Deprotonation activation

Preliminary mechanistic studies show no polymerization of the unsaturated aldehydes under Cinchona alkaloid catalysis, thereby indicating that the chiral tertiary amine catalyst does not act as a nucleophilic promoter, similar to Baylis-Hilhnan type reactions (Scheme 1). Rather, the quinuclidine nitrogen acts in a Brpnsted basic deprotonation-activation of various cychc and acyclic 1,3-dicarbonyl donors. The conjugate addition of the 1,3-dicarbonyl donors to a,(3-unsaturated aldehydes generated substrates with aU-carbon quaternary centers in excellent yields and stereoselectivities (Scheme 2) Utility of these aU-carbon quaternary adducts was demonstrated in the seven-step synthesis of (H-)-tanikolide 14, an antifungal metabolite. 

At around the same time, other groups further reported the deprotonation-activation of malonates for the asymmetric addition to imines. Various malonates and aromatic V-acyl imines produced high yielding adducts with excellent stereoselectivities [87, 88]. 

The parameters that control epimerization in a peptide-bond-forming reaction can be assessed in terms of their thermodynamic and kinetic components. Thermodynamic effects are those that stabilize the deprotonated activated intermediate or the protonated tertiary amine. Kinetic effects are expressed based on the degree of steric hindrance between the tertiary amine and activated intermediate. Table 4 summarizes these contributions and shows examples of high, moderate, and low propensities for contribution to the intrinsic rate of racemization among the various parameters. 

In the previous section, we showed that the active site Mg2+ ion prefers to occupy the C-site and B-site in the reactant state and in the deprotonated active precursor, respectively. Starting with these two possible sites, simulations have been performed for transition state (TS) mimics to explore the possible roles of the Mg2+ ion in the chemical reaction step, including four MD simulations of the reactant state in protonated (RT) or activated/deprotonated (dRT) form, two simulations of the early TS (ETS) and two simulations of the late TS (LTS) with the Mg2+ ion initially placed at C-site (c-) or B-site (b-), and finally two additional QM/MM simulations of the ETS and LTS. 

The developed model for the deprotonation activated complexes described above has been used as a starting point for structural modification of the lithium amide in order to increase the energy difference between the diastereomeric-activated complexes and thus the stereoselectivity. Computational chemistry has been used to predict the stereoselectivity with modified chiral lithium amides. Some of these designed novel lithium amides have been synthesized and investigated experimentally with respect to their stereoselectivity. One of these is the lithium amide 5 (shown in Scheme 8 as monomer 5a) which, like the previously discussed lithium amides, appear to be a dimer (5b or 5c) in THF solution as shown by multinuclear NMR spectroscopy and computational chemistry [19,38]. 

Allylic carbonates produce the required alkoxide by decarboxylation of the carbonate anion that is displaced in the formation of the c-allyl palladium intermediate. Deprotonation activates the nucleophile, which rapidly traps the w-allyl palladium complex to give the allylated product, regenerating the palladium(0) catalyst. 

A ternary soft Lewis-acid/hard Bronsted-base/hard Lewis-base catalytic system for the direct catal5rtic enantioselective addition of allyl cyanide 37 to ketones to give tertiary alcohols with a Z-olefin (38) has been developed by Shibasaki (Scheme 2.24). Mechanistic studies revealed that Cu(i)/chiral phosphine ligand 35 and Li(OC6H4-p-OMe) serve as a soft Lewis acid and a hard Bronsted base, respectively, allowing for deprotonative activation of 37 as the rate-determining step. The hard Lewis base, bis(phosphine oxide) 36,... 

Figure 16.2 Proposed mechanism for compound I formation in chioroperoxidase [25]. The deprotonated active site Giu-183 first abstracts a proton from the incoming hydrogen peroxide. The generated hydroperoxo anion then binds to the heme yielding...

In the Tsuji-Tnost reaction, an allylic acetate first oxidatively adds to the Pd(0) catalyst to give a n -allyl complex, which undergoes nucleqphilic attack by the carbanion derived from the deprotonated active methylene compound to give the coupled product allyl alcohols and aldehydes can be coupled by a related procedure. ... 

Michael donors and acceptors are common components in Brmsted base-mediated catalysis. Such transformations offer an uncomplicated route towards all-carbon quaternary stereocenters. In the most basic form, a,P-unsaturated aldehydes are highly reactive templates towards nucleophilic reactions. Under such conditions, mechanistic studies show no polymerization of the unsaturated aldehydes under cinchona alkaloid catalysis [10]. This absence of polymerization is a key mechanistic indicator that the quinucHdine nitrogen of the catalyst does not act as a nucleophilic promoter. Rather, the quinucHdine nitrogen acts, as predicted, in a Bronsted basic deprotonation-activation of various cyclic and acyclic... 

Two efficient syntheses of strained cyclophanes indicate the synthetic potential of allyl or benzyl sulfide intermediates, in which the combined nucleophilicity and redox activity of the sulfur atom can be used. The dibenzylic sulfides from xylylene dihalides and -dithiols can be methylated with dimethoxycarbenium tetrafiuoroborate (H. Meerwein, 1960 R.F. Borch, 1968, 1969 from trimethyl orthoformate and BFj, 3 4). The sulfonium salts are deprotonated and rearrange to methyl sulfides (Stevens rearrangement). Repeated methylation and Hofmann elimination yields double bonds (R.H. Mitchell, 1974). 

Later it turned out that activation of enamine components could not only be achieved by deprotonation of the nitrogen atom but also by connecting it with certain metals, e.g. Ni(II), Pd(II), or Co(II), and subsequent treatment with base. 

Dimethyl acetylenedicarboxylate (DMAD) has also been used to catalyse gramine alkylations (see Entry 7). It may function by both activating the dialkylamino leaving group and deprotonating the nucleophile[3]. 

Engineering the pH Proji/e of Subtilisin. The activity of subtilisin BPN increases between pH 6 and 8 as His64 7.2) is deprotonated (68). Changes in... 

Discernible associative character is operative for divalent 3t5 ions through manganese and the trivalent ions through iron, as is evident from the volumes of activation in Table 4. However, deprotonation of a water molecule enhances the reaction rates by utilising a conjugate base 7T- donation dissociative pathway. As can be seen from Table 4, there is a change in sign of the volume of activation AH. Four-coordinate square-planar molecules also show associative behavior in their reactions. 

Alkyl groups attached to pyridopyrimidines adjacent to a nitrogen are activated , i.e. they are readily deprotonated and react with electrophilic reagents as their anions, or resonance stabilized equivalents, e.g. (64). This ready deprotonation, of course, leads to facile exchange of the alkyl protons for deuterium (Sections 2.15.2.2.1, 2.15.4.2), but, in... 

In theory two carbanions, (189) and (190), can be formed by deprotonation of 3,5-dimethylisoxazole with a strong base. On the basis of MINDO/2 calculations for these two carbanions, the heat of formation of (189) is calculated to be about 33 kJ moF smaller than that of (190), and the carbanion (189) is thermodynamically more stable than the carbanion (190). The calculation is supported by the deuterium exchange reaction of 3,5-dimethylisoxazole with sodium methoxide in deuterated methanol. The rate of deuterium exchange of the 5-methyl protons is about 280 times faster than that of the 3-methyl protons (AAF = 13.0 kJ moF at room temperature) and its activation energy is about 121 kJ moF These results indicate that the methyl groups of 3,5-dimethylisoxazole are much less reactive than the methyl group of 2-methylpyridine and 2-methylquinoline, whose activation energies under the same reaction conditions were reported to be 105 and 88 kJ moF respectively (79H(12)1343). 

This mechanism can reduce the overall activation energy of the reaction in at least two ways. The partial transfer of a proton to the carbonyl oxygen increases the electrophilicity of the carbonyl. Likewise, partial deprotonation of the amino group increases its nucleophilicity. 

The reactivity of the coordinated, deprotonated nucleophile is typically intermediate between that of the un-ionized and ionized forms of the nucleophile. Carboxypeptidase (Chapter 5) contains an active site Zn, which facilitates deprotonation of a water molecule in this manner. 

If activity increases dramatically as pH is increased, catalysis may depend on a deprotonated group that may normally act as a general base, accepting a proton from the substrate or a water molecule, for example (a). Protonation of this group at lower pH prevents it from accepting another proton (from the substrate or water, for example). 

Bell-shaped activity versus pH profiles arise from two separate active-site ionizations, (a) Enzyme activity increases upon deprotonation of (b) Enzyme activity decreases upon deprotonation of A-H. (c) Enzyme activity is maximal in the pH range where one ionizable group is deprotonated (as B ) and the odier group is protonated (as A-H). 

Ohta and Kato found that in the presence of bases the OMe group of 22 may be displaced by compounds with active methylene groups (ethyl cyanoacetate, malonodinitrile), yielding 27, which can be deprotonated to a methylenepyran derivative (28, R = CN, B =CNorC02Et). 

To avoid die difliculties in bandling die bigbly air-sensitive copper arenediiolates, a metliod for dieir preparation and utilization in situ bas been developed, die aren-ediiol 29 being deprotonated witii n-BuLi and mixed widi a coppetfl) salt to yield die active catalyst [34]. 

The hydroxylation of a phenol 1 upon treatment with a peroxodisulfate in alkaline solution, to yield a 1,2- or 1,4-dihydroxybenzene 3, is called the Elbs reaction The phenol is deprotonated by base to give a phenolate anion 4, that is stabilized by resonance, and which is activated at the ortho or the para position towards reaction with an electrophilic agent ... 

Asymmetric Michael addition of chiral enolates to nltroalkenes provides a useful method for the preparation of biologically important compotmds. The Michael addition of doubly deprotonated, optically active fi-hydroxycarboxylates to nltroalkenes proceeds v/ith high dias-tereoselecdvity to give fityr/iro-hydroxynitroesters fEq, 4,58, ... 

The ease of formation of the carbene depends on the nucleophilicity of the anion associated with the imidazolium. For example, when Pd(OAc)2 is heated in the presence of [BMIM][Br], the formation of a mixture of Pd imidazolylidene complexes occurs. Palladium complexes have been shown to be active and stable catalysts for Heck and other C-C coupling reactions [34]. The highest activity and stability of palladium is observed in the ionic liquid [BMIM][Brj. Carbene complexes can be formed not only by deprotonation of the imidazolium cation but also by direct oxidative addition to metal(O) (Scheme 5.3-3). These heterocyclic carbene ligands can be functionalized with polar groups in order to increase their affinity for ionic liquids. While their donor properties can be compared to those of donor phosphines, they have the advantage over phosphines of being stable toward oxidation. 

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