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1.
Chem Sci ; 13(43): 12906-12912, 2022 Nov 09.
Article in English | MEDLINE | ID: mdl-36519062

ABSTRACT

The high cost and negative environmental impact of precious metal catalysts has led to increased demand for nonprecious alternatives for widely practiced reactions such as the Suzuki-Miyaura coupling (SMC). Ni-catalyzed versions of this reaction have failed to achieve high reactivity with Lewis-basic arylboron nucleophiles, especially pinacolboron esters. We describe the development of (PPh2Me)2NiCl2 as an inexpensive and air-stable precatalyst that addresses this challenge. Under activation by n-BuMgCl, this complex can catalyze the coupling of synthetically important heteroaryl pinacolborons with heteroaryl halides. Mildly basic conditions (aqueous K3PO4) allow the reaction to tolerate sensitive functional groups that were incompatible with other Ni-SMC methods. Experimental and computational studies suggest that catalyst inhibition by substitution of PPh2Me from Ni(ii) intermediates by Lewis basic reactants and products is disfavored relative to more commonly employed ligands in the Ni-SMC, which allows it to operate efficiently in the presence of Lewis bases such as unhindered pyridines.

2.
J Org Chem ; 87(4): 1986-1995, 2022 02 18.
Article in English | MEDLINE | ID: mdl-34280307

ABSTRACT

Foslevodopa (FLD, levodopa 4'-monophosphate, 3) and foscarbidopa (FCD, carbidopa 4'-monophosphate, 4) were identified as water-soluble prodrugs of levodopa (LD, 1) and carbidopa (CD, 2), respectively, which are useful for the treatment of Parkinson's disease. Herein, we describe asymmetric syntheses of FLD (3) and FCD (4) drug substances and their manufacture at pilot scale. The synthesis of FLD (3) employs a Horner-Wadsworth-Emmons olefination reaction followed by enantioselective hydrogenation of the double bond as key steps to introduce the α-amino acid moiety with the desired stereochemistry. The synthesis of FCD (4) features a Mizoroki-Heck reaction followed by enantioselective hydrazination to install the quaternary chiral center bearing a hydrazine moiety.


Subject(s)
Parkinson Disease , Pharmaceutical Preparations , Carbidopa , Humans , Hydrogenation , Levodopa/therapeutic use , Parkinson Disease/drug therapy
3.
Org Lett ; 22(14): 5363-5368, 2020 Jul 17.
Article in English | MEDLINE | ID: mdl-32589034

ABSTRACT

A general method to prepare valuable chiral synthon ß-aryl-ß-aryloxy esters from enantioselective hydrogenation of (E)-ß-aryl-ß-aryloxy-α,ß-unsaturated esters is described. The E-isomer was prepared via isomerization of the mixture of E- and Z-isomers using photocatalyst [Ir(ppy)2(dtbbpy)]PF6. A laser as the light source facilitated isomerization with only 0.05 mol % catalyst. The enantioselective hydrogenation was conducted with (NBD)2Rh(BF4) and a commercially available Josiphos ligand to provide the synthons in up to 95% yield with 97% ee.

4.
J Org Chem ; 84(8): 4873-4892, 2019 04 19.
Article in English | MEDLINE | ID: mdl-30629443

ABSTRACT

Dasabuvir (1) is an HCV polymerase inhibitor which has been developed as a part of a three-component direct-acting antiviral combination therapy. During the course of the development of the synthetic route, two novel coupling reactions were developed. First, the copper-catalyzed coupling of uracil with aryl iodides, employing picolinamide 16 as the ligand, was discovered. Later, the palladium-catalyzed sulfonamidation of aryl nonaflate 33 was developed, promoted by electron-rich palladium complexes, including the novel phosphine ligand, VincePhos (50). This made possible a convergent, highly efficient synthesis of dasabuvir that significantly reduced the mutagenic impurity burden of the process.


Subject(s)
Antiviral Agents/pharmacology , Enzyme Inhibitors/pharmacology , Hepacivirus/drug effects , Palladium/chemistry , Sulfonamides/pharmacology , Uracil/analogs & derivatives , Viral Nonstructural Proteins/antagonists & inhibitors , 2-Naphthylamine , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Catalysis , Drug Development , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Hepacivirus/enzymology , Microbial Sensitivity Tests , Molecular Structure , Sulfonamides/chemical synthesis , Sulfonamides/chemistry , Uracil/chemical synthesis , Uracil/chemistry , Uracil/pharmacology , Viral Nonstructural Proteins/metabolism
5.
J Org Chem ; 76(11): 4552-63, 2011 Jun 03.
Article in English | MEDLINE | ID: mdl-21510695

ABSTRACT

A general method for Pd-catalyzed sulfonamidation of aryl nonafluorobutanesulfonates (aryl nonaflates) is described. A biaryl phosphine ligand, t-BuXPhos, formed the most active catalyst, and K(3)PO(4) in tert-amyl alcohol was found to be the optimal base-solvent combination for the reaction. The reaction conditions were tolerant of various functional groups such as cyano, nitro, ester, aldehyde, ketone, chloride, carbamate, and phenol. Heterocyclic aryl nonaflates were found to be suitable coupling partners. High yields of the coupled products were obtained from the reactions between inherently disfavored substrates such as electron-rich nonaflates and electron-poor sulfonamides. Kinetic data suggest reductive elimination to be the rate-limiting step for the reaction. The only limitation of this methodology that we have identified is the inability of 2,6-disubstituted aryl nonaflates to efficiently participate in the reaction.


Subject(s)
Palladium/chemistry , Sulfonamides/chemistry , Sulfonic Acids/chemistry , Catalysis , Hydrolysis , Kinetics , Ligands , Phosphines/chemistry
6.
Org Lett ; 11(4): 947-50, 2009 Feb 19.
Article in English | MEDLINE | ID: mdl-19178160

ABSTRACT

A general and practical method for the preparation of unsymmetrically substituted ureas has been developed utilizing palladium-catalyzed amidation. Both aryl bromides and chlorides, as well as heteroaryl chlorides, have been coupled to aryl, benzyl, and aliphatic ureas by using a novel nonproprietary bipyrazole ligand (bippyphos).


Subject(s)
Palladium/chemistry , Urea/analogs & derivatives , Urea/chemical synthesis , Catalysis , Combinatorial Chemistry Techniques , Molecular Structure , Urea/chemistry
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