Stereomutation

Natural unsaturated acids are almost entirely cis isomers and their conversion to trans compounds has been well studied. Sometimes this change occurs inadvertently during processing, sometimes it is promoted with appropriate reagents. 

Cis and trans isomers can be interconverted by a sequence of stereospecific reactions which add up to stereomutation. There are a number of procedures for doing this of which the following is typical  

Reaction with selenium at 190-200 °C is not much used now because some double-bond migration also occurs. More often sodium nitrite-nitric acid (a source of nitrogen dioxide) or a sulphur-containing compound (3-mercaptopropionic acid, 2-mercapto-ethanoic acid, 2-mercaptoethylamine, thiophenol, or an arylsulphonic acid) is used. 

In monoenes and non-conjugated polyenes each cis double bond is converted to the trans form in 75-80% yield. Conjugated polyenes isomerize more readily and give a higher proportion of the 2 [-trans isomer. This change is simply effected with iodine and light. 

The proportion of trans isomer in a reaction mixture can be determined by gas chromatography, infrared spectroscopy, NMR, infrared attenuated total reflectance spectrometry, or by preparative silver ion chromatography (Section 4.6). 

Interest in the decomposition of cyclopropanes and the role of the trimethylene biradical in the decay mechanism has spanned more than three decades and has been fueled by two experiments that give apparently irreconcilable results. Experiments of S,S-trans-cyclopropane-l,2-d2 at 695 K indicate that isomerization via double-terminal rotation (i.e., con- and disro-tation of the terminal methylene groups) is at least 6 times more prevalent than isomerization via single-terminal rotation. Similar experiments with chiral 

A kinetic scheme that includes the role of the trimethylene biradical intermediate is required to obtain the relative rates of single- and doubleterminal rotations from the experimental observables (i.e., the rate loss of optical activity and the rate of trans cis isomerization). Understanding the dynamics of the biradical is thus of pivotal importance. Doubleday has determined an accurate PES for trimethylene from a high level CASSCF ab initio calculation. Trimethylene has a very shallow potential energy minimum 

Semiempirical direct dynamics was used to study trimethylene s unimo-lecular dynamics and the thermal stereomutation of cyclopropane.The semiempirical model used in these simulations is AMI with specific reaction parameters (SRPs see discussion of semiempirical electronic structure theory in the section on BO direct dynamics) chosen to fit the CASSCF PES. In choosing the SRPs, the AMI barrier for propene formation was lowered by 

Additional work needs to be done to develop a theoretical model to represent the trimethylene kinetics. The dynamics in the trimethylene region of the potential energy surface is neither statistical nor direct, and instead contains both these elements. Future work on the kinetics of cyclopropane stereomutation will include developing a theoretical model for trimethylene s dynamics, assessing the accuracy of assuming RRKM dynamics for cyclopropane, and determining a more accurate PES for trimethylene. 

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Fehrensen B, Luckhaus D and Quack M 1999 Mode selective stereomutation tunnelling in hydrogen peroxide isotopomers Chem. Phys. Lett. 300 312-20... 

Marquardt R and Quack M 1996 Radiative excitation of the harmonic oscillator with applications to stereomutation in chiral molecules Z. Rhys. D 36 229-37... 

Phosphine-borane 63a (75% ee) was obtained by reduction of compound (Sp)-62a using LDBB at -60°C and nucleophilic substitution with iodomethane in 72 % yield. The observed loss of optical purity may be ascribed to stereomutation of the generated tricoordinated phosphorus species. Recrystallization afforded (S)-63a in > 99% ee. On the other hand, severe racemization was observed using the same method with (Rp)-62b. An alternative strategy consisted of deborana-tion of (Rp)-62b using ZSl-methylpyrrolidine, methylation with methyl triflate. 

The NMR spectroscopy has been widely used in the studies of different types of equilibria like ring-chain tautomerism, racemisation or stereomutation and proton transfer equilibrium in Schiff bases. 

The dynamic NMR (DNMR) spectroscopy has been used in studies of stereomutations of non-symmetrical di-Schiff bases [18].39 It was shown that the hindered Schiff bases exist in DMSO in two chiral conformations. The presence of a pair of conformers being in equilibrium was explained by the existence of two stereogenic axes a g (aligned to Cl—N8 bond) and a 7 (aligned to C6—N7 bond) due to restricted rotation around two Ar—N bonds. The trans to cis interconversion as well as enantio- or diastereoisomerisation barriers for the compounds studied have been established using line shape analysis. 

Although acetylenic bonds are more reactive than C=C bonds, the reactions are often initiated by AIBN or UV radiation. Baldwin and Barden119 have used the latter method to treat a doubly labelled phenylacetylene with triphenyltin deuteride (Scheme 19). The addition of the triphenyltin deuteride was both regiospecific and gave a stereochemically pure product. A five-step synthesis (Scheme 20) converted this product into an optically pure trideuterophenylcyclopropane, which was used to study the thermal stereomutations that these compounds undergo. 

In the kinetic resolution, the yield of desired optically active product cannot exceed 50% based on the racemic substrate, even if the chiral-discriminating ability of the chiral catalyst is extremely high. In order to obtain one diastereomer selectively, the conversion must be suppressed to less than 50%, while in order to obtain one enantiomer of the starting material selectively, a higher than 50% conversion is required. If the stereogenic center is labile in the racemic substrate, one can convert the substrate completely to gain almost 100% yield of the diastereomer formation by utilizing dynamic stereomutation. 

NL Benoiton. Sometimes it is neither a racemisation nor an epimerisation but an enantiomerisation. A plea for preciseness in the use of terms describing stereomutations in peptide synthesis. Int J Pept Prot Res 44, 399, 1994. 

FIGURE 4.8 Racemization tests employed for acquiring information on stereomutation. Couplings are carried out, and the isomeric content of the products is determined by a variety of techniques. AAA = amino acid analyzer GLC = gas-liquid chromatography. 

EXTERNAL FACTORS THAT EXERT AN INFLUENCE ON THE EXTENT OF STEREOMUTATION DURING COUPLING... 

FIGURE 4.11 Data showing the effect of the /V -substituent of the activated residue on stereomutation.31 Percentable -d-l-isomer formed in couplings in dimethylformamide at+5°C. Ester.HCl salts neutralized with /V-methyl morpholi ne. MxAn = Mixed anhydride using ClC02iPr with 5-minute activation time at -5°C. DCC = dicyclohexylcarbodiimide, HOBt = 1-hydroxybenzotriazole. 

FIGURE 4.13 Data showing the effect of the carboxy substituent of the aminolyzing residue on stereomutation.43 Percentage -d-l- isomer formed in couplings in dimethylformamide at 23°C. Ester.HCl salts neutralized with /V-methylmorpholine. MxAn using CICOjiBu with 2-minute activation time. Xbb = Lys(Z) when Xaa = Leu, Xbb = Leu... 

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