalization from a a-diazoketone precursor [15]. In the CeH functionalization step, they also observed a C12eH insertion byproduct, the regioselective ratio is 1.8:1. This key intermediate finally allowed them to finish the total synthesis of aplydactone [16]. In the same year, Reisman and co-workers completed the first enantioselective synthesis of (þ)-psiguadial B (Scheme 1d) through a Pd-catalyzed CeH alkenylation strategy [17]. The alkenylation precursor was synthesized from
Current Opinion in Green and Sustainable Chemistry 2018, 11:9–14
10 Pharmaceuticals
Figure 1
Advantages of CeH functionalization.
diazo ketone through several transformations. Unexpectedly iodide 11 was an 8:1 mixture of olefin isomers, which was used in CeH allkenylation in the presence of Pd(OAc)2 and Ag2CO3 at 90 C. After 11 additional steps, aldehyde was transformed to (þ)-psiguadial B. Recently, Chen and co-workers reported the total synthesis of communesin F (Scheme 1e) via a late stage CeH functionalization [18]. The prerequisite oxalamide precursor was prepared from N-MOM-protected isatin easily. Fortunately, the late stage CeH allkenylation reaction proceeded smoothly on gram scale with high efficiency to generate the key intermediate 15.
Constructing CeN bond via CeH functionalization The Dueber, Yu and Sarpong groups jointly reported a formal synthesis of ()-herbindole B (Scheme 1f) via a Pd-catalyzed CeH functionalization strategy as a key transformation [19]. First, a Rh-catalyzed [2þ2þ1þ1] cycloaddition was used to prepare meso-hydroquinone. Then, triflamide was transformed to the desired product in the presence of catalytic [Pd(OTf)2(MeCN)2] at 100 C, and the compound 18 was obtained in moderate yield. Since compound 18 was an intermediate in the total synthesis of ()-herbindole B by Jackson and Kerr, thus a formal synthesis was achieved [20].
disclosed by Maimone and co-workers, using sequential CeH oxidation reactions [22]. The authors began their synthetic study by oxidizing the inert gem-dimethyl group of (þ)-cedrol, a cheap chemical reagent. During the synthesis, selective functionalization of a tertiary CeH bond in the presence of a number of other CeH bonds presented in acid 25 has been proven to be a formidable synthetic challenge. After extensive experimentation, the authors found Costas’ catalyst could directly activate the desired CeH bond. When treated with this iron catalyst, a putative oxidation product was obtained. Furthermore, silyl ether and methyl group cleavage products were obtained. After additional 6 steps, the total synthesis of pseudoanisatin was smoothly accomplished. In 2015, Baudoin and co-workers reported the total syntheses of aeruginosins 98B and 298A (Scheme 2b) [23]. Two different CeH activation reactions of methyl groups were used to construct the basic skeleton. One was used to prepare an indoline intermediate 31 and the other was applied to generate the functionalized aryl lactate 33. The first CeH allkenylation catalyzed by Pd(Pcy3)2 was performed in gram scale. With the two fragments in hand, they finally finished the total syntheses of aeruginosins 98B and 298A efficiently.
In 2016, the first chemical synthesis of (þ)-pseudoanisatin (Scheme 2a), a highly oxidative sesquiterpene, was
In 2016, Lei group disclosed the first total synthesis of ()-incarviation A (Scheme 2c), featuring sequential CeH functionalization reactions [24]. ()-Incarviatone A was first isolated by Zhang group in 2012 which showed notable potentials as a novel monoamine oxidase (MAO) inhibitor. In this route, Lei et al. used four scalable and sequential CeH functionalization reactions as well as a biomimetic cascade strategy to obtain the nature product. The synthesis started with ortho-CeH alkylation of phenylacetic acid. With large amount of acid 37 in hand, they turned to study Rh-catalyzed asymmetric CeH insertion to construct chiral dihydrobenzofuran structure. After extensive experiments, they found the desired trans-indane acid 39 could be obtained in 93% ee on gram scale using (þ)-borneyl as a chiral auxiliary. Next they used Yu’s methods to conduct the C8-iodination of acid 39. After extensive screening of different palladium catalysts and additives, they found Pd(dppf)2Cl2 was an optimal catalyst. Although the conversation was not very high, the yield based on recovered starting materials on gram scale was acceptable. After several steps, 41 was obtained in 70% overall yield from acid 40. Then they used Hartwig’s metaborylation method to transform 41 to 42 in 56% yield on 3 g scale. After additional 3 steps, the aldol precursor 43 was smoothly prepared. Finally a biomimetic cascade process was extensively investigated. Compound 43 was utilized to undergo the TBAF-mediated TBS deprotection, oxa-Michael addition, and intramolecular aldol reaction cascade sequentially to afford compound 44.
Current Opinion in Green and Sustainable Chemistry 2018, 11:9–14
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Constructing C–X bond via CeH functionalization CeH functionalization has been remarkably used for a direct transformation of an inert CeH bond to CeCl through visible light irradiation. In 2016, Vanderwal et al. disclosed a synthesis of (þ)-chlorolissoclimide (Scheme 1g) [21]. The synthesis started from CeH chlorination of cyclohexane as a model reaction, where chloroamide was identified as the best reagent to achieve high selectivity and efficiency for monochlorination. Then this method was applied to the selective CeH chlorination of sclareolide to generate (þ)-chlorolissoclimide. Applying this strategy, compound 20 was converted to 2-chlorosclareolide with high efficiency on gram scale. In additional 8 steps, (þ)-chlorolissoclimide was prepared in 14% yield.
Iterative CeH functionalization strategy in natural product total synthesis
C-H Functionalization in Organic Synthesis Chen and Lei
11
Scheme 1
Selected recent examples of natural product synthesis applying CeH functionalization.
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Current Opinion in Green and Sustainable Chemistry 2018, 11:9–14
12 Pharmaceuticals
Scheme 2
Selected recent examples of sequential functionalization in natural product total synthesis.
Scheme 3
Scalable synthesis of anacetrapib via selective CeH Arylation. Current Opinion in Green and Sustainable Chemistry 2018, 11:9–14
www.sciencedirect.com
C-H Functionalization in Organic Synthesis Chen and Lei
13
Ultimately, the Suzuki coupling was applied to finish the total synthesis.
6.
Mccallum ME, Rasik CM, Wood JL, Brown MK: Collaborative total synthesis: routes to (±)-Hippolachnin a enabled by quadricyclane cycloaddition and late-stage C–H oxidation. J Am Chem Soc 2016, 138:2437–2442.
Application of CeH functionalization in drug molecule synthesis
7.
Rasik CM, Brown MK: Total synthesis of gracilioether F: development and application of lewis acid promoted ketene–alkene [2+2] cycloadditions and late-stage C-H oxidation. Angew Chem Int Ed 2014, 53:14522–14526.
8.
Xu ZJ, Wu YK: Efficient synthetic routes to (±)-Hippolachnin A, (±)-Gracilioethers E and F and the alleged structure of (±)-Gracilioether I. Chem Eur J 2017, 23:2026–2030.
9.
Wang B, Liu Y, Jiao R, Feng YQ, Li Q, Chen C, Liu L, He G, Chen G: Total synthesis of mannopeptimycins a and b. J Am Chem Soc 2016, 138:3926–3932.
As a powerful strategy, CeH functionalization has been broadly employed in medicinal and process chemistry for drug development. Anacetrapib, a potent and selective CETP inhibitor, was synthesized successfully in process chemistry by Merck via Ru-catalyzed CeH Functionalization (Scheme 3). [25,26], In this scalable synthesis, oxazoline was used as a directing group, which could be facilely transformed to the desired alcohol at latter stage. Using this strategy, anacetrapid was efficiently prepared in only 5 steps.
Conclusion To conclude, CeH functionalization has proven to be an extremely powerful approach in organic synthesis. It shows extraordinary atom, step and operational economy as well as remarkable flexibility for late stage structural modification. In addition, in some recent cases, CeH functionalization has demonstrated its scalability in multi-step synthesis of complex molecules. However, selective CeH functionalization remains a growing field and many significant synthetic challenges are yet to be solved. We hope this short review will stimulate the further development of robust CeH functionalization methods and inspire organic chemists to broadly use this approach to achieve highly efficient synthesis of complex molecules.
Acknowledgments We thank Prof. Chao Li (NIBS) and Dr. Benke Hong (Peking University) for helpful discussions. Financial support from the National Key Research and Development Program of China (2017YFA0505200), National High Technology Project 973 (2015CB856200) and NNSFC (21472010, 21521003, 21561142002 and 21625201) is gratefully acknowledged.
References Papers of particular interest, published within the period of review, have been highlighted as: * of special interest * * of outstanding interest
10. Panish RA, Chintala SR, Fox JM: A mixed-ligand chiral rhodium(II) catalyst enables the enantioselective total synthesis of piperarborenine B. Angew Chem Int Ed 2016, 55: 4983–4987. 11. Mercer JA, Cohen CM, Shuken SR, Wagner AM, Smith MW, Moss FRIII, Smith MD, Vahala R, Martinez AG, Boxer SG, Burns NZ: Chemical synthesis and self-assembly of a ladderane phospholipid. J Am Chem Soc 2016, 138: 15845–15848. 12. Cherney EC, Lopchuk JM, Green JC, Baran PS: A unified approach to ent-atisane diterpenes and related alkaloids: synthesis of (−)-Methyl atisenoate, (−)-Isoatisine, and the hetidine skeleton. J Am Chem Soc 2014, 136:12592–12595. 13. Kawamura S, Chu H, Felding J, Baran PS: Nineteen-step total * * synthesis of (+)-phorbol. Nature 2016, 532:90–93. The synthesis of phorbol employed the two-phase terpene synthesis strategy, carbocycle formation followed by CeH oxidation. 14. Kawamata Y, Yan M, Liu ZQ, Bao DH, Chen JS, Starr JT, * Baran PS: Scalable, electrochemical oxidation of unactivated C−H bonds. J Am Chem Soc 2017, 139:7448–7451. This work applies a method we can transfer non-actived methylene and methyne to carbonyl group or hydroxyl group. 15. Liu CG, Chen RZ, Shen Y, Liang ZH, Hua YH, Zhang YD: Total synthesis of aplydactone via a conformationally controlled C–H functionalization. Angew Chem Int Ed 2017, 56: 8187–8190. 16. Obradors C, Martinez RM, Shenvi RA: Ph(i-PrO)SiH2: an exceptional reductant for metal-catalyzed hydrogen atom transfers. J Am Chem Soc 2016, 138:4962–4971. 17. Chapman LM, Beck JC, Wu L, Reisman SE: Enantioselective total synthesis of (+)-Psiguadial B. J Am Chem Soc 2016, 138: 9803–9806. 18. Park J, Jean A, Chen DYK: Asymmetric total syntheses of * communesin F and a putative member of the communesin family. Angew Chem Int Ed 2017, 129:1–5. The syntheses were involved a late-stage CeH functionalization strategy in complex nature product skeleton.
1.
Gutekunst WR, Baran PS: C–H functionalization logic in total synthesis. Chem Soc Rev 2011, 40:1976–1991.
19. Leal RA, Bischof C, Lee YV, Sawano S, McAtee CC, Latimer LN, Russ ZN, Dueber JE, Yu JQ, Sarpong R: Application of a palladium-catalyzed C−H functionalization/indolization method to syntheses of cis-trikentrin A and herbindole B. Angew Chem Int Ed 2016, 128:12003–12007.
2.
Brady PB, Bhat V: Recent applications of Rh- and PdCatalyzed C(sp3)–H functionalization in natural product total synthesis. Eur J Org Chem 2017:5179–5190.
20. Jackson SK, Kerr MA: Total synthesis of (±)-herbindole A,(±)herbindole B, and (±)-cis-trikentrin A. J Org Chem 2007, 72: 1405–1411.
3.
Meng Z, Yu H, Li L, Tao WY, Chen H, Wan M, Yang P, Edmonds DJ, Zhang J, Li A: Total synthesis and antiviral activity of indolosesquiterpenoids from the xiamycin and oridamycin families. Nat Commun 2015, 6:6096.
4.
Siler DA, Mighion JD, Sorensen EJ: An enantiospecific synthesis of jiadifenolide. Angew Chem Int Ed 2014, 53: 5332–5335.
21. Quinn RK, Könst ZA, Michalak SE, Schmidt Y, Szklarski AR, Flores AR, Nam S, Horne DA, Vanderwal DC, Alexanian EJ: Siteselective aliphatic C–H chlorination using N-Chloroamides enables a synthesis of chlorolissoclimide. J Am Chem Soc 2016, 138:696–702.
5.
Sharpe RJ, Johnson JS: A global and local desymmetrization approach to the synthesis of steroidal alkaloids: stereocontrolled total synthesis of paspaline. J Am Chem Soc 2015, 137:4968–4971.
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22. Hung K, Condakes ML, Morikawa T, Maimone TJ: Oxidative entry into the illicium sesquiterpenes: enantiospecific synthesis of (+)-Pseudoanisatin. J Am Chem Soc 2016, 138: 16616–16619. 23. Dailler D, Danoun G, Baudoin O: A general and scalable synthesis of aeruginosin marine natural products based on two Current Opinion in Green and Sustainable Chemistry 2018, 11:9–14
14 Pharmaceuticals
strategic C (sp3)-H activation reactions. Angew Chem Int Ed 2015, 54:4919–4922. 24. Hong B, Li C, Wang Z, Chen J, Li HH, Lei XG: Enantioselective * * total synthesis of (−)-Incarviatone A. J Am Chem Soc 2015, 137:11946–11949. This work provides an example how to use sequential CeH functionalization and a biomimetic cascade to do the total synthesis of complex nature product.
Current Opinion in Green and Sustainable Chemistry 2018, 11:9–14
25. Ouellet SG, Roy A, Molinaro C, Angelaud R, Marcoux JF, O’Shea PD, Davies IW: Preparative scale synthesis of the biaryl core of anacetrapib via a ruthenium-catalyzed direct arylation reaction: unexpected effect of solvent impurity on the arylation reaction. J Org Chem 2011, 76:1436–1439. 26. Seki M: A new catalytic system for Ru-Catalyzed C–H arylation reactions and its application in the practical syntheses of pharmaceutical agents. Org Process Res Dev 2016, 20:867–877.
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ScienceDirect
Current Opinion in
Green and Sustainable Chemistry
Recent applications of CeH functionalization in complex molecule synthesis Kaiqi Chen and Xiaoguang Lei We have witnessed the striking advancement of CeH functionalization in organic synthesis over the past decade. This short review spotlights the very recent applications of CeH functionalization in natural product synthesis and drug synthesis. Some representative examples of natural product total synthesis facilitated by CeH functionalization are classified by CeO, CeC, CeN or C–X bond formation. Three different total syntheses are highlighted in details, in which iterative CeH functionalization strategy is involved. Another example of Merck’s synthesis of anacetrapib is also discussed to briefly demonstrate the broad application of CeH functionalization strategy in process chemistry of pharmaceutical industry. Addresses Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Department of Chemical Biology, College of Chemistry and Molecular Engineering, Synthetic and Functional Biomolecules Center, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China Corresponding author: Lei, Xiaoguang ([email protected])
Current Opinion in Green and Sustainable Chemistry 2018, 11:9–14 This review comes from a themed issue on Pharmaceuticals Edited by Fabrice Gallou and Kian Tan Available online 31 January 2018 https://doi.org/10.1016/j.cogsc.2018.01.001 2452-2236/© 2018 Elsevier B.V. All rights reserved.
Introduction We have witnessed the striking advancement of CeH functionalization in organic synthesis over the past decade [1,2]. The continuous development of new CeH functionalization methodologies allows us to achieve more efficient synthesis and modification of complex molecules. CeH functionalization has been increasingly used in the synthesis of both natural product and drug molecule. To construct the CeC or CeX bond, we need to transfer reactive functional groups to what we want in traditional methods. There is a potentially significant advantage to employing CeH functionalization over the conventional methods considering atom, redox and step economy. In addition, CeH functionalization is normally catalyzed by a transition metal, which has great potential in large-scale industrial production (Figure 1). www.sciencedirect.com
Applications of CeH functionalization in nature product total synthesis We have selected a few representative examples of natural product total synthesis facilitated by CeH functionalization which have been published in recent years (within 5 years). We sincerely apologize that due to the limited space we could not include all excellent works in the field. These examples are classified by CeO, CeC, CeN or CeX bond formation.
Constructing CeO bond via CeH functionalization Constructing CeO bond through CeH functionalization has been used in total synthesis widely [3e7]. In 2016, Baran group reported a nineteen-step total synthesis of (þ)-phorobol (Scheme 1a) [13]. In this approach, a CeH oxidation strategy was used to increase the oxidative state. The TMS-protected alcohol 1 was oxidized to compound 2 by TFDO. This method activated inert methylene to a hydroxyl group, which demonstrated the atom economy and redox economy of CeH functionalization. In the same year, Baran group also reported that the carbonyl or hydroxyl groups on the non-activated methylene and methyne groups could be obtained in a moderate to good yield by electrochemical oxidation (Scheme 1b) [14]. Respectively, silicon, free hydroxyl, amine, amide, lactone and other groups were tolerable during this process. (þ)-2-oxo-yahazunone was efficiently prepared from 50 g of compound 4, which proved the utility of this methodology.
Constructing CeC bond via CeH functionalization CeC bond formation enabled by CeH functionalization has been increasingly applied in natural product synthesis over the past decade [8e12]. In 2016, Zhang et al. disclosed a Rh-Catalyzed C(sp3)eH insertion strategy for the total synthesis of aplydactone (Scheme 1c) which is a successful example of late stage CeH functionalization from a a-diazoketone precursor [15]. In the CeH functionalization step, they also observed a C12eH insertion byproduct, the regioselective ratio is 1.8:1. This key intermediate finally allowed them to finish the total synthesis of aplydactone [16]. In the same year, Reisman and co-workers completed the first enantioselective synthesis of (þ)-psiguadial B (Scheme 1d) through a Pd-catalyzed CeH alkenylation strategy [17]. The alkenylation precursor was synthesized from
Current Opinion in Green and Sustainable Chemistry 2018, 11:9–14
10 Pharmaceuticals
Figure 1
Advantages of CeH functionalization.
diazo ketone through several transformations. Unexpectedly iodide 11 was an 8:1 mixture of olefin isomers, which was used in CeH allkenylation in the presence of Pd(OAc)2 and Ag2CO3 at 90 C. After 11 additional steps, aldehyde was transformed to (þ)-psiguadial B. Recently, Chen and co-workers reported the total synthesis of communesin F (Scheme 1e) via a late stage CeH functionalization [18]. The prerequisite oxalamide precursor was prepared from N-MOM-protected isatin easily. Fortunately, the late stage CeH allkenylation reaction proceeded smoothly on gram scale with high efficiency to generate the key intermediate 15.
Constructing CeN bond via CeH functionalization The Dueber, Yu and Sarpong groups jointly reported a formal synthesis of ()-herbindole B (Scheme 1f) via a Pd-catalyzed CeH functionalization strategy as a key transformation [19]. First, a Rh-catalyzed [2þ2þ1þ1] cycloaddition was used to prepare meso-hydroquinone. Then, triflamide was transformed to the desired product in the presence of catalytic [Pd(OTf)2(MeCN)2] at 100 C, and the compound 18 was obtained in moderate yield. Since compound 18 was an intermediate in the total synthesis of ()-herbindole B by Jackson and Kerr, thus a formal synthesis was achieved [20].
disclosed by Maimone and co-workers, using sequential CeH oxidation reactions [22]. The authors began their synthetic study by oxidizing the inert gem-dimethyl group of (þ)-cedrol, a cheap chemical reagent. During the synthesis, selective functionalization of a tertiary CeH bond in the presence of a number of other CeH bonds presented in acid 25 has been proven to be a formidable synthetic challenge. After extensive experimentation, the authors found Costas’ catalyst could directly activate the desired CeH bond. When treated with this iron catalyst, a putative oxidation product was obtained. Furthermore, silyl ether and methyl group cleavage products were obtained. After additional 6 steps, the total synthesis of pseudoanisatin was smoothly accomplished. In 2015, Baudoin and co-workers reported the total syntheses of aeruginosins 98B and 298A (Scheme 2b) [23]. Two different CeH activation reactions of methyl groups were used to construct the basic skeleton. One was used to prepare an indoline intermediate 31 and the other was applied to generate the functionalized aryl lactate 33. The first CeH allkenylation catalyzed by Pd(Pcy3)2 was performed in gram scale. With the two fragments in hand, they finally finished the total syntheses of aeruginosins 98B and 298A efficiently.
In 2016, the first chemical synthesis of (þ)-pseudoanisatin (Scheme 2a), a highly oxidative sesquiterpene, was
In 2016, Lei group disclosed the first total synthesis of ()-incarviation A (Scheme 2c), featuring sequential CeH functionalization reactions [24]. ()-Incarviatone A was first isolated by Zhang group in 2012 which showed notable potentials as a novel monoamine oxidase (MAO) inhibitor. In this route, Lei et al. used four scalable and sequential CeH functionalization reactions as well as a biomimetic cascade strategy to obtain the nature product. The synthesis started with ortho-CeH alkylation of phenylacetic acid. With large amount of acid 37 in hand, they turned to study Rh-catalyzed asymmetric CeH insertion to construct chiral dihydrobenzofuran structure. After extensive experiments, they found the desired trans-indane acid 39 could be obtained in 93% ee on gram scale using (þ)-borneyl as a chiral auxiliary. Next they used Yu’s methods to conduct the C8-iodination of acid 39. After extensive screening of different palladium catalysts and additives, they found Pd(dppf)2Cl2 was an optimal catalyst. Although the conversation was not very high, the yield based on recovered starting materials on gram scale was acceptable. After several steps, 41 was obtained in 70% overall yield from acid 40. Then they used Hartwig’s metaborylation method to transform 41 to 42 in 56% yield on 3 g scale. After additional 3 steps, the aldol precursor 43 was smoothly prepared. Finally a biomimetic cascade process was extensively investigated. Compound 43 was utilized to undergo the TBAF-mediated TBS deprotection, oxa-Michael addition, and intramolecular aldol reaction cascade sequentially to afford compound 44.
Current Opinion in Green and Sustainable Chemistry 2018, 11:9–14
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Constructing C–X bond via CeH functionalization CeH functionalization has been remarkably used for a direct transformation of an inert CeH bond to CeCl through visible light irradiation. In 2016, Vanderwal et al. disclosed a synthesis of (þ)-chlorolissoclimide (Scheme 1g) [21]. The synthesis started from CeH chlorination of cyclohexane as a model reaction, where chloroamide was identified as the best reagent to achieve high selectivity and efficiency for monochlorination. Then this method was applied to the selective CeH chlorination of sclareolide to generate (þ)-chlorolissoclimide. Applying this strategy, compound 20 was converted to 2-chlorosclareolide with high efficiency on gram scale. In additional 8 steps, (þ)-chlorolissoclimide was prepared in 14% yield.
Iterative CeH functionalization strategy in natural product total synthesis
C-H Functionalization in Organic Synthesis Chen and Lei
11
Scheme 1
Selected recent examples of natural product synthesis applying CeH functionalization.
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Current Opinion in Green and Sustainable Chemistry 2018, 11:9–14
12 Pharmaceuticals
Scheme 2
Selected recent examples of sequential functionalization in natural product total synthesis.
Scheme 3
Scalable synthesis of anacetrapib via selective CeH Arylation. Current Opinion in Green and Sustainable Chemistry 2018, 11:9–14
www.sciencedirect.com
C-H Functionalization in Organic Synthesis Chen and Lei
13
Ultimately, the Suzuki coupling was applied to finish the total synthesis.
6.
Mccallum ME, Rasik CM, Wood JL, Brown MK: Collaborative total synthesis: routes to (±)-Hippolachnin a enabled by quadricyclane cycloaddition and late-stage C–H oxidation. J Am Chem Soc 2016, 138:2437–2442.
Application of CeH functionalization in drug molecule synthesis
7.
Rasik CM, Brown MK: Total synthesis of gracilioether F: development and application of lewis acid promoted ketene–alkene [2+2] cycloadditions and late-stage C-H oxidation. Angew Chem Int Ed 2014, 53:14522–14526.
8.
Xu ZJ, Wu YK: Efficient synthetic routes to (±)-Hippolachnin A, (±)-Gracilioethers E and F and the alleged structure of (±)-Gracilioether I. Chem Eur J 2017, 23:2026–2030.
9.
Wang B, Liu Y, Jiao R, Feng YQ, Li Q, Chen C, Liu L, He G, Chen G: Total synthesis of mannopeptimycins a and b. J Am Chem Soc 2016, 138:3926–3932.
As a powerful strategy, CeH functionalization has been broadly employed in medicinal and process chemistry for drug development. Anacetrapib, a potent and selective CETP inhibitor, was synthesized successfully in process chemistry by Merck via Ru-catalyzed CeH Functionalization (Scheme 3). [25,26], In this scalable synthesis, oxazoline was used as a directing group, which could be facilely transformed to the desired alcohol at latter stage. Using this strategy, anacetrapid was efficiently prepared in only 5 steps.
Conclusion To conclude, CeH functionalization has proven to be an extremely powerful approach in organic synthesis. It shows extraordinary atom, step and operational economy as well as remarkable flexibility for late stage structural modification. In addition, in some recent cases, CeH functionalization has demonstrated its scalability in multi-step synthesis of complex molecules. However, selective CeH functionalization remains a growing field and many significant synthetic challenges are yet to be solved. We hope this short review will stimulate the further development of robust CeH functionalization methods and inspire organic chemists to broadly use this approach to achieve highly efficient synthesis of complex molecules.
Acknowledgments We thank Prof. Chao Li (NIBS) and Dr. Benke Hong (Peking University) for helpful discussions. Financial support from the National Key Research and Development Program of China (2017YFA0505200), National High Technology Project 973 (2015CB856200) and NNSFC (21472010, 21521003, 21561142002 and 21625201) is gratefully acknowledged.
References Papers of particular interest, published within the period of review, have been highlighted as: * of special interest * * of outstanding interest
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