Aldol-Michael sequence

The hetero -Diels-Alder (HDA) reaction provides the opportunity to incorporate a heteroatom into the Diels-Alder product. Most commonly the catalytic asymmetric version of this reaction involves the reaction between an aldehyde (8.122) and a reactive diene (8.123) (typically with one or two oxygen substituents attached). Normally, the isolated products, after acidic work-up, are the enones (8.124). The products can either be formed by a direct cycloaddition or via a two step aldol-Michael sequence, according to Figure 8.5. 

Alternatively, the first Aldol-Michael sequence to give chiral products 77 is depicted in Scheme 11.30. This sequential process gave rapid access to the optically active p-arylated ketones 77 in good yields and enantioselectivities [79]. 

Domino transformations combining two consecutive anionic steps exist in several variants, but the majority of these reactions is initiated by a Michael addition [1]. Due to the attack of a nucleophile at the 4-position of usually an enone, a reactive enolate is formed which can easily be trapped in a second anionic reaction by, for example, another n,(5-urisalurated carbonyl compound, an aldehyde, a ketone, an inline, an ester, or an alkyl halide (Scheme 2.1). Accordingly, numerous examples of Michael/Michael, Michael/aldol, Michael/Dieckmann, as well as Michael/SN-type sequences have been found in the literature. These reactions can be considered as very reliable domino processes, and are undoubtedly of great value to today s synthetic chemist... 

Alkenones were used by Rao and coworkers [40] to prepare cyclohexane derivatives which, for example, can be transformed into substituted arenes in a single step. Another interesting intermolecular Michael/intramolecular aldol reaction sequence for the construction of the highly substituted 2-hydroxybicy-clo[3.2.1]octan-8-one framework has been described by Rodriguez group [41]. This process can be extended to a three- and even a fourfold domino reaction [41a, 42, 43],... 

Domino processes involving Homer-Wadsworth-Emmons (HWE) reactions constitute another important approach. Among others, HWE/Michael sequences have been employed by the group of Rapoport for the synthesis of all-cis-substituted pyrrolidines [143], and by Davis and coworkers to access new specific gly-coamidase inhibitors [144]. Likewise, arylnaphthalene lignans, namely justicidin B (2-281) and retrojusticidin B (2-282) [145], have been synthesized utilizing a domino HWE/aldol condensation protocol developed by Harrowven s group (Scheme 2.65) [146]. 

Recently, the Texier-Boullet group [26] has prepared nitrocyclohexanols 10-77 by a twofold Michael addition/aldol reaction sequence (Scheme 10.19). Simply mixing chalcone 10-75 with nitromethane in the presence of a mixture of KF and A1203 under microwave irradiation gave 10-79 via the proposed intermediates 10-76, 10-77 and 10-78 as a single diastereomer in 65 % yield. One possible explanation for the stereoselectivity of the transformation is fixation of the reactive species onto the solid KF/A1203, as depicted in 10-79. 

In the Weiss reaction (Scheme 4), an 7-dicarbonyl compound (38) condenses with two molecules of dimethyl 3-oxoglutarate (39 E = CC Me) to give a c w-bicyclo [3.3.0] oct-ane-3,7-dione tetraester (40) the one-pot reaction produces considerable complexity, with the sequential formation of four C—C bonds. Simple acid treatment removes the carbomethoxy groups, if deshed. While die reaction involves aldol and Michael sequences, die intermediacy of a cyclopentenone [4-hydroxycyclopent-2-enone (41)] has up to now been unproven. A series of such 1 1 adducts has now been reported for a variety of diketones, together with evidence diat diey are indeed intermediates en route to the bicyclo system.62 Electronic and steric effects on the reaction are also discussed in detail. 

Recently, a similar Michael-aldol tandem sequence has been reported, using catalytic amounts of the organolithium reagent. Reactions of a,f)-unsaturated esters with aldehydes were catalyzed by 0.2 equivalents of lithium phenylthiolate in the presence of phenyl... 

The assembly of the cyclohexene derivatives D should be feasible via an organocatalyzed domino Michael/Michael/aldol condensation sequence starting from a linear aldehyde A, a nitroalkene B and an a,(->-unsaturated aldehyde C. 

More significant results are the multi-component condensation by way of Michael-aldol and Michael-Michael-aldol reaction sequences and the Michael-Baylis-Hillman tandem, each leading to cyclohexenes bearing multiple functional groups and stereogenic centers. 

In a related work, a useful procedure for the synthesis of cyclohexenones was also developed by means of the reaction of ethyl benzoylacetate with methyl alkenyl ketones, using primary amine 129 as catalyst in this case. This reaction also consisted of a Michael/intramolecular aldol reaction sequence starting... 

Scheme 7.16 Synthesis of cyclohexenones by cascade Michael/aldol/dehydration sequence.

On the other hand, a triple Michael/Michael/Aldol cascade sequence has been developed for the synthesis of highly substituted cyclohexanes starting from dimethylmalonate, an a,p-unsaturated aldehyde and a nitroalkene in which H-bonding catalysis and iminium activation were jointly employed for the simultaneous activation of the two Michael acceptors involved in the... 

Similarly the bicyclic cyclopropyl ketone 134 is readily converted to the tricyclo[5.3.0.0 - ]decane 135 under similar conditions via a domino ring opening/Michael/aldol reaction sequence as shown in the Scheme 4.27 [45]. The selective attack of the iodide ion at the 6-position of 136 leading to the intermediate 137 may be due to the effective overlap between cleaved bond and the % orbital of the carbonyl group. This novel domino reaction producing polycyclic cyclobutanes was exploited for the synthesis of natural products like ( )-anthoplalone and ( )-lepidozene by the same workers [45]. 

In 2009, Dixon and co-workers [73] developed a nice cascade reaction for the synthesis of cyclohexanes using a similar strategy. Malonates (119), nitroalkenes 28 and a, 3-unsaturated enals 15 reacts in a Michael-Michael-aldol reaction sequence forming the cyclohexanes 122 in good yields and stereoselectivities. The reaction... 

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... 

Enders described a fascinating organocatalytic one-pot asymmetric synthesis of tricyclic compounds using a triple-cascade/Diels-Alder reaction sequence. Combination of dieneal 110 with enal 111 and nitro alkene 112 in the presence of a chiral amine catalyst results in a Michael/Michael/aldol condensation sequence to yield cycloaddition precursor 113. Cooling the reaction mixture and addition of a Lewis acid promotes the desired intramolecular Diels-Alder reaction to selectively afford the highly functionalized tricyclic target 114. ... 

Relying, as in the previous studies, on the capability of secondary amine catalysts to activate both nucleophile and electrophile, Enders assembled a quadruple domino Friedel-Crafts-type/Michael/Michael/aldol condensation sequence, affording an efficient and direct asymmetric synthesis of polyfunctionalized 3-(cyclohexenylmethyl)-indoles 172 with moderate to high yields (Scheme 2.55) [82]. 

SCHEME 2.56 Postulated mechanism for the Friedel-Crafts-type/Michael/Michael/Aldol domino sequence. 

A method for the preparation of higher sugars with an aromatic branch has been developed which involves a Michael addition - aldol condensation sequence and uses carbohydrate silylenol ethers, e.g. compound (42), as starting materials. As is demonstrated in Scheme 9, the Michael addition product was obtained as the stable silylenol ether (43). On desilylation, aldol condensation took place to give the cyclic hydroxyketone (44) which aromatised under acetylation conditions. The introduction of an aromatic branch by Diels-Alder cyclisation of a carbohydrate diene is referred to in Chapter 19. 

One of the first examples of this type of reactions was reported in 2009 by Melchiorre and coworkers with a three-component cascade Michael-Michael-aldol reaction with unsaturated aldehydes as electrophiles or a complementary consecutive Michael-Michael sequence with enones [9]. In the first case (Scheme 10.1),... 

Finally, the most recent efforts of the Hong group provided the tetracyclic scaffold of steroids in a two-component, three-step Michael/Michael/aldol/Henry cascade (Scheme 14.8c) [19]. The preferred catalyst ent)-ll, however, could not deliver the high diastereoselectivity that was obtained in the previous syntheses (56 44 dr). The excellent enantiomeric excess (98/99% ee), on the other hand, encouraged further development of the cascade (Scheme 14.8c). After the Michael/Michael sequence, the medium was acidified to complete the Robinson annulation to enone 64. Interestingly, subsequent treatment with only 0.5 equiv of tetrabutylammonium fluoride (TBAF) effected a very fast reaction to the target tetracycle (63%) at low temperature. 

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