Michael addition carbocycles

The asymmetric Michael addition of chiral nonracemic ketone enolates has most frequently been used as part of the Robinson annulation methodology in the synthesis of natural products171-172. The enolates are then derived from carbocyclic chiral ketones such as (+)-nopinone, (-)-dihydrocarvone, or (-)-3-methylsabinaketone. 

When the cnolate of an enone is brought into reaction with an enone, usually a carbocyclic system is prepared by two consecutive Michael additions (M1MIRC reactions). Due to the lower temperatures employed and the absence of diene polymerization these reactions are useful alternatives for Diels-Alder reactions and proceed in general with high diastereoselectivities. When neither enolate nor enone is cyclic a monocyclic system is formed 338 which can be converted into a bicyclic system when the Michael addition is followed by an aldol reaction339. When, however, the enolate is cyclic a bicyclic or a tricyclic system is formed340 341. 

Another domino cuprate 1,4-addition-initiated threefold anionic domino sequence was developed by Chemla and coworkers (Scheme 2.93) [214]. Michael addition of the a, 3-unsaturated ester 2-387 with PhCu(CN)ZnBr was followed by a carbocyclization to give the zinc species 2-388 which can be intercepted by iodine or an allyl bromide affording substituted pyrrolidines 2-389 and 2-390, respectively. 

Michael addition has been shown to lead to useful building blocks. According to a publication by Johnson and coworkers, highly functionalized unsymmetrical malonic acid derivatives are accessible in this way [268]. Moreover, as described by Takeda and coworkers, substituted four- to six-membered carbocycles 2-507 can be prepared starting from 2-504 by reaction with PhLi via the intermediates 2-505 and 2-506 (Scheme 2.115) [269]. 

The reaction of enaminones with nitroalkenes gives a pentalenone system via the Michael addition and aldol reaction (Eq. 4.66).85a Linear a-keto enamines react with nitroalkenes to afford [3 + 2] carbocyclized products.8515... 

Amino-substituted dienes are also important dienophiles in Diels-Alder reactions. Recently, chiral and achiral 2-amino-l,3-dienes have been prepared to study their reactivity (see also asymmetric Diels-Alder reaction Section 8.1.2). The reaction of 2,3-diamino-l,3-butadienes with nitrostyrene gives unusual [3+2]carbocyclization products, 2-aminocyclopentanones, which are not formed by the direct cycloaddition but derived from the Michael addition products (see section discussing the Michael addition Section 4.1.3).42... 

The use of oxygen-containing dienophiles such as enol ethers, silyl enol ethers, or ketene acetals has received considerable attention. Yoshikoshi and coworkers have developed the simple addition of silyl enol ethers to nitroalkenes. Many Lewis acids are effective in promoting the reaction, and the products are converted into 1,4-dicarbonyl compounds after hydrolysis of the adducts (see Section 4.1.3 Michael addition).156 The trimethylsilyl enol ether of cyclohexanone reacts with nitrostyrenes in the presence of titanium dichloride diisopropoxide [Ti(Oi-Pr)2Cl2], as shown in Eq. 8.99.157 Endo approach (with respect to the carbocyclic ring) is favored in the presence of Ti(Oi-Pr)2Cl2. Titanium tetrachloride affords the nitronates nonselectively. 

Michael additions of 7r-allyl species to alkynes were employed for the synthesis of elaborated carbocycles as in the ruthenium-catalyzed cycloisomerization of 1,6-enynes (Equation (188)).1... 

The Michael addition followed by Intramolecular Ring Closure (MIRC) reactions have been recognized as a general synthetic approach to carbocyclic three-membered ring derivatives [1]. The enhanced Michael reactivity of methyl 2-chloro-2-cyclopropylideneacetate (1-Me) towards thiolates, alkoxides, lithiated amides and cyclohexadienolates (see below) allows one to perform highly efficient assemblies of spiropentane, tricyclo [3.2.1.0 ]octane, bicyclo [2.2.2] octane... 

EXAMPLES OF CARBOCYCLIC ESTERS PREPARED BY THE APROTIC DOUBLE MICHAEL ADDITION... 

Chemla, Normant and coworkers also reported a one-pot 1,4-addition/carbocyclization domino sequence as a new access to 3-carbomethoxypyrrolidines. Conjugate addition of the mixed organocopper-zinc reagent n-BuCu(CN)ZnBr LiBr to the Michael acceptor 427 in ether at room temperature directly led after hydrolysis to the 3-carbomethoxypyr-rolidine 428 as a 84/16 diastereomeric mixture, the trans disubstituted isomer being predominant (equation 185). A similar explanation as described above was proposed for the stereochemical outcome264. 

The Michael addition of nuleophiles to acceptors carrying a leaving group at the y-posi-tion leads to intermediates capable of undergoing an intramolecular displacement to afford three-membered carbocycles (equation 28). A major side-reaction is direct Sw2... 

Nitrones can be generated by Michael reaction of oximes with appropriate conjugated substrates.25 If a generated nitrone has a built-in dipolarophile, cyclization can ensue (Scheme 15). There are three synthetic variations on this theme.25a,b First, the oxime may contain the dipolarophile as in (56). Reaction of (56) with phenyl vinyl sulfone provided a quantitative yield of the tandem product as one stereoisomer. Alternatively, die dipolarophile can reside in the Michael substrate as in (57). Reaction of (57) with cyclohexanone oxime produced two isoxazolidines from competitive cyclization of the intermediate nitrone through six- and seven-membered carbocyclic transition states. It is also possible to carry out an intramolecular Michael addition followed by an intramolecular nitrone cyclization as in thermolysis of (58) to produce a tricyclic isoxazolidine. Very recently several examples of a tandem Diels-Alder, Michael addition, nitrone cyclization sequence have been reported.250... 

Carbocyclization of m-alkcnyl-z-methoxybcnzy I lithiums to form five- or six-membered rings has been studied 101 the five-membered ring is formed with a cis-stereochemical relationship between the methoxy substituent and the adjacent methyl group. Intramolecular carbolithiation of vinyl sulfides at — 105°C in THF has been found to occur non-stereospecifically with regard to the newly formed C—Li centre.102. The stereochemistry of selective tandem Michael addition alkylation reactions of vinylphosphonates has been explored.103... 

An interesting sequence based on an intermolecular Michael addition and a subsequent transition metal-catalyzed carbocyclization was recently explored. Much of the development of this strategy relies on recent studies related to the intramolecular carbometalation reaction of stabilized carbanions bearing an unactivated alkynyl group. Several transition metal complexes such as Cu [52], Pd [53], Ti [54], Zn [55], Co [56] and Sn [57] have been reported to catalyze this reaction (Scheme 17). 

Simple tertiary enaminones derived from acetylacetone and benzoylacetone react with acryloyl chloride to yield carbocyclic derivatives. The reaction proceeds via an initial Michael addition of the enaminone / -carbon to the enone107 (equation 76). Analogous behavior of cyclic enaminones leads, according to ring size, to tetrahydroindole, quinoline and benzazepine derivatives108 (equation 77). 

Trisubstituted six-member carbocycles were also prepared. Condensation of LI with commercial acetoacetanUides 9.14a-f produced, by one-pot Michael addition and Robinson annulation, the cyclohexenone library L4 (7680 members. Fig. 9.11). Noncommercial acetoacetamides Mi, prepared by condensation of diketene 9.15 with 40 primary and secondary amines (structures not shown in the paper), were used as monomers and condensed with a 320-member LI subset to give the expanded cyclohexenone library L5 (12,800 members). Difficulties in preparing extremely large discrete libraries, even using fuUy automated robotic workstations, and the need to diversify the screening set obliged the authors to limit the number of monomers and chalcones for any specific library/scaffold (see also LIO below). 

Keywords. Selenium-stabUized carbanions, a-Selanyl enolates, Selenides, Selenoacetals, Alkylation, Aldolization, Carbocyclization, Michael addition... 

SMP enamines have a very broad range of applications as d synthons. Cyclohexanone SMP enamine can be used for efficient Michael additions to nitroalkenes, Knoevenagel acceptors, and to a nitroallylic ester in a [3 + 3] carbocyclization with excellent stereoselectivities (eq 1). The synthesis of y-oxo-a-amino acids using SMP enamines has been developed (eq 2). ... 

A variant of the above method is the nitrone-olefin cycloaddition, exploited for the synthesis of shikimic acid [349] and for the synthesis of the carbocyclic nucleoside neplanocin [350]. RCM has been recently exploited in Ziegler s synthesis of cyclophellitol [351]. This synthesis encompasses a number of steps described throughout this chapter, including chain extensions at Cl, at C6 and branching by Michael addition followed by carbocyclization. 

The usual reactions involved in carbocyclic cyclization of the aforementioned open-chain intermediates are aldol and Claisen condensations as well as Michael additions. Some examples of the Wadsworth-Emmons reactions have been also published. 

An approach to carbocyclic arenes by cyclative cleavage is presented in Scheme 37 [53]. Merrifield resin was etherified with 3-hydroxypyridine (140), and then the pyridine moiety was quaternized with bromoacetone to yield 141. Formation of an yhde 142 with NaOH/ethanol and subsequent reaction with a chalcone (143) produced the intermediates 144 after a Michael addition. A subsequent condensation reaction released the phenolates 145 from the solid phase with restoration of the pyridine moiety on the solid support. Acidic work-up and filtration furnished... 

---