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. 2025 May 14;147(19):16270-16281.
doi: 10.1021/jacs.5c01753. Epub 2025 Apr 29.

Dynamic Kinetic Asymmetric Hydroacylation: Racemization by Soft Enolization

Mengfei Xu  1 , Stephanie A Corio  2 , Josephine M Warnica  1 , Erin L Kuker  1 , Alexander Lu  1 , Jennifer S Hirschi  2 , Vy M Dong  1
Affiliations

Dynamic Kinetic Asymmetric Hydroacylation: Racemization by Soft Enolization

Mengfei Xu et al. J Am Chem Soc. .

Abstract

We report a dynamic kinetic asymmetric transformation (DyKAT) of racemic aldehydes by Rh-catalyzed hydroacylation of acrylamides. This intermolecular hydroacylation generates 1,4-ketoamides with high enantio- and diastereoselectivity. DFT and experimental studies provide mechanistic insights and reveal an unexpected Rh-catalyzed pathway for aldehyde racemization. Our study represents a pioneering kinetic resolution by intermolecular hydroacylation and contributes to the growing field of stereoconvergent catalysis featuring C-C bond construction.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Racemization’s central role in diverse phenomena. (a) Racemization of l-amino acids in vivo via enzymes called racemases leads to D-amino acids while racemization of drug molecules such as thalidomide can lead to inactivity or toxicity. (b) Facile racemization of starting material is the key to DKR (left) and DyKAT (right). (c) Various racemization mechanisms exist for kinetic resolutions of carbonyls but the use of soft enolization is often overlooked. (d) State-of-art dynamic asymmetric hydroacylations are limited to cyclizations while we proposed a DKR/DyKAT of intermolecular hydroacylation using soft enolization for aldehyde racemization, generating a 1,4-ketoamide with remote stereocontrol.
Figure 2
Figure 2
Proposed mechanism for Rh-catalyzed hydroacylation.
Figure 3
Figure 3
Potential energy surface depicting the relative barriers of oxidative addition, hydrorhodation and reductive elimination in this Rh-catalyzed intermolecular hydroacylation reaction. DFT calculations were performed at B3LYP-D3/6–311+G(d,p) LANL2DZ (Rh, Fe) PCM (DCE)//B3LYP-D3/6–31G(d) LANL2DZ (Rh, Fe) level of theory.
Scheme 1
Scheme 1. Isotopic Labeling and KIE Experiments,,
Isolated yields. Due to the overlap of α-proton and trans β-proton, 83% represents the total percent of deuterium incorporation of both positions (orange); 14% refers to the percent of deuterium incorporation of the cis α-position (black). Reaction conditions: 1a (0.15 mmol, 0.75 equiv), 2a (0.2 mmol, 1.0 equiv), Rh(nbd)2BF4 (10 mol %), L4 (10 mol %), 1-AdNH2 (10 mol %), DCE (0.4 mL), 60 °C, 30 min.
Scheme 2
Scheme 2. Enamine Formation Studies,
Reaction conditions: 1a (0.15 mmol, 1.0 equiv), 1-AdNH2 (7 mol % or 1.0 equiv), DCE (0.2 mL), 60 °C, 30 min. Ratio determined by 1H NMR analysis of a portion of unpurified reaction mixture. With 1.0 equiv of 1-AdNH2, aldehyde: enamine = 1:1.7.
Scheme 3
Scheme 3. Racemization of Enantioenriched Aldehyde
Figure 4
Figure 4
Proposed mechanisms for Rh-catalyzed epimerization of 1a.
Figure 5
Figure 5
Free energy surface comparing the potential racemization pathways of (R)-1a and (S)-1a. Key transition state structures for deprotonation by 1-AdNH2 (TSDepS) and β-hydride elimination by Rh (TSBHE-S) are highlighted. DFT calculations were performed at B3LYP-D3/6–311+G** LANL2DZ (Rh, Fe) PCM (DCE)//B3LYP-D3/6-31G* LANL2DZ (Rh, Fe) level of theory.
Figure 6
Figure 6
Revised mechanism for Rh-catalyzed hydroacylation involving racemization of substrate 1 prior to oxidative addition and an unproductive, reversible α-migratory insertion to IV’.
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References

    1. Gu S.-X.; Wang H.-F.; Zhu Y.-Y.; Chen F.-E. Natural occurrence, biological functions, and analysis of D-Amino acids. Pharm. Fronts 2020, 02, e79–e8710.1055/s-0040-1713820. - DOI
    1. Ali I.; Gupta V. K.; Aboul-Enein H. Y.; Singh P.; Sharma B. Role of Racemization in Optically Active Drugs Development. Chirality 2007, 19, 453–463. 10.1002/chir.20397. - DOI - PubMed

    1. For emerging use of epimerization, see:

    2. Carder H. M.; Wang Y.; Wendlandt A. E. Selective Axial-to-Equatorial epimerization of carbohydrates. J. Am. Chem. Soc. 2022, 144, 11870–11877. 10.1021/jacs.2c04743. - DOI - PMC - PubMed
    3. Zhang Y.-A.; Palani V.; Seim A. E.; Wang Y.; Wang K. J.; Wendlandt A. E. Stereochemical editing logic powered by the epimerization of unactivated tertiary stereocenters. Science 2022, 378, 383–390. 10.1126/science.add6852. - DOI - PMC - PubMed
    4. Wang Y.; Carder H. M.; Wendlandt A. E. Synthesis of rare sugar isomers through site-selective epimerization. Nature 2020, 578, 403–408. 10.1038/s41586-020-1937-1. - DOI - PubMed

    1. For a review on stereoconvergent catalysis:

    2. Bhat V.; Welin E. R.; Guo X.; Stoltz B. M. Advances in Stereoconvergent Catalysis from 2005 to 2015: Transition-Metal-Mediated Stereoablative Reactions, Dynamic Kinetic Resolutions, and Dynamic Kinetic Asymmetric Transformations. Chem. Rev. 2017, 117, 4528–4561. 10.1021/acs.chemrev.6b00731. - DOI - PMC - PubMed

    1. For a review on stereoablative transformations:

    2. Mohr J. T.; Ebner D. C.; Stoltz B. M. Catalytic enantioselective stereoablative reactions: An unexploited approach to enantioselective catalysis. Org. Biomol. Chem. 2007, 5, 3571.10.1039/b711159m. - DOI - PMC - PubMed

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