Computational investigations on the general reaction profile and diastereoselectivity in sulfur ylide promoted aziridination

Mechanism and diastereoselectivity of sulfur ylide promoted aziridination reactions were studied by density functional theory with inclusion of solvent effects through the continuum solvation model. The general reaction pathway was modeled for the addition of substituted sulfur ylides (Me(2)S(+)CH(-)R) to an aldimine ((E)-methyl ethylidenecarbamate, MeHC=NCO(2)Me). The nature of the substituents on the ylidic carbon atom substantially affects the reaction profile. The stabilized (R=COMe) and semistabilized (R=Ph) ylides follow a cisoid addition mode leading to trans aziridines via anti betaine intermediates. The simplest model ylide (unstabilized, R=H) underwent cisoid addition in a similar fashion. In the case of stabilized ylides product diastereoselectivity is controlled by the barriers of the elimination step leading to the 2,3-trans aziridine, whereas it is decided in the addition step in the case of semistabilized ylides. The importance of steric and electronic factors in diastereoselective addition (2 and 5) and elimination (5) transition states was established. Comparison of results obtained with the gas-phase optimized geometries and with the fully optimized solvent-phase geometries reveals that the inclusion of solvent effects does not bring about any dramatic changes in the reaction profiles for all three kinds of ylides. In particular, diastereoselectivity for both kinds of ylides was found to be nearly the same in both these approaches.     

Density functional theory investigations on sulfur ylide promoted cyclopropanation reactions: insights on mechanism and diastereoselection issues

The mechanism and diastereoselectivity of synthetically useful sulfur ylide promoted cyclopropanation reactions have been studied using the density functional theory method. Addition of different substituted ylides (Me2S+CH-R) to enone ((E)-pent-3-en-2-one, MeHC=CH-COMe) has been investigated. The nature of the substituent on the ylidic carbon brings about subtle changes in the reaction profile. The stabilized (R=COMe) and semistabilized (R=Ph) ylides follow a cisoid addition mode, leading to 1,2-trans and 1,2-cis cyclopropanes, respectively, via syn and anti betaine intermediates. The simplest and highly reactive model ylide (R=H) prefers a transoid addition mode. Diastereoselectivity is controlled by the barrier for cisoid-transoid rotation in the case of stabilized ylides, whereas the initial electrophilic addition is found to be the diastereoselectivity-determining step for semistabilized ylides. High selectivity toward trans cyclopropanes with stabilized ylides are predicted on the basis of the relative activation energies of diastereomeric torsional transition states. The energy differences between these transition states could be rationalized with the help of weak intramolecular as well as other stereoelectronic interactions.     

Reactivity and selectivity in the Wittig reaction: a computational study

The salt-free Wittig reaction of non-, semi-, and stabilized ylides has been investigated on realistic systems using density functional theory (DFT) calculations, including continuum solvation. Our results provide unequivocal support for the generally accepted mechanism and are in very good agreement with experimental selectivities. This study shows that E/Z selectivity of non- and semi-stabilized ylides cannot be fully understood without considering the energy of the elimination TS. The influence of ylide stabilization and the nature of phosphorus substituents on reversibility of oxaphosphetane formation is clarified. Unexpectedly, the puckering ability of addition TSs is shown not to depend on ylide stabilization, but the geometry of the TS is decided by an interplay of 1,2; 1,3; and C-H...O interactions in the case of non- and semi-stabilized ylides, whereas a dipole-dipole interaction governs the addition TS structures for stabilized ylides. The well-known influence of ylide stabilization on selectivity of PPh(3) derivatives is explained as follows: in non- and semi-stabilized ylides reactions, cis and trans addition TSs have, respectively, puckered and planar geometries, and selectivity is governed by an interplay of 1,2 and 1,3 interactions. For stabilized ylides, the high E selectivity is due to a strong dipole-dipole interaction at the addition TS. The influence of the nature of phosphorus substituents on selectivity is also detailed, the different behavior of (MeO)(3)PCHCO(2)Me ylides being explained by their lower dipole. This novel picture of the factors determining TS structures and selectivity provides a sound basis for the design of new ylides.     

Enantio- and diastereoselectivities in chiral sulfur ylide promoted asymmetric aziridination reactions

Density functional theory investigation on the factors controlling enantio- and diastereoselection in asymmetric aziridination reaction by the addition of chiral bicyclic sulfur ylides to substituted aldimines is presented. High levels of enantioselection are predicted toward the formation of (2S,3S)-cis and (2R,3S)-trans aziridines by the addition of stabilized ylide (R = COMe) respectively to SO2Me and CO2Me protected aldimines. Similarly, high %ee is predicted for the formation of (2S,3R)-cis aziridines from semistabilized (R = Ph) ylide. Moderate to high levels of diastereoselectivity is noticed as well. The present study highlights that a correct prediction on extent of enantioselection requires the knowledge of the activation barriers for elementary steps beyond the initial addition step. In the case of stabilized ylides the ring-closure (or elimination of sulfur compound) is found to be crucial in controlling enantio- and diastereoselection. A cumulative effect of electronic as well as other weak interactions is identified as factors contributing to the relative energies of transition states leading to enantio- and diastereomeric products for the stabilized ylide addition to aldimines. On the contrary, steric control appears quite dominant with semistabilized ylide addition. With the smallest substituent on ylide (R = Me), high enantioselectivity is predicted for the formation of (2R,3R)-trans aziridines although the %de in this case is found to be very low.     

Selectivity guidelines and a reductive elimination-based model for predicting the stereochemical course of conjugate addition reactions of organocuprates to gamma-alkoxy-alpha,beta-enoates

Current models used to predict the stereochemical outcome of organocopper conjugate addition processes focus on the nucleophilic addition step as stereochemistry-determining. Recent kinetic, NMR, kinetic isotope effect, and theoretical density functional studies strongly support the proposal that stereochemical preferences in these processes are dictated by the reductive elimination step, transforming Cu(III) to Cu(I) intermediates. A new model that considers various steric and stereoelectronic factors involved in the transition state of the reductive elimination step is proposed and then used to interpret the results of systematic studies of arylcuprate conjugate addition reactions with cis and trans gamma-alkoxy-alpha,beta-enoates. The results give rise to the following selectivity guidelines for this process. To achieve high anti-addition diastereoselectivities the use of trans esters with a bulky nonalkoxy substituent at the gamma-position is recommended. While stereoelectronics disfavor syn-addition, a judicious choice of properly sized gamma-substituents may lead to the predominant formation of syn-products, especially with cis enoates. However, high syn-selectivities may be achieved by using gamma-amino-alpha,beta-enoates.     

Sulfur Ylide Promoted Synthesis of N‐Protected Aziridines: A Combined Experimental and Computational Approach

A range of N‐protected aziridines [N‐Tosyl (N‐Ts), N‐2‐trimethylsilylethanesulfonamide (N‐SES), N‐tert‐butoxycarbonylamido (N‐Boc), and N‐o‐nitrobenzenesulfonamide (oNs)] were prepared in moderate to good yield and with high enantiomeric excess of both isomers starting from N‐protected imines, using a sulfonium salt derived from Eliel’s oxathiane. The diastereoselectivities of the reactions are influenced by the imine N‐protecting group, the imine substituent, and the sulfide structure. An unusual cis selectivity was observed in the formation of N‐tosyl‐2‐phenyl‐3‐tert‐butylaziridine and N‐o‐trimethylsilylethanesulfonamide‐2‐phenyl‐3‐tert‐butylaziridine, which was explained by using computational models. The analysis suggests that betaine formation in the case of N‐tosyl‐tert‐butylaldimine aziridination using oxathiane benzyl sulfonium ylide 1 ′ is reversible and that the selectivity is determined at the rotation step, which is unusual for semistabilized ylide aziridination. We have shown herein that the steric bulk of an imine substituent, in combination with a sterically demanding sulfonium ylide, can also affect the reversibility of the reaction. This is the first example of this sort involving aziridinations using semistabilized ylides.     

On the origin of high E selectivity in the Wittig reaction of stabilized ylides: importance of dipole-dipole interactions

The salt-free Wittig reaction of stabilized ylides Ph3PCHCO2Me 1 and (MeO)3PCHCO2Me 2 has been investigated using DFT method including solvation. This analysis shows that TS structures and E/Z selectivity in the phosphine stabilized ylide 1, which gives high E selectivity with PhCHO, are predominantly controlled by a dipole-dipole interaction between the two reactants at the TS (as well as the well-known 1,2 and 1,3 steric interactions). The surprisingly different behavior of the phosphite ylide 2, which gives only 69:31 E/Z ratio with PhCHO, is accounted for by its much smaller overall dipole. The introduction of this new parameter (dipole-dipole interactions), which has not previously been invoked in discussions of this important reaction, accommodates all the experimental observations relating to selectivity in the Wittig reaction of stabilized ylides under salt-free conditions.     

Highly enantioselective synthesis of glycidic amides using camphor-derived sulfonium salts. Mechanism and applications in synthesis

The reactions of a range of amide-stabilized sulfur ylides derived from readily available camphor-derived sulfonium salts for the synthesis of glycidic amides have been studied. Primary, secondary, and tertiary amides were tested, and it was found that the highest enantioselectivities were observed with tertiary amides, which provided glycidic amides in good to excellent yields, exclusive trans selectivity, and excellent enantioselectivities. The reaction was general for aromatic aldehydes, but aliphatic aldehydes gave more variable enantioselectivities. The epoxy amides could be converted cleanly into epoxy ketones by treatment with organolithium reagents. We were also able to effect selective ring opening of the epoxy amides with a variety of nucleophiles, followed by hydrolysis of the amide to yield the corresponding carboxylic acid. This methodology was applied to the total synthesis of the target compound SK&F 104353. A combination of crossover experiments and theoretical calculations has revealed that the rate- and selectivity-determining step is ring closure, not betaine formation as was the case for phenyl-stabilized ylides.     

A new route to diastereomerically pure cyclopropanes utilizing stabilized phosphorus ylides and gamma-hydroxy enones derived from 1, 2-dioxines: mechanistic investigations and scope of reaction

A new chemical transformation for the construction of diversely functionalized cyclopropanes utilizing 1,2-dioxines and stabilized phosphorus ylides as the key precursors is presented. Through a series of mechanistic studies we have elucidated a clear understanding of the hitherto unknown complex relationship between 1, 2-dioxines 1a-e, and their isomeric cis/trans gamma-hydroxy enones (23 and 21a-e), cis/trans hemiacetals 24a-e, and beta-ketoepoxides (e.g., 26), and how these precursors can be utilized to construct diversely functionalized cyclopropanes. Furthermore, several new synthetically useful routes to these structural isomers are presented. Key features of the cyclopropanation include the ylide acting as a mild base inducing the ring opening of the 1,2-dioxines to their isomeric cis gamma-hydroxy enones 23a-e, followed by Michael addition of the ylide to the cis gamma-hydroxy enones 23a-e and attachment of the electrophilic phosphorus pole of the ylide to the hydroxyl moiety, affording the intermediate 1-2lambda(5)-oxaphospholanes 4 and setting up the observed cis stereochemistry between H1 and H3. Cyclization of the resultant enolate (30a or 30b), expulsion of triphenylphosphine oxide, and proton transfer from the reaction manifold affords the observed cyclopropanes in excellent diastereomeric excess. The utilization of Co(SALEN)(2) in a catalytic manner also allows for a dramatic acceleration of reaction rates when entering the reaction manifold from the 1,2-dioxines. While cyclopropanation is favored by the use of ester-stabilized ylides, the use of keto- or aldo-stabilized ylides results in a preference for 1,4-dicarbonyl formation through a competing Kornblum-De La Mare rearrangement of the intermediate hemiacetals. This finding can be attributed to subtle differences in ylide basicity/nucleophilicity. In addition, the use of doubly substituted ester ylides allows for the incorporation of another stereogenic center within the side chain. Finally, our studies have revealed that the isomeric trans gamma-hydroxy enones and the beta-keto epoxides are not involved in the cyclopropanation process; however, they do represent an alternative entry point into this reaction manifold.     

Unraveling the mechanism of epoxide formation from sulfur ylides and aldehydes

Sulfur ylides R(2)S(+)-C(-)HR' react with aldehydes R' '-CHO to form epoxides, predominantly as the trans isomers, in a synthetically useful reaction which is increasingly used in its asymmetric variant with chiral sulfides. The mechanisms of the "model" reaction (R = Me, R' = R' ' = H) and the reaction forming stilbene oxide (R = Me, R' = R' ' = Ph) have been studied in detail using density functional theory, the B3LYP density functional, and flexible basis sets. It has been shown that for this reaction involving highly polar intermediates, continuum solvation models need to be used throughout to obtain reasonable results. For the reaction of benzaldehyde with dimethylsulfonium benzylide, the key steps are shown to be quasi [2 + 2] addition of the ylide to the aldehyde to form a betaine R'-CH(S(+)Me(2))-CH(O(-))-R' ' in which the charged groups are gauche to one another, and torsional rotation around the C-C single bond of the betaine to form its rotamer with the two charged groups anti. The final step, elimination of sulfide from this second rotamer of the betaine, is found to be facile. In the case of the anti pathway, leading to trans-stilbene epoxide, the initial addition is found to be rate-determining, whereas for the diastereomeric syn pathway, leading to the cis-epoxide, it is instead the torsional rotation which is slowest. These results are in excellent agreement with experiment, unlike previous computational work. The unexpected and apparently unprecedented (for C-C bond-forming reactions) importance of the torsional rotation step, especially in the syn case, is due to the fact that all the barriers involved are low-lying. This novel picture of the mechanism provides a sound basis for the future development of chiral sulfides for enantioselective epoxide synthesis.     

The complexity of catalysis: origins of enantio- and diastereocontrol in sulfur ylide mediated epoxidation reactions

The reaction of chiral sulfur ylides with aldehydes and ketones has emerged as a useful asymmetric process for the synthesis of epoxides. Processes employing either catalytic or stoichiometric amounts of sulfides have been developed. Although a large number of chiral sulfur ylides have been tested in the epoxidation process, only a few have delivered high diastereo- and enantio- selectivity. This review examines the factors that influence stereocontrol (steric hindrance of the sulfide, ylide conformation, ylide face selectivity, reversibility of betaine formation, solvent, and metal salts). This analysis leads to the conclusion that high reversibility in betaine formation leads to high diastereoselectivity but low enantioselectivity, and non-reversible betaine formation leads to low diastereoselectivity and high enantioselectivity (provided that other criteria are met). To achieve both high diastereoselectivity and high enantioselectivity simultaneously, requires non-reversible formation of the anti-betaine and reversible formation of the syn-betaine. Thus, factors that influence the degree of reversibility in betaine formation are critically important since with subtle changes in reaction conditions (solvent, temperature, metal ions) both high enantio- and diastereoselectivity can often be achieved.     

Aminals as substrates for sulfur ylides: a synthesis of functionalized aziridines and N-heterocycles

Sulfur ylides stabilized by Ar, vinyl, or amide groups react with five-membered-ring tert-butylsulfinyl aminals to give functionalized chiral, nonracemic aziridines in high yield and with good selectivities (up to 15:1 trans:cis, up to >95:5 trans dr, always >95:5 cis dr). The intermediate aziridines can be converted into pyrrolidines or piperidines depending on the reaction conditions.     

Carboxylate-stabilised sulfur ylides (thetin salts) in asymmetric epoxidation for the synthesis of glycidic acids. Mechanism and implications

The reaction of carboxylate-stabilised sulfur ylides (thetin salts) with aldehydes and ketones has been investigated. Using both achiral and chiral sulfur ylides, good yields were obtained with dimsylsodium or LHMDS as bases in DMSO or THF-DMSO mixtures. However, the enantioselectivities observed with a camphor-based sulfide were only moderate (up to 67%). The reaction was studied mechanistically by independent generation of the betaine (via the hydroxyl sulfonium salt) in the presence of a more reactive aldehyde, which resulted in incorporation of the more reactive aldehyde and showed that betaine formation was reversible. Thus, the moderate enantiomeric excess observed is a consequence of the enantiodifferentiating step being the ring closure step rather than the betaine forming step. We had expected betaine formation might be non-reversible because a carboxylate-stabilised ylide has only slightly higher stability than a phenyl-stabilised ylide, which does largely react non-reversibly with aldehydes. Evidently, a carboxylate-stabilised ylide is significantly more stable than a phenyl-stabilised ylide and as such reacts reversibly with aldehydes.     

Selectivity in platinum-catalyzed cis-trans carbon-carbon double-bond isomerization

The isomerization of trans-2-butene to its cis conformer was found to be easier on Pt111 surfaces than the opposite cis to trans conversion. This kinetic trend, which is opposite to what would be expected on thermodynamic grounds, is explained by an increased stability of the cis isomer upon adsorption. A model where adsorption energies are affected by steric interactions between the side moieties of the olefin and the surface suggests that selectivity toward cis versus trans formation may be manipulated by controlling the structure of the surface of the catalyst.     

Wittig Reaction: Role of Steric Effects in Explaining the Prevalent Formation of Z Olefin from Nonstabilized Ylides

Abstract

For understanding the mechanism involved in the Wittig reaction, it is important to know the factors which influence the stability of 1,2-oxaphosphetane intermediates with pentacoordinate phosphorus; in these intermediates, the steric factor plays a predominant role. Studying the Wittig reaction between nonstabilized ylides and different aldehydes, we noted that the stereochemical outcome driving toward Z-olefin formation was influenced only by different steric factors. The proposed mechanism differs from those previously reported because it underlines the fundamental role of the two cis/trans oxaphosphetane intermediates with the oxygen atom in equatorial position.     

Detection and Reaction of Oxaphosphetanes Derived from Benzaldehyde and 1-Adamantylmethylidene Ylide

The Wittig reaction of (1-adamantylmethylidene)triphenylphosphorane (Ph(3)P=CH(1-Ad)) with benzaldehyde was investigated, and the results were compared with those of other ylides. The substituent effect in the reaction of the ylide with benzaldehydes was determined by competition experiments, which gave a Hammett rho value of 3.2. The rho value is much larger than those reported for analogous reactions of Ph(3)P=CH(CH(2))(2)CH(3) (rho = 0.20) and Ph(3)P=CH(CH(3))(2) (rho = 0.59), indicating that the reaction mechanism differs for Ph(3)P=CH(1-Ad) and the other ylides. The cis/trans ratio of the product alkene is 74/26 for the reaction with the parent benzaldehyde and highly depends on the position of the substituent; ortho substituted benzaldehydes gave the trans alkenes up to 90%. Monitoring the reaction by means of (31)P NMR revealed that both cis and trans oxaphosphetane intermediates were formed and that the formation and decomposition of the cis oxaphosphetane are 7-12 times faster than those of the trans oxaphosphetane. From the comparison of the reaction of Ph(3)P=CH(1-Ad) + benzaldehyde with those of Ph(3)P=CH(CH(2))(2)CH(3) + benzaldehyde and benzophenone, and Ph(3)P=CH(CH(3))(2) + benzophenone, it was concluded that all the reactions with these nonstabilized ylides proceed via an electron-transfer mechanism and that the rate-determining step changes from the electron transfer step to that of radical combination when the substrate or ylide becomes more sterically demanding.     

Scope and limitations of cyclopropanations with sulfur ylides

The rates of the reactions of the stabilized and semistabilized sulfur ylides 1a-g with benzhydrylium ions (2a-e) and Michael acceptors (2f-v) have been determined by UV-vis spectroscopy in DMSO at 20 °C. The second-order rate constants (log k(2)) of these reactions correlate linearly with the electrophilicity parameters E of the electrophiles 2 as required by the correlation log k(2) = s(N + E), which allowed us to calculate the nucleophile-specific parameters N and s for the sulfur ylides 1a-g. The rate constants for the cyclopropanation reactions of sulfur ylides with Michael acceptors lie on the same correlation line as the rate constants for the reactions of sulfur ylides with carbocations. This observation is in line with a stepwise mechanism for the cyclopropanation reactions in which the first step, nucleophilic attack of the sulfur ylides at the Michael acceptors, is rate determining. As the few known pK(aH) values for sulfur ylides correlate poorly with their nucleophilic reactivities, the data reported in this work provide the first quantitative approach to sulfur ylide reactivity.     

Reagent controlled addition of chiral sulfur ylides to chiral aldehydes

The degree of reagent and substrate control in the reaction of chiral sulfur ylides with chiral aldehydes has been investigated. Specifically, the reactions of the two enantiomers of the chiral benzyl sulfonium salt 1 with glyceraldehyde acetonide were studied in detail. Of the two new stereogenic centers created, it was found that the C1 stereochemistry was largely controlled by the reagent, whereas control at the C2 center was dependent on the aldehyde used. In one case, the trans isomer was produced via reversible formation of the intermediate betaine, whereas in the alternative case, the C2 center was under Felkin Anh/Cornforth control through non-reversible formation of the betaine. Thus, the aldehyde stereocenter influenced the degree of reversibility in betaine formation, which impacted on the stereocontrol at the C2 position.     

A concise synthesis of substituted stilbenes and styrenes from propargylic phosphonium salts by a cobalt-catalyzed Diels-Alder/Wittig olefination reaction sequence

The cobalt(I)-catalyzed Diels-Alder reaction of propargylic phosphonium salts and longer chained alkyne-functionalized phosphonium salts with 1,3-dienes led to dihydroaromatic phosphonium salt intermediates which were directly used in a one-pot Wittig-type olefination reaction with aldehydes. Subsequent oxidation led to styrene- and stilbene-type products under formation of three new carbon-carbon bonds in a single synthetical step starting from three variable starting materials. The E/Z stereoselectivities of the products revealed that the dihydroaromatic phosphonium ylides behave as semistabilized ylides giving predominantly the E-configured products. The application of unsymmetrical 1,3-dienes as well as internal phosphonium functionalized alkynes is also described.     

The mechanism of cis-trans isomerization of prolyl peptides by cyclophilin

The mechanism of cis-trans isomerization of prolyl peptides catalyzed by cyclophilin (CyP) was studied computationally via molecular dynamics (MD) simulations of the transition state (TS) and the cis and trans forms of the ground state (GS), when bound to CyP and when free in aqueous solution. The MD simulations include four enzyme-bound species of tetrapeptide (Suc-Ala-XC([double bond]O)-NPro-Phe-pNA; X = Gly, Trp, Ala, and Leu). In water, the prolyl amide bond is favorably planar with the presence of conformers exhibiting +/-20 degrees twist of the C-N dihedral. In the active site a hydrogen bond between the cis-prolyl amide carbonyl O and the backbone amide N-H of Asn102 retains the 20 degrees twist of the C-N dihedral. The TS structure is characterized by a 90 degrees twist of the amide C-N bond and a more favorable interaction with Asn102 due to the shorter distance between Asn102(HN) and the amide carbonyl O. The conformational change of cis --> TS also involves pyramidalization of the amide N, which results in the formation of a hydrogen bond between the amide N and the guanidino group of Arg55. Both Asn102 and Arg55 are held in the same position in CyP.cis-isomer as in CyP.TS. In the ligand-free CyP the Arg55 guanidino group is highly disorganized and Asn102 is displaced 1 A from the position in the ligand-bound CyP. Thus, the organization of Arg55 and Asn102 occurs upon substrate binding. The geometrical complimentarity of the organized enzyme structure to the TS structure is a result of preferential binding of the proline N and the amide carbonyl of the TS compared to that of GS. However, the N-terminal part (Suc-Ala) becomes repositioned in the TS such that two hydrogen bonds disappear, one hydrogen bond appears and two other hydrogen bonds becomes weaker on the conversion of CyP.cis to CyP.TS. During this conversion, total hydrophobic contact between enzyme and the peptide is preserved. Thus, the interaction energies of GS and TS with enzyme are, as a whole, much alike. This does not support the contention that TS is bound more tightly than GS by K(m)/K(TS) = 10(6) in the cis --> trans reaction. Repositioning of the N-terminal part of the peptide on CyP.TS formation becomes more pronounced when the substrate X residue is changed from Gly < Trp < Ala < Leu. We propose that the larger turning of the N-terminus is responsible for the larger value of the experimentally observed Delta S(++) and Delta H(++), which sum up to little change in Delta G(++). The positioning of the Arg55 and the degree of 20 degrees twist of the amide C-N bond are considered as criteria for Near Attack Conformers (NACs) in cis-trans isomerization. NACs account for approximately 30% of the total GS populations of the cis-isomer. Similar NAC populations were observed with four different substrates. This is consistent with the insensitivity of enzymatic activity to the nature of the X residue. Also, the NAC population in CyP.trans-AAPF was comparable to that in CyP.cis-AAPF, in accord with similar experimentally measured rates of the cis --> trans and trans --> cis reaction in CyP. These NACs, found in CyP.cis and CyP.trans, resemble only one of the four possible TS configurations in the water reaction. The identity of this TS structure (syn/exo) is in accord with experimentally determined KIE values in the enzymatic reaction. However, the geometry of the active site was also complementary to another TS structure (anti/exo) that was not detected in the active site by the same KIE measurements, implying that the geometrical fitness of the TS cannot be a single determining factor for enzymatic reactions.