Synthetic Studies of Haliclonin A: Construction of the 3-Azabicyclo[3.3.1]nonane Skeleton with a Bridge that Forms the 17-Membered Ring

Abstract

The core structure of haliclonin A, a 3-azabicyclo[3.3.1]­nonane with a bridge that forms a 17-membered ring, was constructed. The synthesis features a ring-closing metathesis that constructs the macrocyclic ring, the stereoselective introduction of carbon units via the intra­molecular cyclopropanation of a diazoester, the conjugate addition of an organocopper reagent, and the formation of 3-azabi­cyclo­[3.3.1]­nonane skeleton via an unexpected 1,5-hydride shift.

Key words

alkaloids - conjugate addition - heterocycles - hydride shift - macrocycles - marine natural products - ring-closing metathesis

• References and Notes

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The stereochemistry of 7 was deduced according to the literatures:
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• 10 (1R,15R,22R,Z)-4-Tosyl-22-vinyl-17-oxa-4-azatricyclo[13.6.2.015,20]tricos-18-en-21-one To a solution of 15 (25.9 mg, 53.4 μmol) and CuI (7.5 mg, 53.4 μmol) in THF (1.5 mL) was added vinylmagnesium chloride in THF (1.45 M, 73.6 μL, 0.107 mmol) at 0 °C. After stirring for 1 h at 0 °C, aq NH₃ was added, and the mixture was extracted with EtOAc. The combined organic phases were washed with brine, dried over anhydrous MgSO₄, and concentrated under reduced pressure. The residue was purified by preparative TLC (30% EtOAc/hexane) to afford 16 (20.0 mg, 39.0 μmol, 73%) as a colorless foam. IR (neat): 2930, 2856, 1700, 1645, 1540, 1456, 1339, 1157, 913. ¹H NMR (400 MHz, CDCl₃): δ = 7.70 (d, J = 8.2 Hz, 2 H), 7.26 (d, J = 8.2 Hz, 2 H), 6.37 (dd, J = 6.0, 2.8 Hz, 1 H), 5.65 (ddd, J = 16.6, 10.1, 9.1 Hz, 1 H), 5.16 (d, J = 16.6 Hz, 1 H), 5.13 (d, J = 9.1 Hz, 1 H), 4.42 (dd, J = 6.0, 2.3 Hz, 1 H), 3.65 (d, J = 11.0 Hz, 1 H), 3.51 (d, J = 11.0 Hz, 1 H), 3.34 (t, J = 6.4 Hz, 2 H), 3.20 (ddd, J = 16.0, 11.0, 5.5 Hz, 1 H), 3.09 (ddd, J = 16.0, 11.0, 4.6 Hz, 1 H), 2.98 (m, 1 H), 2.43 (m, 1 H), 2.41 (s, 3 H), 2.27 (ddd, J = 11.5, 5.5, 2.8 Hz, 1 H), 2.07 (dd, J = 13.3, 13.3 Hz, 1 H), 1.94 (m, 1 H), 1.64 (m, 1 H), 1.55 (m, 2 H), 1.26–1.37 (m, 17 H). ¹³C NMR (100 MHz, CDCl₃): δ = 213.0 (C), 143.8 (CH), 142.7 (CH), 140.7 (C), 138.1 (C), 129.4 (CH), 127.1 (CH), 115.9 (CH₂), 98.7 (CH), 72.2 (CH₂), 50.6 (CH), 47.0 (CH₂), 46.8 (CH), 44.3 (CH₂), 40.8(CH), 36.4 (C), 35.5 (CH₂), 34.1 (CH₂), 28.1 (CH₂), 27.8 (CH₂), 27.5 (CH₂), 27.4 (CH₂), 27.3 (CH₂), 26.5 (CH₂), 24.8 (CH₂), 24.6 (CH₂), 21.5 (CH₃), 20.8 (CH₂). HRMS (ESI+): m/z calcd for C₃₀H₄₃N₁O₄SNa: 536.2811; found: 536.2803.
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• 12 After acidic hydrolysis of the cyclic acetal moiety in 20 with aqueous acetic acid at 80 °C, the resulting hemiacetal was treated with O-methylhydroxylamine hydrochloride in pyridine with the goal of cleaving the hemiacetal. The reaction did not occur, even at 80 °C. When the reaction was carried out at 100 °C, the hemiacetal moiety was opened, forming an oxime ether, and lactone formation occurred between the liberated hydroxy group and the amide moiety.
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• 14 Swern or PCC oxidation caused oxidation of the thioacetal moiety, giving the mono-S-oxide. TPAP oxidation yielded the desired aldehyde 21 in a moderate yield, accompanied by the production of a sizable amount of the corresponding S-oxide.
• 15 (1R,15R,16S,20R,21R)-20-[(1,3-Dithian-2-ylidene)methyl]-18-[(Z)-octa-4,7-dien-1-yl]-17-oxo-12-tosyl-12,18-diazatricyclo[13.4.2.1^1,16]docosan-21-yl acetate To a solution of 21 (2.0 mg, 2.53 μmol) in toluene (0.5 mL) was added CSA (1.2 mg, 5.17 μmol) and quinoline (0.3 μL, 24.9 μmol) at room temperature. After stirring for 9.5 h at 80 °C, 1 N HCl was added, and the mixture was extracted with EtOAc. The combined organic phases were washed with brine, dried over Na₂SO₄, and concentrated under reduced pressure. This material was used for the next step without further purification. To a solution of the crude material in 5% TFA/DCE (0.5 mL) was stirred at 50 °C. After stirring for 1 h at 50 °C, the mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (50% EtOAc/hexane) to afford 24 (1.2 mg, 1.56 μmol, 62%, 2 steps) as a colorless oil. IR (neat): 2923, 2551, 1737, 1541, 1276, 1159, 1000, 990 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.67 (d, J = 8.2 Hz, 2 H), 7.30 (d, J = 8.2 Hz, 2 H), 5.80 (dddd, J = 17.4, 11.9, 6.4, 3.7 Hz, 1 H), 5.74 (d, J = 10.0 Hz, 1 H), 5.47 (ddd, J = 10.1, 6.4, 5.5 Hz, 1 H), 5.42 (ddd, J = 10.1, 6.4, 6.4 Hz, 1 H), 5.03 (dd, J = 17.4, 1.8 Hz, 1 H), 4.97 (m, 1 H), 4.97 (m, 1 H), 3.52 (ddd, J = 13.7, 10.1, 6.4 Hz, 1 H), 3.31–3.24 (m, 3 H), 3.19–3.00 (m, 3 H), 2.92–2.74 (m, 8 H), 2.50 (m, 1 H), 2.41 (s, 3 H), 2.29 (m, 1 H), 2.17–1.97 (m, 4 H), 1.97 (s, 3 H), 1.82 (m, 1 H), 1.74 (m, 1 H), 1.73 (m, 1 H), 1.68 (m, 1 H), 1.56–1.25 (m, 19 H), 0.96 (m, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 170.6 (C), 169.7 (C), 143.1 (C), 136.9 (CH), 136.1 (C), 132.5 (C), 129.8 (CH), 129.7 (CH), 128.6 (CH), 127.6 (CH), 127.1 (CH), 114.7 (CH₂), 70.9 (CH), 54.5 (CH₂), 50.3 (CH₂), 48.2 (CH₂), 46.5 (CH₂), 43.2 (CH), 41.6 (CH), 38.3 (CH₂), 37.8 (CH), 31.5 (CH₂), 30.4 (CH₂), 30.0 (CH₂), 29.7 (CH₂), 29.6 (C), 29.4 (CH₂), 29.0 (CH₂), 28.6 (CH₂), 28.1 (CH₂), 27.7 (CH₂), 27.1 (CH₂), 26.9 (CH₂), 26.5 (CH₂), 25.8 (CH₂), 25.0 (CH₂), 24.7 (CH₂), 23.1 (CH₂), 21.5 (CH₃), 21.1 (CH₃). HRMS (ESI+): m/z calcd for C₄₂H₆₂N₂O₅S₃Na 793.3718; found: 793.3699