Unreactive substrates

EinaHy, kinetic resolution of racemic olefins and aHenes can be achieved by hydroboration. The reaction of an olefin or aHene racemate with a deficient amount of an asymmetric hydroborating agent results in the preferential conversion of the more reactive enantiomer into the organoborane. The remaining unreacted substrate is enriched in the less reactive enantiomer. Optical purities in the range of 1—65% have been reported (471). 

Trifluoromethanesulfonate (triflate) ion is an exceptionally good leaving grov. It can be used for nucleophilic substitution reactions on unreactive substrates. Acetolysis of cyclopropyl triflate, for example, occurs 10 times faster than acetolysis of cyclopropyl tosylate. Table 5.11 gives a conqiarison of the triftate group with some other common leaving groups. 

TWo types of rate expressions have been found to describe the kinetics of most aromatic nitration reactions. With relatively unreactive substrates, second-order kinetics, first-order in the nitrating reagent and first-order in the aromatic, are observed. This second-order relationship corresponds to rate-limiting attack of the electrophile on the aromatic reactant. With more reactive aromatics, this step can be faster than formation of the active electrq)hile. When formation of the active electrophile is the rate-determining step, the concentration of the aromatic reactant no longer appears in the observed rate expression. Under these conditions, different aromatic substrates undergo nitration at the same rate, corresponding to the rate of formation of the active electrophile. 

Measured activation energies, which are not independent of temperature nor of the acid concentration, vary between 13.3 and 24.2, show a minimum at the acid concentration giving the maximum rate and these fairly low energies for such unreactive substrates are consistent with a highly reactive electrophile. 

The equilibrium constant for the second-order attachment of a substrate to the active site of an enzyme was found to be 326 at 310 K. At the same temperature, the rate constant for the second-order attachment is 7.4 X 107 L-mol-s. What is the rare constant for the loss of unreacted substrate from the active site (the reverse of the attachment reaction) ... 

If R is tertiary, RCOmay lose CO to give R, so that the alkylarene ArR is often a side product or even the main product. This kind of cleavage is much more likely with relatively unreactive substrates, where the acylium ion has time to break down. For example, pivaloyl chloride (McaCCOCl) gives the normal acyl product with anisole, but the alkyl product MesCPh with benzene. In the other mechanism an acyl cation is not involved, but the 1 1 complex attacks directly. 

Separation of the unreacted substrate from the resulting product may in certain cases be difficult or troublesome. 

The assay of enzymes whose reactions are not accompanied by a change in absorbance or fluorescence is generally more difficult. In some instances, the product or remaining substrate can be transformed into a more readily detected compound. In other instances, the reaction product may have to be separated from unreacted substrate prior to measurement—a process facili-... 

However, when subtilisin E was replaced by subtilisin Carlsberg, the hydrolysis of the S-N bond in some A(-acyl arenesulfinamides 34 unexpectedly became the main hydrolytic process giving under the kinetic resolution conditions, in addition to the unreacted substrates, the corresponding sulfinic acids and... 

The results presented in Tables 3 and 4 deserve some comments. First, a variety of enzymes, including whole-cell preparations, proved suitable for the resolution of different hydroxyalkanephosphorus compounds, giving both unreacted substrates and the products of the enzymatic transformation in good yields and, in some cases, even with full stereoselectivity. Application of both methodologies, acylation of hydroxy substrates rac-41 and rac-43 or the reverse (hydrolysis of the acylated substrates rac-42 and rac-44), enables one to obtain each desired enantiomer of the product. This turned out to be particularly important in those cases when a chemical transformation OH OAc or reverse was difficult to perform. As an example, our work is shown in Scheme 3. In this case, chemical hydrolysis of the acetyl derivative 46 proved difficult due to some side reactions and therefore an enzymatic hydrolysis, using the same enzyme as that in the acylation reaction, was applied. Not only did this provide access to the desired hydroxy derivative 45 but it also allowed to improve its enantiomeric excess. In this way. 

Stereoselective hydrolysis of racemic l-(//-phenylacetylamino) alkanephos-phonic acids performed in the presence of penicillin acylase under the kinetic resolution conditions gave both the unreacted substrates and the products - the corresponding 1-aminophosphonic acids in high yields and with full enantioselec-tivity. The unreacted A -acyl derivatives were hydrolysed chemically and in this way each enantiomer of the free acid was obtained (Scheme 5). ... 

The aminoalkanephosphonic acids which bear an additional hydroxy group in the molecule were usually resolved via enzymatic acylation of this hydroxy group. For example, resolution of //-Cbz-phosphoserine dimethyl ester 60 using various lipases gave poor results. However, lipase PS-promoted acetylation of //-Chz-phosphoisoserine diethyl ester 61 gave both the unreacted substrate 61 and the 0-acetylated product 62 with almost 100% enantiomeric excess (E = 1000). ... 

Much was unknown for the halogenation for unreactive substrates until very recently, when the biosynthesis of the cyclopropyl amino acid side chain of coronatine was elucidated. This intriguing pathway, which involves /-chlorination of an enzyme-bound L-isoleucine followed by chloride displacement by the a-carbon, yields the cyclopropanated precursor... 

The soluble polymer support was dissolved in dichloromethane and treated with 3 equivalents of chloroacetyl chloride for 10 min under microwave irradiation. The subsequent nucleophilic substitution utilizing 4 equivalents of various primary amines was carried out in N,N-dimethylformamide as solvent. The resulting PEG-bound amines were reacted with 3 equivalents of aryl or alkyl isothiocyanates in dichloromethane to furnish the polymer-bound urea derivatives after 5 min of micro-wave irradiation (Scheme 7.75). After each step, the intermediates were purified by simple precipitation with diethyl ether and filtration, so as to remove by-products and unreacted substrates. Finally, traceless release of the desired compounds by cyclative cleavage was achieved under mild basic conditions within 5 min of micro-wave irradiation. The 1,3-disubstituted hydantoins were obtained in varying yields but high purity. 

Another method is based on the same principle,112 in which the [14C]labelled methyl ester of D-galacturonan is prepared by esterification of pectic acid with [,4C]diazomethane. In the course of the enzymic de-esterification, aliquots are removed, and the unreacted substrate is precipitated with acidified ethanol or 1-propanol. After centrifugation, the labelled methanol in the supernatant liquor is determined in a liquid scintillation counter. An advantage of this method lies in the possibility of using, as substrates, short-chain oligo-D-galactosiduronates partially esterified with [14C]methanol. These substrates, beginning with the trisaccharide, are not soluble in 1 4 80% phenol-diethyl ether, which is used for the extraction of enzymically released, labelled methanol. 

Perez and co-workers reported the electron-deficient copper homoscorpionate catalyst TpBr3Cu(NCMe)-catalyzed nitrene insertion into C-H bonds of toluene, mesitylene, and cyclohexane, which are very unreactive substrates (Equations (100)—(102)). In contrast to the former reports, they obtained very high yields for these products. 

Molybdenum catalysts that contain enantiomerically pure diolates are prime targets for asymmetric RCM (ARCM). Enantiomerically pure molybdenum catalysts have been prepared that contain a tartrate-based diolate [86], a binaph-tholate [87], or a diolate derived from a traris-1,2-disubstituted cyclopentane [89, 90], as mentioned in an earlier section. A catalyst that contains the diolate derived from a traris-1,2-disubstituted cyclopentane has been employed in an attempt to form cyclic alkenes asymmetrically via kinetic resolution (inter alia) of substrates A and B (Eqs. 45,46) where OR is acetate or a siloxide [89,90]. Reactions taken to -50% consumption yielded unreacted substrate that had an ee between 20% and 40%. When A (OR=acetate) was taken to 90% conversion, the ee of residual A was 84%. The relatively low enantioselectivity might be ascribed to the slow interconversion of syn and anti rotamers of the intermediates or to the relatively floppy nature of the diolate that forms a pseudo nine-membered ring containing the metal. 

Substituting deuterium for hydrogen gas in the reduction of BT to DHBT with the catalyst precursor [Rh(NCMe)3(Cp )](BF4)2 has shown that the stereoselective ds-deuteration of the double bond is kinetically controlled by the tj2-C,C coordination of BT. The incorporation of deuterium in the 2- and 3-positions of unreacted substrate and in the 7-position of DHBT has been interpreted in terms of reversible double-bond reduction and arene-ring activation, respectively (Scheme 16.14) [55]. 

The sulfoxide method was introduced by Kahne and coworkers,1 and was heralded as a new method for rapid glycosylation of unreactive substrates in high yield under mild conditions. The reaction involves the sulfoxide donor [sulfoxide (I)], an activating agent (usually triflic anhydride), a hindered, nonnucleophilic base (2,6-di-tert-butyl-4-mcthylpyridine, DTBMP) and a nucleophilic acceptor (most often an alcohol) (Scheme 3.1). The glycosylation of sterically hindered steroidal alcohols, phenols and the /V-glycosylation of an acetamide was reported (Table 3.1). 

Dicyclohexylamine (10) is a base employed as counter ion for crystallizing acid-sensitive -protected amino acids and /V-protected amino acids that do not crystallize as the acids. Its use allows removal of unreacted substrate after /V-methylation of trifunctional amino acid derivatives (see Section 8.13). 

A nickel catalysed aldoxime rearrangement, to an amide, went out of control after changing the solvent employed. This was found to be due to a slow start and consequent accumulation of unreacted substrate. Changing to a higher operating temperature restored control to the process [3]. 

This complex easily looses CO, which enables co-ordination of a molecule of alkene. As a result the complexes with bulky phosphite ligands are very reactive towards otherwise unreactive substrates such as internal or 2,2-dialkyl 1-alkenes. The rate of reaction reaches the same values as those found with the triphenylphosphine catalysts for monosubstituted 1-alkenes, i.e. up to 15,000 mol of product per mol of rhodium complex per hour at 90 °C and 10-30 bar. When 1-alkenes are subjected to hydroformylation with these monodentate bulky phosphite catalysts an extremely rapid hydroformylation takes place with turnover frequencies up to 170,000 mole of product per mol of rhodium per hour [65], A moderate linearity of 65% can be achieved. Due to the very fast consumption of CO the mass transport of CO can become rate determining and thus hydroformylation slows down or stops. The low CO concentration also results in highly unsaturated rhodium complexes giving a rapid isomerisation of terminal to internal alkenes. In the extreme situation this means that it makes no difference whether we start from terminal or internal alkenes. 

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