Combining two-directional synthesis and tandem reactions:? an efficient strategy for the total syntheses of (±)-hippodamine and (±)-epi-hippodamine

Article abstract of DOI:10.1039/b413052a

Two-directional total stereoselective syntheses of (±)-hippodamine and (±)-epi-hippodamine, utilising a tandem deprotection/intramolecular double Michael addition sequence as the key step, are presented.

Full text of DOI:10.1039/b413052a

View Article Online / Journal Homepage / Table of Contents for this issue
A R T I C L E
Combining two-directional synthesis and tandem reactions:† an
efficient strategy for the total syntheses of ( )-hippodamine and
( )-epi-hippodamine‡
Martin Rejzek,a Robert A. Stockman*a and David L. Hughesb
a School of Chemical Sciences and Pharmacy, University of East Anglia, Norwich, UK NR4
7TJ. E-mail: r.stockman@uea.ac.uk; Fax: +44 (0)1603 592003; Tel: +44 (0)1603 593890
b X-Ray Crystallography Unit, School of Chemical Sciences and Pharmacy, University of East
Anglia, Norwich, UK NR4 7TJ
Received 25th August 2004, Accepted 30th September 2004
First published as an Advance Article on the web 8th November 2004
Two-directional total stereoselective syntheses of ( )-hippodamine and ( )-epi-hippodamine, utilising a tandem
deprotection/intramolecular double Michael addition sequence as the key step, are presented.
attraction of parasitic insects to the ladybird alkaloids suggests
that there is potential for development of control strategies for
this particular natural enemy.
Introduction
Ladybird beetles (Coleoptera: Coccinellidae) are important
predators contributing to the natural control of pest aphid
populations and are therefore of considerable interest for insect
pest management. However, ladybirds themselves are attacked
by a range of natural enemies. General predation on ladybirds
by vertebrates such as birds is largely prevented by highly toxic,
bitter tasting, defence alkaloids contained in a reflex bleed
released when the ladybird is attacked. To date, eight alkaloids
of this type have been isolated from coccinellid beetles,1 all of
them being formally derivatives of perhydro-9b-azaphenalene
(or dodecahydro-pyrido[2,1,6-de]quinolizine) (Fig. 1).
In addition to their bitter taste, the coccinellid alkaloids
also seem to interfere with the nervous systems of higher
animals. Certain derivatives of coccinellid alkaloids have re-
cently been shown3 to be potent receptor antagonists of the
neurotransmitter serotonin. This pharmacological property
makes these compounds attractive for the treatment of a
number of gastrointestinal and brain disorders. One of the most
intriguing properties is the ability of these compounds to prevent
behavioural consequences of the withdrawal of drugs such as
nicotine. For these reasons much attention has been paid to
developing syntheses of the coccinellid defence alkaloids.1
Hippodamine (1) is a naturally occurring alkaloid isolated
from a ladybird beetle Hippodamia convergens by Tursch and
co-workers in 1972.4 The structure of hippodamine (1) was
established two years later by the same group5 on the basis
of a single-crystal X-ray diffraction experiment (Fig. 1). epi-
Hippodamine (2) is a non-natural isomer with an axial C(2)
methyl group. Both hippodamine (1)6,7,8 and epi-hippodamine
(2)9 have been the subjects of total synthesis.
In our previous short communication10 we reported on the
formation of quinolizidine 8. Herein, we give a full account of a
concise synthetic strategy to the title azaphenalene alkaloids
1 and 2 using a two-directional approach to a common
key intermediate, with a tandem deprotection/intramolecular
double Michael addition (IDM) sequence as the key step.
Results and discussion
Retrosynthesis
Assembling the tricyclic skeleton and controlling the stereo-
chemistry of the title azaphenalene alkaloids in a minimum
of synthetic steps represents a formidable synthetic challenge.
Our plan was to establish the axial or equatorial C(2) methyl
substituents of the title compounds by manipulation of the
exocyclic double bond in 3 (Fig. 2). The olefin 3 could be
formed by de-alkoxycarbonylation of A and a subsequent Wittig
olefination.
Dieckmann condensation of diester B would in turn furnish
the third ring of the tricyclic structure. The formation of trans-
4,6-disubstituted quinolizidine derivative B represents the key
step in the synthetic plan. It was assumed that the quinolizidine
derivative B could be accessed via an intramolecular double
Michael addition of the acyclic intermediate C and the desired
trans-relative configuration of the substituents in B could be
installed at the same time. The acyclic intermediate C is a sym-
metric molecule opening up the possibility of two-directional
Fig. 1 Structures of hippodamine (1) and epi-hippodamine (2), deriva-
tives of perhydro-9b-azaphenalene.
Another group of natural enemies, parasitic insects, can cause
substantial reductions in populations of ladybird species. Recent
research2 has shown that the parasites locate the ladybirds
through perception of certain defence alkaloids that they emit.
If ladybirds are to be used effectively in insect pest control
then their parasites must be controlled as well. The significant
† Part 5. For Part 4 in the series see: L. G. Arini, P. Szeto, D. L. Hughes
and R. A. Stockman, Tetrahedron Lett., 2004, 45, 8371.
‡ Electronic supplementary information (ESI) available: 13C NMR
spectra for compounds 1, 2, 3, 7, 10, 13, 14, 18, 22, 23, and 25. X-
Ray data for compounds 22 and 25. See http://www.rsc.org/suppdata/
ob/b4/b413052a/
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 7 3 – 8 3
7 3
©

View Article Online
out to give diene 5 in 97% yield after column chromato-
graphy.
Oxidative cleavage of the terminal alkenes in 5 was evaluated
using three different methods: treatment of 5 with sodium
periodate (6 eq.) and a catalytic amount of osmium tetroxide
(2 mol%) in 3 : 1 THF–water13 (Method A); ruthenium(III)
chloride (4.1 mol%) and sodium periodate (4 eq.) in 6 : 1
CH3CN–water14 (Method B); and ozone in dichloromethane
15
and subsequent treatment with Me2S and PPh3 (Method C).
The resulting crude dialdehyde 6 was doubly homologated under
standard Wadsworth–Emmons conditions16 to yield acyclic
diester 7 in 75% (Method A), 71% (Method B) or 45% (Method
C) yield respectively over two steps from diene 5 as a single E,E-
stereoisomer. The ruthenium(III) chloride catalysed oxidation
(Method B) gave varying results which was later put down to
the varying quality of the catalyst batches. Ozonolysis (Method
C) proved to be difficult to perform on a larger scale. The osmium
tetroxide catalysed oxidative cleavage (Method A) gave excellent
yields on a small scale (up to 92%).10 Although the yield dropped
to some extent (75%) when performed on a large scale (>10 g),
Method A was the method of choice for preparation of 7 as the
results were easily reproducible.
With the successful formation of protected amine 7, the
stage was now set for the key tandem deprotection/double
intramolecular Michael addition, which we surmised should give
our desired trans-4,6-disubstituted quinolizidine 8. Following
Ganem’s protocol,17 the phthalimide group was removed by
selective hydride reduction (Scheme 2) of the alkyl succinimide 7
to furnish an ortho-hydroxymethyl benzamide 10 (probably via
hemiaminal 9). Addition of acetic acid to the reaction solution (c
in Scheme 2) promotes lactonisation of the ortho-hydroxymethyl
benzamide 10 to form phthalide 11 with concomitant release
of the primary amine, or its hydroacetate 15 respectively. The
hydroacetate must however, at least to some extent, equilibrate
with the free amine representing the reactive species in the
desired Michael addition. Under the acidic conditions the
amine undergoes an intramolecular Michael addition to give
the product of the first cyclisation 12, which could be isolated
from the reaction mixture with 13. The second cyclisation can
follow to give the desired quinolizidine derivative 8. However,
under the initial unoptimised conditions (c in Scheme 2) other
side-reactions were noted: the side chain double bond of 12 was
partially reduced (to give 13) and so were both double bonds in
15 (to give 14). As a consequence the Michael addition could
not occur and the yield of 8 was low. We suspected that sodium
triacetoxyborohydride18 formed in situ from sodium borohydride
and acetic acid might be responsible for this undesired over-
reduction.
Fig. 2 Retrosynthesis for ( )-hippodamine (1) and ( )-epi-hippo-
damine (2).
synthesis. It was thought that C could be obtained from undeca-
1,10-dien-6-ol (4) by firstly installing and protecting the required
amino group, and secondly by oxidative cleavage of both double
bonds and by a subsequent olefination. Finally, undeca-1,10-
dien-6-ol (4) can be obtained from 5-bromo-1-pentene by a
known procedure.
Synthesis of common intermediate 3
Diester 7 (Scheme 1) was prepared using the principles of two-
directional synthesis. The symmetrical alcohol (4) was prepared
in 89% yield following the method of Kitching et al.11 Mitsunobu
substitution12 of alcohol 4 with phthalimide was then carried
To overcome this problem any surplus of the hydride was
quenched by addition of an aliquot of acetone prior to addition
of the acetic acid (d in Scheme 2). When all remaining hydride
was removed acetic acid was added promoting lactonisation
as in the previous case and liberating the amine hydroacetate
15. Under the acidic conditions the acyclic unsaturated amine
undergoes the intramolecular double Michael addition to give
the desired quinolizidine derivative 8 in high yield.
The 2,6-disubstituted piperidine 13 showed a cis-relative
configuration of the ring substituents. The cis-configuration
was assigned on the basis of NMR spectra and from analogy
with spectra of a cis/trans pair of another 2,6-dialkyl piperidine
compound.19 The structure of 12 was assigned from analogy
with 13. From this observation it is possible to conclude that
the first Michael addition of 15 leads to a thermodynamically
more stable cis-2,6-dialkyl piperidine 12. The stereochemistry
of the subsequent Michael addition of 12 is then controlled by
the stereochemistry of the first ring. As a result the formation
of trans-4,6-disubstituted quinolizidine 8 as a single isomer is
observed.
Scheme 1 (a) Phthalimide, PPh3, DIAD, THF (97%); (b) Method A:
OsO4, NaIO4, Method B: RuCl3, NaIO4, Method C: (1) O3, CH2Cl2,
−78 ◦C, (2) Me2S, PPh3, rt; (c) Et2O(O)PCH2CO2Et, NaH, THF (over 2
steps Method A: 75%, Method B: 71%, Method C: 45%); (d) (1) NaBH4
(1.4 eq.), i-PrOH/H2O (6.2:1), (2) AcOH glac. (71%).
Optimal conditions for the tandem deprotection/double cy-
clisation were as follows: N-alkyl phthalimide 7 (Scheme 1) was
7 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 7 3 – 8 3

View Article Online
Scheme 2 Proposed mechanism of the tandem deprotection/intramolecular double Michael addition sequence: (a) NaBH4 (0.25 eq.), i-PrOH–H2O
(6.2 : 1) (product not isolated); (b) NaBH4 (0.25 eq.), i-PrOH–H2O (6.2 : 1) (67%); (c) (1) AcOH glac., (2) K2CO3, benzene (mixture of products 8,
11, 12, 13 and 14); (d) (1) acetone, 12 h, (2) AcOH glac., (3) K2CO3, benzene (71%).
subjected to sodium borohydride (1.4 eq.) in 6.2 : 1 isopropanol–
a double c-gauche effect20 experienced by the axial C(4)-CH2
methylene group from C(2) and C(9a). No such effect is suffered
by the respective equatorial C(6)-CH2 group. In addition, in
the 13C NMR, 16 signals were detected rather than the 9 that
would be expected for the more symmetric cis-isomer of the
quinolizidine 8.
◦
water mixture at 25 C for 24 hours.17 After this time acetone
(3.6 eq.) was added and stirring was continued overnight to
quench any remaining hydride. Then glacial acetic acid (30 eq.)
was added d◦ropwise at 0 ◦C, and the reaction mixture was
heated to 80 C (bath temperature) for a further 24 hours. An
aqueous work-up gave a crude hydroacetate of quinolizidine
8. The free base 8 was liberated by treating the hydroacetate
with K2CO3 in benzene. Final purification on activity IV neutral
alumina produced pure quinolizidine 8 as a single ( )-trans-
isomer (according to NMR) in 71% yield.
The trans relative configuration of substituents in positions
C(4) and C(6) of the quinolizidine 8 was determined by
NMR. Protons C(4)-H and C(6)-H (Scheme 1) situated on the
a-carbon atoms to the nitrogen atom show different behaviour
in the 1H NMR spectrum. Proton C(6)-H (2.78–2.72, m) is
more shielded than C(4)-H (3.83–3.80, m), the deshielding being
about 1 ppm. This can only be explained by an antiperiplanar
spatial arrangement assumed by C(6)-H and the nitrogen lone
pair. Consequently C(6)-H proton must be in an axial and
C(4)-H in an equatorial position with respect to the trans-
quinolizidine moiety. Moreover, in the 13C NMR spectrum, the
axial methylene group C(4)-CH2 (26.3, t) of the side chain, is
more shielded than the respective equatorial C(6)-CH2 (38.5,
t), the deshielding being 12.2 ppm. This can be explained by
We had planned that the formation of the third ring of the
perhydro-9b-azaphenalene skeleton would be achieved using a
Dieckmann condensation.9,21 To this effect, the 4,6-disubstituted
quinolizidine derivative 8 was subjected to a variety of bases
and reaction conditions. Two methods were found to give the
desired cyclisation product. When 8 was treated with LDA in
THF at −78 ◦C (Scheme 3) a mixture of b-ketoester 16 and its
corresponding enol form 17 was obtained. Initially when the
reaction mixture was directly subjected to an aqueous work-up
the resulting yields were very low. This was later put down to the
low stability of the cyclic products 16 and 17 towards aqueous
basic solutions. This problem was circumvented by removal of
THF and by taking the residue into benzene prior to quenching
of the reaction by an aqueous solution. This method eventually
gave a reasonable yield (48%) of the desired products 16 and
17. To further improve the yield we explored the alternative of
performing the Dieckmann condensation in a lipophilic solvent.
When 8 was treated with tBuOK in refluxing benzene (Scheme 3)
under continuous azeotropic removal of EtOH using a
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 7 3 – 8 3
7 5

View Article Online
( )-Hippodamine (1)
In order to achieve our objective the exocyclic double bond of
the olefin 3 had to be hydrogenated in a stereoselective way. In
fact the olefin 3 would have to approach the catalyst surface via
its more hindered face in order to obtain the required equatorial
methyl on C(2) (Scheme 4) which of course is less likely than
the opposite case. Indeed, when a catalytic hydrogenation using
10% palladium on carbon in absolute methanol was performed
(Table 1, Entry 1) a mixture of ( )-hippodamine (1) and ( )-epi-
hippodamine (2) was obtained in a high combined yield (99%),
but in a ratio 1 : 2 of 1 : 1.4, thus supporting the theory that
the olefin 3 is much more likely to approach the catalyst surface
via its less hindered face, with the hydrogenation resulting in an
axial methyl substituent.
Scheme 3 (a) Method A: tBuOK, Li, benzene, azeotropic removal of
EtOH (84%), Method B: LDA, THF, −78 ◦C (48%); (b) (1) HClg, Et2O,
(2) LiCl, wet DMF, reflux (66%); (c) CH3PPh3Br, nBuLi, THF (87%).
Scheme 4 (a) Pd–C 10%, H2 (normal pressure), solvent, additive (for
details see Table 1).
In order to prepare the target compound ( )-hippodamine
(1) the selectivity of the hydrogenation had to be reversed. In
order to achieve this we decided to make use of the nitrogen
lone pair in 3. Reacting the nitrogen lone pair with a convenient
reagent would hopefully block one face of the rigid olefin 3 thus
allowing the resulting product (a salt or a complex) to approach
the catalyst via the desired opposite face only.
When the free base of olefin 3 was reacted at room temperature
with 0.5 equivalent of oxalic acid in MeOH a dimeric salt was
formed immediately (Table 1, Entry 2). This salt was subjected to
catalytic hydrogenation at room temperature and atmospheric
pressure of hydrogen. The hydrogenation was monitored using
TLC. When the conversion was complete, the mixture was
filtered, evaporated and the residue treated with K2CO3 in
benzene to liberate the free base. After purification on activity
IV neutral alumina a mixture of ( )-hippodamine (1) and ( )-
epi-hippodamine (2) was obtained in a high combined yield
(98%). This time the ratio 1 : 2 amounted to 1.2 : 1 in favour
of the desired ( )-hippodamine (1). Although not a significant
advance, this experiment did show that it was possible to reverse
the stereoselectivity of the hydrogenation.
Dean–Stark trap with lithium in the trap to remove EtOH,
a mixture of b-ketoester 16 and its corresponding enol form
17 was obtained in a very good yield (84%). The Dieckmann
condensation gave a mixture of regioisomeric b-ketoesters 16
differing in the position of the ester moiety on either C(1) or
C(3). Moreover, both regioisomers of 16 are in equilibrium
with their enol forms 17. However, the following step, a de-
ethoxycarbonylation of all the possible isomers, would lead to
the ketone 18 only and consequently we did not purify and
identify the components of the isomeric mixture any further.
The de-ethoxycarbonylation of the isomeric mixture of 16 and
17 gave initially only limited yields of 18 when the mixture was
directly subjected to LiCl in wet refluxing DMF. It appeared
that only the b-ketoester 16 was able to undergo the desired
decarboxylation. The enol form 17 was either recovered or it
decomposed after a prolonged reaction time. This problem was
eventually solved by exposing the isomeric mixture 16 and 17 to
HCl in Et2O prior to the treatment with LiCl in wet refluxing
DMF. This method gave the desired ketone 18 in 66% yield after
purification.
Wittig olefination7 of the ketone 18 using methyltriph-
enylphosphonium bromide in THF and nBuLi gave low yields
of the desired product 3 when the olefination was performed
between −78 ◦C and room temperature. However, a short reflux
of the reaction mixture gave the desired product 3 in a good yield
(87%) after purification.
To further increase the selectivity of the hydrogenation for
( )-hippodamine (1) a range of salts and boron complexes were
screened for their behaviour in hydrogenation (Table 1). The best
results were obtained when a salt of 3 with mesitylenesulfonic
acid (Table 1, entries 7–9) was hydrogenated. A variety of
solvents and salt formation conditions were tested to show that
Table 1 Stereoselectivity of hydrogenation of olefin 3 and its salts or complexes
Combined yield
(%)
Entry
Additive
Solvent
Time/days
T/◦C; solventb
Ratio 1 : 2a
dsc (%)
1
2
3
4
5
6
7
8
9
—
MeOH
MeOH
Et2O
MeOH
AcOEt
THF
THF
THF
Et2O–THF
4 : 1
1
1
1
1
2
3
2
rt
rt
99
98
92
99
97
97
93
95
99
1 : 1.4
1.2 : 1
2.0 : 1
1.8 : 1
2.7 : 1
3.3 : 1
3.5 : 1
2.8 : 1
2.0 : 1
17.4 (2)
10.0 (1)
34.0 (1)
28.0 (1)
46.0 (1)
54.0 (1)
56.0 (1)
48.0 (1)
34.0 (1)
Oxalic acid (0.5 eq.)
Diphenylacetic acid
−20
(1S)-(+)-10-Camphorsulfonic acid
(1S)-(+)-10-Camphorsulfonic acid
(1S)-(+)-10-Camphorsulfonic acid
Mesitylenesulfonic acid
Mesitylenesulfonic acid
Mesitylenesulfonic acid
rt; CH2Cl2
rt; CH2Cl2
rt; CH2Cl2
rt
2 at −20 ◦C
−20
2
rt; Et2O
10
11
2,4,6-Triisopropylbenzenesulfonic acid
9-Cyclohexyl
9-borabicyclo[3.3.1]nonane
Et2O
MeOH
1
1
rt
rt
98
79
1.8 : 1
1 : 1.6
28.0 (1)
24.0 (2)
a The ratio was determined from relative intensities of the C(2) methyl substituent signals in 400 MHz 1H NMR spectra. b Temperature and solvent
(if other than the hydrogenation solvent) of the salt formation. c Diastereoselectivity in favour of either (1) or (2).
7 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 7 3 – 8 3

View Article Online
THF at room temperature gave a 1 : 2 ratio of 3.5 : 1 (56% ds) in a
very high combined yield (93%). This mixture was then subjected
to multiple column chromatography on neutral aluminium oxide
activity IV affording isomerically pure hippodamine in 37%
yield.
was not very stable and consequently it was used after a short
filtration through a column of neutral alumina without further
purification. Finally, xanthate 26 was subjected to the Barton–
McCombie deoxygenation conditions giving 46% combined
yield of a mixture of 1 and 2 in a ratio of 2.3 : 1.
In summary, we have achieved the synthesis of ( )-
hippodamine (1) in 8 synthetic steps in an overall yield of 7.2%,
using the concept of combining two-directional synthesis and
tandem reactions.
The predicted donation of the nitrogen lone pair in the planar
radical intermediate of the Barton–McCombie deoxygenation
is very likely operative but the control over the formation of the
desired equatorial methyl substituent was only limited, most
likely due to the high reaction temperature employed. The
desired ( )-hippodamine (1) was formed in 39.4% ds.
In an attempt to further improve the control over the
formation of the equatorial methyl substituent in 1 we planned
to perform a deoxygenation of tertiary alcohol 25 (Scheme 5)
via its xanthate 26. The Barton–McCombie deoxygenation of
xanthate ester 26 should in theory proceed via a planar radical
species. We assumed that the nitrogen lone pair might donate
into the half-filled p-orbital and force the unpaired electron into
the opposite face. As a consequence, the hydrogen radical should
only react from the required face which would then lead to the
desired equatorial methyl substituent of 1.
( )-epi-Hippodamine (2)
With the successful completion of our synthesis of ( )-
hippodamine (1) we also wished to prepare the non-natural
epimer ( )-epi-hippodamine (2) as it was thought that it might
provide insight into the influence of stereochemistry on the
biological activity of these compounds.
We surmised that we could use the nitrogen lone pair to deliver
a borohydride reagent selectively to one face of the exocyclic
olefin 3. Hydroboration of the exocyclic double bond in 3
(Scheme 6) shouldleadtoan anti-Markovnikov primary alcohol.
The hydroboration however can proceed from two possible faces
leading to either the equatorial 21 or the axial alcohol 22. The
tertiary amine moiety in 3 makes this molecule a good Lewis
base. Such a base should be capable of quickly replacing ligands
of ether type (weaker Lewis bases) in borane etherate complexes
and form complexes such as 19 and 20 at low temperatures. At
elevated temperatures the hydroboration should hopefully then
occur in an intramolecular fashion.
Scheme 5 (a) (1) MeLi, toluene, 0 ◦C, (2) crystallization from Et2O
(61%); (b) (1) nBuLi, THF, −78 ◦C, (2) CS2, rt, (3) MeI (42%); (c)
Bu3SnH, AIBN, toluene, reflux (46%).
The tricyclic ketone 18 was transformed into tertiary alcohol
25 (Scheme 5). Interestingly, when the ketone was treated with
MeMgBr in either polar or lipophilic aprotic solvents, no or
only very limited formation of the desired alcohol was observed.
This was most likely due to competing enol formation. When
the ketone 18 was treated with MeLi in THF the outcome was
very similar. When however toluene was used as a solvent and
the reaction was performed at 0 ◦C the desired tertiary alcohol
was formed and isolated in 61% yield after crystallization from
diethyl ether.
A single crystal X-ray diffraction experiment of 2522 (Fig. 3)
confirmed isolation of a single isomer only with axial hydroxyl
and equatorial methyl substituents. It also confirmed the
expected trans,cis,trans-stereochemistry of the tricyclic system.
The ability of this alcohol to crystallize was greatly enhanced by
formation of a hydrogen bond between the hydroxy group and
the nitrogen lone pair of a neighbouring molecule.
Scheme 6 (a) BH3·THF, THF, −78 ◦C; (b) (1) BH3·THF, THF, rt to
reflux, (2) H2O2, NaOH, H2O (21 + 22 90%); (c) 9-BBN·THF, THF,
−78 ◦C; (d) (1) 9-BBN·THF, THF, rt to reflux, (2) H2O2, NaOH, H2O
(22 only 84%).
Olefin 3 was treated◦with borane tetrahydrofuran complex in
absolute THF at −78 C for a short time period. The mixture
was then allowed to warm up to room temperature and finally
the mixture was heated at reflux. Oxidative work-up under basic
conditions furnished a mixture of alcohols 21 and 22 in a ratio 1 :
4.3, with the axial alcohol being favoured, to our gratification. In
an attempt to further increase the selectivity olefin 3 was treated
with 9-borabicyclo[3.3.1]nonane tetrahydrofuran complex. The
hydroboration furnished exclusively the axial alcohol 22 in a
high yield (84%) after crystallization from Et2O.
A single crystal X-ray diffraction experiment of the alcohol
2223 (Fig. 4) confirmed the axial position of the hydroxymethy-
lene moiety. Similarly to the alcohol 25 the ability of this
compound to crystallize was greatly enhanced by formation of
hydrogen bonds between the hydroxy group and the nitrogen
lone pair of a neighbouring molecule.
Fig. 3 Crystal structure of alcohol 25.
The alcohol 25 was then reacted with 1,1ꢀ-thiocarbonyl-
diimidazole in THF in an attempt to prepare the corresponding
xanthate. This method failed, probably due to steric hindrance.
For this reason the alcohol 25 was first deprotonated using
nBuLi in THF at −78 ◦C. The corresponding alkoxide was
then treated with CS2 and the reaction mixture was allowed
to reach room temperature. The reaction was then quenched
using MeI to give the desired xanthate 26. This compound
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 7 3 – 8 3
7 7

View Article Online
routinely carried out under argon atmosphere. Compound 4
was synthesized according to literature procedure.11
2-(1ꢀ-Pent-4ꢀꢀ-enyl-hex-5ꢀ-enyl)-isoindole-1,3-dione (5)
A 2-necked 1000 mL flask equipped with addition funnel and
magnetic stirrer was charged with triphenyl phosphine (42.9 g,
163.4 mmol), phthalimide (24.0 g, 163.4 mmol), anhydrous THF
(700 mL) and undeca-1,10-dien-6-ol (4) (25 g, 148.6 mmol).
The mixture was cooled to −20 ◦C under stirring and argon
atmosphere. Diisopropyl azodicarboxylate (33.0 g, 32.4 mL,
163.4 mmol) in anhydrous THF (100 mL) was added dropwise
over 1 h. When the addition was finished the mixture was stirred
overnight at room temperature. The solvent was evaporated
under reduced pressure and the oily residue was purified
by three subsequent crystallizations from first EtOAc, then
Et2O and finally petroleum ether–Et2O (1 : 1) in order to
remove triphenylphosphine oxide. The resulting oily mixture
was purified by column chromatography on silica gel (stepwise
gradient of petroleum ether–Et2O 20 : 3 to pure Et2O) to afford
5 (42.4 g, 96%) as a yellow oil: Rf 0.54 (petroleum ether–EtOAc
10 : 1); IR (cm−1) 3076, 3040, 2927, 2860, 1772, 1708, 1641,
1614, 1468, 1459, 1441, 1396, 1372, 1334; 1H NMR (400 MHz,
CDCl3) 7.85–7.82 (2H, m), 7.73–7.70 (2H, m), 5.74 (2H, ddt,
J = 16.8, 10.0 and 6.8), 5.01–4.90 (4H, m), 4.26–4.18 (1H, m),
2.16–1.99 (6H, m), 1.78–1.69 (2H, m), 1.51–1.23 (4H, m); 13C
NMR (75 MHz, CDCl3) 169.0 (2C, s), 138.6 (2C, d), 134.1 (2C,
d), 132.1 (2C, s), 123.3 (2C, d), 115.0 (2C, t), 52.0 (d), 33.4 (2C,
t), 31.9 (2C, t), 26.0 (2C, t); MS (EI) m/z 297 (43, M+), 256
(47), 242 (25), 228 (29), 159 (40), 147 (100), 129 (63), 81 (65), 41
(76); HRMS calcd for C19H27N2O2 (M + NH4) 315.2073, found
315.2072.
Fig. 4 Crystal structure of alcohol 22.
Scheme 7 (a) Method A: TsCl, Et3N, Me3N·HCl, CH2Cl2 (25%),
Method B: (1) nBuLi, THF, (2) TsCl, THF (95%); (b) NaI, 2-butanone
(usually not isolated); (c) (1) Zn activated, AcOH glac., (2) filtration,
evaporation, (3) K2CO3, benzene (83%).
Removal of the oxygen functionality (Scheme 7) by conversion
to the iodide 24 via tosylate 2324 followed by reduction with zinc25
in refluxing acetic acid gave the desired ( )-epi-hippodamine
(2) in a good yield (83% from 23) after purification. Attempts
to directly reduce (LiAlH4, LiAlH4–AlCl3 to give AlH3, super-
hydride LiB(C2H5)3H) the tosylate 23 to the corresponding
alkane 2 failed. Similarly all attempts to proto-deborylate the
putative alkyl borane intermediate formed on hydroboration of
3 also failed.
In summary, we have managed to synthesise isomerically pure
( )-epi-hippodamine (2) in 11 synthetic steps in an overall yield
of 17.0%.
Studies on syntheses of the other members of the perhydro-9b-
azaphenalene class of alkaloids and their application in insect
pest management are ongoing in these laboratories, and will be
reported in due course.
7-(1ꢀ,3ꢀ-Dioxo-1ꢀ,3ꢀ-dihydro-isoindol-2ꢀ-yl)-trideca-2,11-diene-
dioic acid diethyl ester (7)
Method A: Alkyl phthalimide 5 (8.751 g, 29.43 mmol) was
dissolved in THF (437.6 mL) and distilled water (145.9 mL). A
solution (2.5% wt in 2-methyl-2-propanol) of osmium tetroxide
(5.984 g, 0.59 mmol, 2 mol%) was added in one portion. After
5 min stirring at room temperature the mixture was cooled by
water bath to about 15 ◦C and sodium periodate (37.769 g,
176.58 mmol) was added in portions over 20 min. The mixture
was stirred at room temperature for 20 h. Volatiles were evapo-
rated under reduced pressure (bath temperature did not exceed
◦
30 C) to give a white solid. The solid was extracted/decanted
Experimental
with dichloromethane (3 × 100 mL). Combined extracts were
dried over Na2SO4 and concentrated to give a crude dialdehyde
6 (10.7 g) that was used for the subsequent reaction without
purification. To an oven dried flask a 60% dispersion of NaH
in mineral oil (3.95 g, 98.8 mmol) was added and washed with
n-pentane (3 × 20 mL) under argon atmosphere. The remaining
solvent was evaporated under reduced pressure and freshly
distilled THF (400 mL) was added. Triethyl phosphonoacetate
(17.52 mL, 19.80 g, 88.3 mmol) was added dropwise over 40 min
at room temperature. Stirring was continued for 2 h. The mixture
was cooled to 0 ◦C. A solution of the crude dialdehyde 6 in
freshly distilled THF (100 mL) was added dropwise over 2 h and
the mixture was stirred for 48 h. A saturated solution of NH4Cl
(100 mL) and ethyl acetate (100 mL) were added, the organic
layer was separated and the aqueous one was extracted with
ethyl acetate (3 × 200 mL). Combined organic extracts were
washed with sodium bicarbonate (20 mL), brine (10 mL) and
dried over Na2SO4. Evaporation gave a crude product (13 g)
that was purified using column chromatography on silica gel
(stepwise gradient of petroleum ether–ethyl acetate 9 : 1 to 1 :
1) to afford 7 (9.76 g, 75.1% over 2 steps). Method B: A stock
solution of ruthenium(III) chloride was prepared by dissolving
RuCl3·(H2O)2 (842 mg, 3.5 mmol) in distilled water (100 mL) to
give a concentration of 0.035 M. To a stirred solution of alkyl
General methods
All chemicals were purchased as reagent grade and used without
further purification. Tetrahydrofuran was freshly distilled from
sodium diphenyl ketyl just prior to use. Dichloromethane was
freshly distilled over CaH2. Other solvents for experiments
were purified by the usual methods or purchased from a
commercial source. If not stated otherwise TLC was performed
on precoated silica plates containing a fluorescence indicator.
Silica gel (63–200 lm) was used for analytical and preparative
TLC (PLC) and for column chromatography, unless otherwise
noted. Compounds were visualised under UV (254 nm), by
heating after dipping in a solution of alkaline KMnO4, or by
exposing to iodine vapours. NMR spectra were recorded on 300
or 400 MHz instruments. Chemical shifts are reported in ppm
with respect to TMS. Coupling constants are reported in Hz.
Multiplicity of signals in 13C NMR spectra was determined from
DEPT or gHSQC spectra. IR spectra of neat (unless otherwise
noted) compounds were expressed as wave numbers (cm−1). The
Mass Spectrometry Service Centre at the University of Wales,
Swansea performed the low- and high-resolution mass spectra.
Melting points were taken on a micro melting point apparatus
and are uncorrected. Water- and air-sensitive reactions were
7 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 7 3 – 8 3

View Article Online
phthalimide 5 (9.432 g, 31.7 mmol) and RuCl3 stock solution
(31.7 mL, 1.11 mmol, 3.5 mol%) in CH3CN (158.6 mL) and
distilled water (26.4 mL) was added in portions NaIO4 (27.2 g,
127.2 mmol) over a period of 5 min at room temperature. After
completion (TLC monitoring) in 3 h, the reaction was quenched
with a saturated aqueous solution of Na2S2O3 (100 mL). The
resulting mixture was filtered through sintered glass and the
aqueous layer was extracted with AcOEt (3 × 100 mL). The
combined organic layers were washed with water (50 mL), brine
(50 mL) and dried over Na2SO4. The solvents were evaporated
under reduced pressure to give a crude dialdehyde 6 (10.9 g)
that was used for the subsequent reaction without purification.
To an oven dried flask a 60% dispersion of NaH in mineral oil
(7.75 g, 194.0 mmol) was added and washed with n-pentane
(3 × 20 mL) under argon atmosphere. The remaining solvent
was evaporated under reduced pressure and freshly distilled
THF (700 mL) was added. Triethyl phosphonoacetate (31.5 mL,
35.60 g, 159.1 mmol) was added dropwise over 40 min at room
temperature. Stirring was continued for 2 h. The mixture was
cooled to 0 ◦C. A solution of the crude dialdehyde 6 in freshly
distilled THF (100 mL) was added dropwise over 2 h and the
mixture was stirred for 48 h. A saturated solution of NH4Cl
(100 mL) and ethyl acetate (100 mL) were added, the organic
layer was separated and the aqueous one was extracted with ethyl
acetate (3 × 200 mL). Combined organic extracts were washed
with sodium bicarbonate (20 mL), brine (10 mL) and dried
over Na2SO4. Evaporation gave a crude product (15 g) that was
purified using column chromatography on silica gel (stepwise
gradient of petroleum ether–ethyl acetate 9 : 1 to 1 : 1) to afford
7 (9.9 g, 70.7% over 2 steps). Method C: Alkyl phthalimide 5
(1.03 g, 3.477 mmol) was dissolved in dichloromethane (20 mL).
Ozone was passed through the mixture at −78 ◦C until a
blue colour persisted. The excess of O3 gas was removed by
blowing argon through the mixture for 15 min. Me2S (5 mL,
large excess) was added and the mixture was stirred 0.5 h at
−78 ◦C. The cold bath was removed and stirring was continued
for another 2 h. Triphenylphosphine (600 mg, 2.29 mmol) in
dichloromethane (5 mL) was added and stirring was continued
until no more ozonide could be detected (TLC). The mixture
was concentrated under reduced pressure. The residue was
triturated with Et2O (3 × 10 mL) and the combined extracts
were washed with water (5 mL), brine (5 mL) and dried over
Na2SO4. Evaporation gave a crude dialdehyde 6 (1.2 g) that was
used for the subsequent reaction without purification. To an
oven dried flask a 60% dispersion of NaH in mineral oil (0.51 g,
12.8 mmol) was added and washed with n-pentane (3 × 5 mL)
under argon atmosphere. The remaining solvent was evaporated
under reduced pressure and freshly distilled THF (40 mL) was
added. Triethyl phosphonoacetate (2.07 mL, 2.339 g, 10.4 mmol)
was added dropwise over 20 min at room temperature. Stirring
was continued for 1 h. The mixture was cooled to 0 ◦C. A solution
of the crude dialdehyde 6 in freshly distilled THF (10 mL) was
added dropwise over 1 h and the mixture was stirred for 48 h. A
saturated solution of NH4Cl (10 mL) and ethyl acetate (10 mL)
were added, the organic layer was separated and the aqueous
one was extracted with ethyl acetate (3 × 20 mL). Combined
organic extracts were washed with sodium bicarbonate (5 mL),
brine (5 mL) and dried over Na2SO4. Evaporation gave a crude
product (1.7 g) that was purified using column chromatography
on silica gel (stepwise gradient of petroleum ether–ethyl acetate
9 : 1 to 1 : 1) to afford 7 (0.688 g, 44.8% over 2 steps) as a yellow
oil: Rf 0.56 (petroleum ether–EtOAc 3 : 1); IR (cm−1) 3462, 3411,
2980, 2924, 2852, 1767, 1705, 1643, 1607, 1464, 1444, 1398, 1367;
1H NMR (400 MHz, CDCl3) 7.86–7.84 (2H, m), 7.78–7.75 (2H,
m), 6.90 (2H, dt, J = 15.6 and 6.8), 5.79 (2H, d, J = 15.6),
4.25–4.20 (1H, m), 4.18 (4H, q, J = 7.2), 2.30–2.12 (6H, m),
1.80–1.72 (2H, m), 1.48–1.43 (4H, m), 1.27 (6H, t, J = 7.2);
13C NMR (100 MHz, CDCl3) 168.1 (2C, s), 165.9 (2C, s), 147.8
(2C, d), 133.6 (2C, d), 131.2 (2C, s), 122.8 (2C, d), 121.3 (2C, d),
59.6 (2C, t), 50.9 (d), 31.4 (2C, t), 31.2 (2C, t), 24.6 (2C, t), 13.8
(2C, q); MS (EI) m/z 441 (7, M+), 254 (13), 185 (40), 147 (100),
129 (59); HRMS calcd for C25H32NO6 (M + H) 442.2230, found
442.2227.
7-(2ꢀ-Hydroxymethyl-benzoylamino)-trideca-2,11-dienedioic
acid diethyl ester (10)
To a flask containing NaBH4 (0.166 g, 4.39 mmol) a solution
of diester 7 (1.292 g, 2.93 mmol) in isopropanol (47.4 mL) and
water (7.6 mL) was added. The mixture was stirred for 24 h
at room temperature. The formation of 10 (Rf 0.63, petroleum
ether–EtOAc 1 : 1) was monitored by TLC. Brine (10 mL) was
added and the mixture was extracted with Et2O (4 × 20 mL).
Combined organic layers were dried over Na2SO4. Evaporation
gave a crude product (1.771 g) that was purified using column
chromatography on silica gel (stepwise gradient of petroleum
ether–EtOAc 3 : 1 to 1 : 1) to afford 10 (0.873 g, 66.9%) as a
yellow oil: IR (cm−1) 3344, 3288, 3062, 2980, 2934, 2852, 1716,
1629, 1536, 1454, 1362, 1311, 1260, 1178; 1H NMR (400 MHz,
CDCl3) 7.54–7.34 (4H, m), 6.96–6.88 (2H, m), 6.51–6.39 (1H,
m), 5.82 (2H, dd, J = 15.6 and 1.2), 4.57 (2H, s), 4.20–4.10 (5H,
m), 2.31–2.22 (4H, m), 2.0 (1H, bs), 1.63–1.31 (8H, m), 1.30–
1.23 (6H, m); 13C NMR (100 MHz, CDCl3) 173.8 (s), 169.7 (s),
166.7 (s), 148.5 (2C, d), 139.6 (s), 136.0 (s), 131.1 (d), 130.7 (d),
128.2 (d), 127.7 (d), 121.8 (2C, d), 64.6 (t), 60.3 (2C, t), 49.4 (d),
34.8 (2C, t), 31.8 (2C, t), 24.5 (2C, t), 14.3 (2C, q); MS (EI) m/z
445 (21, M+), 428 (100), 427 (48), 416 (25), 135 (75), 132 (99);
HRMS calcd for C25H36NO6 (M + H) 446.2542, found 446.2543.
(4S*, 6S*)-(6-Ethoxycarbonylmethyl-octahydro-quinolizin-4-
yl)-acetic acid ethyl ester (8)
To a flask containing NaBH4 (1.046 g, 27.65 mmol) a solution
of diester 7 (8.721 g, 19.75 mmol) in isopropanol (320.0 mL)
and water (51.6 mL) was added. The mixture was stirred for
24 h at room temperature. The formation of 10 was monitored
by TLC. Acetone (5.23 mL, 71.23 mmol) was added and stirring
◦
was continued overnight. The mixture was cooled to 0 C and
glacial AcOH (33.9 mL, 592.76 mmol) was added dropwise.
The mixture was heated to 80 ◦C (bath temperature) under
stirring for 24 h. The mixture was allowed to cool and brine
(20 mL) was added. Solids were filtered off and petroleum ether
(100 mL) was added to the filtrate to initiate separation of
organic and aqueous layers. The aqueous layer was extracted
with ethyl acetate (3 × 100 mL). Combined organic layers were
washed with brine (20 mL) and dried over Na2SO4. Evaporation
gave a crude hydroacetate of quinolizidine 8 that was taken into
benzene (200 mL) and K2CO3 (5.6 g) was added. The mixture
was stirred overnight. Solids were filtered off and the filtrate
was evaporated. The residue was crystallized from first Et2O
and then from Et2O–petroleum ether 1 : 1 to separate phthalide
11 (Rf 0.48, alumina, petroleum ether–EtOAc 5 : 1). Crystals
of phthalide 11 were filtered off, washed with Et2O–petroleum
ether 1 : 1 (3 × 2 mL) and the combined filtrates were evaporated
to give crude free base 8 (5.3 g) that was purified using column
chromatography on activity IV neutral alumina (40 g, petroleum
ether–EtOAc 30 : 1) to afford 8 (4.38 g, 71.2%) as a yellow oil:
Rf 0.79 (alumina, petroleum ether–EtOAc 5 : 1); IR (cm−1) 2980,
2929, 2853, 1726, 1465, 1445, 1368, 1337, 1301, 1276, 1163, 1096,
1030; 1H NMR (400 MHz, benzene-d6) 4.04–3.93 (4H, m), 3.83–
3.80 (1H, m), 2.81 (1H, dd, J = 14.2 and 4.4), 2.78–2.72 (1H, m),
2.65 (1H, dd, J = 14.6 and 3.2), 2.41 (1H, dd, J = 14.6 and 10.4),
2.29 (1H, dd, J = 14.2 and 6.8), 1.98–1.92 (1H, m), 1.72–1.66
(3H, m), 1.47–1.36 (2H, m), 1.34–1.29 (4H, m), 1.24–1.04 (3H,
m), 1.02–0.98 (6H, m); 13C NMR (75 MHz, benzene-d6) 171.9
(s), 170.9 (s), 59.0 (t), 58.9 (t), 53.9 (d), 52.9 (d), 50.0 (d), 38.5
(t), 33.7 (t), 33.6 (t), 32.0 (t), 28.6 (t), 26.3 (t), 22.9 (t), 17.7 (t),
12.9 (2C, q); MS (EI) m/z 311 (60, M+), 224 (100), 167 (57), 149
(95), 136 (62); HRMS calcd for C17H30NO4 (M + H) 312.2175,
found 312.2171.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 7 3 – 8 3
7 9

View Article Online
(4S*, 6S*)-(6-Ethoxycarbonylmethyl-octahydro-quinolizin-4-
yl)-acetic acid ethyl ester (8), (2ꢀS*, 6ꢀS*)-6-(6ꢀ-ethoxycarbonyl-
methyl-piperidin-2ꢀ-yl)-hexanoic acid ethyl ester (13) and
7-amino-tridecanedioic acid diethyl ester (14)
and enol tautomers 16 and 17 (3.85 g, 83.5%) as a yellow oil.
The mixture of 16 and 17 (1.6 g, 6.03 mmol) was dissolved in
CHCl3 (10 mL) and 2 M HClg in Et2O (40 mL) was added.
The mixture was stirred for 1 h at room temperature. The
volatiles were evaporated under reduced pressure and the residue
was taken into DMF (50 mL). Water (540 lL, 30.15 mmol)
and LiCl (1.278, 30.15 mmol) were added. The mixture was
heated at reflux (oil bath 140 ◦C) for 4 h. The volatiles were
evaporated at 60 ◦C under reduced pressure. The residue was
taken into dichloromethane (20 mL) and filtered through a
pad of activity IV neutral alumina (2 g, dichloromethane).
Evaporation gave a crude product (0.97 g) that was purified
using column chromatography on activity IV neutral alumina
(10 g, stepwise gradient of hexane–Et2O 20 : 1 to 1 : 1) to afford 18
(0.764 g, 65.6%) as a yellow oil. Method B: To a stirred solution
of quinolizidine 8 (108.2 mg, 0.347 mmol) in absolute THF
(10 mL) was added LDA (74.3 mg, 0.694 mmol) via septum at
−78 ◦C and under argon atmosphere. The formation of 16 and
17 was monitored by TLC. After 8 h the mixture was allowed to
reach room temperature. THF was evaporated and the residue
was taken into benzene (10 mL). Water (10 mL) was added. The
organic layer was separated and the aqueous one was extracted
with EtOAc (3 × 10 mL). Combined organic layers were dried
over Na2SO4. Evaporation gave a crude mixture of 16 and 17
(100 mg) that was purified by filtration through a pad of activity
IV neutral alumina (2 g, EtOAc) to afford a mixture of pure
16 and 17 (44.3 mg, 48.1%) as a yellow oil. This mixture was
directly converted to ketone 18 in the same way as in Method
A. For 18: Rf 0.49 (alumina, petroleum ether–EtOAc 1 : 1): IR
(cm−1) 3422, 2932, 2853, 1715, 1460, 1442, 1367, 1340, 1288; 1H
NMR (400 MHz, CDCl3) 3.43–3.38 (1H, m), 3.23–3.13 (2H, m),
2.89 (1H, dd, J = 13.6 and 6.8), 2.26–2.14 (3H, m), 1.93–1.82
(3H, m), 1.72–1.67 (1H, m), 1.61–1.48 (5H, m), 1.46–1.00 (3H,
m); 13C NMR (100 MHz, CDCl3) 209.1 (s), 61.0 (d), 57.9 (d),
48.9 (d), 48.7 (t), 47.5 (t), 34.9 (t), 30.9 (t), 25.6 (t), 23.8 (t), 21.6
(t), 18.6 (t); MS (EI) m/z 193 (49, M+), 178 (22), 150 (100), 122
(80), 82 (42); HRMS calcd for C12H20NO (M + H) 194.1539,
found 194.1535.
To a flask containing NaBH4 (261 g, 6.9 mmol) a solution
of diester 7 (2.437 g, 5.52 mmol) in isopropanol (89.4 mL)
and water (14.4 mL) was added. The mixture was stirred for
24 h at room temperature. The formation of 10 was monitored
by TLC. The mixture was cooled to 0 ◦C and glacial AcOH
(9.46 mL, 165.4 mmol) was added dropwise. The mixture was
heated to 80 ◦C (bath temperature) under stirring for 24 h. The
mixture was allowed to cool down and brine (10 mL) was added.
Solids were filtered off and petroleum ether (10 mL) was added
to the filtrate to initiate separation of organic and aqueous layers.
The aqueous layer was extracted with ethyl acetate (3 × 100 mL).
Combined organic layers were washed with brine (5 mL) and
dried over Na2SO4. Evaporation gave a mixture of crude amine
hydroacetates that was taken into benzene (50 mL) and K2CO3
(3 g) was added. The mixture was stirred overnight. Solids were
filtered off and the filtrate was evaporated. The residue was
crystallized from first Et2O and then from Et2O–petroleum ether
1 : 1 to separate phthalide 11. Crystals of phthalide 11 were
filtered off, washed with Et2O–petroleum ether 1 : 1 (3 × 2 mL)
and the combined filtrates were evaporated to give a mixture
of crude free amines (2.5 g) that was purified using column
chromatography on activity IV neutral alumina (40 g, stepwise
gradient petroleum ether–EtOAc 30 : 1 to MeOH pure) to afford
8 (0.539 g, 31.4%), 13 (0.36 g, 21.0%) and 14 (0.275 g, 15.8%) as
yellow oils.
For 13: Rf 0.30 (alumina, petroleum ether–EtOAc 5 : 1);
1
IR (cm−1) 3385, 2929, 2852, 1731, 1454, 1372, 1183; H NMR
(400 MHz, CDCl3) 4.17–4.10 (4H, m), 2.98–2.90 (1H, m), 2.56–
2.50 (1H, m), 2.41 (2H, d, J = 6.0), 2.29 (2H, t, J = 7.6), 2.20
(1H, bs), 1.81–1.76 (2H, m), 1.66–1.58 (6H, m), 1.50–1.30 (6H,
m), 1.28–1.24 (6H, m); 13C NMR (100 MHz, CDCl3) 173.8 (s),
172.6 (s), 60.4 (t), 60.2 (t), 56.7 (d), 53.4 (d), 41.5 (t), 37.1 (t), 34.3
(t), 32.5 (t), 32.1 (t), 29.3 (t), 25.6 (t), 24.9 (t), 24.6 (t), 14.2 (2C,
q); MS (EI) m/z 313 (2, M+), 300 (99), 290 (20), 276 (26), 226
(15), 156 (100), 124 (29), 82 (44); HRMS calcd for C17H32NO4
(M + H) 314.2326, found 314.2324.
For 14: Rf 0.07 (alumina, petroleum ether–EtOAc 5 : 1); IR
(nujol, cm−1) 3426, 2955, 2852, 1726, 1577; 1H NMR (300 MHz,
CDCl3) 4.12 (4H, q, J = 7.2), 3.02–3.19 (1H, m), 2.30 (4H, t,
J = 7.1), 1.98–1.32 (16H, m), 1.25 (6H, t, J = 7.2); 13C NMR
(100 MHz, CDCl3) 173.6 (2C, s), 60.3 (2C, t), 52.2 (d), 34.2 (2C,
t), 33.0 (2C, t), 28.8 (2C, t), 25.1 (2C, t), 24.7 (2C, t), 14.3 (2C, q);
MS (EI) m/z 315 (1, M+), 184 (25), 170 (100), 82 (38); HRMS
calcd for C17H34NO4 (M + H) 316.2488, found 316.2492.
(3aS*, 9aS*)-2-Methylene-dodecahydro-pyrido[2,1,6-de]
quinolizine (3)
To a stirred suspension of methyltriphenylphosphonium bro-
mide (1.0314 g, 2.89 mmol) in absolute THF (69 mL) was added
2.5M nBuLi in hexanes (1 mL, 2.5 mmol) at −78 ◦C and under
argon atmosphere. When the addition was complete, the cold
bath was removed and the yellow mixture was stirred for 75 min.
A solution of ketone 18 (382 mg, 1.98 mmol) in absolute THF
(10 mL) was added over 5 min. The mixture◦was stirred at room
temperature for 1 h and then heated to 60 C for 30 min. The
mixture was allowed to cool down and water (10 mL) was added.
The mixture was extracted with EtOAc (3 × 30 mL). Combined
extracts were washed with brine (2 × 10 mL) and dried over
Na2SO4. Evaporation gave a mixture (0.8 g) that was purified by
crystallization from EtOAc and then from petroleum ether–Et2O
1 : 1 to get rid of Ph3PO. The remaining oil (0.4 g) was further
purified using column chromatography on activity IV neutral
alumina (71 g, hexane–Et2O 500 : 75) to afford 3 (330.45 g,
87.4%) as a yellow oil: Rf 0.59 (alumina, MeOH–EtOAc 1 : 1);
(3aS*, 9aS*)-2-Oxo-dodecahydro-pyrido[2,1,6-de]
quinolizine (18)
Method A: An oven dried double-neck flask was equipped
with magnetic stirring bar and a Dean–Stark trap. The flask
was charged with tBuOK (3.899 g, 34.74 mmol) and absolute
benzene (180 mL). The Dean–Stark trap was filled with absolute
benzene and charged with a lithium stick (1 g). Quinolizidine 8
(5.41 g, 17.37 mmol) was added in absolute benzene (20 mL) via
a septum. The mixture was refluxed (bath temperature 120 ◦C)
under continuous removal of EtOH for 2 h. The septum was
replaced by a glass stopper and reflux was continued for another
17 h. The formation of 16 (Rf 0.46, MeOH–EtOAc 1 : 10) and
17 (Rf 0.33, MeOH–EtOAc 1 : 10) was monitored by TLC. The
mixture was allowed to cool down and water (50 mL) was added.
The organic layer was separated and the aqueous layer was
extracted with EtOAc (3 × 100 mL). Combined organic layers
were washed with brine (25 mL) and finally dried over Na2SO4.
Evaporation gave a crude mixture of 16 and 17 (4.1 g) that
was purified by filtration through a pad of activity IV neutral
alumina (2 g, EtOAc) to afford a regioisomeric mixture of keto
1
IR (cm−1) 3067, 2924, 2847, 1737, 1650, 1460, 1440; H NMR
(400 MHz, CDCl3) 4.78–4.59 (2H, m), 3.18–3.05 (2H, m), 3.00–
2.86 (1H, m), 2.72–2.56 (1H, m), 2.22–1.26 (1H, m), 2.12–2.02
(1H, m), 2.00–1.85 (5H, m), 1.78–1.44 (5H, m), 1.36–1.18 (1H,
m), 1.12–0.92 (2H, m); 13C NMR (100 MHz, CDCl3) 144.3 (s),
108.3 (t), 59.6 (d), 58.2 (d), 49.4 (d), 42.7 (t), 40.5 (t), 34.5 (t),
31.1 (t), 25.7 (t), 22.6 (t), 21.9 (t), 19.4 (t); MS (EI) m/z 191
(61, M+), 176 (52), 162 (38), 148 (100), 136 (82), 120 (52), 94
(57), 79 (57); HRMS calcd for C13H22N (M + H) 192.1747, found
192.1749.
8 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 7 3 – 8 3

View Article Online
( )-Hippodamine (1)
(2S*, 3aS*, 6aR*, 9aS*)-2-Hydroxymethyl-dodecahydro-
pyrido[2,1,6-de]quinolizine (21) and (2R*, 3aS*, 6aS*, 9aS*)-
2-hydroxymethyl-dodecahydro-pyrido[2,1,6-de]quinolizine (22)
Mesitylenesulfonic acid dihydrate (245.3 mg, 1.04 mmol) was
dissolved in THF (25 mL). To this solution olefin 3 (99.3 mg,
0.52 mmol) in THF (25 mL) was added in one portion. The
mixture was allowed to stir at room temperature for 1 h. Then
10% palladium on carbon (100 mg) was added and hydrogen
(normal pressure) was applied. The formation of 1 (Rf 0.46,
alumina, MeOH–EtOAc 1 : 1) was monitored by TLC after a
mini work-up. After 2 days the solids were filtered off and THF
evaporated. The residue was taken into benzene and K2CO3
(1 g) was added. The mixture was stirred overnight. Solids were
filtered off and the filtrate was evaporated. The remaining oil
(95 mg) was further purified using column chromatography
on activity IV neutral alumina (2.3 g, hexane–Et2O 5 : 1) to
Olefin 3 (10.0 mg, 0.052 mmol) was dissolved in absolute THF
(10 mL) and the solution was stirred at −78 ◦C under argon
atmosphere. A 1 M THF solution of borane·THF (210 lL,
0.210 mmol) was added dropwise via a septum. Stirring was
◦
continued for 1 h at −78 C. Then the mixture was allowed to
reach room temperature and stirring was continued overnight.
The mixture was then refluxed for 4 h. The mixture was allowed
to reach room temperature and water (11.2 lL, 0.624 mmol) was
added followed by MeOH (109 lL) and 3 N NaOH (208 lL,
◦
0.624 mmol). The mixture was cooled to 0 C and 11.6 M (or
30%) H2O2 (44.9 lL, 0.520 mmol) was added dropwise over
10 min. The mixture was stirred for 2 h. A white precipitate was
filtered off. The filtrate was evaporated under reduced pressure
and the residue was taken into Et2O (10 mL). This solution was
washed with water (5 mL), brine (5 mL) and finally dried over
Na2SO4. Evaporation gave a crude product (20 mg) that was
purified using column chromatography on activity IV neutral
alumina (2.5 g, stepwise gradient hexane–Et2O 5 : 1, pure Et2O
to pure MeOH) to afford a white solid. According to 1H NMR
the solid was a mixture of 21 and 22 in a ratio 1 : 4.25 (9.81 mg,
90.0%).
1
afford a 3.5 : 1 mixture (by H NMR) of 1 and 2 (93.3 mg,
93.0%). The mixture was further subjected to a multiple column
chromatography (4 times) on activity IV neutral alumina (12 g,
hexane–Et2O 10 : 1, sample applied in a small amount of
chlorobenzene) to finally afford isomerically pure hippodamine
(1) (37.1 mg, 37.0%): Rf 0.46 (alumina, MeOH–EtOAc 1 : 1);
IR (cm−1) 2920, 2859, 1455, 1443, 1294, 1132, 1102; H NMR
1
(400 MHz, CDCl3) 3.00–2.95 (2H, m), 2.83 (1H, dddd, J = 11.2,
11.2, 2.8, 2.8), 1.93–1.77 (4H, m), 1.70–1.63 (1H, m), 1.59–1.43
(8H, m), 1.21–1.12 (1H, m), 1.04–0.94 (2H, m), 0.87–0.78 (1H,
m), 0.85 (3H, d, J = 6.4); 13C NMR (100 MHz, CDCl3) 58.8
(d), 58.1 (d), 47.8 (d), 43.4 (t), 40.0 (t), 34.6 (t), 31.4 (t), 26.1
(t), 25.7 (d), 23.1 (t), 22.5 (q), 22.3 (t), 19.7 (t); MS (EI) m/z
193 (22, M+), 192 (42), 178 (18), 164 (26), 151 (35), 150 (45), 137
(28), 136 (42), 105 (25), 77 (35), 67 (31), 55 (54), 43 (43), 41 (100);
HRMS calcd for C13H24N (M + H) 194.1903, found 194.1902.
Synthetic hippodamine proved identical to the natural material
by IR, 1H NMR, 13C NMR, and MS spectral comparison.26,27
(2R*, 3aS*, 6aS*, 9aS*)-2-(p-Toluenesulfonyloxymethyl)-
dodecahydro-pyrido[2,1,6-de]quinolizine (23)
A solution of alcohol 22 (10 mg, 0.05 mmol) and triphen◦yl-
methane (2 mg) in absolute THF (10 mL) was cooled to 0 C
under stirring and argon atmosphere. A 2.5 M solution of
nBuLi in hexanes (21 lL, 0.053 mmol) was added from a
syringe via a septum until the solution became slightly pink. The
precipitated lithium alkoxide was stirred for 10 min at 0 ◦C. Then
p-toluenesulfonyl chloride (9.1 mg, 0.05 mmol) in absolute THF
(5 mL) was added dropwise. The resulting solution was stirred
for 2.5 h at 0 ◦C. The formation of 23 was monitored by TLC. The
mixture was diluted with Et2O (10 mL), washed with water
(2 mL), brine (2 mL) and dried over Na2SO4. The volatiles were
evaporated to give a crude product (30 mg) that was purified
using column chromatography on activity IV neutral alumina
(15 g, stepwise gradient of hexane–Et2O 5 : 1, 1 : 1 to 1 : 5) to
afford 23 (16.5 mg, 94.8%) as a yellow oil: IR (cm−1) 2925, 2853,
1598, 1460, 1440, 1363, 1255, 1178, 1196; 1H NMR (400 MHz,
CDCl3) 7.82–7.80 (2H, m), 7.38–7.36 (2H, m), 4.20 (1H, t, J =
9.6), 3.99 (1H, dd, J = 9.6 and 6.0), 2.93–2.86 (2H, m), 2.63–
2.57 (1H, m), 2.46 (3H, s), 2.17–2.02 (2H, m), 1.82–1.66 (3H,
m), 1.51–1.20 (9H, m), 1.18–0.78 (3H, m); 13C NMR (100 MHz,
CDCl3) 144.8 (s), 133.0 (s), 129.8 (2C, d), 128.0 (2C, d), 73.3 (t),
58.1 (d), 57.3 (d), 43.2 (d), 34.5 (t), 34.4 (t), 31.5 (t), 31.2 (t), 31.0
(d), 26.6 (t), 26.3 (t), 23.0 (t), 21.7 (q), 19.5 (t); MS (EI) m/z 363
(6, M+), 208 (100), 188 (50), 176 (51), 148 (50), 91 (99); HRMS
calcd for C20H30NO3S (M + H) 364.1941, found 364.1942.
(2R*, 3aS*, 6aS*, 9aS*)-2-Hydroxymethyl-dodecahydro-
pyrido[2,1,6-de]quinolizine (22)
Olefin
3 (53.4 mg, 0.279 mmol) was dissolved in ab-
solute THF (20 mL) and the solution was stirred at
−78 ◦C under argon atmosphere. A 0.5 M THF solution
of 9-borabicyclo[3.3.1]nonane·THF (9-BBN·THF) (136.1 mg,
1.116 mmol) was added dropwise via a septum. Stirring was
◦
continued for 1 h at −78 C. Then the mixture was allowed to
reach room temperature and stirring was continued overnight.
The mixture was then refluxed for 2 h. The mixture was allowed
to reach room temperature and water (1 mL) was added followed
by MeOH (9.4 mL) and 3 N NaOH (0.93 mL, 1.116 mmol).
The mixture was cooled to 0 ◦C and 11.6 M (or 30%) H2O2
(241 lL, 2.79 mmol) was added dropwise over 10 min. The
mixture was stirred for 2 h. A white precipitate was filtered
off. The filtrate was evaporated under reduced pressure and the
residue was taken into Et2O (10 mL). This solution was washed
with water (5 mL), brine (5 mL) and finally dried over Na2SO4.
Evaporation gave a crude product (97 mg) that was purified
using column chromatography on activity IV neutral alumina
(5 g, stepwise gradient hexane–Et2O 5 : 1, pure Et2O to pure
MeOH) to afford 22 (54 mg) as a white solid. The solid was
further crystallized from Et2O to give 22 (49.3 mg, 84.4%) as
crystals (clear, colourless, tapered rectangular prisms): Rf 0.32
(alumina, MeOH–EtOAc 1 : 1); mp 145.5–146.0 ◦C (Et2O): IR
(cm−1) 3652, 3354, 2930, 2848, 1731, 1644, 1582, 1460, 1440; 1H
NMR (400 MHz, CDCl3) 3.79 (1H, bt, J = 9.6), 3.63 (1H, bdd,
J = 9.6 and 6.0), 2.96–2.84 (3H, m), 2.14–2.07 (1H, m), 1.95–
1.77 (4H, m), 1.67–1.38 (9H, m), 1.28–1.13 (2H, m), 1.06–1.00
(1H, m); 13C NMR (100 MHz, CDCl3) 66.5 (t), 58.2 (d), 57.8 (d),
43.6 (d), 35.1 (t), 34.8 (d), 34.6 (t), 32.0 (t), 31.4 (t), 26.7 (t), 26.4
(t), 23.2 (t), 19.7 (t); MS (EI) m/z 209 (38, M+), 208 (100), 178
(69), 167 (47), 150 (55), 137 (40); HRMS calcd for C13H24NO
(M + H) 210.1852, found 210.1855. Anal. Calcd. for C13H23NO:
C, 74.59; H, 11.07; N, 6.69. Found: C, 74.65; H, 11.13; N, 6.38%.
epi-( )-Hippodamine (2)
To a solution of tosylate 23 (26.75 mg, 0.0736 mmol) in
2-butanone (20 mL) was added sodium iodide (110.21 mg,
0.735 mmol). The mixture was refluxed for 24 h under argon
atmosphere and exclusion of light. The mixture was evaporated
to dryness. Water (5 mL) was added and the resulting solution
was extracted with EtOAc (3 × 10 mL). Combined extracts
were washed with a saturated solution of sodium thiosulfate
(5 mL), brine (2 mL) and dried over Na2SO4. The volatiles
were evaporated to give crude 24 (23.4 mg) as a yellow oil
(Rf 0.45, alumina, MeOH–EtOAc 1 : 1) that was used without
further purification. A 5 mL round-bottom flask was charged
with activated zinc25 (0.2 g, 3.06 mmol) and glacial acetic acid
(3 mL) was added. The mixture was exposed to sonication for
5 min. Then crude iodide 24 (∼23.4 mg, 73.3 lmol) was added
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 7 3 – 8 3
8 1

View Article Online
in glacial acetic acid (0.5 mL). The mixture was refluxed for 3 h.
The mixture was allowed to reach room temperature and then
filtered. The solids were washed with MeOH (1 mL) and the
filtrate was evaporated. The residue was diluted with benzene
(10 mL) and K2CO3 (1 g) was added. The mixture was stirred
for 4 h. Solids were filtered off and the filtrate was evaporated to
dryness to give a crude product (22 mg) that was purified using
column chromatography on activity IV neutral alumina (1 g,
hexane–Et2O 4 : 1) to afford 29 (11.8 mg, 83.1% over two steps)
as a colourless oil: Rf 0.40 (alumina, MeOH–EtOAc 1 : 1); IR
(cm−1) 2925, 2853, 1455, 1440, 1378, 1265, 1122, 1075, 1024; 1H
NMR (400 MHz, CDCl3) 2.97–2.88 (3H, m), 2.13–2.06 (1H, m),
1.98–1.92 (1H, m), 1.89–1.79 (4H, m), 1.52–1.15 (10H, m), 1.10
(3H, d, J = 7.2), 1.03–0.9 (1H, m); 13C NMR (100 MHz, CDCl3)
58.4 (d), 58.3 (d), 43.1 (d), 40.5 (t), 36.6 (t), 34.7 (t), 31.5 (t), 27.0
(t), 26.7 (t), 25.7 (d), 23.4 (t), 22.1 (q), 19.8 (t); MS (EI) m/z
193 (54, M+), 192 (100), 178 (57), 165 (54), 151 (60), 150 (71),
111 (97); HRMS calcd for C13H24N (M + H) 194.1903, found
194.1905.
Acknowledgements
The authors would like to thank the Leverhulme Trust for
funding this research. They would also like to thank Astra
Zeneca for generous unrestricted funding of their research
programme and the EPSRC Mass Spectrometry Service at the
University of Wales, Swansea for carrying out high resolution
mass spectra. The authors also acknowledge the use of the
EPSRC’s Chemical Database Service at Daresbury.28
References
1 A. G. King and J. Meinwald, Chem. Rev., 1996, 96, 1105.
2 S. Al Abassi, M. A. Birkett, J. Pettersson, J. A. Pickett, L. J. Wadhams
and C. M. Woodcock, J. Chem. Ecol., 2001, 27, 33.
3 M. Langlois, J. L. Soulier, D. Yang, B. Bremont, C. Florac, V.
Rampillon and A. Giudice, Eur J. Med. Chem., 1993, 28, 869.
4 B. Tursch, D. Daloze, A. Pasteels, A. Cravador, J. C. Braekman, C.
Hootele and D. Zimmermann, Bull. Soc. Chim. Belg., 1972, 81, 649.
5 B. Tursch, D. Daloze, J. C. Braekman, C. Hootele, A. Cravador, D.
Losman and R. Karlsson, Tetrahedron Lett., 1974, 5, 409.
6 R. H. Mueller and M. E. Thompson, Tetrahedron Lett., 1980, 21,
1093.
7 R. H. Mueller, M. E. Thompson and R. M. DiPardo, J. Org. Chem.,
(2R*, 3aS*, 6aS*, 9aS*)-2-Hydroxy-2-methyl-dodecahydro-
pyrido[2,1,6-de]quinolizine (25)
1984, 49, 2217.
8 W. A. Ayer, R. Dawe, R. A. Eisner and K. Furuichi, Can. J. Chem.,
1976, 54, 473.
To a stirred solution of ketone 18 (87.2 mg, 0.451 mmol) in
toluene (10 mL) cooled to 0 ◦C under argon atmosphere was
added 1.6 M MeLi in Et2O (846.0 lL, 1.353 mmol) in three
portions over 3 h. Stirring was continued for another 5 h. A
saturated solution of NH4Cl (1 mL) was added. The organic
layer was separated and the aqueous one was extracted with
benzene (3 × 5 mL). Combined extracts were dried over Na2SO4.
The volatiles were evaporated to give a crude product (67 mg)
that was purified using column chromatography on activity IV
neutral alumina (10.6 g, stepwise gradient of hexane–Et2O 5 :
1 to 1 : 1 and finally pure Et2O). The product was allowed to
crystallize from Et2O to afford 25 (57.8 mg, 61.2%) as crystals
(clear, colourless plates): Rf 0.38 (alumina, MeOH–EtOAc 1 :
1); mp 146.8–147.1 ◦C (Et2O): IR (cm−1) 3365, 2919, 2854, 1459,
9 D. R. Adams, W. Carruthers and P. J. Crowley, J. Chem. Soc., Chem.
Commun., 1991, 1261.
10 M. Rejzek and R. A. Stockman, Tetrahedron Lett., 2002, 43,
6505.
11 W. Kitching, J. A. Lewis, M. V. Perkins, R. Drew, C. J. Moore, V.
Schurig, W. A. Ko¨nig and W. Francke, J. Org. Chem., 1989, 54, 3893.
12 O. Mitsunobu, Synthesis, 1981, 1.
13 R. Pappo, D. S. Jr. Allen, R. U. Lemieux and W. S. Johnson, J. Org.
Chem., 1956, 21, 478.
14 D. Yang and C. Zhang, J. Org. Chem., 2001, 66, 4814.
15 B. Tse and Y. Kishi, J. Org. Chem., 1994, 59, 7807.
16 W. S. Wadsworth, J. Org. React., 1977, 25, 73.
17 Handbook of Reagents for Organic Synthesis: Oxidizing and Reducing
Agents, ed. S. D. Burke and R. L. Danheiser, John Wiley & Sons,
New York, 2000, 550 pp.
18 J.-C. Braekman, A. Charlier, D. Daloze, S. Heilporn, J. Pasteels, V.
Plasman and S. Wang, Eur. J. Org. Chem., 1999, 1749.
19 O. J. Osby, M. G. Martin and B. Ganem, Tetrahedron Lett., 1984, 25,
2093.
1
1442; H NMR (400 MHz, CDCl3) 3.14–3.06 (1H, m), 3.02–
2.94 (2H, m), 2.36–2.24 (1H, m), 1.96–1.76 (4H, m), 1.64–1.40
(8H, m), 1.36–1.24 (1H, m), 1.20 (3H, s), 1.17–0.99 (2H, m); 13
C
NMR (100 MHz, CDCl3) 69.2 (s), 58.2 (d), 58.1 (d), 47.4 (t),
43.7 (d), 42.8 (t), 34.3 (t), 32.7 (q), 31.5 (t), 26.6 (t), 25.1 (t), 23.0
(t), 19.5 (t); MS (EI) m/z 209 (64, M+), 208 (100), 190 (42), 176
(35), 167 (61), 150 (66), 55 (54), 43 (90), 41 (99); HRMS calcd
for C13H24NO (M + H) 210.1852, found 210.1851.
20 F. W. Wehrli, A. P. Marchand and S. Wehrli, Interpretation of Carbon-
13 NMR Spectra, 2nd edn., John Wiley & Sons, Chichester, New
York, Brisbane, Toronto, Singapore, 1983, 484 pp.
21 W. Dieckmann, Ber. Dtsch. Chem. Ges., 1900, 33, 2670.
22 Compound 25. Crystal data: C13H23NO, M = 209.3. Monoclinic,
space group P21/c (no. 14), a = 9.766(3), b = 9.337(2), c = 13.767(2)
◦
3
−3
˚
˚
A, b = 102.38(2) , V = 1226.1(5) A , Z = 4, Dc = 1.134 g cm
,
F(000) = 464, T = 293(2) K, l(Mo-Ka) = 0.7 cm−1, k(Mo-Ka) =
˚
0.71069 A. A clear, colourless plate crystal, ca. 0.62 ×0.21 ×0.05 mm,
Deoxygenation of 25
was mounted on a Nonius CAD4 diffractometer; of the 2511 reflec-
tions measured to hmax = 25◦, 2146 were unique (Rint = 0.012) and
1263 ‘observed’ with I > 2rI. Refinement gave wR2 = 0.136 and R1 =
To a solution of tertiary alcohol 25 (23.5 mg, 0.112 mmol)
in absolute THF (10 mL) 2.5 M nBuLi in hexanes (49.3 lL,
0.123 mmol) was added dropwise under stirring, argon atmo-
sphere and at −78 ◦C. After 1 h carbon disulfide (26.9 lL,
0.448 mmol) was added and the mixture was allowed to reach
room temperature. Stirring was continued for 3 h. MeI (27.9 lL,
0.448 mmol) was added and the mixture was stirred overnight.
The mixture was filtered. The filtrate was evaporated and filtered
again through a short column of neutral alumina activity
IV. The crude xanthate 26 (14.0 mg) was used without any
further purification. To a refluxing solution of tri-n-butyltin
hydride (27.4 mg, 0.094 mmol) and AIBN (0.8 mg, 4.7 lmol) in
toluene (10 mL) was added a solution of xanthate 26 (14.0 mg,
0.047 mmol) in toluene (7 mL) dropwise over 1 h. The mixture
was refluxed for a further 4 h and left to stand overnight. Neutral
alumina activity IV (0.5 g) was added and the mixture was
evaporated to dryness under reduced pressure. The solid was
purified using column chromatography on activity IV neutral
alumina (10.0 g, hexane–Et2O 10 : 1) to give a mixture of 1 and
2 (combined yield 4.1 mg, 19% over 2 steps) in a ratio 2.3 : 1 (by
1H NMR).
0.08129 for all 2146 reflections weighted w = [r2(Fo2) + (0.0645P)2]−1
;
for the ‘observed’ data only, R1 = 0.047. CCDC reference number
248862. See http://www.rsc.org/suppdata/ob/b4/b413052a/ for
crystallographic data in .cif or other electronic format.
23 Compound 22. Crystal data: C13H23NO, M = 209.3. Monoclinic,
space group P21/n (equiv. to n◦o. 14), a = 7.660(2), b = 14.610(3),
3
˚
˚
c = 10.367(2) A, b = 91.13(3) , V = 1160.0(4) A , Z = 4, Dc
=
1.199 g cm−3, F(000) = 464, T = 140(1) K, l(Mo-Ka) = 0.7 cm−1
,
˚
k(Mo-Ka) = 0.71069 A. A clear, colourless tapered, rectangular
prismatic crystal, ca. 0.50 × 0.25 × 0.20 mm, was mounted on a
Rigaku R-Axis IIc image-plate diffractometer. Total no. of reflections
recorded to hmax = 25.4◦, was 6174 of which 2043 were unique
(Rint = 0.052); 1851 were ‘observed’ with I > 2rI. Refinement gave
wR2 = 0.103 and R1 = 0.04229 for all 2043 reflections weighted
w = [r2(Fo2) + (0.0384P)2 + 0.38P]−1 with P = (Fo + 2Fc2)/3;
2
for the ‘observed’ data only, R1 = 0.039. CCDC reference number
248861. See http://www.rsc.org/suppdata/ob/b4/b413052a/ for
crystallographic data in .cif or other electronic format.
24 Tosylation of alcohol 22 using tosyl chloride, triethyl amine and
trimethylammonium hydrochloride in dichloromethane gave a low
yield of 23 (Method A in Scheme 7). For this reason 22 was first
deprotonated using n-BuLi and then tosyl chloride was added giving
8 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 7 3 – 8 3

View Article Online
the desired tosylate 23 in 95% yield (Method B in Scheme 7).
B. L. Murr, B. J. Parkhill and A. Nickon, Tetrahedron, 1992, 48,
4845.
28 D. A. Fletcher, R. F. McMeeking and D. Parkin, J. Chem. Inf.
Comput. Sci., 1996, 36, 746.
29 Both structures were determined by direct methods procedures in
SHELXS and refined by full-matrix least-squares methods, on F2’s,
in SHELXL. In both structures, the hydroxyl hydrogen atom was
25 L. F. Fieser and M. Fieser, Reagents for Organic Synthesis,
John Wiley & Sons, Inc., New York, London, Sydney, 1967,
p. 1276.
located in a difference Fourier map and refined freely. In the final
−3
˚
26 B. Lebrun, J. C. Braekman and D. Daloze, Magn. Reson. Chem.,
difference maps, the highest peaks were ca. 0.19 e A in 22 and ca.
−3
˚
1999, 37, 60.
0.15 e A in 25. G. M. Sheldrick, SHELX-97 - Programs for crystal
27 W. A. Ayer, M. J. Bennett, L. M. Browne and J. T. Purdham,
Can. J. Chem., 1976, 54, 1807.
structure determination (SHELXS) and refinement (SHELXL),
University of Go¨ttingen, Germany, 1997.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 7 3 – 8 3
8 3