Diastereoselectivity repulsive interactions

If the substituents are nonpolar, such as an alkyl or aryl group, the control is exerted mainly by steric effects. In particular, for a-substituted aldehydes, the Felkin TS model can be taken as the starting point for analysis, in combination with the cyclic TS. (See Section 2.4.1.3, Part A to review the Felkin model.) The analysis and prediction of the direction of the preferred reaction depends on the same principles as for simple diastereoselectivity and are done by consideration of the attractive and repulsive interactions in the presumed TS. In the Felkin model for nucleophilic addition to carbonyl centers the larger a-substituent is aligned anti to the approaching enolate and yields the 3,4-syn product. If reaction occurs by an alternative approach, the stereochemistry is reversed, and this is called an anti-Felkin approach. 

Obviously, the nature of the organocopper reagent is an important factor with respect to the stereochemical outcome of the cuprate addition. This is nicely illustrated for the cuprate addition reaction of enoate 75 (Scheme 6.15). Here, lithium di-n-butylcuprate reacted as expected by way of the modified Felkin-Anh transition state 77 (compare also 52), which minimizes allylic A strain, to give the anti adduct 76 with excellent diastereoselectivity [30]. Conversely, the bulkier lithium bis-(methylallyl)cuprate preferentially yielded the syn diastereomer 78 [30, 31]. It can be argued that the bulkier cuprate reagent experiences pronounced repulsive interactions when approaching the enoate system past the alkyl side chain, as shown in transition state 77. Instead, preference is given to transition state 79, in which repulsive interactions to the nucleophile trajectory are minimized. 

The analysis and prediction of the direction of preferred reaction depend on the same principles as for simple diastereoselectivity and are done by analysis of the attractive and repulsive interactions in the presumed transition state. 

Scheme 23 shows how four possible diastereomers can arise from the combination of two sp -carbon centers C-1 and C-2 in a donor component 23-1 and an acceptor component 23-2. Species 23-3 and 23-4 are two diastereomers and 23-5 and 23-6 are their enantiomers.The problem of simple diastereoselection is the control of the diastereomer ratio 23-3-1-23-5/23-4-1-23-6. The enantiocontrol of 23-3 vs 23-5 or of 23-4 vs 23-6 cannot be achieved by simple diastereoselection in this case an external source of chirality has to be applied, for instance a chiral catalyst or the incorporation of stereogenic units in one of the components. Simple diastereoselection can be exerted in terms of closed and open transition states, depending on the mutual interaction of the termini X and Do, respectively. If these termini are linked via a six-membered chelate, a closed ( Zimmerman-Traxler ) transition state 23-7 with synperiplanar olefinic units is formed. On the other hand, if the termini have a repulsive interaction an open transition state 23-8 with an antiperiplanar arrangement of the olefinic units is adopted. Efficient stereocontrol via Zimmerman-Traxler transition states 24-1 to 24-4 is observed in aldol-type and allylborane carbonyl additions (Scheme 24). The crucial stereo differentiating interaction is the diaxial repulsion between Rax and R, which must be kept as low as possible. Only small substituents (nor-...

Kuroda et al. have found that the diastereoselectivity of the Lewis acid-promoted cyclization of 132 is highly dependent on the geometry of the allylsilane moiety (Scheme 10.154) [429]. The stereochemical outcomes can be rationalized by chair transition structures involving a secondary orbital interaction wifhout severe steric repulsion. 

The reaction between l-acetoxy-3-methylbutadiene preferentially affords exo adduct 33 in high enantioselectivity (Scheme 27) 33 was elaborated in four steps to enf-A -tetrahydrocannabinol [87]. The turnover in diastereoselectivity is thought to be a result of a steric interaction between the 3-methyl group of the diene and the chiral ligand, a repulsion which is not present for the parent 1-ac-etoxybutadiene (an endo selective diene). 

The influence of adjacent stereogenic centers on the diastereoselectivity of the cyclization is addressed in entries 4 13. Alkyl or aryl substituents in the homoallylic position lead only to a moderate preference for the 4,6-m-product (Table 14, entries 4 7)9. Surprisingly, the triflu-oromethyl group exerts complete stereocontrol, which is attributed to its steric and additional electronic repulsion of the enolate moiety in the cyclization transition state (for a detailed discussion see the preceding section). The intramolecular reactions of the bissulfone derivatives (Table 14, entries 11 -14)19 feature a contrathermodynamic production of mainly civ-substituted vinylcyclopentanes. Epimerization of the zr-allyl complex is faster than cyclization, so that an equilibrium between the different isomeric zwitterions is established. Due to unfavorable steric interactions with the substituent R, palladium is preferentially located irunx to R in the cyclization transition state favoring the m-product. The use of toluene, tetrahydrofuran, and acetonitrile as solvents results in poorer diastereoselectivities. Some restrictions apply to the kind of nucleophile employed, thus 2-oxo esters may only give the 0-alkylated product (cf. Table 12)2 19-20. 

Chiral ketene equivalent 60 was prepared from pulegone (63), a common monoterpene. Both enantiomers of 63 are known and thus, both enantiomers of 60 are available. A model that rationalizes the observed diastereoselectivity follows. The model emphasizes three points (1) The ester reacts from a conformation that minimizes dipole-dipole repulsion in terms of conformation around the 0-acyl bond. This is normally the lowest energy conformation for any ester. (2) Steric effects are minimized in the presumed reactive complex between 60 and the Lewis acid. The metal complexes opposite the large ester alkyl group, and the vinyl dienophile reacts from an -trans conformation to minimize metal-vinyl group interactions. (3) r-Stacking contributes to shielding of one face of the olefin from the diene. It is notable that the non-catalyzed process shows little asymmetric induction. 

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