Chiral auxiliaries, in enantioselective

The syntheses in Schemes 13.45 and 13.46 illustrate the use of oxazolidinone chiral auxiliaries in enantioselective synthesis. Step A in Scheme 13.45 established the configuration at the carbon that becomes C(4) in the product. This is an enolate alkylation in which the steric effect of the oxazolidinone chiral auxiliary directs the approach of the alkylating group. Step C also used the oxazolidinone structure. In this case, the enol borinate is formed and condensed with an aldehyde intermediate. This stereoselective aldol addition established the configuration at C(2) and C(3). The configuration at the final stereocenter at C(6) was established by the hydroboration in Step D. The selectivity for the desired stereoisomer was 85 15. Stereoselectivity in the same sense has been observed for a number of other 2-methylalkenes in which the remainder of the alkene constitutes a relatively bulky group.28 A TS such as 45-A can rationalize this result. 

One example of the use of 2D-NMR experiments in conformational analysis is the study of molecular interactions between cinchonidine and acetic acid [26]. These alkaloids are used as chiral auxiliaries in enantioselective hydrogenations, and the enantiomeric excess is dependent on solvent polarity, acetic acid being a good solvent This suggests that protonation and a preferred conformation play a role in achieving high enantioselectivities. With a combination of COSY-experiments, 3J coupling constants and NOESY experiments, it was shown that one conformer is preferred in acidic solutions. 

C. Rosini, L. Franzini, A. Raffaelli, P. Salvadori, Synthesis and Applications of Binaphthylic ( -Symmetry Derivatives as Chiral Auxiliaries in Enantioselective Reactions, Synthesis 1992, 503-517. 

Most recent research has been focused on the application of polymers as chiral auxiliaries in enantioselective Lewis-acid-catalyzed reactions. Studies of Itsuno and co-workers [44] culminated in the development of a polymer-supported catalyst containing a chiral oxazaborolidinone with oxyethylene crosslinkages which gave the Diels-Alder adduct of cyclopentadiene and methacrolein in 88 % isolated yield with an exotendo ratio of 96 4 and 95 % e. e. for the exo adduct. A variety of polymer-supported chiral Lewis acids was also investigated by Mayoral et al. [45]. Some supported catalysts were more active than their homogeneous analogs, but enantioselectivity was always lower. 

Tungler, A., Mathe, T., Fodor, K., Sheldon, R.A., Gallezot, P. (1996) A new chiral auxiliary in enantioselective hydrogenations (-)-dihydrovinpo-cetine. Hydrogenation of ethyl pyruvate II, J. Mol. Catal. A. Chem. 108, 145-151. 

Papers covering the use of carbohydrates as chiral auxiliaries in enantioselective syntheses are mentioned in Chapters 6,7, and 10. 

Enantioselective enolate alkylation can be done using chiral auxiliaries. (See Section 2.6 of Part A to review the role of chiral auxiliaries in control of reaction stereochemistry.) The most frequently used are the A-acyloxazolidinones.89 The 4-isopropyl and 4-benzyl derivatives, which can be obtained from valine and phenylalanine, respectively, and the c -4-methyl-5-phenyl derivatives are readily available. Another useful auxiliary is the 4-phenyl derivative.90... 

Chapters 1 and 2 focus on enolates and other carbon nucleophiles in synthesis. Chapter 1 discusses enolate formation and alkylation. Chapter 2 broadens the discussion to other carbon nucleophiles in the context of the generalized aldol reaction, which includes the Wittig, Peterson, and Julia olefination reactions. The chapter and considers the stereochemistry of the aldol reaction in some detail, including the use of chiral auxiliaries and enantioselective catalysts. 

Scheme 3.20. Mn(OAc)3-mediated chiral auxiliary-assisted enantioselective domino radical cyclization in the total synthesis of (+)-triptocallol (3-79).

The literature presents a large number of examples concerning the use of known oxazolidinones as chiral auxiliaries in many kinds of reactions. Rare is the use of A-amino derivatives of oxazolidinones, which were used to synthesise new A-acylhydrazones 207. Radical addition reactions occurred with high diastereoselectivity <00JA8329>. The use of glycolate oxazolidinones 210 proved to be efficient for the enantioselective preparation of a-alkoxy carboxylic acid derivatives . Photochemical reaction of vinyl... 

Chiral amines were always considered important targets for synthetic chemists, and attempts to prepare such compounds enantioselectively date back to quite early times. Selected milestones for the development of enantioselective catalysts for the reduction of C = N functions are listed in Table 34.1. At first, only heterogeneous hydrogenation catalysts such as Pt black, Pd/C or Raney nickel were applied. These were modified with chiral auxiliaries in the hope that some induction - that is, transfer of chirality from the auxiliary to the reactant -might occur. These efforts were undertaken on a purely empirical basis, without any understanding of what might influence the desired selectivity. Only very few substrate types were studied and, not surprisingly, enantioselectivities were... 

Hydride reductions of C = N groups are well known in organic chemistry. It was therefore obvious to try to use chiral auxiliaries in order to render the reducing agent enantioselective [88]. The chiral catalyst is prepared by addition of a chiral diol or amino alcohol, and the active species is formed by reaction of OH or NH groups of the chiral auxiliary with the metal hydride. A major drawback of most hydride reduction methods is the fact that stoichiometric or higher amounts of chiral material are needed and that the hydrolyzed borates and aluminates must be disposed of, which leads to increased costs for the reduction step. 

With 55 as the chiral auxiliary, good enantioselectivity can be obtained in reactions between aldehydes and esters. In the case of phenyl thioacetate, as depicted in Scheme 3-21, an aldol reaction induced by 55a or 55b can also give acceptable stereoselectivity. 

Certain examples are known for asymmetric induction in domino reactions using either chiral substrates or educts with removable chiral auxiliaries. In contrast, only a few enantioselective domino reactions have been developed so far. The first example was described by us using a titanium complex of glucose diacetonide with 88% ee.[101 Quite... 

The chiral A/ -propionyl-2-oxazolidones (32 and 38) are also useful chiral auxiliaries in the enantioselective a-alkylation of carbonyl compounds, and it is interesting to observe that the sense of chirality transfer in the lithium enolate alkylation is opposite to that observed in the aldol condensation with boron enolates. Thus, whereas the lithium enolate of 37 (see Scheme 9.13) reacts with benzyl bromide to give predominantly the (2/ )-isomer 43a (ratio 43a 43b = 99.2 0.8), the dibutylboron enolate reacts with benzaldehyde to give the (3R, 25) aldol 44a (ratio 44a 44b = 99.7 0.3). The resultant (2R) and (25)-3-phenylpropionic acid derivatives obtained from the hydrolysis of the corresponding oxazolidinones indicated the compounds to be optically pure substances. 

The enantioselective addition of organomagnesium compounds to ketones can be most conveniently performed by using a chiral auxiliary in the substrate molecule. Primary aUsyhnagnesium reagents react with aryl and heteroaryl ketones in the presence of magnesium TADDOLate at — 100°C, yielding products with up to 98% ee (equation 143). Chiral a-ketoacetals 214, prepared in two steps from a-substituted cinnamic aldehydes, add organomagnesium species with up to 98% diastereoselectivity (equation 144). 

Chiral sulfoxides have emerged as versatile building blocks and chiral auxiliaries in the asymmetric synthesis of pharmaceutical products. The asymmetric oxidation of prochiral sulfides with chiral metal complexes has become one of the most effective routes to obtain these chiral sulfoxides.We have recently developed a new heterogeneous catalytic system (WO3-30% H2O2) which efficiently catalyzes both the asymmetric oxidation of a variety of thioethers (1) and the kinetic resolution of racemic sulfoxides (3), when used in the presence of cinchona alkaloids such as hydroquinidine 2,5-diphenyl-4,6-pyrimidinediyl diether [(DHQD)2-PYR], Optically active sulfoxides (2) are produced in high yields and with good enantioselectivities (Figure 9.3). ... 

It has been shown that the S-amino alcohol (—)-3-exo-(dimethylamino)isobomeol (DAIB) serves as an excellent chiral auxiliary in the enantioselective addition of Ft2Zn to aldehydes. As a model compound for the anticipated intermediate, the structure of MeZn(DAIB) (142) in the solid state was determined by X-ray crystallography. In the... 

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