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Abstract

Routes are reported for the synthesis of both (1R)- and (1S)-tert-butyl-(4-oxocyclopent-2-en-1-yl)carbamate 2. Featuring Mitsunobu reactions with di-tert-butyl iminodicarbonate, both syntheses begin from (S)-4-[(tert-butyldimethylsilyl)oxy]cyclopent-2-en-1-one (3) and take advantage of the 1,4-cyclopentenyl dioxygenation pattern of this optically active starting material. Thus both (−)- and (+)-2 have been accessed from 3 in an enantiodivergent manner in 11% and 10% overall yield over five and seven reaction steps, respectively.

Keywords

Mitsunobu reaction O-protecting groups prostaglandin analogue reduction stereoselective transformation

Introduction

Substituted cyclopentyl and cyclopentenyl compounds are useful building blocks for the construction of natural products and other compounds of interest: many of which feature heteroatom substituents.¹ In relation to this, we have recently reported the preparation of aza-analogues of the unsaturated prostaglandin Δ^12,14-15-deoxy-PGJ₂ (Scheme 1).² This type of prostaglandin possesses an interesting biological profile and attempts to explore how the structure of this compound affects its activity are hampered because it is not amenable to ready synthetic divergence from an advanced intermediate.^3–10 In relation to this point, we demonstrated that incorporation of a nitrogen atom at the 4-position in the cyclopentenone enabled ready modification of the α-prostanoid side chain.² In addition, alkylidination/arylidination was successfully used to instal the unsaturated exocyclic side chain present in the natural product analogue 1.

Scheme 1.

Structure of the cross-conjugated cyclopentenone prostaglandin Δ^12,14-15-deoxy-PGJ₂, its 4-aza analogue 1 and its retrosynthesis to optically active 4-substituted cyclopentenones 2 and 3 [Boc = tert-butyloxycarbonyl; TBS = tert-butyldimethylsilyl].

This enables 1 to be traced to the optically active N-Boc-protected functionalised cyclopentenone 2. Since some compounds of the type 1 demonstrated comparable activities to Δ^12,14-15-deoxy-PGJ₂ in assays relevant to inflammation and anticancer activity,² a robust supply of optically active compound (R)-2 was required. In addition, we were also interested to explore how the stereogenicity of the α-side chain affected biological action, and consequently also required access to the (S)-enantiomer of compound 2. It should be noted that several methods for the synthesis of optically active forms of 2 have been reported,^11–15 and in this article, we show how (S)-4-[(tert-butyldimethylsilyl)oxy]cyclopent-2-en-1-one (3)^16–20 can be used to prepare both (R)- and (S)-2.

Results and discussion

Optically active (−)-3 is commercially available and can be prepared with high levels of enantioexcess in several ways.^16–20 Since the direct nucleophilic displacement of an activated form of 4-hydroxycyclopentenone is problematic and has scarce literature precedence^21,22 alternative methods for the stereocontrolled construction of 2 were considered. From 3, the ketone was initially converted into alcohol 4 via a Luche reduction. As described in the literature,²³ following this reaction, an 85:15 mixture of diastereomers (4a:4b) was formed and these isomers proved not to be chromatographically separable. Therefore, this mixture was directly converted, in moderate yield, into compound 5 by a Mitsunobu reaction involving di-tert-butyl iminodicarbonate.^24,25 Again, the mixture of the minor cis- and major trans-1,4-difunctionalised cyclopentenyl compounds proved inseparable. However, on removal of the silyl protecting group (under typical conditions), the more polar alcohol 6 was separable from its minor cis-isomer by flash column chromatography. Oxidation using Dess–Martin periodinane (DMP) then gave cyclopentenone (−)-7, which subsequently could be readily mono-Boc deprotected to provide N-Boc-protected cyclopentenone (−)-2 in 11% overall yield over the five reaction steps (Scheme 2). The specific rotation of the synthetic material obtained over this sequence {[α]_D = –75.5 (c = 0.1, CHCl₃)} is consistent with reported values.^11,12

Scheme 2.

Asymmetric synthesis of (−)-2 from (−)-3.

Based on the successful synthesis described in Scheme 2, attention next focused on the related preparation of (+)-2. In a first attempt, we envisaged, that a double inversion of the alcohol present in the major isomer from the Luche reduction (compound 4a in Scheme 2) would provide material that could be converted through to the target (+)-2. As shown in Scheme 3, 4a was inverted into the minor diastereomer from the Luche reduction (4b) via a classic Mitsunobu ester formation with benzoic acid, followed by hydrolysis.

Scheme 3.

The Mitsunobu reaction for the epimerisation of 4a into 4b.

Although this sequence was successful, in our hands the yield (12%) for this two-step process was unacceptably low. Consequently, an alternative approach was employed which takes advantage of the symmetrical 1,4-cis-dioxygenation pattern in compound 4a. As shown in Scheme 4, compound 4 (4a:4b = 85:15) was converted into compound 8.²⁶ The two alcohol functionalities are now orthogonally protected meaning that treatment of 8 with fluoride gave alcohol 9. Mitsunobu reaction of 9 with di-tert-butyl iminodicarbonate gave compound 10, which could be isolated as a single stereoisomer in moderate yield. This reaction sets the stereogenic centre bearing the nitrogen substituent required in target (+)-2. From 10, ester cleavage, oxidation with Dess–Martin periodinane and mono-N-Boc deprotection gave compound (+)-2.

Scheme 4.

Asymmetric synthesis of (+)-2 from 4a.

Following this route, (+)-2, with optical properties in accordance with the literature {[α]_D = +74.4 (c = 0.1, CHCl₃) – roughly equal and opposite in value compared to (−)-2, see Scheme 2},^13,14 was prepared from (−)-3 in seven steps and 10% overall yield.

Conclusion

In conclusion, routes are described for the synthesis of both enantiomers of tert-butyl-(4-oxocyclopent-2-en-1-yl)carbamate (2). These optically active compounds are of broad utility for the synthesis of 1,4-difunctionalised cyclopentenyl compounds which are of synthetic and biological interest. It should be noted again that the direct nucleophilic attack on activated forms of 3 has been infrequently reported due to competitive formation of cyclopentadienone (which subsequently undergoes cycloaddition chemistry).^21,22,27

Experimental

General directions

Starting materials were obtained from commercial suppliers and were used without further purification unless otherwise stated. CAS number for (S)-4-[(tert-butyldimethylsilyl)oxy]cyclopent-2-en-1-one (3): 61305-36-0. All commercially available solvents were used as supplied unless otherwise stated. All ‘dry’ solvents were dried and distilled by standard procedures. Glassware was either dried in an oven, or flame-dried with a Bunsen burner before use and assembled hot then cooled to room temperature under a stream of nitrogen. Oxygen-free, anhydrous nitrogen was obtained from BOC. Thin-layer chromatography (TLC) was carried out on Merck silica gel aluminium sheets (60 F254). Ultraviolet (UV) light and a mixture of KMnO₄ (1.5 g), K₂CO₃ (10 g), 10% NaOH (1.25 mL) in water (200 mL) was used to visualise spots. Merck silica 60 Å (230–400 mesh) 9385 was used for flash column chromatography. Nuclear magnetic resonance (NMR) spectra were recorded on Varian Unit 300, 400 or 500 MHz spectrometers as specified. Spectra were calibrated using trimethylsilane (TMS) or the residual protiated solvent. Coupling constants (J) are quoted in Hertz. ¹H and ¹³C NMR chemical shift assignments are based on two-dimensional NMR techniques, including ¹H-¹H-gCOSY and heteronuclear single quantum coherence (HSQC) experiments. All values are reported in parts per million (ppm). Infrared (IR) spectra were recorded on a Bruker Alpha Fourier-transform infrared (FTIR) spectrometer. High-resolution mass spectrometry (HRMS) was performed using a Waters Crop, Micromass LCT, electrospray ionisation (ESI) spectrometer. Melting points were determined in an open capillary on a Gallenkamp melting point apparatus and are uncorrected. Compound names were generated using ChemDraw software. Known compounds are referenced accordingly.

(1R,4S)-4-[(tert-Butyldimethylsilyl)oxy]cyclopent-2-enol (4a) and (1S,4S)-4-[(tert-butyldimethylsilyl)oxy]cyclopent-2-enol (4b)

Cerium chloride heptahydrate (1.76 g, 4.72 mmol, 1.0 equiv.) was added to a solution of (S)-4-(tert-butyldimethylsilyl)cyclopent-2-enone (3) (1.01 g, 4.76 mmol, 1.0 equiv.) in MeOH (15 mL) and the resulting suspension was stirred vigorously for 5 min until fully dissolved.²³ The solution was cooled to −20 °C (adjusted with dry ice in acetone) and sodium borohydride (0.18 g, 4.76 mmol, 1.0 equiv.) was added slowly. After stirring at this temperature for 10 min, the cooling bath was removed and the suspension was stirred at room temperature for an additional 20 min. Following this, sat. NH₄Cl (40 mL) was added dropwise and the mixture was then extracted with CH₂Cl₂ (3 × 50 mL). The combined organic phases were dried over MgSO₄, filtered and the solvent removed in vacuo, which resulted in the formation of the desired product 4 (0.79 g, 78%) as a colourless oil and as a mixture of diastereomers. The crude mixture, containing 15% of the diastereomer 4b (as determined by ¹H NMR spectroscopy), with data as reported,²³ was used further without additional purification. Data for the major diastereomer 4a: ¹H NMR (400 MHz, CDCl₃): δ 0.09 (s, 6H, CH₃), 0.90 (s, 9H, CH₃), 1.52 (dt, J = 14.0, 4.5 Hz, 1H, CH₂), 1.85 (br s, 1H, OH), 2.69 (dt, J = 14.0, 7.0 Hz, 1H, CH₂), 4.59 (br s, 1H, CH), 4.64–4.69 (m, 1H, CH), 5.89 (d, J = 5.5 Hz, 1H, CH), 5.95 (d, J = 5.5 Hz, 1H, CH) ppm;¹³C NMR (101 MHz, CDCl₃): δ −4.55 (CH₃), −4.5 (CH₃), 18.3 (C), 26.0 (CH₃), 44.8 (CH₂), 75.3 (CH), 75.35 (CH), 135.8 (CH), 137.1 (CH) ppm (see below for NMR spectroscopic data for 4b).

Di-tert-butyl{(1S,4S)-4-[(tert-butyldimethylsilyl)oxy]cyclopent-2-en-1-yl}imidodicarboxylate [(–)-5]:

Alcohol 4 (0.36 g, 1.68 mmol, 1.0 equiv.) was added to a solution of triphenylphosphine (1.32 g, 5.03 mmol, 3.0 equiv.) and di-tert-butyl-iminodicarboxylate (0.55 g, 2.53 mmol, 1.5 equiv.) in dry THF (20 mL). Diisopropyl azodicarboxylate (0.82 mL, 4.16 mmol, 2.5 equiv.) was added, and the solution was stirred at room temperature for 18 h. After this time, the reaction mixture was concentrated in vacuo and purified by column chromatography (c-Hex/EtOAc; 95:5→9:1), affording the desired product (−)-5 (0.295 g, 42%) as a colourless oil. R_f = 0.5 (c-Hex/EtOAc; 9:1); IR (neat): ν_max = 3007, 2979, 2955, 2857, 1743, 1704, 1473, 1461, 1391, 1346, 1252, 1149, 1113 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 0.07 (br s, 6H, CH₃), 0.89 (s, 9H, CH₃), 1.48 (s, 18H, CH₃), 2.06 (ddd, J = 14.0, 8.5, 2.5 Hz, 1H, CH₂), 2.24 (ddd, J = 14.0, 7.5, 5.0 Hz, 1H, CH₂), 5.03–5.09 (m, 1H, CH), 5.41–5.47 (m, 1H, CH), 5.78–5.85 (m, 2H, CH) ppm; ¹³C NMR (101 MHz, CDCl₃): δ −4.5 (CH₃), −4.45 (CH₃), 18.4 (C), 26.1 (CH₃), 28.1 (CH₃), 39.5 (CH₂), 62.0 (CH), 77.2 (CH), 82.4 (C), 133.8 (CH), 135.8 (CH), 153.1 (CO) ppm; HRMS (ES⁺): m/z C₂₁H₃₉NO₅SiNa (MNa⁺) calcd. 436.2490; found 436.2493; [α]_D = −112.6 (c = 0.1, CHCl₃).

Di-tert-butyl[(1S,4S)-4-hydroxycyclopent-2-en-1-yl]imidodicarboxylate [(−)-6]

A 1 M solution of TBAF in THF (3.02 mL, 3.02 mmol, 1.5 equiv.) was added to a solution of TBS ether 5 (831 mg, 2.01 mmol, 1.0 equiv.) in dry THF (30 mL). The solution was stirred at room temperature for 1 h 30 min. After this time, the reaction mixture was concentrated under a flow of air and the resulting residue was directly purified by column chromatography (c-Hex/EtOAc; 2:1), affording the desired product (−)-6 (498 mg, 83%) as a white solid. M.p. = 60–62 °C; R_f = 0.5 (c-Hex/EtOAc; 1:1); IR (neat): ν_max = 3250, 2980, 2933, 1746, 1706, 1477, 1456, 1390, 1345 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 1.49 (s, 18 H, CH₃), 2.11 (ddd, J = 14.0, 8.5, 2.0 Hz, 1H, CH₂), 2.34 (ddd, J = 14.0, 7.5, 5.5 Hz, 1H, CH₂), 5.06 (br s, 1H, CH), 5.44–5.53 (m, 1H, CH), 5.91 (ddd, J = 5.5, 2.0, 1.0 Hz, 1H, CH), 5.93–5.98 (m, 1H, CH) ppm; ¹³C NMR (101 MHz, CDCl₃): δ 28.1 (CH₃), 39.3 (CH₂), 61.8 (CH), 76.8 (CH), 82.6 (C), 134.8 (CH), 135.6 (CH), 153.0 (CO) ppm; HRMS (ES⁺): m/z C₁₅H₂₆NO₅ (MH⁺) calcd. 300.1805; found 300.1806; [α]_D = −142.6 (c = 0.1, CHCl₃).

Di-tert-butyl[(1S)-4-oxocyclopent-2-en-1-yl]imidodicarboxylate [(−)-7]

Dess–Martin periodinane (651 mg, 1.53 mmol, 1.0 equiv.) was added to a solution of alcohol 6 (441 mg, 1.47 mmol, 1.0 equiv.) in dry CH₂Cl₂ (40 mL). The solution was stirred at room temperature for 2.5 h. (The reaction was monitored by TLC.) An additional aliquot of Dess–Martin periodinane (126 mg, 0.30 mmol, 0.2 equiv.) was added, and the reaction mixture was stirred for a further 45 min. The reaction mixture was filtered through Celite and concentrated under a flow of air. The resulting residue was purified by column chromatography (c-Hex/EtOAc; 4:1), affording the desired product (−)-7 (216 mg, 49%) as a colourless solid. M.p. = 62–64 °C; R_f = 0.3 (c-Hex/EtOAc; 4:1); IR (neat): ν_max = 2976, 2925, 2852, 1750, 1705, 1367, 1345, 1262, 1232, 1134, 1101 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 1.49 (s, 18 H, CH₃), 2.54 (dd, J = 18.0, 3.0 Hz, 1H, CH₂), 2.73 (dd, J = 18.0, 7.0 Hz, 1H, CH₂), 5.48–5.53 (m, 1H, CH), 6.22 (dd, J = 5.5, 2.5 Hz, 1H, CH), 7.52 (dd, J = 5.5, 2.5 Hz, 1H, CH) ppm; ¹³C NMR (101 MHz, CDCl₃): 28.1 (CH₃), 40.6 (CH₂), 56.1 (CH), 83.7 (C), 134.1 (CH), 152.3 (CH), 163.0 (CO), 206.3 (CO) ppm; HRMS (ES⁺): m/z C₁₅H₂₃NO₅Na (MNa⁺) calcd. 320.1468; found 320.1471; [α]_D = −82.4 (c = 0.1, CHCl₃).

(S)-tert-Butyl (4-oxocyclopent-2-en-1-yl)carbamate [(−)-2]

Trifluoroacetic acid (70 μL, 0.97 mmol, 1.9 equiv.) was added to a solution of cyclopentenone (−)-7 (152 mg, 0.51 mmol, 1.0 equiv.) in dry CH₂Cl₂ (7 mL) and the solution was stirred under an inert atmosphere for 1.5 h. After this time, the solution was diluted with CH₂Cl₂ (8 mL) and washed with NaHCO₃ (10 mL). The aqueous phase was extracted with CH₂Cl₂ (3 × 10 mL) and the combined organic phases were dried over MgSO₄ and the solvent removed in vacuo. Purification by column chromatography (c-Hex/EtOAc; 2:1) afforded the desired product (−)-2 (83 mg, 83%) with data as reported.^11–15 M.p. = 110–111 °C; R_f = 0.2 (c-Hex/EtOAc; 2:1); IR (neat): ν_max = 3325, 2981, 2932, 1719, 1673, 1529, 1366, 1252, 1159 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 1.46 (s, 9H, CH₃), 2.16 (dd, J = 18.5, 2.5 Hz, 1H, CH₂), 2.86 (dd, J = 18.5, 6.5 Hz, 1H, CH₂), 4.73 (br s, 1H, NH), 4.95 (br s, 1H, CH), 6.24 (dd, J = 5.5, 2.0 Hz, 1H, CH), 7.53 (dd, J = 5.5, 2.5 Hz, 1H, CH) ppm; ¹³C NMR (101 MHz, CDCl₃): 28.5 (CH₃), 42.6 (CH₂), 51.2 (CH), 80.4 (C), 135.4 (CH), 155.2 (CH), 162.3 (CO), 206.6 (CO) ppm; HRMS (ES⁺): m/z C₁₀H₁₅NO₃Na (MNa⁺) calcd. 220.0944; found 220.0945; [α]_D = −75.5 (c = 0.1, CHCl₃), {Lit.¹¹ [α]_D = −73 (c = 0.1, CHCl₃)}.

(1S,4S)-4-((tert-Butyldimethylsilyl)oxy)cyclopent-2-enol (4b)

Alcohol 4 (100 mg, 0.47 mmol, 1.0 equiv.) was added to a solution of triphenylphosphine (241 mg, 0.92 mmol, 2.0 equiv.) and benzoic acid (88 mg, 0.71 mmol, 1.5 equiv.) in dry THF (5 mL). The solution was cooled to 0 °C and DIAD (0.2 mL, 0.94 mmol, 2.0 equiv.) was added. Following this, the reaction was allowed to warm to room temperature and stirred for 16 h under an inert atmosphere. After this time, the solvent was removed under a flow of air and the residue was diluted with Et₂O (10 mL) and washed with NaHCO₃ (3 × 10 mL). The organic phase was dried over MgSO₄ and the solvent removed in vacuo. The intermediate was then diluted in methanol (5 mL) and K₂CO₃ (326 mg, 2.35 mmol, 5.0 equiv.) was added. The resulting suspension was stirred under an inert atmosphere for 4 h, after which the suspension was filtered and concentrated in vacuo. The resulting residue was dissolved in Et₂O (10 mL) and water (10 mL) and washed with water (3 × 10 mL) and brine (10 mL). The organic phase was dried over MgSO₄ and the solvent removed in vacuo. Purification by column chromatography (c-Hex/EtOAc; 3:1) afforded the desired product 4b (12 mg, 12%) with data as reported.^{23
¹}H NMR (400 MHz, CDCl₃): δ 0.06−0.10 (m, 6H, CH₃), 0.89 (s, 9H, CH₃), 1.96−2.10 (m, 2H, CH₂), 5.02 (s, 1H, CH), 5.06−5.12 (m, 1H, CH), 5.91−5.97 (m, 2H, CH) ppm; ¹³C NMR (101 MHz, CDCl₃): −4.5 (CH₃), 18.4 (C), 26.1 (CH₃), 44.7 (CH₂), 76.4 (CH), 76.7 (CH), 135.6 (CH), 138.6 (CH) ppm.

(1R,4S)-4-((tert-Butyldimethylsilyl)oxy)cyclopent-2-en-1-yl acetate (8)

DMAP (cat.) was added to a solution of alcohol 4 (785 mg, 3.66 mmol, 1.0 equiv.) in dry CH₂Cl₂ (30 mL). The solution was cooled to 0 °C and Et₃N (0.70 mL, 5.02 mmol, 1.3 equiv.) was added, followed by acetic anhydride (0.40 mL, 4.23 mmol, 1.2 equiv.). The cooling bath was removed, and the solution was stirred for 2.5 h. After this time, NH₄Cl (20 mL) was added to the solution and the resulting mixture was stirred for 10 min. The phases were separated, and the aqueous phase was extracted with CH₂Cl₂ (2 × 20 mL). The combined organic phase was washed with NaHCO₃ (40 mL) and dried over MgSO₄. Filtration and solvent removal in vacuo gave the desired product 8 (782 mg, 3.05 mmol, 83%) as a yellow liquid. The crude product (8), with data as reported,²⁶ was used without further purification. ¹H NMR (400 MHz, CDCl₃): δ 0.04–0.12 (m, 6H, CH₃), 0.90 (s, 9H, CH₃), 1.61 (dt, J = 14.0, 5.0 Hz, 1H, CH₂), 2.05 (s, 3H, CH₃), 2.81 (dt, J = 14.0, 7.5 Hz, 1H, CH₂), 4.68–4.76 (m, 1H, CH), 5.42–5.50 (m, 1H, CH), 5.89 (dt, J = 5.5, 1.5 Hz, 1H, CH), 5.97 (dt, J = 5.5, 1.5 Hz, 1H, CH) ppm; ¹³C NMR (101 MHz, CDCl₃): −4.54 (CH₃), −4.49 (CH₃), 18.3 (C), 21.3 (CH₃), 26.0 (CH₃), 41.3 (CH₂), 75.0 (CH), 77.1 (CH), 131.3 (CH), 139.1 (CH), 171.0 (CO) ppm.

(1R,4S)-4-Hydroxycyclopent-2-en-1-yl acetate (9)

A 1 M solution of TBAF in THF (2.8 mL, 2.80 mmol, 1.15 equiv.) was added to a solution of TBS ether 8 (637 mg, 2.48 mmol, 1.0 equiv.) in dry THF (35 mL). The solution was stirred at room temperature for 1 h. After this time, the reaction mixture was concentrated under a flow of air, and the resulting residue was purified by column chromatography (c-Hex/EtOAc; 1:1), affording the desired product 9 (308 mg, 87%) as a white solid, with data as reported.^{26
¹}H NMR (400 MHz, CDCl₃): δ 1.65 (dt, J = 14.5, 4.0 Hz, 1H, CH₂), 2.05 (s, 3H, CH₃), 2.81 (dt, J = 14.5, 7.5 Hz, 1H, CH₂), 4.69–4.75 (m, 1H, CH), 5.46–5.53 (m, 1H, CH), 5.98 (ddd, J = 5.5, 2.0, 1.0 Hz, 1H, CH), 6.08–6.15 (m, 1H, CH) ppm; ¹³C NMR (101 MHz, CDCl₃): 21.3 (CH₃), 40.6 (CH₂), 74.9 (CH), 77.2 (CH), 132.6 (CH), 138.7 (CH), 171.0 (CO) ppm.

Di-tert-butyl[(1S,4R)-4-acetoxycyclopent-2-en-1-yl]imidodicarboxylate (10)

Alcohol 9 (0.29 g, 2.04 mmol, 1.0 equiv.) was added to a solution of triphenylphosphine (1.59 g, 6.05 mmol, 3.0 equiv.) and di-tert-butyl-iminodicarboxylate (0.67 g, 3.07 mmol, 1.5 equiv.) in dry THF (30 mL). Diisopropyl azodicarboxylate (1.00 mL, 5.08 mmol, 2.5 equiv.) was added and the solution was stirred at room temperature for 18 h. After this time, the reaction mixture was concentrated and purified by column chromatography (c-Hex/EtOAc; 9:1), affording the desired product 10 (0.287 g, 41%) as a colourless oil. R_f = 0.4 (c-Hex/EtOAc; 9:1); IR (neat): ν_max = 2980, 2936, 1736, 1701, 1344, 1234, 1146, 1112 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 1.48 (s, 18 H, CH₃), 2.02 (s, 3H, CH₃), 2.19 (ddd, J = 14.5, 8.0, 2.0 Hz, 1H, CH₂), 2.35 (ddd, J = 14.5, 7.5, 5.5 Hz, 1H, CH₂), 5.41–5.51 (m, 1H, CH), 5.77–5.82 (m, 1H, CH), 5.89–5.96 (m, 1H, CH), 6.02 (dd, J = 5.5, 2.0 Hz, 1H, CH) ppm; ¹³C NMR (101 MHz, CDCl₃): 21.3 (CH₃), 28.1 (CH₃), 36.0 (CH₂), 61.4 (CH), 79.4 (CH), 82.7 (C), 130.5 (CH), 138.3 (CH), 152.8 (CO), 171.1 (CO) ppm; HRMS (ES⁺): m/z C₁₇H₂₇NO₆Na (MNa⁺) calcd. 364.1731; found 364.1732; [α]_D = +150.4 (c = 0.1, CHCl₃).

Di-tert-butyl[(1R,4R)-4-hydroxycyclopent-2-en-1-yl]imidodicarboxylate [(+)-6]

K₂CO₃ (172 mg, 1.24 mmol, 2.0 equiv.) was added to a solution of acetate 10 (210 mg, 0.62 mmol, 1.0 equiv.) in MeOH (5 mL). The solution was stirred for 2 h, after which NaHCO₃ (15 mL) was added. The phases were separated, and the aqueous phase was extracted with EtOAc (3 × 15 mL). The combined organic phases were dried over MgSO₄ and the solvent removed in vacuo. Purification by column chromatography (c-Hex/EtOAc; 3:1), afforded the desired product (+)-6 (134 mg, 71%) as a colourless waxy solid with data as described above for (−)-6. R_f = 0.2 (c-Hex/EtOAc; 3:1); [α]_D = +142.6 (c = 0.1, CHCl₃).

Di-tert-butyl[(1S)-4-oxocyclopent-2-en-1-yl]imidodicarboxylate [(+)-7]

Dess–Martin periodinane (561 mg, 1.32 mmol, 1.2 equiv.) was added to a solution of alcohol (+)-6 (328 mg, 1.10 mmol, 1.0 equiv.) in dry CH₂Cl₂ (30 mL) and the solution was stirred at room temperature for 2.5 h. Following this, the reaction mixture was filtered through Celite, concentrated in vacuo and the resulting residue was purified by column chromatography (c-Hex/EtOAc; 4:1), affording the desired product (+)-7 (251 mg, 77%) as a colourless solid with data as previously stated for (−)-7. [α]_D = +79.3 (c = 0.1, CHCl₃).

(R)-tert-Butyl (4-oxocyclopent-2-en-1-yl)carbamate [(+)-2]:

Trifluoroacetic acid (0.10 mL, 1.31 mmol, 1.9 equiv.) was added to a solution of cyclopentenone (+)-7 (206 mg, 0.69 mmol, 1.0 equiv.) in dry CH₂Cl₂ (10 mL), and the solution was stirred under an inert atmosphere for 2.5 h. After this time, the solution was diluted with CH₂Cl₂ (10 mL) and washed with NaHCO₃ (15 mL). The aqueous phase was extracted with CH₂Cl₂ (3 × 15 mL) and the combined organic phases were dried over MgSO₄ and the solvent removed in vacuo. Purification by column chromatography (c-Hex/EtOAc; 2:1) afforded the desired product (+)-2 (111 mg, 82%) with data as described above for (−)-2. [α]_D = +74.4 (c = 0.1, CHCl₃), {Lit.¹³ [α]_D = +66.8 (c = 1.0, CHCl₃)}.

Supplemental Material

sj-pdf-1-chl-10.1177_17475198211047780 – Supplemental material for An enantiodivergent synthesis of N-Boc-protected (R)- and (S)-4-amino cyclopent-2-en-1-one

Supplemental material, sj-pdf-1-chl-10.1177_17475198211047780 for An enantiodivergent synthesis of N-Boc-protected (R)- and (S)-4-amino cyclopent-2-en-1-one by Lorna Conway and Paul Evans in Journal of Chemical Research

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship and/or publication of this article: The Irish Research Council is acknowledged for the provision of a postgraduate scholarship (grant no. GOIPG/2017/1702).

ORCID iD

Paul Evans

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