Intramolecular double Michael addition

M. ihara and co-workers utilized an intramolecular double Michael addition for the efficient and completely stereoselective construction of the tricyclo[6.3.0.0 ]undecan-10-one framework during the total synthesis of (+)-longiborneol. The substituted cyciopentenone precursor was exposed to several different reaction conditions, and the highest yield was obtained when LHMDS was used as the base. The first deprotonation took place at C11 the resulting enolate added to C9, and the ester enolate (negative charge located at CIO) in turn added to the cyciopentenone at C3. 

The Larock modified Saegusa oxidation conditions were utilized in the total synthesis of ( )-8,14-cedranoxide by M. lhara et al. The main strategy was to apply an intramolecular double Michael addition reaction to assemble the tricyclic cedranoid skeleton. The precursor five-membered enone was prepared in high yield from the corresponding substituted cyclopentanone in two steps. 

Takasu, K., Mizutani, S., Noguchi, M., Makita, K., lhara, M. Total Synthesis of ( )-Culmorin and ( )-Longiborneol An Efficient Construction of Tricyclo[6.3.0.03,9]undecan-10-one by Intramolecular Double Michael Addition. J. Org. Chem. 2000, 65, 4112-4119. 

On the other hand, the vinylphosphonate 186 easily underwent the intramolecular double Michael addition of diethyl sodiomalonate to give the bicycle 189. Moreover, by making use of the -ketovinylphosphonate moiety in 186 the Japanese group was able to synthesize dicyclopent-l-enyl ketones which, when treated with acid, led to the Nazarov cyclization products 190 having three condensed five-membered rings (Scheme 46). 

Forsyth, C.J. Hao, J. Aiguade, J. (2001) Synthesis of the (-i-)-C26-C40 domain of the azaspiric acids by a novel double intramolecular hetero-Michael addition strategy. Angew. Che. Int. Ed. Engl., 40, 3663-7. 

Only three examples of intramolecular organocatalyzed and enantioselective Michael additions of C-nucleophiles seem to have been reported in the literature. In 1979 Wynberg and ten Hoeve reported the (—)-quinine-catalyzed double Michael addition of the 1,3-diones 74a,b to the 1,5-disubstituted pentadien-3-ones 75a-c (Scheme 4.37) [61]. 

Scheme 16.6. Construction of the FGHI rings of azaspiracid-1 using a double intramolecular hetero-Michael addition (Forsyth 2001).

Special attention should be given to the MIRC reaction of 2-bromobut-2-enoates with cyclohexenones, e.g. 1 and Table 10. When first cyclohexenone was added to a lithium diiso-propylamide solution, tricyclo[3.2.1.0 ]octan-6-ones were formed in 20-55% yield via double Michael addition, followed by intramolecular displacement. However, when ethyl 2-bro-mobut-2-enoate was first added to a lithium diisopropylamide solution, vinylcyclopropanes were formed in good yield (Table 10, entries 1-2). Other chalcones have also been used to produce vinylcyclopropanes (entries 3-8) with reasonable success. 

Synthesis by Other Cyclizations. The epimeric amines (49) have been made by means of a novel S 2 reaction of the corresponding 2-bromo-6-amino-cyclohexanone derivative. Double Michael addition of (+)-a-methylbenzyl-amine to cyclo-octa-2,7-dienone derivatives forms the basis of a synthesis of the enantiomeric forms of adaline (50). Intramolecular Friedel-Crafts alkylation has been used in the synthesis of derivatives of the 2,6-methanobenz-azepine, 2,6-methano-3-benzazocine, 2,6-methano-3-benzazonine, and... 

A double Michael addition has been observed in the intermolecular reaction of the a, p-unsaturatedacylanthraquinone, 1 -hydroxy-2-(1 -oxopent-2-enyl)anthra-quinone illustrated with tert-butyl cyanoacetate followed by an intramolecular cyclisation of the product. The whole sequence was conducted at ambient temperature during 6 hours in dimethylformamide to give a substituted benzohydroxyanthraquinone in 75% yield (ref.84). 

Intramolecular tandem Michael addition-amide formation in the intermediate (291) afforded an epilupinine precursor (Scheme 60) <89H(29)1209>. Another quinolizidine synthesis forming two a bonds in its key step is the reductive double alkylation of azido epoxides with an (o leaving group (292). This strategy has been applied to the synthesis of ring-expanded analogues of indolizidine alkaloids (e.g. (293)) from D-arabinose (Scheme 61) <93TL822l>. 

Numerous new examples of cyclopentenone synthesis from acetylenehexacarbonyl-dicobalt complexes and norbornene derivatives have been disclosed there is evidence of steric control, and the bulky trimethylsilyl group can be employed as a removable direction-determining group to allow synthesis of 3- instead of 2-sub-stituted cyclopentenones. Reaction of (731) with sodamide in toluene gave the new octahydro-2,5-methanoazulene system (732 R = CONHj) successive hydrolysis, reduction, and esterification converted (732 R = CONHj) into (732 R = CHjOTs) which, on solvolysis, gave the homoprotoadamantane derivative (733 X = H, R R = CH2) in high yield.The carboxylic acid (732 R = COjH) underwent spontaneous Friedel-Crafts intramolecular acylation on conversion into its acid chloride to give (733 XX = O R R = CHj) and (733 XX = O, R = Cl, R = Me). Reaction of methyl a-bromocrotonate (mixture of E- and Z-isomers) with the enolates of cyclohex-2-enone affords a mixture of stereoisomeric tricyclo-[3,2,l,0 ]octan-6-ones (734 R —R are variously H or alkyl) in moderate yield. The reaction involves double Michael addition and subsequent substitution. 

Several elegant examples of a double Michael addition sequence (inter-molecular followed by intramolecular) leading to complex fused-ring systems have been published this year (Scheme and Ghatak et al. ° describe... 

This was shown with ketoester 231. The reaction sequence starting with enolate 232 can be interpreted either as a double Michael addition or as an intramolecular Diels-Alder cycloaddition (see 232). 

Double Intramolecular Hetero-Michael Addition (DIHMA)... 

Alternatively, a double intramolecular hetero-Michael addition (DIHMA) can be used to assemble a spiroacetal from an a,p-ynone (Scheme 61). NMR smdies have shown that, in accordance with Baldwin s rules, initial 6-endo-dig cyclization rather than 6-exo-dig is favored. Subsequent 5-exo-trig cyclization furnishes the 5,6-spiroacetal [132]. The corresponding 6,6-spiroacetals are obtained in an analogous manner. 

Scheme 61 Double intramolecular hetero-Michael addition in the synthesis of spiroacetals...

The synthesis of a series of 6,6-bisbenzannulated spiroketals has been achieved by a novel microwave-assisted double intramolecular hetero-Michael addition approach, with good yield (Choi et al, 2009). In this synthesis, coupling of an aryl acetylene and an aryl aldehyde led to an alky mol via acetylide anion addition, which was followed by oxidation to give the desired ynone. Spirocyclization afforded bis-benzannulated spiroketals. 

The TT-allylpalladium complexes 241 formed from the ally carbonates 240 bearing an anion-stabilizing EWG are converted into the Pd complexes of TMM (trimethylenemethane) as reactive, dipolar intermediates 242 by intramolecular deprotonation with the alkoxide anion, and undergo [3 + 2] cycloaddition to give five-membered ring compounds 244 by Michael addition to an electron-deficient double bond and subsequent intramolecular allylation of the generated carbanion 243. This cycloaddition proceeds under neutral conditions, yielding the functionalized methylenecyclopentanes 244[148], The syn-... 

Michael addition of the enamine to the 1,3-enyne double bond (intermediate 151) and subsequent intramolecular attack of the triple bond by the amino group (intermediate 152) with the r XH elimination (formation of 2,6-isomer 148). 

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