Perlmutter Conjugate Addition Reactions in Organic Synthesis

1. Auflage 2013
ISBN: 978-1-4832-9378-3
Verlag: Elsevier Science & Techn.
Format: EPUB
Kopierschutz: Adobe DRM (»Systemvoraussetzungen)

E-Book, Englisch, Band Volume 9, 394 Seiten

Reihe: Tetrahedron Organic Chemistry

This book provides an introduction to the chemistry of conjugate reactions, a group of reactions that constitute one of the most important classes of chemical reactions in organic synthesis. The book is organised in terms of the major classes of conjugate acceptors. Within each of these classes, the chemistry and applications of conjugate additions with several different categories of nucleophiles have been examined. Where several different nucleophiles achieve the same synthetic transformation, they are cross-referenced within the book and qualitative comparisons offered where appropriate. Examples of the use of conjugate additions in total synthesis of important molecules are included, with a special emphasis throughout the book on stereoselectivity. This will be a useful main text for graduate and postgraduate courses on conjugate addition reactions or the Michael reaction. It could also serve as a supplementary text for courses on topics such as the chemistry of organocopper reagents, enamines and carbanion chemistry.

Autoren/Hrsg.

Perlmutter, P.

Perlmutter, Patrick

Leseproben

Chapter Two

Alkenals and Acyclic Alkenones

Publisher Summary

This chapter discusses the intermolecular reactions and intramolecular reactions of alkenais and acyclic alkenones. It presents with conjugate additions of the individual classes of nucleophiles relevant to alkenais and acyclic alkenones. Acyclic alkenones are one of the most important classes of conjugate acceptors. Much of the early work on these additions focused on developing the annulation reaction invented by Robinson. The need to develop an enantioselective version of this reaction led to the investigation of numerous combinations of chiral ligands and catalysts. The failure of organometallic reagents to add to alkenones reproducibly, in a conjugate fashion, also provided the impetus for determining the reasons for this. This led to the discovery of the crucial role of copper in these reactions. There are some aspects that are of particular relevance to the Robinson annulation. In general, it has been found that for the case of unsymmetrical monoketones, reaction usually occurs at the more substituted a-carbon, that is, via the thermodynamic enolate. However, steric constraints can reverse this selectivity. Another useful application of the Robinson annulation is in the synthesis of spirocyclic compounds. The Robinson annulation may also be carried out under acidic conditions. This method, introduced by Heathcock and McMurry in 1971, simply consists of heating a benzene solution of the two reactants in the presence of a catalytic amount of concentrated sulfuric acid.

2 Introduction

Acyclic alkenones are one of the most important classes of conjugate acceptors. Much of the early work on these additions focussed on developing the annulation reaction invented by Robinson (see the first section of this chapter). The need to develop an enantioselective version of this reaction led to the investigation of numerous combinations of chiral ligands and catalysts. Some of these are outlined in the sections that follow. The failure of organometallic reagents to add to alkenones (albeit, originally, cycloalkenones) reproducibly, in a conjugate fashion, also provided the impetus for determining the reasons for this. This led to the discovery of the crucial role of copper in these reactions.

2.1 Intermolecular reactions

2.1.1 Stabilized carbanions

2.1.1.1 Carbanions stabilized by p-conjugation with one heteroatom

Ketone enolates give only products of conjugate addition, even at low temperatures. However, this is probably due to the extended reaction times, as it has been observed previously that aldolates do form, reversibly, at these temperatures.1 Remarkably, the stereoselectivity of the conjugate additions both at low temperature and after allowing the reaction mixtures to warm up is often excellent.2 Furthermore, the stereostructure of the adducts appears to correlate strongly with the enolate geometry. In general, Z enolates gave adducts whereas E enolates gave adducts.

By observing the stereochemical outcome caused by varying the steric demand of substituents in both the enolate and alkenone, Heathcock’s group were able to develop a transition state model for these additions. As shown below the model is based upon an eight-membered, chelated transition state. Everything else being equal, transition states A and C are preferred as these minimize any steric interactions between R1 and R. However, the enolate- correlation breaks down when R is small.

Figure 2.1 Proposed transition state structures for ketone enolate additions to acyclic alkenones

The Robinson annulation3

Of all the applications of the Michael reaction to organic synthesis, the Robinson annulation is undoubtedly the best known.4 The first reaction, reported by Robinson and Rapson,5 involved adding 4-phenyl-3-buten-2-one (benzalacetone) to an ice-cooled solution of the sodium enolate of cyclohexanone (1) producing the octalone (3) in 43% yield.

In the following paper on this topic, Robinson and his co-workers reported that all attempts to apply this method to reactions involving either simple alkenones such as 3-buten-2-one (methyl vinyl ketone) or ß-chloroketones failed.6 Successful annulation was finally achieved by generating the alkenones , using “Mannich salts” such as the methiodide of 1-(diethylamino)butan-3-one:300

This was the first synthetic method for preparing octalone systems bearing an “angular” methyl group, a characteristic feature of the corresponding portion of the steroid nucleus. A reasonable mechanism is provided in the following scheme.

The Robinson annulation suffered from several limitations, each of which has been addressed over the years, and for which solutions have been found, with varying degrees of success. These include:

1. Selectivity of enolate formation

2. Michael addition/competing polymerization

3. Equilibration of intermediate enolates

4. Ring closure (aldol)

5. Dehydration

Only the first two of these issues are directly relevant to this book.

Enolate formation

A general discussion of enolate formation is included in Chapter 1 (carbanions stabilized by p-conjugation with one heteroatom). However, there are some aspects which are of particular relevance to the Robinson annulation. In general, it has been found that, for the case of unsymmetrical monoketones, reaction usually occurs at the more substituted a-carbon, i.e. via the thermodynamic enolate, as in the example of 2-methylcyclohexanone shown above. However, steric constraints can reverse this selectivity,7 e.g.:

A remarkably simple and stereoselective Robinson annulation has been reported by Scanio and Starrett.8 By simply varying the solvent, either or 4,10-dimethyl-1(9)-octal-2-one may be obtained in = 95% isomeric purity. The authors suggested that the

stereoselection obtained in the first case occurs during the initial conjugate addition. A more intriguing mechanism was offered for the second case. As proton transfer is rapid in polar solvents,9 it is possible that 2-methylcyclohexanone is regenerated and the resulting enolate (4) (the butenone serves as the acid) adds to the cyclohexanone. Dehydration, followed by electrocylic rearrangement gives the product with the correct relative stereochemistry. Unfortunately, no supporting mechanistic study has appeared since this work was published.

Takagi’s group has also found that switching from dioxane to dimethylsulfoxide changes the ratio of product isomers significantly.10 The pure isomer is actually obtained in best yield by reacting 3-penten-2-one with a temporarily blocked 2-methylcyclohexanone, (5) in the presence of a catalytic amount of potassium -butoxide.

In order to avoid equilibration, the generation and reaction of a specific enolate must be carried out under kinetic control. (An alternative to this approach is to use the corresponding enamine. Enamines of unsymmetrical ketones generally form at the less substituted a-carbon, i.e. the equivalent to a kinetic enolate, see section 2.1.5). This generally requires the use of aprotic conditions. Even under these circumstances, the rate of conjugate addition still needs to be greater than that of proton transfer from any carbon acid intermediates if reasonable yields of products are to be achieved. The yields can be good, as in the low temperature deprotonation of carvomenthone, which was used in a synthesis of 7-hydroxycalamenene.11

An alternative is to generate the enolate from a trimethylsilylenol ether:12

Various stabilizing groups attached to the a-carbon of (usually cyclic) alkenones ensure that anion generation is regiospecific (also see section 2.1.1.2). An example of the use of a stabilizing group (in this case there is no alternative acidic site!) comes from Woodward’s total synthesis of cholesterol.13

Temporary a-blocking groups

Alternatively, temporary blocking groups can be used to direct enolate formation to the required a-carbon. For example, in his synthesis of (±)-nootkatone, Takagi used a thioalkylidene group to direct enolate formation to the more substituted site of 2-methylcyclohexanone.14 Better selectivity for (±)-nootkatone could be achieved under more forcing conditions using benzyl in place of -butyl, however the yield was low (30%...