[131833-93-7]  · C17H30N2O2  · (S,S)-2,2-(Dimethylmethylene)bis(4-t-butyl-2-oxazoline)  · (MW 294.49)

(versatile chiral ligands for enantiocontrol of metal-catalyzed reactions such as copper-catalyzed cyclopropanation2-5 and aziridination of alkenes,6 addition of cyanotrimethylsilane to aldehydes,7 or Lewis acid-catalyzed Diels-Alder reactions8,9)

Physical Data: mp 88-89 °C; [a]D -108°; [a]365 -394° (c 0.97, CH2Cl2).

Solubility: insol H2O; sol all common organic solvents.

Preparative Methods: ligand (1) and related C2-symmetric bisoxazolines are readily prepared from chiral b-amino alcohols using standard methods for the synthesis of 2-oxazolines.1 This is exemplified by the simple three-step procedure shown in eq 1, involving amide formation, conversion of the resulting bis(2-hydroxyalkyl)amide to the corresponding bis(2-chloroalkyl)amide, and subsequent base-induced cyclization.3a,4,8a,10,11

There are several other convenient one- and two-step syntheses leading to enantiomerically pure bisoxazolines, e.g. condensation of amino alcohols with dicarboxylic acids,2,7 dinitriles,10a,12 or diimino esters4,10,13 (cf. eq 2),4,10a or acid-catalyzed cyclization of (2-hydroxyalkyl)amides.8b By these methods, various types of differently substituted bisoxazoline ligands are readily available in both enantiomeric forms, often in high overall yield.

Purification: (1) can be purified by column chromatography (silica gel, hexane/EtOAc 7:3) and by recrystallization from pentane.

Handling, Storage, and Precautions: as a crystalline solid, (1) is stable at ambient temperature; for longer periods, storage at -20 °C is recommended.

C2-Symmetric Bisoxazolines as Ligands in Asymmetric Catalysis.

Methylenebis(oxazolines) such as (1), (3), and (5) are patterned after the semicorrins,1 which have been successfully employed as ligands in enantioselective Cu-catalyzed cyclopropanations and other reactions (see (1S,9S)-1,9-Bis{[(t-butyl)dimethylsilyloxy]methyl}-5-cyanosemicorrin). The potential of bisoxazoline ligands of this type, which has been recognized independently by a number of research groups,1-11,13-15 is demonstrated by a remarkable variety of different applications in asymmetric catalysis.

The short and simple syntheses of these compounds and the ease of modifying their structures make them ideal ligands for the stereocontrol of metal-catalyzed reactions. Using different amino alcohols and dicarboxylic acid derivatives as precursors, the steric and electronic properties, as well as the coordination geometry, can be adjusted to the specific requirements of a particular application. The neutral methylenebis(oxazoline) ligands (1) and (2), which form six-membered chelate rings, the bioxazolines (4), a class of neutral ligands with p-acceptor properties forming five-membered chelate rings, and the anionic methylenebis(oxazolines) of type (3) and (5) are representative examples.

Enantioselective Cyclopropanation of Alkenes.

Cationic CuI complexes of methylenebis(oxazolines) such as (1), which have been developed by Evans and co-workers,3 are remarkably efficient catalysts for the cyclopropanation of terminal alkenes with diazoacetates. The reaction of styrene with ethyl diazoacetate in the presence of 1 mol % of catalyst, generated in situ from Copper(I) Trifluoromethanesulfonate and ligand (1), affords the trans-2-phenylcyclopropanecarboxylate in good yield and with 99% ee (eq 3). As with other catalysts, only moderate trans/cis selectivity is observed. Higher trans/cis selectivities can be obtained with more bulky esters such as 2,6-di-t-butyl-4-methylphenyl3 or dicyclohexylmethyl diazoacetate5 (94:6 and 95:5, respectively). The efficiency of this catalyst system is illustrated by the cyclopropanation of isobutene, which has been carried out on a 0.3 molar scale using 0.1 mol % of catalyst derived from the (R,R)-enantiomer of ligand (1) (eq 4).3 The remarkable selectivity of >99% ee exceeds that of Aratani's catalyst16 which is used in this reaction on an industrial scale.

For the cyclopropanation of terminal mono- and disubstituted alkenes, the cationic CuI complex derived from ligand (1) is clearly the most efficient catalyst available today, giving consistently higher enantiomeric excesses than related neutral semicorrin1,17 or bisoxazoline CuI complexes of type (3),1,2,4 which can induce enantiomeric excesses of up to 92% ee in the cyclopropanation of styrene with ethyl diazoacetate. High enantioselectivities, ranging between the selectivities of the Evans catalyst (eq 3) and complex (3) (M = CuI, R = t-Bu), have also been observed with cationic CuI complexes of azasemicorrins.1,10a,18

For analogous cyclopropanation reactions of trisubstituted and 1,2-disubstituted (Z)-alkenes, ligand (1) is less well suited. In these cases, better results have been obtained with the bisoxazoline ligand (6).5 This is illustrated by the enantioselective cyclopropanation of 1,5-dimethyl-2,4-hexadiene, leading to chrysanthemates (eq 5).5 The enantioselectivity in this reaction is comparable to the best results reported for Aratani's catalyst.16 Ligand (6) has also been reported to induce high enantiomeric excesses in the cyclopropanation of (Z)-4,4-dimethyl-2-pentene, (Z)-1-phenylpropene, and 1,1-dichloro-4-methyl-1,3-pentadiene with (-)-menthyl diazoacetate (92-95% ee).5 A mechanistic model rationalizing the stereoselectivity of Cu catalysts of this type has been published;17 a comparison of different cyclopropanation catalysts is also available.19

Enantioselective Aziridination of Alkenes.

Copper complexes with neutral methylenebis(oxazoline) ligands (1) and (2) have also been employed as enantioselective catalysts for the reaction of alkenes with (N-tosylimino)phenyliodinane, leading to N-tosylaziridines.6 The best results have been reported for cinnamate esters as substrates, using 5 mol % of catalyst prepared from CuOTf and the phenyl-substituted ligand (2) (eq 6). The highest enantiomeric excesses are obtained in benzene, whereas in more polar and Lewis basic solvents, such as acetonitrile, the selectivities are markedly lower. The chemical yield can be substantially improved by addition of 4Å molecular sieves. Both CuI- and CuII-bisoxazoline complexes, prepared from CuI or CuII triflate, respectively, are active catalysts, giving similar results. In contrast to the Cu-catalyzed cyclopropanation reactions discussed above, in which only CuI complexes are catalytically active, here CuII complexes are postulated as the actual catalysts.6

Analogous naphthylacrylates also react with excellent enantioselectivity under these conditions. Styrene and (E)-b-methylstyrene afford the corresponding N-tosylaziridines with 63 and 70% ee, respectively. For these two substrates, the t-butyl-substituted bisoxazoline (1) rather than (2) proved to be the most effective ligand.

Similarly high enantioselectivities in aziridination reactions of this type have been reported for Cu catalysts with C2-symmetric diimine ligands, derived from 1,2-diaminocyclohexane and aromatic aldehydes.20 The best results in this case have been obtained with 7-cyano-2,2-dimethylchromene as substrate (>98% ee). At present, it is difficult to compare the diimine-based with the bisoxazoline-based catalysts because different substrates were examined in these studies, with the exception of styrene which gave very similar results with the two catalysts (66 and 63% ee, respectively).20,6 Thus further work will be necessary to establish the full scope of these promising catalyst systems.

Enantioselective Diels-Alder Reactions.

Methylenebis(oxazoline) complexes of FeIII, MgII, and more recently also CuII, have been successfully employed as enantioselective Lewis acid catalysts in Diels-Alder reactions.8,9 The most promising results have been obtained with CuII catalysts prepared from ligand (1) and Copper(II) Trifluoromethanesulfonate (eq 7).9 In the presence of 10 mol % of catalyst in CH2Cl2 at -78 °C, acrylimide (7a) smoothly reacts with cyclopentadiene to afford the Diels-Alder product (8a) in 86% yield with excellent enantio and endo/exo selectivity. The crotonate derivative (7b) is less reactive, but at higher temperature also undergoes highly selective cycloaddition with cyclopentadiene. The fumarate (7c) gives similar results. In terms of selectivity and efficiency, this catalyst system can compete against the most effective chiral Lewis acid catalysts developed so far.21

The thiazolidine-2-thione analogs of (7b) and (7c) are more reactive dienophiles and, therefore, the cycloaddition can be carried out at lower temperature. However, the selectivities and yields are similar as with (7b) and (7c).9 The corresponding cinnamate derivative (7) (R = Ph), on the other hand, reacts with substantially lower enantioselectivity than the corresponding thiazolidine-2-thione analog (90% vs. 97% ee).

The stereochemical course of these reactions has been rationalized assuming a chelate complex between the (bisoxazoline)Cu catalyst and the dienophile as the reactive intermediate, with square planar coordination geometry of the CuII ion.9

Enantioselective Cyanohydrin Formation.

Magnesium complexes formed with the anionic semicorrin-type ligand (5) catalyze the addition of Cyanotrimethylsilane to aldehydes, leading to optically active trimethylsilyl-protected cyanohydrins.7 In the presence of 20 mol % of the chloromagnesium complex (9), prepared from equimolar amounts of (5) and BuMgCl, cyclohexanecarbaldehyde is smoothly converted to the corresponding cyanohydrin derivative with 65% ee. Addition of 12 mol % of the bisoxazoline (10) results in a dramatic increase of enantioselectivity to 94% ee (eq 8). Replacement of (10) by its enantiomer reduces the selectivity to 38% ee. This remarkable effect has been proposed to arise from hydrogen-bond formation between the bisoxazoline (10) and HCN, which is generated in small amounts by hydrolysis of Me3SiCN due to traces of water present in the reaction mixture. The chiral [(10)&dotbond;HCN] aggregate is postulated as the reactive species undergoing nucleophilic addition to the aldehyde which, at the same time, is activated by coordination with the chiral magnesium complex (9).

Heptanal, 2-ethylbutanal, and pivalaldehyde react with similarly high enantioselectivities, whereas benzaldehyde (52% ee) and certain a,b-unsaturated aldehydes such as geranial (63% ee) afford considerably lower enantiomeric excesses. Most other catalysts used for the addition of HCN or Me3SiCN to aldehydes usually exhibit higher enantioselectivities with aromatic or a,b-unsaturated aldehydes than with alkyl carbaldehydes.22

Enantioselective Allylic Alkylation.

Most ligands that have been employed in enantioselective Pd-catalyzed allylic substitutions are chiral diphosphines.23 Recently, it has been found that chiral nitrogen ligands can also induce high enantioselectivities in such reactions.1,18,24 The best results have been obtained with neutral azasemicorrin and methylenebis(oxazoline) ligands. In the presence of 1-2 mol % of catalyst, generated in situ from Bis(allyl)di-m-chlorodipalladium and ligand (11), and a mixture of N,O-Bis(trimethylsilyl)acetamide (BSA) and catalytic amounts of KOAc in an apolar solvent like CH2Cl2 or toluene, racemic 1,3-diphenyl-2-propenyl acetate smoothly reacts with dimethyl malonate to afford the corresponding substitution product in high yield and with excellent enantioselectivity (eq 9).

More recently, even higher selectivities of up to 99% ee have been achieved in this reaction with chiral phosphinooxazolines (see (S)-2-[2-(Diphenylphosphino)phenyl]-4-phenyloxazoline).24-26 The application range of (bisoxazoline)Pd catalysts is limited to relatively reactive substrates such as aryl-substituted allylic acetates.24 Analogous reactions of 1,3-dialkyl-2-propenyl acetates, for example, are impracticably slow and unselective. In this case, phosphinooxazolines have proved to be the ligands of choice.24,25

The crystal structures of some (allyl)PdII-bisoxazoline complexes have been determined by X-ray analysis.1 The structural data of these complexes provide some clues about how the chiral ligand controls the stereochemical course of eq 9.

Other Applications.

In the reactions discussed so far, methylenebis(oxazolines) were found to be superior to bioxazolines of type (4). However, there are some enantioselective metal-catalyzed processes for which the bioxazolines (4) are better suited than neutral or anionic methylenebis(oxazolines). Two examples, the Ir-catalyzed transfer hydrogenation of aryl alkyl ketones4 and the Rh-catalyzed hydrosilylation of acetophenone,11 are given in eqs 10 and 11.

Using 1 mol % of catalyst generated in situ from Di-m-chlorobis(1,5-cyclooctadiene)diiridium(I) and the bioxazoline (12) in refluxing isopropanol, various aryl alkyl ketones have been reduced in good yield with enantioselectivities ranging between 50-90% ee (eq 10).10b Dialkyl ketones are unreactive under these conditions. The highest enantiomeric excesses are obtained with phenyl isopropyl ketone (91% ee at 70% conversion, 88% ee at 93% conversion). Although these results compare favorably with the enantioselectivities reported for other Ir catalysts,27 at present, (bioxazoline)Ir complexes cannot compete with the most efficient catalysts available for the enantioselective reduction of ketones28 (see Tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborole). Recently, high enantioselectivities in the transfer hydrogenation of certain aryl alkyl ketones have been achieved with chiral samarium catalysts.29

The dibenzylbioxazoline derivative (13) has been found to induce up to 84% ee in the Rh-catalyzed hydrosilylation of acetophenone with diphenylsilane (eq 11).11 A large excess of ligand relative to [Rh] is necessary for optimal selectivity. Analogous bithiazoline derivatives were also investigated, but gave lower selectivities. In this case too, there are more selective catalysts available which afford high enantiomeric excesses in the hydrolsilylation of a wide range of ketones.30

Bioxazolines have also been employed in the enantioselective dihydroxylation of alkenes with Osmium Tetroxide.15 The best results have been obtained in the dihydroxylation of 1-phenylcyclohexene with a complex, formed between OsO4 and the diisobutylbioxazoline (4) (R = CH2CHMe2), as a stoichiometric reagent (70% ee). Styrene and trans-stilbene afford enantioselectivities below 20% ee under these conditions (for highly enantioselective dihydroxylation catalysts,31 see Dihydroquinine Acetate and Osmium Tetroxide).

Related Reagents.

(R)-1,1-Bi-2,2-naphthotitanium Dichloride; (R)-1,1-Bi-2,2-naphthotitanium Diisopropoxide; Dihydroquinine Acetate; (1S,9S)-1,9-Bis{[(t-butyl)dimethylsilyloxy]methyl}-5-cyanosemicorrin; 2,2-Dimethyl-a,a,a,a-tetraphenyl-1,3-dioxolane-4,5-dimethanolatotitanium Diisopropoxide.

1. Pfaltz, A. ACR 1993, 26, 339.
2. Lowenthal, R. E.; Abiko, A.; Masamune, S. TL 1990, 31, 6005.
3. (a) Evans, D. A.; Woerpel, K. A.; Hinman, M. M.; Faul, M. M. JACS 1991, 113, 726. (b) Evans, D. A.; Woerpel, K. A.; Scott, M. J. AG 1992, 104, 439; AG(E) 1992, 31, 430.
4. Müller, D.; Umbricht, G.; Weber, B.; Pfaltz, A. HCA 1991, 74, 232.
5. Lowenthal, R. E.; Masamune, S. TL 1991, 32, 7373.
6. Evans, D. A.; Faul, M. M.; Bilodeau, M. T.; Anderson, B. A.; Barnes, D. M. JACS 1993, 115, 5328.
7. Corey, E. J.; Wang, Z. TL 1993, 34, 4001.
8. (a) Corey, E. J.; Imai, N.; Zhang, H.-Y. JACS 1991, 113, 728. (b) Corey, E. J.; Ishihara, K. TL 1992, 33, 6807.
9. Evans, D. A.; Miller, S. J.; Lectka, T. JACS 1993, 115, 6460.
10. (a) Umbricht, G. Dissertation, University of Basel, 1993. (b) Müller, D. W. Dissertation, University of Basel, 1993.
11. Helmchen, G.; Krotz, A.; Ganz, K. T.; Hansen, D. SL 1991, 257.
12. Witte, H.; Seeliger, W. LA 1974, 996.
13. Hall, J.; Lehn, J.-M.; DeCian, A.; Fischer, J. HCA 1991, 74, 1.
14. Onishi, M.; Isagawa, K. ICA 1991, 179, 155.
15. Yang, R.; Chen, Y.; Dai, L. Acta Chim. Sinica 1991, 49, 1038 (CA 1992, 116, 41 342v).
16. Aratani, T. PAC 1985, 57, 1839.
17. (a) Fritschi, H.; Leutenegger, U.; Pfaltz, A. HCA 1988, 71, 1553. (b) Piqué, C. Dissertation, University of Basel, 1993.
18. Leutenegger, U.; Umbricht, G.; Fahrni, C.; von Matt, P.; Pfaltz, A. T 1992, 48, 2143.
19. (a) Doyle, M. P. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH: New York, 1993; pp 63-99. (b) Doyle, M. P. RTC 1991, 110, 305.
20. Li, Z.; Conser, K. R.; Jacobsen, E. N. JACS 1993, 115, 5326.
21. Kagan, H. B.; Riant, O. CRV 1992, 92, 1007. Narasaka, K. S 1991, 1.
22. (a) North, M. SL 1993, 807. (b) Hayashi, M.; Miyamoto, Y.; Inoue, T.; Oguni, N. JOC 1993, 58, 1515.
23. (a) Consiglio, G.; Waymouth, R. M. CRV 1989, 89, 257. (b) Howarth, J.; Frost, C. G.; Williams, J. M. J. TA 1992, 3, 1089.
24. von Matt, P. Dissertation, University of Basel, 1993.
25. von Matt, P.; Pfaltz, A. AG 1993, 105, 614; AG(E) 1993, 32, 566.
26. (a) Sprinz, J.; Helmchen, G. TL 1993, 34, 1769. (b) Dawson, G. J.; Frost, C. G.; Williams, J. M. J.; Coote, S. J. TL 1993, 34, 3149.
27. Zassinovich, G.; Mestroni, G.; Gladali, S. CRV 1992, 92, 1051.
28. (a) Singh, V. K. S 1992, 605. (b) Wallbaum, S.; Martens, J. TA 1992, 3, 1475.
29. Evans, D. A.; Nelson, S. G.; Gagné, M. R.; Muci, A. R. JACS 1993, 115, 9800.
30. Brunner, H.; Nishiyama, H.; Itoh, K. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH: New York, 1993; pp 303-322.
31. (a) Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH: New York, 1993; pp 227-272. (b) Lohray, B. B. TA 1992, 3, 1317.

Andreas Pfaltz

University of Basel, Switzerland

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