Total Synthesis and Absolute Configuration of the Guaiane Sesquiterpene Englerin A

Willot, Matthieu; Radtke, Lea; Könning, Daniel; Fröhlich, Roland; Gessner, Viktoria H.; Strohmann, Carsten; Christmann, Mathias

doi:10.1002/anie.200905032

Cited by 126 publications

(65 citation statements)

References 38 publications

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“…Christmann and co-workers recorded the first synthesis and confirmed the absolute configuration of ent -(+)-englerin A in 2009. These authors published a follow-up synthesis of the natural enantiomer along with several analogs in 2011 [10,11]. Bicycle 2 is synthesized in 11 steps from (−)-nepetalactone and can be engaged in a transannular epoxide opening to generate the bridging ether with high regioselectivity.…”

Section: Stereochemistry-based Strategies: the Power Of Substrate Relaymentioning

confidence: 99%

Synthesis of Medicinally Relevant Terpenes: Reducing the Cost and Time of Drug Discovery

Jansen

Shenvi

2014

Future Med. Chem.

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Terpenoids constitute a significant fraction of molecules produced by living organisms that have found use in medicine and other industries. Problems associated with their procurement and adaptation for human use can be solved using chemical synthesis, which is an increasingly economical option in the modern era of chemistry. This article documents, by way of individual case studies, strategies for reducing the time and cost of terpene synthesis for drug discovery. A major trend evident in recent syntheses is that complex terpenes are increasingly realistic starting points for both medicinal chemistry campaigns and large-scale syntheses, at least in the context of the academic laboratory, and this trend will likely penetrate the commercial sector in the near future.

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Section: Stereochemistry-based Strategies: the Power Of Substrate Relaymentioning

confidence: 99%

Synthesis of Medicinally Relevant Terpenes: Reducing the Cost and Time of Drug Discovery

Jansen

Shenvi

2014

Future Med. Chem.

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“…This natural product is structurally related to englerin A (39), a sesquiterpene that has been shown to selectively inhibit the growth of renal cancer cell lines at the nanomolar level [94]. The absolute configuration of englerin A (39) was established by the total synthesis of its enantiomer [95].…”

Section: Gold-catalyzed Cyclization Of Simple 16-enynesmentioning

confidence: 99%

Complexity via Gold-Catalyzed Molecular Gymnastics

Echavarren

Jiménez‐Núñez

2010

Top Catal

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Reactions of 1,6-enynes catalyzed by gold(I) complexes usually proceed stereospecifically through highly distorted cyclopropyl gold carbenes. Substrates with an alkoxy substituent at the propargylic position undergo stereoselective transformations through intermediates in which the OR group and the gold carbene are anti-oriented. Intramolecular attack of carbonyl groups to the cyclopropyl gold carbene is faster than the 1,5-migration of the OR groups, which itself is faster than the intramolecular cyclopropanation by a pendant alkenyl group. The intramolecular attack of carbonyl groups is the key transformation in the [2?2?2] gold-catalyzed cycloaddition, which has been applied in the total synthesis of (?)-orientalol F.Electrophilic metals catalyze the cyclization of 1,n-enynes to give a variety of cyclic structures (recent reviews in [1-4]) [5][6][7][8][9][10][11][12][13][14][15][16]. In the absence of nucleophiles, simple 1,6-enynes 1 undergo skeletal rearrangement to give products 2 (single exo-cleavage) and 3 (double exo-cleavage) ( Fig. 1) . In a third type skeletal rearrangement, dienes 4 (single endo-cleavage) were found using cationic Au(I) catalysts [5,38]. Products of type 4 were later found in reactions catalyzed by InCl 3 [27, 28], Fe(III) [6], or Ru(II) [39]. Cyclobutenes resulting from a [2?2] cycloaddition process have also been obtained from 1,6-[40], 1,7-[25, 29-31, 34, 41], and 1,8-enynes [42, 43]. Other type of cyclobutenes have been obtained in the palladium-[17, 18], platinum-[44], and gold-catalyzed cyclization of enynes [15,16,[45][46][47].Although dienes 2 obtained by the single exo-cleavage are identical to those formed by the metal-catalyzed metathesis of enynes [48,49], the mechanism of the skeletal rearrangement is very different [50,51]. For Au(I), the rearrangement was proposed to proceed via intermediates 5 (Fig. 2) [52]. On the other hand, the double-cleavage skeletal rearrangement usually leads to dienes 3 with predominant [1-4, 17-21, 38], or exclusive Z [53, 54] configuration. For Au(I), products of type 3 are obtained via rearranged carbene 6, followed by 1,2-H shift and protodemetalation [52]. Experimental support for the involvement of 6 has been obtained in reactions in which these intermediates have been trapped with alkenes [55], indoles, allyl silanes [56][57][58], and carbonyl compounds [59,60]. Proton loss from 6 can form 1,4-dienes in InCl 3 -catalyzed reactions of substrate in which R 0 is an alkyl group [27].The dual character of intermediates 5 as metal carbenes and carbocationic species has been recently discussed [1][2][3][4][61][62][63]. Conventionally, these complexes are often depicted as cyclopropyl gold carbenes 5, although DFT calculations show that these species have highly distorted structures, intermediate between cyclopropyl gold carbenes and gold-stabilized homoallylic carbocations [38,52]. A gold carbene has been formed in the gas phase, see [64,65]. Intermediates of type 5 are involved in other processes such as nucleophilic additions of heteronucleo...

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“…This established the absolute configuration of the natural product as 1 R , 3a R , 4 S , 5R, 7 R , 8 S , 8a R . 22 The (+)-enantiomer was later found to be inactive at 1 μ M in A498 cells, while the IC 50 of the synthetic (−)-enantiomer was 45 nM. 23 Synthesis of the natural (−)-enantiomer of englerin A, which required synthesis of the unnatural (−)-nepetalactone, was reported by the same group in 2011.…”

Section: Introductionmentioning

confidence: 99%

Englerins: A Comprehensive Review

Zhao

Fash

et al. 2017

J. Nat. Prod.

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Graphical Abstract In the decade since the discovery of englerin A (1) and its potent activity in cancer models, this natural product and its analogues have been the subject of numerous chemical, biological, and preclinical studies by many research groups. This review summarizes published findings and proposes further research directions required for entry of an englerin analogue into clinical trials for kidney cancer and other conditions.

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Total Synthesis and Absolute Configuration of the Guaiane Sesquiterpene Englerin A

Cited by 126 publications

References 38 publications

Synthesis of Medicinally Relevant Terpenes: Reducing the Cost and Time of Drug Discovery

Synthesis of Medicinally Relevant Terpenes: Reducing the Cost and Time of Drug Discovery

Complexity via Gold-Catalyzed Molecular Gymnastics

Englerins: A Comprehensive Review

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