Efficient synthesis of the azabicyclo[3.3.1]nonane ring system in the alkaloid methyllycaconitine using bis(alkoxymethyl)alkylamines as aminoalkylating agents in a double Mannich reaction

Article abstract of DOI:10.1002/ejoc.200500003

The double Mannich reaction of cyclic β-keto esters with bis-(alkoxymethyl)alkylamines provides an efficient and versatile method for the construction of azabicyclo[3.3.1]nonanes and azabicyclo[3.2.1]octanes. The optimum conditions for efficient reaction involve use of the activator trichloromethylsilane in acetonitrile as solvent at ambient temperature. The utility of this synthetic method is further demonstrated by the facile synthesis of several AE ring analogues 39, 42 of the alkaloid methyllycaconitine by appendage of the key N-(methylsuccininimido)anthranilate pharmacophore to the N-(3-phenylpropyl)-substituted double Mannich adducts 18, 27. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005.

Full text of DOI:10.1002/ejoc.200500003

FULL PAPER
Efficient Synthesis of the Azabicyclo[3.3.1]nonane Ring System in the Alkaloid
Methyllycaconitine Using Bis(alkoxymethyl)alkylamines as Aminoalkylating
Agents in a Double Mannich Reaction
Margaret A. Brimble*[a] and Constanze Brocke[a]
Keywords: Alkaloids / Mannich bases / Aminoalkylation / Synthetic methods
The double Mannich reaction of cyclic β-keto esters with bis-
(alkoxymethyl)alkylamines provides an efficient and versa-
tile method for the construction of azabicyclo[3.3.1]nonanes
and azabicyclo[3.2.1]octanes. The optimum conditions for ef-
ficient reaction involve use of the activator trichloromethylsil-
ane in acetonitrile as solvent at ambient temperature. The
utility of this synthetic method is further demonstrated by the
facile synthesis of several AE ring analogues 39, 42 of the
alkaloid methyllycaconitine by appendage of the key N-
(methylsuccininimido)anthranilate pharmacophore to the N-
(3-phenylpropyl)-substituted double Mannich adducts 18,
27.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
Introduction
The Mannich reaction is a versatile method for the syn-
thesis of β-amino ketones and esters which are key synthetic
intermediates for the construction of nitrogen containing
natural products.[1] The inter- and intramolecular version
of the Mannich reaction provides a powerful method for
the preparation of azacyclic products from acyclic precur-
sors and has formed the crucial step in a number of synthe-
ses of alkaloids.[2] As part of a synthetic programme di-
rected towards the synthesis of simpler bicyclic AE and tri-
cyclic ABE analogues of the complex alkaloid methyllyca-
conitine (MLA, 1) (Figure 1)[3] we made use of a classical
double Mannich reaction to construct the azabicyclo[3.3.1]-
nonane AE ring system.[4] The classical Mannich reaction
involved heating a β-keto ester with aqueous formaldehyde
in the presence of ethylamine as base, however, we like
others,[5] found this procedure only proceeded in low yield
and the reaction could not be readily extended to the use
of alternative primary amines thus limiting our analogue
development programme.
Figure 1. Structure of the alkaloid methyllycaconitine (MLA) illus-
trating the ABE rings.
the 3-phenylpropyl-substituted double Mannich adducts 18,
27 to the AE analogues 39, 42 of methyllycaconitine.
Results and Discussion
The bis(alkoxymethyl)alkylamines 2–9 (Table 1) were
prepared by reaction of the appropriate amine (1.0 equiv.)
with paraformaldehyde (2.0 equiv.) and potassium carbon-
ate (1.0 equiv.) in the presence of excess ethanol.[8–11] Purifi-
cation by vacuum distillation gave the desired products as
colourless oils.
Prompted by the report by Heaney and Papageorgiou[6]
on the use of bis(alkoxymethyl)alkylamines derived from
primary amines as bis(amino)alkylating agents for use in
the synthesis of tertiary amines, we herein report the full
details[7] of our study on the bis(amino)alkylation of cyclic
β-keto esters using bis(alkoxymethyl)alkylamines as an ef-
ficient entry to azabicyclo[3.3.1]nonanes and azabicy-
clo[3.2.1]octanes. Furthermore we report the conversion of
Previous studies[6] on Mannich reactions of bis(alkoxy-
methyl)alkylamines with aromatic nucleophiles provided a
number of acidic reagents suitable for activation, including
acetyl chloride, trifluoroacetic anhydride, sulfur dioxide and
titanium tetrachloride. In these cases, both secondary and
tertiary amines were isolated as products. Higher yields of
secondary amines were obtained using hydrogen chloride in
ether, whereas chlorosilane derivatives promoted the forma-
tion of tertiary amines. In order to establish a procedure for
double Mannich reactions of bis(alkoxymethyl)alkylamines
affording bicyclic tertiary amines, a model reaction of N,N-
bis(ethoxymethyl)benzylamine (7)[6] with ethyl 2-oxocy-
[a] Department of Chemistry, The University of Auckland,
23 Symonds St., Auckland, New Zealand
Fax: +64-9-373599-88259
E-mail: m.brimble@auckland.ac.nz
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DOI: 10.1002/ejoc.200500003
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M. A. Brimble, C. Brocke
FULL PAPER
Table 1. Synthesis of bis(alkoxymethyl)alkylamines 2–9.
amines was achieved in 75% yield, with the less-hindered
bicyclic systems such as the N-butyl, N-(2-phenylethyl) and
N-(3-phenylpropyl) derivatives being formed quantitatively.
Table 3. Synthesis of 3-azabicyclo[3.3.1]nonanes from bis(alkoxy-
methyl)alkylamines using a double Mannich reaction.
Entry
1
R
Product
Yield Boiling point
105–110 °C/
47%
Et
2
100 Torr[6]
2
3
4
5
6
7
8
iPr
nBu
tBu
cyclohexyl
benzyl
2-phenylethyl
3-phenylpropyl
3
4
5
6
7
8
9
29%
28%
42%
24%
27%
11%
40%
66–72 °C/16 Torr[6]
66–68 °C/5.3 Torr[6]
73–76 °C/16 Torr
112–118 °C/10 Torr
90 °C/0.75 Torr[6]
110 °C/3.5 Torr[12]
80 °C/0.34 Torr
En- Bis(alkoxymethyl)-
R
Product Yield (%)
try
alkylamine
clohexanecarboxylate (10) was investigated. A summary of
the different activators used to prepare the bicyclic adduct
11 through a double Mannich reaction is provided
(Table 2). Superior results were obtained using trichlorome-
thylsilane as the promoter. Mannich adduct 11 was isolated
in 75% yield by treatment of β-keto ester 10 with the bis-
(alkoxymethyl)alkylamine 7 (2.0 equiv.) and trichloro-
methylsilane (2.0 equiv.) in acetonitrile at room temperature
for 20 h (Entry 8, Table 2).
1
2
3
4
5
6
7
2
3
4
5
6
8
9
Et
iPr
nBu
tBu
cyclohexyl
2-phenylethyl
3-phenylpropyl
12[5c]
13
92
75
Ͼ99
Ͼ99
92
Ͼ99
Ͼ99
14
15
16
17
18
The double Mannich reaction was also applied to the
synthesis of smaller N-substituted 3-azabicyclo[3.2.1]octane
derivatives by reaction of the β-keto ester 19 with bis-
(alkoxymethyl)alkylamines 2–9 (Table 4). In this case, the
bicyclic products 20–27 were isolated in most cases in an
average yield of 80–90%, regardless of the size of the sub-
stituent attached to nitrogen.
Table 2. Optimization of the double Mannich reaction of bis-
(alkoxymethyl)alkylamine 7 with β-keto ester 10.
Table 4. Synthesis of 3-azabicyclo[3.2.1]octanes from bis(alkoxyme-
thyl)alkylamines using a double Mannich reaction.
Entry
Activator
Equiv. of
Activator
Equiv. of Yield of 11
7
(%)
1
2
3
4
5
6
7
8
9
Me3SiCl
Me3SiOTf
Sc(OTf)3
AlCl3
1.1
1.1
0.1
1.1
0.25
1.0
2.0
2.0
4.0
1.1
1.1
1.1
1.1
1.1
1.1
1.1
2.0
4.0
–
–
7
19
22
66
64
75
53
En- Bis(alkoxymethyl)-
R
Product Yield (%)
TiCl4
try
alkylamine
MeSiCl3
MeSiCl3
MeSiCl3
MeSiCl3
1
2
3
4
5
6
7
8
2
3
4
5
6
7
8
9
Et
iPr
nBu
tBu
cyclohexyl
benzyl
2-phenylethyl
3-phenylpropyl
20
21
22
23
24
25
26
27
56
81
97
89
83
83
81
84
A variety of N-substituted 3-azabicyclo[3.3.1]nonane de-
rivatives were prepared following these optimized condi-
tions (Table 3). Use of several bis(alkoxymethyl)alkylamines
2–6, 8, 9 afforded the corresponding double Mannich prod-
Finally, the formation of azabicyclic ring systems con-
ucts 12–18 in good yield after purification by flash taining two quaternary centres at the points of ring fusion
chromatography. Conversion of the more sterically de- was investigated. The allyl-substituted cyclohexanone and
manding N-isopropyl- and N-benzylbis(alkoxymethyl)- cyclopentanone derivatives 28[13] and 29[13,14] were con-
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Synthesis of the Azabicyclo[3.3.1]nonane Ring System by a Double Mannich Reaction
FULL PAPER
verted into the corresponding bicyclic amines in good yield
Reduction of 18 with lithium aluminium hydride in THF
(Table 5). In the case of the cyclohexanone precursor, the gave the corresponding diol as a mixture of diastereomers
allyl derivative 28 gave ca. 20% lower yields of the bicyclic 33a and 33b, which could be separated by flash chromatog-
products 30 and 31 than the unsubstituted analogues 11 raphy (Scheme 1). The stereoisomers were formed in an
and 18. In contrast, the yield of the allylated bicyclic pro- overall yield of 65% in a ratio of 33a:33b = 3.2:1, favouring
duct 32 derived from cyclopentanone precursor 29 was in- the diastereomer containing the equatorial hydroxy group
creased by ca. 20% compared to 20.
vs. the axial isomer. Evidence for this stereochemistry was
obtained by H NMR NOESY experiments showing NOE
1
effects between 9-H and 2-Hax in the case of diastereomer
33a, whereas NOEs between 9-H and 6-Hax as well as 8-Hax
were observed for the other diastereomer 33b (Figure 2).
Table 5. Application of the double Mannich reaction to the synthe-
sis of allyl-substituted 3-azabicyclic compounds.
Entry Starting Bis(alkoxymethyl)-
R
Product
Yield
(%)
material
alkylamine
1
2
3
28
28
29
7
9
2
benzyl
30 (n = 2) 58%
3-phenylpropyl 31 (n = 2) 77%
ethyl 32 (n = 1) 75%
The results described above demonstrate that double
Scheme 1.
Mannich reactions carried out using preformed bis(alkoxy-
methyl)alkylamines provides a powerful tool for the synthe-
sis of azabicyclic N-substituted ring systems in high yields.
The use of mild reaction conditions involving activation of
the bis(alkoxymethyl)alkylamines with trichloromethylsil-
ane at room temperature affords significantly improved
yields compared to conventional aminomethylation proto-
cols using a refluxing mixture of primary amine and form-
aldehyde. By applying this new methodology, the yield for
the formation of compound 12[5c] was increased from 47%
to 92%, with compound 11 being prepared in 75% rather
than 30% yield.
We next focused on the synthesis of biologically active
AE ring mimics of methyllycaconitine, in which the key
pharmacophore, the N-substituted anthranilate ester is at-
tached to the bicyclic AE ring system that in turn is readily
prepared using the double Mannich reaction described
Figure 2. NOE effects observed for the diastereomers 33a and 33b.
In the case of compound 33a, no interactions were detected be-
tween 9-H and 6-Hax or 8-Hax, while compound 33b showed no
NOE between 9-H and 2-Hax.
Alternatively, comparison of the 13C NMR spectroscopic
above. The use of several different preformed bis(alkoxy- data of the alcohols 33a and 33b can be used to determine
methyl)alkylamines allows the incorporation of various the stereochemistry of the 9-hydroxy group. The 9-OH has
substituents at the ring nitrogen atom, thus providing access a shielding effect on the carbon atoms in the bicyclic ring
to a library of bicyclic AE ring analogues of methyllycacon- structure that are syn to the hydroxy group. This γ-gauche
itine. Studies on the nicotine-stimulated catecholamine re- effect has been extensively studied in 3-azabicyclo[3.3.1]-
lease by nicotinic antagonists have shown that analogues of nonane ring systems.[16] The chemical shifts of the ring car-
methyllycaconitine, in which the N-ethyl group is replaced bons that are syn to the hydroxy group are shifted upfield
by a 3-phenylpropyl group, are more efficient than the cor- when compared to the chemical shifts of the non-hydroxy
responding N-ethyl-substituted compounds.[15] Therefore, ring system. Both diastereomers 33a and 33b exhibit similar
the N-(3-phenylpropyl)-substituted bicyclic compounds 18, C-7 shifts consistent with a chair-chair conformation of the
27 were chosen as starting materials for further elaboration azabicyclo[3.3.1]nonane ring system as depicted (Figure 2).
to include the N-substituted anthranilate pharmacophore.
The resonances assigned to C-6 and C-8 of the azabicy-
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M. A. Brimble, C. Brocke
FULL PAPER
clo[3.3.1]nonane ring are shifted 6.8 ppm and 7.0 ppm up-
field, respectively, in 33a compared to 33b, due to the
shielding γ-effect of the 9-hydroxy group (Table 6). Consis-
tent with this analysis, the chemical shifts of C-2 and C-4
appear upfield in 33b relative to 33a.
Table 6. Selected 13C NMR chemical shifts δ (ppm) of the 9-hy-
droxyazabicyclo[3.3.1]nonane diastereomers 33a and 33b.
Carbon atom
Diastereomer 33a
Diastereomer 33b
C-2
C-4
C-6
C-7
60.9
58.7
23.9
20.6
54.9
52.4
30.7
19.6
The ester side-chain was then introduced by condensing
diol 33a with one equiv. of N-(trifluoroacetyl)anthranilic
acid (34),[17] followed by reductive cleavage of the N-pro-
tecting group.[18] The condensation was carried out under
Steglich conditions,[19] with the reaction occurring predomi-
nantly at the primary hydroxy function (Scheme 2). After
deprotection with sodium borohydride and subsequent
flash chromatography, the corresponding ester 35 was iso-
lated in 30% yield (over two steps). However, the regioisom-
eric ester 36, derived from the secondary alcohol, also
formed as a by-product in 6% yield together with diester
37 in 19% yield.
Scheme 2.
In the final step, the condensation of the aromatic amine
with methylsuccinic anhydride was planned in order to ob-
tain the AE ring analogues of methyllycaconitine. Recent
structure-activity studies have established that the methyl
group of the succinimido moiety is crucial for the binding
affinity of methyllycaconitine analogues, although a change
in the absolute configuration of this methyl group has no
significant effect.[20] The fusion of the amine 35 with race-
mic methylsuccinic anhydride was carried out as a melt at
125 °C.[21] Under these conditions, the methylsuccinic imide
was formed, however, excess reagent also reacted with the
secondary hydroxy group to produce the corresponding es-
ters 38a and 38b (Scheme 3). After purification by flash
chromatography, an inseparable mixture of regioisomers
38a and 38b was obtained in 47% yield. The same reaction
conditions were then used for fusion of the diester 37 with
methylsuccinic anhydride, resulting in the formation of the
methyllycaconitine analogue 39. This compound, which
contains two pharmacophoric units as well as the aza-
bicyclic AE methyllycaconitine core structure, was isolated
in 93% yield after flash chromatography (Scheme 4).
Scheme 3.
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Synthesis of the Azabicyclo[3.3.1]nonane Ring System by a Double Mannich Reaction
FULL PAPER
Conclusions
In conclusion, a novel double Mannich reaction has been
successfully used as the key step in the synthesis of two
methyllycaconitine analogues 39 and 42, that both contain
an azabicyclic AE ring system as well as the crucial N-
(methylsuccinimido)anthranilate pharmacophore. For the
preparation of the bicyclic AE ring precursor, a novel inter-
and intramolecular double Mannich reaction has been es-
tablished using preformed bis(alkoxymethyl)alkylamines as
bis(amino)alkylating reagents. The use of mild reaction
conditions involving activation of the bis(alkoxymethyl)al-
kylamines with trichloromethylsilane in acetonitrile at room
temperature affords high yields of the azabicyclic products.
This new synthetic method provides a powerful tool for the
formation of azabicyclic N-substituted ring systems present
in the alkaloid methyllycaconitine and other related alka-
loids.
Scheme 4.
A similar reaction sequence was performed using 3-aza-
bicyclo[3.2.1]octane derivative 27 as the starting material
(Scheme 5). In this case, reduction of 27 with lithium alu-
minium hydride proceeded diastereoselectively to afford the
diol 40 as the only product in 54% yield. The methyllyca-
conitine noranalogue 42 was then prepared by condensing
two equiv. of N-(trifluoroacetyl)anthranilic acid 34 with
diol 40 to give the corresponding diester 41 in 33% yield
(over two steps) after reductive N-deprotection. Diester 41
was then converted into the methylsuccinic bisimide 42 in
76% yield.
Experimental Section
General Methods: Analytical thin layer chromatography (TLC) was
performed using 0.2 mm thick precoated silica gel plates (Merck
Kieselgel 60 F254). Compounds were visualized by ultraviolet fluo-
rescence or by staining with potassium permanganate in aqueous
sodium hydroxide. Flash chromatography was performed using
Riedel-de Haën silica gel (0.032–0.063 mm) with the indicated sol-
vents. 1H NMR spectra were recorded with a Bruker DRX 300
(300 MHz) or a Bruker DRX 400 (400 MHz) spectrometer at ambi-
ent temperature using CDCl3 as a solvent. Chemical shifts are given
in parts per million (ppm) downfield shift from tetramethylsilane
as an internal standard, and reported as position (δ), multiplicity
(s = singlet, sbr = broad singlet, d = doublet, dd = double doublet,
ddd = double double doublet, dddd = double double double doub-
let, t = triplet, dt = double triplet, tt = triple triplet, q = quartet,
quin = quintet, sept = septet, m = multiplet), relative integral, as-
signment and coupling constant (J in Hz). 13C NMR spectra were
recorded with a Bruker DRX 300 (75 MHz) or a Bruker DRX 400
(100 MHz) spectrometer at ambient temperature with complete
proton decoupling. Chemical shifts are expressed in parts per mil-
lion referenced to the residual chloroform peak (δ = 77.0 ppm),
and reported as position (d) and assignment, aided by DEPT 135
1
1
experiments. In addition, H-1H-COSY and H-13C-HSQC corre-
lation spectra were used for the complete assignment of the proton
and carbon resonances. 1H-1H-NOESY NMR spectra were re-
corded in special cases to determine the constitution of dia-
stereomers. The NMR spectroscopic data for the bicyclic analogues
of methyllycaconitine were assigned using the following descrip-
tors: bicyclic ring system (no primes), anthranilate ester (one prime
Ј) and methylsuccinimide (two primes ЈЈ). High resolution mass
spectra were recorded with a VG-70SE mass spectrometer op-
erating with an ionisation potential of 70 eV at nominal resolutions
of 5000 to 10000 as appropriate. Ionisation methods employed were
either electron impact (EI) or fast atom bombardment (FAB) using
m-nitrobenzyl alcohol as matrix. Major fragments are given as
mass to charge ratios. Melting points were determined on a Kofler
hot-stage apparatus and are uncorrected. β-Keto esters 28 and 29
were prepared as described in the literature.[13,14] N-(Trifluoroace-
tyl)anthranilic acid was prepared as reported.[17]
Scheme 5.
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M. A. Brimble, C. Brocke
General Procedure A for the Preparation of N,N-Bis(ethoxymethyl)- was added trichloromethylsilane (2 equiv.). The reaction mixture
FULL PAPER
amines:[8–11] A mixture of dry amine (1 equiv., freshly distilled from
calcium hydride where appropriate) and oven-dried potassium car-
bonate (1 equiv.) in dry ethanol (freshly distilled from magnesium
turnings) was treated with paraformaldehyde (2 equiv.) that had
been dried overnight under vacuum and the mixture stirred vigor-
ously with a magnetic stirer for 2 days at room temperature. The
suspension was filtered, washed with dry ethanol, and excess
alcohol was removed from the filtrate by distillation. The residue
was purified by fractional vacuum distillation using a Vigreux col-
umn to give the N,N-bis(ethoxymethyl)amine. Bis(ethoxymethyl)al-
kylamines 2–9 were prepared according to this general procedure.
1H NMR spectroscopic data and boiling points for bis(aminol)
ethers 2, 3, 4, 7 were in agreement with that reported in the litera-
ture.[6,12]
was stirred for 20 h at room temperature, then quenched with aq.
NaHCO3 and extracted with ethyl acetate (3×). The combined or-
ganic extracts were dried (MgSO4) and concentrated in vacuo. The
crude azabicyclic product was purified by flash chromatography on
silica gel (EtOAc/hexane). Compounds 11–18, 20–27 and 30–32
were prepared according to this general procedure.
Ethyl 3-Benzyl-9-oxo-3-azabicyclo[3.3.1]nonane-1-carboxylate (11):
The title compound was prepared according to general procedure B
using β-keto ester 10 (100 mg, 0.59 mmol), N,N-bis(ethoxymethyl)
benzylamine (7) (264 mg, 1.18 mmol) and trichloromethylsilane
(139 μL, 1.18 mmol) in acetonitrile (2 mL). Yield 133 mg
(0.44 mmol, 75%) of a clear oil; Rf = 0.36 (5% EtOAc in hexane).
HRMS (EI): m/z calcd. for C18H23NO3: 301.1678, found: 301.1670
[M+]. 1H NMR (400 MHz, COSY, CDCl3): δ (ppm) = 7.34–7.26
3
N,N-Bis(ethoxymethyl)-tert-butylamine (5): The title compound was
prepared according to general procedure A using tert-butylamine
[m, 5 H, Harom. (Bn)], 4.18 [dq, J = 7.1 Hz, 2 H, CH2 (Et)], 3.51
2
4
[s, 2 H, CH2 (Bn)], 3.19 [dd, Jgem = 11.4, J2eq,4eq = 2.3 Hz, 1 H,
2
3
4
(10.00 g,
136.72 mmol),
potassium
carbonate
(18.90 g,
2-Heq], 3.12 (ddd, Jgem = 11.2, J4eq,5 = J2eq,4eq = 2.3 Hz, 1 H, 4-
2
4
136.72 mmol) and paraformaldehyde (8.21 g, 273.43 mmol) in dry
ethanol (30 mL). Yield 10.99 g (58.06 mmol, 42%) of a clear oil;
boiling point 73–76 °C/16 Torr. HRMS (EI): m/z calcd. for
C10H23NO2: 189.1729, found: 189.1729 [M+]. 1H NMR (400 MHz,
CDCl3): δ (ppm) = 4.40 [s, 4 H, NCH2O (2×)], 3.38 [q, 3J = 7.0 Hz,
Heq), 3.01–2.91 (m, 1 H, 7-Hax), 2.99 (dd, Jgem = 11.4, J2ax,8ax
=
2
4
1.8 Hz, 1 H, 2-Hax), 2.62 (dd, Jgem = 11.0, J4ax,6ax = 2.5 Hz, 1 H,
4-Hax), 2.54 (dddd, Jgem = 3J7ax,8ax = 12.3, J7eq,8ax = 6.3, J2ax,8ax
= 1.6 Hz, 1 H, 8-Hax), 2.46–2.43 (m, 1 H, 5-H), 2.27–2.21 (m, 1 H,
8-Heq), 2.14–2.07 (m, 2 H, 6-Hax, 6-Heq), 1.62–1.57 (m, 1 H, 7-Heq),
1.26 [t, 3J = 7.1 Hz, 3 H, CH3 (Et)]. 13C NMR (100 MHz, BB,
DEPT, HSQC, CDCl3): δ (ppm) = 212.3 (C-9), 170.9 [C=O (ester)],
138.2 (C-1arom.), 128.6 (C-2arom., C-6arom.), 128.4 (C-3arom., C-
2
3
4
3
4 H, CH2 (2× Et)], 1.21 [s, 9 H, NC(CH3)3], 1.18 [t, J = 7.0 Hz,
6 H, CH3 (2× Et)]. 13C NMR (100 MHz, BB, DEPT, CDCl3): δ
(ppm) = 81.6 [NCH2O (2×)], 61.6 [CH2 (2× Et)], 53.3 [NC-
(CH3)3], 29.3 [NC(CH3)3], 15.3 [CH3 (2× Et)].
5
arom.), 127.2 (C-4arom.), 62.0 [CH2 (Bn)], 61.7 (C-2), 61.0 [CH2
(Et)], 60.1 (C-4), 58.8 (C-1), 47.1 (C-5), 36.6 (C-8), 34.0 (C-6), 20.6
(C-7), 14.0 [CH3 (Et)].
N,N-Bis(ethoxymethyl)cyclohexylamine (6): The title compound
was prepared according to general procedure A using cyclohex-
ylamine (10.00 g, 100.83 mmol), potassium carbonate (13.93 g,
100.83 mmol) and paraformaldehyde (6.06 g, 201.65 mmol) in dry
ethanol (25 mL). Yield 5.29 g (24.57 mmol, 24%) of a clear oil;
boiling point 112–118 °C/10 mm/Hg. HRMS (EI): m/z calcd. for
C12H25NO2: 215.1885, found: 215.1882 [M+]. 1H NMR (400 MHz,
CDCl3): δ (ppm) = 4.35 [s, 4 H, NCH2O (2×)], 3.40 [q, 3J = 7.0 Hz,
4 H, CH2 (2× Et)], 2.75 (tt, 3J = 3.5, 3J = 11.3 Hz, 1 H, 1-H),
[1.88–1.85 (m, 2 H), 1.78–1.75 (m, 2 H)] (2-Ha, 2-Hb, 6-Ha, 6-Hb)],
1.61–1.59 (m, 2 H, 4-Ha, 4-Hb), 1.20–1.35 (m, 4 H, 3-Ha, 3-Hb, 5-
Ha, 5-Hb), 1.18 [t, 3J = 7.0 Hz, 6 H, CH3 (2× Et)]. 13C NMR
(100 MHz, BB, DEPT, CDCl3): δ (ppm) = 82.9 [NCH2O (2×)],
61.8 [CH2 (2× Et)], 58.7 (C-1), 32.4 (C-2, C-6), 26.2 (C-3, C-5),
26.0 (C-4), 15.3 [CH3 (2× Et)].
Ethyl
3-Ethyl-9-oxo-3-azabicyclo[3.3.1]nonane-1-carboxylate
(12):[5c] The title compound was prepared according to general pro-
cedure B using β-keto ester 10 (100 mg, 0.59 mmol), N,N-bis(e-
thoxymethyl)ethylamine (2) (190 mg, 1.18 mmol) and trichlorome-
thylsilane (139 μL, 1.18 mmol) in acetonitrile (2 mL). Yield 129 mg
(0.54 mmol, 92%) of a clear oil; Rf = 0.47 (10% EtOAc in hexane).
HRMS (EI): m/z calcd. for C13H21NO3: 239.1521, found: 239.1523
1
3
[M+]. H NMR (400 MHz, CDCl3): δ (ppm) 4.21 [q, J = 7.1 Hz,
2
4
2 H, CH2 (Et)], 3.21 (dd, Jgem = 11.4, J2eq,4eq = 2.2 Hz, 1 H, 2-
Heq), 3.15 (ddd, Jgem = 11.1, J4eq,5
Heq), 2.93 (dd, Jgem = 11.4, J2ax,8ax = 1.6 Hz, 1 H, 2-Hax), 2.92–
=
4J2eq,4eq = 2.1 Hz, 1 H, 4-
2
3
2
4
2.80 (m, 1 H, 7-Hax), 2.59–2.49 (m, 2 H, 4-Hax, 8-Hax), 2.47–2.45
3
(m, 1 H, 5-H), 2.41 (dq, J = 7.3 Hz, 2 H, NCH2CH3), 2.26–2.21
(m, 1 H, 8-Heq), 2.17–2.03 (m, 2 H, 6-Hax, 6-Heq), 1.56–1.49 (m,
1 H, 7-Heq), 1.28 (t, 3J = 7.2 Hz, 3 H, CH3 (Et)], 1.10 (t, 3J =
7.2 Hz, 3 H, NCH2CH3). 13C NMR (100 MHz, BB, DEPT,
CDCl3): δ (ppm) = 212.7 (C-9), 171.1 [C=O (ester)], 61.6 (C-2),
61.0 [CH2 (Et)], 59.9 (C-4), 58.8 (C-1), 51.0 (NCH2CH3), 47.2 (C-
5), 36.8 (C-8), 34.1 (C-6), 20.5 (C-7), 14.1 [CH3 (Et)], 12.7
(NCH2CH3).
N,N-Bis(ethoxymethyl)-3-phenylpropylamine (9): The title com-
pound was prepared according to general procedure A using 3-
phenylpropylamine (25.00 g, 184.90 mmol), potassium carbonate
(25.56 g,
184.90 mmol)
and
paraformaldehyde
(11.11 g,
369.80 mmol) in dry ethanol (400 mL). Yield 18.74 g (74.55 mmol,
40%) of a clear oil; boiling point 80 °C/ 0.34 Torr. HRMS (EI):
m/z calcd. for C15H25NO2: 251.1885, found: 251.1891 [M+].
1H NMR (400 MHz, CDCl3): δ (ppm) = 7.28–7.16 [m, 5 H, Harom.
Ethyl
3-Isopropyl-9-oxo-3-azabicyclo[3.3.1]nonane-1-carboxylate
3
(Ph)], 4.29 [s, 4 H, NCH2O (2×)], 3.43 [q, J = 7.0 Hz, 4 H, CH2
(13): The title compound was prepared according to general pro-
cedure B using β-keto ester 10 (100 mg, 0.59 mmol), N,N-bis-
(ethoxymethyl)isopropylamine (3) (207 mg, 1.18 mmol) and tri-
chloromethylsilane (139 μL, 1.18 mmol) in acetonitrile (2 mL).
Yield 111 mg (0.44 mmol, 75%) of a clear oil; Rf = 0.57 (10%
EtOAc in hexane). HRMS (EI): m/z calcd. for C14H23NO3:
253.1678, found: 253.1674 [M+]. 1H NMR (400 MHz, CDCl3): δ
3
3
(2× Et)], 2.87 [t, J = 7.3 Hz, 2 H, N(CH2)2CH2Ph], 2.63 [t, J =
7.6 Hz, 2 H, NCH2(CH2)2Ph], 1.88–1.80 (m, 2 H,
NCH2CH2CH2Ph), 1.18 [t, 3J = 7.0 Hz, 6 H, CH3 (2× Et)].
13C NMR (100 MHz, BB, DEPT, CDCl3): δ (ppm) = 142.3 (C-
1arom.), 128.3 (C-3arom., C-5arom.), 128.2 (C-2arom., C-6arom.), 125.6
(C-4arom.), 84.7 [NCH2O (2×)], 62.6 [CH2 (2× Et)], 49.4
[NCH2(CH2)2Ph], 33.4 [N(CH2)2CH2Ph], 30.5 (NCH2CH2CH2Ph),
15.1 [CH3 (2× Et)].
3
(ppm) = 4.22 [q, J = 7.1 Hz, 2 H, CH2 (Et)], 3.13 (s, 2 H, 2-Hax,
2
2-Heq), 3.06 (d, Jgem = 10.9 Hz, 1 H, 4-Heq), 2.87 [sept, 3J =
General Procedure B for the Double Mannich Reaction Using Pre-
formed Bis(alkoxymethyl)alkylamines: To a mixture of β-keto ester
(1 equiv.) and N,N-bis(ethoxymethyl)amine (2 equiv.) in acetonitrile
6.6 Hz, 1 H, NCH(CH3)2], 2.81–2.71 (m, 1 H, 7-Hax), 2.80 (dd,
3
2
2Jgem = 11.0, J4ax,5 = 3.5 Hz, 1 H, 4-Hax), 2.54 (ddd, Jgem
=
3
3J7ax,8ax = 13.6, J7eq,8ax = 6.2 Hz, 1 H, 8-Hax), 2.47–2.45 (m, 1 H,
2390
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 2385–2396

Synthesis of the Azabicyclo[3.3.1]nonane Ring System by a Double Mannich Reaction
FULL PAPER
2
3
3
5-H), 2.22 (ddd, Jgem = 13.7, J7ax,8eq = J7eq,8eq = 4.2 Hz, 1 H, 8-
6-Heq), 1.82–1.76 (m, 4 H, 2Ј-Ha, 2Ј-Hb, 6Ј-Ha, 6Ј-Hb), 1.64–1.59
Heq), 2.12–2.07 (m, 2 H, 6-Hax, 6-Heq), 1.52–1.48 (m, 1 H, 7-Heq), (m, 1 H, 4Ј-Ha), 1.53–1.46 (m, 1 H, 7-Heq), 1.28 [t, 3J = 7.1 Hz, 3 H,
1.29 [t, 3J = 7.1 Hz, 3 H, CH3 (Et)], 1.05 [dd, 3J = 6.6 Hz, 6 H,
CH3 (Et)], 1.30–1.21 (m, 4 H, 3Ј-Ha, 3Ј-Hb, 5Ј-Ha, 5Ј-Hb), 1.17–1.11
NCH(CH3)2]. 13C NMR (100 MHz, BB, DEPT, CDCl3): δ (ppm) (m, 1 H, 4Ј-Hb). 13C NMR (100 MHz, BB, DEPT, CDCl3): δ (ppm)
= 213.0 (C-9), 171.5 [C=O (ester)], 61.0 [CH2 (Et)], 59.0 (C-1), 57.4 = 213.0 (C-9), 171.4 [C=O (ester)], 62.4 (C-1Ј), 60.9 [CH2 (Et)],
(C-2), 55.5 (C-4), 53.5 [NCH(CH3)2], 47.1 (C-5), 36.5 (C-8), 33.8 59.1 (C-1), 58.1 (C-2), 56.1 (C-4), 47.3 (C-5), 36.5 (C-8), 33.8 (C-
(C-6), 20.6 (C-7), 18.2, 18.1 [NCH(CH3)2], 14.1 [CH3 (Et)].
6), 28.8, 28.7, 26.2, 25.6 (C-2Ј, C-3Ј, C-4Ј, C-5Ј, C-6Ј), 20.6 (C-7),
14.1 [CH3 (Et)].
Ethyl 3-Butyl-9-oxo-3-azabicyclo[3.3.1]nonane-1-carboxylate (14):
The title compound was prepared according to general procedure B
Ethyl 9-Oxo-3-(2-phenylethyl)-3-azabicyclo[3.3.1]nonane-1-carbox-
using β-keto ester 10 (100 mg, 0.59 mmol), N,N-bis(ethoxymethyl)- ylate (17): The title compound was prepared according to general
butylamine (4) (223 mg, 1.18 mmol) and trichloromethylsilane procedure B using β-keto ester 10 (100 mg, 0.59 mmol), N,N-bis(e-
(139 μL, 1.18 mmol) in acetonitrile (2 mL). Yield 157 mg thoxymethyl)-2-phenylethylamine (8) (280 mg, 1.18 mmol) and
(0.59 mmol, Ͼ99%) of a clear oil; Rf = 0.67 (10% EtOAc in hex-
ane). HRMS (EI): m/z calcd. for C15H25NO3: 267.1834, found:
267.1833 [M+]. 1H NMR (400 MHz, CDCl3): δ (ppm) = 4.21 [q, 3J
trichloromethylsilane (139 μL, 1.18 mmol) in acetonitrile (2 mL).
Yield 185 mg (0.59 mmol, Ͼ99%) of a clear oil; Rf = 0.45 (10%
EtOAc in hexane). HRMS (EI): m/z calcd. for C19H25NO3:
315.1834, found: 315.1829 [M+]. 1H NMR (400 MHz, CDCl3): δ
4
= 7.1 Hz, 2 H, CH2 (Et)], 3.20 (dd, 2Jgem = 11.4, J2eq,4eq = 2.2 Hz,
2
3
3
1 H, 2-Heq), 3.13 (ddd, Jgem = 11.1, J4eq,5
=
4J2eq,4eq = 2.2 Hz, (ppm) = 7.31–7.18 [m, 5 H, Harom. (Ph)], 4.21 [q, J = 7.1 Hz, 2 H,
2
4
2
4
1 H, 4-Heq), 2.91 (dd, Jgem = 11.4, J2ax,8ax = 1.7 Hz, 1 H, 2-Hax), CH2 (Et)], 3.27 (dd, Jgem = 11.4, J2eq,4eq = 2.0 Hz, 1 H, 2-Heq),
2.902.80 (m, 1 H, 7-Hax), 2.57–2.49 (m, 2 H, 4-Hax, 8-Hax), 2.46– 3.18 (d, 2Jgem = 11.1 Hz, 1 H, 4-Heq), 3.02 (d, 2Jgem = 10.7 Hz, 1 H,
2.44 (m, 1 H, 5-H), 2.33 [t, 3J = 7.0 Hz, 2 H, NCH2(CH2)2CH3],
2-Hax), 2.82 (t, 3J = 7.8 Hz, 2 H, NCH2CH2Ph), 2.66–2.56 (m, 2 H,
3
2.26–2.21 (m, 1 H, 8-Heq), 2.18–2.02 (m, 2 H, 6-Hax, 6-Heq), 1.56– 4-Hax, 7-Hax), 2.64 (t, J = 7.9 Hz, 2 H, NCH2CH2Ph), 2.52–2.42
1.52 (m, 1 H, 7-Heq), 1.52–1.45 (m, 2 H, NCH2CH2CH2CH3), (m, 2 H, 8-Hax, 5-H), 2.18–2.13 (m, 1 H, 8-Heq), 2.06–2.01 (m, 2 H,
3
1.41–1.35 [m, 2 H, N(CH2)2CH2CH3], 1.28 [t, 3J = 7.1 Hz, 3 H,
6-Hax, 6-Heq), 1.43–1.38 (m, 1 H, 7-Heq), 1.28 [t, J = 7.1 Hz, 3 H,
CH3 (Et)], 0.94 [t, 3J = 7.3 Hz, 3 H, N(CH2)3CH3]. 13C NMR CH3 (Et)]. 13C NMR (100 MHz, BB, DEPT, CDCl3): δ (ppm) =
(100 MHz, BB, DEPT, CDCl3): δ (ppm) = 212.6 (C-9), 171.1 [C=O 212.4 (C-9), 171.0 [C=O (ester)], 140.1 (C-1arom.), 128.5 (C-3arom.
(ester)], 62.0 (C-2), 61.0 [CH2 (Et)], 60.4 (C-4), 58.8 (C-1), 56.7 C-5arom.), 128.3 (C-2arom., C-6arom.), 126.0 (C-4arom.), 61.7 (C-2),
[NCH2(CH2)2CH3], 47.2 (C-5), 36.8 (C-8), 34.1 (C-6), 29.3 61.0 [CH2 (Et)], 60.2 (C-4), 58.8 (C-1), 58.5 (NCH2CH2Ph), 47.2
,
(NCH2CH2CH2CH3), 20.5, 20.4 [C-7, N(CH2)2CH2CH3], 14.1
[CH3 (Et)], 13.9 [N(CH2)3CH3].
(C-5), 36.7 (C-8), 34.0 (C-6), 33.7 (NCH2CH2Ph), 20.2 (C-7), 14.1
[CH3 (Et)].
Ethyl
3-tert-Butyl-9-oxo-3-azabicyclo[3.3.1]nonane-1-carboxylate
Ethyl 9-Oxo-3-(3-phenylpropyl)-3-azabicyclo[3.3.1]nonane-1-carbox-
ylate (18): The title compound was prepared according to general
procedure B using β-keto ester 10 (100 mg, 0.59 mmol), N,N-bis-
(ethoxymethyl)-3-phenylpropylamine (9) (297 mg, 1.18 mmol) and
trichloromethylsilane (139 μL, 1.18 mmol) in acetonitrile (2 mL).
Yield 193 mg (0.59 mmol, Ͼ99%) of a clear oil; Rf = 0.57 (10%
EtOAc in hexane). HRMS (EI): m/z calcd. for C20H27NO3:
(15): The title compound was prepared according to general pro-
cedure B using β-keto ester 10 (100 mg, 0.59 mmol), N,N-bis(e-
thoxymethyl)-tert-butylamine (7) (223 mg, 1.18 mmol) and trichlo-
romethylsilane (139 μL, 1.18 mmol) in acetonitrile (2 mL). Yield
157 mg (0.59 mmol, Ͼ99%) of a clear oil; Rf = 0.47 (10% EtOAc in
hexane). HRMS (EI): m/z calcd. for C15H25NO3: 267.1834, found:
267.1833 [M+]. H NMR (400 MHz, CDCl3): δ (ppm) = 4.22 [dq, 329.1991, found: 329.1988 [M+]. 1H NMR (400 MHz, CDCl3): δ
1
3J = 7.1 Hz, 2 H, CH2 (Et)], 3.35 (dd, Jgem = 11.3, J2eq,4eq
=
=
(ppm) = 7.30–7.16 [m, 5 H, Harom. (Ph)], 4.20 [q, J = 7.1 Hz, 2 H,
2
4
3
2
3
2
4
3.0 Hz, 1 H, 2-Heq), 3.27 (ddd, Jgem = 11.0, J4eq,5
2.8 Hz, 1 H, 4-Heq), 3.04 (dd, Jgem = 11.3, J2ax,8ax = 1.3 Hz, 1 H,
2-Hax), 2.78–2.69 (m, 1 H, 7-Hax), 2.73 (dd, Jgem = 10.8, J4ax,5
=
4J2eq,4eq
CH2 (Et)], 3.20 (dd, Jgem = 11.4, J2eq,4eq = 1.9 Hz, 1 H, 2-Heq),
2
4
2
3.13 (d, Jgem = 11.1 Hz, 1 H, 4-Heq), 2.96–2.86 (m, 1 H, 7-Hax),
2
3
2
=
2.94 (d, Jgem = 12.0 Hz, 1 H, 2-Hax), 2.68 [t, 3J = 7.7 Hz, 2 H,
3.1 Hz, 1 H, 4-Hax), 2.572.48 (m, 1 H, 8-Hax), 2.44–2.42 (m, 1 H, N(CH2)2CH2Ph], 2.59–2.51 (m, 2 H, 4-Hax, 8-Hax), 2.46–2.43 (m,
5-H), 2.26–2.20 (m, 1 H, 8-Heq), 2.132.08 (m, 2 H, 6-Hax, 6-Heq), 1 H, 5-H), 2.35 [t, 3J = 6.7 Hz, 2 H, NCH2(CH2)2Ph], 2.27–2.21
3
1.50–1.43 (m, 1 H, 7-Heq), 1.29 (t, 3J = 7.1 Hz, 3 H, CH3 (Et)], 1.13 (m, 1 H, 8-Heq), 2.16–2.06 (m, 2 H, 6-Hax, 6-Heq), 1.82 (quin, J =
[s, 9 H, NC(CH3)3]. 13C NMR (100 MHz, BB, DEPT, CDCl3): δ
(ppm) = 213.4 (C-9), 171.6 [C=O (ester)], 60.9 [CH2 (Et)], 59.0 (C-
7.3 Hz, 2 H, NCH2CH2CH2Ph), 1.59–1.54 (m, 1 H, 7-Heq), 1.27 [t,
3J = 7.1 Hz, 3 H, CH3 (Et)]. 13C NMR (100 MHz, BB, DEPT,
1), 55.5 (C-2), 53.5 (C-4), 53.4 [NC(CH3)3], 47.1 (C-5), 36.2 (C-8), CDCl3): δ (ppm) = 212.2 (C-9), 170.9 [C=O (ester)], 141.8 (C-
33.6 (C-6), 26.4 [NC(CH3)3], 20.6 (C-7), 14.1 [CH3 (Et)].
1arom.), 128.2 (C-2arom., C-3arom., C-5arom., C-6arom.), 125.7 (C-
4arom.), 61.9 (C-2), 60.9 [CH2 (Et)], 60.2 (C-4), 58.6 (C-1), 56.2
[NCH2(CH2)2Ph], 47.0 (C-5), 36.6 (C-8), 34.0 (C-6), 33.3 [N-
(CH2)2CH2Ph], 28.9 (NCH2CH2CH2Ph), 20.4 (C-7), 14.0 [CH3
(Et)].
Ethyl 3-Cyclohexyl-9-oxo-3-azabicyclo[3.3.1]nonane-1-carboxylate
(16): The title compound was prepared according to general pro-
cedure B using β-keto ester 10 (100 mg, 0.59 mmol), N,N-bis-
(ethoxymethyl)cyclohexylamine (6) (254 mg, 1.18 mmol) and tri-
chloromethylsilane (139 μL, 1.18 mmol) in acetonitrile (2 mL).
Ethyl 3-Ethyl-8-oxo-3-azabicyclo[3.2.1]octane-1-carboxylate (20):
Yield 157 mg (0.54 mmol, 92%) of a clear oil; Rf = 0.57 (10% The title compound was prepared according to general procedure B
EtOAc in hexane). HRMS (EI): m/z calcd. for C17H27NO3:
using β-keto ester 19 (100 mg, 0.64 mmol), N,N-bis(ethoxymethyl)
ethylamine (2) (206 mg, 1.28 mmol) and trichloromethylsilane
293.1991, found: 293.1984 [M+]. 1H NMR (400 MHz, CDCl3): δ
3
(ppm) = 4.21 [q, J = 7.1 Hz, 2 H, CH2 (Et)], 3.22–3.16 (m, 2 H, (150 μL, 1.28 mmol) in acetonitrile (2 mL). Yield 80 mg
2
3
4
2-Hax, 2-Heq), 3.11 (ddd, Jgem = 10.9, J4eq,5 = J2eq,4eq = 1.9 Hz, (0.36 mmol, 56%) of a clear oil; Rf = 0.31 (17% EtOAc in hexane).
2
3
1 H, 4-Heq), 2.84 (dd, Jgem = 11.0, J4ax,5 = 3.3 Hz, 1 H, 4-Hax), HRMS (EI): m/z calcd. for C12H19NO3: 225.1365, found: 225.1366
2
1
3
2.82–2.72 (m, 1 H, 7-Hax), 2.52 (ddd, Jgem
=
3J7ax,8ax = 11.6, [M+]. H NMR (400 MHz, COSY, CDCl3): δ (ppm) = 4.21 [q, J
3J7eq,8ax = 6.4 Hz, 1 H, 8-Hax), 2.45–2.43 (m, 1 H, 5-H), 2.43–2.36
= 7.1 Hz, 2 H, CH2 (Et)], 3.15 (dd, 2Jgem = 10.9, J2eq,4eq = 2.6 Hz,
4
2
3
4
(m, 1 H, 1Ј-H), 2.24–2.18 (m, 1 H, 8-Heq), 2.112.04 (m, 2 H, 6-Hax, 1 H, 2-Heq), 3.02–2.98 (ddd, Jgem = 10.5, J4eq,5 = 4.0, J2eq,4eq
=
Eur. J. Org. Chem. 2005, 2385–2396
www.eurjoc.org © 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 2391

M. A. Brimble, C. Brocke
FULL PAPER
2.8 Hz, 1 H, 4-Heq), 2.70 (d, Jgem = 10.9 Hz, 1 H, 2-Hax), 2.55 (q, (CH3)3]. 13C NMR (100 MHz, BB, DEPT, CDCl3): δ (ppm) = 214.4
2
3J = 7.2 Hz, 2 H, NCH2CH3), 2.59 (d, 2Jgem = 9.3 Hz, 1 H, 4-Hax),
(C-8), 170.7 [C=O (ester)], 61.0 [CH2 (Et)], 58.1 (C-1), 56.3 (C-2),
2.39–2.34 (m, 1 H, 7-Hexo), 2.35–2.33 (m, 1 H, 5-H), 2.28–2.21 (m,
54.9 (C-4), 53.1 [NC(CH3)3], 46.7 (C-5), 27.4 (C-7), 27.0 [NC-
1 H, 7-Hendo), 2.00–1.91 (m, 2 H, 6-Hendo, 6-Hexo), 1.28 (t, 3J = (CH3)3], 21.6 (C-6), 14.1 [CH3 (Et)].
7.1 Hz, 3 H, CH3 (Et)], 1.09 (t, 3J = 7.2 Hz, 3 H, NCH2CH3).
Ethyl 3-Cyclohexyl-8-oxo-3-azabicyclo[3.2.1]octane-1-carboxylate
13C NMR (100 MHz, BB, DEPT, HSQC, CDCl3): δ (ppm) = 213.6
(C-8), 170.3 [C=O (ester)], 62.2 (C-2), 61.1 (C-4), 61.0 [CH2 (Et)],
57.6 (C-1), 49.7 (NCH2CH3), 46.3 (C-5), 27.5 (C-7), 21.7 (C-6),
14.1 [CH3 (Et)], 12.6 (NCH2CH3).
(24): The title compound was prepared according to general pro-
cedure B using β-keto ester 19 (100 mg, 0.64 mmol), N,N-bis-
(ethoxymethyl)cyclohexylamine (6) (276 mg, 1.28 mmol) and tri-
chloromethylsilane (150 μL, 1.28 mmol) in acetonitrile (2 mL).
Yield 147 mg (0.53 mmol, 83%) of a clear oil; Rf = 0.48 (10%
EtOAc in hexane). HRMS (EI): m/z calcd. for C16H25NO3:
Ethyl
3-Isopropyl-8-oxo-3-azabicyclo[3.2.1]octane-1-carboxylate
(21): The title compound was prepared according to general pro-
cedure B using β-keto ester 19 (100 mg, 0.64 mmol), N,N-bis-
279.1834, found: 279.1833 [M+]. 1H NMR (400 MHz, CDCl3): δ
(ethoxymethyl)isopropylamine (3) (224 mg, 1.28 mmol) and tri- (ppm) = 4.21 [q, 3J = 7.1 Hz, 2 H, CH2 (Et)], 3.09 (dd, Jgem
=
2
chloromethylsilane (150 μL, 1.28 mmol) in acetonitrile (2 mL).
Yield 125 mg (0.52 mmol, 81%) of a clear oil; Rf = 0.38 (10% = J2eq,4eq = 3.5 Hz, 1 H, 4-Heq), 2.93 (d, Jgem = 10.8 Hz, 1 H, 2-
10.7, 4J2eq,4eq = 2.7 Hz, 1 H, 2-Heq), 2.93 (ddd, 2Jgem = 10.8, 3J4eq,5
4
2
2
EtOAc in hexane). HRMS (EI): m/z calcd. for C13H21NO3:
Hax), 2.76 (d, Jgem = 9.7 Hz, 1 H, 4-Hax), 2.49–2.43 (m, 1 H, 1Ј-
H), 2.35–2.30 (m, 2 H, 5-H, 7-Hexo), 2.21–2.14 (m, 1 H, 7-Hendo),
1.91–1.86 (m, 2 H, 6-Hendo, 6-Hexo), 1.82–1.75 (m, 4 H, 2Ј-Ha, 2Ј-
239.1521, found: 239.1521 [M+]. 1H NMR (400 MHz, CDCl3): δ
2
(ppm) = 4.21 [q, 3J = 7.1 Hz, 2 H, CH2 (Et)], 3.05 (dd, Jgem
=
4
3
10.8, J2eq,4eq = 2.7 Hz, 1 H, 2-Heq), 2.97–2.86 [m, 2 H, NCH-
Hb, 6Ј-Ha, 6Ј-Hb), 1.64–1.59 (m, 1 H, 4Ј-Ha), 1.27 [t, J = 7.1 Hz,
(CH3)2, 4-Heq], 2.87 (d, 2Jgem = 10.6 Hz, 1 H, 2-Hax), 2.71 (d, 2Jgem 3 H, CH3 (Et)], 1.30–1.20 (m, 4 H, 3Ј-Ha, 3Ј-Hb, 5Ј-Ha, 5Ј-Hb),
= 10.3 Hz, 1 H, 4-Hax), 2.37–2.31 (m, 1 H, 7-Hexo), 2.36–2.35 (m, 1.15–1.08 (m, 1 H, 4Ј-Hb). 13C NMR (100 MHz, BB, DEPT,
1 H, 5-H), 2.21–2.14 (m, 1 H, 7-Hendo), 1.92–1.87 (m, 2 H, 6-Hendo
,
CDCl3): δ (ppm) = 214.0 (C-8), 170.5 [C=O (ester)], 61.5 (C-1Ј),
61.0 [CH2 (Et)], 58.7 (C-2), 58.1 (C-1), 57.4 (C-4), 46.8 (C-5), 29.6,
29.5, 26.1, 25.7 (C-2Ј, C-3Ј, C-4Ј, C-5Ј, C-6Ј), 27.5 (C-7), 21.7 (C-
6), 14.1 [CH3 (Et)].
3
6-Hexo), 1.28 [t, J = 7.1 Hz, 3 H, CH3 (Et)], 1.05 [dd, 3J = 6.6 Hz,
6 H, NCH(CH3)2]. 13C NMR (100 MHz, BB, DEPT, CDCl3): δ
(ppm) = 214.1 (C-8), 170.6 [C=O (ester)], 61.0 [CH2 (Et)], 58.1 (C-
1, C-2), 56.8 (C-4), 52.7 [NCH(CH3)2], 46.7 (C-5), 27.6 (C-7), 21.8
(C-6), 18.9, 18.8 [NCH(CH3)2], 14.2 [CH3 (Et)].
Ethyl 3-Benzyl-8-oxo-3-azabicyclo[3.2.1]octane-1-carboxylate (25):
The title compound was prepared according to general procedure B
Ethyl 3-Butyl-8-oxo-3-azabicyclo[3.2.1]octane-1-carboxylate (22): using β-keto ester 19 (100 mg, 0.64 mmol), N,N-bis(ethoxymethyl)
The title compound was prepared according to general procedure B benzylamine (7) (286 mg, 1.28 mmol) and trichloromethylsilane
using β-keto ester 19 (100 mg, 0.64 mmol), N,N-bis(ethoxymethyl)- (150 μL, 1.28 mmol) in acetonitrile (2 mL). Yield 151 mg
butylamine (4) (242 mg, 1.28 mmol) and trichloromethylsilane (0.53 mmol, 83%) of a clear oil; Rf = 0.40 (10% EtOAc in hexane).
(150 μL, 1.28 mmol) in acetonitrile (2 mL). Yield 157 mg HRMS (EI): m/z calcd. for C17H21NO3: 287.1521, found: 287.1523
1
(0.62 mmol, 97%) of a clear oil; Rf = 0.66 (10% EtOAc in hexane).
HRMS (EI): m/z calcd. for C14H23NO3: 253.1678, found: 253.1677
[M+]. 1H NMR (400 MHz, CDCl3): δ (ppm) = 4.21 [q, 3J = 7.1 Hz,
[M+]. H NMR (400 MHz, CDCl3): δ (ppm) = 7.35–7.24 [m, 5 H,
3
2
Harom. (Bn)], 4.17 [q, J = 7.1 Hz, 2 H, CH2 (Et)], 3.66 [d, Jgem
13.3 Hz, 1 H, CH2a (Bn)], 3.60 [d, Jgem = 13.3 Hz, 1 H, CH2b
=
2
2
4
2
4
2 H, CH2 (Et)], 3.14 (dd, Jgem = 10.9, J2eq,4eq = 2.6 Hz, 1 H, 2- (Bn)], 3.13 (dd, Jgem = 10.9, J2eq,4eq = 2.6 Hz, 1 H, 2-Heq), 2.96
2
3
Heq), 2.98 (ddd, Jgem = 10.5, J4eq,5
=
4J2eq,4eq = 2.9 Hz, 1 H, 4-
(ddd, 2Jgem = 10.5, 3J4eq,5 = 4J2eq,4eq = 3.0 Hz, 1 H, 4-Heq), 2.78 (d,
2Jgem = 10.9 Hz, 1 H, 2-Hax), 2.56 (d, 2Jgem = 10.5 Hz, 1 H, 4-Hax),
Heq), 2.69 (d, 2Jgem = 10.9 Hz, 1 H, 2-Hax), 2.50 (d, 2Jgem = 10.5 Hz,
1 H, 4-Hax), 2.46 [dt, 3J = 6.8, 3J = 1.8 Hz, 2 H, NCH2(CH2)2CH3], 2.41 (ddd, Jgem
=
3J6endo,7exo = 12.1, J6exo,7exo = 4.7 Hz, 1 H, 7-
2
3
2.41–2.34 (m, 1 H, 7-Hexo), 2.36–2.33 (m, 1 H, 5-H), 2.27–2.20 (m,
H
exo), 2.34–2.32 (m, 1 H, 5-H), 2.32–2.27 (m, 1 H, 7-Hendo), 2.05–
3
1 H, 7-Hendo), 1.97–1.91 (m, 2 H, 6-Hendo, 6-Hexo), 1.49–1.42 (m, 1.92 (m, 2 H, 6-Hendo, 6-Hexo), 1.25 [t, J = 7.1 Hz, 3 H, CH3 (Et)].
2 H, NCH2CH2CH2CH3), 1.40–1.35 [m, 2 H, N(CH2)2CH2CH3], 13C NMR (100 MHz, BB, DEPT, CDCl3): δ (ppm) = 213.2 (C-8),
1.27 [t, 3J = 7.1 Hz, 3 H, CH3 (Et)], 0.93 [t, 3J = 7.2 Hz, 3 H,
170.0 [C=O (ester)], 138.3 (C-1arom.), 128.5 (C-2arom., C-6arom.),
N(CH2)3CH3]. 13C NMR (100 MHz, BB, DEPT, CDCl3): δ (ppm) 128.3 (C-3arom., C-5arom.), 127.2 (C-4arom.), 62.3 (C-2), 61.1 (C-4),
= 213.6 (C-8), 170.3 [C=O (ester)], 62.6 (C-2), 61.6 (C-4), 61.0 [CH2
(Et)], 57.6 (C-1), 55.2 [NCH2(CH2)2CH3], 46.4 (C-5), 29.4
(NCH2CH2CH2CH3), 27.5 (C-7), 21.8 (C-6), 20.3 [N(CH2)2-
CH2CH3], 14.1 [CH3 (Et)], 13.9 [N(CH2)3CH3].
61.0 [CH2 (Et)], 60.0 [CH2 (Bn)], 57.7 (C-1), 46.3 (C-5), 27.4 (C-7),
21.7 (C-6), 14.0 [CH3 (Et)].
Ethyl 8-Oxo-3-(2-phenylethyl)-3-azabicyclo[3.2.1]octane-1-carboxyl-
ate (26): The title compound was prepared according to general
Ethyl
3-tert-Butyl-8-oxo-3-azabicyclo[3.2.1]octane-1-carboxylate procedure B using β-keto ester 19 (100 mg, 0.64 mmol), N,N-bis(e-
(23): The title compound was prepared according to general pro-
thoxymethyl)-2-phenylethylamine (8) (304 mg, 1.28 mmol) and
cedure B using β-keto ester 19 (100 mg, 0.64 mmol), N,N-bis- trichloromethylsilane (150 μL, 1.28 mmol) in acetonitrile (2 mL).
(ethoxymethyl)-tert-butylamine (5) (242 mg, 1.28 mmol) and tri-
chloromethylsilane (150 μL, 1.28 mmol) in acetonitrile (2 mL).
Yield 157 mg (0.52 mmol, 81%) of a clear oil; Rf = 0.35 (10%
EtOAc in hexane). HRMS (EI): m/z calcd. for C18H23NO3:
Yield 144 mg (0.57 mmol, 89%) of a clear oil; Rf = 0.40 (10% 301.1678, found: 301.1674 [M+]. 1H NMR (400 MHz, CDCl3): δ
3
EtOAc in hexane). HRMS (EI): m/z calcd. for C14H23NO3:
(ppm) = 7.30–7.17 [m, 5 H, Harom. (Ph)], 4.20 [q, J = 7.1 Hz, 2 H,
253.1678, found: 253.1678 [M+]. 1H NMR (400 MHz, CDCl3): δ
CH2 (Et)], 3.18 (dd, Jgem = 10.8, J2eq,4eq = 2.5 Hz, 1 H, 2-Heq),
2
4
2
2
3
(ppm) = 4.21 [q, 3J = 7.1 Hz, 2 H, CH2 (Et)], 3.26 (dd, Jgem
=
3.01 (ddd, Jgem = 10.3, J4eq,5
=
4J2eq,4eq = 2.8 Hz, 1 H, 4-Heq),
10.8, 4J2eq,4eq = 3.2 Hz, 1 H, 2-Heq), 3.11 (ddd, 2Jgem = 10.4, 3J4eq,5 2.81–2.73 (m, 5 H, 2-Hax, NCH2CH2Ph), 2.60 (d, Jgem = 10.4 Hz,
= J2eq,4eq = 3.7 Hz, 1 H, 4-Heq), 2.79 (d, Jgem = 10.8 Hz, 1 H, 2- 1 H, 4-Hax), 2.37–2.30 (m, 2 H, 5-H, 7-Hexo), 2.17–2.10 (m, 1 H, 7-
Hax), 2.63 (d, Jgem = 10.1 Hz, 1 H, 4-Hax), 2.34–2.29 (m, 2 H, 5-
H, 7-Hexo), 2.21–2.14 (m, 1 H, 7-Hendo), 1.90–1.86 (m, 2 H, 6-Hendo
6-Hexo), 1.28 [t, 3J = 7.2 Hz, 3 H, CH3 (Et)], 1.12 [s, 9 H, NC-
2
4
2
2
Hendo), 1.89–1.83 (m, 2 H, 6-Hendo, 6-Hexo), 1.26 [t, 3J = 7.1 Hz,
3 H, CH3 (Et)]. 13C NMR (100 MHz, BB, DEPT, CDCl3): δ (ppm)
,
= 213.3 (C-8), 170.2 [C=O (ester)], 140.0 (C-1arom.), 128.5 (C-3arom.
,
2392
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org Eur. J. Org. Chem. 2005, 2385–2396

Synthesis of the Azabicyclo[3.3.1]nonane Ring System by a Double Mannich Reaction
FULL PAPER
C-5arom.), 128.2 (C-2arom., C-6arom.), 125.9 (C-4arom.), 62.3 (C-2),
1 H, CH2CH=CHaHb), 5.01 (dd, 2Jgem = 2.0, 3Jtrans = 16.8 Hz, 1 H,
3
61.3 (C-4), 61.0 [CH2 (Et)], 57.5 (C-1), 56.8 (NCH2CH2Ph), 46.3
CH2CH=CHaHb), 4.21 [q, J = 7.1 Hz, 2 H, CH2 (Et)], 3.18 (dd,
(C-5), 33.7 (NCH2CH2Ph), 27.4 (C-7), 21.6 (C-6), 14.1 [CH3 (Et)]. 2Jgem = 11.4, J2eq,4eq = 2.2 Hz, 1 H, 4-Heq), 3.02–2.91 (m, 1 H, 7-
4
2
4
Hax), 3.00 (dd, Jgem = 11.2, J2eq,4eq = 2.1 Hz, 1 H, 2-Heq), 2.94
Ethyl 8-Oxo-3-(3-phenylpropyl)-3-azabicyclo[3.2.1]octane-1-carbox-
ylate (27): The title compound was prepared according to general
procedure B using β-keto ester 19 (100 mg, 0.64 mmol), N,N-bis(e-
thoxymethyl)-3-phenylpropylamine (9) (322 mg, 1.28 mmol) and
trichloromethylsilane (150 μL, 1.28 mmol) in acetonitrile (2 mL).
Yield 169 mg (0.54 mmol, 84%) of a clear oil; Rf = 0.49 (10%
EtOAc in hexane). HRMS (EI): m/z calcd. for C19H25NO3:
315.1834, found: 315.1833 [M+]. 1H NMR (400 MHz, CDCl3): δ
(dd, Jgem = 11.8, J4ax,6ax = 1.1 Hz, 1 H, 4-Hax), 2.68 [t, 3J =
7.5 Hz, 2 H, N(CH2)2CH2Ph], 2.58–2.50 (m, 1 H, 6-Hax), 2.34 [t,
3J = 7.0 Hz, 2 H, NCH2(CH2)2Ph], 2.31–2.27 (m, 1 H, 2-Hax),
2.24–2.20 (m, 1 H, 6-Heq), 2.17 (t, 2 H, CH2CH=CH2, 3J = 6.9 Hz),
2.14–2.08 (m, 1 H, 8-Heq), 1.85–1.78 (m, 1 H, 8-Hax), 1.82 (quin,
3J = 7.3 Hz, 2 H, NCH2CH2CH2Ph), 1.57–1.53 (m, 1 H, 7-Heq),
1.29 [t, 3J = 7.1 Hz, 3 H, CH3 (Et)]. 13C NMR (100 MHz, BB,
DEPT, HSQC, CDCl3): δ (ppm) = 212.6 (C-9), 171.3 [C=O (ester)],
2
4
3
(ppm) = 7.30–7.16 [m, 5 H, Harom. (Ph)], 4.20 [q, J = 7.1 Hz, 2 H,
142.1 (C-1arom.), 133.7 (CH2CH=CH2), 128.4 (C-2arom., C-3arom.
,
2
4
CH2 (Et)], 3.14 (dd, Jgem = 10.9, J2eq,4eq = 2.5 Hz, 1 H, 2-Heq),
C-5arom., C-6arom.), 125.9 (C-4arom.), 118.1 (CH2CH=CH2), 65.0 (C-
2), 62.1 (C-4), 61.2 [CH2 (Et)], 59.0 (C-1), 56.5 [NCH2(CH2)2Ph],
49.0 (C-5), 39.4 (CH2CH=CH2), 39.3 (C-8), 36.9 (C-6), 33.5
[N(CH2)2CH2Ph], 29.1 (NCH2CH2CH2Ph), 20.4 (C-7), 14.2 [CH3
(Et)].
2
3
2.98 (ddd, Jgem = 10.4, J4eq,5
=
4J2eq,4eq = 3.0 Hz, 1 H, 4-Heq),
2.72 (d, Jgem = 10.9 Hz, 1 H, 2-Hax), 2.69 [t, 3J = 7.0 Hz, 2 H,
N(CH2)2CH2Ph], 2.52–2.44 [m, 3 H, 4-Hax, NCH2(CH2)2Ph], 2.43-
2.38 (m, 1 H, 7-Hexo), 2.37–2.34 (m, 1 H, 5-H), 2.30–2.23 (m, 1 H,
7-Hendo), 2.00–1.93 (m, 2 H, 6-Hendo, 6-Hexo), 1.81 (quin, 3J =
7.3 Hz, 2 H, NCH2CH2CH2Ph), 1.27 [t, 3 H, CH3 (Et), 3J =
7.1 Hz]. 13C NMR (100 MHz, BB, DEPT, CDCl3): δ (ppm) = 213.4
(C-8), 170.2 [C=O (ester)], 141.9 (C-1arom.), 128.4 (C-3arom., C-
2
Ethyl 3-Ethyl-8-oxo-5-(2-propenyl)-3-azabicyclo[3.2.1]octane-1-car-
boxylate (32): The title compound was prepared according to gene-
ral procedure B using β-keto ester 29 (100 mg, 0.51 mmol), N,N-
bis(ethoxymethyl)ethylamine (5) (164 mg, 1.02 mmol) and trichlor-
omethylsilane (120 μL, 1.02 mmol) in acetonitrile (2 mL). Yield
101 mg (0.38 mmol, 75%) of a clear oil; Rf = 0.30 (10% EtOAc in
hexane). HRMS (EI): m/z calcd. for C15H23NO3: 265.1678, found:
5
arom.), 128.3 (C-2arom., C-6arom.), 125.8 (C-4arom.), 62.5 (C-2), 61.5
(C-4), 61.0 [CH2 (Et)], 57.6 (C-1), 54.4 [NCH2(CH2)2Ph], 46.3 (C-
5), 33.1 [N(CH2)2CH2Ph], 28.9 (NCH2CH2CH2Ph), 27.6 (C-7),
21.8 (C-6), 14.1 [CH3 (Et)].
1
265.1676 [M+]. H NMR (400 MHz, CDCl3): δ (ppm) = 5.78–5.68
Ethyl
3-Benzyl-9-oxo-5-(2-propenyl)-3-azabicyclo[3.3.1]nonane-1-
(m, 1 H, CH2CH=CH2), 5.06–5.02 (m, 2 H, CH2CH=CH2), 4.21
3
2
carboxylate (30): The title compound was prepared according to
general procedure B using β-keto ester 28 (100 mg, 0.48 mmol),
N,N-bis(ethoxymethyl)benzylamine (2) (214 mg, 0.96 mmol) and
trichloromethylsilane (113 μL, 0.96 mmol) in acetonitrile (2 mL).
Yield 95 mg (0.28 mmol, 58%) of a clear oil; Rf = 0.37 (5% EtOAc
in hexane). HRMS (EI): m/z calcd. for C21H27NO3: 341.1991,
found: 341.1994 [M+]. 1H NMR (400 MHz, COSY, CDCl3): δ
(ppm) = 7.34–7.25 [m, 5 H, Harom. (Bn)], 5.78–5.71 (m, 1 H,
[dq, J = 7.1 Hz, 2 H, CH2 (Et)], 3.13 (d, Jgem = 10.8 Hz, 1 H, 4-
Heq), 2.85 (d, 2Jgem = 10.4 Hz, 1 H, 2-Heq), 2.69 (d, 2Jgem = 10.7 Hz,
1 H, 4-Hax), 2.53 (q, 3J = 7.2 Hz, 2 H, NCH2CH3), 2.33 (ddd, 2Jgem
= 3J6endo,7exo = 12.1, 3J6exo,7exo = 4.4 Hz, 1 H, 7-Hexo), 2.25–2.12 (m,
4 H, 2-Hax, 7-Hendo, CH2CH=CH2), 1.99 (ddd, 2Jgem = 3J6exo,7endo
=
12.2, 3J6exo,7exo = 4.3 Hz, 1 H, 6-Hexo), 1.75 (ddd, 2Jgem = 3J6endo,7exo
3
= 12.2, J6endo,7endo = 4.7 Hz, 1 H, 6-Hendo), 1.27 [t, 3 H, CH3 (Et),
3J = 7.1 Hz], 1.08 (t, 3J = 7.2 Hz, 3 H, NCH2CH3). 13C NMR
(100 MHz, BB, DEPT, CDCl3): δ (ppm) = 213.9 (C-8), 170.3 [C=O
(ester)], 133.6 (CH2CH=CH2), 117.9 (CH2CH=CH2), 65.6 (C-2),
62.2 (C-4), 61.0 [CH2 (Et)], 58.6 (C-1), 50.7 (C-5), 49.7
(NCH2CH3), 35.1 (CH2CH=CH2), 27.1 (C-7), 26.6 (C-6), 14.1
[CH3 (Et)], 12.5 (NCH2CH3).
2
3
CH2CH=CH2), 5.01 (dd, Jgem = 2.2, Jcis = 10.2 Hz, 1 H,
2
3
CH2CH=CHaHb), 4.98 (dd, Jgem = 2.1, Jtrans = 16.8 Hz, 1 H,
3
CH2CH=CHaHb), 4.17 [dq, J = 7.1 Hz, 2 H, CH2 (Et)], 3.56 [d,
2
2
1 H, CH2a (Bn), Jgem = 13.1 Hz], 3.43 [d, Jgem = 13.1 Hz, 1 H,
2
4
CH2b (Bn)], 3.14 (dd, Jgem = 11.4, J2eq,4eq = 2.3 Hz, 1 H, 4-Heq),
3.08–2.98 (m, 1 H, 7-Hax), 3.01 (dd, 2Jgem = 11.1, 4J2eq,4eq = 2.5 Hz,
(1R*,5S*,9S*)-1-Hydroxymethyl-3-(3-phenylpropyl)-3-azabicyclo-
[3.3.1]nonan-9-ol (33a) and (1R*,5S*,9R*)-1-Hydroxymethyl-3-(3-
phenylpropyl)-3-azabicyclo-[3.3.1]nonan-9-ol (33b): To a slurry of
lithium aluminium hydride (334 mg, 8.79 mmol) in dry THF
(80 mL) was added dropwise a solution of β-keto ester 18 (965 mg,
2.93 mmol) in dry THF (20 mL) under nitrogen. The reaction mix-
ture was stirred for 1 h at room temperature. Sodium sulphate deca-
hydrate (excess, 1 g) was added and stirring was continued for 1 h.
The mixture was filtered through Celite and the solvent removed
under reduced pressure. The residue was dissolved in diethyl ether
(100 mL), washed with aq. NaHCO3 (50 mL) and brine (50 mL),
dried (MgSO4) and concentrated in vacuo. The alcohols 33a and
33b were isolated by flash chromatography (3% MeOH in CH2Cl2).
Diastereomer 33a: Yield 419 mg (1.45 mmol, 50%) of a yellow oil;
Rf = 0.34 (5% MeOH in CH2Cl2). HRMS (EI): m/z calcd. for
C18H27NO2: 289.2042, found: 289.2040 [M+]. 1H NMR (400 MHz,
COSY, NOESY, CDCl3): δ (ppm) = 7.29–7.15 [m, 5 H, Harom. (Ph)],
2
4
1 H, 2-Heq), 2.96 (dd, Jgem = 11.4, J4ax,6ax = 1.7 Hz, 1 H, 4-Hax),
2
3
4
2.54 (dddd, Jgem
= =
3J6ax,7ax = 12.1, J6ax,7eq = 6.4, J4ax,6ax
2
4
1.8 Hz, 1 H, 6-Hax), 2.37 (dd, Jgem = 11.2, J2ax,8ax = 1.8 Hz, 1 H,
2-Hax), 2.22–2.17 (m, 1 H, 6-Heq), 2.15 (t, 3J = 7.8 Hz, 2 H,
CH2CH=CH2), 2.12–2.07 (m, 1 H, 8-Heq), 1.84–1.73 (m, 1 H, 8-
Hax), 1.62–1.55 (m, 1 H, 7-Heq), 1.26 (t, 3J = 7.1 Hz, 3 H, CH3
(Et)]. 13C NMR (100 MHz, BB, DEPT, HSQC, CDCl3): δ (ppm) =
212.4 (C-9), 171.0 [C=O (ester)], 138.2 (C-1arom.), 133.6
(CH2CH=CH2), 128.6 (C-2arom., C-6arom.), 128.4 (C-3arom., C-
5arom.), 127.2 (C-4arom.), 118.0 (CH2CH=CH2), 65.0 (C-2), 62.1
[CH2 (Bn)], 61.7 (C-4), 61.0 [CH2 (Et)], 58.9 (C-1), 49.0 (C-5), 39.2
(CH2CH=CH2), 39.1 (C-8), 36.6 (C-6), 20.5 (C-7), 14.0 [CH3 (Et)].
Ethyl 9-Oxo-3-(3-phenylpropyl)-5-(2-propenyl)-3-azabicyclo[3.3.1]-
nonane-1-carboxylate (31): The title compound was prepared ac-
cording to general procedure B using β-keto ester 28 (650 mg,
3.09 mmol), N,N-bis(ethoxymethyl)-3-phenylpropylamine (11)
(1.55 g, 6.18 mmol) and trichloromethylsilane (726 μL, 6.18 mmol)
in acetonitrile (15 mL). Yield 882 mg (2.39 mmol, 77%) of a clear
oil; Rf = 0.40 (5% EtOAc in hexane). HRMS (EI): m/z calcd. for
C23H31NO3: 369.2304, found: 369.2301 [M+]. 1H NMR (400 MHz,
COSY, CDCl3): δ (ppm) = 7.31–7.19 [m, 5 H, Harom. (Ph)], 5.82–
3
2
3.70 (d, J5,9 = 3.7 Hz, 1 H, 9-H), 3.40 (d, Jgem = 10.7 Hz, 1 H,
2
CHaHbOH), 3.34 (d, Jgem = 10.8 Hz), , 1 H, CHaHbOH3.11 (br.,
1 H, OH), 2.94 (d, 2Jgem = 10.9 Hz, 1 H, 4-Heq), 2.70–2.59 (m, 2 H,
2-Heq, 7-Hax), 2.64 [t, 2 H, N(CH2)2CH2Ph, 3J = 7.7 Hz], 2.20–2.15
[m, 3 H, 4-Hax, NCH2(CH2)2Ph], 2.05–1.89 (m, 2 H, 6-Hax, 8-Hax),
5.73 (m, 1 H, CH2CH=CH2), 5.05 (dd, Jgem = 2.0, Jcis = 9.9 Hz, 1.85–1.80 (m, 2 H, 2-Hax, 5-H), 1.75 (quin, 3J = 7.4 Hz, 2 H,
2
3
Eur. J. Org. Chem. 2005, 2385–2396
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2393

M. A. Brimble, C. Brocke
NCH2CH2CH2Ph), 1.55–1.51 (m, 2 H, 6-Heq, 7-Heq), 1.28 (dd, reaction mixture was stirred for 8 h at 40 °C. The reaction mixture
FULL PAPER
3
2Jgem = 13.5, J7ax,8eq = 6.2 Hz, 1 H, 8-Heq). 13C NMR (100 MHz,
BB, DEPT, HSQC, CDCl3): δ (ppm) = 142.5 (C-1arom.), 128.4 (C-
3arom., C-5arom.), 128.2 (C-2arom., C-6arom.), 125.6 (C-4arom.), 75.3
(C-9), 71.0 (CH2OH), 60.9 (C-2), 58.7 (C-4), 57.5 [NCH2(CH2)2-
was cooled, filtered, and the filtrate evaporated to dryness. The
residue was dissolved in dichloromethane (30 mL), washed with aq.
NaHCO3 (20 mL) and brine (20 mL), dried (MgSO4) and concen-
trated in vacuo. The crude ester was dissolved in dry ethanol
Ph], 38.1 (C-1), 36.2 (C-5), 33.4 [N(CH2)2CH2Ph], 29.0 (20 mL), treated with sodium borohydride (73 mg, 1.94 mmol) and
(NCH2CH2CH2Ph), 26.6 (C-8), 23.9 (C-6), 20.6 (C-7). The 1H-1H- stirred for 20 h at room temperature. The reaction mixture was
NOESY NMR spectra (300 MHz, CDCl3, Tmix. = 800 ms) shows
NOEs between 9-H and 2-Hax. NOEs between 9-H and 6-Hax or
8-Hax are not observed. Diastereomer 33b: Yield 131 mg
quenched with dist. water (20 mL), and the volatiles were removed
at reduced pressure. The residue was dissolved in ethyl acetate
(50 mL), washed with brine (20 mL), dried (MgSO4) and concen-
(0.45 mmol, 15%) of a yellow oil; Rf = 0.26 (5% MeOH in trated in vacuo. The title compounds 35, 36 and 37 were separated
CH2Cl2). HRMS (EI): m/z calcd. for C18H27NO2: 289.2042, found:
by flash chromatography (15% EtOAc in hexane).
289.2041 [M+]. 1H NMR (400 MHz, COSY, NOESY, CDCl3): δ
Monoester 35: Yield 117 mg (0.29 mmol, 30%) of a yellow oil; Rf
= 0.27 (20% EtOAc in hexane); HRMS (EI): m/z calcd. for
C25H32N2O3: 408.2413, found: 408.2410 [M+]. 1H NMR
(300 MHz, COSY, CDCl3): δ (ppm) = 7.84 (d, 3J5Ј,6Ј = 8.1 Hz, 1 H,
3
(ppm) = 7.29–7.15 [m, 5 H, Harom. (Ph)], 3.62 (d, J5,9 = 3.0 Hz,
1 H, 9-H), 3.48 (d, 2Jgem = 10.9 Hz, 1 H, CHaHbOH), 3.40 (d, 2Jgem
= 11.0 Hz, 1 H, CHaHbOH), 2.71 (d, 2Jgem = 11.6 Hz, 1 H, 2-Hax),
2.69–2.66 (m, 1 H, 4-Hax), 2.63 [t, 3J = 7.5 Hz, 2 H, N(CH2)2-
6Ј-Harom.), 7.30–7.18 [m, 6 H, Harom. (Ph), 4Ј-Harom.], 6.67–6.63 (m,
2
CH2Ph], 2.50 (d, Jgem = 11.5 Hz, 1 H, 2-Heq), 2.47–2.38 (m, 1 H,
2
2 H, 3Ј-Harom., 5Ј-Harom.), 5.72 (br., 2 H, NH2), 4.46 (d, Jgem
=
2
7-Hax), 2.35 (d, Jgem = 11.3 Hz, 1 H, 4-Heq), 2.31–2.27 [m, 2 H,
2
11.4 Hz, 1 H, CHaHbO), 3.66 (d, Jgem = 11.4 Hz, 1 H, CHaHbO),
NCH2(CH2)2Ph], 1.97 (br., 1 H, 5-H), 1.83–1.74 (m, 1 H, 6-Heq),
1.79 (quin, 3J = 7.4 Hz, 2 H, NCH2CH2CH2Ph), 1.61–1.53 (m, 1 H,
6-Hax), 1.45–1.38 (m, 2 H, 7-Heq, 8-Heq), 1.26–1.21 (m, 1 H, 8-Hax).
13C NMR (100 MHz, BB, DEPT, HSQC, CDCl3): δ (ppm) = 142.3
(C-1arom.), 128.4 (C-3arom., C-5arom.), 128.2 (C-2arom., C-6arom.),
125.6 (C-4arom.), 75.8 (C-9), 71.3 (CH2OH), 57.6 [NCH2(CH2)2Ph],
54.9 (C-2), 52.4 (C-4), 39.0 (C-1), 36.4 (C-5), 33.6 (C-8), 33.4
[N(CH2)2CH2Ph], 30.7 (C-6), 28.7 (NCH2CH2CH2Ph), 19.6 (C-7).
2
3.51 (br., 1 H, 9-H), 2.94 (d, Jgem = 11.1 Hz, 1 H, 4-Heq), 2.85 (d,
2Jgem = 10.4 Hz, 1 H, 2-Heq), 2.83 (br., 1 H, OH), 2.68–2.63 (m,
3
3
1 H, 7-Hax), 2.65 [t, J = 7.4 Hz, 2 H, N(CH2)2CH2Ph], 2.20 [t, J
2
= 7.3 Hz, 2 H, NCH2(CH2)2Ph], 2.15 (d, Jgem = 13.0 Hz, 2 H, 2-
Hax, 4-Hax), 2.08–1.94 (m, 1 H, 6-Hax), 1.90 (br., 1 H, 5-H), 1.81–
1.72 (m, 3 H, NCH2CH2CH2Ph, 8-Hax), 1.57–1.50 (m, 2 H, 6-Heq,
7-Heq), 1.411.35 (m, 1 H, 8-Heq). 13C NMR (75 MHz, BB, DEPT,
HSQC, CDCl3): δ (ppm) = 168.7 (C=O (ester)], 150.8 (C-2Јarom.),
The 1H-1H-NOESY NMR spectra (300 MHz, CDCl3, Tmix.
=
142.5 (C-1arom.), 134.4 (C-4Јarom.), 131.2 (C-6Јarom.), 128.4 (C-3arom.
,
800 ms) shows NOEs between 9-H and 6-Hax and between 9-H and
8-Hax. NOEs between 9-H and 2-Hax or 4-Hax are not observed.
C-5arom.), 128.3 (C-2arom., C-6arom.), 125.6 (C-4arom.), 116.8 (C-
5Јarom.), 116.3 (C-3Јarom.), 110.3 (C-1Јarom.), 71.0 (C-9), 68.9
(CH2O), 61.1 (C-2), 59.1 (C-4), 57.5 (NCH2(CH2)2Ph), 39.0 (C-1),
35.4 (C-5), 33.4 (N(CH2)2CH2Ph), 29.1 (NCH2CH2CH2Ph), 27.3
(C-8), 24.1 (C-6), 20.7 (C-7).
(1R*,5S*,8S*)-1-Hydroxymethyl-3-(3-phenylpropyl)-3-azabicyclo-
[3.2.1]octan-8-ol (40): To a slurry of lithium aluminium hydride
(47 mg, 1.23 mmol) in dry THF (10 mL) was added dropwise a
solution of β-keto ester 27 (130 mg, 0.41 mmol) in dry THF (5 mL)
at 0 °C. The reaction mixture was stirred for 3 h at room tempera-
ture. The reaction was quenched by the addition of distilled water
(20 mL), and the volatiles were removed at reduced pressure. The
remaining aqueous solution was extracted with diethyl ether
(3×50 mL) and the combined organic phases were dried (MgSO4)
and concentrated in vacuo. The crude product was purified by flash
chromatography (10% MeOH in CH2Cl2). Yield 60 mg
(0.22 mmol, 54%) of a yellow oil; Rf = 0.34 (10% MeOH in
CH2Cl2). HRMS (EI): m/z calcd. for C17H25NO2: 275.1885, found:
275.1886 [M+]. 1H NMR (300 MHz, COSY, CDCl3): δ (ppm) =
Monoester 36: Yield 26 mg (0.06 mmol, 6%) of a yellow oil; Rf =
0.33 (20% EtOAc in hexane). HRMS (EI): m/z calcd. for
C25H32N2O3: 408.2413, found: 408.2413 [M+].
Diester 37: Yield 97 mg (0.18 mmol, 19%) of a yellow oil; Rf = 0.44
(20% EtOAc in hexane). HRMS (EI): m/z calcd. for C32H37N3O4:
527.2784, found: 527.2776 [M+]. 1H NMR (300 MHz, COSY,
3
4
CDCl3): δ (ppm) = 7.91 (dd, J5Ј,6Ј = 8.3, J4Ј,6Ј = 1.2 Hz, 1 H, 6Ј-
Harom.), 7.85 (dd, 3J5Ј,6Ј = 8.3, 4J4Ј,6Ј = 1.4 Hz, 1 H, 6Ј-Harom.), 7.31–
7.18 [m, 7 H, Harom. (Ph), 4Ј-Harom. (2×)], 6.67–6.60 [m, 4 H, 3Ј-
Harom. (2×), 5Ј-Harom. (2×)], 5.71 (br., 2 H, NH2), 5.65 (br., 2 H,
3
7.29–7.16 [m, 5 H, Harom. (Ph)], 3.88 (d, J5,8 = 4.8 Hz, 1 H, 8-H),
3
2
NH2), 5.11 (d, J5,9 = 3.6 Hz, 1 H, 9-H), 4.08 (d, Jgem = 11.1 Hz,
3.61 (s, 2 H, CH2OH), 2.68–2.61 [m, 3 H, 2-Heq, N(CH2)2CH2Ph],
2.53–2.46 (m, 2 H, 4-Heq, 4-Hax), 2.41–2.32 [m, 3 H, 2-Hax,
2
1 H, CHaHbO), 4.01 (d, Jgem = 11.1 Hz, 1 H, CHaHbO), 3.01 (d,
2Jgem = 11.5 Hz, 2 H, 2-Heq, 4-Heq), 2.87–2.72 (m, 1 H, 7-Hax), 2.67
NCH2(CH2)2Ph], 2.09 (br., 1 H, 5-H), 1.82–1.62 (m, 5 H, 6-Hendo
,
[t, 3J = 7.4 Hz, 2 H, N(CH2)2CH2Ph], 2.39 (d, Jgem = 11.5 Hz,
2
6-Hexo, 7-Hexo, NCH2CH2CH2Ph), 1.32–1.22 (m, 1 H, 7-Hendo).
13C NMR (75 MHz, BB, DEPT, HSQC, CDCl3): δ (ppm) = 142.5
(C-1arom.), 128.5 (C-3arom., C-5arom.), 128.2 (C-2arom., C-6arom.),
125.6 (C-4arom.), 75.9 (C-8), 69.6 (CH2OH), 56.9 [NCH2(CH2)2Ph],
54.7 (C-2), 51.8 (C-4), 44.7 (C-1), 39.7 (C-5), 33.4 [N(CH2)2-
CH2Ph], 29.0 (C-7), 28.7 (NCH2CH2CH2Ph), 24.2 (C-6).
3
1 H, 4-Hax), 2.29–2.23 (m, 2 H, 2-Hax, 5-H), 2.25 [t, J = 6.9 Hz,
2 H, NCH2(CH2)2Ph], 2.01–1.90 (m, 2 H, 6-Hax, 8-Hax), 1.83–1.73
(m, 3 H, NCH2CH2CH2Ph, 8-Heq), 1.68–1.60 (m, 2 H, 6-Heq, 7-
Heq). 13C NMR (75 MHz, BB, DEPT, HSQC, CDCl3): δ (ppm) =
167.8, 167.2 [C=O (2× ester)], 150.7, 150.5 [C-2Јarom. (2×)], 142.4
(C-1arom.), 134.1, 134.0 [C-4Јarom. (2×)], 131.1, 131.0 [C-6Јarom.
(2×)], 128.4 (C-3arom., C-5arom.), 128.3 (C-2arom., C-6arom.), 125.7
(C-4arom.), 116.7, 116.6 [C-5Јarom. (2×)], 116.3 [C-3Јarom. (2×)],
110.9, 110.7 [C-1Јarom. (2×)], 74.3 (C-9), 68.7 (CH2O), 61.5 (C-2),
58.4 (C-4), 57.3 [NCH2(CH2)2Ph], 37.9 (C-1), 33.4 [C-5, N(CH2)2-
CH2Ph], 29.0 (NCH2CH2CH2Ph), 28.6 (C-8), 25.1 (C-6), 20.6 (C-
7).
(1R*,5S*,9S*)-9-Hydroxy-3-(3-phenylpropyl)-3-azabicyclo[3.3.1]-
non-1-ylmethyl 2-Aminobenzoate (35), (1R*,5S*,9S*)-1-Hy-
droxymethyl-3-(3-phenylpropyl)-3-azabicyclo[3.3.1]non-9-yl 2-Ami-
nobenzoate (36) and (1R*,5S*,9S*)-9-(2-Aminobenzoyl)-3-(3-phen-
ylpropyl)-3-azabicyclo[3.3.1]non-1-ylmethyl 2-Aminobenzoate (37):
To a solution of diol 33a (280 mg, 0.97 mmol), N-(trifluoroacetyl)
anthranilic acid (34)[17] (226 mg, 0.97 mmol) and 4-(dimeth-
ylamino)pyridine (60 mg, 0.49 mmol) in acetonitrile (10 mL) was
added 1,3-dicyclohexylcarbodiimide (200 mg, 0.97 mmol), and the
(1R*,5S*,8S*)-8-(2-Aminobenzoyl)-3-(3-phenylpropyl)-3-azabicyclo-
[3.2.1]oct-1-ylmethyl 2-Amino-benzoate (41): Diol 40 (75 mg,
2394
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 2385–2396

Synthesis of the Azabicyclo[3.3.1]nonane Ring System by a Double Mannich Reaction
FULL PAPER
0.27 mmol) was converted directly into the diester 41 using a sim-
ilar procedure to that described above using two equiv. of N-(tri-
fluoroacetyl)anthranilic acid 34 (126 mg, 0.54 mmol), two equiv. of
1,3-dicyclohexylcarbodiimide (111 mg, 0.54 mmol) and 0.1 equiv.
of 4-(dimethylamino)pyridine (4 mg, 0.03 mmol) in acetonitrile
(10 mL). Subsequent N-deprotection with four equiv. of sodium
borohydride (41 mg, 1.08 mmol) in dry ethanol (10 mL) gave dies-
ter 41 after purification by flash chromatography (25% EtOAc in
hexane). Yield 44 mg (0.09 mmol, 33% over 2 steps) of a clear oil;
Rf = 0.69 (33% EtOAc in hexane). HRMS (EI): m/z calcd. for
C31H35N3O4: 513.2628, found: 513.2630 [M+]. 1H NMR
(300 MHz, COSY, CDCl3): δ (ppm) = 7.89 (d, 3J5Ј,6Ј = 7.9 Hz, 1 H,
(NCH2CH2CH2Ph), 28.3, 28.2 (C-8), 24.7 (C-6), 20.5, 20.4 (C-7),
17.2, 17.1 (2ЈЈЈ-CH3 or 3ЈЈЈ-CH3), 16.4, 16.2 (3ЈЈ-CH3).
(1R*,5S*,9S*)-9-(2-[3-Methyl-2,5-dioxopyrrolidin-1-yl]benzoyl)-3-
(3-phenylpropyl)-3-azabicyclo[3.3.1]non-1-ylmethyl 2-(3-methyl-2,5-
dioxopyrrolidin-1-yl)benzoate (39): A mixture of amine 37 (30 mg,
0.057 mmol) and methylsuccinic anhydride (39 mg, 0.342 mmol)
was heated at 125 °C for 4 h. The reaction mixture was then dis-
solved in warm ethyl acetate (20 mL), washed with aq. NaHCO3
(10 mL) and brine (10 mL), dried (MgSO4) and concentrated in
vacuo. The residue was purified by flash chromatography (100%
CHCl3). Yield 38 mg (0.053 mmol, 93%) of a yellow oil; Rf = 0.28
(100% CHCl3). HRMS (FAB): m/z calcd. for C42H46N3O8:
720.3285, found: 720.3292 ([M + H]+), calcd. for C42H45N3O8:
719.3207, found: 719.3196 [M+]. 1H NMR (400 MHz, COSY,
3
6Ј-Harom.), 7.76 (d, J5Ј,6Ј = 7.2 Hz, 1 H, 6Ј-Harom.), 7.30–7.17 [m,
3
3
7 H, Harom. (Ph), 4Ј-Harom. (2×)], 6.62 [t, J3Ј,4Ј = J4Ј,5Ј = 8.1 Hz,
3
3 H, 3Ј-Harom. (2×), 5Ј-Harom.], 6.52 (t, J4Ј,5Ј = 7.4 Hz, 1 H, 5Ј-
3
CDCl3): δ (ppm) = 8.08 [d, J5Ј,6Ј = 7.5 Hz, 2 H, 6Ј-Harom. (2×)],
3
Harom.), 5.70 (br., 2 H, NH2), 5.64 (br. s, 2 H, NH2), 5.06 (d, J5,8
7.64 [t, 3J3Ј,4Ј = 3J4Ј,5Ј = 7.5 Hz, 2 H, 4Ј-Harom. (2×)], 7.51–7.48 [m,
2 H, 5Ј-Harom. (2×)], 7.30–7.16 [m, 7 H, 3Ј-Harom. (2×), Harom.
(Ph)], 5.03 (br. s, 1 H, 9-H), 4.13–4.02 (m, 2 H, CH2O), 3.10–2.88
[m, 6 H, 2-Heq, 4-Heq, 3ЈЈ-H (2×), 4ЈЈ-Ha (2×)], 2.82–2.72 (m, 1 H,
7-Hax), 2.66 [t, 2 H, N(CH2)2CH2Ph, 3J = 7.3 Hz], 2.56–2.36 [m,
= 4.8 Hz, 1 H, 8-H), 4.25 (d, 2Jgem = 11.2 Hz, 1 H, CHaHbO), 4.17
2
(d, Jgem = 11.2 Hz, 1 H, CHaHbO), 2.69 (t, 3J = 7.5 Hz, 4 H,
NCH2CH2CH2Ph), 2.66–2.55 (m, 1 H, 4-Heq), 2.54–2.42 (m, 4 H,
2-Hax, 2-Heq, 4-Hax, 5-H), 2.08–1.96 (m, 1 H, 7-Hexo), 1.921.77 (m,
2
4 H, NCH2CH2CH2Ph, 6-Hendo, 6-Hexo), 1.70 (ddd, Jgem = 15.5,
2
3
2 H, 4ЈЈ-Hb (2×)], 2.34 (d, Jgem = 11.1 Hz, 1 H, 4-Hax), 2.24 [t, J
= 6.8 Hz, 2 H, NCH2(CH2)2Ph], 2.24–2.22 (m, 1 H, 2-Hax), 2.16 (s,
1 H, 5-H), 2.02–1.92 (m, 1 H, 6-Hax), 1.92–1.82 (m, 1 H, 8-Hax),
1.78 (quin, 3J = 7.3 Hz, 3 H, NCH2CH2CH2Ph), 1.72–1.55 (m, 3 H,
6-Heq, 7-Heq, 8-Heq), 1.40 (s, 3 H, 3ЈЈ-CH3), 1.39 (s, 3 H, 3ЈЈ-CH3).
13C NMR (100 MHz, BB, DEPT, HSQC, CDCl3): δ (ppm) = 179.8
[C-2ЈЈ (2×)], 175.9 [C-5ЈЈ (2×)], 163.9 [C=O (2× ester)], 142.4 (C-
4
3J6exo,7endo = J5,7endo = 4.4 Hz, 1 H, 7-Hendo). 13C NMR (75 MHz,
BB, HSQC, CDCl3): δ (ppm) = 167.8, 167.2 [C=O (2× ester)],
150.7, 150.5 [C-2Јarom. (2×)], 142.4 (C-1arom.), 134.2, 134.0 [C-
4Јarom. (2×)], 131.2, 131.0 [C-6Јarom. (2×)], 128.5 (C-3arom., C-
5arom.), 128.3 (C-2arom., C-6arom.), 125.7 (C-4arom.), 116.7, 116.6 [C-
5Јarom. (2×)], 116.3, 116.2 [C-3Јarom. (2×)], 110.9, 110.7 [C-1Јarom.
(2×)], 74.8 (C-8), 67.3 (CH2O), 56.8 (C-2), 55.6 [NCH2(CH2)2Ph],
52.6 (C-4), 44.2 (C-1), 37.4 (C-5), 33.3 [N(CH2)2CH2Ph], 28.9 (C-
7), 28.7 (NCH2CH2CH2Ph), 23.9 (C-6).
1
arom.), 133.3, 133.1 [C-4Јarom. (2×)], 133.0 [C-2Јarom. (2×)], 131.6,
131.0 [C-6Јarom. (2×)], 130.9 [C-1Јarom. (2×)], 129.8, 129.6 [C-3Јarom.
(2×)], 129.3, 129.2 [C-5Јarom. (2×)], 128.4 (C-3arom., C-5arom.), 128.3
(C-2arom., C-6arom.), 125.7 (C-4arom.), 75.3 (C-9), 69.1 (CH2O), 61.2
(C-2), 58.4 (C-4), 57.2 [NCH2(CH2)2Ph], 37.8 (C-1), 36.9 [C-4ЈЈ
(2×)], 35.2 [C-3ЈЈ (2×)], 33.4 (N(CH2)2CH2Ph), 33.1 (C-5), 29.0
(NCH2CH2CH2Ph), 28.3 (C-8), 24.9 (C-6), 20.4 (C-7), 16.3 [3ЈЈ-
CH3 (2×)].
(1R*,5S*,9S*)-2-Methyl-4-{[1-({[2-(3-methyl-2,5-dioxo-1-pyrrolidi-
nyl)benzoyl]oxy}methyl)-4-oxo-3-(3-phenylpropyl)-3-azabicyclo[3.3.1]-
non-9-yl]oxy}butanoic Acid (38a) and (1R*,5S*,9S*)-3-Methyl-4-
{[1-({[2-(3-methyl-2,5-dioxo-1-pyrrolidinyl)benzoyl]oxy}methyl)-4-oxo-
3-(3-phenylpropyl)-3-azabicyclo[3.3.1]non-9-yl]-oxy}butanoic Acid
(38b): A mixture of the amine 35 (68 mg, 0.17 mmol) and methyl-
succinic anhydride (58 mg, 0.51 mmol) was heated at 125 °C for
4 h. The reaction mixture was then dissolved in warm ethyl acetate
(30 mL), washed with aq. NaHCO3 (10 mL) and brine (10 mL),
dried (MgSO4) and concentrated in vacuo. The residue was purified
(1R*,5S*,8S*)-8-(2-[3-Methyl-2,5-dioxopyrrolidin-1-yl]benzoyl)-3-
(3-phenylpropyl)-3-azabicyclo[3.2.1]oct-1-ylmethyl 2-(3-Methyl-2,5-
dioxopyrrolidin-1-yl)-benzoate (42):
A mixture of diamine 41
(37 mg, 0.072 mmol) and methylsuccinic anhydride (49 mg,
0.432 mmol) was heated at 125 °C for 4 h. The reaction mixture
by flash chromatography (100% EtOAc). Yield 49 mg (0.08 mmol, was then dissolved in warm ethyl acetate (20 mL), washed with aq.
47%) of a yellow oil; Rf = 0.40 (20% hexane in EtOAc). HRMS
(FAB): m/z calcd. for C35H43N2O8: 619.3019, found: 619.3024
NaHCO3 (10 mL) and brine (10 mL), dried (MgSO4) and concen-
trated in vacuo. The residue was purified by flash chromatography
(2% MeOH in CHCl3). Yield 39 mg (0.055 mmol, 76%) of a yellow
1
([M + H]+). H NMR (400 MHz, COSY, CDCl3): δ (ppm) = 8.17,
3
3
3
8.09 (2× d, J5Ј,6Ј = 7.3 Hz, 1 H, 6Ј-Harom.), 7.65 (t, J3Ј,4Ј = J4Ј,5Ј
oil; Rf = 0.64 (5% MeOH in CHCl3). HRMS (FAB): m/z calcd.
3
1
= 7.6 Hz, 1 H, 4Ј-Harom.), 7.55 (dd, J4Ј,5Ј
=
3J5Ј,6Ј = 8.1 Hz, 1 H, for C41H44N3O8: 706.3128, found: 706.3120 ([M + H]+). H NMR
5Ј-Harom.), 7.30–7.16 [m, 6 H, Harom. (Ph), 3Ј-Harom.,], 5.08, 4.91
(400 MHz, COSY, CDCl3), δ (ppm) = 8.09–8.00 [m, 2 H, 6Ј-Harom.
(2× sb, 1 H, 9-H), 4.00–3.76 (m, 2 H, CH2O), 3.15–2.82 (m, 5 H, (2×)], 7.65–7.58 [m, 2 H, 4Ј-Harom. (2×)], 7.46–7.37 [m, 2 H, 5Ј-
2-Heq, 4-Heq, {2ЈЈЈ-H, 3ЈЈЈ-Ha, 3ЈЈЈ-Hb} or {2ЈЈЈ-Ha, 2ЈЈЈ-Hb, 3ЈЈЈ- Harom. (2×)], 7.29–7.16 [m, 7 H, 3Ј-Harom. (2×), Harom. (Ph)], 4.95
3
2
H}), 2.74–2.63 (m, 2 H, 7-Hax, 3ЈЈ-H), 2.64 [t, 3J = 7.2 Hz, 2 H,
(d, J5,8 = 4.8 Hz, 1 H, 8-H), 4.20 (d, Jgem = 11.0 Hz, 1 H,
2
N(CH2)2CH2Ph], 2.54–2.44 (m, 1 H, 4ЈЈ-Ha), 2.42–2.24 [m, 5 H, 2- CHaHbO), 4.10 (d, Jgem = 11.2 Hz, 1 H, CHaHbO), 3.11–2.95 [m,
3
Hax, 4-Hax, NCH2(CH2)2Ph, 4ЈЈ-Hb], 2.12, 2.06 (2× br, 1 H, 5-H),
4 H, 3ЈЈ-H (2×), 4ЈЈ-Ha (2×)], 2.67 [t, J = 7.4 Hz, 2 H, N(CH2)2-
1.90–1.73 (m, 3 H, 6-Hax, NCH2CH2CH2Ph), 1.64–1.44 (m, 7 H, CH2Ph], 2.62–2.40 [m, 7 H, 2-Hax, 2-Heq, 4-Hax, 4-Heq, 5-H, 4ЈЈ-
6-Heq, 7-Heq, 8-Hax, 8-Heq, 3ЈЈ-CH3), 1.30–1.15 (m, 3 H, 2ЈЈЈ-CH3 Hb (2×)], 2.43 [t, 3J = 6.8 Hz, 2 H, NCH2(CH2)2Ph], 2.02–1.92 (m,
3
or 3ЈЈЈ-CH3). 13C NMR (75 MHz, BB, HSQC, CDCl3): δ (ppm) =
1 H, 7-Hexo), 1.89–1.72 (m, 2 H, 6-Hendo, 6-Hexo), 1.80 (quin, J =
180.4 (C-1ЈЈЈ), 176.2 (C-2ЈЈ), 174.0 (C-5ЈЈ), 171.5 (C-4ЈЈЈ), 170.8 7.4 Hz, 3 H, NCH2CH2CH2Ph), 1.72–1.60 (m, 1 H, 7-Hendo), 1.42
[C=O (ester)], 142.4 (C-1arom.), 133.5, 133.4 (C-4Јarom.), 132.7 (C-
2Јarom.), 131.9, 131.4 (C-6Јarom.), 129.8, 129.7 (C-3Јarom.), 129.6,
(s, 3 H, 3ЈЈ-CH3), 1.41 (s, 3 H, 3ЈЈ-CH3). 13C NMR (100 MHz, BB,
DEPT, HSQC, CDCl3): δ (ppm) = 179.8 [C-2ЈЈ (2×)], 175.8 [C-5ЈЈ
129.5 (C-5Јarom.), 128.4 (C-3arom., C-5arom.), 128.3 (C-2arom., C- (2×)], 164.1, 163.9 [C=O (2× ester)], 142.4 (C-1arom.), 133.3 [C-
6arom.), 127.1 (C-1Јarom.), 125.7 (C-4arom.), 74.5, 73.8 (C-9), 69.1 4Јarom. (2×)], 132.8 [C-2Јarom. (2×)], 131.5, 131.2 [C-6Јarom. (2×)],
(CH2O), 61.5 (C-2), 58.5, 58.3 (C-4), 57.3 [NCH2(CH2)2Ph], 38.0, 129.7 [C-3Јarom. (2×)], 129.2 [C-5Јarom. (2×)], 128.5 (C-3arom., C-
37.8 (C-1), 37.3, 37.2, 37.0, 35.8, 35.7, 35.3 (C-3ЈЈ, C-4ЈЈ, C-2ЈЈЈ, C- 5arom.), 128.2 (C-2arom., C-6arom.), 127.1 [C-1Јarom. (2×)], 125.6 (C-
3ЈЈЈ), 33.4 [N(CH2)2CH2Ph], 33.1, 32.8 (C-5), 28.9 4arom.), 75.6 (C-8), 67.7 (CH2O), 56.5 (C-2), 55.2 [NCH2(CH2)2Ph),
Eur. J. Org. Chem. 2005, 2385–2396
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© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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M. A. Brimble, C. Brocke
FULL PAPER
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Acknowledgments
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Received: January 5, 2005
2396
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 2385–2396