Enantiospecificity

Nonpolar organic mobile phases, such as hexane with ethanol or 2-propanol as typical polar modifiers, are most commonly used with these types of phases. Under these conditions, retention seems to foUow normal phase-type behavior (eg, increased mobile phase polarity produces decreased retention). The normal mobile-phase components only weakly interact with the stationary phase and are easily displaced by the chiral analytes thereby promoting enantiospecific interactions. Some of the Pirkle-types of phases have also been used, to a lesser extent, in the reversed phase mode. 

Hybridalactone, a novel marine derived eicosanoid from Laurencia hybrida, appears to be biosynthesized by a unique pathway from eicosapentaenoic acid. The synthesis of hybridalactone was carried out enantiospecifically from (+)-bicyclo[3.2.0]hept-4-ene-l-one so as to provide proof of stereochemistry (Ref. 4). 

Another example of this preference is found in the enantiospecific syntheses of tritium-labeled leukotrienes(/i). Commercially available 3-nonyn-l-ol was converted to its phosphorane (16) and Wittig-coupled with the unsaturated aldehyde (17) to afford 18, which was reduced over Lindlar catalyst to give 19. 

In general, a liquid membrane for chiral separation contains an enantiospecific carrier which selectively forms a complex with one of the enantiomers of a racemic mixture at the feed side, and transports it across the membrane, where it is released into the receptor phase (Fig. 5-1). 

The development of a single enantiomer as a new active substance should be described in the same manner as for any other new chemical entity. Studies should be carried out with the single enantiomer, but if development began with the race-mate then these studies may also be taken into account. Chiral conversion should be considered early on so that enantiospecific bioanalytical methods may be developed. These methods should be described in chemistry and pharmacy part of the dossier. If the opposite enantiomer is formed in vivo, then it should be evaluated in the same way as other metabolites. For endogenous human chiral compounds, enantiospecific analysis may not be necessary. The enantiomeric purity of the active ingredient used in preclinical and clinical studies should be stated. 

The applicant should provide justification for using the racemate. Where the interconversion of the enantiomers in vivo is more rapid than the distribution and elimination rates, then use of the racemate is justified. In cases where there is no such interconversion or it is slow, then differential pharmacological effects and fate of the enantiomers may be apparent. Use of the racemate may also be justified if any toxicity is associated with the pharmacological action and the therapeutic index is the same for both isomers. For preclinical assessment, pharmacodynamic, pharmacokinetic (using enantiospecific analytical methods) and appropriate toxicological studies of the individual enantiomers and the racemate will be needed. Clinical studies on human pharmacodynamics and tolerance, human pharmacokinetics and pharma-cotherapeutics will be required for the racemate and for the enantiomers as appropriate. 

Generic applications for chiral medicinal products should be supported by bioequivalence studies using enantiospecific bioanalytical methods unless both products contain the same, stable, single enantiomer or both products contain a racemate where both enantiomers show linear pharmacokinetics. 

There will be a continued need for enantiospecific methods of preparation and analysis, not only to ensure the quality of the final drug substance and reference materials, but also to control starting materials used for their manufacture, and key intermediates during synthesis. Likewise, specific and sensitive bioanalytical methods will be required to follow the fate of individual enantiomers after their administration. 

The elegant, enantiospecific synthesis of biotin (1) by Hoffmann-La Roche1 is based on a strategy that takes advantage of the powerful intramolecular nitrone-olefin cycloaddition reaction. Our analysis begins with model studies in which the straightforward conversion of L-cysteine (2) into aldehyde 3 (see Scheme 1) constitutes... 

The carbanions of 1-alkenyl sulphoxides 400 also react with carbonyl compounds to give the corresponding condensation products384 (equation 237). Solladie and Moine have used this type of reaction in their enantiospecific synthesis of the chroman ring of a-tocopherol 401. Addition of the lithio reagent 402 to the aldehyde 403 affords the allylic alcohol 404 in 75% yield as a sole diastereoisomer481 (equation 238). 

Keywords enantiospecific synthesis, intramolecular Diels-Alder approaches... 

An intramolecular lactonisation features as the final stage in an enantiospecific assembly of the pentacyclic quassinoid framework <96CC2369>. 

Levitt MS, RE Newton, SM Roberts, AJ Willetts (1990) Preparation of optically active 6 -fluorocarbocyclic nucleosides utilising an enantiospecific enzyme-catalysed Baeyer-Villiger type oxidation. J Chem Soc Chem Comm 619-620. 

Carless HAJ (1992) The use of cyclohexa-3,5-diene-l,2-diols in enantiospecific synthesis. Tetrahedron Asymmetry 3 795-826. 

Another advantage of biocatalysis is that chemo-, regio-, and stereoselectivities are attainable that are difficult or impossible to achieve by chemical means. A pertinent example is the production of the artificial sweetener, aspartame, which has become somewhat of an industrial commodity. The enzymatic process (Fig. 2.31), operated by the Holland Sweetener Company (a joint venture of DSM and Tosoh), is completely regio- and enantiospecific (Oyama, 1992). 

Substances such as carbohydrates and amino acids as well as other small molecules available from natural sources are valuable starting materials in enantiospecific syntheses. Suggest reagents that could effect the following transformations, taking particular care to ensure that the product will be enantiomer-ically pure. 

Tocopherol can be produced as the pure 2R,4 R,8 R stereoisomer from natural vegetable oils. This is the most biologically active of the stereoisomers. The correct side-chain stereochemistry can be obtained using a process that involves two successive enantioselective hydrogenations.28 The optimum catalyst contains a 6, 6 -dimethoxybiphenyl phosphine ligand. This reaction has not yet been applied to the enantioselective synthesis of a-tocopherol because the cyclization step with the phenol is not enantiospecific. 

In Entry 11 the dienophile is an a-methylene lactam. As noted for this class of dienophiles, the stereoselectivity results from preferred exo addition (see p. 471). The reaction in Entry 12 was used in an enantiospecific synthesis of estrone. The dienophile was used in enantiomerically pure form and the dioxolane ring imparts a high facial selectivity to the dienophile. The reaction occurs through an endo TS. 

Owing to the concerted mechanism, chirality at C(3) [or C(4)] leads to enantiospecific formation of new stereogenic centers formed at C(l) [or C(6)].203 These relationships are illustrated in the example below. Both the configuration of the new stereocenter and the new double bond are those expected on the basis of a chairlike TS. Since there are two stereogenic centers, the double bond and the asymmetric carbon, there are four possible stereoisomers of the product. Only two are formed. The Zs-double bond isomer has the 5-con figuration at C(4) and the Z-isomer has the -configuration. These are the products expected for a chair TS. The stereochemistry of the new double bond is determined by the relative stability of the two chair TSs. TS B is less favorable than A because of the axial placement of the larger phenyl substituent. 

Scheme 6.17 gives some examples of the orthoamide and imidate versions of the Claisen rearrangement. Entry 1 applied the reaction in the synthesis of a portion of the alkaloid tabersonine. The reaction in Entry 2 was used in an enantiospecific synthesis of pravastatin, one of a family of drugs used to lower cholesterol levels. The product from the reaction in Entry 3 was used in a synthesis of a portion of the antibiotic rampamycin. Entries 4 and 5 were used in the synthesis of polycyclic natural products. Note that the reaction in Entry 4 also leads to isomerization of the double bond into conjugation with the ester group. Entries 1 to 5 all involve cyclic reactants, and the concerted TS ensures that the substituent is introduced syn to the original hydroxy substituent. 

Entry 10 was used in conjunction with dihydroxylation in the enantiospecific synthesis of polyols. Entry 11 illustrates the use of SnCl2 with a protected polypropionate. Entries 12 and 13 result in the formation of lactones, after MgBr2-catalyzed additions to heterocyclic aldehyde having ester substituents. The stereochemistry of both of these reactions is consistent with approach to a chelate involving the aldehyde oxygen and oxazoline oxygen. 

Section B shows some Hofmann rearrangements. Entry 9, using basic conditions with bromine, provided an inexpensive route to an intermediate for a commercial synthesis of an herbicide. Entry 10, which uses the Pb(OAc)4 conditions (see p. 949), was utilized in an enantiospecific synthesis of the naturally occurring analagesic (-)-epibatidine. Entry 11 uses phenyliodonium diacetate as the reagent. The product is the result of cyclization of the intermediate isocyanate and was used in an enantioselective synthesis of the antianxiety drug (tf)-fluoxetine. 

Entry 6 involves formation of a stabilized benzylic carbocation and results in a very efficient closure of a six-membered ring. Entry 7 involves an activated ring. The reaction was done using enantiomerically pure alcohol, but, as expected for a carbocation intermediate, the product was nearly racemic (6% e.e.). This cyclization was done enantiospecifically by first forming the Cr(CO)3 complex (see Section 8.5). 

Tomoxetine and fluoxetine are antidepressants. Both enantiomers of each compound can be prepared enantiospecifically starting from cinnamyl alcohol. Give a reaction sequence that will accomplish this objective. 

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