5′-Noraristeromycin C-Nucleosides Based on Imidazo[1,2-a]pyrazine

Abstract

The preparation of two C-5′-nor-3-deazaaristeromycin dia­stereomeric analogues possessing a bridgehead nitrogen is described from (3aR,4R,6S,6aS)-2,2-dimethyl-6-vinyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ol that served as the cyclopentyl unit of the target carbocyclic nucleosides and as the scaffold upon which the compounds were built. The process evolved via a de novo approach for constructing the requisite fused imidazo unit between the aforementioned cyclopentyl ring and a readily available 2,3-dichloropyrazine. The syntheses were accomplished in 11 and 8 steps depending on the diastereomer sought.

Metabolic processes in microorganisms produce a number of unique nucleosides critical to their replication or survival.[1] Among these constituents are C-nucleosides and carbocyclic nucleosides.[2] Formycin (1; Figure [1]) represents the former category[3] with aristeromycin (2) and neplanocin A (3), and structural variations therefrom being members of the latter.[4] Because of their structural resemblance to adenosine, 1 and 2 have found their way onto the drug design and discovery palette.[5]

Combining the features of 1 and 2 in the same structure (as a carbocyclic C-nucleoside) is a nascent area of research with studies from our lab and others.[6] To continue developing this platform, we sought to build on our 5′-noraristeromycin (4) investigations[7] with the bridgehead nitrogen series 5, which can be correlated to the biological significance of 3-deaza-5′-noraristeromycin (6).[8] The synthetic steps to 5a and the diastereomeric 5b are reported here.

Construction of the substituted imidazo[1,2-a]pyrazine ring of 5 called for the preparation[9] of the hydroxyamine 6 (Scheme [1]) for subsequent reaction with 2,4-dichloropyrazine followed by development of the fused imidazole. Thus, the steps to 6 began with a vinyl 1,4-addition[10] to the known enone 7 [11] (Scheme [1]) to produce 8. Lithium aluminum hydride reduction of 8 to 9 was followed by a Mitsunobu inversion[12] to 10. Saponification of 10 to 11 and subsequent benzyl protection of the secondary alcohol provided 12 as the requisite precursor to 6. Compound 12 was moved forward by treatment with dimethyldioxirane (DMDO) to the epoxide 13, which became 6 upon ring opening with ammonium hydroxide.

Completion of the synthesis of 5a took place by, first, a heteroaromatic nucleophilic substitution by reaction of 6 with 2,4-dichloropyrazine to 14. Swern oxidation of 14 to 15 followed by imidazole formation created the bicyclic system 16 (structure assigned by X-ray crystallographic determination, see the experimental section) of 5a. Ammonolysis of 16 to 17 with subsequent debenzylation (to 18) and then removal of the 2′,3′-ketal protection center yielded 5a.

The preparation of 5b followed a similar pathway as that to 5a beginning with the silyl protected 19 (Scheme [2]). Each step in this route proceeded as expected.

In should be noted that consideration was given to synthesizing 5a from the silylated diastereomer of 19 (i.e., 26) (Scheme [3]). Oxidation of 26 to 27 occurred with no difficulties; however, upon treatment of 27 with ammonium hydroxide (as with 13 and 20) epoxide ring opening was accompanied with loss of the silyl protecting group to produce 28. As a consequence, this approach to 5a was abandoned.

In conclusion, a practical synthesis of a new series of carbocyclic C-nucleosides possessing a bridgehead nitrogen has been reported. These new entities unite the formycin and aristeromycin structural frameworks into a molecule that lacks the fourth ring nitrogen atom and, hence, represents the deazapurine series of targets.

¹H and ¹³C NMR spectra were recorded on a Bruker AV-400 or Bruker AC-250 spectrometer. ¹H chemical shifts are reported relative to CDCl_3­ at δ = 7.27 (or MeOD at δ = 3.51, or DMSO-d ₆ at δ = 2.51) and TMS as an internal standard. ¹³C chemical shifts are reported relative to CDCl₃/MeOD/DMSO-d ₆ . Standard abbreviations were used to indicate the spin multiplicities. The mass spectral data were obtained using a Waters Micromass Q-TOF Premier Mass Spectrometer. Reactions were monitored by TLC using 0.25 mm E. Merck silica gel 60-F254 precoated silica gel plates with visualization by irradiation with a Mineral light UVGL-25 lamp or exposure to I₂ vapor. Column chromatography was performed on Whatman silica gel (average particle size 5–25 mm, 60 Å) and elution with the indicated solvent system. Yields refer to chromatographically and spectroscopically (¹H and ¹³C NMR) homogeneous materials. The reactions were generally carried out in N₂ atmosphere under anhydrous conditions.

(3aS,6S,6aS)-2,2-Dimethyl-6-vinyldihydro-3aH-cyclopenta[d][1,3]dioxol-4(5H)-one (8)

Under N₂, to a suspension of CuBr·SMe₂ (133 mg, 5% mol) in THF (100 mL) was added a 1 M THF solution of vinylmagnesium bromide (15.6 mL, 15.6 mmol) at –78 °C dropwise. The mixture was stirred for 10 min and HMPA (5.5 mL, 31.2 mmol) was added followed by a solution of 7 [10] (2.00 g, 13.0 mmol) and TMSCl (3.33 mL, 26.0 mmol) in THF (20 mL), dropwise. After stirring the reaction at –78 °C for 3 h, the mixture was quenched by sat. aq NH₄Cl (20 mL). The aqueous phase was extracted with EtOAc (3 × 20 mL). The combined organic phases were washed with brine (20 mL) and dried (MgSO₄). Filtration and evaporation of the filtrate in vacuo followed by column chromatography (hexanes–EtOAc, 9:1) afforded 8 as a colorless liquid; yield: 1.80 g (77%).

¹H NMR (250 MHz, CDCl₃): δ = 5.88–5.74 (m, 1 H), 5.15–5.04 (m, 2 H), 4.62 (d, J = 5.2 Hz, 1 H), 4.18 (d, J = 5.2 Hz, 1 H), 3.12–3.06 (m, 1 H), 2.81 (dd, J = 18.1, 8.5 Hz, 1 H), 2.27 (d, J = 18.2 Hz, 1 H), 1.42 (s, 3 H), 1.33 (s, 3 H).

¹³C NMR (62.9 MHz, CDCl₃): δ = 213.1, 137.2, 116.4, 112.4, 81.4, 77.9, 39.8, 38.6, 26.9, 25.0.

(3aR,4R,6S,6aS)-2,2-Dimethyl-6-vinyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ol (9)

To a suspension of LiAlH₄ (95%, 1.18 g, 29.5 mmol) in THF (50 mL) was added dropwise a solution of 8 (2.69 g, 14.8 mmol) in THF (20 mL) at 0 °C. The reaction mixture was stirred at r.t. for 4 h and quenched with H₂O (1.2 mL), NaOH (15%, 1.2 mL), and H₂O (3.6 mL) sequentially. After filtration, the filtrate was evaporated in vacuo to give 9 as a colorless liquid; yield: 2.64 g (93%).

¹H NMR (250 MHz, CDCl₃): δ = 5.75–5.68 (m, 1 H), 5.12–5.04 (m, 2 H), 4.49–4.47 (m, 2 H), 4.11–4.06 (m, 1 H), 2.76–2.73 (m, 2 H), 2.45 (d, J = 8.1 Hz, 1 H), 1.97–1.83 (m, 2 H), 1.52 (s, 3 H), 1.36 (s, 3 H).

¹³C NMR (62.9 MHz, CDCl₃): δ = 138.2, 115.5, 111.8, 84.5, 79.2, 71.3, 44.5, 36.2, 26.3, 24.5.

(3aR,4S,6S,6aS)-2,2-Dimethyl-6-vinyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl 2-Chloroacetate (10)

To a solution of 9 (220 mg, 1.19 mmol) in THF (20 mL) was added chloroacetic acid (226 mg, 2.39 mmol), Ph₃P (626 mg, 2.39 mmol), and DIAD (0.47 mL, 2.39 mmol) at 0 °C under N₂. After 10 min, the reaction mixture was warmed to r.t. and stirred for 15 h. This mixture was washed with sat. aq NaHCO₃ (5 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried (Na₂SO₄), filtered, and the filtrate concentrated in vacuo. The residue was purified by column chromatography (hexanes–EtOAc, 9:1) to give 10 as a colorless liquid; yield: 250 mg (80%).

¹H NMR (400 MHz, CDCl₃): δ = 5.91 (ddd, J = 17.2, 10.3, 7.86 Hz, 1 H), 5.21–5.11 (m, 3 H), 4.65 (m, 1 H), 4.59 (dd, J = 6.2, 2.5 Hz, 1 H), 4.11 (d, J = 1.3 Hz, 2 H), 2.91 (m, 1 H), 2.53 (m, 1 H), 1.83 (dddd, J = 8.7, 4.7, 1.8, 0.9 Hz, 1 H), 1.55 (s, 3 H), 1.27 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 168.1, 140.3, 117.4, 113.2, 86.5, 86.3, 83.2, 50.0, 42.5, 35.5, 28.4, 26.0.

(3aR,4S,6S,6aS)-2,2-Dimethyl-6-vinyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ol (11)

LiOH·H₂O (2.43 g, 58.0 mmol) was added to a solution of 10 (3.00 g, 11.6 mmol) in THF–H₂O (100 mL, 1:1) at 0 °C and this mixture stirred for 3 h. The mixture was extracted with EtOAc (3 × 40 mL) and the combined organic layers were washed with H₂O (20 mL) and brine (20 mL), and dried (Na₂SO₄). The filtrate was evaporated in vacuo and the residue was purified by column chromatography (hexanes–EtOAc, 3:1) to give 11 as colorless liquid whose structure was confirmed by NMR analysis;[13] yield: 1.90 g (89%).

(3aR,4S,6S,6aS)-4-Benzyloxy-2,2-dimethyl-6-vinyltetrahydro-3aH-cyclopenta[d][1,3]dioxole (12)

To a suspension of powdered 60% NaH (412 mg, 10.7 mmol) in THF (50 mL) was added 11 (1.80 g, 9.77 mmol) dropwise at 0 °C. After stirring at this temperature for 30 min, BnBr (1.22 mL, 10.3 mmol) and NaI (20 mg) were added, and the reaction mixture allowed to slowly warm to r.t. After 24 h, the mixture was quenched with sat. aq NH₄Cl (15 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried (Na₂SO₄), filtered, and the filtrate evaporated in vacuo. The residue was purified by column chromatography (hexanes–EtOAc, 8:1) to afford 12 as a colorless oil; yield: 2.53 g (94%).

¹H NMR (600 MHz, CDCl₃): δ = 7.30 (m, 4 H), 7.23 (m, 1 H), 5.89 (ddd, J = 8.0, 10.2, 17.1 Hz, 1 H), 5.08 (m, 1 H), 4.99 (m, 1 H), 4.52 (m, 3 H), 4.41 (dd, J = 3.7, 6.6 Hz, 1 H), 3.93 (dt, J = 2.1, 5.7 Hz, 1 H), 2.67 (dq, J = 3.8, 7.3 Hz, 1 H), 2.21 (m, 1 H), 1.73 (m, 1 H), 1.45 (s, 3 H), 1.27 (s, 3 H).

¹³C NMR (150 MHz, CDCl₃): δ = 139.8, 138.4, 128.5, 127.68, 127.67, 115.1, 111.5, 85.4, 85.1, 84.2, 71.2, 48.7, 35.6, 27.1, 24.7.

HRMS: m/z calcd for C₁₇H₂₂O₃ [M]⁺: 274.1569; found: 274.1609.

(3aR,4S,6S,6aS)-4-Benzyloxy-2,2-dimethyl-6-(oxiran-2-yl)tetrahydro-3aH-cyclopenta[d][1,3]dioxole (13)

To a stirred solution of 12 (1.70 g, 6.20 mmol) in acetone (50 mL) at 0 °C was added dropwise a freshly prepared DMDO (0.5 M)[14] solution (40 mL) and the stirring was continued at r.t. overnight. The reaction mixture was concentrated in vacuo and the residue purified by column chromatography (hexanes–EtOAc, 6:1) to afford compound 13 as a colorless oil; yield: 1.65 g (92%).

¹H NMR (600 MHz, CDCl₃): δ = 7.29 (m, 4 H), 7.23 (m, 1 H), 4.64 (dd, J = 2.3, 6.3 Hz, 0.5 H), 4.52 (m, 3.5 H), 3.92 (dddd, J = 1.5, 4.1, 5.3, 11.6 Hz, 1 H), 3.02 (ddd, J = 2.7, 4.0, 7.4 Hz, 1 H), 2.69 (ddd, J = 3.9, 4.9, 8.8 Hz, 1 H), 2.48 (ddd, J = 2.7, 5.0, 11.4 Hz, 1 H), 2.15 (dddd, J = 5.6, 7.4, 13.1, 30.6 Hz, 1 H), 1.94 (m, 0.5 H), 1.89 (m, 1 H), 1.74 (td, J = 4.3, 13.8 Hz, 0.5 H), 1.41 and 1.40 (s, 3 H), 1.26 (s, 3 H).

2-Amino-1-[(3aS,4S,6S,6aR)-6-benzyloxy-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]ethanol (6)

A solution of 13 (1.60 g, 5.51 mmol) in NH₄OH (25 mL) and EtOH (25 mL) was heated at 60 °C in a Parr stainless steel sealed reaction vessel overnight. The reaction mixture was concentrated in vacuo to afford 6 as a colorless oil; yield: 1.53 g (90%).

¹H NMR (400 MHz, CDCl₃): δ = 7.34 (m, 4 H), 7.28 (m, 1 H), 4.82 (br, 3 H), 4.71 (dd, J = 3.6, 6.9 Hz, 0.5 H), 4.50 (m, 3 H), 4.43 (dd, J = 5.0, 7.2 Hz, 0.5 H), 3.92 (m, 1 H), 3.52 (m, 1 H), 2.75 (m, 1 H), 2.60 (m, 1 H), 2.23 (td, J = 6.5, 13.0 Hz, 0.5 H), 2.10 (td, J = 7.7, 14.2 Hz, 0.5 H), 2.05 (m, 1 H), 1.75 (m, 1 H), 1.44 and 1.43 (s, 3 H), 1.293 and 1.292 (s, 3 H).

HRMS: m/z calcd for C₁₇H₂₆NO₄ [M + H]⁺: 308.1862; found: 308.1884.

1-[(3aS,4S,6S,6aR)-6-Benzyloxy-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-2-[(3-chloropyrazin-2-yl)amino]ethanol (14)

A solution of 2,3-dichloropyrazine (1.38 g, 9.27 mmol), Et₃N (1.74 mL, 12.4 mmol), and 6 (1.50 g, 4.88 mmol) in anhydrous 1,4-dioxane (12 mL) was heated at 100 °C for 3 days under N₂. The reaction mixture was concentrated in vacuo and CH₂Cl₂ (100 mL) was added to the residue. The resultant organic solution was washed with H₂O (20 mL) and brine (20 mL), and dried (Na₂SO₄). Concentration in vacuo and purification of the residue by column chromatography (hexanes–EtOAc­, 2:1) afforded 14 as a light yellow oil; yield: 1.9 g (93%).

¹H NMR (400 MHz, CDCl₃): δ = 7.84 and 7.83 (d, J = 2.8 Hz, 1 H), 7.50 (t, J = 2.7 Hz, 1 H), 7.29 (m, 4 H), 7.24 (m, 1 H), 5.82 (m, 1 H), 4.88 (dd, J = 1.7, 6.4 Hz, 0.5 H), 4.58 (m, 2.5 H), 4.52 (dd, J = 2.6, 11.7 Hz, 1 H), 3.95 (m, 1 H), 3.80 (m, 2 H), 3.44 (m, 0.5 H), 3.34 (ddd, J = 4.7, 7.2, 13.7 Hz, 0.5 H), 2.25 (m, 2 H), 1.83 (m, 0.5 H), 1.72 (m, 0.5 H), 1.46 and 1.44 (s, 3 H), 1.30 and 1.29 (s, 3 H).

HRMS: m/z calcd for C₂₁H₂₇ClN₃O₄ [M + H]⁺: 420.1690; found: 420.1690.

1-[(3aS,4R,6S,6aR)-6-Benzyloxy-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-2-[(3-chloropyrazin-2-yl)amino]ethanone (15)

To a solution of TFAA (0.79 mL, 5.7 mmol) in CH₂Cl₂ (20 mL) was added anhydrous DMSO (0.54 mL, 7.6 mmol) at –78 °C. After 20 min, 14 (800 mg, 1.90 mmol) in CH₂Cl₂ (5 mL) was added dropwise. The resulting mixture was stirred at this temperature for 30 min and warmed to r.t. To this, Et₃N (2 mL) was added. After 2 h, the reaction mixture was diluted with CH₂Cl₂ (15 mL) and the organic layer washed with aq 10% NaHCO₃ (5 mL), H₂O (5 mL), and brine (5 mL). After drying (Na₂SO₄) the organic phase and evaporation in vacuo, the resulting yellow residue was purified by column chromatography (hexanes–EtOAc, 5:1) to afford 15 as a light yellow oil; yield: 630 mg (79%).

¹H NMR (600 MHz, CDCl₃): δ = 7.84 (d, J = 2.8 Hz, 1 H), 7.56 (d, J = 2.7 Hz, 1 H), 7.21 (m, 2 H), 7.17 (m, 3 H), 5.97 (t, J = 4.4 Hz, 1 H), 5.19 (dd, J = 1.8, 6.0 Hz, 1 H), 4.57 (d, J = 6.1 Hz, 1 H), 4.50 (d, J = 11.9 Hz, 1 H), 4.42 (m, 1 H), 4.39 (m, 1 H), 4.26 (dd, J = 4.6, 19.5 Hz, 1 H), 3.93 (m, 1 H), 3.02 (ddd, J = 1.8, 4.3, 6.8 Hz, 1 H), 2.31 (m, 2 H), 1.46 (s, 3 H), 1.32 (s, 3 H).

¹³C NMR (150 MHz, CDCl₃): δ = 204.1, 150.2, 140.3, 137.6, 135.0, 131.2, 128.3, 127.6, 127.3, 111.1, 83.2, 82.7, 80.2, 70.8, 54.6, 49.4, 32.0, 26.5, 24.2.

HRMS: m/z calcd for C₂₁H₂₅ClN₃O₄ [M + H]⁺: 418.1534; found: 418.1532.

3-[(3aS,4S,6S,6aR)-6-Benzyloxy-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-8-chloroimidazo[1,2-a]pyrazine (16)

To a solution of 15 (520 mg, 1.24 mmol) in toluene (10 mL) at 0 °C was added pyridine (1.21 mL, 14.9 mmol) followed by TFA (0.67 mL, 8.7 mmol). After 30 min, TFAA (1.21 mL, 8.71 mmol) was added dropwise, and the resulting mixture was allowed to warm to r.t. and further stirred for 24 h. The mixture was diluted with toluene (20 mL), washed with aq 10% NaHCO₃ (8 mL), H₂O (10 mL), and brine (8 mL). After drying (Na₂SO₄), the solution was concentrated in vacuo and the residue purified by column chromatography (hexanes–EtOAc, 2:1) to afford 16 as a light yellow solid; yield: 210 mg (42%).

¹H NMR (600 MHz, CDCl₃): δ = 8.20 (d, J = 4.6 Hz, 1 H), 7.68 (d, J = 4.6 Hz, 1 H), 7.64 (d, J = 0.5 Hz, 1 H), 7.33 (m, 4 H), 7.28 (m, 1 H), 4.70 (m, 2 H), 4.58 (m, 2 H), 4.19 (dt, J = 2.6, 6.7 Hz, 1 H), 3.44 (ddd, J = 4.8, 7.8, 9.0 Hz, 1 H), 2.71 (m, 1 H), 2.33 (ddd, J = 7.0, 9.2, 13.3 Hz, 1 H), 1.61 (s, 3 H), 1.34 (s, 3 H).

¹³C NMR (150 MHz, CDCl₃): δ = 143.7, 138.2, 137.7, 133.1, 129.2, 128.5, 127.9, 127.8, 127.7, 117.3, 113.1, 85.4, 84.1, 83.3, 71.8, 40.6, 34.4, 27.2, 24.7.

HRMS: m/z calcd for C₂₁H₂₃ClN₃O₃ [M + H]⁺: 400.1428; found: 400.1425.

X-ray Crystallographic Analysis

The structure of 16 was further confirmed by an X-ray crystal structure analysis.[15]

3-[(3aS,4S,6S,6aR)-6-Benzyloxy-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]imidazo[1,2-a]pyrazin-8-amine (17)

A solution of 16 (200 mg, 0.50 mmol) in MeOH (5 mL) saturated with NH₃ was heated at 110 °C for 2 days in a Parr stainless steel sealed reaction vessel. The solvent was evaporated in vacuo and the residue was purified by column chromatography with EtOAc to give 17 as a light yellow solid; yield: 150 mg (79%).

¹H NMR (600 MHz, CDCl₃): δ = 7.61 (d, J = 4.8 Hz, 1 H), 7.37 (s, 1 H), 7.35 (m, 4 H), 7.32 (d, J = 4.8 Hz, 1 H), 7.30 (m, 1 H), 5.80 (s, 2 H), 4.68 (m, 2 H), 4.57 (m, 2 H), 4.16 (dt, J = 2.7, 6.6 Hz, 1 H), 3.41 (dt, J = 4.5, 8.2 Hz, 1 H), 2.70 (m, 1 H), 2.28 (ddd, J = 7.0, 9.0, 13.4 Hz, 1 H), 1.59 (s, 3 H), 1.33 (s, 3 H).

¹³C NMR (150 MHz, CDCl₃): δ = 150.0, 137.8, 133.1, 129.6, 128.5, 128.2, 128.1, 127.8, 127.7, 112.8, 109.5, 85.4, 84.3, 83.4, 71.7, 40.2, 34.4, 27.1, 24.7.

HRMS: m/z calcd for C₂₁H₂₅N₄O₃ [M + H]⁺: 381.1927; found: 381.1942.

(3aR,4S,6S,6aS)-6-(8-Aminoimidazo[1,2-a]pyrazin-3-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ol (18)

A solution of 17 (130 mg, 0.34 mmol) and 20 mol% Pd(OH)₂/C (150 mg) in cyclohexene (2 mL) and EtOH (3 mL) was heated at reflux for 48 h and then filtered through Celite. The filtrate was evaporated to dryness in vacuo and the residue purified by column chromatography (CH₂Cl₂–MeOH, 9:1) to give 18 as a light yellow solid; yield: 70 mg (71%).

¹H NMR (600 MHz, CD₃OD): δ = 7.71 (d, J = 4.8 Hz, 1 H), 7.45 (d, J = 0.5 Hz, 1 H), 7.26 (d, J = 4.8 Hz, 1 H), 4.68 (dd, J = 4.0, 6.6 Hz, 1 H), 4.54 (dd, J = 2.6, 6.6 Hz, 1 H), 4.30 (dt, J = 2.6, 5.9 Hz, 1 H), 3.47 (dt, J = 4.0, 7.7 Hz, 1 H), 2.61 (ddd, J = 5.7, 7.5, 13.3 Hz, 1 H), 2.11 (ddd, J = 6.3, 7.7, 13.6 Hz, 1 H), 1.54 (s, 3 H), 1.32 (s, 3 H).

¹³C NMR (150 MHz, CD₃OD): δ = 151.6, 134.0, 130.1, 130.4, 128.8, 113.7, 110.4, 88.7, 85.9, 77.7, 41.7, 37.5, 27.5, 25.1.

HRMS: m/z calcd for C₁₄H₁₉N₄O₃ [M + H]⁺: 291.1457; found: 291.1444.

(1S,2R,3S,4S)-4-(8-Aminoimidazo[1,2-a]pyrazin-3-yl)cyclopentane-1,2,3-triol (5a)

To a solution of 18 (50 mg, 0.17 mmol) in MeOH (3 mL) was added aq 2 M HCl (5 mL) and the reaction mixture stirred for 4 h. The solution was then neutralized with IRA-67 and the filtrate was evaporated in vacuo to give 5a as a dark white solid; yield: 35 mg (81%).

¹H NMR (600 MHz, CD₃OD): δ = 7.85 (d, J = 4.6 Hz, 1 H), 7.48 (s, 1 H), 7.22 (br, 1 H), 4.28 (dd, J = 8.1, 4.8 Hz, 1 H), 4.15 (ddd, J = 7.2, 4.5, 3.0 Hz, 1 H), 3.89 (dd, J = 4.7, 3.0 Hz, 1 H), 3.48 (dt, J = 11.0, 5.5 Hz, 1 H), 2.71 (ddd, J = 13.8, 7.0, 6.9 Hz, 1 H), 1.74 (ddd, J = 13.6, 8.9, 4.6 Hz, 1 H).

¹³C NMR (150 MHz, CD₃OD): δ = 151.5, 132.2, 130.0, 128.1, 111.0, 79.6, 78.1, 76.5, 50.0, 39.2, 36.3.

HRMS: m/z calcd for C₁₁H₁₅N₄O₃ [M + H]⁺: 251.1144; found: 251.1141.

tert-Butyl{[(3aS,4R,6S,6aS)-2,2-dimethyl-6-vinyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]oxy}dimethylsilane (19)

Under N₂, 9 (1.1 g, 5.97 mmol) in anhydrous CH₂Cl₂ (80 mL) was treated with 2,6-lutidine (2.09 mL, 6.44 mmol) and TBSOTf (1.44 mL, 6.28 mmol) at –78 °C. The resultant mixture was stirred at –78 °C for 2 h and poured into H₂O (50 mL), extracted with CH₂Cl₂ (3 × 50 mL), and the combined extracts dried (MgSO₄). Filtration, evaporation of the filtrate, and column chromatography of the residue (hexanes–EtOAc, 20:1) afforded 19 as a colorless liquid; yield: 1.58 g (89%). The ¹H and ¹³C NMR spectral data agreed with the literature.[10]

tert-Butyl{[(3aS,4R,6S,6aS)-2,2-dimethyl-6-[(S)-oxiran-2-yl]tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]oxy}dimethylsilane (20)

To a solution of 19 (1.0 g, 3.4 mmol) in acetone (34 mL) at 0 °C was added dropwise a freshly prepared DMDO (0.5 M)[14] solution (30 mL) and the solution warmed to r.t. and stirred at this temperature overnight. The reaction mixture was concentrated in vacuo and purified by column chromatography (hexanes–EtOAc, 6:1) to afford compound 20 as a colorless oil; yield: 900 mg (85%).

¹H NMR (400 MHz, CDCl₃): δ = 4.43 (dd, J = 2.0, 6.0 Hz, 0.53 H), 4.36 (m, 1 H), 4.24 (dd, J = 2.0, 6.1 Hz, 0.47 H), 4.12 (m, 1 H), 2.89 (m, 0.53 H), 2.80 (m, 0.47 H), 2.73 (m, 1 H), 2.58 (dd, J = 2.7, 4.6 Hz, 0.47 H), 2.51 (dd, J = 2.8, 4.7 Hz, 0.53 H), 2.19 (m, 1 H), 2.07 (m, 0.47 H), 1.90 (m, 0.53 H), 1.67 (m, 0.47 H), 1.55 (m, 0.53 H), 1.46 (s, 1.59 H), 1.45 (s, 1.41 H), 1.30 (s, 1.59 H), 1.28 (s, 1.41 H), 0.89 (s, 4.23 H), 0.88 (s, 4.77 H), 0.08 (s, 1.41 H), 0.07 (s, 1.41 H), 0.07 (s, 1.59 H), 0.06 (s, 1.59 H).

2-Amino-1-{(3aS,4S,6R,6aS)-6-[(tert-butyldimethylsilyl)oxy]-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}ethanol (21)

A solution of 20 (1.40 g, 4.45 mmol) in NH₄OH (25 mL) and EtOH (25 mL) was heated at 60 °C in a Parr stainless steel sealed reaction vessel overnight. The reaction mixture was concentrated in vacuo to afford 21 as a colorless oil; yield: 1.35 g (91%).

¹H NMR (400 MHz, CD₃OD): δ = 4.59 (dd, J = 2.3, 6.2 Hz, 0.48 H), 4.38 (m, 1.52 H), 4.27 (m, 1 H), 3.46–3.36 (m, 1 H), 2.70 (m, 1 H), 2.59 (m, 1 H), 2.05 (m, 1 H), 1.94 (m, 1 H), 1.81 (m, 0.52 H), 1.68 (m, 0.48 H), 1.46 (s, 3 H), 1.31 (s, 3 H), 0.92 (s, 9 H), 0.10 (s, 6 H).

HRMS: m/z calcd for C₁₆H₃₄NO₄Si [M + H]⁺: 332.2257; found: 332.2291.

(S)-1-{(3aS,4S,6R,6aS)-6-[(tert-Butyldimethylsilyl)oxy]-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}-2-[(3-chloropyrazin-2-yl)amino]ethanol (22)

A solution of 2,3-dichloropyrazine (0.94 g, 6.3 mmol), Et₃N (1.19 mL, 8.45 mmol), and 21 (1.4 g, 4.22 mmol) in anhydrous 1,4-dioxane (10 mL) was heated at 100 °C for 3 days under N₂. The reaction mixture was concentrated in vacuo and CH₂Cl₂ (100 mL) was added to the residue. This organic solution was washed with H₂O (15 mL) and brine (15 mL), and dried (Na₂SO₄). Following concentration of the organic phase in vacuo and purification of the residue by column chromatography (hexanes–EtOAc, 4:1), 22 was obtained as a light yellow oil; yield: 1.0 g (54%).

¹H NMR (400 MHz, CDCl₃): δ = 7.85 (d, J = 2.8 Hz, 1 H), 7.56 (d, J = 2.8 Hz, 0.63 H), 7.55 (d, J = 2.8 Hz, 0.37 H), 5.76 (m, 1 H), 4.60 (m, 0.63 H), 4.37 (m, 1.37 H), 4.18 (m, 1 H), 3.96 (m, 0.37 H), 3.86 (m, 0.63 H), 3.71 (m, 2 H), 3.48 (m, 1 H), 2.25 (m, 1 H), 1.95 (m, 1 H), 1.76 (m, 0.37 H), 1.65 (m, 0.63 H), 1.49 (s, 1.1 H), 1.48 (s, 1.9 H), 1.30 (s, 1.1 H), 1.29 (s, 1.9 H), 0.87 (s, 9 H), 0.06 (s, 3 H), 0.05 (s, 3 H).

HRMS: m/z calcd for C₂₀H₃₅ClN₃O₄Si [M + H]⁺: 444.2085; found: 444.2089.

1-{(3aS,4R,6R,6aS)-6-[(tert-Butyldimethylsilyl)oxy]-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}-2-[(3-chloropyrazin-2-yl)amino]ethanone (23)

To a solution of TFAA (0.19 mL, 1.3 mmol) in CH₂Cl₂ (10 mL) was added anhydrous DMSO (0.13 mL, 1.8 mmol) at –78 °C. After 20 min, 22 (400 mg, 0.9 mmol) in CH₂Cl₂ (1 mL) was added dropwise. The resulting mixture was stirred at this temperature for 30 min and then warmed to r.t. To this, Et₃N (1 mL) was added. After 2 h, the reaction mixture was diluted with CH₂Cl₂ (15 mL) and washed with aq 10% NaHCO₃ (5 mL), H₂O (5 mL), and brine (5 mL). After drying (Na₂SO₄) and evaporation of the CH₂Cl₂, the resulting yellow residue was purified by column chromatography (hexanes–EtOAc, 9:1) to afford 23 as a light yellow oil; yield: 250 mg (63%).

¹H NMR (400 MHz, CDCl₃): δ = 7.90 (d, J = 2.8 Hz, 1 H), 7.61 (d, J = 2.7 Hz, 1 H), 5.91 (t, J = 4.7 Hz, 1 H), 4.68 (dd, J = 1.8, 5.8 Hz, 1 H), 4.43 (m, 1 H), 4.37 (m, 2 H), 4.12 (m, 1 H), 3.12 (m, 1 H), 2.16 (m, 1 H), 1.96 (m, 1 H), 1.49 (s, 3 H), 1.31 (s, 3 H), 0.89 (s, 9 H), 0.08 (s, 3 H), 0.07 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 206.5, 150.2, 140.3, 135.0, 131.6, 112.2, 80.5, 80.3, 72.4, 52.0, 50.1, 33.8, 26.5, 26.0, 24.8, 18.4, –4.5, –4.8.

HRMS: m/z calcd for C₂₀H₃₃ClN₃O₄Si [M + H]⁺: 442.1929; found: 442.1931.

3-{(3aS,4S,6R,6aS)-6-[(tert-Butyldimethylsilyl)oxy]-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}-8-chloroimidazo[1,2-a]pyrazine (24)

To a solution of 23 (200 mg, 0.45 mmol) in toluene (5 mL) at 0 °C was added pyridine (0.44 mL, 5.4 mmol) followed by TFA (0.24 mL, 3.2 mmol). After 30 min, TFAA (0.44 mL, 3.2 mmol) was added dropwise, and the resulting mixture allowed to warm to r.t., and then stirred at this temperature for 24 h. This mixture was diluted with toluene (15 mL), washed with aq 10% NaHCO₃ (5 mL), H₂O (5 mL), and brine (5 mL). After drying (Na₂SO₄) the organic phase, the solution was concentrated in vacuo and the residue purified by column chromatography (hexanes–EtOAc, 3:1) to give 24 as a light yellow solid; yield: 100 mg (52%).

¹H NMR (400 MHz, CDCl₃): δ = 8.20 (d, J = 4.6 Hz, 1 H), 7.74 (d, J = 4.6 Hz, 1 H), 7.55 (s, 1 H), 4.53 (dd, J = 4.6, 6.7 Hz, 1 H), 4.44 (dd, J = 3.6, 6.7 Hz, 1 H), 4.33 (m, 1 H), 3.60 (dt, J = 3.6, 7.4 Hz, 1 H), 2.45 (m, 1 H), 2.19 (m, 1 H), 1.61 (s, 3 H), 1.34 (s, 3 H), 0.94 (s, 9 H), 0.14 (s, 3 H), 0.13 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 143.8, 138.3, 131.9, 129.4, 128.0, 117.2, 113.9, 83.4, 81.2, 71.8, 38.6, 36.0, 26.5, 26.0, 25.1, 18.4, –4.4, –5.0.

HRMS: m/z calcd for C₂₀H₃₁ClN₃O₃Si [M + H]⁺: 424.1823; found: 424.1848.

3-{(3aS,4S,6R,6aS)-6-[(tert-Butyldimethylsilyl)oxy]-2,2-dimethyl­tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}imidazo[1,2-a]pyrazin-8-amine (25)

A solution of 24 (90 mg, 0.21 mmol) in propan-2-ol (5 mL) saturated with NH₃ was heated at 110 °C for 2 days in a Parr stainless steel sealed reaction vessel. The solvent was evaporated in vacuo and the residue was purified by column chromatography with EtOAc to give 25 as a light yellow solid; yield: 70 mg (82%).

¹H NMR (400 MHz, CDCl₃): δ = 7.55 (d, J = 4.8 Hz, 1 H), 7.33 (d, J = 4.8 Hz, 1 H), 7.26 (d, J = 0.8 Hz, 1 H), 6.06 (br, 2 H), 4.49 (m, 2 H), 4.33 (m, 1 H), 3.47 (m, 1 H), 2.43 (dt, J = 7.6, 12.8 Hz, 1 H), 2.14 (dt, J = 5.3, 12.7 Hz, 1 H), 1.60 (s, 3 H), 1.34 (s, 3 H), 0.93 (s, 9 H), 0.14 (s, 3 H), 0.12 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 150.3, 133.4, 128.7, 128.4, 128.3, 113.0, 109.3, 83.4, 81.0, 72.5, 38.2, 35.5, 26.6, 26.2, 25.1, 18.6, –4.2, –4.7.

HRMS: m/z calcd for C₂₀H₃₃N₄O₃Si [M + H]⁺: 405.2322; found: 405.2329.

(1R,2R,3S,4S)-4-(8-Aminoimidazo[1,2-a]pyrazin-3-yl)cyclopentane-1,2,3-triol (5b)

To a solution of 25 (60 mg, 0.15 mmol) in MeOH (3 mL) was added aq 2 M HCl (5 mL) and the reaction mixture stirred at r.t. for 4 h. The solution was then neutralized with IRA-67 and the filtrate was evaporated in vacuo to give 5b as a dark white solid; yield: 30 mg (80%).

¹H NMR (400 MHz, DMSO): δ = 7.65 (d, J = 4.8 Hz, 1 H), 7.36 (d, J = 0.6 Hz, 1 H), 7.18 (d, J = 4.7 Hz, 1 H), 6.74 (s, 2 H), 4.86 (d, J = 7.3 Hz, 1 H), 4.67 (d, J = 4.4 Hz, 1 H), 4.59 (d, J = 6.0 Hz, 1 H), 4.10 (m, 1 H), 3.89 (m, 1 H), 3.79 (m, 1 H), 3.48 (m, 1 H), 2.1 (m, 1 H), 1.9 (m, 1 H).

¹³C NMR (100 MHz, DMSO): δ = 150.4, 132.4, 130.0, 128.0, 127.8, 108.7, 76.5, 73.4, 70.0, 38.3, 35.0.

HRMS: m/z calcd for C₁₁H₁₅N₄O₃ [M + H]⁺: 251.1144; found: 251.1131.

tert-Butyl{[(3aS,4S,6S,6aS)-2,2-dimethyl-6-vinyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]oxy}dimethylsilane (26)

The residue containing 11 (confirmed by ¹H and ¹³C NMR analysis) arising via the same procedure described previously herein for 11 from 10 (250 mg, 0.959 mmol) was dissolved in MeCN (10 mL). TBDMSCl (173 mg, 1.15 mmol), imidazole (98 mg, 1.44 mmol), and DMAP (141 mg, 1.15 mmol) were then added at r.t. After 15 h, the solution was diluted with EtOAc and quenched with aq 10% NaHCO₃. The organic layer was dried (Na₂SO₄), filtered, and concentrated in vacuo. The residue was purified by column chromatography (hexanes–EtOAc, 15:1) to afford 26 as a light yellow oil; yield: 250 mg (87%).

¹H NMR (400 MHz, CDCl₃): δ = 5.94 (ddd, J = 17.2, 10.2, 8.6 Hz, 1 H), 5.03 (ddd, J = 17.2, 1.8, 1.2 Hz, 1 H), 4.94 (ddd, J = 10.2, 1.8, 1.0 Hz, 1 H), 4.44 (dd, J = 6.1, 2.4 Hz, 1 H), 4.37 (m, 1 H), 4.16 (ddd, J = 5.2, 3.8, 1.5 Hz, 1 H), 2.69 (m, 1 H), 2.19 (ddd, J = 12.9, 7.4, 5.2 Hz, 1 H), 1.56 (m, 1 H), 1.43 (s, 3 H), 1.27 (s, 3 H), 0.88 (s, 9 H), 0.08 (s, 3 H), 0.06 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 140.9, 114.5, 110.7, 88.0, 85.7, 78.2, 49.6, 38.6, 27.0, 25.9, 24.6, 18.1, –4.67, –4.72.

tert-Butyl{[(3aS,4S,6S,6aS)-2,2-dimethyl-6-(oxiran-2-yl)tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]oxy}dimethylsilane (27)

To a stirred solution of 26 (250 mg, 0.838 mmol) in acetone (5 mL) at 0 °C was added dropwise a freshly prepared DMDO (0.5 M)[14] solution (10 mL) and the stirring was continued at r.t. overnight. The reaction mixture was concentrated in vacuo and the residue purified by column chromatography (hexanes–EtOAc, 6:1) to give compound 27 as a colorless oil; yield: 230 mg (87%).

¹H NMR (400 MHz, CDCl₃): δ = 4.78 (d, J = 5.6 Hz, 0.56 H), 4.56 (d, J = 5.6 Hz, 0.44 H), 4.44 (d, J = 5.3 Hz, 0.56 H), 4.39 (d, J = 5.4 Hz, 0.44 H), 4.20 (m, 1 H), 3.16 (m, 0.56 H), 3.07 (m, 0.44 H), 2.68 (m, 1 H), 2.54 (m, 1 H), 2.21 (m, 1 H), 1.95 (m, 0.44 H), 1.79 (m, 1 H), 1.61 (m, 0.56 H), 1.44 (s, 1.32 H), 1.43 (s, 1.68 H), 1.31 (s, 1.32 H), 1.30 (s, 1.68 H), 0.89 (s, 3.96 H), 0.88 (s, 5.04 H), 0.11 (s, 3 H), 0.10 (s, 1.32 H), 0.09 (s, 1.68 H).

(3aR,4S,6S,6aS)-6-(2-Amino-1-hydroxyethyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ol (28)

A solution of 27 (220 mg, 0.70 mmol) in NH₄OH (5 mL) and EtOH (5 mL) was heated at 60 °C in a Parr stainless steel sealed reaction vessel overnight. The reaction mixture was concentrated in vacuo to afford 28 as a colorless oil; yield: 135 mg (89%).

¹H NMR (600 MHz, CD₃OD): δ = 4.87 (br, 4 H), 4.72 (dd, J = 2.5, 6.4 Hz, 0.57 H), 4.52 (dd, J = 3.3, 6.5 Hz, 0.43 H), 4.37 (dd, J = 1.6, 6.5 Hz, 1 H), 4.08 (dtd, J = 2.1, 5.6, 13.0 Hz, 1 H), 3.60 (m, 1 H), 2.78 (dd, J = 3.6, 13.1 Hz, 0.57 H), 2.75 (dd, J = 3.5, 13.2 Hz, 0.43 H), 2.67 (dd, J = 8.2, 13.1 Hz, 0.57 H), 2.61 (dd, J = 8.4, 13.1 Hz, 0.43 H), 2.20 (dt, J = 7.1, 13.5 Hz, 1 H), 2.11 (m, 1 H), 1.68 (m, 0.43 H), 1.60 (td, J = 5.2, 13.1 Hz, 0.57 H), 1.44 and 1.43 (s, 3 H), 1.31 and 1.30 (s, 3 H).

HRMS: m/z calcd for C₂₀H₂₀NO₄ [M + H]⁺: 218.1392; found: 218.1427.

Acknowledgment

We are grateful to the Molette Fund and Auburn University for support of this research. We also appreciate the assistance of Dr. John Gorden at Auburn University for providing the X-ray crystal structure analysis for 16.

• References


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  CrossrefSearch in Google Scholar
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  Thieme ConnectSearch in Google Scholar
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• 8 Siddiqi SM, Chen X, Rao J, Schneller SW, Ikeda S, Snoeck R, Andrei G, Balzarini J, De Clercq E. J. Med. Chem. 1995; 38: 1035
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  CrossrefSearch in Google Scholar
• 10 Li W, Ye W, Schneller SW. Tetrahedron 2012; 68: 65
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  CrossrefSearch in Google Scholar
• 12 Saïah M, Bessodes M, Antonakis K. Tetrahedron Lett. 1992; 33: 4317
  CrossrefSearch in Google Scholar
• 13 For the ¹H NMR for the enantiomer of 11, see: Marschner C, Penn G, Griengl H. Tetrahedron 1993; 49: 5067
  CrossrefSearch in Google Scholar
• 14 Murray RW, Singh M. Org. Synth. 1997; 74: 91
  CrossrefSearch in Google Scholar
• 15 Crystallographic data for 16 have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication number CCDC 1005186. Copies of the data can be obtained, free of charge, on request to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: +44 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk.

• References


See, for example:
• 1a Goodman HM, Abelson J, Landy A, Brenner S, Smith JD. Nature 1968; 217: 1019
  CrossrefSearch in Google Scholar
• 1b Jackson KE, Pogula PK, Patterson SE. Heterocycl. Commun. 2013; 19: 375
  Search in Google Scholar
• 2a Stambasky J, Hocek M, Kocovsky P. Chem. Rev. 2009; 109: 6729
  CrossrefSearch in Google Scholar
• 2b Jenkins GN, Turner NJ. Chem. Soc. Rev. 1995; 24: 169
  CrossrefSearch in Google Scholar
• 3a Bzowska A In Modified Nucleosides . Herdewijn P. Wiley-VCH; Weinheim: 2008: 473
  CrossrefSearch in Google Scholar
• 3b Simons C. Nucleoside Mimetics: Their Structure and Biological Properties. Gordon and Breach; Amsterdam: 2000: 117
  Search in Google Scholar
• 4a Simons C. Nucleoside Mimetics: Their Structure and Biological Properties. Gordon and Breach; Amsterdam: 2000: 137
  Search in Google Scholar
• 4b Crimmins MT. Tetrahedron 1998; 54: 9229
  CrossrefSearch in Google Scholar
• 5a Mieczkowski A, Agrofoglio LA In Modified Nucleosides . Herdewijn P. Wiley-VCH; Weinheim: 2008: 393
  CrossrefSearch in Google Scholar
• 5b Tosh DK, Kim HO, Pal S, Lee JA, Jeong LS In Modified Nucleosides . Herdewijn P. Wiley-VCH; Weinheim: 2008: 525
  CrossrefSearch in Google Scholar
• 6 For a leading reference, see: Zhang Y, Ye W, Wang H, Schneller SW. Synthesis 2012; 44: 723
  Thieme ConnectSearch in Google Scholar
• 7 For a leading reference, see: Chong L, Chen Q, Yang M, Schneller SW. Bioorg. Med. Chem. 2013; 21: 359
  CrossrefSearch in Google Scholar
• 8 Siddiqi SM, Chen X, Rao J, Schneller SW, Ikeda S, Snoeck R, Andrei G, Balzarini J, De Clercq E. J. Med. Chem. 1995; 38: 1035
  CrossrefSearch in Google Scholar
• 9 MacCoss M, Meurer LC, Hoogsteen K, Springer JP, Koo G, Peterson LB, Tolman RL. J. Heterocycl. Chem. 1993; 30: 1213
  CrossrefSearch in Google Scholar
• 10 Li W, Ye W, Schneller SW. Tetrahedron 2012; 68: 65
  CrossrefSearch in Google Scholar
• 11 Smith AB. III, Han Q, Breslin PA. S, Beauchamp GK. Org. Lett. 2005; 7: 5075
  CrossrefSearch in Google Scholar
• 12 Saïah M, Bessodes M, Antonakis K. Tetrahedron Lett. 1992; 33: 4317
  CrossrefSearch in Google Scholar
• 13 For the ¹H NMR for the enantiomer of 11, see: Marschner C, Penn G, Griengl H. Tetrahedron 1993; 49: 5067
  CrossrefSearch in Google Scholar
• 14 Murray RW, Singh M. Org. Synth. 1997; 74: 91
  CrossrefSearch in Google Scholar
• 15 Crystallographic data for 16 have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication number CCDC 1005186. Copies of the data can be obtained, free of charge, on request to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: +44 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk.