Introducing the element F into drug molecules can effectively alter their physicochemical and biological properties. Therefore, selective Enantioselective synthesis of C-F bonds has always been a hot topic. Electrophilic fluorinated reaction blocks (F+), such as Selectfluoror, N-F pyridine salts, NFSI, etc., have been widely used in the synthesis of fluorinated chiral centers. Most of these reactions are obtained through enol tautomerism α- F substituted carbonyl compounds. In addition, selective fluorination of olefins with molecules capable of producing F+is also an important method for constructing fluorinated chiral centers. Recently, Professor Eric N. Jacobsen from Harvard University (click to view the introduction) reported on an asymmetric fluorination reaction using nucleophilic F - as the fluorination reagent. Enantioselective, Catalytic Fluorolactation Reactions with a Nuclear Fluoride Source. J. Am. Chem. Soc., 2016, 138, 13858-13861 DOI: 10.1021/jacs.6b09499)

Previous literature has reported that electrophilic fluorination reagents react with olefins to obtain exocyclic fluoromethyl substituted compounds with medium to high asymmetric selectivity γ- Butyrolactone (Scheme 1, above). The author hopes to obtain nucleophilic F - through the catalysis of high valent iodine reagents, which can serve as a supplement to the construction of chiral C-F centers for asymmetric synthesis of F substituted lactones (Scheme 1, figure below).

Jacobsen's research group recently reported that using HF pyridine (pyr.9HF) as a nucleophilic fluorine source, Meta-Chloroperoxybenzoic acid (mCPBA) as an oxidant, aryl Iodide catalyzed olefins to obtain Stereoselectivity 1,2-difluoro products (JACS, 2016, 138, 5000); And under the same catalytic system, different olefin substrates were used to obtain 1,1-difluoro products (Science, 2016, 353, 51, click to read related information). The author assumes that the weakly nucleophilic group (such as o-nitro, Scheme 2) substituted at the appropriate position can replace the aryl iodine in intermediate I to form an unstable bridged intermediate II, which then undergoes Substitution reaction with F to obtain the trans product. This ortho involved reaction implies that if the ortho of styrene contains other nucleophilic groups (such as ester or carboxyl groups), fluorinated lactone products may be obtained (Scheme 2). This path can obtain the fluorinated chiral center, which has two new Chemical bond located in the cis form, which is different from the conformation of the in-situ bromination/iodolactonation reaction.

The author used Methyl benzoate derivative 1a as the substrate to screen the reaction conditions, and evaluated the catalytic activity of a variety of chiral aryl iodides (2a-2d). These compounds have been well applied in the asymmetric oxidation of olefins (Table 1). The configuration of product 3 was also determined as a cis product through X-ray crystal diffraction analysis, which is consistent with the mechanism speculated in Scheme 2. The catalytic activity of 2c and 2d is much higher than that of 2b and 2a; By changing the substituent portion of the ester group, although free carboxylic acids can also react, the activity of the methyl ester is affected.

In the study of substrate universality, the reaction of alkyl, halogen and trifluoro Methoxy group substituents on the aromatic ring at the 4, 5 and 6 positions has good tolerance, and the ee value of 80-96% is obtained; However, when the substrate contains stronger electron withdrawing trifluoromethyl and ester groups, the yield and enantioselectivity of the reaction decrease. Under all conditions, the resulting product is a single isomer configuration. For compounds containing different substituents β- In general, the substituents of different sizes and functional groups on styrene substrates have little effect on the asymmetric selectivity of the reaction, and the yield may change. For ethers and cyanides with certain nucleophilicity, although they may have an impact on the reaction due to the involvement of neighboring sites, the ee value does not decrease significantly.

The same alkenyl substrate reacts with nucleophilic and electrophilic fluorination reagents, resulting in products with significant structural differences. The product obtained by reacting 1d with electrophilic fluorination reagents has poor enantioselectivity; Under the conditions adopted in this paper, it can introduce C-F chiral center with high Stereoselectivity, providing a new catalytic approach (Scheme 3).

Summary:

Jacobsen research group has developed a highly Stereoselectivity synthesis of 4-fluoroheterochromones using HF pyridine as a nucleophilic fluorinating reagent. Further mechanism research is underway to construct a chiral C-F center by catalyzing styrene based substrates with easily prepared chiral aryl iodine.