:Josiphos ligands

File:CSD CIF ASERAR.png structure of [(josiphos)Ir(cod)]⁺. 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.{{Cite book |last1=Spessard |first1=Gary O. |title=Organometallic chemistry |last2=Miessler |first2=Gary L. |date=2010 |publisher=Oxford University Press |isbn=978-0-19-533099-1 |edition=2 |location=New York |pages=378–379}}Elschenbroich, Christopher (2006). Organometallics: Third Edition. pp.518-519

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.{{Cite journal |last=Togni |first=Antonio |date=1996-03-27 |title=Developing New Chiral Ferrocenyl Ligands for Asymmetric Catalysis: A Personal Account |url=https://chimia.ch/chimia/article/view/1996_086 |journal=CHIMIA |volume=50 |issue=3 |pages=86 |doi=10.2533/chimia.1996.86 |issn=2673-2424|doi-access=free }}{{Cite journal |last1=Ito |first1=Yoshihiko. |last2=Sawamura |first2=Masaya. |last3=Hayashi |first3=Tamio. |date=October 1986 |title=Catalytic asymmetric aldol reaction: reaction of aldehydes with isocyanoacetate catalyzed by a chiral ferrocenylphosphine-gold(I) complex |url=https://pubs.acs.org/doi/abs/10.1021/ja00280a056 |journal=Journal of the American Chemical Society |language=en |volume=108 |issue=20 |pages=6405–6406 |doi=10.1021/ja00280a056 |issn=0002-7863|url-access=subscription }} 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.

{{cite journal |doi=10.1002/hlca.202000192 |title=Having Fun (And Commercial Success) with Josiphos and Related Chiral Ferrocene Based Ligands |date=2021 |last1=Blaser |first1=Hans Ulrich |last2=Pugin |first2=Benoît |last3=Spindler |first3=Felix |journal=Helvetica Chimica Acta |volume=104 |s2cid=229427019 }}

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,{{Cite journal |last1=Littke |first1=Adam F. |last2=Fu |first2=Gregory C. |date=2002-11-15 |title=Palladium-Catalyzed Coupling Reactions of Aryl Chlorides |url=https://onlinelibrary.wiley.com/doi/10.1002/1521-3773(20021115)41:223.0.CO;2-U |journal=Angewandte Chemie International Edition |volume=41 |issue=22 |pages=4176–4211 |doi=10.1002/1521-3773(20021115)41:22<4176::AID-ANIE4176>3.0.CO;2-U|pmid=12434342 |url-access=subscription }} catalytic carbonylation,{{Cite journal |last1=Cai |first1=Chaoxian |last2=Rivera |first2=Nelo R. |last3=Balsells |first3=Jaume |last4=Sidler |first4=Rick R. |last5=McWilliams |first5=J. Christopher |last6=Shultz |first6=C. Scott |last7=Sun |first7=Yongkui |date=2006-10-01 |title=An Efficient Catalyst for Pd-Catalyzed Carbonylation of Aryl Arenesulfonates |url=https://pubs.acs.org/doi/10.1021/ol062208g |journal=Organic Letters |language=en |volume=8 |issue=22 |pages=5161–5164 |doi=10.1021/ol062208g |pmid=17048868 |issn=1523-7060|url-access=subscription }} or Grignard and Negishi couplings{{Cite journal |last1=Limmert |first1=Michael E. |last2=Roy |first2=Amy H. |last3=Hartwig |first3=John F. |date=2005-11-01 |title=Kumada Coupling of Aryl and Vinyl Tosylates under Mild Conditions |url=https://pubs.acs.org/doi/10.1021/jo051394l |journal=The Journal of Organic Chemistry |language=en |volume=70 |issue=23 |pages=9364–9370 |doi=10.1021/jo051394l |issn=0022-3263 |pmid=16268609|url-access=subscription }}{{Cite journal |last1=Vo |first1=Giang D. |last2=Hartwig |first2=John F. |date=2009-08-12 |title=Palladium-Catalyzed Coupling of Ammonia with Aryl Chlorides, Bromides, Iodides, and Sulfonates: A General Method for the Preparation of Primary Arylamines |journal=Journal of the American Chemical Society |language=en |volume=131 |issue=31 |pages=11049–11061 |doi=10.1021/ja903049z |issn=0002-7863 |pmc=2823124 |pmid=19591470}} 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).

The ferrocene scaffold has proved to be versatile.{{cite journal |doi=10.1021/cr000427o |title=A Concise Update on the Applications of Chiral Ferrocenyl Phosphines in Homogeneous Catalysis Leading to Organic Synthesis |date=2003 |last1=Colacot |first1=Thomas J. |journal=Chemical Reviews |volume=103 |issue=8 |pages=3101–3118 |pmid=12914493 }}

{{Cite journal |last1=Blaser |first1=Hans-Ulrich |last2=Malan |first2=Christophe |last3=Pugin |first3=Benoît |last4=Spindler |first4=Felix |last5=Steiner |first5=Heinz |last6=Studer |first6=Martin |date=January 2003 |title=Selective Hydrogenation for Fine Chemicals: Recent Trends and New Developments |url=https://onlinelibrary.wiley.com/doi/10.1002/adsc.200390000 |journal=Advanced Synthesis & Catalysis |language=en |volume=345 |issue=1–2 |pages=103–151 |doi=10.1002/adsc.200390000 |issn=1615-4150|url-access=subscription }}Chen, W. and Blaser, H.U 2008 in Phosphorus Ligands in Asymmetric Catalysis: Synthesis and Applications. (e.d. A. Borner) pp. 359-393

The 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.

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|date=January 2021}}

; Hydroboration of styrene

:File:HB of styrene.png

:Conducted at -78 °C, the above reaction has e.e.'s up to 92% and TOF of 5-10 h⁻¹.T. Hayashi, Comprehensive Asymmetric Catalyst, eds. E.N. Jacobsen, A. Pfaltz and H. Yamamoto, 1999 pp. 247 Hayashi's Rh-binap complex gives better yield.{{Cite journal |last1=Blaser |first1=Hans-Ulrich |last2=Buser |first2=Hans-Peter |last3=Jalett |first3=Hans-Peter |last4=Pugin |first4=Benoit |last5=Spindler |first5=Felix |date=1999-12-31 |title=Iridium Ferrocenyl Diphosphine Catalyzed Enantioselective Reductive Alkylation of a Hindered Aniline |url=http://www.thieme-connect.de/DOI/DOI?10.1055/s-1999-3106 |journal=Synlett |language=en |volume=1999 |issue=Sup. 1 |pages=867–868 |doi=10.1055/s-1999-3106 |s2cid=99845649 |issn=0936-5214|url-access=subscription }}

; Hydroformylation of Styrene

:File:Hydroformylation of styrene.png

: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).{{Cite journal |last1=Godard |first1=Cyril |last2=Ruiz |first2=Aurora |last3=Claver |first3=Carmen |date=August 2006 |title=Systematic Study of the Asymmetric Methoxycarbonylation of Styrene Catalyzed by Palladium Systems Containing Chiral Ferrocenyl Diphosphine Ligands |url=https://onlinelibrary.wiley.com/doi/10.1002/hlca.200690161 |journal=Helvetica Chimica Acta |language=en |volume=89 |issue=8 |pages=1610–1622 |doi=10.1002/hlca.200690161 |issn=0018-019X|url-access=subscription }}

;Reductive amination

:File:Amination of s metolachlor.png

:Above is the preparation of (S)-metolachlor. Good yields and a 100% conversion crucially require AcOH solvent.

;Hydrogenation of exocyclic methyl imine

:File:Exocyclic imine hydrogenation.png

: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.R.Fuchs, EP 803502(1996) assigned to Lonza A.G{{Cite journal |last1=Studer |first1=Martin |last2=Wedemeyer-Exl |first2=Christina |last3=Spindler |first3=Felix |last4=Blaser |first4=Hans-Ulrich |date=2000-12-13 |title=Enantioselective Homogeneous Hydrogenation of Monosubstituted Pyridines and Furans |url=http://link.springer.com/10.1007/s007060070013 |journal=Monatshefte fuer Chemie/Chemical Monthly |volume=131 |issue=12 |pages=1335–1343 |doi=10.1007/s007060070013|url-access=subscription }}

;Asymmetric synthesis of chromanoylpyridine derivatives

:File:HIV rxn.png

:This reaction, for an intermediate in synthesis of an antihypertensive and anti-alopecic chromanoylpyridine derivative, exhibits high enantioselectivity, but low activity.E. Broger, Y. Crameri and P. Jones, WO 99/01 453. (1997), assigned to Hoffman-La Roche

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

File:Josiphos_synth_scheme.png

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.

{{cite journal |doi=10.1021/acs.chemrev.9b00682 |title=Trends in the Usage of Bidentate Phosphines as Ligands in Nickel Catalysis |date=2020 |last1=Clevenger |first1=Andrew L. |last2=Stolley |first2=Ryan M. |last3=Aderibigbe |first3=Justis |last4=Louie |first4=Janis |journal=Chemical Reviews |volume=120 |issue=13 |pages=6124–6196 |pmid=32491839 }}

Category:Coordination chemistry

Category:Phosphines

Category:Ferrocenes

Category:Ligands

Category:Diphosphines