The asymmetric addition of alkyl groups to aldehydes catalyzed by BINOLate-titanium complexes has become the testing grounds to evaluate the potential of new BINOL-based ligands. We have investigated the mechanism of this reaction and report our findings here. Model systems for the open form of the catalyst, (BINOLate)[Ti(O-i-Pr)(3)](2), based on mono-oxygen-alkylated BINOL ligands have been examined. Comparison of the reactivity and enantioselectivity of the mono-alkyl BINOL derivatives with those of BINOL indicate that the open form of the catalyst, (BINOLate)[Ti(O-i-Pr)(3)](2), is not active in the asymmetric addition reaction. Several BINOLate-titanium complexes have been synthesized and characterized by X-ray crystallography. These include the dinuclear (BINOLate)Ti(O-i-Pr)(2).Ti(O-i-Pr)(4), which contains a bridging naphtholate and isopropoxy group, trinuclear (BINOLate)Ti(O-i-Pr)(2).[Ti(O-i-Pr)(4)](2), and trimeric [(BINOL)Ti(O-i-Pr)(2)](3). The solid-state and solution structures reported here indicate that (BINOLate)Ti(O-i-Pr)(2) prefers to bind to titanium tetraisopropoxide rather than to itself, explaining why no nonlinear effects are observed in the catalytic reaction. Additionally, experimental evidence suggests that the BINOLate-titanium species responsible for the catalytic and stoichiometric asymmetric addition reactions are different, indicating that the proposed intermediate, (BINOLate)Ti(R)(aldehyde)(O-i-Pr), is not involved in either of these processes. Reactions were examined using different sources of the alkyl group [ZnMe(2) or MeTi(O-i-Pr)(3)]. Under similar conditions, it was found that the product ee's were the same, independent of whether ZnMe(2) or Me-Ti(O-i-Pr)(3) was used as the source of the alkyl groups. This indicates that the role of the dialkylzinc is not to add the alkyl group to the carbonyl but rather to transfer the alkyl group to titanium. On the basis of these results, we hypothesize that the intermediate in the asymmetric addition involves (BINOLate)Ti(O-i-Pr)(2)(aldehyde).MeTi(O-i-Pr)(3).
A highly efficient synthesis of sitagliptin, a potent and selective DPP-4 inhibitor for the treatment of type 2 diabetes mellitus (T2DM), has been developed. The key dehydrositagliptin intermediate 9 is prepared in three steps in one pot and directly isolated in 82% yield and >99.6 wt % purity. Highly enantioselective hydrogenation of dehydrositagliptin 9, with as low as 0.15 mol % of Rh(I)/(t)Bu JOSIPHOS, affords sitagliptin, which is finally isolated as its phosphate salt with nearly perfect optical and chemical purity. This environmentally friendly, 'green' synthesis significantly reduces the total waste generated per kilogram of sitagliptin produced in comparison with the first-generation route and completely eliminates aqueous waste streams. The efficiency of this cost-effective process, which has been implemented on manufacturing scale, results in up to 65% overall isolated yield.
Neurofibrillary tangles (NFTs) made up of aggregated tau protein have been identified as the pathologic hallmark of several neurodegenerative diseases including Alzheimer's disease. In vivo detection of NFTs using PET imaging represents a unique opportunity to develop a pharmacodynamic tool to accelerate the discovery of new disease modifying therapeutics targeting tau pathology. Herein, we present the discovery of 6-(fluoro-(18)F)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine, 6 ([(18)F]-MK-6240), as a novel PET tracer for detecting NFTs. 6 exhibits high specificity and selectivity for binding to NFTs, with suitable physicochemical properties and in vivo pharmacokinetics.
Achiral tetrahydrosalen ligands have been employed in the synthesis of chiral C(2)-symmetric titanium complexes. When combined with tetrahydrosalen ligands 2a and 2b, titanium tetraisopropoxide liberated 2 equiv of isopropyl alcohol and generated the (tetrahydrosalen)Ti(O-i-Pr)(2) complexes 3a and 3b. These complexes were shown to be C(2)-symmetric by (1)H and (13)C[(1)H] NMR spectrometry and X-ray crystallography. X-ray structures of 3a and 3b indicate that the bonding of the tetrahydrosalen ligand to titanium is different than the bonding of salen ligands to titanium. Whereas salen ligands usually bind to titanium in a planar arrangement, the tetrahydrosalen is bonded with the phenoxide oxygens mutually trans. When bound in this fashion, the nitrogens of the tetrahydrosalen ligand and the titanium become stereogenic centers. The use of titanium complexes of high enantiopurity in the generation of tetrahydrosalen titanium adducts resulted in a maximum diastereoselectivity of 2:1. The diastereoselectivity obtained using chiral titanium alkoxide complexes was greater than the diastereoselectivity observed when a tetrahydrosalen ligand derived from (S,S)-trans-diaminocyclohexane was employed.
1. Introduction and Scope 3297 2. The Use of Achiral Salen Ligands in Asymmetric Catalysis 3305 3. Use of Achiral Biphenol-Based Ligands in Asymmetric Catalysis 3308 3.1. Asymmetric Carbonyl−Ene Reaction 3308 3.2. Asymmetric Addition of Methyl Groups to Aldehydes 3309 3.3. Asymmetric Baeyer−Villiger Oxidation 3309 4. Atropisomeric Biphenyl-Based Phosphines and Related Ligands in Asymmetric Catalysis 3310 4.1. Asymmetric Hydrogenation Reactions Using BIPHEP-Derived Ligands 3311 4.2. Asymmetric Diels−Alder and Carbonyl−Ene Reactions with BIPHEP-Derived Ligands 3313 4.3. Interconversion of Diastereomeric Catalysts and Catalyst Precursors Containing BIPHEP Derivatives 3315 4.4. Mechanistic Aspects of Atropisomerization of BIPHEP 3317 4.5. A Potentially Useful New Class of Achiral Diphosphine Ligands (NUPHOS) 3319 4.6. Complexes of a Meso Cyclohexane-Based Diphosphine 3320 4.7. Spontaneous Resolution of an Asymmetric Catalyst Bearing a Bis(phosphole) Ligand 3320 4.8. A Metallocene Catalyst with a Biphenyl Backbone 3322 4.9. Use of Bis(diphenylphosphino)ferrocene and Related Ligands in Asymmetric Catalysis 3323 4.10. Dynamic Resolution of Bis(phospholyl)−Zr Complexes 3325 5. Examination of the Barrier to Atropisomerization in Biphenyl-Based Diamines 3326
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