Enantioselective Total Synthesis of (+)‐Homochelidonine by a Pd<sup>II</sup>‐Catalyzed Asymmetric Ring‐Opening Reaction of a <i>meso</i>‐Azabicyclic Alkene with an Aryl Boronic Acid

McManus, Helen A.; Fleming, Matthew J.; Lautens, Mark

doi:10.1002/ange.200603945

Cited by 14 publications

(4 citation statements)

References 41 publications

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“…We were attracted to this class of natural products since it appeared the core structure could be prepared using our recently developed Pd II ‐catalyzed ring‐opening reaction of meso ‐azabicyclic‐alkenes with aryl boronic acids 16. In this paper, we report the evolution of the asymmetric version of this reaction into a strategy for the total synthesis of (+)‐homochelidonine17 and subsequently the 4 other hexahydrobenzo[ c ]phenanthridine alkaloids, (+)‐chelamidine, (+)‐chelidonine, (+)‐chelamine, and (+)‐norchelidonine.…”

Section: Introductionmentioning

confidence: 99%

Concise Enantioselective Total Syntheses of (+)‐Homochelidonine, (+)‐Chelamidine, (+)‐Chelidonine, (+)‐Chelamine and (+)‐Norchelidonine by a Pd^II‐Catalyzed Ring‐Opening Strategy

Fleming

McManus

Rudolph

et al. 2008

Chemistry A European J

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New enantioselective syntheses of the B/C hexahydrobenzo[c]phenanthridine alkaloids (+)-homochelidonine, (+)-chelamidine, (+)-chelidonine, (+)-chelamine, and (+)-norchelidonine are described. Our rapid and convergent route to this class of natural products involved the development and application of a Pd II-catalyzed asymmetric ring-opening reaction of a meso-azabicyclic alkene with an aryl boronic acid as the key step. By screening a variety of functionalized ortho-substituted aryl boronic acids, chiral ligands and reaction conditions we were able to prepare the requisite cis-1-amino-2-aryldihydronaphthalenes in high yield and in up to 90 % ee. Early attempts to complete the synthesis of (+)-homochelidonine using an N-Boc azabicyclic alkene are described in full. The successful route required a protecting group alteration followed by B ring formation and then stereoselective installation of the C-11 syn-hydroxy group by regioselective epoxide ring-opening using a hydride source. Ring-opening of the same epoxide intermediate with water ultimately led to the synthesis of (+)-chelamidine. The same strategy was then used to synthesize the other structurally similar B/C hexahydrobenzo[c]phenanthridine alkaloids, (+)-chelidonine, (+)-chelamidine, and (+)-norchelidonine.

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Section: Introductionmentioning

confidence: 99%

Concise Enantioselective Total Syntheses of (+)‐Homochelidonine, (+)‐Chelamidine, (+)‐Chelidonine, (+)‐Chelamine and (+)‐Norchelidonine by a Pd^II‐Catalyzed Ring‐Opening Strategy

Fleming

McManus

Rudolph

et al. 2008

Chemistry A European J

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“…However, although the ring‐opening reactions of azabicyclic alkenes with various carbon nucleophiles provide efficient methods for biologically important nitrogen‐containing compounds, the asymmetric versions of these reactions are rarely reported 3. To date, only few ARO of azabicyclic alkenes with organozinc reagents,3a–c organoboronic acids,3d,e and silylacetylenes3f,g as carbon nucleophiles have been reported. The direct utilization of easily accessible organic halides instead of organometallic reagents for better functional group tolerance in the non‐asymmetric ring‐opening reactions of azabicyclic alkenes has been realized 4.…”

Section: Methodsmentioning

confidence: 99%

Oxygenation of Ruthenium Carbene Complexes Containing Naphthothiophene or Naphthofuran: Spectroscopic and DFT Studies

Tsai

Hsu

et al. 2013

Chemistry An Asian Journal

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The aryl propargylic alcohol 1-[2-(thiophen-3-yl)phenyl]prop-2-yn-1-ol (1a) is readily prepared from 2-(thiophen-3-yl)benzaldehyde. In the presence of visible light, treatment of 1a with one-half mole equivalent of [Ru]Cl ([Ru]=Cp(dppe)Ru) (dppe=1,2-bis(diphenylphosphino)ethane) and NH4PF6 in O2 affords the naphtha[2,1-b]thiophene-4-carbaldehyde (4a) in high yields. The cyclization reaction of 1a proceeds through the formation of the carbene complex 2a that contains the naphtha[2,1-b]thiophene ring, which is isolated in a 1:1 stoichiometric reaction. The C-C bond formation between the inner carbon of the terminal triple bond and the heterocyclic ring is confirmed by structure determination of 2a using single-crystal X-ray diffraction analysis. Facile oxygenation of 2a by O2 yields the aldehyde product 4a accompanied by the formation of phosphine oxide of dppe. Oxygen is most likely activated by coordination to the ruthenium center when one PPh2 unit of the dppe ligand dissociates. This dissociated PPh2 unit then reacts with the coordinated oxygen nearby to generate half-oxidized dppe ligand and an unobserved oxo-carbene intermediate. Coupling of the oxo/carbene ligands followed by demetalation then yields 4a. Presumably the resulting complex with the half-oxidized dppe ligand continuously promotes cyclization/oxygenation of 1a to yield the second aldehyde molecule. In alcohol such as MeOH or EtOH, the oxygenation reaction affords a mixture of 4a and the corresponding esters 5a or 5a'. Four other aryl propargylic alcohols 1b-e, which contain thiophen-2-yl, isopropenyl, fur-3-yl, and fur-2-yl, respectively, on the aryl ring are also prepared. Analogous aldehydes 4b-e are similarly prepared from 1b-e, respectively. For oxygenations of 1b, 1d, and 1e in alcohol, mixtures of aldehyde 4, ester 5, and acetal 8 are obtained. The carbene complex 2b obtained from 1b was also characterized by single-crystal X-ray diffraction analysis. The UV/Vis spectra of 2a and 2b consist of absorption bands with a high extinction coefficient. From DFT calculations on 2a and 2b, the visible light is found to populate the LUMO antibonding orbital of mainly Ru=C bonds, thereby weakening the Ru=C bond and promoting the oxygenation/demetalation reactions of 2.

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“…[64] In 2008, Lautens and co-workers applied this methodology to the enantioselective synthesis of a number of isoquinoline alkaloids 95-99 (Scheme 13). [65] Lautens anticipated that two of the three contiguous stereocenters with syn configuration present within this class of natural products along with the entire carbon framework could arise in one step from the asymmetric ring-opening of meso-azabicyclic alkene 91. Alkene 91 was readily accessible on a multigram scale from the [4+2] cycloaddition of benzyne intermediate 88, generated in situ from dibromobenzene 87, with pyrrole 89 followed by protecting-group exchange (90 to 91).…”

Section: Addition To Strained Azabicyclic Alkenesmentioning

confidence: 99%

“…Synthesis of the B/C hexahydrobenzo [c]phenanthridine alkaloids 95-99 described by Lautens and co-workers in 2008. [65] BINAP = 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl Cbz = benzyloxycarbonyl, MOM = methoxymethyl.…”

Section: Nucleophilic Addition 241 Intramolecular Trans-cyclooctenmentioning

confidence: 99%

Strained Alkenes in Natural Product Synthesis

Wilson

Taylor

2013

Angew Chem Int Ed

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Strained molecules continue to challenge the ingenuity of chemists as their high-energy bonds serve as fuel for the promotion of complex synthetic transformations. Developments in this area have resulted in the recent emergence of strained alkenes as intermediates in natural product synthesis. This Minireview highlights these recent advances along with current developments toward understanding the unique reactivity of strained alkenes.

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Enantioselective Total Synthesis of (+)‐Homochelidonine by a Pd^II‐Catalyzed Asymmetric Ring‐Opening Reaction of a meso‐Azabicyclic Alkene with an Aryl Boronic Acid

Cited by 14 publications

References 41 publications

Concise Enantioselective Total Syntheses of (+)‐Homochelidonine, (+)‐Chelamidine, (+)‐Chelidonine, (+)‐Chelamine and (+)‐Norchelidonine by a Pd^II‐Catalyzed Ring‐Opening Strategy

Concise Enantioselective Total Syntheses of (+)‐Homochelidonine, (+)‐Chelamidine, (+)‐Chelidonine, (+)‐Chelamine and (+)‐Norchelidonine by a Pd^II‐Catalyzed Ring‐Opening Strategy

Oxygenation of Ruthenium Carbene Complexes Containing Naphthothiophene or Naphthofuran: Spectroscopic and DFT Studies

Strained Alkenes in Natural Product Synthesis

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Enantioselective Total Synthesis of (+)‐Homochelidonine by a PdII‐Catalyzed Asymmetric Ring‐Opening Reaction of a meso‐Azabicyclic Alkene with an Aryl Boronic Acid

Cited by 14 publications

References 41 publications

Concise Enantioselective Total Syntheses of (+)‐Homochelidonine, (+)‐Chelamidine, (+)‐Chelidonine, (+)‐Chelamine and (+)‐Norchelidonine by a PdII‐Catalyzed Ring‐Opening Strategy

Concise Enantioselective Total Syntheses of (+)‐Homochelidonine, (+)‐Chelamidine, (+)‐Chelidonine, (+)‐Chelamine and (+)‐Norchelidonine by a PdII‐Catalyzed Ring‐Opening Strategy

Oxygenation of Ruthenium Carbene Complexes Containing Naphthothiophene or Naphthofuran: Spectroscopic and DFT Studies

Strained Alkenes in Natural Product Synthesis

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Product

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Enantioselective Total Synthesis of (+)‐Homochelidonine by a Pd^II‐Catalyzed Asymmetric Ring‐Opening Reaction of a meso‐Azabicyclic Alkene with an Aryl Boronic Acid

Concise Enantioselective Total Syntheses of (+)‐Homochelidonine, (+)‐Chelamidine, (+)‐Chelidonine, (+)‐Chelamine and (+)‐Norchelidonine by a Pd^II‐Catalyzed Ring‐Opening Strategy

Concise Enantioselective Total Syntheses of (+)‐Homochelidonine, (+)‐Chelamidine, (+)‐Chelidonine, (+)‐Chelamine and (+)‐Norchelidonine by a Pd^II‐Catalyzed Ring‐Opening Strategy