Proline, 5- -!-methyl

Figure 56.3 The preparation of Boc-protected L-proline methyl ester.

General procedure for the production of Boc-protected a,a-diaryl-L-prolinols (6). To 100 mL of a 0.42 M solution of ArMgBr in THF (0.042 mol) at 0°C was added N- t- BOC)-L-proline methyl ester (5) (3.0 mL, 0.014 mol) dropwise via syringe over a five-minute period. The solution was stirred for at least 4 h at 25°C and then cooled to 0°C. After slow addition of 3 mL of water, the solution was slowly warmed to ft with stirring. The mixture was decanted and the solid was washed with 100 mL of ethyl ether. The organics were pooled and washed with brine, dried with sodium sulfate and evaporated to yield the final compound. 

Boc-O-benzyl-L-homoserine (Boc = t-butoxicarbonyl) was transformed to L-proline methyl ester, and the benzyl ether was removed by hydrogenolysis. The compound was dissolved in 50% acetic acid in methanol and the reaction mixture was degassed by bubbling nitrogen for 5 minutes then 10% Pd/C was added. The system was evacuated for 5 minutes and then pressured to 45 psi of hydrogen for 48 hours at room temperature.66... 

Proline methyl esters with A-Boc-4-acetoxy or 4-0-TBDMS groups were converted by RuClj/aq. Na(IO )/EtOAc or CC1 -CH3CN to the corresponding pyrrolidin-5-ones... 

Bycroft and Lee (75CC988) developed this into a general method for the asymmetric synthesis of a-amino acids, wherein the chiral auxiliary (L-proline) could be recovered and recycled. Condensation of L-proline methyl ester with a-keto acids using DCC, followed by a treatment with anhydrous ammonia at room temperature, gave the 3-hydroxypiperazine-2,5-diones with high stereoselectivity (cf. Scheme 79). These could be... 

The A-pivaloyl-L-prolyl-D-proline methyl ester (82MI5) (97) and N-pivaloyl-L-prolyl-D-prolylmonomethylamide (85MI7) (98) have opposite... 

Fused l,2,5-triazepine-3,6-diones 88-90 were synthesized from (2 S )-proline methyl ester 205 by treating the latter with bromoacetic acid 206 in the presence of tiro-butyl chloroformate 207 (Scheme 46). The resultant bromoacetamide 208 on further treatment with hydrazine hydrate in EtOH gave 88-90 via cyclization through displacement of bromine <1996CC85>. 

Biginelli synthesis of 3,4-dihydropyrimidin-2( 1 //)-oncs (99) from an aldehyde, a /3-diketone, and urea is catalysed by L-proline methyl ester hydrochloride.276 Although evidence strongly supports an enamine mechanism, the products were essentially racemic. 

The treatment AT-carbonyl pyrrolidine derivatives with PhIO/TMSN3 (1 2) leads to a-azidonation of the pyrrolidine ring (Scheme 7) [25]. Similar results were obtained with the piperidine analogs, although product yields were much improved when iodosylbenzene was replaced with o-iodosylbenzoic acid and the reactions were conducted under reflux. Extension of the azidonation methodology to carbonyl derivatives of L-proline methyl ester was successful, although the product mixtures were generally more complex [26]. 

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. 

The order of transformations was reversed to obtain the corresponding methyl ester 45. rrans-4-Hydroxy-L-proline methyl ester was prepared... 

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. 

Amine catalyst can be prepared in three steps from N-Boc-i-proline methyl ester [63]. 

Barbiturates (mephobarbital, hexobarbital, pentobarbital, l-methyl-5-(2-propyl)-5-(n-propyl)barbituric acid, 5-ethyl-1 -methyl-5-(n-propyl) barbituric acid), benzoin, a-methyl-a-phenylsuccinimide, gluthethimide, methylthiohy-dantoin-proline, methyl mandelate... 

Mephobarbital, hexobarbital, MTH proline, methyls of mecoprop, diclofop and fenoxaprop, barbiturates, chlorinated alkyl phenoxy- Silica gel (Nucleosil, 5 pm) coated with Chirasil-Dex Methanol-20 mAT MES buffer, pH 6 (1 1, 2 3 or 7 3) 290 (400) mm x 100 pm i.d. 200 (250) mm effective length, pressure-supported chiral separation 53... 

The use of proline methyl ester as a chiral auxiliary in the asymmetric synthesis of alanine is shown on the following page. The idea is to start with 2-oxopropanoic acid (pyruvic acid), which has the correct carbon skeleton, and replace tire oxygen on carbon 2 with an amino group and a hydrogen. This must be done in such a manner as to produce only the S-enantiomer of the amino acid, that is, L-alanine. This is accomplished by first attaching a chiral auxiliary, the methyl ester of L-proline, to the acid. In the critical step of the process, the catalytic hydrogenation, the chirality of the... 

What starting material would be used for the synthesis of L-phenylalanine by the method using proline methyl ester as a chiral auxiliary ... 

Addition of (S)-proline ethyl ester to phenylmagnesium chloride to give (S)-a,a-diaryl-2-pyrrolidinemethanol (2 steps, 21% yield from (S)-proline) (a) Roussel-UCLAF French Patent FR M3638, 1965 Chem. Abstr. 1969, 70, 106375m An earlier report (26% yield) did not indicate the enantiomeric purity of the product (b) Kapfhammer, J. Matthes, A. Z physiol. Chem. 1933, 223, 43-52. In the submitters hands, addition of (S)-proline methyl ester hydrochloride to phenylmagnesium chloride, afforded (S)-a,a-diphenyl-2-pyrrolidinemethanol in 20% yield and 80% e.e. See also ref. 5d. 

---