Total Synthesis of Danshenspiroketallactone

Abstract

Described herein is the first synthesis of the monobenz­annulated 5,5-spiroketals danshenspiroketallactone and epi-danshen­spiroketallactone, two components of the traditional Chinese medicine Danshen. Key features of the synthesis include a directed metallation-lactonisation sequence to install the isobenzofuranone moiety and an oxidative radical cyclisation to afford the monobenz­annulated 5,5-spiroketal.

Key words

Danshen - spiroketal - oxidative radical cyclisation - natural product

References and Notes

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14

The full results of the extensive optimisation study conducted to ensure the satisfactory reaction between 9 and 10 will be reported in due course.

15

At the conclusion of the previously reported total synthesis of a member of this family of natural products, crypto-acetalides 3 and 5 were obtained as an inseparable 2:1 mixture of spiroketal epimers, respectively (ref. 8).

17

Synthesis of Danshenspiroketallactone (1) and epi -Danshenspiroketallactone (2) A mixture of alcohol 7 (50 mg, 0.19 mmol), PhI(OAc)₂ (119 mg, 0.37 mmol), and iodine (108 mg, 0.43 mmol) in anhyd cyclohexane (15.3 mL) was degassed with nitrogen at r.t. for 15 min. The resulting solution was cooled in an ice-water bath (10 ˚C) and irradiated with a desk lamp (60 W) for 3.5 h. The solution was poured onto a mixture of sat. aq Na₂S₂O₃ (20 mL) and sat. aq NaHCO₃ (20 mL) and diluted with Et₂O (100 mL). The organic layer was separated and the aqueous layer further extracted with Et₂O (2 × 100 mL). The organic fractions were combined and dried over anhyd MgSO₄, filtered, and the solvent was removed under reduced pressure. The crude product was purified by flash chroma-tography on silca gel using hexanes-EtOAc (3:1, R _f = 0.52) as eluent to afford the title compounds 1 and 2 (23.3 mg, 0.09 mmol, 47%; Figure  [²] ) as an orange solid and an inseparable mixture of diastereomers (1.5:1). IR (neat): ν_max = 2957, 2928, 2876, 1925, 1749, 1601, 1588, 1526, 1470, 1454, 1375, 1342, 1322, 1254, 1211, 1183, 1159, 1136, 1110, 1083, 1070, 1047, 1003, 981, 950, 928, 915, 882, 847, 811, 777, 769, 737, 700, 684, 658, 646, 628 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 1.26 (1.5 H, d, J = 7.0 Hz, H-17), 1.32 (1.5 H, d, J = 7.0 Hz, H-17*), 2.11 (0.5 H, dd, J = 10.5, 13.0 Hz, H-16_a), 2.22 (0.5 H, dd, J = 4.7, 13.2 Hz, H-16_b*), 2.53 (0.5 H, dd, J = 7.0, 13.0 Hz, H-16_b), 2.70 (0.5 H, dd, J = 9.5, 13.4 Hz, H-16_a*), 2.74 (3 H, s, H-18, H-18*), 2.76 (0.5 H, m, H-15*), 2.95 (0.5 H, m, H-15), 3.82 (0.5 H, t, J = 8.2 Hz, H-14_a), 3.93 (0.5 H, dd, J = 7.2, 8.2 Hz, H-14_b*), 4.42 (0.5 H, t, J = 7.8 Hz, H-14_a*), 4.47 (0.5 H, t, J = 8.2 Hz, H-14_b), 7.46 (1 H, dd, J = 1.0, 7.0 Hz, H-3, H-3*), 7.53 (0.5 H, d, J = 8.8 Hz, H-7*), 7.57 (0.5 H, d, J = 8.4 Hz, H-7), 7.60 (1 H, dd, J = 7.0, 8.5 Hz, H-2, H-2*), 8.34 (1 H, m, H-6, H-6*), 8.87 (1 H, d, J = 8.4 Hz, H-1, H-1*). ^¹³C NMR (100 MHz, CDCl₃): δ = 17.4 (CH₃, C-17), 18.2 (CH₃, C-17*), 19.9 (2 × CH₃, C-18, C-18*), 32.6 (CH, C-15), 33.5 (CH, C-15*), 44.6 (CH₂, C-16*), 45.4 (CH₂, C-16), 77.37, 77.39 (2 × CH₂, C-14, C-14*), 113.2 (2 × C, C-13, C-13*), 118.1 (ArH, C-7*), 118.2 (ArH, C-7), 121.7 (C, C-9*), 122.1 (ArH, C-1), 122.17 (ArH, C-1*), 122.21 (C, C-9), 128.5 (2 × ArH, C-3, C-3*), 129.0 (2 × ArH, C-2, C-2*), 129.2 (ArH, C-10*), 129.3 (ArH, C-10), 131.9 (ArH, C-6), 132.0 (ArH, C-6*), 133.4 (C, C-5*), 133.5 (C, C-5), 135.1 (2 × C, C-4, C-4*), 147.1 (C, C-8), 147.8 (C, C-8*), 168.4 (2 × C=O, C-11, C-11*). MS (ESI⁺): m/z (%) = 291 (100) [M + Na]⁺, 259 (29), 214 (18), 165 (22), 89 (27). HRMS: m/z calcd for C₁₇H₁₆O₃Na: 291.0992; found: 291.0991 [M + Na]⁺. The spectroscopic data are in full agreement with that reported in the literature.^³,4

Figure 2