Alkylidene Enolates

Enolates derived from cyclic compounds such as cyclohexane carboxylic acid or cyclohexane carboxalde-hyde generate enolates that are unique. These enolates have an exocyclic double bond that can exist as ( ) and (Z) isomers. The facial and orientational bias in alkylation and condensation reactions of such enolates is influenced by the conformation of the ring it is attached to. Alkylidene cyclohexane enolates show a preference for equatorial attack, just as cyclohexanone derivatives do (sec. 4.7.C,D). 

The position of a substituent on the ring also influences the selectivity. In 1,2-asymmetric systems such as 485, treatment with LDA leads to an equilibrating mixture of enolates (486A and 486B). The destabilizing Me OMe interaction in 486A is alle iaied in 486B and reaction with iodomethane proceeds from the less 

3-disubstituted system is shown by ester 489. Treatment with LDA generates the equilibrating enolates 490A and 490B, favoring 490B. Using the acid as the enolate precursor (R = H in 489), alkylation with iodo- 

This corresponds to delivery of iodomethane from path a in 490B (equatorial attackPresumably, steric interactions with the OR group of the enolate moiety are minimal (or equal) in both conformations, making 

Five- and six-membered ring enolates with an endocyclic double bond also react to deliver an electrophile from the sterically less hindered face. Enolate 498 was obtained by treatment of 497 with lithium amide. Subsequent reaction with an alkyl halide led to delivery of the halide from the face opposite the alkenyl group (path a) and the trans product shown (499) was isolated in 60% yield.-. Approach via path b would have serious steric consequences, and that transition state is destabilized. Similar effects are observed with 3-alkyl-cyclohexanone derivatives. 

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Oxo esters are accessible via the diastereoselective 1,4-addition of chiral lithium enamine 11 as Michael donor. The terr-butyl ester of L-valine reacts with a / -oxo ester to form a chiral enamine which on deprotonation with lithium diisopropylamide results in the highly chelated enolate 11. Subsequent 1,4-addition to 2-(arylmethylene) or 2-alkylidene-l,3-propanedioates at — 78 °C, followed by removal of the auxiliary by hydrolysis and decarboxylation of the Michael adducts, affords optically active -substituted <5-oxo esters232 (for a related synthesis of 1,5-diesters, see Section 1.5.2.4.2.2.1.). In the same manner, <5-oxo esters with contiguous quaternary and tertiary carbon centers with virtually complete induced (> 99%) and excellent simple diastereoselectivities (d.r. 93 7 to 99.5 0.5) may be obtained 233 234. 

Recently, Nicolaou and coworkers have devised a novel, one-pot strategy for the direct transformation of acyclic olefinic esters to cyclic enol ethers [34]. Unlike the molybdenum alkylidene 1 (see Sect. 3.2), initial reaction between the Tebbe reagent 93 and an olefinic ester results in rapid carbonyl olefination to afford a diene intermediate. Subsequent heating initiates RCM to afford the desired cyclic product (Scheme 17). 

An alternative approach involves a two-step procedure, in which carbonyl olefination, using the Tebbe reagent 93, generates an acyclic enol ether-olefin (Scheme 16). In this case, subsequent RCM using molybdenum alkylidene 1 proceeds to give cyclic enol ethers. An efficient, one-pot carbonyl olefination-RCM approach has been developed by Nicolaou et al. for the formation of cyclic enol... 

Tandem carbonyl olefmation—olefm metathesis utilizing the Tebbe reagent or dimethyl-titanocene is employed for the direct conversion of olefmic esters to six- and seven-mem-bered cyclic enol ethers. Titanocene-methylidene initially reacts with the ester carbonyl of 11 to form the vinyl ether 12. The ensuing productive olefm metathesis between titano-cene methylidene and the cis-1,2 -disubstituted double bond in the same molecule produces the alkylidene-titanocene 13. Ring-closing olefin metathesis (RCM) of the latter affords the cyclic vinyl ether 14 (Scheme 14.8) [18]. This sequence of reactions is useful for the construction of the complex cyclic polyether frameworks of maitotoxin [19]. 

The utilization of copper complexes (47) based on bisisoxazolines allows various silyl enol ethers to be added to aldehydes and ketones which possess an adjacent heteroatom e.g. pyruvate esters. An example is shown is Scheme 43[126]. C2-Symmetric Cu(II) complexes have also been used as chiral Lewis acids for the catalysis of enantioselective Michael additions of silylketene acetals to alkylidene malonates[127]. 

Alkylidenation of silyl esters.1 Application of this alkylidenation process to silyl esters provides (Z-)silyl enol ethers stereoselectively. 

Alkylidene lactones. In the presence of this catalyst, alkynoic acids (2) can cyclize to exocyclic enol lactones (3) with marked preference for the Z-isomer. The reaction in CH,C12 proceeds at room temperature. Cyclization to five-mem-... 

Mukaiyama Michael reactions of alkylidene malonates and enolsilanes have also been examined (244). The stoichiometric reaction between enolsilane (342a) and alkylidene malonate (383) proceeds in high selectivity however, catalyst turnover is not observed under these conditions. The addition of HFIP effectively promotes catalyst turnover, presumably by protonation and silyl transfer from the putative copper malonyl enolate generated in this reaction. The reaction proved general for bulky P-substituents (aryl, branched alkyl), Eq. 209. 

Optically active 2-alkylidene-l,3-dithiane 1,3-dioxides have been prepared as chiral Michael-type acceptors. It was shown that these compounds react under nucleophilic epoxidation conditions to give diastereoselectively the epoxides. Other heteroatom nucleophiles reacted as well <1998JOC7128, 1999PS(153/4)337>. It was further demonstrated that enolates were also effective nucleophiles for the stereoselective addition to 2-alkylidene-l,3-dithiane 1,3-dioxides (Scheme 48) <20050L4013>. 

Radical cations of 2-alkylidene-l,3-dithianes can be generated electrochemically by anodic oxidation using a reticulated vitreous carbon (RVC) anode <2002TL7159>. These intermediates readily react with nucleophiles at C-1. Upon removal of the second electron, the sulfur-stabilized cations were trapped by nucleophilic solvents, such as MeOH, to furnish the final cycloaddition products. Hydroxy groups <20010L1729> and secondary amides <2005OL3553> were employed as O-nucleophiles and enol ethers as C-nucleophiles (Scheme 50) <2002JA10101>. 

An interesting case of ruthenium-catalyzed isomerization versus ring opening of differently substituted 2-vinyl-l,3-dioxanes has been reported. It was found that 5,5-dialkyl-substituted dioxanes gave the ring-opened enol ethers and 5,5-unsubstituted dioxanes afforded the (expected) 2-alkylidene-l,3-dioxanes (Scheme 89) <1996PJC1087>. 

Die Palladium-katalysierte Allylierung der Enolate von achiralem N-Alkyliden-glycin (s.S. 492) verlauft mit 3-Acetoxy-l-propen und optisch-aktiven, Phosphan-Liganden tra-genden Palladium-Katalysatoren2 stereoselektiv zum entsprechenden 2-(Diphenyl-me-thylenamino)-4-pen ten saure-Derivat3-5. 

One of the first examples of addition of a zinc enolate to an alkyne was a report dealing with the zinc or cadmium stearate-catalyzed addition of substituted malonates to acetylene under pressure250. Later, Schultze described the intermolecular nucleophilic addition of the zinc enolate derived from diethyl bromomalonate to phenylacetylene in refluxing xylene leading to the alkylidene malonate 392 (equation 171)251. 

Recently, Nakamura and coworkers described a related reaction of the zinc enolates derived from /3-aminocrotonamides of type 395256. In the presence of a stoichiometric amount of Et2Zn, the latter underwent smooth addition to terminal alkynes upon heating in hexane and afforded the corresponding tetrasubstituted 2-alkylidene acetoacetamides 396 (after acidic hydrolysis of the imine) with high (Z)-stereoselectivity (equation 173). 

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