Stereoselectivity deprotonation

Stereoselective deprotonation of componnd 581 is possible (Scheme 233), bnt the yields and enantioselectivities obtained are poorer than for the chromium-complexed analogues (see below). With an internal electrophilic quench it was possible to form the axially chiral benzamide 582 in 89% ee using hthium amide 360 . 

Some further examples of stereoselective deprotonation/alkylation reactions of tricarbonyl-chromium complexed (V-methyl tetrahydroisoquinolines have been reported27. Starting with the enantiomerically pure (35)-methyl tetrahydroisoquinoline reaction with hexacarbonyl-chromium led to a mixture of endo- (40%) and exo- (60%) complexes, which were deprotonated with butyllithium and subsequently methylated with iodomethane. In this way methylation occurred firstly at the 4- and secondly at the 1-position. In all cases, the methyl group entered anti to the chromium complexed face. After separation of the alkylated complexes by chromatography and oxidative decomplexation, the enantiomerically pure diastereomers (—)-(l 5,35,47 )-and ( + )-(17 ,35,45)-1,2,3,4-tetrahydro-l,2,3,4-tetramethylisoquinolme were obtained, benzylic amines such as tetrahydroisoquinoline to 2-amino-4,5-dihydrooxazoles. Deprotona... 

A mechanistic study28,31 on deuterated compounds showed that stereoselective deprotonation occurs to give the (S.Sj-configurated lithio compound with a selectivity of about 6 1. This is of no consequence for the overall alkylation process, since its stereochemistry is determined by the reaction of the equlibrated organolithium compounds. This conclusion was drawn from the result, that the same stereochemical outcome is observed in reactions starting with an a 1 1 mixture of (R,S)- and (S,S )-configurated lithio compound as from the case with selectively formed (S,S)-lithio compound only. Hence the (R,S)- and (5,5)-lithio compounds equilibrate rapidly on the timescale of the experiment and the question as to whether the (R,S)- or ( S iSj-lithio compound is the actual reacting species cannot be answered. 

Regio- and stereoselective deprotonation/alkylation reactions of substituted 4,5-dihydroisoxazoles provide another access to these valuable chiral intermediates141518 20. Thus regio- and stereoisomers which are not available from cycloaddition reactions can be prepared. 

It must be noted that this selective synthesis of enethiols from thioketones is restricted to cases for which regio- and stereoselective deprotonation occurs, as was achieved above with the symmetrical thiones (2a)-(2d). 

Schwerdtfeger, J. Kolczewski, S. Weber, B. Frohlich, R. Hoppe, D. Stereoselective deprotonation of chiral and achiral 2-aminoalkyl car-... 

Investigation of site selectivity of the stereoselective deprotonation of cyclohexene oxide has been performed using kinetic resolution of isotopic enantiomers in natural abundance.40... 

Carbamate 282, derived from (V-benzylpiperidine-2-methanol 281, undergoes stereoselective deprotonation when treated with. r-butyllithium and tetramethylethylenediamine to give lithiate 283, which can be trapped with numerous electrophiles to give, after hydrolysis of the carbamate, a single diastereoisomer of /(-hydroxy piperidines 284 (Scheme 67) <1999S1915>. 

Fig. 13.4. Stereoselective deprotonation of a /J-ketoester to trialkylammonium or sodium enolates. The E- and Z-enolates are formed when NEt3 and NaH, respectively, are employed.

Fig. 13.5. Stereoselective deprotonation of a /J-ketoalde-hyde and its enol tautomer to substituted pyridinium or lithium enolates, respectively. Similar to the deprotonation of Figure 13.4, the f-enolate is formed when the amine is used and the Z-enolate is formed when the metal-containing base is employed.

Further evidence in favour of this explanation of the mechanism comes from the cyclisation of racemic, deuterated d-395.172 Deuterated starting materials are useful tools in this area because the outcome of the often competing stereoselective deprotonation and kinetic isotope effect sheds useful light on the mechanism of the lithiation reactions. The general principle is... 

Disubstituted 1,3-oxathianes 316, prepared from benzaldehyde and the corresponding 3-mercaptoalkanol, have been stereoselectively deprotonated at the equatorial position to yield, after reaction with electrophiles, 2,2-disubstituted products. t.S j-Benzoin was obtained in 75% ee in the case of using compound 316 (R = OTBS), after reaction with benzaldehyde and final deprotection of the major product 317 with NCS and silver nitrate (Scheme 83)490. 

The substituted A,A-diisopropyl enol carbamates 563 were prepared by reaction of metallated allylic carbamates with aldehydes839-843. The stereoselective deprotonation of compound 563 can be performed with f-BuLi841 or n-BuLi-TMEDA839 in THF at —70 to —85 °C to give the lithio derivatives 564 (Scheme 153). These intermediates reacted with... 

More recently, along with an increased understanding of the mechanisms for stereoselective deprotonations more rational approaches, e.g. using computational chemistry, have been used. Easily accessible and inexpensive homochiral lithium amides have been designed having broad applicability. Products in high yields and enantiomeric excess have been obtained. These achievements are also reviewed below. 

So far, chiral lithium amides for asymmetric deprotonation have found use only with a few types of substrates. The following sections deal with deprotonation of epoxides to yield chiral allylic alcohols in high enantiomeric excess, deprotonation of ketones, deprotonation of tricarbonylchromium arene complexes and miscellaneous stereoselective deprotonations. These sections are followed by sections in which various chiral lithium amides used in stereoselective deprotonations have been collected and various epoxides that have been stereoselectively deprotonated. The review ends with a summary of useful synthetic methods for chiral lithium amide precursors. 

Computational chemistry has been employed to calculate energy differences between diastereomeric activated complexes in the stereoselective deprotonations of cyclohexene oxide by monomeric, homo- and heterodimeric lithium amides (see Section II.A.2). Computational chemistry has also been used as a tool for design of highly stereoselective amides. Such a design approach has resulted in the homochiral base 20 and its enantiomer. These are readily available from both enantiomers of norephedrine, by inexpensive routes... 

The driving force for the development of catalysts for stereoselective deprotonations is similar to that of other asymmetric catalysts. It is desirable to have access to highly reactive and stereoselective deprotonation catalysts of general applicability. However, the experimental situation for deprotonations differs from that for many other catalyzed... 

The asymmetric synthesis of coordinated (/ H—)-H has been effected by the stereoselective deprotonation and ethylation at —65 °C of the diastereomer [(1 p,/1p),11as]"(+) 80 (equation 13) . The pure diastereomer of the secondary arsine complex was obtained... 

Systematic investigations into the stereoselective deprotonation and silylation of esters show that the stereochemistry of the enolate formed in THF is virtually unchanged by subsequent addition of HMPA or DMPU474. The trapping agent (rcrt-butylchlorodimethylsilane) may be present during the enolization or added afterwards with no change in the stereochemical outcome. 

Remarkably, the enantioselective deprotonation with (-)-3 can be extended to various systems. Thus, substituted indenes like 22 can be stereoselectively deprotonated leading to chiral allyllithiums which after reaction with electrophiles furnish chiral 1,3-disubsti-tuted indenes such as 23 with excellent enan-tioselectivity (Eq. 12). [19]... 

Chiral benzylic amines have been synthesized from an optically pure arene tricarbonyl chromium complex via a stereoselective deprotonation/alkylation step (Scheme 35). 

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