L-proline derivatives

Scheme 3.1 L-Proline-derived P-amino thiol and disulfide ligands for additions of ZnEt2 to aldehydes.

Reciystallizations of the Gringard addition product as the toluenesulfonate salt were less detailed, providing students the opportunity to optimize their purification procedures. Figure 56.3 shows the synthesis of the starting L-proline derivative used in the laboratoiy. 

A C2-chiral bisformamide (18) derived from diaminocyclohexane catalyses the enantioselective allylation of simple aldimines, using allyltrichlorosilane in the presence of L-proline.44 The more immediate allylating agent is, in fact, L-proline derivative (19), formed in situ, and observed by NMR and MS. 

The first asymmetric direct aldol of 1,2-diketones and ketones, to give 2-hydroxy-1,4-diketones, has been reported.100 L-Proline derivatives give high regio-, diastereo-, and enantio-selectivity in the reaction of l-arylpropane-l,2-diones with simple ketones. 

Cheap and readily available L-proline has been used numerous times for the intermediate and reversible generation of chiral iminium ions from a,/ -unsaturated carbonyl compounds. For example, Yamaguchi et al. reported in 1993 that the rubidium salt of L-proline catalyzes the addition of di-iso-propyl malonate to the acyclic Michael acceptors 40a-c (Scheme 4.13), with enantiomeric excesses as high as 77% [22], With 2-cycloheptenone and 2-cyclohexenone as substrates ca 90% yield and ee of 59% and 49% were obtained. Later the enantioselectivity of this process was increased to a maximum of 88% ee in the addition of di-tert-butyl malonate to the E-pentenone 40a in the presence of 20 mol% Rb-L-prolinate and 20 mol% CsF [23], Taguchi and Kawara employed the L-proline-derived ammonium salts 41a and... 

As shown in cycle (b) in Scheme 10.1, the iminium-oxaziridinium pair can also effect catalytic asymmetric epoxidation of alkenes. Early work in this field by Bohe et al. included investigation of the norephedrine-derived oxaziridinium salt 34 (33% ee in the catalytic epoxidation of traws-stilbene [41] ee up to 61% was achieved when 34 was employed stoichiometrically [42]), or the L-proline-derived material 35 (39% ee in the epoxidation of trans-3-phenyl-2-propenol [43]). Rapid... 

Zamifenacin may be also synthesized from L-proline methyl ester in 4 steps an overall yield of 20% by using a ring enlargement of L-proline derivative. 

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... 

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). 

Proline analogs, (2S,4R)-4-methylproline (/ra .s-4-methyl-l-proline) and (2S, 4S)-4-methylproline (ris-4-methyl-l-proline), derive from reduction of their corresponding cyclic Schiff bases (F22) (Fig. 3). 

Asymmetric induction has been observed in some of these cycloaddition reactions with the use of chiral enamines52-54. For example, reaction of L-proline derived enamines (e.g. 95) with methyl vinyl ketone (equation 17) afforded, after hydrolysis, chiral cyclohexenones (e.g. 96) with optical yields up to 50%52. 

Synthesis of Morpholin-2,5-diones via Diastereoselective Halolactonization Mediated by L-Proline Derivatives... 

FeCl3 catalyzes the intramolecular hetero-Diels-Alder reaction of L-prolinal-derived A-arylimine to yield the trara,frans-diazacyclopenta[a]anthracene derivative with a dr of 84 16 (Sch. 54) [199], In this reaction, SnCU results in higher trans,trans selectivity (99 1) and RAICI2 (R = Me, Et) gives the cis,cis isomer with high selectivity (99 1). 

Similarly, Shono studied the diastereoselective introduction of the allyl group into the 5-position of A/ -acylated L-proline derivatives by reaction of the N,0-aceia with allyltrimethylsilane in the presence of titanium tetrachloride [214]. Substitution of the anodically introduced methoxy group by cyanide using trimethylsilyl cyanide [215,216] or an isocyanide [217] as the nucleophile can be used to generate a-amino acids via hydrolysis of the cyano function. Equation (41) shows an example [216]. 

We also applied these conditions of selective deprotection on amino acids it was possible to cleave the N-allyloxycarbamate of the L-proline derivative 16 without affecting the carboxylic acid protected by the dimethylallyl moiety (entry 3). 

The L-proline derived diketopiperazine 27 and diazomethane afford a 1-pyrazoline diastereo-mer which is photolyzed to give the cyclopropane derivative 28 in high yield. Acid hydrolysis then provides (+)-1-amino-2-phenylcyclopropanecarboxylic acid (29) [a] 5 +105 (c = 0.69, water) 81. The optical purity of this amino acid is not reported. Similarly the (—)-enantiomer of l-amino-2-phenylcyclopropanecarboxylic acid is available from a dehydroamino acid using (-)-Ar-methylephedrine as auxiliary81. 

In a recent study, hydrolysis of peptide bonds at neutral pH values with Pd(II) complexes was achieved (100). Since the amide nitrogen of an A-acyl-L-proline derivative lacks ionizable hydrogen, formation of hydrolytically inactive Pd(II)-amidate complex indicated by AJ-b is not possible for the peptide bond of the acyl-proline. When AcAla-Ala-Pro-Ala-naphthyl amide (1 mM) was treated with [Pd(H20)4] " (10 mM) at pH 7.0 and 60°C, the Ala-Pro peptide bond was hydrolyzed exclusively with the half-life of 3 h. 

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