Dihydroquinidine Acetate1

(R = Ac)

[72989-10-7]  · C22H28N2O3  · Dihydroquinidine Acetate  · (MW 368.47) (R = p-ClC6H4C(O)-)

[113162-02-0]  · C27H29ClN2O3  · Dihydroquinidine p-Chlorobenzoate  · (MW 464.99) (R = H)

[1435-55-8]  · C20H26N2O2  · Dihydroquinidine  · (MW 326.44)

(asymmetric dihydroxylation;2 conjugate additions;3 carbonyl additions3)

Alternate Name: DHQD-Ac.

Physical Data: p-ClC6H4C(O)-: mp 102-105 °C; [a]D -73° (c = 1, EtOH).

Solubility: p-ClC6H4C(O)-: sol CH2Cl2, Et2O, EtOH, EtOAc.

Form Supplied in: the p-chlorobenzoate is available as a white foam.

Preparative Methods: the acetate is prepared from dihydroquinidine4 and the p-chlorobenzoate is commercially available. The phthalazine-derived bis(dihydroquinidine) ligand is commercially available.5 A formulation of the standard reactants for the asymmetric dihydroxylation (AD-mix-b) on the small scale has been developed and is commercially available.6 AD-mix-b (1 kg) consists of potassium osmate (0.52 g), the phthalazine-derived ligand (5.52 g), K3Fe(CN)6 (700 g), and powdered K2CO3 (294 g).

Purification: the recovery of dihydroquinidine p-chlorobenzoate after a dihydroxylation reaction is accomplished in the following manner:7 the crude dihydroquinidine p-chlorobenzoate (DHQD-CLB) is dissolved in ether, cooled to 0 °C, and HCl gas is bubbled into the solution until a pH of 1-2 is obtained using wet pH paper. The pale yellow precipitate of the hydrochloride salt is collected by filtration and dried under high vacuum (0.01 mmHg). The free base is liberated by suspending the salt in EtOAc, cooling the heterogeneous mixture to 0 °C, and adding 28% NH4OH (or 15% NaOH) until a pH = 11 is obtained. After separation, the aqueous layer is extracted with portions of EtOAc, the combined organic layers are dried over Na2SO4, and the solvent removed in vacuo to give the pure DHQD-CLB as a white foam.

Handling, Storage, and Precautions: toxic; use in a fume hood.

Chiral Ligand for the Asymmetric Dihydroxylation of Alkenes.

Dihydroquinidine acetate (DHQD-Ac) was found to be one of the first efficient cinchona-derived chiral ligands for the asymmetric dihydroxylation reaction of substituted alkenes.8 For example, styrene could be dihydroxylated in 61% ee (62% yield) using a mixture of 1.1 equiv of DHQD-Ac and 1.1 equiv of Osmium Tetroxide in toluene. An osmium-catalyzed asymmetric process, in which the co-oxidant is N-Methylmorpholine N-Oxide (NMO) and the chiral ligand is DHQD-CLB, was described later.9 The other enantiomer of the diol could also be obtained by using the analogous dihydroquinine ester (Dihydroquinine Acetate), which acts as a pseudoenantiomer of the dihydroquinidine ester. Significant increases in the level of asymmetric induction of the dihydroxylation were later observed if the re-oxidant NMO was replaced by potassium hexacyanoferrate(III) (K3Fe(CN)6) (eq 1).10

The nature of the group attached to the 9-O position of dihydroquinidine was found to have a profound impact on the level of stereochemical induction in these reactions and a variety of new ligands have been developed (see 1-5).11

The phthalazide bis(cinchona) derivatives [(DHQD)2-PHAL]5,6,12 are the best ligands for the asymmetric dihydroxylation of trans, 1,1-disubstituted,13 and trisubstituted alkenes, enol ethers,14 a,b-unsaturated ketones,15 and a,b- and b,g-unsaturated esters,16 whereas the DHQD-IND ligand17 turns out to be superior for cis-alkenes (Table 1). The bis(cinchona) alkaloid-substituted pyrimidine ligand was found to be the best for monosubstituted terminal alkenes.18 The addition of Methanesulfonamide to enhance the rate of osmate(VI) ester hydrolysis is recommended for all nonterminal alkenes.

Asymmetric dihydroxylation of substituted aryl allyl ethers also proceeds with high enantioselectivities (89-95% ee) providing that there are no ortho substituents on the aryl group.19 Dienes,20 polyenes,21 and enynes22 can also be regioselectively dihydroxylated (eqs 2-5). In some cases, such as in the asymmetric dihydroxylation of a,b- and b,g-unsaturated amides,23 the amount of ligand and potassium osmate in the AD-mix content has to be increased fivefold to achieve good catalytic turnover rates.

The prediction of the absolute stereochemistry of the predominant enantiomer obtained is provided by the model shown in Scheme 1.

By employing polymer-bound alkaloid derivatives, heterogeneous catalytic asymmetric dihydroxylation has been achieved with good to excellent enantioselectivities in the dihydroxylation of trans-stilbene.24 These polymers can be recovered and reused while both the yields and the optical purities of diols were maintained.

Double Diastereoselection in the Dihydroxylation Reaction.

The dihydroxylation reaction of chiral nonracemic substrates using the cinchona-derived ligand leads to a matched and mismatched pair (eq 6).25 Kinetic resolution of several racemic secondary alcohols has also been examined.26

Additional examples of asymmetric dihydroxylation are provided under the entry for Dihydroquinine Acetate.

Chiral Ligand for other Stereoselective Reactions.1

The effect of the addition of dihydroquinidine-derived alkaloids on the product enantioselectivity has also been investigated in the addition reaction of Diethylzinc to aldehydes,27 in the addition of aromatic thiols to conjugated cycloalkenones,28 and in the heterogeneous hydrohalogenation of a,a-dichlorobenzazepinone-2.29 In these cases, the dihydroquinidine derivatives were not the optimal ligands.


1. Wynberg, H. Top. Stereochem. 1986, 16, 87.
2. (a) Lohray, B. B. TA 1992, 3, 1317. (b) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. CRV 1994, 94, 2483.
3. Blaser, H.-U. CRV 1992, 92, 935.
4. (a) Rabe, P.; Huntenburg, W.; Schultze, A.; Volger, G. CB 1931, 64, 2487. (b) Hesse, O. LA 1882, 214, 1. (c) Hesse, O. LA 1887, 241, 255.
5. Amberg, W.; Bennani, Y. L.; Chadha, R. K.; Crispino, G. A.; Davis, W. D.; Hartung, J.; Jeong, K.-S.; Ogino, Y.; Shibata, T.; Sharpless, K. B. JOC 1993, 58, 844.
6. Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.; Hartung, J.; Jeong, K.-S.; Kwong, H.-L.; Morikawa, K.; Wang, Z.-M.; Xu, D.; Zhang, X.-L. JOC 1992, 57, 2768.
7. Jacobsen, E. N.; Markõ, I.; Mungall, W. S.; Schröder, G.; Sharpless, K. B. JACS 1988, 110, 1968.
8. Hentges, S. G.; Sharpless, K. B. JACS 1980, 102, 4263.
9. (a) Wai, J. S. M.; Markõ, I.; Svendsen, J. S.; Finn, M. G.; Jacobsen, E. N.; Sharpless, K. B. JACS 1989, 111, 1123. (b) Lohray, B. B.; Kalantar, T. H.; Kim, B. M.; Park, C. Y.; Shibata, T.; Wai, J. S. M.; Sharpless, K. B. TL 1989, 30, 2041.
10. Kwong, H.-L.; Sorato, C.; Ogino, Y.; Chen, H.; Sharpless, K. B. TL 1990, 31, 2999.
11. For 9-O-aryl dihydroquinidine ligands, see: (a) Shibata, T.; Gilheany, D. G.; Blackburn, B. K.; Sharpless, K. B. TL 1990, 31, 3817. (b) Sharpless, K. B.; Amberg, W.; Beller, M.; Chen, H.; Hartung, J.; Kawanami, Y.; Lübben, D.; Manoury, E.; Ogino, Y.; Shibata, T.; Ukita, T. JOC 1991, 56, 4585. (c) Ogino, Y.; Chen, H.; Manoury, E.; Shibata, T.; Beller, M.; Lübben, D.; Sharpless, K. B. TL 1991, 32, 5761.
12. For a similar C2-symmetric bisether, see: Lohray, B. B.; Bhushan, V. TL 1992, 33, 5113.
13. Wang, Z.-M.; Sharpless, K. B. SL 1993, 603.
14. Hashiyama, T.; Morikawa, K.; Sharpless, K. B. JOC 1992, 57, 5067.
15. Walsh, P. J.; Sharpless, K. B. SL 1993, 605.
16. (a) Wang, Z.-M.; Zhang, X.-L.; Sharpless, K. B.; Sinha, S. C.; Sinha-Bagchi, A.; Keinan, E. TL 1992, 33, 6407. (b) Keinan, E.; Sinha, S. C.; Sinha-Bagchi, A.; Wang, Z.-M.; Zhang, X.-L.; Sharpless, K. B. TL 1992, 33, 6411.
17. Wang, L.; Sharpless, K. B. JACS 1992, 114, 7568.
18. Crispino, G. A.; Jeong, K.-S.; Kolb, H. C.; Wang, Z.-M.; Xu, D.; Sharpless, K. B. JOC 1993, 58, 3785.
19. Wang, Z.-M.; Zhang, X.-L.; Sharpless, K. B. TL 1993, 34, 2267.
20. Xu, D.; Crispino, G. A.; Sharpless, K. B. JACS 1992, 114, 7570.
21. Crispino, G. A.; Sharpless, K. B. TL 1992, 33, 4273.
22. Jeong, K.-S.; Sjö, P.; Sharpless, K. B. TL 1992, 33, 3833.
23. Bennani, Y. L.; Sharpless, K. B. TL 1993, 34, 2079.
24. (a) Kim, B. M.; Sharpless, K. B. TL 1990, 31, 3003. (b) Lohray, B. B.; Thomas, A.; Chittari, P.; Ahuja, J. R.; Dhal, P. K. TL 1992, 33, 5453.
25. (a) Annunziata, R.; Cinquini, M.; Cozzi, F.; Raimondi, L.; Stefanelli, S. TL 1987, 28, 3139. (b) Annunziata, R.; Cinquini, M.; Cozzi, F.; Raimondi, L. T 1988, 44, 6897. (c) Gurjar, M. K.; Mainkar, A. S. TA 1992, 3, 21.
26. Lohray, B. B.; Bhushan, V. TL 1993, 34, 3911.
27. Smaardijk, A. A.; Wynberg, H. JOC 1987, 52, 135.
28. (a) Hiemstra, H.; Wynberg, H. JACS 1981, 103, 417. (b) Kobayashi, N.; Iwai, K. TL 1980, 21, 2167.
29. Blaser, H.-U.; Boyer, S. K.; Pittelkow, U. TA 1991, 2, 721.

André B. Charette

Université de Montréal, Québec, Canada



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