ABSTRACT
We describe a full account of our synthetic strategy leading to the first total synthesis of the manzamine alkaloid lissodendoric acid A . These efforts demonstrate that strained cyclic allenes are valuable synthetic building blocks and can be employed efficiently in total synthesis.
Subject(s)
Alkaloids , Stereoisomerism , Alkaloids/chemical synthesis , Alkaloids/chemistry , Molecular StructureABSTRACT
In this study, we establish that conjugated enynes undergo selective 1,4-hydroamination under Pd catalysis to deliver chiral allenes with pendant allylic amines. Several primary and secondary aliphatic and aryl-substituted amines couple with a wide range of mono- and disubstituted enynes in a nonenantioselective reaction where DPEphos serves as the ligand for Pd. Benzophenone imine acts as an ammonia surrogate to afford primary amines in a two-step/one-pot process. Examination of chiral catalysts revealed a high degree of reversibility in the C-N bond formation that negatively impacted enantioselectivity. Consequently, an electron-poor ferrocenyl-PHOX ligand was developed to enable efficient and enantioselective enyne hydroamination.
Subject(s)
Alkadienes/chemical synthesis , Alkynes/chemistry , Palladium/chemistry , Alkadienes/chemistry , Amination , Catalysis , Molecular Structure , StereoisomerismABSTRACT
We report a highly enantioselective Pd-PHOX-catalyzed intermolecular hydroalkylation of acyclic 1,3-dienes. Meldrum's acid derivatives and other activated C-pronucleophiles, such as ß-diketones and malononitriles, react with a variety of aryl- and alkyl-substituted dienes in ≤20 h at room temperature. The coupled products, obtained in up to 96% yield and 97.5:2.5 er, are easily transformed into useful chemical building blocks for downstream synthesis.
Subject(s)
Alkadienes/chemistry , Ketones/chemistry , Nitriles/chemistry , Palladium/chemistry , Alkylation , Catalysis , Molecular Structure , Stereoisomerism , TemperatureABSTRACT
We report a method for the catalytic, enantioselective intermolecular addition of aliphatic amines to acyclic 1,3-dienes. In most cases, reactions proceed efficiently at or below room temperature in the presence of 5 mol % of a Pd catalyst bearing a PHOX ligand, generating allylic amines in up to 97:3 er. The presence of an electron-deficient phosphine within the ligand not only leads to a more active catalyst but also is critical for achieving high site selectivity in the transformation.
Subject(s)
Alkadienes/chemistry , Allyl Compounds/chemical synthesis , Amines/chemistry , Amines/chemical synthesis , Organometallic Compounds/chemistry , Oxazoles/chemistry , Palladium/chemistry , Allyl Compounds/chemistry , Catalysis , Molecular Structure , StereoisomerismABSTRACT
Small rings that contain allenes are unconventional transient compounds that have been known since the 1960s. Despite being discovered around the same time as benzyne and offering a number of synthetically advantageous features, strained cyclic allenes have seen relatively little use in chemical synthesis. We report a concise total synthesis of the manzamine alkaloid lissodendoric acid A, which hinges on the development of a regioselective, diastereoselective, and stereospecific trapping of a fleeting cyclic allene intermediate. This key step swiftly assembles the azadecalin framework of the natural product, allows for a succinct synthetic endgame, and enables a 12-step total synthesis (longest linear sequence; 0.8% overall yield). These studies demonstrate that strained cyclic allenes are versatile building blocks in chemical synthesis.
ABSTRACT
We report the enantioselective formation of quaternary stereogenic centers by the intermolecular addition of malononitrile, an acyl anion equivalent, and related pronucleophiles to several 1,3-disubstituted acyclic 1,3-dienes in the presence of a Pd-PHOX catalyst. Products are obtained in up to 88% yield and 99:1 er and in most cases are formed as a single regioisomer. The products' malononitrile unit undergoes oxidative functionalization to afford ß,γ-unsaturated carbonyls bearing internal olefins and α-quaternary stereogenic centers.
ABSTRACT
We describe the development of Pd-PHOX-catalysed enantioselective couplings of internal dienes with malononitrile and other activated C-pronucleophiles. Reactions are dramatically accelerated by the addition of Et3N·HBArF 4 as a Brønsted acid co-catalyst, enabling a suite of products bearing a variety of alkyl substituents at the stereogenic carbon to be prepared. A series of mechanism-oriented experiments reveal key aspects of the catalytic cycle and the importance of the non-coordinating BArF 4 counterion in not only promoting reactions of internal dienes but also additions of previously unreactive nucleophiles towards terminal dienes.