Michael addition cinchona-alkaloid-catalysed

The adducts were isolated in good yield and up to 75% ee. Experimental findings and DFT calculations were both consistent with noncovalent catalysis, highlighting the ability of diatyl prolinols to behave in a similar mode of action as previously attested by die pivotal work of Wynberg and coworkers in natural Cinchona alkaloid-catalysed Michael addition reactions. ... 

Cinchona-alkaloid-catalysed conjugate cyanation of enones has enabled the synthesis of trifluoromethyl-substituted diarylpyrroles with ee<96%P° Thiochro-manes have been formed by asymmetric domino sulfa-Michael-aldol reactions of 2-mercaptobenzaldehyde with a,/ -unsaturated A-acylpyrazoles. Asymmetric organocatalysed oxy-Michael addition to y-hydroxy a,/ -unsaturated thioesters on reaction with t-BuCHO has been used to form -hydroxy carbonyl compounds HOCH2C H(OH)CH2CO.SAr via cyclic hemiacetal intermediates. 

Cinchona alkaloids and their derivatives have been reported to catalyse the Michael addition of (V-heterocycles, such as benztriazole, to nitroalkenes in moderate to high enantioselectivities (<94% ee) 15 The thiourea derivative (149) catalysed Michael addition of thioacetic acid to a range of frafts-/f-nitrostyrenes to afford RCH(SAc)- CH2NO2 (<70% ee) 16 The thiourea derivative (149) and its congeners have been identified as efficient organocatalysts for the Michael addition of a-substituted cyano-acetates RCH(CN)C02Et to vinyl sulfones CH2=C(R)S02Ph (72-96% ee) 17 ... 

Michael addition of nitromethane to chalcones can be catalysed by cinchona alkaloid-derived chiral bifunctional thiourea (142) (0.5-10 mol%) to give the corresponding products at 25-100 °C in high chemical yields and high enantioselectivity ... 

The substrate reactivity problem was solved by developing an intramolecular oxa-Michael addition/decarbo>ylation tandem reaction of allq lidene p-ketoesters catalysed by modified Cinchona alkaloids.By using 0-benzylcupreidine (O-Bn-CPD) as catalyst, a series of chiral flavanone derivatives have been prepared with high enantioselectivities (up to 93% ee) and excellent yields (Scheme 15.26). 

In addition to flavone synthesis, Hintermann also studied the kinetics and mechanism of natural Cinchona alkaloids (cinchonine and cinhonidine) catalysed oxa-Michael cyclisation of 4-(2-hydroigratyl)-2-hutenoates. Various henzodihydrofuranyl acetates and related products were obtained in up to 99% yield and with 91% ee. ... 

Aminothiourea-prolinal dithioacetal (234), in the presence of PhC02H, can catalyse Michael addition of ketones R CH2COR and aldehydes to nitroalkenes at 3 mol% loading to afford the 3yn-configured products with <99 1 dr and <99% ee under solvent-free conditions at room temperature. The related carbohydrate-derived thiourea is believed to activate both 8-diketones and nitroalkenes via coordination (235) the Michael adducts were obtained in <89% ee " Another variant of the thiourea motif with a cinchona alkaloid scaffold exhibited higher stereocontrol in the same reaction (<98% ee), carried out in MeCN at —40°C ... 

The cinchona alkaloid-derived thioureas (237a,b) and their squaramide counterparts (238a,b) have been employed to catalyse the Michael addition of a-alkyl and of-phenylselenenyl ketones R CH(X)COR (X=alkyl, SePh) and the corresponding... 

On the other hand, several cinchona alkaloid-derived primary amines have been successfully investigated as organocatalysts for asymmetric Michael additions of ketones to Michael acceptors. As an example, Lu et al. have described the first Michael addition of cyclic ketones to vinyl sulfone catalysed by a catalyst of this type, providing an easy access to chiral a-alkylated carbonyl compounds with high yields and enantioselectivities of up to 96% ee, albeit with moderate diastereoselectivities (<72% de), as shown in Scheme 1.21. This novel methodology was apphed to the synthesis of sodium cyclamate, an important compound in the artificial sweeteners industry. 

Scheme 1.20 Michael additions of nitroalkanes to vinyl sulfone catalysed by cinchona alkaloid-derived thiourea.

Acrylic esters, thioesters and A-acryloyl pyrrole have been identified by Dixon and Rigby as elfective electrophiles in the enantioselective Michael addition reaction with p-keto esters catalysed by a cinchona alkaloid bearing a bulky phenanthrene group (Scheme 1.27). High yields combined with excellent enantioselectivities of up to 96% ee were obtained in almost all cases of substrates. 

Scheme 1.23 Michael additions of malononitrile to o,P-unsaturated ketones catalysed by cinchona alkaloid-derived primary amine.

Scheme 1.25 Michael additions of a-substituted cyanosulfones to vinyl ketones catalysed by cinchona alkaloid.

Scheme 1.27 Michael additions of P-keto esters to acrylic esters, thioesters and N-acryloyl pyrrole catalysed by cinchona alkaloid.

Scheme 1.28 Michael additions of dicyanoalkylidenes to quinones catalysed by dimeric cinchona alkaloid.

A DPT and ONIOM study has probed the mechanism of 1,4-Michael addition of mal-onitrile to unsaturated aryl ketones catalysed by 9-cpi-amino-cinchona alkaloids. The proton from an acidic additive is critical in the formation of the key ketiminium ion intermediate, with the protonated tertiary amine of the alkaloid activating the carbonyl via hydrogen bonding. The origin of the high ee is also explored. 

Mechanistic details of the Michael addition of CH2(CN)2 to enones RCH=CHCOPh, catalysed by the cinchona alkaloid-derived primary amines, such as (265a,b), have been illuminated by using DPT and ONIOM calculation methods (i) the acidic additive pro-tonates the quinuclidine nitrogen, which activates the carbonyl substrate by hydrogen... 

A double-Michael addition of benzofuran-2-ones to divinyl ketones (RCH=CH)2CO, catalysed by various cinchona alkaloid-derived thioureas, has been shown to form spiro-cyclic benzofuran-2-ones (291) with <92% ee and <10 1 dr. DFT calculations were used to shed light on the origin of the stereoselectivity. ... 

Finally, a remarkable four-component tandem Michael-aza-Henry-hemi-aminalisation-dehydration tandem reaction was recently developed by Lin and co-workers on the basis of a dual organocatalysis involving a chiral diaryl prolinol trimethylsilyl ether and a chiral cinchona alkaloid." As shown in Scheme 2.37, the reaction began with the Michael addition of an aldehyde to a nitroalkene catalysed by the L-proline-derived catalyst, giving the corresponding intermediate aldehyde. The latter intermediate... 

In 2010, Jorgensen et al. developed an enantioselective tandem reaction of propargylated malononitriles with cyclic enones sequentially catalysed by a cinchona alkaloid-derived primary amine catalyst in the presence of (J )-mandelic acid as an additive for the first Michael step, and a gold catalyst for the second tandem exo-dig cyclisation-isomerisation reaction. " As shown in Scheme 7.62, the corresponding chiral bicyclic enones were achieved in good yields and high enantioselectivities of up to 96% ee, albeit low to moderate diastereoselectivities (34-66% de). 

Michael addition of benzofiiran-2(3//)-ones (370) to l,l-bis(phenylsulfonyl)ethylene, catalysed by the Cinchona alkaloid-derived thiourea (372), has been reported to exhibit good to excellent stereoselectivities (<99% ee). An interesting effect of the substituent position on stereoselectivity was observed and rationalized by a theoretical study. ... 

Similarly, high enantioselectivities have been reported for the Michael addition of mono thiomalonates RO2CCH2COSR to nitroalkenes, catalysed by the ureas derived from cinchona alkaloids (90 to >99% ee), at 1 mol% loading. The thiourea (426), derived from isosteviol and cyclohexyl diamine, can catalyse the addition of acetylace-tone to nitroalkene in toluene at -40 °C with <97% ee. By contrast, the diastereoisomer derived from the opposite enantiomer of cyclohexyl diamine was found to catalyse the formation of the enantiomeric product (<91 % ee), demonstrating the decisive role of the diamine moiety on the reaction outcome. ... 

---