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Alexander Deiters

Publications and source records attributed to Alexander Deiters.

15 recordsLinked to original sources
PubMed2006

General strategy for the syntheses of corynanthe, tacaman, and oxindole alkaloids.

We report herein the total synthesis of the corynanthe alkaloid dihydrocorynantheol and the formal syntheses of the indole alkaloids tacamonine, rhynchophylline, and hirsutine. The strategies for assembling the corynanthe and tacaman skeletal frameworks comprised of both the classical ABD --> ABCD and ABC --> ABCD approaches wherein the variously substituted piperidinone D-rings were formed via ring-closing metathesis (RCM) followed by a 1,4-addition to introduce the requisite side chain at C(15). Since 1,4-additions to alpha,beta-unsaturated lactams represent an underdeveloped field, we conducted a series of studies with two unsaturated lactams employing organocuprates and metal enolates as the nucleophiles. These studies revealed that organocuprates derived from Grignard reagents and either stoichiometric amounts of CuCN or catalytic amounts of CuBr.DMS complex are excellent nucleophiles for such additions; TMSCl was a crucial additive for optimizing these reactions. The anion derived from ethyl 1,3-dithiolane-2-carboxylate was also an excellent nucleophile in these 1,4-additions, although the stereochemistry of such 1,4-additions to carboline-derived, unsaturated lactams was sensitive to substitution on the indole nitrogen atom. The ABD --> ABCD approach to these alkaloids featured a novel one-pot sequence of an RCM reaction and a zirconocene-catalyzed carbomagnesation followed by a second RCM to generate the D-ring.

Alkaloids↗
PubMed2006

Solid-supported [2+2+2] cyclotrimerizations.

The transition-metal-catalyzed [2+2+2] cyclotrimerization of a diyne and an alkyne provides a convergent route to highly-substituted aromatic rings. This reaction possesses distinct drawbacks, especially low chemo- and regioselectivities, which hamper its application in combinatorial synthesis. These problems have been solved by the development of solid-supported [2+2+2]-cycloaddition reactions. If conducted on a solid-support, this reaction enables rapid combinatorial access to diverse sets of carbo- and heterocyclic small-molecule arrays. The scope of this methodology has been investigated by examining different immobilization strategies, different diyne precursors, and a variety of functionalized alkyne reaction partners. Overall, isoindoline, phthalan, and indan libraries were assembled in good to excellent yields and with high purities.

Journal Article↗
PubMed2006

A genetically encoded fluorescent amino acid.

The ability to introduce fluorophores selectively into proteins provides a powerful tool to study protein structure, dynamics, localization, and biomolecular interactions both in vitro and in vivo. Here, we report a strategy for the selective and efficient biosynthetic incorporation of a low-molecular-weight fluorophore into proteins at defined sites. The fluorescent amino acid 2-amino-3-(5-(dimethylamino)naphthalene-1-sulfonamide)propanoic acid (dansylalanine) was genetically encoded in Saccharomyces cerevisiae by using an amber nonsense codon and corresponding orthogonal tRNA/aminoacyl-tRNA synthetase pair. This environmentally sensitive fluorophore was selectively introduced into human superoxide dismutase and used to monitor unfolding of the protein in the presence of guanidinium chloride. The strategy described here should be applicable to a number of different fluorophores in both prokaryotic and eukaryotic organisms, and it should facilitate both biochemical and cellular studies of protein structure and function.

Alanine↗
PubMed2006

Photochemical hammerhead ribozyme activation.

We report the light-activation of allosteric cis and trans acting ribozymes via decaging of a small organic molecule ligand. To achieve this effectively, we introduce an optimized N-caging group based on a nitrobenzyl core structure. This approach can potentially be employed toward a light-induced control of gene function.

Base Sequence↗
PubMed2005

In vivo incorporation of an alkyne into proteins in Escherichia coli.

Using a genetic selection we identified mutants of the M. janaschii tyrosyl-tRNA synthetase that selectively charge an amber suppressor tRNA with para-propargyloxyphenylalanine in Escherichia coli. These evolved tRNA-synthetase pairs were used to site-specifically incorporate an alkynyl group into a protein, which was subsequently conjugated with fluorescent dyes by a [3+2]-cycloaddition reaction under mild reaction conditions.

Alkynes↗
PubMed2004

Site-specific PEGylation of proteins containing unnatural amino acids.

Here, we report a generally applicable PEGylation methodology based on the site-specific incorporation of para-azidophenylalanine into proteins in yeast. The azido group was used in a mild [3+2] cycloaddition reaction with an alkyne derivatized PEG reagent to afford selectively PEGylated protein. This strategy should be useful for the generation of selectively PEGylated proteins for therapeutic applications.

Amino Acids↗
PubMed2004

A genetically encoded photocaged amino acid.

We have developed a second orthogonal tRNA/synthetase pair for use in yeast based on the Escherichia coli tRNALeu/leucyl tRNA-synthetase pair. Using a novel genetic selection, we have identified a series of synthetase mutants that selectively charge the amber suppresor tRNA with the C8 amino acid, alpha-aminocaprylic acid, and the photocaged amino acid, o-nitrobenzyl cysteine, allowing them to be inserted into proteins in yeast in response to the amber nonsense codon, TAG.

Base Sequence↗
PubMed2003

Adding amino acids with novel reactivity to the genetic code of Saccharomyces cerevisiae.

Using a novel genetic selection, we have identified a series of mutants of the E. coli tyrosyl-tRNA synthetase that selectively charge an amber suppressor tRNA with p-(propargyloxy)phenylalanine and p-azidophenylalanine in yeast. These evolved tRNA-synthetase pairs can be used to site-specifically label proteins with functional groups orthogonal to normal biological chemistries. As an example, we have shown that proteins containing these amino acids can be efficiently bioconjugated with small organic molecules by a [3 + 2] cycloaddition reaction that is mild enough for the manipulation of biological samples.

Acetylene↗
PubMed2003

Biomimetic entry to the sarpagan family of indole alkaloids: total synthesis of +-geissoschizine and +-N-methylvellosimine.

A concise synthesis of (+)-geissoschizine (1), a biosynthetic precursor of a variety of monoterpenoid indole alkaloids, from d-tryptophan (19) was performed as a critical prelude to achieving the first biomimetic, enantioselective synthesis of the sarpagine alkaloid (+)-N(a)-methylvellosimine (5). The approach to (+)-geissoschizine was designed to address the dual problems of stereocontrolled formation of the E-ethylidene moiety and the correct relative configuration at C(3) and C(15). Key steps in the synthesis involve a vinylogous Mannich reaction to prepare the carboline 22, which has the absolute stereochemistry at C(3) corresponding to that in 1 and 5, and an intramolecular Michael addition that leads to the tetracyclic corynantheane derivative 24, which possesses the correct stereochemical relationship between C(3) and C(15). Compound 24 was then transformed into 27, the pivotal intermediate in the syntheses of 1 and 5, by a sequence that allowed the stereospecific introduction of the E-ethylidene moiety. Selective reduction of the lactam in 27 followed by removal of the C(5) carboxyl group by radical decarbonylation gave deformylgeissoschizine (2) that was converted into (+)-geissoschizine (1) by formylation. The common intermediate 27 was then converted via a straightforward sequence of reactions into the alpha-amino nitrile 39. The derived silyl enol ether 40 underwent ionization upon exposure to BF(3).OEt(2) to give the intermediate iminium ion 41 that then cyclized in a biomimetically inspired intramolecular Mannich reaction to deliver (+)-N(a)-methylvellosimine (5). This transformation provides experimental support for the involvement of such a cyclization as one of the key steps in the biosynthesis of the sarpagine and ajmaline alkaloids.

Biomimetic Materials↗
PubMed2002

Stereoselective total synthesis of dihydrocorynantheol.

[reaction: see text] A stereoselective synthesis of the indole alkaloid dihydrocorynantheol (1) from indole-3-acetic acid has been achieved by a sequence involving 9 as a key intermediate. The synthesis of the unsaturated lactam ring in 9 highlights a series of catalytic organometallic reactions featuring two ring-closing metatheses and a zirconocene-catalyzed carbomagnesation. Since no protecting groups were used, the present synthesis of 1 is exceedingly concise, consisting of only eight distinct operations.

Alkaloids↗
PubMed2002

Planar-chiral (2E,7Z)- and (2Z,7E)-cyclonona-2,7-dien-1-yl carbamates by asymmetric, bis-allyic, alpha, alpha'-cycloalkylation--studies on their conformational stability.

Enantiomerically enriched (>80 % ee) (M,1R,2Z,7E)- and (M,1R,2E,7Z)-cyclonona-2,7-dienyl carbamates have been synthesized by an intramolecular cycloalkylation of the corresponding 1-lithio-9-chloronona-2,7-dienyl carbamates. The enantioenriched precursors were generated by asymmetric deprotonation of the dienyl carbamates by means of n-BuLi/(-)-sparteine. The primarily obtained cyclononadienes, each bearing one element of planar and centre chirality, were formed by an , coupling of both allylic moieties. These are the thermodynamically less favoured epimers, which arise from those allyllithiums bearing the carbamoyloxy residue in a 1-endo position. Both (M,R)-cyclononadienes epimerize slowly (t(1/2) = 209 min and 328 min at 308 K) with inversion of the planar chirality to the corresponding, more stable (P)-epimers (ratios 3:97 and 30:70). The kinetics were measured by 1H NMR spectroscopy, the activation energies EA were found to be 26.4 and 27.5 kcal mol(-1). From quantum-chemical calculations with the B3LYP density functional, the epimerization process was shown to consist of two coupled major conformational changes with high energy barriers. The calculated values match well with the observed ones.

Journal Article↗