TADDOL and Its Derivatives – Our Dream of Universal Chiral Auxiliaries

Seebàch, Dieter; Beck, Albert K.; Heckel, Alexander

doi:10.1002/9783906390451.ch7

Cited by 6 publications

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“…This NRPS machinery is capable of processing not only the proteinogenic amino acids, but also a great range of non-proteinogenic a-amino acids, including d-configured ones, Nmethyl-amino acids, b-, g-, d-, and e-amino acid derivatives, and various hydroxy acids (including b-hydroxybutanoic acid) 37 ); over 300 components have so far been identified [120]. The activities of the often cyclic NRPS products (cyclopeptides, cyclopeptolides, oligolides) range from tensidic, siderophoric, antibiotic, fungicidal, antiviral, insecticidal, cytotoxic, neurotoxic, nephrotoxic, and cancerostatic to immunosuppressive activity 38 ).…”

Section: B-amino Acids In Naturementioning

confidence: 98%

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The World of β‐ and γ‐Peptides Comprised of Homologated Proteinogenic Amino Acids and Other Components

Seebàch

Beck

Bierbaum

2004

Chemistry & Biodiversity

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The origins of our nearly ten-year research program of chemical and biological investigations into peptides based on homologated proteinogenic amino acids are described. The road from the biopolymer poly[ethyl (R)-3-hydroxybutanoate] to the beta-peptides was primarily a step from organic synthesis methodology (the preparation of enantiomerically pure compounds (EPCs)) to supramolecular chemistry (higher-order structures maintained through non-covalent interactions). The performing of biochemical and biological tests on the beta- and gamma-peptides, which differ from natural peptides/proteins by a single or two additional CH(2) groups per amino acid, then led into bioorganic chemistry and medicinal chemistry. The individual chapters of this review article begin with descriptions of work on beta-amino acids, beta-peptides, and polymers (Nylon-3) that dates back to the 1960s, even to the times of Emil Fischer, but did not yield insights into structures or biological properties. The numerous, often highly physiologically active, or even toxic, natural products containing beta- and gamma-amino acid moieties are then presented. Chapters on the preparation of homologated amino acids with proteinogenic side chains, their coupling to provide the corresponding peptides, both in solution (including thioligation) and on the solid phase, their isolation by preparative HPLC, and their characterization by mass spectrometry (HR-MS and MS sequencing) follow. After that, their structures, predominantly determined by NMR spectroscopy in methanolic solution, are described: helices, pleated sheets, and turns, together with stack-, crankshaft-, paddlewheel-, and staircase-like patterns. The presence of the additional C--C bonds in the backbones of the new peptides did not give rise to a chaotic increase in their secondary structures as many protein specialists might have expected: while there are indeed more structure types than are observed in the alpha-peptide realm - three different helices (10/12-, 12-, and 14-helix) if we include oligomers of trans-2-aminocyclopentanecarboxylic acid, for example - the structures are already observable with chains made up of only four components, and, having now undergone a learning process, we are able to construct them by design. The structures of the shorter beta-peptides can also be reliably determined by molecular-dynamics calculations (in solution; GROMOS program package). Unlike in the case of the natural helices, these compounds' folding into secondary structures is not cooperative. In beta- and gamma-peptides, it is possible to introduce heteroatom substituents (such as halogen or OH) onto the backbones or to incorporate heteroatoms (NH, O) directly into the chain, and, thanks to this, it has been possible to study effects unobservable in the world of the alpha-peptides. Tests with proteolytic enzymes of all types (from mammals, microorganisms, yeasts) and in vivo examination (mice, rats, insects, plants) showed beta- and gamma-peptides to be completely stable towards proteolysis and, as ...

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Section: B-amino Acids In Naturementioning

confidence: 98%

“…A −knock-out× organism no longer capable of producing cPHB has recently been described for the first time [159]. 38 ) Compounds such as bleomycin, cyclosporin, enterobactin, mycobactin, and vancomycin, for example, are NRPS products. .…”

Section: B-amino Acids In Naturementioning

confidence: 99%

The World of β‐ and γ‐Peptides Comprised of Homologated Proteinogenic Amino Acids and Other Components

Seebàch

Beck

Bierbaum

2004

Chemistry & Biodiversity

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926

562

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Preparation of Polystyrene Beads with Dendritically Embedded TADDOL and Use in EnantioselectiveLewis Acid Catalysis

Sellner

Rheiner

Seebàch

2002

HCA

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Dedicated to Professor Barry M. Trost on the occasion of his 60th birthday A full account is given of the preparation and use of TADDOLates, which are dendritically incorporated in polystyrene beads (Scheme 1). A series of styryl-substituted TADDOLs with flexible, rigid, or dendritically branching spacers between the TADDOL core and the styryl groups (2 ± 16 in number) has been prepared (5 ± 7, 20, 21, 26 in Schemes 2 ± 4 and Fig. 1 ± 3). These were used as cross-linkers in styrene-suspension polymerization, leading to beads of ca. 400-mm diameter (Schemes 5 and 6, b). These, in turn, were loaded with titanate and used for the Lewis acid catalyzed addition of Et 2 Zn to PhCHO as a test reaction (Scheme 6). A comparison of the enantioselectivities and degrees of conversion (both up to 99%), obtained under standard conditions, shows that these polymer-incorporated Ti-TADDOLates are highly efficient catalysts for this process ( Table 1). In view of the effort necessary to prepare the novel, immobilized catalysts, emphasis was laid upon their multiple use. The performance over 20 cycles of the test reaction was best with the polymer obtained from the TADDOL bearing four first-generation Fre¬chet branches with eight peripheral styryl groups (6, p-6, p-6 ¥ Ti(O i Pr) 2 ): the enantioselectivity (Fig. 4), the rate of reaction (Fig. 5), and the swelling factor (Fig. 6) were essentially unchanged after numerous operations carried out with the corresponding beads of 400-mm diameter and a degree of loading of 0.1 mmol TADDOLate/g polymer, with or without stirring (Fig. 7). The rate with the dendritically polymer-embedded Ti-TADDOLate (p-6 ¥ Ti(O i Pr) 2 ) was greater than that measured with the corresponding monomer, i.e., 6 ¥ Ti(O i Pr) 2 (Fig. 8). Possible interpretations of this phenomenon are proposed. A polymer-bound TADDOL, generated on a solid support (by Grignard addition to an immobilized tartrate ester ketal) did not perform well (Scheme 4 and Table 2). Also, when we prepared polystyrene beads by copolymerization of styrene, a zero-, first-, or second-generation dendritic cross-linker, and a mono-styrylsubstituted TADDOL derivative, the performance in the test reaction did not rival that of the dendritically incorporated Ti-TADDOLate ((p-6 ¥ Ti(O i Pr) 2 ) (Scheme 7 and Fig. 10). Finally, we have applied the dendritically immobilized Cl 2 and (TsO) 2 Ti-TADDOLate as chiral Lewis acid to preferentially prepare one enantiomer of the exo and the endo (3 2) cycloadduct, respectively, of diphenyl nitrone to 3-crotonoyl-1,3-oxazolidinone; in one of these reaction modes, we have observed an interesting conditioning of the catalyst: with an increasing number of application cycles, the amount of polymer-incorporated Lewis acid required to induce the same degree of enantioselectivity, decreased; the degrees of diastereo-and enantioselectivity were, again, comparable to those reported for homogeneous conditions (Fig. 9).

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