Biomedical subjects
Publications and source records attributed to Stefan Bräse.
The synthesis of a multifunctional building block for polyketide construction and several subsequent reactions are presented.
[reaction: see text] A series of aliphatic and aromatic carbonyl compounds has been transformed into the corresponding sulfamidated products by means of amine-catalyzed nitrene transfer of chloramine-T. Depending on the residues R, either alpha-sulfamidation in the case of aromatic aldehydes and acetone derivatives or direct sulfamidation at the carbonyl functionality of aliphatic aldehydes has been observed. Applying microwave conditions, good to excellent yields under significantly reduced reaction times could be obtained, thus providing a facile access to alpha,alpha-disubstituted amino acids.
Tetrahydroxanthenones, which can be easily prepared by a domino oxa-Michael aldol condensation, offer various possibilities for diastereoselective functionalization, giving access to the stereocontrolled synthesis of stereochemical triades or tetrades, which represent privileged structural motifs. In most cases, the relative stereochemistry was unequivocally established by crystal structure analysis.
The creation of novel diverse heterocycle libraries is an indispensable requirement of modern drug discovery processes. Currently, library sizes of over 10,000 discrete compounds are viable using programmed synthesis on solid supports. This review discusses the recent advances in the automated solid-phase syntheses of heterocycles to generate libraries of bioactive products, and illustrates library sizes that have been obtained, robots used for production of libraries, points of diversity and number of steps on the resin.
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A Hartwig-Buchwald addition of a variety of chiral amines to rac-4-bromo-[2.2]paracyclophane and rac-trifluoromethanesulfonic acid (4-[2.2]paracyclophane) ester was performed with high diastereoselectivities. Kinetic racemic resolution of the starting materials was achieved, providing a rapid access to enantiomerically enriched 4-bromo-[2.2]paracyclophane and the corresponding enantiomerically pure [2.2]paracyclophane amines. Additionally, the first reaction of a secondary amine with a [2.2]paracyclophane halide was achieved.
Since the discovery of organic azides by Peter Griess more than 140 years ago, numerous syntheses of these energy-rich molecules have been developed. In more recent times in particular, completely new perspectives have been developed for their use in peptide chemistry, combinatorial chemistry, and heterocyclic synthesis. Organic azides have assumed an important position at the interface between chemistry, biology, medicine, and materials science. In this Review, the fundamental characteristics of azide chemistry and current developments are presented. The focus will be placed on cycloadditions (Huisgen reaction), aza ylide chemistry, and the synthesis of heterocycles. Further reactions such as the aza-Wittig reaction, the Sundberg rearrangement, the Staudinger ligation, the Boyer and Boyer-Aubé rearrangements, the Curtius rearrangement, the Schmidt rearrangement, and the Hemetsberger rearrangement bear witness to the versatility of modern azide chemistry.
A set of 20 novel [2.2]paracyclophane ketimines with planar and central chirality has been synthesized from enantiomerically pure and racemic 5-acyl-4-hydroxy[2.2]paracyclophane and alpha-branched chiral amines. Their X-ray structures were determined to elucidate the three-dimensional structures and the absolute configuration. The ketimines were used as catalysts in the asymmetric 1,2-addition reactions of diethylzinc with substituted benzaldehydes to furnish chiral alcohols in up to 95 % ee.
Due to their widespread biological activities and favorable pharmacokinetic properties, benzodiazepines were among the first classes of small molecules to be synthesized on solid supports. Since then, there have been numerous reports on the synthesis of similar skeletons. We have employed the T1 triazene linker to yield 1,4-benzodiazepin-5-one. Starting from various substituted triazene resins, cleavage in the presence of an azide donor, such as trimethylsilylazide, gave rise to aryl azides. Intramolecular aza-Wittig reactions produced the appropriately functionalized N-heterocycles. By using this route, the natural product deoxyvasicinone and related compounds were prepared.
The first solid-phase synthesis of benzo[1,2,3]thiadiazoles was achieved by starting from resin bound ortho bromo or iodo triazenes and using a functionalization on cleavage.
The domino-type combination of consecutive palladium-catalyzed cross-coupling reactions with subsequent pericyclic transformations offers a very fast access to various oligocyclic skeletons. This Account highlights all-intramolecular, intra-intermolecular, and all-intermolecular organopalladation cascades leading to 1,3,5-hexatrienes, which undergo consecutive 6pi-electrocyclizations with closure of three, two, or just one ring, respectively. Sequences of cross-coupling reactions and Diels-Alder additions are also discussed, as well as tricyclizations of 2-bromoenediynes giving rise to bisannelated benzene and fulvene derivatives.
Various new diazonium ions on a polymeric support that have a variety of counterions and complexation with crown ethers have been prepared, and the thermal stability of these resins over a larger temperature interval has been investigated. Nonisothermal kinetics applied to DSC data have been used predicting the lifetime of the resins.
Biaryls play an important role in modern organic chemistry. Although a large number of protocols for the synthesis of symmetrical and unsymmetrical biaryls already exist, most of them are not generally applicable. In our studies toward the total synthesis of the secalonic acids, we were interested in bis(pinacolato)diboron as a reagent for transforming haloarenes into arylboronic esters. By optimizing the reaction conditions, we were able to obtain biaryls containing various functional groups in good to excellent yields.
The combinatorial synthesis of novel biphenyl tetrazoles is described. Key steps include the simultaneous biphenyl formation and phenol deallylation under Suzuki cross-coupling conditions as well as the tetrazole ring formation on solid support. A representative library of 20 biphenyl tetrazoles was synthesized.
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Numerous developments in useful linkers are closely related with the advances in solid-phase organic synthesis. These linkers allow facile attachment functionalization and release molecules of interest. Designing a new anchoring group can be essential for synthesis success, especially for small molecules on solid supports. Many novel linkers have recently been developed. Traceless linkers can be excised efficiently and quantitatively when desired while leaving behind no trace of the solid-phase synthesis. However, multi-functional cleavage allows the introduction of new functionalities during cleavage from the resin.
With the implementation of combinatorial chemistry into the modern drug discovery process, the approach to novel diverse heterocycle libraries is an indispensable requirement. Triazenes, which are concealed diazonium salts, can be used to link functionalized arenes and amines to generate various heterocyclic structures, namely, benzoannelated nitrogen heterocycles, upon cleavage from the resin. Since triazene anchors are stable toward various reagents and perform well under a range of reaction conditions, these multifunctional linkers are well suited for automated solid-phase syntheses and the syntheses of complex organic molecules, such as natural products, on solid supports.