Epoxidation of cinnamyl alcohol

A 50 mL two-necked flask equipped with a stirrer bar was placed in an oven at 120 °C overnight, cooled under vacuum and flushed with nitrogen. 

The flask was filled with activated powdered 4 A molecular sieves (500 mg), dry dichloromethane (40 mL) and L-(+)-diisopropyl tartrate (400 mg). 

The mixture was cooled to —5 °C with the cooling bath, stirred and titanium isopropoxide (297 pL) was added. After cooling the bath to —20 °C, a solution of tert-butyl hydroperoxide (5.5 M in Aooctane, 5.5 mL) was added and the mixture was stirred at —20 °C for 1 hour. 

The solution of cinnamyl alcohol (2.68 g in 3mL of dry dichloromethane) was added dropwise over 1 hour via a syringe. 

The reaction was monitored by TLC (eluent petroleum ether-diethyl ether, 1 1). The visualization of the cinnamyl alcohol (UV active) with p-anisalde-hyde dip gave a blue stain, Rf 0.35, and a brown stain for the epoxycinnamyl alcohol, Rf 0.25. 

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Figure 14.7. Electronic effects in asymmetric epoxidation of cinnamyl alcohols...

The Sharpless synthesis (Scheme 17.13) begins with the asymmetric epoxidation of cinnamyl alcohol (50) using (-l-)-di-isopropyl tartarate (DIPT) as the chiral ligand for the... 

The second stoichiometry consideration is the ratio of catalyst to substrate. As noted in the preceding section, virtually all asymmetric epoxidations can be performed with a catalytic amount of Ti-tartrate complex if molecular sieves are added to the reaction milieu. A study of catalyst/substrate ratios in the epoxidation of cinnamyl alcohol revealed a significant loss in enantioselectivity (Table 6A.2) below the level of 5 mol % catalyst. At this catalyst level, the reaction rate also decreases, with the consequence that incomplete epoxidation of the substrate may occur. Presendy, the recommended catalyst stoichiometry is from 5% Ti and 6% tartrate ester to 10% Ti and 12% tartrate ester [4],... 

Preliminary results for asymmetric epoxidations of ( )-cinnamyl alcohol and geraniol using (15,25)-... 

Long-range electron transfer is postulated to occur from ferrocene to tris(bipyridine)iron(lll) constructed within the pores of a NaY zeoUte. The iron bipyridine complex is too large to move throughout the faujasite pores to the surface, thus requiring the long-range transfer. The asyimnetric catalyst, titanium tartrate, has been prepared inside NaY and used as an immobilized catalyst for the epoxidation of cinnamyl alcohol. ... 

Preliminary results for asymmetric epoxidations of ( )-cinnamyl alcohol and geraniol using (15,25)-l,2-di(2-methoxyphenyl)ethane-l,2-diol or (15,25)-l,2-di(4-methoxyphenyl)ethane-l,2-diol as chiral auxiliaries with titanium(IV) isopropoxide and TBHP have been described. High enantioselectivity (95% ee) is observed when the 2-methoxyphenyl compound is used, while somewhat lower enantioselectivity (64% ee) and opposite face selectivity is described for the catalyst comprised of the 4-methoxyphenyl analog.Further elaboration of the scope and generality of these observations will be of interest. 

Dimitrova, R., Neinska,Y., Mihalyi, M. R., Tsoncheva, T. and Spassova, M., Catalytic activity of boron-beta zeolite modified with indium in the epoxidation of cinnamyl alcohol, Reaction Kinetics and Catalysis Letters 74(2), 353-362 (2001). 

When heated in the presence of a carboxyHc acid, cinnamyl alcohol is converted to the corresponding ester. Oxidation to cinnamaldehyde is readily accompHshed under Oppenauer conditions with furfural as a hydrogen acceptor in the presence of aluminum isopropoxide (44). Cinnamic acid is produced directly with strong oxidants such as chromic acid and nickel peroxide. The use of t-butyl hydroperoxide with vanadium pentoxide catalysis offers a selective method for epoxidation of the olefinic double bond of cinnamyl alcohol (45). 

Henegar et al. [78] at Pfizer developed an efficient and greener synthesis of the (S, 5)-reboxetine 157, which is being evaluated for the treatment of neuropathic pain and a variety of other indications (Scheme 9.42). The reported chiral synthesis of 157 starts by SAE of cinnamyl alcohol 154 to give R, R)-epoxide 155 in 89% yield (> 98% ee). Reaction of 155 with 2-ethoxyphenol gave crystallized product 156. The overall yield of (S, 5)-reboxetine succinate increased by 9%, compared to resolution method. The catalytic asymmetric process offers use of less solvent and reduces waste generation by approximately 50%, compared to the resolution route. 

While most of the iminium salts studied are cyclic, several acyclic iminium salts have also been investigated. In 1997, Armstrong and coworkers reported the use of acyclic iminium salt 83 as chiral epoxidation promoter (Fig. 27) [156, 157]. 1-Phenylcyclohexene oxide could be obtained in 100% conversion and 22% ee with stoichiometric amounts of 83. In 2002 acyclic iminium salt 84, prepared from L-prolinol, was investigated by Komatsu and coworkers, and cinnamyl alcohol was epoxidized in 70% yield and 39% ee (Fig. 27) [158]. 

The concentration of substrate used in the asymmetric epoxidation must be given consideration because competing side reactions may increase with increased reagent concentration. The use of catalytic quantities of the Ti-tartrate complex has greatiy reduced this problem. The epoxidation of most substrates under catalytic conditions may be performed at a substrate concentration up to 1 M. By contrast, epoxidations using stoichiometric amounts of complex are best run at substrate concentrations of 0.1 M or lower. Even with catalytic amounts of the complex, a concentration of 0.1 M may be maximal for substrates such as cinnamyl alcohol, which produce sensitive epoxy alcohol products [4]. 

The enantioselective synthesis (51) of the side chain 30 of taxol had been achieved by way of stereospecific Sharpless epoxidation of cij-cinnamyl alcohol (29a), giving 29b (see Scheme 6). Following oxidation of the alcohol group, protection of the resulting carboxylic acid, regioselective opening of the epoxide with azide, benzoylation, and reduction, a suitably substituted moiety (28) was available which, after protection and deprotection of the acid function to form 30, was coupled to baccatin III. 

Tiialkylsilyl metals, such as trimethylsilylpotassium," dimethylphenylsilyllithium, " and dimethyl-phenylsilyldiethylaluminum, " have been known to induce deoxygenation of epoxides. The reaction with TMSK and PhMe2SiLi proceeds with inversion of stereochemistry (Table 14) whereas PhMe2SiAlEt2 shows complete retention in the case of tran.r-stilbene oxide and cinnamyl alcohol epoxide. 

Recently, two other groups have shown that exocyclic iminium salts can be useful mediators in asymmetric epoxidation. Komatsu has developed a system based on ketiminium salts [14], prepared through the condensation of aliphatic cyclic amines with ketones. A chiral variant was also produced, derived from prolinol and cyclohexanone, which gave 70% yield and 39% ee for cinnamyl alcohol (Scheme 5.7). 

The hydroperoxide isolated after epoxidation shows optical activity. However, the polarimetric data measured were difficult to reproduce and, moreover, the rotation data for the pure hydroperoxide enantiomer are not known because, as yet, it has not been isolated. Therefore, we determined the ratio of hydroperoxide enantiomers according to a method we have recently elaborated. In the case of prenol the e.e. is only indicated, on geraniol it is a little bit higher and using cinnamyl alcohol it reaches about 12% both in the stoichiometric and in the catalytic modification of the reaction. Of course, these results are not applicable for preparative purposes and, therefore, we intend to continue these investigations... 

Bonini C, Righi G (1994) Enantio- and Stereo-selective Route to the Taxol Side Chain via Asymmetric Epoxidation of ran -Cinnamyl Alcohol and Subsequent Epoxide Ring Opening. J Chem Soc Chem Comm 2767... 

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