Bifunctional Organocatalysts for the Enantioselective Synthesis of Axially Chiral Isoquinoline <i>N</i>-Oxides

Miyaji, Ryota; Asano, Keisuke; Matsubara, Seijiro

doi:10.1021/jacs.5b04151

Cited by 127 publications

(49 citation statements)

References 55 publications

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“…11 Gratifyingly, a related approach has also been recently reported to access chiral isoquinoline N -oxides using a cinchona alkaloid-derived urea catalyst. 12 It is interesting to note that the enantioselective synthesis of axially chiral quinazolinones is a subject with a limited literature, 13 and most methods have either involved racemic synthesis followed by resolution or diastereoselective synthesis using chiral auxiliaries. Given the growing interest in these compounds in medicinal chemistry, we targeted a catalytic asymmetric approach (Figure 1b).…”

Section: Introductionmentioning

confidence: 99%

Enantioselective Synthesis of 3-Arylquinazolin-4(3H)-ones via Peptide-Catalyzed Atroposelective Bromination

et al. 2015

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We report the development of a tertiary amine-containing β-turn peptide that catalyzes the atroposelective bromination of pharmaceutically relevant 3-arylquinazolin-4(3H)-ones (quinazolinones) with high levels of enantioinduction over a broad substrate scope. The structure of the free catalyst and the peptide-substrate complex were explored using X-ray crystallography and 2D-NOESY experiments. Quinazolinone rotational barriers about the chiral anilide axis were also studied using DFT calculations and are discussed in light of the high enantioselectivities observed. Mechanistic studies also suggest that the initial bromination event is stereo-determining, and the major monobromide intermediate is an atropisomerically stable, mono-ortho-substituted isomer. The observation of stereoisomerically stable monobromides stimulated the conversion of the tribromide products to other, atropisomerically-defined products of interest. For example, (1) a dehalogenation-Suzuki-Miyaura cross-coupling sequence delivers ortho-arylated derivatives, and (2) a regioselective Buchwald-Hartwig amination procedure installs para-amine functionality. Stereochemical information was retained during these subsequent transformations.

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Section: Introductionmentioning

confidence: 99%

Enantioselective Synthesis of 3-Arylquinazolin-4(3H)-ones via Peptide-Catalyzed Atroposelective Bromination

et al. 2015

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“…BINOLderived phosphoric acids have been utilized as Brønsted acid catalysts, [2] and atropisomeric quinoline N-oxides such as QUINOX [3] are excellent Lewis base catalysts for various asymmetric transformations including asymmetric allylation of substituted benzaldehydes, [4,5] asymmetric desymmetrizations of meso epoxides, [6] and asymmetric aldol reactions. [12] Thep otential for subtle control of racemization rates in atropisomeric and near-atropisomeric structures allows the efficient use of dynamic kinetic [13] or thermodynamic [14] resolution. [12] Thep otential for subtle control of racemization rates in atropisomeric and near-atropisomeric structures allows the efficient use of dynamic kinetic [13] or thermodynamic [14] resolution.…”

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confidence: 99%

Biocatalytic Dynamic Kinetic Resolution for the Synthesis of Atropisomeric Biaryl N‐Oxide Lewis Base Catalysts

et al. 2016

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Atropisomeric biaryl pyridine and isoquinoline N-oxides were synthesized enantioselectively by dynamic kinetic resolution (DKR) of rapidly racemizing precursors exhibiting free bond rotation. The DKR was achieved by ketoreductase (KRED) catalyzed reduction of an aldehyde to form a configurationally stable atropisomeric alcohol, with the substantial increase in rotational barrier arising from the loss of a bonding interaction between the N-oxide and the aldehyde. Use of different KREDs allowed either the M or P enantiomer to be synthesized in excellent enantiopurity. The enantioenriched biaryl N-oxide compounds catalyze the asymmetric allylation of benzaldehyde derivatives with allyltrichlorosilane.

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“…Owing to the importance of this structural motif, the catalytic atroposelective construction of axially chiral biaryls has been intensively investigated123456 and could be accessed by enantioselective oxidative/cross coupling of two aryl counterparts,78910111213 asymmetric construction of an aromatic ring14151617181920 and kinetic resolution/desymmetrization of biaryl compounds (Fig. 1a, left)21222324252627282930313233343536. However, in sharp contrast, the axially chiral styrenes bearing a chiral axis between a simple alkene and an aromatic ring have been rarely studied with respect to asymmetric synthesis and applications3738.…”

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confidence: 99%

Organocatalytic atroposelective synthesis of axially chiral styrenes

et al. 2017

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Axially chiral compounds are widespread in biologically active compounds and are useful chiral ligands or organocatalysts in asymmetric catalysis. It is well-known that styrenes are one of the most abundant and principal feedstocks and thus represent excellent prospective building blocks for chemical synthesis. Driven by the development of atroposelective synthesis of axially chiral styrene derivatives, we discovered herein the asymmetric organocatalytic approach via direct Michael addition reaction of substituted diones/ketone esters/malononitrile to alkynals. The axially chiral styrene compounds were produced with good chemical yields, enantioselectivities and almost complete E/Z-selectivities through a secondary amine-catalysed iminium activation strategy under mild conditions. Such structural motifs are important precursors for further transformations into biologically active compounds and synthetic useful intermediates and may have potential applications in asymmetric synthesis as olefin ligands or organocatalysts.

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Bifunctional Organocatalysts for the Enantioselective Synthesis of Axially Chiral Isoquinoline N-Oxides

Cited by 127 publications

References 55 publications

Enantioselective Synthesis of 3-Arylquinazolin-4(3H)-ones via Peptide-Catalyzed Atroposelective Bromination

Enantioselective Synthesis of 3-Arylquinazolin-4(3H)-ones via Peptide-Catalyzed Atroposelective Bromination

Biocatalytic Dynamic Kinetic Resolution for the Synthesis of Atropisomeric Biaryl N‐Oxide Lewis Base Catalysts

Organocatalytic atroposelective synthesis of axially chiral styrenes

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