Cycloalkenones, a-substituted

The addition of the lithium enolates of methyl acetate and methyl (trimelhylsilyl)acetate to ( + )-(S)-2-(4-methylphenylsulfinyl)-2-cycloalkenones gives, after desulfurization, (/ -substituted cycloalkenones. A higher level of selectivity is observed with the a-silyl ester enolate and in the cyclohexenone series13. The stereochemical outcome is rationalized by assuming attack on a ground-state conformation analogous to that in Section 1.5.3.2.1. 

Cycloalkenones are ubiquitous as reactive intermediates and bioactive materials. Modification of a simple cycloalkenone by addition of a carbon substituent at the o-position should be a useful transformation, but one that is not readily accomplished by conventional enone chemistry. a-Substituted cycloalkenones could of themselves be of interest, but perhaps, of more general importance would be their use as intermediates for the production of substituted cycloalkanones or a, 5-disubstituted cycloalkanones by a subsequent conjugate addition procedure.2 These strategies avoid many of the limitations attendant to the trapping of enolates with carbon electrophiles. The method of Kim involving treatment of enones with the combination of a dimethyl acetal, pyridine and trimethylsilyl triflates results in a-(1-methoxyalkyljenones.3 The metallation of a-bromoenones masked as ketals for [Pg.184]

This preparation illustrates an efficient two-step process for the transformation of a cycloalkenone to the corresponding a-substituted derivative. The first step involves the installation of an a-iodo substituent by a process thought to involve nucleophilic addition of pyridine, iodine capture of the resulting enolate, and pyridine-promoted elimination of pyridine.5 The resulting vinyl iodides are superior to other vinyl halides as participants in a variety of transition-metal catalyzed coupling reactions, illustrated here by the Suzuki coupling with an arylboronic acid. Other coupling partners that... 

Carbon-carbon bond formation via the Michael addition of a,P-unsaturated ketone and 1,3-diketone is achieved in high yields and short times to give (61) by employing catalytic amounts of EUCI3 in dry media under microwave irradiation (Soriente et al, 1997). Ranu et al. (1997) reported the Michael addition of ethyl acetoacetate, acetyl acetone, and ethyl cyanoacetate to cycloalkenones, P-substituted enones and enal. The reaction accomplished efficiently on the surface of alumina under microwave irradiation in dry media. Baruah et al. (1997a,b) also demonstrated the BiClj and Cdl2 catalyzed solvent-free Michael addition of 1,3-dicarbonyl compounds under microwave irradiations with good yields. 

Catalytic, Enantioselective Addition of Arylboronic Acids to Cycloalkenones. A complex between ligand 1 and a rhodium(I) salt was found to catalyze the asymmetric 1,4-addition reaction of arylboronic acids to cyclohexenone and cyclohep-tenone. The reaction proceeds with high enantiocontrol and excellent yields (eq 4). Lower enantiomeric excesses were observed with cyclopentenone (83% ee), but a variety of substituted phenyl-boronic acids could be used. 

Another chiral cuprate that shows high diastereoselectivity on addition to cycloalkcnones is the dihydropyrazine derivative 12. The adducts 13 were obtained in good chemical yield with diastereoselectivities exceeding 90% A Lower diastereoselectivities resulted on addition of 12 to /(-substituted cycloalkenones or to acyclic ( )-enones. 

Posner and coworkers have published a series of papers in which they described a successful application of the Michael reaction between a variety of carbanionic reagents and chiral cycloalkenone sulphoxides 557 to the synthesis of chiral organic compounds (for reviews see References 257, 649, 650). In several cases products of very high optical purity can be obtained. Subsequent removal of the sulphinyl group, serving as a chiral adjuvant, leads to optically active 3-substituted cycloalkenones 558 (equation 356 Table 27). 

Prior to our original report7 on this method, acceptable and general preparative routes to a-iodocycloalkenones had not been described. Treatment of a p-substituted cycloalkenone with trimethylsilyl azide and a mixture of iodine and pyridine sequentially in dichloromethane has now been reported as a method for the preparation of p-substituted-a-iodocycloalkenones.8 The combination of iodine and pyridinium dichromate has also been reported to provide a-iodoenones from enones as well as from ethynyl carbinols.9 10 Some successes have also been achieved with enones and iodine azide (IN3)11 and iodine/ceric ammonium nitrate.12-14 The submitters first variant5 of the present procedure used carbon tetrachloride as a solvent. In this procedure this solvent has been replaced with the more benign diethyl ether. 

Since allyl sulfoxides may quite easily undergo racemization at the sulfur atom via a reversible [2,3] sigmatropic process, the configurationally more stable chiral allylic phosphine oxides were also investigated.201 Compounds (184) and (185), prepared as a 1 1 mixture from allylphosphonyl dichloride and (-)-ephedrine, were shown to add to cycloalkenones with reasonably high diastereoselectivities. Ozono-lysis of the initially formed 1,4-adducts affords the respective optically active ketoaldehydes (Scheme 67). With a / /-isopropyl-substituted derivative even higher selectivities (88-98% ee) could be obtained. 

Asymmetric Coiyugate Addition of Allyl- and Crotylphosphonamides/ The asymmetric C-allylation of a, 3-unsaturated carbonyl compounds is a powerful tool for the functionalization of a carbonyl compound in the P-position. Since such a process normally leads to the corresponding enolate derivative when anionic reagents are used, there exists the possibility of trapping with an electrophile. Thus sequential addition and trapping can lead to vicinally substituted carbonyl compounds. Asymmetric allylation has been achieved previously with simple cycloalkenones using phosphorus and sulfur based reagents that must be prepared in diastereomerically pure form. 

Also of interest are cyclohexenones with the tether attached at the 4-position, which have not been as widely applied as the 2- and 3-substituted cycloalkenones. Croft and Jeffries irradiated the dia-stereomeric enones (61) and obtained two cycloaddition products and two products from intramolecular hydrogen atom abstraction (equation 98). All the products contained a trans decalin, however. This re-... 

The Lewis acid mediated cyclopentadiene addition to cycloalkenone 12. derived from a chiral sulfoxide, has been reported38. Virtually complete diastereoselection and formation of a separable endoiexo mixture in good yield was observed. In contrast, the quinone89 15 undergoes exclusive endo addition to the less substituted double bond with lower diastereoselection due to a greater distance between the reaction site and the stereogenic center. 

It may be seen from the scheme that although //ww-substituted olefins lead essentially to tran.v-substituted cyclopentanes, stereochemistry is not maintained in the case of n s-olefins. Thus, dialkylmaleates form a cisjtrans mixture of products. This is a result of palladium(0)-me-diated isomerization prior to codimerization. By employing the above-mentioned pumping technique, the yield of the same addition is nearly quantitative after 2 h at 130°C with 90% predominance of the m-isomer41. As with the TMM-Pd procedure, cyclodimerization with 2-cycloalkenones can only be achieved with 2-cyclopentenone in satisfactory yields wiLh the unsubstituted methylenecyclopropane. 

Cyclopentenes. Zirconacyclopentadienes prepared from two alkynes react with CO in the presence of BuLi to give substituted cyclopentenones. With CuCl as catalyst, the reaction of zirconacyclopentadienes with p-iodo-a,p-unsaturated carbonyl compounds provides cyclopentadienes. In the cases of 3-iodo-2-cycloalkenones, the products are spirocycles. 

Cycloalkenones. The nucleophilic at disubstituted 1,3-cycloalkanediones re Wadsworth reaction to give 3-substituted 2 The reaction of the same reagent wit phonates), which may undergo cyclization. rapid aldolization, permitting subsequent a 2-cyclohexenones. 

These optically active cyclopentanoids have been synthesized from tartaric acids or their derivatives employing a new phosphonate-based strategy for the construction of substituted cycloalkenones. Therefore, before presenting total syntheses of terreins it is desirable to outline this new strategy because it was used in the synthesis of other bioactive products. It was found [33, 34] that 3-(phosphorylmethyl)-2-cycloalkenones 23 are formed in good yields by intramolecular Horner-Wittig reaction of the corresponding bis- -ketophos-phonates which, in turn, are easily prepared from dicarboxylic acid esters and a-phosphonate carbanions (Scheme 10). 

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