An Asymmetric Approach towards (–)‐Aphanorphine and Its Analogues

Donets, Pavel A.; Goeman, Jan; Eycken, Johan Van der; Robeyns, Koen; Meervelt, Luc Van; Eycken, Erik Van der

doi:10.1002/ejoc.200801175

Cited by 40 publications

(21 citation statements)

References 19 publications

(15 reference statements)

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“…This core has been described in the structure of few natural products, whose leading members are (i) apogalanthamine (15), an alkaloid from the Amaryllidaceae family and (ii) buflavine (16), a natural extract from Boophane flava ( Figure 2) [11,12]. Interestingly, the profile of the temperature ramp exerts a strong influence on the chemoselectivity of this reaction.…”

Section: -Benzazepines and Their Derivativesmentioning

confidence: 99%

“…In the second step, the propargylamines 32 undergo a stereoselective Pd-catalysed (PdPPh3, 3%) intramolecular hydroarylation reaction of the acetylene group under MW-irradiation (110 °C, 100 W, 15 min), leading to the expected 3-benzazepines in 32-91% yield (33, Scheme 4) [16]. In this synthesis, the MW-assisted Heck reaction allowed the cyclisation of the 3-benzazepine ring 27, as outlined in Scheme 3 [15]. This intramolecular coupling has been carried out by applying a maximum power level of 300 W at 100˝C for 20 min, in presence of Hermann's palladacycle as catalyst (2.5%) and NaHCO 2 as reducing agent.…”

Section: -Benzazepines and Their Derivativesmentioning

confidence: 99%

“…This intramolecular coupling has been carried out by applying a maximum power level of 300 W at 100˝C for 20 min, in presence of Hermann's palladacycle as catalyst (2.5%) and NaHCO 2 as reducing agent. In this synthesis, the MW-assisted Heck reaction allowed the cyclisation of the 3-benzazepine ring 27, as outlined in Scheme 3 [15]. This intramolecular coupling has been carried out by applying a maximum power level of 300 W at 100 °C for 20 min, in presence of Hermann's palladacycle as catalyst (2.5%) and NaHCO2 as reducing agent.…”

Section: -Benzazepines and Their Derivativesmentioning

confidence: 99%

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Microwave-Assisted Syntheses of Bioactive Seven-Membered, Macro-Sized Heterocycles and Their Fused Derivatives

et al. 2016

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This review describes the recent advances in the microwave-assisted synthesis of 7-membered and larger heterocyclic compounds. Several types of reaction for the cyclization step are discussed: Ring Closing Metathesis (RCM), Heck and Sonogashira reactions, Suzuki-Miyaura cross-coupling, dipolar cycloadditions, multi-component reactions (Ugi, Passerini), etc. Green syntheses and solvent-free procedures have been introduced whenever possible. The syntheses discussed herein have been selected to illustrate the huge potential of microwave in the synthesis of highly functionalized molecules with potential therapeutic applications, in high yields, enhanced reaction rates and increased chemoselectivity, compared to conventional methods. More than 100 references from the recent literature are listed in this review.

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Section: -Benzazepines and Their Derivativesmentioning

confidence: 99%

Section: -Benzazepines and Their Derivativesmentioning

confidence: 99%

Section: -Benzazepines and Their Derivativesmentioning

confidence: 99%

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Microwave-Assisted Syntheses of Bioactive Seven-Membered, Macro-Sized Heterocycles and Their Fused Derivatives

et al. 2016

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“…The fused ring system of the tricyclic alkaloid had posed a challenge in its construction due to the congested quaternary carbon attached to the aromatic ring. To tackle this problem, we designed a synthetic route featuring “dual” radical bond formation onto a γ‐lactam by combining sp 3 C–H transformation and radical cyclization . In our proposed route, the radical sp 3 C–H hydroxyalkylation methodology would provide the appropriate key scaffold 25 (although its hydroxyl group would be eventually removed), which would further be converted into alkene 27 and subjected to radical cyclization to afford the tricyclic aphanorphine motif (Scheme ) …”

Section: Free‐radical‐mediated Sp3c–h Transformations In Natural Prodmentioning

confidence: 99%

Endeavors to Access Molecular Complexity: Strategic Use of Free Radicals in Natural Product Synthesis

Yoshimitsu

2014

The Chemical Record

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Free radicals, which in the past were considered unruly chemical species, have become manageable and indispensable for synthetic organic chemistry. The unique nature of free radicals has allowed practitioners in organic synthesis to design flexible approaches to produce various materials ranging from small molecules to polymers. The present Personal Account describes the author's endeavors to create molecular complexity by the strategic use of free radicals, with an emphasis on the synthesis of bioactive natural products.

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“…Aphanorphine (1) 1 is an alkaloid that shares structural features with the analgesic benzomorphan alkaloids eptazocine (3), pentazocine (4) and morphine (5, Fig. 1).…”

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confidence: 99%

An enantioselective approach to (−)-aphanorphine featuring a stereoselective oxidative amidation

Pansare

Kulkarni

2013

RSC Adv.

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A formal enantioselective synthesis of (2)-aphanorphine (91% ee), that culminates with the preparation of (+)-O-methyl aphanorphine, was achieved. The methodology involves the diastereoselective synthesis of a key 3,5-disubstituted pyrrolidinone intermediate by the intramolecular oxidative amidation of a suitably functionalized a-hydroxy pentenoic acid derivative. A late-stage N-formyl protection, which functions as a latent N-methyl group, is utilized as a simple alternative to a protecting group switch and subsequent N-methylation strategy implemented in all other syntheses of aphanorphine related to the present approach.Aphanorphine (1) 1 is an alkaloid that shares structural features with the analgesic benzomorphan alkaloids eptazocine (3), pentazocine (4) and morphine (5, Fig. 1). This structural resemblance and the synthetically intriguing 3-benzazepine ring system and quaternary stereocenter have all contributed to significant interest in the synthesis of aphanorphine, 2-4 which continues to be a popular target for showcasing new methodology leading to the benzazepine motif. We describe here a synthesis of (+)-O-methyl aphanorphine (2), an immediate synthetic precursor of (2)-aphanorphine.Our interest in aphanorphine stems from our studies on the enantioselective synthesis and applications of a-alkyl a-hydroxy acid derivatives as intermediates to biologically relevant motifs and natural products. 5 We therefore envisaged an a-hydroxy acid based route to aphanorphine as detailed in Scheme 1. The strategy utilizes a stereoselective, intramolecular C-N bond formation as a pivotal step in the synthesis of a key pyrrolidine intermediate. A cyclative Friedel-Crafts alkylation in this pyrrolidine is used, as in previous aphanorphine syntheses, 2a,3a,4f for constructing the bridged benzazepine motif in aphanorphine. The precursor of the pyrrolidine is obtained by a cross metathesis reaction of an enantiomerically enriched a-hydroxy pentenoic acid derivative which, in turn, is obtained by asymmetric allylation of a chiral pyruvate (Scheme 1).Initially, we chose to explore the synthesis of a suitably substituted N-methyl pyrrolidinone as a precursor to the functionalized pyrrolidine motif in aphanorphine. The motivation for this approach was twofold: 1) several substituted N-methyl pyrrolidinones are natural products 6 or motifs in bioactive molecules, 7 and the present study could potentially provide methodology for their synthesis as well; and 2) the starting material for the pyrrolidinone based approach, the a-hydroxy N-methyl amide (R)-8 5f (Scheme 2) is directly obtained by our asymmetric allylation protocol 5f employing an ephedrine-derived chiral pyruvamide. Furthermore, the intramolecular Friedel-Crafts alkylation (Scheme 1) of the N-methyl pyrrolidine, obtained from the pyrrolidinone, could potentially provide the aphanorphine framework. Our studies therefore commenced with (R)-8 (92% ee) which was prepared by the asymmetric allylation of an ephedrine and pyruvic acidderived morpholinone 6 as shown in Sche...

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An Asymmetric Approach towards (–)‐Aphanorphine and Its Analogues

Cited by 40 publications

References 19 publications

Microwave-Assisted Syntheses of Bioactive Seven-Membered, Macro-Sized Heterocycles and Their Fused Derivatives

Microwave-Assisted Syntheses of Bioactive Seven-Membered, Macro-Sized Heterocycles and Their Fused Derivatives

Endeavors to Access Molecular Complexity: Strategic Use of Free Radicals in Natural Product Synthesis

An enantioselective approach to (−)-aphanorphine featuring a stereoselective oxidative amidation

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