Titanium-catalyzed Epoxidations

The Sharpless-Katsuki asymmetric epoxidation (AE) procedure for the enantiose-lective formation of epoxides from allylic alcohols is a milestone in asymmetric catalysis [9]. This classical asymmetric transformation uses TBHP as the terminal oxidant, and the reaction has been widely used in various synthetic applications. There are several excellent reviews covering the scope and utility of the AE reaction 

The reason for the efficient epoxidation of explicitly allylic alcohols with this system can be found in the strong associative interactions occurring between the substrate and the catalyst. The [Ti(tartrate)(OR)2]2 dimer 1, which is considered to be the active catalyst in the reaction, will generate structure 2 after the addition of 

The AE reaction catalyzed by titanium tartrate 1 and with alkyl hydroperoxide as terminal oxidant has been applied to a large variety of primary allylic alcohols containing all eight basic substitution patterns. A few examples are presented in Table 6.2. 

The titanium-catalyzed AE reaction is a fairly robust system and it can be performed on substrates containing a wide range of different functional groups (FGs) (Table 6.3) [13]. However, it is important to point out that an intramolecular reaction with the formed epoxide is possible whenever the FG present in the molecule has a favorable position to facilitate such a transformation. An illustration of this phenomenon is presented in Eq. (1) [28]. 

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While the titanium-catalyzed epoxidation reaction was flourishing, the pioneer version of the reaction remained undeveloped and it was not until 1999 that new... 

SCHEME 70. Titanium-catalyzed epoxidation of ene-diols 145 by, 6-hydroperoxy alcohols 148... 

Since the introduction of the titanocene chloride dimer 67a to radical chemistry, much attention has been paid to render these reactions catalytic. This field was reviewed especially thoroughly for epoxides as substrates [123, 124, 142-145] so only catalyzed reactions using non-epoxide precursors and a few very recent examples of titanium-catalyzed epoxide-based cyclization reactions, which illustrate the principle, will be discussed here. A very useful feature of these reactions is that their rate constants were determined very recently [146], The reductive catalytic radical generation using 67a is not limited to epoxides. Oxetanes can also act as suitable precursors as demonstrated by pinacol couplings and reductive dimerizations [147]. Moreover, 5 mol% of 67a can serve as a catalyst for the 1,4-reduction of a, p-un saturated carbonyl compounds to ketones using zinc in the presence of triethylamine hydrochloride to regenerate the catalyst [148]. 

Titanium-Catalyzed Epoxidations of 4-Cyclohexyl-4-hydroxy-3-metliylene-2-butanone Typical Procedure32 ... 

Katsuki, T. Titanium-catalyzed epoxidation. Transition Metals for Organic Synthesis A99S, 2, 261-271. 

For the titanium catalyzed epoxidation, only 1 mol% of catalyst and 1.05 equiv. of H2O2 are required to obtain high yields and selectivities. Not only activated olefins gave excellent results, but also for simple styrene a 93% ee can be achieved by using this chiral titanium complex." It was speculated that this peroxotitanium species is activated by an intramolecular hydrogen bond with the amine proton (Scheme 19). 

The calculated activation energy for olefin epoxidation occurring via the above transition state structure is quite low, which is in agreement with the observation that the titanium-catalyzed epoxidation is a highly efficient reaction. The barrier calculated at the MP2 level is 15.1 kcal/mol. This value compares well with the 12-15 kcal/mol reported by Wu and Lai (see above). 

Many hydroxylated linalools [including compounds 105, 106, 108, and 110, both (Z)- and ( )-isomers], as well as the epoxides of both furanoid (109) and pyranoid (see section on pyrans) linalyl oxides, have been identified in papaya fruit (Carica papaya). At the same time, the first reported occurrence of die two linalool epoxides (112) in nature was made. These epoxides are well known to be unstable and easily cyclized (see Vol. 2, p. 165) and have been made by careful peracid oxidation of linalool. An interesting new method has now been described. While the vanadium- or titanium-catalyzed epoxidation of geraniol (25) gave the 2,3-epoxide (see above), as does molybdenum-catalyzed epoxidation with hydrogen peroxide, the epoxidation of linalool (28) with molybdenum or tungsten peroxo complexes and hydrogen peroxide led, by reaction on the 6,7-double bond, to 112. ... 

Transition metal-catalyzed epoxidations, by peracids or peroxides, are complex and diverse in their reaction mechanisms (Section 5.05.4.2.2) (77MI50300). However, most advantageous conversions are possible using metal complexes. The use of t-butyl hydroperoxide with titanium tetraisopropoxide in the presence of tartrates gave asymmetric epoxides of 90-95% optical purity (80JA5974). 

A number of additional metal-catalyzed epoxidations have been reported in the past year. Platinum is a rarely used catalyst in oxidation reactions. The use of chiral Pt-catalyst 2 in the epoxidation of terminal alkenes provides the epoxide products in moderate yield and enantiomeric excess <06JA14006>. The chiral hydroxamide 3 is used with a Mo catalyst to provide the epoxide product in excellent yields and moderate enantioselectivity <06AG(I)5849>. A bis-titanium catalyst, 4, has also been used to epoxidize the usual set of alkenes with H202 as the oxidant <06AG(I)3478>. 

A conveniently prepared amorphous silica-supported titanium catalyst exhibits activity similar to that of Ti-substituted zeolites in the epoxidation of terminal linear and bulky alkenes such as cyclohexene (22) <00CC855>. An unusual example of copper-catalyzed epoxidation has also been reported, in which olefins are treated with substoichiometric amounts of soluble Cu(II) compounds in methylene chloride, using MCPBA as a terminal oxidant. Yields are variable, but can be quite high. For example, cis-stilbene 24 was epoxidized in 90% yield. In this case, a mixture of cis- and /rans-epoxides was obtained, suggesting a step-wise radical mechanism <00TL1013>. 

This approach provides a new method for carbohydrate synthesis. In the synthesis of tetritols, pentitols, and hexitols, for example, titanium-catalyzed asymmetric epoxidation and the subsequent ring opening of the thus formed 2,3-epoxy alcohols can play an essential role. 

SCHEME 59. Titanium-catalyzed asymmetric epoxidation of both enantiomers of aUyUc alcohol 39j... 

SCHEME 62. Titanium-catalyzed enantioselective epoxidation with different chiral hydroperoxides... 

In 2003, Lattanzi and coworkers reported on the use of the tertiary camphor-derived hydroperoxide 61 in the titanium-catalyzed asymmetric epoxidation of allylic alcohols (equation 39f. Yields were moderate and ranged between 30 and 59%. Also, the enantio-selectivities obtained were only moderate (24-46%). After the reaction, the enantiomeri-cally pure camphor-derived alcohol can be recovered in good yields by chromatography without loss of optical purity and can be reconverted into the corresponding hydroperoxide. 

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