Chiral stereospecificity

Enzymes are highly selective of the substrates with which they interact and in the reactions that they catalyze. This selective nature of enzymes collectively known as enzyme specificity can be best illustrated with oxidoreductases (dehydrogenases), which display substrate and bond specificities (e.g., acting on —CHOH—, versus —CHO versus —CH—CH— versus —CHNH2, and cis versus trans for unsaturated substrates), coenzyme specificity (e.g., NAD(H) versus NADP(H)), chiral stereospecificity (d- versus l- or R- versus S-stereoisomers), and prochiral stereospecificity (A versus B corresponding to proR- versus proS isomers and re face versus si face, respectively). The table lists some dehydrogenases and their coenzyme, substrate, product and stereospecificities (You, 1982) ... 

For a key/critical intermediate (defined as one in which an essential molecular characteristic[s] is first introduced), specifications and test methodologies should be used that assure that the molecular architecture intended to be conferred (e.g., chirality, stereospecificity) has occurred in the expected yield and required purity. At least one test methodology should be used that can quantitate levels of undesired impurities, such as isomers, reaction by-products, or starting materials. For other intermediates, controls may not have to be as extensive. One or more tests monitoring the progress of the synthesis may be all that is necessary. 

Co(trien)(NH3)2] + has been isolated, and only the meso trans isomers (197-198) with two different axial ligands, remain to be distinguished. There is also an extensive chemistry of N and C-alkylated derivatives of (178 180) as cA-[Co(OH)(trien)(OH2)] assists the hydrolysis of amino acid esters, amino acid amides, and peptides to form cis-fi (194) and cA-jS2-[Co(OA0(trien)] + (195)(( A = amino acid) complexes. Chiral alkylated trien ligands have the potential for chiral stereospecificity in such reactions. 

Stereospecificity Enzymes are also steiicaUy specific when acting on substrates that are stereoisomeric, i.e. isomers in which the atoms are oriented differently in space. The presence of a chiral (asymmetric) center (carbon) in a molecule gives rise to an enatiomeric pair, D and L or R and S (Cahn et al, 1966). Stereospecific enzymes that act on only one enantiomer but not the other are known as chiral stereospecificity. For example, o-lactate dehydrogenase oxidizes only D-lactate to pyruvate and L-lactate dehydrogenase, its c-enantiomer ... 

Chiral monomers are converted to polymers with chiral groups in chiral stereospecific or chirality transfer polymerizations. An example of this is the polymerization of (R)-propylene oxide to poly(R-propylene oxide). 

Further special cases can be distinguished among the chiral stereospecific and the prochiral stereospecific polymerizations. If one starts with... 

Polymerization of racemic vinyl monomers with chiral stereospecific catalysts yields, in general, a mixture of macromolecules of different stereoregularity, also containing different types of sequences of d- and /-monomeric units as a result of stereoselective or stereoelective processes (see the review by Pino [106]. 

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.

Not stereospecific racemization ac companies inversion when leaving group IS located at a chirality cen ter (Section 8 10) Stereospecific 100% inversion of configuration at reaction site Nu cleophile attacks carbon from side opposite bond to leaving group (Section 8 4)... 

Recall from Section 7 13 that a stereospecific reaction is one in which each stereoiso mer of a particular starting material yields a different stereoisomeric form of the reaction product In the ex amples shown the product from Diels-Alder cycloaddi tion of 1 3 butadiene to as cinnamic acid is a stereo isomer of the product from trans cinnamic acid Each product although chiral is formed as a racemic mixture... 

A variety of strategies have been devised to obtain chiral separations. Although the focus of this article is on chromatographicaHy based chiral separations, other methods include crystallisation and stereospecific ensymatic-catalysed synthesis or degradation. In crystallisation methods, racemic chiral ions are typically resolved by the addition of an optically pure counterion, thus forming diastereomeric complexes. 

Deamination, Transamination. Two kiads of deamination that have been observed are hydrolytic, eg, the conversion of L-tyrosiae to 4-hydroxyphenyUactic acid ia 90% yield (86), and oxidative (12,87,88), eg, isoguanine to xanthine and formycia A to formycia B. Transaminases have been developed as biocatalysts for the synthetic production of chiral amines and the resolution of racemic amines (89). The reaction possibiUties are illustrated for the stereospecific synthesis of (T)-a-phenylethylamine [98-84-0] (ee of 99%) (40) from (41) by an (5)-aminotransferase or by the resolution of the racemic amine (42) by an (R)-aminotransferase. 

Some of the newer compounds may contain both saturated and unsaturated rings, heteroatoms such as oxygen, nitrogen, or sulfur, and halogen substituents. Others, such as synthetic pyrethroids, may have one or more chiral centers, often needing stereospecific methods of synthesis or resolution of isomers (42). Table 4 Hsts examples of some more complex compounds. Stmctures are shown ia Eigure 1 (25). 

Fig. 5. Synthetic pathway for d-hioXin. (Lonza synthesis). An improved process uses the chiral ferrocenyldisphoshine (36) to iatroduce stereospecificity...

Aziridines have been prepared stereospecifically by the nucleophilic addition of the nitrogen residue to alkenes <80T73). Introduction of the nitrene is accomplished readily via a Michael-type addition with free diphenylsulfilimine (Scheme 12), and where a chiral sulfilimine is used the chirality is transferred to the aziridine with optical yields in excess of 25%. 

The remarkable stereospecificity of TBHP-transition metal epoxidations of allylic alcohols has been exploited by Sharpless group for the synthesis of chiral oxiranes from prochiral allylic alcohols (Scheme 76) (81JA464) and for diastereoselective oxirane synthesis from chiral allylic alcohols (Scheme 77) (81JA6237). It has been suggested that this latter reaction may enable the preparation of chiral compounds of complete enantiomeric purity cf. Scheme 78) ... 

An interesting feature of the synthesis is the use of allyl as a two-carbon extension unit. This has been used in the stereospecific synthesis of dicyclohexano-18-crown-6 (see Eq. 3.13) and by Cram for formation of an aldehyde unit (see Eq. 3.55). In the present case, mannitol bis-acetonide was converted into its allyl ether which was ozonized (reductive workup) to afford the bis-ethyleneoxy derivative. The latter two groups were tosylated and the derivative was allowed to react with its precursor to afford the chiral crown. The entire process is shown below in Eq. (3.59). 

This reaction, now termed hydroboration, has opened up the quantitative preparation of organoboranes and these, in turn, have proved to be of outstanding synthetic utility. It was for his development of this field that H. C. Brown (Purdue) was awarded the 1979 Nobel Prize in Chemistry . Hydroboration is regiospecific, the boron showing preferential attachment to the least substituted C atom (anti-Markovnikov). This finds ready interpretation in terms of electronic factors and relative bond polarities (p. 144) steric factors also work in the same direction. The addition is stereospecific cis (syn). Recent extensions of the methodology have encompassed the significant development of generalized chiral syntheses. 

Optical resolution of the dithiirane 1-oxides 2 and 3 was accomplished by HPLC equipped with a chiral column (97T12203). Absolute configurations of 2a and 2b were determined by X-ray crystallography. Tire stereospecific isomerization (epimerrzation) of 2a to 3b and 2b to 3a was observed during the resolution study. 

For the construction of oxygen-functionalized Diels-Alder products, Narasaka and coworkers employed the 3-borylpropenoic acid derivative in place of 3-(3-acet-oxypropenoyl)oxazolidinone, which is a poor dienophile in the chiral titanium-catalyzed reaction (Scheme 1.55, Table 1.24). 3-(3-Borylpropenoyl)oxazolidinones react smoothly with acyclic dienes to give the cycloadducts in high optical purity [43]. The boryl group was converted to an hydroxyl group stereospecifically by oxidation, and the alcohol obtained was used as the key intermediate in a total synthesis of (-i-)-paniculide A [44] (Scheme 1.56). 

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