C2-symmetric Chiral Bisoxazolines (BOX) Ligands

C₂-symmetric chiral bisoxazolines (BOX) are privileged structures because they promote a great number of transformations with unprecedented selectivity.¹ In 1991, in the same Journal of American Chemistry issue, two communications appeared by Evans² and Corey.³ These two publications paved the way for a rapidly and ever-growing number of examples where BOX ligands are used successfully as chiral ligands.

Evans described the cyclopropanation of alkenes using diazo esters catalyzed by a complex formed of 2,2′-Isopropylidenebis[(4S)-4-tert-butyl-2-oxazoline] (Product 406147) and Cu(I)OTf. With the ester derived from 2,6‑di-tert-butyl-4‑methylphenol (BHT) it was found that the increased steric demand displays increased trans selectivity (Scheme 1).²

Scheme 1

In a related experiment, Evans announced the first catalytic enantioselective aziridination of styrene.⁴ Two years later, he reported on an extension of this preliminary work in a full communication (Scheme 2). Using BOX ligand (Product No. 405000), complexed to Cu(I)OTf, in the catalytic enantioselective aziridination of styrene, the BOX ligand having phenyl substituents proved to be superior to the one bearing sterically demanding t-Bu groups (Scheme 2).

Scheme 2

Reiser et al. discovered a general route to disubstituted γ-butyrolactones. In an Cu(I)-catalyzed asymmetric cyclopropanation of furans with diazo esters, bis(4‑isopropyloxazoline) (Product No. 680192) was used as chiral ligand (Scheme 3). This transformation was performed on 50–100 g scale without a detectable loss of enantioselectivity.⁵

Scheme 3

In his 1991 Journal of American Chemical Society communication, Corey used BOX ligand (Product No. 405000) in an Fe(III)-catalyzed enantioselective Diels–Alder reaction (Scheme 4).³

Scheme 4

Two year later, Evans described the Cu(II)-catalyzed version of the enantioselective Diels–Alder reaction of unsubstituted acrylimides using BOX ligand (Product No. 406147) as a chiral Lewis acid.⁶ The reaction proceeded in good yield exhibiting excellent enantioselectivity for the endo diastereoisomer (Scheme 5). From further investigations by Evans et al., it appears that the best combination is BOX (Product No. 406147) and Cu(II), and the best counterions are OTf and SbF₆.¹

Scheme 5

4‑Aryl- and 4‑alkylsubstituted BOX-based catalysts were widely used in a large number of reactions¹ and their behavior can provide a good representation of their efficiency. But BOX ligands with other structural motifs have been successfully used too. BOX ligand (Product No. 405981) has been used in the Cu(I)-catalyzed highly enantioselective Mannich reactions to efficiently produce highly functionalized 4‑oxo-glutamic ester derivatives (Scheme 6).⁷

Scheme 6

Ma et al. reported on the enantioselective CuI/bis(oxazoline)- catalyzed addition of propiolates and terminal ynones to 1‑acylpyridinium salt to afford highly functionalized dihydropyridines with excellent enantioselectivity using Product No. 464155 (Scheme 7).⁸ It is found that the carbonyl group adjacent to the alkyne moiety is essential for the enantioselectivity of the addition.

Scheme 7

References

1. Desimoni G, Faita G, Jørgensen KA. 2006. C2-Symmetric Chiral Bis(Oxazoline) Ligands in Asymmetric Catalysis. Chem. Rev.. 106(9):3561-3651. https://doi.org/10.1021/cr0505324

2. Ghosh AK, Mathivanan P, Cappiello J. 1998. C2-Symmetric chiral bis(oxazoline)?metal complexes in catalytic asymmetric synthesis. Tetrahedron: Asymmetry. 9(1):1-45. https://doi.org/10.1016/s0957-4166(97)00593-4

3. Johnson JS, Evans DA. 2000. Chiral Bis(oxazoline) Copper(II) Complexes:  Versatile Catalysts for Enantioselective Cycloaddition, Aldol, Michael, and Carbonyl Ene Reactions. Acc. Chem. Res.. 33(6):325-335. https://doi.org/10.1021/ar960062n

4. Evans DA, Woerpel KA, Hinman MM, Faul MM. 1991. Bis(oxazolines) as chiral ligands in metal-catalyzed asymmetric reactions. Catalytic, asymmetric cyclopropanation of olefins. J. Am. Chem. Soc.. 113(2):726-728. https://doi.org/10.1021/ja00002a080

5. Corey EJ, Imai N, Zhang HY. 1991. Designed catalyst for enantioselective Diels-Alder addition from a C2-symmetric chiral bis(oxazoline)-iron(III) complex. J. Am. Chem. Soc.. 113(2):728-729. https://doi.org/10.1021/ja00002a081

6. Evans DA, Faul MM, Bilodeau MT, Anderson BA, Barnes DM. 1993. Bis(oxazoline)-copper complexes as chiral catalysts for the enantioselective aziridination of olefins. J. Am. Chem. Soc.. 115(12):5328-5329. https://doi.org/10.1021/ja00065a068

7. Reiser O, Jezek E, Schall A, Kreitmeier P. Radical Cyclizations as Key Step for the Stereoselective Synthesis of Bi- and Tricyclic Sesquiterpene Lactones. Synlett. 2005(06):0915-0918. https://doi.org/10.1055/s-2005-864827

8. Chhor RB, Nosse B, Sörgel S, Böhm C, Seitz M, Reiser O. 2003. Enantioselective Synthesis of Paraconic Acids. Chem. Eur. J.. 9(1):260-270. https://doi.org/10.1002/chem.200390019

9. Evans DA, Miller SJ, Lectka T. 1993. Bis(oxazoline)copper(II) complexes as chiral catalysts for the enantioselective Diels-Alder reaction. J. Am. Chem. Soc.. 115(14):6460-6461. https://doi.org/10.1021/ja00067a091

10. Sun Z, Yu S, Ding Z, Ma D. 2007. Am. Chem. Soc.. 1299300‑9301.

11. Sun Z, Yu S, Ding Z, Ma D. 2007. Enantioselective Addition of Activated Terminal Alkynes to 1-Acylpyridinium Salts Catalyzed by Cu?Bis(oxazoline) Complexes. J. Am. Chem. Soc.. 129(30):9300-9301. https://doi.org/10.1021/ja0734849