Alcohols chiral secondary

Chirobiotic R (Astec) Macrocyclic glycoprotein Ristocetin A Covalently bonded Anionic analytes a-hydroxy acids, substituted aliphatic acids, chiral alcohols, secondary and tertiary amines... 

Among the most active catalysts for the asymmetric transfer hydrogenation of prochiral ketones and imines to chiral alcohols and amines are arene-ruthenium(II) amino-alcohol (or primary/ secondary 1,2-diamine)-based systems, with an inorganic base as co-catalyst, developed by Noyori139-141 and further explored by others (Scheme 27).142-145... 

Intermolecular reactions of hydroxylamines with secondary alkyl halides and mesylates proceed slower than with alkyl triflates and may not provide sufficiently good yield and/or stereoselectivity. A nseful alternative for these reactions is application of more reactive anions of 0-alkylhydroxamic acids or 0-alkoxysulfonamides ° like 12 (equation 8) as nucleophiles. The resulting Af,0-disubstituted hydroxamic acids or their sulfamide analogs of type 13 can be readily hydrolyzed to the corresponding hydroxylamines. The same strategy is also helpful for synthesis of hydroxylamines from sterically hindered triflates and from chiral alcohols (e.g. 14) through a Mitsunobu reaction (equation 9). 

Efficient kinetic resolution of chiral unsaturated secondary alcohols by irreversible enzyme-mediated acylation (with vinyl acetate as acylating agent, a crude preparation of Pseudomonas AK, and hexane as solvent) is possible, provided one relatively large and one small substituent are attached to the carbinol carbon. However, the method can be used to resolve substrates that are not amenable to asymmetric epoxidation (see examples 23, 25, 27, 29, where the double bond is either deactivated by an electron-withdrawing substituent, or is of the propargyl alcohol type). Acylation of the / -enantiomer consistently proceeds faster than that of the 5-enantiomer. An example of an allenic alcohol was also reported248. 

Yeast-mediated reductions predominantly form a single enantiomer and it is often difficult to find conditions which produce the opposite stereoisomer selectively. It has, however, been possible to obtain both enantiomers in 50% yield in 100% via enzymatic optical resolution. Chiral fluorinated secondary alcohols possessing the mono-, di- and/or trifluoromethyl group have been prepared by enzyme-catalyzed kinetic resolutions [27]. 

BINAP-Ru(II) diacetate complex also allows the resolution of chiral allylic secondary alcohols (66) (Scheme 32). 

A somewhat different approach to determining the enantiopurity of a sample is based on the idea that an appropriate enzyme selectively processes one enantiomer, giving rise to a UV/visible signal [17]. An example concerns determination of the enantiopurity of chiral secondary alcohols, the (S) enantiomer being oxidized selectively by the alcohol dehydrogenase from Thermoanaerobium sp. The rate of this process can be monitored by a UV/visible plate reader due to the formation of NADPH (absorption at 340 nm), which relates to the quantity of the (S) enandomer present in the mixture. About 4800 ee determinadons are possible per day, accuracy amoundng to 10%. Although the screen was not specifically developed to evaluate chiral alcohols produced by an enzymadc process, it is conceivable that this could be possible after an appropriate extraction process. 

Alkanes are preferentially hydroxylated at the more nucleophilic C—H bonds, with relative reactivities tertiary secondary primary hydrogens = 7000 110 l.303 This reaction occurs with a high retention of configuration at the hydroxylated carbon atom, as shown by the selective formation of cis-9-decalol from the oxidation of cis-decalin with chromyl acetate in an acidic medium304 and the hydroxylation of chiral (+)-3-methylheptane (91) to chiral alcohol (92) with 72 to 85% retention of configuration.305... 

O) to give a hydroxylamino alcohol, Ph-N(OH)- CH(Me)CH2OH, using an axially chiral BINAP secondary amine catalyst in THF at 0 °C, followed by methanolic treatment with sodium borohydride.261 Yields up to 90% and ees up to 99% were recorded, and one-pot conversions to the corresponding /3-amino alcohol or /3-diamine are described. 

The chemoenzymatic synthesis of chiral alcohols is a field of major interest within biocatalytic asymmetric conversions. A convenient access to secondary highly enan-tiomerically enriched alcohols is the usage of alcohol dehydrogenases (ADHs) (ketoreductases) for the stereoselective reduction of prochiral ketones. Here, as in many other cases in asymmetric catalysis, enzymes are not always only an alternative to chemical possibilities, but are rather complementary. Albeit biocatalysts might sometimes seem to be more environmentally friendly, asymmetric ketone reduction... 

Rate of complex formation between chiral alcohols and DBTA monohydrate in hexane suspension is quite slow (see Figure 1) and numerous separation steps are necessarry for isolation of the alcohol isomers (filtration of the diastereoisomeric complex then concentration of the solution, decomposition of the complex, separation of the resolving agent and the enantiomer, distillation of the product). To avoid these problems, alternative methods have been developed for complex forming resolution of secondary alcohols. In a very first example of solid phase one pot resolution [40] the number of separation steps was decreased radically. Another novel method [41] let us to increase the rate of complex forming reaction in melt. Finally, first examples of the application of supercritical fluids for enantiomer separation from a mixture of diastereoisomeric complexes and free enantiomers [42, 43] are discussed in this subchapter. 

Fig. 3.39. Sharpless epoxida-tions of chiral racemic secondary allylic alcohols if they are stopped at (a good) 50% conversion they become kinetic resolutions. The unreacted allylic alcohol is obtained as enantiomerically pure(st) material.

Fig. 3.40. Sharpless epoxida-tions of chiral racemic secondary allylic alcohols (in contrast to the upper half of Figure 3.39) driven to a 100% conversion divided into 50% rapid and also highly diastere-oselective epoxidation of the matched pair, and 50% slow epoxidation in the mismatched pair where hardly any diastere-ocontrol occurs.

Fig. 3.41. Mechanistic details of Sharpless epoxidations, part III epoxidations of chiral racemic secondary allylic alcohols in the presence of l-(+)-DET and their diastereo-selectivities. Transition state of the matched pair (top), transition states of the mismatched pair (bottom).

Fig. 3.31. Sharpless kinetic resolution of chiral racemic secondary allyl alcohols.

The first parameter to optimize was the nature of the base used. While there were precedents in the literature for the change in the starting chiral alcohol, to the best of our knowledge there was no report on the effect of the base on the stereocourse of the formation of sulfmate esters. In the literature on the asymmetric synthesis of sulfinate esters, statements such as asymmetric synthesis of sulfinate esters is achieved by the reaction of sulfmyl chloride with a chiral secondary alcohol in the... 

Investigation on the enantiomeric composition of chiral secondary alcohols will, however, require either derivatization with an optically active reagent and separation on a conventional column or enantioselective GC using an optically active stationary phase. Today, the latter approach most frequently involves modified cyclodextrins.135 Enantioselective HPLC has also been successfully applied to separate enantiomers.136,137 Several reagents have been used in the transformation of chiral alcohols into diastereomers. Among these, acetyllactic acid138 or chlorofluoroacetic acid139 furnish volatile derivatives of pheromone... 

Kinetic Resolution by Transesterification. Asymmetric transformation involving acylation of chiral alcohols is by far the most common example of kinetic resolution by lipase-catalyzed transesterification, most commonly with irreversible vinyl esters. This field is now becoming the most widely applied technique involving lipases. Recent reports of the numerous secondary alcohol substrates include various monocyclic (eq 6) andacyclic compounds, cyanohydrins, sulfones, and glycals, to name a few. 

Surprisingly, the introduction of the pyridine ring not only influences the velocity of the enzymatic transformations, but also induces promising stereochemical effects (Table 1). For instance, at 40% conversion (R)-phenylethanol is obtained from the pyridyl acetate 25 with 73 % ee, whereas the value for the corresponding phenylacetate is only 28%. Also, the secondary alcohol liberated from the ester 26 displays 98% ee at 40% conversion, whereas the respective phenylacetate leads to 1-phenylpropanol with 94% ee but at a conversion rate of 12% only [19,20]. These results demonstrate that the stereoselecting properties of penicillin acylase may be enhanced by appropriate engineering of the substrate. This is of particular interest since this enzyme has already been used for the kinetic resolution of various chiral alcohols [21-24], e.g. furyl alkyl carbinols [24], which are valuable precursors for the de novo synthesis, with moderate to high ee values, of carbohydrates. 

Many microorganisms possessing alcohol dehydrogenases that are capable of reducing ketones and diketones have been demonstrated to produce chiral alcohols. Examples of such enantioselective reductions have been reviewed on many occasions (3-8). The main advantage of a secondary alcohol dehydrogenase for the production of chiral alcohols... 

Treatment of a primary aliphatic amine with nitrous acid or its equivalent produces a diazonium Ion which results in the formation of a variety of products through solvent displacement, elimination and solvolysis with 1,2-shift and concurrent elimination of nitrogen. The stereochemistry of the deamination-substitution reaction of various secondary amines was investigated as early as 1950, when an Swl-type displacement was suggested. Thus, the process can hardly be utilized for the preparation of alcohols except in cases where additional factors controlling the reaction course exist. Deamination-substitution of a-amino acids can be utilized for the preparation of chiral alcohols. 

Although many useful methods to produce chiral alcohols have recently been developed, there is still need of a convenient procedure to invert the configurations of secondary carbinol centers. In principle, the inversion of configuration could be accomplished by initial activation of the R—OH bond of an alcohol and subsequent 5n2 displacement using oxyanions. The reaction sequences that can be used in the inversion of configuration are summarized in Scheme 42. 

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