Efficient Stereo-Selective Fluorination on Vitamin D₃ Side-Chain Using Electrophilic Fluorination

Abstract

Our research regarding side-chain fluorinated vitamin D₃ analogues has explored a series of efficient fluorination methods. In this study, a new electrophilic stereo-selective fluorination methodology at C24 and C22 positions of the vitamin D₃ side-chain was developed using N-fluorobenzenesulfonimide (NFSI) and CD-ring imides with an Evans chiral auxiliary (26,27,30).

1. Introduction

Regio- and stereo-selective fluorination of the vitamin D₃ side-chain is one of the efficient methods used to modulate biological activities, such as binding affinity to the vitamin D receptor (VDR), transactivation activity through the VDR, and metabolic stability against CYP24A1 [1]. We have reported the regio- and stereo-selective fluorination of the CD-ring side-chain starting from the Inhoffen–Lythgoe diol (1) and constructed C26,27-fluoro-CD-rings (2–4) [2,3], C24-fluoro-CD-rings (5–7) [4,5], C23-fluoro-CD-rings (8–10) [6,7], and C22-fluoro-CD-rings (11–13) [8] (Figure 1) to create a chemical library of side-chain fluorovitamin D₃ analogues using a convergent method (Scheme 1) [9,10,11].

1.1. Previous Studies of C24-Stereoselective Fluorination

On the vitamin D₃ side-chain, the C24 position is an important site for metabolic inactivation via CYP24A1 hydroxylation [12,13,14]. Therefore, structural modifications, especially fluorination and difluorination, of the C24 position have been actively investigated [15,16,17,18,19,20,21,22,23,24,25].

We previously reported the stereo-selective fluorination method at the C24 position of the CD-ring side-chain for stereo-selective synthesis of (24R)-fluoro-25-hydroxyvitamin D₃ and its 24S isomer [5]. The key step for introducing the C24-fluoro unit was achieved via osmium-catalyzed diastereoselective dihydroxylation followed by deoxy-fluorination reactions. However, multi-step synthesis was required (13 steps), and harmful osmium and excess amounts of the fluorinating reagent, DAST, were used in this synthetic route (Scheme 2).

1.2. Previous Studies of C22-Stereoselective Fluorination

Until 2023, there was only one example of 22-fluorovitamin D synthesis, and the stereochemistry of C22 was unknown [26]. We recently reported the first stereo-selective fluorination at the C22 position of the CD-ring side-chain and synthesis of (22R)- and (22S)-fluoro-25-hydroxyvitamin D₃ [8]. However, multiple synthetic steps were required, including separation of the diastereomer mixture of C22-allylalcohols (19,20) and the deoxyfluorination step using DAST, resulting in low overall yields (Scheme 3).

In the report [8], we also developed an alternative C22-fluorination methodology using a cationic fluorination reaction between the methyl ester (23) and N-fluorobenzenesulfonimide (NFSI) under basic conditions. However, this route yielded only the (22R)-fluoro product (21); efficient cationic fluorination of the (22S)-fluoro counterpart to yield the (22R)-CD-ring (11) has yet to be explored (Scheme 4).

To overcome these drawbacks in order to introduce C24- and C22-monofluoro moieties, here we describe an alternative stereo-selective fluorination methodology at these positions via electrophilic fluorination using an Evans chiral auxiliary-based aldol reaction with NFSI [27,28,29].

The retrosynthetic paths are shown in Scheme 5. Evans oxazolidinone ligands could be introduced to the side-chain carboxylic acids (28,31), which were synthesized from the Inhoffen–Lythgoe diol (1), and NFSI could be used as a cationic fluorination reagent in the presence of lithium hexamethyldisilazide (LHMDS).

2. Results and Discussion

2.1. Synthesis of 24-Fluoro-CD-Rings (5,6) via Electrophilic Fluorination

The synthetic route of the 24-fluoro-CD-rings (5,6) is illustrated in Scheme 6. We synthesized methyl ester (32) from the Inhoffen–Lythgoe diol (1) in three steps [30], and hydrolysis of 32 afforded the corresponding carboxylic acid (28) [31], which was subsequently converted to N-acyloxazolidinones (26,27) via acid chlorides. The C24-position was effectively fluorinated in a high diastereoselective manner to yield (24R)-product 24 from 26 and (24S)-product 25 from 27, respectively. Displacement of the oxazolidinone ligand to 26,27-dimethyl units with the 25-hydroxy group using an excess amount of methyl magnesium chloride successfully proceeded with preservation of the stereochemistry at the C24-position, and removal of the silyl protective group under acidic conditions yielded the target (24R)-fluoro-CD-ring 5 (62% in 8 steps) and (24S)-fluoro-CD-ring 6 (53%).

2.2. Synthesis of (22R)-Fluoro-CD-Ring (11) via Electrophilic Fluorination

The synthetic route to the (22R)-fluoro-CD-ring (11) started from carboxylic acid (31), which was readily available from the Inhoffen–Lythgoe diol in five steps [32]. This was converted to amide (30) followed by fluorination at the C22-position using NFSI in the presence of LHMDS to give the desired (22S)-fluoro-CD-ring (29) as a major product, along with (22R)-fluoro-CD-ring (33) at a ratio of 1.4:1. After separating 29 and 33 using silica gel column chromatography, they were converted to the corresponding Weinreb amides (34,35), which were the synthetic intermediates of C22-fluoro-CD-rings 11 and 12 [8], using methoxy(methyl)amine hydrochloride and LHMDS in moderate yields and with a rigid stereochemical integrity (Scheme 7).

3. Conclusions

In conclusion, we developed an improved stereo-selective fluorination method at C24 and C22 positions to synthesize C24- and C22-fluoro-CD-rings utilizing an Evans chiral auxiliary for a cationic fluorination reaction as a key step. The side-chain carboxylic acids (28,31) were prepared from the Inhoffen–Lythgoe diol. These synthetic routes are more efficient than previous ones reported regarding both total yields and reaction steps.

• Experimental Section

¹H and ¹³C NMR spectra were recorded on JEOL AL-400 NMR (400 MHz) and ECP-600 NMR (600 MHz) spectrometers (Tokyo, Japan). ¹H NMR spectra were referenced using (CH₃)₄Si (δ 0.00 ppm) or CHCl₃ (δ 7.26 ppm) as an internal standard. ¹³C NMR spectra were referenced using deuterated solvent (δ 77.0 ppm for CDCl₃). IR spectra were recorded using a JASCO FT-lR-800 Fourier transform infrared spectrophotometer (Tokyo, Japan). High-resolution mass spectra were obtained using a SHIMADZU LCMS-IT-TOF mass spectrometer (Kyoto, Japan) using a positive electrospray ionization (ESI) method. Optical rotations were measured using a JASCO DIP-370 digital polarimeter (Tokyo, Japan). Column chromatography was performed on silica gel 60N (Kanto Chemical Co., Inc., 40–50 μm, Tokyo, Japan) or silica gel 60 (Merck, 0.040–0.063 mm, Tokyo, Japan). All experiments were performed under anhydrous conditions in an atmosphere of argon, unless otherwise stated. Supporting information regarding ¹H and ¹³C NMR spectra of all new compounds (26, 27, 29, 30, and 33) is available via the link in Supplementary Materials.

• (4R)-3-[(5R)-5-{(1R,3aR,4S,7aR)-4-[(tert-Butyldimethylsilyl)oxy]-7a-methyloctahydro-1H-inden-1-yl}hexanoyl]-4-isopropyloxazolidin-2-one (26)

Carboxylic acid 28 [31] (403.6 mg, 1.05 mmol) was dissolved in thionyl chloride (3.0 mL, 4.97 g, 41.8 mmol) at room temperature, and the solution was refluxed for 1 h 30 min. The mixture was evaporated in vacuo, and the crude acyl chloride was used for the next reaction without further purification.

nBuLi (1.59 M in hexane, 5.3 mL, 8.40 mmol) was added to a precooled solution of (R)-4-isopropyloxazolidinone (1.09 g, 8.40 mmol) in THF (20 mL) at −78 °C, and the mixture was stirred at the same temperature for 10 min. The above acyl chloride in THF (3 mL) was added to the solution and stirred at the same temperature for 10 min. After the reaction was quenched with H₂O and saturated aqueous NH₄Cl at room temperature, the mixture was extracted with EtOAc three times. The organic layer was dried over Na₂SO₄, filtered, and concentrated. The residue was purified via flash column chromatography on silica gel (hexane:EtOAc = 3:1) to obtain 26 (513.6 mg, 99%, in 2 steps) as a colorless oil.

26: [α] _D²⁷ + 6.1 (c 2.01, CHCl₃); IR (neat) 1786, 1704, 1383, 1252, 1208, 1085, 1023, 841 cm⁻¹; ¹H NMR (600 MHz, CDCl₃) δ –0.02 (s, 3H), –0.01 (s, 3H), 0.86–0.91 (m, 21H), 1.02–1.12 (m, 3H), 1.18–1.25 (m, 2H), 1.29–1.44 (m, 5H), 1.47–1.56 (m, 2H), 1.64–1.66 (m, 1H), 1.69–1.83 (m, 3H), 1.92–1.95 (m, 1H), 2.34–2.39 (m, 1H), 2.80–2.95 (m, 2H), 3.97–3.99 (m, 1H), 4.18–4.27 (m, 2H), 4.42 (dt, J = 3.0, 8.4 Hz, 1H); ¹³C NMR (150 MHz, CDCl₃) δ –5.2, –4.8, 13.7, 14.6, 17.6, 18.0, 18.0, 18.5, 21.0, 23.0, 25.8, 27.2, 28.4, 34.4, 35.1, 35.2, 35.9, 40.7, 42.1, 53.0, 56.5, 58.4, 63.3, 69.4, 154.0, 173.4; HRMS (ESI⁺) calcd for C₂₈H₅₁NO₄SiNa [M+Na]⁺ 516.3480, found 516.3489.

• (4S)-3-[(5R)-5-{(1R,3aR,4S,7aR)-4-[(tert-Butyldimethylsilyl)oxy]-7a-methyloctahydro-1H-inden-1-yl}hexanoyl]-4-isopropyloxazolidin-2-one (27)

Carboxylic acid 28 (606.2 mg, 1.58 mmol) was dissolved in thionyl chloride (3.4 mL, 5.6 g, 47.0 mmol) at room temperature, and the solution was refluxed for 1 h 30 min. The mixture was evaporated in vacuo, and the crude acyl chloride was used for the next reaction without further purification.

nBuLi (1.59 M in hexane, 5.9 mL, 9.42 mmol) was added to a precooled solution of (S)-4-isopropyloxazolidinone (1.24 g, 9.60 mmol) in THF (20 mL) at −78 °C, and the mixture was stirred at the same temperature for 10 min. The above acyl chloride in THF (4 mL) was added to the solution and stirred at the same temperature for 20 min. After the reaction was quenched with H₂O and saturated aqueous NH₄Cl at room temperature, the mixture was extracted with EtOAc three times. The organic layer was dried over Na₂SO₄, filtered, and concentrated. The residue was purified via flash column chromatography on silica gel (hexane:EtOAc = 3:1) to obtain 27 (729.5 mg, 93%, in 2 steps) as a colorless oil.

27: [α] _D²⁷ + 78.4 (c 1.58, CHCl₃); IR (neat) 1786, 1704, 1387, 1255, 1208, 1089, 1027, 841 cm⁻¹; ¹H NMR (600 MHz, CDCl₃) δ –0.02 (s, 3H), 0.00 (s, 3H), 0.86–0.92 (m, 21H), 1.00–1.11 (m, 3H), 1.19–1.25 (m, 2H), 1.29–1.44 (m, 5H), 1.49–1.57 (m, 2H), 1.61–1.83 (m, 4H), 1.92–1.95 (m, 1H), 2.33–2.40 (m, 1H), 2.76–2.99 (m, 2H), 3.97–3.99 (m, 1H), 4.18–4.27 (m, 2H), 4.42 (dt, J = 3.3, 8.4 Hz, 1H); ¹³C NMR (150 MHz, CDCl₃) δ –5.2, –4.8, 13.7, 14.6, 17.6, 18.0, 18.0, 18.5, 21.0, 23.0, 25.8, 27.2, 28.4, 34.4, 35.1, 35.2, 36.0, 40.7, 42.1, 53.0, 56.5, 58.3, 63.3, 69.4, 154.1, 173.5; HRMS (ESI⁺) calcd for C₂₈H₅₁NO₄SiNa [M+Na]⁺ 516.3480, found 516.3495.

• (1R,3aR,4S,7aR)-1-[(2R,5R)-5-Fluoro-6-hydroxy-6-methylheptan-2-yl]-7a-methyloctahydro-1H-inden-4-ol (5)

To a solution of 26 (168.9 mg, 0.34 mmol) in THF (2 mL) and hexamethylphosphoric triamide (HMPA) (200 μL) was added LHMDS (lithium hexamethyldisilazide) (359 μL, 1 M THF solution, 0.36 mmol) at −78 °C, the mixture was stirred at the same temperature for 10 min, and N-fluorobenzenesulfonimide (NFSI) (117.8 mg, 0.37 mmol) was added. After being stirred at the same temperature for 40 min, the reaction mixture was quenched with H₂O and saturated aqueous NH₄Cl at −78 °C. The mixture was extracted with EtOAc three times. The organic layer was washed with brine, dried over Na₂SO₄, filtered, and concentrated. Crude 24 was used for the next reaction without further purification.

To a solution of the above crude 24 in THF (10 mL) was added MeMgCl (1.14 mL, 3.0 M THF solution, 3.42 mmol) at 0 °C, and the mixture was stirred at 0 °C for 10 min. After the reaction was quenched with H₂O, the mixture was extracted with EtOAc three times. The organic layer was washed with saturated aqueous NH₄Cl, dried over Na₂SO₄, filtered, and concentrated. The crude residue was used for the next reaction without further purification.

To the above crude residue in MeOH (15 mL) was added p-toluenesulfonic acid monohydrate (479.9 mg, 2.52 mmol), and the mixture was stirred at room temperature for 63 h under air. After the reaction was quenched with H₂O and saturated aqueous NaHCO₃ at room temperature, the mixture was extracted with EtOAc three times. The organic layer was dried over Na₂SO₄, filtered, and concentrated. The residue was purified via flash column chromatography on silica gel (hexane:EtOAc = 2:1) to obtain 5 (77.5 mg, 75%, in 3 steps) as a white powder. The spectral data matched with those reported in the literature [5].

• (1R,3aR,4S,7aR)-1-[(2R,5S)-5-Fluoro-6-hydroxy-6-methylheptan-2-yl]-7a-methyloctahydro-1H-inden-4-ol (6)

To a solution of 27 (111.0 mg, 0.23 mmol) in THF (2 mL) and hexamethylphosphoric triamide (HMPA) (200 μL) was added LHMDS (lithium hexamethyldisilazide) (236 μL, 1 M THF solution, 0.24 mmol) at −78 °C, the mixture was stirred at the same temperature for 10 min, and N-fluorobenzenesulfonimide (NFSI) (76.4 mg, 0.24 mmol) was added. After being stirred at the same temperature for 40 min, the reaction mixture was quenched with H₂O and saturated aqueous NH₄Cl at −78 °C. The mixture was extracted with EtOAc three times. The organic layer was washed with brine, dried over Na₂SO₄, filtered, and concentrated. Crude 25 was used for the next reaction without further purification.

To a solution of the above crude 25 in THF (7 mL) was added MeMgCl (0.75 mL, 3.0 M THF solution, 2.25 mmol) at 0 °C, and the mixture was stirred at 0 °C for 10 min. After the reaction was quenched with H₂O, the mixture was extracted with EtOAc three times. The organic layer was washed with saturated aqueous NH₄Cl, dried over Na₂SO₄, filtered, and concentrated. The crude residue was used for the next reaction without further purification.

To the above crude residue in MeOH (10 mL) was added p-toluenesulfonic acid monohydrate (558.3 mg, 2.94 mmol), and the mixture was stirred at room temperature for 18 h under air. After the reaction was quenched with H₂O and saturated aqueous NaHCO₃ at room temperature, the mixture was extracted with EtOAc three times. The organic layer was dried over Na₂SO₄, filtered, and concentrated. The residue was purified via flash column chromatography on silica gel (hexane:EtOAc = 2:1) to obtain 6 (45.9 mg, 68%, in 3 steps) as a white powder. The spectral data matched with those reported in the literature [5].

• (4S)-3-[(3R)-3-{(1R,3aR,4S,7aR)-4-[(tert-Butyldimethylsilyl)oxy]-7a-methyloctahydro-1H-inden-1-yl}butanoyl]-4-isopropyloxazolidin-2-one (30)

Carboxylic acid 31 [32] (613.8 mg, 1.73 mmol) was dissolved in thionyl chloride (2.5 mL, 4.12 g, 34.6 mmol) at room temperature, and the solution was refluxed for 1 h 30 min. The mixture was evaporated in vacuo, and the crude acyl chloride was used for the next reaction without further purification.

nBuLi (1.59 M in hexane, 3.3 mL, 5.19 mmol) was added to a precooled solution of (S)-4-isopropyloxazolidinone (673.3 mg, 5.21 mmol) in THF (6 mL) at −78 °C, and the mixture was stirred at the same temperature for 15 min. The above acyl chloride in THF (6 mL) was added to the solution and stirred at the same temperature for 15 min. After the reaction was quenched with H₂O and saturated aqueous NH₄Cl at room temperature, the mixture was extracted with EtOAc three times. The organic layer was dried over Na₂SO₄, filtered, and concentrated. The residue was purified via flash column chromatography on silica gel (hexane:EtOAc = 4:1) to obtain 30 (679.3 mg, 84%, in 2 steps) as a colorless oil.

30: [α] _D²⁷ +67.9 (c 1.28, CHCl₃); IR (neat) 1778, 1700, 1471, 1383, 1259, 1212, 1104, 1019, 960, 849, 779 cm⁻¹; ¹H NMR (600 MHz, CDCl₃) δ –0.02 (s, 3H), 0.00 (s, 3H), 0.86 (d, J = 6.6 Hz, 3H), 0.88 (s, 9H), 0.91 (d, J = 6.6 Hz, 3H), 0.94 (d, J = 6.6 Hz, 3H), 0.95 (s, 3H), 1.10–1.17 (m, 2H), 1.23–1.27 (m, 1H), 1.32–1.43 (m, 4H), 1.53–1.61 (m, 1H), 1.64–1.68 (m, 1H), 1.76–1.84 (m, 2H), 1.94 (dt, J = 3.0, 12.6 Hz, 1H), 2.03–2.10 (m, 1H), 2.32–2.40 (m, 1H), 2.58 (dd, J = 9.6, 16.2 Hz, 1H), 2.58 (dd, J = 3.6, 15.6 Hz, 1H), 3.99–4.00 (m, 1H), 4.19 (dd, J = 3.3, 9.3 Hz, 1H), 4.25 (t, J = 8.7 Hz, 1H), 4.45 (dt, J = 3.6, 8.4 Hz, 1H); ¹³C NMR (150 MHz, CDCl₃) δ –5.2, 4.8, 13.8, 14.5, 17.6, 18.0, 19.3, 23.0, 25.8, 27.0, 28.3, 32.6, 23.4, 40.6, 42.0, 42.3, 53.0, 56.9, 58.3, 63.1, 69.4, 154.0, 173.2; HRMS (ESI⁺) calcd for C₂₆H₄₇NO₄SiNa [M+Na]⁺ 488.3167, found 488.3183.

• (4S)-3-[(2S,3S)-3-{(1R,3aR,4S,7aR)-4-[(tert-Butyldimethylsilyl)oxy]-7a-methyloctahydro-1H-inden-1-yl}-2-fluorobutanoyl]-4-isopropyloxazolidin-2-one (29) and (4S)-3-[(2R,3S)-3-{(1R,3aR,4S,7aR)-4-[(tert-Butyldimethylsilyl)oxy]-7a-methyloctahydro-1H-inden-1-yl}-2-fluorobutanoyl]-4-isopropyloxazolidin-2-one (33)

To a solution of 30 (207.6 mg, 0.45 mmol) in THF (3 mL) was added LHMDS (lithium hexamethyldisilazide) (472 μL, 1 M THF solution, 0.472 mmol) at −78 °C, the mixture was stirred at 0 °C for 1 h, and N-fluorobenzenesulfonimide (NFSI) (168.6 mg, 0.53 mmol) was added to the mixture at −78 °C. After being stirred at the same temperature for 2 h, the reaction was quenched with H₂O and saturated aqueous NH₄Cl at −78 °C. The mixture was extracted with EtOAc three times. The organic layer was washed with brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified via flash column chromatography on silica gel (hexane:EtOAc = 2:1) to obtain 29 (108.4 mg, 50%) (less polar) and 33 (74.9 mg, 35%) (more polar), each as a colorless oil.

29: [α] _D²⁷ + 83.1 (c 1.08, CHCl₃); IR (neat) 1786, 1718, 1384, 1256, 1201, 1025, 834 cm⁻¹; ¹H NMR (600 MHz, CDCl₃) δ –0.02 (s, 3H), 0.00 (s, 3H), 0.88 (s, 9H), 0.89 (d, J = 7.2 Hz, 3H), 0.92 (s, 3H), 0.94 (d, J = 6.6 Hz, 3H), 1.14–1.39 (m, 9H), 1.52–1.67 (m, 3H), 1.74–1.94 (m, 3H), 2.08–2.18 (m, 1H), 2.51–2.56 (m, 1H), 3.98–4.00 (m, 1H), 4.29 (dd, J = 1.8, 9.0 Hz, 1H), 4.35 (t, J = 8.7 Hz, 1H), 4.38–4.40 (m, 1H), 5.74 (dd, J =2.7, 47.4 Hz, 1H); ¹³C NMR (150 MHz, CDCl₃) δ –5.2, –4.8, 13.3, 14.4, 17.2 (d, J = 2.9 Hz), 17.5, 18.0, 18.0, 23.5, 25.8, 26.9, 28.0, 34.3, 40.1, 40.2, 40.3, 42.9, 51.6, 52.3, 59.1, 64.0, 69.3, 93.8 (d, J = 180.9 Hz), 153.5, 170.1 (d, J = 23.1 Hz); HRMS (ESI⁺) calcd for C₂₆H₄₆NO₄FSiNa [M+Na]⁺ 506.3072, found 506.3075.

33: [α] _D²⁷ +1.2 (c 0.57, CHCl₃); IR (neat) 1790, 1718, 1391, 1260, 1204, 1097, 1025, 978, 842, 774 cm⁻¹; ¹H NMR (600 MHz, CDCl₃) δ –0.01 (s, 3H), 0.01 (s, 3H), 0.87 (d, J = 7.2 Hz, 3H), 0.88 (s, 9H), 0.92–0.95 (m, 9H), 1.18 (td, J = 2.4, 12.6 Hz, 1H), 1.32–1.43 (m, 4H), 1.49–1.68 (m, 4H), 1.76–1.93 (m, 4H), 2.03–2.17 (m, 1H), 2.30–2.37 (m, 1H), 4.00–4.02 (m, 1H), 4.26 (dd, J = 3.6, 9.0 Hz, 1H), 4.37 (t, J = 9.0 Hz, 1H), 4.57 (dt, J = 3.9, 9.0 Hz, 1H), 5.96 (dd, J = 1.5, 49.2 Hz, 1H); ¹³C NMR (150 MHz, CDCl₃) δ –5.2, –4.9, 12.4 (d, J = 4.4 Hz), 13.7, 14.3, 17.6, 17.7, 17.9, 22.7, 25.0, 25.8, 28.0, 34.2, 37.1, 37.2, 40.6, 42.0, 52.7, 52.9, 57.7, 64.0, 69.3, 91.9 (d, J = 182.4 Hz), 153.4, 169.7 (d, J = 23.0 Hz); HRMS (ESI⁺) calcd for C₂₆H₄₆NO₄FSiNa [M+Na]⁺ 506.3072, found 506.3091.

• (2S,3S)-3-{(1R,3aR,4S,7aR)-4-[(tert-Butyldimethylsilyl)oxy]-7a-methyloctahydro-1H-inden-1-yl}-2-fluoro-N-methoxy-N-methylbutanamide (34)

To a solution of 29 (105.9 mg, 0.22 mmol) and Me(MeO)NH·HCl (48.8 mg, 0.50 mmol) in THF (10 mL) was added LHMDS (972 μL, 1 M in THF, 0.972 mmol) at 0 °C, and the mixture was stirred at the same temperature for 25 min. After the reaction was quenched with water and aqueous saturated NH₄Cl, the mixture was extracted with EtOAc three times. The organic layer was dried over Na₂SO₄, filtered, and concentrated. The residue was purified via flash column chromatography on silica gel (hexane:EtOAc = 4:1) to obtain 34 (45.4 mg, 50%) as a colorless oil. The spectral data matched with those reported in the literature [8].

• (2R,3S)-3-{(1R,3aR,4S,7aR)-4-[(tert-Butyldimethylsilyl)oxy]-7a-methyloctahydro-1H-inden-1-yl}-2-fluoro-N-methoxy-N-methylbutanamide (35)

To a solution of 33 (39.4 mg, 0.081 mmol) and Me(MeO)NH·HCl (17.2 mg, 0.18 mmol) in THF (5 mL) was added LHMDS (324 μL, 1 M in THF, 0.324 mmol) at 0 °C, and the mixture was stirred at the same temperature for 4 min. After the reaction was quenched with water and aqueous saturated NH₄Cl, the mixture was extracted with EtOAc three times. The organic layer was dried over Na₂SO₄, filtered, and concentrated. The residue was purified via flash column chromatography on silica gel (hexane:EtOAc = 4:1) to obtain 35 (18.7 mg, 55%) as a colorless oil. The spectral data matched with those reported in the literature [8].