Hydroxylated chiral amines

A number of ketones, pharmaceutical compounds, alcohols and hydroxy acids have also been resolved on this phase [724,765-767]. A chiral polysiloxane phase with tartramide substituents has been used for the separation of enantiomers capable of hydrogen bonding interactions with the stationary phase, such as enantiomers containing carboxylic, hydroxyl and amine functional groups [768]. 

Scheme 12.8. Enantioselective Hydroxylation Using Other Chiral Amines...

While reaction of the acetate 40 as well as the acetyl- and phthalimide derivatives of chiral amine (41b and 41c) proceeded with erythro diastereoselectivity (in accordance with the classical cis effect, minimization of 1,3-allyhc strain) (Table 6, entries 8, 10, 11), for the allylic alcohols 39, primary allyhc amine 41a, silyl enol ethers 42 and enol ether 43 threo selectivity was observed (Table 6, entries 1-7, 9, 12-14) (see also Scheme 24). For allyhc alcohols with an alkyl group R cis to the substituent carrying the hydroxyl group, diastereoselectivity was high (Table 6, entries 1-7) in contrast, stereoselection was low for allylic alcohols which lack such an R cis) substituent (substrates 39h and 39i, see Figure 4). 

Some enantiomerically pure substituted 2-oxazolidinones are excellent as chiral auxiliaries. From the pioneering studies 2 conducted in the early 1980 s of the uses of such auxiliaries has emerged what is perhaps the most widely used method today for the preparation of enantiomerically highly enriched a-alkylalkanoic acids, alcohols and aldehydes, that is, the alkylation of enolates from chiral 3-acylated 2-oxazolidinones followed by auxiliary removal2 59. The early work has been reviewed60-62. These enantiomerically pure cyclic imide auxiliaries have been used not only for alkylations but also in a plethora of a-functionalization reactions, such as diastereoselective aldol, a-hydroxylation, a-amination and Diels-Alder reactions and these are discussed elsewhere in this volume. 

Optically active ds.vic-diofa.1 It is known that pyridine catalyzes the hydroxyl-ation of alkenes with Os04 and that the osmate ester intermediates form an isolable complex with pyridine (1, 760-761). Hentges and Sharpless reasoned that a similar chiral amine could induce chirality in the diol. And indeed addition of 1 equivalent of 1 or of the C8-diastereoisomer, dihydroquinidine acetate (2), does result in vic-diols in fair to high enantiomeric excess, particularly in reactions performed in toluene at —78°. Opposite stereoselectivities are exhibited by 1 and 2. Optical yields range from 25 to 85%. Use of an amine in which the chiral center is two carbon atoms removed from the coordination site lowers the optical yield to 3 18%. 

Asymmetric Michael addition. Michael addition of nitromethane to chalcone (equation I) in the presence of a chiral amine (quinine, N-methylephedrine) proceeds in methanol (but not in aprotic solvents) in 60-807) yield, but the optical yield at best is 17>. However, if these amines are converted into aminium fluorides, the addition takes place in aprotic solvents (CaHsCHg, CH3CN) in 50-100% yield of more interest, asymmetric inductions of 207, can be obtained. (- )-BenzyIquininium fluoride (1) is particularly effective. The hydroxyl group in these salts is believed to play an important role in the stereochemical outcome of the reaction. Moreover, the fluoride ion is important as a strong base. 

In general, the level of asymmetric induction achieved with imines derived from achiral aldehydes and chiral amines is lower than that observed when a chiral aldehyde or chiral ketene is used. Nevertheless, threonine-derived imines 52 give the cis-P-lactams 53 with diastereoselectivity which increases as the size of the protecting group on the hydroxyl group increases <00SC3685>. 

A significant advance in the resolution of asymmetric alcohols has been the formation of carbamates from the reaction with a chiral isocyanate. Isocyanates are highly reactive and are widely used for the derivatization of hydroxyl and amine functional groups. Alcohols react relatively slowly and require heating for several hours, whereas phenols react rapidly, even at room temperature. Reagents used have included (R(-P)/S(—) phenylethyl isocyanate (15) and R(-p)/S( —)- -( -naphthyl)ethyl isocyanate (16) the diastereomeric carbamates are stable and no evidence for racemization has been recorded. The individual enantiomers can be recovered by refluxing the dias-tereomeric carbamates... 

An extension of a method developed for the preparation of butyl radicals from t-butyIhydrazine and lead dioxide, allowed synthesis of hindered chiral amines via generation of secondary radicals from bornylhydrazine and menthyIhydrazine. The radicals were trapped with nitroso-tert-octane and the resultant hydroxyl-amine mixtures reduced to give readily separable mixtures of borny1-tert-octyl amines (2),(3) and menthyl-tert-octylamines... 

The addition of allylboronates 1 to the chiral oxime 2 results in the formation of a hydroxyl-amine. This is a general method for the subsequent reductive generation of primary homoallyl-amines, but with poor diastereoselectivity in the case of 3 and 4. A diastereomeric ratio of 90 10 is achieved in the addition reaction, using the chiral allylboronate 59 (double stcrcodifferenti-ation). 

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