Efficient Synthesis of New α - β -Unsaturated Alkyl-Ester Peptide-Linked Chiral Amines †

: Four new α - β -unsaturated alkyl-ester chiral amines were synthesized in excellent yields (77–95%) via peptide couplings from their corresponding α - β -unsaturated alkyl-ester anilines and N -Boc protected chiral aminoacids. To our delight, these polyfunctionalized compounds are being used as starting reagents in Ugi-type three-component reactions (Ugi-3CR) together with alkyl-and aryl-aldehydes and a chain-ring tautomerizable amino acid-containing isocyanide to synthesize novel oxazole-based macrocycle precursors. Thus, the aim of this communication is to show our most recent results of the synthesis and use of new and complex chiral amines to assemble macrocyclic polypeptides with potential application in medicinal chemistry, such as the post-surgical antibiotic Vancomycin.


Introduction
Multicomponent reactions (MCRs) are highly convergent one-pot processes [1] in which three or more reagents are combined sequentially to construct complex products [2] with most atoms present in the starting materials [3].Thus, MCRs are commonly used to synthesize compounds with potential applications in various fields of science and technology.However, most of the MCR's synthetic targets are prepared considering their potential pharmaceutical properties [4], from a combinatorial chemistry [5], diversity-oriented synthesis [6] or target-directed synthesis [7] approaches.In this context, we recently reviewed the use of MCR-based strategies to synthesize novel bioactive products, for example, pharmacophore-containing polyheterocycles [8].Particularly, there are reports describing the use of MCRs to synthesize-often efficiently-series of new/novel sugar-containing products [9], peptide-based compounds [10], macrocycles [11], macro-polyheterocycles [12], as well as polycyclic analogues of natural products [13], all of them using exotic amines as starting reagents.
Thus, the aim of this communication is to show our most recent results about the synthesis of the four new α-β-unsaturated alkyl-ester chiral amines 2a-d, which have begun to be used as precursors of the chiral macrocyclic polypeptides 1, compounds with potential application in medicinal chemistry (Scheme 1).It is worthy to note that the amines 2a-d have not been synthesized or isolated anywhere.In the same way, the use of chiral amines as starting reagents for Ugi-type reactions (or other MCRs) has been little reported in comparison to non-chiral amines [14].

Results and Discussion
To prepare the desired α-β-unsaturated alkyl-ester chiral amines 2a-d, it was necessary first to synthesize the N-Boc protected amino acids 5a-d from its corresponding chiral amino acids 7a-b, as well as the ortho-aminocinnamates 6a-b from their corresponding ortho-nitrocinnamates 8a-b.Thus, the L-phenylalanine and L-alanine were N-protected following the protocol described by Ragnarsson and co-workers [18] using di-tert-butyl dicarbonate (Boc2O) in basic conditions for 48 hours at room temperature to give the N-Boc protected amino acids 5a-b in 58% (phe) and 89 (ala) yields, respectively (Scheme 3).It is worthy to note that both amino acids 5 were used for further peptidic couplings, and for this reason, they had to be N-protected to avoid the inherent formation of by-products just under peptidic coupling conditions.Additionally, the α-β-unsaturated ortho-nitrocinnamates 8a-b were reduced chemoselectively via a modified version of the method reported by Porter and co-workers [19] using Fe[0] and FeSO4 in aqueous media for 12 hours at room temperature to afford the α-β-unsaturated ortho-aminocinnamates 6a-b, yielding 88 (R 2 = Et) and 89% (R 2 = Me) (Scheme 3).Then, having in hand the compounds 5 and 6, peptidic couplings were carried out to afford the α-β-unsaturated alkyl-ester chiral amines 2a (77%), 2b (95%), 2c (86%), and 2d (94%), which were excellent yields considering: i) that the formation of by-products were kept to a minimum, ii) asymmetric centers were retained, and iii) the molecular complexity of the final products (Scheme 3).As seen, better yields were observed for the L-phenylalanine derivatives 2b (95%) and 2d (94%) (Scheme 3).[1,3]dioxol-5-yl)acrylate) 2a was selected to discuss, in succinct manner, the key signals from their 1 H and 13 C NMR spectra.Thus, with respect to the 1 H NMR spectrum (Figure 1a), there were two doublets at 7.72 and 6.21 ppm with J = 15.7 Hz, which were attributed to the trans-alkene system.Besides, with respect to the 13 C NMR spectrum (Figure 1b), there were two peaks at 172.0 and 166.9 ppm, which were attributed to both carbonyls (Figure 1b).Currently, the first attempts using the chiral amine 2a as reagent in an Ugi-3CR are being performed.Thus, the amine 2a is first N-Boc deprotected using trifluoroacetic acid (TFA) and then, combined sequentially with heptanaldehyde 3a and the chain-ring tautomerizable isocyanide to give the polyfunctionalized oxazole 9a, which in turn may perform an aza Diels-Alder cycloaddition coupled to a further aromatization process to construct the peptide-containing macrocyclic structure 1a (Scheme 4).The results will be published soon.

Conclusions
Four new exotic and polyfunctionalyzed α-β-unsaturated alkyl-ester chiral amines were synthesized in excellent yields (77-95%) via peptidic couplings from their corresponding ortho-aminocinnamates and N-Boc protected chiral aminoacids.The use of chiral and complex amines as starting reagents in MCRs toward macro-polyheterocyclic architectures is the main contribution of this work, which is a practically unexplored field in the MCR chemistry.To our delight, the first attempts are being performed, giving a product that seems to be an oxazole-based precursor of the desired peptide-containing macrocycles 1.

General Information, Instrumentation and Chemicals
1 H and 13 C NMR spectra were acquired on a Bruker Advance III (500 MHz) spectrometer.The solvent was deuterated chloroform (CDCl3).Chemical shifts are reported in parts per million (δ/ppm).Internal reference for NMR spectra is in respect to tetramethyl silane (TMS) at 0.0 ppm.Coupling constants are reported in Hertz (J/Hz).Multiplicities of the signals are reported using the standard abbreviations: singlet (s), doublet (d), triplet (t), quartet (q), and multiplet (m).NMR data were treated using the MestReNova software (12.0.0-20080).IR spectra were acquired on a Perkin-Elmer series 1600 spectrophotometer.The absorbance peaks are reported in reciprocal centimeters (cm −1 ).Elemental analyses were performed using a Cole-Palmer 2400 Series II.Reaction progress was monitored by TLC on precoated Kieselgel 60 F254 plates, and the spots were visualized under UV lights (254 or 365 nm).Melting points were determined on a Fisher-Johns apparatus and are uncorrected.Structure drawings were done using the ChemDraw software (15.0.0.106).Mixtures of hexanes with ethyl acetate in 3:1 proportion (v/v) were used as mobile phase to perform flash column chromatography.All starting materials were purchased from Sigma-Aldrich-Merck and used without further purification.The solvents were distilled and dried according to standard procedures.The N-Boc protections of amino acids [18] and chemoselective reductions of ortho-nitrocinnamates were carried out using classical reported conditions [19].

Synthesis and Characterization of the α-β-Unsaturated Alkyl-Ester Chiral Amines 2a-d
General Method: In a round-bottomed flask equipped with a magnetic stirring bar under inert atmosphere (Ar), 1.0 equiv.(1.0 mmol) of the corresponding N-Boc protected aminoacids 5, 1.2 equivalent of N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC), and 1.5 equivalent of hydroxybenzotriazole (HOBt) were added sequentially into 2 mL of anhydrous dichloromethane.After one hour, 1.0 equivalent of the corresponding ortho-aminocinnamates 6 was carefully added.The reaction mixture was stirred at room temperature for 92 hours keeping the inert atmosphere.Then, the reaction was stopped by adding 5 mL of a concentrated aqueous solution of sodium bicarbonate (NaHCO3).Further extractions with dichloromethane (3 × 5 mL) were performed, and the organic phase was collected, washed with brine, dried using anhydrous sodium sulfate, filtered over a celite pad, and concentrated to dryness under vacuum.The crude was purified by flash column chromatography using mixtures of hexanes with ethyl acetate (3:1 v/v) to afford the products 2a-d as white solids.