Quaternary centres

The quaternary centre must be removed before an aromatic ring can be seen so a reverse Michael disconnection gives enone (29)j available from (30j) bj ... 

Smith and co-workers have employed NHC 81 to catalyse the 0- to C-carboxyl transfer of a range of oxazolyl carbonates 80, forming 82 with the generation of a C-C bond at a quaternary centre with good catalytic efficiency [27], This transformation presumably proceeds via the generation of an intermediate carboxyazolium species, and has been utihsed as a component of domino multi-component reactions [28], as well as the rearrangement of indolyl and benzofuranyl carbonates (Scheme 12.15) [29]. 

Nair and co-workers have demonstrated NHC-catalysed formation of spirocyclic diketones 173 from a,P-unsaturated aldehydes 174 and snbstitnted dibenzylidine-cyclopentanones 175. Where chalcones and dibenzylidene cyclohexanones give only cyclopentene products (as a result of P-lactone formation then decarboxylation), cyclopentanones 175 give only the spirocychc diketone prodncts 173 [73]. Of particular note is the formation of an all-carbon quaternary centre and the excellent level of diastereoselectivity observed in the reaction. An asymmetric variant of this reaction has been demonstrated by Bode using chiral imidazolium salt 176, obtaining the desymmetrised product with good diastereo- and enantioselectivity, though in modest yield (Scheme 12.38) [74],... 

As an extension of this work, these authors have applied this catalyst system to vinylogous asymmetric Mukaiyama-type aldol reactions, involving silyl vinyl ketene acetals and pyruvate esters. These reactions afforded the corresponding y,5-unsaturated a-hydroxy diesters with quaternary centres in high yields and enantioselectivities of up to 99% ee (Scheme 10.25). It was shown that the presence of CF3CH2OH as an additive facilitated the turnover of the catalyst. 

The interaction between two adjacent bulky groups can depend on steric factors which are not necessarily related to the stability of the radicals produced on homolysis. It is estimated from linear free energy relationships that only 65-70% of the ground-state strain energy is relieved in the transition state for homolysis of a bond between two quaternary centres (Ruchardt and Beckhaus, 1980, 1986). Thus steric constraints to delocalization in the radicals produced may persist. A pertinent example is 2,3-di(l-adamantyl)-2,3-dimethylbutane [123] which has four such centres, linked by the long C-C bonds characteristic of this sort of structure. The strongest... 

The synthesis of modhephene (54), which proceeds according to plan in an overall yield of >16%, with complete control of relative stereochemistry, demonstrates the ability of radical cyclisations to form propellane systems and generate highly crowded neopentyl quaternary centres. The accepted pathway for the cyclisation of the vinyl trimethylstannane is shown in Scheme 7.25. The chair-like transition state in which the methyl substituent on the radical is pseudoequatorial, accounts for the observed endo stereoselectivity. 

It is found that quaternary salts of 1,3-azoles are deprotonated at C-2 in the same way. Rates of deprotonation are considerably faster because of the influence of the quaternary centre that provides a favourable inductive effect. The conjugate base bearing opposite charges on adjacent atoms is termed an... 

More recently, an elegant strategy for the creation of chiral quaternary centres was reported by Marek and coworkers (equation 27)30. 

The chromium(II) version of the Reformatsky reaction of 191 with ketones also generates a-adducts, thus giving access to adjacent quaternary centres. Reactions are carried out using the CrCl2/LiI system65 at room temperature in a variety of polar solvents. The... 

At Tokyo College of Pharmacy [284], esters of 2-(trifluoromethyl)propenoic acid were used to synthesise 16,16,16-trifluororetinal (Eq. 101). Intermolecular Lewis acid-catalysed Diels-Alder reaction with a pantolactone chiral auxiliary allowed the diastereoselective construction of the core cyclohexenone portion with the quaternary centre set in the desired absolute configuration. 

The experiment is used for solving simple structural problems, for the evaluation of chemical shifts and the determination of the multiplicities of individual carbon signals (including quaternary centres). 

An efficient way to create, enantioselectively, all-carbon quaternary centres, by the unprecedented asymmetric conjugate addition of Grignard reagents to enones has been developed using a copper catalyst and a chiral diaminocarbene ligand of the corresponding salt (19) or (20).87... 

The mechanism was deduced by a number of mechanistic arguments. As in most mechanistic determinations, the first conclusions come from eliminating other mechanisms. In this case, Sn2 substitution is not possible because of the steric hindrance at quaternary centres where substitution takes place. Likewise, an SN1 mechanism can be ruled out because the intermediate, R2(N02)C+, would have a cationic centre on the carbon next to the strongly electron-withdrawing nitro group. 

Hydroxyaldehydes, with an intervening quaternary centre, have been synthesized enantioselectively by direct aldol reactions of oqa-dialkylaldehydes with aromatic aldehydes, using a chiral bifunctional pyrrolidine sulfonamide organocatalyst.118... 

This time another cyclic amine, pyrrolidine was used to make the enamine 107 and acylation occurred cleanly at carbon in spite of the formation of a quaternary centre. The wide ranging yields are for different Ar groups.21 The intermediate is an iminium salt 108 that can be isolated. The equilibrium methods used earlier for 1,3-dicarbonyl compounds would not work here as the product 104 cannot form a stable enolate. 

An example1 that shows how good these reactions can be is the addition of the cyclopentadione 21 with acrolein in water to give the adduct 23 in 100% yield. This must be a reaction of the enol 22 and, even though the Michael acceptor is an aldehyde and a new quaternary centre is created, no acid or base is needed. 

Among the best specific enol equivalents for Michael addition are silyl enol ethers that are rather beyond the scope of this book but are treated in detail in Strategy and Control. So the silyl enol ether 54 of the ester 53 adds to the enone 55 with Lewis acid catalysis to give a reasonable yield of the ketoester 56 considering that two quaternary centres are joined together.6... 

A diastereoselective synthesis of all. fy -2,3,6-trisubstitutcd tetrahydropyran-4-ones 1039 via an intramolecular Prins cyclization of enecarbamates 1038 with aldehydes is used during a formal synthesis of (+)-ratjadone (Equation 403) <2004JA12216>. Similarly, tetrahydropyran-4-ones bearing quaternary centres a-to the carbonyl are accessible via a Lewis acid-mediated Prins cyclization of silyl enol ether substrates <2004JA15662>. 

Cuparene 244 contains two adjacent quaternary centres, and by adding TMEDA Bailey was able to make it in 76% yield from 243.126 Although the standard conditions for halogen-metal exchange employ two equivalents of f-BuLi, in this case it turned out that the second equivalent added directly to the styrene double bond.127 One equivalent turned out to give acceptable yields. 

When the alkene trap is 1,1-disubstituted, cyclisation of a tertiary benzylic organolithium gives a product with two adjacent quaternary centres. Krief applied this type of cyclisation to the synthesis of cuparene 244136 using a different disconnection from the one used by Bailey (above). Though it is irrelevant to the synthesis of cuparene, the cyclisation of 257 to 258 is also stereoselective and produces a single stereoisomer of 259 on carbonation of the cyclised organolithium. The tertiary organolithium is too basic to cyclise in THF and in this solvent... 

Nitrile-stabilized anions are so nucleophilic that they will react with alkyl halides rather well even when a crowded quaternary centre (a carbon bearing no H atoms) is being formed. In this example the strong base, sodium hydride, was used to deprotonate the branched nitrile completely and benzyl chloride was the electrophile. The greater reactivity of benzylic electrophiles compensates for the poorer leaving group. In DMF, the anion is particularly reactive because it is not solvated (DMF solvates only the Na+ cation). 

Base catalysis is not required for conjugate addition. If the nucleophile is sufficiently enolized under the reaction conditions then the enol form is perfectly able to attack the unsaturated carbonyl compound. Enols are neutral and thus soft nucleophiles favouring conjugate attack, and p-dicarbonyl compounds are enolized to a significant extent (Chapter 21). Under acidic conditions there can be absolutely no base present but conjugate addition proceeds very efficiently. In this way methyl vinyl ketone (butenone) reacts with the cyclic P-diketone promoted by acetic acid to form a quaternary centre. The yield is excellent and the triketone product is an important intermediate in steroid synthesis as you will see later in this chapter. 

It is even possible to use a silyl enol ether to create a new C-C bond that joins two new quaternary centres. In this example the silyl ketene acetal does conjugate addition on an unsaturated ketone catalysed by the usual Lewis acid (TiCl4) for such reactions. 

Anions of nitro compounds form quaternary centres with ease in additions to a,(3-unsaturated mono- and diesters. The difference between acidity of the protons next to a nitro group and those next to the esters in the products combined with the very mild basic conditions ensure that no unwanted Claisen condensations oecur. 

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