Investigating direct routes to an advanced intermediate for the synthesis of C-20 diterpene alkaloids

Article abstract of DOI:10.1016/j.tet.2005.02.014

Rapid access to the ABCE ring system of the C-20 diterpene alkaloids was achieved by silver (I) promoted intramolecular Friedel-Crafts arylation of a functional group specific 5-bromo-3-azabicyclo[3.3.1]nonane derivative.

Full text of DOI:10.1016/j.tet.2005.02.014

Tetrahedron 61 (2005) 3759–3769
Investigating direct routes to an advanced intermediate for the
synthesis of C-20 diterpene alkaloids
b
a
b
Craig M. Williams,a, Lewis N. Mander, Paul V. Bernhardt and Anthony C. Willis
*
aSchool of Molecular and Microbial Sciences, University of Queensland, St Lucia, 4072 Brisbane, Qld, Australia
bResearch School of Chemistry, Australian National University, Canberra, ACT, Australia
Received 17 September 2004; revised 18 January 2005; accepted 3 February 2005
Abstract—Rapid access to the ABCE ring system of the C-20 diterpene alkaloids was achieved by silver (I) promoted intramolecular
Friedel–Crafts arylation of a functional group specific 5-bromo-3-azabicyclo[3.3.1]nonane derivative.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
developed by Shimizu et al.15 The rapid assembly of
3-azabicyclo[3.3.1]nonan-7-ones on cyclohexanone based
starting materials,16 provides a particularly direct and
efficient method for assembling the E-ring of these alkaloids
and when applied to the aryl substituted cyclohexanone 3,
afforded a particularly direct synthesis of the tetracyclic
intermediate 4, although with poor stereochemical control
(Scheme 1).17
Diterpene alkaloids have been isolated from a range
of plants including Aconitum, Delphinium, Consolida,
Thalictrum and Spiraea species.1,2 There has been some
interest in their biological activity,3 but it is their complex
highly functionalised skeletons that have attracted the
attention of numerous synthetic4 chemists. Of particular
note is the work of the Wiesner,5 Masamune,6 Fukumoto,7
and Nagata groups8 all of whom have shown enormous
creativity and ingenuity in their efforts to assemble these
complex structures. The construction of the highly bridged
structures of the kobusine9 (1)–hetisine10 (2) family11
(Fig. 1) of alkaloids, however, has remained elusive.
Some progress has been made12–14 and these reports prompt
us to disclose our own endeavours in the field.
Scheme 1.
Shimizu et al. also prepared 3-methyl-9-(4-methoxyphenyl-
ethyl)-3-azabicyclo[3.3.1]nonan-9-ol 5 by a similar
approach, but were unable to convert it into the target
phenanthrene derivative 6 (Scheme 2).15
Figure 1.
In designing our approach, we were mindful of the
formidable logistical challenges that were likely to develop
in pursuing a target possessing such a complex skeleton and
were consequently drawn to the double Mannich strategy
Keywords: Diterpene alkaloids; Silver (I); Intramolecular Friedel–Crafts
arylation; 3-Azabicyclo[3.3.1]nonane.
*
Corresponding author. Tel.: C61 7 3365 3530; fax: C61 7 3365 4299;
e-mail: c.williams3@uq.edu.au
Scheme 2.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.02.014

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C. M. Williams et al. / Tetrahedron 61 (2005) 3759–3769
Although equivalent arene carbinols have been cyclised to
give hydrophenanthrenes this must occur via alkene
formation or a 1,2-hydride shift to give cation 7 (Fig. 2).18
With the azabicyclononane, however, the formation of the
necessary bridgehead alkene or cation would constitute a
violation of Bredt’s rule.19
2. Results and discussion
Attempts were made to prepare 10 either by treating 8 with
the metalated cis-styrene26 11, derived from the telluride 12,
or the less sterically demanding alkyne analogue 1327
followed by reduction. It was hoped that the cis stereo-
chemistry of the alkene bond in 10 would reduce the degrees
of freedom relative to the saturated analogue and maximize
the chances of the planned cyclisation. Both reagents were
synthesised from ortho-vanillin in good overall yield, using
Comasseto–Marino26 and Corey–Fuchs methodology,28
respectively. The robust isopropylether masking function
as developed by Banwell29 had been chosen for both of
these approaches so as to allow for selective de-alkylation at
the appropriate juncture without the risk of premature
deprotection. In the event, only small amounts of the
rearranged product 14 were obtained when 11 was
employed (Fig. 3).
Figure 2.
To address the problem, we elected to begin with the bromo-
3-azabicyclo[3.3.1]nonanone 8 (the N-methyl analogue of
an intermediate that had been prepared previously by Kraus
and Shi20) in the knowledge that intermolecular bridgehead
arylation had been achieved with 1-bromoadamantane using
palladium (Pd/C) at high temperature (de Meijere21) and
with 1-bromobicyclo[2.2.2]octane using silver (I) salts at
room temperature (Kraus22). As an alternative coupling
strategy, we could also envisage a free radical based
approach initiated by loss of a bromine radical.23 For the
elaboration of the C- and D-rings, we planned to utilise an
aromatic C-ring that would serve as a precursor to an ortho-
quinonoid moiety in anticipation of the addition of the
D-ring by means of a [4C2] cycloaddition, a tactic that has
been used so effectively by Wiesner.24 If we could combine
these various elements into a viable strategy, then there was
a reasonable expectation of restricting the complete
sequence to a manageable length. Thus, we arrived at the
synthetic plan outlined in Scheme 3 and now describe in full
our investigations, which have culminated in an exception-
ally direct approach to the advanced intermediate 9.25
We therefore deprotonated arylacetylene 13 with methyl-
magnesium bromide (i.e., 15) and added it to bicycle 8
dissolved in toluene, thereby affording a 3:2 mixture of
diastereomers 16 and 17, respectively, in 94% yield. With
THF as solvent, however, mainly the desired epimer30 16
(64% yield) was obtained, accompanied this time by the
by-product 18 from rearrangement of 17 (Scheme 4). This
kind of rearrangement had also been observed by Kraus and
put to good effect in the synthesis of epi-modhephene.20
Catalytic hydrogenation of the alkyne bond in 16 without
hydrogenolysis of the bridgehead bromo substitutent
proved, not surprisingly, to be unattainable, but could be
achieved with diimide, generated in situ from 1,3,5-tri-
isopropylbenzenesulfonylhydrazide,31 to afford the cis-
alkene 10 in 74% yield as the sole product (Fig. 3). With
this intermediate in hand we embarked upon the cyclisation
Scheme 3.
Figure 3.

C. M. Williams et al. / Tetrahedron 61 (2005) 3759–3769
3761
Scheme 4.
studies. Treatment of 10 with silver trifluoroacetate at
various temperatures or with palladium (Pd/C), however,
resulted in rearrangement32 to ketone 14 (Fig. 3). Although,
acylation of the hydroxyl could be expected to retard the
rearrangement, this deceptively simple step proved to be
surprisingly difficult.33 Nevertheless, when 16 was treated
with acetic anhydride and trimethylsilyl triflate, the desired
acylation was achieved (i.e., 19). While replacement of
the isopropyloxy function by acetate also occurred34
(Scheme 5), it was considered to be of no significance as
the acetylene was resistant to hydrogenation.
Further modification of the functionality in these intermedi-
ates by routine procedures to afford substrates 20–23
(Scheme 6) and subsequent treatment with silver trifluoro-
acetate still failed to result in cyclisation, affording only
rearranged products.
However, when both ester and isopropyl functionality were
modified, that is, as in diacetate 24, intramolecular arylation
induced by treatment with silver trifluoroacetate was at
last observed, producing 25, albeit in only 18% yield,
the remainder consisting of the rearranged product 26
(Scheme 7). Then, after extensive small scale experimen-
tation with different solvents and silver salts [e.g.,
AgOCOCF3, AgBF4, AgB(C6F5)435] we found that the
yield of cyclisation could be increased to 53% using silver
2,4,6-trinitrobenzenesulfonate36 in nitromethane. Changing
the solvent system and investigating solvent mixtures gave
no improvement on nitromethane. Although it is not entirely
clear as to why silver 2,4,6-trinitrobenzenesulfonate
Scheme 5.
Scheme 6.
Scheme 7.

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C. M. Williams et al. / Tetrahedron 61 (2005) 3759–3769
Figure 4. X-ray crystal structure diagrams for compounds 10, 22, 23 and 24. In the case of 24 only one of the two crystallographically independent molecules is
shown for this structure.
provides such a dramatic improvement in yield it is
conceivable, however, that the 2,4,6-trinitrobenzene-
sulfonate counter ion provides increased silver(I)
solubility.
and increasing electron density on the hydroxyl oxygen both
favouring the undesired pinacol-type rearrangement.
Attempts were made to circumvent the medium yielding
silver (I) induced cyclisation by investigating radical based
processes. As aromatic rings are generally not amenable to
radical mediated substitution (addition/elimination) reac-
tions the aryl ring was firstly dearomatised. Treatment of 21
with aluminium trichloride29 removed the isopropyl pro-
tecting group affording the phenol 27 (56%), which
underwent oxidation to the unstable ortho-quinone acetal
28 (w53%) with phenyliododiacetate37 (Scheme 8). Using
radical inducing conditions applicable to the azabicyclo-
[3.3.1]nonane system23 (Vitamin B12) resulted in rapid
decomposition. Tin based procedures gave similar results.
In an attempt to understand why 24 is amenable to
cyclisation while derivatives 10 and 20–23 fail to bridge-
head arylate X-ray crystal structure analysis was performed
and data obtained for compounds 10, 22, 23 and 24 (Fig. 4).
1
On close inspection of the H NMR spectrum, sharp OH
singlets are observed for the hydroxyl proton [10
(5.01 ppm), 20 (4.26 ppm), 21 (4.05 ppm), 22 (3.63 ppm)
and 23 (4.46 ppm)] suggesting strong intramolecular
hydrogen bonding interactions have formed, but for
compound 24 the OH peak is not observed. In the solid
state hydrogen bonding is seen for all compounds 10, 22, 23
and 24, but, 24 maintains the longest non-covalent
Finally, in view of the results above N-phenethyl derivatives
29 and 30 were synthesised to further probe silver (I)
mediated bridgehead arylation. Derivative 29, obtained in
40% yield from a double Mannich reaction of bromide 31
and amine 32 in the presence of formaldehyde, afforded no
˚
hydrogen–oxygen bond length (2.14–2.19 A). In the case
of strong intramolecular hydrogen bonding (e.g., 10, 20, 21,
22 and 23) this has two implications: restricted aryl rotation
Scheme 8.

C. M. Williams et al. / Tetrahedron 61 (2005) 3759–3769
3763
cyclised products when subjected to a variety of silver (I)
salts. Conversion of 29 into 30 proceeded smoothly (66%)
using the TMSOTf/Ac2O/CH3CN protocol developed
above. Treatment with silver (I) 2,4,6-trinitrobenzenesulfo-
nate36 in nitromethane, did not lead to a cyclised product but
gave instead, alcohol 33 (82%) (Scheme 9).
prepared according to Perin and Armarego, ‘Purification of
laboratory solvents’, 3rd Ed. Melting points were deter-
mined on a Fischer Johns Melting Point apparatus and are
uncorrected. Methylmagnesium bromide was purchased
from the Aldrich Chem. Co.
4.2. X-ray crystallography
Data for compounds 22, 23 and 24 were collected at 293 K
on an Enraf-Nonius CAD4 diffractometer. Data reduction,
structure solution and refinement (SHELX9740) were
performed with the WINGX package.41 For compound 10
data were collected at 200 K on a Nonius Kappa CCD
diffractometer. Structure solution and refinement of this
structure was carried out with the teXsan package.42
Drawings of all molecules were created with ORTEP3.43
Data in CIF format have been deposited with the Cambridge
Crystallographic Data Centre (CCDC Deposition Nos.
247761–247764). Copies of the data can be obtained free
of charge upon request to deposit@ccdc.cam.ac.uk.
4.2.1. Ethyl 5-bromo-3-methyl-9-oxo-3-azabicyclo-
[3.3.1]nonanecarboxylate 8. To a solution of ethyl
Scheme 9.
6-bromocyclohexanone-2-carboxylate44
31
(10 g,
0.040 mol) and formaldehyde (39.1 mL, 0.482 mol, 37%
in water) in methanol (160 mL) at 0 8C was added a solution
of methylamine (9.35 mL, 0.120 mol, 40% in water) in
methanol (90 mL) dropwise over 3 h. The solution was then
allowed to warm to room temperature over 20 h followed by
refluxing for 30 min. On cooling the volatiles were removed
in vacco and the residue diluted with water (100 mL) and
extracted with diethyl ether (3!50 mL). The ether layers
were dried (Na2SO4) and evaporated affording an oil which
was passed through a plug of alumina. The residue was then
purified by distillation (1168/0.01 mmHg) affording a pale
yellow solid (8.30 g, 68%) on cooling, mp 49–51 8C. Five
fold scale-up afforded ethyl 5-bromo-3-methyl-9-oxo-3-
azabicyclo[3.3.1]nonanecarboxylate in 50% yield. 1H NMR
(400 MHz, CHCl3) d 1.27 (t, 3H, JZ7.2 Hz), 1.56–1.63 (m,
1H), 2.21–2.27 (m, 1H), 2.27 (s, 3H), 2.54–2.60 (m, 2H),
2.72–2.82 (m, 1H), 2.96 (dd, 1H, JZ11.1, 2.3 Hz), 3.03–
3.17 (m, 3H), 3.50 (dd, 1H, JZ11.1, 2.3 Hz), 4.20 (q, 2H,
JZ7.2 Hz). 13C NMR (100 MHz, CDCl3) d 14.1, 22.7, 36.4,
44.3, 46.3, 59.9, 61.5, 63.7, 68.9, 71.2, 169.7, 201.9. Near IR
(Nujol) y (cmK1) 1747, 1736. MS m/z (EI) 305 (MC%, 20%),
303 (MC%, 20%), 288 (13), 286 (13), 260 (19), 258 (16), 232
(8), 224 (100), 206 (8), 197 (15), 178 (74), 150 (37), 135
(11), 125 (15), 122 (14), 108 (10), 94 (10), 86 (43), 84 (68),
79 (27). Anal. Calcd for C12H18BrNO3: C, 47.38; H, 5.96;
N, 4.60; MC% 305.0451. Found: C, 47.26; H, 6.00; N, 4.47;
305.0451.
3. Conclusion
We have demonstrated that intramolecular bridgehead
arylation of a functional group specific 5-bromo-3-azabi-
cyclo[3.3.1]nonane derivative (24) affords a viable route to
a highly functionalized, advanced intermediate (25), the
brevity of the route (the longest linear sequence is only 8
steps) compensating for the modest yield of cyclization.
While the kobusine family of alkaloids (O100 in number11)
remain our main objective, we note that 25 and its analogues
may also have the potential to serve as an intermediate for
the synthesis of denudatine38 and dictysine39 type alkaloids
(Fig. 5).
Figure 5.
4. Experimental
4.1. General experimental
4.2.2. 2-Isopropoxy-3-methoxyphenylacetylene 13.27 The
procedure of Banwell29 was used. To a suspension of
o-vanillin (20 g, 131 mmol) and potassium carbonate
(63.6 g, 460 mmol) in N,N-dimethylformamide (200 mL)
was added isopropyl bromide (15.4 mL, 164 mmol). The
mixture was then heated at 100 8C for 4 h. On cooling the
reaction mixture was diluted with water (w500 mL) and
washed with diethyl ether (3!100 mL). The ether layers
were combined, dried (Na2SO4) and evaporated. The
residue (O90% yield) was dried under high vacuum and
used in the next step without purification. Spectral data was
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 chromato-
graphy was undertaken on silica gel (Flash Silica gel 230–
400 mesh), with distilled solvents. Anhydrous solvents were

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C. M. Williams et al. / Tetrahedron 61 (2005) 3759–3769
in agreement with that reported.45 1H NMR (400 MHz,
TMS) d 1.30 (d, JZ6.4 Hz, 6H), 3.86 (s, 3H), 4.61 (sep, JZ
6.4 Hz, 1H), 7.05–7.12 (m, 2H), 7.38–7.41 (m, 1H), 7.43 (s,
1H). 13C NMR (400 MHz, CHCl3) d 22.3, 56.0, 76.2, 117.8,
118.9, 123.6, 130.9, 150.6, 153.2, 190.9. MS m/z (EI) 194
(MC%, 11%), 152 (100), 122 (12), 106 (47), 84 (6), 62 (18),
51 (6), 45 (38). Anal. Calcd for C11H14O3: MC% 194.0943.
Found: 194.0942.
1.16 M, tetrahydrofuran/toluene) was then added and the
flask taken out of the bath and stirred at room temperature
for 2.5 h. In a separate flask azabicyclo[3.3.1]nonane 8
(3.91 g, 12.9 mmol) was dissolved in anhydrous tetra-
hydrofuran (130 mL) and cooled to K78 8C (dry-ice/
acetone bath) under nitrogen. To this was added the above
solution dropwise over 5 min. The reaction mixture was
then allowed to reach 15–20 8C over 80 min in the bath
before being quenched with acetic acid (1 mL) in tetra-
hydrofuran (16 mL). After 5 min saturated sodium hydro-
gencarbonate solution (5 mL) was added followed by
extraction into diethyl ether, drying (Na2SO4) and evapo-
ration in vacco. The residue was subjected to column
chromatography (t-butylmethylether/light petroleum; 3:7),
which firstly eluted recovered excess phenyl acetylene 13
followed by the titled compound (4.54 g, 71%) as a mixture
of diasteroisomers [9(16):1(17)]. Flushing the column with
ethyl acetate afforded ethyl 3-methyl-5-[2-(3-methoxy-2-
isoproxy)phenylethynyl]-oxo-3-azabicyclo[3.3.0]octane-
carboxylate 18.
Following the method of Corey and Fuchs28 triphenylphos-
phine (108.0 g, 412 mmol) was dissolved in dichloro-
methane (400 mL) at 0 8C and to this was added
carbontetrabromide (68.3 g, 206 mmol) portionwise. After
15 min the aldehyde above was added to the mixture
portionwise over 10 min and allowed to stir for a further
10 min at 0 8C followed by stirring at room temperature for
30 min. The mixture was then preabsorbed onto silica gel
(w400 g) and the pure product eluted from the silica gel
plug (diethyl ether/light petroleum; 1:1) (600–700 mL).
Evaporation of the eluent afforded a pale yellow oily residue
(22 g, 61%) after distillation (1058/0.01 mm). 1H NMR
(400 MHz, CHCl3) d 1.27 (d, JZ6.2 Hz, 6H), 3.82 (s, 3H),
4.37 (sep, JZ6.2 Hz, 1H), 6.89 (dd, JZ8.15, 1.4 Hz, 1H),
7.02 (t, JZ8.15 Hz, 1H), 7.25–7.27 (m, 1H), 7.63 (s, 1H).
13C NMR (400 MHz, CHCl3) d 22.5, 55.8, 76.0, 89.9, 112.6,
120.9, 123.2, 130.8, 134.1, 144.9, 152.9. Near IR (film) y
(cmK1) 1577. MS m/z (EI) 350 (MC%, 9%), 308 (26), 228
(5), 226 (5), 214 (8), 212 (9), 199 (1), 185 (4), 183 (5), 170
(1), 155 (1), 148 (100), 133 (2), 105 (9), 89 (5), 76 (10), 63
(2). Anal. Calcd for C12H14Br2O2: C, 41.17; H, 4.03; MC%
347.9361. Found: C, 41.08; H, 4.01; 347.9363.
Method B. Phenylacetylene 13 (0.136 g, 0.714 mmol) was
reacted with methylmagnesium bromide (0.47 mL,
0.655 mmol, 1.4 M, THF) as above in toluene (2 mL).
This was added to azabicyclo[3.3.1]nonane 8 (0.181 g,
0.595 mmol) as above in toluene (7 mL) and quenched with
acetic acid (0.6 mL) in tetrahydrofuran (2 mL) followed by
saturated sodium hydrogencarbonate solution (1 mL). Work
up as above gave 16 and 17 (3:2) (0.275 mg, 94%).
Ethyl 5-bromo-3-methyl-9-exo-hydroxy-9-[2-(3-methoxy-
2-isopropoxy)phenylethynyl]-3-azabicyclo[3.3.1]nonane-
carboxylate 16 (major diasteromer reported only). 1H NMR
(400 MHz, CHCl3) d 1.22 (t, JZ7.1 Hz, 3H), 1.29 (d, JZ
6.2 Hz, 6H), 1.47–1.62 (m, 1H), 1.72–1.83 (m, 1H), 2.22 (s,
3H), 2.21–2.36 (m, 2H), 2.72–2.90 (m, 2H), 2.98 (dd, JZ
12.0, 2.5 Hz, 1H), 3.13 (d, JZ12 Hz, 1H), 3.19 (d, JZ
11.1 Hz, 1H), 3.28 (dd, JZ11.1, 12.0 Hz, 1H), 3.79 (s, 3H),
4.13–4.23 (m, 2H), 4.67 (sep, JZ6.2 Hz, 1H), 5.04 (s, 1H,
OH), 6.83 (dd, JZ8.1, 1.7 Hz, 1H), 6.91 (t, JZ8.1 Hz, 1H),
6.97 (dd, JZ8.1, 1.7 Hz, 1H). 13C NMR (100 MHz, CDCl3)
d 14.0, 22.50, 22.54, 23.1, 29.1, 36.8, 44.8, 53.2, 55.8, 59.2,
61.5, 67.1, 69.1, 74.8, 75.3, 85.1, 92.5, 112.8, 118.2, 123.2,
125.6, 148.0, 153.2, 175.1. MS m/z (EI) 495 (MC%, 2%), 493
(MC%, 2%), 478 (6), 476 (6), 458 (1), 452 (2), 450 (2), 436
(1), 414 (100), 370 (11), 368 (10), 340 (18), 326 (10), 324
(7), 298 (17), 190 (14), 177 (64), 161 (10), 148 (30), 134 (9),
122 (36), 105 (9). Anal. Calcd for C24H32BrNO5: MC%
495.1444. Found: 495.1432.
The above material (20 g, 57.1 mmol) was dissolved in
anhydrous tetrahydrofuran (450 mL) and cooled to K78 8C
under nitrogen. To this was added n-BuLi (82 mL,
123 mmol, 1.5 M in hexanes) dropwise over 15 min. The
reaction mixture was stirred at K78 8C for 1 h and then
removed from the cold bath and stirred for 2 h. The flask
was then placed in an ice-bath and the reaction quenched
with saturated ammonium chloride solution (200 mL). The
phases were partitioned and the aqueous phase washed with
diethyl ether (100 mL). The combined ether phases were
dried (Na2SO4) and evaporated affording the product, which
was purified by distillation (758/0.1 mm) giving the pure
product (8.30 g, 76%) as a colourless oil. The oil slowly
solidified on refrigeration as a colourless solid, mp 48–
1
50 8C. H NMR (400 MHz, CHCl3) d 1.31 (d, JZ6.2 Hz,
6H), 3.20 (s, 1H), 3.81 (s, 3H), 4.56 (sep, JZ6.2 Hz, 1H),
6.88 (dd, JZ8.2, 1.7 Hz, 1H), 6.94 (t, JZ8.2 Hz, 1H), 7.03
(dd, JZ8.2, 1.7 Hz, 1H). 13C NMR (400 MHz, CHCl3) d
22.6, 55.9, 76.2, 80.6, 80.8, 113.3, 117.9, 123.4, 125.6,
149.3, 153.2. Near IR (Nujol) y (cmK1) 1917, 1836. MS m/z
(EI) 190 (MC%, 24%), 148 (100), 133 (10), 118 (8), 105
(14), 91 (8), 84 (8), 77 (15). Anal. Calcd for C12H14O2: C,
75.76; H, 7.42; MC% 190.0994. Found: C, 76.06; H, 7.61;
190.0997.
Ethyl 3-methyl-5-[2-(3-methoxy-2-isoproxy)phenylethy-
nyl]-oxo-3-azabicyclo[3.3.0]octanecarboxylate 18 was
1
obtained as a pale yellow oil. H NMR (400 MHz, CHCl3)
d 1.16 (t, JZ7.1 Hz, 3H), 1.30 (d, JZ6.2 Hz, 6H), 1.80–
1.94 (m, 4H), 2.29–2.39 (m, 1H), 2.33 (s, 3H), 2.49–2.57
(m, 1H), 2.79 (d, JZ6.0 Hz, 1H), 2.81 (d, JZ6.0 Hz, 1H),
2.91 (d, JZ9.4 Hz, 1H), 3.00 (d, JZ9.4 Hz, 1H), 3.82 (s,
3H), 4.05 (q, JZ7.1 Hz, 2H), 4.59 (sep, JZ6.2 Hz, 1H),
6.94 (m, 3H), 7.00–7.09 (m, 1H). 13C NMR (400 MHz,
CDCl3) d 13.8, 22.5, 26.0, 38.0, 39.5, 42.0, 55.9, 60.9, 64.1,
66.5, 67.3, 70.3, 76.4, 90.0, 90.1, 115.0, 116.0, 123.7, 126.0,
149.9, 153.1, 174.5, 188.3. Near IR (film) y (cmK1) 2192,
1729, 1664, 1572. MS m/z (EI) 413 (MC%, 12%), 398 (2),
4.2.3. Ethyl 5-bromo-3-methyl-9-exo-hydroxy-9-[2-(3-
methoxy-2-isopropoxy)phenylethynyl]-3-azabicyclo-
[3.3.1]nonanecarboxylate 16. Method A. Phenylacetylene
13 (5.16 g, 27.1 mmol) was dissolved in anhydrous tetra-
hydrofuran (40 mL) and placed in an ice-bath under
nitrogen. Methylmagnesium bromide (21 mL, 24.4 mmol,

C. M. Williams et al. / Tetrahedron 61 (2005) 3759–3769
3765
370 (14), 354 (6), 340 (13), 324 (2), 312 (2), 298 (10), 281
(3), 260 (3), 242 (2), 224 (6), 209 (8), 196 (8), 182 (9), 175
(15), 161 (27), 142 (18), 122 (44), 110 (14), 94 (15), 84 (45),
72 (100). Anal. Calcd for C24H31NO5: MC% 413.2202.
Found: 413.2189.
nonanecarboxylate 19. Acetylene 16 (63 mg, 0.127 mmol)
was dissolved in anhydrous acetonitrile (0.2 mL) and
anhydrous acetic anhydride (0.2 mL) under a nitrogen
atmosphere. To this solution was added one half
portion of trimethylsilyltrifluoromethanesulfonate (0.1 mL,
0.51 mmol) dropwise over 1 min. After 10 min the remain-
ing half portion was added and the reaction mixture stirred
for 10 min. The reaction flask was placed in an ice-bath and
the reaction quenched with saturated sodium hydrogen
carbonate solution (1–2 mL) followed by solid sodium
hydrogen carbonate (w300 mg) and dilution with water
(3 mL). Extraction with diethyl ether (3!5 mL), drying
(Na2SO4), and evaporation in vacco afforded a residue
which was subjected to column chromatography (diethyl
ether/light petroleum; 7:3) affording ethyl 5-bromo-3-
methyl-9-exo-acetoxy-9-[2-(3-methoxy-2-acetoxy)phenyl-
ethynyl]-3-azabicyclo[3.3.1]nonanecarboxylate as a colour-
less glass (59 mg, 87%) and trace amounts of a triacetylated
derivative. Compound 19 was crystallised by slow evapo-
4.2.4. Ethyl 5-bromo-3-methyl-9-exo-hydroxy-9-[2-(3-
methoxy-2-isopropoxy)phenyl-Z-ethenyl]-3-azabicyclo-
[3.3.1]nonanecarboxylate 10. Method A. Acetylene 16
(213 mg, 0.14 mmol) was dissolved in distilled methanol
(9 mL) and to this was added pyridine (9 drops) and
palladium on carbon (21 mg, 10%). The mixture was
degassed/gassed three times with hydrogen and stirred
under a hydrogen atmosphere for 24–27 h. Filtration of the
reaction mixture through celite followed by evaporation
afforded an oily residue which was subjected to column
chromatography (t-butylmethylether/light petroleum; 1:17)
affording recovered starting material (w50 mg), ethyl
5-bromo-3-methyl-9-exo-hydroxy-9-[2-(3-methoxy-2-iso-
propoxy)phenyl-Z-ethenyl]-3-azabicyclo[3.3.1]nonanecar-
boxylate (100 mg, 47%) and a mixture of unidentified
products (20 mg).
1
ration from chloroform, mp 98–100 8C (white crystals). H
NMR (400 MHz, CHCl3) d 1.21 (t, JZ7.2 Hz, 3H), 1.47–
1.62 (bm, 1H), 1.78 (bdd, JZ14.0, 5.2 Hz, 1H), 2.11 (s, 3H),
2.20 (bs, 3H), 2.29–2.50 (m, 2H), 2.35 (s, 3H), 2.68–2.90
(m, 3H), 3.10–3.40 (bm, 3H), 3.79 (s, 3H), 4.04–4.18 (m,
2H), 6.89–6.95 (m, 1H), 7.10–7.15 (m, 2H). Near IR (Nujol)
y (cmK1) 1764, 1756, 1716. MS m/z (EI) 537 (MC%, 15%),
535 (MC%, 12%), 478 (56), 476 (54), 456 (93), 414 (40), 396
(100), 382 (13), 368 (16), 354 (17), 340 (12), 324 (21), 308
(14), 280 (25), 246 (12), 206 (16), 175 (23), 161 (14), 148
(24), 122 (22), 94 (12). Anal. Calcd for C25H30Br1N1O7: C,
55.98; H, 5.64; N, 2.61; MC% 535.1206. Found: C, 55.72; H,
5.65; N, 2.52; MC% 535.1206.
Method B. Acetylene 16 (4.32 g, 8.74 mmol) was dissolved
in anhydrous tetrahydrofuran (200 mL) and to this was
1,3,5-triisopropylbenzenesulfonohydrazide31 (5.48 g,
18.4 mmol). The mixture was refluxed for 2 h. To the hot
mixture was added a solution of sodium acetate (1 M,
18.5 mL) and reflux continued for 5 min. Tetrahydrofuran
was evaporated and the residue diluted with saturated
sodium hydrogen carbonate (100 mL) and extracted with
diethyl ether (3!50 mL). The organic layer was dried
(Na2SO4), and evaporated in vacco afforded an oily residue,
which was dried under high vacuum for 30 min. The above
procedure was repeated two more times and the resulting
residue subjected to column chromatography (t-butyl-
methylether/ethyl acetate/light petroleum; 2:1:7) affording
recovered starting material (0.786 g, 18%) and ethyl
5-bromo-3-methyl-9-exo-hydroxy-9-[2-(3-methoxy-2-iso-
propoxy)phenyl-Z-ethenyl]-3-azabicyclo[3.3.1]nonanecar-
boxylate (3.21 g, 74%) (91% based on starting material
recovery). Mp 123–125 (diethyl ether). 1H NMR (400 MHz,
CHCl3) d 0.98 (t, JZ7.1 Hz, 3H), 1.21 (d, JZ6.2 Hz, 3H),
1.27 (d, JZ6.2 Hz, 3H), 1.66–1.77 (m, 2H), 2.10–2.21 (m,
1H), 2.21–2.27 (m, 1H), 2.58–2.63 (m, 1H), 2.93–3.03 (m,
1H), 2.96 (s, 3H), 3.60 (dd, JZ13.6, 2.4 Hz, 1H), 3.67 (dd,
JZ13.6, 2.4 Hz, 1H), 3.72 (dq, JZ10.7, 7.1 Hz, 1H), 3.81
(s, 3H), 3.99 (d, JZ13.5 Hz, 1H), 4.01 (dq, JZ10.7, 7.1 Hz,
1H), 4.42 (d, JZ13.5 Hz, 1H), 4.51 (sep, JZ6.2 Hz, 1H),
5.01 (s, 1H), 5.87 (d, JZ13.1 Hz, 1H), 6.72 (d, JZ13.1 Hz,
1H), 6.79–6.85 (m, 1H), 6.96–7.01 (m, 2H). 13C NMR
(400 MHz, CDCl3) d 13.6, 20.0, 22.4, 22.6, 27.1, 35.8, 47.0,
52.3, 55.6, 57.5, 61.5, 62.3, 67.3, 75.6, 75.8, 77.3, 111.8,
122.3, 123.0, 126.7, 130.8, 132.2, 152.4, 170.4. MS m/z (EI)
497 (MC%, 15%), 495 (MC%, 12%), 454 (2), 452 (2), 438
(1), 436 (1), 416 (51), 398 (11), 372 (16), 370 (13), 356 (7),
354 (5), 342 (17), 340 (9), 313 (7), 300 (9), 288 (6), 286 (7),
284 (5), 282 (7), 238 (20), 224 (37), 195 (25), 177 (47), 162
(10), 150 (40), 142 (14), 122 (100), 94 (20). Anal. Calcd for
C24H34BrNO5: MC% 495.1620. Found: 495.1612.
4.2.6.
5-Bromo-1-hydroxymethyl-3-methyl-9-exo-
hydroxy-9-[2-(3-methoxy-2-isopropoxy)phenyl-Z-ethe-
nyl]-3-azabicyclo[3.3.1]nonane 20. Alkene 10 (3.21 g,
6.48 mmol) was dissolved in anhydrous tetrahydrofuran
(120 mL) under nitrogen and the flask placed in an ice-bath.
Diisobutylaluminium hydride (31.1 mL, 31.1 mmol, 1 M
solution in hexanes) was added dropwise over 5 min. The
reaction was stirred for 1 h and then at room temperature for
1 h before quenching with saturated ammonium chloride
solution (50 mL). Tetrahydrofuran was evaporated in vacco
and the aqueous extracted with diethyl ether (3!50 mL).
The organic layer was partitioned, dried (Na2SO4), and
evaporation in vacco afforded a residue which was subjected
to column chromatography (t-butylmethylether/light petro-
leum; 6:4) on silica gel affording a white solid (2.92 g,
99%), mp 134–136 8C. 1H NMR (400 MHz, CHCl3) d 1.19
(d, JZ6.1 Hz, 3H), 1.34 (d, JZ6.1 Hz, 3H), 1.41–1.50 (bm,
1H), 1.66–1.84 (m, 2H), 2.07–2.15 (m, 1H), 2.23 (bs, 3H),
2.32 (bd, JZ11.4 Hz, 1H), 2.6–2.75 (bm, 1H), 2.77–2.87
(m, 1H), 2.96 (bd, JZ11.4 Hz, 1H), 3.18 (bd, JZ11.2 Hz,
1H), 3.31 (bd, JZ11.2 Hz, 1H), 3.40 (AB, JZ11.1 Hz, 2H),
3.81 (s, 3H), 4.45 (bs, 1H), 4.48 (sep, JZ6.1 Hz, 1H), 6.17
(d, JZ13.0 Hz, 1H), 6.54 (d, JZ13.0 Hz, 1H), 6.69 (d, JZ
7.7 Hz, 1H), 6.79 (d, JZ7.7 Hz, 1H), 7.00 (t, JZ7.7 Hz,
1H). 13C NMR (100 MHz, CDCl3) d 22.2, 22.7, 23.1, 27.5,
38.8, 45.0, 47.1, 52.8, 55.6, 60.2, 66.5, 75.9, 77.5, 78.4,
111.0, 120.9, 123.7, 128.5, 131.6, 133.5, 142.7, 153.0. Near
IR (Nujol) y (cmK1) 3447, 3381, 1569. MS m/z (EI) 455
(MC%, 12%), 453 (MC%, 13%), 412 (2), 410 (2), 396 (10),
394 (10), 374 (100), 356 (12), 332 (10), 314 (48), 282 (5),
4.2.5. Ethyl 5-bromo-3-methyl-9-exo-acetoxy-9-[2-(3-
methoxy-2-acetoxy)phenylethynyl]-3-azabicyclo[3.3.1]-

3766
C. M. Williams et al. / Tetrahedron 61 (2005) 3759–3769
244 (9), 196 (8), 177 (28), 164 (25), 150 (12), 137 (18), 122
(25), 91 (8). Anal. Calcd for C22H32BrNO4: C, 58.15; H,
7.09; N, 3.08; MC% 453.1515. Found: C, 58.35; H, 7.20; N,
3.14; 453.1526.
1H). 13C NMR (100 MHz, CDCl3) d 13.9, 20.6, 23.0, 30.4,
38.2, 44.9, 53.4, 55.9, 58.8, 61.3, 66.2, 71.7, 78.3, 111.1,
123.0, 125.4, 127.0, 130.8, 131.1, 137.5, 150.6, 168.4,
174.0. Near IR (Nujol) y (cmK1) 3447, 1752, 1701. MS m/z
(EI) 497 (MC%, 43%), 495 (MC%, 44%), 454 (1), 434 (1),
424 (1), 416 (83), 398 (17), 374 (17), 356 (9), 342 (11), 324
(8), 314 (9), 305 (15), 303 (15), 288 (21), 286 (21), 257 (7),
248 (18), 238 (23), 232 (6), 224 (100), 206 (8), 195 (28), 177
(43), 162 (10), 150 (36), 137 (12), 122 (67), 94 (13), 84 (66).
Anal. Calcd for C23H30BrNO6: C, 55.65; H, 6.09; N, 2.82;
MC% 495.1256. Found: C, 55.56; H, 6.14; N, 2.77; MC%
495.1259.
4.2.7.
5-Bromo-1-chloromethyl-3-methyl-9-exo-
hydroxy-9-[2-(3-methoxy-2-isopropoxy)phenyl-Z-ethe-
nyl]-3-azabicyclo[3.3.1]nonane 21. Diol 20 (1.0 g,
2.20 mmol) from above and triphenylphosphine (2.31 g,
8.80 mmol) were dissolved in anhydrous carbon tetra-
chloride (50 mL) under a nitrogen atmosphere and to this
was added N,N-diisopropylethylamine (6.13 mL,
35.2 mmol). The mixture was then refluxed for 14 h. On
cooling the solvent was removed and the residue dissolved
in dichloromethane (50 mL) and washed with saturated
sodium hydrogen carbonate solution (100 mL). The organic
layer was then partitioned, dried (Na2SO4), and evaporation
in vacco afforded a white solid residue which was subjected
to column chromatography (dichloromethane) affording a
white amorphous solid (960 mg, 92%), mp 168–170 8C. 1H
NMR (400 MHz, CHCl3) d 1.16–1.22 (m, 1H), 1.27 (d, JZ
6.2 Hz, 6H), 1.4–1.54 (m, 1H), 2.04–2.14 (m, 1H), 2.15–
2.25 (m, 1H), 2.22 (bs, 3H), 2.39 (AB, JZ11.7 Hz, 2H),
2.65–2.85 (m, 3H), 3.07 (AB, JZ8.2 Hz, 1H), 3.23 (AB,
JZ11.4 Hz, 2H), 3.52–3.57 (m, 1H), 3.80 (s, 3H), 4.05 (s,
1H), 4.53 (sep, JZ6.2 Hz, 1H), 6.24 (d, JZ12.8 Hz, 1H),
6.56 (d, JZ12.8 Hz, 1H), 6.79 (d, JZ8.0 Hz, 1H), 6.88–
6.91 (m, 1H), 7.02 (t, JZ8.0 Hz, 1H). 13C NMR (100 MHz,
CDCl3) d 22.4, 22.6, 23.2, 27.9, 38.9, 45.0, 46.2, 55.6, 60.2,
66.3, 68.4, 75.8, 80.2, 111.1, 121.2, 123.9, 127.8, 132.2,
133.6, 142.1, 152.6. Near IR (Nujol) y (cmK1) 3400, 1569.
MS m/z (EI) 473 (MC%, 37%), 471 (MC%, 26%), 438 (58),
436 (56), 394 (38), 392 (100), 374 (5), 350 (18), 314 (21),
262 (22), 246 (93), 244 (92), 214 (24), 200 (19), 183 (5), 177
(39), 164 (56), 150 (18), 137 (38), 122 (30), 91 (14). Anal.
Calcd for C22H31BrClNO3: C, 55.88; H, 6.61; N, 2.96; MC%
471.1176. Found: C, 55.73; H, 6.59; N, 2.70; MC%
471.1184.
4.2.9.
1-Acetoxymethyl-5-bromo-3-methyl-9-exo-
hydroxy-9-[2-(3-methoxy-2-isopropoxy)phenyl-Z-ethe-
nyl]-3-azabicyclo[3.3.1]nonane 23. Diol 20 (201 mg,
0.442 mmol) was dissolved in anhydrous dichloromethane
(3 mL) under an argon atmosphere. The solution was cooled
in an ice-bath and acetic anhydride (0.33 mL, 3.54 mmol),
pyridine (0.11 mL, 1.37 mmol) and 4-(dimethylamino)pyr-
idine (10 mg) were added. After 2 h at room temperature the
reaction was heated at 40 8C for 3 h. Solvents were then
removed and the residue subjected to column chroma-
tography (diethyl ether/light petroleum, 1:1) affording 1-
acetoxymethyl-5-bromo-3-methyl-9-exo-hydroxy-9-[2-(3-
methoxy-2-isopropoxy)phenyl-Z-ethenyl]-3-azabicyclo-
[3.3.1]nonane (210 mg, 95%) which solidified on standing,
mp 117–118 8C. 1H NMR (400 MHz, CHCl3) d 1.19 (d, JZ
6.1 Hz, 3H), 1.33 (d, JZ6.1 Hz, 3H), 1.39–1.48 (m, 1H),
1.51–1.58 (m, 1H), 1.77–1.90 (m, 1H), 1.92 (s, 3H), 2.06–
2.15 (m, 1H), 2.21 (s, 3H), 2.36 (dd, JZ11.6, 2.5 Hz, 1H),
2.59–2.79 (m, 1H), 2.70 (d, JZ12.1 Hz, 1H), 2.78–2.89 (m,
1H), 3.17 (dd, JZ11.6, 2.5 Hz, 1H), 3.31 (d, JZ11.8 Hz,
1H), 3.59 (d, JZ11.1 Hz, 1H), 3.79 (s, 3H), 4.03 (d, JZ
11.1 Hz, 1H), 4.46 (s, OH), 4.46 (sep, JZ6.1 Hz, 1H), 6.17
(d, JZ13.0 Hz, 1H), 6.53 (d, JZ13.0 Hz, 1H), 6.76–6.84
(m, 2H), 7.01 (t, JZ8.0 Hz, 1H). 13C NMR (100 MHz,
CDCl3) d 20.8, 22.2, 22.7, 23.1, 27.5, 38.9, 45.0, 46.2, 55.5,
60.3, 66.5, 69.9, 75.9, 77.2, 77.5, 110.9, 121.6, 123.5, 128.3,
131.6, 133.5, 142.6, 152.7, 170.9. MS m/z (EI) 497 (MC%
,
4.2.8. Ethyl 5-bromo-3-methyl-9-exo-hydroxy-9-[2-(3-
methoxy-2-acetoxy)phenyl-Z-ethenyl]-3-azabicyclo-
[3.3.1]nonanecarboxylate 22. Alcohol 10 (104 mg,
0.209 mmol) was dissolved in anhydrous acetonitrile
(0.7 mL), anhydrous dichloromethane (0.35 mL) and acetic
anhydride (0.35 mL) under a nitrogen atmosphere. To this
solution was added trimethylsilyltrifluoromethanesulfonate
(0.14 mL, 0.733 mmol) dropwise over 1 min. The reaction
mixture was stirred for 15 min then quenched with saturated
sodium hydrogen carbonate solution (1–2 mL) followed by
solid sodium hydrogen carbonate (w300 mg) and dilution
with water (3 mL). Extraction with diethyl ether (3!5 mL),
drying (Na2SO4), and evaporation in vacco afforded a
residue which was subjected to column chromatography
(dichloromethane/ethyl acetate; 24:1) on silica gel affording
a colourless glass which was crystallised from diethyl ether
7%), 495 (MC%, 9%), 454 (4), 452 (2), 438 (4), 436 (4), 415
(5), 372 (8), 356 (17), 342 (35), 314 (8), 312 (13), 300 (15),
282 (12), 270 (10), 240 (15), 195 (29), 177 (54), 164 (25),
150 (38), 137 (28), 122 (100). Anal. Calcd for
C24H34BrNO5: C, 58.07; H, 6.90; N, 2.82; MC% 495.1621.
Found: C, 58.00; H, 7.15; N, 2.64; MC% 495.1614.
4.2.10.
1-Acetoxymethyl-5-bromo-3-methyl-9-exo-
hydroxy-9-[2-(3-methoxy-2-acetoxy)phenyl-Z-ethenyl]-
3-azabicyclo[3.3.1]nonane 24. Method A. The diol 20
(86 mg, 0.189 mmol) was dissolved in anhydrous aceto-
nitrile (0.35 mL), and acetic anhydride (0.35 mL) under a
nitrogen atmosphere. To this solution was added one
half portion of trimethylsilyltrifluoromethanesulfonate
(0.22 mL, 1.15 mmol) dropwise over 30 s. After 10 min
the remaining half portion was added and the reaction
mixture stirred for 10 min. The reaction flask was placed in
an ice-bath and the reaction quenched with saturated sodium
hydrogen carbonate solution (2–3 mL) followed by solid
sodium hydrogen carbonate (w400 mg) and dilution with
water (5 mL). Extraction with diethyl ether (3!5 mL),
drying (Na2SO4), and evaporation in vacco afforded a
residue which was subjected to column chromatography
1
as transparent prisms (56 mg, 54%), mp 169–171 8C. H
NMR (400 MHz, CHCl3) d 1.13 (t, JZ7.2 Hz, 3H), 1.44–
1.64 (m, 2H), 2.10–2.20 (m, 1H), 2.25 (s, 3H), 2.28 (bs, 3H),
2.33–2.44 (m, 1H), 2.70–2.83 (bm, 1H), 2.84–3.40 (m, 3H),
3.12–3.35 (bm, 2), 3.63 (bs, 1H), 3.79 (s, 3H), 4.04 (dq, JZ
10.8, 7.2 Hz, 1H), 4.17 (dq, JZ10.8, 7.2 Hz, 1H), 6.18 (bd,
JZ12.6 Hz, 1H), 6.39 (bd, JZ12.6 Hz, 1H), 6.85 (bd, JZ
8.0 Hz, 1H), 7.12 (t, JZ8.0 Hz, 1H), 7.38 (bd, JZ8.0 Hz,

C. M. Williams et al. / Tetrahedron 61 (2005) 3759–3769
3767
(diethyl ether/light petroleum; 6:4) affording 1-acetoxy-
methyl-5-bromo-3-methyl-9-exo-hydroxy-9-[2-(3-meth-
oxy-2-acetoxy)phenyl-Z-ethenyl]-3-azabicyclo[3.3.1]no-
nane as a white solid (64 mg, 68%) and triacetylated
material (8 mg, 8%).
Pipette) and the solid residue washed three times with
dichloromethane. The combined dichloromethane extracts
were passed through glass wool and evaporated. Column
chromatography (dichloromethane/ethyl acetate, 3:1)
afforded 7-acetoxy-4a-exo-hydroxy-8-methoxy-2-methyl-
4-acetoxymethyl-2,3,4,4a-tetrahydro-1HK4,10b-propano-
benz[h]isoquinoline 25 (4.5 mg, 54%) 1H NMR (400 MHz,
CHCl3) d 1.56 (bs, 1H), 1.57–1.72 (m, 2H), 1.89–2.31 (m,
5H), 2.02 (s, 3H), 2.07 (s, 3H), 2.33 (s, 3H), 2.57 (d, JZ
11.3 Hz, 1H), 2.73 (d, 11.3, 1H), 2.77 (m, 1H), 3.79 (s, 3H),
4.18 (AB, 2H), 6.38 (d, JZ10.1 Hz, 1H), 6.64 (d, JZ
10.1 Hz, 1H), 6.84 (d, JZ8.6 Hz, 1H), 7.21 (d, JZ8.6 Hz,
1H). 13C NMR (100 MHz, CDCl3) d 20.40, 20.43, 21.0,
28.8, 28.9, 40.2, 42.6, 45.5, 56.0, 61.0, 66.2, 67.7, 71.5,
111.5, 122.1, 123.6, 124.7, 130.9, 133.2, 135.9, 149.8,
168.8, 171.0. Near IR (Nujol) y (cmK1) 3463, 1743. MS m/z
(EI) 415 (MC%, 22%), 372 (17), 356 (8), 330 (42), 282 (11),
240 (31), 203 (12), 71 (11), 43 (100). Anal. Calcd for
C23H29NO6: MC% 415.1995. Found: MC% 415.1989.
Method B. Compound 23 (56 mg, 0.113 mmol) was reacted,
as above in method A, with acetic anhydride (0.3 mL),
anhydrous acetonitrile (0.3 mL) and trimethylsilyltrifluoro-
methanesulfonate (0.14 mL, 0.677 mmol). Column chro-
matography as above afforded 1-acetoxymethyl-5-bromo-3-
methyl-9-exo-hydroxy-9-[2-(3-methoxy-2-acetoxy)phenyl-
Z-ethenyl]-3-azabicyclo[3.3.1]nonane (48 mg, 86%) as a
white solid, mp 127–129 8C. 1H NMR (400 MHz, CHCl3) d
1.45–1.63 (m, 1H), 1.84–1.94 (m, 1H), 1.98 (s, 3H), 2.10–
2.17 (m, 1H), 2.23 (s, 3H), 2.28 (s, 3H), 2.43–2.48 (m, 1H),
2.44 (s, OH), 2.62–2.79 (m, 1H), 2.77 (d, JZ11.8 Hz, 1H),
3.16 (dd, JZ11.5 Hz, 1H), 3.28 (d, JZ11.5 Hz, 1H), 3.79
(s, 3H), 3.93 (bd, JZ11.0 Hz, 1H), 4.13 (d, JZ11.0 Hz,
1H), 6.22 (d, JZ12.8 Hz, 1H), 6.50 (d, JZ12.8 Hz, 1H),
6.86 (d, JZ8.0 Hz, 1H), 7.06 (d, JZ8.0 Hz, 1H), 7.16 (t,
JZ8.0 Hz, 1H). 13C NMR (100 MHz, CDCl3) d 20.7, 20.8,
23.1, 27.6, 39.0, 44.9, 45.2, 55.8, 60.2, 66.4, 69.9, 76.6,
78.9, 110.96, 121.0, 126.2, 126.8, 131.9, 132.7, 136.6,
150.9, 169.6, 170.9. Near IR (Nujol) y (cmK1) 3452, 1745,
1731, 1725. MS m/z (EI) 497 (MC%, 14%), 495 (MC%, 14%),
454 (2), 452 (2), 438 (3), 436 (2), 416 (92), 398 (10), 374
(14), 356 (26), 342 (15), 328 (5), 314 (4), 300 (9), 286 (17),
272 (5), 246 (16), 195 (25), 177 (56), 164 (70), 150 (19), 136
(19), 134 (17), 122 (90), 105 (22). Anal. Calcd for
C23H30Br1N1O6: C, 55.65; H, 6.09; N, 2.82; MC%
495.1257. Found: C, 55.75; H, 6.23; N, 2.68; MC% 495.1257.
4.2.12. o-Quinone acetal 28. To a solution of 21 (20 mg,
0.042 mmol) in anhydrous dichloromethane (2 mL) under a
nitrogen atmosphere was added solid aluminium chloride
(7 mg, 0.055 mmol) in one portion. The mixture was then
stirred at room temperature for 16 h. The reaction was
quenched with saturated sodium hydrogencarbonate solu-
tion (2 mL) and extracted with dichloromethane/diether
ether (1:1) (5 mL). The combined organic layers were dried
(Na2SO4) and evaporated. The residue was subjected to
column chromatography (t-butyl methyl ether/light petro-
leum, 3:7), which afforded two fractions. The first (8 mg)
was recovered starting material and the second was 5-
bromo-1-chloromethyl-3-methyl-9-exo-hydroxy-9-[2-(3-
methoxy-2-hydroxy)phenyl-Z-ethenyl]-3-azabicyclo[3.3.1]-
nonane 27 (10 mg, 56%) as an orange oil. 1H NMR
(300 MHz, CHCl3) d 1.45–1.60 (m, 1H), 1.74–1.97 (m, 3H),
2.16–2.25 (m, 1H), 2.32 (s, 3H), 2.50 (dd, 1H), 2.69–2.87
(m, 2H), 3.07 (d, JZ12 Hz, 1H), 3.24–3.39 (m, 2H), 3.65
(AB, 2H), 3.95 (s, 3H), 5.96 (bs, OH), 6.31 (d, JZ13 Hz,
1H), 6.68 (d, JZ13 Hz, 1H), 6.78–6.94 (m, 3H).
4.2.11. 7-Acetoxy-4a-exo-hydroxy-8-methoxy-2-methyl-
4-acetoxymethyl-2,3,4,4a-tetrahydro-1H-4,10b-propa-
nobenz[h]isoquinoline 25. Method A. Diacetate 24 (33 mg,
0.066 mmol) was dissolved in anhydrous dichloromethane
(2 mL) under a nitrogen atmosphere and the reaction flask
covered with aluminium foil. The reaction flask was cooled
in an ice-bath and solid silver trifluoroacetate (31 mg,
0.140 mmol) added to the vigorously stirring solution. After
1 h the reaction was quenched with concd ammonia solution
(15 drops) followed by addition of solid sodium sulfate.
Filtration through glass wool and evaporation of the filtrate
afforded an oily residue which was subjected to column
chromatography (t-butyl methyl ether). The 7-acetoxy-4a-
exo-hydroxy-8-methoxy-2-methyl-4-acetoxymethyl-2,3,4,
4a-tetrahydro-1H-4,10b-propanobenz[h]isoquinoline 25
(5 mg, 18%) was eluted first followed by the more polar
by-product 26, which underwent significant isomerization
on the column (ethyl acetate/methanol).
Phenol 27 (68 mg, 0.158 mmol) was dissolved in anhydrous
dichloromethane (2 mL) under a nitrogen atmosphere and
added dropwise to a solution of iodobenzene diacetate
(51 mg, 0.158 mmol) in anhydrous dichloromethane
(1.5 mL) and acetic acid (0.5 mL) all at room temperature.
After 1.5 h the reaction was quenched with excess solid
sodium hydrogen carbonate followed by saturated sodium
hydrogen carbonate solution (5 mL). Extraction with
dichloromethane, drying (Na2SO4) and evaporation
afforded the crude product (w48 mg, 53%), which was
found to decompose on silica gel and hence was used
without further purification. 1H NMR (300 MHz, CHCl3) d
1.46–1.60 (m, 1H), 1.85–1.95 (m, 2H), 2.14 (s, 3H), 2.10–
2.30 (m, 1H), 2.28 (s, 3H), 2.46 (dd, 1H), 2.65 (d, 1H), 2.67–
2.85 (m, 2H), 3.00–3.10 (bdd, 1H), 3.12–3.50 (m, 2H), 3.53
(s, 3H), 3.64 (s, 1H), 3.39 (d, 1H), 6.20–6.50 (m, 3H), 6.80–
6.88 (m, 1H), 7.07–7.14 (m, 1H).
Method B. Diacetate 24 (10 mg, 0.020 mmol) was dissolved
in anhydrous nitromethane (2 mL) under an argon atmo-
sphere and the reaction flask covered with aluminium foil.
The reaction flask was cooled in an ice-bath and solid silver
2,4,6-trinitrobenzenesulfonate36 (24 mg, 0.060 mmol)
added to the vigorously stirring solution. The reaction was
allowed to reach room temperature over 14 h. The solvent
was removed under high vacuum, the residue redissolved in
dichloromethane (w 2–3 mL) and concd ammonia solution
(20 drops) added followed by addition of solid sodium
sulfate. The dichloromethane layer was removed (Pastuer
4.2.13. Ethyl 5-bromo-3-[2-(3-methoxy-2-isopropoxy)-
ethyl]-9-oxo-3-azabicyclo[3.3.1]nonanecarboxylate 29.
To a solution of ethyl 6-bromocyclohexanone-2-carb-
oxylate 31 (0.30 g, 1.20 mmol) and formaldehyde

3768
C. M. Williams et al. / Tetrahedron 61 (2005) 3759–3769
(1.2 mL, 14.5 mmol, 37% in water) in methanol (2.0 mL) at
0 8C was added a solution of 2-(3-methoxy-2-isopropoxy)-
ethylamine46 32 (0.756 mg, 3.61 mmol) in methanol
(2.0 mL) dropwise over 1 h. The solution was then allowed
to warm to room temperature over 22 h followed by
refluxing for 10 min. On cooling the volatiles were removed
in vacco and the residue subjected to column chromato-
graphy (dichloromethane) affording a colourless oil
solid residue redissolved in dichlormethane (w2 mL) and
concd ammonia solution (50 drops) added. After 5 min solid
Na2SO4 was added and the dichloromethane removed
(Pasteur Pipette) followed by multiple dichloromethane
washes. The combined extracts were evaporated and the
residue subjected to column chromatography [dichloro-
methane then dichloromethane/ethyl acetate (95:5)], which
afforded recovery of starting material (w5 mg) and the
titled compound as a pale yellow oil (27 mg, 82%). 1H NMR
(200 MHz, CHCl3) d 1.27 (t, JZ7.3 Hz, 3H), 1.38–1.54 (m,
1H), 1.76–1.96 (m, 1H), 2.08–2.47 (m, 4H), 2.32 (s, 3H),
2.47–2.79 (m, 5H), 2.96–3.06 (m, 1H), 3.21–3.35 (m, 2H),
3.61 (s, OH), 3.80 (s, 3H), 4.21 (q, JZ7.3 Hz, 2H), 6.78–
6.87 (m, 2H), 7.11 (t, 7.9, 1H). 13C NMR (50 MHz, CDCl3)
d 14.1, 19.8, 20.1, 20.5, 27.9, 36.6, 42.1, 55.9, 56.5, 58.6,
61.5, 61.8, 66.4, 75.0, 110.3, 121.9, 126.3, 133.1, 138.3,
151.2, 168.9, 169.9, 211.5. MS m/z (EI) 419 (MC%, 3%), 402
(1), 374 (2), 332 (1), 302 (1), 286 (1), 254 (1), 240 (100),
212 (1), 194 (1), 176 (5), 164 (1), 151 (2), 136 (1), 107 (1),
91 (1). Anal. Calcd for C22H29NO7: MC% 419.1944. Found:
MC% 419.1955.
1
(231 mg, 40%). H NMR (400 MHz, CHCl3) d 1.15–1.34
(m, 9H), 1.34–1.44 (m, 1H), 2.10–2.18 (m, 1H), 2.41–2.53
(m, 1H), 2.60–2.76 (m, 2H), 2.78–2.87 (m, 1H), 2.98 (dd,
JZ11.0, 1.8 Hz, 1H), 3.07 (dd, JZ11.5, 1.8 Hz, 1H), 3.30
(dd, JZ11.5, 2.2 Hz, 1H), 3.65 (dd, JZ11.0, 2.2 Hz, 1H),
3.80 (s, 3H), 4.16–4.24 (m, 2H), 4.50 (sep, JZ6.2 Hz, 1H),
6.73–6.77 (m, 2H), 6.93 (t, JZ7.9 Hz, 1H). 13C NMR
(100 MHz, CDCl3) d 14.0, 22.4, 22.63, 22.67, 28.1, 36.2,
46.2, 55.6, 56.6, 60.0, 61.2, 61.4, 68.7, 69.4, 74.4, 110.5,
121.9, 123.2, 134.1, 145.1, 152.9, 169.8, 202.2. MS m/z (EI)
483 (MC%, 5%), 481 (MC%, 5%), 466 (4), 438 (20), 436
(21), 402 (5), 304 (98), 302 (100), 226 (10), 224 (5), 222
(11), 194 (3), 164 (4), 150 (14), 137 (8), 122 (7), 107 (5).
Anal. Calcd for C23H32BrNO5: MC% 483.1444. Found: MC%
483.1431.
Acknowledgements
4.2.14. Ethyl 5-bromo-3-[2-(3-methoxy-2-acetoxy)ethyl]-
9-oxo-3-azabicyclo[3.3.1]nonanecarboxylate 30. Ethyl 5-
bromo-3-[2-(3-methoxy-2-isopropoxy)ethyl]-9-oxo-3-aza-
bicyclo[3.3.1]nonanecarboxylate 29 (58 mg, 0.12 mmol)
was dissolved in anhydrous acetonitrile (0.3 mL) and acetic
anhydride (0.3 mL) under a argon atmosphere. To this
solution was added one half portion of trimethylsilyltri-
fluoromethanesulfonate (0.13 mL, 0.733 mmol). After
5 min the remaining half portion was added and the reaction
mixture stirred for 5 min. The reaction was then transferred
to a separatory funnel containing saturated sodium hydro-
gen carbonate solution (10 mL). Extraction with diethyl
ether (3!5 mL), drying (Na2SO4), and evaporation in
vacco afforded a residue which was subjected to column
chromatography (dichloromethane) affording the title
The authors thank the following people for their assistance
with this body of research: Dr. Tri Le for performing NMR
analysis and Mr. Graham McFarlane for mass spectroscopy.
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at doi:10.1016/j.tet.2005.02.014. Both
1H and 13C NMR spectra of compounds 8, 10, 13, 16, 18,
20–25, 29–30 and 33 are available.
1
compound as a pale yellow oil (38 mg, 66%). H NMR
(200 MHz, CHCl3) d 1.27 (t, JZ7.1 Hz, 3H), 1.34–1.51 (m,
1H), 2.07–2.22 (m, 1H), 2.33 (s, 3H), 2.39–2.84 (m, 8H),
2.99 (dd, JZ11.0, 1.6 Hz, 1H), 3.07 (dd, JZ11.5, 2.2 Hz,
1H), 3.25 (dd, JZ11.5, 2.2 Hz, 1H), 3.60 (dd, JZ11.0,
2.2 Hz, 1H), 3.79 (s, 3H), 4.20 (q, JZ7.1 Hz, 2H), 6.76–
6.86 (m, 2H), 7.12 (dd, JZ7.3, 8.5 Hz, 1H). MS m/z (EI)
483 (MC%, 5%), 481 (MC%, 5%), 438 (2), 436 (2), 402 (5),
356 (1), 342 (1), 330 (1), 328 (1), 304 (95), 302 (100), 222
(13), 210 (2), 164 (2), 162 (2), 150 (12), 137 (8), 122 (5),
107 (5), 91 (5). Anal. Calcd for C22H28BrNO6: MC%
483.1081. Found: MC% 483.1069.
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