Prostaglandin synthesis aldol reaction

Organometallic reagents are well known for 1,4-additions and can hence be utilized to catalyze domino Michael/aldol reactions. Based on a methodology published by Noyori et al. [24], the group of Feringa estabhshed a catalytic enantios-elective protocol for the synthesis of (—)-prostaglandin Ej methyl ester [25]. There,... 

I.4.3. Synthesis of Prostaglandin ll-deoxy-PGFj via Tandem Michael-Aldol Reaction (Scheme 9.14f ... 

SCHEME 9.14. The synthesis of prostaglandin 11-deoxy-PGFiaVW tandem Michael-aldol reaction. 

When the Claisen ester condensation is intramolecular, it goes by the name of the Dieckmann condensation. As with the intramolecular aldol reactions, only processes that give rise to five- or six-membered rings are favorable (Figure 17.33). This process has been used in the total synthesis of prostaglandin A2 (Figure 17.34). 

Shibasaki also disclosed an application that incorporates an asymmetric tandem Michael addition-aldol reaction sequence with this family of bimetallic catalysts [117], as shown for the synthesis of the prostaglandin 11-deoxy-PGF (132, Scheme 12.16) [119]. In this route, the first two stereo-genic centers in the cyclopentane ring are installed in the course of an asymmetric Michael addition of malonate 128, followed by trapping of the resulting enolate 129 with aldehyde 130. The sequence provided the trans-cyclo-pentanone 131 in 92% ee. The stereoinduction at Cy was observed to range from dr 6 1 to dr 17 1, although this was inconsequential, as the secondary alcohol at C7 was later excised. 

According to these heuristic principles, a possible synthesis of prostaglandins that proceeds via an aldol condensation in the last step, would be in principle valid for synthesis of prostanoids of the A and the B series (26a or 26b). but not for those of the E series owing to the great unstability of the resulting aldol (P-hydroxyketone or 1,3-C system) under the reaction conditions [20] (Scheme 4.7). 

The chiral oxazaborolidines introduced in Section 2.1.3.5 as enantioselective aldol addition catalysts have also been found to be useful in Diels-Alder reactions. The tryptophan-derived catalyst A, for example, can achieve 99% enantioselectivity in the Diels-Alder reaction between 5-benzyloxymethyl-l,3-cyclopentadiene and 2-bromopro-penal. The adduct is an important intermediate in the synthesis of prostaglandins.64... 

The most impressive result of the catalytic Michael-aldol cascade is the kinetic resolution of the racemic cyclopentenone 458 shown in Sch. 64. The reaction is performed with 10 mol % (S)-ALB to give the tandem Michael-aldol adduct 459 in 97 % ee and 75 % yield based on malonate 390f. Asymmetric induction in 459 was measured after dehydration of the hydroxyl group, as was done for 451. Clearly, this demonstrates the viability of this new asymmetric strategy for the synthesis of a variety of fully functionalized prostaglandins. 

Moreover, y-diketones are easily transformed into cyclopenteno-nes by base-catalyzed, intramolecular aldolization and subsequent dehydration. The reaction sequences represented by equations (20-24) indicate the utility of the method for the synthesis of dihydrojasmones and jasmone (fragrance), a prostaglandin intermediate, an acoranic sesquiterpene precursor, a-cuprarenone and 3-vetivone [66]. 

Michael addition of the reagent to enoates and enones occurs at low temperature (—50 to —78 °C) in the presence of catalytic amounts of various Lewis acids. A catalytic amount of triph-enylmethyl perchlorate (5 mol %) effectively catalyzes the tandem Michael reaction of ethyl acetate-derived silyl ketene acetal to a, -unsaturated ketones and the sequential aldol addition to aldehydes with high stereoselectivity.HgL mediates the Michael addition to chiral enones, followed by Lewis acid-mediated addition to aldehydes. The Michael-aldol protocol has been used for the stereoselective synthesis of key intermediates on the way to prostaglandins, compactin, and ML-236A (eq 19). ... 

Even more extensive optimization of reaction conditions was performed in the group of Aggarwal [10]. With the aim to synthesize prostaglandins, their primary goal was to obtain the intermediate bicyclic lactol 30, which allows stereoselective conjugate addition of organocuprates and derivatization of the cyclopentane scaffold. For the synthesis of the bicyclic intermediate, the researchers envisioned an asymmetric aldol dimerization of succinaldehyde (23) by means of a proline-based... 

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