Elucidation of structure and stereochemistry of myriocin. Novel antifungal antibiotic

Bagli, Jehan F.; Kluepfel, Dieter; Jacques, Maurice St.

doi:10.1021/jo00947a001

Cited by 92 publications

(18 citation statements)

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“…Fortunately, the mixture could be separated via chromatography to afford 10 in 16% yield and 11 in 77% yield. The two-step dedihydroxylation 65) of 11 was achieved by thiocarbonation (93%) of diol and the following reduction of the resulting thiocarbonate 12 with P(OMe) 3 (92%) to afford 7a which can be used for reoxidation to 10 under Donohoe dihydroxylation conditions. Second, we investigated synthesis of 3 and 4 from 10 and 11, respectively (Chart 4).…”

Section: Resultsmentioning

confidence: 99%

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Total Synthesis of Sphingofungin E and 4,5-Di-<i>epi</i>-sphingofungin E

Noda

Nambu

Fujiwara

et al. 2017

CHEMICAL & PHARMACEUTICAL BULLETIN

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Total synthesis of sphingofungin E and 4,5-di-epi-sphingofungin E was achieved from an intermediate same as that of myriocin and mycestericin D via antipodal stereoselective dihydroxylations.Key words sphingofungin E; dihydroxylation; stereoselectivity; osmium tetroxide; total synthesis Myriocin (1), [1][2][3][4] mycestericin D (2), 5,6) sphingofungins E (3), 7) and F 7) are classified as members of a unique family in sphingosine-related natural products (Fig. 1). They have an additional carbon substituent at the C-2 position and contiguous stereogenic centers. They act as antifungal and immunosuppressive agents through the inhibitory activity of serine palmitoyl transferase. [8][9][10][11][12] Because of interesting structural features and potent biological activities, these natural products have attracted considerable attention of synthetic organic chemists and several total syntheses have already been reported. Recently, we reported total synthesis of 1 and 2 from the same intermediate 5, which was derived from commercially available diethyl D-tartrate using rhodium(II)-catalyzed C-H amination, following stereoselective vinylation 45,46) (Chart 1). As part of our synthetic investigations of sphingosine natural products, [47][48][49][50][51] herein, we report the total synthesis of 3 and 4,5-di-epi-sphingofungin E (4) from the intermediate 5 via antipodal stereoselective dihydroxylations. Results and DiscussionOur synthetic plan for 3 and 4 is illustrated in Chart 2. By expanding the utility of our recently reported synthetic procedure 45,46) for the synthesis of sphingosine natural products having C-2 quaternary centers, we planned to investigate the synthesis of the more structurally complicated analog 3 and its 4,5-di-epimer 4 from the common intermediate 5.After conversion of aldehyde into alkene, the stereoselective introduction of a diol group via dihydroxylation [52][53][54] of 7 would result in both vinyl intermediates 8 and 9. Such antipodal diastereoselectivity has already been demonstrated in dihydroxylations of substrates having an allylic and/or homoallylic functionality. [55][56][57][58][59][60][61][62] Finally, cross metathesis reaction with known alkene 6 63) would afford 3 and 4. The stereoselective dihydroxylation of 7 was investigated, as illustrated in Chart 3. First, we examined a reagentcontrolled dihydroxylation method. The Wittig reaction of 5 45) afforded the α,β-unsaturated ester 7a 46) (R=CO 2 Me). The reactions of 7a with an AD-mix β under several conditions did not proceed at all, probably due to the steric hindrance of the allylic and homoallylic substituents of 7a. Subsequently, we investigated dihydroxylation of 7a under usual reaction conditions [using OsO 4 and N-methylmorpholine N-oxide (NMO)]. The OsO 4 /NMO dihydroxylation usually results in diastereoselectivity under steric or stereoelectronic control.52-54) The reaction of 7a with catalytic amounts of OsO 4 in the presence of NMO proceeded with the complete facial selectivity to produce diol 11 with 89% yield as a single...

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Section: Resultsmentioning

confidence: 99%

“…

…”

mentioning

confidence: 99%

Total Synthesis of Sphingofungin E and 4,5-Di-<i>epi</i>-sphingofungin E

Noda

Nambu

Fujiwara

et al. 2017

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…Extracts from the fungus Isaria sinclairii were tested for their immunosuppressive activity in a mouse allogenic mixed lymphocyte response (MLR) assay [55]. ISP-1 was isolated from the active extract and found to be identical to the known natural product myriocin [56,57] or thermozymocidin [58].…”

Section: Examples Of Small Molecules Under Clinical Evaluation For Aumentioning

confidence: 99%

Development of small-molecule therapies for autoimmune diseases

Bürli¹,

Haughan²,

Hodges³

2010

Autoimmunity

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Until the recent advent of genetically engineered drugs, small molecules constituted the predominant method of treatment for autoimmune diseases. Both modalities have advantages and disadvantages; while protein-based therapeutics interfere very selectively with the function of their biological targets, they have to be administered subcutaneously or intravenously. Small molecules have the potential for oral administration. Due to their cell permeability, they can interact with extra- and intracellular targets, thus opening opportunities for interfering with novel biochemical pathways. We herein describe the preclinical stages of typical small-molecule research programmes and outline hurdles that may have to be overcome. A few examples of small molecules that are currently under clinical evaluation and arose from diverse discovery pathways will be discussed.

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“…(6, 7) The chemical structure of ISP-I since proved to be identical to those of myriocin and thermozymocidine, which had been isolated as an antifungal agent from Myriococcum albomyces (ATCC16425) and Mycelia sterilia (ATCC20349), respectively. (8, 9, 10)…”

Section: Introductionmentioning

confidence: 99%

FTY720 Story. Its Discovery and the following Accelerated Development of Sphingosine 1-Phosphate Receptor Agonists as Immunomodulators Based on Reverse Pharmacology

Adachi

Chiba

2007

Perspect Medicin Chem

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Fingolimod (FTY720) is the first of a novel class: sphingosine 1-phosphate (S1P) receptor modulator and is currently in phase 3 clinical trials for multiple sclerosis (MS). FTY720 was first synthesized in 1992 by chemical modification of an immunosuppressive natural product, ISP-I (myriocin). ISP-I was isolated from the culture broth of Isaria sinclairii, a type of vegetative wasp that was an ‘eternal youth’ nostrum in traditional Chinese medicine. ISP-I is an amino acid having three successive asymmetric centers and some functionalities. We simplified the structure drastically to find a nonchiral symmetric 2-substitued-2-aminopropane-1,3-diol framework for an in vivo immunosuppressive activity (inhibition of rat skin allograft rejection test or prolonging effect on rat skin allograft survival) and finally discovered FTY720. During the course of the lead optimization process, we encountered an unexpected dramatic change of the mechanism of action with an in vivo output unchanged. Since it proved that FTY720 did not inhibit serine palmitoyltransferase that is the target enzyme of ISP-I, reverse pharmacological approaches have been preformed to elucidate that FTY720 is mainly phosphorylated by sphingosine kinease 2 in vivo and the phosphorylated drug acts as a potent agonist of four of the five G protein coupled receptors for S1P: S1P1, S1P3, S1P4 and S1P5. Evidence has accumulated that immunomodulation by FTY720-P is based on agonism at the S1P1 receptor. Medicinal chemistry targeting S1P1 receptor agonists is currently in progress. The FTY720 story provides a methodology where in vivo screens rather than in vitro screens play important roles in the lead optimization. Unlike recent drug discovery methodologies, such a strategy as adopted by the FTY720 program would more likely meet serendipity.

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Elucidation of structure and stereochemistry of myriocin. Novel antifungal antibiotic

Cited by 92 publications

References 0 publications

Total Synthesis of Sphingofungin E and 4,5-Di-<i>epi</i>-sphingofungin E

Total Synthesis of Sphingofungin E and 4,5-Di-<i>epi</i>-sphingofungin E

Development of small-molecule therapies for autoimmune diseases

FTY720 Story. Its Discovery and the following Accelerated Development of Sphingosine 1-Phosphate Receptor Agonists as Immunomodulators Based on Reverse Pharmacology

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