Concise Synthesis and Antimalarial Activity of All Four Mefloquine Stereoisomers Using a Highly Enantioselective Catalytic Borylative Alkene Isomerization

Ding, Jinyue; Hall, Dennis G.

doi:10.1002/ange.201303931

Cited by 35 publications

(13 citation statements)

References 45 publications

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“…In conclusion, we have reported a five-step total synthesis of all four stereoisomers of mefloquine. In contrast to previous syntheses, [15] excepting the most recent synthesis, [16] we have obtained all four possible stereoisomers of mefloquine, including (À)-(11R,12S)-erythro-mefloquine 1 a and (+)-(11S,12R)-erythro-mefloquine ent-1 a. This constitutes a synthetic approach that synthesises all four stereoisomers of mefloquine correctly and supports the recent enantioselective synthesis [16] according to a different synthetic pathway.…”

Section: Resultssupporting

confidence: 83%

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Trapped in Misbelief for Almost 40 Years: Selective Synthesis of the Four Stereoisomers of Mefloquine

Schützenmeister

Müller

Reinscheid

et al. 2013

Chemistry A European J

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Here we report the synthesis of all four stereoisomers of mefloquine. Mefloquine (Lariam) is an important anti‐malaria drug that is applied as a racemate of the erythro form. However, the (−)‐isomer induces psychosis, while the (+)‐enantiomer does not have this undesired side effect. There are six syntheses of which five lead to the wrong enantiomer without the authors of these syntheses noting that they had synthesized the wrong compound. At the same time physical chemistry investigations had assigned the absolute configuration correctly and the last enantioselective synthesis that took these results into account delivered the correct absolute configuration. Since various synthetic approaches failed to provide the correct stereoisomers in previous syntheses, we submit here a synthetic approach with a domino Sonogashira‐6π‐electrocyclisation as key step that confirmed synthetically the correct absolute configuration of all four isomers.

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Section: Resultssupporting

confidence: 83%

“…While preparing this manuscript, Hall and co-workers published the first synthetic approach, which delivered the correct stereochemical outcome. [16]…”

Section: Introductionmentioning

confidence: 99%

Trapped in Misbelief for Almost 40 Years: Selective Synthesis of the Four Stereoisomers of Mefloquine

Schützenmeister

Müller

Reinscheid

et al. 2013

Chemistry A European J

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“…Removal of the solvent under vacuum and crystallization from Et 2 O gave (11 R ,12 S )‐(−)‐ erythro ‐mefloquine hydrochloride as a white solid; yield: 76 mg (88%). Spectral and rotation data match those reported 29. [α]${{{20\hfill \atop {\rm D}\hfill}}}$ : −33.7 ( c =0.5, MeOH); 1 H NMR (DMSO‐ d 6 , 400 MHz): δ =10.48 (br s, 1 H), 9.04 (d, 1 H, J =8.4 Hz), 8.50 (br s, 1 H), 8.39 (d, 1 H, J =7.2 Hz), 8.10 (s, 1 H), 7.97 (t, 1 H, J =8.0 Hz), 6.85 (d, 1 H, J =4.4 Hz), 6.15 (s, 1 H), 3.30 (m, 1 H), 3.25 (m, 1 H), 2.91 (m, 1 H), 1.66 (m, 4 H), 1.33(m, 2 H); 13 C NMR (DMSO‐ d 6 , 100 MHz): δ =151.8, 147.1 (q, J =34.3 Hz), 143.2, 130.4 (q, J =5.4 Hz), 129.8, 128.8, 127.6 (q, J =29.4 Hz), 126.9, 124.1 (q, J =272 Hz), 121.7 (q, J =280 Hz), 115.8, 67.1, 59.2, 44.6, 22.0, 21.6, 21.3.…”

Section: Methodssupporting

confidence: 84%

“…After submission of this manuscript, Hall reported the stereoselective synthesis and antimalarial activity of all four mefloquine stereoisomers 29. In this elegant work, they validated the absolute configurations of mefloquine stereoisomers for the first time utlizing a chemical method, and demonstrated that the most potent stereoisomer in antimalarial assays is (11 S ,12 S )‐(+)‐ threo ‐mefloquine rather than (11S,12 R )‐(+)‐ erythro ‐mefloquine!…”

Section: Methodsmentioning

confidence: 98%

A Stereospecific Synthesis and Unambiguous Assignment of the Absolute Configuration of (−)‐erythro‐Mefloquine Hydrochloride

Zhou

Liu

et al. 2013

Adv Synth Catal

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Cl complexes-catalyzed enantioselective transfer hydrogenation of pyridyl ketone 7 as the key step, and the sense of asymmetric induction of 2-pyridyl ketone 7 is opposite to that of normal ketones in the transfer hydrogenation. Our results confirm the correctness of the determination of the absolute configuration by three physical chemistry methods, and, unbelievably, the erroneous assignments by all previous five asymmetric syntheses.

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“…2). 33,34 The resulting chiral pyranyl and piperidyl allylic boronates 3 and 4 can lead to either a-or gregioselectivity in a Suzuki Miyaura cross-coupling with organohalide electrophiles (RX). This regioselectivity is tied to the mechanistic nature of the transmetallation step and whether it occurs with or without allylic rearrangement [22][23][24][25][26][27] .…”

Section: Resultsmentioning

confidence: 99%

Synthesis of chiral heterocycles by ligand-controlled regiodivergent and enantiospecific Suzuki Miyaura cross-coupling

2014

Self Cite

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Non-aromatic nitrogen-and oxygen-containing heterocycles such as piperidines and pyrans are prevalent components of natural products and pharmaceutical drugs. Although it has been a workhorse as a synthetic method for assembling unsaturated sp 2 -hybridized substrates, transition metal-catalysed cross-coupling chemistry is traditionally not a suitable approach to prepare chiral non-aromatic heterocycles. Several mechanistic issues hamper the coupling of stereogenic secondary sp 3 -hybridized carbon-metal centres. Moreover, use of unsymmetrical allylic boronates in the Suzuki Miyaura cross-coupling is further complicated by the possibility of forming two regioisomeric products. Here we address this two-pronged problem and demonstrate that chiral enantiomerically enriched heterocyclic allylic boronates can be coupled with high stereochemical retention with a wide variety of aryl and alkenyl halides to independently afford both regioisomeric 2-and 4-substituted dihydropyrans and dehydropiperidines in high selectivity. A divergent mechanism is proposed where regiochemistry is governed by the nature of the ligands on the palladium catalyst. This scalable method is applied to the efficient preparation of the neuroactive alkaloid anabasine and the antidepressant drug paroxetine.

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Concise Synthesis and Antimalarial Activity of All Four Mefloquine Stereoisomers Using a Highly Enantioselective Catalytic Borylative Alkene Isomerization

Cited by 35 publications

References 45 publications

Trapped in Misbelief for Almost 40 Years: Selective Synthesis of the Four Stereoisomers of Mefloquine

Trapped in Misbelief for Almost 40 Years: Selective Synthesis of the Four Stereoisomers of Mefloquine

A Stereospecific Synthesis and Unambiguous Assignment of the Absolute Configuration of (−)‐erythro‐Mefloquine Hydrochloride

Synthesis of chiral heterocycles by ligand-controlled regiodivergent and enantiospecific Suzuki Miyaura cross-coupling

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