HETEROCYCLES

Paper | Special issue | Vol. 79, No. 1, 2009, pp. 791-804
Received, 29th September, 2008, Accepted, 10th November, 2008, Published online, 14th November, 2008.
DOI: 10.3987/COM-08-S(D)48

■ Synthesis of the Bicyclo[3.3.1]nonane Core of Huperzine A and Novel Pyridine-Fused Tricycles by Cyclisation of Pyridine-Based Radicals

Jarrod Ward and Vittorio Caprio*

Department of Chemistry, University of Auckland, 23 Symonds Street, Auckland, New Zealand

Abstract

The cyclisation of 3-pyridyl radicals and (2-pyridyl)methyl radicals, generated from (pyridyl)cyclohexenols 5 to 8, has been examined as part of a model study directed towards the synthesis of huperzine A. The 3-pyridyl radical, generated from 3-bromopyridine 5, undergoes 5-exo-trig cyclisation to give hexahydroindenopyridine 10. Related pyridine-fused tricycle 12 is formed by 5-exo-trig cyclization of the (2-pyridyl)methyl radical derived from selenide 7b, while the radicals generated from selenides 8b and 19 undergo 6-exo-trig cyclisation to give the bicyclo[3.3.1]nonane core of huperzine A.

INTRODUCTION

Huperzine A 1 is a Lycopodium alkaloid isolated from the Chinese club moss Huperzia serrata1 and the New Zealand club moss Lycopodium varium.2 This compound is a potent, selective and reversible inhibitor of acetylcholine esterase3 and is a useful lead in the palliative treatment of disorders, such as Alzheimer’s disease, that are attributed, in part, to a depletion of brain levels of acetylcholine. Indeed, clinical studies have shown that huperzine A effectively improves cognitive function in the elderly.4 In addition, huperzine A functions as a pretreatment for organophosphate poisoning5 and recent studies have shown that this compound also displays neuroprotective properties.6

The important bioactivity of huperzine A has stimulated the development of a number of total7 and partial syntheses of this compound8 and analogues.9 In an effort to develop a novel synthesis of 1, and as part of a research programme aimed at probing the scope and utility of pyridine-based radicals in synthesis, we have investigated a novel synthetic approach to core structure 2. This strategy centres on the 6-exo-trig cyclisation of either the 3-pyridyl radical generated from intermediate 3, or the (2-pyridylmethyl) radical generated from 4a/b (Scheme 1).

While there are a small number of reports documenting the generation and reaction of 3-pyridyl radicals,10 the use of (2-pyridyl)methyl radicals has not been studied. Thus, prior to embarking on a synthesis of 2, we have carried out a programme of model studies to validate the proposed strategy.11These studies, reported in full herein, have focused on investigating the synthesis of compounds 5-8 and the predominant mode of cyclisation of the radicals generated from each (Figure 2).

RESULTS AND DISCUSSION
Cyclisation precursor 5 was synthesized, according to the method of Gray et al.,12 by addition of the ((2-pyridyl)methyl)lithium, generated from bromopyridine 9,8e,12 to 2-cyclohexenone. Radical cyclisation of 5 was initiated under standard conditions, using nBu3SnH and AIBN. As predicted, cyclisation proceeded via a 5-exo-trig pathway to give novel annulated pyridine 10, with cis-stereochemistry at the ring junction (Scheme 2). The stereochemistry of cyclisation was assigned by analysis of 2D-NOESY spectral data (Figure 3.)

Unfortunately, attempts to probe the 6-exo-trig cyclisation of 3-pyridyl radicals, using compound 6, were stymied by the difficulty in accessing this compound. We planned to synthesise 6, in similar fashion to 5. However, addition of the 3-lithiopyridine, generated from 9,8e,12 to 3-cyclohexenone13 only proceeded in a poor yield of 6%.
Our attention next turned to a study of the cyclisation of (2-pyridyl)methyl radicals. We planned to access compounds 7a/b by direct functionalisation at the methyl position of (3-pyridyl)cyclohexenol 11.12 Attempts to access bromide 7a, by NBS bromination of 11,12 were unsuccessful. However, synthesis of selenide 7b was achieved, albeit in low yield, by deprotonation of 11 with nBuLi followed by addition of diphenyl diselenide (Scheme 3). Radical cyclisation of 7b was, again, achieved under standard conditions, to give the cis-fused product 12, arising from 5-exo-trig cyclisation, in near quantitative yield. Stereochemistry at the ring junction was, again, assigned with the aid of 2D-NOESY data (Figure 3).

The third stage of this model study involved an investigation of the cyclisation of 8a/b, which we planned to access by selective functionalisation at the benzylic position of (3-pyridyl)cyclohexenol 13. The most direct synthesis of 13, by addition of 3-cyclohexenone to the 3-pyridyllthium derived from bromopyridine 9,8e,12 met with limited success, proceeding in a maximum yield of 20%. This prompted us to develop a more circuitous route to 13, utilizing an iterative nucleophilic addition/oxidation sequence followed by ring-closing metathesis, to construct the cyclohexene moiety (Scheme 4). Thus, formylation of 9,12 followed by addition of but-3-enylmagnesium bromide, gave alcohol 15. Oxidation of 15, to ketone 16, followed by addition of allylmagnesium bromide gave RCM substrate 17. Grignard addition to 16 initially proved difficult, owing to additional allylation by displacement of the 6-methoxy group on the pyridine ring. This problem was overcome, by performing the reaction under higher dilution, to give the required addition product in high yield. Ruthenium-catalysed ring closing metathesis of pyridine-containing substrates has been reported as problematic, owing to competing coordination of the pyridine nitrogen to the catalyst.14 Nevertheless, diene 17 underwent smooth RCM using 3 mol% Grubbs’ first generation catalyst to give (3-pyridyl)cyclohexenol 13 in excellent yield.

Again, direct bromination of 13, using NBS, failed. We thus turned our attention to effecting a direct selenation via deprotonation of 13 at the benzylic position. As selenophenylmethylpyridine 7b was only obtained in low yield, by direct selenation of 11, a variety of bases and electrophiles were screened in an effort to more efficiently access selenide 8b.11 After some optimization, it was discovered that use of 2.2 equivalents of tBuLi as base, THF/DMPU as solvent and phenylselenium chloride as electrophile furnished 8b in 79% yield (Scheme 5).11 With quantities of selenide 8b in hand, we next embarked on a study of the 6-exo-trig radical cyclisation of this compound, in an effort to access the bicyclo[3.3.1]nonane core of huperzine A. Cyclisation of 8b, under the conditions previously developed for cyclisation of 5 and 7b, gave the desired bicyclo[3.3.1]nonane 18 in 46% yield along with the reduced product 13 in 54% yield. While the yield of cyclised product is only moderate, this result, and the excellent yield achieved during cyclisation of 7b, indicates that the (2-pyridyl)methyl radical is being formed quantitatively under these reaction conditions. In an effort to more fully probe the 6-exo-trig radical cyclisation of compounds of type 8b we also investigated the triethylsilyl ether 19, readily accessed by treatment of alcohol 8b with TESCl in the presence of imidazole. We were delighted to find that 6-exo-trig radical cyclisation of 19 occurs in 79% yield.

The increase in yield may be attributable to stereoelectronic factors. It is probable that the optimal conformation for SOMO-LUMO overlap is 21a, with the pyridylmethyl moiety occupying a pseudo-axial position. However, when R = H, the more stable transition-state conformer is likely to be 21b, and thus, reduction of the radical with tributyltin hydride, or intramolecular abstraction of an allylic hydrogen,15 competes with cyclisation. However, the transition state conformer 21a may be more favourable when a bulky geminal substituent such as a silyloxy ether is present. Unfortunately, attempts to further verify this theory have, so far, been thwarted by difficulties encountered in the conversion of tertiary alcohol 8b to the more bulky tert-butyldimethylsilyl ether under a variety of reaction conditions.

In conclusion, we have further broadened the scope and utility of 3-pyridyl radicals by the use of these species in the synthesis of novel hexahydroindenopyridines. Furthermore, we have shown that, hitherto unaccessed, (2-pyridyl)methyl radicals can be formed quantitatively from 2-(phenylselenylmethyl)pyridines under standard conditions. These species undergo 5-exo-trig cyclisation, in excellent yield, to give hexahydroindenopyridines and have also been revealed to undergo 6-exo-trig cyclisation to give bicyclo[3.3.1]nonanes related to the core structure of huperzine A. Future work will concentrate on further optimizing the yield of the latter mode of cyclisation and on investigating the radical cyclisation of more functionalized substrates in an effort to achieve a total synthesis of huperzine A.

EXPERIMENTAL
General. All reactions were performed under a nitrogen atmosphere using oven-dried glassware. All solvents were dried by distillation from calcium hydride (CH2Cl2, benzene, DMF) or sodium-benzophenone (THF and diethyl ether). Benzene was degassed by sonication before use. Flash chromatography was performed using Scharlau 60 (230-400 mesh ASTM) silica gel and thin layer chromatography was performed on Merck silica gel 60 F254 plates. IR spectra were recorded using a Perkin-Elmer Spectrum 1000 Fourier-Transform IR spectrometer. NMR spectra were recorded using a Bruker Avance 300 Spectrometer or a Bruker DRX 400 Spectrometer. 1H NMR chemical shifts are reported in parts per million (ppm) relative to the tetramethylsilane peak (δ 0.00 ppm). 1H NMR values are reported as chemical shift δ, multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet), coupling constant (J)2 and relative integral. Coupling constants were taken directly from the spectra. Assignments were made with the aid of DEPT, COSY, HSQC, HMBC and NOESY experiments. Low resolution and accurate mass data were recorded on a VG70SE spectrometer operating at a nominal accelerating voltage of 70 eV. Ionisation was effected using electron impact (EI+), or chemical ionisation (CI+) using ammonia as a carrier gas. Major and significant fragments are quoted in the form x (y), where x is the mass to charge ratio (m/z) and y is the percentage abundance relative to the base peak (100%).

2-Methoxy-5,6,7,8,8a,9-hexahydroindeno[2,1-b]pyridine-8a-ol (10)
A solution of tributyltin hydride (0.06 mL, 0.21 mmol) and AIBN (0.0041 g, 0.03 mmol) in degassed benzene (40 mL) was added over 4.5 h, using a syringe pump, to a solution of bromopyridine 5 (0.04 g, 0.14 mmol) in degassed benzene (150 mL) under reflux. The reaction mixture was stirred under reflux for a further 2 h then cooled to rt and concentrated in vacuo. A saturated aqueous solution of potassium fluoride (25 mL) was added to the residue and the mixture stirred at rt overnight. The reaction mixture was extracted with Et2O (3 x 25 mL) and the combined organic extracts washed with brine (25 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography eluting with diethyl Et2O:hexane (2:1) to give the title compound (0.02 g, 64%) as a colourless oil. IR (neat) 3392, 2929, 2855, 1591, 1472, 1416, 1297 cm-1; 1H-NMR (300 MHz, CDCl3) δ 1.34−1.45 (m, 3H), 1.61-1.72 (m, 3H), 1.82-1.86 (m, 1H), 1.92-1.96 (m, 1H), 2.85 (d, J = 16.2 Hz, 1H), 2.90 (t, J = 5.7 Hz, 1H), 3.05 (d, J = 16.2 Hz, 1H), 3.91 (s, 3H), 6.52 (d, J = 8.3 Hz, 1H), 7.31 (d, J = 8.3 Hz, 1H); 13C-NMR (75 MHz, CDCl3) δ 22.4, 22.5, 28.5, 35.1, 46.6, 49.6, 53.5, 79.6, 108.1, 131.7, 133.9, 159.3, 164.2; MS (EI) m/z: 219 (100, M+), 190 (53), 176 (75). HRMS (EI): M+, found 219.1256, C13H17NO2 requires 219.1259.

1-(6-Methoxy-2-(phenylselenylmethyl)pyridin-3-yl)cyclohex-2-en-ol (7b)
A solution of nBuLi (1.5 M in hexane, 2.31 mL, 3.15 mmol) was added to a solution of (3-pyridyl)cyclohexenol 1112 (0.31 g, 1.43 mmol) in THF (10 mL) at -78 °C. The mixture was stirred at -78 °C for 30 min then a solution of diphenyl diselenide (0.33 g, 1.72 mmol) in THF (7 mL) was added dropwise. The reaction mixture was stirred at -78 °C for a further 30 min then warmed to rt and quenched by the addition of a solution of saturated aqueous ammonium chloride (15 mL) The mixture was extracted with Et2O (2 x 15 mL) and the combined organic layers were dried over anhydrous magnesium sulphate and concentrated in vacuo. The residue was purified by flash column chromatography eluting with EtOAc:hexane (3:97) to give the title compound (0.11 g, 20%) as a yellow oil; IR (neat) 3400, 2934, 1591, 1475, 1421, 1314, 1262, 1032; 1H-NMR (300 MHz, CDCl3) δ 1.50−2.12 (m, 6H), 3.83 (s, 3H), 4.40 (d, J = 11.2 Hz, 1H), 4.61 (d, J = 11.2 Hz, 1H), 5.82 (d, J = 10.0 Hz, 1H), 5.96-6.03 (m, 1H), 6.53 (d, J = 8.4 Hz, 1H), 7.21-7.30 (m, 3H), 7.60-7.65 (m, 2H), 7.69 (d, J = 8.4, 1H); 13C-NMR (75 MHz, CDCl3) δ 19.0, 24.7, 33.2, 37.8, 53.1, 71.8, 108.6, 126.7, 128.8, 129.2, 130.8, 132.0, 132.7, 133.0, 138.6, 153.6, 161.9; MS (EI) m/z: 375(18, M+), 314 (68), 200 (82), 176 (93), 157 (93), 97 (91), 77(100). HRMS (EI): M+, found 375.0736, C19H21NO280Se requires 375.0738.

2-Methoxy-5,6,7,8,8a,9-hexahydroindeno[2,1-b]pyridine-4b-ol (12)
A solution of tributyltin hydride (0.03 mL, 0.01 mmol) and AIBN (0.003 g, 0.02 mmol) in degassed benzene (3 mL) was added dropwise over 4.5 h, using a syringe pump, to a solution of selenide 7b (0.02 g, 0.01 mmol) in degassed benzene (10 mL) under reflux. The reaction mixture was stirred under reflux for a further 2 h then cooled to rt and concentrated in vacuo. A saturated aqueous solution of potassium fluoride (25 mL) was added to the residue and the mixture stirred at rt overnight. The reaction mixture was extracted with Et2O (3 x 25 mL) and the combined organic extracts washed with brine (25 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography eluting with EtOAc:hexane (1:9) to give the title compound (0.02 g, 97%) as a colourless oil; IR (neat) 3392, 2929, 2855, 1591, 1472, 1416, 1297; 1H-NMR (400 MHz, CDCl3) δ 1.10-1.32 (m, 4H), 1.52-1.58 (m, 1H), 1.76-1.81 (m, 3H), 2.29-2.33 (m, 1H), 2.51 (dd, J = 16.2, 4.9 Hz, 1H), 3.15 (dd, J = 16.2, 16.1 Hz, 1H), 3.94 (s, 3H), 6.57 (d, J = 8.3 Hz, 1H), 7.48 (d, J = 8.3 Hz, 1H); 13C-NMR (100 MHz, CDCl3) δ 22.1, 23.0, 28.5, 34.7, 37.6, 46.9, 53.5, 79.8, 109.4, 132.7, 133.0, 156.5, 162.1; MS (EI) m/z: 219 (26, M+), 201 (42), 176 (100). HRMS (EI): M+, found 219.1259, C13H17NO2 requires 219.1259.

1-(6-Methoxy-2-methylpyridin-3-yl)cyclohex-3-enol (13)
Method 1. A solution of nBuLi (1.5M in hexane, 0.39 mL, 1.48 mmol) was added dropwise to a solution of bromopyridine 98e,12 (0.10 g, 0.49 mmol) in THF (3 mL) at -78 °C. The reaction mixture was stirred at this temperature for 30 min then a solution of 3-cyclohexen-1-one13 (0.33 mL, 3.39 mmol) in THF (3 mL) was added dropwise. The reaction mixture was stirred for a further 30 min at ¬-78 °C then warmed to rt and quenched by the addition of saturated aqueous ammonium chloride (15 mL). The mixture was extracted with Et2O (2 x 5 mL) and the combined organic layers were dried over anhydrous magnesium sulfate, concentrated in vacuo and the residue purified by flash column chromatography eluting with EtOAc:hexane (1:9) to give the title compound (0.02 g, 18%) as a colourless oil.
Method 2. Grubbs’ first generation catalyst (0.04 g, 0.05 mmol) was added to a solution of diene 17 (0.40 g, 1.62 mmol) in CH2Cl2 (15 mL) at rt. The reaction mixture was stirred at this temperature for 2 h then concentrated in vacuo. The residue was purified by flash column chromatography eluting with EtOAc:hexane (1:9) to give the title compound (0.34 g, 94%) as a colourless oil; IR (neat) 3421, 2927, 1590, 1475, 1422, 1304; 1H-NMR (300 MHz, CDCl3) δ 2.06−2.12 (m, 4Η), 2.46-2.53 (m, 2H), 2.72 (s, 3H), 3.09 (s, 3H), 5.72-5.76 (m, 1H), 5.76-5.82 (m, 1H), 6.53 (d, J = 8.6 Hz, 1H), 7.57 (d, J = 8.6 Hz, 1H); 13C-NMR (75 MHz, CDCl3) δ 23.1, 25.0, 33.4, 39.2, 53.3, 71.9, 106.7, 124.5, 127.2, 132.0, 136.9, 154.8, 161.9; MS (EI) m/z: 219 (17, M+), 165 (73), 150 (100). HRMS (EI): M+, found 219.1257, C13H17NO2 requires 219.1259.

1-(6-Methoxy-2-methylpyridin-3-yl)pent-4-en-1-ol (15)
A solution of but-3-enyl bromide (1.48 g, 14.6 mmol) in Et2O (5 mL) was added dropwise to a mixture of magnesium (0.36 g, 14.6 mmol) and a crystal of iodine in Et2O (5 mL), at such a rate as to maintain a gentle reflux. The reaction mixture was then stirred under reflux for 1 h then cooled to 0 °C. A solution of aldehyde 1412 (1.00 g, 6.62 mmol) in Et2O (5 mL) was added dropwise and the reaction mixture stirred at 0 °C for 1 h, warmed to rt and quenched by the addition of saturated aqueous ammonium chloride (20 mL). The mixture was extracted with Et2O (2 x 20 mL) and the combined organic layers washed with brine (2 x 10 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography eluting with Et2O:hexane (1:9) to give the title compound (1.0 g, 77%) as a colourless oil; IR (neat) 3392, 2941, 1597, 1478, 1309, 1041; 1H-NMR (400 MHz, CDCl3) δ 1.82−1.86 (m, 2Η), 2.12−2.18 (m, 2Η), 2.45 (s, 3H), 3.91 (s, 3H), 4.89-4.92 (m, 1H), 5.08-5.13 (m, 2H), 5.81-5.89 (m, 1H), 6.10 (d, J = 8.5, 1H), 7.65 (d, J = 8.5, 1H); 13C-NMR (100 MHz, CDCl3) δ 21.6, 30.1, 37.1, 53.3, 69.4, 107.8, 115.2, 130.1, 136.5, 137.0, 154.8, 162.4; MS (EI) m/z: 207 (8, M+), 152 (100). HRMS (EI): M+, found 207.1255, C12H17NO2 requires 207.1259.

1-(6-Methoxy-2-methylpyridin-3-yl)pent-4-en-1-one (16)
Dess-Martin periodinane (4.14 g, 9.74 mmol) was added in one portion to a solution of alcohol 15 (1.0 g, 4.87 mmol) and pyridine (2.35 mL, 29.2 mmol) in CH2Cl2 (50 mL) at rt and the reaction mixture stirred at this temperature for 2 h. Saturated aqueous sodium thiosulfate (10 mL) and saturated aqueous sodium hydrogen carbonate (10 mL) were added and the mixture extracted with CH2Cl2 (2 x 10 ml). The combined organic extracts were dried over anhydrous magnesium sulfate, concentrated in vacuo and the residue purified by flash column chromatography eluting with Et2O:hexane (1:19) to give the title compound (0.84 g, 84%) as a colourless oil; IR (neat) 2943, 1682, 1587, 1478, 1313, 1128; 1H-NMR (400 MHz, CDCl3) δ 2.46-2.49 (m, 2H), 2.69 (s, 3H), 2.95 (t, J = 7.2 Hz, 2H), 4.01 (s, 3H), 5.02-5.11 (m, 2H), 5.88-5.93 (m, 1H), 6.60 (d, J = 8.6, 1H), 7.93 (d, J = 8.6, 1H); 13C-NMR (100 MHz, CDCl3,) δ 25.0, 28.4, 40.0, 53.7, 107.3, 115.4, 125.8, 137.2, 139.5, 159.0, 164.2, 200.4; MS (EI) m/z: 205 (8, M+), 150 (100), 56 (20). HRMS (EI): M+, found 205.1110, C12H15NO2 requires 205.1103.

4-(6-Methoxy-2-methylpyridin-3-yl)octa-1,7-dien-4-ol (17)
A solution of allyl bromide (0.76 mL, 9.02 mmol) in Et2O (10 mL) was added dropwise to a mixture of magnesium (0.22 g, 9.02 mmol) and a crystal of iodine in Et2O (40 mL), at such a rate as to maintain a gentle reflux. The reaction mixture was then stirred under reflux for 1 h then cooled to 0 °C and a solution of ketone 16 (0.84 g, 4.10 mmol) in Et2O (40 mL) added dropwise. The reaction mixture was stirred at 0 °C for 1 h then warmed to rt and quenched by the addition of saturated aqueous ammonium chloride (20 mL) and extracted with Et2O (2 x 20 mL). The combined organic layers were dried over anhydrous magnesium sulfate, concentrated in vacuo and the residue purified by flash column chromatography eluting with Et2O:hexane (1:9) to give the title compound (0.82 g, 79%) as a colourless oil; IR (neat) 3504, 3076, 2944, 1592, 1475, 1307, 1043; 1H-NMR (400 MHz, CDCl3) δ 1.82−2.01 (m, 2Η), 2.02−2.15 (m, 2Η), 2.55 (dd, J = 14.0, 8.3 Hz, 1H), 2.61 (s, 3H), 2.85 (dd, J = 14.0, 6.3 Hz, 1H), 3.89 (s, 3H), 4.92-5.00 (m, 2H), 5.05-5.15 (m, 2H), 5.54-5.62 (m, 1H), 5.72-5.83 (m, 1H), 6.52 (d, J = 8.6 Hz, 1H), 7.73 (d, J = 8.6 Hz, 1H); 13C-NMR (100MHz, CDCl3) δ 24.9, 28.0, 39.8, 45.7, 53.6, 75.3, 106.4, 114.2, 119.5, 130.7, 133.1, 138.2, 138.3, 152.5, 161.5; MS (CI, NH3) m/z: 248 (100, MH+), 230 (60), 206 (55), 150 (30). HRMS (CI): MH+, found 248.1647, C15H22NO2 requires 248.1651.

1-(6-Methoxy-2-(phenylselenylmethyl)pyridin-3-yl)cyclohex-3-en-1-ol (8b)
A solution of tert-butyllithium (1.5 M in pentane, 0.73 mL, 1.10 mmol) was added to a solution of pyridinylcyclohexenol 13 (0.10 g, 0.46 mmol) and DMPU (0.12 mL, 1.01 mmol) in THF (4 mL) at -78 °C. The mixture was stirred at 78 °C for 30 min then a solution of phenylselenium chloride (0.11 g, 0.55 mmol) was added dropwise. The reaction mixture was stirred for a further 30 min then warmed to rt and quenched by the addition of saturated aqueous ammonium chloride (5 mL). The mixture was extracted with Et2O (2 x 10 mL), the combined organic layers dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography using EtOAc:hexane (3:97) to give the title compound (0.13 g, 77%) as a yellow oil; IR (neat) 3447, 3014, 2923, 1591, 1475, 1313; 1H-NMR (400 MHz, CDCl3) δ 1.78-1.82 (m, 2H), 2.15-2.19 (m, 2H), 2.47-2.51 (m, 2H), 3.72 (s, 3H), 4.53 (d, J = 11.2 Hz, 1H), 4.64 (d, J = 11.2 Hz, 1H), 5.68-5.76 (m, 2H), 6.52 (d, J = 8.7 Hz, 1H), 7.29-7.28 (m, 2H), 7.48 (d, J = 8.7 Hz, 1H), 7.62-7.68 (m, 2H); 13C-NMR (100 MHz, CDCl3) δ 23.1, 34.2, 34.3, 40.0, 53.3, 72.2, 108.1, 124.4, 126.7, 127.2, 128.8, 131.3, 131.8, 133.1, 137.3, 155.0, 161.8; MS (EI) m/z: 375 (49, M+), 356 (33), 294 (19), 218 (100), 200 (97); HRMS (EI): M+, found 375.0736, C19H21NO280Se requires 375.0738.

5-Methoxy-6-azatricyclo[7.3.1.02,7]trideca-2,4,6-trien-1-ol (18)
A solution of tributyltin hydride (0.06 mL, 0.18 mmol) and AIBN (0.0035 g, 0.02 mmol) in degassed benzene (40 mL) was added dropwise over 4.5 h, using a syringe pump, to a solution of selenide 8b (0.04 g, 0.12 mmol) in degassed benzene (150 mL) under reflux. The reaction mixture was stirred under reflux for a further 2 h then cooled to rt and concentrated in vacuo. A saturated aqueous solution of potassium fluoride (50 mL) was added to the residue and the mixture stirred at rt overnight. The reaction mixture was extracted with Et2O (3 x 50 mL) and the combined organic extracts washed with brine (50 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography eluting with EtOAc:hexane (1:9) to give compound 13 (0.02 g, 54%) as a colourless oil and the title compound (0.01 g, 46%) as a colourless oil; IR (neat) 3394, 2928, 1579, 1477, 1311; 1H-NMR (400 MHz, CDCl3) δ 1.09-1.12 (m, 1H), 1.52-1.56 (m, 3H), 1.59-1.62 (m, 2H), 1.85 (dd, J = 11.5, 1.3 Hz, 1H), 1.90 (d, J = 11.5, 1H), 2.47-2.51 (m, 1H), 2.62 (d, J = 18.6 Hz, 1H), 3.15 (dd, J = 18.6, 7.1 Hz, 1H), 3.92 (s, 3H), 6.56 (d, J = 8.5 Hz, 1H), 7.73 (d, J = 8.5 Hz, 1H); 13C-NMR (100 MHz, CDCl3) δ 20.8, 29.9, 32.4, 38.0, 40.8, 41.6, 53.3, 70.9, 107.9, 130.1, 154.3, 162.5; MS (EI) m/z: 219 (8, M+), 176 (100). HRMS (EI): M+, found 219.1262, C13H17NO2 requires 219.1259.

1-(6-Methoxy-2-(phenylselenylmethyl)pyridin-3-yl)-3-(1-(triethylsilyloxy)cyclohex-3-ene (19)
A mixture of alcohol 8b (0.19 g, 0.51 mmol), imidazole (0.26 g, 3.81 mmol) and triethylsilyl chloride (0.51 mL, 2.54 mmol) in DMF (10 mL) was stirred at rt for 12 h. Water (10 mL) was added and the mixture extracted with Et2O (2 x 15 mL). The combined organic layers were dried over anhydrous magnesium sulfate, concentrated in vacuo and the residue purified by flash column chromatography eluting with hexane to give the title compound (0.16 g, 63%) as a colourless oil; IR (neat) 2954, 2876, 1591, 1475, 1313, 1237, 1074; 1H-NMR (400 MHz, CDCl3) δ 0.46 (t, J = 7.9 Hz, 9H), 0.81 (q, J = 7.9 Hz, 6H), 1.51-1.62 (m, 1H), 1.89-1.98 (m, 1H), 2.26-2.33 (m, 1H), 2.41-2.51 (m, 1H), 2.48-2.53 (m, 1H), 2.69-2.71 (m, 1H), 3.81 (s, 3H), 4.58 (d, J = 11.7 Hz, 1H), 4.89 (d, J = 11.7 Hz, 1H), 5.60-5.72 (m, 1H), 5.70-5.73 (m, 1H), 6.43 (d, J = 8.5 Hz, 1H), 7.20-7.29 (m, 2H), 7.63-7.65 (m, 2H), 7.30 (d, J = 8.5 Hz, 1H); 13C-NMR (100 MHz, CDCl3) δ 6.5, 7.0, 24.6, 33.4, 36.3, 40.0, 53.4, 75.0, 107.1, 124.7, 126.4, 127.9 (2C), 128.8, 130.4, 132.3, 137.7, 155.2, 161.9; MS (EI) m/z: 489 (20, M+), 358 (55), 200 (100). HRMS (EI): M+, found 489.1598, C22H35NO2Si80Se requires 489.1602.

1-(Triethylsilyloxy)-5-methoxy-6-azatricyclo[7.3.1.02,7]trideca-2,4,6-triene (20)
A solution of tributyltin hydride (0.04 mL, 0.15 mmol) and AIBN (0.003 g, 0.02 mmol) in degassed benzene (40 mL) was added dropwise over 4.5 h, using a syringe pump, to a solution of selenide 19 (0.05 g, 0.10 mmol) in degassed benzene (150 mL) under reflux. The reaction mixture was stirred under reflux for a further 2 h then cooled to rt and concentrated in vacuo. A saturated aqueous solution of potassium fluoride (50 mL) was added to the residue and the mixture stirred at rt overnight. The reaction mixture was extracted with Et2O (3 x 50 mL) and the combined organic extracts washed with brine (50 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography eluting with EtOAc:hexane (1:19) to give the title compound (0.03 g, 73%) as a colourless oil; IR (neat) 2934, 2874, 1594, 1476, 1419, 1312, 1122; 1H-NMR (400 MHz, CDCl3) δ 0.57 (q, J = 7.9, 6H), 0.91 (t, J = 7.9, 9H), 1.41-1.70 (m, 6H), 1.90-2.05 (m, 2H), 2.41-2.50 (m, 1H), 2.65 (dd, J = 18.5, 8.4 Hz, 1H), 3.11 (dd, J = 18.5, 7.3 Hz, 1H), 3.91 (s, 3H), 6.54 (d, J = 8.5, 1H), 7.69 (d, J = 8.5, 1H); 13C-NMR (100 MHz, CDCl3) δ 6.2, 7.1, 52.2, 29.1, 29.6, 32.6, 38.1, 40.5, 42.7, 73.3, 107.7, 132.0, 136.0, 154.0, 162.3. MS (EI) m/z: 333 (13, M+), 290 (100), 202 (22). HRMS (EI): M+, found 333.2124, C19H31NO2Si requires 333.2124.

ACKNOWLEDGEMENTS
We thank the Royal Society of New Zealand Marsden Fund for financial support.

References

1. J.-S. Liu, Y.-L. Zhou, C.-M. Yu, Y.-Z. Zhou, Y.-Y. Han, F.-W. Wu, and B.-F. Qi, Can. J. Chem., 1986, 64, 837. CrossRef
2. G. D. Ainge and S. D. Lorimer, J. Agric. Food Chem., 2002, 50, 491. CrossRef
3. (a) H. Wang and X. C. Tang, Acta Pharmacol. Sin., 1998, 19, 27; (b) X. C. Tang and Y. F. Han, CNS Drug Review, 1999, 5, 281.
4. (a) S. S. Xu, Z. Y. Cai, Z. W. Qu, R. M. Yang, Y. L. Cai, G. Q. Wang, X. Q. Su, X. S. Zhong, R. Y.Cheng, W. A. Xu, J. X. Li, and B. Feng, Acta Pharmacol. Sin., 1999, 20, 486; (b) H. Jiang, X. Luo, and D. Bai, Curr. Med. Chem., 2003, 10, 2231; CrossRef (c) A. Zangara, Curr. Top. Neutraceutical Res., 2003, 1, 193.
5. (a) G. Lallement, J. P. Demoncheaux, A. Foquin, D. Baubichon, M. Galonnier, D. Clarencon, and F. Dorandeu, Drug Chem. Toxicol., 2002, 25, 309; CrossRef (b) G. Lallement, V. Baille, D. Baubichon, P. Carpentier, J. M. Collombet, P. Filliat, A. Foquin, E. Four, C. Masquiliez, G. Testylier, L. Tonduli, and F. Dorandeu, Neurotoxicology, 2002, 23, 1. CrossRef
6. (a) H. S. Ved, M. L. Koening, J. R. Dave, and B. P. Doctor, Neuroreport, 1997, 8, 963; CrossRef (b) X. Q. Xiao, R. Wang. Y. Han, and X. C. Tang, Neurosci. Lett., 2000, 286, 155; CrossRef (c) R. K. Gordon, S. V. Nigam, J. A. Weitz, J. A. Dave, J. R. Dave, B. P. Doctor, and H. S. Ved, J. Appl. Toxicol., 2001, 21(suppl. 1), S47-S51; CrossRef (d) X. Q. Xiao, H. Y. Zhang, and X. C. Tang, J. Neurosci. Res., 2002, 67, 30; CrossRef (e) H. Y. Zhang, H. Yan, and X. C. Tan, Cell Mol. Neurobiol., 2008, 28, 173. CrossRef
7. (a) L. Qian and R. Ji, Tetrahedron Lett., 1989, 30, 2089; CrossRef (b) F. Yamada, A. P. Kozikowski, E. R. Reddy, Y. P. Pang, J. H. Miller, and M. McKinney, J. Am. Chem. Soc., 1991, 113, 4695; CrossRef (c) A. P. Kozikowski, G. Campiani, P. Aagaard, and M. J. McKinney, J. Chem. Soc., Chem. Commun., 1993, 10; (d) G. Campiani, L. Q. Sun, A. P. Kozikowskii, P. Aagaard, and M. J. McKinney, J. Org. Chem., 1993, 58, 860; CrossRef (e) S. Kaneko, T. Yoshino, T. Katoh, and S. Terashima, Tetrahedron, 1998, 54, 5471; CrossRef (f) P. Camps, J. Contreras, R. El Achab, J. Morral, D. Munoz-Torrero, M. Font-Bardia, X. Solans, A. Badia, and N. M. Vivas, Tetrahedron, 2000, 56, 4541; CrossRef (g) Y. Xia and A. P. Kozikowski, J. Am. Chem. Soc., 1989, 111, 4116; CrossRef (h) C. Lucey, S. A. Kelly, and J. Mann, Org. Biomol. Chem., 2007, 5, 301. CrossRef
8. (a) A. P. Kozikowski, R. E. Reddy, and C. P. Miller, J. Chem. Soc., Perkin Trans. 1, 1990, 195; CrossRef (b) G. Kraus, J. Hanson, and D. Vines, Synth. Commun., 1992, 22, 2625; CrossRef (c) C. Chassaing, A. Haudrechy, and Y. Langlois, Synth. Commun., 1997, 27, 61; CrossRef (d) S. Kaneko, T. Yoshino, T. Katoh, and S. Terashima, Tetrahedron Lett., 1997, 8, 829; (e) V. Caprio and J. Mann, J. Chem. Soc., Perkin Trans. 1, 1998, 3151; CrossRef (f) X.-C. He, B. Wang, and D. Bai, Tetrahedron Lett., 1998, 39, 411; CrossRef (g) C. Chassaing, A. Haudrechy, and Y. Langlois, Tetrahedron Lett., 1999, 40, 8805; CrossRef (h) Y. Foricher and J. Mann, Tetrahedron Lett., 2000, 41, 2007; CrossRef (i) A. Haudrechy, C. Chassaing, C. Riche, and Y. Langlois, Tetrahedron, 2000, 56, 3181; CrossRef (j) K. Hogenauer, K. Baumann, and J. Mulzer, Tetrahedron Lett., 2000, 41, 9229; CrossRef (k) X.-C. He, B. Wang, G. Yu, and D. Bai, Tetrahedron: Asymmetry, 2001, 12, 3213; CrossRef (l) S. A. Kelly, Y. Foricher, J. Mann, and J. M. Bentley, Org. Biomol. Chem., 2003, 1, 2865; CrossRef (m) Q.-B. Pan and D.-W. Ma, Chin. J. Chem., 2003, 21, 793.
9. (a) Y. Xia, E. R. Reddy, and A. P. Kozikowski, Tetrahedron Lett., 1989, 30, 3291; CrossRef (b) A. P. Kozikowski, F. Yamada, and Y. P. Pang, Tetrahedron Lett., 1992, 33, 2653; CrossRef (c) X. He, Z. Wang, Y. Li, Z. Xu, and D. Bai, Chin. Chem. Lett., 1993, 4, 597; (d) A. P. Kozikowski, W. Tuckmantel, A. Saxena, and B. P. Doctor, Helv. Chim. Acta, 1994, 77, 256; CrossRef (e) X. He, X. Chang, R. Zhen, Y. L. Li, Z. Y. Wang, and D. L. Bai, Chin. Chem. Lett., 1994, 5, 471; (f) A. P. Kozikowski, G. Campiani, A. Saxena, and B. P. Doctor, J. Chem. Soc., Chem. Commun., 1995, 283; CrossRef (g) D. M. Fink, G. M. Bores, R. C. Effland, F. P. Huger, B. E. Kurys, D. K. Rush, and D. E. Selk, J. Med. Chem., 1995, 38, 3645; CrossRef (h) A. P. Kozikowski, Q. Ding, A. Saxena, and B. P Doctor, Bioorg. Med. Chem. Lett., 1996, 6, 259; CrossRef (i) A. P. Kozikowski, G. Campiani, V. Nacci, A. Sega, A. Saxena, and B. P. Doctor, J. Chem. Soc. Perkin Trans. 1, 1996, 1287; CrossRef (j) S. Kaneko, N. Nakajima, M. Shikano, T. Katoh, and S. Terashima, Bioorg. Med. Chem. Lett., 1996, 6, 1927; CrossRef (k) A. P. Kozikowski, G. Campiani, L.-Q. Sun, S. Wang, A. Saxena, and B. P. Doctor, J. Am. Chem. Soc., 1996, 118, 11357; CrossRef (l) S. Kaneko, T. Yoshino, T. Katoh, and S. Terashima, Heterocycles, 1997, 46, 27; CrossRef (m) P. Camps, J. Contreras, M. Font-Bardia, J. Morral, D. Munoz-Terrero, and X. Solans, Tetrahedron: Asymmetry, 1998, 9, 835; CrossRef (n) G. Campiani, A. P. Kozikowski, S. Wang, L. Ming, V. Nacci, A. Saxena, and B. P. Doctor, Bioorg. Med Chem. Lett., 1998, 8, 1413; CrossRef (o) S. Kaneko, N. Nakajima, M. Shikano, T. Katoh, and S. Terashima, Tetrahedron, 1998, 54, 5485; CrossRef (p) P. Camps, J. Contreras, J. Morral, D. Munoz-Torrero, M. Font-Bardia, and X. Solans, Tetrahedron, 1999, 55, 8481; CrossRef (q) F. Zeng, H. Jiang, Y. Zhai, H. Zhang, K. Chen, and R. Ji,, Bioorg. Med. Chem. Lett., 1999, 9, 3279; CrossRef (r) P. R. Carlier, D.-M. Du, Y.-F. Han, J. Liu, E. Perola, I. D. Williams, and Y.-P. Pang, Angew. Chem. Int. Ed., 2000, 39, 1775; CrossRef (s) P. Camps, R. El Achab, J. Morral, D. Munoz-Torrero, A. Badia, J. E. Banos, N. M. Vivas, X. Barril, M. Orozco, and F. J. Luque, J. Med. Chem., 2000, 43, 4657; CrossRef (t) P. Camps and D. Munoz-Torrero, Mini-Rev. Med. Chem., 2001, 1, 163; CrossRef (u) V. Rajendran, S.-B. Rong, A. Saxena, B. P. Doctor, and A. P. Kozikowski, Tetrahedron Lett., 2001, 42, 5359; CrossRef (v) P. Camps, D. Munoz-Torrero, and M. Simon, Synth. Commun., 2001, 31, 3507; CrossRef (w) K. Hogenauer, K. Baumann, A. Enz, and J. Mulzer, Bioorg. Med. Chem. Lett., 2001, 11, 2627; CrossRef (x) G. Y. Jin, X. C. He, H. Y. Zhang, and D. L. Bai, Chin. Chem. Lett., 2002, 12, 23; (y) G.-C. Zhou and D.-Y. Zhu, Synth. Commun., 2002, 32, 37; CrossRef (z) S. Gemma, S. Butini, C. Fattorusso, I. Fiorini, V. Nacci, K. Bellebaum, D. McKissic, S. Ashima, and G. Campiani, Tetrahedron, 2002, 59, 87. CrossRef
10. (a) V. Snieckus, Bull. Chem. Soc. Fr., 1988, 67; (b) K. Shankaran, C. P. Sloan, and V. Snieckus, Tetrahedron Lett., 1985, 26, 6001; CrossRef (c) D. Harrowven, Tetrahedron Lett., 1993, 34, 5653; CrossRef (d) K. Jones and A. Fiumana, Tetrahedron Lett., 1996, 37, 8049; CrossRef (e) A. Nadin and T. Harrison, Tetrahedron Lett., 1999, 40, 4073; CrossRef (f) K. Jones, A. Fiumana, and M. L. Escudero-Hernandez, Tetrahedron, 2000, 56, 397; CrossRef (g) S. Maiti, B. Achari, R. Mukhopadhyay, and A. K. Banerjee, J. Chem. Soc., Perkin Trans. 1, 2002, 1769; CrossRef (h) R. S. Baker, M. Cases, M. Keenan, R. A. Lewis, and P. Tan, Tetrahedron, 2003, 44, 2995. CrossRef
11. J. Ward and V. Caprio, Tetrahedron Lett., 2006, 47, 553. CrossRef
12. M. A Gray, L. Konopski, and Y. Langlois, Synth. Commun., 1994, 24, 1367. CrossRef
13. G. M. Rubottom and G. M. Gruber, J. Org. Chem., 1977, 42, 1051. CrossRef
14. (a) F.-X. Felpin, M.-J. Bertrand, and J. Lebreton, Tetrahedron, 2002, 58, 7381; CrossRef (b) F.-X. Felpin, S. Girard, G. Vo-Thanh, R. J. Robins, J. Villiéras, and J. Lebreton, J. Org. Chem., 2001, 66, 6305. CrossRef
15. A. L. J. Beckwith and G. Moad, J. Chem. Soc., Chem. Commun., 1974, 472. CrossRef