Claisen condensation stereochemistry

The reactions catalyzed by extension modules 2,5, and 6 are similar to those of module 1, although the stereochemistries of the Claisen condensation and reduction steps may differ. The reactions in modules 3 and 4, however, are different. Module 3 lacks a KR domain, so no reduction occurs and the tetraketide product contains a ketone carbonyl group (Figure 25.17). Module 4 contains a KR and two additional enzyme domains, so it catalyzes a ketone reduction plus two additional reactions. Following the reduction by KR4 of the pentaketide, a dehydratase (DH) dehydrates the pentaketide alcohol to an a, 8-unsaturated thioester and the double bond is then reduced by an enoyl reductase (ER) domain (Figure 25.20). 

Davis and coworkers have exploited the reactions of chiral JV-sulfinyl-amines in the synthesis of numerous alkaloids. Their route to (—)-epimyr-tine (1098) began with the diastereoselective addition of the enolate anion of methyl acetate to the (Ss)-(4-)-sulfmimine (+)-1128, from which the (Ss,S)-p-amino ester derivative (- -)-1129 was obtained in better than 97% de (Scheme 144). After Claisen condensation of 1129 with ierf-butyl acetate, the sulfmyl group was removed from the resulting P-keto ester (4-)-1130 by treatment with acid, the desuhinylated product then undergoing Mannich cyclization with acetaldehyde. The relative stereochemistry of the sole product, 2,6-a5-disubstituted piperidine (4-)-1131, was corroborated by nOe experiments, which indicated that no epimerization at the stereogenic centers had occurred. After hydrolysis and decarboxylation of... 

In this second synthesis of the problematic steroid trans ring junction, the idea is to make the five-membered ring by a Claisen ester condensation and to direct the stereochemistry by tethering the cis groups with a sulfur atom. We can represent this easily in disconnection terms (Chapter 31). The cis-carbons to be joined through sulfur are shown in black. 

The Claisen ester condensation involves the only possible enolate attacking the only possible electrophilic carbonyl group. The stereochemistry of the ring junction cannot be changed by the reaction, and the two ester groups that started tram must end up trans in the product. 

The next stage is an intramolecular Claisen ester condensation. We can easily discover which enolate reacts with which ester by drawing the starting material in the shape of the product. The alternatives are three- or sbt-membered rings five-membered rings are more stable than three- and more rapidly formed than six-membered. Under the reaction conditions there is no stereochemistry as the product exists as a stable conjugated enolate ion (p. 724). 

In many reactions there is an equilibrium between reactants and products so that only the more stable of the two alkenes is produced. In the Claisen ester condensation of cyclohexanone 8 with ethyl formate, the true product under the conditions of the reaction is the stable enolate 9 and this is reversibly protonated on workup to give the more stable H-bonded enol of the ketoaldehyde Z-10. In the aldol reaction between the same ketone and benzaldehyde, the initial product 7 gives the enolate 6 and dehydration is reversible only the more sterically favourable E isomer of 5 is formed. Note that it is irrelevant that the aldol 7 is a mixture of diastereoisomers all stereochemistry is lost in the formation of the enolate 6. In later parts of this chapter a more specific relationship between 3D and 2D stereochemistry will be established. 

V. Enzyme-Catalyzed Aldol- and Claisen-Type Condensations /3-Keto Acid Decarboxylases Stereochemistry versus Stability of Reaction Intermediates... 

Scheme 7.4 presents some representative examples of Claisen-Schmidt reactions. Entries 1 and 2 are typical base-catalyzed condensations at methyl groups. Entry 3 illustrates the use of a cyclic ketone, and reaction occurs at the methylene group, where dehydration is possible. The stereochemistry presumably places the furan ring trans to the carbonyl group for maximum conjugation. Entry 4 shows the use of phthalaldehyde to effect a cyclization. Entry 5 illustrates the preference for condensation at the more-substituted position under acidic conditions. 

A partial synthesis of villalstonine (322) has been achieved by Cook, following the biomimetic method of LeQuesne (223), by condensation of synthetic (-i-)-macroline (338), or the more stable macroline equivalent (341), with natural pleiocarpamine (342) in ().2N HCl, to furnish villalstonine (Scheme 22). The (+)-macroline was prepared starting from the optically active tetracyclic ketone 343, prepared from D-(-i-)-tryptophan by an en-antiospecific Pictet Spengler reaction and stereocontrolled Dieckmann cyclization. The synthesis (Scheme 23) features the use of a stereoselective Claisen rearrangement, followed by stereospecific hydroboration-oxidation of the exocyclic methylene function at C(16), to install the required C(15) and C(16) stereochemistry (225-227). 

In 1972, Ireland and Mueller reported the transformation that has come to be known as the Ireland-Claisen rearrangement (Scheme 4.2) [1]. Use of a lithium dialkylamide base allowed for efficient low temperature enolization of the allyUc ester. They found that sUylation of the ester enolate suppressed side reactions such as decomposition via the ketene pathway and Claisen-type condensations. Although this first reported Ireland-Claisen rearrangement was presumably dia-stereoselective vide infra, Section 4.6.1), the stereochemistry of the alkyl groups was not an issue in its application to the synthesis of dihydrojasmone. 

In the synthesis in Scheme 13.34, the first configuration that is established after construction of the decalin system is the one at C-8 in step A. An enolate alkylation is carried out with methallyl iodide. The observed, and desired, stereochemistry is governed by the C-10 methyl group, which blocks attack from the top side of the molecule. In step B, the five-membered ring is formed by intramolecular aldol condensation. The reduction of the enone (step C) establishes the configuration at C-13, and this chirality is subsequently transferred to C-9 by the intramolecular Claisen rearrangement in step D. 

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