Michael intermolecular

As shown in Scheme 2.20, selective lithiation of substrate 2-87 by treatment with LDA in THF at -78 °C triggers an intramolecular Michael/intermolecular aldol addition process with benzaldehyde to give a mixture of diastereomers 2-90 and 2-91. 2-91 was afterwards transformed into 2-92, which is used as a chiral ligand for Pd-catalyzed asymmetric allylic substitution reactions [29]. 

These results differ considerably from those obtained by Lubineau reactions. In the Lubineau series, a Knoevenagel condensation followed by an oxa-Michael/intermolecular retro-Claisen process is proposed. As a result of the Lubineau sequence, the loss of an acetate-fragment occurs in reactions with acetylacetone. 

In the Michael addition of achiral enolates and achiral Michael acceptors the basic general problem of simple diastereoselection (see Section D.1.5.1.3.2.), as described in Section 1.5.2.3.2. is applicable. Thus, the intermolecular 1,4-addition of achiral metal enolates to enones, a.jS-unsat-urated esters, and thioamides, results in the formation of racemic syn-1,2 and/or anti-3,4 adducts. 

I.5.2.4.5. Formation of Stereogenic Centers After the Michael Addition Step I.5.2.4.5.I. Intermolecular Additions... 

The well-defined copper complexes 94 and 95 (Fig. 2.16) have been used as catalysts for the intermolecular hydroamination of electron-deficient alkenes [Michael acceptors, X=CN, C(=0)Me, C(=0)(0Me)] and vinyl arenes substituted... 

On the other hand, many reactions are known where in a first intermolecular step a functionality is introduced which than can undergo an intramolecular reaction. A nice example is the reaction of dienone 0-34 with methyl acrylate in the presence of diethylaluminum chloride to give the bridged compound 0-35 (Scheme 0-11). The first step is an intermolecular Michael addition, which is followed by an intramolecular Michael addition. This domino process is the key step of the total synthesis of valeriananoid A, as described by Hagiwara and coworkers [21]. 

Scheme 2.16. Intermolecular domino Michael/aldol process initiated by the addition of...

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],... 

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-... 

In continuation of the aforementioned reaction, Hiroya and coworkers used cop-per(II) acetate for the synthesis of indoles 2-943 in reasonable yields from the corresponding ethynylanilines 2-941 by a domino intermolecular Michael addition/cop-per-assisted nucleophilic tosylate displacement reaction via 2-942 (Scheme 2.211) [482],... 

The first propynoate molecule undergoes a carbon—carbon bond-forming reaction with the zirconacyclopentadiene. The second molecule of the propynoate then donates a proton to the zirconacycle to open the ring. Further intermolecular Michael addition to the resulting carbon—carbon double bond produces the cyclopentadiene compounds. Investigations using deuterated propynoate were clearly indicative of the reaction mechanism shown in Eq. 2.47. 

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... 

The second synthetically useful general transformation of any of the chloro esters 1,2 consists of an intra- or intermolecular nucleophilic substitution of the chlorine atom in any of the Michael adducts. Several examples of such reactions have been mentioned above (Table 1 and Scheme 26), and substitutions of any specific importance (for example, with hydride or azide anion [9,10,62]) as well as subsequent transformations of such substitution products will be discussed in the corresponding Sections [66]. 

Mechanistically, the formation of the tricychc y-keto esters 231 can be rationalized in three different ways. Most probably, an intermolecular Michael addition of... 

Chiral pyrrolo[d]thiepine 166 can be obtained efficiently in 63% yield starting from N-alkylated maleimide 164. Successive Michael addition of phenethyl thiol and regioselective reduction are followed by spontaneous loss of hydrogen by N-acyliminium intermediates 165 and 7r-aromatic intermolecular a-amidoalkylation... 

Mahboobi et al. described a novel synthesis of staurosporinone (293) (791). The intermolecular Michael addition of l-(indol-3-yl)-2-nitroethene (1472) to methyl indol-3-ylacetate (1313) provided with high diastereoselectivity methyl 2,3-bis(indol-3-yl)-4-nitrobutanoate (1473). Catalytic hydrogenation and lactamization afforded 2,3-bis(indol-3-yl)-y-butyrolactam (1474) in 87% yield. Oxidative cyclization of the ds-lactam 1474 with DDQ in the presence of catalytic amounts of p-TsOH led to staurosporinone (293) (791) (Scheme 5.249). 

In a synthesis of the terpene longifolene, the tricyclic intermediate D was obtained from a bicyclic intermediate by an intermolecular Michael addition. Deduce the possible structure(s) of the bicyclic precursor. 

The synthesis of lanthionines via dehydroalanines has been carried out using an (9,5-di-benzoylated Z-L-Cys-L-Ser-OMe. 31 Using (3-elimination under basic conditions in sodium methoxide and subsequent intramolecular Michael addition, the corresponding L-lanthio-nine derivative was formed. However, as a final step the cyclolanthionyl dipeptide would have to be cleaved at the amide bond to obtain lanthionine. The same authors reported the use of the O-tosylated serine dipeptide which was subjected to (3-elimination, forming the desired dehydroalanine derivative. However, this synthesis also yielded cyclic L-lanthionine dimers as a result of an intermolecular Michael addition. The amounts of cyclolanthionine and lanthionine dimer derivatives depended on the initial concentration of the dipeptides. In addition, the directed synthesis of cyclic lanthionine dimers, which were produced from N-benzyloxycarbonyl-W-trityllanthionine monomethyl ester, has been reported. 32 ... 

At the beginning of our investigations enantioselective intermolecular oxa-Michael additions with removable chirality information in the oxygen-nucleophile had not been reported. Therefore we developed a highly diastereo- and enantiose-... 

Intermolecular Michael reactions continue to be developed. Karl Anker Jorgensen of Aarhus University, Denmark, has found (Angew. Chem. Ini. Ed. 2004,43, 1272) that the organocatalyst 3 mediates the addition of 2 to 1 with high enantiomeric excess. What is more, under the reaction conditions the intial Michael addition is followed by an aldol condensation, to give 4 as essentially a single diastereomer. 

Macrolactone synthesis 6,51, 71, 72, 94, 124,131,163,187,195 McMurry coupling 43 Medium ring synthesis 43,45,75, 77 Metathesis, Alkene (see Grubbs) Metathesis, Alkyne (see alkyne metathesis) Michael addition Intramolecular 166,166, 167,201 Intermolecular 57,84, 153, 166,204... 

It is true that highly enantioselective reactions are possible with proline in the asymmetric a-amination of aldehydes by azodicarboxylates and in a-oxidation with nitrosobenzene. However, good rather than excellent yields and enantioselectivities are more common in intermolecular Michael and aldol reactions. Moreover, the high catalyst loadings required for proline-catalyzed aldol reactions (up to 30%), and low TOFs (from hours to days to achieve a good conversion, even at a high catalyst... 

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