BOC-L-Proline

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. 

Examples of aldol condensations involving chiral aldehydes have also been reported. Condensation of the aluminum enolate derived from (2) with Boc-L-prolinal has been shown to proceed in a highly stereoselective manner and the iron chirality overpowered the latent stereoselectivity inherent in Boc-L-prolinal. ... 

A number of heterocyclic amines has been prepared. The lactam (68), which possesses the pyrrolizidine alkaloid skeleton, was synthesized from Boc-L-prolinal via conversion of an epimeric mixture of N-protected hydroxy esters into a single crystalline amine salt (67) (Scheme 104). Protected pyrrole-2-carboxylic... 

For binding Damen and Neckers (71) used an ester group to introduce -boc-L-proline as a template. Rebinding was effected through an ester bond as well. This binding occurred under kinetic control and yielded a separation factor of only a - 1.015 - 1.038. Under nonequilibrium conditions, in our case (55), no enrichment of enantiomers was observed. This means that this kind of separation is thermodynamically and not kinetically controlled. 

To a solution of 0.31 g 3-(2-bromopropionyl)-4/f-methyl-5iS-phenyloxazolidin-2-one (1 mmol) in 5 mL anhydrous THF cooled to 0°C, was added 1 mmol Co[PPh3l4 solution dropwise over 30 min. Then 0.20 g A -Boc-L-prolinal (1 mmol) was added to the dark brown solution. After being stirred for 2 h, the reaction mixture was poured into cold 0.1 HCl and extracted with EtOAc. Upon removal of solvent under reduced pressure, the residue was purified by flash column chromatography using hexane/EtOAc (4 1) as the eluent to afford 0.30 g (4R,5S,2 R,3 R,2"S)-3-[ i -(N-tert-hutoxycarbony -2"-pyrrolidinyl)-3 -hydroxy-2 -methylpropanoyl)-4-methyl-5-phenyl-2-oxazolidinoneasa colorless foam, in a yield of 70%. 

The Hantzsch synthesis has been used to prepare a number of natural and synthetic cyclic peptides incorporating thiazoles. Pattenden and coworkers used the Hantzsch thiazole synthesis in their preparation of an N-Boc protected L-proline thiazole based amino acid, which was subsequently used to generate cyclic hexaeptides and octapeptides. Thioamide 165, prepared from commercially available Boc-L-proline, was subjected to Holzapfel s modified conditions to generate the desired thiazole 166 in 61% yield. The biological evaluation of these compounds is currently under investigation. 

Very recently, Zhu and Cheng reported an organocatalytic Michael-type addition of phosphorus ylides 93 to a,(i-unsaturated ketones 94 using a chiral dual organo-catalyst system composed of 9-amino-(9-deoxy)-epi-quinine with Boc-L-proline (Scheme 43.20) [31]. The Michael-type/Wittig reactions proceeded smoothly to provide chiral a-methylene-6-ketoesters 95 with good to excellent enantioselectivi-ties (up to 95% ee). 

Enantiomers of phenylpropanolamine, octopamine, pindolol, norphenyl-ephedrine, propanolol, and isoproterenol were separated with Rf differences of 0.05-0.24 by development of Whatman HP-KF HPTLC plates with dichloro-methane/methanol (75 25) containing different amounts of A-benzoxycarbonyl (BOC)-alanyl-L-proline (ZAP), BOC-isoleucyl-L-proline (ZIP), BOC-L-proline (ZP), BOC-glycyl-L-proline (ZGP), (lR)-(—)-ammonium-10-camphorsulfonate (CSA), and triethylamine (TEA). Visualization was under 254 nm UV light [29]. 

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

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... 

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 ... 

Table 1 Selected adamantanyl derivatives and their corresponding mass spectral data. HPLC data supplied by the author. Cyclopropyl-fused dehydro pyrrolidines were prepared using (C2H5)2Zn, C1CH2I, and A-Boc-4,5-L-proline ester derivatives in CH2C12 according to the method of co-author Robl (1)...

A similar reaction has been used for the synthesis in 50% yield of l-aza-6-oxa-2-oxobicyclo[5.3.0]decane ring skeleton (IX) in a one-step electrochemical cyclization from the dipeptide Boc-L-homoserine-L-proline-OMe (X). The reaction is highly diastereoselec-tive, generating a new chirale center having an S configuration [37]. 

Tetrapropylammonium perruthenate (TPAP 63 mg) was added in 1 portion to a stirred mixture of A -Boc-4-fra .y-hydroxy-L-proline (1 g, 3.47 mmol), A-methyl-morpholine A-oxide (0.62 g, 15.6 mmol), and powdered molecular sieves (4 A, 1.78 g) in CH2CI2 (7 mL) at room temperature under argon. The mixture was stirred for 3 h, filtered, and evaporated in vacuo to give a black residue. The product was purified by... 

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