Cyclization of enones

Scheme 22.6 Catalytic hydrogen-mediated reductive aldol cyclization of enone-diones.

Photochemical cyclization of enones with olefins is followed by a retro-aldol reaction to give 1,5-diketones. 

Analogous cyclizations can also be accomplished electrochemically79. In 1988, Kariv-Miller s group reported that cyclization of enone 44 could be achieved at a mercury electrode in the presence of dimethylpyrrolidinium ion (DMP+)80. DMP+ was a critical component for the success of this reaction, as direct reduction in the absence of DMP+... 

Fig. (2). The cyclization of enone (9), gives origin of two Cyclized products (10) and (11). Ketone (10), Ketone (10) is converted to the saturated ketone (14)under standard organic reactions.Bromination and dehydrobromination of ketone (14) yields the a,P-unsaturated ketone (IS), which on subjection to catalytic hydrogenation affords (16) and this on reduction, produces alcohol (17). The compound (13) yields (18) by standard reactions that are used for the transformation of (12) to (16). Reduction with metal hydride followed by oxidation affords ketone (11), which is converted to alcohol (17)...

Matsumoto and Usui [8] reported the first total synthesis of ( )-pisiferic acid (1) and ( )-methylpisiferate (3) and this is depicted in Fig. (2). In this synthesis the fundamental skeleton of pisiferic acid has been constructed by the cyclization of enone (9). The introduction of C-10 carboxylic acid in pisiferic acid was accomplished by transannular oxidation. The depicted synthesis has been divided in two parts, Fig. (2) describes the preparation of the alcohol (17) and Fig. (3) deals with the conversion of the alcohol (17) to pisiferic acid (1). 

Cyclization of enone (9) in hexane with boron trifluorideetherate in presence of 1,2-ethanedithiol, followed by hydrolysis with mercury (II) chloride in acetonitrile, yielded the cis-isomer (10) (16%) and transisomer (11) (28%). Reduction of (10) with lithium aluminium hydride in tetrahydrofuran followed by acetylation with acetic anhydride and pyridine gave two epimeric acetates (12) (32%) and (13) (52%) whose configuration was determined by NMR spectroscopy. Oxidation of (12) with Jones reagent afforded ketone (14) which was converted to the a, 3-unsaturated ketone (15) by bromination with pyridinium tribromide in dichloromethane followed by dehydrobromination with lithium carbonate and lithium bromide in dimethylformamide. Ketone (15), on catalytic hydrogenation with Pd-C in the presence of perchloric acid, produced compound (16) (72%) and (14) (17%). The compound (16) was converted to alcohol (17) by reduction with lithium aluminium hydride. 

Buchwald and his group have also synthesized y-butyrolactones successfully by a metallocene mediated cyclization of enones (and ynones) with carbon monoxide in a formal [2-r2-rl]-ad-dition, and have thus achieved the first hetero-Pauson-Khand reaction [31]. The reactions can be conducted in high yields with either stoichio-metrical or catalytical amounts of [Cp2Ti(PMe,)2] as the example in Scheme 9 shows. 

Diels-Alder cyclization of enone silyloxyvinylallenes. The cyclization of the enone silyloxyvinylallene (1) can be effected thermall, but occurs in higher yield and with higher stereoselectivity with (CjHjljAlCl (1.1 cquiv.) at -78 0°. The product 2 is converted into the sesquiterpene dehydrofukinont (3) in several steps. 

Vinylsilanes and enol ethers are also useful as ir-nucleophiles. A vinylsilane cyclization is an important step in a synthesis of (-i-)-streptazoline from tartaric acid (equation 68)." This reaction also nicely illustrates the high trans stereoselectivity of cyclization with respect to the C-4 oxygen substituent." The use of enol ethers is exemplified by two special cases (equations 69 and 70). The keto amide (103) is converted into tetracyclic (104) in a one-pot procedure involving (105) as a key intermediate. " A remarkable process is the quantitative cyclization of enone (106), despite the low nucleophilicity of an enone double bond (equation 70)." The most likely mechanism involves enol ether (107). It must be added that the conditions, saturated methanolic HCl, are crucial for the success of this reaction. 

Additive cyclization of enones. Enones containing an unsaturation linkage that is reactive to organozinc/nickel species readily undergo cyclization. Two new C-C bonds are formed. 

Br0nsted and Lewis acid-catalyzed cyclizations of enones have become important methods for the synthesis of fused-flirans and benzofurans. Mukai and co-workers recently applied this strategy to the synthesis of the tetracylic ring system of (+)-nakadomarin A, a compound with cyctotoxic, inhibitory and antimicrobial activity. Dihydroxylation of the isolated double bond of the a-pentenyl-a,P-cyclopentenone framework, followed by acid-catalyzed ring closure, gave the desired tetracyclic product in 80% yield. A similar acid-catalyzed strategy was employed by Dixon and co-workers in their synthesis of the furan moiety of (-)-nakadomarin A. ... 

Scheme 2-88. Rh-catalyzed reductive aldol cyclizations of enone-aldehyde.

The reductive aldol cyclization of enone-ketone substrate 550c, wherein the aromatic enone moiety is tethered to a ketone moiety, afforded five- and six-membered ring products 551c in good yields and excellent diastereoselectivities (dr > 95 5) (Scheme 2-89). In the reaction, however, considerable amounts of the reduced products 554c were formed. ... 

Scheme 2-90. Rh-catalyzed reduction aldol cyclization of enone-dione.

A proposed mechanism for the Rh-catalyzed reductive aldol cyclization of enone/enal-ketone/aldehyde 550A ( = 1) is illustrated in Figure 2-25. Oxidative addition of hydrogen is followed by deprotonation to generate Rh-monohydride... 

Whereas the preceding processes involving ring openings of cyclopropanes provide useful [3+2] entries to cyclopentanes, the use of simpler substrates in [3+2] cycloadditions is made possible by the development of reductive cycloaddition pathways. Such reactions were initially developed in the context of stoichiometric processes, where metallacycles were prepared by oxidative cyclizations of enones and alkynes, followed by either protonation or alkylation of the nickel 0-enolate functionality. Catalytic protocols involving various intramolecular combinations of 7t-systems include formal [3+2] reductive cycloadditions of bis-enones to form bicyclooctanols (Scheme 3-33), of enones with unsaturated acyl oxazolidinones to form triquinane derivatives, and of enals with alkynes to form bicyclooctenols. ... 

Lam [77] has described highly enantioselective Cu(I)-catalyzed borylative aldol cyclizations of enone diones 237 via a chair-like transition state 238, which resulted in densely functionalized decalin-, hydrindane-, and diquinane-based products 239 containing four contiguous stereocenters, two of which are quaternary (Scheme 11.51). 

Fig. 11. Intramolecular cyclization of enone-alk5mes with [CpRuCCHsCNlsllPFe].

The ketyl intermediates in Sml2 reductions can also be trapped by carbon-carbon double bonds, leading to cyclization of, -enones to cyclopentanols. 

Figure 21. Lewis acid catalyzed cyclization of enones...

The intramolecular hydroalkylation of enones could be readily implemented as well via this strategy (Scheme 63) [38]. The addition of ethylene glycol had a dramatic effect on the reaction rate as demonstrated in the cyclization of enones 168 the reaction could be completed within 12 h, furnishing the cyclized products... 

Kablaoui NM, Buchwald SL (1995) Reductive cyclization of enones by a titanium catalyst. J Am Chem Soc 117 6785-6786... 

Scheme 33 Copper(I)-catalyzed enantioselective borylative aldol cyclization of enone diones by Lam...

Optically active allenes have been extensively studied by Tius for the asymmetric formation of the corresponding Nazarov cyclization products (Scheme 16.36) [132, 133], As an illustrative example, cyclization of enone 264 furnished cyclopentenone 265 with a high degree of stereoinduction (95% ee) [132], The intermediate cyclization precursor 264 had been prepared by addition of vinyllithium 263 to optically active allene amide 262 (98% ee). 

Intramolecular cyclization of enone-diyne with t-BuLi in the presence of ZnCh and Ni(COD)2 catalyst yields the tricyclic product in 52% yield [181]. 

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