Aldol condensation-intramolecular cyclization

Category Ih cyclizations effect closure of the C2 C3 bond. Scheme 3.1 depicts retrosynthetic transformations corresponding to syntheses in category lb. Included are three variations of the intramolecular aldol condensation and reductive coupling of o,/V-diacylanilines,... 

Forty years after the initial proposal, Sweet and Fissekis proposed a more detailed pathway involving a carbenium ion species. According to these authors the first step involved an aldol condensation between ethyl acetoacetate (6) and benzaldehyde (5) to deliver the aldol adduct 11. Subsequent dehydration of 11 furnished the key carbenium ion 12 which was in equilibrium with enone 13. Nucleophilic attack of 12 by urea then delivered ureide 14. Intramolecular cyclization produced a hemiaminal which underwent dehydration to afford dihydropyrimidinone 15. These authors demonstrated that the carbenium species was viable through synthesis. After enone 13 was synthesized, it was allowed to react with N-methyl urea to deliver the mono-N-methylated derivative of DHPM 15. 

Intramolecular Claisen condensations can be carried out with diesters, just as intramolecular aldol condensations can be carried out with diketones (Section 23.6). Called the Dieckmann cyclization, the reaction works best on 1.6-diesters and 1,7-diesters. Intramolecular Claisen cyclization of a 1,6-diester gives a five-membered cyclic /3-keto ester, and cyclization of a 1,7-diester gives a six-membered cyclic /3-keto ester. 

In this example, the /3-diketone 2-methyJ-l,3-cyclopentanedione is used to generate the enolate ion required for Michael reaction and an aryl-substituted a,/3-unsaturated ketone is used as the acceptor. Base-catalyzed Michael reaction between the two partners yields an intermediate triketone, which then cyclizes in an intramolecular aldol condensation to give a Robinson annulation product. Several further transformations are required to complete the synthesis of estrone. 

The intramolecular Michael addition of acyclic systems is often hampered by competing reactions, i.e., aldol condensations. With the proper choice of Michael donor and acceptor, the intramolecular addition provides a route to tram-substituted cyclopentanones, and cyclopentane and cyclohexane derivatives. Representative examples are the cyclizations of /3-oxo ester substituted enones and a,/J-unsaturated esters. 

The aldol reaction can be applied to dicarbonyl compounds in which the two groups are favorably disposed for intramolecular reaction. Kinetic studies on cyclization of 5-oxohexanal, 2,5-hexanedione, and 2,6-heptanedione indicate that formation of five-membered rings is thermodynamically somewhat more favorable than formation of six-membered rings, but that the latter is several thousand times faster.170 A catalytic amount of acid or base is frequently satisfactory for formation of five- and six-membered rings, but with more complex structures, the techniques required for directed aldol condensations are used. 

A tandem enzymatic aldol-intramolecular Homer-Wadsworth-Emmons reaction has been used in the synthesis of a cyclitol.310 The key steps are illustrated in Scheme 8.33. The phosphonate aldehyde was condensed with dihydroxyacetone phosphate (DHAP) in water with FDP aldolase to give the aldol adduct, which cyclizes with an intramolecular Horner-Wadsworth-Emmons reaction to give the cyclo-pentene product. The one-pot reaction takes place in aqueous solution at slightly acidic (pH 6.1-6.8) conditions. The aqueous Wittig-type reaction has also been investigated in DNA-templated synthesis.311... 

A trifold anionic/pericyclic domino reaction was used for the synthesis of the dioxapyrrolizidine 2-655 combining a nitro aldol condensation, SN-type cyclization, SN-type etherification, and an intramolecular 1,3-dipolar cyclization as described by Rosini and coworkers (Scheme 2.148) [339]. 

Intramolecular aldol condensation.1 This base can be effective for intramolecular aldol condensation of extremely hindered diketones that resist cyclization with the usual bases. 

The intramolecular Michael reaction is also a powerful transformation. In the cyclizations reported by Tetsuaki Tanaka of Osaka University (J. Org. Chem. 2004, 69, 6335), the stereochemical outcome is controlled by the chirality of the sulfoxide. Remarkably, subsequent alkylation or aldol condensation leads to one or two additional off-ring stereocenters with high diastereocontrol. Note that the high stereoselectivity in the cyclization is only observed with the (Z)-unsaturated ester. 

The simplest approach which can be envisaged to 4/f-pyrans involves the ring closure of 1,5-diketones. However, such molecules are frequently able to undergo a facile intramolecular aldol condensation leading to cyclohexenones, which competes successfully with cyclization to the pyran. 

The coumarin is probably derived from the initial acylated hydroxyacetophenone which, in addition to undergoing a Baker-Venkataraman rearrangement, may cyclize through an intramolecular aldol condensation. Elimination of water then gives rise to the coumarin (Scheme 161). 

Cyclization of the resulting keto aldehyde is an intramolecular aldol condensation. Base is required. 

Cyclization of the dione to the final product is a base-catalyzed intramolecular aldol condensation and was accomplished in 71% yield by treatment of the dione with a 2% solution of sodium hydroxide in aqueous ethanol. 

Intramolecular Mukaiyama aldol condensation.5 The silyl ketene acetal 1 cyclizes to the tetrahydrofuran 2 in 32% yield on exposure to TiCl4 (1 equiv.) in CH2C12 at 0°. The product is convertible into 3, an analog of cycloleucine. 

Earlier syntheses of arylquinolizidine alkaloids mainly utilized the pelletierine condensation to construct the basic skeleton, 4-aryl-2-quinolizidinone (11) (Scheme 1). Two mechanistic pathways, involving (a) initial aldol condensation of pelletierine (8) with an aromatic aldehyde followed by intramolecular Michael-type addition of the resulting enone 9 (6, 7) and (b) a Mannich-type reaction through 10 (8, 9), were proposed without any experimental evidence. Preparation and cyclization studies of the intermediate 9, however, gave conclusive evidence to show that the pelletierine condensation proceeded through pathway a (10). 

The product of Michael addition of an enolate to an a,p-unsaturated carbonyl compound will normally be a 1,5-dicarbonyl compound. The two reactive carbonyl groups separated from one another by three carbon atoms present the opportunity for ring formation by intramolecular aldol condensation. If one of the carbonyls acts as an electrophile while the other forms a nucleophilic enolate, this cyclization gives a six-membered ring. 

Hydrogenation of 1,4- and 1,5-diketones over platinum metals may be accompanied by cyclization to give tetrahydrofurans and terahydropyrans, respectively.133,134 The hydrogenation of 2,6-heptanedione over Pt-C at 200°C in cyclohexane gave 40% of 2,6-dimethyltetrahydropyran, together with 43% of 3-methylcyclohexanone and 15% of 3-methylcyclohexanol, which resulted by an intramolecular aldol condensation and subsequent hydrogenation.134... 

Since simple aliphatic aldehydes readily undergo aldol condensation under basic conditions, their intermolecular a-arylation is not successful. However, the intramolecular reaction is possible (Eq. 20) [59]. It is interesting that an unusual cyclization product via cleavage of the aldehyde C-H bond is observed in addition to the normal a-arylation product. Other examples of this kind of arylation are described in Sect. 3.3. 

Aldol condensation. The final step in a synthesis of the tricyclic taxane ring system involves an intramolecular aldol condensation of 2. Treatment with the usual bases results in a retro Michael reaction, but the desired cyclization to 3 can be effected in 90% yield by use of bromomagnesium diisopropylamide (1) or isopropylcyclohexylamide. The hydroxy ketone undergoes retroaldolization in the presence of mild acids or bases, but can be reduced and stored as the corresponding stable diol. 

Intramolecular Mukaiyama aldol condensation. This reaction can be used to obtain six-, seven-, and eight-membered rings. Thus the reaction of the r /.v-dioxolanc la with TiCL (1-2 equiv.) gives 2a as the exclusive product. The isomeric /ran.v-dioxolane lb under similar conditions gives a I I mixture of 2a and 2b (72% yield). No cyclization products are obtained with SnCL or ZnCL. 

This cyclization has obvious applications to the synthesis of steroids and indeed Johnson et al. applied this reaction to a synthesis of dZ-progcsterone. The key step in the synthesis involves the cyclization of (3) to give (4). This reaction was carried out with trifluoroacetic acid as above, but ethylene carbonate was added to the reaction to trap the vinyl cation. After cyclization potassium carbonate was added to hydrolyze the enol complex. In this way (3) was converted into (4) in 71 % yield. The tetracyclic ketone (4) was converted into progesterone (6) by ozonization followed by intramolecular aldol condensation. Nole that (4) is a 5 1 mixture of the 17/7- and 17a-epimeric ketones. The mixture was converted into (6) and then separated by fractional crystallization. 

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