The one-pot intramolecular double Michael reaction of compounds having two different α, β-unsaturated carbonyl groups to form polycyclic compounds can be carried out by three different methods: in the first the substrate is treated with lithium hexamethyldisilazide, in the second with chlorotrimethylsilane, triethylamine, and zinc chloride at an elevated temperature, and in the third with tert-butyldimethylsilyl trifluoromethanesulfonate and triethylamine. The reaction proceeds with complete regioselectivity and high stereoselectivity following a stepwise mechanism. Spiro-fused bicyclo[2.2.2]octane derivatives can be constructed with high stereoselectivity by the intromolecular double Michael reaction by using the first method. Enantiomerically pure atisine and the enantiomer of atisirene were synthesized stereoselectively by application of this methodology. The syntheses of steroids and angular triquinane-type sesquiterpenoids were possible with the second method. Heterocyclic compounds with a bridgehead nitrogen atom were obtained by the reaction of α, β-unsaturated amides following the second and third methods. The asymmetric synthesis of tylophorine with diastereofacial control was achieved by the intramolecular reaction according to the third method. The sulfur-mediated intramolecular double Michael reaction utilizing the third method produced trans-hydroindane derivatives. Furthermore, the intramolecular Michael-aldol reaction can be employed in synthesizing polycyclic systems with cyclobutane units by treatment with tert-butyldimethylsilyl trifluoromethanesulfonate in the presence of triethylamine. The intermolecular double Michael reaction and related reactions will also be described.

Syntheses of Polycyclic Natural Products Employing the Intramolecular Double Michael Reaction

Stereochemistry of the Base‐Promoted Michael Addition Reaction

The addition of stabilized nucleophiles to activated π-systems is one of the oldest and most useful constructive methods in organic synthesis, dating back more than a hundred years. In 1887 Michael, after whom the most well-known example of this reaction was named, published the first of a series of papers on this reaction describing the addition of the sodium salt of both diethyl malonate (1) and ethyl acetoacetate (2) to ethyl cinnamate (3) to give the products (4) and (5), respectively (equation 1).1 This Michael reaction, in which a carbanion stabilized by one or usually two electron-withdrawing groups adds to the β-carbon of an α,β-unsaturated carbonyl derivative, represents one of the earliest and most highly utilized methods for carbon–carbon bond formation. In that same 1887 paper,1a Michael also reported the synthesis of triethyl cyclopropane-1,1,2-tricarboxylate (9) from (1) and ethyl α-bromoacrylate (6) via the intermediates (7) and (8), a synthetic route to cyclopropanes used often today (Scheme 1). In 1894 he showed that an alkynic ester could also function as the electrophilic component in these reactions, e.g. (1) and (10a) or (10b) giving (11a) or (11b), respectively (equation 2).2 This reaction and its variants were in wide use around the turn of the century to prepare straight chain polycarboxylates, e.g. the reaction of (12) to give (13; equation 3) and cyclohexane-1,3-diones, e.g. (15; equation 4) (via Knoevenagel and Claisen condensations).3 The combination of Michael addition followed by intramolecular aldol condensation and decarboalkoxylation furnishes cyclohexenones, e.g. isophorone (17; equation 5), from enones such as mesityl oxide (16) and the salt of ethyl acetoacetate (2).4 This process of annulation was made much more general in the 1930s by Robinson and his coworkers,5 who showed that vinyl ketones and their derivatives, e.g. Mannich bases, could be used with simple ketone enolates to produce cyclohexenones of a wide variety, e.g. (20; equation 6), a process which has come to be known as the Robinson annulation.6

Stabilized Nucleophiles with Electron Deficient Alkenes and Alkynes

Recent advances in the synthesis of indan systems. a review

Like its intermolecular counterpart, the intramolecular Michael reaction involves the addition of a nucleophile, often referred to as the donor, to an acceptor, usually an olefin bearing one or more functional groups capable of stabilizing a carbanion.



Strictly speaking, the term Michael reaction refers to the 1,4-, or conjugate, addition of a carbanion to an acceptor under basic conditions. However, just as the scope of a previous review dealing with the Michael reaction was expanded to encompass a wide range of acceptors and noncarbon-centered donors, so too has the scope of this chapter. Furthermore, reactions occurring under both basic and acidic conditions are discussed.



As suggested by the name, the intramolecular Michael reaction most often leads to the formation of a ring, either carbo- or heterocyclic. However, there are many examples of sequential, or tandem, Michael reactions wherein the first inter- or intramolecular Michael reaction is followed directly by an intramolecular variant leading to the formation of more than one ring. In other instances, a nucleophile is delivered to the β-carbon atom of an acceptor in a process which does not lead to the production of a ring. These transformations are referred to as heteroconjugate addition reactions.



In contrast to the intermolecular counterpart, the intramolecular Michael reaction has been formally reviewed only once. Two contemporary publications, however, have focused on the reaction and serve to highlight recent developments. The first example dates back to 1898 when Guthzeit reported that on standing at room temperature for a year, or upon treatment with a “small amount” of pyridine, ethyl α-carboxyglutaconate transforms to the “bimeric” ester. Subsequent reinvestigation by Ingold and co-workers led to the revised structure and to the suggestion that it arose via an initial inter- followed by an intramolecular Michael reaction.



The first systematic study of the intramolecular Michael reaction appeared in 1945. Thus, treatment of a variety of substituted ethyl coumarinates with sodium alkoxide in alcohol solvent leads to coumarins. Of particular interest is the fact that the reaction proceeds efficiently even when the β carbon of the acceptor is substituted with two sterically demanding groups. This apparent lack of retardation by double substitution at the β carbon contrasts sharply with the intermolecular Michael reaction and appears to be general. Another example highlighting the susceptibility of sterically hindered systems to participate in intra- but not intermolecular Michael reactions comes from studies concerning the mode of activation of the antibiotics calicheamicin and esperamicin.



Access to the tetracyclic precursor of a taxol analog was achieved via an intramolecular Michael addition to the relatively hindered β carbon of enone.



The intramolecular Michael reaction again formed the subject of publications appearing in 1951, 1957, and 1962. During the 1960s, comparatively little study or use of the reaction was reported. A notable and historically significant exception, however, was Corey's use of it in a total synthesis of longifolene.



This approach to the construction of tricyclic systems is similar to that suggested mechanistically in the base-induced conversion of santonin to santonic acid.



The 1970s and 1980s witnessed a dramatic increase in uses of the intramolecular Michael reaction. Much of the chemistry discussed in this chapter focuses upon material discovered during this time period.


Keywords:

intramolecular Michael reaction;
mechanism;
stereoelectronic control;
scope;
limitations;
retro reactions;
sequential reactions;
Lewis acid promoted cyclizations;
method comparisons;
oxygen donor;
nitrogen donor;
carbon donor;
acceptors;
silyl enol ethers;
allylic silanes;
propargylic silanes;
Diels-Alder reaction;
experimental procedure;
chelation control;
aldol condensation

The Intramolecular Michael Reaction

Intramolecular double Michael reaction of the α,β-unsaturated enone ester (5) using lithium hexamethyldisilazide produced the tricyclo[5.2.2.01,5] undecane derivative (4) in a highly stereoselective manner. The annulation of (5) was further investigated under various conditions. The tricyclic compound (4) was converted into the tetracyclo[7.3.1.04,12.05,13]tridecane derivative (31), the CDF part of Aconitum alkaloids, via a Wagner–Meerwein-type rearrangement.

Stereocontrolled synthesis of the CDF part of Aconitum alkaloids via intramolecular double Michael reaction

o-Anisaldehyde has been converted, via a [3,3]sigmatropic reaction and a Birch reduction, into the cyclohexenone (10) bearing an α,β-unsaturated group. Treatment of the latter with lithium hexamethyldisilazide induced an intramolecular double Michael reaction to give the tricyclo[6.2.2.01,6]dodecane derivative (12)(60%) as a single isomer. The annelation of (20) also yielded the corresponding tricyclic compound (21)(50%).

Highly stereocontrolled construction of tricyclo[6.2.2.0]dodecanes by intramolecular double Michael reaction

Intramolecular double Michael reaction of the α,β-unsaturated enone ester gave the tricyclo[ 5.2.2.01,5]undecane derivative, which was stereoselectively converted into the tricyclo[6.2.1.04,9]undecane derivative.

Stereocontrolled synthesis of tricyclo[6.2.1.04.9]undecane ring system of aconitium alkaloids

The title reaction of the ester (II) yields the derivative (III), which is transformed to the product (VIII) via a Wagner-Meerwein-type rearrangement of the mesylated precursor (VI).

Mariko Abe

Papers

Stereocontrolled synthesis of the CDF part of Aconitum alkaloids via intramolecular double Michael reaction

Highly stereocontrolled construction of tricyclo[6.2.2.0]dodecanes by intramolecular double Michael reaction

Stereocontrolled synthesis of tricyclo[6.2.1.04.9]undecane ring system of aconitium alkaloids

Stereocontrolled Synthesis of the CDF Part of Aconitum Alkaloids via Intramolecular Double Michael Reaction.