Use of bis-(aminol) ethers derived from N-(S)-(-)-α-methylbenzylamine in reactions with resorcinarenes and double Mannich reactions

Article abstract of DOI:10.1016/j.tet.2005.03.130

The synthesis of some chiral bis-(aminol)ethers are described. Reaction of a solution of the resorcin[4]arene derived from propanal with N,N-bis(methoxymethyl)-N-(S)-(-)-α-methylbenzylamine in toluene at 85°C initially afforded a 1:1 mixture of two diastereoisomeric tetrakis(benzoxazines). Further, heating of this mixture under reflux in ethanol for 24 h afforded the crystalline (αS),(S)-diastereoisomer in 77% yield. N,N-bis(ethoxymethyl)-N-(S)-(-)-α-methylbenzylamine and N,N-bis(ethoxymethyl)-N-(R)-(+)-α-methylbenzylamine were reacted with β keto esters to afford a 1:1 mixture of the diastereoisomeric double Mannich adducts. Two of the double Mannich adducts were converted into tricyclic ABE analogues of the alkaloid methyllycaconitine 1.

Full text of DOI:10.1016/j.tet.2005.03.130

Tetrahedron 61 (2005) 5876–5888
Use of bis-(aminol) ethers derived from
N-(S)-(K)-a-methylbenzylamine in reactions with
resorcinarenes and double Mannich reactions
a
Benjamin R. Buckley,a Philip C. Bulman Page,a Harry Heaney,a, Edward P. Sampler,
*
Sarah Carley,b Constanze Brockeb and Margaret A. Brimbleb,
*
aDepartment of Chemistry, Loughborough University, Loughborough, Leicestershire LE11 3TU, UK
bDepartment of Chemistry, University of Auckland, 23 Symonds St., Auckland, New Zealand
Received 19 January 2005; revised 16 March 2005; accepted 31 March 2005
Available online 10 May 2005
Abstract—The synthesis of some chiral bis-(aminol)ethers are described. Reaction of a solution of the resorcin[4]arene derived from
propanal with N,N-bis(methoxymethyl)-N-(S)-(K)-a-methylbenzylamine in toluene at 85 8C initially afforded a 1:1 mixture of two
diastereoisomeric tetrakis(benzoxazines). Further, heating of this mixture under reflux in ethanol for 24 h afforded the crystalline (aS),(S)-
diastereoisomer in 77% yield. N,N-bis(ethoxymethyl)-N-(S)-(K)-a-methylbenzylamine and N,N-bis(ethoxymethyl)-N-(R)-(C)-a-methyl-
benzylamine were reacted with b keto esters to afford a 1:1 mixture of the diastereoisomeric double Mannich adducts. Two of the double
Mannich adducts were converted into tricyclic ABE analogues of the alkaloid methyllycaconitine 1.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
effort to exert diastereocontrol in reactions to prepare
tetrakis(benzoxazines) and the double Mannich reaction.
Bis-(aminol) ethers derived from primary amines are
efficient bis-aminoalkylating agents used for the synthesis
of tertiary amines upon reaction with a nucleophilic source.
Our synthetic work in this area has focused on their use for
the efficient preparation of secondary and tertiary amines
using aromatic nucleophiles1 and for the construction of the
azabicyclo[3.3.1]nonane ring system present in the alkaloid
methyllycaconitine 12 via use of ethyl 2-oxocyclohexane1-
carboxylate as the nucleophile in a double Mannich
2. Results and discussion
Some time ago we4 and others5,6showed that the reactions of
formaldehyde and either (R)-(C)-a-methylbenzylamine or
(S)-(K)-a-methylbenzylamine with a number of resorcin-
[4]arenes in ethanol led to the formation of crystalline
tetrakis(benzoxazines) with high diastereoselectivity and in
high yield, also that the 1H and 13C NMR spectroscopic data
for the two sets of diastereoisomers were identical and their
optical rotation values were of opposite signs. These data
established that the two sets of diastereoisomers were
enantiomers. Further, we also showed that the bis-(aminol)
ethers derived from either (R)-(C)-a-methylbenzylamine or
(S)-(K)-a-methylbenzylamine together with methanol and
paraformaldehyde gave the same diastereoisomeric tetra-
kis(benzoxazines) in high yield in ethanol.7 The diastereo-
isomerization of the tetrakis(benzoxazines) in, for example,
carefully purified and acid-free deuteriochloroform, must
proceed via a series of iminium ions that are generated
intramolecularly as a result of hydrogen bonding between
the residual phenolic hydroxyl groups and the adjacent
benzoxazine oxygen atoms and led to an approximately 2:1
reaction.3 We herein report our studies on the use of chiral
bis-(aminol) ether N,N-bis(methoxymethyl)-N-(S)-(K)-a-
methylbenzylamine 2 as a bis-aminoalkylating agent in an
Keywords: Chiral bis-(aminol) ether; Mannich reaction; Resorcinarenes;
Methyllycaconitine.
*
Corresponding authors. Tel.: C64 9 3737599x88259; fax: C64 9
3737422 (H.A.); e-mail: m.brimble@auckland.ac.nz
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.03.130

B. R. Buckley et al. / Tetrahedron 61 (2005) 5876–5888
5877
reported earlier,4 together with a small amount of other
regioisomers. The AB quartets for the methylene group(s)
between the oxygen and nitrogen atoms are the diagnostic
resonances and were observed for one diastereoisomer at dH
5.16 and 4.96 and for the second diastereoisomer at dH 5.02
and 4.74 ppm. Ethanol was then added to the oily mixture of
products and the mixture was heated under reflux for a
further, 24 h, after which time the cooled solution gave a
crystalline product in 77% yield which was shown to be the
(aS),(S)-diastereoisomer 4a dH 5.16 and 4.96 for the O–
CH2–N AB quartet, by comparison with data from related
compounds. These results establish that the tetrakis-(3,4-
dihydro-2HK1,3-benzoxazines) are initially formed as a
random mixture of regio- and diastereo-isomers and that
isomerization under equilibrium reaction conditions leads
eventually to the two thermodynamically favoured dia-
stereoisomers, one of which crystallizes from ethanolic
solution. We were interested to establish whether the
equilibrium position for the two major diastereoisomers
was solvent dependent, particularly in view of the observed
ratios in deuteriochloroform (2:1) and toluene (1:1). A
sample of the 1:1 mixture of diastereoisomers, obtained
from the reaction carried out in toluene, was dissolved in
[2H4]methanol and its 1H NMR spectrum was taken after ca.
Scheme 1.
mixture of the previously isolated product together with its
diastereoisomer (Scheme 1).4
We presumed that the reason for the diastereoselectivity in
ethanol was related to the isolated products being the most
thermodynamically stable stereoisomers as a result of
intramolecular hydrogen bonding and gearing of the phenyl
groups that are evident in the X-ray structure that we had
8
obtained.4 Bohmer carried out an experiment of the
¨
dodecanal derived resorcin[4]arene with formaldehyde
and (R)-(C)-a-methylbenzylamine in ethanol in which an
aliquot was taken and quenched just as precipitation had
started, that reaction established that the initial reaction
involved the random formation of benzoxazines in equili-
brium and that the observed diastereoselectivity resulted
from the lower solubility of one of the two diastereoisomers.
We had also carried out experiments that were designed to
establish the reason for the preferred isolation of a single
diastereoisomer in related reactions.9
1
1.5 h. The H NMR spectrum showed that the diastereo-
isomer that crystallized from ethanol was the major isomer
present in solution, the second diastereoisomer was only
present in a trace amount. These results support the view
that, in solution, the position of the equilibrium between the
two major diastereoisomers is dependent on the polarity of
the solvent and that the isolation of a single diastereoisomer
from an ethanolic solution results from a solvent–solute
interaction that results in the equilibrium favouring its
preferential formation both as a result of the hydrogen
bonding between the residual phenolic hydroxyl groups and
the adjacent benzoxazine oxygen atoms and the gearing of
the phenyl residues, as observed previously in the X-ray
crystal structures.
We now present details of our experiments using N,N-
bis(methoxymethyl)-N-(S)-(K)-a-methylbenzylamine 2a
(Scheme 2). When a solution of the resorcin[4]arene 3
derived from propanal was heated in toluene at 85 8C with
N,N-bis(methoxymethyl)-N-(S)-(K)-a-methylbenzylamine
1
2a the reaction mixture remained homogeneous and a H
NMR spectrum of an aliquot taken after a few hours showed
that a complex mixture of products was present. The solvent
was removed after 24 h and a portion of the residue was
examined by 1H NMR spectroscopy. The spectrum showed
that the product was made up of an approximately 1:1
mixture of two diastereoisomers 4a, 4b related to those that
had been observed in the diastereoisomerization reactions
In light of the ability of N,N-bis(methoxymethyl)-N-(S)-
(K)-a-methylbenzylamine 2a to influence diastereocontrol
in the above reaction with resorcinarene 3, it was decided to
investigate the ability of chiral bis-(aminol) ether 5 to exert
Scheme 2.

5878
B. R. Buckley et al. / Tetrahedron 61 (2005) 5876–5888
diastereocontrol in double Mannich reactions with cyclic b-
keto esters. Use of ethyl 2-oxocyclohexane-1-carboxylate 6
in this latter reaction provides an efficient entry to the AE
bicyclic ring system present in methyllycaconitine 1, an
alkaloid that binds with high affinity to the a7 nicotinic
acetylcholine receptor.10 A number of approaches to the
synthesis of small molecule analogues of methyllycaconi-
tine have been reported, including the synthesis of E,11 AE12
and AEF13 ring systems, some of which display significant
biological activity.11,14 The present investigation provided
an opportunity to construct the AE azabicyclo[3.3.1]nonane
ring system in enantiopure form through implementation of
an asymmetric variant of the key double Mannich reaction
we had previously developed using bis-(aminol) ethers
derived from achiral amines.
silane (2.0 equiv) with stirring for 20 h (Scheme 4). It was
envisaged that the reaction would result in the formation of
a mixture of two diastereomeric bicyclic ketones 7a, 7b
which would then be separated by flash chromatography and
further, elaborated to provide the azabicyclo[3.3.1]nonane
ring system in enantiopure AE analogue of MLA after
removal of the chiral amine group. Disappointingly the two
diastereomeric double Mannich products 7a, 7b only
appeared as a single spot upon analysis by TLC using
several solvent systems. Numerous attempts to separate the
diastereomers by flash chromatography and HPLC were
fruitless. The double Mannich product albeit as a 1:1
mixture of diastereomers 7a, 7b was afforded as a colourless
oil in 76% yield.
A similar reaction of the five membered b-keto ester 8 with
bis-(aminol) ether 5a afforded an inseparable 1:1 mixture of
the diastereoisomeric adducts 9a, 9b in 74% yield. It was
next, decided to investigate the use of allylated keto ester 10
in the double Mannich reaction with bis-(aminol) ether 2a
hoping that the presence of an allyl side chain would afford
separable diastereomeric adducts 11a, 11b. As it transpired
the adducts 11a, 11b were afforded in 77% yield also as an
inseparable 1:1 mixture. Similar yields were obtained for
the analogous reaction of the enantiomeric chiral bis-
(aminol) ether 5b with b-keto esters 6, 8 and 10.
Chiral bis-(aminol)ethers 2a, 2b and 5a, 5b were prepared
by reaction of (S)-(K)-a-methylbenzylamine or (R)-(C)-a-
methylbenzylamine with potassium carbonate (1.0 equiv)
and paraformaldehyde (2.0 equiv) in either methanol or
ethanol for 48 h followed by purification by vacuum
distillation (Scheme 3). The double Mannich reaction of
chiral bis-(aminol) ether 5a with keto ester 6 was carried out
in an analogous manner to the racemic work.3 Thus, a
mixture of b-keto ester 6 and bis-(aminol)ether 5a
(2.0 equiv) in acetonitrile was treated with trichloromethyl-
The structures of the adducts 7a, 7b were supported by a
molecular ion at m/z 315.1830 (MC) in the high resolution
mass spectrum, corresponding to the molecular formula
C19H25NO3. The 1H NMR spectrum of
a basic
3-azabicyclo[3.3.1]nonane ring system is complex yet
distinct due to the non-equivalence of the methylene
protons in the bicyclic ring system. The 1H NMR spectrum
of bicyclic ketones 7a, 7b was further, complicated due to
the doubling of signals resulting from the presence of a 1:1
diastereomeric mixture of products. Using 2D COSY and
heteronuclear 1H-13C correlated NMR spectra it was
possible to completely assign all protons and carbons
relating to either diasteromeric adduct 7a or 7b. Using data
Scheme 3. Reagents, conditions and yields: (a) K2CO3, CH2O, MeOH,
48 h, 2a, 65%; 2b, 66%. (b) K2CO3, CH2O, EtOH, 48 h, 5a, 40%; 5b, 22%.
´
obtained through structural studies performed by Arias-Perez
Scheme 4. Reagents, conditions and yields: (a) 5a, SiCl3Me, acetonitrile, 20 h, 7a:7b (1:1), 76%; (b) 5a, SiCl3Me, acetonitrile, 20 h, 9a:9b (1:1), 74%; (c) 5a,
SiCl3Me, acetonitrile, 20 h, 11a:11b (1:1), 77%.

B. R. Buckley et al. / Tetrahedron 61 (2005) 5876–5888
5879
The axial protons of 2-Hax and 4-Hax are more shielded than
the equatorial protons 2-Heq and 4-Heq due to delocalisation
of the nitrogen lone pair electrons into the trans-coplanar
C–H bond15 (Fig. 1). The assignment of the 4-H and 2-H
protons is usually derived from the four-bond coupling
constants; however, the presence of a diastereomeric
mixture in this case complicated the assignment.
Given that the two diastereomers of the double Mannich
adduct 11a, 11b were also not separable by flash chroma-
tography, it was decided to pursue the synthesis of the
oxygen containing tricyclic analogues of methyllycaco-
nitine 12a/12b and 13a/13b (Scheme 5) and the all carbon
tricyclic analogues of methyllycaconitine 14a/14b, 15a/15b
(Scheme 6) with the hope that separation of the individual
diastereoisomers would be possible at a later stage in the
synthesis.
Figure 1. Conformation of the 3-azabicyclo[3.3.1]nonane-1-carboxylate
ring system.
et al15 it was possible to assign the protons on the bicyclic ring
to axial or equatorial positions (Fig. 1).
The axial proton attached to C-7 at dH 2.83–3.00 resonates
further, downfield than the equatorial proton positioned on
the same carbon that resonates at dH 1.51–1.69, due to the
intense deshielding effect by the nitrogen lone pair that lies
in close proximity to the axial proton.15 A doublet of
doublets at dH 2.88 (JZ1.6, 11.7 Hz) was assigned to 2-Hax
and a multiplet at dH 2.98–3.02 was assigned to 4-Heq and
2-Hax*. The deshielded doublet of doublets at dH 3.10 (JZ
2.3, 11.7 Hz) was assigned to 2-Heq, while the doublet of
doublets of doublets at dH 3.30 (JZ2.3, 2.3, 11.0 Hz) was
assigned to 4-Heq*. The doublet of doublets at dH 3.36 (JZ
2.7, 11.3 Hz) was assigned to the more deshielded 2-Heq*.
The next, step in the synthesis of the ABE tricyclic
analogues 12a/12b and 13a/13b involved reduction of the
allyl substituted bicyclic ketones 11a, 11b using sodium
borohydride in aqueous THF. After careful purification by
flash chromatography the major alcohols 16a, 16b, were
afforded in 39% yield as an inseparable 1:1 mixture of the
two diastereomers together with a 1:1 mixture of the minor
alcohols 17a, 17b isolated in 32% yield.
1
The H NMR spectra of the major 16a, 16b and minor
alcohols 17a, 17b displayed a broad singlet at dH 3.61
Scheme 5. Reagents, conditions and yields: (a) NaBH4, 1:1 THF–H2O, 2 h, 16a:16b (1:1), 39%; 17a:17b (1:1), 32%; (b) NaH, 0 8C to room temperature, THF,
30 min, allyl bromide, THF, 48 h, 18a:8b (1:1), 68%; 19a:19b (1:1), 67%; (c) Cl2(PCy3)3RuZCHPh (5 mol %), CH2Cl2, 48 h, 12a:12b (1:1), 95%; 13a:13b
(1:1), 95%.

5880
B. R. Buckley et al. / Tetrahedron 61 (2005) 5876–5888
Scheme 6. Reagents, conditions and yields: (a) allyl magnesium bromide, 0 8C to room temperature, 30 min, THF, 20a:20b: 21a:21b (1:1:1:1), 74%; (b)
Cl2(PCy3)3RuZCHPh (10 mol %), CH2Cl2, 48 h, 14a:14b (1:1), 41%; 15a:15b (1:1), 36%.
(major) and dH 2.72 (minor), assigned to the hydroxyl
protons. Doublets at dH 3.10 (major) and dH 3.69 (minor)
were assigned to the methine CHOH proton. The 13C NMR
data was used to assign the stereochemistry of the 9-OH
group. The g-gauche effect establishes that the alcohols with
a syn hydroxyl group experiences an upfield shift of the
neighbouring bicyclic ring carbons in the 13C NMR
spectrum.16 Using this analysis the stereochemistry of
alcohols 16a, 16b was established to be (1R*, 5R*, 9R*)
and hence the stereochemistry of alcohols 17a, 17b was
established to be (1R*, 5R*, 9S*).
decided to investigate the synthesis of the six-membered all
carbon tricyclic analogues of methyllycaconitine 14a, 14b
and 15a, 15b as outlined in Scheme 6.
The first, step involved treatment of bicyclic ketones 11a,
11b with allyl magnesium bromide in THF to afford an
inseparable 1:1:1:1 mixture of the four possible isomeric
alcohols 20a, 20b and 21a, 21b in 74% yield. Ring closing
metathesis of the 1:1:1:1 mixture of isomeric dienes 20a/
20b, 21a/21b was next, carried out by treatment with
10 mol % Grubbs’ catalyst under reflux in dichloromethane
for 24 h to afford the ABE tricyclic carbon analogues of
methyllycaconitine 14a, 14b and 15a, 15b. After work-up of
the reaction mixture careful separation by flash chromato-
graphy afforded the tricyclic ABE analogues 14a, 14b and
15a, 15b in 41% and 36% yield respectively, both as a 1:1
mixture of diastereomers.
The next, step in the synthesis of tricyclic methyllycaco-
nitine analogues 12a, 12b required the allylation of alcohols
16a, 16b by treatment with sodium hydride and allyl
bromide to afford the allyl ethers 18a, 18b in 67% yield as a
1:1 mixture of diastereomers. Allylation of the 1:1 mixture
of the minor alcohols 17a, 17b in a similar fashion afforded
the desired allyl ethers 19a, 19b, in 68% yield.
It was next, decided to continue with the attachment of the
methylsuccinimido anthranilate ester pharmacophore to the
ether containing ABE analogues 12a, 12b with the hope that
later separation of the individual diastereomers would be
possible when further, functionality had been added to the
molecule (Scheme 7).
With the necessary diene functionality installed in the AE
bicyclic dienes 18a, 18b and 19a, 19b, subsequent ring
closing metathesis using Grubbs’ first, generation catalyst
was undertaken. Dienes 18a, 18b (1:1 mixture) were treated
with 5 mol % Grubbs’ catalyst in dichloromethane at room
temperature for 22 h. Work-up and chromatography
afforded the tricyclic ethers 12a, 12b in 95% yield as a
1:1 mixture of diastereomers. Subsequent treatment of
dienes 19a, 19b with 5 mol % Grubbs’ catalyst afforded
tricyclic ethers 13a, 13b in 95% yield also as a 1:1 mixture
of diastereomers.
Reduction of the ethyl esters 12a, 12b was performed by
treatment with lithium aluminium hydride in THF affording
alcohols 22a, 22b in 85% yield. The next, step involved the
attachment of the pharmacophore, using N-(trifluoroacetyl)-
anthranilic acid 23 following a well established protocol.3
Alcohols 22a, 22b were treated with N-(trifluoroacetyl)-
anthranilic acid 23, DMAP and DCC in acetonitrile to afford
trifluoroacetyl anthranilate esters 24a, 24b that were
subsequently treated with sodium borohydride to afford
anthranilates 25a, 25b. Finally fusion with methylsuccini-
mide afforded the substituted methyllycaconitine analogues
26a, 26b. Disappointingly the individual diastereomers
were not able to be separated during any of the steps in the
further, conversion of esters 12a, 12b to methylsuccinimido
anthranilate esters 26a, 26b.
It was hoped that the diastereomeric adducts of the
azabicyclic ring system could be separated during one of
the steps in the conversion of the allyl keto esters 11a, 11b
to the tricyclic compounds 12a, 12b and 13a, 13b.
Disappointingly, no separation of the individual isomers
by flash chromatography was possible in any of the
synthetic steps undertaken. Attempts to separate the
diastereomeric mixture of tricyclic ethers 12a, 12b by
HPLC were also unsuccessful. At this stage it was therefore,

B. R. Buckley et al. / Tetrahedron 61 (2005) 5876–5888
5881
Scheme 7. Reagents, conditions and yields: (a) LiAlH4, THF, 24 h, 22a:22b (1:1), 86%; (b) 23, DCC, DMAP, CH3CN, 24a:24b (1:1), 53%; (c) NaBH4, EtOH,
25a: 25b (1:1), 82%; (d) methylsuccinic anhydride, 125 8C, 26a:26b (1:1), 55%.
In summary, the synthesis of four analogues of the alkaloid
methyllycaconitine albeit as a 1:1 mixture of diastereomers
was successfully completed. Tricyclic ABE analogues 12a,
12b and 13a, 13b contained a seven membered ether B ring
whereas tricyclic analogues 14a, 14b and 15a, 15b
contained a six membered all carbon B ring. The AE
azabicyclo[3.3.1]nonane ring system was constructed using
a key double Mannich reaction starting from a chiral
bis(aminol)ether. The attempted asymmetric variant of the
double Mannich reaction was the first, example of the use of
a chiral bis(aminol)ether as an electrophile in a reaction
with a cyclic b-keto ester, however, disappointingly no
diastereomeric excess was observed.
sulfuric acid and heating. Infrared spectra were recorded
with a Perkin–Elmer 1600 series Fourier-transform infrared
spectrometer as thin films between sodium chloride plates.
Absorption maxima are expressed in wavenumbers (cmK1
)
with the following abbreviations: sZstrong, mZmedium,
1
wZweak and brZbroad. H and 13C NMR spectra were
obtained using Bruker AC 200B, AM 400, and DPX400
spectrometers and a JEOL EX400 spectrometer. All
chemical shifts are given in parts per million (ppm)
downfield from tetramethylsilane as internal standard (1H)
or relative to CDCl3 (13C) and J values are given in Hz. 1H
NMR data are tabulated as s, singlet; d, doublet; t, triplet; q,
quartet: m, multiplet, br, broad. High resolution mass
spectra were recorded using a VG70-SE spectrometer
operating at nominal accelerating voltage of 70 eV.
Chemical ionisation (CI) mass spectra were obtained with
ammonia as the reagent gas.
3. Experimental
3.1. General details
3.2. Standard procedure for the formation of N,N-
bis(alkoxymethyl)amines
All reactions were conducted in flame-dried or oven-dried
glassware under a dry nitrogen atmosphere unless otherwise
noted. Tetrahydrofuran was dried over sodium/benzo-
phenone and distilled prior to use. Flash chromatography
was performed using Merck Kieselgel 60 (230–400 mesh)
with the indicated solvents. Thin layer chromatography
(TLC) was carried out on precoated silica plates (Merck
Kieselgel 60F254) and compounds were visualized by UV
fluorescence or by staining with vanillin in methanolic
Dry potassium carbonate (1 mol equiv) was added to a
mixture of dry amine (1 mol equiv) and anhydrous ethanol
or methanol (4 mol equiv). Dry paraformaldehyde (2 mol
equiv) was added and the resulting mixture stirred for 48 h.
The suspension was filtered to remove all solids. Excess
ethanol or methanol was removed by distillation at ambient
pressure. The crude product was purified by vacuum

5882
B. R. Buckley et al. / Tetrahedron 61 (2005) 5876–5888
distillation to afford the N,N-bis(alkoxymethyl)amine as a
colourless oil.
nmax (thinfilm) 3355, 3034, 2962, 2928, 2870, 1601, 1468,
885; dH (400 MHz, CDCl3) 0.95 (12H, t, JZ6.8 Hz,
–CH2CH3), 1.33 (12H, d, JZ6.4 Hz, ArCHCH3), 2.24
(8H, m, CHCH2CH3), 3.75 (4H, d, JABZ17.6 Hz, NCHA-
3.2.1. N,N-Bis(methoxymethyl)-N-(R)-a-methylbenzyl-
amine 2b. The reaction was carried out according to the
standard procedure using dry (R)-a-methylbenzylamine
(5.32 mL, 41.3 mmol), anhydrous methanol (6.7 mL,
165 mmol), potassium carbonate (5.70 g, 41.26 mmol) and
paraformaldehyde (2.47 g, 82.5 mmol). The crude product
was purified by Kugelrohr distillation to afford the title
compound 2b (5.69 g, 66%) as a colourless oil; [a]DC4.5 (c
1.32, CHCl3); (Found: MC, 209.1412, C12H19NO2 requires
209.1416); nmax (neat)/cmK1 3509 (C]H), 2924, 1492
(C]C, Ar), 1382 (C]H), 1066 (C]O, ether); dH
(400 MHz, CDCl3), 1.54 (3H, d, JZ6.7 Hz, CH3), 3.08
(6H, s, OCH3) 4.20 (2H, d, JZ9.8 Hz, NCH2O), 4.28 (2H,
d, JZ9.8 Hz, NCH2O), 4.29 (1H, q, JZ6.7 Hz, CHN),
7.24–7.28 (5H, m, PhH); dC (100 MHz, CDCl3), 20.3 (CH3,
CHCH3), 54.7 (OCH3), 57.7 (CH, PhCH), 84.6 (NCH2O),
126.6 (CH, C-4), 127.5 (CH, C-3, C-5), 128.3 (CH, C-2,
C-6), 144.2 (quat., C-1); m/z (EI, %) 209 (MC, 1).
HBAr), 3.83 (4H, q, JZ6.0 Hz, CHCH3), 4.01 (4H, d, JAB
17.6 Hz, NCHAHBAr), 4.14 (4H, t, JZ7.6 Hz, CHCH2),
4.96 (4H, d, JABZ10.0 Hz, NCHAHBO), 5.16 (4H, d, JAB
Z
Z
10.0 Hz, NCHAHBO), 6.96–7.21 (24H, m, ArH) and 7.71
(4H, s, ArOH); dC (100 MHz, CDCl3) 12.73 (CH3), 21.47
(CH3), 26.76 (CH), 34.85 (CH2), 44.58 (CH), 58.06 (CH2),
80.93 (CH2), 108.98 (C), 121.00 (CH), 123.38 (C), 124.14
(C), 127.04 (CH), 127.07 (CH), 128.25 (CH), 144.55 (C),
148.84 (C) 149.70 (C).
3.3. General procedure for the double mannich reaction
To a mixture of b-ketoester (1 mol equiv) and N,N-
bis(ethoxymethyl)amine (2 mol equiv) in acetonitrile
(2 mL) was added trichloromethylsilane (2 mol equiv).
The mixture was stirred under an atmosphere of nitrogen at
room temperature for 20 h. The reaction was quenched by
the addition of sat. NaHCO3 (20 mL) and the aqueous layer
extracted with ethyl acetate (3!20 mL). The combined
organic extracts were dried (MgSO4) and concentrated in
vacuo. The crude product was purified by flash chromato-
graphy to afford the double Mannich adduct.
3.2.2. N,N-Bis(ethoxymethyl)-N-(S)-a-methylbenzyl-
amine 5a. The reaction was carried out according to the
standard procedure using dry (S)-a-methylbenzylamine
(15.0 g, 123.8 mmol), anhydrous ethanol (27.9 mL, 22.8 g,
495.1 mmol), potassium carbonate (17.1 g, 123.8 mmol)
and paraformaldehyde (7.4 g, 247.6 mmol). The crude
product was purified by vacuum distillation to afford the
title compound 5a (11.7 g, 40%) as a colourless oil (bp 95–
105 8C at 0.75 mmHg); [a]2D2K15.8 (c 2.08, CHCl3);
(Found: MC, 237.1727, C14H23NO2 requires 237.1729);
nmax (NaCl)/cmK1 2973 (C]H), 1453 (C]C, Ar), 1376
(C]H), 1072 (C–O, ether); dH (400 MHz, CDCl3) 1.15
(6H, t, JZ7.0 Hz, 2!CH2CH3), 1.48 (3H, q, 6.9 Hz,
CHCH3), 3.34–3.40 (4H, m, 2!OCH2CH3), 4.25 (1H, q,
JZ7.0 Hz, CHN), 4.29 (4H, s, 2!NCH2O), 7.24–7.38 (5H,
m, PhH); dC (100 MHz, CDCl3) 15.2 (2!CH3, CH2CH3),
20.2 (CH3, CHCH3), 57.0 (CH, PhCH), 62.3 (2!CH2,
OCH2CH3), 82.3 (NCH2O), 126.8 (CH, C-4), 127.5 (CH,
C-3, C-5), 128.1 (CH, C-2, C-6), 144.5 (quat., C-1); m/z (EI,
%) 237 (MC, 1), 192 (10), 118 (11), 105 (100), 91 (11), 79
(12), 77 (12).
3.3.1. Ethyl (1R*,5R*)-3-((S)-1-methylbenzyl)-9-oxo-3-
azabicyclo[3.3.1]nonane-1-carboxylate 7a, 7b. The reac-
tion was carried out according to the standard procedure
using ethyl 2-oxo-cyclohexane-1-carboxylate 6 (100 mg,
0.59 mmol), N,N-bis(ethoxymethyl)-(S)-a-methylbenzyl-
amine 5a (280 mg, 1.17 mmol) and trichloromethylsilane
(140 mL, 1.17 mmol). Use of 19:1 hexane–ethyl acetate as
eluent for flash chromatography afforded the title com-
pounds 7a, 7b (141 mg, 76%) as a colourless oil and as a 1:1
mixture of diastereomers; (Found: MC, 315.1830,
C19H25NO3 requires 315.1834); nmax (NaCl)/cmK1 1732
(C]O, ester), 1716 (C]O, ketone), 1453 (C]C, Ar), 1257
(tert-N, amine); dH (300 MHz, CDCl3) 1.22–1.33 (3H, m,
OCH2CH3 and OCH2CH3*), 1.39–1.42 (3H, m, CHCH3Ph
and CHCH3Ph*), 1.51–1.69 (1H, m, 7-Heq, 7-Heq*), 2.01–
2.14 (1H, m, 6-Hax, 6-Heq), 2.15–2.26 (1.5H, m, 6-Hax*,
6-Heq*, 8-Heq), 2.27–2.32 (0.5H, m, 8-Heq*), 2.34–2.41
(0.5H, m, 5-H), 2.44–2.60 (2H, m, 8-Hax, 8-Hax*, 5-H*,
4-Hax), 2.64 (0.5H, dd, JZ2.3, 11.0 Hz, 4-Hax*), 2.83–3.00
(1H, m, 7-Hax,7-Hax*), 2.88 (0.5H, dd, JZ1.6, 11.7 Hz,
2-Hax), 2.98–3.03 (1H, m, 4-Heq, 2-Hax*), 3.10 (0.5H, dd,
JZ2.3, 11.7 Hz, 2-Heq), 3.30 (0.5H, ddd, JZ2.3, 2.3,
11.0 Hz, 4-Heq*), 3.36 (0.5H, dd, JZ2.7, 11.3 Hz, 2-Heq*),
3.42 (1H, q, JZ6.7 Hz, CHCH3Ph), 4.10–4.20 (1H, m,
OCH2CH3), 4.18–4.25 (1H, m, OCH2CH3*), 7.23–7.34
(5H, m, Ar-H, Ar-H*); dC (75 MHz, CDCl3), 14.0 (CH3,
OCH2CH3), 14.1 (CH3, OCH2CH3*), 19.7 (CH3, CHCH3-
Ph), 19.9 (CH3, CHCH3Ph*), 20.6 (CH2, C-7), 20.7 (CH2,
C-7*), 33.7 (CH2, C-6), 34.1 (CH2, C-6*), 36.3 (CH2, C-8),
36.7 (CH2, C-8*), 47.1 (2!CH, C-5, C-5*), 56.9 (CH2,
C-4), 58.3 (CH2, C-4*), 58.8 (CH2, C-2), 60.0 (CH2, C-2*),
61.0 (CH2, OCH2CH3), 61.1 (CH2, OCH2CH3*), 64.2 (2!
CH, CHCH3Ph, CHCH3Ph*), 127.1, 127.2, 127.3, 128.4,
128.5 (10!CH, Ar, Ar*), 143.8 (quat., Ar), 143.9 (quat.,
Ar*), 171.1 (quat., OC]O), 171.2 (quat., OC]O*), 212.7
3.2.3. Synthesis of tetrakis-(3,4-dihydro-2H-1,3-benz-
oxazine) 4a. A solution of C-ethylcalix[4]resorcinarene 3
(500 mg, 0.83 mmol) and N,N-bis(methoxymethyl)-N-(S)-
a-methylbenzylamine 2a (710 mg, 3.4 mmol) in toluene
(20 mL) was heated at 85 8C for 24 h. After this time the
reaction mixture was allowed to cool to room temperature
and the solvent removed under reduced pressure to give a
pale brown oil. A sample was submitted for analysis by 1H
NMR spectroscopy and showed the presence of resonances
at dH 5.16 and 4.96 and at dH 5.02 and 4.74 ppm in a 1:1
ratio. Ethanol (20 mL) was added to the mixture which was
then heated under reflux for a further, 24 h. After this time
the reaction mixture was cooled using an ice-bath and the
resulting off-white precipatate was collected by filtration
and washed with cold anhydrous ethanol to give the
tetrakis(3-[1S)-1-phenylethyl]-3,4-dihydro-2H-1,3-benz-
oxazine) derivative 4a (720 mg, 77%); [a]2D2 K102.2 (c
1.19, CHCl3); (Found: CZ76.86, HZ7.16, NZ4.77%
C76H84N4O8 requires CZ77.26, HZ7.17, NZ4.74%);

B. R. Buckley et al. / Tetrahedron 61 (2005) 5876–5888
5883
(quat., C-9), 212.8 (quat., C-9*); m/z (EI, %) 315 (MC,10),
300 (22), 298 (27), 272 (21), 105 (100), 79 (13), 44 (22).
3.47 (0.5H, q, JZ6.7 Hz, CHCH3Ph*), 4.17 (2H, m,
OCH2CH3, OCH2CH3*), 4.95–4.98 (1H, m, 30-HB, 30-
HB*), 5.03–5.06 (1H, m, 30-HA, 30-HA*), 5.62–5.86 (1H, m,
20-H, 20-H*), 7.23–7.34 (5H, m, Ar-H, Ar-H*); dC (75 MHz,
CDCl3), 14.0 (CH3, OCH2CH3), 14.1 (CH3, OCH2CH3*),
18.9 (CH3, CHCH3Ph), 20.1 (CH3, CHCH3Ph*), 20.5 (2!
CH2, C-7, C-7*), 36.3 (CH2, C-8), 36.6 (CH2, C-8*), 38.7
(CH2, C-6), 39.1 (quat., C-5), 39.3 (CH2, C-10), 39.4 (CH2,
C-10*), 48.8 (quat., C-1), 48.9 (quat., C-1*), 58.6 (CH2,
C-2), 59.0 (CH2, C-2*), 60.9 (CH2, OCH2CH3), 61.0 (CH2,
OCH2CH3*), 61.7 (CH2, C-4), 62.8 (CH2, C-4*), 63.9 (CH,
CHCH3Ph), 64.3 (CH, CHCH3Ph*), 117.8 (CH2, C-30),
118.0 (CH2, C-30*), 127.0, 127.2, 127.3, 128.3, 128.4 (10!
CH, Ar, Ar*), 133.7 (2!CH, C-20, C-20*), 143.4 (quat., Ar),
143.7 (quat., Ar*), 171.1 (quat., OC]O), 171.3 (quat.,
OC]O*), 212.7 (2!quat., C-9, C-9*); m/z (EI, %) 355
(MC, 6), 340 (33), 312 (14), 209 (12), 105 (100), 79 (14), 42
(16).
3.3.2. Ethyl (1R*,5R*)-3-((S)-1-methylbenzyl)-9-oxo-3-
azabicyclo[3.2.1]octane-1-carboxylate 9a, 9b. The reac-
tion was carried out according to the standard procedure
using ethyl 2-oxo-cyclopentane-1-carboxylate 8 (100 mg,
0.64 mmol), N,N-bis(ethoxymethyl)-(S)-a-methylbenzyl-
amine 5a (300 mg, 1.28 mmol) and trichloromethylsilane
(150 mL, 1.28 mmol). Use of 19:1 hexane–ethyl acetate as
eluent for flash chromatography afforded the title com-
pounds 9a, 9b (131 mg, 74%) as a colourless oil and as a 1:1
mixture of diastereomers; (Found: MC, 301.1679,
C18H23NO3 requires 301.1678); nmax (NaCl)/cmK1 1759
(C]O, ester), 1726 (C]O, ketone), 1453 (C]C, Ar), 1262
(tert-N, amine); dH (400 MHz, CDCl3) 1.22–1.28 (3H, m,
OCH2CH3 and OCH2CH3*), 1.37–1.41 (3H, m, CHCH3Ph
and CHCH3Ph*), 1.88–2.01 (2H, m, 7-HA, 7-HA*, 7-HB,
7-HB*), 2.23–2.31 (1.5H, m, 5-H, 6-HB, 6-HB*), 2.33–2.42
(1.5H, m, 5-H*, 6-HA, 6-HA*), 2.51 (0.5H, d, JZ11.0 Hz,
4-Hax), 2.58 (0.5H, d, JZ11.0 Hz, 4-Hax*), 2.74–2.79 (1H,
m, 2-HA, 2-Hax*), 2.99 (0.5H, ddd, JZ3.5, 3.5, 11.0 Hz,
4-Heq), 3.01 (0.5H, ddd, JZ2.8, 2.8, 11.0 Hz, 4-Heq*), 3.08
(0.5H, dd, JZ2.8, 11.0 Hz, 2-Heq), 3.21 (0.5H, dd, JZ2.8,
11.0 Hz, 2-Heq*), 3.68 (1H, dq, JZ2.7, 11.0 Hz, CHCH3-
Ph), 4.15–4.22 (2H, m, OCH2CH3, OCH2CH3*), 7.23–7.36
(5H, m, Ar-H, Ar-H*); dC (100 MHz, CDCl3), 14.2 (2!
CH3, OCH2CH3*), 18.7 (CH3, CHCH3Ph), 19.1 (CH3,
CHCH3Ph*), 21.7 (2!CH2, C-7, C-7*), 27.4 (CH2, C-6),
27.5 (CH2, C-6*), 46.6 (2!CH, C-5, C-5*), 57.3 (CH2,
C-4), 58.8 (CH2, C-2), 59.6 (CH2, C-4*), 60.6 (CH2, C-2*),
60.9 (CH2, OCH2CH3), 61.9 (CH, CHCH3Ph), 62.2 (CH,
CHCH3Ph*), 127.1, 127.2, 127.3, 128.3, 128.4 (10!CH,
Ar, Ar*), 143.5 (quat., Ar), 143.6 (quat., Ar*), 170.2 (quat.,
OC]O), 170.4 (quat., OC]O*), 213.5 (quat., C-8, C-8*);
m/z (EI, %) 301 (MC, 12), 286 (17), 105 (100), 79 (13), 77
(12), 57 (15), 44 (30).
3.3.4. Ethyl (1R*,5R*,9R*)-9-hydroxy-3-((S)-1-methyl-
benzyl)-5-(20-propenyl)-3-azabicyclo[3.3.1]nonane-1-
carboxylate 16a,16b and ethyl (1R*, 5R*, 9S*)-9-
hydroxy-3-((S)-1-methylbenzyl)-5-(20-propenyl)-3-aza-
bicyclo[3.3.1]nonane-1-carboxylate 17a, 17b. To a sol-
ution of sodium borohydride (43 mg, 1.125 mmol) in THF
(7 mL) and distilled water (14 mL) at 0 8C was added
dropwise a solution of ketones 11a, 11b (0.80 g, 2.25 mmol)
in THF (7 mL). The reaction mixture was stirred for 2 h then
quenched with water (14 mL) and the volatile solvents were
removed in vacuo. The residual aqueous layer was then
extracted with ethyl acetate (3!25 mL). The combined
organic extracts were washed with brine (50 mL), dried
(MgSO4) and concentrated in vacuo. The crude product was
purified by flash chromatography using 32:1 hexane–ethyl
acetate as eluent to afford: (i) alcohols 16a, 16b (0.31 g,
39%) as a colourless oil and as a 1:1 mixture of
diastereomers; (Found: MC, 357.2298, C22H31NO3 requires
357.2304); nmax (NaCl)/cmK1 3535 (O]H), 1710 (C]O,
ester), 1638 (C]C), 1452 (C]C, Ar), 1259 (tert-N,
amine); dH (400 MHz, CDCl3) 1.26 (3H, t, JZ7.1 Hz,
OCH2CH3 and OCH2CH3*), 1.30–1.33 (3H, m, CHCH3Ph
and CHCH3Ph*), 1.51–1.59 (1H, m, 7-Heq, 7-Heq*), 1.63–
1.71 (1H, m, 6-Heq, 6-Heq*), 1.78–1.85 (1H, m, 6-Hax,
6-Hax*), 1.86 (0.5H, dd, JZ1.8, 11.4 Hz, 4-Hax), 1.96–2.13
(3.5H, m, 10-CH2, 10-CH2*, 4-Hax*, 8-Heq, 8-Heq*), 2.20
(0.5H, dd, JZ1.8, 11.4 Hz, 2-Hax), 2.58 (0.5H, dd, JZ1.8,
11.4 Hz, 4-Heq), 2.78–2.86 (1H, m, 7-Hax, 7-Hax*), 2.89
(0.5H, dd, JZ1.8, 11.4 Hz, 2-Hax*), 2.96 (0.5H, dd, JZ1.8,
11.4 Hz, 2-Heq), 3.03 (0.5H, d, JZ7.3 Hz, 9-H), 3.10 (0.5H,
d, JZ7.3 Hz, 9-H*), 3.17–3.22 (1.5H, m, CHCH3Ph,
CHCH3Ph*, 4-Heq*), 3.29 (0.5H, dd, JZ1.8, 11.0 Hz,
2-Heq*), 3.61 (1H, br s, O–H), 4.01–4.19 (2H, m,
OCH2CH3, OCH2CH3*), 4.92–4.96 (1H, m, 30-HB, 30-
HB*), 5.02–5.06 (1H, m, 30-HA, 30-HA*), 5.68–5.88 (1H, m,
20-H, 20-H*), 7.21–7.33 (5H, m, Ar-H, Ar-H*); dC
(100 MHz, CDCl3), 14.0 (2!CH3, OCH2CH3,
OCH2CH3*), 20.1 (2!CH3, CHCH3Ph, CHCH3Ph*), 20.9
(CH2, C-7), 21.0 (CH2, C-7*), 26.8 (CH2, C-8), 27.2 (CH2,
C-8*), 29.5 (CH2, C-6), 37.5 (quat., C-5), 37.6 (quat., C-5*),
42.5 (CH2, C-10), 42.9 (CH2, C-10*), 48.0 (quat., C-1), 57.7
(CH2, C-2), 59.3 (CH2, C-2*), 60.3 (CH2, OCH2CH3), 60.7
(CH2, C-4), 60.8 (CH2, C-4*), 65.1 (CH, CHCH3Ph), 74.0
(CH, C-9), 74.4 (CH, C-9*), 117.3 (CH2, C-30), 117.4 (CH2,
3.3.3. Ethyl (1R*,5R*)-3-((S)-1-methylbenzyl)-9-oxo-5-
(20-propenyl)-3-azabicyclo[3.3.1]nonane-1-carboxylate
11a, 11b. The reaction was carried out according to the
standard procedure using ethyl 2-oxo-3-(20-propenyl)cyclo-
hexane-1-carboxylate 1017 (100 mg, 0.51 mmol), N,N-
bis(ethoxymethyl)-(S)-a-methylbenzylamine 5a (240 mg,
1.02 mmol), and trichloromethylsilane (110 mL,
1.02 mmol). Use of 19:1 hexane–ethyl acetate as eluent
for flash chromatography afforded the title compounds 11a,
11b (0.14 g, 77%) as a colourless oil and as a 1:1 mixture of
diastereomers; (Found: MC, 355.2148, C22H29NO3 requires
355.2147); nmax (NaCl)/cmK1 1732 (C]O, ester), 1714
(C]O, ketone), 1639 (C]C), 1454 (C]C, Ar), 1259 (tert-
N, amine); dH (300 MHz, CDCl3) 1.26 (3H, m, OCH2CH3
and OCH2CH3*), 1.39 (3H, dq, JZ1.9, 6.7 Hz, CHCH3Ph
and CHCH3Ph*), 1.48–1.62 (1H, m, 7-Heq, 7-Heq*),
1.71–1.89 (1H, m, 6-Heq, 6-Heq*), 1.95–2.07 (1H, m,
6-Hax, 6-Hax*), 2.09–2.20 (3H, m, 10-CH2, 10-CH2*,
8-Heq, 8-Heq*), 2.22–2.30 (0.5H, dd, JZ1.6, 11.0 Hz,
4-Hax), 2.35 (0.5H, dd, JZ1.4, 11.0 Hz, 4-Hax*), 2.44–
2.58 (1H, m, 8-Hax, 8-Hax*), 2.84–2.92 (1H, m, 2-Hax,
4-Heq), 2.92–3.02 (1H, m, 7-Hax, 7-Hax*), 2.99–3.04 (0.5H,
m, 2-Hax*), 3.08 (0.5H, dd, JZ2.5, 11.0 Hz, 2-Heq), 3.18
(0.5H, dd, JZ2.5, 11.0 Hz, 4-Heq*), 3.28 (0.5H, dd, JZ2.4,
11.0 Hz, 2-Heq*), 3.38 (0.5H, q, JZ6.7 Hz, CHCH3Ph),

5884
B. R. Buckley et al. / Tetrahedron 61 (2005) 5876–5888
C-300*), 126.7, 127.3, 128.3 (10!CH, Ar, Ar*), 134.3 (CH,
C-2 ), 134.4 (CH, C-20*), 144.2 (quat., Ar), 144.3 (quat.,
Ar*), 176.7 (quat., OC]O), 176.9 (quat., OC]O*); m/z
(EI, %) 357 (MC, 10), 342 (46), 315 (15), 242 (28), 105
(100), 91 (23), 79 (18).
4-Hax*, 8-Hax, 8-Hax*), 2.09–2.21 (2H, m, 10-CH2,
10-CH2*), 2.19 (0.5H, dd, JZ1.8, 11.0 Hz, 2-Hax), 2.39
(0.5H, dd, JZ1.8, 11.0 Hz, 4-Heq), 2.62 (0.5H, dd, JZ1.8,
11.0 Hz, 2-Hax*), 2.73 (0.5H, dd, JZ1.8, 11.0 Hz, 2-Heq),
2.69–2.83 (1H, m, 7-Hax, 7-Hax*), 2.99 (0.5H, dd, JZ1.8,
11.0 Hz, 4-Heq*), 3.04 (0.5H, dd, JZ1.8, 11.0 Hz, 2-Heq*),
3.11 (0.5H, q, JZ6.7 Hz, CHCH3Ph), 3.21 (0.5H, q, JZ
6.7 Hz, CHCH3Ph*), 3.43 (1H, br s, 9-H), 3.94–4.14 (4H,
m, OCH2CH3, OCH2CH3*, 100-CH2, 100-CH2*), 4.89–4.94
(1H, m, 30-HB, 30-HB*), 4.98–5.08 (2H, m, 300-HB, 300-HB*,
30-HA, 30-HA*), 5.19–5.24 (1H, m, 300-HA, 300-HA*), 5.62–
5.72 (0.5H, m, 20-H), 5.78–5.87 (1.5H, m, 20-H*, 200-H, 200-
H*), 7.21–7.30 (5H, m, Ar-H, Ar-H*); dC (100 MHz,
CDCl3), 14.1 (CH3, OCH2CH3), 14.2 (CH3, OCH2CH3*),
19.6 (2!CH3, CHCH3Ph, CHCH3Ph*), 20.7 (CH2, C-7),
21.0 (CH2, C-7*), 26.2 (CH2, C-8), 26.6 (CH2, C-8*), 30.0
(CH2, C-6), 30.1 (CH2, C-6*), 39.0 (quat., C-5), 39.1 (quat.,
C-5*), 43.0 (CH2, C-10), 43.3 (CH2, C-10*), 48.0 (quat.,
C-1), 58.5 (2!CH2, C-2, C-2*), 59.8 (CH2 C-4), 59.9 (CH2,
C-4*), 60.5 (CH2, OCH2CH3), 60.6 (CH2, OCH2CH3*),
64.9 (CH, CHCH3Ph), 65.5 (CH, CHCH3Ph*), 73.7 (CH2,
C-100), 84.3 (CH, C-9), 84.7 (CH, C-9*), 115.2 (CH2, C-300),
117.2 (CH2, C-30), 117.4 (CH2, C-30*), 126.7, 127.2, 127.3,
128.2, 128.3 (10!CH, Ar, Ar*), 134.1 (CH, C-20), 134.2
(CH, C-20*), 135.4 (CH, C-200), 135.5 (CH, C-200*), 144.3
(quat., Ar), 144.7 (quat., Ar*), 175.6 (quat., OC]O), 175.8
(quat., OC]O*); m/z (EI, %) 397 (MC, 7) 382 (50), 356
(18), 206 (16), 105 (100), 91 (15), 41 (15).
(ii) Alcohols 17a, 17b (0.25 g, 32%) as a colourless oil and
as a 1:1 mixture of diastereomers; (Found: MC, 357.2298,
C22H31NO3 requires 357.2304); nmax (NaCl)/cmK1 3536
(O]H), 1710 (C]O, ester), 1638 (C]C), 1452 (C]C),
1259 (tert-N, amine); dH (400 MHz, CDCl3) 1.26 (3H, t, JZ
7.1 Hz, OCH2CH3 and OCH2CH3*), 1.30–1.33 (3H, m,
CHCH3Ph and CHCH3Ph*), 1.41–1.61 (2H, m, 6-Heq,
6-Heq*, 7-Heq, 7-Heq*), 1.73–1.91 (1H, m, 6-Hax, 6-Hax*),
1.96–2.07 (3.5H, m, 10-CH2, 10-CH2*, 4-Hax, 8-Heq,
8-Heq*), 2.11–2.31 (1.5H, m, 4-Hax*, 8-Hax, 8-Hax*), 2.62
(0.5H, dd, JZ1.8, 11.0 Hz, 2-Hax), 2.72 (1H, br s, OH),
2.74–2.87 (2H, m, 2-Hax, 4-Heq, 7-Hax, 7-Hax*), 2.89 (0.5H,
dd, JZ1.8, 11.4 Hz, 2-Heq), 2.96 (0.5H, dd, JZ1.8,
11.4 Hz, 4-Heq*), 3.19–3.31 (1.5H, m, CHCH3Ph, CHCH3-
Ph*, 2-Heq*), 3.69 (1H, d, JZ7.5 Hz, 9-H), 4.01–4.18 (2H,
m, OCH2CH3, OCH2CH3*), 4.96–5.01 (1H, m, 30-HB, 30-
HB*), 5.02–5.07 (1H, m, 30-HA, 30-HA*), 5.76–5.86 (1H, m,
20-H, 20-H*), 7.21–7.33 (5H, m, Ar-H, Ar-H*); dC
(100 MHz, CDCl3), 14.1 (CH3, OCH2CH3) 14.2 (CH3,
OCH2CH3*), 20.1 (CH3, CHCH3Ph), 20.2 (CH3, CHCH3-
Ph*), 20.8 (CH2, C-7), 20.9 (CH2, C-7*), 34.3 (CH2, C-8),
34.7 (CH2, C-8*), 34.9 (CH2, C-6), 35.2 (CH2, C-6*), 38.1
(quat., C-5), 41.6 (CH2, C-10), 42.0 (CH2, C-10*), 48.9
(quat., C-1), 51.6 (CH2, C-2), 54.1 (CH2, C-2*), 60.6 (CH2,
OCH2CH3), 60.7 (CH2, C-4), 65.1 (CH, CHCH3Ph), 65.2
(CH, CHCH3Ph*), 74.0 (CH, C-9), 74.4 (CH, C-9*), 117.6
(CH2, C-30), 117.7 (CH2, C-30*), 126.6, 126.8, 127.3, 127.4,
128.3 (10!CH, Ar, Ar*), 134.2 (CH, C-20), 134.3 (CH,
C-20*), 145.1 (quat., Ar), 176.5 (quat., OC]O); m/z (EI, %)
357 (MC, 11), 342 (100), 252 (33), 242 (27), 105 (90), 91
(16), 79 (14).
3.3.6. Ethyl (1R*,5R*,9S*)-3-((S)-1-methylbenzyl)-5-(20-
propenyl)-9-(20-propenyloxy)-3-azabicyclo[3.3.1]-
nonane-1-carboxylate 19a, 19b. To a suspension of
sodium hydride (33 mg, 1.38 mmol) in dry THF (9 mL) at
0 8C was added a solution of alco hols 17a, 17b (123 mg,
0.34 mmol) in dry THF (1.0 mL) and the mixture was stirred
for 30 mins. Allyl bromide (167 mg, 120 mL, 1.38 mmol)
was then added and the reaction mixture stirred for 48 h at
room temperature. The reaction was quenched by the
addition of distilled water (10 mL) and the volatile solvents
were removed in vacuo. The residual aqueous layer was
extracted with ethyl acetate (2!15 mL). The combined
organic extracts were washed with brine (20 mL), dried
(MgSO4) and concentrated in vacuo. The crude product was
purified by flash chromatography (19:1 hexane–ethyl
acetate) to afford the title compounds 19a, 19b (90 mg,
68%) as a colourless oil and as a 1:1 mixture of
diastereomers; (Found: MC, 397.2606, C25H35NO3 requires
397.2617); nmax (NaCl)/cmK1 2924 (C]H), 1731 (C]O,
ester), 1639 (C]C), 1452 (C]C, Ar), 1258 (tert-N,
amine);); dH (400 MHz, CDCl3) 1.22–1.28 (3H, m,
OCH2CH3, OCH2CH3*), 1.30–1.33 (3H, m, CHCH3Ph
and CHCH3Ph*), 1.46–1.63 (2H, m, 6-Heq, 6-Heq*, 7-Heq,
7-Heq*), 1.62–1.83 (2H, m, 8-Heq, 8-Heq*, 6-Hax, 6-Hax*),
1.81–2.23 (3H, m, 10-CH2, 1-CH2*, 8-Hax, 8-Hax*),
2.69–2.91 (1H, m, 7-Hax, 7-Hax*), 2.58–2.82 (2H, m,
2-Hax, 2-Heq, 2-Hax*, 4-Heq), 3.01 (0.5H, dd, JZ1.8,
11.0 Hz, 4-Heq*), 3.08–3.31 (1.5H, m, CHCH3Ph, CHCH3-
Ph*, 2-Heq*), 3.42–3.44 (1H, m, 9-H, 9-H*), 3.97–4.13 (4H,
m, OCH2CH3, OCH2CH3*, 100-CH2, 100-CH2*), 4.85–4.97
(1H, m, 30-HB, 30-HB*), 4.98–5.08 (2H, m, 300-HB, 300-HB*,
30-HA, 30-HA*), 5.16–5.26 (1H, m, 300-HA, 300-HA*), 5.62–
5.75 (0.5H, m, 20-H), 5.77–5.91 (1.5H, m, 200-H, 200-H*,
20-H*), 7.21–7.30 (5H, m, Ar-H, Ar-H*); dC (100 MHz,
3.3.5. Ethyl (1R*,5R*,9R*)-3-((S)-1-methylbenzyl)-5-(20-
propenyl)-9-(20-propenyloxy)-3-azabicyclo[3.3.1]-
nonane-1-carboxylate 18a, 18b. To a suspension of
sodium hydride (78 mg, 3.25 mmol), in dry THF (15 mL)
at 0 8C was added a solution of alcohols 16a, 16b (290 mg,
0.81 mmol) in dry THF (1.5 mL) and the mixture was stirred
for 30 mins. Allyl bromide (393 mg, 280 mL, 3.25 mmol)
was then added and the reaction mixture stirred for 48 h at
room temperature. The reaction was quenched by the
addition of distilled water (15 mL) and the volatile solvents
were removed in vacuo. The residual aqueous layer was
then extracted with ethyl acetate (2!20 mL). The com-
bined organic extracts were washed with brine (30 mL),
dried (MgSO4) and concentrated in vacuo. The crude
product was purified by flash chromatography using 19:1
hexane–ethyl acetate as eluent to afford the title compounds
18a, 18b (220 mg, 67%) as a colourless oil and as a 1:1
mixture of diastereomers; (Found: MC, 397.2603,
C25H35NO3 requires 397.2617); nmax (NaCl)/cmK1 2924
(C]H), 1731 (C]O, ester), 1638 (C]C), 1452 (C]C,
Ar), 1258 (tert-N, amine); dH (400 MHz, CDCl3) 1.22–1.28
(3H, m, OCH2CH3, OCH2CH3*), 1.30–1.33 (3H, m,
CHCH3Ph and CHCH3Ph*), 1.51–1.57 (1H, m, 6-Heq,
6-Heq*), 1.61–1.72 (2H, m, 7-Heq, 7-Heq*, 8-Heq, 8-Heq*),
1.79–1.84 (1H, m, 6-Hax, 6-Hax*), 1.90–2.02 (2H, m, 4-Hax,

B. R. Buckley et al. / Tetrahedron 61 (2005) 5876–5888
5885
CDCl3), 14.1 (2!CH3, OCH2CH3, OCH2CH3*), 20.3
(CH3, CHCH3Ph), 20.5 (CH3, CHCH3Ph*), 20.9 (CH2,
C-7), 26.4 (CH2, C-8), 30.0 (CH2, C-6), 39.4 (quat., C-5),
41.7 (CH2, C-10), 42.2 (CH2, C-10*), 48.9 (quat., C-1), 50.6
(CH2, C-2) 52.4 (CH2, C-2*), 59.8 (CH2, C-4), 59.9 (CH2,
C-4*), 60.2 (CH2, OCH2CH3), 65.6 (CH, CHCH3Ph), 65.7
(CH, CHCH3Ph*), 73.7 (CH2, C-100), 73.8 (CH2, C-100*),
83.2 (CH, C-9), 83.5 (CH, C-9*), 114.8 (CH2, C-300), 114.9
(CH2, C-300*), 117.4 (CH2, C-30), 117.6 (CH2, C-30*), 126.4,
126.5, 127.2, 127.3, 128.2, 128.3 (10!CH, Ar, Ar*), 134.2
(CH, C-20), 135.4 (2!CH, C-200, C-200*), 145.9 (2!quat.,
Ar, Ar*), 175.7 (quat., OC]O), 175.9 (quat., OC]O*); m/z
(EI, %) 397 (MC, 3) 382 (33), 156 (35), 141 (51), 105 (84),
71 (61), 57 (100).
dichloromethane (1 mL). The mixture was stirred for 22 h,
concentrated in vacuo and the crude product purified by
flash chromatography using 19:1 hexane–ethyl acetate as
eluent to afford the title compounds 13a, 13b (53 mg, 95%)
as a colourless oil and as a 1:1 mixture of diastereomers;
(Found: MC, 369.2297, C23H31NO3 requires 369.2304);
nmax (NaCl)/cmK1 2975 (C]H), 1731 (C]O, ester), 1652
(C]C), 1452 (C]C, Ar), 1257 (tert-N, amine); dH
(400 MHz, CDCl3) 1.17–1.21 (3H, m, OCH2CH3,
OCH2CH3*), 1.17–1.34 (5H, m, 12-Heq, 12-Heq*, 14-Heq,
14-Heq*, CHCH3Ph, CHCH3Ph*), 1.41–1.57 (1H, m, 13-
Heq, 13-Heq*), 1.81–2.16 (4H, m, 2-HA, 2-HB, 9-Hax, 11-
Hax, 12-Hax, 12-Hax*,14-Hax, 14-Hax*), 1.61–1.77 (1.5H, m,
2-HB*, 9-Hax*, 11-Hax*), 2.24–2.33 (0.5H, m, 2-HA*),
2.50–2.53 (0.5H, m, 9-Heq), 2.54–2.56 (0.5H, m, 11-Heq),
2.72–2.74 (0.5H, m, 9-Heq*), 2.75–2.77 (0.5H, m, 11eq*),
2.83–3.01 (1H, m, 13-Hax, 13-Hax*), 3.13–3.18 (1H, m,
CHCH3Ph, CHCH3Ph*), 3.69 (1H, s, 7-H, 7-H*), 3.96–4.26
(4H, m, 5-CH2, 5-CH2*, OCH2CH3, OCH2CH3*), 5.69–
5.75 (2H, m, 3-H, 3-H*, 4-H, 4-H*), 7.19–7.32 (5H, m, Ar-
H, Ar-H*); dC (100 MHz, CDCl3), 14.2 (CH3, OCH2CH3)
14.3 (CH3, OCH2CH3*), 20.6 (CH3, CHCH3Ph), 20.7 (CH3,
CHCH3Ph*), 21.2 (CH2, C-13), 21.3 (CH2, C-13*), 26.0
(CH2, C-14), 29.2 (CH2, C-12), 38.2 (quat., C-1), 39.2 (CH2,
C-2), 39.5 (CH2, C-2*), 48.8 (quat., C-8), 49.1 (quat., C-8*),
59.8 (CH2, C-9), 60.0 (CH2, C-9*), 60.2 (CH2, C-11), 60.4
(CH2, C-11*), 62.2 (CH2, OCH2CH3), 65.1 (CH, CHCH3-
Ph), 65.3 (CH, CHCH3Ph*), 68.3 (CH2, C-5), 68.8 (CH2,
C-5*), 85.5 (CH, C-7), 85.6 (CH, C-7*), 126.4, 126.8,
127.3, 127.4, 128.2, 128.3 (10!CH, Ar, Ar*), 129.1 (CH,
C-3), 130.3 (CH, C-4), 130.5 (CH, C-4*), 145.6 (quat., Ar),
146.2 (quat., Ar*), 175.1 (quat., OC]O), 175.4 (quat.,
OC]O*); m/z (EI, %) 369 (MC, 19), 354 (76), 264 (32),
105 (100), 91 (35), 79 (25), 41 (29).
3.3.7. Ethyl (1R*,7R*,8R*)-10-((S)-1-methylbenzyl)-6-
oxa-10-azatricyclo[6.3.3.0]tetradec-3-ene-8-carboxylate
12a, 12b. To a solution of bis(tricyclohexylphosphine)-
benzylidene ruthenium(IV) dichloride (7 mg, 0.009 mmol)
in dry dichloromethane (2.5 mL) was added dropwise a
solution of dienes 18a, 18b (70 mg, 0.176 mmol) in dry
dichloromethane (1 mL). The mixture was stirred for 22 h,
concentrated in vacuo and the crude product purified by
flash chromatography using 19:1 hexane–ethyl acetate as
eluent to afford the title compounds 12a, 12b (62 mg, 95%)
as a colourless oil and as a 1:1 mixture of diastereomers;
(Found: MC, 369.2301, C23H31NO3 requires 369.2304);
nmax (NaCl)/cmK1 2974 (C]H), 1734 (C]O, ester), 1654
(C]C), 1451 (C]C, Ar), 1255 (tert-N, amine); dH
(400 MHz, CDCl3) 1.17–1.20 (3H, m, OCH2CH3,
OCH2CH3*), 1.23–1.32 (5H, m, 12-Heq, 12-Heq*, 14-Heq,
14-Heq*, CHCH3Ph, CHCH3Ph*), 1.53–1.60 (1H, m, 13-
Heq, 13-Heq*), 1.68–1.84 (1.5H, m, 2-HB, 11-Hax, 11-Hax*),
1.87–2.16 (4H, m, 2-HA, 2-HA*, 2-HB*, 9-Hax, 12-Hax,
12-Hax*, 14-Hax, 14-Hax*), 2.25 (0.5H, dd, JZ1.8, 11.0 Hz,
11-Hax), 2.42 (0.5H, dd, JZ1.8, 11.0 Hz, 9-Hax), 2.53
(0.5H, dd, JZ1.8, 11.0 Hz, 9-Heq), 2.75 (0.5H, dd, JZ1.8,
11.0 Hz, 11-Heq), 2.77–2.91 (1H, m, 13-Hax, 13-Hax*), 2.89
(0.5H, dd, JZ1.8, 11.0 Hz, 9-Heq), 3.09–3.17 (1H, m,
CHCH3Ph, CHCH3Ph*), 3.61 (1H, br s, 7-H, 7-H*), 3.96–
4.23 (4H, m, 5-CH2, 5-CH2*, OCH2CH3, OCH2CH3*),
5.61–5.89 (2H, m, 3-H, 3-H*, 4-H, 4-H*), 7.21–7.32 (5H,
m, Ar-H, Ar-H*); dC (100 MHz, CDCl3), 14.2 (2!CH3,
OCH2CH3, OCH2CH3*), 20.5 (CH3, CHCH3Ph), 20.6
(CH2, C-13), 20.7 (CH2, C-13*), 26.0 (CH2, C-14), 26.4
(CH2, C-14*), 28.8 (CH2, C-12), 29.2 (CH2, C-12*), 37.0
(quat., C-1), 37.1 (quat., C-1*), 40.0 (CH2, C-2), 40.3 (CH2,
C-2*), 49.0 (quat., C-8), 49.1 (quat., C-8*), 58.8 (CH2, C-9),
59.8 (CH2, C-9*), 60.2 (CH2, C-11), 60.3 (CH2, C-11*),
62.2 (CH2, OCH2CH3), 65.1 (CH, CHCH3Ph), 65.3 (CH,
CHCH3Ph*), 68.4 (CH2, C-5), 88.5 (CH, C-7), 88.6 (CH,
C-7*), 126.8, 127.2, 128.3 (10!CH, Ar, Ar*), 130.2 (CH,
C-3), 130.3 (CH, C-3*), 130.7 (CH, C-4), 130.8 (CH, C-4*),
144.4 (quat., Ar), 144.7 (quat., Ar*), 175.1 (quat., OC]O),
175.3 (quat., OC]O*); m/z (EI, %) 369 (MC, 20), 354 (59),
264 (25), 134 (28), 105 (100), 91 (26), 44 (28).
3.3.9. Ethyl (1R*,5R*,9R*)-9-hydroxy-3-((S)-1-methyl-
benzyl)-5-(20-propenyl)-9-(20-propenyl)-3-azabicyclo-
[3.3.1]nonane-1-carboxylate 20a, 20b and ethyl (1R*,
5R*, 9S*)-9-hydroxy-3-((S)-1-methylbenzyl)-5-(20-pro-
penyl)-9-(20-propenyl)-3-azabicyclo[3.3.1]nonane-1-car-
boxylate 21a, 21b. To a solution of ketones 11a, 11b
(330 mg, 0.928 mmol) in THF (10 mL) at 0 8C was added
dropwise allyl magnesium bromide (1.4 mL, 1 M in diethyl
ether, 1.4 mmol) under an atmosphere of nitrogen. The
reaction was stirred for 1 h then warmed to room
temperature and stirred for a further, 48 h. The reaction
was quenched by the addition of sat. NH4Cl (10 mL) and the
residual aqueous layer was extracted with diethyl ether (1!
20 mL, 2!10 mL). The aqueous mixture was further,
extracted with diethyl ether (2!10 mL) and the combined
organic extracts washed with brine (20 mL), dried (MgSO4)
and concentrated in vacuo. The crude product was purified
by flash chromatography using 19:1 hexane–ethyl acetate as
eluent to afford the title compounds 20a/20b, 21a/21b
(265 mg, 74%) as a colourless oil and as a 1:1:1:1 mixture of
four diastereomers; (Found: MC, 397.2621, C25H35NO3
requires 397.2617); nmax (NaCl)/cmK1 3463 (O]H), 2984
(C]H), 1741 (C]O, ester), 1639 (C]C), 1447 (C]C,
Ar), 1373 (tert-N, amine), 1241 (tert-N, amine); dH
(400 MHz, CDCl3) 1.18–1.23 (3H, m, CHCH3Ph,
CHCH3Ph*, CHCH3Ph*0, CHCH3Ph*00), 1.27–1.34 (1.5H,
m, CHCH3Ph, CHCH3Ph*), 1.34–1.41 (1.5H, m,
CHCH3Ph*0, CHCH3Ph*00), 1.43–2.99 (11.5H, m, 10-HA,
3.3.8. Ethyl (1R*,7S*,8R*)-10-((S)-1-methylbenzyl)-6-
oxa-10-azatricyclo[6.3.3.0]tetradec-3-ene-8-carboxylate
13a, 13b. To a solution of bis(tricyclohexylphosphine)-
benzylidene ruthenium(IV) dichloride (6 mg, 0.007 mmol)
in dry dichloromethane (2.5 mL) was added dropwise a
solution of dienes 19a, 19b (60 mg, 0.151 mmol) in dry

5886
B. R. Buckley et al. / Tetrahedron 61 (2005) 5876–5888
10-HB, 10-HA*, 10-HB*, 100-HA, 100-HB, 100-HA*, 100-HB*,
2-Hax, 2-Hax*, 2-Heq, 2-Heq*, 2-Heq*0, 2-Heq*00, 4-Heq,
4-Heq*, 4-Heq*0, 4-Heq*00, 4-Hax, 4-Hax*, 4-Hax*0,
4-Hax*00,6-Heq, 6-Heq*, 6-Heq*0, 6-Heq*00, 6-Hax, 6-Hax*,
6-Hax*0,6-Hax*00, 7-Heq, 7-Heq*, 7-Heq*0, 7-Heq*00, 7-Hax,
7-Hax*, 7-Hax*0, 7-Hax*00, 8-Heq, 8-Heq*, 8-Heq*0, 8-Heq*00,
8-Hax, 8-Hax*, 8-Hax*0, 8-Hax*00), 3.12–3.36 (1.5H, m,
2-Hax*0, 2-Hax*00, CHCH3Ph, CHCH3Ph*,CHCH3Ph*0,
CHCH3Ph*00), 3.97–4.14 (2.5H, m, OCH2CH3,
OCH2CH3*, OCH2CH3*0, OCH2CH3*00, OH, OH*), 4.54
(0.25, s, 0OH*0), 4.59 (0.25, s, OH*00), 4.87–5.07 (4H, m,
30-HA, 3 -HA*, 30-HA*0, 30-HA*00, 30-HB, 30-HB*, 30-HB*0,
30-HB*00, 300-HA, 300-HA*, 300-HA*0, 300-HA*00, 300-HB,
300-HB*, 300-HB*0, 300-HB*00), 5.65–5.91 (2H, m, 20-HA,
20-HA*, 20-HA*0, 20-HA*00, 200-HB, 200-HB*, 200-HB*0,
200-HB*00), 7.23–7.37 (5H, m, Ar-H, Ar-H*, Ar-H*0,
Ar-H*00); dC (100 MHz, CDCl3), 13.6 (CH3, OCH2CH3),
13.8 (CH3, OCH2CH3*), 13.9 (CH3, OCH2CH3*0), 14.1
(CH3, OCH2CH3*00), 18.8, 19.7, 20.0, 20.1, 20.2, 20.4, 21.2
m, 2-HA, 2-HB, 2-HA*, 2-HB*, 5-HA, 13-Heq, 13-Heq*), 2.23
(0.5H, dd, JZ1.8, 11.0 Hz, 10-Hax), 2.36 (0.5H, d, JZ
11.0 Hz, 5-HA*), 2.47 (0.5H, dd, JZ1.8, 11.0 Hz, 10-Heq),
2.52–2.68 (2.5H, m, 8-Hax, 8-Hax*, 10-Hax*, 13-Hax,
13-Hax*), 2.72 (0.5H, dd, JZ1.8, 11.0 Hz, 8-Heq), 2.94–
3.06 (2H, m, 12-Hax, 12-Hax*, 8-Heq*, 10-Heq*), 3.21 (0.5H,
q, JZ6.7 Hz, CHCH3Ph) 3.33 (0.5H, q, JZ6.7 Hz,
CHCH3Ph*), 3.41 (0.5H, d, JZ11.0 Hz, OH), 3.67 (0.5H,
d, JZ11.0 Hz, OH*), 4.13 (1H, q, JZ7.1 Hz, OCH2CH3),
4.23 (1H, q, JZ7.1 Hz, OCH2CH3*), 5.53–5.69 (2H, m,
3-H, 4-H), 7.25–7.36 (5H, m, Ar-H, Ar-H*); dC (100 MHz,
CDCl3), 14.1 (CH3, OCH2CH3), 14.2 (CH3, OCH2CH3*),
19.4 (CH2, C-12), 20.9 (CH3, CHCH3Ph), 20.1 (CH3,
CHCH3Ph*), 31.4 (CH2, C-2), 31.8 (CH2, C-13), 33.9 (CH2,
C-11), 34.2 (CH2, C-11*), 35.0 (CH2, C-5), 35.4 (CH2,
C-5*), 49.6 (quat., C-7), 49.7 (quat., C-7*), 54.8 (CH2, C-8),
56.0 (CH2, C-8*), 57.4 (CH2, C-10), 59.4 (CH2, C-10*),
60.7 (CH2, OCH2CH3), 60.8 (CH2, OCH2CH3*), 65.1 (CH,
CHCH3Ph), 65.7 (CH, CHCH3Ph*), 71.3 (quat., C-6), 71.4
(quat., C-6*), 121.7 (CH, C-4), 121.9 (CH, C-4*), 125.4
(CH, C-3), 125.5 (CH, C-3*), 126.7, 127.2, 127.3, 128.2,
128.3 (10!CH, Ar, Ar*), 144.7 (quat., Ar), 145.3 (quat.,
Ar*), 176.4 (quat., OC]O), 176.6 (quat., OC]O*); m/z
(EI, %) 369 (MC, 37), 354 (100), 296 (14), 264 (26), 105
(81), 91 (15), 79 (13).
(4!CH3,
CHCH3Ph,
CHCH3Ph*,
CHCH3Ph*0,
CHCH3Ph*00 and 4!CH2, C-7, C-7*, C-7*0, C-7*00), 29.5,
29.8, 30.5, 30.7, 31.8, 32.4, 32.6, 32.8 (8!CH2, C-6, C-6*,
C-6*0, C-6*00, 00C-8, C-8*, C-80*0, C-080 *00), 37.8, 37.9, 38.0
(4!CH2, C-1 , C-100*, C-100* , C-1 *00), 39.0, 39.1, 39.4,
39.5 (4!CH2, C-10, C-10*, C-10*0, C-10*00), 50.3, 50.6, 50.7
(4!quat., C-1, C-1*, C-1*0, C-1*00), 53.1, 54.0, 55.1, 55.3,
56.6, 57.1, 57.2 (8!CH2, C-2, C-2*, C-2*0, C-2*00, C-4,
C-4*, C-4*0, C-4*00), 60.6, 60.7, 60.9, 61.0 (4!CH2,
OCH2CH3, OCH2CH3*, OCH2CH3*0, OCH2CH3*00), 64.8,
65.1, 65.2, 65.8 (4!CH, CHCH3Ph, CHCH3Ph*,
CHCH3Ph*0, CHCH3Ph*00), 74.0, 74.1, 74.4, 74.5 (4!
quat., C-9, C-9*, C-9*0, C-9*00), 116.7, 116.8, 117.0, 117.2
(8!CH2, C-30, C-30*, C-30*0, C-30*00, C-300, C-300*, C-300*0,
C-300*00), 126.6, 126.7,0 127.2, 127.3, 128.1, 128.2, 128.3
(10!CH, Ar, Ar*, Ar* , Ar*00), 134.6, 1034.7, 134.8, 134.9,
135.0, 135.1, 135.20 (8!CH, C-20, C-2 *, C-20*0, C-20*00,
C-200, C-200*, C-200* , C-200*00), 144.2, 144.3, 144.8, 145.6
(4!quat., Ar, Ar*, Ar*0, Ar*00), 177.0, 177.2, 177.4 (4!
OC]O, OC]O*, OC]O*0, OC]O*00); m/z (EI, %) 397
(MC, 13), 382 (36), 292 (18), 206 (9), 105 (100), 79 (13), 41
(13).
(ii) Alkenes 15a, 15b (80 mg, 36%) as a colourless oil and as
a 1:1 mixture of diastereomers; (Found: MC, 369.2297,
C23H31NO3 requires 369.2304); nmax (NaCl)/cmK13507
(O–H), 2911 (C–H), 1731 (C]O),1698 (C]C), 1452
(C]C, Ar), 1262 (tert-N, amine); dH (400 MHz, CDCl3)
1.21–1.49 (7.5H, m, 5-HB, 11-Heq, 11-Heq*, CHCH3Ph,
CHCH3Ph*, OCH2CH3, OCH2CH3*), 1.51–1.63 (1.5H, m,
12-Heq, 12-Heq*, 5-HB*), 1.72–2.24 (6H, m, 2-HA, 2-HB,
2-HA*, 2-HB*, 5-HA, 10-Hax, 10-Hax*, 13-Heq, 13-Heq*,
11-Hax, 11-Hax*), 2.28 (0.5H, d, JZ11.0 Hz, 5-HA*), 2.52
(0.5H, dd, JZ1.8, 11.0 Hz, 10-Heq), 2.58–2.65 (1.5H, m,
10-Hax*, 13-Hax, 13-Hax*), 2.96 (0.5H, dd, JZ1.8, 11.0 Hz,
10-Heq*), 2.94–3.11 (3H, m, 8-Hax, 8-Hax*, 8-Heq, 8-Heq*,
12-Hax, 12-Hax*), 3.24–3.31 (1H, m, CHCH3Ph,
CHCH3Ph*), 3.63–3.68 (1H, m, OCH2CH3), 4.19–4.24
(1H, m, OCH2CH3*), 5.57–5.70 (2H, m, 3-H, 3-H*, 4-H,
4-H*), 7.24–7.37 (5H, m, Ar-H, Ar-H*); dC (100 MHz,
CDCl3), 14.1 (CH3, OCH2CH3), 14.2 (CH3, OCH2CH3*),
19.4 (CH2, C-12), 20.0 (CH2, C-12*), 20.7 (CH3,
CHCH3Ph), 20.9 (CH3, CHCH3Ph*), 31.2 (CH2, C-2),
31.6 (CH2, C-2*), 31.7 (CH2, C-13), 31.8 (CH2, C-13*),
33.9 (CH2, C-11), 34.0 (CH2, C-11*), 34.2 (CH2, C-5), 34.5
(CH2, C-5*), 50.3 (quat., C-7), 50.4 (quat., C-7*), 54.5
(CH2, C-8), 54.8 (CH2, C-8*), 56.1 (CH2, C-10), 59.0 (CH2,
C-10*), 60.8 (CH2, OCH2CH3), 60.9 (CH2, OCH2CH3*),
65.1 (CH, CHCH3Ph), 65.5 (CH, CHCH3Ph*), 71.4 (quat.,
C-6), 71.5 (quat., C-6*), 122.6 (CH, C-4), 122.7 (CH, C-4*),
125.4 (CH, C-3), 125.5 (CH, C-3*), 126.6, 126.7, 127.2,
127.3, 128.3 (10!CH, Ar, Ar*), 145.5 (quat., Ar), 145.6
(quat., Ar*), 175.9 (quat., OC]O), 176.2 (quat., OC]O*);
m/z (EI, %) 369 (MC, 40), 354 (100), 292 (11), 164 (62),
105 (73), 91 (14), 44 (20).
3.3.10. Ethyl (1R*, 6R*, 7R*)-6-hydroxy-9-((S)-1-methyl-
benzyl)-9-azatricyclo[5.3.3.01,6]tridec-3-ene-7-carboxyl-
ate 14a, 14b and ethyl (1R*, 6S*, 7R*)-6-Hydroxy-9-((S)-
1-methylbenzyl)-9-azatricyclo[5.3.3.01,6]tridec-3-ene-7-
carboxylate 15a, 15b. To a solution of bis(tricyclohexyl-
phosphine)benzylidene ruthenium(IV) dichloride (46 mg,
0.06 mmol) in dry dichloromethane (7 mL) was added
dropwise a solution of dienes 20a/20b, 21a/21b (0.22 g,
0.6 mmol) in dry dichloromethane (3 mL). The mixture was
heated under reflux for 48 h, concentrated in vacuo and the
crude product purified by flash chromatography using 19:1
hexane–ethyl acetate as eluent to afford:
(i) alkenes 14a, 14b (91 mg, 41%) as a colourless oil and as
a 1:1 mixture of diastereomers; (Found: MC, 369.2305,
C23H31NO3 requires 369.2304); nmax (NaCl)/cmK1 3518
(O–H), 2976 (C–H), 1731 (C]O, ester), 1698 (C]C), 1453
(C]C,Ar), 1261 (tert-N, amine); dH (400 MHz, CDCl3)
1.22–1.45 (7H, m, 11-Heq, 11-Heq*, CHCH3Ph, CHCH3Ph*,
OCH2CH3, OCH2CH3*), 1.57–1.64 (1.5H, m, 12-Heq, 12-
Heq*, 5-HB), 1.73–1.78 (0.5H, m, 5-HB*), 1.82–2.19 (3.5H,
3.3.11. (1R*,7S*,8R*)-10-((S)-1-Methylbenzyl)-6-oxa-10-
azatricyclo[6.3.3.0]tetradec-3-en-8-yl)methanol 22a,
22b. To a slurry of lithium aluminium hydride (17 mg,
0.44 mmol) in dry THF (5 mL) was slowly added a solution

B. R. Buckley et al. / Tetrahedron 61 (2005) 5876–5888
5887
of esters 12a, 12b (33 mg, 0.088 mmol) in dry THF (2 mL)
and the mixture stirred under an atmosphere of nitrogen for
24 h. The reaction was quenched on the addition of
Na2SO4$10H2O and stirring was continued for 1 h. The
mixture was filtered through Celitew and the filtrate
concentrated in vacuo. The residue was dissolved in ethyl
acetate (50 mL) washed with sat. NaHCO3 (20 mL), brine
(20 mL) then dried (MgSO4) and concentrated in vacuo.
The crude product was purified by flash chromatography
using 19:1 hexane–ethyl acetate as eluent to afford the title
compounds 22a, 22b (25 mg, 85%) as a colourless oil and as
a 1:1 mixture of diastereomers; (Found: MC, 327.2199,
C21H29NO2 requires 327.2198); nmax (NaCl)/cmK1 3429
(O–H), 2921 (C–H), 1451 (C]C, Ar), 1105 (C]O, ether),
1255 (tert-N, amine); dH (400 MHz, CDCl3) 0.82–1.23 (1H,
m, 12-Heq, 14-Heq) 1.26–1.33 (4H, m, 12-Heq*, 14-Heq*,
CHCH3Ph, CHCH3Ph*), 1.54–1.59 (1H, m, 13-Heq, 13-
Heq*), 1.64–1.71 (1H, m, 2-HB, 11-Hax), 1.76 (0.5H, dd, JZ
1.8, 11.0 Hz, 9-Hax), 1.85–2.01 (4H, m, 2-HA*, 2-HB*,
9-Hax*, 11-Hax*, 12-Hax, 12-Hax*, 14-Hax, 14-Hax*), 2.10–
2.17 (0.5H, m, 2-HA), 2.44 (0.5H, dd, JZ1.8, 11.0 Hz,
9-Heq), 2.49 (0.5H, dd, JZ1.8, 11.0 Hz, 11-Heq), 2.68–2.93
(2H, m, 9-Heq*, 11-Heq*, 13-Hax, 13-Hax*), 3.06–3.11 (1H,
m, CHCH3Ph, CHCH3Ph*), 3.12–3.19 (0.5H, m,
CHAHBOH), 3.27–3.28 (1H, m, 7-H, 7-H*), 3.27–3.34
(0.5H, m, CHAHBOH), 3.32 (0.5H, d, JZ11.0 Hz,
CHAHBOH*), 3.48 (0.5H, d, JZ11.0 Hz, CHAHBOH*),
4.00–4.07 (1H, m, 5-HB), 4.23–4.30 (1H, m, 5-HA), 5.69–
5.93 (2H, m, 3-H, 4-H), 7.22–7.30 (5H, m, Ar-H, Ar-H*); dC
(100 MHz, CDCl3) 20.5 (CH3, CHCH3Ph), 20.7 (CH2,
C-13), 20.8 (CH2, C-13*), 26.6 (CH2, C-14), 27.0 (CH2,
C-14*), 29.1 (CH2, C-12), 29.5 (CH2, C-12*), 36.9 (quat.,
C-1), 37.0 (quat., C-1*), 39.7 (quat., C-8), 39.9 (CH2, C-2),
40.0 (CH2, C-2*), 58.6 (CH2, C-9), 59.5 (CH2, C-9*), 62.4
(CH2, C-11), 63.7 (CH2, C-11*), 65.4 (CH, CHCH3Ph), 65.6
(CH, CHCH3Ph*), 67.9 (CH2, C-5), 70.8 (CH2, CH2OH),
71.0 (CH2, CH2OH*), 92.8 (CH, C-7), 92.9 (CH, C-7*),
126.7, 127.2, 127.3, 128.3 (10!CH, Ar, Ar*), 129.7 (CH,
C-3), 129.8 (CH, C-3*), 132.1 (CH, C-4), 132.3 (CH, C-4*),
144.6 (quat., Ar), 145.0 (quat., Ar*); m/z (EI, %) 327 (MC,
34), 312 (78), 222 (23), 134 (39), 105 (100), 91 (23), 44
(25).
1.88–2.28 (4H, m, 2-Ha, 2-Ha*, 2-Hb, 9Hax*, 11Hax, 11Hax*,
14Heq, 14Heq*), 2.56 (0.5H, d, 2JgemZ12.8 Hz, 9Heq), 2.80–
2.98 (2H, m, 9Heq*, 11-Heq, 13Hax, 13Hax*), 3.07–3.19
(2.5H, m, 7H, 7H*, 11-Heq*, NCH(CH3)Ph, NCH(CH3)-
Ph*), 3.86–4.28 (m, 4H, 5Ha, 5Ha*, 5-Hb, 5-Hb*, CH2O,
CH2O*), 5.67 5.96 (2H, m, 3-H, 3-H*, 4-H, 4-H*), 7.13–
7.31 (6H, m, 40-H, 40-H*, H(Ph), H*(Ph*)), 7.59–7.72
3
(1.5H, m, 30-H*, 50-H, 50 H*), 8.05 (0.5H, dd, J3 ,4
Z
Z
0
0
4
3
0
0
0
0
0
8.0 Hz, J3 ,5 Z1.5 Hz, 3 -H), 8.64 (0.5H, d, J5 *,6 *
3
8.4 Hz 60-H*), 8.69 (0.5H, d, J5 ,6 Z8.4 Hz 6 -H), 12.33
(0.5H, s, NH*), 12.40 (0.5H, s, NH); dC (75 MHz, CDCl3)
20.4 (NCH(CH3)Ph*), 20.6 (C-13, C 13*), 20.7
(NCH(CH3)Ph), 27.5 (C 12*), 27.8 (C 12), 29.3 (C-14*),
29.7 (C-14), 36.7 (C-1*), 36.9 (C-1), 39.9 (C-8, C-8*), 40.0
(C-2*), 40.2 (C-2), 58.6 (C-11*), 59.8 (C-11), 62.7 (C-9*),
63.7 (C-9), 65.4 (NCH(CH3)Ph*), 65.5 (NCH(CH3)Ph),
68.4 (C-5, C-5*), 71.0 (CH2O*), 71.3 (CH2O), 88.2 (C 7*),
88.6 (C 7), 116.4 (C-10*), 116.5 (C-10), 120.7 (C 60*), 120.8
(C 60), 124.7 (C-40*), 124.8 (C-40), 126.7 (C-4*), 126.8
(C-4), 127.3 (C-2, C-2*, C 6, C 6*), 128.3 (C 3, C 3*, C-5,
C-5*), 130.2 (C-3*), 130.3 (C-3), 130.7 (C-30, C 30*), 131.2
(C-4*), 131.3 (C-4), 134.7 (C 50*), 134.9 (C 50), 139.1
(C-20*), 139.2 (C-20), 144.6 (C-1*), 144.8 (C-1), 168.0
(C]O* (ester)), 168.2 (C]O (ester)).
0
0
0
3.3.13. (1S,7R,8S)-(10-((1S)-1-phenylethyl)-6-oxa-10-
azatricyclo[6.3.3.01,7]-tetradec-3-en-8-yl)methyl 2-amino-
benzoate 25a and (1R,7S,8R)-(10-((1S)-1-phenylethyl)-6-
oxa-10-azatricyclo[6.3.3.01,7]tetradec-3-en-8-yl)methyl
2-aminobenzoate 25b. To a mixture of trifluoroaceates 24a,
24b (24 mg, 0.044 mmol) in dry ethanol (5 mL) was added
sodium borohydride (7 mg, 0.176 mmol) and the reaction
mixture was stirred for 20 h at room temperature. The
reaction was quenched with water (5 mL) and the volatiles
were removed at reduced pressure. The residue was
dissolved in ethyl acetate (30 mL), washed with aq.
NaHCO3 (10 mL) and brine (10 mL), dried (MgSO4) and
concentrated in vacuo. The crude product was purified by
flash chromatography (10% EtOAc in hexane) to afford the
title compounds 25a,25b (16 mg, 82%) as a colourless oil
and as a 1:1 mixture of diastereomers; (Found: MC,
446.2573, C28H34N2O3 requires 446.2569); dH (400 MHz,
CDCl3) 1.07–1.16 (0.5H, m,14-Hax*), 1.22–1.44 (4H, m,
12-Hax*, 14-Hax, NCH(CH3)Ph, NCH(CH3)Ph*), 1.47–1.76
(3.5H, m, 2-Hb*, 9Hax, 12Hax, 12-Heq, 12-Heq*, 13Heq,
13Heq*), 1.87 2.17 (3.5H, m, 2-Ha, 2Ha*, 2-Hb, 9Hax*,
3.3.12. (1S,7R,8S)-(10-((1S)-1-Phenylethyl)-6-oxa-10-
azatricyclo[6.3.3.01,7]tetra-dec-3-en-8-yl)methyl 2-(N-
trifluoroacetyl)aminobenzoate 24a and (1R,7S,8R)-(10-
((1S)-1-phenylethyl)-6-oxa-10-azatricyclo[6.3.3.01,7]-
tetradec-3-en-8-yl)methyl 2-(N-trifluoroacetyl)amino-
benzoate 24b. To a mixture of alcohols 22a, 22b (32 mg,
0.098 mmol), N (trifluoroacetyl)anthranilic acid 2318
(69 mg, 0.294 mmol) and 4 (dimethylamino)pyridine
(6 mg, 0.049 mmol) in acetonitrile (10 mL) was added
1,3-dicyclohexyl-carbodiimide (61 mg, 0.294 mmol), and
the reaction mixture was stirred for 20 h at 40 8C. The
reaction mixture was cooled, filtered, and the filtrate
evaporated to dryness. The residue was purified by flash
chromatography (10% EtOAc in hexane) to afford the title
compounds 24a, 24b (28 mg, 53%) as a colourless oil and as
a 1:1 mixture of diasteromers; (Found: MC, 542.2391,
C30H33F3N2O4 requires 542.2392); dH (400 MHz, CDCl3)
1.08–1.17 (0.5H, m, 14-Hax*), 1.23–1.43 (4H, m, 12-Hax*,
14-Hax, NCH(CH3)Ph, NCH(CH3)Ph*), 1.48–1.77 (3.5H,
m, 2-Hb*, 9Hax, 12-Hax, 12-Heq, 12-Heq*, 13Heq, 13Heq*),
2
11Hax, 14Heq, 14Heq*), 2.25 (0.5H, dd, JgemZ10.7 Hz,
2
4J11ax*,12ax*Z1.8 Hz, 11Hax*), 2.53 (0.5H, d, Jgem
Z
11.4 Hz, 9Heq), 2.78–2.95 (2H, m, 9Heq*, 11-Heq, 13Hax,
13Hax*), 3.05–3.17 (1.5H, m, 11-Heq*, NCH(CH3)Ph,
NCH(CH3)Ph*), 3.21 (0.5H, s, 7H*), 3.22 (0.5H, s, 7H),
3.86–4.27 (4H, m, 5Ha, 5Ha*, 5-Hb, 5-Hb*, CH2O, CH2O*),
5.62 5.91 (4H, m, 3-H, 3-H*, 4-H, 4-H*, NH2, NH2*),
6.56–6.69 (2H, m, 30-H, 30 H*, 50-H, 50 H*), 7.20–7.34 (6H,
3
m, 40-H, 40-H*, H(Ph), H*(Ph*)), 7.56 (0.5H, dd, J5 *,6 *
Z
Z
0
0
4
3
8.0 Hz, J4 *,6 *Z1.4 Hz, 60-H*), 7.84 (0.5H, dd, J5 ,6
0
0
0
0
4
0
0
0
8.3 Hz, J4 ,6 Z1.5 Hz, 6 -H); dC (75 MHz, CDCl3) 20.5
(NCH(CH3)Ph*), 20.7 (C-13, C 13*), 20.8 (NCH(CH3)Ph),
27.6 (C 12*), 27.9 (C 12), 29.5 (C-14*), 29.9 (C-14), 36.7
(C-1*), 36.9 (C-1), 39.8, 39.9, 40.0, 40.3 (C-2, C-2*, C-8,
C-8*), 58.8 (C 11*), 59.8 (C-11), 62.6 (C-9*), 64.0 (C-9),
65.4 (NCH(CH3)Ph*), 65.6 (NCH(CH3)Ph), 68.4 (C-5,
C-5*), 69.2 (CH2O*), 69.4 (CH2O), 88.1 (C 7*), 88.4 (C 7),

5888
B. R. Buckley et al. / Tetrahedron 61 (2005) 5876–5888
111.1 (C-10, C-10*), 116.2 (C-30*), 116.3 (C-30), 116.6 (C
50*), 116.7 (C 50), 126.7 (C-4, C-4*), 127.3 (C-2*, C-6*),
127.4 (C-2, C-6), 128.3 (C 3, C 3*, C-5, C-5*), 130.2
(C-3*), 130.4 (C-3), 131.0 (C 60, C 60*), 131.1 (C-4*), 131.2
(C-4), 133.9 (C-40*), 134.0 (C-40), 144.9 (C-1*), 145.1
(C-1), 150.4 (C-20*), 150.5 (C-20), 167.9 (C]O* (ester)),
168.1 (C]O (ester)).
References and notes
1. (a) Earle, M. J.; Fairhurst, R. A.; Heaney, H.; Papageorgiou,
G.; Wilkins, R. F. Tetrahedron Lett. 1990, 31, 4229. (b)
Cooper, M. S.; Earle, M. J.; Fairhurst, R. A.; Heaney, H.;
Papageorgiou, G.; Wilkins, R. F. Synlett 1990, 617. (c)
Heaney, H.; Papageorgiou, G.; Wilkins, R. F. Tetrahedron
1995, 51, 10737.
3.3.14. (1S,7R,8S)-(10-((1S)-1-Phenylethyl)-6-oxa-10-
azatricyclo[6.3.3.01,7]-tetradec-3-en-8-yl)methyl 2-(3-
methyl-2,5-dioxopyrrolidin-1-yl)benzoate 26a and
(1R,7S,8R)-(10-((1S)-1-phenylethyl)-6-oxa-10-azatricyclo-
[6.3.3.01,7]tetra-dec-3-en-8-yl)-methyl 2-(3-methyl-2,5-
dioxopyrrolidin-1-yl)benzoate 26b. A mixture of amines
25a, 25b (14 mg, 0.031 mmol) and methylsuccinic
anhydride (11 mg, 0.093 mmol) was heated at 125 8C for
4 h. The reaction mixture was dissolved 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) to afford the title compounds 26a, 26b (9 mg, 55%)
as a colourless oil and as a 1:1 mixture of diastereomers;
(Found: MC, 542.2776, C33H38N2O5 requires 542.2781); dH
(400 MHz, CDCl3) 1.06–1.14 (0.5H, m, 12-Hax*), 1.40–
1.62 (4.5H, m, 12Hax, 14-Hax, 14Hax*, NCH(CH3)Ph,
NCH(CH3)Ph*), 1.55–1.62 (4H, m, 13Heq, 13Heq*,
300-CH3, 300-CH3*), 1.60–1.74 (1.5H, m, 9Hax, 12-Heq,
12-Heq*), 1.85–2.23 (4.5H, m, 2-Ha, 2Ha*, 2-Hb, 2-Hb*,
9Hax*, 11Hax, 11Hax*, 14Heq, 14Heq*), 2.45–2.62 (1.5H, m,
9Heq, 400 Hb, 400-Hb*), 2.76 2.93 (2H, m, 9Heq*, 11-Heq,
13Hax, 13Hax*), 3.00–3.18 (4.5H, m, 300 H, 300-H*, 400-Ha,
400-Ha*, 7H, 7H*, 11-Heq*, NCH(CH3)Ph, NCH(CH3)Ph*),
3.87 4.26 (4H, m, 5Ha, 5Ha*, 5-Hb, 5-Hb*, CH2O, CH2O*),
2. (a) Manske, R. H. Can. J. Res. 1938, 16B, 57. (b) Pelletier,
S. W.; Joshi, B. S. In Pelletier, S. W., Ed.; Alkaloids: Chemical
and Biological Perspectives; Springer: New York, 1991; 7,
p 297.
3. Brocke, C.; Brimble, M. A.; Lin, D. S.; McLeod, M. D. Synlett
2004, 2359.
4. El Gihani, M. T.; Heaney, H.; Slawin, A. M. Z. Tetrahedron
Lett. 1995, 36, 4905.
5. Iwanek, W.; Mattay, J. Liebigs Ann. Chem. 1995, 1463.
¨
6. Arnecke, R.; Bohmer, V.; Friebe, S.; Gebauer, S.; Krauss,
G. J.; Thondorf, I.; Vogt, W. Tetrahedron Lett. 1995, 36, 6221.
7. Page, P. C. B.; Heaney, H.; Sampler, E. P. J. Am. Chem. Soc.
1999, 121, 6751.
¨
8. Schmidt, C.; Paulus, E. F.; Bohmer, V.; Vogt, W. New
J. Chem. 2001, 25, 374.
9. Sampler, E. P. PhD Thesis, Loughborough University, 2001.
10. Davies, A. R. L.; Hardick, D. J.; Blagbrough, I. S.; Potter,
B. V. L.; Wolstenholme, A. J.; Wonnacott, S. Neuropharma-
cology 1999, 38, 679.
11. (a) Bergmeier, S. C.; Lapinsky, D. J.; Free, R. B.; McKay,
D. B. Bioorg. Med. Chem. Lett. 1999, 9, 2263. (b) Doisy, X.;
Blagbrough, I. S.; Wonnacott, S.; Potter, B. V. L. Pharm.
Pharmacol. Commun. 1998, 4, 313.
12. Trigg, W. J.; Hardick, D. J.; Grangier, G.; Wonnacott, S.;
Lewis, T.; Rowan, M. G.; Potter, B. V. L.; Blagbrough, I. S.
ACS Symp. Ser. 1998, 686, 194.
5.63 5.92 (2H, m, 3-H, 3-H*, 4-H, 4-H*), 7.21–7.36 (6H, m,
0
3
30-H, 30 H*, H(Ph), H(Ph*)), 7.44 (0.5H, ddd, J4 *,5 *
Z
0
3
4
7.7 Hz, J5 *,6 *Z7.7 Hz, J3 *,5 *Z1.1 Hz, 50 H*), 7.54
0
0
0
0
13. (a) Baillie, L. C.; Bearder, J. R.; Li, W.-S.; Sherringham, J. A.;
Whiting, D. A. J. Chem. Soc., Perkin Trans. 1 1998, 4047. (b)
Kraus, G. A.; Dneprovskaia, E. Tetrahedron Lett. 1998, 39,
2451.
3
3
4
0
0
0
0
0
0
(0.5H, ddd, J4 ,5 Z7.7 Hz, J5 ,6 Z7.7 Hz, J3 ,5 Z1.1 Hz,
50-H), 7.61–7.70 (1H, m, 40-H, 40-H*), 7.75 (0.5H, d,
3
3
J5 *,6 *Z7.9 Hz, 60-H*), 8.08 (0.5H, d, J5 ,6 Z7.8 Hz,
0
0
0
0
60-H,); dC (75 MHz, CDCl3) 16.3 (300 CH3*), 16.5 (300-CH3),
20.6 (C-13, C-13*, NCH(CH3)Ph, NCH(CH3)Ph*), 27.5
(C-12*), 27.8 (C-010 2), 29.4 (C-14*), 29.8 (C-14), 35.2
(C-300*), 35.4 (C-3 ), 36.6 (C-1*), 36.8 (C-1), 37.0 (C-400,
C-400*), 39.8, 39.9, 40.3 (C-2, C-2*, C-8, C-8*), 58.6
(C-11*), 59.7 (C-11), 62.6 (C-9*), 63.8 (C-9), 65.4
(NCH(CH3)Ph*), 65.5 (NCH(CH3)Ph), 68.4 (C-5, C-5*),
70.1 (CH2O, CH2O*), 88.0 (C 7*), 88.4 (C 7), 126.6 (C-4*),
126.7 (C-4), 127.3 (C-2*, C-6*, C-10, C-10*),0 127.4 (C 2,
C-6), 128.3 (C 3, C 3*, C-5, C-5*), 129.4 (C 5 *), 129.5 (C
50), 129.9 (C-30*), 130.00(C-30), 130.3 (C-3, C-3*), 1300.4
(C-4, C-4*), 131.2 (C 6 *), 131.4 (C 60), 132.9 (C-2 *),
133.0 (C-20), 133.3 (C-40*), 133.4 (C-40), 144.9 (C-1, C-1*),
164.0 (C]O, C]O* (ester)), 176.1 (C 500, C 500*), 180.0
(C-200, C-200*).
14. (a) Davies, A. R. L.; Hardick, D. J.; Blagbrough, I. S.; Potter,
B. V. L.; Wolstenholme, A. J.; Wonnacott, S. Biochem. Soc.
Trans. 1997, 25, 545S. (b) Bryant, D. L.; Free, R. B.; Thomasy,
S. M.; Lapinsky, D. J.; Ismail, K. A.; McKay, S. B.;
Bergmeier, S. C.; McKay, D. B. Neurosci. Res. 2002, 42, 57.
´ ´ ´
15. Arias-Perez, M. S.; Alejo, A.; Galvez, E.; Perez, S. M.; Santos,
M. J. J. Mol. Struct. 1995, 349, 169.
16. Jeyaraman, R.; Jawaharsingh, C. B.; Avila, S.; Eliel, E. L.;
Ganapathy, K.; Manoharan, M.; Morris-Natschke, S.
J. Heterocycl. Chem. 1982, 19, 449.
17. Gravel, D.; Labelle, M. Can. J. Chem. 1985, 63, 1874.
18. Schepartz, A.; Breslow, R. J. Am. Chem. Soc. 1987, 109, 1814.