Conception and Evolution of Stereocontrolled Strategies toward Functionalized 8-Aryloctanoic Acids Related to the Total Synthesis of Aliskiren

Hanessian, Stephen; Chénard, Étienne; Guesné, Sébastien; Cusson, Jean-Philippe

doi:10.1021/jo5015195

Cited by 10 publications

(11 citation statements)

References 83 publications

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“…[36][37][38] The exclusive selectivity for 8 can be rationally understood and explained by looking at proposed conformation of oxonium intermediate 9, in which the least hindered approach of the nucleophile led to the important C1, C10 trans configuration of 8. Conversion of 8 to Ambrox ® -like 39 compound 10 was achieved through a ruthenium-catalyzed ring-closing olefin metathesis (RCM) in the presence of 10 mol% ruthenium catalyst at 10 mmol L −1 in dry and degassed, refluxing dichloromethane for 24 h, 40,41 and deacetylation of compound 8 with potassium carbonate gave alcohol 11 in a high yield (85%). Alternatively, the tricyclic lactone molecular scaffold could undergo a variety of further manipulations as a result of the cyclic olefin, such as oxidation, epoxidation, halogenation, and cross-coupling, to afford more complex compounds.…”

Section: Chemistrymentioning

confidence: 99%

Synthesis, bioactivity and mode of action of 5_A5_B6_C tricyclic spirolactones as novel antiviral lead compounds

Zhu

Fan

et al. 2018

Pest Management Science

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The results of the bioassays and QSAR studies indicated that the carbon-containing cyclic moiety was the antiviral pharmacophore, and derivative 19, which showed the best inactivation activity, could emerge as a potential antiviral agent against TMV. In vitro capsid protein (CP) assembly and TMV assembly inhibition determinations indicated that these compounds induced crosslinking in the TMV and prevented its uncoating, which was a putative new mode of action for TMV inactivation. © 2018 Society of Chemical Industry.

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Section: Chemistrymentioning

confidence: 99%

Synthesis, bioactivity and mode of action of 5_A5_B6_C tricyclic spirolactones as novel antiviral lead compounds

Zhu

Fan

et al. 2018

Pest Management Science

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“…The structure of the C 2 -symmetrical dilactone 6 was ascertained by X-ray crystallography (Scheme 2). 14 In view of the continuing interest to develop viable synthetic routes to aliskiren, we focused on the key ring-closing metathesis step in our original synthesis. 7 In this paper, we report our qualitative observations pertaining to the reaction of the p-methoxyphenyl analogues 1b and 3b as well as their mono-and disubstituted diastereomeric esters in the presence of a variety of catalysts, in order to determine the influence of the isopropyl and vicinal aryl substituents and their relative stereochemistry on the nature of the products (Figure 1).…”

Section: Syn Thesismentioning

confidence: 99%

“…We then returned to the original disubstituted model (S,R,S)-ester 1b, and studied the reaction in the presence of G2 and then H-G2 catalysts and the newer generation catalysts ( Figure 1). 16 Using 5 mol% catalyst in refluxing toluene led to the nine-membered lactone 2b in good yield, al-though the reaction was 2-3 times slower with the new generation catalysts (entries [13][14][15][16][17]. Finally, the (S,S,S)-ester 3b was subjected to the same reactions conditions, leading solely to the dilactones 5 and 6 as previously observed with the G2 and H-G2 catalysts (entries 18-22).…”

Section: Syn Thesismentioning

confidence: 99%

On the Importance of the Relative Stereochemistry of Substituents in the Formation of Nine-Membered Lactones by Ring-Closing Metathesis

2015

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The effects of isopropyl substituents and molar concentration of diastereomeric esters toward the formation of nine-membered unsaturated lactones, in the context of the synthesis of the intermediates of the antihypertensive drug aliskiren, have been studied.The now-venerable Grubbs olefin metathesis reaction 1 and its many recent variants 2 is an exceedingly useful and versatile method to construct internally unsaturated compounds of varying ring sizes. 3 Among these, the synthesis of nine-membered unsaturated lactones 4 and ethers 5 is of particular interest because of their limited occurrence in nature and their interesting biological activity. 6 In a recent paper 7 on the total synthesis of the marketed antihypertensive drug aliskiren (Tekturna TM ) 8 we utilized a ring-closing metathesis reaction with the ester 1a using Grubbs' 1st generation catalyst (G1) 9 to obtain a critical nine-membered unsaturated lactone intermediate 2a that harbored two isopropyl groups in strategically pre-defined positions on an 8-aryloctanoic acid core unit (Scheme 1). The lactone 2a was further elaborated to provide aliskiren in seven steps and 7% overall yield from readily available starting materials. 7 Compared to recent syntheses, 10 and a plethora of published patents, 11 our synthesis proved to be the shortest to date.During the ring-closing metathesis reaction of a mixture of esters 1a and diastereomeric 3a with G1 catalyst in refluxing toluene at a concentration of 10 mM, we observed that only the (S,R,S)-ester 1a was converted into the lactone 2a. The same observation was made with the (S,R,S)-ester of the corresponding p-methoxyphenyl analogue 1b. The diastereomeric ester 3b did not give the expected lactone 4b and remained unchanged. Further studies with Grubbs second-generation (G2) 12 and Hoveyda-Grubbs secondgeneration (H-G2) 2b catalysts with a 4:1 diastereomeric mixture of p-methoxyphenyl analogue 1b led to the lactone 2b in excellent yield and in much shorter time. Under these conditions, the diastereomeric (S,S,S)-ester 3b, obtained independently from a stereoselective reduction of the correScheme 1 Synthetic route to aliskiren via a nine-membered lactone G1 (5 mol%) toluene (10 mM) r.t. O O MeO MeO O O 7 steps MeO OH H 2 N O H N NH 2 O R 1a, R = O(CH 2 ) 3 OMe 1b, R = H R 2a, R = O(CH 2 ) 3 OMe 2b, R = H aliskiren (Tekturna TM ) R = O(CH 2 ) 3 OMe G1 (5 mol%) O O MeO MeO O O R 3a, R = O(CH 2 ) 3 OMe 3b, R = H R 4a, R = O(CH 2 ) 3 OMe 4b, R = H R S S S S S R toluene (10 mM) r.t.

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“…Starting from the first Novartis–Speedel synthesis, − several research groups, from both academia and industry, have reported brilliant solutions to the problem of aliskiren synthesis. − …”

Section: Introductionmentioning

confidence: 96%

Convergent Synthesis of the Renin Inhibitor Aliskiren Based on C5–C6 Disconnection and CO₂H–NH₂ Equivalence

Cini

Banfi

Barreca³

et al. 2016

Org. Process Res. Dev.

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A novel synthesis of the renin inhibitor aliskiren based on an unprecedented disconnection between C5 and C6 was developed, in which the C5 carbon acts as a nucleophile and the amino group is introduced by a Curtius rearrangement, which follows a simultaneous stereocontrolled generation of the C4 and C5 stereogenic centers by an asymmetric hydrogenation. Operational simplicity, step economy, and a good overall yield makes this synthesis amenable to manufacture on scale.

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Conception and Evolution of Stereocontrolled Strategies toward Functionalized 8-Aryloctanoic Acids Related to the Total Synthesis of Aliskiren

Cited by 10 publications

References 83 publications

Synthesis, bioactivity and mode of action of 5_A5_B6_C tricyclic spirolactones as novel antiviral lead compounds

Synthesis, bioactivity and mode of action of 5_A5_B6_C tricyclic spirolactones as novel antiviral lead compounds

On the Importance of the Relative Stereochemistry of Substituents in the Formation of Nine-Membered Lactones by Ring-Closing Metathesis

Convergent Synthesis of the Renin Inhibitor Aliskiren Based on C5–C6 Disconnection and CO₂H–NH₂ Equivalence

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Conception and Evolution of Stereocontrolled Strategies toward Functionalized 8-Aryloctanoic Acids Related to the Total Synthesis of Aliskiren

Cited by 10 publications

References 83 publications

Synthesis, bioactivity and mode of action of 5A5B6C tricyclic spirolactones as novel antiviral lead compounds

Synthesis, bioactivity and mode of action of 5A5B6C tricyclic spirolactones as novel antiviral lead compounds

On the Importance of the Relative Stereochemistry of Substituents in the Formation of Nine-Membered Lactones by Ring-Closing Metathesis

Convergent Synthesis of the Renin Inhibitor Aliskiren Based on C5–C6 Disconnection and CO2H–NH2 Equivalence

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Synthesis, bioactivity and mode of action of 5_A5_B6_C tricyclic spirolactones as novel antiviral lead compounds

Synthesis, bioactivity and mode of action of 5_A5_B6_C tricyclic spirolactones as novel antiviral lead compounds

Convergent Synthesis of the Renin Inhibitor Aliskiren Based on C5–C6 Disconnection and CO₂H–NH₂ Equivalence