Epimerization process

There was, however, no significant selectivity in the initial hydroboration of the terminal double bond. As a result, both configurations are formed at C(6). This problem was overcome using the epimerization process from Scheme 13.34. 

Epimerization Process of inter-conversion of one epimer to the other. The process is usually base-mediated as abstraction of a proton is often the first step in the process. 

Compounds 818-820 are kinetically labile and undergo epimerization in solution. The rates of these epimerization processes were determined by kinetic measurements. Owing to the hydrolytic sensitivity of compounds 821 and 822, a conceivable role of bidentate amino acid ligands in the silicon biomineralization process has been denied.821... 

During this epimerization process, it was found that the reactivity in the 4-position was however much higher than in the 2-position. At room temperature, the epimerizatiou reaction in the 4-position occurred instantaneously, completed withiu teu to tweuty minutes, whereas in the 2-position the epimerization reaction proceeded very slowly under these conditions. This result incited us to make use of the reactivity difference between the different positions to develop a new method, stepwise inversion of the hydroxyl groups amounting to a double serial inversion protocol, by which carbohydrate structures where one position is a hydroxyl group and the other positions were protected with ester groups could be obtained. 

The UNCAs are ideal activated intermediates for the study of intrinsic rates of racemization. Epimerization can occur only via the direct abstraction mechanism, because the five-membered ring structure precludes formation of an oxazol-5(4//)-one. In addition, the UNCA maintains its structural integrity during the epimerization process. A report by Rom off129 describes two simple methods for the measurement of intrinsic rates of racemization under a wide variety of reaction conditions utilizing UNCAs as the prototypical activated intermediates. 

This polarimetric method was made even more general by utilizing chiral HPLC techniques. The L-UNCAwas dissolved in the solvent at a concentration of 0.33 M at 20 °C. The tertiary amine (1.5 equiv) was added at time zero. The solution was allowed to stand for an experimentally determined delay time, during which the only process that can occur was epimerization, since there is no nucleophile present. The delay time was determined after carrying out several experiments with different delay times and chosen so as to fall within or just after the first half-life for racemization. At the end of the delay period, benzylamine was added. Benzylamine is a very powerful nucleophile that reacts virtually instantly (regardless of the type of activation) with the resulting mixture of l- and d-UNCAs to form the benzyl amides and quench the epimerization process. Thus, a snapshot of the ratio of l/d activated intermediates at the instant of benzylamine addition was obtained by measurement of the l/d ratio of the benzyl amide products. 

The mechanistic studies of the epimerization reaction still cause confusion. For the first time, direct evidence for Mechanism 1 has been presented based on the incapability of the C-12b methyl substituted vinylogous urethanes to epimerize. Further evidence for Mechanism 1 was provided by deuterium incorporation at the epimeric centre of various compounds (see above), a process most likely due to a mechanism analogous to Mechanism 1. The difference in epimerization rate and deuterium incorporation states merely that Mechanism 1 is not primarily responsible for the acid-catalysed epimerization reaction and hence does not completely discredit it. Evidence for all three mechanisms therefore now exists, revealing the complexity of the epimerization process. The results with p-carbolines and the trapping of 3,4-secoreserpine (27) and secolactam 38 provide strong evidence for Mechanism 3. Mechanism 2, which was earlier considered to be responsible for the epimerization reaction, has since been discredited. Nevertheless, the presence of 2,3-secoreserpine (26) in the trapping reaction remains undisputed and indicates that Mechanism 2 is active under the conditions employed. Thus, several mechanisms may be active simultaneously in the epimerization reaction, so further complicating the matter. 

Kinetic work on the isomeric 1,2-diphenylcyclopropanes (Scheme 2) made evident a substantial reduction in Ed and thus implied a stabilization of trimethylene diradical transition structure(s) by phenyl substituents142. In further work with 0.2 M (-)-l,2-diphenylcyclopropane in 1 -butanol, Crawford and Lynch143 uncovered a direct route from one trans antipode to the other at 220.7 °C the measured ratio of rate constants /trac(for loss of optical activity) to kK (for trans to cis geometrical isomerization) was found to be 1.49 0.05 and since krdC is (2k12 + 2/c,). and klc is 2/c,(Scheme 2), the implication is that one-center epimerizations (2kt) are favored over the two-center epimerization process (ka) by... 

When enantiomerically pure CR)c(R)sn (2-[l-(dimethylamino)ethyl] phenyl)methylphenyltin bromide 41b is dissolved in toluene, the H NMR spectrum at — 30° C shows the presence of only one diastereoisomer. However, at — 13°C an epimerization process starts, finally resulting in the formation of a 40 60 equilibrium mixture of the (i )cWsn and (R)d(S)Sn diastereoisomers (114) (Fig. 14B). 

Isotactic polystyrene was epimerized to various extents by reaction with KOtBu in hexamethylphosphor-amide solution at 100°. The 13C-NMR spectra of the epimerized samples and of polystyrene in 9 1 trichlorobenzene nitrobenzene-d6 solution at 150° were recorded and analyzed using stereosequence distributions that were calculated for the samples by Monte Carlo simulation of the epimerization process. 

Two different V values were used for the Monte Carlo calculations. A value of 0.5 was used to predict the effect of a completely random epimerization process that yields a perfectly atactic polymer when equilibration is complete. Our previous work employed a V value of 0.65 and this was also used here. The 0.65 value, which yields a slightly syndiotactic polymer (P(m)=0.43), was selected initially because it predicts a rr-content for the completely equilibrated polymer that agrees with theoretical predictions of Flory and Williams(36). 

Figures 1-6 compare observed aromatic C-l carbon resonance spectra with simulated spectra based on the heptad chemical shifts given in Table VI and on heptad stereosequence concentrations calculated by Monte Carlo simulation of the epimerization process, using V=0.65. The simulation spectra reproduce the general features of the observed spectra very well and can be considered to be in at least semi-quantitative agreement with the observed spectra. The agreement between observed and simulated spectra might be improved if spectra with higher S/N ratios were employed and if additional parameter adjustments were made. It seems, however, that the heptad assignments developed in this work are reasonably correct.

The same authors have developed an alternative metiiod for the synthesis of 6)8-eudesmanolides from santonin (Scheme 15) [26]. The epimerization process at C(6) consisted of the LiAlH4 reduction of the trans-6oc- actone moiety in compound 122, followed by selective protection of the hydroxyl groups at C(3) and C(12), oxidation of C(6) to give compound 128, and stereoselective reduction of the carbonyl group by attack with sodium borohydride from the less hindered a-side. Re-lactonization was achieved by oxidation, after prior deprotection of the C(12)-hydroxyl group, with RuH2(Ph3P)4 or tetra- -propylammonium... 

At this juncture, the stereochemistry of the amine-substituted carbon required inversion to the correct configuration of the natural product. Toward this end, lactone 354 was treated with tetramethylguanidine and 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) under an air atmosphere in THE. These conditions led to oxidation to yield enamine 355, which was subsequendy reduced with sodium cyanoborohydride to complete the epimerization process. These conditions were also sufficiently hydridic to reduce the ketone carbonyl. Heating in ethyl acetate then led to cycHza-tion to yield lactam 356. Oxidation using IBX next provided ketone 357, which was employed as a coupling partner for 2-iodoanihne in the key indolization step (Scheme 51). 

When the target bicycle lacks a suitably placed double bond in a six-membered ring, retrosynthesis starts with FGA (= add double bond) [95, 96, 97, 98]. In bicyclization reactions forming an endoendo bond, the stereochemistry of the reaction has to be monitored (formation of a cis or of a trans fusion of the two rings). With anellated systems of a five- to a six-membered ring the cis juncture is thermodynamically favored. This renders it possible to reach a cis fused bicyclo[4.3.0]nonane system by an epimerization process following the bicyclization reaction [99] (Scheme 6.25). 

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