# Access to Unnatural Enantioenriched Amino Acids Derived from Phenylglycine through Nickel-Catalyzed Suzuki–Miyaura Coupling Involving Carbon–Oxygen Bond Insertion

Jiaxiao Yang, Mamoudou Doucoure, Yasmine Charifi, Gustave Villard, Ying Xu, Joëlle Perard-Viret, Marie-Isabelle Lannou

► To cite this version:

Jiaxiao Yang, Mamoudou Doucoure, Yasmine Charifi, Gustave Villard, Ying Xu, et al.. Access to Unnatural Enantioenriched Amino Acids Derived from Phenylglycine through Nickel-Catalyzed Suzuki–Miyaura Coupling Involving Carbon–Oxygen Bond Insertion. Journal of Organic Chemistry, 2025, 90 (30), pp.10927-10933. 10.1021/acs.joc.5c00844. hal-05346705

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# Access to Unnatural Enantioenriched Amino Acids Derived from Phenylglycine through Nickel-Catalyzed Suzuki-Miyaura Coupling Involving Carbon-Oxygen Bond Insertion

Jiaxiao Yang,<sup>a†</sup> Mamoudou Doucoure,<sup>a†</sup> Yasmine Charifi,<sup>a</sup> Gustave Villard,<sup>a</sup> Ying Xu,<sup>a</sup>

Joëlle Perard-Viret,<sup>a</sup> and Marie-Isabelle Lannou<sup>a*</sup>

<sup>a</sup>: Université Paris Cité, CNRS UMR 8038, F-75006 Paris, France

E-mail: [marie-isabelle.lannou@u-paris.fr](mailto:marie-isabelle.lannou@u-paris.fr)

<figure><img src="image_2.png" /></figure>

**Abstract:** We report herein the optimization of a nickel-catalyzed Suzuki-Miyaura coupling for the synthesis of unnatural bi/polyaryl and heteroaryl amino acid derivatives (28 examples). The aim is to provide an inexpensive and efficient alternative to palladium-catalyzed reactions, exploiting nickel's reactivity towards oxygen-based electrophiles. To this end, easily racemizable hydroxyphenylglycine derivatives are used. The reaction involves an air-stable nickel-precatalyst in association with an electron-rich phosphine and potassium carbonate in water-free conditions, to ensure the highest enantiomeric purities and conversions.

Chiral α-amino acids are fundamental elements in the chemistry of life, particularly in the design of therapeutic agents where selective interactions with biological targets are crucial.¹ However, a problem often encountered in this field is the inaccessibility of certain chiral derivatives of non-natural amino acids in their enantiomerically pure form. It is therefore crucial to develop efficient and economical approaches for the straightforward synthesis of unnatural chiral α-amino acids.²

The Suzuki-Miyaura coupling is a fundamental tool in modern synthetic chemistry. Remarkable features such as high selectivity, low production of toxic by-products, tolerance to various functional groups and commercial availability of the reactants have contributed to its wide application in the pharmaceutical industry.³ This reaction is also a standard in the site-selective derivatization of non-proteinogenic amino-acids for peptide diversification.⁴ In this field, we have been interested in commercial enantiopure 4-hydroxyphenylglycine (HPG),⁵ a non-proteogenic amino acid found in the vancomycin class of antibiotics (GPAs)⁶ and extensively used for the production of β-lactam antibiotics.⁷
Hydroxyphenylglycine therefore appears to be the reagent of choice for direct functionalization into mesylate or tosylate that could readily be used in Suzuki-Miyaura reactions. Through this route, an unprecedented direct access to enantioenriched non-proteogenic amino acid derivatives could be targeted. However, such substrates appear particularly challenging due to the low reactivity of oxygen-based electrophiles (mesylates, tosylates, phosphates, sulfamates...)⁸ associated to the well-known base-induced racemization of phenylglycine derivatives.⁹

To date, a single racemic amino acid derived from phenylglycine (2aa) results from the insertion of Ni(0) into a low-reactive C-O bond.¹⁰ This reaction, described by Ueda, was carried out from tosylate (+/-)-1a using air-sensitive Ni(cod)₂ (10 mol%) and tricyclohexylphosphine (20 mol%) in dioxane at 70 °C (patents 2003, 2007, Scheme 1-A). Access to enantio-enriched phenylglycine derivatives through Suzuki-Miyaura coupling remains therefore limited to (pseudo)haloaryl substrates, mainly in position 3, in association with palladium catalysts. The most challenging works, realized by the groups of Nicolaou¹¹ and Boger,¹²a,b concern the construction of the AB ring system of vancomycin and related glycopeptide antibiotics via an atroposelective Suzuki-Miyaura cross-coupling. Latest developments by Boger¹²b allowed to produce biaryl 4 (Scheme 1-B) in 89% yield with an excellent diastereoselectivity from (R)-3 however a high loading of catalyst and chiral ligand is required. Beside these works, only a few reports have been published. In 2007, Lloyd-Williams' group underlined the problematic of racemization of phenylglycine derivatives using (R)-3,¹³ and showed that the process could be avoided by using sodium succinate, but with an alteration in yield (4 compounds - 5aa, 5ba-c, Scheme 1-C).¹⁴ Lastly, scarce articles ¹⁵,¹⁶,¹⁷ report on the coupling of 4-(pseudo)-haloaryls derivatives of phenylglycine, and this field is even more restricted when (hetero)arylboronic acids are used.¹⁵a,¹⁶,¹⁷ In 2010, Vogel¹⁶ investigated the reactivity of enantiopure triflate (R)-1b for an access to three α-mannosidase inhibitors (6, Scheme 1-D). Although specific rotations were provided, enantiopurities of the products (2aa, 2ab, 2ba) were not mentioned, making the potential of the method difficult to assess. Another study, in racemic series, was realized by Scammells in 2016¹⁷ from a 4-bromophenylglycine ester for the synthesis of 17 hydroxamic acids, inhibitors of aminopeptidases involved in malaria.

A Ueda, 2007: one example *racemic series*

<figure><img src="image_3.png" /></figure>

B Boger 2020: vancomycin *enantio-enriched series*

<figure><img src="image_4.png" /></figure>

C Lloyd-Williams, 2007: 4 examples *enantio-enriched series*

<figure><img src="image_5.png" /></figure>

Ar = 1-Hydroxy-5,7-dimethoxy-3H-2,1-benzoxaborole
HetAr = indolyl-5-yl, indolyl-6-yl, indolyl-7-yl boronic acid

5ba-c
42-52%
R/S 100:0

D Vogel, 2010: 3 examples *enantio-enriched series*

<figure><img src="image_6.png" /></figure>
Scheme 1: State of the art of Suzuki coupling reactions involving phenylglycine (PhGly) derivatives

As evidenced above,¹¹⁻¹⁷ palladium, although over-exploited and scarcely available, remains the metal of choice in cross-coupling reactions due to its excellent catalytic properties and reactivity towards (pseudo)halogen derivatives.¹⁸ However, its high price ($29.67/g)¹⁹ has led to the search for more affordable alternatives. Therefore, we wish to take advantage of the good reactivity of abundant and inexpensive nickel ($0.0146/g)²⁰ towards oxygen-based electrophiles⁸ for synthesizing new enantiо-enriched phenyl glycine derivatives. To this end, we aim at performing Suzuki-Miyaura cross-couplings involving low-reactive mesylate (R)-1c or tosylate (R)-1a derivatives of commercial HPG-OMe and aryl/heteroarylboronic acids. Noteworthy, to date, the reactivity of mesylate (R)-1c remains unstudied and only racemic tosylate (+/-)-1a has been used (1 example).¹⁰ In parallel, preventing racemization will constitute a main challenge as introduction of an (hetero)aromatic ring in position 4 may favor the racemization process. This point has not been explored so far with Boc-HPG-OMe derivatives bearing a substituent in 4-position, since most compounds have been prepared as racemic mixtures.¹⁷

Optimization of the catalytic system

The optimization of the reaction conditions for the nickel-catalyzed Suzuki-Miyaura was conducted using enantiopure mesylate **1c** (ee > 99%), which shows the best atom economy (Scheme 2).

<figure><img src="image_7.png" /></figure>

Scheme 2: Optimization of the Suzuki-Miyaura reaction

For this purpose, we selected and synthesized four bench-stable Ni(II) precatalysts, described by Jamison (**Cat 1**),²¹ Buchwald (**Cat 2**),²² Grimaud (**Cat 3**),²³ and Beckmann (**Cat 4**).²⁴ able to generate the Ni(0) complexes *in situ* under the reaction conditions. After screening of the array of nickel catalysts (**Cat 1-4**), additional ligands,²⁵ bases, solvents²⁶ and temperatures (see the supplementary material for details), we set up a simple experimental procedure and the reaction of (R)-1c (0.5 mmol) with phenylboronic acid (0.6 equiv.), 3 mol% of **Cat. 3**, 6 mol% tricyclohexylphosphonium tetrafluoroborate salt and 4 equiv. K₂CO₃ in degassed dry toluene or MeTHF quantitatively yielded **2ad** with an excellent optical purity (94%) in 4 h at 80 °C after aqueous work-up. Noteworthy, both precatalyst and phosphine are bench stable, avoiding the need for glovebox techniques.
Exemplifications with various boronic acids

The scope of the Suzuki-Miyaura cross-coupling involving mesylate (R)-1c, and in a lesser extent, tosylate (R)-1a derivatives of Boc-HPG-OMe was investigated with various (poly)arylboronic acids under optimized conditions (Scheme 3).

<figure><img src="image_8.png" /></figure>

Scheme 3: Suzuki-Miyaura cross-couplings involving Boc-HPG-OMe derivatives (R)-1a and (R)-1c
and arylboronic acids

Reacting **1a** or **1c** with unsubstituted (H) and monosubstituted boronic aryl acids (*p*-OEt, *p*-OMe, *p*-TMS) delivered the corresponding biaryl compounds (**2ab**, **2ad**, **2ae**, **2af**) with good enantiomeric excesses in both toluene and 2-MeTHF. Ortho substitution (*o*-OMe) resulted in a decrease in yield, however **2ag** was obtained from tosylate **1a**, which may be more sensitive to steric bulk than mesylate **1c**. Disubstituted arylboronic acids were next examined. Cross-coupling between **1c** and 3,5-dimethylphenyl-, 2,3-dihydro-1-benzofuran-5-yl- and 2,4-dimethoxyphenylboronic acids efficiently

<footnote>a: performed with 1.2 equiv. of boronic acid, b: performed with 1.6 equiv. of boronic acid,</footnote>

<footnote>c: Performed at C = 0.2 mol.L⁻¹, d: from 4-cyanophenylboronic acid pinacol ester.</footnote>
provided biaryl amino esters **2ah**, **2ai** and **2aj** with good yields and *ee*. The reaction involving 3,4-methylenedioxyphenylboronic acid was sluggish in toluene (16 h) due to solubility issues, providing **2ak** with 65% yield and 75% *ee*, however, running the reaction in 2-MeTHF led to a significant enhancement in yield and optical purity (*ee* = 89%).

Reactions with arylboronic acids type substrates bearing electron-withdrawing groups were next examined. 3-fluoro-4-methoxyphenyl-, 4-fluorophenyl-, 2,3-difluorophenyl, 3- and 4-trifluoromethylphenyl- and 3,5-ditrifluoromethylphenyl boronic acids delivered the corresponding amino-esters (**2al**, **2am**,²⁸ **2an**,²⁸ **2ao**, **2ac** and **2ap**) with good yields and excellent enantiomeric purities. However, reaction involving 4-cyanophenylboronic acid was hampered by solubility issues and delivered **2aq** with a low yield and enantiomeric excess (7%). The alternative use of 4-cyanophenylboronic acid pinacol ester furnished **2aq** in 42% yield as a racemic mixture in 2-MeTHF while the reaction did not proceed in toluene. Finally, 3-acetylphenyl- and 3-ethoxycarbonyl-phenylboronic acids respectively provided **2ar** and **2as** in moderate to good yields as well as excellent enantioselectivities in toluene and 2-MeTHF, evidencing that the sensitive functions are not altered during the reaction.

Polyarylboronic acids (1-naphthyl-, 2-naphthyl and 9-phenanthrenyl-) were also successfully coupled with **1c** yielding **2at**, **2au**, and **2av** with good yields and high enantiomeric purities. Finally, it should be mentioned that reactions between **1c** and 4-methoxyphenyl-, 3,5-dimethylphenyl- and 2-naphthylboronic acids could be performed on respectively 4.2, 3.4 and 5 mmol scale, providing **2ae**, **2ah** and **2au** with both excellent yields and enantiomeric purities.

In order to better understand the loss of optical purity of the products, racemization tests were carried out in toluene and in 2-MeTHF. In general, racemization of the substrate (**1a**/*1c*) is faster than racemization of the product under the reaction conditions, and this tendency is greater in 2-MeTHF than in toluene. Therefore, the optical purity of synthetic phenyl glycine derivatives is multifactorial, depending on both the epimerization of the product, which correlates with its pK<sub>a</sub>, and that of substrate **1a**/*1c* (see the supplementary information, section 4.2 for details).

We next turned our attention to the couplings involving heteroarylboronic acids (Scheme 4).
<figure><img src="image_9.png" /></figure>

<caption>Scheme 4: Suzuki-Miyaura cross-couplings involving Boc-HPG-OMe derivatives (R)-1a and (R)-1c and heteroarylboronic acids</caption>

Dibenzofuran-4-boronic acid was successfully coupled with **1a** and **1c** to deliver **2bb** with excellent enantiomeric excesses. A marked improvement in yield was observed in 2-MeTHF by increasing the amount of boronic acid to 1.6 equivalent. Reactions of **1c** with dibenzothiophene-4-boronic acid and furan-3-boronic acid in toluene delivered **2bc** and **2bd** with low yields, due to solubility issues, along with average enantiomeric excesses (respectively 55% and 69%), which may result from extended reaction times. Performing the reactions in 2-MeTHF lead to slight improvement in yield (38% over 6h) for **2bc** along with a significant increase in optical purity (ee = 81%); in addition, **2bd** was obtained in six hours with good yield (65%) and high enantiopurity (87%). Coupling of **1c** with furan-2-boronic acid provided **2be** in 15 h with a good yield but a low enantiopurity (ee ≈ 33%) in 2-MeTHF. Next, reaction with benzothiophene-3-boronic acid delivered the expected amino ester **2bf** with satisfactory enantioselectivity but in moderate yield due to solubility issues. Finally, pyridine derived boronic acids bearing either an electron withdrawing or an electron donating group (2-trifluoromethyl- or 2-methoxy pyridine-5-boronic acid) were successfully coupled with **1c** to give respectively **2bg** and **2bh** with good yields and enantioselectivities in toluene (see the supplementary information, section 4.2 for details).

Synthesis of **2ap** and **2bd** was also attempted from enantioenriched more reactive triflate (R)-1b (ee = 97%) in 2-MeTHF, at 50 °C with two equivalents of base (Scheme 5).

<figure><img src="image_10.png" /><figcaption>Scheme 5: Suzuki-Miyaura cross-couplings involving triflate (R)-1b</figcaption></figure>

<footnote>a: performed with 1.2 equiv. of boronic acid, b: performed with 1.6 equiv. of boronic acid.</footnote>
Under these smooth conditions (50 °C, 2 equiv. of base), conversions were good, however, a decrease in yield (due to difficulties at the purification step) and *ee* was observed for **2ap** whereas a better yield and a similar *ee* was obtained for **2bd** compared to reaction with **1c** (*ee* = 87%).

Finally, in order to estimate the amount of residual nickel in the products, inductively coupled plasma mass spectrometry (ICP-MS) analyses were carried out on a set of phenylglycine derivatives after flash chromatography. Interestingly, compounds **2ae**, **2al** and **2as** retained very low amounts of nickel respectively <0.1, 1.7 and 2.5 ppm, while 16.6 ppm nickel were found for **2bh** which features a pyridine ring. All these values are in line with the worldwide permitted daily exposure (PDE = 220 µg/day - oral ingestion), making the compounds suitable for potential pharmaceutical application.²⁹

## Conclusions

The nickel-catalyzed Suzuki-Miyaura coupling of a wide range of aryl/heteroarylboronic acids with low-reactive enantiopure 4-mesyl/4-tosylhydroxyphenylglycine derivatives (*R*)-1a/1c has been achieved using a bench-stable nickel complex at low catalyst loading (3 mol%). The process is easily scalable (up to 5 mmol), tolerant to functional groups such as ester and ketone and leads to unprecedented amino-acid derivatives with high enantiopurities (19 examples > 90% *ee* and 6 examples with *ee* ranging from 81 to 89%) using a variety of aryl/polyaryl- and heteroarylboronic acids. Some limitations have arisen due to solubility issues with *p*-cyanophenyl boronic acid (*ee* = 7%) or heteroarylboronic acids (2 examples, *ee* ranging from 33 to 72%), however, further optimization using triflate (*R*)-1b under milder conditions could be promising. Resulting unnatural amino-esters appear to be good candidates for incorporation in peptides, for the design of new active drugs for cancer therapy³⁰ or as precursors of new Box-type ligands,³¹ which are highly valuable tools in asymmetric catalysis.

## ASSOCIATED CONTENT

### Data Availability Statement

The data underlying this study are available in the published article and its online Supporting Information.

### Supporting Information

The Supporting Information is available free of charge at

Experimental details and data, NMR spectra (PDF) and HPLC chromatograms.

## AUTHOR INFORMATION

### Corresponding Author

Marie-Isabelle Lannou – Faculté de Pharmacie de Paris, Université Paris Cité, CNRS UMR 8038, Paris F-75006, France
Email : marie-isabelle.lannou@u-paris.fr

orcid.org/0000-0002-3042-2058

Authors

Jiaxiao Yang – Faculté de Pharmacie de Paris, Université Paris Cité, CNRS UMR 8038, Paris F-75006, France

Mamoudou Doucoure – Faculté de Pharmacie de Paris, Université Paris Cité, CNRS UMR 8038, Paris F-75006, France

Yasmine Charifi – Faculté de Pharmacie de Paris, Université Paris Cité, CNRS UMR 8038, Paris F-75006, France

Gustave Villard – Faculté de Pharmacie de Paris, Université Paris Cité, CNRS UMR 8038, Paris F-75006, France

Ying Xu – Faculté de Pharmacie de Paris, Université Paris Cité, CNRS UMR 8038, Paris F-75006, France

Joëlle Perard-Viret – Faculté de Pharmacie de Paris, Université Paris Cité, CNRS UMR 8038, Paris F-75006, France

orcid.org/0000-0002-4419-8499

Author Contributions

†J.Y. and M.D. contributed equally to this work. The manuscript was written through contributions of all authors.

All authors have given approval to the final version of the manuscript.

Notes

The authors declare no competing financial interest.

Acknowledgments

This work was supported by ANR ChirMetNit no. ANR-20-CE07-0016 allowing the PhD financial support of M.D. The authors would like to thanks Cyril Colas from the "Fédération de Recherche" ICOA/CBM (FR2708)" for HRMS analysis and Dr. Joël Poupon from the Laboratoire de Toxicologie biologique, Groupe hospitalier Saint Louis – Lariboisière for ICP-MS analysis.

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