1,2-Bis((2S,5S)-2,5-dimethylphospholano)benzene (S,S)-Me-DuPhos, 1,2-Bis((2R,5R)-2,5-dimethylphospholano)benzene (R,R)-Me-DuPhos

[147253-67-6], [136735-95-0]  · C18H28P2, C18H28P2

Physical Data: mp 79-81 °C, [a]D25 + 476 +/- 5 (c 1, hexanes) for the S,S-enantiomer.

Form Supplied in: colorless crystals, Strem chemicals.

Preparative Methods: the DuPhos ligands are readily synthesized from the corresponding chiral 1,4-diols via the derived cyclic sulfate (1).1 The intermediate cyclic sulfate is isolable as a crystalline solid, and can be recrystallized from hexane/diethyl ether. The ligands are then obtained by treatment with lithiated 1,2-phenylene bisphosphine. After nucleophilic ring opening, treatment with two additional equivalents of n-butyllithium gives facile ring closure to generate the five-membered phospholane ligands. The analogous four-membered phospholane has been prepared in the same manner.2

Purification: recrystallized from methanol at -10 °C.

Handling, Storage, and Precautions: crystalline Me-DuPhos is stable to air oxidation for over 10 days. However, it is generally prudent to store the DuPhos ligands under an inert atmosphere. In benzene solution, the DuPhos ligands are prone to oxidation with ca. 65% conversion to phosphine oxide after 3 weeks. Toxicity data are not available.

Bisphospholanes as Ligands in Asymmetric Catalysis

Bisphospholanes such as 1-5, first reported by Burk,3 have found use as ligands in transition metal-catalyzed asymmetric transformations. While metal complexes derived from the bis(phospolano)ethane (BPE) ligands (5) exhibit dynamic behavior, those of the more rigid DuPhos ligands (1-4) do not. In contrast to chiral triaryl phosphines, the DuPhos and BPE ligands are more basic and provide more electron-rich metal centers which often lead to differences in reactivity and selectivity. The modular ligand synthesis also allows access to a rich array of steric environments and allows for a significant degree of steric tuning between the ligand and substrate.

Rhodium-Catalyzed Asymmetric Hydrogenation

Cationic rhodium catalysts derived from the DuPhos ligands are highly effective in catalytic enantioselective alkene hydrogenation. a-Amino acids are produced in a predictable fashion by reduction of the corresponding enamide esters. Coordination of the enamide group to the metal center is a prerequisite for reduction and, as a result, regioselective hydrogenations are possible (2).4 When the b-position of the substrate is not prochiral, both alkene stereoisomers provide the same enantiomer of amino acid, such that readily available E/Z mixtures of the enamide ester may be used (3). In addition to enamide coordinating groups, hydrogenation may also be directed by benzoates which provides a route to chiral a-hydroxy esters5 and a-hydroxy phosponates (4).6 Catalytic hydrogenation of more elaborate substrates has also been employed for the synthesis of candoxatril and C-linked glycopeptides.7

Ruthenium-Catalyzed Hydrogenations

Ru-DuPhos complexes are commonly prepared by reacting [RuCl2(cod)]n with methallylmagnesium chloride to generate [Ru(cod)(methallyl)2] which when treated with DuPhos and HX forms the catalytically active complex (DuPhos)RuX2. The procedure can be performed in a single pot or in stepwise fashion.8 Ru-DuPhos complexes effectively reduce a variety of substrates to provide chiral materials.

Both aromatic and aliphatic b-ketoesters are hydrogenated yielding the corresponding b-hydroxy esters in good yields and enantioselectivities (5).9 The ruthenium-DuPhos catalyst generated in situ from (cod)RuBr2, methallylmagnesium bromide, and (R,R)-1 efficiently reduces phenylpyruvate in quantitative yield and high enantioselectivity (6). Symmetric 1,3-diketones are effectively hydrogenated to anti-1,3-diols by the same Ru-DuPhos complexes (7). In these examples Me-DuPhos affords products in slightly higher selectivity than Et-DuPhos (93 versus 85% ee).10

Simple a-substituted styrenes are reduced in the presence of RuCl2(DuPhos)(DMF)n. The reactivity of the ruthenium catalyst is enhanced by the addition of potassium tert-butoxide, which may facilitate generation of a ruthenium hydride. The products are obtained under low hydrogen pressures and selectivities obtained are up to 89% ee (8).11 Neutral Rh-DuPhos complexes catalyze the hydrogenation of a,b-unsaturated acids such as tiglic acid (9). The product is obtained in quantitative yield and good enantioselectivity.9

Miscellaneous Reactions

The cationic species [(cod) Rh(R,R)-4]OTf efficiently performs the intramolecular hydrosilation of a-hydroxy esters (10). In these transformations, increased steric congestion at the prochiral center correlates with increased enantioselection. It is also noteworthy that, in some cases, the absolute configuration of the product inverts when (R,R)-Me DuPhos is employed as opposed to (R,R)-i-PrDuPhos. In these examples, reactions in the presence of DuPhos were found to proceed in higher selectivity than either BINAP or chiraPhos.12 Platinum DuPhos catalysts have also been applied to the hydrophosphination of various acrylonitriles and acrylates. High regioselectivity is obtained in the hydrophosphination reaction with phosphine attachment beta to the cyano or ester moiety (11).13 Platinum salts complexed with DuPhos also effectively desymmetrize meso-cyclohexanones (12).14 The reactions are performed under Baeyer-Villager oxidation conditions utilizing hydrogen peroxide as the terminal oxidant. Enantioselection is dependent on the substitution pattern in the starting meso ketone. For 2,6-dimethylcyclohexanone, Pt-DuPhos oxidation yields the lactone product with enantioselectivity comparable to Pt-BINAP, both of which are superior to Pt-DIOP and Pt-norPhos.

Hydroacylation of 4-substituted pentenals using a cationic Rh-DuPhos catalyst provides chiral cyclopentanones ranging in enantioselectivity from 91 to 94% ee (13).15 In these examples, the nature of the R substituent on the olefin has little effect on the selectivity of the reaction. Aldol products are obtained from the reductive coupling between aldehydes methyl acrylate and dichloromethylsilane when employing [(cod)RhCl]2 and Me-DuPhos as the catalyst system. The b-hydroxy esters are obtained in excellent diastereoselectivity for a range of aldehyde-acrylate combinations, although yields are inferior with aliphatic aldehydes (14).16 Frauenrath and co-workers have reported that chiral dihalogeno nickel complexes are efficient catalyst precursors for the asymmetric isomerization of cyclic allylic acetals (15).17 It was previously shown that the ring size of the acetal as well as the ring size of the metal-ligand chelate have a bearing on the enantioselectivity of the reaction. Me-DuPhos was thus found to be a suitable ligand for these types of reactions. It was later discovered that yields and enantioselectivities are also dependent on the counter ion. When iodide was used as the counter ion and upon activation with LiBHEt3, the reaction proceeded with high enantioselectivity at low temperatures.

Polymerization Reactions

Lee and Alper have shown that the use of a Pd(II)-Me-DuPhos catalyst produces highly functionalized alternating polyketones derived from CO and a-olefins (16).18 Notably, the polymers are exclusively head-to-tail selective, isotactic, high molecular weight, and, when prepared with the Pd-DuPhos catalyst, can contain functionality in the polymer side chain. Sen et al. have demonstrated that Pd(II)-Me-DuPhos complexes are excellent catalysts for alternating copolymerizations of ethene, propene, and cyclopentene with SO2 (17).19 The copolymers that were produced were 1:1 alternating and atactic with exclusive head-to-tail enchainment as shown for propene. The ability of the Pd(II) catalyst to promote the polymerization depended strongly on the nature of the ligand bound to palladium. It was discovered that monodentate phosphines as well as bidentate nitrogen ligands were ineffective as ligands for catalysis. Only bidentate phosphines acted as ligands to generate the active catalyst.

1. Burk, M. J.; Feaster, J. E.; Nugent, W. A.; Harlow, R. L., J. Am. Chem. Soc. 1993, 115, 10125
2. Marinetti, A.; Kruger, V.; Fancois-Xavier, B., Tetrahedron Lett. 1997, 38, 2947.
3. Burk, M. J., J. Am. Chem. Soc. 1991, 113, 8518.
4. Burk, M. J.; Allen, J. G.; Kiesman, W. F., J. Am. Chem. Soc. 1998, 120, 657.
5. Burk, M. J.; Kalberg, C. S.; Pizzano, A., J. Am. Chem. Soc. 1998, 120, 4345.
6. Burk, M. J.; Stammer, T. A.; Straub, J. A., Organic Lett. 1999, 1, 387.
7. (a) Burk, M. J.; Bienewald, F.; Challenger, S.; Derrick, A.; Ramsden, J. A., J. Org. Chem. 1999, 64, 3290. (b) Debenham, S. D.; Debenham, J. S.; Burk, M. J.; Toone, E. J., J. Am. Chem. Soc. 1997, 119, 9897.
8. Guerreiro, P.; Cano de Andrade, M.; Henry, J.; Tranchier, J.; Phansavath, P.; Ratovelomana-Vidal, V.; Genet, J.; Homri, T.; Touati, A. R.; Ben Hassine, B., C. R. Acad. Sci. Paris 1999, 175.
9. Genet, J. P.; Pinel, C.; Ratovelomana-Vidal, V.; Mallart, S.; Pfister, X.; Bischoff, L.; Cano de Andrade, M.; Darses, S.; Galopin, C.; Lafitte, J. A., Tetrahedron: Asymm. 1994, 5, 675.
10. Blanc, D.; Ratovelomana-Vidal, V.; Marinetti, A.; Genet, J. P., Synlett 1999, 480.
11. Forman, G. S.; Ohkuma, T.; Hems, W. P.; Noyori, R., Tetrahedron Lett. 2000, 41, 9471.
12. Burk, M. J.; Feaster, J. E., Tetrahedron Lett. 1992, 33, 2099.
13. Kovacik, I.; Wicht, D. K.; Grewal, N. S.; Glueck, D. S., Organometallics 2000, 19, 950.
14. Paneghetti, C.; Gavagnin, R.; Pinna, F.; Strukul, G., Organometallics 1999, 18, 5057.
15. Barnhart, R. W.; McMorran, D. A.; Bosnich, B., Chem Commun. 1997, 589.
16. Taylor, S. J.; Morken, J. P., J. Am. Chem. Soc. 1999, 121, 12202.
17. Frauenrath, H.; Brethauer, D.; Reim, S.; Maurer, M.; Raabe, G., Angew. Chem. Int. Ed. Engl. 2001, 40, 177.
18. Lee, J. T.; Alper, H., Chem Commun. 2000, 2189.
19. Wojcinski, L. M.; Boyer, M. T.; Sen, A., Inorg. Chem. Acta 1998, 270, 8.

James P. Morken, Albert E. Russell & Steven J. Taylor

UNC Chapel Hill, North Carolina, USA

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