Influence of relative configuration of disubstituted cyclopentanes and ‐hexanes on <sup>13</sup>C shifts

Winkler, Margit; Klempier, Norbert; Weber, Hansjörg; Grünwald, Katrin R.; Flock, Michaela; Dransfeld, Alk

doi:10.1002/mrc.2261

Cited by 3 publications

(5 citation statements)

References 27 publications

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“…When directly extracted in deuterated chloroform (without further purification), NMR analysis of the product showed a relatively clean spectrum and was consistent with the expected cis -stereoisomer, further confirming the stereochemical assignment ( Figures S16–S18 ). 27 This one-pot three-step UPO-ER-ADH multienzymatic system therefore provides access to an oxyfunctionalized chiral API with two stereocenters with high purity and enantiomeric excess.…”

Section: Results and Discussionmentioning

confidence: 99%

Peroxygenase-Catalyzed Allylic Oxidation Unlocks Telescoped Synthesis of (1S,3R)-3-Hydroxycyclohexanecarbonitrile

Heckmann,

Bürgler,

Paul

2024

ACS Catal.

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The unmatched chemo-, regio-, and stereoselectivity of enzymes renders them powerful catalysts in the synthesis of chiral active pharmaceutical ingredients (APIs). Inspired by the discovery route toward the LPA1-antagonist BMS-986278, access to the API building block (1S,3R)-3-hydroxycyclohexanecarbonitrile was envisaged using an ene reductase (ER) and alcohol dehydrogenase (ADH) to set both stereocenters. Starting from the commercially available cyclohexene-1-nitrile, a C–H oxyfunctionalization step was required to introduce the ketone functional group, yet several chemical allylic oxidation strategies proved unsuccessful. Enzymatic strategies for allylic oxidation are underdeveloped, with few examples on selected substrates with cytochrome P450s and unspecific peroxygenases (UPOs). In this case, UPOs were found to catalyze the desired allylic oxidation with high chemo- and regioselectivity, at substrate loadings of up to 200 mM, without the addition of organic cosolvents, thus enabling the subsequent ER and ADH steps in a three-step one-pot cascade. UPOs even displayed unreported enantioselective oxyfunctionalization and overoxidation of the substituted cyclohexene. After screening of enzyme panels, the final product was obtained at titers of 85% with 97% ee and 99% de, with a substrate loading of 50 mM, the ER being the limiting step. This synthetic approach provides the first example of a three-step, one-pot UPO-ER-ADH cascade and highlights the potential for UPOs to catalyze diverse enantioselective allylic hydroxylations and oxidations that are otherwise difficult to achieve.

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Section: Results and Discussionmentioning

confidence: 99%

Peroxygenase-Catalyzed Allylic Oxidation Unlocks Telescoped Synthesis of (1S,3R)-3-Hydroxycyclohexanecarbonitrile

Heckmann,

Bürgler,

Paul

2024

ACS Catal.

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“…The following factors should be taken into account (Figure 8): For example, axial conformer of 2-fluorocyclohexanone is slightly more preferable in gaseous phase due to the hypercon-jugation, while the equatorial conformer with higher net dipole moment prevails in polar solvents (Scheme 147). [344] The diequatorial conformer dominated for trans-2-fluorocyclohexanecarbonitrile [76] and trans-2-fluorocyclohexanol (Figure 9). [345] The latter fact was partially addressed to the OÀ H…F interaction, albeit the steric effects also favor this substituent disposition.…”

Section: Chemmedchemmentioning

confidence: 99%

“… [345] The latter fact was partially addressed to the O−H…F interaction, albeit the steric effects also favor this substituent disposition. For cis ‐2‐fluorocyclohexanol, [346] cis ‐2‐fluorocyclohexanecarbonitrile, [76] and cis ‐2‐fluorocyclohexylamine, [347] the conformers with axial position of the fluorine atom prevailed according to the calculations (although the difference was small), which was addressed to the hyperconjugation effects.…”

Section: Key In Vitro Properties Of Fluorinated Cycloalkyl Derivativesmentioning

confidence: 99%

“…Nevertheless, the reaction of nitriles 80 and 81 with DAST allowed preparation of target fluorides, albeit the yield was very low for the second substrate, likely due to the elimination process (59 % and 8 %, respectively) (Scheme 29). [76] In 2019, Gouverneur and co-authors reported asymmetric synthesis of fluorinated dibenzylamines 86 involving the use of chiral hydrogen bonding phase-transfer catalyst 85 (Scheme 30). [77] Albeit the method had moderate enantioselectivity, it could be used at up to 200 g (0.5 mol % of 85, CsF as the fluoride source, n = 2) since the er value of the product could be improved to 98 : 2 after a single recrystallization.…”

Section: Synthesis Of β-Fluorinated Cycloalkyl Building Blocksmentioning

confidence: 99%

Section: Synthesis Of Monofluorinated Cycloalkyl Building Blocksmentioning

confidence: 99%

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Fluorinated Cycloalkyl Building Blocks for Drug Discovery

et al. 2022

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The review covers various aspects of fluorinated cycloalkyl (C3−C7) building blocks for drug discovery, including their synthesis, key physicochemical properties, and biological and medicinal applications of their derivatives. The discussed synthetic methods include classical nucleophilic fluorinations of various substrates, the addition of fluorine and another heteroatom to double bonds, cycloadditions and other transformations of fluorine‐containing substrates, as well as some newer reactions like fluorination of non‐activated and remotely activated C−H bonds, decarboxylative and deborylative fluorinations, etc. The known data on the effect of introducing the fluorinated cycloalkyl groups on the compound's key in vitro parameters (such as acidity/basicity, lipophilicity, conformational behavior, and short contact capabilities) are surveyed. Finally, applications of fluorinated cycloalkyl building block derivatives in the design of biologically active compounds (including marketed drugs Maraviroc, Ivosidenib, and Sitafloxacin) are covered, with a focus on the fluorination impact.

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Theoretical prediction and assignment of vicinal ¹H–¹H coupling constants of diastereomeric 3‐alkoxy‐6,7‐epoxy‐2‐oxabicyclo[3.3.0]octanes

Aav

Pehk

Tamp

et al. 2011

Magnetic Reson in Chemistry

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Spin-spin coupling constants between nuclei in NMR spectroscopy reflect their spatial arrangement. A number of calculation methods, applying different levels of theory, have been developed to support the stereochemical assignment of novel compounds. Nevertheless, revisions of the assignment of structures in the literature are not rare. In the present work, the reliability of the calculation methods amenable for a theoretical prediction of spin-spin coupling constants of vicinal protons to support correct stereochemical assignment of substitution at five-membered rings of 3-alkoxy-6,7-epoxy-2-oxabicyclo[3.3.0]octanes was studied. Experimental (3)J(H,H) coupling constants were compared with the coupling constants calculated for all possible diastereomers. The fully quantum chemical approach provided theoretical (3)J(H,H) coupling constants with an absolute deviation of no more than 1.1 Hz for 91% of the experimentally studied coupled spins, whereas the methods without quantum chemical geometry optimization resulted in completely unreliable predictions. Consequently, for a reliable stereochemical assignment of small and medium size molecules, the protocol for calculating the coupling constants based on the results of the quantum chemical geometry optimization is recommended.

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Influence of relative configuration of disubstituted cyclopentanes and ‐hexanes on ¹³C shifts

Cited by 3 publications

References 27 publications

Peroxygenase-Catalyzed Allylic Oxidation Unlocks Telescoped Synthesis of (1S,3R)-3-Hydroxycyclohexanecarbonitrile

Peroxygenase-Catalyzed Allylic Oxidation Unlocks Telescoped Synthesis of (1S,3R)-3-Hydroxycyclohexanecarbonitrile

Fluorinated Cycloalkyl Building Blocks for Drug Discovery

Theoretical prediction and assignment of vicinal ¹H–¹H coupling constants of diastereomeric 3‐alkoxy‐6,7‐epoxy‐2‐oxabicyclo[3.3.0]octanes

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Influence of relative configuration of disubstituted cyclopentanes and ‐hexanes on 13C shifts

Cited by 3 publications

References 27 publications

Peroxygenase-Catalyzed Allylic Oxidation Unlocks Telescoped Synthesis of (1S,3R)-3-Hydroxycyclohexanecarbonitrile

Peroxygenase-Catalyzed Allylic Oxidation Unlocks Telescoped Synthesis of (1S,3R)-3-Hydroxycyclohexanecarbonitrile

Fluorinated Cycloalkyl Building Blocks for Drug Discovery

Theoretical prediction and assignment of vicinal 1H–1H coupling constants of diastereomeric 3‐alkoxy‐6,7‐epoxy‐2‐oxabicyclo[3.3.0]octanes

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Influence of relative configuration of disubstituted cyclopentanes and ‐hexanes on ¹³C shifts

Theoretical prediction and assignment of vicinal ¹H–¹H coupling constants of diastereomeric 3‐alkoxy‐6,7‐epoxy‐2‐oxabicyclo[3.3.0]octanes