Desymmetrization processes

Substantial improvements of the ee of another desymmetrization process are also observed in the presence of LiCl (Sch. 16). Results obtained for formation of enol silane 36 show that when a base is reacted with the ketone before MeaSiCl treatment (external quench EQ method), the ee is low (33 %). Under the external quench technique in the presence of LiCl (10 mol %), however, the ee is enhanced to 84 %, comparable with the 82 % ee obtained by an internal quench technique (IQ method addition of MeaSiCl before treatment with 35). It should be noted that unlike the E/Z ratios and ee mentioned above (Sch. 12), no subsequent drop in ee is seen when 1 equiv. or more LiCl is used. Further experiments involving the LiCl-assisted aldol reaction of tropinone 37 also resulted in increased ee [57]. 

SCHEME 11.33. Desymmetrization process via asymmetric intramolecular aza-Michael reaction. 

The Hajos-Parrish-Eder-Sauer-Wiechert synthesis (Scheme 5) was the first example of an intramolecular proline-catalyzed asymmetric aldol reaction. Systematically, this reaction can be described as a 6-enolendo cyclization. In 2003, List et al. described the first example of an intramolecular enolexo aldolization 85). This approach was then used by Pearson and Mans for the synthesis of (-i-)-cocaine 92, starting from the weso-dialdehyde 90 on treatment with (S)-12 86). This desymmetrization process gave 91 as a mixture of epimers with good enantio-selectivity. The tropane skeleton 91 could be further transformed into +)-92 by conventional means (Scheme 21). 

A miscellaneous chapter contains processes that do not readily fit into the preceding sections (kinetic resolution and desymmetrization processes and certain transition-metal-controlled processes). 

Another reaction that has been successfully employed as an enantioselective desymmetrization processes is the Heck reaction. The Heck reaction, which is described in more detail in Chapter 19, couples an aryl or vinyl electrophile with an olefin. As shown in Equation 14.19, this reaction can be run as a desymmetrization in which the catalyst reacts preferentially at one of the enantiotopic olefins over the other to generate the intermediate enol that undergoes isomerization to the ketone product. This ketone as formed in 76% yield and 86% enantioselectivity and was an intermediate in the synthesis of vemolepin. ... 

One valuable application of desymmetrization processes is the formation of quaternary stereocenters. In this case, a fully substituted carbon that lies in the plane of symmetry of the reactant becomes a stereocenter by reaction at one of the two substituents. This type of desymmetrization in the context of olefin metathesis is shown in Equation 21.14. In this example, the achiral, symmetric triene is converted to the chiral, non-racemic diene with 87% ee. 

Last but not least, all enzymes are made from L-amino acids and thus are chiral catalysts. As a consequence, any type of chirality present in the substrate molecule is recognized upon formation of the enzyme-substrate complex. Thus, a prochiral substrate may be transformed into an optically active product through a desymmetrization process and both enantiomers of a racemic substrate usually react at different rates, affording a kinetic resolution. 

The fragrance industry has taken advantage of the use of enantioselective desymmetrization processes for instance, the selective acylation of 2-hydroxymethyl-3-(4-isopropylphenyl)-l-propanol with vinyl butanoate led to the corresponding enantiopure monoester in 97% yield (Figure 9.13), which is a precursor of cyclamen aldehyde, an important component for obtaining special blossom notes in perfume compositions [151]. In a 5g scale the successful desymmetrization of 2-(2, 2 -dimethoxyethyl) propane-l,3-diol has been reported using PFL and 1.3 equivalents of VinOAc in... 

Studies conducted thus far to develop synthetic apphcations of this chemistry have relied heavily on the earlier finding that the tra s,tra s-amidocyclopentenyl acetate 40 can be prepared readily by irradiation of pyridine in aqueous acid solution (Scheme 14). This substance is functionally similar to compounds that have been converted to non-racemic mono-alcohols by enzymatic desymmetrization processes. Thus, treatment of diacetate 40 with the electric eel acetylcholinesterase (EEACE) was found to generate the mono-ester 41 in a 68% yield and 80% ee (Scheme 16). In addition, Mariano and coworkers have demonstrated that stereochemical diversity can be introduced into the aminocyclopentene ring system using hydroxyl inversion procedures.An example of this is found in the conversion of 41 to its ds-trans-diastereomer 42 by employment of the amide directed inversion method developed by Wipf and co-workers " (Scheme 16). These observations have estabhshed the foundation for applications of pyridinium salt photochemistry to the synthesis of the biomedically important aminocyclopentitols and aminoaldopentoses shown in Schemes 17,18 and 19.13.15-17... 

Enantioselective alkylation of achiral enolates can provide an alternative to desymmetrization processes for the preparation of optically active Ca-substituted ketones. Alkylation of enolate 190 thus furnishes ketone 193 in 96 % ee and 76 % yield in the presence of chiral tetraamine 191 (Equation 14) (107). The reaction protocol prescribes the use of MeLi-LiBr for the generation of enolate 190 from enolsilane 189. The presence of lithium bromide was important, as it had a pronounced effect both on the subsequent rate of alkylation and on the stereoselectivity. Interestingly, the use of LiBr in combination with excess N,N,N, N -tetramethylpropylenediamine (192) enables the use of substoichiometric amounts of the chiral tetramine 191 (5mol%) (108). It has been suggested that diamine 192 functions as a trapping agent for LiBr, which otherwise complexes with and deactivates 191 in the course of the reaction. 

Extension of these processes to provide enantio-enriched products was successfully applied after desymmetrization of the starting materials. An example is shown below (Reaction 76), where silane-mediated xanthate deoxygenation-rearrangement-electrophile trapping afforded the conversion of (+)-94 to (+)-95 in 56% yield. ... 

The high chemoselectivity for the Baeyer-Villiger process was utilized in the synthetic elaboration of another hetero-bicyclic substrate. The biooxidation only provides the expected unsaturated lactone in a desymmetrization reaction without compromising the olefin functionality. The biotransformation product was then converted to pivotal intermediates for C-nucleosides like showdomycin, tetrahydro-furan natural products like kumausyne, and goniofufurone analogs in subsequent chemical operations (Scheme 9.17) [161]. 

Of the two former processes shown in Scheme 5.2, the kinetic resolution of race-mates has found a much greater number of applications than the desymmetrization of prochiral or meso compounds. This is due to the fact that racemic substrates are much more common than prochiral ones. However, kinetic resolution suffers from a number of drawbacks, the main being the following ... 

Bergeron, S., Chaplin, D.A., Edwards, J.H. et al. (2006) Nitrilase-catalyzed desymmetrization of 3-hydroxy-glutaronitrile preparation of a statin side-chain intermediate. Organic Process Research Development, 10, 661-665. 

Tryptophan (and also tryptophanol) undergoes a stereoselective cyclocondensation with racemic compound 249, in a very interesting process involving a kinetic resolution with epimerization of the tryptophan stereocenter and simultaneous desymmetrization of the two diastereotopic acetate chains <2005CC1327>, affording the enantiomeri-cally pure lactam 250. A subsequent treatment of the latter compound with trifluoroacetic acid led to the indolo[2,3- ]quinolizidine 251 through an intermediate acyliminium cation (Scheme 50) <20050L2817>. 

Desymmetrization, which refers to a process of efficiently desymmetrizing maw-molecules or achiral molecules to produce chiral ones, is a versatile method for preparing chiral nonracemic molecules.90 Desymmetrization of meso-compounds generally leads to the formation of a C-C or a C-X (X is a hetero atom) bond. The reaction normally uses a functional group residing on the symmetric element (in most cases the C2 axis or a plane) to differentiate two (or more) symmetrically equivalent functionalities elsewhere within the substrate molecule. This work was first reported by Hoye et al.91 and Mislow and Siegel92 in 1984. 

Related catalytic enantioselective processes [115] Two catalytic procedures for asymmetric addition of cyanides to meso epoxides have been reported [116]. One is the result of work carried out in these laboratories, shown in Eq. 6.24, promoted by Ti-peptide chiral complexes, while the other, developed by Jacobsen and Schaus, is a Yb-catalyzed enantioselective reaction that is effected in the presence of pybox ligands (Eq. 6.25) [117]. Although the Shibasaki method (Eq. 6.21) is not as enantioselective as these latter methods, it has the advantage that it accomplishes both the epoxidation and subsequent desymmetrization in a single vessel. 

The process of obtaining homochiral product from a prochiral starting material is known as asymmetrization. This encompasses reactions where a faster rate of attack of a reactive species occurs on one enantiotopic face of a prochiral trigonal biplanar system, or at one enantiotopic substituent of a C2 symmetrical system, resulting in the preferential formation of one product enantiomer. The latter is also frequently referred to as the meso-trick or desymmetrization . These transformations can be more easily defined in pictorial form (Figure 1.8). 

To avoid the inherent limitations of a kinetic resolution process, the reaction was extended to desymmetrization of prochiral meso epoxides. A number of cyclic di-methylidene epoxides were synthesized and subjected to treatment with Et2Zn in the presence of Cu(OTf)2 and ligands 42 or 43. As in the case mentioned above, ligand 42 was superior in terms of selectivity. Cydohexane derivative 46 gave the ring-opened product with a 97% ee and in a 90% isolated yield, with a y/a ratio of 98 2 (Scheme 8.28). The other substrates investigated produced sigmficantly lower ees of between 66% and 85%. 

If the 3-position is a quaternary stereocenter, then Rh(I)/Tol-BINAP is the catalyst of choice for the hydroacylation process. With this catalyst, both kinetic resolutions (Eq. 20) and desymmetrization reactions (Eq. 21) may be accomplished. 

Zopiclone is a chiral cyclopyrrolone with hypnotic properties, possessing a pharmaceutical profile of high efficacy and low toxicity, similar to that of benzodiazepines. Zopiclone has been commercialized as a racemic mixture however, the (S)-enantiomer is more active and less toxic than the (R)-enantiomer [11]. Although enzymatic hydrolysis of esters or transesteriflcation processes of alcohols have been widely applied for enzymatic resolution or desymmetrization... 

This process has been employed successfully for a number of enantioselective BV reactions, including kinetic resolution of racemic ketones and desymmetrization of prochiral substrates (172-175). An example is the desymmetrization of 4-methyl-cyclohexanone, which affords the (5)-configurated 7-membered lactone with 98% ee (172,175). Of course, many ketones fail to react with acceptable levels of en-antioselectivity or are not even accepted by the enzyme. 

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