Auxiliary-Based Oxidation of Enolates

The amide 445 (MeO instead of OH) derived from (methoxymethyl)pyrrohdine gives different results in the analogous hydroxylation reactions. Not only lower diastereoselectivity is observed, but the stereochemical outcome is now solvent dependent and opposite in the absence of HMPA and in the presence of high levels of HMPA. The disruption of the chelated lithium enolate by the cosolvent might be the reason for the opposite stereochemical outcome - another showcase for the consequences subtle changes in the enolate structure may have on the configuration of the newly created stereogenic center. The mechanism of the 

To a solution of amide 464 (2.27 g, 8.31 mmol) in THF (85 ml) stirred under argon at —78 was added a solution of NaHMDS (8.31 ml, 1.5 M in THF, 16.6 mmol). The reaction mixture was stirred for 45 min at -78 °C and triethylphosphite (1.53 ml, 9.14 mmol, 1.1 equiv.) was added. Then, molecular oxygen was bubbled through the reaction mixture for 2 h. The reaction mixture was quenched with an aqueous 1N HCl solution (85 ml). The aqueous layer was extracted with diethyl ether (3 ml X 75 mi). The organic layers were combined and dried with MgS04, filtered, and concentrated under reduced pressure. Purification by flash chromatography (cyclohexane/ethyl acetate 80/20 to 60/40) afforded the alcohol 465, (R = Me) (2.15 g, 90%) as a white solid d.r. 97 3 (determined by F NMR of the crude mixture). 

R = Me, CHMej, CMsg, CHsPh, CH2CH=CH2, Ph Ar= 2,4,6-(Me2CH)3CsH2 

More recently, Chen and coworkers used azodicarboxylate 477 as nitrogen electrophile in reactions with camphor-based N-acyl phenylpyrazolidinones 481. A remarkable stereodivergence was observed, depending on the metal in the enolate. When the deprotonation was performed with KHMDS, hydrazides 482 resulted predominantly, whereas the diastereomers 485 were obtained 

They served for the preparation of halohydrins (after reductive cleavage from the auxiliary) and epoxides but were also used as intermediates en route to a-amino acids via azide substitution of the halide, saponification, and hydrogenolysis of the azide. 

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An impressive showpiece of Evans auxiliary-based asymmetric syntheses enolates was delivered in the total synthesis of the marine natural product calyculin A, shown in Scheme 4.56, where the Evans enolate chemistry was utilized to create 10 out of 15 stereogenic centers [126] In detail CIO and C36 by enolate alkylation, C12/C13, C22/23 as well as C34/35 by aldol reactions, C17 by enolate oxidation (cf. Section 4.6), and C30 by a Michael addition (cf Section 4.5). This achievement is not only an acid test of these methods, but it may be considered as a plea for the auxiliary approach in general. 

While more plentiful, alcohol-based chiral auxiliaries have been limited in their ability to direct the diastereoselective hydroxylation for the preparation of tertiary a-hydroxy acids. Among these, the best results in this series were obtained when oxidation of the enolate of chiral ester substrate 24 with (+)-5 yielded (5)-25.ub The use of (-)-S as the hydroxylating agent, provided a reversal in stereoselectivity, providing (i )-25. Interestingly, when substoichiometric amounts (0.5 equiv) of (+)-5 were used, stereoselectivity improves (94% de), a fact attributed to the matching of the enolate geometry to the oxidant. This speculation is credible, as evidenced by the fact that oxidation with 0.50 equivalent of (-)-5 produces (5)-25 in only 37% de in a stereochemically mismatched case. 

In any treatment of auxiliary-based alkylations (as well as aldol additions, enolate oxidations, Mannich and Michael reactions), clearly, the carboximide enolates pioneered by the group of Evans are the center of attention. Developed in the early 1980, JV-acyl derivatives of oxazolidinones 45-47 (Scheme 4.9) became the epitomes of chiral auxiliaries [7,28] with countless applications in natural products and drug syntheses. The enantiomeric oxazolidinones (S)- and (R)-47 derived from the corresponding enantiomer of phenylalanine have the advantage that, when used for various transformations, the corresponding products have a higher tendency to crystallization and were shortly later added [29] to this collection of classics. 

Page et al. (see [298] and references therein) have shown that generally excellent stereocontrol in organic reactions can be obtained by using DITOX (1,3-dithiane-l-oxide) derivatives as chiral auxiliaries. The one-pot stereo-controlled cycloalkanone synthesis given here outlines some aspects of the chemistry worked out for efficient acylation-alkylations steps. Of note are the use of N-acyl imidazoles under mixed base (sodium hexamethyldisilazide/n-butyllithium) conditions to yield the lithium enolates of 2-acyl-l,3-dithiane-l-oxides) and the sequential alkylation-cyclization of the latter (steps (iv) and (v)). 

A variety of methods exists for the synthesis of optically active amino acids, including asymmetric synthesis [85-93] and classic and enzymatic resolutions [94-97], However, most of these methods are not applicable to the preparation of a,a-disubstituted amino acids due to poor stereoselectivity and lower activity at the a-carbon. Attempts to resolve the racemic 2-amino-2-ethylhexanoic acid and its ester through classic resolution failed. Several approaches for the asymmetric synthesis of the amino acid were evaluated, including alkylation of 2-aminobutyric acid using a camphor-based chiral auxiliary and chiral phase-transfer catalyst. A process based on Schollkopf s asymmetric synthesis was developed (Scheme 12) [98]. Formation of piperazinone 24 through dimerization of methyl (5 )-(+)-2-aminobutyrate (25) was followed by enolization and methylation to give (35.6S)-2,5-dimethoxy-3,6-diethyl-3.6-dihydropyrazine (26) (Scheme 12). This dihydropyrazine intermediate is unstable in air and can be oxidized by oxygen to pyrazine 27, which has been isolated as a major impurity. 

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