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An asymmetric synthesis of the 2,5-diphenylphosphol-2-ene fragment (! 95% ee) has been realized via enantioselective Cinchona-alkaloid catalyzed double bond isomerization of a meso-2,5-diphenylphosphol-3-ene amide to a 2,5-diphenylphosphol-2-ene amide (up to 83% ee), followed by enantiomeric enrichment to ! 95% ee by crystallization. The 2,5-diphenylphosphol-2-ene amide (a cyclic phosphinic acid amide) was hydrolyzed to the 2,5-diphenylphosphol-2-ene acid (a cyclic phosphinic acid) with retention of configuration at C-5.Keywords: alkaloids; alkenes; asymmetric catalysis; Cinchona alkaloids; isomerization; phosphorus heterocycles Enantiopure phospholanes are building blocks in the synthesis of chiral 2,5-dialkylphospholane ligands that find widespread use in asymmetric transition metalcatalyzed hydrogenation and other reactions.[1] Limitations in synthetic methodology had prevented the access to 2,5-diarylphospholanes, until Fiaud and coworkers presented a synthesis and resolution of rac-2,5-diphenylphospholanic acid (AE )-1 [2,3] via the McCormack reaction of 1,4-diphenyl-1,3-butadiene (2) (Scheme 1).[4] The resolved acid 1 is the starting material for the synthesis of a number of 2,5-diphenylphospholane ligands that have already proved successful in various transition metal-catalyzed asymmetric reactions and other applications. [3,5,6] The procedure of Scheme 1 requires stoichiometric quantities of chiral resolving agents and obviously yields a maximum of 50% for each enantiomer of 1. An attempt to convert this route to an enantioselective synthesis via sparteine/sec-BuLi deprotonation/reprotonation of meso-1,2,5-triphenylphospholane oxide suffered from low yields or selectivities, [7] even though a corresponding a-alkylation via deprotonation with chiral lithium amides and an electrophilic quench was possible. [8] We now present a catalytic asymmetric synthesis of phospholenes that relies on the new concept of organocatalytic enantioselective double-bond isomerization.[9] This chemistry represents another extension of organocatalysis towards a reaction type that has previously been associated with the field of metal catalysis. [10,11] For realizing an efficient asymmetric synthesis of phospholane acid 1, the catalytic asymmetric isomerization of meso-phospholane 4 to enriched A C H T U N G T R E N N U N G cis,trans-phospholane 5 is a very desirable reaction, since it would convert the existing efficient synthetic sequence [3] into an asymmetric catalytic one (Scheme 2, a).Initial experiments showed that such a process is difficult to realize because it requires strongly basic reaction conditions that are difficult to achieve with usual types of chiral base catalysts.[12] On the other hand, the meso-phospholene 3, which is the initial Scheme 1. Fiauds route (R = Me) to 2,5-diphenylphospholanic acid 1.

Abstract:The nickel-catalyzed coupling of thiophene with aryl Grignard reagents (Wenkert reaction) is accelerated by N-heterocyclic carbene or trialkylphosphane ligands, providing a general, scalable direct synthesis of symmetrical 1,4-diarylbutadienes.

The potential for an organocatalytic asymmetric stereoisomerization or alkene isomerization as atom-economic reaction with minimal structural change was investigated. The McCormack cycloaddition of 1,4-diarylbuta-1,3-dienes with (dialkylamino)dichlorophosphane and aluminum trichloride gives meso-2,5-diaryl-1-(dialkylamino)-1-oxo-2,5-dihydro-1H-phospholes, which were identified as suitable substrates for asymmetric isomerization to (1R,5R)-2,5-diaryl-1-(dialkylamino)-1-oxo-4,5-dihydro-1H-phospholes in the presence of bifunctional organocatalysts (cinchona alkaloids, Takemoto catalyst) in up to 91% ee and quantitative yield. The substrate range and the mechanism of the catalysis were studied. The reaction involves proton abstraction by the base, but a primary deuterium KIE is absent. Enriched (1R,5R)-1-(diethylamino)-1-oxo-2,5-diphenyl-4,5-dihydro-1H-phosphole was hydrolyzed to (5R)-1-hydroxy-1-oxo-2,5-diphenyl-4,5-dihydro-1H-phosphole, which was hydrogenated diastereoselectively under dissolving metal conditions to give (2R,5R)-1-hydroxy-1-oxo-2,5-diphenylphospholane (Fiaud's acid) in preference to meso-1-hydroxy-1-oxo-2,5-diphenylphospholane. An asymmetric catalytic total synthesis of Fiaud's acid, which is a building block for chiral phospholane synthesis, has been realized in five steps from thiophene, using nickelcatalyzed Wenkert arylation, McCormack cycloaddition, asymmetric dihydro-1H-phosphole isomerization, hydrolysis, and diastereoselective hydrogenation.

Aminale à la carte: Grignard‐Reagentien gehen mit China‐Alkaloiden eine überraschende nucleophile aromatische Addition ein, bei der stereoselektiv cyclische Aminale entstehen. Dieses simple Verfahren zur nucleophilen Alkylierung macht eine Vielzahl strukturell unterschiedlicher Alkaloidderivate mit starren Gerüsten und reaktiven funktionellen Gruppen (Beispiele sind gezeigt) einfach zugänglich.