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.[1] They are named after the technician who made the first one, Josi Puleo.[2]

Introduction

Modern enantioselective synthesis typically applies a well-chosen homogeneous catalyst for key steps. The ligands on these catalysts are essential to a reaction's success (or failure): they influence the chemoselectivity of the catalyst, especially the catalyzed reaction's chirality. Thus a powerful technique in the development of homogenously-catalyzed reactions is to modify ligands to select the desired substrates. 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[5] previously-known[6] ferrocenyl ligands for a Au(I)-catalyzed aldol reaction.[5] 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]

Xyliphos ligand

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.[1][3][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]

General conformation in a Josiphos ligand complex

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).[2][12]

The ferrocene scaffold has proved to be versatile.[2][13][14][15][16] One structural parameter that influences reactivity is the bite angle. The P1-M-P2 angle has an average value of 92.7°.[2]

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.[1]

Synthesis of Josiphos ligands

The modern preparation of Josiphos ligands starts from Ugi's amine.

Scheme for general synthesis of the 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.[5]

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.[17] Hayashi's Rh-binap complex gives better yield.[18]
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).[1][19]
Reductive amination
Above is the preparation of (S)-metolachlor. Good yields and a 100% conversion crucially require AcOH solvent.[18]
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.[20][21]
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.[22]

References

  1. 1 2 3 4 5 H-U. Blaser, W. Brieden, B. Pugin, F. Spindler, M. Studer and A. Togni, Top. Catal., 2002, 19, 3.
  2. 1 2 3 4 Qi-Lin Zhou (2011), Privileged Chiral Ligands and Catalysts, pp. 93-127
  3. 1 2 Spessard, Gary and Miessler, Gary (2010). Organometallic Chemistry: Second Edition. pp. 378-379.
  4. ↑ Elschenbroich, Christopher (2006). Organometallics: Third Edition. pp.518-519
  5. 1 2 3 4 Togni, Chimia., 1996, 50, 86.
  6. 1 2 Ito, M. Sawamura and T. Hayashi, J. Am. Chem. Soc. 1986, 108, 6405.
  7. ↑ Desai, A. (4 Oct 2009). "The Story of (S)-Metolachlor: An Industrial Odyssey in Asymmetric Catalysis" (lecture slides). Lansing: Michigan State University. Archived 31 May 2017 at the Internet Archive.
  8. ↑ Littke, A.F and Fu, GG, Angew. Chem. Int. Ed., 2002, 41, 4176.
  9. ↑ Cai, C., Rivera, N.R., Balsells, J., Sidler, R.S., MC Williams, J.C., Schultz, C.S and Sun Y, Org. Lett, 2006, 8, 5161
  10. ↑ Limmert, M.E., Roy., A.J and Hartwig J.F, J. Org. Chem., 2005, 70, 9364
  11. ↑ Alvaro, E and Hartwig, J.F, J. Am. Chem. Soc., 2009, 131, 7858
  12. ↑ Thommen, M and Blasr, H.U Pharma Chem, 2002, 33-34
  13. ↑ Blaser, H.U., Malan,C., Pugin, B., Spindler, F.,Steiner, H., and Studer, M, 2003. Adv. Synth. Catal, 345, 103-152
  14. ↑ Whitesell, J.K Chem. Rev,. 1989, 89, 1581
  15. ↑ Inoguchi, K., Sakuraba, S., and Achiwa, K. Synlett, 1992, 169
  16. ↑ Chen, W. and Blaser, H.U 2008 in Phosphorus Ligands in Asymmetric Catalysis: Synthesis and Applications. (e.d. A. Borner) pp. 359-393
  17. ↑ T. Hayashi, Comprehensive Asymmetric Catalyst, eds. E.N. Jacobsen, A. Pfaltz and H. Yamamoto, 1999 pp. 247
  18. 1 2 H.U. Blaser, H.P. Buser, H.P. Jalett, B. Pugin and F. Spindler, Synlett. 1999, 867
  19. ↑ Godard, C., Ruiz, A., and Claver C. Helv. Chim. Acta, 2006, 89, 1610
  20. ↑ R.Fuchs, EP 803502(1996) assigned to Lonza A.G
  21. ↑ M.Studer, C. Wedemeyer-Exl, F.Spindler and H.U Blaser, Monatsh. Chem, 2000, 131, 1335
  22. ↑ E. Broger, Y. Crameri and P. Jones, WO 99/01 453. (1997), assigned to Hoffman-La Roche
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