A Formal Synthesis of Psymberin

Shangguan, Ning; Kiren, Sezgin; Williams, Lawrence J.

doi:10.1021/ol063143k

Cited by 80 publications

(43 citation statements)

References 36 publications

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“…With this overview in mind, disconnection of the amide bond in (+)- 1 (Scheme 1), as with the earlier reported syntheses, 5,7,8 leads to a side chain acid ( 2 ) and amide coupling precursor ( 3 ), the latter bearing a Teoc-protected N , O -aminal. We envisioned that elaboration of the N , O aminal could be achieved in a highly stereoselective fashion exploiting a late-stage Curtius rearrangement similar to that developed and employed in our total syntheses of (+)- dactylolide and (+)-zampanolide.10 Further disconnection at the C(16,17) bond leads to aldehyde 4 and 2,6- trans tetrahydropyran 5 , which would be joined via a 1,4- substrate controlled boron-mediated aldol reaction to control the configurations of the C(16,17) stereogenic centers.…”

supporting

confidence: 57%

Total Synthesis of (+)-Psymberin (Irciniastatin A): Catalytic Reagent Control as the Strategic Cornerstone

2008

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An effective total synthesis of the marine sponge cytotoxin (+)-psymberin [irciniastatin (1)] has been achieved. Highlights of the strategy include a Diels-Alder reaction between a bissiloxy diene and an allene to construct the aromatic ring, a boron-mediated aldol to elaborate the C(15-17) all syn stereotriad, catalytic reagent control to set the C(8, 9, 11 and 13) stereogenic centers of the tetrahydropyran core, and a late-stage Curtius rearrangement to install the sensitive N,O-aminal moiety. The synthesis proceeds with a longest linear sequence of 21 steps from commercially a v a2,2i-diml ethayl-1b,3-plropaenediol.In 2004, the laboratories of Pettit and Crews independently disclosed the isolation of ircinistatin A 1 and psymberin (1), 2 respectively from the marine sponges Ircinia ramose and Psammocinia sp. A closely related compound, irciniastatin B, possessing a carbonyl moiety at C(11) was also reported by the Pettit group. From the outset, irciniastatin A and psymberin appeared to be constitutionally equivalent based on high resolution mass spectrometry, in conjunction with the 1D and 2D NMR data. The absolute configuration of psymberin was assigned by the Crews group based on a combination of CD studies along with the assumed analogy to the structure of pederin. 3 Neither group however assigned the relative stereogenecity at C(4); also recorded were conflicting stereochemical assignments for the C(8) N,O-aminal. Importantly, both isolates displayed significant cancer cell growth inhibitory activity against a wide variety of human cancer cell lines. The potent cytotoxicity data, in conjuction with the conflicting and smithab@sas.upenn.edu. Shortly thereafter, the DeBrabander group announced completion of the first total synthesis of (+)-psymberin, complete with construction of the four possible C(4)-C(8) epimers, which not only completed the structural assignment, including absolute configuration, but also confirmed that irciniastatin A and psymberin (1) were in fact one and the same. 5 Related synthetic work followed quickly, 6 with a formal synthesis in 2007 7 and a second total synthesis reported by the Schering-Plough group, 8 the latter exploiting a novel (diacetoxyiodo)benzene-mediated cyclization to construct the central tetrahydropyran core. NIH Public AccessWe also were intrigued with (+)-psymberin (1) as a potential new cancer therapeutic lead. Herein we report our efforts recently culminating in an effective total synthesis of (+)-1. Central to our synthetic plan was the use of catalytic reagent control to set the stage for an eventual structure-activity study to define the structural elements required for biological activity. 9With this overview in mind, disconnection of the amide bond in (+)-1 (Scheme 1), as with the earlier reported syntheses, 5,7,8 leads to a side chain acid (2) and amide coupling precursor (3), the latter bearing a Teoc-protected N,O-aminal. We envisioned that elaboration of the N,Oaminal could be achieved in a highly stereoselective fashion exploiting a late-stag...

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confidence: 57%

Total Synthesis of (+)-Psymberin (Irciniastatin A): Catalytic Reagent Control as the Strategic Cornerstone

2008

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“…53 Advanced allene 95 was subjected to DMDO oxidation to give the intermediate 1,4-dioxaspiro[2.2]pentane, which cyclized to dihydropyranone 96 upon the addition of methanol. Dihydropyranone 96 was transformed into a known intermediate in the synthesis of psymberin 97 .…”

Section: 1 4-dioxaspiro[22]pentanesmentioning

confidence: 99%

Synthesis of unusually strained spiroheterocyclic ring systems and their exploits in synthesis

2009

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“…Through the total synthesis of several diastereoisomers consistent with partially assigned structures of 1 and 2 , our group concluded that psymberin and irciniastatin are actually identical compounds. 6 Several other total syntheses, 7 formal syntheses, 8 fragment syntheses, 9 as well as analog syntheses, 10 have appeared during recent years. A combined supply of natural psymberin and material prepared by our group enabled further in vivo evaluation by the NCI Developmental Therapeutics Program, which indicated encouraging therapeutic efficacy.…”

Section: Introductionmentioning

confidence: 99%

Studies toward the Unique Pederin Family Member Psymberin: Full Structure Elucidation, Two Alternative Total Syntheses, and Analogs

2012

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Two synthetic approaches to psymberin have been accomplished. A highly convergent first generation synthesis led to the complete stereochemical assignment and demonstrated that psymberin and irciniastatin A are identical compounds. This synthesis featured a diastereoselective aldol coupling between the aryl fragment and a central tetrahydropyran core, and a novel one-pot procedure to convert an amide, via intermediacy of a sensitive methyl imidate, to the N-acyl aminal reminiscent of psymberin. The highlights of the second generation synthesis include an efficient iridium-catalyzed enantioselective bis-allylation of neopentyl glycol, and a stepwise Sonogashira coupling/cycloisomerization/reduction sequence to construct the dihydroisocoumarin unit. The two synthetic avenues were achieved in 17–18 steps (longest linear sequence, ~14–15 isolations) from 3 fragments prepared in 7–8 steps (1st generation) and 3–8 steps (2nd generation) each. This convergent approach allowed for the preparation of sufficient amounts of psymberin (~ 0.5 g) for follow-up biological studies. Meanwhile, our highly flexible strategy enabled the design and synthesis of multiple analogs, including a psymberin-pederin hybrid termed psympederin that proved crucial to a comprehensive understanding of the chemical biology of psymberin and related compounds that will be described in a subsequent manuscript.

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A Formal Synthesis of Psymberin

Cited by 80 publications

References 36 publications

Total Synthesis of (+)-Psymberin (Irciniastatin A): Catalytic Reagent Control as the Strategic Cornerstone

Total Synthesis of (+)-Psymberin (Irciniastatin A): Catalytic Reagent Control as the Strategic Cornerstone

Synthesis of unusually strained spiroheterocyclic ring systems and their exploits in synthesis

Studies toward the Unique Pederin Family Member Psymberin: Full Structure Elucidation, Two Alternative Total Syntheses, and Analogs

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