(1a; (S,S), R = H); [203399-79-5]  · C31H32NO3P  · (MW 497.56)

(2a; (S,S), R = Me); [284019-78-9]  · C33H36NO3P  · (MW 525.62)

(3a; (S,S), R = Ph); [284019-79-0]  · C43H40NO3P  · (MW 649.76)

(4a; (S,S), R = p-Ph-C6H4); [284019-80-3]  · C55H48NO3P  · (MW 801.95)

(5a; (S,S), R = 2,4,6-Me3C6H2); [284019-81-4]  · C49H52NO3P  · (MW 733.92)

(6a; (S,S), R = 3,5-tBu2C6H3); [284019-82-5]  · C58H70NO4P  · (MW 876.15)

(1b; (R,S), R = H); [203312-03-2]  · C31H32NO3P  · (MW 497.56)

(2b; (R,S), R = Me); [203312-04-3]  · C33H36NO3P  · (MW 525.62)

(3b; (R,S), R = Ph); [284019-32-5]  · C43H40NO3P  · (MW 649.76)

(4b; (R,S), R = p-Ph-C6H4); [284019-33-6]  · C55H48NO3P  · (MW 801.95)

(5b; (R,S), R = 2,4,6-Me3C6H2); [284019-35-8]  · C49H52NO3P  · (MW 733.92)

(modular chiral ligands for regio- and enantiocontrolled palladium-catalyzed allylic substitution reactions1,2 and enantioselective copper-catalyzed 1,4-addition of organozinc reagents to enones3,4)

Physical Data: (1a) colorless solid, mp 94 °C, [a]D25 +269 (c 3.10, CHCl3); (1b) colorless solid, [a]D25 -360 (c 0.49, CHCl3); (2a) colorless solid, [a]D25 +339 (c 0.45, CHCl3); (2b) colorless solid, [a]D25 -379 (c 0.92, CHCl3); (3a) colorless solid, mp 121 °C, [a]D20 +312 (c 0.46, CHCl3); (3b) colorless solid, mp 106 °C, [a]D25 -366 (c 0.94, CHCl3); (4a) colorless solid, mp 121 °C, [a]D25 +253 (c 1.19, CHCl3); (4b) colorless solid, mp 125 °C, [a]D25 -301 (c 0.89, CHCl3); (5a) colorless solid, mp 130 °C, [a]D23 +74 (c 1.08, CHCl3); (5b) colorless solid, mp 223 °C, [a]D23 -126 (c 0.52, CHCl3); (6a) colorless solid, mp 113 °C, [a]D23 +164 (c 0.41, CHCl3).

Purification: column chromatography on aluminum oxide (basic). Silica gel can also be used, however, with highly active silica gel, partial hydrolysis of the phosphite was observed.

Solubility: insoluble in H2O; soluble in most organic solvents.

Handling, Storage, and Precautions: phosphite oxazolines of this type are sufficiently stable to be handled in air. For longer periods of time, they should be stored at -20 °C under nitrogen or argon.

Preparative Methods: Preparation of the phosphite-oxazoline ligands and metal complexes: the phosphite-oxazoline ligands are readily prepared in enantiomerically pure form from the BINOL derivative 7 and the oxazoline 8 (1).4 The BINOL derivative (7) is synthesized from the corresponding diol and phosphorus trichloride; oxazoline 8 is synthesized from commercially available (S)-tert-leucinol (2).5 By varying the R groups on 7, a range of ligands can easily be synthesized. The modular design of the phosphite-oxazoline ligands allows a wide range of analogs to be readily prepared. Palladium and zinc complexes of the phosphite-oxazoline ligands are generally formed in situ. Palladium-allyl complexes have been prepared and characterized by NMR spectroscopy and X-ray diffraction.2,6

Regio- and Enantiocontrolled Palladium-Catalyzed Allylic Substitution Reactions7

Although a wide range of efficient catalysts are available for enantioselective allylic substitution reactions of substrates such as 9, monosubstituted allylic substrates 10 and 11 generally react predominantly at the unsubstituted allyl terminus with these catalysts, producing achiral products (13) (3). Palladium complexes of chiral phosphite-oxazoline ligands show improved regioselectivity favoring the chiral product with good enantioselectivity for monosubstituted aryl-allyl substrates.1,2

Reaction of the palladium complex of ligand 1a with 10a in the presence of N,O-bis(trimethylsilyl)acetamide (BSA), catalytic KOAc as the base, and dimethyl malonate results in good yield and high selectivities for 12a (4). The most efficient ligand in terms of regio- and enantioselectivity is 1a. In benzene, the regio- and enantioselectivity are further improved (1).

Even better regio- and enantioselectivities were observed when 1-naphthyl-substituted allylic acetates (10b and 11b) were used. The regio- and enantioselectivities were essentially the same using either the achiral substrates (10) or the racemic isomers (11) (3, 1).

There have been several other reports of allylic substitution reactions that proceed with high selectivity for the chiral product 12. Tungsten-phosphinooxazoline complexes give enantioselectivities of up to 96% ee and branched-to-linear ratios of up to 96:4 with aryl-allyl substrates.2 Molybdenum-catalyzed allylic substitution reactions have been reported by Trost and by Pfaltz. Molybdenum complexes with a tetradentate nitrogen ligand (derived from trans-1,2-diaminocyclohexane) gave excellent branched to linear ratios (up to 99:1, generally >20:1) and high enantiomeric excesses (up to 99%) also for aryl-allyl substrates.8 The related bisoxazolines with a trans-1,2-diaminocyclohexane backbone gave branched to linear ratios of 2:1 to 49:1 for a range of aryl- and alkyl-allyl substrates with enantiomeric excesses generally >90%.9 Iridium complexes with phosphoramidite ligands developed by Helmchen are also efficient catalysts, giving branched to linear ratios of up to 99:1 with ees of up to 91%.10

Enantioselective 1,4-Addition of Organozinc Reagents to Enones11

Phosphite-oxazoline copper complexes are highly efficient catalysts for the 1,4-addition of organozinc reagents to 5-, 6- and 7-membered cyclic enones.3,4 Both the chiral oxazoline and the chiral phosphite unit have a significant influence on the enantioselectivity.

The chiral ligands are used in a ligand to copper ratio of 1.2:1 along with 2-3 mol% of Cu(OTf)2 and 1.3 equiv of diethylzinc in toluene, usually for 15 h. All ligands formed catalysts which were highly reactive in the reaction with cycloheptenone (14, n = 3) with enantiomeric excess reaching >80% (5, 2). Surprisingly, the product configuration was reversed going from ligand 4a to 5a, whilst the enantiomeric excesses were almost identical. Excellent yields and enantioselectivities were obtained in the reaction with cyclohexenone (5, n = 2, 2). In each of the above cases, there is no obvious correlation between steric bulk in the ligand and the observed enantioselectivity. Unsurprisingly, only moderate yields were obtained for the addition to cyclopentenone (5, n = 1, 2). This is a general problem with this substrate; although the reaction goes to full conversion, a number of by-products are formed containing more than one cyclopentenone unit, because the enolate produced in the 1,4-addition has a high tendency to add to cyclopentenone. Bulky ligands resulted in reduced enantioselectivity and the (R,S) diastereoisomer (2-5b) gave higher enantioselectivities than the corresponding (S,S) isomer (2-5a).

Acyclic substrates were also investigated and promising results were obtained with trans-4-phenylbut-3-en-2-one (6).

Several other phosphorus ligands produce high enantioselectivities in the 1,4-addition of organozinc reagents. A range of chiral phosphites has been investigated by Alexakis et al. with enantioselectivities of up to 96% for the addition of diethylzinc to cyclohenenone.12 Yan and Chan have used chiral diphosphites and achieved enantiomeric excesses of 89-90% in the addition of diethylzinc to cyclohexenone and cyclopentenone.13 Feringa has developed a range of phosphoramidites for the 1,4-diethylzinc additions.14,15 Enantioselectivities of >98% have been reported for the addition to cyclohexenone and up to 82% for acyclic substrates. Hu et al. have used P,N-ligands derived from binaphthyl, recording enantiomeric excesses of 90% for the addition of diethylzinc to cyclohenanone and 98% for arylsubstituted acyclic enones.16 The best reported method for the addition of a range of dialkylzincs to several different cyclopentenones has been reported by Degrado et al. using peptide-based P,N-ligands.17 Isolated yields were 55-92% with enantioselectivities as high as >98%. The same ligands also gave excellent results (>95% ee) for the addition of dialkylzincs to cylohexenones and cycloheptenones.

Related Reagents.

Phosphinoxazolines (PHOX ligands), BINAP, chiraphos, bisoxazolines.

1. Prétôt, R.; Pfaltz, A., Angew. Chem. 1998, 110, 337; Angew. Chem., Int. Ed. Engl. 1998, 37, 323.
2. Prétôt, R.; Lloyd-Jones, G. C.; Pfaltz, A., Pure Appl. Chem. 1998, 70, 1035.
3. Knöbel, A. K. H.; Escher, I.; Pfaltz, A., Synlett 1997, 1429.
4. Escher, I. H.; Pfaltz, A., Tetrahedron 2000, 56, 2879.
5. (a) Allen, J. V.; Williams, J. M. J., Tetrahedron: Asymm. 1994, 5, 277. (b) Pridgen, L. N.; Miller, G., J. Heterocyclic Chem. 1983, 20, 1223.
6. Prétôt, R., PhD Thesis, University of Basel, 1997.
7. Pfaltz, A.; Lautens, M., In Comprehensive Asymmetric Catalysis; Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H., Eds.; Springer: Berlin, 1999, Vol. 2, p 833.
8. Trost, B. M.; Hachiya, I., J. Am. Chem. Soc. 1998, 120, 1104.
9. Glorius, F.; Pfaltz, A., Org. Lett. 1999, 1, 141.
10. Bartels, B.; Helmchen, G., Chem. Commum. 1999, 741.
11. Tomioka, K.; Nagaoka, Y., In Comprehensive Asymmetric Catalysis; Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H., Eds.; Springer: Berlin, 1999, Vol. 3, p 1105.
12. Alexakis, A.; Burton, J.; Vastra, J.; Benhaim, C.; Fournioux, X.; van de Heuvel, A.; Levêque J.-M.; Mazé, F.; Rosset, S., Eur. J. Org. Chem. 2000, 4011.
13. Yan, M.; Chan, A. S. C., Tetrahedron Lett. 1999, 40, 6645
14. Feringa, B. L., Acc. Chem. Res. 2000, 33, 346.
15. Arnold, L. A.; Imbos, R.; Mandoli, A.; de Vries, A. H. M.; Naasz, R.; Feringa, B. L., Tetrahedron 2000, 56, 2865.
16. Hu, X.; Chen, H.; Zhang, X., Angew. Chem. 1999, 111, 3720; Angew. Chem., Int. Ed. Engl. 1999, 38, 3518.
17. Degrado, S. J.; Mizutani, H.; Hoveyda, A. H., J. Am. Chem. Soc. 2001, 123, 755.

Jonathan A. Medlock & Andreas Pfaltz

University of Basel, Basel, Switzerland

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