Stereoisomers equilibrating

Even when the retroaldol reaction is fairly facile, stereoisomer equilibration can be slow. This phenomenon is illustrated in Scheme 16. A solution of the lithium aldolate (243) and benzaldehyde equilibrates to (244) and p-anisaldehyde with a half-life of 15 min at 0 °C. However, the syn lithium aldolate (244) equilibrates with its anti diastereomer (246) with a half-life of approximately 8 h at room temperature. The reason for this apparent dichotomy is that enolate (245) is so stereoselective in its reactions with aldehydes. Since the kinetic syn.anti ratio is 98.7 1.3, the syn aldolate must dissociate approximately 75 times in order for one syn aldolate molecule to be converted into one anti aldolate molecule. Of course, for less stereoselective enolates, such as the cyclohexanone enolate referred to above, stereochemical isomerization will more nearly parallel the rate of actual aldol reversal. 

The cyclization requires that the intermediate have a cis ring fusion. The stereochemistry of the ring junction was established when the double bond was moved into conjugation in Step B-2. The product was not stereochemically characterized, and need not be, because the stereochemically important site at C(l) can be epimerized under the basic cyclization conditions. Thus, the equilibration of the ring junction through a dienol allows the cyclization to proceed to completion from either stereoisomer. 

Hufford et al [57] used proton and 13C NMR spectrometric data to establish the novel sulfur-containing microbial metabolite of primaquine. Microbial metabolic studies of primaquine using Streptomyces roseochromogenus produced an A-acety-lated metabolite and a methylene-linked dimeric product, both of which have been previously reported, and a novel sulfur-containing microbial metabolite. The structure of the metabolite as an S-linked dimer was proposed on the basis of spectral and chemical data. The molecular formula C34H44N604S was established from field-desorption mass spectroscopy and analytical data. The 1H- and 13C NMR spectra data established that the novel metabolite was a symmetrical substituted dimer of primaquine A-acetate with a sulfur atom linking the two units at carbon 5. The metabolite is a mixture of stereoisomers, which can equilibrate in solution. This observation was confirmed by microbial synthesis of the metabolite from optically active primaquine. 

For 1,3,2,5-dioxaboraphosphorinanes with a tricoordinated phosphorus atom, equilibration of the stereoisomers has been observed after a few hours at 20°C without any catalyst. In the case of the sulfide and selenide the equilibrium is established in 11-20 h at 80°C in the presence of p-toluenesulfonic acid. The equilibrium composition of 2,5-diphenyl-4,6-... 

An alternative mode to release the strain of the four membered ring of vinylcyclobutanones arises from the addition of vinylorganometallics to the carbonyl group whereby a divinylcyclobutane is created 78,120,121). Since equilibration of the stereoisomers 78 and 79 is fast relative to rearrangement78), both stereoisomers nicely rearrange even though a cis divinyl orientation is required (Eq. 95). 

The diazomethane methodology has previously been applied by several other groups to expand cyclobutanones. For example, in Fleming s loganin synthesis, 53,54) when the cyclobutanone (151) was allowed to react with diazoethane, (152) was isolated as a mixture of stereoisomers. Removal of the chlorine atom and equilibration of the methyl group with NaOMe converted (152) to the ketone (153) 53,54). 

A more complicated picture arises with substrates containing more than one stereocentre which could be subject to redox stereoinversion of the type described in the previous examples. With two carbinol stereocentres in a symmetrical substrate there exist a maximum of five stereoisomers (the R,R and S,S enantiomers and meso isomer of the diol and two enantiomers of the intermediate a-hydroxyketone) for the dehydrogenase enzyme(s) to discriminate and transform irreversibly to a single enantiomer. Of course for 1,2-diols the intermediate j -hydroxyketone may be spontaneously equilibrating through an... 

Anodic oxidation of halogenated tyrosines was studied in connection with some sponge metabolites (cavemicolin model compounds). The methyl exter of 3,5-dibromotyrosine afforded four different products in a 41 10 26 23 ratio with 23% overall yield as a result of equilibration. (Scheme 44) [93JCS(P2)3117], A related compound was obtained as a mixture of stereoisomers 56 from a Diels-Alder reaction between N-acetyldehydroalanine methyl ester and l-methoxy-l,3-cyclohexadiene (87TL2371). 

However, the syn and anti isomers of imines are easily thermally equilibrated. They cannot be prepared as single stereoisomers directly from ketones and amines so this method cannot be used to control regiochemistry of deprotonation. By allowing lithiated ketimines to come to room temperature, the thermodynamic composition is established. The most stable structures are those shown below, which in each case represent the less substituted isomer. 

The greater stability of the anti isomer is attributed to the pseudoequatorial position of the methyl group in the chair-like chelate. With larger substituent groups, the thermodynamic preference for the anti isomer is still greater.10 11 Thermodynamic equilibration can be used to control product composition if one of the desired stereoisomers is significantly more stable than the other. 

All of the stereoselective transformations described so far originate from kinetic control. Therefore, the ratio of stereoisomers obtained does not reflect their relative energies and, provided that the reaction conditions allow a subsequent equilibration, this ratio may change during prolonged reaction periods. The two principal possibilities arising from thermodynamically controlled (equilibrating) conditions and are shown below. 

The reaction of rac-4 with lithium dimethylcuprate yielded two of the four possible pairs of addition products (rac-5-rac-8) in a 4 1 ratio (see Section 4.3.3.2.2., p411). Treatment of the major stereoisomer with pyridine gave (presumably via the enolale) an 87 13 mixture containing the minor isomer from the cuprate addition as one component. In this case equilibration did not provide a full answer as to the relative configuration but it showed, that either rac-S/rac-6 or rac-1 jrac-% were formed from rac-4, whereas combinations such as rac-5jrac-1 were excluded (see p 480 for further assignment)108. 

In the iV-acetylhexahydro-l,2-diazepine 141 (R = Ph), experimental evidence suggests (80JOC5216) the presence of only one rotational isomer, whereas the NMR spectrum at low temperature (—48°) showed (71JOC2467) the presence of three of the eight possible stereoisomers, which equilibrate completely at 68°C. These are probably not caused by restricted rotation of the acyl group. 

Thus, the (3-ionone was smoothly deconjugated and ethynylated to give ethynyl-retro-ionol as a mixture of E/Z stereoisomers. Formation of the carbonate and its Pd-catalyzed rearrangement produced straightforward a mixture of aldehydes and a allene compound. After silica-gel chromatography, the allenic-aldehyde was conjugated with a catalytic amount of HBr in acetone. Retinal was obtained as a mixture of E and Z isomers (75/25), which could be converted into the all E isomer by simple equilibration, Fig. (33). 

Tetrahydrofuran is partially fluorinated over cobalt(III) fluoride81 and potassium tetra-fluorocobaltate(III).82 With cobalt(III) fluoride at 100-1 IO C,27 products are obtained with an overall yield of about 50 60%. Most are polyfluorooxolanes 2-4, and the rest (13% of the product mixture) polyfluoropropanes. The major products are 2 (15%), 3 (29%), and 4 (29%) (since the various stereoisomers are equilibrated at the positions next to oxygen in the fluorination process, the total percentages for each set of constitutional isomers are shown, and not the percentages for each stereoisomer). 

The mode of the elimination can be recognised by the composition of the products if the olefin formed has such substituents on the double bond that cis and trans stereoisomers may be distinguished. The question is of interest with respect to the concerted E2 mechanism, because in the pure El and ElcB processes, the intermediate carbonium ion or carbanion, respectively, usually have enough time to rotate around the Ca—Cp bond, equilibrate and give the same cis/trans ratio from different conformers. 

Alkyne complexes of Os(II) are observed to undergo addition of water and methanol across the alkyne bond, resulting in stable vinyl alcohol and vinyl ether complexes, respectively (168). When an aqueous solution of [Os(NH3)5(CH3C=CCH3)]2+ is allowed to stand, the initial product observed is the cis-2-hydroxy-2-butene complex. Over a period of several days, this species equilibrates with its trans stereoisomer, the latter being slightly favored in aqueous solution (Keq = 1.5). 

Ring closure after rotation of the bonds of the open chain betaine can lead to stereoisomers (71JA4004). Two examples are shown in Scheme 28. 31P NMR shifts are useful for the identification of the different species. In the case of (178) and (179), prepared by the reaction of benzil with trisdimethylaminophosphine, two crystalline forms were isolated. They equilibrate in solution. 

Exercise 30-12 Reduction of the double bond of cholesterol can be carried out so as to produce either 5a- or5/3-cholestanol. Equilibration of 5a-cholestanol with a trace of 5a-cholestanone and base (Section 16-4E) gives 90% 5a-cholestanol and 10% of a stereoisomer known as epicholestanol. Similar equilibration of 5/6-cholestanol (in the presence of 5 -cholestanone) gives 10% 5/8-cholestanol and 90% of a stereoisomer of 5/3-cholestanol known as epicoprostanol. Write the configurations of each of these compounds and explain the orders of stabilities that are observed. 

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