Synthesis of Brombyins II and III, Cyclostachines A and B, and Cyclopiperstachine, Plant-Derived Octahydronaphthalenes

Abstract

In this paper we present a study into the direct formation of five plant-derived natural products via intramolecular Diels-­Alder cycloaddition of a series of 1,7,9-decatriene precursors. Methods for the preparation of the trienes are also discussed.

Key words

natural products - Diels-Alder - diene synthesis

References and Notes

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• 5b Joshi BS. Viswanathan N. Gawad DH. von Philipsborn W. Helv. Chim. Acta  1975,  58:  1551 
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• For other examples of thermal IMDA reactions involving 1,7,9-decatrienes, which illustrate typical reaction conditions for a variety of dienophiles, see:
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• 9 For a closely related sequence of transformations, see: Roush WR. Sciotti RJ. J. Am. Chem. Soc.  1994,  116:  6457 
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• Diels-Alder reactions involving substrates of this type would be expected to have highly asynchronous transition states. For further discussion, see:
• 13a Raimondi L. Brown FK. Gonzalez J. Houk KN. J. Am. Chem. Soc.  1992,  114:  4796 
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3

It is also conceivable that brombyin IV(4) could arise via autoxidation of 2, followed by epimerization at the ring junction.

11

A solution of aldehyde 16 (4.00 g, 22.7 mmol) in anhyd THF (100 mL) was placed under an argon atmosphere and cooled to 0 ˚C. BF₃˙OEt₂ (21.0 mL, 162 mmol) was added dropwise and the mixture stirred for 10 min. A solution of cyclo-hexanone (2.40 mL, 22.7 mmol) in anhyd THF (50 mL) was then added over 20 min. The mixture was then allowed to warm to r.t. and stirred for a further 30 min. Propan-1,3-diol (8.60 mL, 119 mmol) was then added and the mixture stirred for 12 h before being quenched by pouring onto sat. aq Na₂CO₃ (250 mL). The aqueous layer was extracted with Et₂O (3 × 150 mL), and the combined organics were washed sequentially with sat. aq Na₂CO₃ (2 × 150 mL) and brine (2 × 150 mL). The organic phase was then dried (MgSO₄), filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (2:1 increasing to 1:1 PE-EtOAc) to give diene 20 (2.64 g, 7.95 mmol, 35%) as a pale yellow oil. R _f = 0.16 (2:1 PE-EtOAc). IR (neat): ν_max = 3435, 2930, 1731 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 6.92 (1 H, d, J = 1.5 Hz, ArH), 6.80 (1 H, dd,
J = 8.0, 1.5 Hz, ArH), 6.74 (1 H, d, J = 8.0 Hz, ArH), 6.58 (1 H, dd, J = 15.5, 10.5 Hz, CH=CHAr), 6.36 (1 H, d, J = 15.5 Hz, C=CHAr), 6.17 (1 H, dd, J = 15.5, 10.5 Hz, CH=CHCH₂), 5.94 (2 H, s, OCH₂O), 5.75 (1 H, dt, J = 15.5, 7.0 Hz, C=CHCH₂), 4.24 (2 H, t, J = 6.0 Hz, CH₂OCO), 3.69 (2 H, t, J = 6.0 Hz, CH ₂OH), 2.34 (2 H, t, J = 7.5 Hz, CH₂CO), 2.16 (2 H, dt, J = 7.0, 7.0 Hz, CH ₂CH=C), 1.87 (2 H, tt, J = 6.0, 6.0 Hz, CH ₂CH₂OH), 1.66 (2 H, tt, J = 7.5, 7.5 Hz, CH₂), 1.46 (2 H, tt, J = 7.5, 7.0 Hz, CH₂). ^¹³C NMR (125 MHz, CDCl₃): δ = 174.3 (CO), 148.1 (C), 147.0 (C), 134.3 (CH), 132.2 (C), 131.0 (CH), 130.0 (CH), 127.7 (CH), 121.0 (CH), 108.4 (CH), 105.4 (CH), 101.1 (CH₂), 61.3 (CH₂), 59.3, (CH₂), 34.2 (CH₂), 32.5 (CH₂), 31.8 (CH₂), 28.9 (CH₂), 24.6 (CH₂). MS: (ES⁺): m/z (%) = 355 (100) [M + Na⁺], 333 (35) [M + H⁺]. MS (ES⁺): m/z calcd for C₁₉H₂₅O₅ ⁺: 333.1697; found: 333.1704 [M + H⁺].

15

Reactions in water alone were irreproducible due to insolubility of the substrate and product.

17

Method 1 (PhMe, 165 ˚C)
Triene 25 (330 mg, 1.11 mmol) was dissolved in anhyd toluene (10 mL), the solution degassed (freeze-thaw) and placed in a sealed tube under argon. The solution was heated at 165 ˚C for 14 h then allowed to cool to r.t. The solvent was removed under reduced pressure and the residue purified by chromatography on silica gel (95:5 PE-EtOAc) to give brombyin II(2) (100 mg, 0.33 mmol, 30%) and brombyin III (3) (185 mg, 0.62 mmol 56%) as colourless low-melting solids.
Method 2 (MeOH, 50 ˚C)
Triene 25 (39.0 mg, 0.13 mmol) was dissolved in MeOH (2.5 mL) and placed in a sealed tube under argon. The solution was heated at 50 ˚C for 15 h. The solvent was removed under reduced pressure and the residue passed through a plug of silica gel (9:1 PE-EtOAc) to give a 90:10 mixture of brombyin III (3) and brombyin II (2) (26 mg, 0.09 mmol, 67%).
Method 2 (H ₂ O-SDS, 40 ˚C)
SDS (0.50 g, 1.74 mmol) was dissolved in H₂O (10 mL) and stirred for 5 min. Triene 25 (30 mg, 0.10 mmol) was added and the mixture stirred vigorously at 40 ˚C for 72 h. The mixture was then extracted with EtOAc (3 × 20 mL), and the combined organic phases were washed with brine (20 mL), dried (MgSO₄), filtered, and concentrated under reduced pressure. The residue was passed through a plug of silica gel (9:1 PE-EtOAc) to provide a 95:5 mixture of brombyin III (3) and brombyin II (2) (18 mg, 0.06 mmol, 60%).
Brombyin II (2):^¹ R _f = 0.39 (9:1 PE-EtOAc). IR (neat): ν_max = 2925, 1705 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 6.71 (1 H, d, J = 8.0 Hz, ArH), 6.64 (1 H, d, J = 1.5 Hz, ArH), 6.57 (1 H, dd, J = 8.0, 1.5 Hz, ArH), 5.93 (2 H, s, OCH₂O), 5.80 (1 H, ddd, J = 10.0, 5.0, 2.5 Hz, CH=CHCHAr), 5.49 (1 H, dt, J = 10.0, 1.5 Hz, CH=CHCHCH₂), 3.54 (1 H, ddd, J = 10.0, 5.0, 2.0 Hz, CHAr), 3.00 (1 H, dd, J = 11.5, 10.5 Hz, CHCO), 2.23 (1 H, m, CH), 2.14 (1 H, m, CH), 1.88 (3 H, s, CH₃), 1.83-0.83 (8 H, m, 4 × CH₂). ^¹³C NMR (100 MHz, CDCl₃): δ = 214.0 (CO), 147.9 (C), 146.4 (C), 138.0 (CH), 132.7 (C), 128.8 (CH), 121.0 (CH), 108.4 (CH), 108.1 (CH), 101.1 (CH₂), 54.4 (CH), 47.9 (CH), 36.9 (CH), 36.3, (CH), 33.0 (CH₂), 30.2 (CH₂), 28.7 (CH₂), 26.3 (CH₂), 21.4 (CH₃). MS (ES⁺): m/z (%) = 321 (50) [M + Na⁺], 299 (100) [M + H⁺]. MS (ES⁺): m/z calcd for C₁₉H₂₃O₃ ⁺: 299.1642; found: 299.1664 [M + H⁺].


Brombyin III (3):^² R _f = 0.24 (9:1 PE-EtOAc). IR (neat):
ν_max = 2920, 1713 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 6.72 (1 H, d, J = 8.0 Hz, ArH), 6.66 (1 H, d, J = 1.5 Hz, ArH), 6.56 (1 H, dd, J = 8.0, 1.5 Hz, ArH), 5.94 (2 H, s, OCH₂O), 5.68 (1 H, br d, J = 10.0 Hz, CH=CHCHCH₂), 5.58 (1 H, ddd, J = 10.0, 4.5, 2.5 Hz, CH=CHCHAr), 3.69 (1 H, ddd, J = 6.5, 4.5, 2.5 Hz, CHAr), 2.85 (1 H, dd, J = 12.0, 6.5 Hz, CHCO), 1.81 (3 H, s, CH₃), 1.89-0.70 (10 H, m, 2 × CH, 4 × CH₂). ^¹³C NMR (125 MHz, CDCl₃): δ = 210.8 (CO), 147.6 (C), 146.7 (C), 134.3 (CH), 132.8 (C), 127.4 (CH), 122.7 (CH), 109.9 (CH), 108.1 (CH), 101.1 (CH₂), 58.9 (CH), 43.9 (CH), 42.0 (CH), 36.4 (CH), 33.2 (CH₂), 30.4 (CH₂), 30.3 (CH₃), 26.8 (CH₂), 26.5 (CH₂). MS (ES⁺): m/z (%) = 321 (70) [M + Na⁺], 299 (100) [M + H⁺]. MS (ES⁺): m/z calcd for C₁₉H₂₃O₃ ⁺: 299.1642; found: 299.1655 [M + H⁺].

18

Cyclostachine B (7a):⁴ R _f = 0.25 (1:1 PE-EtOAc). IR (neat): ν_max = 2923, 1632 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 6.71-6.64 (3 H, m, 3 × ArH), 5.94 (1 H, ddd, J = 10.0, 5.0, 2.0 Hz, CH=CHCHCH₂), 5.92 (2 H, s, OCH₂O), 5.58 (1 H, dt, J = 10.0, 2.0 Hz, CH=CHCHAr), 3.68 (1 H, dq, J = 10.0, 2.0 Hz, CHAr), 3.39 (2 H, dt, J = 7.5, 2.0 Hz, CH₂N), 3.13 (1 H, dt, J = 9.5, 7.0, CH=CHCHCH₂), 2.75 (1 H, dd,
J = 11.5, 10.0 Hz, CHCO), 2.43-2.13 (3 H, m, CH₂N, CHCHCO), 2.04-1.12 (12 H, m, 6 × CH₂). ^¹³C NMR (100 MHz, CDCl₃): δ = 173.6 (CO), 147.6 (C), 146.1 (C), 138.7 (CH), 133.3 (C), 128.3 (CH), 122.0 (CH), 108.3 (CH), 108.1 (CH), 100.9 (CH₂), 46.8 (CH), 47.2 (CH), 46.4 (CH₂), 45.5 (CH₂), 36.5 (CH), 35.5 (CH), 30.6 (CH₂), 28.8 (CH₂), 26.5 (CH₂), 26.1 (CH₂), 24.4 (CH₂), 22.1 (CH₂). MS (ES⁺): m/z (%) = 376 (20) [M + Na⁺], 354 (100) [M + H⁺]. MS (ES⁺): m/z calcd for C₂₂H₂₈NO₃ ⁺: 354.2064; found: 354.2062 [M + H⁺].
Cyclopiperstachine (7b):⁴ mp 167-168 ˚C (lit.⁴ 220 ˚C). R _f = 0.20 (1:1 PE-EtOAc). IR (neat): ν_max = 3329, 2925, 1641, 1486, 1250 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 6.75-6.62 (3 H, m, 3 × ArH), 5.93 (1 H, ddd, J = 10.0, 5.0, 2.5 Hz, CH=CHCHCH₂), 5.91 (2 H, s, OCH₂O), 5.52 (1 H, dt, J = 10.0, 1.5 Hz, CH=CHCHAr), 5.14 (1 H, br t, J = 5.5 Hz, NH), 3.68 (1 H, m, CHAr), 2.93 (2 H, dt, J = 7.0, 5.5 Hz, CH ₂NH), 2.65 (1 H, dd, J = 11.5, 6.5 Hz, CHCO) 2.28 (1 H, m, CH), 2.19 (1 H, m, CH), 1.88-1.17 (9 H, m, CH, 4 × CH₂), 0.75, 0.70 (2 × 3 H, d, J = 6.5 Hz, 2 × CH₃). ^¹³C NMR (100 MHz, CDCl₃): δ = 174.1 (CO), 147.8 (C), 146.2 (C), 138.7 (CH), 135.1 (C), 128.6 (CH), 121.2 (CH), 110.0 (CH), 108.1 (CH), 101.0 (CH₂), 53.9 (CH), 50.8 (CH), 46.9 (CH₂), 46.8 (CH), 36.5 (CH), 35.3, (CH), 30.3 (CH₂), 28.4 (CH₂), 26.6 (CH₂), 21.6 (CH₂), 20.1 (CH₃). MS (ES⁺): m/z (%) = 378 (20) [M + Na⁺], 356 (100) [M + H⁺]. MS (ES⁺): m/z calcd for C₂₂H₃₀NO₃ ⁺: 356.2221; found: 356.2252 [M + H⁺].