Domino Michael/intramolecular aldol reactions

Application of this work to a domino process using 51 involves Michael addition of P-ketoesters [91], p-diketones or P-ketosulfones [92] to a,P-unsaturated ketones followed by an intramolecular aldol reaction provides highly functionalised cyclohexanone building blocks with up to four contiguous chiral centres. Gryko has also reported examples of this domino Michael/intramolecular aldol reaction in the coupling of 1,3-diketones and methyl vinyl ketone using L-proUne as catalyst [93],... 

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],... 

Cortistatin A has been synthesized by the Nicolaou and Chen groups and includes a domino sequence of Michael addition, generating a specific enolate and intramolecular aldol reaction. The cycloheptane unit is formed with an ether bridge which is an integral part of the final structure (Scheme 7) [42]. 

The precursor dihydroxyacetone dimer 223 and aldehyde 27.7. underwent a domino sequence to afford the interesting hexahydrofuro[3,4-c]furane in excellent yields [114]. In this example by Vicario, in the oxa-Michael/aldol/hemiacetalization process, an iminium ion species formed between organocatalyst 1 and enal 222 reacts with the structurally interesting dihydroxyacetone dimer 223, providing the intermediate enamine which undergoes an intramolecular aldol reaction (Scheme 7-47). The high stereocontrol of the reaction (about 90-99% ee and 10 1 dr) was proposed to involve the reversibility of oxa-Michael addition and a predicted fast aldol condensation and/or dynamic kinetic resolution process where the chiral catalyst 1 accelerates the aldol reaction for one diastereoisomer over the other. For a mechanistic rationale of this reaction please, see Chapter 8. 

Chen and co-workers [72] reported an asymmetric quadruple amino catalytic domino reaction catalyzed by secondary amines. The reaction consists of a quadruple iminium-enamine-iminium-enamine cascade reaction initiated by a Michael addition of oxindole 114 to the enal and a subsequent intramolecular Michael reaction between the enamine formed in the previous step and the unsaturated oxindole to yield intermediate 116. Next, this intermediate reacts with another molecule of enal via a Michael addition of the oxindole to the enal. The sequence ends with an intramolecular aldol reaction between the preformed enamine and the aldehyde. This organocascade reaction affords highly complex spirooxindoles 118 bearing six contiguous chiral centers in excellent yields and with excellent diastereo- and enantioselectivities (Scheme 10.31). 

Domino Sequences Involving Oxindoles as Pronucleophiles Another commonly used approach for the synthesis of spirooxindoles relies on the use of simple oxindoles as pronucleophiles with several Michael acceptors. For example, we developed a highly enantioselective methodology for the synthesis of spirooxindoles by a Michael-Michael-aldol cascade (Scheme 10.19) [30]. Simple 2-oxindole (58) undergoes two consecutive Michael reactions with enals 16 catalyzed by the Jprgensen-Hayashi catalyst I. Next, an intramolecular aldol reaction catalyzed by the same catalyst takes place to afford, after dehydration, the corresponding spirooxindoles 59. 

Alternatively, Wang and coworkers reported a highly enantioselective domino thia-Michael/aldol sequence using bifunctional thiourea-tertiary amine catalysts to afford spirocyclic compound 76 [43]. ( )-Benzylidene chromanone derivatives 74 reacted with 2-mercaptobenzaldehydes 75 in the presence of a bifunctional tertiary amine-thiourea catalyst XVIII. The thia-Michael addition to the benzylidene was followed by an intramolecular aldol reaction between the resulting enolate and the aldehyde moiety. As shown in Scheme 10.26, the reaction afforded the highly functionalized spirocycles in excellent yields and stereoselectivities. 

With regard to the reaction mechanism of the asymmetric domino Michael-aldol reaction, it was proposed that the diphenylprolinol ether 34 formed the intermediate iminium ion 147a from a,p-unsaturated aldehyde (Scheme 1.56). 1,4-Addition then occurred with the tautomeric structure of 1,2-cyclohexadione, resulting in the Michael adduct 147b, an activated enamine that subsequently underwent an intramolecular aldol reaction. 

A SN reaction-based domino route to clerodane diterpenoid tanabalin (2-488) [258] has been described by Watanabe s group (Scheme 2.111) [259]. This natural product is interesting as it exhibits potent insect antifeedant activity against the pink bollworm, Pectinophora gossypiella, a severe pest of the cotton plant The domino sequence towards the substituted trans-decalin 2-487 as the key scaffold is induced by an intermolecular alkylation of the (5-ke toes ter 2-484 with the iodoalkane 2-483 followed by an intramolecular Michael addition/aldol condensation (Robin-... 

Application of an organocatalytic domino Michael addition/intramolecular aldol condensation to the preparation of a series of important heterocycles has recently received much attention [158] with methods being disclosed for the preparation of benzopyrans [159-161], thiochromenes [162-164] and dihydroquinolidines [165, 166]. The reports all use similar conditions and the independent discovery of each of these reactions shows the robust nature of the central concept. A generalised catalytic cycle which defines the principles of these reports is outlined in Fig. 10. Formation of iminium ion 102 is followed by an intermolecular Michael addition of an oxygen, sulfur or nitrogen based nucleophile (103) to give an intermediate... 

Using diarylprolinol ether 55 in conjunction with an additional base, a domino Michael/aldol/intramolecular Sj 2 process has been developed that led to highly functionalised epoxy cyclohexanones 110, with excellent control of three of the chiral centres generated (Scheme 42) [169]. Despite the apparent complexity, these reactions proceed at room temperature in less than 24 h and the products contain significant potential for a host of further transformations. 

Scheme 42 Organocatalytic domino Michael/aldol/intramolecular S 2 reactions...

The Baylis-Hillman reaction of pyran-4-ones and chromones with aldehydes is efficiently catalysed by NaOMe or DBU <04JOC8413> and when applied to salicylaldehyde and cyclohexenone a tetrahydroxanthen-l-one results possibly via a domino Michael addition and intramolecular aldol condensation <04AG(E)115>. 

The reactions of malonate derivatives 62 and Michael acceptor 63 have delivered cyclohexene derivatives 67 in moderate to good yields in the presence of DBU (Scheme 4.22). This domino process involves the sequential Michael addition of 62 to the appropriate Michael acceptor 63 to give 64, intramolecular aldol-type cyclization to 65, dehydration to 66, and DBU-promoted dealkoxycarbonylation to 67. This method provides an efficient construction of highly functionalized cyclohexene derivatives starting from easily available MBH adducts. 

When a vinylogous aldol reaction occurs, an a,P-unsaturated carbonyl compound is generated, which may react in a subsequent intramolecular Michael addition. In 2005, the group of Erase [20] introduced a domino reaction of several salicylaldehy-des and senecioaldehydes to produce tricyclic hemiacetals 39 (Scheme 8.12). Only one stereoisomer was formed in the presence of sodium carbonate with various salicylaldehydes. y-Deprotonation of senecioaldehyde followed by a vinylogous aldol... 

An intramolecular domino Michael/aldol reaction starting from the chiral Cope products 58 was developed by the group of Schneider [27], After 1,4-addition of... 

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