Total synthesis of (±)-Vertine with Z-selective RCM as a key step

Chausset‐Boissarie, Laëtitia; Àrvai, Roman; Cumming, Graham R.; Besnard, Céline; Kündig, E. Peter

doi:10.1039/c0cc01885f

Cited by 22 publications

(20 citation statements)

References 38 publications

(8 reference statements)

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“…The conjugated diarylhepten-3-one 2d was obtained by Claisen-Schmidt condensation of 8 with MOM-protected benzaldehyde 10 , 22 followed by chemoselective hydrogenation to give the 1,7-diphenylheptan-3-one 3d . 23 Intramolecular macrocyclic Ullmann reaction was then performed under microwave irradiation to give the MOM-protected macrocycle 11 in good yield (85%).…”

Section: Resultsmentioning

confidence: 99%

Syntheses and evaluation of macrocyclic engelhardione analogs as antitubercular and antibacterial agents

Shen¹,

Maddox²,

Adhikari³

et al. 2013

J Antibiot

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The natural product engelhardione is an underexplored chemotype for developing novel treatments for bacterial infections; we therefore explored this natural product scaffold for chemical diversification and structure-activity relationship studies. Macrocyclic engelhardione and structural regioisomers were synthesized using a series of aldol condensations and selective hydrogenations to generate the 1,7-diarylheptan-3-one derivatives, followed by microwave-assisted intramolecular Ullmann coupling to afford a series of macrocyclic diaryl ether analogs. An extended macrocyclic chemical library was then produced by oxime formation, reductive amination, and O-alkylation. Antibacterial evaluation revealed that the reductive amination derivatives 7b and 7d showed moderate activities (minimum inhibitory concentrations: 12.5-25 μg ml−1) against Mycobacterium tuberculosis and Gram-positive pathogens, as well as anti-Gram-negative activity against an efflux impaired E. coli strain. These results provide validated leads for further optimization and development.

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Section: Resultsmentioning

confidence: 99%

Syntheses and evaluation of macrocyclic engelhardione analogs as antitubercular and antibacterial agents

Shen¹,

Maddox²,

Adhikari³

et al. 2013

J Antibiot

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“…Synthesis of the biaryl linkers commenced with phenols 45 29 and 46 (Scheme 5). Conversion of 45 or 46 to the triflate 47 or 48 , followed by conversion to the boronic ester, 30 allowed subsequent Suzuki coupling with the triflate-containing compounds ( 47, 48 ) or with the commercially available iodo-containing compound ( 49 ), to afford biaryl diesters 53–56 in good yield.…”

Section: Resultsmentioning

confidence: 99%

Targeting the Heat Shock Protein 90 Dimer with Dimeric Inhibitors

et al. 2011

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The design, synthesis and biological evaluation of conformationally constrained coumermycin A1 analogues are reported. Compounds were evaluated against both breast cancer (SKBr3 and MCF7) and prostate cancer (PC3mm2, A549 and HT29) cell lines. Non-noviosylated coumermycin A1 analogues that manifest potent anti-proliferative activity resulting from Hsp90 inhibition are provided, wherein replacement of the stereochemically complex noviose sugar with readily available piperidine rings resulted in ~100 fold increase in anti-proliferative activities as compared to coumermycin A1, producing small molecule Hsp90 inhibitors that exhibit nanomolar activities.

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“…Tilve and co-workers 80 with RCM as a key macrocyclisation step. 89 Experimental details of this work have been published in a full paper detailing the synthesis of (+)-vertine (1-166) and its epimer, (+)lythrine (1-163) ( Figure 1.3-6). 90 Various macrocyclisation strategies were attempted and the synthesis will be reviewed in greater detail in Chapter 3.…”

Section: Scheme 13-14 Kim's Synthesis Of (-)-Lasubine IImentioning

confidence: 99%

“…The synthesis of vertine (1-166) has been reported by Kündig, both in racemic 89 and enantiomeric forms. 90…”

Section: Prior Syntheses Of Vertinementioning

confidence: 99%

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Synthesis of piperidine and quinolizidine alkaloids

Nur¹

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Natural products have been, and will continue to be, an important starting point for researchers in the quest for novel treatments for today's ailments. While these molecules often have very highly potent or specialised activities, they may not be the perfect drug candidate. Medicinal chemists aim to improve their therapeutic activity and at the same 6 1-11 to give a rather low diastereomeric mixture (2.3:1) of alcohols 1-12 and 1-13 which were separable by silica gel chromatography. Acetonide cleavage of 1-12 by treatment with aqueous HCl followed by the key intramolecular cyclisation step under Mitsunobu conditions furnished pyridinium salt 1-14. Subsequent reduction with hydrogen in the presence of PtO 2 as catalyst produced a 0.8:1 mixture of diastereomers. Subsequent treatment of each diastereomer with concentrated aqueous KOH yielded (-)-lentiginosine, ent-1-1, and its 8a-epimer, 1-15. 1-epi-lentiginosine, 1-16, was also synthesised in a similar fashion. Preparation of the 1-epimer began with alcohol 1-13 and the reduction step proceeded with high yields and diastereoselectivity. Scheme 1.2-2 Fruit's synthesis of (-)-lentiginosine, analogues 1-15 and 1-16 Brandi and co-workers also used a pyridine-based strategy to synthesise racemic lentiginosine (Scheme 1.2-3). 16 Here, pyridyl alcohol 1-17 was identified as a good starting point. Brandi reasoned that the double bond present could undergo electrophilic addition and then cyclise to form the bicyclic skeleton. Bromination of pyridyl alcohol 1-17 with NBS in aqueous THF furnished pyridinium salt 1-18 diastereoselectively with a yield of 53%. Similar to Fruit's work, the pyridinium salt was reduced by hydrogenation with catalytic amounts of PtO 2 to furnish a 0.7:1 mixture of diastereomers 1-19a and 1-19b. The group demonstrated that the presence of a good leaving group i.e. bromine, enabled facile

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Total synthesis of (±)-Vertine with Z-selective RCM as a key step

Abstract: A concise total synthesis of the strained pentacyclic alkaloid (+/-)-Vertine has been achieved in eleven steps with the key steps being pelletierine condensation, Suzuki-Miyaura coupling, and ring-closing metathesis.

Cited by 22 publications

References 38 publications

Syntheses and evaluation of macrocyclic engelhardione analogs as antitubercular and antibacterial agents

Syntheses and evaluation of macrocyclic engelhardione analogs as antitubercular and antibacterial agents

Targeting the Heat Shock Protein 90 Dimer with Dimeric Inhibitors

Synthesis of piperidine and quinolizidine alkaloids

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