Proline nitroalkenes

Chiral enolates of l,3-dioxalan-4-ones, methyl l,3-oxazolidine-4-carboxylates, and 1,3-imi-dazolidine-4-ones derived from chiral natural sources such as (S )-proline, (Sj-serine, and (S )-threonine are added to nitroalkenes in high diastereoselectivity (Scheme 4.12).77... 

Dipolar addition to nitroalkenes provides a useful strategy for synthesis of various heterocycles. The [3+2] reaction of azomethine ylides and alkenes is one of the most useful methods for the preparation of pyrolines. Stereocontrolled synthesis of highly substituted proline esters via [3+2] cycloaddition between IV-methylated azomethine ylides and nitroalkenes has been reported.147 The stereochemistry of 1,3-dipolar cycloaddition of azomethine ylides derived from aromatic aldehydes and L-proline alkyl esters with various nitroalkenes has been reported. Cyclic and acyclic nitroalkenes add to the anti form of the ylide in a highly regioselective manner to give pyrrolizidine derivatives.148... 

A series of diaryl-2-pyrrolidinemethanols have been tested as catalysts for the enan-tioselective Michael addition of malonate esters to nitroalkenes.30 Bis-(3,5-dimethyl-phenyl)[(S)-pyrrolidin-2-yl]methanol (6), easily prepared from L-proline, has been found the most efficient bifunctional organocatalyst, providing up to 56% ee. 

The catalytic application of L-proline in the asymmetric Michael addition of unmodified aldehydes or ketones with nitroalkenes in ionic liquids has been studied. The ... 

The organocatalytic asymmetric Michael addition of 2,2-dimethyl-l,3-dioxan-5-one (143) to various nitroalkenes (144), using a number of proline-based catalysts, afforded... 

Scheme 2.5 Enantioselective Michael reactions of ketones with nitroalkenes catalyzed by proline and proline-tetrazole analogues.

Nevertheless, as was pointed out before, a straightforward solution to the rather limited substrate scope of the reaction with regard to the ketone reagent and also a good way to overcome the lack of reactivity of ketones toward enamine activation has been the use of primary amines as organocatalysts. In fact, literature examples indicate that primary amines are much more active catalysts for the Michael addition of both cyclic and acyclic ketones to nitroalkenes compared to the same reaction using a secondary amine catalyst like most of the proline-based derivatives already presented before. 

In 2006 Palomo and coworkers tested several prolinamides in the asymmetric Michael addition of aliphatic aldehydes to nitroalkenes. Hydroxy-proline-derived amides 13 were found to be the most active catalysts for this transformation, establishing the importance of the hydrojy group not only for reaction stereocontrol, but also for catalyst activity. However, 3-hydro>y-prolinamide 13b gave less satisfactory results in terms of stereocontrol, compared to the 4-hydro>y-prolinamide analogue 13a (Scheme 11.11). 

The 0-TBS-hydro>y-diphenylprolinol silyl ethers 14, analogues of the Jorgensen-Hayashi catalyst 3a, were tested in 2008 by List and coworkers for the challenging catalytic asymmetric Michael reactions of acetaldehyde with nitroalkenes. While 4-hydroxy-proline derivative 14a displayed diminished activity, but slightly better enantioselectivity with respect to 3a, the 3-hydroxy-proline derivative 14b gave in this case very poor results (Scheme 11.12). 

Scheme 11.16 Aqmametric Michael addition of cyclohexanone to nitroalkenes cata-tysed by proline-derived triamine 17.

In 2007 Sun and coworkers reported the use of the proline derived triamine 17 in the presence of weak acids as a highly stereoselective organocatalyst for the asymmetric Michael addition of cyclohexanone to nitroalkenes (Scheme 11.16). All selected aromatic nitroalkenes gave excellent yields and selectivities, with the exception of electron-deficient substrates (Ar = 4-CN-Ph, 4-N02-Ph), which also require much longer reaction times. 

Between 2009 and 2011, Peng and coworkers reported the asymmetric Michael addition of cyclohexanone and other carbonyl compounds to nitroalkenes, catalysed by different fra s-4-amino substituted proline derivatives (18-20, Scheme 11.17). The sulfonimide 18 gave very high yields and enantioselectivities, whereas the analogous polystyrene-supported... 

The constrained diphenylperhydroindolinol silyl ether 40 was proposed in 2009 by Lu and coworkers for the highly efficient asymmetric Michael reaction of aldehydes with nitroalkenes and gave excellent enantioselectivity (99% enantiomeric excess) in most of the cases examined (Scheme 11.42). Armstrong and coworkers studied in 2009 the use of constrained bicyclic p-proline 41 in the benchmark aldol reaction between acetone and 4-nitro-benzaldehyde, comparing it with its monocyclic analogue 42 and with (S)-proline 1 (Scheme 11.43). DFT calculations were performed to rationalise the poor selectivity of p-prolines as well as to explain the better performance of constrained p-proline 41 versus 42. ... 

Proline derivatives possess a prominent position among the aminocatalysts utilised for carbonyl activation. In combination with the readily tunable properties of the (thio)urea functionality for electrophile activation, the development of bifunctional chiral pyrrolidine-based (thio)ureas was a rational extension. In 2006, Tang and coworkers reported thiourea 55 that can catalyse the conjugate addition reaction between cyclohexanone and nitroalkenes (Scheme 19.63). In the presence of 20 mol% of chiral thiourea 55 and butyric acid as the cocatalyst, the q -products were delivered in high yields (up to 98%) and in excellent diastereo- (up to >99 1 dr) and enan-tioselectivities (up to 98% enantiomeric excess). In addition to aromatic nitroalkenes, aliphatic nitroalkenes were also tolerated, but required a long reaction time (6 days). 

The proline-catalyzed intermolecular Michael reaction of unactivated ketones with nitroalkenes [33] can also be fitted in a mechanistic scenario involving the List-Houk transition state model (Figpre 2.11). 

A re-examination of proline-catalysed enantioselective Michael addition of aldehydes (R CH2CH0) with fran -nitroalkenes (R CH=CHN02) has identified a cyclobutane intermediate (109) derived from the reactants and catalyst. In situ NMR was used to discover the presence of (109) and to And that it represents a parasitic or resting state, arising from the iminium nitronate zwitterionic intermediate, siphoning it out of the productive catalytic cycle. Detailed kinetic studies also shed light on the role of acid catalysts and stability of the cyclobutanes (109) towards water and 0 aldehyde. For a similar possibly parasitic intermediate (72), see section titled The 0 Henry (Nitroaldol) Reaction . 

Excellent stereoselectivities (<99 1 dr and <99% ee) have been attained for the Michael addition of ketones to nitroalkenes, catalysed by the polyfunctional secondary-secondary-tertiary triamines (216) and (217). ° The proline-derived phosphine oxide (218) also exhibited a high level of stereocontrol (<99 1 dr (syn/anti) and <96% Catalyst (219) has been designed computationally for... 

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 ... 

On the other hand, several other analogues of proline were also capable of inducing chirality for the Michael addition of various aldehydes to nitroalkenes. 

Catalytic reactions proceeding via enamines as intermediates. A DFT study at the B3LYP/6-31H-G(2df,p)//B3LYP/6-31G(d) level of the proline-catalysed Michael addition of ketones (via enamines) to nitroalkenes has revealed that the added benzoic acids play two major roles, namely assisting the proton transfer and activating the nitro group. °... 

The Michael addition of aldehydes R R CHCH=0 to nitroalkenes R CH=CHN02, catalysed by a proline lithium salt, afforded the products 0=CHCR R CHR CH2N02 with <95% ee and >20 1 t/r on a 50 mmol scale ... 

The proline-derived biaryls (369a,b) have been developed as yet another example of organocatalyst types for the addition of aldehydes to -nitroalkenes, matching the performance of its counterparts (<96% ee and <99 1 dr in favour of the iyn-diastereoisomer) ... 

Addition of acylsilanes RCH2COSiMe2Ph to nitroalkenes R CH=CHN02, catalysed by the proline-derived guanidine (397), has been found to proceed with <97% ee and up to >99 1 dr ... 

The 3 + 2-cycloaddition reaction of azomethine ylides with c-deficient alkenes produced polysubstituted l- and D-unnatural prolines. Also, phosphoramidite-(7u(OTf)2 complexes catalyse the 1,3-dipolar cycloaddition reactions of azomethine ylides with nitroalkenes to yield exo-tetrasubstituted proline esters." The 1,3-dipolar cycloaddition of non-stabilized azomethine ylides, from iV-alkyl-a-amino acids and aldehydes, with 3-substituted coumarins provides l-benzopyrano[3,4-c]pyrrolidines in good yields and high regio- and stereo-selectivity." The organocatalytic 1,3-dipolar cycloaddition of azomethine ylides, derived from azlactones, with methyleneindolinones produced spirooxindoles with high yields (up to 95%) and high diastereo- (93 7 dr) and enantioselectivity (98% ee). ... 

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