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
enamidehydrogenation 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]
Conducted at -78 °C, the above reaction has e.e.'s up to 92% and TOF of 5-10 h−1.[16] Hayashi's Rh-binap complex gives better yield.[17]
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][18]
Reductive amination
Above is the preparation of
(S)-metolachlor. Good yields and a 100% conversion crucially require AcOH solvent.[17]
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.[19][20]
Asymmetric synthesis of chromanoylpyridine derivatives
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]
References
^
abcdBlaser, Hans Ulrich; Pugin, Benoît; Spindler, Felix (2021). "Having Fun (And Commercial Success) with Josiphos and Related Chiral Ferrocene Based Ligands". Helvetica Chimica Acta. 104.
doi:
10.1002/hlca.202000192.
S2CID229427019.