A Josiphos ligand is a family of chiral diphosphine ligands that are used for asymmetric catalysis. They feature a 1,2-disubstituted ferrocene backbone.
History
Modern enantioselective synthesis typically applies a well-chosen homogeneous catalyst for key steps. The ligands on these catalysts confer chirality. The Josiphos family of privileged ligands provides especially high yields in enantioselective synthesis.Elschenbroich, Christopher (2006). Organometallics: Third Edition. pp.518-519
In the early 1990s, Antonio Togni began studying at the Ciba (now Novartis) Central Research Laboratories previously-known ferrocenyl ligands for a Au(I)-catalyzed aldol reaction. Togni's team began considering diphosphine ligands, and technician Josi Puleo prepared the first ligands with secondary phosphines. The team applied Puleo's products in an Ru-catalyzed enamide hydrogenation synthesis; in a dramatic success, the reaction had e.e. >99% and a turnover frequency (TOF) 0.3 s−1. The same ligand proved useful in production of (S)-metolachlor, active ingredient in the most common herbicide in the United States. Synthesis requires enantioselective hydrogenation of an imine; after introduction of the catalyst, the reaction proceeds with 100% conversion, turnover number (TON) >7mil, and turnover frequency >0.5 ms−1. This process is the largest-scale application of enantioselective hydrogenation, producing over 10 kilotons/year of the desired product with 79% e.e.
Josiphos ligands also serve in non-enantioselective reactions: a Pd-catalyzed reaction of aryl chlorides and aryl vinyl tosylates with TON of 20,000 or higher, catalytic carbonylation, or Grignard and Negishi couplings A variety of Josiphos ligands are commercially available under licence from Solvias. The (R-S) and its enantiomer provide higher yields and enantioselectivities than the diastereomer (R,R).
The consensus for the naming is abbreviating the individual ligand as (R)-(S)-R2PF-PR'2. The substituent on the Cp is written in front of the F and the R on the chiral center after the F.
Reactions using Josiphos ligands Some reactions that are accomplished using M-Josiphos complexes as catalyst are listed below. Other reactions where Josiphos ligands can be used are: hydrogenation of C=N, C=C and C=O bonds, catalyzed allylic substitution, hydrocarboxylation, Michael addition, allylic alkylation, Heck-type reactions, oxabicycle ring-opening, and allylamine isomerization. Hydroboration of styrene
Conducted at -78 °C, the above reaction has e.e.'s up to 92% and TOF of 5-10 h−1.T. Hayashi, Comprehensive Asymmetric Catalyst, eds. E.N. Jacobsen, A. Pfaltz and H. Yamamoto, 1999 pp. 247 Hayashi's Rh-binap complex gives better yield. Hydroformylation of Styrene
This reaction scheme yields of up to 78% ee of the (R) product, but low TON and TOF of 10-210 and 1-14h−1 (respectively). Reductive amination
Above is the preparation of (S)-metolachlor. Good yields and a 100% conversion crucially require AcOH solvent. Hydrogenation of exocyclic methyl imine
This key step to synthesize a HIV integrase inhibitor, Crixivan, is one of the few known homogeneous heteroarene hydrogenation reactions. Bulky R groups increase the catalyst's performance, with 97% e.e. and TON and TOF of 1k and 8 min−1, respectively.R.Fuchs, EP 803502(1996) assigned to Lonza A.G Asymmetric synthesis of chromanoylpyridine derivatives
This reaction, for an intermediate in synthesis of an antihypertensive and anti-alopecic chromanoylpyridine derivative, exhibits high enantioselectivity, but low activity.E. Broger, Y. Crameri and P. Jones, WO 99/01 453. (1997), assigned to Hoffman-La Roche
Modified Josiphos ligands The ferrocene scaffold has proved to be versatile.Chen, W. and Blaser, H.U 2008 in Phosphorus Ligands in Asymmetric Catalysis: Synthesis and Applications. (e.d. A. Borner) pp. 359-393
Many variations of Josiphos ligands have been reported. One family is prepared from Ugi's amine.
An important improvement on initial syntheses has been using N(CH3)2 as a leaving group over acetate, although an acetic acid solvent gives better yields.
Further reading
References