Allylic alcohols resolution

Finally, the use of stoichiometric amounts of transition metal complexes can play an important role in the synthesis of functionalized piperidines. <01H14.39> Liebeskind and coworkers have developed a chiral transition metal complex and have used it in the synthesis of (-)-indolizidine 209B <01JA12477>. A lipase mediated allylic alcohol resolution provides access to both antipodes of enantiomerically pure allyl acetates (115) which can be used to form an ri -allyl molybdenum complex (116), Hydride abstraction followed by methoxide quench yields a reactive species 117 which may be further functionalized through reactions with Grignard reagents. The eventual products 119 arc 2,3,6-trisubstituted piperidines in enantiomerically pure form. 

Sharpless epoxidations can also be used to separate enantiomers of chiral allylic alcohols by kinetic resolution (V.S. Martin, 1981 K.B. Sharpless, 1983 B). In this procedure the epoxidation of the allylic alcohol is stopped at 50% conversion, and the desired alcohol is either enriched in the epoxide fraction or in the non-reacted allylic alcohol fraction. Examples are given in section 4.8.3. 

Enzymatic hydrolysis of A/-acylamino acids by amino acylase and amino acid esters by Hpase or carboxy esterase (70) is one kind of kinetic resolution. Kinetic resolution is found in chemical synthesis such as by epoxidation of racemic allyl alcohol and asymmetric hydrogenation (71). New routes for amino acid manufacturing are anticipated. 

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 application of the AE reaction to kinetic resolution of racemic allylic alcohols has been extensively used for the preparation of enantiomerically enriched alcohols and allyl epoxides. Allylic alcohol 48 was obtained via kinetic resolution of the racemic secondary alcohol and utilized in the synthesis of rhozoxin D. Epoxy alcohol 49 was obtained via kinetic resolution of the enantioenriched secondary allylic alcohol (93% ee). The product epoxy alcohol was a key intermediate in the synthesis of (-)-mitralactonine. Allylic alcohol 50 was prepared via kinetic resolution of the secondary alcohol and the product utilized in the synthesis of (+)-manoalide. The mono-tosylated 3-butene-1,2-diol is a useful C4 building block and was obtained in 45% yield and in 95% ee via kinetic resolution of the racemic starting material. 

A noteworthy feature of the Sharpless Asymmetric Epoxidation (SAE) is that kinetic resolution of racemic mixtures of chiral secondary allylic alcohols can be achieved, because the chiral catalyst reacts much faster with one enantiomer than with the other. A mixture of resolved product and resolved starting material results which can usually be separated chromatographically. Unfortunately, for reasons that are not yet fully understood, the AD is much less effective at kinetic resolution than the SAE. 

Figure 6.4 Some successful examples of kinetic resolution of allylic alcohols by enantioselective epoxidation [21, 27].

The empirical rule described above for the enantiofacial differentiation in AE of primary allylic alcohols also applies to secondary allylic alcohols. The new aspect that needs to be taken into consideration in this case is the steric hindrance arising from the presence of a substituent (R4) at the carbon bearing the hydroxy group (Figure 6.3). This substituent will interfere in the process of oxygen delivery, making the oxidation of one enantiomer much faster than the reaction of the other one. The phenomenon is so acute that in practice kinetic resolution is often achieved (Figure 6.4) [27]. 

Andersson also showed that, in addition to meso-desymmetrization, kinetic resolution of some cyclic epoxides by use of the first-generation catalyst was also possible, giving both epoxides and allylic alcohols in good yields (Scheme 7.51) [108], Kozmin reported the effective use of the same catalyst in the desymmetrization of diphenylsilacyclopentene oxide. The resulting products could be used in the ster-eocontrolled syntheses of various acyclic polyols (Scheme 7.52) [109]. 

Stopping the reaction before completion. This method is very similar to the asymmetric syntheses discussed on page 132. A method has been developed to evaluate the enantiomeric ratio of kinetic resolution using only the extent of substrate conversion. An important application of this method is the resolution of racemic alkenes by treatment with optically active diisopinocampheylborane, since alkenes do not easily lend themselves to conversion to diastereomers if no other functional groups are present. Another example is the resolution of allylic alcohols such as (56 with one... 

Bellemin-Laponnaz S, Twedel J, Ruble JC, Breitling FM, Fu GC (2000) The kinetic resolution of allylic alcohols by a non-enzymatic acylation catalyst application to natural product synthesis. Chem Conunun 1009-1010... 

An effective deoxygenation using enantiomerically pure epoxides from primary allylic alcohols ( Sharpless epoxides ) [44] to give enantiomerically pure secondary allylic alcohols was described by Yadav [45]. This approach circumvented a kinetic resolution of secondary allylic alcohols that implies a maximum yield of 50% ( Scheme 5). 

The great selectivity of Ru-BINAP species is also evident when they are used in kinetic resolution of enantiomers. When a racemic allylic alcohol reacts with H2 in the presence of Ru-(A)-BINAP, the (R)-alcohol reacts preferentially, thus leaving the (S)-enantiomer unreacted (Equation (7)).71... 

Kinetic resolution can also be accomplished via eliminative pathways. Thus, the enantiomerically enriched allylic alcohol 102 can be prepared from the meso epoxide 96 with up to 96% ee by the action of LDA in the presence of the chiral diamine 101 and 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU). The DBU is believed to function as an aggregation modifier, and the active catalyst is theorized to be a heterodimer of the lithium amide (deprotonated 101) and DBU, although some nonlinear effects have been observed at low DBU concentrations <00JA6610>. Dipyrrolidino derivatives (e.g., 104) have also demonstrated utility with regard to kinetic resolution <00H1029>. 

In the case of acyclic allylic alcohols, an efficient kinetic resolution of l-buten-3-ol was achieved using [Ru((7 )-BINAP)(H)(CH3CN)(THF)2]BF4 as catalyst (Equation (16)).55... 

Scheme 4-1. Kinetic resolution of secondary allylic alcohols.

Many methods have been reported for the enantioselective synthesis of the remaining PG building block, the (J )-4-hydroxy-cyclopent-2-enone. For example, the racemate can be kinetically resolved as shown in Scheme 7-28. (iS )-BINAP-Ru(II) dicarboxylate complex 93 is an excellent catalyst for the enantioselective kinetic resolution of the racemic hydroxy enone (an allylic alcohol). By controlling the reaction conditions, the C C double bond in one enantiomer, the (S )-isomer, will be prone to hydrogenation, leaving the slow reacting enantiomer intact and thus accomplishing the kinetic resolution.20... 

Similarly,110 (lR,2S )-ephedrine is an effective poison in the kinetic resolution of allylic alcohols using racemic BINAP instead of the expensive (R)-BINAP. (/ )-2-cycIohexenoI can thus be obtained in >95% ee using a racemic... 

Related catalytic enantioselective processes It is worthy of note that the powerful Ti-catalyzed asymmetric epoxidation procedure of Sharpless [27] is often used in the preparation of optically pure acyclic allylic alcohols through the catalytic kinetic resolution of easily accessible racemic mixtures [28]. When the catalytic epoxidation is applied to cyclic allylic substrates, reaction rates are retarded and lower levels of enantioselectivity are observed. Ru-catalyzed asymmetric hydrogenation has been employed by Noyori to effect the resolution of five- and six-membered allylic carbinols [29] in this instance, as with the Ti-catalyzed procedure, the presence of an unprotected hydroxyl function is required. Perhaps the most efficient general procedure for the enantioselective synthesis of this class of cyclic allylic ethers is that recently developed by Trost and co-workers, involving Pd-catalyzed asymmetric additions of alkoxides to allylic esters [30]. 

Another interesting application of the deoxygenation reaction is shown in Scheme 12.6. Sharpless epoxides are transformed to enantiomerically pure allylic alcohols [14]. It should be noted that the disadvantage of the loss of one-half of the allylic alcohol, as in the case of kinetic resolutions of allylic alcohols, is not a problem when this protocol is employed. 

Secondary allylic alcohols also undergo asymmetric epoxidation in many cases, when the alcohol unit is attached to a stereogenic centre, kinetic resolution of the enantiomers takes place. This is particularly apparent for compounds of type (25), where the two enantiomers are epoxidized at rates which are different by two orders of magnitude1861. 

Kinetic resolution ofallylic alcohols. The (R)- and (S)-BINAP-Ru diacetate complexes can resolve racemic allylic alcohols, both acyclic and cyclic, with high enantiomeric selectivity. Thus hydrogenation of ( )-2 catalyzed by (S)-l at 76% conversion provides (S)-2 (>99% ee) and anti-3 (49 1, 39% ee). Hydrogenation of (S)-2 catalyzed by either (R)- or (S)-l provides anti-3 (>23 1). Similar results obtain with ( )-4. 

The three-step procedure described for the preparation of the illustrated crotylsilanes is initiated with the hydrosilation of rac-3-butyn-2-ol. This procedure is significantly improved with respect to the positional selectivity of the hydrosilation resulting in exclusive formation of the racemic (E)-vinylsilane, and as a result the present procedure is much more amenable to scale-up than those previously described in the literature.8 The enzymatic resolution of the racemic secondary allylic alcohol (vinylsilane) has also been reported using commercially available lipase extracts. The use of a Johnson ortho ester Claisen rearrangement affords the (E)-crotylsilanes 4 in nearly enantiomerically pure form. 

In principle, any reaction with a racemate using a chiral reagent can be used to effect a kinetic resolution. Kagan (56) has recently given an analysis of the relationship between the extent of reaction and die enantiomeric excess that can be achieved, while Sharpless (57) has applied kinetic resolution successfully to racemic allyl alcohols using his titanium alkoxide tartrate epoxidation reaction. 

The presence of the stereogenic centre at C(l) introduces an additional factor in the asymmetric epoxidation now, besides the enantiofacial selectivity, the diastereoselectivity must also be considered, and it is helpful to examine epoxidation of each enantiomer of the allylic alcohol separately. As shown in Fig. 10.2, epoxidation of an enantiomer proceeds normally (fast) and produces an erythro epoxy alcohol. Epoxidation of the other enantiomer proceeds at a reduced rate (slow) because the steric effects between the C(l) substituent and the catalyst. The rates of epoxidation are sufficiently significative to achieve the kinetic resolution and either the epoxy alcohol or the recovered allylic alcohol can be obtained with high enantiomeric purity [9]. 

Sharpless "asymmetric epoxidation" has been used in the enantioselective synthesis of several natural products, including the kinetic resolution of allylic alcohols [11] and the creation of ... 

Correlate reaction tellurium-mediated resolution of racemic allyl alcohols... 

The combination of the preceding method of obtaining allyl alcohols with the Sharpless kinetic resolution (SKR) of secondary allyl alcohols allows conversion of the original racemic allyl alcohol into a pure enantiomer with a 100% theoretical yield. By this procedure, the glycidol obtained by the SKR epoxidation of the secondary allyl alcohol is converted into the corresponding mesylate and then treated with the Te ion, furnishing the allylic alcohol with the same configuration of the enantiomer in the SKR which... 

Berkessel and co-workers have demonstrated the utility of the bifunctional cyclohexane-diamine catalysts in the dynamic kinetic resolution of azalactones (Schemes 60 and 61) [111, 112]. The authors proposed that the urea/thiourea moiety of the catalyst coordinates and activates the electrophilic azlactone. The allyl alcohol nucleophilicity is increased due to the Brpnsted base interaction with the tertiary amine of the catalyst. 

The growing interest in enantioselective isomerization of meso oxiranes to allylic alcohols arises from the ready availabihty of starting materials and the synthetic value of the homochiral products. First apphed to simple meso cycloalkene oxides, this methodology has been successfully exteuded to fuuctioualized meso oxiranes, and even to the kinetic resolution of racemic oxiranes, demonstrating its potential in accessing highly advanced synthons. 

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