Chlorocyclopropane Macrolides from the Marine Sponge <i>Phorbas</i> sp. Assignment of the Configurations of Phorbasides A and B by Quantitative CD

Skepper, Colin K.; MacMillan, John B.; Zhou, Guang Xiong; Masuno, Makoto N.; Molinski, Tadeusz F.

doi:10.1021/ja0703978

Cited by 43 publications

(35 citation statements)

References 19 publications

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“…From the outset we recognized the possibility that the carbohydrate moieties of callipeltosides A-C might, in fact, be of the same enantiomeric series (in contrast to the findings of the isolation paper). Indeed, the recent isolation of phorbaside A, [19] which contains l-2-O-methylevalose, provides additional support for such a possibility. With this in mind, we thought that a de novo carbohydrate synthesis seemed logical as it would provide access to both enantiomers of the callipeltose C sugar (a convenience not likely available by synthetic manipulation of a naturally abundant carbohydrate).…”

Section: Dedicated To Professor Luigi Minale and Co-workersmentioning

confidence: 99%

Total Synthesis and Structural Revision of Callipeltoside C

et al. 2008

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Dedicated to Professor Luigi Minale and co-workersThe continual search for new antitumor and antiviral agents from marine sponge extracts has resulted in the identification of a number of structurally complex and diverse natural products with intriguing biological activity. In 1996 and 1997 Minale and co-workers reported the isolation and structural assignment of callipeltosides A-C (Figure 1), the first three members of a new class of marine macrolides from the lithistid sponge Callipelta sp. indigenous to the shallow waters off New Caledonia. [1] Biological activity, in particular cytotoxicity, varies among the callipeltosides, and their IC 50 values range from 11.3 to 30.0 mg mL À1 against human bronchopulmonary NSCLC-N6 cell lines.[1] These natural isolates were shown to block cell proliferation in the G1 phase, but unfortunately the exact mode of action cannot as yet be determined owing to the prohibitively small quantities of callipeltosides A-C that have been isolated to date ( 3.5 mg).[1] A more detailed annotation of the biological mechanism will await the availability of substantial synthetic quantities of the callipeltosides and their analogues as the natural isolates have been consumed. [1] In terms of structural complexity, the callipeltosides share a common 12-membered macrocycle comprising seven stereocenters and a unique dienyne chlorocyclopropane side chain; this class is differentiated only by the composition of the saccharide moiety. In particular, callipeltosides A and B are characterized by the presence of two unique deoxyamino sugars, while callipeltoside C incorporates the novel deoxy sugar 2-O-methylevalose. Perhaps more notable, the carbohydrate moieties of callipeltosides B and C were reported to exist in the opposite enantiomeric series to that found in callipeltoside A (callipeltosides B and C = d sugar, callipeltoside A = l sugar).Their stereochemical and structural complexity coupled with their unique biological activity make the callipeltoside family an attractive target for total synthesis. Indeed, to date, the groups of Trost, [2] Evans, [3] Paterson, [4] and Panek [5] have completed the asymmetric construction of callipeltoside A, yet surprisingly callipeltosides B and C have remained unchallenged by chemical synthesis. In this communication we describe the first total synthesis of callipeltoside C and present a structural revision with respect to the enantioseries of the pendent 2-O-methylevalose carbohydrate. This synthetic sequence, which is founded upon the use of organocatalytic and organometallic technologies, provides access to useful quantities of callipeltoside C in 18 chemical steps and 12 % overall yield.Our disconnection of callipeltoside C into four components 2-5 of similar complexity (Figure 2) revealed the possibility of a convergent synthesis with broad latitude in the sequence of fragment coupling. Inspection of fragments 2-4 brought to mind the possibility of exploiting three asymmetric organocatalytic transformations that have recently been developed i...

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Section: Dedicated To Professor Luigi Minale and Co-workersmentioning

confidence: 99%

Total Synthesis and Structural Revision of Callipeltoside C

et al. 2008

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“…Ten new polyoxygenated diterpenes (7)(8)(9)(10)(11)(12)(13)(14)(15)(16) along with six known gagunin compounds (1)(2)(3)(4)(5)(6) were isolated from the sponge Phorbas sp. collected in the Korean Sea.…”

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Polyoxygenated Diterpenes from the Sponge Phorbas sp.

et al. 2008

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Ten new polyoxygenated diterpenes (7-16) along with six known gagunin compounds (1-6) were isolated from the sponge Phorbas sp. collected in the Korean Sea. On the basis of a combination of NMR and mass spectroscopic analyses, the molecular structures of these diterpenes, designated as gagunins H-Q, were determined to be penta- or hexa-oxygenated diterpenes of the 10,13-bis-epi-homoverrucosane class. A new diterpene acid (17) of a bisabolane-related skeletal class was also isolated and structurally defined by the spectroscopic analyses. These compounds exhibited moderate to significant cytotoxicity against the K-562 cell line as well as weak inhibitory activity against isocitrate lyase (ICL).

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“…The 1 H NMR signals for both H-1 and H-2 in evalose residues are singlets that lack vicinal couplings that would otherwise resolve axial or equatorial dispositions from simple Karplus relationships. D’Auria and coworkers assigned a β-L configuration to callipeltosides B and C,9 however, we assigned α-L to the anomeric carbons C-1′ and C-1″ in 3 , 4 and other phorbasides4 based on consistent observation of a weak ROESY cross peak between each acetal proton (H-1′ or H-1″) and the adjacent syn -C-2′-OMe group. Similar ROE’s were observed for phorbasides G ( 7 ) and phorbaside H ( 8 , see Figure 1).…”

Section: Resultsmentioning

confidence: 81%

“…Reexamination of the CCl 4 -soluble fraction of sponge Phorbas sp., which previously afforded 3 and 4 ,4 revealed very minor components that were further purified by reversed phase HPLC to give total yields of pure compounds in amounts ranging from 7 to 9.5 μg (quantitation by comparative NMR ‘ 13 C satellite’ integration)5: phorbaside F 5 ( 5 ), 8 μ g (3.8 × 10 −6 %), phorbaside G ( 7 ), 9.5 μ g (4.0 × 10 −6 %), phorbaside H ( 8 ), 7.0 μ g (2.9 × 10 −6 %) and phorbaside I ( 9 ), 9.4 μ g (3.9 × 10 −6 % dry wt).…”

Section: Resultsmentioning

confidence: 89%

“…collected off the Muiron Island in Western Australia, has been shown to contain highly cytotoxic macrolides including phorboxazoles A ( 1 ) and B ( 2 ),3 and phorbasides A ( 3) and B ( 4 ). 4 Recently, the structures of very minor natural products from this one specimen of Phorbas were elucidated to reveal appreciably broader chemical diversity within the sponge than encountered in earlier studies. The new compounds, which were fully characterized by MS, CD and NMR (COSY, ROESY, HSQC, HMBC), include phorbaside F ( 5 , 8 μ g, 13 nmol),5 , hemi-phorboxazole A (16.5 μg)6 and muironolide A ( 6 , 90 μg) 7.…”

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Structure Elucidation at the Nanomole Scale. 3. Phorbasides G−I from Phorbas sp.

Dalisay

Molinski

2010

J. Nat. Prod.

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Three new phorbasides (G-I), chlorocyclopropyl-ene-yne macrolide glycosides, were isolated from the sponge Phorbas sp. in yields of 7-9.5 μg and fully characterized by MS, CD and microcryoprobe NMR. The structures of the new compounds differ only in the nature of the sugar residues. The absolute configurations of the new compounds were correlated by ROESY and CD with the parent compounds phorbasides A and B.The use of cryo-microprobe NMR spectroscopy, integrated with other 'nanomole-scale' techniques (CD, FTIR, FTMS) for natural products discovery has expanded our view to extremely minute amounts of compound. 1 Nanomole-scale methods exploit technical improvements in signal-to-noise of spectroscopic methods, but more importantly they open new vistas for discovery of new compounds from rare organisms and uncovering chemical complexity and diversity within single specimens.2 The marine sponge Phorbas sp. collected off the Muiron Island in Western Australia, has been shown to contain highly cytotoxic macrolides including phorboxazoles A (1) and B (2), 3 and phorbasides A (3) and B (4). 4 Recently, the structures of very minor natural products from this one specimen of Phorbas were elucidated to reveal appreciably broader chemical diversity within the sponge than encountered in earlier studies. The new compounds, which were fully characterized by MS, CD and NMR (COSY, ROESY, HSQC, HMBC), include phorbaside F (5, 8 μg, 13 nmol), 5 , hemi-phorboxazole A (16.5 μg) 6 and muironolide A (6, 90 μg). 7 The latter represents the first member of an entirely new carbon skeleton based on a hexahydro-1H-isoindolin-1-one. We now report additional phorbasides G-I (7-9) in total yields of 7-9.5 μg. The structures were solved by integrated application of microcryoprobe NMR, including quantitative analysis, MS and CD analysis. Results and DiscussionReexamination of the CCl 4 -soluble fraction of sponge Phorbas sp., which previously afforded 3 and 4, 4 revealed very minor components that were further purified by reversed phase HPLC to give total yields of pure compounds in amounts ranging from 7 to 9.5 μg (quantitation by comparative NMR ' 13 C satellite' integration) 5 × 10 −6 %), phorbaside G (7), 9.5 μg (4.0 × 10 −6 %), phorbaside H (8), 7.0 μg (2.9 × 10 −6 %) and phorbaside I (9), 9.4 μg (3.9 × 10 −6 % dry wt).The molecular formula of phorbaside G (7) (Tables 1 and 2). The second sugar unit of 7 is oxidized with respect to 4 and has a keto group at C-4″ (δ 208.0). In addition, the 13 C NMR chemical shifts of C-3′ (δ 80.5) and C-4′ (δ 70.4) in the first sugar unit appeared downfield of those in 4 by ~10 ppm. The configuration of the sugar unit was established by ROESY as a 6-deoxy-2,3-Careful analysis of the HMBC spectrum showed that the anomeric proton signal H-1″ (δ 5.82, s) was correlated with the quaternary C-3′, thus indicating a 1″→ 3′ disaccharide linkage. The downfield 13 C NMR chemical shift of C-3′ at δ 80.5 is characteristic of a 1″→ 3′ linkage when the tertiary OH of C-methyl sugars is glycosylated and matche...

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Chlorocyclopropane Macrolides from the Marine Sponge Phorbas sp. Assignment of the Configurations of Phorbasides A and B by Quantitative CD

Cited by 43 publications

References 19 publications

Total Synthesis and Structural Revision of Callipeltoside C

Total Synthesis and Structural Revision of Callipeltoside C

Polyoxygenated Diterpenes from the Sponge Phorbas sp.

Structure Elucidation at the Nanomole Scale. 3. Phorbasides G−I from Phorbas sp.

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