# Expanding the Scope of Azole-Based γ-Amino Acids – Synthesis and Structural Diversity

Samantha Chaise, Audrey Gacogne, Ilan Garcin, Renata Marcia de Figueiredo, Jean-Marc Campagne, Baptiste Legrand, Ludovic Maillard

► To cite this version:

Samantha Chaise, Audrey Gacogne, Ilan Garcin, Renata Marcia de Figueiredo, Jean-Marc Campagne, et al.. Expanding the Scope of Azole-Based γ-Amino Acids – Synthesis and Structural Diversity. Synthesis: Journal of Synthetic Organic Chemistry, 2025, 57, pp.2363-2372. 10.1055/a-2551-8275. hal-05163670

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# Expanding the Scope of Azole-Based γ-Amino Acids – Synthesis and Structural Diversity

Samantha Chaiseª

Audrey Gacogneª

Ilan Garcinᵇ

Renata Marcia de Figueiredoᵇ

Jean-Marc Campagneᵇ

Baptiste Legrandª

Ludovic T. Maillard*ª

**Abstract** The development of non-canonical amino acids is pivotal to peptide engineering, enabling the design of molecules with novel structural features, improved activities, and optimized metabolic profiles. Among these, heteroaromatic γ-amino acids have attracted significant attention for their ability to mimic native peptide folds while accessing novel conformational spaces. In this study, the chemical diversity of heteroaromatic γ-amino acids was expanded by introducing two new monomers, ATC* and AOC*, designed around a thiazole and an oxazole scaffold, respectively. These analogues, characterized by their tunable substitution patterns and precise stereochemical control significantly expand the well-established ATC family.

**Key words** γ-amino acid, heterocycles, azole scaffold, peptide engineering, peptidomimetic, solid-phase synthesis

The design of non-canonical amino acids (NCAAs) is a cornerstone of peptide and protein engineering.¹ In drug development, they are extensively used to enhance the pharmacological profiles of peptides by addressing challenges such as increasing membrane permeability, improving potency, selectivity and tissue distribution, and enhancing *in vivo* stability.² NCAAs can also act as molecular probes providing valuable insights into the functions of biological systems and unraveling biochemical pathways.³ In addition, they are key structural elements that can tune the peptide three-dimensional structures and stabilize protein secondary structures mimics. For example, the backbone extensions of homologated amino acids (AAs), such as β- and γ-AAs, have enabled the exploration of new chemical spaces.⁴ However, the incorporation of additional backbone

atoms increases the conformational intrinsic flexibility of NCAAs, which can challenge the control of peptide folding. Thus, several strategies allow the restriction of the amino acid backbone torsional angles. In the case of γ-amino acids, such control has been achieved by varying the degree of substitution and the configuration of substituents at the α-, β-, and γ-positions of the main chain atoms,⁵ by introducing unsaturation within the scaffold,⁶ or by incorporating constrained cyclic pre-organized building blocks⁷ (Figure 1). In such a context, over the past few years, we have investigated heteroaromatic γ-amino acids (Het-γAAs) built around thiazole scaffolds, known as ATCs [4-amino(methyl)-1,3-thiazole-5-carboxylic acids].⁸ Due to the presence of the aromatic ring which limits the dihedral rotation about the αC-βC bond around 0° (ζ 70°), ATCs are structurally elated to Z-vinylogous γ-amino acids (Z-dγAAs) and fold around a 9-membered hydrogen bond.⁹ ATCs have been successfully used as β-turn mimetics for the design of antimicrobial Gramicidin-S analogues¹⁰ as well as building blocks in γ-peptides targeting amyloid aggregation,¹¹ and for the development of glycovectors.¹²

To expand the chemical diversity of Het-γAAs, we explored the possibility of modifying the nature of the heterocycle. Our efforts have centered on two novel monomers: the first, designated as ATC*, features a swapped arrangement of nitrogen and sulfur atoms while the second, termed AOC*, is an oxazole analogue (Figure 1). Herein, we present the synthesis of both ATC* and AOC*. The challenge was to design sufficiently flexible synthetic pathways that allow for straightforward modulation of the two substitution positions while maintaining precise control over the stereochemistry at the γ-carbon atom. Addition-

<footnote>ªIBMM, UMR5247 Univ. Montpellier, CNRS, ENSCM, Montpellier, France
ludovic.maillard@umontpellier.fr</footnote>

<footnote>ᵇICGM, UMR 5253, Univ. Montpellier, CNRS, ENSCM, Montpellier, France</footnote>
<figure><img src="image_2.png" /><figcaption>**Figure 1** a) Selected examples of polysubstituted, cyclic, and vinylogous γ-amino acids; b) General structures of ATC, ATC*, and AOC* Het-γAAs.</figcaption></figure>

ally, the selection of orthogonal protecting groups was considered to ensure compatibility with peptide elongation methodologies.

Our approach (Scheme 1) was inspired by the protocol previously reported by Mann and Kessler¹³ for the synthesis of oxazole-based γ-amino acids. However, we adapted it to maintain the orthogonality of the protecting groups and to increase the diversity of the side chains both on the aromatic core and at the γ-position. Additionally, we extended the reaction sequence to the construction of the ATC* thiazole analogues. One of the key steps was the preparation of a set of α-amino-β-keto esters by cross-Claisen condensation reaction between N-(diphenylmethylene)-glycine benzyl ester and activated N-Fmoc-amino acids. Although the Fmoc protecting group is generally considered unstable under strongly basic conditions, we previously demonstrated that strict temperature control and short reaction times reduce the risk of degradation. Our initial plan was to employ the procedure previously described,¹³ which involves the use of Fmoc-amino acid chlorides as acylating agents. However, we encountered partial racemization issues, likely stemming from the formation of an oxazolone intermediate. The same problem arose when using carbonyldiimidazole as activating agent for Fmoc-amino acids. To overcome these difficulties, we activated the N-Fmoc-amino acids as acyl-benzotriazole (Bt) 3 using T3P® and benzotriazole in a pyridine/DMF mixture following the protocol by Laconde et al.¹⁴ Compared to other activation methods, pre-activated N-protected amino acids can be easily isolated with high chemical and optical purity (>95%; ee >98%) by precipitation in water and stored for later use without decomposition. The optimized cross-Claisen reaction thus involved the *in situ* deprotonation of N-(diphenylmethylene)-glycine benzyl ester by potassium tert-butoxide and its condensation with the N-Fmoc-AA-Bt derivatives. Subsequently, hydrolysis of the resulting Schiff bases in 3 N aqueous HCl yielded the α-amino-β-keto esters 4 in good to excellent yields (Table 1).

<figure><img src="image_3.png" /><figcaption>**Scheme 1** Chemical route to ATC* and AOC* from commercially available N-Fmoc-AA-OH</figcaption></figure>

<table><caption>**Table 1** Isolated Yields of 3 and 4 Starting from Fmoc-AA-OH</caption><thead><tr><th rowspan="2">Entry</th><th rowspan="2">Fmoc-AA-OH</th><th colspan="2">Isolated yield (%)</th></tr><tr><th>3<sup>a</sup></th><th>4<sup>b</sup></th></tr></thead><tbody><tr><td>1</td><td>Fmoc-Gly-OH</td><td>99</td><td>75</td></tr><tr><td>2</td><td>Fmoc-Ala-OH</td><td>99</td><td>77</td></tr><tr><td>3</td><td>Fmoc-Leu-OH</td><td>99</td><td>80</td></tr><tr><td>4</td><td>Fmoc-Phe-OH</td><td>98</td><td>99</td></tr><tr><td>5</td><td>Fmoc-Lys(NBoc)-OH</td><td>100</td><td>79</td></tr><tr><td>6</td><td>Fmoc-Asp(OtBu)-OH</td><td>100</td><td>71</td></tr></tbody></table>

<footnote>a Synthesized according to the procedure reported by Laconde et al.¹⁴</footnote>

<footnote>b Synthesized starting from 3 (20 mmol) with N-(diphenylmethylene)glycine benzyl ester (2 equiv.) and tBuOK (2 equiv.) in anhyd THF at -80 °C.</footnote>
Starting from the α-amino-β-keto esters **4** we accessed both AOC\* and ATC\* by N-acylation of the amino group followed by treatment either with PPh₃, I₂, TEA, or Lawesson reagent (2 equiv.), respectively. The N-acylation step, however, required some optimization. For example, using acetic anhydride in the presence of N,N-diisopropylethylamine (DIPEA) gave a low product yield, attributed to over-acetylation occurring at the β-oxygen atom (Scheme 1, compound **8**). Consequently, alternative acylation conditions were investigated on **4** (R¹ = CH₃). Despite low conversions with EDC-HCl/HOBt, Oxyma Pure/DIC, or BOP, a 60% yield was achieved with PyBOP. Ultimately, the best results were obtained using HATU/DIPEA (1.3 equiv. each) (Table 2, entries 1–4). These conditions were found to be applicable to other carboxylic acids, such as isobutyric acid (entry 6) and N-Boc-proline (entry 7), while the overall chemical synthesis proceeded without any detectable racemization (See SI, section I.1). Finally, deprotection of the benzyl ester was performed via hydrogenolysis using 5% Pd/BaSO₄ (10 mol%), which demonstrated lower sensitivity to sulfur poisoning compared to Pd/C.

<figure><img src="image_4.png" /><figcaption>**Table 2** Isolated Yields of ATC\* and AOC\* Starting from α-Amino-β-keto Esters **4**</figcaption></figure>

<table><thead><tr><th>Entry</th><th>R<sup>1</sup></th><th>R<sup>2</sup></th><th colspan="2">Compound (Yield %)</th></tr></thead><tbody><tr><td>1</td><td>H</td><td>CH<sub>3</sub></td><td><b>6a</b> (77)<sup>a,b</sup></td><td><b>7a</b> (31)<sup>a,c</sup></td></tr><tr><td>2</td><td>CH<sub>3</sub></td><td>CH<sub>3</sub></td><td><b>6b</b> (81)<sup>a,b</sup></td><td><b>7b</b> (86)<sup>a,c</sup></td></tr><tr><td>3</td><td>iBu</td><td>CH<sub>3</sub></td><td><b>6c</b> (88)<sup>a,b</sup></td><td><b>7c</b> (50)<sup>a,c</sup></td></tr><tr><td>4</td><td>Bn</td><td>CH<sub>3</sub></td><td><b>6d</b> (90)<sup>a,b</sup></td><td><b>7d</b> (69)<sup>a,c</sup></td></tr><tr><td>5</td><td>(CH<sub>2</sub>)<sub>4</sub>NHBoc</td><td>CH<sub>3</sub></td><td><b>6e</b> (38)<sup>a,b</sup></td><td><b>7e</b> (77)<sup>a,c</sup></td></tr><tr><td>6</td><td>CH<sub>2</sub>CO<sub>2</sub>tBu</td><td>iPr</td><td><b>6f</b> (67)<sup>a,b</sup></td><td><b>7f</b> (72)<sup>a,c</sup></td></tr><tr><td>7</td><td>(CH<sub>2</sub>)<sub>2</sub>CO<sub>2</sub>tBu</td><td></td><td><b>6g</b> (42)<sup>a,b</sup></td><td></td></tr></tbody></table>

<sup>a</sup> N-Acylation of **4** was performed using R²CO₂H (1.3 equiv.) and HATU (1.3 equiv.)/DIPEA (2.3 equiv.) yielding **5**.

<sup>b</sup> Synthesized from **5** (1.0 equiv.) in CH₂Cl₂ using Lawesson reagent (2.0 equiv.).

<sup>c</sup> Synthesized from **5** (1.0 equiv.) in CH₂Cl₂ using PPh₃ (2.0 equiv.), I₂ (2.0 equiv.) and TEA (4.0 equiv.).

To increase diversity at position 2 of the heterocycles, α-amino-β-keto ester **4** (R¹ = iBu) was also reacted at 0 °C in anhydrous THF with trimethylsilyl isothiocyanate or trimethylsilyl isocyanate and DIPEA to form either a thiourea or a urea, which were converted *in situ* to 2-amino-substituted ATC\* **6h** and AOC\* **7h** by increasing the temperature to 35 °C (Scheme 2).

<figure><img src="image_5.png" /><figcaption>**Scheme 2** Conversion of α-amino-β-keto ester **4c** to 2-amino-substituted ATC\* **6h** and AOC\* **7h**</figcaption></figure>

To assess the compatibility of ATC\* and AOC\* with Fmoc/tBu SPPS strategies, we synthesized the hybrid peptides **P1** and **P2** (Figure 2). Elongation was carried out on AmphiSpheres™ 40 Rink amide resin (loading: 0.31 mmol·g⁻¹). α-Amino acids were coupled in 5 minutes using HBTU/NMM (5 equiv. each) in N-methylpyrrolidone (NMP). For the incorporation of the γ-amino acids, we employed reaction conditions previously optimized for the synthesis of ATC oligomers. Thus, each coupling step of ATC\* and AOC\* was performed at room temperature in NMP using 2

<figure><img src="image_6.png" /></figure>

a) Fmoc-Ala-OH, HBTU, NMM (5 equiv. each) in NMP, 5 min, rt.

b) Pip/MDF (2:8), 3 x 15 min, rt. c) Fmoc-ATC\*-OH or Fmoc-AOC\*-OH (1.75 equiv.), DIC (1.75 equiv.), Oxyma Pure (1.75 equiv.) in NMP, overnight, rt. d) Ac₂O/DCM (1:1), 2 x 5 min, rt. e) TFA/TIS/H₂O (95:2.5:2.5).

<figure><img src="image_7.png" /><figcaption>**Figure 2** a) Synthesis of the two model hybrid peptides **P1** and **P2**, along with b) representative chromatograms of the corresponding crude products</figcaption></figure>
equivalents of the corresponding N-Fmoc-protected mono-
mer and DIC/OxymaPure (2 equiv. each) as coupling re-
agents, followed by a capping step with Ac₂O/DCM (1:1
v/v). Deprotection of the transient Fmoc protecting group
was achieved using piperidine/DMF (2:8 v/v). At the end of
the oligomerization process, the N-terminus was acetylated
with Ac₂O/DCM (1:1 v/v), and the oligomer was cleaved
from the resin using TFA/TIS/H₂O (95:2.5:2.5 v/v/v). Follow-
ing solvent evaporation, the crude product was analyzed by
LC-MS to assess its overall purity. Representative chromato-
grams for sequences P1 and P2 (Figure 2) confirmed the ef-
ficiency of the procedure. After purification via semi-pre-
parative reverse-phase chromatography, P1 and P2 were
recovered in 67% and 58% overall yields.

In conclusion, we have successfully expanded the chem-
ical diversity of Het-γAAs by synthesizing the ATC* and
AOC* monomers. The optimized synthetic routes developed
in this work provide robust control over stereochemistry
and enable fine-tuning of substituents at both the aromatic
core and the γ-position. Our approach demonstrates the in-
corporation of a wide variety of side chains. These features,
combined with the compatibility of ATC* and AOC* with
Fmoc/tBu SPPS strategies, highlight their potential as versa-
tile building blocks for the design of peptidomimetics. The
next steps will focus on incorporating these monomers into
bioactive peptides to evaluate their impact on the pharma-
cological and structural properties of the parent peptides.
Furthermore, a comprehensive structural analysis will be
undertaken to compare their conformational preferences.
Future applications may exploit their unique properties to
create innovative biomimetic structures or develop next-
generation therapeutic peptides, thereby contributing sig-
nificantly to advancements in peptide engineering.

Commercially available reagents and solvents were used without any further purification. Solid-phase synthesis was performed on an AmphiSpheres™ 40 RAM, 75–150 µm resin loaded at 0.31 mmol/g using Fmoc/tBu chemistry. Reactions were monitored by HPLC using an analytical Chromolith® HighResolution RP-18e column (50 × 4.6 mm, 5 µm) using a flow rate of 5.0 mL/min, and gradients from 100/0 to 0/100 eluents A/B over 5 minutes, in which eluents A = H₂O/TFA 0.1% and B = CH₃CN/TFA 0.1%. Detection was done at 214 nm using a Photodiode Array Detector. Retention times were reported as follows: LC: *t*<sub>R</sub> = min. LC-MS spectra (ESI) were recorded on an HPLC using an analytical HSS T3pept100A 1.8 microns 50 × 2.1 m using a flow rate of 0.8 mL/min, and gradients of 100/0 to 0/100 eluents A/B over 5 minutes, in which eluent solvent A = H₂O/HCO₂H 0.1% and solvent B = CH₃CN/HCO₂H 0.1%. High-resolution mass spectrometric analyses were performed with a Time-Of-Flight (TOF) mass spectrometer fitted with an Electrospray Ionization Source (ESI). All measurements were performed in the positive ion mode. ¹H and ¹³C NMR spectra were recorded at rt in deuterated solvents. Chemical shifts (δ) are given, in this document, in parts per million, relative to TMS or relative to the solvent [¹H NMR (600 MHz, CDCl₃): δ = 7.26, ¹³C NMR (400

MHz, CDCl₃): δ = 77.2]. The following abbreviations are used to designate the signal multiplicities: s (singlet), d (doublet), dd (doublet of doublets), t (triplet), q (quartet), m (multiplet), br (broad).

**N-Acylbenzotriazoles 3; General Procedure**

The *N*-acylbenzotriazole derivatives were synthesized according to the procedure reported by Laconde and al.¹⁴ To a mixture of the respective carboxylic acid (1.0 equiv., 30.00 mmol) and benzotriazole (1.2 equiv., 36.00 mmol) in DMF (1 mol/L concentration) was added pyridine (3.0 equiv., 90.00 mmol), followed by T3P®/DMF 50% (1.5 equiv., 45.00 mmol) dropwise. The mixture was stirred at rt for 1 h. The reaction was monitored by HPLC analysis. At completion, the mixture was poured into cold H₂O (4 °C, 200 mL). The precipitated compound was filtered and washed with H₂O (2 ×). Compound **3** was then dried under vacuum (P <1 mmbar) for 24 h and used without purification. NMR and LC-MS analyses correspond to those reported by Laconde et al.¹⁴

**α-Amino β-Keto Benzyl Esters 4; General Procedure**

In a 250 mL three-necked flask, a solution of tBuOK (2.0 equiv., 54.00 mmol) in anhyd THF (50 mL) was cooled under argon to -80 °C. Then, the benzyl 2-[(diphenylmethylene)amino]acetate (2.0 equiv., 54.00 mmol) in anhyd THF (50 mL) was added dropwise while maintaining the reaction temperature at -80 °C. The mixture was stirred during 10 min at -80 °C, then at rt for 10 min and finally at -80 °C for 20 min. *N*-Acylbenzotriazole derivative **3** (1.0 equiv., 27.00 mmol) in anhyd THF (100 mL) was added dropwise to the orange solution at -80 °C over 5 min. After stirring for 30 min (HPLC monitoring), the mixture was removed from the cold bath and quenched with 3 N aq HCl (50 mL). The mixture was then stirred at rt for 30 min in order to deprotect the amine group. THF was evaporated and the resultant aqueous phase was extracted with Et₂O (2 × 50 mL). The combined organic layers were dried, filtered, and evaporated under reduced pressure. The crude was taken up in a minimum of MeOH then washed with hexane (3 × 50 mL). The MeOH phase was evaporated under reduced pressure to give compound **4**, which was used without further purification.

**4-(*N*-Fmoc-amino)-1-(benzyloxy)-1,3-dioxobutan-2-amine Hydrochloride (4a)**

White solid; yield: 75%.

LC: *t*<sub>R</sub> = 2.37 min; LC-MS (ESI+): *m/z* (%) = 445.3 (100, [M + H]<sup>+</sup>), 467.3 (20, [M + Na]<sup>+</sup>).

HRMS (ESI): *m/z* calcd for C₂₆H₂₅N₂O₅ [M + H]<sup>+</sup>: 445.1758; found: 445.1757.

**(4S)-4-(*N*-Fmoc-amino)-1-(benzyloxy)-1,3-dioxopentan-2-amine
Hydrochloride (4b)**

White solid; yield: 77%.

LC: *t*<sub>R</sub> = 2.41 min; LC-MS (ESI+): *m/z* (%) = 459 (100, [M + H]<sup>+</sup>).

HRMS (ESI): *m/z* calcd for C₂₇H₂₇N₂O₅ [M + H]<sup>+</sup>: 459.1914; found: 459.1919.

**(4S)-4-(*N*-Fmoc-amino)-1-(benzyloxy)-6-methyl-1,3-dioxoheptan-2-amine Hydrochloride (4c)**

White solid; yield: 80%.

LC: *t*<sub>R</sub> = 2.59 min; LC-MS (ESI+): *m/z* (%) = 501.4 (100, [M + H]<sup>+</sup>), 523.4 (10, [M + Na]<sup>+</sup>).

HRMS (ESI): *m/z* calcd for C₃₀H₃₃N₂O₅ [M + H]<sup>+</sup>: 501.2384; found: 501.2387.
(4S)-4-(N-Fmoc-amino)-1-(benzyloxy)-1,3-dioxo-5-phenylpentan-2-amine Hydrochloride (4d)

White solid; yield: 99%.

LC: *t*<sub>R</sub> = 2.58 min; LC-MS (ESI+): *m/z* (%) = 549.3 (100, [M + Na]<sup>+</sup>).

HRMS (ESI): *m/z* calcd for C₃₃H₃₁N₂O₅ [M + H]<sup>+</sup>: 535.2227; found: 535.2230.

(4S)-4-(N-Fmoc-amino)-1-(benzyloxy)-8-((tert-butoxycarbonyl)-amino)-1,3-dioxooctan-2-amine Hydrochloride (4e)

White solid; yield: 79%.

LC: *t*<sub>R</sub> = 2.65 min; LC-MS (ESI+): *m/z* (%) = 573.4 (100, [M + H]<sup>+</sup>), 595.4 (10, [M + Na]<sup>+</sup>).

HRMS (ESI): *m/z* calcd for C₃₅H₄₂N₂O₇ [M + H]<sup>+</sup>: 616.3017; found: 616.2016.

(4S)-4-(N-Fmoc-amino)-1-(benzyloxy)-6-(tert-butoxy)-1,3,6-trioxohexan-2-amine Hydrochloride (4f)

White solid; yield: 71%.

LC: *t*<sub>R</sub> = 2.65 min; LC-MS (ESI+): *m/z* (%) = 559.1 (100, [M + H]<sup>+</sup>), 581.3 (30, [M + Na]<sup>+</sup>).

HRMS (ESI): *m/z* calcd for C₃₂H₃₅N₂O₇ [M + H]<sup>+</sup>: 559.2439; found: 559.2434.

(4S)-4-(N-Fmoc-amino)-1-(benzyloxy)-7-(tert-butoxy)-1,3,7-trioxohetpan-2-amine Hydrochloride (4g)

White solid; yield: quantitative.

LC: *t*<sub>R</sub> = 3.01 min; LC-MS (ESI+): *m/z* (%) = 573.4 (100, [M + H]<sup>+</sup>), 595.4 (10, [M + Na]<sup>+</sup>).

HRMS (ESI): *m/z* calcd for C₃₃H₃₇N₂O₇ [M + H]<sup>+</sup>: 573.2601; found: 573.2608.

Benzyl 2-(N-Fmoc-amino)-3-(acylamino)-3-oxobutanoates 5; General Procedure

To a solution of **4** (1.0 equiv., 15.00 mmol) in DMF (55 mL) was added N,N-diisopropylethylamine (2.3 equiv., 34.50 mmol) at 0 °C. The solution was stirred for 5 min, then the respective carboxylic acid (1.3 equiv., 19.50 mmol) followed by HATU (1.3 equiv., 19.50 mmol) were added to the reaction mixture at 0 °C. The reaction was completed after 30 min stirring at 0 °C (HPLC monitoring). The solution was evaporated under reduced pressure, then dissolved in Et₂O (150 mL). The organic layer was washed with H₂O (3 × 50 mL), dried (MgSO₄), filtered, and evaporated under reduced pressure to yield the crude product. Purification by flash column chromatography with EtOAc/cyclohexane gave **5** as =1:1 mixture of the two diastereoisomers.

Benzyl 4-(N-Fmoc-amino)-2-acetamido-3-oxobutanoate (5a)

White solid; yield: 57%.

¹H NMR (600 MHz, CDCl₃): δ = 7.77 (d, *J* = 7.4 Hz, 2 H), 7.59 (d, *J* = 7.4 Hz, 2 H), 7.42–7.30 (m, 9 H), 6.62 (d, *J* = 6.0 Hz, 1 H), 5.3 (t, *J* = 5.7 Hz, 1 H), 5.34 (d, *J* = 6.0 Hz, 1 H), 5.27 (AB, *J* = 12.8 Hz, 1 H), 5.22 (AB, *J* = 12.8 Hz, 1 H), 4.46 (dd, *J* = 5.7, 20.0 Hz, 1 H), 4.39 (d, *J* = 7.0 Hz, 2 H), 4.38 (dd, *J* = 5.7, 20.0 Hz, 1 H), 4.23 (t, *J* = 7.0 Hz, 1 H), 2.08 (s, 3 H).

¹³C NMR (125 MHz, CDCl₃): δ = 197.5, 170.0, 165.4, 156.1, 143.8, 141.3, 134.2, 129.0, 128.8, 128.6, 127.8, 127.1, 125.1, 120.0, 68.8, 67.3, 60.2, 49.9, 47.1, 22.6.

LC: *t*<sub>R</sub> = 2.62 min; LC-MS (ESI+): *m/z* (%) = 487.2 (70, [M + H]<sup>+</sup>), 509.2 (100, [M + Na]<sup>+</sup>).

HRMS (ESI): *m/z* calcd for C₂₈H₂₇N₂O₆ [M + H]<sup>+</sup>: 487.1864; found: 487.1867.

Benzyl (4S)-2-Acetamido-4-(N-Fmoc-amino)-3-oxopentanoate (5b)

White solid; yield: 74%; mixture of 2 diastereomers.

¹H NMR (600 MHz, CDCl₃): δ = 7.77 (d, *J* = 7.5 Hz, 1 H, Dia 1), 7.76 (d, *J* = 7.5 Hz, 1 H, Dia 2), 7.59 (d, *J* = 7.5 Hz, 1 H, Dia 1), 7.58 (d, *J* = 7.5 Hz, 1 H, Dia 2), 7.42–7.37 (m, 2 H), 7.36–7.27 (m, 7 H), 6.80 (d, *J* = 5.5 Hz, 0.5 H, NHb Dia 1), 6.70 (d, *J* = 6.0 Hz, 0.5 H, NHb Dia 1), 5.66 (d, *J* = 8.5 Hz, 0.5 H, NHa Dia 1), 5.52 (t, *J* = 6.7 Hz, 1 H), 5.40 (d, *J* = 7.3 Hz, 0.5 H, NHa Dia 2), 5.27–5.19 (m, 2 H), 4.85 (m, 0.5 H, Dia 2), 4.66 (m, 0.5 H, Dia 1), 4.42–4.37 (m, 2 H), 4.20 (t, *J* = 6.9 Hz, 1 H), 2.07 (s, 3 H), 1.42 (d, *J* = 6.9 Hz, 1.5 H, Dia 2), 1.28 (d, *J* = 6.9 Hz, 1.5 H, H-19 Dia 1).

¹³C NMR (151 MHz, CDCl₃): δ = 201.9 (Dia 1), 201.0 (Dia 2), 170.3 (Dia 1), 170.0 (Dia 2), 166.3 (Dia 1), 165.4 (Dia 2), 156.02 (Dia 1), 155.5 (Dia 2), 143.8, 141.4, 134.5 (Dia 1), 134.3 (Dia 2), 128.9, 128.4, 128.4, 127.8, 127.2, 125.1, 120.0, 68.9 (Dia 2), 68.2 (Dia 2), 67.2, 59.8 (Dia 2), 58.7 (Dia 1), 54.3 (Dia 2), 54.1 (Dia 1), 47.1, 27.78, 17.6 (Dia 2), 16.4 (Dia 1).

LC: *t*<sub>R</sub> = 3.32 min; LC-MS (ESI+): *m/z* (%) = 501.1 (80, [M + H]<sup>+</sup>), 523.1 (40, [M + Na]<sup>+</sup>).

HRMS (ESI): *m/z* calcd for C₂₉H₂₉N₂O₆ [M + H]<sup>+</sup>: 501.1020; found: 501.2010.

Benzyl (4S)-2-Acetamido-4-(N-Fmoc-amino)-6-methyl-3-oxoheptanoate (5c)

White solid; yield: 59%; mixture of 2 diastereomers.

¹H NMR (600 MHz, CDCl₃): δ = 7.76 (t, *J* = 8.0 Hz, 2 H), 7.59 (t, *J* = 8.4 Hz, 2 H), 7.46–7.27 (m, 9 H), 6.74 (d, *J* = 6.4 Hz, 0.4 H, Dia 2), 6.64 (d, *J* = 7.0 Hz, 0.6 H, Dia 1), 5.53 (d, *J* = 7.0 Hz, 0.6 H, Dia 1), 5.50 (d, *J* = 6.4 Hz, 0.4 H, Dia 2), 5.34 (d, *J* = 8.9 Hz, 0.4 H, Dia 2), 5.29–5.15 (m, 2.6 H), 4.90–4.83 (m, 0.6 H, Dia 1), 4.65–4.58 (m, 0.4 H, Dia 2), 4.49–4.32 (m, 2 H), 4.22–4.19 (m, 1 H), 2.07 (s, 1.2 H, Dia 2), 2.07 (s, 1.8 H, Dia 1), 1.73–1.61 (m, 1.2 H, Dia 1), 1.61–1.50 (m, 0.8 H, Dia 2), 1.41–1.29 (m, 1 H), 0.98–0.80 (m, 6 H).

¹³C NMR (151 MHz, CDCl₃): δ = 201.9 (Dia 1), 201.1 (Dia 2), 170.0 (Dia 1), 169.8 (Dia 2), 166.3 (Dia 1), 165.4 (Dia 2), 156.3 (Dia 1), 155.9 (Dia 2), 143.8, 141.4, 135.4 (Dia 1), 134.5 (Dia 2), 128.6, 128.4, 128.4, 127.8, 127.1, 125.1, 120.0, 68.8 (Dia 1), 68.2 (Dia 2), 60.2 (Dia 1), 58.9 (Dia 2), 57.0 (Dia 1), 56.6 (Dia 2), 47.1, 40.2 (Dia 1), 39.3 (Dia 2), 25.0 (Dia 1), 24.6 (Dia 2), 23.2 (Dia 1), 23.2 (Dia 2), 22.7 (Dia 1), 22.6, 21.4 (Dia 2), 21.15 (Dia 1).

LC: *t*<sub>R</sub> = 3.21 min; LC-MS (ESI+): *m/z* (%) = 543.1 (100, [M + H]<sup>+</sup>).

HRMS (ESI): *m/z* calcd for C₃₂H₃₅N₂O₆ [M + H]<sup>+</sup>: 543.2495; found: 543.2496.

Benzyl (4S)-2-Acetamido-4-(N-Fmoc-amino)-3-oxo-5-phenylpentanoate (5d)

White solid; yield: 70%; mixture of 2 diastereomers.

¹H NMR (600 MHz, CDCl₃): δ = 7.70 (t, *J* = 7.1 Hz, 2 H), 7.48–7.40 (m, 2 H), 7.37–7.10 (m, 12 H), 7.03–6.97 (m, 2 H), 6.66 (d, *J* = 6.3 Hz, 0.5 H, Dia 1), 6.54 (d, *J* = 6.7 Hz, 0.5 H, Dia 2), 5.46 (d, *J* = 6.7, 0.5 H, Dia 2), 5.45 (d, *J* = 6.3, 0.5 H, Dia 1), 5.41 (d, *J* = 8.4 Hz, 0.5 H, Dia 1), 5.26–4.78 (m, 3 H), 4.75–4.68 (m, 0.5 H, Dia 2), 4.60–4.15 (m, 2 H), 4.12–4.04 (m, 1 H), 3.16 (dd, *J* = 14.2, 5.8 Hz, 0.5 H, Dia 1), 3.08 (dd, *J* = 14.2, 5.8 Hz, 0.5 H, Dia 2), 2.86 (dd, *J* = 14.2, 7.5 Hz, 0.5 H, Dia 1), 2.79 (dd, *J* = 14.2, 7.5 Hz, 0.5 H, Dia 2), 2.01 (s, 3 H).
¹³C NMR (151 MHz, CDCl₃): δ = 200.5 (Dia 1), 200.0 (Dia 2), 170.1, 169.8, 166.1, 165.3, 156.0 (Dia 1), 155.5 (Dia 2), 143.7, 141.4, 136.1 (Dia 1), 135.2 (Dia 2), 134.5, 134.4, 129.4, 128.7, 128.6, 128.5, 127.8, 127.3, 127.12, 127.1, 127.0, 125.1, 120.0, 68.8 (Dia 1), 68.3 (Dia 2), 67.2 (Dia 1), 67.1 (Dia 2), 60.5 (Dia 1), 59.2 (2 C, Dia 2, Dia 1), 59.2 (Dia 2), 47.1, 37.3 (Dia 1), 36.2 (Dia 2), 22.8 (Dia 1), 22.7 (Dia 2).

LC: *t*<sub>R</sub> = 3.17 min; LC-MS (ESI+): *m/z* (%) = 577.3 (100, [M + H]<sup>+</sup>), 599.4 (80, [M + Na]<sup>+</sup>).

HRMS (ESI): *m/z* calcd for C₃₅H₃₃N₂O₆ [M + H]<sup>+</sup>: 577.2333; found: 577.2334.

## Benzyl (4S)-4-(N-Fmoc-amino)-2-acetamido-8-(N-Boc-amino)-3-oxooctanoate (5e)

White solid; yield: 55%; mixture of 2 diastereomers.

¹H NMR (600 MHz, CDCl₃): δ = 7.76 (d, *J* = 8.1 Hz, 2 H), 7.59 (br, 2 H), 7.42–7.29 (m, 9 H), 6.70 (d, *J* = 6.0 Hz, 0.5 H Dia 1), 6.63 (d, *J* = 6.8 Hz, 0.5 H, Dia 2), 5.66 (d, *J* = 7.8 Hz, 0.5 H, Dia 1), 5.51 (d, *J* = 6.0 Hz, 0.5 H, Dia 1), 5.47 (br, 1 H, Dia 2), 5.46 (d, *J* = 6.8 Hz, 0.5 H, Dia 2), 5.26–5.17 (m, 2 H), 4.84 (br, 0.5 H, Dia 1), 4.76 (br, 0.5 H.), 4.55 (br, 0.5 H, Dia 2), 4.42–4.38 (m, 2 H), 4.21 (*t*, *J* = 6.8 Hz, 1 H), 3.07 (br, 2 H), 2.07 (s, 3 H), 1.94–1.78 (m, 2 H), 1.66–1.52 (m, 2 H), 1.43 (s, 9 H), 1.32–1.24 (m, 2 H).

¹³C NMR (125 MHz, CDCl₃): δ = 201.2 (Dia 2), 200.5 (Dia 2), 170.1 (Dia 1), 169.9 (Dia 2), 166.2 (Dia 1), 165.3 (Dia 2), 156.4 (Dia 1), 156.2 (Dia 2), 155.8, 143.8, 141.4, 134.5 (Dia 1), 134.4 (Dia 2), 128.9, 128.8, 128.5, 127.8, 127.1, 125.1, 120.0, 79.1, 68.9 (Dia 1), 68.3 (Dia 2), 67.1, 60.1 (Dia 1), 58.9 (Dia 2), 58.3 (Dia 1), 58.0 (Dia 2), 47.2, 40.0 (Dia 1), 39.6 (Dia 2), 30.6, 29.8 (Dia 1), 29.4 (Dia 2), 28.5, 22.6, 22.3 (Dia 1), 21.9 (Dia 2).

LC: *t*<sub>R</sub> = 2.89–2.92 min; LC-MS (ESI+): *m/z* (%) = 658.3 (10, [M + H]<sup>+</sup>), 680.3 (100, [M + Na]<sup>+</sup>).

HRMS (ESI): *m/z* calcd for C₃₇H₄₄N₃O₈ [M + H]<sup>+</sup>: 658.3123; found: 658.3122.

## 1-Benzyl 6-tert-Butyl (4S)-4-(N-Fmoc-amino)-2-isobutyramido-3-oxohexanedioate (5f)

White solid; yield: 49%; mixture of 2 diastereomers.

¹H NMR (600 MHz, CDCl₃): δ = 7.77 (d, *J* = 3.3 Hz, 1 H), 7.76 (d, *J* = 3.3 Hz, 1 H), 7.60–7.56 (m, 2 H), 7.41–7.27 (m, 9 H), 6.70 (d, *J* = 6.4 Hz, 0.5 H, Dia 1), 6.67 (d, *J* = 6.2 Hz, 0.5 H, Dia 2), 6.14 (d, *J* = 9.1 Hz, 0.5 H, Dia 1), 5.94 (d, *J* = 9.1 Hz, 0.5 H, Dia 2), 5.57 (d, *J* = 6.2 Hz, 0.5 H, Dia 2), 5.55 (d, *J* = 6.4 Hz, 0.5 H, Dia 1), 5.22 (br, 2 H), 4.93–4.86 (m, 1 H), 4.40–4.35 (m, 2 H), 4.23–4.19 (m, 1 H), 2.99 (ABx, *J* = 16.3, 5.0 Hz, 0.5 H, Dia 1), 2.84 (ABx, *J* = 16.3, 5.0 Hz, 0.5 H, Dia 1), 2.75 (ABx, *J* = 16.8, 5.4 Hz, 0.5 H, Dia 2), 2.68 (ABx, *J* = 16.8, 5.4 Hz, 0.5 H, Dia 2), 2.50–2.45 (m, 1 H), 1.42 (s, 4.5 H, Dia 1), 1.41 (s, 4.5 H, Dia 2), 1.21–1.15 (m, 6 H).

¹³C NMR (150 MHz, CDCl₃): δ = 199.8 (Dia 1), 199.1 (Dia 2), 176.9 (Dia 1), 176.7 (Dia 2), 170.1 (Dia 1), 169.9 (Dia 2), 166.1 (Dia 1), 165.7 (Dia 2), 156.1 (Dia 1), 155.7 (Dia 2), 143.8 (Dia 1), 143.7 (Dia 2), 141.3, 134.6 (Dia 1), 134.4 (Dia 2), 128.8, 128.7, 128.4, 127.8, 127.1, 125.2 (Dia 1), 125.1 (Dia 2), 120.0, 82.2 (Dia 1), 81.6 (Dia 2), 68.7 (Dia 1), 68.4 (Dia 2), 67.5 (Dia 1), 67.4 (Dia 2), 59.5 (Dia 1), 58.5 (Dia 2), 56.0 (Dia 1), 55.2 (Dia 2), 47.1, 37.4 (Dia 1), 36.3 (Dia 2), 35.0, 28.0, 19.3 (Dia 1), 19.2 (Dia 2).

LC: *t*<sub>R</sub> = 3.13 min; LC-MS (ESI+): *m/z* (%) = 629.4 (10) [M + H]<sup>+</sup>, 651.3 (100) [M + Na]<sup>+</sup>.

HRMS (ESI): *m/z* calcd for C₃₆H₄₁N₂O₈ [M + H]<sup>+</sup> 629.2857; found: 629.2854.

## (4S)-1-Benzyl 7-tert-Butyl 4-(N-Fmoc-amino)-2-(N-Boc-pyrrolidine-2-carboxamido)-3-oxoheptanedioate (5g)

White solid; yield: 53%; mixture of 2 diastereomers.

¹H NMR (500 MHz, DMSO-d₆): δ = 8.80–8.64 (m, 1 H), 7.89 (d, *J* = 7.6 Hz, 2 H), 7.72–7.69 (m, 2 H), 7.43–7.30 (m, 10 H), 5.59–5.51 (m, 1 H), 5.25–5.06 (m, 2 H), 4.46–4.35 (m, 1 H) 4.32–4.21 (m, 4 H), 3.32–3.22 (m, 2 H), 2.23–1.94 (m, 4 H), 1.83–1.65 (m, 4 H), 1.37 (s, 12 H), 1.26 (s, *J* = 5.7 Hz, 6 H).

¹³C NMR (126 MHz, DMSO-d₆): δ = 199.8, 172.1, 172.1, 165.3, 156.3, 155.9, 143.9 (Dia 1), 143.8 (Dia 2) 141.0, 134.5, 128.9, 128.8, 128.8, 127.8, 127.5, 125.2, 120.0, 80.8, 80.7, 68.7 (Dia 1), 68.1 (Dia 2), 67.2, 60.8, 59.9, 58.6 (Dia 1), 58.1 (Dia 2), 47.2 (C-28), 31.3 (C-20), 28.3, 28.3 (Dia 1), 28.1, 28.1 (Dia 2), 24.6, 24.5 (Dia 1), 23.7, 23.6 (Dia 2).

LC: *t*<sub>R</sub> = 3.75–3.79 min; LC-MS (ESI+): *m/z* (%) = 770.3 (10, [M + H]<sup>+</sup>), 792.4 (60, [M + Na]<sup>+</sup>).

HRMS (ESI): *m/z* calcd for C₄₃H₅₂N₃O₁₀ [M + H]<sup>+</sup>: 770.3647; found: 770.3667.

## AOC* Benzyl Esters 6; General Procedure

To a solution of 5 (1.0 equiv., 10.00 mmol) in anhyd THF (90 mL) was added a solution of the Lawesson's reagent (2.0 equiv., 20.00 mmol). The reaction was completed after 1 h stirring at reflux (HPLC monitoring). The mixture was concentrated in vacuo and purified by flash column chromatography with EtOAc/cyclohexane to afford the pure product 6.

## Benzyl 5-(N-Fmoc-aminomethyl)-2-methylthiazole-4-carboxylate (6a)

White solid; yield: 77%.

¹H NMR (600 MHz, CDCl₃): δ = 7.76 (d, *J* = 7.8 Hz, 2 H), 7.56 (d, *J* = 7.8 Hz, 2 H), 7.45–7.28 (m, 9 H), 5.48 (br, 1 H), 5.37 (s, 2 H), 4.66 (d, *J* = 6.3 Hz, 2 H), 4.41 (d, *J* = 7.1 Hz, 2 H), 4.21 (*t*, *J* = 7.1 Hz, 1 H), 2.47 (s, 3 H).

¹³C NMR (150 MHz, CDCl₃): δ = 161.9, 160.6, 156.2, 155.6, 143.8, 141.3, 135.4, 128.7, 128.6, 127.8, 127.1, 125.0, 120.0, 67.2, 67.2, 41.2, 35.9, 13.9; C-4 of the thiazole ring is missing.

LC: *t*<sub>R</sub> = 2.82 min; LC-MS (ESI+): *m/z* (%) = 485.2 (100, [M + H]<sup>+</sup>), 507.2 (20, [M + Na]<sup>+</sup>).

HRMS (ESI): *m/z* calcd for C₂₈H₂₅N₂O₄S [M + H]<sup>+</sup>: 485.1530; found: 485.1532.

## Benzyl (S)-5-(1-N-Fmoc-aminoethyl)-2-methylthiazole-4-carboxylate (6b)

Yellow solid; yield: 81%; [a]D<sub>50</sub> = +13.4 (c 1, CHCl₃).

¹H NMR (600 MHz, DMSO-d₆): δ = 8.18 (d, *J* = 6.8 Hz, 1 H), 7.89 (d, *J* = 7.2 Hz, 2 H), 7.68 (*t*, *J* = 7.7 Hz, 2 H), 7.47–7.29 (m, 9 H), 5.48–5.43 (m, 1 H), 5.31 (d, *J* = 3.1 Hz, 2 H), 4.35 (dd, *J* = 10.6, 6.7 Hz, 1 H), 4.28 (dd, *J* = 10.5, 6.7 Hz, 1 H), 4.20 (d, *J* = 6.4 Hz, 1 H), 2.59 (s, 3 H), 1.37 (d, *J* = 6.7 Hz, 3 H).

¹³C NMR (150 MHz, DMSO-d₆): δ = 162.2, 161.3, 157.1, 155.4, 143.7, 140.7, 138.0, 128.5, 128.4, 128.2, 127.6, 127.0, 125.1, 120.1, 66.1, 65.3, 46.7, 45.3, 22.1, 18.8.

LC: *t*<sub>R</sub> = 2.76 min; LC-MS (ESI+): *m/z* (%) = 499.4 (100, [M + H]<sup>+</sup>), 521.4 (10, [M + Na]<sup>+</sup>).

HRMS (ESI): *m/z* calcd for C₂₉H₂₇N₂O₄S [M + H]<sup>+</sup>: 499.1686; found: 499.1683.
## Benzyl (S)-5-(1-N-Fmoc-amino-3-methylbutyl)-2-methylthiazole-4-carboxylate (6c)

Yellow solid; yield: 88%; $[\alpha]_D^{20} = +1.0$ (c 1, CHCl₃).

¹H NMR (400 MHz, DMSO-d₆): $\delta$ = 8.06 (d, *J* = 7.7 Hz, 1 H), 7.89 (d, *J* = 7.5 Hz, 2 H), 7.71–7.64 (m, 2 H), 7.47–7.27 (m, 9 H), 5.56–5.48 (m, 1 H), 5.31 (s, 2 H), 4.33 (d, *J* = 6.8 Hz, 2 H), 4.20 (t, *J* = 6.8 Hz, 1 H), 2.59 (s, 3 H), 1.74–1.59 (m, 2 H), 1.43–1.33 (m, 1 H), 0.83 (d, *J* = 7.0 Hz, 3 H), 0.82 (d, *J* = 7.0 Hz 3 H).

¹³C NMR (125 MHz, DMSO-d₆): $\delta$ = 163.0, 161.8, 156.7, 156.1, 144.2, 141.2, 138.7, 136.4, 129.0, 128.8, 128.7, 128.1, 127.5, 125.6, 120.6, 66.5, 65.7, 48.0, 47.3, 45.3, 25.1, 23.5, 21.2, 19.3.

LC: $t_R$ = 3.20 min; LC-MS (ESI+): *m/z* (%) = 541.5 (100, [M + H]⁺), 536.4 (10, [M + Na]⁺).

HRMS (ESI): *m/z* calcd for C₃₂H₃₃N₂O₄S [M + H]⁺: 541.2156; found: 541.2150.

## Benzyl (S)-5-(1-N-Boc-amino-2-phenylethyl)-2-methylthiazole-4-carboxylate (6d)

Yellow solid; yield: 90%; $[\alpha]_D^{20} = +37.4$ (c 1, CHCl₃).

¹H NMR (600 MHz, CDCl₃): $\delta$ = 7.74 (d, *J* = 7.7 Hz, 2 H), 7.55–7.17 (m, 14 H), 7.08–7.05 (m, 2 H), 5.82 (s, 1 H), 5.69–5.65 (m, 1 H), 5.48–5.43 (m, 2 H), 4.31 (br, 2 H), 4.15 (br, 1 H), 3.22 (br, 1 H), 3.07 (br, 1 H), 2.65 (s, 3 H).

¹³C NMR (150 MHz, CDCl₃): $\delta$ = 163.2, 162.3, 155.5, 151.6, 143.8, 141.3, 140.0, 136.6, 135.6, 128.8, 128.7, 128.7, 128.7, 128.4, 127.7, 127.0, 127.0, 125.1, 120.0, 67.3, 66.9, 50.4, 47.2, 41.7, 19.3.

LC: $t_R$ = 3.60 min; LC-MS (ESI+): *m/z* (%) = 575.4 (100, [M + H]⁺).

HRMS (ESI): *m/z* calcd for C₃₅H₃₁N₂O₄S [M + H]⁺: 575.1999; found: 575.2001.

## Benzyl (S)-5-(1-N-Fmoc-amino-4-N-Boc-amino)butyl)-2-methylthiazole-4-carboxylate (6e)

White solid; yield: 38%; $[\alpha]_D^{20} = +1.5$ (c 1, CDCl₃).

¹H NMR (600 MHz, CDCl₃): $\delta$ = 7.76 (d, *J* = 7.4 Hz, 2 H), 7.57 (d, *J* = 6.9 Hz, 2 H, H-14), 7.47 (d, *J* = 6.8 Hz, 2 H), 7.43–7.28 (m, 7 H), 5.91 (br, 1 H), 5.47–5.37 (m, 3 H), 4.50 (br, 1 H), 4.45–4.42 (m, 1 H), 4.32 (br, 1 H), 4.18 (br, 1 H), 3.07 (br, 2 H), 2.67 (s, 3 H), 1.84–1.80 (m, 2 H), 1.43–1.24 (m, 4 H), 1.40 (s, 9 H).

¹³C NMR (126 MHz, CDCl₃): $\delta$ = 162.9, 162.1, 156.3, 155.8, 152.8 (C-8), 144.0, 141.4, 139.6, 135.7, 128.7, 128.6, 128.4, 127.7, 127.1, 125.1, 120.0, 79.3, 67.2, 66.7, 49.2, 47.3, 39.8, 35.4, 29.6, 28.5, 23.2, 19.3.

LC: $t_R$ = 2.96 min; LC-MS (ESI+): *m/z* (%) = 656.4 (100, [M + H]⁺), 678.3 (90, [M + Na]⁺).

HRMS (ESI): *m/z* calcd for C₃₇H₄₂N₃O₆S [M + H]⁺: 656.2789; found: 656.2783.

## Benzyl (S)-5-(1-N-Fmoc-amino-3-(tert-butoxy)-3-oxopropyl)-2-isopropylthiazole-4-carboxylate (6f)

White solid; yield: 67%; $[\alpha]_D^{20} = +0.8$ (c 1, CDCl₃).

¹H NMR (600 MHz, CDCl₃): $\delta$ = 7.76 (d, *J* = 7.3 Hz, 2 H), 7.57 (br, 2 H), 7.48 (d, *J* = 7.4 Hz, 2 H), 7.40–7.29 (m, 7 H), 6.55 (d, *J* = 8.1 Hz, 1 H), 5.86–5.83 (m, 1 H), 5.47 (d, *J* = 12.3 Hz, 1 H), 5.40 (d, *J* = 12.3 Hz, 1 H), 4.38–4.32 (m, 2 H), 4.22–4.20 (m, 1 H), 3.35–3.31 (m, 1 H), 2.94–2.82 (m, 2 H), 1.37–1.36 (m, 15 H).

¹³C NMR (125 MHz, CDCl₃): $\delta$ = 175.5, 170.1, 162.3, 155.5, 149.5, 143.9, 141.3, 139.6, 135.7, 128.6, 128.6, 128.3, 127.7, 127.1, 125.1, 120.0, 81.8, 67.1, 67.05, 47.2, 46.2, 40.5, 33.6, 28.0, 24.9, 23.3.

LC: $t_R$ = 3.23 min; LC-MS (ESI+): *m/z* (%) = 627.3 (100, [M + H]⁺), 649.3 (70, [M + Na]⁺).

HRMS (ESI): *m/z* calcd for C₃₆H₃₉N₂O₆S [M + H]⁺: 627.2523; found: 627.2519.

## Benzyl 5-((S)-1-N-Fmoc-amino-4-(tert-butoxy)-4-oxobutyl)-2-((S)-Boc-pyrrolidin-2-yl)thiazole-4-carboxylate (6g)

White solid; yield: 42%; $[\alpha]_D^{20} = +6.7$ (c 1, CHCl₃).

¹H NMR (500 MHz, DMSO-d₆): $\delta$ = 8.19 (d, *J* = 7.6 Hz, 1 H), 7.90 (d, *J* = 7.6 Hz, 2 H), 7.67 (d, *J* = 7.7 Hz, 2 H), 7.47–7.28 (m, 9 H), 5.44–5.39 (m, 1 H), 5.32 (s, 2 H), 5.02–4.85 (m, 1 H), 4.29 (d, *J* = 7.0 Hz, 2 H), 4.20 (t, *J* = 7.0 Hz, 1 H), 2.35–1.84 (m, 8 H), 1.37 (s, 18 H).

¹³C NMR (125 MHz, DMSO-d₆): $\delta$ = 172.67, 171.56, 161.65, 156.08, 155.22, 154.9, 153.5, 144.2, 141.2, 136.3, 129.0, 128.9, 128.75, 128.1, 127.5, 125.6, 120.7, 80.2, 79.7, 66.7, 59.3, 49.1, 47.1, 34.05, 34.0, 32.1, 31.8, 28.2, 24.1.

LC: $t_R$ = 3.85 min; LC-MS (ESI+): *m/z* (%) = 768.4 (100, [M + H]⁺), 790.4 (10, [M + Na]⁺).

HRMS (ESI): *m/z* calcd for C₄₃H₅₀N₃O₈S [M + H]⁺: 768.3313; found: 768.3322.

## ATC* Benzyl Esters 7; General Procedure

To a stirred solution of compound 5 (1.0 equiv., 10.00 mmol) in CH₂Cl₂ (150 mL) were added PPh₃ (2.0 equiv., 20.00 mmol), I₂ (2.0 equiv., 20.00 mmol), and Et₃N (4.0 equiv., 40.00 mmol) at 0 °C. The reaction was completed after 30 min stirring at 0 °C (HPLC monitoring). The organic solution was wahsed with water (1 × 100 mL) and brine (3 × 150 mL), dried (MgSO₄) and concentrated in vacuo. Purification by flash column chromatography with EtOAc/cyclohexane gave the pure product 7.

## Benzyl 5-(N-Fmoc-aminomethyl)-2-methyloxazole-4-carboxylate (7a)

Yellow solid; yield: 31%.

¹H NMR (600 MHz, CDCl₃): $\delta$ = 7.76 (d, *J* = 7.4 Hz, 2 H), 7.55 (d, *J* = 7.4 Hz, 2 H), 7.47 (d, *J* = 7.4 Hz, 2 H), 7.41–7.28 (m, 7 H), 5.66 (t, *J* = 6.5 Hz, 1 H), 5.42 (s, 2 H), 4.71 (d, *J* = 6.5 Hz, 2 H), 4.40 (d, *J* = 7.0 Hz, 2 H), 4.19 (t, *J* = 7.0 Hz, 1 H), 2.69 (s, 3 H).

¹³C NMR (500 MHz, CDCl₃): $\delta$ = 164.1, 162.2, 156.2, 146.3, 143.8, 141.0, 135.6, 128.7, 128.6, 128.5, 127.7, 127.1, 125.1, 124.7, 120.0, 67.2, 66.9, 47.2, 36.8, 29.7, 19.3.

LC: $t_R$ = 2.77 min; LC-MS (ESI+): *m/z* (%) = 469.2 (100, [M + H]⁺), 491.1 (50, [M + Na]⁺).

HRMS (ESI): *m/z* calcd for C₂₈H₂₅N₂O₅ [M + H]⁺: 469.1758; found: 469.1762.

## Benzyl (S)-5-(1-N-Fmoc-aminoethyl)-2-methyloxazole-4-carboxylate (7b)

Yellow solid; yield: 86%; $[\alpha]_D^{20} = -18.7$ (c 1, CHCl₃).

¹H NMR (600 MHz, CDCl₃): $\delta$ = 7.76 (d, *J* = 7.6 Hz, 2 H), 7.57 (t, *J* = 6.0 Hz, 2 H), 7.48–7.20 (m, 9 H), 5.95 (d, *J* = 9.2 Hz, 1 H), 5.43–5.35 (m, 3 H), 4.37 (d, *J* = 7.1 Hz, 2 H), 4.20 (t, *J* = 7.1 Hz, 1 H), 2.46 (s, 3 H), 1.48 (d, *J* = 7.1 Hz, 3 H).

¹³C NMR (150 MHz, CDCl₃): $\delta$ = 162.1, 159.7, 155.5, 155.4, 143.9, 141.3, 135.4, 128.7, 127.65, 128.5, 127.7, 127.1, 126.7, 125.1, 120.0, 67.1, 66.9, 47.2, 43.7, 20.4, 13.8.
LC: *t*<sub>R</sub> = 3.07 min; LC-MS (ESI+): *m/z* (%) = 483.4 (100) [M + H]<sup>+</sup>, 505.3 (30) [M + Na]<sup>+</sup>.

HRMS (ESI): *m/z* calcd for C₂₉H₂₇N₂O₅ [M + H]<sup>+</sup>: 483.1914; found: 483.1918.

### Benzyl (S)-5-(1-N-Fmoc-amino-3-methylbutyl)-2-methyloxazole-4-carboxylate (7c)

White solid; yield: 50%; [α]<sub>D</sub><sup>20</sup> = +23.1 (c 1, CDCl₃).

¹H NMR (400 MHz, CDCl₃): δ = 7.76 (d, *J* = 7.6 Hz, 2 H), 7.56 (d, *J* = 7.2 Hz, 2 H), 7.45 (d, *J* = 7.2 Hz, 2 H), 7.39 (*t*, *J* = 7.2 Hz, 2 H), 7.36–1.27 (m, 5 H), 5.84 (d, *J* = 9.6 Hz, 1 H), 5.41–5.29 (m, 3 H), 4.41–4.35 (m, 2 H), 4.19 (*t*, *J* = 6.9 Hz, 1 H), 2.46 (s, 3 H), 1.74–1.70 (m, 1 H), 1.54–1.49 (m, 2 H), 0.91 (d, *J* = 6.5 Hz, 3 H), 0.87 (d, *J* = 6.5 Hz, 3 H).

¹³C NMR (150 MHz, CDCl₃): δ = 162.1, 159.6, 155.7, 143.9, 141.3, 128.8, 128.7, 128.5, 127.1, 125.1, 120.0, 67.2, 66.8, 47.3, 46.2, 43.3, 24.8, 22.6, 21.9, 13.8; C-4 of the oxazole is missing.

LC: *t*<sub>R</sub> = 3.07 min; LC-MS (ESI+): *m/z* (%) = 525.2 (90, [M + H]<sup>+</sup>), 547.3 (100, [M + Na]<sup>+</sup>).

HRMS (ESI): *m/z* calcd for C₃₂H₃₃N₂O₅ [M + H]<sup>+</sup>: 525.2384; found: 525.2381.

### Benzyl (S)-5-(1-N-Boc-amino-2-phenylethyl)-2-methyloxazole-4-carboxylate (7d)

Yellow solid; yield: 69%; [α]<sub>D</sub><sup>20</sup> = -3.4 (c 1, CHCl₃).

¹H NMR (600 MHz, CDCl₃): δ = 7.76 (d, *J* = 7.6 Hz, 2 H), 7.58–7.11 (m, 14 H), 7.00–6.96 (m, 2 H), 6.01 (d, *J* = 8.1 Hz, 1 H), 5.54 (q, *J* = 8.15 Hz, 1 H), 5.36 (*t*, *J* = 8.9 Hz, 2 H), 4.38 (dd, *J* = 10.6, 7.2 Hz, 1 H), 4.29 (dd, *J* = 10.6, 7.2 Hz, 1 H), 4.17 (*t*, *J* = 7.2 Hz, 1 H), 3.08 (d, *J* = 8.1 Hz, 2 H), 2.40 (s, 3 H).

¹³C NMR (151 MHz, CDCl₃): δ = 162.0, 159.9, 158.2, 155.5, 143.8, 141.3, 135.9, 135.3, 129.2, 128.8, 128.7, 128.65, 128.5, 127.7, 127.6, 127.1, 127.0, 125.1, 120.0, 67.2, 67.0, 49.2, 47.2, 40.5, 13.7.

LC: *t*<sub>R</sub> = 3.36 min; LC-MS (ESI+): *m/z* (%) = 559.5 (100, [M + H]<sup>+</sup>), 581.4 (20, [M + Na]<sup>+</sup>).

HRMS (ESI): *m/z* calcd for C₃₅H₃₁N₂O₅ [M + H]<sup>+</sup>: 559.2227; found: 559.2215.

### Benzyl (S)-5-(1-N-Fmoc-amino-4-N-Boc-amino)butyl)-2-methyloxazole-4-carboxylate (7e)

White solid; yield: 77%; [α]<sub>D</sub><sup>20</sup> = -1.1 (c 1, CDCl₃).

¹H NMR (600 MHz, CDCl₃): δ = 7.76 (d, *J* = 7.4 Hz, 2 H), 7.57 (d, *J* = 6.6 Hz, 2 H), 7.46 (d, *J* = 7.4 Hz, 2 H), 7.41–7.28 (m, 7 H), 5.95 (d, *J* = 8.2 Hz, 1 H), 5.38 (dd, *J* = 30.8, 12.1 Hz, 2 H), 5.25 (q, *J* = 8.2 Hz, 1 H), 4.47 (br, 1 H), 4.39 (d, *J* = 6.9 Hz, 2 H), 4.20 (*t*, *J* = 6.9 Hz, 1 H), 3.05 (br, 2 H), 2.46 (s, 3 H), 1.83–1.72 (m, 2 H), 1.43 (s, 11 H), 1.37–1.23 (m, 2 H).

¹³C NMR (126 MHz, CDCl₃): δ = 162.1, 159.9, 159.0, 155.0, 155.8, 143.8, 141.3, 135.3, 128.8, 128.7, 128.6, 127.7, 127.2, 127.1, 125.1, 120.0, 79.2, 67.2, 66.9, 47.7, 47.2, 40.1, 34.1, 29.4, 28.5, 22.9, 13.8.

LC: *t*<sub>R</sub> = 2.99 min; LC-MS (ESI+): *m/z* (%) = 662.3 (100, [M + Na]<sup>+</sup>).

HRMS (ESI): *m/z* calcd for C₃₇H₄₂N₃O₇ [M + H]<sup>+</sup>: 640.3017; found: 640.3018.

### Benzyl (S)-5-(1-N-Fmoc-amino-3-(tert-butoxy)-3-oxopropyl)-2-isopropyloxazole-4-carboxylate (7f)

White solid; yield: 72%; [α]<sub>D</sub><sup>20</sup> = +0.8 (c 1, CDCl₃).

¹H NMR (600 MHz, CDCl₃): δ = 7.76 (d, *J* = 7.5 Hz, 2 H), 7.56 (*t*, *J* = 6.9 Hz, 2 H), 7.46 (*d*, *J* = 6.9 Hz, 2 H), 7.40–7.27 (m, 7 H), 6.26 (*d*, *J* = 9.3 Hz, 1 H), 5.69–5.65 (m, 1 H), 5.43 (AB, *J* = 12.5 Hz, 1 H), 5.37 (AB, *J* = 12.5 Hz, 1 H), 4.38–4.33 (m, 2 H), 4.20 (*t*, *J* = 6.9 Hz, 1 H), 3.12–3.07 (m, 1 H), 2.81–2.79 (m, 2 H), 1.38 (s, 9 H), 1.35 (*d*, *J* = 2.1 Hz, 3 H), 1.34 (*d*, *J* = 2.1 Hz, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 168.9, 167.5, 162.1, 157.2, 155.4, 143.8, 141.3, 135.4, 128.7, 128.75, 128.5, 127.7, 127.3, 127.1, 125.1, 120.0, 81.6, 67.1, 67.05, 47.1, 45.0, 39.7, 28.5, 28.0, 20.3.

LC: *t*<sub>R</sub> = 3.20 min; LC-MS (ESI+): *m/z* (%) = 611.4 (90, [M + H]<sup>+</sup>), 633.3 (100, [M + Na]<sup>+</sup>).

HRMS (ESI): *m/z* calcd for C₃₆H₃₉N₂O₇ [M + H]<sup>+</sup>: 611.2749; found: 611.2752.

### ATC* and AOC* Benzyl Esters 6h and 7h; General Procedure

To a solution of α-amino β-keto ester 4c (1.0 equiv., 0.19 mmol) in anhyd THF (2 mL) at 0 °C was added N,N-diisopropylethylamine (1.0 equiv., 0.19 mmol). To the mixture was added dropwise trimethylsilyl isothiocyanate or trimethylsilyl isocyanate (1.5 equiv., 0.28 mmol) at 0 °C. The reaction was stirred for 2 h at 0°C, then overnight at 35 °C until the cyclization was completed. Purification was performed by preparative RP-HPLC on a Gilson system controller equipped with a C18 Luna column (100 × 21.2 mm, 5 µm) at a flow of 20 mL/min, UV detection at 214 nm and a gradient of A = H₂O and B = CH₃CN.

### Benzyl (S)-5-(1-N-Fmoc-amino-3-methylbutyl)-2-aminothiazole-4-carboxylate (6h)

White solid; yield: 32%; [α]<sub>D</sub><sup>20</sup> = -2.7 (c 1, CDCl₃).

¹H NMR (600 MHz, CDCl₃): δ = 11.32 (br, 1 H), 9.75 (br, 1 H), 7.73 (d, *J* = 7.3 Hz, 2 H), 7.56 (br, 2 H), 7.38–7.28 (m, 9 H), 5.66 (br, 1 H) 5.30–5.23 (m, 2 H), 5.12 (br, 1 H), 4.45–4.41 (m, 2 H), 4.16 (*t*, *J* = 6.4 Hz, 1 H), 1.75 (br, 1 H), 1.52–1.49 (m, 2 H), 0.83 (d, *J* = 5.7 Hz, 3 H), 0.79 (d, *J* = 5.7 Hz, 3 H).

¹³C NMR (150 MHz, CDCl₃): δ = 162.0, 157.8, 157.75, 156.2, 143.7, 141.3, 134.5, 128.9, 128.8, 128.5, 127.8, 127.1, 125.1, 120.0, 115.5, 67.6, 67.0, 47.2, 45.3, 42.9, 24.8, 22.7, 21.6.

LC: *t*<sub>R</sub> = 2.81 min; LC-MS (ESI+): *m/z* (%) = 542.3 (100, [M + H]<sup>+</sup>), 564.2 (50, [M + Na]<sup>+</sup>).

HRMS (ESI): *m/z* calcd for C₃₁H₃₂N₃O₄S [M + H]<sup>+</sup>: 542.2108; found: 542.2108.

### Benzyl (S)-5-(1-N-Fmoc-amino-3-methylbutyl)-2-aminooxazole-4-carboxylate (7h)

White solid; yield: 27%; [α]<sub>D</sub><sup>20</sup> = +0.3 (c 1, CHCl₃).

¹H NMR (600 MHz, CDCl₃): δ = 11.00 (br, 1 H), 9.09 (br, 1 H), 7.67 (d, *J* = 7.8 Hz, 2 H), 7.51 (*d*, *J* = 7.2 Hz, 2 H), 7.37–7.14 (m, 9 H), 6.11 (br, 1 H) 5.29–5.19 (m, 3 H), 4.33–4.30 (m, 2 H), 4.10 (*t*, *J* = 6.7 Hz, 1 H), 1.67–1.26 (m, 3 H), 0.80 (*d*, *J* = 6.0 Hz, 3 H), 0.75 (*d*, *J* = 6.0 Hz, 3 H).

¹³C NMR (150 MHz, CDCl₃): δ = 159.4, 156.1, 156.05, 153.3, 143.8, 141.3, 135.2, 128.7, 128.6, 128.5, 127.7, 127.0, 125.1, 125.0, 124.8, 119.9, 66.9, 66.8, 47.2, 45.5, 43.4, 24.8, 22.8, 21.5.

LC: *t*<sub>R</sub> = 3.26 min; LC-MS (ESI+): *m/z* (%) = 526.2 (100, [M + H]<sup>+</sup>), 548.2 (10, [M + Na]<sup>+</sup>).

HRMS (ESI): *m/z* calcd for C₃₁H₃₂N₃O₅ [M + H]<sup>+</sup>: 526.2336; found: 526.2332.
## Benzyl Deprotection; General Procedure

Pd/BaSO₄ (5% ww, 10 mol%) was dispersed into a solution of O-benzyl ester (1.0 equiv., 10.00 mmol) in DCM (50 mL) and EtOH (100 mL). The mixture was degassed and saturated with H₂. After 2 h of vigorous stirring at 30 °C, HPLC monitoring showed 100% conversion. The catalyst was removed by filtration through a Celite pad with DCM as eluent. After evaporation in vacuo, the filtrate afforded the desired product, which was used without any further purification.

## Hybrid Peptide P1 and P2; General Procedure

Solid-phase synthesis was performed with an AmphiSpheres™ Rink Amide resin loaded at 0.31 mmol/g using Fmoc chemistry. Resin (0.50 mmol) was swollen in DMF for 30 min and filtered. Fmoc deprotection was performed using piperidine/DMF solution (2:8 vv) (3 × 15 min at rt), then the resin was washed with DMF (3 ×), MeOH (3 ×), DCM (3 ×), DMF (1 ×), MeOH (1 ×), and DCM (1 ×). α-Amino acids were coupled in 5 min using HBTU/NMM (5 equiv. each) in N-methylpyrrolidone (NMP). Coupling of Fmoc-ATC*-OH or Fmoc-AOC*-OH (1.75 equiv.) were done overnight at rt using DIC (1.75 equiv.), Oxyma Pure (1.75 equiv.) in NMP (30 ml/g). After draining, the resin was washed with DMF (3 ×), MeOH (3 ×), DCM (3 ×), DMF (1 ×), MeOH (1 ×), and DCM (1 ×). Each coupling was followed by a capping step with Ac₂O/DCM (1:1 vv) (2 × 5 min at rt). After completion of the oligomerization process, the peptide was capped using Ac₂O/DCM (1:1 vv) (2 × 5 min at rt) and cleaved from the resin with a TFA/TIS/H₂O (95:2.5:2.5 vvv) solution (3 h at rt and overnight at rt). The resin was washed with DCM (3 ×). The collected filtrate was evaporated under reduced pressure. Purification was performed by preparative RP-HPLC on a Gilson system controller equipped with a C18 Luna column (100 × 21.2 mm, 5 µm) at a flow of 20 mL/min, UV detection at 214 nm and a gradient of A = H₂O (0.1% TFA) and B = CH₃CN (0.1% TFA).

### Peptide P1

LC: $t_R$ = 1.51 min; LC-MS (ESI+): *m/z* (%) = 525.3 (100, [M + H]⁺).

### Peptide P1

LC: $t_R$ = 1.51 min. LC-MS (ESI+): *m/z* (%) = 509.4 (100, [M + H]⁺).

## Conflict of Interest

The authors declare no conflict of interest.

## Funding Information

The AtzC Project (ANR-21-CE07-0039) is funded by the ANR (French National Research Agency).

## Acknowledgment

The authors acknowledge the LMP (Laboratoire de Mesures Physiques, IBMM, Montpellier) for the acquisition of NMR spectra.

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