Quench, internal

Enantioselective deprotonation of prochiral 4-alkylcyclohexanones using certain lithium amide bases derived from chiral amines such as (1) has been shown (73) to generate chiral lithium enolates, which can be trapped and used further as the corresponding trimethylsilyl enol ethers trapping was achieved using Corey s internal quench described above. 

Conjugate addition, 34-5, 51-2,53, 132, 133 Conjugate hydroxymethylation, 59-60 Copper(n) bromide, 54 Copper([) chloride, 120 Copper(n) chloride, 120 Copper(i) cyanide, 7,52, 53 Copper(i) iodide, 54 Corey s internal quench, 104 Cyanohydrin trimethylsilyl ether, 137 Cycloaddition. 34,112 Cydobutane-l,2-dione, 135 Cyclohept-2-dione, 135 Cyclohex-2-enone, 52,123 Cyclohcxa-1,3-diene, 26 Cyclohexane carboxaldehyde, 22-3,69 73,78... 

Maggiora LL, Smith CW, Zhang ZY (1992) A general method for the preparation of internally quenched fluorogenic protease substrates using solid-phase peptide synthesis. J Med Chem 35 3727-3730... 

Warfield, R., Bardelang, P., Saunders, H., Chan, W. C., Penfold, C., James, R. and Thomas, N. R. (2006). Internally quenched peptides for the study of lysostaphin An antimicrobial protease that kills Staphylococcus aureus. Org. Biomol. Chem. 4, 3626-3638. 

Class C Fluorophores that undergo no photoinduced proton transfer but only photoinduced electron transfer. The fluorescence quantum yield of these fluorophores is very low when they are in the non-protonated form because of internal quenching by electron transfer. Protonation (which suppresses electron transfer) induces a very large enhancement of fluorescence (see Section 10.2.2.5). The bandshapes of the excitation and fluorescence spectra are independent of pH. 

Adding electrophiles externally (after complete lithiation) failed, and in order to make potential ligands based upon the arenechromium skeleton, it was necessary to useBusSnCl in an internal quench procedure. Reduction of 430 (X = Sn) yielded a phosphine without decomplexation, and tin-lithium exchange can lead to a variety of products 431 in about 70% ee. 

The carbonyl ylide precursor can be generated by lead tetraacetate oxidation of the hydrazone 58. Thermolysis of 59 in the presence of perdeuterated acetone led to a variety of products, some of which are shown above. An internal quench of the ylide via a 1,4-proton migration led to enol ether 61, while cycloaddition with perdeuterated acetone formed the dioxolane 62 and its regioisomer. Interestingly, the presence of products such as acetone and propene-t/s are proposed to indicate a reversible fragmentation of the ylide to a carbonyl derivative and a carbene. 

Substituted cyclohexanones, bearing a methyl, isopropyl, tert-butyl or phenyl group, give, on deprotonation with various chiral lithium amides in the presence of chlorotrimethylsilane (internal quench), the corresponding chiral enol ethers with moderate to apparently high enantioselec-tivity and in good yield (see Table 2)13,14,24> 29 36,37,55. Similar enantioselectivities are obtained with the external quench " technique when deprotonation is carried out in the presence of added lithium chloride (see Table 2, entries 5, 10, and 30)593. 

The feasibility of a deprotonation of cyclohexanone derivatives bearing a chiral heterocyclic substituent in the 4-position with the C2-symmetric base lithium bis[(/f)-l-phenylethyl]amide with internal quenching of the lithium enolate formed with chlorotrimethylsilane is shown in entries 32 and 33 of Table 229,25a. The silyl enol ethers are obtained in a diastereomeric ratio of 79.5 20.5. By using lithium bis[(1S)-l-phenylethyl]amide the two diastereomers are formed in a ratio of 20 80 indicating that the influence of the chirality of the substituent is negligible. 

Enantioselective deprotonation can also be successfully extended to 4,4-disubstituted cyclohexanones. 4-Methyl-4-phenylcyclohexanone (3) gives, upon reaction with various chiral lithium amides in THF under internal quenching with chlorotrimethylsilane, the silyl enol ether 4 having a quaternary stereogenic carbon atom. Not surprisingly, enantioselectivities are lower than in the case of 4-tm-butylcyclohexanone. Oxidation of 4 with palladium acetate furnishes the a./i-unsaturated ketone 5 whose ee value can be determined by HPLC using the chiral column Chiralcel OJ (Diacel Chemical Industries, Ltd.)59c... 

The enantioselectivity of the two-step process (deprotonation and trapping of the enolate) is considerably higher in the case of internal quenching with chlorotrimethylsilane as shown by the results of the external quenching of the lithium enolate with acetic anhydride (Table 4)20. 

Deprotonation of the 9-azabicyclo 3.3.11nonan-3-one derivative 1 with chiral lithium amides in tetrahdyrofuran at low temperatures in the presence of chlorotrimethylsilane (internal quench) gives the trimethylsilyl enol ether (lS,5/ )-2 in high yield with high enantiomeric excess. The absolute configuration and enantiomeric excess of 2 are based on chemical correlation and HPLC on a chiral Daicel OJ column, respectively38. The 2,2-dimethylpropyl- and 4-methyl-l-piperazinyl- substituted lithium amide is, as noted in other cases, superior. The bicyclic trimethylsilyl enol ether 2 serves as intermediate in the synthesis of piperidine alkaloids. 

The apparent low stability (or nonexistence) of an n -> it excited state leading to photoproducts of the carbonyl in benzoylferrocene may be due to internal quenching or masking by the charge transfer bands which lie in the customary region (see Table I). This latter postulate might be... 

An excited molecule X can pass into the basic level again. This can be performed by radiation—i.e., by emission of the energy difference as a photon hvx—or by nonradiation by internal quenching where the energy difference is dissipated as thermal energy. Furthermore there is the possibility that the excitation energy is not dissipated by radiation but by interaction with a guest molecule Y. This interaction can be described by diffusion of excitons and/or dipole-dipole resonance. 

M Meldal, K Breddam. Anthranilamide and nitrotyrosine as a donor-acceptor pair in internally quenched fluorescent substrates for endopeptidases multicolumn peptide synthesis of enzyme substrates for subtilisin Carlsberg and pepsin. Anal Biochem 195 141-147, 1991. 

Similarly, when, attempted tritiation of the anthryllithium 30 with T20 as an external quench failed because of competing protonation, the solution was to use T20 as an internal quench halogen-metal exchange of 29 proceeds in the presence of the T20 at -70 °C.36... 

No organolithium a to phosphorus has been shown unequivocally to be configurationally stable. The phosphonamide 279 is configurationally unstable on a macroscopic timescale,128 the phosphine oxide 280 gives racemic products on lithiation even in the presence of an internal quench,129 and in a Hoffmann test the phosphine oxide 281 gave the same ratio of diastereoisomers with either racemic or enantiomerically pure 6.129... 

Angliker, H. et al. 1995. Internally quenched fluorogenic substrate for furin. Anal. Biochem. 224, 409-412. 

Mao, S.S. et al. 2008. A time-resolved, internally quenched fluorescence assay to characterize inhibition of hepatitis C virus nonstructural protein 3-4A protease at low enzyme concentrations. Anal Biochem. 373, 1-8. 

Using Corey and Gross s internal quench method48 with TMSC1, silylenol ethers have been generated upon deprotonation of 4-substituted cyclohexanone with chiral lithium amides as shown in Scheme 20. It has been noted that the internal quench condition is crucial for achieving high level of enantioselectivity. 

This finding has been exploited using other ketones and chiral bases. Thus deprotonation of the bicyclic ketone 30 by chiral base 3 in THF yielded the silylenol ether 31 in 84% ee under external quench conditions with added LiCl (Scheme 22)49. In absence of LiCl the ee was lowered to 33%. Internal quench conditions gave an ee of 82%. 

Similarly, chiral bases have found use in the preparation of building blocks for synthesis of alkaloids. A range of A-protected azabicyclic ketones was deprotonated to yield corresponding silylenol ethers (Scheme 30)68-70. The highest ee (93%) was obtained using 42 under internal quench conditions. These chiral ethers found use as key intermediates in the preparation of naturally occurring alkaloids. 

More recently, Amedjkouh has described the use of 48 in deprotonation of 28. Silylenol ethers could be obtained with 85% and 75% ee under internal quench and external quench conditions, respectively (Scheme 32). Mixed dimers 49 and 50 (see Section II.E.2) proved to be effective under external quench conditions and provided silylenol ether in up to 63% ee73. 

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