Retro-pericyclic reactions

In this section are described those domino reactions which start with a retro-pericy-clic reaction. This may be a retro-Diels-Alder reaction, a retro-l,3-dipolar cycloaddition, or a retro-ene reaction, which is then usually followed by a pericyclic reaction as the second step. However, a combination is also possible with another type of transformation as, for example, an aldol reaction. 

A retro-l,3-dipolar cycloaddition followed by an 1,3-dipolar cycloaddition was used for a highly efficient total synthesis of (-)-histrionicotoxin (4-354) (HTX) by Holmes and coworkers [123]. HTX is a spiropiperidine-containing alkaloid which was isolated by Doly, Witkop and coworkers [124] from the brightly colored poison-arrow frog Dendrobates histrionicus. It is of great pharmacological interest as a noncompetitive inhibitor of acetylcholine receptors. 

Soldermann, J. Velker, O. Vallat, H. Stockli-Evans, R. Neier, Helv. Chim. Acta 2000, 83, 2266-2276. 

Carreno, M. Belen Cid,). L. Garda Ruano, Tetrahedron Asymm. 1996, 7, 2151-2158. 

Sanz Tejedor, I. Vaca,). L Garcia Ruano, Tetrahedron Asymm. 2004, 1059-1063. 

Chowdhury, A. Prelle, D. Schom-burg, M. Thiemann, E. Winterfeldt, Liebigs Ann. Chem. 1987, 1095-1099. 

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In organic chemistry this is called a retro-pericyclic reaction and it should indeed have a low barrier of activation. Under the high vacuum techniques applied, on clean surfaces, the reaction proceeds already below 140 K (the temperature at which desorption of the weakly co-ordinated butadiene is observed). 

An interesting pericyclic-anionic-pericyclic domino reaction showing a high stereoselectivity is the cycloaddition-aldol-retro-ene process depicted in scheme 20.1581 The procedure presumably starts with a [4+2]-cycloaddition of diene 98 and S02 in presence of a Lewis acid. After opening of the formed adduct reaction with (Z)-silyl vinyl ether 99 leads to a mixture of alk-2-enesulfinic acids 101. It follows a retro-ene reaction which affords a 7 3 mixture of the products 102 and 103. The reaction described by Vogel et al is a nice example for the efficient generation of polypropionate chains with the stereoselective formation of three stereogenic centers and one (0-double bond in a three-component domino reaction in its strict definition. 

In the present chapter, however, because the problem is considered from a retrosynthetic point of view, we will distinguish only between heterolytic and homolytic disconnections -to which we will refer to as "retro-annulations"- and concerted or "pericyclic (or cheletropic) cycloreversions". In the same way that Woodward-Hoffmann rules [2] apply to pericyclic reactions, the Baldwin rules [3] may be said to apply to heterolytic as well as to homolytic "monotopic" annulations (see Table 6.1). Although in the preceding Chapter (see 5.5) we have already described some radical "monotopic" annulations, later on in this Chapter (see 6.1.3) and mainly in Chapter 7 we will refer to some new methods, syntheses and strategies which have been developed recently. 

The intermediates 2 and 4 can then be traced back to simple precursors via retro-Diels-Alder condensations, which are very well known stereospecific pericyclic reactions. 

Several types of 1,2-oxazines undergo thermal pericyclic reactions in which the N—O bond is cleaved. Thus (506, R = Me, Ph) undergo a thermal retro Diels-Alder reaction on heating to give the corresponding nitrile and o-benzoquinone methide, which can be intercepted by alkenes (Scheme 56) (90JA5341, 94TL7273). 

On treatment with weak base, 1,3-oxathiolane sulfoxide (80) was shown to undergo a reversible intramolecular ene reaction to sulfenic acid (81). Using stronger base, it was found that this pericyclic reaction cannot compete with elimination to enone (82), which then oxidizes or dimerizes to the observed products (83) and (84). The diastere-omeric sulfoxide (79) was found to undergo retro-ene elimination then dimerization to (85) or to (83) and (84) with even a weak base.85... 

Pericyclic reactions in the synthesis of heterocycles 87YGK60. Pummerer reaction in the synthesis of heterocycles 89KGS1299. Retro-Diels-Alder strategy in the synthesis of heterocycles 87S207. Solid-phase synthesis of heterocycles 89BSF237. 

The factors that make ene and retro-ene reactions proceed are nicely illustrated by a synthesis of enantiopure, isotopically labeled acetic acid CH(D)(T)C02H, a useful compound for studying the mechanisms of enzyme-catalyzed reactions. One ene and one retro-ene reaction occur in this synthesis. The ene reaction is driven by formation of a new tr bond at the expense of a C=C tt bond the retro-ene reaction is driven by the formation of a C=0 77 bond. Note that both pericyclic reactions proceed stereospecifically, even at the very high temperatures required for them to proceed ... 

The oxy-Cope rearrangement can be thermally induced (equation 223, path a) but this process competes with an other well-established, concerted pericyclic reaction, i.e. the /1-hydroxyolefin retro-ene cleavage (path h)-- -. However, it was found that the oxy-Cope rearrangement can be accelerated under base-catalysis conditions (e.g. in the presence of potassium alkoxides) by a factor of I O - (the so-called anionic oxy-Cope rearrangement , path This base-induced acceleration is attributable to a dramatic decrease in the... 

Cycloadditions are characterised by two components coming together to form two new a bonds, one at each end of both components, joining them together to form a ring, with a reduction in the length of the conjugated system of orbitals in each component (Fig. 6.1a). Cycloadditions like the Diels-Alder reaction are by far the most abundant, varied, featureful and useful of all pericyclic reactions. They are inherently reversible, and the reverse reaction is called a retro-cycloaddition or a cycloreversion. 

For some time it has been known that many pericyclic reactions can be greatly accelerated if they are run under single electron transfer (SET) conditions (also known as electron transfer catalysis, ETC). Examples include Diels-Alder reactions, electrocyclic openings of cyclobutenes, and retro [2-1-2] cycloadditions. From the beginning it has been debated whether these SET reactions really are concerted processes with aromatic transition states, or whether they are better thought of as stepwise processes involving radical cation intermediates. 

A major problem in interpreting pericyclic reactions of radical ions is the difficulty of distinguishing between concerted and nonconcerted paths. The same difficulty occurs in the case of thermal reactions, but the problem here is more acute since there is less scope for the application of subtle experimental techniques. Thus cyclohexene (6) undergoes a retro-Diels-Alder reaction to (7) in the mass spectrometer but the products formed do not enable us to distinguish between a two-step process via the intermediate radical ion (8) and a pericyclic process involving the cyclic transition state (9). 

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