Hydroxy-pyrrolidine

The tosyl protecting group of 4a is removed with sodium naphthalide at -60 °C, and an intramolecular nucleophilic attack of the nitrogen lone pair to the epoxide takes place spontaneously to afford the pyrrolidine hydroxy ester as a labile reaction product, which is immediately protected as the corresponding silyl ether 3a in 68%... 

In peptide syntheses, where partial racemization of the chiral a-carbon centers is a serious problem, the application of 1-hydroxy-1 H-benzotriazole ( HBT") and DCC has been very successful in increasing yields and decreasing racemization (W. Kdnig, 1970 G.C. Windridge, 1971 H.R. Bosshard, 1973), l-(Acyloxy)-lif-benzotriazoles or l-acyl-17f-benzo-triazole 3-oxides are formed as reactive intermediates. If carboxylic or phosphoric esters are to be formed from the acids and alcohols using DCC, 4-(pyrrolidin-l -yl)pyridine ( PPY A. Hassner, 1978 K.M. Patel, 1979) and HBT are efficient catalysts even with tert-alkyl, choles-teryl, aryl, and other unreactive alcohols as well as with highly bulky or labile acids. 

The acid catalyzed condensation of benzaldehydes with 2-acetyIpyridine provides access to hydroxy- or amino-indolizines (Scheme 58a) (71CB1629,71CB1645). A remarkable synthesis of fused pyrrolidines in which aldehydes also provide C-2 is exemplified in Scheme 58b... 

Succinimides — see also Pyrrolidine-2,5-diones as anticonvulsants, I, 166 synthesis, 4, 120 Succinimides, N-hydroxy-polymerization, I, 271-272 Sudoxicam... 

Cyanogen azide is a useful reagent for conversion of pyrrolidine enamines of 3-keto steroids to A-norsteroids. " Ring contractions can be carried out in the presence of 17j5-hydroxy, 17j -acetoxy, 20-keto groups and isolated double bonds. In a typical procedure, 17j -hydroxy-5a-androstan-3-one (partial formula 8) is converted into the enamine (9) by pyrrolidine in benzene... 

A solution of 30 g (0.1 mole) of 17j5-hydroxy-5a-androstan-3-one (androstano-lone), 20 ml of pyrrolidine and 200 ml of benzene is heated at reflux temperature for 2.5 hr under a Bidwell-Sterling water trap. The benzene solution is evaporated to dryness in a rotating evaporator connected to a water aspirator. The white cake which remains is broken up and dried further by immersing the flask in a water bath at 60-75° and evacuating the flask with a mechanical vacuum pump. After 0.5 hr the solid cake is broken up again and dried for another 0.5 hr at 60-75°. The enamine (9) obtained should smell only faintly of pyrrolidine. 

Both the infrared and ultraviolet spectra of pyrrolidine-2,3,5-triones (75) have been interpreted to support their existence as hydroxy-maleimides (76), and the occurrence of a strong OH stretching band in the infrared spectrum of 4-phenylpyrrolidine-2,3,5-trione has been taken as evidence that it too exists in a hydroxy form, probably 76 (R CeHg). However, the trioxo formulation is suggested by t/j the infrared spectra of jV-substituted pyrrolidine-2,3,5-triones, although an equilibrium apparently occurs depending upon the substituents and conditions. The zwitterion formulation 77 has been advanced for 4-aminopyrrolidine-2,3,5-trione. For chemical evidence... 

The first step involves the preparation of 1 -(3-isobutoxy-2-chloro)propyl pyrrolidine as an intermediate. 345 ml of thionyl chloride dissolved in 345 ml of chloroform are added, drop by drop, to 275 g of 1 -(3-isobutoxy-2-hydroxy)propyl pyrrolidine dissolved in 350 ml of chloroform, while maintaining the temperature at approximately 45°C. The reaction mixture is heated to reflux until gas is no longer evolved. The chloroform and the excess of thionyl chloride are removed under reduced pressure. The residue is poured on to 400 g of crushed ice. The reaction mixture is rendered alkaline with soda and the resulting mixture is extracted twice with 250 ml of diethyl ether. The combined ethereal extracts are dried over anhydrous sodium sulfate. After evaporation of the solvent the residue is distilled under reduced pressure. 220 g of product are obtained having the following properties boiling point = 96°C/3 mm, n074 = 1.4575. 

The first cyclopent[A]azepine 19 was obtained as dark-green crystals by the acid-catalyzed condensation of 4-hydroxy-2,3,4-triphenylcyclopent-2-en-l-one (18) with pyrrolidine in refluxing toluene.106... 

Use of the valine derived (4S )-3-acetyl-4-isopropyl-1,3-oxazolidine (8)92, the C2-symmetric reagents (2.5,55)-l-acetyl-2,5-bissubstituted pyrrolidine 994, or the doubly deprotonated acetyl urea /V-acetyl- V..V -bis[(.S)-l-phcnylethyl]urea (10), also does not lead to sufficient induced stereoselectivity combined with acceptable chemical yield. When the acetyl urea enolate is reacted with aliphatic and aromatic aldehydes, the diastereomeric adducts (ratios ranging from 1 1 to 3 1) may be separated by column chromatography to give ultimately both enantiomers of the 3-hydroxy acids in 99% ee110. 

The naphthyl derived ligand, (5)-1-mcthyl-2-[(l-naphthylamino)methyl]pyrrolidine (4) is especially effective in the stereoselective additions of (Z)-l-cthylthio-l-trimethylsilyloxy-l-propene to aldehydes. Thus, quantitative formation of. yyn-adducts is achieved, in addition to high reagent-induced stereoselectivity (>98% ee for the 3-hydroxy thioester products)23 32. 

D. 2(S)-(fl-tert-Butoxycarbonyl-a-(R)-hydroxyethyl)-4-(R)-hydroxy-pyrrolidine- 1-carboxylic acid, tert-butyl ester. The identical procedure was followed, in this case using the (,S)-BINAP catalyst (5)-l. Hydrogenation is conducted for 64 hr, and the reaction mixture is then transferred to a 250-mL, round-bottomed flask and concentrated to dryness. The residue is dissolved in 17 mL of methanol and cooled to 15°C. After the slow addition of 7 mL of DI water, the solution is aged for 15 min gradually forming a thin slurry. More DI water (75 mL) is added over 1 hr and the mixture is allowed to stand for an additional 1 hr at 15°C. The resulting crystals (Note 19) are filtered at 15°C, washed with 10 mL of 1 4-MeOH water, and then dried overnight in a vacuum oven (35°C, 686 mm) to yield 7.0 g (70%) of (R)-hydroxy ester 4b (Note 20). 

Die Reduktion enolisierbarer /J-Oxo-carbonsaure-ester mitNatriumboranat er-gibt bessere Resultate als mit Lithiumalanat, da kein Olefin gebildet wird (s. S. 215). Aus 4-Oxo-l-benzyl-3-athoxycarbonyl-pyrrolidin erhalt man z. B. das Diol mit Natriumbo-ranat in 72%iger, mit Lithiumalanat in 51%iger Ausbeute. Die selektive Reduktion zum Hydroxy-carbonsaure-ester liefert schlechtere Ergebnisse2 ... 

Hydroxy-butandisaure-propyl- —> 3-Hydroxy-l-propyl-pyrrolidin -, 88,65% d.Th. ... 

Zur Reduktion von 4-Oxo-l-benzyl-3-athoxycarbonyl-pyrrolidin s.S. 217. Oxo-lactone werden am besten mit Zinkboranat selektivzu Hydroxy-lactonen re-duziert4,5 mit Natriumboranat wird zusatzlich die Lacton-Gruppe reduktiv gespalten z.B.4 ... 

Hydroxy-L-prolin is converted into a 2-methoxypyrrolidine. This can be used as a valuable chiral building block to prepare optically active 2-substituted pyrrolidines (2-allyl, 2-cyano, 2-phosphono) with different nucleophiles and employing TiQ as Lewis acid (Eq. 21) [286]. Using these latent A -acylimmonium cations (Eq. 22) [287] (Table 9, No. 31), 2-(pyrimidin-l-yl)-2-amino acids [288], and 5-fluorouracil derivatives [289] have been prepared. For the synthesis of p-lactams a 4-acetoxyazetidinone, prepared by non-Kolbe electrolysis of the corresponding 4-carboxy derivative (Eq. 23) [290], proved to be a valuable intermediate. 0-Benzoylated a-hydroxyacetic acids are decarboxylated in methanol to mixed acylals [291]. By reaction of the intermediate cation, with the carboxylic acid used as precursor, esters are obtained in acetonitrile (Eq. 24) [292] and surprisingly also in methanol as solvent (Table 9, No. 32). Hydroxy compounds are formed by decarboxylation in water or in dimethyl sulfoxide (Table 9, Nos. 34, 35). 

Enantiopure (R)- and (S)-nipecotic acid (Nip) derivatives 64 were obtained following classical resolution of ethyl nipecotate with either enantiomer of tartaric acid and successive recrystallization of the corresponding salts [153, 154, 156] or by resolution of racemic nipecotic acid with enantiomerically pure camphorsul-fonic acid [154]. N-Boc protected pyrrolidine-3-carboxylic acid (PCA) 65 for the synthesis of homo-ohgomers [155] was prepared by GeUman from trans-4-hydroxy-L-prohne according to a known procedure [157]. 

Recently, SB-269970 (l-[3-hydroxy-phenyl-sulphonyl]-2-[2-(4-methyl-l-piperidinyl)-ethyl] pyrrolidine) and SB-656104 (6-((R)-2- 2-[4-(4-chloro-phenoxy)-piperidin-l-yl]-ethyl pyrrolidine-l-sulphonyl)-lH-indole) have been reported to be potent 5-HT7 receptor antagonists (Hagan et al., 2000 Forbes et al., 2002). Selective 5-HT7 receptor agonists are not available at the present time. Systemic administration of SB-269970 or SB-656104 to rats at the beginning of the light period has been shown to reduce the total amount of REMS and to increase REMS latency. Values of W and SWS were not significantly modified (Hagan et al., 2000 Thomas et al., 2003). Hedlund et al. (2005) established that 5-HT7... 

Naturally occurring and synthetic polyhydroxylated pyrrolidine and piperidines have recently received considerable attention due to their biological activities. Barco has used tandem Michael-Henry reactions to synthesize 2-hydroxymethyl-3-hydroxy-4-nitro-pyrrolidines, from which the nitro group is removed to give the natural product, trans 2-hydroxymethyl-3-hy-droxypyrrolidine (Eq. 7.72).91... 

Under similar conditions, reactions between pyrrolidine derivatives 632 and MTAD proceed much more slowly and less cleanly with formation of a polymeric material. When the reaction is stopped before 50% conversion is reached, starting compound 632 is isolated as the main component (c. 40%) and compound 637 as a minor product (10-14%). Mechanistically, the most difficult problem lies in the fact that a reduction step has to be involved and no particular reduction agent is present. A proposed mechanism is shown in Scheme 103. The pathway includes a Cannizzaro-type hydride transfer between dipole 633 and product 634 (keto tautomer), resulting in the formation of the iminium derivative 635, which might be responsible for the polymeric material, and hydroxy derivative 636, the direct precursor of the final products 637. The low experimental yield of 637 could be explained by this mechanism <2003EJ01438>. 

The reaction of 5-[2-(iV,./V-dimethylamino)ethyl]-l,2,4-oxadiazole with methyl iodide forms the quaternary ammonium salt 170 (Scheme 22), which undergoes elimination in the presence of base (diisopropylethylamine (DIEA), TEA, l,8-diazabicyclo[4.3.0]undec-7-ene, etc.) to form an intermediate 5-vinyl-l,2,4-oxadiazole 171, which undergoes in situ Michael addition with nucleophiles to furnish the Michael adducts 172. As an example, also shown in Scheme 22, 3-hydroxy-pyrrolidine allows the synthesis of compound 172a in 97% yield. Mesylation followed by deprotonation of the 1,2,4-oxadiazole methylene at C-5 enables Sn2 displacement of the mesylate to give the 5-azabicycloheptyl derivative 173, which is a potent muscarinic agonist <1996JOC3228>. 

Later on, other hydroxylamine derivatives such as 1-hydroxy-2,2,6,6-tetramethyl-4-oxo-piperidine (TEMPONEH) and l-hydroxy-3-carboxy-pyrrolidine (CP-3) have been used for superoxide detection [26]. It was found that these spin traps react with both superoxide and peroxynitrite and that they might be applied for quantification of these reactive species [27]. The CP-3 radical is less predisposed to reduction by ascorbic acid and therefore is probably more suitable for superoxide detection in biological systems. 

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