Michael-induced cyclization

Gallagher has reported a convenient synthesis of functionalized phosphorinans (102) by Michael addition of methyl hypophosphite to methyl acrylate, followed by base-induced cyclization.78... 

Michael additions to acceptor-substituted dienes are often followed by (spontaneous or induced) cyclizations. This was already noted by Vorlander and Groebel4 who obtained a substituted 1,3-cyclohexanedione by treatment of 6-phenyl-3,5-hexadien-2-one with diethyl malonate (equation 5). Obviously, the 1,4-addition product which is formed initially then undergoes cyclization, ester hydrolysis and decarboxylation. Similarly, reaction of methyl sorbate with methyl 4-nitrobutyrate gave the 1,6-adduct which was reductively cyclized to 6-methyl-l-azabicyclo[5.3.0]decane18 (equation 6). 

Aliphatic substrates also perform well, forming five membered rings in good yield and high enantioselectivity Eq. 6a. Typical Michael acceptors, however, are not sufficiently electrophilic to induce cyclization to form six-membered aliphatic rings. In order to effect this cyclization, use of a more electrophilic Michael acceptor, such as alkylidene malonate 83, was required Eq. 6b [70]. The difference in reactivity is presumably due to the extra conformational freedom of the aliphatic linker compared to the fused aromatic linker of substrate 79 coupled with potential competing non-productive pathways. 

The 3-benzyloxyisoxazole system has functioned as a storable /3-keto amide unit in the construction of tetracyclines (78JA3609). Michael addition of the anion of the 3-benzyloxyisoxazole (442) to the dienolone (441) followed by deesterification-decarboxylation gave rise to (443) in 80% yield. Dehydration of this material and sodium hydride-induced cyclization afforded (445). Hydrogenolysis over palladium on carbon produced the desired ( )-dedimethylamino-12a-deoxyanhydrotetracycline (446 Scheme 99). This isoxazole route has also been extended to the preparation of a tetracycline having the usual amino function in the A ring. 

An elegant and very efficient synthesis of thietanes has been reported <2002S1502>. The Michael addition of phosphorodithioate to a,/3-unsaturated ketones led to the formation of 3-oxopropyl phosphorodithioate, which then underwent nucleophile-induced cyclization to form a series of variously substituted thietanes 60a-i (Table 5) <2002S1502>. 

An expeditious and highly diastereoselective synthesis of (Z)-2-alkylsulfenyl (or 2-cyano) -2,4-diarylthietanes 53 has been reported by nucleophile (CN, RS") induced cyclization of the corresponding O,O-diethyl 5-(l,3-diaryl-3-oxopropyl) phosphorodithionates under microwave irradiation in solvent free conditions <02S1502>. This reductive cyclization can be considered to be induced by the attack of a hydride ion on the carbonyl carbon of the Michael adduct precursor to give an alkoxide ion, which attacks the phosphorus atom intramolecularly. 

On the basis of this palladium-mediated Michael addition cyclization process, a novel two-step synthetic entry into functionalized furan derivatives 67 has also been devised (Scheme 28). Substitution of benzylidene (or alkyli-dene) malonates for their ethoxymethylene analog (65) as activating olefins gave rise to the formation of the corresponding 2-ethoxy-4-arylidene tetrahy-drofurans 66. An in situ addition of potassium ferf-buloxidc induced a decar-boxylative elimination reaction which was followed by an isomerization of the exocyclic double bond. The entire process successively involved a conjugate addition, a palladium-catalyzed cyclization-coupling reaction, a base-induced eliminative decarboxylation, and finally, a double bond isomerization [73]. 

Gordon and Danishefsky [112] used the reaction of a chromium Fischer car-bene complex 164 with a cycloalkine 163 to build the naphthoquinone core 165 (Dotz reaction, review [113]), a procedure often used for synthesis of the linearly condensed anthracyclinones (e.g., [114]). The quinone ketone 165 has nucleophilic and electrophilic centers correctly positioned to furnish a ben-zo[fl]anthraquinone. However, treatment with NaH or Triton B gave the spiro-compounds 166 as a mixture of two stereoisomers. These products evidently arose from Michael addition of the ketone enolate to the naphthoquinone double bond. But the weaker base DBU induced cyclization at ambient temperature to the benzo[a]anthraquinone 167 in 65% yield (Scheme 42). The primary aldol adduct apparently eliminated water and the resulting dihydrobenzo[a]anthraquinone aromatized under basic conditions in the presence of air. This is an instructive example of the influence of the base on the cyclization mode. 

The second procedure worth presenting involves the Michael addition of tryptophan ester (22) to pro-pynoate ester (33 R = H) to give (34 R = H), and subsequent acid-induced cyclization via the iminium salt (35 R = H Scheme 19), to afford tetrahydro-P-carboline (36 R = H), which could not be prepared by the simple Pictet-Spengler reaction with malonic hemialdehyde. Again, asymmetric induction can be achieved through the amino acid derived ester function. Extension of this procedure to... 

We further explored the steric effect of this Michael addition-cyclization reaction sequence. A series of secondary amines 13a-f were prepared and subjected to the Michael addition and acid-induced cyclization (Scheme 6) [12]. The results are summarized in Table 2. In general, we found that the secondary amines were less reactive in this Michael addition-cyclization reaction sequence. The p-toluene acetylenic sulfoxide la was not reactive enough and only the stronger electron-withdrawing o-nitrophenyl acetylenic sulfoxide 1 b achieved the transformation. In contrast to the primary amine approach, the secondary amine approach resulted in a reversed diastereoselectivity bias with compounds 14 as the major isolated products (except 13e). In general, a lower reaction temperature and increase in the steric hindrance of the secondary amine improved the diastereoselectivity. Exceptionally good diastereoselectivity was observed for the cyclization of 13 f (Scheme 6) (Table 2)... 

Alkyl-3-(styrylsulfonyl)thioureas, obtained in the form of their potassium salt by reaction of styrylsulfonamides with alkyl isothiocyanates and potassium carbonate in refluxing acetone, cyclize in weakly alkaline solution, or thermally upon melting (usually at 130 160 °C) via a Michael-induced ring closure to give AT-alkyl-5-aryl-5,6-dihydro-1,4,2-dithiazin-3-amine 1,1-dioxides l.9,16,I9,31,32... 

A very similar process can be used in the synthesis of fully conjugated 1,2-thiazine 1-oxides. Ethoxyalkylidenemalononitriles (152a) or the related dithioacetal (152b), can be reacted with S,S-dimethylsulfoximide (153) to yield Michael adducts (154). These compounds undergo base-induced cyclization to afford 1,2-thiazines (155) <88CB1005>. The ketene dithioacetal (156) reacts with the sulfoximide (153) at 100-150°C to yield the thiazine (157) (Scheme 28) <83S926>. 

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. 

Iminocyclopropanes result from the base-induced cyclization of a-bromoimines, and imines from the Michael addition of enaminostannanes to a,/0-unsaturated esters and nitriles. ... 

The capnellane (109) has been synthesized, using two dififerent annulation procedures (Scheme 11). The a/b ring junction was formed through consecutive Michael and ene-type reactions by addition of a lithium cuprate to 3-methyl-cyclopent-2-enone and trapping of the enolate anion that is thus formed as the enol acetate (110). Lewis-acid-induced cyclization then formed the ketone (111). 

The mechanism is presumed to involve a pathway related to those proposed for other base-catalyzed reactions of isocyanoacetates with Michael acceptors. Thus base-induced formation of enolate 9 is followed by Michael addition to the nitroalkene and cyclization of nitronate 10 to furnish 11 after protonation. Loss of nitrous acid and aromatization affords pyrrole ester 12. 

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... 

Scheme 6.141 Mechanistic proposal for the 121-catalyzed asymmetric intramolecular Michael addition exemplified for the model substrates ( )-4-hydroxy-l-phenyl-2-buten-l-one (n = 0) and ( )-5-hydroxy-l-phenyl-2-buten-l-one (n = 1) 121 functions as push/pull-type bifunctional catalyst inducing the cyclization of boronic acid hemiester (1) to form intermediate (2) release ofdiol product (3) by oxidation.

The 3(2ff)-benzofuranone 98 undergoes Michael addition with ( )-pent-3-en-2-one (100, Scheme 25) in the presence of sodium ethoxide to afford the adduct 101 as a mixture of two racemates. Cyclization to the 2-dibenzo-furanone 102 can be induced by boiling with dilute aqueous sodium hydroxide under nitrogen or to the aromatized compound 103 in the presence of air. The dechloro compound (104) has been synthesized from 99 by 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. 

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. 

Bicyclic 3a//-cyclopentene[8 annulcnc-l,4-(5//,9a//)-dioncs undergo three types of acid-induced transannular reactions (1) Michael addition (5-exo-trig or 6-exo-trig) leading to the tetracyclic diones, (2) 3 + 2-cycloaddition followed by a novel sequential skeletal rearrangement to 2-naphthalenone derivatives, (3) ipso-Friedel-Crafts alkylation accompanied by the rearomatization and the loss of water (Scheme 25). The factors that control the reaction mode of these transannular cyclizations are discussed... 

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