Chiral centers

A phase change takes place when one enantiomer is converted to its optical isomer. As illustrated in Figure 9, when the chiral center is a tetra-substituted carbon atom, the conversion of one enantiomer to the other is equivalent to the exchange of two electron pairs. This transformation is therefore phase inverting. 

The transformation of ethylene to the carbene requires the re-pairing of three electron pairs. It is a phase-preserving reaction, so that the loop is an ip one. The sp -hybridized carbon atom formed upon H transfer is a chiral center consequently, there are two equivalent loops, and thus conical intersections, leading to two enantiomers. 

Figure 2-69. The two enantiomers of lactic acid assignment of R and S configurations to the enantiomers of lactic acid after ranking the four ligands attached to the chiral center according to the Cl P rules (OH > COjH > Me > H).

In most common chiral molecules, chirality arises from chiral tetravalent atoms. A conformation-independent chirality code (CICC) was developed that encodes the molecular chirality originating from a chiral tetravalent atom [42], For more generality, a conformation-dependent chirality code (CDCC) is used [43]. CDCC ti cats a molecule as a rigid set of points (atoms) linked by bonds, and it accounts for chirality generated by chirality centers, chirality axes, or chirality planes. 

The neighborhoods of the atoms directly bonded to tbe chiral center must be defined. The neighborhood of an atom A. dircetly bonded to the ehiral eenter, is dc-fned as the set of atoms whose distance (in number of bonds) to A is less than their distance to any of the other three atoms bonded to the chiral center (Figure 8-9. In cyclic structures different neighborhoods can overlap. 

The value of embodies the conformation-independent 3D arrangement of the atoms of the ligands of a chirality center in distance space and thus cannot distinguish between enantiomers. This distinction is introduced by the descriptor S , , . 

The two values, e and s, calculated for all the combinations of four atoms (each one sampled from a different ligand of a chiral center) are then combined to generate a conformation-independent ckirality code, fcjcC rising Eq. (28). 

The conformation-dependent chirality code constitutes a more general description of molecular chirality, which is formally comparable with the CICC [43], The main difference is that chiral carbon atoms arc now not explicitly considered, and combinations of any four atoms are now used, independently of the existence or nonexistence of chiial centers, and of their belonging or not belonging to ligands of chiral centers. 

Figure 10.3-40. The rating for the disconnection strategy carbon-heteroatom bonds is illustrated, Please focus on the nitrogen atom of the tertiary amino group. It is surrounded by three strategic bonds with different values. The low value of 9 for one ofthese bonds arises because this bond leads to a chiral center. Since its formation requires a stereospecific reaction the strategic weight of this bond has been devalued. In contrast to that, the value of the bond connecting the exocyclic rest has been increased to 85, which may be compared with its basic value as an amine bond.

Ketene formation is a common side reaction- scambling of chiral centers... 

The target molecule above contains a chiral center. An enantioselective synthesis can therefore be developed We use this opportunity to summarize our knowledge of enantioselective reactions. They are either alkylations of carbanions or addition reactions to C = C or C = 0 double bonds ... 

This target molecule again contains a chiral center and we inspect Table 18 for help. Table 18. Some enantioselective reactions that produce difunctional products... 

The 1,6-difunctional hydroxyketone given below contains an octyl chain at the keto group and two chiral centers at C-2 and C-3 (G. Magnusson, 1977). In the first step of the antithesis of this molecule it is best to disconnect the octyl chain and to transform the chiral residue into a cyclic synthon simultaneously. Since we know that ketones can be produced from add derivatives by alkylation (see p. 45ff,), an obvious precursor would be a seven-membered lactone ring, which is opened in synthesis by octyl anion at low temperature. The lactone in turn can be transformed into cis-2,3-dimethyicyclohexanone, which is available by FGI from (2,3-cis)-2,3-dimethylcyclohexanol. The latter can be separated from the commercial ds-trans mixture, e.g. by distillation or chromatography. 

Benzyl bromide can be converted into ethylbenzene (731) by the reaction of Me4Sn. The use of HMPA as a solvent is important. Overall inversion of configuration takes place at the chiral center of deuterated benzyl bro-mide[598]. The cyanomethyiation[599] and methoxymethyiation[600] of aromatic rings are carried out by the reaction of cyanomethyltributyltin (732) and methoxymethyltributyltin. 

A key intermediate, 163, which possesses all but one chiral center of (+ )-brefeldin, has been prepared by the enantiocontrolled cycloaddition of the chiral fi,/3-unsaturated ester 162 to 154[107], Synthesis of phyllocladane skeleton 165 has been carried out by the Pd-catalyzed cycloaddition of the unsaturated diester 164 and cobalt-catalyzed cycloaddition of alkynes as key reactions[108]. Intramolecular cycloaddition to the vinylsulfone in 166 proceeds smoothly to give a mixture of the trans and cis isomers in a ratio of 2.4 1[109], Diastereocontrolled cycloaddition of the hindered vinylsulfone 167 affords a single stereoisomeric adduct, 168, which is used for the synthesis of the spirocarbocyclic ring of ginkgolide[l 10],... 

Noting the presence of one (but not more than one) chirality center is a simple rapid way to determine if a molecule is chiral For example C 2 is a chirality center m... 

A carbon with four different groups attached to it is a chi rality center (a) In 2 bromopentane C 2 satisfies this requirement (b) None of the carbons in 3 bromopentane has four different substituents and so none of its atoms IS a chirality center... 

Molecules with chirality centers are very common both as naturally occurring sub stances and as the products of chemical synthesis (Carbons that are part of a double bond or a triple bond can t be chirality centers)... 

A carbon atom in a ring can be a chirality center if it bears two different sub stituents and the path traced around the ring from that carbon m one direction is differ ent from that traced m the other The carbon atom that bears the methyl group m 1 2 epoxypropane for example is a chirality center The sequence of groups is O—CH2 as one proceeds clockwise around the ring from that atom but is CH2—O m the counter clockwise direction Similarly C 4 is a chirality center m limonene... 

Even isotopes qualify as different substituents at a chirality center The stereo chemistry of biological oxidation of a derivative of ethane that is chiral because of deu terium (D = H) and tritium (T = H) atoms at carbon has been studied and shown to... 

One final very important point Everything we have said in this section concerns molecules that have one and only one chirality center molecules with more than one chirality center may or may not be chiral Molecules that have more than one chirality center will be discussed m Sections 7 10 through 7 13... 

Identify the substituents at the chirality center and rank them in order of decreasing precedence accord mg to the system described in Section 5 4 Precedence IS determined by atomic number working outward from the point of attachment at the chirality center... 

In order of decreasing precedence the four substitu ents attached to the chirality center of 2 butanol are... 

As represented in the wedge and dash drawing at the top of this table the molecule is already appro priately oriented Hydrogen is the lowest ranked atom attached to the chirality center and points away from us... 

The order of decreasing precedence is counterclockwise The configuration at the chirality center is S... 

Compounds in which a chirality center is part of a ring are handled in an analo gous fashion To determine for example whether the configuration of (+) 4 methyl cyclohexene is R or S treat the right and left hand paths around the nng as if they were independent substituents... 

To verify that the Fischer jjrojection has the R configuration at its chirality center rotate the three dimensional representation so that the lowest ranked atom (H) points away from you Be careful to maintain the proper stereochemical relationships during the operation... 

Switching the positions of two groups in a Fischer projection reverses the config ration of the chirality center... 

Many of the reactions we ve already encountered can yield a chiral product from an achi ral starting material Epoxidation of propene for example creates a chirality center by adding oxygen to the double bond... 

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