Aldol reaction predict stereoselection

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. 

After mercury(II)-assisted hydrolysis of the thioenol ether, aldehyde 3 was obtained. This was then subjected to the critical vinylogous aldol reaction needed to complete the carbon backbone of the natural product. The latter process furnished a 3.5 1 mixture of the y to ot addition products. The stereoselectivity observed in the installation of the C(5)-hydroxyl (natural product numbering) was only 2 1. Fortunately, the predominant isomer was the desired product 2. In retrospect, it can be seen that the level of selectivity attained conformed to the predictions of the Still model.4... 

Bahmanyar S, Houk KN (2001a) The origin of stereoselectivity in proline-catalyzed intramolecular aldol reactions. J Am Chem Soc 123 12911-12912 Bahmanyar S, Houk KN (2001b) Transition states of amine-catalyzed aldol reactions involving enamine intermediates theoretical studies of mechanism, reactivity, and stereoselectivity. J Am Chem Soc 123 11273-11283 Bahmanyar S, HoukKN, Martin HJ, ListB (2003) Quantum mechanical predictions of the stereoselectivities of proline-catalyzed asymmetric intermolec-ular aldol reactions. J Am Chem Soc 125 2475-2479 Barbas CF 3rd, Heine A, Zhong G, Hoffmann T, Gramatikova S, Bjoernstedt R, List B, Anderson J, Stura EA, Wilson I, Lemer RA (1997) Immune versus natural selection antibody aldolases with enzymic rates but broader scope. Science 278 2085-2092... 

The Mukaiyama aldol reaction could be catalyzed by chiral bis(oxazoline) copper(II) complexes resulting in excellent enantioselectivities (Fig. 7) [23]. A wide range of silylketene acetals 46 and 49 were added to (benzyloxy[acetaldehyde 45 and pyruvate ester 48 in a highly stereoselective manner. The authors were also able to propose a model to predict the stereochemical outcome of these reactions. 

Bahmanyar, S. Honk, K. N. Martin, H. J. List, B. Quantum mechanical predictions of the stereoselectivities of proUne-catalyzed asymmetric intermolecular aldol reactions, J. Am. Chem. Soc. 2003,125, 2475-2479. 

Cheong, P. H.-Y Houk, K. N. Origins and predictions of stereoselectivity in intramolecular aldol reactions catalyzed by proline derivatives, Synthesis 2005, 1533-1537. 

Since the stereochemical outcome of the aldol reaction with these enolates is predictable from the above results, selection of either (5)-(29b) or (R)-(29b) for a matched or mismatched pair can easily be made. Thus, in the reaction of chiral aldehyde (24) with (5)-(29b) (matched) the product ratio exceeds 1(X) 1, favoring formation of (33), whereas when reagent (R)-(29b) is used, (34) l omes the predominant product with a respectable stereoselection (mismatched) (Scheme 24). Compared to the ratios observed for the reaction with an achiral enolate (Scheme 22), it is clear that the facial selectivity of the enolates dictates the 3,4-stereochemistry of the aldol reaction and either the 2,3-jy -3,4-an or 2,3-syn-3,4-syn units can be constructed in a predictable manner. 

Stereoselective aldol reactions are limited by their ability to obtain stereoisomerically pure ( )- or (Z)-enolates separately, and it has been suggested that equilibration may be occurring to erode the enolate selectivities. However, it would appear that the measured rate of enolate equilibration appears to be too low to be much of an influence.It was suggested by Ireland in 1976 that LDA-mediated enolizations may proceed by cycUc transition states via disolvated LDA monomers. Tbis mecbanism bas since been widely cited for its predictive power. Ireland proposed that the deprotonation process may be proceeding via one of two proposed transition states, where proton transfer is synchronous with metal ion transfer. Non-bonded interactions between amide alkyl groups and the enolate alkyl group cause a preference for E-enolate formation (Scheme 1, refs 124,136). 

The Exterior Frontier Orbital Extension model, described earlier under Regio-, Enantio-, and Distereo-selective Aldol Reactions, can also be applied to predict stereoselectivity of carbonyl reduction." ... 

Interestingly, the stereoselectivity of reactions of cyclohexanone vith iso-butyraldehyde and benzaldehyde vere first predicted by using density functional theory calculations on models based on Houk s calculated transition state of the Hajos-Parrish-Eder-Sauer-Wiechert reaction [125]. The transition states of inter- and intramolecular aldol reactions are almost super-imposable and readily explain the observed enantiofacial selectivity. Relative transition state energies vere then used to predict the diastereo- and enan-tioselectivity of the proline-catalyzed reactions of cyclohexanone vith iso-butyraldehyde and benzaldehyde. The predictions are compared vith the experimental results in Scheme 4.30. The good agreement clearly validates the theoretical studies, and provides support for the proposed mechanism. Additional density functional theory calculation also support a similar mechanism [126, 127]. 

In summary, 1,3-diols are prominent motives in polyketides, and they can be constmcted by various advanced methods. A practical access to 1,3-diols starts often with an aldol reaction. This aldol reaction can already construct a 1,3-diol if one hydroxyl group is already present in the starting material. Alternatively, syn- or anti-selective reductions of carbonyl groups offer an easy to predict stereoselective way to 1,3-diols. As we have seen in particular in the synthesis of roxaticin, direct reduction of diketones or p-keto esters proves an efficient entry into 1,3-diol segments. 

The stereoselectivity of the addition of pinacolone enolsilane 1 to P-alkoxy aldehydes bearing two stereocenters depends on the ability of the metal to form intermediate chelates. Those metals that monocoordinate the carbonyl group form Fel-kin products and the stereochemistry of these aldols is predicted by the Felkin-Anh s model. For metals chelating both the carbonyl and alkoxy groups, anti-Felkin products are obtained. In these cases the cyclic-Cram s model has to be used to predict the stereochemical outcome of the reaction. Therefore, non-chelated (Felkin-Ahn) and chelated models (cyclic-Cram) have been successively applied to understand the stereochemistry of the final reaction products. 

Mechanistically, the stereoselective aldol reaction can be divided into several different subclasses. Aldol reactions of metal enolates follow some general mechanistic pathways that facilitate prediction of the relative configuration of the products. The reactions can be described as proceeding via chelated, closed, Zimmerman-Traxler transition states [33]. The positioning of substi-... 

Summary of Facial Stereoselectivity in Aldol and Mukaiyama Reactions. The examples provided in this section show that there are several approaches to controlling the facial selectivity of aldol additions and related reactions. The E- or Z-configuration of the enolate and the open, cyclic, or chelated nature of the TS are the departure points for prediction and analysis of stereoselectivity. The Lewis acid catalyst and the donor strength of potentially chelating ligands affect the structure of the TS. Whereas dialkyl boron enolates and BF3 complexes are tetracoordinate, titanium and tin can be... 

The aldol condensation of benzaldehyde with the thioacetamide carbanion (RCHCSNRV), derived from the desilylation of the silyl-thioether with tetra-/i-buty-lammonium fluoride, is stereoselective at—80°C producing the erythro isomer of the p-hydroxy thioamide preferentially (Scheme 6.18, R = Me, erythro threo 95 5) via a conformationally mobile intermediate. However, when R is bulky, a greater amount of the threo isomer is formed. Predictably, as the reaction temperature is raised, so the stereoselectively decreases. This procedure contrasts with the corresponding condensation catalysed by titanium salts, where the complexed intermediate produces the threo isomer [47, 48],... 

The synthesis in Scheme 13.30 uses stereoselective aldol condensation methodology. Both the lithium enolate and the boron enolate method were employed. The enol derivatives were used in enantiomerically pure form, so the condensations are examples of double stereodifferentiation (Section 2.1.3). The stereoselectivity observed in the reactions is that predicted for a cyclic transition state for the aldol condensations. 

Lithium enolates, in contrast, either give predominantly the product predicted by the Cram-Felkin-Anh model or react more or less non-stereoselectively. Thus, the favored formation of the syn-aldol product in the reaction of 2-phenylpropanal with the lithium enolates of acetone, pina-colone, methyl acetate, or N,N-dimethylacetamide is in accordance with Cram s rule or the Felkin-Anh model (Eq. (35)). However, a rather moderate syyr.anti ratio of 3 1 is typical of this type of reaction [51, 67]. 

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