Betaine reversal

There are four main factors that affect the enantioselectivity of sulfur ylide-mediated reactions i) the lone-pair selectivity of the sulfonium salt formation, ii) the conformation of the resulting ylide, iii) the face selectivity of the ylide, and iv) betaine reversibility. 

Meury, J. (1988). Glycine betaine reverses the effects of osmotic stress on DNA replication and cell division in Escherichia coli. Arch. Microbiol. 149 232-239. 

A variety of anionic ylides reacts with high E selectivity with the reversal-prone aromatic aldehydes. On the other hand, aliphatic aldehyde adducts are more resistant to Li -induced betaine equilibration. The y-oxido ylides appear to have the optimal substitution pattern for betaine reversal, and these reagents afford useful ( )-alkene selectivity with aliphatic as well as aromatic aldehydes, results that are tabulated later. Only the aromatic aldehyde example (Table 7, entry 4) has been studied in depth, but it seems safe to conclude that all of the E-selective y-oxido ylide reactions are dominated by betaine reversal (23b). Other anionic ylides react with aliphatic aldehydes to give lower, less predictable ( )-alkene selectivity (for example. Table 7, entry 5 42 58 Z E). 

Several puzzling entries in Table 14 remain to be explained, including reactions where hydroxylic solvents or alkoxide bases are used (entries 11-14). Betaine reversal was demonstrated under hydroxylic conditions in the original Trippet-Jones experiment (Scheme 4) (13), and it is conceivable that interconversion between oxaphosphetanes and betaines could be fast enough in hydroxylic solvents to allow significant betaine reversal to the ylide and aldehyde in some cases. However, there is no clear evidence to implicate stereochemical equilibration of benzylide-derived Wittig intermediates in ether solvents. 

Factors that affect the iyn-betaine reversibility are (a) thermodynamic stability of starting materials (b) steric hindrance of the ylide and/or the aldehyde (c) effect of the solvents and if applicable metal ions. With chiral sulfides (/ =non racemic) additionally enantioselection is possible [212],... 

Betaine formation is reversible and the reaction becomes under thermodynamic control to give the most stable product. 

Stereoselective epoxidation can be realized through either substrate-controlled (e.g. 35 —> 36) or reagent-controlled approaches. A classic example is the epoxidation of 4-t-butylcyclohexanone. When sulfonium ylide 2 was utilized, the more reactive ylide irreversibly attacked the carbonyl from the axial direction to offer predominantly epoxide 37. When the less reactive sulfoxonium ylide 1 was used, the nucleophilic addition to the carbonyl was reversible, giving rise to the thermodynamically more stable, equatorially coupled betaine, which subsequently eliminated to deliver epoxide 38. Thus, stereoselective epoxidation was achieved from different mechanistic pathways taken by different sulfur ylides. In another case, reaction of aldehyde 38 with sulfonium ylide 2 only gave moderate stereoselectivity (41 40 = 1.5/1), whereas employment of sulfoxonium ylide 1 led to a ratio of 41 40 = 13/1. The best stereoselectivity was accomplished using aminosulfoxonium ylide 25, leading to a ratio of 41 40 = 30/1. For ketone 42, a complete reversal of stereochemistry was observed when it was treated with sulfoxonium ylide 1 and sulfonium ylide 2, respectively. ... 

The fourth factor becomes an issue when anti betaine formation is reversible or partially reversible. This can occur with more hindered or more stable ylides. In these cases the enantiodifferentiating step becomes either the bond rotation or the ring-closure step (Scheme 1.12), and as a result the observed enantioselectivities are generally lower (Entry 5, Table 1.5 the electron-deficient aromatic ylide gives lower enantioselectivity). However the use of protic solvents (Entry 6, Table 1.5) or lithium salts has been shown to reduce reversibility in betaine formation and can result in increased enantioselectivities in these cases [13]. Although protic solvents give low yields and so are not practically useful, lithium salts do not suffer this drawback. [18]... 

As the formation of betaines from amide-stabilized ylides is known to be reversible (in contrast with aryl- or semistabilized ylides, which can exhibit irreversible anti betaine formation see Section 1.2.1.3), the enantiodifferentiating step cannot be the C-C bond-forming step. B3LYP calculations of the individual steps along the reaction pathway have shown that in this instance ring-closure has the highest barrier and is most likely to be the enantiodifferentiating step of the reaction (Scheme 1.16) [25]. 

Although the exact mechanism of the Tschitschibabin cyclisation has not been elucidated, it is reasonable, as shown in Scheme 4, to assume a series of reversible steps from the vinylogous ylide (or methylide) to a methine and an enol-betaine intermediate and then finally an irreversible dehydration to the indolizine nucleus. The reaction might be related to the modern electrocyclic 1,5 dipolar cyclization. 

C=C double bonds (15-62). The stereochemical difference in the behavior of 60 and 61 has been attributed to formation of the betaine 64 being reversible for 60 but not for the less stable 61, so that the more-hindered product is the result of kinetic control and the less hindered of thermodynamic control. ... 

Large concentrations of halide ions, preferably iodide, favour the formation of /ra/i5-stilbene from benzaldehyde and benzyltriphenylphosphonium halides in methanol with methoxide as base, whereas large concentrations of methoxide ions slightly favour formation of the m-isomer. These effects have been explained by the preferential solvation of P+ by halide ions, leading to greater reversibility of betaine formation. Methoxide ions, on the other hand, are preferentially solvated by methanol. 

Solvatochromic pareuaeters, so called because they were Initially derived from solvent effects on UV/visible spectra, have been applied subsequently with success to a wide variety of solvent-dependent phenomena and have demonstrated good predictive ability. The B jo) scale of solvent polarity is based on the position of the intermolecular charge transfer absorption band of Reichardt s betaine dye [506]. Et(io> values are available for over 200 common solvents and have been used by Dorsey and co-%rarkers to study solvent interactions in reversed-phase liquid chromatography (section 4.5.4) [305,306]. For hydrogen-bonding solvents the... 

Dimethylsulfonium methylide is both more reactive and less stable than dimethylsulfoxonium methylide, so it is generated and used at a lower temperature. A sharp distinction between the two ylides emerges in their reactions with a, ( -unsaturated carbonyl compounds. Dimethylsulfonium methylide yields epoxides, whereas dimethylsulfoxonium methylide reacts by conjugate addition and gives cyclopropanes (compare Entries 5 and 6 in Scheme 2.21). It appears that the reason for the difference lies in the relative rates of the two reactions available to the betaine intermediate (a) reversal to starting materials, or (b) intramolecular nucleophilic displacement.284 Presumably both reagents react most rapidly at the carbonyl group. In the case of dimethylsulfonium methylide the intramolecular displacement step is faster than the reverse of the addition, and epoxide formation takes place. 

Betaines may be considered to be the intermediate products in the displacement of the C—O fragment from the P—C—O—B system, whereas the addition of aldehydes to the P—C—O—B system constitutes the first stage. This reaction is due to the fact that phosphorus and boron atoms can change their coordination reversibly and convert into the tetra-coordinated state. The displacement of one aldehyde by another is carried out in a solvent or in excess aldehyde. In general this reaction is represented by the following scheme [Eq. (107)]. 

The reaction of 18 and 19 with phosphorus ylides occurs as a stepwise process. Betaine (21) can be isolated when (Me2SiS)3 reacts with Ph3P=CHMe in a 3 2 ratio of the reactants (Scheme 11). This substance is quite stable in the solid state but on dissolving in pyridine it is reversibly transformed into a mixture of 20k and (Me2SiS)3. The equilibrium concentration of 21 in a solution at room temperature is at most 28% according to the NMR data, and the addition of one more equivalent of Ph3P=CHMe to the solution results in the quantitative transformation of 21 into 20k. 

The X-ray diffraction data for this compound are presented in Section 3. Betaines containing a hydrogen atom in the a-position to the phosphonium center and capable of reversible isomerization to silylated ylides are alkylated by ethyl bromide in a different ways. This reaction resulting in a complex mixture of products is considered below in Section 5.4. 

Betaines 13 containing hydrogen atoms in the a-position to the triphenyl-phosphonium center are reversibly isomerized in a solution to form phosphoranylidenealkane dithiocarboxylic acids 68 or their salts 69 (Scheme 30).48 49... 

The components of a technical cocamidopropyl betaine (CAPB Fig. 2.13.1) mixture were separated under reversed phase conditions in the order of increasing length of the alkyl chain (Fig. 2.13.2) [1]. Since the hydrophobic moiety of the surfactant molecule is derived from coconut oil, the two homologues Ci2 and C14 form the major constituents according to the distribution in the natural raw product containing approximately 49% of Ci2- and 19% of C14-fatty acid [2],... 

Many compounds have been tested simultaneously with (2-chloroethyl)tri-methylammonium chloride on Thatcher wheat, to ascertain, if possible, whether these chemicals were affecting a particular metabolic process. Other cholinesterase inhibitors such as eserine, diisopropyl fluorophosphate, and nitrogen mustard, neither negated the effect from (2-chloroethyl)trimethylammonium chloride nor altered the growth of the plant themselves. Many other substances were also without effect on the action of (2-chloroethyl)trimethylammonium chloride. A very slight reversal of the alteration by (2-chloroethyl)trimethylam-monium chloride was obtained by 10 2 and 10 3 M choline, betaine, and adenine. Only gibberellin completely and rapidly reversed the shorter growth pattern of a plant which had been treated with (2-chloroethyl)trimethylammonium chloride. 

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