Peptidmimetica – maßgeschneiderte Enzyminhibitoren

Gante, Joachim

doi:10.1002/ange.19941061705

Cited by 129 publications

(23 citation statements)

References 297 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…[18] We reacted 10 a and N,N-di-tert-butyl-A C H T U N G T R E N N U N G azodicarboxylate as substrates in the presence of HB-donor catalysts (Table 2).…”

Section: Resultsmentioning

confidence: 99%

Bifunctional Hydrogen‐Bond Donors That Bear a Quinazoline or Benzothiadiazine Skeleton for Asymmetric Organocatalysis

Inokuma

Furukawa

Uno

et al. 2011

Chemistry A European J

124

View full text Add to dashboard Cite

Hydrogen-bond (HB)-donor catalysts that bear a 2-aminoquinazolin-4-(1H)-one or a 3-aminobenzothiadiazine-1,1-dioxide skeleton have been developed, and it has been shown that these catalyst motifs act similarly to other HB-donor catalysts such as thioureas. The highly enantioselective hydrazination of 1,3-dicarbonyl compounds was realized even at room temperature with up to 96% ee for 2-aminoquinazolin-4-(1H)-one-type catalysts, which were more effective than the corresponding urea and thiourea catalysts. In addition, benzothiadiazine-1,1-dioxide-type catalysts were shown to promote the isomerization of alkynoates to allenoates with high enantioselectivity. To overcome the problem that the products were obtained as mixtures with the starting alkynoates, we developed the tandem isomerization and cycloaddition of alkynoates for the synthesis of advanced chiral compounds such as bicyclo[2.2.1]heptenes and 3-alkylidene pyrrolidine without a significant loss of enantioselectivity.

show abstract

“…[18] We reacted 10 a and N,N-di-tert-butyl-A C H T U N G T R E N N U N G azodicarboxylate as substrates in the presence of HB-donor catalysts (Table 2).…”

Section: Resultsmentioning

confidence: 99%

Bifunctional Hydrogen‐Bond Donors That Bear a Quinazoline or Benzothiadiazine Skeleton for Asymmetric Organocatalysis

Inokuma

Furukawa

Uno

et al. 2011

Chemistry A European J

124

View full text Add to dashboard Cite

show abstract

“…[13] We have previously used this strategy in the mechanistic dissection of peptide-based asymmetric acylation catalysts. [14] We therefore sought to synthesize and study catalyst 9 (Scheme 4 a).…”

mentioning

confidence: 99%

Functional Analysis of an Aspartate‐Based Epoxidation Catalyst with Amide‐to‐Alkene Peptidomimetic Catalyst Analogues

2008

View full text Add to dashboard Cite

Keywordsepoxidation; peptide; asymmetric catalysis; olefin isostere; fluorine; peptidomimetic The biosynthesis of natural products that contain epoxides represents a powerful stimulus for the study of "epoxidase" enzymes. [i] Likewise, these processes have inspired a generation of science focused on small molecule catalysts that mediate selective epoxidations through a variety of mechanisms. [ii] With respect to the naturally occurring epoxidases, the mechanistic basis of O-atom transfer is often associated with the chemistry of either flavinoid cofactors, P450 enzymes containing a heme group, or chloroperoxidases that lead to stepwise ring formation. [iii] In thinking about the known biosynthetic apparatus for epoxide formation, we became curious about an alternative mode for O-atom transferone based on functional groups available in proteins, but perhaps not well-documented in the biosynthesis of epoxides. In particular, we speculated and recently showed that asparticacid-containing peptides (e.g., 1; Figure 1a) might shuttle between the side-chain carboxylic acid and the corresponding peracid (e.g., 2) creating a catalytic cycle competent for asymmetric epoxidation with turnover of the aspartate-derived catalyst. Such an approach is orthogonal to the Julia-Colonna epoxidation, a complementary peptide-based epoxidation based on a nucleophilic mechanism. [iv] Indeed, as shown in Figure 1b, this new electrophilic epoxidation catalytic cycle mediates the asymmetric epoxidation of substrates like 3 to give products like 4 with up to 92% ee. [v] Mechanistic questions abound in this catalytic system. To date, we have identified a number of relevant aspects. For example, we observed off-catalytic cycle intermediates, including catalytically inactive diacyl peroxides (6). [vi] We also showed that these off-cycle intermediates could be reinserted into the productive pathway through the action of nucleophiles such as DMAP or DMAP-N-oxide (7). On the other hand, the basis of stereochemical information transfer was not immediately clear. Indeed, the high precision delineation of the stereochemical mode of action of chiral catalysts is a critical frontier in the discipline of asymmetric catalysis, whether the catalysts are enzymes or small molecules. With this back-drop, we began a detailed study of the mode of action for catalyst 5.The conversion of 3 to 4 was originally undertaken with the hypothesis that substratecatalyst hydrogen bonding might contribute to transition state organization. [vii] Indeed, a substrate lacking obvious H-bonding capability (phenylcyclohexene) was found to undergo epoxidation with catalyst 5 with low enantioselectivity (~10% ee). Thus, we envisioned several potential loci for contacts between 3 and 5 (Figure 2a). Shown in blue is the site that

show abstract

“…Enantiopure b-branched a-amino acids [2] are highly valuable because the incorporation of the b-substituent generally imposes severe conformational restraints, thus allowing the de novo design of peptidic entities with a predetermined three-dimensional structure. [3] Because glutamic acid is the main excitatory amino acid in the central nervous system, its derivatives have attracted great interest as essential components of peptides, as well as potential signal mediators of neurotransmission. [4] The catalytic asymmetric alkylation of Schiff bases of glycine esters is one of the most reliable and straightforward synthetic routes to optically active a-amino acid derivatives.…”

mentioning

confidence: 99%

Enantiocontrolled Synthesis of β‐Branched α‐Amino Acids by Using Cu^I‐Catalyzed 1,4‐Addition of Glycine Imines to β‐Substituted gem‐Diactivated Olefins

Hernandez‐Toribio

Arrayás

Carretero

2011

Chemistry A European J

View full text Add to dashboard Cite

Peptide-based therapies are emerging at an increasingly rapid pace because peptides offer lower toxicity, show higher specificity, and demonstrate fewer toxicology issues compared with small molecule drugs.[1] Modification of these therapeutics with non-natural amino acids of desired structural complexity is instrumental to identify target-specific peptides. Enantiopure b-branched a-amino acids [2] are highly valuable because the incorporation of the b-substituent generally imposes severe conformational restraints, thus allowing the de novo design of peptidic entities with a predetermined three-dimensional structure.[3] Because glutamic acid is the main excitatory amino acid in the central nervous system, its derivatives have attracted great interest as essential components of peptides, as well as potential signal mediators of neurotransmission. [4] The catalytic asymmetric alkylation of Schiff bases of glycine esters is one of the most reliable and straightforward synthetic routes to optically active a-amino acid derivatives. [5] In particular, the asymmetric conjugate addition of glycinate imines to a,b-unsaturated carbonyl compounds [6] (mainly acrylates) is a highly versatile reaction to afford optically active glutamic acid derivatives. However, in contrast to the number of examples able to provide enantioenriched a-amino acid derivatives, the application of this methodology to the synthesis of b-substituted a-amino acids has proven frustratingly elusive. In addition to the difficulty of controlling both diastereo-and enantioselectivity in the two new contiguous stereogenic centers, a major obstacle is the much lower reactivity of b-substituted a,b-unsaturated carbonyl compounds (e.g., crotonates) compared to simple acrylates. The use of strong bases to overcome this limitation has been reported to be detrimental to enantiocontrol.[6a]In a seminal work, the group of Kobayashi recently described, to our knowledge, the only existing general precedent for the catalytic asymmetric 1,4-addition of glycine derivatives to b-substituted acrylic acid derivatives. [6b, 7] High yields and high levels of diastereo-and enantiocontrol were attained with b-alkyl-substituted substrates by using calcium complexes of chiral deprotonated bisoxazoline (Box) ligands as catalysts. In spite of these excellent results, there is room for innovation, especially with regard to the substrate scope of the electrophile component. For instance, the potential of this reaction has not been applied so far to Michael-type acceptors with aromatic substituents at the b-position (i.e., cinnamates), even though the resulting products would offer unique opportunities for further functionalization.[8] We disclose herein a catalytic enantioselective and diastereoselective method for the synthesis of b-branched a-amino acids (up to 99 % enantiomeric excess (ee) and 99:1 diastereomeric ratio (d.r.)), due to the use of the more reactive gemdiactivated olefins such as alkylidene malonates.On the basis of our previous results, which report highly enanti...

show abstract

Peptidmimetica – maßgeschneiderte Enzyminhibitoren

Cited by 129 publications

References 297 publications

Bifunctional Hydrogen‐Bond Donors That Bear a Quinazoline or Benzothiadiazine Skeleton for Asymmetric Organocatalysis

Bifunctional Hydrogen‐Bond Donors That Bear a Quinazoline or Benzothiadiazine Skeleton for Asymmetric Organocatalysis

Functional Analysis of an Aspartate‐Based Epoxidation Catalyst with Amide‐to‐Alkene Peptidomimetic Catalyst Analogues

Enantiocontrolled Synthesis of β‐Branched α‐Amino Acids by Using Cu^I‐Catalyzed 1,4‐Addition of Glycine Imines to β‐Substituted gem‐Diactivated Olefins

Contact Info

Product

Resources

About

Peptidmimetica – maßgeschneiderte Enzyminhibitoren

Cited by 129 publications

References 297 publications

Bifunctional Hydrogen‐Bond Donors That Bear a Quinazoline or Benzothiadiazine Skeleton for Asymmetric Organocatalysis

Bifunctional Hydrogen‐Bond Donors That Bear a Quinazoline or Benzothiadiazine Skeleton for Asymmetric Organocatalysis

Functional Analysis of an Aspartate‐Based Epoxidation Catalyst with Amide‐to‐Alkene Peptidomimetic Catalyst Analogues

Enantiocontrolled Synthesis of β‐Branched α‐Amino Acids by Using CuI‐Catalyzed 1,4‐Addition of Glycine Imines to β‐Substituted gem‐Diactivated Olefins

Contact Info

Product

Resources

About

Enantiocontrolled Synthesis of β‐Branched α‐Amino Acids by Using Cu^I‐Catalyzed 1,4‐Addition of Glycine Imines to β‐Substituted gem‐Diactivated Olefins