828933-86-4

Upstream product

• 828933-85-3 (2S,4R)-6-Methyl-4-phenyl-2-((1R,2S)-2-phenyl-cyclohexyloxy)-chroman 
• 16299-22-2 6-methyl-4-phenylchromen-2-one 
• 1152781-52-6 (R)-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanenitrile 
• 175647-90-2 (E)-ethyl 3-(2-hydroxy-5-methylphenyl)acrylate 
• 6627-55-0 2-bromo-p-cresol 
• 1450-72-2 5-methyl-2-hydroxyacetophenone 
• 108-86-1 bromobenzene 
• 86608-97-1 2-(1-hydroxy-1-phenylethyl)-4-methylphenol 
• 100-58-3 phenylmagnesium bromide 
• 828933-84-2 tert-butyl (2-formyl-4-methylphenyl) carbonate 
• 613-84-3 2-hydroxy-5-methylbenzaldehyde 
• 98-80-6 phenylboronic acid 
• 92-48-8 6-methylcoumarin 
• 827007-19-2 (R)-6-methyl-4-phenyl-3,4-dihydrochromen-2-one 

Downstream Products

• 124937-51-5 (R)-(+)-tolterodine 
• 827007-19-2 (R)-6-methyl-4-phenyl-3,4-dihydrochromen-2-one 
• 851789-43-0 3-phenyl-3-(2'-hydroxy-5'-methyl)phenylpropanol-1 
• 124937-52-6 tolterodine tartrate 

Relevant academic research and scientific papers

Asymmetric Hydroesterification of Diarylmethyl Carbinols

An efficient asymmetric hydroesterfication of diarylmethyl carbinols is developed for the first time with a Pd-WingPhos catalyst, resulting in a series of chiral 4-aryl-3,4-dihydrocoumarins in excellent enantioselectivities and good yields. The method features mild reaction conditions, a broad substrate scope, use of easily accessible starting materials, and low palladium loadings. A plausible stereochemical model is also proposed with the Pd-WingPhos catalyst. This method has enabled a 4-step asymmetric synthesis of (R)-tolterodine from readily available starting materials.

Chiral Inductive Diastereoconvergent Allylation Reactions of Allyltrimethylsilane and Diastereomixtures of Diarylmethanols Catalyzed by FeCl3

We report the chiral-auxiliary-controlled diastereoconvergent allylation reactions of allyltrimethylsilane with diastereomeric mixtures of diarylmethanols in the presence of FeCl3 as a Lewis acid catalyst. This reaction was successfully applied to a variety of substrates; it proceeded irrespective of the substituent on the aromatic ring of the substrate. The present method was used as the key step in synthesizing (R)-tolterodine.

Computationally-Led Ligand Modification using Interplay between Theory and Experiments: Highly Active Chiral Rhodium Catalyst Controlled by Electronic Effects and CH–π Interactions

A chiral ligand for the rhodium-catalyzed asymmetric 1,4-addition of an arylboronic acid to a coumarin substrate that could markedly reduce catalyst loading was developed using interplay between theoretical and experimental approaches. Evaluation of the transition states for insertion and for hydrolysis of intermediate complexes (which were emphasized in response to the experimental results) using DFT calculations at the B97D/6-31G(d) level with the LANL2DZ basis set for rhodium revealed that: (i) the electron-poor nature of the ligands and (ii) CH–π interactions between the ligand and coumarin substrates played significant roles in both acceleration of insertion and inhibition of ArB(OH)2 decomposition (protodeboronation). The computationally-designed ligand, incorporating the above information, enabled a decrease in the catalyst loading to 0.025 mol% (S/C=4,000), which is less than one one-hundredth relative to past catalyst loadings of typically 3 mol%, with almost complete enantioselectivity. Furthermore, the gram-scale synthesis of the urological drug, (R)-tolterodine (l)-tartrate, was demonstrated without the need of intermediate purification. (Figure presented.).

Hydrolase-mediated resolution of the hemiacetal in 2-chromanols: The impact of remote substitution

Hydrolase-catalysed dynamic kinetic resolutions of chroman-2-ol and 3-methyl chroman-2-ol can be effected with up to 88% conversion and 92% ee through the use of organic solvents. Extension to the resolution of the tolterodine precursor 1 proved more challenging. The presence of the remote phenyl substituent had a significant impact on the resolution and it was not possible to achieve high enantioselectivity together with efficient conversion from the focussed panel of enzymes screened.

Coumarins from free ortho -hydroxy cinnamates by Heck-Matsuda arylations: A scalable total synthesis of (R)-tolterodine

Free ortho-hydroxy cinnamate ester derivatives are evaluated in the synthesis of structurally diverse 4-aryl-coumarins via a tandem Heck-Matsuda cyclization reaction. Free phenolic groups were considered incompatible with such a reaction, which usually provide the corresponding diazo dyes. A concise and scalable route employing a ligand-free, Pd-catalyzed Heck-Matsuda arylation under aerobic conditions for the preparation of (R)-Tolterodine in high overall yield and ee is also presented.

Asymmetrie Conjugate reductions of coumarins. A new route to tolterodine and related coumarin derivatives

"Chemical Equation Presented" The combination of catalytic amounts of [(R)-DTBM-SEGPHOS]CUH In the presence of stoichiometric DEMS (dlethoxymethylsllane) In toluene at room temperature leads to asymmetric reductions of 4-substituted coumarins. Several targets or their known precursors can be prepared In high yields and ee's, Including the muscarine receptor antagonist (R)-tolterodine.

Enantioselective synthesis of (R)-tolterodine via CuH-catalyzed asymmetric conjugate reduction

(Chemical Equation Presented) An efficient and highly enantioselective method for the preparation of (R)-tolterodine is described. The synthesis was performed by CuH-catalyzed asymmetric conjugate reduction of a β,β-diaryl-substituted unsaturated nitrile

Enantioselective synthesis of (S)- and (R)-tolterodine by asymmetric hydrogenation of a coumarin derivative obtained by a Heck reaction

(Chemical Equation Presented) An efficient and short enantioselective synthesis of (S)- and (R)-tolterodine was performed by asymmetric hydrogenation of a coumarin intermediate, easily obtained by a Heck reaction from inexpensive and commercially available starting materials.

Rhodium-catalyzed asymmetric 1,4-addition of arylboronic acids to coumarins: Asymmetric synthesis of (R)-tolterodine

(Chemical Equation Presented) Rhodium-catalyzed asymmetric 1,4-addition of arylboronic acids to coumarins proceeded with high enantioselectivity in the presence of a rhodium catalyst (3 mol %) generated from Rh(acac)(C 2H4)2 and (R)-Segphos to give the corresponding (R)-4-arylchroman-2-ones in over 99% ee. This asymmetric reaction was applied to the synthesis of (R)-tolterodine.

Enantioselective [4 + 2] cycloadditions of o-quinone methides: Total synthesis of (+)-mimosifoliol and formal synthesis of (+)-tolterodine

The first example of an enantioselective cycloaddition of an o-quinone methide (o-QM) with a chiral enol ether is described along with the total synthesis of (+)-mimosifoliol and the formal synthesis of (+)-tolterodine. These syntheses exemplify a three-c