Reinhold Tacke

Novel Transition‐Metal (M=Cr, Mo, W, Fe) Carbonyl Complexes with Bis(guanidinato)silicon(II) Ligands

The donor-stabilized silylene 2 (the first bis(guanidinato)silicon(II) complex) reacts with the transition-metal carbonyl complexes [M(CO)6 ] (M=Cr, Mo, W) to form the respective silylene complexes 7-10. In the reactions with [M(CO)6 ] (M=Cr, Mo, W), the bis(guanidinato)silicon(II) complex 2 behaves totally different compared with the analogous bis(amidinato)silicon(II) complex 1, which reacts with [M(CO)6 ] as a nucleophile to replace only one of the six carbonyl groups. In contrast, the reaction of 2 leads to the novel spirocyclic compounds 7-9 that contain a four-membered SiN2 C ring and a five-membered MSiN2 C ring with a MSi and MN bond (nucleophilic substitution of two carbonyl groups). Compounds 7-10 were characterized by elemental analyses (C, H, N), crystal structure analyses, and NMR spectroscopic studies in the solid state and in solution.

Neutral Six-Coordinate and Cationic Five-Coordinate Silicon(IV) Complexes with Two Bidentate Monoanionic N,S-Pyridine-2-thiolato(−) Ligands

A series of neutral six-coordinate silicon(IV) complexes (4-11) with two bidentate monoanionic N,S-pyridine-2-thiolato ligands and two monodentate ligands R(1) and R(2) was synthesized (4, R(1) = R(2) = Cl; 5, R(1) = Ph, R(2) = Cl; 6, R(1) = Ph, R(2) = F; 7, R(1) = Ph, R(2) = Br; 8, R(1) = Ph, R(2) = N3; 9, R(1) = Ph, R(2) = NCO; 10, R(1) = Ph, R(2) = NCS; 11, R(1) = Me, R(2) = Cl). In addition, the related ionic compound 12 was synthesized, which contains a cationic five-coordinate silicon(IV) complex with two bidentate monoanionic N,S-pyridine-2-thiolato ligands and one phenyl group (counterion: I(-)). Compounds 4-12 were characterized by elemental analyses, NMR spectroscopic studies in the solid state and in solution, and crystal structure analyses (except 7). These structural investigations were performed with a special emphasis on the sophisticated stereochemistry of these compounds. These experimental investigations were complemented by computational studies, including bonding analyses based on relativistic density functional theory.

Can silicon make an excellent drug even better? An in vitro and in vivo head-to-head comparison between loperamide and its silicon analogue sila-loperamide.

Loperamide (1a), an opioid receptor agonist, is in clinical use as an antidiarrheal agent. Carbon/silicon exchange (sila‐substitution) at the 4‐position of the piperidine ring of 1a (R3COH→R3SiOH) leads to sila‐loperamide (1b). Sila‐loperamide was synthesized in a multistep procedure, starting from triethoxyvinylsilane and taking advantage of the 4‐methoxyphenyl (MOP) unit as a protecting group for silicon. The in vitro and in vivo pharmacokinetic (PK) and pharmacodynamic (PD) properties of the C/Si analogues 1a and 1b were determined and compared. Despite significant differences in the in vitro PK properties of loperamide and sila‐loperamide regarding clearance, permeability, and efflux, both compounds exhibited nearly identical in vivo PK profiles. The increase in metabolic stability of the silicon compound 1b observed in vitro seems to be counterbalanced by an increase in efflux and diminished permeability compared to the parent carbon compound 1a. Overall, sila‐loperamide exhibits high unbound clearance (CLu), leading to a significant decrease in unbound concentration (Cu) and unbound area under the curve (AUCu) after oral exposure, compared to loperamide. In vitro and in vivo metabolic studies showed an altered profile of biotransformation for the silicon compound 1b, leading to the formation of a more polar and quickly cleared metabolite and preventing the formation of the silicon analogue of the neurotoxic metabolite observed for the parent carbon compound 1a. These differences can be correlated with the different chemical properties of the C/Si analogues 1a and 1b. This study provides some of the most detailed insights into the effects of a carbon/silicon switch and how this carbon/silicon exchange affects overall drug properties.

Disila-galaxolide and derivatives: synthesis and olfactory characterization of silicon-containing derivatives of the musk odorant galaxolide.

A series of silicon-containing derivatives of the polycyclic musk odorant galaxolide (4 a) was synthesized, that is, disila-galaxolide ((4RS,7SR)-4 b/(4RS,7RS)-4 b), its methylene derivative rac-9, and its nor analogue rac-10. The tricyclic title compounds with their 7,8-dihydro-6,8-disila-6 H-cyclopenta[g]isochromane skeleton were prepared in multistep syntheses by using a cobalt-catalyzed [2+2+2] cycloaddition of the mono- yne H2C=CHCH2 OCH2 C≡CB(pin) (B(pin)=4,4,5,5-tetramethyl-1,3,2-di- oxaborolan-2-yl) with the diynes H2C=C[Si(CH3 )2 C≡CH]2 or H2C- [Si(CH3)2 C≡CH]2 as the key step. Employing [Cr(CO)3 (MeCN)3 ] as an auxiliary, the disila-galaxolide diastereomers (4RS,7SR)-4 b and (4RS,7RS)-4 b could be chromatographically separated through their tricarbonylchromium(0) complexes, followed by oxidative decomplexation. The identity of the title compounds and their precursors was established by elemental analyses and multinuclear NMR spectroscopic studies and in some cases additionally by crystal structure analyses. Compounds (4RS,7SR)-4 b, (4RS,7RS)-4 b, rac-9, and rac-10 were characterized for their olfactory properties, including GC-olfactory studies of the racemic compounds on a chiral stationary phase. As for the parent galaxolide stereoisomers 4 a, only one enantiomer of the silicon compounds (4RS,7SR)-4 b, (4RS,7RS)-4 b, rac-9, and rac-10, smelt upon enantioselective GC-olfactometry, which according to the elution sequence is assumed to be also (4S)-configured as in the case of the galaxolide stereoisomers. The disila-analogues (4S,7R)-4 b and (4S,7S)-4 b were, however, about one order of magnitude less intense in terms of their odor threshold than their parent carbon compounds (4S,7R)-4 a and (4S,7S)-4 a. The introduction of a 7-methylene group in disila-galaxolide (4 b→rac-9) improved the odor threshold by a factor of two. With the novel silicon-containing galaxolide derivatives, the presumed hydrophobic bulk binding pocket of the corresponding musk receptor(s) could be characterized in more detail, which could be useful for the design of novel musk odorants with an improved environmental profile.

Si- and C-Functional Organosilicon Building Blocks for Synthesis Based on 4-Silacyclohexan-1-ones Containing the Silicon Protecting Groups MOP (4-Methoxyphenyl), DMOP (2,6-Dimethoxyphenyl), or TMOP (2,4,6-Trimethoxyphenyl)

4-Silacyclohexan-1-ones 1a-1c, 4-silacyclohexan-1-one oximes 2a-2c, 1,4-azasilepan-7-ones 3a-3c, 1,4-azasilepanes 4a-4c, and 2-bromo-4-silacyclohexan-1-ones 5a and 5b were prepared in multistep syntheses, starting from trimethoxypropylsilane. All of these compounds represent C-functional (R2C═O, R2C═N-OH, R-NH(C═O)-R, R2NH, or R3C-Br) silicon-containing heterocycles that contain Si-MOP, Si-DMOP, or Si-TMOP moieties (MOP = 4-methoxyphenyl; DMOP = 2,6-dimethoxyphenyl; TMOP = 2,4,6-trimethoxyphenyl), which can be cleaved under mild conditions by protodesilylation. As a proof of principle, compounds 3a-3c were transformed quantitatively and selectively into the chlorosilane 6 (treatment with hydrogen chloride in dichloromethane). Thus, the C- and Si-functional compounds 1a-1c, 2a-2c, 3a-3c, 4a-4c, 5a, and 5b represent versatile building blocks for synthesis.