Cyclization Michael

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). 

Hetero substituted 2-cyclopropylideneacetates are ring-strain activated acrylates, highly reactive dienophiles in Diels-Alder reactions, but also powerful Michael acceptors. The reactivity of these compounds is enhanced by the same strain release in the Diels-Alder cycloadditions as well as in the 1,4-additions, and indeed the borderline between tandem Michael-cyclization and Diels-Alder-type cycloaddition is not well defined in many cases. 

In contrast to the nickel-organozinc catalyst system, which induces /3,/3-coupling of bis(enones), the use of cobalt(ll) catalysts in the presence of silane results in a,/3-coupling to provide products of reductive Michael cyclization.48,48a,48b Both five- and six-membered ring products 26b and 25d are formed in good yields and with complete diastereoselection. The choice of silane is critical. Whereas exposure of bis(enone) 25a to Co(dpm)2... 

Most recently, reductive Michael cyclization catalyzed by In(OAc)3 in the presence of PhSiH3 was reported.50 As demonstrated by the reductive cyclization of the homologous bis(enones) 25a and 26a, both five- and six-membered ring formation occurs in good yield to afford cycloalkanes 25d and 26b as single trails-Aiastereorncrs (Scheme 20). 

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... 

In the same year, Enders and coworkers reported an asymmetric one-pot, two-step synthesis of substituted isoindolines 159 in the presence of chiral A-triflyl phosphoramide (R)-Ae (10 mol%, R = d-NO -C H ) (Scheme 67) [87]. The cascade was triggered by a Brpnsted acid-catalyzed aza-Friedel-Crafts reaction of indoles 29 and A-tosyliminoenoates 160 followed by a DBU-mediated aza-Michael cyclization of intermediates 161 to afford the isoindolines 159 in high yields (71-99%) and short reaction times (10 min to 4 h) along with good enantioselectivities (52-90% ee). Longer reaction times (16 h to 10 days) caused increasing formation of the bisindole byproduct 162 (Scheme 68) along with amplified optical purity of isoindolines 159. 

Andreana and Santra have investigated the influence of the solvent on the generation of molecular diversity arising from a set of MCR substrates under microwave irradiation [36]. They have found that by using water as solvent, both 2,5-DKPs and 2-azaspiro[4.5]deca-6,9-diene-3,8-diones were obtained through aza-Michael reaction and 5-exo Michael cyclization, respectively. Nevertheless,... 

Other approaches to synthesize highly substituted cyclopentanes, including amino and hydroxy groups, from y- and lactones, has been radical and anionic Michael cyclizations of the a-iodo-y- and -<5-lactones [94]. Likewise, methods using radical cyclization to oxime ethers have been reported to give amino substituted cyclopentanes [95,103,104]. It should be noted that although only one isomer is often obtained [103], such cyclizations generating a secondary radical may not be stereospecific [95,100,101]. 

Very special amphiphilic properties of a divalent sulfur atom is witnessed in the reaction of a-thiomethylenecycloalkanones with acrylic esters under basic conditions [141]. The donor character of the allylic methylene group is enhanced by the sulfur (acting as an acceptor), yet the Michael cyclization that follows would be facilitated by a donor at that position. 

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. 

Michael cyclization of diazetidine 124 gave 5-azacarbapenem 125 in moderate yield. 

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. 

Yang JW, Hechavarria Fonseca MT, List B (2005) Catalytic asymmetric reductive Michael cyclization. J Am Chem Soc 127 15036-15037 Yoshikawa N, Chiba N, Mikawa T, Ueno S, Harimaya K, Iwata M (1994) Mitsubishi Chemical Industries patent. Jpn Kokai Tokkyo Koho JP 0630600 Zeitler K (2005) Extending mechanistic routes in heterazolium catalysis— promising concepts for versatile synthetic methods. Angew Chem Int Ed Engl 44 7506-7510... 

As a final illustration, an unprecedented approach was discovered, wherein an in situ aza-Michael reaction was used that allowed the development of bridged tetrahydroquinoline-based tricyclic architectures under very mild reaction conditions [30]. In a typical example, enantio-enriched compound 52 (Figure 17.12) was converted to 53 in a series of steps. Following the acetonide and the N-Alloc removal, to our surprise there was no sign of the free amine derivative 54. Instead, compound 55 was obtained as single diastereomer. Under these mild reaction conditions, the in situ aza-Michael cyclization produced the bridged architectures. 

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

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