L-Amino alcohols

Oxazolidines are five-membered cyclic ft-Mannich bases, some of which have, indeed, been examined as potential produgs of /l-amino alcohols of medicinal relevance such as ephedrines and /3-blockers. For example, 3,4-dime-thyl-5-phenyloxazolidine (11.106), the oxazolidine of ephedrine (11.107) undergoes hydrolysis to ephedrine and formaldehyde slowly at pH 1 and 12, but very rapidly in the neutral pH range (tm < 1 min at 37°) [135], Interestingly, the equilibrium reached between the reactants and products of hydrolysis was markedly pH- and concentration-dependent. However, despite its poor stability in aqueous solution, the oxazolidine was delivered through human skin significantly faster than ephedrine when applied as 1% aqueous solutions of pH 7 - 11. The lower basicity of the oxazolidine (pKa 5.5) compared to that of ephedrine (pKa 9.6) may explain the efficient skin permeation. 

Amino-alcohols inhibit their respective aminoacyl-tRNA synthetases, thereby increasing the concentration of deacylated tRNA (Hansen et al., 1972). Injection of L-threoninol or L-leucinol, but not D-threoninol or a dispensable AA, into the APC decreases food intake at 20 min and increases other downstream events the same as eating a threonine-devoid diet. The effects of L-amino-alcohols are stereospecific, competitive, selective for their respective AAs, and mimic the effects of lAA depletion (Hao et al., 2005a). 

The nitro alcohols in Table 1 are manufactured in commercial quantities however, three of the five of them are used only for the production of the corresponding amino alcohols. 2-Methyl-2-nitro-l-propanol (NMP) is available as the crystalline soHd or as a mixture with siHcon dioxide. 2-Hydroxymethyl-2-nitro-1,3-propanediol is available as the soHd ( 9.15/kg), a 50% solution in water ( 2.33/kg), a 25% solution in water ( 1.41/kg), or as... 

Amino alcohols can be resolved by a number of pathways including hydrolysis, esterification, and transesterification. For example, hydrolysis of Ai,0-diacet5l-2-amino-l-butanol with PPL followed by recrystallization results in (80a) with 95% ee (108). Hydrolysis of racemic acetates or butyrates of 2-[(aLkoxycarbonyl)amino]-l-aLkanols with PFL gives (R)-alcohol (81) with 95% ee (109). (3)-(81) can be obtained by transesterification of the racemic (81) with ethyl acetate which also serves as the reaction medium (109). 

These hydrazides on treatment with nitrous acid are converted into azides, which with appropriate amino-alcohols, furnish ergometrine and its isomerides and analogues. The four pairs of stereoisomeric ergo-metrines and ergometrinines in the following list have been prepared in this way with l-( -(-)-)S-aminopropyl alcohol or its d-( —)-isomeride. 

Due to the abundance of epoxides, they are ideal precursors for the preparation of P-amino alcohols. In one case, ring-opening of 2-methyl-oxirane (18) with methylamine resulted in l-methylamino-propan-2-ol (19), which was transformed to 1,2-dimethyl-aziridine (20) in 30-35% yield using the Wenker protocol. Interestingly, l-amino-3-buten-2-ol sulfate ester (23) was prepared from l-amino-3-buten-2-ol (22, a product of ammonia ring-opening of vinyl epoxide 21) and chlorosulfonic acid. Treatment of sulfate ester 23 with NaOH then led to aziridine 24. ... 

Metal ion complexes. These classic CSPs were developed independently by Davankov and Bernauer in the late 1960s. In a typical implementation, copper (II) is complexed with L-proline moieties bound to the surface of a porous polymer support such as a Merrifield resin [28-30]. They only separate well a limited number of racemates such as amino acids, amino alcohols, and hydroxy acids. 

As described in Section 2.3.2, vinylaziridines are versatile intermediates for the stereoselective synthesis of (E)-alkene dipeptide isosteres. One of the simplest methods for the synthesis of alkene isosteres such as 242 and 243 via aziridine derivatives of type 240 and 241 (Scheme 2.59) involves the use of chiral anti- and syn-amino alcohols 238 and 239, synthesizable in turn from various chiral amino aldehydes 237. However, when a chiral N-protected amino aldehyde derived from a natural ot-amino acid is treated with an organometallic reagent such as vinylmag-nesium bromide, a mixture of anti- and syn-amino alcohols 238 and 239 is always obtained. Highly stereoselective syntheses of either anti- or syn-amino alcohols 238 or 239, and hence 2,3-trans- or 2,3-as-3-alkyl-2-vinylaziridines 240 or 241, from readily available amino aldehydes 237 had thus hitherto been difficult. Ibuka and coworkers overcame this difficulty by developing an extremely useful epimerization of vinylaziridines. Palladium(0)-catalyzed reactions of 2,3-trons-2-vinylaziri-dines 240 afforded the thermodynamically more stable 2,3-cis isomers 241 predominantly over 240 (241 240 >94 6) through 7i-allylpalladium intermediates, in accordance with ab initio calculations [29]. This epimerization allowed a highly stereoselective synthesis of (E) -alkene dipeptide isosteres 243 with the desired L,L-... 

Treatment of m-butyl (S )-4-formyl-2,2-dimethyl-3-oxazolidinccarboxylate ( Garner aldehyde, 3), readily available from /V-Boc-l-serine and configurationally extremely stable49,50, with various nucleophiles preferentially yields the n n(nonchelation)-diastereomeric amino alcohols 4 in high chemical yield51 -55,57-61. 

A solution of 3.7 g (12 mmol) of the pure (l R)-diastereomer 6 is stirred under nitrogen in 15 mL of iodomethane and 5 mL of dry DMSO for 36 h. The excess iodomethanc is evaporated leaving a viscous red oil which is heated under reflux in 25 mL of 2N KOI for 5 h. After cooling, the amino alcohol is removed from the aqueous phase by extraction with Et20. The alkaline aqueous layer is acidified with 12 N HC1 and extracted with Ei,0. The crude product is recrystallized from benzene/petroleum ether to give enantiomer-ically pure (R)-2-hydroxy-2-phenylpropanoic acid [(-)-(R)-atrolaclic acid] (7) yield 1.4 g (71%) mp U5-116X [x]25 - 38.4 (< = 2.5, EtOH). 

An interesting case of product-controlled simple diastereoselectivity has been reported103. [l-[Methyl(nitrosoamino)]-2-propenyl]lithium adds to benzaldehyde at — 78°C to give the amino alcohol with an anti/syn ratio of 65 35, but equilibration of the reversible reaction at room temperature leads exclusively to the more stable, vv -product. 

In some cases the yields were poor due to competing deprotonation of the substrate by the organolithium reagent. Deprotonation was the predominant reaction with methyllithium or when (Z)-2-(l-alkenyl)-4,5-dihydrooxazoles were employed. The stereochemical outcome has been rationalized as occurring from a chelated transition state. The starting chiral amino alcohol auxiliary can also be recovered without racemization for reuse. 

The reaction between epoxides and ammonia is a general and useful method for the preparation of P-hydroxyamines. " Ammonia gives largely the primary amine, but also some secondary and tertiary amines. The useful solvents, the ethanolamines, are prepared by this reaction. For another way of accomplishing this conversion, see 10-54. The reaction can be catalyzed with Yb(OTf)3 and in the presence of a-BINOL is l,l -bi-2-naphthol derivative gives amino alcohols with high asymmetric induction. A variation used Yb(OTf)3 at lOkbar or at ambient pressure. Lithium triflate can also be used. Primary and secondary amines give, respectively, secondary and tertiary amines, for example. 

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]. 

Scheme 7 Synthesis of (11 )- and (11 , 2S)-l,2-amino alcohols starting from...

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