Asymmetric synthesis, auxiliary-directe

To date, direct asymmetric synthesis of optically active chiral-at-metal complexes, which by definition leads to a mixture of enantiomers in unequal amounts thanks to an external chiral auxiUary, has never been achieved. The most studied strategy is currently indirect asymmetric synthesis, which involves (i) the stereoselective formation of the chiral-at-metal complex thanks to a chiral inductor located either on the ligand or on the counterion and then (ii) removal of this internal chiral auxiliary (Fig. 4). Indeed, when the isomerization of the stereogenic metal center is possible in solution, in-... 

The auxiliary-controlled reaction (Fig. 1-30, 2) is referred to as the second generation of asymmetric synthesis. This approach is similar to the first-generation method in which the asymmetric control is achieved intramolecu-larly by a chiral group in the substrate. The difference is that the directing... 

Among chiral auxiliaries, l,3-oxazolidine-2-thiones (OZTs) have attracted important interest thanks to there various applications in different synthetic transformations. These simple structures, directly related to the well-documented Evans oxazolidinones, have been explored in asymmetric Diels-Alder reactions and asymmetric alkylations (7V-enoyl derivatives), but mainly in condensation of their 7V-acyl derivatives on aldehydes. Those have shown interesting characteristics in anti-selective aldol reactions or combined asymmetric addition. Normally, the use of chiral auxiliaries which can accomplish chirality transfer with a predictable stereochemistry on new generated stereogenic centers, are indispensable in asymmetric synthesis. The use of OZTs as chiral copula has proven efficient and especially useful for a large number of stereoselective reactions. In addition, OZT heterocycles are helpful synthons that can be specifically functionalized. 

The utilization of a-amino acids and their derived 6-araino alcohols in asymmetric synthesis has been extensive. A number of procedures have been reported for the reduction of a variety of amino acid derivatives however, the direct reduction of a-am1no acids with borane has proven to be exceptionally convenient for laboratory-scale reactions. These reductions characteristically proceed in high yield with no perceptible racemization. The resulting p-amino alcohols can, in turn, be transformed into oxazolidinones, which have proven to be versatile chiral auxiliaries. Besides the highly diastereoselective aldol addition reactions, enolates of N-acyl oxazolidinones have been used in conjunction with asymmetric alkylations, halogenations, hydroxylations, acylations, and azide transfer processes, all of which proceed with excellent levels of stereoselectivity. 

Despite growing importance of axially chiral biaryls as chiral auxiliaries in asymmetric synthesis, direct synthetic methods accessing to the enantiomerically enriched biaryls from achiral precursors are still very rare, Application of asymmetric cross-coupling to construction of the chiral biaryls is one of the most exciting strategies to this goal. The reported application... 

Camphor and camphor-derived analogues are used frequently as chiral auxiliaries in asymmetric synthesis (cf Chapter 23). There have been numerous reports in the use of camphor imine as templates to direct enantioselective alkylation for the synthesis of a-amino acids, a-amino phos-phonic acids, a-substituted benzylamines, and a-amino alcohols (e.g., Scheme 5.9).43 47 Enantiomeric excesses of the products range from poor to excellent depending on the type of alkyl halides used. 

A wide variety of substituted y-butyrolactones can be prepared directly from olefins and aliphatic carboxylic acids by treatment with manganic acetate. This procedure is illustrated in the preparation of 7-( -OCTYL)-y-BUTYROLACTONE. Methods for the synthesis of chiral molecules are presently the target of intensive investigation. One such general method developed recently is the employment of certain chiral solvents as auxiliary agents in asymmetric synthesis. The preparation of (S.SM+H, 4-BIS(DIMETHYLAMINO)-2,3-DIMETHOXY-BUTANE FROM TARTARIC ACID DIETHYL ESTER provides a detailed procedure for the production of this useful chiral media an example of its utility in the synthesis of (+)-(/ )-l-PHENYL-l-PEN-TANOL from benzaldehyde and butyllithium is provided. 

It is worthwhile to apply the memory of chirality principle to asymmetric alkylation of a-amino acids because nonproteinogenic a,a-disubstituted-a-amino acids are important class of compounds in the fields of medicinal and biological chemistry.21 Typical methods for their asymmetric synthesis involve chiral auxiliary-based enolate chemistry 22-24 However, the most straightforward synthesis would be direct asymmetric a-alkylation of the parent a-amino acids in the absence of external chiral sources. Asymmetric... 

Aromatic C-H bond activation opens an attractive pathway to achieve cyclizations with tethered alkenes for the synthesis of dihydrobenzofurans <2001JA%92> <20030L1301>. An auxiliary-directed asymmetric alkylation via C-H bond activation to yield a virtually enantiomerically pure 2,3-enantioselective synthesis of (-l-)-lithospermic acid has been reported by Bergman, Ellman, and co-workers (Scheme 97) <2005JA134%>. 

An auxiliary-directed asymmetric Simmons-Smith reaction was used by a Hoff-mann-La Roche group88 for the synthesis of an ethynyl cyclopropane that served as the A-ring precursor to Vitamin D derivatives [Scheme 2.41]. High diastereoselectivity was achieved with the aid of the dioxolane ring prepared from (/ft/f)-(-)-butane-2,3-diol. The acid conditions for hydrolysis of the dioxolane ring were mild enough to leave the cyclopropane ring unperturbed. Dia-stereoselective cyclopropanation of acetals derived from 1,2-di-O-benzyl-L-threi-tol have also been reported 90... 

Chiral auxiliaries are optically active compounds which are used to direct asymmetric synthesis. The chiral auxiliary is temporarily incorporated into an organic synthesis which introduces chirality in otherwise racemic compounds. This temporary stereocentre then forces the asymmetric formation of a second stereocentre. The synthesis is thus diastere-oselective, rather than enantioselective. After the creation of the second stereocentre the original auxiliary can be removed in a third step and recycled. E. J. Corey in 1975, B. M. Trost in 1980 and J. K. Whitesell in 1985 introduced the chiral auxiliaries 8-phenylmenthoT (1.40), chiral mandelic acid (1.41) and frans-2-phenyl-l-cyclohexanoT (1.42), respectively. 

Chiral Amines with C2 Symmetry, trans-2,5-Dimethylpyrrolidine (1) was the first chiral amine possessing C2 symmetry used as a chiral auxiliary in asymmetric synthesis. Since that time a number of related systems have been developed including the title compound (2) and (4). These amines were developed as C2-symmetric analogs to the commercially available prolinol derivative (5). While proline-derived chiral auxiliaries have been widely used in asymmetric synthesis, the C2-symmetric chiral auxiliaries often give enhanced stereoselectivity when compared directly to the prolinol derivatives. Unfortunately the preparation of the C2-symmetric compounds is more tedious and, at the time of writing, none are commercially available. For example, the standard route to chiral pyrrolidines (2) and (3) involves the resolution of tranf-N-benzylpyrrolidine-2,5-dicarboxylic acid, although other preparations have been... 

With regard to asymmetric synthesis, the possibility that a stereogenic center outside the sigmatropic framework can direct the stereochemical outcome of the electrocyclic process has been intensively exploited recentlyOne method for asymmetric induction has been realized with X representing a chiral carboxylic acid derivative. From the various chiral auxiliaries studied, the C2 symmetrical amide (32) seems to be the most effective, giving via its zirconium enolate) essentially 100% diastereoselectivity and erythro selection, thus permitting ready access to optically active a-hydroxycarboxylic acids (equation 40). 

The Zambon process also starts from P-naphthol, and affords S-naproxen directly avoiding resolution and recycling. It is one of the few examples of a non-enzymatic, non-fermentation industrial asymmetric synthesis. Clearly, the early stages of the process produce similar waste streams to the Syntex process, with additionally waste from the Friedel-Crafts step. In principle, however, the aluminium salts can be recycled by work-up involving conversion back to aluminium chloride. The key step in this route is the highly diastereoselective (94 6) bromination of the ketal diester, derived from chirality pool 2R, 3R tartaric acid, which is used as an auxiliary. The subsequent acid catalysed 1,2-aryl shift occurs with complete inversion of configuration at the migration terminus [17]. The tartaric acid auxiliary can be efficiently recycled, but clearly there is a... 

The asymmetric synthesis of cyclopropanes has attracted continual efforts in organic synthesis, due to their relevance in natural products and biologically active compounds. The prevalent methods employed include halomethylmetal mediated processes in the presence of chiral auxiliaries/catalysts (Simmons-Smith-type reactions), transition-metal-catalyzed decomposition of diazoalkanes, Michael-induced ring closures, or asymmetric metalations [8-10,46], However, the asymmetric preparation of unfunctionahzed cyclopropanes remains relatively undisclosed. The enantioselective activation of unactivated C-H bonds via transition-metal catalysis is an area of active research in organic chemistry [47-49]. Recently, a few groups investigated the enantioselective synthesis of cyclopropanes by direct functionalization reactions. 

Directed and Asymmetric Oxidation The traditional method of asymmetric synthesis involves modifying the substrate with a resolved chiral auxiliary and finding a reagent that introduces an asymmetric center in a defined way relative to the auxiliary. The auxiliary is then removed, ideally leaving a single enantiomer of the product. This method requires a mole of auxiliary per mole of product formed. A more sophisticated approach is to mimic Nature s own solution the use of an enantiomerically pure catalyst. In this case the handedness of the product is decided by the handedness of the catalyst, and only a small amount of resolved catalyst produces a large amount of asymmetric product. 

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