Proline methyl ether

P, P] Seebach and Blarer examined the addition of the enamine derived from proline methyl ether and cyclohexanone to arylidene malonates (Scheme 14, Table 3) (32,33). The process is uniformly selective for the syn, S,S diastereomer. Diastereoselectivities from 88% to > 95% and enantiomeric excesses (for the syn product) of 80-92% were observed. The results were... 

Addition of the Proline Methyl Ether Enamine of Cyclohexanone to Arylidene Malonate (Scheme 14)... 

The enantioselective Michael addition of enamines derived from / -tetralone and proline methyl ether to nitrostyrenes has been described by Blarer and Seebach (33,45). Enamines of /1-tetralone have two potential sites of nucleophilicity, C-l and C-3 in 21.1 and 21.2(Scheme 21). For the substrates studied, attack occurs preferentially at C-3. The results of this study are summarized in Table 7 and Scheme 21. 

Addition of Proline Methyl Ether Enamines of /1-Tetralone to Nitrostyrenes (Scheme 21). 

Nishihara et al [11] have also reported that an asymmetric structure is induced into the polymer main chain by copolymerization of methacryl-1-valine methyl ether and methacryl-1-proline methyl ether with maleic anhydride. 

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... 

Azacyclols arising from amide-amide interaction have been extensively investigated. The p-nitrophenyl ester (60) of the linear tripeptide N-benzyloxycarbonyl-L-alanyl-L-phenylalanyl-L-proline undergoes a double cyclization when left in an aqueous buffer-dioxane (1 1) solution for 1 h, to produce cyclol (61) (7 ICC 1605). The hydroxyl group of the cyclol could be converted to the methyl ether by treatment with methyl iodide-silver oxide. The structure of the cyclol (61) could be confirmed by X-ray crystallography of the corresponding p-bromobenzyloxycarbonyl derivative (7 ICC 1607). 

The aldimine of Figure 13.34 is a chiral and enantiomerically pure aldehydrazone C. This hydrazone is obtained by condensation of the aldehyde to be alkylated, and an enantiomerically pure hydrazine A, the S-proline derivative iS-aminoprolinol methyl ether (SAMP). The hydrazone C derived from aldehyde A is called the SAMP hydrazone, and the entire reaction sequence of Figure 13.34 is the Enders SAMP alkylation. The reaction of the aldehydrazone C with LDA results in the chemoselective formation of an azaenolate D, as in the case of the analogous aldimine A of Figure 13.33. The C=C double bond of the azaenolate D is fraws-configured. This selectivity is reminiscent of the -preference in the deprotonation of sterically unhindered aliphatic ketones to ketone enolates and, in fact, the origin is the same both deprotonations occur via six-membered ring transition states with chair conformations. The transition state structure with the least steric interactions is preferred in both cases. It is the one that features the C atom in the /3-position of the C,H acid in the pseudo-equatorial orientation. 

The aldimine of Figure 10.31 is a chiral and enantiomerically pure aldehydrazone C. This hydrazone is obtained by condensation of the aldehyde, which shall be alkylated, and an enantiomerically pure hydrazine A (see Table 7.2 for the mechanism), the S-proline derivative Aaminoprolinol methyl ether (SAMP). The hydrazone C derived from aldehyde A is called the SAMP hydrazone, and the entire reaction sequence of Figure 10.31 is the Enders SAMP procedure. The reaction of the aldehydrazone... 

Prolinol methyl ether 31 is used in Enders s SAMP and RAMP chiral auxiliaries (chapter 27) and (S)-()-SAMP 32 can be made in 50-58% overall yield from (S)-L-(—) -proline on a 75 g scale.12... 

Danishefsky and Cain examined several amino acids for asymmetric aldolization of trione (118 equation 141). With L-proline, the hydrindenedione (119) was obtained in only 27% ee. However, L-pheny-lalanine was more effective, giving (119) with 85% ee. Other amino acids (tyrosine 0-methyl ether. 

The case of UCST > LCST is observed with water-soluble polymers. Examples of these are poly(vinyl alcohol) (see Figure 6-14), poly(vinyl methyl ether), methyl cellulose, and poly(L-proline). The heating of aqueous solutions of these polymers causes a decreasing solvation of the polymer and thus a demixing. In some cases, closed miscibility loops can be observed. 

Proline and proline derivatives have been utilized extensively as chiral catalysts for a wide range of asymmetric transformations [40, 132]. Gelman has documented a remarkable case in which enolizable aldehydes undergo selective Michael additions to enone acceptors (Equation 28) [133]. Diphenylpro-linol methyl ether (165) proved superior to other prolinol derivatives in terms of enantioselectivity and reactivity. As an example, the addition of oc-tanal (163) to ethyl vinyl ketone (164) in the presence of 5 mol% of 165 was carried out without solvent to furnish 166 in 87% yield and >95% ee. 

Then, 1-(3-acetylthio-2-methylpropanoyl)-L-proline is produced. The 1-(3-acetylthio-3-methyl-propanoyl)-L-proline tert-butyl ester (7.8 g) is dissolved in a mixture of anisole (55 ml) and trifluoroacetic acid (110 ml). After one hour storage at room temperature the solvent Is removed in vacuo and the residue is precipitated several times from ether-hexane. The residue (6.8 g) is dissolved in acetonitrile (40 ml) and dicyclohexylamine (4.5 ml) is added. The crystalline salt is boiled with fresh acetonitrile (100 ml), chilled to room temperature and filtered, yield 3 g, MP 187°C to 188°C. This material is recrystallized from isopropanol [ttlo -67° (C 1.4, EtOH). The crystalline dicyclohexylamine salt is suspended in a mixture of 5% aqueous potassium bisulfate and ethyl acetate. The organic phase is washed with water and concentrated to dryness. The residue is crystallized from ethyl acetate-hexane to yield the 1-(3-acetylthio-2-D-methylpropanoyl-L-proline, MP83°Cto 85°C. 

O-Methylation of N-methylated derivatives under basic conditions is disappointing, 5063 but improved results are obtained using trimethyloxonium tetrafluoroborate (Scheme 13), or boron trifluoride-diethyl ether complex with diazomethane. 671 Conversely, methylation of the proline derived P-hydroxy acid using sodium hydride and iodomethane, as well as using trimethyloxonium tetrafluoroborate, gives the dolaproine unit (8) of dolastatin 10 in good yield. 68,691... 

A slurry of methyl-l-(l-oxopropoxy)propoxy](4-phenylbutyl)phosphinyl]acetic acid (B-isomer), dried in vacuo at room temperature for 72 hours, (230.4 g, 0.6 moles) and hydroxybenzotriazole hydrate, dried, in vacuo at 80°C for 24 hours, (101.1 g, 0.66 mole) dichloromethane (sieved dried) (6 L) was chilled in an ice/acetone bath and treated with N,N-dicyclohexylcarbodiimide (136 g, 0.66 mole). The mixture was warmed to room temperature and stirred for 3 hours. The mixture was then chilled in ice/acetone and treated with (trans)-4-cyclohexyl-L-proline, hydrochloride (154.2 g, 0.66 mole) followed by diisopropylethylamine (170.7 g, 1.32 mole). The reaction mixture was stirred at room temperature for 18 hours. The mixture was then chilled, treated with water (1 L) and concentrated in vacuo to remove dichloromethane. The residue was diluted with ether (3600 ml) and water (3600 ml) and filtered. 

The filtrate was brought to pH = 1.8 with 10% hydrochloric acid. The ether layer was separated and the aqueous layer washed with ethyl acetate (3x2 L). The combined organic layers were washed with 5% KHS04 (3x1 L), water (3 x 1 L) and brine (1 L), dried over magnesium sulfate and concentrated in vacuo to yield 398.9 g of crude [R,lS,4S]-4-Cyclohexyl-l-[[[2-methyl-l-(l-oxopropoxy)propoxy](4-phenylbutyl)phosphinyl]acetyl]-L-proline, monosodium salt (isomer B). The crude product was dissolved in acetone (4393 ml), treated with a solution of 2-ethyl hexanoic acid, sodium salt (117.3 g) in acetone (1468 ml), then stirred at room temperature overnight. The resultant precipitate was collected by filtration, washed with acetone (3 x 400 ml) and hexane (1 L) then dried in vacuo. Yield 277 g, m.p. 195-196°C, [a]D= -5.1° (MeOH, c = 2), HI = 99.8%. Isomer "A" was not detectable. 

To a solution of this cis-l-[D-3-(benzoylthyo)-2-methyl-l-oxopropyl]-4-(phenylthio)-L-proline hydrochloride 11.8 g (0.027 mole) in 70 ml of acetonitrile there is added about 6.0 g of dicyclohexylamine in 25 ml of ether. A white crystalline precipitate forms immediately. After standing overnight in the cold room, the solid is filtered and washed with ether to yield (cis)-l-[D-3-(benzoylthio)-2-methyl-l-oxopropyl]-4-(phenylthio)-L-proline, dicyclohexylamine salt (1 1). 

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