Diketones aldol cyclization

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... 

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. 

Table 5 Rh-catalyzed hydrogenative aldol cyclization of l,3-diketone-enonesa... 

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). 

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... 

A similar regioselectivity under different conditions for aldol cyclization of 1,5-diketones obtained by the Michael addition of substituted acetoacetic esters to methyl vinyl ketones has been reported by another laboratory (equation IV),5... 

Intramolecular aldol reactions of diketones are often useful for making five- and six-Aldol Cyclizations membered rings. Aldol cyclizations of rings larger than six and smaller than five are less... 

Now the diketone is cyclized in HC1 to give a bicyclic enone. A new six-membercd ring has been formed but the old three-membered ring has disappeared. First, an intramolecular aldol reaction closes the new six-membered ring to form an enone and then the stage is set for a fragmentation. 

Aldol cyclization. Although the keto aldehyde 1 is resistant to aldol cyclization under normal, alkaline conditions, this reaction can be accomplished by a method originally developed by Raphael et Reduction of the enol lactone (2), derived from 1, with DIBAH produces a bridged ketol, which is oxidized to 3 with chromic add. This diketone was employed as an intermediate in a synthesis of the sesquiterpene gymnomitrol (4). 

The final stage in the synthesis of the second compound must be an aldol reaction as the produ is an enone. That leaves us with a diketone (the aldol cyclization is shown with a dotted arrow) ar., this could be made by two different conjugate additions. 

Transition metal catalysis of the Michael reaction of 1,3-dicarbonyl compounds with acceptor activated alkenes has been known since the early 1980 s 2>3 It is a valuable alternative to the classic base catalysis of the reaction. Because of the mild and neutral conditions, the chemoselectivity of these reactions is superior to that provided by base catalysis, since the latter suffers from various unwanted side or subsequent reactions, such as aldol cyclizations, ester solvolyses or retro-Claisen type decompositions. A number of transition metal and lanthanide compounds have been reported to catalyze the Michael reaction, but FeCb 6 H20 is one of the most efficient systems to date. A number of 3-diketones or p-oxo esters and MVK are cleanly converted to the corresponding Michael reaction products within a few hours at room... 

Aldol cyclization of 1,4-diketones yields cyclopentenones. Indeed, this excellent cyclization has been employed dozens of times in syntheses of the perfumery material cis-jasmone (58 equation 116). ... 

Aldol cyclization can be used as a method of annotating a cyclopentenone ring onto another ring, provided the necessary 1,4-diketone is readily available. A pertinent example is seen in equation (119) in the... 

Macrocyclic diketones can undergo transannular aldol cyclization reactions, giving bicyclic aldols. A representative example is seen in the cyclization of 1,6-cyclodecanedione to the corresponding hy-droazulenone (equation 142). Aldolization of the related cyclodecadienedione (120) has also been examined under mildly basic conditions aldols (121) and (122) are the main products, being formed in a ratio of 1 4 (equation 143). Control experiments with the pure aldols showed that this is the thermodynamic ratio of isomers. 

This complex transform can be envisaged by assuming that one equivalent of 3-8 attacks the enol lactone carbonyl group to afford the hydroxylactone 4-2 (Scheme 4.4). This unstable intermediate actually comprises a hemiacetal of an enol lactone. The reaction medium is sufficiently basic to cause the underlying diketone (4-3) to undergo aldol cyclization to form cyclohexenone 4-4. 

Zinnes and co-workers prepared pyrido[l,2-b][l,2]benzothiazines (Scheme 8) 1,2-benzothiazine 182 with isopropyl iodide and potassium carbonate resulted in spontaneous aldol cyclization of the intermediate enol ether 183 to 7,8-dihydro-8-hydroxy-ll-isopropyloxy 8-substituted pyrido[l,2-b][l,2]benzothiazin-10(9//)-one 5,5 dioxide (184). In sulfuric acid, dehydration and ether cleavage of 184 gave the corresponding unsaturated )3-diketone 185. Hydrogenation gave the saturated analogs 186. An attempt to prepare 186 directly by base-catalyzed cyclization of 187 afforded a high yield of 2,3-dihydro-6/f-oxepino [3,2-c][l,2]benzothiazin-5(4H)-one 7,7-dioxide (188) (Eq. 39). 

The mode of intramolecular aldol cyclization of 1,5-diketones (113) has been shown to be strongly dependent on reaction conditions. Treatment of (113) with strong bases (e.g. LDA) in aprotic solvents leads to the kinetically controlled product... 

In this process, the 1,3-diketone acts as the initial nucleophile and then acts as an electrophile via one of its ketones in the final intramolecular aldol cyclization. 

SCHEME 8.13 Products expected from aldol cyclizations of 1,4- to 1,7-diketones. 

Cydopentane reagents used in synthesis are usually derived from cyclopentanone (R.A. Ellison, 1973). Classically they are made by base-catalyzed intramolecular aldol or ester condensations (see also p. 55). An important example is 2-methylcydopentane-l,3-dione. It is synthesized by intramolecular acylation of diethyl propionylsucdnate dianion followed by saponification and decarboxylation. This cyclization only worked with potassium t-butoxide in boiling xylene (R. Bucourt, 1965). Faster routes to this diketone start with succinic acid or its anhydride. A Friedel-Crafts acylation with 2-acetoxy-2-butene in nitrobenzene or with pro-pionyl chloride in nitromethane leads to acylated adducts, which are deacylated in aqueous acids (V.J. Grenda, 1967 L.E. Schick, 1969). A new promising route to substituted cyclopent-2-enones makes use of intermediate 5-nitro-l,3-diones (D. Seebach, 1977). 

A green chemistry variation makes use of solventless conditions to minimize the waste stream from reactions of this type. To a mortar are added aldehyde 67, ketone 68 and solid sodium hydroxide. The mixture is ground and within 5 minutes aldol product 69 is produced. Addition of the second ketone and further grinding affords the 1,5-diketone 70, which can be isolated and cyclized to pyridine 71 with ammonium acetate. The authors report that this method can substantially reduce the solid waste (by over 29 times) and is about 600% more cost effective than previously published procedures. 

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