Reductive Michael cyclization

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). 

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]. 

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... 

Scheme 2.10 Oiganocattilytic asymmetric reductive Michael cyclization...

Other iminium-activated cascade reactions, including [4-e3] cycloaddition, Robinson annulations, and reductive Michael cyclization, were also developed to furnish useful synthons [133]. 

The utilization of both enamine- and iminium-activation enables rapid access to complex structures from simple starting materials. The first examples were reported for the deployment of one catalyst in these transformations, list and coworkers described a highly selective reductive Michael cyclization (Scheme 4.27). In a first catalytic cycle a hydride transfer occurs yielding an enamine inter-... 

Scheme 2.7 Asymmetric reductive Michael cyclization and schematic representation of the tandem iminium-enamine catalysis mechanism...

Reaction of phenyl vinyl ketone with cyclopentanone under thermal conditions resulted in a diastereomeric mixture of 1,5,9-triketones 374 via a double Michael reaction. Treatment of this mixture with ammonium formate in polyethyleneglycol-200 under microwave irradiation conditions led to the very fast and efficient formation of a 2 1 diastereomeric mixture of cyclopental flquinolizidines 375 and 376 <2002T2189>. When this reductive amination-cyclization procedure was carried out starting from the purified /ra r-isomer of 374, the result was identical to that obtained from the cis-trans mixture, showing the operation of thermodynamic control (Scheme 86). 

Two new types of optically active 1,3-oxazines (41) were synthesized by Rassat and Rey (74T265, 74T3315). The epimeric 1,3-amino alcohols 40, prepared from (-l-)-pulegone 39 by Michael addition of ammonia and subsequent reduction, were cyclized with acetone, cyclohexanone, and 4-tert-... 

In the synthesis of ( )-D-homoestrone (Scheme 7), Michael addition of the monoketal 42 of the Wieland-Miescher enedione to 6-vinyl-2-methylpyridine 41 led to tricyclic adduct 43 in good yield. Reduction to the 17a-P-alcohol, double bond hydrogenation, and ketalization produced 44 with the requisite 8 J,14a-stereochemistry in 58% yield. However, modification of the hydrogenation conditions from ethyl acetate-triethylamine to ethanol-perchloric acid raised the yield to 82%.Birch reduction, hydrolysis, cyclization, and ketal reversal... 

The extended thymidine analogues 264 and 265 (both anomers in both cases) have been prepared and incorporated into oligodeoxynucleosides by both 3 - 3 and 3 —>5 linkages to study conformational aspects of o/r-DNA sequences. The synthesis of 264 involved reduction of a glycosyl cyanide, followed by elaboration of the heterocycle, whilst 265 was made by Wittig reaction-Michael cyclization on a 2-deoxyribose derivative, again followed by reduction and heterocycle synthesis. Some compounds with heterocyclic groups attached at C-5 of a ribose unit are mentioned in Chapter 10. 

Scheme 9.14 Domino reductive aldol or Michael cyclization.

Substituted a,(3-unsaturated mono(sulfone) with other activating groups such as nitrile or ester were also applicable in the Michael addition with aldehydes. As reported by the group headed by Palomo [26], a-ethoxycarbonyl vinyl sulfones could react with aldehydes in the presence of 7 or 25 to give, after reduction and cyclization, the corresponding lactone adducts in nearly optical pure form with reasonable diastereoselectivity. Similar results were also obtained for a-cyano vinyl sulfones (Scheme 5.14). 

Intramolecular nitro-Michael cyclization to 29 is completed in THF at room temperature with 2 mol of cesium fluoride and myristyltrimethylammonium bromide as promoters. Prevailing trans,trans-isomet 29 is separated by crystallization and the nitro derivative reduced to amine 30 in 98 % yield. Treatment with MeONa in MeOH afforded lactame 31, which is reduced by LiAUTi to known pyrrolidine derivative 2. Direct conversion of 2 to P-lycorane by Pictet-Spengler type cyclization using paraformaldehyde and mineral acid failed. Synthesis was accomplished in high yield by a detour, methoxycarbonylation to 32, cyclization to 33 and final LiAllTj-reduction of six-membered lactame to ( )- lycorane TM 9.5. 

Scheme 42.37 Enantioselective domino phosphoric acid-catalyzed Michael-cyclization-reduction sequence catalyzed by the sterically demanding phosphoric acid 101a (Figure 42.5).

At least two pathways have been proposed for the Nenitzescu reaction. The mechanism outlined below is generally accepted." Illustrated here is the indolization of the 1,4-benzoquinone (4) with ethyl 3-aminocrotonate (5). The mechanism consists of four stages (I) Michael addition of the carbon terminal of the enamine 5 to quinone 4 (II) Oxidation of the resulting hydroquinone 10 to the quinone 11 either by the starting quinone 4 or the quinonimmonium intermediate 13, which is generated at a later stage (HI) Cyclization of the quinone adduct 11, if in the cw-configuration, to the carbinolamine 12 or quinonimmonium intermediate 13 (IV) Reduction of the intermediates 12 or 13 to the 5-hydroxyindole 6 by the initial hydroquinone adduct 7 (or 8, 9,10). 

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