Synthesis and Absolute Stereochemistry of Roseophilin

Harrington, Paul E.; Tius, Marcus A.

doi:10.1021/ja011242h

Cited by 140 publications

(76 citation statements)

References 21 publications

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“…[122] In the presence of 10 mol-% of the proline-key step in their elegant synthesis of roseophilin (Scheme 57). [125] A ring-closing metathesis reaction served to join the unsaturated side chains and the 1,4-dicarbonyl functionality in 215 acted as a precursor for the central pyrrole unit of the natural product. [126] …”

Section: Asymmetric Oxidationsmentioning

confidence: 99%

Organocatalytic Synthesis of Drugs and Bioactive Natural Products

2007

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Section: Asymmetric Oxidationsmentioning

confidence: 99%

Organocatalytic Synthesis of Drugs and Bioactive Natural Products

2007

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“…[70][71][72][73][74][75][76][77][78][79][80] Trotz der offensichtlichen Verwandtschaft fehlt ihm jedoch die Kupfernuclease-Aktivität der Prodigiosine. [23] Außerdem stellt Roseophilin einen äußerst seltenen Fall dar, bei dem das nichtnatürliche Enantiomer eine um den Faktor 2-10 höhere Schema 15.…”

Section: Totalsynthese Nach Fürstnerunclassified

“…[71] Beim direktem Vergleich erwies sich das so erzeugte Material als identisch mit dem Naturstoff, womit dessen Konfiguration nun als geklärt gelten kann.…”

Section: Totalsynthese Von (22r23r)-roseophilin Nach Tiusunclassified

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Chemie und Biologie des Roseophilins und der Prodigiosin‐Alkaloide: 2500 Jahre im Überblick

Fürstner

2003

Angewandte Chemie

178

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Die Pyrrolalkaloide der Prodigiosin‐Familie haben ein ungewöhnliches Kapitel der Alkaloidchemie geschrieben. Aufgrund ihrer charakteristischen roten Farbe können Kolonien der Prodigiosin‐produzierenden Gram‐negativen Bakterien Blutstropfen zum Verwechseln ähneln. Dies hat in der Vergangenheit offenbar für Verwirrung gesorgt und dürfte wohl zahlreiche scheinbar “wundersame” Ereignisse erklären. Seitdem jedoch der Schritt vom Aberglauben zur Naturwissenschaft vollzogen ist, ziehen die Prodigiosine wegen ihrer vielversprechenden physiologischen Eigenschaften einige Aufmerksamkeit auf sich. Besonders relevant sind in diesem Zusammenhang ihre immunsuppressiven Wirkungen, zumal In‐vivo‐Studien einen synergetischen Effekt bei gemeinsamer Verabreichung mit den klinisch eingesetzten Medikamenten Cyclosporin A und FK 506 nachweisen. Des Weiteren wird in diesem Aufsatz die Chemie des mit den Prodigiosinen nahe verwandten, strukturell ungewöhnlichen Alkaloids Roseophilin zusammengefasst, eines cytotoxischen Naturstoffs, der in den letzten Jahren Gegenstand zahlreicher innovativer Totalsynthesen war.

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“…The absolute stereochemistry of roseophilin has been identified as 22R,23R by synthetic studies. 6,7 Roseophilin and 1 exhibited similar 13 C chemical shifts ( ± 0.4 p.p.m.) 1 in the alkyl region and were required to have the same relative stereochemistry.…”

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confidence: 92%

Dechlororoseophilin: a new cytotoxic metabolite from Streptomyces griseoviridis

2009

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Roseophilin, 1 a cytotoxic pigment produced by Streptomyces griseoviridis 2464-S5, has a unique structure containing two pyrrole and one furan rings as shown in Figure 1. The strain also produces a structurally related tripyrrole antibiotic, prodigiosin R1. 2 Recently, we identified the rph gene cluster for prodigiosin biosynthesis in S. griseoviridis. 3 The rph cluster, however, does not contain genes characteristic of roseophilin biosynthesis, although roseophilin is considered to be biosynthesized partially with the same pathway as prodigiosin R1. We attempted to search the biosynthetic intermediates of roseophilin for further biosynthetic study. Color-guided fractionation of the culture extract resulted in the isolation of a new metabolite, dechlororoseophilin (1, Figure 1). We report herein the fermentation, isolation, structure elucidation and biological activity of 1.The producing organism was cultivated in 500-ml Erlenmeyer flasks containing 100 ml of a medium consisting of glycerol 4.0%, soybean meal 1.5%, molasses 1% and calcium carbonate 0.4% (pH 6.8) on a rotary shaker at 27 1C for 5 days. The fermentation broth (2.0 l) was centrifuged and the mycelium was extracted with acetone. After evaporation, the aqueous concentrate was extracted with ethyl acetate. The extract was applied to a silica gel column, which was washed with chloroform-methanol (10:1) and eluted with chloroform-methanol-29% ammonia water (200:20:1). The eluted pigment was subjected to reversed-phase HPLC (XBridge C 18 , Waters Corporation, Milford, MA, USA) using 88% methanol with 0.2% triethylamine. A pigment fraction was concentrated and dissolved in ethyl acetate. After the solution was washed with 0.1 M hydrochloric acid and water, the organic layer was concentrated to dryness to give a red powder of 1 (8.2 mg). The physico-chemical properties of 1 are summarized as follows: m.p. 81-86 1C; high-resolution FAB-MS m/z 419.2697 (MH + , calcd for C 27 H 35 N 2 O 2 , 419.2701); UV l max (e) 536 nm (142 000) in methanol, 536 nm (143 000) in 0.01 M HCl-methanol, 300 nm (43 400), 485 nm (42 100) in 0.01 M NaOH-methanol; IR (KBr) n max 3450, 2910, 1590, 1290 cm À1 .The molecular formula of 1 was established as C 27 H 34 N 2 O 2 by high-resolution FAB-MS. 13 C and 1 H NMR data for 1 are summarized in Table 1. All one-bond 1 H-13 C connectivities were confirmed by the heteronuclear multiple-quantum coherence (HMQC) 4 spectrum. COSY and heteronuclear multiple-bond correlation (HMBC) 5 experiments identified three partial structures as shown in Figure 2. Three aromatic protons (1-H-3-H) were coupled with each other and an exchangeable proton (1-NH) was coupled with 1-H. A pyrrole moiety was constructed by 1 H-13 C long-range correlations from 1-H to C-2, C-3 and C-4, from 2-H to C-1 and C-4, and from 3-H to C-1 and C-4. NOESY correlations on 1-H, 2-H and 3-H confirmed the structure of a 2-pyrrolyl group and their assignments. 1 H-13 C long-range couplings were observed from 6-H to C-5, C-7 and C-8, and from a methoxy proton (27-H 3 ) to C-7. A...

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Synthesis and Absolute Stereochemistry of Roseophilin

Cited by 140 publications

References 21 publications

Organocatalytic Synthesis of Drugs and Bioactive Natural Products

Organocatalytic Synthesis of Drugs and Bioactive Natural Products

Chemie und Biologie des Roseophilins und der Prodigiosin‐Alkaloide: 2500 Jahre im Überblick

Dechlororoseophilin: a new cytotoxic metabolite from Streptomyces griseoviridis

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