Keto-enones, intramolecular

The intramolecular reductive aldol reaction of keto-enones was successfully conducted under conditions similar to those described above, employing a cationic Rh complex and PI13P (Scheme 20) [34]. The keto-enone 63 was cyclized in the presence of added K2CO3 to give the ketone-aldol 64 in 72% yield with exclusive ds-selectivity. Dione-enone derivatives, for example 68 and 70, were efficiently cyclized to furnish bicyclic aldol products 69 and 71, respectively, wherein three stereogenic centers of the bicyclic product form stereoselectivity through the intermediacy of a Rh-enolate. 

Scheme 20 Hydrogen-mediated intramolecular reaction of keto-enones...

Copper hydride species, notably Stryker s reagent [Ph3PCuH]6, are capable of promoting the conjugate reduction of a,( >-unsalurated carbonyl compounds [42], Taking advantage of this trustworthy method, Chiu et al. demonstrated in 1998 an intramolecular reductive aldol reaction in the synthesis of novel terpenoid pseudolaric acids isolated from Chinese folk medicine (Scheme 28) [43]. Two equivalents of [Ph3PCuH]6 enabled cycli-zation of keto-enone 104 to provide the bicyclic diastereomers 105 (66%) and 106 (16%). The reaction also was applied to the transformation of 107... 

Krische and coworkers employed a rhodiumconjugate addition in combination with an intramolecular enolate trapping by a ketone (Scheme 8.15). Starting from simple keto enones 53, they obtained five- and six-membered carbocycles 54 with high levels of relative and absolute stereochemical control and created three new stereogenic centers in the domino process accordingly [26b]. 

Keto-enone (106) undergoes an intramolecular Michael reaction, giving the pharmaceutically valuable frani-dihydrobenzofuran skeleton (107). Using a bifunctional primary amine-squaramide catalyst, yielAldelee of up to 98/94/>99% have been achieved. 

The bifunctional squaramide (304), in combination with AcOH, enabled the catalytic formation of tra i-2,3-disubstituted dihydrobenzofurans (303) from keto-enones (302) with up to >99% ee and <97 3 dr via an intramolecular Michael addition. ... 

In the presence of a double bond at a suitable position, the CO insertion is followed by alkene insertion. In the intramolecular reaction of 552, different products, 553 and 554, are obtained by the use of diflerent catalytic spe-cies[408,409]. Pd(dba)2 in the absence of Ph,P affords 554. PdCl2(Ph3P)3 affords the spiro p-keto ester 553. The carbonylation of o-methallylbenzyl chloride (555) produced the benzoannulated enol lactone 556 by CO, alkene. and CO insertions. In addition, the cyclobutanone derivative 558 was obtained as a byproduct via the cycloaddition of the ketene intermediate 557[4I0]. Another type of intramolecular enone formation is used for the formation of the heterocyclic compounds 559[4l I]. The carbonylation of the I-iodo-1,4-diene 560 produces the cyclopentenone 561 by CO. alkene. and CO insertions[409,4l2]. 

The Pd enolates also undergo intramolecular Michael addition when an enone of suitable size is present in the allyl d-keto ester 744[465]. The main product is the saturated ketone 745, hut the unsaturated ketone 746 and ally-lated product 747 are also obtained as byproducts. The Pd-catalyzed Michael... 

Intramolecular Michael addition.1 Cesium carbonate catalyzes the intramolecular Michael addition of a cyclic (3-keto ester to an a,(3-ynone to form a cyclic enone after protonation. This reaction proceeds readily when a five- or six-mem-bered ring is formed higher rings can be formed, but in low yield.1... 

Further research on intramolecular photocyclization of amino enones and amino ketones based on electron transfer has been made by Kraus and Chen [228]. In analogy to the earlier results of Roth and El Raie [229], Kraus and Chen obtain the cyclopropanol derivative 286 as single stereoisomer by direct irradiation of 285. Photolysis of the amino enone 287 does not lead to a three-membered ring product, but only to pyrrolidine 288. The irradiation of the unsaturated keto ester 289 results in the even more unexpected formation of a nine-membered ring product 290. Such remote photocyclizations have rarely been described so far. 

Molander and Hiersemann (60) reported the preparation of the spirocyclic keto aziridine intermediate 302 in an approach to the total synthesis of (zb)-cephalotax-ine (304) via an intramolecular 1,3-dipolar cycloaddition of an azide with an electron-deficient alkene (Scheme 9.60). The required azide 301 was prepared by coupling the vinyl iodide 299 and the aryl zinc chloride 300 using a Pd(0) catalyst in the presence of fni-2-furylphosphine. Intramolecular 1,3-dipolar cycloaddition of the azido enone 301 in boiling xylene afforded the desired keto aziridine 302 in 76% yield. Hydroxylation of 302 according to Davis s procedure followed by oxidation with Dess-Martin periodinane delivered the compound 303, which was converted to the target molecule (i)-cephalotaxine (304). 

An alternative concept is asymmetric desymmetrization of a prochiral molecule of type 83. The starting materials 83 have three keto groups and one carbon atom bearing at least three substituents. A prerequisite is the presence of a prochiral carbon atom with two identical substituents bearing a keto functionality (Scheme 6.39, Eq. (2)). This type of asymmetric intramolecular aldol reaction proceeds with formation of cyclic ketols of type 84 with two stereogenic centers. Dehydration can subsequently be performed, leading to optically active enones of type 85. The two types of intramolecular aldol reaction are shown conceptually in Scheme 6.39. 

The Pd enolates also undergo the intramolecular Michael addition when the allyl / -keto carboxylate or diallyl malonate 450, in which an enone is present at a suitable position, is treated with Pd(0) catalyst [190], The main product is the saturated ketone 451, and the allylated product 452 is obtained as a byproduct. 

The synthesis of the tricyclic enone (237) has been reported (Scheme 35). The carbonyl group has previously been removed from this ketone to produce isolongifolene. The key step in this synthesis is the facile intramolecular y-alkylation of the keto-tosylate (236). 

The first modem thinking about the mechanism of the Nazarov cyclization is due to Braude and Coles,who suggested the intermediacy of a P-keto carbocation from either divinyl or allyl vinyl ketones. The ring is formed by intramolecular attack on the enone with concomitant generation of an a-keto carbocation. Loss of a -proton from this intermediate affords the product. Nazarov - himself provided support for this proposal by demonstrating the incorporation of deuterium from D3PO4 in different positions ftom divinyl or allyl vinyl ketones. 

X -.".e third case, cyclopentanone has self-condensed and ignored the enone to which it was to add in a conjugate fashion and continue with a Robinson annelation (p. 761). The liiis - - again is to use a specific enolate such as an enamine though the simplest here is a keto-ester can be easily prepared by intramolecular Claisen ester condensation (p. 727). 

A distinctly different reaction cascade leading to tetrahydrofurans is illustrated in Scheme 40 [74]. It was proposed that these reactions proceed by iodine-mediated deoxygenation of the peroxyl radical to an alkoxyl radical, which undergoes intramolecular C-H abstraction to form a y9-keto radical [74], Elimination of an a-hydrogen atom generates an enone, which is ultimately captured intramolecularly by conjugate hydroxyl addition to give a tetrahydrofuran (Scheme 40). 

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