Late-Stage Conversion of a Metabolically Labile Aryl Methyl Ether-Containing Natural Product to Fluoroalkyl Analogs

Abstract

We report the conversion of aryl methyl ethers and phenols into six fluoroalkyl analogs through late-stage functionalization of a natural product-derived FDA-approved therapeutic. This series of short synthetic sequences exploits a combination of both modern and traditional methods, and demonstrates that some recently reported methods do not always work as well as desired on a natural product-like scaffold. Nonetheless, reaction optimization can deliver sufficient quantities of each target analog for medicinal chemistry purposes. In some cases, classical reactions and synthetic sequences still outcompete modern organofluorine transformations, which should encourage the continued search for improved reactions. Overall, the project provides a valuable synthetic roadmap for medicinal chemists to access a range of fluorinated therapeutic candidates with distinct physicochemical properties relative to the original O-based analog.

Graphical Abstract

INTRODUCTION

The physicochemical and biophysical perturbations imparted by fluorine and fluorinated substituents on small molecule therapeutics^1–4 have inspired the development of many new synthetic methods capable of accessing fluorinated functional groups.^4–7 However, most of these methods are demonstrated on simple substrates that lack the complexity of real-life therapeutic candidates. Even fewer of these methods are demonstrated on natural products and/or natural product-derived scaffolds, which have a longstanding history for providing therapeutically relevant biological activities.^8,9 Thus, the ability to exploit many of these new methods for developing next-generation fluorinated therapeutics remains, in many cases, uncertain. To push the limits of and to probe the medicinal chemistry potential of several recently published methods, we herein test these reactions within the context of natural product-based drug discovery, and demonstrate that, though not all reactions perform as anticipated, insightful organic troubleshooting and optimization improves many of these transformations. Further, we demonstrate that some classical reactions and synthetic sequences still outcompete modern organofluorine transformations, which should encourage the continued search for new robust and efficient reactions. Overall, this work provides a roadmap for medicinal chemists and chemical biologists to deliver a series of fluoroalkyl analogs of a single target molecule through late-stage functionalization.

To bridge the gap between methodology and application towards natural product-based drug development, we selected aryl methyl ethers due to both their presence in many biologically active natural products,^10,11 as well as their well-documented metabolic liabilities.^12,13 Specifically, aryl methyl ethers commonly undergo rapid metabolism in the liver by P450 enzymes leading to short in vivo half-lives.^12,13 This three-step mechanism involves: 1) abstraction of a hydrogen atom to generate a radical, 2) oxidation of the radical to form a formyl hemiacetal, and 3) decomposition to release formaldehyde and phenol (Figure 1A). To prevent or slow the oxidation of aryl methyl ethers, medicinal chemists have exploited several strategies, including the substitution of weak C–H bonds with stronger C–D or C–F bonds that can improve metabolic stability (Figure 1B).^2,14,15 In the former case, the replacement of the weaker C–H bond with stronger C–D bonds slows the initial C–H abstraction, in turn slowing the overall metabolic process.^14,16–18 In contrast, the introduction of fluorinated groups presents P450 enzymes with substructures that are not subject to the mechanistic steps of the O-dealkylation process, and that might not be recognized by the P450’s active site.^3,19 Such fluorinated substructures might include fluoroalkyl ethers and fluoroalkyl groups that present considerably distinct properties relative to the methyl ether substructure (Figure 1C). Even further, considering the metabolic liability and potential for fluoroalkyl groups to stabilize the molecule against liver metabolism, the ability to synthetically convert the aryl methyl ether to a series fluoroalkyl analogs at the late stage of a synthesis (Figure 1) would provide a valuable roadmap for medicinal chemists to modify therapeutic candidates, including those derived from natural products.

Figure 1:

Metabolism of Aryl Methyl Ethers

As a prototypical example, dextromethorphan (DXM) is an aryl methyl ether containing active pharmaceutical ingredient that acts as a cough suppressant through agonism of the σ₁ receptor.^20–22 This approved drug bears the aryl methyl ether group that undergoes rapid in vivo metabolism through O-dealkylation by CYP2D6 ^21,23 to produce the psychoactive phenolic metabolite dextrorphan (DXO). ^21,23 This metabolite antagonizes the NMDA receptor and has opioid activity, ²¹ which combined cause dissociative sedation and lead to recreational use, particularly amongst adolescents.²⁴ Thus, for DXM, introduction of the aforementioned fluoroalkyl groups might deliver analogs bearing improved in vivo pharmacokinetic properties, as well as minimal abuse potential. Considering the natural product-like complexity of DXM, the conversion of the parent compound into fluoroalkyl analogs presents a formidable synthetic challenge on which to test modern synthetic methods. Herein, we present a series of synthetic strategies for accessing six fluoroalkyl functional groups with an emphasis placed on late-stage functionalization with minimal steps. In many cases, we exploit recently reported methods that do not always work as well as desired on this natural product-like scaffold, though through organic chemistry optimization, sufficient quantities of each target analog can be obtained for biological evaluation. Overall, this work provides a template for medicinal chemists to follow for delivering a cluster of fluoroalkyl analogs from a single analog bearing Ar–OH or Ar–OMe groups.

RESULTS AND DISCUSSION

Considering the goal of delivering fluoroalkyl analogs of DXM in the fewest possible steps, we exploited a late-stage functionalization strategy as opposed to de novo synthesis of each analog. Considering the potential incompatibilities of the basic amine with reaction conditions, this group was masked as a carbamate, which could be reduced back to the tertiary methylamine at a late stage of the synthesis using LiAlH₄. Additionally, this strategy would allow for late-stage installation of alternate substituents of the N-atom. As such, all analogs in this series were prepared from the commercially available salt, DXM•HBr 1 (Scheme 1). To convert DXM•HBr to the carbamate, we followed a previously published procedure,²⁵ in which the salt (1) was neutralized with NH₄OH, and the free base was reacted with acetyl chloride to produce amide 2. Cleavage of 2 in refluxing methanol generated a secondary amine, which was subsequently protected as an ethyl carbamate (3). Finally, O-dealkylation of the methyl ether using BBr₃ afforded phenol 4,²⁵ which served as a key synthetic intermediate for all subsequent reaction sequences.

Scheme 1:

Preparation of Phenol 4²⁵

Ar–OCF₂H:

Several reagents successfully converted phenol 4 to Ar–OCF₂H (5) in synthetically useful yields. These reactions function by generating free “:CF₂,” which formally inserts into phenolic O–H bonds by nucleophilic addition of the phenolate to :CF₂ to generate Ar–OCF₂^– and subsequent protonation. Initial screening on small scales demonstrated that multiple :CF₂-generating reagents performed similarly giving the desired product in 42–56% yield (Scheme 2).^26–31 Ultimately, the use of diethyl bromodifluoromethyl-phosphonate²⁶ delivered Ar–OCF₂H 5 in 56% yield.

Scheme 2:

Synthesis of Aryl Difluoromethyl Ether Analog 5

Ar–OCF₃:

Despite the many recently developed strategies to convert phenols to aryl trifluoromethyl ethers,^32–36 few of these methods have been demonstrated on complex natural product-like substrates. Direct conversion of phenols to aryl trifluoromethyl ethers has been reported utilizing TMSCF₃, silver, and oxidants such as NFSI or Selectfluor.^35,37 When applied to DXM-derived phenol 4, these conditions formed the desired Ar–OCF₃ (6, 45% ¹⁹F NMR, Scheme 3, Route A); however, the concurrent formation of Ar−CF₃ derived side products restricted purification.³⁷ Attempts to optimize the reaction (e.g. adjustment of time, temperature, reagent equivalents, and use of related reagents) were unsuccessful, and thus, we evaluated other strategies. Subsequent effort explored Ag-mediated decarboxylative fluorination reactions,^34,35 though these sequences also provided only low yields of products (Scheme 3, Route B). Specifically, alkylation of phenol 4 with potassium bromodifluoroacetate proceeded smoothly to provide acid 7 (78% yield), which was then subjected to Ag-mediated decarboxylation using SelectFluor II or AgF₂ as oxidants and sources of fluorine. Though both systems provided Ar–OCF₃ product 6, yields were poor (12–25% ¹⁹F NMR yield) and difluoromethylether 5 (Ar–OCF₂H) was formed as a major side product. Further, routine optimization of the system, including screening of decarboxylation initiators, fluorinating reagents, solvents, and temperatures did not improve the yield of 6 beyond 25%.

Scheme 3:

Synthesis of Aryl Trifluoromethyl Ether Analog 6

Ultimately, oxidative desulfurization-fluorination reactions of methyl xanthates delivered the desired aryl trifluoromethyl ether.^38,39 In practice, reaction of phenol 4 with NaH, CS₂, and MeI afforded methyl xanthate 8 (87% yield), which was subjected to oxidative desulfurization-fluorination using 1,3-dibromo-5,5-dimethylhydantoin (DBH) and HF-pyridine (Scheme 3, Route C).^38,39 This reaction afforded a mixture of several inseparable products (9), including the desired product (Ar–OCF₃), aryl bromodifluoromethyl ether (Ar–OCF₂Br), and aryl bromide adducts derived from both ethers. This complex mixture of products (9) was resolved to provide the desired Ar–OCF₃ product (6) by (1) treating the mixture with AgBF₄ to convert the Ar–OCF₂(Br/F) ether to a mixture of desired Ar–OCF₃ and the aryl bromide adducts, ⁴⁰ and subsequently (2) promoting reductive dehalogenation of the Ar–Br using Pd/C/H_2(g). Ultimately, this sequence afforded desired product 6 in 49% yield over three steps (Scheme 3, Route C).⁴¹ While this strategy delivered an initial batch of material, more modern conditions involving use of the new Fluolead⁴² combined with SbCl₃ cleanly converted xanthate 8 to Ar–OCF₃ 6 in 54% yield (Scheme 3, Route D). These conditions negated the formation of the brominated side products generated using DBH/HF-pyridine, and improved the overall yield, while also reducing the number of synthetic steps (3 vs. 1).⁴² Overall, this sequence highlights how continued reagent development enhances discovery chemistry.

Ar–CF₃ and Ar–CF₂CF₃:

Aryl fluoroalkyl analogs 12 and 13 were obtained from phenol 4 in a 3-step synthetic sequence using (phen)CuCF₃ and (phen)CuCF₂CF₃ as key reagents (Scheme 4).⁴³ Specifically, phenol 4 was first converted into triflate 10 (97% yield), and subsequent Pd-catalyzed borylation⁴³ afforded pinacol boronic ester 11 (68% yield). Finally, reaction of 11 with the copper-based perfluoroalkylating reagents provided desired fluoroalkyl analogs 12 (53% yield) and 13 (43% yield) without need to further optimize the reaction conditions.⁴³

Scheme 4:

Synthesis of Perfluorinated Alkyl Analogs 12 and 13

Ar–CF₂H:

Reaction sequences based off of both classical (Scheme 5A) and modern cross-coupling reactions (Scheme 5C, D) delivered Ar–CF₂H analog 15.^44–46 In one sequence, triflate 10 was cross-coupled with tributyl(vinyl)tin to generate a styrene, and subsequent oxidative cleavage of the alkene using OsO₄ and NaIO₄ delivered benzaldehyde 14 (50% yield over 2 steps).^47,48 Deoxyfluorination of 14 using diethylaminosulfur trifluoride (DAST) afforded Ar–CF₂H analog 15 (68% yield).⁴⁹

Scheme 5:

Synthesis of Difluoromethyl Analog 15

Alternatively, optimization of a metal-catalyzed cross-coupling strategy using aryl sulfonates and TMS–CF₂H as a difluoromethyl source provided direct access to Ar–CF₂H analog 15. Initially, conditions were adapted from Pd-catalyzed difluoromethylation reactions of aryl halides,^45,46 which required in situ generation of (SIPr)AgCF₂H, generated by reacting (SIPr)AgCl with TMSCF₂H and Na^tOBu, to stabilize the nucleophile (Scheme 5B). However, using these conditions, triflate-based electrophile 10 did not successfully generate the desired product in synthetically useful yields (10% yield), as the conditions hydrolyzed the substrate to generate phenol 4 as the major product (Scheme 5C). Control experiments confirmed that conversion of triflate to phenol was facilitated by NaO^tBu, and further routine optimization of time, temperature, loading of catalyst and reagents failed to substantially improve the reaction. Further optimization was conducted using a model substrate [(1,1’-biphenyl)-4-yl trifluoromethanesulfonate] on which standard conditions generated product in low yield (18% ¹⁹F NMR yield), though portion wise addition of triflate over 5 h increased yields of Ar–CF₂H product (29% ¹⁹F NMR yield). Moreover, addition of the model triflate via syringe pump over 18 h further improved the yield of product (53% ¹⁹F NMR yield). Additionally, use of stochiometric preformed (SIPr)AgCF₂H⁴⁶ instead of (SIPr)AgCl/TMSCF₂H/NaO^tBu avoided hydrolysis of the triflate, but did not improve the yield (50% ¹⁹F NMR yield) versus slow addition. Unfortunately, when applied to triflate 10, the slow addition strategy only modestly improved the yield of Ar–CF₂H product (~40% ¹⁹F NMR yield). To resolve this problem, use of the more stable aryl nonafluorobutanesulfonate^50,51 (Ar–ONf, 16), effectively suppressed hydrolysis, and after minor optimization, provided the highest yield of product 15 (61%) without requiring a slow addition technique or preforming transition metal complexes (Scheme 5D).⁵¹

Ar–CF₂CH₃:

A 3-step sequence converted benzaldehyde to 1,1-difluoroethyl analog 18. Initially, addition of MeMgBr to benzaldehyde 14 and oxidation of the resulting alcohol with Dess-Martin periodinane afforded aryl methyl ketone 17 (73% yield; Scheme 6). Subsequent deoxyfluorination of 17 with Deoxo-Fluor delivered difluorinated product 18 (41% yield),⁴⁹ though we are optimistic that other recently published mild deoxyfluorination reagents might also perform this transformation.^44,52

Scheme 6:

Synthesis of Difluoroethyl Analog 18

Reduction to Amine:

All analogs in the series were deprotected by reduction of the carbamate with LiAlH₄ to give products 19–24 68–90% yield (Scheme 7). After reverse phase LC purification, products were isolated in freebase form in >95% HPLC purity. Pharmacological analysis of these analogs will be reported in future work.

Scheme 7:

Reduction of Ar–R_f and Ar–OR_f Products to Afford DXM Analogs

CONCLUSION

The synthetic roadmap presented above enables conversion of aryl methyl ethers and phenols into fluoroalkyl analogs through late-stage functionalization of DXM, a natural product-derived FDA-approved therapeutic (Scheme 8). This set of short synthetic sequences enables access to sufficient quantities of each target analog for initial pharmacological and PK studies, as well as backup strategies for some less reliable reactions. Overall, the project provides a valuable synthetic template for medicinal chemists to access a range of fluorinated therapeutic candidates, both synthetic and natural product-derived, at a late stage of a synthesis, which avoids time- and material-consuming de novo synthesis of each analog. Further, each fluoroalkyl analog likely possessing distinct physicochemical and possibly pharmacological properties relative to the original Ar–OMe-derived compound. On the DXM scaffold, such physicochemical perturbations imparted by the fluoroalkyl groups, as well as pharmacodynamic properties of the new analogs will be reported separately in due course.

Scheme 8:

Synthetic Roadmap to Fluorinated DXM Analogs

EXPERIMENTAL SECTION

General Information:

Air- and moisture-sensitive reactions were carried out in oven-dried one-dram vials sealed with PTFE-lined septa or glassware sealed with rubber septa under an atmosphere of dry nitrogen. PTFE syringes equipped with stainless-steel needles were used to transfer air- and moisture-sensitive liquid reagents. Reactions were stirred using teflon-coated magnetic stir bars, and elevated temperatures were maintained using thermostat-controlled heating mantles. Organic solvents were removed using a rotary evaporator with a diaphragm vacuum pump. Thin-layer analytical chromatography was performed on silica gel UNIPLATE Silica Gel HLF UV254 plates, and spots were visualized by quenching of ultraviolet light (λ = 254 nm). Purification of products was accomplished by automated flash column chromatography on silica gel (VWR Common Silica Gel 60 Å, 40–60 μm). Unless otherwise noted, reagents were purchased from various commercial sources and used as received. NMR spectra were recorded on a Bruker DRX 500 MHz (¹H at 500 MHz, ¹⁹F at 471 MHz, ²H at 61 MHz) or a Bruker AVIIIHD 400 MHz (¹³C at 126 MHz) nuclear magnetic resonance spectrometer. ¹H NMR spectra were calibrated against the peak of the residual CHCl₃ (7.26 ppm) or residual (CH₃)₂SO (2.50 ppm) in the solvent. ¹⁹F NMR spectra were calibrated against the peak of the internal standard using CFCl₃ (0.00 ppm). ¹³C NMR spectra were calibrated against the peak of CDCl₃ (77.2 ppm) or (CD₃)₂SO (39.5 ppm). NMR data are represented as follows: chemical shift (ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, m = multiplet), coupling constant in Hertz (Hz), integration. To resolve carbamate rotamers, ¹H and ¹³C NMR spectra for compounds 3–15, 17, and 18 were measured at 343 K. High-resolution mass determinations were obtained by electrospray ionization (ESI) on a Waters LCT Premier™ mass spectrometer. Infrared spectra were measured on a Perkin Elmer Spectrum Two Fourier Transform Infrared Spectrometer by drying samples on a diamond ATR sample base plate. Uncorrected melting points were measured on a Thomas Hoover Uni-melt Capillary Melting Point apparatus.

(4bS,8aS,9S)-ethyl 3-methoxy-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-11-carboxylate (3)

Dextromethorphan hydrobromide hydrate 1 (3.70 g, 10.0 mmol) was dissolved in CHCl₃ (0.10 L) and washed with a saturated aqueous solution of ammonia (2 x 50 mL). The organic solution was dried over Na₂SO₄, filtered, and the solvent was removed in vacuo. The resulting oil was transferred to a 100 mL Schlenk flask and K₂CO₃ (5.53 g, 40.0 mmol) and anhydrous DCE (50 mL) were added. The flask was attached to a reflux condenser and acetyl chloride (4.3 mL, 40 mmol) was injected dropwise. The flask was placed in a 70 °C oil bath and the mixture was heated for 4 h. The reaction was allowed to cool to rt, the mixture was filtered through a pad of celite, and the pad was washed with DCE (2 x 10 mL). The solvent was removed in vacuo, and the resulting oil was dissolved in MeOH (25 mL). The flask was attached to a reflux condenser, and placed in a 70 °C oil bath. After heating for 30 min, the reaction was cooled to 23 °C, and the solvent was removed in vacuo. The resulting oil was dissolved in DCM (100 mL) and washed with a saturated aqueous solution of ammonia (50 mL). The organic solution was dried over Na₂SO₄, filtered, and the solvent was removed in vacuo. The resulting oil was transferred to a 100 mL Schlenk flask and CHCl₃ (50 mL) and NEt₃ (7.0 mL, 50 mmol) were injected. The flask was attached to a reflux condenser and placed in a 0 °C ice bath. Ethyl chloroformate (2.9 mL, 30 mmol) was injected dropwise and the flask was removed from the ice bath. The flask was placed in a 70 °C oil bath for 6 h and then cooled to rt. The organic solution was dried over Na₂SO₄, filtered, and the solvent was removed in vacuo. Chromatographic purification (hexanes : EtOAc, 1:0 → 9:1) provided 3.09 g (94%) of the title compound as a faint yellow oil. ¹H NMR (500 MHz, DMSO-d₆, 343 K) δ 7.03 (d, J = 8.4 Hz, 1H), 6.82 (d, J = 2.5 Hz, 1H), 6.74 (dd, J = 8.4, 2.6 Hz, 1H), 4.21 (s, 1H), 3.77 (s, 1H), 3.73 (s, 3H), 3.61 (s, 3H), 3.04 (dd, J = 18.0, 6.0 Hz, 1H), 2.68–2.55 (m, 1H), 2.38 (d, J = 13.7 Hz, 1H), 1.62 (td, J = 9.3, 4.7 Hz, 2H), 1.56–1.41 (m, 3H), 1.38–1.23 (m, 3H), 1.22–1.13 (m, 1H), 0.97 (qd, J = 12.8, 3.8 Hz, 1H). ¹³C NMR (126 MHz, DMSO-d₆, 343 K) δ 158.0, 154.8, 139.6, 128.5, 127.6, 111.4, 110.5, 54.7, 51.7, 49.3, 43.1, 40.7, 37.6, 36.8, 35.5, 30.6, 25.9, 25.5, 21.4. IR (film) 2996, 2930, 2855, 1697, 1609, 1568, 1495, 1447, 1435, 1408, 1366, 1327, 1298, 1271, 1242, 1188, 1163, 1128, 1098, 1065, 1040, 1009, 853, 768 cm⁻¹. HRMS (ESI) m/z: [M + H]⁺ Calcd for C₂₀H₂₈NO₃ 330.2069; Found 330.2083 (4.2 ppm).

(4bS,8aS,9S)-ethyl 3-hydroxy-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-11-carboxylate (4)

Aryl methyl ether 3 (3.1 g, 9.4 mmol) was added to a 250 mL round bottom flask, which was sealed with a rubber septum, and evacuated and backfilled with N₂ (3x). Anhydrous DCM (30 mL) was injected, and the flask was placed in a 0 °C ice bath. A solution of BBr₃ (1.0 M in DCM, 30 mL, 30 mmol) was injected dropwise over a 10 min period. The reaction mixture was allowed to warm to rt and stirred for 1 h. The mixture was cooled to 0 °C, and a saturated aqueous solution of NaHCO₃ (50 mL) was slowly added over a 10 min period. The mixture was stirred for 1 h, diluted with DCM (50 mL), and the organic solution was washed with H₂O (75 mL), and brine (75 mL). The organic solution was dried over Na₂SO₄, filtered, and the solvent was removed in vacuo. Chromatographic purification (hexanes : EtOAc, 1:0 → 4:1) provided 2.75 g (93%) of the title compound as a colorless solid. ¹H NMR (500 MHz, DMSO-d₆, 343 K) δ 8.85 (s, 1H), 6.90 (d, J = 8.2 Hz, 1H), 6.71 (d, J = 2.3 Hz, 1H), 6.58 (dd, J = 8.2, 2.3 Hz, 1H), 4.20 (s, 1H), 3.73 (d, J = 11.2 Hz, 1H), 3.61 (s, 3H), 3.00 (dd, J = 17.9, 5.9 Hz, 1H), 2.53 (d, J = 17.8 Hz, 2H), 2.29 (d, J = 13.2 Hz, 1H), 1.65–1.56 (m, 2H), 1.51 (td, J = 12.9, 5.2 Hz, 2H), 1.44 (d, J = 12.4 Hz, 1H), 1.39–1.13 (m, 5H), 1.00 (qd, J = 12.7, 3.8 Hz, 1H). ¹³C NMR (126 MHz, DMSO-d₆, 343 K) δ 155.8, 154.9, 139.3, 128.4, 125.6, 113.3, 111.3, 51.7, 49.4, 43.2, 40.8, 37.7, 36.6, 35.6, 30.6, 25.9, 25.5, 21.5. IR (film) 3325, 3019, 2982, 2932, 2857, 1661, 1611, 1582, 1495, 1435, 1377, 1348, 1331, 1314, 1298, 1273, 1234, 1186, 1165, 1140, 1101, 1020, 990, 963, 912, 868, 837, 812, 772, 731 cm^–1. HRMS (ESI) m/z: [M + H]⁺ Calcd for C₁₉H₂₆NO₃ 316.1913; Found 316.1901 (3.8 ppm).

(4bS,8aS,9S)-ethyl 3-(difluoromethoxy)-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)-phenanthrene-11-carboxylate (5)

KOH (1.12 g, 20.0 mmol) and H₂O (5.0 mL) were added to a 50 mL round bottom flask, and the solution was cooled to 0 °C. MeCN (5 mL) and phenol 4 (315 mg, 1.00 mmol) were added to the mixture. Diethyl(bromodifluoromethyl)phosphonate (0.4 mL, 2.0 mmol) was injected and the mixture was allowed to warm to 23 °C and stirred for 1 h. The mixture was diluted with Et₂O (50 mL), and then washed with H₂O (50 mL) and brine (50 mL). The organic solution was dried over Na₂SO₄, filtered, and the solvent was removed in vacuo. Chromatographic purification (hexanes : EtOAc, 1:0 → 9:1) provided 204 mg (56%) of the title compound as a colorless oil. ¹H NMR (500 MHz, DMSO-d₆, 343 K) δ 7.18 (d, J = 8.4 Hz, 1H), 7.12 (t, J = 70.5 Hz, 1H), 7.09 (d, J = 2.2 Hz, 1H), 6.97 (dd, J = 5.8, 1.5 Hz, 1H), 4.25 (s, 1H), 3.76 (d, J = 11.2 Hz, 1H), 3.62 (s, 3H), 3.09 (dd, J = 18.3, 6.0 Hz, 1H), 2.66 (d, J = 18.4 Hz, 1H), 2.39 (d, J = 13.8 Hz, 1H), 1.76–1.43 (m, 6H), 1.40–1.24 (m, 4H), 1.16 (dtd, J = 16.5, 13.1, 11.6, 8.5 Hz, 1H), 0.94 (qd, J = 12.8, 3.8 Hz, 1H). ¹³C NMR (126 MHz, DMSO-d₆, 343 K) δ 154.8, 149.6 (t, J = 3.0 Hz), 140.0, 132.8, 129.1, 116.2, 116.1 (t, J = 257.8 Hz), 115.6, 51.8, 49.1, 42.9, 40.5, 37.5, 36.9, 35.2, 30.7, 25.8, 25.3, 21.3. ¹⁹F NMR (376 MHz, CDCl₃) δ −80.29 (d, J = 74.3 Hz). IR (film) 2982, 2930, 2859, 1694, 1611, 1580, 1495, 1427, 1377, 1327, 1296, 1267, 1236, 1184, 1169, 1128, 1099, 1042, 990, 964, 914, 880, 839, 812, 768, 729, 667 cm⁻¹. HRMS (ESI) m/z: [M + H]⁺ Calcd for C₂₀H₂₆F₂NO₃ 366.1881; Found 366.1895 (3.8 ppm).

(4bS,8aS,9S)-ethyl 3-(((methylthio)carbonothioyl)oxy)-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-11-carboxylate (8)

In a N₂-filled glovebox, NaH (14 mg, 0.60 mmol) and DMF (1.0 mL) were added to a 10 mL round bottom flask. The flask was removed from the glovebox, attached to a Schlenk line (N₂), and placed in a 0 °C ice bath. A solution of phenol 4 (0.20 g, 0.50 mmol) in DMF (1.0 mL) was injected, and the reaction mixture was allowed to warm to 23 °C and stirred for 1 h. CS₂ (60 μL, 1.0 mmol) was injected, and the mixture was stirred for 1 h. Next, MeI (0.11 mL, 1.8 mmol) was injected, and the mixture was stirred for 14 h. The reaction was quenched with 1 N HCl (5 mL), and diluted with Et₂O (15 mL). The mixture was washed with 1 N HCl (2 × 15 mL), H₂O (15 mL), and brine (15 mL). The organic solution was dried over Na₂SO₄, filtered, and the solvent was removed in vacuo. Chromatographic purification (hexanes : EtOAc, 1:0 → 4:1) afforded the title compound as a colorless oil (0.175 g, 87%). ¹H NMR (500 MHz, DMSO-d₆, 343 K) δ 7.24 (d, J = 8.3 Hz, 1H), 7.11 (d, J = 2.4 Hz, 1H), 6.97 (dd, J = 8.3, 2.4 Hz, 1H), 4.28 (s, 1H), 4.09 (d, J = 7.0 Hz, 2H), 3.80 (dd, J = 13.6, 4.4 Hz, 1H), 3.15 (dd, J = 19.1, 5.4 Hz, 1H), 2.72 (s, 3H), 2.37 (d, J = 13.7 Hz, 1H), 1.70 (dt, J = 12.7, 3.2 Hz, 1H), 1.65 (d, J = 12.7 Hz, 1H), 1.59 (td, J = 13.1, 5.4 Hz, 2H), 1.55–1.46 (m, 4H), 1.34 (ddd, J = 16.8, 13.1, 6.3 Hz, 4H), 1.22 (t, J = 7.0 Hz, 4H), 0.99 (qd, J = 12.9, 3.9 Hz, 1H). ¹³C NMR (126 MHz, DMSO-d₆, 343 K) δ 215.3, 154.4, 152.8, 140.3, 134.3, 128.9, 118.9, 118.6, 60.2, 49.0, 42.8, 40.4, 37.4, 37.0, 35.3, 31.9, 25.8, 25.4, 21.3, 19.1, 14.2. IR (film) 2980, 2930, 2857, 1694, 1682, 1607, 1582, 1493, 1464, 1454, 1427, 1375, 1327, 1296, 1269, 1234, 1173, 1157, 1099, 1044, 990, 964, 914, 814, 768, 731 cm⁻¹. HRMS (ESI) m/z: [M + H]⁺ Calcd for C₂₁H₂₈NO₃S₂ 406.1511; Found 406.1504 (1.7 ppm).

(4bS,8aS,9S)-ethyl 3-(trifluoromethoxy)-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)-phenanthrene-11-carboxylate (6)

Conditions A: 1,3-Dibromo-5,5-dimethylhydantoin (1.56 g, 5.45 mmol) was added to a 10 mL round bottom flask. DCM (1.0 mL) was injected, and the solution was cooled to –78 °C. HF•Pyridine (0.4 mL) and a solution of xanthate 8 (762 mg, 1.88 mmol) in DCM (1.0 mL) were injected. The reaction mixture was allowed to warm to 0 °C and stirred for 1 h. The mixture was poured over a saturated aqueous solution of NaHCO₃ (20 mL) and extracted with Et₂O (2 × 20 mL). The combined organic solution was dried over Na₂SO₄, filtered, and the solvent was removed in vacuo. Chromatographic purification (hexanes : EtOAc, 1:0 → 9:1) afforded a mixture of the title compound 6, bromoaryl trifluoromethyl ether, and aryl bromodifluoromethyl ether 9 as a colorless oil (445 mg). The material was dissolved in DCM (2.0 mL) and AgBF₄ (389 mg, 0.0200 mmol) was added. The mixture was stirred at 23 °C for 1 h and filtered through celite. Chromatographic purification (hexanes : EtOAc, 1:0 → 9:1) afforded a mixture of title compound and bromoaryl trifluoromethyl ether as a colorless oil (0.410 g). The material was dissolved in MeOH (2.0 mL) and 10% Pd/C (40.0 mg) was added. The system was flushed with N₂ and then evacuated and backfilled with H₂ (3x). The mixture was stirred at 23 °C for 16 h, filtered through a pad of celite, and diluted with EtOAc (30 mL). The solution was washed with H₂O (30 mL) and brine (30 mL). The organic solution was dried over Na₂SO₄, filtered, and the solvent was removed in vacuo. Chromatographic purification (hexanes : EtOAc, 1:0 → 9:1) afforded the title compound as a colorless oil (353 mg, 49%). ¹H NMR (500 MHz, DMSO-d₆, 343 K) δ 7.26 (d, J = 8.4 Hz, 1H), 7.23 (s, 1H), 7.13 (d, J = 8.4 Hz, 1H), 4.27 (s, 1H), 4.08 (s, 2H), 3.78 (d, J = 9.8 Hz, 1H), 3.13 (dd, J = 18.4, 6.1 Hz, 1H), 2.69 (d, J = 18.5 Hz, 1H), 2.45 (s, 1H), 2.40 (d, J = 14.1 Hz, 1H), 1.69 (d, J = 12.6 Hz, 1H), 1.66–1.45 (m, 4H), 1.45–1.30 (m, 3H), 1.21 (t, J = 6.9 Hz, 3H), 1.11 (q, J = 13.3 Hz, 1H), 0.93 (qd, J = 12.9, 3.3 Hz, 1H). ¹³C NMR (126 MHz, DMSO-d₆, 343 K) δ 155.2, 148.0, 141.9, 136.1, 130.3, 120.7 (q, J = 255.6 Hz), 118.7, 118.4, 61.1, 49.7, 43.6, 41.2, 38.2, 37.8, 36.0, 31.6, 26.6, 26.1, 22.0, 15.0. ¹⁹F NMR (376 MHz, CDCl₃) δ –57.86. IR (film) 3024, 2980, 2932, 2860, 1693, 1609, 1582, 1489, 1454, 1427, 1375, 1327, 1296, 1258, 1236, 1223, 1161, 1099, 1022, 989, 972, 914, 849, 837, 816, 768 cm^–1. HRMS (ESI) m/z: [M + H]⁺ Calcd for C₂₀H₂₅F₃NO₃ 384.1787; Found 384.1799 (3.1 ppm). Conditions B: Xanthate 8 (40 mg, 0.10 mmol) and Fluolead (125 mg, 0.500) were added to a 5 mL fluoropolymer vessel equipped with a 3-way adaptor and evacuated and backfilled with N₂ (3x). DCM (0.50 mL) was injected, and the solution was cooled to 0 °C. A solution of SbCl₃ (1.1 mg, 0.0050 mmol) in DCM (0.20 mL) was injected. The reaction stirred at 0 °C for 10 min before heating to 65 °C for 20 h. The reaction was then allowed to cool to 23 °C and NaF (40 mg, 1.00 mmol) was added into the vessel. The mixture was then filtered through a pad of celite, and 1N aqueous NaOH (1.0 mL) was added. The mixture was then stirred for 30 min. The mixture was diluted in DCM (10 mL) and washed with H₂O (30 mL) and brine (30 mL). The organic solution was dried over Na₂SO₄, filtered, and the solvent was removed in vacuo. Chromatographic purification (hexanes : EtOAc, 1:0 → 9:1) afforded the title compound as a colorless oil (19 mg, 54%).

2-(((4bS,8aS,9S)-11-(ethoxycarbonyl)-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthren-3-yl)oxy)-2,2-difluoroacetic acid (7)

Phenol 4 (0.630 g, 2.00 mmol) was added to a 25 mL Schlenk flask (N₂). 1,4-Dioxane (10 mL) was injected. NaH (0.050 mg, 2.2 mmol) in 1,4-dioxane (1.3 mL) was injected dropwise and stirred for 30 min. BrCF₂CO₂K (0.468 mg, 2.20 mmol) in 1,4-dioxane (2 mL) was injected into the mixture. The mixture was placed in a 110 °C oil bath for 18 h. The mixture was then allowed to cool to 23 °C and 1N HCl (10 mL) was added. The mixture was then extracted with DCM (10 x 2 mL), and the combined organic extracts were dried over Na₂SO₄, filtered, and the solvent was removed in vacuo. Chromatographic purification (hexanes : EtOAc, 1:0 → 0:1) afforded the title compound as a colorless solid (0.640 g, 78%). ¹H NMR (500 MHz, DMSO-d₆, 343 K) δ 7.18 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 2.0 Hz, 1H), 7.01 (dd, J = 8.3, 2.0 Hz, 1H), 4.24 (s, 1H), 3.76 (d, J = 10.3 Hz, 1H), 3.62 (s, 3H), 3.10 (dd, J = 18.4, 6.0 Hz, 1H), 2.66 (d, J = 18.4 Hz, 1H), 2.46 (s, 1H), 2.34 (d, J = 13.9 Hz, 1H), 1.67 (dt, J = 12.7, 3.1 Hz, 1H), 1.62 (d, J = 12.8 Hz, 1H), 1.59–1.54 (m, 1H), 1.54–1.44 (m, 3H), 1.42–1.28 (m, 4H), 1.13 (qt, J = 13.2, 3.2 Hz, 2H), 0.94 (qd, J = 12.9, 3.8 Hz, 1H). ¹³C NMR (126 MHz, DMSO-d₆, 343 K) δ 160.8 (t, J = 39.1 Hz), 155.6, 148.9 (t, J = 2.5 Hz), 141.1, 134.5, 129.8, 119.1, 118.4, 116.2 (t, J = 272.2 Hz), 52.6, 49.9, 43.6, 41.3, 40.9, 38.3, 37.7, 36.1, 31.6, 26.6, 26.1, 22.0. IR (film) 2930, 2859, 1773, 1632, 1436, 1238, 1172, 1103, 1019, 913, 737 cm⁻¹. HRMS (ESI) m/z: [M - H]⁻ Calcd for C₂₁H₂₅F₂NO₅ 408.1628; Found 408.1650 (5.4 ppm).

(4bS,8aS,9S)-ethyl 3-(((trifluoromethyl)sulfonyl)oxy)-6,7,8,8a,9,10-hexahydro-5H-9,4b-(ep-iminoethano)phenanthrene-11-carboxylate (10)

Phenol 4 (1.58 g, 5.00 mmol) was added to a 50 mL Schlenk flask (N₂). DCM (25.0 mL) and pyridine (0.810 mL, 10.0 mmol) were injected, and the solution was cooled to 0 °C. Trifluoromethanesulfonic anhydride (1.0 mL, 6.0 mmol) was injected dropwise over a 10 min period. The mixture was allowed to warm to 23 °C and stirred for 1 h. The reaction was quenched with 1N HCl (10 mL), and the mixture was diluted with DCM (50 mL). The organic solution was washed with 1N HCl (50 mL), H₂O (50 mL), and brine (50 mL). The organic solution was dried over Na₂SO₄, filtered, and the solvent was removed in vacuo. Chromatographic purification (hexanes : EtOAc, 1:0 → 17:3) afforded the title compound as a colorless solid (2.17 g, 97%). ¹H NMR (500 MHz, DMSO-d₆, 343 K) δ 7.34 (s, 1H), 7.33 (d, J = 7.5 Hz, 1H), 7.24 (dd, J = 8.5, 2.6 Hz, 1H), 4.28 (s, 1H), 4.15–4.00 (m, 2H), 3.79 (dd, J = 13.6, 4.4 Hz, 1H), 3.15 (dd, J = 18.7, 6.0 Hz, 1H), 2.40 (d, J = 14.0 Hz, 2H), 1.71 (dt, J = 12.6, 3.2 Hz, 1H), 1.60 (td, J = 13.1, 5.4 Hz, 2H), 1.56–1.46 (m, 3H), 1.36 (dtt, J = 16.5, 7.6, 3.5 Hz, 3H), 1.20 (t, J = 7.0 Hz, 3H), 1.09 (qt, J = 13.2, 3.2 Hz, 1H), 0.91 (qd, J = 12.9, 3.9 Hz, 1H). ¹³C NMR (126 MHz, DMSO-d₆, 343 K) δ 155.2, 148.7, 142.5, 137.9, 130.7, 119.0, 118.8 (q, J = 321.9 Hz), 118.8, 61.1, 49.6, 43.4, 41.10, 38.1, 38.0, 36.0, 31.7, 26.5, 26.1, 21.9, 15.0. ¹⁹F NMR (376 MHz, CDCl₃) δ –72.79. IR (film) 2988, 2932, 2861, 1699, 1607, 1580, 1489, 1447, 1424, 1368, 1327, 1298, 1267, 1234, 1211, 1142, 1099, 1036, 1009, 990, 949, 926, 910, 899, 878, 870, 829, 766, 700, 637, 608 cm⁻¹. HRMS (ESI) m/z: [M + H]⁺ Calcd for C₂₀H₂₅F₃NO₅S 448.1406; Found 448.1388 (4.0 ppm).

(4bS,8aS,9S)-ethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-11-carboxylate (11)

In a N₂-filled glovebox, aryl triflate 10 (1.7 g, 3.7 mmol), bis(pinacolato)diboron (1.1 g, 4.5 mmol), Pd(dppf)Cl₂ (0.27 g, 0.37 mmol), 1,1′-ferrocenediyl-bis(diphenylphosphine) (0.25 g, 0.45 mmol), and potassium acetate (1.1 g, 11 mmol) were added to a 100 mL pressure vessel. 1,4-Dioxane (37 mL) was injected, and the vessel was sealed with a PTFE cap. The vessel was removed from the glovebox and placed in an 80 °C oil bath, and the mixture was stirred for 16 h. The reaction was cooled to 23 °C and diluted with EtOAc (50 mL). The mixture was washed with H₂O (100 mL) and brine (100 mL). The layers were separated, and the organic solution was dried over Na₂SO₄, filtered, and the solvent was removed in vacuo. Chromatographic purification (hexanes : EtOAc, 9:1 → 4:1) afforded the title compound as a colorless solid (1.1 g, 68%). ¹H NMR (500 MHz, DMSO-d₆, 343 K) δ 7.34 (s, 1H), 7.33 (d, J = 7.5 Hz, 1H), 7.24 (dd, J = 8.5, 2.6 Hz, 1H), 4.28 (s, 1H), 4.15–4.00 (m, 2H), 3.79 (dd, J = 13.6, 4.4 Hz, 1H), 3.15 (dd, J = 18.7, 6.0 Hz, 1H), 2.40 (d, J = 14.0 Hz, 2H), 1.71 (dt, J = 12.6, 3.2 Hz, 1H), 1.60 (td, J = 13.1, 5.4 Hz, 2H), 1.56 – 1.46 (m, 3H), 1.36 (dtt, J = 16.5, 7.6, 3.5 Hz, 3H), 1.20 (t, J = 7.0 Hz, 3H), 1.09 (qt, J = 13.2, 3.2 Hz, 1H), 0.91 (qd, J = 12.9, 3.9 Hz, 1H). ¹³C NMR (126 MHz, DMSO-d₆, 343 K) δ 155.2, 148.7, 142.5, 137.9, 130.7, 119.0, 118.8 (q, J = 321.9 Hz), 118.8, 61.1, 49.6, 43.4, 41.10, 38.1, 38.0, 36.0, 31.7, 26.5, 26.1, 21.9, 15.0. IR (film) 3040, 2978, 2932, 2859, 1697, 1609, 1505, 1427, 1415, 1404, 1389, 1371, 1348, 1327, 1312, 1296, 1285, 1266, 1233, 1219, 1190, 1167, 1146, 1103, 1022, 990, 964, 914, 864, 847, 827, 768, 735, 689, 667 cm^–1. HRMS (ESI) m/z: [M + Na]⁺ Calcd for C₂₅H₃₆BNO₄Na 448.2635; Found 448.2638 (0.7 ppm).

(4bS,8aS,9S)-ethyl 3-(trifluoromethyl)-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)-phenanthrene-11-carboxylate (12)

Aryl boronic ester 11 (0.21 g, 0.50 mmol) and (1,10-phenanthroline)(trifluoromethyl)copper(I) (0.19 g, 0.60 mmol) were added to a 15 mL resealable vial. DMF (5.0 mL) was injected, and air was bubbled through the mixture for 5 min. The vial was sealed with a PTFE-lined cap and placed in a 50 °C oil bath for 18 h. The reaction was cooled to 23 °C, diluted with Et₂O (20 mL), and filtered through SiO₂ (washed with 2 × 20 mL Et₂O). The solvent was removed in vacuo. Chromatographic purification (hexanes : Et₂O, 1:0 → 9:1) afforded the title compound as a faint yellow oil (98 mg, 53%). ¹H NMR (500 MHz, DMSO-d₆, 343 K) δ 7.59 (s, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 4.28 (s, 1H), 3.78 (d, J = 10.2 Hz, 1H), 3.63 (s, 3H), 3.20 (dd, J = 18.9, 5.9 Hz, 1H), 2.77 (d, J = 18.9 Hz, 1H), 2.45 (dd, J = 23.7, 13.3 Hz, 2H), 1.73 (dt, J = 12.6, 3.1 Hz, 1H), 1.62 (dt, J = 12.9, 6.4 Hz, 2H), 1.57–1.46 (m, 2H), 1.37 (qt, J = 13.1, 3.6 Hz, 3H), 1.08 (qt, J = 13.2, 3.3 Hz, 1H), 0.91 (qd, J = 12.9, 4.0 Hz, 1H). ¹³C NMR (126 MHz, DMSO-d₆, 343 K) δ 155.6, 141.9, 140.6, 129.5, 128.1 (q, J = 31.4 Hz), 125.0 (q, J = 271.8 Hz), 122.8 (q, J = 4.0 Hz), 122.6 (q, J = 4.2 Hz), 52.7, 49.7, 43.7, 41.2, 38.1, 37.7, 35.9, 32.2, 31.0, 26.5, 26.1, 22.0. ¹⁹F NMR (376 MHz, CDCl₃) δ –62.2 (s). IR (film) 3011, 2982, 2932, 2860, 1693, 1464, 1427, 1418, 1375, 1352, 1325, 1308, 1298, 1265, 1232, 1221, 1190, 1163, 1146, 1123, 1099, 1086, 1022, 989, 945, 914, 896, 825, 798, 770, 729 cm⁻¹. HRMS (ESI) m/z: [M + H]⁺ Calcd for C₂₀H₂₅F₃NO₂ 368.1837; Found 368.1839 (0.5 ppm).

(4bS,8aS,9S)-ethyl 3-(perfluoroethyl)-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)-phenanthrene-11-carboxylate (13)

Aryl boronic ester 11 (43 mg, 0.10 mmol) and (1,10-phenanthroline)(pentafluoroethyl)copper(I) (44 mg, 012 mmol) were added to a 1 dram vial. DMF (1.0 mL) was injected and air was bubbled through the mixture for 5 min. The vial vas sealed with a PTFE-lined cap and placed in a 50 °C oil bath for 36 h. The reaction was cooled to 23 °C, diluted with Et₂O (10 mL), and filtered through SiO₂ (washed with 2 × 10 mL Et₂O). The solvent was removed in vacuo. Chromatographic purification (hexanes : Et₂O, 1:0 → 9:1) afforded the title compound as a faint yellow oil (18 mg, 43%). ¹H NMR (500 MHz, DMSO-d₆, 343 K) δ 7.53 (s, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 4.29 (s, 1H), 3.79 (d, J = 11.0 Hz, 1H), 3.63 (s, 3H), 3.21 (dd, J = 18.9, 5.8 Hz, 1H), 2.78 (d, J = 18.9 Hz, 1H), 2.44 (d, J = 13.9 Hz, 2H), 1.74 (d, J = 12.7 Hz, 1H), 1.62 (dt, J = 12.7, 5.9 Hz, 2H), 1.57–1.46 (m, 2H), 1.46–1.24 (m, 4H), 1.05 (q, J = 13.2 Hz, 1H), 0.90 (qd, J = 12.7, 3.4 Hz, 1H). ¹³C NMR (126 MHz, DMSO-d₆, 343 K) δ 155.6, 142.1 (t, J = 1.9 Hz), 140.7, 129.6, 126.0 (t, J = 23.7 Hz), 123.8 (t, J = 6.6 Hz), 123.7 (t, J = 6.9 Hz), 119.5 (qt, J = 270.5, 40.2 Hz), 114.0 (tq, J = 254.5, 37.8 Hz), 52.7, 49.7, 43.7, 41.3, 38.1, 37.7, 35.9, 32.1, 31.0, 26.5, 26.1, 21.9. ¹⁹F NMR (376 MHz, CDCl₃) δ −84.8 (s, 3F), −114.6 (s, 2F). IR (film) 2986, 2932, 1261, 1699, 1472, 1456, 1418, 1375, 1327, 1298, 1265, 1206, 1136, 1126, 1098, 1003, 943, 914, 893, 818, 770, 743 cm⁻¹. HRMS (ESI) m/z: [M + Na]⁺ Calcd for C₂₁H₂₄F₅NO₂Na 440.1625; Found 440.1624 (0.2 ppm).

(4bS,8aS,9S)-ethyl 3-formyl-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-11-carboxylate (14)

In a N₂-filled glovebox, Pd(PPh₃)₄ (112 mg, 0.100 mmol), LiCl (617 mg, 15.0 mmol), and 2,6-di-tert-butyl-4-methylphenol (5.0 mg) were added to a 100 mL pressure vessel. Aryl triflate 10 (2.17 g, 4.80 mmol) was dissolved in 1,4-dioxane (25 mL) and transferred to the vessel. Tributyl(vinyl)tin (1.5 mL, 5.0 mmol) was injected and the vessel was sealed with a PTFE cap. The vessel was removed from the glovebox and placed in a 110 °C oil bath for 3 h. The reaction was cooled to 23 °C, pyridine (1.0 mL) and HF•pyridine (0.50 mL) were injected, and the mixture was stirred for 24 h. The mixture was diluted with Et₂O (50 mL) and washed with 1N HCl (50 mL), H₂O (50 mL), and brine (50 mL). The organic solution was dried over Na₂SO₄, filtered, and the solvent was removed in vacuo. The residue was dissolved in Et₂O (50 mL) and stirred for 1 h with crushed NaOH (0.5 g), CsF (1 g), and SiO₂ (4 g). The solvent was removed in vacuo, and chromatographic purification (hexanes : EtOAc, 1:0 → 9:1) afforded (4bS,8aS,9S)-ethyl 3-vinyl-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-11-carboxylate (Styrene) as a colorless oil (1.17 g, 74%). ¹H NMR (500 MHz, DMSO-d₆, 343 K) δ 9.98 (s, 1H), 7.88 (s, 1H), 7.68 (dd, J = 7.8, 1.5 Hz, 1H), 7.36 (d, J = 7.9 Hz, 1H), 4.29 (s, 1H), 4.08 (dq, J = 11.5, 6.7 Hz, 2H), 3.78 (dd, J = 13.6, 4.2 Hz, 1H), 3.21 (dd, J = 19.2, 6.0 Hz, 1H), 2.76 (d, J = 19.2 Hz, 1H), 2.44 (t, J = 11.4 Hz, 1H), 1.72 (dt, J = 12.6, 3.1 Hz, 1H), 1.62 (td, J = 12.9, 5.3 Hz, 2H), 1.58–1.46 (m, 2H), 1.44–1.30 (m, 3H), 1.20 (t, J = 7.0 Hz, 3H), 1.13 (dddd, J = 16.6, 13.2, 8.4, 3.4 Hz, 1H), 0.92 (qd, J = 12.9, 3.9 Hz, 1H). ¹³C NMR (126 MHz, DMSO-d₆, 343 K) δ 193.0, 155.2, 144.4, 140.5, 135.9, 129.5, 128.0, 126.8, 61.1, 49.7, 43.8, 41.4, 38.1, 37.7, 35.9, 32.7, 26.6, 26.2, 22.1, 15.0. IR (film) 3086, 3042, 2980, 2930, 2857, 1694, 1632, 1564, 1499, 1427, 1375, 1327, 1296, 1269, 1234, 1215, 1186, 1169, 1150, 1099, 1022, 990, 907, 853, 826, 768, 735 cm⁻¹. HRMS (ESI) m/z: [M + Na]⁺ Calcd for C₂₁H₂₇NO₂Na 348.1939; Found 348.1938 (0.3 ppm).

The intermediate styrene (0.49 g, 1.5 mmol) was added to a 50 mL round bottom flask. THF (12 mL) and H₂O (4.0 mL) were injected, and the flask was sealed with a rubber septum. A solution of OsO₄ (ca. 0.020 mL, 4% in H₂O) was injected, and the reaction mixture was stirred for 10 min. The septum was removed, and NaIO₄ (1.1 g, 5.3 mmol) was slowly added. The flask was resealed with a septum, and the mixture was stirred for 90 min. The flask was placed in a 0 °C ice bath, Na₂S₂O₃ was added, and the mixture was stirred for 30 min. The mixture was diluted with EtOAc (0.050 L), and washed with H₂O (50 mL) and brine (50 mL). The organic solution was dried over Na₂SO₄, filtered, and the solvent was removed in vacuo. Chromatographic purification (hexanes : EtOAc, 1:0 → 4:1) afforded the title compound as a colorless oil (0.33 g, 68%). ¹H NMR (500 MHz, DMSO-d₆, 343 K) δ 7.35 (s, 1H), 7.27 (dd, J = 7.9, 1.4 Hz, 1H), 7.10 (d, J = 7.9 Hz, 1H), 6.72 (dd, J = 17.6, 10.9 Hz, 1H), 5.75 (d, J = 17.6 Hz, 1H), 5.19 (d, J = 11.1 Hz, 1H), 4.25 (s, 1H), 4.18–3.97 (m, 2H), 3.76 (dd, J = 13.3, 3.9 Hz, 1H), 3.26–2.99 (m, 1H), 2.64 (d, J = 18.6 Hz, 1H), 2.48 (s, 1H), 1.69–1.41 (m, 5H), 1.41–1.27 (m, 3H), 1.20 (t, J = 6.9 Hz, 3H), 1.15 (ddd, J = 16.4, 8.3, 3.4 Hz, 1H), 0.97 (qd, J = 12.8, 3.9 Hz, 1H). ¹³C NMR (126 MHz, DMSO-d₆, 343 K) δ 155.2, 139.4, 137.5, 136.5, 136.2, 128.8, 124.8, 123.8, 113.5, 61.0, 49.9, 44.1, 41.6, 38.3, 37.5, 36.1, 32.1, 26.7, 26.3, 22.2, 15.0. IR (film) 3007, 2978, 2930, 2856, 2721, 1693, 1601, 1570, 1464, 1425, 1389, 1375, 1325, 1296, 1267, 1236, 1211, 1188, 1165, 1148, 1099, 1080, 1020, 914, 824, 768, 731 cm⁻¹. HRMS (ESI) m/z: [M + H]⁺ Calcd for C₂₀H₂₆NO₃ 328.1913; Found 328.1906 (2.1 ppm).

(4bS,8aS,9S)-ethyl 3-(difluoromethyl)-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)-phenanthrene-11-carboxylate (15)

Conditions A: Aldehyde 14 (33 mg, 0.10 mmol) was added to a 1 dram vial, which was sealed with a PTFE cap, and evacuated and backfilled with N₂ (3x). DCM (0.1 mL) was injected, and the vial was placed in a 0 °C ice bath. DAST (26 μL, 0.2 mmol) was injected, and the reaction mixture was allowed to warm to 23 °C and stir for 16 h. The mixture was diluted with DCM (15 mL) and washed with H₂O (15 mL) and brine (15 mL). The organic solution was dried over Na₂SO₄, filtered, and the solvent was removed in vacuo. Chromatographic purification (hexanes : EtOAc, 1:0 → 9:1) afforded the title compound as a colorless oil (24 mg, 68%). ¹H NMR (500 MHz, DMSO-d₆, 343 K) δ 7.50 (s, 1H), 7.34 (d, J = 7.9 Hz, 1H), 7.27 (d, J = 7.9 Hz, 1H), 6.94 (t, J = 56.2 Hz, 1H), 4.27 (s, 1H), 4.07 (dt, J = 11.5, 5.7 Hz, 2H), 3.77 (dd, J = 13.6, 4.4 Hz, 1H), 3.17 (dd, J = 18.7, 5.9 Hz, 1H), 2.71 (d, J = 18.7 Hz, 1H), 2.45 (d, J = 13.7 Hz, 2H), 1.70 (dt, J = 12.6, 3.2 Hz, 1H), 1.65–1.54 (m, 2H), 1.55–1.44 (m, 2H), 1.36 (ddd, J = 21.5, 10.8, 7.4 Hz, 3H), 1.20 (t, J = 7.0 Hz, 3H), 1.11 (qt, J = 13.2, 3.3 Hz, 1H), 0.93 (qd, J = 12.9, 3.9 Hz, 1H). ¹³C NMR (126 MHz, DMSO-d₆, 343 K) δ 155.2, 140.0, 139.9 (t, J = 2.3 Hz), 133.1 (t, J = 22.0 Hz), 129.1, 123.4 (t, J = 6.5 Hz), 123.3 (t, J = 6.0 Hz), 115.7 (t, J = 235.8 Hz), 61.2, 49.8, 43.9, 41.4, 38.1, 37.6, 36.0, 32.2, 26.6, 26.2, 22.1, 15.0. IR (film) 3004, 2980, 2930, 2858, 1693, 1425, 1373, 1350, 1327, 1298, 1269, 1221, 1188, 1169, 1148, 1099, 1022, 989, 914, 825, 771, 733 cm⁻¹. HRMS (ESI) m/z: [M + H]⁺ Calcd for C₂₀H₂₆F₂NO₂ 350.1932; Found 350.1920 (3.4 ppm). Conditions B: In a N₂-filled glovebox, nonaflate 16 (180 mg, 0.30 mmol), Pd(dba)₂ (17 mg, 0.030 mmol), 1,1′-ferrocenediyl-bis(diphenylphosphine) (33 mg, 0.060 mmol), [SIPr]AgCl (63 mg, 0.12 mmol), sodium tert-butoxide (57 mg, 0.60 mmol), and toluene (3 mL) were added to 15 mL vial. The vessel was sealed with a PTFE cap and removed from the glovebox. TMSCF₂H (0.10 mL, 0.72 mmol) was injected, and the reaction mixture was placed in a 110 °C oil bath for 18 h. The mixture was then filtered through celite, diluted with EtOAc (15 mL) and washed with H₂O (15 mL) and brine (15 mL). The organic solution was dried over Na₂SO₄, filtered, and the solvent was removed in vacuo. Chromatographic purification (hexanes : EtOAc, 1:0 → 9:1) afforded the title compound as a colorless oil (64 mg, 61%).

ethyl (4bS,8aS,9S)-3-(((perfluorobutyl)sulfonyl)oxy)-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-11-carboxylate (16)

Phenol 4 (0.63 g, 2.00 mmol) was added to a 50 mL round bottom flask (N₂). DCM (10 mL) and triethylamine (0.42 mL, 3.0 mmol) were injected, and the solution was cooled to −78 °C. Perfluoro-1-butanesulfonyl fluoride (0.50 mL, 3.0 mmol) was injected dropwise over a 10 min period. The mixture was warmed to 23 °C and stirred for 18 h. The reaction was quenched with 1N HCl (5.0 mL), and the mixture was diluted with DCM (25 mL). The organic solution was washed with 1N HCl (25 mL), H₂O (25 mL), and brine (25 mL). The organic solution was dried over Na₂SO₄, filtered, and the solvent was removed in vacuo. Chromatographic purification (hexanes : EtOAc, 1:0 → 16:4) afforded the title compound as a colorless solid (0.771 g, 72%). The NMR data are reported as a 58:42 rotameric ratio at room temperature in CDCl₃. ¹H NMR for the major rotamer (500 MHz, CDCl₃) δ 7.17 (s, 1H), 7.17 (s, 1H), 4.45 (s, 1H), 3.82 (d, J = 14.0 Hz, 1H), 3.69 (s, 3H3.13 (d, J = 6.6 Hz, 0H), 2.77 (s, 1H), 2.55 (dt, J = 25.2, 13.5 Hz, 1H), 2.32 (d, J = 14.0 Hz, 1H), 1.81–1.48 (m, 5H), 1.45–1.27 (m, 5H), 0.99 (qd, J = 12.9, 3.9 Hz, 1H). ¹³C{¹H} NMR for the major rotamer (126 MHz, CDCl₃) δ 156.2, 149.0, 142.3, 137.2, 130.1, 118.9, 118.7, 117.2 (qtt, J = 282.5, 32.4, 6.1 Hz), 114.9 (ttt, J = 292.9, 35.5, 5.3 Hz), 109.9 (tp, J = 266.6, 28.5 Hz), 108.5 (ttq, J = 268.4, 39.2, 32.48 Hz), 52.7, 49.5, 43.6, 41.5, 41.2, 38.1, 38.1, 36.5, 31.8, 26.5, 26.3, 21.8. ¹H NMR for the minor rotamer (500 MHz, CDCl₃) δ 7.17 (s, 1H), 7.17 (s, 1H), 4.29 (s, 1H), 3.96 (d, J = 13.6 Hz, 1H), 3.72 (s, 3H), 3.17 (d, J = 6.0 Hz, 1H), 2.73 (s, 1H), 2.55 (dt, J = 25.2, 13.5 Hz, 1H), 2.32 (d, J = 14.0 Hz, 1H), 1.81–1.48 (m, 5H), 1.45–1.27 (m, 5H), 0.99 (qd, J = 12.9, 3.9 Hz, 1H). ¹³C{¹H} NMR for the minor rotamer (126 MHz, CDCl₃) δ 156.0, 149.0, 142.3, 137.0, 130.0, 118.9, 118.7, 117.2 (qtt, J = 282.5, 32.4, 6.1 Hz), 114.9 (ttt, J = 292.9, 35.5, 5.3 Hz), 109.9 (tp, J = 266.6, 28.5 Hz), 108.5 (ttq, J = 268.4, 39.2, 32.48 Hz), 52.8, 49.8, 43.7, 41.5, 41.2, 38.1, 38.0, 36.5, 32.1, 26.6, 26.3, 21.8. ¹⁹F NMR (470 MHz, CDCl₃) δ −81.1 (t, J = 9.8 Hz), −109.4 (t, J = 14.2 Hz), (−121.3)–(−121.4) (m), (−126.3)–(−126) (m). IR (film) 2934, 2861, 1698, 1448, 1426, 1236, 1206, 1144 cm⁻¹. HRMS (ESI) m/z: [M + H]⁺ Calcd for C₂₃H₂₅F₉NO₅S 598.1310; Found 598.1334 (4.0 ppm).

(4bS,8aS,9S)-ethyl 3-acetyl-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-11-carboxylate (17)

Aldehyde 14 (130 mg, 0.40 mmol) was added to a 25 mL round bottom flask, which was sealed with a rubber septum, and evacuated and backfilled with N₂ (3x). THF (4.0 mL) was injected, and the flask was placed in a 0 °C ice bath. A solution of MeMgBr (3.0 M in Et₂O, 0.14 mL, 0.42 mmol) was injected dropwise, and the mixture was allowed to warm to 23 °C and stir for 2 h. The reaction was quenched with saturated NaHCO₃ solution (15 mL) and diluted with EtOAc (25 mL). The organic solution was washed with 1N HCl (25 mL), H₂O (25 mL), and brine (25 mL). The organic solution was dried over Na₂SO₄, filtered, and the solvent was removed in vacuo. Flash column chromatography (hexanes : EtOAc, 1:0 → 3:1) afforded a mixture of benzylic alcohol diastereomers as a faint yellow oil (120 mg), which was subjected to the next step without further purification. The benzylic alcohol (120 mg, 0.35 mmol) and NaHCO₃ (59 mg, 0.71 mmol) were added to a 25 mL round bottom flask. DCM (3.5 mL) was injected, and the flask was placed in a 0 °C ice bath. Dess-Martin periodinane (180 mg, 0.42 mmol) was added, and the flask was sealed with a rubber septum. The reaction was stirred for 1 h, after which the mixture was allowed to warm to 23 °C. The reaction was then stirred an additional 1 h, and then quenched with saturated solutions of NaHCO₃ (5 mL) and Na₂S₂O₃ (5 mL). After stirring for 15 min, the mixture was diluted with DCM (25 mL) and washed with H₂O (25 mL) and brine (25 mL). The organic solution was dried over Na₂SO₄, filtered, and the solvent was removed in vacuo. Chromatographic purification (hexanes : EtOAc, 1:0 → 4:1) afforded the title compound as a faint yellow oil (0.10 g, 73% over 2 steps). ¹H NMR (500 MHz, DMSO-d₆, 343 K) δ 7.88 (s, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 4.28 (s, 1H), 4.20–4.05 (m, 2H), 3.78 (dd, J = 13.6, 4.2 Hz, 1H), 3.22–3.16 (m, 1H), 2.74 (d, J = 19.0 Hz, 1H), 2.56 (s, 3H), 2.47–2.39 (m, 1H), 1.71 (dt, J = 12.8, 3.0 Hz, 1H), 1.65–1.45 (m, 4H), 1.44–1.31 (m, 3H), 1.21 (t, J = 6.9 Hz, 3H), 1.14 (ddt, J = 16.4, 13.2, 6.7 Hz, 1H), 0.92 (qd, J = 12.9, 3.8 Hz, 1H). ¹³C NMR (126 MHz, DMSO-d₆, 343 K) δ 198.0, 155.2, 142.7, 139.8, 136.4, 128.9, 126.3, 125.7, 61.1, 49.7, 43.9, 41.4, 38.1, 37.7, 36.0, 32.4, 26.9, 26.6, 26.2, 22.1, 15.0. IR (film) 2980, 2930, 2859, 1694, 1682, 1603, 1566, 1454, 1424, 1416, 1373, 1354, 1327, 1298, 1263, 1231, 1190, 1171, 1150, 1101, 1022, 990, 859, 945, 916, 826, 768, 731, 646 cm⁻¹. HRMS (ESI) m/z: [M + Na]⁺ Calcd for C₂₁H₂₇NO₃Na 364.1889; Found 364.1875 (3.8 ppm).

(4bS,8aS,9S)-ethyl 3-(1,1-difluoroethyl)-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)-phenanthrene-11-carboxylate (18)

Ketone 17 (0.14 g, 0.41 mmol) was transferred to a 1 dram screw-top vial, which was capped with a PTFE septum. The vial was evacuated and backfilled with N₂ (3x), and a solution of bis(2-methoxyethyl)aminosulfur trifluoride (50% wt in PhMe, 1.0 mL, ca. 2.2 mmol) was injected. The reaction was placed in an 85 °C heating plate and stirred for 18 h. The mixture was cooled to rt and poured into a saturated aqueous solution of NaHCO₃ (20 mL). The aqueous layer was extracted with DCM (3 × 10 mL), and then the combined organic solution was washed with brine (30 mL). The organic solution was dried over MgSO₄, filtered, and the solvent was removed in vacuo. Chromatographic purification (hexanes : EtOAc, 1:0 → 9:1) afforded the title compound as a yellow oil (62 mg, 41%). ¹H NMR (500 MHz, DMSO-d₆, 343 K) δ 7.45 (s, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 4.27 (s, 1H), 4.12–4.02 (m, 2H), 3.77 (dd, J = 13.5, 4.1 Hz, 1H), 3.16 (dd, J = 18.7, 5.9 Hz, 2H), 2.70 (d, J = 18.7 Hz, 1H), 2.47 (d, J = 14.1 Hz, 2H), 1.97 (t, J = 18.7 Hz, 3H), 1.75–1.67 (m, 1H), 1.65–1.45 (m, 4H), 1.37 (tdd, J = 13.4, 9.0, 3.4 Hz, 3H), 1.20 (t, J = 6.9 Hz, 3H), 1.12 (qt, J = 13.1, 3.1 Hz, 1H), 0.93 (qd, J = 12.9, 3.8 Hz, 1H). ¹³C NMR (126 MHz, DMSO-d₆, 343 K) δ 155.22, 139.71, 138.85, 136.34 (t, J = 26.2 Hz), 128.82, 122.87 (t, J = 237.3 Hz), 122.54 (t, J = 5.8 Hz), 121.96 (t, J = 6.0 Hz), 61.05, 49.76, 43.92, 41.40, 38.18, 37.66, 36.03, 32.04, 26.57, 26.18, 25.59 (t, J = 29.3 Hz), 22.08, 15.04. ¹⁹F NMR (376 MHz, CDCl₃) δ (−86.56)–(−86.87) (m). IR (film) 2980, 2930, 2859, 1694, 1464, 1454, 1428, 1418, 1375, 1327, 1294, 1265, 1233, 1190, 1191, 1150, 1130, 1103, 1022, 990, 928, 914, 897, 824, 797, 768, 735 cm⁻¹. HRMS (ESI) m/z: [M + H]⁺ Calcd for C₂₁H₂₈F₂NO₂ 364.2088; Found 364.2076 (3.3 ppm).

(4bS,8aS,9S)-11-methyl-3-(trifluoromethoxy)-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epimino-ethano)phenanthrene (19)

LiAlH₄ (18 mg, 0.47 mmol) was added to a 10 mL round bottom flask. THF (0.50 mL) was injected and the suspension was cooled to 0 °C. A solution of carbamate 6 (0.06 g, 0.16 mmol) in THF (1.0 mL) was injected dropwise. The reaction mixture was allowed to warm to 23 °C and stirred for 16 h. The mixture was cooled to 0 °C, and 1N NaOH (3 mL) was injected dropwise. Et₂O (3 mL) was injected, and the mixture was stirred for 1 h. The mixture was diluted with Et₂O (20 mL) and washed with a saturated aqueous solution of NH₃ (2 x 20 mL). The organic solution was dried over Na₂SO₄, filtered, and the solvent was removed in vacuo to afford the title compound (45 mg, 86%) as a colorless oil. ¹H NMR (500 MHz, CDCl₃) δ 7.12 (dt, J = 8.3, 1.0 Hz, 1 H), 7.09–7.07 (m, 1 H), 6.99–6.95 (m, 1 H), 3.03 (d, J = 18.5 Hz, 1 H), 2.83 (dd, J = 5.8, 3.1 Hz, 1 H), 2.61 (dd, J = 18.5, 5.8 Hz, 1 H), 2.45 (ddd, J = 12.0, 4.7, 1.7 Hz, 1 H), 2.40 (s, 3 H), 2.32 (dq, J = 13.7, 2.7 Hz, 1 H), 2.03 (td, J = 12.4, 3.3 Hz, 1 H), 1.85 (dt, J = 12.9, 3.0 Hz, 1 H), 1.77 (td, J = 12.7, 4.8 Hz, 1 H), 1.69–1.61 (m, 1 H), 1.58–1.51 (m, 1 H), 1.47–1.16 (m, 5 H), 1.07 (qd, J = 12.8, 3.8 Hz, 1 H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 147.9 (q, J = 1.8 Hz), 142.6, 136.5, 128.9, 120.5 (q, J = 256.2 Hz), 118.1, 118.0, 57.7, 47.0, 45.1, 42.8, 42.0, 37.4, 36.5, 26.7, 26.5, 23.6, 22.0. ¹⁹F NMR (376 MHz, CDCl₃) δ −57.9. IR (film) 3026, 2928, 2859, 2799, 1611, 1578, 1493, 1449, 1429, 1379, 1256, 1225, 1155, 1121, 1099, 1055, 909, 880, 849, 816, 689 cm⁻¹. HRMS (ESI) m/z: [M + H]⁺ Calcd for C₁₈H₂₃F₃NO 326.1732; Found 326.1742 (3.1 ppm).

(4bS,8aS,9S)-3-(difluoromethoxy)-11-methyl-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epimino-ethano)phenanthrene (20)

LiAlH₄ (11 mg, 0.30 mmol) was added to a 5 mL round bottom flask. THF (0.25 mL) was injected, and the suspension was cooled to 0 °C. A solution of carbamate 5 (37 mg, 0.10 mmol) in THF (0.75 mL) was injected dropwise. The reaction mixture was allowed to warm to 23 °C and stirred for 16 h. The mixture was cooled to 0 °C, and 1N NaOH (1 mL) was injected dropwise. Et₂O (2 mL) was injected, and the mixture was stirred for 1 h. The mixture was diluted with Et₂O (10 mL) and washed with a saturated aqueous solution of NH₃ (2 x 10 mL). The organic solution was dried over Na₂SO₄, filtered, and the solvent was removed in vacuo to afford the title compound (26 mg, 84%) as a colorless oil. ¹H NMR (500 MHz, CDCl₃) δ 7.10 (dt, J = 8.3, 0.9 Hz, 1 H), 7.00 (d, J = 2.6 Hz, 1 H), 6.88 (dd, J = 8.3, 2.5 Hz, 1 H), 6.48 (t, J = 74.5 Hz, 1 H), 3.02 (d, J = 18.4 Hz, 1 H), 2.82 (dd, J = 5.8, 3.1 Hz, 1 H), 2.60 (dd, J = 18.4, 5.8 Hz, 1 H), 2.44 (ddd, J = 12.0, 4.9, 1.9 Hz, 1 H), 2.40 (s, 3 H), 2.35–2.29 (m, 1 H), 2.03 (td, J = 12.3, 3.3 Hz, 1 H), 1.84 (dt, J = 12.8, 3.2 Hz, 1 H), 1.76 (td, J = 12.7, 4.8 Hz, 1 H), 1.69–1.62 (m, 1 H), 1.57–1.50 (m, 1 H), 1.46–1.29 (m, 4 H), 1.24 (qt, J = 13.2, 3.2 Hz, 1 H), 1.08 (qd, J = 12.7, 3.9 Hz, 1 H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 150.0 (t, J = 2.7 Hz), 142.8, 135.2, 129.0, 116.8, 116.7, 116.4 (t, J = 258.6 Hz), 57.8, 47.2, 45.3, 43.0, 42.1, 37.5, 36.7, 26.8, 26.6, 23.7, 22.2. ¹⁹F NMR (376 MHz, CDCl₃) δ −80.0 (d, J = 7.4 Hz, 1 F), −80.2 (d, J = 7.2 Hz, 1 F). IR (film) 3019, 2928, 2857, 2799, 1611, 1578, 1493, 1474, 1449, 1431, 1379, 1356, 1294, 1275, 1225, 1128, 1044, 961, 893, 853, 816, 762, 723, 638 cm⁻¹. HRMS (ESI) m/z: [M + H]⁺ Calcd for C₁₈H₂₄F₂NO 308.1826; Found 308.1831 (1.6 ppm).

4bS,8aS,9S)-11-methyl-3-(trifluoromethyl)-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epimino-ethano)phenanthrene (21)

LiAlH₄ (11 mg, 0.30 mmol) was added to a 5 mL round bottom flask. THF (0.50 mL) was injected, and the suspension was cooled to 0 °C. A solution of carbamate 12 (67 mg, 0.10 mmol) in THF (0.50 mL) was injected dropwise. The reaction mixture was allowed to warm to 23 °C and stirred for 16 h. The mixture was cooled to 0 °C, and 1N NaOH (1 mL) was injected dropwise. Et₂O (1 mL) was injected, and the mixture was stirred for 1 h. The mixture was diluted with Et₂O (10 mL) and washed with a saturated aqueous solution of NH₃ (2 x 10 mL). The organic solution was dried over Na₂SO₄, filtered, and the solvent was removed in vacuo to afford the title compound (21 mg, 68%) as a faint yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 7.50–7.47 (m, 1 H), 7.37–7.34 (m, 1 H), 7.22 (d, J = 7.9 Hz, 1 H), 3.09 (d, J = 18.8 Hz, 1 H), 2.85 (dd, J = 5.8, 3.1 Hz, 1 H), 2.67 (dd, J = 18.8, 5.7 Hz, 1 H), 2.49–2.39 (m, 2 H), 2.40 (s, 3 H), 1.99 (td, J = 12.4, 3.3 Hz, 1 H), 1.88 (dt, J = 12.9, 3.0 Hz, 1 H), 1.79 (td, J = 12.7, 4.8 Hz, 1 H), 1.70–1.62 (m, 1 H), 1.59–1.52 (m, 1 H), 1.49–1.30 (m, 4 H), 1.20 (qt, J = 13.3, 3.4 Hz, 1 H), 1.05 (qd, J = 12.7, 3.8 Hz, 1 H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 142.2 (q, J = 1.1 Hz), 141.5, 128.7 (q, J = 31.8 Hz), 128.3, 124.7 (q, J = 271.9 Hz), 122.5 (q, J = 3.8 Hz), 122.2 (q, J = 3.7 Hz), 57.7, 47.1, 45.4, 43.0, 42.1, 37.4, 36.5, 26.8, 26.6, 24.4, 22.1. ¹⁹F NMR (376 MHz, CDCl₃) δ −62.1. IR (film) 3032, 2928, 2857, 2799, 1616, 1580, 1503, 1462, 1447, 1427, 1379, 1331, 1306, 1277, 1261, 1198, 1177, 1159, 1121, 1086, 1057, 1037, 895, 837, 822, 764, 735, 723 cm⁻¹. HRMS (ESI) m/z: [M + H]⁺ Calcd for C₁₈H₂₃F₃N 310.1783; Found 310.1786 (1.0 ppm).

(4bS,8aS,9S)-3-(difluoromethyl)-11-methyl-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epimino-ethano)phenanthrene (22)

LiAlH₄ (6.8 mg, 0.18 mmol) was added to a 5 mL round bottom flask. THF (0.3 mL) was injected, and the suspension was cooled to 0 °C. A solution of carbamate 15 (21 mg, 0.060 mmol) in THF (0.7 mL) was injected dropwise. The reaction mixture was allowed to warm to 23 °C and stirred for 16 h. The mixture was cooled to 0 °C, and 1N NaOH (1 mL) was injected dropwise. Et₂O (1 mL) was injected, and the mixture was stirred for 1 h. The mixture was diluted with Et₂O (10 mL) and washed with a saturated aqueous solution of NH₃ (2 x 5 mL). The organic solution was dried over Na₂SO₄, filtered, and the solvent was removed in vacuo to afford the title compound (14 mg, 80%) as a colorless oil. ¹H NMR (500 MHz, CDCl₃) δ 7.37 (s, 1 H), 7.27–7.24 (m, 1 H), 7.20 (d, J = 7.9 Hz, 1 H), 6.61 (t, J = 56.7 Hz, 1 H), 3.07 (d, J = 18.7 Hz, 1 H), 2.84 (dd, J = 5.8, 3.1 Hz, 1 H), 2.70–2.62 (m, 1 H), 2.47–2.39 (m, 2 H), 2.40 (s, 3 H), 2.01 (td, J = 12.3, 3.3 Hz, 1 H), 1.87 (dt, J = 12.9, 3.0 Hz, 1 H), 1.78 (td, J = 12.7, 4.8 Hz, 1 H), 1.68–1.62 (m, 1 H), 1.57–1.51 (m, 1 H), 1.47–1.31 (m, 4 H), 1.28–1.17 (m, 1 H), 1.07 (qd, J = 12.7, 3.8 Hz, 1 H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 141.3, 141.0 (t, J = 2.2 Hz), 132.5 (t, J = 22.1 Hz), 128.3, 122.9 (t, J = 6.2 Hz), 122.6 (t, J = 5.8 Hz), 115.3 (t, J = 238.0 Hz), 57.8, 47.2, 45.5, 43.0, 42.2, 37.4, 36.6, 26.8, 26.6, 24.3, 22.2. ¹⁹F NMR (376 MHz, CDCl₃) δ −109.2 (d, J = 18.4 Hz, 1 F), −109.3 (d, J = 18.4 Hz, 1 F). IR (film) 3024, 2928, 2857, 2799, 1616, 1578, 1503, 1462, 1445, 1427, 1379, 1371, 1352, 1296, 1277, 1248, 1229, 1194, 1173, 1159, 1121, 1071, 1057, 1024, 953, 928, 895, 868, 853, 824, 789, 764, 748, 727 cm⁻¹. HRMS (ESI) m/z: [M + H]⁺ Calcd for C₁₈H₂₄F₂N 292.1877; Found 292.1875 (0.7 ppm).

(4bS,8aS,9S)-3-(1,1-difluoroethyl)-11-methyl-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epimino-ethano)phenanthrene (23)

LiAlH₄ (5.4 mg, 0.14 mmol) was added to a 1 dram vial sealed with a PTFE-lined puncturable cap. THF (0.30 mL) was injected and the suspension was cooled to 0 °C. A solution of carbamate 23 (17 mg, 0.047 mmol) in THF (0.70 mL) was injected dropwise. The reaction mixture was allowed to warm to 23 °C and stirred for 16 h. The mixture was cooled to 0 °C, and 1N NaOH (1 mL) was injected dropwise. Et₂O (1 mL) was injected, and the mixture was stirred for 1 h. The mixture was diluted with Et₂O (15 mL) and washed with a saturated aqueous solution of NH₃ (2 x 15 mL). The organic solution was dried over Na₂SO₄, filtered, and the solvent was removed in vacuo to afford the title compound (13 mg, 90%) as a colorless oil. ¹H NMR (500 MHz, CDCl₃) δ 7.39–7.38 (m, 1 H), 7.26–7.22 (m, 1 H), 7.16 (d, J = 7.9, 1.1 Hz, 1 H), 3.06 (d, J = 18.6 Hz, 1 H), 2.84 (dd, J = 5.6, 3.1 Hz, 1 H), 2.65 (dd, J = 18.7, 5.6 Hz, 1 H), 2.47–2.40 (m, 2 H), 2.41 (s, 3 H), 2.03 (td, J = 12.4, 3.3 Hz, 1 H), 1.92 (t, J = 18.1 Hz, 3 H), 1.88–1.84 (dt, J = 12.8, 3.1 Hz, 1 H), 1.77 (td, J = 12.7, 4.8 Hz, 1 H), 1.69–1.62 (m, 1 H), 1.57–1.51 (m, 1 H), 1.46–1.31 (m, 4 H), 1.28–1.18 (m, 1 H), 1.08 (qd, J = 12.6, 3.8 Hz, 1 H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 141.0, 139.8 (t, J = 1.9 Hz), 136.2 (t, J = 26.3 Hz), 128.0, 122.3 (t, J = 238.4 Hz), 121.8 (t, J = 6.1 Hz), 121.7 (t, J = 6.1 Hz), 57.9, 47.2, 45.6, 43.0, 42.2, 37.4, 36.6, 26.8, 26.7, 26.2 (t, J = 30.2 Hz), 24.2, 22.2. ¹⁹F NMR (376 MHz, CDCl₃) δ (−86.4)–(−86.6) (m). IR (film) 3001, 2928, 2857, 2799, 1501, 1445, 1427, 1381, 1317, 1294, 1277, 1261, 1198, 1175, 1163, 1123, 1099, 1057, 949, 928, 909, 895, 853, 827, 762, 729, 677, 658 cm⁻¹. HRMS (ESI) m/z: [M + H]⁺ Calcd for C₁₉H₂₆F₂N 306.2033; Found 306.2019 (4.6 ppm).

(4bS,8aS,9S)-11-methyl-3-(perfluoroethyl)-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epimino-ethano)phenanthrene (24)

LiAlH₄ (6.0 mg, 0.15 mmol) was added to a 1 dram vial sealed with a PTFE-lined puncturable cap. THF (0.20 mL) was injected, and the suspension was cooled to 0 °C. A solution of carbamate 13 (21 mg, 0.050 mmol) in THF (0.3 mL) was injected dropwise. The reaction mixture was allowed to warm to 23 °C and stirred for 16 h. The mixture was cooled to 0 °C, and 1N NaOH (1 mL) was injected dropwise. Et₂O (1 mL) was injected, and the mixture was stirred for 1 h. The mixture was diluted with Et₂O (10 mL) and washed with a saturated aqueous solution of NH₃ (2 x 10 mL). The organic solution was dried over Na₂SO₄, filtered, and the solvent was removed in vacuo to afford the title compound (13 mg, 72%) as a colorless oil. ¹H NMR (500 MHz, CDCl₃) δ 7.46–7.44 (m, 1 H), 7.33 (dd, J = 8.0, 1.8 Hz, 1 H), 7.24 (d, J = 8.0 Hz, 1 H), 3.09 (d, J = 18.8 Hz, 1 H), 2.85 (dd, J = 5.9, 3.1 Hz, 1 H), 2.68 (dd, J = 18.9, 5.7 Hz, 1 H), 2.49–2.39 (m, 2 H), 2.41 (s, 3 H), 2.00 (td, J = 12.4, 3.2 Hz, 1 H), 1.89 (dt, J = 13.0, 3.0 Hz, 1 H), 1.80 (td, J = 12.7, 4.8 Hz, 1 H), 1.69–1.62 (m, 1 H), 1.59–1.52 (m, 1 H), 1.48–1.30 (m, 4 H), 1.18 (ddt, J = 16.6, 13.4, 6.6 Hz, 1 H), 1.06 (qd, J = 12.7, 3.8 Hz, 1 H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 142.4 (t, J = 1.6 Hz), 141.5, 128.3, 126.7 (t, J = 23.7 Hz), 123.8 (t, J = 6.4 Hz), 123.3 (t, J = 6.2 Hz), 119.3 (qt, J = 285.8, 39.9 Hz), 113.8 (tq, J = 253.8, 37.9 Hz), 57.7, 47.1, 45.4, 43.0, 42.1, 37.4, 36.6, 26.8, 26.6, 24.4, 22.0. ¹⁹F NMR (376 MHz, CDCl₃) δ −84.9 (s, 3 F), −114.5 (d, J = 8.6 Hz, 2 F). IR (film) 3032, 2930, 2859, 2799, 1616, 1501, 1464, 1447, 1427, 1379, 1335, 1317, 1290, 1275, 1206, 1175, 1142, 1128, 1099, 1057, 1005, 980, 912, 895, 818, 743, 677 cm⁻¹. HRMS (ESI) m/z: [M + H]⁺ Calcd for C₁₉H₂₃F₅N 360.1751; Found 360.1751 (3.3 ppm).