Allylic Alcohol Substrates

SCHEME 21. Asymmetric epoxidation of allylic and homoallylic alcohols. 

ASYMMETRIC CATAIYSIS VIA C. l IIRAI META I COMRI EXLS 

The original procedure required a stoichiometric amount of the tar-trate-complexed Ti promoter, but now the asymmetric reaction can be 

Although the reaction system contains several Ti-tartrate complexes, the species containing equimolar amounts of Ti and tartrate is the most active catalyst. The reaction is much faster than Ti(IV) tetra-alkoxide alone or Ti-tartrates of other stoichiometry and exhibits selective ligand-accelerated catalysis (64). The rate is first order in substrate and oxidant and inverse second order in inhibitor alcohol, under pseudo-first-order conditions in catalyst. The crystal and molecular structures 

---

N,O-acetal intermediate 172, y,<5-unsaturated amide 171. It is important to note that there is a correspondence between the stereochemistry at C-41 of the allylic alcohol substrate 173 and at C-37 of the amide product 171. Provided that the configuration of the hydroxyl-bearing carbon in 173 can be established as shown, then the subsequent suprafacial [3,3] sigmatropic rearrangement would ensure the stereospecific introduction of the C-37 side chain during the course of the Eschenmoser-Claisen rearrangement, stereochemistry is transferred from C-41 to C-37. Ketone 174, a potential intermediate for a synthesis of 173, could conceivably be fashioned in short order from epoxide 175. 

To account for stereochemical results for the epoxidation of allyl alcohols, a slightly different intermediate has been proposed as shown in Fig. 6.9.16 The authors propose an intermediate (A) analogous to the intermediate in peracid oxidations. A small molecule of alcohol or water is coordinated to Ti with deprotonation and another is coordinatively ligated to Ti without deprotonation to achieve a pentacoordinated ligand sphere. During epoxidation, the allyl alcohol substrate is held in position by a hydrogen bond. 

An interesting variant involves the use of an allylic alcohol as the alkene component. In this process, re-oxidation of the catalyst is unnecessary since the cyclization occurs with /Uoxygen elimination of the incipient cr-Pd species to effect an SN2 type of ring closure. Both five- and six-membered oxacycles have been prepared in this fashion using enol, hemiacetal, and aliphatic alcohol nucleophiles.439,440 With a chiral allylic alcohol substrate, the initial 7r-complexation may be directed by the hydroxyl group,441 as demonstrated by the diastereoselective cyclization used in the synthesis of (—)-laulimalide (Equation (120)).442 Note that the oxypalladation takes place with syn-selectivity, in analogy with the cyclization of phenol nucleophiles (1vide supra). 

Predictable absolute stereochemistry Thus far, when dealing with a pro-chiral allylic alcohol substrate, no exception to the rules laid down in Figure 4-1 has been observed. 

N/L recorded was 16,000 for the reactions using the magnesium aUcoxide of 3-methyl-2-buten-l-ol as a multisubstituted internal allylic alcohol substrate, which is why regiocontrol is still effective in the reactions in a highly coordinating solvent such as THE. Rate enhancement is much lower in the nitrile oxide cycloaddition reactions using homoallylic alcohol substrates. 

A limited number of allylic alcohols of the (2,3Z)-disubstituted type have been subjected to asymmetric epoxidation. With one exception, the C-2 substituent in these substrates has been a methyl group, the exception being a f-butyl group [38]. The (3Z)-substituents have been more varied, as illustrated by structures 61-64, which show the epoxy alcohols derived from the corresponding allylic alcohol substrates. 

Much of the experimental success of asymmetric epoxidation lies in exercising proper control of Eq. 6A.4 [6]. Both TI(OR)4 and Ti(tartrate)(OR)2 are active epoxidation catalysts, and because the former is achiral, any contribution by that species to the epoxidation will result in loss of enantioselectivity. The addition to the reaction of more than one equivalent of tartrate, relative to Ti, will have the effect of minimizing the leftward component of the equilibrium and will suppress the amount of Ti(OR)4 present in the reaction. The excess tartrate, however, forms Ti(tartrate)2, which has been shown to be a catalytically inactive species and will cause a decrease in reaction rate that is proportional to the excess tartrate added. The need to minimize Ti(OR)4 concentration and, at the same time, to avoid a drastic reduction in rate of epoxidation is the basis for the recommendation of a 10-20 mol % excess of tartrate over Ti for formation of the catalytic complex. After the addition of hydroperoxide and allylic alcohol to the reaction, the concentration of ROH will increase accordingly, and this will increase the leftward pressure on the equilibrium shown in Eq. 6A.4. Fortunately, in most situations this shift apparently is extremely slight and is effectively suppressed by the use of excess tartrate. A shift in the equilibrium does begin to occur, however, when the reaction is run in the catalytic mode and the amount of catalyst used is less than 5 mol % relative to allylic alcohol substrate. Loss in enantioselectivity then may be observed. This factor is the basis of the recommendation for use of 5-10 mol % of Ti-tartrate complex when the catalytic version of asymmetric epoxidation is used. 

Asymmetric epoxidation of allylic alcohols is a very reliable chemical reaction. More than a decade of experience has confirmed that the Ti-tartrate catalyst is extremely tolerantof structural diversity in the allylic alcohol substrate for epoxidation yet is highly selective in its ability to discriminate between the enantiofaces of the prochiral olefin. Today the practitioner of organic chemistry need provide only the allylic alcohol to perform the reaction. All other reagents and materials required for the reaction are available from supply houses and usually are sufficiently pure as received to be used directly in the asymmetric epoxidation process. [When purchasing f-butyl hydroperoxide in prepared solutions, however, the more concentrated 5.5-M solution in isooctane (2,2,4-trimethylpentane) should always be chosen over the 3.0-M solution.] If the considerations presented in this chapter are observed, with attention to the moderately stringent technique outlined, no difficulty should be encountered in performing this reaction. 

Both the synthetic 3 and mechanistic 1 aspects of this asymmetric epoxidatlon process have been reviewed recently. While the process has great scope regarding the allylic alcohol substrate, there are two classes of substrates which present difficulties. These limitations will be best appreciated by reference to the recent reviews however, the main problems are worth mentioning here. When difficulties arise, they are almost never due to the failure of the asymmetric epoxidatlon process Itself, but can be traced instead to the nature of the epoxy alcohol product. 

The oxidative rearrangement of allylic alcohols to a -unsaturated kelmies or alddiydes is one of the most widely used synthetic reactions in this group, and forms part of a 1,3-carbonyl tran sition sequence. Scheme 7 shows this reaction and the related conversion of the allylic alcdiol to an a,p-epoxy carbonyl compound. Chromate reagents induce some allylic alcohol substrates to undergo a directed qmxidation of the alkene without rearrangement, but this reaction is beyond the scope of the present discussion. 

The essence of titanium-catalyzed asynunetric epoxidation is illustrated in Figure 1. As shown there, the four essential components of the reaction are tiie allylic alcohol substrate, a titanium(IV) alkoxide, a chiral tartrate ester and an alkyl hydroperoxide. The asynunetric complex formed from these reagents de-... 

The first step of the reaction is the rapid ligand exchange of Ti(0/-Pr)4 with DET (6). The resulting complex undergoes further ligand exchange with the allylic alcohol substrate and finally with TBHP. As shown in the margin, the active catalyst is likely to have the dimeric structure 7, in which the hydroperoxide and the allylic alcohol occupy axial coordination sites on titanium. 

This asymmetric epoxidation technology affords high yields and enantiose-lectivities with a broad range of allylic alcohol substrates, and has been widely applied in organic synthesis [34-38], The original procedure [33] required stoichiometric amounts of the titanium tartrate (titanium is a rather unreactive epoxidation catalyst) but was subsequently improved to the extent that 5-10 wt.% is sufficient. 

For acyclic allylic alcohols, very little a,p-unsaturated enone formation was observed besides epoxidation. Chemoselectivity was much less for cyclic allylic alcohols, for which oxidation of fhe allylic alcohol group competed significantly with epoxidation. In the case of 2-cyclohexenol as the substrate, the enone was even found to be the main product. A comparative sandwich POM-catalyzed epoxidation study of various (subsfifufed) cycloalkenols revealed that the enone versus epoxide chemoselectivity is controlled by the C=C-C-OH dihedral angle Ma in the allylic alcohol substrate. The more this dihedral angle deviates from fhe optimum C=C-C-OW dihedral angle otw for allylic acohol epoxidation, the more enone is formed (Fig. 16.5). 

---