Transition-state structures rationalization

Conformational analysis using the Sybyl 6.8 program was performed on the proposed transition state structure of the pyrazino[2,l-A [l,3]thiazine 288 (R =Me, R2 = H, R3 = Arg-Trp-NH2) formed by solid-phase synthesis, to rationalize the stereochemical outcome of the ring formation <2004TL6333>. 

A reaction in which an electrophile participates in het-erolytic substitution of another molecular entity that supplies both of the bonding electrons. In the case of aromatic electrophilic substitution (AES), one electrophile (typically a proton) is substituted by another electron-deficient species. AES reactions include halogenation (which is often catalyzed by the presence of a Lewis acid salt such as ferric chloride or aluminum chloride), nitration, and so-called Friedel-Crafts acylation and alkylation reactions. On the basis of the extensive literature on AES reactions, one can readily rationalize how this process leads to the synthesis of many substituted aromatic compounds. This is accomplished by considering how the transition states structurally resemble the carbonium ion intermediates in an AES reaction. 

The computed transition state also rationalizes the observed stereochemistry. For the current reactions, a transition structure represented in Figure 31 appears to be appropriate. This structure indicates that the three substituents R and R are all equatorial and give rise to the anti product. The corresponding syn product would require a highly strained structure in which one R group is axial. 

Each of the following cycloaddition reactions exhibits a good degree of diastereo-selectivity. Provide a rationalization of the observed diastereoselectivity in terms of a preferred transition-state structure. 

A double ir-face selective aptotic Michael addition of the lithium dienolate, derived from the chiral senecioate (119), to cyclopentenone served for the total synthesis of (-)-kushimone (120 Scheme 45).137-138 The selectivity of the key reaction was rationalized by the assumption of a transition state as shown in (121a). A related approach involves the Michael addition of enolates, derived from chiral propionates, to methyl ( )-crotonate (Scheme 46).139 The formation of the threo isomer (122) as the major product indicates a transition state structure as shown in (121b). This method was utilized in the synthesis of the marine natural product 7,20-diisocyanoadociane (123 Scheme 47).140... 

Direct observation of complex in the a-deprotonation of N,N-dimethylbenzamide and kinetic studies are interpreted in terms of a tetrameric cube-like transition state structure typical of solid-state RLi structures in which ligands bound to the Li centers facilitate the release of the a-carbanion species. The continuing existence of the RLi tetramer on addition of TMEDA contrasts with the dogma that this additive breaks up aggregates and is rationalized by TMEDA advancing the formation of the a-carbanion in the transition state analogous to the effect of the R carbanion character in the tetramer. 

Jencks (1972, 1969b) has proposed a model which maintains the significance of a as a measure of transition state structure and yet provides a very elegant rationalization of the fact that linear Br nsted plots are often obtained over large reactivity ranges, both by variation in catalyst pKa and substrate reactivity. Jencks noted that the acid catalysed nucleophilic addition to carbonyl compounds (21) yielded linear Br nsted plots (in apparent violation of the reactivity-selectivity principle) yet as the basicity of the nucleophile N was increased the Br nsted slope decreased (in agreement with the... 

The clearest example of the danger in using a as a measure of transition state structure is illustrated in the work of Bordwell et al. (1969, 1970, 1975). In the rate-equilibrium relationship for the deprotonation of a series of nitroalkanes the unprecedented Br nsted slopes of 1 61 for l-aryl-2-nitropropanes and 1-37 for 1-arylnitro-ethanes were obtained. The simple exposition of the mechanistic significance of a disallows values greater than 1. This, coupled with the fact that the transition state for the proton transfer is not product-like (as established by alternative criteria) indicates at best that, in at least some cases, a does not reflect the selectivity of a particular reaction. Several attempts to rationalize these anomalous results have been made. 

The aldol reactions of the titanium Z-enolates proceeded smoothly with various aldehydes precomplexed with titanium chloride at -78° C. The diastereose-lectivity is high to excellent, with the single exception of benzaldehyde. The high degree of diastereoselection associated with this current asymmetric anti-aldol process can be rationalized by a Zimmerman-Traxler type of six-membered chairlike transition state Al9fl (Scheme 2.2r). The model is based on the assumptions that the titanium enolate is a seven-membered metallocycle with a chairlike conformation, and a second titanium metal is involved in the transition state, where it is chelated to indanolyloxy oxygen as well as to the aldehyde carbonyl in a six-membered chairlike transition-state structure. 

To probe the transition state structure for these reactions further, the effect of para substituents on amide rotation rates was measured for a series of N,Af-dimethylbenzamides (Berarek, 1973). When the data are correlated with cTp (Ritchie and Sager, 1964), a p value of —1.14 0.06 is obtained (see Fig. 2). The negative p value indicates that electron-donating substituents accelerate the reaction. This can rationalized in the context of Scheme III, where resonance forms for these substrates are shown. The rotational barrier about the C—N bond is decreased as resonance forms I and III predominate. If R is electron donating, these resonance forms will contribute more to the structure of the amide than will II and C-N rotation will therefore be accelerated. 

The stereochemical outcome of this new annulation process can be rationalized by assuming the transition state structure 10. The synclinal arrangement of the respective hydrogen atoms exclusively gives the all-cw-annulation product 9a. 

The model correctly predicts (rationalizes) the observed preference for formation of Ae anti raAer than Ae syn product in the cycloaddition reactions of a wide variety of chiral allylic eAers, Aus successfully laying to rest years of frustrated discussion. - It also correctly predicts Aat as Ae size of R increases (Me - Ph < Et < Pr < Bu ), Ae preference for transition state structure (18 ) should increase leading to enhanced anti stereoselectivity (Table 15). At first, Ais prediction seems strange. However, once it is realized Aat, like Ae Felkin-Anh model for nucleophilic addition to a carbonyl, Ae outside position is actually more sterically demanAng Aan Ae inside, Aen Ae prediction is sensible on purely steric grounds. Thus, Ae angle d approach of Ae nitrile oxide oxygen to Ae alkene actually places it nearer Ae outside Aan Ae inside substituent located at Ae allylic carbon. ... 

The formation of propyne and allene by pyrolysis of cyclopropene arises from opposite [1,2]H shifts in diradicals 191 or 192 The substantially larger activation energy (by some 24.5 kJ mol" ) for formation of allene reflects differences in the transition state structures for the two processes. Thus, the propyne-forming reaction requires the migrating hydrogen atom to span a single bond (see 194), whilst in the allene-forming process a double bond is involved and a more strained situation ensues (see 195). The formation of but-2-yne from 3-methylcyclopropene is similarly rationalized but the... 

The rational design of potent glycosidase inhibitors may be based on the transition state structures of the enzymatic reaction because this is the point of greatest stabilization by the enzyme — in the case of glycosidases with K s up to However, the true catalytic... 

Entries 1-4 in Table 3 illustrate the tendency for a Cram selective process in additions to aldehydes of type (4 equation 1). In contrast, when (4) is treated with the aluminum additive (1) prior to exposure to organometallics, the nucleophilic addition results in an anti-Cram product. The resulting facial selectivity may be most easily rationalized by considering transition state structure (6), which defmes the anti-Cram face of the aldehyde to be less hindered by virtue of precoordination of the aluminum reagent (1) to the less sterically demanding Cram face. For example, comparison of entries 2, 6 and 9 to the corresponding entries 5, 8 and 10 in Table 3 illustrates the dranuitic effect that the aluminum additive (1) has on the facial selectivity of the reaction. This approach to anti-Cram selectivity, however, does suffer... 

Computational studies designed to rationalize the observed sense of stereoselectivity revealed that the chalcone is linked to the 9-0 H group of the catalyst by hydrogen bonding. The aromatic Jt-Jt interactions between the quinoline ring of catalyst 56a and chalcone further stabilize the transition-state structure and direct the FBSM to approach from the Re-face of the chalcone, affording the R-isomer of 59. The Si-face is blocked by the bulky parts of the benzyl substituent of the catalyst (Figure 9.3). 

Structure III represents an antibonding, triplet repulsion between the atoms or groups transferring the hydrogen atom (here, a carbon-centered and a thiyl radical), which has a significant influence on the activation barrier. They conclude that polar transition state structures are not necessary to rationalize experimental re-... 

When TiCU is used as a catalyst with substituted dienes such as (14), a predominant route is the Mu-kaiyama aldol process, " When diene (14) reacts with benzaldehyde the trans (anti) product is observed. When compound (42) is used as the aldehyde, one observes exclusive formation of the (erythro) aldol products (Table 14). These stereochemical results can be rationalized by using a Zimmerman-Traxler transition state (Scheme 18). Chelation by the metal of the aldehyde a-alkoxy group causes it to be placed in a pseudo axial position in the transition state structure. This results in a stereochemical relationship that gives syn aldol products. ... 

The above discussion shows that relationships between bond valences, bond lengths, dissociation energies and stretching force constants may also be connected, at least conceptually, to our ideas on energy surfaces and energy perturbations described in sections 5.5.3 and 5.5.4. There we have shown that for rather diverse reactions small structural differences of reactant molecules are associated with leu-ge changes in activation energies and that this correlation can be rationalized in terms of simple models of reaction profiles. As a spin-off from such models, structural parameters of transition-state structures have been estimated. 

Structure correlation to map reaction pathways might become important in the field of the monoclonal catalytic antibodies [145, 146]. These proteins are produced by the immune system to bind molecules which resemble the transition state of a chemical reaction. They show catalytic properties with high substrate specificity. Reactions can be imagined for which a biochemical catalyst is not yet known (e.g. the Diels-Alder reaction). The rational design of catalysts for these reactions requires detailed information about possible transition-state structures, geometrical and energetic aspects of the ligand/receptor interface and results from structure/reactivity relationships which are available from structure correlation. 

For example, (-)-P-pinene 19 has been used to construct such a modified catalyst.10 Oxazaborolidine 21 could be prepare in three steps from the monoterpene and was found to be an efficient catalyst for the reduction of ketones. Thus 22 could be reduced with precatalyst 20 and trimethoxyboron to alcohol 23. The chirality of 23 could be rationalized based on the transition-state structure 24. 

An extension to enones has been accomplished but opposite face selectivities were observed. To rationalize this result, an alternate transition-state structure 52 was formulated. Single crystal X-ray structure analysis examining the coordination of BF3-etherate with enones and enoates was used to provide support for this novel mode of complexation. 

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