Cycloaddition reactions allowed stereochemistry

The Diels-Alder reaction is an allowed thermal six-electron (4 + 2) cycloaddition reaction between a diene (contributing four pi electrons to the transition state) and dienophile (contributing two pi electrons). It is an extremely useful cycloaddition because it goes in high yield and with predictable stereochemistry. The stereochemistry of both the starting pieces is preserved in the product for example, if two groups on the dienophile are cis, they remain cis in the product. 

A firm mechanistic understanding of concerted cycloadditions had to await the formulation of the reaction mechanism within the framework of molecular orbital theory. Consideration of the molecular orbitals of reactants and products revealed that in some cases a smooth transformation of orbitals of the reactant to those of the product is possible. In other cases, reactions that appear feasible, if no consideration is given to the symmetry and spatial orientation of the orbitals, are found to require high-energy transition states when the orbital properties are considered in detail. Those considerations have permitted description of many types of cycloadditions as allowed or forbidden. As has been discussed (Part A, Chapter 10), the application of orbital-symmetry relationships permits a conclusion as to whether a given concerted reaction is or is not energetically feasible. In this chapter, the synthetic application of these reactions will be emphasized. The same orbital-symmetry relationships that are informative as to the feasibility of a given reaction often are predictive of features of the stereochemistry of cycloaddition products. This predictable stereochemistry is an attractive feature for synthetic purposes. 

The addition of alkenes to dienes is a very useful method for the formation of six-membered carbocyclic rings. The reaction is known as the Diels-Alder reaction. The concerted nature of the mechanism was generally agreed on and the stereospecificity of the reaction was firmly established even before the importance of orbital symmetry was recognized. In the terminology of orbital-symmetry classification, the Diels-Alder reaction is a [ 4,+ 2 ] cycloaddition, an allowed process. The stereochemistry of both the diene and the alkene (the alkene is often called the dienophile) is retained in the cyclization process. The transition state for addition requires the diene to adopt the s-cis conformation. The diene and alkene approach... 

Diastereomers of 13 were separated before the cycloaddition reaction since only one isomer was expected to adopt the sterically less demanding conformation in the transition state while the other diastereomer would suffer from severe steric congestion. Both diastereomers of precursor 13 were treated with KHMDS and the propynyliodonium salt, 12. The tandem cycloaddition reaction of the substrate 13a, to our pleasant surprise, gave tetraquinane product 11 in 50% yield, while 13b did not yield any cycloaddition product. These results allowed us to determine the relative stereochemistry of 13a and 13b as depicted. The sequential formation of alkylidene carbene and the TMM diradical intermediates transformed the cyclopentane substrate with a linear chain into the tetracyclic compound (Scheme 4). The core stmcture... 

Among the cycloaddition reactions that have been shown to have general synthetic utility are the [2 + 2] cycloadditions of ketenes and alkenes. The stereoselectivity of ketene-alkene cycloaddition can be analyzed in terms of the Woodward-Hoffmann rules. To be an allowed process, the [ 2 + 2] cycloaddition must be suprafacial in one component and antarafacial in the other. Figure 6.5 illustrates the transition state. The ketene, utilizing the low-lying LUMO, is the antarafacial component and interacts with the HOMO of the alkene. The stereoselectivity of ketene cycloadditions can be rationalized in terms of steric effects in this transition state. Minimization of interaction between the substituents R and R leads to a cyclobutanone in which these substituents are cis. This is the stereochemistry observed in these reactions. 

Our synthesis of the p-lactam nucleus was based upon the highly efficient [2+2] cycloaddition approach.(14) Thus fluoroacetyl chloride is allowed to react with an optically active imine 8, which was obtained by condensation of p-anisidine with (D)-glyceraldehyde acetonide. The product of this cycloaddition reaction, a single diastereomer of 3-fluoro-2-azetidinone 9, was formed in 68% yield in 99% ee.(14) The absolute stereochemistry of this product was confirmed by single-crystal X-ray diffraction studies.(14)... 

According to frontier molecular orbital theory (FMO), the reactivity, regio-chemistry and stereochemistry of the Diels-Alder reaction are controlled by the suprafacial in phase interaction of the highest occupied molecular orbital (HOMO) of one component and the lowest unoccupied molecular orbital (LUMO) of the other. [17e, 41-43, 64] These orbitals are the closest in energy Scheme 1.14 illustrates the two dominant orbital interactions of a symmetry-allowed Diels-Alder cycloaddition. 

Reactions of 1 with epoxides involve some cycloaddition products, and thus will be treated here. Such reactions are quite complicated and have been studied in some depth.84,92 With cyclohexene oxide, 1 yields the disilaoxirane 48, cyclohexene, and the silyl enol ether 56 (Eq. 29). With ( )- and (Z)-stilbene oxides (Eq. 30) the products include 48, ( > and (Z)-stilbenes, the E- and Z-isomers of silyl enol ether 57, and only one (trans) stereoisomer of the five-membered ring compound 58. The products have been rationalized in terms of the mechanism detailed in Scheme 14, involving a ring-opened zwitterionic intermediate, allowing for carbon-carbon bond rotation and the observed stereochemistry. 

In this primer, Ian Fleming leads you in a more or less continuous narrative from the simple characteristics of pericyclic reactions to a reasonably full appreciation of their stereochemical idiosyncrasies. He introduces pericyclic reactions and divides them into their four classes in Chapter 1. In Chapter 2 he covers the main features of the most important class, cycloadditions—their scope, reactivity, and stereochemistry. In the heart of the book, in Chapter 3, he explains these features, using molecular orbital theory, but without the mathematics. He also introduces there the two Woodward-Hoffmann rules that will enable you to predict the stereochemical outcome for any pericyclic reaction, one rule for thermal reactions and its opposite for photochemical reactions. The remaining chapters use this theoretical framework to show how the rules work with the other three classes—electrocyclic reactions, sigmatropic rearrangements and group transfer reactions. By the end of the book, you will be able to recognize any pericyclic reaction, and predict with confidence whether it is allowed and with what stereochemistry. 

The Woodward-Hoffmann rules also allow the prediction of the stereochemistry of pericyclic reactions. The Diels-Alder reaction is an example of (re4s + re2s) cycloaddition. The subscript s, meaning suprafacial, indicates that both elements of the addition take place on the same side of the re-system. Addition to opposite sides is termed antarafacial. The Woodward-Hoffmann rules apply only to concerted reactions and are derived from the symmetry properties of the orbitals involved in the transition state. These rules may be summarised as shown in Table 7.1. 

No reaction is observed when 50 and 1,1-dimethoxyethene are allowed to stand in the dark for an equivalent period of time. Irradiation of 50 with 4 equiv. of cyclohexene in methylene chloride solvent gives a 51% isolated yield of the (2 + 2)-cyclo-adduct 52 assigned cis-anti-cis stereochemistry. These two cycloadditions were the first two well defined examples of the (2 + 2)-photocycloaddition reaction of an olefin to a carbon-nitrogen double bond. With furan the (2 + 2)-photocycloadduct 53 is formed, again regiospecifically. 

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