Abstract
Chiral mono-N-protected aminomethyl oxazoline (MPAO) ligands are found to promote enantioselective C–H arylation and vinylation of the cyclobutyl carboxylic acid derivatives via Pd(II)/Pd(IV) redox catalysis. This ligand scaffold overcame two important limitations of the previous MPAHA (mono-N-protected α-amino-O-methylhydroxamic acid) ligands-enabled asymmetric C–H activation/C–C coupling reactions of cyclic carboxylic amides through Pd(II)/Pd(0) catalysis: substrates containing α-hydrogen atoms are not compatible; vinylation has not been developed. Sequential C–H arylation and vinylation of cyclobutanes are also accomplished to construct three consecutive chiral centers on the crowded cyclobutane rings, rendering this reaction highly versatile for the preparation of chiral cyclobutanes.
Keywords: C–H activation, MPAO ligands, cyclobutanes, α-hydrogen atom, vinylation
Graphical Abstract
1. Introduction
Cyclobutanes are prevalent motifs embedded in a diverse family of alkaloids, and important synthetic intermediates with unique bioactivity owing to their structural rigidity—a feature that is often desirable in drug design (Figure 1).1 Pipercyclobutanamide A demonstrate a selective inhibition of cytochrome P450 2D6 (CYP2D6) and Piperarborenine B was found to exhibite activity against P-388, A-549, and HT-29 cancer cell lines.2 Other natural products such as Incarvillateine as well as the synthetic SB-FI-26 containing the cyclobutane core have also exhibited promising biological activities.3 However, cyclobutanes are not widely present in marketed drugs, partially due to the lacking of concise, general, and especially enantioselective strategies for the synthesis of cyclobutanes.
Figure 1.
Biologically Active Compounds Containing Cyclobutanes
Enormous efforts have been devoted to the development of efficient synthetic protocols for the enantioselective construction of cyclobutane skeletons.4 Despite the remarkable progress on the asymmetric cyclobutanations and enantioselective functionalizations of cyclobutanes, constructing chiral cyclobutanes using exiting methods are not always successful depending on the substitution pattern on the cyclobutyl rings. For example, current methods for constructing three or four consecutive chiral centers on the cyclobutyl ring have extremely limited substrate scope.4 Thus, development of new strategies for the synthesis of enantiopure cyclobutanes remains an important task. Considering the challenges associated with the asymmetric ring forming reactions, rapid generation of chiral cyclobutanes through diversification of readily available cyclobutanes via enantioselective C–H activation offers an attractively alternative approach.5–8
The combination of mono-dentate coordinating substrates with three classes of bi-dentate chiral ligands has led to the development of a wide range of Pd(II)-catalyzed enantioselective C–H activation reactions.9–12 In 2014, our group disclosed the first example of Pd(II)-catalyzed enantioselective cross-coupling of methylene β-C–H bonds in cyclobutyl carboxylic acid derivatives with arylboron reagents using the mono-N-protected α-amino-O-methylhydroxamic acid (MPAHA) ligands (Scheme 1).7 However, cyclobutane substrates containing α-hydrogen atoms gave poor yields and enantioselectivities (25% yield, 77:23 er). Recently, we reported the first example of Pd(II)-catalyzed enantioselective β-C–H borylation of carboxylic acid derivatives.8 Using MPAO ligands, a range of cyclic carboxylic acid derivatives were borylated with bis(pinacolato)diboron in high yields and enantioselectivities. While this C–H borylation can tolerate α-hydrogen atoms, subsequent synthetic elaborations of the congested chiral cyclobutyl borons are limited in scope and efficiency. Despite these preliminary advances through Pd(II)/Pd(0) catalysis, enantioselective C–H functionalizations of cyclobutyl carboxylic amides suffers from severe limitations: arylation with Ar-Bpin is not compatible with α-hydrogen atoms;7 transformations are limited to arylation7 and borylation.8 The development of broadly useful enantioselective C–H activation/C–C coupling reactions of cyclobutane substrates containing α-hydrogen atoms has two-fold challenges: substrates bearing α-hydrogen atom are significantly less reactive than that bearing quaternary centers due to Thorpe-Ingold effect; the presence of the small α-hydrogen atom instead of an α-alkyl group renders the chiral differentiation more challenging as the latter has a bulkier steric influence. These obstacles are reflected by a significant decrease in both yield and enantioselectivity when α-hydrogen atom-containing substrate is employed in our previous enantioselective arylation reaction.7
Scheme 1.
Enantioselective C–H Functionalization of Cyclobutyl Carboxylic Amide
Herein, we report a Pd(II)-catalyzed enantioselective arylation of the cyclobutyl carboxylic amide bearing α-hydrogen atoms using chiral mono-N-protected aminomethyl oxazoline (MPAO) ligands. Enantioselective C(sp3)–H vinylation of cyclobutyl carboxylic amide is developed for the first time. Compared to our previous enantioselective C–H arylation of cyclobutyl amides via Pd(II)/Pd(0) catalysis, the MPAO ligand enabled Pd(II)/Pd(IV) catalysis entails significantly broader substrate scope. The sequential C–H arylation and vinylation also successfully construct three consecutive chiral centers on crowded cyclobutane rings, which are still challenging for previous ring forming methods.4
2. Results and Discussion
2.1 Arylation of Cyclobutyl Carboxylic Amide
The presence of multiple β-C–H bonds in simple mono-substituted cyclobutanes offers possibility for sequential di-C–H functionalizations. If both mono/di- selectivity and stereoselectivity can be controlled, such diversification processes using various coupling partners could provide a large number of chiral cyclobutane compounds that are difficult to access using existing methods. Our experimental efforts began with establishing conditions for the enantioselective C(sp3)–H arylation of the readily available cyclobutyl carboxylic amide 1 (Table 1). Brief survey of reaction conditions led to the initial finding of encouraging reactivity. Substrate 1 was stirred with 2.0 equiv. of 4-iodotoluene in the presence of 10 mol% of Pd(MeCN)2Cl2, 10 mol% of the chiral bi-dentate ligand L1, and 2.0 equiv. of Ag2CO3 (in CHCl3 at 80 °C for 24 h). The arylated product 2a was obtained in 20% yield, albeit in racemic form (entry 1, Table 1). Switch to ligand L2 containing a chiral side chain and achiral oxazoline moiety gave a slightly improved yield, and most importantly, moderate enantioselectivity (50% yield, 75:25 er, entry 2). While L3 containing both chiral centers gave poor yield and enantioselectivity (26% yield, 68:32 er, entry 3), the diastereomer L4 significantly improved both the yield and enantioselectivity (63% yield, 95.5:4.5 er, entry 4). Increasing the steric hindrance on the oxazoline ring (L5) only improved the yield and enantioselectivity slightly (65% yield, 96:4 er, entry 5). Ligand containing bulky tert-butyl group on the oxazoline ring (L6) gave lower yield and enantioselectivity (50% yield, 94:6 er, entry 6), presumably due to its less effective coordination with Pd(II) species. Increasing the loading of L5 from 10 mol% to 15 mol% slightly improved the yield and enantioselectivity (68% yield, 96.5:3.5 er, entry 7). Further increase the loading of L5 to 20 mol% led to the drop of the yield with similar enantioselectivity (58% yield, 96:4 er, entry 8). Extending the reaction time to 48 hours (entry 9) and increase the loading of 4-iodotoluene to 3.0 equiv. (entry 10) impacted the results drastically, affording the product in excellent yield and enantioselectivity (81% yield, 97:3 er). (see Supporting Information for extensive optimizations of Pd sources, solvents, and additives). Interestingly, while this new protocol provides a solution for the challenging cyclobutane substrates containing α-hydrogen, it is not compatible with cyclobutanes containing α-substituents which indicates the importance of ligand design for substrates possessing different steric environment.
Table 1.
| ||||||
|---|---|---|---|---|---|---|
| entry | L | x | y | t (h) | yield (%) | er |
| 1 | L1 | 10 | 2.0 | 24 | 20 | 50:50 |
| 2 | L2 | 10 | 2.0 | 24 | 50 | 75:25 |
| 3 | L3 | 10 | 2.0 | 24 | 26 | 68:32 |
| 4 | L4 | 10 | 2.0 | 24 | 63 | 95.5:4.5 |
| 5 | L5 | 10 | 2.0 | 24 | 65 | 96:4 |
| 6 | L6 | 10 | 2.0 | 24 | 50 | 94:6 |
| 7 | L5 | 15 | 2.0 | 24 | 68 | 96.5:3.5 |
| 8 | L5 | 20 | 2.0 | 24 | 58 | 96:4 |
| 9 | L5 | 15 | 2.0 | 48 | 75 | 96.5:3.5 |
| 10 | L5 | 15 | 3.0 | 48 | 87(81)c | 97:3 |
|
| ||||||
| ||||||
Reaction conditions: Pd(MeCN)2Cl2 (0.01 mmol), L (x mol%), 1 (0.1 mmol), 4-iodotoluene (y equiv.), Ag2CO3 (0.2 mmol), CHCl3 (0.5 mL), 80 °C.
Yields determined by 1H NMR analysis of the crude reaction mixture using CH2Br2 as internal standard. Enantiomeric ratios (er) were determined by chiral high-performance liquid chromatography.
Isolated yield.
The scope of aryl iodides was surveyed under the optimized conditions (Table 2). Arylation by para-methyl phenyl iodide provided 2a in 81% yield and 97:3 er. Arylation with simple iodobenzene gave 2b in 85% yield and 97:3 er. Methoxy group at the para-position is tolerated (67% yield and 96.5:3.5 er). Aryl iodides containing various halogen groups (2d–2f) and other electron-withdrawing groups (2g–2k) at para-position are also compatible, affording the corresponding products in moderate to good yields and excellent enantioselectivities (45%–72% yields, 95:5–97:3 er). The tolerance of acetyl, formyl, and nitro groups are particularly worth-noting (2h–2j). Meta-substituted aryl iodides bearing either electron-donating (Me, OMe) or electron-withdrawing (halides, CF3, and acetyl) functional groups are reactive, providing the desired products in good yields and excellent enantioselectivities (58%–73% yields, 95:5–96.5:3.5 er, 2l–2q). Ortho-fluoro, ortho-methylcarboxyl, 3,5-dimethyl, and 3,5-ditrifluoromethyl aryl iodides gave the corresponding products in high yields and enantioselectivities (63%–80% yields, 93:7–97:3 er, 2r–2u). A number of heteroaryl iodides are also suitable coupling partners, affording products with high enantioselectivities, albeit in lower yields (50%–65% yields, 91:9–96:4 er, 2v–2y).
Table 2.
|
Conditions: 1 (0.1 mmol), Ar(Het)–I (0.3 mmol), Pd(MeCN)2Cl2 (0.01 mmol), L5 (0.015 mmol), Ag2CO3(0.2 mmol), CHCl3 (0.5 mL), 80 °C, 48 h.
Isolated yields. Enantiomeric ratios (er) were determined by chiral high-performance liquid chromatography.
2.2 Vinylation of Cyclobutyl Carboxylic Amide
To enable the access to more diverse chiral cyclobutanes via enatioselective C–H activation, we embarked on the development of enantioselective vinylation of 1. We envision the combination of vinylation and arylation of cyclobutane will expand the diversity significantly. Despite recent advances of Pd(II)-catalyzed enantioselective C(sp3)–H activation reactions, vinyl-based coupling partners remains incompatible with these chiral catalysts. Such challenge is also reflected by the underdevelopment of C–H vinylation in general.1g,1h,13 Through modification of the reaction conditions, we were able to couple 1 with (E)-styrenyl iodide using ligand L5 to give the vinylation product in moderate yield and excellent enantioselectivity (3a, Table 3). Either electron donating or electron withdrawing substitute groups on the para-, and meta-positions of the phenyl ring are all well tolerated, affording the desired products in moderate yields and excellent enantioselectivities (43–58% yields, 96:4–97:3 er, 3a–3h). Ortho substituents, including methyl, methoxy, -(CH)4-, fluoro, bromo, and trifluoromethyl groups, were compatible with this method (34–65% yields, 3i–3n). The use of (E)-styrenyl iodide with 2,4-disubstituted on the phenyl ring or disubstituted on the olefin bouble bond also gave good enantioselectivities, albeit in lower yields (35–40% yields, 96:4–97:3 er, 3o, 3p). In general, vinylation is less efficient partly due to their instability under these conditions.
Table 3.
|
Conditions: 1 (0.1 mmol), Vinyl–I (0.3 mmol), Pd(MeCN) 2Cl2 (0.01 mmol), L5 (0.015 mmol), Ag2CO3 (0.2 mmol), CHCl3 (0.5 mL), 60 °C, 48 h.
Isolated yields. Enantiomeric ratios (er) were determined by chiral high-performance liquid chromatography.
2.4 Absolute Stereochemistry and Proposed Catalytic Cycle
The absolute configuration of 2j was unambiguously confirmed by using a HPLC standard of which the absolute configuration was established by X-ray crystallographic analysis in our previous study.8 This enantioselective C–H coupling reaction is likely to proceed through a Pd(II)/Pd(IV) catalysis (Scheme 2). Pre-coordination of the ligand to palladium to form the active Pd(II) species I. Coordination of substrate 1 to this species followed by a enantiodetermining C–H metalation step to form the chiral Pd(II) intermediate II. Oxidative addition of aryl or vinyl iodides to intermediate II generates the Pd(IV) species III. Reductive elimination provides the products and closes the catalytic cycle.
Scheme 2.
Proposed Catalytic Cycle
2.4 Diverse Chiral Cyclobutanes via Sequential C–H Arylation and Vinylation
To demonstrate the robustness of the reaction, a gram-scale reaction was carried out (Scheme 3). Arylation of 1 under the standard conditions with the iodobenzene as the coupling partner gave 1.6 g of enantioenriched product 2b in 86% isolated yield and 97:3 er. Treatment of 2b with 2.0 equiv. Sodium tert-butoxide in toluene successfully epimerized the C-1 stereocenter to gave 4 in 92% yield without erosion in enantioselectivity.1f To further broaden the diversity of the chiral cyclobutanes accessible through this method, 4 was subjected to the standard arylation conditions with methyl 4-iodobenzoate as the coupling partner, affording the enantiopure cyclobutanes bearing two distinct aryl rings 5 in 85% yield. In addition, the (E)-styrenyl group can also be installed efficiently to give 6 with excellent enantioselectivity and synthetically useful yield. These chiral cyclobutanes bearing three consecutive chiral centers are not readily accessible by previous ring forming approaches.4
Scheme 3.
Diversification of the Chiral Cyclobutanes
2.5 Removal of Directing Auxiliary
To meet the needs for various synthetic applications, different protocols are also established to deprotect the amide auxiliary (Scheme 4). Treatment of 2b with BF3·Et2O in methanol resulted in removal of the auxiliary to give the cis-disubstituted cyclobutane 7 in 92% yield without erosion in enantioselectivity (97:3 er).8 Deprotection can also be accomplished using our recently developed conditions using epoxide and KOAc.15 Auxiliary cleavage and the in situ epimerization of the C-1 stereocenter afforded the trans-disubstituted cyclobutane 8 in 90% yield and 97:3 er.
Scheme 4.
Removal of the amide auxiliary
3. Conclusion
In conclusion, we have developed a Pd(II)-catalyzed enantioselective arylation and vinylation of cyclobutyl carboxylic amides using chiral MPAO ligands. Sequential C–H arylation and vinylation provides an efficient methodology for the construction of diverse chiral cyclobutanes from simple mono-substituted cyclobutane. The rapid preparation of chiral cyclobutanes bearing three consecutive chiral centers are especially valuable as previous ring forming approaches to access these compounds have highly limited substrate scope.
Supplementary Material
Acknowledgments
We gratefully acknowledge The Scripps Research Institute and the NIH (NIGMS, 2R01GM084019) for financial support.
Footnotes
Notes. The authors declare no competing financial interest.
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acscatal.XXXX.
Experimental details on experimental procedures for the catalytic reactions and spectroscopic data for the products (PDF).
References
- 1.Hansen TV, Stenstrøm Y. Naturally Occurring Cyclobutanes. In: Hudlicky T, editor. Organic Synthesis: Theory and Applications. Vol. 5. Elsevier Science; Oxford, U.K: 2001. p. 1.. Bioactive Cyclobutane-Containing Alkaloids. Dembitsky VM. J Nat Med. 2008;62:1. doi: 10.1007/s11418-007-0166-3.. Cyclobutane-Containing Alkaloids: Origin, Synthesis, and Biological Activities. Sergeiko A, Poroikov VV, Lumir O, Hanu LO, Dembitsky VM. Open Med Chem J. 2008;2:26. doi: 10.2174/1874104500802010026.. A Monoterpene Alkaloid from Incarvillea sinensis. Chi YM, Nakamura M, Zhao XY, Yoshizawa T, Yan WM, Hashimoto F, Kinjo J, Nohara T. Chem Pharm Bull. 2005;53:1178. doi: 10.1248/cpb.53.1178.. SNF4435C and D, Novel Immunosuppressants Produced by a Strain ofStreptomyces spectabilis. Kurosawa K, Takahashi K, Tsuda E. J Antibiot. 2001;54:541. doi: 10.7164/antibiotics.54.541.. Total Synthesis and Structural Revision of the Piperarborenines via Sequential Cyclobutane C–H. Gutekunst WR, Baran PS. J Am Chem Soc. 2011;133:19076. doi: 10.1021/ja209205x.. Arylation Sequential Csp3–H Arylation and Olefination: Total Synthesis of the Proposed Structure of Pipercyclobutanamide A. Gutekunst WR, Gianatassio R, Baran PS. Angew Chem Int Ed. 2012;51:7507. doi: 10.1002/anie.201203897.. Applications of C–H Functionalization Logic to Cyclobutane Synthesis. Gutekunst WR, Baran PS. J Org Chem. 2014;79:2430. doi: 10.1021/jo4027148.. A Mixed-Ligand Chiral Rhodium(II) Catalyst Enables the Enantioselective Total Synthesis of Piperarborenine. Panish BRA, Chintala SR, Fox JM. Angew Chem Int Ed. 2016;55:4983. doi: 10.1002/anie.201600766.
- 2.Cyclobutanoid Amides from Piper arborescens. Lee FP, Chen YC, Chen JJ, Tsai IL, Chen IS. Helv Chim Acta. 2004;87:463.. New Cytotoxic Cyclobutanoid Amides, a New Furanoid Lignan and Anti-Platelet Aggregation Constituents from Piper arborescens. Tsai I-L, Lee F-P, Wu C-C, Duh C-Y, Ishikawa T, Chen J-J, Chen Y-C, Seki H, Chen I-S. Planta Med. 2005;71:535. doi: 10.1055/s-2005-864155.
- 3.Strong Antinociceptive Effect of Incarvillateine, a Novel Monoterpene Alkaloid from Incarvillea sinensis. Nakamura M, Chi Y-M, Yan W-M, Nakasugi Y, Yoshizawa T, Irino N, Hashimoto F, Kinjo J, Nohara T, Sakurada S. J Nat Prod. 1999;62:1293. doi: 10.1021/np990041c.. Pharmacological Study on the Novel Antinociceptive Agent, a Novel Monoterpene Alkaloid from Incarvillea sinensis. Chi Y-M, Nakamura M, Yoshizawa T, Zhao X-Y, Yan W-M, Hashimoto F, Kinjo J, Nohara T, Sakurada S. Biol Pharm Bull. 2005;28:1989. doi: 10.1248/bpb.28.1989.. Targeting Fatty Acid Binding Protein (FABP) Anandamide Transporters – A Novel Strategy for Development of Anti-Inflammatory and Anti-Nociceptive Drugs. Berger WT, Ralph BP, Kaczocha M, Sun J, Balius TE, Rizzo RC, Haj-Dahmane S, Ojima I, Deutsch DG. PLoS ONE. 2012;7:e50968. doi: 10.1371/journal.pone.0050968.
- 4.For reviews on the synthesis of enantiopure cyclobutane derivatives, see: Enantiomerically Pure Cyclobutane Derivatives and Their Use in Organic Synthesis. Lee-Ruff E, Mladenova G. Chem Rev. 2003;103:1449. doi: 10.1021/cr010013a.. Stereocontrolled Synthesis and Functionalization of Cyclobutanes and Cyclobutanones. Secci F, Frongia A, Piras PP. Molecules. 2013;18:15541. doi: 10.3390/molecules181215541.. For selected examples of enantioselective synthesis of cyclobutane derivatives, see: Asymmetric [2+2] Cycloaddition Reaction Catalyzed by a Chiral Titanium Reagent. Hayashi Y, Narasaka K. Chem Lett. 1989;18:793.. Asymmetric [2 + 2] Cycloaddition Reaction Catalyzed by a Chiral Titanium Reagent. Narasaka K, Hayashi Y, Shimadzu H, Niihata S. J Am Chem Soc. 1992;114:8869.. Highly Enantioselective [2+2]-Cycloaddition Reactions Catalyzed by a Chiral Aluminum Bromide Complex. Canales E, Corey EJ. J Am Chem Soc. 2007;129:12686. doi: 10.1021/ja0765262.. Gold(I)-Catalyzed Enantioselective Ring Expansion of Allenylcyclopropanols. Kleinbeck F, Toste FD. J Am Chem Soc. 2009;131:9178. doi: 10.1021/ja904055z.. Enantioselective Lewis Acid Catalysis in Intramolecular [2+2] Photocycloaddition Reactions of Coumarins. Guo H, Herdtweck H, Bach T. Angew Chem Int Ed. 2010;49:7782. doi: 10.1002/anie.201003619.. Enantioselective Intramolecular [2 + 2]-Photocycloaddition Reactions of 4-Substituted Quinolones Catalyzed by a Chiral Sensitizer with a Hydrogen-Bonding Motif. Muller C, Bauer A, Maturi MM, Cuquerella MC, Miranda MA, Bach T. J Am Chem Soc. 2011;133:16689. doi: 10.1021/ja207480q.. Asymmetric Organocatalytic Formal [2 + 2]-Cycloadditions via Bifunctional H-Bond Directing Dienamine Catalysis. Albrecht Ł, Dickmeiss G, Acosta FC, Rodriguez-Escrich C, Davis RL, J⊘rgensen KA. J Am Chem Soc. 2012;134:2543. doi: 10.1021/ja211878x.. Cooperative Dienamine/Hydrogen-Bonding Catalysis: Enantioselective Formal [2+2] Cycloaddition of Enals with Nitroalkenes. Talavera G, Reyes E, Vicario JL, Carrillo L. Angew Chem Int Ed. 2012;51:4104. doi: 10.1002/anie.201200269.. Enantioselective Construction of α-Quaternary Cyclobutanones by Catalytic Asymmetric Allylic Alkylation. Reeves M, Eidamshaus C, Kim J, Stoltz BM. Angew Chem Int Ed. 2013;52:6718. doi: 10.1002/anie.201301815.. Enantioselective Synthesis of Cyclobutanes via Sequential Rh-catalyzed Bicyclobutanation/Cu-catalyzed Homoconjugate Addition. Panish R, Chintala SR, Boruta DT, Fang Y, Taylor MT, Fox JM. J Am Chem Soc. 2013;135:9283. doi: 10.1021/ja403811t.. A Dual-Catalysis Approach to Enantioselective [2 + 2] Photocycloadditions Using Visible Light. Du JN, Skubi KL, Schultz DM, Yoon TP. Science. 2014;344:392. doi: 10.1126/science.1251511.. Catalytic Enantioselective Allenoate–Alkene [2 + 2] Cycloadditions. Conner ML, Xu Y, Brown MK. J Am Chem Soc. 2015;137:3482. doi: 10.1021/jacs.5b00563.. Cyclobutane and Cyclobutene Synthesis: Catalytic Enantioselective [2+2] Cycloadditions. Xu Y, Conner ML, Brown MK. Angew Chem Int Ed. 2015;54:11918. doi: 10.1002/anie.201502815.. Enantioselective Synthesis of Cyclobutylboronates via a Copper-Catalyzed Desymmetrization Approach. Guisán-Ceinos M, Parra A, Martín-Heras V, Tortosa M. Angew Chem Int Ed. 2016;55:6969. doi: 10.1002/anie.201601976.. Enantioselective Construction of Cyclobutanes: A New and Concise Approach to the Total Synthesis of (+)-Piperarborenine B. Hu J-L, Feng L-W, Wang L, Xie Z, Tang Y, Li X. J Am Chem Soc. 2016;138:13151. doi: 10.1021/jacs.6b08279.
- 5.For reviews on enantioselective C–H activation, see: Transition Metal-Catalyzed C–H Activation Reactions: Diastereoselectivity and Enantioselectivity. Giri R, Shi B-F, Engle KM, Maugel N, Yu J-Q. Chem Soc Rev. 2009;38:3242. doi: 10.1039/b816707a.. Diastereotopos-Differentiating C–H Activation Reactions at Methylene Groups. Herrmann P, Bach T. Chem Soc Rev. 2011;40:2022. doi: 10.1039/c0cs00027b.. Recent Development of Direct Asymmetric Functionalization of Inert C–H Bonds. Zheng C, You S-L. RSC Adv. 2014;4:6173.. Catalytic Enantioselective Transformations Involving C–H Bond Cleavage by Transition-Metal Complexes. Newton CG, Wang S-G, Oliveira CC, Cramer N. Chem Rev. 2017;117:8908. doi: 10.1021/acs.chemrev.6b00692.
- 6.For an Pd(0)-catalyzed intramolecular enantioselective C–H arylation of cyclobutanes (excellent enantioselectivities but low yields), see: Palladium(0)-Catalyzed Asymmetric C(sp3)–H Arylation Using a Chiral Binol-Derived Phosphate and an Achiral Ligand. Yang L, Melot R, Neuburger M, Baudoin O. Chem Sci. 2017;8:1344. doi: 10.1039/c6sc04006c.
- 7.Palladium(II)-Catalyzed Enantioselective C(sp3)–H Activation Using a Chiral Hydroxamic Acid Ligand. Xiao K-J, Lin DW, Miura M, Zhu R-Y, Gong W, Wasa M, Yu J-Q. J Am Chem Soc. 2014;136:8138. doi: 10.1021/ja504196j.
- 8.Pd(II)-Catalyzed Enantioselective C(sp3)–H Borylation. He J, Shao Q, Wu Q-F, Yu J-Q. J Am Chem Soc. 2017;139:3344. doi: 10.1021/jacs.6b13389.
- 9.Weak Coordination as a Powerful Means for Developing Broadly Useful C–H Functionalization Reactions. Engle KM, Mei T-S, Wasa M, Yu J-Q. Acc Chem Res. 2012;45:788. doi: 10.1021/ar200185g.. Pd(II)-Catalyzed Enantioselective C–H Activation of Cyclopropanes. Wasa M, Engle KM, Lin DW, Yoo EJ, Yu J-Q. J Am Chem Soc. 2011;133:19598. doi: 10.1021/ja207607s.
- 10.PdII-Catalyzed Enantioselective Activation of C(sp2)–H and C(sp3)–H Bonds Using Monoprotected Amino Acids as Chiral Ligands. Shi B-F, Maugel N, Zhang Y-H, Yu J-Q. Angew Chem Int Ed. 2008;47:4882. doi: 10.1002/anie.200801030.
- 11.Ligand-Accelerated Enantioselective Methylene C(sp3)–H Bond Activation. Chen G, Gong W, Zhuang Z, Andrä MS, Chen Y-Q, Hong X, Yang Y-F, Liu T, Houk KN, Yu J-Q. Science. 2016;353:1023. doi: 10.1126/science.aaf4434.
- 12.Formation of α-chiral Centers by Asymmetric β-C(sp3)–H Arylation, Alkenylation, and Alkynylation. Wu Q-F, Shen P-X, He J, Wang X-B, Zhang F, Shao Q, Zhu R-Y, Mapelli C, Qiao JX, Poss MA, Yu J-Q. Science. 2017;355:499. doi: 10.1126/science.aal5175.
- 13.For a review on C–H vinylation, see: Transition-Metal-Catalyzed Direct C–H Alkenylation, Alkynylation, Benzylation, and Alkylation of (Hetero)arenes. Messaoudi S, Brion J-D, Alami M. Eur J Org Chem. 2010:6495.. For selected examples of C(sp3)–H vinylation, see: A Practical Strategy for the Structural Diversification of Aliphatic Scaffolds through the Palladium-Catalyzed Picolinamide-Directed Remote Functionalization of Unactivated C(sp3)–H Bonds. He G, Chen G. Angew Chem Int Ed. 2011;50:5192. doi: 10.1002/anie.201100984.. Palladium-Catalyzed Stereoretentive Olefination of Unactivated C(sp3)–H Bonds with Vinyl Iodides at Room Temperature: Synthesis of β-Vinyl α-Amino Acids. Wang B, Lu C, Zhang S-Y, He G, Nack WA, Chen G. Org Lett. 2014;16:6260. doi: 10.1021/ol503248f.. Ni(II)/BINOL-Catalyzed Alkenylation of Unactivated C(sp3)–H Bonds. Liu Y-J, Zhang Z-Z, Yan S-Y, Liu Y-H, Shi B-F. Chem Commun. 2015;51:7899. doi: 10.1039/c5cc02254a.. β,γ-Vicinal Dicarbofunctionalization of Alkenyl Carbonyl Compounds via Directed Nucleopalladation. Liu Z, Zeng T, Yang KS, Engle KM. J Am Chem Soc. 2016;138:15122. doi: 10.1021/jacs.6b09170.. Iron/Zinc-Co-catalyzed Directed Arylation and Alkenylation of C(sp3)–H Bonds with Organoborates. Ilies L, Itabashi Y, Shang R, Nakamura E. ACS Catal. 2017;7:89..Palladium Catalyzed Direct Aliphatic γC(sp3)–H Alkenylation with Alkenes and Alkenyl Iodides. Thrimurtulu N, Khan S, Maity S, Volla CMR, Maiti D. Chem Commun. 2017;53:12457. doi: 10.1039/c7cc05703b.
- 14.A Graphical Journey of Innovative Organic Architectures That Have Improved Our Lives. McGrath NA, Brichacek M, Njardarson JT. J Chem Educ. 2010;87:1348.. Improving Drug Candidates by Design: A Focus on Physicochemical Properties As a Means of Improving Compound Disposition and Safety. Meanwell NA. Chem Res Toxicol. 2011;24:1420. doi: 10.1021/tx200211v.. Escape from Flatland: Increasing Saturation as an Approach to Improving Clinical Success. Lovering FJ, Humblet C. J Med Chem. 2009;52:6752. doi: 10.1021/jm901241e.
- 15.An Epoxide-Mediated Deprotection Method for Acidic Amide Auxiliary. Pei Q-L, Che G-D, Zhu R-Y, He J, Yu J-Q. Org Lett. 2017;19:5860. doi: 10.1021/acs.orglett.7b02841.
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.