PHOX

William Sommer, Daniel Weibel

Of the thousands of chiral ligands used in asymmetric synthesis a relatively large number exhibit C₂-symmetry. More recently, non-symmetrical modular P,N-ligands have been introduced independently by Pfaltz, Helmchen, and Williams and applied successfully in various metal-catalyzed reactions.¹ These phosphinooxazolines (PHOX) are a highly versatile class of ligands.⁴

PHOX ligand (43158) was successfully used in Pd-catalyzed asymmetric allylic alkylation reactions. Racemic allyl acetates were transformed into their Pd allyl complex, which is subsequently attacked by a nucleophile to give the corresponding addition adduct (Scheme 1).^1-3

Scheme 1.

Phosphinooxazoline (688495) can induce very high enantioselectivities in the Heck reaction.^5-6 In contrast to analogous reactions with diphosphine-Pd catalysts, virtually no C=C double bond migration is observed in the primary product. Hence, particularly in cases where double bond migration leads to undesired products or mixtures of isomers, phosphinooxazolines are the ligands of choice (Scheme 2).

Scheme 2.

Cationic iridium-phosphinooxazoline complexes have proved to be effective catalysts for the enantioselective hydrogenation of imines and trisubstituted olefins (Scheme 3).⁷ In a systematic study, PHOX ligand with a bis(o-tolyl)phosphanyl moiety gave highest enantioselectivities (up to 97% ee).

Scheme 3.

The cationic iridium complex with PHOX ligand (91716) is an efficient catalyst for the enantioselective intramolecular Pauson-Khand reaction.⁸ Under optimized conditions, enantioselectivities of >90% ee were obtained with 9 mol% of catalyst (Table 1). The anion proved to be important, as it had a significant influence on the enantioselectivity and yield. Best results obtained with relatively small, weakly coordinating anions such as tetrafluoroborate and hexafluorophosphate, but also triflate.

Recently, Rovis et al. used PHOX ligand (688495) in a rhodium(I)-catalyzed enantioselective desymmetrization reaction of meso-3,5‑dimethyl glutaric anhydride, providing rapid access to substituted syn-deoxypolypropionate fragments in a single transformation (Scheme 4).⁹

Scheme 4.

Table 1

Entry	z	R	X	solvent	%yield	%ee
1	0	H	OTf	DME	85	91
2	0	H	BF4	DME	89	91
3	0	H	PF6	DME	93	91
4	NTs	H	OTf	DME	93	81
5	NTs	H	PF6	DME	95	77
6	C(CO2CH3)2	H	BF4	THF	76	91
7	C(CO2CH3)2	H	PF6	THF	71	91
8	0	CH3	OTf	THF	10	71
9	0	CH3	BF4	THF	6	64

References

1. von Matt P, Pfaltz A. 1993. Chiral Phosphinoaryldihydrooxazoles as Ligands in Asymmetric Catalysis: Pd-Catalyzed Allylic Substitution. Angew. Chem. Int. Ed. Engl.. 32(4):566-568. https://doi.org/10.1002/anie.199305661

2. Sprinz J, Helmchen G. 1993. Phosphinoaryl- and phosphinoalkyloxazolines as new chiral ligands for enantioselective catalysis: Very high enantioselectivity in palladium catalyzed allylic substitutions. Tetrahedron Letters. 34(11):1769-1772. https://doi.org/10.1016/s0040-4039(00)60774-8

3. Dawson GJ, Frost CG, Williams JM, Coote SJ. 1993. Asymmetric palladium catalysed allylic substitution using phosphorus containing oxazoline ligands. Tetrahedron Letters. 34(19):3149-3150. https://doi.org/10.1016/s0040-4039(00)93403-8

4. Helmchen G, Pfaltz A. 2000. PhosphinooxazolinesA New Class of Versatile, Modular P,N-Ligands for Asymmetric Catalysis. Acc. Chem. Res.. 33(6):336-345. https://doi.org/10.1021/ar9900865

5. Loiseleur O, Meier P, Pfaltz A. 1996. Chiral Phosphanyldihydrooxazoles in Asymmetric Catalysis: Enantioselective Heck Reactions. Angew. Chem. Int. Ed. Engl.. 35(2):200-202. https://doi.org/10.1002/anie.199602001

6. Loiseleur O, Hayashi M, Schmees N, Pfaltz A. 1997. Enantioselective Heck Reactions Catalyzed by Chiral Phosphinooxazoline-Palladium Complexes. Synthesis. 1997(11):1338-1345. https://doi.org/10.1055/s-1997-1341

7. Lightfoot, A.; Schnider, P.; Pfaltz, A. Angew. Chem., Int. Ed. 1998, 37, 2897‑2899. For enantioselective reductions of imines using PHOX ligands, see: Schnider, P.; Koch, G.; Prétôt, R.; Wang, G.; Bohnen, F. M.; Krüger, C.; Pfaltz, A. Chem. — Eur. J. 1997, 3, 887‑892..

8. Lu Z, Neumann E, Pfaltz A. 2007. Asymmetric Catalytic Intramolecular Pauson?Khand Reactions with Ir(phox) Catalysts. Eur. J. Org. Chem.. 2007(25):4189-4192. https://doi.org/10.1002/ejoc.200700330

9. Cook MJ, Rovis T. 2007. Rhodium-Catalyzed Enantioselective Desymmetrization ofmeso-3,5-Dimethyl Glutaric Anhydride:  A General Strategy tosyn-Deoxypolypropionate Synthons. J. Am. Chem. Soc.. 129(30):9302-9303. https://doi.org/10.1021/ja073269s