Silicon-Containing Amino Acids: Synthetic Aspects, Conformational

Review pubs.acs.org/CR

Silicon-Containing Amino Acids: Synthetic Aspects, Conformational Studies, and Applications to Bioactive Peptides Emmanuelle Rémond,† Charlotte Martin,†,‡ Jean Martinez, and Florine Cavelier* Institut des Biomolécules Max Mousseron, Unité Mixte de Recherche 5247 de Centre National de la Recherche Scientifique, École Nationale Supérieure de Chimie de Montpellier, Université Montpellier, Place Eugène Bataillon, 34095 Montpellier Cedex 5, France ABSTRACT: Unnatural α-amino acids form a family of essential molecules used for, among other applications, the synthesis of modified peptides, to improve resistance to proteolytic enzyme degradation, and to modulate physico- and biochemical properties of bioactive peptides as well as chiral inducers in asymmetric synthesis. Among them, silicon-containing unnatural amino acids are becoming an interesting new class of building blocks. The replacement of carbon atoms in bioactive substances with silicon is becoming increasingly popular. Peptides containing silyl amino acids hold great promise for maintaining or reinforcing the biological activity of active compounds, while they simultaneously enhance their resistance to enzyme degradation. In addition, the lipophilicity of the silicon atom facilitates their membrane crossing and their bioavailability. Nowadays, the interest of the pharmaceutical industry in peptide- and protein-based therapies is increasing. In this respect, silicon-containing amino acids and peptides are likely to be a significant part of future innovations in this area, and more generally in the area of biomolecules. In this process, commercial availability of silicon-containing amino acids is necessary: new syntheses have been developed, and work in this area is ongoing. This review aims to be a comprehensive and general summary of the different methods used to prepare silicon-containing amino acids and their implications on conformational structures and biological applications when they are incorporated into bioactive molecules.

CONTENTS 1. Introduction 2. Silyl Amino Acids 3. α-Silyl α-Amino Acids 3.1. Racemic Synthesis 3.1.1. Metalation 3.1.2. Insertion into the N−H Bond Catalyzed by Rhodium 3.1.3. Reverse Aza-Brook Rearrangement 3.2. Kinetic Resolution 3.2.1. By Use of Zirconaziridine 3.2.2. Reverse Aza-Brook Rearrangement 4. β-Silyl α-Amino Acids 4.1. Racemic Synthesis 4.1.1. Starting from Ethyl Acetamido(cyano)acetate 4.1.2. Starting from Dihydropyrazine 4.1.3. Starting from Diethyl Malonate 4.2. Enantioselective Synthesis 4.2.1. Diastereoselective Alkylation of Imidazolidinone 4.2.2. Diastereoselective Alkylation of Pseudoephedrine Glycinamide 4.2.3. Diastereoselective Alkylation of Pyrazine 4.2.4. Diastereoselective Alkylation of Hydroxy-3-pinanone 4.2.5. Use of Electrophilic/Nucleophilic Alanine Equivalent 4.2.6. Addition of Electrophiles to Imides © XXXX American Chemical Society

4.3. Enzymatic Resolution 4.3.1. Via Acylase I 4.3.2. Via Hydantoinases 4.4. β-Silyl α,α′-Disubstituted Amino Acids 4.4.1. Racemic Synthesis by Use of Benzophenone Schiff Bases 4.4.2. Racemic Synthesis by Use of Malonate 4.4.3. Stereoselective Synthesis from a Chiral Pool 5. γ-Silyl α-Amino Acids 5.1. Asymmetric Synthesis by Silylcupration 5.2. Asymmetric Synthesis by Hydrosilylation 6. δ-Silyl α-Amino Acids 6.1. Asymmetric Synthesis by Use of Oxazolidines 6.2. Asymmetric Synthesis by Hydrosilylation 6.3. δ-Silyl α,α′-Disubstituted Amino Acids 6.3.1. Racemic Synthesis via the Schiff Base of Benzophenone 6.3.2. Diastereoselective Synthesis via the Schö llkopf Method 7. Other Silicon-Containing Amino Acids 7.1. p-(Trimethylsilyl)phenylalanine 7.2. Cyclic Derivatives of α,α′-Disubstituted Amino Acids 7.3. Silaproline 7.3.1. Racemic Synthesis 7.3.2. Diastereoselective Synthesis

B B C C C C C D D D D E E E F G G G G H H H

I I I J J J J J J J J J K K K K K K L L M M

Received: February 22, 2016

A

DOI: 10.1021/acs.chemrev.6b00122 Chem. Rev. XXXX, XXX, XXX−XXX

Chemical Reviews 7.4. Synthesis of a Constrained Silicon-Containing γ-Aminobutyric Acid Derivative 7.5. α,α′-Disilyl Amino Acids 7.6. Other Silyl Amino Acids 7.6.1. Silyl β-Amino Acids 7.6.2. Silyl γ-Amino Acids 8. Conformational Studies 8.1. Silaproline-Containing Peptides 8.1.1. Short Model Peptides 8.1.2. Homopolypeptides 8.2. Triethylsilyl di-n-Propylglycine-Containing Peptides 9. Biologically Active Silyl Amino Acid-Containing Peptides 9.1. Renin Inhibitors 9.2. Substance P 9.3. Gonadotropin-Releasing Hormone Receptor Antagonist 9.4. Captopril 9.5. Octadecaneuropeptide 9.6. Cell-Penetrating Peptides 9.7. Neurotensin 10. Summary 11. Conclusion Author Information Corresponding Author Present Address Author Contributions Notes Biographies Acknowledgments Abbreviations References

Review

an enolate derived from a chiral glycine equivalent. However, chiral electrophilic glycine equivalents, asymmetric alkylations starting from achiral glycine derivatives under phase transfer, have also been reported for their synthesis. This review summarizes the various methods that have been described in the literature for preparation of silicon-containing amino acids, as well as their implications on conformational structures of peptides and biological applications.

N P P P Q Q Q Q R

2. SILYL AMINO ACIDS R

Silicon is a chemical element that belongs to the crystallogen family, an isostere of sp3-hybridized carbon. Carbon and silicon are in the same group (14) of elements in the periodic table. However, some differences exist: (i) Silicon can lead to stable penta- and hexacoordinated complexes. (ii) Their atomic radii are markedly different, 0.91 Å for carbon and 1.46 Å for silicon. (iii) The average carbon−carbon bond length is 1.54 Å, while the average carbon−silicon bond length is 1.87 Å. These differences confer a characteristic size and shape of siliconcontaining compounds, influencing particularly the pharmacological and pharmacodynamic properties of silicon-containing amino acids and peptides. (iv) Carbon and silicon also differ in their electronic properties; according to the Pauling scale, silicon is more electropositive (1.8) than carbon (2.5), which leads to differences of bond polarizations. (v) Finally, silicon strongly increases the lipophilicity of compounds when compared to their carbon-containing analogues.12 However, in some cases, this increased lipophilicity might be a limitation for a compound’s water solubility, which is a major concern in medicinal chemistry. In the late 1970s, Tacke and Wannagat12 were pioneers in the concept of substitution of carbon atoms by silicon atoms. Some restrictions related to incorporating silicon as a carbon isostere should be mentioned, however. The polarity of the silicon−hydrogen bond, due to the more electropositive character of silicon compared to hydrogen (2.1), leads to weaker Si−H bonds, which are often easily cleavable in water under non-acidic conditions, resulting in formation of the corresponding silanols. The presence of a silicon atom in an amino acid significantly modifies its chemical and physicochemical properties. Siliconcontaining α-amino acids are classified into different families according to the position of the silicon atom in the side chain (Figure 1). The location of the silicon atom in the amino acid strongly influences both its stability and the reactivity of the amino and carboxylic acid functions. α-Trialkylsilyl α-amino acids 1 are poorly stable toward hydrolysis due to the presence of amine, carboxylic acid groups, and silicon all bound to the same carbon atom, which significantly destabilizes the silicon−carbon bond. However, Liu and Sieburth13 have shown that changing a single methyl group to an ethyl on silicon led to a dramatic stability enhancement, as well as converting the acid into an ester or an amide. The β-silyl α-amino acids derivatives represented by the general structure 2 are the most extensively studied; however, γ-silyl 3 or δ-silyl derivatives 4 as well as substituted phenylalanine 5 are also popular.

S S T T T T U U Z Z Z Z Z Z Z Z AA AA AA

1. INTRODUCTION Unnatural amino acids are non-proteinogenic amino acids whose structures may be either issued from the natural environment or designed by chemists. Various types of unnatural amino acids exist, including β-amino acids, D-amino acids, and N-methylamino acids as well as α-amino acids with modified side chains, including those prepared by side-chain homologation and introduction of heteroatoms. These compounds are widely used in the synthesis of modified peptides, mainly because they are not recognized by proteolytic enzymes, resulting in improved resistance of the peptides in which they are incorporated toward biodegradation.1 Unnatural amino acids have also been used as chiral auxiliaries in asymmetric synthesis.2 Owing to their usefulness, the preparation of enantiopure unnatural amino acids remains an interesting challenge for both chemistry and life sciences.3−7 In this context, silicon-containing amino acids are particularly attractive, specifically in view of their incorporation into bioactive compounds, including peptides, to modify their structure and increase their lipophilicity.8 On the other hand, peptides incorporating a silicon atom in their backbone as a silanediol group have been used as mimics of transition state and have acted as potent protease inhibitors, as reviewed by Sieburth.9,10 Several compounds with silicon-containing amino acids have entered clinical studies or have been developed for applications in agriculture.11 One of the most efficient enantioselective methods for preparation of α-amino acids is by alkylation of the α-carbon of B


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Figure 1. Structure of silicon-containing α-amino acids 1−5.

Scheme 1. Synthesis of α-Trialkylsilyl α-Amino Ester 10 by Metalation

3. α-SILYL α-AMINO ACIDS

HPLC (Scheme 2, Table 1). Hydrogenation of 13i afforded the optically pure unprotected amino acid.15 3.1.3. Reverse Aza-Brook Rearrangement. The reverse aza-Brook rearrangement was used for preparation of αaminosilanes.14 The Brook rearrangement allowed the transformation of alkoxide 14a into carbanion 15a (Scheme 3).17−19 The driving force for this rearrangement comes from the stability of the anions and the strength of the carbon−silicon and oxygen−silicon bonds, which are 375 and 475 kJ/mol, respectively. The inverse version of the rearrangement has been developed for synthesis of α-hydroxysilanes 15a. Due to the high basicity of the nitrogen anion, which causes secondary reactions, the aza-Brook rearrangement was not used as often. An alternative route consists of the use of a Boc protecting group, which increases the acidity of the nitrogen to favor the 14b to 15b switch. This method was then applied to the synthesis of α-silyl amino acids, starting from N-Boc-Nmethyltrialkylsilyl furylamines 17a−d (Scheme 4).13 Silylation

α-Silyl α-amino acids are unstable, due to their high sensitivity to protodesilylation and the tendency of enolates to undergo O-silylation rather than C-silylation. 3.1. Racemic Synthesis

3.1.1. Metalation. α-Trimethylsilyl α-amino ester 10 was identified for the first time as a minor component of an isomeric mixture, after metalation of amino methylsilane 8 with lithium in the presence of ethyl chloroformate (Scheme 1).14 The two isomers 9 and 10 (ratio 1:1) could not be separated by column chromatography. Therefore, this method was not suitable for the synthesis of α-silyl α-amino acids.14 3.1.2. Insertion into the N−H Bond Catalyzed by Rhodium. Bolm et al.15 described an efficient synthesis of αsilyl α-amino acids by insertion of carbenes into an N−H group, catalyzed by rhodium. Insertion into the N−H bond was achieved by reaction of Tos-, Boc-, or Z-protected amines with a dirhodium tetraacetate complex by cleavage of the diazo substituent, followed by an intermolecular carbenoid reaction. α-Trialkylsilyl α-diazoacetates 11a−i were easily obtained through reaction of the corresponding α-diazoacetates with trialkylsilyltriflates in the presence of tertiary amine bases.16 The reaction of 11a-i with protected primary amine 12 led to a racemic mixture of α-silyl α-amino acids 13a−i. The αtrialkylsilyl α-amino acid enantiomers, bearing a range of protecting groups, were then separated by preparative chiral

Scheme 2. Synthesis of α-Trialkylsilyl α-Amino Ester Acetates 13a−i Catalyzed by Rhodium

C


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Table 1. Synthesis of α-Silyl α-Amino Acids product

R

R1/R2

R3

protecting group

yield (%)

13a 13b 13c 13d 13e 13f 13g 13h 13i

Et Et Et Et Et Et Et Bn Bn

Me Me Me Me Me Et Et Me Me

tBu tBu tBu Me Me Et Et tBu tBu

Tos Boc Z Boc Z Boc Z Boc Z

58 72 83 65 69 77 86 47 53

This synthesis also yielded type 2 and 5 silyl amino acid derivatives with respective diastereomeric excesses of 68% and 83% (Scheme 6). Diastereomers 30 and 31 were separated by HPLC, and in both cases the transesterification proceeds with quantitative yields to afford enantiopure silyl amino esters 32 and 33. 3.2.2. Reverse Aza-Brook Rearrangement. The second method, developed by Liu and Sieburth21 for preparation of type 1 trialkylsilyl derivatives, was based on the reverse azaBrook rearrangement described previously. Metalation of 35 with (−)-sparteine and sec-butyllithium afforded 36 in good yields and an enantiomeric excess of 95% (Scheme 7). Only the 1,2 migration of silicon was observed during this reaction. The stereochemistry of alkene 36 was determined by X-ray diffraction. When (−)-sparteine was used, aza-Brook rearrangement gave silyl amino acid analogues with L configuration. Then the action of ozone in the presence of triphenylphosphine afforded aldehyde 37, which was immediately oxidized to give the silyl amino acid (S)-18d in 73% yield without epimerization. The use of 1 equiv of (+)-sparteine during the rearrangement afforded the (R)-18d enantiomer.22 These examples show that preparation of α-silyl α-amino acids remains challenging. The most powerful method consists of synthesizing a racemic mixture of enantiomers, and no other route can provide these enantiopure α-silyl α-amino acids efficiently. The difficulties of their preparation, in addition to their instability, place limitations on their applications. Nevertheless, one example of incorporation into a tripeptide has been reported, demonstrating the compatibility of these modified amino acids with classical peptide coupling procedures.21

Scheme 3. Brook and Aza-Brook Rearrangements

Scheme 4. Reverse Aza-Brook Rearrangement of N-Boc-NTrialkylsilyl Furylamines 17a−d

of 16 followed by addition of n-butyllithium gave the C-silyl amines 17a−d. Ozonolysis induced cleavage of the furyl ring to directly obtain α-trialkylsilyl α-amino acids 18a−d. 3.2. Kinetic Resolution

3.2.1. By Use of Zirconaziridine. Asymmetric synthesis of α-silyl amino acids can be achieved by dynamic kinetic splitting of zirconaziridine with a cyclic carbonate. The α-trialkylsilyl αamino ester 24 was prepared from a lithium silyl amide 19 and zirconium triflate 20 at low temperature (Scheme 5).20 This first step results in a racemic mixture of zirconaziridine, (S)-21 and (R)-21, which was treated with optically active carbonate 22. This dynamic kinetic resolution step induces the stereochemistry of the carbon bearing the silicon group, affording 23. Zirconium was finally released in methanol and the 2hydroxyethyl ester 24 was isolated in 64% yield (de 80%). However, saponification of 24 did not afford the corresponding free acid due to loss of the silicon group under these basic conditions.

4. β-SILYL α-AMINO ACIDS Although the preparation of α-silyl amino acids is only infrequently described, the literature is rich in publications dealing with the synthesis of β-silyl amino acids of type 2.23 This difference is explained by the relative stability of the carbon−silicon bond. TMSAla (trimethylsilylalanine) (Figure 2, R1 = R2 = R3 = CH3) belongs to β-silyl amino acid class 2, the most studied class of silicon-containing amino acids. Although the syntheses presented below have frequently been applied to the preparation of TMSAla 38a, they have also been used to prepare various alkylsilyl alanine derivatives (Figure 2, Table 2).

Scheme 5. Synthesis of α-Silyl Amino Esters

D


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Scheme 6. Synthesis of Compounds of Type 2 and 5 by Dynamic Kinetic Transformation of Zirconaziridine

Scheme 7. Reverse Aza-Brook Rearrangement of N-Boc-N-(Trialkylsilyl)allylamines 36

the first silyl amino acid characterized by X-ray diffraction.26 The majority of methods used for preparation of β-silyl αamino acid 38 involve an anionic equivalent of glycine 39 and a β-silyl derivative 40 bearing a good leaving group to introduce the silicon group by nucleophilic substitution (Scheme 8).

Figure 2. Structure of trialkylsilyl alanine derivatives 38a−u.

Table 2. Synthesis of TMSAla Analogues 38a−x product

R1

R2

R3

R

38a 38b 38c 38d 38e 38f 38g 38h 38i 38j 38k 38l 38m 38n 38p 38q 38r 38s 38t 38u

Me Me -(CH2)4Me Me Me Me Me Me Me Me Me Ph Ph Me Ph Ph Me Me Me

Me Me Me Me Me Me Me Me Me Me Me Me Ph Ph Me Me tBu Me Me Me

Me Ph H Me Ph CHCH2 CHCH2 CH2NH2 CH2OH CH2SH Me Ph Me Ph Ph Ph Ph Me SMe OH

H H Et Et Et H H H H H H H Me Me Me Me Me H H

Scheme 8. Reaction of Anionic Glycine Equivalent with Silicon-Containing Compounds

protecting group

These syntheses depend on the nature of the glycine anionic equivalent that is used. 4.1.1. Starting from Ethyl Acetamido(cyano)acetate. Racemic TMSAla 38a was obtained by reaction between anionic glycine equivalent N-ethyl acetamido(cyano)acetate 42 and (iodomethyl)trialkylsilane 41.24,25 Two other derivatives, β-phenyldimethylsilyl and β-silacyclopentyl alanines 38b and 38c, respectively, were also synthesized by reaction of 42 with the corresponding (iodomethyl)trialkylsilane 41. After alkylation, a single step is necessary using 3 equiv of base to afford the free amino acids 38a−c (Scheme 9).27,28 4.1.2. Starting from Dihydropyrazine. β-Silylation of dihydropyrazine 44 affords the racemic mixture of TMSAla 38a and two derivatives 38b and 38g (Scheme 10).29 This synthesis was performed in three or four steps from dihydropyrazine 44 by metalation with n-butyllithium and monoalkylation with a silicon-containing derivative, affording a mixture of 45 and unreactive dehydropyrazine 44. After treatment under acidic conditions, the β-silyl α-amino esters 38d−f were isolated and

Fmoc Fmoc Boc Boc Boc Boc Boc

4.1. Racemic Synthesis

TMSAla 38a was the first silicon-containing amino acid described in the literature by Birkofer and Ritter24,25 and was E


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Scheme 9. Alkylation/Decyanation Strategy

Scheme 10. Synthesis of β-Silyl α-Amino Acids by Metalation of Dihydropyrazine 44

Scheme 11. Preparation of Functionalized β-Silyl α-Amino Acids

Scheme 12. Racemic Synthesis of TMSAla from Diethyl Malonate

free β-aminomethyl-, β-hydroxymethyl-, and β-mercaptomethyl-dimethylsilylalanine amino acid hydrochloride salts 38h−j were obtained as racemic mixtures in 22−48% yields (Scheme 11). 4.1.3. Starting from Diethyl Malonate. Although various syntheses were described for the preparation of TMSAla, an alternative and inexpensive method, transposable in large scale, was described more recently starting from diethyl malonate.31 Reaction of diethyl malonate 49 with sodium ethoxide in the presence of (chloromethyl)trimethylsilane afforded diethyl (trimethylsilylmethyl)malonate 50. After saponification, the monocarboxylic acid 51 was activated with thionyl chloride and treated with sodium azide at reflux to afford racemic TMSAla 38a in an overall yield of 25% (Scheme 12).

hydrolyzed to afford the corresponding free amino acids in overall yields of 42% (38a), 21% (38b), and 12% (38g). To improve yields and for atom economy, a second alkylation step of 45 was performed to afford dihydropyrazine 46. The following cleavage and saponification process remained identical to the first method. The overall yields of β-silyl αamino acids 38a,b,g were improved by about 10%, and the enantiomers were subsequently separated by chiral preparative HPLC. To obtain β-silyl α-amino acids, alkylation was performed in the presence of bis(chloromethyl)dimethylsilane as alkylating agent to afford the monoalkylated bis(lactim) 47.30 Then addition of potassium phthalimide, potassium acetate, or potassium thioacetate afforded 48. Finally, after acidolysis, the F


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Scheme 13. Synthesis of (R)-TMSAla by Use of the Seebach Imidazolidinone

Scheme 14. Synthesis of (S)-TMSAla by Use of the Myers Auxiliary

Scheme 15. Synthesis of β-Silyl α-Amino Acids by Use of a Schöllkopf Bis(lactim) Ether

Scheme 16. Synthesis of TMSAla and Its Derivatives Exploiting Hydroxy-3-pinanone Induction

4.2. Enantioselective Synthesis

previous route described by Seebach, with the chiral auxiliary used being pseudoephedrine glycinamide (Scheme 14).34 Alkylation of the lithium enolate by (bromomethyl)trimethylsilane results in the formation of a single diastereomer (S)-55. Compound 55 was then hydrolyzed under mild conditions to yield amino acid (S)-38a with an enantiomeric excess higher than 99% and an overall yield of 40%. Use of this chiral inductor has the advantage of providing the desired product in higher yields compared to the imidazolidinone, and hydrolysis of the chiral auxiliary does not require drastic conditions that can lead to racemization. 4.2.3. Diastereoselective Alkylation of Pyrazine. The chiral Schöllkopf auxiliary 56 is widely used for preparation of β-silyl α-amino acids (Scheme 15).30,35−37 Alkylation of pyrazine 56 with organyl (chloromethyl)dimethylsilane (meth-

4.2.1. Diastereoselective Alkylation of Imidazolidinone. An enantioselective α-alkylation was reported by Seebach and Naef in 198132 and has been used for the synthesis of various enantiopure amino acids with specific side chains. Imidazolidinone 52 was used as chiral auxiliary in the synthesis of enantiomerically enriched β-silyl α-amino acid 38a (Scheme 13).33 The first alkylation step led to the single diastereomer 53, followed by deprotection of the amine function and cleavage of the chiral auxiliary to afford (R)-38a in a 20% yield. However, the drastic hydrolysis conditions (HCl at 100 °C) cause partial epimerization, thus decreasing the utility of this synthesis. 4.2.2. Diastereoselective Alkylation of Pseudoephedrine Glycinamide. This synthetic route is related to the G


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silyl cuprates. The use of iodine derivatives led to better yields compared to tosylates. The cuprate was stabilized with a phenyl substituent on the silicon atom, limiting the diversity of amino acids that can be synthesized. Protection of the amine, followed by hydrolysis of the auxiliary, afforded the amino alcohol 67. Finally, amino acids (S)-38n,p−r were obtained by oxidation and esterification in respective yields of 39%, 19%, 30%, and 20% and greater than 98% enantiomeric excess. Nucleophilic alanine equivalents were also used for the synthesis of enantiopure α-amino acids (Figure 4).42,43The

od A) or bis(chloromethyl)dimethylsilane (method B) respectively led to 57 and 58 with a diastereomeric excess of 70%. The diastereomers were separated by chromatography (for method B, the separation was carried out after the functionalization step). According to method A, the standard cleavage conditions of the chiral auxiliary afforded the corresponding free α-amino acids (R)-38a,b,g in 15−35% yields. For amino acids bearing a functionalized siliconcontaining moiety on the side chain, pyrazine 58 was transformed into the corresponding free amino acid according to the procedure described in Scheme 11, affording enantiopure amino acids (R)-38h−j in similar yields to those observed for (R)-38a,b,g (Scheme 15). 4.2.4. Diastereoselective Alkylation of Hydroxy-3pinanone. Chiral Schiff bases derived from (+)-(1R,2R,3R)2-hydroxy-3-pinanone 60 have also been widely used as chiral inductors for diastereoselective alkylations.38,39 This method has been used for the preparation of silicon-containing α-amino acids (Scheme 16). Schiff base 61 was obtained by condensation of tert-butyl glycinate 59 with hydroxypinanone 60 and alkylated by addition of (iodomethyl)trimethylsilane or (iodomethyl)dimethylphenylsilane at low temperature to control the diastereoselectivity. Diastereomer 62 was isolated and subjected to acid hydrolysis. Protection of the amine function, followed by saponification, afforded Fmoc-TMSAla (R)-38k and its analogue (R)-38l in overall yields of 58% and 51%, respectively, and enantiomeric excesses above 98%.40 4.2.5. Use of Electrophilic/Nucleophilic Alanine Equivalent. Similar to anionic glycine equivalents, nucleophilic or electrophilic alanine equivalents have been exploited to prepare enantiomerically pure α-amino acids (Figure 3).

Figure 4. Anionic alanine equivalent.

anionic equivalent of alanine was obtained by transformation of Boc-Ser-OH 70 into its chloro derivative 71, which led to precursor 72 following protection of the alcohol function. After halogen/metal exchange in the presence of n-butyllithium and naphthalenide lithium (LiNp) and reaction with trimethylsilyl chloride, 73 was obtained in 78% yield. Further steps including deprotection and oxidation of the alcohol gave the protected TMSAla (R)-38s, which was then deprotected to yield (R)-38a in 20% overall yield (Scheme 18). 4.2.6. Addition of Electrophiles to Imides. Another approach for the preparation of enantiopure β-silyl α-amino acids was based on addition of an electrophilic amine equivalent to β-silyl propanoic acid 75 in order to avoid acid hydrolysis for cleavage of the chiral inductor. Then 76, resulting from reaction of 75 with the Evans asymmetric auxiliary, was transformed into the single azido diastereomer 77 after selective bromination and substitution.44 Hydrolysis and reduction afforded the amino acids (R)-38a,b,m in overall yields from 26% to 50% (Scheme 19). This method was also applied to preparation of functionalized silicon-containing amino acids. α-Azido-N-acyl oxazolidinone 79 allowed the formation of homomethionine (R)-38t and homoserine (R)-38u in greater than 90% yields and with enantiomeric excesses above 99% (Scheme 20).45 In all the asymmetric syntheses described above, the need to use chiral auxiliaries in stoichiometric amounts, and the low

Figure 3. Cationic alanine equivalent.

Substituted oxazolidinones 64 reacted with nucleophilic silicon-containing species (silylcuprates) obtained by lithiation in “umpolung” reactions (Scheme 17).41 Substituted oxazolidinone 64, prepared from L-serine methyl ester, led to a variety of β-silyl oxazolidinones 65 by reaction with in situ-generated

Scheme 17. Synthesis of β-Silyl α-Amino Acids by Use of Electrophilic Alanine Equivalents

H


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Scheme 18. Synthesis of TMSAla by Use of a Nucleophilic Alanine Equivalent

Scheme 19. Synthesis of β-Silyl α-Amino Acids by Diastereoselective Introduction of the Amine Function

Scheme 20. Diastereoselective Synthesis of Functionalized β-Silyl α-Amino Acids

Scheme 21. Enzymatic Resolution of Racemic TMSAla

presence of cobalt(II) afforded (R)-38a in 72% yield and greater than 99% enantiomeric excess. Enantiomer (S)-38a was obtained in 76% yield and 96% enantiomeric excess after deacylation of (S)-80 (Scheme 21). In addition to the efficiency of this method, the other advantages of acylase are that is commercially available, inexpensive and stable, enabling extension of its application to the synthesis of other siliconcontaining α-amino acids. 4.3.2. Via Hydantoinases. Hydantoins are good substrates for synthesis of β-silyl α-amino acids.53 Successive reaction with hydantoinase and N-carbamoylase led to partial hydrolysis of

chemical yields observed, led to the development of alternative methods involving enzymes.46−50 4.3. Enzymatic Resolution

4.3.1. Via Acylase I. In 1996, Tanaka and co-workers51 published the first biotransformation for preparation of enantiopure silicon-containing amino acids. Enantiopure TMSAla was obtained by enzymatic resolution of racemic acetyl derivatives.52 N-Acetylated racemic TMSAla 80 was prepared according to the method of Porter and Shive.27 The reaction with N-acetyl amino acid hydrolases from pig kidney (acylase I) in the I


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Table 3. β-Silyl α,α′-Disubstituted Amino Acids 88a−f

hydantoin 81 into the corresponding N-carbamoyl amino acids (S)-82a−c (Scheme 22). N-carbamoylase afforded free amino Scheme 22. Enzymatic Resolution of β-Silyl α-Amino Acids

product

R1

R4X

yield (%)

88a 88b 88c 88d 88e 88f

Me Me Me Me Me Ph

MeI EtBr n-PrI n-BuBr Me2CCHCH2Br MeI

78 72 69 69 55 50

4.4.3. Stereoselective Synthesis from a Chiral Pool. In order to prepare 83a enantioselectively, Falgner et al.31 realized the enantioselective cleavage of malonic diester 89a in the presence of pig liver esterase to yield the corresponding malonic monoester (R)-90a with 85% enantiomeric excess (Scheme 25). The chiral malonic monoester was used to synthesize both enantiomers (R)-83a and (S)-83a (Scheme 26) in 42% and 14% yields, respectively, and 99% enantiomeric excess after successive recrystallization.

acids (S)-38a−c by deaminocarbonylation. Free amine (S)-38a was obtained in 88% yield and 95% enantiomeric excess after incubation of (S)-82a under anaerobic conditions. When Anthrobacter aurescens DSM 3747 cells having L-N-carbamoylases were used as biocatalyst, (R)-38a TMSAla was obtained. The biotransformation was also applied to sterically hindered hydantoins. (S)-38b,c were both obtained with 50% conversion and enantiomeric excess higher than 98%.54 4.4. β-Silyl α,α′-Disubstituted Amino Acids

5. γ-SILYL α-AMINO ACIDS

Most silicon-containing amino acids described in the literature have resulted from monoalkylation with TMSAla as leader. In order to enrich this family, β-silyl α,α′-disubstituted amino acids were developed (Figure 5).

5.1. Asymmetric Synthesis by Silylcupration

Enantioselective silylcupration proceeded with 4-ethynyloxazolidine as unsaturated α-amino acid precursors affording vinylglycine or ethyl glycine derivatives.57,58 Oxazolidine 94 reacted with an alkylsilane cuprate to regio- and stereoselectively afford the syn addition product 95a,b. Then hydrogenation of the unsaturated oxazolidine 95, followed by Jones oxidation, afforded the γ-trialkylsilyl α-amino acids 98a,b in 65% and 57% yield, respectively. From 95, this approach also offered the possibility to prepare β,γ-unsaturated amino acid 96b in 64% yield (Scheme 27).

Figure 5. Structure of β-silyl α,α′-disubstituted amino acids.

5.2. Asymmetric Synthesis by Hydrosilylation

Hydrosilylation of chiral unsaturated α-amino acids afforded γsilyl α-amino acids (Scheme 28).59 Thus, hydrosilylation of Lvinylglycine derivative 99 catalyzed by a Pt(II) complex led selectively to γ-silyl amino esters 100a−c in 45−88% yields.

4.4.1. Racemic Synthesis by Use of Benzophenone Schiff Bases. By use of an imine of benzophenone, racemic α,α′-disubstituted amino acids were obtained (Scheme 23).55 In this synthesis, the order of addition of the alkylating agent was important. The most bulky group had to be introduced first, yielding 85, which was then alkylated with methyl iodide to give 86a. After successive protection and deprotection steps, unusual amino acids 88a−f were isolated in good yields (Table 3). 4.4.2. Racemic Synthesis by Use of Malonate. Another racemic synthesis of 83a,b was obtained by an alkylation step on silyl malonate derivative 50, providing the corresponding dialkyl derivative 89 in 95% yield.56 Finally, β-silyl α,α′disubstituted amino acids 83a,b were prepared in 11% and 28% overall yields, respectively (Scheme 24).

6. δ-SILYL α-AMINO ACIDS 6.1. Asymmetric Synthesis by Use of Oxazolidines

The oxazolidine method was also exploited for stereoselective synthesis of amino acids bearing an allylsilane moiety side chain (Scheme 29).60 In both cases, the Garner aldehyde 101 synthesized from L-serine was used. Acetate 105 was prepared without racemization and with a moderate selectivity (syn/anti = 10:2.5), by addition of vinyl magnesium chloride to aldehyde 101, followed by esterification with acetyl chloride. Reaction with trimethylsilyl cyanocuprate led to a mixture of allylsilane

Scheme 23. Synthesis of β-Silyl α,α′-Disubstituted Amino Acids from Glycine

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Scheme 24. Synthesis of β-Silyl α,α′-Disubstituted Amino Acids from Malonate

6.3.2. Diastereoselective Synthesis via the Schöllkopf Method. To access enantiopure δ-silyl α,α′-disubstituted amino acids, Cavelier et al.55 developed an asymmetric synthesis by hydrosilylation of dialkylated amino acids bearing an unsaturated side chain. However, direct alkylation of a bulky silyl derivative was not possible (Scheme 32). Thus pyrazine 113, obtained from D-valine and L-alanine, was alkylated to afford the unsaturated derivative 114 with a diastereomeric excess of 98%. Opening of the bis(lactim) ether led to unsaturated amino ester 115. Then, hydrosilylation reaction as described above yielded δ-silyl α,α′-disubstituted amino esters (S)-116a−c in 31−55% overall yields.

Scheme 25. Enzymatic Deracemization Affording Chiral Malonate (R)-90a

isomers (E)- and (Z)-106 in a 95/5 ratio. Opening of the oxazolidine with trifluoroacetic acid at 0 °C gave the corresponding amino alcohol without removal of the Boc protecting group, and amino ester (E)-104 was obtained in an overall yield of 43% after oxidation. Isomer (Z)-104 was synthesized according to the following steps: alkylation of ethynyl oxazolidine 94, hydrogenation of propargylsilane 102 with Lindlar palladium catalyst, and hydrolysis of the isomer oxazolidine cis-103 in 31% yield.

7. OTHER SILICON-CONTAINING AMINO ACIDS 7.1. p-(Trimethylsilyl)phenylalanine

Due to the important role of phenylalanine in biological metabolism, syntheses of analogues containing substituted benzene rings (type 5, Figure 1) have been developed to obtain competitive phenylalanine and tyrosine antagonists. Thus, p(trimethylsilyl)phenylalanine 121 was obtained by alkylation of N-protected amino malonic diethyl ester 118 with pbromobenzyltrimethylsilylane 117 to yield diester 119 (Scheme 33).61 Then hydrolysis, deformylation, and decarboxylation of the corresponding malonate 120 afforded the racemic free amino acid 121 in 73% yield. More recently, Tanaka and co-workers62 developed the enzymatic resolution of racemic precursor 126 by use of hydantoin 123 (Scheme 34). The racemate was obtained by condensation of p-trimethylsilylbenzaldehyde 122 with hydantoin 123 in the presence of catalytic amounts of glycine,

6.2. Asymmetric Synthesis by Hydrosilylation

The same hydrosilylation procedure previously applied to vinylglycine derivatives allowed the synthesis of δ-silyl amino esters 108a−c, which were obtained in respective yields of 85%, 87%, and 55% starting from allylglycine 107 (Scheme 30).59 6.3. δ-Silyl α,α′-Disubstituted Amino Acids

6.3.1. Racemic Synthesis via the Schiff Base of Benzophenone. The procedure described for preparation of β-silyl α,α′-disubstituted amino acids was applied to preparation of δ-silyl α,α′-disubstituted amino acids. Thus various alkyl chains were introduced starting from the benzophenone Schiff base, and racemic δ-silyl α,α′-disubstituted amino acids were obtained in moderate yields (Scheme 31, Table 4).59

Scheme 26. Synthesis of Enantiopure β-Silyl α,α′-Disubstituted Amino Acids from Chiral Malonate

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Scheme 27. Synthesis of γ-Silyl α-Amino Acids by Silylcupration

Scheme 28. Synthesis of γ-Silyl α-Amino Acids by Hydrosilylation

Scheme 30. δ-Silyl α-Amino Acids Obtained by Hydrosilylation Starting from Allylglycine

followed by hydrogenation of the corresponding olefin 124 and hydrolysis of hydantoin 125. Enzymatic resolution of Ncarbamoyl 126 in the presence of N-carbamoyl amino acid aminohydrolase (DCase) from Blastobacter sp. afforded p(trimethylsilyl)phenylalanine (R)-121 in 34% yield and 98% enantiomeric excess. As in the case of TMSAla, use of the acylase led to cleavage of Si−C bonds.

ester 132, which can be subjected to electrophilic substitution reactions to yield the corresponding halogenated derivative 133 in 81% yield. 7.3. Silaproline

Silaproline (Sip), a proline analogue in which the γ-carbon has been replaced by a dimethylsilyl group, presents similarities with proline. The carbon−silicon bond is approximately 0.35 Å longer than the proline carbon−carbon bond, and the C−Si−C angle is significantly smaller (93°) than the C−C−C angle of proline (105°).64 The silicon atom lies in the plane containing the N−Cα−Cδ atoms, unlike the γ-carbon, which sits out of the plane in the case of proline. Furthermore, the presence of the dimethylsilyl group increases the lipophilicity as demonstrated by the octanol−water partition coefficient of Fmoc-SipOH, which was experimentally determined to be 14 times greater than that of Fmoc-Pro-OH. 65 Silaproline was synthesized simultaneously by two different teams in 2000.66,67 Efficient preparation of silaproline is based on the

7.2. Cyclic Derivatives of α,α′-Disubstituted Amino Acids

The cyclic amino ester 132 is an interesting intermediate in organic synthesis, either for its use in increasing diversity through substitutions on the aromatic ring and/or to provide steric hindrance in peptides. Compound 132 was obtained by catalytic [2 + 2 + 2] cycloaddition and insertion of alkylsilyl groups (Scheme 35).63 Double alkylation of cyano ester 128 with propargyl bromide 127 afforded isonitrile 129. Since the isonitrile group was labile under the reaction conditions, it was converted into the more stable amine 130 by hydrolysis. Then acetylation of the amine function, followed by cyclotrimerization in the presence of the silyl alkyne, yielded silyl cyclic amino

Scheme 29. Synthesis of δ-Unsaturated Silicon-Containing α-Amino Acids

L


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Scheme 31. Synthesis of δ-Silyl α,α′-Disubstituted Amino Acids

Table 4. δ-Silyl α,α′-Disubstituted Amino Acids product

4

RX

yield (%)

112a 112b 112c 112d

MeI EtBr n-PrI n-BuBr

50 44 39 38

enantiomer with ee values above 99%. The next step of the synthesis was performed with Boc-L-Sip-OtBu (L-137), which was treated with 6 N HCl followed by Fmoc introduction to afford Fmoc-L-Sip-OH ( L-139). Several grams of each protected version of silaproline have been obtained. 7.3.2. Diastereoselective Synthesis. Among the various methods of diastereoselective alkylation investigated, use of the Schöllkopf bis(lactim) was the most efficient.66 The first step consists of O-methylation of diketopiperazine D-Val-Gly 141 in the presence of trimethyloxonium tetrafluoroborate. The bis(lactim) ether 142 thus obtained was then deprotonated in the presence of n-BuLi and alkylated by bis(iodomethyl)dimethylsilane. Compound 144 was obtained in 72% diastereomeric excess. After separation of diastereoisomers, hydrolysis of 144, cyclization, and saponification afforded Nprotected silaprolines L-139 and L-145 in 13% and 38% overall yields, respectively (Scheme 38). Handmann et al.67 synthesized enantiopure silaprolines in 27% overall yield and greater than 99% enantiomeric excess, starting from 3,6-diethoxy-2,5-dihydropyrazine instead of 3,6dimethoxy-2,5-dihydropyrazine 142, by reaction with bis(chloromethyl)dimethylsilane. Recently, to fulfill the need for silaprolines for patented active molecules, alkylation of 3,6dimethoxy-2,5-dihydropyrazine 142 in the presence of bis(chloromethyl)dimethylsilane was optimized, affording more than 100 g of enantiopure Boc-L-Sip-OH (L-145) in 60% overall yield (Scheme 38).69 Recently, an asymmetric synthesis of silaproline was described by N-alkylation of N-Boc-dehydroalanine ester with (chloromethyl)dimethylsilane under flow conditions, followed by hydrosilylation of the N-alkylated product. The silaproline ester was isolated with 85−90% yield and >95% ee.70

specificity of the alkylating agent that should bear two halogens, bis(halomethyl)dimethylsilane, allowing cyclization on nitrogen after C-alkylation. 7.3.1. Racemic Synthesis. Synthesis of racemic silaproline was reported by metalation of 2,5-dihydropyrazine 44 with nbutyllithium, followed by addition of bis(chloromethyl)dimethylsilane (Scheme 36).67 Subsequently, treatment of monoalkylated intermediate 47 with hydrochloric acid allowed the opening of the pyrazine. Washing with ammonia afforded cyclization, forming silaproline ethyl ester H-D,L-Sip-OEt 134 in 20% yield over the two steps (Scheme 36). Recently, various syntheses of racemic, protected silaprolines were described, on several gram scales, starting from protected glycine and bis(iodomethyl)dimethylsilane in the presence of NaH, in anhydrous THF.68 Boc-D,L-Sip-OtBu 137 and Z-D,LSip-OtBu 138 were prepared in 71% and 85% yields, respectively (Scheme 37). In solid-phase peptide synthesis, amino acids are commonly used as Fmoc-protected derivatives. Thus, Fmoc-L-Sip-OH (L139) was obtained from either Boc-D,L-Sip-OtBu 137 or Z-D,LSip-OtBu 138 according to two strategies as depicted in Figure 6. In the first strategy, removal of the tert-butyl ester of Fmoc-LSip-OtBu ( L -140) was performed after separation of enantiomers in quantitative yield with TFA in dichloromethane. The second strategy consisted of separation of Boc-D,L-SipOtBu 137 or Z-D,L-Sip-OtBu 138 enantiomers under semipreparative conditions to afford several grams of each

Scheme 32. Hydrosilylation Starting from α,α′-Disubstituted Allylic Amino Acids

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Scheme 33. Synthesis of Racemic p-(Trimethylsilyl)phenylalanine 121

Scheme 34. Synthesis of (R)-p-(Trimethylsilyl)phenylalanine by Biocatalysis

Scheme 35. Synthesis of 5,6-Bis(trimethylsilyl)indanylglycine 132 and Its Halogenation

Scheme 36. Synthesis of Racemic Silaproline Starting from 2,5-Dihydropyrazine

Scheme 37. Synthesis of Racemic Silaprolines

7.4. Synthesis of a Constrained Silicon-Containing γ-Aminobutyric Acid Derivative

Recently, Ramesh and Reddy71 reported the preparation of new unnatural α, β and γ silicon-containing amino acids starting from the crucial intermediate 3,4-bis(iodomethyl)-1,1-dimethylsilane 147 (Scheme 39). Treatment of 147 in the presence of ethyl isocyanoacetate 148, with K2CO3 as base and a phasetransfer catalyst (18-crown-6), produced cyano ester 149 in 74% yield. The facile formation of this constrained compound could be attributed to the longer Si−C bond length, which

Figure 6. Strategies for preparation of Fmoc-L-Sip-OH.

made the reaction feasible under mild conditions. Hydrolysis of the isocyano group gave the corresponding amino ester in 91% N


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Scheme 38. Enantioselective Synthesis of N-Protected Silaproline

Scheme 39. Synthesis of a Silicon-Containing GABA Analogue

Scheme 40. Synthesis of Disilyl Amino Acids

yield. Then protection of the amino group as the tert-butyl carbamate afforded the orthogonally protected α-amino acid 150. For the synthesis of β-amino acids, 3,4-bis(iodomethyl)-

1,1-dimethylsilane 147 was treated with ethyl cyanoacetate under the same conditions to give α-cyano ester 151 in 89% isolated yield. After hydrogenation in the presence of Raney O


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Scheme 41. Synthesis of Sila-Substituted β-Amino Acids

Scheme 42. Synthesis of β-Silyl β3 Amino Acids

nickel, the β-amino ester was obtained. When hydrogenation was carried out in the presence of Boc anhydride, the Bocprotected amino acid 153 was obtained in an improved yield of 71%. Synthesis of the γ-aminobutyric acid (GABA) analogue with the same skeleton was achieved by starting from intermediate 151. Selective ester hydrolysis, followed by decarboxylation of the resulting α-cyano carboxylic acid, led to nitrile 154. Subsequently, alkylation of 154 with 3,3dimethylallyl bromide, followed by an oxidative cleavage step by ozonolysis in methanolic NaOH, furnished the cyano ester 156 in 25% yield. Finally, reduction in the presence of Boc anhydride afforded the novel, more lipophilic and conformationally rigid GABA analogue 157, which is structurally close to gabapentin. The compound was expected to be useful for the modulation of various CNS disorders.

unsaturated amino ester 160, which provided disilyl amino esters 162a,b after protection and hydrosilylation reactions (Scheme 40). To demonstrate the compatibility of such amino acids with solid-phase peptide synthesis (SPPS), the Fmoc derivative of (triethylsilyl)dipropylglycine (TES-Dpg), 163b, has been introduced to replace Aib in alamethicin F50/5. Alamethicin is a peptaibol with a helical conformation that has been studied in detail.73 Despite the obvious steric hindrance caused by the bulky side chains, microwave-assisted SPPS couplings were achieved with moderate to good yields, depending on amino acids linked to TES-Dpg.74 Four hydrophobic alamethicin analogues were obtained and it was demonstrated that the helical structure was conserved to a high degree.72

7.5. α,α′-Disilyl Amino Acids

7.6.1. Silyl β-Amino Acids. β-Amino acids have received a great deal of attention over the past decade, due to important applications in medicinal chemistry, including the field of foldamers. In this context, Muir and co-workers75 reported a highly efficient and stereoselective synthesis of unnatural cyclic sila-substituted β-amino acids 168a−c by following the route

7.6. Other Silyl Amino Acids

A new class of α,α′-disubstituted amino acids bearing a silicon moiety on both side chains has been recently described.72 These new bulky amino acids have been synthesized in four steps from the benzophenone Schiff base of glycine tert-butylate 84. A double alkylation with allyl bromide 158 afforded P


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Scheme 43. Synthesis of (R)- and (S)-4-Amino-3-(trimethylsilyl)methylbutanoic Acids

treat neuropathic pain without CNS-related side effects. Synthetic routes to (R)- and (S)-4-amino-3-(trimethylsilyl)methylbutanoic acids (R)- and (S)-185 are presented in Scheme 43. 78 Alkylation of cyanoacetate 128 with (chloromethyl)trimethylsilane 6 in the presence of potassium carbonate and potassium iodide in refluxing acetonitrile afforded the monoalkylated ethyl-3-(trimethylsilyl)methyl-2cyanopropionate 181 in 81% yield. Then 181 was further alkylated with ethyl bromoacetate to afford the corresponding cyanodiester 183, which was treated with lithium bromide in DMF at 150 °C to afford cyano ester 184 in 78% yield. LiOH hydrolysis of 184 followed by hydrogenation in the presence of Pd(OH)2 readily afforded (±)-185 in 83%. However, optical resolution of cyano ester 184 was achieved by enzymatic hydrolysis with Novozym 435 to obtain the optically active carboxylic acid (R)-enriched 186 with the recovery of (S)enriched 184. Finally, (R)-enriched 186 was hydrogenated as described above and recrystallized to obtain optically pure (R)185 in 15−25% yield from (±)-184, along with a mother liquid contaminated with the antipode (S)-185 in a comparable yield. The absolute configuration of these enantiomers was assigned by single-crystal X-ray analysis of a urea compound derived from (R)-185 and (R)-(+)-α-methylbenzyl isocyanate (Scheme 43).

outlined in Scheme 41. The key intermediate aziridines 166a−c were directly prepared from 165a−c in 65−89% yield by use of the chloramine T/phenyltrimethylammonium tribromide (PTAB) system of Sharpless. The method of choice for stereoselective aziridine ring opening involves the use of Et2AlCN (Nagata’s reagent) and proceeds exclusively through anti attack at the aziridine ring to yield racemic nitrile products 167a−c in yields up to 75%. The stereochemistry of 167b was proven by X-ray crystal structure analysis. The tosylamine was protected with a Boc group by use of Boc2O under DMAP catalysis, followed by treatment with magnesium chips to remove the tosyl group under mild conditions. Finally, esterification followed by saponification with NaOH afforded amino acids 169a−c in 67−77% yield over all steps (Scheme 41). Recently, Skrydstrup and co-workers76 reported the synthesis of amino acid analogues that contain silicon in the β3-position, as depicted in Scheme 42. The key step in synthesis of the silicon-containing amino acids 176 and 177 was the addition of a silyl lithium reagent to an Ellman sulfinimine. This synthesis proceeds with a high diastereoselective ratio of 95:5. On the other hand, the synthesis of β,β-disubstituted amino acid 180 proceeds via sulfinyl ketimine intermediate 171. Unfortunately, subsequent addition of silyl lithium reagent did not provide any diastereoselective control, and the reaction resulted in a 1:1 mixture of diastereoisomers in 68% global yield. After separation by column chromatography, protection of the amino group, and oxidation, enantiopure β,β-disubstituted amino acid 180 was obtained in 96% yield (Scheme 42). The three amino acid analogues were incorporated into the antimicrobial peptide alamethicin by solid-phase peptide synthesis (SPPS). In particular, introduction of amino acid 176 as a replacement for Aib provided a peptide that exhibited the best membrane-permeabilizing properties, with up to 20fold increases in calcein release compared to wild-type alamethicin. 7.6.2. Silyl γ-Amino Acids. Pregabalin and gabapentin, structurally related to γ-aminobutyric acid (GABA), are usually used for the treatment of neuropathic pain, a chronic pain stemming from neuronal damage. These compounds were originally developed as anticonvulsant drugs. Shudo and coworkers77 reported the synthesis and pharmacology of (R)- and (S)-4-amino-3-(trimethylsilyl)methylbutanoic acids 185, which are promising candidates for selective therapeutic agents to

8. CONFORMATIONAL STUDIES Among all the silicon-containing amino acids reported above, only two silyl derivatives have been used for conformational studies of key sequences. 8.1. Silaproline-Containing Peptides

Due to its unique structural properties, proline (the only natural cyclic amino acid, presenting a pyrrolidine ring with conformational restrictions) has an important role in biological processes and peptide folding. In order to improve the efficacy and/or the structure for higher receptor recognition and selectivity, several research groups have developed proline mimics.79−85 8.1.1. Short Model Peptides. The influence of siliconcontaining amino acid derivatives on peptide conformation is illustrated in the literature by conformational studies on model di- and tripeptides containing silaproline.65 The X-ray diffraction structure of dipeptide Piv-Sip-Ala-NHiPr depicted the secondary structure revealing a type II β-turn, which is quite Q


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Finally, on the basis of NOE data obtained from NMR experiments, molecular modeling of silaproline-containing peptides (using AMBER 11) afforded the 20 calculated lowest-energy structures that converged toward PPII structures (Figure 9). The silaproline helical mimics were characterized as left-handed PPII helices containing three residues per turn with all peptide bonds in trans configuration. 8.1.2.2. Polydisperse Polysilaproline Oligomers. Synthesis of homopolysilaprolines with longer chain lengths was performed via polymerization of silaproline N-carboxyanhydride (Sip-NCA).88 Due to the cyclic structure of the amino acid, synthesis of NCA was not direct and required the addition of HCl as scavenger to achieve cyclization of the N-carbamoyl chloride intermediate. Starting from free amino acid in the presence of trisphosgene, a mixture composed of 50% NCA and 50% N-carbamoyl chloride was obtained. To obtain complete cyclization and formation of Sip-NCA, [(N,Ndiethylamino)methyl]polystyrene resin was used to avoid diketopiperazine formation and to facilitate the purification step. Under these conditions, Sip-NCA 190 was isolated in 72% yield and high purity, allowing its crystallization (Figure 10). Homopolypeptides with different degrees of polymerization (determined by NMR) were successfully prepared by ringopening polymerization of Sip-NCA following a normal amine mechanism (NAM). MALDI (matrix-assisted laser desorption ionization) and CD (circular dichroism) were used to characterize the homopolysilaprolines. The high lipophilic character of the resulting polymers prevented the use of water as solvent, and the CD analyses of polysilaprolines were recorded in trifluoroethanol (TFE), showing a curve typical for a PPII helix with a strong negative band at 207 nm and a weak positive band at 228 nm. Thermal denaturation (from 0 to 70 °C) of polysilaprolines showed only a slight reduction of the minimum without any changes of the maximum, clearly indicating a more thermally stable PPII helix compared to the polyproline counterpart.

uncommon in the case of homochiral dipeptides, presumably due to intermolecular interactions. Another crucial piece of information is the preference for a β-endo conformation of the puckering of the silaproline ring, which is not usual for proline pyrrolidine rings, showing the influence of the silicon atom.64 Conformational analyses in solution, by NMR spectroscopy and IR absorption, were also performed to compare the conformational preferences of proline- and silaproline-containing tripeptides. The results showed that γ-substitution of the methylene by a dimethylsilyl group has almost no influence on the amide cis-isomer percentage.65 Another model using the rigidity of bicyclic systems was also reported in order to investigate the influence of modified prolines on pyrrolidine ring shape, resulting in modulation of structural properties.86 Cis/trans isomerization of the amide bond was studied with diketopiperazines by NMR spectroscopy. While in the case of cyclo(Pro-Gly) a flexibility was observed due to the dynamic equilibrium between Cγ-endo and exo positions, for cyclo(Sip-Gly) the rigidity of the siliconcontaining five-membered ring allowed only very slow interconversion between Cβ-exo and endo conformations (Figure 7). Although small differences were noticed, the conformational properties between proline and silaproline are similar.

Figure 7. Structures of Pro- and Sip-containing diketopiperazines.

8.1.2. Homopolypeptides. The influence of repetitive units of silaproline in peptides was also investigated through synthesis of homopolypeptides that mimic well-defined secondary structures.87,88 Proline-rich motifs are well-known to play an important role in molecular interactions.89,90 For instance, the presence of proline-rich regions can induce formation of specific secondary structures like polyproline type II helices (PPII), which are involved in transcription, signaling, immune response, and cell penetration.91,92 In this way, silaproline was used as a proline template to evaluate the influence of silyl analogues on the physicochemical properties and conformation of PPII helices. 8.1.2.1. Monodisperse Homopolysilaprolines. Silaproline homo-oligomers from dimers to pentamers were synthesized and their secondary structure was studied by NMR, circular dichroism, and molecular modeling.87 A circular dichroic spectrum of the silaproline pentamer presented a PPII signature with a maximal ellipticity that was not affected by temperature increasing from 20 to 55 °C, indicating its high stability. NMR studies allowed determination of the propensity for such homooligomers to adopt cis/trans conformers compared to proline oligomers (Figure 8). Seven percent cis isomer was detected in the dipeptide H-Sip-Pro-OBn, and 15% in H-Pro-Pro-OBn. However, in the case of silaproline-containing peptides, when longer oligomers were considered, only the trans isomer was observed, while in proline-containing peptides the percentage of cis isomers remained quite constant (∼10%).

8.2. Triethylsilyl di-n-Propylglycine-Containing Peptides

Incorporation of α,α′-disubstituted α-amino acids into peptides is used to modulate their physicochemical properties as well as their secondary structures. Recently a new α,α′-dialkylated amino acid bearing two silyl groups, called TES-Dpg, was designed.72 The crystal structure of Z-N-protected TES-Dpg tert-butyl ester was obtained, showing a fully extended conformation named the C5 conformation, a base unit of the 2.05-helix motif. TES-Dpg was used to replace aminoisobutyric acid (Aib) in the amphipathic α-helical peptide alamethicin F50/5. Replacement of only one Aib by TES-Dpg, at both the polar and apolar helix face, drastically increased the peptide lipophilicity by a factor of 100. The secondary structure of these TES-Dpg-containing peptides was also studied by circular dichroism. Comparison of the spectra of TES-Dpg-containing alamethicin with those of the reference peptide (alamethicin F50/5) indicated a right-handed α-helical structure with characteristic bands at 222, 208, and 190 nm. Insertion of silyl α-amino acids into peptides that fold into a well-defined secondary structure allowed the design of mimics maintaining and stabilizing the native structuration while changing the physicochemical properties as the result of their increased lipophilicity. R


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Figure 8. NMR determination of cis and trans conformers. (A) 18Si NMR spectrum of dimer 2 in CD3OD at 298 K. (B) ROESY spectrum of dimer 2 in CD3OD at 298 K. NOE correlations between αCH(i) and αCH(i + 1) in the cis conformer (600 MHz spectrometer, mixing time = 300 ms). Reprinted with permission from ref 87. Copyright 2014 Wiley.

Figure 10. X-ray structure (left) and Chemdraw representation (right) of D-Sip-NCA.

amino acid side chains within a peptide would presumably increase the peptide’s stability by preventing enzymatic degradation and improve membrane permeability by providing lipophilicity. In addition, the peptide backbone conformation should be preserved to maintain the receptor affinity of bioactive peptides. For this purpose, no α-silyl α-amino acids have been exploited due to the instability of the carbon−silicon bond. However, two β-silyl α-amino acids, trimethylsilylalanine (TMSAla) and silaproline (Sip), have been introduced into biologically active peptides. When the essential role of cyclic amino acids such as proline and its analogues in the threedimensional conformations of peptides is considered, Sip is of particular relevance.

Figure 9. Molecular modeling of silaproline-containing oligomers. (A) NMR solution structures of dimer 2 (green), trimer 3 (cyan), tetramer 4 (pink), and pentamer 5 (purple). (B) Overlay of structures of 2−5 optimized by DFT. (C) Axial view of tetramer 4 PPII helical structure. Hydrogen atoms and the disordered OBn C-terminal moiety are omitted for clarity. Reprinted with permission from ref 87. Copyright 2014 Wiley.

9.1. Renin Inhibitors

To the best of our knowledge, the first example of a silyl amino acid-containing bioactive peptide described in the literature concerns a renin inhibitor (Figure 11). TMSAla has been introduced in place of phenylalanine, allowing better in vivo stability with only a slight decrease in affinity for the enzyme.35 However, no other replacement of phenylalanine has confirmed the significance of this residue in the compound’s activity.

9. BIOLOGICALLY ACTIVE SILYL AMINO ACID-CONTAINING PEPTIDES As underlined earlier, the introduction of unatural amino acids (including silyl amino acids) into peptides is a very active and innovative area of research. The presence of a silicon atom on S


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immediate and strong decrease in LH serum levels in castrated male rats with an increased duration of effect.37

Figure 13. Gonadotropin-releasing hormone receptor antagonist (Cetrorelix).

Figure 11. Renin inhibitor 191.

9.2. Substance P

Substance P (SP) is a natural neuropeptide belonging to the tachykinin family (Figure 12).93,94 Two nonstoichiometric SP binding sites are associated with the NK1 receptor. The more abundant binding site (NK-1M) represents approximately 80% of the receptor’s population and is related to adenylate cyclase activation. The less abundant binding site (NK-1m) represents 20% of the receptor’s population and is responsible for phospholipase C (PLC) activation. In SP, replacing glycine with proline does not significantly modify the binding affinity for either site. In the C-terminal hexapeptide series, the prolinecontaining peptide, called septide, is selective for NK-1m binding sites. Consequently, for binding assays on NK-1 receptors and second-messenger assays on whole cells,95 SP and [Pro9]SP were taken as reference peptides for NK-1M, while [pGlu6]SP(6−11) and [pGlu6, Pro9]SP(6−11) were used as selective peptides for NK-1m (Figure 12).

9.4. Captopril

Captopril is an orally active molecule that is currently used in treatment of hypertension and heart failure.98 It is an inhibitor of angiotensin-converting enzyme or ACE, a zinc metalloenzyme, which plays a fundamental role in blood pressure regulation by converting the inactive decapeptide angiotensin I into the potent vasopressor octapeptide angiotensin II. Captopril can compete with the endogenous substrates of the enzyme and be effective in therapeutic doses to lower blood pressure by reducing plasma levels of angiotensin II. It has been shown that proline is crucial for enzyme recognition.99 Siliconcontaining inhibitors incorporating silanediol structures that chelate the zinc anion contained in the active site of ACE have been synthesized.100 On the basis of the hypothesis that the inhibitory potency of captopril is mediated through hydrophobic interactions, increasing the lipophilicity of the proline moiety may therefore amplify these interactions and improve the affinity. New captopril analogues were investigated in silico by docking on the ACE crystal structure (Figure 14).101,102 Provided that the site can accommodate more steric hindrance, more lipophilic proline surrogates, such as silaproline, could enhance hydrophobic interactions with ACE. Several substitutions with different alkyl groups on the silicon atoms of silaproline were evaluated, and the resulting data showed that the lower the steric hindrance, the lower the docking energy (substitution with two methyl groups, silacaptopril). This analogue has been synthesized and tested in vitro for its ability to inhibit ACE enzymatic activity, and it showed the same potency as captopril.103

Figure 12. Sequences of substance P (SP) and septide [pGlu6, Pro9]SP(6−11).

As described in the literature, TMSAla can be used to replace phenylalanine. Therefore, a series of analogues with TMSAla in either position 7 or 8 and in both positions 7 and 8 were synthesized. The three resulting peptides lost affinity for the two NK-1 binding sites; [TMSAla8]SP was the more potent peptide with only 10-fold lower affinity than SP. As expected, their activity was in accordance with their affinity for the two binding sites, and these SP analogues lacked the potency to stimulate either of the two second-messenger pathways, with the exception of [TMSAla8]SP. However, replacing proline at position 9 by silaproline led to SP analogues that retained both the affinity and activity of the natural compound. Furthermore, the Sip-containing septide analogue showed a different pharmacological pattern than septide, behaving as a full agonist for PLC activation but as partial agonist on the adenylate cyclase pathway.96 This substitution also resulted in improved stability toward angiotensin-converting enzyme; after 1 h of incubation at 37 °C, SP was degraded by 80% while [Pro9]SP and [Sip9]SP were fully resistant.

9.5. Octadecaneuropeptide

Octadecaneuropeptide (ODN) of sequence HQATVGDVNTDRPGLLDLK-OH belongs to the endozepin family and exerts anxiogenic and anorexigenic activities. ODN has been previously shown to stimulate the intracellular calcium concentration increase ([Ca2+]i) in cultured rat astrocytes through activation of a metabotropic receptor positively coupled to phospholipase C.104 The C-terminal octapeptide (OP) of sequence H-RPGLLDLK-OH (Figure 15) is the minimum active sequence able to retain ODN activity on [Ca2+]i, which is partially antagonized (about 40%) by the linear analogue [D-Leu5]OP.105 Proline in position 2 is involved in the bioactive conformation of both OP and [D-Leu5]OP. It has been replaced by silaproline, leading to silyl OP analogues, [Sip2]OP and [Sip2,D-Leu5]OP, that have been tested for their ability to act as either agonists or antagonists on [Ca2+]i release. In rat astrocytes, [Sip2]OP (10−8 M) provoked a transient and robust increase in [Ca2+]i with an amplitude significantly higher than that induced by the same dose of ODN. A short pulse of [Sip2,D-Leu5]OP (10−8−10−6 M) did not affect the basal calcium level. However, it partially reduced the ODNstimulated [Ca2+]i increase with the same efficacy (−37%) as its nonsilyl counterpart, [D-Leu5]OP.

9.3. Gonadotropin-Releasing Hormone Receptor Antagonist

Gonadotropin-releasing hormone (GnRH) induces the production and release of luteinizing hormone (LH) and folliclestimulating hormone (FSH) by gonadotropic cells of the anterior pituitary. Cetrorelix, a GnRH receptor antagonist (Figure 13), competes with natural GnRH for binding to membrane receptors on pituitary cells and thus controls the release of LH and FSH in a dose-dependent manner.97 GnRH analogues containing TMSAla in position 5 behave as potent GnRH receptor antagonists. This substitution led to an T


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Figure 14. Role of ACE and structures of captopril and silacaptopril.

Table 5. Binding Affinity of Silicon-Containing Neurotensin Analogues Figure 15. C-terminal octapeptide (OP) sequence.

IC50 (nM) product NT(8−13)

9.6. Cell-Penetrating Peptides

Cell-penetrating peptides (CPPs) have great potential as delivery vectors, based on their ability to facilitate cellular uptake of nonpermeant drugs.106 CPPs are usually composed of charged residues, including arginine moieties, and typically have properties such as amphipathicity and hydrophobicity that are crucial for successful translocation through the cell membrane. These features should be considered in the design of CPPs. In this context, promising results were reported with a series of amphipathic proline-rich vectors, which are structured in the amphipathic polyproline II (PPII) helix.107,108 Replacement of proline on the hydrophobic face of this amphipathic peptide by the more lipophilic silaproline (Figure 16) favored the interaction with the amphipathic environment of the cell membrane. The presence of silaproline significantly improved the peptide’s translocation properties, as shown by flow cytometry and confocal microscopy techniques. In addition, cytotoxic studies revealed the absence of toxicity of silaproline-containing CPP.109 Cellular uptake ability was shown to be linked to PPII helix formation, which is not

JMV438 JMV2006 JMV2007 JMV2008 JMV2009

peptide sequence H-Arg-Arg-Pro-Tyr-IleLeu-OH H-Lys-Lys-Pro-Tyr-IleLeu-OH H-Lys-Lys-Pro-TyrTMSAla-Leu-OH H-Lys-Lys-Pro-Tyr-IleTMSAla-OH H-Lys-Lys-Pro-TyrTMSAla-TMSAla-OH H-Lys-Lys-Sip-Tyr-IleLeu-OH

hNTS1 receptors

hNTS2 receptors

0.82 ± 0.003

7.52 ± 4.8

0.33 ± 0.002

0.95 ± 0.03

93.8 ± 3.5

405 ± 39

0.02 ± 0.002

0.26 ± 0.13

15.4 ± 2.4

28.9 ± 12

15.2 ± 4.7

21.2 ± 1.9

biological activity, with the N-terminal portion having a modulatory role. One of the major drawbacks of peptide therapeutic applications concerns their short half-life in vivo, due to rapid enzymatic degradation. NT hypothermic and analgesic responses are triggered by brain injection along with a cocktail of enzyme inhibitors. NT stabilization has been investigated through cyclization114,115 peptide bond modifications,116−118 and unnatural amino acid incorporation.119−125 Structure−activity relationship studies highlighted that lipophilic Ile12 and Leu13 C-terminal residues bind a hydrophobic pocket of NT receptors,126 recently confirmed by resolution of the X-ray structure of NTS1.127 Incorporation of TMSAla at positions 12 and 13 of NT(8−13) was investigated to increase hydrophobicity in the C-terminal part. Among these modified analogues, peptide H-Lys-Lys-Pro-Tyr-Ile-TMSAla-OH (JMV2007) exhibited a high binding affinity toward NT receptors, with an increase of 2 orders of magnitude over human NTS1 receptors and 1 order of magnitude over human NTS2 receptors, compared to NT(8−13) (Table 5). JMV2007 showed potent functional activities on transduction pathways associated with NTSI, such as Gαq activation and β-arrestin2 recruitment. JMV2007 was effective in reversing carbachol-induced contraction in the isolated strip preparation assay and in inducing a drop in blood pressure. Finally, intrathecal administration of JMV2007 produced powerful analgesia in experimental models of acute and persistent pain.128 Proline in position 10 is very important for the conformation of the peptide. Structure−activity relationship studies showed that position 10 cannot accommodate any structural element other than a five-membered ring. In general, substitutions that

Figure 16. Silaproline-containing sequence of an amphipatic helix designed to act as a CPP.

disrupted by silaproline, and to the amplified amphipathic character, resulting in higher internalization inside HeLa cells. 9.7. Neurotensin

Neurotensin (NT) is a tridecapeptide distributed throughout the central nervous system, originally isolated from bovine hypothalamus (Figure 17).110 This neuropeptide elicits a naloxone-insensitive analgesic response following peripheral or central administration.111 Importantly, NT exerts more potent analgesia than morphine at an equimolar dose, without having the associated side effects of opioid drugs, such as ventilatory depression, drowsiness, nausea, or tolerance.112,113 The C-terminal region, NT(8−13), is responsible for the full

Figure 17. Neurotensin sequence. U


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Table 6. Summary of Silyl Amino Acids

V


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Table 6. continued

W


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Table 6. continued

X


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Table 6. continued

Y


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Table 6. continued

acids allows modulation of physicochemical properties of bioactive peptides, which is of major consequence to enhance membrane permeability. Future prospects should aim at the large-scale synthesis of silicon-containing amino acids, as well as further diversity in their side chains.

favor a reverse turn seem more suitable than those that induce an extended conformation.126,129 The influence of silaproline in position 10 of NT(8−13) was evaluated with the peptide H-Lys-Lys-Sip-Tyr-Ile-Leu-OH (JMV2009). Despite somewhat disappointing binding affinity values, JMV2009 slightly increased the selectivity for the NTS2 receptor subtype and maintained biological activity (Table 5). Central administration of JMV2009 in rats induced dosedependent analgesic activity in a broad variety of acute, tonic, visceral, and chronic animal pain models, including reduction of ongoing tactile allodynia in neuropathic rats [chronic constriction injury (CCI) model].130 Thus, NTS2 agonists may offer promising new avenues for limiting pain associated with peripheral neuropathies.

AUTHOR INFORMATION Corresponding Author

*E-mail fl[email protected]; phone +33 (0)467 143 765. Present Address ‡

(C.M.) Research Group of Organic Chemistry, Departments of Bioengineering Sciences and Chemistry, Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussels, Belgium.

10. SUMMARY Results from sections 3−7 of this review are summarized in Table 6.

Author Contributions †

E.R. and C.M. contributed equally to this work.

Notes

The authors declare no competing financial interest.

11. CONCLUSION The field of silicon-containing amino acids is becoming more and more attractive as a source of diversity in drug design. The development of silicon organic chemistry has greatly assisted in this respect. The replacement of carbon atoms by silicon atoms is now commonplace and several drugs in clinical use have silicon analogues, such as silaloperamide131 and silahaloperidol or silavenlafaxine,132 as well as silaproline-containing hepatitis C virus inhibitors,133 as recent examples. A synthetic siliconcontaining agent related to camptothecin,134 called karenitecin, has been developed due to its superior oral bioavailability and increased lactone stability and is currently in an international phase III clinical trial for the treatment of advanced ovarian cancer. Particularly, the development of silicon-containing amino acids, which are significant elements in medicinal chemistry, is of great importance. Nowadays, the pharmaceutical industry is looking toward peptide- and protein-based therapies in drug design.135 Increasing peptide stability still remains a challenge. One way to achieve this goal is to incorporate unnatural amino acids into bioactive peptides, including silicon-containing amino acids. In addition, the introduction of highly lipophilic silicon-containing amino

Biographies Emmanuelle Rémond was born in Dijon, France, in 1984. She defended her Ph.D. in 2010 under the supervision of Professor S. Jugé at the Institut de Chimie Moléculaire de l’Université de Bourgogne on stereoselective synthesis of chiral phosphonium salts and their application in the preparation of unsaturated amino acids. She completed her research training through an internship with the team of Professor N. Chatani in Osaka, Japan, and later a postdoctoral fellowship with the team of Professor K. Maruoka in Kyoto, Japan, where she was interested in catalyzed borylation of unactivated substrates and in organocatalyzed asymmetric conjugate addition using chiral primary diamines. In 2012, she was appointed assistant professor at the University of Bourgogne, France, and then associate professor in 2013 at the University of Montpellier. To date she is currently working with the team of Dr. F. Cavelier at the Institut des Biomolécules Max Mousseron, where she is developing stereoselective syntheses of heterosubstituted (P,B,Si)-amino acids for customized peptides. Charlotte Martin was born in Montpellier, France, in 1984. She completed her Ph.D. under the supervision of Florine Cavelier at the Institute of Biomolecules Max Mousseron in Montpellier. She received Z


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DCM DIPEA DMAP DMF DMSO de dr ee er Fmoc FmocCl FmocOSu HPLC LDA LiBH4 LiNp MALDI MeONa NaHMDS NBS n-BuLi NT ODN PCC PDC Phth rt SEMCl Sip SP SPPS TBAHS TBSOTf t-BuOK TEA TES-Dpg TFA THF TMEDA TMGN3 TMS TMSAla TMSCHN2 Tos Z

her Ph.D. in chemical sciences (specialized in molecular engineering) from Montpellier University in 2013, with work focused on the preparation of silicon-containing amino acids for the synthesis of polyproline type II helix mimics. She is currently undertaking a postdoctoral fellowship at the Vrije Universiteit Brussel (Research Group of Organic Chemistry) with Professor Steven Ballet as principal investigator. Her current endeavors comprise the rational development of peptide hydrogels for controlled drug delivery and peptide-based molecular probes that copy the CDR3 loop of promising nanobodies. Jean Martinez is a professor of organic chemistry and medicinal chemistry at the University of Montpellier, France. He studied chemistry at the Ecole Nationale Supérieure de Chimie de Montpellier, France. After receiving his Ph.D. in 1972, he was awarded a permanent position at the Centre National de la Recherche Scientifique (CNRS). He completed his “Thèse d’Etat” in 1976 under the direction of Professor F. Winternitz and performed postdoctoral studies with Professor E. Bricas in Orsay, France, and at Case Western University in Cleveland, OH with Professor M. Bodanszky. On his return to France, he pursued research at the interface of chemistry and biology in the field of peptides. He became successively the head of various research laboratories in Montpellier including the Laboratory of Chemistry and Pharmacology of Biologically Interesting Molecules, the Laboratory of Amino Acids, Peptides and Proteins, and the Institute of Biomolecules Max Mousseron (IBMM). He has also served the European Peptide Society as member of the executive committee (1991−1998), scientific officer (1998−2001), and president (2001−2010). He is currently head of the Department of Amino Acids, Peptides and Proteins at IBMM. Part of his research interests concern peptide chemistry and pharmacology, stereoselective synthesis of amino acids, and design and preparation of biomaterials. Florine Cavelier obtained her Ph.D. in organic chemistry from Montpellier University, France, in 1989. She spent two years as a Royal Society Fellow at the Dyson Perrins Laboratory under the supervision of Professor Jack Baldwin in Oxford, U.K. In 1991, she obtained an academic position at CNRS. In 2003 she was promoted to CNRS Research Director. She is currently at the Institute of Biomolecules Max Mousseron (IBMM) in Montpellier, leading the team for stereoselective synthesis and unnatural amino acids. She is currently serving as officer of the Groupe Français des Peptides et Protéines (2007−) and served as president of this group from 2011 to 2013. In 2012 she was elected as the French representative for the Council of the European Peptide Society, and in 2016 she has been nominated as a member of the Scientific Affairs Committee. Her research interests focus on nonnatural amino acids and biologically active peptides.

dichloromethane N,N-diisopropylethylamine 4-(dimethylamino)pyridine N,N-dimethylformamide dimethyl sulfoxide diastereomeric excess diastereomeric ratio enantiomeric excess enantiomeric ratio 9-fluorenylmethoxycarbonyl 9-fluorenylmethoxycarbonyl chloride N-(9-fluorenylmethoxycarbonyloxy)succinimide high-performance liquid chromatography lithium diisopropylamide lithium borohydride lithium naphthalenide matrix-assisted laser desorption ionization sodium methoxide sodium bis(trimethylsilyl)amide N-bromosuccinimide n-butyllithium neurotensin octadecaneuropeptide pyridinium chlorochromate pyridinium dichromate phthaloyl room temperature 2-(trimethylsilyl)ethoxymethyl chloride silaproline substance P solid-phase peptide synthesis tetrabutylammonium hydrogen sulfate trimethylsilyl trifluoromethanesulfonate potassium tert-butoxide triethylamine triethylsilyl di-n-propylglycine trifluoroacetic acid tetrahydrofuran tetramethylethylenediamine tetramethylguanidinium azide trimethylsilyl trimethylsilyl alanine trimethylsilyl diazomethane tosyl carboxybenzyl

REFERENCES

ACKNOWLEDGMENTS We thank Montpellier University for a grant to C.M.

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ABBREVIATIONS Ac acetyl ACE angiotensin-converting enzyme ACN acetonitrile AcOH acetic acid Bn benzyl Boc tert-butoxycarbonyl Boc2O di-tert-butyl dicarbonate Bu2BOTf di-n-butylboryl trifluoromethanesulfonate Cp cyclopentenyl CD circular dichroism CPP cell-penetrating peptides CNS central nervous system AA


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