ARTICLE https://doi.org/10.1038/s41467-021-24278-3 OPEN Catalytic asymmetric nucleophilic fluorination using BF3·Et2Oasfluorine source and activating reagent Weiwei Zhu1, Xiang Zhen2, Jingyuan Wu1, Yaping Cheng1, Junkai An2, Xingyu Ma1, Jikun Liu2, Yuji Qin1, ✉ Hao Zhu2, Jijun Xue2 & Xianxing Jiang 1 1234567890():,; Fluorination using chiral catalytic methods could result in a direct access to asymmetric fluorine chemistry. However, challenges in catalytic asymmetric fluorinations, especially the longstanding stereochemical challenges existed in BF3·Et2O-based fluorinations, have not yet been addressed. Here we report the catalytic asymmetric nucleophilic fluorination using BF3·Et2O as the fluorine reagent in the presence of chiral iodine catalyst. Various chiral fluorinated oxazine products were obtained with good to excellent enantioselectivities (up to >99% ee) and diastereoselectivities (up to >20:1 dr). Control experiments (the desired fluoro-oxazines could not be obtained when Py·HF or Et3N·3HF were employed as the fluorine source) indicated that BF3·Et2O acted not only as a fluorine reagent but also as the activating reagent for activation of iodosylbenzene. 1 Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China. 2 State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, ✉ Gansu, China. email: [email protected] NATURE COMMUNICATIONS | (2021) 12:3957 | https://doi.org/10.1038/s41467-021-24278-3 | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-021-24278-3 eing called as “a small atom with a big ego”, fluorine acts as utilization in the area: the high toxicity and biohazard for HF- Ba significant and increasingly important role in the fields of bases, and metal fluorides poor solubility in organic solvents organic chemistry, pharmaceuticals, agrochemicals and coupled with limited strategies to control reactivity. material chemistry1–4. The fluorinated molecules often display Ideally, one low-toxic, stable and commercially cheap available higher thermal and metabolic stabilities, lower polarity, and nucleophilic fluorine reagent would drastically promote enan- weaker intermolecular interactions due to the strong C−F bond tioselective fluorine synthetic innovation and industrial develop- 5 and unique properties of F atom . Therefore, these unique ment. As a versatile Lewis acid, commercially available BF3·Et2O properties of fluorine-contained compounds make the develop- is easy to prepare and is widely being used in various organic ment of efficient strategies, especially of catalytic asymmetric transformations. As early as 1960, it was discovered that as a reaction for fluorination of molecules as one of the hottest areas nucleophilic fluorine reagent could be applied in the fluorination 2,3 33 in organic synthesis . Nevertheless, the asymmetric fluorine of ring opening of mesoepoxides . The development of BF3·Et2O organic chemistry still represents a considerable challenge to mediated reactions in half a century reveals that the BF3·Et2O can date6. In the wake of the emergence of the first electrophilic also be applied to fluorinations of alkenes34–36, alkynes37, enantioselective fluorination of enolates using chiral N-fluoro arenes38,39 and other fluorine organic chemistry40–43. Although camphorsultam reagent reported by the group of Lang7, sig- these efficient achiral methodologies have been well-established, nificant progress for enantioselective fluorination studies to date, the longstanding stereochemical challenges of the 4,8,9 have been presented because of contributing to the BF3·Et2O-based fluorination have not yet been addressed, prob- development of catalytic asymmetric methodologies for electro- ably impeded by several hurdles: intense competition for the role fl + fl fl philic uorine reagents (F reagents), such as N- uor- of BF3 between a nucleophilic uorine reagent and a Lewis acid, obenzenesulfonimide (NFSI)10–12, N-fluoropyridinium salts3, and the difficulty in achieving stereocontrol of fluorine atom, the Selectfluor (Fig. 1a)13–18. These reagents exhibited efficient competition from the uncatalyzed background reaction and other transfer of fluorine atom under the asymmetric fluorination, side reactions. Undoubtedly, the advent of enantioselective however, their industrial applications were significantly restricted approach is long overdue that would be welcome. by the poor atom economy in fluorination, expensive synthesis In terms of the operational and environmental advantages and other inherent characteristics of electrophilic reagent. Alter- associated with organocatalysis, we speculated that a metal-free natively, nucleophilic fluorine reagents (F− reagents) have been mild reaction system with a chiral iodine catalyst (CIC) might attracting considerable interest recently since the relative stability meet the aforementioned challenges21,44,45. Its activated oxidants and low-cost. Considerable advances have recently been achieved forms could form the iodine (III) catalyst with a typical structure in this field involving catalytic asymmetric fluorination of keto type of trigonal bipyramidal geometry, thus this type of robust esters19,20 and alkenes21–25 employing pyridine·HF as a fluorine organocatalyst has been commonly used for asymmetric reagent, catalytic asymmetric fluorination of allylic tri- nucleophilic addition reactions44,45. The unique stereoscopic fi fi chloroacetimidates using a combination of Et3N·HF with Iridium con guration of iodine (III) and well-de ned steric hindrance of complex26, asymmetric ring-opening fluorinations of meso- the iodine (III) catalyst bearing chiral ligand can be readily epoxides (aziranes) using PhCOF, HF-reagents or AgF as the applied, leading to complete stereo-control in fluorination of fl 27–29 fi uorine source in metal-catalyzed system , and other asym- ole ns using BF3·Et2O as a nucleophilic reagent. Rapid cyclization fl fl metric transformations in the presence of metal uorides (KF, and its simultaneous BF3·Et2O nucleophilic uorination are viable CsF or AgF)30–32 (Fig. 1b). Despite these elegant works, several with a CIC to suppress the pure intramolecular cycloaddition and practical disadvantages still discouraged their further large-scale other side reactions. O Y O X 1 1 XH F a + F b R R O [M] R1 [F ] 1 G 1 O [M] [F ] H 3 R 3 R 3 OO 1 2 R R + G NXG R O O R1 R2 X [M] R R 2 Cat. 2 *2 S S F 2 2 R R F R Ph N Ph R R F F •(HF)n 1 1 N 1 O O R 1 R R1 1 R + - R Y R [F+] Cl R * F F F Y Y O O N N HBPTC E-LG X + P X N N N N + F 2 3 2 3 N X X F Reagents R R R R R PTC R R O O R2 R3 M F H H H H F * M E R R F R 1 KF F R O R3 Cl CsF X + O O N 1 F F [M], L L O A [F ] - (HF) R Ar F 2 O 2 N 2BF4 • n F H F 2 F H F FG R A M R 1 A 3 ArI, [O] I 2 1 R 1 * R * R F N 1 R R 3 R * 2 3 L 2 3 2 R R R R O F R R R [F ] R3 R1 3 I R Ar c F F O 2 B - Ar F Ar F O F Me Me +I OBF F F 1 N 2 2 Me F Ar H Ar BF3·Et2O N I 3 BF3·Et2O Ar 3 Ar1 Ar Ar3 Ar3 Ar O CIC1 (15% mol) up to 99% ee NH CIC (15% mol) m NH NH NH N ArI -CPBA and > 20:1 dr m-CPBA • Et2O solvent O 4 m-CPBA 4 solvent 4 O O O Ar Ar Ar Ar4 Ar4 -H+ F F up to 85% ee B Ar O F Ar2 I O F O O O O - -BF2OBF3 -ArI R O O R R =benzyl,CIC1 N N 2 NH Ar = O O 1 F H 2 1 H Ar Ar F Ar Ar I Bn Bn R = 1,2,3,4-tetrahydronaphthalen-1-yl , CIC2 B Ar F F Fig. 1 Examples of common fluorine reagents applied in asymmetric fluorinations. a Asymmetric fluorinations using electrophilic fluorine (F+) reagents. − − b Asymmetric fluorinations using nucleophilic fluorine (F ) reagents. c The first example of using BF3·Et2OasF Reagent for asymmetric fluorinations (this work). [F+], electrophilic fluorine reagents; [F−], nucleophilic fluorine reagents; PTC, phase-transfer catalyst; [M], metal catalyst; L, ligand; HBPTC, hydrogen bonding phase-transfer catalysis; [O], oxidant; m-CPBA, Meta-Chloroperoxybenzoic acid. 2 NATURE COMMUNICATIONS | (2021) 12:3957 | https://doi.org/10.1038/s41467-021-24278-3 | www.nature.com/naturecommunications NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-021-24278-3 ARTICLE “ ” 2 – O CIC (15 mol%) F complex substituents on Ar ring (Fig. 3b, 35b 42b), again BF ·Et O (10 equiv) O N 3 2 leading to good yields (45–72%) in high to excellent diastereos- H m-CPBA (1.2 equiv) N electivities (10:1–>20:1dr) and enantioselectivities (80-99% ee). It 1a o 1b DCE, -25 C, 48 h is worth noting that the catalytic asymmetric aminofluorination CIC1, R1 =R2 =benzyl, of complex natural product structures could also be achieved 70% yield, 86% ee, and > 20:1 dr fi 1 2 ef ciently in high to excellent diastereoselectivities and O I O CIC2,R =benzyl,R = 1,2,3,4-tetrahydronaphthalen-1-yl, R2 O O R2 70% yield, 74% ee, and > 20:1 dr enantioselectivities. O O CIC3,R1 =methyl,R2 =ethyl, 1 1 Additionally, the gram-scale experiment was conducted to R R 68% yield, 73% ee, and > 20:1 dr fl CIC4,R1 =methyl,R2 = t-butyl, evaluate the applicability of our asymmetric uorination method 65% yield, 74% ee, and > 20:1 dr by using 4a (Fig. 3c), the desired product was obtained with CIC5,R1 =methyl,R2 =benzyl, excellent diastereoselectivity (>20:1 dr) and enantioselectivity 70% yield, 76% ee, and > 20:1 dr CIC6,R1 =methyl,R2 =1-iPr-4-Methylcyclohexane-2-yl , (92% ee).