Synthesis and vitamin D receptor affinity of 16-oxa vitamin D3 analogues.

Two novel 16-oxa-vitamin D3 analogues were synthesized using a tandem Ti(ii)-mediated enyne cyclization/Cu-catalyzed allylation, Ru-catalyzed ring-closing metathesis reaction, and a low-valent titanium (LVT)-mediated stereoselective radical reduction of 8α,14α-epoxide as the key steps for the synthesis of the 16-oxa-C,D ring unit. The vitamin D receptor-binding affinity of the synthesized analogues, 16-oxa-1α,25-(OH)2VD3 and 16-oxa-19-nor-1α,25-(OH)2VD3, was evaluated by fluorescence polarization vitamin D receptor competitor assay and time-resolved fluorescence energy transfer vitamin D receptor co-activator assay.

Synthetic Reactions Using Low-valent Titanium Reagents Derived from Ti(OR)4 or CpTiX3 (X = O-i-Pr or Cl) in the Presence of Me3SiCl and Mg.

In the presence of Me3SiCl, Ti(OR)4 or CpTiX3 (X = O-i-Pr or Cl) is reduced by Mg powder in THF to gradually generate a specific low-valent titanium (LVT) species that mediates several synthetic reactions. The LVT-catalyzed C-O bond-cleaving reactions of allyl and propargyl ethers and esters generate parent alcohols and carboxylic acids, respectively. O-allyl and propargyl carbamates are also readily deprotected by the LVT to afford parent amines. In addition, the respective reductive N-S or O-S bond cleavage of sulfonamides or sulfonyl esters mediated by the LVT was developed as a novel facile deprotection method. The reagent catalyzes intra- and intermolecular alkyne or alkyne/nitrile cycloaddition to produce substituted benzenes and pyridines, while epoxides and oxetanes are reduced to alcohols via an LVT-mediated homolytic ring opening. The McMurry coupling of aryl aldehydes and ketones proceeds with the LVT under homogeneous and mild reaction conditions and is effective for the polymerization of aromatic dialdehydes, generating conjugated polymers. Finally, imino-pinacol coupling of imines is mediated by the LVT to provide 1,2-diamines.

Cobalt-catalyzed cross addition of silylacetylenes to internal alkynes.

A CoCl2·6H2O/Zn reagent using 2-(2,6-diisopropylphenyl)iminomethylpyridine (dipimp), 1,2-bis(diphenylphosphino)ethane (dppe), or 1,2-bis(diphenylphosphino)benzene (dppPh) as a ligand effectively catalyzed the cross-addition reaction of silylacetylene to internal alkynes. The reaction of some unsymmetrical internal alkynes, such as 3-arylpropargyl alcohols, proceeded in a highly regioselective manner in the presence of dppe or dppPh but gave a nearly 1:1 mixture of regioisomers in the presence of dipimp. The results of reactions using 1-deuterated 2-silylacetylene revealed that the reaction involves a direct oxidative addition of the silylacetylenic C-H bond to cobalt.

Organocatalytic multicomponent coupling to access a highly functionalised tetracyclic furoindoline: interrupted Passerini/Joullié-Ugi cascade reaction.

The interrupted Passerini reaction of 3-(2-isocyanoethyl)-indole catalysed by 3,5,6-trifluoro-2-pyridone is described. The reaction diastereoselectively provided a tetracyclic furolindoline, which proved to be a good substrate for the Joullié-Ugi reaction; therefore, the sequential Passerini/Joullié-Ugi reactions were performed in one-pot to rapidly provide versatile and highly functionalised furoindolines from 3-(2-isocyanoethyl)-indole.

Design, synthesis, and properties of des-D-ring interphenylene derivatives of 1α,25-Dihydroxyvitamin D3.

Novel des-D-ring interphenylene analogs of vitamin D3 were designed on the basis of their conformational analysis and affinity to vitamin D receptor (VDR) estimated using ligand-protein docking simulation. According to this design, a series of the des-D-ring interphenylene analogs were synthesized via Suzuki-Miyaura coupling reactions of des-D, C-ring and A-ring intermediates. A fluorescence polarization VDR competitor assay, a time-resolved fluorescence resonance energy transfer VDR coactivator binding assay, and a human VDR (NR1I1) reporter assay revealed that the des-D-ring interphenylene analogs exhibited a certain VDR binding affinity and ability to promote gene transcription. In particular, analogs having a side chain with an appropriate length at meta position showed high gene transcription promoting activities comparable to those of 1α,25-dihydroxyvitamin D3 and its 19-nor derivative.

Chain-growth cycloaddition polymerization via a catalytic alkyne [2 + 2 + 2] cyclotrimerization reaction and its application to one-shot spontaneous block copolymerization.

A cobalt-catalyzed alkyne [2 + 2 + 2] cycloaddition reaction has been applied to polymerizations yielding linear polymers via selective cross-cyclotrimerization of yne-diyne monomers, which occurs in a chain-growth manner. Additionally, through control of the alkyne reactivity of the two monomers, this method was efficiently applied to the spontaneous block copolymerization of their mixture. Here we present the proposed mechanism of the catalyst transfer process of this cycloaddition polymerization.

Synthesis and catalytic properties of 4-aryl-2,3-dihydro-4H-pyrimido[2,3-b]benzothiazoles for asymmetric acyl or carboxyl group transfer reactions.

4-Aryl-2,3-dihydro-4H-pyrimido[2,3-b]benzothiazoles (4-Ar-DHPBs) were synthesized and their catalytic activity and selectivity in kinetic resolution of a secondary alcohol as well as in the Steglich rearrangement and related reactions were evaluated. 4-Aryl-DHPBs showed low enantioselectivity in the acylative kinetic resolution of 1-phenylethanol. Conversely, they catalyzed the Steglich rearrangement with moderate to excellent enantioselectivity, demonstrating the possibility for remote stereocontrol by introduction of a substituent at the 4-position of DHPB.

Deuteration of Indole Compounds: Synthesis of Deuterated Auxins, Indole-3-acetic Acid-d5 and Indole-3-butyric Acid-d5.

In this study, we describe a practical and facile synthesis of deuterium-labeled indoles via acid-catalyzed hydrogen-deuterium exchange. 3-Substituted indoles were efficiently deuterated through treatment with 20 wt % D2SO4 in CD3OD at 60-90 °C. A deuterium incorporation reaction of 3-unsubstituted indoles was accomplished through treatment with CD3CO2D at 150 °C. The in situ preparation of a 20 wt % D2SO4/CH3OD/D2O solution enabled a large-scale and low-cost synthesis of auxins, indole-3-acetic acid-d5 and indole-3-butyric acid-d5.

6-Halo-2-pyridone as an efficient organocatalyst for ester aminolysis.

It was found that 6-halo-2-pyridones catalysed ester aminolysis in which not only reactive aryl esters but also relatively less reactive methyl and benzyl esters could be used as a substrate. The reaction could be performed without strictly dry and anaerobic conditions and the 6-chloro-2-pyridone catalyst could be recovered quantitatively after reaction. The method could be applied to dipeptide synthesis from methyl or benzyl esters of amino acids, where a high enantiomeric purity of the products was maintained. The mechanism involving dual activation of ester and amine substrates through hydrogen bonding between catalyst and substrates is proposed where 6-halo-2-pyridones act as a bifunctional Brønsted acid/base catalyst.

Selective dimerization of 1,6-diynes catalyzed by ionic liquid-supported nickel complexes in an ionic liquid/toluene biphasic system.

A NiCl(2)-6H(2)O/Zn reagent with a 2-aryliminomethylpyridine ligand catalyzed cyclization/polymerization of 1,6-diynes to yield mainly the corresponding poly(1,3-butadienylene) compounds, whereas NiBr(2)-3H(2)O/Zn with the use of 3-(2-(2-methoxyethoxy)-ethyl)-1-methyl-1H-imidazol-3-ium bromide as a ligand converted 1,6-diynes to the corresponding annulated 1,3,5,7-cyclooctatetraenes in a biphasic solvent system consisting of toluene and an ionic liquid.

On-demand generation of an efficient catalyst for pyridine formation from unactivated nitriles and alpha,omega-diynes using CoCl2-6H2O, dppe, and Zn.

[reaction: see text] A highly practical, general method for catalytic formation of substituted pyridines from a variety of unactivated nitriles and alpha,omega-diynes is given. The reactions which were catalyzed by 5 mol % of dppe/CoCl2-6H2O in the presence of Zn powder (10 mol %) could proceed at rt to approximately 50 degrees C with high functional compatibility and regioselectivity.

Selective cleavage of allyl and propargyl ethers to alcohols catalyzed by Ti(O-i-Pr)4/MXn/Mg.

[reaction: see text] Allyl and propargyl ethers were effectively deallylated or depropargylated to the parent alcohols via a C-O bond cleavage catalyzed by a low-valent titanium reagent (LVT), Ti(O-i-Pr)4/TMSCl/Mg or Ti(O-i-Pr)4/MgBr2/Mg, under mild reaction conditions. Differentiation between the allyl and propargyl ethers was achieved by the reaction in the presence of AcOEt as an additive. The reagent also catalyzed intra- and intermolecular cyclotrimerization reactions of alkynes to substituted benzenes.

A highly practical instant catalyst for cyclotrimerization of alkynes to substituted benzenes.

[reaction: see text] A 2-(2,6-diisopropylphenyl)iminomethylpyridine (1a)/CoCl(2).6H(2)O/Zn reagent has been developed as an effective instant catalyst for the intra- and intermolecular cyclotrimerization of alkynes to substituted benzenes, making the method extremely practical since the reagent, 1a/CoCl(2).6H(2)O/Zn, is inexpensive and easy to handle and the reaction is less sensitive to moisture and is reasonably general.

Intramolecular cyclotrimerization of triynes catalyzed by N-heterocyclic carbene-CoCl2/Zn or -FeCl3/Zn.

[reaction: see text] Triynes 1 could effectively be cyclotrimerized to annulated benzenes 2 by treatment with a catalytic amount of zinc powder, N-heterocyclic carbene, and CoCl(2) or FeCl(3).

Asymmetric synthesis of allyl- and alpha-allenylamines from chiral imines and alkynes via (eta(2)-imine)Ti(O-i-Pr)2 complexes.

[reaction: see text] The reaction of a divalent titanium reagent Ti(O-i-Pr)(4)/2i-PrMgX with optically active arylaldimines derived from arylaldehydes and O-methylphenylglycinol provided, in a highly diastereoselective manner, chiral (eta(2)-imine)Ti(O-i-Pr)(2) complexes, which in turn reacted with 1-alkynes or propargyl compounds to give optically active allyl- and alpha-allenylamines, respectively.

Efficient convergent synthesis of 1alpha,25-dihydroxyvitamin D3 and its analogues by Suzuki-Miyaura coupling.

[reaction: see text] 1alpha,25-Dihydroxyvitamin D(3) was synthesized by the Suzuki-Miyaura coupling of the A-ring intermediate 1, which was efficiently prepared from readily available 1,7-enyne 2, with the corresponding boronate compound of the C,D-ring portion. The method was applied to prepare des-C,D analogues of 1alpha,25-dihydroxyvitamin D(3).

Intramolecular Nucleophilic Acyl Substitution Reaction of 3,4-Alkadienyl Carbonates Mediated by Ti(O-i-Pr)(4)/2 i-PrMgCl Reagent. Efficient Synthesis of Optically Active beta,gamma-Unsaturated Esters with an alpha-Substituent.

Treatment of 3,4-alkadienyl carbonates 2a-i with a low-valent titanium reagent diisopropoxy(eta(2)-propene)titanium (1), readily generated by the reaction of Ti(O-i-Pr)(4) with 2 i-PrMgCl, resulted in an intramolecular nucleophilic acyl substitution (INAS) reaction to afford vinyltitanium compounds 3 which, in turn, reacted with H(3)O(+), D(2)O, or iodine to give alpha-substituted beta,gamma-unsaturated esters 4 in good to excellent yields. The olefin moiety of the hydrolysis product 4 has (Z)-geometry mainly except for 4h. Starting from chiral 2f or 2g, the reaction proceeded stereospecifically to give optically active alpha-substituted beta,gamma-unsaturated ester 4f or 4g having (Z)-olefin geometry exclusively.

Iron-catalyzed reductive magnesiation of oxetanes to generate (3-oxidopropyl)magnesium reagents.

In the presence of FeCl(n)-(bisphosphine) or FeCl(n)-(2-iminomethylpyridine) (n = 2 or 3), 2-substituted oxetanes reacted with Grignard reagents undergoing reductive magnesiation at the 2-position to afford substituted 3-oxidopropylmagnesium compounds, which are useful nucleophiles in reactions with a variety of electrophiles.

Ti(O-i-Pr)4/Me3SiCl/Mg-mediated reductive cleavage of sulfonamides and sulfonates to amines and alcohols.

A low-valent titanium generated in situ from Ti(O-i-Pr)(4), Me(3)SiCl, and Mg powder in THF reacted with aryl- and alkyl-sulfonamides of aryl and alkyl amines in a reductive N-S/S-O/S-C bond cleaving pathway to provide the corresponding amines and hydrocarbons (and thiols) derived from the sulfonyl moiety. The reagent could also cleave sulfonates to the corresponding alcohols.

Non-Cp titanium alkoxide-based homolytic ring-opening of epoxides by an intramolecular hydrogen abstraction in ß-titanoxy radical intermediates.

A low-valent titanium species derived in situ from Ti(O-i-Pr)(4), Me(3)SiCl and Mg powder in tetrahydrofuran reacted with epoxides to selectively provide less hindered alcohols via a homolytic ring-opening of epoxides, in which the intermediate ß-titanoxy radical intramolecularly abstracted a hydrogen atom from an alkoxy moiety in the titanium complexes.