Nitrogen is a requirement for the photochemical induced 3-azabicyclo[3.3.1]nonane skeletal rearrangement!

Article abstract of DOI:10.1016/j.tet.2005.02.013

Specific 3-azabicyclo[3.3.1]nonane derivatives undergo skeletal cleavage when subjected to light or Lewis acidic conditions affording novel heterotricycles, which is in stark contrast to 3-oxabicyclo[3.3.1]nonanes.

Full text of DOI:10.1016/j.tet.2005.02.013

Tetrahedron 61 (2005) 3771–3779
Nitrogen is a requirement for the photochemical induced
3-azabicyclo[3.3.1]nonane skeletal rearrangement!
†
*
Craig M. Williams, Ralf Heim and Paul V. Bernhardt
School of Molecular and Microbial Sciences, University of Queensland, St. Lucia, Qld 4072, Australia
Received 17 September 2004; revised 18 January 2005; accepted 3 February 2005
Abstract—Specific 3-azabicyclo[3.3.1]nonane derivatives undergo skeletal cleavage when subjected to light or Lewis acidic conditions
affording novel heterotricycles, which is in stark contrast to 3-oxabicyclo[3.3.1]nonanes.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
(e.g., 5) when treated chemically (1. NBS; 2. MeI; 3. NaOH)
(Scheme 1).8
The 3-azabicyclo[3.3.1]nonane (3-ABN) skeleton 1 is well
known1 to both natural product2,3 and synthetic4 chemists
alike as it appears as the AE ring motif in the prolific C19-
(e.g., chasmanine 2) and C20- (e.g., atisine 3) diterpene
alkaloid series5,6 (Fig. 1).
Furthermore, synthetic 3-ABNs have been observed in only
three instances to undergo rearrangement [i.e., retroaldol9
(6 to 7), pinacol-type10 (8 to 9) and thermal11 (10 to 11)]
(Scheme 2).
Figure 1.
In comparison, however, rearrangement of the 3-ABN
skeleton is not so well known. For example, biosynthetic
rearrangement is seldom observed (e.g., arcutin7), although,
3-acetylyunaconitine 4 affords AE ring rearranged products
Scheme 2.
Recently, however, during the course of attempting to
optimise our direct route to C19- and C20-diterpene alkaloid
advanced intermediate 12,12 we discovered that certain
3-ABNs (e.g., 14) undergo unprecedented photochemical
rearrangement affording novel heterotricycles 15 (Scheme
3).13 Unfortunately, however, photochemical rearrangement
is not general and we herein disclose these results in full.
Scheme 1.
Keywords: Photochemistry; 3-Azabicyclo[3.3.1]nonane.
*
Corresponding author. Tel.: C61 7 3365 3530; fax: C61 7 3365 4299;
e-mail address: c.williams3@uq.edu.au
2. Results and discussion
† To whom correspondence should be made regarding X-ray crystal
structure analysis.
Paramount to studying the photochemical rearrangement of
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.02.013

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C. M. Williams et al. / Tetrahedron 61 (2005) 3771–3779
Scheme 3.
Scheme 4.
3-ABNs of type 14 was their synthesis and in this regard a
Meyer–Schuster rearrangement14 was found to be the
method of choice. Treatment of the propargylic alcohol
1312 with a selection of Lewis acids in trifluoroacetic acid
(TFA) gave the isopropyl deprotected enone 16 (Meyer–
Schuster product) and the corresponding deprotected
a-hydroxyketone 17 (triple bond hydration) in varying
ratios (Scheme 4). Trimethylsilyl trifluorosulfonate
(TMSOTf) in TFA was found to be the optimum conditions
affording a 9:1 ratio in favour of the enone 16. In stark
contrast treatment of propargylic alcohol 18 using the
successful conditions (TMSOTf/TFA) developed for 13,
gave the Meyer–Schuster product 19 only in low yield
(13%) along with pyranone 20 (19%) [confirmed by X-ray
crystal analysis (Fig. 2)], derived from a sequential [1,3]-
sigmatropic shift followed by enolic ring closure. Changing
the Lewis acid to borotrifluoride etherate, however, gave 19
in 89% (Scheme 4).
Photochemical rearrangement of 3-ABNs seem to be very
functional group specific, for example, photolysis of 16 at
300 nm in various oxygen free deuterated solvents results in
photochemical isomerization (cis to trans) of enone 16 to
enone 21 without the formation of any rearranged product
(Scheme 5). This is not easily explained, but maybe due to
one of a number of processes, which prevent n to p*
transitions, for example, nitrogen or oxygen protonation, or
hydrogen bonding.15
Figure 2.

C. M. Williams et al. / Tetrahedron 61 (2005) 3771–3779
3773
In contrast, irradiation of 19 gave the rearranged product 25
in very high yield (86%) (Scheme 7). To evaluate the scope
of this process the ketone functionality of 19 was replaced
with CH2 (e.g., 26), in an attempt to emulate a-hydrogen
abstraction reported by Grainger18 and Reddy (Scheme 7)19
and the ring N substituted with oxygen (27) (Scheme 8).
Conversion to diene 26 via standard Wittig methodology
(CH2]PPh3) proceeded smoothly (64%), however, photo-
lysis at 254 and 300 nm resulted in decomposition.
Scheme 5.
Whereas conversion of the phenol to an isopropyl ether
followed by photolysis afforded rearranged products (e.g.,
14 to 15). However, the etherfication procedure of
Banwell16 gave in addition to the isopropyl ether [i.e., 14
(48%)] pyranones 22 and 23 (29%) (Fig. 3), which was
easily circumvented using the procedure of Sargent17 in
conjunction with a large excess of iso-propylbromide (93%)
(Scheme 6). Pyranones 22 and 23 could be obtained in 26
and 61% yields, respectively, in the absence of isopropyl
bromide. Irradiation of 14, gave the rearranged product 15
(18%) along with a mixture (2:8) of 15 and 24 (51%)
(Scheme 4). Unfortunately, conversion to 15 cannot be
driven to completion, extended radiation leads to substantial
decomposition mostly likely due to complications arising
from the single electron susceptible bridgehead bromide
function. A photochemical equilibrium between 14/24 and
15 was dismissed when pure 15 was irradiated affording
slow decomposition.
Scheme 7.
Construction of 27, confirmed by X-ray crystal structure
analysis (Fig. 4), was achieved following similar protocols
used to synthesise 19, except starting from dimethyl 9-oxo-
3-oxabicyclo[3.3.1]nonane-1,5-dicarboxylate.20
Figure 3.
Figure 4.
Scheme 6.

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C. M. Williams et al. / Tetrahedron 61 (2005) 3771–3779
Scheme 10.
Scheme 8.
than oxa groups, however, it is difficult to transpose
intermediate 37 into product (e.g., 15 and 25) (Scheme 10).
Unfortunately, however, photolysis of 27 at 300 nm
returned starting material and irradiation at 254 nm resulted
in slow decomposition (Scheme 8).
3. Conclusion
Two mechanistic pathways to 15 and 25 (e.g., 29) are
proposed of which only mechanistic pathway B arrives at
the observed stereochemistry for the non-bridgehead ester
group [29 (b)] whereas pathway A would afford stereo-
chemistry opposite [29 (a)] to that seen in the X-ray crystal
structures of 15 and 25 (Scheme 9). Both mechanisms
involve a 1,2-sigmatropic shift (30 to 31) initiated by ketone
32 excitation (triple state). The subsequent formation of
radical 33 (Path A) appears justified on the basis of recent
data provided by Croft et al.21 Ring closure of 33 leads to
the final tricycle 29. Alternatively, rearrangement of radical
31 (Path B) leads to the unstable cyclopropane intermediate
34. Anionic ring opening of 34 would afford 35, which
undergoes immediate proton exchange on the less hindered
face with concomitant ring closure, via the oxyanion 36,
affording 29. An intermolecular pathway has been ruled out
in this instance as deuterium atom abstraction from d7-DMF
was not observed.
We have discovered for the first time a photochemical
rearrangement of the 3-ABN skeleton, which affords a
unique heterotricyclic system. It should be noted that all
attempts to ring open the aminal moiety of 15 and 25 so as to
gain access to alkaloid type skeletons have failed.
4. Experimental
4.1. General experimental
1H and 13C NMR spectra were recorded on a Bruker AV400
(400.13 MHz; 100.62 MHz) or
a
Bruker AC200
(200.13 MHz; 50.32 MHz) in deuteriochloroform
(CDCl3). Coupling constants are given in Hz and chemical
shifts are expressed as d values in ppm. High and low
resolution EI mass spectral data were obtained on a
KRATOS MS 25 RFA. Microanalyses were performed by
the University of Queensland Microanalytical Service.
Column chromatography was undertaken on silica gel
(Flash Silica gel 230–400 mesh), with distilled solvents.
Anhydrous solvents were prepared according to Perin and
Armarego, ‘Purification of laboratory solvents’, 3rd Ed.
Melting points were determined on a Fischer Johns
Melting Point apparatus and are uncorrected. Methyl-
magnesium bromide and n-BuLi was purchased from the
Aldrich Chem. Co.
4.2. X-ray crystallography
Data for all compounds were collected at 293 K on an
Enraf-Nonius CAD4 diffractometer. Data reduction, direct
methods structure solution and full least squares refinement
(SHELX9723) were performed with the WINGX package.24
Drawings of all molecules were created with ORTEP3.25
Data in CIF format have been deposited with the Cambridge
Crystallographic Data Centre (CCDC Deposition Nos.
248300–248302). Copies of the data can be obtained free
of charge upon request to deposit@ccdc.cam.ac.uk
Scheme 9.
The observation that oxabicyclo 27 does not undergo
photochemical reaction suggests that the oxa substituent
cannot suitably stabilise the 1,2-shift (i.e., 30 to 31), which,
if radical in nature would concur with recent calculations22
(i.e., nitrogen has the greatest stabilisation of lone pair donor
groups). It is also conceivable that photochemical induced
heterolytic sigma bond cleavage may occur to give
intermediate 37, which would be favoured by aza more
4.2.1. Ethyl 5-bromo-3-methyl-9-[2-oxo-2-(2-hydroxy-3-
methoxyphenyl)-E-ethylidene]-3-azabicyclo[3.3.1]nonane-
carboxylate 16. Ethyl 5-bromo-3-methyl-9-exo-hydroxy-9-
[2-(3-methoxy-2-isopropoxy)phenylethynyl]-3-azabi-
cyclo[3.3.1]nonanecarboxylate12 13 (0.205 g, 0.041 mmol)
was rapidly dissolved in trifluoroacetic acid (3 mL) at room
temperature. The solution was cooled in an ice-bath and
trimethylsilyltrifluorosulfonate (0.23 mL, 1.29 mmol)

C. M. Williams et al. / Tetrahedron 61 (2005) 3771–3779
3775
added rapidly. After addition the flask was taken out of the
bath and stirred at room temperature for 1 h. The reaction
mixture was then transferred, via Pasteur pipette, to a
separatory funnel containing a saturated solution of sodium
hydrogen carbonate (50 mL) and extracted with dichloro-
methane (3!10 mL). The residue was dried under vacuum,
redissolved in anhydrous THF (3 mL) and sodium hydride
added until effervescence ceased. The mixture was
quenched with saturated ammonium chloride solution and
extracted with dichloromethane (3!10 mL). Column
chromatography (ethyl acetate/dichloromethane, 5:95)
afforded the title compound as a bright yellow viscous oil
the residue suspended in dichloromethane (5 mL) and
passed through celite. Column chromatography (diethyl
ether/light petroleum, w1:4) of the residue on silica gel
afforded the title compound (0.159 g, 93%) and 22 (0.004 g,
3%) both as pale yellow oils. 1H NMR (400 MHz, CHCl3) d
1.22–1.30 (m, 9H), 1.54–1.63 (m, 1H), 1.96–2.05 (m, 1H),
2.17 (s, 3H), 2.36–2.49 (m, 2H), 2.51–2.60 (m, 1H), 2.79
(dd, JZ10.7, 2.4 Hz, 1H), 2.87 (dd, JZ11.1, 2.4 Hz, 1H),
2.89–3.03 (m, 1H), 2.97 (dd, JZ11.1, 1.3 Hz, 1H), 3.28 (dd,
JZ10.7, 1.3 Hz, 1H), 3.82 (s, 3H), 4.13–4.25 (m, 2H), 4.59
(sept, JZ6.2 Hz, 1H), 6.99–7.07 (m, 2H), 7.42 (AB, 1H).
13C NMR (100 MHz, CDCl3) d 14.1, 22.3, 22.4, 23.6, 35.9,
44.8, 46.2, 54.9, 56.1, 61.2, 63.1, 65.4, 71.3, 76.1, 116.1,
122.8, 123.7, 125.7, 134.3, 142.4, 147.0, 153.5, 172.7,
195.3. Near IR (Nujol) n (cmK1) 1729, 1713, 1681, 1666.
MS m/z (EI) 494 (MC%, 0.5%), 492 (MC%, 0.5%), 414 (77),
368 (7), 354 (7), 340 (2), 326 (9), 315 (1), 302 (11), 300
(12), 283 (2), 256 (2), 220 (27), 208 (5), 206 (8), 193 (49),
174 (2), 151 (100), 148 (6), 146 (5), 134 (6), 120 (4). Anal.
Calcd for C24H32BrNO5: MC% 414.2280 (KHBr). Found:
414.2277.
1
(0.13 g, 70%). H NMR (400 MHz, CHCl3) d 0.83 (t, JZ
7.1 Hz, 3H), 1.56–1.65 (m, 1H), 2.20 (s, 3H), 2.21–2.28 (m,
2H), 2.40–2.51 (m, 1H), 2.63 (d, JZ11.1 Hz, 1H), 2.69–
2.76 (m, 1H), 2.85 (dd, JZ10.6, 2.4 Hz, 1H), 2.93–3.07 (m,
2H), 3.50 (dd, JZ10.6, 1.3 Hz, 1H), 3.66–3.85 (m, 2H),
3.89 (s, 3H), 6.87 (t, JZ8.1 Hz, 1H), 7.03–7.07 (m, 1H),
7.38 (s, 1H), 7.42 (dd, JZ8.1, 1.4 Hz, 1H), 12.26 (s, OH).
13C NMR (100 MHz, CDCl3) d 13.3, 23.6, 36.3, 44.6, 47.3,
52.4, 56.2, 60.9, 64.1, 71.1, 71.5, 117.1, 118.4, 120.1, 122.6,
123.0, 148.7, 152.7, 153.0, 172.3, 199.5. MS m/z (EI) 453
(MC%, 4%), 451 (MC%, 5%), 408 (2), 406 (2), 372 (80), 326
(20), 302 (20), 300 (21), 298 (14), 286 (6), 283 (6), 279 (15),
256 (8), 222 (17), 220 (30), 206 (19), 167 (39), 151 (98), 149
(100), 129 (11), 113 (18). Anal. Calcd for C21H26BrNO5:
MC% 451.0995. Found: 451.0989.
4.2.4. Pyranones 22 and 23. Ethyl 5-bromo-3-methyl-9-[2-
oxo-2-(2-hydroxy-3-methoxyphenyl)-E-ethylidene]-3-aza-
bicyclo[3.3.1]nonanecarboxylate 16 (0.023 g, 0.051 mmol)
was dissolved in N,N-dimethylformamide (2.0 mL) fol-
lowed by addition of potassium carbonate (0.021 g,
0.15 mmol). The mixture was then heated at 80 8C for
15 min. On cooling N,N-dimethylformamide was removed
under high vacuum and the residue suspended in dichloro-
methane (5 mL) and passed through celite. Column
chromatography (dichloromethane/ethyl acetate, gradient)
of the residue on silica gel afforded two fractions. Fraction
one (22) (6 mg, 26%) was obtained as colourless crystals.
4.2.2. Photolysis of ethyl 5-bromo-3-methyl-9-[2-oxo-2-
(2-hydroxy-3-methoxyphenyl)-E-ethylidene]-3-azabi-
cyclo[3.3.1]nonanecarboxylate 16. Ethyl 5-bromo-3-
methyl-9-[2-oxo-2-(2-hydroxy-3-methoxyphenyl)-E-ethyl-
idene]-3-azabicyclo[3.3.1]nonanecarboxylate 16 (0.020 g,
0.044 mmol) was dissolved in oxygen free D7-N,N-
dimethylformamide (1 mL) in a 5 mm NMR tube (PP-
528) and irradiated with a Hanovia high pressure mercury–
xeon vapour lamp (1000 W). [Note. The light was passed
through a w5 8C water filter (30 cm long) and the sample
placed 10 cm from the end of the cooling tube.] The
1
Mp 116–118 8C (diethyl ether/dichloromethane) H NMR
(400 MHz, CHCl3) d 0.89 (t, JZ7.2 Hz, 3H), 1.63–1.78 (m,
2H), 2.22 (s, 3H), 2.31–2.38 (m, 1H), 2.67–2.97 (m, 5H),
3.15–3.27 (m, 2H), 3.34 (d, JZ14.7 Hz, 1H), 3.52–3.73 (m,
3H), 3.88 (s, 3H), 6.86 (t, JZ8.0 Hz, 1H), 7.03 (dd, JZ8.0,
1.6 Hz, 1H), 7.37 (dd, JZ8.0, 1.6 Hz, 1H). 13C NMR
(100 MHz, CDCl3) d 13.4, 23.2, 29.4, 39.0, 41.3, 44.7, 52.8,
56.7, 59.7, 61.3, 65.5, 74.6, 83.1, 117.2, 117.9, 120.1, 120.4,
149.3, 150.7, 172.2, 189.8. MS m/z (EI) 453 (MC%, 30%),
451 (MC%, 32%), 408 (8), 372 (74), 328 (46), 315 (7), 298
(34), 283 (14), 270 (4), 255 (27), 220 (27), 151 (57), 138
(17), 136 (21), 122 (21), 105 (13). Anal. Calcd for
C21H26BrNO5: MC% 451.0995. Found: 451.0992. Fraction
two (23) (14 mg, 61%) was obtained as colourless needles.
1
isomerization was monitored by H NMR every 15 min
until a 1:1 mixture of 16 and 21 was evident. The solvent
was removed and the residue subjected to column
chromatography (dichloromethane) affording an insepar-
able 1:1 mixture of 16 and 21 (0.015 g, 75%).
The relevant 1H NMR values for 21 are listed only and are
a result from subtracting isolated peaks observed from a
spectrum of pure 16.
1
Mp 131–133 8C (diethyl ether/dichloromethane) H NMR
1H NMR (200 MHz, CHCl3) d 1.27 (t, JZ7.4 Hz, 3H), 3.32
(AB, 1H), 3.885 (s, 3H), 4.12–4.26 (m, 2H), 5.80 (s, 1H).
(400 MHz, CHCl3) d 0.94 (t, JZ7.2 Hz, 3H), 1.48–1.58 (m,
1H), 1.84 (dd, JZ14.9 Hz, 6.5, 1H), 2.26 (s, 3H), 2.32–2.48
(m, 3H), 2.72 (d, JZ11.6 Hz, 1H), 2.85–3.02 (m, 1H), 3.16
(d, JZ10.8 Hz, 1H), 3.32 (dd, JZ11.6, 2.6 Hz, 1H), 3.47–
3.65 (m, 5H), 3.88 (s, 3H), 6.86 (t, JZ7.9 Hz, 1H), 7.01 (dd,
JZ7.9, 1.5 Hz, 1H), 7.38 (dd, JZ7.9, 1.5 Hz, 1H). 13C
NMR (100 MHz, CDCl3) d 13.4, 22.7, 32.1, 39.8, 40.5,
45.1, 52.3, 56.8, 57.7, 61.2, 64.4, 74.8, 83.1, 117.1, 117.9,
120.2, 120.6, 149.3, 149.9, 172.3, 189.9. MS m/z (EI) 453
(MC%, 30%), 451 (MC%, 29%), 372 (43), 328 (27), 298 (14),
283 (10), 255 (13), 227 (4), 220 (7), 194 (6), 151 (32), 138
(10), 136 (9), 122 (11), 105 (6). Anal. Calcd for
C21H26BrNO5: C, 55.76; H, 5.79; N, 3.10; MC% 451.0995.
Found: C, 55.53; H, 5.76; N, 3.07; MC% 451.0986.
4.2.3. Ethyl 5-bromo-3-methyl-9-[2-oxo-2-(2-isopro-
poxy-3-methoxyphenyl)-E-ethylidene]-3-azabicyclo-
[3.3.1]nonanecarboxylate 14. Ethyl 5-bromo-3-methyl-9-
[2-oxo-2-(2-hydroxy-3-methoxyphenyl)-E-ethylidene]-3-
azabicyclo[3.3.1]nonanecarboxylate
16
(0.156 g,
0.345 mmol) was dissolved in N,N-dimethylformamide
(1.5 mL) followed by addition of 2-bromopropane
(0.97 mL, 10.3 mmol) and potassium carbonate (0.095 g,
0.69 mmol). The mixture was then stirred at room
temperature for 16 h. Excess 2-bromopropane and N,N-
dimethylformamide were removed under high vacuum and

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C. M. Williams et al. / Tetrahedron 61 (2005) 3771–3779
4.2.5. Photolysis of ethyl 5-bromo-3-methyl-9-[2-oxo-2-
(2-isopropoxy-3-methoxyphenyl)-E-ethylidene]-3-azabi-
cyclo[3.3.1]nonanecarboxylate 14. Ethyl 5-bromo-3-
methyl-9-[2-oxo-2-(2-isopropoxy-3-methoxyphenyl)-E-
ethylidene]-3-azabicyclo[3.3.1]nonanecarboxylate 14
(0.171 g, 0.346 mmol) was dissolved in oxygen free
N,N-dimethylformamide (150 mL) and irradiated through
pyrex in a 1 L Hanovia photochemical reactor using a 4 W
arc lamp for 10 days. The solvent was then removed under
high vacuum using an in-line trap and the residue subjected
to column chromatography (diethyl ether/light petroleum,
3:7–6:4), which afforded tricycle 15 (0.030 g, 18%) in
fraction one and a mixture of 14 and 24 (1:1) (0.088 g, 51%)
in fraction two.
(2 mL, 2.86 mmol, 1.4 M, tetrahydrofuran/toluene) was
then added and the flask taken out of the bath and stirred
at room temperature for 1.3 h. In a separate flask diethyl
3-(4-methoxyphenylmethyl)-9-oxo-3-azabicyclo[3.3.1]no-
nane-1,5-dicarboxylate (1.0 g, 2.48 mmol) was dissolved in
anhydrous tetrahydrofuran (30 mL) and cooled to K78 8C
(dry-ice/acetone bath) under argon. To this was added
the above solution dropwise via cannular over 5 min. The
reaction mixture was then allowed to reach 15–20 8C over
1.5 h and was stirred at room temperature for 1 h, before
quenching with saturated ammonium chloride solution. The
phases were partitioned and the aqueous washed with
diethyl ether (2!20 mL). The combined organic layers
were evaporated and the residue subjected to column
chromatography (diethyl ether/light petroleum, gradient)
affording diethyl 3-(4-methoxyphenylmethyl)-9-exo-
hydroxy-9-[2-(3,4-dimethoxy)phenylethynyl]-3-azabi-
cyclo[3.3.1]nonane-1,5-dicarboxylate (1.0 g, 71%) (pale
yellow oil) as a mixture of diastereomers [7(exo):3(endo)].
Near IR (film) n (cmK1) 3468, 3272, 1725, 1511. MS
{mixture of diastereomers [7(exo):3(endo)]} m/z (EI) 565
(MC%, 31%), 547 (1), 536 (2), 519 (3), 492 (10), 474 (6),
464 (1), 444 (4), 424 (3), 416 (3), 398 (4), 378 (3), 370 (4),
342 (1), 324 (4), 309 (1), 296 (2), 282 (2), 269 (1), 256 (2),
248 (4), 232 (1), 218 (2), 204 (1), 189 (8), 175 (3), 162 (5),
154 (9), 149 (3), 136 (3), 121 (100). Anal. Calcd for
C32H39NO8: MC% 565.2676. Found: 565.2674.
Ethyl 3a-bromo-2-methyl-1,3,3a,4,5,6,7,7a-octahydro-9-(2-
isopropoxy-3-methoxyphenyl)-isoindolo[1,7a-b]furan-7-
carboxylate 15. 1H NMR (400 MHz, CHCl3) d 1.00 (t, JZ
7.1 Hz, 3H), 1.23 (d, JZ6.2 Hz, 3H), 1.29 (d, JZ6.2 Hz,
3H), 1.54–1.82 (m, 3H), 1.84–1.91 (m, 1H), 2.19–2.26 (m,
1H), 2.34–2.44 (m, 1H), 2.51 (s, 3H), 2.83–2.92 (m, 2H),
3.35 (d, JZ8.0 Hz, 1H), 3.81 (s, 3H), 3.84–4.00 (m, 2H),
4.67 (sept, JZ6.2 Hz, 1H), 5.63 (s, 1H), 5.67 (s, 1H), 6.80–
6.84 (m, 1H), 6.96 (t, JZ16 Hz, 1H), 7.22–7.27 (m, 1H).
13C NMR (100 MHz, CDCl3) d 13.9, 21.3, 22.2, 22.5, 26.3,
34.3, 40.0, 45.9, 55.9, 60.4, 65.18, 65.25, 69.5, 74.2, 94.4,
107.4, 112.7, 119.6, 122.9, 125.2, 144.7, 152.95, 153.04,
173.8. Near IR (Nujol) n (cmK1) 1731. MS m/z (EI) 494
(MC%, 0.5%), 492 (MC%, 0.5%), 414 (100), 368 (29), 326
(6), 298 (5), 282 (2), 270 (2), 256 (2), 220 (63), 208 (10),
193 (87), 175 (2), 151 (89), 148 (6), 146 (8), 134 (22), 120
(8). Anal. Calcd for C24H32BrNO5: MC% 414.2280 (KHBr).
Found: 414.2279.
Method A. To diethyl 3-(4-methoxyphenylmethyl)-9-exo-
hydroxy-9-[2-(3,4-dimethoxy)phenylethynyl]-3-azabi-
cyclo[3.3.1]nonane-1,5-dicarboxylate [7(exo):3(endo)]
(0.430 g, 0.76 mmol) at room temperature was added a
mixture of trifluoroacetic acid (0.5 mL) and borontriflouride
diethyl etherate (0.3 mL, 2.36 mmol). After stirring at room
temperature for 1 h the reaction mixture was then
transferred, via Pasteur pipette, to a separatory funnel
containing a saturated solution of sodium hydrogen
carbonate (50 mL) and extracted with dichloromethane
(3!10 mL). The residue was subjected to column chroma-
tography (diethyl ether/dichloromethane/light petroleum,
gradient) afforded diethyl 3-(4-methoxyphenylmethyl)-9-
[2-oxo-2-(3,4-dimethoxyphenyl)ethylidene]-3-azabicyclo-
[3.3.1]nonane-1,5-dicarboxylate 19 (0.381 g, 89%), as a
4.2.6. Diethyl 3-(4-methoxyphenylmethyl)-9-[2-oxo-2-
(3,4-dimethoxyphenyl)ethylidene]-3-azabicyclo[3.3.1]-
nonane-1,5-dicarboxylate 19. Following the procedure of
Fukumoto.4g,h Diethyl cyclohexanone-2,6-dicarboxylate
(3.20 g, 13.2 mmol) was dissolved in distilled ethanol
(120 mL) and p-methoxybenzylamine (2.16 mL,
16.5 mmol) added followed by formaldehyde (4.8 mL,
54.2 mmol, 37% in water). After stirring the solution in
the dark at room temperature for 48 h the solvent was
removed in vacuo and the residue subjected to column
chromatography (diethyl ether/light petroleum, w1:4)
affording diethyl 3-(4-methoxyphenylmethyl)-9-oxo-3-aza-
bicyclo[3.3.1]nonane-1,5-dicarboxylate as a viscous colour-
less oil (4.67 g, 88%). 1H NMR (400 MHz, CHCl3) d 1.24 (t,
JZ7.2 Hz, 6H), 1.58–1.67 (m, 1H), 2.16–2.24 (m, 2H),
2.53–2.62 (m, 2H), 2.83–2.99 (m, 1H), 2.98–3.03 (m, 2H),
3.11–3.17 (m, 2H), 3.48 (s, 2H), 3.79 (s, 3H), 4.10–4.21 (m,
4H), 6.81–6.90 (m, 2H), 7.18–7.27 (m, 2H). 13C NMR
(100 MHz, CDCl3) d 14.1, 20.2, 36.3, 55.2, 58.4, 61.2, 61.4,
61.7, 113.8, 129.9, 130.0, 158.9, 170.4, 207.3. Near IR
1
colourless crystals, mp 168–170 8C. H NMR (400 MHz,
CHCl3) d 0.74 (t, JZ7.2 Hz, 3H), 1.29 (t, JZ7.1 Hz, 3H),
1.60–1.71 (m, 1H), 1.99–2.08 (m, 1H), 2.13–2.22 (m, 1H),
2.24–2.42 (m, 2H), 2.66 (dd, JZ11.1, 1.6 Hz, 1H), 2.82 (dd,
JZ11.1, 1.6 Hz, 1H), 2.90–3.07 (m, 3H), 3.41 (AB, 2H),
3.57–3.74 (m, 2H), 3.79 (s, 3H), 3.89 (s, 3H), 3.93 (s, 3H),
4.14–4.26 (m, 2H), 6.24 (s, 1H), 6.82–6.87 (m, 3H), 7.19–
7.22 (m, 2H), 7.46 (d, JZ1.9 Hz, 1H), 7.54 (dd, JZ8.3 Hz,
1.9, 1H). 13C NMR (100 MHz, CDCl3) d 13.3, 14.3,
20.9, 36.6, 36.9, 49.9, 53.2, 55.22, 55.97, 55.05, 60.3,
61.0, 61.9, 62.0, 62.5, 109.9, 110.2, 113.8, 119.7, 123.9,
129.8, 130.3, 130.6, 149.1, 152.4, 153.3, 158.7, 173.0,
173.7, 191.5. MS m/z (EI) 565 (MC%, 13%), 536 (2), 520
(3), 492 (10), 474 (2), 444 (4), 429 (2), 416 (2), 400 (16),
385 (2), 370 (3), 354 (4), 343 (2), 330 (1), 312 (3), 297 (1),
278 (1), 263 (2), 206 (1), 191 (1), 180 (2), 165 (26), 121
(100). Anal. Calcd for C32H39NO8: C, 67.95; H, 6.95; N,
2.48; MC% 565.2676. Found: C, 68.05; H, 7.07; N, 2.34;
565.2676.
(film) n (cmK1) 1730, 1611, 1510. MS m/z (EI) 403 (MC%
,
5%), 398 (1), 386 (2), 358 (2), 330 (4), 302 (1), 282 (2), 272
(1), 254 (2), 242 (8), 226 (2), 209 (7), 196 (25), 168 (30),
140 (19), 135 (17), 121 (100). Anal. Calcd for C22H29NO6:
MC% 403.1995. Found: 403.1986.
3,4-Dimethoxyphenylacetylene26 (0.442 g, 2.73 mmol) was
dissolved in anhydrous tetrahydrofuran (3 mL) and placed
in an ice-bath under argon. Methylmagnesium bromide

C. M. Williams et al. / Tetrahedron 61 (2005) 3771–3779
3777
Method B. Diethyl 3-(4-methoxyphenylmethyl)-9-exo-
hydroxy-9-[2-(3,4-dimethoxy)phenylethynyl]-3-azabi-
cyclo[3.3.1]nonane-1,5-dicarboxylate [7(exo):3(endo)]
(0.069 g, 0.122 mmol) was rapidly dissolved in trifluoro-
acetic acid (1 mL) at 0 8C (ice-bath) under argon.
Trimethylsilyltrifluorosulfonate (0.07 mL, 0.378 mmol)
was added rapidly and the flask then taken out of the bath
and stirred at room temperature for 1 h. The reaction
mixture was then transferred, via Pasture pipette, to a
separatory funnel containing a saturated solution of sodium
hydrogen carbonate (50 mL) and extracted with dichloro-
methane (3!10 mL). The residue was dried under vacuum
and subjected to column chromatography (ethyl acetate/
dichloromethane, 1:9) affording two fractions. Fraction one
contained the title compound 19 (0.009 g, 13%) and fraction
two afforded ethyl 1-(3,4-dimethoxyphenyl)-8-(4-methoxy-
phenylmethyl)-4,5,6,6a,7,9-hexahydro-3H-pyrano[4,4a,5,
d-e]isoquinolin-3-on-6a-carboxylate 20 (0.012 g, 19%) as a
123.4, 129.6, 131.1, 148.6, 149.5, 157.1, 158.6, 173.9,
174.5. Near IR (Nujol) n (cmK1) 1729, 1715. MS m/z (EI)
565 (MC%, 13%), 520 (11), 492 (10), 474 (5), 444 (4), 424
(2), 416 (3), 400 (16), 165 (26), 121 (100). Anal. Calcd for
C32H39NO8: C, 67.95; H, 6.95; N, 2.48; MC% 565.2676.
Found: C, 67.79; H, 6.90; N, 2.41; 565.2674.
4.2.8. Diethyl 3-(4-methoxyphenylmethyl)-9-[2-methyl-
ene-2-(3,4-dimethoxyphenyl)ethylidene]-3-azabicyclo-
[3.3.1]nonane-1,5-dicarboxylate 26. Methylphosphonium
bromide (0.047 g, 0.133 mmol) was predried under high
vacuum and suspended in anhydrous THF (0.5 mL) under
argon. The flask was placed in an ice-bath and n-BuLi
(0.08 mL, 1.5 M in hexanes) added. After 15 min diethyl
3-(4-methoxyphenylmethyl)-9-[2-oxo-2-(3,4-dimethoxy-
phenyl)ethylidene]-3-azabicyclo[3.3.1]nonane-1,5-dicar-
boxylate 19 (0.050 g, 0.088 mmol) was introduced, via
cannular, to the flask as a solution in THF (0.5 mL). The
mixture was stirred at room temperature for 1.5 h followed
by addition of saturated ammonium chloride solution (20
drops). The solvent was then removed under vacuum and
the residue extracted with dichloromethane (10 mL).
Evaporation of the organic layer and column chromatog-
raphy (dichloromethane/ethyl acetate, gradient) afforded the
title compound 26 (0.023 g, 46%) and recovered starting
material 19 (0.014 g, 28%) in that order. The yield based on
1
yellow amorphous solid. H NMR (400 MHz, CHCl3) d
1.15 (t, JZ7.1 Hz, 3H), 1.40–1.65 (m, 2H), 1.87–1.98 (m,
1H), 2.06–2.14 (m, 1H), 2.18 (d, JZ11.2 Hz, 1H), 2.42–
2.55 (m, 1H), 2.63–2.74 (m, 1H), 3.17 (d, JZ14.6 Hz, 1H),
3.28–3.35 (m, 1H), 3.42–3.55 (AB, 2H), 3.76 (s, 3H), 3.79
(s, 3H), 3.89 (s, 3H), 3.91–3.98 (m, 1H), 4.00–4.21 (m, 2H),
6.76–6.87 (m, 3H), 6.97 (d, JZ2.0 Hz, 1H), 7.03 (dd, JZ
8.4, 2.0 Hz, 1H), 7.08–7.13 (m, 2H). 13C NMR (100 MHz,
CDCl3) d 14.1, 18.1, 23.1, 29.3, 49.8, 53.0, 55.2, 55.89,
55.93, 58.1, 61.3, 61.8, 110.4, 110.5, 111.4, 113.6, 121.0,
121.6, 125.0, 129.3, 130.0, 148.7, 148.9, 150.0, 152.3,
158.9, 163.0, 173.4. MS m/z (EI) 519 (MC%, 5%), 504 (1),
490 (2), 474 (1), 446 (1), 398 (100), 370 (4), 354 (4), 324
(4), 297 (2), 269 (1), 165 (6), 121 (55). Anal. Calcd for
C30H33NO7: MC% 519.2257. Found: 519.2261.
1
recovered starting material is 64%. H NMR (400 MHz,
CHCl3) d 0.68 (t, JZ7.1 Hz, 3H), 1.22 (t, JZ7.2 Hz, 3H),
1.62–1.74 (m, 1H), 1.94–2.10 (bm, 2H), 2.17–2.28 (m, 1H),
2.31–2.43 (m, 1H), 2.61–2.67 (m, 1H), 2.80 (bd, JZ
10.6 Hz, 1H), 2.87–3.09 (m, 3H), 3.32–3.66 (vbm, 2H), 3.41
(s, 2H), 3.79 (s, 3H), 3.867 (s, 3H), 3.875 (s, 3H), 4.04–4.21
(m, 2H), 4.80 (s, 1H), 5.34 (s, 1H), 5.67 (s, 1H), 6.78–6.88
(m, 3H), 7.00–7.06 (m, 2H), 7.18–7.25 (m, 2H). 13C NMR
(100 MHz, CDCl3) d 13.2, 14.2, 21.0, 37.0, 48.7, 52.6, 55.2,
55.81, 55.88, 60.1, 60.8, 62.3, 62.5, 63.4, 109.5, 110.7,
111.3, 113.7, 119.5, 122.2, 126.4, 129.8, 130.6, 131.2,
141.6, 142.2, 148.5, 148.9, 158.7, 174.3, 174.4. MS m/z (EI)
563 (MC%, 30%), 518 (1), 490 (4), 471 (1), 442 (17), 414
(1), 414 (1), 396 (2), 368 (3), 340 (2), 324 (1), 294 (2), 267
(3), 253 (1), 165 (6), 151 (2), 135 (1), 121 (100). Anal. Calcd
for C33H41NO7: MC% 563.2883. Found: 563.2878.
4.2.7. Diethyl 2-(4-methoxyphenylmethyl)-1,3,3a,4,5,
6,7,7a-octahydro-9-(3,4-dimethoxyphenyl)-isoindolo-
[1,7a-b]furan-3a,7-dicarboxylate 25. Diethyl 3-(4-meth-
oxyphenylmethyl)-9-[2-oxo-2-(3,4-dimethoxyphenyl)ethyl-
idene]-3-azabicyclo[3.3.1]nonane-1,5-dicarboxylate 19
(0.100 g, 0.177 mmol) was dissolved in oxygen free
N,N-dimethylformamide (10 mL) under argon in a 10 mm
NMR tube (PP-528) and irradiated for 1 h with a Hanovia
high pressure mercury–xeon vapour lamp (1000 W). [Note.
The light was passed through a water filter (30 cm long) at
w5 8C and the sample placed 10 cm from the end of the
cooling tube.] The solvent was then removed under high
vacuum using an in-line trap and the residue subjected to
column chromatography (diethyl ether/dichloromethane/
light petroleum, gradient), which afforded the title com-
pound 25 (0.076 g, 76%), as a pale yellow solid, and
recovered starting material 19 (0.012 g, 12%) in that order.
Yield based on recovered starting material 86%, mp 109–
111 8C (partial), 115–116 8C. 1H NMR (400 MHz, CHCl3) d
0.99 (t, JZ7.1 Hz, 3H), 1.23 (t, JZ7.1 Hz, 3H), 1.55–1.73
(m, 3H), 1.78–1.91 (m, 2H), 2.01–2.11 (m, 1H), 2.52 (d, JZ
8.7 Hz, 1H), 3.10 (d, JZ8.7 Hz, 1H), 3.14–3.20 (m, 1H),
3.72 (d, JZ13.6 Hz, 1H), 3.78 (s, 3H), 3.87 (s, 3H), 3.88 (s,
3H), 3.88–4.03 (m, 2H), 4.09–4.17 (m, 2H), 4.16 (d, JZ
13.6 Hz, 1H), 4.90 (s, 1H), 5.90 (s, 1H), 6.78–6.88 (m, 3H),
7.03 (d, JZ2.0 Hz, 1H), 7.14 (dd, JZ2.0, 8.3 Hz, 1H),
7.23–7.28 (m, 2H). 13C NMR (100 MHz, CDCl3) d 14.1,
14.2, 21.4, 25.6, 33.1, 46.8, 51.2, 54.4, 55.2, 55.90, 55.93,
56.3, 60.1, 60.3, 60.8, 96.7, 97.9, 108.6, 110.7, 113.7, 118.4,
4.2.9. Dimethyl 9-[2-oxo-2-(3,4-dimethoxyphenyl)ethyli-
dene]-3-oxabicyclo[3.3.1]nonane-1,5-dicarboxylate 27.
3,4-Dimethoxyphenylacetylene26 (0.211 g, 1.30 mmol)
was dissolved in anhydrous THF (4 mL) and cooled to
K78 8C (dry-ice/acetone bath) under argon. To this solution
was added n-butyllithium (1.0 mL, 1.40 mmol, 1.4 M
solution in n-hexane) via syringe during 2 min and the
mixture was stirred at K78 8C for 1 h. After removing the
cooling-bath the mixture was allowed to reach 20 8C over
2 h and was stirred at room temperature for 1 h. After
cooling this mixture to K78 8C a solution of dimethyl
9-oxo-3-oxabicyclo[3.3.1]nonane-1,5-dicarboxylate20
(0.308 g, 1.20 mmol) in anhydrous THF (3 mL) was quickly
added (1 s) and stirred at K78 8C. After 1 h at K78 8C the
reaction mixture was allowed to reach room temperature
over 2–3 h, before quenching with saturated ammonium
chloride solution (25 mL). The phases were partitioned and
the aqueous washed with diethyl ether (5!25 mL). The
combined organic layers were washed with distilled water
(2!20 mL) and brine (1!20 mL), dried (Na2SO4) and

3778
C. M. Williams et al. / Tetrahedron 61 (2005) 3771–3779
´
379–380. (d) Grandez, M.; Madinaveitia, A.; Gavın, J. A.;
Alva, A.; de la Fuente, G. J. Nat. Prod. 2002, 65, 513–516.
(e) Saidkhodzhaeva, Sh. A.; Bessonova, I. A.; Abdullaev,
N. D. Chem. Nat. Comp. 2001, 37, 466–469.
evaporated. The residue was then purified by flash
chromatography (light petroleum/ethyl acetate, 3:1) afford-
ing dimethyl 9-(3,4-dimethoxyphenylethynyl)-9-hydroxy-
3-oxabicyclo[3.3.1]nonane-1,5-dicarboxylate (0.402 g
80%) (colourless oil) as a mixture of diastereomeres (exo/
endoZ94: 6, detected by H NMR). H NMR (400 MHz,
CDCl3) d 1.59–1.65 (m, 1H), 1.81–1.85 (m, 2H), 2.35–2.55
(m, 3H), 3.72 (s, 6H), 3.84 (s, 3H), 3.86 (s, 3H), 4.08 (d, JZ
12.2 Hz, 2H), 4.25 (dd, JZ12.1, 2.3 Hz, 2H), 4.75 (s, 1H,
OH), 6.77 (d, JZ8.3 Hz, 1H), 6.84 (d, JZ1.8 Hz, 1H), 6.97
(dd, JZ8.3, 1.9 Hz, 1H). 13C NMR (100 MHz, CDCl3) d
18.7, 27.7, 31.3, 49.7, 51.8, 55.5, 70.4, 71.4, 85.9, 88.1,
110.6, 113.8, 113.9, 124.7, 148.2, 149.4, 173.1.
3. See for example, (a) Xu, L.; Chen, Q.-H.; Wang, F.-P.
Tetrahedron 2002, 58, 4267–4271. (b) Chen, Q.-H.; Xu, L.;
Wang, F.-P. Tetrahedron 2002, 58, 9431–9444. (c) Wang,
F.-P.; Chen, Q.-H.; Li, Z.-B.; Li, B.-G. Chem. Pharm. Bull.
2001, 49, 689–694.
1
1
4. (a) Barker, D.; McLeod, M. D.; Brimble, M. A.; Savage, G. P.
Tetrahedron Lett. 2002, 43, 6019–6022. (b) Barker, D.;
Brimble, M. A.; McLeod, M. D.; Savage, G. P.; Wong, D. J.
J. Chem. Soc., Perkin Trans. 1 2002, 924–931. (c) Baillie,
L. C.; Bearder, J. R.; Whiting, D. A. J. Chem. Soc., Chem.
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Tetrahedron 1985, 41, 485–497. (f) Masamune, S. J. J. Am.
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therein.
Cooled (K15 8C) trifluoroacetic acid (1.5 mL) was rapidly
added, under argon at K15 8C via syringe, to dimethyl
9-(3,4-dimethoxyphenylethynyl)-9-hydroxy-3-oxabicyclo-
[3.3.1]nonane-1,5-dicarboxylate (0.230 g, 0.55 mmol). The
reaction mixture was vigorously stirred while warming to
room temperature over 2 h. The reaction was quenched with
saturated sodium hydrogen carbonate solution and extracted
with dichloromethane (5!15 mL). After solvent evapo-
ration, the residue (pale yellow oil) was crystallised by
adding diethyl ether. Recrystallisation from anhydrous
methanol afforded the titled compound (0.197 g, 86%) as
colourless crystals, mp 169.5–170.5 8C. 1H NMR
(400 MHz, CDCl3) d 1.68–1.75 (m, 1H), 2.13–2.17 (m,
1H), 2.25–2.43 (m, 3H), 2.52–2.66 (m, 1H), 3.24 (s, 3H),
3.77 (s, 3H), 3.80 (s, 3H), 3.93 (s, 3H), 3.97–4.07 (m, 2H),
4.09–4.21 (m, 2H), 6.24 (s, 1H), 6.87 (d, JZ8.0 Hz, 1H),
7.45 (d, JZ1.9 Hz, 1H), 7.52 (dd, JZ8.3 Hz, 1.9, 1H). 13C
NMR (100 MHz, CDCl3) d 20.2, 36.2, 36.6, 50.1, 51.3,
52.2, 52.9, 56.0, 56.1, 75.3, 75.8, 110.1, 110.2, 120.0, 124.0,
130.3, 149.1, 150.2, 153.4, 172.0, 172.9, 191.4. Near IR
(Nujol) n (cmK1) 1738, 1717. Anal. Calcd for C22H26O8: C,
63.15; H, 6.26. Found: C, 63.16; H, 6.31.
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The authors would like to thank Mr. Graham McFarlane for
mass spectrometry. We also thank the University of
Queensland for providing support for this work.
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Supplementary data
13. Williams, C. M.; Heim, R.; Brecknell, D. J.; Bernhardt, P. V.
Org. Biomol. Chem. 2004, 2, 806–807.
Supplementary data associated with this article can be found,
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