Asymmetric allylation kinetic resolution

Palladium-Catalyzed Allylic Alkylation of Sulfur and Oxygen Nucleophiles -Asymmetric Synthesis, Kinetic Resolution and Dynamic Kinetic Resolution... 

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. 

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. 

This type of asymmetric conjugate addition of allylic sulfinyl carbanions to cyclopen-tenones has been applied successfully to total synthesis of some natural products. For example, enantiomerically pure (+ )-hirsutene (29) is prepared (via 28) using as a key step conjugate addition of an allylic sulfinyl carbanion to 2-methyl-2-cyclopentenone (equation 28)65, and (+ )-pentalene (31) is prepared using as a key step kinetically controlled conjugate addition of racemic crotyl sulfinyl carbanion to enantiomerically pure cyclopentenone 30 (equation 29) this kinetic resolution of the crotyl sulfoxide is followed by several chemical transformations leading to (+ )-pentalene (31)68. 

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... 

Kinetic resolution of racemic allylic acetates has been accomplished via asymmetric dihydroxylation (p. 1051), and 2-oxoimidazolidine-4-carboxy-lates have been developed as new chiral auxiliaries for the kinetic resolution of amines. Reactions catalyzed by enzymes can be utilized for this kind of resolution. ... 

An interesting extension of this reaction is shown in the asymmetric kinetic resolution of cyclic allylic ether 44 under alkene coupling conditions. Use of (R)-12 as the catalyst gives (R)-45 in > 99% ee at 58% conversion. The ethylated product 46 is also formed in the reaction in 94% ee (Eq. 7) [25]. The reaction is effective for six- to eight-membered 3-oxacycloalkenes 47 as well as for a wide variety of alkoxycycloalkenes 48 [27], with some resolution dependency on the ring size of 47 (Fig. 2) [26]. 

Sharpless epoxidation reactions are thoroughly discussed in Chapter 4. This section shows how this reaction is used in the asymmetric synthesis of PG side chains. Kinetic resolution of the allylic secondary alcohol ( )-82 allows the preparation of (R)-82 at about 50% yield with over 99% ee (Scheme 7-23).19... 

As depicted in Eqs. 6.5—6.7, kinetic resolution of a variety of cyclic allylic ethers is effected by asymmetric Zr-catalyzed carbomagnesation. Importantly, besides six-membered ethers, seven- and eight-membered ring systems can readily be resolved by the Zr-catalyzed protocol. 

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]. 

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. 

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 ... 

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. 

In 2001, Takahashi and his co-workers developed the first asymmetric ruthenium-catalyzed allylic alkylation of allylic carbonates with sodium malonates which gave the corresponding alkylated compounds with an excellent enantioselectivity (Equation (Sy)). Use of planar-chiral cyclopentadienylruthenium complexes 143 with an anchor phosphine moiety is essential to promote this asymmetric allylic alkylation efficiently. The substituents at the 4-position of the cyclopentadienyl ring play a crucial role in controlling the stereochemistry. A kinetic resolution of racemic allylic carbonates has been achieved in the same reaction system (up to 99% ee). ... 

Asymmetric Synthesis of Allylic Sulfones and Allylic Sulfides and Kinetic Resolution of Allylic Esters... 

This method is particularly effective with cyclic substrates, and the combined effects of intramolecular and intermolecular asymmetric induction give up to 76 1 (kf/ks) differentiation between enantiomers of a cyclic allylic alcohol. This kinetic resolution provides a practical method to resolve 4-hydroxy-2-cyclopentenone, a readily available but sensitive compound. Hydrogenation of the racemic compound at 4 atm H2 proceeds with kf/ks =11, and, at 68% conversion, gives the slow-reacting R enantiomer in 98% ee. The alcoholic product is readily convertible to its crystalline, enantiomerically pure fert-butyldimethylsilyl ether, an important building block in the three-component coupling synthesis of prostaglandins (67). 

The Sharpless epoxidation is sensitive to preexisting chirality in selected substrate positions, so epoxidation in the absence or presence of molecular sieves allows easy kinetic resolution of open-chain, flexible allylic alcohols (Scheme 26) (52, 61). The relative rates, kf/ks, range from 16 to 700. The lower side-chain units of prostaglandins can be prepared in high ee and in reasonable yields (62). A doubly allylic alcohol with a meso structure can be converted to highly enantiomerically pure monoepoxy alcohol by using double asymmetric induction in the kinetic resolution (Scheme 26) (63). A mathematical model has been proposed to estimate the degree of the selectivity enhancement. 

The first example of Pd-catalyzed enantioselective allylation to be reported was the reaction of l-(l -acetoxyethyl)cyclopentene and the sodium salt of methyl benzenesulfonylacetate in the presence of 10 mol % of a DIOP-Pd complex, which led to the condensation product in 46% ee (Scheme 85) (200). This reaction used a racemic starting material, but the enantioselection was not a result of kinetic resolution of the starting material, because the chemical yield was above 80%. However, in certain cases, the selectivity is controlled at the stage of the initial oxidative addition to a Pd(0) species. In a related reaction, a BINAP-Pd(0) complex exhibits excellent enantioselectivity the chiral efficiency is affected by the nature of the leaving group of the allylic derivatives (Scheme 85) (201). It has been suggested that this asymmetric induction is the result of the chiral Pd catalyst choosing between two reactive conformations of the allylic substrate. 

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