Vitamin D receptor (VDR) antagonist has attracted significant level of interests because of its potential utility in the treatment of Paget's disease, which is known as the most flagrant example of disordered bone remodeling and the second most common bone disease after osteoporosis in Anglo-Saxons. Recent studies on Paget's disease suggested a specific increase in osteoclasts sensitivity to the differentiation activity of active vitamin D3 as the principal mechanism for abnormal bone formation. We set out to conduct a structure-activity relationship study on the first VDR antagonists of TEI-9647 and TEI-9648 (25-dehydro-1α-hydroxyvitamin D3-26, 23-lactone) toward improved VDR antagonistic activity. Given that both potent agonists and antagonists must have high affinity for the VDR, we hoped that our accumulated knowledge in VDR agonists would help us identify potent antagonists. First, 2α-modified TEI analogs were synthesized to improve VDR binding affinity, and then, 24-substitution was next investigated to enhance lactone stability under physiological conditions. Finally, 2α-modified 24-alkyl-, 24, 24-dimethyl-, and 24, 24-ethano-25-dehydro-1α-hydroxyvitamin D3-26, 23-lactones were synthesized. It was found that (23S, 24S) -2α- (3-hydroxypropoxy) -24-propyl-TEI-9647 was found to possess almost 1000-fold improved antagonistic activity (IC50=7.4 pM) over the original TEI-9647 (IC50= 6.3 nM).
Tandem Claisen rearrangement enabled us to produce noncyclic and macrocyclic catechol ligands with plural phenolic hydroxy groups from the corresponding di-isobutenyl polyether derivatives having various functional groups such as ester, amide, and aromatic rings. Complexation of the resultant catechol ligands with boronic acid selectively and effectively gave supramolecular boron complexes, in which only the catechol moiety reacted with boronic acid. The free phenolic hydroxy and ester groups assembled in the boron complex B1 was able to act as metal binding site, while the amide groups, quinoline, and oxyethylene moieties in the boron complex B2-B5 form multiple hydrogen bond formation with anions such as halogen, phosphate, acetate, and sulfate ions. The selectivity and the binding strength on the molecular recognition strongly depend on the variation and stereospecificity of the functional groups in the boron complexes, in addition to the coordination structure and charge of the boron in the boron complexes. Thus, introduction of chromophoric or fluorophoric group into the boron complexes allowed us to construct optical sensing systems for target molecules.
Attempt for obtaining both enantiomers in high enantiomeric excess is attractive and important challenges, because it is often the case that each enantiomer exhibits different bioactivity. Since our first report on the chiral Schiff base-Ti (O-i-Pr) 4-catalyzed trimethylsilylcyanation of aldehydes in 1991 (Aldimine type; the 1 st generation), this catalyst system has been proven to be efficient in a variety of asymmetric reactions. One of such reactions is the enantioselective addition of diketene to aldehydes. We succeeded in obtaining optically active 5-hydroxy-3-ketoesters in high optical yield (Ketimine type; the 2 nd generation). Herein, we report the first example of complete reversal of enantioselection using oxazoline-containing Schiff bases derived from L-serine, that is, from one stereogenic center of L-serine, both enantiomers of 5-hydroxy-3-keto-esters were obtained in high enantiomeric excess (Oxazoline containing type; the 3 rd generation).
Some chiral rare earth metal complexes were prepared and used as efficient catalysts for various enantioselective reactions. Rare earth organophosphates effectively catalyzed the hetero-Diels-Alder reaction (up to 99% ee), the Michael addition of nitrogen-nucleophiles (up to 99% ee), and the electrophilic fluorination of β-keto esters (up to 88% ee). Epoxidation of conjugated enones using chiral lanthanum complexes prepared in situ from lanthanum triisopropoxide, (R)-BINOL, triarylphosphine oxide, and alkyl hydroperoxide, afforded the desired products in excellent chemical yields and enantioselectivities (up to >99% ee). Also, chiral and porous polymeric lanthanum complex (particle size : 50-200 nm) prepared by the self-organization of lanthanum ion, a chiral ligand containing two or three (R)-BINOL units linked with multi-ways spacer, and an achiral ligand, was found to work as an excellent reusable heterogeneous catalyst for the enantioselective epoxidation (99% ee in the third run using the recovered catalyst). The catalyst system could also be successfully applied to the flow reaction. Remarkably large positive non-linear effects (asymmetric amplification) were observed in these reactions.
Structure and reactivity of C- and N-bound isomers of transition metal cyanocarbanions are described. A series of C-bound ruthenium phosphine complexes, RuCp [CH (CN) SO2Ph] L2 and their N-bound isomers, Ru+Cp (NCCH-SO2Ph) L2 have been synthesized by the reactions of RuCp-ClL2 with the sodium salt of (phenylsulfonyl) acetonitrile and subsequent ligand exchange reactions. Structural characterization by X-ray diffraction indicated that carbanion moiety of the C-bound complexes has complete α-metalated structure, while that of the N-bound ones has zwitter ionic structure. Interconversions between C- and N-bound complexes have been observed upon heating, where relative stabilities of the C- and N-bound complexes are drastically changed depending mainly on the steric factors of ligands. The intra- and intermolecular mechanisms of the C-N interconversions were explored by means of kinetic studies and DFT calculations. The N-bound complexes have proven to show high catalytic activities for aldol and Michael reactions of nitriles. Kinetic studies revealed that the catalytic reaction proceeds via direct C-C bond formation of N-bound complexes and subsequent nitrile exchange reaction.
Cleavage of C-CN bonds of nitriles followed by addition of the resulting organic and cyano groups across alkynes, namely carbocyanation reaction, is demonstrated to be catalyzed by nickel. The reaction allows straightforward and simultaneous formation of two C-C bonds without any by-product formation to afford a wide range of substituted acrylonitriles in highly stereo- and chemoselective manners. Lewis acid catalysts such as BPh3, A1Me3, and AIMe2Cl are found to significantly accelerate the reaction, presumably by the coordination of a cyano group to the Lewis acids, achieving addition of a range of nitriles including alkyl, alkenyl, aryl, and alkynyl cyanides.
Polarity inversion (umpolung or charge affinity inversion) of functional groups is widely recognized as a powerful and efficient synthetic method because it makes possible not only to offer strategic flexibilities but also to form carbon-car-bon bonds in the design of complex molecules. Recently, the new approaches of carbonyl synthons employing N-hetero-cyclic carbene catalyzed homoenolate reactions have been utilized in a variety of applications. In this review, the chemistry highlight in development of the catalytic generation of homoenolates and their application to the novel carbon-car-bon bond-forming process is described.