Enantiomers effects

Wynberg studied stereochemistry of the McMurry reductive dimerization of camphor in detail (64). In Scheme 37, A and B are homochiral dimerization products derived by the low-valence Ti-promoted reduction, while C and D are achiral heterochiral dimers. The reaction of racemic camphor prefers homochiral dimerization (total 64.9%) over the diastereomeric heterochiral coupling (total 35.1 %). Similarly, as illustrated in Scheme 38, oxidative dimerization of the chiral phenol A can afford the chiral dimers B and C (and the enantiomers) or the meso dimer D. In fact, a significant difference is seen in diastereoselectivity between the enaritiomerically pure and racemic phenol as starting materials. The enantiomerically pure S substrate produces (S,S)-B exclusively, while the dimerization of the racemic substrate is not stereoselective. In the latter case, some indirect enantiomer effect assists the production of C, which is absent in the former reaction. Thus, it appears that, even though the reagents and reaction conditions are identical, the chirality of the substrate profoundly affects the stability of the transition state. 

One further point which should be considered is the importance of dose size. Because of the (R) — (S) conversion, the dosage of the (S) form administered may be as much as two or three times the anticipated dose. One can visualize an elderly 90 lb lady, with decreased renal function, who is administered a racemic drug. She receives the normal dose calculated for a 150 lb person (because of the way the tablets are made up). Because of decreased renal function and increased retention there is time for all the (i ) enantiomer to be converted to the (S) enantiomer. Effectively, she will receive three times the needed dose of the active drug and the area under the dose—time curve will be much greater. It is hardly surprising that adverse side effects sometimes occur.99... 

In addition to the difference in bioavailabilities for the two enantiomers of verapamil, other pharmacokinetic parameters show an enantiomer effect. Although the actual extent of binding of verapamil to plasma proteins appears to be dependent on the route of administration, the free fraction of S-verapamil (approximately 12% after intravenous dosing and 23% after oral dosing) is always about twice that of R-verapamil (approximately 6% after intravenous dosing and 13% after oral) (7,10,11). This difference in the free fractions contributes to the volume of distribution of S-verapamil being about twice that of R-verapamil (6.4 L/kg vs. 2.7 L/kg), and the plasma clearance of S-verapamil being about twice that of R-verapamil (18 mL/min/kg vs. 10 mL/min/kg) (7,11), The terminal half-lives at approximately 4-5 hr are similar, but not identical for the two enantiomers... 

It is a combination of these twin goals that has led to the evolution of classical kinetic resolution into DKR. In such a process, one can in principle obtain a quantitative yield of one of the enantiomers. Effectively, DKR combines the resolution step of kinetic resolution with an in situ equilibration or racemisation of the chirally labile substrate. In DKR, the enantiomers of a... 

In the Sharpless epoxidation of divinylmethanols only one of four possible stereoisomers is selectively formed. In this special case the diastereotopic face selectivity of the Shaipless reagent may result in diastereomeric by-products rather than the enantiomeric one, e.g., for the L -(-(-)-DIPT-catalyzed epoxidation of (E)-a-(l-propenyl)cyclohexaneraethanol to [S(S)-, [R(S)-, [S(R)- and [R(R)-trans]-arate constants is 971 19 6 4 (see above S.L. Schreiber, 1987). This effect may strongly enhance the e.e. in addition to the kinetic resolution effect mentioned above, which finally reduces further the amount of the enantiomer formed. 

Section 7 8 Both enantiomers of the same substance are identical m most of then-physical properties The most prominent differences are biological ones such as taste and odor m which the substance interacts with a chiral receptor site m a living system Enantiomers also have important conse quences m medicine m which the two enantiomeric forms of a drug can have much different effects on a patient... 

Stereochemistry (Chapter 7) Chemistry in three dimensions the relationship of physical and chemical properties to the spatial arrangement of the atoms in a molecule Stereoelectron ic effect (Section 5 16) An electronic effect that depends on the spatial arrangement between the or bitals of the electron donor and acceptor Stereoisomers (Section 3 11) Isomers with the same constitu tion but that differ in respect to the arrangement of their atoms in space Stereoisomers may be either enantiomers or diastereomers... 

Although it might seem that adrninistration of enantiomericaHy pure substances would always be preferred, the diuretic indacrinone (3), is an example of a dmg for which one enantiomer mediates the harmful effects of the other enantiomer (4). (+)-Indacrinone, the diureticaHy active enantiomer or eutomer causes uric acid retention. Fortunately, the other enantiomer distomer) causes uric acid elimination. Thus, adrninistration of a mixture of the two enantiomers, although not necessarily racemic, may have therapeutic value. 

Chiral separatioas oa proteia-based phases may also provide useful information oa dmg iateractioas. For iastance, the effect of the iadividual enantiomers of warfaria oa the eaantioselectivity of human semm albumin toward benzodiazepiaones has been studied usiag a human semm albumin... 

The optical activity of malic acid changes with dilution (8). The naturally occurring, levorotatory acid shows a most peculiar behavior in this respect a 34% solution at 20°C is optically inactive. Dilution results in increasing levo rotation, whereas more concentrated solutions show dextro rotation. The effects of dilution are explained by the postulation that an additional form, the epoxide (3), occurs in solution and that the direction of rotation of the normal (open-chain) and epoxide forms is reversed (8). Synthetic (racemic) R,.9-ma1ic acid can be resolved into the two enantiomers by crystallisation of its cinchonine salts. 

The amino acids L-leucine, T-phenylalanine, L-tyrosine, and L-tryptophan all taste bitter, whereas their D-enantiomers taste sweet (5) (see Amino ACIDS). D-Penicillamine [52-67-5] a chelating agent used to remove heavy metals from the body, is a relatively nontoxic dmg effective in the treatment of rheumatoid arthritis, but T.-penicillamine [1113-41 -3] produces optic atrophy and subsequent blindness (6). T.-Penicillamine is roughly eight times more mutagenic than its enantiomer. Such enantioselective mutagenicity is likely due to differences in renal metaboHsm (7). (R)-ThaHdomide (3) is a sedative—hypnotic (3)-thaHdomide (4) is a teratogen (8). 

Care should be exercised when attempting to interpret in vivo pharmacological data in terms of specific chemical—biological interactions for a series of asymmetric compounds, particularly when this interaction is the only parameter considered in the analysis (10). It is important to recognize that the observed difference in activity between optical antipodes is not simply a result of the association of the compound with an enzyme or receptor target. Enantiomers differ in absorption rates across membranes, especially where active transport mechanisms are involved (11). They bind with different affinities to plasma proteins (12) and undergo alternative metaboHc and detoxification processes (13). This ultimately leads to one enantiomer being more available to produce a therapeutic effect. 

Cromakalim (137) is a potassium channel activator commonly used as an antihypertensive agent (107). The rationale for the design of cromakalim is based on P-blockers such as propranolol (115) and atenolol (123). Conformational restriction of the propanolamine side chain as observed in the cromakalim chroman nucleus provides compounds with desired antihypertensive activity free of the side effects commonly associated with P-blockers. Enantiomerically pure cromakalim is produced by resolution of the diastereomeric (T)-a-meth5lben2ylcarbamate derivatives. X-ray crystallographic analysis of this diastereomer provides the absolute stereochemistry of cromakalim. Biological activity resides primarily in the (—)-(33, 4R)-enantiomer [94535-50-9] (137) (108). In spontaneously hypertensive rats, the (—)-(33, 4R)-enantiomer, at dosages of 0.3 mg/kg, lowers the systoHc pressure 47%, whereas the (+)-(3R,43)-enantiomer only decreases the systoHc pressure by 14% at a dose of 3.0 mg/kg. 

Antineoplastic Drugs. Cyclophosphamide (193) produces antineoplastic effects (see Chemotherapeutics, anticancer) via biochemical conversion to a highly reactive phosphoramide mustard (194) it is chiral owing to the tetrahedral phosphoms atom. The therapeutic index of the (3)-(-)-cyclophosphamide [50-18-0] (193) is twice that of the (+)-enantiomer due to increased antitumor activity the enantiomers are equally toxic (139). The effectiveness of the DNA intercalator dmgs adriamycin [57-22-7] (195) and daunomycin [20830-81-3] (196) is affected by changes in stereochemistry within the aglycon portions of these compounds. Inversion of the carbohydrate C-1 stereocenter provides compounds without activity. The carbohydrate C-4 epimer of adriamycin, epimbicin [56420-45-2] is as potent as its parent molecule, but is significandy less toxic (139). 

This chemical bond between the metal and the hydroxyl group of ahyl alcohol has an important effect on stereoselectivity. Asymmetric epoxidation is weU-known. The most stereoselective catalyst is Ti(OR) which is one of the early transition metal compounds and has no 0x0 group (28). Epoxidation of isopropylvinylcarbinol [4798-45-2] (1-isopropylaHyl alcohol) using a combined chiral catalyst of Ti(OR)4 and L-(+)-diethyl tartrate and (CH2)3COOH as the oxidant, stops at 50% conversion, and the erythro threo ratio of the product is 97 3. The reason for the reaction stopping at 50% conversion is that only one enantiomer can react and the unreacted enantiomer is recovered in optically pure form (28). 

In common with the naturally occurring carbapenem thienamycin (2), the introduction of the /n j -6-[l-(R)-hydroxyethyi] group had a profound effect on the biological properties of the penems. This, together with an indication from an early study (93) that, as with other P-lactams, the 5(R)-enantiomer was solely responsible for antibacterial activity, provided impetus for the development of methods for the synthesis of chiral penems. 

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