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A NONENZYMATIC ILLUSTRATION OF "CITRIC ACID TYPE" ASYMMETRY: THE MESO-CARBON ATOM

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New definitions of prochiral and of pseudoasymmetric elements have been proposed by Prelog and Helmchen [Helv. Chim. Acta55, 2581 (1972)]. The revised definition of prochiral centers would fail to identify many centers bearing like ligands that can be distinguished experimentally. The new definition of the pseudoasymmetric center would cause some that were previously so designated to be considered chiral. Whenever this occurs, concepts like retention and inversion of configuration would no longer have their customary meaning. Concomitant changes in the sequence subrules would not always provide reliable information about the possibilities of stereoisomerism. A modification of the rules is outlined which would avoid this, but secure similar benefits.
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1. The reaction of exo-cis-3,6-endoxo-Delta(4)-tetrahydrophthalic anhydride with amino groups of model compounds and lysozyme is described. 2. Reaction with the in-amino group of N(alpha)-acetyl-l-lysine amide gives rise to two diastereoisomeric products; at acid pH the free amino group is liberated with anchimeric assistance by the neighbouring protonated carboxyl group with a half-time of 4-5h at pH3.0 and 25 degrees C. 3. The amino groups of lysozyme can be completely blocked, with total loss of enzymic activity. Dialysis at pH3.0 results in complete recovery of the native primary and tertiary structure of lysozyme and complete return of catalytic activity. 4. The specificity of reaction of this and other anhydrides with amino groups in proteins is discussed.
Article
The auther has developed numerous new reactions utilizing sulfur-containing leaving groups and attempted to use them for the synthesis of biologically active natural products. As shown in Chart 2, the mode of elimination of the sulfur-containing leaving groups is classified into two types. In the first half of this review, a type 2 reaction, in which 3-acyl-1, 3-thiazolidine-2-thione is used as Y-[○!S]and an amine as the nucleophile, is outlined. In the latter half, its application is described. It is concerned with the total synthesis of macrocyclic spermidine alkaloids (codonocarpine, (±)-lunarine, and (±)-lunaridine), the peptide synthesis, the total synthesis of parabactin, a spermidine-containing siderophore, the synthesis of new hypoxic cell sensitizers, FNT-1 and FNT-2, and a new design for chiral induction to the prochiral a cyclic molecules.
Article
Constitutionally equivalent groups that occur in a single molecule are classified on the basis of their topic relationships by comparing their environments. The proposed classification extends earlier suggestions of Mislow and Raban. The existence of homotopic groups (those indistinguishable under any conditions) is related to the symmetry properties (gyrosymmetry) of rigid as well as flexible finite molecules. Stereoheterotopic groups (those that are distinguishable but occur in constitutionally equivalent environments) may be associated with various steric elements which will be fully discussed in a second paper. Each of these elements, the center, the axis, the plane and the torsional element, is divided into four mutually exclusive classes: the chiral and achiral elements of stereoisomerism; the prochiral and proachiral elements of prostereoisomerism. Of these classes, only the various centers of stereoisomerism and of prostereoisomerism are discussed in this report. Some modifications in our earlier proposals for the naming of individual stereoheterotopic groups are introduced. The utility of these new and revised terminologies for biochemical discussions is indicated.
Article
In biology, chiral recognition usually implies the ability of a protein, such as an enzyme or a drug receptor, to distinguish between the two enantiomeric forms of a chiral substrate or drug. Both diastereoisomerism and specific contacts between enzyme/receptor and substrate/drug are necessary. The minimum requirement is for four contact points including four nonplanar atoms (or groups of atoms) in both probe and target. The molecular models described by Easson and Stedman and by Ogston require three binding sites in a plane. A modified model with three binding sites in three dimensions is described. Under certain circumstances this model allows binding of both enantiomeric forms of a substrate or a drug. Enantiomer superposition of two enantiomers at an active site occurs in some specific cases (e.g., phenylalanine ammonia-lyase, isocitrate dehydrogenase) and is likely in others. The nature of enantiomer binding to racemase enzymes is discussed.
Article
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Article
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Article
The property of many enzymes to attack one of a pair of stereoisomers selectively, ‘stereochemical specificity’, has been known for many years. In 1925, Cushny 1) wrote ‘the reactions of the enzymes to optically active isomers have been the subject of a large number of researches’. In the latter half of the previous century, Pasteur had been impressed with the abundance of optically active compounds in nature. Subsequent work has demonstrated that the majority of chemical substances formed and broken down in metabolic processes are optically active.
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Some observations on the reactions within the tricarboxylic acid cycle ; involving the reversible formation of carbon--carbon unsaturations are reviewed, ; and the results of a study on an anaerobic exchange of deuterium from the medium ; into succinate, as catalyzed by heart particle succinic oxidase preparations, are ; discussed in terms of the stereochemistry of the succinic dehydrogenase reaction. ; The stereospecific nature of the reversible hydrations of fumarate and cis-; aconitate are described, and theoretical implications as regards the mechanism of ; the enzymatically catalyzed reactions are considered. Evidence is also presented ; that establishes the configuration of the product of the stereospecific enzymatic ; hydration of fumarate in Dâ0 in relation to the stereospecificity of the ; aconitase-catalyzed reaction. The consequences of the configurational ; interrelationship are shown to provide evidence for a trans fumarase-catalyzed ; addition reaction. (P. C. H.);
Article
The geometrical foundations of ‘pseudoasymmetry’ and several other related concepts of organic stereochemistry such as ‘prochirality’ and ‘propseudoasymmetry’ in two- and three-dimensional space have been explored. As a consequence some modifications of the R,S system for specification of molecular chirality and stereoisomerism are proposed.
Chapter
Intra- and intermolecular interactions involving the residual forces leading to the formation of bonds other than covalent ones are of paramount biological importance. If these residual forces did not exist no aggregate of organic molecules would appear, this means that at submicroscopic level a random mixture of molecules would exist; at microscopic level, well defined membrane structures would not appear; and at macroscopic level no beings like plant, bird or man would be born. Aspects of these interactions are discussed in respect to the structure of nucleic acids, to their replication, to the conformation of proteins and the regulation of their genesis and their function, to the cohesion of membrane structures, in a word in connection with many basic processes of life; the concept of complementarity governs the enzyme-sub strate interaction.
Chapter
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Chapter
The contributions of chemical methods and principles to the study of stereochemical problems in biology have, of course, been prodigious. They have ranged from determinations of configurations and conformations of many compounds, through syntheses of substrates and products, to studies of model compounds and reactions. An interesting development is that increasingly, biochemical methods are being applied in organic chemistry. It would be impossible to give a complete account of all of the chemical investigations in this chapter. This chapter attempts to cover some of the important work. In many investigations, chemical and biochemical methods have been used together. The terminology and nomenclature used in this chapter are those generally accepted.
Chapter
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Ogston's explanation for differentiation of identical groups in symmetrical compounds led to the important stereochemical concept of prochirality, which in turn, has made significant contributions to the understanding of enzyme reaction mechanisms.
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Article
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The decarboxylation-dehydration of 5-pyrophosphomevalonate to isopentenyl pyrophosphate (isopentenyl-PP) and the mechanism of the carbon to carbon bond formation between an allyl pyrophosphate (3,3-dimethylallyl or geranyl pyrophosphate) and isopentenyl-PP have been studied with the aid of two specimens of mevalonate labeled stereospecifically with deuterium at C-2 (2R-2D1-mevalonate and 2S-2D1-mevalonate). Preparation of these specimens from stereospecifically labeled 4D1-mevalonates by an interchange of the carboxyl and carbinol groups is described. Both of these substrates have been converted enzymically into isopentenyl-PP, and one of them, the 2R-2D1-mevalonate, has been converted into farnesyl pyrophosphate from which the free alcohols were isolated for chemical study. A chemical method has been evolved for the determination of the steric positions of hydrogen and deuterium attached to the terminal doubly bound methylene carbon atom of isopentenol. It was shown that the 2R-mevalonate gave cis-4D1-isopentenol and the 2S-mevalonate gave trans-4D1-isopentenol, indicating that the decarboxylation of 5-pyrophosphomevalonate was a trans elimination of the tertiary hydroxyl and of the carboxyl group. It was deduced from the steric position of deuterium at C-4 and C-8 of farnesol biosynthesized from 2R-2D1-mevalonate that the allyl pyrophosphate was added to C-4 of isopentenyl-PP from that side of the molecule on which the four substituents, —CH2CH2OPP, —CH3, —H, and —H, around the double bond of isopentenyl-PP appeared in a clockwise order. These observations, taken in conjuction with the authors' previous findings, show that there are probably two steps in the formation of the C—C bond between an allyl pyrophosphate and isopentenyl-PP. First the allyl residue and an as yet unidentified nucleophilic X group are added across the double bond in a trans manner; this is then followed by a trans elimination of X and of a proton from C-2 of isopentenyl-PP.
Article
Diamide 8, prepared by treatment of 3-methylglutaric acid (1) with 4(R)-MCTT (5) in the presence of DCC in pyridine, was subjected to aminolysis with 1 equiv of piperidine in CH 2Cl 2 at -30°C to give a mixture of diastereomers 9a and 10a in a 88:12 ratio. Compound 9a, separated by silica gel column chromatography, was treated with various nucleophiles to give optically pure bifunctional synthons 11a-k in high yields. Highly selective chiral induction into cis-4-cyclohexen-1,2-ylenebis(acetic acid) (4) was also performed. Aminolysis of 19 with 1 mol equiv of piperidine gave a mixture of 20 and 21 with 94% selectivity of the former. Similar chiral induction into cis-cyclohexan-1,2-ylenebis(acetic acid) (23) was tried. Aminolysis of its 4(R)-MCTT diamide (24) with piperidine gave 25 and 26 in a 89:11 ratio; the opposite selectivity was obtained with 19. The conformations of 19 and 24 in a solvent, the relationship between the susceptibility of their conformations and environmental temperature, and the diastereoselectivity of the reaction are discussed on the basis of the 400-MHz 1H NMR spectra.
Article
The R/S system of Cahn, Ingold, and Prelog for specifying absolute configurations is extended in two ways. I. The pro-R/pro-S System. Rules are provided for naming the paired ligands g,g at tetrahedral atoms Xggij, e.g., the two hydrogens at the methylene carbon of ethanol. A new geometrical concept, that of prochirality, is defined, and atoms of the type Xggij are said to be prochiral. The symbols used in naming the paired ligands are pro-R and pro-S or, in certain circumstances, pro-r and pro-s. II. The re/si System. Rules are provided for naming the two faces of a trigonal atom Yghi, e.g., the faces of the carbonyl carbon of acetaldehyde. The symbols used in naming the two faces are re and si. The naming of the two faces of isolated double bonds and mesomeric systems is also discussed. Examples are given of the way in which the R/S, pro-R/pro-S, and re/si systems, when used in conjunction with standard chemical nomenclature, may serve to transmit stereochemical information in a brief and unambiguous manner without the use of projection or structural formulas. The systems are of value in discussing the stereochemistry of enzyme reactions.
Article
Malate-synthase catalyzes an aldol condensation: The enzyme enolizes acetyl-CoA and hydrolyzes malyl-CoA. I. Acetyl-CoA-enolase, “monofunctional”. Enolization of acetyl-CoA by malate-synthase was demonstrated by isotopic-exchange between the methyl hydrogen of the acetyl group and tritiated water. [3H]Acetyl-CoA was determined as [3H] p-nitroacetanilide. Under optimal conditions, the rate of enolization was approximately a thousand times slower than that of the synthesis of malate. The isotopic exchange was dependent on high Mg++ and enzyme concentrations, pH and on long incubation times. Mg++ ions could be partially replaced by other divalent metal ions. The action of the metal ions is considered an acid catalysis, i.e. the thioester carbonyl when bound to the Lewis acid becomes polarized, the methyl hydrogen becomes acidic. The fact, that the related enzyme citrate-synthase required base-catalysis for the enolization of acetyl-CoA, suggested that a partial mechanism was demonstrated with each enzyme (acid- and base-catalysis) both of which are active cooperatively in both the enzymes. The chemical model of this cooperative action is the bifunctional catalyst of Swain and Brown. With malate-synthase it was therefore attempted to demonstrate the participation of the carboxylate anion of glyoxylate as a base-catalyst in the enolization of acetyl-CoA, using substrate-analogues of glyoxylate. II. Acetyl-CoA-enolase, “bifunctional”. α-Ketoacids stimulated the rate of enolization in the order pyruvate > oxalacetate ≫α-ketobutyrate > α-ketoglutarate ≅α-ketovalerate, i.e. the more, the greater the structural similarity to glyoxylate. Other carboxylic acids were inactive. Tritio-acetyl-CoA-yielding side reactions were excluded. Pyruvate inhibited the synthesis of malate competitively (Ki= 10−3 M). The affinity of pyruvate for the enzyme yielded ordinary kinetics (Km= 10−3 M) as determined by the isotopic-exchange. No sign of aggregation or dissociation of the enzyme was detectable, as judged from sedimentation studies with and without acetyl-CoA and pyruvate. Taken together these results exclude an allosteric action of the α-ketoacids and agree with their action as base-catalysts. The fact, that citramalyl-CoA, the condensation product of acetyl-CoA and pyruvate, was not attacked by the enzyme, suggested that only the carboxylate anion of the α-ketoacids participated in the enolization. Due to steric hindrance at the active site, the ketocarbonyl of these acids is in a position too far removed for reaction with the acetyl-CoA carbanion formed. The α-ketoacids therefore induce the isotopic exchange. The rate of enolization in the presence of pyruvate was stimulated a thousand times and was nearly equal to that of the synthesis of malate. As in the chemical model both the nucleophilic and the electrophilic groups act cooperatively: removal of either Mg++ or pyruvate abolished the enolization. Taken all together, these results provide proof for the participation of the carboxylate anion of glyoxylate in the enolization of acetyl-CoA in the natural system. III. Malyl-CoA-hydrolase. A coupled optical test was used for the enzymatic hydrolysis of malyl-CoA, in which the hydrolysis of the substrate with the subsequent oxidation of CoA-SH by ferricyanide was determined from the decrease of absorption. Both the affinity and turnover number of malyl-CoA when used as a substrate, were approximately 10−3 times less than those of the natural reactants. This is in agreement with the existence of enzyme bound malyl-CoA in the natural system. The enzyme required Mg++ and catalyzed the hydrolysis of (S)-malyl-CoA faster than that of the diastereomeric mixture and of the (R)-diastereomer. IV. Rate Determining Step. Malate, when synthesized in tritiated water in the absence of pyruvate contained no tritium; acetyl-CoA after partial reaction with glyoxylate remained unlabelled: the enolization of acetyl-CoA is the rate-determining step in the synthesis of malate. V. Equivalence of the Methyl Hydrogens in Enolization and Synthesis. In the equilibium of the isotopic exchange, the specific (sA) acitivity of p-nitroacetanilide, corrected for losses during its isolation, corresponded to sA (acetyl-CoA) = 0.94 × sA(H2O). Theoretically it should be sA (acetyl-CoA) = 3/2 sA(H2O) without mass effect, since the methyl hydrogens are chemically equivalent. The value obtained experimentally may reflect a thermodynamic isotopic effect and may also indicate stereospecific exchange of two methyl hydrogens with tritium. The latter was excluded by using chemically prepared [3H-2C]acetyl-CoA, which, in the presence of pyruvate and malate- synthase in water lost its tritium content completely. [3H]malate, synthesized enzymatically from either chemically or enzymatically prepared tritio-acetyl-CoA was recognized as (S)-2- hydroxy-3,3-ditritio-succinate by the isotopic exchange catalyzed by fumarase. As expected, the methyl hydrogens of the acetyl group are thus equivalent in the reaction with either pyruvate for the enolization, or glyoxylate for the enolization and subsequent synthesis of malate. VI. Principle of Catalysis. The following results illustrate that the principle of catalysis is the approximation of the reactants: The facts, that Mg++ was required for the enolization of acetyl-CoA as well as for the hydrolysis of malyl-CoA, and that the enolization was abolished when either acid- or base-catalyst was removed, indicate the formation of a complex between Mg++ and the substrates on the enzyme. In this complex the reactants with both their carbonyls are coordinatively bound to the Lewis acid and then by a forced intramolecular reaction are converted to the products. VII. Related Enzyme Catalyses. In the related catalyses the Mg++ may be replaced by a Lewis acid constituitively present in the protein, and the ketoacid may be arranged sterically opposite to the position of either glyoxylate on malate-synthase or oxalacetate on citrate-synthase. The carbonyl group is then attacked from the R-side by the acetyl-CoA-carbanion and the (R)-hydroxyacid is formed as the product. acetyl-CoA.
Chapter
IntroductionBiological Formation of Carbonyl GroupsBiological Reactions of Carbonyl GroupsReferences
Chapter
Development of efficient methodology to produce an optically pure enantiomer is of fundamental importance, particularly for the synthesis of biologically active natural products. Optically active compounds can be obtained by three different approaches, that is, resolution of racemates, use of a chiral pool or “chiron” (which are enantiomerically pure synthons), or asymmetric synthesis. Of these, one of the more challenging tasks involves asymmetric synthesis, which may be carried out either enzymatically or nonenzymatically. Whereas the nonenzymatic method enables us to introduce a chiral center with either a stoichiometric or catalytic amount of a chiral compound, the enzymatic method uses biological systems, such as microorganisms or isolated enzymes, to create the center of asymmetry. The purpose of this chapter is to survey asymmetric synthesis via the production of enantiomerically pure or enriched organic molecules by the enzymatic method focusing on the use of a hydrolytic enzyme, pig liver esterase (PLE; Enzyme Commission classification number, E.C. 3.1.1.1).
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