Synthesis, Conformational Properties, and Synthetic Applications of Novel Optically Pure α,α‐Disubstituted (<i>R</i>)‐ and (<i>S</i>)‐Glycines (‘α‐Chimeras’) Combining Side Chains of Asp, Glu, Leu, Phe, Ser, and Val

Obrecht, Daniel; Abrecht, Christine; Altorfer, Michael; Bohdal, Udo; Grieder, A.; Kleber, M.; Pfyffer, Patrick; Müller, Klaus

doi:10.1002/hlca.19960790508

Cited by 41 publications

(7 citation statements)

References 34 publications

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“…A large body of other chiral C α ‐tetrasubstituted α‐amino acids (Figure 12) has been synthesized, and the conformational preference of some of their derivatives and very short peptides analyzed by experiments and/or computations 68, 221–245. However, since the examples are scattered, the model compounds are not always appropriately selected, and in general they are too short, in our view it is undoubtedly premature to extract any definitive conclusion from these studies.…”

Section: Discussionmentioning

confidence: 99%

Control of peptide conformation by the Thorpe-Ingold effect (C?-tetrasubstitution)

et al. 2001

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The preferred conformations of peptides heavily based on the currently extensively exploited achiral and chiral α‐amino acids with a quaternary α‐carbon atom, as determined by conformational energy computations, crystal‐state (x‐ray diffraction) analyses, and solution (1H‐NMR and spectroscopic) investigations, are reviewed. It is concluded that 310/α‐helical structures and the fully extended (C5) conformation are preferentially adopted by peptide sequences characterized by this family of amino acids, depending upon overall bulkiness and nature (e.g., whether acyclic or C αi ↔ C αitalici cyclized) of their side chains. The intriguing relationship between α‐carbon chirality and bend/helix handedness is also illustrated. γ‐Bends and semiextended conformations are rarely observed. Formation of β‐sheet structures is prevented. © 2002 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 60: 396–419, 2001

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Section: Discussionmentioning

confidence: 99%

Control of peptide conformation by the Thorpe-Ingold effect (C?-tetrasubstitution)

et al. 2001

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“…For instance, introduction of succinimides 1 in peptidomimetics results in a high preference for b-turn type-II/type-II' conformations. [3,4] Related N-mesyloxysuccinimides 2 behave as irreversible mechanism-based inhibitors of serine proteases. [5] Of particular value is Ranirestat (AS-3201) which is an aldose reductase inhibitor currently in the final stage of clinical phase III trials.…”

mentioning

confidence: 99%

Asymmetric Palladium(II)‐Catalyzed Cascade Reaction Giving Quaternary Amino Succinimides by 1,4‐Addition and a Nef‐Type Reaction

Weber¹,

Frey²,

Peters³

2013

Angew Chem Int Ed

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Chiral succinimides play a vital role in pharmaceutical sciences. [1] They are typically synthesized by 1,4-additions to maleimides. [1] The pharmacologically important class of quaternary a-amino succinimides-formal derivatives of aalkyl aspartic acid [2] -has received particular attention from both academic and industrial laboratories for its benefit for application in drug design (Figure 1). For instance, introduction of succinimides 1 in peptidomimetics results in a high preference for b-turn type-II/type-II' conformations. [3,4] Related N-mesyloxysuccinimides 2 behave as irreversible mechanism-based inhibitors of serine proteases. [5] Of particular value is Ranirestat (AS-3201) which is an aldose reductase inhibitor currently in the final stage of clinical phase III trials. [6,7] a-Amino succinimide 3 is a late-stage precursor in the elegant recent total syntheses of all six amathaspiramides A-F by Fukuyama et al. [8,9] Despite the value of quaternary a-aminosuccinimides, few catalytic asymmetric methods are known for a direct catalytic asymmetric access. [10] Driven by the need for efficient approaches towards Ranirestat, methods have been developed for the asymmetric amination of a-carboxylated succinimides. [7] Here we report a new cascade reaction [11] for a rapid divergent asymmetric access to quaternary succinimides 4 using very simple starting materials. This development is based on the retrosynthetic analysis depicted in Scheme 1. The quaternary stereocenter [12] should be formed by the regio-, enantio-, and diastereoselective C4 alkylation of azlactone 8, which acts as a synthetic equivalent for the d 2 /a 1 synthon 7. [13] We speculated that nitroolefins 6 might be suitable synthetic equivalents for the a 2 /d 0 synthon 5, [14] since they can act as Michael acceptors [15] and the nitro group might allow for a subsequent Nef-type reaction, [16] in which Ac 2 O and an acetate salt would be involved. [17] We have recently shown that ferrocene-based palladacycles are capable of catalyzing 1,4-additions of azlactones to enones. [18] The azlactones could also be generated in situ from a-amino acid precursors and carboxylic acid anhydrides. We thus examined racemic N-benzoyl alanine 9 a as an azlactone source in a model reaction with 2-nitrostyrene (6 a, Table 1).Scheme 2. Proposed mechanism of the title reaction and structural proof of the 1,4-adduct intermediate 10 c by X-ray analysis.Scheme 3. Confirmation of the Nef-type reactivity by formation of 15.Scheme 4. Examples of the derivatization of title compounds 4 and the X-ray crystal structure of the bicyclic oxazoline 18.

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“…Beispielsweise führt der Einbau von Succinimiden 1 in Peptidmimetika zu einer hohen Präferenz für bSchleifen mit Typ-II/-II'-Konformationen. [3,4] Verwandte NMesyloxysuccinimide 2 wirken als irreversible mechanismusbasierte Inhibitoren von Serinproteasen. [5] Von besonderem Wert ist zudem Ranirestat (AS-3201), ein Aldosereductase-Inhibitor, der sich gegenwärtig im finalen Stadium von klinischen Phase-III-Studien befindet.…”

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Asymmetrische Palladium(II)‐katalysierte Kaskadenreaktion zu quartären Aminosuccinimiden über 1,4‐Addition und eine Nef‐artige Reaktion

2013

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Synthesis, Conformational Properties, and Synthetic Applications of Novel Optically Pure α,α‐Disubstituted (R)‐ and (S)‐Glycines (‘α‐Chimeras’) Combining Side Chains of Asp, Glu, Leu, Phe, Ser, and Val

Cited by 41 publications

References 34 publications

Control of peptide conformation by the Thorpe-Ingold effect (C?-tetrasubstitution)

Control of peptide conformation by the Thorpe-Ingold effect (C?-tetrasubstitution)

Asymmetric Palladium(II)‐Catalyzed Cascade Reaction Giving Quaternary Amino Succinimides by 1,4‐Addition and a Nef‐Type Reaction

Asymmetrische Palladium(II)‐katalysierte Kaskadenreaktion zu quartären Aminosuccinimiden über 1,4‐Addition und eine Nef‐artige Reaktion

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