Stereo-determining step

Hydrogen atom transfer implies the transfer of hydrogen atoms from the chain carrier, which is the stereo-determining step in enantioselective hydrogen atom transfer reactions. These reactions are often employed as a functional group interconversion step in the synthesis of many natural products wherein an alkyl iodide or alkyl bromide is converted into an alkane, which, in simple terms, is defined as reduction [ 19,20 ]. Most of these reactions can be classified as diastereoselective in that the selectivity arises from the substrate. Enantioselective H-atom transfer reactions can be performed in two distinct ways (1) by H-atom transfer from an achiral reductant to a radical complexed to a chiral source or alternatively (2) by H-atom transfer from a chiral reductant to a radical. 

With regard to the origin of stereoselectivity in these reactions catalyzed by Rh/ (X)-binap, the stereo-determining step is the insertion of an enone to the carbon-rhodium species coordinated with (5)-binap. As shown in Eq. (3.10), for example, 2-cyclohexen-l-one should approach from its Isi face to avoid the steric hindrance of the phenyl groups of the ligand, leading to the 1,4-adduct in (5) configuration, which is consistent with the observed stereochemical outcome ... 

Scheme 5.4 A revised mechanism, which underlines the importance of the proton-transfer, as the rate-determining and stereo-determining steps.

Mlynarski et al. [16] developed ytterbium-catalyzed enantio- and diastereoselective aldol-Tishchenko reactions of symmetrical dialkyl ketones as enol components for the first time. As chiral ytterbium ligand, they employed the amino alcohol 32, which gave rise to aldol-Tishchenko products such as 33 with up to 86% ee (Scheme 8.10). As documented by control experiments and very similar to the above discussed processes, the rate- and stereo-determining step in this reaction was proven to be the Tishchenko reduction with a rapid pre-retro-aldol equilibrium of the initially formed aldol products. This process may be utilized for reactions of alkyl aryl ketones as well, broadening its scope significantly. 

Most asymmetric reactions catalysed by metal complexes proceed via a multistep mechanism. The stereo-determining step must be carefully identified. Sometimes the (R)- and (S)-enantiomers of a racemic substrate react at almost the same... 

The computed mechanism (Scheme 3.26) implied that the direct protonation of the enolate carbon in 24 is a stereo-determining step of the reaction, since it could occur through either of its prochiral faces. 

The mechanism proposed by the authors involved the rapid formation of a transient acyl pyridinium species (ion-pair) followed by a slow transfer of the methoxycarbonyl group to the amine (stereo-determining step) to afford the corresponding enantio-enriched carbamate (Scheme 41.44). 

In the (—)-DAIB-catalyzed reaction of diethylzinc and benzaldehyde, the rate is first-order in the amino alcohol. The initial alkylation rate is influenced by the concentration of diethylzinc and benzaldehyde but soon becomes unaffected by increased concentration. Thus, under the standard catalytic reaction conditions, the reaction shows saturation kinetics the rate is zeroth order with respect to both dialkylzinc reagent and aldehyde substrate. These data support the presence of the equilibrium of A-D, and alkyl transfer occurs intramolecularly from the dinuclear mixed-ligand complex D. This is the stereo-determining and also turnover-limiting step. 

Enantioselectivity is determined in the first irreversible step after the stereo-genic-centre was formed which is not always the rate-determining step. 

The first DFT studies performed on the PK reaction pathway were published in 2001 by Nakamura and co-workers.81 They used ethyne and ethene as substrates and confirmed that the alkene insertion step is the critical stereo- and regiochemical determining step in the mechanism and that it is reversible. They also showed that although the coordination and insertion steps take place on one cobalt atom, the other cobalt atom exerts an electronic influence through the Co Co bond by donating and excepting electron density. 

The extreme flexibility of these scaffolds would definitely allow the preparation of other large, primary libraries using chemistry-friendly synthetic schemes. The epoxide could be touched, as could the N-O function, which could be reductively cleaved and eventually used to obtain two new handles on constrained, stereo-determined novel scaffolds. The potential of such an integrated approach, where all the steps toward a large bead-based library are carefully assessed, is clearly enormous, especially if any library prepared would contain embedded biological information (starting from nam-... 

Woerpel has recently reported a tandem double asymmetric aldol/C=0 reduction sequence that diastereoselectively affords propionate stereo-triads and -pentads commonly found in polyketide-derived natural products (Scheme 8-2) [14], When the lithium enolate of propiophenone is treated with excess aldehyde, the expected aldolates 30/31 are formed however, following warming to ambient temperature a mono-protected diol 34 can be isolated. In a powerful demonstration of the method, treatment of 3-pentanone with 1.3 equiv of LDA and excess benzaldehyde yielded product in corporating five new stereocenters in 81% as an 86 5 5 3 mixture of diastereomers (Eq. (8.8)). A series of elegant experiments have shown that under the condition that the reaction is conducted, the aldol addition reaction is rapidly reversible with an irreversible intramolecular Tischenko reduction serving as the stereochemically determining step (32 34, Scheme 8-2). 

Thus, the enantio-face differentiation of the substrate occurs in an adsorption step, which is followed by a rate determining hydrogenation step. This hypothesis, which is based on stereochemical and kinetic information, is the focus of the "Reaction Process Model" as illustrated in Figure 5. An important implication is that the activated complex of the rate-determining step need not be considered in order to explain or improve the stereo-control of the reaction. 

The role of the catalyst is to encourage both the phosphonate and carbonyl to come together in the crucial stereo-determining P-C bond formation step. 

The mechanism and stereochemistry of hydrophosphonylation of a-ketoesters by dimethylphosphonate [H-P(=0)(0Me)2l has been studied theoretically by the ONIOM method, for catalysis by cinchona-thioureas. Deprotonation of the phosphonate 0 is rate determining. It is followed by C-P bond formation (the stereo-controlhng step) via nucleophilic addition, and then reprotonation (regenerating the catalyst). Multiple hydrogen bonds activate the substrates, facilitate charge transfer and stabihze transition states. 

Enamine catalysis provided the synthetic platform for a second example of asymmetric MCR. In 2001, Barbas and colleagues described a Knoevenagel/Michael reaction sequence between acetone, benzaldehyde (14), and diethyl malonate (15) catalyzed by the chiral secondary amine 16 (Scheme 42.4). Despite the moderate level of enantioselectivity, this reaction was engineered upon rather sophisticated catalytic machinery [21]. The catalyst promoted both individual steps of the MCR, although only the second enamine-catalyzed process was stereo-determining. The... 

Scheme 42.4 Three-component Knoevenagel/Michael reaction both steps are catalyzed by the amine 16 only the second enamine path is stereo-determining.

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