Sterically demanding

Ketones, in which one alkyl group R is sterically demanding, only give the trans-enolate on deprotonation with LDA at —12°C (W.A. Kleschick, 1977, see p. 60f.). Ketones also enolize regioseiectively towards the less substituted carbon, and stereoselectively to the trans-enolate, if the enolates are formed by a bulky base and trapped with dialkyl boron triflates, R2BOSO2CF3, at low temperatures (D A. Evans, 1979). Both types of trans-enolates can be applied in stereoselective aldol reactions (see p. 60f.). 

TBDMSCl, imidazole, DMF, 25°, 10 h, high yields. This is the most common method for the introduction of the TBDMS group on alcohols with low steric demand. The method works best when the reactions are mn in very concentrated solutions. This combination of reagents also silylates phenols, hydroperoxides, and hydroxyl amines. Thiols, amines, and carboxylic acids are not effectively silylated under these conditions. ... 

Although boronates are quite susceptible to hydrolysis, they have been found useful for the protection of carbohydrates. It should be noted that as the steric demands of the diol increase, the rate of hydrolysis decreases. For example, pin-acol boronates are rather difficult to hydrolyze in fact, they can be isolated from aqueous systems with no hydrolysis. 

Fig, 10. Activation entropy requireinents by reacting position as affected by previous substitutions based on Zavitsas [80], As the activation entropy becomes more negative, steric demands on the transition state are more stringent. The effect of previous or/ho-substitution on reaction at the para position is hard to explain, in light of both the reciprocal effect of para substitution on ortho and the effect seen with the d -oriho pre-substitution. 

Acetone, AICI3, Et20, rt, 3.5 h, 80% yield. " Other methods failed in this sterically demanding case. 

Silyl-derived protective groups are also used to mask the thiol function. A complete compilation is not given here, since silyl derivatives are described in the section on alcohol protection. The formation and cleavage of silyl thioethers proceed analogously to those of simple alcohols. The Si-S bond is weaker than the Si-O bond, and therefore, sulfur derivatives are more susceptible to hydrolysis. For the most part, silyl ethers are rarely used to protect the thiol function, because of their instability. Silyl ethers have been used for in situ protection of the-SH group during amide formation. The use of the sterically demanding and thus more stable triisopropylsilyl thioether may prove worthwhile. ... 

Thermal cyclization of the 3-nitro anilide 107 gave a 1 1 mixture of 108 and 109 in excellent yield, though one would expect the nitro group to be more sterically demanding than a hydrogen An interesting difference in the reported... 

Tautomeric equilibrium in the symmetrical phenoxy-substituted derivative 136 (R = Ph, r = R = OPh) is fast at ambient temperature on the NMR time scale however, at —84°C the proton exchange becomes frozen and both annular tautomers 136a and 136b can be observed (Scheme 40). The similar exchange was also found for P-aryl-substituted 136 (R = Me, Ft, Ph R = R = Ph). In these cases, the equilibrium is very slow, even at ambient temperature, which was attributed to increased steric demands of four phenyl substituents. Unsymmetrically substituted azaphosphorinanes (R R ) provide even more interesting examples. These compounds (R = Ph R = Me, -Pr R = MeO, -PrO) were found to... 

The Corey-Winter reaction provides a useful method for the preparation of olefins that are not accessible by other routes. For instance it may be used for the synthesis of sterically crowded targets, since the initial attack of phosphorus at the sulfur takes place quite distantly from sterically demanding groups that might be present in the substrate molecule. Moreover the required vicinal diols are easily accessible, e.g. by the carbon-carbon bond forming acyloin ester condensation followed by a reductive step. By such a route the twistene 10 has been synthesized ... 

Depending on the specific reaction conditions, complex 4 as well as acylium ion 5 have been identified as intermediates with a sterically demanding substituent R, and in polar solvents the acylium ion species 5 is formed preferentially. The electrophilic agent 5 reacts with the aromatic substrate, e.g. benzene 1, to give an intermediate cr-complex—the cyclohexadienyl cation 6. By loss of a proton from intermediate 6 the aromatic system is restored, and an arylketone is formed that is coordinated with the carbonyl oxygen to the Lewis acid. Since a Lewis-acid molecule that is coordinated to a product molecule is no longer available to catalyze the acylation reaction, the catalyst has to be employed in equimolar quantity. The product-Lewis acid complex 7 has to be cleaved by a hydrolytic workup in order to isolate the pure aryl ketone 3. 

The Heck reaction is considered to be the best method for carbon-carbon bond formation by substitution of an olefinic proton. In general, yields are good to very good. Sterically demanding substituents, however, may reduce the reactivity of the alkene. Polar solvents, such as methanol, acetonitrile, N,N-dimethylformamide or hexamethylphosphoric triamide, are often used. Reaction temperatures range from 50 to 160 °C. There are various other important palladium-catalyzed reactions known where organopalladium complexes are employed however, these reactions must not be confused with the Heck reaction. 

In the next step, one of the borane-hydrogens is transferred to a sp -carbon center of the alkene and a carbon-boron bond is formed, via a four-membered cyclic transition state 6. A mono-alkyIborane R-BH2 molecule thus formed can react the same way with two other alkene molecules, to yield a trialkylborane R3B. In case of tri- and tctra-substituted alkenes—e.g. 2-methylbut-2-ene 7 and 2,3-dimethylbut-2-ene 9—which lead to sterically demanding alkyl-substituents at the boron center, borane will react with only two or even only one equivalent of alkene, to yield a alkylborane or mono alky Iborane respectively ... 

The coupling of unsymmetrical ketones leads to formation of stereoisomeric alkenes the ratio depending on steric demand of substituents R ... 

The Pauson-Khand reaction was originally developed using strained cyclic alkenes, and gives good yields with such substrates. Alkenes with sterically demanding substituents and acyclic as well as unstrained cyclic alkenes often are less suitable substrates. An exception to this is ethylene, which reacts well. Acetylene as well as simple terminal alkynes and aryl acetylenes can be used as triple-bond component. 

Of particular synthetic importance is the coupling of aryl- and hetarylboronic acids to aryl- and hetaryl halides (or triflates), allowing for a convenient synthesis of biphenyls, even sterically demanding derivatives such as 14, hetaryl phenyls and Zj/ -hetaryls. With appropriately disubstituted aromatic substrates, the Suzuki coupling reaction can be applied in the synthesis of polyphenylene materials. 

A recently discovered reduction procedure provides a convenient route to axial alcohols in cyclohexyl derivatives (5). The detailed mechanism of the reaction remains to be elucidated, but undoubtedly the reducing agent is an iridium species containing one or more phosphate groups as ligands. In any case, it is clear that the steric demands of the reducing agent must be extraordinary since the stereochemical outcome of the reaction is so specific. The procedure below is for the preparation of a pure axial alcohol from the ketone. 

Some degree of regioselectivity can be imposed on l//-azepine formation if the arene has substituents of high steric demand.63 For example, the thermolysis of ethyl azidoformate in a tenfold molar excess of 1,4-di-fert-butylbenzene yields a 95 5 mixture of the di-zerr-butyl-l//-azcpincs 3 and 4, crystallization of which yields the pure 3,6-di-/er/-butyl isomer 3. 

In some cases, if necessary, a C(3)-regioselective addition of cuprate can be accomplished by the use of a sterically demanding protecting group - such as an -OTr or -OMMTr group - on C(l), as described in the synthesis of the polypropionate segment present in (-)-amphidinolide P and (+)-amphidinolide K [54]. 

In accord with the Felkin-Anh model, a-chiral ketones react more diastereoselectively than the corresponding aldehydes. Increasing steric demand of the acyl substituent increases the Cram selectivity. Due to the size of the acyl substituent, the incoming nucleophile is pushed towards the stereogenic center and therefore the diastereoface selection becomes more effective (see also Section 1.3.1.1.). Thus, addition of methyllithium to 4-methyl-4-phenyl-3-hexanonc (15) proceeds with higher diastercoselectivity than the addition of ethyllithium to 3-methyl-3-phenyl-2-pen-tanone (14)32. 

As well as the modified cuprate reagents, Grignard reagents in the presence of the highly sterically demanding methylaluminum bis(2,4,6-tri-fcrr-butylphenoxide) (MAT, 8) also show considerable anti-Cram selectivity35 36 (Table 9). 

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