Conformational equilibria diastereomers

Conformational equilibrium of diastereomers, optical ectivities and their temperature coefficients. 

Toth et fl/.w9.35o.w7.408 established the conformations of three diaste-reomers of the dodecahydropyrido[2,l-i>]quinazolin-l 1-ones 343,346, and 347 (R = H or Me). In the diastereomers 343, characterized at positions C-4a, C-1 la, and C-5a by relative configurations the predominant conformation is 445, which contains 4a-H and the lone-pair electrons of N-5 in the antiperiplanar disposition. In the a,a,a diastereoisomers 346 the conformational equilibrium is shifted toward conformer 446, in which N-5 is axial with respect to ring A, while the equatorial position is preferred for the iV-methyl group and the axial position for the N-H proton. 

In the a,a,fi diastereomers 347 the conformational equilibrium is shifted toward conformer 448, in which the carbonyl group is axial with respect to ring A. In the methyl derivatives 347 (R = Me) the methyl group occupies the axial position. 

The more stable diastereomer in each case is the one having both methyl groups equatorial. The free-energy difference favoring the diequatorial isomer is about the same for each equilibrium (about 1.9 kcal/mol), and is close to that for the conformational equilibrium between equatorial and axial methylcyclohexane (1.8 kcal/mol). This near agreement is reasonable, since the equilibria are, in all cases, established between an isomer having no axial substituents and an isomer with one axial methyl substituent. 

In the third sequence, the diastereomer with a /i-epoxide at the C2-C3 site was targeted (compound 1, Scheme 6). As we have seen, intermediate 11 is not a viable starting substrate to achieve this objective because it rests comfortably in a conformation that enforces a peripheral attack by an oxidant to give the undesired C2-C3 epoxide (Scheme 4). If, on the other hand, the exocyclic methylene at C-5 was to be introduced before the oxidation reaction, then given the known preference for an s-trans diene conformation, conformer 18a (Scheme 6) would be more populated at equilibrium. The A2 3 olefin diastereoface that is interior and hindered in the context of 18b is exterior and accessible in 18a. Subjection of intermediate 11 to the established three-step olefination sequence gives intermediate 18 in 54% overall yield. On the basis of the rationale put forth above, 18 should exist mainly in conformation 18a. Selective epoxidation of the C2-C3 enone double bond with potassium tm-butylperoxide furnishes a 4 1 mixture of diastereomeric epoxides favoring the desired isomer 19 19 arises from a peripheral attack on the enone double bond by er/-butylper-oxide, and it is easily purified by crystallization. A second peripheral attack on the ketone function of 19 by dimethylsulfonium methylide gives intermediate 20 exclusively, in a yield of 69%. 

If the carbanion has even a short lifetime, 6 and 7 will assume the most favorable conformation before the attack of W. This is of course the same for both, and when W attacks, the same product will result from each. This will be one of two possible diastereomers, so the reaction will be stereoselective but since the cis and trans isomers do not give rise to different isomers, it will not be stereospecific. Unfortunately, this prediction has not been tested on open-chain alkenes. Except for Michael-type substrates, the stereochemistry of nucleophilic addition to double bonds has been studied only in cyclic systems, where only the cis isomer exists. In these cases, the reaction has been shown to be stereoselective with syn addition reported in some cases and anti addition in others." When the reaction is performed on a Michael-type substrate, C=C—Z, the hydrogen does not arrive at the carbon directly but only through a tautomeric equilibrium. The product naturally assumes the most thermodynamically stable configuration, without relation to the direction of original attack of Y. In one such case (the addition of EtOD and of Me3CSD to tra -MeCH=CHCOOEt) predominant anti addition was found there is evidence that the stereoselectivity here results from the final protonation of the enolate, and not from the initial attack. For obvious reasons, additions to triple bonds cannot be stereospecific. As with electrophilic additions, nucleophilic additions to triple bonds are usually stereoselective and anti, though syn addition and nonstereoselective addition have also been reported. 

In the determination of the relative configurations in acyclic diastereomers with the aid of lanthanide shift reagents (LSR), conformation plays a major role and the equilibrium of rotamers in the complex may differ from that of the pure solute. 

Several cyclodipeptides have been subjected to base-catalyzed epimerization (EtOH/NaOEt at 30-75°C) and the ratio of cis-to-trans isomers at equilibrium has been determined (74JA3985). The results have been correlated with the conformation of the molecules. Thus, cyclo(Pro-Pro) NMR studies (73JA6142) have indicated a boat form in the cis and a planar form in the trans diastereomer. In the latter, the pyrrolidine rings take up a half-chair conformation, which is greatly strained as long as the amide bonds are planar. This renders the trans less stable than the cis diastereomer. Consequently, at equilibrium, only cis diastereomer is found the trans isomer occurs to the extent of less than 0.5%. 

Mixtures of diastereomers of 2,4,6-trlphenylheptane are epimerized. The mole fractions olisotactic, heterotactic, and syndiotactic isomers at equilibrium at 343 K are 0.217, 0.499, and 0.284, respectively. There results are interpreted according to the theory of stereochemical equilibrium. The theory of equilibria between isomers and the associated theory of the conformer populations for each isomer provide a mutually consistent interpretation of the two kinds of results, the same arbitrary parameters being used for both. Stereochemical equilibria and conformer population calculated for PS for the same parameters differ considerably from those for the oligomers. 

One molecule of this type is tris-l-(2-methylnaphthyl)borane (6), 32> for which four isomeric propeller conformations are possible (Table 1). These isomers make up two diastereomeric cW-pairs (Fig. 8). One set of enantiomers (A and A, hereafter A A) are of C3 symmetry and consequently each enantiomer has three equivalent methyl groups. The other two (B and B, hereafter BB) have Ci symmetry and each enantiomer has three diastereotopic methyl groups. These facts are reflected in the TH-nmr spectrum of the methyl region at — 70 °C (Fig. 9). The three resonances of equal intensity are those arising from BB whereas the more intense upheld singlet derives from the methyl groups of AA. At this temperature, the ratio of BB to AA is 3.0 to 2.7. As the sample is warmed, the population of BB increases relative to that of AA, indicating a positive entropy for the equilibrium AA BB, and a crossover temperature (zl( 0=0) below which AA is more stable. A plot of AGt vs T yields, for the equilibrium AA BB, AH0 0.61 0.05 kcal/mol and zJS° 3.1 0.2 eu. The crossover temperature is therefore ca. — 76 °C. The major part of this entropy difference is accounted for by the differ ence in symmetry (C3 vs Ci) of the two diastereomers (R In 3=2.18 eu, for the equilibrium as shown). 

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