Enantioselective Synthesis of (R)-Tiagabine via Asymmetric Hydrogen Atom Transfer Protocol

Key words

analogue synthesis - chiral tertiary center - enantioselective - hydrogen atom transfer - tiagabine - titanium catalysis

Tiagabine (1) is an antispasmodic drug marketed for the treatment of epilepsy.[1] Its mechanism of action is selective and novel when compared with that of other marketed AEDs, relying on its structural features with nipecotic acid moiety being the potent γ-aminobutyric acid (GABA) uptake inhibitor, and the lipophilic biaryl-appendage on the nitrogen atom ensuring the requisite blood-brain barrier transport.[2] Notably, the chirality of the sole stereocenter in the alkaloid ring is essential for its activity, with the R-(–)-enantiomer being four times more potent than its S-(+)-enantiomer.[3] Efficient construction of the chiral tertiary carbon center is therefore the key for the asymmetric synthesis of tiagabine.

To date, there have been only a few strategies to achieve the essential chiral stereocenter relying on either resolution of racemate ethyl nipecotate (rac-3) with l-tartaric acid[4] or asymmetric hydrogenation of guvacine 4 with noble metal catalysts at elevated hydrogen pressures (Scheme [1], upper part).[5] Nucleophilic substitution of the resulting enantioenriched 3 with homoallylic bromide 2 followed by sequential alkaline hydrolysis and acidification furnished the target tiagabine (1).[5c] Access to guvacine 4 was accomplished through hydrogenation of ethyl nicotinate (5) with Pd/C catalysis.[5b] In particular, the abundance and commercial accessibility of the starting material 5 renders this synthetic route concise. On the other hand, due to the well-structurally defined nature of the starting material nicotinate, it can be difficult to employ this strategy to access analogues of tiagabine such as isosteres, positional isomers, and distinct ring systems in the alkaloid moiety, which can be otherwise significant in drug development and research.[6] [7]

Scheme 1 Comparison of the strategies for the synthesis of (R)-tiagabine

We recently reported a catalytic asymmetric hydrogen atom transfer (HAT) reaction that proceeded via a radical approach to the chiral tertiary carbon center, as part of our program directed toward the development of catalytic enantioselective radical reactions.[8] The reaction enantioconvergently transforms racemic glycidic ester 8 into an enantioenriched β-hydroxy ester featuring an α-tertiary carbon center, which we envisioned can be readily transformed to the dibromo intermediate 7 to construct the alkaloid ring of tiagabine via a di-N-substitution cyclization reaction with homoallylic amine 6 (Scheme [1], lower part). The glycidic ester 8 can be accessed via epoxidation of acrylate 9. Compared with the previous synthetic strategy, the modular accessible and readily modifiable starting material 9 enables this strategy to favorable synthesize the analogues or derivatives of tiagabine.

The synthesis began with the preparation of the bithienyl homoallylic amine 6 (Scheme [2]). According to the known procedure reported by Clausen and Zhou,[5a] [9] commercially available brominated thiophene 10 was treated with magnesium, followed by nucleophilic addition of the resultant Grignard reagent with γ-butyrolactone to give 11, which underwent elimination and sulfonation to afford 12 in 70% overall yield. Azide substitution of 12 followed by Staudinger reduction[10] proceeded cleanly to provide 6 in 77% yield.

Scheme 2 Synthesis of dithiophenyl homoallylic amine 6

Having obtained building block 6 in hand, we then focused our attention on the construction of its substitution counterpart 7 which bears a multiple-functionalized chiral tertiary carbon center (Scheme [3]). Commercially available phosphonate ester 13 was treated with commercially available bromide 14, followed by olefination with paraformaldehyde to afford tert-butyl acrylate 15 in 55% overall yield. Sequential removal of the tert-butyl group of 15 with trifluoroacetic acid and esterification of the resulting acid with 1-naphthol by di-tert-butyl dicarbonate ((Boc)₂O) activation under basic conditions[11] provided naphthyl acrylate 9, which was used directly for the next step without further purification. The naphthyl ester is better suited to the HAT reaction in terms of enantioselectivity.[8] Epoxidation of 9 with m-chloroperoxybenzoic acid (mCPBA) generated glycidic ester 8 in an overall 39% yield for two steps.

Scheme 3 Synthesis of racemic alkaloid ring structure of tiagabine

Next, 8 was subjected to our standard catalytic asymmetric HAT reaction, with (salen)TiCl₂ as precatalyst, zinc as reductant, (TMS)₃SiH as hydrogen atom donor, and imidazolium tosylate (IMTS) as acid to furnish the catalytic cycle. The reaction went through a cascade regioselective homolytic epoxide opening and an enantioselective hydrogen atom transfer to the resulting tertiary carbon radical to provide the β-hydroxy ester 16 with 85% yield and 92% ee. Removal of the benzyl group of 16 under catalytic hydrogenation conditions followed by bromination of the resulting diol by the Appel reaction[12] furnished the dibromo compound 7 in 52% yield.

With 7 in hand, we then conducted the planned cyclization reaction with primary amine 6 in the presence of K₂CO₃­ in acetonitrile at an elevated temperature. The expected piperidine structure was readily formed within 2 hours in a yield of 36%, however, detection of its enantiopurity on HPLC indicated that racemic product rac-17 was generated without any enantiomeric excess value. The unexpected formation of racemic cyclization product can be rationalized by a sequential E1_cb elimination/Michael addition and intramolecular substitution reaction process[13] (Scheme [4]). Therein, the loss of the essential chiral stereocenter arises from the enolization of 7 due to the relatively high acidity of the H atom adjacent to the ester group under basic conditions. Extensive screening of the bases and solvents led to racemic cyclization products as well.

Scheme 4 Investigation of the racemization process in the cyclization reaction

Moving forward, we continue toward the final stage of the construction of the alkaloid ring while retaining the chiral stereocenter. Given that the ester group readily initiated the unexpected elimination reaction, we assumed that a reduction of the ester to the alcohol before the cyclization reaction would inhibit the elimination reaction and therefore maintain the chiral carbon center. Oxidation of the primary alcohol to the acid after ring closure would then furnish­ the target molecular. As shown in Scheme [5], the reduction­ of 7 to alcohol 18 was effected with diisobutylaluminum hydride (DIBAL-H) in toluene in 90% yield. Treatment of 18 with 6 in the presence of K₂CO₃ at 70 °C furnished the alkaloid ring 19 in a nice yield without any loss of enantioselectivity. Finally, a decent sequential Swern[14] and Pinnick oxidation[15] followed by acidification with HCl provided the target molecular (R)-tiagabine (1).

Scheme 5 Synthesis of (R)-tiagabine

In summary, we have achieved the enantioselective synthesis of tiagabine utilizing a catalytic asymmetric HAT strategy to construct its essential tertiary carbon center. Given that a readily modifiable glycidic ester is used as the crucial starting material, this work will serve as a basis for the asymmetric synthesis of analogues and derivatives of tiagabine to facilitate further biological studies.

¹H and ¹³C NMR spectra were measured on Bruker 400 MHz spectrometers. ¹H NMR spectra were calibrated by using the residual undeuterated solvent as internal reference (CDCl₃ δ = 7.26, DMSO-d ₆ δ = 2.50). ¹³C NMR spectra used the solvent peak as internal reference (CDCl₃ δ = 77.0, DMSO-d ₆ δ = 39.5). IR spectra were measured on an ATR-IR-Spectrometer Nicolet TM 380 instrument as a neat film. HRMS analysis data were obtained on a Thermoquest MAT 95 XL instrument. Chiral HPLC analysis was performed with a Shimadzu HPLC instrument.

4,4-Bis(3-methylthiophen-2-yl)but-3-en-1-amine (6)

According to the reported procedure,[5a] [9] Mg (7.92 g, 330 mmol), 2-bromo-3-methylthiophene (38.9 g, 220 mmol), and γ-butyrolactone (4.8 mL, 79.2 mmol) yielded the crude product 11 (19.7 g, 89%), which was used directly without further purification with HCl (4N, 50 mL) and MeOH (250 mL), and then MeSO₂Cl (5.9 g, 77 mmol), Et₃N (13.6 mL, 98 mmol, 1.4 equiv) to afford 12 (19 g, 79%) as a yellow oil.

A mixture of compound 12 (6.84 g, 20 mmol, 1.0 equiv) and NaN₃ (6.5 g, 100 mmol, 5.0 equiv) in DMF (80 mL) was stirred at 80 °C for 3 h. Then, the reaction mixture was treated with a mixture of Et₂O and water, the ether extract was dried (MgSO₄), and the ether was removed under reduced pressure to give a yellow oil. To a solution of this oil in THF (75 mL) was added Ph₃P (10.5 g, 40 mmol, 2.0 equiv) and H₂O (25 mL). The reaction mixture was stirred for 2 h at 50 °C. The resulting suspension was filtered. The precipitate was washed with Et₂O and the filtrate was evaporated in vacuo. The residue was purified by chromatography (silica gel, CH₂Cl₂/MeOH 9:1) to afford the crude product 6 (4.0 g, 77%) as a yellow oil.

IR (neat): 2922, 1450, 844, 724, 456 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.22 (d, J = 5.1 Hz, 1 H), 7.05 (d, J = 5.1 Hz, 1 H), 6.84 (d, J = 5.1 Hz, 1 H), 6.76 (d, J = 5.1 Hz, 1 H), 6.05 (t, J = 7.5 Hz, 1 H), 2.81 (t, J = 6.9 Hz, 2 H), 2.30 (q, J = 7.1 Hz, 2 H), 2.04 (s, 3 H), 2.00 (s, 3 H), 1.73 (s, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 139.4, 135.4, 135.2, 133.7, 132.6, 131.2, 129.6, 129.3, 124.4, 122.8, 41.9, 34.1, 14.9, 14.4.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₄H₁₈NS₂: 264.0875; found: 264.0874.

tert-Butyl 5-(Benzyloxy)-2-methylenepentanoate (15)

To a solution of NaH (1.3 g, 33 mmol, 60% in mineral oil) in DMF (120 mL), tert-butyl diethylphosphonoacetate (7 mL, 30 mmol) was added dropwise at r.t. After stirring at r.t. for 30 min, ((3-bromopropoxy)methyl)benzene (14; 5.8 mL, 33 mmol) was added. The mixture was heated at 100 °C for 16 h and then cooled to r.t. K₂CO₃ (12.0 g, 90 mmol) and paraformaldehyde (5.4 g, 60 mmol) were then added, and the mixture was stirred at 100 °C for 6 h. After cooling down to r.t., the mixture was extracted with EtOAc, washed with brine, and dried (MgSO₄). After removal of the solvent under reduced pressure, the crude product was purified by flash column chromatography (silica gel, hexane/EtOAc 9:1) to give 15 (4.5 g, 55%) as a colorless oil.

IR (neat): 2977, 2858, 1631, 1453, 1252, 738, 638 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.41–7.19 (m, 5 H), 6.05 (d, J = 1.6 Hz, 1 H), 5.44 (d, J = 1.5 Hz, 1 H), 4.49 (s, 2 H), 3.48 (t, J = 6.4 Hz, 2 H), 2.43–2.28 (m, 2 H), 1.87–1.73 (m, 2 H), 1.48 (s, 9 H).

¹³C NMR (100 MHz, CDCl₃): δ = 166.4, 141.8, 138.6, 128.4, 127.6, 127.5, 123.8, 80.4, 72.9, 69.6, 28.7, 28.6, 28.1.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₇H₂₅O₃: 277.1798; found: 277.1804.

Naphthalen-1-yl 2-(3-(Benzyloxy)propyl)oxirane-2-carboxylate (8)

Compound 15 (4.1 g, 15 mmol) was dissolved in a mixed solution of CF₃CO₂H (15 mL) and CH₂Cl₂ (30 mL). The mixture was stirred for 30 min at r.t., and then it was washed with water (3 ×), dried (MgSO₄), filtered, and evaporated to dryness. To a solution of the crude product in THF (50 mL) were added (Boc)₂O (3.3 g, 15 mmol), 1-naphthol (2.2 g, 15 mmol), LiOH (29 mg, 1.2 mmol), and Mg(OH)₂ (17 mg, 0.3 mmol). The mixture was stirred for 3 h at 75 °C and then quenched with water and extracted with EtOAc. The combined layers were dried (MgSO₄), filtered, and the solvent was removed under reduced pressure to give the crude product 9 which was used directly for the next without further purification.

To a solution of the crude product 9 in CH₂Cl₂ (70 mL) was added mCPBA (85 wt%, 6 g, 30 mmol). The mixture was stirred at reflux for 48 h, then cooled down to 0 °C. The precipitated 3-chlorobenzoic acid was removed by vacuum filtration. The resultant reaction mixture was washed with sat. aq Na₂S₂O₃ and extracted with CH₂Cl₂. After removal of the solvent under reduced pressure, the crude product was purified by flash column chromatography (silica gel, hexane/EtOAc 9:1) to give 8 (2.3 g, 42% overall yield from 15) as a yellow oil.

IR (neat): 2858, 1599, 1453, 1225, 798, 678 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.76 (dd, J = 6.5, 2.9 Hz, 2 H), 7.64 (d, J = 8.3 Hz, 1 H), 7.45–7.38 (m, 2 H), 7.35 (t, J = 7.9 Hz, 1 H), 7.29–7.20 (m, 4 H), 7.17 (t, J = 4.9 Hz, 2 H), 4.43 (s, 2 H), 3.49 (dd, J = 8.7, 3.6 Hz, 2 H), 3.31 (d, J = 5.8 Hz, 1 H), 2.90 (d, J = 5.8 Hz, 1 H), 2.26 (dd, J = 7.9, 6.3 Hz, 1 H), 2.02–1.93 (m, 1 H), 1.92–1.81 (m, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 169.2, 146.3, 138.5, 134.7, 128.5, 128.2, 127.8, 127.7, 126.8, 126.6, 126.6, 126.4, 125.4, 121.0, 117.9, 72.9, 69.7, 57.1, 52.3, 28.4, 25.3.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₃H₂₃O₄: 363.1591; found: 363.1596.

Naphthalen-2-yl (R)-5-(Benzyloxy)-2-(hydroxymethyl)pentanoate (16)

To a heat-dried Schlenk tube were added IMTS (1.87 g, 7.8 mmol), Zn (680 mg, 10.4 mmol), (Salen)TiCl₂ (567 mg, 0.52 mmol), and freshly distilled EtOAc (10 mL) under an argon atmosphere subsequently, the mixture was stirred for 2 h at the indicated temperature, (TMS)₃SiH (1.95 g, 7.8 mmol) was then added, followed by addition of 8 (1.9 g, 5.2 mmol) after 1 h. The mixture was stirred at the indicated temperature for 72 h, quenched with sat. aq NaHCO₃ solution, diluted with EtOAc, washed with brine, and dried (MgSO₄). After removal of the solvent under reduced pressure, the crude product was purified by flash column chromatography (silica gel, hexane/EtOAc 4:1) to give 16 (1.6 g, 85%) as a yellow oil, 92% ee [Daicel Chiral OD-H (0.46 cm × 25 cm), n-hexane/i-PrOH 90:10, flow rate (v) = 1.0 mL·min^–1, λ = 221 nm: t _R = 25.21 (major), 28.75 min (minor)].

IR (neat): 2857, 1758, 1692, 832, 790, 560 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.99–7.81 (m, 2 H), 7.74 (d, J = 8.3 Hz, 1 H), 7.48 (ddd, J = 18.7, 10.7, 5.0 Hz, 3 H), 7.40–7.30 (m, 4 H), 7.31–7.25 (m, 1 H), 7.25–7.18 (m, 1 H), 4.54 (s, 2 H), 4.07–3.88 (m, 2 H), 3.59 (dd, J = 8.8, 3.0 Hz, 2 H), 3.04 (dd, J = 11.9, 6.2 Hz, 1 H), 2.25 (td, J = 6.1, 2.6 Hz, 1 H), 2.07–1.93 (m, 1 H), 1.94–1.76 (m, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 173.8, 146.5, 138.4, 134.7, 128.5, 128.0, 127.7, 127.7, 126.8, 126.6, 126.5, 126.2, 125.4, 73.1, 69.8, 63.3, 47.8, 27.6, 25.5.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₃H₂₅O₄: 365.1747; found: 365.1742.

Naphthalen-1-yl (S)-5-Bromo-2-(bromomethyl)pentanoate (7)

To a solution of 16 (980 mg, 2.7 mmol) in EtOH was added Pd/C (wet, 100 mg), and the resulting mixture was stirred at r.t. under a H₂ balloon overnight. After filtration, the solvent was removed under vacuum to give the crude product. Then the crude product was dissolved in dry CH₂Cl₂ (30 mL) at 0 °C, Ph₃P (1.8 g, 7 mmol) and CBr₄ (2.3 g, 7 mmol) were then added. The ice bath was removed, and the reaction was allowed to stir for 0.5 h. The reaction mixture was then concentrated and purified directly with chromatography (silica gel, hexane/EtOAc 9:1) to give pure dibromide 7 (560 mg, 52%); 90% ee [Daicel Chiral OD-H (0.46 cm × 25 cm), n-hexane/i-PrOH 95:5, flow rate (v) = 1.0 mL·min^-1, λ = 221 nm: t _R = 13.76 (minor), 17.22 min (major)].

IR (neat): 3326, 1754, 1596, 1285, 1139, 771 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.00–7.92 (m, 1 H), 7.91–7.83 (m, 1 H), 7.76 (d, J = 8.3 Hz, 1 H), 7.58–7.42 (m, 3 H), 7.28–7.22 (m, 1 H), 3.77 (ddd, J = 15.3, 10.3, 6.5 Hz, 2 H), 3.60–3.44 (m, 2 H), 3.33–3.21 (m, 1 H), 2.22–1.97 (m, 4 H).

¹³C NMR (100 MHz, CDCl₃): δ = 172.46, 146.56, 139.54, 135.32, 134.67, 133.71, 131.21, 129.68, 128.04, 126.85, 126.47, 125.95, 125.41, 124.40, 122.83, 121.18, 118.05, 58.07, 55.25, 53.42, 41.83, 27.32, 27.03, 24.26, 14.86, 14.45.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₆H₁₇Br₂O₂: 398.9590; found: 398.9599.

(rac)-Tiagabine (17)

Compound 6 (130 mg, 0.5 mmol) was mixed with 7 (200 mg, 0.5 mmol) and K₂CO₃ (207 mg, 1.5 mmol) in MeCN (5 mL). The mixture was heated at 70 °C for 2 h. After cooling, the solution was concentrated. The residue was purified by flash column chromatography (hexane/EtOAc 3:1) to afford 17 (90 mg, 36%) as a brown oil; 2% ee [Daicel Chiral OD-H (0.46 cm × 25 cm), n-hexane/i-PrOH 95:5, flow rate (v) = 1.0 mL·min^–1, λ = 221 nm: t _R = 11.26 (minor), 13.21 min (major)].

IR (neat): 2921, 1754, 1452, 1261, 1121, 800 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.85 (t, J = 5.8 Hz, 2 H), 7.73 (d, J = 8.3 Hz, 1 H), 7.52–7.40 (m, 3 H), 7.21–7.17 (m, 2 H), 7.05 (d, J = 5.1 Hz, 1 H), 6.83 (d, J = 5.0 Hz, 1 H), 6.76 (d, J = 5.1 Hz, 1 H), 3.27–3.19 (m, 1 H), 3.09 (s, 1 H), 2.82 (s, 1 H), 2.62 (d, J = 6.9 Hz, 2 H), 2.58–2.52 (m, 1 H), 2.47–2.40 (m, 2 H), 2.21 (s, 2 H), 2.04 (s, 3 H), 2.02 (s, 3 H), 1.89–1.82 (m, 1 H), 1.78–1.70 (m, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 171.21, 146.39, 134.69, 128.09, 126.67, 126.59, 126.37, 125.37, 121.16, 118.01, 47.65, 32.66, 31.91, 30.02, 29.98.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₀H₃₁NO₂S₂: 502.1869; found: 502.1872.

The formation of Int-1 can be detected by TLC and confirmed by crude NMR spectra:

¹H NMR (400 MHz, CDCl₃): δ = 7.84–7.79 (m, 1 H), 7.78–7.74 (m, 1 H), 7.69 (d, J = 8.3 Hz, 1 H), 7.46–7.37 (m, 3 H), 7.20 (t, J = 3.3 Hz, 1 H), 6.57 (s, 1 H), 5.86 (s, 1 H), 3.47–3.39 (m, 2 H), 2.63–2.57 (m, 2 H), 2.11 (dt, J = 13.5, 6.6 Hz, 2 H).

(S)-5-Bromo-2-(bromomethyl)pentan-1-ol (18)

A solution of 7 (258 mg, 0.65 mmol) in dry toluene (1 mL) was cooled to –78 °C and DIBAL-H (1 M in toluene, 0.7 mmol) was added dropwise. After stirred at –78 °C for 1 h, the mixture was then allowed to warm to r.t. slowly and stirred overnight. The reaction was quenched with sat. Rochelle salt solution, extracted with Et₂O, and dried (Na₂SO₄). After removal of the solvent under reduced pressure, the crude product was purified by flash column chromatography (silica gel, hexane/EtOAc 4:1) to afford the alcohol 18 (150 mg, 90%) as a brown oil.

IR (neat): 2929, 1715, 1382, 1268, 817 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 3.76–3.63 (m, 2 H), 3.61 (dd, J = 10.3, 4.3 Hz, 1 H), 3.50 (dd, J = 10.2, 5.4 Hz, 1 H), 3.42 (t, J = 6.7 Hz, 2 H), 1.98–1.82 (m, 3 H), 1.61 (d, J = 1.6 Hz, 1 H), 1.57 (m, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 63.43, 41.44, 35.58, 33.35, 30.03, 28.12.

HRMS (ESI): m/z [M + H]⁺ calcd for C₆H₁₃Br₂O: 258.9328; found: 258.9331.

(R)-(1-(4,4-Bis(3-methylthiophen-2-yl)but-3-en-1-yl)piperidin-3-yl)methanol (19)

Compound 6 (92 mg, 0.35 mmol) was mixed with 18 (90 mg, 0.35 mmol) and K₂CO₃ (140 mg, 1 mmol) in MeCN (5 mL). The mixture was heated at 70 °C for 2 h. After cooling, the solution was concentrated, and the crude product was purified by flash column chromatography (silica gel, hexane/EtOH 5:1) to afford 19 (105 mg, 83%) as a brown oil; 92% ee [Daicel Chiral IC (0.46 cm × 25 cm), n-hexane/i-PrOH 95:5, flow rate (v) = 1.0 mL·min^–1, λ = 257 nm: t _R = 11.92 (minor), 15.15 min (major)].

IR (neat): 2926, 2762, 1442, 1263, 1034, 805 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.13 (d, J = 5.1 Hz, 1 H), 6.97 (d, J = 5.1 Hz, 1 H), 6.77 (d, J = 5.1 Hz, 1 H), 6.68 (d, J = 5.1 Hz, 1 H), 5.96 (t, J = 7.3 Hz, 1 H), 3.48 (ddd, J = 16.8, 10.6, 5.7 Hz, 2 H), 2.74 (d, J = 9.0 Hz, 1 H), 2.59–2.52 (m, 1 H), 2.41 (m, 4 H), 2.35–2.23 (m, 2 H), 2.10–2.03 (m, 1 H), 1.97 (s, 3 H), 1.94 (s, 3 H), 1.74–1.66 (m, 2 H), 1.59 (m, 1 H), 1.51 (m, 1 H).

¹³C NMR (100 MHz, CDCl₃): δ = 138.53, 134.38, 134.18, 132.58, 132.10, 130.13, 128.59, 127.38, 123.29, 121.71, 65.95, 57.30, 56.20, 52.98, 36.81, 26.41, 26.28, 23.45, 13.77, 13.38.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₀H₂₇NOS₂: 362.1607; found: 362.1598.

(R)-Tiagabine (1)

To a solution of oxalyl chloride (32 mg, 0.25 mmol) in anhyd CH₂Cl₂ (5 mL) was added dropwise DMSO (20 mg, 0.25 mmol) at –78 °C. The mixture was stirred for 10 min and a solution of alcohol 19 (45 mg, 0.125 mmol) in anhyd CH₂Cl₂ (1 mL) was added dropwise over 5 min; the mixture was stirred at –78 °C for 10 min. Subsequently, Et₃N (101 mg, 1 mmol) was added dropwise to the reaction mixture at –78 °C over 2 min. The mixture was warmed to r.t. for 0.5 h and then poured into water. The organic phase was separated, and the aqueous phase was extracted with CH₂Cl₂. The combined organic phases were dried (MgSO₄) and concentrated in vacuo to give the crude product. To a solution of the crude product in a mixture of THF/ ^t BuOH (1:1.8 mL) was added 2-methylbut-2-ene (18 mg, 0.25 mmol) and a solution of sodium chlorite (24 mg, 0.19 mmol) and sodium phosphate monobasic (45 mg, 0.375 mmol) in H₂O (2 mL). The mixture was stirred for 0.5 h. Aq 1 M HCl was added to the mixture until it reached pH 1. CH₂Cl₂ was then added and the phases were separated. The aqueous phase was extracted with CH₂Cl₂ (3 ×), and the combined organic phases were washed with brine (1 ×), dried (MgSO₄), filtered, and concentrated in vacuo to give an off-white solid. The solid was recrystallized to provide (R)-tiagabine hydrochloride (20.0 mg, 40%) as a white solid; mp 180–181 °C; [α]_D ²⁵ –8.9 (c = 1.0, H₂O).

IR (neat): 2939, 2540, 1725, 1195, 855, 723 cm^–1.

¹H NMR (400 MHz, DMSO): δ = 12.79 (s, 1 H), 11.01 (s, 1 H), 7.52 (d, J = 4.9 Hz, 1 H), 7.33 (d, J = 4.9 Hz, 1 H), 6.96 (d, J = 4.9 Hz, 1 H), 6.85 (d, J = 4.9 Hz, 1 H), 6.00 (t, J = 7.0 Hz, 1 H), 3.47 (s, 2 H), 3.17 (d, J = 7.3 Hz, 2 H), 2.94 (d, J = 6.0 Hz, 2 H), 2.81 (s, 1 H), 2.56 (m, 2 H), 2.00 (d, J = 19.8 Hz, 7 H), 1.82 (s, 2 H), 1.47 (s, 1 H).

¹³C NMR (100 MHz, DMSO): δ = 173.33, 138.79, 135.97, 134.38, 134.28, 131.88, 130.41, 129.91, 129.80, 126.06, 124.44, 55.44, 52.41, 51.62, 25.36, 24.77, 22.17, 21.25, 15.05, 14.69.

HRMS (ESI): m/z [M – HCl + H]⁺calcd for C₂₀H₂₆ClNO₂S₂: 376.1399; found: 376.1406.

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