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Josiphos ligands

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General scheme for a Josiphos ligand[1]

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]

History

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X-ray crystallographic structure of [(josiphos)Ir(cod)]+.[1] Color code: violet = P, blue = Fe, Ir.

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]

Reactions using Josiphos ligands

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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.[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
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

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Many variations of Josiphos ligands have been reported. One family is prepared from Ugi's amine.

Scheme for synthesis of modified Josiphos ligands

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

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  1. ^ a b c d Blaser, 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. S2CID 229427019.
  2. ^ a b c d 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. doi:10.1023/A:1013832630565.
  3. ^ a b c Blaser, Hans-Ulrich; Pugin, Benoît; Spindler, Felix; Mejía, Esteban; Togni, Antonio (2011-04-06). Zhou, Qi-Lin (ed.). Josiphos Ligands: From Discovery to Technical Applications (1 ed.). Wiley. pp. 93–136. doi:10.1002/9783527635207.ch3. ISBN 978-3-527-32704-1.
  4. ^ Spessard, Gary O.; Miessler, Gary L. (2010). Organometallic chemistry (2 ed.). New York: Oxford University Press. pp. 378–379. ISBN 978-0-19-533099-1.
  5. ^ Elschenbroich, Christopher (2006). Organometallics: Third Edition. pp.518-519
  6. ^ a b c d Togni, Antonio (1996-03-27). "Developing New Chiral Ferrocenyl Ligands for Asymmetric Catalysis: A Personal Account". CHIMIA. 50 (3): 86. doi:10.2533/chimia.1996.86. ISSN 2673-2424.
  7. ^ a b 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. 108 (20): 6405–6406. doi:10.1021/ja00280a056. ISSN 0002-7863.
  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. doi:10.1002/1521-3773(20021115)41:22<4176::AID-ANIE4176>3.0.CO;2-U. PMID 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. 8 (22): 5161–5164. doi:10.1021/ol062208g. ISSN 1523-7060. PMID 17048868.
  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. 70 (23): 9364–9370. doi:10.1021/jo051394l. ISSN 0022-3263. PMID 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. 131 (31): 11049–11061. doi:10.1021/ja903049z. ISSN 0002-7863. PMC 2823124. PMID 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. 345 (1–2): 103–151. doi:10.1002/adsc.200390000. ISSN 1615-4150.
  13. ^ Whitesell, James K. (1989-11-01). "C2 symmetry and asymmetric induction". Chemical Reviews. 89 (7): 1581–1590. doi:10.1021/cr00097a012. ISSN 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. 1992 (3): 169–178. doi:10.1055/s-1992-21306. ISSN 0936-5214. S2CID 196807901.
  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. ^ a b 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. 1999 (Sup. 1): 867–868. doi:10.1055/s-1999-3106. ISSN 0936-5214. S2CID 99845649.
  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. 89 (8): 1610–1622. doi:10.1002/hlca.200690161. ISSN 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. doi: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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