PYBOX Ligand - Large Binding Site & Rigid Scaffold

William Sommer, Daniel Weibel

Chemfiles Volume 8 Article 2

The PYBOX ligand,¹ consisting of a pyridine ring flanked by two oxazoline groups, was introduced in 1989 by Nishiyama.² PYBOX evolved directly from the BOX ligands. In comparing them, two points merit to be mentioned: (1) the binding site of PYBOXes is big enough to complex even lanthanide cations and (2) the rigidity of the tridentate PYBOX scaffold is increased.

In his very first application, Nishiyama showed that isopropyl-PYBOX 407151 rhodium(III) catalyst effectively promotes the asymmetric hydrosilylation of ketones giving extremely high enantioselectivities (Scheme 1).³

Scheme 1. Catalyst effectively promotes the asymmetric hydrosilylation of ketones giving extremely high enantioselectivities

Li and Wei reported in 2002 the copper(I)-catalyzed enantioselective direct-addition of terminal alkynes to imines. The most successful ligand tested was PYBOX 496073 bearing phenyl groups (Scheme 2).⁴

Scheme 2. Catalyzed enantioselective direct-addition of terminal alkynes to imines

Recently, Shibasaki's group reported on lanthanum aryl oxide/PYBOXcatalyzed direct asymmetric Mannich-type reactions using a trichloromethyl ketone as a propionate equivalent donor.⁵ The La(OAr)₃-i-Pr-PYBOX 407151 + LiOAr system gave products in 72 to >99% yield, 8:1 to >30:1 dr, and 92‑98% ee (Table 1).

Figure 1. Propionate equivalent donor

Table 1 The La(OAr)3-i-Pr-PYBOX 407151 + LiOAr system gave products in 72 to >99% yield, 8:1 to >30:1 dr, and 92‑98% ee

Entry		R	% Yield	dr (syn:anti)		% ee (syn)
1		Ph	96	21:1		96
2		4-Cl-C6H4	97	20: 1		96
3		2-thienyl	98	20:1		95
4		cyclohexyl	85	>30:1		96
5		i-Pr	74	>30:1		97

The chiral indium(III)-PYBOX complex prepared from indium triflate and C2-symmetric chiral PYBOX 673986 was found to be an effective chiral ligand for the enantioselective allylation reaction of aldehydes with allyltributylstannane, giving high enantioselectivities.⁶ Using this methodology, the chiral steroidal aldehyde could be allylated with excellent enantioselectivity ((22S):(22R)= >99:1) and in good yield (78%). Furthermore, the reaction was highly chemoselective, reacting only with the aldehyde functionality. No reaction was observed with the enone functionality in the A ring (Scheme 3).

Scheme 3. The chiral indium(III)-PYBOX

References

1. Desimoni G, Faita G, Quadrelli P. 2003. Pyridine-2,6-bis(oxazolines), Helpful Ligands for Asymmetric Catalysts. Chem. Rev.. 103(8):3119-3154. https://doi.org/10.1021/cr020004h

2. Nishiyama H, Sakaguchi H, Nakamura T, Horihata M, Kondo M, Itoh K. 1989. Chiral and C2-symmetrical bis(oxazolinylpyridine)rhodium(III) complexes: effective catalysts for asymmetric hydrosilylation of ketones. Organometallics. 8(3):846-848. https://doi.org/10.1021/om00105a047

3. Nishiyama H, Park S, Itoh K. 1992. Stereoselectivity in hydrosilylative reduction of substituted cyclohexanone derivatives with chiral rhodium-bis(oxazolinyl)pyridine catalyst. Tetrahedron: Asymmetry. 3(8):1029-1034. https://doi.org/10.1016/s0957-4166(00)86036-x

4. Wei C, Li C. 2002. Enantioselective Direct-Addition of Terminal Alkynes to Imines Catalyzed by Copper(I)pybox Complex in Water and in Toluene. J. Am. Chem. Soc.. 124(20):5638-5639. https://doi.org/10.1021/ja026007t

5. Morimoto H, Lu G, Aoyama N, Matsunaga S, Shibasaki M. 2007. Lanthanum Aryloxide/Pybox-Catalyzed Direct Asymmetric Mannich-Type Reactions Using a Trichloromethyl Ketone as a Propionate Equivalent Donor. J. Am. Chem. Soc.. 129(31):9588-9589. https://doi.org/10.1021/ja073285p

6. Lu J, Hong M, Ji S, Loh T. Enantioselective synthesis of homoallylic alcohols via a chiral In(iii)?PYBOX complex. Chem. Commun..(8):1010-1012. https://doi.org/10.1039/b415550e