Stefan Bienz

Chiral silicon groups as auxiliaries for enantioselective synthesis: access to optically active silanes by biotransformation and the enantiospecific preparation of (R)-(+)-1-phenylethanol

Abstract The synthesis of the optically active alkoxymethyl-substituted acetylsilanes (+)-3 and (−)-b was achieved by the bioreduction of (±)-3 with resting cells of Trigonopsis variabilis to the diastereoisomeric alcohols (+)-4 and (+)-5. These two compounds were separated by chromatography and separately reoxidized to the desired optically active silyl ketones. As a simple example of the use of chiral alkoxymethyl-substituted silyl groups as auxiliaries for the synthesis of enantiomerically enriched silicon-free compounds, the chelate controlled 1,2-addition of phenyl lithium to (−)-3 and the stereospecific conversion of the corresponding major addition product to (R)-(+)-1-phenylethanol (+)-10 is presented.

Solid-phase synthesis of polyamine spider toxins and correlation with the natural products by HPLC-MS/MS

A recently developed new and divergent approach for the solid-phase synthesis of polyamines and polyamine derivatives was extended to the preparation of linear pentamines, and it was applied to the synthesis of three quartets of isomeric polyamine spider toxins. The twelve synthetic acylpolyamines were investigated by HPLC-UV(DAD)-MS and HPLC-UV(DAD)-MS/MS and compared with the natural products in the complex mixture of the venom of Agelenopsis aperta. The comparative investigation supported the structures and assignments of seven previously found toxins and allowed the identification of an additional five polyamine derivatives in the natural sample. The MS/MS study of the isomerically pure polyamine derivatives revealed furthermore a characteristic pattern for the fragmentation of these compounds, which can possibly be used as evidence in the trace analysis of other polyamine derivatives.

Putrescine, spermidine, spermine, and related polyamine alkaloids.

Publisher Summary This chapter discusses the chemistry, biological, and pharmacological aspects of putrescine, spermidine, spermine, and related polyamine alkaloids. Aliphatic di- and polyamines are widespread in microorganisms, plants, and animals, as conjugates to a number of different biological structures, and also in free form. They are known since; Lewenhoeck examined a linear tetra-amine derivative obtained from sperm, spermine phosphate. In addition to the almost ubiquitous spermine, and the two equally abundant compounds putrescine and spermidine, a great number of other biogenic di-, tri-, and tetra-amine compounds are known. Among these, sym -nor-spermidine, homospermidine, sym-homospennidine, and sym-homospermine are of particular relevance for this treatise because they occur together with putrescine, spermidine, and spermine as fundamental building blocks in polyamine alkaloids. For pharmacological studies, two biological properties of the polyamines and their derivatives are of significance. The first concerns the influence of polyamines on cell proliferation, which makes the polyamines and their derivatives interesting compounds for investigations in the field of neoplastic diseases. The second concerns the interactions of polyamines with ion channels and related receptors, which is interesting with regard to diseases of the central nervous system. With respect to cancer research, the biosynthetic enzymes of polyamines were considered as promising targets for chemotherapy. In particular, spermidine/spermine N 1 -acetyltransferase, the highly regulated key enzyme of polyamine degradation, represents a new target for novel antineoplastic agents. Many synthetic analogs of the natural polyamines have been tested as agents against different cancers, and in some cases the results are rather promising. The interaction of polyamines with ion channels is of central importance for neurotransmittance.

Enzymatic synthesis of enantiomerically enriched d- and l-3-silylated alanines by deracemization of dl-5-silylmethylated hydantoins

Abstract The hydantoinase process was shown to be extendable to the production of highly lipophilic, silicon-containing amino acids. Two hydantoinases of different origin and stereoselectivities and one l - N -carbamoylase were used for the highly stereoselective bioconversion of (dimethyl)phenylsilyl- and 1-methyl-1-silacyclopentyl substituted alanine derivatives. The enantiomeric purities and absolute configuration of the products were determined with reference compounds that were synthesized with the aid of the Evans oxazolidinone auxiliary.

A new approach in the solid-phase synthesis of polyamine derivatives: construction of polyamine backbones from the center

Abstract A new and divergent approach for the solid-phase synthesis of polyamines and polyamine derivatives is shown. Monoprotected diamines are coupled to the Merrifield resin and alkylated at the resin-bound benzylic amine with masked ω-aminoalkyl groups. Selective deprotection of either of the two terminal amino functions allows the specific prolongation or derivatization of the resin-bound triamines at the two ends of the molecules.

Synthesis of silicon-containing α-amino acids and hydantoins

Abstract Three new silicon-containing α-amino acids 6a-c and their respective hydantoin derivatives 8a-c have been prepared in racemic form. Alkylation of an α-amino cyanoacetate derivative with iodomethyl-substituted silanes, followed by hydrolysis gave the amino acids, and the subsequent reactions with KOCN and with HCl gave the hydantoins. The hydantoins are planned to be subjected to a biotechnological deracemization process.

The cram rule revisited once more - Revision of the Felkin-Anh model

The reaction mechanism of the LiH addition to α-chiral ketones and acylsilanes was calculated at the ab initio MP2/6-311+G**//RHF/6-31G* level. The selectivities predicted on the basis of the computed transition states and reaction barriers compare well with the experimental data. For compounds possessing very large groups, anti-Cram selectivity was found; silicon-containing compounds should show the same types of selectivity as their carbon analogs. The calculations suggest that a revision of the Felkin−Anh model is necessary and a proposal for such a revision is given. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

Synthesis of 4(benzyloxymethyl)(tert.-butyl)methylsilyloxy-1,2,3-pentatriene via Brook rearrangement

Abstract The reaction of 1-lithium-3-tetrahydropyranyloxy-1-propyne with (benzyloxymethyl)-( tert. -butyl)methylsilyl methyl ketone gave rise to the corresponding α-silylated propargylic alcoholate anion, which led in a succession of Brook rearrangement and 1,4-elimination to the title compound in good yield.

A chiral (alkoxy)methyl-substituted silicon group as an auxiliary for the stereoselective cuprate addition to α,β-unsaturated ketones: synthesis of (−)-(R)-phenyl 2-phenylpropyl ketone

Abstract The [(benzyloxy)methyl]( tert -butyl)methylsilyl group was used as the chiral auxiliary to effect highly diastereoselective conjugate additions of oranocuprates to enones. Thus, reaction of several R 2 CuLi with α-silylated α,β-unsaturated ketones afforded the respective addition products with π-face selectivities of up to 99%. Starting with an optically active substrate, enantiomerically enriched (−)-( R )-phenyl 2-phenylpropyl ketone was prepared with virtually no loss of chiral information in a reaction sequence involving cuprate addition, hydrolysis, and removal of the silicon group.

A chiral silyl ether as auxiliary for the asymmetric nucleophilic addition to α- and β-silyloxy carbonyl compounds

Chiral silicon groups, attached as protective group in proximity to a prostereogenic functionality by means of an ether linkage, can act, at least in specific cases, efficiently as stereochemical directors. The addition of Grignard reagents to α- and β-silyloxy carbonyl compounds (silyloxy is the stereogenic (Me3C)(BnOCH2)MeSiO-group) afforded the respective products with stereofacial selectivities of up to 92%. The source of the selectivities is discussed and their dependence upon structural parameters. The potential of the described principle might be increased by the structural optimization of the auxiliary group, which has not been performed yet.