Michael-Dieckmann condensation

The atroposelective construction of the 6,6 -biaryl linkage was recognized as the key step in the synthesis of viriditoxin. Although many atroposelective couplings of complex molecules have been completed and have been the subject of many reviews,most of these approaches relied on either proximal stereogenic centers or covalently linked chiral auxiliaries. Our objective was to explore the influence of distal chiral centers on the catalytic oxidative dimerization of naphthopyran-2-ones using vanadium catalysis (Scheme 7). Assembly of naphthopyran-2-ones has been well studied and recently reviewed." The Staunton-Weinreb annulation or the Michael-Dieckmann condensation is ideally suited for the rapid... 

In a more recent publication the same research group described a Cu(OTF)2/(POEt)3-catalyzed two-component Michael/aldol protocol of 2-112 and ZnEt2 leading to annulated cyclopentanols [46]. They showed that the enolate formed in the 1,4-addition can be trapped not only by a keto moiety, but also by an ester (Dieckmann condensation) or a nitrile functionality present in the molecule. Thus, as depicted in Scheme 2.26, there is a broad product variety. Starting from 2-112, compounds of type 2-114, 2-115 and 2-116 can be obtained via the enolate 2-113. 

Scheme 2.29. Domino Michael addition/Dieckmann condensation sequences leading to precursors of natural products.

Besides the Michael addition-initiated domino reactions presented here, a multitude of other anionic domino reactions exist. Many of these take advantage of an incipient SN-type reaction (for a discussion, see above). In addition to the presented SN/Michael transformations [97, 98, 100], a SN/retro-Dieckmann condensation was described by Rodriguez and coworkers, which can be used for the construction of substituted cycloheptanes as well as octanes [123]. Various twofold SN-type domino... 

The reaction starts with the formation of a mixed anhydride and an acetate on treatment with an excess of acetic anhydride at 80 °C. There follows a Dieckmann condensation to give 2-590 and an intramolecular rearrangement/Michael addi-hon/retro Michael addition to afford the desired tetracyclic compound 2-592 via 2-591 in an overall yield of remarkable 92%. 

One of the best methods to synthesize cyclopentenone derivatives is the Pauson-Khand procedure. However, Shindo s group have recently developed a domino process consisting of a [2+2] cycloaddition of a ketone with anynolate, followed by a Dieckmann condensation to give a 3-lactone as 4-190 which is decarboxylated under reflux in toluene in the presence of silica gel to afford cyclopentenones [64a]. Thus, the reaction of 4-188 and 4-189 led to 4-190, which on heating furnished the linear cucumin 4-191 (Scheme 4.41). This natural product has been isolated from the mycelial cultures of the agaric Macrocystidia cucumis [65, 66]. The domino procedure described was also used to synthesize dihydrojasmone and a-cuparenone. Moreover, the [2+2] cycloaddition can be combined with a Michael reaction [64b]. 

Dihydrofuranones can be generated by Michael addition of anions derived from a-hydroxyesters to a,/3-unsaturated substrates. The resulting intramolecular Dieckmann condensation yields substituted furanone rings (Scheme 82) (57HCA1157). 

A very useful method for generating 3 (2H)- dihydrofuranones is based on the Michael addition of anions derived from a-hydroxyesters to a,/3-unsaturated substrates (Scheme 82). The intermediate anion attacks the adjacent ester moiety via a Dieckmann condensation reaction to produce a substituted furanone ring which usually bears useful functionality. Overall yields of 45-60% have been obtained for this reaction. 

Bicyclic keto esters can easily be prepared by a process called a,a -annulation.29 Thus, treatment of the enamine of cyclopentanone (64) with ethyl a-(bromomethyl)acrylate (98) affords, after work-up, the bicyclic keto ester (99) in 80% yield (equation IS).2911 The mechanism probably involves an initial Michael addition and elimination (or a simple Sn2 or Sn2 alkylation) followed by an intramolecular Michael addition of the less-substituted enamine on the acrylate unit. The use of the enamine of 4,4-bis(ethoxycarbonyl)cyclohexanone (100 equation 26) with (98) gives a 45% yield of the adaman-tanedione diester (101) (yield based on 100 70% when based on 98) via a,a -annulation followed by Dieckmann condensation.29 Enamines of heterocyclic ketones can also serve as the initial nucleophiles, e.g. (102) and (103) give (105) via (104), formed in situ, in 70% yield (Scheme 11 ).29>... 

Bridged systems can also be prepared in high yield by this process.84 For example, treatment of the keto diester (348 Scheme 43) with (61) in basic DMSO gave a 41% yield of the diketo diester (352) by way of the intermediates (349) to (351), involving two Michael additions and final Dieckmann condensation.84 Similar processes have also been used to make other bicyclo[3.3.1]nonanes and related com-... 

Key Mechanism 22-12 The Claisen Ester Condensation 1071 22-13 The Dieckmann Condensation A Claisen Cyclization 1074 22-14 Crossed Claisen Condensations 1074 22-15 Syntheses Using /3-Dicarbonyl Compounds 1077 22-16 The Malonic Ester Synthesis 1079 22-17 The Acetoacetic Ester Synthesis 1082 22-18 Conjugate Additions The Michael Reaction 1085 Mechanism 22-13 1,2-Addition and 1,4-Addition (Conjugate Addition) 1085... 

The Dieckmann condensation in tandem with the Claisen condensation or Michael reaction can be used to assemble highly functionalized carbocycles, including the 1,2-, 1,3", and 1,4-dione species depicted belowd ... 

The synthesis of both enantiomers of the antitumor-antibiotic fredericamycin A was achieved in the laboratory of D.L. Boger. The DE ring system of the natural product was assembled via a tandem Michael addition-Dieckmann condensation. The highly substituted 4-methylpyridine precursor was treated with excess LDA followed by the addition of the Michaei acceptor cyciopentenone. The Michael adduct underwent an intramolecular acylation with the ester functionaiity in situ to afford the desired DEF tricycie. 

Synthesis of decalin-1,8-diotte systems. Magnesium methoxide has been used as the base in a one-step synthesis of the above system from cyclohexene-3-one and esters of 2-carboxyglutaric acid. The reaction involves a combined Michael addition and Dieckmann condensation.1 The diketone exists as the ra-enol... 

Synthesis of pyrrolizidines by Dieckmann condensation continues to receive wide attention. It is a useful method for producing pyrrolizidines with oxygen substituents and has been exploited in a number of syntheses by Viscontini and co-workers. For their attempted preparation of 1,7-dioxopyrrolizidine, the very unstable 3-oxopyrrolidine was required as an intermediate.29 This compound was stabilized by ketalization (37), and by this means N-substituted 3-oxopyrrolidines are readily accessible. The 1,7-dioxopyrrolizidine was synthesized as the sodium enolate (38) as shown in Scheme 3. The dione itself is unstable and could not be isolated. Analogous Michael addition of the pyrrolidine (37) to a-chloroacrylic ester gave the corresponding 5,6-dihydropyrrolizine as the sodium salt (39).30 Treatment of this salt with acid produced a very stable H-bonded aromatic species. 

In an aldol addition, the enolate of an aldehyde or a ketone reacts with the carbonyl carbon of a second molecule of aldehyde or ketone, forming a j8-hydroxyaldehyde or a jS-hydroxyketone. The new C—C bond forms between the a-carbon of one molecule and the carbon that formerly was the carbonyl carbon of the other molecule. The product of an aldol addition can be dehydrated to give an aldol condensation product. In a Claisen condensation, the enolate of an ester reacts with a second molecule of ester, eliminating an OR group to form a j8-keto ester. A Dieckmann condensation is an intramolecular Claisen condensation. A Robinson annulation is a ring-forming reaction in which a Michael reaction and an intramolecular aldol addition occur sequentially. 

The product of the double Michael reaction in Example 15.12 is a diester that, when treated with sodium ethoxide in ethanol, undergoes a Dieckmann condensation. Draw the structural formula for the product of this Dieckmann condensation followed by acidification with aqueous HCI. 

Note that aldol, Claisen, and Dieckmann condensations all give primary products with oxygens in a 1,3 relationship. The Michael reaction with enolate anions gives products with oxygens in a 1,5 relationship. These relationships are a consequence of the polarization of the reagents. In aldol, Claisen, and Dieckmann condensations, the carbonyl carbon is positive and the a-position is negative. 

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