1,4-addition cyclic enones

MeOC6H4, respectively. The titanium enolates were converted into silyl enol ethers 54 by treatment with chlorotrimethylsilane and lithium isopropoxide. Additionally, cyclic enones lb and Ic, and linear enones Id and le, are also good substrates for the asymmetric conjugate addition of phenyltitanium triisopropoxide, giving the corresponding arylation products with over 97% enantioselectivity. 

The reduction of a,p-unsaturated ketones is equally fast and remarkably selective for 1,2-addition of the silane. A variety of both cyclic and acyclic a,p-unsaturated ketones were reduced with diphenylsilane under the standard conditions with yields ranging from 66-99% for 1,2-addition. Cyclic enones were reduced with a higher degree of regioselectivity than the acyclic enone, mesityl oxide. 

Hie examples given in Tab. 7.1 illustrate tlie scope of tlie CufOTf i/(S, R, i j-18-catalyzed 1,4-addition. Witli various RyZri reagents, excellent yields and enantiose-lectivities ate obtained for cyclic enones fexcept for cydopentenone, vide infra) [6, 38, 80]. 

Optically active y-alkoxycyclopentenones have become popular in the diastereoselective synthesis of hms-3,4-disubstituted cyclopentanones. The Michael addition to these cyclic enones catalyzed by sodium ethoxide in ethanol277 or by potassium tm-butoxide278 279 proceeds under kinetic control trans with respect to the y-substituent. 

When the cyclic enone is unsubstituted, but the resulting enolate is quenched with an electrophile under conditions of kinetic control the irons adduct is formed exclusively303. Particularly successful is the sequential Michael addition/enolate alkylation in diastereoselective routes to frans-a,/j-difunctionalized cycloalkanones and lactones304-308. The key steps in the synthesis of methyl ( + )-jasmonate (3)309-310 (syn/anti diastereoselection) and (-)-khushimone (4) (syn/anti and induced diastereoselection) illustrate this sequence311 (see also Section D. 1.1.1.3.). 

Bentrude et al. [46] developed the 1,4-conjugate addition of silylphosphites to cyclic enones induced by photochemical SET. They showed that high yields... 

The optimal reaction conditions were applied with 59d in the addition of various aryl boronic acids and potassium trifluoroborates to several cyclic and acyclic enones (Fig. 8). Arylboronic acids added to cyclic enones in high yields (89-97%) and with good to excellent selectivities (85-98% ee). Under these conditions, the potassium trifluoroborate reagents reacted at faster rates, but with slightly lower selectivities (83-96% ee). The reactions of acyclic enones with aryl boron reagents gave also excellent yields (83-96%). 

Scheme 2.12 Cu-catalysed 1,4-additions of RMgCl to cyclic enones with mercaptoaryloxazoline ligands.

In 2004, excellent enantioselectivities of up to 98% ee were obtained by Morimoto et al. by using a phosphine-sulfonamide-containing 1,1 -binaphthyl-based ligand in the enantioselective copper-catalysed conjugate addition of ZnEt2 to several benzylideneacetones (Scheme 2.27). Similar levels of enan-tioselectivity (up to 97% ee) combined with excellent yields (up to 90%) were obtained by Leighton et al. for the copper-catalysed enantioselective addition of various alkylzincs to cyclic enones performed in the presence of other chiral phosphine-sulfonamide ligands (Scheme 2.27). ... 

In 2000, Gennaii et al. discovered a new family of chiral Schiff-base ligands, with the general structure, Af-alkyl-p-(A -salicylideneamino)alkanesulfonamide, depicted in Scheme 2.28. These ligands were successfully implicated in the copper-catalysed conjugate addition of ZnEt2 to cyclic enones (Scheme 2.28) and, less efficiently, to acyclic enones such as benzalacetone (50% ee) or chalcone... 

There have been many applications of conjugate additions in synthesis. Some representative reactions are shown in Scheme 8.2. Entries 1 and 2 are examples of addition of lithium dimethylcuprate to cyclic enones. The stereoselectivity exhibited in Entry 2 is the result of both steric and stereoelectronic effects that favor the approach syn to the methyl substituent. In particular, the axial hydrogen at C(6) hinders the a approach. 

Addition of azide ion to conjugated systems can be carried out by using NaN3 and acetic acid in water (Eq. 10.18).38 Some reactions were very rapid while others took 1 to 3 days to complete. Lewis base was found to catalyze such conjugate additions of azide ion to cyclic enones in water.39... 

Using a cyclic enone 2-29b and an ester-TMS enolate 2-30 in the presence of catalytic amounts of SmI2(THF)2, the Michael addition and the Mukaiyama/aldol reaction with the added aldehyde 2-32 led to the diastereomeric adducts 2-33 and 2-34 via 2-31 with a dr =80 20 to 98 2 and 70-77% yield (Scheme 2.7) [13]. The major product is the trans-l,2-disubstituted cycloalkanone. 

The addition of a Ni-catalyst to an alkyne as 6/4-47 and a cyclic enone as 6/4-46 in the presence of the chiral ligand 6/4-49 followed by a methyl transfer using Me2Zn led to 3-substituted cycloalkanones as 6/4-48 in good to medium yield, with an ee-... 

A summary of other chiral ligands with corresponding enantioselectivities in the copper-catalyzed 1,4-addition of dialkylzinc to cyclic enones is shown in Figure 5.55-58... 

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