Aryl proline

A. Znabet, S. Blanken, E. Janssen, F. J. J. de Kanter, M. Helliwell, N. J. Turner, E. Ruijter, R. V. A. Orru, Org. Biomol. Chem. 2012,10,941-944. Stereoselective synthesis of V-aryl proline amides by biotransformation-Ugi-Smiles sequence. 

Procedures for catalytic enantioselective C-N ring construction have also been developed. Armando Cordova of Stockholm University has shown (Tetrahedron Lett. 2007, 48, 8695) that condensation of 11 with 12 led to 14, which on reduction and hydrolysis delivered the 3-aryl proline 15. In an even simpler case, Santos Fustero of the Universidad de Valencia found (Organic Lett. 2007, 9, 5283) that the aldehyde 16 could cyclize to 17 with... 

The proline-catalyzed reaction has been extend to the reaction of propanal, butanal, and pentanal with a number of aromatic aldehydes and proceeds with high syn selectivity.197 The reaction can also be carried out under conditions in which the imine is formed in situ. Under these conditions, the conjugative stabilization of the aryl imines leads to the preference for the aryl imine to act as the electrophile. A good yield of the expected P-aminoalcohol was obtained with propanal serving as both the nucleophilic and the electrophilic component. The product was isolated as a 7-amino alcohol after reduction with NaBH4. 

The TS proposed for these proline-catalyzed reactions is very similar to that for the proline-catalyzed aldol addition (see p. 132). In the case of imines, however, the aldehyde substituent is directed toward the enamine double bond because of the dominant steric effect of the (V-aryl substituent. This leads to formation of syn isomers, whereas the aldol reaction leads to anti isomers. This is the TS found to be the most stable by B3LYP/6-31G computations.199 The proton transfer is essentially complete at the TS. As with the aldol addition TS, the enamine is oriented anti to the proline carboxy group in the most stable TS. 

A more recent report by Sibi and co-workers displayed the utility of chiral lanthanide Lewis acids for addition-trapping reactions [150]. An exhaustive screening of lanthanide Lewis acids and several chiral ligands revealed that Y(OTf)3 and proline derived ligand 138 was optimal (data not shown). Upon further optimization it was discovered that achiral additives 139 and 212 increased ee s (Scheme 56, entries 2 and 3). Bulkier radicals were found to decrease the enantioselectivity (entries 4 and 5). Also, larger aryl substituents on the ligand gave similar ee s as observed for 138 (compare entries 1, 6, and 7). 

Racemic mixtures of underivatized amino acids N-alkyl- and N-aryl-substitued derivates of amino acids (phenylalanine and proline) on graphitic carbon 0.001 M Cu(acetate)2 aqueous solution 229, 230... 

In extending this concept to transformations that formally deliver Diels-Alder products, a one-pot three-component Mannich/Michael reaction pathway was developed in which simple cyclic enones, formaldehyde, and aryl amines were treated with catalytic amounts of proline (2) to provide regio-, diastereo-, and enantioselective bicyclic compounds in high yields (Scheme ll.lOb). Multicomponent domino... 

A novel one-pot synthesis of various fused lactones has been achieved via a domino sequence of Knoevenagel/ hetero-Diels-Alder/elimination reactions of N- and 0-prenyl aryl aldehyde derivatives with Meldrum s acid in the presence of D- or L-proline with high diastereoselectivity (Scheme 68) <2005MI1353>. 

Carboxypeptidase A catalyzes the hydrolysis of carboxyl-terminal acidic or neutral amino acids however, the rate of hydrolysis depends on the structure of the side chain R. Amino acids with nonpolar aryl or alkyl side chains are cleaved more rapidly. Carboxypeptidase B is specific for the hydrolysis of basic COOH-terminal amino acids (lysine and arginine). Neither peptidase functions if proline occupies the COOH-terminal position or is the next to last amino acid. 

Enanantioselective aldol reactions. Divalent tin enolates of aldehydes and aryl ketones generated with tin(II) triflate undergo aldol condensation with aldehydes to form aldols.2 The reaction is highly enantioselective if conducted in the presence of chiral diamines derived from (S)-proline, such as l.3... 

The direct alkenylation of arylamines at the ortho position has been reported in reactions of o -chloroalkenylmagnesium chloride with N-lithioarylamines.22 Use of the CuI-L-proline catalyst system in DMSO has been found to be successful in promoting reactions of aryl iodides and bromides with activated methylene compounds, such as ethyl acetoacetate and diethyl malonate.23 The same catalyst in dioxane has been used in intramolecular cyclization of ene-carbamates leading to indoles or pyrrolo[2,3-cjpyridines.24... 

The arylation of ethyl acetoacetate, ethyl benzoylacetate, and diethyl malonate under the catalysis of CuI/L-proline in DMSO has been performed at 40-50 °C in the presence of CS2CO3 to provide the 2-aryl-1,3-dicarbonyl compounds in good yields.38 Both aryl iodides and aryl bromides are compatible with these reaction conditions. 

Addition of dialkylzinc reagents to /3-aryl- and /3-alkyl-nitroalkcncs, RCH=CHN02, catalysed by a complex of (TfO)2Cu with the proline-derived amidophosphine (193), afforded the corresponding nitroalkanes with moderate to good enantioselectivities (54-80% ee). The performance was highly dependent on the reaction procedure thus,... 

Diphenylprolinol (4) itself is now commercially available at scale, or it can be prepared several ways (Scheme 16.2) Direct addition of an aryl Grignard reagent to a proline ester leads to the diarylprolinol with a low yield in the range of 20-25%.33 A more efficient route is based on an... 

A report that aryl Grignard reagents add to A-protected 4-keto-L-proline derivatives to give the corresponding cw-carbinols52 led to an examination of such reactions with 4-keto-L-prolines 39 and 53. 

Despite this disappointing result, aryl Grignard additions were attempted on C-3-alkylated 4-keto-L-proline derivative 53. Using THF as solvent, a disappointing 30% yield of the corresponding tertiary carbinol 64 was obtained on treatment with 4 equiv of phenylmagnesium bromide (Scheme 27). 

So far, the results suggested a versatile synthesis of C-4 aryl kainoid analogues (or acromelic acid analogues) had been developed. In summary form, the most efficient synthesis achieved involves 12 steps from rrtww-4-hydroxy-L-proline 34 (Scheme 62). This route allows access to these biologically important molecules on a relatively large scale. 

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