Enones cuprate addition

Details of the Janda-Chen synthesis were as follows. A tetrahydropyran (THP) linker was attached to the NCPS support enabling attachment of alcohols via THP ether formation.13 The THP-NCPS resin 1 is derivatized with / -(+)-4-hydroxy-2-cyclopentanone 2, giving the THP ether-based resin 3, followed by coupling of the C13 20 fragment by enone-cuprate addition. The cuprate required was generated from the corresponding E-vinyl stannane 4. The resulting enolate was trapped as the silyl end ether... 

Sdieine 6.12. Diactereocelective cuprate addition to 2 enone 61 - Ice/ ctep towardc the cynthecic of ico[7]-levnglandin D . TBS = t-biityidimethylcilyl)... 

Sdieire 6.20. Diactereocelective cuprate addition to cteroidal enone 95 (MOM = methoKymethyl). 

RCuCNLi (25-62%)]. Successful conjugate addition required the activating influence of TMSCl [11c], and rather modest yields (25-64%) were obtained with dialkyl-substituted 2-enones. Cuprate preparation directly from the organolithium... 

The poor diasteroselectivity at the yS-carbon of cyclic enones arises from poor facial selectivity during cuprate addition. Acyclic enones may also give poor dia-stereoselectivity at the y8-carbon center because of E Z isomerization arising from an equilibrium between an enone-cuprate d-re complex and starting materials. Much work remains to be done in the development of asymmetric variations in a-aminoalkylcuprate chemistry. 

Scheme 6.12. Diastereoselective cuprate addition to Z enone 61 - key step towards the synthesis of iso[7]-levuglandin D2. (TBS = t-butyidimethylsilyl)...

Scheme 6.20. Diastereoselective cuprate addition to steroidal enone 95 (MOM = methoxymethyl).

Tab. 6.2. HMPT = Results of diastereoselective cuprate additions to enone hexamethylphosphoric triamide). 95 (TMS = trimethylsilyl,...

Ar= Ph, p-MePh, o-MePh R = allyl, Me, Ph, cyclopropyl, n-butyl Scheme 6.28. Diastereoselective cuprate addition to a planar chiral a lchromium enone complex 145. 

Scheme 6.29. Diastereoselective cuprate addition to chiral molybdenum Ti-allyl enone complex 147.

ESR and CIDNP studies intended to detect the radical intermediates failed [63], Conjugate addition of a vinylcuprate reagent to an enone takes place with retention of the vinyl geometry indicating that no vinyl radical intermediate is involved [64, 65], Kinetic isotope effects and substituent effects in cuprate addition to benzophenone indicate that C-C bond formation is rate-determining, which is not consistent with the involvement of a radical ion pair intermediate [66]. 

The synthesis of the non-racemic cyclopentanone (+)-93 is outlined in Scheme 15. Starting with 2-methyl-cyclopent-2-enone (90), sequential cuprate addition and enolate alkylation afforded the racemic cyclopentanone rac-92 as a single diastereomer. The double bond was cleaved by ozonolysis, the resulting aldehyde chemoselectively reduced in the presence of the keto function and the primary hydroxyl function was subsequently protected as a silyl ether to provide racemic rac-93. This sequence has been applied fre-... 

The formal total synthesis of racemic guanacastepene (rac-187) from Snider and co-workers (Fig. 20) was submitted six months later than the completed synthesis of Danishefsky s group [116-118]. The shortest sequence developed by the Snider group utilized the sequential cuprate addition/enolate alkylation of 2-methylcyclopent-2-enone 90 previously exploited by Piers, Williams and Danishefsky (Schemes 15 and 31). As outlined in Figs. 19 and 20, the strategies of Danishefsky and Snider are closely related. Both rely on stepwise annulations to build up the tricyclic ring system. They differ only in respect to the particular reactions that converted the monocyclic starting material (90) via bicyclic hydroazulenes (207 vs 227) into the desired tricyclic 5-7-6-system (224). 

Ether cleavage and further functionalization afforded the intermediate 268. The [5+2]-cycloaddition provided the hydroazulene 267 with the correct relative configuration at and C. Tracing back the synthesis of the pyryli-um ylide 266 leads to the astonishing realization that 2-methyl cyclopent-2-enone (90) was the original cyclic starting material and that the methyl as well as the isopropyl group were introduced by a sequence of cuprate addition and enolate alkylation (see Schemes 15, 31 and 36 for comparison). 

The photochemically induced radical addition of alcohols to enones has been described by Fraser-Reid [104-109]. Here again, the sense of addition depends on the steric effects of substituents, attack anti to the C-5 substituent being preferred [108,110]. Other uses of sugar-derived enones to trap radicals have been reported [111]. Enolone 77 gave interesting results in terms of selectivity [112]. In this instance, radical addition occurs with an equatorial selectivity, whereas cuprate addition occurs with an axial selectivity [9,62]. 

Cyclopentanones. Hewson et ah have used the related reagent, 1-methylthiovi-nyl(triphenyl)phosphonium chloride (1) for a synthesis of prostaglandin D, methyl ester (8). Thus reaction of the diketodithiane 2 with 1 in the presence of NaH gives 3, which is readily converted into the enone 4. Addition of the cuprate reagent 5 to 4 shows unexpected selectivity in favor of the natural (rani-arrangement of the side chains, perhaps because of the spiro dithiane unit. 

Cyclic amino-carbenes, in molybdenum carbonyls, 5, 457 Cyclic bis(phosphine) dichlorides, with iron carbonyls, 6, 48 Cyclic carbenes, as gold atom ligands, 2, 289 Cyclic carbometallation, zirconium complexes, 10, 276 Cyclic carbozirconation characteristics, 10, 276 intermolecular reactions, 10, 278 intramolecular reactions, 10, 278 Cyclic dinuclear ylides, and gold , 2, 276 Cyclic 1,2-diols, intramolecular coupling to, 11, 51 Cyclic enones, diastereoselective cuprate additions, 9, 515 Cyclic esters, ring-opening polymerization, via lanthanide catalysis, 4, 145 Cyclic ethers... 

The methyl group at C-2 was introduced by cuprate addition to the enone 11 on the face opposite the large TBDMS group and the lithium enolate 12 trapped with Me3SiCl to give 13. This silyl enol ether was ozonised, reduced, and the silyl group hydrolysed whereupon oxidation gave spontaneous lactonisation to 1 in 12% yield from 11. 

Although lower-order cuprate reagents will often engage in displacement reactions with alkyl halides, such reactions are usually slow. They are generally much less facile than 1,4-addition reactions to a,P-unsaturated enones or enoates. The latter processes are particularly facile when trimethylsilyl chloride is employed as an additive. It was Corey and Boaz10 who first recognised the accelerating effect of trimethylsilyl chloride on cuprate addition reactions to a,p-unsaturated carbonyls. Buszek therefore capitalised on Corey s earlier observations in his reaction of 10 with lithium dimethylcuprate to obtain 15. 

Cossy and co-workers reported the synthesis of a variety of 3-oxacycloalkenes via RCM <02TL7263> (Scheme 37). Further transformations of these compounds, such as oi-oxyalkylation and cuprate addition to the enone were also reported. 

Among various recent applications of diastereoselective cuprate addition reactions to cyclic enones in target-oriented synthesis,81,81a 81c,83 87 the synthesis of (—)-dihydrocodeinone and (—)-morphine by Mulzer and co-work-... 

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