Dihydroquinine Acetate1

(R = Ac)

[75917-54-3]  · C22H28N2O3  · Dihydroquinine Acetate  · (MW 368.47) (R = p-ClC6H4C(O)-)

[113162-88-9]  · C27H29ClN2O3  · Dihydroquinine p-Chlorobenzoate  · (MW 464.99) (R = H)

[522-66-7]  · C20H26N2O2  · Dihydroquinine  · (MW 326.44)

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

Alternate Name: DHQ-Ac.

Physical Data: p-ClC6H4C(O)-: mp 130-133 °C; [a]D +150° (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 dihydroquinine4 and the p-chlorobenzoate is commercially available. The phthalazine-derived bis(dihydroquinine) ligand is commercially available.5 A formulation of the standard reactants for the asymmetric dihydroxylation (AD-mix-a) on the small scale has been developed and is commercially available.6 AD-mix-a (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: dihydroquinine p-chlorobenzoate is recovered after a dihydroxylation reaction using the same method as that described for Dihydroquinidine Acetate.

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

Chiral Ligand for the Asymmetric Dihydroxylation of Alkenes.

Dihydroquinine-derived chiral ligands have been used as pseudoenantiomers of the dihydroquinidine analog in the catalytic asymmetric dihydroxylation of alkenes. In general, the enantioselectivities with these ligands are as good as or slightly lower than those obtained with the dihydroquinidine ligand. For example, styrene could be dihydroxylated in 62% ee using a mixture of dihydroquinidine p-chlorobenzoate (DHQD-CLB, 0.13 equiv), Osmium Tetroxide (0.13 equiv), and N-Methylmorpholine N-Oxide, whereas the analogous reaction with dihydroquinine p-chlorobenzoate produced the diol of opposite absolute stereochemistry in 54% ee.7

As in the dihydroquinidine series, the phthalazide cinchona derivative [(DHQ)2-PHAL] (1)6 is the best ligand for the asymmetric dihydroxylation of terminal, trans, 1,1-disubstituted, and trisubstituted alkenes, and enol ether,8 whereas the DHQ-IND ligand (2)9 turns out to be superior for cis-alkenes (Table 1). The addition of Methanesulfonamide to enhance the rate of osmate(VI) ester hydrolysis is recommended for all nonterminal alkenes.

For additional examples of regioselective asymmetric dihydroxylations, see Dihydroquinidine Acetate.

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.10 The dihydroquinine-derived ligand was found to be superior to its pseudoenantiomer in the dihydroxylation of carbohydrate derivatives (eq 1).11

For additional examples and an extensive discussion on the use of these ligands in asymmetric dihydroxylation reactions, see Dihydroquinidine Acetate.

Chiral Ligand for Other Stereoselective Reactions.

The effect of the addition of dihydroquinine-derived alkaloids on the product enantioselectivity has also been investigated in the addition reaction of Diethylzinc to aldehydes,12 in the addition of aromatic thiols to conjugated cycloalkenones,13 and in the heterogeneous hydrohalogenation of a,a-dichlorobenzazepinone-2.14

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, 64B, 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.; Markõ, I.; Mungall, W. S.; Schröder, G.; Sharpless, K. B. JACS 1988, 110, 1968.
8. Hashiyama, T.; Morikawa, K.; Sharpless, K. B. JOC 1992, 57, 5067.
9. Wang, L.; Sharpless, K. B. JACS 1992, 114, 7568.
10. (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.
11. Brimacombe, J. S.; McDonald, G.; Rahman, M. A. Carbohydr. Res. 1990, 205, 422.
12. Smaardijk, A. A.; Wynberg, H. JOC 1987, 52, 135.
13. (a) Hiemstra, H.; Wynberg, H. JACS 1981, 103, 417. (b) Kobayashi, N.; Iwai, K. TL 1980, 21, 2167.
14. Blaser, H.-U.; Boyer, S. K.; Pittelkow, U. TA 1991, 2, 721.

André B. Charette

Université de Montréal, Québec, Canada

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