First Synthesis of a β²-Homoamino Acid by Enantioselective Catalysis

The enantioselective conjugate addition of diethylzinc to the activated nitroolefin methyl 3-nitropropenoate is efficiently catalyzed by copper(I) complexes with BINOL-based enantiopure phosphoramidite ligands. The nitroolefin moiety acts as the predominant Michael acceptor, giving rise to the unambiguous formation of 2-alkyl-3-nitro-propanoates. Moderate to excellent enantioselectivities and high chemical yields are obtained. The product can easily be transformed into a β2-homoamino acid

DataSheet1_Synthesis and Evaluation of a Non-Peptide Small-Molecule Drug Conjugate Targeting Integrin αVβ3.pdf

An integrin αVβ3-targeting linear RGD mimetic containing a small-molecule drug conjugate (SMDC) was synthesized by combining the antimitotic agent monomethyl auristatin E (MMAE), an enzymatically cleavable Val-Ala-PABC linker with a linear conjugable RGD mimetic. The structure proposal for the conjugable RGD mimetic was suggested upon the DAD mapping analysis of a previously synthesized small-molecule RGD mimetic array based on a tyrosine scaffold. Therefore, a diversifying strategy was developed as well as a novel method for the partial hydrogenation of pyrimidines in the presence of the hydrogenolytically cleavable Cbz group. The small-molecule RGD mimetics were evaluated in an ELISA-like assay, and the structural relationships were analyzed by DAD mapping revealing activity differences induced by structural changes as visualized in dependence on special structural motifs. This provided a lead structure for generation of an SMDC containing the antimitotic drug MMAE. The resulting SMDC containing a linear RGD mimetic was tested in a cell adhesion and an in vitro cell viability assay in comparison to reference SMDCs containing cRGDfK or cRADfK as the homing device. The linear RGD SMDC and the cRGDfK SMDC inhibited adhesion of αVβ3-positive WM115 cells to vitronectin with IC50 values in the low µM range, while no effect was observed for the αVβ3-negative M21-L cell line. The cRADfK SMDC used as a negative control was about 30-fold less active in the cell adhesion assay than the cRGDfK SMDC. Conversely, both the linear RGD SMDC and the cRGDfK SMDC are about 55-fold less cytotoxic than MMAE against the αVβ3-positive WM115 cell line with IC50 values in the nM range, while the cRADfK SMDC is 150-fold less cytotoxic than MMAE. Hence, integrin binding also influences the antiproliferative activity giving a targeting index of 2.8.</p

6‑Alkynyl- and 6‑Aryl-Substituted (<i>R</i>)‑Pipecolic Acid Derivatives

(R)-α-Aminoadipic acid is a readily available enantiomerically pure starting material for the synthesis of (R)-pipecolic acid and its derivatives. Sonogashira or Suzuki cross-coupling reactions of an N-formyl pipecolate-derived vinyl bromide furnish 6-alkynyl or aryl derivatives. Reduction with sodium cyanoborohydride and subsequent N-deformylation provide 6-alkynyl substituted (R)-pipecolic acid derivatives, valuable building blocks for amino acid and peptide chemistry

Conjugate Addition of Mixed Diorganozinc Compounds and Functionalized Organozinc Cuprates to Nitroolefins

The copper-catalyzed conjugate addition of symmetrical and mixed diorganozinc compounds as well as functionalized diorganozinc cuprates to nitroolefins leads to synthetically versatile nitro compounds in moderate to good yields. Mixed TMSM-organozinc compounds are suitable reagents for conjugate addition, since the TMSM group is not being transferred. Ipso substitution is observed in the absence of a catalytic amount of copper(I) salt. The nitroalkene moiety in 3-nitroacrylates proved to be the predominant Michael acceptor

One-Pot Azidochlorination of Glycals

A simple one-pot azidochlorination for the preparation of nitrogen-containing Koenigs−Knorr glycosyl donors proceeds upon reaction of protected glycals with sodium azide, ferric chloride, and hydrogen peroxide. Different mono- and disaccharide galactals and glucals are converted in a highly α-selective manner to the 2-azido glycosyl chlorides. Starting from disaccharide galactals, building blocks for the synthesis of the T-antigen are obtained in a straightforward manner. The simplicity of the reaction conditions allows for an efficient and scalable α-selective synthesis of 2-azido substituted glycosyl chlorides

New flavonoids from the stem bark of <i>Erythrina caffra</i> Thunb.

<div><p>Three new flavonoids 5,7-dihydroxy-2′,4′-dimethoxy-5′-formylisoflavanone (<i>erycaffra</i> E) (<b>1</b>), 5,7-dihydroxy-3′-(2″-hydroxy-3″-methylbut-3-enyl)-5′-(3‴-hydroxy-3‴-methyl-<i>trans</i>-but-1-enyl)-4′-methoxyflavanone (<i>erycaffra</i> D) (<b>2</b>) and 5,7-dihydroxy-4′-methoxy-3′,5′-di-(3″-hydroxy-3″-methyl-<i>trans</i>-but-1-enyl)flavanone (<i>erycaffra</i> F) (<b>3</b>) were isolated from the stem bark of <i>Erythrina caffra</i> along with four known compounds, namely 5,4′-dihydroxy-6-(3″-methylbut-2″-enyl)-5‴-hydroxyisopropyldihydrofurano[2‴,3‴:7,8]isoflavone (isosenegalensein) (<b>4</b>), 5,7-dihydroxy-4′-methoxy-3′-(3″-methylbut-2-enyl)-5′-(3‴-hydroxy-3‴-methylbut-1-enyl)flavanone (burttinone) (<b>5</b>), 5,4′-dihydroxy-5″-hydroxyisopropyldihydrofurano[2‴,3‴:7,6]isoflavone (erythrinin C) (<b>6</b>) and 5,4′-dihydroxy-6″-hydroxymethyl-6″-methylpyrano[2″,3″:6,7]isoflavone (erysubin B) (<b>7</b>). The structures were determined on the basis of spectroscopic data (1D, 2D NMR and MS) and by comparison with literature values.</p></div

Are β-Amino Acids γ-Turn Mimetics? Exploring A New Design Principle for Bioactive Cyclopeptides

Are β-Amino Acids γ-Turn Mimetics? Exploring A New Design Principle for Bioactive Cyclopeptide

Approaches for the Synthesis of Functionalized Cryptophycins

The first syntheses of bioactive cryptophycins functionalized at unit D were accomplished in a one-pot Staudinger reduction/cyclization step. An azido precursor for the lower part of the backbone was introduced to minimize protective group chemistry and enable a very convenient synthesis of cryptophycin-52 and unit D cryptophycin analogues containing an ester or a free carboxylic acid for bioconjugations. Both new cryptophycin derivatives show high biological activity in cytotoxicity assays

“Clicktophycin-52”: A Bioactive Cryptophycin-52 Triazole Analogue

An endocyclic trans-amide linkage within the macrocyclic antitumor agent cryptophycin-52 was replaced by a 1,4-disubstituted 1H-1,2,3-triazole ring. Macrocyclisation of the triazole analogue was accomplished by macrolactamization as well as by Cu(I)-mediated “click”-cyclization. Compared to cryptophycin-52, in vitro cytotoxicity of “clicktophycin-52” against the multidrug resistant human cancer cell line KB-V1 is only slightly reduced

Short and Efficient Synthesis of Cryptophycin Unit A

Two short synthetic approaches toward cryptophycin unit A comprise a catalytic asymmetric dihydroxylation as the sole source of chirality, while all further stereogenic centers are introduced under substrate control. The key step of the first route is a vinylogous Mukaiyama aldol addition, which introduces the α,β-unsaturated ester moiety with defined configuration at the δ-carbon atom. Likewise, allylation with allyltributylstannane diastereoselectively gives the homoallylic alcohol that can be converted by a metathesis reaction to a unit A precursor