Assembly of the antifungal agent FR-900848 and the CETP inhibitor U-106305: studies on remarkable multicyclopropane natural products

Barrett, Anthony G. M.; Doubleday, Wendel W.; Hamprecht, Dieter; Kasdorf, K.; Tustin, Gary J.; White, Andrew J. P.; Williams, David J.

doi:10.1039/a700487g

Cited by 19 publications

(11 citation statements)

References 34 publications

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“…These conformations must result from energetic compromises between intramolecular van der Waals interactions between hydrogen atoms or simply from crystal packing effects. It is noteworthy that such a conformation has never been observed in the solid state for either of the quater‐ or quinquecyclopropane derivatives along the routes to FR‐900848 ( 1 ) (all‐ gauche conformation10b, 12) and to U‐106305 ( 2 ) ( gauche / trans / gauche / gauche conformation13c), or the macrocyclic compounds containing a quinquecyclopropane fragment (predominating trans / trans / gauche / trans conformation15a).…”

Section: Resultsmentioning

confidence: 99%

“…[7][8][9][10] The total synthesis of FR-900848 1 [11,12] and U-106305 2 [12,13] was achieved in 1996 by Barrett et al, and the key step for the stereoselective assembly of the quatercyclopropane moiety was the enantioselective Simmons-Smith-type cyclopropanation of 2-butene-1,4-diol as developed by Charette et al [14] The higher acyclic and even cyclic syn-all-trans-oligocyclopropyl-1,n-dimethanol derivatives have been prepared not only as precursors to the natural products 1 and 2 but also out of interest in their conformational behavior. [15] Having gained some experience with the conformational analysis of bicyclopropyl early on, [16,17] we were intrigued by the conformational features of the quater-and quinquecyclopropane units in 1 and 2.…”

Section: Introductionmentioning

confidence: 99%

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Stereoselective Preparation of Six Diastereomeric Quatercyclopropanes from Bicyclopropylidene and Some Derivatives

Seebach

Kozhushkov

Schill

et al. 2006

Chemistry A European J

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Diastereomeric meso‐ and d,l‐bis(bicyclopropylidenyl) (5) were obtained upon oxidation with oxygen of a higher‐order cuprate generated from lithiobicyclopropylidene (4) in 50 and 31 % yield, respectively. Their perdeuterated analogues meso‐[D14]‐ and d,l‐[D14]‐5 were obtained along the same route from perdeuterated bicyclopropylidene [D8]‐3 (synthesized in six steps in 7.4 % overall yield from [D8]‐THF) in 20.5 % yield each. Dehalogenative coupling of 1,1‐dibromo‐2‐cyclopropylcyclopropane (6) gave a mixture of all possible stereoisomers of 1,5‐dicyclopropylbicyclopropylidene 16 in 69 % yield, from which (Z)‐cis‐16 was separated by preparative gas chromatography (26 % yield). The crystal structure of meso‐5 looks like a superposition of the crystal structures of two outer bicyclopropylidene units (3) and one inner s‐trans‐bicyclopropyl unit, whereas the two outer cyclopropyl moieties adopt a gauche orientation with respect to the cyclopropane rings at the inner bicyclopropylidene units in (Z)‐cis‐16. Birch reduction with lithium in liquid ammonia of meso‐5 and d,l‐5 gave two pairs of diastereomeric quatercyclopropanes trans,trans‐(R*,S*,R*, S*)‐17/cis,trans‐(R*,S*,R*,R*)‐18 and trans,trans‐(R*,S*,S*,R*)‐19/cis,trans‐(R*,S*,S*,S*)‐20 in 97 and 76 % yield, respectively, in a ratio 9:1 for every pair. The latter diastereomer was also obtained as the sole product by Birch reduction of (Z)‐cis‐16 in 96 % yield. Under the same conditions, tetradecadeuterio analogues trans,trans‐[D14]‐(R*,S*,R*,S*)‐17/cis,trans‐[D14]‐(R*, S*,R*,R*)‐18 (8:1) and trans,trans‐[D14]‐(R*,S*,S*,R*)‐19/cis,trans‐[D14]‐(R*,S*,S*,S*)‐20 (12:1) were prepared from meso‐[D14]‐5 and d,l‐[D14]‐5 in 37 and 63 % yield, respectively. Reduction of meso‐5 with diimine gave the cis,cis‐quatercyclopropane (S*,S*,R*,R*)‐21 as the main product (58 % yield) along with the cis,trans‐diastereomer (S*,S*,R*,S*)‐18 (29 % yield). Thus, five of the six possible diastereomeric quatercyclopropanes were obtained from meso‐5, d,l‐5, and (Z)‐cis‐16. The X‐ray crystal structure analyses of trans,trans‐(R*,S*,R*,S*)‐17 and cis,cis‐(S*,S*,R*,R*)‐21 revealed for the both an unusual conformation in which the central bicyclopropyl unit adopts an s‐trans‐(antiperiplanar) orientation with ϕ=180.0°, and the two terminal bicyclopropyl moieties adopt a synclinal conformation with ϕ=49.8 and 72.0°, respectively. In solution the vicinal coupling constants 〈3JH,H〉 in trans,trans‐(R*,S*,R*,S*)‐[D14]‐17, trans,trans‐(R*,S*,S*,R*)‐[D14]‐19, trans,cis‐(R*,S*,R*,R*)‐[D14]‐18 and trans,cis‐(R*,S*,S*,S*)‐[D14]‐20 were found to be 4.1, 4.7, 5.9 and 5.9 Hz, respectively. This indicates a predominance of the all‐gauche conformer in (R*,S*,R*,S*)‐17 and a decreasing fraction of it in this sequence of the other diastereomers.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Stereoselective Preparation of Six Diastereomeric Quatercyclopropanes from Bicyclopropylidene and Some Derivatives

Seebach

Kozhushkov

Schill

et al. 2006

Chemistry A European J

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“…118 However, the stereochemistry of 62 was completely elucidated only seven years later. 119 FR-900848 (62) had a high specific activity against filamentous fungi at concentrations ranging from 0.05 to 0.5 mg ml À1 , suppressing the growth of Aspergillus niger, Mucor rouxianus, Penicillium chrysogenum, Aureobasidium pullulans, Trichophyton species, Fusarium oxysporum and Sclerotinia arachidis. This compound caused the hyphae of fungi to branch frequently and the filaments to swell.…”

Section: Other Peptidesmentioning

confidence: 99%

Natural products as antifungal agents against clinically relevant pathogens

Santo

2010

Nat. Prod. Rep.

104

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Fungi have emerged worldwide as increasingly frequent causes of healthcare-associated infections, but fungal infections have generally been considered curable, and thus the demand for new antifungal agents has been very low. Although superficial fungal infections of the skin and nails are common and are for the most part treated successfully with existing antifungal agents, serious fungal infections are becoming a growing danger for human health. This is particularly true for AIDS patients, but also for recipients of transplants, and users of antineoplastic agents, corticoids, and even antibiotics. A major problem is the increasing emergence of resistance to antimycotic agents, and since azoles--the most used class of antifungals--suffer a significant incidence of resistance, new efforts are now devoted to the discovery of new agents with different mechanisms of action. Not so long ago, combinatorial chemistry appeared to be the future for drug discovery, but in the late 1990s synthetic chemists realized that combinatorial libraries lacked the "complexity" usually associated with natural compounds. Research into biologically active natural products has thus had a reprise, in particular with the advent of the concept of diversity-oriented synthesis. This review reports what is so far known about natural products as antifungal agents, and provides an overview of natural compounds with both known and unknown mechanisms of action.

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“…Since the 50% lethal dose of FR-900848 ( 1 ) for mice by intraperitoneal injection to mice was more than 1 g/kg, the compound can be classified as essentially nontoxic. It was proposed that this natural product could represent a significant new lead for the design of nucleoside antifungal agent against the major human pathogen Aspergillus fumigatus 6 t …”

Section: B Physiological Propertiesmentioning

confidence: 99%

Synthesis and Properties of Oligocyclopropyl-Containing Natural Products and Model Compounds

Pietruszka

2003

Chem. Rev.

255

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Assembly of the antifungal agent FR-900848 and the CETP inhibitor U-106305: studies on remarkable multicyclopropane natural products

Abstract: INCREASING PLATINATION RATES S S d(T 8 p(S)T 8 ) d(Tp(S)T 15 ) d(Tp(S)T)

Cited by 19 publications

References 34 publications

Stereoselective Preparation of Six Diastereomeric Quatercyclopropanes from Bicyclopropylidene and Some Derivatives

Stereoselective Preparation of Six Diastereomeric Quatercyclopropanes from Bicyclopropylidene and Some Derivatives

Natural products as antifungal agents against clinically relevant pathogens

Synthesis and Properties of Oligocyclopropyl-Containing Natural Products and Model Compounds

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