Enantioselectivity natural product synthesis

Part B discusses enantioselective natural product synthesis from monosaccharides. Nowadays, most natural product syntheses are performed in an asymmetric manner. This development is due principally to the realisation... 

Like many other antibodies, the activity of antibody 14D9 is sufficient for preparative application, yet it remains modest when compared to that of enzymes. The protein is relatively difficult to produce, although a recombinant format as a fusion vdth the NusA protein was found to provide the antibody in soluble form with good activity [20]. It should be mentioned that aldolase catalytic antibodies operating by an enamine mechanism, obtained by the principle of reactive immunization mentioned above [15], represent another example of enantioselective antibodies, which have proven to be preparatively useful in organic synthesis [21]. One such aldolase antibody, antibody 38C2, is commercially available and provides a useful alternative to natural aldolases to prepare a variety of enantiomerically pure aldol products, which are otherwise difficult to prepare, allovdng applications in natural product synthesis [22]. 

One of the first enantioselective transition metal-catalyzed domino reactions in natural product synthesis leading to vitamin E (0-23) was developed by Tietze and coworkers (Scheme 0.7) [18]. This transformation is based on a Pdn-catalyzed addition of a phenolic hydroxyl group to a C-C-double bond in 0-20 in the presence of the chiral ligand 0-24, followed by an intermolecular addition of the formed Pd-spe-cies to another double bond. 

Keywords Asymmetric Catalysis a Natural Product Synthesis a Chiral Metal-Based Complexes a Enantioselective C-C Bond Formation a Enantioselective C-O Bond Formation... 

The first chapter in this volume is a particularly timely one given the recent surge of activity in natural product synthesis based upon stereocontrolled Aldol Condensations. D. A. Evans, one of the principal protagonists in this effort, and his associates, J. V. Nelson and T. R. Taber, have surveyed the several modem variants of the Aldol Condensation and discuss models to rationalize the experimental results, particularly with respect to stereochemistry, in a chapter entitled Stereoselective Aldol Condensations. The authors examine Aldol diastereoselection under thermodynamic and kinetic control as well as enantioselection in Aldol Condensations involving chiral reactants. 

Keywords a-Hydroxylated lignans Natural product synthesis Enantioselective hydrogenation Chiral building blocks Malic acid... 

It is interesting to note that the oxa-analogous Michael addition was reported for the first time in 1878 by Loydl et al. [19] in their work on the synthesis of artificial malic acid, which was five years ahead of the discovery of the actual Michael reaction described first by Komnenos [20], Claisen [21], and later Michael in 1887 [22] as one of the most important methods for C—C bond formation. In continuation of the early work on the oxa-Michael addition [23], the inter- and intramolecular additions of alkoxides to enantiopure Michael acceptors has been investigated, leading to the diastereo- and enantioselective synthesis of the corresponding Michael adducts [24]. The intramolecular reaction has often been used as a key step in natural product synthesis, for example as by Nicolaou et al. in the synthesis of Brevetoxin B in 1989 [25]. The addition of oxygen nucleophiles to nitro-alkenes was described by Barrett et al. [26], Kamimura et al. [27], and Brade and Vasella [28]. 

An example for the application of enzymatic kinetic resolutions with high E values in natural product synthesis is the chemoenzymatic synthesis of the northern half of epothilones (also see Sect. 4.1). Various lipases and esterases could be found with outstanding enantioselectivity (up to >100) among these were lipase B from Candida antarctica, a lipase from Burkholderia cepacia, a lipase from Pseudomonas sp., and a lipase from Streptomyces diastochromogenes, all affording the desired (S)-configurated alcohol with >99% enantiomeric excess (Fig. 4) [65],... 

Osmium-catalysed dihydroxylation of olefins is a powerful route towards enantioselective introduction of chiral centers into organic substrates [82]. Its importance is remarkable because of its common use in organic and natural product synthesis, due to its ability to introduce two vicinal functional groups into hydrocarbons with no functional groups [83]. Prof. Sharpless received the 2001 Nobel Prize in chemistry for his development of asymmetric catalytic oxidation reactions of alkenes, including his outstanding achievements in the osmium asymmetric dihydroxylation of olefins. 

The enantioselective cyclopropanation of acyclic allylic alcohols can be achieved with excellent enantioselectivities when the reaction is carried out in the presence of the chiral dioxaborolane ligand 18 (Equation 13.6, Protocol 11). This reaction also features the preparation of Zn(CH2I)2 DME complex which is soluble in dichloromethane.32 This chiral additive is also very effective for the synthesis of 1,2,3-substituted cyclopropanes, when 1,1-substituted diiodoalkanes are used as precursors.33 Finally, this method has been used extensively in natural product synthesis.34... 

Application of the pyrroloindoline-forming protocol in natural product synthesis was demonstrated by the first enantioselective synthesis of (—)-flustramine B (Scheme 3.16) [21]. Moreover, this amine-catalyzed transformation has also been extended to the enantioselective construction of furanoindoline frameworks, a widely represented substructure among natural isolates of biological relevance [21]-... 

Biaryls merit special interest due to their axial element of chirality and are among the most widely used ligands in enantioselective synthesis and catalysis. Their coordination by a tricarbonyl chromium fragment following benzannulation provides an additional stereogenic element in terms of a chiral plane to the molecule [68]. Biaryl quinones are similarly relevant to natural product synthesis and enantioselective catalysis. 

In conjunction with work in natural products synthesis, the controlled installation of stereocenters alpha to indole C2 remains of significant interest. In their approach to Clausena alkaloids, e.g., (-)-(5R, 6S)-balasubramide, Wang and co-workers employed an intramolecular 8-CMc/o-epoxide-arene cyclization for installation of a C2-C3 8-membered lactam moiety with excellent enantioselectivity <07OL1387>. The Chen group has reported a diastereoselective reaction between 2-lithioindoles and chiral A -terf-but ane sulfinyl... 

As the factors governing regio-, chemo-, dia-stereo- and enantioselectivity come to be better understood, the Rh-mediated cyclization of an a-diazocarbonyl derivative will come to be a powerful tool for natural product synthesis. 

Chiral Ligand of LiAlH4 for the Enantioselective Reduction of a,p-Unsaturated Ketones. Enantioselective reductions of a,p-unsaturated ketones afford optically active ally lie alcohols which are useful intermediates in natural product synthesis. Enantioselective reduction of a,p-unsaturated ketones with LiAlH4 modified with chiral amino alcohol (1) affords optically active (S)-allylic alcohols with high ee s. When 2-cyclohexen-l-one is employed, (5)-2-cyclohexen-l-ol with 100% ee is obtained in 95% yield (eq 2). This is comparable with the results obtained using LiAlH4-chiral binaphthol and chiral 1,3,2-oxazaborolidine. ... 

Considering the industrial importance of cyclopropanes in the pesticide field, it is not surprising that chiral ferrocenylphosphines have been applied as control ligands for the palladium-catalyzed enantioselective formation of cyclopropanes from the dicarbonate of 2-butene-1,4-diol and malonates, leading to 70% ee (Fig. 4-32e) [179]. Ferrocenylphosphines also induce chirality in the reaction of sulfonyl-substituted propenyl carbonates and acrylic esters to methylenecyclopentanes (up to 78% ee (Fig. 4-321)) [180], with potential applications in natural product synthesis. These examples show that the synthetic potential of chiral ferrocene derivatives is not yet fully exploited, and one may look forward to new applications. 

Alkynic ketones have been used extensively in natural product synthesis, due in large part to the contributions of Midland and coworkers and the development of generd methods for enantioselective reduction of this moiety to afford optically active propargyl alcohols using chiral trialkylboranes. Furthermore, the derived alkynic alcohol is a versatile system which can be manipulated directly into cis-or rra 5-allylic alcohols and as a precursor for vinylorganometallic species. This section will briefly cover progress made in the direct acylation of alkynic organolithiums with the acylation protocol d veloped by Weinreb (see also Section 1.13.2.7). 

Mutants of Pseudomonas putida were found to exhibit an arene dioxygenase activity, which has been exploited in whole-cell reactions for the regio- and enantioselective preparation of cw-dihydrodiols starting from benzene, substituted benzenes, and polycyclic or heteroaromatic compounds [48], The products are invaluable precursors for natural product synthesis, as exemplified in Scheme 8 [49],... 

Selected Applications of the Catalytic Enantioselective Allylation Reaction in Natural Product Synthesis... 

A second example of the use of directed molecular evolution for natural product synthesis is the use of lipases by Reetz and colleagues. This work is based on the kinetic hydrolytic resolution of racemic mixtures, in which one enantiomer is preferentially hydrolyzed and the chiral product is thus enriched. Utilizing both random mutagenesis and directed techniques such as CAST,64 they have improved the stereoselectivity of a lipase from Pseudomonas aeruginosa (PAL) on a number of occasions with different substrates. One of the first examples utilized the model substrate 2-methyldecanoic acid /xnitrophenyl ester, for which the wild-type enzyme has an enantioselectivity of E= 1.1. As a consequence of five mutations accumulated through random mutagenesis, followed by saturation mutagenesis, the enantioselectivity was increased to 25.8.123 More... 

Recently, Loh s indium-mediated enantioselective allylation procedure was applied by Frejd and coworkers to the synthesis of optically active bicyclic hydro-xyketones, such as (-)-endo-5, which are useful chiral building blocks in asymmetric catalysis and natural product synthesis (Scheme 4.7) [22]. 

Scheme 19. Natural product synthesis using an antibody-catalyzed enantioselective protonation as key step...

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