Hydroxy ephedrine

In this thiamine pyrophosphate-mediated process, ben2aldehyde (29), added to fermenting yeast, reacts with acetaldehyde (qv) (30), generated from glucose by the biocatalyst, to yield (R)-l-phen5l-l-hydroxy-2-propanone (31). The en2ymatically induced chiral center of (31) helps in the asymmetric reductive (chemical) condensation with methylamine to yield (lR,23)-ephedrine [299-42-3] (32). Substituted ben2aldehyde derivatives react in the same manner (80). 

The hydroxy acid A was resolved with (+)-ephedrine and converted to optically active and PGEj (Ref. 2). 

Addition of a hydroxyl group to the aromatic ring of ephedrine as well as changing the substitution on nitrogen leads to a compound whose main activity is to raise blood pressure. Thus, lormation of the Shiff base of the m-hydroxy analog of 30 with bcnzylamine (34), followed by catalytic reduction, yields metar- uiiinol (35). When optically active hydroxyketone is employed in... 

New modifiers have traditionally been discovered by the trial-and-error method. Many naturally occurring chiral compounds (the chiral pool38) have been screened as possible modifiers. Thus, the hydrogenation product of the synthetic drug vinpocetine was discovered to be a moderately effective modifier of Pt and Pd for the enantioselective hydrogenation of ethyl pyruvate and isophorone.39 Likewise, ephedrine, emetine, strychnine, brucine, sparteine, various amino acids and hydroxy acids, have been identified as chiral modifiers of heterogeneous catalysts.38... 

The transformation of the cyano group could also introduce a new chiral center under diastereoselective control (Figure 5.13). Grignard-transimination-reduction sequences have been employed in a synthesis of heterocyclic analogues of ephedrine [81]. The preferential formation of erythro-/3-amino alcohols may be explained by preferential hydride attack on the less-hindered face of the intermediate imine [82], and hydrocyanation of the imine would also appear to proceed via the same type of transition state. In the case of a,/3-unsaturated systems, reduction- transimination-reduction may be followed by protection of the /3-amino alcohol to an oxazolidinone, ozonolysis with oxidative workup, and alkali hydrolysis to give a-hydroxy-/3-amino acids [83]. This method has been successfully employed in the synthesis L-threo-sphingosine [84]. 

As it can be observed in Fig. 2, three out of the 16 investigated compounds, namely, heroin, lysergic acid diethylamide (LSD), and its metabolite 2-oxo, 3-hydroxy-LSD (O-H-LSD), were not detected in any wastewater sample. Two other target analytes, 6-acetyl morphine (6ACM) and A9-tetrahydrocannabinol (THC), were only present in influent wastewaters and with low detection frequencies. The most ubiquitous compounds, present in all influent and effluent wastewater samples analyzed, were the cocaine metabolite benzoylecgonine, and the amphetamine-like compounds ephedrine (EPH) and 3,4-methylenedioxymethamphetamine (MDMA or ecstasy). Cocaine, cocaethylene (CE, transesterification product of cocaine formed after the joint consumption of cocaine and ethanol), and morphine (MOR) were detected in all influent, but not in all effluent wastewaters (see Fig. 2). 

Another chiral auxiliary for controlling the absolute stereochemistry in Mukaiyama aldol reactions of chiral silyl ketene acetals has been derived from TV-methyl ephedrine.18 This has been successfully applied to the enantioselec-tive synthesis of various natural products19 such as a-methyl-/ -hydroxy esters (ee 91-94%),18,20 a-methyl-/Miydroxy aldehydes (91% ee),21 a-hydrazino and a-amino acids (78-91% ee),22 a-methyl-d-oxoesters (72-75% ee),20b cis- and trans-l1-lactams (70-96% ee),23 and carbapenem antibiotics.24... 

Until now, only a limited number of ionic hquids have been prepared from renewable sources. Eor instance, some anions were synthesized from naturally occurring hydroxy acids (lactic [55] and malic [56] acids) or proteinogenic amino acids [57], whereas cations were obtained from amino alcohols (choline [58] and ephedrine [59, 60]), hydroxy acids (lactic and tartaric acid [61]), amino acids [57], and terpenes [62-64]. 

Alkylated /V- (l/ , 2.y )-2-Hydroxy-l-methyl-2-phenylethyl -/V-niethylalkananiides (Alkylated /V-Acyl-ephedrines, 3/4) General Procedure2 ... 

O HN, OCaH5 Tr 0 L1[AIH4]/THF 60° 2 h l-Hydroxy-2-methylamino-l-phenyl- propan (2 Diastereoisomere Ephedrin + Pseudoephedrin, 4 1) 93 5... 

A number of methods for the synthesis of piperazic acid (7) and related derivatives are currently available as a result of growing interest in natural product chemistry and in their potential in medicinal chemistry. Their chemistry and conformational properties have been comprehensively reviewed. 2451 Racemic piperazic acid is obtained by condensation of penta-2,4-dienoic acid with phthalazinedione and subsequent reductive deprotection of the resulting A,A -bis(phthaloyl)-l,2,3,6-tetrahydropyridazine-3-carboxylic acid.12431 Resolution of racemic piperazic acid is achieved by fractional crystallization of the ephedrine salt of Nl-(benzyloxycarbonyl)piperazic acid from ethyl acetate. 246,2471 A typical route to enantiomerically pure (3S)-piperazic acid 56 starts from chiral 2-amino-5-hydroxyvaleric acid 55 as shown in Scheme 12.1248 Convenient stereoselective syntheses have been reported for 5-hydroxy- and 5-chloropiperazic acids as important constituents of natural cyclic peptides and depsipep-tides.1249,2521... 

With benzaldehyde 144 or halogenated derivatives (Cl, F) as acceptors the yeast-PDC-catalyzed addition proceeds with almost complete stereoselectivity to furnish the corresponding (R)-configurated 1-hydroxy-1-phenylpropanones 145 [447]. For practical reasons, whole yeast cells are most often used as the catalyst, with only small loss of enantioselectivity [423,424]. The conversion of benzaldehyde in particular has gained industrial importance because the acyloin is an important precursor for the synthesis of L-(-)-ephedrine [448]. Otherwise, the substrate tolerance is remarkably broad for aromatic aldehydes on the laboratory scale, however, yields of acyloins are usually low because of the prior or consequent reductive metabolism of aldehyde substrate and product, giving rise to considerable quantities of alcohol 146 and vicinol diols 147, respectively [423,424,449], The range of structural variability covers both higher a-oxo-acids (e.g. -butyrate, -valerate) as the donor component, as well as a,/J-un-saturated aldehydes (e.g. cinnamaldehyde 148) as the acceptor [450]. 

Pyruvate decarboxylase (PDC, E.C. 4.1.1.1) accepts other substrates besides pyruvate, its natural reactant As early as 1921, Neubergand Hirsch described the reaction of yeast with benzaldehyde and pyruvate to phenylacetylcarbinol (2-keto-3-hydroxy-propylbenzene) (Neuberg, 1921) in a carboligase side reaction which yields ephedrine after reaction with methylamine and catalytic hydrogenation (Figure 7.37). 

The a-keto acid decarboxylases such as pyruvate (E.C. 4.1.1.1) and benzoyl formate (E.C. 4.1.1.7) decarboxylases are a thiamine pyrophosphate (TPP)-dependent group of enzymes, which in addition to nonoxidatively decarboxylating their substrates, catalyze a carboligation reaction forming a C-C bond leading to the formation of a-hydroxy ketones.269-270 The hydroxy ketone (R)-phenylacetylcarbinol (55), a precursor to L-ephedrine (56), has been synthesized with pyruvate decarboxylase (Scheme 19.35). BASF scientists have made mutations in the pyruvate decarboxylase from Zymomonas mobilis to make the enzyme more resistant than the wild-type enzyme to inactivation by acetaldehyde for the preparation of chiral phenylacetylcarbinols.271... 

Phenylethylamine deriva- Nucleosil 5C8, 3 pm tives (epinephrine, DOPA, 2-amino-3-hydroxy-3-phenyl-propanol, ephedrine)... 

The subsequent steps in the French and Czech modifications follow the Woodward synthesis in its broad lines, but it should be noted that Velluz already resolves Woodward s XXXV into optical isomers with the help of either brucine or ephedrine (185). In an analogous study, the Czech investigators resolve a hydroxy acid (XXXVIII), obtained by hydrolysis of the Velluz compound (XXXVII) (185), with the help of brucine (187). Also, another dihydroxy acid (XXXIX), obtained from Woodward s lactone acid (XXXVI), has been resolved, again by use of... 

D-Cathine (= 2-Amino-1-hydroxy-1 -phenylpropane Katine t t-Norephedrine Nor-i]j-ephedrine Norpseudoephedrine Pseudonorepinephrine) (phenylpropanoid) D-Cathinone (= (S)-2-Amino-1 -phenyl-1-propanone) (phenylpropanoid)... 

I -Ephedrine (= R, 2S)-1 -Phenyl-1 -hydroxy-2-methylaminopropane) (phenylpropanoid amino alcohol)... 

The reaction of a chiral Grignard reagent derived from ephedrine with the oxathiane 2 was used to prepare the 8-hydroxy acid 5 in 34% overall yield. On standing, 5 lactonizes to (— )-malyngolide (6). ... 

SYNS BIOPHEDRIN ECIPHIN EFEDRIN EPHEDRAL EPHEDRATE EPHEDREMAL EPHEDRIN 1-EPHEDRINE l(-)-EPHEDRINE EPHEDRITAL EPHEDROL EPHEDROSAN EPHEDROTAL EPHEDSOL EPHENDRONAL EPHOXAMIN FEDRIN O-HYDROXY-p-METHYL AMINE PROPYLBENZENE l-HYDROXY-2-METHYLAMINO-l-PHENYLPROPANE I-SEDRIN ISOFEDROL KRATEDYN MANADRIN ... 

The /i-amino nitrates are generally unstable, hence the crude reaction mixture is usually converted to //-hydroxy amines with moderate yield and low diastereoselectivity (Table 5). The oxidative photoaddition of A-nitroso amines was applied to the preparation of ephedrine-like compounds98, however, a mixture of diastereomers was produced which can be separated. 

On the other hand, by bond formation with amino and hydroxy groups of ephedrine, ephedrine can be converted into chiral ring systems such as imidazolidinones, - oxazepinediones, and oxazolidines. - Diastereoselective reactions of derivatives of these chiral ring systems afford compounds with high de. The relatively rigid conformation of these ring systems is one of the reasons for high diastereoselectivities. 

Ephedrine becomes a chiral ligand of metal atoms by the deprotonation of the hydroxy group and by the presence of the nitrogen atom. - Highly enantioselective asymmetric reactions are known using chiral ephedrine-type ligands. 

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