Concerning the Stereoselectivity of the Oxidative Dimerization of 3-Alkyl-2-Hydroxy-1,4-Naphthoquinones in the Synthesis of Hybocarpone

Abstract

Reinvestigation of 2-hydroxy-3-alkylnaphthoquinones oxidative dimerization was carried out. On the example of dihydrolapachol it is shown that the oxidative dimerization of 2-hydroxy-3-alkylnaphthoquinones upon treatment with lead tetraacetate or cerium ammonium nitrate in aprotic media leads to the formation of diastereomeric 5aS*,6aS*,12aS*,12bS*- and 5aS*,6aR*,12aR*,12bS*-dihydrobinaphthofurantetraones (1:1). This result is significantly different from the previous one.

The cytotoxic pentacyclic naphthazarin-derived dimer, hybocarpone (1a), was isolated from the lichen Lecanora hybocarpa by Elix and co-workers in 1999. ¹ More recently, the total synthesis of 1a and the related (5aS*,6aS*,12aS*,12bS*)-binaphtho[2,3-b;2,3-d]furantetraones, 1b,c was realized (Figure 1). ^{2 -4} One of the key steps in this synthesis was the stereoselective oxidative dimerization of the appropriate 2-hydroxy-1,4-naphthoquinones, 2a-c, by treatment with cerium ammonium nitrate (CAN) in acetonitrile.

Figure 1

The products of the oxidative coupling of hydroxy-1,4-naphthoquinones 2a-c (cerium ammonium nitrate in acetonitrile). ^{2 -4}

The use of the direct 2-hydroxynaphthazarin (2,5,8-trihydroxy-1,4-naphthoquinone) precursors 3a,b oxidative dimerization was explored in another synthetic approach to hybocarpone (1a) and its analogs (Figure 2). ⁵ These compounds are more readily available ^6,7 than the 1,4-naphthoquinone precursors 2a-c. ^3,8 However, all attempts to construct the appropriate binaphtho[2,3-b; 2,3-d]furantetraone skeleton by the action of CAN in MeCN ^{2 -4} led to degradation of the starting structures 3a,b. Upon screening a number of reagents and conditions success was finally achieved with the use of Pb(OAc)₄ as an oxidant in benzene. Upon treatment with Pb(OAc)₄ in benzene, the oxidative dimerization of the hydroxynaphthazarins 3a,b yielded diastereomeric 5aS*,6aS*,12aS*,12bS*-(4a,b) and 5aS*,6aR*,12aR*,12bS*-(5a,b) dihydrobinaphthofurantetraones in a ratio of circa 1:1 (Figure 2). ⁵

Figure 2

The products of the oxidative coupling of hydroxynaphthazarins 3a,b upon treatment with Pb(OAc)₄ in benzene.

The ratio of the resulting compounds 4a,b and 5a,b (1:1) was determined by the equally possible formation of the S*S* (6a,b) and R*S* (7a,b) hexaketone intermediates (Figure 3). ⁵

Figure 3

S*S*- (6a,b) and R*S*- (7a,b) hexaketone intermediates, the precursors of the S*,S*,S*,S*- (4a,b) and S*,R*,R*,S*- (5a,b) binaphthofurantetraones.

¹ H and ¹³C nuclear magnetic resonance (NMR) spectral regularities of hybocarpone (1a) and its derivatives 4a,b and 5a,b were established. Moreover, the structure of the 5aS*,6aR*,12aR*,12bS*-dihydrobinaphthofurantetraone, 5a, was also established by X-ray analysis. ⁵

It should be noted that in the previous reports ^{2 -4} the course of the reaction through the S*,S* hexaketone intermediate was only postulated, and the possibility of R*,S* diastereomer formation was not discussed. Based on this, the authors reported on the synthesis of only one 5aS*,6aS*,12aS*,12bS* diastereomeric product 1 c. In this regard, we compared our results for the oxidative dimerization of dihydrolapachol (2 c) with Pb(OAc)₄ in benzene to those previously reported with CAN in MeCN. ³

Dihydrolapachol (2c) (Scheme 1) was prepared by C-alkylation of commercially available lawsone (8) with 4-methylpentanoyl peroxide. Oxidative dimerization of substrate 2 c upon treatment with Pb(OAc)₄ in benzene yielded 3 products isolated after chromatographic purification. A yellow product was determined as 3-isopentyl-3-(3-isopentyl-1,4-dioxo-1,4-dihydronaphthalen-2-yloxy)naphthalene-1,2,4(3H)-trione (9; 42%) based on its spectral data (¹H, ¹³C NMR and mass spectrometry) and comparison with the authentic sample. ⁹ The formation of a high percentage of 9 resulted due to the steric bulk around the reacting carbon in starting substrate 2 c; thus, С-О coupling was more probable than C-C coupling. It is interesting that the authors of the work ³ do not report the formation of a product 9.

Scheme 1

Oxidative coupling reaction of dihydrolapachol (2 c).

Two colorless products were determined to be pentacyclic compounds 1 c (24%) and 5 c (21%) based on the spectral data and comparison of its ¹H and ¹³C NMR data with spectral data of derivatives 4a,b and 5a,b (Table 1). We found that the same mixture was obtained upon exposure of the monomeric unit 2 c to CAN in acetonitrile under the previously reported conditions. ³

Table 1

¹H and ¹³C Nuclear Magnetic Resonance Data of 1 c, 4a,b, 5a,b, and 5 c in CDCl₃ (Signals of Tetrahydrofuran Ring Moiety).

Compounds	С (5a,6a)	HOH (5a,6a)	С (12a,12b)	С (14,15)	Ha (14,15)	Hb (14,15)	H (16,17)
4a	99.4	4.90	67.2	25.2	2.33	2.62	0.69
5a	100.2	4.73	69.4	24.4	2.35	2.51	0.81
4b	99.4	4.87	67.3	25.2	2.32	2.62	0.70
5b	100.2	4.63	69.4	24.3	2.34	2.50	0.82
1c	100.7	4.82	67.5	30.4	2.23	2.35	0.76
5c	101.4	4.81	70.2	29.5	2.32	2.40	0.81

Chemical shifts of 5aS*,6aR*,12aR*,12bS* diastereomers are highlighted in bold.

In general, 2-hydroxy-3-alkylnaphthazarins ⁵ and 2-hydroxy-3-alkyl-1,4-naphthoquinones undergo oxidative dimerization upon treatment with lead tetraacetate or CAN in aprotic media to give diastereomeric 5aS*,6aS*,12aS*,12bS*- and 5aS*,6aR*,12aR*,12bS*-dihydrobinaphthofurantetraones in a ratio of circa 1:1. The ratio of arising compounds is determined by the equally possible formation of the corresponding S*,S* and R*,S* hexaketone intermediates. This conclusion is completely different from the results described in the article ³ where synthesis of only one 5aS*,6aS*,12aS*,12bS* diastereomeric product is noted.

Experimental

The melting points were determined with a Boetius apparatus and are uncorrected. For all purposes analytical grade solvents were used. ¹H and ¹³C NMR spectra were recorded on Bruker Avance-300, Avance-500, Avance-700 spectrometers at 300 and 75 MHz, 500 and 125 MHz, and 700 and 176 MHz, respectively. The chemical shifts (δ) are represented as parts per million (ppm) relative to tetramethylsilane. High-resolution electrospray ionization mass spectra were measured on an Agilent 6510Q-TOF LC mass spectrometer. The course of reactions and the purity of the compounds obtained were assessed by thin-layer chromatography (TLC). Merck Kieselgel 60 F-254 plates were preliminarily treated with 0.05 M tartaric acid in MeOH and dried at ~50°C for 1 hour. Preparative TLC was performed on glass plates (20 × 20 cm) precoated with silica gel (Merck), 5 to 40 μm. The yields were not optimized.

C-Alkylation of Lawsone (8) With 4-Methylpentanoyl Peroxide

Alkanoyl peroxide was added dropwise to a boiling solution of lawsone (1.74 g, 10 mmol) in t-BuOH (30 mL), monitoring the reaction course by TLC. When the conversion reached 50% to 60%, by TLC the reaction was stopped by cooling, the solvent was removed in vacuo, and the residue was separated by column chromatography on silica gel in a hexane-acetone, 3:1 to give compound 2 c (0.83 g, 34%). The starting material 8 (1.06 g, 61%) was recovered.

2-Hydroxy-3-Isopentylnaphthalene-1,4-Dione (2c)

MP: 88–90°C (MP: 92°C ¹⁰ ).

R_f : 0.65 (hexane-acetone, 3: 1).

¹H NMR (300 MHz, CDCl₃): 0.95 (6H, d, J = 6.6 Hz, 2Me), 1.35-1.46 (2H, m), 1.59-1.67 (1H, m), 2.58 (2H, dd, J ₁ = 8.2 Hz, J ₂ = 8.0 Hz), 7.34 (1H, br. s, OH), 7.69 (1H, dt, J ₁ = 7.5 Hz, J ₂ = 1.4 Hz, H_arom), 7.77 (1H, dt, J ₁ = 7.5 Hz, J ₂ = 1.5 Hz, H_arom), 8.06 (1H, dd, J ₁ = 7.5 Hz, J ₂ = 1.5 Hz, H_arom), 8.09 (1H, dd, J ₁ = 7.3 Hz, J ₂ = 1.4 Hz, H_arom).

¹³C NMR (75 MHz, CDCl₃): 2 × 21.2, 22.1, 28.2, 37.1, 73.9, 125.7, 2 × 126.4, 132.7, 132.9, 134.6, 152.8, 181.3, 184.3.

HRMS: m/z [M + H⁺] calcd for C₁₅H₁₇O₃: 245.1172; found: 245.1128.

Oxidative Coupling of 2c

Commercially available Pb(OAc)₄ (135 mg, 0.3 mmol) was added with vigorous stirring to a solution of 2 c (122 mg, 0.5 mmol) in benzene (5 mL). The reaction mixture was vigorously stirred at room temperature for 2 hours and filtered. The filtrate was evaporated at a temperature <60°C, the residue was diluted with water (20 mL) and extracted with ethyl acetate (3 × 30 mL). The organic layer was dried (Na₂SO₄), concentrated in vacuo, the residue was chromatographed in hexane-acetone, 4:1, affording compounds 9 (yellow solid, 102 mg, 42%), 1 c (colorless oil, 50.4 mg, 24%) and 5 c (colorless oil, 52.9 mg, 21%). The starting material (2 c) (16 mg, 13%) was recovered.

3-Isopentyl-3-(3-Isopentyl-1,4-Dioxo-1,4-Dihydronaphthalen-2-Yloxy)naphthalene-1,2,4(3H)-Trione (9)

MP: 76-79°C (MP: 77-81°C ⁹ ).

R_f : 0.50 (hexane-acetone, 3:1).

¹H NMR (500 MHz, CDCl₃): 0.82 (3H, d, J = 6.5 Hz, Me-11a), 0.84 (3H, d, J = 6.5 Hz, Me-11b), 1.02 (6H, d, J = 6.6 Hz, 2 × Me-11′), 1.33 (1H, m, H-11), 1.42 (1H, m, H-11′), 1.46 (1H, m, H_a-9), 1.56 (2H, m, H-10), 1.74 (1H, m, H_b-9), 2.03 (2H, m, H-10′), 2.80 (2H, t, J = 7.1 Hz, H-9′), 7.50 (1H, dt, J ₁ = 7.5 Hz, J ₂ = 1.3 Hz, H _arom-7′), 7.64 (1H, dt, J ₁ = 7.4 Hz, J ₂ = 1.3 Hz, H _arom-6′), 7.65 (1H, d, J = 7.2 Hz, H _arom-8′), 7.92 (1H, dt, J ₁ = 7.2 Hz, J ₂ = 1.6 Hz, H_arom-6), 7.95 (1H, dt, J ₁ = 7.4 Hz, J ₂ = 2.0 Hz, H_arom-7), 8.02 (1H, m, H_arom-5′), 8.22 (1H, dd, J ₁ = 7.0 Hz, J ₂ = 2.0 Hz, H_arom-5), 8.41 (1H, dd, J ₁ = 7.0 Hz, J ₂ = 2.0 Hz, H_arom-8).

¹³C NMR (125 MHz, CDCl₃): 2 × 22.2, 22.4, 2 × 22.5, 28.0, 28.8, 31.6, 35.6, 37.0, 93.2, 126.2, 126.6, 128.5, 129.0, 130.7, 131.7, 132.9, 133.0, 133.7, 134.0, 134.4, 134.8, 136.1, 150.9, 180.8, 182.2, 184.3, 184.4, 189.1.

HRMS: m/z [M + H⁺] calculated for C₃₀H₃₁O₆: 487.2115; found: 487.1092.

(5aS*,6aS*,12aS*,12bS*)-12a,12b-Diisopentyl-5a,6a-Dihydroxy-Dinaphtho[2,3-B:2′,3′-d]furan-5,7,12,13(5aH,6aH,12aH,12bH)-Tetraone (1c)

R_f : 0.40 (hexane-acetone, 3:1).

¹H NMR (700 MHz, CDCl₃): 0.73 (2H, m, H_a-15,15′), 0.76 (12H, d, J = 6.7 Hz, 4Me-16,16′), 0.93 (2H, m, H_b-15,15′) 1.45 (2H, m, H-16,16′), 2.23 (2H, dt, J ₁ = 13.2 Hz, J ₂ = 4.2 Hz, H_a-14,14′), 2.35 (2H, dt, J ₁ = 13.2, J ₂ = 4.1 Hz, H_b-14,14′), 4.82 (2H, br. s, OH-5a,6a), 7.74 (2H, dt, J ₁ = 7.5 Hz, J ₂ = 1.2 Hz, H_arom-2,10), 7.83 (2H, dt, J = 7.6 Hz, 0.8 Hz, H_arom-3,9), 8.02 (2H, dd, J ₁ = 7.6 Hz, J ₂ = 0.8 Hz, H_arom-1,11), 8.19 (2H, dd, J ₁ = 7.9 Hz, J ₂ = 0.8 Hz, H_arom-4,8).

¹³C NMR (176 MHz, CDCl₃): 22.1, 22.3, 28.8, 30.4, 34.1, 67.6, 100.6, 127.1, 127.6, 129.7, 133.6, 135.3, 137.5, 191.1, 193.9.

HRMS: m/z [M + H⁺] calculated for C₃₀H₃₃O₇: 505.2221; found 505.2202.

(5aS*,6aR*,12aR*,12bS*)-12a,12b-Diisopentyl-5a,6a-Dihydroxy-Dinaphtho[2,3-B:2′,3'-d]furan-5,7,12,13-(5aH,6aH,12aH,12bH)-Tetraone (5c)

R_f : 0.35 (hexane-acetone, 3: 1).

¹H NMR (500 MHz, CDCl₃): 0.81 (12H, d, J = 6.7 Hz, Me-16,16’), 0.86 (2H, m, H_a-15,15’), 1.03 (2H, m, H_b-15,15’), 1.50 (2H, m, H-16,16’), 2.32 (2H, dt, J ₁ = 12.5 Hz, J ₂ = 4.9 Hz, H_a-14,14’), 2.39 (2H, dt, J ₁ = 12.5 Hz, J ₂ = 4.2 Hz, H_b-14,14’), 4.81 (2H, br. s, OH-5a,6a), 7.69 (2H, dt, J ₁ = 7.5 Hz, J ₂ = 1.4 Hz, H_arom-2,10), 7.73 (2H, dt, J ₁ = 7.4 Hz, J ₂ = 1.5 Hz, H_arom-3,9), 7.85 (2H, dd, J ₁ = 7.6 Hz, J ₂ = 1.4 Hz, H_arom-1,11), 7.95 (2H, dd, J ₁ = 7.4 Hz, J ₂ = 1.3 Hz, H_arom-4,8).

¹³C NMR (125 MHz, CDCl₃): 2 × 22.3, 29.0, 29.5, 34.3, 70.2, 101.4, 2 × 127.3, 130.9, 134.1, 135.4, 136.4, 191.1, 195.3.

HRMS: m/z [M + H⁺] calculated for C₃₀H₃₃O₇: 505.2221; found 505.2202.