Enantioselective Synthesis of 2-Substituted Pyrrolidines via Intramolecular­ Reductive Amination

Zhou, Huan; Zhao, Wenguang; Zhang, Tao; Guo, Haodong; Huang, Hefei; Chang, Mingxin

doi:10.1055/s-0037-1611533

Cited by 8 publications

(13 citation statements)

References 6 publications

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“…Of particular interest are products 3f and 3k , which are motifs featured in the APIs larotrectinib, and MSC2530818 (Figure ), respectively. In contrast, recent examples of the asymmetric synthesis of 2-aryl- N -heterocycles employing a reductive amination strategy using transition-metal catalysts are mostly limited to <90% ee , with only a few exceptions. − Biocatalytic imine reduction using IREDs generally reaches >99 ee ; however, the starting imines for this strategy are typically not commercially available. Fanourakis et al reported the synthesis of ( R )- 3c in 33% yield and 89% ee starting from readily available 4-phenylbutan-1-ol by employing an asymmetric benzylic C-H activation strategy, followed by Mitsunobu cyclization and deprotection.…”

Section: Resultsmentioning

confidence: 99%

Enantio-Complementary Synthesis of 2-Substituted Pyrrolidines and Piperidines via Transaminase-Triggered Cyclizations

Heckmann

Paul

2023

JACS Au

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Chiral N-heterocycles are a common motif in many active pharmaceutical ingredients; however, their synthesis often relies on the use of heavy metals. In recent years, several biocatalytic approaches have emerged to reach enantiopurity. Here, we describe the asymmetric synthesis of 2substituted pyrrolidines and piperidines, starting from commercially available ω-chloroketones by using transaminases, which has not yet been comprehensively studied. Analytical yields of up to 90% and enantiomeric excesses of up to >99.5% for each enantiomer were achieved, which has not previously been shown for bulky substituents. This biocatalytic approach was applied to synthesize (R)-2-(p-chlorophenyl)pyrrolidine on a 300 mg scale, affording 84% isolated yield, with >99.5% ee.

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Section: Resultsmentioning

confidence: 99%

Enantio-Complementary Synthesis of 2-Substituted Pyrrolidines and Piperidines via Transaminase-Triggered Cyclizations

Heckmann

Paul

2023

JACS Au

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“…Protecting groups are an important consideration in the manufacture of pharmaceuticals and fine chemicals. However, iridium catalysts are sensitive to NH-protecting groups and generally Boc protection is used. ,, Thus, we next examined the tolerance of different protecting groups at a substrate/catalyst ratio of 10,000, with the results summarized in Table . Pleasingly, a variety of the NH-protecting groups were well tolerated, such as N-Ts ( 3a ), N–Ac ( 3b ), N-Cbz ( 3c ), N-Bz ( 3d ), N-COOEt ( 3f ), and N-COO i Pr ( 3g ), and high turnovers and excellent enantioselectivities were obtained (>10,000 TON, 97–99% yields, >99% ee).…”

Section: Resultsmentioning

confidence: 99%

PPM Ir-f-phamidol-Catalyzed Asymmetric Hydrogenation of γ-Amino Ketones Followed by Stereoselective Cyclization for Construction of Chiral 2-Aryl-pyrrolidine Pharmacophores

Yin,

Zhang,

Pan

et al. 2023

J. Org. Chem.

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Transition metal catalysts with a million turnovers and excellent selectivity are rarely reported but are crucial for the industrial manufacture of optical pure pharmaceuticals, natural products, and fine chemicals. In this paper, we report an unprecedented aninoic Ir-f-phamidol catalyst for asymmetric hydrogenation of γ-amino ketones followed by stereoselective cyclization for construction of valuable chiral 2-aryl-pyrrolidine pharmacophores. The Ir-f-phamidol catalyst showed up to 1,000,000 TON and >99% ee, as well as excellent tolerance of substrates and protecting groups, providing various chiral amino alcohol intermediates. Upon optimization of the conditions, the stereoselective cyclization reaction was highly smooth and efficient (quantitative conversions, 92 to >99% ee). Finally, this solution was applied in the preparation of high-value chiral entities containing such chiral 2-aryl-pyrrolidine pharmacophores.

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“…The synthesis of N ‐substituted α‐diazo‐γ‐lactams 1 by diazo transfer required that the starting γ‐lactam be activated via α‐ethoxalylation . Unfortunately, neither ethoxalylation nor formylation of the enolate generated from known (as well as commercially available) N ‐Boc 2‐pyrrolidone ( 4 ) with respective esters did not produce the desired derivative, most likely, due to the removal of the Boc group by the alkoxy group liberated in the course of the reaction (as judged by the observed extensive gas evolution). So, it was decided to introduce a ( N , N ‐dimethylamino)methylene moiety as an equivalent to formylation.…”

Section: Resultsmentioning

confidence: 99%

tert‐Butyl 3‐Diazo‐2‐oxopyrrolidine‐1‐carboxylate – A New Reagent for Introduction of the 2‐Oxopyrrolidin‐3‐yl Motif via Rh^II‐Catalyzed X–H Insertion Reactions

2020

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tert-Butyl 3-diazo-2-oxopyrrolidine-1-carboxylate synthesized on multigram scale has been employed to introduce a privileged NH-2-pyrrolidone moiety via oxygen, sulfur[a] Saint 3013 and nitrogen atom to partner molecules via Rh II -catalyzed X-H insertion followed by Boc group removal. Further manipulation of pyrrolidine moiety has been exemplified. periphery element -endows the resulting compounds with diverse biological activities as the result of affinity to respective protein targets. [1] Besides approved drugs based on 2-pyrrolidone as a scaffold (e.g., natural metabolite of nicotine, antidepressant cotinine, [2] respiratory stimulant doxapram, [3] nootropic and cognition-modulating drug piracetam [4] and antiseizure ethosuximide [5] ), there is a wealth of bioactive molecules featured in the recent patent literature which contains an N-unsubstituted ("NH-") 2-pyrrolidone moiety as an element of molecular periphery, linked via a bond between C-3 and a heteroatom (mostly nitrogen, less frequently oxygen or sulfur). Relevant examples, include Bruton's tyrosine kinase inhibitor Full Paper 1, [6] inhibitor of respiratory syncytial virus (RSV) 2, [7] Syngenta's fungicide 3, [8] immunomodulating inhibitor of IL-17 4, [9] hepatitis B virus capsid assembly modulator 5, [10] adenosine receptor modulator 6, [11] ghrelin O-acyl transferase (GOAT) inhibitor 7 for treatment of diabetes and obesity, [12] ubiquitin-specific processing protease 7 (USP7) inhibitor 8 for cancer treatment [13] and cannabinoid receptor hCB2 agonist 9 [14] (Figure 1).From drug design prospective, the advantages of using NH-2-pyrrolidone are quite intuitive as this polar (cLog P = -0.18 [15] ) motif contains a hydrogen-bond donor/acceptor pair capable of building cooperative interactions with protein backbone, would likely improve drug candidate's aqueous solubility and will not reflect negatively on the molecule's degree of saturation (F sp3 ), a routinely observed parameter in modern drug discovery. [16,17] The primary means of introducing the NH-2-pyrrolidone moiety is via the use of either 3-amino-2-pyrrolidone or 3-bromo-2-pyrrolidone. Recently, we have been investigating synthesis and Rh II -catalyzed X-H insertion reactions of a novel type of α-diazocarbonyl compounds -α-diazo-γ-lactams 1. [18][19][20] The primary limitation of this chemistry was identified with respect to the substituents on the lactam nitrogen atom: the diazo compounds were stable to isolation and use in subsequent transformation only for N-aryl lactams, i.e. when the nitrogen lone pair is delocalized thereby increasing the electron-withdrawing character of the aminocarbonyl moiety. In contrast, N-alkyl derivatives (as well as o-substituted aromatic groups incapable of effective conjugation for steric reasons) are unstable due to nitrogen-extrusive dimerization [18] and can only be used in situ, as soon as they have been obtained. [21] We reasoned that if an alkoxycarbonyl-type protecting group (e.g., Boc as in 2) was placed on the nitrogen atom of α-diazo-γ-lactam core...

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Enantioselective Synthesis of 2-Substituted Pyrrolidines via Intramolecular Reductive Amination

Cited by 8 publications

References 6 publications

Enantio-Complementary Synthesis of 2-Substituted Pyrrolidines and Piperidines via Transaminase-Triggered Cyclizations

Enantio-Complementary Synthesis of 2-Substituted Pyrrolidines and Piperidines via Transaminase-Triggered Cyclizations

PPM Ir-f-phamidol-Catalyzed Asymmetric Hydrogenation of γ-Amino Ketones Followed by Stereoselective Cyclization for Construction of Chiral 2-Aryl-pyrrolidine Pharmacophores

tert‐Butyl 3‐Diazo‐2‐oxopyrrolidine‐1‐carboxylate – A New Reagent for Introduction of the 2‐Oxopyrrolidin‐3‐yl Motif via Rh^II‐Catalyzed X–H Insertion Reactions

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Enantioselective Synthesis of 2-Substituted Pyrrolidines via Intramolecular­ Reductive Amination

Cited by 8 publications

References 6 publications

Enantio-Complementary Synthesis of 2-Substituted Pyrrolidines and Piperidines via Transaminase-Triggered Cyclizations

Enantio-Complementary Synthesis of 2-Substituted Pyrrolidines and Piperidines via Transaminase-Triggered Cyclizations

PPM Ir-f-phamidol-Catalyzed Asymmetric Hydrogenation of γ-Amino Ketones Followed by Stereoselective Cyclization for Construction of Chiral 2-Aryl-pyrrolidine Pharmacophores

tert‐Butyl 3‐Diazo‐2‐oxopyrrolidine‐1‐carboxylate – A New Reagent for Introduction of the 2‐Oxopyrrolidin‐3‐yl Motif via RhII‐Catalyzed X–H Insertion Reactions

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Product

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About

Enantioselective Synthesis of 2-Substituted Pyrrolidines via Intramolecular Reductive Amination

tert‐Butyl 3‐Diazo‐2‐oxopyrrolidine‐1‐carboxylate – A New Reagent for Introduction of the 2‐Oxopyrrolidin‐3‐yl Motif via Rh^II‐Catalyzed X–H Insertion Reactions