Biocatalytic Synthesis of Metaxalone and Its Analogues

Wang, Zhu-Xiang; Fu, Hong-Kang; Da, Xin-Yu; Wang, Hui-Hui; Cui, Bao-Dong; Han, Wen-Yong; Chen, Yong-Zheng; Wan, Nan-Wei

doi:10.1021/acs.orglett.3c01752

Cited by 4 publications

(3 citation statements)

References 34 publications

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“…We next investigated the coupling of amino alcohol substrates. The transition-metal-catalyzed arylation of amino alcohols is challenged by chemoselectivity issues, with most catalytic methods leading to N -arylation, and/or ligand displacement upon both N - and O -coordination. , Despite this, several small-molecule pharmaceuticals rely on the chemoselective incorporation of groups containing contending alcohol and amine nucleophiles. ,− The most common strategy employed to obtain the O -arylated derivative of amino alcohols is using N -protecting groups. As an example, a discovery chemistry group at Novartis reported on the Pd-catalyzed C–O coupling of amino alcohols in which the amine component was protected with a Boc group .…”

Section: Resultsmentioning

confidence: 99%

Cu-Catalyzed Amination of Base-Sensitive Aryl Bromides and the Chemoselective N- and O-Arylation of Amino Alcohols

Strauss,

Liu,

Greaves

et al. 2024

J. Am. Chem. Soc.

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We report a general and functional-group-tolerant method for the Cu-catalyzed amination of base-sensitive aryl bromides including substrates possessing acidic functional groups and small five-membered heteroarenes. The results presented herein substantially expand the scope of Cu-catalyzed C−N coupling reactions. The combination of L8, an anionic N 1 ,N 2diarylbenzene-1,2-diamine ligand, along with the mild base NaOTMS leads to the formation of a stable yet reactive catalyst that resists deactivation from coordination to heterocycles or charged intermediates. This system enables the use of low catalyst and ligand loadings. Exploiting the differences in nucleophile deprotonation in C−O and C−N coupling reactions catalyzed by Cu•L8 we developed a method to chemoselectively N-and Oarylate a variety of amino alcohol substrates. Employing NaOt-Bu as the base resulted exclusively in C−O coupling when the amino alcohols featured primary alcohols and more hindered amines or aniline groups. Utilizing NaOTMS enabled the ability to override the steric-based selectivity of these reactions completely and exclusively promoted C−N coupling regardless of the structure of the amino alcohol. The ability to invert the observed chemoselectivity is distinct from previously described methods that require protecting group manipulations or rely entirely on steric effects to control reactivity. These results substantially improve the scope of Cu-catalyzed C−N coupling reactions using N 1 ,N 2 -diarylbenzene-1,2-diamine ligands and introduce a new chemoselective method to arylate amino alcohols.

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Section: Resultsmentioning

confidence: 99%

Cu-Catalyzed Amination of Base-Sensitive Aryl Bromides and the Chemoselective N- and O-Arylation of Amino Alcohols

Strauss,

Liu,

Greaves

et al. 2024

J. Am. Chem. Soc.

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“…In the specific case of the HHDH-catalyzed reaction of epoxides with cyanate (OCN – ), the reaction leads to the final formation of oxazolidinones via the spontaneous isomerization of the unstable intermediates that are generated by enzymatic ring opening . Several HHDHs have been investigated for the synthesis of chiral aryl- and alkyl-substituted oxazolidinones from epoxides. − Recently, we have also developed a biocatalytic desymmetrization approach to 5,5-disubstituted oxazolidinones from 2-substituted-1,3-dichloro-2-propanols and a two-enzyme cascade strategy for synthesizing 4-aryloxazolidinones from styrenes …”

Section: Introductionmentioning

confidence: 99%

Biocatalytic Construction of Spiro-Oxazolidinones via Halohydrin Dehalogenase-Catalyzed Ring Expansion of Spiro-Epoxides

Ma,

Wang,

Miao

et al. 2024

ACS Catal.

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Spiro-oxazolidinones are highly valuable compounds in the fields of medicinal and organic chemistry; however, the methods for synthesizing these compounds have not been well established. Herein, we present a biocatalytic methodology for the construction of spirooxazolidinones through the halohydrin dehalogenase-catalyzed ring expansion of spiro-epoxides. By performing screening and protein engineering of halohydrin dehalogenases, both chiral and racemic spirooxazolidinones were synthesized in 24−47% yields (90−98% ee) and 69−98% yields, respectively. The biocatalytic method was also applied to the efficient synthesis of the drug fenspiride at a high substrate concentration of 200 mM (44 g/L). In addition, a chemo-enzymatic strategy was proposed to overcome the limitation of the maximum 50% yield inherent in the kinetic resolution process. Moreover, large-scale synthesis and representative transformations of the spiro-oxazolidinones were carried out to provide additional evidence of the practicality and applicability of the biocatalytic approach.

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“…A chemoenzymatic synthesis of metaxalone 31 , an oxazolidinone-containing compound that is marketed as a pain-relief drug, has been developed using engineered halohydrin dehalogenase (HHDH) from Acidimicrobiia bacterium . 31 Reaction of the racemic epoxide substrate with cyanate, using an ( R )-selective HHDH in whole cells resulted in the scalable-synthesis of metaxalone with excellent stereoselectivity (Scheme 3). Flow chemistry has been used for some of the steps in a total synthesis of the alkaloid, (−)-agelastatin A 32 from pyridine.…”

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confidence: 99%