Next Article in Journal
Reactivity of Rare-Earth Oxides in Anhydrous Imidazolium Acetate Ionic Liquids
Next Article in Special Issue
Direct Aniline Formation with Benzene and Hydroxylamine
Previous Article in Journal
The Anion Impact on Dimensionality of Cadmium(II) Complexes with Nicotinamide
Previous Article in Special Issue
Investigation of the Properties of Mo/ZSM-5 Catalysts Based on Zeolites with Microporous and Micro–Mesoporous Structures
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Communication

Palladium-Catalyzed sp3 C–H Acetoxylation of α,α-Disubstituted α-Amino Acids

Department of Chemistry, Graduate School of Science, Osaka Metropolitan University, 3-3-138 Sugimoto, Sumiyoshi-ku, Osaka 558-8585, Japan
*
Authors to whom correspondence should be addressed.
Chemistry 2023, 5(2), 1369-1377; https://doi.org/10.3390/chemistry5020093
Submission received: 27 April 2023 / Revised: 23 May 2023 / Accepted: 31 May 2023 / Published: 1 June 2023

Abstract

:
The sp3 C–H acetoxylation at the β-position of α,α-disubstituted α-amino acids proceeds smoothly under palladium catalysis in the presence of PhI(OAc)2. This reaction provides a straightforward synthetic route to non-natural β-acetoxy-α-amino acids. The reaction of α-aminocyclopropanecarboxylic acid takes place via ring-opening to selectively afford an acyclic γ-acetoxy-α,β-unsaturated amino acid.

1. Introduction

α-Amino acid scaffolds can be seen in a wide range of natural products. Recently, the class of non-proteinogenic α,α-disubstituted α-amino acids has been focused on in biochemical research and drug discovery [1,2]. The biological and chemical properties of these molecules have inspired various new synthetic methodologies [3,4,5,6]. Especially β-hydroxy-α,α-disubstituted amino acids, a key component in the structure of many biologically active natural products, such as sphingofungin F [7] and kaitocephalin [8,9], are highly challenging target molecules due to the motif’s densely functionalized structure [10].
One of the most powerful methods for their synthesis is the modification of readily available, natural α-amino acids such as α-aminoisobutyric acid (Aib). Specifically, Aib and its analogues have been recognized as important building blocks for functional peptides because their introduction induces drastic macrostructural changes due to their bulky α,α-disubstituted structure [11,12].
Meanwhile, transition-metal-catalyzed C–H functionalization has been developed and has provided step- and atom-economical routes in the organic synthesis field [13,14,15,16,17,18,19,20,21,22,23,24,25,26]. A number of sp3 C–H arylations and alkylations at the β-position of α-amino acids have been developed to enable the direct production of non-natural α-amino acids [27,28,29,30,31,32]. Compared to such C–C coupling, C–heteroatom coupling including the acetoxylation of α-amino acids has been relatively less explored. Corey first reported palladium-catalyzed β-acetoxylation of α-N-phthaloylamino acid 8-aminoquinoline amides (Scheme 1a) [33]. Daugulis reported a single example for the β sp3 C–H acetoxylation of a phenylalanine derivative utilizing the same bidentate directing group (Scheme 1b) [34]. Yu achieved acetoxylation on the methyl carbon of alanine moiety of tripeptides (Scheme 1c) [35]. Recently, Kanyiva and Shibata reported the benzoxylation of alanine derivatives using benzaldehydes as benzoxyl reagents (Scheme 1d) [36]. Since bidentate directing groups were employed in these precedents, substrate scope was limited mostly to sterically less-hindered ones. At least to the best of our knowledge, there is no precedent for effective sp3 C–H acetoxylation of bulky α,α-disubstituted α-amino acids. During our studies on transition-metal-catalyzed C–H functionalization utilizing the monodentate directing group [37,38,39,40,41], we succeeded in finding that β sp3 C–H acetoxylation of α,α-disubstituted α-amino acid derivatives proceeds efficiently under palladium catalysis directed by their monodentate amide functional group to provide a straightforward synthetic route to non-natural β-acetoxylated amino acids. It has also been shown that the acetoxylated products can be readily transformed to β-hydroxy amino acids. These new findings are described herein.

2. Materials and Methods

2.1. General

1H and 13C NMR spectra were recorded at 400 and 100 MHz, respectively, for CDCl3 and DMSO- d 6 solutions. NMR measurements were performed at 80 °C, if necessary. HRMS data were obtained by DART using a TOF mass spectrometer. The structures of all products listed below were unambiguously determined by 1H and 13C NMR, and X-ray crystal structure analysis.
Amino acid derivatives 1 and 3 [35,42,43,44,45] and mono-N-protected amino acid ligand L6 [46] were prepared according to published procedures. Other reagents were purchased from commercial sources and used without further purification.
The following experimental procedures may be regarded as typical in methodology and scale.

2.2. General Procedure for Pd-Catalyzed Acetoxylation of 1 and 3

To a flame-dried 5 mL vial or 15 mL pressure-resistant tube, 1 or 3 (0.3 mmol), PhI(OAc)2 (0.9 mmol, 290 mg), Pd(CH3CN)4(BF4)2 (0.015 mmol, 7 mg), N-acetyl-l-valine (L1, 0.03 mmol, 5 mg), and HFIP/DME/Ac2O (5/4/1, 0.7 mL) were added. The mixture was stirred under argon (1 atm) at 80 °C (hot plate temperature or oil bath) for 20 h. The mixture was diluted with EtOAc (1 mL) and then passed through a short column with activated alumina to remove insoluble solids. After removal of the solvents under vacuum, the crude residue was purified by column chromatography on silica gel using hexane−EtOAc as eluent to afford acetoxylated products 2 or 4. Further purification by GPC (gel permeation chromatography) was performed, if needed.

2.3. Procedure for Methanolysis of 2a [47]

To a 50 mL flask, 2a (0.26 mmol, 89 mg), HCl-MeOH (5–10%, 10 mL), and MeOH (5 mL) were added. The mixture was stirred under air (1 atm) at 60 °C for 0.5 h. After removal of the solvents under vacuum, the product was purified by column chromatography on silica gel using hexane−EtOAc as eluent. Further purification by GPC (gel permeation chromatography) was performed to afford 5 (63 mg, 80%).

3. Results and Discussion

3.1. Optimization of Reaction Conditions

In an initial attempt, 2-(2-methyl-1-oxo-1-(pyrrolidin-1-yl)propan-2-yl)isoindoline-1,3-dione (1a) (0.3 mmol) was treated with PhI(OAc)2 (0.9 mmol) in the presence of Pd(OAc)2 (0.015 mmol) in HFIP/Ac2O (9/1, 0.7 mL) [48] (HFIP = hexafluoro-2-propanol) under argon at 80 °C for 20 h. As a result, a trace amount of 2-(1,3-dioxoisoindolin-2-yl)-2-methyl-3-oxo-3-(pyrrolidin-1-yl)propyl acetate (2a) was formed (Table 1, entry 1). The use of cationic palladium precursor Pd(MeCN)4(BF4)2 in place of Pd(OAc)2 improved the acetoxylation efficiency to give 2a a 19% yield (entry 2). The addition of an ethereal co-solvent was found to influence the reaction efficiency. Thus, the addition of THF or 1,4-dioxane enhanced the yield to 24 and 44% yield (entries 3 and 4, respectively). The use of solvent system HFIP/DME/Ac2O brought about further improvements of up to 45% (entry 5), while HFIP/diglyme/Ac2O was less suitable (entry 6). It has been reported that mono-N-protected amino acid (MPAA) ligands effectively enhanced the activity of palladium catalysts toward C–H functionalization [49,50,51]. Therefore, N-acetyl-l-valine (N-Ac-l-Val-OH (L1), 0.03 mmol) was added to the present reaction system. To our delight, the reaction efficiency was significantly improved to afford 2a with a 65% isolated yield (entry 7). In this case, a small amount of diacetoxylated product was also detected by crude NMR analysis. Moreover, it was confirmed that this reaction could easily be scaled up to a 1 mmol scale. Thus, the reaction of 1a (1 mmol) with PhI(OAc)2 (3 mmol) gave 2a in a reasonable yield (214 mg, 62%) (entry 8). Both decreasing and increasing the amount of DME slightly reduced the product yield (entries 9 and 10). Even under conditions with L1, Pd(OAc)2 was not effective (entry 11). At 100 °C, the 2a yield decreased to 59% (entry 12).

3.2. Screening of Ligands

As described above, the addition of N-Ac-l-Val-OH ligand (L1) had a significant impact in determining the reaction efficiency. We next examined the effect of other MPAA ligands (Scheme 2). Under standard conditions using 1a (0.3 mmol) and PhI(OAc)2 (0.9 mmol) in the presence of Pd(OAc)2 (0.015 mmol) in HFIP/DME/Ac2O (5/4/1, 0.7 mL) at 80 °C for 20 h, the addition of N-Ac-Gly-OH (L2, 0.03 mmol) decreased the 2a yield to 36%. In contrast, other α-alkylated MPAAs L36 enhanced the yield (51–59%), although they were somewhat less effective than L1. While N-Ac-l-Phe-OH similarly increased the yield, N-acetyl-α-phenylglycine (L8) decreased the yield. The addition of N-Ac-β-Ala-OH (L9) and N-Boc-Val-OH (L10) did not show any significant positive effect.

3.3. Scope and Limitations

Under conditions using L1 as a ligand, 2-(2-methyl-1-oxo-1-(piperidin-1-yl)propan-2-yl)isoindoline-1,3-dione (1b) underwent the acetoxylation to form 2b in 54% yield (Scheme 3). Other amide functions also acted as a monodentate directing group. The reaction of 1c possessing a diethylaminocarbonyl directing group gave 2c with a 51% yield. The (4-morpholinyl)carbonyl and isopropylaminocarbonyl directing groups of 1d and 1e, respectively, were less effective to afford 2d and 2e in low yields. These results suggest that a pyrrolidylcarbonyl directing group is suitable for the present acetoxylation.
Finally, the acetoxylation of variously substituted α-amino acids with the aid of a pyrrolidylcarbonyl directing group was examined (Scheme 4). Treatment of 2-(1-(pyrrolidine-1-carbonyl)cyclopropyl)isoindoline-1,3-dione (1f) under the standard conditions did not give the expected acetoxylated product 2f at all. Instead, acetoxylation took place accompanied by ring-opening [52,53,54,55] to produce (E)-3-(1,3-dioxoisoindolin-2-yl)-4-oxo-4-(pyrrolidin-1-yl)but-2-en-1-yl acetate (2f’) with a 46% yield. The structure of 2f’ was determined by X-ray crystallography (Figure S1 in the Supplementary Materials). Contrastingly, α-amino acids possessing five- and six-membered side chains 1g and 1h showed low reactivity and formed only trace amounts of acetoxylation products. An alanine derivative, 2-(1-oxo-1-(pyrrolidin-1-yl)propan-2-yl)isoindoline-1,3-dione (1i) underwent acetoxylation to afford 2i with a 21% yield. However, the present procedure was not applicable to 2-(1-oxo-1-(pyrrolidin-1-yl)butan-2-yl)isoindoline-1,3-dione (1j) and 2-(4-methyl-1-oxo-1-(pyrrolidin-1-yl)pentan-2-yl)isoindoline-1,3-dione (1k). In both cases, the acetoxylation was sluggish to form trace amounts of 2j and 2k.

3.4. Reaction Mechanism

Based on the literature concerning related reactions [48,49], a plausible mechanism for the present acetoxylation of 1a is illustrated in Scheme 5. Coordination of carbonyl oxygen to PdII species triggers sp3 C–H bond cleavage to form a five-membered palladacycle intermediate, A. Then, oxidation of A to B by PhI(OAc)2 and subsequent reductive elimination may occur to form 2a and active PdII species. In the case with 1f, the corresponding palladacycle intermediate C may undergo ring-opening through β-carbon elimination to form D, which seems to be transformed to the final acetoxylation product 2f’.

3.5. Acetoxylation of Dipeptide Derivatives 3

The present acetoxylation procedure was found to be applicable to dipeptide substrates 3 (Scheme 6). Thus, the reaction of methyl (2-(1,3-dioxoisoindolin-2-yl)-2-methylpropanoyl)-L-prolinate (3a) gave a mixture of separable diastereomers, (S)-4a and (R)-4a, with 24 and 8% yields, respectively. The stereochemistry of the major diastereomer (S)-4a was verified by X-ray crystallography (Figure S2 in the Supplementary Materials). Another dipeptide, methyl N-(2-(1,3-dioxoisoindolin-2-yl)-2-methylpropanoyl)-N-methylglycinate (3b), also underwent the acetoxylation to form 4b with a 21% yield.

3.6. Methanolysis of 2a

It was confirmed that an acetoxylation product can be converted to the corresponding alcohol via methanolysis (Scheme 7). Thus, treatment of 2a (0.2 mmol) with HCl in MeOH (5–10 wt%, 10 mL) in MeOH (5 mL) at 60 °C for 0.5 h gave 5 with an 80% yield. The hydroxy group is well-known to be usable in further transformations.

4. Conclusions

We have demonstrated that α,α-disubstituted α-amino acids undergo sp3 C–H acetoxylation at their β-position upon treatment with PhI(OAc)2 in the presence of a palladium catalyst in HFIP/DME/Ac2O to give β-acetoxylated α-amino acids. It was also shown that the procedure is applicable to the acetoxylation of dipeptides. Work is now underway for synthesizing a wide range of non-natural α-amino acids.

Supplementary Materials

The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/chemistry5020093/s1. The Supplementary Materials contain detailed procedures for synthesizing compounds and analytical data including 1H and 13C NMR spectra [56,57,58,59].

Author Contributions

Conceptualization, T.S. and Y.U.; methodology, T.S.; validation, A.M., Y.U., and T.S.; formal analysis, A.M.; structures, T.S. and Y.U.; experiments, A.M.; writing—original draft preparation, T.S. and Y.U.; writing—review and editing, T.S. and Y.U.; project administration, T.S. All authors have read and agreed to the published version of the manuscript.

Funding

This work was partly supported by JSPS KAKENHI grant numbers 20H02745 and 18K19083, and the 2022 Osaka Metropolitan University (OMU) Strategic Research Promotion Project (Priority Research) to T.S. and JSPS KAKENHI grant number JP18H04627 to Y.U.

Data Availability Statement

The data presented in this study are available on request from the corresponding author.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Szekeres, A.; Leitgeb, B.; Kredics, L.; Antal, Z.; Hatvani, L.; Manczinger, L.; Vágvölgyi, C. Peptaibols and related peptaibiotics of Trichoderma. A review. Acta Microbiol. Immunol. Hung. 2005, 52, 137–168. [Google Scholar] [CrossRef] [PubMed]
  2. Degenkolb, T.; Berg, A.; Gams, W.; Schlegel, B.; Gräfe, U. The occurrence of peptaibols and structurally related peptaibiotics in fungi and their mass spectrometric identification via diagnostic fragment ions. J. Pept. Sci. 2003, 9, 666–678. [Google Scholar] [CrossRef] [PubMed]
  3. Kang, S.H.; Kang, S.Y.; Lee, H.-S.; Buglass, A.J. Total Synthesis of Natural tert-Alkylamino Hydroxy Carboxylic Acids. Chem. Rev. 2005, 105, 4537–4558. [Google Scholar] [CrossRef] [PubMed]
  4. Ohfune, Y.; Shinada, T. Enantio- and Diastereoselective Construction of α,α-Disubstituted α-Amino Acids for the Synthesis of Biologically Active Compounds. Eur. J. Org. Chem. 2005, 2005, 5127–5143. [Google Scholar] [CrossRef]
  5. Shibasaki, M.; Kanai, M.; Fukuda, N. Total Synthesis of Lactacystin and Salinosporamide A. Chem.—Asian J. 2007, 2, 20–38. [Google Scholar] [CrossRef]
  6. Vogt, H.; Bräse, S. Recent approaches towards the asymmetric synthesis of α,α-disubstituted α-amino acids. Org. Biomol. Chem. 2007, 5, 406–430. [Google Scholar] [CrossRef]
  7. Horn, W.S.; Smith, J.L.; Bills, G.F.; Raghoobar, S.L.; Helms, G.L.; Kurtz, M.B.; Marrinan, J.A.; Frommer, B.R.; Thornton, R.A.; Mandala, S.M. Sphingofungins E and F: Novel serinepalmitoyl trans-ferase inhibitors from Paecilomyces variotii. J. Antibiot. 1992, 45, 1692–1696. [Google Scholar] [CrossRef]
  8. Shin-ya, K.; Kim, J.-S.; Furihata, K.; Hayakawa, Y.; Seto, H. Structure of kaitocephalin, a novel glutamate receptor antagonist produced by Eupenicillium shearii. Tetrahedron Lett. 1997, 38, 7079–7082. [Google Scholar] [CrossRef]
  9. Kobayashi, H.; Shin-ya, K.; Furihata, K.; Hayakawa, Y.; Seto, H. Absolute configuration of a novel glutamate receptor antagonist kaitocephalin. Tetrahedron Lett. 2001, 42, 4021–4023. [Google Scholar] [CrossRef]
  10. Sugai, T.; Usui, S.; Tsuzaki, S.; Oishi, H.; Yasushima, D.; Hisada, S.; Fukuyasu, T.; Oishi, T.; Sato, T.; Chida, N. Synthesis of β-Hydroxy-α,α-disubstituted Amino Acids through the Orthoamide-Type Overman Rearrangement of an α,β-Unsaturated Ester and Stereodivergent Intramolecular SN2′ Reaction: Development and Application to the Total Synthesis of Sphingofungin F. Bull. Chem. Soc. Jpn. 2018, 91, 594–607. [Google Scholar] [CrossRef]
  11. Aravinda, S.; Shamala, N.; Balaram, P. Aib residues in peptaibiotics and synthetic sequences: Analysis of nonhelical conformations. Chem. Biodivers. 2008, 5, 1238–1262. [Google Scholar] [CrossRef] [PubMed]
  12. Toniolo, C.; Benedetti, E. Structures of polypeptides from α-amino acids disubstituted at the α-carbon. Macromolecules 1991, 24, 4004–4009. [Google Scholar] [CrossRef]
  13. Karle, I.L.; Balaram, P. Structural characteristics of α-helical peptide molecules containing Aib residues. Biochemistry 1990, 29, 6747–6756. [Google Scholar] [CrossRef] [PubMed]
  14. Dalton, T.; Faber, T.; Glorius, F. C–H Activation: Toward Sustainability and Applications. ACS Cent. Sci. 2021, 7, 245–261. [Google Scholar] [CrossRef]
  15. Rej, S.; Ano, Y.; Chatani, N. Bidentate Directing Groups: An Efficient Tool in C–H Bond Functionalization Chemistry for the Expedient Construction of C–C Bonds. Chem. Rev. 2020, 120, 1788–1887. [Google Scholar] [CrossRef]
  16. Sambiagio, C.; Schöbauer, D.D.; Blieck, R.; Dao-Huy, T.; Pototschnig, G.; Schaaf, P.; Wiesinger, T.; Zia, M.F.; Wencel-Delord, J.; Besset, T.; et al. A comprehensive overview of directing groups applied in metal-catalysed C–H functionalisation chemistry. Chem. Soc. Rev. 2018, 47, 6603–6743. [Google Scholar] [CrossRef]
  17. Gulías, M.; Mascareñas, J.L. Metal-Catalyzed Annulations through Activation and Cleavage of C−H Bonds. Angew. Chem. Int. Ed. 2016, 55, 11000–11019. [Google Scholar] [CrossRef]
  18. Chen, Z.; Wang, B.; Zhang, J.; Yu, W.; Liu, Z.; Zhang, Y. Transition metal-catalyzed C–H bond functionalizations by the use of diverse directing groups. Org. Chem. Front. 2015, 2, 1107–1295. [Google Scholar] [CrossRef]
  19. Song, G.; Li, X. Substrate Activation Strategies in Rhodium(III)-Catalyzed Selective Functionalization of Arenes. Acc. Chem. Res. 2015, 48, 1007–1020. [Google Scholar] [CrossRef]
  20. Ye, J.; Lautens, M. Palladium-catalysed norbornene-mediated C–H functionalization of arenes. Nat. Chem. 2015, 7, 863–870. [Google Scholar] [CrossRef]
  21. Miura, M.; Satoh, T.; Hirano, K. Development of Direct Aromatic Coupling Reactions by Transition-Metal Catalysis. Bull. Chem. Soc. 2014, 87, 751–764. [Google Scholar] [CrossRef]
  22. De Sarkar, S.; Liu, W.; Kozhushkov, S.I.; Ackermann, L. Weakly Coordinating Directing Groups for Ruthenium(II)-Catalyzed C–H Activation. Adv. Synth. Catal. 2014, 356, 1461–1479. [Google Scholar] [CrossRef]
  23. Colby, D.A.; Tsai, A.S.; Bergman, R.G.; Ellman, J.A. Rhodium Catalyzed Chelation-Assisted C–H Bond Functionalization Reactions. Acc. Chem. Res. 2012, 45, 814–825. [Google Scholar] [CrossRef] [PubMed]
  24. Engle, K.M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Weak Coordination as a Powerful Means for Developing Broadly Useful C–H Functionalization Reactions. Acc. Chem. Res. 2012, 45, 788–802. [Google Scholar] [CrossRef]
  25. Cho, S.H.; Kim, J.Y.; Kwak, J.; Chang, S. Recent advances in the transition metal-catalyzed twofold oxidative C–H bond activation strategy for C–C and C–N bond formation. Chem. Soc. Rev. 2011, 40, 5068–5083. [Google Scholar] [CrossRef]
  26. Satoh, T.; Miura, M. Oxidative Coupling of Aromatic Substrates with Alkynes and Alkenes under Rhodium Catalysis. Chem. Eur. J. 2010, 16, 11212–11222. [Google Scholar] [CrossRef]
  27. Shen, P.-X.; Hu, L.; Shao, Q.; Hong, K.; Yu, J.-Q. Pd(II)-Catalyzed Enantioselective C(sp3)–H Arylation of Free Carboxylic Acids. J. Am. Chem. Soc. 2018, 140, 6545–6549. [Google Scholar] [CrossRef]
  28. Chen, G.; Zhuang, Z.; Li, G.-C.; Saint-Denis, T.G.; Hsiao, Y.; Joe, C.L.; Yu, J.-Q. Ligand-Enabled β-C–H Arylation of α-Amino Acids Without Installing Exogenous Directing Groups. Angew. Chem. Int. Ed. 2017, 56, 1506–1509. [Google Scholar] [CrossRef]
  29. Wu, Q.-F.; Shen, P.-X.; He, J.; Wang, X.-B.; Zhang, F.; Shao, Q.; Zhu, R.-Y.; Mapelli, C.; Qiao, J.X.; Poss, M.A.; et al. Formation of α-chiral centers by asymmetric β-C(sp3)–H arylation, alkenylation, and alkynylation. Science 2017, 355, 499–503. [Google Scholar] [CrossRef]
  30. Zhu, Y.; Chen, X.; Yuan, C.; Li, G.; Zhang, J.; Zhao, Y. Pd-catalysed ligand-enabled carboxylate-directed highly regioselective arylation of aliphatic acids. Nat. Commun. 2017, 8, 14904. [Google Scholar] [CrossRef]
  31. Zhang, G.; Xie, X.; Zhu, J.; Li, S.; Ding, C.; Ding, P. Pd(II)-catalyzed C(sp3)–H arylation of amino acid derivatives with click-triazoles as removable directing groups. Org. Biomol. Chem. 2015, 13, 5444–5449. [Google Scholar] [CrossRef] [PubMed]
  32. Wang, D.-H.; Wasa, M.; Giri, R.; Yu, J.-Q. Pd(II)-Catalyzed Cross-Coupling of sp3 C−H Bonds with sp2 and sp3 Boronic Acids Using Air as the Oxidant. J. Am. Chem. Soc. 2008, 130, 7190–7191. [Google Scholar] [CrossRef]
  33. Reddy, B.V.S.; Reddy, L.R.; Corey, E.J. Novel Acetoxylation and C−C Coupling Reactions at Unactivated Positions in α-Amino Acid Derivatives. Org. Lett. 2006, 8, 3391–3394. [Google Scholar] [CrossRef] [PubMed]
  34. Tran, L.D.; Daugulis, O. Nonnatural Amino Acid Synthesis by Using Carbon–Hydrogen Bond Functionalization Methodology. Angew. Chem. Int. Ed. 2012, 51, 5188–5191. [Google Scholar] [CrossRef] [PubMed]
  35. Gong, W.; Zhang, G.; Liu, T.; Giri, R.; Yu, J.-Q. Site-Selective C(sp3)–H Functionalization of Di-, Tri-, and Tetrapeptides at the N-Terminus. J. Am. Chem. Soc. 2014, 136, 16940–16946. [Google Scholar] [CrossRef]
  36. Kanyiva, K.S.; Tang, K.H.N.; Wang, J.; Shibata, T. Palladium-Catalyzed sp3 C–H Benzoxylation of Alanine Derivatives Using Aldehydes under Ambient Conditions. Synthesis 2021, 53, 3085–3093. [Google Scholar] [CrossRef]
  37. Ochiai, S.; Sakai, A.; Usuki, Y.; Kang, B.; Shinada, T.; Satoh, T. Synthesis of Indenones through Rhodium(III)-catalyzed [3+2] Annulation Utilizing a Recyclable Carbazolyl Leaving Group. Chem. Lett. 2021, 50, 585–588. [Google Scholar] [CrossRef]
  38. Okada, T.; Nobushige, K.; Satoh, T.M.; Miura, M. Ruthenium-Catalyzed Regioselective C–H Bond Acetoxylation on Carbazole and Indole Frameworks. Org. Lett. 2016, 18, 1150–1153. [Google Scholar] [CrossRef]
  39. Yokoyama, Y.; Unoh, Y.; Bohmann, R.A.; Satoh, T.; Hirano, K.; Bolm, C.; Miura, M. Rhodium-catalyzed Direct Coupling of Benzothioamides with Alkenes and Alkynes through Directed C–H Bond Cleavage. Chem. Lett. 2015, 44, 1104–1106. [Google Scholar] [CrossRef]
  40. Hashimoto, Y.; Hirano, K.; Satoh, T.; Kakiuchi, F.; Miura, M. Regioselective C–H Bond Cleavage/Alkyne Insertion under Ruthenium Catalysis. J. Org. Chem. 2013, 78, 638–646. [Google Scholar] [CrossRef]
  41. Mochida, S.; Umeda, N.; Hirano, K.; Satoh, T.; Miura, M. Rhodium-catalyzed Oxidative Coupling/Cyclization of Benzamides with Alkynes via C–H Bond Cleavage. Chem. Lett. 2010, 39, 744–746. [Google Scholar] [CrossRef]
  42. DeNardo, M.A.; Mills, M.R.; Ryabov, A.D.; Collins, T.J. Unifying Evaluation of the Technical Performances of Iron-Tetra-amido Macrocyclic Ligand Oxidation Catalysts. J. Am. Chem. Soc. 2016, 138, 2933–2936. [Google Scholar] [CrossRef] [PubMed]
  43. Vicens, L.; Bietti, M.; Costas, M. General Access to Modified α-Amino Acids by Bioinspired Stereoselective γ-C−H Bond Lactonization. Angew. Chem. Int. Ed. 2021, 60, 4740–4746. [Google Scholar] [CrossRef] [PubMed]
  44. Chen, G.; Shigenari, T.; Jain, P.; Zhang, Z.; Jin, Z.; He, J.; Li, S.; Mapelli, C.; Miller, M.M.; Poss, M.A.; et al. Ligand-Enabled β-C–H Arylation of α-Amino Acids Using a Simple and Practical Auxiliary. J. Am. Chem. Soc. 2015, 137, 3338–3351. [Google Scholar] [CrossRef] [PubMed]
  45. Park, H.; Li, Y.; Yu, J.-Q. Utilizing Carbonyl Coordination of Native Amides for Palladium-Catalyzed C(sp3)−H Olefination. Angew. Chem. Int. Ed. 2019, 58, 11424–11428. [Google Scholar] [CrossRef]
  46. Erdélyi, M.; Langer, V.; Karlén, A.; Gogoll, A. Insight into β-hairpin stability: A structural and thermodynamic study of diastereomeric β-hairpin mimetics. New J. Chem. 2002, 26, 834–843. [Google Scholar] [CrossRef]
  47. Caillard, M.; Emm, A.; Jones, A.; Matthews, T.; Williams, M. Serendipitous Synthesis of N-Tetrachlorophthaloyldehydroalanine Methyl Ester, a Michael Acceptor which is a Potential Precursor of γ-Carboxyglutamic Acid. J. Chem. Res. Synop. 1998, 12, 806–807. [Google Scholar] [CrossRef]
  48. Vijaykumar, M.; Punji, B. Pd(II)-Catalyzed Chemoselective Acetoxylation of C(sp2)–H and C(sp3)–H Bonds in Tertiary Amides. J. Org. Chem. 2021, 86, 8172–8181. [Google Scholar] [CrossRef]
  49. Zhuang, Z.; Herron, A.N.; Fan, Z.; Yu, J.-Q. Ligand-Enabled Monoselective β-C(sp3)–H Acyloxylation of Free Carboxylic Acids Using a Practical Oxidant. J. Am. Chem. Soc. 2020, 142, 6769–6776. [Google Scholar] [CrossRef]
  50. Engle, K.M.; Wang, D.H.; Yu, J.-Q. Ligand-Accelerated C−H Activation Reactions: Evidence for a Switch of Mechanism. J. Am. Chem. Soc. 2010, 132, 14137–14151. [Google Scholar] [CrossRef]
  51. Shao, Q.; Wu, K.; Zhuang, Z.; Qian, S.; Yu, J.-Q. From Pd(OAc)2 to Chiral Catalysts: The Discovery and Development of Bifunctional Mono-N-Protected Amino Acid Ligands for Diverse C–H Functionalization Reactions. Acc. Chem. Res. 2020, 53, 833–851. [Google Scholar] [CrossRef] [PubMed]
  52. Nakamura, I.; Yamamoto, Y. Transition Metal-Catalyzed Reactions of Methylenecyclopropanes. Adv. Synth. Catal. 2002, 344, 111–129. [Google Scholar] [CrossRef]
  53. Satoh, T.; Miura, M. Catalytic Processes Involving β-Carbon Elimination. Palladium Org. Synth. 2005, 14, 1–20. [Google Scholar] [CrossRef]
  54. Tran, V.T.; Gurak, J.A., Jr.; Yang, K.S.; Engle, K.M. Activation of diverse carbon–heteroatom and carbon–carbon bonds via palladium(II)-catalysed β-X elimination. Nat. Chem. 2018, 10, 1126–1133. [Google Scholar] [CrossRef]
  55. Zhang, P.; Zeng, J.; Pan, P.; Zhang, X.-j.; Yan, M. Palladium-Catalyzed Migratory Insertion of Carbenes and C–C Cleavage of Cycloalkanecarboxamides. Org. Lett. 2022, 24, 536–541. [Google Scholar] [CrossRef]
  56. El-Zahabi, M.A.; Gad, L.M.; Bamanie, F.H.; Al-Marzooki, Z. Synthesis of new cyclic imides derivatives with potential hypolipidemic activity. Med. Chem. Res. 2012, 21, 75. [Google Scholar] [CrossRef]
  57. Singh, A.K.; Kishan, R.; Balachandran, V.; Singh, T.; Tiwari, H.K.; Singh, B.K.; Rathi, B. Entry of chiral phthalimides with significant second order nonlinear optical and piezoelectric properties. RSC Adv. 2013, 3, 14750. [Google Scholar] [CrossRef]
  58. Matsumoto, A.; Wang, Z.; Maruoka, K. Radical-Mediated Activation of Esters with a Copper/Selectfluor System: Synthesis of Bulky Amides and Peptides. J. Org. Chem. 2021, 86, 5401. [Google Scholar] [CrossRef] [PubMed]
  59. Zhang, J.; Chen, Z.X.; Du, T.; Li, B.; Gu, Y.; Tian, S.-K. Aryne-Mediated [2,3]-Sigmatropic Rearrangement of Tertiary Allylic Amines. Orig. Lett. 2016, 18, 4872. [Google Scholar] [CrossRef]
Scheme 1. Acyloxylation utilizing bidentate directing group. (a) Corey’s work; (b) Daugulis’s work; (c) Yu’s work; (d) Kanyiva & Shibata’s work.
Scheme 1. Acyloxylation utilizing bidentate directing group. (a) Corey’s work; (b) Daugulis’s work; (c) Yu’s work; (d) Kanyiva & Shibata’s work.
Chemistry 05 00093 sch001
Scheme 2. Screening of ligands. The yield of 2a was determined by 1H NMR using 1,4-dimethoxybenzene as internal standard.
Scheme 2. Screening of ligands. The yield of 2a was determined by 1H NMR using 1,4-dimethoxybenzene as internal standard.
Chemistry 05 00093 sch002
Scheme 3. Screening of directing groups.
Scheme 3. Screening of directing groups.
Chemistry 05 00093 sch003
Scheme 4. Substrate scope of α-amino acids 1.
Scheme 4. Substrate scope of α-amino acids 1.
Chemistry 05 00093 sch004
Scheme 5. A plausible mechanism.
Scheme 5. A plausible mechanism.
Chemistry 05 00093 sch005
Scheme 6. Acetoxylation of dipeptide derivative 3.
Scheme 6. Acetoxylation of dipeptide derivative 3.
Chemistry 05 00093 sch006
Scheme 7. Methanolysis of 2a.
Scheme 7. Methanolysis of 2a.
Chemistry 05 00093 sch007
Table 1. Optimization of the acetoxylation reaction conditions 1.
Table 1. Optimization of the acetoxylation reaction conditions 1.
Chemistry 05 00093 i001
EntryL1 (mol%)SolventYield of 2a (%) 2
1 30HFIP/Ac2O (9:1)tr.
20HFIP/Ac2O (9:1)19
30HFIP/THF/Ac2O (5:4:1)24
40HFIP/dioxane/Ac2O (5:4:1)44
50HFIP/DME/Ac2O (5:4:1)45
60HFIP/diglyme/Ac2O (5:4:1)36
710HFIP/DME/Ac2O (5:4:1)67 (65)
8 310HFIP/DME/Ac2O (5:4:1)(62)
910HFIP/DME/Ac2O (6:3:1)59
1010HFIP/DME/Ac2O (4:5:1)58
11 410HFIP/DME/Ac2O (5:4:1)tr.
12 510HFIP/DME/Ac2O (5:4:1)59
1 Reaction conditions: 1a (0.3 mmol), PhI(OAc)2 (0.9 mmol), Pd(MeCN)4(BF4)2 (0.015 mmol), (L1 (0.03 mmol)) in solvent (0.7 mL) under argon (1 atm) at 80 °C for 20 h, unless otherwise noted. 2 Determined by 1H NMR using 1,4-dimethoxybenzene as internal standard. Value in parentheses indicates yield after purification. 3 Together, 1a (1 mmol), PhI(OAc)2 (3 mmol), Pd(MeCN)4(BF4)2 (0.05 mmol), and L1 (0.1 mmol) were used in solvent (2.1 mL). 4 Pd(OAc)2 was used in place of Pd(MeCN)4(BF4)2. 5 At 100 °C.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Matsumura, A.; Usuki, Y.; Satoh, T. Palladium-Catalyzed sp3 C–H Acetoxylation of α,α-Disubstituted α-Amino Acids. Chemistry 2023, 5, 1369-1377. https://doi.org/10.3390/chemistry5020093

AMA Style

Matsumura A, Usuki Y, Satoh T. Palladium-Catalyzed sp3 C–H Acetoxylation of α,α-Disubstituted α-Amino Acids. Chemistry. 2023; 5(2):1369-1377. https://doi.org/10.3390/chemistry5020093

Chicago/Turabian Style

Matsumura, Atsushi, Yoshinosuke Usuki, and Tetsuya Satoh. 2023. "Palladium-Catalyzed sp3 C–H Acetoxylation of α,α-Disubstituted α-Amino Acids" Chemistry 5, no. 2: 1369-1377. https://doi.org/10.3390/chemistry5020093

Article Metrics

Back to TopTop