Aldol cyclization

Induction of Asymmetry by Amino Acids. No fewer than sis types of reactions can be carried out with yields of 75—100% usiag amino acid catalysts, ie, catalytic hydrogenation, iatramolecular aldol cyclizations, cyanhydrin synthesis, alkylation of carbonyl compounds, hydrosdylation, and epoxidations (91). 

Hie metliod involves a tegioselective, /vons-diasteteoselective, and eaantioselective tliree-component coupling, as shown in Sdieme 7.26. In tliis case, tlie zinc eaolate tesulling from tlie 1,4-addilion is trapped in a palladiuni-calalyzed allyla-tion [64] to afford /voiis-2,3-disubstituted cyclobexanone 96. Subsequent palladiuni-calalyzed Wacket oxidation [82] yields tlie metliylketone 97, wbidi in tlie presence of/-BuOK undergoes an aldol cyclization. This catalytic sequence provides tlie 5,6-i98) and 5,7- i99) annulated structures witli ees of 9696. 

Reaction of the potassium salt of salicylaldehyde with chlo-roacetone affords first the corresponding phenolic ether aldol cyclization of the aldehyde with the ketonic side chain affords the benzofuran (1). Reduction of the carbonyl group by means of the Wolf-Kischner reaction affords 2-ethyl-benzofuran. Friedel-Crafts acylation with anisoyl chloride proceeds on the remaining unsubstituted position on the furan ring (2). The methyl ether is then cleaved by means of pyridine hydrochloride (3). lodina-tion of the phenol is accomplished by means of an alkaline solution of iodine and potassium iodide. There is thus obtained benziodarone (4)... 

Carbonyl condensation reactions are widely used in synthesis. One example of their versatility is the Robinson anuulation reaction, which leads to the formation of an substituted cyclohexenone. Treatment of a /3-diketone or /3-keto ester with an a,/3-unsaturated ketone leads first to a Michael addition, which is followed by intramolecular aldol cyclization. Condensation reactions are also used widely in nature for the biosynthesis of such molecules as fats and steroids. 

What product would you expect to obtain from aldol cyclization of hexanc-dial, OHCCH2Cn2CH2Cll2CHO ... 

Intramolecular aldol cyclization of 2,5-heptanedione with aqueous NaOH yields a mixture of two enone products in the approximate ratio 9 1. Write their structures, and show how each is formed. 

Treatment of the minor product formed in the intramolecular aldol cyclization of 2,5-heptanedione (Problems 23.30 and 23.31) with aqueous NaOH converts it into the major product. Propose a mechanism to account for this base-catalyzed isomerization. 

Table 2 Hydrogenative aldol cyclization is promoted through the use of cationic Rh precatalysts and substoichiometric quantities of mild basic additives a... 

Table 3 Rh-catalyzed hydrogenative aldol cyclization of aldo-enonesa...

Krische et al. demonstrated intramolecular reaction with Co(dpm)2 (5mol%) and PhSiH3 (120 mol %) as a hydride donor (Scheme 8) [14-16]. Addition of aldehyde-enone 17 to a solution of the Co catalyst and phenylsi-lane resulted in the formation of the corresponding aldol cyclization product... 

Chiu et al. developed a catalytic reductive aldol cyclization of alkyne-diones such as 115 and 117 using [Ph3PCuH]6 (10mol%) as catalyst and polymethylhydrosiloxane PMHS (200 mol %) as terminal reductant. The... 

A proposed simplified mechanism for the conjugate addition/aldol cyclization, as depicted in Scheme 2.25, is based on detailed mechanistic studies performed on related Rh-catalyzed enone conjugate additions [45]. A model accounting for the observed relative stereochemistry invokes the intermediacy of a (Z)-enolate and a Zimmerman-Traxler-type transition state as shown in 2-110 to give 2-111. 

Furthermore, as described by Mori and coworkers, the domino aldol/cyclization reaction of the 3-keto sulfoxide 2-422 with succindialdehyde (2-423) in the presence of piperidine at r.t. afforded the chromone 2-424 which, on heating to 140 °C, underwent a thermal syn-elimination of methanesulfenic acid to provide 2-426 in 22 % overall yield (Scheme 2.100) [227]. This approach was then used for the synthesis of the natural products coniochaetones A (2-425) and B (2-427) [228]. 

Scheme 7.11. Domino ozonolysis/aldol cyclization of unsaturated ketonitriles.

The stereoselective intramolecular Henry reactions have been reported by Seebach. The Michael addition of doubly deprotonated acetyl acetaldehyde to l-methylenedioxyphenyl-2-nitroethene followed by subsequent intramolecular nitro-aldol cyclization leads to the diastereomerically pure cyclohexanone derivative, where the nitro and OH groups are cis as shown in Eq. 3.73.114 This reaction is applied to the synthesis of l-desoxy-2-lycorinone as shown in Eq. 3.74.115... 

The present tandem nitro aldol-cyclization process is used for the preparation of the enantiomerically pure 4-hydroxy-2-isoxazoline-2-ones. They are prepared starting from chiral a-mesyloxy aldehydes and ethyl nitroacetate under mild reaction conditions (Eq. 8.85).136... 

With a synthesis of 58 completed, the key intramolecular diketone aldol cyclization was investigated. Precedent for this type of 1,8-dicarbonyl aldol reaction is rare, although an aldol reaction has been proposed in the biosynthetic pathway to the hypocrellins. The only reported examples of such diketone aldol cyclizations involve multicyclic or bridged bicyclic systems, and of these no examples exist for 1,8-diketones forming 7-membered rings. MM2 calculations indicated that a... 

Recently, Krische and co-workers developed an effective protocol for the catalytic desymmetrization and parallel kinetic resolution of enone-diones via tandem conjugate addition-aldol cyclization (Scheme 66).150 This transformation, involving enantioselective rhodium-catalyzed conjugate addition methodology, enabled the formation of two C-G bonds and four contiguous stereogenic centers from simple precursors with high diastereo- and enantiocontrol. 

Application of this tandem conjugate addition-aldol cyclization methodology may lead to the concise synthesis of digitoxin (Scheme 67) and related cardiac steroids. 

Feringa and co-workers described the tandem addition-aldol cyclization protocol leading to the formation of 6,6-, 6,7-, and 6,8-annulated bicyclic systems (Scheme 68).39 Using Cu(n)-29 as catalyst and functionalized organozinc reagents as nucleophiles, the conjugate addition reaction followed by aldol cyclization can offer highly enantioselec-tive annulation products (up to 98% ee). This method can be used in the synthesis of carbocyclic compounds, such as steroids, terpenes, and other natural products. 

Reductive Cyclization of Activated Olefinic Carbonyl Compounds 10.10.3.2.1 Reductive aldol cyclization... 

Though several intermolecular catalytic reductive aldol additions are reported, corresponding reductive cyclizations have received less attention. The first reported reductive aldol cyclization involves use of a (diketonato)cobalt(ll) precatalyst in conjunction with PhSiHj as terminal reductant.48,486 The reductive cyclization is applicable to aromatic and heteroaromatic enone partners to form five- and six-membered rings. As demonstrated by the reductive cyclization of mono-enone mono-aldehyde 65a to afford aldol 65b, exceptionally high levels of ty -diastereoselectivity are observed. Interestingly, exposure of the substrate 65a to low-valent nickel in the presence of excess Et2Zn provides the isomeric homoaldol cyclization product 65c via reductive coupling to the enone /3-position (Scheme 43).47a... 

Most recently, reductive aldol cyclization catalyzed by In(OAc)3 in the presence of PhSiH3 was reported.50 This catalytic system is applicable to both aldehyde and ketone acceptors. As demonstrated by the reductive cyclization of 65a and 68a, cycloaldol products are produced in good yields and excellent ry -diastereoselectivity (Scheme 48). 

Table 22.2 Catalytic hydrogen-mediated reductive aldol cyclization of keto-enones.

Treatment of the ketone (105) with methanolic KOH led to hydrolysis of the acetate group, retro-aldol reaction and aldol cyclization, which eventually afforded a mixture of epimeric alcohols (106) 33). This strategy was used to construct the basic skeletons of various alkaloids, e.g. talatisamine 34), atisine 35) and chasmanine36). 

The ozonolysis of cyclobutene derivatives in the preparation of 1,4-diketones was also applied to the total synthesis of eyclopentanoid antibiotics 161 162k The oxidative cleavage of (470) by ozone and reductive work-up yielded the diketone (471) in 73 % yield. Diketone (471) underwent intramolecular aldol cyclization to give the key intermediate (472), which was used to synthesize ( )-xanthocidin161,162), (+)-epi-xanthocidin 162), ( )-p-isoxanthocidin161,162) as well as ( )-desdihydroxy-4,5-didehydroxanthocidin162). 

The biomimetic cationic domino cyclization of an acyclic unsaturated substrate to give the tetracyclic scaffold of triterpenes and steroids is intensively described in the literature.1121 The concept has recently been used by Corey et al. to prepare enanti-opure (+)-dammarenediol II 18 in an exceptional short way.1131 The synthesis demonstrates the power of the combination of cation-olefin polyannulation with the aldol cyclization for tetraannulation (scheme 4). Successive treatment of the acylsilane 13 with 2-propenyllithium 14 and the iodoalkane 15 efficiently yidds the epoxytriene 16. The Lewis acid... 

Cyclopentenones. 1,3-Dicarbonyl compounds add to enol ethers or esters (terminal) in the presence of Mn30(OAc)7 (excess) to form l-alkoxy-l,2-dihydro-furans. These can be converted to a 1,4-diketone, which undergoes aldol cyclization to fused (or spiro) cyclopentenones.1... 

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