Conjugate addition catalysis

Another example of resort to heteroatoms to obtain both oral potency and a split between androgenic and anabolic activities Ls tiomestrone (99). Trienone, 98, prepared in much the same way as 23, undergoes sequential 1,6 and 1,4 conjugate addition of thioacetic acid under either irradiation or free radical catalysis to afford the compound containing two sulfur atoms. 

Tomioka K, Nagaoka Y (1999) Conjugate addition of organometallic reagents. In Jacobsen EN, Pfaltz A, Yamamoto H (eds) Comprehensive asymmetric catalysis, vol 3. Springer, Berlin Heidelberg New York, chap 31.1... 

Whereas the mono- and the S/S-dithioether moieties have been used to date, the 1,3-dithianyl motif was used for the first time in 2005 by Ricci et al. as a new hybrid ligand in asymmetric catalysis. Hence, a series of new chiral oxazoline-1,3-dithianes have been successfully applied to the copper-catalysed conjugate addition of ZnEt2 to enones (Scheme 2.16). The expected products were obtained in almost quantitative yields and enantioselectivities of up to 69% ee. 

Nickel catalysts can be used instead of copper catalysts to promote the conjugate addition reaction, providing, in some cases, better results than the corresponding copper catalysts. In 2000, Yang et al. discovered a series of (li ,25, 3i )-3-mercaptocamphan-2-ol derivatives, which proved to be efficient ligands in the conjugate addition of ZnEt2 to chalcone upon catalysis with Ni(acac)2 (Scheme 2.29). 

A series of chiral p-hydroxysulfoximine ligands have been synthesised by Bolm et al. and further investigated for the enantioselective conjugate addition of ZnEt2 to various chalcone derivatives. The most eiScient sulfoximine, depicted in Scheme 2.33, has allowed an enantioselectivity of up to 72% ee to be obtained. These authors assumed a nonmonomeric nature of the active species in solution, as suggested by the asymmetric amplification in the catalysis with a sulfoximine of a low optical purity. 

Pentadienyltrimethylstannanes undergo regioselective conjugate additions to aldehydes, catalysed by Lewis acids. The dominant product obtained depends on the catalyst used, as shown in reaction 46. In the case of titanium tetrachloride catalysis the reaction is also stereoselective and only one diasteroisomer is obtained297. Reaction with chiral aldehydes leads to asymmetric induction with similar organotin compounds298. 

This chapter will begin with a discussion of the role of chiral copper(I) and (II) complexes in group-transfer processes with an emphasis on alkene cyclo-propanation and aziridination. This discussion will be followed by a survey of enantioselective variants of the Kharasch-Sosnovsky reaction, an allylic oxidation process. Section II will review the extensive efforts that have been directed toward the development of enantioselective, Cu(I) catalyzed conjugate addition reactions and related processes. The discussion will finish with a survey of the recent advances that have been achieved by the use of cationic, chiral Cu(II) complexes as chiral Lewis acids for the catalysis of cycloaddition, aldol, Michael, and ene reactions. 

The conjugate addition of organometallic reagents R M to an electron-deficient alkene under, for instance, copper catalysis conditions results in a stabilized car-banion that, upon protonation, affords the chiral yS-substituted product (Scheme 7.1, path a). Quenching of the anionic intermediate with an electrophile creates a disubstituted product with two new stereocenters (Scheme 1, path b). With a pro-chiral electrophile, such as an aldehyde, three new stereocenters can be formed in a tandem 1,4-addition-aldol process (Scheme 1, path c). 

In conjunction with the Knoevenegal reaction, a Michael addition (Figure 22) reaction was also described by Jaekson et al. using the same siliea supported tertiary amines for the catalysis of conjugate addition of nitroalkenes to a,y9-unsaturated carbonyl compounds. At a flow rate of 6.6 pL/min the eonversion rate was constant with a high yield for 7 hours reaction time. 

Conjugate Additions and Baylis-Hillman Reactions Peptide catalysts have reemerged as a viable approach to asymmetric catalysis. In particular, Miller... 

Preliminary mechanistic studies show no polymerization of the unsaturated aldehydes under Cinchona alkaloid catalysis, thereby indicating that the chiral tertiary amine catalyst does not act as a nucleophilic promoter, similar to Baylis-Hilhnan type reactions (Scheme 1). Rather, the quinuclidine nitrogen acts in a Brpnsted basic deprotonation-activation of various cychc and acyclic 1,3-dicarbonyl donors. The conjugate addition of the 1,3-dicarbonyl donors to a,(3-unsaturated aldehydes generated substrates with aU-carbon quaternary centers in excellent yields and stereoselectivities (Scheme 2) Utility of these aU-carbon quaternary adducts was demonstrated in the seven-step synthesis of (H-)-tanikolide 14, an antifungal metabolite. 

The majority of the Michael-type conjugate additions are promoted by amine-based catalysts and proceed via an enamine or iminium intermediate species. Subsequently, Jprgensen et al. [43] explored the aza-Michael addition of hydra-zones to cyclic enones catalyzed by Cinchona alkaloids. Although the reaction proceeds under pyrrolidine catalysis via iminium activation of the enone, and also with NEtj via hydrazone activation, both methods do not confer enantioselectivity to the reaction. Under a Cinchona alkaloid screen, quinine 3 was identified as an effective aza-Michael catalyst to give 92% yield and 1 3.5 er (Scheme 4). 

The conjugate addition of nitro olefins under chiral Cmc/mna-thiourea catalysis has shown promising results with a variety of Michael donors. Dixon conducted a screen of various chiral thioureas and identified catalyst 117 as a versatile catalyst that works well with p-substituted nitro-olefms (78) [74]. Aromatic, heteroaromatic... 

As previously noted (Scheme 1), prior to the explosion of interest in iminium ion catalysis as a platform for the activation of a,P-unsaturated carbonyl compounds in 2000, Yamaguchi [29-33] and Taguchi [34] showed that proline derived bi-func-tional catalysts could provide an effective platform for the ion-pair controlled conjugate addition of malonates and nitroalkanes to a, 3-unsaturated ketones with good levels of stereocontrol. 

Scheme 30 Conjugate addition of A-silyloxycarbamates using iminium ion catalysis...

However, formation of this bond through the conjugate addition of a soft sulfur nucleophile to a,P-unsaturated aldehydes is efficiently catalysed using iminium ion catalysis [116], Using diarylprolinol silyl ether 55 the addition of a series of sulfur based nucleophiles to a variety of a,P-unsaturated aldehydes was shown to be effective (73-87% yield 89-97% ee). The products were isolated as their p-hydroxy sulfide derivatives 73 after in situ reduction of the products (Scheme 33). 

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