A stannous chloride-induced deacetalisation-cyclisation process to prepare the ABC ring system of 'upenamide

Article abstract of DOI:10.1016/j.tetlet.2004.03.119

A stannous chloride-induced deacetalisation-cyclisation approach to the ABC core of the macrocyclic alkaloid, 'upenamide is reported. The use of a substituted β-lactone to prepare a C-2 substituted 'upenamide analogue is also disclosed.

Full text of DOI:10.1016/j.tetlet.2004.03.119

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4181–4183
A stannous chloride-induced deacetalisation–cyclisation
process to prepare the ABC ring system of ꢀupenamide
Mark Reid and Richard J. K. Taylor*
Department of Chemistry, University of York, Heslington, York YO10 5DD, UK
Received 16 February 2004; accepted 19 March 2004
Abstract—A stannous chloride-induced deacetalisation–cyclisation approach to the ABC core of the macrocyclic alkaloid, ꢀupen-
amide is reported. The use of a substituted b-lactone to prepare a C-2 substituted ꢀupenamide analogue is also disclosed.
Ó 2004 Elsevier Ltd. All rights reserved.
Upenamide 1 is a unique macrocyclic alkaloid isolated1
from the branching sponge, Echinochalina sp. (Proto-
lithospongia) (order Poecilosclerida) collected from
Derawan Island, Indonesia. Due to the scarcity of the
natural product the biological activity of ꢀupenamide has
not yet been widely screened although no anticancer
activity was seen in in vitro screening. The name ꢀupe-
namide is coined from ꢁꢀupena’, meaning fishing net or
trap in Hawaiiwan, and reflects its mesh-like structure
consisting of two main core systems (A, B, C and D, E
rings) linked in a 20-membered macrocycle.2 The ABC
core comprises a novel spiro-oxaquinolizidinone system
and accounts for five of the eight chiral centres within
ꢀupenamide––four of which are contiguous and one
quaternary. The D and E ring system is based on a
hemiaminal cis-decalin-type system and contains the
remaining three chiral centres. The C and D ring systems
are linked by an all trans-triene system and a fully sat-
urated aliphatic chain then completes the 20-membered
macrocycle adjoining rings A and E. The architectural
complexity and novel structure of ꢀupenamide make
its total synthesis an attractive challenge. As part
of our ongoing program to prepare novel natural
products, we have turned our attention towards the total
synthesis of ꢀupenamide and herein report a novel
diastereoselective approach to the unique ABC spiro-
cyclic core 2.
The ABC ring system appears completely novel in nat-
ure and indeed synthesis of oxaquinolizidinone ring
systems have received little attention.3;4 However, Win-
terfeld and Michael have prepared oxaquinolizidinone 4
in 48% yield by treatment of the diethyl acetal b-
hydroxyamide 3 with 2 M aq HCl (Scheme 1).
We hoped to utilise this approach to prepare ꢀupen-
amide, and therefore decided to first test its utility to
prepare model system 2 (R ¼ H). The ideal cyclisation
precursor was identified as protected amide 10, which
was prepared by the route shown in Scheme 2. Thus,
cyclohexane carboxaldehyde 5 was converted into tert-
butyl imine 6,5 which was directly transformed into
amine 9 using the sequence described by Maison et al.6
Hence, 6 was alkylated using acrylonitrile and catalytic
hydroquinone and the product subjected to acidic
deprotection and distillation to give the desired aldehyde
25
22
H
28
D
N
H
32
E
20
19
30
O
C
B
H
34
17
R
H
13
H
O
36
C
A
2
H O
10 A
N
H
N
11
HO
1
HO
O
O
B
O
4
2 M aq. HCl
48%
2
7
H
O
EtO
N
N
OEt
O
3
4
* Corresponding author. Tel.: +44-1904-432606; fax: +44-1904-4345-
23; e-mail: rjktl@york.ac.uk
Scheme 1.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.119

4182
M. Reid, R. J. K. Taylor / Tetrahedron Letters 45 (2004) 4181–4183
i. Hydroquinone,
Acrylonitrile,
Ethylene glycol,
Tol., cat. H2SO4,
reflux
t-butylamine
Toluene, reflux
H
O
88%
MgSO4, CH2Cl2,
reflux
ii. CH2Cl2,
10% aq. HCl
79%
O
H
H
NBut
O
O
N
5
95%
6
7
8
N
LiAlH4, THF
reflux
39%
O
SnCl2.2H2O,
CH2Cl2, rt
O
O
O
O
100%
benzene, rt
54%
O
O
N
10
9
2
HO
NH
NH2
O
O
Scheme 2.
7 in 79% yield from 6. Aldehyde 7 was then protected as
the corresponding dioxolane in 88% yield after distilla-
tion. With the reactive carbonyl function protected,
nitrile 8 was then reduced to afford primary amine 9
using lithium aluminium hydride. Initially, attempts to
purify 9 by an acid/base extraction, using 5% aq HCl
solution, proved unsuccessful, resulting in degradation.
However, switching to 0.1 M tartaric acid allowed amine
9 to be accessed in high purity in a moderate, but
unoptimised, 39% yield. With free amine 9 in hand,
b-hydroxy amide 10 was then furnished through nucleo-
philic ring opening of b-propiolactone in an unopti-
mised 54% yield after silica chromatography (Scheme
2).7
whether the subsequent hydrolysis–cyclisation reaction
would still proceed using secondary alcohol 11. Fur-
thermore it was hoped to gain knowledge of the ste-
reochemical outcome of the cyclisation.
To this end (ꢀ)-4-(benzyloxymethyl)oxetan-2-one 12
was prepared using the Al(SbF6)3 mediated [2þ2]-
cycloaddition of benzyloxyacetaldehyde and ketene
(derived from acetyl chloride), as described by Nelson
et al. (Scheme 3)9 With lactone 12 in hand, nucleophilic
ring opening using primary amine 9 then afforded the
desired b-substituted-b-hydroxy amide 11 in 72% yield.
Stirring dioxolane 11 with SnCl2Æ2H2O in CH2Cl2 then
smoothly afforded the desired cyclisation to furnish
spiro-hemiaminal 13 in a near quantitative yield, as a 1:1
mixture of diastereomers.10 These diastereomers 13a and
13b were, however, readily separated by silica column
chromatography and the diastereomers crystallised and
the relative stereochemistry of 13b assigned by X-ray
crystallography (Fig. 1).11
With cyclisation precursor 10 in hand, we then pro-
ceeded to investigate the deacetalisation–cyclisation to
give the ABC model system 2. Use of Winterfeld’s
conditions (2 M HCl) gave the expected product 2 in
70% yield after chromatography although the reaction
was slow and gave a number of other by-products. The
use of stannous chloride dihydrate (SnCl2Æ2H2O) was
then investigated as it is known to hydrolyse effectively
dioxolanes under mild conditions8 and furthermore, it
was hoped that the Lewis acidity of SnCl2Æ2H2O would
then facilitate the cyclisation by activating the interme-
diate aldehyde. Thus, dioxolane 10 was stirred in
dichloromethane at room temperature with 2.3 equiv of
SnCl2Æ2H2O and, to our delight, furnished spiro-oxa-
quinolizidinone 2 in quantitative yield after simple fil-
tration and silica column chromatography. These mild
conditions represent a new and efficient procedure for
the synthesis of spiro-oxaquinolizidinones.
It was, however, postulated that, under the Lewis acid
conditions, the hemiaminal cyclisation may be revers-
ible. With this in mind, the cyclisation of 11 was
repeated in the presence of an increased quantity of
stannous chloride and for an increased reaction time
(2 days vs 1 h previously). Pleasingly, this produced an
88% yield of the cyclised product but now in a 96:4 ratio
of diastereomers in favour of the ‘natural’ diastereomer
13b in which the protons at C-1 and C-8 have a syn-
relationship. Furthermore, it was found that 13a could
be isomerised to give a 92:8 mixture of diastereomers in
Attention was next turned to the synthesis of C-2
substituted model systems to investigate methods of
introducing additional functionality and to ascertain the
stereochemical outcome of the cyclisation. It was hoped
that the use of substituted b-lactones to alkylate amine 9
would allow several important questions regarding the
synthesis of the ABC system in ꢀupenamide itself.
Namely, if we could open the substituted lactone to
afford the substituted b-hydroxyamide and, if so,
Figure 1. ORTEP drawing of 13b (50% probability thermal ellipsoids).

M. Reid, R. J. K. Taylor / Tetrahedron Letters 45 (2004) 4181–4183
4183
OBn
O
SnCl2.2H2O,
CH2Cl2, rt
12
H
H
O
O
O
O
O
OBn
+
OBn
benzene, rt
72%
O
O
N
N
11
9
NH2
NH
O
O
BnO
(+/-)-13a
(+/-)-13b
OH
O
:
:
50
6
50
94
1 h, 96%
2 d, 88%
Scheme 3.
3. Winterfeld, K.; Michael, H. Arch. Pharm. Ber. Dtsch.
Pharm. Ges. 1961, 65–76.
4. Okita, M.; Wakamatsu, T.; Mori, M.; Ban, Y. Hetero-
cycles 1980, 14, 1089–1092.
5. Kimpe, N. D.; Smaele, D. D.; Hofkens, A.; Dejaegher, Y.;
Kesteleyn, B. Tetrahedron 1997, 53, 10803–10816.
6. Maison, W.; Kosten, M.; Charpy, A.; Kintscher-Langen-
favour of the desired diastereomer 13b in 89% yield by
stirring in dichloromethane with SnCl2Æ2H2O for 46 h. A
control experiment was also carried out whereby 13a
was stirred in dichloromethane for 40 h showing no
isomerisation and thus confirming that the Lewis acid
conditions are essential for the transformation to the
thermodynamically more stable 13b.
€
hagen, J.; Schlemminger, I.; Lutzen, A.; Westerhoff, O.;
Martens, J. Eur. J. Org. Chem. 1999, 2433–2441.
7. All novel compounds were characterised by high resolu-
tion mass spectrometry and IR and NMR spectroscopy
(COSY and HMQC experiments were used to assign any
ambiguous peaks).
8. Ford, K. L.; Roskamp, E. J. Tetrahedron Lett. 1992, 33,
1135–1138.
9. Nelson, S. G.; Wan, Z.; Peelen, T. J.; Spencer, K. L.
Tetrahedron Lett. 1999, 40, 6535–6539.
In summary, we have developed a novel stannous
chloride-induced deacetalisation–cyclisation procedure
to spiro-oxaquinolizidinones 2 and 13. This represents
the first approach to the ABC ring system of ꢀupena-
mide. We are now applying this methodology to an
enantioselective total synthesis of the natural product.
10. To a solution of dioxolane 11 (27 mg, 0.067 mmol) in
CH2Cl2 (2 mL) was added stannous chloride dehydrate
(38 mg, 0.17 mmol). The reaction mixture was then stirred
for 1 h at rt and filtered through Celiteâ, washing with
CH2Cl2. The filtrate was then concentrated in vacuo to
give a colourless residue, which was purified by silica
column chromatography (eluting with 50–60% EtOAc/
petroleum ether) to afford 13a (11 mg, 48%) as a colourless
solid; mp 90–92 °C (from EtOAc/petroleum ether), Rf 0.39
(EtOAc), which was fully characterised and 13b (11 mg,
48%) as a colourless solid; mp 85–87 °C (from petroleum
ether) Rf 0.29 (EtOAc); IR (neat) 2929, 2858, 1653,
1447 cmꢁ1; dH (400 MHz, CDCl3) 7.29–7.19 (5H, m, Ar–
H), 4.63 (1H, ddd, app dt, J 13.0, 4.0 Hz, H-6eq), 4.55 (2H,
s, benzylic CH2), 4.23 (1H, s, H-10), 3.86 (1H, m, H-2),
3.50 [1H, dd, (ABX system), J 10.5, 6.0, CH2OBn], 3.45
[1H, dd, (ABX system), J 10.5, 3.5, CH2OBn], 2.42 (1H,
app td, J 13.0, 4.0, H-6ax), 2.35–2.25 (2 H, m, H-3), 2.16–
2.12 (1H, m,CH), 1.76 (1H, app td, J 13.0, 4.5, CH), 1.60–
1.07 (11H, m, CH), 0.93 (1H, app td, J 14.0, 4.5, CH); dC
(100 MHz, CDCl3) 167.1 (C-4), 138.2 (Ar–C), 128.6 (Ar–
C), 127.9 (Ar–C), 127.7 (Ar–C), 92.9 (C-10), 73.5 (Benzy-
lic-C), 72.2 (C-2), 71.9 (CH2OBn), 40.5 (C-6), 38.2 (C-9),
35.3 (C-3), 34.2, 30.1, 26.5, 24.0, 21.4, 20.9, 19.5 (C-3, C-4,
C-5, C-6, C-7, C-8, C-9); m=z (CI) 344 (MHþ, 100)
[HRMS (CI): calcd for C21H30NO3, 344.2226. Found:
MHþ, 344.2228 (0.6 ppm error)].
Acknowledgements
We are grateful to Dr. A. C. Whitwood for carrying out
the crystallography study. We are also grateful to the
EPSRC and Oxford Chemicals for CASE studentship
funding and to the Gen Foundation for further financial
assistance (M.R.).
References and notes
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11. Cambridge Crystallographic Data Centre reference no
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2999.