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ChemInform Abstract: Silicon-Containing Amino Acids: Synthetic Aspects, Conformational Studies, and Applications to Bioactive Peptides
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Subject of this study are the structures and electron densities of the carbon/silicon analogues haloperidol/sila-haloperidol (1a/1b) and venlafaxine/sila-venlafaxine (2a/2b). The parent carbon compounds 1a (an antipsychotic agent) and 2a (an antidepressant) are both in clinical use. For haloperidol/sila-haloperidol, three published structures were studied in more detail: the structures of haloperidol hydrochloride (1a•HCl), haloperidol hydropicrate (1a•HPic) and sila-haloperidol hydrochloride (1b•HCl). For venlafaxine/sila-venlafaxine, the published structures of venlafaxine (2a), venlafaxine hydrochloride (2a•HCl; as orthorhombic (2a•HCl-ortho) and monoclinic polymorph (2a•HCl-mono)) and sila-venlafaxine hydrochloride (2b•HCl) were investigated. Based on these structures, the molecular electron densities were reconstructed by using the invariom formalism. They were further analysed in terms of Bader’s quantum theory of atoms in molecules, electrostatic potentials mapped onto electron density isosurfaces and Hirshfeld surfaces. These studies were performed with a special emphasis on the comparison of the corresponding carbon/silicon analogues.
The asymmetric synthesis of a new proline surrogate, incorporating the dimethylsilyl group at position 4 of proline using Schöllkopf's bis-lactim ether method, is described.
A straightforward synthesis of L-azetidine-2-carboxylic acid is described, leading to both orthogonally protected versions or totally deprotected L-Aze. The starting material is a commercially available aspartic acid derivative, whose chirality is conserved. The (2-trimethylsilyl)ethanesulfonyl protecting group (SES) acts as a leaving group on the hydroxy function and serves as an activator for the amine function, which is the key-step of the reaction. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)
Management of painful peripheral neuropathies remains challenging, since patients with chronic pain respond poorly to the available pharmacopeia. In recent years, the G-protein-coupled receptor neurotensin (NT) type 2 (NTS2) emerged as an attractive target for treating transitory pain states. To date, however, there is no evidence for its role in the regulation of chronic peripheral neuropathies. Here, we found that NTS2 receptors were largely localized to primary afferent fibers and superficial dorsal horns. Changes in the time course of the gene expression profile of NT, NTS1, and NTS2 were observed over a 28-d period following the sciatic nerve constriction [chronic constriction injury (CCI) model]. We next determined the effects of central delivery of selective-NTS2 agonists to CCI-treated rats on both mechanical allodynia (evoked withdrawal responses) and weight-bearing deficits (discomfort and quality-of-life proxies). The NTS2 analogs JMV431, levocabastine, and β-lactotensin were all effective in reducing ongoing tactile allodynia in CCI-treated rats. Likewise, amitriptyline, pregabalin, and morphine significantly attenuated CCI-induced mechanical hypersensitivity. NTS2 agonists were also efficient in reversing weight-bearing and postural deficits caused by nerve damage, unlike reference analgesics currently used in the clinic. Thus, NTS2 agonists may offer new treatment avenues for limiting pain associated with peripheral neuropathies and improve functional rehabilitation and well-being.-Tétreault, P., Beaudet, N., Perron, A., Belleville, K., René, A., Cavelier, F., Martinez, J., Stroh, T., Jacobi, A. M., Rose, S. D., Behlke, M. A., Sarret, P. Spinal NTS2 receptor activation reverses signs of neuropathic pain.
New enantiomerically enriched polyfunctionalized allylsilanes have been obtained from the synthetic elaboration of naturally occurring serine. In particular, an oxazolidine bearing an allylsilane framework on the lateral chain proved to be a suitable precursor for the corresponding silylated vinyl glycine derivatives.
The polyproline-II helix (PPII) in the recent years has emerged clearly as a structural class of not only fibrillar proteins (in collagen PPII is a dominant conformation) but also of the folded and unfolded proteins. Although much less abundant in folded proteins than the alpha-helix and beta-structure, the left-handed, extended PPII-helix represent the only frequently occurring regular structure apart from these two structure classes. Natively unfolded proteins have high content of the PPII-helices identified by spectroscopic methods. Apart from the structural function, PPII is favourable for protein-protein and protein-nucleic acid interactions and plays a major role in signal transduction and protein complex assembly, as this structure is often found in binding sites, specifically binding sites of widely spread SH3 domains. PPII-helices do not necessarily contain proline, but proline has high PPII propensity. Commonly occurring proline-rich regions, serving as recognition sites, are likely to have PPII structure. PPII-helices are involved in transcription, cell motility, self-assembly, elasticity, bacterial and viral pathogenesis, and has an important structural role in amyloidogenic proteins. However, PPII-helices are not always assigned in experimentally solved structures, and they are rarely used in protein structure modelling. We aim to give an overview of this structural class and of the place it holds in our current understanding of protein structure and function. This review is subdivides into three main parts, the first part covering PPII-helices in unfolded peptides and proteins, second part includes studies of the PPII-helices in folded proteins, and the third - functional role of the PPII.
Three new silicon-containing alpha-amino acids 6a-c and their respective hydantoin derivatives 8a-c have been prepared in racemic form. Alkylation of an alpha-amino cyanoacetate derivative with iodomethyl-substituted silanes, followed by hydrolysis gave the amino acids,and the subsequent reactions with KOCN and with HCl gave the hydantoins. The hydantoins are planned to be subjected to a biotechnological deracemization process. (C) 1997 Elsevier Science Ltd.
The preparation of protected derivatives of enantiomerically pure ?-(trimethylsilyl)alanine (1) and their chemical properties are decribed. Examples of renin inhibitory peptides, containing 1 are given, which demonstrates its use as a 'bio-isosteric' replacement
for phenylalanine (2).
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.
An asymmetric synthesis of a silicon-containing proline surrogate, N-Boc-(R)-silaproline (1), is described. Starting from N-Boc-dehydroalanine ester, deprotonation, followed by N-alkylation with chloromethyldimethylsilane under flow conditions, afforded the N-alkylated product 8 in 91% yield. An unprecedented enantioselective (NBD)2RhBF4/Josiphos 404-1 catalyzed 5-endo-trig hydrosilylation afforded the silaproline ester in 85-90% yield and >95% ee. Subsequent saponification and salt formation upgraded 1 to >99% ee.
BNP1350, 7-[(2-trimethylsilyl)ethyl]-20(S)-camptothecin, is a novel semi-synthetic, highly lipophilic, silicon-containing camptothecin and an inhibitor of topoisomerase I. It has been supercomputer engineered for superior oral bioavailability, superior lactone stability, broad anti-tumor activity, increased potency and insensitivity to Pgp/MRP/LRP drug resistance. We determined the efficacy of BNP1350 in experimental human colon cancer and compared its anti-tumor effects with those of CPT-11/SN-38. We also determined a possible influence of Pgp, MRP and LRP on the efficacy of BNP1350. The in vitro anti-proliferative capacity of the compounds using various exposure times was assessed in five colon cancer cell lines and indicated that BNP1350 was similarly effective or slightly more potent than SN-38. Four cell lines of other origin with sublines expressing Pgp, MRP and/or LRP showed that BNP1350 was significantly more effective than SN-38 (p < 0.05) and that the activity of BNP1350 was not reduced in multidrug-resistant cells. For in vivo experiments, BNP1350 was given 1.0 mg/kg i.p. or 1.5 mg/kg p.o, daily x 5 and CPT-11 20 mg/kg i.p. daily x 5 being equitoxic schedules in nude mice bearing s.c. human tumor xenografts, The schedules were studied in colon cancer xenografts COLO320, COLO205 or WiDr as well as in two Pgp-positive xenografts 2780AD and BRO/mdr1.1 and the parental Pgp-negative A2780 ovarian cancer xenografts and BRO melanoma xenografts. Growth inhibition of >50% was obtained for BNP1350 given i.p. in six out of the seven xenografts studied. BNP1350 was similarly effective when given i.p. or p.o. CPT-11 was as effective as BNP1350, except in BRO and BRO/mdr1.1 xenografts. Pgp expression in xenografts in vivo confirmed that there was no negative influence on the efficacy of BNP1350. In conclusion, BNP1350 shows a broad spectrum of activity in experimental human tumors and is a suitable candidate for oral treatment of cancer. Int. J. Cancer 88:260-266, 2000. (C) 2000 Wiley-Liss, Inc.
Silylation of diazoacetic esters with (t-Bu)(2)Si(Cl)OTf or Ph(t-Bu)Si(Cl)OTf (Tf = SO2CF3) yields alpha(chrorosilyl)-alpha-diazoacetates 3a-d, which can be converted into azidosilyl- (7), isocyanatosilyl- (8), and isothiocyanatosilyl- (9) substituted diazoacetates. Acid-catalyzed hydrolysis of 8a or 9a generates (hydroxysilyl)diazoacetate 10. (Allylaminosilyl)diazoacetates 12a,b can be prepared from diisopropylsilyl bis(triflate) by successive treatment with diazoacetic esters and allylamine.
HCV NS5A inhibitors have shown impressive in vitro potency profiles in HCV replicon assays thus making them attractive components for inclusion in an all oral fixed dose combination treatment regimen. Herein we describe the research efforts that led to the discovery of silyl proline containing HCV NS5A inhibitors such as 7e and 8a with pan-genotype activity profile and acceptable pharmacokinetic properties.
A concise synthetic pathway yielding to hydrophobic α,α-disubstituted disilylated amino acids based on a hydrosilylation reaction is described. As a first example of utilization in solid-phase peptide synthesis, TESDpg was introduced in replacement of Aib in an alamethicin sequence, leading to analogues with modified physicochemical properties and conserved helical structures. This study highlights the potential of these new amino acids as tools for peptide modulation.
The ability to incorporate unnatural amino acids into proteins directly in living cells will provide new tools to study protein and cellular function, and may generate proteins or even organisms with enhanced properties. Due to the limited promiscuity of some synthetases, natural amino acids can be substituted with close analogs at multiple sites using auxotrophic strains. Alternatively, this can be achieved by deactivating the editing function of some synthetases. The addition of new amino acids to the genetic code, however, requires additional components of the protein biosynthetic machinery including a novel tRNA-codon pair, an aminoacyl-tRNA synthetase, and an amino acid. This new set of components functions orthogonally to the counterparts of the common 20 amino acids, i.e., the orthogonal synthetase (and only this synthetase) aminoacylates the orthogonal tRNA (and only this tRNA) with the unnatural amino acid only, and the resulting acylated tRNA inserts the unnatural amino acid only in response to the unique codon. Using this strategy, the genetic code of Escherichia coli has been expanded to incorporate unnatural amino acids with a fidelity rivaling that of natural amino acids. This methodology is being applied to other cell types and unnatural analogs with a variety of functionalities.
For Abstract see ChemInform Abstract in Full Text.
A copper-based catalytic technique for the regioselective hydroboration and hydrosilylation of dehydroalanine derivatives has been developed. This method introduces synthetically versatile boron and silicon groups, while simultaneously performing a catalytic anti-Markovnikov hydrofunctionalization of dehydroalanines and dehydropeptides for the synthesis of amino acids and peptides bearing unnatural side-chains. The products obtained were expediently converted into valuable nonproteinogenic amino acid building blocks for polypeptide synthesis.
Loperamide (1a), an opioid receptor agonist, is in clinical use as an antidiarrheal agent. Carbon/silicon exchange (sila-substitution) at the 4-position of the piperidine ring of 1a (R3 COH→R3 SiOH) leads to sila-loperamide (1b). Sila-loperamide was synthesized in a multistep procedure, starting from triethoxyvinylsilane and taking advantage of the 4-methoxyphenyl (MOP) unit as a protecting group for silicon. The in vitro and in vivo pharmacokinetic (PK) and pharmacodynamic (PD) properties of the C/Si analogues 1a and 1b were determined and compared. Despite significant differences in the in vitro PK properties of loperamide and sila-loperamide regarding clearance, permeability, and efflux, both compounds exhibited nearly identical in vivo PK profiles. The increase in metabolic stability of the silicon compound 1b observed in vitro seems to be counterbalanced by an increase in efflux and diminished permeability compared to the parent carbon compound 1a. Overall, sila-loperamide exhibits high unbound clearance (CLu ), leading to a significant decrease in unbound concentration (Cu ) and unbound area under the curve (AUCu ) after oral exposure, compared to loperamide. In vitro and in vivo metabolic studies showed an altered profile of biotransformation for the silicon compound 1b, leading to the formation of a more polar and quickly cleared metabolite and preventing the formation of the silicon analogue of the neurotoxic metabolite observed for the parent carbon compound 1a. These differences can be correlated with the different chemical properties of the C/Si analogues 1a and 1b. This study provides some of the most detailed insights into the effects of a carbon/silicon switch and how this carbon/silicon exchange affects overall drug properties.
© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
In context with studies on silicon-containing α-amino acids and peptides, a strategy for the synthesis of the 4-sila-proline skeleton was developed. The synthesis of rac- and (R)-4,4-dimethyl-4-sila-proline ethyl ester [rac-2 and (R)-2] is described. Compounds rac-2 and (R)-2 (≥ 99% ee) were prepared by two-step syntheses, starting from 3,6-diethoxy-2,5-dihydropyrazine and (R)-3,6-diethoxy-2-isopropyl-2,5-dihydropyrazine, respectively.
The polyproline II helix (PPII) is increasingly recognized as an important element in peptide and protein structures. The discovery of pertinent PPII peptidomimetics is of great interest to tune physical properties of the targeted structure. A series of silaproline oligomers from dimer to pentamer were synthesized. CD studies, NMR spectroscopy and molecular modeling revealed that the ribbon preferentially populates the polyproline type II secondary structure in both [D]chloroform and [D4]MeOH. The characteristics of this new lipophilic PPII-like helix were determined.
A simple, fast and efficient method for allylation and propargylation of chlorosilanes through zinc mediation and ultrasound promotion is reported. As a direct application of the resulting bis-allylsilanes, three novel, constrained sila amino acids are prepared for the first time. The design and synthesis of the constrained sila analogue of GABA (γ-amino butyric acid) is a highlight of this work.
Neuropathic pain is a chronic condition resulting from neuronal damage. Pregabalin, the (S)-isomer of 3-isobutyl-γ-aminobutyric acid (GABA), is widely used to treat neuropathic pain, despite the occurrence of central nervous system (CNS)-related side effects such as dizziness and somnolence. Here we describe the pharmacology of novel GABA derivatives containing silicon-carbon bonds, silagaba compounds. Silagaba131, 132 and 161 showed pregabalin-like analgesic activities in animal models of neuropathic pain, but in contrast to pregabalin, they did not impair neuromuscular coordination in rotarod tests. Pharmacokinetic studies showed that brain exposure to silagaba compounds was lower than that to pregabalin. Surprisingly, despite their potent analgesic action in vivo, silagaba compounds showed only weak binding to α2-δ protein. These compounds may be useful to study mechanisms of neuropathic pain. Our results also indicate that silagaba132 and 161 are candidates for orally effective treatment of neuropathic pain without CNS-related side effects.
A diisopropylcarbodiimide/Oxyma (ethyl 2-cyano-2-(hydroxyimino)acetate) coupling cocktail was successfully incorporated into the automated microwave-assisted synthesis of two peptaibols and one analog, whose previously reported syntheses were complicated by steric hindrance. This method utilizes commercially available reagents and affords alamethicin F50/5 and bergofungin D in high yields and purities along with an appreciable reduction of synthesis time and cost when compared to previously reported methods.
Polyprolines are attractive polymers because of their folding property into polyproline II (PPII) structure, their significance in protein/protein interactions, and their potential as new therapeutic targets. Silaproline (Sip) is an analogue of proline, which exhibits similar conformational properties. The presence of dimethylsilyl group confers to Sip a higher lipophilicity as well as an improved resistance to biodegradation. Enantiomerically pure Sip was available in gram quantities from resolution of the enantiomers by chiral high performance liquid chromatography. This study describes the first synthesis of Sip N-carboxyanhydride (NCA) and shows preliminary results on comparison of polymerization of (l)Pro-NCA and (d)Sip-NCA to obtain homopolypeptides with PPII structure, polyproline, and polysilaproline polymers. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013, 51, 3103–3109
The factors controlling the diastereoselective alkylation and protonation reactions of chiral Schiff bases prepared from 2-hydroxypinan-3-one and α-aminoesters are reported: nature of the ester, of the alkylating agent and of the base.
The imidazolidinones (rac.-1 and rac.-2) obtained from pivalaldehyde and glycine amides are resolved efficiently by crystallization of diastereoisomeric ammonium salts with chiral acids (mandelates and a gulonate respectively). The free bases are acylated under Schotten-Baumann conditions to give enantiomerically pure 1-Bz., 1-BOC-, 1-2- or 1-formyl -2-t-butyl-3-methyl- or -3-benzyl-4-imidazolidinones. Diastereoselective alkylation of the 3-methyl derivatives (BMI) with a variety of electrophiles (LDA/THF -70 to + 25°) gives trans- disubstituted imidazolidinones exclusively (3–22). Some of these are hydrolysed by a procedure employing excess acidic ion exchange resin to give enantiomerically pure (R)- or (S)- amino acids. The procedure is compared with other methods of generating chiral glycine enolates.
DL-p-Trimethylsilylphenylalanine has been prepared in good yield by condensation of 4-trimethylsilylbenzyl bromide with diethyl formamidomalonate, followed by mild hydrolysis and decarboxylation of the resulting disodium α-(4-trimethylsilylbenzyl)formamidomalonate. Its N-carboxyanhydride was obtained on reaction of the amino-acid with carbonyl chloride, and it has been polymerised in pyridine.
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The influence of sequence on turn geometry was examined by incorporating (2S,5R)-5-tertbutylproline (5-(t)BuPro) into a series of dipeptides and tetrapeptides. (2S,5R)-5-tert-Butylproline and proline were respectively introduced at the C-terminal residue of N-acetyl dipeptide N-methylamides 1 and 2. The conformational analysis of these analogues was performed using NMR and CID spectroscopy as well as X-ray diffraction to examine the factors that control the prolyl amide (in this text, the term ''prolyl amide'' refers to the tertiary amide composed of the pyrrolidine nitrogen of the prolyl residue and the carbonyl of the N-terminal residue) equilibrium and stabilize type VI beta-turn conformation. The high cis-isomer population with aromatic residues N-terminal to proline was shown to result from a stacking interaction between the partial positive charged prolyl amide nitrogen and the aromatic pi-system as seen in the crystal structure of 1c. The effect of sequence on the prolyl amide equilibrium of 5-(t)BuPro-tetrapeptides (Ac-Xaa-Yaa-5-(t)BuPro-Zaa-XMe, 13 and 14) was studied by varying the amino acids at the Xaa, Yaa, and Zaa positions. High (>80%) cis-isomer populations were obtained with alkyl groups at the Xaa position, an aromatic residue at the Yaa position, and either an alanine or a lysine residue at the Zaa position of the 5-(t)BuPro-tetrapeptide methyl esters in water. Tetrapeptides Ac-Ala-Phe-5(t)BuPro-Zaa-OMe (Zaa = Ala, Lys), 14d and 14f, with high cis-isomer content adopted type Via beta-turn conformations as shown by their NMR and CD spectra. Although a pattern of amide proton temperature coefficient values indicative of a hairpin geometry was observed in peptides 14d and 14f, the value magnitudes did not indicate strong hydrogen bonding in water.
William Moser was born in Duluth, Minnesota, and received a BA in Chemistry from St. Olaf College in Northfield, Minnesota. After completing a Ph.D. in Organic Chemistry with Professor Louis S. Hegedus at Colorado State University, he continued his studies as a National Institute of Health Postdoctoral Research Fellow in the research group of Professor Amos B. Smith III at the University of Pennsylvania in Philadelphia, Pennsylvania. He is currently an Assistant Professor of Chemistry at Indiana University–Purdue University Indianapolis, where his research interests include synthetic organic and organometallic methodology, and novel applications of the Brook rearrangement.
tert-Butyl carbamate derivatives of readily available aminomethyltrialkylsilanes have been studied for their ability to undergo metalation between nitrogen and silicon, followed by reaction with an electrophile. Metalation is rapid and reaction with a variety of electrophiles proceeds efficiently. When a benzyl group is attached to nitrogen, benzylic deprotonation competes with deprotonation next to silicon.Metalation of tert-butyl carbamate derivatives of aminomethyltrimethylsilane can be used to prepare α-functionalized α-amino silanes.
A simple synthesis of a new amino acid derivative 5,6-bis(trimethylsilyl)indanylglycine via cobalt mediated [2+2+2] cycloaddition strategy is described. Co-trimerization of diyne building block containing amino acid moiety with bis(trimethylsilyl)acetylene in presence of CpCo(CO)2 catalyst afforded the silylated indane-based α-amino acid (AAA) derivative. Electrophilic aromatic substitution reaction, ipso to the trimethylsilyl group gave highly functionalised indane-based AAA derivatives.
Pure erythro-m-chloro-3-hydroxytyrosine having the (2R,3R)) configuration, a residue of Vancomycin and Aridicin A, has been prepared in 4 steps using an aldol addition involving a directly generated titanium enolate derived from a chiral iminoglycinate. (+)-Hydroxypinanone was used as a recoverable chiral auxiliary. The (2S,3S)-erythro isomer will be, of course, available from (−)-hydroxypinanone.
The synthesis of silicon containing alanines in optically pure form from an electrophilic alaninol synthon is described. The overall chemical yields for the synthesis of the novel amino acids range from 19–39%.
The synthesis of enantiomerically enriched silicon containing amino acids is described. Silylcupration of 2,2-dimethyl-3-(tert-butoxycarbonyl)-4-ethynyloxazolidine, easily derived from serine aldehyde, afforded regio- and stereoselectively γ-silylated ethenyloxazolidines of (E)-geometry as useful precursors of saturated and unsaturated γ-silylated amino acids.
The hydantoinase process was shown to be extendable to the production of highly lipophilic, silicon-containing amino acids. Two hydantoinases of different origin and stereoselectivities and one L-N-carbamoylase were used for the highly stereoselective bioconversion of (dimethyl)phenylsilyl- and 1-methyl-1-silacyclopentyl substituted alanine derivatives. The enantiomeric purities and absolute configuration of the products were determined with reference compounds that were synthesized with the aid of the Evans oxazolidinone auxiliary. (C) 2001 Elsevier Science Ltd. All rights reserved.
Neuropathic pain is a chronic pain condition resulting from neuronal damage, and is usually treated with pregabalin or gabapentin, which are structurally related to γ-aminobutyric acid (GABA) and are originally developed as anticonvulsant drugs. Here, we report the synthesis and pharmacology of (R)- and (S)-4-amino-3-(trimethylsilyl)methylbutanoic acids (1a and 1b), which showed analgesic activity as potent as that of pregabalin in the Chung spinal nerve ligation model. However, unlike pregabalin, 1a and 1b do not have antiepileptic effects, and they are therefore promising candidates for selective therapeutic agents to treat neuropathic pain without central nervous system-related side effects.
Kinetic resolution of ethylmethylphenylsilylmethanol, a primary alcohol having a stereogenic silicon atom, was tried by hydrolase-catalyzed enantioselective reactions. Among twenty kinds of hydrolases examined, a commercial crude papain preparation was found to exhibit the highest enantioselectivity with moderate activity toward the silicon-containing alcohol on esterification with 5-phenylpentanoic acid in an organic solvent system, and the (+)-enantiomer of 92 %ee was obtained as the remaining substrate. Several silylmethanol derivatives could be also resolved by this enantioselective esterification, even though it was difficult to synthesize such chiral quaternary silanes with high optical purity by chemical methods due to the absence of leaving groups on the silicon atom. These results demonstrate that enzymes can recognize the configuration not only of carbon atoms but also of silicon atoms, and indicate the usefulness of biocatalysts for preparing optically active silanes.
An efficient, convenient, and reliable multi-step synthesis of rac-2′-(trimethylsilyl)isovaline (rac-3) that uses inexpensive reagents in all steps has been developed, starting from diethyl malonate (overall yield 28%). Compound rac-3 is the first α-ethylated α,α-dialkylated silicon-containing α-amino acid.Graphical abstractAn efficient, convenient, and reliable multi-step synthesis of rac-2′-(trimethylsilyl)isovaline (rac-3) that uses inexpensive reagents in all steps has been developed, starting from diethyl malonate (overall yield 28%). Compound rac-3 is the first α-ethylated α,α-dialkylated silicon-containing α-amino acid.
Enantioselective bioconversion of organosilicon compounds was successfully carried out with hydrolases and a dehydrogenase. Substituents on silicon atom were found to affect the efficiency of the reactions. In many cases, the characteristics of silicon atom reflected the reactivity.
The unnatural silicon-containing α-amino acids (R)- and (S)-H2NCH(CH2SiMe3)COOH [(R)-2 and (S)-2], (R)-H2NCH(CH2SiMe2Ph)COOH [(R)-4], and (R)-H2NCH(CH2SiMe2CHCH2)COOH [(R)-6] as well as the unnatural germanium-containing α-amino acids (R)- and (S)-H2NCH(CH2GeMe3)COOH [(R)-3 and (S)-3] and (R)-H2NCH(CH2GeMe2Ph)COOH [(R)-5] were prepared in three-step syntheses, starting from (R)-3,6-diethoxy-2-isopropyl-2,5-dihydropyrazine [(R)-10]. All amino acids were isolated as enantiomerically pure (≥99% ee) compounds. The (R)- and (S)-enantiomers of β-(trimethylsilyl)alanine [(R)-2 and (S)-2] and β-(trimethylgermyl)alanine [(R)-3 and (S)-3] are sila-analogues and germa-analogues, respectively, of the (S)- and (R)-enantiomers of the nonproteinogenic amino acid β-tert-butylalanine [(S)- and (R)-H2NCH(CH2CMe3)COOH; (S)-1 and (R)-1]. The C/Si/Ge-analogous (l-configurated) amino acids (S)-1, (R)-2, and (R)-3 were treated with (fluoren-9-yl)methyl chloroformate to give the corresponding N-Fmoc derivatives (S)-26, (R)-27, and (R)-28. These N-Fmoc-protected amino acids were used as building blocks for the solid-phase syntheses of the C/Si/Ge-analogous decapeptides 7−9 [Ac-d-Nal1-4-Cl-d-Phe2-d-Pal3-Ser4-Me3El-Ala5-d-Cit6-Leu7-Arg8-Pro9-d-Ala10-NH2 (7, El = C; 8, El = Si; 9, El = Ge)]. The C/Si/Ge analogues 7−9 are derivatives of the GnRH antagonist CetrorelixINN, which bears an (S)-tyrosine residue [instead of the (S)-Me3C-Ala, (R)-Me3Si-Ala, or (R)-Me3Ge-Ala residue] in position 5 of its decapeptide backbone. The decapeptides 7−9 were studied in vitro in receptor binding and functional assays using recombinant cell lines expressing the human GnRH receptor. All compounds behaved as potent GnRH antagonists, the binding affinities and antagonistic potencies of the three C/Si/Ge analogues being quite similar. Compounds 7−9 were also studied for their in vivo activities in the male rat after s.c. administration. They produced both a strong testosterone suppression (single-dose treatment, 1.5 mg/kg) and a strong LH suppression (castrated male rat; single-dose treatment, 0.05 mg/kg). For the silicon- and germanium-containing decapeptides 8 and 9 the testosterone and LH suppression lasted for a significantly longer period of time compared with the effects of the carbon analogue 7.
Enantioselective synthesis of γ-silylated amino acids is reported, using a four-step procedure based on the silylcupration of ethynyloxazolidine 2. Silylcuprates 6a−c are highlighted as useful reagents to be employed with enantiomerically enriched substrates. Vinylsilanes 5 are easily prepared and highlighted as useful intermediates to yield the final compounds after reduction, opening of the oxazolidine ring, and oxidation. Moreover, β,γ-unsaturated amino acids are obtained as very interesting vinylglycine derivatives. The capability of silicon-containing amino acids to be incorporated into dipeptides is also shown.
Full details are provided for an exceedingly practical method to synthesize d- and l-α-amino acids, N-protected α-amino acids, and N-methyl-α-amino acids, employing as a key step the asymmetric alkylation of pseudoephedrine glycinamide (1) or pseudoephedrine sarcosinamide (2). Practical procedures for the synthesis of 1 and 2 from pseudoephedrine and glycine methyl ester or sarcosine methyl ester, respectively, are presented. Optimum protocols for the enolization and subsequent alkylation of 1 and 2 are described. Alkylation reactions of 1 and 2 are found to be quite efficient with a wide range of alkyl halide substrates, and the products are formed with high diastereoselectivity. The products of these alkylation reactions are hydrolyzed efficiently and with little to no racemization simply by heating in water or water−dioxane mixtures. This protocol provides an exceedingly practical method for the preparation of salt-free α-amino acids of high enantiomeric purity. Alternatively, the alkylation products may be hydrolyzed in high yield and with little to no racemization by heating with aqueous sodium hydroxide. The alkaline hydrolyzate can then be treated with an acylating reagent to provide directly highly enantiomerically enriched N-protected derivatives such as N-Boc and N-Fmoc. Key features necessary for the successful execution of these experimental procedures are identified.
Beim Behandeln benzolischer Lösungen von Aminomethyl- bzw. -benzylsilanen (I) mit geringen Mengen von n-Butyllithium tritt, abhängig vom Amin bei Raumtemperatur oder bei 100°C, Umlagerung zu den Silylaminen (II) ein, die gaschromatographisch und durch spektralen Vergleich mit nach anderen Verfahren erhaltenen Proben identifiziert wurden.
In this account several tools necessary for the synthesis of peptides from α-amino acids are considered. Different strategies for the asymmetric synthesis of α-amino acids are studied. New chiral glycine and alanine imines as acyclic and cyclic templates for the asymmetric synthesis of different types of mono as well as dialkylated α-amino acids with acyclic and heterocyclic structures are reviewed. Their diastereoselective alkylation and final hydrolysis takes place under very mild reaction conditions. New polymer-supported cinchonidine and cinchonine ammonium salts and chiral binaphthol-derived aminoalkoxides (BINOLAMs), have been developed as catalysts for the asymmetric PTC alkylation of imino esters. The use of chiral oxazinone and pyrazinone α,β-didehydroamino acid derivatives in hydrogenation, Heck-arylation, cyclopropanation and Diels-Alder cycloaddition reactions for the asymmetric synthesis of α-amino acids are also studied. Azomethine ylides derived from saturated oxazinones can also be used in the asymmetric synthesis of prolines by means of diastereoselective dipolar cycloadditions. For the protection of α-amino acids new efficient reagents, Fmoc-P-OSu and Cbz-P-OSu, derived from poly(styrene-co-N-hydroxymaleimide) named as polymeric N-hydroxysuccinimide (P-HOSu), have been developed. Several new systems such as polymer-supported P-HOSu/DCC and polystyrene-bound P-TBTU or P-HBTU, together with non- polymeric thiouronium salts derived from 2-mercaptopyridine-1-oxide and TMU, such as HOTT and TOTT, and from DMPU, such as HODT and TODT, have been used as peptide coupling reagents, in solution and solid phase peptide synthesis, as well as for the preparation of primary amides, Weinreb amides and other hydroxamates, directly from carboxylic acids.
1 Introduction
2 Asymmetric Synthesis of α-Amino Acids
2.1 Electrophilic Alkylation of Chiral Glycine and Alanine
Templates
2.2 Electrophilic Alkylation with Chiral Phase-transfer
Catalysts
2.3 Chiral α,β-Didehydroamino Acid Derivatives
2.4 Chiral Azomethine Ylides
3 Protecting-group Reagents
4 Peptide Coupling Reagents
5 Conclusion
The homoserine and homomethionine sila analogs, (R)-HOSi(Me2)CH2CH(NH2)CO2H ((R)-21) and (R)-MeSCH2Si(Me2)CH2CH(NH2)CO2H ((R)-24), respectively, were each synthesized in nine steps and in 30 and 23% overall yield, respectively, from commercially available ClSiMe2CH2Cl. The key step of both syntheses was the asymmetric α-bromination of an Evans amide to introduce the stereogenic center of the amino acids with defined absolute configuration. While the preparation of the homomethionine analog (R)-24 followed the expected pathway, the sila analog of homoserine, (R)-21, was unexpectedly formed during the catalytic hydrogenation of an N3CH2-substituted silane derivative.