Proline catalysts hydrogenation

A highly enantioselective intramolecular version, catalysed by proline, undergoes an inversion of enantioselectivity on addition of imidazole.173 The imidazole substantially increases the reaction rate it is proposed to act as a co-catalyst, hydrogen bonding to the proline s acid hydrogen, blocking a reactant face which is otherwise available in the proline-only route. 

In the aldol reaction itself, proline s carboxyl group has a key role to play because it can participate in a hydrogen bond that organizes the slx-membered transition state in such a way that only one of the possible enantiomeric products can form. The diagram below shows how. Water generated in the initial condensation hydrolyses the iminium product of the aldol and regenerates the proline catalyst. 

A dual-activation way is invoked based on the similar widely accepted catalytic mode of activation for L-proline catalyst. In this context, the acidic tetrazole moiety activates the electrophilic imine by a hydrogen-bonding interaction, and the pyrrolidine moiety would activate the nucleophilic P-ketoester via formation of an enamine intermediate. The stereochemistry of the acidic tetrazole moiety seems to be crucial for the stereoselectivity in the final products. This... 

Prepared by heating ammonium mucate, or from butyne-l,4-diol and ammonia in the presence of an alumina catalyst. The pyrrole molecule is aromatic in character. It is not basic and the imino-hydrogen atom can be replaced by potassium. Many pyrrole derivatives occur naturally, e.g. proline, indican, haem and chlorophyll. 

Benzyloxycarbonyl-L-proline tert-butyl ester (205 g) is dissolved in absolute ethanol (1.2 ) and hydrogenated at normal pressure with 10% Pd on carbon (10 g) until only a trace of carbon dioxide is observed in the hydrogen exit gas (24 hours). The catalyst is filtered off and the filtrate is concentrated in vacuo at 30 mm Hg. The residue is distilled in vacuo, to obtain L-proline tert-butyl ester, BPimm... 

The pyrrolidine-oxazoline catalysts 26 (Fig. 29.13) can be conveniently synthesized from proline in five steps, and have been used to hydrogenate the methyl-stilbenes 1 and 8 in 92% ee and 94% ee, respectively [26]. 

Corma and coworkers tested a number of rhodium and other transition metal complexes with ligands based on proline (Fig. 29.23). These authors reported ee-values of 54—90% for the hydrogenation of dehydroamino acid derivatives with a catalyst prepared from ligand 38 [51]. With ligand 39, an ee-value of 34% was recorded for the hydrogenation of ethyl acetamidocinnamate 10 [52]. 

The hexahydro-l//-pyrrolo[2,l-f][l,4]oxazin-l-one 82 (obtained by radical cyclization see Section 11.11.7.3) was transformed into the proline derivative 83 by hydrogenation in the presence of the Pearlman s catalyst and a stoichiometric amount of trifluoroacetic acid (TFA) (Scheme 10). This reaction led with high yield to the disub-stituted proline 83 in an enantiomerically pure form <2003SL1058>. In an analogous approach, the chiral (4/ ,7/ ,8aA)-methyl 6,6-dimethyl-l-oxo-4-phenylhexahydro-l//-pyrrolo[2,l-r-][l,4]oxazine-7-carboxylate 84 was hydrogenated on Pd(OH)2 in the presence of TFA to give enantiomerically pure 5,5-dimethylproline derivatives 85 <2001SL1836> (Scheme 10). 

Type A enamine catalysts include simple amino acids, such as proline 6, and most of their derivatives (such as the tetrazole 44 and various sulfonamides, e.g. 45). They are typically used for aldol, Mannich, a-amination and a-oxygenation reactions - these are all reactions where the electrophile can readily be activated by hydrogen bonding (Scheme 12) [8, 9, 12, 46],... 

In order to validate this hypothesis, a series of octapeptide catalysts known to possess four intramolecular hydrogen bonds [164] which confer conformational rigidity were synthesised and screened for activity in the KR of ( )-trans-l,2-acetamidocyclohexanol. Among them, (/ )-proline containing octapeptide 50 (Fig. 12) was found to afford an excellent level of enantioselection (.y = 51) while its (5)-proline analogue 51 (Fig. 12), which is structurally less well-defined, was substantially less selective (s = 1) [164]. 

Enalapril Enalapril, (S)-l-[iV-[l-(ethoxycarbonyl)-3-phenylpropyl]-L-alanyl]-L-proline (22.7.12), is synthesized by reacting the benzyl ester of L-alanyl-L-proline with the ethyl ester of 3-benzoylacrylic acid, which forms the product 22.7.11, the reduction of which with hydrogen using a Raney nickel catalyst removes the protective benzyl group, giving the desired enalapril (22.7.12) [24], Alternative methods of syntheses have also been proposed [25-29]. 

Asymmetric reduction of the double bond of the dehydroamino acid residue in 522 can be effected in different ways since the peptide moiety can act as a chiral auxiliary. Heterogeneous hydrogenations using a Pd/C catalyst are the most frequently used conditions. Among the different amino acids evaluated as chiral auxiliaries, proline is the auxiliary of choice and has led to the best diastereodiffer-... 

The development of chiral peptide-based metal catalysts has also been studied. The group of Gilbertson has synthesized several phosphine-modified amino adds and incorporated two of them into short peptide sequences.[45J,71 They demonstrated the formation of several metal complexes, in particular Rh complexes, and reported their structure as well as their ability to catalyze enantioselectively certain hydrogenation reactions.[481 While the enantioselectivities observed are modest so far, optimization through combinatorial synthesis will probably lead to useful catalysts. The synthesis of the sulfide protected form of both Fmoc- and Boc-dicyclohexylphosphinoserine 49 and -diphenylphosphinoserine 50 has been reported, in addition to diphenylphosphino-L-proline 51 (Scheme 14).[49 To show their compatibility with solid-phase peptide synthesis, they were incorporated into hydrophobic peptides, such as dodecapeptide 53, using the standard Fmoc protocol (Scheme 15).[451 For better results, the phosphine-modified amino acid 50 was coupled as a Fmoc-protected dipeptide 56, rather than the usual Fmoc derivative 52.[471 As an illustrative example, the synthesis of diphe-nylphosphinoserine 52 is depicted in Scheme 16J45 ... 

Enantioselective heterogeneous catalytic hydrogenation of acetophenone469 -471 to (R)-(-l-)-l-phenylethanol (ee 20%) in the presence of (S )-proline (the chiral auxiliary) was investigated. The effect of various catalytically active metals (Pt, Rh, Raney Ni, Pd), the reaction temperature and the amount of catalyst on the optical purity was studied. The correlation between the optical yield and the conversion, the concentration of the reactants, different pretreatment methods and additives was also investigated469 (equation 49). 

L-Prolinethioamides (39, R = alkyl including chiral alkyl), prepared from proline and amines, are effective in acetone-benzaldehyde reactions.110 Mechanistic studies focused in particular on suppression of non-enantioselective side-reactions, and also on the role of the side-chain of the catalyst acting as hydrogen bond donor, especially as the thioamides (with their more acidic N—H protons) are more catalytic than their amide analogues. 

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