Preparation of H,4 PyrrolidineQuin-BAM (PBAM)

Davis, Tyler A.; Dobish, Mark C.; Schwieter, Kenneth E.; Chun, Aspen; Johnston, Jeffrey N.

doi:10.15227/orgsyn.089.0380

Cited by 19 publications

(11 citation statements)

References 10 publications

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“…23,31 Several minor modifications were introduced in order to improve yields and overall throughput of the material (Scheme 4). In the Combes synthesis of 2,4-dichloro-8-methoxyquinoline 12 , dilution of the reaction mixture improved the yield of the quinoline 3-fold.…”

Section: Resultsmentioning

confidence: 99%

Development of an Intermittent-Flow Enantioselective Aza-Henry Reaction Using an Arylnitromethane and Homogeneous Brønsted Acid–Base Catalyst with Recycle

Tsukanov

Johnson

May

et al. 2016

Org. Process Res. Dev.

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A stereoselective aza-Henry reaction between an arylnitromethane and Boc-protected aryl aldimine using a homogeneous Brønsted acid–base catalyst was translated from batch format to an automated intermittent-flow process. This work demonstrates the advantages of a novel intermittent-flow setup with product crystallization and slow reagent addition which is not amenable to the standard continuous equipment: plug flow tube reactor (PFR) or continuous stirred tank reactor (CSTR). A significant benefit of this strategy was the integration of an organocatalytic enantioselective reaction with straightforward product separation, including recycle of the catalyst, resulting in increased intensity of the process by maintaining high catalyst concentration in the reactor. A continuous campaign confirmed that these conditions could effectively provide high throughput of material using an automated system while maintaining high selectivity, thereby addressing nitroalkane safety and minimizing catalyst usage.

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Section: Resultsmentioning

confidence: 99%

Development of an Intermittent-Flow Enantioselective Aza-Henry Reaction Using an Arylnitromethane and Homogeneous Brønsted Acid–Base Catalyst with Recycle

Tsukanov

Johnson

May

et al. 2016

Org. Process Res. Dev.

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“…When using aryl nitromethane pronucleophiles, enantioselectivity observed when using 4-pyrrolidine bisamidine (PBAM, 17 ) 29 is not improved by the addition of an equal amount of triflic acid, as is often the case with most other nitroalkanes. 30, 31 Our hypothesis is that the acidic aryl nitroalkane serves as the Brønsted acid cocatalyst in these reactions.…”

Section: Resultsmentioning

confidence: 99%

Preparation of (−)-Nutlin-3 Using Enantioselective Organocatalysis at Decagram Scale

et al. 2013

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Chiral nonracemic cis-4,5-bis(aryl) imidazolines have emerged as a powerful platform for the development of cancer chemotherapeutics, stimulated by the Hoffmann-La Roche discovery that Nutlin-3 can restore apoptosis in cells with wild-type p53. The lack of efficient methods for the enantioselective synthesis of cis-imidazolines, however, has limited their more general use. Our disclosure of the first enantioselective synthesis of (−)-Nutlin-3 provided a basis to prepare larger amounts of this tool used widely in cancer biology. Key to the decagram-scale synthesis described here was the discovery of a novel bis(amidine) organocatalyst that provides high enantioselectivity at warmer reaction temperature (−20 °C) and low catalyst loadings. Further refinements to the procedure led to the synthesis of (−)-Nutlin-3 in a 17 gram batch, and elimination of all but three chromatographic purifications.

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“…The role of synthetic peptides and peptidomimetics among marketed pharmaceuticals continues to increase, with over 50 approved as medicines. 4 This has resulted in substantial pressure to improve amide bond-forming methods, particularly those reliant on ‘coupling reagents’ used for carboxylic acid-amine condensations. 5 This has accelerated innovation in amide bond synthesis, leading to a range of new methods.…”

Section: Discussionmentioning

confidence: 99%

“…3 The final enantioselective organocatalytic aza-Henry step with bromonitromethane was conducted in the presence of the 5% of PBAM catalyst. 4 Filtration of the reaction through a plug of silica gel alleviates the need for chromatography and simplifies the isolation of the product. The α-bromonitroalkanes 3 are obtained with high ee (95–97%) and good overall yield for use directly in an UmAS coupling.…”

Section: Discussionmentioning

confidence: 99%

Enantioselective Synthesis of α-Bromonitroalkanes for Umpolung Amide Synthesis: Preparation of tert-Butyl ((1R)-1-(4-(benzyloxy)phenyl)-2-bromo-2-nitroethyl)carbamate

et al. 2016

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Preparation of H,4 PyrrolidineQuin-BAM (PBAM)

Cited by 19 publications

References 10 publications

Development of an Intermittent-Flow Enantioselective Aza-Henry Reaction Using an Arylnitromethane and Homogeneous Brønsted Acid–Base Catalyst with Recycle

Development of an Intermittent-Flow Enantioselective Aza-Henry Reaction Using an Arylnitromethane and Homogeneous Brønsted Acid–Base Catalyst with Recycle

Preparation of (−)-Nutlin-3 Using Enantioselective Organocatalysis at Decagram Scale

Enantioselective Synthesis of α-Bromonitroalkanes for Umpolung Amide Synthesis: Preparation of tert-Butyl ((1R)-1-(4-(benzyloxy)phenyl)-2-bromo-2-nitroethyl)carbamate

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