Allylic Acetal Substrates

The chiral ir-allyl-Pd(II) intermediates shown in Scheme 84 undergo epimerization. The efficiency of this step and the regiochemistry of the nucleophilic attack to the exo face are very important for obtaining enantioface selection (Scheme 89). Bosnich analyzed the general characteristics of the asymmetric alkylation in terms of the properties of the allylic acetate substrates and of the 7T-allyl-Pd(II) intermediates, which undergo facile o-tc-o rearrangement, readily switching the face of Pd coordination (208). Examination of the dynamic equilibria of a series of cationic ir-allyl-Pd-chiral phosphine complexes has indicated that the 7r-allyl intermediates epimerize 10-100 times faster than the nucleo-... 

The first example of the use of enzyme and metal combinations to provide a dynamic resolution procedure was reported by Allen and Williams in 1996[18. In this case, a palladium (II) catalyst was employed that was able to racemize the allylic acetate substrate, but did not erode the enantioselectivity of the product allylic alcohol (Fig. 9-11). For example, a cyclic acetate was shown to undergo a simple kinetic resolution, affording enantiomerically enriched starting material and product at approximately 50 % conversion. However, performing the reaction in the presence of a palladium (II) catalyst facilitated a dynamic resolution by continuously racemiz-ing the starting material as the reaction progressed. 

Allylation under basic conditions. Allylation can be carried out under basic conditions with allylic acetates and phosphates, and under neutral conditions with carbonates and vinyloxiranes. The allylations under neutral conditions are treated separately in Section 2.2.2.1 from those under basic conditions. However, in some cases, allylations of the same substrates are carried out under both basic and neutral conditions to give similar results. These reactions are treated together in this section for convenience. Allylic acetates are widely used for Pd-catalyzed allylation in the presence of bases tertiary amines or NaH are commonly used[6,7,4l]. As a base, basic alumina or ICF on alumina is conveniently used, because it is easy to remove by filtration after the reaction[42]. Allyl phosphates are more reactive than acetates. The allylation with 40 proceeds stepwise. At first allylic phosphate reacts with malonate and then allylic acetate reacts with amine to give 41(43]. 

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. 

A novel approach was developed very recently by Kita et al. [15]. DKR of allylic alcohols was performed by combining a lipase-catalyzed acylation with a racemization through the formation of allyl vanadate intermediates. Excellent yields and enantioselectivities were obtained. An example is shown in Figure 4.4. A limitation with this approach for the substrates shown in Figure 4.4 is that the allylic alcohol must be equally disubstituted in the allylic position (R = R ) since C—C single bond rotation is required in the tertiary alkoxy intermediate. Alternatively, R or R can be H if the two allylic alcohols formed by migration of the hydroxyl group are enantiomers (e.g. cyclic allylic acetates). 

When the Pd bears chiral ligands, these reactions can be enantioselective. TT-Allylmolybdenum compounds behave similarly.Because palladium compounds are expensive, a catalytic synthesis, which uses much smaller amounts of the complex, was developed. That is, a substrate such as an allylic acetate, carbo-... 

Years earlier, Nicholas and Ladoulis had found another example of reactions catalyzed by Fe2(CO)9 127. They had shown that Fe2(CO)9 127 can be used as a catalyst for allylic alkylation of allylic acetates 129 by various malonate nucleophiles [109]. Although the regioselectivites were only moderately temperature-, solvent-, and substrate-dependent, further investigations concerned with the reaction mechanism and the catalytic species were undertaken [110]. Comparing stoichiometric reactions of cationic (ri -allyl)Fe(CO)4 and neutral (rj -crotyl ace-tate)Fe(CO)4 with different types of sodium malonates and the results of the Fe2(CO)9 127-catalyzed allylation they could show that these complexes are likely no reaction intermediates, because regioselectivites between stoichiometric and catalytic reactions differed. Examining the interaction of sodium dimethylmalonate 75 and Fe2(CO)9 127 they found some evidence for the involvement of a coordinated malonate species in the catalytic reactions. With an excess of malonate they... 

The hydrolytic DKR of allyl esters has been studied as a DKR of esters. The first DKR was accomplished through Pd-catalyzed racemization and enzymatic hydrolysis of allylic acetates in a buffer solution. However, the DKR under these conditions was limited to cyclohexenyl acetates to give symmetrical palladium-allyl intermediates. Among them, 2-phenyl-2-cyclohexenyl acetate 9 was the only substrate to have been resolved with good results (81% yield, 96% ee). 

Allyl acetate and allyl alcohol can be employed as substrates, too. The reaction using 46 took place with retention of the stereochemistry (Eq. 7.34), indicating that the... 

Allyl acetals154). Allyl ethers give no or only trace amounts of ylide-derived products in the Rh2(OAc)4-catalyzed reaction with ethyl diazoacetate, thus paralleling the reactivity of allyl chloride. In contrast, cyclopropanation must give way to the ylide route when allyl acetals are the substrates and ethyl diazoacetate or dimethyl diazomalonate the carbenoid precursors. 

An allene moiety can serve as a nucleophile vis-a-vis a 7r-allylpalladium species generated from an allylic acetate moiety in substrates such as 495 (Scheme 124). The cyclization involving these two moieties generates another 7r-allyl intermediate, and the stage is set for the subsequent carbonylative cascade process as demonstrated by the transformation of 495 to 496.402... 

In the 1952 paper mentioned above [3], Gilman reported on the formation of lithium dimethylcuprate from polymeric methylcopper and methyllithium. These so-called Gilman cuprates were later used for substitution reactions on both saturated [6] and unsaturated [7, 8, 9] substrates. The first example of a cuprate substitution on an allylic acetate (allylic ester) was reported in 1969 [8], while Schlosser reported the corresponding copper-catalyzed reaction between an allylic acetate and a Grignard reagent (Eq. 2) a few years later [10]. 

Similar to the case of Suzuki couplings (6.1.2), ally lie alkylations can also be run in neat water as solvent in the presence of surfactants. In addition to the general solubihzation effect, the amphiphiles may also have a specific influence on the reaction rate. For example, the reaction of the P-ketoester substrate on Scheme 6.22 with allyl acetate, catalyzed by [Pd(PPh3)4] was only slightly accelerated by the anionic SDS (1.5 h, 18 % yield), however, the reaction rate dramatically increased in the presence of the cationic CTAB and the neutral Triton X-100 detergents, leading to 74 % and 92% yields in 1.5 h and 5 min ( ), respectively [51]. Several other carbonucleophiles were alkylated in such emulsions with excellent yields. 

Tab. 10.12 summarizes the application of the optimized reaction conditions to a series of racemic secondary allylic acetates, wherein the reaction demonstrates remarkable enantioselectivity for an array of substrates. However, the regioselectivity of this... 

At the same time and in the years to follow, several other groups reported the observation of high selectivities in the Pd-catalyzed resolution of racemic substrates [6]. The kinetic resolution depicted in Scheme 2.1.4.2 gives access to both the enantio-enriched allylic acetate and sulfone. Because of the many applications chiral allylic alcohols and allylic sulphur derivatives have found in the synthesis... 

The kinetic resolution of the racemic allylic acetates rac-3ab, rac-ldb, rac-lab, and rac-lbb with thiocarboxylate ions and BPA were investigated in more detail (Scheme 2.1.4.22). The acetates were selected instead of the corresponding carbonates in order to avoid the competing formation of the corresponding allylic alcohols (vide supra). All reactions were carried out in CH2CI2/H2O (9 1) using 2 mol% of Pd(0)/L and 8 mol% of BPA. Termination of the reaction of the pen-tenyl acetate rac-3ab with KSAc at 35% conversion showed the operation of highly selective kinetic resolution (entry 4). However, 50% conversion of the substrate could be achieved neither at room nor at reflux temperature. This is in contrast to the reactivity of carbonate roc-3aa (cf. Table 2.1.4.14, entry 1) and perhaps reflects the lower reactivity of allylic acetates in Pd-catalyzed alkylation. This... 

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