Dinuclear Tricyclic Transition State Model for Carbonyl Addition of Organotitanium Reagents: DFT Study on the Activity and Enantioselectivity of BINOLate Titanium Catalysts.

In the presence of a catalytic amount of chiral BINOL derivatives (or BINOLs), a mixture of various organometallic compounds with Ti(O iPr)4 undergoes enantioselective addition to aldehydes and ketones. Although the catalyst and reacting nucleophile of the reaction have been elucidated to be ( BINOLate)Ti2(O iPr)6 and RTi(O iPr)3, respectively, little is known about the properties of short-lived intermediates and transition structures. In this work, the mechanism of this reaction is investigated with the aid of DFT (M06) calculations. The study provides support for the following mechanistic understandings: (i) The direct racemic reaction proceeds through a pathway involving initial aggregation of RTi(O iPr)3 with Ti(O iPr)4 followed by carbonyl addition of the resulting dinuclear aggregate. (ii) The enantioselective reaction takes place through a pathway involving initial ligand exchange of RTi(O iPr)3 with ( BINOLate)Ti2(O iPr)6 followed by the addition of the resulting chiral dinuclear titanium species via a chiral BINOLate-chelated, tricyclic transition structure. (iii) The enantioselective pathway is favorable not because BINOLate ligands accelerate the carbonyl addition but because the ligands stabilize the chiral dinuclear species against deaggregation through a chelating bridge. (iv) The chiral transition structure serves as a model accounting for the re-face addition generally observed in the reaction of aldehydes with ( R)- BINOLs.

Method for Catalytic Enantioselective Alkylation of Aldehydes Using Grignard Reagents as Alkyl Sources.

Alkyltitanium reagents, generated in situ from Grignard reagents and ClTi(O iPr)3, can be employed without further manipulation in the enantioselective alkylation of aldehyde by the catalysis of a chiral titanium complex derived from DTBP-H8-BINOL. The reaction is performed with good stoichiometry [1.5 equiv each of Grignard reagents and ClTi(O iPr)3] at a low catalyst loading (2 mol %), affording a variety of chiral secondary alcohols in high enantioselectivity and yields and, hence, realizing an asymmetric version of the Grignard reaction in an indirect manner.

Catalytic Enantioselective Arylation and Heteroarylation of Ketones with Organotitanium Reagents Generated In Situ.

A practical and useful, catalytic enantioselective method has been developed for the synthesis of tertiary diaryl and aryl heteroaryl carbinols starting from commercially available aromatic ketones and aryl or heteroaryl bromides. In this method, organotitanium reagents are generated in situ from the bromides by lithiation with nBuLi followed by transmetallation of the resulting organolithiums with ClTi(OiPr)3 . Treatment of the ketones with the titanium reagents in the presence of (R)-3-(3,5-bistrifluoromehthylphenyl)-1,1'-bi-2-naphthol (BTFP-BINOL) affords the corresponding tertiary alcohols in high enantioselectivities and yields. The reaction can also start with furan and 2-thienyllithium. The method is operationally simple and can be conducted on a 10-mmol scale without any difficulties.

Enhancement of the Catalytic Activity of Chiral H8 -BINOL Titanium Complexes by Introduction of Sterically Demanding Groups at the 3-Position.

The activity of chiral titanium catalysts derived from H8 -BINOL ligands in the enantioselective arylation of an aldehyde with PhTi(OiPr)3 is significantly enhanced by an increase of the size of the substituent at the 3-position. High enantioselectivity (> 90 % ee) can be obtained even at a substrate/catalyst ratio (S/C) of 800 for DTBP-H8 -BINOL (DTBP=3,5-di-tert-butylphenyl) and DAP-H8 -BINOL (DAP=3,5-di(9-anthraceny)phenyl). These titanium catalysts are successfully applied to the enantioselective arylation and heteroarylation of aldehydes at a S/C ratio of 400 by using organotitanium reagents generated in situ from bromide precursors. The remarkable weakening of the intramolecular aggregation of the two -Ti(OiPr)3 units in a DPP-H8 -BINOL (DPP=3,5-diphenylpheny)-derived bis-titanium complex is revealed by X-ray and variable-temperature (VT)-NMR studies. Based on these observations, a catalytic cycle, involving the rate-limiting aryl group transfer followed by aldehyde complexation and enantioselective arylation, is proposed to account for the high activity of the 3-substituted H8 -BINOL catalyst system.

Development of Highly Active Chiral Titanium Catalysts for the Enantioselective Addition of Various Organometallic Reagents to Aldehydes.

The catalytic enantioselective carbonyl addition reaction has long attracted the interest of chemists because of its synthetic importance. Although many highly enantioselective reactions have been developed, with few exceptions the reactions are carried out at relatively high catalyst loadings, making them less practical for scale-up applications. In addition, organometallic reagents employed as carbon nucleophiles have been limited to those with relatively low reactivity, such as diorganozincs and arylboronic acids. In an effort to enhance the practicality, a highly active and enantioselective chiral titanium catalyst system was recently developed in our laboratory, enabling the enantioselective carbonyl addition reaction to aldehydes using various organometallic reagents (RM; M = MgX, Li, BY2 , ZnX, AlMe2 ) at lower catalyst loadings (≤5 mol %).

Catalytic enantioselective alkylation of aldehydes by using organozinc halide reagents.

Functionalized alkylzinc halides can be employed in the enantioselective addition to aldehydes by using a titanium(IV) catalyst derived from a H(8)-binaphthol derivative in the presence of [Ti(OiPr)(4)] and MgBr(2). A range of functionalities, including olefin, chlorine atoms, protected alcohols, amides, and cyano groups, are tolerated in the present reaction, providing the corresponding functionalized alcohols in high yields and enantioselectivities (see scheme).

Practical enantioselective arylation and heteroarylation of aldehydes with in situ prepared organotitanium reagents catalyzed by 3-aryl-H8-BINOL-derived titanium complexes.

A highly efficient and practical method for the catalytic enantioselective arylation and heteroarylation of aldehydes with organotitanium reagents, prepared in situ by the reaction of aryl- and heteroaryllithium reagents with ClTi(OiPr)3, is described. Titanium complexes derived from DPP-H8 -BINOL (3d; DPP=3,5-diphenylphenyl) and DTBP-H8 -BINOL (3e; DTBP=3,5-di-tert-butylphenyl) exhibit excellent catalytic activity in terms of enantioselectivity and turnover efficiency for the transformation, providing diaryl-, aryl heteroaryl-, and diheteroarylmethanol derivatives in high enantioselectivity at low catalyst loading (0.2-2 mol%). The reaction begins with a variety of aryl and heteroaryl bromides through their conversion into organolithium intermediates by Br/Li exchange with nBuLi, thus providing straightforward access to a range of enantioenriched alcohols from commercially available starting materials. Various 2-thienylmethanols can be synthesized enantioselectively by using commercially available 2-thienyllithium in THF. The reaction can be carried out on a 10 mmol scale at 0.5 mol% catalyst loading, demonstrating its preparative utility.

Alkylative carbocyclization of omega-iodoalkynyl tosylates with alkynyllithium compounds through a carbenoid-chain process leading to (1-iodoprop-2-ynylidene)tetrahydrofurans and -cyclopropanes.

Alkylative carbocyclization reactions of omega-iodoalkynyl tosylates with alkynyllithium compounds to give products with incorporated iodine atoms are described. Slow addition of 2-(3-iodoprop-2-ynyloxy)ethyl tosylates to 1-alkynyllithium compounds in tetrahydrofuran at 40 degrees C followed by additional stirring at this temperature gives (Z)-3-(1-iodoprop-2-ynylidene)tetrahydrofurans stereoselectively in good to moderate yields. Under similar conditions at 0 degrees C, 4-iodobut-1-ynyl tosylates react with 1-alkynyllithium compounds to give (1-iodoprop-2-ynylidene)cyclopropanes. The carbocyclization reactions are proposed to proceed through a new carbenoid-chain process involving the exo cyclization of a lithium acetylide intermediate and the vinylic substitution of the resulting TsO,Li-cycloalkylidenecarbenoids (Ts=tosyl) by 1-alkynyllithium compounds.

Silica-Supported Catalyst for Enantioselective Arylation of Aldehydes under Batch and Continuous-Flow Conditions.

A silica-supported 3-aryl H8-BINOL-derived titanium catalyst exhibited high performance in the enantioselective arylation of aromatic aldehydes using Grignard and organolithium reagents not only under batch conditions but also under continuous-flow conditions. Even with a simple pipet reactor packed with the heterogeneous catalyst, the enantioselective production of chiral diarylmethanols could be achieved through a continuous introduction of aldehydes and mixed titanium reagents generated from the organometallic precursors. The pipet reactor could be used repeatedly in different reactions without appreciable deterioration of the activity.

Incomplete restoration of the secretion of ghrelin and PYY compared to insulin after food ingestion following weight gain in anorexia nervosa.

BACKGROUND: In humans, ghrelin has been found to stimulate appetite while PYY3-36 to reduce it; these orexigenic and anorexigenic peptides play significant roles in appetite control. We investigated pre- and postprandial responses of ghrelin and PYY in anorexia nervosa (AN) and the influence of weight gain. METHODS: Plasma ghrelin, PYY3-36, glucose and insulin responses after ingestion of a 400 kcal standard meal were measured in 14 patients with restricting type of AN and 12 controls. The AN patients were evaluated before therapy and after inpatient therapy. Psychometry was performed by the use of Eating Disorders Inventory. RESULTS: Ghrelin was suppressed during the meal test, while PYY3-36 was increased in all of the groups. Before therapy, AN patients had significantly increased levels of ghrelin and PYY3-36 compared to the control (P<0.01). After therapeutic intervention, as the nutritional status of AN patients improved, the secretion of these hormones were increased (P<0.05), but not normalized as in psychological testing. In contrast, insulin and glucose responses were normalized after inpatient therapy. CONCLUSIONS: We found that both ghrelin and PYY3-36 increased in AN patients and these changes were not normalized in contrast to insulin after treatment. The increase in both orexigenic ghrelin and anorexigenic PYY3-36 may have a role in pathological eating behavior in AN.

Application of a Heterogeneous Chiral Titanium Catalyst Derived from Silica-Supported 3-Aryl H8-BINOL to Enantioselective Alkylation and Arylation of Aldehydes.

A 3-aryl H8-BINOL was grafted on the surface of silica gel using a hydrosilane derivative as a precursor, and the resulting silica-supported ligand (6 mol %) was employed in the enantioselective alkylation and arylation of aldehydes in the presence of Ti(OiPr)4. The reactions using Et2Zn, Et3B, and aryl Grignard reagents all afforded the corresponding adducts in high enantioselectivities and yields. The silica-immobilized titanium catalyst could be reused up to 14 times without appreciable deterioration of the activity.

Enantioselective alkylation of aldehydes catalyzed by a highly active titanium complex of 3-substituted unsymmetric BINOL.

[reaction: see text] A titanium complex derived from 3-(3,5-diphenylphenyl)-BINOL exhibits an enhanced catalytic activity in the asymmetric alkylation of aldehydes, allowing the reduction of the catalyst amount to less than 1 mol % without deterioration in enantioselectivity.

Novel cyclization reaction of 1,omega-diiodo-1-alkynes without the loss of iodine atoms.

In the presence of 1-hexynyllithium (0.2-0.6 equiv.), 1,omega-diiodo-1-alkynes undergo a new type of cyclization reaction without the loss of two iodine atoms to afford (diiodomethylene)cycloalkanes.

LDA-catalyzed cycloisomerization of 2-(2-propynyloxy)ethyl iodides leading to 3-(iodomethylene)tetrahydrofurans.

LDA catalyzes cycloisomerization of 2-(2-propynyloxy)ethyl iodides to give 3-(iodomethylene)tetrahydrofurans. The reaction is proposed to proceed through a mechanism involving exo-cyclization of an alkynyllithium intermediate and protonation of the resulting alkylidene carbenoid by the starting iodide. [reaction: see text]

High facial selectivity observed in amine coordination to chiral oxazaborolidinones.

A variety of 1,3,2-oxazaborolidin-5-ones (OXB) derived from N-sulfonyl amino acids exhibit a high top-face selectivity in complexation with pyridines under thermodynamically controlled conditions.

Dimethylsilyl ketene acetal as a nucleophile in asymmetric Michael reaction: enhanced enantioselectivity in oxazaborolidinone-catalyzed reaction.

[reaction: see text] Dimethylsilanyl [Me2Si(H)] ketene S,O-acetal 6b is an effective nucleophile that retards the undesirable Si+-catalyzed racemic pathway in the oxazaborolidinone-catalyzed asymmetric Michael reaction. Through the further suppression of the Si+-catalyzed pathway by carrying out the reaction in the presence of 2,6-diisopropylphenol and t-BuOMe as additives, enantioselectivity up to 98% ee could be achieved for a variety of acyclic enones.

Phenylenebis(ethynyl)-tethered bis-BINOL ligands for enantioselective catalyst based on dimeric TiIV aggregate.

Bis-BINOLs 7a-c in which two BINOL units are tethered by phenylenebis(ethynyl) groups react with titanium tetraisopropoxide (2 equiv) to form intramolecular dimeric titanium(IV) aggregates 2a-c. Of these, 2a,b with an o-phenylenebis(ethynyl) tether are stable in the presence of excess titanium tetraisopropoxide. Complex 2a exhibits a relatively high enantioselectivity in asymmetric addition of diethylzinc to an aldehyde. [structure: see text]

Novel Homologation Reaction of Arylzincates Bearing a Leaving Group at the Ortho and Meta Positions.

Arylzincates bearing a leaving group at the ortho, meta, and para positions were generated by iodine/zinc exchange reaction of the corresponding iodoaryl sulfonates with Bu(3)ZnLi, and their reactivity was investigated via product analysis after hydrolysis and treatment with iodine. Zincates derived from o-iodophenyl triflates and tosylate underwent homologation reaction to give o-butylphenylzinc species. o-Benzyne as an intermediate of the reaction was demonstrated by the lack of regioselectivity for trisubstituted zincates. Zincates derived from m-iodophenyl triflates also underwent homologation leading to m-butylphenylzinc species. Similar product ratios observed in the reactions of regioisomeric trisubstituted iodophenyl triflates as well as the formation of radical reaction byproducts suggested the involvement of m-benzyne intermediate. p-(Trifluoromethanesulfonyloxy)phenylzincate was thermally stable at room temperature; generation of p-benzyne was not observed.