Synthesis of 7-azabicyclo[4.3.1]decane ring systems from tricarbonyl(tropone)iron via intramolecular Heck reactions

Abstract

The 7-azabicyclo[4.3.1]decane ring system, common to a number of biologically active alkaloids, was accessed from tropone (via its η4-diene complex with Fe(CO)3) in a short sequence of steps: 1) nucleophilic amine addition and subsequent Boc-protection, 2) photochemical demetallation of the iron complex, and 3) an intramolecular Heck reaction. Minor modifications to the protocol enabled access to the related 2-azabicyclo[4.4.1]undecane system, albeit in lower yield.

Synthesis of the ABC Core of Daphniphyllum Alkaloids with a [5–6–7] Azatricyclic Scaffold via Ring Expansion of Azabicyclic and Azatricyclic Building Blocks

“…Morphan 5c (88 mg, 0.45 mmol, 1 equiv) was subjected to the ring expansion procedure being performed as described before for 1a synthesis. After chromatography (1:0 → 9:1 CH 2 Cl 2 /EtOAc), homomorphan 1c was obtained as an oil (28.9 mg, 31%) along with 1c′ (36.2 mg, 38%): IR (neat) 2952, 1697, 1447 cm −1 ; 1 H NMR (400 MHz, CDCl 3 ) δ 4.55 and 4.44 (2 s, 1H, H-6), 4.10 and 3.95 (2d, J = 11.6 Hz, 1H, H-8), 3.70 (s, 3H, OMe), 2.95−2.78 (m, 2H, H-8 and H-3), 2.62−2.58 (m, 1H, H-1), 2.54 (dd, J = 13.0, 6.6 Hz, 1H, H-3), 2.21−2.17 (m, 3H, H-10, H-9 and H-5), 2.03−1.89 (m, 2H, H-10 and H-4), 1.72−1.58 (m, 3H, H-9, H-5 and H-4); 13 C{ 1 H} NMR (101 MHz, CDCl 3 ) δ 216.4 and 216.3 (C-2), 156.5 and 156.2 (CO 2 Me), 52.5 (OMe), 48.5 (C-6), 44.1 (C-3), 43.0 (C-1), 40.4 (C-8), 35.9 and 34.9 (C-5), 29.5 (C-10), 28 (1RS,6SR,9SR)-7-Methoxycarbonyl-9-methyl-7-azabicyclo[4.3.1]decan-2-one (2c). Morphan 8c (50 mg, 0.24 mmol, 1 equiv) was subjected to the ring expansion procedure being performed as described above for the preparation of 1b.…”

“…The organics were dried, filtered, and concentrated. The crude residue was purified by chromatography (1:0 → 4:1 CH 2 Cl 2 /EtOAc), and compound 7 was obtained (0.50 g, 77%) as a colorless oil: IR (NaCl) 2937, 1634, 1449, 1113 cm −1 ; 1 H NMR (400 MHz, CDCl 3 ) δ 7.34−7.22 (m, 5H, Ph), 5.28 (d, J = 14.8 Hz, 1H, CH 2 Ph), 3.99−3.87 (m, 5H, OCH 2 and CH 2 Ph), 3.40 (br s, 1H, H-1), 2.78 (q, J = 7.4 Hz, 1H, H-4), 1.91 (br s, 2H, H-9), 1.81−1.69 (m, 3H, H-5 and H-8), 1.65−1.56 (m, 2H, H-7), 1.39 (d, J = 7.4 Hz, 3H, Me); 13 C{ 1 H} NMR (101 MHz, CDCl 3 ) δ 173.9 (C-3), 137.8, 128.6, 127.7, and 127.3 (Ph), 109.5 (C-6), 64.5 and 64.5 (OCH 2 ), 50.5 (C-1), 47.9 (CH 2 Ph), 43.6 (C-5), 37.9 (C-4), 27 (1RS,4RS,5SR)-2-Benzyl-4-methyl-2-azabicyclo[3.3.1]nonan-6one (8b). To a solution of AlCl 3 (0.18 g, 1.35 mmol, 1.5 equiv) in THF (4 mL) was added dropwise a solution of LiAlH 4 (1 M in THF, 1.8 mL, 2 equiv) at room temperature.…”

“…Morphan 8c (50 mg, 0.24 mmol, 1 equiv) was subjected to the ring expansion procedure being performed as described above for the preparation of 1b. After chromatography (1:0 → 9:1 CH 2 Cl 2 /EtOAc), homomorphan 2c was obtained as a colorless oil (30 mg, 56%) along with 2c′ (7.5 mg, 14%): IR (neat) 2954, 2874, 1697, 1448 cm −1 ; 1 H NMR (400 MHz, CDCl 3 ) δ 4.48 and 4.43 (2 s, 1H, H-6), 3.70 (s, 3H, OMe), 3.59 (br s, 1H, H-8), 3.18 (dd, J = 14.0, 3.6 Hz, 1H, H-8), 2.80 (dd, J = 13.6, 4.8 Hz, 1H, H-3), 2.56 (dd, J = 13.6, 6.6 Hz, 1H, H-3), 2.39 (br s, 1H, H-9), 2.30 (br s, 1H, H-1), 2.24−2.19 (m, 2H, H-10 and H-5), 1.99 (d, J = 14.8 Hz, 1H, H-10), 1.90−1.85 (m, 1H, H-4), 1.78−1.61 (m, 2H, H-5 and H-4), 1.09 (d, J = 7.2 Hz, 3H, Me); 13 Ring Expansion from Azatricyclo 9. (3RS,3aSR,7SR,8aSR,9RS)-3-Allyl-3a,9-dimethylhexahydro-2H-7,1-ethanocyclohepta [b]pyrrole-2,6(3H)-dione (10a).…”

“…Tricyclic compound 9 (34 mg, 0.14 mmol, 1 equiv) was subjected to the ring expansion procedure being performed as described before for the preparation of 1b. After purification by chromatography (1:0 → 3:2 hexane/EtOAc), homologated compound 10a was obtained as a colorless oil (11.7 mg, 33%) along with compound 10b (5.4 mg, 15%): IR (NaCl) 2955, 1694, 1456, 1434, 912 cm −1 ; 1 H NMR (400 MHz, CDCl 3 ) δ 6.00− 5.90 (m, 1H, �CH), 5.13 (d, J = 16.8 Hz, 1H, �CH 2 , H-trans), 5.04 (d, J = 10.0 Hz, 1H, �CH 2 , H-cis), 4.08 (dd, J = 13.6, 7.6 Hz, 1H, H-10), 3.63−3.61 (m, 1H, H-8a), 2.69−2.62 (m, 1H, CH 2 -3), 2.50− 2.45 (m, 2H, H-5), 2.43−2.30 (m, 3H, H-10, H-3, and H-7), 2.16− 2.03 (m, 4H, H-8, CH 2 -3, and H-9), 1.71 (ddd, J = 15.5, 8.8, 2.4 Hz, 1H, H-4), 1.48 (ddd, J = 15.5, 9.6, 4.0 Hz, 1H, H-4), 1.17 (s, 3H, Me-3a), 1.08 (d, J = 6.8 Hz, 3H, Me-9); 13 (3RS,3aSR,7RS,8aSR,9RS)-3-Allyl-3a,9-dimethylhexahydro-2H-7,1-ethanocyclohepta [b]pyrrole-2,5(3H)-dione (10b). IR (NaCl) 2957, 1699, 1459, 903 cm −1 ; 1 H NMR (400 MHz, CDCl 3 ) δ 5.98−5.88 (m, 1H, �CH), 5.17 (br d, J = 17 Hz, 1H, �CH 2 , Htrans), 5.02 (br d, J = 10 Hz, 1H, �CH 2 , H-cis), 4.00 (dd, J = 13.6, 8.0 Hz, 1H, H-10), 3.58 (d, J = 8.4 Hz, 1H, H-8a), 2.88−2.80 (m, 1H, CH 2 -3), 2.64 (dd, J = 12.0, 7.2 Hz, 1H, H-6), 2.55−2.50 (m, 1H, CH 2 -3), 2.48 and 2.40 (2d, J = 11.8 Hz, 1H each, H-4), 2.35−2.19 (m, 4H, H-6, H-10, H-3, and H-8), 2.02 (dd, J = 15.4, 2.2 Hz, H-8), 1.95−1.88 (m, 2H, H-7 and H-9), 1.18 (s, 3H, Me-3a), 0.96 (d, J = 6.8 Hz, Me-9); 13 C{ 1 H} NMR (101 MHz, CDCl 3 ) δ 208.1 (C-5), 172.7 (C-2), 137.4 (�CH), 116.0 (�CH 2 ), 61.1 (C-8a), 54.5 (C-6), 52.0 (C-3), 45.9 (C-4), 44.1 (C-3a), 41.1 (C-10), 33.5 (C-9), 32.9 (C-7), 30.3 (CH 2 -3), 25.7 (Me-3a), 22.0 (C-8), 20.0 (Me-9).…”

“…The reaction mixture was heated to reflux with a Dean-Stark apparatus over 5 h. Then, after the mixture had cooled, a saturated NaHCO 3 solution (300 mL) was added and the mixture was extracted with EtOAc (3 × 150 mL). The combined organics were dried, filtered, concentrated, and purified by chromatography (9:1 → 4:1 hexane/EtOAc) to afford protected compound 17 (3.64 g, 84%) as a waxy solid: IR 2933, 1682, 1434, 1036, 700 cm −1 ; 1 H NMR (400 MHz, CDCl 3 ) δ 7.34−7.20 (m, 5H, Ph), 6.00−5.90 (m, 1H, �CH), 5.13−5.01 (m, 3H, �CH 2 and CH 2 Ph), 3.92−3.83 (m, 5H, OCH 2 and CH 2 Ph), 2.98 (dd, J = 11.0, 2.0 Hz, 1H, H-8a), 2.49−2.40 (m, 2H, 3-CH 2 ), 2.15−2.10 (m, 1H, H-3), 2.12 (d, J = 13.8 Hz, 1H, H-4), 1.92−1.88 (m, 1H, H-8), 1.76−1.67 (m, 2H, H-7 and H-6), 1.62 (d, J = 13.8 Hz, 1H, H-4), 1.64−1.56 (m, 1H, H-6), 1.55−1.46 (m, 1H, H-8), 1.40−1.32 (m, 1H, H-7), 1.12 (s, 3H, Me); 13 (3RS,3aSR,8aSR)-1-Benzyl-3a-methyl-3-(3′-hydroxypropyl)hexahydrocyclohepta [b]pyrrole-2,5(1H,3H)-dione Ethylene Acetal (18). A solution of 17 (3.61 g, 10.2 mmol) and a 9-BBN solution (0.5 M in THF, 40.6 mL, 20.3 mmol) was stirred for 5 h at room temperature.…”