Natural products chirality

The preparation of stereochemically-enriched compounds by asymmetric acyl transfer using chiral nucleophihc catalysts has received significant attention in recent years [1-8]. One of the most synthetically useful and probably the most studied acyl transfer reaction to date is the kinetic resolution (KR) of ec-alcohols, a class of molecules which are important building blocks for the synthesis of a plethora of natural products, chiral ligands, auxiliaries, catalysts and biologically active compounds. This research area has been in the forefront of the contemporary organocatalysis renaissance [9, 10], and has resulted in a number of attractive and practical KR protocols. 

Of even greater importance than a 172° selectivity is the differentiation between secondary alcohols, e.g. in sugars and other natural products (chiral pool). 

Advantages of Brown s chiral allylboranes (isopinocampheyl and later caranyl borane) are the easy access to the ligands (a-pinene is a natural product, chiral pool), the availability of both enantiomers and their low price. Excellent selectivities (96-99% ee) can be obtained at reaction temperatures of -100 °C. Other important mediators for enantioselective allylation of aldehydes are shown below.14... 

Chromatogram (A) is a sample of the synthesized racemic material, (B) is a sample of the natural product and (C) is a sample of the opposite enantiomer of the natural product. Chiral liquid chromatography is widely used for this type of investigation providing a fast and accurate means of enantiomer identification. 

Natural products Chiral molecules Sugars from starch... 

Aryl Transfer. The biaryl skeleton is pharmacologically interesting and important as a building block for a large number of natural products, chiral ligands in asymmetric synthesis, polymers, and advanced materials. Treatment of various... 

Chiral Lewis acid-catalyzed HDA reactions have foimd application in the asymmetric synthesis of THP-containing natural products. Chiral chromium complexes, especially the adamantyl-Cr(III) complexes discovered by Jacobsen et al., have been applied to the use of unactivated aldehyde dienophiles with various diene partners [111]. Paterson and coworkers employed this variation in the synthesis of... 

To start from a pure enantiomer of a natural product (chiral pool)... 

The achiral triene chain of (a//-rrans-)-3-demethyl-famesic ester as well as its (6-cis-)-isoiner cyclize in the presence of acids to give the decalol derivative with four chirai centres whose relative configuration is well defined (P.A. Stadler, 1957 A. Escherunoser, 1959 W.S. Johnson, 1968, 1976). A monocyclic diene is formed as an intermediate (G. Stork, 1955). With more complicated 1,5-polyenes, such as squalene, oily mixtures of various cycliz-ation products are obtained. The 18,19-glycol of squalene 2,3-oxide, however, cyclized in modest yield with picric acid catalysis to give a complex tetracyclic natural product with nine chiral centres. Picric acid acts as a protic acid of medium strength whose conjugated base is non-nucleophilic. Such acids activate oxygen functions selectively (K.B. Sharpless, 1970). 

Because there are four chirality centers and no possibility of meso forms there are 2" or 16 stereoisomeric hexoses All 16 are known having been isolated either as natural products or as the products of chemical synthesis... 

Steroids are another class of natural products with multiple chirality centers One such compound is cholic acid which can be obtained from bile Its structural formula IS given m Figure 7 12 Cholic acid has 11 chirality centers and so a total (including cholic acid) of 2" or 2048 stereoisomers have this constitution Of these 2048 stereoiso mers how many are diastereomers of cholic acid s Remember Diastereomers are stereoisomers that are not enantiomers and any object can have only one mirror image Therefore of the 2048 stereoisomers one is cholic acid one is its enantiomer and the other 2046 are diastereomers of cholic acid Only a small fraction of these compounds are known and (+) cholic acid is the only one ever isolated from natural sources... 

The reaction is used for the chain extension of aldoses in the synthesis of new or unusual sugars In this case the starting material l arabinose is an abundant natural product and possesses the correct configurations at its three chirality centers for elaboration to the relatively rare l enantiomers of glucose and mannose After cyanohydrin formation the cyano groups are converted to aldehyde functions by hydrogenation m aqueous solution Under these conditions —C=N is reduced to —CH=NH and hydrolyzes rapidly to —CH=0 Use of a poisoned palladium on barium sulfate catalyst prevents further reduction to the alditols... 

Synthetic utility of stereoselective alkylations in natural product chemistry is exemplified by the preparation of optically active 2-arylglycine esters (38). Chirally specific a-amino acids with methoxyaryl groups attached to the a-carbon were prepared by reaction of the dimethyl ether of a chiral bis-lactam derivative with methoxy arenes. Using SnCl as the Lewis acid, enantioselectivities ranging from 65 to 95% were obtained. 

PLE catalyzes the hydrolysis of a wide range of meso-diesters (Table 2). This reaction is interesting from both theoretical and practical standpoints. Indeed, the analysis of a large range of kinetic data provided sufficient information to create a detailed active site model of PLE (31). From a practical standpoint, selective hydrolysis of y j (9-cyclo-I,2-dicarboxylates leads to chiral synthons that are valuable intermediates for the synthesis of a variety of natural products. 

The structure of a natural product is shown without any specification of stereochem-istiy. It is a pure substance which gives no indication of being a mixture of stereoisomers and has zero optical rotation. It is not a racemic mixture because it does not yield separate peaks on a chiral HPLC column. When the material is completely hydrolyzed, it gives a racemic sample of the product shown. Deduce the complete stereochemical structure of the natural product fiom this information. 

Chiral oxazoline-based synthetic methods have been employed in the asymmetric synthesis of a large number of natural products. A few representative examples of these applications are shown below. 

The sesquiterpenoid hydrocarbons (5)-a-curcumene (59) and (5)-xanthorrhizol (60) were prepared by asymmetric conjugate addition of the appropriate aryllithium reagent to unsaturated oxazoline 56 to afford alcohols 57 (66% yield, 96% ee) and 58 (57% yield, 96% ee) upon hydrolysis and reduction. The chiral alcohols were subsequently converted to the desired natural products. ... 

The asymmetric addition of organolithium reagents to arylox azolines has been used to construct highly complex polycyclic terpene structures found in natural products. For example, the asymmetric addition of vinyllithium to chiral naphthyloxazoline 3 followed by treatment of the resulting anionic intermediate with iodoethyl dioxolane 61... 

The axially chiral natural product mastigophorene A (70) was synthesized via a copper-catalyzed asymmetric homocoupling of bromooxazoline 68. Treatment of 68 with activated copper in DMF afforded 69 in 85% yield as a 3 1 mixture of atropisomers. The major atropisomer was converted into mastigophorene A (70) the minor regioisomer was transformed into the atropisomeric natural product mastigophorene... 

Marazano and co-workers have used the Zincke reaction extensively to prepare chiral templates for elaboration to substituted piperidine and tetrahydropyridine natural products and medicinal agents. For example, 3-picoline was converted to Zincke salt 40 by reaction with 2,4-dinitrochlorobenzene in refluxing acetone, and treatment with R- -)-phenylglycinol in refluxing n-butanol generated the chiral pyridinium 77. Reduction to... 

Likewise, a cis-2,6-disubstituted piperidine natural product, (-)-lobeline (98, Scheme 8.4.30) was synthesized from the chiral Af-alkyl pyridinium salt ent-80 via a sequence that included addition of a Reformatsky reagent to an intermediate oxazolidine. °... 

Atroposelective cleavage of configurationally unstable lactone cycle in biaryl derivatives as effective route to chiral natural products and useful reagents 99S525. 

Cyclitols as novel chiral building blocks in synthesis of heterocyclic natural products 97CC807. 

Among the many chiral Lewis acid catalysts described so far, not many practical catalysts meet these criteria. For a,/ -unsaturated aldehydes, Corey s tryptophan-derived borane catalyst 4, and Yamamoto s CBA and BLA catalysts 3, 7, and 8 are excellent. Narasaka s chiral titanium catalyst 31 and Evans s chiral copper catalyst 24 are outstanding chiral Lewis acid catalysts of the reaction of 3-alkenoyl-l,2-oxazolidin-2-one as dienophile. These chiral Lewis acid catalysts have wide scope and generality compared with the others, as shown in their application to natural product syntheses. They are, however, still not perfect catalysts. We need to continue the endeavor to seek better catalysts which are more reactive, more selective, and have wider applicability. 

The [ 2 + 4]-cycloaddition reaction of aldehydes and ketones with 1,3-dienes is a well-established synthetic procedure for the preparation of dihydropyrans which are attractive substrates for the synthesis of carbohydrates and other natural products [2]. Carbonyl compounds are usually of limited reactivity in cycloaddition reactions with dienes, because only electron-deficient carbonyl groups, as in glyoxy-lates, chloral, ketomalonate, 1,2,3-triketones, and related compounds, react with dienes which have electron-donating groups. The use of Lewis acids as catalysts for cycloaddition reactions of carbonyl compounds has, however, led to a new era for this class of reactions in synthetic organic chemistry. In particular, the application of chiral Lewis acid catalysts has provided new opportunities for enantioselec-tive cycloadditions of carbonyl compounds. 

With the use of chiral reagents a differentiation of enantiotopic faces is possible, leading to an enantioselective reaction. The stereoselective version of the Michael addition reaction can be a useful tool in organic synthesis, for instance in the synthesis of natural products. 

The introduction of synthetic materials into natural products, often described as adulteration , is a common occurrence in food processing. The types of compounds introduced, however, are often chiral in nature, e.g. the addition of terpenes into fruit juices. The degree to which a synthetic terpene has been added to a natural product may be subsequently determined if chiral quantitation of the target species is enabled, since synthetic terpenes are manufactured as racemates. Two-dimensional GC has a long history as the methodology of choice for this particular aspect of organic analysis (38). 

The study of biochemical natural products has also been aided through the application of two-dimensional GC. In many studies, it has been observed that volatile organic compounds from plants (for example, in fruits) show species-specific distributions in chiral abundances. Observations have shown that related species produce similar compounds, but at differing ratios, and the study of such distributions yields information on speciation and plant genetics. In particular, the determination of hydroxyl fatty acid adducts produced from bacterial processes has been a successful application. In the reported applications, enantiomeric determination of polyhydroxyl alkanoic acids extracted from intracellular regions has been enabled (45). 

We can list the following areas as prime targets essential oil and natural product analysis, chiral analysis (e.g. of fragrances), trace multi-residue analysis, pesticide monitoring, and further petroleum products applications, in fact any separation where simply greater resolution and sensitivity is demanded-which means probably almost... 

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