Bruno Schönecker

A nickelacycle as propionic acid equivalent for carbon-carbon coupling reactions; application to the synthesis of C25 steroid carboxylic acids

β-Substituted propionic acids are prepared in good yields by carbon-carbon coupling reaction of the nickelacycle 1 with organic iodides and anhydrous manganese(II) iodide. This new reaction is used to the synthesis of C25 steroid carboxylic acids from C22 steroid iodides.

Novel (N-Ferrocenylmethyl)amines and (N-Ferrocenylmethylen)imines derived from vicinal steroid amino alcohols and amines: synthesis, molecular structure, and biological activity

Novel steroidal (N-ferrocenylmethyl)amines with potential biologic activity and of potential interest as chiral ligands for metal complexation were synthesized. The new compounds were screened in vitro for their potential as antimicrobial agents. The synthesis of the new steroidal ferrocenes, including two X-ray crystal structures and biologic assays, are described. The 16-(ferrocenylmethyl)amino-estratrienes 4a-d, 7b, and 10b exhibited outstanding broad antimicrobial activity particularly against mycobacteria and multi-resistant staphylococci. Thus, they can be considered as new lead structures. In contrast, the analogous 3 alpha-(ferrocenylmethyl)amino-cholestanes 12 possessed only weak activity. The reaction of the four isomeric amino alcohols 1a-d (Scheme 1) with ferrocenecarbaldehyde was studied. 1b and 1c with 16/17-trans configuration yielded nearly quantitatively the (E)-Schiff bases 2b and 2c (Scheme 2). In contrast to the trans-compounds, condensation of the cisconfigurated amino alcohols 1a and 1d furnished tautomeric mixtures of the Schiff bases (2a and 2d, respectively) and their corresponding 1,3-oxazolidines (3a and 3d, respectively). The novel (N-ferrocenylmethyl)amines 4a-d were obtained in excellent yields by reduction of the tautomer mixtures and the uniform Schiff bases with sodium borohydride in ethanol. Starting with the 16 beta-hydroxy compound 5a, the synthesis of 16 beta- and 16 alpha-amino-3-methoxy-estra-1,3,5(10)-triene (6b, 9b) is described. The corresponding 16-(N-ferrocenylmethyl)amines 7b and 10b and the 3 alpha-(N-ferrocenylmethyl)amino-cholestanes 12 were synthesized (Scheme 3) for comparison in biologic tests.

O-Silylated steroidal cis-aminoalcohols as chiral auxiliaries: highly diastereoselective Pd-catalyzed cyclopropanation of α,β-unsaturated aldimines

Abstract α,β-Unsaturated imines, obtained from cis -17-silyloxy-16-amino steroids and α,β-unsaturated aldehydes, react with diazomethane in the presence of a catalytic amount of Pd(OAc) 2 with high chemo- and diastereoselectivities to form steroidal cyclopropanocarbaldimines; chromatography on silica gel gives the substituted cyclopropanocarbaldehydes with a high enantiomeric excess and allows recovery of the chiral steroidal auxiliaries.

The Stereoselective Ru3(CO)12-Catalyzed Synthesis of Steroidal 1,3-Dihydropyrrol-2-one Derivatives from α,β-Unsaturated Imines, Carbon Monoxide and Ethylene

The reaction of α,β-unsaturated imines, derived from steroidal amines and cinnamaldehyde, with carbon monoxide and ethylene leads to the formation of steroids with a 1,3-dihydropyrrol-2-one ring system attached to the D-ring of the steroid. In addition, a new stereogenic center at C-3 of the pyrrolone ring is produced during the reaction sequence. In the case of a 16-position of the imine moiety the yields are nearly quantitative but the diastereoselectivity is low whereas the sterically more hindered 17-position shows a decreased reactivity but quite good diastereoselectivities. Complete diastereoselectivity is achieved if the starting compound exhibits an additional silyl ether group in the 17β-position besides the imine subunit in the 16β-position. The compound bearing the pyrrolone substituent at 17β-position was characterized by means of X-ray crystallography showing that the rotation of the pyrrolone ring is hindered by a strong intramolecular hydrogen bond between the carbonyl oxygen of the pyrrolone moiety and the hydrogen at C-17. The question of whether this intramolecular hydrogen bond is also responsible for the observed diastereoselectivities is discussed.

Synthesis of N,N-bis[2-(2-pyridyl)ethyl]amino steroids and related compounds intended as chiral ligands for copper ions

Abstract Compounds with the N , N -bis[2-(2-pyridyl)ethyl]amino structure (RPY2) are useful tridentate ligands for copper(I) ions, which can bind and activate oxygen from the atmosphere. For diastereoselective and enantioselective oxidation reactions, hitherto unknown chiral ligands possessing tripodal structures have been synthesized starting from homochiral steroids. The double Michael addition of primary steroidal amines and aminoalcohols to 2-vinyl pyridine was not very succesful. However, homochiral bidentate ligands with N- [2-(2-pyridyl)ethyl]amino steroid structure could be obtained by this procedure in most cases. New routes (acylation of the bidentate ligands with 2-pyridylacetic acid followed by BH 3 ·THF reduction, or reductive amination of steroidal ketones, acylation and borane reduction) to the desired tridentate RPY2, also at sterically hindered positions, are described. In the last reaction sequence, ‘mixed’ tridentate ligands can also be obtained. Copper complexation and oxygen activation with these ligands are briefly discussed.

Reactions of the four diastereomeric 16-amino-17-hydroxy-3-methoxy-estra-1,3,5(10)-trienes with aromatic ortho-hydroxy and heteroaromatic α-aldehydes and with 1,3-dicarbonyl compounds—molecular structures of condensation products and of copper(II) complexes ☆

Vicinal amino alcohols of steroids have been used as starting materials for the synthesis of chiral ligands with defined arrangements of functional groups. Condensation of the four diastereomeric 16,17-steroid amino alcohols 1a-1d with aromatic o-hydroxy and heteroaromatic alpha-aldehydes afforded the Schiff bases 2-6. When the 16,17-substituted compounds 2d, 5d, 6a, and 6d were in solution, the isomeric oxazolidines were detectable by (1)H NMR spectroscopy. The formation of oxazolidines could be avoided by using bulky aldehydes. Reduction of the Schiff bases (also in mixtures with oxazolidines) with NaBH(4) yielded the new N-substituted amino alcohols 12-15. The condensation products of 1a-1d with 1,3-dicarbonyl compounds (7 and 8) exhibited the 1-enamino-3-oxo structure ((1)H NMR spectroscopy). By means of X-ray analysis of 2a-2d, 3d, 7a, and 7c, the torsion angles for the 16N, 17O substituents, which are important for a participation of the 17O substituent in the complexation of metal ions, have been determined. Furthermore, a preferred arrangement between the chelate ring and the steroid plane existed in all investigated condensation products attributable to torsion angles 16H-C16-16N-C of 5-61 degrees. This arrangement was also preserved in the copper(II) complex 11 with 16alpha,17beta-trans configuration of the bidentate steroid ligand and a ratio of 2:1 for ligand: copper in contrast with dimeric copper(II) complexes with a tridentate steroid ligand of 16beta, 17beta-cis configuration (ratio of 1:1 for ligand:copper). The crystal structures of the condensation products are also discussed. In most cases, intermolecular hydrogen bonds between 17-hydroxy groups and the chelate oxygen caused polymeric strands.

Steroid imines as chiral ligands. Diastereoselective formation of (1-azadiene)Fe(CO)3 complexes by sterically tuning the ligand coordination spheres

Abstract The condensation of steroid amines with α,β-unsaturated aldehydes leads to the formation of chiral 1-azadiene ligands with a steroid core attached to nitrogen. If the azadiene chain is situated at the D-ring of the steroid at C 16 or C 17 , respectively, the two diastereotopic faces of the ligand may be discriminated by different neighbouring substituents and their configuration. The reaction of these ligands with Fe 2 (CO) 9 produces mixtures of diastereomeric (1-azadiene)Fe(CO) 3 complexes. By increasing the steric demands of the neighbouring groups it is possible to improve the diastereoselectivity of this complexation reaction from 1:1 mixtures using the least sterically hindered ligands to complete diastereoselectivity using the azadiene derived from cinnamaldehyde and 16β-amino-3-methoxy-estra-1,3,5(10)-triene-17β-ol. In addition, the molecular structure of [17β-(3-phenyl-prop-2-enyliden)-amino-3-methoxy-estra-1,3,5(10)-triene]Fe(CO) 3 was determined by X-ray structure analysis.

CO2 als synthesebaustein: Seitenkettenaufbau von steroid-17β-pentensäuren via oxidative kopplung von CO2 mit einem steroiddien an nickel(0)-verbindungen

Abstract The 2-substituted steroidal butadienes 2, obtained from the aldehydes 1 by Wittig reaction, react smoothly with (bipy)Ni(COD) and CO2 to give the nickelalactones 3 in high yields. Protonation and esterification of 3a gives the 4-substituted methyl 3-pentenoate 4a. Ultrasound-activated cross coupling of 3a with cyclohexyliodide gives the 4-substituted 5-cyclohexyl-3-pentenoic acid 5a. These results demonstrate the synthetic potential of the metalla-ring closure reaction between CO2 and dienes at nickel(0): the regioselectivity is high and strongly depends on the steric hindrance of the 2-substituent, and reactive functional groups (OH, COOR) are tolerated.

“Reversed-phase”-dünnschichtchromatographie von steroiden : I. Bestimmung und interpretation von RM-werten

Abstract Reversed-phased thin-layer chromatography of sterioids. I. Measurement and interpretation of R M values. R M values of about one hundred steroids with hetero substituents have been measured, using reversed-phase thin-layer chromatography. Silica gel (PF 254 )-silanised served as the stationary non-polar phase and acetone in various mixtures with water as the mobile polar phase. The Δ R M values of substituents have been calculated and correlated with different parameters of hydrophobicity (π ar, π al, V I ). Neighbouring effects were investigated.

Synthesis, structure and catechol-oxidase activity of copper(II) complexes of 17-hydroxy-16-(N-3-oxo-prop-1-enyl)amino steroids

Copper is next to iron the most important element in the biological transport, storage and in redox reactions of dioxygen. A bioanalogous activation of dioxygen with copper complexes is used for catalytical epoxidation, allylic hydroxylation and oxidative coupling of aromatic substrates, for example. With stereochemical information in form of chiral ligands, enantioselective reactions may be possible. Another aspect of interest on copper catalyzed reactions with dioxygen is that the exact mechanism and biological function of some enzymes (especially catechol oxidase) is yet not fully clear. For studies mimicking the copper-containing catechol oxidase appropriate chiral steroid ligands with defined stereochemistry and conformation have been synthesized. The four diastereomeric 16,17-aminoalcohols of the 3-methoxy-estra-1,3,5(10)-triene series have been condensed with salicylic aldehyde and different beta-ketoenols to the chiral ligand types 1-5. These compounds with different steric and electronic properties and different arrangements of the neighboring hydroxy and nitrogen functions were reacted with copper(II) acetate to copper complexes. The structure of these complexes will be discussed. The bioanalogous oxidation of 3,5-di-tbutyl-catechol (dtbc) to the corresponding quinone was catalyzed by most of the complexes, indicating their ability to activate dioxygen. The trans configurations c and d showed an activity one magnitude higher than the cis configurations a and b. Comparing compounds with the same diastereomeric configuration, the main influence was that of the peripheral R(1-3) substituents at the beta-ketoenaminic group which are useful for the fine-tuning of the properties of the copper atoms like redox potential and Lewis acidity.