Asymmetric epoxidation 1-substituted allyl alcohols

The development of transition metal mediated asymmetric epoxidation started from the dioxomolybdcnum-/V-cthylcphcdrinc complex,4 progressed to a peroxomolybdenum complex,5 then vanadium complexes substituted with various hydroxamic acid ligands,6 and the most successful procedure may now prove to be the tetroisopropoxyltitanium-tartrate-mediated asymmetric epoxidation of allylic alcohols. 

Several factors contribute to the frequent use of (3 )-substituted allylic alcohols (13) for asymmetric epoxidation. The allylic alcohols are easily prepared, conversion to epoxy alcohol normally proceeding with good chemical yields and with >95% ee, and a large variety of ftmctionality in the (3 -position is tolerated by the epoxidation catalyst. Representative epoxy alcohols (14) are summarized in Table 4 and Figure 3, with results divided arbitrarily according to whether the (3 ) substituent is a hydrocarbon... 

Recent literature refers to the stereoselective and asymmetric epoxidation of allylic alcohols with organoaluminium peroxides. PhaSiOOH epoxidizes olefins with a stereoselectivity similar to that with peracid. Reports have been made of a-substituted hydroperoxides (acids, esters, ketones, amides, and nitriles) as effective epoxidizing reagents and the application of hexachloroacetone, tetrachloracetone, and hexafluoroacetone hydroperoxide, as well as the HaOa-Vilsmeier reagent system. ... 

W. Adam, P. L. Alsters, R. Neumann, C. R. Saha-Moller, D. Seebach, R. Zhang, Highly efficient catalytic asymmetric epoxidation of allylic alcohols by an oxovanadium-substituted polyoxome-talate with a regenerative TADDOL-Derived hydroperoxide, Org. Lett. 5 (2003) 725. 

The methodology described above allows the asymmetric epoxidation of allylic alcohols or cis-substituted conjugated alkenes and the resolution of terminal epoxides. The asymmetric synthesis of trans-di- and trisubstituted epoxides can be achieved with the dioxirane formed from the fructose-derived ketone 64, developed by Shi and co-workers. The oxidizing agent potassium peroxomonosulfate... 

Chiral alkenyl and cycloalkenyl oxiranes are valuable intermediates in organic synthesis [38]. Their asymmetric synthesis has been accomplished by several methods, including the epoxidation of allyl alcohols in combination with an oxidation and olefination [39a], the epoxidation of dienes [39b,c], the chloroallylation of aldehydes in combination with a 1,2-elimination [39f-h], and the reaction of S-ylides with aldehydes [39i]. Although these methods are efficient for the synthesis of alkenyl oxiranes, they are not well suited for cycloalkenyl oxiranes of the 56 type (Scheme 1.3.21). Therefore we had developed an interest in the asymmetric synthesis of the cycloalkenyl oxiranes 56 from the sulfonimidoyl-substituted homoallyl alcohols 7. It was speculated that the allylic sulfoximine group of 7 could be stereoselectively replaced by a Cl atom with formation of corresponding chlorohydrins 55 which upon base treatment should give the cycloalkenyl oxiranes 56. The feasibility of a Cl substitution of the sulfoximine group had been shown previously in the case of S-alkyl sulfoximines [40]. 

Asymmetric epoxidation of ailylic alcohols.1 Epoxidation of allylic alcohols with r-bulyl hydroperoxide in the presence of titanium(lV) isopropoxide as the metal catalyst and either diethyl D- or diethyl L-tartrate as the chiral ligand proceeds in > 90% stereoselectivity, which is independent of the substitution pattern of the allylic alcohol but dependent on the chirality of the tartrate. Suggested standard conditions are 2 equivalents of anhydrous r-butyl hydroperoxide with 1 equivalent each of the alcohol, the tartrate, and the titanium catalyst. Lesser amounts of the last two components can be used for epoxidation of reactive allylic alcohols, but it is important to use equivalent amounts of these two components. Chemical yields are in the range of 70-85%. 

When the allylic alcohol needed for asymmetric epoxidation is unavailable from a commercial source, reasonably general synthetic routes have been developed to allylic alcohols of several different substitution patterns. Good methods are available for the preparation of 3-substituted allylic alcohols, whereas synthesis of 2-substituted allylic alcohols is more problematic. The substrates for kinetic resolution, 1-substituted allylic alcohols, frequently can be derived by addition of alkenyl or alkynyl organometallic reagents to aldehydes followed by modification of the resulting product as required. 

At the end of 1989, the number of 1-substituted allylic alcohols that had been used in kinetic resolution/asymmetric epoxidation experiments exceeded 75. In slightly more than half of these experiments, the desired product was the kinetically resolved allylic alcohol, whereas in the remainder the epoxy alcohol was desired. In addition to the compounds in Table 6A.8, experimental results for other kinetically resolved alcohols are summarized in Table 6A. 10 [38,77,110-115a-d]. From these results, it appears that kinetic resolution is successful regardless of the nature of the (3E) substituent and is successful with any except the most bulky substituents at C-2. 

A number of derivatives of the tartaric acid structure have been examined as substitutes for the tartrate ester in the asymmetric epoxidation catalyst. These derivatives have included a variety of tartramides, some of which are effective in catalyzing asymmetric epoxidation (although none display the broad consistency of results typical of the esters). One notable example is the dibenzyltartramide, which in a 1 1 ratio (in reality, a 2 2 complex as shown by an X-ray crystallographic structure determination [138]) with Ti(0-i-Pr)4 catalyzes the epoxidation of allylic alcohols with the same enantiofacial selectivity as does the Ti-tartrate ester complex [18], It is remarkable that, when the ratio of dibenzyltartramide to Ti is changed to 1 2, epoxidation is catalyzed with reversed enantiofacial selectivity. These results are illustrated for the epoxidation of a-phenylcinnamyl alcohol (Eq. 6A.12a). 

Sharpless asymmetric epoxidation ° is an enantioselective epoxidation of an allylic alcohol with ferf-butyl hydroperoxide (f-BuOOH), titanium tetraisopropoxide [Ti(0-fPr)4] and (-b)- or (—)-diethyl tartrate [(-b)- or (—)-DET] to produce optically active epoxide from achiral allylic alcohol. The reaction is diastereoselective for a-substituted allylic alcohols. Formation of chiral epoxides is an important step in the synthesis of natural products because epoxides can be easily converted into diols and ethers. 

Asymmetric Methods of Epoxidation Table 10 Representative Kinetic Resolutions of 1-Substituted Allylic Alcohols... 

The development of simple systems that allow for the asymmetric oxidation of allyl alcohols and simple alkenes to epoxides or 1,2-diols has had a great impact on synthetic methodology as it allows for the introduction of functionality with concurrent formation of one or two stereogenic centers. This functionality can then be used for subsequent reactions tliat usually fall into the substitution reaction class. Because these transition metal catalysts do not require the use of low temperatures to ensure high degrees of induction, they can be considered robust. However, the sometimes low catalyst turnover numbers and the synthesis of the substrate can still be crucial economic factors. Aspects of asymmetric oxidations are discussed in Chapter 12. 

The main goal of recent research in this area has been to find efficient asymmetric versions of nonradical metal-catalyzed epoxidation and hydroxylation reactions. The Sharpless epoxidation converts allyl alcohols to the epoxides with exceptionally high e.e.s. and with predictable absolute configuration. The catalyst dictates the configuration independent of the substitution pattern. 

A wide selection of substituted allylic alcohols are amenable to asymmetric epoxidation under these conditions. Allylic alcohols with E-geometry or unhindered Z-allylic alcohols are excellent substrates (5.57). However, branched Z-allylic alcohols, particularly those branched at C-4, exhibit decreased reactivity and... 

Full mechanistic details of asymmetric epoxidation (AE) reactions can be found in a comprehensive review. The features of the transition state which leads to high enantioselectivities over such a wide range of allyl functions have been intensively studied, but it is arguably more instructive from a practical point of view to indicate the behaviour of some commonly encoim-tered substrates with this catalyst. Tri- and tetra-substituted allylic alcohols with their electron-rich double bonds react rapidly, even at -35 °C. 3-( )-Monosubstituted allylic alcohols also react rapidly (1-4 h, as in Protocol 1) while other mono-substitution patterns dramatically slow down the reaction (10-50 h), necessitating the use of cryostatic cooling units. These reactivity patterns are summarised in Scheme 1.2. 

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