Stereochemistry diastereomeric transition states

To rationalize the enantioselectivity of the TADDOL-catalyzed HDA reaction between Danishefsky s diene and benzaldehyde, eight possible diastereomeric transition states of different regio- and stereochemistry should in principle be considered for comprehensive analysis. The cycloaddition between the model diene and benzaldehyde can take place along two regio-isomeric meta (C1-06, C4-C5 bond formation) and ortho (C1-C5, C4-06 bond formation) reaction channels. For both of these pathways, an exo- and an endo-approach can be formulated (Scheme 11) [64]. 

Dimethyloxazolidines have been utilized as chiral auxiliaries for the diastere-oselective functionalization of the optically active tiglic acid derivatives by means of epoxidation with dimethyldioxirane (DMD) or m-CPBA and ene reactions with 02 or 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD). In the DMD and m-CPBA epoxidations, high diastereoselectivities but opposite senses of diastereomer selection was observed. In contrast, the stereochemistry of the 102 and PTAD ene reactions depended on the size of the attacking enophile whereas essentially perfect diastereoselectivity was obtained with PTAD, much lower stereoselection was observed with 02. The stereochemical results for the DMD and m-CPBA epoxidations and the PTAD ene reaction are explained in terms of the energy differences for the corresponding diastereomeric transition states, dictated by steric and electronic effects.200... 

R,R-diphenyl ethylene carbonate CR,R-DPEC)) with a racemic zirconaaziridine. (C2-symmetric, cyclic carbonates are attractive as optically active synthons for C02 because optically active diols are readily available through Sharpless asymmetric dihydroxylations [67].) Reaction through diastereomeric transition states affords the two diastereomers of the spirocyclic insertion product protonolysis and Zr-mediated transesterification in methanol yield a-amino acid esters. As above, the stereochemistry of the new chiral center is determined by the competition between the rate of interconversion of the zirconaaziridine enantiomers and the rate of insertion of the carbonate. As the ratio of zirconaaziridine enantiomers (S)-2/(R)-2 is initially 1 1, a kinetic quench of their equilibrium will result in no selectivity (see Eq. 32). Maximum diastereoselec-tivity (and, therefore, maximum enantioselectivity for the preparation of the... 

Steric features in the diastereomeric transition states are no doubt the governing factor in determining the extent and direction of selectivity in asymmetric hydro-borations. A number of varying representations of the transition states have been offered, however, and it is not clear exactly which interactions are dominant in controlling stereochemistry. ... 

The computed relative stabilities of four diastereomeric transition states (Figure 3.15) are in accord with experimentally observed preferential Ph migration and high R-enantioselectivity. However, it is not easy to understand the reasons of the relative stabilities of these transition states. The computations had not supported the initial mechanistic idea of Ryu et al. on the n-n controlled stereochemistry. On the other hand, the interactions claimed by the authors of the computational paper i do not seem to be unique for the more stable transition states TS2SR and TS2SS. 

I-Oialkoxy carbonyl compounds are a special class of chiral alkoxy carbonyl compounds because they combine the structural features, and, therefore, also the stereochemical behavior, of 7-alkoxy and /i-alkoxy carbonyl compounds. Prediction of the stereochemical outcome of nucleophilic additions to these substrates is very difficult and often impossible. As exemplified with isopropylidene glyceraldehyde (Table 15), one of the most widely investigated a,/J-di-alkoxy carbonyl compoundsI0S, the predominant formation of the syn-diastereomer 2 may be attributed to the formation of the a-chelate 1 A. The opposite stereochemistry can be rationalized by assuming the Felkin-Anh-type transition state IB. Formation of the /(-chelate 1C, which stabilizes the Felkin-Anh transition state, also leads to the predominant formation of the atm -diastereomeric reaction product. 

The two chair-like transition states 48 and 49 have been suggested to explain the stereochemistry in the reaction. Here structure 48, leading to (S )-carbinol, is favored over the diastereomeric 49, which gives the (R)-enantiomer, because the latter structure with axial-R and equatorial-R group is destablized by the n-n... 

The correlation of metal enolate geometry and aldol product stereochemistry via diastereomeric chair-preferred transition states has been widely accepted (2,5,6,16). The observations that the steric bulk of the enolate ligand Rj and attendant aldol diastereoselection are directly coupled are consistent with the elaborated Zimmerman model illustrated in Scheme 3 for chair-preferred transition states. For example, for ( )-enoIates, transition state Q is predicted to be destabilized relative to Ci because of the Rj R3 variable steric... 

Most enolates can exist as two stereoisomers. Also, most aldol condensation products formed from a ketone enolate and an aldehyde can have two diastereomeric structures. These are designated as syn and anti. The cyclic-transition-state model provides a basis for understanding the relationship between enolate geometry and the stereochemistry of the aldol product. 

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. 

Enzymatic enantioselectivity in organic solvents can be markedly enhanced by temporarily enlarging the substrate via salt formation (Ke, 1999). In addition to its size, the stereochemistry of the counterion can greatly affect the enantioselectivity enhancement (Shin, 2000). In the Pseudomonas cepacia lipase-catalyzed propanolysis of phenylalanine methyl ester (Phe-OMe) in anhydrous acetonitrile, the E value of 5.8 doubled when the Phe-OMe/(S)-mandelate salt was used as a substrate instead of the free ester, and rose sevenfold with (K)-maridelic acid as a Briansted-Lewis acid. Similar effects were observed with other bulky, but not with petite, counterions. The greatest enhancement was afforded by 10-camphorsulfonic acid the E value increased to 18 2 for a salt with its K-enanliomer and jumped to 53 4 for the S. These effects, also observed in other solvents, were explained by means of structure-based molecular modeling of the lipase-bound transition states of the substrate enantiomers and their diastereomeric salts. 

While the stereochemistry of the major diastereomeric adducts from the reaction of lithiated 48 and carbonyl compounds can be rationalized as arising from cyclic boat transition states (52a,b), the transition state 52b, which is analogous to the transition state 41 (Scheme 1) proposed for the reaction of 2f with aldehydes, appears unlikely because of a number of severe 1,2-steric interactions, in particular the SMe group and the benzylic phenyl group are eclipsed in 52b. Indeed, when the aldehyde is precomplexed with BF3, a cyclic transition state cannot occur. 

The high diastereoselectivity observed in the crotylmetallation of vinyl metals may be accounted for by a preferential or kinetically favored Z-configuration of the crotylmetal species, if we consider a chair-like transition state [101]. The other diastereomer, syn-(35, 45 )-dimethyl-l-nonene, is obtained with a high diastereomeric purity only by changing the stereochemistry of the starting vinyllithium [101, 105] (Scheme 7-90). 

The asymmetric total syntheses of mtamycin B and oligomycin C was accomplished by J.S. Panek et al. In the synthesis of the C3-C17 subunit, they utilized a Mukaiyama aldol reaction to establish the C12-C13 stereocenters. During their studies, they surveyed a variety of Lewis acids and examined different trialkyl silyl groups in the silyl enol ether component. They found that the use of BFs OEta and the sterically bulky TBS group was ideal with respect to the level of diastereoselectivity. The stereochemical outcome was rationalized by the open transition state model, where the orientation of the reacting species was anti to each other, and the absolute stereochemistry was determined by the chiral aldehyde leading to the anti diastereomeric Felkin aldol product. 

These aldols have all had just one chiral centre in the starting material. Should there be more than one, double diastereomeric induction produces matched and mismatched pairs of substrates and reagents, perfectly illustrated by the Evans aldol method applied to the syn and anti aldol products 205 themselves derived from asymmetric aldol reactions. The extra chiral centre, though carrying just a methyl group, has a big effect on the result. The absolute stereochemistry of the OPMB group is the same in both anti-205 and yvn-205 but the stereoselectivity achieved is very different. The matched case favours Felkin selectivity as well as transition state 201 but, with the mismatched pair, the two are at cross purposes. It is interesting than 1,2-control does not dominate in this case.33... 

The preference for the open-extended transition state and thus the anti product can be visualized as follows. If two prostereogenic centers with groups that are effectively large, medium, and small (Scheme 60) are combined, two possible diastereomeric products are possible (A and B). Assuming that no associative phenomenon exists, then the stereochemistry of the reaction should be determined solely by the steric demand of the substituents. If it is further assumed that the reaction proceeds only through staggered transition states, the elimination of detrimental eclipsing interactions results in only six possible transition structures (60.1-60.6, Scheme 60). 

In connection with the synthesis of podophyllum lignans, ester (62) was deprotonated and the resulting enolate condensed with 3,4,5-trimethoxybenzaldehyde to give a 1 1 mixture of diastereomeric aldols (equation 68). The structure of (63) was established by X-ray analysis the other diastereomer was assigned the 2,3-anti relative stereochemistry (64) on circumstantial evidence. It was suggested that the 1 1 mixture of isomeric products results from a 1 1 mixture of the ( )- and (Z)-enolate, each of which shows complete simple and diastereofacial selectivity in its reactions with 3,4,5-trimethoxybenzaldehyde. For this to be true, it is also necessary that the ( )-enolate reacts through a non-Zimmerman , boat-like transition state, whereas the (Z)-enolate reacts through the normal chair-like transition state. 

The Weinreb group has recently examined the reaction of chiral N-sulfinyl dienophile 23, prepared from (+)-camphor, with 1,3-cyclohex-adiene (Scheme 1-VIII). Whereas the uncatalyzed cycloadcUtion afforded a mixture of diastereomeric adducts, the reaction promoted by TiCU gave a single adduct 24 having the 35,6/ configuration. Stereochemistry at sulfur in this compound could not be determined. As in the phenylmenthol series, one can reasonably consider two reacting dienophile conformations 23A and 23B (Scheme 1-VIU). If conformer 23A is attacked by the diene in an endo manner from the most exposed face, the observed adduct 24 will be formed. Similarly, if conformer 23B reacts with cyclohexadiene via an exo transition state, 24 will result. 

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