Anti-β-substituted γ,δ-unsaturated amino acids have been synthesized via a novel design of the Eschenmoser-Claisen rearrangement. The rearrangement gives good isolated yields and excellent diastereoselectivity due to (Z)-N,O-ketene acetal formation and the pseudochairlike conformations of the reaction intermediates. Upon reductive hydrolysis, important novel amino acids and amino alcohols were synthesized for the first time via this methodology.In the course of synthesis and conformational studies of biological active peptide ligands, a universal methodology is needed for the synthesis of nonproteinogenic amino acids with terminal unsaturation. 1 The double bond has been a useful building block in organic synthesis due to its potential conversion to aldehydes, alcohols, halides, epoxides, amines, or carboxylic acids. 2 It also can be used in peptide macro-cyclization via ring-closing metathesis. 3 In addition, various β-side chain groups can be introduced in the synthesis so that the amino acid will provide biologically active functionalities in conformational constrained peptides. 4 The Kazmaier-Claisen rearrangement has turned out to be very useful in the synthesis of this kind of amino acids and their applications in peptidomimetics. 5 However, the Kazmaier strategy does not work well for racemic anti-β-substituted γ,δ-unsaturated amino acids. It is difficult to introduce an anti-β-substituent using the Z-allyl alcohol as a starting material, which is not always commercially available. Furthermore, the cis-oriented side chain can destabilize the hruby@u.arizona.edu. Supporting Information Available: Experimental procedures and spectroscopic characterization ( 1 H NMR, 13 C NMR, HRMS, IR) of all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org. chairlike transition state resulting in poor diastereoselectivities. 6 The rearrangement product is a diastereomeric mixture that is usually hard to purify. Previous studies also have generated other ω-unsaturation by Ni(II) complex alkylation. 7 However, attempts to prepare the anti product have failed due to epimerization. On the other hand, the Eschenmoser-Claisen rearrangement has been developed as a useful methodology for synthesis of γ,δ-unsaturated carboxylic amide derivatives. 8 We envisioned that if an N,O-ketene acetal intermediate could be generated in its cis configuration, a chairlike transition state conformation would provide an anti-β-substituted product after rearrangement ( Figure 1). During this study, we found that the Eschenmoser-Claisen rearrangement was a straightforward methodology for the synthesis of the desired amino acids. This methodology also can be used for the synthesis of amino alcohols which are common structural components in bioactive nature products and important synthetic building blocks in organic synthesis. 9 NIH Public AccessGlycine amide derivatives 4 were synthesized using the secondary amine pyrrolidine 3a and N,N-diisopropylamine 3b (Scheme 1), as we expected that a 2,5-...
Optically active anti-β-substituted γ,δ-unsaturated amino acids are important synthetic building blocks in organic synthesis and for peptidomimetics. A novel asymmetric Eschenmoser-Claisen rearrangement with use of a C 2 -symmetric chiral auxiliary was developed to generate this type of amino acid. Excellent diastereoselectivities and high enantioselectivities (87-93% ee) were obtained after the chiral auxiliary was removed via iodolactonization/zinc reduction.γ,δ-Unsaturated amino acids are important naturally occurring nonproteinogenic amino acids found in plants 1 and microorganism. 2 They are also very important building blocks in organic synthesis for the potential conversion of their terminal double bonds to many other functionalities, and for their applications in peptidomimetic drug discovery. 3 A well-known strategy to synthesize this type of amino acid is via a Claisen rearrangement. 4 The related methodologies to synthesize optically active syn-β-substituted γ,δ-unsaturated amino acids have also been developed by using chiral ligands, 5 or chirality transfer from available chiral sources. 6 However, no satisfactory Claisen rearrangement has been reported for optically active anti-β-substituted γ,δ-unsaturated amino acids. In general, the chirality transfer method can also be expanded to the anti-products; however, it suffers from limited chiral starting materials and epimerization to the syn epimer. 6 In Welch's report of an asymmetric Eschenmoser-Claisen rearrangement, 7 the remote chiral center provided low diastereofacial selectivity as a consequence of the C-N bond rotation in the N,O-ketene acetal intermediate.Most recently, we have reported that racemic anti-β-substituted γ,δ-unsaturated amino acids can be generated with good diastereoselectivities via the Eschenmoser-Claisen rearrangement. 8 We envisioned that an asymmetric Eschenmoser-Claisen rearrangement also could be performed using a C 2 -symmetric chiral auxiliary. The use of a C 2 -symmetric chiral auxiliary was expected to preclude the rotamer problem mentioned above and therefore provide an improved asymmetric induction. We report here a novel synthesis of the optically active anti-β-substituted γ,δ-unsaturated amino acids using a C 2 -symmetric chiral auxiliary.The C 2 -symmetric chiral auxiliary (2R,5R)-dimethylpyrrolidine 1 was synthesized in excellent ee according to a literature reported method. 9 It was then coupled to a Cbz-protected glycine using DIC/HOAT to afford amide 2 in excellent yield despite the steric hindrance of the secondary amine (Scheme 1). The Meerwein salt formation and rearrangement was conducted in similar conditions as reported previously for the synthesis of the racemic anti-β-substituted γ,δ-unsaturated amino acids. Although, in general, high temperature would provide low diastereoselectivities, a couple of these reactions had to be heated to 60 °C (entries 2 and 3) to Correspondence to: Victor J. Hruby. Supporting Information Available: Experimental procedures and spectroscopic characterization ( 1...
A novel synthesis of optically active anti-1β-substituted γ,δ-unsaturated amino acids via a thioClaisen rearrangement has been achieved. A 2,5-diphenylpyrrolidine was used as a C 2 -symmetric chiral auxiliary to control the stereochemistry, giving good yields and excellent diastereoselectivities and enantioselectivities.Synthesizing optically active nonproteinogenic amino acids has played a crucial role in the development of peptides and peptidomimetics as therapeutic agents. 1 β-Substituted γ,δ-unsaturated amino acids have turned out to be especially important building blocks for these studies due to the diversified reactivities of the terminal double bond and their ability to introduce biologically active functionalities. 2 Constructing this type of structural skeleton has been under investigation for many years, and one of the most powerful synthetic methods toward these goals is the Claisen rearrangement. 3 Kazmaier et al. have reported stereoselective syntheses of syn-β-substituted γ,δ-unsaturated amino acids via a chelate Claisen rearrangement. 4 However, progress on making anti-β-substituted γ,δ-unsaturated amino acids was not satisfying due to the relative unavailability of Z-allylic alcohol sources, and due to the competing rearrangement boat like transition state when a Z-allylic alcohol is applied. 5 The ester-enolate Claisen rearrangement has been reported for the synthesis of these molecules; however, limited chiral starting materials and epimerization during the synthesis are problems that remain to be solved. 6 Most recently, our group has achieved a synthesis of such amino acids via the Eschenmoser-Claisen rearrangement with excellent diastereoselectivity and good enantioselectivity. 7 Here we report on another novel, complementary synthesis via a thioClaisen rearrangement. This method is straightforward and highly selective using a bulky C 2 symmetric chiral auxiliary, and the chiral auxiliary can be recycled after producing the final amino acids.The C 2 symmetric chiral auxiliary, (2R,5R)-2,5-diphenylpyrrolidine 1, was prepared in optically pure form, 8 and coupled to N α -Cbz glycine to generate amide 2 using DIC/HOAT as the coupling reagent. This coupling reaction gave excellent yields despite the steric hindrance of the phenyl rings (Scheme 1). A thionation reaction with Lawesson's reagent converted the amide to the thioamide 3 in quantitative yield. 9 The thio-enolate was made by treatment of 3 with freshly prepared LDA in THF at −78 °C, and then the allylic bromide was added to the reaction to alkylate the enolate at the sulfur position. Thio-Claisen rearrangement occurred when the reaction mixture was warmed up slowly to room temperature or higher (when necessary) to afford thioamides 5 and 6 (Scheme 1).Our first attempts at this reaction with 2.2 equivalents of LDA gave unsatisfactory results. The yields were extremely low with large amounts of starting materials recovered. After examining the structure more carefully, we realized that this might be caused by a two-step deprotona...
A substituted hydropyrazino[1,2-a]pyrimidin-6-one derivative was synthesized stereoselectively via the intramolecular N-acyliminium ion cyclization between an amide nitrogen and an N α -acetal derived from Cbz-protected aminopropyl-phenylalaninamide in very good yields. The formation of a single diastereomer is due to the low energy chairlike conformation of its bicyclic structure. This methodology provides a convenient tool to build internal bicyclic peptidomimetics. Keywords internal bicyclic peptidomimetics; N-acylimnium ion cyclization; acetalsIt has been well recognized that β-turns are important structural features in biologically active peptides and proteins in terms of their function. 1 A large amount of research has been pursued to investigate peptide-protein or protein-protein interactions that also could be induced by small molecules bearing similar local structural features. 2 Recently, our group has developed the external β-turn mimetics 1 (Figure 1) containing the thiazolo[3,2-a]pyridine-5-one moiety via both solution and solid phase synthesis. 3 It has been known that for interactions with a target protein, side chains of internal β-turn mimetics are more accessible than those of external mimetics, which are more sterically hindered by the support. 4 Therefore, we have designed and synthesized a novel internal bicyclic scaffold for peptidomimetic 2 (Figure 1). For structure characterization and configuration assignment, a density functional theory (DFT) calculation, solution NMR spectroscopy, and X-ray crystallography were performed.Compound 8 was designed as a model compound to investigate the synthesis of 1,3,6,8-substituted tetrahydro-2H-pyrazino[1,2-a]pyrimidine-4,-7-diones (2) derivatives (Scheme 1). The straight forward approach to this bicyclic scaffold was to introduce an acetal moiety at the α-amino group of the phenylalanine, which can be attacked first by the amide to yield the acyliminium ion 7 and then by the carbamate nitrogen atoms in a one-pot fashion to construct the bicyclic structure. The reaction was expected to give a corresponding diastereomeric mixture, as the nucleophilic attack may take place from both the si-face and re-face of the planar iminium ion double bond. 4,5 Surprisingly, a single diastereomer was generated and isolated from the reaction, and its purity was confirmed by HPLC. Here we provide details for the synthesis, the rationalization of diastereoselectivity, and its absolute stereochemistry.* Corresponding Author. Phone: 520-621-6332; Fax: 520-621-8407; email: hruby@u.arizona.edu Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the ...
Parallel synthesis of peptides and peptidomimetics has been an important approach to [6,[5][6][7]
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