Biomimetic approach to Galbulimina type I alkaloids

Article abstract of DOI:10.1016/j.tet.2005.09.050

On treatment with trifluoroacetic acid the tetraene precursor 23 underwent Boc deprotection, condensation and an iminium ion accelerated intramolecular Diels-Alder cycloaddition resulting in an iminium species 12, which was further converted into himbacin

Full text of DOI:10.1016/j.tet.2005.09.050

Tetrahedron 61 (2005) 11649–11656
Biomimetic approach to Galbulimina type I alkaloids
Kirill Tchabanenko, Richard Chesworth, Jeremy S. Parker, Neel K. Anand, Andrew T. Russell,
*
Robert M. Adlington and Jack E. Baldwin
Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, United Kingdom
Received 4 August 2005; revised 31 August 2005; accepted 15 September 2005
Available online 14 October 2005
Abstract—On treatment with trifluoroacetic acid the tetraene precursor 23 underwent Boc deprotection, condensation and an iminium ion
accelerated intramolecular Diels–Alder cycloaddition resulting in an iminium species 12, which was further converted into himbacine 1,
himbeline 3 and himandravine 4, three out of four Galbulimina type I alkaloids thus providing strong evidence for the proposed biogenesis of
this important family of alkaloids.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Alzheimer’s disease.5 Mostly due to the latter discovery
himbacine has attracted significant synthetic attention.6–9
As early as 1948 Webb discovered that the bark of relic trees
belonging to the Galbulimina baccata genus and found in
New Guinea and North Queensland (Australia) reacted
strongly to alkaloid tests and this was subsequently verified
by Ritchie 7 years later when he isolated nine novel
alkaloids from the same bark.1 So far 28 Galbulimina
alkaloids have been isolated and they appear to fall into four
classes based upon their structures.2 Class I consists of four
tetracyclic lactones as shown in Figure 1.
Three successful total syntheses of himbacine have been
reported, each having similar features in common. A Diels–
Alder cycloaddition was employed to construct the decalin
fragment and all of the authors approached himbacine 1 via
methylation of the piperidine nitrogen of himbeline 3. Hart
has synthesised the tricyclic fragment via a highly
stereoselective Lewis acid catalysed cycloaddition of
thioester 5 (Scheme 1, Eq. 1). Completion of the tetracycle
Figure 1. Class I Galbulimina alkaloids.
Himbacine 1, being the major representative of the family,
was the first to have it’s structure identified.3 It was
originally shown to exhibit anti-spasmodic activity with low
toxicity and few side effects.4 In the 1990s though,
himbacine has been shown to be a selective muscarinic
antagonist and thus a potential new lead in the treatment of
Keywords: Biomimetic synthesis; Galbulimina alkaloids; Himbacine;
Himandravune; Himbeline.
*
Corresponding author. Tel.: C44 1865 275 67; fax: C44 1865 275 670;
e-mail: jack.baldwin@chem.ox.ac.uk
Scheme 1. Previous successful syntheses of himbacine 1.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.09.050

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required nine extra synthetic steps7 including a forced
reduction, protection and further reoxidation of the lactone.
In what is considered as the most efficient published total
synthesis of himbacine 1, Chackalamannil performed a
reverse electron demand Diels–Alder of teraene 6 (Scheme 1
Eq. 2). The exo-selective cycloaddition resulted in a
compound with opposite stereochemistry at the centre a to
the lactone to the one required for the total synthesis.
Epimerization was achieved on treatment of the tetracycle
with DBU in toluene and the total synthesis was
accomplished in four further synthetic steps.8 Terashima’s
synthesis has employed an intermolecular Diels–Alder of
furan derivative 7 and butenolide 8 (Scheme 1 Eq. 3).
Completion of the total synthesis required over 15 synthetic
steps, although a more modular approach allowed synthesis
of multiple unnatural analogues.9 Remarkably, only
Chackalamannil has synthesized himandravine 4 in a later
synthetic effort.10
Our interest in the Galbulimina alkaloids dates back to the
late 1980s when we decided to establish a general
biomimetic approach to all members of the class I
alkaloids.11 The proposed approach should also be
applicable, with modification, to the synthesis of more
structurally complex class II and class III alkaloids.
2. Biomimetic approach
Ritchie speculated that nine C2 acetate units, one C3
pyruvate unit and a molecule of NH3 were used to construct
the alkaloids (Scheme 2),12 without being specific on the
particular biotransformations involved. Our biosynthetic
pathway for the Galbulimina class I alkaloids13 postulates
ketide 9 formation from the same nine acetates and a
pyruvate via standard polyketide biosynthesis. Reductive
lactonisation would result in butenolide 10, which on
reductive amination followed by iminium ion formation via
N-methylation or N-protonation would provide the Diels–
Alder precursor 11. Intramolecular Diels–Alder cyclo-
addition via an endo transition state would afford tetracycle
12. Finally, hydride reduction of the iminium from either the
a or b face would furnish either the himbacine (trans-
piperidine ring) precursor 13 or the himandravine (cis-
piperidine ring) precursor 14 (Scheme 2). Our primary goal
was to establish the possibility of a biological iminium
catalysed Diels–Alder reaction leading to the tricyclic
lactone core of these alkaloids.
Scheme 2. Postulated biogenesis of class I alkaloids.
Scheme 3. Approaches to aldehyde 15.
Our initial approach to aldehyde 15 is outlined in Scheme 3
and was based on a Suzuki reaction of the trans-bromide
followed by carboxylation of the cis-position of the
dibromo-alkene 16.13 Later, we adopted a more elegant
approach by Hart7 and accessed 15 from cycloheptene in
seven synthetic steps and 29.5% overall yield.
3. Results and discussion
3.1. Gassman Diels–Alder
First, we attempted a thermal cycloaddition of aldehyde 15
(Scheme 4). A solution of the enal 15 in d8-toluene was
heated in the presence of 0.2 equiv of the radical inhibitor,
3-tert-butyl-4-hydroxy-5-methylphenyl sulphide, at 130 8C
in a sealed tube for 24 h. Pleasingly an IMDA process
occurred and the cycloaddition product appeared to consist
of a 2.5:2.3:1.0:0.25 mixture of diastereoisomers. The
isolated yield after column chromatography was a reason-
able 61%, although the diastereoisomers could not be
separated.
It was our expectation, that the Diels–Alder type reaction of
butenolides like 10 would require strong activation of the
dienophile. Aldehydes are known to be among the best
substituents for such activation, as their LUMO energy
lowering effect can be dramatically enhanced via formation
of oxacarbenium species on treatment with Lewis Acids.
Thus, we chose the aldehyde 15 (Scheme 3) as our initial
model to study the possibility of a biological Diels–Alder.

K. Tchabanenko et al. / Tetrahedron 61 (2005) 11649–11656
11651
at C4 position in the alcohol 20. Quite unexpectedly 1,4-
addition of the hydride was competitive under the same
conditions resulting in formation of a minor saturated
tricycle 21 (Scheme 6).
Scheme 4. Thermal cycloaddition of enal 15.
Attempts to accelerate the Diels–Alder by use of Me2AlCl
or SnCl4 were unsuccessful. This was attributed to the more
likely coordination of the Lewis Acids to the more basic
carbonyl of the butenolide, rather then the enal.
Scheme 6. Synthesis of alcohol 20.
The alcohol 20 is a white crystalline solid and we expected
to obtain crystals of the major component on attempted
crystallization of the mixture of 20 and 21. To our surprise
the single crystal that was chosen for X-ray analysis
contained the minor component 21. Gratifyingly, the
diffraction analysis data16 (Fig. 2) confirmed that the
stereochemistry of the tricyclic core of 21 is the same as
that of himbacine 1.
Next, our attention was drawn to Gassman’s findings
indicating that acrolein acetals in the presence of Lewis or
protic acids form oxonium ions, which undergo accelerated
IMDA cycloadditions with a range of dienes at low
temperatures.14 At first we attempted to form a cyclic
acetal of the enal 15. The Noyori procedure involves low
temperature conditions using 1,2-bis(trimethylsilyloxy)-
ethane as the acetal source and TMSOTf as catalyst.15
Application of these conditions to the enal 15 at K78 8C
afforded the acetal 16, which could be isolated if the
reaction was quenched by addition of pyridine. However, if
the reaction was allowed to warm to K20 8C, the presence
of TMSOTf, acting as a Lewis Acid, promoted a Gassman
intramolecular Diels–Alder reaction presumably via the
formation of an oxonium ion intermediate 17. Pleasingly,
tricyclic acetal 18 was isolated in a 53% yield with a 40:1
ratio of diastereomers (Scheme 5).
Figure 2. Chem 3D plot of the X-ray of 21.
Having obtained proof that with sufficient dienophile activation,
the intramolecular Diels–Alder reaction of a butenolide like 15
givesendo-cyclisationproductswithhighlevel of stereocontrol,
we moved on to investigate the proposed biomimetic
cycloaddition of iminium species like 11.
3.2. Biomimetic Diels–Alder reaction
Two possible synthetic pathways towards the iminium 11
were investigated. The first one centered on a Polonovski17
generation of 11 (RZMe) from the piperidine species 22.
The second envisaged formation of the iminium species 11
(RZH) on acid catalysed cleavage of the N-Boc protecting
group and condensation of the tethered amine in an open
chain precursor 23 (Scheme 7).
Scheme 5. Gassman Diels–Alder.
At first we expected the minor cycloadduct to be an exo-
pathway product, but our first attempt to hydrolyse the
acetal 18 led to isolation of the aldehyde 19 as a 3:1 mixture
of epimers. Epimerisation under the hydrolysis conditions
could only have occurred at C4 and this suggested that the
Gassman Diels–Alder produced only endo-cycloaddition
product with some minor epimerization at C4 position
occurring under the reaction conditions. Our next aim was to
obtain unambiguous proof of the stereochemistry of the
cycloadduct. A briefer aqueous hydrolysis and an in situ
NaBH4 reduction of the aldehyde 19 avoided epimerization
Our multiple attempts to synthesise himgravine 2 type
adducts in Polonovski-type oxidations of the piperidine
compound 21 were unsuccessful18 and will not be discussed
further in this publication. On the other hand, positive
results were obtained in the investigation of the alternative
condensation pathway.
It was expected that the cyclisation precursor 23 would be
accessed via a Wittig type olefination of aldehyde 15 and
phosphonate 24.

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K. Tchabanenko et al. / Tetrahedron 61 (2005) 11649–11656
Scheme 7. Approaches to iminium species 11.
The synthesis of the chiral phosphonate 24 was accom-
plished in three steps. 2-Methyl piperidine was resolved via
crystallization with L-tartaric acid,19 which was followed by
Boc protection and oxidation.20 Treatment of the piper-
idinone with a small excess of the lithiated dimethyl
methylphosphonate produced the desired Horner–Emmons
reagent 24 in 54% yield after column chromatography
(Scheme 8).
Reaction of the phosphonate 24 with the aldehyde 15
Scheme 9. Completeion of synthesis.
Scheme 8. Synthesis of phosphonate 23.
followed by a highly selective hydrogeneation of the tri-
substituted double bond over Adam’s catalyst3 in order to
separate the N-Boc protected himbeline 27 and himandra-
vine 28 derivatives. Boc deprotection of 27 yielded
synthetic himbeline 3, which was N-methylated following
literature method7 to give synthetic himbacine 1, whose
structure was confirmed via 1H NMR in a doping
experiment with an authentic sample of the natural
product.22
employing the modified Masamune–Roush conditions21
produced the tetraene 23, which was treated with
trifluoroacetic acid at 0 8C in dichloromethane effecting
Boc cleavage and condensation to the desired iminium
species 11. The reaction mixture was then allowed to warm
up slowly to room temperature and stirred for an additional
hour then quenched by addition of an excess of sodium
cyanoborohydride almost immediately followed by addition
1
of saturated aqueous sodium bicarbonate. At this point H
N-Boc deprotection of 28 led to isolation of synthetic
himandravine 4 (Scheme 10). In absence of a natural
product sample to run a doping experiment, it was decided
to establish the structure via X-ray analysis. Thus, 4 was
converted into a dinitro-benzoate derivative 29. The results
of the single crystal X-ray analysis of 29 are presented in
Figure 3.
NMR analysis of the crude reaction mixture showed
complete disappearance of resonances corresponding to
the starting material along with the appearance of two
characteristic peaks at d 6.62 and 6.69 ppm, corresponding
to the resonances of the protons of the a,b unsaturated
double bond of two epimeric products 25 and 26 derived
from consecutive N-Boc deprotection, condensation, IMDA
cycloaddition and iminium ion reduction (Scheme 9). The
reduction proved to be non-facial selective and both
b-hydrogen peaks had identical integration in the
500 MHz 1H NMR.
In summary, we have demonstrated a single step biomimetic
transformation of 23 into a tetracyclic iminium species 12,
which was further transformed into himbeline 3, himbacine
1 and himandravine 4. We believe this proceeds via a
consecutive N-Boc deprotection, condensation and iminium
ion activated intramolecular Diels–Alder cycloaddition
process. This provides strong support for our proposed
biogenesis of these class 1 Galbulimina alkaloids.
We found that direct separation of the diastereomeric
mixture of 25 and 26 from the complex crude reaction
mixture was impossible and required N-Boc protection

K. Tchabanenko et al. / Tetrahedron 61 (2005) 11649–11656
11653
Analysis of both structures shows that the class II
alkaloids have extra carbon–carbon bonds between C22
and C2, C14 and C15 and that the piperidine nitrogen
becomes connected to C4. Extra oxygenation of C8, C7, and
C13 of the decalin unit could be attributed to later metabolic
oxidation steps.
Our successful biomimetic synthesis of the class I alkaloids
(notably both major alkaloids himbacine 1 and himandra-
vine 2 were synthesized in the same synthetic route)
employing an iminium ion activated intramolecular
Diels–Alder reaction allows us to postulate that similar
chemistry would be involved in the biosynthesis of the class
II and III alkaloids. Our proposed biosynthetic pathway is
presented in Scheme 11. The scheme starts with the same
polyketide 9, which would not undergo a reductive
lactonisation, but would directly give the iminium 31 on
condensation with ammonia. 31 is set for an iminium ion
activated intramolecular Diels–Alder reaction producing the
tricyclic 32. The iminium activates the exocyclic double
bond as an acceptor and the tautomerised enolic form of
the ketone would add in a conjugate fashion to give the
C14–C15 carbon–carbon bond. Further tautomerisation of
the enamine 33 accompanied by double bond migration
into 34 would be followed by Michael addition to give the
N–C4 connectivity in 35. 1,2-Addition of the enamine
would accomplish the C2–C22 bond in polycycle 36, which
on iminium reduction would give 37, a possible inter-
mediate in the biosynthesis of class II and III Galbulimina
alkaloids.
Scheme 10. Synthesis of himandravine derivative 29.
Figure 3. Chem 3D plot of the X-ray structure of 29.
3.3. A new hypothesis
It was our original intent to propose a more complete
biogenetic pathway analysis, which would be applicable not
only to the class I but to other classes of Galbulimina
alkaloids as well. Himbosine 30 is a representative of the
highly oxygenated hexacyclic class II alkaloids. Similarities
between alkaloids of the two classes is indicated by
numbering in Figure 4.
Figure 4. Class I and II Galbulimina alkaloids.
Scheme 11. Postulated biogenesis of class II and III alkaloids.

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K. Tchabanenko et al. / Tetrahedron 61 (2005) 11649–11656
4. Experimental
chromatography (diethyl ether/pet. ether 2:3) giving the
product 20 as a white crystalline solid (20 mg, 42%); mp
149–151.5 8C; [a]2D2 C52.5 (c 0.4, CHCl3); m/z (CIC) found
254.1756, C14H20O3CNHC4 requires 254.1756; nmax/cmK1
(KBr) 3435 (br s), 2839 (s), 1735 (s), 1630 (m), 1442 (m),
1380 (m); dH (500 MHz, CDCl3) 0.87 (1H, m), 1.13 (1H,
m), 1.25–1.39 (3H, m), 1.56 (3H, d, JZ6.0 Hz), 1.76–1.84
(3H, m), 1.90 (1H, ddt, JZ9.5, 7.0, 6.5 Hz), 1.97 (1H, m),
2.07 (1H, m), 2.70 (1H, ddd, JZ12.5, 7.0, 3.5 Hz), 3.73
(2H, d, JZ6.5 Hz) 4.80 (1H, dq, JZ12.5, 6.0 Hz), 6.65 (1H,
dd, JZ3.5, 3.0 Hz); dc (125 MHz, CDCl3) 21.62, 26.04,
26.44, 31.79, 32.43, 40.56, 40.83, 42.99, 45.76, 61.68,
78.28, 131.4, 140.9, 169.5.
4.1. General
4.1.1. Preparation of ketal 18. To a solution of enal7 15
(88.9 mg, 0.38 mmol) in dichloromethane (6 ml) cooled to
K78 8C under an atmosphere of argon was added 1,2-bis-
(trimethylsiloxy)-ethane (235 mg, 1.14 mmol). This
solution was stirred at K78 8C for 15 min at which stage
trimethylsilyltrifluoromethylsulphonate (84.4 mg, 0.38 mmol)
was added dropwise. The resultant bright yellow solution
was stirred at K78 8C for a further 3 h, at which stage the
temperature of the reaction mixture was rapidly increased to
K20 8C. The reaction mixture was stirred for 2 h between
K30 and K20 8C during which time the colour of the
reaction mixture darkened considerably. Excess pyridine
(0.5 ml) was added discharging the dark colour. The
reaction mixture was then warmed to room temperature,
diluted with dichloromethane (20 ml) and poured into
saturated sodium hydrogen carbonate (30 ml). The layers
were separated and the aqueous layer extracted with
dichloromethane (2!20 ml). The organics were combined,
dried over magnesium sulphate, filtered and volatiles
removed in vacuo. The obtained yellow oil was purified
by flash chromatography (diethyl ether/pet. ether 4:7) to
yield the product 18 as a colourless oil (56 mg, 53%); [a]D22
C54.3 (c 1, CHCl3); m/z (CIC) found 279.1596,
C16H22O4CHC requires 279.1596; nmax/cmK1 (film) 2854
(m), 1757 (s), 1683 (m), 1408 (m), 1226 (m), 979 (m); dH
(500 MHz, CDCl3) 1.12 (1H, m), 1.16 (1H, m), 1.26–1.46
(3H, m), 1.47 (3H, d, JZ6.0 Hz), 1.72 (1H, m), 1.75–1.80
(2H, m), 2.05–2.11 (2H, m), 2.15 (1H, ddd, JZ9.5, 7.5,
4.0 Hz), 2.61 (1H, ddd, JZ9.5, 7.5, 3.0 Hz), 3.81–3.83 (2H,
m), 3.94–3.96 (2H, m), 4.78 (1H, d, JZ4.0 Hz), 4.94 (1H,
dq, JZ7.5, 6.0 Hz), 6.71 (1H, dd, JZ3.5, 3.0 Hz); dc
(125 MHz, CDCl3) 21.84, 26.12, 26.58, 32.24, 33.86, 41.28,
41.35, 43.51, 44.31, 64.37, 64.62, 77.47, 105.1, 131.4,
141.2, 169.3.
4.1.3. Preparation of phosphonate 24. To a stirred solution
of dimethyl methylphosphonate (1.86 g, 15 mmol) in THF
(50 ml) was added n-butyl lithium (1.6 M solution in
hexanes, 10 ml) dropwise at K78 8C. The reaction mixture
was stirred for an hour and (2S)-methyl-N-Boc-piperidi-
none20 (2.13 g, 10 mmol) was added. Reaction mixture was
allowed to warm to room temperature and stiring was
continued for an additional hour. Water (20 ml) was added
and the resulting mixture was poured into a separating
funnel containing ethyl acetate (100 ml) and water (100 ml).
Layers were separated and the aqueous layer was extracted
with ethyl acetate (2!25 ml). Combined organics were
dried (MgSO4), filtered and volatiles removed in vacuo.
Flash chromatography (short column, EtOAc with 2.5%
MeOH) yielded the title compound as a colourless oil
(1.86 g, 54%); [a]2D2 K2.9 (c 1.0, CHCl3); m/z (CIC) found
337.1661, C14H28NO6PCHC requires 337.1654; nmax/cmK1
(film) 3318 (br m), 2972 (s), 1710 (s), 1690 (s), 1253 (m),
1174 (m), 1033 (s); dP (125 MHz, CDCl3) 23.91; dH
(500 MHz, CDCl3) 1.09 (3H, d, JZ6.5 Hz), 1.31–1.46
(2H, m), 1.39 (9H, s), 1.59 (2H, m), 2.62 (2H, m), 3.07 (2H,
d, JZ22.5 Hz), 3.59 (1H, m), 3.73 (3H, s), 3.79 (3H, s), 4.39
(1H, br s); dc (125 MHz, CDCl3) 19.63, 21.08, 26.28, 36.11,
40.63, 41.66, 43.59, 45.98, 52.85, 78.85, 155.29, 201.48.
4.1.2. Preparation of alcohol 20. To a solution of ketal 18
(56 mg, 0.2 mmol) in acetone–water (2/1, 9 ml) was added
para-toluenesulfonic acid (114 mg, 0.6 mmol). The solution
was brought to a gentle reflux which was maintained for 6 h.
The reaction mixture was then cooled, diluted with
dichloromethane (50 ml) and washed with water (25 ml).
The aqueous portion was extracted with dichloromethane
(25 ml), the organics combined, dried over magnesium
sulphate, filtered and the volatiles removed in vacuo. The
crude mixture was dissolved in ethanol (7 ml) and the
solution was cooled to 0 8C. To this rapidly stirred solution
was added sodium borohydride (15 mg, 0.4 mmol). The
reaction mixture was then stirred at room temperature for
20 min at which stage excess sodium borohydride (30 mg,
0.8 mmol) was added and the reaction mixture was stirred
for a further 10 min. The reaction was quenched by careful
addition of acetone (6 ml) over a period of 2 min and then
poured into water (20 ml) and diluted with dichloromethane
(20 ml). Dilute hydrochloric acid (1 M, 3 ml) was added to
the biphasic mixture, the layers were separated and the
aqueous portion was extracted with dichloromethane
(20 ml). The organics were combined, dried over
magnesium sulphate, filtered and the volatiles removed in
vacuo. The obtained yellow oil was purified by flash
4.1.4. Preparation of tetraene 23. A mixture of aldehyde
15 (270 mg, 1.15 mmol), phosphonate 24 (656 mg,
1.94 mmol), lithium chloride (210 mg, 5 mmol) and
diisopropyl ethyl amine (246 mg, 2 mmol) in acetonitrile
(10 ml) was stirred for 12 h. Water (10 ml) and diethyl ether
(10 ml) were added and layers were separated. Aqueous
layer was extracted with diethyl ether (2!10 ml), combined
organics dried (MgSO4), filtered and concentrated in vacuo.
Flash chromatography (petrol ether/ethyl acetate 6:1) gave
the title compound 23 as a colourless oil (256 mg, 50%);
[a]2D2 C48.1 (c 1.0, CHCl3); m/z (CIC) found 446.2898,
C26H39NO5CHC requires 446.2906; nmax/cmK1 (film)
3320 (br m), 2971 (s), 1735 (s), 1710 (s), 1650 (s), 1630
(m), 1525 (m), 1253 (s), 1033 (m); dH (500 MHz, CDCl3)
1.10 (3H, d, JZ5.5 Hz), 1.36–158 (8H, m), 1.40 (9H, s),
1.43 (3H, d, JZ6.0 Hz), 1.62 (2H, m), 2.12–2.30 (2H, m),
2.54 (2H, m), 3.62 (1H, m), 4.40 (1H, br s), 5.10 (1H, dq,
JZ2.5, 6.0 Hz), 5.84 (1H, m), 5.90 (1H, m), 6.06–6.11 (2H,
m), 6.81 (1H, dt, JZ16.0, 5.5 Hz), 7.07 (1H, m), 7.16 (1H,
d, JZ2.5 Hz); dc (125 MHz, CDCl3) 17.9, 19.1, 20.3, 21.1,
27.6, 28.3, 28.5, 29.3, 32.0, 36.5, 39.5, 46.0, 77.4, 116.8,
122.2, 128.4, 130.3, 138.9, 146.7, 146.9, 148.9, 171.0,
172.9, 200.3.

K. Tchabanenko et al. / Tetrahedron 61 (2005) 11649–11656
11655
4.1.5. Preparation of N-Boc-himbeline 27 and N-Boc-
himandravine 28. To a stirred solution of tetraene 23
(120 mg, 0.27 mmol) in DCM (5 ml) at 0 8C was added
trifluoroacetic acid (100 ml, 1.34 mmol), the reaction
mixture was stirred for 30 min and allowed to warm to
room temperature. Stirring was continued for an additional
hour, when ethanol (5 ml) and sodium cyanoborohydride
(100 mg, 1.6 mmol) were added. The reaction was stirred
for 30 s and quenched by addition of saturated aqueous
sodium bicarbonate solution (10 ml). The resulting mixture
was poured into a separating funnel and diluted with ethyl
acetate (20 ml). Layers were separated and the aqueous
phase was extracted with ethyl acetate (2!10 ml).
Combined organics were dried (Na2SO4), filtered and
concentrated to give crude cycloaddition products as a
yellow oil, which was diluted with dichloromethane
(10 ml). Triethylamine (30 mg, 0.3 mmol) and di-tert-
butyl-dicarbonate (65 mg, 0.3 mmol) were added and the
resulting solution was stirred for 14 h. The volatiles were
removed in vacuo and the residue was dissolved in ethanol
(20 ml). To the solution was added platinum (IV) oxide
(10 mg, cat.) and the resulting mixture was stirred under
atmosphere of hydrogen for 12 h. Filtration through a plug
of Celite, which was washed with ethyl acetate (10 ml), and
concentration in vacuo afforded the crude products as a
brown oil, which was purified by flash chromatography
(petrol ether/ethyl acetate 6:1).
extracted with dichloromethane (2!5 ml) and the com-
bined organic phase was dried (K2CO3), filtered and
evaporated to give the title compound 3 as an oil (9.3 mg,
95%) which required no further purification. [a]2D2 C17.5 (c
0.95, CHCl3); lit.3 C19 (2.4% in CHCl3); m/z (FAB) found
332.2595, C21H33NO2CHC requires 332.2590; nmax/cmK1
(film) 3055 (s), 1765 (s), 1670 (m); dH (500 MHz, CDCl3)
0.72 (1H, m), 1.00 (3H, m), 1.08 (3H, d, JZ6.5 Hz), 1.10–
1.30 (4H, m), 1.40 (3H, d, JZ6.0 Hz), 1.42 (1H, m), 1.45–
1.80 (10H, m), 2.09 (1H, m), 2.23 (1H, dt, JZ10.0, 6.5 Hz),
2.62 (1H, dt, JZ13.0, 6.0 Hz), 3.09 (1H, m), 3.53 (1H, m),
4.64 (1H, dq, JZ10.5, 6.0 Hz), 5.24 (1H, dd, JZ15.5,
10.5 Hz), 5.70 (1H, dd, JZ15.5, 6.5 Hz); dc (125 MHz,
CDCl3) 19.62, 21.31, 22.22, 26.07, 26.37, 30.96, 31.27,
31.93, 32.51, 33.58, 39.88, 41.42, 42.22, 45.50, 46.28,
48.96, 53.01, 76.80, 131.46, 135.00, 178.32.
4.1.7. Preparation of himbacine 1.7 Synthetic himbeline 3
(6.5 mg, 0.02 mmol) in acetonitrile (4 ml) was added
sodium cyanoborohydride (6.5 mg, 0.1 mmol) and 37%
aqueous formaldehyde solution (25 mg, 0.03 mmol). The
reaction mixture was stirred at room temperature for 1 h and
neutralized (pH 7) by dropwise addition of glacial acetic
acid and allowed to stir for an additional 2 h. The solvents
were removed in vacuo and the residue was dissolved in
dichloromethane (10 ml). The solution was washed with
saturated aqueous sodium bicarbonate solution (10 ml), the
aqueous phase was extracted with dichloromethane (4!
5 ml) and the combined organics were dried over potassium
carbonate, filtered and evaporated. The crude product was
purified by flash chromatography on basic alumina (petrol
ether/ethyl acetate 5:1) to give the title compound 1 as an
oil23 (5.0 mg, 74%); [a]D22 C47.5 (c 0.25, CHCl3); lit.7
C51.4 (c 1.01, CHCl3); dH (500 MHz, CDCl3) 0.74 (1H,
m), 1.00 (3H, d, JZ6.5 Hz), 0.91–1.08 (3H, m), 1.10–1.30
(3H, m), 1.40 (3H, d, JZ6.0 Hz), 1.37–1.48 (2H, m), 1.50–
1.58 (2H, m), 1.63–1.80 (6H, m), 1.87 (1H, m), 2.10 (1H,
m), 2.20–2.27 (1H, m), 2.22 (3H, s), 2.62 (1H, dt, JZ12.5,
6.5 Hz), 2.84 (1H, m), 3.02 (1H, m), 4.63 (1H, dq, JZ10.5,
6.0 Hz), 5.26 (1H, dd, JZ15.0, 10.0 Hz), 5.57 (1H, dd, JZ
15.0, 9.0 Hz); dc (125 MHz, CDCl3) 13.95, 18.91, 22.19,
26.06, 26.43, 31.41, 31.98, 32.57, 33.21, 33.54, 39.83,
41.15, 41.49, 42.18, 45.67, 49.09, 53.35, 61.29, 76.77,
133.30, 133.48, 178.32.
N-Boc-himbeline 27. A colourless oil (12.4 mg, 11%); [a]D22
C58.2 (c 0.5, CHCl3); lit.7 C60.6 (c 0.55, CHCl3); m/z
(CIC) found 432.3111, C26H41NO4CHC requires
432.3114; nmax/cmK1 (film) 3055 (s), 1765 (s), 1670 (m);
dH (500 MHz, CDCl3) 0.69 (1H, m), 0.97 (3H, m), 1.08–
1.36 (3H, m), 1.22 (3H, d, JZ8.0 Hz), 1.40 (3H, d, JZ
6.0 Hz), 1.43 (9H, s), 1.45–2.10 (12H, m), 2.23 (1H, m),
2.61 (1H, dt, JZ6.5, 12.5 Hz), 4.00 (1H, m), 4.42 (1H, m),
4.62 (1H, dq, JZ10.0, 6.0 Hz), 5.21 (1H, dd, JZ15.0,
10.0 Hz), 5.52 (1H, dd, JZ15.0, 6.0 Hz); dc (125 MHz,
CDCl3) 13.05, 20.66, 21.92, 25.19, 25.86, 25.95, 26.10,
28.22, 30.95, 31.75, 33.40, 39.78, 41.30, 42.0, 45.41, 46.76,
48.47, 51.95, 78.85, 131.05, 133.89, 154.74, 178.21.
N-Boc-himandravine 28. A colourless oil (12.2 mg, 11%);
[a]2D2 C62.1 (c 0.6, CHCl3); m/z (CIC) found 432.3118,
C26H41NO4CHC requires 432.3114; nmax/cmK1 (film)
3055 (s), 1765 (s), 1670 (m); dH (500 MHz, CDCl3) 0.72
(1H, m), 0.99 (2H, m), 1.11 (3H, d, JZ6.0 Hz), 1.11–1.29
(4H, m), 1.29 (3H, d, JZ6.5 Hz), 1.43 (9H, s), 1.45–1.90
(11H, m), 2.08 (1H, m), 2.21 (1H, m), 2.60 (1H, dt, JZ6.0,
13.0 Hz), 4.30 (1H, m), 4.61 (1H, dq, JZ10.0, 6.0 Hz), 4.73
(1H, m), 5.31 (1H, dd, JZ15.0, 10.5 Hz), 5.53 (1H, dd, JZ
15.0, 7.5 Hz); dc (125 MHz, CDCl3) 14.48, 20.48, 22.25,
26.14, 26.45, 28.28, 28.50, 30.10, 31.39, 32.04, 33.60,
40.04, 41.76, 42.32, 45.65, 46.08, 48.98, 50.22, 77.05,
79.28, 131.73, 134.32, 154.82, 178.34.
4.1.8. Preparation of himandravine 4. To a solutiom of
N-Boc-himandravine 28 (11.2 mg, 0.026 mmol) in
dichloromethane (3 ml) was added TFA (0.3 ml) and the
reaction mixture was stirred for 1 h. The volatiles were
removed in vacuo and the residual oil dissolved in
dichloromethane (10 ml). The solution was washed with
saturated aqueous sodium bicarbonate solution (2!5 ml).
The aqueous phase was extracted with dichloromethane
(2!5 ml) and the combined organic phase was dried
(K2CO3), filtered and evaporated to give the title compound
4 as an oil (7.9 mg, 92%) which required no further
purification. [a]2D2 C20.5 (c 0.25, CHCl3); lit.3 C23 (1.9%
in CHCl3); m/z (FAB) found 332.2595, C21H33NO2CHC
requires 332.2590; nmax/cmK1 (film) 3055 (s), 1765 (s),
1670 (m); dH (500 MHz, CDCl3) 0.69 (1H, m), 0.92–1.43
(8H, m), 1.07 (3H, d, JZ6.5 Hz), 1.42 (3H, d, JZ6.0 Hz),
1.53–1.89 (9H, m), 2.03 (1H, m), 2.21 (1H, m), 2.59 (1H, dt,
JZ13.0, 6.5 Hz), 2.69 (1H, m), 3.11 (1H, m), 4.61 (1H, dq,
4.1.6. Preparation of himbeline 3. To a solution of N-Boc-
himbeline 27 (12.4 mg, 0.027 mmol) in dichloromethane
(3 ml) was added TFA (0.3 ml) and the reaction mixture was
stirred for 1 h. The volatiles were removed in vacuo and the
residual oil dissolved in dichloromethane (10 ml). The
solution was washed with saturated aqueous sodium
bicarbonate solution (2!5 ml). The aqueous phase was

11656
K. Tchabanenko et al. / Tetrahedron 61 (2005) 11649–11656
5. Kozikowski, A. P.; Fauq, A. H.; Miller, J. H.; McKinney, M.
BioMed. Chem. Lett. 1992, 2, 797.
JZ10.0, 6.0 Hz), 5.28 (1H, dd, JZ15.0, 10.5 Hz), 5.51 (1H,
dd, JZ15.0, 6.5 Hz); dc (125 MHz, CDCl3) 19.79, 22.52,
23.11, 24.67, 26.25, 26.55, 31.32, 32.13, 32.46, 33.79,
40.02, 41.53, 42.36, 45.40, 48.83, 52.45, 59.46, 77.50,
131.40, 136.04, 178.47.
6. De Baecke, G.; De Clercq, P. J. Tetrahedron Lett. 1995, 36,
7515. Hofman, S.; De Baecke, G.; Kenda, B.; De Clercq, P. J.
Synthesis 1998, 479. Hofman, S.; Gao, L.-J.; Van Dingenen,
H.; Hosten, N. G. C.; Van Haver, D.; De Clercq, P. J.;
Milanesio, M.; Viterbo, D. Eur. J. Org. Chem. 2001, 2851.
Wong, L. S.-M.; Sherburn, M. S. Org. Lett. 2003, 5, 3603.
7. Hart, D. J.; Wu, W.-L.; Kozikowski, A. P. J. Am. Chem. Soc.
1995, 117, 9369. Hart, D. J.; Li, J.; Wu, W.; Kozikowski, A. P.
J. Org. Chem. 1997, 62, 5023.
4.1.9. Preparation of benzoate 29. To a stirred solution of
3,5-dinitro benzoyl chloride (30 mg, 0.13 mmol) in
dichloromethane (5 ml) was added solution of himandra-
vine 4 (22.3 mg, 0.067 mmol) in pyridine (5 ml) dropwise
over 10 min. The resulting mixture was stirred at room
temperature for 6 h and poured into water (20 ml). Organics
were extracted with ethyl acetate (3!10 ml), dried
(MgSO4), filtered and concentrated in vacuo to give a
brown oil. Flash chromatography (petrol ether/ethyl acetate
2:1) gave the product as an oil (19.3 mg, 50%). The product
was obtained as white prisms on slow evaporation of a
diethyl ether solution. [a]2D2 C29.9 (c 0.83, CHCl3); mp
166–167 8C; nmax/cmK1 (film) 2930 (m), 1772 (s), 1756 (s),
1629 (s), 1544 (s), 1418 (m), 1344 (s); dH (500 MHz,
CDCl3) 0.76 (1H, m), 0.98–1.12 (2H, m), 1.06 (3H, d, JZ
7.0 Hz), 1.15–1.30 (3H, m), 1.28 (3H, d, JZ6.0 Hz), 1.34–
1.47 (2H, m), 1.58–1.94 (11H, m), 2.02 (1H, m), 2.20 (1H,
m), 2.27 (1H, m), 2.66 (1H, dt, JZ13.0, 6.5 Hz), 4.66 (1H,
dq, JZ10.0, 6.0 Hz), 5.50 (1H, dd, JZ15.5, 10.0 Hz), 5.78
(1H, dd, JZ15.5, 5.5 Hz), 8.52 (2H, d, JZ2.0 Hz), 9.08
(1H, t, JZ2.0 Hz); dc (125 MHz, CDCl3) (one carbon not
identified due to peak broadening) 14.40, 20.90, 21.93,
25.89, 26.26, 27.66, 30.22, 31.42, 31.80, 33.37, 39.84,
41.56, 42.08, 45.81, 48.87, 76.36, 77.09, 119.05, 126.33,
132.31, 133.59, 140.30, 148.47, 166.04, 177.77.
8. Chackalamannil, S.; Davies, R. J.; Asberom, T.; Doller, D.;
Leone, D. J. Am. Chem. Soc. 1996, 118, 9812.
Chackalamannil, S.; Davies, R. J.; Wang, Y.; Asberom, T.;
Doller, D.; Wong, J.; Leone, D. J. Org. Chem. 1999, 64, 1932.
9. Takadoi, M.; Katoh, T.; Ishiwata, A.; Terashima, S.
Tetrahedron Lett. 1999, 40, 3399. Takadoi, M.; Katoh, T.;
Ishiwata, A.; Terashima, S. Tetrahedron 2002, 58, 9903.
10. Chackalamannil, S.; Davies, R. Org. Lett. 2001, 3, 1427.
11. Our original ideas on a biological Diels–Alder approach to
himbacine 1 were published in: Bennet, P. A. R, DPhil,
Oxford, 1988.
12. Mander, L. N.; Prager, R. H.; Rasmussen, M.; Ritchie, E.;
Taylor, W. C. Aust. J. Chem. 1967, 20, 1705.
13. Baldwin, J. E.; Chesworth, R.; Parker, J. S.; Russell, A. T.
Tetrahedron Lett. 1995, 36, 9551.
14. Gassman, P. G.; Singleton, D. A.; Wilwending, J. J.; Chavan,
S. P. J. Am. Chem. Soc. 1987, 109, 2182.
15. Tsunoda, T.; Suzuki, M.; Noyori, R. Tetrahedron Lett. 1980,
21, 1357.
16. CCDC 255393 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
Acknowledgements
17. Grierson, D. S. The Polonovski Reaction; Organic reactions;
Wiley: New York, 1990; Vol. 39, p 85.
We would like to acknowledge James Bartleet and Andrew
Cowley for X-ray Crystallographic Analysis, CRL NMR
stuff for their help with structure elucidation, BBSRC and
EPSRC for financial support (to R.C., J.S.P. and N.K.A.).
18. Anand N. K. A Biomimetic approach towards the synthesis of
(C)-himbacine, DPhil, Oxford, 1999.
19. Doller, D.; Davies, R.; Chackalamannil, S. Tetrahedron:
Asymmetry 1997, 7, 1275.
20. Occhiato, E. G.; Prandi, C.; Ferrali, A.; Guarna, A.;
Venturello, P. J. Org. Chem. 2003, 68, 9728.
21. Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett.
1984, 2183.
References and notes
1. Brown, R. F. C.; Drummond, R.; Fogerty, A. C.; Hughes,
G. K.; Pinhey, J. T.; Ritchie, E.; Taylor, W. C. Aust. J. Chem.
1956, 9, 284.
22. It was observed that on standing in chloroform Galbulimina
alkaloids were undergoing protonation resulting in significant
broadening of peaks in NMR spectra. All characterisations
were carried out on samples, which were freshly filtered
through a short plug of basic alumina.
2. Ritchie, E.; Taylor, W. C. In The Galibulimina Alkaloids;
Manske, R. H. F., Ed.; The Alkaloids; Academic: New York,
1967; Vol. 9, p 529.
23. No attempts to obtain crystalline form of the product were
undertaken due to low availability of the synthetic material.
The identity of the synthetic and natural compounds was
established via NMR experiment of a sample premixed with
reference 1 mg sample obtained from Fisher Scientific UK
(Acros cat. no. 32912 0010).
3. Pinhey, J. T.; Ritchie, E.; Taylor, W. C. Aust. J. Chem. 1961,
14, 106.
4. Collins, D. J.; Culvnor, C. C. J.; Lamberton, J. A.; Loder,
J. W.; Price, J. R. Plants for Medicines; C.S.I.R.O.:
Melbourne, 1990.