Abstract
Through an analogical study of the transition states of CH oxidation and asymmetric epoxidation of terminal alkenes, the first dioxirane-mediated catalytic highly enantioselective CH oxidation method was realized with the Shi’s oxazolidinone ketone derivatives. Very good enantioselectivity (up to 92% ee) may be obtained for both asymmetrization of meso vic-diols and kinetic resolution of racemic vic-diols.
In the past decades, dioxirane has been shown to be a powerful and highly selective oxidant, demonstrating excellent chemoselectivity, regioselectivity, diastereoselectivity and enantioselectivity during the oxygen-transfer.1 Moreover, since dioxirane is normally obtained by the reaction of a suitable ketone and potassium monoperoxysulfate (KHSO5), the oxidation may be carried out in a catalytic manner under in-situ conditions. One of the highlights of the dioxirane chemistry is its ability to oxidize sp3-hybridized CH bond with complete retention of configuration under mild conditions.2, 3 Although high regioselectivity and diastereoselectivity have been achieved in the CH bond oxidation, it is still a great challenge to achieve highly enantioselective CH oxidation by using optically active dioxiranes.1,4 A few years ago, Adam and co-workers demonstrated the feasibility of enantioselective CH oxidation mediated by dioxirane with Shi’s fructose-derived ketone 1 (Figure1);5 however, the enantioselectivity obtained was only mediocre (<65% ee in most cases). Furthermore, ketone 1 is not stable under the reaction conditions, such that an excessive amount of ketone 1 (3 equiv) is required to achieve reasonable conversions. Herein we wish to report the first catalytic and highly enantioselective CH oxidation protocol for the oxidation of vic-diols.
Figure 1.
Ketone Catalysts Utilized for CH Oxidation
Although ketone 1 is an excellent catalyst for the asymmetric epoxidation of trans- and trisubstituted alkenes,6 the asymmetric induction is considerably lower in CH bond oxidation.5 The reason for this is probably due to totally different steric requirements for these two oxidations. Through the comparison of the transition state (TS) of CH oxidation7 and those of epoxidation of different alkene substrates, we found that these distinct TS3,8 achieve the closest resemblance of each other in the case of CH oxidation and epoxidation of terminal alkene (Figure 2): 1) Both TS are asynchronous spiro; 2) in the terminal alkene cases (TSE), the terminal CH2 group is small and not differentiated in space (regarding to the left and right sides of the forming oxirane plane); likewise is the hydrogen atom end of the CH bond (TSCH); and 3) in both cases, the steric and/or electronic communications between the substrate and the dioxirane are mainly coming from the more substituted end. Based on this analysis, we hypothesized that ketone catalyst that induces high enantioselectivity in the epoxidation of terminal alkenes should also induce high enantioselectivity in CH bond oxidation.
Figure 2.
Transition States for the Epoxidation of Terminal Alkene (TSE) and the CH Oxidation (TSCH)
Shi and co-workers have reported that oxazolidinone ketones 2 and 3 are very good catalysts for the asymmetric epoxidation of terminal alkenes such as styrenes.9 Based on the recent theoretic work on the origin of the enantioselectivity in this asymmetric epoxidation8d and our above analogy, we reasoned that these catalysts should be also good for CH oxidation of benzylic alcohols, since in both cases there is a phenyl group to interact with dioxirane to direct the substrate approach.8d,9 By using a modified procedure, we synthesized the known ketones 2 and 3, and the new derivatives 4 and 5, and applied them for the asymmetric CH oxidation of some benzylic vic-diols. The results are collected in Table 1.
Table 1.
Enantioselective C-H Oxidation of vic-Diolsa
 | |||||||
|---|---|---|---|---|---|---|---|
| entry | diol |
catalyst | time (h) | yield (%)b | ee (%)c | con-figd | |
| X | config | ||||||
| 1 | H | meso | 2e | 1.5 | 60 | 70 | R |
| 2 | H | meso | 3 | 1.8 | 80 | 87 | R |
| 3 | H | meso | 4 | 1.8 | 90 | 80 | R |
| 4 | H | meso | 5 | 1.3 | 85 | 80 | R |
| 5 | Me | meso | 3 | 1.5 | 85 | 77 | R |
| 6 | OMe | meso | 3 | 1.8 | 60 | 76 | R |
| 7 | F | meso | 3 | 1.8 | 65 | 87 | R |
| 8 | Cl | meso | 3 | 1.8 | 80 | 77f | R |
| 9 | Br | meso | 3 | 1.8 | 74 | 76f | R |
| 10 | H | rac | 3 | 1.5 | 48 | 87g | S |
| 11 | Me | rac | 3 | 1.3 | 42 | 85g | S |
| 12 | F | rac | 3 | 1.3 | 45 | 90g | S |
| 13 | Cl | rac | 3 | 1.3 | 38 | 84f,g | S |
| 14 | Br | rac | 3 | 1.3 | 40 | 84f,g | S |
| 15 | CNh | rac | 3 | 2.0 | 10i | 92g | S |
Unless otherwise specified, all reactions were carried out with the diol (0.10 mmol), the ketone catalyst (0.05 mmol, 50 mol %) and Bu4NHSO4 (4 µmol) in CH3CN (1.5 mL) and Na2B4O7 (0.5 mL) / K2CO3 buffer at 0–5 °C. For asymmetrization of meso-diols, Oxone® (0.15 mmol, in 1.0 mL of 4 × 10−4 M aq solution of Na2EDTA) and K2CO3 (0.63 mmol) were used; for kinetic resolution of rac-diols, Oxone® (0.12 mmol, in 1.0 mL of 4 × 10−4 M aq solution of Na2EDTA) and K2CO3 (0.58 mmol) were used.
Yield of isolated product after chromatography.
Determined by HPLC analyses.
Determined by comparison the measured optical rotation with the reported data (ref 5).
0.10 mmol (100 mol %) catalyst was used.
Determined based on its acetate.
The ee values of the remaining diols were not determined.
0.20 mmol of Oxone® and 0.72 mmol of K2CO3 were used.
Conversion.
To our pleasure, ketone 2 indeed yields a much improved enantioselectivity in the asymmetrization of meso-hydrobenzoin, and an ee value of 70% was obtained with 1 equiv of the catalyst (Table 1, entry 1). For comparison, catalyst 1 yields only 45% ee of the product of this substrate.5 Ketone 3 is an even better catalyst for this oxidation, as a high ee value of 87% was obtained and only 50 mol % catalyst loading was necessary (entry 2). This is the first example of dioxirane-mediated asymmetric CH oxidation using a catalytic amount of the ketone catalyst. The remote substituent on the oxazolidinone ring was found to have subtle influence on the enantioselectivity of the reaction: With the size of R reduced from t-Bu to Et or Me, the enantioselectivity dropped slightly from 87% to 80% (entries 3 and 4). Based on our preliminary screening, catalysts 3–5 are comparable in reactivity, while catalyst 3 always yields slightly higher enantioselectivity than the other two.
Further study with catalyst 3 reveals that very good ee values may obtained for the asymmetrization of various meso-4,4′-disubstitued hydrobenzoins (≥76% ee, entries 5–9). However, the dependence of the enantioselectivity on the electronic nature the para substituents that has been observed for catalyst 15 did not happen in the case of catalyst 3.
The kinetic resolution of racemic hydrobenzoins was also studied with catalyst 3. Again, improved enantioselectivity was observed as compared with catalyst 1. For example, with 3 as catalyst, an ee value of 87% was obtained for the product of rac-hydrobenzoin, while the reported result with catalyst 1 was only 65% ee.5 In most cases, the racemic substrates yield better enantioselectivities of the products than their meso counterparts (entries 10–15). For example, the fluoro-substitued racemic diol generates an ee value of 90% for the product (entry 12), while the corresponding meso diol gives slightly inferior 87% (entry 7). Racemic 4,4'-dicyanohydrobenzoin produces the highest ee value of 92% (entry 15). The low conversion obtained in this case was probably due to the low solubility of this substrate in such a reaction medium.5
In the asymmetrization of meso-diols, the R-configured α-hydroxy ketones were obtained as the major products, while in the kinetic resolution of racemic diols, the S-configured ones were obtained (Table 1). The results indicate that in both cases, the S-configured center is preferably oxidized. According to the recent theoretical work on the asymmetric epoxidation of cis-alkenes with ketone 3,8d the phenyl group has to be aligned roughly parallel with the oxazolidinone ring to lower the energy of the transition state. Based on this and the theoretical work on the CH oxidations,3a–c the following TS were proposed to account for these results (Figure 3).
Figure 3.
Transition States for the Asymmetric CH Oxidation
When the substrate is using its S-configured center to approach the dioxirane, the favored TS may be achieved (Figure 3, left), as the smaller hydroxy group will interact direct with the oxazolidinone ring. If the R-configured center is used, then the large secondary alcohol group will have to interact with the oxazolidinone ring (Figure 3, right), which will cause the energy of the TS to increase. Therefore, the S-configured center will be preferably oxidized to generate the R-product for meso substrate (from S,R) and S-product for the racemic substrate (from S,S).
In summary, based on the transition state analogy hypothesis, we have developed the first dioxirane-mediated highly enantioselective CH oxidation method with the Shi’s oxazolidinone ketone catalyst 3. Although the catalytic efficiency of the ketone is still to be improved, very good enantioselectivity may be obtained for both asymmetrization of meso vic-diols and kinetic resolution of racemic vic-diols. These new results demonstrate the potential of chiral dioxiranes in highly enantioselective CH oxidations.
Supplementary Material
Experimental procedures, NMR spectra for all new compounds and HPLC analysis data. This material is available free of charge via Internet at http://pubs.acs.org.
Acknowledgment
The authors thank the NIH-MBRS program (Grant No. S06 GM 08194) for the generous financial support of this project.
References
- 1.For reviews, see: Adam W, Curci R, Edwards JO. Acc. Chem. Res. 1989;22:205–211.Murray RW. Chem. Rev. 1989;89:1187–1201.Curci R, Dinoi A, Rubino MF. Pure Appl. Chem. 1995;67:811–822.Adam W, Smerz AK. Bull. Soc. Chim. Belg. 1996;105:581–599.Frohn M, Shi Y. Synthesis. 2000:1979–2000.Adam W, Saha-Möller CR, Zhao C-G. Org. React. 2002;61:219–516.Shi Y. Acc. Chem. Res. 2004;37:488–496. doi: 10.1021/ar030063x.Adam W, Zhao C-G, Jakka K. Org. React. submitted.
- 2.(a) Murray RW, Jeyaraman R, Mohan L. J. Am. Chem. Soc. 1986;108:2470–2472. doi: 10.1021/ja00269a069. [DOI] [PubMed] [Google Scholar]; (b) Mello R, Fiorentino M, Fusco C, Curci R. J. Am. Chem. Soc. 1989;111:6749–6757. [Google Scholar]; (c) Adam W, Asensio G, Curci R, González-Nuñez ME, Mello R. J. Org. Chem. 1992;57:953–955. [Google Scholar]; (d) Adam W, Curci R, D’Accolti L, Dinoi A, Fusco C, Gasparrini F, Kluge R, Paredes R, Schulz M, Smerz AK, Veloza LA, Weinkötz S, Winde R. Chem. Eur. J. 1997;3:105–109. [Google Scholar]; (e) Curci R, D’Accolti L, Detomaso A, Fusco C, Takeuchi K, Ohga Y, Eaton P, Yip Y-C. Tetrahedron Lett. 1993;34:4559–4562. [Google Scholar]; (f) D’Accolti L, Detomaso A, Fusco C, Rosa A, Curci R. J. Org. Chem. 1993;58:3600–3601. [Google Scholar]; (g) Bovicelli P, Sanetti A, Lupattelli P. Tetrahedron. 1996;52:10969–10978. [Google Scholar]
- 3.For theoretical treatments, see: Glukhovtsev MN, Canepa C, Bach RD. J. Am. Chem. Soc. 1998;120:10528–10533.Houk KN, Du X. J. Org. Chem. 1998;63:6480–6483.Shustov GV, Rauk A. J. Org. Chem. 1998;63:5413–5422. doi: 10.1021/jo971612d.Freccero M, Gandolfi R, Sarzi-Amadé M, Rastelli A. J. Org. Chem. 2003;68:811–823. doi: 10.1021/jo0266184.
- 4.For a recent review, see: Adam W, Zhao C-G. In: Handbook of CH Transformations: Applications in Organic Synthesis. Dyker G, editor. Vol. 2. Weinheim: Wiley-VCH; 2005. pp. 507–516.
- 5.(a) Adam W, Saha-Möller CR, Zhao C-G. Tetrahedron: Asymmetry. 1998;9:4117–4122. [Google Scholar]; (b) Adam W, Saha-Möller CR, Zhao C-G. J. Org. Chem. 1999;64:7492–7497. [Google Scholar]
- 6.(a) Tu Y, Wang Z-X, Shi Y. J. Am. Chem. Soc. 1996;118:9806–9807. [Google Scholar]; (b) Wang Z-X, Tu Y, Frohn M, Shi Y. J. Org. Chem. 1997;62:2328–2329. doi: 10.1021/jo962392r. [DOI] [PubMed] [Google Scholar]; (c) Wang Z-X, Tu Y, Frohn M, Zhang J-R, Shi Y. J. Am. Chem. Soc. 1997;119:11224–11235. [Google Scholar]; (d) Frohn M, Dalkiewicz M, Tu Y, Wang Z-X, Shi Y. J. Org. Chem. 1998;63:2948–2953. [Google Scholar]; (e) Cao G-A, Wang Z-X, Tu Y, Shi Y. Tetrahedron Lett. 1998;39:4425–4428. [Google Scholar]; (f) Wang Z-X, Shi Y. J. Org. Chem. 1998;63:3099–3104. doi: 10.1021/jo980604+. [DOI] [PubMed] [Google Scholar]; (g) Wang Z-X, Cao G-A, Shi Y. J. Org. Chem. 1999;64:7646–7650. [Google Scholar]; (h) Frohn M, Zhou X, Zhang J-R, Tang Y, Shi Y. J. Am. Chem. Soc. 1999;121:7718–7719. [Google Scholar]; (i) Lorenz JC, Frohn M, Zhou X, Zhang J-R, Tang Y, Burke C, Shi Y. J. Org. Chem. 2005;70:2904–2911. doi: 10.1021/jo048217p. [DOI] [PubMed] [Google Scholar]
- 7.As one reviewer pointed out, the most recent theoretic work by Sarzi-Amadéorkers described a perpendicular radicaloid transition state for this oxidation; however, as the authors conceded, such a mechanism cannot explain the high selectivity data obtained experimentally (ref 3d).
- 8.(a) Houk KN, Liu J, DeMello NC, Condroski KR. J. Am. Chem. Soc. 1997;119:10147–10152. [Google Scholar]; (b) Crehuet R, Anglada JM, Cremer D, Bofill JM. J. Phys. Chem. A. 2002;106:3917–3929. [Google Scholar]; (c) Bach RD, Dmitrenko O, Adam W, Schambony S. J. Am. Chem. Soc. 2003;125:924–934. doi: 10.1021/ja026882e. [DOI] [PubMed] [Google Scholar]; (d) Singleton DA, Wang Z. J. Am. Chem. Soc. 2005;127:6679–6685. doi: 10.1021/ja0435788. [DOI] [PubMed] [Google Scholar]
- 9.(a) Tian H, She X, Shu L, Yu H, Shi Y. J. Am. Chem. Soc. 2000;122:11551-1152. [Google Scholar]; (b) Tian H, She X, Xu J, Shi Y. Org. Lett. 2001;3:1929–1931. doi: 10.1021/ol010066e. [DOI] [PubMed] [Google Scholar]; (c) Tian H, She X, Yu H, Shu L, Shi Y. J. Org. Chem. 2002;67:2435–2446. doi: 10.1021/jo010838k. [DOI] [PubMed] [Google Scholar]; (d) Shu L, Wang P, Gan Y, Shi Y. Org. Lett. 2003;5:293–296. doi: 10.1021/ol020229e. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Experimental procedures, NMR spectra for all new compounds and HPLC analysis data. This material is available free of charge via Internet at http://pubs.acs.org.