i VIETNAM NATIONAL UNIVERSITY, HANOI VNU UNIVERSITY OF SCIENCE FACULTY OF CHEMISTRY Trần Thị Minh Châu Synthesis of Cyclic β Peptidomimetics by Ring Closing Metathesis Submitted in partial fulfillment of the requirements for the course of CHE4050 in Chemistry (Advanced program in Chemistry) Hanoi 2021 ITY OF SCIENCE ii VIETNAM NATIONAL UNIVERSITY, HANOI VNU UNIVERSITY OF SCIENCE FACULTY OF CHEMISTRY Trần Thị Minh Châu Synthesis of Cyclic β Peptidomimetics by Ring Closing Metathesis Submi.
VIETNAM NATIONAL UNIVERSITY, HANOI VNU UNIVERSITY OF SCIENCE FACULTY OF CHEMISTRY - - Trần Thị Minh Châu Synthesis of Cyclic β-Peptidomimetics by Ring Closing Metathesis Submitted in partial fulfillment of the requirements for the course of CHE4050 in Chemistry (Advanced program in Chemistry) Hanoi - 2021 i VIETNAM NATIONAL UNIVERSITY, HANOI VNU UNIVERSITY OF SCIENCE FACULTY OF CHEMISTRY - - Trần Thị Minh Châu Synthesis of Cyclic β-Peptidomimetics by Ring Closing Metathesis Submitted in partial fulfillment of the requirements for the course of CHE4050 in Chemistry (Advanced program in Chemistry) Supervisor: Assoc Prof Mạc Đình Hùng Hanoi - 2021 ii Acknowledgement Firstly, I would like to express deep gratitude to my supervisor, Assoc prof Mac Dinh Hung for accepting me in Medicinal Chemistry laboratory, as well as supervising and supporting my work throughout these past years Throughout this journey, I have gained a lot of invaluable theoretical and practical knowledge from him I would like to show my appreciation towards Dr Nguyen Hoang Yen for being a great source of support and encouragement throughout my senior year I wish to express my sincere gratitude to To Dong Quang and Le Quy Hien for always provide considerable assistance for any problems I encountered during my study at university I would like to extend my appreciation to my laboratory members for helping me and making the time I worked here enjoyable Finally, I am profoundly grateful for the great support of my family I am also thankful for all of my friends especially, Nguyen Doan Thu Thuy and Pham Anh Thu, for always being there for me i Table of contents Acknowledgement i Table of contents ii List of figures and schemes iv List of abbreviation vi Chapter 1: General Introduction Chapter 2: Literature Review 2.1 Overview of peptides 2.1.1 Proteins and amino acids 2.1.2 Protein-protein interaction 2.1.3 Mediating protein-protein interactions 2.1.3.1 Peptides as drugs 2.1.3.2 Disadvantages of peptides 2.2 Overview of peptidomimetics 2.2.1 Peptidomimetics 2.2.2 Classification of peptidomimetics 2.2.3 Synthetic approaches towards peptidomimetics design 2.2.3.1 Side chain modification 2.2.3.2 Strategies for restriction of φ, ψ, and ω torsion angles 2.2.3.2.1 Backbone modification 2.2.3.2.2 Introduction of global restriction 11 2.3 Ring closing metathesis route to cyclic β-peptidomimetics 12 2.3.1 A brief history of metathesis 12 ii 2.3.2 Peptidomimetics by ring closing metathesis 13 2.3.3 Peptidomimetics from β-amino acids 15 2.4 Research described in this thesis 18 Chapter 3: Experimental Method 19 3.1 Subject and purpose 19 3.2 Experimental procedure 19 3.2.1 Materials 19 3.2.2 N-alkylation procedure 20 3.2.3 Amide coupling procedure 21 3.2.4 Ring closing metathesis procedure 21 Chapter 4: Results and Discussions 23 4.1 Synthesis of N-alkylated β-amino acid 23 4.2 Synthesis of cyclic β-peptidomimetic 25 Chapter 5: Conclusion 27 Reference 28 iii List of figures and schemes A Figures Figure General structure of an α-amino acid Figure Dihedral angles that define peptide structure The backbone is defined by φ, ψ, ω, the side chain geometry is defined by 𝜒 Figure Newman projections of low energy staggered conformers in α-amino acids Figure Natural phenylalanine and β-alkyl analogue 1.01 Figure Structure of tera-substituted Aib 10 Figure The three principles arrangements of peptide cyclization 11 Figure Hormones containing a disulfide bridge 12 Figure Ring closing metathesis mechanism 12 Figure An early example of the use of RCM to mimic a disulfide bond 13 Figure 10 Recent peptidomimetics cyclized by RCM 14 Figure 11 Examples of bi-cyclics lactams where RCM is facilitates cyclic constraint 16 Figure 12 Top: RCM is not possible with a trans-amide as the diene groups are too far apart for the intramolecular reaction Bottom: the DMB group stabilizes the cis geometry of the amide bond facilitating RCM 17 Figure 13 Cyclization of Cβ-N’ by RCM to give 8-membered ring 1.17 17 B Table Table The most common forms of backbone modification of peptides to create peptidomimetics C Schemes Scheme Synthesis scheme 19 Scheme Synthesis of mono-alkylated product 20 Scheme Amine protection 21 iv Scheme Synthesis of dienes 21 Scheme Ring closing metathesis reaction 22 v List of abbreviation Bn Et Me Boc Cbz RCM DCM DMF EDCI HCl HOBt UV NMR equiv temp h r.t TLC : benzyl : etyl : methyl : tert-butoxycarbonyl : carboxybenzyl : ring closing metathesis : dichloromethane : dimethylformamide : 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride : hydroxy benzotriazole : ultraviolet : Nuclear Magnetic Resonance : equivalent : temperature : hour(s) : room temperature : thin-layer chromatography vi Chapter General Introduction More than 7000 naturally occurring peptides have been identified, and these compounds influence many important physiological mechanisms in the human body, such as immune defense, metabolism, digestion, respiration and sensitivity to pain [1] Peptides are acknowledged for being highly selective and efficacious as well as relatively safe and well-tolerated as therapeutics [2] Due to these advantages, an increasing number of peptides are entering clinical trials and being approved as therapeutics: An approximate of 60 peptides are approved for human use worldwide, and 140 therapeutic peptides are in different stages of clinical development [1] However, natural endogenous peptide sequences have intrinsic weaknesses, including limited stability towards proteolysis, rapid excretion, poor cell penatration and non-specific interactions with multiple targets [2] The limitations associated with therapeutic peptides can be overcome by modifying existing peptide sequences to create peptidomimetics These molecules are developed to display metabolic stability, good bioavailability, and enhanced receptor affinity and selectivity [2] Synthetic strategies focusing on optimizing the structure of the lead peptide by introducing functional modifications are able to address the intrinsic disadvantages of peptides, while maintaining the structural features responsible for the biological activity [2] A peptidomimetic approach that has extensive opportunities, is the use of βamino acids [3] β-peptides differ from their natural counterpart, α-peptides, by having a CH2 group inserted into every amino acid residue As reported by Seebach [4], the incorporation of an additional carbon would not increase the number of the possible configurational isomers but rather it would enhance the stability of the secondary structure comparing to their α-peptide counterparts The cyclization of β-peptides could potentially stabilize the bioactive conformation and enhance its metabolic stability by introducing additional conformational constraint [3] Due to the significant potential of the incorporation of β-amino acids in creating peptidomimetics, we have chosen to investigate the design of cyclic peptide mimics This study describes the efficient synthesis strategies of a conformationally constrained peptidomimetic containing a 9-atom-membered ring by ring closing metathesis 3.2.3 Amide coupling procedure To the solution of amine (1 equiv.) in methanol (50 mL) was added a solution of NaOH 2M (5 equiv.) The mixture was stirred at room temperature for 4h and evaporated under vacuum The resulting crude was dissolved with water (50 mL) and extracted with dichloromethane (2 x 50 mL) The aqueous phase was acidified to pH 2-3 by a solution of HCl 6M and then extracted with dichloromethane (3 x 50 mL) The organic phase was combined, washed with water (2 x 50 mL), dried over Na2SO4, filtered, and evaporated under vacuum The crude acid was used for the next step without further purification Scheme Amine protection c) Cbz-Cl, CH2Cl2, Et3N, r.t., 4h; MeOH/NaOH 2M, 2h, r.t The reaction was quenched with water and extracted with ethyl acetate (3 x 50 mL) The combined organic phase was washed with a solution of 2M HCl (50 mL), water (50 mL), and a solution of brine (50 mL) The organic phase was dried over Na2SO4, filtered, and evaporated under vacuum The crude product was purified by column chromatography on silica gel (Hexane: ethyl acetate 2:1) to give diamide as a viscous liquid Scheme Synthesis of dienes EDCI, HOBt, CH2Cl2, Et3N, and 4, r.t 3.2.4 Ring closing metathesis procedure Grubbs’ second-generation catalyst (5 mol%) was added to a 10-3 M solution of diene in degassed dichloromethane under an atmosphere of dry nitrogen 21 employing flame-dried glassware The mixture was heated to reflux for 4h and another portion of catalyst (5 mol%) was added The mixture was heated to reflux overnight After evaporation of the solution, the resulting residue was purified by column chromatography on Merck silica gel (40-60 mesh) using hexane: ethyl acetate (1:1 to 1:9) Scheme Ring closing metathesis reaction 22 Chapter Results and Discussions 4.1 Synthesis of N-alkylated β-amino acid For the synthesis of the bis-N-alkenylated peptide containing two terminal alkene chains used as starting material for the RCM reaction, β-glycine was initially converted to its methyl ester form which then underwent N-alkylation to give mono-alkylated product with 68% yield The resulting secondary amine was then protected by Cbz-Cl, followed by a saponification reaction to give acid product in good yield overall Finally, the βamino acid was coupled with N-alkenyl methyl ester using the EDCI-HOBtEt3N coupling procedure to give desired dipeptide with excellent yield (80%) As seen in the 1H NMR data of 4, the hydrogen nuclei of the Cbz protecting group were represented by the signal found in the chemical shift range of aromatic protons (7.29 - 7.39 ppm), proving that the protection procedure was succeeded Due to the deshelding effect of double bond and electronegative oxygen atom, a shift of 5.14 ppm was observed in hydrogen atoms; furthermore, a signal at 5.77 ppm also belong to a hydrogen of the double bond The nitrogen and oxygen desheilding the CH2 signals causing chemical shift (δ = 3.93 ppm, δ = 3.55 ppm, and δ = 2.65 ppm) H NMR data of showed that the coupling of N-alkenyl methyl ester gave the desired dipeptide By integrating peaks in 1H NMR, the total number of hydrogen atoms was 28 corresponding the chemical formula of the compound The present of nitrogen atoms cause overlapping and complex splitting pattern of hydrogen signal in dipeptide The new signal clusters found in the chemical shift range of ester protons (3.54 - 3.65 ppm) represent the hydrogen atom of the COOMe group The signal for two double bonds and CH2 of the carbamate group were found in 5.11 - 5.82 ppm region 23 3-(allyl((benzyloxy)carbonyl) amino) propanoic acid (4) H NMR (400 MHz, Chloroform-d) δ 7.39 – 7.29 (m, 5H), 5.77 (s, 1H), 5.14 (s, 4H), 3.93 (d, J = 5.8 Hz, 2H), 3.55 (t, J = 7.1 Hz, 2H), 2.65 (d, J = 25.4 Hz, 2H) Methyl 3-(N-allyl-3-(allyl((benzyloxy)carbonyl) propanoate (5) amino) propanamido) H NMR (500 MHz, Chloroform-d) δ 7.33 (d, J = 5.3 Hz, 5H), 5.82 – 5.52 (m, 2H), 5.11 (td, J = 12.3, 9.9, 5.5 Hz, 7H), 3.95 – 3.77 (m, 4H), 3.65 (s, 2H), 3.54 (dt, J = 14.3, 6.3 Hz, 4H), 2.72 – 2.40 (m, 4H) C NMR (126 MHz, CDCl3) δ 172.4, 171.6, 171.3, 170.9, 156.0, 156.0, 133.8, 133.8, 133.5, 133.5, 133.1, 132.9, 132.7, 128.5, 128.1, 127.9, 127.7, 117.4, 117.3, 116.7, 116.6, 67.2, 67.1, 51.9, 51.7, 51.1, 51.1, 50.7, 50.6, 47.9, 47.9, 44.4, 44.3, 43.2, 42.7, 33.4, 33.3, 32.7, 32.5, 32.0, 31.8 13 HRMS m/z calculated for [M+Na]+ C21H28N2NaO5 Exact Mass: 411.1896 Found 411.1899 24 4.2 Synthesis of cyclic β-peptidomimetic The obtained N-alkylated β-amino acid were subjected to RCM by using Grubbs’ catalyst We observed the formation of product which was later confirmed by 1H and 13C NMR and MS spectral as 9-membered cyclic product The first tentative was performed with toluene as solvent and 5% of Grubbs’ second-generation catalyst When toluene was replaced by dichloromethane, a better yield has been obtained probably due to the reaction occurred at a lower temperature reaction giving a more stable condition for catalyst When 5% of catalyst was used, cyclic product and the unreacted starting material was obtained with a ratio of approximately 2:1 This phenomenon was often observed in RCM which was explained by the decomposition of Grubbs’ catalyst at high dilution So as to achieve a full conversion reaction, another portion of catalyst was added after 4h of reaction A total of 10% Grubbs’ secondgeneration catalyst, which was applied in reflux system, has proven to achieve an effective quantitative synthesis by crude NMR (45% of isolated yield) and thinlayer chromatography By comparing 1H NMR data of and we could see these two data were quite similar; however, there were differences in the intensity of hydrogen signals At 5.70 - 5.99 ppm region, in comparison to 5, peptide would have the chemical shift of hydrogen atoms signals further downfield and the peaks spilt to three multiplets, this phenomenon may due to the formation of the 9-membered ring A significant increase was observed in the intensity of -COOMe peak; similarly, this increment also showed in CH2 peak at 2.63 - 2.73 ppm region 25 Benzyl5-(3-methoxy-3-oxopropyl)-4-oxo-2,3,4,5,6,9-hexahydro-1H-1,5 diazonine-1-carboxylate (6) H NMR (500 MHz, Chloroform-d) δ 7.38 – 7.29 (m, 5H), 5.99 – 5.91 (m, 1H), 5.88 – 5.77 (m, 2H), 5.77 – 5.70 (m, 1H), 5.14 (s, 2H), 5.11 (s, 2H), 4.02 (dd, J = 6.6, 3.2 Hz, 2H), 3.82 (dd, J = 16.6, 5.4 Hz, 2H), 3.67 (s, 3H), 3.63 (d, J = 6.8 Hz, 2H), 3.55 (q, J = 6.6 Hz, 2H), 2.71 (ddd, J = 16.2, 6.9, 3.7 Hz, 2H), 2.63 (t, J = 7.0 Hz, 2H) C NMR (126 MHz, CDCl3) δ 172.5, 172.5, 172.2, 171.9, 156.0, 155.2, 136.5, 136.4, 132.7, 132.1, 128.6, 128.4, 128.2, 128.1, 128.0, 127.9, 126.1, 126.0, 67.5, 67.5, 51.7, 47.2,47.0, 46.4, 46.4, 45.3, 45.3, 42.2, 42.1, 35.3, 34.8, 32.3 13 HRMS m/z calculated for [M+Na]+ C19H24N2NaO5 Exact Mass: 383.1583 Found 383.1588 26 Chapter Conclusion In summary, we have successfully synthesized a 9-membered ring cyclic peptidomimetic by using ring closing metathesis reaction The product was achieved in good yield and selectivity at high dilution of the reactants The synthesis strategy studied in this research enables an approach in synthesis of cyclic peptidomimetics consisting of β-amino acids Moreover, it opens up new opportunities to discover more structural variants of peptidomimetics which can serve as a valuable addition to chemical biology and drug design In the future research, we will investigate the biological activity as well as introduction of chiral β-amino acid to the cyclic ring 27 Reference [1] Fosgerau, K.; 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HANOI VNU UNIVERSITY OF SCIENCE FACULTY OF CHEMISTRY - - Trần Thị Minh Châu Synthesis of Cyclic β-Peptidomimetics by Ring Closing Metathesis Submitted in partial fulfillment of the requirements... history of metathesis Ring closing metathesis has emerged as an efficient method for the synthesis of carbon-carbon bonds in complex molecules including peptidomimetics Ring closing metathesis. .. and potential of this field of research The work in this thesis describes the design and synthesis of medium-sized ring peptidomimetic comprised of β-amino acid by ring closing metathesis Our