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]
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]
![X-ray crystallographic structure of [(josiphos)Ir(cod)] . Color code: violet = P, blue = Fe, Ir. CSD CIF ASERAR.png](http://upload.wikimedia.org/wikipedia/commons/thumb/8/84/CSD_CIF_ASERAR.png/220px-CSD_CIF_ASERAR.png)
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. [3] [12] [13] [14] [15] One structural parameter that influences reactivity is the bite angle. The P1-M-P2 angle has an average value of 92.7°. [3]
The general 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 ]
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]
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