Amino alcohols resolution

The homolog of epinephrine in this series is a potent vasoconstrictor. Reaction of 3,4-dimethoxypropiophenone with butyl nitrite leads to nitrosation at the a position (36). Stepwise reduction of the nitrosoketone leads to the amino alcohol (37). Removal of the methyl ether affords racemic 38. Resolution of this last followed by separation of the (-) isomer gives levonor-defrine (38). ... 

Since the addition of dialkylzinc reagents to aldehydes can be performed enantioselectively in the presence of a chiral amino alcohol catalyst, such as (-)-(1S,2/ )-Ar,A -dibutylnorephedrine (see Section 1.3.1.7.1.), this reaction is suitable for the kinetic resolution of racemic aldehydes127 and/or the enantioselective synthesis of optically active alcohols with two stereogenic centers starting from racemic aldehydes128 129. Thus, addition of diethylzinc to racemic 2-phenylpropanal in the presence of (-)-(lS,2/ )-Ar,W-dibutylnorephedrine gave a 75 25 mixture of the diastereomeric alcohols syn-4 and anti-4 with 65% ee and 93% ee, respectively, and 60% total yield. In the case of the syn-diastereomer, the (2.S, 3S)-enantiomer predominated, whereas with the twtf-diastereomer, the (2f ,3S)-enantiomer was formed preferentially. 

The importance of proper immobilization of enzymes can be shown in the kinetic resolution of racemic a-acetoxyamides. This group of compounds is an important class of chemicals since they can be readily transformed into a-amino acids [17], N-methylated amino acids, and tripeptide mimetics [18], amino alcohols [19], 1,2-diols [20], 1,2-diamines [21], and enantiopure l,4-dihydro-4-phenyl isoquinolinones [22]. 

The low-temperature method was then applied to the resolution of ( )-2-hydroxy-2-(pentafluorophenyl)acetonitrile (7) (Fig. which is usahle for the syntheses of a variety of ethane diols, amino alcohols containing CgFj groups as novel chiral ligands. After screening lipases such as Amano PS and AK, lipase LIP Pseudomonas aeruginosa lipase immobilized on Hyflo Super-Cel, Toyobo,... 

Optically active 5-(hydroxymethyl)-3-phenyl-2-isoxazoline 13 is a versatile key intermediate for the syntheses of /3-hydroxy ketones, y-amino alcohols,and y-amino acids. However, the Upase-catalyzed kinetic resolution of isoxazoline ( )-13 has not been reported so far probably because of the low enantioselectivity expected for primary alcohols (Scheme 3). The enantioselectivity was found to be very low E value = 4-5 in /-Pr20) at room temperature however, it could be markedly improved up to an value of 249 at —60°C by using lipase PS-C 11 in acetone, which was the best solvent among those tested (THF, /-Pt20) 1 )-... 

Introduction Since we had already developed the novel asymmetric addition of lithium acetylide to ketimine 5, we did not spend any time on investigating any chiral resolution methods for Efavirenz . Our previous method was applied to 41. In the presence of the lithium alkoxide of cinchona alkaloids, the reaction proceeded to afford the desired alcohol 45, as expected, but the enantiomeric excess of 45 was only in the range 50-60%. After screening various readily accessible chiral amino alcohols, it was found that a derivative of ephedrine, (1J ,2S) l-phenyl-2-(l-pyrrolidinyl)propan-l-ol (46), provided the best enantiomeric excess of 45 (as high as 98%) with an excellent yield (vide infra). Prior to the development of asymmetric addition in detail, we had to prepare two additional reagents, the chiral modifier 46 and cyclopropylacetylene (37). 

Various catalytic or stoichiometric asymmetric syntheses and resolutions offer excellent approaches to the chiral co-side chain. Among these methods, kinetic resolution by Sharpless epoxidation,14 amino alcohol-catalyzed organozinc alkylation of a vinylic aldehyde,15 lithium acetylide addition to an alkanal,16 reduction of the corresponding prochiral ketones,17 and BINAL-H reduction18 are all worth mentioning. 

A systematic investigation of the free amino acids of the Leguminosae led to the isolation of a novel ninhydrin-positive compound from the leaves of Derris elliptica Benth. (Papilionidae) (93). This substance was analyzed as C6H,3N04 (microanalysis and high resolution mass spectrometry) and was shown to be an amino alcohol. The absence of a carbonyl in the 1R, the loss of 31 mass units in the mass spectrum, and a positive periodate cleavage reaction were best embodied into a dihydroxydihydroxymethylpyrrolidine structure. The relative simplicity of the NMR spectra (three peaks in the 13C spectrum four spin-system in the H spectrum) pointed out a symmetrical structure. Inasmuch as the material was optically active ([a]D 56.4, c = 7, H20), meso structures were ruled out, and the 2R, 3R, 4R, 5R relative configuration was retained (93). This structure (53) was further confirmed by an X-ray determination (94). 

F]Fluorobenzaldehydes have also been used as starting materials for the preparation of enantiomers of [6- F]fluoronorepinephrine,a myocardial marker [166]. The key step is the formation of a protected F-cyanhydrine which is reduced into an amino alcohol. Deprotection, purification and resolution on a chiral column provide both enantiomers (Scheme 30). 

P-Adrenergic-blocking agents, such as propranolol, have been synthesized by different chemoenzymatic methods where the key step to introduce the chirality is an enzymatic acylation or a hydrolysis process. The main reason to prepare these amino alcohols in optically pure form is due to the fact that the activity of these pharmaceuticals resides in the (S)-enantiomer. In Scheme 10.1 we have represented a chemoenzymatic approach that has been carried out for the preparation of this dmg where the key step is the resolution of the key intermediate 1-chloro-... 

A subsequent process, still reliant on salt resolution, is described in Scheme 14.8. In this case, (3-keto amine 34 was converted to carbamate 35, which was then transformed into the desired amino alcohol intermediate 36. The resolution was performed in three distinct stages (1) initial resolution of the racemate, (2) racemization of the (/J)-enriched mixture, and (3) second-order asymmetrically induced crystallization of the (5)-salt. 

An improved route to the enantiomerically pure 5,6-diphenyltetrahydro-l,4-oxazin-2-ones is shown in Scheme 44 <2005SL693>. The starting amino alcohols are commercially available but can also be obtained by resolution of the (-)-mandelic acid salts of the two enantiomers. The reaction time was significantly shorter than with older methods and the yields over the three steps were 75% for the A-/-butoxycarbonyl oxazinone and 86% for the A -benzylox-ycarbonyl oxazinone. 

The logical extension of the ion-pair chromatographic technique, using chiral counterions as CMPAs has been impressively applied, for the first time, to the resolution of chiral amino alcohols (betablockers) by Pettersson and co-workers142. 

Only in a few cases has the measurement of the enantiomeric purity via the Mosher amides or esters of amino alcohols been reported51. Kinetic resolution and racemization was observed in the case of timolol 52. This could be due to the presence of two functional groups completing in the reaction. A simple and efficient method is the following selective O-derivatization with tartaric anhydride. 

These intermediates were used to synthesize optically pure ephedrines and amphetamines without recourse to resolution, since the chirality of the amino acid educt was entirely conserved throughout the process. The reduction of (S)-2-(ethoxycarbo-nyl)amino-propiophenone (74) first produced a mixture of alcohols (75a, b) Lithium aluminium hydride reduction then produced the desired secondary amino alcohols (76a, b). Table 1 illustrates the reduction scheme and the diastereomer ratios obtained "K... 

The enzymatically catalyzed kinetic resolution of amino alcohols has been established on the multi-ton scale by BASF [7] (Scheme 7.14). Initial studies gave poor selectivity for the unprotected alcohols, as the resolution of trows-2-aminocyclopen-tanol (racemic 28) gave the amine (S,S) 29 and the amide (R,R) 30 in 25% . When the hydroxy functionality was protected as an ether, then resolution of racemic benzyl ether 31 proceeds with high to the give the amine (S,S) 32 and the RR amide 33 with >99.5 and 93 % respectively [33, 34]. 

Mercedes Amat and Joan Bosch of the University of Barcelona have been exploring (Cltem. Commun. 2005, 1327) a kinetic resolution route to piperidines. Condensation of a ketone or aldehyde ester such as 7 with an enantiomerically-pure amino alcohol such as 8 with proceeds with high (15 1) diastereoselectivity, to give 9. Reduction of 9 then delivers the piperidine 10 in high enantiomeric excess. 

SCHEME 46. Kinetic resolution of amino alcohols by asymmetric oxidation. 

Stoichiometric oxidation using TBHP and a 2 1 Ti tetraisopropox-ide-diisopropyl tartrate system can kinetically resolve racemic dialkyl-amino alcohols (Scheme 46) (106). The efficiency, which ranges from 0-95% ee, is largely dependent on the substrates. When methyl groups or polymethylene rings are used, the reaction proceeds to afford greater than 90% ee, whereas iV.iV-dibenzyl derivatives show little or no resolution. Use of natural (2/ ,3/ )-diisopropyl tartrate consistently gives R amino alcohols. 

Chiral to side-chain units can also be obtained by various catalytic and stoichiometric asymmetric synthesis as well as by resolution (30). Scheme 14 shows the preparation of these side-chain units using kinetic resolution by the Sharpless epoxidation (31), amino alcohol-catalyzed organozinc alkylation of a vinylic aldehyde (32), lithium acetylide ad-... 

Resolution of Racemic Amines and Amino Acids. Acvlases (EC 3.5.1.14) are the most commonly used enzymes for the resolution of amino acids. Porcine kidney acylase (PKA) and the fungal Aspergillus acylasc (AA) are commercially available, inexpensive, and stable. Amino alcohols can be resolved by a number of pathways, including hydrolysis, esterification, and transesterification. 

Amines containing a chiral carbon atom in the aliphatic residue attached to the nitrogen atom are of considerable interest to the coordination chemist as, when coordinated, these ligands can induce chirality in the metal-ligand chromophore. The recent compilation27 on the methods of optical resolution of more than 1000 amines and amino alcohols (Chapter 20.3) is an excellent resource. 

Fuji and co-workers have demonstrated the use of a PPY derivative that utilizes remote stereochemistry and an interesting induced fit process to control selectivity [21]. Upon acylation of catalyst 20, a conformational change occurs, stabilizing the intermediate N-acyliminium ion 21 (Fig. 2a,b). Chemical shifts in the XH NMR and nOes observed support a Jt-Jt interaction between the electron-rich naphthyl ring and the electron-deficient pyridinium ring. This blocks the top face of the catalyst and directs attack of the alcohol from the bottom face. Catalyst 20 effects resolutions of diol-monoesters and amino alcohol derivatives such as 22 and 23 with moderate to good selectivity factors (fcrei=4.7-21, see Fig. 2c) [22]. 

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