Josiphos ligands explained

A Josiphos ligand is a type of chiral diphosphine which has been modified to be substrate-specific; they are widely used for enantioselective synthesis.[1] They are widely used in asymmetric catalysis.[2]

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.[3] [4]

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.[5] [6] 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.[7]

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).[7]

The ferrocene scaffold has proved to be versatile.[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°.

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.

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.[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).[18]
    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.[19] [20]
    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.[21]

    Modified Josiphos ligands

    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.

    References

    1. Blaser . Hans-Ulrich . Brieden . Walter . Pugin . Benoit . Spindler . Felix . Studer . Martin . Togni . Antonio . 2002 . Solvias Josiphos Ligands: From Discovery to Technical Applications . Topics in Catalysis . 19 . 1 . 3–16 . 10.1023/A:1013832630565.
    2. Book: Blaser . Hans-Ulrich . Josiphos Ligands: From Discovery to Technical Applications . Pugin . Benoît . Spindler . Felix . Mejía . Esteban . Togni . Antonio . 2011-04-06 . Wiley . 978-3-527-32704-1 . Zhou . Qi-Lin . 1 . 93–136 . en . 10.1002/9783527635207.ch3.
    3. Book: Spessard . Gary O. . Organometallic chemistry . Miessler . Gary L. . 2010 . Oxford University Press . 978-0-19-533099-1 . 2 . New York . 378–379.
    4. Elschenbroich, Christopher (2006). Organometallics: Third Edition. pp.518-519
    5. Togni . Antonio . 1996-03-27 . Developing New Chiral Ferrocenyl Ligands for Asymmetric Catalysis: A Personal Account . CHIMIA . 50 . 3 . 86 . 10.2533/chimia.1996.86 . 2673-2424. free .
    6. Ito . Yoshihiko. . Sawamura . Masaya. . Hayashi . Tamio. . October 1986 . Catalytic asymmetric aldol reaction: reaction of aldehydes with isocyanoacetate catalyzed by a chiral ferrocenylphosphine-gold(I) complex . Journal of the American Chemical Society . en . 108 . 20 . 6405–6406 . 10.1021/ja00280a056 . 0002-7863.
    7. 10.1002/hlca.202000192 . Having Fun (And Commercial Success) with Josiphos and Related Chiral Ferrocene Based Ligands . 2021 . Blaser . Hans Ulrich . Pugin . Benoît . Spindler . Felix . Helvetica Chimica Acta . 104 . 229427019 .
    8. Littke . Adam F. . Fu . Gregory C. . 2002-11-15 . Palladium-Catalyzed Coupling Reactions of Aryl Chlorides . Angewandte Chemie International Edition . 41 . 22 . 4176–4211 . 10.1002/1521-3773(20021115)41:22<4176::AID-ANIE4176>3.0.CO;2-U. 12434342 .
    9. Cai . Chaoxian . Rivera . Nelo R. . Balsells . Jaume . Sidler . Rick R. . McWilliams . J. Christopher . Shultz . C. Scott . Sun . Yongkui . 2006-10-01 . An Efficient Catalyst for Pd-Catalyzed Carbonylation of Aryl Arenesulfonates . Organic Letters . en . 8 . 22 . 5161–5164 . 10.1021/ol062208g . 17048868 . 1523-7060.
    10. Limmert . Michael E. . Roy . Amy H. . Hartwig . John F. . 2005-11-01 . Kumada Coupling of Aryl and Vinyl Tosylates under Mild Conditions . The Journal of Organic Chemistry . en . 70 . 23 . 9364–9370 . 10.1021/jo051394l . 0022-3263 . 16268609.
    11. Vo . Giang D. . Hartwig . John F. . 2009-08-12 . Palladium-Catalyzed Coupling of Ammonia with Aryl Chlorides, Bromides, Iodides, and Sulfonates: A General Method for the Preparation of Primary Arylamines . Journal of the American Chemical Society . en . 131 . 31 . 11049–11061 . 10.1021/ja903049z . 0002-7863 . 2823124 . 19591470.
    12. Blaser . Hans-Ulrich . Malan . Christophe . Pugin . Benoît . Spindler . Felix . Steiner . Heinz . Studer . Martin . January 2003 . Selective Hydrogenation for Fine Chemicals: Recent Trends and New Developments . Advanced Synthesis & Catalysis . en . 345 . 1–2 . 103–151 . 10.1002/adsc.200390000 . 1615-4150.
    13. Whitesell . James K. . 1989-11-01 . C2 symmetry and asymmetric induction . Chemical Reviews . en . 89 . 7 . 1581–1590 . 10.1021/cr00097a012 . 0009-2665.
    14. Inoguchi . Kiyoshi . Sakuraba . Shunji . Achiwa . Kazuo . 1992 . Design Concepts for Developing Highly Efficient Chiral Bisphosphine Ligands in Rhodium-Catalyzed Asymmetric Hydrogenations . Synlett . en . 1992 . 3 . 169–178 . 10.1055/s-1992-21306 . 196807901 . 0936-5214.
    15. Chen, W. and Blaser, H.U 2008 in Phosphorus Ligands in Asymmetric Catalysis: Synthesis and Applications. (e.d. A. Borner) pp. 359-393
    16. T. Hayashi, Comprehensive Asymmetric Catalyst, eds. E.N. Jacobsen, A. Pfaltz and H. Yamamoto, 1999 pp. 247
    17. Blaser . Hans-Ulrich . Buser . Hans-Peter . Jalett . Hans-Peter . Pugin . Benoit . Spindler . Felix . 1999-12-31 . Iridium Ferrocenyl Diphosphine Catalyzed Enantioselective Reductive Alkylation of a Hindered Aniline . Synlett . en . 1999 . Sup. 1 . 867–868 . 10.1055/s-1999-3106 . 99845649 . 0936-5214.
    18. Godard . Cyril . Ruiz . Aurora . Claver . Carmen . August 2006 . Systematic Study of the Asymmetric Methoxycarbonylation of Styrene Catalyzed by Palladium Systems Containing Chiral Ferrocenyl Diphosphine Ligands . Helvetica Chimica Acta . en . 89 . 8 . 1610–1622 . 10.1002/hlca.200690161 . 0018-019X.
    19. R.Fuchs, EP 803502(1996) assigned to Lonza A.G
    20. Studer . Martin . Wedemeyer-Exl . Christina . Spindler . Felix . Blaser . Hans-Ulrich . 2000-12-13 . Enantioselective Homogeneous Hydrogenation of Monosubstituted Pyridines and Furans . Monatshefte fuer Chemie/Chemical Monthly . 131 . 12 . 1335–1343 . 10.1007/s007060070013.
    21. E. Broger, Y. Crameri and P. Jones, WO 99/01 453. (1997), assigned to Hoffman-La Roche

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