MCR-Based Exploitation and Application of Diverse (Poly)Heterocyclic Scaffolds
Wang, Qian
DOI:
10.33612/diss.133937133
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Wang, Q. (2020). MCR-Based Exploitation and Application of Diverse (Poly)Heterocyclic Scaffolds. University of Groningen. https://doi.org/10.33612/diss.133937133
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Chapter 2
WITH UNPROTECTED AMINO ACIDS TO TETRAZOLO
PEPTIDOMIMETICS
This chapter is published
Rudrakshula Madhavachary,
†Qian Wang,
†and Alexander Dömling
† the authors contributed equally
Chem. Comm. 2017, 53, 8549-8552.
56
ABSTRACT
Here we describe the direct usage of C,N-unprotected amino acids in the Ugi-tetrazole reactions to produce a novel class of acid-tetrazole compounds. Surprisingly, only tetrazole Ugi product is found and not traces of other possible Ugi type reactions. Based on this reaction pathway we have designed the synthesis of novel tetrazole-peptidomimetics. A high level of structural diversity can be achieved with this isocyanide based multicomponent reactions (IMCRs), providing a platform for the production of functionalized building blocks for novel bioactive molecules and nontraditional scaffolds which previously were not accessible.
57 INTRODUCTION
There have been enormous developments in both the Ugi- and Ugi-tetrazole reactions since 1959, which provides a general route to diverse peptide, peptidomimetics and other complex molecules.1 In multicomponent reactions (MCR), isocyanide based multicomponent reactions (IMCRs) are highly convergent processes which have had a great impact in pharmaceutical and drug discovery research.2 Although IMCRs have proven to be a solution for many common problems in synthetic chemistry such as diversity, complexity and harsh conditions, novel scaffolds, for example by the use of bi-functional substrates are of high interest.3
N-substituted amino acids are interesting scaffolds as their parent play a key role in biochemistry and are the structural units of peptides, proteins and enzymes. Moreover protected amino acid derived Ugi/Ugi-tetrazole products can efficiently act as biomimetics undergoing competing interactions at the active site of enzymes and cell receptors. In 1996 Ugi reported the use of -amino acids as bifunctional educts in the Ugi-5-center-4-component reaction (U-5C-4CR) instead of the amine and acid components in the familiar Ugi-4-component reaction (U-4CR).4 Later on very effective variations of the Ugi-reaction were reported by using amino acids as one of the starting component.5 Yudin et al., Orru et al. and Paixão et al. have shown the great impact of the direct use of amino acid in Ugi-type reactions.5d, 5c & 5h Our group also reported a “truly” four-component reaction for the synthesis of iminodicarboxamides by employing amino acids directly in an U-5C-4CR.5e In 2013, Lämmerhofer et.al reported the synthesis of phosphopeptidomimetics by utilizing aminophosphonic acids in U-5C-4CR.5g Even though unprotected amino acids and aminophosphonic acids are utilized in various Ugi-type reactions, to the best of our knowledge, this is the first study on the use of unprotected amino acids in the Ugi-tetrazole reaction (Scheme 1).
58
This finding is of importance since the tetrazole is a known bioisostere of the carboxylic acid with often superior pharmacokinetic/pharmacodynamic (PKPD) properties.6 Even so the Ugi tetrazole reaction has developed tremendously in recent years the use of unprotected amino acids is unprecedented and surprising.7
RESULTS AND DISCUSSION
Therefore we report herein a mild and efficient technology for the synthesis of highly substituted N,C-unprotected but N-substituted acid-tetrazoles 4 and peptido-tetrazoles 6 using Ugi-tetrazole/Ugi reactions from natural N,C-unprotected amino acids, di and tripeptides and commercially available aldehydes/ketones, amines and isocyanides [Scheme 1, eq. (2)]. In continuation of our previous tetrazole work, we decided to explore the direct usage of amino acids in Ugi-tetrazole reaction.8 We expected that the reaction of L-proline 1a with paraformaldehyde 2a, benzyl isocyanide 3a and sodium azide would lead to the Ugi-tetrazole (4a) or U-5C-4CR or the U-4CR product, all in principal possible reaction pathways for these reactants. Initial attempts in DCM interestingly furnished the Ugi-tetrazole product (4a) without any other possible by-product, however in only 15% yield, the remainder was recovered starting materials. A subsequent solvent optimization exercise of this amino acid based Ugi-tetrazole reaction is summarized in Table 1.
We started optimization by screening different solvents for the Ugi-tetrazole reaction of 1.0 equivalent of L-proline 1a, 1.0 equivalent of paraformaldehyde 2a, 1.0 equivalent of benzyl isocyanide 3a and 1.2 equivalents of sodium azide. As expected, non-polar solvents and polar-aprotic solvents gave us very poor yield of the Ugi-tetrazole product due to the low solubility of the starting materials. Interestingly, polar-protic solvents like trifluoroethanol (TFE) and isopropanol gave only 35% and 20% yields of the Ugi-tetrazole product 4a, respectively. Similar related reactions of C,N-unprotected dipeptides toward diketopiperazine via the Ugi reaction explicitly require the protic polar solvent TFE. When we used methanol as a solvent, it furnished the desired product in 78% yield after 12 h. We also tested zinc chloride as a Lewis-acid catalyst (10 mol%) but without any increase of the yield. When we used methanol and water in a 5 : 1 ratio, the Ugi-tetrazole product was furnished in 71% yield after 12 h. Thus 1.0 equivalent of amino acid, 1.0 equivalent of aldehyde, 1.0 equivalent of isocyanide and 1.2 equivalents of sodium azide in 1.0 M of methanol or methanol : H2O (5 : 1) for 12 h was the optimized conditions for the Ugi-tetrazole reaction.
59 Table 1. Optimization for the Ugi-tetrazole reaction of L-proline.a,b
S. no. Solvent (1.0 M) Time (h) Yield (%)
1 THF 12 <10 2 DCM 12 15 3 CH3CN 12 <10 4 Toluene 12 10 5 TFE 12 35 6 Isopropanol 12 20 7 MeOH 12 78 8 MeOH + H2O (1:1) 12 61 9c MeOH + H 2O (1:1) 12 50 10 MeOH + H2O (5:1) 12 71 11 MeOH + ZnCl2 12 50 12 H2O 12 50
a The reactions were run using 1a (1.0 mmol), 2a (1.0 mmol), 3a (1.0 mmol) and NaN
3 (1.2 mmol) in the
indicated solvent for 12 h. b Isolated yield. c Reaction at 50 °C.
With the optimized reaction conditions in hand, the scope of the “Ugi-tetrazole” reaction was further investigated by reacting a library of natural/unnatural −amino acids, -amino acids and /-amino acids with different aldehydes, isocyanides and sodium azide in methanol or methanol : H2O (5:1) solvent system to furnish an amino acid-tetrazole library 4b-p. All the substrates 1, 2 and 3 furnished the expected Ugi-tetrazole products 4b-p in 27-74% yields, almost irrespective of the electronic and steric factors of the substituents present. L-Proline reacted with paraformaldehyde 2a, glycine methyl ester isocyanide 3b to furnished the excepted Ugi-tetrazole product 4b in 74% yield (see Table 1). Similarly, alanine, phenylalanine, 4-hydroxy-proline, isoleucine, valine, glycine, tyrosine, L-methionine and L-selenoL-methionine also furnished the Ugi-tetrazole products in good yields as ~3:1 diasteriomeric mixtures, respectively. Interestingly histidine is also a valid substrate with modest yield (27% 4k). Surprisingly, higher non α-amino acids worked as well. Thus, the reaction of -alanine with piperonal, phenylethyl isocyanide also furnished the excepted Ugi-tetrazole product 4n in good 48% yield with very low yield of Ugi side product (-lactam, only observed in MS, not isolatable). Next, -aminobutyric acid was reacted with 2-methoxy benzaldehyde, and tert-butyl isocyanide furnishing the
60
Ugi-tetrazole product 4o in good 53% yield. -Aminovaleric acid is also valid substrate in this reaction, and it produces the tetrazole product 4p in 66% yield with great purity.
After synthesizing a library of acid-tetrazoles in an Ugi-tetrazole reaction, we further transformed them into biologically important peptidomimetics 6 through another Ugi-4CR. The reaction of the acid-tetrazole product 4b with 1.0 equivalent of paraformaldehyde, 1.0 equivalent tert-butyl isocyanide and 1.0 equivalent of 2-(4-chlorophenyl)ethanamine in methanol at room temperature for 24 h furnished the Ugi-product 6a in 50% yield. This compound 6 has a unique and defined structure which consists of an amino acid inside the chain, a small peptidomimetic chain but with potentially enhanced stability or biological activity and at the end a tetrazole unit which is a bioisostere for cis-amide groups. This interesting structural unit in one molecule was achieved only two synthetic steps. In a similar manner, the selective two-step sequential Ugi-tetrazole/Ugi-reaction strategy was demonstrated with five more substrates in good overall yields (see Table 2; 6b–f). Finally, we investigated the synthetic utility of this methodology by reacting the N,C-unprotected dipeptide Gly–Gly and tripeptide Gly–Gly– Gly. To our great delight, these reactions also worked accordingly and afforded the products 4p and 4q in 69% and 58% yields, respectively (see Scheme 2).
A plausible mechanism of this Ugi-tetrazole reaction is shown in scheme 3 and it involves Schiff base formation, which leads to the intermediate nitrilium ion after the addition of isocyanide, followed by azide attack, and a final irreversible sigmatropic rearrangement to the tetrazole product.9 In the case of amino acids, the Ugi-tetrazole reaction may also proceed through pathway B, there after the addition of the isocyanide 3 to the Schiff base, an O-acylamide (II) is formed. Due to the nucleophilic attack of the azide at the isocyanide carbon, it leads to the original intermediate (III) of Ugi-tetrazole reaction and the subsequent rearrangement leads to the acid-tetrazole product 4.
62
aUgi-tetrazole reaction was carried out in MeOH or MeOH:H
2O (5:1) (1.0 M) with 1.0 equiv. of amino acid 1
relative to the aldehyde 2, isocyanide 3 and 1.2 equiv. of NaN3 at 25 °C for 12 h. bUgi-reactions was carried out
in MeOH (1.0 M) with 1.0 equiv. of aldehyde 2, amine 5 after 10 mints addition of 1.0 equiv. of acid-tetrazole 4 and isocyanide 3 (1.0 equiv.) at 25 °C and stirred for 24 h. cYield refers to the column-purified product. ddr was
determined by NMR analysis. ereaction was carried out in MeOH:H
63 Scheme 2. Di- and tripeptides in Ugi-tetrazole reaction.
64
We have performed an appropriate control experiment to investigate the competitive nature of azide anions in the Ugi-tetrazole reaction with C,N-unprotected amino acids as shown in Scheme 4. In the presence of sodium azide and an external acid (propionic acid) along with 2-amino-2-methylpropanoic acid, cyclopropanecarbaldehyde and benzyl isocyanide under standardized reaction conditions, after 12 h, we have carefully examined the NMR and ESI-HRMS spectra of the crude reaction mixture (see ESI†). As expected, the crude NMR spectrum and the ESI-HRMS experiment showed the major Ugi-tetrazole product (4d) along with a trace amount of the Ugi-product (7). These results indicate that the three different Ugi products are formed in substantial kinetic difference 4d >> 7 > 8.
65 CONCLUSIONS
Chemistry at its best, by the ‘lego’ approach is the great advantage of MCR to afford outstanding scaffold diversity. Here, we have identified a novel ‘lego-like’ approach towards the synthesis of substituted amino acid-tetrazoles and tetrazoles-peptidomimetics. This robust and air- and moisture-tolerant procedure is a valuable addition to MCR chemistry and expands the substrate scope to include amino acids, peptide like chains and 1,5-disubstituted tetrazoles in one molecule.
66
REFERENCES
1. a) Domling, A. Chem. Rev. 2006, 106, 17; b) Akritopoulou-Zanze, I. Curr. Opin. Chem. Biol. 2008, 12, 324; c) Zarganes-Tzitzikas, T.; Chandgude, A. L.; Domling, A. Chem. Rec. 2015, 15, 981.
2. a) Hulme, C.; Gore, V. Curr. Med. Chem. 2003, 10, 51; b) Plant, A.; Thompson, P.; Williams, D. M. J. Org. Chem. 2009, 74, 4870; c) Ruijter, E.; Scheffelaar, R.; Orru, R. V. A. Angew. Chem. Int. Ed. 2011, 50, 6234; d) Domling, A.; Wang, W.; Wang, K. Chem. Rev. 2012, 112, 3083; e) Koopmanschap, G.; Ruijter, E.; Orru, R. V. A. Beilstein J. Org. Chem. 2014, 10, 544.
3. a) Zhang, J. D.; Jacobson, A.; Rusche, J. R.; Herlihy, W. J. Org. Chem. 1999, 64, 1074; b) Sinha, M. K.; Khoury, K.; Herdtweck, E.; Domling, A. Org. Biomol. Chem. 2013, 11, 4792; c) Brauch, S.; van Berkel, S. S.; Westermann, B. Chem. Soc. Rev. 2013, 42, 4948.
4. Demharter, A.; Horl, W.; Herdtweck, E.; Ugi, I. Angew. Chem. Int. Ed. 1996, 35, 173.
5. a) Ugi, I. K.; Ebert, B.; Horl, W. Chemosphere 2001, 43, 75; b) Gedey, S.; Van der Eycken, J.; Fulop, F. Org. Lett. 2002, 4, 1967; c) Elders, N.; van der Born, D.; Hendrickx, L. J. D.; Timmer, B. J. J.; Krause, A.; Janssen, E.; de Kanter, F. J. J.; Ruijter, E.; Orru, R. V. A. Angew. Chem. Int. Ed. 2009, 48, 5856; d) Hili, R.; Rai, V.; Yudin, A. K. J. Am. Chem. Soc. 2010, 132, 2889; e) Khoury, K.; Sinha, M. K.; Nagashima, T.; Herdtweck, E.; Domling, A. Angew. Chem. Int. Ed. 2012, 51, 10280; f) Saito, K.; Nishimori, A.; Mimura, R.; Nakano, K.; Kotsuki, H.; Masuda, T.; Ichikawa, Y. Eur J. Org. Chem. 2013, 2013, 7041; g) Gargano, A. F. G.; Buchinger, S.; Kohout, M.; Lindner, W.; Lammerhofer, M. J. Org. Chem. 2013, 78, 10077; h) de la Torre, A. F.; Rivera, D. G.; Concepcion, O.; Echemendia, R.; Correa, A. G.; Paixao, M. W. J. Org. Chem. 2016, 81, 803; i) Orru, R.; Ruijter, E.; Cioc, R.; Schaepkens van Riempst, L.; Schuckman, P. Synthesis 2016, 49, 1664.
6. Herr, R. J. Bioorgan Med. Chem. 2002, 10, 3379.
7. Maleki, A.; Sarvary, A. RSC Adv. 2015, 5, 60938 and here in references.
8. a) Patil, P.; Madhavachary, R.; Kurpiewska, K.; Kalinowska-Tluscik, J.; Domling, A. Org. Lett. 2017, 19, 642; b) Chandgude, A. L.; Domling, A. Org. Lett. 2016, 18, 6396; c) Abdelraheem, E. M. M.; Kurpiewska, K.; Kalinowska-Tluscik, J.; Domling, A. J. Org. Chem. 2016, 81, 8789; d) Neochoritis, C. G.; Stotani, S.; Mishra, B.; Domling, A. Org. Lett. 2015, 17, 2002; e) Patil, P.; Khoury, K.; Herdtweck, E.; Domling, A. Org. Lett. 2014, 16, 5736.
67 EXPERIMENTAL SECTION
GENERAL EXPERIMENTAL PROCEDURES
Procedure A: General procedure for Ugi-tetrazole adducts 4: To the stirred solution of amino acid 1 (1.0 mmol) in methanol (1.0 mL), was added aldehyde/ketone 2 (1.0 mmol). The mixture was stirred for 10 min at rt. Then isocyanide 3 (165 mg, 1 mmol) followed by NaN3 was added to the solution. The reaction mixture was stirred at rt for about over night and reaction was monitored by TLC. After completion of reaction, the solvent was evaporated under reduced pressure and the residue was purified by flash chromatography (DCM/MeOH 85:15) to give the desired product 4.
Procedure B: General procedure for Ugi-tetrazole-Ugi adducts 6: To the stirred solution of amino acid 1 (1.0 mmol) in methanol (1.0 mL), was added aldehyde/ketone 2 (1.0 mmol). The mixture was stirred for 10 min at rt. Then isocyanide 3 (1.0 mmol) followed by NaN3 (1.2 mmol) was added to the solution. The reaction mixture was stirred at rt for about over night. After completion of reaction, the pure products were abtained by flash chromatography (DCM/MeOH 85:15). This Ugi-tetrazole pure products were used further in Ugi-reaction. In an ordinary glass vial equipped with a magnetic stirring bar, to a mixture of amine 5 (1.0 mmol) and aldehyde (1.0 mmol) were added methanol (1.0 M). The reaction mixture was stirred at 25 °C for 30 min. Then isocyanide 3 (1.0 mmol) followed by Ugi-tetrazole product 4 (as acid component) were added to the solution. The resulting mixture was stirred at same temperature for 24 hr. Solvents were removed under vacuum. The crude product was purified by flash column chromatography using petroleum ether/ethyl acetate (9:1 to 20:1) to afford the product 6.
(S)-1-((1-Benzyl-1H-tetrazol-5-yl)methyl)pyrrolidine-2-carboxylic acid 4a:
Synthesized according to procedure A in 1 mmol scale, afforded 4a (223 mg, 78 %) as yellow semi-solid. 1H NMR (500 MHz, Methanol-d
4) δ 7.46 – 7.27 (m, 5H), 5.95 – 5.76 (m, 2H), 4.45 (d, J = 14.2 Hz, 1H), 4.09 (d, J = 14.3 Hz, 1H), 3.58 – 3.45 (m, 1H), 3.02 – 2.88 (m, 1H), 2.56 (q, J = 8.7 Hz, 1H), 2.36 – 2.17 (m, 1H), 2.08 – 1.92 (m, 1H), 1.90 – 1.79 (m, 1H), 1.79 – 1.67 (m, 1H); 13C NMR (126 MHz, Methanol-d 4) δ 175.2, 152.1, 134.4, 128.6, 128.3, 128.0, 66.2, 53.7, 50.6, 46.0, 28.9, 22.6; HRMS calcd for C14H18N5O2 [M+H]+ : 288.1455, found [M+H]+: 288.1455. (S)-1-((1-(2-Methoxy-2-oxoethyl)-1H-tetrazol-5-yl)methyl)pyrrolidine-2-carboxylic acid 4b:
Synthesized according to procedure A in 1 mmol scale, afforded 4b (199 mg, 74%) as yellow semi-solid. 1H NMR (500 MHz, Methanol-d
4) δ 5.91 – 5.54 (m, 2H), 4.39 (d, J = 14.3 Hz, 1H), 4.02 (d, J = 14.4 Hz, 1H), 3.82 (s, 3H), 3.47 – 3.39 (m, 1H), 2.95 – 2.79 (m, 1H), 2.46 (q, J = 8.7 Hz, 1H), 2.36 – 2.20 (m, 1H), 2.03 – 1.92 (m, 1H), 1.92 – 1.83 (m, 1H), 1.83 – 1.71 (m, 1H); 13C NMR (126 MHz, Methanol-d
4) δ 174.9, 167.2, 153.6, 65.2, 53.2, 52.0, 48.0, 46.1, 28.8, 22.5; HRMS calcd for C10H16N5O4 [M+H]+: 270.1197, found [M+H]+: 270.1192.
68
(2S)-2-((1-(1-Cyclohexyl-1H-tetrazol-5-yl)-2-phenylethyl)amino)propanoic acid 4c:
Synthesized according to procedure A in 1 mmol scale, afforded 4c (178 mg, 52%) as white solid. 1H NMR (500 MHz, Methanol-d
4, 1:1 diatereomeric mixture) δ 7.29 – 7.20 (m, 5H), 7.09 – 7.00 (m, 5H), 4.86 – 4.77 (m, 1H), 4.73 – 4.61 (m, 1H), 4.00 (tt, J = 11.8, 3.8 Hz, 1H), 3.84 (tt, J = 11.7, 3.8 Hz, 1H), 3.77 – 3.67 (m, 1H), 3.62 – 3.47 (m, 3H), 3.26 – 3.13 (m, 2H), 3.08 – 2.96 (m, 2H), 2.15 – 2.00 (m, 1H), 1.97 – 1.72 (m, 5H), 1.72 – 1.60 (m, 5H), 1.56 – 1.37 (m, 8H), 1.28 – 1.08 (m, 5H), 0.74 – 0.58 (m, 2H); 13C NMR (126 MHz, Methanol-d4) δ 174.9, 174.8, 153.9, 153.2, 135.6, 135.4, 129.1, 129.0, 128.6, 128.5, 127.1, 127.0, 57.8, 57.6, 55.3, 54.9, 52.9, 52.6, 40.8, 39.5, 32.8, 32.5, 32.2, 32.0, 24.8, 24.8, 24.7, 24.6, 24.5, 17.2, 16.9; HRMS calcd for C18H26N5O2 [M+H]+: 344.2081, found [M+H]+: 344.2081.
2-(((1-Benzyl-1H-tetrazol-5-yl)(cyclopropyl)methyl)amino)-2-methylpropanoic acid 4d:
Synthesized according to procedure A in 1 mmol scale, afforded 4d (195 mg, 62%) as white solid. 1H NMR (500 MHz, Methanol-d
4) δ 7.40 – 7.26 (m, 5H), 6.01 (d, J = 15.3 Hz, 1H), 5.80 (d, J = 15.3 Hz, 1H), 3.63 (d, J = 9.4 Hz, 1H), 1.26 (s, 3H), 1.05 – 0.94 (m, 1H), 0.87 (s, 3H), 0.62 – 0.52 (m, 1H), 0.50 – 0.42 (m, 1H), 0.32 – 0.21 (m, 1H), 0.15 – 0.06 (m, 1H); 13C NMR (126 MHz, Methanol-d 4) δ 176.1, 155.4, 133.1, 127.0, 126.7, 126.2, 58.3, 53.4, 49.4, 24.4, 21.0, 14.2, 3.0, 1.0; HRMS calcd for C16H22N5O2 [M+H]+: 316.1768, found [M+H]+: 316.1768.
(2R,3S)-2-(((1-(2-(1H-Indol-3-yl)ethyl)-1H-tetrazol-5-yl)methyl)amino)-3-methylpentanoic acid 4e: Synthesized according to procedure A in 1 mmol scale, afforded 4e (138 mg, 39%) as yellow semi-solid. 1H NMR (500 MHz, Chloroform-d, racemization occurred during the reaction) δ 7.35 – 7.29 (m, 5H), 7.28 – 7.21 (m, 5H), 5.72 – 5.59 (m, 2H), 4.52 – 4.30 (m, 2H), 4.28 – 4.19 (m, 1H), 4.11 – 4.02 (m, 1H), 3.95 – 3.80 (m, 1H), 3.45 – 3.34 (m, 1H), 3.34 – 3.24 (m, 1H), 3.02 (s, 1H), 2.89 (s, 1H), 1.89 – 1.72 (m, 1H), 1.68 – 1.52 (m, 2H), 1.50 – 1.35 (m, 2H), 1.35 – 1.19 (m, 2H), 1.15 – 0.99 (m, 1H), 0.97 – 0.88 (m, 1H), 0.88 – 0.78 (m, 9H), 0.74 (t, J = 7.4 Hz, 3H); 13C NMR (126 MHz, Chloroform-d) δ 172.5, 171.0, 152.5, 137.5, 133.3, 129.2, 128.9, 128.8, 127.9, 127.7, 127.6, 70.7, 68.1, 59.4, 58.6, 51.2, 43.3, 36.7, 34.2, 25.5, 25.5, 15.7, 15.0, 11.9, 11.7, 10.8; HRMS calcd for C18H25N6O2 [M+H]+: 357.2034, found [M+H]+: 357.2034.
69 (2S)-2-((1-(1-(3,4-Dimethoxybenzyl)-1H-tetrazol-5-yl)-2-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)ethyl)amino)-3-methylbutanoic acid 4f:
Synthesized according to procedure A in 1 mmol scale, afforded 4f (269 mg, 57%) as yellow semi-solid. 1H NMR (500 MHz, Methanol-d
4, 3:1 diastereomeric mixture, major isomer) δ 7.47 (d, J = 7.9 Hz, 1H), 7.01 (d, J = 2.1 Hz, 1H), 6.94 – 6.90 (m, 1H), 6.84 – 6.79 (m, 1H), 5.78 – 5.67 (m, 2H), 5.55 – 5.50 (m, 2H), 4.38 (t, J = 6.7 Hz, 1H), 4.11 – 4.01 (m, 2H), 3.85 (s, 6H), 2.81 (d, J = 5.2 Hz, 1H), 1.87 – 1.77 (m, 1H), 0.84 (d, J = 4.9 Hz, 3H), 0.83 (d, J = 4.9 Hz, 3H); 13C NMR (126 MHz, Methanol-d4) δ 177.4, 165.1, 154.9, 151.1, 149.3, 146.8, 126.5, 120.3, 111.6, 111.5, 111.4, 100.1, 66.2, 55.1, 55.1, 50.9, 50.5, 31.4, 18.5, 16.9; HRMS calcd for C21H28N7O6 [M+H]+: 474.2096, found [M+H]+: 474.2092.
(2S)-2-((1-(1-Benzyl-1H-tetrazol-5-yl)-3-methylbutyl)amino)-3-phenylpropanoic acid 4g:
Synthesized according to procedure A in 1 mmol scale, afforded 4g (137 mg, 35%) as yellow semi-solid. 1H NMR (500 MHz, DMSO-d
6, 3:1 diastereomers, major isomer) δ 7.40 – 7.33 (m, 3H), 7.28 – 7.25 (m, 2H), 7.20 – 7.12 (m, 5H), 5.72 – 5.55 (m, 2H), 4.15 – 4.07 (m, 1H), 3.41 – 3.36 (m, 1H), 2.88 (dd, J = 13.6, 5.7 Hz, 1H), 2.70 (dd, J = 13.6, 8.0 Hz, 1H), 1.50 – 1.41 (m, 1H), 1.33 – 1.21 (m, 1H), 1.14 – 1.04 (m, 1H), 0.60 (d, J = 6.5 Hz, 3H), 0.51 (d, J = 6.6 Hz, 3H); 13C NMR (126 MHz, DMSO-d 6, 3:1 diastereomers, major isomer) δ 175.5, 156.7, 138.5, 135.3, 129.7, 129.3, 128.6, 128.5, 127.9, 126.7, 60.3, 50.4, 49.7, 42.1, 39.2, 24.6, 22.7, 22.2; HRMS calcd for C22H28N5O2 [M+H]+: 394.2238, found [M+H]+: 394.2238.
(2S,4R)-1-((1-Benzyl-1H-tetrazol-5-yl)methyl)-4-hydroxypyrrolidine-2-carboxylic acid 4h:
Synthesized according to procedure A in 1 mmol scale, afforded 4h (157 mg, 52%) as white semi-solid. 1H NMR (500 MHz, DMSO-d
6) δ 7.43 – 7.30 (m, 5H), 5.99 – 5.75 (m, 2H), 4.31 (d, J = 13.9 Hz, 1H), 4.05 (q, J = 5.1 Hz, 1H), 3.90 (d, J = 13.9 Hz, 1H), 3.49 (t, J = 8.3 Hz, 1H), 2.80 (dd, J = 9.7, 5.8 Hz, 1H), 2.23 (dd, J = 9.7, 4.4 Hz, 1H), 2.06 – 1.92 (m, 2H); 13C NMR (126 MHz, DMSO-d
6) δ 175.3, 153.2, 135.5, 129.1, 128.8, 128.6, 68.6, 64.4, 61.7, 50.3, 46.8; HRMS calcd for C14H18N5O3 [M+H]+: 304.1404, found [M+H]+: 304.1404.
70
(S)-2-((1-(1-(2-Methoxybenzyl)-1H-tetrazol-5-yl)cyclopentyl)amino)-4-(methylthio)butanoic acid 4i: Synthesized according to procedure A in 1 mmol scale, afforded 4i (178 mg, 44%) as brown semi-solid. 1H NMR (500 MHz, Methanol-d
4) δ 7.31 (td, J = 7.8, 1.7 Hz, 1H), 7.26 (dd, J = 7.5, 1.7 Hz, 1H), 7.01 (dd, J = 8.3, 1.0 Hz, 1H), 6.95 (td, J = 7.4, 1.0 Hz, 1H), 5.53 (s, 1H), 4.59 (s, 2H), 3.89 (s, 3H), 2.75 – 2.65 (m, 1H), 2.65 – 2.46 (m, 4H), 2.44 – 2.32 (m, 1H), 2.13 (s, 3H), 2.12 – 2.09 (m, 2H), 1.97 – 1.86 (m, 4H); 13C NMR (126 MHz, Methanol-d4) δ 175.2, 157.4, 128.6, 128.2, 124.9, 120.0, 110.1, 54.4, 41.7, 37.1, 35.6, 31.3, 29.4, 25.8, 25.6, 13.7; HRMS calcd for C19H28N5O3S [M+H]+: 406.1907, found [M+H]+: 406.1893.
(2S)-2-(((1-(Tert-butyl)-1H-tetrazol-5-yl)(4-chlorophenyl)methyl)amino)-4-(methylselanyl)butanoic acid 4j:
Synthesized according to procedure A in 1 mmol scale, afforded 4j (226 mg, 51%) as yellow semi-solid. 1H NMR (500 MHz, Chloroform-d, 1.2:1 diastereomers, major isomer) δ 7.37 – 7.31 (m, 4H), 5.55 (s, 1H), 4.59 (dd, J = 9.5, 4.0 Hz, 1H), 3.43 – 3.30 (m, 2H), 2.64 – 2.57 (m, 2H), 1.92 (s, 3H), 1.64 (s, 9H); 13C NMR (126 MHz, Chloroform-d, 1.2:1 diastereomers, major isomer) δ 177.2, 155.1, 134.9, 131.5, 130.0, 129.4, 62.0, 58.2, 56.5, 33.0, 30.0, 21.1, 4.0; 1H NMR (500 MHz, Chloroform-d, 1.2:1 diastereomers, minor isomer) δ 7.35 – 7.28 (m, 4H), 5.55 (s, 1H), 4.59 (dd, J = 9.5, 4.0 Hz, 1H), 2.96 – 2.80 (m, 2H), 2.77 – 2.65 (m, 2H), 1.97 (s, 3H), 1.78 (s, 9H); 13C NMR (126 MHz, Chloroform-d, 500 MHz, Chloroform-d, 1.2:1 diastereomers, minor isomer) δ 177.8, 157.4, 135.9, 129.8, 129.3, 128.8, 61.7, 59.3, 52.7, 33.3, 30.3, 20.9, 4.4; HRMS calcd for C17H25ClN5O2Se [M+H]+: 446.0857, found [M+H]+: 446.0856.
(2S)-2-((Benzo[d][1,3]dioxol-5-yl(1-(4-chlorobenzyl)-1H-tetrazol-5-yl)methyl)amino)-3-(1H-imidazol-5-yl)propanoic acid 4k:
Synthesized according to procedure A in 1 mmol scale, afforded 4k (130 mg, 27%) as yellow semi-solid; 1H NMR (500 MHz, Methanol-d
4, 1:1 diastereomers) δ 8.05 (s, 2H), 7.28 – 7.22 (m, 3H), 7.22 – 7.14 (m, 1H), 7.02 – 6.94 (m, 4H), 6.88 – 6.81 (m, 1H), 6.68 – 6.54 (m, 5H), 5.94 – 5.84 (m, 4H), 5.76 – 5.56 (m, 3H), 5.52 (s, 1H), 5.41 – 5.29 (m, 1H), 5.23 (s, 1H), 3.24 – 3.14 (m, 2H), 3.09 – 3.00 (m, 2H), 2.97 – 2.80 (m, 2H); 13C NMR (126 MHz, Methanol-d 4, 1:1 diastereomers) δ 178.5, 178.4, 156.7, 156.3, 148.0, 147.9, 147.8, 147.7, 133.8, 133.7, 133.6, 132.9, 132.7, 131.1, 130.4, 128.8, 128.6, 128.4, 128.3, 121.9, 121.1, 118.8, 107.8, 107.8, 107.6, 107.5, 101.3, 101.2, 61.5, 60.4, 55.8, 55.2, 49.6, 49.5, 29.6, 29.3; HRMS calcd for C22H21ClN7O4 [M+H]+: 482.1338, found [M+H]+: 482.1338.
71
(2S)-3-(4-Hydroxyphenyl)-2-((3-(methylthio)-1-(1-(2,4,4-trimethylpentan-2-yl)-1H-tetrazol-5-yl)propyl)amino)propanoic acid 4l:
Synthesized according to procedure A in 1 mmol scale, afforded 4l (202 mg, 45%) as yellow solid; 1H NMR (500 MHz, Methanol-d
4) δ 6.97 (d, J = 8.4 Hz, 2H), 6.72 – 6.65 (m, 2H), 4.92 (s, 2H), 4.58 (dd, J = 8.3, 5.1 Hz, 1H), 3.57 – 3.50 (m, 1H), 2.97 (dd, J = 13.8, 4.6 Hz, 1H), 2.69 – 2.56 (m, 2H), 2.53 – 2.46 (m, 1H), 2.15 – 2.07 (m, 1H), 2.05 (s, 3H), 2.01 (s, 2H), 1.80 (s, 3H), 1.69 (s, 3H), 0.83 (s, 9H); 13C NMR (126 MHz, Methanol-d 4) δ 176.7, 157.0, 155.8, 130.0, 128.3, 114.8, 65.6, 60.0, 53.6, 51.1, 38.8, 33.7, 31.1, 29.8, 29.3, 29.0, 14.1; HRMS calcd for C22H36N5O3S [M+H]+: 450.2533, found [M+H]+ : 450.2533.
2-(((1-Benzyl-1H-tetrazol-5-yl)(phenyl)methyl)amino)acetic acid 4m:
Synthesized according to procedure A in 1 mmol scale, afforded 4m (119 mg, 37%) as green semi-solid; 1H NMR (500 MHz, Methanol-d
4) δ 8.68 – 8.50 (m, 1H), 7.40 – 7.36 (m, 3H), 7.35 – 7.30 (m, 2H), 7.26 – 7.19 (m, 4H), 7.10 – 7.05 (m, 2H), 5.43 (s, 1H), 4.41 (s, 1H), 4.22 – 4.13 (m, 1H), 3.69 (d, J = 14.6 Hz, 1H), 3.24 (d, J = 14.5 Hz, 1H), 3.00 (d, J = 17.5 Hz, 1H); 13C NMR (126 MHz, Methanol-d 4) δ 170.0, 155.9, 134.5, 133.2, 128.1, 127.8, 127.2, 127.1, 126.8, 126.7, 126.6, 126.5, 125.4, 125.2, 79.5, 66.7, 41.0; HRMS calcd for C17H18N5O2 [M+H]+: 324.1455, found [M+H]+: 324.1455.
3-((Benzo[d][1,3]dioxol-5-yl(1-phenethyl-1H-tetrazol-5-yl)methyl)amino)propanoic acid 4n:
Synthesized according to procedure A in 1 mmol scale, afforded 4n (189 mg, 48%) as semi-solid; 1H NMR (500 MHz, Methanol-d
4) δ 7.22 – 7.11 (m, 3H), 6.99 – 6.88 (m, 2H), 6.78 – 6.68 (m, 3H), 5.88 (s, 2H), 4.86 (s, 1H), 4.59 – 4.48 (m, 1H), 4.48 – 4.36 (m, 1H), 3.06 – 2.84 (m, 2H), 2.62 (t, J = 6.6 Hz, 2H), 2.37 (t, J = 6.6 Hz, 2H); 13C NMR (126 MHz, Methanol-d4) δ 174.7, 153.9, 146.9, 146.7, 135.2, 128.3, 127.0, 126.9, 125.2, 120.1, 106.6, 106.1, 99.9, 54.7, 47.1, 41.2, 33.5, 32.2; HRMS calcd for C20H22N5O4 [M+H]+: 396.1666, found [M+H]+: 396.1662.
4-(((1-(Tert-butyl)-1H-tetrazol-5-yl)(2-methoxyphenyl)methyl)amino)butanoic acid 4o:
Synthesized according to procedure A in 1 mmol scale, afforded 4o (184 mg, 53%) as yellow solid; 1H NMR (500 MHz, Methanol-d
4) δ 7.47 – 7.40 (m, 1H), 7.20 – 7.14 (m, 2H), 7.04 – 6.98 (m, 1H), 6.15 (s, 1H), 3.97 (s, 3H), 2.90 – 2.75 (m, 2H), 2.43 – 2.32 (m, 2H), 1.88 (p, J = 6.9 Hz, 2H), 1.64 (s, 9H); 13C NMR (126
72
MHz, Methanol-d4) δ 177.5, 156.7, 154.1, 130.7, 128.4, 123.7, 121.0, 111.2, 62.2, 55.0, 50.2, 46.7, 33.2, 28.5, 23.6; HRMS calcd for C17H26N5O3 [M+H]+: 378.2030, found [M+H]+: 348.2027.
6-((1-(1-(3,4-Dimethoxybenzyl)-1H-tetrazol-5-yl)-2-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)ethyl)amino)hexanoic acid 4p:
Synthesized according to procedure A in 1 mmol scale, afforded 4p (321 mg, 66%) as white solid. 1H NMR (500 MHz, DMSO-d
6) δ 7.58 (d, J = 7.9 Hz, 1H), 6.98 (d, J = 2.0 Hz, 1H), 6.93 (d, J = 8.3 Hz, 1H), 6.82 (dd, J = 8.3, 2.1 Hz, 1H), 5.71 (d, J = 15.2 Hz, 1H), 5.58 (d, J = 15.3 Hz, 1H), 5.54 (d, J = 7.8 Hz, 1H), 4.46 (dd, J = 8.2, 5.4 Hz, 1H), 4.09 – 3.96 (m, 2H), 3.73 (s, 3H), 3.73 (s, 3H), 2.35 – 2.24 (m, 1H), 2.12 (t, J = 7.4 Hz, 2H), 2.09 – 2.02 (m, 1H), 1.36 (p, J = 7.4 Hz, 2H), 1.20 – 1.04 (m, 4H); 13C NMR (126 MHz, DMSO-d 6) δ 174.9, 164.2, 154.9, 151.6, 149.3, 149.2, 147.0, 127.1, 120.8, 112.2, 100.8, 56.0, 55.9, 50.8, 50.3, 50.1, 45.9, 34.1, 29.5, 26.5, 24.8; HRMS calcd for C22H30N7O6 [M+H]+: 488.2252, found [M+H]+: 488.2246. 2-(2-(((1-Benzyl-1H-tetrazol-5-yl)(phenyl)methyl)amino)acetamido)acetic acid 4q:
Synthesized according to procedure A in 1 mmol scale, afforded 4q (262 mg, 69%) as yellow solid; 1H NMR (500 MHz, Methanol-d
4) δ 7.35 – 7.31 (m, 2H), 7.31 – 7.27 (m, 3H), 7.26 – 7.20 (m, 3H), 7.05 – 6.91 (m, 2H), 5.70 – 5.52 (m, 2H), 5.40 (s, 1H), 3.79 (s, 2H), 3.37 – 3.20 (m, 2H); 13C NMR (126 MHz, Methanol-d4) δ 175.1, 171.8, 156.2, 137.1, 133.7, 128.8, 128.6, 128.4, 128.2, 127.9, 127.4, 56.5, 50.6, 49.4, 42.9; HRMS calcd for C19H21N6O3 [M+H]+: 381.1670, found [M+H]+: 381.1669.
2-(2-(2-(((1-Benzyl-1H-tetrazol-5-yl)(phenyl)methyl)amino)acetamido)acetamido)acetic acid 4r: Synthesized according to procedure A in 1 mmol scale, afforded 4r (253 mg, 58%) as semi-solid; 1H NMR (500 MHz, Methanol-d 4) δ 7.36 – 7.29 (m, 5H), 7.29 – 7.23 (m, 3H), 7.05 – 6.98 (m, 2H), 5.69 – 5.53 (m, 2H), 5.41 (s, 1H), 3.97 (s, 1H), 3.93 (s, 1H), 3.89 (s, 2H), 3.29 (s, 2H); 13C NMR (126 MHz, Methanol-d4) δ 173.9, 172.9, 170.2, 156.1, 137.0, 133.8, 128.7, 128.5, 128.4, 128.1, 127.9, 127.4, 127.3, 56.4, 50.4, 49.2, 42.0, 41.8; HRMS calcd for C21H24N7O4 [M+H]+: 438.1884, found [M+H]+: 438.1884.
73 (S)-Methyl 2-(5-((2-((2-(tert-butylamino)-2-oxoethyl)(4-chlorophenethyl)carbamoyl)pyrrolidin-1-yl)methyl)-1H-tetrazol-1-yl)acetate 6a:
Synthesized according to procedure B in 1 mmol scale, afforded 6a (259 mg, 50%) as yellow semi-solid; 1H NMR (500 MHz, Chloroform-d, two rotamers were prevalent) δ 7.30 – 7.26 (m, 2H), 7.24 – 7.20 (m, 5H), 7.11 – 7.09 (m, 6H), 6.18 (s, 1H), 6.11 (s, 1H), 5.85 (dd, J = 17.3, 1.9 Hz, 2H), 5.74 (d, J = 17.3 Hz, 1H), 5.59 (d, J = 17.3 Hz, 1H), 4.14 (s, 1H), 4.01 (dd, J = 20.9, 14.5 Hz, 2H), 3.90 (s, 1H), 3.87 (s, 1H), 3.79 (s, 2H), 3.77 (s, 3H), 3.72 (d, J = 5.6 Hz, 1H), 3.71 – 3.66 (m, 1H), 3.58 – 3.51 (m, 2H), 3.43 – 3.37 (m, 2H), 3.20 (t, J = 8.2 Hz, 1H), 3.15 (dd, J = 8.7, 7.1 Hz, 1H), 2.96 – 2.88 (m, 2H), 2.86 – 2.81 (m, 2H), 2.80 – 2.75 (m, 2H), 2.73 – 2.67 (m, 4H), 2.67 – 2.62 (m, 4H), 2.35 – 2.23 (m, 2H), 2.14 – 2.00 (m, 2H), 1.84 – 1.73 (m, 3H), 1.37 (s, 6H), 1.33 (s, 9H); 13C NMR (126 MHz, Chloroform-d, two rotamers were prevalent) δ 173.2, 173.1, 167.7, 167.1, 167.0, 166.8, 153.5, 153.4, 152.8, 138.7, 138.0, 137.2, 136.2, 132.9, 132.2, 131.7, 130.2, 130.1, 130.0, 129.0, 128.6, 128.4, 74.3, 64.0, 63.0, 54.1, 53.7, 53.0, 52.8, 52.8, 52.0, 51.8, 51.6, 51.3, 50.4, 50.2, 49.5, 48.5, 48.4, 46.5, 45.8, 44.3, 35.6, 34.3, 33.8, 32.9, 29.5, 29.3, 28.7, 28.7, 23.0, 22.9; HRMS calcd for C24H35ClN7O4 [M+H]+: 520.2434, found [M+H]+: 520.2425.
(2S)-2-((1-(1-Benzyl-1H-tetrazol-5-yl)-3-methylbutyl)amino)-N-(2-(cyclohexylamino)-2-oxoethyl)-3-phenyl-N-propylpropanamide 6b:
Synthesized according to procedure B in 1 mmol scale, afforded 6b (315 mg, 55%) as yellow semi-solid; 1H NMR (500 MHz, Methanol-d
4) δ 7.35 – 7.31 (m, 6H), 7.29 – 7.25 (m, 4H), 7.24 – 7.21 (m, 6H), 7.19 – 7.15 (m, 4H), 5.70 – 5.49 (m, 4H), 4.26 – 4.15 (m, 2H), 3.99 – 3.87 (m, 4H), 3.81 – 3.62 (m, 4H), 3.33 – 3.18 (m, 3H), 3.18 – 3.07 (m, 1H), 3.04 – 2.91 (m, 2H), 2.77 – 2.63 (m, 2H), 1.93 – 1.84 (m, 4H), 1.80 – 1.70 (m, 5H), 1.66 – 1.57 (m, 3H), 1.53 – 1.43 (m, 5H), 1.37 – 1.26 (m, 10H), 1.23 – 1.12 (m, 5H), 0.87 (t, J = 7.4 Hz, 3H), 0.80 (d, J = 7.4 Hz, 3H), 0.67 (d, J = 6.6 Hz, 3H), 0.62 (d, J = 6.6 Hz, 3H), 0.57 (d, J = 6.6 Hz, 3H), 0.50 (d, J = 6.7 Hz, 3H); 13C NMR (126 MHz, Methanol-d 4) δ 175.3, 174.8, 168.1, 167.6, 156.5, 156.2, 138.1, 137.9, 134.6, 134.5, 129.2, 129.1, 128.8, 128.7, 128.7, 128.3, 128.3, 128.2, 128.2, 127.6, 127.5, 126.4, 126.4, 78.3, 57.7, 56.7, 50.6, 50.5, 50.4, 50.0, 49.9, 49.8, 49.6, 49.4, 49.3, 48.8, 48.4, 48.4, 48.2, 48.0, 47.9, 47.7, 47.5, 47.4, 42.4, 41.9, 39.8, 39.7, 32.6, 32.5, 32.5, 25.3, 24.8, 24.8, 24.8, 24.5, 24.4, 21.7, 21.6, 21.5, 21.3, 21.2, 20.2, 10.6, 10.4; HRMS calcd for C33H48N7O2 [M+H]+: 574.3864, found [M+H]+: 574.3864.
74
(2S)-N-(4-Chlorobenzyl)-2-((1-(1-(3,4-dimethoxybenzyl)-1H-tetrazol-5-yl)-2-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)ethyl)amino)-3-methyl-N-(2-oxo-2 (phenethylamino)ethyl)butanamide 6c:
Synthesized according to procedure B in 1 mmol scale, afforded 6c (310 mg, 41%) as semi-solid. 1H NMR (500 MHz, Chloroform-d) δ 9.93 – 9.64 (m, 2H), 7.46 (d, J = 8.0 Hz, 1H), 7.34 – 7.31 (m, 3H), 7.29 – 7.28 (m, 2H), 7.27 (s, 2H), 7.26 – 7.24 (m, 2H), 7.23 – 7.17 (m, 6H), 7.03 (d, J = 8.1 Hz, 2H), 6.95 – 6.93 (m, 2H), 6.84 – 6.73 (m, 2H), 6.72 – 6.61 (m, 2H), 6.55 (t, J = 5.8 Hz, 1H), 6.31 (t, J = 5.9 Hz, 1H), 5.77 – 5.48 (m, 6H), 4.91 (d, J = 14.9 Hz, 1H), 4.51 – 4.43 (m, 1H), 4.42 – 4.31 (m, 3H), 4.21 (dd, J = 14.0, 7.3 Hz, 1H), 4.15 – 4.05 (m, 2H), 3.81 (s, 3H), 3.78 (s, 3H), 3.77 (s, 3H), 3.76 (s, 3H), 3.63 – 3.56 (m, 2H), 3.56 – 3.44 (m, 3H), 3.41 – 3.33 (m, 1H), 3.26 – 3.18 (m, 1H), 2.88 (t, J = 7.2 Hz, 3H), 2.86 – 2.77 (m, 3H), 2.61 – 2.49 (m, 1H), 1.77 – 1.61 (m, 2H), 0.82 – 0.68 (m, 12H); 13C NMR (126 MHz, Chloroform-d) δ 174.7, 174.6, 167.9, 167.5, 163.7, 154.4, 154.3, 151.5, 151.0, 149.4, 149.3, 149.3, 146.2, 146.0, 138.8, 138.6, 134.9, 134.1, 133.7, 133.5, 129.7, 129.3, 128.9, 128.8, 128.7, 128.7, 128.6, 128.6, 128.5, 126.6, 126.4, 126.1, 125.9, 120.5, 120.3, 111.3, 111.3, 111.2, 101.7, 101.5, 61.2, 60.6, 56.0, 55.9, 55.8, 52.1, 51.4, 51.3, 50.7, 50.5, 49.9, 49.2, 49.2, 49.1, 40.8, 35.6, 35.3, 31.3, 31.0, 20.0, 20.0, 16.2, 15.9; HRMS calcd for C38H45ClN9O6 [M+H]+: 758.3176, found [M+H]+: 758.3175.
3-((Benzo[d][1,3]dioxol-5-yl(1-phenethyl-1H-tetrazol-5-yl)methyl)amino)-N-(cyclopropylmethyl)-N-(2-((3,4-dimethoxybenzyl)amino)-2-oxoethyl)propanamide 6d:
Synthesized according to procedure B in 1 mmol scale, afforded 6d (294 mg, 45%) as yellow semi-solid. 1H NMR (500 MHz, Chloroform-d) δ 7.26 – 7.19 (m, 3H), 6.98 – 6.93 (m, 2H), 6.76 – 6.65 (m, 4H), 6.63 – 6.60 (m, 1H), 6.56 (dd, J = 8.0, 1.8 Hz, 1H), 5.89 (s, 2H), 4.58 (s, 1H), 4.44 – 4.19 (m, 4H), 4.09 (d, J = 2.5 Hz, 1H), 3.79 (s, 3H), 3.78 (s, 3H), 3.24 – 3.17 (m, 2H), 2.98 – 2.86 (m, 2H), 2.72 – 2.57 (m, 2H), 2.51 – 2.38 (m, 3H), 0.91 – 0.81 (m, 1H), 0.54 – 0.46 (m, 2H), 0.17 (q, J = 5.1 Hz, 1H); 13C NMR (126 MHz, Chloroform-d) δ 172.3, 169.0, 155.9, 148.3, 147.8, 136.6, 131.4, 131.1, 128.9, 128.7, 127.2, 121.0, 119.5, 111.2, 110.9, 108.4, 107.6, 101.4, 57.2, 55.9, 55.8, 53.7, 50.1, 48.7, 48.7, 43.4, 42.7, 35.6, 33.1, 10.0, 3.8; HRMS calcd for C35H42N7O6 [M+H]+: 656.3191, found [M+H]+: 656.3182.
75 4-(((1-(Tert-butyl)-1H-tetrazol-5-yl)(2-methoxyphenyl)methyl)amino)-N-(2-(cyclohexylamino)-2-oxoethyl)-N-propylbutanamide 6e:
Synthesized according to procedure B in 1 mmol scale, afforded 6e (195 mg, 37%) as semi-solid. 1H NMR (500 MHz, Chloroform-d) δ 7.05 – 6.98 (m, 1H), 6.98 – 6.92 (m, 1H), 6.74 – 6.67 (m, 1H), 6.67 – 6.62 (m, 1H), 6.53 (d, J = 8.3 Hz, 1H), 5.59 (s, 1H), 3.72 – 3.66 (m, 2H), 3.64 (s, 3H), 3.56 – 3.40 (m, 1H), 3.08 (t, J = 7.8 Hz, 1H), 3.02 – 2.94 (m, 1H), 2.45 – 2.33 (m, 2H), 2.30 – 2.19 (m, 1H), 2.10 (t, J = 7.2 Hz, 1H), 1.93 (s, 1H), 1.69 – 1.52 (m, 5H), 1.40 (s, 9H), 1.37 – 1.28 (m, 3H), 1.13 – 0.98 (m, 3H), 0.96 – 0.85 (m, 3H), 0.59 (t, J = 7.3 Hz, 3H); 13C NMR (126 MHz, Chloroform-d) δ 173.4, 168.4, 155.9, 155.8, 129.2, 127.8, 127.0, 120.9, 110.7, 77.7, 61.1, 55.3, 51.0, 50.7, 50.4, 47.8, 46.9, 32.5, 30.1, 29.4, 25.3, 24.5, 21.6, 11.1, 10.9; HRMS calcd for C28H46N7O3 [M+H]+: 528.3657, found [M+H]+ : 528.3657.
6-((1-(1-(3,4-Dimethoxybenzyl)-1H-tetrazol-5-yl)-2-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)ethyl)amino)-N-(2-oxo-2-((2,4,4-trimethylpentan-2-yl)amino)ethyl)-N-phenethylhexanamide 6f: Synthesized according to procedure B in 1 mmol scale, afforded 6f (487 mg, 64%) as semi-solid.; 1H NMR (500 MHz, Methanol-d4) δ 7.49 (d, J = 7.9 Hz, 1H), 7.31 – 7.23 (m, 2H), 7.22 – 7.16 (m, 3H), 7.03 – 6.96 (m, 1H), 6.92 – 6.80 (m, 2H), 5.78 – 5.69 (m, 1H), 5.68 – 5.60 (m, 1H), 5.58 (d, J = 7.8 Hz, 1H), 4.50 (t, J = 6.7 Hz, 1H), 4.18 – 4.08 (m, 1H), 4.07 – 3.99 (m, 1H), 3.96 (s, 1H), 3.89 (s, 1H), 3.78 (s, 6H), 3.66 – 3.54 (m, 2H), 2.93 – 2.79 (m, 2H), 2.42 – 2.28 (m, 1H), 2.23 (t, J = 7.4 Hz, 1H), 2.18 – 2.08 (m, 2H), 1.85 – 1.75 (m, 2H), 1.55 – 1.44 (m, 1H), 1.39 (s, 3H), 1.38 (s, 3H), 1.36 – 1.32 (m, 1H), 1.27 – 1.05 (m, 4H), 1.00 (s, 9H); 13C NMR (126 MHz, Methanol-d4) δ 174.5, 174.5, 168.5, 167.9, 165.0, 154.8, 151.4, 149.5, 149.4, 146.8, 139.1, 138.5, 128.8, 128.5, 128.5, 128.3, 126.5, 126.4, 126.1, 120.4, 111.7, 111.5, 111.5, 100.6, 78.3, 55.3, 55.2, 54.9, 54.7, 50.9, 50.5, 50.3, 49.1, 46.4, 34.3, 33.5, 32.8, 32.0, 31.2, 30.7, 29.2, 28.7, 26.4, 24.6; HRMS calcd for C40H58N9O6 [M+H]+: 760.4505, found [M+H]+: 760.4492.
