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. 2019 Aug;11(8):710-715.
doi: 10.1038/s41557-019-0289-7. Epub 2019 Jul 15.

Enantioselective construction of remote tertiary carbon-fluorine bonds

Jianbo Liu  1 , Qianjia Yuan  1 , F Dean Toste  2 , Matthew S Sigman  3
Affiliations

Enantioselective construction of remote tertiary carbon-fluorine bonds

Jianbo Liu et al. Nat Chem. 2019 Aug.

Abstract

The carbon-fluorine bond engenders distinctive physicochemical properties and significant changes to general reactivity. The development of catalytic, enantioselective methods to set stereocentres that contain a benzylic C-F bond is a rapidly evolving goal in synthetic chemistry. Although there have been notable advances that enable the construction of secondary stereocentres that contain both a C-F and a C-H bond on the same carbon, significantly fewer strategies are defined to access stereocentres that incorporate a tertiary C-F bond, especially those remote from pre-existing activating groups. Here we report a general method that establishes C-F tertiary benzylic stereocentres by forging a C-C bond via a Pd-catalysed enantioselective Heck reaction of acyclic alkenyl fluorides with arylboronic acids. This method provides a platform to rapidly incorporate significant functionality about the benzylic tertiary fluoride by virtue of the diversity of both reaction partners, as well as the ability to install the stereocentres remotely from pre-existing functional groups.

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Conflict of interest statement

The authors declare no competing financial interests.

Figures

Figure 1 |
Figure 1 |. Constructing chiral, non-racemic tertiary fluorides.
OTs, tosylate; M.S., molecular sieves; dba, dibenzylideneacetone; A, Conventional enantioselective, catalytic approaches. B, Strategy to use alkenyl fluorides as substrates in enantioselective C‒C forming arylation reactions to form remote F-bearing benzylic, tertiary stereocenters. C, preliminary results and optimization of reaction conditions.
Figure 2 |
Figure 2 |. Enantioselective construction of remote tertiary fluorine-containing stereocenters.
Condition adjustments for 2w: 20 mol % Pd(CH3CN)2(OTs)2, 24 mol % ligand, 40 mol % dba. OTs, tosylate; Bn, benzyl; Ar, tolyl; A, Exploration of scope using various arylboronic acids. B, Evaluation of various alkene substituents and attached functional groups on reaction efficiency.
Figure 3 |
Figure 3 |. Evaluation of alkene substrates to establish remote stereocenters and mechanistic studies.
Condition adjustments for 3f: 30 mol % Pd(CH3CN)2(OTs)2, 36 mol % ligand, 60 mol % dba. A, Effect of chain length between the alcohol and the alkenyl fluoride on reaction. B, Mechanistic experiments and analysis.
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References

    1. Brunet VA & O’Hagan D Catalytic asymmetric fluorination comes of age. Angew. Chem. Int. Ed 47, 1179–1182 (2008). - PubMed
    1. Ma J-A & Cahard D Update 1 of: asymmetric fluorination, trifluoromethylation, and perfluoroalkylation reactions. Chem. Rev 108, PR1–PR43 (2008). - PubMed
    1. Yang X, Wu T, Phipps RJ & Toste FD Advances in catalytic enantioselective fluorination, mono-, di-, and trifluoromethylation, and trifluoromethylthiolation reactions. Chem. Rev 115, 826–870 (2015). - PMC - PubMed
    1. Zhu Y et al. Modern approaches for asymmetric construction of carbon−fluorine quaternary stereogenic centers: synthetic challenges and pharmaceutical needs. Chem. Rev 118, 3887–3964 (2018). - PMC - PubMed
    1. Differding E & Lang RW New fluorinating reagents-I. the first enantioselec-tive fluorination reaction. Tetrahedron Lett. 29, 6087–6090 (1988).

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