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Synthesis
DOI: 10.1055/a-2609-9601
paper

Fluorinative Difunctionalization of a Cyclooctene-Fused β-Lactam and Cyclooctene-Fused β-Amino Esters

Tamás T. Novák
a   Institute of Organic Chemistry, Stereochemistry Research Group, HUN-REN Research Centre for Natural Sciences, Magyar tudósok krt. 2, 1117 Budapest, Hungary
b   Department of Organic Chemistry and Technology, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, Műegyetem rkp. 3, 1111 Budapest, Hungary
,
Gábor Turczel
c   Centre for Structural Science, HUN-REN Research Centre for Natural Sciences, Budapest, Magyar tudósok krt. 2, 1117 Budapest, Hungary
,
Gábor Hornyánszky
b   Department of Organic Chemistry and Technology, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, Műegyetem rkp. 3, 1111 Budapest, Hungary
,
Pál T. Szabó
c   Centre for Structural Science, HUN-REN Research Centre for Natural Sciences, Budapest, Magyar tudósok krt. 2, 1117 Budapest, Hungary
,
Loránd Kiss∗
a   Institute of Organic Chemistry, Stereochemistry Research Group, HUN-REN Research Centre for Natural Sciences, Magyar tudósok krt. 2, 1117 Budapest, Hungary
,
Santos Fustero
d   Department of Organic Chemistry, University of Valencia, Pharmacy Faculty, 46100-Burjassot, Valencia, Spain
,
Melinda Nonn∗
e   MTA TTK Lendület Artificial Transporter Research Group, Institute of Materials and Environmental Chemistry, HUN-REN Research Center for Natural Sciences, Hungarian Academy of Sciences, Magyar Tudósok krt. 2, 1117 Budapest, Hungary
f   National Drug Research and Development Laboratory, HUN-REN Research Centre for Natural Sciences, Magyar tudósok krt. 2, 1117 Budapest, Hungary
› Author Affiliations

The authors gratefully acknowledge financial support from the Nemzeti Kutatási Fejlesztési és Innovációs Hivatal (NKFIH/OTKA) (National Research, Development and Innovation Office) of Hungary (FK 145394 and K 142266). We are also grateful for the support provided by the European Union (Project no. RRF-2.3.1-21-2022-00015). This work was supported by the János Bolyai Research Scholarship to M.N. from Magyar Tudományos Akadémia (Hungarian Academy of Sciences).
› Further Information
 
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Abstract

The synthesis of novel arylfluorinated cyclic β-amino acid and β-lactam derivatives is accomplished. Studies on the Pd-catalyzed arylfluorination of the double bond of a cyclooctene-fused azetidine-2-one and various β-amino esters are performed under versatile experimental conditions. The arylfluorinative difunctionalization of a cyclooctene-fused β-lactam, performed with phenylboronic acid in the presence of Selectfluor, palladium diacetate, azacyclic ligands and different solvents, gave a separable mixture of fluorinated and non-fluorinated products. In contrast, arylfluorination of cyclooctane-β-amino esters, performed under similar conditions, proceed with full regio- and stereoselective control, leading to single phenyl-fluorinated products. Possible synthetic pathways for these transformations are also proposed.


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Keywords

amino acids - arylation - difunctionalization - fluorine - lactams

Organofluorine chemistry is a key research area in synthetic organic chemistry and drug discovery, since every year, approximately 25% of newly introduced small-molecule-based drugs approved by the FDA contain a fluorinated active ingredient.[1] Incorporation of a fluorine atom into the structure of an organic molecular entity has a profound effect on its acid–base character, lipophilicity, polar hydrophobicity, and metabolic stability, thus increasing the bioavailability of fluorine-containing molecules of pharmaceutical interest.[2] New synthetic methodologies for the introduction of a fluorine atom into the framework of an organic structure have emerged over recent years. This development has increased the significance of fluorination in preparative organic chemistry.[3] Therefore, the development of novel, effective, and selective synthetic fluorinative strategies remains a worthwhile challenge.

Late-stage fluorination of organic derivatives is a highly relevant field of organofluorine chemistry, and there is a continuous demand for the development of sustainable methodologies that enable the efficient construction of novel fluorine-containing molecular entities that are applicable for drug design.[3] Late-stage olefin bond functionalizations across fluorinative transformations (e.g., trifluoromethylations, nucleophilic, electrophilic or radical monofluorinations) are a significant area of research, directed towards the addition of one or more fluorine atoms into the structure of an organic scaffold.[4] Among fluorinative olefin bond difunctionalizations, Pd-catalyzed arylfluorination is a major area of focus, which has attracted significant attention recently.[5]

Compounds containing the β-lactam (2-azetidinone) moiety are of major interest because of their biological properties, with examples including antibacterials (β-lactam-based antibiotics) and enzyme inhibitors. Moreover, they are important as intermediates in organic chemistry (for example, β-amino acids).[6]

Cyclic amino acids, as representative small molecules, possess a wide range of biological and pharmaceutical potential. Several of these compounds are recognized as antifungal or antiviral agents, antibiotics, or as components in various pharmacologically important bioactive derivatives (anticancer agents, antineuralgics, cardioprotective or anti-inflammatory agents) (Figure [1]).[7] In addition, they may function as building blocks in foldamer chemistry.[7] Furthermore, conformationally restricted or non-canonical amino acid derivatives possess either an aryl moiety or a fluorine-containing element in their structure. Because of their influence on the secondary structures of peptides, they can be considered as highly interesting building blocks in foldamer chemistry.[8] [9]

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Figure 1 Selected bioactive alicyclic amino acid derivatives

The aim of our research was to investigate the Pd-catalyzed arylfluorination of the ring C–C double bond of cyclic substrates with phenylboronic acid in selected model compounds. Taking into consideration the above-described relevance of β-lactam derivatives and conformationally rigid cyclic amino acids, as well as their fluorinated and arylated counterparts in pharmaceutical research,[6] [7] [8] [9] we selected a cycloalkene-fused azetidinone derivative and β-amino esters with a cycloalkene system. During difunctionalization reactions of the ring olefin bond involving simultaneous fluorination and arylation, we focused, under various experimental conditions, on studying the stereo- and regiocontrol, the substrate-dependence, and the intramolecular functional group directing effect (Scheme [1]).

We intended to study the behavior of the β-lactam and N-protected β-amino esters with a cyclooctene-based, conformationally semi-flexible structure under arylfluorination. Based on a recent literature survey (across our published review on arylfluorination)[5a] as well as our preliminary experience with different scaffolds and versatile conditions,[5b] [c] we began by studying the arylfluorination of unsaturated racemic bicyclic lactam (±)-1 with phenylboronic acid in the presence of palladium acetate, Selectfluor, an N-ligand (2,2′-bipyridyl), and CH2Cl2/MeCN (1.5:1) as the solvent system. During these investigations, a series of experiments, by changing the nature of the catalyst, the ligand, the solvent, the reaction temperature and time, were systematically conducted in order to assess the conversion, yield, and selectivity (Table [1]). Unfortunately, and somewhat curiously, we found that in most of the cases arylfluorination either did not occur (only the starting material could be recovered), or in the case of partial conversion of lactam (±)-1, the formation of traces (1–8%; we were unable to isolate pure substances or identify product distributions) and mixtures of the desired olefin-bond difunctionalized product were observed alongside polymeric or unidentifiable materials as byproducts.

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Scheme 1 Aim of the current work: Studies on the Pd-catalyzed olefin bond arylfluorination of cycloalkene-based β-lactam and β-amino esters (Pg = Boc, Cbz, Ts, R = Et, Me)

Table 1 Investigation of the Experimental Conditions for the Arylfluorination of Lactam (±)-1 a

Arylating agent

(PhB(OH)2)

Pd source

Ligand

Selectfluor

Solvent

system

Time (h)

Temp

(a) 1.5 equiv

(b) 2 equiv

(c) 2.5 equiv

(a) Pd(OAc)2

(b) PdCl2

(c) [(Ph)3P]2PdCl2

(a) 2,2′-bipyridyl

(b) 4,4′-di-tert-butyl 2,2′-bipyridyl

(a) 1.5 equiv

(b) 2 equiv

(c) 2.5 equiv

(a) CH2Cl2/MeCN (1.5:1)

(b) CH2Cl2/MeCN/H2O (8:5:1)

(c) CH2Cl2/MeCN/MeOH (8:5:1)

(d) CH2Cl2/acetone/MeOH (8:5:1)

(e) CH2Cl2/MeCN/DMF (8:5:1)

(a) 1 h

(b) 2 h

(c) 3 h

(d) 16 h

(a) 0 °C

(b) RT

(c) 50 °C

(d) reflux

a Optimum conditions: PhB(OH)2 (2 equiv), Pd(OAc)2 (10 mol%), 2,2′-bipyridyl (15 mol%), Selectfluor (2 equiv), CH2Cl2/MeCN/MeOH (8:5:1), RT, 2 h.

During our investigations we found that the optimum reaction conditions for the ring olefin bond arylfluorinative difunctionalization (regarding the conversion) of azetidinone (±)-1 were as follows: phenylboronic acid (2 equiv), palladium acetate (10 mol%), 2,2′-bipyridyl (15 mol%), Selectfluor (2 equiv), CH2Cl2/MeCN/MeOH (8:5:1) as the solvent system, room temperature, 2 hours. Under these reaction conditions, arylfluorinative transformation of lactam (±)-1 yielded a mixture (overall yield: 47%; note that unidentifiable polymeric materials were also formed) of four products, which could be separated and isolated by means of column chromatography on silica gel. Structure elucidation by NMR analyses indicated that two phenyl-fluorinated isomers, (±)-2 and (±)-3, were formed in a ratio of approximately 1:1.7, with yields of 11% and 19%, respectively. The other two isolated products were identified as the elimination derivative (±)-4 (11%) and the methoxy-substituted lactam (±)-5 (6%) (Scheme [2]).

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Scheme 2 Phenylfluorination of cyclooctene-fused β-lactam (±)-1

Based on NOE analyses and on coupling constant values (see the Supporting Information) both fluorinated products (±)-2 and (±)-3 were formed in a boat-like conformational arrangement. This is most probably due to steric factors since both the phenyl group and the fluorine atom are oriented opposite to the lactam ring. In addition, steric factors might explain the regioselectivity of this transformation. Namely, in the major isomer, the phenyl group is furthest from the bulky Boc moiety. Interestingly, elimination product (±)-4 was identified to possess a C–C double bond located between C-2 and C-3, while the phenyl substituent was attached to the ring C-5 atom. This is a clear indication that this product is formed solely from intermediate T5 (not from T6) (Scheme [3]).

The proposed pathways for the formation of fluorinated compounds (±)-2 and (±)-3, as well as elimination product (±)-4, are depicted in Scheme [3]. In the first step, after transmetalation, the Pd(II) species, through coordination to the lactam ring olefin bond, furnishes intermediate T1. Following allylic migratory insertion through the T2 π-allyl complex involving Pd migration, the two intermediates T3 and T4 are formed. Next, in the presence of the fluoronium ion (derived from Selectfluor), both T3 and T4 are converted into the corresponding Pd(IV)-containing species T5 and T6. Finally, in the reductive elimination step, T6 gives (±)-3 as the major fluorine-containing product, while T5 provides fluorinated compound (±)-2 and elimination derivative (±)-4. Somewhat surprisingly the formation of an unsaturated product with the double bond located between C3–C4 was never observed; the reason for this phenomenon is not yet known. Note, another surprising finding was that an elimination product from T6 with the double bond located between C6–C7 was not formed. It should also be mentioned that β-hydride elimination may take place on Pd(II) intermediates (across T3), while E2-elimination is more likely to occur on Pd(IV) intermediates (through T5). The above observations and assumptions need further investigation.

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Scheme 3 Proposed synthetic pathway for the phenylfluorination of cyclooctene-fused β-lactam (±)-1

Regarding the fourth product of arylfluorination, NMR analyses of (±)-5 revealed that the phenyl ring is connected at C-5, while the methoxy group at C-4, surprisingly, is oriented on the same side relative to the azetidinone skeleton. The phenyl ring in turn, as in previous cases, is in a relative trans position. The proposed route for the formation of (±)-5 in the arylfluorination reaction of lactam (±)-1 is described in Scheme [4].

In this case, most probably, a 1,2-syn addition takes place across the T1 intermediate leading to T7 in a cis-selective manner. In the next steps, through the involvement of MeOH as a nucleophilic solvent in the system, across oxidation, structure (±)-5 is generated by reductive elimination (Scheme [4]). It is very interesting and somewhat surprising that contrary to the formation of compounds (±)-2, (±)-3, and (±)-4, the phenyl group, in this case, is trans oriented, while the MeO moiety is attached in a cis relative position to the lactam ring in the difunctionalization process, which suggest an SN2-like step with inversion from T8 to (±)-5. In the case of compounds (±)-2, (±)-3, and (±)-4, the addition was opposite, with the incorporation of fluorine in a trans arrangement.

Zoom Image
Scheme 4 Proposed synthetic pathway for the phenylfluorination of cyclooctene-fused β-lactam (±)-1 involving the attack of MeOH
Zoom Image
Scheme 5 Phenylfluorination of cyclooctene β-amino esters (±)-6
Zoom Image
Figure 2 Conformational structure of intermediate T7 during coordination of the amide O atom to Pd (overridden by steric factors in the formation of (±)-2, (±)-3, and (±)-4)

The cis orientation of the Pd moiety during olefin bond difunctionalization might be explained by the ability of the lactam O atom to coordinate to Pd after the addition step (Figure [2]) (for similar phenomena, see references 5e,f). However, the seven-membered chelate ring is not highly favored; therefore, the steric repulsion during the formation of (±)-2, (±)-3, and (±)-4 overrides the chelating effect between the lactam O and Pd.

Next, our objective was to analyze the arylfluorination of β-amino esters with a cyclooctene ring (e.g., (±)-6), as more ring-flexible derivatives of lactam (±)-1. Similar to lactam (±)-1, a study on variation of the experimental conditions was undertaken. These investigations revealed that the optimum conditions for the arylfluorination of the various protected amino acid derivatives (±)-6a–d were the same as those established previously for lactam (±)-1, albeit requiring a longer reaction time. First, N-Boc-protected ethyl ester (±)-6a was subjected to phenylfluorination. However, rather unexpectedly and to our delight, the transformation proceeded in a completely regio- and stereoselective manner, affording a single difunctionalized product. This product was identified by means of NMR analyses to be (±)-7a (31% yield), with the fluorine atom located at C-7 and the phenyl group attached to C-5; both functional groups have a cis relative arrangement regarding the ester and carbamate functionalities (Scheme [5]). Note that this reaction did not afford any elimination product (in contrast with lactam (±)-1), although formation of a substantial amount of polymeric material was detected.

Zoom Image
Scheme 6 Proposed synthetic pathway for the phenylfluorination of cyclooctene β-amino esters (±)-6

In addition, the same reaction was carried out by changing the nature of the substrate, with respect to the ester and amino protecting groups (Scheme [5]). Unfortunately, in the case of a methyl ester, the yield substantially decreased ((±)-7b: 16%), while the N-Cbz-protected ethyl ester derivative furnished the corresponding difunctionalized product (±)-7c in a yield of 29%. Moreover, a similar reaction was accomplished using the N-tosyl-protected counterpart (±)-6d as the substrate, affording product (±)-7c in a slightly improved yield of 37%. We expected that, according to previous literature data,[5d] the tosyl-protected substrate would exert a directing effect, which may influence the selectivity of phenylfluorination. However, the outcome of the reaction was found to be the same as in previous cases, providing (±)-7d as a single isomer with an architecture similar to those of (±)-7a–c.

The mechanism behind this the regio- and stereoselective phenylfluorination might be explainable on the basis of the pathway depicted in Scheme [6]. In the first step coordination of the transmetalated species to the ring olefin bond in (±)-6 takes place to afford intermediate structure T9. Next, cis-selective addition with allylic migratory insertion through T10 furnishes T11, which in turn gives structure (±)-7 through fluoronium transfer and reductive elimination.

The substrate-directing effect across chelate ring formation between Pd and the ester O atom might be responsible for the regio- and stereoselectivity of the phenylfluorination of compounds (±)-6. Structure T9, as a result of the intramolecular coordination effect, provides intermediate T11 with a favored six-membered chelate ring system fused with the cyclooctane ring (for a similar phenomenon, see references 5e,f). This latter preferred structure leads to (±)-7 as the sole product formed during phenylfluorination (Scheme [7]).

Zoom Image
Scheme 7 Substrate-directing effect on the phenylfluorination of cyclooctene β-amino esters (±)-6

Herein, we have described some preliminary experimental data that provides an insight into the chemical behavior of a cyclooctene-based β-lactam and β-amino esters under Pd-catalyzed ring olefin bond arylfluorination. We investigated a range of different experimental conditions in terms of the ligand, solvent, temperature, and reaction time. Phenylfluorination of the cyclooctene-fused β-lactam afforded a separable mixture of four products. Transformation of β-amino esters possessing a cyclooctene framework, most probably due to stable chelate ring formation in the transition state, proceeded selectively under regio- and stereocontrol, furnishing single phenylfluorinated products. Based on the above-mentioned observations and preliminary experimental findings, further studies and extensions of the arylfluorination regarding the type of the substrate (with different ring sizes), the Pd catalyst source, and the substitution pattern of the arylboronic acid, will be undertaken in our laboratory .

Chemicals were purchased from Sigma-Aldrich and Merck. Thin-layer chromatography plates (TLC 60 F254 25 Silica gel on aluminium sheets) were purchased from Merck. Silica gel for flash chromatography (pore size 15–40 μm) was purchased from Merck. Flash chromatography purifications were performed with a CombiFlash Rf + (on normal phase) or with a CombiFlasf Rf EZ Prep (on reversed phase) using gradient eluent systems: hexane/EtOAc, CH2Cl2/MeOH or MeCN/H2O. Melting points were determined with a PGH Rundfunk-Fernsehen Niederdorf instrument with a Multi-Thermometer apparatus. LC-MS samples were analyzed with an LC-MS 2020 Shimadzu instrument. NMR spectra were recorded at room temperature using Varian NMR System spectrometers operating at 300 MHz, 400 MHz, 500 MHz, or 600 MHz (1H NMR frequency). The samples were dissolved in CDCl3. All spectra are referenced to the residual solvent signal of CHCl3 (7.26 ppm). 1H and 13C assignments were confirmed using the combination of two-dimensional homonuclear (1H–1H TOCSY, 1H–1H COSY, 1H–1H ROESY) and heteronuclear (1H–13C HSQC, 1H–13C HMBC) measurements. Chemical shifts are reported in ppm, and coupling constants (J) in Hz. Spectra were analyzed using MestreNova software. Conformational analysis was performed using the Conformer-Rotamer Ensemble Sampling Tool (CREST) developed by the Grimme group.[10] The resulting lowest energy conformer was subsequently optimized at the m062x/6-31+G(d,p) level, and frequency calculations were conducted using the ORCA software package.[11] HRMS data were acquired on a Sciex 5600+ Triple TOF high-resolution mass spectrometer in flow injection mode. The resolution was over 30000 in the entire mass range.


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Arylfluorination; General Procedure

Initially, the catalyst solution was prepared by mixing Pd(OAc)2 (10 mol%) and the ligand (4,4′-di-tert-butyl 2,2′-bipyridyl or 2,2′-bipyridyl) (15 mol%) in CH2Cl2 (3 mL), and the resulting mixture was stirred under an Ar atmosphere at room temperature for 15 min. The reactant solution was prepared by adding compound (±)-1 or (±)-6 (0.50 mmol) to a mixture of PhB(OH)2 (2 equiv) and Selectfluor (2 equiv) in CH2Cl2 (5 mL), MeCN (5 mL), and MeOH (1 mL). Next, the catalyst solution was added under Ar. The resulting mixture was stirred at room temperature for the indicated time. Subsequently, the mixture was diluted with CH2Cl2 (25 mL) and washed with H2O (3 × 20 mL) (in the case of emulsion formation, some solid NaCl was added to the contents of the separating funnel). The organic phase was then dried over Na2SO4. Finally, after filtering out the drying agent, the filtrate was evaporated under reduced pressure onto silica gel and purified by column chromatography (n-hexane/EtOAc).


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tert-Butyl (1R*,3S*,5S*,8S*)-3-Fluoro-10-oxo-5-phenyl-9-azabicyclo[6.2.0]decane-9-carboxylate [(±)-2]

Prepared according to the arylfluorination general procedure from tert-butyl (1R*,8S*,Z)-10-oxo-9-azabicyclo[6.2.0]dec-4-ene-9-carboxylate [(±)-1] (100 mg, 0.6 mmol). Purification of the crude product by column chromatography afforded the product as a white-yellowish oil.

Yield: 18 mg (11%); Rf = 0.58 (hexane/EtOAc, 3:1).

1H NMR (400 MHz, CDCl3): δ = 7.33–7.29 (m, 2 H), 7.23–7.18 (m, 1 H), 7.14–7.11 (m, 2 H), 4.82 (ddq, J = 45.2, 11.4, 5.1, 2.9 Hz, 1 H), 4.18 (ddt, J = 8.7, 5.9, 2.6 Hz, 1 H), 3.57 (ddd, J = 12.9, 6.2, 2.1 Hz, 1 H), 2.62 (td, J = 9.4, 2.8 Hz, 1 H), 2.46–2.33 (m, 1 H), 2.38–2.31 (m, 1 H), 2.26–2.24 (m, 1 H), 2.23–2.15 (m, 1 H), 1.96 (s, 1 H), 1.77–1.74 (m, 1 H), 1.73–1.65 (m, 2 H), 1.53 (s, 9 H).

13C NMR (101 MHz, CDCl3): δ = 167.20, 148.90, 147.99, 128.94, 126.54, 126.45, 90.14 (d, J = 171.5 Hz), 83.57, 57.24, 46.13, 40.59 (d, J = 13.3 Hz), 40.03 (d, J = 20.3 Hz), 37.40, 28.21, 28.16, 26.02 (d, J = 21.9 Hz).

19F NMR (376 MHz, CDCl3): δ = –173.25 (m).

HRMS (ES+): m/z [M + Na]+ calcd for C20H26FNNaO3: 370.17889; found: 370.1776.


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tert-Butyl (1R*,4R*,6R*,8S*)-6-Fluoro-10-oxo-4-phenyl-9-azabicyclo[6.2.0]decane-9-carboxylate [(±)-3]

Prepared according to the arylfluorination general procedure from tert-butyl (1R*,8S*,Z)-10-oxo-9-azabicyclo[6.2.0]dec-4-ene-9-carboxylate [(±)-1] (100 mg, 0.6 mmol). Purification and crystallization of the crude residue afforded the product as white solid.

Yield: 29 mg (19%); Rf = 0.50 (hexane/EtOAc, 3:1); mp 152–153 °C.

1H NMR (600 MHz, CDCl3): δ = 7.30 (m, 2 H), 7.22–7.18 (m, 1 H), 7.12 (m, 2 H), 4.83 (dddt, J = 44.6, 11.7, 5.6, 2.9 Hz, 1 H), 4.35 (ddd, J = 12.3, 6.1, 1.9 Hz, 1 H), 3.34 (ddd, J = 12.8, 6.1, 2.6 Hz, 1 H), 2.77 (t, J = 16.3 Hz, 1 H), 2.39 (dt, J = 14.1, 7.3 Hz, 1 H), 2.27 (m, 1 H), 2.23 (m, 1 H), 2.14 (dddd, J = 43.3, 15.3, 12.3, 3.1 Hz, 1 H), 2.06–1.99 (m, 1 H), 1.93–1.86 (m, 1 H), 1.86–1.77 (m, 1 H), 1.60–1.53 (m, 1 H), 1.54 (s, 9 H).

13C NMR (151 MHz, CDCl3): δ = 167.72, 148.84, 128.94, 126.50, 126.47, 90.32 (d, J = 170.4 Hz), 83.60, 53.98, 50.75, 40.82 (d, J = 13.1 Hz), 39.29, 39.19 (d, J = 20.7 Hz), 29.41 (d, J = 21.4 Hz), 28.21, 24.36.

19F NMR (376 MHz, CDCl3): δ = –170.96 (tdt, J = 43.2, 16.3, 7.6 Hz).

HRMS (ES+): m/z [M + Na]+ calcd for C20H26FNNaO3: 370.17889; found: 370.1787.


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tert-Butyl (1R*,5S*,8S*,Z)-10-Oxo-5-phenyl-9-azabicyclo[6.2.0]dec-2-ene-9-carboxylate [(±)-4]

Prepared according to the arylfluorination general procedure from tert-butyl (1R*,8S*,Z)-10-oxo-9-azabicyclo[6.2.0]dec-4-ene-9-carboxylate [(±)-1] (100 mg, 0.6 mmol). Purification of the crude product by column chromatography afforded the product as white-yellowish oil.

Yield: 18 mg (11%); Rf = 0.68 (hexane/EtOAc, 3:1).

1H NMR (600 MHz, CDCl3): δ = 7.30 (t, J = 7.5 Hz, 2 H), 7.19 (t, J = 7.4 Hz, 1 H), 7.15 (m, 2 H), 5.97 (tdd, J = 10.2, 7.0, 3.2 Hz, 1 H), 5.63 (dd, J = 10.2, 3.4 Hz, 1 H), 4.22 (ddd, J = 10.9, 6.5, 1.7 Hz, 1 H), 4.16 (dtd, J = 6.6, 3.3, 1.7 Hz, 1 H), 2.63 (td, J = 11.1, 4.3 Hz, 1 H), 2.41 (dd, J = 14.3, 8.7 Hz, 1 H), 2.32 (dd, J = 13.1, 7.4 Hz, 1 H), 2.22 (dt, J = 13.2, 10.1 Hz, 1 H), 2.13 (ddd, J = 13.8, 8.8, 4.1 Hz, 1 H), 1.81 (dt, J = 14.3, 11.0 Hz, 1 H), 1.61 (dt, J = 14.9, 11.8 Hz, 1 H), 1.52 (s, 9 H).

13C NMR (151 MHz, CDCl3): δ = 166.78, 148.39, 134.34, 128.73, 126.56, 126.34, 120.16, 83.49, 61.03, 51.44, 45.03, 38.74, 36.00, 28.22, 26.74.

HRMS (ES+): m/z [M + Na]+ calcd for C20H25NNaO3: 350.17267; found: 370.1726.


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tert-Butyl (1R*,4S*,5R*,8S*)-4-Methoxy-10-oxo-5-phenyl-9-azabicyclo[6.2.0]decane-9-carboxylate [(±)-5]

Prepared according to the arylfluorination general procedure from tert-butyl (1R*,8S*,Z)-10-oxo-9-azabicyclo[6.2.0]dec-4-ene-9-carboxylate [(±)-1] (100 mg, 0.6 mmol). Purification of the crude product by column chromatography afforded the product as white-yellowish oil.

Yield: 10 mg (6%); Rf = 0.36 (hexane/EtOAc, 3:1).

1H NMR (600 MHz, CDCl3): δ = 7.29–7.26 (m, 2 H), 7.18 (t, J = 7.4 Hz, 1 H), 7.13–7.10 (m, 2 H), 4.09 (ddd, J = 11.4, 6.2, 2.9 Hz, 1 H), 3.24 (ddd, J = 12.5, 6.2, 2.3 Hz, 1 H), 3.05 (m, 4 H), 2.74 (dd, J = 11.0, 5.7 Hz, 1 H), 2.61 (dd, J = 14.6, 7.6 Hz, 1 H), 2.08 (m, 1 H), 2.07 (m, 1 H), 2.02–1.93 (m, 1 H), 1.89 (tt, J = 11.8, 4.6 Hz, 1 H), 1.82 (m, 1 H), 1.78 (m, 1 H), 1.71 (m, 1 H), 1.52 (s, 9 H).

13C NMR (101 MHz, CDCl3): δ = 167.44, 144.21, 128.33, 127.99, 126.12, 84.17, 83.47, 57.88, 57.35, 52.52, 51.28, 34.21, 33.03, 28.39, 28.24, 17.34.

HRMS (ES+): m/z [M + Na]+ calcd for C21H29NNaO4: 382.19888; found: 382.1977.


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Ethyl (1R*,2S*,5R*,7R*)-2-((tert-Butoxycarbonyl)amino)-7-fluoro-5-phenylcyclooctane-1-carboxylate [(±)-7a]

Prepared according to the arylfluorination general procedure from ethyl (1R*,8S*,Z)-8-((tert-butoxycarbonyl)amino)cyclooct-4-ene-1 carboxylate [(±)-6a] (100 mg, 0.34 mmol). Purification and crystallization of the crude residue afforded the product as a white solid.

Yield: 45 mg (31%); Rf = 0.66 (hexane/EtOAc, 3:1); mp 116–117 °C.

1H NMR (600 MHz, CDCl3): δ = 7.29 (dd, J = 8.4, 6.9 Hz, 2 H), 7.21–7.17 (m, 1 H), 7.17–7.12 (m, 2 H), 4.90 (d, J = 9.3 Hz, 1 H), 4.72 (dt, J = 43.4, 11.1 Hz, 1 H), 4.25–4.14 (m, 2 H), 4.13 (br s, 1 H), 3.01 (dt, J = 9.5, 4.4 Hz, 1 H), 2.79 (s, 1 H), 2.64–2.50 (m, 1 H), 2.34–2.24 (m, 1 H), 2.16–2.10 (m, 1 H), 2.10–2.01 (m, 1 H), 1.98–1.90 (m, 2 H), 1.88–1.81 (m, 2 H), 1.43 (s, 9 H), 1.30 (t, J = 7.1 Hz, 3 H).

13C NMR (151 MHz, CDCl3): δ = 173.22, 155.05, 149.14, 128.85, 126.66, 126.35, 92.61 (d, J = 167.2 Hz), 79.69, 61.29, 49.62, 44.11 (d, J = 11.9 Hz), 42.43 (d, J = 22.2 Hz), 39.06 (d, J = 13.9 Hz), 32.93, 32.50 (d, J = 26.0 Hz), 30.63, 28.52, 14.33.

19F NMR (376 MHz, CDCl3): δ = –154.37 (br s).

HRMS (ES+): m/z [M + Na]+ calcd for C22H32FNNaO4: 416.22076; found: 416.2222.


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Methyl (1R*,2S*,5R*,7R*)-2-((tert-Butoxycarbonyl)amino)-7-fluoro-5-phenylcyclooctane-1-carboxylate [(±)-7b]

Prepared according to the arylfluorination general procedure from methyl (1R*,8S*,Z)-8-((tert-butoxycarbonyl)amino)cyclooct-4-ene-1-carboxylate [(±)-6b] (100 mg, 0.35 mmol). Purification of the crude product by column chromatography afforded the product as a white-yellowish solid.

Yield: 30 mg (16%); Rf = 0.46 (hexane/EtOAc, 3:1); mp 76–77 °C.

1H NMR (400 MHz, CDCl3): δ = 7.32–7.27 (m, 2 H), 7.22–7.17 (m, 1 H), 7.17–7.12 (m, 2 H), 4.92 (d, J = 9.3 Hz, 1 H), 4.72 (dt, J = 43.4, 10.9 Hz, 1 H), 4.24–4.03 (m, 1 H), 3.74 (s, 3 H), 3.03 (dt, J = 9.6, 4.5 Hz, 1 H), 2.79 (s, 1 H), 2.55 (dddd, J = 22.3, 12.9, 4.8, 2.4 Hz, 1 H), 2.30 (tdd, J = 13.6, 3.9, 1.8 Hz, 1 H), 2.15 (m, 1 H), 2.05 (m, 1 H), 1.97–1.79 (m, 4 H), 1.44 (s, 9 H).

13C NMR (101 MHz, CDCl3): δ = 173.75, 155.05, 149.09, 128.85, 126.65, 126.36, 92.50 (d, J = 167.1 Hz), 79.78, 52.31, 49.52, 44.14 (d, J = 11.8 Hz), 42.45 (d, J = 22.7 Hz), 39.06 (d, J = 14.2 Hz), 32.88, 32.60 (d, J = 26.0 Hz), 30.62, 28.52.

19F NMR (376 MHz, CDCl3): δ = –154.52.

HRMS (ES+): m/z [M + Na – Boc]+ calcd for C16H22FNNaO2: 402.2159; found: 302.1527.


#

Ethyl (1R*,2S*,5R*,7R*)-2-(((Benzyloxy)carbonyl)amino)-7-fluoro-5-phenylcyclooctane-1-carboxylate [(±)-7c]

Prepared according to the arylfluorination general procedure from ethyl (1R*,8S*,Z)-8-(((benzyloxy)carbonyl)amino)cyclooct-4-ene-1-carboxylate [(±)-6c] (100 mg, 0.66 mmol). Purification of the crude product by column chromatography afforded the product as a white oil.

Yield: 42 mg (29%); Rf = 0.5 (hexane/EtOAc, 3:1).

1H NMR (400 MHz, CDCl3): δ = 7.37–7.33 (m, 5 H), 7.32–7.27 (m, 2 H), 7.22–7.17 (m, 1 H), 7.15 (d, J = 7.6 Hz, 2 H), 5.19 (d, J = 9.2 Hz, 1 H), 5.09 (s, 2 H), 4.73 (dt, J = 43.6, 10.9 Hz, 1 H), 4.20–4.16 (m, 1 H), 4.15 (q, J = 7.3 Hz, 2 H), 3.03 (dt, J = 9.5, 5.1 Hz, 1 H), 2.79 (s, 1 H), 2.66–2.48 (m, 1 H), 2.39–2.22 (m, 1 H), 2.15 (m, 1 H), 2.06 (m, 1 H), 1.97 (m, 1 H), 1.93 (m, 1 H), 1.86 (m, 2 H), 1.28–1.22 (m, 3 H).

13C NMR (101 MHz, CDCl3): δ = 173.00, 155.56, 148.99, 136.55, 128.86, 128.69, 128.32, 128.23, 126.63, 126.39, 92.50 (d, J = 167.4 Hz), 66.92, 61.39, 50.09, 44.16 (d, J = 11.2 Hz), 42.49 (d, J = 22.5 Hz), 39.08 (d, J = 13.9 Hz), 32.83, 32.59 (d, J = 25.9 Hz), 30.60, 14.27.

19F NMR (376 MHz, CDCl3): δ = –154.28.

HRMS (ES+): m/z [M + Na]+ calcd for C25H30FNNaO4: 450.20510; found: 450.2063.


#

Methyl (1R*,2S*,5R*,7R*)-7-Fluoro-2-((4-methylphenyl)sulfonamido)-5-phenylcyclo-octane-1-carboxylate [(±)-7d]

Prepared according to the arylfluorination general procedure from methyl (1R*,8S*,Z)-8-((4-methylphenyl)sulfonamido)cyclooct-4-ene-1-carboxylate [(±)-6d] (100 mg, 0.3 mmol). Purification and crystallization of the crude residue afforded the product as a white solid.

Yield: 54 mg (37%); Rf = 0.48 (hexane/EtOAc, 2:1); mp 180–181 °C.

1H NMR (600 MHz, CDCl3): δ = 7.79–7.74 (m, 2 H), 7.35–7.31 (m, 2 H), 7.30–7.26 (m, 2 H), 7.22–7.13 (m, 1 H), 7.09–7.01 (m, 2 H), 5.13 (d, J = 9.0 Hz, 1 H), 4.61 (dtt, J = 44.1, 10.7, 3.7, 2.4 Hz, 1 H), 3.68 (ddt, J = 12.8, 8.4, 3.9 Hz, 1 H), 3.60 (s, 3 H), 2.93 (dt, J = 9.7, 4.6 Hz, 1 H), 2.62–2.53 (m, 1 H), 2.53–2.44 (m, 1 H), 2.43 (s, 3 H), 2.26 (ddt, J = 15.6, 13.6, 2.2 Hz, 1 H), 2.16 (dtd, J = 15.1, 10.1, 2.8 Hz, 1 H), 2.04–1.93 (m, 2 H), 1.78–1.73 (m, 2 H), 1.69–1.60 (m, 1 H).

13C NMR (151 MHz, CDCl3): δ = 173.09, 148.62, 143.76, 138.07, 129.97, 128.87, 127.19, 126.51, 126.47, 92.32 (d, J = 167.8 Hz), 52.58, 52.36, 44.96 (d, J = 11.3 Hz), 42.42 (d, J = 22.7 Hz), 39.36 (d, J = 13.3 Hz), 32.79 (d, J = 26.5 Hz), 32.53, 31.23, 21.67.

19F NMR (376 MHz, CDCl3): δ = –153.67 (dt, J = 42.3, 19.3 Hz).

HRMS (ES+): m/z [M + Na]+ calcd for C23H28FNNaO4S: 456.15153; found: 456.1611.


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Conflict of Interest

The authors declare no conflict of interest.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-2609-9601.
  • Supporting Information

Corresponding Authors

Loránd Kiss
Institute of Organic Chemistry, Stereochemistry Research Group, HUN-REN Research Centre for Natural Sciences
Magyar tudósok krt. 2, 1117 Budapest
Hungary   
Email: kiss.lorand@ttk.hu   

Melinda Nonn
MTA TTK Lendület Artificial Transporter Research Group, Institute of Materials and Environmental Chemistry, HUN-REN Research Center for Natural Sciences, Hungarian Academy of Sciences
Magyar Tudósok krt. 2, 1117 Budapest
Hungary   

Publication History

Received: 11 April 2025

Accepted after revision: 14 May 2025

Accepted Manuscript online:
14 May 2025

Article published online:
11 June 2025

© 2025. Thieme. All rights reserved

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Zoom Image
Figure 1 Selected bioactive alicyclic amino acid derivatives
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Scheme 1 Aim of the current work: Studies on the Pd-catalyzed olefin bond arylfluorination of cycloalkene-based β-lactam and β-amino esters (Pg = Boc, Cbz, Ts, R = Et, Me)
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Scheme 2 Phenylfluorination of cyclooctene-fused β-lactam (±)-1
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Scheme 3 Proposed synthetic pathway for the phenylfluorination of cyclooctene-fused β-lactam (±)-1
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Scheme 4 Proposed synthetic pathway for the phenylfluorination of cyclooctene-fused β-lactam (±)-1 involving the attack of MeOH
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Scheme 5 Phenylfluorination of cyclooctene β-amino esters (±)-6
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Figure 2 Conformational structure of intermediate T7 during coordination of the amide O atom to Pd (overridden by steric factors in the formation of (±)-2, (±)-3, and (±)-4)
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Scheme 6 Proposed synthetic pathway for the phenylfluorination of cyclooctene β-amino esters (±)-6
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Scheme 7 Substrate-directing effect on the phenylfluorination of cyclooctene β-amino esters (±)-6