Hydroxy enone

The primary disadvantage of the conjugate addition approach is the necessity of performing two chiral operations (resolution or asymmetric synthesis) ia order to obtain exclusively the stereochemicaHy desired end product. However, the advent of enzymatic resolutions and stereoselective reduciag agents has resulted ia new methods to efficiently produce chiral enones and CO-chain synthons, respectively (see Enzymes, industrial Enzymes in ORGANIC synthesis). Eor example, treatment of the racemic hydroxy enone (70) with commercially available porciae pancreatic Hpase (PPL) ia vinyl acetate gave a separable mixture of (5)-hydroxyenone (71) and (R)-acetate (72) with enantiomeric excess (ee) of 90% or better (204). 

Key features of the cyclopropanation include the ylide acting as a mild base to isomerize the 1,2-dioxines into cis-y-hydroxy enones, followed by Michael addition of the ylide and last by cyclization of the intermediate enolate [35]. It must be noted that the trans-y-hydroxyenones do not give the cyclopropanation. 

As discussed in Section 12.2.2, homoenolates can be accessed from a-hydroxy-enones, and an asymmetric synthesis of cyclopentenes has been achieved using this strategy with enones (Scheme 12.42) [15]. 

Nonsymmetric divinyl ketone 86 was employed as an enolate precursor en route to P-hydroxy-enones, which are formed in high yield and syn-selectivity... 

Scheme 24) [38]. Chemoselective enolization of the less substituted enone moiety under hydrogenation conditions accompanied by subsequent aldol reaction provided the corresponding hydroxyl-enones, such as 87-89, which could be converted to various building blocks for polypropionate synthesis. p-Me2N styryl vinyl enone also was employed successfully as an enolate precursor, as demonstrated by the formation of hydroxy enone 90. 

We had two possible routes in which alcohol 72 could be used (Scheme 8.19). Route A would involve rearrangement of tertiary alcohol 72 to enone 76. Deprotonation at C5 and generation of the enolate followed by exposure to an oxaziridine or other oxygen electrophile equivalents might directly afford the hydrated furan C-ring of phomactin A (see 82) via hydroxy enone 81. We had also hoped to make use of a chromium-mediated oxidative rearrangement of tertiary allylic alcohols. Unfortunately, treatment of 72 to PCC produced only unidentified baseline materials, thereby quickly eliminating this route. 

Similarly, Scheme 44 indicates that Selvan et al. utilized -hydroxy enones (e.g., 169) to synthesize pyrazoles (e.g., 170) [87]. Although this example is a cur cumin analog and not a chalcone derivative, it has been included as this class of compounds exhibited anti-oxidant and COX-l/COX-2 activity. 

The isoxazoles 184a and b were synthesized by Selvam et al., and the synthesis is described in Scheme 50 [87]. As with Scheme 49, this group utilized hydroxyl amine reacted with the /1-hydroxy enones (169 and 185) to form the isoxazoles (184a and b). 

Many methods have been reported for the enantioselective synthesis of the remaining PG building block, the (J )-4-hydroxy-cyclopent-2-enone. For example, the racemate can be kinetically resolved as shown in Scheme 7-28. (iS )-BINAP-Ru(II) dicarboxylate complex 93 is an excellent catalyst for the enantioselective kinetic resolution of the racemic hydroxy enone (an allylic alcohol). By controlling the reaction conditions, the C C double bond in one enantiomer, the (S )-isomer, will be prone to hydrogenation, leaving the slow reacting enantiomer intact and thus accomplishing the kinetic resolution.20... 

Asymmetric ring opening of 3,4-epoxy cyclopentanone (desymmetrization) catalyzed by 2 mol% of an (R)-BINOL modified aluminum complex affords the (4/ )-hydroxy enone in 95% ee at 98% yield (Scheme 7-29).2... 

Two consecutive enolate alkylations were utilized to generate the quaternary carbon atom (Scheme 38). Alcohol 238 was transformed into the protected hydroxy enone 244. Regioselective deprotonation at the a-position of the ketone 244 led to a cross-conjugated enolate that was alkylated with the allylic iodide 245. The vinyl silyl moiety in 245 represents a masked keto group [127]. The choice of the TBS protecting group for the hydroxyl group at of 244 was crucial in order to prevent the deprotonation at the y-posi-... 

There has been a continuing effort to make the Baylis-Hillman reaction a catalytic asymmetric process. Scott Schnauss of Boston University recently reported (J. Am. Chem. Soc. 125 12094, 2003) an elegant solution to this problem, based on the use of Binol-derived Bronsted acids as catalysts. The product hydroxy enones such as 6 are interesting in themselves, and also as substrates for further transformation, for instance by Claisen rearrangement. 

The preparation of a-hydroxy carbonyl compounds has been accomplished by the oxidation of enolates using both oxygen6 and MoC PyHMPA-(MoOPh).7 Acyl anion equivalents offer another route to this useful class of compounds. The procedure presented here for the synthesis of 6-hydroxy-3,5,5-tr1methyl-2-cyclohexen-l-one illustrates the use of MCPBA oxidation of an enol silyl ether as a method for obtaining an a-hydroxy enone. The procedure is a scaleup of a published synthesis. ... 

More recently, Hoppe et all63 also reported a stereoselective synthesis of a P -amino-u -hydroxy enone and its transformation to a 1,2-dihydroxyethylene isostere (Scheme 29). The addition of dilithium dimethylcyanocuprate to the conjugated C=C bond proceeds smoothly to produce a Z-enolate. The C-methoxycarbonylation with methyl cyanoformate forms the epimeric mixture of the 3-oxo ester. The product is then reduced with sodium cyanobo-rohyde to provide a protected form of the 1,2-dihydroxyethylene isostere. 

Oxidation of enediols.1 The cw-enediol 1 undergoes facile oxidative cleavage, but is oxidized by DDQ in quantitative yield to the hydroxy enone 2. 

Soon after the original development of exciton chirality method346,347 for steroidal diols, Koreeda, Harada and Nakanishi348 extended its application to exciton interaction between benzoate transition at 230 nm (e 14,000) and enone n —> n transition at 230-260 nm (e 7,000-15,000). The p-chlorobenzoate of 3/J-hydroxycholest-5-en-7-one (151, Figure 17) exemplifies the application of this method348. The 3/J-hydroxy-enone has a As typical of the s-trans enone chromophore, and the relative orientation (helicity) of the two interacting dipoles in p-chlorobenzoate 151 is shown in Figure 17. Such positive exciton chirality... 

The epoxidation of electron-deficient alkenes with either vanadium or titanium catalysts give syw-epoxides347 a free hydroxy group and a ketone or ester function are necessary for the reaction to take place, and a modest level of asymmetric induction can be achieved with y-hydroxy enone substrates and chiral titanium catalysts348. 

Baldwin and co-workers (56, 57) have reported that all attempts to cyclize hydroxy-enones 162 and 164 (R=H or OCH3) under basic conditions failed to give the corresponding furanones 163 and 165 (R=H or 0CH3). The susceptibility of these systems to conjugate addition of alkoxide nucleophile was verified by conducting the attempted cyclization with sodium methoxide in deute-... 

The acid-catalyzed cyclization of hydroxy-enones 162 and 164 (R=H or OCH3) gives the corresponding furanones 163 and 165. The success of these reac-... 

An alternative was used by Baldwin in the work that led to his famous rules for cyclisation.8 He needed to study the cyclisation of the hydroxy-enone 36 and an obvious aldol disconnection led back to the a-hydroxy-ketone 37. The same disconnection requires the addition of an acyl anion equivalent 39 to cyclohexanone and Baldwin chose the lithium derivative 40 of a vinyl ether. 

Stereospecific epoxidation of hydroxy enones.1 Epoxidation of the racemic i>droxy enones 1 with H202 in a basic medium shows only a slight preference for the... 

The enantioselective alkylation of indoles catalyzed by C2-symmetric chiral bisoxazoline-metal complexes 90 encouraged many groups to develop superior asymmetric catalysts which are cheap, accessible, air-stable and water-tolerant. Other analogs of the bisoxazoline-metal complex 90 as chiral catalysts and new Michael acceptors have also been studied. The enantioselective alkylations of indole derivatives with of-hydroxy enones using Cu(II)-bis(oxazoline) catalysts 93 and 94 provided the adducts in good yields... 

The reaction of both pyrrole and N-methylpyrrole (321) with dimethyl p-nitrobenzylidene malonate (326) in the presence of the catalyst (S)-93 gave the Michael adducts 327-328 in excellent yields (99%) [98], but the enantioselectivity of the products was quite low (28-36% ee), respectively (Scheme 71). Regarding catalyst 93, the Michael adduct 329 was obtained from N-methylpyrrole (321) and the alkylidene malonate in moderate yield (62%) and low enantioselectivity 18% ee (Scheme 71) [100]. But, the bis(oxazoline) 93-catalyzed reaction of both pyrrole (1) and N-methylpyrrole (321) with various (/-hydroxy enones 95 as Michael acceptor worked perfectly (Scheme 71) [99]. The elaboration of these adducts through sequen-... 

Noyori and colleagues investigated the ring opening of unsaturated mono- and bicyclic endoperoxides catalyzed by 5-10 mol% of Pd(PPh3)4 [226, 227]. Similarly to the cobalt-catalyzed reactions, (Z)-4-hydroxy enones resulted as the main products, which were accompanied by (Z)-2-ene-l, 4-diols and diepoxides. The latter are formed as the major products under either ruthenium or cobalt catalysis (see Part 2, Sects. 3.5 and 5.8). Both two-electron and radical mechanisms were considered for this transformation. Saturated bicyclic endoperoxides gave mixtures of cyclic 4-hydroxy ketones and 1,4-diols and their formation may be a result of a radical process [227, 228]. 

Dioxins behave as masked cis y-hydroxy enones and as such are an excellent source of y-lactones, notably in an enantio-enriched form <02JOC5307>. Treatment of the dioxin with an amine base results in rearrangement to 1,4-dicarbonyl compounds from which pyrroles and thiophenes are available in a one-pot synthesis <02TL3199>. Stabilised phosphonates add to 1,2-dioxins to yield diastereo-pure substituted cyclopropanes <02JOC3142>. 

Very interesting results were obtained during studies on the epoxidation of /f-hydroxy enones 8. Attempts at selective epoxidation under typical basic conditions failed and 2 3 mixtures of syn- and anf/-epoxides 9 were obtained. Surprisingly, epoxidation using Sharpless conditions, titanium tetraisopropoxide/tm-butyl hydroperoxide or vanadyl acetylacetonate/rm-butyl hydroperoxide, which are normally unreactive towards simple enones, proceeded smoothly, yielding exclusively syn-epoxy alcohols syn-9. No epoxidation took place for the corresponding nitrile or when the hydroxy function was blocked as a silyl ether32. 

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