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Tandem Alkylation–Second-Order Asymmetric Transformation Protocol for the Preparation of Phenylalanine-Type Tailor-Made α-Amino Acids

In this work, we disclose an advanced general process for the synthesis of tailor-made α-amino acids (α-AAs) via tandem alkylation–second-order asymmetric transformation. The first step is the alkylation of the chiral Ni(II) complex of glycine Schiff base, which is conducted under mild phase-transfer conditions allowing the structural construction of target α-AAs. The second step is based on the methodologically rare second-order asymmetric transformation, resulting in nearly complete precipitation of the corresponding (SC,RN,RC)-configured diastereomer, which can be collected by a simple filtration. The operational convenience and potential scalability of all experimental procedures, coupled with excellent stereochemical outcome, render this method of high synthetic value for the preparation of various tailor-made α-AAs.


■ INTRODUCTION
Amino acids (AAs) are among a handful of paramount molecules involved in virtually all aspects of the phenomenon of life. Quite naturally, they played a significant role in organic, bioorganic, medicinal, and pharmaceutical chemistry from the earliest days of modern healthcare and life sciences. 1 In particular, the use of tailor-made 2 AAs in the design of peptides/peptidomimetics with restricted number of conformations and precise positioning of the side-chains in the χ-space 3 is a well-established paradigm in the modern pharmaceutical industry. 1,4,5 Quite interestingly, one of the emerging areas of tailor-made AA application is the biological containment strategy of the produced genetically modified organisms. 6 Accordingly, the current interest in the asymmetric synthesis of tailor-made AAs 7 and their analogues, such as amino sulfonic, 8 phosphonic, 9 and fluorine-containing 10 acids, is at an all-time high, targeting novel structural motifs, functions, and properties. Consistent with our continuous interest in asymmetric synthesis of various tailor-made AAs, for example, fluorine-11 and phosphorus-containing, 12 sterically constrained, 13 and their nonlinear chiroptical properties, such as self-disproportionation of enantiomers, 14 we were actively developing the Ni(II) complex chemistry of AA Schiff bases 4d,7d,e as a general approach for the preparation of tailor-made AAs (Scheme 1).
As shown in Scheme 1, trichloro-substituted ligand (S)-or (R)-1, currently the most frequently used source of recyclable chirality in this method, 15 is reacted with glycine and a source of Ni(II) ions to produce the Schiff base complex 2. 16 The square-planar Ni(II) complex 2 serves as a versatile chiral nucleophilic glycine equivalent to afford products 3 by the reactions with various electrophilic reagents. Most commonly used reaction types include, for example, alkyl halide alkylations, 17 Michael,18 aldol,19 and Mannich 20 addition reactions. Intermediate products 3 can be conveniently disassembled to release target AAs 4−10 and to recycle chiral tridentate ligand 1. This method can be used for the preparation of general type α-AAs 4, β-functionalized/ substituted derivatives 5, sym-6, 21 or chiral quaternary 7 22 α-AAs, in particular, (1R,2S)-1-amino-2-vinylcyclopropane-1carboxylic acid 8 23 and bis-α-AAs of type 9. 24 Moreover, the major advantage of this method over other well-developed general approaches 7b,c,25 is its exceptionally successful application for kinetic resolution of unprotected αand β-AAs of types 4 26 and 10, 27 respectively. This latter application was shown to be competitive with traditionally economically attractive enzymatic approaches. 28 Most recently, using the modular approach 29 for the design of chiral tridentate ligands, we developed a series of ligands featuring free N−H functionality and multiple stereogenic centers. 30 In particular, the adamantyl-containing derivative 11 (Scheme 2) was found to possess some remarkable physicochemical properties for the development of second-order asymmetric transformation (SOAT) approach for the general synthesis of α-AAs. 31 As presented in Scheme 2, in the previous work, we demonstrated that the newly designed ligand 11 readily reacts with racemic α-AAs 12 to produce a mixture of four theoretically possible diastereomeric products. 31 However, because of the extreme lipophilicity of the adamantyl moiety, 32 one of the diastereomers, (S C ,R N ,R C )-configured 13, precipitates from the methanol or aqueous methanol solution, thus driving the equilibrium of all other diastereomers to the one major reaction product. As the next logical step in the advancement of this methodology, we now report a tandem alkylation−SOAT protocol, which includes synthesis of glycine Schiff base Ni(II) complex 14 and its alkylation under phasetransfer catalysis (PTC) conditions followed by SOAT via equilibration/precipitation of major products 15.

■ RESULTS AND DISCUSSION
Unlike the asymmetric synthesis, where the major product is a result of preferential stereochemical interactions, which can be comprehended, predicted, and rationally designed, the SOAT is essentially a serendipitous approach resulting from rather complex and multifactorial interplay of numerous chemical/ steric/physical properties. 33 Nevertheless, success in developing a SOAT process using ligand 11 was predicated on the idea of "extreme" lipophilic properties 32 of the corresponding rimantadine-containing Ni(II) complexes. 31 Drawing from the previous results, we decided to extend the synthetic versatility of this approach by preparing the required diastereomeric complexes not via the reactions of ligand 11 with racemates of the target α-AAs but via homologation of the intermediate glycine derivative. To this end, we focused on the synthesis of required glycine complexes 14 (Scheme 3).
After some extensive experimentation, we found that the application of Na 2 CO 3 as a base, in combination with catalytic amounts of n-Bu 4 NI, provides for the most practical preparation of the target glycine complexes (S C ,R N )-14 and (S C ,S N )-14, in about 3:1 ratio. Under these conditions, using only 10% excess of glycine and the Ni(II) source allowed for the complete conversion of the starting ligand (S)-11 to products 14, isolated with quantitative chemical yield. Clean preparation of glycine complexes 14 was very important part of the project allowing us to avoid any unnecessary purification of the intermediate derivatives. Having achieved virtually byproduct-less synthesis of glycine complexes 14, we focused on the next alkylation step. On the basis of the previous research, 4d we selected PTC conditions 34 allowing for very mild homologation of the glycine moiety with usually excellent chemical yields. The results obtained are summarized in Scheme 4.
As a model experiment, we selected the alkylation reaction using m-bromobenzyl bromide 16 (Scheme 4). In this case, the expected product 15a was previously obtained using the reaction of racemic AA with ligand (S)-11, 31 thus facilitating Scheme 1. General Approach for the Asymmetric Synthesis of AAs via Ni(II) Complexes of Schiff Bases the identification and stereochemical assignments. Starting glycine complexes 14 were used as obtained, without any purification, as a 3:1 mixture of (S C ,R N )-14 and (S C ,S N )-14 diastereomers. We found that using 1,2-dichloroethane as an organic solvent, 30% aqueous NaOH as a base, and 25 mol % of n-Bu 4 NI as a phase-transfer catalyst, virtually complete consumption of starting glycine complexes 14 can be achieved in about 10 min of the reaction time. Analysis of the reaction mixture by thin-layer chromatography (TLC) showed expected alkylation products 15a as a major (>50%) product and 17a−19a as minor products. The stereogenic nitrogen and AA α-carbon atoms in compounds 15a and 17a−19a are configurationally unstable. Therefore, under the basic conditions, all four diastereomers undergo rapid epimerization and interconversion via stepwise inversion of either nitrogen or αcarbon or both atoms. Nonetheless, diastereomeric products 15a and 17a−19a are compounds of different chemical properties, in particular, the solubility in a given solvent, providing the opportunity for a SOAT process. Indeed, the major diastereomer (S C ,R N ,R C )-15a was found to gradually precipitate from the reaction mixture, leading to a progressive transformation of more soluble 17a−19a to the crystalline precipitate of compound 15a. Thus, after about 1 h of stirring at room temperature, the reaction mixture was filtered affording diastereomerically pure (S C ,R N ,R C )-15a with 92.4% yield.
This tandem alkylation−SOAT protocol was found to be of general application for the preparation of various phenylalanine-type tailor-made α-AAs. For example, the derivatives of p-bromo-(15b), p-chloro-(15c), p-trifluoromethyl-(15d), piodo-(15e), and p-nitro-substituted (15f) phenylalanines were readily prepared in diastereomerically pure form under the same conditions using filtration as the final isolation procedure. Of particular interest is the preparation of naphthylalanine derivative (S C ,R N ,R C )-15g, which was isolated with respectable chemical yield. In the case of compounds 15c,e, and f, the application of the standard conditions gave relatively lower isolated yields of ∼50−56%. In this regard, we would like to emphasize that relatively modest isolated yields are the result of incomplete precipitation of the major diastereomer from the reaction mixture. Furthermore, it should be noted that under the SOAT conditions, the isolated yield depends on a physicochemical property which can be conditioned by optimizing the solvent system for each particular case. 33 For instance, a gradual addition of water to the reaction mixture leads to a lower solubility of products allowing increasing precipitation of the target products. This possibility was demonstrated on the example of product 15f, yield of which was improved from 56.5 to 86.5% by adding about 20% of water to the reaction mixture (see Supporting Information). It should be noted, however, that the diastereomeric purity of thus prepared complex 15f was 93.2% de. On the other hand, attempts to use this tandem procedure for the preparation of α-AA-containing alkyl side-chains were unsuccessful. The major problem we encountered was low reactivity of alkyl halides under the PTC conditions.
Diastereomerically pure Ni(II) complexes 15 can be readily disassembled to release the target AAs or their protected derivatives. 4d For example, diastereomer (S C ,R N ,R C )-15a was treated with 3 N HCl in methanol to produce m-bromophenylalanine (R)-20 and chiral ligand (S)-11 (Scheme 5). The latter, configurationally uncompromised, was almost quantitatively recovered and reused for continuous synthesis of other AAs.
AA (R)-20 was not isolated in analytically pure form but transformed in situ to the corresponding Fmoc derivative (R)-21. The standard protection protocol with application of N-(9fluorenylmethoxycarbonyloxy)succinimide (Fmoc-OSu) was used, with an exception that ethylenediaminetetraacetic acid (EDTA) was added to chelate the Ni(II) ions.
In another example, presented in Scheme 6, we demonstrate the isolation of free p-nitro-phenylalanine (R)-23. Thus, after the disassembly of diastereomerically pure Ni(II) complex (S C ,R N ,R C )-15f in methanol under the action of 3 N HCl, AA (R)-23 was isolated by precipitation at the isoelectric point (pH 5.5) in the presence of EDTA to chelate the Ni(II) ions. For the further use of this tailor-made AA in our peptiderelated projects, we also prepared Fmoc-protected derivative (R)-24, similar to the preparation of m-bromo-phenylalanine (R)-21 (Scheme 6).

■ CONCLUSIONS
We demonstrate that Ni(II) complexes (S C ,R N )-and (S C ,S N )-14, derived from glycine Schiff base and (S)-rimantadine, can be regioselectivity alkylated on the glycine residue under the PTC conditions affording a mixture of up to four diastereomeric products. Without purification, the alkylated products can be submitted to the SOAT conditions allowing a transformation of the diastereomeric mixture to single precipitated stereoisomer 15 of (S C ,R N ,R C ) absolute configuration. The operational convenience and chromatographyfree experimental procedures render this method of potentially high synthetic value for the preparation of phenylalanine-type tailor-made α-AAs.

■ EXPERIMENTAL SECTION
General Information. All reagents and solvents were used as received. The reaction mixture was magnetically stirred and monitored with the aid of TLC on precoated silica gel plates, and visualization was carried out using UV light and ninhydrin. Flash chromatography was performed with the indicated solvents on silica gel (particle size 0.040−0.063 mm). Yields reported are for isolated, spectroscopically pure compounds.

Scheme 3. Optimized Conditions for the Preparation of the Requisite Ni(II) Complexes of Glycine (S C ,R N )-14 and (S C ,S N )-14
1 H and 13 C spectra were recorded on a 300 MHz Bruker instrument. Chemical shifts are given in ppm (δ), referenced to the residual proton resonances of the solvents. Coupling constants (J) are given in Hz. The letters s, d, t, q, m, and br stand for singlet, doublet, triplet, quartet, multiplet, and broad, respectively. High-resolution mass spectra (HRMS) were recorded using an ultraperformance liquid chromatography/ quadrupole time-of-flight mass spectrometry system in the ESI mode.

Procedure for the Preparation of Ni(II) Complexes by
Reaction of Ligand (S)-11 with Glycine. To a mixture of ligand (S)-11 (1.0 g, 2.22 mmol), nickel(II) nitrate hexahydrate (0. 71 g, 2.44 mmol), glycine (0.18 g, 2.44 mmol), tetrabutylammonium iodide (0.08 g, 10 mol %), and methanol (40 mL) was added sodium carbonate (1.18 g, 11.1 mmol), and the reaction mixture was stirred at reflux for 2 h. After the ligand (S)-11 was consumed, the reaction was quenched by pouring icy 5% aqueous acetic acid (200 mL) to give a precipitate. The precipitate was filtrated, washed with 5% aqueous acetic acid, and dried in vacuo at 50°C overnight to afford the diastereomixture of Ni(II) complex (S C ,R N )-14 and (S C ,S N )-14. A 3:1 ratio mixture of two diastereomers was obtained. The spectral data were reported in our previous literature.
General  (8 volumes), 30% aqueous sodium hydroxide solution (40 equiv) was added followed by tetrabutylammonium iodide (25 mol %) and the corresponding alkyl halide (1.1 equiv). After stirring at room temperature (rt) for 10−30 min, the reaction mixture was diluted with water and extracted with dichloromethane; then, the organic layer was evaporated to dryness. The obtained residue and potassium carbonate (4 equiv) were stirred in methanol (40 volumes) at reflux for 1 h. After the reaction, several amounts of water were dropped to the mixture to give a precipitate. The precipitate was filtrated, washed with aqueous methanol, and dried in vacuo at 60°C overnight to afford the corresponding Ni(II) complex.

* S Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.8b01424. Chiral high-performance liquid chromatography analysis data, copies of 1 H and 13 C NMR spectra, and modified precipitation of complex 15f (PDF) Vadim A. Soloshonok: 0000-0003-0681-4526

Notes
The authors declare no competing financial interest.

■ ACKNOWLEDGMENTS
We gratefully acknowledge the financial support from the IKERBASQUE, Basque Foundation for Science, and the Basque Government. We are also grateful to Servicios Generales de Investigacioń (SGIker, UPV/EHU) for HRMS analyses.