Allylic substitution kinetic resolution

The AE reaction has been applied to a large number of diverse allylic alcohols. Illustration of the synthetic utility of substrates with a primary alcohol is presented by substitution pattern on the olefin and will follow the format used in previous reviews by Sharpless but with more current examples. Epoxidation of substrates bearing a chiral secondary alcohol is presented in the context of a kinetic resolution or a match versus mismatch with the chiral ligand. Epoxidation of substrates bearing a tertiary alcohol is not presented, as this class of substrate reacts extremely slowly. 

The reaction of aryldiazoacetates with cyclohexene is a good example of the influence of steric effects on the chemistry of the donor/acceptor-substituted rhodium carbenoids. The Rh2(reaction with cyclohexene resulted in the formation of a mixture of the cyclopropane and the G-H insertion products. The enantios-electivity of the C-H insertion was high but the diastereoselectivity was very low (Equation (31)). 0 In contrast, the introduction of a silyl group on the cyclohexene, as in 15, totally blocked the cyclopropanation, and, furthermore, added sufficient size differentiation between the two substituents at the methylene site to make the reaction to form 16 proceed with high diastereoselectivity (Equation (32)).90 The allylic C-H insertion is applicable to a wide array of cyclic and acyclic substrates, and even systems capable of achieving high levels of kinetic resolution are known.90... 

Zr-Catalyzed Kinetic Resolution of Allylic Ethers and Ru- and Mo-Catalyzed Synthesis of 2-Substituted Chromenes... 

Catalytic RCM and another Zr-catalyzed process, the kinetic resolution of cyclic allylic ethers, joined forces in our laboratories in 1995 to constitute a fully-cata-lytic two-step synthesis of optically pure 2-substituted chromenes. These structural units comprise a critical component of a range of medicinally important agents (see below). Our studies arose from unsuccessful attempts to effect the catalytic kinetic resolution of the corresponding chromenes [13] a representative example is illustrated in Eq. 3. 

Scheme 8. Zr-catalyzed kinetic resolution of allylic styrenyl ethers may be followed by a Ru-or Mo-catalyzed rearrangement to afford 2-substituted chromenes...

The synthetic versatility and significance of the Zr-catalyzed kinetic resolution of exocyc-lic allylic ethers is demonstrated by the example provided in Scheme 6.9. The optically pure starting allylic ether, obtained by the aforementioned catalytic kinetic resolution, undergoes a facile Ru-catalyzed rearrangement to afford the desired chromene in >99% ee [20], Unlike the unsaturated pyrans discussed above, chiral 2-substituted chromenes are not readily resolved by the Zr-catalyzed protocol. Optically pure styrenyl ethers, such as that shown in Scheme 6.9, are obtained by means of the Zr-catalyzed kinetic resolution, allowing for the efficient and enantioselective preparation of these important chromene heterocycles by a sequential catalytic protocol. 

Realising that the bite angle was important in these ligands, a chiral ligand in the Xantphos series has been developed [4], which contains the phospholane moiety discovered by Burk as the chiral entity (Fig. 13.8). This ligand turned out to be very useful in several common allylic substitution reactions (1,3-dimethylallyl, 1,3-diphenylallyl, cyclohex-2-ene-l-yl) and kinetic resolution. 

Catalysts lacking phosphorus ligands have also been used as catalysts for allylic substitutions. [lr(COD)Cl]2 itself, which contains a 7i-accepting diolefin ligand, catalyzes the alkylation of allylic acetates, but the formation of branched products was only favored when the substitution reaction was performed with branched allylic esters. Takemoto and coworkers later reported the etherification of branched allylic acetates and carbonates with oximes catalyzed by [lr(COD)Cl]2 without added ligand [47]. Finally, as discussed in Sect. 6, Carreira reported kinetic resolutions of branched allylic carbonates from reactions of phenol catalyzed by the combination of [lr(COE)2Cl]2 and a chiral diene ligand [48]. 

Substituted acrylates (which reseitible the enamide substrates employed 1n asymmetric hydrogenation) may be deracemized by reduction with an optically active catalyst, especially DIPAMPRh . Selectivity ratios of 12 1 to 22 1 have been obtained for a variety of reactants with compounds of reasonable volatility, separation of starting material and product may be effected by preparative GLC. Recovered starting material can then be reduced with an achiral catalyst to give the optically pure anti product. Examples of kinetic resolutions by this method are given in Table II. More recently very successful kinetic resolutions of allylic alcohols have been carried out with Ru(BINAP) catalysts. 

Kinetic resolution through Sharpless epoxidation of the trimethylsilyl-substituted allyl alcohol, rac-( )-4-trimethylsilyl-3-buten-2-ol (rac-14), which provides the S-enantiomer [( )-14, see p 476 for chemical correlation]81. 

Various racemic secondary alcohols with different substituents, eg, a-hydroxyester (60), are resolved by PFL neady quantitatively (75). The effect of adjacent unsaturation on enzyme-catalyzed kinetic resolutions was thoroughly studied for a series of allylic (61), propargylic (62), and phenyl-substituted 2-alkanols (76,77). Excellent selectivity was observed for (E)-allylic alcohols whereas (Z)-isomers showed poor selectivity (76). 

In the kinetic resolution of chiral 1-substituted allylic alcohols, there clearly is benefit to be gained in the choice of tartrate ester used for the reaction. In these reactions, the efficiency of kinetic resolution increases as the size of the tartrate alkyl ester group increases. Data for DMT, DET, and DIPT are summarized below (see Table 6A.8 [6 J), and the trend shown there continues with the use of the crystalline dicyclohexyl and dicyclododecyl tartrates [4],... 

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. 

Before commencing, the attention of the reader is drawn to the terms enantiofacial selectivity and diastereoselectivity. The usage in this chapter does not conform to the strictest possible definitions of these terms. In particular, enantiofacial selectivity is used with reference to the selection and delivery of oxygen by the epoxidadon catalyst to one face of the olefin in preference to the other. This usage extends to chiral allylic alcohols (primarily the 1-substituted allylic alcohols) when the focus of the discussion is on face selection in the epoxidation process. Diastereoselectivity is used in the discussion of kinetic resolution when the generation of diastereomeric compounds is emphasized. 

If values are known for two of the three variables, the third can be predicted by use of this graph. Inspection of the graph reveals that relative rates of 25 or more are very effective for achieving kinetic resolution of 1-substituted allylic alcohols. With a relative rate of 25, the epoxidation need be carried to <60% conversion to achieve essentially 100% ee for the unreacted alcohol. A convenient method for limiting the extent of epoxidation to 60% is simply by controlling the amount of oxidant used in the reaction. However, for some substrates (see Table 6A.8, entries 1, 9, or 10) even fcfast is extremely slow and the epoxidation takes several days [2,13,104-106]. To shorten the time needed for such reactions, an alternate practice is to use an... 

TABLE 6A.8. Relative Rate Data for Kinetic Resolution of 1-Substituted Allylic Alcohols... 

Relative rate data for the kinetic resolution/epoxidation of 1-substituted allylic alcohols of varying structure are summarized in Table 6A.8. The j values at -20°C for all entries in Table 6A.8 were determined using DIPT as the chiral ligand. Additionally, for several entries (1-3, 10, 11) the dependence of rel on temperature, 0 versus -20°C, and on steric bulk of the tartrate ester (DIPT vs. DET vs. DMT) has been measured. Lower reaction temperature and larger tartrate ester groups are factors that clearly increase the magnitude of kre] and, therefore, improve the efficiency of the kinetic resolution process. Although the results summarized in Table 6A.8... 

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 small, structurally distinct class of 1 -substituted allylic alcohols consists of those that are conformationally restricted by incorporation into a ring system. These allylic alcohols may be further subdivided into two types, depending on whether the double bond is endocyclic or exocyclic. For allylic alcohols with endocyclic double bonds, kinetic resolution gives 2-cyclohexen-l-ol (71) with 30% ee [14], (4a.S, 2/ )-4a-methyl-2,3,4,4a,5,6,7,8-octahydro-... 

TABLE 6A.9. Kinetic Resolution of 3-Silyl-, Halo-, and Stannyl-Substituted Allylic Alcohols... 

Three different principles of selectivity are required to achieve this result. First, the difference in rate of epoxidation by the catalyst of a disubstituted versus a monosubstituted olefin must be such that the propenyl group is epoxidized in complete preference to the vinyl group. The effect of this selectivity is to reduce the choice of olefinic faces to four of the two propenyl groups. Second, the inherent enantiofacial selectivity of the catalyst as represented in Figure 6A.1 will narrow the choice of propenyl faces from four to two. Finally, the steric factor responsible for kinetic resolution of 1-substituted allylic alcohols (Fig. 6A.2) will determine the final choice between the propenyl groups in the enantiomers of 80. The net result is the formation of epoxy alcohol 81 and enrichment of the unreacted allylic alcohol in the (35)-enantiomer. 

An interesting use of the nickel-catalyzed allylic alkylation has prochiral allylic ketals as substrate (Scheme 8E.47) [206]. In contrast to the previous kinetic-resolution process, the enantioselectivity achieved in the ionization step is directly reflected in the stereochemical outcome of the reaction. Thus, the commonly observed variation of the enantioselectivity with respect to the structure of the nucleophile is avoided in this type of reaction. Depending on the method of isolation, the regio- and enantioselective substitution gives an asymmetric Michael adduct or an enol ether in quite good enantioselectivity to provide further synthetic flexibility. 

Kinetic resolution of chiral aUylic alcohols.7 Partial (at least 60% conversion) asymmetric epoxidation can be used for kinetic resolution of chiral allylic alcohols, particularly of secondary allylic alcohols in which chirality resides at the carbinol carbon such as 1, drawn in accordance with the usual enantioface selection rule (Scheme I). (S)-l undergoes asymmetric epoxidation with L-diisopropyl tartrate (DIPT) 104 times faster than (R)-l. The optical purity of the recovered allylic alcohol after kinetic resolution carried to 60% conversion is often > 90%. In theory, any degree of enantiomeric purity is attainable by use of higher conversions. Secondary allylic alcohols generally conform to the reactivity pattern of 1 the (Z)-allylic alcohols are less satisfactory substrates, particularly those substituted at the /1-vinyl position by a bulky substituent. 

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