[136705-64-1]  · C22H36P2  · 1,2-Bis(2,5-diethylphospholano)benzene  · (MW 362.47)

(ligand for asymmetric catalysis;1 rhodium complexes are efficient catalyst precursors for highly enantioselective hydrogenation of a-(N-acylamino)acrylates,1,2 enol acetates,1 and N-acylhydrazones3,4)

Alternate Name: (R,R)- and (S,S)-Ethyl-DuPHOS.

Physical Data: bp 138-143 °C/0.045 mmHg; (R,R)-Ethyl-DuPHOS, [a]25D = -265° (c 1, hexane).

Form Supplied in: colorless viscous liquid; both enantiomers available commercially.

Analysis of Reagent Purity: optical rotation, 1H NMR, 31P NMR, 13C NMR.

Preparative Methods: preparation of (R,R)-Ethyl-DuPHOS requires the use of (3S,6S)-3,6-octanediol.1,2 Enantiomerically pure (3S,6S)-octanediol is obtained in 35-45% overall yields via a simple three-step procedure5,6 involving the Ru-(S)-BINAP-catalyzed asymmetric hydrogenation7 of methyl propionylacetate to methyl (3S)-3-hydroxypentanoate (95% yield, 99% ee), followed by quantitative hydrolysis to the corresponding b-hydroxy acid, and subsequent electrochemical Kolbe coupling (eq 1). This sequence has been used for the synthesis of multigram quantities of (3S,6S)-octanediol, as well as a series of related chiral 1,4-diols.2,6 Antipodal (3R,6R)-octanediol was prepared in a similar fashion by employing the (R)-BINAP-Ru catalyst in the first step.6

The crystalline (3S,6S)-octanediol (mp 51-52 °C; [a]25D = +22.8° (c 1, CHCl3)) is next converted to the corresponding (3S,6S)-octanediol cyclic sulfate (mp 80-81 °C; [a]25D = +28.6° (c 1, CHCl3)) through reaction with Thionyl Chloride, followed by oxidation with Sodium Periodate and a catalytic amount (0.1 mol%) of Ruthenium(III) Chloride (eq 2).2 The final step involves successively treating 1,2-bis(phosphino)benzene8 with n-Butyllithium (2 equiv 1.6 M in hexane), followed by (3S,6S)-octanediol cyclic sulfate (2 equiv), and then n-BuLi (2.2 equiv) to provide the product (R,R)-Ethyl-DuPHOS in 78% yield after purification by distillation (eq 2). The use of (3R,6R)-octanediol cyclic sulfate in eq 2 allows the analogous preparation of (S,S)-Ethyl-DuPHOS. In addition to Ethyl-DuPHOS (R = Et), a series of other DuPHOS derivatives (R = Me, Pr, i-Pr, Cy, Bn) have been prepared in this manner.1,2

Handling, Storage, and Precautions: somewhat air sensitive and should be handled and stored in a nitrogen or argon atmosphere. Metal complexes generally are sensitive to oxygen in solution. Use in a fume hood.

Catalyst Precursors: Rhodium Complexes.

The cationic rhodium complexes [(cod)Rh(Ethyl-DuPHOS)]+X- (X = OTf, PF6, BF4, SbF6) serve as efficient catalyst precursors for both enantioselective hydrogenation1-6 and intramolecular hydrosilylation9 reactions. These complexes are most conveniently prepared by reacting the ligand, either (R,R)-Ethyl-DuPHOS or (S,S)-Ethyl-DuPHOS, with the complexes [(cod)2Rh]+X- in THF.2,10 Since the solid rhodium catalysts are less air-senstive than the ligands, they may be weighed quickly in air, although storage under nitrogen or argon is recommended.

Enantioselective Hydrogenations.


The cationic Ethyl-DuPHOS-Rh catalysts are particularly well-suited for highly enantioselective hydrogenation of a-(N-acylamino)acrylates to a-amino acid derivatives (eq 3).1,2

The reactions proceed under mild conditions (1 atm H2, 25 °C, MeOH) and are extremely efficient (substrate-to-catalyst ratios S/C up to 50 000 have been demonstrated). The breadth of the Ethyl-DuPHOS-Rh catalyst is noteworthy; extremely high enantioselectivities (&egt;99% ee) are achieved over a broad range of substrates (Table 1). Accordingly, the Ethyl-DuPHOS-Rh catalysts can provide practical access to a wide variety of natural, unnatural, nonproteinaceous, and labeled a-amino acids. The absolute configurations of the products are very predictable; (R,R)-Ethyl-DuPHOS-Rh complexes consistently afford products of (R) absolute configuration, while (S,S)-Ethyl-DuPHOS-Rh complexes provide (S)-a-amino acid derivatives. Similarly high ees are obtained with the corresponding carboxylic acid substrates (R3 = H), as well as with N-benzoyl (R2 = Ph) and N-Cbz (R2 = OBn) a-(N-acylamino)acrylates. Significantly, the Ethyl-DuPHOS-Rh catalysts allow hydrogenation of both (Z) and (E) isomeric a-(N-acetylamino)acrylates in high enantiomeric excess (>99% ee) to afford products with the same absolute configuration. Many desirable a-(N-acylamino)acrylates are unavoidably synthesized as a mixture of (E) and (Z) isomers, and a separation step generally is required prior to hydrogenation. When using the Ethyl-DuPHOS-Rh catalysts, however, the need to separate isomeric substrates is often eliminated, thus providing a practical route to many amino acid derivatives.

Enol Acetates.

Several enol acetates are hydrogenated with high enantioselectivities using the Ethyl-DuPHOS-Rh catalysts (eqs 4 and 5).1 The selectivities are significantly higher than any previously reported for these substrates.11 The scope of these reactions and substrates bearing b-substituents have not yet been examined.


The C=N double bond of N-benzoylhydrazones may be hydrogenated with high enantioselectivities using the Ethyl-DuPHOS-Rh catalyst systems (eq 6).3,4

Under optimized conditions (0 °C, 60 psi H2, i-PrOH, S/C 500), the (R,R)-Et-DuPHOS-Rh catalyst predictably provides a variety of N-benzoylhydrazine products in high enantiomeric excess and with (S) absolute configuration (Table 2).

An interesting and potentially useful property of the Et-DuPHOS-Rh catalyst system is the high level of chemoselectivity exhibited in the hydrogenation of N-benzoylhydrazones. Little or no reduction of various functional groups including alkenes, alkynes, ketones, aldehydes, nitriles, imines, carbon-halogen, and nitro groups is observed under conditions required for complete reduction of the hydrazones.

Enantioselective hydrogenation of N-benzoylhydrazones represents a key transformation in a three-step asymmetric catalytic reductive amination process that involves: (1) treating a ketone with benzoic acid hydrazide; (2) Ethyl-DuPHOS-Rh-catalyzed hydrogenation of the N-benzoylhydrazone; and (3) hydrolysis of the product N-benzoyl group (3 M HCl) to provide the corresponding hydrazine, or reductive cleavage of the product N-N bond with Samarium(II) Iodide to directly afford the corresponding amine (eq 7).4

1. Burk, M. J. JACS 1991, 113, 8518.
2. Burk, M. J.; Feaster, J. E.; Nugent, W. A.; Harlow, R. L. JACS 1993, 115, 10 125.
3. Burk, M. J.; Feaster, J. E.; JACS 1992, 114, 6266.
4. Burk, M. J.; Feaster, J. E.; Cosford, N.; Martinez, J. P. T 1994, 50, 4399.
5. Burk, M. J.; Feaster, J. E.; Harlow, R. L. OM 1990, 9, 2653.
6. Burk, M. J.; Feaster, J. E.; Harlow, R. L. TA 1991, 2, 569.
7. (a) Noyori, R.; Ohkuma, T.; Kitamura, M.; Takaya, H.; Sayo, N.; Kumobayashi, H.; Akutagawa, S. JACS 1987, 109, 5856. (b) Kitamura, M.; Ohkuma, T.; Inoue, S.; Sayo, N.; Kumobayashi, H.; Akutagawa, S.; Ohta, T.; Takaya, H.; Noyori, R. JACS 1988, 110, 629. (c) Kawano, H.; Ikariya, T.; Ishii, Y.; Saburi, M.; Yoshikawa, S.; Uchida, Y.; Kumobayashi, H. JCS(P1) 1989, 1571.
8. Kyba, E. P.; Liu, S.-T.; Harris, R. L. OM 1983, 2, 1877.
9. Burk, M. J.; Feaster, J. E. TL 1992, 33, 2099.
10. Schrock, R. R.; Osborn, J. A. JACS 1971, 93, 2397.
11. Koenig, K. E.; Bachman, G. L.; Vineyard, B. D. JOC 1980, 45, 2362.

Mark J. Burk

Duke University, Durham, NC, USA

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