Enantioselective formation mechanism

In 1997, Whitby reported that treatment of 2,5-dihydrofuran with Et3Al in the presence of 5 mol% 31 leads to the enantioselective formation of 39 (Scheme 6.13), rather than the product obtained from catalytic carbomagnesations (40) [34]. This outcome can be rationalized on the basis of Dzhemilev s pioneering report that with Et3Al, in contrast to the mechanism that ensues with EtMgCl (see Scheme 6.2), the intermediate alumina-cyclopentane (i) is converted to the corresponding aluminaoxacyclopentane ii. To ensure the predominant formation of 39, catalytic alkylations must be carried out in absence of solvent. 

Preliminary results on the enantioselective formation of sulfur and nitrogen mediumsized heterocycles by base-induced ring opening of hetero-oxabicyclic [3.2.1] and [3.3.1] systems have been reported.91 The reaction involves a deprotonation-C—O bond elimination sequence. The kinetics and mechanism of gas-phase unimolecular elimination reactions of some substituted aminoazoles have been studied as an aid to heterocycle synthesis.92... 

Chiral ligands can promote the enantioselective formation of chiral organolithiums by asymmetric deprotonation. This mechanism was discussed in section 5.4. 

This asymmetric version of Levy s disconnection exploits diaryl prolinol 141 as a catalyst to induce the enantioselective formation of tetra-hydro(iminoethano)carbazole 142 from vinylindole 139 and trans-formyla-crylate 140. The sequence proceeds via a similar mechanism as that seen in Scheme 9. 

A chiral selenophosphoramide catalyst was employed for the intramolecular cyclization of an alkenyl sulfonamide to achieve the enantioselective formation of N-heterocycles including an azepane derivative via a mechanism proposed to include formation of a three-membered sulfur-containing ring (14JA8915). A [4 + 3]-cycloaddition reaction of methyl coumalate 12 with an azomethine ylide, formed from imine esters 13 yielded functionalized azepine derivatives 14 (14OL4508). 

Imamoto, T. Yashio, K. Crepy K. V. L. Katagiri, K. Takahashi, H. Kouchi, M. Gridnev ID., P-chiral tetraphosphine dirhodium complex as a catalyst for as5mi-metric hydrogenation Synthesis, structure, enantioselectivity, and mechanism, stereoselective formation of a dirhodium tetrahydride complex and its reaction with methyl (Z)-a-acetamidocinnamate. Organometallics 2006,25,908-914. 

The mechanism of the rearrangement of the aUylesters I, promoted by the catalyst 9, is shown in Scheme 6.6. /Z-Diastereoselectivity of this process is determined by the topology of the intermediate boron enolate II in its preferred geometry. The enantioselective formation of (2S,35)-III is governed by the absolute (S,S)-configuratiOTi of the Wr-aryl-sulphonamide unit in the boron reagent 9A. 

The dependence of chiral recognition on the formation of the diastereomeric complex imposes constraints on the proximity of the metal binding sites, usually either an hydroxy or an amine a to a carboxyHc acid, in the analyte. Principal advantages of this technique include the abiHty to assign configuration in the absence of standards, enantioresolve non aromatic analytes, use aqueous mobile phases, acquire a stationary phase with the opposite enantioselectivity, and predict the likelihood of successful chiral resolution for a given analyte based on a weU-understood chiral recognition mechanism. 

Absorption, metaboHsm, and biological activities of organic compounds are influenced by molecular interactions with asymmetric biomolecules. These interactions, which involve hydrophobic, electrostatic, inductive, dipole—dipole, hydrogen bonding, van der Waals forces, steric hindrance, and inclusion complex formation give rise to enantioselective differentiation (1,2). Within a series of similar stmctures, substantial differences in biological effects, molecular mechanism of action, distribution, or metaboHc events may be observed. Eor example, (R)-carvone [6485-40-1] (1) has the odor of spearrnint whereas (5)-carvone [2244-16-8] (2) has the odor of caraway (3,4). 

Chiral salen chromium and cobalt complexes have been shown by Jacobsen et al. to catalyze an enantioselective cycloaddition reaction of carbonyl compounds with dienes [22]. The cycloaddition reaction of different aldehydes 1 containing aromatic, aliphatic, and conjugated substituents with Danishefsky s diene 2a catalyzed by the chiral salen-chromium(III) complexes 14a,b proceeds in up to 98% yield and with moderate to high ee (Scheme 4.14). It was found that the presence of oven-dried powdered 4 A molecular sieves led to increased yield and enantioselectivity. The lowest ee (62% ee, catalyst 14b) was obtained for hexanal and the highest (93% ee, catalyst 14a) was obtained for cyclohexyl aldehyde. The mechanism of the cycloaddition reaction was investigated in terms of a traditional cycloaddition, or formation of the cycloaddition product via a Mukaiyama aldol-reaction path. In the presence of the chiral salen-chromium(III) catalyst system NMR spectroscopy of the crude reaction mixture of the reaction of benzaldehyde with Danishefsky s diene revealed the exclusive presence of the cycloaddition-pathway product. The Mukaiyama aldol condensation product was prepared independently and subjected to the conditions of the chiral salen-chromium(III)-catalyzed reactions. No detectable cycloaddition product could be observed. These results point towards a [2-i-4]-cydoaddition mechanism. 

While the mechanism of the ammonium salt catalyzed alkylation is unclear, in polar solvents the enantioselectivity of the addition of dialkylzincs to aldehydes generally drops considerably, probably due to uncatalyzed product formation or complexation of the zinc reagent with the polar solvent rather than with the chiral auxiliary. 

In nature, aminotransferases participate in a number of metabolic pathways [4[. They catalyze the transfer of an amino group originating from an amino acid donor to a 2-ketoacid acceptor by a simple mechanism. First, an amino group from the donor is transferred to the cofactor pyridoxal phosphate with formation of a 2-keto add and an enzyme-bound pyridoxamine phosphate intermediate. Second, this intermediate transfers the amino group to the 2-keto add acceptor. The readion is reversible, shows ping-pong kinetics, and has been used industrially in the production ofamino acids [69]. It can be driven in one direction by the appropriate choice of conditions (e.g. substrate concentration). Some of the aminotransferases accept simple amines instead of amino acids as amine donors, and highly enantioselective cases have been reported [70]. 

Like many other antibodies, the activity of antibody 14D9 is sufficient for preparative application, yet it remains modest when compared to that of enzymes. The protein is relatively difficult to produce, although a recombinant format as a fusion vdth the NusA protein was found to provide the antibody in soluble form with good activity [20]. It should be mentioned that aldolase catalytic antibodies operating by an enamine mechanism, obtained by the principle of reactive immunization mentioned above [15], represent another example of enantioselective antibodies, which have proven to be preparatively useful in organic synthesis [21]. One such aldolase antibody, antibody 38C2, is commercially available and provides a useful alternative to natural aldolases to prepare a variety of enantiomerically pure aldol products, which are otherwise difficult to prepare, allovdng applications in natural product synthesis [22]. 

The variation of enantioselectivities with temperature and pressure was investigated. The effects of these two factors are very substrate dependent and difficult to generalize even in a single substrate serie. However, it seems that enantioselectivities are shghly better at 25-40 °C than at lower temperatures (0 °C or less). The stereoselectivity can be inverted for specific alkenes (formation of the S or R enantiomer preferentially). For several substrates, the reactions tend to proceed to completion with optimal ee s when performed at lower hydrogen pressure (2 bar) instead of 50 bar (Fig. 13). Pronoimced variation of enantioselectivities with hydrogen concentration in solution may indicate the presence of two (or even more) different mechanisms which happen to give opposite enantiomers for some substrates. 

Bode and co-workers have extended the synthetic ntility of homoenolates to the formation of enantiomerically enriched IV-protected y-butyrolactams 169 from saccharin-derived cyclic sulfonylimines 167. While racemic products have been prepared from a range of P-alkyl and P-aryl substitnted enals and substitnted imi-nes, only a single example of an asymmetric variant has been shown, affording the lactam prodnct 169 with good levels of enantioselectivity and diastereoselectivity (Scheme 12.36) [71], As noted in the racemic series (see Section 12.2.2), two mechanisms have been proposed for this type of transformation, either by addition of a homoenolate to the imine or via an ene-type mechanism. 

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