Stereoselective Synthesis of a Ceramide Transporter Protein (CERT)-Dependent Ceramide-Trafficking Inhibitor, (1R,3S)-HPA-12, via Gold(I)-Catalyzed Cyclization of a Propargylic N-Hydroxylamine

Chandrasekhar, B.; Ahn, Sewon; Ryu, Jae Sang

doi:10.1055/s-0036-1588369

Cited by 4 publications

(1 citation statement)

References 7 publications

(7 reference statements)

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“…1) using a Zn-catalyzed asymmetric Mannich-type reaction in water, and unambiguously ascertained the revised configuration by X-ray crystallography [14]. The other syntheses of (1 R ,3 S )-HPA-12 ( 2 ) used the chiral pool approach [15–16], crystallization-induced asymmetric transformation [17], diastereoselective reduction of γ-aryl-γ-oxo-β-amino alcohol [18], cycloaddition of oxime with alkenes [19], enantioselective carbonyl reduction followed by an organocatalyzed α-amination reaction [20], tandem approach from ( S )-Wynberg lactone [21], chiral ruthenium-catalyzed N -demethylative rearrangement of 1,2-isoxazolidines [22], gold(I)-catalyzed cyclization of a propargylic N -hydroxylamine [23], from β-sulfinamido ketones derived from chiral sulfinimines [24], and a Kornblum–DeLaMare/aza-Michael reaction of 3,6-dihydro-1,2-dioxines followed by diastereoselective reduction [25]. Most of these methods employ starting materials or catalysts, which are not commercially available, and also require operationally demanding reaction conditions.…”

Section: Introductionmentioning

confidence: 99%

A chemoenzymatic synthesis of ceramide trafficking inhibitor HPA-12

Kanojia

Chatterjee

Chattopadhyay

et al. 2019

Beilstein J. Org. Chem.

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A chemoenzymatic synthesis of the title compound has been developed using an efficient and highly enantioselective lipase-catalyzed acylation in a hydrophobic ionic liquid, [bmim][PF6], followed by a diastereoselective asymmetric dihydroxylation as the key steps for incorporating the stereogenic centers. The further conversion to the appropriate intermediates and subsequent acylation with lauric acid furnished the target compound.

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Section: Introductionmentioning

confidence: 99%

A chemoenzymatic synthesis of ceramide trafficking inhibitor HPA-12

Kanojia

Chatterjee

Chattopadhyay

et al. 2019

Beilstein J. Org. Chem.

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Asymmetric Clicking of Alkynyl Dipolarophiles and Nitrones Catalyzed by a Well-Defined Chiral Iron Complex

Zhao,

He,

Wang

et al. 2024

ACS Catal.

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The enantioselective 1,3-dipolar cycloaddition of alkynes and α-aliphatic nitrones has long been recognized as an important challenge, while considerable progress has been made for the alkenes and aromatic nitrones. We herein report an example of an earth-abundant iron-catalyzed enantioselective click-approach 1,3-dipolar cycloaddition of nonterminal alkynyl imides and αaliphatic nitrones, and highly functionalized chiral 4-isoxazolines having a 3-alkyl-substituted stereogenic carbon center are modularly generated in up to >99% yield and 98% ee (54 examples). Although the steric bulk substituent on the nitrone plays a key role in achieving effective enantiocontrol, the challenge of steric bias differentiation between linear alkyl chain (Me, Et, etc.) and H of nitrones is also successfully overcome. The enantioface discrimination is presumably rooted in the well-defined octahedral mononuclear ferrous complex containing dual tridentate ligands (L*•Fe(OTf) 2 •L*, L* = (R,R)-DBFOX-Ph) and possible dual-mode σ,π-binding activation, which is evidenced by ESI-HRMS and single crystal X-ray analysis, as well as the L*/Fe ratio effect and DFT calculations. Arguably, the most interesting aspect is that the chiral iron complex can induce a superpositive nonlinear effect and the chiral bisoxazoline ligand with a low enantiopurity of 22% ee results in an 84% ee for the cycloadduct. Practicability and utility are demonstrated by the gram-scale synthesis and ready downstream functionalization based on the chiral 4isoxazoline core and imide functional group.

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Fast MacMillan’s Imidazolidinone-Catalyzed Enantioselective Synthesis of Polyfunctionalized 4-Isoxazoline Scaffolds

et al. 2022

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The enantioselective 1,3-dipolar cycloaddition of nitrones and arylpropionaldehydes to generate highly functionalized scaffolds for application in drug discovery was herein investigated. The use of a second-generation MacMillan catalyst as hydrochloride salt consistently accelerated the reaction speed, allowing a decrease in the reaction time up to >100 times, still affording 4-isoxazolines with good to excellent enantiomeric ratios at room temperature. As a proof of concept, further functionalization of the isoxazoline core through Pd-catalyzed cross-coupling was performed, generating differently functionalized chemical architectures in high yield.

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Stereoselective Synthesis of a Ceramide Transporter Protein (CERT)-Dependent Ceramide-Trafficking Inhibitor, (1R,3S)-HPA-12, via Gold(I)-Catalyzed Cyclization of a Propargylic N-Hydroxylamine

Cited by 4 publications

References 7 publications

A chemoenzymatic synthesis of ceramide trafficking inhibitor HPA-12

A chemoenzymatic synthesis of ceramide trafficking inhibitor HPA-12

Asymmetric Clicking of Alkynyl Dipolarophiles and Nitrones Catalyzed by a Well-Defined Chiral Iron Complex

Fast MacMillan’s Imidazolidinone-Catalyzed Enantioselective Synthesis of Polyfunctionalized 4-Isoxazoline Scaffolds

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