Michael addition Subject

The intramolecular Michael addition of an achiral metal enolate is similarly subject to simple diastereoselection. 

Et2Zn also participates in the reductive coupling as a formal hydride source. Results for the Ni-catalyzed, Et2Zn-promoted homoallylation of carbonyl compounds with isoprene are summarized in Table 7 [30]. Et2Zn is so reactive that for the reaction with reactive aromatic aldehydes it causes direct ethylation of aldehydes, and the yields of homoallylation are diminished (runs 1 and 2). Unsaturated aldehydes seem to be subject to the Michael addition of Et2Zn. Accordingly, for the reaction with cinnamaldehyde, none of the expected homoallylation product is produced instead, the 1,4-addition product of Et2Zn, 3-phenylpentanal is produced exclusively (run 3). 

A diverse group of organic reactions catalyzed by montmorillonite has been described and some reviews on this subject have been published.19 Examples of those transformations include addition reactions, such as Michael addition of thiols to y./bunsatu rated carbonyl compounds 20 electrophilic aromatic substitutions,19c nucleophilic substitution of alcohols,21 acetal synthesis196 22 and deprotection,23 cyclizations,19b c isomerizations, and rearrangements.196 24... 

Recently, a synthesis of tetrodotoxin from D-glucose was described (Scheme 36). After a Michael addition of the lithium salt of bis(phenylthio)-methane to the nitroolefin 116, the major component (117b) of the resulting epimeric mixture 117a + 117b was subjected to a reaction sequence that involved an intramolecular nitroaldol reaction, to give the complex nitro cyclohexane derivative 118. 

Another advantage of this method is that no catalyst is needed for the addition reaction this means that the base-catalyzed polymerization of the electrophilic olefin (i.e., a,j8-unsaturated ketones, esters, etc.) is not normally a factor to contend with, as it is in the usual base-catalyzed reactions of the Michael typCi It also means that the carbonyl compound is not subject to aldol condensation which often is the predominant reaction in base-catalyzed reactions. An unsaturated aldehyde can be used only in a Michael addition reaction when the enamine method is employed. 

Recall that the LUMO shows which regions of a molecule are most electron deficient, and hence most subject to nucleophilic attack. One such region is over the carbonyl carbon, consistent with the observation that carbonyl compounds undergo nucleophilic addition at the carbonyl carbon. Another region is over the P carbon, again consistent with the known chemistry of a,P-unsaturated carbonyl compounds, in this case conjugate or Michael addition. 

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 ... 

An alternate route to substituted tetrahydrobenzazepines (Scheme 33) commenced with the Michael addition of the ester 351 to acrylonitrile in the presence of Triton B, and the intermediate cyanoester was converted to 352 by reduction of the ester function with lithium borohydride and O-benzylation (168). Base-induced hydrolysis of the nitrile group of 352 delivered the corresponding acid, which was transformed to 353 via a Curtius rearrangement. Subjection of 353 to a modified two-step Tschemiac-Einhom reaction involving AMiydroxymethyla-tion and subsequent acid-catalyzed cyclization gave 354. 

Michael additions of C-nudeophiles such as the indanone 1 have been the subject of numerous further studies For example, the reaction between the indanone 1 and methyl vinyl ketone was effected by a solid-phase-bound quinine derivative in 85% yield and with remarkable 87% ee by d Angelo, Cave et al. [5], Co-polymers of cinchona alkaloids with acrylonitrile effected the same transformation Kobaya-shi and Iwai [6a] achieved 92% yield and 42% ee and Oda et al. [6b] achieved almost quantitative yield and up to 65% ee. Similarly, partially resolved 2-(hydroxy-methyl)quinudidine was found to catalyze the reaction between 1 and acrolein and a-isopropyl acrolein with induction of asymmetry, but no enantiomeric excesses were determined [7]. As shown in Scheme 4.4, the indanone 7 could be added to MVK with up to 80% ee under phase-transfer conditions, by use of the Cinchona-derived PT-catalysts 9a and 9b, affording the Michael-product 8 or enf-8, respectively [8]. The adducts 8 or ent-8 were intermediates in the stereoselective Robinson anellation of a cydohexenone ring to the indanone 7 [8],... 

If alkenes or alkynes are subjected to strain, their jt bonds are weakened, and such compounds often behave chemically as diradicals. Their tendency to dimerize or polymerize will be significantly enhanced, and quick reaction with oxygen will occur in air [18, 19]. Reactions of strained alkenes which lead to a decline of strain, for example Michael additions or cycloadditions, can proceed significantly faster than with related, unstrained alkenes (Scheme 3.6). 

The Aspidosperma family of indole alkaloids has inspired many synthetic strategies for the construction of their pentacyclic framework of the parent compound aspidospermidine (366), since the initial clinical success of two derivatives, vinblastine (10) and vincristine, as anticancer agents. The alkaloids such as (-)-rhazinal (369) and (-)-rhazinilam (6) have been identified as novel leads for the development of new generation anticancer agents [10,11]. Bis-lactams (-)-leucunolam (370) and (-t-)-epi-leucunolam (371) have bio-genetic and structural relationships with these compounds [236]. Recently, enantioselective or racemic total syntheses of some of the these natural product were achieved. One successful synthesis was the preparation of the tricyclic ketone 365, an advanced intermediate in the synthesis of aspidospermidine (366), from pyrrole (1) (Scheme 76) [14]. The key step is the construction of the indolizidine 360, which represents the first example of the equivalent intramolecular Michael addition process [14,237,238]. The DIBAL-H mediated reduction product was subject to mesylation under the Crossland-... 

The starting material for the present synthesis was Wieland-Miescher ketone (24), which was converted to the known alcohol (25) by the published procedure [10], Tetrahydropyranylation of alcohol (25) followed by hydroboration-oxidation afforded the alcohol (26), which on oxidation produced ketone (27). Reduction of (27) with metal hydride gave the alcohol (28) (56%). This in cyclohexane solution on irradiation with lead tetraacetate and iodine produced the cyclic ether that was oxidized to obtain the keto-ether (29). Subjection of the keto-ether (29) to three sequential reactions (formylation, Michael addition with methyl vinyl ketone and intramolecular aldol condensation) provided tricyclic ether (30) whose NMR spectrum showed it to be a mixture of C-10 epimers. The completion of the synthesis of pisiferic acid (1) did not require the separation of epimers and thus the tricyclic ether (30) was used for the next step. The conversion of (30) to tricyclic phenol (31) was... 

Fig (8) The transformation of lactone (53) to keto ester (58) is described. The unsaturated aldehyde (59) is converted to tricyclic ketone (60) by two steps (Michael addition, and intramolecular aldol condensation). And this on subjection to aromatization and hydrogenation respectively leads the formation of (62) whose transformation to (+)0-methyl pisiferic acid (2) is accomplished by methylation and hydrolisis. 

Fig (12) Transformation of keto ester (94) to (96) is described. Michael addition leads the formation of the adduct (97) which is subjected to cyclization, aromatization and hydrogenolysis to obtain the phenol (99). This on diazotization, methylation and reduction afforded the amino ether (100). Further diazotization, methanolysis and saponification produce ethyl (+)-camosic acid dimethylether (102). 

In this approach the keto aldehyde (96) was subjected to Michael addition with p-keto sulphide to obtain the adduct (103) in quantitative yield. These adducts differ in configuration only at C-ll or at sulfur... 

Baylis-Hillman adducts such as 55 and 56 derived from 2-nitrobenzaldehydes were shown to function as useful precursors to functionalized (1H)-quinol-2-ones and quinolines. Treatment of 55 and 56 with iron and acetic acid at 110 °C afforded 57 and 58, respectively <02T3693>. A variety of other cyclization reactions utilized in the preparation of the quinoline scaffold were also reported. An iridium-catalyzed oxidative cyclization of 3-(2-aminophenyl)propanols afforded 1,2,3,4-tetrahydroquinolines <02OL2691>. The intramolecular cyclization of aryl radicals to prepare pyrrolo[3,2-c]quinolines was studied <02T1453>. Additionally, photocyclization reactions of /rans-o-aminocinnamoyl derivatives were reported to provide 2-quinolones and quinolines <02JHC61>. Enolizable quinone and mono- and diimide intermediates were shown to provide quinolines via a thermal 6jt-electrocyclization <02OL4265>. Quinoline derivatives were also prepared from nitrogen-tethered 2-methoxyphenols. The corresponding 2-methoxyphenols were subjected to a iodine(III)-mediated acetoxylation which was followed by an intramolecular Michael addition to afford the quinoline OAc O... 

The Michael addition /ring-closure reaction of the imines 68 and 69 with the ester nitrostyrene 67 proceeded smoothly in refluxing anhydrous acetonitrile in the presence of NaHCOs to give pyrroles 70 and 71. The syntheses were completed by subjecting pyrroles 70 and 71 to hydrogenolysis to give compounds 72 and 73 quantitatively, followed by base-mediated lactonization with sodium hydride in dry THF to produce lamellarin K in 93% and lamellarin L in 87% yield over two steps. Lamellarins K and L were successfully prepared in three steps in 65% and 61% overall yields, respeetively. 

Michael addition of trialkylstannyllithium to cyclohexenone SAMP- or RAMP-hydrazone gives 3-stannyl derivatives with de values of 42-44%, while subsequent alkylation of the enolate formed affords trans-products with de values >96%. The hydrazones obtained are subjected to ozonolysis to give 3-stannylcyclohexanones trans-1 with ee values up to 96%17. 

A number of papers have been devoted to the subject of hydrocyanation reactions which introduce a cyano-group at different positions of the steroid molecule [including C(2), C(3), C(4), C(5), C(6), C(9), C(10), C(ll), and C(16)]. "3 The reactivity during the Michael addition reactions to the conjugated enones O... 

Vinyl sulfone-modifled carbohydrates, such as 111, can be subjected to Michael addition reaction with primary or secondary amines to constmct 112 bearing amino groups at the C-2 carbon... 

Disappointing results have been obtained from the Michael addition of compounds containing active methylene groups to vinylphosphonates. For example, cyanoacetate reacts with the diethyl vinyphosphonate under the conditions of base catalysis to give a mixture of 1 1 and 1 2 adduct resulting of one or two additions to the vinylphosphonate. When 2-pyridylacetonitrile and cyanomethylphosphonate are subjected to this reaction, diethyl 3-(2-pyridyl)- or 3-diethoxy-phosphinyl-3-cyanopropylphosphonates are obtained in 61% and 98% yields, respectively (Scheme 6.35). 

---