A tandem Diels-Alder/Mannich approach to the synthesis of AE and ABE ring analogues of Delphinium alkaloids

Article abstract of DOI:10.1016/j.tet.2012.05.037

The one-pot TiCl₄ catalysed Diels-Alder/Mannich reaction of α-cyanoaminoacrylates with 2-silyloxy-1,4-butadienes gives 6-keto-3-azabicyclo[3.3.1]nonane-1-carboxylates. Reduction of the ketone and alkylation of the resultant alcohol gives 6-alkoxy-3-azabicyclo[3.3.1]nonanes mimicking the AE rings of a number of Delphinium and Aconitum alkaloids, with the same stereochemistry as the natural products.

Full text of DOI:10.1016/j.tet.2012.05.037

Tetrahedron 68 (2012) 5759e5778
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A tandem DielseAlder/Mannich approach to the synthesis of AE and ABE ring
analogues of Delphinium alkaloids
*
Kirsten J. Goodall, Margaret A. Brimble, David Barker
School of Chemical Sciences, University of Auckland, 23 Symonds St, Auckland, New Zealand
a r t i c l e i n f o
a b s t r a c t
Article history:
The one-pot TiCl4 catalysed DielseAlder/Mannich reaction of a-cyanoaminoacrylates with 2-silyloxy-1,4-
Received 27 February 2012
Received in revised form 18 April 2012
Accepted 8 May 2012
butadienes gives 6-keto-3-azabicyclo[3.3.1]nonane-1-carboxylates. Reduction of the ketone and alkyl-
ation of the resultant alcohol gives 6-alkoxy-3-azabicyclo[3.3.1]nonanes mimicking the AE rings of
a number of Delphinium and Aconitum alkaloids, with the same stereochemistry as the natural products.
Ó 2012 Elsevier Ltd. All rights reserved.
Available online 15 May 2012
Keywords:
Delphinium alkaloids
azabicyclo[3.3.1]nonanes
Mannich reaction
DielseAlder reaction
1. Introduction
base silver (I) oxide to prevent retro-aldol decomposition, however
these conditions resulted in epimerisation at C-6, resulting in
6-Alkoxy-3-azabicyclo[3.3.1]nonanes are a common structural
motif found in numerous Delphinium and Aconitum alkaloids, such
as eldeline 1 and methyllycaconitine (MLA) 2 (Fig. 1). Substitution
at the C-1 position has been found to have a considerable effect on
biological activity, to the extent that compounds with a C-1 hy-
droxyl group, e.g., grandiflorine 3, exhibits 100e1000 times less
binding efficiency than MLA 2, with a C-1 methoxy group, at the
a mixture of poorly-separable diastereomers 14, favouring the
unnatural stereochemistry 14a8 (Fig. 2).
These complications led us to investigate an alternative syn-
thesis of 6-oxygenated azabicyclononanes that did not involve the
incorporation of a ketone at C-9. We envisaged that selective re-
duction of 6-keto azabicyclononane 15 would afford 6-hydroxy
azabicyclononane 16, with the same configuration found in MLA
2 (Fig. 3). Alkylation of alcohol 16 would then proceed readily due
to the absence of retro-aldol complicating factors that were pre-
viously observed for the alkylation of the 9-keto-6-hydroxy-3-
azabicyclononane.8
neuronal a
7 nicotinic acetylcholine receptor.1 Other structurally-
related Delphinium and Aconitum alkaloids 4e11 exhibit various
biological activities, such as inuline 4 and ajacine 5, which have
hypotensive and ganglion-blocking effects,2 talatisamine 8, a po-
tassium channel blocker,3 delcosine 9, a plant growth inhibitor4 and
takaosamine 11, an insect antifeedant.5
2. Results and discussion
Although there have been previous syntheses of the 3-
azabicyclo[3.3.1]nonane core of Delphinium and Aconitum alka-
loids,6 few have included oxygenated substitution at the C-1 posi-
tion.7 This observation led us to investigate the activity of 6-
methoxy-9-methylene-3-azabicyclononanes as analogues of the
AE rings of MLA 2.8 Synthesis of these analogues involved alkyl-
ation of a 6-hydroxy-9-oxo-3-azabicyclo[3.3.1]nonane 13, which
itself results from successive Michael/aldol addition of acrolein to
an ethyl 4-piperidin-2-onecarboxylate 12. Methylation of the 6-
hydroxy-9-keto-azabicyclononanes 13 required use of the soft
2.1. Synthesis of C6-keto azabicyclononanes
The synthesis of bicyclic ketone 17a, similar to the desired ke-
tone 15 has been reported9 from the TiCl4-promoted, one-pot
DielseAlder/Mannich reaction of a-cyanoaminoacrylate 18a with
diene 19a (Scheme 1). The reaction proceeds by initial DielseAlder
cycloaddition of diene 19a to dienophile 18a, forming a cyclic in-
termediate that undergoes intramolecular Mannich reaction to give
the racemic bicyclic product 17a.
Whilst the synthesis of 17a has been reported9 we decided to
further develop the synthetic method and demonstrate the utility
of the reaction of analogues of 17a with a range of acrylates
and 2-silyloxy-1,4-butadienes. We therefore herein report the
* Corresponding author. Tel.: þ64 9 373 7599; fax: þ64 64 373 7422; e-mail
address: d.barker@auckland.ac.nz (D. Barker).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.05.037

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K.J. Goodall et al. / Tetrahedron 68 (2012) 5759e5778
Fig. 1. Delphinium and Aconitum alkaloids.
Fig. 2. Epimerisation of C-9 keto-azabicyclononanes.
synthesis of
a series 6-oxygenated-3-azabicyclo[3.3.1]nonanes
lacking C-9 oxo-substitution, as analogues of the AE rings of Del-
phinium and Aconitum alkaloids using this DielseAlder/Mannich
reaction as the key step.
Cyanoaminoacrylate 18b was synthesised using literature
methods9 from ethyl 2-(bromomethyl)acrylate,10,11 and 2-
benzylaminoacetonitrile.12 Diene 19a was prepared using litera-
ture methods13,14 though yields were generally low due to the
Fig. 3. Key intermediates in the synthesis of 6-alkoxy-3-azabicyclononanes.
Scheme 1. Titanium tetrachloride catalysed one-pot bicyclization.

K.J. Goodall et al. / Tetrahedron 68 (2012) 5759e5778
5761
difficulties encountered with the purification step that were com-
pounded by the instability of the diene.15
diene 19b19 and TBDMS diene 19c19 were therefore subjected to
reaction with -cyanoaminoacrylate 18b under the conditions
a
Having prepared both of the required starting materials, atten-
tion turned to the key DielseAlder/Mannich reaction. Initially,
1 equiv of diene 19a was added to 1 equiv of a-cyanomethylami-
previously described (Scheme 2). The results observed however
were disappointing, as TES diene 19b only afforded 12% yield of
azabicyclononane 17b, while TBDMS diene 19c gave only 2%,
establishing that highly reactive trimethylsilyloxydienes are re-
quired for this procedure.
Our initial optimisation of the synthesis of C6-keto azabicyclo-
nonanes was performed using a benzylamino substituent, however
the natural diterpenoid alkaloids of interest have an N-ethyl sub-
stituent. Bergmeier et al. reported that replacing the N-ethyl sub-
stituent with an N-3-(phenylpropyl) group increased the activity of
simple monocyclic analogues at nicotinic acetylcholine receptors.20
We also envisaged that replacement of the achiral N-benzyl moiety
with a chiral substituent would afford the opportunity to prepare
chiral azabicyclononanes.
noacrylate 18b (0.5 M in CH2Cl2) followed by cooling to ꢀ78 ꢁC
and the addition of TiCl4 (4 equiv). After 2 h none of the desired
product was observed in the crude 1H NMR spectrum. Increasing
the reaction time to 24 h and modifying the workup procedure16
gave azabicyclononane 17b in 17% yield (Table 1, entry 1).
The use of TiCl4 as a 1 M solution in CH2Cl2,17 improved the
yields to ca. 30% (entry 2), while increasing the amount of diene 19a
to 1.5 equiv increased the yield to 46% (entry 3), with further
quantities of diene offering no improvement (entry 4). Reducing
the amount of TiCl4 to 3 equiv caused a substantial decrease in yield
to 24% (entry 5). Substituting ethyl
a-cyanoaminoacrylate 18b for
methyl -cyanoaminoacrylate 18a led to no appreciable difference
a
N-3-Phenylpropyl
methylphenyl- -cyanomethylaminoacrylate 21 were prepared in
a similar manner to acrylates 18a/b, requiring only an alternate
base12 for the synthesis of the more hindered 21. Both
-cyanoa-
minoacrylates 20 and 21 underwent TiCl4 catalysed cyclisation with
diene 19a (Scheme 3), however disappointingly, yields of bicycles
a-cyanomethylaminoacrylate 20 and (R)-a-
in yields. Yang et al. reported that reverse addition of the reagent to
the TiCl4 solution gave improved yields,16 however the examples
cited were all single substrate systems. Adding the combined
acrylate-diene mixture to the TiCl4 solution afforded 17b in 22%
yield (Table 1, entry 6). However pre-forming the iminium ion by
adding acrylate 18b to the TiCl4 solution at ꢀ78 ꢁC, allowing the
mixture to warm to room temperature over 1 h, then adding diene
19a gave 17b in 46% yield (entry 7) in only a 4 h reaction time.
Under these conditions reaction times longer than 4 h did not
improve the yield of 17b. This yield compares favourably with
traditional double Mannich reactions to form 9-keto-azabicyclo-
nonanes, which have reported yields in the 20e30% range.18
Silyloxydienes bearing larger silyl groups, such as triethylsilyl
(TES) and tert-butyldimethylsilyl (TBDMS) are more stable than
trimethylsilyl (TMS) analogues and may survive the harsh TiCl4
conditions to give an improved yield of azabicyclononane 17b. TES
a
a
22 and 23 never exceeded 8%. Reaction of chiral a-cyanoaminoa-
crylate 21 produced an inseparable mixture of the two di-
astereomers of 23 in a 1:1.2 ratio, as determined by 1H NMR
spectroscopy, and the stereochemistry of the individual isomers
could not be assigned.
Table 1
Optimisation of the DielseAlder/Mannich reaction
Scheme 3. DielseAlder/Mannich reaction of different amino-substituted acrylates. a22
is racemic, one enantiomer is shown.
Entry
TiCl4
Diene 16a
Conditions
Time
Yield
14b
Given the low yields obtained for the above reactions we pos-
1
2
4 equiv, neat
4 equiv,
1 M in CH2Cl2
4 equiv,
1 M in CH2Cl2
4 equiv,
1 M in CH2Cl2
3 equiv,
1 M in CH2Cl2
4 equiv,
1 M in CH2Cl2
4 equiv,
1 equiv
1 equiv
TiCl4 to 18bþ19a
TiCl4 to 18bþ19a
24 h
50 h
17%
31%
tulated that the electron donating benzyl group of
a-cyanoami-
noacrylates 18a/b stabilises the iminium ion intermediate formed
in the Mannich reaction. It is plausible that the more hindered
nature of the a-methylphenylamino substituent in 21 disfavours
3
4
5
6
7
1.5 equiv
2 equiv
TiCl4 to 18bþ19a
TiCl4 to 18bþ19a
TiCl4 to 18bþ19a
18bþ19a to TiCl4
18b to TiCl4 then 19a
18 h
18 h
18 h
18 h
4 h
46%
41%
24%
22%
46%
the reaction, whilst the 3-(phenylpropyl)amino substituted cya-
noacrylate 20 is not electron donating. Fortunately, there are many
reported methods for the conversion of an N-benzyl group into
other substituents.21
In order to investigate the scope of the DielseAlder/Mannich
reaction with respect to the introduction of substituents at other
positions to further elaborate the bicyclic compounds towards the
1.5 equiv
1.5 equiv
1.5 equiv
1 M in CH2Cl2
Scheme 2. Synthesis of azabicyclononane 17b using different silyloxydienes 19aec.

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K.J. Goodall et al. / Tetrahedron 68 (2012) 5759e5778
hexacyclic structure present in the natural alkaloids, methyl
substituted cyanoacrylate 24 was prepared. This required the in situ
preparation of 2-iodopropionitrile and using a longer reaction time
to form the cyanoamine intermediate, affording acrylate 24 in 59%
yield over two steps.
Reaction of substituted cyanoacrylate 24 with diene 19a affor-
ded C4-substituted azabicyclononanes 25a and 25b in 9% overall
yield, as a 5:1 inseparable mixture of diastereomers (Scheme 4).
Whilst the NMR spectra of the 25a/b mixture were complex they
could be fully assigned by extensive use of 2D NMR experiments.
Significant NOE’s between the resonance due to the C4-methyl
group and the equatorial 7-H resonance in the major isomer 25a
confirmed the equatorial orientation of the C-4 methyl, while NOE’s
between the C4-methyl group and axial 2-H and 9-H signals in the
minor isomer 25b confirmed the axial configuration of the C-4
methyl substituent.
The observed stereoselectivity for the equatorial isomer 25a can
be rationalised by the methyl substituent being orientated away
from the attacking enolate, thereby minimizing steric interactions
in the transition state. Unfortunately, the equatorial stereochem-
istry of the C-4 methyl group in the major isomer 25a is opposite to
that found in the natural alkaloids.
In order to further investigate the one-pot DielseAlder/Mannich
reaction and to introduce other appropriate substitution for future
elaboration of the bicyclic compounds, we prepared known cyclic
silyloxydiene 26.22,23 Titanium tetrachloride mediated reaction of
Extensive 2D NMR spectroscopy experiments allowed assign-
ment of all the ring proton signals. From analysis of NOE’s, the
stereochemistry at C-6 was determined to be R*, the opposite re-
lationship to that found in the natural alkaloids. The formation of
a single diastereomer of the tricyclic compound 27 suggests that
the mechanism proceeds by an endo DielseAlder reaction between
diene 26 and dienophile 18a.
2.2. Synthesis of AE and ABE ring analogues of
methyllycaconitine and grandiflorine
With the racemic 3-azabicyclo[3.3.1]nonanes 17a/b and 9-
azatricyclo[5.3.3.01,6]tridecane 27 in hand, attention turned to re-
duction and methylation of the ketone (Scheme 6). We envisaged
a two step reduction/alkylation procedure to afford the S* methyl
ether present in the parent alkaloids. Accordingly, ketones 17a/
b and 27 were separately subjected to sodium borohydride
reduction.
Reduction of ketones 17a/b with NaBH4 for 2 h gave alcohols
28a/b in excellent yields of up to 98%, and the reduction was
completely specific for the desired 6S* diastereoisomer. In contrast,
the reduction of tricyclic ketone 27 proceeded much more slowly,
affording, after 23 h, a 58% combined yield of a 2.9:1 ratio of al-
cohols 29a/b. The assignment of stereochemistry of alcohols 29a to
11S* and 29b to 11R* was determined using a range of 2D NMR
spectroscopy experiments.24
silyloxydiene 26 with a-cyanoaminoacrylate 18a proceeded in 20%
yield to afford 11-keto-tricyclotridecane 27 as the sole product
(Scheme 5).
It is postulated that the selectivity of the bicyclic reduction re-
sults from the steric influence of the bulky N-benzylpiperidine ring
hindering hydride attack from the lower face. The slower reaction
Scheme 4. DielseAlder/Mannich reaction of substituted cyanoacrylate 24.
time and loss of specificity observed in the reduction of tricyclic
ketone 24 can be rationalised by increased steric hindrance due to
the additional cyclohexyl ring to attack on the top face.
Having prepared alcohols 28a/b and 29a, we next proceeded
with the methylation step, which has proven to be problematic for
other azabicyclononanes.8 When a ketone is present at C-9 in the
bicycle, the soft base silver (I) oxide is required to prevent retro-
aldol fragmentation of the C5eC6 bond,8 however in the absence
of a C-9 ketone, stronger bases can be used.
Alkylation of alcohol 28b with iodomethane was attempted
under a variety of conditions, utilising different bases and solvents.
Attempts were also made using trimethyl phosphate and by using
a microwave reactor, however it was not until the use of sealed
tubes was trialled that reasonable yields were achieved. Ultimately
for this conversion, treatment of 28b with sodium hydride and
methyl iodide in a sealed tube at 60 ꢁC for 3 days afforded ether 30b
in 75% yield, with 16% returned starting material. Ether 30a was
produced in similar yield, however application of these optimised
conditions to the methylation of alcohol 29a proved less effective,
Scheme 5. Synthesis of tricycle 27.

K.J. Goodall et al. / Tetrahedron 68 (2012) 5759e5778
5763
Scheme 6. Synthesis of methyl ethers 30a/b and 31. a60% of 29a was also returned.
affording only 28% of ether 31, together with 60% recovered starting
material.
The synthesis of grandiflorine analogue 39 could be achieved
using a similar approach. In this case ketone 17a underwent di-
reduction to afford diol 37 in 67% yield, retaining the stereo-
selectivity of the previous ketone reduction (Scheme 8). Diol 37 was
coupled with 33 to afford a 4.4:1 mixture of the desired mono-ester
38a along with diester 38b. Selective hydrogenation of the mal-
eimide moiety of 38a gave grandiflorine analogue 39 in 58% yield.
As previously noted, yields of alternatively N-substituted 6-keto
azabicyclo[3.3.1]nonanes 22 and 23 were disappointingly low, so it
was necessary to investigate methods for the interconversion of the
N-benzyl group to other substituents.
With ethers 30 and 31 in hand, it remained to functionalise C-1
of the bicycle to append the methylsuccinimidoanthranilate moi-
ety. Accordingly, esters 30a/b and 31 were reduced with lithium
aluminium hydride, to afford C-1 neopentyl-like alcohols 29
(Scheme 7). These were then coupled with 2-(3-methyl-2,5-dioxo-
2,5-dihydro-1H-pyrrol-1-yl)benzoic acid25 33 to give the respective
maleimides, which were then selectively hydrogenated in
the presence of the N-benzyl moiety to produce MLA analogues 35
and 36.
Scheme 7. Synthesis of MLA analogues 35 and 36.

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K.J. Goodall et al. / Tetrahedron 68 (2012) 5759e5778
Scheme 8. Synthesis of grandiflorine analogue 39.
Vafina et al.26 have reported the N-debenzylation of other
with hydrocinnamoyl chloride to form amide 42, which un-
derwent double reduction with lithium aluminium hydride THF at
reflux to afford aminoalcohol 43 in 70% yield over two steps. N-
Ethyl analogues were formed by reaction of 40a and 41 with
acetic anhydride to give acetamides 44 and 45, then similarly
completely reduced to produce amino alcohols 46 and 47 in 51%
and 57% yields, respectively, over two steps. Appendage of the
methylsuccimidoanthranilate moiety was achieved by the two
step method used above, to afford analogues 48e50 in 22e60%
yields.
azabicyclononanes, while Ismail and Bergmeier27 have reported
acylation and double reduction of piperidine carboxylates to in-
troduce 3-phenylpropyl substitution. Accordingly, we attempted
N-debenzylation of C6-ether 30a using literature procedures,26
finding the reaction generally successful, though the yields of
secondary amine 40a were erratic, ranging from 25 to 99%
(Scheme 9). The same variability was observed in the debenzy-
lation of ether 40b. N-Debenzylation of C6ealcohol 28a, how-
ever, proceeded much more reliably, affording secondary amine
41 consistently in quantitative yield. Extensive investigation of
the debenzylation reaction of azabicyclononanes 28a/b, 30a/
b and 32 established that long reaction times and higher catalyst
loading were required to effect reliable, quantitative N-deben-
zylation when the C6-substituent was a methyl ether, rather than
an alcohol and changes in the C1-substituent did not appear to
influence the reaction. Interestingly, attempted N-debenzylation
of C6-ketone 17a failed completely under all conditions
attempted.
2.3. Synthesis of analogues of other Delphinium and Aconitum
alkaloids
As previously mentioned other Delphinium and Aconitum alka-
loids, that do not contain the methylsuccinimidoanthranilate
group, also exhibit interesting biological activity. It was therefore
decided to expand the scope of the synthetic route developed to
synthesize additional AE bicyclic analogues of other bioactive
alkaloids.
N-3-Phenylpropyl substitution20 was achieved following the
procedure of Bergmeier27 by reaction of secondary amine 40b
Scheme 9. Synthesis of MLA and grandiflorine analogues 48e50.

K.J. Goodall et al. / Tetrahedron 68 (2012) 5759e5778
5765
Notably, synthesized compounds 32, 37, 46 and 47 are in
themselves bicyclic analogues of the alkaloids lycoctonine 10 and
takaosamine 11. Analogues of talatisamine 8 and delcosine 9 were
synthesised by selective methylation of diols 37 and 47 (Scheme
10). Use of 1.25 equiv of methyl iodide resulted in preferentially
alkylation of the primary alcohol giving ethers 53 and 54 in 49% and
36%, respectively. Use of 10 equiv of methyl iodide and longer re-
action time gave the dialkylated products 51 and 52, it was, how-
ever, found that ether 52 was more easily prepared by methylation
of alcohol 46.
reduction of 56 gave the N-ethyl analogue 58, however in this case
only in 11% yield, due to decomposition upon purification by flash
chromatography.
The alkaloids inuline 4, ajacine 5, delvestine 6 and majusine A 7
contain anthranilate and N-acetylanthranilate esters. Coupling of
alcohols 32 and 46 with N-trifluoroacetylanthranilic acid 59,28
gave inuline analogues 60 and 61 in 87% and 60%, respectively.
Coupling of diols 37 and 47 with acid 59 gave delvestine analogues
62a and 63a in 40% and 44% yields, respectively, with di-adducts
62b and 63b also present, no C-6 mono-adduct were produced.
This is in contrast to previous examples of the coupling of 3-
azabicyclononane diols, with a C-1 and C-9 alcohol,29 where
mono-adducts of both alcohols were formed. The ratio of the de-
sired C-1 mono-adduct to di-adduct was improved, especially in
the case of N-benzyl analogue 62. Acetylation of 60 and 61 afforded
ajacine analogues 64 and 65 in 61% and 52% yields, respectively.
Selective acetylation of amino alcohols 62a and 63a afforded
majusine
A analogues 66 and 67 in 50% and 62% yields,
respectively.
3. Conclusions
The preparation of 6-keto-3-azabicyclononanes lacking C-9
oxygenated substituents has been achieved. The key TiCl4 cata-
lysed bicyclization reaction required the use of a reactive trime-
Scheme 10. Synthesis of talatisamine and delcosine analogues 51e54. a10 equiv MeI, 3
days; bfrom alcohol 46.
thylsilyloxydiene with
a
benzylamino substituent on the
dienophile to achieve reasonable yields. Elaboration of the C-6
oxygenated moiety was achieved by selective reduction followed
by methylation. Modification of the amino substituent was ac-
complished via debenzylation with ammonium formate, followed
by acylation and reduction. Appendage of a methylsuccinimidoan-
thranilate moiety at C-1 afforded bicyclic and tricyclic analogues of
MLA 2 with various N-substituents. AE ring bicyclic analogues of
The synthesis of C1-methyl analogues 57 and 58 of eldeline 1
was achieved via tosylates 55 and 56 (Scheme 11). These were
generated by separate reaction of 32 and 46 with tosyl chloride in
the presence of triethylamine and DMAP to afford tosylates 55
and 56 in 80% and 40%, respectively. Reduction of 55 with LiAlH4 in
THF at reflux gave N-benzyl analogue 57 in 75% yield. Similarly,
Scheme 11. Synthesis of eldeline, inuline, ajacine, delvestine and majusine A analogues 56e67.

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K.J. Goodall et al. / Tetrahedron 68 (2012) 5759e5778
other biologically active alkaloids 1 and 3e11 with N-benzyl and
N-ethyl substitution were produced from the common in-
termediates 32, 37, 46 and 47.
pressure. The crude product was purified by flash chromatog-
raphy to give the product.
4.2.3. Standard procedure C: synthesis of
a-cyanomethylaminoacry-
4. Experimental section
lates. To a solution of -cyanoamine (10 mmol) in chloroform
a
(22.5 mL) was added a solution of bromoacrylate (10 mmol) in
chloroform (22.5 mL) followed by freshly distilled triethylamine
(0.73 mL, 10 mmol) and the mixture was heated at reflux for
1.5 h. The reaction mixture was allowed to cool to room tem-
perature, washed with saturated aqueous sodium hydrogen car-
bonate (50 mL), followed by brine (50 mL), dried (Na2SO4),
filtered and the solvent removed at reduced pressure to give the
product.
4.1. General methods and materials
Reactions were monitored by TLC, using pre-coated silica gel
TLC plates obtained from Merck. Flash chromatography was car-
ried out on silica gel, particle size 0.032e0.063 mm. Melting point
determinations were performed on an ElectrothermalÒ melting
point apparatus. Infrared (IR) spectra were recorded using a Per-
kin Elmer Spectrum 1000 FT-IR spectrometer with the absorption
peaks expressed in wavenumbers (cmꢀ1) and recorded between
450 cmꢀ1 and 4000 cmꢀ1. High resolution mass spectra were
recorded using a VG70-SE spectrometer or microTOF-Q mass
spectrometer. 1H NMR and 13C NMR spectra were recorded on
Bruker Avance DRX 300 MHz or 400 MHz spectrometers at am-
4.2.4. Standard procedure D: sodium borohydride reduction of a ke-
tone. To a solution of ketone (3.35 mmol) in THF (8.0 mL) was
added dropwise a solution of sodium borohydride (63.0 mg,
1.67 mmol) in 2:1 water/THF (24 mL) and the mixture stirred at
room temperature for 2.5 h. Water (32 mL) was added, the volatiles
removed under reduced pressure and the aqueous residue extrac-
ted with ethyl acetate (3ꢂ50 mL). The combined organic extracts
were washed with brine (100 mL), dried (Na2SO4), filtered, con-
centrated under reduced pressure and purified by flash chroma-
tography to give the alcohol.
bient temperatures. Chemical shifts
d are expressed in parts per
million and coupling constants J are reported in hertz. TMS served
as internal standard (
d
¼0 ppm) for 1H NMR, and CDCl3 served as
internal standard (
d
¼77.0 ppm) for 13C NMR. Resonances were
assigned using a mixture of NMR methods including NOESY, COSY
HSQC and HMBC. The non-equivalent ring protons of the azabi-
cyclo[3.3.1]nonanes and azatricyclo[5.3.3.01,6]tridecanes ring sys-
tems are designated A or B where HA are axial and HB are
equatorial. Retention times (Rf) were determined with the solvent
mixture used for chromatography unless otherwise stated. 2-
(Bromomethyl)acrylates,10,11 2-benzylaminoacetonitrile,12 acid
33,25 acid 5928 and diene 19a13,14 were prepared using literature
methods. Diene 19 was also purchased from Fluorochem. All other
reagents were purchased from SigmaeAldrich or Acros and used
without purification, unless stated.
4.2.5. Standard procedure E: sodium hydride-iodomethane methyl-
ation of an alcohol. To a 60% dispersion of sodium hydride (128 mg,
5.32 mmol) in oil, washed with pentane (4ꢂ2 mL), dried with
heating and suspended in anhydrous THF (27 mL) under an at-
mosphere of nitrogen at 0 ꢁC, was slowly added a solution of al-
cohol (2.66 mmol) in THF (27 mL) and the mixture stirred at 0 ꢁC for
1 h. Iodomethane (0.83 mL, 13.3 mmol) was added, the reaction
vessel sealed and heated to 60 ꢁC with stirring for 3 days (CAUTION:
pressure). The reaction was quenched with water (108 mL) and the
volatiles removed under reduced pressure. The aqueous residue,
was extracted with ethyl acetate (3ꢂ100 mL), then the combined
organic extracts were washed with brine (200 mL), dried (MgSO4),
filtered and the solvent removed under reduced pressure. The
crude product was purified by flash chromatography to give the
product.
4.2. Standard procedures
4.2.1. Standard procedure A: DielseAlder/Mannich bicyclization. To
a solution of titanium tetrachloride (1.00 mL, 1.78 g, 9.37 mmol) in
dry DCM (8.40 mL) at ꢀ78 ꢁC under an atmosphere of nitrogen was
slowly added a solution of acrylate (2.34 mmol) in dry DCM
(4.80 mL) and the mixture allowed to warm to room temperature
and stirred for 1 h. To this was added dropwise a solution of diene
(3.51 mmol) in dry DCM (0.67 mL) and the reaction mixture stirred
for a further 4 h. The reaction was quenched by careful addition of
saturated aqueous ammonium chloride (10 mL), followed by sat-
urated aqueous potassium sodium tartrate (10 mL) and the mixture
allowed to stir for 10 min. The organics were separated and the
aqueous residue was extracted with DCM (2ꢂ20 mL). The com-
bined organics were washed with brine (30 mL), dried (MgSO4),
filtered and the solvent removed under reduced pressure. The
crude product was purified by flash chromatography to give the
product.
4.2.6. Standard procedure F: LAH reduction of the ester. To a solu-
tion of ester (0.10 mmol) in dry THF (8 mL) was added lithium
aluminium hydride (38.0 mg, 1.00 mmol) and the mixture
stirred under an atmosphere of nitrogen for 15 min. The re-
action was quenched by dropwise addition of water (8 mL) and
the volatiles removed under reduced pressure. The aqueous
residue was filtered through Celite and the solids washed with
water (8 mL), ethyl acetate (2ꢂ8 mL) and brine (8 mL). The
filtrate was separated and the aqueous portion extracted with
ethyl acetate (2ꢂ8 mL). The organic filtrate and extracts were
combined, washed with brine (16 mL), dried (Na2SO4), filtered
and the solvent removed under reduced pressure. The crude
product was purified by column chromatography to give the
product.
4.2.2. Standard procedure B: alternate DielseAlder/Mannich bicycli-
zation. To a solution of acrylate (3.48 mmol) in DCM (7 mL) was
added diene (5.24 mmol) and the mixture stirred at room
temperature for 30 min. The mixture was cooled to ꢀ78 ꢁC
before titanium tetrachloride (1 M in DCM, 13.9 mmol) was
added over 10 min, after which time the reaction mixture was
allowed to warm to room temperature and stirred for 17.5 h.
The reaction was quenched by slow addition of 5% aqueous
sodium carbonate (30 mL) and the organic layer separated. The
aqueous residue was extracted with DCM (3ꢂ20 mL), then the
combined organic extracts washed with brine (30 mL), dried
(Na2SO4), filtered and the solvent removed under reduced
4.2.7. Standard procedure G: preparation of maleimido esters. To
a solution of neopentyl-like alcohol (0.20 mmol), 2-(3-methyl-2,5-
dioxo-2,5-dihydro-1H-pyrrol-1-yl)benzoic acid 3025 (93 mg,
0.40 mmol) and DMAP (2.00 mg, 20.0
mmol) in acetonitrile
(1.6 mL) was added DCC (83 mg, 0.40 mmol) and the mixture
stirred, under an atmosphere of nitrogen, at 40 ꢁC for 18 h. The
mixture was cooled, filtered through Celite and the filtrate evap-
orated to dryness under reduced pressure. The residue was dis-
solved in ethyl acetate (7.5 mL), washed with aqueous saturated
sodium bicarbonate (7.5 mL), brine (7.5 mL), dried (MgSO4),

K.J. Goodall et al. / Tetrahedron 68 (2012) 5759e5778
5767
filtered and the solvent removed under reduced pressure. The
crude product was purified by flash chromatography to give the
product.
reduced pressure. The crude product was purified by flash chro-
matography to give the product.
4.2.13. Standard procedure M: preparation of acetylanthranilates. To
a solution of anthranilate (0.10 mmol) in dry DCM (2.00 mL) under
an atmosphere of nitrogen was added dropwise acetic anhydride
4.2.8. Standard procedure H: preparation of succinimides. To a so-
lution of maleimide (0.50 mmol) in ethyl acetate (50 mL) was added
10% palladium on charcoal (10%/weight of maleimide) and the
mixture stirred under an atmosphere of hydrogen for 24 h. The
mixture was filtered through Celite and the solvent removed under
reduced pressure. The crude product was purified by flash chro-
matography to give the product.
(28.0 mL, 0.30 mmol) and the mixture was allowed to stir at room
temperature for 24 h. The reaction was quenched by addition of
saturated aqueous sodium hydrogen carbonate (4 mL), separated,
then the organic residue washed with brine (6 mL), dried (MgSO4),
filtered and the solvent removed under reduced pressure. The
crude product was purified by flash chromatography to give the
acetylanthranilate.
4.2.9. Standard procedure I: ammonium formate hydrogenolysis of
the benzylamine. To a solution of benzylamine (1.00 mmol) in dry
methanol (6.0 mL) was added 10% palladium on charcoal (100%/
weight of amine) followed by ammonium formate (315 mg,
5 mmol) and the mixture heated to reflux, with stirring, under an
atmosphere of nitrogen for 45 min. The mixture was allowed to
cool to room temperature, filtered through Celite, the solids washed
with chloroform (6 mL) and the volatiles removed at reduced
pressure to give the product.
4.3. Synthesis of ketones 17a, 17b, 22, 23a/b, 25a/b and 27
4.3.1. Methyl 2-((benzyl(cyanomethyl)amino)methyl)acrylate 18a. The
reaction was carried out according to standard procedure C, using 2-
(benzylamino)acetonitrile (9.02 g, 61.7 mmol), methyl 2-(bromo-
methyl)acrylate (11.0 g, 61.7 mmol) and triethylamine (8.60 mL,
61.7 mmol), heating for 2 h to give the title compound 18a (15.0 g,
99%) as a dark orange oil, which was used without further purifica-
tion. Rf 0.50 (hexane/ethyl acetate 1:1); nmax(NaCl)/cmꢀ1 2952, 2254,
1727, 1635, 1454, 1161, 1120; dH(400 MHz; CDCl3) 3.44 (2H, s,
NCH2C^N), 3.48 (2H, s, NCH2C]CH2), 3.73 (2H, s, NCH2Ar), 3.78 (3H,
s, OCH3), 5.83e5.87 (1H, m, C]CHAHB), 6.29e6.35 (1H, m, C]
CHAHB), 7.26e7.34 (5H, m, AreH); dC(100 MHz; CDCl3) 40.9
(NCH2C^N), 51.9 (OCH3), 54.8 (NCH2C]CH2), 58.0 (NCH2Ar), 114.7
(C^Ν), 127.7 (C]CH2), 127.8 (AreCH),128.5 (AreCH),128.9 (AreCH),
136.8 (C]CH2), 136.8 (AreC), 166.7 (C]O); m/z (EI) 244 (Mþ, 3%),
204 (13%), 153 (47%), 145 (26%), 121 (34%), 91 (C6H5CH2, 100%); found
4.2.10. Standard procedure J: amine acetylation. To a stirred solu-
tion of secondary amine (1.00 mmol) in DCM (5.0 mL) was added
freshly distilled triethylamine (5.00 mL, 36 mmol) and the mixture
cooled to 0 ꢁC. DMAP (1.00 mg, 10.0
mmol) was added, followed by
acetic anhydride (0.10 mL, 1.10 mmol), then the mixture was
allowed to warm to room temperature and stirred for 20 h. The
reaction mixture was acidified with 2 M HCl (20 mL), the organic
layers separated and the aqueous residue washed with DCM
(2ꢂ20 mL). The combined organic extracts were washed with brine
(40 mL), dried (Na2SO4), filtered and the solvent removed at re-
duced pressure to give the product.
M
þ 244.1216, C14H16N2O2 requires Mþ 244.1212.
4.3.2. Methyl (1S*,5S*)-3-benzyl-6-oxo-3-azabicyclo[3.3.1]nonane-
1-carboxylate 17a. The reaction was carried out according to
standard procedure A, using titanium tetrachloride (1.00 mL,
1.78 g, 9.37 mmol), acrylate 18a (0.572 g, 2.34 mmol) and 2-
trimethylsilyloxy-1,3-butadiene 19a (0.50 g, 3.51 mmol), stirring
for 4 h with hexane/ethyl acetate 4:1 as the solvent for flash
chromatography to give the title compound 17a (0.31 g, 46%) as
a colourless oil. Rf 0.24; nmax(NaCl)/cmꢀ1 2950, 1725, 1495, 1453,
1258, 1128; dH(300 MHz; CDCl3) 1.91 (1H, dd, J¼13.3, 2.4 Hz, 9A-H),
2.10e2.28 (4H, m, 8A-H, 8B-H, 4A-H & 9B-H), 2.37 (1H, d, J¼11.1 Hz,
2A-H), 2.42e2.53 (2H, m, 7B-H & 5-H), 2.95e3.07 (2H, m, 7A-H & 4B-
H), 3.11 (1H, d, J¼11.1 Hz, 2B-H), 3.43 (1H, d, J¼13.2 Hz, NCHAHBAr),
3.50 (1H, d, J¼13.2 Hz, NCHAHBAr), 3.68 (3H, s, OCH3), 7.20e7.32
(5H, m, AreH); dC(300 MHz; CDCl3) 31.2 (C-8), 33.3 (C-9), 38.8 (C-7),
41.5 (C-1), 45.2 (C-5), 52.2 (OCH3), 56.3 (C-4), 61.1 (C-2), 62.9
(NCH2Ar), 127.2 (AreCH), 128.4 (AreCH), 128.7 (AreCH), 137.7
(AreC), 176.0 (C]O), 213.8 (C-6); m/z (EI) 287 (Mþ, 18%), 272 (2%),
256 (MꢀOCΗ3, 5%), 228 (3%), 196 (MꢀC6H5CH2, 7%), 185 (9%), 134
(10%), 91 (C6H5CH2, 100%); found Mþ 287.1521, C17H21NO3 requires
4.2.11. Standard procedure K: LAH reduction. To a solution of amide
(0.186 mmol) in dry THF (7.5 mL) was added LAH (35.0 mg,
0.928 mmol) and the mixture heated at reflux under an atmo-
sphere of nitrogen for 23 h. The reaction was cooled to 0 ꢁC and
quenched by dropwise addition of water (15 mL), then the vola-
tiles were removed under reduced pressure. Ethyl acetate (7.5 mL)
was added and the residue filtered through Celite, which was
washed with water (7.5 mL), ethyl acetate (7.5 mL) and brine
(7.5 mL). The filtrate was separated and the aqueous portion
extracted with ethyl acetate (2ꢂ7.5 mL). The organic filtrate and
extracts were combined, washed with brine (15 mL), dried
(Na2SO4), filtered and the solvent removed under reduced pres-
sure to give the product.
4.2.12. Standard procedure L: preparation of anthranilate esters. To
a solution of neopentyl-like alcohol (0.20 mmol) in dry acetonitrile
(1.60 mL) under an atmosphere of nitrogen was added N-(tri-
fluoroacetyl)anthranilic acid 5628 (93.0 mg, 0.40 mmol) and DMAP
(2.00 mg, 20.0
m
mol) followed by DCC (83.0 mg, 0.40 mmol) and the
M
þ 287.1521.
mixture heated at 40 ꢁC for 24 h. The mixture was cooled to room
temperature, filtered through Celite and the solvent removed under
reduced pressure. The residue was dissolved in DCM (7.5 mL),
washed with saturated aqueous sodium hydrogen carbonate
(7.5 mL) and brine (7.5 mL), dried (MgSO4), filtered and the volatiles
removed under reduced pressure. The resulting residue was dis-
solved in absolute ethanol (2.0 mL) then sodium borohydride
(0.400 mmol) was added and the mixture stirred at room tem-
perature for 2 h. The reaction was quenched by addition of water
(4.0 mL) then the organic volatiles removed under reduced pres-
sure. The aqueous residue was extracted with ethyl acetate
(3ꢂ5 mL), then the combined organic extracts washed with brine
(10 mL), dried (MgSO4), filtered and the solvent removed under
4.3.3. Ethyl 2-((benzyl(cyanomethyl)amino)methyl)acrylate 18b. The
reaction was carried out according to standard procedure C, using 2-
(benzylamino)acetonitrile (4.20 g, 28.7 mmol), ethyl 2-(bromo-
methyl)acrylate (5.55 g, 28.7 mmol) and triethylamine (3.98 mL,
2.91 g, 28.7 mmol), heating for 1.5 h to give the title compound 18b
(7.42 g, 100%) as an orange oil, which was used without further
purification. Rf 0.50 (hexane/ethyl acetate 1:1); nmax(NaCl)/cmꢀ1
2982, 2231, 1717, 1636, 1454, 1177, 1117; dH(400 MHz; CDCl3) 1.31
(3H, t, J¼7.2 Hz, OCH2CH3), 3.43 (2H, s, NCH2C^N), 3.48 (2H, s,
NCH2C]CH2), 3.73 (2H, s, NCH2Ar), 4.24 (2H, q, J¼7.2 Hz, OCH2CH3),
5.83 (1H, s, C]CHAHB), 6.31 (1H, s, C]CHAHB), 7.25e7.35 (5H, m,
AreH); dC(100 MHz; CDCl3) 14.1 (OCH2CH3), 40.8 (NCH2C^N), 54.8

5768
K.J. Goodall et al. / Tetrahedron 68 (2012) 5759e5778
(NCH2C]CH2), 58.0 (NCH2Ar), 60.8 (OCH2CH3), 114.7 (C^Ν), 127.4
(C]CH2), 127.7 (AreCH), 128.5 (AreCH), 128.8 (AreCH), 136.8
(AreC), 136.9 (C]CH2), 166.2 (C]O); m/z (EI) 258 (Mþ, 2%), 218
(14%), 167 (MꢀC6H5CH2, 42%), 145 (28%), 121 (33%), 91 (C6H5CH2,
100%); ound Mþ 258.1371, C15H18N2O2 requires Mþ 258.1368.
(100%); found MHþ 330.2060, C20H28NO3 requires Mþ 330.2064.
In a second fraction was returned acrylate 17 (0.177 g, 24%) as
a yellow oil.
4.3.7. Ethyl (R)-2-(((cyanomethyl)(1-phenylethyl)amino)methyl)ac-
rylate 21. The reaction was carried out according to standard
procedure C, using (R)-2-((1-phenylethyl)amino)acetonitrile
(2.39 g, 14.9 mmol), ethyl 2-(bromomethyl)acrylate (2.88 g,
14.9 mmol) and triethylamine (2.07 mL, 1.51 g, 14.9 mmol),
heating for 1 h to give the title compound 21 (3.32 g, 82%) as a pale
yellow oil, which required no further purification. Rf 0.55 (hexane/
ethyl acetate 1:1); nmax(NaCl)/cmꢀ1 2980, 2231, 1719, 1636, 1453,
1177, 1124; dH(400 MHz; CDCl3) 1.31 (3H, t, J¼7.2 Hz, OCH2CH3),
1.45 (3H, d, J¼6.6 Hz, CHCH3), 3.35e3.58 (4H, m, NCH2C^N &
NCH2C]CH2), 3.81 (1H, q, J¼6.6 Hz, CHCH3), 4.20e4.23 (2H, m,
OCH2CH3), 5.80e5.82 (1H, m, C]CHAHB), 6.26e6.29 (1H, m, C]
CHAHB), 7.23e7.36 (5H, m, AreH); dC(100 MHz; CDCl3) 14.1
(OCH2CH3), 20.5 (CHCH3), 39.0 (NCH2C^N), 51.7 (NCH2C]CH2),
60.8 (OCH2CH3), 61.6 (NCH(CH3)Ar), 115.4 (C^Ν), 127.1 (C]CH2),
127.2 (AreCH), 127.6 (AreCH), 128.6 (AreCH), 137.4 (C]CH2),
143.1 (AreC), 166.3 (C]O); m/z (EI) 272 (Mþ, 2%), 253 (MꢀCH3,
19%), 232 (11%), 167 (65%), 121 (26%), 105 (C6H5CHCH3, 100%), 77
(C6H5, 16%); found Mþ 272.1529, C16H20N2O2 requires Mþ
272.1525.
4.3.4. Ethyl (1S*,5S*)-3-benzyl-6-oxo-3-azabicyclo[3.3.1]nonane-1-
carboxylate 14b. The reaction was carried out according to stan-
dard procedure B, using acrylate 15b (0.90 g, 3.48 mmol), 2-
trimethylsilyloxy-1,3-butadiene 16a (0.92 mL, 5.24 mmol) and ti-
tanium tetrachloride (1 M in DCM, 13.9 mL, 13.9 mmol), stirring for
17.5 h with hexane/ethyl acetate 3:1 as the solvent for flash chro-
matography to give the title compound 14b (0.478 g, 46%) as a col-
ourless oil. Rf 0.35; nmax(NaCl)/cmꢀ1 2941, 1725, 1453, 1258, 1129;
dH(400 MHz; CDCl3) 1.24 (3H, t, J¼7.1 Hz, OCH2CH3), 1.91 (1H, dt,
J¼13.4, 2.5 Hz, 9A-H), 2.11e2.27 (4H, m, 8A-H, 8B-H, 4A-H & 9B-H),
2.39 (1H, d, J¼11.1 Hz, 2A-H), 2.45e2.53 (2H, m, 7B-H & 5-H),
2.97e3.07 (2H, m, 7A-H & 4B-H), 3.12 (1H, d, J¼11.1 Hz, 2B-H), 3.48
(2H, s, NCH2Ar), 4.13 (2H, q, J¼7.1 Hz, OCH2CH3), 7.20e7.36 (5H, m,
AreH); dC(100 MHz; CDCl3) 14.0 (OCH2CH3), 31.1 (C-8), 33.2 (C-9),
38.7 (C-7), 41.3 (C-1), 45.1 (C-5), 56.1 (C-4), 60.8 (OCH2CH3), 61.1 (C-
2), 62.8 (NCH2Ar), 127.1 (AreCH), 128.3 (AreCH), 128.6 (AreCH),
137.7 (AreC), 175.4 (C]O), 213.8 (C-6); m/z (EI) 301 (Mþ, 28%), 272
(10%), 256 (5%), 210 (MꢀC6H5CH2, 12%), 91 (C6H5CH2, 100%); found
Mþ 301.1675, C18H23NO3 requires Mþ 301.1678.
4.3.8. Ethyl (1S,5S,10R)-3-(10-phenylethyl)-6-oxo-3-azabicyclo[3.3.1]
nonane-1-carboxylate 23a and ethyl (1R,5R,10R)-3-(10-phenylethyl)-
6-oxo-3-azabicyclo[3.3.1]nonane-1-carboxylate 23b. The reaction
was carried out according to standard procedure B, using acrylate
21 (0.280 g, 1.03 mmol), diene 19a (0.220 g, 1.54 mmol) and tita-
nium tetrachloride (1 M in DCM, 4.10 mL, 4.11 mmol), stirring for
19 h with hexane/ethyl acetate 3:1 as the solvent for flash chro-
matography to give the title compound 23a and 23b (26.0 mg, 8%) as
a colourless oil, in an inseparable, undetermined, 1:1.2 mixture of
diastereomers. Rf 0.36; nmax(NaCl)/cmꢀ1 2935, 1722, 1453, 1250,
1132; [*denotes minor diastereomer] dH(400 MHz; CDCl3) 1.21 (3H,
t, J¼7.2 Hz, OCH2CH3*), 1.26 (3H, t, J¼7.0 Hz, OCH2CH3), 1.32 (3H, d,
J¼6.9 Hz, NCH(CH3)), 1.35 (3H, d, J¼6.8 Hz, NCH(CH3)*), 1.80e1.90
(2H, m, 9A-H & 9A-H*), 2.09e2.24 (8H, m, 4A-H, 8A-H, 8A-H*, 9B-H,
9B-H* & 4A-H*), 2.27 (1H, dd, J¼11.2, 1.3 Hz, 2A-H*), 2.39 (1H, dd,
J¼11.0, 1.1 Hz, 2A-H), 2.42e2.52 (4H, m, 5-H, 7B-H, 7B-H* & 5-H*),
2.91e3.01 (3H, m, 7A-H, 7A-H* & 4B-H), 3.04 (1H, dt, J¼11.2, 1.8 Hz,
2B-H*), 3.17 (1H, dd, J¼10.8, 1.5 Hz, 4B-H*), 3.22 (1H, dd, J¼11.0,
1.5 Hz, 2B-H), 3.40e3.47 (2H, m, NCH(CH3)* & NCH(CH3)), 4.09, (2H,
q, J¼7.2 Hz, OCH2CH3*), 4.15 (2H, q, J¼7.0 Hz, OCH2CH3), 7.17e7.36
(10H, m, AreH & AreH*); dC(100 MHz; CDCl3) 14.0 & 14.1 (OCH2CH3
& OCH2CH3*), 18.1 (NCH(CH3)*), 19.0 ( NCH(CH3)), 30.5 & 31.0 (C-8 &
C-8*), 33.1 (C-9 & C-9*), 38.6 & 38.7 (C-7 & C-7*), 41.2 & 41.3 (C-1 &
C-1*), 45.0 & 45.1 (C-5 & C-5*), 53.3 (C-4*), 53.8 (C-4), 58.1 (C-2),
58.7 (C-2*), 60.7 & 60.8 (OCH2CH3 & OCH2CH3*), 64.2 & 64.3
(NCH(CH3) & NCH(CH3)*), 127.1 (AreCH & AreCH*), 127.4 (AreCH &
AreCH*), 128.3 (AreCH & AreCH*), 129.2 (AreCH & AreCH*), 142.5
(AreC),142.9 (AreC*),175.6 (C]O*),175.8 (C]O), 214.1 (C-6), 214.4
(C-6*); m/z (EI) 315 (Mþ, 16%), 300 (MꢀCΗ3, 82%), 105
(C6H5CH(CH3), 100%); found Mþ 315.1831, C19H25NO3 requires
Mþ 315.1834. In a second fraction was returned acrylate 18
(50.0 mg, 18%).
4.3.5. Ethyl 2-(((cyanomethyl)(3-phenylpropyl)amino)methyl)acry-
late 20. The reaction was carried out according to standard pro-
cedure C, using 2-((3-phenylpropyl)amino)acetonitrile (1.22 g,
6.99 mmol), ethyl 2-(bromomethyl)acrylate (1.35 g, 6.99 mmol) and
triethylamine (0.97 mL, 6.99 mmol), heating for 1 h to give the title
compound 20 (1.82 g, 91%) as an orange oil, which required no
further purification. Rf 0.60 (hexane/ethyl acetate 1:1); nmax(NaCl)/
cmꢀ1 2940, 2231, 1716, 1636, 1454, 1176, 1120; dH(400 MHz; CDCl3)
1.30 (3H, t, J¼7.1 Hz, OCH2CH3), 1.79e1.83 (2H, m, NCH2CH2CH2),
2.59 (2H, t, J¼7.1 Hz, NCH2CH2CH2), 2.64 (2H, t, J¼7.7 Hz,
NCH2CH2CH2), 3.37 (2H, s, NCH2C]CH2), 3.53 (2H, s, NCH2C^N),
4.22 (2H, q, J¼7.1 Hz, OCH2CH3), 5.75 (1H, d, J¼1.2 Hz, C]CHAHB),
6.27 (1H, d, J¼1.2 Hz, C]CHAHB), 7.15e7.30 (5H, m, AreH);
dC(100 MHz; CDCl3) 14.1 (OCH2CH3), 28.9 (NCH2CH2CΗ2), 32.9
(NCH2CΗ2CΗ2), 41.6 (NCH2C^N), 53.3 (NCH2CΗ2CΗ2), 54.5
(NCH2C]CH2), 60.8 (OCH2CH3), 114.9 (C^Ν), 125.8 (AreCH), 127.4
(C]CH2), 128.3 (2ꢂ AreCH), 137.0 (C]CH2), 141.5 (AreC), 166.2
(C]O); m/z (EI) 286 (Mþ, 15%), 246 (MꢀCH2C^N, 37%), 181
(MꢀC6H5CH2, 100%), 91 (C6H5CH2, 50%), 69 (32%), 42 (CH2NCH2,
73%); ound Mþ 286.1685, C17H22N2O2 requires Mþ 286.1681.
4.3.6. Ethyl (1S*,5S*)-3-(3-phenylpropyl)-6-oxo-3-azabicyclo[3.3.1]
nonane-1-carboxylate 22. The reaction was carried out according to
standard procedure A, using titanium tetrachloride (1.11 mL, 1.92 g,
10.1 mmol), acrylate 20 (0.724 g, 2.53 mmol) and diene 19a
(0.67 mL, 3.79 mmol), stirring for 21 h with hexane/ethyl acetate
4:1 as the solvent for flash chromatography to give the title com-
pound 22 (57.0 mg, 7%) as a pale yellow oil. Rf 0.31; nmax(NaCl)/cmꢀ1
2943, 1713, 1454, 1257, 1130; dH(400 MHz; CDCl3) 1.26 (3H, t,
J¼7.1 Hz, OCH2CH3), 1.74e1.78 (2H, m, NCH2CH2CH2), 1.89 (1H, dt,
J¼13.4, 2.4 Hz, 9A-H), 2.12e2.19 (3H, m, 8A-H, 8B-H & 4A-H), 2.25
(1H, dd, J¼13.4, 1.6 Hz, 9B-H), 2.28e2.33 (3H, m, NCH2CH2CH2 & 2A-
H), 2.42e2.52 (2H, m, 7B-H & 5-H), 2.58 (2H, t, J¼7.5 Hz,
NCH2CH2CH2), 2.89e2.95 (1H, m, 7A-H), 3.00 (1H, dt, J¼11.0, 1.4 Hz,
4B-H), 3.14 (1H, d, J¼11.0 Hz, 2B-H), 4.15 (2H, q, J¼7.1 Hz, OCH2CH3),
7.13e7.29 (5H, m, AreH); dC(100 MHz; CDCl3) 14.1 (OCH2CH3), 28.4
(NCH2CH2CH2), 31.1 (C-8), 33.0 (C-9), 33.3 (NCH2CH2CH2), 38.5 (C-
7), 41.2 (C-1), 45.1 (C-5), 56.3 (C-4), 57.1 (NCH2CH2CH2), 60.8
(OCH2CH3), 61.4 (C-2), 125.7 (AreCH), 128.2 (AreCH), 128.3
(AreCH), 141.9 (AreC), 175.5 (C]O), 214.1 (C-6); m/z (ESIþ) 330
4.3.9. Methyl 2-((benzyl(1-cyanoethyl)amino)methyl)acrylate24. The
reaction was carried out according to standard procedure C, using
2-benzylamino-2-methylacetonitrile (0.577 g, 3.60 mmol), methyl
2-(bromomethyl)acrylate (0.645 g, 3.60 mmol) and triethylamine
(0.364 g, 3.60 mmol), heating for 2 h, with purification by flash
chromatography (hexane/ethyl acetate 3:1) to give the title com-
pound 24 (0.84 g, 90%) as a bright yellow oil. Rf 0.50; nmax(NaCl)/
cmꢀ1 2952, 2842, 1720, 1636, 1496, 1452, 1263, 1197, 1149, 1133;

K.J. Goodall et al. / Tetrahedron 68 (2012) 5759e5778
5769
dH(300 MHz; CDCl3) 1.45 (3H, d, J¼7.2 Hz, NCH(CH3)), 3.18e3.21
(1H, m, NCHACHBC]CH2), 3.43 (1H, d, J¼13.8 Hz, NCHACHBAr),
3.63e3.66 (1H, m, NCHACHBC]CH2), 3.73 (1H, q, J¼7.2 Hz,
NCH(CH3)), 3.76 (3H, s, OCH3), 3.95 (1H, d, J¼13.8 Hz, NCHACHBAr),
5.85e5.87 (1H, m, C]CHAHB), 6.26e6.31 (1H, m, C]CHAHB),
7.27e7.33 (5H, m, AreH); dC(75 MHz; CDCl3) 17.7 (NCHCH3), 40.8
(NCHCΗ3), 51.6 (NCH2C]CH2), 51.8 (OCH3), 55.7 (NCH2Ar), 118.1
(C^Ν), 127.1 (C]CH2), 127.6 (AreCH), 128.5 (AreCH), 128.6
(AreCH), 137.4 (C]CH2), 137.5 (AreC), 166.8 (C]O); m/z (ESIþ) 281
(MNaþ, 100%); found MNaþ 281.1250, C15H18NaN2O2 requires MNaþ
281.1260.
requires Mþ 341.1991. In a separate fraction was returned acrylate
18a (0.281 g, 47%).
4.4. Synthesis of AE ring analogues of methyllycaconitine and
grandiflorine 35, 36, 39, 48e50
4.4.1. Methyl (1S*,5S*,6S*)-3-benzyl-6-hydroxy-3-azabicyclo[3.3.1]
nonane-1-carboxylate 28a. The reaction was carried out according
to standard procedure D, using ketone 17a (1.53 g, 5.33 mmol) and
sodium borohydride (0.101 g, 2.33 mmol), stirring for 3 h, with
hexane/ethyl acetate 1:1 as the solvent for flash chromatography to
give the title compound 28a (1.46 g, 95%) as a pale yellow oil. Rf 0.49;
nmax(NaCl)/cmꢀ1 3353, 2949, 1725, 1494, 1453, 1255, 1075, 1209;
dH(400 MHz; CDCl3) 1.39 (1H, br s, OeH), 1.76e1.85 (3H, m, 9A-H,
9B-H & 8A-H), 1.90e2.00 (3H, m, 7B-H, 8B-H & 5-H), 2.07 (1H, dd,
J¼11.4, 2.2 Hz, 4A-H), 2.25 (1H, dd, J¼11.0, 2.2 Hz, 2A-H), 2.68e2.80
(1H, m, 7A-H), 3.08 (1H, d, J¼11.0 Hz, 2B-H), 3.16 (1H, d, J¼11.4 Hz,
4B-H), 3.40 (1H, d, J¼13.2 Hz, NCHAHB), 3.45 (1H, d, J¼13.2 Hz,
NCHAHB), 3.63 (3H, s, OCH3), 3.82e3.93 (1H, m, 6-H), 7.22e7.34 (5H,
m, AreH); dC(100 MHz; CDCl3) 31.5 (C-7), 32.6 (C-8), 34.8 (C-9), 35.7
(C-5), 41.8 (C-1), 51.8 (OCH3), 52.1 (C-4), 60.3 (C-2), 63.5 (NCH2Ar),
71.8 (C-6), 127.0 (AreCH), 128.3 (AreCH), 128.7 (AreCH), 138.7
(AreCH), 176.7 (C]O); m/z (EI) 289 (Mþ, 26%), 272 (MꢀOH, 28%),
134 (37%), 91 (C6H5CH2, 100%), 47 (57%); found Mþ 289.1682,
C17H23NO3 requires Mþ 289.1678.
4.3.10. Methyl (1S*,4S*,5S*)-3-benzyl-4-methyl-6-oxo-3-azabicyclo
[3.3.1]nonane-1-carboxylate 25a and methyl (1S*,4R*,5S*)-3-benzyl-
4-methyl-6-oxo-3-azabicyclo[3.3.1]nonane-1-carboxylate 25b. The
reaction was carried out according to standard procedure A, us-
ing titanium tetrachloride (1.00 mL, 1.78 g, 9.37 mmol), acrylate
24 (0.605 g, 2.34 mmol) and diene 19a (0.500 g, 3.51 mmol),
stirring for 20 h with hexane/ethyl acetate 4:1 as the solvent for
flash chromatography to give the title compound (61.8 mg, 9%) as
an orange oil in a 5:1 inseparable mixture of 25a/25b. Rf 0.26;
nmax(NaCl)/cmꢀ1 2951, 1729, 1704, 1495, 1449, 1235, 1153; [*de-
notes signals from 25b] dH(400 MHz; CDCl3) 1.08 (3H, d,
J¼6.4 Hz, CCH3*), 1.19 (3H, d, J¼6.4 Hz, CCH3), 1.92e1.99 (1H, m,
8B-H*), 2.02e2.07 (4H, m, 8A-H, 8B-H, 9B-H* & 9B-H), 2.11e2.15
(1H, m, 8A-H*), 2.16e2.22 (2H, m, 9A-H* & 9A-H), 2.31 (1H, s, 5-
H*), 2.38 (1H, d, J¼11.2 Hz, 2A-H), 2.43e2.49 (3H, m, 7B-H, 5-H
& 7B-H*), 2.54 (1H, m, 4-H), 2.69 (1H, d, J¼11.6 Hz, 2B-H*), 2.83
(1H, d, J¼11.6 Hz, 2A-H*), 2.93 (1H, m, 7A-H*), 2.99 (1H, d,
J¼13.4 Hz, NCHAHB), 3.11 (1H, dd, J¼11.2, 2.0, 2B-H), 3.18e3.24
(1H, m, 7A-H), 3.29e3.31 (1H, m, 4-H*), 3.42 (1H, d, J¼13.4 Hz,
NCHAHB*), 3.59e3.65 (4H, m, NCHAHB* & OCH3), 3.67 (3H, s,
OCH3*), 4.16 (1H, d, J¼13.4 Hz, NCHAHB), 7.20e7.34 (10H, m,
AreH & AreH*); dC(100 MHz; CDCl3) 7.8 (CCH3*), 18.6 (CCH3),
26.7 (C-9*), 30.3 (C-8*), 32.4 (C-8), 35.3 (C-9), 38.2 (C-7*), 39.8
(C-7), 41.2 (C-1*), 41.8 (C-1), 50.3 (C-5*), 52.0 (OCH3 & OCH3*),
53.0 (C-5), 53.1 (C-2*), 55.6 (C-4*), 58.0 (NCH2Ar), 58.4 (C-4), 59.0
(NCH2Ar*), 59.9 (C-2), 126.9 (AreCH), 127.1 (AreCH*), 128.3
(AreCH & AreCH*), 128.6 (AreCH & AreCH*), 138.4 (AreC*),
138.8 (AreC), 175.5 (C]O*), 176.2 (C]O), 212.3 (C-6), 214.2 (C-
6*); m/z (ESIþ) 302 (MHþ, 100%); found MHþ 302.1738,
C18H24NO3 requires MHþ 302.1751.
4.4.2. Ethyl (1S*,5S*,6S*)-3-benzyl-6-hydroxy-3-azabicyclo[3.3.1]non-
ane-1-carboxylate 28b. The reaction was carried out according to
standard procedure D, using ketone 17b (1.01 g, 3.35 mmol) and
sodium borohydride (63.0 mg, 1.67 mmol), stirring for 2.5 h with
hexane/ethyl acetate 1:1 as the solvent for flash chromatography to
give the title compound 28b (0.993 g, 98%) as a pale yellow oil. Rf
0.51; nmax(NaCl)/cmꢀ1 3420, 2916, 1723, 1453, 1255, 1074, 1125;
dH(400 MHz; CDCl3) 1.21 (3H, t, J¼7.1 Hz, OCH2CH3), 1.64 (1H, br s,
OeH), 1.76e1.84 (3H, m, 9A-H, 9B-H & 8A-H),1.89e2.00 (3H, m, 7B-H,
5-H & 8B-H), 2.05 (1H, dd, J¼11.4, 2.8 Hz, 4A-H), 2.25 (1H, dd, J¼11.0,
2.2 Hz, 2A-H), 2.69e2.80 (1H, m, 7A-H), 3.07 (1H, d, J¼11.0 Hz, 2B-H),
3.15 (1H, d, J¼11.4 Hz, 4B-H), 3.42 (2H, s, NCH2Ar), 3.80e3.92 (1H, m,
6-H), 4.09 (2H, q, J¼7.1 Hz, OCH2CH3), 7.22e7.36 (5H, m, AreH);
dC(100 MHz; CDCl3) 14.1 (OCH2CH3), 31.3 (C-7), 32.5 (C-8), 34.7 (C-
9), 35.6 (C-5), 41.6 (C-1), 52.0 (C-4), 60.3 (C-2), 60.4 (OCH2CH3), 63.4
(NCH2Ar), 71.8 (C-6), 126.9 (AreCH), 128.2 (AreCH), 128.6 (AreCH),
137.8 (AreC), 176.2 (C]O); m/z (EI) 303 (Mþ, 26%), 286 (MꢀOH,
50%), 91 (C6H5CH2, 100%); found Mþ 303.1836, C18H25NO3 requires
Mþ 303.1834.
4.3.11. Methyl (1S*,6R*,7S*)-9-benzyl-11-oxo-9-azatricyclo[5.3.3.01,6
]
tridecane-7-carboxylate 27. The reaction was carried out according
to standard procedure A, using titanium tetrachloride (1.07 mL,
1.84 g, 9.71 mmol), acrylate 18a (0.594 g, 2.45 mmol) and 1-(1-
cyclohexenyl)-1-trimethylsilyloxyethene 26 (0.717 g, 3.47 mmol),
stirring for 5 h with hexane/ethyl acetate 4:1 as the solvent for
flash chromatography to give the title compound 27 (0.162 g, 20%)
as a bright yellow oil. Rf 0.41; nmax(NaCl)/cmꢀ1 2930, 1728, 1701,
1495, 1453, 1263, 1239, 1128; dH(400 MHz; CDCl3) 0.84e0.88 (1H,
m, 2A-H), 1.01e1.07 (1H, m, 5A-H), 1.23e1.32 (2H, m, 4A-H, & 3A-H),
1.46e1.55 (2H, m, 5B-H & 3B-H), 1.72e1.77 (1H, m, 4B-H), 1.97e2.07
4.4.3. Methyl (1S*,6R*,7S*,11S*)-9-benzyl-11-hydroxy-9-azatricyclo
[5.3.3.01,6]tridecane-7-carboxylate 29a and methyl (1S*,6R*,7S*,11R*)-
9-benzyl-11-hydroxy-9-azatricyclo[5.3.3.01,6]tridecane-7-carboxylate
29b. The reaction was carried out according to standard procedure
D, using ketone 27 (0.374 g, 1.10 mmol) and sodium borohydride
(0.165 g, 4.38 mmol), stirring for 23 h with hexane/ethyl acetate 4:1
as the solvent for flash chromatography to give (i) methyl
(1S*,6R*,7S*,11R*)-9-benzyl-11-hydroxy-9-azatricyclo[5.3.3.01,6]tride-
cane-7-carboxylate 29b (57.0 mg, 15%) as a bright yellow oil. Rf 0.34;
nmax(NaCl)/cmꢀ1 3505, 2924, 1723, 1495, 1448, 1264, 1247, 1160;
dH(400 MHz; CDCl3) 1.08e1.18 (2H, m, 2A-H & 5B-H), 1.25e1.29 (1H,
m, 4A-H), 1.50e1.62 (3H, m, 3A-H, 12B-H & 6-H), 1.63e1.76 (3H, m,
2B-H,10A-H & 13B-H),1.77e1.85 (2H, m, 4B-H & 5A-H),2.00e2.07 (1H,
m, 3B-H), 2.17 (1H, tdd, J¼14.0, 6.4, 2.5 Hz, 13A-H), 2.47e2.52 (2H, m,
8A-H & 10B-H), 2.91 (1H, dd, J¼10.9, 0.6, 8B-H), 3.29e3.40 (3H, m,
12A-H & NCH2Ar), 3.64 (3H, s, OCH3), 3.72e3.85 (1H, m, 11-H),
7.23e7.32 (5H, m, AreH); dC(400 MHz; CDCl3) 22.7 (C-13), 23.5
(C-3), 23.6 (C-5), 26.4 (C-4), 32.3 (C-12), 35.7 (C-2), 37.5 (C-1), 46.9
(C-6), 47.2 (C-7), 51.6 (OCH3), 63.1 (C-8), 63.2 (NCH2Ar), 67.2 (C-10),
76.6 (C-11), 126.9 (AreCH), 128.3 (AreCH), 128.7 (AreCH), 138.7
(3H, m, 6-H, 10A-H
&
13B-H), 2.16 (1H, d, J¼13.3 Hz, 2B-
H),2.33e2.39 (1H, m, 13A-H), 2.47 (1H, dd, J¼12.4, 2.5 Hz, 12B-H),
2.55 (1H, dd, J¼10.7, 2.1 Hz, 8A-H), 2.70 (1H, dd, J¼10.8, 1.4 Hz, 10B-
H), 3.00 (1H, dd, J¼10.7, 1.6 Hz, 8B-H), 3.08e3.14 (1H, m, 12A-H),
3.33 (1H, d, J¼13.2 Hz, NCHAHB), 3.49 (1H, d, J¼13.2 Hz, NCHAHB),
3.66 (3H, s, OCH3), 7.18e7.35 (5H, m, AreH); dC(100 MHz; CDCl3)
22.3 (C-3), 26.2 (C-4), 26.3 (C-5), 26.6 (C-13), 31.2 (C-2), 38.2 (C-
12), 46.4 (C-7), 47.4 (C-6), 50.0 (C-1), 52.0 (OCH3), 62.7 (NCH2Ar),
63.6 (C-8), 64.8 (C-10), 127.2 (AreCH), 128.4 (AreCH), 128.6
(AreCH), 137.7 (AreC), 175.1 (C]O), 214.9 (C-11); m/z (EI) 341
(Mþ, 28%), 250 (MꢀC6H5CH2, 9%), 245 (12%), 218 (9%), 134
(28%), 91 (C6H5CH2, 100%); found Mþ 341.1993, C21H27NO3

5770
K.J. Goodall et al. / Tetrahedron 68 (2012) 5759e5778
(AreC), 176.2 (C]O); m/z (ESIþ); found MHþ 344.2229, C21H30NO3
requires MHþ 344.2220 and (ii) methyl (1S*,6R*,7S*,11S*)-9-benzyl-
(87 mL, 0.198 g, 1.39 mmol), stirring for 3 days with hexane/ethyl
acetate 9:1 as the solvent for flash chromatography to give the title
compound 31 (27.5 mg, 28%) as a yellow oil. Rf 0.37; nmax(NaCl)/
cmꢀ1 2925, 1731, 1495, 1451, 1264, 1240, 1111, 1096; dH(400 MHz;
CDCl3) 0.76e0.80 (1H, m, 2A-H), 1.14 (1H, dq, J¼12.3, 3.6 Hz, 5B-H),
1.27e1.33 (1H, m, 4A-H), 1.40 (1H, dd, J¼12.3, 3.6 Hz, 5A-H),
1.46e1.52 (2H, m, 3A-H & 3B-H), 1.66e1.70 (2H, m, 6-H & 10A-H),
1.75e1.90 (3H, m, 4B-H, 13B-H & 2B-H), 1.96e2.00 (1H, m, 13A-H),
2.06e2.11 (1H, m, 12B-H), 2.35 (1H, dd, J¼10.6, 2.3 Hz, 8A-H),
2.74e2.86 (2H, m,12A-H & 8B-H), 3.12e3.17 (2H, m, NCHACHB & 10B-
H), 3.38 (3H, s, OCH3 ether), 3.59 (3H, s, OCH3 ester), 3.62 (1H, d,
J¼13.4 Hz, NCHACHB), 3.71e3.74 (1H, m, 11-H), 7.21e7.31 (5H, m,
AreH); dC(100 MHz; CDCl3) 21.0 (C-3), 22.5 (C-5), 26.1 (C-12), 26.4
(C-4), 26.8 (C-13), 32.2 (C-2), 37.6 (C-1), 46.7 (C-7), 48.0 (C-6), 51.6
(OCH3 ester), 57.3 (OCH3 ether), 62.8 (C-8), 63.2 (C-10 & NCH2Ar),
75.9 (C-11), 126.7 (AreCH), 128.1 (AreCH), 128.7 (AreCH), 138.8
(AreC), 176.0 (C]O); m/z (ESIþ); found MHþ 358.2367, C22H32NO3
requires MHþ 358.2377. In a separate fraction was returned alcohol
29a (57.5 mg, 60%).
11-hydroxy-9-azatricyclo[5.3.3.01,6]tridecane-7-carboxylate
29a
(0.160 g, 43%) as a pale yellow oil. Rf 0.23; nmax(NaCl)/cmꢀ1 3439,
2929, 1727, 1495, 1452, 1265, 1240, 1163; dH(400 MHz; CDCl3)
0.80e0.84 (1H, m, 2A-H), 1.13e1.21 (1H, m, 5B-H), 1.27e1.35 (1H, m,
4A-H), 1.37 (1H, dd, J¼12.6, 3.2 Hz, 5A-H), 1.47e1.51 (2H, m, 3A-H &
3B-H), 1.65 (1H, d, J¼11.3 Hz, 10A-H), 1.73e1.81 (3H, m, 6-H, 4B-H &
2B-H), 1.87 (1H, dd, J¼13.1, 7.1 Hz, 13B-H), 2.00e2.06 (2H, m, 12B-H &
13A-H), 2.46 (1H, dd, J¼10.6, 1.7 Hz, 8A-H), 2.75e2.85 (1H, m,12A-H),
2.92 (1H, d, J¼10.6 Hz, 8B-H), 3.00 (1H, d, J¼11.3 Hz, 10B-H), 3.37
(2H,s, NCH2Ar), 3.62 (3H, s, OCH3), 4.15e4.20 (1H, m, 11-H),
7.23e7.31 (5H, m, AreH); dC(100 MHz; CDCl3) 20.7 (C-3), 22.5 (C-5),
26.3 (C-4), 27.2 (C-13), 31.0 (C-12), 31.9 (C-2), 37.5 (C-1), 46.8 (C-7),
47.8 (C-6), 51.7 (OCH3), 62.0 (C-10), 63.3 (NCH2Ar), 63.4 (C-8), 67.1
(C-11), 127.0 (AreCH), 128.4 (AreCH), 128.7 (AreCH), 138.7 (AreC),
175.8 (C]O); m/z (ESIþ); ound MHþ 344.2222, C21H30NO3 requires
MHþ 343.2220.
4.4.4. Methyl (1S*,5S*,6S*)-3-benzyl-6-methoxy-3-azabicyclo[3.3.1]
nonane-1-carboxylate 30a. The reaction was carried out according
to standard procedure E, using sodium hydride (0.213 g,
5.32 mmol), alcohol 28a (0.770 g, 2.66 mmol) and iodomethane
(0.83 mL, 1.89 g, 13.3 mmol), stirring for 3 days with hexane/ethyl
acetate 2:1 as the solvent for flash chromatography to give the title
compound 30a (0.670 g, 83%) as a yellow oil. Rf 0.59; nmax(NaCl)/
cmꢀ1 2929, 1729, 1493, 1454, 1265, 1102; dH(400 MHz; CDCl3)
1.70e1.82 (3H, m, 8A-H, 9A-H & 9B-H), 1.92e1.98 (2H, m, 8B-H & 7B-
H), 2.08 (1H, dd, J¼11.0, 2.9 Hz, 4A-H), 2.13e2.19 (2H, m, 5-H & 2A-
H), 2.75e2.32 (1H, m, 7A-H), 3.01 (1H, d, J¼10.9 Hz, 2B-H), 3.17 (1H,
d, J¼11.0 Hz, 4B-H), 3.26 (1H, d, J¼13.4 Hz, NCHAHBAr), 3.34 (3H, s,
C6eOCH3), 3.35e3.42 (1H, m, 6-H), 3.57e3.64 (4H, m, NCHAHBAr &
C1eCO2CH3), 7.19e7.32 (5H, m, AreH); dC(100 MHz; CDCl3) 28.2 (C-
7), 31.9 (C-5), 32.4 (C-8), 34.6 (C-9), 42.0 (C-1), 51.7 (CO2CH3), 52.7
(C-4), 55.8 (OCH3), 59.7 (C-2), 63.4 (NCH2Ar), 80.6 (C-6), 126.7
(AreCH), 128.1 (AreCH), 128.6 (AreCH), 138.6 (AreC), 176.7 (C]O);
m/z (EI) 303 (Mþ, 11%), 288 (MꢀOCH3, 8%), 272 (MꢀOCH3, 100%),
212 (6%), 134 (14%), 91 (C6H5CH2, 77%); found Mþ 303.1832,
C18H25NO3 requires Mþ 303.1834.
4.4.7. ((1S*,5S*,6S*)-3-Benzyl-6-methoxy-3-azabicyclo[3.3.1]nonan-
1-yl)methanol 32. The reaction was carried out according to stan-
dard procedure F, using ester 30b (0.110 g, 0.347 mmol), stirring for
15 min with hexane/ethyl acetate 1:2 as the solvent for flash
chromatography to give the title compound 32 (60.0 mg, 63%) as
a colourless oil. Rf 0.51; nmax(NaCl)/cmꢀ1 3400, 2916, 1454, 1100,
1065, 1028; dH(400 MHz; CDCl3) 1.25e1.27 (1H, m, 9B-H), 1.35 (1H,
tdd, J¼13.4, 6.3, 2.5 Hz, 8A-H), 1.42 (1H, dt, J¼12.5, 3.6 Hz, 9A-H),
1.60e1.66 (2H, m, 8B-H & OeH), 1.86 (1H, dd, J¼11.4, 2.3 Hz, 2A-H),
1.92e1.94 (1H, m, 7B-H), 2.07 (1H, dd, J¼11.0, 2.3 Hz, 4A-H),
2.14e2.15 (1H, m, 5-H), 2.68 (1H, d, J¼11.4 Hz, 2B-H), 2.72e2.78
(1H, m, 7A-H), 3.17e3.21 (4H, m, CH2OH, 4B-H & NCHAHBAr),
3.33e3.40 (4H, m, OCH3 & 6-H), 3.60 (1H, d, J¼13.4 Hz, NCHAHBAr),
7.18e7.30 (5H, m, AreH); dC(100 MHz; CDCl3) 27.9 (C-7), 31.8 (C-8),
32.3 (C-5), 34.5 (C-9), 35.3 (C-1), 53.3 (C-4), 55.7 (OCH3), 60.8 (C-2),
63.6 (NCH2Ar), 71.7 (CH2OH), 81.7 (C-6), 126.6 (AreCH), 128.1
(AreCH), 128.6 (AreCH), 139.0 (AreC); m/z (EI) 275 (Mþ, 8%), 274
(MꢀH, 6%), 260 (MꢀCH3, 4%), 244 (MꢀOCH3, 100%), 134 (18%), 91
(C6H5CH2, 61%); found Mþ 275.1882, C17H25NO2 requires Mþ
275.1885.
4.4.5. Ethyl (1S*,5S*,6S*)-3-benzyl-6-methoxy-3-azabicyclo[3.3.1]non-
ane-1-carboxylate 30b. The reaction was carried out according to
standard procedure E, using sodium hydride (66.0 mg, 1.65 mmol),
alcohol 28b (0.250 g, 0.824 mmol) and iodomethane (0.26 mL,
0.585 g, 4.12 mmol), stirring for 3 days with hexane/ethyl ace-
tate 2:1 as the solvent for flash chromatography to give the title
compound 30b (0.197 g, 75%) as a pale yellow oil. Rf 0.63; nmax(NaCl)/
cmꢀ1 2926, 1726, 1454, 1263, 1102; dH(400 MHz; CDCl3) 1.20 (3H,
t, J¼7.1 Hz, OCH2CH3), 1.71e1.80 (3H, m, 8A-H, 9A-H & 9B-H),
1.93e1.98 (2H, m, 8B-H & 7B-H), 2.07 (1H, dd, J¼11.1, 2.9 Hz, 4A-H),
2.15e2.20 (2H, m, 5-H & 2A-H), 2.75e2.80 (1H, m, 7A-H), 3.02 (1H, d,
J¼11.0 Hz, 2B-H), 3.16 (1H, d, J¼11.1 Hz, 4B-H), 3.29 (1H, d,
J¼13.4 Hz, NCHAHBAr), 3.34 (3H, s, OCH3), 3.38e3.42 (1H, m, 6-H),
3.57 (1H, d, J¼13.4 Hz, NCHAHBAr), 4.06 (2H, q, J¼7.1 Hz, OCH2CH3),
7.20e7.31 (5H, m, AreH); dC(400 MHz; CDCl3) 14.1 (OCH2CH3), 28.2
(C-7), 32.0 (C-5), 32.4 (C-8), 34.6 (C-9), 41.9 (C-1), 52.6 (C-4),
55.8 (OCH3), 59.8 (C-2), 60.4 (OCH2CH3), 63.4 (NCH2Ar), 80.7 (C-6),
126.7 (AreCH), 128.2 (AreCH), 128.7 (AreCH), 138.7 (AreC), 176.3
(C]O); m/z (EI) 317 (Mþ, 9%), 286 (MꢀOCH3, 90%), 134 (14%), 91
(C6H5CH2, 100%); found Mþ 317.19953, C19H27NO3 requires Mþ
317.1990.
4.4.8. ((100S*,500S*,600S*)-300-Benzyl-600-methoxy-300-azabicyclo[3.3.1]
nonan-100-yl)methyl 2-(30-methyl-20,50-dioxo-20,50-dihydro-10H-pyr-
rol-10-yl)benzoate 34. The reaction was carried out according to
standard procedure G, using alcohol 32 (50.0 mg, 0.182 mmol), acid
33 (84.0 mg, 0.363 mmol), DMAP (2.00 mg, 18.0 mmol) and DCC
(75.0 mg, 0.363 mmol), heating for 18 h, with hexane/ethyl acetate
1:1 as the solvent for flash chromatography to give the title com-
pound 34 (64.0 mg, 72%) as a pale yellow oil. Rf 0.57; nmax(NaCl)/
cmꢀ1 2922, 1789, 1710, 1653, 1494, 1453, 1258, 1116, 1084;
dH(400 MHz; CDCl3) 1.35 (1H, d, J¼13.0 Hz, 900B-H), 1.39e1.53 (2H,
m, 800A-H & 900A-H), 1.70e1.75 (1H, m, 800B-H), 1.89e1.97 (2H, m, 700
-
B
H & 200A-H), 2.07 (1H, dd, J¼11.2, 2.8 Hz, 400A-H), 2.14 (3H, d, J¼1.8 Hz,
C30eCH3), 2.15e2.17 (1H, m, 500-H), 2.71e2.83 (2H, m, 200B-H & 700
-
A
H), 3.19 (1H, d, J¼11.2 Hz, 400B-H), 3.25 (1H, d, J¼13.3 Hz, NCHAHBAr),
3.32e3.44 (4H, m, OCH3 & 600-H), 3.58 (1H, d, J¼13.3 Hz, NCHAHBAr),
3.81 (2H, d, J¼2.1 Hz, C100eCH2Oe), 6.46 (1H, q, J¼1.8 Hz, 40-H),
7.20e7.31 (6H, m, AreH, 3-H) 7.46 (1H, td, J¼7.7, 1.2 Hz, 5-H), 7.63
(1H, td, J¼7.7, 1.5 Hz, 4-H), 7.94 (1H, dd, J¼7.9, 1.5 Hz, 6-H);
dC(100 MHz; CDCl3) 11.1 (C30eCH3), 27.7 (C-700), 32.1 (C-500 & C-800),
34.2 (C-100), 34.7 (C-900), 53.0 (C-400), 55.7 (OCH3), 60.8 (C-200), 63.4
(NCH2Ar), 72.8 (C100eCH2O), 81.2 (C-600),126.6 (AreCH),127.8 (C-1 &
C-40), 128.1 (AreCH), 128.6 (AreCH), 128.9 (C-5), 130.4 (C-3), 131.2
(C-6), 131.8 (C-2), 133.2 (C-4), 138.7 (AreC), 146.1 (C-30), 164.5 (C]
O), 169.6 (C-50), 170.7 (C-20); m/z (EI) 448 (Mþ, 16%), 473 (MꢀCH3,
4%), 457 (MꢀOCH3, 100%), 397 (MꢀC6H5CH2, 3%), 286 (7%), 258
4.4.6. Methyl (1S*,6R*,7S*,11S*)-9-benzyl-11-methoxy-9-azatricyclo
[5.3.3.01,6]tridecane-7-carboxylate 31. The reaction was carried out
according to standard procedure E, using sodium hydride (22.3 mg,
0.557 mmol), alcohol 29a (95.5 mg, 0.278 mmol) and iodomethane

K.J. Goodall et al. / Tetrahedron 68 (2012) 5759e5778
5771
(11%), 214 (13%), 134 (36%), 91 (C6H5CH2, 80%); found Mþ 488.2310,
C29H32N2O5 requires Mþ 488.2311.
7.64 (1H, td, J¼7.8, 1.5 Hz, 4-H), 7.86 (1H, dd, J¼7.8, 1.5 Hz, 6-H);
dC(100 MHz; CDCl3) 11.2 (C30eCH3), 20.7 (C-500), 20.9 (C-300), 26.1 (C-
1200), 26.5 (C-400), 28.3 (C-1300), 32.2 (C-200), 36.9 (C-700), 37.7 (C-100),
47.2 (C-600), 57.3 (OCH3), 63.0 (C-800), 63.3 (C-1000 & NCH2Ar), 70.7
(C700eCH2O), 76.5 (C-1100), 126.6 (AreCH), 127.9 (C-1 & C-40), 128.1
(AreCH), 128.8 (AreCH), 129.0 (C-5), 130.5 (C-3), 131.2 (C-6), 131.9
(C-2), 133.2 (C-4), 139.0 (AreC), 146.2 (C-30), 164.5 (C]O), 169.7 (C-
50), 170.8 (C-20); m/z (ESIþ) found MHþ 543.2860, C33H39N2O5 re-
quires MHþ 543.2853.
4.4.9. ((100S*,500S*,600S*)-300-Benzyl-600-methoxy-300-azabicyclo[3.3.1]
nonan-100-yl)methyl 2-(30-methyl-20,50-dioxopyrrolidin-10-yl)benzo-
ate 35. The reaction was carried out according to standard pro-
cedure H, using maleimide 34 (45.0 mg, 92.1 mmol) for 2 h, with
hexane/ethyl acetate 1:1 as the solvent for flash chromatography to
give the title compound 35 (20.0 mg, 44%) as a yellow oil. Rf 0.30;
nmax(NaCl)/cmꢀ1 2934, 1779, 1709, 1493, 1454, 1260, 1183;
dH(400 MHz; CDCl3) 1.36 (1H, d, J¼12.6 Hz, 900B-H), 1.40e1.54 (5H,
m, C30eCH3, 800A-H & 900A-H), 1.75 (1H, dd, J¼13.5, 6.1 Hz, 800B-H),
4.4.12. ((100S*,600S*,700S*,1100S*)-900-Benzyl-1100-methoxy-900-azabicyclo
[5.3.3.01,6]tridecan-700-yl)methyl 2-(30-methyl-20,50-dioxopyrrolidin-
10-yl)benzoate 36. The reaction was carried out according to
standard procedure H, using ((100S*,600S*,700S*,1100S*)-900-benzyl-1100-
methoxy-900-azabicyclo[5.3.3.01,6]tridecan-700-yl)methyl 2-(30-met-
hyl-20,50-dioxo-20,50-dihydro-10H-pyrrol-10-yl)benzoate (22.0 mg,
1.89e1.98 (2H, m, 700B-H & 200A-H), 2.09 (1H, dd, J¼11.0, 2.8 Hz, 400
-
A
H),2.15e2.19 (1H, m, 500-H), 2.51e2.53 (1H, m, 40A-H), 2.70e2.85
(2H, m, 700A-H & 200B-H), 2.98e3.11 (2H, m, 40B-H & 30-H), 3.18e3.28
(2H, m, 400B-H & NCHACHB), 3.32e3.43 (4H, m, OCH3 & 600-H), 3.60
(1H, d, J¼13.3 Hz, NCHACHB), 3.79e3.84 (2H, m, C100eCH2Oe),
7.21e7.32 (6H, m, 3-H & AreH), 7.48 (1H, td, J¼7.7, 1.2 Hz, 5-H), 7.65
(1H, td, J¼7.7, 1.6 Hz, 4-H), 7.96 (1H, d, J¼7.9 Hz, 6-H); dC(100 MHz;
CDCl3) 16.3 & 16.5 (C30eCH3), 27.8 (C-700), 32.2 (C-500 & C-800), 34.3
(C-100), 34.8 (C-900), 35.2 & 35.4 (C-30), 37.0 (C-40), 53.0 (C-400), 55.8
(OCH3), 60.8 (C-200), 63.4 (NCH2Ar), 72.8 (C100eCH2O), 81.3 (C-600),
126.4 (C-1), 126.6 (AreCH), 128.1 (AreCH), 128.8 (AreCH), 129.4 (C-
5), 129.9 (C-3), 131.4 (C-6), 132.9 (C-2), 133.4 (C-4), 138.þ8 (AreC),
164.1 (C]O), 175.8 & 176.0 (C-50), 179.9 (C-20); m/z (ESI ); found
MHþ 491.2537, C29H35N2O5 requires MHþ 491.2540. In a second
fraction was returned maleimide 34 (12.5 mg, 28%).
40.5 mmol), stirring for 2 h, with hexane/ethyl acetate 2:1 as the sol-
vent for flash chromatography to give the title compound 36 (12.5 mg,
57%) as a pale yellow oil. Rf 0.24; nmax(NaCl)/cmꢀ1 2931, 1779, 1713,
1494,1452,1260,1185; dH(400 MHz;CDCl3)0.77e0.80(1H, m, 200A-H),
1.20e1.63 (12H, m, 400A-H, 600-H, 500A-H, 500B-H, C30eCH3, 300A-H, 300B-H,
1300A-H, 1300B-H & 1000A-H), 1.83 (1H, d, J¼11.0 Hz, 400B-H), 1.90 (1H, d,
J¼13.2 Hz, 200B-H), 2.02e2.10 (2H, m, 800A-H & 1200B-H),2.50e2.52 (1H,
m, 40A-H), 2.78e2.88(2H, m,1200A-H& 800B-H), 3.02e3.11 (2H, m, 40B-H
& 30-H), 3.13e3.19 (2H, m, 1000B-H & NCHAHBAr), 3.39 (3H, s, OCH3),
3.60 (1H, d, J¼13.3 Hz, NCHAHBAr), 3.75(1H, dd, J¼11.0, 6.8 Hz,1100-H),
3.80e3.88 (2H, m, C700eCH2Oe), 7.22e7.33 (6H, m, AreH & 3-H), 7.48
(1H, td, J¼7.7, 0.9 Hz, 5-H), 7.65 (1H, td, J¼7.7,1.4Hz, 4-H), 7.88 (1H, dd,
J¼7.9, 1.5 Hz, 6-H); dC(100 MHz; CDCl3) 16.3 & 16.5 (C30eCH3), 20.7
(C-500), 21.0 (C-300), 26.1 (C-1200), 26.5 (C-400), 28.3 (C-1300), 32.2 (C-200),
35.2 & 35.4 (C-30), 36.9 (C-700), 37.0 (C-40), 37.7 (C-100), 47.3 (C-600), 57.3
(OCH3), 63.0 (C-800), 63.3 & 63.4 (C-1000 & NCH2Ar), 70.6 (C700eCH2O),
76.5 (C-1100), 126.6 (AreCH), 127.1 (C-1), 128.1 (AreCH), 128.8
(AreCH), 129.4 (C-5), 129.9 (C-3), 131.3 (C-6), 132.9 (C-2), 133.4 (C-4),
139.0 (AreC),164.1 (C]O),175.8 (C-50),179.9 (C-20); m/z (ESIþ) found
4.4.10. ((1S*,6S*,7S*,11S*)-9-Benzyl-11-methoxy-9-azatricyclo
[5.3.3.01,6]tridecan-7-yl)methanol. The reaction was carried out
according to standard procedure F, using ester 31 (50.0 mg,
0.140 mmol), stirring for 10 min with hexane/ethyl acetate 1:2 as
the solvent for flash chromatography to give the title compound
(23.0 mg, 50%) as a pale yellow oil. Rf 0.44; nmax(NaCl)/cmꢀ1 3373,
2926, 1495, 1452, 1097, 1071, 1169; dH(400 MHz; CDCl3) 0.75e0.78
(1H, m, 2A-H), 1.23e1.52 (8H, m, 4A-H, 5A-H, 6-H, 5B-H, 13B-H, 3B-H,
13A-H & 3A-H), 1.60 (1H, d, J¼10.6 Hz, 10A-H), 1.82 (1H, d, J¼11.6 Hz,
4B-H), 1.88 (1H, d, J¼13.2 Hz, 2B-H), 2.02e2.09 (2H, m, 12B-H & 8A-
H), 2.71 (1H, d, J¼10.5 Hz, 8B-H), 2.79e2.80 (1H, m, 12A-H),
3.09e3.19 (3H, m, 10B-H, C7-CHACHBOH & NCHACHB), 3.32 (1H, d,
J¼11.0 Hz, C7-CHACHBOH), 3.38 (3H, s, OCH3), 3.59 (1H, d, J¼13.4 Hz,
NCHACHB), 3.73 (1H, dd, J¼11.0, 6.7 Hz, 11-H), 7.20e7.33 (5H, m,
AreH); dC(100 MHz; CDCl3) 20.5 (C-5), 21.0 (C-3), 26.2 (C-12), 26.5
(C-4), 28.3 (C-13), 32.4 (C-2), 37.7 & 37.8 (C-1 & C-7), 46.2 (C-6), 57.3
(OCH3), 62.8 (C-8), 63.6 (NCH2Ar & C-10), 68.8 (CH2OH), 76.9 (C-11),
126.6 (AreCH), 128.1 (AreCH), 128.7 (AreCH), 139.3 (AreC); m/z
(ESIþ) found MHþ 330.2432, C21H32NO2 requires MHþ 330.2428.
M
þ 545.3008, C33H41N2O5 requires Mþ 545.3010.
4.4.13. ((1S*,5S*,6S*)-3-Benzyl-6-hydroxy-3-azabicyclo[3.3.1]nonan-
1-yl)methanol 37. The reaction was carried out according to stan-
dard procedure F, using ester 17a (0.365 g, 1.27 mmol), stirring for
15 min with hexane/ethyl acetate 1:2 as the solvent for flash
chromatography to give the title compound 37 (0.224 g, 67%) as
a colourless oil. Rf 0.20; nmax(NaCl)/cmꢀ1 3375, 2908, 1494, 1453,
1043, 1102; dH(400 MHz; CDCl3) 1.29 (1H, dd, J¼12.5, 2.0 Hz, 9B-H),
1.34e1.43 (2H, m, 8A-H & 9A-H), 1.65 (1H, dd, J¼14.0, 6.7 Hz, 8B-H),
1.84e1.96 (5H, m, 2ꢂ OeH, 7B-H, 2A-H & 5-H), 2.04 (1H, dd, J¼11.2,
2.8 Hz, 4A-H), 2.65e2.76 (2H, m, 7A-H & 2B-H), 3.16 (1H, d,
J¼11.2 Hz, 4B-H), 3.19 (2H, s, OCH2), 3.22 (1H, d, J¼13.2 Hz,
NCHAHBAr), 3.45 (1H, d, J¼13.2 Hz, NCHAHBAr), 3.80e3.83 (1H, m,
6-H), 7.19e7.29 (5H, m, AreH); dC(100 MHz; CDCl3) 31.0 (C-7), 31.9
(C-8), 34.5 (C-9), 34.9 (C-1), 36.0 (C-5), 52.7 (C-4), 61.2 (C-2), 63.6
(NCH2Ar), 71.4 (OCH2), 72.6 (C-6), 126.7 (AreCH), 128.1 (AreCH),
128.5 (AreCH), 139.0 (AreC); m/z (EI) 261 (Mþ, 24%), 244 (MꢀOH,
58%), 91 (C6H5CH2, 100%); found Mþ 261.1726, C16H23NO2 requires
4.4.11. ((100S*,600S*,700S*,1100S*)-900-Benzyl-1100-methoxy-900-azabicyclo
[5.3.3.01,6]tridecan-700-yl)methyl 2-(30-methyl-20,50-dioxo-20,50-dihy-
dro-10H-pyrrol-10-yl)benzoate. The reaction was carried out
according to standard procedure G, using ((1S*,6S*,7S*,11S*)-9-
benzyl-11-methoxy-9-azatricyclo[5.3.3.01,6]tridecan-7-yl)metha-
nol (20.0 mg, 60.7 mmol), acid 33 (28.0 mg, 0.121 mmol), heating for
21.5 h, with hexane/ethyl acetate 2:1 as the solvent for flash
chromatography to give the title compound (32.0 mg, 97%) as a pale
yellow oil. Rf 0.45; nmax(NaCl)/cmꢀ1 2930, 1783, 1710, 1646, 1495 &
1453, 1258, 1099; dH(400 MHz; CDCl3) 0.77e0.79 (1H, m, 200A-H),
1.20e1.61 (9H, m, 400A-H, 600-H, 500A-H, 500B-H, 300A-H, 300B-H, 1300B-H,
1300A-H & 1000A-H), 1.82 (1H, d, J¼11.2 Hz, 400B-H), 1.88 (1H, d,
J¼13.3 Hz, 200B-H), 2.01e2.08 (2H, m, 800A-H & 1200B-H), 2.15 (3H, d,
J¼1.9 Hz, C30eCH3), 2.77e2.86 (2H, m, 1200A-H & 800B-H), 3.14 (1H, d,
J¼10.8 Hz, 1000B-H), 3.18 (1H, d, J¼13.3 Hz, NCHAHBAr), 3.38 (3H, s,
OCH3), 3.58 (1H, d, J¼13.3 Hz, NCHAHBAr), 3.74 (1H, dd, J¼11.0,
6.8 Hz, 1100-H), 3.84 (2H, m, C700eCH2Oe), 6.47 (1H, q, J¼1.8 Hz, 40-
H), 7.21e7.33 (6H, m, AreH & 3-H) 7.46 (1H, td, J¼7.7, 1.2 Hz, 5-H),
M
þ 261.1729.
4.4.14. ((100S*,500S*,600S*)-300-Benzyl-600-hydroxy-300-azabicyclo[3.3.1]
nonan-100-yl)methyl 2-(30-methyl-20,50-dioxo-20,50-dihydro-10H-pyr-
rol-10-yl)benzoate 38a and (100S*,500S*,600S*)-300-benzyl-100-(((2000-(30000
-
methyl-20000,50000-dioxo-20000,500-dihydro-10000H-pyrrol-10000-yl)benzoyl)
oxy)methyl)-300-azabicyclo[3.3.1]nonan-600-yl 2-(30-methyl-20,50-di-
oxo-20,50-dihydro-10H-pyrrol-10-yl)benzoate 38b. The reaction was
carried out according to standard procedure G, using alcohol 37
(34.0 mg, 0.130 mmol), acid 33 (38.0 mg, 0.163 mmol), heating for
18 h, with hexane/ethyl acetate 1:1 as the solvent for flash chro-
matography to give (i) diester 38b (9.3 mg, 10%) as an orange oil. Rf

5772
K.J. Goodall et al. / Tetrahedron 68 (2012) 5759e5778
0.40; nmax(NaCl)/cmꢀ1 2931, 1782, 1708, 1645, 1493, 1453, 1257,
1084; dH(400 MHz; CDCl3) 1.50e1.60 (3H, m, 900B-H, 800A-H & 900A-H),
to give the title compound 40a (84.0 mg, 99%) as a yellow oil, which
was used without further purification. nmax(NaCl)/cmꢀ1 3343, 2930,
1722, 1239, 1099; dH(400 MHz; CDCl3) 1.81e1.88 (3H, m, NeH, 8A-H
& 9B-H), 1.93e1.98 (1H, m, 9A-H), 2.02e2.10 (3H, m, 8B-H, 5-H & 7B-
H), 2.25e2.28 (1H, m, 7A-H), 2.75 (1H, dd, J¼12.6, 2.6 Hz, 4A-H), 3.01
(1H, dd, J¼12.4, 2.6 Hz, 2A-H), 3.21e3.30 (2H, m, 4B-H & 2B-H), 3.36
(3H, s, OCH3 ether), 3.43e3.49 (1H, m, 6-H), 3.65 (3H, s, OCH3 es-
ter); dC(100 MHz; CDCl3) 28.5 (C-7), 31.0 (C-5), 31.9 (C-8), 34.1 (C-9),
40.6 (C-1), 44.2 (C-4), 51.7 (OCH3), 52.9 (C-2), 55.8 (OCH3), 80.0 (C-
6), 176.7 (C]O); m/z (ESIþ) 214 (MHþ, 100%); found MHþ 214.1438,
C11H20NO3 requires MHþ 214.1438.
1.88 (1H, dd, J¼13.6, 6.0 Hz, 800B-H), 1.92e2.05 (2H, m, 700B-H & 400
-
A
H), 2.10e2.22 (8H, m, 500-H, C30eCH3, C30000eCH3, & 200A-H), 2.94 (1H,
d, J¼10.8 Hz, 200B-H), 2.99e3.06 (1H, m, 700A-H), 3.14 (1H, d,
J¼11.2 Hz, 400B-H), 3.27 (1H, d, J¼13.2 Hz, NCHAHBAr), 3.60 (1H, d,
J¼13.2 Hz, NCHAHBAr), 3.88 (2H, s, C100eCH2Oe), 5.07e5.09 (1H, m,
600-H), 6.40e6.50 (2H, m, 40-H & 40000-H), 7.24e7.41 (8H, m, 3000-H, 5000-
H, 5ꢂ AreH & 3-H), 7.51 (1H, td, J¼7.6, 1.2 Hz, 5-H), 7.60 (1H, td,
J¼7.7, 1.5 Hz, 4000-H), 7.64e7.69 (2H, m, 4-H & 6000-H), 8.03 (1H, dd,
J¼7.8, 1.4 Hz, 6-H); dC(100 MHz; CDCl3) 11.2 (C30eCH3 & C30000eCH3),
26.9 (C-700), 32.2 (C-800), 33.0 (C-500), 34.1 (C-100), 34.7 (C-900), 52.7 (C-
400), 62.0 (C-200), 63.5 (NCH2Ar), 72.7 (C100eCH2O), 75.5 (C-600), 126.8
(AreCH), 127.8 (C-1), 127.9 (C-40 & C-40000), 128.2 (C-1000), 128.3
(AreCH), 128.9 (AreCH & C-5000), 129.0 (C-5), 130.3 (C-3000), 130.5 (C-
3), 131.3 (C-6), 131.6 (C-6000), 131.7 (C-2000), 131.9 (C-2), 133.0 (C-4000),
133.4 (C-4), 138.9 (AreC), 146.2 (C-30 & C-30000), 164.0 (OC]O), 164þ.6
(CH2OC]O), 169.8 (C-50 & C-50000), 170.8 (C-20 & C-20000); m/z (ESI )
688 (MHþ, 100%); found MHþ 688.2641, C40H38N3O8 requires MHþ
688.2653 and (ii) ester 38a (27.4 mg, 44%) as a yellow oil. Rf 0.24;
nmax(NaCl)/cmꢀ1 3420, 2918, 1781, 1708, 1645, 1494, 1258, 1108;
dH(400 MHz; CDCl3) 1.39 (1H, d, J¼15.2 Hz, 900B-H), 1.44e1.52 (2H,
m, 800A-H & 900A-H), 1.62 (1H, br s, OeH), 1.76 (1H, dd, J¼13.6, 6.4 Hz,
800B-H), 1.90e1.94 (1H, m, 700B-H), 1.95e1.99 (1H, m, 500-H),
2.02e2.07 (2H, m, 400A-H & 200A-H), 2.16 (3H, d, J¼1.7 Hz, C30eCH3),
2.70e2.78 (1H, m, 700A-H), 2.83 (1H, d, J¼10.8 Hz, 200B-H), 3.18 (1H, d,
J¼11.6 Hz, 400B-H), 3.39 (1H, d, J¼13.4 Hz, NCHAHBAr), 3.43 (1H, d,
J¼13.4 Hz, NCHAHBAr), 3.81e3.88 (3H, m, C100eCH2Oe & 600-H), 6.48
(1H, q, J¼1.7 Hz, 40-H), 7.21e7.35 (6H, m, AreH & 3-H) 7.48 (1H, td,
J¼7.8, 1.2 Hz, 5-H), 7.65 (1H, td, J¼7.8, 1.7 Hz, 4-H), 7.98 (1H, dd,
J¼7.8, 1.7 Hz, 6-H); dC(100 MHz; CDCl3) 11.2 (C30eCH3), 31.1 (C-700),
32.3 (C-800), 34.1 (C-100), 34.9 (C-900), 35.9 (C-500), 52.4 (C-400), 61.4 (C-
200), 63.5 (NCH2Ar), 72.4 (C-600), 72.8 (C100eCH2O), 126.9 (AreCH),
127.9 (C-1 & C-40), 128.3 (AreCH), 128.7 (AreCH), 129.0 (C-5), 130.4
(C-3), 131.3 (C-6), 131.8 (C-2), 133.3 (C-4), 138.8þ(AreC), 146.2 (C-30),
164.6 (CO2), 169.7 (C-50), 170.8 (C-20); m/z (ESI ) 475 (MHþ, 100%);
found MHþ 475.2237, C28H31N2O5 requires MHþ 475.2227.
4.4.17. Ethyl (1S*,5S*,6S*)-6-methoxy-3-azabicyclo[3.3.1]nonane-1-
carboxylate 40b. The reaction was carried out according to stan-
dard procedure I, using benzylamine 30b (90.0 mg, 0.284 mmol) to
give the title compound 40b as a pale yellow oil (64.0 mg, 99%),
which was used without further purification. nmax(NaCl)/cmꢀ1
3584, 2934, 1723, 1240, 1101; dH(400 MHz; CDCl3) 1.24 (3H, t,
J¼7.1 Hz, OCH2CH3), 1.76e1.88 (3H, m, NeH, 9B-H & 8A-H), 1.97 (1H,
ddd, J¼13.3, 3.3, 3.3 Hz, 9A-H), 2.04e2.10 (3H, m, 5-H, 8B-H & 7B-H),
2.17e2.23 (1H, m, 7A-H), 2.77 (1H, dd, J¼12.8, 2.2 Hz, 4A-H), 3.02
(1H, dd, J¼12.6, 2.2 Hz, 2A-H), 3.23e3.32 (2H, m, 2B-H & 4B-H), 3.36
(3H, s, OCH3), 3.44e3.46 (1H, m, 6-H), 4.11, (2H, q, J¼7.1 Hz,
OCH2CH3); dC(100 MHz; CDCl3) 14.1 (CH3, OCH2CH3), 28.4 (C-7),
30.9 (C-5), 31.8 (C-8), 33.8 (C-9), 40.4 (C-1), 43.9 (C-4), 52.5 (C-2),
55.8 (OCH3), 60.5 (OCH2CH3), 80.0 (C-6), 176.2 (C]O); m/z (EI) 227
(Mþ, 5%), 196 (MꢀOCH3, 100%), 154 (MꢀCOOCH2CH3, 11%); found
M
þ 227.1523, C12H21NO3 requires Mþ 227.1521.
4.4.18. Methyl (1S*,5S*,6S*)-6-hydroxy-3-azabicyclo[3.3.1]nonane-1-
carboxylate 41. The reaction was carried out according to stan-
dard procedure I, using benzylamine 28a (60.0 mg, 0.207 mmol)
to give the title compound 41 as a yellow oil (41.0 mg, 99%), which
was used without further purification. nmax(NaCl)/cmꢀ1 3368,
3350, 2924, 1722, 1255, 1073; dH(400 MHz; CDCl3) 1.86e1.93 (3H,
m, 9B-H, 8A-H & 9A-H), 1.95e2.00 (1H, m, 5-H), 2.01e2.08 (2H, m,
7B-H & 8B-H), 2.26e2.31 (1H, m, 7A-H), 2.84 (1H, dd, J¼13.0, 2.0 Hz,
4A-H), 3.08 (1H, dd, J¼12.4, 2.0 Hz, 2A-H), 3.33 (1H, d, J¼12.4 Hz,
2B-H), 3.52 (1H, d, J¼13.0 Hz, 4B-H), 3.57e3.65 (2H, m, NeH &
OeH), 3.67 (3H, s, OCH3), 3.93e3.97 (1H, m, 6-H); dC(100 MHz;
CDCl3) 30.8 (C-7), 31.8 (C-8), 33.7 (C-9), 34.3 (C-5), 40.1 (C-1), 43.4
(C-4), 51.6 (C-2), 51.99 (OCH3), 70.9 (C-6), 176.1 (C]O); m/z (ESIþ)
200 (Mþ, 100%); found MHþ 200.1280, C10H18NO3 requires MHþ
200.1281.
4.4.15. ((100S*,500S*,600S*)-300-Benzyl-600-hydroxy-300-azabicyclo[3.3.1]
nonan-100-yl)methyl 2-(30-methyl-20,50-dioxopyrrolidin-10-yl)benzo-
ate 39. The reaction was carried out according to standard pro-
cedure H, using maleimide 38a (22.0 mg, 46.4 mmol), stirring for
3 h, with hexane/ethyl acetate 1:2 as the solvent for flash chro-
matography to give the title compound 39 (12.8 mg, 58%) as a yellow
oil. Rf 0.26; nmax(NaCl)/cmꢀ1 3423, 2926, 1392, 1780, 1712, 1494,
1455, 1262, 1188; dH(400 MHz; CDCl3) 1.39e1.53 (6H, m, 900B-H,
C30eCH3, 800A-H & 900A-H), 1.64 (1H, br s, OeH),1.77e1.80 (1H, m,
800B-H) 1.88e1.92 (1H, m, 700B-H), 1.99e2.00 (1H, m, 500-H),
2.02e2.09 (2H, m, 400A-H & 200A-H), 2.52e2.56 (1H, m, 40A-H),
2.74e2.77 (1H, m, 700A-H), 2.85 (1H, d, J¼10.5 Hz, 200B-H), 2.99e3.16
(2H, m, 40B-H & 30-H), 3.19 (1H, d, J¼11.4 Hz, 400B-H), 3.38 (1H, d,
J¼13.2 Hz, NCHAHBAr), 3.45 (1H, d, J¼13.2 Hz, NCHAHBAr),
3.82e3.90 (3H, m, C100eCH2Oe& 600-H), 7.23e7.32 (6H, m, 3-H &
AreH), 7.49 (1H, td, J¼7.7, 1.2 Hz, 5-H), 7.66 (1H, td, J¼7.7, 1.5 Hz, 4-
H), 7.99 (1H, dd, J¼7.7, 1.5 Hz, 6-H); dC(100 MHz; CDCl3) 16.3
(C30eCH3), 31.0 (C-700), 32.3 (C-800), 34.1 (C-100), 34.9 (C-900), 35.2 (C-
30), 35.9 (C-500), 37.0 (C-40), 52.4 (C-400), 61.4 (C-200), 63.5 (NCH2Ar),
72.3 (C-600), 72.7 (C100eCH2O), 127.0 (C-1 & AreC), 128.3 (AreCH),
128.8 (AreCH), 129.4 (C-5), 129.9 (C-3), 131.3 (C-6), 132.9 (C-2),
133.5 (C-4), 138.8 (AreC), 164.0 (CO2), 176.0 (C-50), 179.9 (C-20); m/z
(ESIþ) 477 (MHþ, 100%); found MHþ 477.2407, C28H33N2O5 requires
MHþ 477.2384.
4.4.19. ((1S*,5S*,6S*)-6-Methoxy-3-(3-phenylpropyl)-3-azabicyclo
[3.3.1]nonan-1-yl)methanol 43. To a solution of amine 40b (0.174 g,
0.766 mmol) in DCM (3.4 mL) was added triethylamine (3.40 mL,
2.47 g, 24.4 mmol) and the mixture cooled to 0 ꢁC with stirring.
DMAP (9.0 mg, 0.077 mmol) was added, followed by hydro-
cinnamoyl chloride (0.136 mL, 0.155 g, 0.919 mmol), then the
mixture was allowed to warm to room temperature and stirred for
22 h. The solvent was removed from the reaction mixture under
reduced pressure and the residue was redissolved in ethyl acetate
(30 mL). The organic residue was washed with 2 M HCl (2ꢂ30 mL)
and the combined aqueous washings back-extracted with ethyl
acetate (2ꢂ30 mL). The combined organic extracts were washed
with saturated aqueous sodium bicarbonate (2ꢂ30 mL), then brine
(30 mL), dried (MgSO4), filtered and the solvent removed at re-
duced pressure to give a crude amide 42 (0.250 g, 0.682 mmol, 91%)
as a colourless oil. To amide 42, dissolved in dry THF (27 mL), was
added lithium aluminium hydride (0.129 g, 3.41 mmol) and the
mixture refluxed under an atmosphere of nitrogen for 21 h. The
reaction was cooled to 0 ꢁC and quenched by dropwise addition of
water (50 mL), then the volatiles were removed under reduced
pressure. Ethyl acetate (25 mL) was added and the residue filtered
4.4.16. Methyl (1S*,5S*,6S*)-6-methoxy-3-azabicyclo[3.3.1]nonane-
1-carboxylate 40a. The reaction was carried out according to
standard procedure I, using benzylamine 30a (0.120 g, 0.396 mmol)

K.J. Goodall et al. / Tetrahedron 68 (2012) 5759e5778
5773
through Celite, which was washed with water (25 mL), ethyl ace-
tate (25 mL) and brine (25 mL). The filtrate was separated and the
aqueous portion extracted with ethyl acetate (2ꢂ25 mL). The
combined organic filtrate and extracts were extracted with 2 M
hydrochloric acid (2ꢂ50 mL), then the acidic extracts basified with
4 M aqueous sodium hydroxide. The aqueous residue was extracted
with ethyl acetate (3ꢂ50 mL), then the combined organic extracts
washed with brine (100 mL), dried (MgSO4), filtered and the sol-
vent removed under reduced pressure to give the title compound 43
(0.160 g, 77%) as an orange oil, which was used without further
purification. nmax(NaCl)/cmꢀ1 3363, 2922, 1495, 1217, 1099;
dH(300 MHz; CDCl3) 1.23e1.28 (1H, m, 9B-H), 1.30e1.44 (2H, m, 8A-
H & 9A-H), 1.68e1.82 (4H, m, CH2eOH, 8B-H & NCH2CH2CH2Ar),
1.87e1.95 (3H, m, 7B-H, 2A-H & 4A-H), 2.09e2.30 (3H, m, 5-H &
NCH2CH2CH2Ar), 2.48e2.72 (3H, m, NCH2CH2CH2Ar & 7A-H), 2.80
(1H, d, J¼10.4 Hz, 2B-H), 3.15 (1H, d, J¼11.1 Hz, 4B-H), 3.26 (2H, s,
CH2OH), 3.31e3.39 (4H, m, 6-H & OCH3), 7.13e7.29 (5H, m, AreH);
dC(75 MHz; CDCl3) 27.7 (C-7), 28.9 (NCH2CH2CH2Ar), 32.1 (C-8),
32.5 (C-5), 33.5 (NCH2CH2CH2Ar), 34.7 (C-9), 35.3 (C-1), 52.8 (C-4),
55.7 (OCH3), 58.0 (NCH2CH2CH2Ar), 61.4 (C-2), 72.1 (CH2OH), 81.7
(C-6) 125.5 (AreCH), 128.2 (AreCH), 128.5 (AreCH), 142.8 (AreC);
m/z (EI) 303 (Mþ, 10%), 272 (MꢀOCH3, 24%) 198 (MꢀCH2CH2C6H5,
100%); found Mþ 303.2203, C19H29NO2 requires Mþ 303.2198.
3.99 (1H, d, J¼13.2 Hz, 2B-H*), 4.07 (1H, d, J¼13.3 Hz, 4B-H), 4.80
(1H, d, J¼14.0, 1.3 Hz, 4B-H*), 4.86 (1H, d, J¼13.8 Hz, 2B-H),
4.89e4.92 (1H, m, 6-H*), 4.99e5.02 (1H, m, 6-H); dC(100 MHz;
CDCl3) 21.2, 21.3, 22.2 & 22.3 (2ꢂ O]CCH3 & 2ꢂ O]CCH3*), 25.2 (C-
7*), 25.5 (C-7), 31.3 (C-5*), 31.6 (C-8), 31.9 (C-8*), 32.0 (C-5), 33.6 (C-
9*), 33.9 (C-9), 40.2 (C-4*), 40.3 (C-1), 40.7 (C-1*), 45.4 (C-4), 47.3
(C-2), 52.2 (OCH3), 52.3 (OCH3*), 52.5 (C-2*), 72.7 (C-6), 72.9 (C-6*),
169.7, 169.8, 170.0, & 170.7 (2ꢂ O]CCH3 & 2ꢂ O]CCH3*), 175.2
(O]COCH3 & O]COCH3*); m/z (ESIþ) 306 (MNaþ, 100%); found
MNaþ 306.1309, C14H21NNaO5 requires MNaþ 306.1312.
4.4.22. ((1S*,5S*,6S*)-3-Ethyl-6-methoxy-3-azabicyclo[3.3.1]nonan-
1-yl)methanol 46. The reaction was carried out according to stan-
dard procedure K, using amide 44 (0.100 g, 0.392 mmol) and LAH
(74.3 mg, 1.96 mmol), heating for 19 h to give the title compound 46
(68.5 mg, 82%) as a yellow oil, which was used without further
purification. nmax(NaCl)/cmꢀ1 3391, 2918, 1094, 1040; dH(400 MHz;
CDCl3) 1.07 (3H, t, J¼7.2 Hz, NCH2CH3), 1.22e1.26 (2H, m, 9B-H &
OeH),1.35 (1H, tdd, J¼13.4, 6.1, 2.3, 8A-H),1.49 (1H, d, J¼12.3 Hz, 9A-
H), 1.69e1.72 (1H, m, 8B-H), 1.85e1.88 (1H, m, 7B-H), 1.98e2.08 (2H,
m, 2A-H & 4A-H),2.16e2.18 (1H, m, 5-H), 2.33 (2H, m, NCH2CH3),
2.48e2.53 (1H, m, 7A-H), 2.81 (1H, d, J¼10.5 Hz, 2B-H), 3.12 (1H, d,
J¼11.2 Hz, 4B-H), 3.24e3.38 (6H, m, CH2OH, 6-H
& OCH3);
dC(100 MHz; CDCl3) 12.1 (NCH2CH3), 27.2 (C-7), 31.9 (C-5), 32.0 (C-
8), 34.0 (C-9), 35.2 (C-1), 52.1 (C-4), 52.8 (NCH2CH3), 55.8 (OCH3),
60.4 (C-2), 71.8 (CH2OH), 81.6 (C-6); m/z (EI) 213 (Mþ, 12%), 182
(MꢀOCH3, 100%); found Mþ 213.1731, C12H23NO2 requires Mþ
213.1729.
4.4.20. Methyl (1S*,5S*,6S*)-3-acetyl-6-methoxy-3-azabicyclo[3.3.1]
nonane-1-carboxylate 44. The reaction was carried out according to
standard procedure J, using amine 40a (0.151 g, 0.708 mmol),
triethylamine (3.10 mL, 22.2 mmol), DMAP (8.70 mg, 70.8
mmol)
and acetic anhydride (86.7 mg, 80 L, 0.850 mmol), stirring for
m
42.5 h with the following additional workup. The residue was
dissolved in ethyl acetate (15 mL) and washed with water
(2ꢂ15 mL). The combined aqueous washings were back-extracted
with ethyl acetate (15 mL), the combined organic extracts were
washed with brine (15 mL), dried (MgSO4), filtered and the solvent
removed under reduced pressure to give the title compound 44
(0.113 g, 63%) as a pale yellow oil (3.2:1 mixture of rotomers), which
was used without further purification. nmax(NaCl)/cmꢀ1 2926, 1726,
1642, 1231, 1100; dH(400 MHz; CDCl3) [*denotes minor rotomer]
1.51e1.68 (2H, m, 7B-H, 7B-H* & 8A-H*), 1.77 (1H, tdd, J¼13.5, 6.2,
2.6 Hz, 8A-H), 1.85e2.21 (16H, m, 9B-H, 9B-H*, 9A-H*, 7A-H*, 7A-H,
9A-H, 8B-H, 8B-H*, CCH3*, CCH3, 5-H & 5-H*), 2.60 (1H, dd, J¼13.6,
3.8 Hz, 4A-H*), 2.81 (1H, dd, J¼13.5, 3.0 Hz, 2A-H), 3.05 (1H, dd,
J¼13.5, 3.0 Hz, 4A-H), 3.31e3.45 (9H, m, 2A-H*, OCH3 ether*, 6-H*,
OCH3 ether & 6-H), 3.69 (3H, s, OCH3 ester), 3.72 (3H, s, OCH3 es-
ter*), 3.96 (1H, d, J¼13.2 Hz, 2B-H*), 4.08 (1H, dd, J¼13.5, 1.5 Hz, 4B-
H), 4.75 (1H, d, J¼13.6 Hz, 4B-H*), 4.83 (1H, dt, J¼13.5, 1.5 Hz, 2B-H);
dC(100 MHz; CDCl3) 22.2 (CCH3 & CCH3*), 26.0 (C-7*), 26.1 (C-7),
30.5 (C-5*), 31.6 (C-5), 31.7 (C-8), 32.1 (C-8*), 33.6 (C-9*), 33.9 (C-9),
39.7 (C-4*), 40.6 (C-1 & C-1*), 44.8 (C-4), 47.2 (C-2), 52.0 (OCH3),
52.2 (OCH3*), 52.4 (C-2*), 55.8 (OCH3*), 55.9 (OCH3), 78.9 (C-6),
79.4 (C-6*), 170.0 (C]O* & C]O), 175.7 (C]O & C]O*); m/z (ESIþ)
278 (MNaþ, 100%), 256 (MHþ, 34%); found MNaþ 278.1368,
C13H21NNaO4 requires MNaþ 278.1363.
4.4.23. ((1S*,5S*,6S*)-3-Ethyl-6-hydroxy-3-azabicyclo[3.3.1]nonan-
1-yl)methanol 47. The reaction was carried out according to stan-
dard procedure K, using amide 45 (0.193 g, 0.681 mmol) and LAH
(0.129 g, 3.406 mmol), heating for 21 h to give the title compound 47
(78.0 mg, 58%) as a yellow oil, which was used without further
purification. nmax(NaCl)/cmꢀ1 3344, 2918, 1111, 1049; dH(400 MHz;
CDCl3) 1.05 (3H, t, J¼7.2 Hz, NCH2CH3), 1.24e1.44 (5H, m, 2ꢂ OeH,
9B-H, 9A-H & 8A-H), 1.68e1.71 (1H, m, 8B-H), 1.84e1.87 (1H, m, 7B-
H), 1.91 (1H, dd, J¼10.4, 2.4 Hz, 2A-H), 1.94e1.98 (2H, m, 4A-H & 5-
H), 2.25 (2H, m, NCH2CH3), 2.56e2.61 (1H, m, 7A-H), 2.82 (1H, d,
J¼10.4 Hz, 2B-H), 3.22 (1H, d, J¼10.0 Hz, 4B-H), 3.26 (2H, s, CH2OH),
3.82e3.85 (1H, m, 6-H); dC(100 MHz; CDCl3) 12.4 (NCH2CH3), 30.8
(C-7), 32.0 (C-8), 34.7 (C-9), 34.9 (C-1), 36.0 (C-5), 52.3 (C-4), 52.7
(NCH2CH3), 60.1 (C-2), 71.8 (CH2OH), 72.7 (C-6); m/z (ESIþ) 200
(MHþ, 100%); found MHþ 200.1645, C11H22NO2 requires MHþ
200.1645.
4.4.24. ((100S*,500S*,600S*)-600-Methoxy-300-(3-phenylpropyl)-300-azabi-
cyclo[3.3.1]nonan-100-yl)methyl 2-(30-methyl-20,50-dioxo-20,50-dihy-
dro-10H-pyrrol-10-yl)benzoate. The reaction was carried out
according to standard procedure G, using alcohol 43 (0.160 g,
0.527 mmol) and acid 33 (0.244 g, 1.06 mmol) heating for 19 h,
with hexane/ethyl acetate 1:1 as the solvent for flash chroma-
tography to give the title compound (0.170 g, 62%) as a yellow oil. Rf
0.38; nmax(NaCl)/cmꢀ1 2924, 1784, 1713, 1645, 1494, 1259, 1106;
dH(400 MHz; CDCl3) 1.32 (1H, d, J¼12.4 Hz, 900B-H), 1.37e1.49 (2H,
m, 800A-H & 900A-H), 1.72e1.82 (3H, m, NCH2CH2CH2Ar & 800B-H),
1.86e1.97 (3H, m, 700B-H, 200A-H & 400A-H), 2.11e2.13 (1H, m, 500-H),
2.14 (3H, d, J¼1.8 Hz, C30eCH3), 2.21 (2H, m, NCH2CH2CH2Ar),
2.57e2.72 (3H, m, NCH2CH2CH2Ar & 700A-H), 2.83 (1H, d, J¼10.4 Hz,
4.4.21. Methyl (1S*,5S*,6S*)-3,6-acetyl-3-azabicyclo[3.3.1]nonane-1-
carboxylate 45. The reaction was carried out according to stan-
dard procedure J, using amine 41 (0.137 g, 0.688 mmol) stirring for
23 h to give the title compound 45 (0.193 g, 99%) as an orange oil
(1.8:1 mixture of rotomers), which was used without further pu-
rification. nmax(NaCl)/cmꢀ1 2941, 1724, 1666, 1643, 1235, 1078;
dH(400 MHz; CDCl3) [*denotes minor rotomer] 1.72e1.95 (5H, m,
7B-H, 7B-H*, 8A-H, 7A-H* & 7A-H), 1.96e2.05 (6H, m, 9A-H*, 8A-H*,
9A-H, 9B-H, 8B-H* & 9B-H*), 2.06e2.23 (15H, m, 8B-H, 2ꢂ CCH3*, 2ꢂ
CCH3, 5-H & 5-H*), 2.65 (1H, d, J¼13.7, 3.4 Hz, 4A-H*), 2.84 (1H, dd,
J¼13.9, 1.9 Hz, 2A-H), 3.14 (1H, dd, J¼13.3, 2.8 Hz, 4A-H), 3.35 (1H,
dd, J¼13.2, 1.9 Hz, 2A-H*), 3.70 (3H, s, OCH3), 3.73 (3H, s, OCH3*),
200B-H), 3.17 (1H, d, J¼11.0 Hz, 400B-H), 3.33e3.40 (4H, m, OCH3
&
600-H), 3.86 (2H, s, C100eCH2Oe), 6.47 (1H, q, J¼1.8 Hz, 40-H),
7.13e7.28 (5H, m, AreH), 7.30 (1H, dd, J¼7.8, 1.2 Hz, 3-H) 7.50 (1H,
td, J¼7.8, 1.2 Hz, 5-H), 7.64 (1H, td, J¼7.8, 1.6 Hz, 4-H), 8.07 (1H, dd,
J¼7.9, 1.6 Hz, 6-H); dC(100 MHz; CDCl3) 11.1 (C30eCH3), 27.5 (C-700),
28.8 (NCH2CH2CH2Ar), 32.2 (C-500), 32.3 (C-800), 33.3
(NCH2CH2CH2Ar), 34.1 (C-100), 34.8 (C-900), 52.3 (C-400), 55.6 (OCH3),

5774
K.J. Goodall et al. / Tetrahedron 68 (2012) 5759e5778
57.8 (NCH2CH2CH2Ar), 61.4 (C-200), 73.0 (C100eCH2O), 81.1 (C-600),
125.4 (AreCH), 127.8 (C-40), 127.9 (C-1), 128.1 (AreCH), 128.4
(AreCH), 128.8 (C-5), 130.3 (C-3), 131.2 (C-6), 131.7 (C-2), 133.1 (C-
4), 142.6 (AreC), 146.1 (C-30), 164.6 (CO2), 169.6 (C-50), 170.6 (C-20);
m/z (EI) 516 (Mþ, 6%), 411 (MꢀCH2CH2C6H5, 41%), 214 (C5H4O2N-
C6H4CO, 100%); found Mþ 516.2621, C31H36N2O5 requires Mþ
516.2624.
24 h, with hexane/ethyl acetate 1:1 as the solvent for flash chro-
matography to give the title compound 49 (19.0 mg, 95%) as a yellow
oil. Rf 0.35; nmax(NaCl)/cmꢀ1 2928, 1777, 1713, 1492, 1454, 1261,
1188; dH(300 MHz; CDCl3) 1.03 (3H, t, J¼7.1 Hz, NCH2CH3), 1.35 (1H,
d, J¼13.2 Hz, 900B-H), 1.39e1.53 (5H, m, 800A-H, C30eCH3 & 900A-H),
1.76e1.90 (2H, m, 800B-H & 700B-H), 1.91e1.98 (2H, m, 400A-H & 200A-H),
2.12e2.16 (1H, m, 500-H), 2.26 (2H, m, NCH2CH3), 2.45e2.71 (2H, m,
40A-H & 700A-H), 2.88 (1H, d, J¼10.7 Hz, 200B-H), 2.97e3.18 (3H, m,
400B-H, 40B-H & 30-H), 3.31e3.40 (4H, m, OCH3 & 600-H), 3.87 (2H, s,
C100eCH2Oe), 7.26 (1H, dd, J¼7.7, 1.2 Hz, 3-H) 7.53 (1H, td, J¼7.7,
1.2 Hz, 5-H), 7.67 (1H, td, J¼7.7, 1.5 Hz, 4-H), 8.11 (1H, dd, J¼7.7,
1.5 Hz, 6-H); dC(75 MHz; CDCl3) 12.4 (NCH2CH3), 16.5 (C30eCH3),
27.6 (C-700), 32.1 (C-500), 32.5 (C-800), 34.3 (C-100), 35.0 (C-900), 35.3 (C-
30), 37.0 (C-40), 52.2 (C-400), 52.6 (NCH2CH3), 55.9 (OCH3), 61.1 (C-200),
73.1 (C100eCH2O), 81.5 (C-600), 129.4 (C-5), 129.7 (C-1), 129.9 (C-3),
131.4 (C-6), 132.9 (C-2), 133.4 (C-4), 164.0 (CO2), 175.9 (C-50), 179.9
(C-20); m/z (EI) 428 (Mþ, 9%), 397 (MꢀOCH3, 100%), 216
(C5H6O2NC6H4CO, 14%), 196 (40%); found Mþ 428.2313, C24H32N2O5
requires Mþ 428.2311.
4.4.25. ((100S*,500S*,600S*)-600-Methoxy-300-(3-phenylpropyl)-300-azabi-
cyclo[3.3.1]nonan-100-yl)methyl 2-(30-methyl-20,50-dioxopyrrolidin-
10-yl)benzoate 48. The reaction was carried out according to
standard procedure H, using ((100S*,500S*,600S*)-600-methoxy-300-(3-
phenylpropyl)-300-azabicyclo[3.3.1]nonan-100-yl)methyl 2-(30-methy
l-20,50-dioxo-20,50-dihydro-10H-pyrrol-10-yl)benzoate
(77.0
mg,
0.149 mmol), stirring for 8 h, with hexane/ethyl acetate 1:1 as the
solvent for flash chromatography to give the title compound 48
(75.0mg, 97%)asayellowoil. Rf 0.51;nmax(NaCl)/cmꢀ12931,1777,1710,
1494, 1261, 1082; dH(400 MHz; CDCl3) 1.36 (1H, d, J¼12.1 Hz, 900B-H),
1.41e1.53 (5H, m, 800A-H, C30eCH3 & 900A-H), 1.73e1.86 (3H, m,
NCH2CH2CH2 & 800B-H), 1.87e2.00 (3H, m, 700B-H, 400A-H & 200A-H),
2.12e2.18 (1H, m, 500H), 2.23 (2H, m, NCH2CH2CH2), 2.48e2.52 (1H, m,
40A-H), 2.60e2.70 (3H, m, NCH2CH2CH2 & 700A-H), 2.86 (1H, d,
J¼10.5 Hz, 200B-H), 3.02e3.14 (2H, m, 3-0H & 40B-H), 3.18 (1H, d,
J¼11.0 Hz, 400B-H), 3.35e3.42 (4H, m, OCH3 & 600-H), 3.87 (2H, br s,
C100eCH2Oe), 7.14e7.29 (6H, m, AreH & 3-H) 7.53 (1H, t, J¼7.7 Hz, 5-
H), 7.67 (1H, td, J¼7.7, 1.3 Hz, 4-H), 8.11 (1H, dd, J¼7.7, 1.3 Hz, 6-H);
dC(100 MHz; CDCl3) 16.3 (C30eCH3), 27.6 (C-700), 28.9 (NCH2CH2CH2),
32.3 (C-500), 32.4 (C-800), 33.5 (NCH2CH2CH2), 34.3 (C-100), 34.9 (C-900),
35.4 (C-30), 37.0 (C-40), 52.4 (C-400), 55.8 (OCH3), 57.9 (NCH2CH2CH2),
61.6 (C-200), 73.0 (C100eCH2O), 81.3 (C-600), 125.5 (AreCH), 127.3 (C-1),
128.2 (AreCH), 128.5 (AreCH), 129.4 (C-5), 129.9 (C-3), 131.4 (C-6),
132.9(C-2),133.5(C-4),142.7(AreC),164.1(CO2),175.9(C-50),179.9(C-
20); m/z (ESIþ) 519 (MNHþ, 100%); found MHþ 519.2852, C31H39N2O5
requires Mþ 519.2853.
4.4.28. ((100S*,500S*,600S*)-300-Ethyl-600-hydroxy-300-azabicyclo[3.3.1]
nonan-100-yl)methyl 2-(30-methyl-20,50-dioxo-20,50-dihydro-10H-pyr-
rol-10-yl)benzoate
and
(100S*,500S*,600S*)-300-ethyl-100-(((2000-(30000
-
methyl-20000,50000-dioxo-20000,50000-dihydro-10000H-pyrrol-10000-yl)benzoyl)
oxy)methyl)-300-azabicyclo[3.3.1]nonan-600-yl 2-(30-methyl-20,50-di-
oxo-20,50-dihydro-10H-pyrrol-10-yl)benzoate. The reaction was car-
ried out according to standard procedure G, using alcohol 47
(50.0 mg, 0.251 mmol) and acid 33 (72.5 mg, 0.314 mmol), heating
for 20 h, with hexane/ethyl acetate 1:3 as the solvent for flash
chromatography to give (i) (100S*,500S*,600S*)-300-benzyl-100-(((200-
(30000-methyl-20000,50000-dioxo-20000,50000-dihydro-10000H-pyrrol-10000-yl)ben-
zoyl)oxy)methyl)-300-azabicyclo[3.3.1]nonan-600-yl
2-(30-methyl-
20,50-dioxo-20,50-dihydro-10H-pyrrol-10-yl)benzoate (10.0 mg, 6%) as
a yellow oil. Rf 0.60; nmax(NaCl)/cmꢀ1 2929, 1785, 1711, 1644, 1494,
1259, 1109, 1085; dH(400 MHz; CDCl3) 1.06 (3H, t, J¼7.2 Hz,
NCH2CH3), 1.47e1.56 (3H, m, 900B-H, 900A-H & 800A-H), 1.78e1.90 (2H,
m, 800B-H & 700B-H), 1.96e2.00 (2H, m, 200A-H & 400A-H), 2.14e2.18
(7H, m, 500-H, C30eCH3 & C30000eCH3), 2.22e2.34 (2H, m, NCH2CH3),
2.77e2.92 (2H, m, 700A-H & 200B-H), 3.15 (1H, d, J¼9.6 Hz, 400B-H), 3.87
(2H, s, C100eCH2Oe), 5.08e5.11 (1H, m, 600-H), 6.49e6.52 (2H, m, 40-
H & 40000-H), 7.28e7.33 (2H, m, 3-H & 3000-H), 7.48e7.55 (2H, m, 5-H &
5000-H), 7.61e7.69 (2H, m, 4-H & 4000-H), 8.06e8.11 (2H, m, 6-H & 6000-
4.4.26. ((100S*,500S*,600S*)-300-Ethyl-600-methoxy-300-azabicyclo[3.3.1]
nonan-100-yl)methyl 2-(30-methyl-20,50-dioxo-20,50-dihydro-10H-pyr-
rol-10-yl)benzoate. The reaction was carried out according to stan-
dard procedure G, using alcohol 46 (67.0 mg, 0.314 mmol) and acid
33 (0.146 g, 0.628 mmol), heating for 20 h, with hexane/ethyl ac-
etate 1:1 as the solvent for flash chromatography to give the title
compound (44.0 mg, 33%) as a pale yellow oil. Rf 0.41; nmax(NaCl)/
cmꢀ1 2927, 1784, 1714, 1644, 1494, 1454, 1260, 1105; dH(400 MHz;
H); dC(100 MHz; CDCl3) 11.2 (C30eCH3
&
C30000eCH3), 12.4
CDCl3) 1.03 (3H, t, J¼7.2 Hz, NCH2CH3), 1.32 (1H, d, J¼11.4 Hz, 900
-
B
(NCH2CH3), 26.8 (C-700), 32.3 (C-800), 33.0 (C-500), 33.9 (C-100), 34.9 (C-
900), 52.4 (NCH2CH3), 52.7 (C-400), 61.0 (C-200), 72.8 (C100eCH2O), 76.1
(C-600), 127.9 (C-40, C-40000, C-1 & C-1000), 128.9 & 129.0 (C-5000 & C-5),
130.2 & 130.5 (C-3000 & C-3), 131.3 & 131.5 (C-6000 & C-6), 131.6 & 131.9
(C-2000 & C-2), 133.0 & 133.3 (C-4000 & C-4),146.2 & 146.3 (C-30 & C-
H), 1.36e1.49 (2H, m, 800A-H & 900A-H), 1.74e1.88 (2H, m, 800B-H &
700B-H), 1.90e1.95 (2H, m, 400A-H & 200A-H), 2.11e2.15 (1H, m, 500-H),
2.17 (3H, d, J¼1.8 Hz, C30eCH3), 2.20e2.30 (2H, m, NCH2CH3),
2.59e2.67 (1H, m, 700A-H), 2.85 (1H, d, J¼10.6 Hz, 200B-H), 3.15 (1H, d,
J¼11.0 Hz, 400B-H), 3.31e3.39 (4H, m, OCH3 & 600-H), 3.86 (2H, s,
C100eCH2Oe), 6.51 (1H, q, J¼1.8 Hz, 40-H), 7.31 (1H, dd, J¼7.8, 1.1 Hz,
3-H) 7.52 (1H, td, J¼7.8, 1.1 Hz, 5-H), 7.65 (1H, td, J¼7.8, 1.6 Hz, 4-H),
8.09 (1H, dd, J¼7.8,1.6 Hz, 6-H); dC(400 MHz; CDCl3) 11.2 (C30eCH3),
12.4 (NCH2CH3), 27.5 (C-700), 32.1 (C-500), 32.4 (C-800), 34.2 (C-100),
34.9 (C-900), 52.2 (C-400), 52.6 (NCH2CH3), 55.8 (OCH3), 61.0 (C-200),
73.2 (C100eCH2O), 81.5 (C-600), 127.9 (C-40 & C-1), 129.0 (C-5), 130.4
(C-3), 131.3 (C-6), 131.8 (C-2), 133.2 (C-4), 146.2 (C-30), 164.7 (CO2),
169.7 (C-50), 170.8 (C-20); m/z (EI) 426 (Mþ, 14%), 411 (MꢀCH3, 23%),
395 (MꢀOCH3, 100%); found Mþ 426.2157, C24H30N2O5 requires Mþ
426.2155.
3
0000), 164.5 (CO2), 169.8 (C-50 & C-50000), 170.7 (C-20 & C-20000); m/z
(ESIþ) 626 (MHþ, 100%)l found MHþ 626.2510, C35H36N3O8 requires
MHþ 626.2497 and (ii) ((100S*,500*,600S*)-300-benzyl-600-hydroxy-300-
azabicyclo[3.3.1]nonan-100-yl)methyl 2-(30-methyl-20,50-dioxo-20,50-
dihydro-10H-pyrrol-10-yl)benzoate (26.5 mg, 26%) as an orange oil. Rf
0.03; nmax(NaCl)/cmꢀ1 3337, 2928, 1784, 1708, 1645, 1494,1259,
1108, 1083; dH(400 MHz; CDCl3) 1.05 (3H, t, J¼7.2 Hz, NCH2CH3),
1.35e1.48 (4H, m, 900A-H, 900B-H, 800A-H & OeH), 1.76e1.86 (2H, m,
800B-H & 700B-H), 1.93e2.00 (3H, m, 500-H, 400A-H & 200A-H), 2.18 (3H, d,
J¼2.0 Hz, C30eCH3), 2.23e2.30 (2H, m, NCH2CH3), 2.58e2.63 (1H,
m, 700A-H), 2.86 (1H, d, J¼10.0 Hz, 200B-H), 3.25 (1H, d, J¼10.0 Hz, 400
-
B
H), 3.82e3.91 (3H, m, 600-H & C100eCH2Oe), 6.51 (1H, d, J¼2.0 Hz, 40-
H), 7.31 (1H, d, J¼7.8 Hz, 3-H) 7.52 (1H, t, J¼7.8, 5-H), 7.66 (1H, t,
J¼7.8 Hz, 4-H), 8.08 (1H, d, J¼7.8 Hz, 6-H); dC(100 MHz; CDCl3) 11.2
(C30eCH3), 12.4 (NCH2CH3), 30.8 (C-700), 32.4 (C-800), 33.9 (C-100),
34.9 (C-900), 35.8 (C-500), 51.9 (C-400), 52.6 (NCH2CH3), 61.2 (C-200),
72.4 (C-600), 73.1 (C100eCH2O), 127.9 (C-1 & C-40), 129.0 (C-5), 130.4
(C-3), 131.3 (C-6), 131.8 (C-2), 133.3 (C-4), 146.2 (C-30), 164.7 (CO2),
4.4.27. ((100S*,500S*,600S*)-300-Ethyl-600-methoxy-300-azabicyclo[3.3.1]
nonan-100-yl)methyl 2-(30-methyl-20,50-dioxopyrrolidin-10-yl)benzo-
ate 49. The reaction was carried out according to standard
procedure H, using ((100S*,500S*,600S*)-300-ethyl-600-methoxy-300-aza-
bicyclo[3.3.1]nonan-100-yl)methyl 2-(30-methyl-20,50-dioxo-20,50-
dihydro-10H-pyrrol-10-yl)benzoate (20.0 mg, 47.0
mmol), stirring for

K.J. Goodall et al. / Tetrahedron 68 (2012) 5759e5778
5775
169.7 (C-50), 170.8 (C-20); m/z (ESIþ) 413 (MHþ, 100%); found MHþ
8B-H), 1.79e1.94 (3H, m, 7B-H, 2A-H & 4A-H),2.06e2.10 (1H, m, 5-
H), 2.20e2.28 (2H, m, NCH2CH3), 2.58e2.64 (1H, m, 7A-H), 2.81
(1H, d, J¼10.5 Hz, 2B-H), 2.98 (2H, s, CH2OCH3), 3.11 (1H, d,
J¼11.0 Hz, 4B-H), 3.29e3.37 (7H, m, CH2OCH3, 6-H & C6eOCH3);
dC(75 MHz; CDCl3) 12.5 (NCH2CH3), 27.8 (C-7), 32.4 (C-5), 32.6 (C-
8), 34.8 (C-1), 35.2 (C-9), 52.6 (C-4), 52.7 (NCH2CH3), 55.8
(C6eOCH3), 59.4 (CH2OCH3), 61.3 (C-2), 81.9 (C-6), 82.4
(CH2OCH3); m/z (ESIþ) 228 (MHþ, 100%); found MHþ 228.1965,
C13H26NO2 requires MHþ 228.1958.
413.2070, C23H29N2O5 requires MHþ 413.2071.
4.4.29. ((100S*,500S*,600S*)-300-Ethyl-600-hydroxy-300-azabicyclo[3.3.1]
nonan-100-yl)methyl
2-(30-methyl-20,50-dioxopyrrolidin-10-yl)ben-
zoate 50. The reaction was carried out according to standard
procedure H, using ((100S*,500S*,600S*)-300-benzyl-600-hydroxy-
300-azabicyclo[3.3.1]nonan-100-yl)methyl 2-(30-methyl-20,50-dioxo-
20,50-dihydro-10H-pyrrol-10-yl)benzoate (14.5 mg, 35.1
mmol),
stirring for 4 h, with DCM/methanol 9:1 as the solvent for flash
chromatography to give the title compound 50 (12.5 mg, 86%) as
a yellow oil. Rf 0.40; nmax(NaCl)/cmꢀ1 3408, 2925, 1795, 1714, 1455,
1262, 1188; dH(400 MHz; CDCl3) 1.40e1.52 (6H, m, 900B-H, C30eCH3,
4.5.3. (1S*,5S*,6S*)-3-Benzyl-6-hydroxy-1-methoxymethyl-3-
azabicyclo[3.3.1]nonane 53. The reaction was carried out according
to standard procedure E, using sodium hydride (14.0 mg,
0.354 mmol), diol 37 (31.0 mg, 0.118 mmol) and iodomethane
(0.15 mL, 0.148 mmol, 1 M in THF), stirring for 16 h at 40 ꢁC, with
hexane/ethyl acetate 1:1 as the solvent for flash chromatography to
give the title compound 53 (16.0 mg, 49%) as a pale yellow oil. Rf 0.38;
nmax(NaCl)/cmꢀ1 3375, 2920, 1657, 1452, 1266, 1194, 1101;
dH(400 MHz; CDCl3) 1.33 (1H, dd, J¼12.6, 1.9 Hz, 9B-H), 1.38e1.49
(3H, m, 8A-H, 9A-H & OeH), 1.70 (1H, tdd, J¼13.6, 6.5, 2.3 Hz, 8B-H),
1.87e1.92 (1H, m, 7B-H), 1.93e1.97 (1H, m, 5-H), 1.98e2.06 (2H, m,
2A-H & 4A-H),2.68e2.73 (1H, m, 7A-H), 2.77 (1H, d, J¼10.8 Hz, 2B-H),
2.96 (2H, s, CH2OCH3), 3.14 (1H, d, J¼11.4 Hz, 4B-H), 3.27 (3H, s,
OCH3), 3.36 (1H, d, J¼13.2 Hz, NCHAHBAr), 3.41 (1H, d, J¼13.2 Hz,
NCHAHBAr), 3.80e3.85 (1H, m, 6-H), 7.20e7.31 (5H, m, AreH);
dC(100 MHz; CDCl3) 31.4 (C-7), 32.5 (C-8), 34.6 (C-1), 35.1 (C-9), 36.1
(C-5), 52.7 (C-4), 59.4 (OCH3), 61.9 (C-2), 63.7 (NCH2Ar), 72.8 (C-6),
82.0 (CH2OCH3), 126.7 (AreCH), 128.2 (AreCH), 128.6 (AreCH),
139.2 (AreC); m/z (EI) 275 (Mþ, 19%), 258 (MꢀOH, 41%), 91
(C6H5CH2, 100%); found Mþ 275.1879, C17H25NO2 requires
Mþ 275.1885. In a second fraction was obtained diether 51
(10.0 mg, 29%).
800A-H & 900A-H), 1.62 (1H, br s, OeH), 1.80e1.89 (2H, m, 800B-H & 700
-
B
H), 1.97e2.01 (3H, m, 400A-H, 200A-H & 500-H), 2.28 (2H, qd, J¼7.1,
1.3 Hz, NCH2CH3), 2.48e2.69 (2H, m, 40A-H & 700A-H), 2.89 (1H, d,
J¼10.5 Hz, 200B-H), 3.02e3.13 (2H, m, 40B-H & 30-H), 3.26 (1H, d,
J¼10.4 Hz, 400B-H), 3.84e3.88 (3H, m, 600-H & C100eCH2Oe), 7.26 (1H,
dd, J¼7.8, 1.1 Hz, 3-H), 7.54 (1H, td, J¼7.7, 0.9 Hz, 5-H), 7.67 (1H, td,
J¼7.6, 1.6 Hz, 4-H), 8.11 (1H, d, J¼7.6 Hz, 6-H); dC(100 MHz; CDCl3)
12.3 (CH2, NCH2CH3), 16.3 & 16.5 (CH3, br, C30eCH3), 30.7 (CH2, C-
700), 32.4 (CH2, C-800), 34.0 (quat., C-100), 34.8 (CH2, C-900), 35.2 & 35.4
(CH, br, C-30), 35.7 (CH, C-500), 37.0 (CH2, C-40), 51.9 (CH2, C-400), 52.8
(CH2, NCH2CH3), 61.1 (CH2, C-200), 72.3 (CH, C-600), 72.9 (CH2, C100-
CH2O), 127.0 & 127.1 (quat., br, C-1), 129.4 (C-5), 129.9 (CH, C-3),
131.3 (CH, br, C-6), 132.9 (quat., C-2), 133.5 (CH,C-4), 164.1 & 164.2
(quat., C]O ester), 175.9 & 176.0 (quat., br, C-50), 179.9 (quat., C-20);
m/z (ESIþ) found MHþ 415.2233, C23H31N2O5 requires MHþ
415.2227.
4.5. Synthesis of analogues of other Delphinium and Aconitum
alkaloids
4.5.1. (1S*,5S*,6S*)-3-Benzyl-6-methoxy-1-methoxymethyl-3-
azabicyclo[3.3.1]nonane 51. The reaction was carried out according
to standard procedure E, using sodium hydride (51.0 mg,
1.29 mmol), diol 37 (84.0 mg, 0.321 mmol) and iodomethane
(0.20 mL, 0.457 g, 3.21 mmol), stirring for 3 days at 60 ꢁC, with
hexane/ethyl acetate 1:1 as the solvent for flash chromatography to
give the title compound 51 (54.0 mg, 58%) as a yellow oil. Rf 0.67;
nmax(NaCl)/cmꢀ1 2924, 1452, 1273, 1194, 1102; dH(400 MHz; CDCl3)
1.29 (1H, dd, J¼12.6, 2.0 Hz, 9B-H), 1.38 (1H, tdd, J¼13.4, 6.3, 2.4 Hz,
8A-H),1.42 (1H, ddd, J¼12.6, 3.6, 3.6 Hz, 9A-H),1.63e1.67 (1H, m, 8B-
H), 1.88e1.94 (2H, m, 7B-H & 2A-H), 2.06 (1H, dd, J¼10.9, 2.9 Hz, 4A-
H), 2.09e2.18 (1H, m, 5-H), 2.68 (1H, d, J¼10.6 Hz, 2B-H), 2.70e2.80
(1H, m, 7A-H), 2.93 (2H, s, CH2OCH3), 3.16 (1H, d, J¼10.9 Hz, 4B-H),
3.22 (1H, d, J¼13.4 Hz, NCHAHBAr), 3.25 (3H, s, CH2OCH3), 3.33e3.40
(4H, m, C6OCH3 & 6-H), 3.57 (1H, d, J¼13.4 Hz, NCHAHBAr), 7.20e7.32
(5H, m, AreH); dC(100 MHz; CDCl3) 28.0 (C-7), 32.4 (C-5 & C-8), 34.8
(C-1), 35.0 (C-9), 53.3 (C-4), 55.7 (C6OCH3), 59.4 (CH2OCH3), 61.2 (C-
2), 63.6 (NCH2Ar), 81.7 (C-6), 82.1 (CH2OCH3), 126.5 (AreCH), 128.1
(AreCH), 128.6 (AreCH), 139.2 (AreC); m/z (FABþ) 290 (MHþ, 40%),
289 (Mþ, 41%), 288 (MꢀH, 100%), 258 (MꢀOCH3, 74%); found MHþ
290.2118, C18H28NO2 requires MHþ 290.2120. In a second fraction
was obtained alcohol 50 (20.0 mg, 23%).
4.5.4. (1S*,5S*,6S*)-3-Ethyl-6-hydroxy-1-methoxymethyl-3-
azabicyclo[3.3.1]nonane 54. The reaction was carried out according
to standard procedure E, using sodium hydride (27.0 mg,
0.675 mmol), diol 47 (45.0 mg, 0.226 mmol) and iodomethane
(0.28 mL, 0.282 mmol, 1 M in THF), stirring for 5 h at room tem-
perature, with 100% methanol as the solvent for flash chromatog-
raphy to give the title compound 54 (17.5 mg, 36%) as an orange oil.
Rf 0.47; nmax(NaCl)/cmꢀ1 3364, 2923, 1258, 1194, 1099, 1064;
dH(400 MHz; CDCl3) 1.07 (3H, t, J¼7.2 Hz, NCH2CH3), 1.25e1.44 (4H,
m, OeH, 9B-H, 8A-H & 9A-H),1.71e1.73 (1H, m, 8B-H),1.79e1.83 (1H,
m, 7B-H), 1.91e1.98 (3H, m, 5-H, 2A-H & 4A-H), 2.22e2.30 (2H, m,
NCH2CH3), 2.55e2.59 (1H, m, 7A-H), 2.82 (1H, d, J¼10.9 Hz, 2B-H),
2.99 (2H, s, CH2OCH3), 3.23 (1H, d, J¼10.8 Hz, 4B-H), 3.31 (3H, s,
OCH3), 3.82e3.87 (1H, m, 6-H); dC(100 MHz; CDCl3) 12.1
(NCH2CH3), 30.7 (C-7), 32.5 (C-8), 34.4 (C-9), 34.7 (C-1), 35.8 (C-5),
52.2 (C-4), 53.3 (NCH2CH3), 59.4 (OCH3), 61.0 (C-2), 72.4 (C-6), 81.9
(CH2OCH3); m/z (ESIþ) 214 (MHþ, 100%); found MHþ 214.1794,
C12H24NO2 requires MHþ 214.1802. In a second fraction was
obtained diether 52 (3.00 mg, 6%).
4.5.5. ((1S*,5S*,6S*)-3-Benzyl-6-methoxy-3-azabicyclo[3.3.1]nonan-
1-yl)methyl 4-methylbenzenesulfonate 55. To a solution of alcohol
32 (50.0 mg, 0.182 mmol) in dry DCM (2.9 mL) under an atmo-
4.5.2. (1S*,5S*,6S*)-3-Ethyl-6-methoxy-1-methoxymethyl-3-
azabicyclo[3.3.1]nonane 52. The reaction was carried out according
to standard procedure E, using sodium hydride (11.8 mg,
0.295 mmol), alcohol 46 (31.5 mg, 0.148 mmol) and iodomethane
sphere of nitrogen was added DMAP (2.00 mg, 18.2
uenesulfonyl chloride (0.104 g, 0.545 mmol) and triethylamine
(76 L, 55.0 mg, 0.545 mmol) and the mixture stirred at room
temperature for 3 days. The mixture was quenched by addition of
water (3 mL), separated and the aqueous residue extracted with
DCM (2ꢂ3 mL). The combined organics were washed with water
(6 mL), dried (MgSO4), filtered and the solvent removed under
reduced pressure. The crude product was purified by flash chro-
matography (hexane/ethyl acetate 1:1) to give the title compound
55 (62.5 mg, 80%) as a pale yellow oil. Rf 0.63; nmax(NaCl)/cmꢀ1
mmol), p-tol-
m
(46.0 mL, 0.105 g, 0.738 mmol), stirring for 3 days at room tem-
perature, with 100% ethyl acetate as the solvent for flash chro-
matography to give the title compound 52 (10.0 mg, 30%) as
a yellow oil. Rf 0.08; nmax(NaCl)/cmꢀ1 2907, 1194, 1100, 1121;
dH(300 MHz; CDCl3) 1.02 (3H, t, J¼7.2 Hz, NCH2CH3), 1.23e1.29
(1H, m, 9B-H), 1.31e1.45 (2H, m, 8A-H & 9A-H), 1.70e1.73 (1H, m,

5776
K.J. Goodall et al. / Tetrahedron 68 (2012) 5759e5778
2918, 1453, 1358, 1174, 1189, 1096, 960; dH(400 MHz; CDCl3)
1.23e1.36 (2H, m, 9B-H & 8A-H),1.38e1.42 (1H, m, 9A-H), 1.60 (1H,
dd, J¼10.9, 5.3 Hz, 8B-H), 1.80 (1H, dd, J¼10.7, 2.1 Hz, 2A-H),
1.85e2.02 (1H, m, 7B-H), 2.02 (1H, dd, J¼10.5, 2.1 Hz, 4A-H),
2.10e2.14 (1H, m, 5-H), 2.44 (3H, s, ArCH3), 2.60 (1H, d, J¼10.7 Hz,
228 (MꢀOCH3, 44%), 46 (100%); found Mþ 259.1943, C17H25NO
requires Mþ 259.1936.
4.5.8. (1S*,5S*,6S*)-3-Ethyl-6-methoxy-1-methyl-3-azabicyclo[3.3.1]
nonane 58. To a suspension of lithium aluminium hydride (13.5 mg,
0.354 mmol) in dry THF (1.15 mL) at 0 ꢁC under an atmosphere of
nitrogen was added dropwise a solution of tosylate 56 (26.0 mg,
2B-H), 2.68e2.72 (1H, m, 7A-H), 3.13e3.19 (2H, m, 4B-H
&
NCHAHBAr), 3.28e3.35 (4H, m, 6-H & OCH3), 3.52e3.57 (3H, m,
NCHAHBAr & OCH2), 7.19e7.32 (7H, m, AreH), 7.71 (2H, d, J¼8.3 Hz,
AreH); dC(100 MHz; CDCl3) 21.5 (ArCH3), 27.6 (C-7), 31.5 (C-8), 31.9
(C-5), 34.1 (C-9), 34.2 (C-1), 52.8 (C-4), 55.8 (OCH3), 60.1 (C-2), 63.3
(NCH2Ar), 77.6 (CH2OS), 80.9 (C-6), 126.7 (AreCH), 127.8 (AreCH),
128.1 (AreCH), 128.6 (AreCH), 129.7 (AreCH), 132.7 (AreC), 139.2
(AreC), 144.6 (AreC); m/z (EI) 429 (Mþ, 6%), 398 (MꢀOCH3, 55%),
91 (C6H5CH2, 100%); found Mþ 429.1976, C24H31NO4S requires Mþ
429.1974.
70.7
mmol) in dry THF (1.15 mL) and the mixture heated under
reflux for 2 h. The mixture was allowed to cool to room temperature
and stirred for 20 h before being heated under reflux for a further
3.5 h, then stirred at room temperature for another 2 h. The mixture
was then cooled to 0 ꢁC and quenched with sodium hydroxide
solution (1 M, five drops), dried (MgSO4), filtered and the volatiles
removed under reduced pressure. The crude product was purified
by flash chromatography (hexane/ethyl acetate 1:1) to give the title
compound 58 (1.5 mg, 11%) as an orange oil. Rf 0.06; nmax(NaCl)/
cmꢀ1 2925, 1252, 1159; dH(400 MHz; CDCl3) 1.02 (3H, t, J¼7.2 Hz,
NCH2CH3), 1.25e1.38 (3H, m, 9B-H, 8A-H & 9A-H), 1.58e1.63 (1H, m,
8B-H), 1.72e1.79 (2H, m, 2A-H & 7B-H), 1.86 (1H, dd, J¼10.9, 2.9 Hz,
4A-H), 2.04e2.10 (1H, m, 5-H), 2.15e2.24 (2H, m, NCH2CH3),
2.62e2.67 (1H, m, 7A-H), 2.70 (1H, d, J¼10.9 Hz, 2B-H), 3.10 (1H, d,
J¼10.7 Hz, 4B-H), 3.30e3.35 (4H, m, 6-H & OCH3); dC(100 MHz;
CDCl3) 12.5 (NCH2CH3), 28.1 (C-7), 28.8 (CCH3), 30.4 (C-1), 33.0 (C-
5), 37.3 (C-8), 40.1 (C-9), 52.3 (C-4), 52.6 (NCH2CH3), 55.8 (OCH3),
65.4 (C-2), 81.8 (C-6); m/z (ESIþ) 198 (MHþ, 100%); found MHþ
198.1859, C12H24NO requires MHþ 198.1852.
4.5.6. ((1S*,5S*,6S*)-3-Ethyl-6-methoxy-3-azabicyclo[3.3.1]nonan-1-
yl)methyl 4-methylbenzenesulfonate 56. To a solution of alcohol 46
(38.0 mg, 0.178 mmol) in dry DCM (2.85 mL) under an atmosphere
of nitrogen was added DMAP (2.00 mg, 17.8
mmol), p-toluene-
sulfonyl chloride (0.102 g, 0.534 mmol) and triethylamine (75
mL,
54.0 mg, 0.534 mmol) and the mixture stirred at room tempera-
ture for 5 days. The mixture was quenched by addition of water
(3 mL), separated and the aqueous residue extracted with DCM
(2ꢂ3 mL). The combined organics were washed with brine (6 mL),
dried (MgSO4), filtered and the solvent removed under reduced
pressure. The crude product was purified by flash chromatography
(hexane/ethyl acetate 1:1) to give the title compound 56 (26.0 mg,
40%) as an orange oil. Rf 0.14; nmax(NaCl)/cmꢀ1 2924, 1455, 1361,
1176, 1189, 1096, 955; dH(300 MHz; CDCl3) 0.98 (3H, t, J¼7.2 Hz,
NCH2CH3), 1.19e1.31 (2H, m, 9B-H & 8A-H), 1.36 (1H, ddd, J¼12.4,
3.6, 3.6 Hz, 9A-H), 1.66e1.71 (1H, m, 8B-H), 1.76e1.81 (2H, m, 7B-H
& 2A-H), 2.89 (1H, dd, J¼11.1, 2.9 Hz, 4A-H), 2.04e2.10 (1H, m, 5-H),
2.20 (2H, m, NCH2CH3), 2.45 (3H, s, ArCH3), 2.54e2.61 (1H, m, 7A-
H), 2.73 (1H, d, J¼10.6 Hz, 2B-H), 3.09 (1H, d, J¼11.1 Hz, 4B-H),
3.25e3.29 (1H, m, 6-H), 3.32 (3H, s, OCH3), 3.59e3.63 (2H, m,
OCH2), 7.35 (2H, d, J¼8.1 Hz, AreH), 7.77 (2H, d, J¼8.3 Hz, AreH);
dC(75 MHz; CDCl3) 12.3 (CH3, NCH2CH3), 21.6 (ArCH3), 27.4 (C-7),
31.9 (C-8), 32.0 (C-5), 34.3 (C-1), 34.4 (C-9), 52.2 (C-4), 52.4
(NCH2CH3), 55.9 (OCH3), 60.3 (C-2), 78.1 (CH2OS), 81.3 (C-6), 127.9
(AreCH), 129.8 (AreCH), 132.9 (AreC), 144.7 (AreC); m/z (ESIþ)
369 (MHþ, 100%); found MHþ 368.1889, C19H30NO4S requires MHþ
368.1890.
4.5.9. ((10S*,50S*,60S*)-30-Benzyl-60-methoxy-30-azabicyclo[3.3.1]
nonan-10-yl)methyl 2-aminobenzoate 60. The reaction was carried
out according to standard procedure L, using alcohol 32 (50.0 mg,
0.182 mmol) and acid 59 (84.0 mg, 0.363 mmol), with hexane/ethyl
acetate 2:1 as the solvent for flash chromatography to give the title
compound 60 (62.5 mg, 87%) as a yellow oil. Rf 0.47; nmax(NaCl)/
cmꢀ1 3476, 3375, 2917, 1689, 1487, 1455, 1243, 1161, 1100;
dH(400 MHz; CDCl3) 1.40 (1H, d, J¼13.7 Hz, 90B-H),1.46e1.51 (1H, m,
80A-H),1.51e1.58 (1H, m, 90A-H), 1.78 (1H, dd, J¼11.6, 5.8 Hz, 80B-H),
1.91e1.98 (1H, m, 70B-H), 2.00 (1H, dd, J¼10.8, 2.1 Hz, 20A-H), 2.08
(1H, dd, J¼10.8, 2.7 Hz, 40A-H), 2.14e2.20 (1H, m, 50-H), 2.75e2.84
(2H, m, 70A-H & 20B-H), 3.21 (1H, d, J¼10.8 Hz, 40B-H), 3.26 (1H, d,
J¼13.3 Hz, NCHAHBAr), 3.35 (3H, s, OCH3), 3.38e3.42 (1H, m, 60-H),
3.59 (1H, d, J¼13.3 Hz, NCHAHBAr), 3.82e3.90 (2H, m, C10eCH2Oe),
5.68 (2H, br s, NH2), 6.59e6.64 (2H, m, 3-H & 5-H), 7.20e7.33 (6H,
m, AreH & 4-H) 7.73 (1H, dd, J¼8.0, 1.4 Hz, 6-H); dC(100 MHz;
CDCl3) 27.8 (C-70), 32.2 (C-50), 32.3 (C-80), 34.3 (C-10), 34.9 (C-90),
53.0 (C-40), 55.7 (OCH3), 61.0 (C-20), 63.4 (NCH2Ar), 71.9
(C10eCH2O), 81.3 (C-60), 110.7 (C-1), 116.2 & 116.6 (C-3 & C-5), 126.6
(AreCH), 128.1 (AreCH), 128.7 (AreCH), 130.9 (C-6), 134.0 (C-4),
138.8 (AreC), 150.5 (C-2), 167.8 (C]O); m/z (EI) 394 (Mþ, 10%), 363
(MꢀOCH3, 52%), 137 (HOOCC6H4NH2, 64%), 120 (OCC6H4NH2,
100%); found Mþ 394.2249, C24H30N2O3 requires Mþ 394.2256.
4.5.7. (1S*,5S*,6S*)-3-Benzyl-6-methoxy-1-methyl-3-azabicyclo
[3.3.1]nonane 57. To a suspension of lithium aluminium hydride
(24.0 mg, 0.640 mmol) in dry THF (1.3 mL) at 0 ꢁC under an at-
mosphere of nitrogen was added dropwise a solution of tosylate 55
(55.0 mg, 0.128 mmol) in dry THF (1.3 mL) and the mixture heated
under reflux for 9 h, then allowed to cool to room temperature and
stirred for a further 15 h. The mixture was then cooled to 0 ꢁC and
quenched with sodium hydroxide solution (1 M, five drops), dried
(MgSO4), filtered and the volatiles removed under reduced pres-
sure. The crude product was purified by flash chromatography
(hexane/ethyl acetate 4:1) to give the title compound 57 (25.0 mg,
75%) as a pale yellow oil. Rf 0.54; nmax(NaCl)/cmꢀ1 2903, 1494, 1454,
1150, 1103; dH(400 MHz; CDCl3) 0.74 (3H, s, C1-CH3), 1.25e1.43 (3H,
m, 9B-H, 8A-H & 9A-H), 1.56e1.61 (1H, m, 8B-H), 1.74 (1H, dd, J¼10.7,
2.3 Hz, 2A-H), 1.82e1.89 (1H, m, 7B-H), 2.03 (1H, dd, J¼11.0, 2.9 Hz,
4A-H), 2.09e2.12 (1H, m, 5-H), 2.58 (1H, d, J¼10.7 Hz, 2B-
H),2.74e2.79 (1H, m, 7A-H), 3.14e3.18 (2H, m, NCHAHBAr & 4B-H),
3.33e3.39 (4H, m, OCH3 & 6-H), 3.58 (1H, d, J¼13.4 Hz, NCHAHBAr),
7.19e7.33 (5H, m, AreH); dC(100 MHz; CDCl3) 28.4 (C-7), 28.7
(CCH3), 30.5 (C-1), 33.1 (C-5), 37.1 (C-8), 40.0 (C-9), 53.1 (C-4), 55.8
(OCH3), 63.6 (NCH2Ar), 65.3 (C-2), 81.6 (C-6), 126.5 (AreCH), 128.1
(AreCH), 128.7 (AreCH), 139.3 (AreC); m/z (EI) 259 (Mþ, 18%),
4.5.10. ((10S*,50S*,60S*)-30-Ethyl-60-methoxy-30-azabicyclo[3.3.1]
nonan-10-yl)methyl 2-aminobenzoate 61. The reaction was carried
out according to standard procedure L, using alcohol 46 (39.0 mg,
0.183 mmol) and acid 59 (85.0 mg, 0.366 mmol), heating for 20 h,
with hexane/ethyl acetate 1:1 as the solvent for flash chromatog-
raphy to give the title compound 61 (36.4 mg, 60%) as a pale yellow
oil. Rf 0.21; nmax(NaCl)/cmꢀ1 3473, 3364, 2926, 1687, 1488, 1455,
1293, 1242, 1160, 1097; dH(400 MHz; CDCl3) 1.05 (3H, t, J¼7.2 Hz,
NCH2CH3), 1.38 (1H, d, J¼13.6 Hz, 90B-H), 1.43e1.49 (1H, m, 80A-H),
1.54 (1H, dt, J¼13.6, 3.3 Hz, 90A-H), 1.82e1.90 (2H, m, 80B-H & 70B-H),
1.99e2.04 (2H, m, 40A-H & 20A-H), 2.14e2.19 (1H, m, 50-H),
2.24e2.34 (2H, m, NCH2CH3), 2.60e2.66 (1H, m, 70A-H), 2.92 (1H, d,
J¼10.8 Hz, 20B-H), 3.16 (1H, d, J¼11.2 Hz, 40B-H), 3.34e3.41 (4H, m,
OCH3 & 60-H), 3.92 (2H, s, C10eCH2Oe), 5.68 (2H, br s, NH2),
6.63e6.68 (2H, m, 3-H & 5-H), 7.27 (1H, td, J¼7.6, 1.4 Hz, 4-H) 7.85

K.J. Goodall et al. / Tetrahedron 68 (2012) 5759e5778
5777
(1H, dd, J¼7.8, 1.4 Hz, 6-H); dC(100 MHz; CDCl3) 12.3 (NCH2CH3),
27.5 (C-70), 32.0 (C-50), 32.5 (C-80), 34.2 (C-10), 34.8 (C-90), 52.1 (C-
40), 52.6 (NCH2CH3), 55.8 (OCH3), 61.0 (C-20), 72.2 (C10eCH2O), 81.5
(C-60), 110.8 (C-1), 116.3 & 116.7 (C-3 & C-5), 131.0 (C-6), 134.1 (C-4),
150.5 (C-2), 168.0 (C]O); m/z (ESIþ) 333 (MHþ, 100%) found MHþ
333.2181, C19H29N2O3 requires MHþ 333.2173.
70), 32.4 (C-80), 33.3 (C-50), 34.0 (C-10), 35.0 (C-90), 52.4 (NCH2CH3),
52.7 (C-40), 61.6 (C-20), 71.9 (C10eCH2O), 74.9 (C-60), 110.6 (C-100),
111.4 (C-1), 116.2, 116.3, 116.6, 116.7 (C-500, C-5, C-300 & C-3), 131.0 (C-
6), 131.1 (C-600),133.9 (C-400), 134.1 (C-4), 150.4 (C-200), 150.5 (C-2),
167.5 (C60eOC]O), 167.9 (C10eCH2OC]O); m/z (ESIþ) 438 (MHþ,
100%); found MHþ 438.2397, C25H32N3O4 requires MHþ 438.2387
and (ii) ester 63a (35.0 mg, 44%) as a yellow oil. Rf 0.15; nmax(NaCl)/
cmꢀ1 3471, 3374, 2919, 1684, 1487, 1454, 1241, 1161, 1103;
dH(400 MHz; CDCl3) 1.06 (3H, t, J¼7.2 Hz, NCH2CH3), 1.43 (1H, d,
J¼10.8 Hz, 90B-H), 1.46e1.56 (2H, m, 80A-H & 90A-H), 1.82e1.87 (2H,
m, 80B-H & 70B-H),1.97e2.04 (3H, m, 40A-H, 20A-H & 5-H), 2.28 (2H, q,
J¼7.2 Hz, NCH2CH3), 2.61e2.68 (1H, m, 70A-H), 2.93 (1H, d,
J¼10.4 Hz, 20B-H), 3.27 (1H, d, J¼9.2 Hz, 40B-H), 3.85e3.92 (3H, m,
60-H & C10eCH2Oe), 5.73 (2H, br s, NH2), 6.64e6.68 (2H, m, 3-H & 5-
H), 7.27 (1H, td, J¼7.6, 1.8 Hz, 4-H) 7.85 (1H, dd, J¼8.2, 1.8 Hz, 6-H);
dC(100 MHz; CDCl3) 12.5 (NCH2CH3), 30.9 (C-70), 32.5 (C-80), 34.0
(C-10), 35.1 (C-90), 35.9 (C-50), 52.0 (C-40), 52.7 (NCH2CH3), 61.5 (C-
20), 72.1 (C10eCH2O), 72.5 (C-60), 110.7 (C-1), 116.3 & 116.7 (C-3 & C-
5), 131.0 (C-6), 134.1 (C-4), 150.5 (C-2), 168.5 (C]O); m/z (ESIþ) 319
(MHþ, 100%); found MHþ 319.2024, C18H27N2O3 requires MHþ
319.2016.
4.5.11. ((10S*,50S*,60S*)-30-Benzyl-60-hydroxy-30-azabicyclo[3.3.1]
nonan-10-yl)methyl 2-aminobenzoate 62a and (100S*,500S*,600S*)-(600-
((20-aminobenzoyl)oxy)-300-benzyl-300-azabicyclo[3.3.1]nonan-100-yl)
methyl 2-aminobenzoate 62b. The reaction was carried out
according to standard procedure L, using alcohol 37 (34.0 mg,
0.130 mmol) and acid 59 (38.0 mg, 0.163 mmol), heating for 21 h,
with hexane/ethyl acetate 2:1 as the solvent for flash chromatog-
raphy to give (i) diester 62b (13.0 mg, 20%) as an orange oil. Rf 0.47;
nmax(NaCl)/cmꢀ1 3485, 3375, 2932, 1683, 1487, 1454, 1239, 1161,
1101; dH(400 MHz; CDCl3) 1.56e1.71 (3H, m, 90B-H, 90A-H & 80A-H),
1.93e2.06 (3H, m, 80B-H, 40A-H & 70B-H), 2.15e2.20 (1H, m, 50-H),
2.26 (1H, dd, J¼10.8, 2.4 Hz, 20A-H), 3.01e3.17 (2H, m, 20B-H & 70A
-
H), 3.20e3.27 (2H, m, 40B-H & NCHAHBAr), 3.68 (1H, d, J¼13.2 Hz,
NCHAHBAr), 3.96 (2H, s, C10eCH2Oe), 5.20e5.25 (1H, m, 60-H), 5.63
& 5.72 (4H, br s, 2ꢂ NH2), 6.53e6.72 (4H, m, 300-H, 500-H, 3-H & 5-H),
7.19e7.40 (7H, m, 400-H, 4-H & AreH), 7.53 (1H, dd, J¼8.1, 1.2 Hz, 600-
H), 7.84 (1H, dd, J¼8.4, 1.5 Hz, 6-H); dC(100 MHz; CDCl3) 27.3 (C-70),
32.4 (C-80), 33.3 (C-10), 34.3 (C-50), 35.0 (C-90), 52.9 (C-40), 62.5 (C-
20), 63.7 (NCH2Ar), 71.9 (C10eCH2O), 74.3 (C-60),110.7 (C-1),111.3 (C-
100),116.2 (C-500),116.3 (C-5),116.5 (C-300),116.7 (C-3),126.8 (AreCH),
128.3 (AreCH),128.8 (AreCH),131.0 (C-6),131.4 (C-600),133.9 (C-400),
134.2 (C-4), 139.0 (AreC), 150.4 (C-200), 150.6 (Cþ-2), 167.4 (C60eOC]
O), 167.9 (C10eCH2OC]O); m/z (ESIþ) 500 (MH , 100%); found MHþ
500.2541, C30H34N3O4 requires MHþ 500.2544 and (ii) ester 62a
(20.0 mg, 40%) as a yellow oil. Rf 0.34; nmax(NaCl)/cmꢀ1 3485 & 3373
(NeH), 2912, 1686, 1487 & 1454, 1241 (CeO), 1161 & 1104;
dH(300 MHz; CDCl3) 1.40 (1H, d, J¼12.0 Hz, 90B-H),1.50e1.60 (2H, m,
80A-H & 90A-H),1.82 (1H, dd, J¼13.6, 6.6 Hz, 80B-H),1.90e1.98 (1H, m,
4.5.13. ((10S*,50S*,60S*)-30-Benzyl-60-methoxy-30-azabicyclo[3.3.1]
nonan-10-yl)methyl 2-acetaminobenzoate 64. The reaction was
carried out according to standard procedure M, using anthranilate
60 (42.0 mg, 0.107 mmol), stirring for 4 days with hexane/ethyl
acetate 2:1 as the solvent for flash chromatography to give the title
compound 64 (28.3 mg, 61%) as a yellow oil. Rf 0.35; nmax(NaCl)/
cmꢀ1 3317, 3278, 2925, 1700, 1685, 1526, 1448, 1258, 1237, 1144,
1086; dH(400 MHz; CDCl3) 1.42 (1H, d, J¼13.9 Hz, 90B-H), 1.47e1.52
(1H, m, 80A-H), 1.56 (1H, ddd, J¼13.9, 3.3, 3.3 Hz, 90A-H), 1.78e1.82
(1H, m, 80B-H), 1.94e2.02 (2H, m, 70B-H & 20A-H), 2.11 (1H, dd,
J¼11.0, 2.6 Hz, 40A-H), 2.19e2.24 (4H, m, 50-H & CCH3), 2.75e2.85
(2H, m, 70A-H & 20B-H), 3.21e3.28 (2H, m, 40B-H & NCHAHBAr),
3.35e3.45 (4H, m, OCH3 & 60-H), 3.62 (1H, d, J¼13.3 Hz, NCHAH-
BAr), 3.91 (2H, br s, C10eCH2Oe), 7.05 (1H, td, J¼8.0, 1.0 Hz, 5-H),
7.23e7.32 (5H, m, AreH), 7.54 (1H, td, J¼8.0, 1.2 Hz, 4-H), 7.87 (1H,
dd, J¼8.0, 1.2 Hz, 6-H), 8.69 (1H, dd, J¼8.0, 1.0 Hz, 3-H), 11.02 (1H,
br s, NeH); dC(100 MHz; CDCl3) 25.5 (CCH3), 27.8 (C-70), 32.2 (C-50),
32.3 (C-80), 34.4 (C-10), 34.9 (C-90), 53.0 (C-40), 55.8 (OCH3), 60.8 (C-
20), 63.4 (NCH2Ar), 72.9 (C10eCH2O), 81.2 (C-60), 114.8 (C-1), 120.3
(C-3), 122.4 (C-5), 126.7 (AreCH), 128.1 (AreCH), 128.7 (AreCH),
130.5 (C-6), 134.6 (C-4), 138.7 (AreC), 141.6 (C-2), 168.1 (OC]O),
169.0 (NC]O); m/z (EI) 436 (Mþ, 17%), 405 (MꢀOCH3, 88%), 91
(C6H5CH2, 100%); found Mþ 436.2355, C26H32N2O4 requires Mþ
436.2362.
70B-H), 1.99e2.03 (1H, m, 50-H), 2.04e2.12 (2H, m, 40A-H & 20A
-
H),2.72e2.80 (1H, m, 70A-H), 2.89 (1H, d, J¼10.5 Hz, 20B-H), 3.19 (1H,
d, J¼11.4 Hz, 40B-H), 3.39 (1H, d, J¼13.2 Hz, NCHAHBAr), 3.45 (1H, d,
J¼13.2 Hz, NCHAHBAr), 3.83e3.93 (3H, m, 60-H & C10eCH2Oe), 5.69
(2H, br s, NH2), 6.60e6.66 (2H, m, 3-H & 5-H), 7.20e7.36 (6H, m,
AreH & 4-H) 7.77 (1H, dd, J¼8.4, 1.2 Hz, 6-H); dC(400 MHz; CDCl3)
31.2 (C-70), 32.4 (C-80), 34.1 (C-10), 35.0 (C-90), 35.9 (C-50), 52.4 (C-
40), 61.6 (C-20), 63.6 (NCH2Ar), 71.9 (C10eCH2O), 72.5 (C-60), 110.7 (C-
1), 116.2 & 116.7 (C-3 & C-5), 126.9 (AreCH), 128.2 (AreCH), 128.7
(AreCH), 131.0 (C-6), 134.1 (C-4), 138.9 (AreC), 150.5 (C-2), 167.9
(C]O); m/z (ESIþ) 381 (MHþ, 100%); found MHþ 381.2181,
C23H29N2O3 requires MHþ 381.2173.
4.5.14. ((10S*,50S*,60S*)-30-Ethyl-60-methoxy-30-azabicyclo[3.3.1]
nonan-10-yl)methyl 2-acetaminobenzoate 65. The reaction was car-
ried out according to standard procedure M, using anthranilate 61
4.5.12. ((10S*,50S*,60S*)-30-Ethyl-60-hydroxy-30-azabicyclo[3.3.1]
nonan-10-yl)methyl 2-aminobenzoate 63a and (100S*,500S*,600S*)-(600-
((20-aminobenzoyl)oxy)-300-ethyl-300-azabicyclo[3.3.1]nonan-100-yl)
methyl 2-aminobenzoate 63b. The reaction was carried out
according to standard procedure L, using alcohol 47 (50.0 mg,
0.251 mmol) and acid 59 (73.0 mg, 0.314 mmol), heating for 21 h,
with hexane/ethyl acetate 3:1 as the solvent for flash chromatog-
raphy to give (i) diester 63b (39.5 mg, 36%) as a yellow oil. Rf 0.80;
nmax(NaCl)/cmꢀ1 3480, 3372, 2929, 1683, 1487, 1454, 1237, 1160,
1100; dH(400 MHz; CDCl3) 1.10 (3H, t, J¼7.2 Hz, NCH2CH3),
1.56e1.65 (3H, m, 900B-H, 90A-H & 80A-H), 1.90e1.98 (2H, m, 80B-H &
70B-H), 2.02 (1H, dd, J¼11.2, 2.4 Hz, 40A-H), 2.08 (1H, dd, J¼10.8,
2.4 Hz, 20A-H), 2.20e2.24 (1H, m, 50-H), 2.27e2.35 (2H, m,
NCH2CH3), 2.93e3.04 (2H, m, 20B-H & 70A-H), 3.32 (1H, d, J¼10.8 Hz,
40B-H), 3.94 (2H, s, C10eCH2Oe), 5.18e5.20 (1H, m, 60-H), 5.74 (4H,
br s, 2ꢂ NH2), 6.64e6.70 (4H, m, 300-H, 500-H, 3-H & 5-H), 7.23e7.30
(2H, m, 400-H & 4-H), 7.87 (1H, dd, J¼8.4, 1.2 Hz, 6-H), 7.91 (1H, dd,
J¼8.2, 1.4 Hz, 600-H); dC(100 MHz; CDCl3) 12.5 (NCH2CH3), 27.0 (C-
(27.5 mg, 82.7 mmol) stirring for 4 h with 100% ethyl acetate as the
solvent for flash chromatography to give the title compound 65
(16.0 mg, 52%) (Rf 0.29) as a pale yellow oil. nmax(NaCl)/cmꢀ1 3316,
3282, 2923, 1704, 1684, 1525, 1447, 1257, 1236, 1145, 1086;
dH(300 MHz; CDCl3) 1.05 (3H, t, J¼7.2 Hz, NCH2CH3), 1.39 (1H, dd,
J¼12.5, 1.7 Hz, 90B-H), 1.44e1.57 (2H, m, 80A-H & 90A-H), 1.82e1.92
(2H, m, 80B-H & 70B-H), 1.94e2.02 (2H, m, 40A-H & 20A-H), 2.13e2.19
(1H, m, 50-H), 2.21e2.36 (5H, m, CCH3 & NCH2CH3), 2.64e2.70 (1H,
m, 70A-H), 2.92 (1H, d, J¼10.3 Hz, 20B-H), 3.18 (1H, d, J¼11.1 Hz, 40B-
H), 3.34e3.43 (4H, m, OCH3 & 60-H), 3.96 (2H, s, C10eCH2Oe), 7.10
(1H, td, J¼7.7, 1.3 Hz, 5-H), 7.55 (1H, td, J¼7.7, 1.6 Hz, 4-H), 8.02 (1H,
dd, J¼7.7, 1.6 Hz, 6-H), 8.71 (1H, dd, J¼7.7, 1.3 Hz, 3-H), 11.05 (1H, br
s, NeH); dC(75 MHz; CDCl3) 12.4 (NCH2CH3), 25.5 (NHC(]O)CH3),
27.6 (C-70), 32.1 (C-50), 32.5 (C-80), 34.3 (C-10), 35.0 (C-90), 52.2 (C-
40), 52.6 (NCH2CH3), 55.9 (OCH3), 61.2 (C-20), 73.2 (C10eCH2O), 81.5
(C-60), 114.9 (C-1), 120.4 (C-3), 122.4 (C-5), 130.5 (C-6), 134.7 (C-4),

5778
K.J. Goodall et al. / Tetrahedron 68 (2012) 5759e5778
141.7 (C-2), 168.2 (OC]O), 169.0 (NC]O); m/z (ESIþ) 375 (MHþ,
Supplementary data
100%); found MHþ 375.2288, C21H31N2O4 requires MHþ 375.2275.
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2012.05.037. These data in-
clude MOL files and InChiKeys of the most important compounds
described in this article.
4.5.15. ((10S*,50S*,60S*)-30-Benzyl-60-hydroxy-30-azabicyclo[3.3.1]
nonan-10-yl)methyl 2-acetaminobenzoate 66. The reaction was car-
ried out according to standard procedure M, using anthranilate 62a
(9.0 mg, 23.7 mmol) stirring for 4 h with hexane/ethyl acetate 1:1 as
the solvent for flash chromatography to give the title compound 66
(5.0 mg, 50%) as a colourless oil. Rf 0.35; nmax(NaCl)/cmꢀ1 3392,
3314, 3273, 2921, 1683, 1526, 1449, 1260, 1242, 1145, 1089;
dH(400 MHz; CDCl3) 1.46 (1H, d, J¼12.7 Hz, 90B-H),1.50e1.59 (2H, m,
80A-H & 90A-H), 1.83 (1H, dd, J¼13.8, 6.6 Hz, 80B-H),1.93e1.99 (1H, m,
70B-H), 2.00e2.05 (1H, m, 50-H), 2.07e2.12 (2H, m, 40A-H & 20A-H),
2.22 (3H, s, CCH3), 2.73e2.80 (1H, m, 70A-H), 2.89 (1H, d, J¼10.8 Hz,
20B-H), 3.22 (1H, d, J¼11.3 Hz, 40B-H), 3.44 (2H, m, NCH2Ar),
3.86e3.93 (1H, m, 60-H), 3.94 (2H, s, C10eCH2Oe), 7.07 (1H, t,
J¼7.2 Hz, 5-H), 7.22e7.35 (5H, m, AreH), 7.55 (1H, td, J¼7.2, 1.6 Hz,
4-H), 7.91 (1H, dd, J¼7.2, 1.6 Hz, 6-H), 8.70 (1H, d, J¼7.2 Hz, 3-H),
11.02 (1H, br s, NeH); dC(100 MHz; CDCl3) 25.5 (CCH3), 31.2 (C-70),
32.5 (C-80), 34.2 (C-10), 35.0 (C-90), 35.9 (C-50), 52.5 (C-40), 61.5 (C-
20), 63.6 (NCH2Ar), 72.4 (C-60), 72.9 (C10eCH2O), 114.8 (C-1), 120.4
(C-3), 122.4 (C-5), 127.0 (AreCH), 128.3 (AreC), 128.7 (2ꢂ AreCH),
130.5 (C-6), 134.7 (C-4), 138.8 (AreC), 141.7 (C-2), 168.1 (OC]O),
169.1 (NC]O); m/z (ESIþ) 423 (MHþ, 100%); found MHþ 423.2280,
C25H31N2O4 requires MHþ 423.2278.
References and notes
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nonan-10-yl)methyl 2-acetaminobenzoate 67. The reaction was car-
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(22.0 mg, 69.1 mmol) stirring for 2 h with DCM/methanol 9:1 as the
solvent for flash chromatography to give the title compound 67
(15.5 mg, 62%) as an orange oil. Rf 0.39; nmax(NaCl)/cmꢀ1 3423, 3314,
3273, 2925, 1728, 1685, 1526, 1448, 1258, 1239, 1145, 1088;
dH(400 MHz; CDCl3) 1.07 (3H, t, J¼7.2 Hz, NCH2CH3), 1.44 (1H, dd,
J¼12.5, 1.9 Hz, 90B-H), 1.49e1.67 (3H, m, 90A-H, 80A-H & OeH),
1.82e1.89 (2H, m, 80B-H & 70B-H), 1.99e2.05 (3H, m, 40A-H, 50-H &
20A-H), 2.23 (3H, s, CCH3), 2.53 (2H, q, J¼7.2, NCH2CH3), 2.86e2.95
(2H, m, 70A-H & 20B-H), 3.29 (1H, d, J¼9.9 Hz, 40B-H),3.86e3.92 (1H,
m, 60-H), 3.97 (2H, s, C10eCH2Oe), 7.11 (1H, td, J¼7.9, 1.3 Hz, 5-H),
7.56 (1H, td, J¼7.9, 1.6 Hz, 4-H), 8.01 (1H, dd, J¼7.9, 1.7 Hz, 6-H), 8.71
(1H, dd, J 7.9, 1.3 Hz, 3-H), 11.04 (1H, br s, NeH); dC(100 MHz; CDCl3)
12.4 (NCH2CH3), 25.5 (CCH3), 30.8 (C-70), 32.5 (C-80), 34.1 (C-10), 35.1
(C-90), 35.8 (C-50), 52.0 (C-40), 52.7 (NCH2CH3), 61.4 (C-20), 72.5 (C-
60), 73.1 (C10eCH2O), 114.9 (C-1), 120.4 (C-3), 122.5 (C-5), 130.5 (C-
6), 134.7 (C-4), 141.7 (C-2), 168.2 (OC]O), 169.1 (NC]O); m/z (ESIþ)
361 (MHþ, 100%); found MHþ 361.2128, C20H29N2O4 requires MHþ
361.2122.
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Acknowledgements
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We are grateful for financial support from The University of
Auckland for a Doctoral Scholarship (K.J.G.).
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