Bulky esters

The conversion of carboxylic acid derivatives (halides, esters and lactones, tertiary amides and lactams, nitriles) into aldehydes can be achieved with bulky aluminum hydrides (e.g. DIBAL = diisobutylaluminum hydride, lithium trialkoxyalanates). Simple addition of three equivalents of an alcohol to LiAlH, in THF solution produces those deactivated and selective reagents, e.g. lithium triisopropoxyalanate, LiAlH(OPr )j (J. Malek, 1972). 

E. Vedejs (1978) developed a general method for the sterically controlled electrophilic or-hydroxylation of enolates. This uses a bulky molybdenum(VI) peroxide complex, MoO(02)2(HMPTA)(Py), which is rather stable and can be stored below 0 °C. If this peroxide is added to the enolate in THF solution (base e.g. LDA) at low temperatures, oneO—O bond is broken, and a molybdyl ester is formed. Excess peroxide is quenched with sodium sulfite after the reaction has occurred, and the molybdyl ester is cleaved to give the a-hydroxy car-... 

The first practical method for asymmetric epoxidation of primary and secondary allylic alcohols was developed by K.B. Sharpless in 1980 (T. Katsuki, 1980 K.B. Sharpless, 1983 A, B, 1986 see also D. Hoppe, 1982). Tartaric esters, e.g., DET and DIPT" ( = diethyl and diisopropyl ( + )- or (— )-tartrates), are applied as chiral auxiliaries, titanium tetrakis(2-pro-panolate) as a catalyst and tert-butyl hydroperoxide (= TBHP, Bu OOH) as the oxidant. If the reaction mixture is kept absolutely dry, catalytic amounts of the dialkyl tartrate-titanium(IV) complex are suflicient, which largely facilitates work-up procedures (Y. Gao, 1987). Depending on the tartrate enantiomer used, either one of the 2,3-epoxy alcohols may be obtained with high enantioselectivity. The titanium probably binds to the diol grouping of one tartrate molecule and to the hydroxy groups of the bulky hydroperoxide and of the allylic alcohol... 

A catalytic enantio- and diastereoselective dihydroxylation procedure without the assistance of a directing functional group (like the allylic alcohol group in the Sharpless epox-idation) has also been developed by K.B. Sharpless (E.N. Jacobsen, 1988 H.-L. Kwong, 1990 B.M. Kim, 1990 H. Waldmann, 1992). It uses osmium tetroxide as a catalytic oxidant (as little as 20 ppm to date) and two readily available cinchona alkaloid diastereomeis, namely the 4-chlorobenzoate esters or bulky aryl ethers of dihydroquinine and dihydroquinidine (cf. p. 290% as stereosteering reagents (structures of the Os complexes see R.M. Pearlstein, 1990). The transformation lacks the high asymmetric inductions of the Sharpless epoxidation, but it is broadly applicable and insensitive to air and water. Further improvements are to be expected. 

In peptide syntheses, where partial racemization of the chiral a-carbon centers is a serious problem, the application of 1-hydroxy-1 H-benzotriazole ( HBT") and DCC has been very successful in increasing yields and decreasing racemization (W. Kdnig, 1970 G.C. Windridge, 1971 H.R. Bosshard, 1973), l-(Acyloxy)-lif-benzotriazoles or l-acyl-17f-benzo-triazole 3-oxides are formed as reactive intermediates. If carboxylic or phosphoric esters are to be formed from the acids and alcohols using DCC, 4-(pyrrolidin-l -yl)pyridine ( PPY A. Hassner, 1978 K.M. Patel, 1979) and HBT are efficient catalysts even with tert-alkyl, choles-teryl, aryl, and other unreactive alcohols as well as with highly bulky or labile acids. 

The o-keto ester 513 is formed from a bulky secondary alcohol using tricy-clohexylphosphine or triarylphosphine, but the selectivity is low[367-369]. Alkenyl bromides are less reactive than aryl halides for double carbonyla-tion[367], a-Keto amides are obtained from aryl and alkenyl bromides, but a-keto esters are not obtained by their carbonylation in alcohol[370]. A mechanism for the double carbonylation was proposed[371,372],... 

Increa sing the bulkiness of the alkyl group from the esterifying alcohol in the ester also restricts the motion of backbone polymer chains past each other, as evidenced by an increase in the T within a series of isomers. In Table 1, note the increase in T of poly(isopropyl methacrylate) over the / -propyl ester and similar trends within the butyl series. The member of the butyl series with the bulkiest alcohol chain, poly(/-butyl methacrylate), has a T (107°C) almost identical to that of poly(methyl methacrylate) (Tg = 105° C), whereas the butyl isomer with the most flexible alcohol chain, poly( -butyl methaciylate), has a T of 20°C. Further increase in the rigidity and bulk of the side chain increases the T. An example is poly(isobomyl methacrylate)... 

The separation of Hquid crystals as the concentration of ceUulose increases above a critical value (30%) is mosdy because of the higher combinatorial entropy of mixing of the conformationaHy extended ceUulosic chains in the ordered phase. The critical concentration depends on solvent and temperature, and has been estimated from the polymer chain conformation using lattice and virial theories of nematic ordering (102—107). The side-chain substituents govern solubiHty, and if sufficiently bulky and flexible can yield a thermotropic mesophase in an accessible temperature range. AcetoxypropylceUulose [96420-45-8], prepared by acetylating HPC, was the first reported thermotropic ceUulosic (108), and numerous other heavily substituted esters and ethers of hydroxyalkyl ceUuloses also form equUibrium chiral nematic phases, even at ambient temperatures. 

In contrast to the hydrolysis of prochiral esters performed in aqueous solutions, the enzymatic acylation of prochiral diols is usually carried out in an inert organic solvent such as hexane, ether, toluene, or ethyl acetate. In order to increase the reaction rate and the degree of conversion, activated esters such as vinyl carboxylates are often used as acylating agents. The vinyl alcohol formed as a result of transesterification tautomerizes to acetaldehyde, making the reaction practically irreversible. The presence of a bulky substituent in the 2-position helps the enzyme to discriminate between enantiotopic faces as a result the enzymatic acylation of prochiral 2-benzoxy-l,3-propanediol (34) proceeds with excellent selectivity (ee > 96%) (49). In the case of the 2-methyl substituted diol (33) the selectivity is only moderate (50). 

The bulky triphenylmethyl group has been used to protect a variety of amines such as amino acids, penicillins, and cephalosporins. Esters of N-trityl a-amino acids are shielded from hydrolysis and require forcing conditions for cleavage. The a-proton s also shielded from deprotonation, which means that esters elsewhere in the molecule can be selectively deprotonated. 

The stereoselective reactions in Scheme 2.10 include one example that is completely stereoselective (entry 3), one that is highly stereoselective (entry 6), and others in which the stereoselectivity is modest to low (entries 1,2,4, 5, and 7). The addition of formic acid to norbomene (entry 3) produces only the exo ester. Reduction of 4-r-butylcyclohexanone (entry 6) is typical of the reduction of unhindered cyclohexanones in that the major diastereomer produced has an equatorial hydroxyl group. Certain other reducing agents, particularly sterically bulky ones, exhibit the opposite stereoselectivity and favor the formation of the diastereomer having an axial hydroxyl groi. The alkylation of 4-t-butylpiperidine with benzyl chloride (entry 7) provides only a slight excess of one diastereomer over the other. 

The most satisfactory method of dehydrating 12a-alcohols appears to be through the sulfonate esters Engel and coworkers have shown (ref. 236 and ref. cited therein) that treatment of such sulfonates with alumina gives A -compounds. The reaction appears to be subject to steric acceleration in that bulky IToc-substituents and cw-fused A-rings aid elimination, and that yields increase with increasing size of the sulfonate employed. 

In contrast to phosphorus esters, sulfur esters are usually cleaved at the carbon-oxygen bond with carbon-fluorine bond formation Cleavage of esteri nf methanesulfonic acid, p-toluenesidfonic acid, and especially trifluoromethane-sulfonic acid (tnflic acid) by fluoride ion is the most widely used method for the conversion of hydroxy compounds to fluoro derivatives Potassium fluoride, triethylamine trihydrofluoride, and tetrabutylammonium fluoride are common sources of the fluoride ion For the cleavage of a variety of alkyl mesylates and tosylates with potassium fluoride, polyethylene glycol 400 is a solvent of choice, the yields are limited by solvolysis of the leaving group by the solvent, but this phenomenon is controlled by bulky substituents, either in the sulfonic acid part or in the alcohol part of the ester [42] (equation 29)... 

The Diels-Alder reactions of the methyl or ethyl ester of benzenesulfonylindole-2-acrylic acid with several l-alkoxycarbonyl-l,2-dihydropyridines are reported and only a single stereoisomer was obtained, as in the case of l-methoxy(ethoxy)-carbonyl-1,2-dihydropyridines. However, when the Diels-Alder reaction of 17 was carried out with 8g[R = (CHsjsC], a mixture of two stereoisomers 18gand25were obtained in a 1 1 ratio (65% total yield). The bulky rerr-butyl group creates sufficient steric interference with the indole ring to cause the loss of stereochemistry ... 

In these equations, Dmax is the larger of the summed values of STERIMOL parameters, Bj, for the opposite pair 68). It expresses the maximum total width of substituents. The coefficients of the ct° terms in Eqs. 37 to 39 were virtually equal to that in Eq. 40. This means that the a° terms essentially represent the hydrolytic reactivity of an ester itself and are virtually independent of cyclodextrin catalysis. The catalytic effect of cyclodextrin is only involved in the Dmax term. Interestingly, the coefficient of Draax was negative in Eq. 37 and positive in Eq. 38. This fact indicates that bulky substituents at the meta position are favorable, while those at the para position unfavorable, for the rate acceleration in the (S-cyclodextrin catalysis. Similar results have been obtained for a-cyclodextrin catalysis, but not for (S-cyclodextrin catalysis, by Silipo and Hansch described above. Equation 39 suggests the existence of an optimum diameter for the proper fit of m-substituents in the cavity of a-cyclodextrin. The optimum Dmax value was estimated from Eq. 39 as 4.4 A, which is approximately equivalent to the diameter of the a-cyclodextrin cavity. The situation is shown in Fig. 8. A similar parabolic relationship would be obtained for (5-cyclodextrin catalysis, too, if the correlation analysis involved phenyl acetates with such bulky substituents that they cannot be included within the (5-cyclodextrin cavity. 

For acyclic systems, the anti diastereoselectivity of the (i )-enolates is lower than the syn diastereoselectivity of comparable (Z)-enolates. For example, carboxylic acid esters, which form predominantly ( )-enolates, react with aldehydes with high anti selectivity only in those cases where bulky aromatic substituents are in the alcoholic part of the ester22 25. 

Enhancement of anti selectivity can be achieved by using more bulky alkyl groups (see table over, entries 1 -4) or phenoxy esters (entries 5 7)11. 

As first described by Krizan and Martin,6 the in situ trapping protocol, i.e., having the base and electrophile present in solution simultaneously, makes it possible to lithiate substrates that are not applicable in classical ortho-lithiation reactions.7 Later, Caron and Hawkins utilized the compatibility of lithium diisopropylamide and triisopropyl borate to synthesize arylboronic acid derivatives of bulky, electron deficient neopentyl benzoic acid esters.8 As this preparation illustrates, the use of lithium tetramethylpiperidide instead of lithium diisopropylamide broadens the scope of the reaction, and makes it possible to functionalize a simple alkyl benzoate.2... 

The primary OH group can be selectively blocked by the bulky triphenyl-methyl (trityl) moiety, followed by esterification at the secondary OH groups and removal of the protecting trityl group. Thus 2,3-di-O-acetyl cellulose has been obtained by this procedure. Moreover, regioselectively substituted mixed cellulose esters, acetate/propionate, were prepared by subsequent acy-... 

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