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. 2024 Jun;11(24):e2309645.
doi: 10.1002/advs.202309645. Epub 2024 Apr 22.

Catalytic Asymmetric Construction of α,α-Diaryl Aldehydes via Oxo-Hydroarylation of Terminal Alkynes

Xueting Zhou  1   2 , Qingqin Huang  1   2 , Jiami Guo  1   2 , Lei Dai  2 , Yixin Lu  1   2
Affiliations

Catalytic Asymmetric Construction of α,α-Diaryl Aldehydes via Oxo-Hydroarylation of Terminal Alkynes

Xueting Zhou et al. Adv Sci (Weinh). 2024 Jun.

Abstract

Chiral aldehydes containing a tertiary stereogenic center are versatile building blocks in organic chemistry. In particular, such structural motifs bearing an α,α-diaryl moiety are very challenging scaffolds and their efficient asymmetric synthesis is not reported. In this work, a phosphoric acid-catalyzed enantioselective synthesis of α,α-diaryl aldehydes from simple terminal alkynes is presented. This approach yields a wide range of highly enolizable α,α-diaryl aldehydes in good yields with excellent enantioselectivities. Facile transformations of the products, as well as an efficient synthesis of bioactive molecules, including an effective anti-smallpox agent and an FDA-approved antidepressant drug (+)-sertraline, are demonstrated.

Keywords: chiral aldehydes; chiral phosphoric acid; oxo‐hydroarylation of alkynes; tertiary stereocenters; α,α‐diaryl aldehydes.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Background and our working hypothesis. a) Previous work: asymmetric synthesis of α‐aryl aldehydes with a tertiary stereocenter b) Our hypothesis: synthesis of α,α‐diaryl aldehydes via oxo‐hydroarylation of terminal alkynes. PC, photocatalyst; CPA, chiral phosphoric acid.
Figure 2
Figure 2
Reaction scope. Reaction conditions: step I: terminal alkyne 1 (0.1 mmol) and 2a (0.05 mmol) in CH2Cl2 (0.5 mL) were irradiated using 440 nm Kessil LEDs at room temperature for 2  h; step II: at −80 °C, CPA 4a (5 mol%) in the mixed CH2Cl2 (2.5 mL)/ether (2.0 mL) was introduced, followed by 3 g (0.06 mmol), stirring for 12 h.
Figure 3
Figure 3
Further reaction scope. Reaction conditions: step I: terminal alkyne 1 (0.1 mmol) and 2a (0.05 mmol) in CH2Cl2 (0.5 mL) were irradiated using 440 nm Kessil LEDs at room temperature for 2 h; step II: at −80 °C, CPA 4a (5 mol%) in the mixed CH2Cl2 (2.5 mL)/ether (2.0 mL) was introduced, followed by 3 (0.06 mmol), stirring for 12 h.
Figure 4
Figure 4
Mechanistic studies. a) Deuterium experiments; b) The key intermediate; c) Proposed mechanism.
Figure 5
Figure 5
Synthetic applications. a) Downstream transformation for detosylation and cross‐coupling reactions; b) Synthesis of an anti‐smallpox agent; c) Formal synthesis of an antidepressant drug (+)‐sertraline.
See this image and copyright information in PMC

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