In chemistry, bisoxazoline ligands (BOX ligands for short) are chiral ligands based on a bis oxazoline skeleton and used in combination with a metal compound in asymmetric synthesis as a chiral catalyst [1]. Three frequently encountered such ligands are PyBOX, tBuBOX and PhBOX. BOX ligands exist as organic compounds with the organometallic complex formed in-situ or as pre-prepared metal complexes.
| Bisoxazoline | R | Systematic name | CAS number | Melting point °C | |
| PyBOX | phenyl | 2,6-Bis[(4R)-4-phenyl-2-oxazolinyl]pyridine | 128249-70-7 | 171-175 | |
| tBuBOX | tert-butyl | (S,S)-2,2′-Methylenebis(4-tert-butyl-2-oxazoline) | 131833-93-7 | 51-53 | |
| PhBOX | phenyl | (S,S)-2,2-Bis(4-phenyl-2-oxazolin-2-yl)propane | 131457-46-0 | 56-58 | |
| Representative bisoxazolines [2] | |||||
In 1968 Ryōji Noyori and William S. Knowles independently developed the first chiral ligands, with those of Knowles based on phosphorus and those of Noyori based on nitrogen. One advantage of chiral nitrogen-containing compounds is that they are cheaply available for instance from naturally occurring chiral amino acids. The Noyori ligand [3] is based on a reaction of salicylaldehyde with chiral methylbenzylamine to the imine followed by complexation with copper(II) acetate to the dinuclear copper complex. The cyclopropanation of styrene with ethyl diazoacetate results in a mixture of cis and trans isomers with a very modest enantiomeric excess of 6%.
| Noyori ligand synthesis 1968 | Noyori cyclopropanation 1968 |
In 1975 Aratani [4] used a similar ligand in the asymmetric cyclopropanation of another diene to the insecticide chrysanthemic acid. His ligand was derived from reaction of salicylaldehyde with a chiral amino alcohol (the latter synthesized from a Grignard reaction with an ester of chiral alanine).
| Aratani ligand synthesis 1975 | Aratani cyclopropanation 1975 |
In 1984 Brunner [5] started the development of nitrogen containing ligands because phosphine ligands tended to fail in enantioselective hydrosilylations which was the focus of many research groups. One 1984 study describes a nitrogen-nitrogen bidentate ligand with a pyridine group fused to a thiazolidine group.
In 1989 Brunner replaced the thiazolidine (difficult to control stereochemistry) by an oxazoline group [6] and demonstrated the new ligand in a monophenylation of a diol by the organobismuth compound triphenylbismuth diacetate.
| Enantioselective hydrosilylation Brunner 1984.[7] | Enantioselective phenylation Brunner 1989 |
In the same year hydrosilylation was demonstrated with a closely related pyridine-oxazoline by Balavoine [8].
As a logical follow-up step, PyBOX with pyridine flanked by two oxazoline groups, was also introduced in 1989 by Nishiyama [9]. With three nitrogen atoms this ligand is tridentate with bite angle 158.7° in a complex with rhodium(III) chloride. The isobutyl derivate is synthesized in several steps starting from pyridine-2,6-dicarboxylic acid. The nitrogen fragment is easily obtained from naturally occurring valine.
| Enantioselective hydrosilylation Balavoine 1989 | Enantioselective hydrosilylation Nishiyama 1989 |
BOX-type ligands based on malonate esters and chiral amino alcohols (obtained by reduction of the corresponding amino acids) were first described by in 1990 by Masamune [10] and in 1991 by David Evans.[11][12]
| PyBOX synthesis Nishiyama 1989 | Bisoxazoline synthesis Evans 1991 |
As before, the ligands are obtained by reaction of an acid chloride with L-valinol (which is the reduced form of valine) followed by ring-closure to the acetal and an elimination reaction (facilitated by either thionyl chloride or tosyl chloride) to the oxazoline.
Both Masamune and Evans demonstrated their nearly identical BOX ligands in a cyclopropanation reaction via diazotation.
| Bisoxazoline ligand in cyclopropanation Evans 1991 [13] | Bisoxazoline ligand in cyclopropanation Masamune 1990 |
Many organic reactions (not just hydrosilylations or cyclopropanations) are found to display enantioselectivity when performed in presence of a BOX ligand. The obvious targets are 100% enantiomeric excess (ee) with the use of as little as possible amounts of metal and ligand, usually between 0.01 equivalent and 0.1 equivalent. Selecting the ligand most suitable for a particular reaction is most often a process of trial and error.
| Aldol addition [14] | Copper catalyzed nucleophilic addition of an alkyne to pyridinium chloride [15] |
| Friedel-Crafts alkylation at indole[16] | Henry reaction [17] |
| Diels-Alder reaction resulting in verbenone synthesis [18][19] | Copolymerization of cyclohexene oxide and carbon dioxide [20] |