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Communication

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

by
Atsushi Matsumura
,
Yoshinosuke Usuki
* and
Tetsuya Satoh
*
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
(This article belongs to the Special Issue Catalytic Organic Synthesis—a Special Issue in Honor of Professor Masahiro Miura)
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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 L3–6 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.

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Chemistry 05 00093 sch001 550
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.
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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.
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Chemistry 05 00093 sch003 550
Scheme 3. Screening of directing groups.
Scheme 3. Screening of directing groups.
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Scheme 4. Substrate scope of α-amino acids 1.
Scheme 4. Substrate scope of α-amino acids 1.
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Scheme 5. A plausible mechanism.
Scheme 5. A plausible mechanism.
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Scheme 6. Acetoxylation of dipeptide derivative 3.
Scheme 6. Acetoxylation of dipeptide derivative 3.
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Scheme 7. Methanolysis of 2a.
Scheme 7. Methanolysis of 2a.
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Table
Table 1. Optimization of the acetoxylation reaction conditions 1.
Table 1. Optimization of the acetoxylation reaction conditions 1.
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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.
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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

APA Style

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

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