4-keto-L-proline

Of the several studies made of enolates derived from such a-aminoke-tones,37 the most interesting one from the point of view of this work came from Holladay and co-workers who studied alkylation reactions of pyrrolidine enamine 40 derived from protected 4-keto-L-proline 41 with allyl bromide (Scheme 10).38 A 44% yield of two diastereoisomers of allylated material 42 was obtained with a quoted isomer ratio of trans cis of 2 1. 

It was felt that a similar alkylation reaction would allow the facile introduction of the kainoid C-3 side chain if a bromoacetate ester was used in place of allyl bromide as the alkylating agent. The aim was to attempt to increase stereoselectivity by using the bulky ester tert-butyl bromoacetate. Appropriately protected 4-keto-L-proline 39 derivatives... 

Methods were then investigated for oxidation of carbinols 44 and 45 to the corresponding 4-keto-L-proline derivatives. 

A procedure using ruthenium(IV) oxide and sodium metaperiodate43 was chosen initially for 44. Protected 4-keto-L-proline derivative 47 was obtained in 76% yield, a reaction that could be satisfactorily repeated on several occasions using the same batch of ruthenium(IV) oxide (Scheme 15). Attempts to repeat the procedure using different batches of ruthe-nium(IV) oxide, however, gave variable results, the exact reasons for this not being clear. 

Prior to the work of Holladay and co-workers,38 there was good literature precedent for 4-keto-L-proline derivatives 39 giving the required 3,4-dehydro isomer of the enamine rather than the 4,5-dehydro isomer in a report by Friary and co-workers.46 It was found that the protected 4-keto-L-proline derivative 49 gave enamine 50 on treatment with morpholine in the presence of molecular sieves (Scheme 17). 

Repeating the enamine formation conditions of Holladay and coworkers38 using 4-keto-L-proline derivative 47 and pyrrolidine (1.2 equiv) in the presence of activated 5-A molecular sieves at room temperature gave essentially quantitative conversion to required enamine 51 after a reaction time of 16 h (Scheme 18). Analytical data were consistent... 

Although this method proved successful for 4-keto-L-proline methyl ester 48, it was decided to investigate the conventional azeotropic dehydration method. Derivative 48 and pyrrolidine (1.2 equiv) were heated under reflux in benzene, collecting the water produced using a Dean and Stark apparatus. A quantitative yield of the corresponding enamine 52 was obtained after only 30 min (Scheme 19). Again, full assignment of NMR spectra was complicated by the apparent presence of rotameric structures. 

Gill and Lubell have also reported a complementary 4-keto-L-proline alkylation procedure using the potassium enolate of ketone 55.50 In this instance, regiospecific alkylation using methyl bromoacetate gave a 91% yield of a 2 1 trans cis ratio of diastereoisomers of ketone 56 (Scheme... 

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. 

Using 4-keto-L-proline derivative 47 as a model for the C-3-alkylated derivatives, phenylmagnesium bromide was found to add in disappointing (35%) yield to give tertiary carbinol 61 (Scheme 25).54... 

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). 

Removal of the sterically more accessible protons at C-5 was required and hence it was reasoned that kinetic deprotonation conditions were required, namely, strong, nonnucleophilic base and low temperature. Model reactions were carried out initially on 4-keto-L-proline ester 47, in the hope of optimizing the triflation conditions before moving to C-3-alkylated derivatives 53 and 54. 

Smith and Mitoma (43) have found an enzyme activity in mammalian tissues capable of reducing 4-keto-L-proline to L-hydroxyproline such a reaction (perhaps involving bound forms of ketoproline or hydroxyproline) might conceivably function in hydroxyproline formation. 

Scheme 4.10 L-Proline promoted aldol reaction between acetone and a-keto phosphonates...

Some workers avoid delay. Pai)adium-on-carbon was used effectively for the reductive amination of ethyl 2-oxo-4-phenyl butanoate with L-alanyl-L-proline in a synthesis of the antihyperlensive, enalapril maleate. SchifTs base formation and reduction were carried out in a single step as Schiff bases of a-amino acids and esters are known to be susceptible to racemization. To a solution of 4,54 g ethyl 2-oxO 4-phenylbutanoate and 1.86 g L-alanyl-L-proline was added 16 g 4A molecular sieve and 1.0 g 10% Pd-on-C The mixture was hydrogenated for 15 hr at room temperature and 40 psig H2. Excess a-keto ester was required as reduction to the a-hydroxy ester was a serious side reaction. The yield was 77% with a diastereomeric ratio of 62 38 (SSS RSS)((55). 

Addition of nucleophiles to electrophilic glycine templates has served as an excellent means of synthesis of a-amino acid derivatives [2c, 4—6]. In particular, imines derived from a-ethyl glyoxylate are excellent electrophiles for stereoselective construction of optically active molecules [32], This research and retrosyn-thetic analysis led us to believe that amine-catalyzed asymmetric Mannich-type additions of unmodified ketones to glyoxylate derived imines would be an attractive route for synthesis of y-keto-ce-amino acid derivatives [33], Initially, L-proline-catalyzed direct asymmetric Mannich reaction with acetone and N-PMP-protected a-ethyl glyoxylate was examined in different solvents. The Mannich-type reaction was effective in all solvents tested and the corresponding amino acid derivative was isolated in excellent yield and enantioselectivity (ee >95 %). Direct asymmetric Mannich-type additions with other ketones afford Mannich adducts in good yield and excellent regio-, diastereo- and enantioselectivity (Eq. 8). 

An efficient one-pot, four-component reaction of hydrazine derivatives 37, p-keto ester 33, isatins 20, and malono-nitrile 3 leading to the S5nthesis of spiro[indoline-3,4 -pyrano[2,3-c]pyrazole derivatives 38 catalyzed by L-proline in water under heating conditions with good yields has recently been reported by Yu et al. [121] (Scheme 20). 

A striking solvent effect was observed in the reduction of a chiral a-keto amide, C6H5-CO-CO-NR2 (NR2 = (5)-proline methyl ester), with sodium tetrahy-dridoborate, leading to mandelic acid after hydrolysis [704]. When the a-keto amide was reduced in pure tetrahydrofuran or methanol, the resulting enantiomeric excess of (5)-mandelic acid produced was 36% and 4%, respectively. However, when a tetrahydrofuran/methanol (99 1 cL/L) solvent mixture was used, the enantiomeric excess increased to 64% ( ). In other solvent mixtures, a catalytic amount of a protic solvent (CH3OH or H2O) was found to be necessary for good asymmetric induction [704]. 

Kemp, D.S. and Curran, T.P. (1988) (2S,5S,8S.llS)-l-acetyl-1.4-diaza-3-keto-5-carboxy-10-thia-tricyclo-[2.8.0 ]-tridecane, 1, synthesis of prolyl-proline-derived, peptide-functionalized templates for a-helix formation. Tet. Lett. 29 4931-4934. 

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