Michael cyclization intramolecular

The first 5-isoxazolidinone was synthesized in 1912 by the cyclization of a-hydroxylamino-/3,/3-diphenylpropionic acid (62HC(l7)l,p. 7). The ester (541) underwent an intramolecular Michael cyclization to produce 2-methyl-3-phenyl-5-isoxazolidinone (542) (78TL3985). 

Asymmetric intramolecular Michael cyclization.1 Reaction of the ketone 2 with (R)-( + )-l (1 equiv.) generates an enatnine that adds to the unsaturated ester group to give 3a. The yield and the ee of 3 are markedly improved when 5 A... 

The reaction mechanism proposed for the LiBr/NEta induced azomethine ylide cycloadditions to a,p-unsaturated carbonyl acceptors is illustrated in Scheme 11.10. The ( , )-ylides, reversibly generated from the imine esters, interact with acceptors under frontier orbital control, and the lithium atom of ylides coordinates with the carbonyl oxygen of the acceptors. Either through a direct cycloaddition (path a) or a sequence of Michael addition-intramolecular cyclization (path b), the cycloadducts are produced with endo- and regioselectivity. Path b is more likely, since in some cases Michael adducts are isolated. 

Oda et al. have synthesized 5-azacarbapenems using the 1,2-diazetidine derivatives 123 (Scheme 13) as intermediates <1996H(42)577>. The diazetidines 123 can be easily prepared in good yield by an intramolecular cyclization of hydrazide followed by catalytic debenzylation using Pd(OH)2 on charcoal (Section 2.13.8.1). They developed a more practical and convenient synthetic route to 1,2-diazetidinones via hydrazones under very mild acidic conditions (Equation 23, Section 2.13.8.1). Michael cyclization of nitroalkenes 124a/b obtained from 123 gave the desired bicyclic 5-azacarbapenems 125. 

On the other hand, treatment of 127 with lithium hexadimethyl disilazide (HMDS) led to ring expansion and formation of the imidazolidinone 130 (Scheme 14). These results suggest that strong electron-withdrawing groups such as cyano or nitro may favor intramolecular Michael cyclization. 

Ring cleavage of a-alkenoyl cyclic ketene dithioacetals by dimsyl sodium generates a thiolate anion and induces an intramolecular Michael cyclization which produces 2,3-dihydrothiopyran-4-ones n good yields (Scheme 218) <2000SL1804, 2007S2115>. 

An enamine intermediate has been proposed as being formed by hydride reduction of a transient iminium ion [14, 15]. The electrophilic capture of the enamine is possible by a Michael acceptor thus, reductive Michael cyclizations of enal enones such as 9 or 11 were described in many cases (intramolecular reactions) (Scheme 11.5) [16]. 

The reaction afforded the tandem cyclization product 170 as a mixture of two separable isomers together with an a,p-unsaturated cyclic bisphosphonate, which is formed by a direct deprotonation of the vinylic a-proton of 168 and subsequent intramolecular Michael cyclization. The authors described the formation of 170 by the conjugated addition of 168 to 2.2 equivalents of PhLi and subsequent intramolecular Michael reaction in the intermediate 169. It is likely that coordination of the lithium atom to the oxygens of the phosphonates favors formation of the /raw.v-isomer. As shown in Scheme 52, the reactions with bulky naphthyllithiums gave only the fraws-170 isomer. This novel methodology can provide a rapid entry into a variety of cyclic bisphosphonates in good stereoselectivity. 

Spiroketal cyclization. Intramolecular spiroketal cyclization via Michael addition of an alcohol to a chiral a,p-unsaturated sulfoxide can proceed with high stereoselectivity. Reactions with KH are more stereoselective than those with NaH or n-BuLi. Thus cy-... 

Stereoselective intramolecular Michael cyclizations. The cyclization of 1 with... 

Compound (120) was prepared from 8,10-dihydrosweroside aglucone (32), which could be alkylated in aprotic solvent in the presence of a strong base to (33). However, under the same conditions, but in the absence of the alkylating agent, a sequence of four base-catalyzed reactions (dimerization by a vinylogous Michael addition, intramolecular aldolization, lactonization and cyclization by hetero Michael addition) gave the final product (120). Detailed analysis of its formation would exceed the frame of this paper [result to be published]. 

Regardless of the precise structure of the chosen half southern synthon, the two main problems to be solved are the establishment of the carbon skeleton and the introduction of the necessary chirahty into the molecule. The published approaches have introduced chirality either by resolution, by starting with a chiral precursor, or via use of asymmetric synthesis techniques. The carbon skeleton has been established by use of a wide variety of techniques including the Diels-Alder and other cycloaddition reactions, heteroatom induced cyclizations, intramolecular Michael or Aldol cyclizations, intramolecular ether formation, and radical cyclization. 

A library of novel 5-amino-2,7-diaryl-2,3-dihydrobenzo[l)]thiophene-4,6-dicarbonitriles was synthesized by a one-pot domino reaction of 5-aryldihydro-3(2H)-thiophenes, malonitrile, and aromatic aldehydes in the presence of morpholine (13BMCL2101). A mechanism was proposed that involves a sequence of Knovenagel condensation, Michael addition, intramolecular Thorpe-Ziegler cyclization, tautomerization, and elimination. The compounds were evaluated for their AChE (acetylcholinase) activity. The 5-amino-2,7-bis(4-methoxyphenyl)-2,3-dihydrobenzo[l)] thiophene-4,6-dicarbonitrile was found to be the most potent with IC50 4.16 xmol/L. 

---