Alcohols, 2-amino threo

Several antidepressants work via mechanisms that are not yet fully understood. Perhaps the best example of this is bupropion (3). Although the mechanism of action of bupropion is most commonly attributed to inhibition of dopamine reuptake, its actions are diverse (215).In addition, one or more bupropion metabolites also seem to be active. In humans, bupropion is metabolized to two amino alcohols, the racemic threo amino alcohol RyR-threo 66) and the racemic erythro amino alcohol (i ,S-erythro 67), threohydroxybupro-pion and crythrohydroxybupropion, respectively and a morpholinol, hydroxybupropion (68 BW 306U). The levels and half-lives of... 

Bupropion hydroxylation of the tert-butyl group to hydroxypropion is mediated almost exclusively by CYP2B6 and, to a lesser extent, by CYP2E1 (74). Other metabolites include reduction of the aminoketone to amino-alcohol isomers, threo-hydrobupropion and erythro-hydrobupropion (Fig. 21.21). Further oxidation of the bupropion side chain results in the formation of m-chlorobenzoic acid, which is eliminated in the urine as its glycine conjugate. Hydroxybupropion is approximately 50% as potent as bupropion, whereas threo-hydrobupropion and erythro-hydrobupropion have 20% of the potency of bupropion. Peak plasma concentrations for hydroxybupropion are approximately 10 times the peak level of the parent drug at steady state, with an elimination half-life of approximately 20 hours. The times to... 

Amino-l-phenylbutan-l-ol [a (a-aminopropyl)benzyl alcohol] [( )-threo 5897-76-7] M 165.1, m 79-80 , pK jt -9.7. Crystd from benzene/pet ether. 

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]. 

The diastereoselectivity of the reduction of a-substiluted ketones has been the subject of much investigation. The reagent combination of trifluoroacetic acid and dimethylphenylsilane is an effective method for the synthesis of erythro isomers of 2-amino alcohols, 1,2-diols, and 3-hydroxyalkanoic acid derivatives.86,87,276,375 Quite often the selectivity for formation of the erythro isomer over the threo isomer of a given pair is >99 1. Examples where high erythro preference is found in the products are shown below (Eqs. 218-220).276 Similar but complementary results are obtained with R3SiH/TBAF, where the threo isomer product... 

The reduction of phenyl mesityl ketone was studied with LAH modified with amino alcohols 65 to 72 in ether (the ratio LAH alcohol ketone = 1.1 1.1 1) (83). Optical yields were modest, with the highest 39%, obtained with 65 as the chiral auxiliary reagent. It was observed that there is a relationship between the preferred enantiomeric product and the structure and absolute configuration of the carbons carrying the hydroxy and amino groups. Thus the threo... 

These results are explained in terms of coordination of the nucleophilic hydroxy-(methoxy-, silyloxy-, amino-) functionality of the stereogenic center with the incoming electrophilic singlet oxygen (Scheme 24, right side, transition states C). Stereodifferentiation results from the preferred conformation of the ally lie alcohol for oxygen transfer, which is mainly determined by 1,3-allylic strain (threo-C favored over erythro-C). The experiments also showed that the optimal dihedral angle of the allylic alcohol (C=C—C—O) in the transition state lies between 90° and 130° and the newly formed double bond in the... 

The principal human metabolite having been identified as the aryl morphohnol 2, subsequent analysis confirmed that 2 was a mixture of (S,S)- and (R,R)- enantiomers, 2a and 2b respectively. Later studies confirmed that the (R,R)-enantiomer 2b was the major metabolite typically 90-95% compared to 5-10% of the (S,S)-enantiomer 2a (radafaxine free base), while the amino alcohol 3 was formed as an approximately 1 1 mix of the erythro and threo isomers. 

The first step in the overall synthetic scheme (Scheme 6) is the condensation of an appropriate carboxylic acid with trifluoroacetaldehyde. The carboxylic acid is chosen to impart specificity for the target enzyme. In one example,[28 the dianion of cyclohexanepropanoic acid (29) was formed by the addition of LDA and then quickly condensed with trifluoroacetaldehyde to form the p-hydroxy acid 30 as a racemic mixture of erythro- and threo-isomers. The p-hydroxy acid 30 is then protected with TBDMSOTf forming 31. Diphenyl phosphorazidate, TEA, and benzyl alcohol were then utilized in a Curtius rearrangement of the protected alcohol 31, which proceeds through an isocyanate intermediate that yields the protected amino alcohol 32 upon reaction with benzyl alcohol. In order for this step to occur at an appreciable rate, a second equivalent of triethylamine had to be added. The amino alcohol 32 was then deprotected and coupled with Boc-Phe-Leu-OH to give the trifluoromethyl alcohol 33, which was oxidized to the corresponding trifluoromethyl ketone 34 as a 1 1.2 mixture of diastereomers using the Dess-Martin periodinane procedure. Thus far, the compound shown in Scheme 6 is the only compound that has been synthesized by this method, but it is reasonable to assume that many other similar fluoro ketones can be produced by this scheme. 

The reaction is also convenient for synthesis of acyclic -amino alcohols. Thus reaction of 1 with benzaldehyde followed by reduction gives a mixture of ( )-ephedrine (2,erylhro) and ( )-i -ephedrine (3, threo) in the ratio 3.3 1. The opposite stereoselectivity obtains when the reaction is used to prepare a tertiary amino alcohol. Thus the same sequence applied to 4 leads mainly to the threo-isomer (5, N-methyl-i r-ephedrine). 

Organolithium reagents (primary, secondary, tertiary, aryl and vinyl) also add in excellent yield to a-alkoxyaldehyde dimethylhydrazones (146) equation 19) with high threo diastereoselectivity (Table 9). Hydrogenolytic cleavage of the resultant hydrazines provide an attractive route to rAreo-2-amino alcohols. 

Another potential approach towards 1 was reported by Seido et al. utilizing an asymmetric reduction of the ketone (57 Scheme 15) as the key step. Acylation of the lithium enolate of methyl phenylacetate with the imidazolide, obtained by treatment of the acid 56 with A, V -carbonyldiimidazole, gave the ketoester 57 in 66.4% yield. Asymmetric reduction of 57 with [RuI(/7-cymene)(5)-binap]I, tin chloride, and cam-phor-lO-sulfonic acid in methanol at 80 °C afforded the alcohol 58 as a mixture of syn and anti forms in 87.4% yield. The ratio of syn to anti isomers was 76.3 23.7 and the enantiomeric purity of each form was 95.6% ee and 97.8% ee, respectively. Tosylation of 58 with p-toluenesulfonyl chloride and pyridine in the presence of catalytic amounts of DMAP yielded a diastereomeric mixture of tosylate 59 in 61.8% yield. Deprotection of the /V-Cbz group in 59 by hydrogenation over 5% Pd-C followed by cyclization of the resulting amino tosylate 60 with potassium carbonate in methanol furnished methylphenidate as a mixture of erythro and threo isomers in a 7 3 ratio and 77.5% yield. 

The methyl 4,6-0-benzylidene-2, S-dideoxy-S-C-nitro-iS-D-er /i/iro- and -threo-hex-2-enosides can be prepared by a facile elimination of acetic acid from the appropriate 2-0-acetyl-3-deoxy-3-C-nitro compounds they add hydrogen, ammonia, acids, and alcohols to give pyranoside products having deoxy, aminodeoxy, acyloxy, and alkoxy groupings at C-2 A wide variety of 3-amino-3-deoxy sugar derivatives may therefore be synthesized from these unsaturated compounds. 

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