Chirality centre

The R, S convention is a scheme which has largely superseded the D, i. system to denote configuration about a chiral centre in a molecule. The convention allows unequivocal designation of the absolute configuration in a description of the positions in space of ligands attached to a chiral centre, in relation to an agreed standard of chirality like a right-hand helix. 

Groups attached to the chiral centre are given an order of priority according to the sequence rules. For an enantiomeric carbon compound the group of lowest priority is... 

With relatively simple spectra, it is usually possible to extract the individual coupling constants by inspection, and to pair them by size in order to discover what atoms they coimect. However, the spectra of larger molecules present more of a challenge. The multiplets may overlap or be obscured by the presence of several unequal but similarly sized couplings. Also, if any chiral centres are present, then the two hydrogens in a... 

Circular dicliroism has been a useful servant to tire biophysical chemist since it allows tire non-invasive detennination of secondary stmcture (a-helices and P-sheets) in dissolved biopolymers. Due to tire dissymmetry of tliese stmctures (containing chiral centres) tliey are biaxial and show circular birefringence. Circular dicliroism is tlie Kramers-Kronig transfonnation of tlie resulting optical rotatory dispersion. The spectral window useful for distinguishing between a-helices and so on lies in tlie region 200-250 nm and hence is masked by certain salts. The metliod as usually applied is only semi-quantitative, since tlie measured optical rotations also depend on tlie exact amino acid sequence. 

We must next disconnect the six-membered ring and the only way we know to set up these chiral centres specifically is by the Diels-Alder reaction. Two alternative sites for the double bond are possible if we convert our NHi to give the necessary activating group (NOi)... 

Alkylation of aldol type educts, e.g., /3-hydroxy esters, using LDA and alkyl halides leads stereoselectively to erythro substitution. The erythro threo ratio of the products is of the order of 95 5. Allylic and benzylic bromides can also be used. The allyl groups can later be ozonolysed to gjve aldehydes, and many interesting oligofunctional products with two adjacent chiral centres become available from chiral aldol type educts (G. Prater, 1984 D. Seebach, 1984 see also M. Nakatsuka, 1990, p. 5586). 

Alcohols can be synthesized by the addition of carbanions to carbonyl compounds (W.C. Still, 1976) or epoxides. Both types of reactions often produce chiral centres, and stereoselectivity is an important aspect of these reactions. 

A more eflicient and general synthetic procedure is the Masamune reaction of aldehydes with boron enolates of chiral a-silyloxy ketones. A double asymmetric induction generates two new chiral centres with enantioselectivities > 99%. It is again explained by a chair-like six-centre transition state. The repulsive interactions of the bulky cyclohexyl group with the vinylic hydrogen and the boron ligands dictate the approach of the enolate to the aldehyde (S. Masamune, 1981 A). The fi-hydroxy-x-methyl ketones obtained are pure threo products (threo = threose- or threonine-like Fischer formula also termed syn" = planar zig-zag chain with substituents on one side), and the reaction has successfully been applied to macrolide syntheses (S. Masamune, 1981 B). Optically pure threo (= syn") 8-hydroxy-a-methyl carboxylic acids are obtained by desilylation and periodate oxidation (S. Masamune, 1981 A). Chiral 0-((S)-trans-2,5-dimethyl-l-borolanyl) ketene thioketals giving pure erythro (= anti ) diastereomers have also been developed by S. Masamune (1986). 

Cram erythro-products" (G.E. Keck, 1984 A, B, C). [3-(Silyloxy)allyl]stannanes and O-pro-tected a- or y -hydroxy aldehydes yield 1,2,3- or 1,2,4-triols with three chiral centres with high regio- and diastereoselectivity (G.E. Keck, 1987). 

Open-chain 1,5-polyenes (e.g. squalene) and some oxygenated derivatives are the biochemical precursors of cyclic terpenoids (e.g. steroids, carotenoids). The enzymic cyclization of squalene 2,3-oxide, which has one chiral carbon atom, to produce lanosterol introduces seven chiral centres in one totally stereoselective reaction. As a result, organic chemists have tried to ascertain, whether squalene or related olefinic systems could be induced to undergo similar stereoselective cyclizations in the absence of enzymes (W.S. Johnson, 1968, 1976). 

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). 

The enantioselective introduction of chiral centres into an achiral molecule can nowadays be achieved most easily using chiral reductants or oxidants. 

A major trend in organic synthesis, however, is the move towards complex systems. It may happen that one needs to combine a steroid and a sugar molecule, a porphyrin and a carotenoid, a penicillin and a peptide. Also the specialists in a field have developed reactions and concepts that may, with or without modifications, be applied in other fields. If one needs to protect an amino group in a steroid, it is advisable not only to search the steroid literature but also to look into publications on peptide synthesis. In the synthesis of corrin chromophores with chiral centres, special knowledge of steroid, porphyrin, and alkaloid chemistry has been very helpful (R.B. Woodward, 1967 A. Eschenmoser, 1970). 

It is conceivable that related ligands, e.g. dehydrocorrins, could be obtained from pyrrolic units using pathways similar to those used for porphyrins and could be hydrogenated to corrins. This has indeed been achieved (I.D. Dicker, 1971), but it is, of course, impossible to introduce the nine chiral centres of cobyrinic acid by such procedures. 

Non-enzymatic cyclizations of educts containing chiral centres can lead to products with additional "asymmetric centres. The underlying effect is called "asymmetric induction . Its systematic exploration in steroid syntheses started when G. Saucy discovered in 1971 that a chiral carbon atom in a cyclic educt induces a stereoselective Torgov condensation several carbon atoms away (M. Rosenberger, 1971, 1972). 

Proton-catalyzed olefin cyclizations of open-chain educts may give tri- or tetracyclic products but low yields are typical (E.E. van Tamelen, 1968, 1977 see p. 91). More useful are cyclizations of monocyclic educts with appropriate side-chains. The chiral centre to which the chain is attached may direct the steric course of the cyclization, and several asymmetric centres may be formed stereoselectively since the cyclizations usually lead to traas-fused rings. 

Analogous definitions and designations apply to molecules containing a chiral centre and a prochiral tetrahedral or trigonal centre. The plane containing the chiral and prochiral centres is called a diastereo-zeroplane (Y. Izumi, 1977). 

Most parent structures consist essentially of an assembly of rings and/or chains, the degree of hydrogenation of which is defined (usually completely saturated or containing the maximum number of non-cumulative double bonds in cyclic portions), and having no attached functional substituents (the carbohydrates are a notable exception to this). The stereochemistry at all (or most) chiral centres is defined thus such parent structures are sometimes referred to as stereoparents . Some examples are shown (77)-(83). 

The absolute configuration of any chiral centre can be unambiguously specified using the RS notation. 

The ending caine stems from cocaine, the first clinically employed local anaesthetic. Procaine and tetracaine are ester-linked substances, the others are amides. Amide bonded local anaesthetics usually contain two i s in their name, ester-bonded only one. In the structure drawings, the lipophilic portion of the molecule is depicted at the left, the amine at the right. The asterisk marks the chiral centre of the stereoisomeric drugs. Lipid solubility is given as the logarithm of the water octanol partition coefficient, log(P). 

Multiple sets of chiral centres 2-Carb-I2. Ketoaldoses (aldoketoses, aldosuloses)... 

Note. In cyclic forms of sugars, the configuration at the anomeric chiral centre is defined in relation to the anomeric reference atom (see 2-Carb-6.2). 

If sequences of chiral centres are separated by non-chiral centres, the non-chiral centres are ignored, and the remaining set of chiral centres is assigned the appropriate configurational prefix (for four centres or less) or prefixes (for more than four centres). 

For ketoses with the carbonyl group at C-3 or a higher-numbered carbon atom, the carbonyl group is ignored and the set of chiral centres is given the appropriate prefix or prefixes according to Chart I (cf. 2-Carb-8.4). 

If the carbonyl group(s) divides the sequence of chiral centres, the configurational prefixes are assigned in the normal manner (see 2-Carb-8.4) for all chiral centres the non-chiral centres are ignored. 

Several deoxy sugars have trivial names established by long usage, e.g. fucose (Fuc), quinovose (Qui) and rhamnose (Rha). They are illustrated here in the pyranose form. These names are retained for the unmodified sugars, but systematic names are usually preferred for the formation of names of derivatives, especially where deoxygenation is at a chiral centre of the parent sugar. (See also the alphabetical listing of trivial names in the Appendix.)... 

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