Isoflavanones synthesis

This method permits vinylation of aromatic compounds. In the isoflavanone synthesis, 4-chromanone (44) is converted to the enol ester 45, which is reacted with phenylpalladium acetate, formed in situ from phenylmercury chloride and Pd(OAc)2, to give — after hydrolysis - isoflavanone (46) (Schema 15). A simple synthesis of... 

Isoflavanones.1 A synthesis of these products from a poly hydroxy desoxy-benzoin such as 2 involves conversion of the nonhydrogen-bonded hydroxyl group to the protected ether by reaction with 1 and K2C03 in acetone at 25°. Further reaction with 1 at 60-70° gives an a-hydroxymethyl ketone 3 in 85-95% yield. This product cyclizes to the isoflavanone 4 in the presence of Na2C03. The final step involves deprotection of the ethoxymethyl group to give 5 (92-94% yield). 

The reactions of arylation of heterocyclic /3-ketoesters were employed in the synthesis of a number of isoflavanones and isoflavones.27,28 cr-Methylene cr-arylketones can be easily and selectively obtained by arylation of allyl /3-ketoesters which are eventually deprotected by the Tsuji s procedures. a Deallyloxycarbonylation was performed by treatment of the allyl cr-aryl-/3-ketoesters with catalytic amounts of palladium(n) acetate, triethylammo-nium formate and triphenylphosphane in THF at room temperature and afforded the a-arylketones in 75-97% yield.27 Deallyloxycarbonylation-dehydrogenation can be realized with the same allyl esters by treatment with catalytic amounts of palladium(n) acetate and l,2-bis(diphenylphosphino)ethane (DPPE) in acetonitrile under reflux and affords the ct-aryl cr,/3-unsaturated ketones in 60-90% yield (Scheme 4).28 In particular, this reaction was used in a direct convergent synthesis of 2 -hydroxyisoflavones involving arylation of an appropriate allyl /3-ketoester with the MOM-protected (2-methoxymethoxyphenyl)lead triacetate derivative (Scheme 4). The reaction of the isomeric... 

The reaction of arylation of 1,3-dicarbonyl derivatives was also used in a new approach towards the synthesis of isoflavanones and 3-aryl-4-hydroxycoumarins. Phenylation of activated chroman-4-ones to isoflavanones was obtained in moderate to good yields. Selective monophenylation was performed in high yield in a low-temperature reaction (- 23 C) of the activated chroman-4-one with pentaphenylbismuth and mixtures of mono- and di-aryl derivatives were obtained in modest yields with other types of arylbismuth reagents. 

Other enolised compounds were also easily arylated. Such was the case of P-ketosulfones, which reacted easily with triphenylbismuth carbonate (5) to afford the corresponding a-phenyl-P-ketosul-fones. This reaction was put to good use in an efficient synthesis of isoflavanone and isoflavone... 

Arylation reactions of heterocyclic P-ketoesters were employed in the synthesis of a number of 2-arylbenzofurans,i i 3 isoflavanones and isoflavones, 44 l 5 as well as for the synthesis of 2-aryl-(2i 7)-indole derivatives. 

A single step synthesis of isoflavanones was reported by Gandhidasan et al., [125] where the required isoflavones (261) was obtained by treating... 

Flavanones and Isoflavanones.- Reaction of the aryl benzyl ketone (120) with formaldehyde and dimethylamine has provided a new synthesis of isoflavanones in good yield.126 The same ketones can be cyclized to isoflavanones in good yield by treatment with di-iodomethane, a phase transfer catalyst (tetrabutylammonium iodide) and sodium thiosulphate.127 Flavanones react with hydroxylamine hydrochloride in ethanol-pyridine to give the oxime and not the oxazoline as previously claimed but when the oxime was heated with trifluoroacetic acid, the oxazoline was formed.128 The first triphenylmethane derivative to be found in nature, the flavanone melanervin (121), has been synthesized. Ammals (not animals, as printed in the abstract ) such as (122) have been applied to the... 

Erhardt and Khupse used an acid-catalyzed cyclization as a key step in their synthesis of the benzofuran-containing lespedezol Ai. Members of this family have been shown to posses significant anti-oxidant, anti-allergic, anticancer, and anti-fungal activities. Treatment of the isoflavanone precursor with a catalytic amount of hydrochloric acid in a methanol/trimediyl-orthoformate mixture gave the target compoimd in 71% yield. 

M.P. Carroll, Development of a Catalytic Asymmetric Synthesis of Isoflavanones. PhD Thesis, University College Dublin, 2012... 

A Stereoselective Switch Enantiodivergent Approach to the Synthesis of Isoflavanones... 

Two examples of these types of isoflavanones are the naturally occurring sativanone la and 3-0-methylviolanone lb (Fig. 5.2). Sativanone la was first isolated in 1973 by Donnelly from the heart wood of Dalbergia stevensonii [6] and has been shown to display activity against human cancer cell lines as well as antibacterial activity [7, 8]. There has been one reported racemic synthesis of sativanone la via a 4 step synthesis involving intramolecular cyclisation to form the B ring of the isoflavanone [9]. 3-0-Methylviolanone, first isolated in 1975 from Dalbergia... 

Recently we reported the first general catalytic asymmetric synthesis of isoflavanones which featured a Pb-mediated arylation to generate 2 followed by an asymmetric Pd-catalysed decarboxylative asymmetric protonation to generate the chiral centre in 3 (Scheme 5.1) [18]. Having applied this methodology to the constmction of several non-natural isoflavanones, we wished to expand its scope to include the asymmetric synthesis of naturally occurring isoflavanones which feature... 

Our synthesis of the 7-hydroxy-substituted isoflavanones la-e had to take into account protection of hydroxy group due to the likely interference with the synthetic route and in particular the key decarboxylative asymmetric protonation step. The synthesis of la-c could be accomplished by a series of Pb-mediated arylations of allyl-P-keto ester 7. This was accessed by Friedel-Crafts acylation, cyclization, NAP-protection and subsequent acylation with allyl cyanoformate (Scheme 5.2) [19-21]. We were able to generate isoflavanone precursors 8a-e from the allyl-P-keto ester (7) by introducing various aryl groups through the use of... 

The isoflavanone precursors 8a-e were then applied in the decarboxylative asymmetric protonation reaction. Recently Pd-catalysed decarboxylative reactions have emerged as a powerful tool in organic synthesis (see Sects. 4.3 and 4.4) [32, 33]. The often mild reaction conditions employed, coupled with the high yields and enantioselectivities attainable has seen this methodology applied in several syntheses [34—37] and continues to be an area of rapid growth in asymmetric catalysis. 

Scheme 5.3 Catalytic asymmetric synthesis of isoflavanones with oxygenation in 7-position...

Scheme 5.4 Decarboxylative asymmetric protonation in the synthesis of 7-substituted isoflavanones...

The final step of our synthesis was the removal of the NAP group to yield the free hydroxy group of the isoflavanones. Several conditions were screened in order to find a mild method of deprotection that would leave the stereocentre intact [39]. Ultimately stirring the protected isoflavanones 9a-e overnight with 10 % Pd/C in ethyl acetate under 1 atmosphere of hydrogen resulted in full deprotection of the isoflavanones without erosion of the enantiomeric excess (Scheme 5.5). The [ajo for sativanone la was measured to be + 31.2 (c 0.50, acetone), the positive rotation indicating that it was the (S)-enantiomer. This was confirmed by obtaining an x-ray crystal stmcture of NAP-protected sativanone 9a (Fig. 5.3). 

In conclusion we have developed a modular, 6 step synthetic sequence to construct isoflavanones with a range of substitution on the C ring and a free hydroxy group on the 7-position. Key features of this synthesis are the Ph-mediated arylation to... 

Following the previous successful application of the asymmetric decarboxylative protonation reaction in the catalytic asymmetric synthesis of isoflavanones we hoped to expand the scope of this work to the catalytic asymmetric synthesis of tertiary a-aryl cyclohexanones and, in particular, cyclopentanones given the dearth of reported methods for their direct asymmetric synthesis to date (see Sect. 4.6). 

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