Crystal Structures– AManifesto for the Superiority of the Valine-Derived 5,5-Diphenyloxazolidinone as an Auxiliary in Enantioselective Organic Synthesis

Gaul, Christoph; Schweizer, W. Bernd; Seiler, Paul; Seebàch, Dieter

doi:10.1002/1522-2675(200206)85:6<1546::aid-hlca1546>3.0.co;2-2

Cited by 33 publications

(10 citation statements)

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“…b 3 -Homoarginine and its derivatives have been prepared according to the previously published method [38] [39] and have become commercially available as Fmoc-b 3 hArg(Pmc)-OH and Bocb 3 hArg(Tos)-OH 6 ). On the other hand, b 2 -homoarginine and its derivatives were prepared more recently, employing the chiral auxiliary DIOZ 1 [40] [41] as outlined in Scheme 1 [42]. Use of the azide group on the side chain (1 3 2 3 3) turned out to be a particularly viable strategy because the azide group is a direct precursor of a Bocprotected guanidinium group by treatment with the pyrazole 7 (6 3 8, 10 3 11), and it is stable under the conditions of enolization (3 3 4), t-Bu cleavage (4 3 5), Curtius degradation (5 3 6), and auxiliary removal (6 3 10).…”

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confidence: 99%

Chemical and Biological Investigations of β‐Oligoarginines

Seebàch¹,

Namoto²,

Mahajan³

et al. 2004

Chemistry & Biodiversity

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In view of the important role arginine plays in living organisms as the free amino acid and, especially, as a residue in peptides and proteins, the homologous beta-homoarginines are central in our investigations of beta-peptides (Fig. 1). The preparation of beta2-homoarginine derivatives suitably protected for solution- or solid-phase peptide syntheses is described with full experimental detail (9 and 12 in Scheme 1). The readily available Fmoc-beta3 hArg(Boc)2-OH is used for manual solid-phase synthesis of beta3-oligoarginines (on Rink amide or Rink amide AM resin) either by single amino acid coupling (Scheme 3) or, much better, by dimer-fragment coupling (Scheme 4). In this way, beta3-oligoarginine amides composed of 4, 6, 7, 8, and 10 residues, both with and without fluorescein labelling, were synthesized (Schemes 2-4), purified by preparative HPLC and identified by high-resolution mass spectrometry. The free amino acids (R)- and (S)-H-beta2 hArg-OH and (S)-H-beta3 hArg-OH were tested for their ability to function as substrates for NO synthase (iNOS); the beta3-oligoarginine amides (5, 6, and 7 residues) were tested for antibacterial (against six pathogens) and hemolytic (against rat and human erythrocytes) activities. All test results were negative: none of the free beta-homoarginines induced NO formation (Fig. 3), and there was no lysis of erythrocytes (concentrations up to 100 microM; Table 1), and no significant antibiotic activity (MIC > or = 64 microg/ml; Table 2). Cell-penetration studies with the fluorescence-labelled, peptidase-resistant beta3-oligoarginine amides were carried out with HeLa cells and human foreskin keratinocytes (HFKs). The results obtained with fluorescence microscopy are: i) the longer-chain beta-oligoarginine amides (8 and 10 residues; Figs. 4-6) enter the cells and end up in the nuclei, especially in the nucleoli, irrespective of temperature (37 degrees and 4 degrees with HFKs) or pretreatment with NaN3 (with HFKs), indicating a non-endocytotic and non-energy-dependent uptake mechanism; ii) the beta-tetraarginine derivative occupies the cell surface but does not enter the cells (with HeLa); iii) the cell-growth rate of the HFKs is not affected by a 1-microM concentration of the fluorescence-labelled beta-octaarginine amide (Fig. 7), i.e., there is no antiproliferative effect. In vivo experiments with mouse skin and the beta-octaarginine derivative show migration of the beta-peptide throughout the epidermis (Fig. 8). As a contribution to understanding the mechanism, we have also studied the behavior of fluorescence-labelled beta-octa- and beta-decaarginine amides (TFA salts) towards giant unilamellar vesicles (GUVs) built of neutral (POPC) or anionic (POPC/POPG mixtures) phospholipids: the beta-oligoarginine amides bind tightly to the surface of anionic GUVs but do not penetrate the lipid bilayer (Fig. 9) as they do with living cells. In contrast, a beta-heptapeptide FL-22, which had been used as a negative control sample for the cell-penetration experiments, entered the GUVs of ne...

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confidence: 99%

Chemical and Biological Investigations of β‐Oligoarginines

Seebàch¹,

Namoto²,

Mahajan³

et al. 2004

Chemistry & Biodiversity

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“…Slow evaporation of an Et 2 O/pentane mixture from a solution of ester 3 led to the formation of crystals suitable for structure determination by single-crystal X-ray diffraction; as evident from the presentation in Scheme 2, the methine H-atom of the i Pr group points towards the cis-Ph group causing a buttressing effect [49] in the face selectivity of reactions of enolates of 3 with electrophiles.…”

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Enantioselective Preparation of β²‐Amino Acids with Aspartate, Glutamate, Asparagine, and Glutamine Side Chains

Lelais

Campo

Kopp

et al. 2004

Helvetica Chimica Acta

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S)-b 2 -Homoamino acids with the side chains of Asp, Glu, Asn, and Gln have been prepared and suitably protected (N-Fmoc, CO 2 t Bu, CONHTrt) for solid-phase peptide syntheses. The key steps of the syntheses are: N-acylation of 5,5-diphenyl-4-isopropyl-1,3-oxazolidin-2-one (DIOZ) with succinic and glutaric anhydrides (Scheme 2), alkylation of the corresponding Li-enolates with benzyl iodoacetate and Curtius degradation (Scheme 4), and removal of the chiral auxiliary (Scheme 5). In addition, numerous functional-group manipulations (CO 2 H > CO 2 t Bu, CO 2 Bn > CO 2 H, CbzNH 3 FmocNH, CO 2 H 3 CO 2 NH 2 3 CONHTrt; Schemes 2, 4, 5, and 6) were necessary, in order to arrive at the four target structures. The configurational assignments were confirmed by X-ray crystal-structure determinations (Scheme 2 and Fig. 3). The enantiomeric purities of a b 2 hAsn and of a b 2 hGln derivative were determined by HPLC on a Chiralcel column to be 99.7 : 0.3 and > 99 : 1, respectively (Fig. 4). Notably, it took up to twelve steps to prepare a suitably protected trifunctional product with a single stereogenic center (overall yield of 10% from DIOZ and succinic anhydride)! Part of the Master Thesis (Diplomarbeit) of S. K., ETH-Z¸rich, 2003. 5 ) With the exceptions of Fmoc-b 3 hHis(Trt)-OH and Fmoc-b 3 hCys(Trt)-OH, all −proteinogenic× b 3 -amino acids, which can be prepared by ArndtÀEistert homologation of the corresponding a-amino acids, are commercially available.compounds for their use in solid-phase b-peptide synthesis is the Fmoc protection of the b-amino group, and the t Bu or Trt protecting group on the side chains. Thus, we thought that 3-acyl-DIOZ derivatives of succinic and glutaric acids could serve as precursors for the corresponding b 2 -homoaspartic and b 2 -homoglutamic acids, respectively. The amino functionality would be introduced either by a diastereoselectiveMannich-type reaction (cf. bond 1 in Fig. 1) or by a carbalkoxymethylation, followed by Curtius degradation (connections 1 2 in Fig. 1), to give the desired amino acid skeleton, which could be further elaborated by protecting-group exchange (Scheme 1). Scheme 1. Retrosynthetic Analysis for the Preparation of the b 2 -Amino Acids with Asx and Glx Side ChainsHelvetica Chimica Acta ± Vol. 87 (2004) 1547 Fig. 2. Target b 2 -amino acid derivatives Scheme 2. Nucleophilic Ring Opening of the Succinic and Glutaric Anhydrides ( 3 1 and 2), N-Acylation of (R)-DIOZ to Form the Acyloxazolidinones 3 and 4, Respectively, and X-Ray-Crystal Structure of 3Helvetica Chimica Acta ± Vol. 87 (2004) 1548 7 ) The reaction was rather messy and the formation of polymerization products were observed.

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“…) I kept telling my coworkers: “Crystals are a gift of nature, which you should never turn down!”. Thus, structures became central in all our synthetic endeavors: TADDOLs, DIOZ and the geminal ‐diaryl effect,, self‐regeneration of stereocenters (SRS), oligo‐ and poly‐(hydroxy‐butanoates) (PHB), chiral dendrimers, β‐ and γ‐peptides consisting of homologated α‐amino‐acid residues, mechanism of organocactalysis with prolin, imidazolidinones,, and diaryl‐prolinol‐silyl ethers . As a demonstration a few selected examples are presented in the following sections.…”

Section: The Importance Of Crystal Structures In a Synthetic Organicmentioning

confidence: 99%

“…the “ gem ‐diaryl effect”) . An example from our group is the superior gem ‐diphenyl‐modified Evans auxiliary DIOZ (Figure c,d),, another example is the diaryl‐prolinol unit of the Hayashi‐Jørgensen organocatalysts …”

Section: The Importance Of Crystal Structures In a Synthetic Organicmentioning

confidence: 99%

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What I Have Learned from Jack Dunitz

Seebàch

2016

Israel Journal of Chemistry

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The lessons taught me by Jack Dunitz about the use of X‐ray crystal structure analysis, far beyond just for determining the structure of an isolated product, are described. The direct and indirect influence Jack had on the way various topics of my synthetic group developed at ETH is demonstrated with selected examples from our various research areas: Li‐enolates, the gem‐diaryl effect and TADDOLs, self‐regeneration of stereocenters, poly(hydroxybutanoates) (PHB), β‐peptides, and mechanistic investigations of organocatalytic reactions. Furthermore, the role Jack plays in the Laboratorium of Organic Chemistry at ETH Zürich is described and appreciated.

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Crystal Structures– AManifesto for the Superiority of the Valine-Derived 5,5-Diphenyloxazolidinone as an Auxiliary in Enantioselective Organic Synthesis

Cited by 33 publications

References 13 publications

Chemical and Biological Investigations of β‐Oligoarginines

Chemical and Biological Investigations of β‐Oligoarginines

Enantioselective Preparation of β²‐Amino Acids with Aspartate, Glutamate, Asparagine, and Glutamine Side Chains

What I Have Learned from Jack Dunitz

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Crystal Structures– AManifesto for the Superiority of the Valine-Derived 5,5-Diphenyloxazolidinone as an Auxiliary in Enantioselective Organic Synthesis

Cited by 33 publications

References 13 publications

Chemical and Biological Investigations of β‐Oligoarginines

Chemical and Biological Investigations of β‐Oligoarginines

Enantioselective Preparation of β2‐Amino Acids with Aspartate, Glutamate, Asparagine, and Glutamine Side Chains

What I Have Learned from Jack Dunitz

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Product

Resources

About

Enantioselective Preparation of β²‐Amino Acids with Aspartate, Glutamate, Asparagine, and Glutamine Side Chains