Oxidation-Michael addition sequence

In 2012, Rueping et al. reported the proline-mediated reaction of 1,3-diketones with aldehydes to provide 2-hydroxy-3,4-dihydro-2//-pyran derivatives in good to excellent yields [46]. The reaction mechanism involves a Knoevenagel-Michael addition sequence with subsequent hemiacetalization. The haniacetal was oxidized with TPAP/ NMO or PCC to give the corresponding lactones 96. An enantioselective variant utilizing stoichiometric amounts of an... 

The method was applied to the synthesis of (-t-)-l9-nortestosterone by the following sequence of reactions. Michael addition of the bisannulation reagent 124 to the optically active keto ester 129 and decarboxylation afforded 130, and subsequent aldol condensation gave 131. Selective Pd-catalyzed oxidation of the terminal double bond afforded the diketone 132 in 78% yield. Reduction of the double bond and aldol condensation gave ( + )-19-nortestosterone (133)[114]. 

Our own group is also involved in the development of domino multicomponent reactions for the synthesis of heterocycles of both pharmacologic and synthetic interest [156]. In particular, we recently reported a totally regioselective and metal-free Michael addition-initiated three-component substrate directed route to polysubstituted pyridines from 1,3-dicarbonyls. Thus, the direct condensation of 1,3-diketones, (3-ketoesters, or p-ketoamides with a,p-unsaturated aldehydes or ketones with a synthetic equivalent of ammonia, under heterogeneous catalysis by 4 A molecular sieves, provided the desired heterocycles after in situ oxidation (Scheme 56) [157]. A mechanistic study demonstrated that the first step of the sequence was a molecular sieves-promoted Michael addition between the 1,3-dicarbonyl and the cx,p-unsaturated carbonyl compound. The corresponding 1,5-dicarbonyl adduct then reacts with the ammonia source leading to a DHP derivative, which is spontaneously converted to the aromatized product. 

An unexpected rearrangement of a 1,3-bishomocubyl ring system [262] accompanies an attempted nitration. The oxidative conditions are requisite for the transformation of a 1,3-dinitro substitution pattern to one with a disjoint polarity sequence (contra-polarization involved). The unusual contrathermodynamic reaction is allowed to occur because of the special steric confinement of the functionalized carbon atoms. The initial fragmentation and Michael addition are also set up by the proper disposition of the nitro groups. 

The important intermediate 66 of the steroid synthesis has been prepared by the application of the same reaction sequence to 2-methyl-1,3-cyclohexanedione (65) (Scheme 22). A synthesis of (+) 19-nortestosterone (69) starts with the Michael addition of the optically active oxo ester 67 to 1,7-octadien-3-one (59) catalyzed by sodium hydride, the ester group being removed by heating in aqueous HMPA with sodium iodide to give the dione 68. The aldol condensation catalyzed by sodium hydroxide proceeds in 90% yield. The terminal double bond is oxidized with PdCl2/CuCl to the methyl ketone and the internal olefinic double bond subsequently hydrogenated. The final reaction step involves aldol condensation in refluxing... 

Michael addition has been applied to the formation of cyclopropanic systems. Thus, the addition of phosphonate carbanions generated by LDA in THF, by NaH in THF, by thallium(I) ethoxide in refluxing THF, or by electrochemical technique to oc,P-unsaturated esters provides a preparation of substituted 2-(alkoxycarbonyl)cyclopropylphosphonates in moderate to good yields via a tandem Michael addition-cyclization sequence (Scheme 8.47). The cyclopropanation has also been achieved via oxidation with iodine in the presence of KF-AI2O3. Nitrile ylides prepared from acyl chlorides and diethyl isocyanomethylphosphonate in the presence of Et3N react with methyl acrylates by a 1,3-dipolar cycloaddition to give phosphoryl pyrrolines or pyrroles. ... 

Phenols have been condensed with alkenoylesters to give chromans by an oxa-Michael addition/electrophilic aromatic addition sequence with magnesium(II)- or copper(II)-bis-oxazoline complexes as chiral Lewis acid catalysts (Scheme 17b) [97]. This reaction may be initiated by an oxa-Michael reaction, followed by a hydroarylation of a carbonyl group. The authors suggest that the initial stereodetermining oxa-Michael addition is followed by a fast diastereoselective aromatic substimtion [97]. A nickel Lewis acid, derived from Ni(hfacac)2 (hfacac = 1,LL5,5,5-hexafluoro-3,5-dioxopentane enolate) and chiral Al-oxide ligands, catalyzes the enantioselective oxa-Michael cyclization of 2-tert-butyloxycarbonyl-2 -hydroxy-chalcones to 3-ferf-butoxycarbonyl flavanones, which can be decarboxylated to flavanons in a separate step (Scheme 17c) [98]. A Lewis acid activation of the unsaturated p-ketoester unit can be assumed. 

Recendy, we described a useful sequence where Michael-acceptor sulfoxides 30 were obtained in two steps from homopropargylic alcohols 29 by radical addition of thiophenol and oxidation with sodium periodate. The unsaturated sulfoxides were used in a highly stereoselective intramolecular oxa-Michael reaction. The sequence provided stereoselective functionalization of the sulfoxide moiety, and the products 31 proved to be useful in the synthesis of modified furanosides 32. This represents a good exanple where sugars are prepared from acyclic precursors. The Michael addition was followed by a hydrolytic Pummerer reaction, yielding protected a-hydroxy aldehydes tScheme 20.8) that upon acidic treatment afforded 3-substituted ribofuranoses. 

A method for the reductive alkylation of enediones was developed by Stork for incorporation in the synthesis of corticosteroids such as ( )-D-homoadrenosterone (48) and ( )-adrenosterone (50). Attempted reductive alkylation of 46 by aprotic Michael addition using silyl enones was found to be ineffective thus equatorial alkylation with the modified Wichterle reagent was found to proceed stereoselectively to afford the dione 47. Subsequent elaboration through a Wichterle sequence and hydrolysis/Jones oxidation of the Cl 7a formate provided ( )-D-homoadrenosterone (48). 

The Michael condensations can take place between molecules or intramolec-ularly to yield a cyclic product. As an example of the former, the reaction between mesityl oxide and acetone yields three products, two of which arise from the aldol-dehydration sequence and the third one is the result of a Michael addition of... 

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