[136779-28-7]  · C22H36P2  · (362.47)

(ligand for asymmetric catalysis; rhodium(I) complexes are efficient catalysts in highly enantioselective hydrogenation of various unsaturated substrates [enol acylates,1,2 (N-acylamino)acrylates,1,3,4 and N-acylhydrazones5])

Alternate Name: (S,S)-ethyl-DuPHOS

Physical Data: bp 138-145 °C/0.04 mmHg; [a]D +265 (c 1, hexane).

Solubility: soluble in most organic solvents.

Form Supplied in: colorless oil; commercially available.

Analysis of Reagent Purity: optical rotation; NMR spectroscopy.

Preparative Methods: the preparation of (S,S)-ethyl-DuPHOS is based on (3R,6R)-octane-3,6-diol as an enantiomerically pure starting compound.1,3 The latter is synthesized by a three-step procedure6,7 starting from methyl 3-oxopentanoate, which is transformed to methyl (R)-3-hydroxypentanoate (99% ee) by enantioselective hydrogenation with a Ru-(R)-BINAP catalyst,8 followed by hydrolysis to the hydroxy acid. The subsequent electrochemical Kolbe coupling reaction leads to (3R,6R)-octane-3,6-diol in a protocol that can be scaled up to multigram quantities (1).3,6

The chiral octanediol in turn is converted into the corresponding cyclic sulfate by reaction with thionyl chloride and subsequent oxidation with sodium periodate and a catalytic amount of ruthenium(III) chloride (0.1 mol%) (2).3 In the final step, 1,2-diphosphinobenzene9 is lithiated by treatment with n-butyllithium (n-BuLi; 2 equiv, 1.6 mol% in hexane) followed by the addition of the (3R,6R)-octane-3,6-diol cyclic sulfate (2 equiv) and a further addition of 2.2 equiv of n-BuLi. (S,S)-Ethyl-DuPHOS is obtained in a yield of over 70% [78% yield was described for the (R,R)-enantiomer by an analogous method3].1 In addition to (S,S)-ethyl-DuPHOS, a variety of related bisphospholanes either linked by an ethylene bridge, or bearing other 2,5-alkyl substituents, or with opposite configuration have been prepared by this methodology.1,3

Handling, Storage, and Precautions: the reagent is sensitive to air and should be handled and stored under argon or nitrogen.

Catalyst Precursors

Rhodium Complexes

Cationic rhodium(I) complexes such as {Rh[(S,S)-ethyl-DuPHOS](cod)}+X- (X=OTf, PF6, BF4, SbF6) are usually employed as precatalysts for enantioselective hydrogenation1-4 or hydrosilylation10 reactions. The precatalysts can be prepared from the chiral ligand and [Rh(cod)2]+X--complexes by a standard method.3,11 The corresponding {Rh[(S,S)-ethyl-DuPHOS](nbd)} complex can be accessed equally well by the method of Schrock and Osborne11 or by exchange of cod in the relevant rhodium complex by norbornadiene (nbd).12

Enantioselective Hydrogenations

C=C Double Bond

The most commonly used reactions that employ {Rh[(S,S)-Et-DuPHOS](cod)}+X- complexes involve the enantioselective hydrogenation of a-(N-acyl)enamide carboxylates. a-Amino acids are obtained in quantitative yield with high optical purity (95-99% ee) (3).1,3,4

In this reaction, the (S,S)-ethyl-DuPHOS-catalyst produces the S-configurated a-amino acid derivatives when the substrate has one substituent in the b-position (R2=H). The catalyst tolerates a range of substituents R1 in the unsaturated substrate. The reaction conditions are mild (25 °C, MeOH, low hydrogen pressure) and the reaction proceeds rapidly (turnover frequencies 5000 h-1). High substrate-to-catalyst ratios can be employed (up to 50 000). In general, high enatiomeric excesses are observed, independent of the geometry of the enamide (E- or Z-isomer) used. This feature is advantageous because frequently the unsaturated a-enamide carboxylic acids derivatives are synthesized as a mixture of both stereoisomers. Due to the high stereodiscriminating ability of the catalyst, separation prior to hydrogenation is not required. Access to a great number of natural, unnatural and nonproteogenic amino acids is possible in this manner (Table 1).

The highly enantioselective hydrogenation of the corresponding dehydroamino acids (R3=H) and the synthesis of N-Cbz-protected a-amino acids (R4=OBn) are likewise possible.3,16 Enantioselectivities of >99% can be achieved after 20-40 hours. Amino acid esters can be used directly for the synthesis of peptides. Deprotection of the amino groups can be carried out under mild conditions, thus avoiding racemization reactions.

Evidence has been given that the use of the Rh(P2)(nbd) precatalyst is favored over the application of the corresponding cod-precatalyst. Börner and Heller17 found that hydrogenation of the cod of the precatalyst takes place in parallel to the enantioselective hydrogenation of methyl (Z)-N-acetylaminocinnamate.17,18 About 50% of the Rh-precatalyst remained unchanged after complete hydrogenation of the prochiral substrate. Therefore, precious ligand and Rh complex are wasted. This can be avoided by the application of {Rh[(S,S)-ethyl-DuPHOS](nbd)}+X- as precatalyst. The hydrogenation of nbd proceeds much faster than that of cyclooctadiene. As an alternative, prehydrogenation of the cod-precatalyst in MeOH is possible for generating the catalytically active species.

Excellent enantio- and regioselectivities were also observed when N-acetylamino acrylates bearing additional functional groups, e.g. alkenes, were applied as substrates (4).3,4

In these hydrogenations, less than 2% of the g,d-double bond was reduced. This feature indicates the ethyl-DuPHOS ligand to be superior in comparison to related DuPHOS/BPE-ligands or other chelating diphosphines. Other functional groups that are generally sensitive to reduction such as carbonyl groups, nitro groups, and halides also survive under the mild conditions applied to hydrogenation of the double bond adjacent to the acylamino group.

Diastereoselective hydrogenation of a bis(dehydroamino acid) derivative, recognized to be important for the syntheses of isotyrosine, in the presence of {Rh[(S,S)-ethyl-DuPHOS](cod)}+OTf- as catalyst yielded excellent results (5).19

The possibility of preparing an isotyrosine derivative with four orthogonal protecting groups gives access to a highly versatile building block for several biologically active natural compounds. Enantioselectivities in excess of 98% ee for the S,S-enantiomer and diastereoselectivities above 84% have been observed. In general, the yields exceeded 90%.

The formation of stereogenic C-N bonds by hydrogenation of the enamine structure is not only limited to amino acids. Likewise, chiral 1,2-aminoalcohols or 1,2-diamines can be produced by the enantioselective hydrogenation of dehydro-b-amino alcohols (or their esters) and of dehydro-a-amino aldoximes, respectively (6 and 7, Table 2).20 Esters and aldoximes thus obtained can be converted into the corresponding alcohols or diamines by standard methods. By this means, simple amines with one aryl group attached to the double bond can also be hydrogenated with high enantioselectivity.21

Enol acetates and corresponding derivatives constitute another class of unsaturated compounds that can advantageously be hydrogenated with high enantiomeric excess. This reaction is related to the enantioselective reduction of ketones. Acylated enol carboxylates (as an equivalent of a-keto carboxylic acid) can likewise be successfully reduced with rhodium(I) catalysts based on (S,S)-ethyl-DuPHOS (8).2 Subsequent deprotection of the hydroxyl group or reduction of the carboxylic acid derivatives so obtained deliver chiral a-hydroxy carboxylates and 1,2-diols, respectively.

Burk et al.2 showed that the Rh-(S,S)-ethyl-DuPHOS complex is able to reduce acylated a-hydroxy carboxylates with high enantiomeric excess independently of the E:Z ratio of the alkene substrate (Table 3). However, the reaction failed when substrates branched in b-position were tested.

Finally, several examples of the enantioselective hydrogenation of unsaturated substrates without any heteroatom attached to the olefinic double bond are noteworthy. Of particular relevance to the production of pharmaceutics, agrochemicals, flavors and aroma stuffs is the formation of the chiral 2-substituted succinates based on relevant itaconic acid derivatives. Burk et al.22 demonstrated that a rhodium(I) catalyst derived from (S,S)-ethyl-DuPHOS is able to hydrogenate aryl- or alkyl-substituted itaconic acid derivatives with excellent enantioselectivity (9, Table 4).

Prior separation of the E:Z mixtures of the itaconic acid substrates (usually representing mixtures of 2:1 to more than 10:1) and also by-products of the synthesis do not affect the results.

A catalyst based on ethyl-DuPHOS also showed its high potential in the enantioselective hydrogenation of a sodium glutarate as the pivotal intermediate in the multi-step synthesis of candoxatril (10).23

By application of the relevant Rh-(S,S)-ethyl-DuPHOS catalyst, no isomerization of the starting material to the enol ether occurred by migration of the double bond. This side reaction operates in the presence of the corresponding ruthenium catalysts. When (S,S)-ethyl-DuPHOS was applied as ligand the R-enantiomer was formed instead of the desired S-enantiomer, necessary for the synthesis of candoxatril.

Another example of the synthesis of a compound with pharmaceutical relevance is the chemical transformation of rac-warfarin into enantiomerically pure (R)- or (S)-warfarin.24 In the first step, rac-warfarin is oxidized to the corresponding a,b-unsaturated ketone. The latter can be easily hydrogenated to the desired enantiomer by application of the appropriate DuPHOS-catalyst (11). Prior transformation of dehydrowarfarin into the sodium salt or its methyl ether improved the yield and suppressed side reactions. Simultaneously, the enantioselectivity of the hydrogenation product was enhanced. The (S,S)-ethyl-DuPHOS-complex leads to R-configured warfarin.

C=N Double Bond

The enantioselective reduction of a C=N double bond is an interesting alternative for the production of chiral amines by hydrogenation of enamides. Required imines or oximes can be prepared by reaction of ketones with amines or hydroxylamines. However, to date, trials to reduce these substrates with ethyl-DuPHOS catalysts gave no satisfying results. Therefore, transformation of ketones or a-keto acids into acylhydrazones and subsequent enantioselective hydrogenation has proven advantageous (12, Table 5).25,26

Chiral hydrazines can be transformed to a-amino acids and amines by cleavage of the N-N bond. Conversion to a-hydrazino acids by hydrolysis of the esters or into hydrazines by deacylation is likewise possible.26

(S,S)-Ethyl-DuPHOS has been employed mainly for enantioselective hydrogenation. Several types of reaction can be run very successfully. In other enantioselective reactions, this ligand has been used only rarely, one example being the enantioselective allylation of benzaldehyde by application of the corresponding silver(I) catalyst. However, in this example, the reaction failed.27

It is likely that several results obtained with the homologous ligands of R-DuPHOS (R=Me, Pr) or their opposite enantiomers can be related also to (S,S)-ethyl-DuPHOS. Recently, Burk has published a review about the application of phospholane ligands in asymmetric catalysis, which gives a good survey of the use of DuPHOS- and BPE-ligands.28

Related Reagents.

The homologous derivatives of DuPHOS- and BPE-ligands. RoPHOS;29-33 PennPHOS;34 BASPHOS;35 CnrPHOS.36-39

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2. Burk, M. J.; Kahlberg, C. S.; Pizzano, A., J. Am. Chem. Soc. 1998, 120, 4345.
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4. Burk, M. J.; Allen, J. G.; Kiesman, W. F., J. Am. Chem. Soc. 1998, 120, 657.
5. Burk, M. J.; Feaster, J. E., J. Am. Chem. Soc. 1992, 114, 6266.
6. Burk, M. J.; Feaster, J. E.; Harlow, R. L., Tetrahedron: Asymmetry 1991, 2, 569.
7. Burk, M. J.; Feaster, J. E.; Harlow, R. L., Organometallics 1990, 9, 2653.
8. Noyori, R.; Ohkuma, T.; Kitamura, M.; Takaya, H.; Sayo, N.; Kumobayashi, H.; Ohkuma, T.; Inoue, S., J. Am. Chem. Soc. 1987, 109, 5856.
9. Kyba, E. P.; Liu, S. T.; Harris, R. L., Organometallics 1983, 2, 1877.
10. Burk, M. J.; Feaster, J. E., Tetrahedron Lett. 1992, 33, 2099.
11. Schrock, R. R.; Osborne, J. A., J. Am. Chem. Soc. 1971, 93, 2397.
12. Heller, D.; Borns, S.; Baumann, W.; Selke, R., Chem. Ber. 1996, 129: 85.
13. Jones, S. W.; Palmer, C. F.; Paul, J. M.; Tiffin, P. D., Tetrahedron Lett. 1999, 40: 1211.
14. Wagaw, S.; Rennels, R. A.; Buchwald, S. L., J. Am. Chem. Soc. 1997, 119, 8451.
15. Aguado, G. P.; Alvarez-Larena, A.; Illa, O.; Moglioni, A. G.; Ortuno, R. M., Tetrahedron: Asymmetry 2001, 12, 25.
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17. Börner, A.; Heller, D., Tetrahedron Lett. 2001, 42, 223.
18. Drexler, H. J.; Baumann, W.; Spannenberg, A.; Fischer, C.; Heller, D., J. Organomet. Chem. 2001, 621, 89.
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24. Robinson, A.; Li, H. Y.; Feaster, J., Tetrahedron Lett. 1996, 37: 8321.
25. Burk, M. J.; Feaster, J. E., J. Am. Chem. Soc. 1992, 114, 6266.
26. Burk, M. J.; Martinez, J. P.; Feaster, J. E.; Cosford, N., Tetrahedron 1994, 50: 4399.
27. Yanagisawa, A.; Nakashima, H.; Ishiba, A.; Yamamoto, H., J. Am. Chem. Soc.1996, 118, 4723.
28. Burk, M. J., Acc. Chem. Res. 2000, 33, 363.
29. Holz, J.; Quirmbach, M.; Schmidt, U.; Heller, D.; Stürmer, R.; Börner, A.; J. Org. Chem. 1998, 63, 8031.
30. Li, W.; Zhang, Z.; Xiao, D.; Zhang, X., Tetrahedron Lett. 1999, 40: 6701.
31. Yan, Y.-Y.; RajanBabu, T. V., J. Org. Chem. 2000, 65, 900.
32. Li, W.; Zhang, Z.; Xiao, D.; Zhang, X., J. Org. Chem. 2000, 65, 3489.
33. Yan, Y.-Y.; RajanBabu, T. V., Org. Lett. 2000, 2, 199.
34. Jiang, Q.; Jiang, Y.; Xiao, D.; Cao, P.; Zhang, X., Angew. Chem., Int. Ed. Engl. 1998, 37, 1100.
35. Holz, J.; Heller, D.; Stürmer, R.; Börner, A., Tetrahedron Lett. 1999, 40, 7059.
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38. Marinetti, A.; Jus, S.; Genêt, J. P., Tetrahedron Lett. 1999, 40, 8365.
39. Marinetti, A.; Jus, S.; Genêt, J. P.; Ricard, L., Tetrahedron 2000, 56, 95.

Armin Börner & Jens Holz

Institut für Organische Katalyseforschung, Rostock, Germany

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