Cyclohexenones Subject

Asymmetric Allylation. One of the recent new developments on this subject is the asymmetric allylation reaction. It was found that native and trimethylated cyclodextrins (CDs) promote enantiose-lective allylation of 2-cyclohexenone and aldehydes using Zn dust and alkyl halides in 5 1 H2O-THF. Moderately optically active products with ee up to 50% were obtained.188 The results can be rationalized in terms of the formation of inclusion complexes between the substrates and the CDs and of their interaction with the surface of the metal. 

Epoxide formation is nearly suppressed when massively subeti-tuted olefine, such as 2,2,4-trimethyl-3-hexene among others, ate subjected to the chromic oxide-acetic anhydride reagent,42 Cyclo-hexene yields primarily 2-cyclohexenone and cyclohexane- 1,2-dione777 although some cyclohexane oxide appears to bo formed also (Eq, 111). 

Stereoelectronic effects should also play an important role in the nucleophilic 1,4-additions of anions to conjugated systems. These effects should therefore influence the Michael reaction as well as the hydrocyanation of a,6-unsaturated ketones. Studies on these reactions provided evidence that the kinetically controlled addition of a nucleophile to a cyclohexenone derivative is indeed subject to stereoelectronic effects. 

The above described total synthesis shows the application of the (7-carbonyl radical-initiated tandem cyclization reaction for the first generation of (+)-paniculatine. With this method starting from 2-substituted-5-(R)-cyclohexenone 5 Sha and co-workers obtained 15 (=1) in 21 steps. Furthermore the HBr-salt of this alkaloid was prepared and subjected to a single X-ray analysis, which unambiguously confirmed the structure and stereochemistry of this synthetic (+)-paniculatine. 

The cyclohexenone 20, when subjected to hydrogenation, undergoes debenzylation followed by reductive amina-tion to give the perhydroquinoline as a 1 1 mixture of cis- and trails-isomers (Equation 37) <2005T8264>. 

Michael addition of trialkylstannyllithium to cyclohexenone SAMP- or RAMP-hydrazone gives 3-stannyl derivatives with de values of 42-44%, while subsequent alkylation of the enolate formed affords trans-products with de values >96%. The hydrazones obtained are subjected to ozonolysis to give 3-stannylcyclohexanones trans-1 with ee values up to 96%17. 

Crabbe and Greene employed a similar approach in their synthesis of a Corey intermediate. The synthesis, depicted in Scheme 1.33, began by construction of cuprate 166 via a slightly different route. 3-Methyl cyclohexenone (180) was epoxidized and subjected to Eschenmoser-Tanabe fragmentation to give the acetylenic ketone 181. Reduction of ketone 181 to the alcohol and protection afforded 164, which had been previously converted to cuprate 166 by Corey. 

The cyclohexenone 272, derived from L-alanine, was subjected to hydrogenation to give a 2 1 mixture of cis- and trara-fused perhydroquinolines 273 <05T8264> (Scheme 83). 

Silyl enol ethers need Lewis acid catalysis for efficient Michael reactions, such as the more substituted (and conjugated) isomer 110 forming a 1,5-diketone 111 from cyclohexenone in good yield.39 This product 111 is a mixture of diastereoisomers as have been many of the products in this chapter. We have also seen some reactions giving single diastereoisomers but without explanation. It is high time that we addressed the question of stereoselectivity and this is the subject of the next chapter. 

The reaction of an olefin with a 1,3-diketone enol, known as the de Mayo reaction [116], is an important member of the [23-2] photocycloaddition reaction family. This and related processes were discussed by Sato et al. [117]. 1,3-Dioxi-nones (62) react with ethylene to give cyclobutane products. (Kaneko et al. [118] and Demuth et al. [119] have written reviews on this subject.) The intermolecular reactions of olefins with enones, carried out by Organ et al. [120], are complementary to the work on spirodioxinone derivatives (e.g., 63) by Sato et al. [121]. Reaction of enone 64 with cyclohexene led to a mixture of seven products, with the all-cis isomer formed in 32% yield. However, higher selectivity was seen for the reaction with a protected cyclohexenone (65), which afforded the all-cis isomer (66) in 54% yield, and reaction with cyclopentene (67), which gave 68 as a single product in 90% yield, as shown in Scheme 17 (also see Fig. 8). 

The stereoselectivity of the hydride reduction of conjugated cyclohexenones has also been subjected to close examination from both experimental and theoretical viewpoints. Much of the work has involved polycyclic systems, e.g.. steroids which have little conformational flexibility and in which axial and equatorial directions of approach can be clearly defined. With small" hydride donors, these substrates show an even clearer preference for axial attack than the corresponding cyclohexanones. For examples involving reductions with lithium aluminum hydride and sodium borohydride, see Table 10. 3/(-Acetylcholest-5-en-7-one and cholest-2-en-l-one are notable in that the analogous saturated substrates are attacked from the equatorial direction115 l16. The reduction of 17/i-hydroxy-4-androsten-3-one (testosterone) to 4-androstene-3/1,17/j-diol with d.r. 90 10 can be compared with the sodium borohydride reduction of 17/i-hy-droxyandrostan-3-one (dihydrotestosterone) to androstane-3/ ,17/ -diol with d.r. 81 19 (see p 4030). 

New and continuing efforts towards the total synthesis of dendrobine (59 R = H) have been reported.In one sequence (Scheme 8), the butyric acid (85) was readily transformed into the ketal (86), which was submitted to a Birch reduction and hydrolysis to yield the cyclohexenone (87) as the single diastereomeric product. Acid treatment of (87) gave a stereoisomeric mixture of products (88) which were not separated but subjected to reaction with base to give compound (89). The same compound was obtained directly by treatment of (87) with strong base (Michael and aldol condensations combined). After some discouraging results, the tricyclic compound (89) was transformed into the desired keto-acid (90) via an abnormal ozonolysis reaction. Compound (90) possesses the correct stereochemistry at three asymmetric centres required for elaboration of dendrobine (59 R = H). 

Synthetic work on the mesembrane group will no doubt be further stimulated by reports on their central nervous system activity and somewhat surprising biosynthesis. An interesting asymmetric synthesis of unnatural (+ )-mesembrine (38) has been announced (Scheme 4). The key intermediate (35), prepared in nine steps from 1,2-dimethoxybenzene, was treated with L-proline pyrrolidide (36) under conditions typical for the preparation of enamines. The product was not isolated but subjected to reaction with methyl vinyl ketone followed by acid treatment to give the cyclohexenone (37) in 38 % overall yield. The last step in the synthesis [(37) — (38)] was based on previous synthetic work on mesembrine alkaloids. The synthetic (+ )-mesembrine (38) was shown to exhibit a positive Cotton effect and thus an antipodal relationship to natural (— )-mesembrine. The mesembrine analogues (40 = H or OMe, = H, Me, or CHjPh) have... 

Olefins are subject to oxidation both at the double bond and at the allylic position. The CrOs-pyridine reagent in methylene chloride appears to be the most satisfactory reagent for allylic oxidation among the Cr(VI) reagents.Several pieces of mechanistic information indicate that allylic radicals or cations are intermediates in these oxidations. Thus, in cyclohexene is distributed in the product cyclohexenone in a manner indicating that a symmetrical allylic intermediate is... 

When 1,2-disubstituted cyclopropane substrates were subjected to the reaction conditions, the cyclohexenones arising from cleavage of less hindered C—C o-bond were usually obtained as the major products (Scheme 17.23). It was noticed that the chirality of reactant 99 can be completely transferred to cyclohexenone 100, indicating cyclohexenones can be enan-tioselectively synthesized from optically pure cyclopropanes. 

The cycloadduct 113 was then transformed into y,3-unsaturated cyclohexenone 114, which was subjected to intramolecular [4 + 2] cycloaddition. Upon exposure to pyrrolidine in MeOH at 60°C, enone 114 afforded intramolecular Diels-Alder adduct 116 in 78% yield after chromatography. This seemed to be the result of initial reversible iminium formation via dehydrative condensation of pyrrolidine and enone 114. Under the reaction condition, isomerization of the transient iminium species to several distinct dienamine constitutional and stereoisomeric forms would occur. Among all possible isomers in dynamic equilibration, only dienamine 115 is conducive to a favorable intramolecular Diels-Alder transition state, resulting in ketone 116 after enamine hydrolysis. The final steps of the synthesis involved Wittig methylenation followed by... 

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