Triketones aldol cyclization

The first results which indicate that stereoelectronic effects play an important role in the aldol condensation were reported by Hajos and Parrish (6) who found that (a) triketone J8 cyclizes to the bicyclo[3.2.1]octane ketol on treatment with piperidinium acetate in water and (b) ketol 19 undergoes an epimerization at C-4 yielding the more stable isomeric ketol 20 on treatment with piperidine. The authors concluded that the formation of ketol 19 from 18 under kinetically controlled conditions is the result of... 

The (S)-(-)-proline catalyzed asyimietric aldol cyclization of the triketone to the optically active bicyclic aldol product, followed by dehydration to the optically active enedione, (+)-(7aS)-2,3,7,7a-tetrahydro-7a-methyl-lH-indene-l,5(6H)-dione, has been described, and two alternative reaction mechanisms have been suggested by the submitters. The exact... 

Asymmetric aldol cyclization of the triketone with (S)-(-)-proline can also be effected in solvents other than N,N-dimethylformamide acetonitrile 1s outstanding. ... 

Asymmetric aldol cyclization. Complete details are available for the cyclization of the triketone 1 to the optically active bicyclic aldol product 2, first reported in 1974 (6, 411). The high asymmetric induction is attributed to formation of the rigid intermediate A by virtue of two hydrogen bonds. Other amino acids are considerably less effective for this asymmetric cyclization. ... 

Developed in the early 1970s, this reaction, also called the Hajos-Parrish reaction or Hajos-Parrish-Ender-Sauer-Wiechert reaction, is one of the earliest processes for the stereoselective synthesis of Wieland-Miescher ketone, an important building block for steroids and terpenoid synthesis. This reaction is a proline mediated asymmetric variation to the Robinson annulation. Hajos and Parrish of Hoffmann-La Roche Inc. in 1971 and 1974 published an asymmetric aldol cyclization of triketones such as that of structure 39, which affords optically active annulation products in the presence of catalytic amounts of (S)-proline (Z-proline). One of the early examples is the synthesis of 41 from the triketone 39 (a product of the Michael addition of MVK to the corresponding 2-methylcyclopentane-l,3-dione), the reaction is performed in two steps first by ring formation in the presence of 3 mol % of (iS)-proline in DMF to afford the ketol 40 in 100% yield after crystallization with 93% ee and then by reaction with toluenesulfonic acid to give the dehydrated adduct 41. The formation of the Wieland-Miescher Ketone 44 follows the same synthetic route, starting from the tri-ketone 42 to give the end product in 75% optical purity and 99.8% of optical yield. 

Sterics can influence the stereochemical outcome of the aldol cyclization, as in the case of the synthesis of the ketol 52 from the triketone... 

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. 

This type of interesting phenomenon has also been observed in non-organometallic reactions. The Hajos-Wiechert intramolecular aldol reaction of the triketone to the bicyclic aldol exhibits a nonlinear relation between the enantiomeric purity of the (S)-proline catalyst and the en-antioselectivity (Scheme 44) (75). With the partially resolved amino acid, the cyclization affords the product in an ee lower than anticipated. The reaction occurring via an enamine intermediate again may be interpreted in terms of participation of two proline molecules in the productdetermining transition state. 

Another example is the cyclization of the racemic allylic alcohol 232 at -80°C which furnished the racemic tetracyclic bis-olefin 233 in 70% yield (89, 90). Ozonolysis of 233 gave the bicyclic triketone aldehyde 234 which underwent under acidic conditions a double intramolecular aldol cyclodehydration to produce racemic 16,17-dehydroprogesterone 235. This represents the first synthesis of a steroid via the now so-called "biomimetic" polyene cyclization method. 

Asymmetric aldol condensation (6, 410-411 7, 307). Terashima and coworkers have examined the effect of various (S)-amino acids on asymmetric cyclization of the acyclic triketone 1. The course of the cyclization is dependent on the solvent. In ether (R,S)-3 is formed preferentially in water (R,S)-2 is the major product. Several amino acids were found to effect asymmetric cyclization, particularly in the cyclization of 1 to 2. The most interesting result is that addition of (S)-phenylalanine gives (R)-2 in 56% enantiomeric excess and that addition of (S)-histidine gives (S)-2 in 54% enantiomeric excess. As expected (S)-proline exerted an effect, but rather slight. 

Enamine-mediated aldolizations offer much better prospects for a stereo-controlled process. The famous enantioselective proline-catalyzed triketone cyclization to the Wieland-Miescher ketone 43 [56], as well as the chemistry of type I aldolase enzymes [57],provide ample precedents for stereo- and enantioselective enamine-mediated reactions. 

As to the applications of proline, it can modify the surface of palladium on charcoal to give an enantioselective hydrogenation catalyst (Section D.2.3.1.). Forming amides with aromatic carboxylic acids, proline has served as an auxiliary in the enantioselective Birch reduction of the aromatic system (Section D. 1.1.1.3.1.). An interesting application is the catalysis of the aldol-type cyclization of triketones. Among the amino acids tested, it is often the best choice for high enantiomeric excess3 4. 

Two competing intramolecular cyclizations (see the aldol condensation-sec. 9.4.A.ii) are illustrated for triketone 205.jn this case, only the favored 6-enolendo-exo-trig product (206) was obtained and not the disfavored 5-enol-endo-exo-trig products (207 and 208). Enolates generally tend to undergo 5-exo-tet reactions at oxygen, whereas 6-enolendo-exo-tet reactions prefer carbon. In order to form a five-membered... 

The 4-(chloromethyl)isoxazole 13, which is readily accessible from 3,5-dimethyloxazole, serves as a C4-building-block in annulations to cycloalkanones (isoxazole annelation according to Stork). The primary step is alkylation leading to product 14, a masked triketone. On hydrogenation, the isoxazole ring is reductively opened and cyclization via the enaminone 15 leads to the enamine 16. On treatment with sodium hydroxide, this is converted into the bicycloenone 17 by hydrolysis, acid fission of the y dicarbonyl system and an intramolecular aldol condensation (analogous to a Robinson annu-lation) ... 

The catalyst we will use Is the amino acid L-proline—no derivatization or protection required. It was actually back in 1971 that it was first noted that L-proline will catalyse asymmetric aldols, but until the year 2000 examples were limited to this one cyclization. Treatment of a triketone with proline leads to selective cyclization onto one of the two enantiotopic carbonyl groups. A molecule of proline must condense with the least hindered ketone, and in this case an enamine (rather than an iminium ion) can form. The chiral enamine can select to react with only one of the two other carbonyl groups, and it turns out that it chooses with rather high selectivity the one coloured green in the scheme below. Cyclization, in the manner of a Robinson annelation, and hydrolysis of the resulting iminium ion follow on, releasing the molecule of L-proline to start another catalytic cycle. The isolated product is the bicyclic ketone, in 93% ee. 

More recently, Gryko reported an isolated example of a proline mediated cyclization of non-cyclic triketones.The reaction followed a domino Michael-Aldol pathway in the preparation of compound 29. The yields and % ee of these reactions are very solvent dependent and much lower than those reported for the Hajos-Wiechert reaction. Typically, the best results were obtained in NMP. 

First, cyclohexanone is alkylated by 32 giving rise to the masked triketone 33. On catalytic hydrogenation of 33, the isoxazole ring is reductively opened to give the enaminone 34, which cyclizes in situ to the enamine 35. On treatment with aqueous NaOH, 34 is converted to the 1,5-dione 36 (by enamine hydrolysis and acid cleavage of the 1,3-dicarbonyl system of the triketone intermediate), which undergoes base-induced intramolecular aldol condensation to the bicycloenone 37 (in analogy to a Robinson annulation) [317] ... 

Hajos and Parrish at Hoffmann La Roche discovered that proline-catalyzed intramolecular aldol reactions of triketones such as 104 and 107 furnish al-dols 105 and 108 in good yields and vith high enantioselectivity (Scheme 4.17). Acid-catalyzed dehydration of the aldol addition products then gave condensation products 106 and 109 (Eqs. (1) and (2)). Independently, Eder, Sauer, and Wiechert at Schering AG in Germany directly isolated the aldol condensation products vhen the same cyclizations vere conducted in the presence of proline (10-200 mol%) and an acid co-catalyst (Eqs. (3) and (4)). 

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