Amino acids with fluorinated olefinic motifs – synthetic approaches

Peptidomimetics are molecules related to natural peptides that have an artificial unit incorporated in their structure. Such structural modifications, mimicking properties of natural amino acids, can be responsible for differently pronounced activity. Among others, amino acid derivatives with fluorinated olefinic motifies can act as building blocks in the synthesis of complex molecules with potential biological activity. Therefore, the synthetic approaches to the fluorinated olefinic moiety amino acids are of interest to organic chemists. There are different synthetic methods yielding fluorinated olefins having significant value in the synthesis of amino acid derivatives. This mini review describes the latest achievements in the synthesis of amino acids bearing mono-, dior trifluorovinyl moiety.


Introduction
The incorporation of fluorine to an organic molecule often induces remarkable changes in their biophysical properties including solubility, lipophilicity, conformational and metabolic stability as well as chemical reactivity. 1,2 The changes in reactivity have far-reaching consequences. Incorporation of fluorine often affects a molecules bond energy, acidity and basicity, ability to form hydrogen bonds and its geometry. [3][4][5][6] Therefore, the incorporation of fluorine or fluoroalkyl moieties into molecules is broadly used in the synthesis of drugs and biologically active compounds. 7,8 This is one of the reasons why fluorination methods are widely studied in synthetic organic chemistry.
Fluorinated amino acids as well as fluorinated peptides have been widely studied and used in the design and synthesis of novel pharmaceuticals. They are very useful building blocks with regards to the synthesis of bioactive compounds. The big interest in the synthesis of fluorinated amino acids and peptides is also notable in the literature. Recently, in 2019 Professor Koksch published a broad review about the synthetic methods of fluorinated amino acids. 9 Additionally, synthetic approaches were also discussed earlier by the Koksch group in 2008. 10 Since the synthetic approaches to amino acids having fluorinated olefinic fragments were not well covered, we present herein, a short overview of the synthetic methods of amino acids bearing a fluorinated olefins. There are various successful syntheses that afford fluorinated olefins, and some have significant methodological value to synthetic chemists in the preparation of fluorinated amino acid libraries.

Monofluoroolefinic Amino Acid Derivatives
The monofluorovinyl moiety is often considered isosteric to the peptide bond. As such, due to the electronic similarity, it can replace the amide bond in peptides. Furthermore, the incorporation of fluorovinyl moieties in simple amino acids can strongly affect their bioactive properties and, therefore, this is a common strategy used in the design and synthesis of amino acid derivatives.
The early synthesis of (E)-β-(fluoromethylene)-m-tyrosine was reported by McDonald et al. in 1984. 11 The first step required the bromination followed by further fluorination by KHF2. Compound 2 was obtained in 54% yield and was further treated with triethyl phosphonoacetate in the presence of NaH to yield 3, as a mixture of Z-and E-isomers in 8:1 ratio and 80% yield. After subsequent bromination and dehydrobromination by piperidine, compound 4 was obtained that was further treated with LDA to give the E-bromide 5. Subsequent reaction of bromide 5 with ammonia in DMSO gave amine 6 in 20% yield. After deprotection of 6 the final product 7 bearing monofluorovinyl moiety was synthesized as a colorless powder in good 86% yield (Scheme 1).

Scheme 4. Synthesis of (E)-and (Z)-3-fluoromethylene-m-tyrosines.
McDonalds's group continued studies on synthetic methodology, and in 1985 proposed the synthesis of (E)-β-fluoromethyleneglutamic acid according to a similar method. 15 The final product was prepared in 11 steps from ethyl 3,3-dimethylacrylate (24) (Scheme 5). First, the substrate was brominated (total 57% yield) and then fluoride exchange took place. The prepared product 25 was obtained as a mixture of isomers in 50% yield. Further the bromination and subsequent dehydrobromination process transformed 25 into 26 in 69% yield. Then, isomerization led to form only the E-isomer 27. The exchange of bromine with phthaloyl dichloride in the presence of dimethyl sulfoxide saturated with ammonia and 4-aminopyridine enabled to obtain Nprotected amino acid derivative 28 in 13% yield. After bromination of methyl group, the compound 29 was synthesized as a mixture of Z-and E-isomers in 2:1 ratio. Finally, the use of sodium cyanide yielded 30, treatment of which with concentrated HCl, then propylene oxide and isopropanol, after several days allowed the formation of the target product 31 in an excellent 95% yield. This multistep synthesis gave access to desired fluoro derivative of glutamic acid.
Similarly, McDonald and Bey presented a general route to fluoroallyl amino acids by modifying the Nprotected substrate bearing fluorovinyl moiety. 16 The starting phthalimide 32 (Scheme 6) was treated with NBS affording bromide as a mixture of E/Z-isomers. Next, only the Z-isomer 33 was used in the reaction with sodium cyanide and was transformed to the corresponding nitrile 34. A subsequent hydrolysis with hydrochloric acid yielded amino acid 35 as a final product.
Another example of synthetic approach has been presented by Berkowitz et al. 23 They reported the threestep synthesis of six fluorovinyl amino acid derivatives employing Horner-Wadsworth-Emmons reaction protocol. As a starting reactant diethyl α-fluoro-α-(phenylsulfonyl)-methyl phosphonate (67) (McCarthy's reagent) was used with corresponding aldehydes 66a-f in the presence of the LiHMDS as a strong base. The reaction was carried out in -78 °C and led to (E)-α-fluorovinyl sulfones 68a-f in good to excellent yield (52-93%) and unusual diastereoselectivity -each compound was obtained as a single geometric isomer (E). The next step included the stereospecific interchange of sulfone to stannane 69. The last step involved protodestannylation, deprotection of amine and carboxylic group with hydrochloric acid and allowed formation of (Z)-α-(2'fluoro)vinyl amino acids 70a-f in yields ranging from 52% for 70f and 93% for DOPA derivative 70d (Scheme 12).
In 2004 Qiu et al. described for the first time the dehydrofluorination process of (2S,4S)-tert-butyl-N-tertbutoxycarbonyl-4-difluoromethylpyroglutamate (71). 24 The starting material 71 was synthesized from trans-4hydroxy-L-proline. 15,16 The reaction course was tested with the use of different bases in CH2Cl2. Triethylamine led to the formation of the desired product in 90% yield, while the use of pyridine yielded 72 only in less than 3%. The effect caused by the use of different solvent in the reaction was also investigated in presence of NEt3 as a base. The best results (90% yield) were obtained for CH3CN and CH2Cl2. Finally, deprotection with CF3CO2H allowed getting the desired 4-monofluoromethylenyl-L-pyroglutamic acid (73) in 72% yield (Scheme 13). . The first step included asymmetric alkylation of 74a-b with fluorovinyl tosylate in the presence of LDA as a base and led to the products 75a-b in 89 and 84% yield, respectively. These compounds were then transformed with the use of HCl/MeOH/H2O to N'-methylamides 76a-b in 43 and 63% yields, respectively. The final products 77a-b were obtained after basic hydrolysis and treatment of propylene oxide in ethanol. After basic hydrolysis of the amide bond of 76a, partial racemization was observed in the formed compound 77a. To minimize this effect, 75a was treated with phthalic anhydride and oxalyl chloride which allowed the formation of the amide 78a in 89% yield. The amide bond was further removed by thermal decomposition of the in situ generated N'-nitrosoamide and the desired product γ-fluoro-α-amino methyl ester 79a was obtained in 91% yield (Scheme 14).