:Bisoxazoline ligand

{{further|Oxazoline#Synthesis}}

The synthesis of oxazoline rings is well established and in general proceeded via the cyclisation of a 2‑amino alcohol with any of a number of suitable functional groups. In the case of bis(oxazoline)s, synthesis is most conveniently achieved by using bi-functional starting materials; as this allows both rings to be produced at once. Of the materials suitable, dicarboxylic or dinitrile compounds are the most commonly available and hence the majority bis(oxazoline) ligands are produced from these materials.

File:BOX and PyBOX general synthesis.png

Part of the success of the BOX and PyBOX motifs lies in their convenient one step synthesis from malononitrile and dipicolinic acid, which are commercially available at low expense.

Chirality is introduced with the amino alcohols, as these are prepared from amino acids and hence are chiral (e.g. valinol).

In general, for methylene bridged BOX ligands the stereochemical outcome is consistent with a twisted square planar intermediate that was proposed based on related crystal structures.{{cite journal|last=Evans|first=David A.|author2=Miller, Scott J. |author3=Lectka, Thomas |author4= von Matt, Peter |title=Chiral Bis(oxazoline)copper(II) Complexes as Lewis Acid Catalysts for the Enantioselective Diels−Alder Reaction|journal=Journal of the American Chemical Society|date=1 August 1999|volume=121|issue=33|pages=7559–7573|doi=10.1021/ja991190k}}{{cite journal|last=Thorhauge|first=Jacob|author2=Roberson, Mark |author3=Hazell, Rita G. |author4= Jørgensen, Karl Anker |title=On the Intermediates in Chiral Bis(oxazoline)copper(II)-Catalyzed Enantioselective Reactions—Experimental and Theoretical Investigations|journal=Chemistry: A European Journal|date=15 April 2002|volume=8|issue=8|pages=1888|doi=10.1002/1521-3765(20020415)8:8<1888::AID-CHEM1888>3.0.CO;2-9}} The substituent at the oxazoline's 4-position blocks one enantiotopic face of the substrate, leading to enantioselectivity. This is demonstrated in the following aldol-type reaction,{{cite journal|last1=Evans|first1=David A.|last2=Burgey|first2=Christopher S.|last3=Kozlowski|first3=Marisa C.|author-link3=Marisa Kozlowski|last4=Tregay|first4=Steven W.|date=1 February 1999|title=Symmetric Copper(II) Complexes as Chiral Lewis Acids. Scope and Mechanism of the Catalytic Enantioselective Aldol Additions of Enolsilanes to Pyruvate Esters|journal=Journal of the American Chemical Society|volume=121|issue=4|pages=686–699|doi=10.1021/ja982983u}} but is applicable to a wide variety of reactions such as Mannich-type reactions,{{cite journal|last=Marigo|first=Mauro|author2=Kjærsgaard, Anne |author3=Juhl, Karsten |author4=Gathergood, Nicholas |author5= Jørgensen, Karl Anker |title=Direct Catalytic Asymmetric Mannich Reactions of Malonates and -Keto Esters|journal=Chemistry: A European Journal|date=23 May 2003|volume=9|issue=10|pages=2359–2367|doi=10.1002/chem.200204679|pmid=12772311}} ene reaction,{{cite journal|last=Evans|first=David A.|author2=Burgey, Christopher S. |author3=Paras, Nick A. |author4=Vojkovsky, Tomas |author5= Tregay, Steven W. |title=C2-Symmetric Copper(II) Complexes as Chiral Lewis Acids. Enantioselective Catalysis of the Glyoxylate−Ene Reaction|journal=Journal of the American Chemical Society|date=1 June 1998|volume=120|issue=23|pages=5824–5825|doi=10.1021/ja980549m}} Michael addition,{{cite journal|last=Evans|first=David A.|author2=Willis, Michael C. |author3=Johnston, Jeffrey N. |title=Catalytic Enantioselective Michael Additions to Unsaturated Ester Derivatives Using Chiral Copper(II) Lewis Acid Complexes|journal=Organic Letters|date=1 September 1999|volume=1|issue=6|pages=865–868|doi=10.1021/ol9901570|pmid=10823215}} Nazarov cyclization,{{cite journal|last=Aggarwal|first=Varinder K.|author2=Belfield, Andrew J.|title=Catalytic Asymmetric Nazarov Reactions Promoted by Chiral Lewis Acid Complexes|journal=Organic Letters|date=1 December 2003|volume=5|issue=26|pages=5075–5078|doi=10.1021/ol036133h|pmid=14682768}} and hetero-Diels-Alder reaction.{{cite journal|last=Yao|first=Sulan|author2=Johannsen, Mogens |author3=Audrain, Hélène |author4=Hazell, Rita G. |author5= Jørgensen, Karl Anker |title=Catalytic Asymmetric Hetero-Diels−Alder Reactions of Ketones: Chemzymatic Reactions|journal=Journal of the American Chemical Society|date=1 September 1998|volume=120|issue=34|pages=8599–8605|doi=10.1021/ja981710w}}

File:Box Stereochemical model.PNG

On the other hand, two-point binding on a Lewis acid bearing the meridially tridentate PyBOX ligand would result in a square pyramidal complex. A study using (benzyloxy)acetaldehyde as the electrophile showed that the stereochemical outcome is consistent with the carbonyl oxygen binding equatorially and the ether oxygen binding axially.{{cite journal|last=Evans|first=David A.|author2=Kozlowski, Marisa C. |author3=Murry, Jerry A. |author4=Burgey, Christopher S. |author5=Campos, Kevin R. |author6=Connell, Brian T. |author7= Staples, Richard J. |title=C₂-Symmetric Copper(II) Complexes as Chiral Lewis Acids. Scope and Mechanism of Catalytic Enantioselective Aldol Additions of Enolsilanes to (Benzyloxy)acetaldehyde|journal=Journal of the American Chemical Society|date=1 February 1999|volume=121|issue=4|pages=669–685|doi=10.1021/ja9829822}}

File:PyBox Stereochemical model.PNG

Metal complexes incorporating bis(oxazoline) ligands are effective for a wide range of asymmetric catalytic transformations and have been the subject of numerous literature reviews.{{cite journal|last=Ghosh|first=Arun K.|author2=Mathivanan, Packiarajan |author3=Cappiello, John |title=C₂-Symmetric chiral bis(oxazoline)–metal complexes in catalytic asymmetric synthesis|journal=Tetrahedron: Asymmetry|year=1998|volume=9|issue=1|pages=1–45|doi=10.1016/S0957-4166(97)00593-4|pmid=30457575|pmc=6234853}}{{cite journal|last=Johnson|first=Jeffrey S.|author2=Evans, David A.|title=Chiral Bis(oxazoline) Copper(II) Complexes: Versatile Catalysts for Enantioselective Cycloaddition, Aldol, Michael, and Carbonyl Ene Reactions|journal=Accounts of Chemical Research|date=1 June 2000|volume=33|issue=6|pages=325–335|doi=10.1021/ar960062n|pmid=10891050}}{{cite journal|last=Desimoni|first=Giovanni|author2=Faita, Giuseppe |author3=Jørgensen, Karl Anker |title=Update 1 of: C₂-Symmetric Chiral Bis(oxazoline) Ligands in Asymmetric Catalysis|journal=Chemical Reviews|date=9 November 2011|volume=111|issue=11|pages=PR284–PR437|doi=10.1021/cr100339a|pmid=22077602}} The neutral character of bis(oxazoline)s makes them well suited to use with noble metals, with copper complexes being particularly common. Their most important and commonly used applications are in carbon–carbon bond forming reactions.

bis(oxazoline) ligands have been found to be effective for a range of asymmetric cycloaddition reactions, this began with the very first application of BOX ligands in carbenoid cyclopropanations and has been expanded to include 1,3-Dipolar cycloaddition and Diels-Alder reactions. Bisoxazoline ligands have also been found to be effective for aldol, Michael and ene reactions, amongst many others

The success of bis(oxazoline) ligands for carbenoid cyclopropanations led to their application for aziridination. Another common reaction is hydrosilylation, which dates back to the first use of PyBOX ligands. Other niche applications include as fluorination catalysts{{cite journal|last=Ma|first=Jun-An|author2=Cahard, Dominique|title=Copper(II) triflate-bis(oxazoline)-catalysed enantioselective electrophilic fluorination of β-ketoesters|journal=Tetrahedron: Asymmetry|year=2004|volume=15|issue=6|pages=1007–1011|doi=10.1016/j.tetasy.2004.01.014}} and for Wacker-type cyclisations.{{cite journal|last=Uozumi|first=Yasuhiro|author2=Kyota, Hirokazu |author3=Kato, Kazuhiko |author4=Ogasawara, Masamichi |author5= Hayashi, Tamio |title=Design and Preparation of 3,3'-Disubstituted 2,2'-Bis(oxazolyl)-1,1'-binaphthyls (boxax): New Chiral Bis(oxazoline) Ligands for Catalytic Asymmetric Wacker-Type Cyclization|journal=The Journal of Organic Chemistry|date=1 March 1999|volume=64|issue=5|pages=1620–1625|doi=10.1021/jo982104m|pmid=11674227}}

File:BOX ligand development.png

Oxazoline ligands were first used for asymmetric catalysis in 1984 when Brunner et al. showed a single example, along with a number of Schiff bases, as being effective for enantioselective carbenoid cyclopropanation.{{cite journal|last=Brunner|first=Henri|author2=Miehling, Wolfgang|title=Enantioselektive Cyclopropanierung von 1,1-Diphenylethylen und Diazoessigester mit Kupfer-Katalysatoren|journal=Monatshefte für Chemie - Chemical Monthly|date=1 October 1984|volume=115|issue=10|pages=1237–1254|doi=10.1007/BF00809355}} Schiff bases were prominent ligands at the time, having been used by Ryōji Noyori during the discovery of asymmetric catalysis in 1968{{cite journal|last=Nozaki|first=H.|author2=Takaya, H. |author3=Moriuti, S. |author4= Noyori, R. |title=Homogeneous catalysis in the decomposition of diazo compounds by copper chelates|journal=Tetrahedron|year=1968|volume=24|issue=9|pages=3655–3669|doi=10.1016/S0040-4020(01)91998-2}} (for which he and William S. Knowles would later be awarded the Nobel Prize in Chemistry). Brunner's work was influenced by that of Tadatoshi Aratani, who had worked with Noyori,{{cite journal|last=Nozaki|first=H.|author2=Aratani, T. |author3=Toraya, T. |author4= Noyori, R. |title=Asymmetric syntheses by means of (−)-sparteine modified organometallic reagents|journal=Tetrahedron|year=1971|volume=27|issue=5|pages=905–913|doi=10.1016/S0040-4020(01)92490-1}} before publishing a number of papers on enantioselective cyclopropanation using Schiff bases.{{cite journal|last=Aratani|first=T.|author2=Yoneyoshi, Y. |author3=Nagase, T. |title=Asymmetric synthesis of chrysanthemic acid. An application of copper carbenoid reaction|journal=Tetrahedron Letters|year=1975|volume=16|issue=21|pages=1707–1710|doi=10.1016/S0040-4039(00)72239-8}}{{cite journal|last=Aratani|first=T.|author2=Yoneyoshi, Y. |author3=Nagase, T. |title=Asymmetric synthesis of chrysanthemic acid. An application of copper carbenoid reaction|journal=Tetrahedron Letters|year=1977|volume=18|issue=30|pages=2599–2602|doi=10.1016/S0040-4039(01)83830-2}}{{cite journal|last=Aratani|first=Tadatoshi|author2=Yoneyoshi, Yukio |author3=Nagase, Tsuneyuki |title=Asymmetric synthesis of permethric acid. stereochemistry of chiral copper carbenoid reaction|journal=Tetrahedron Letters|year=1982|volume=23|issue=6|pages=685–688|doi=10.1016/S0040-4039(00)86922-1}}

In this first usage the oxazoline ligand performed poorly, giving an ee of 4.9% compared to 65.6% from one of the Schiff base ligands. However Brunner reinvestigated oxazoline ligands during research into the monophenylation of diols, leading to the development of chiral pyridine oxazoline ligands, which achieved ee's of 30.2% in 1986{{cite journal|last=Brunner|first=Henri|author2=Obermann, Uwe |author3=Wimmer, Peter |title=Asymmetrische katalysen|journal=Journal of Organometallic Chemistry|date=1 November 1986|volume=316|issue=1–2|pages=C1–C3|doi=10.1016/0022-328X(86)82093-9}} and 45% in 1989.{{cite journal|last=Brunner|first=Henri.|author2=Obermann, Uwe. |author3=Wimmer, Peter. |title=Asymmetric catalysis. 44. Enantioselective monophenylation of diols with cupric acetate/pyridinyloxazoline catalysts|journal=Organometallics|date=1 March 1989|volume=8|issue=3|pages=821–826|doi=10.1021/om00105a039}} In the same year Andreas Pfaltz et al. reported the use of C₂‑symmetric semicorrin ligands for enantioselective carbenoid cyclopropanations, achieving impressive results with ee's of between 92-97%.{{cite journal|last=Fritschi|first=Hugo|author2=Leutenegger, Urs |author3=Pfaltz, Andreas |title=Chiral Copper-Semicorrin Complexes as Enantioselective Catalysts for the Cyclopropanation of Olefins by Diazo Compounds|journal=Angewandte Chemie International Edition in English|date=1 November 1986|volume=25|issue=11|pages=1005–1006|doi=10.1002/anie.198610051}} Reference was made to both Brunner's and Aratani's work, however the design of the ligands was also largely based on his earlier work with various macrocycles.{{cite journal|last=Pfaltz|first=Andreas|title=From Corrin Chemistry to Asymmetric Catalysis - A Personal Account|journal=Synlett|volume=1999|year=1999|issue=S1|pages=835–842|doi=10.1055/s-1999-3122}} A disadvantage of these ligands however, was that they required a multi-step synthesis with a low overall yield of approximately 30%.

File:Axially chiral BOX ligands.png

Brunner's work led to the development of very first bisoxazolines by Nishiyama et al., who synthesised the first PyBox ligands in 1989. These ligands were used in the hydrosilylation of ketones; achieving ee's of up to 93%{{cite journal|last=Nishiyama|first=Hisao.|author2=Sakaguchi, Hisao. |author3=Nakamura, Takashi. |author4=Horihata, Mihoko. |author5=Kondo, Manabu. |author6= Itoh, Kenji. |title=Chiral and C₂-symmetrical bis(oxazolinylpyridine)rhodium(III) complexes: effective catalysts for asymmetric hydrosilylation of ketones|journal=Organometallics|date=1 March 1989|volume=8|issue=3|pages=846–848|doi=10.1021/om00105a047}} The first BOX ligands were reported a year later by Masamune et al.{{cite journal|last=Lowenthal|first=Richard E|author2=Abiko, Atsushi |author3=Masamune, Satoru |title=Asymmetric catalytic cyclopropanation of olefins: bis-oxazoline copper complexes|journal=Tetrahedron Letters|year=1990|volume=31|issue=42|pages=6005–6008|doi=10.1016/S0040-4039(00)98014-6}} and were first used in copper catalysed carbenoid cyclopropanation reactions; achieving ee's of up to 99% with 1% molar loadings. This was a remarkable result for the time and generated significant interest in the BOX motif. As the synthesis of 2-oxazoline rings was already well established at this time (literature reviews in 1949{{cite journal|last=Wiley|first=Richard H.|author2=Bennett, Leonard L.|title=The Chemistry of the Oxazolines.|journal=Chemical Reviews|volume=44|issue=3|pages=447–476|doi=10.1021/cr60139a002|year=1949}} and 1971{{cite journal|last=Frump|first=John A.|title=Oxazolines. Their preparation, reactions, and applications|journal=Chemical Reviews|volume=71|issue=5|pages=483–505|doi=10.1021/cr60273a003|year=1971}}), research proceeded quickly, with papers from new groups being published within a year.{{cite journal|last=Evans|first=David A.|author2=Woerpel, Keith A. |author3=Hinman, Mira M. |author4= Faul, Margaret M. |title=Bis(oxazolines) as chiral ligands in metal-catalyzed asymmetric reactions. Catalytic, asymmetric cyclopropanation of olefins|journal=Journal of the American Chemical Society|date=1 January 1991|volume=113|issue=2|pages=726–728|doi=10.1021/ja00002a080}}{{cite journal|last=Corey|first=E. J.|author2=Imai, Nobuyuki |author3=Zhang, Hong Yue |title=Designed catalyst for enantioselective Diels-Alder addition from a C2-symmetric chiral bis(oxazoline)-iron(III) complex|journal=Journal of the American Chemical Society|date=1 January 1991|volume=113|issue=2|pages=728–729|doi=10.1021/ja00002a081}} and review articles being published by 1996.{{cite journal|last=Pfaltz|first=Andreas|author2=Adolfsson, Hans |author3=Wärnmark, Kenneth |author4=Aasbø, Kari |author5=Klinga, Martti |author6= Romerosa, Antonio |title=Design of Chiral Ligands for Asymmetric Catalysis: from C2-Symmetric Semicorrins and Bisoxazolines to Non-Symmetric Phosphinooxazolines.|journal=Acta Chemica Scandinavica|date=1 January 1996|volume=50|pages=189–194|doi=10.3891/acta.chem.scand.50-0189|url=http://actachemscand.dk/pdf/acta_vol_50_p0189-0194.pdf|doi-access=free}} Today a considerable number of bis(oxazoline) ligands exist; structurally these are still largely based around the classic BOX and PyBOX motifs, however they also include a number of alternative structures, such as axially chiral compounds.{{cite journal|last=Gant|first=Thomas G.|author2=Noe, Mark C. |author3=Corey, E.J. |title=The first enantioselective synthesis of the chemotactic factor sirenin by an intramolecular [2 + 1] cyclization using a new chiral catalyst|journal=Tetrahedron Letters|date=1 November 1995|volume=36|issue=48|pages=8745–8748|doi=10.1016/0040-4039(95)01924-7}}{{cite journal|last=Ohta|first=Tetsuo|author2=Ito, Junji |author3=Hori, Kazushige |author4=Kodama, Hidehiko |author5= Furukawa, Isao |title=Lanthanide-catalyzed asymmetric 1,3-dipolar cycloaddition of nitrones to alkenes using 3,3′-bis(2-oxazolyl)-1,1′-bi-2-naphthol (BINOL-Box) ligands|journal=Journal of Organometallic Chemistry|year=2000|volume=603|issue=1|pages=6–12|doi=10.1016/S0022-328X(00)00024-3}}

• Phosphinooxazolines (PHOX)
• Trisoxazolines (TRISOX)

{{reflist|30em}}

Category:Ligands

Category:Oxazolines