Aqueous reactions amino alcohols

Conversion of the amino alcohol 53 to Efavirenz (1) was readily accomplished by reaction with phosgene or phosgene equivalents. The most convenient and economically sound method is to react 53 with phosgene in the absence of base in THF-heptane at 0-25 °C. After aqueous work-up, Efavirenz was crystallized from THF-heptane in excellent yield (93-95%) and purity (>99.5%, >99.5% ee). 

In 1982 Cardillo used a three-step sequence involving two supported reagent systems to convert /i-iodoamines into amino alcohols (Scheme 2.23) [45]. Polymer-supported acetate ions were used for the substitution of the iodide which immediately underwent acyl transfer to the amine. The resulting compound (10) was directly treated with hydrochloric acid to cleave the amide and the free base was subsequently obtained from the reaction by treatment with a resin-bound carbonate. This was of particularly synthetic value because of the high water solubiHty of these amino alcohol compounds that would have made aqueous work-up challenging. 

Amino Alcohol Catalyzed Alkylation. (—)-3-exo-(Dimethylamino)-isobomeol [( —)-DAIB] is a sterically restrained jS-dialkylamino alcohol that has proven to be an extremely efficient catalyst 13). For instance, in the presence of 2 mol % of (—)-DAIB, the reaction of benzaldehyde and diethylzinc proceeds smoothly to give, after aqueous workup, (5)-1 -phenyl-1 -propanol in 98% ee and in 97% yield along with a small amount of benzyl alcohol (Scheme 9). Nonpolar solvents such as toluene, hexane, ether, or their mixtures produce satisfactory results. The optical yield in toluene is affected by temperature and decreases from 98% at —20°C to less than 95% at 50°C. The catalytic enantioselective reaction has been extended to a range of alkylating agents and aldehyde substrates, which are summarized in Scheme 10 (75). p-Substituted ben-... 

The p-sulfanyl amides 28 are synthesized from N-protected amino acids 24 via amino alcohols 25, which are converted into (5-acetylsulfanyl amides 26 by a Mitsunobu reaction. The (5-amine disulfide 27 is subsequently coupled with a variety of carboxylic acids, followed by reduction with tributylphosphine in aqueous THF in the presence of pyridine to produce the free thiol 28 (Scheme 5).1211 Detailed experimental procedures for these compounds have not been reported. 

Asymmetric hydroboration of enamines with chiral diboranes, followed by oxidation with hydrogen peroxide, in aqueous sodium hydroxide, gives /1-amino alcohols in good yields and high ee (equation 29)153. The products of this reaction are useful in medicinal applications and as synthons for further synthetic elaboration. 

The corresponding /i-amino aldehydes are reduced in situ and the corresponding amino alcohols are isolated in good yield with up to >99 % ee. The Mannich reactions proceed with excellent chemoselectivity and inline formation occurs with the acceptor aldehyde at a faster rate than C-C bond-formation. Moreover, the one-pot three-component direct asymmetric cross-Mannich reaction enables aliphatic aldehydes to serve as acceptors. The absolute stereochemistry of the reaction was determined by synthesis and reveled that L-proline provides syn /i-amino aldehydes with (S) stereochemistry of the amino group. In addition, the proline-catalyzed direct asymmetric Mannich-type reaction has been connected to one-pot tandem cyanation and allylation reaction in THF and aqueous media affording functional a-amino acid derivatives [39, 42]. 

The synthesis of darunavir (1) is shown in Scheme 12. Optically active bis-THF alcohol (-)-ll was converted to activated mixed carbonate 46 by treatment with N,N-disuccinimidyl carbonate (DSC) in the presence of triethylamine.30 For the synthesis of the hydroxyethylsulfonamide isostere, epoxide 38 was treated with isobutyl amine (47) in 2-propanol at reflux to provide the corresponding amino alcohol. Reaction of the resulting amino alcohol with p-nitrophenylsulfonyl chloride in the presence of aqueous NaHC03 afforded the sulfonamide derivative 48 in 95% yield for the two steps. This was converted to darunavir in a three-step process, involving (1) catalytic hydrogenation of nitro to an amine, (2) removal of the Boc group by exposure to trifluoroacetic acid in... 

Asymmetric addition of diorganozincs to aldehydes catalyzed by chiral -amino alcohols provides a general method for the preparation of chiral secondary alcohols. Oguni, Noyori, and co-workers found that the aminoalcohol, (2S)-3-exo-(dimethylamino)isobornenol ((2S)-DAIB), acts as a particularly efficient promoter for this asymmetric reaction [9, 10]. Reaction of benzalde-hyde with diethylzinc in the presence of 2 mol% of (2S)-DAIB gives, after aqueous workup, (S)-l-phenylpropanol in high yield with 99% ee as shown in Scheme 8. Detailed mechanistic and theoretical studies of the (2S)-DAIB-pro-moted asymmetric addition have been reported [11]. 

The success of the method employing Li/MeNH2 again arises from the formation of the aldehyde in a protected form. In this case it is the amino alcohol salt (2 Scheme 2). As shown in Scheme 2, the reaction mixture is quenched with saturated aqueous ammonium chloride and may then be extracted with pentane, to yield an imine, or with ether and washed with acid to give the aldehyde. The imine is clearly not the protected form of the aldehyde, as it is reduced to the corresponding secondary amine under the conditions of the reaction. The reaction succeeds for aliphatic saturated acids, and also for one example... 

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