Stereochemistry Conformational Effects

As with our discussion of the reduction of carbonyl compounds in Chapter 10, f-butyl-cyclohexanone makes an interesting structure to probe stereochemical preferences in carbonyl chemistry. Let s look at two specific cases of enolate alkylation the alkylation of 4-f-butylcyclohexanone, and the alkylation of 4-f-butylcyclohexyl methyl ketone. 

Two different trajectories lead to chair- and boat-like transition states giving trans and cis products, respectively. 

In the alkylation of the exocyclic enolates of cyclohexane rings, the reaction occurs predominately to place the electrophile in the equatorial position (Eq. 11.11, path b). The electrophile avoids the hydrogens placed 1,3 to the nucleophilic carbon. However, because these alkylations are exothermic, the transition states are early, and the stereochemistry is not very sensitive to the alkylating agent. 

Even in those cases where both chair forms of the cyclohexane ring are present, interesting stereochemical results for alkylation can be observed. For example, Eq. 11.12 shows another system where conformational analysis provides the explanation for the stereochemical outcome. In the alkylation of a 2-substituted exocyclic enolate, the major product places 

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N.m.r. spectroscopy has played an important part in determining the stereochemistry of the 1,3-dioxaphosphorinanes (52). The presence of the saturated six-membered ring means that there are usually conformational effects to be unravelled before configurational assignments can be made. The chair conformation is generally dominant. Phosphorus substituents which exhibit shielding effects show that in many P " phosphorinanes this substituent occupies an axial position and Sis( has been used to establish the equatorial conformation of a t-butyl substituent at C(5). Even in P" derivatives the isomer possessing the bulkiest P-substituent in an axial... 

The prediction and interpretation of alkylation stereochemistry requires consideration of conformational effects in the enolate. The decalone enolate 3 was found to have a strong preference for alkylation to give the cis ring junction, with alkylation occurring cis to the f-butyl substituent.58... 

Stereochemistry can be interpreted in terms of conformation effects in the 1,4-biradical intermediates.199 Vinyl enol ethers and enamides add to aromatic ketones to give 3-substituted oxetanes, usually with the cis isomer preferred.200... 

Only octahedral complexes have been discussed, mainly because much less is known about conformational effects in other configurations. In some tetrahedral complexes, for example, [Be(OCH2CH20)2]2 or [B(OCH2 CH20)2]-, the ligands may be sufficiently inert to dissociation to be examined with respect to their stereochemistry. Similar remarks apply to planar and other structures. 

Acetal formation involves nucleophilic attack of the OH group on the aldehyde so there is no change at the stereogenic centre. The stereochemistry of the new (acetal) centre may surprise you— why should the as-isomer be so favoured This is a conformational effect as both substituents can occupy pseudoequatorial positions. 

While carrying out this work, which ultimately secured him his Ph.D. in 1953, Mills s main interest remained the stereochemistry of ring systems. In 1952, the writer and Mills met in Cambridge they soon realized their common interest in conformational effects, although one approached them through the terpenes and the other through carbohydrates. The result of this meeting was a review [Rev. Pure Appl. Chem., 2,185-202(1952)], probably the first one written on conformational analysis. 

Let us examine the stereochemistry of pinacolic deamination in some detail.. In this we shall see the operation of a factor we have not yet encountered in rearrangements conformational effects. More important, we shall get some idea of the methods used to attack problems like this. 

Valuable preparative applications are rare and especially in ring-forming reactions other stereochemical factors such as ring strain and conformational effects will determine the stereochemistry. However the use of metal compounds to influence regio- and stereo-selectivity continues to excite interest. For C—C bond formation the coupling of allylic acetates with organocuprates offers broad synthetic potential as it generally seems to proceed with double bond shift. ... 

Tetrahydronaphthalene epoxide hydrolysis conformational effects on stereochemistry of diol formation 267... 

TETRAHYDRONAPHTHALENE EPOXIDE HYDROLYSIS CONFORMATIONAL EFFECTS ON STEREOCHEMISTRY OF DIOL FORMATION... 

Stereochemistry.—The multiplicity of bands which arise from conformational effects have been analysed and correlated with those obtained by other spectroscopic techniques. Raman spectra and torsional barriers at 14 and 190 K have been reported for trimethylphosphine (128), its chalcogenides, and the deuterium analogues. Rotational barriers have been calculated from the microwave and vibrational spectra of the difluoride (129). Restricted rotation about the P—N bonds of aminophos-... 

The concerted mechanism that operates in Claisen rearrangements permits predictions concerning the stereochemistry of the reaction on the basis of conformational effects in the transition state. This transition state is believed usually to have a chair-like conformation. " The new double bond produced in the rearrangement is... 

These examples serve to illustrate some of the ways in which stereochemistry can affect reactivity. In later chapters and in Part B, other examples will be given as specific reactions are discussed. One other important point relating conformation to reactivity will be raised in Chapter 4. This is the Curtin-Hammett principle, which states an important limitation on the validity of arguments that attribute reactivity differences to conformational effects. 

The importance of conformational effects on RCM-based macrocychzations was also highlighted by Bajwa and Jennings, who discoimected aigialomycin D at the Cl -C2 linkage (Scheme 7.22c) [83]. It was shown that the stereochemistry at C6 dramatically influences the outcome of the macrocyclization. RCM on triene 196 led to the exclusive formation of six-membered ring, whereas the reaction on the 6 -epimer of 196 was efficient in generating the 14-membered macrocycle [83]. 

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