Enantioselective Synthesis and Pharmacological Evaluation of Aza-CGP37157–Lipoic Acid Hybrids for the Treatment of Alzheimer’s Disease

Hybrids based on an aza-analogue of CGP37157, a mitochondrial Na+/Ca2+ exchanger antagonist, and lipoic acid were obtained in order to combine in a single molecule the antioxidant and NRF2 induction properties of lipoic acid and the neuroprotective activity of CGP37157. The four possible enantiomers of the hybrid structure were synthesized by using as the key step a fully diastereoselective reduction induced by Ellman’s chiral auxiliary. After computational druggability studies that predicted good ADME profiles and blood–brain permeation for all compounds, the DPPH assay showed moderate oxidant scavenger capacity. Following a cytotoxicity evaluation that proved the compounds to be non-neurotoxic at the concentrations tested, they were assayed for NRF2 induction capacity and for anti-inflammatory properties and measured by their ability to inhibit nitrite production in the lipopolysaccharide-stimulated BV2 microglial cell model. Moreover, the compounds were studied for their neuroprotective effect in a model of oxidative stress achieved by treatment of SH-SY5Y neuroblastoma cells with the rotenone–oligomycin combination and also in a model of hyperphosphorylation induced by treatment with okadaic acid. The stereocenter configuration showed a critical influence in NRF2 induction properties, and also in the neuroprotection against oxidative stress experiment, leading to the identification of the compound with S and R configuration as an interesting hit with a good neuroprotective profile against oxidative stress and hyperphosphorylation, together with a relevant anti-neuroinflammatory activity. This interesting multitarget profile will be further characterized in future work.

Reduction of Oximes and Hydrazones: Asymmetric and Diastereoselective Approaches

: The asymmetric reduction of oximes and hydrazones is an attractive and versatile strategy for the synthesis of chiral amines, which are valuable building blocks in organic synthesis. This review summarizes the relevant developments made in the last decade on the enantioselective and diastereoselective reduction of oximes and hydrazones involving metal-catalyzed hydrogenation/hydrogenolysis reactions, hydride donor reactions, and electrochemical reactions.

Synthesis of Optically Active N-(4-Hydroxynon-2-enyl)pyrrolidines: Key Building Blocks in the Total Synthesis of Streptomyces coelicolor Butanolide 5 (SCB-5) and Virginiae Butanolide A (VB-A)

Starting from 5-methylhexanal and (S)-configured N-propargylprolinol ethers, coupling delivered N-(4-hydroxynon-2-ynyl)prolinol derivatives as mixtures of C4 diastereomers. Resolution of the epimers succeeded after introduction of an (R)-mandelic ester derivative and subsequent HPLC separation. Alternatively, suitable oxidation gave the corresponding alkynyl ketone. Midland reagent controlled diastereoselective reduction afforded a defined configured propargyl alcohol with high selectivity. LiAlH4 reduction and Mosher analyses of the allyl alcohols enabled structure elucidation. The suitably protected products are used as key intermediates in enantioselective Streptomyces γ-butyrolactone signaling molecule total syntheses.

Unified Strategy to Prostaglandins: Chemoenzymatic Total Synthesis of Cloprostenol, Bimatoprost, PGF2α, Fluprostenol, and Travoprost Guided by Biocatalytic Retrosynthesis

Development of efficient and stereoselective synthesis of prostaglandins (PGs) is of utmost importance, owing to their valuable medicinal applications and unique chemical structures. We report here a unified synthesis of PGs cloprostenol, bimatoprost, PGF2α, fluprostenol, and travoprost from the readily available dichloro-containing bicyclic ketone 6a guided by biocatalytic retrosynthesis, in 11-12 steps with 2.9-6.5% overall yields. A Baeyer-Villiger monooxygenase (BVMO)-catalyzed stereoselective oxidation of 6a (99% ee), and a ketoreductase (KRED)-catalyzed diastereoselective reduction of enones 12 (87 : 13 to 99 : 1 dr) were utilized in combination for the first time to set the critical stereochemical configurations under mild conditions. Another key transformation was the copper (II)-catalyzed regioselective p-phenylbenzoylation of the secondary alcohol of diol 10 (3.8 : 1 rr). This study not only provides an alternative route to the highly stereoselective synthesis of PGs, but also showcases the usefulness and great potential of biocatalysis in construction of complex molecules.

Diastereoselective Reduction of Selected α-substituted β-keto Esters and the Assignment of the Relative Configuration by 1H-NMR Spectroscopy

Background:: Chiral β-hydroxy esters and α-substituted β-hydroxy esters represent versatile building blocks for pheromones, β-lactam antibiotics and 1,2- or 1,3-aminoalcohols. Objective:: Synthesis of versatile α-substituted β-keto esters and their diastereoselective reduction to the corresponding syn- or anti-α-substituted β-hydroxy esters. Assignment of the relative configuration by NMR-spectroscopy after a CURTIUS rearrangement of α-substituted β-keto esters to 4-substituted 5-methyloxazolidin-2-ones. Method:: Diastereoselective reduction was achieved by using different LEWIS acids (zinc, titanium and cerium) in combination with complex borohydrides as reducing agents. Assignment of the relative configuration was verified by 1H-NMR spectroscopy after CURTIUS-rearrangement of α-substituted β-hydroxy esters to 4-substituted 5-methyloxazolidin-2-ones. Results:: For the syn-selective reduction, titanium tetrachloride (TiCl4) in combination with a pyridine-borane complex (py BH3) led to diastereoselectivities up to 99% dr. High anti-selective reduction was achieved by using cerium trichloride (CeCl3) and steric hindered reducing agents such as lithium triethylborohydride (LiEt3BH). After CURTIUS-rearrangement of each α-substituted β-hydroxy ester to the corresponding 4-substituted 5-methyloxazolidin-2-one, the relative configuration was confirmed by 1H NMR-spectroscopy. Conclusion:: We have expanded the procedure of LEWIS acid-mediated diastereoselective reduction to bulky α-substituents such as the isopropyl group and the electron withdrawing phenyl ring.

Diastereoselective reduction of the tricarbonyl moiety in bicyclic tetramates giving pyroglutamates

The formation of densely functionalised bicyclic tetramic acids by both stereoselective reduction and Grignard displacement of a Weinreb amide gives bioactive small molecules, with antibacterial activity along with some cancer-cell line inhibitory activity.

The Trost Synthesis of (−)-Lasonolide A

(−)-Lasonolide A 4, isolated from the Caribbean sponge Forcepia sp., showed remarkable anticancer activity in the NIH 60-cell screen. The central step in the syn­thesis of 4 reported (J. Am. Chem. Soc. 2014, 136, 88) by Barry M. Trost of Stanford University was the remarkably selective, convergent Ru-mediated coupling of 1 with 2 to give 3. To prepare 1, the authors took advantage of the underutilized Cu-mediated addi­tion of a Grignard reagent 6 to propargyl alcohol 5, to give 7. Coupling with the ace­tonide 8 followed by deprotection led to the phosphonium salt 9. The other half of 1 was prepared from the acetonide 10 of the commodity chemical 1,1,1-tris(hydroxymethyl)ethane. Oxidation followed by Zn-catalyzed aldol addition of the ketone 11 led to the alcohol 12. Diastereoselective reduction followed by protection gave 13. Condensation with benzaldehyde proceeded with remarkable diastereoselection, setting the quaternary center of 14. Spontaneous intramolecular Michael addition proceeded under the conditions of the subse­quent Horner-Emmons reaction, leading to the aldehyde 15. Wittig reaction with the phosphonium salt 9 followed by deprotection completed the preparation of the alkyne 1. The β-ketoester 18 prepared by the addition of 17 to 16 was prone to unwanted conjugation, and the terminal alkene was easily reduced under hydrogenation con­ditions. Enzymatic conditions were found to effect dynamic kinetic resolution and reduction, to give 19. The derived ketone 21, from coupling with 20 was reduced using the Corey organocatalyst, then hydrosilated, leading to 22. Under metathesis with 23, the product unsaturated aldehyde cyclized to 24. Homologation followed by allylation then completed the construction of 2. Acetone was the solvent of choice for the coupling of 1 with 2. This led to the acetonide 3, that was hydrolyzed and protected to give 25. Yamaguchi macrolac­tonization followed by deprotection then delivered (−)-lasonolide A 4. It is instruc­tive to compare this work to the four previous total syntheses of 4, one of which (Org. Highlights November 26, 2007) we have previously highlighted.

The Inoue Synthesis of 19-Hydroxysarmentogenin

With the continual improvement in synthetic methods, even highly oxidized ste­roids such as the cardenolide aglycone 19-hydroxysarmentogenin 3 are accessible. A key step in the preparation of 3 described (Angew. Chem. Int. Ed. 2013, 52, 5300) by Masayuki Inoue of the University of Tokyo was the free radical cyclization of the acetal-tethered bromo enone 1 to 2. The cyclopentane component of 1 was prepared from the dione 4. Diastereoselective reduction followed by protection led to 5, that was carried on to the enol ether 6. The preparation of 13 began with the Diels–Alder addition of enantiomerically-pure perillaldehyde 7 to the diene 8. Hydrolysis gave the enone 9, that was converted to the enone 10. Oxidative cleavage of the isopropenyl group gave 11, that was carried on via 12 to 13. Addition of Br2 to 6 gave an unstable dibromide, that was coupled with 13 to give 1 as a mixture of diastereomers. Free radical cyclization proceeded with high diastereo­control, delivering 14. Elimination of methanol followed by reprotection completed the preparation of 2. The intramolecular aldol condensation of the intermediate trione proceeded with a 8.6:1 preference for 15. The minor diastereomer was readily converted to an even more favorable 12:1 mixture on re-exposure to KHMDS. After the unnecessary carbonyl was removed, leading to 16, oxidative cleavage exposed the C-11 ketone. Selective protection, to 17, followed by reduction to 18 and iodin­ation completed the preparation of 19. Pd-mediated coupling with the known stannane 20 led to 21. Direct hydrogenation of 21 gave the wrong C-17 diaste­reomer, but hydrogenation of the derived silyl ether was successful, leading to 19-hydroxysarmentogenin 3. The availability of such highly substituted steroids by total synthesis will reinvigor­ate structure–activity studies.

Synthesis of an Advanced Fragment of (+)-Trienomycinol

The synthesis of the fully functionalized eastern fragment of trienomycins A–F, ansamycin antibiotics is described. A key step involves a peptidic coupling between a sulfonyl aniline and an enantiopure carboxylic acid obtained by a completely diastereoselective reduction of a β-ketosulfoxide to generate the stereogenic carbinol. Studies on the coupling with the western part were also performed, giving access to an advanced fragment of trienomycinol.