Diastereoselective Reduction of a Chiral <i>N</i>-Boc-Protected δ-Amino-α,β-unsaturated γ-Keto Ester Phe-Gly Dipeptidomimetic

Våbenø, Jon; Brisander, Magnus; Lejon, Tore; Luthman, Kristina

doi:10.1021/jo020442o

Cited by 48 publications

(42 citation statements)

References 35 publications

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“…18 In short, ketomethylene derivative 5 14 was first diastereoselectively reduced to the respective alcohol, followed by protective group manipulations and separation of diastereomeric mixtures. Diastereoselective reduction of ketomethylene derivative 5 14 was performed using conditions guided by the work of Hoffman et al 19 and Våbenø et al 20 (Scheme 1). Treatment of 5 with LiAlH(O-tBu) 3 in EtOH 19,20 gave alcohol 6 in 75% yield and with an excellent diastereomeric ratio (dr) 4S : 4R of 1 : 99 according to 1 H NMR analysis.…”

Section: Synthesismentioning

confidence: 99%

Hydroxyethylene isosteres introduced in type II collagen fragments substantially alter the structure and dynamics of class II MHC A^q/glycopeptide complexes

et al. 2015

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Class II major histocompatibility complex (MHC) proteins are involved in initiation of immune responses to foreign antigens via presentation of peptides to receptors of CD4(+) T-cells. An analogous presentation of self-peptides may lead to autoimmune diseases, such as rheumatoid arthritis (RA). The glycopeptide fragment CII259-273, derived from type II collagen, is presented by A(q) MHCII molecules in the mouse and has a key role in development of collagen induced arthritis (CIA), a validated model for RA. We have introduced hydroxyethylene amide bond isosteres at the Ala(261)-Gly(262) position of CII259-273. Biological evaluation showed that A(q) binding and T cell recognition were dramatically reduced for the modified glycopeptides, although static models predicted similar binding modes as the native type II collagen fragment. Molecular dynamics (MD) simulations demonstrated that introduction of the hydroxyethylene isosteres disturbed the entire hydrogen bond network between the glycopeptides and A(q). As a consequence the hydroxyethylene isosteric glycopeptides were prone to dissociation from A(q) and unfolding of the β1-helix. Thus, the isostere induced adjustment of the hydrogen bond network altered the structure and dynamics of A(q)/glycopeptide complexes leading to the loss of A(q) affinity and subsequent T cell response.

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Section: Synthesismentioning

confidence: 99%

Hydroxyethylene isosteres introduced in type II collagen fragments substantially alter the structure and dynamics of class II MHC A^q/glycopeptide complexes

et al. 2015

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“…A similar situation has also been observed in other allylic alcohols derived from phenylalanine. 35 From the chemical shift of this diagnostic proton it was thus possible to assign the S,R and S,S configurations to the major and minor isomers of alcohols 17a,b, respectively. …”

Section: S2mentioning

confidence: 99%

“…Alternatively, the same result could be explained with a Felkin-Anh model in which NHBoc is the medium group and benzyl is the large group 32 ( Figure 4b). Based on calculations of the volume of the two groups, it has been recently suggested that NHBoc is larger than benzyl; 35 however, the bulky t-butyl group of NHBoc is four bonds away from the reaction center, to which it is connected by a linear, and relatively small, array of atoms. Thus the effectiveness of NHBoc in shielding the carbonyl from attack by the nucleophile may be overestimated by these calculations.…”

Section: Scheme 2 Synthesis Of Epoxyalcohol Inhibitorsmentioning

confidence: 99%

Design, synthesis and preliminary evaluation of peptidomimetic inhibitors of HIV aspartic protease with an epoxyalcohol core

Benedetti¹,

Berti²,

Miertuš³

et al. 2003

Arkivoc

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Two peptidomimetic inhibitors based on a novel epoxyalcohol core were designed to target the epoxide ring at the catalytic aspartates of HIV-protease for irreversible inhibition of the enzyme. The inhibitors were synthesized with a multi-step approach which includes Horner-Emmons olefination of a phenylalanine-derived phosphono ketone, stereoselective reduction of the resulting trans-enones to allylic alcohols and syn-epoxidation of the latters. The epoxyalcohols thus obtained were assayed for their ability to inhibit HIV-PR and were shown to inhibit the protease with IC 50 values of 39 and 150 µM, respectively. This confirms that the designed epoxides are recognised with fairly good affinity by the enzyme's active site, a pre-requisite for selective irreversible inhibition.

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“…Conversion of the ketone to the hydroxy group via selective reduction to either of the two diastereoisomers is easily achieved according to literature procedures. [15,16] While coupling reactions of the type described above proved to be successful with a variety of amino acids, they were limited only to reactions of thioesters derived from amino acids, and attempts to extend the method to other substrates were not successful. Furthermore, some amino acids also proved to be problematic, with bulky amino acid side chains, such as with valine, and N-Boc protection being poorly tolerated.…”

Section: General Introductionmentioning

confidence: 99%

Radicals by Design

Croft¹,

Lindsay²,

Renaud³

et al. 2008

Chimia

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Radical reactions offer many advantages over conventional chemical reactions, lending themselves to numerous bond forming processes and rearrangements that are, clean, rapid, and tolerant of a wide range of functional groups. This review provides a brief overview of the design concepts behind new reactions illustrating, in particular, their relevance for the efficient synthesis of biomolecules. Tw o general reactions are highlighted: single electron transfer (SET) using SmI 2 and hydrogen transfer using reagents such as those based on tin, thiols and phosphorous reagents. Intermolecular influences that may direct radical reactions, such as partial protonation and radical complexation, are also discussed.

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Diastereoselective Reduction of a Chiral N-Boc-Protected δ-Amino-α,β-unsaturated γ-Keto Ester Phe-Gly Dipeptidomimetic

Cited by 48 publications

References 35 publications

Hydroxyethylene isosteres introduced in type II collagen fragments substantially alter the structure and dynamics of class II MHC A^q/glycopeptide complexes

Hydroxyethylene isosteres introduced in type II collagen fragments substantially alter the structure and dynamics of class II MHC A^q/glycopeptide complexes

Design, synthesis and preliminary evaluation of peptidomimetic inhibitors of HIV aspartic protease with an epoxyalcohol core

Radicals by Design

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Diastereoselective Reduction of a Chiral N-Boc-Protected δ-Amino-α,β-unsaturated γ-Keto Ester Phe-Gly Dipeptidomimetic

Cited by 48 publications

References 35 publications

Hydroxyethylene isosteres introduced in type II collagen fragments substantially alter the structure and dynamics of class II MHC Aq/glycopeptide complexes

Hydroxyethylene isosteres introduced in type II collagen fragments substantially alter the structure and dynamics of class II MHC Aq/glycopeptide complexes

Design, synthesis and preliminary evaluation of peptidomimetic inhibitors of HIV aspartic protease with an epoxyalcohol core

Radicals by Design

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Product

Resources

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Hydroxyethylene isosteres introduced in type II collagen fragments substantially alter the structure and dynamics of class II MHC A^q/glycopeptide complexes

Hydroxyethylene isosteres introduced in type II collagen fragments substantially alter the structure and dynamics of class II MHC A^q/glycopeptide complexes