Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 Feb;4(2):164-171.
doi: 10.1038/s41929-020-00569-8. Epub 2021 Feb 17.

Gold-catalysed asymmetric net addition of unactivated propargylic C-H bonds to tethered aldehydes

Ting Li  1   2 , Xinpeng Cheng  1 , Pengcheng Qian  2 , Liming Zhang  1
Affiliations

Gold-catalysed asymmetric net addition of unactivated propargylic C-H bonds to tethered aldehydes

Ting Li et al. Nat Catal. 2021 Feb.

Abstract

The asymmetric one-step net addition of unactivated propargylic C-H bond to aldehyde leads to an atom-economic construction of versatile chiral propargylic alcohols but has not been realized previously. Here we show its implementation in an intramolecular manner under mild reaction conditions. Via cooperative gold catalysis enabled by a chiral bifunctional phosphine ligand, this chemistry achieves asymmetric catalytic deprotonation of propargylic C-H (pKa > 30) by a tertiary amine group (pKa ~ 10) of the ligand in the presence of much more acidic aldehydic α-hydrogens (pKa ~ 17). The reaction exhibits a broad scope and readily accommodates various functional groups. The 5-/6-membered ring fused homopropargylic alcohol products are formed with excellent enantiomeric excesses and high trans-selectivities with or without a preexisting substrate chiral center. DFT studies of the reaction support the conceived reaction mechanism and the calculated energetics corroborate the observed stereoselectivity and confirm an additional metal-ligand cooperation.

PubMed Disclaimer

Figures

Fig. 1|
Fig. 1|. Asymmetric propargylation of aldehyde.
a) Strategies for asymmetric propargylation of aldehyde. b) Challenge in direct reacting propargylic C-H bond with aldehyde possessing α-hydrogens. c) Our previous work: intermolecular net racemic addition of propargylic C-H bond to aldehyde without α-C-H bond.
Fig 2|
Fig 2|. ORTEP drawing of crystal structures (ellipsoid probability at 50%).
a) X-ray structure of (S)-L3AuCl (crystal CH2Cl2 omitted, and both N-methyl conformers detected). b) X-ray structure of 11. c) X-ray structure of (2S,3R,4S)-6p.
Fig. 3|
Fig. 3|. DFT-calculated energetics of the reaction of 3a in DCE.
Performed at PBE1PBE level using the effective core potential LANL2DZ for Au, the basis set 6–311g(d,p) for Si and P, and 6–31g(d,p) for the other atoms. The SMD model is employed for solvent DCE. The numbers in structures are in angstrom.
Fig 4|
Fig 4|. Further transformations of the products.
a) the Mitsunobu reactions. b) An reported oxidative rearrangement. c) A reported silaborative cyclization.
See this image and copyright information in PMC

References

    1. Ding C-H & Hou X-L Catalytic asymmetric propargylation. Chem. Rev 111, 1914–1937 (2011). - PubMed
    1. Yang X, Kalita SJ, Maheshuni S & Huang Y-Y Recent advances on transition-metal-catalyzed asymmetric tandem reactions with organoboron reagents. Coord. Chem. Rev 392, 35–48 (2019).
    1. Alvarez LX, Christ ML & Sorokin AB Selective oxidation of alkenes and alkynes catalyzed by copper complexes. Appl. Catal. A 325, 303–308 (2007).
    1. Cheng D & Bao W. Propargylation of 1,3-dicarbonyl compounds with 1,3-diarylpropynes via oxidative cross-coupling between sp3 C−H and sp3 C−H. J. Org. Chem 73, 6881–6883 (2008). - PubMed
    1. Grigg RD, Rigoli JW, Pearce SD & Schomaker JM Synthesis of propargylic and allenic carbamates via the C–H amination of alkynes. Org. Lett 14, 280–283 (2012). - PubMed