Asymmetric aldol reactions are a powerful method for the construction of carbon–carbon bonds in an enantioselective fashion. Historically this reaction has been performed in a stoichiometric fashion to control the various aspects of chemo-, diastereo-, regio- and enantioselectivity, however, a more atom economical approach would unite high selectivity with the use of only a catalytic amount of a chiral promoter. This critical review documents the development of direct catalytic asymmetric aldol methodologies, including organocatalytic and metal-based strategies. New methods have improved the reactivity, selectivity and substrate scope of the direct aldol reaction and enabled the synthesis of complex molecular targets (357 references).

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The Direct Catalytic Asymmetric Aldol Reaction

This review which is the second in this series summarises the most common synthetic routes as applied to the preparation of many modern pharmaceutical compounds categorised as containing a six-membered heterocyclic ring. The reported examples are based on the top retailing drug molecules combining synthetic information from both scientific journals and the wider patent literature. It is hoped that this compilation, in combination with the previously published review on five-membered rings, will form a comprehensive foundation and reference source for individuals interested in medicinal, synthetic and preparative chemistry.

https://www.beilstein-journals.org/bjoc/content/pdf/1860-5397-9-265.pdf

An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles

Large-Scale Applications of Amide Coupling Reagents for the Synthesis of Pharmaceuticals

Rephrasing Fuson's original formulation, the principle of
vinylogy explains how the influence of a functional group may be relayed to a distant point in the molecule when these two sites are connected to by conjugated unsaturated linkages, such as double and triple bonds or aromatic moieties.
This principle has been applied, over the years, to the majority of polar carbon-carbon bond-forming reactions of various repute, including the venerable Michael addition reaction, where the electrophilic -CdX site (1,2-addition) is “usurped” by a remote conjugated -RCdCR-CdX position (1,4-addition). The aldol addition reaction and the related
Mannich process, both fundamental pillars of organic synthesis, have not escaped this fate, and both of their
vinylogous extensions have emerged as extremely valuable
synthetic methodologies.

The Vinylogous Aldol and Related Addition Reactions: Ten Years of Progress†

Muscarine, imidazole, oxazole, and thiazole alkaloids

In this Communication, we report the direct, catalytic, asymmetric aldol addition of methyl ynones using our dinuclear zinc catalyst. A spontaneous reversal in the sense of enantioinduction was observed for these reactions; formation of the (S)-enantiomer is favored in the early stages (69% ee after 5 min), whereas the (R)-enantiomer is isolated as the major product after prolonged reaction times (97% ee after 22 h). It could be shown that this reversal in enantioselectivity is due to formation of a new catalytic species which incorporates the aldol product.

Direct catalytic asymmetric aldol additions of methyl ynones. Spontaneous reversal in the sense of enantioinduction.

The total synthesis of the biologically active marine natural product leucascandrolide A is reported. A convergent strategy is employed, allowing for the rapid assembly of the macrolide moiety. Key steps of our approach include the diastereoselective addition of a zinc alkynilide to (R)-isopropylidene glyceraldehyde, the enantioselective copper(I) fluoride catalyzed aldol addition of a TMS-dienolate to crotonaldehyde, and the formation of a 2,6-trans-substituted tetrahydropyran by selenium-mediated intramolecular cyclization. Moreover, dramatic solvent effects observed in the macrolactonization reaction suggest that hydrogen-bonding effects play a critical role. An improved route to a key intermediate of our synthesis is documented.

Leucascandrolide a: synthesis and related studies.

/pdf/total-synthesis-of-leucascandrolide-a-ujldplf5lh.pdf

Total synthesis of leucascandrolide A.

Obesity is a major risk factor in the development of conditions such as hypertension, hyperglycemia, dyslipidemia, coronary artery disease, and cancer. Several pieces of evidence across different species, including primates, underscore the implication of the histamine 3 receptor (H(3)R) in the regulation of food intake and body weight and the potential therapeutic effect of H(3)R inverse agonists. A pharmacophore model, based on public information and validated by previous investigations, was used to design several potential scaffolds. Out of these scaffolds, the 5-hydroxyindole-2-carboxylic acid amide appeared to be of great potential as a novel series of H(3)R inverse agonist. Extensive structure-activity relationships revealed the interconnectivity of microsomal clearance and hERG (human ether-a-go-go-related gene) affinity with lipophilicity, artificial membrane permeation, and basicity. This effort led to the identification of compounds reversing the (R)-alpha-methylhistamine-induced water intake increase in Wistar rats and, further, reducing food intake in diet-induced obese Sprague-Dawley rats. Of these, the biochemical, pharmacokinetic, and pharmacodynamic characteristics of (4,4-difluoropiperidin-1-yl)[1-isopropyl-5-(1-isopropylpiperidin-4-yloxy)-1H-indol-2-yl]methanone 36 are detailed.

Alec Fettes

Papers

Direct catalytic asymmetric aldol additions of methyl ynones. Spontaneous reversal in the sense of enantioinduction.

Leucascandrolide a: synthesis and related studies.

Total synthesis of leucascandrolide A.

5-hydroxyindole-2-carboxylic acid amides: novel histamine-3 receptor inverse agonists for the treatment of obesity

An Efficient Process for the Manufacture of Carmegliptin