ABSTRACT
An overview of Parkinson's disease (PD) prevalence, diagnosis, and currently available treatment options is provided. A comprehensive list of different classes of marketed pharmaceutical drug products and the syntheses of various drug substances are summarized based on published literature.
Subject(s)
Antiparkinson Agents , Parkinson Disease , Humans , Parkinson Disease/diagnosis , Parkinson Disease/drug therapy , Parkinson Disease/epidemiology , Pharmaceutical Preparations , Antiparkinson Agents/classification , PrevalenceABSTRACT
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 therapyABSTRACT
The total synthesis of N-methylwelwitindolinoneâ D isonitrile (1) has been achieved in 17 steps from a readily available carvone derivative. The route features a double C-H functionalization event involving a keto oxindole substrate to introduce the tetrahydrofuran ring of the natural product.
Subject(s)
Biological Products/chemical synthesis , Indole Alkaloids/chemical synthesis , Nitriles/chemical synthesis , Biological Products/chemistry , Carbon/chemistry , Crystallography, X-Ray , Cyclization , Cyclobutanes/chemistry , Hydrogen/chemistry , Imines/chemistry , Indole Alkaloids/chemistry , Molecular Conformation , Nitriles/chemistry , StereoisomerismABSTRACT
The welwitindolinones with bicyclo[4.3.1] cores are a class of natural products that have attracted tremendous interest from the synthetic community because of their fascinating structures and promising biological profiles. More than 15 research groups worldwide have reported progress toward these elusive natural products. This Minireview describes contemporary studies aimed at the total synthesis of these challenging targets, in addition to the two recently completed syntheses of welwitindolinones with bicyclo[4.3.1] cores reported by Rawal and Garg in 2011. Both of the completed efforts rely on C4-C11 bond constructions to access the congested bicyclic framework of these elusive natural products.
Subject(s)
Biological Products/chemical synthesis , Bridged Bicyclo Compounds/chemistry , Indole Alkaloids/chemistry , Biological Products/chemistry , Catalysis , Indole Alkaloids/chemical synthesis , Palladium/chemistry , Rhodium/chemistryABSTRACT
We report the total synthesis of (-)-N-methylwelwitindolinone C isonitrile, in addition to the total syntheses of the 3-hydroxylated welwitindolinones. Our routes to these elusive natural products feature the strategic use of a deuterium kinetic isotope effect to improve the efficiency of a late-stage nitrene insertion reaction. We also provide a computational prediction for the stereochemical configuration at C3 of the hydroxylated welwitindolinones, which was confirmed by experimental studies.
Subject(s)
Alkaloids/chemical synthesis , Biological Products/chemical synthesis , Alkaloids/chemistry , Biological Products/chemistry , Cyanobacteria/chemistry , Hydroxylation , Models, Molecular , Oxidation-Reduction , StereoisomerismABSTRACT
We report the first total synthesis of (-)-N-methylwelwitindolinone C isothiocyanate. Our route features a number of key transformations, including an indolyne cyclization to assemble the [4.3.1]-bicyclic scaffold, as well as a late-stage intramolecular nitrene insertion to functionalize the C11 bridgehead carbon en route to the natural product.
Subject(s)
Cyanobacteria/chemistry , Indole Alkaloids/chemical synthesis , Chemistry Techniques, Synthetic , Cyclization , Indoles/chemical synthesis , Indoles/chemistry , StereoisomerismABSTRACT
The mechanisms of the Fischer indole synthesis and competing cleavage pathways were explored with SCS-MP2/6-31G(d) and aqueous solvation calculations. Electron-donating substituents divert the reaction pathway to heterolytic N-N bond cleavage and preclude the acid-promoted [3,3]-sigmatropic rearrangement.
Subject(s)
Indoles/chemical synthesis , Indoles/chemistry , Models, Molecular , ThermodynamicsABSTRACT
Vinigrol, a diterpene natural product, has been a fascinating target for total synthesis for over two decades. This minireview describes recent synthetic studies that have ultimately allowed access to the coveted vinigrol scaffold. Barriault's synthesis of the vinigrol core is described, in addition to the elegant strategies disclosed by Njardarson and Hanna. The first total synthesis of vinigrol, reported by Baran in 2009, is also highlighted. This review showcases the fundamental role that natural products play in spawning innovations in synthetic chemistry.
Subject(s)
Diterpenes/chemical synthesis , Diterpenes/chemistry , Molecular Structure , StereoisomerismABSTRACT
A concise synthesis of the N-methylwelwitindolinone C isothiocyanate scaffold is disclosed. The approach relies on an indolyne cyclization to construct the [4.3.1]-bicyclic ring system present in the natural product. Subsequent oxidation of the indole core occurs with excellent diastereoselectivity to afford oxindole 2, the structure of which was confirmed by X-ray crystallographic analysis.
