Hermann Künzer

Reductive desulfonylation of phenyl sulfones by samarium(II) iodide-hexamethylphosphoric triamide

Abstract Samarium(II) iodide in tetrahydrofuran reductively desulfonylates phenyl sulfones in the presence of hexamethylphosphoric triamide. This transformation is illustrated here for ten substrates, which include secondary alicyclic, β-hydroxy, vicinal bis-, and α,β-unsaturated sulfones.

Structurally diverse 2,6-disubstituted quinoline derivatives by solid-phase synthesis

Abstract 2,6-Disubstituted quinoline derivatives 12 are generated by parallel synthesis in seven steps, the last five of which proceed on a polymeric support. Variable building blocks are selected from three commercially available classes of compounds: Ω-functionalized fatty acids, aryl methyl ketones, and primary amines.

A novel, thioacetal based linker for solid-phase synthesis

Abstract Commercially available (±)-α-lipoic acid was employed as a novel, chemically robust linker for the immobilization of ketones. The utility of this thioacetal based linker in solid-phase synthesis was demonstrated by synthesizing several 4-acetylbiphenyls and 4-alkoxyacetophenones via Suzuki and Mitsunobu reactions, respectively. The products were easily cleaved from solid support by treatment with [bis(trifluoroacetoxy)iodo]benzene.

A vinyl sulfone/vinyl sulfoxide based route to C(6)–;C(7) methylene-bridged derivatives of estradiol

Abstract Acceptor substituted 3-methoxyestra-1,3,5(10),6-tetraene derivatives 3 , 4 and 5 have been prepared and exploited in a synthesis of the title compounds 13 and 15 by key Michael-type addition reactions involving dimethylsulfoxonium methylide. α-Cyclopropanation was only slightly favored on the sulfone analogue 3 but strongly so on the (R)-sulfoxide 4 . On the contrary, the (S)-sulfoxide 5 displayed a weak preference for β-face attack.

Stereocontrolled derivatization of 3-methoxyestra-1,3,5(10), n-tetraenes via lewis acid promoted prins reactions, (n=7; 8(9))

Steroidal olefins 1 and 3 undergo dimethylaluminum chloride-mediated Prins reactions with paraformaldehyde to furnish homoallylic alcohols 4 and 16 as major products. These ene reaction-type intermediates are converted into 6 and 17 by hydroxyl group-assisted catalytic hydrogenation, while Birch reduction of 4 proceeds to the 8β-epimer 11. The saturated alcohols thus obtained serve as convenient precursors to methyl derivatives 10, 14, and 20.

A novel route to 3-alkylated estra-1,3,5(10)-trienes

Abstract Nucleophilic attack by the lithium anion of acetonitrile on the diastereomeric chromium tricarbonyl complexes of 17β-(tert-butyldimethylsilyloxy)-3-methoxyestra-1,3,5(10)-triene leads to the corresponding 3-cyanomethyl complexes, useful intermediates en route to 3-alkylated estra- 1,3,5(10)-trienes.

Regioselective functionalization of 3-oxygenated estra-1,3,5(10)-trienes at C-1 via (η6-arene)Cr(CO)3 complexes

Abstract The nucleophilic addition - oxidation reaction between the lithium anion of 1,3-dithiane and a mixture of complexes 3 and 4 installs the heterocycle predominantly at C-1 of the steroid to afford 5. This intermediate is converted into C-1 substituted steroids 6–12.

An oxy-cope rearrangement approach to C(15) α-alkylated derivatives of estradiol

A stereoselective synthesis of C(15) allyl-substituted estrone derivatives 3 and 4 has been accomplished. Starting with 1 as a common precursor, 3 was made available in two steps by allylmagnesium halide addition to C(17) and subsequent oxy-Cope rearrangement, while the epimer 4 emerged from a Cu(I)-mediated 1,4-addition. The utility of intermediates 3 and 4 is highlighted in the construction of potential estrogen receptor agonists/antagonists 5, 6, and 11.

Regioselective synthesis of ring a polymethylated steroids in the androstane series

Abstract Properly protected derivatives 14 and 20 of the common precursor 17β-hydroxy-1-methyl-5α-androst-1-en-3-one ( 13 ) have been transformed in a regioselective manner into highly methylated androsta-1,4-diene-3,17-dione derivatives 6–8 . Access to the manifold of 1,4-dimethylated derivatives was gained by methylation of the kinetic lithium dienolate derived from 20 , while thiomethylation of 14 , via the thermodynamic dienolate or an equivalent, followed by Raney nickel promoted desulfurization gave rise to 28 . A combination of these alkylation methods led successfully to the trimethylated androstane derivative 34 . Benzeneseleninic anhydride (BSA) mediated dehydrogenation of intermediates 23 , 28 , and 34 then furnished the 1,4-dienes 24 , 29 , and 35 , two conventional steps short of the target molecules 6–8 . A facile synthesis of the potent aromatase inhibitors 5 by subjecting 13 to a BSA-promoted oxidation is also described.

Structure-Function Relationships in the Complexation of Steroids by a Synthetic Receptor

The complexation between the double-decker cyclophane (±)-1 and a series of 30 steroids was investigated in CD3OD by 1H-NMR titrations. The geometries of the complexes, in which the substrates are axially included in the 13-A deep and 9 A×12 A wide receptor cavity, were estimated based on the complexation-induced changes in chemical shift (CIS) of the steroidal Me group resonances. Computer modeling provided additional support for the geometries deduced from the experimental data. The log P (octanol/H2O) values of the steroids were determined experimentally by HPLC or calculated using the program CLOGP. Although steroids with a high log P form some of the most stable complexes with (±)-1, a general correlation between the thermodynamic driving force for association −ΔG0 and the partition coefficient was not observed. It can, therefore, be concluded that inclusion complexation is not only driven by the preference of the steroid to transfer from the polar solvent into the lipophilic binding cavity but also by specific host-guest interactions. A series of structure-function relationships was revealed. i) Steroids with an isoprenoidal side chain at C(17) form some of the most stable complexes (−ΔG0 up to 4.8 kcal mol−1), with side-chain encapsulation contributing as much as 1.2 kcal mol−1 to the association strength. In these complexes, the receptor is slipping in a dynamic process over both the tetracyclic core and the lipophilic side chain. ii) Pregnane derivatives, which lack the isoprenoidal side chain, are tightly encapsulated with their tetracyclic core. Upon introduction of double bonds, the core flattens, and binding affinity drops substantially. iii) The presentation of steroidal OH groups to the receptor cavity is accompanied by energetically unfavorable functional-group desolvation, which strongly reduces the host-guest binding affinity. In contrast, inclusion of steroidal carboxylate or keto groups into the cavity does not substantially change complexation strength as compared to the unsubstituted derivatives. iv) Addition of extra Me groups to the steroidal A ring does not have a large effect on the association strength; however, complex geometries may change significantly. v) Receptor (±)-1 shows a remarkably high affinity towards progesterone (−ΔG0=4.7 kcal mol−1) despite the low log P value (3.87) of this steroid. Small changes in the progesterone structure lead to large reductions in complex stability, which clearly demonstrates that the double-decker cyclophane is a selective molecular receptor.