Amination of Chiral Imide Enolates

Nevertheless, despite this advantage a direct comparison of both methods by the same author found that for e.p. (5)-[l- C]phenylalanine (165) the DBAC variant gave a higher overall yield °. This outcome may have to do with the need for careful control of reaction conditions in the a-functionalization step in order to achieve optimal yields (i.e., use of reagents precooled to -78 °C and very short reaction times). 

Though the utility of the diastereoselective a-azide formation has been confirmed by several examples in synthetic organic chemistry, only one additional application has been reported in radiosynthesis, namely in the preparation of (2S,55)-[5- H]omithine (1701. Reaction of the potassium enolate of (5, 5)-3-(5-azido[5- H]pentanoyl)-4-benzyl-l,3-oxazolidin-2-one (168) with trisyl azide proceeded in 45% yield. Subsequent LiOH-promoted hydrolytic removal of the auxiliary and hydrogenolytic cleavage of the two azido functions provided (2S,5S)-[5- H]omithine in 28% overall yield.  

Reaction conditions la. KHMDS, THF -78 °C, 30 min, then trisyi azide, THF  

The need for additional labeling positions may be illustrated by (5)-[4- C]SDZ 1SQ844 11791. whose label was to be located at the benzylic position for metabolic reasons. The synthesis was accomplished starting from 3,4-dimethoxybenz[ C]aldehyde. Reaction with unlabeled PABS followed by catalytic hydrogenation of the resultant 

A-Boc-protected derivatives of aminoalcohols such as 180 are useful for further 

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Preparation of Compounds Labeled with Tritium and Carbon-14 11.3.4 a-Amination of Chiral Imide Enolates... 

Figure 11.54 N-Electrophiles for amination of chiral imide enolates...

The electrophilic introduction of azide with chiral imide enolates has also been used to prepare a-amino acids with high diastereoselection (Scheme 9). The reaction can be performed with either the enolate directly [16-19] or through a halo intermediate [20]. The resultant azide can be reduced to an amine [21]. 

The synthesis of e.p. a-[ " C ]amino acids through diastereoselective homologation of protected acyclic or cyclic homochiral glycine building blocks (Figure 11.62) by alkylation of their enolates is a valuable alternative to the electrophilic a-amination of chiral a-unsubstimted imide enolates ". ... 

Imidate esters can also be generated by reaction of imidoyl chlorides and allylic alcohols. The lithium anions of these imidates, prepared using lithium diethylamide, rearrange at around 0°C. When a chiral amine is used, this reaction can give rise to enantioselective formation of 7, 8-unsaturated amides. Good results were obtained with a chiral binaphthylamine.265 The methoxy substituent is believed to play a role as a Li+ ligand in the reactive enolate. 

The enantioselective amination of iV-acyl oxazolidinones has been studied as part of a general approach to the synthesis of arylglycines. In this case, the enolization is initiated by a chiral magnesium bis(sulfonamide) complex. The oxazolidinone imide enolates are generated using catalytic conditions (10 mol% of magnesium complex) and treated in situ with BocN=NBoc to provide the corresponding hydrazide. 20 mol% of iV-methyl-p-toluensulfonamide are added to accelerate the reaction (equation 117). 

An alternate approach comprises replacing the pendant sugar by either a carbo-cyclic or a heterocyclic ring. The enantioselective synthesis starts by formation of the imide (45-3) by reaction of the aion from the chiral auxiliary (45-2), derived from S-phenylalaninol and the pentene ester (45-1). Treatment of the product with triethyl amine and the trifalate from dibutylboronic acid leads to the transient enol borate (45-4). Aldol addition of that enol to acrolein proceeds stereospecifically to the alcohol (45-5) due to the transfer of chirality from the chiral auxiliary. 

Stereoselective a-halogenation of enolates is an important approach for the generation of synthetically versatile, chiral building blocks. By use of an auxiliary approach, the acylated oxazolidinone derivatives developed by Evans have been showcased in diastereoselective enolate brominations (Scheme 3.33) [125]. Enolization of 226 (BujBOTf, amine base) and exposure of the boron enolate to NBS affords 228 in 95 5 dr. A key application of the bromo imides is their facile conversion into azides upon treatment with tetramethylguanidinium azide (229). The resulting azides such as 230 (dr=95 5) can readily be elaborated into chiral a-amino acids (see also Chapter 10). 

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. 

Titanium enolates have also been obtained by direct deprotonation from ketones and imides upon treatment of titanium tetrachloride in the presence of tertiary amines, preferably, Hiinig s base. As they have been found to be efficient in syn-selective aldol additions [120], their configuration has been assumed to be cis, but they were rarely characterized by NMR spectroscopy. For the titanium enolate derived from Evans-type auxiliaries, the relative ratio of base to titanium tetrachloride was found to have a distinct impact on the selectivity in the addition to aldehydes. This effect has been rationalized by postulating an equilibrium between the tetrachlorotitanate 106/titanium tetrachloride and the titanium enolate 107/pentachlorotitanate, as supported by NMR studies (Scheme 2.30) [121]. Several chiral ketones have been converted into the corresponding cis-enolates by treatment with TiClgOiPr in the presence of Hiinig s base [122]. Titanium tetrachloride and trialkylamines also lead to aldehyde enolates and enable directed aldol additions between aldehydes. This is remarkable in view of the fact that preformed enolates of aldehydes are not readily accessible [123]. 

One of the most attractive options for asymmetric aldol reactions available to the synthetic chemist is to use enolates of carboxylic acid derivatives (inter alia ester, amide, or imide) with an appended chiral auxiliary (alcohol, amine, urethane). An early example of this approach dates back to 1938, when McKenzie reported that benzaldehyde undergoes addition by (-)-menthyl malonate (42) to give propanoic acid derivative 43 in 21 % ee (Equation 4) [43]. The modest selectivity was attributed to the conformational flexibility of ester enolates (cf. 44). 

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