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/anie.200603945

Cited by 81 publications

(34 citation statements)

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“…[15] 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 (+)-homochelidonine [17] 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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“…[39] Methylene acetals are usually obtained by reaction with a methylene dihalide. [40,41] The resulting methylenedioxy group is relatively stable, but can be efficiently deprotected by use of a suitable Lewis acid such as a boron [42,43] or aluminium [44,45] halide. Acetone can be used to convert catechols into the corresponding acetonides [46] which are hydrolyzed in acidic conditions.…”

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confidence: 99%

Redox‐Active Catechol‐Functionalized Molecular Rods: Suitable Protection Groups and Single‐Molecule Transport Investigations

Weibel

Błaszczyk²,

Hänisch³

et al. 2007

Eur J Org Chem

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The synthesis of molecular rod 1 comprising a central redox‐active unit and two terminal acetyl‐protected sulfur groups is reported. Various protecting groups for the catechol moiety were investigated and protected precursors 14–18 were synthesized. In particular, ethyl orthoformate 17 can be easily and selectively deprotected in mild acidic conditions ruling out the need for a strong Lewis acid like boron tribromide. The redox activity of 1 was confirmed by cyclic voltammetric investigations. Gold–molecule–gold junctions were formed with the dimethyl‐protected rod 18. Single‐molecule transport investigations using this molecular rod revealed a set of three single‐junction conductance values varying over two orders of magnitude.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

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“…In 2007, Lautens and co‐workers reported first catalytic asymmetric total synthesis of (+)‐homochelidonine ( 18 c ). The azabicycle 53 c was obtained from a [4+2]‐cycloaddition between an aryne derived from dibromoarene 53 a and N ‐Boc‐pyrrole ( 53 b ) (Scheme ) . Ring opening of aza‐bicycle 53 d was carried out with arylboronic acid 53 e in the presence of 5 mol% of Pd(0) [prepared insitu from 5 mol% of PdCl 2 and 5 mol% ( S )‐BINAP].…”

Section: Synthetic Strategies For Hexahydro[c]phenanthridine Alkaloidsmentioning

confidence: 99%

Biosynthetic Relationships and Total Syntheses of Naturally Occurring Benzo[c]Phenanthridine Alkaloids

et al. 2019

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Benzo[c]phenanthridine alkaloids sharing a tetracyclic structural motif, are an important class of nitrogencontaining small molecules and are used for the treatment of a number of diseases. This review presents a comprehensive survey of the occurrence, chemistry, biochemistry, and biological activity of benzophenanthridine alkaloids. Synthetic approaches to a number of benzo[c]phenanthridine are disclosed in this Minireview. Biosynthetic Relationship of Tetrahydroisoquinoline and Benzo[c]phenanthridine AlkaloidsA plausible biogenetic connection between tetrahydroisoquinoline and benzo[c]phenanthridine alkaloids is shown in Scheme 1. Protopine (3 a) can undergo a demethylation followed by reductive amination to generate tetrahydroisoquinoline alkaloid, stylopine (2 a). The latter can further undergo an [a] Dr. oxidative CÀ N bond cleavage leading to intermediate aldehyde 4 a, which can form a new CÀ C bond (see, 4 c) assisted by in-situ prepared enamine. An elimination followed by oxidation leads to the synthesis of norsanguinarine (1 a).

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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 81 publications

References 43 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

Redox‐Active Catechol‐Functionalized Molecular Rods: Suitable Protection Groups and Single‐Molecule Transport Investigations

Biosynthetic Relationships and Total Syntheses of Naturally Occurring Benzo[c]Phenanthridine Alkaloids

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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 81 publications

References 43 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

Redox‐Active Catechol‐Functionalized Molecular Rods: Suitable Protection Groups and Single‐Molecule Transport Investigations

Biosynthetic Relationships and Total Syntheses of Naturally Occurring Benzo[c]Phenanthridine Alkaloids

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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