A Transient N−O-Linked Pauson−Khand Strategy for the Synthesis of the Deschloro Carbocyclic Core of the Palau'amines and Styloguanidines

Koenig, Stefan G.; Miller, Stefan M; Leonard, Kristi; Löwe, Ralf S; Chen, Betty C; Austin, David

doi:10.1021/ol0344063

Cited by 56 publications

(8 citation statements)

References 35 publications

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“…Moreover, 1 exhibits remarkable immunosuppressive responses in the mixed lymphocyte assay (IC 50 < 18 ng mL À1 ). Elegant strategies for the synthesis of advanced cyclopentane fragments related to 1 have been reported.[4] These include, inter alia, a tethered Pauson-Khand approach, [5] Diels-Alder chlorination/ring contraction, [6,7] Diels-Alder oxidative ring contraction, [8,9] spirocyclization of alkylidene glycolamidines and alkylidene hydantoins, [10,11] 1,3-dipolar cycloaddition of thiosemicarbazide derivatives and alkene/enamide metathesis, [12,13] Diels-Alder cyclopropane fragmentation, [14] oxidative tandem radical cyclization, [15] and most recently intramolecular guanidine-conjugate addition [16,17] in a total synthesis of the related axinellamine alkaloids. Additionally, synthetic efforts toward the phakellin heterocyclic core of 1 have also been reported.…”

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confidence: 99%

Synthetic Access to the Chlorocyclopentane Cores of the Proposed Original and Revised Structures of Palau′amine

Bultman

Gin

2008

Angew Chem Int Ed

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The pyrrole-imidazole alkaloids constitute a family of more than 100 natural products, [1,2] among which palau'amine (1, Scheme 1) exists as one of the more structurally complex members. This polycyclic guanidine alkaloid, which was isolated from Stylotella aurantium, was found to possess potent cytotoxic, antibiotic, and immunosuppressive activities.[3] Despite the fact that its acute toxicity is relatively low (LD 50 = 13 mg kg À1 in mice), palau'amine exhibited significant cytotoxicity in a variety of cancer cell lines, including P-388 (IC 50 = 0.1 mg mL À1 ) and A-549 (IC 50 = 0.2 mg mL À1 ). Moreover, 1 exhibits remarkable immunosuppressive responses in the mixed lymphocyte assay (IC 50 < 18 ng mL À1 ). Elegant strategies for the synthesis of advanced cyclopentane fragments related to 1 have been reported.[4] These include, inter alia, a tethered Pauson-Khand approach, [5] Diels-Alder chlorination/ring contraction, [6,7] Diels-Alder oxidative ring contraction, [8,9] spirocyclization of alkylidene glycolamidines and alkylidene hydantoins, [10,11] 1,3-dipolar cycloaddition of thiosemicarbazide derivatives and alkene/enamide metathesis, [12,13] Diels-Alder cyclopropane fragmentation, [14] oxidative tandem radical cyclization, [15] and most recently intramolecular guanidine-conjugate addition [16,17] in a total synthesis of the related axinellamine alkaloids. Additionally, synthetic efforts toward the phakellin heterocyclic core of 1 have also been reported. [18][19][20][21][22][23][24][25] The construction of the central chlorinated cyclopentane skeleton within 1, with control over the relative stereochemical configuration of all of its substituents, emerges as a demanding challenge in this synthetic target. This synthetic hurdle is further complicated by the recent discovery highlighting the stereochemical revision of palau'amine [26][27][28][29] based on NMR spectroscopy, molecular calculations, and comparison to related natural products. These data suggest that the endo-disposed C17 chloro group and the C12 cis-fused ring junction in the originally proposed structure 1 a instead exists as its C12,C17 diastereomeric counterpart 1 b, which incorporates a rare trans-fused [3.3.0]-bicyclic skeleton.In focusing on the elaborately substituted cyclopentane scaffold 2 (Scheme 2) of 1 a and 1 b, retrosynthetic disconnection of the C18 À However, direct application of a Diels-Alder transform to 3 is likely to be challenging. Indeed, selectively functionalized cyclopentadienes such as 4 are not trivial to access, and diene isomerization is virtually unavoidable if one of the substituents at C17 is a proton, as in the natural product. However, control over the configuration at C17, along with that of the other substituents on the cyclopentane core, could be established indirectly through the [3,3]-sigmatropic rearrangement of bridged tricyclodecadienes. The classic finding by Woodward and Katz [30] which involves the preparation of the bridged allylic alcohol 6 (Scheme 3), detailed its susceptibility to equilibration th...

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confidence: 99%

Synthetic Access to the Chlorocyclopentane Cores of the Proposed Original and Revised Structures of Palau′amine

Bultman

Gin

2008

Angew Chem Int Ed

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“…These include work from the groups of Overman, 9 Carreira, 10 Romo, 11 Lovely, 12 Ohta, 13 Austin, 14 Baran, 15 Birman, 16 Harran, 17 Gin, 18 Gleason, 19 Namba-Williams-Nishizawa 20 and us. 8 Notably, the synthesis of the [2+2] dimer has been accomplished by Baran and coworkers 15a and Birman and co-workers, 16 the [3+2] dimers by Baran and co-workers, 15c–h and the [4+2] dimers by Baran and co-workers 15b and us.…”

Section: Introductionmentioning

confidence: 99%

A Biomimetic Route for Construction of the [4+2] and [3+2] Core Skeletons of Dimeric Pyrrole–Imidazole Alkaloids and Asymmetric Synthesis of Ageliferins

Wang

Tan

et al. 2012

J. Am. Chem. Soc.

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The pyrrole-imidazole alkaloids have fascinated chemists for decades because of their unique structures. The high nitrogen and halogen contents and the densely functionalized skeletons make their laboratory synthesis challenging. We describe herein an oxidative method for accessing the core skeletons of two classes of pyrrole-imidazole dimers. This synthetic strategy was inspired by the putative biosynthesis pathways and its development was facilitated by computational studies. Using this method, we have successfully prepared ageliferin, bromoageliferin, and dibromoageliferin in their natural enantiomeric form.

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“…20 The Harran group has reported an oxidative enolate coupling/skeletal rearrangement approach to synthesize “axinellamines deficient in halogen”. 23 Additional synthetic approaches have been reported by the Austin, 22 Gin, 24 Gleason, 25 Williams, 26 Feldman, 27 and Nagasawa 28 groups.…”

Section: Total Synthesesmentioning

confidence: 99%

Dimeric pyrrole–imidazole alkaloids: synthetic approaches and biosynthetic hypotheses

Wang

et al. 2014

Chem. Commun.

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The pyrrole-imidazole alkaloids are a group of structurally unique and biologically interesting marine sponge metabolites. Among them, the cyclic dimers have caught synthetic chemists’ attention particularly. Numerous synthetic strategies have been developed and various biosynthetic hypotheses have been proposed for these fascinating natural products. We discuss herein the synthetic approaches and the biosynthetic insights obtained from these studies.

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A Transient N−O-Linked Pauson−Khand Strategy for the Synthesis of the Deschloro Carbocyclic Core of the Palau'amines and Styloguanidines

Cited by 56 publications

References 35 publications

Synthetic Access to the Chlorocyclopentane Cores of the Proposed Original and Revised Structures of Palau′amine

Synthetic Access to the Chlorocyclopentane Cores of the Proposed Original and Revised Structures of Palau′amine

A Biomimetic Route for Construction of the [4+2] and [3+2] Core Skeletons of Dimeric Pyrrole–Imidazole Alkaloids and Asymmetric Synthesis of Ageliferins

Dimeric pyrrole–imidazole alkaloids: synthetic approaches and biosynthetic hypotheses

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