Stereoselective multistep reactions

In addition to the two asymmetric syntheses above described, two racemic syntheses of tetraponerines based on the 5=6-5 tricyclic skeleton have been published. Thus, Plehiers et al. [199] have reported a short and practical synthesis of ( )-decahydro-5Tf-dipyrrolo[l,2-a r,2/-c]pyrimidine-5-carbonitrile (238), a pivotal intermediate in the synthesis of racemic tetraponerines-1, -2, -5 and -6, in three steps and 24% overall yield from simple and inexpensive starting materials. The key reaction of the synthesis was a one-pot stereoselective multistep process, whereupon two molecules of A pyrroline react with diethylmalonate to afford the tricyclic lactam ester 239, possessing the 5-6-5 skeleton (Scheme 10). Hydrolysis of the carboethoxy group of 239 followed by decarboxylation yielded lactam 240, that was converted into a-aminonitrile 238 identical in all respects with the pivotal intermediate described by Yue et al. [200] in their tetraponerine synthesis. 

Only very few [4+2]-cycloadditions are known that are not stereoselective with regard to the diene or the dienophile (see, e.g., Figure 15.17), or are stereoselective hut not stereospecific (e.g., Figure 15.19). From these stereochemical outcomes, one can then safely conclude that the latter [4+2]-cycloadditions are multistep reactions. 

A recent study provides comments on the mechanism and origin of stereoselectivity in the Lewis acid catalyzed [2+2] cycloaddition reaction between ketenes and aldehydes to give P-lactones. The observations made in this study highlight the broad range of factors which must be pondered in order to understand and control stereoselectivity in a multistep reaction <02AG(E)1572>. 

Another rapidly progressing field is that of multistep reactions which occur in ordered sequences chemo-, regio- and stereo-selectively on a transition metal species. To this end, it is necessary to delay release of the desired product until the whole series of steps has been completed competitive terminations (such as hydride elimination) must be prevented or must only occur at low rates compared to the main sequence. An example, reported by Chiusoli in the late 50s, is offered by the nickel-catalyzed synthesis of methyl 2,5-heptadienoate from 2-butenyl chloride, acetylene, CO and methanol. The reaction is chemo-, regio- and stereo-selective the four molecules react in the order shown in Equation A3.4 (chemoselectivity) the butenyl group attacks the terminal allylic carbon rather than the internal one (regioselectivity) and acetylene insertion leads to a Z double bond (stereoselectivity). 

When multistep reactions take place, stereoselection may or may not occur at the rate-determining step. Therefore, a careful analysis of the reaction mechanism is mandatoiy if the origin of stereoselection is to be understood. 

Spatial and/or coordinative bias can be introduced into a reaction substrate by coupling it to an auxiliary or controller group, which may be achiral or chiral. The use of chiral controller groups is often used to generate enantioselectively the initial stereocenters in a multistep synthetic sequence leading to a stereochemically complex molecule. Some examples of the application of controller groups to achieve stereoselectivity are shown retrosynthetically in Chart 19. 

Synthetic strategies based on multistep radical reactions have steadily grown in popularity with time. The knowledge of radical reactivity has increased to such a level as to aid in making the necessary predictions for performing sequential transformations.Silanes, and in particular (TMSlsSiH, as mediators have contributed substantially in this area, with interesting results in terms of reactivity and stereoselectivity. ... 

The preparation of ketones and ester from (3-dicarbonyl enolates has largely been supplanted by procedures based on selective enolate formation. These procedures permit direct alkylation of ketone and ester enolates and avoid the hydrolysis and decarboxylation of keto ester intermediates. The development of conditions for stoichiometric formation of both kinetically and thermodynamically controlled enolates has permitted the extensive use of enolate alkylation reactions in multistep synthesis of complex molecules. One aspect of the alkylation reaction that is crucial in many cases is the stereoselectivity. The alkylation has a stereoelectronic preference for approach of the electrophile perpendicular to the plane of the enolate, because the tt electrons are involved in bond formation. A major factor in determining the stereoselectivity of ketone enolate alkylations is the difference in steric hindrance on the two faces of the enolate. The electrophile approaches from the less hindered of the two faces and the degree of stereoselectivity depends on the steric differentiation. Numerous examples of such effects have been observed.51 In ketone and ester enolates that are exocyclic to a conformationally biased cyclohexane ring there is a small preference for... 

Cycloaddition reactions, which increase molecular complexity by formation of a cyclic compound and, simultaneously, two C-C or C-X bonds [1], are among the most widely used reactions in organic synthesis. The reactions are also regio- and stereoselective. For these reasons, such processes are usually the key step in the multistep synthesis of natural products. 

Sulfenyl chlorides and most of the other sulfenyl derivatives react with alkenes to give generally anti addition products with a high stereoselectivity. Although the mechanism of these reactions is still under study, it is usually accepted that sulfenyl transfer from the carrier to nucleophilic double bonds is consistent with the multistep mechanism reported in equation 907b. 

The Claisen rearrangement, discovered in 1912, has proven to be a powerful tool for the stereoselective generation of C—C bonds . It is widely employed in complex multistep syntheses (see, for example. References 86-89) and has inspired many variations, including the Carroll (1940), Eschenmoser (1964), Johnson (1970), Ireland (1972) and Reformatsky-Claisen (1973) reactions . 

Another breakthrough came several years later, when the photoadduct 84 of trans stilbene with chiral bornyl methyl fumarate 82 was obtained with a high diastereomeric excess [60], Here again, a model involving an approach of the reagents in parallel planes was proposed to explain the observed stereoselectivity (Scheme 19). In an attempt to increase the observed de, the cycloaddition reaction of dibornyl fumarates was examined, but a far lower selectivity was observed. On this basis, a multistep process was proposed with control of the asymmetric induction by the rate of cyclization of the 1,4-biradical intermediates. The nature of the substituents, however, the complexity of the reaction mixture, and the low chemical yields of the chiral adducts are major limitations for synthetic applications [61],... 

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