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Phosphinooxazoline Ligands in Asymmetric Synthesis

PHOX Ligands Play Specific Role in Transition Metal Mediated Catalytic Reactions

Phosphinooxazolines, also known as PHOX, are unsymmetrical bidentate P, N ligands which are successfully used in asymmetric catalytic transformations.^{[1, 2]} The symmetrical oxazoline - reaction processes are controlled sterically and electronically by the metal complexes containing a chiral organic ligand. Conversely In hemilabile P,N PHOX ligand-promoted processes, electronic control on enantioselectivity is dominate and nucleophilic attacks occur trans to the better p-acceptor, "soft" phosphorus rather than the s-donor, "hard" nitrogen ligand.^[3] In addition, PHOX ligands are also able to affect enantioselectivity.^{[3, 4]}

The basic phosphinooxazolines, such as (R)-iPr-PHOX (15-1821) and (S)-iPr-PHOX (15-1822) are successfully applied to various transition metal-catalyzed transformations including asymmetric reduction of olefins, the Heck reaction without promoting double bond isomerization, allylic substitution and others. For more detailed applications and reaction descriptions please check the corresponding product technical notes on our website.

Due to a chiral phosphinooxazolines’ modular structure, the steric and electronic properties can be tailored for a specific application by variation of the oxazoline ring, the backbone, and the phosphine moiety.^[1] Therefore, introduction of a chiral spiro group into the phosphino-oxazoline molecule expands the application scope of these SIPHOX ligands. Rigid and sterically hindered spiro phosphinooxazoline ligands create an efficient chiral environment around the catalytic metal center which are responsible for the high level of enantioselectivity of the reaction.^[5]

For example, by using (Ra,S)-Ph-Bn-SIPHOX (15-5186), (Ra,S)-DTB-Bn-SIPHOX (15-5190) or (Sa,S)-DTB-Bn-SIPHOX (15-5191) the asymmetric hydrogenation of α,-oxy-α,β-unsaturated carboxylic acids proceeds smoothly with extremely high enantioselectivities (up to 99.8%) and reactivities (TON up to 10 000) under mild conditions^[5] (Sa,S)-Ph-Bn-SIPHOX (15-5187) isomer is a chiral ligand for the iridium-catalyzed asymmetric hydrogenation of imines.^[6]

For more information on chiral oxazoline ligands, review Strem blogs about Bis-oxazoline Ligands Modified with Side Arms (SaBOX) (07-1235; 07-1228; 07-1219) and PyBOX Ligands (07-0306; 07-0307; 07-0280; 07-0303; 07-0304, 07-0390; 07-0391)

References:

A. Pfaltz et al. Angew. Chem., Int. Ed. Engl., 1993, 32, 566-568.
A. Pfaltz et al, Acc. Chem. Res., 2000, 33, 336-345; A. Pfaltz et al, Acc. Chem. Res., 2007, 40, 1402-1411.
R. N. Constantine et al, Org. Lett., 2003, 5, 2279-2282.
M. Kollmaret al, Chem. Eur. J., 2002, 8, 3103-3114.
S. Li et al, J. Am. Chem. Soc., 2010, 132 (3), 1172-1179.
S.-F. Zhu et al, J. Am. Chem. Soc., 2006, 128 (39), 12886-12891.