Electrophilic Zinc Homoenolates: Synthesis of Cyclopropylamines from Cyclopropanols and Amines

Mills, L. Reginald; Arbelaez, Luis Miguel Barrera; Rousseaux, Sophie

doi:10.1021/jacs.7b07104

Cited by 48 publications

(37 citation statements)

References 37 publications

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“…Recently, our group has discovered a method for making cyclopropylamines from cyclopropanols and amines, a protocol which involves electrophilic zinc homoenolates (Scheme ) . In the presence of a Zn II salt and base, cyclopropanol 185 is converted to zinc homoenolate 188 , revealing an electrophilic aldehyde.…”

Section: Homoenolates As Electrophilic Reagentsmentioning

confidence: 99%

Modern Developments in the Chemistry of Homoenolates

Mills

Rousseaux

2018

Eur J Org Chem

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Homoenolates are unique synthetic intermediates which display umpolung reactivity. Homoenolates and homoenolate equivalents like cyclopropanols have seen a recent surge in popularity due to their particular utility for accessing β‐functionalized carbonyl derivatives. This popularity has been enabled by the development of protocols for facile access to cyclopropanols and homoenolates from a variety of readily available starting materials. This microreview will highlight common strategies for generating cyclopropanols and metal homoenolates, as well as procedures for homoenolate functionalization, with a particular emphasis on protocols that have appeared after 2003. As an amphoteric molecule, two main reactivity modes have been established: the homoenolate reacts as a carbon nucleophile for β‐functionalization reactions and/or as a carbonyl electrophile, a strategy which has only emerged in the past few years. This microreview will highlight the use of homoenolates as convenient intermediates for accessing especially challenging motifs. The use of homoenolate chemistry in the context of natural product and pharmaceutical synthesis will also be presented.

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Section: Homoenolates As Electrophilic Reagentsmentioning

confidence: 99%

Modern Developments in the Chemistry of Homoenolates

Mills

Rousseaux

2018

Eur J Org Chem

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“…Afterward, we applied some chemical modifications to the TCP structure by preparing compounds 4 a – h , in which the primary amine group of TCP has been changed into secondary ( N ‐methyl‐TCP, 4 a ) or tertiary ( N , N ‐dimethyl‐TCP, 4 b ) amine, or transformed into carboxamide ( 4 c ) or carbohydrazide ( 4 d ). The isomeric 1‐phenylcyclopropan‐1‐amine ( 4 e ) and the related benzyl {1‐[(4‐(1‐aminocyclopropyl)phenyl)amino]‐1‐oxo‐3‐phenylpropan‐2‐yl}carbamate hydrochloride ( 4 f , a 2 a isomer) were also prepared, together with the related 1‐phenylcyclopropane‐1‐carboxamide ( 4 g ), (1‐phenylcyclopropyl)methanamine ( 4 h ), and 2‐phenylaziridin‐1‐amine ( 4 i ) .…”

Section: Resultsmentioning

confidence: 99%

“…Afterward, we applied some chemical modifications to the TCP structure by preparing compounds 4 a-h, in which the primary amine group of TCP has been changed into secondary (N-methyl-TCP, 4 a) [15] or tertiary (N,N-dimethyl-TCP, 4 b) [16] amine, or transformed into carboxamide (4 c) [15] or carbohydrazide (4 d). The isomeric 1-phenylcyclopropan-1-amine (4 e) and…”

Section: Design Synthesis and Enzyme Inhibition Datamentioning

confidence: 99%

Tranylcypromine‐Based LSD1 Inhibitors: Structure‐Activity Relationships, Antiproliferative Effects in Leukemia, and Gene Target Modulation

et al. 2020

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LSD1 is a lysine demethylase highly involved in initiation and development of cancer. To design highly effective covalent inhibitors, a strategy is to fill its large catalytic cleft by designing tranylcypromine (TCP) analogs decorated with long, hindered substituents. We prepared three series of TCP analogs, carrying aroyl‐ and arylacetylamino (1 a–h), Z‐amino acylamino (2 a–o), or double‐substituted benzamide (3 a–n) residues at the C4 or C3 position of the phenyl ring. Further fragments obtained by chemical manipulation applied on the TCP scaffold (compounds 4 a–i) were also prepared. When tested against LSD1, most of 1 and 3 exhibited IC50 values in the low nanomolar range, with 1 e and 3 a,d,f,g being also the most selective respect to monoamine oxidases. In MV4‐11 AML and NB4 APL cells compounds 3 were the most potent, displaying up to sub‐micromolar cell growth inhibition against both cell lines (3 a) or against NB4 cells (3 c). The most potent compounds in cellular assays were also able to induce the expression of LSD1 target genes, such as GFI‐1b, ITGAM, and KCTD12, as functional read‐out for LSD1 inhibition. Mouse and human intrinsic clearance data highlighted the high metabolic stability of compounds 3 a, 3 d and 3 g. Further studies will be performed on the new compounds 3 a and 3 c to assess their anticancer potential in different cancer contexts.

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“…Rousseaux and coworkers reported a novel use of cyclopropanol-derived zinc homoenolates as ambident species for the synthesis of cyclopropylamines (Scheme 10). 19 Thus, treatment of a mixture of trans-2-substituted cyclopropanol and secondary amine with Zn(CN)2 and Na2CO3 in 1,4-dioxane under heating conditions furnished trans-2-substituted cyclopropylamine in moderate to good yields with good to high diastereoselectivities. The reaction is proposed to proceed via reversible ring-opening of the cyclopropanol to a zinc aldehyde homoenolate, its condensation with the amine, and ring-closing of the iminium intermediate to furnish the cyclopropylamine product.…”

Section: Methodsmentioning

confidence: 99%

Metal-Catalyzed Transformations of Cyclopropanols via Homoenolates

Sekiguchi

Yoshikai

2020

Bulletin of the Chemical Society of Japan

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Advance Publication is a service for online publication of manuscripts prior to releasing fully edited, printed versions. Entire manuscripts and a portion of the graphical abstract can be released on the web as soon as the submission is accepted. Note that the Chemical Society of Japan bears no responsibility for issues resulting from the use of information taken from unedited, Advance Publication manuscripts.

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Electrophilic Zinc Homoenolates: Synthesis of Cyclopropylamines from Cyclopropanols and Amines

Cited by 48 publications

References 37 publications

Modern Developments in the Chemistry of Homoenolates

Modern Developments in the Chemistry of Homoenolates

Tranylcypromine‐Based LSD1 Inhibitors: Structure‐Activity Relationships, Antiproliferative Effects in Leukemia, and Gene Target Modulation

Metal-Catalyzed Transformations of Cyclopropanols via Homoenolates

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