A Josiphos ligand is a type of chiral diphosphine which has been modified to be substrate-specific; they are widely used for enantioselective synthesis.^[2] They are widely used in asymmetric catalysis.^[3]

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.^[4][5]

In the early 1990s, Antonio Togni began studying at the Ciba (now Novartis) Central Research Laboratories^[6] previously-known^[7] ferrocenyl ligands for a Au(I)-catalyzed aldol reaction.^[6] 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.^[6][7] 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.^{[2] [1]}

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,^[8] catalytic carbonylation,^[9] or Grignard and Negishi couplings^[10][11] 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).^[1]

The ferrocene scaffold has proved to be versatile.^{[12] [13][14]}

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.^[2]

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.^{[citation needed]}

Hydroboration of styrene

Conducted at -78 °C, the above reaction has e.e.'s up to 92% and TOF of 5-10 h⁻¹.^[15] Hayashi's Rh-binap complex gives better yield.^[16]

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).^[2][17]

Reductive amination

Above is the preparation of (S)-metolachlor. Good yields and a 100% conversion crucially require AcOH solvent.^[16]

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.^[18][19]

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.^[20]

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.^[6]

Clevenger, Andrew L.; Stolley, Ryan M.; Aderibigbe, Justis; Louie, Janis (2020). "Trends in the Usage of Bidentate Phosphines as Ligands in Nickel Catalysis". Chemical Reviews. 120 (13): 6124–6196. doi:10.1021/acs.chemrev.9b00682. PMID 32491839.