Michael-aldol cyclization

Intramolecular Michael-aldol cyclization One route to a hydrindane involves base-catalyzed cyclization of the keto aldehyde 1 to the hydrindene 2. Although Zr(0-/-Pr)4 is useful, Zr(0-n-Pr)4 is the most satisfactory base, both in respect to yield and selectivity. 

Intramolecular Michael-aldol cyclization This silyl triflatc (I) in combination with NEt3 can effect cyclization of a, /3-enoalcs substituted by a keto group to a polycyclic system fused to a cyclobutane. Thus reaction of (E)-2 with 4 equiv. of 1 and 7... 

Scheme 8.16 Desymmetrization of enone-diones via a Michael/aldol cyclization [26aj.

Carbonyl condensation reactions are widely used in synthesis. One example of their versatility is the Robinson anuulation reaction, which leads to the formation of an substituted cyclohexenone. Treatment of a /3-diketone or /3-keto ester with an a,/3-unsaturated ketone leads first to a Michael addition, which is followed by intramolecular aldol cyclization. Condensation reactions are also used widely in nature for the biosynthesis of such molecules as fats and steroids. 

Krische and coworkers [44] developed a Rh-catalyzed asymmetric domino Michael/aldol reaction for the synthesis of substituted cyclopentanols and cyclohex-anols. In this process, three contiguous stereogenic centers, including a quaternary center, are formed with excellent diastereo- and enantioselectivity. Thus, using an enantiopure Rh-BINAP catalyst system and phenyl boronic acid, substrates 2-108 are converted into the correspondding cyclized products 2-109 in 69-88% yield and with 94 and 95% ee, respectively (Scheme 2.24). 

Besides the domino Michael/SN processes, domino Michael/Knoevenagel reactions have also been used. Thus, Obrecht, Filippone and Santeusanio employed this type of process for the assembly of highly substituted thiophenes [102] and pyrroles [103]. Marinelli and colleagues have reported on the synthesis of various 2,4-disubstituted quinolines [104] and [l,8]naphthyridines [105] by means of a domino Michael addition/imine cyclization. Related di- and tetrahydroquinolines were prepared by a domino Michael addition/aldol condensation described by the Hamada group [106]. A recent example of a domino Michael/aldol condensation process has been reported by Brase and coworkers [107], by which substituted tetrahydroxan-thenes 2-186 were prepared from salicylic aldehydes 2-184 and cycloenones 2-185 (Scheme 2.43). 

The stereoselective intramolecular Henry reactions have been reported by Seebach. The Michael addition of doubly deprotonated acetyl acetaldehyde to l-methylenedioxyphenyl-2-nitroethene followed by subsequent intramolecular nitro-aldol cyclization leads to the diastereomerically pure cyclohexanone derivative, where the nitro and OH groups are cis as shown in Eq. 3.73.114 This reaction is applied to the synthesis of l-desoxy-2-lycorinone as shown in Eq. 3.74.115... 

Comparison with the Hajos-Parrish asymmetric version of the Robinson annulation [81] (Scheme 7.25(a)) shows the following distinct differences between the two methods. Firstly, the cycloalkenone in the Cu(OTf)2/ligand 18-catalyzed procedure is the Michael acceptor, whereas the cycloalkanone is the Michael donor in the proline-mediated annulation. Secondly, the asymmetric induction occurs in the 1,4-addition step in the new method, in contrast to the asymmetric aldol-cyclization in the Hajos-Parrish procedure. 

A similar regioselectivity under different conditions for aldol cyclization of 1,5-diketones obtained by the Michael addition of substituted acetoacetic esters to methyl vinyl ketones has been reported by another laboratory (equation IV),5... 

Michael addition of tin(II) dienolates.1 The tin(II) dienolates of (3,y-enones undergo y-selective addition to acyclic ot,(3-enones to give frans-l,7-enediones. If the reaction is carried out at high dilution, the intermediate tin(II) enolate can undergo an intramolecular aldol cyclization to give a cyclohexenol. 

The Michael reaction is the conjugate addition of a soft enolate, commonly derived from a P-dicarbonyl compound 24, to an acceptor-activated alkene such as enone 41a, resulting in a 1,5-dioxo constituted product 42 (Scheme 8.14) [52]. Traditionally, these reactions are catalyzed by Bronsted bases such as tertiary amines and alkali metal alkoxides and hydroxides. However, the strongly basic conditions are often a limiting factor since they can cause undesirable side- and subsequent reactions, such as aldol cyclizations and retro-Claisen-type decompositions. To address this issue, acid- [53] and metal-catalyzed [54] Michael reactions have been developed in order to carry out the reactions under milder conditions. 

Paulsen, H., Antons, S., Brandes, A., et al. (1999) Stereoselective Mukaiyama-Michael/Michael/Aldol domino cyclization as the key step in the synthesis of penta-substituted arenes an efficient access to highly active inhibitors of cholesteryl ester transfer protein (CETP). Angew. Chem. Int. Ed. 38, 3373-3375. 

Michael addition followed by an aldol cyclization can be used for stereoselective synthesis of cyclohexanes. 

Moderate yields of 3-hydroxyalkylthiochromones 521 result from a tandem Michael-aldol reaction of l-(2-methyl-s111 I d n y I phenv l)propvnone with aldehydes in the presence of two moles of BF3 etherate as a Lewis acid. The process involves a 6-emfo-dig cyclization (Equation 181) <2002TL7039, 2005PS(180)989>. 

A tandem Michael-aldol reaction of ynone selenides with aldehydes provides a convenient route to 3-substituted selenochromen-4-ones 132 (Equation 49) <2002TL7039>. The reaction proceeds via an intermediate zwitterion formed via a 6-/ r/ -r//g-cyclization. 

This principle is often applied to molecules. If a nucleophile is joined to the carbonyl group it is to attack by a short chain of covalent bonds, it may be able to reach only one side of the carbonyl group. An example from a familiar reaction concerns the Robinson annelation. The first step, Michael addition, creates a stereo genic centre but no relative stereochemistry. It is in the second step—the aldol cyclization—that the stereochemistry of the ring junction is decided. 

An intramolecular tandem Michael aldol reaction was described for esters that have an enolizable aldehyde in the molecule. The lithium ester enolate generated through the Michael reaction undergoes an intramolecular aldol reaction. Thus, the reaction of unsaturated esters 153 with lithium benzylthiolate provided the expected cyclization products 156 and 157 via (w-formylenolate 154 in an excellent cis stereoselectivity (Scheme 49)no. 

The cyclization, presumably via 160, gave the Michael-aldol tandem cyclization products 161 and 162 in a perfect. vyw-aldol stereoselectivity. The stereochemistry of the tandem reaction is rationalized by the model 164, which is sterically more favorable than 165 (Scheme 51). The oxo-ester 158 reacts in s-cis form and generates the d.v-enolatc, 163,... 

SCHEME 126. Stereoselective Michael-aldol tandem cyclization reaction177... 

Robinson annulation reaction (Section 23.12) a multistep sequence for building a new cyclohexenone ring onto a ketone. The sequence involves an initial Michael reaction of the ketone followed by an internal aldol cyclization. 

In an examination of the mechanism of the solvolysis of the tricyclic alcohol (627) which led to the successful synthesis of seychellene (628), Frater has shown that the minor product is the tricyclic olefin (629) which is formed by the process depicted in Scheme 79. An alternative synthesis of seychellene (628) and patchouli alcohol (635) depends upon the construction of the key tricyclic ketol (631) by an intramolecular Michael reaction followed by an aldol cyclization of (630) (Scheme 80). The minor ketol (632) can be converted into epi-sey-... 

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