FR901483, a Novel Immunosuppressant Isolated from Cladobotryum sp. No. 11231. Taxonomy of the Producing Organism, Fermentation, Isolation,Physico-chemical Properties and Biological Activities.

Sakamoto, Kazutoshi; Tsujii, Eisaku; Abe, Fumie; Nakanishi, Tomoko; Yamashita, Michio; Shigematsu, Nobuharu; Izumi, Shizue; Okuhara, Masakuni

doi:10.7164/antibiotics.49.37

Cited by 127 publications

(129 citation statements)

References 7 publications

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“…Nach Hydrogenolyse entstehen deshalb all-cis-Pyrrolidinole. Auf diesem Weg wurde eine Totalsynthese des Pyrrolidinol-Alkaloids ()-Preussin (1) durchgeführt, die ausgehend von l-Pyroglutaminol (11) in einer Gesamtausbeute von 11 % über neun Stufen die Zielverbindung liefert. picture is to be obtained.…”

Section: Resultsunclassified

The Synthesis of (+)-Preussin and Related Pyrrolidinols by Diastereoselective Paternò-Büchi Reactions of Chiral 2-Substituted 2,3-Dihydropyrroles

2000

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The N-alkoxycarbonyl substituted 2,3-dihydropyrroles 3 and 8 are converted to 2-benzyl-3-pyrrolidinols by the Paternò - Büchi reaction followed by hydrogenolysis. Since the addition of the photoexcited benzaldehyde at the unsaturated heterocycle proceeds in a syn fashion, the benzyl group at C-2 and the hydroxy group at C-3 of the product are cis oriented. The simple and facial diastereoselectivities of the Paternò-Büchi reaction were studied more closely and the relative configuration of the products was elucidated. The thermodynamically less stable endo product is formed as a result of simple diastereoselection. The face differentiation in 2-substituted 2,3-dihydropyrroles is presumably due to the nonplanarity of these heterocycles, which forces attack of the carbonyl group on the face with the existing substituent. All-cis-pyrrolidinols are consequently formed after hydrogenolysis. Following this route, a total synthesis of the pyrrolidinol alkaloid (+)-preussin (1) was conducted, which yielded the target compound in a total yield of 11% over nine steps starting from L-pyroglutaminol (11).

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Section: Resultsunclassified

The Synthesis of (+)-Preussin and Related Pyrrolidinols by Diastereoselective Paternò-Büchi Reactions of Chiral 2-Substituted 2,3-Dihydropyrroles

2000

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“…The mixture was extracted with CH 2 Cl 2 (3 × 100 mL). The organic extracts were dried over Na 2 SO 4 …”

Section: (2r*5s*6s*)-2(2-benzyloxymethylallyl)-5-(tert-butyldimethymentioning

confidence: 99%

“…11231 by the Fujisawa research group, and it was shown to significantly prolong the graft survival time in the rat skin allograft model. 4 More importantly, it was suggested that the mechanism of action is quite different as compared to cyclosporin A and FK 506, namely (−)-FR901483 inhibits the adenylosuccinate synthetase and/or adenylosuccinate lyase enzymes in the purine biosynthesis. Because of the high degree of bioactivity and the unprecedented azatricyclic structure of (−)-FR901483, it has become a popular target of synthetic interest.…”

Section: Introductionmentioning

confidence: 99%

“…30 Removal of the terminal trimethylsilyl group in 28 yielded the corresponding acetylene, which was then subjected to B-bromo-9-BBN to yield vinyl bromide 29 as a single regioisomer. 31 Reaction of 29 with Pb(OAc) 4 resulted in the corresponding trans-acetate. 32 Sc(OTf) 3 -mediated hydrolysis of the acetate group was followed by protection of the resulting secondary alcohol as the TBS ether to yield dihydropyridone 25 (57%, 3 steps).…”

Section: Introductionmentioning

confidence: 99%

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Synthetic Studies Toward (−)-FR901483 Using a Conjugate Allylation To Install the C-1 Quaternary Carbon

Gotchev

Comins

2006

J. Org. Chem.

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Two approaches to the aza-tricyclo dodecane skeleton of (−)-FR901483 are reported. Both routes utilized a Grignard addition to an N-acylpyridinium salt to establish the absolute stereochemistry at C-6 and a highly diastereoselective conjugate allylation reaction to form the quaternary center at C-1 of the natural product in excellent yield. Although the desired polysubstituted piperidine intermediates were prepared regio-and stereoselectively, the construction of the C-8/C-9 bond connectivity could not be achieved. All attempts at a pinacol cyclization or an intramolecular 6-exotet epoxide opening were unsuccessful due to unfavorable A 1,3 strain inherent in the molecule.

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“…11231 in the course of a search for new immunosuppressive agents with mechanisms of action different from cyclosporine A and FK-506. 2 The unique and rigid molecular architecture of 1 (Figure 1), which seems to conceal most of the atoms of two molecules of tyrosine, was revealed by an X-ray crystallographic analysis. The phosphate ester is another interesting element of this substance that is essential to its potent immunosuppressive activity in vitro.…”

mentioning

confidence: 99%

A Synthesis of the Tricyclic Core Structure of FR901483 Featuring an Ugi Four-Component Coupling and a Remarkably Selective Elimination Reaction

Seike

Sorensen²

2008

Synlett

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Three key reactions, an efficient Ugi four-component coupling, a regiospecific, base-mediated elimination reaction, and an intramolecular nitrone/alkene [3+2] cycloaddition, were used to achieve an effective synthesis of the tricyclic molecular framework of the immunosuppressant FR901483. The outcome of a control experiment supports the idea that an internal deprotonation by an alkoxide ion is the origin of the site selectivity observed in the base-induced elimination of hydroxy mesylate 17. Keywords Ugi four-component coupling; elimination reaction; [3+2] cycloadditionScientists from the Fujisawa Pharmaceutical Company isolated the natural product FR901483 (1) from the fermentation broth of the fungus Cladobotryum sp. No. 11231 in the course of a search for new immunosuppressive agents with mechanisms of action different from cyclosporine A and FK-506. 2 The unique and rigid molecular architecture of 1 (Figure 1), which seems to conceal most of the atoms of two molecules of tyrosine, was revealed by an X-ray crystallographic analysis. The phosphate ester is another interesting element of this substance that is essential to its potent immunosuppressive activity in vitro. FR901483 significantly extends graft survival time in the rat skin allograft model and is believed to exert its immunosuppressive function by inhibiting purine nucleotide biosynthesis.The status of 1 as a potential immunosuppressant and its attractive structure stimulated much creative research in the field of chemical synthesis. Five laboratories, including ours, published syntheses of the full structure of this natural product. [3][4][5][6][7] In addition to these achievements, several laboratories described either formal syntheses of FR901483 or novel concepts for constructing its rigid, azatricyclic core structure. 8 In 2000, our laboratory described an enantiospecific, nature-inspired synthesis of this natural product from two simple tyrosine derivatives featuring the following key transformations: a C-N bondforming oxidative dearomatization, an aldol cyclization, and a late-stage Mitsunobu substitution that simultaneously produced the phosphate ester of 1 and the desired © Georg Thieme Verlag Stuttgart · New York Correspondence to: Erik J. Sorensen, ejs@princeton.edu. This paper is dedicated to the pioneering achievements of Professor Yoshito Kishi in the field of organic chemistry on the occasion of his 70 th birthday. -9. 4 While the brevity of this design for synthesis was attractive, we were not entirely satisfied with the yields of these three transformations or with the level of selectivity (both regio-and diastereoselectivity) for the aldol cyclization step. This circumstance engendered a new way of thinking about the problem of gaining a rapid access to the azaspirotricyclic core structure of FR901483. The general features of this alternative synthesis are outlined below in Scheme 1. NIH Public AccessThe idea that compounds 2-5 would join spontaneously by the Ugi coupling process 9 to give compound 6 was a key aspect of...

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FR901483, a Novel Immunosuppressant Isolated from Cladobotryum sp. No. 11231. Taxonomy of the Producing Organism, Fermentation, Isolation,Physico-chemical Properties and Biological Activities.

Cited by 127 publications

References 7 publications

The Synthesis of (+)-Preussin and Related Pyrrolidinols by Diastereoselective Paternò-Büchi Reactions of Chiral 2-Substituted 2,3-Dihydropyrroles

The Synthesis of (+)-Preussin and Related Pyrrolidinols by Diastereoselective Paternò-Büchi Reactions of Chiral 2-Substituted 2,3-Dihydropyrroles

Synthetic Studies Toward (−)-FR901483 Using a Conjugate Allylation To Install the C-1 Quaternary Carbon

A Synthesis of the Tricyclic Core Structure of FR901483 Featuring an Ugi Four-Component Coupling and a Remarkably Selective Elimination Reaction

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