Towards a biomimetic synthesis of the marine alkaloids papuamine and haliclonadiamine: Model studies

Article abstract of DOI:10.1016/S0040-4020(99)01011-X

A plausible biosynthetic pathway for the isomeric marine alkaloids papuamine and haliclonadiamine via the double tandem ene cyclisation of a tetraenediimine is proposed. Initial model studies directed toward the biomimetic synthesis of these alkaloids are

Full text of DOI:10.1016/S0040-4020(99)01011-X

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 623–628
Towards a Biomimetic Synthesis of the Marine Alkaloids
Papuamine and Haliclonadiamine: Model Studies
†
*
Robert M. Adlington, Jack E. Baldwin, Gregory L. Challis, Rhona J. Cox and
Gareth J. Pritchard
The Dyson Perrins Laboratory, University of Oxford, South Parks Road, Oxford, OX1 3QY, UK
Received 26 July 1999; revised 27 October 1999; accepted 11 November 1999
Abstract—A plausible biosynthetic pathway for the isomeric marine alkaloids papuamine and haliclonadiamine via the double tandem ene
cyclisation of a tetraenediimine is proposed. Initial model studies directed toward the biomimetic synthesis of these alkaloids are described
which illustrate that the Lewis acid-promoted ene cyclisation of methyl-2-(methoxycarbonyl)dodeca-2,8-dienoate is critically dependent on
the D-8 geometry. ᭧ 2000 Elsevier Science Ltd. All rights reserved.
1
Papuamine 1, a C -symmetric antifungal alkaloid, and hali-
Retrosynthetic analysis suggests that both 1 and 2 may be
biosynthesised from a macrocyclic diimine via a pair of
tandem ene reaction cascades. Thus disconnection of the
C-1, C-9 and C-14, C-22 bonds in 1 or 2 via a pair of
imino–ene reactions gives the tricyclic intermediate 3,
which on further disconnection across the C-3, C-8 and
C-15, C-20 bonds via a pair of all-carbon ene reactions
gives the macrocyclic diimine 4. Finally, disconnection of
the imines in 4 gives the dialdehyde 5, which could be of
either polyketide or fatty acid origin, and 1,3-diamino-
propane (Scheme 1).
2
2
clonadiamine 2, an unsymmetrical diastereomer of 1, were
isolated from apparently identical sponges of the genus
Haliclona collected from Papua New Guinea and Palau,
respectively.
A key issue in the application of this analysis to the
synthesis of 1 and 2 is the effect of D-7 geometry on the
intramolecular ene reaction of disubstituted 1,7-dienes
bearing an electron withdrawing group at C-1. Tietze has
shown that the Knoevenagel adducts from condensation of
trisubstituted-1,6-enals, such as citronellal, with dimethyl
malonate undergo a thermal or Lewis acid promoted
Whilst it has been noted that 1 is formally derivable from an1
unbranched C22 hydrocarbon and 1,3-diaminopropane,
nothing is known about the biosynthesis of these alkaloids.
In this paper a plausible biosynthetic pathway to 1 and 2 is
advanced and the results of initial studies directed towards a
biomimetic synthesis of these alkaloids are reported.
Scheme 1.
Keywords: dienes; enals; ene reactions; steric and strain effects.
*
Corresponding author. Fax: ϩ44-1865-275632; e-mail: jack.baldwin@chem.ox.ac.uk
Current address: Department of Chemistry, Johns Hopkins University, Remsen Hall, 3400 N. Charles Street, Baltimore, MD 21218-2685, USA.
†
0
040–4020/00/$ - see front matter ᭧ 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(99)01011-X

6
24
R. M. Adlington et al. / Tetrahedron 56 (2000) 623–628
Scheme 2. Reagents and conditions: (i) 3,4-dihydro-2H-pyran, TsOH·H
2
O, CH
O, Ϫ33ЊC, ca. 88% (13); (iv) Amberlyst H-15 , MeOH, 45ЊC, 94% (14); (v) DMP, CH
piperidinium acetate, CH Cl , 25ЊC, ca. 51%; (vii) Lindlar’s catalyst, quinoline, CH Cl , 20ЊC, 89% (15); (viii) Amberlyst H-15 , MeOH, 45ЊC, 90% (16); (ix)
DMP, CH Cl , 0ЊC, ca. 97% (7); (x) CH
2
Cl
2
, 0–25ЊC, 78%; (ii) 1-pentyne, n-BuLi, THF, DMPU, Ϫ78 to 20ЊC, 78%;
᭨
3
(iii) Na, NH (l), Et
2
2
Cl , 0ЊC, ca. 94% (6); (vi) CH (CO Me)
2
2
2
2
,
᭨
2
2
2
2
2
2
2
2 2
(CO Me) , piperidine, AcOH, CH
2
Cl
2
, 0–25ЊC, 40%.
Scheme 3.
intramolecular ene reaction to yield trans-1,2-disubstituted
cyclohexanes as the major product. It was therefore
decided to investigate the ene reaction of the corresponding
Knoevenagel adducts derived from the disubstituted
isomeric enals (E)- and (Z)-6-decenal, 6 and 7.
compounds was examined next. Reaction of methyl (E)-2-
(methoxycarbonyl)dodeca-2,8-dienoate 8 with tin tetra-
chloride (1.3 equiv.) in dichloromethane at 0–25ЊC for
16 h afforded the trans-1,2-disubstituted cyclohexane intra-
molecular ene adduct as the major product after aqueous
workup, which could be isolated by chromatography as an
inseparable mixture of geometrical isomers 17 and 18 (E:Z
7:1) in up to 48% yield. Reaction at Ϫ30ЊC for three days
gave yields of up to 53% but no change in the ratio of E to Z
isomers. In contrast, reaction of methyl (Z)-2-(methoxy-
carbonyl)dodeca-2,8-dienoate 9 under the same sets of
conditions gave crude mixtures containing 17 and 18 as
only a minor component (ca. 10%), along with a number
of other products that could not be unambiguously
identified but that lacked alkenyl hydrogens and as such
appeared not to derive from an intramolecular ene reaction
(Scheme 3).
3
(
E)- and (Z)-Knoevenagel adducts 8 and 9 were synthesised
according to the routes outlined in Scheme 2. Thus
5
4
‡
-bromopentan-1-ol 10 was protected as the THP ether
1
5
1
which was reacted with lithium pentynylide in
6
THF/DMPU to give the acetylene 12. Reduction of this
7
acetylene with sodium in liquid ammonia gave the
(
E)-alkene 13 which was deprotected with Amberlyst
᭨ 8
H-15 in methanol to give (E)-decen-1-ol 14. Oxidation
with the Dess–Martin periodinane gave (E)-6-decenal 6.
Similarly, reduction of 12 with Lindlar’s catalyst followed
by deprotection and oxidation gave (Z)-decenal 7. Conden-
sation of these aldehydes with dimethyl malonate was
carried out using modification of the conditions reported
9
1
0
The relative stereochemistry of the ring substituents in 17
3
0
by Tietze to avoid aldol condensation of the aldehyde
could not be determined directly due to overlap of the H-1
0
1
with itself.
and H-2 resonances in the H NMR spectrum of this
compound. Therefore 17 and 18 were hydrogenated over
00 00
palladium on carbon to give the 1 ,2 -dihydro derivative
11
With a synthetic route to the desired isomeric Knoevenagel
adducts established, the effect of the D-8 double bond
geometry on the intramolecular ene reaction of these
0
19. The signal due to H-1 appeared as a complex multi-
plet in the NMR spectrum of this compound, which upon
homonuclear decoupling of the H-2 resonance collapsed to
an apparent triplet of doublets. This splitting pattern is
‡
0
Abbreviations: DMP, Dess–Martin periodinane; DMPU, N,N -dimethyl-
0
0
consistent with the coupling of H-1 to two axial hydrogens
N,N -propylene urea; THF, tetrahydrofuran; THP, tetrahydropyranyl; Ts,
0
0
toluene-4-sulfonyl; ax, axial; eq, equatorial.
(H-2 and H-6 ax, Jˆ10 Hz) and one equatorial hydrogen

R. M. Adlington et al. / Tetrahedron 56 (2000) 623–628
625
0
(
H-6 , Jˆ3 Hz), and thus the trans-orientation of the
Experimental
eq
substituents on the cyclohexane ring.
14
General experimental details are as previously published
with the following amendments:
The reduced tendency toward intramolecular ene reaction of
9
compared with 8 can be rationalised by considering the
1
transition state conformations for concerted cyclisation of
these isomeric substrates. Whilst 8 can undergo cyclisation
via the trans-decalin-like transition state 20, the cyclisation
of 9 to give 17 requires the reaction to proceed via the much
more strained chair/twist boat transition state 21. Thus the
intramolecular ene reaction of 9 is much less facile than that
of 8, allowing other reactions to compete. These results
suggest that the geometry of the D-8 and D-14 double
bonds in the proposed biosynthetic precursor 5 is (E).
Proton magnetic resonance spectra ( H NMR) recorded at
300 MHz were obtained using a Bruker WH 300 spectro-
meter.
1
2
Low resolution mass spectra (m/z) were recorded on a
Micromass Platform APCI (APCI) or VG Mass Lab
Trio-1 (GCMS) spectrometer by chemical ionisation
(CI ). High resolution mass spectra were recorded on a
VG AutoSpec spectrometer by ammonia chemical
ϩ
ionisation in the Dyson Perrins Laboratory.
The Dess–Martin periodinane was prepared according to a
literature method.15 The fractions of light petroleum ether
boiling between 30 and 40ЊC and between 40 and 60ЊC are
referred to as ‘pentanes’ and ‘hexanes’, respectively.
0
2
-(6 -Decynyloxy)tetrahydropyran (12). Following a
6
0
standard procedure, from 2-(5 -bromopentyloxy)tetra-
hydropyran (11) (12.13 g, 48.3 mmol) was obtained 2-(6 -
0
decynyloxy)tetrahydropyran (12) (8.99 g, 78%) as a colour-
Ϫ1
less oil; R 0.2 in 1:19 ether/hexanes; n
(film)/cm
f
max
2
1
1
3
3
937s, 2869s (C–H), 1455m, 1137m, 1120s, 1078s and
036s; dH (300 MHz; CDCl ) 0.97 (3H, t, Jˆ7.5 Hz,
3
0
0
0 -H ), 1.45–1.83 (14H, m, 3-H , 4-H , 5-H , 2 -H ,
-H , 4 -H and 9 -H ), 2.09–2.19 (4H, m, 5 -H , 8 -H ),
.36–3.53 (2H, m, 1 -H ), 3.70–3.87 (2H, m, 6-H ) and 4.59
3
2
2
2
2
0
0
0
0
0
2
2
2
2
2
0
2
2
0
(
1H, t, Jˆ3.5 Hz, 2-H); d (50 MHz; CDCl ) 13.27 (C10 ),
C
3
It is interesting to compare these results with those reported
18.53, 19.46, 20.58, 22.36, 25.36, 28.86, 29.16, 30.62 (C3,
0 0 0 0 0 0
C4, C5, C2 , C3 , C4 , C5 , C8 and C9 (two CH coin-
2
for the tin tetrachloride-promoted reaction of the E- and
1
3
0
0
0
Z-allylsilanes 22 and 23. Whilst the Z-allylsilane 23
gave in 80% yield almost exclusively the trans-1,2-
disubstituted cyclohexane 24 (trans:cis Ͼ96:4), the E-allyl-
silane 22 reacted with lower overall diastereoselectivity, but
cident), 62.21, 67.44 (C6 and C1 ), 80.13 (C6 and C7 ) and
98.86 (C2); m/z (GCMS, CI ) 256 (MNH
(MH , 0.7), 172 (3), 155 (1), 137 (1), 102 (32), 85 (100)
and 55 (6); m/z (accurate) found 239.2010 for MH ,
ϩ
ϩ
, 0.6%), 239
4
ϩ
ϩ
(presumably) still gave 24 as the major product (Scheme 4).
C H O requires 239.2011.
15 27 2
However, the presence of the allylsilyl group means that the
cyclisation mechanism probably differs from the cases
described in this paper.
0
(E)-2-(6 -Decenyloxy)tetrahydropyran (13). Following a
standard procedure,7 from 2-(6 -decynyloxy)tetrahydro-
0
0
pyran (12) (7.10 g, 29.8 mmol) was obtained (E)-2-(6 -
Investigation of the imino–ene reaction is now in progress.
Ultimately we hope to produce a perhydroindane unit
with the same stereochemistry as half of papuamine thus
demonstrating the chemical feasibility of the biogenetic
hypothesis. This methodology, if then applied to the ene
reactions of dialdehyde 5, may allow simultaneous
construction of both halves of papuamine in a very concise
manner.
decenyloxy)tetrahydropyran (13) (7.02 g, 98%; Ͼ90%
pure, the remainder being the alkyne (12)) as a colourless
Ϫ1
oil; R 0.25 in 1:19 ether/hexanes; nmax (film)/cm 2936s,
f
2871s (C–H), 1455w, 1353w, 1120m, 1078m and 1035s; d
H
0
(300 MHz; CDCl
) 0.89 (3H, distorted t, Jˆ7.5 Hz, 10 -
3
0
0
H3), 1.30–1.86 (14H, m, 3-H
, 4-H
, 5-H
, 2 -H
, 3 -H
,
2
2
2
2
2
0
0
0
0
4 -H
and 9 -H
), 1.99 (4H, mc, 5 -H
, 8 -H
), 3.35–3.54
2
2
2
2
0
(2H, m, 1 -H
), 3.70–3.91 (2H, m, 6-H
), 4.58 (1H, t,
2
2
Scheme 4.

6
26
R. M. Adlington et al. / Tetrahedron 56 (2000) 623–628
0
0
Jˆ3.5 Hz, 2-H) and 5.40 (2H, mc, 6 -H and 7 -H); d
(0.156 g, 1.00 mmol) was obtained (Z)-6-decenal (7) (ca.
0.15 g, ca. 97%, the contaminant being residual ether) as a
C
0
(
50 MHz; CDCl ) 13.44 (C10 ), 19.48, 22.57, 25.38,
9.59, 29.31, 29.47, 30.62, 32.39, 34.59 (C3, C4, C5, C2 ,
C3 , C4 , C5 , C8 and C9 ), 62.17, 67.56 (C6 and C1 ),
8.83 (C2) and 130.42 (C6 and C7 ); m/z (GCMS, CI )
58 (MNH , 2%), 241 (MH , 0.5), 174 (2), 138 (1), 103
4), 102 (61), 86 (5), 85 (100) and 84 (5).
3
0
2
pungent volatile colourless oil; R 0.3 in 1:9 ether/hexanes;
f
0
0
0
0
0
0
0
Ϫ1
nmax (film)/cm
3006m, 2931s, 2862s, 2718w (C–H),
0
ϩ
9
2
1727s (CyO), 1460w and 1072w; dH (300 MHz; CDCl3)
ϩ
4
ϩ
0.91 (3H, distorted t, Jˆ7.5 Hz, 10-H ), 1.34–1.45 and
3
(
1.60–1.71 (4H and 2H, 2×m, 3-H , 4-H and 9-H ), 1.97–
2
2
2
2
.11 (4H, m, 5-H and 8-H ), 2.44 (2H, td, Jˆ7.5 and
2
2
0
(
Z)-2-(6 -Decenyloxy)tetrahydropyran (15). Following a
standard procedure, from 2-(6 -decynyloxy)tetrahydro-
pyran (12) (0.240 g, 1.00 mmol) was obtained (Z)-2-(6 -
1.5 Hz, 2-H ), 5.37 (2H, m, 6-H and 7-H) and 9.77 (1H, t,
2
1
0
0
Jˆ1.5 Hz, 1-H); d (50 MHz; CDCl ) 13.59 (C10), 21.49,
C
3
0
22.67, 26.72, 29.05, 43.68 (C2, C3, C4, C5, C8 and C9 (two
decenyloxy)tetrahydropyran (15) (0.213 g, 89%) as a
CH coincident)), 129.27, 130.46 (C6 and C7) and 203.14
2
ϩ
ϩ
colourless oil; R 0.3 in 1:9 ether/hexanes; n
(film)/
(C1); m/z (GCMS, CI ) 172 (MNH , 41%), 136 (100), 121
f
max
4
Ϫ1
cm
2938s, 2870m (C–H), 1138m, 1120m, 1078m,
(22), 112 (30), 107 (32), 98 (41), 95 (36), 81 (70), 67 (39),
1
036m and 668m; d (300 MHz; CDCl ) 0.91 (3H, t,
58 (29) and 54 (45); m/z (accurate) found 155.1430 for
H
3
0
ϩ
Jˆ7.5 Hz, 10 -H ), 1.31–1.86 (14H, m, 3-H , 4-H , 5-H ,
MH , C H O requires 155.1436 found 153.1274 for
3
2
2
2
10 19
0
0
0
0
0
0
ϩ
2
8
4
7
2
-H , 3 -H , 4 -H and 9 -H ), 1.98–2.05 (4H, m, 5 -H and
[MϪH] , C H O requires 153.1279.
2
2
2
2
2
10 17
0
-H ), 3.35–3.54 (2H, m, 1 -H ), 3.70–3.92 (2H, m, 6-H ),
2
2
2
0
.59 (1H, t, Jˆ3.5 Hz, 2-H) and 5.37 (2H, mc, 6 -H and
Methyl (E)-2-(methoxycarbonyl)dodeca-2,8-dienoate (8).
To a stirred solution of dimethyl malonate (183 ml, 1.60
mmol) and piperidinium acetate (48 mg, 0.17 mmol) in
dry CH Cl (1 ml) under argon was added a solution of
0
0
-H); dC (50 MHz; CDCl ) 13.62 (C10 ), 19.50, 22.72,
3
5.38, 25.78, 27.02, 29.16, 29.45, 29.53, 30.65 (C3, C4,
0
0
0
0
0
0
C5, C2 , C3 , C4 , C5 , C8 and C9 ), 62.21, 67.56 (C6
2
2
0
0
0
and C1 ), 98.87 (C2) and 130.02 (C6 and C7 ); m/z
(E)-6-decenal (6) (0.250 g, 1.62 mmol) in CH Cl (1 ml)
2 2
ϩ
ϩ
4
(GCMS, CI ) 258 (MNH , 2%), 103 (6), 102 (100) and
dropwise over 2 h. After 2 h stirring at 25ЊC the solvent
8
5 (71).
was removed in vacuo and the crude material purified by
flash chromatography (SiO , 1:9 ether/hexanes) to yield
2
0
(
E)-6-Decen-1-ol (14). To a solution of (E)-2-(6 -decenyl-
methyl (E)-2-(methoxycarbonyl)dodeca-2,8-dienoate (8)
1
oxy)tetrahydropyran (13) (0.601 g, 2.50 mmol) in methanol
(0.233 g, 57%, ca. 90% purity by H NMR, the contaminant
᭨
(
5 ml) was added Amberlyst H-15 (75 mg). The mixture
being residual dimethyl malonate) as a colourless oil; R
0.15 in 1:9 ether/hexanes; nmax (film)/cm 2954s, 2929s,
f
Ϫ1
was stirred at 45ЊC for 2 h. The catalyst was removed by
filtration and the solvent removed in vacuo. The crude
2858m (C–H), 1730s (CyO), 1644m (CyC), 1437s, 1259s,
material was purified by flash chromatography (SiO , 1:1
1225s and 1063m; dH (300 MHz; CDCl ) 0.89 (3H,
2
3
ether/hexanes) to yield (E)-6-decen-1-ol (14) (0.368 g,
distorted t, Jˆ7.5 Hz, 12-H ), 1.30–1.58 (6H, m, 5-H ,
3
2
9
4%) as a colourless oil with experimental data consistent
with that already published.
6-H and 11-H ), 1.92–2.03 (4H, m, 7-H and 10-H ),
2 2 2 2
1
6
2.30 (2H, q, Jˆ7.5 Hz, 4-H ), 3.79 (3H, s, OCH ), 3.83
2
3
(
3H, s, OCH ), 5.29 (2H, mc, 8-H and 9-H) and 7.04 (1
3
(
Z)-6-Decen-1-ol (16). Following the procedure used to
H, t, Jˆ7.5 Hz, 3-H); d (50 MHz; CDCl ) 13.47 (C12),
C
3
0
prepare 14, from (Z)-2-(6 -decenyloxy)tetrahydropyran
22.53, 27.54, 28.94, 29.56, 32.05, 34.55 (C4, C5, C6, C7,
(
(
15) (0.935 g, 3.90 mmol) was obtained (Z)-6-decen-1-ol
C10 and C11), 52.14, 52.23 (2×OCH ), 128.09 (C2),
3
16) (0.547 g, 90%) as a colourless oil with experimental
129.90, 130.93 (C8 and C9), 150.73 (C3), 164.67 and
1
6
ϩ
ϩ
data consistent with that already published.
166.21 (C1 and 2-CO CH ); m/z (APCI, CI ) 291 (MNa ,
2 3
ϩ
7
%), 269 (MH , 46), 237 (59), 205 (90), 177 (33) and 137
9
ϩ
(
E)-6-Decenal (6). Following a standard procedure and
(100); m/z (accurate) found 269.1741 for MH , C H O
15 25 4
after purification by solution in 1:4 ether/pentanes and filtra-
tion through a plug of silica to remove o-iodobenzoic acid,
from (E)-6-decen-1-ol (14) (0.398 g, 2.55 mmol) was
obtained (E)-6-decenal (6) (ca. 0.37 g, ca. 94%, the
contaminant being residual ether) as a pungent volatile
requires 269.1753.
Methyl (Z)-2-(methoxycarbonyl)dodeca-2,8-dienoate (9).
To a cooled (0ЊC) solution of (Z)-6-decenal (7) (36 mg,
0.23 mmol) and dimethyl malonate (34 mg, 0.26 mmol) in
CH Cl (1 ml) were added piperidine (2.3 ml, 0.023 mmol)
colourless oil; R 0.3 in 1:9 ether/hexanes; n
cm 2958s, 2930s, 2860m (C–H), 1727s (CyO), 1458m,
(film)/
f
max
2
2
Ϫ1
and glacial acetic acid (1.3 ml, 0.023 mmol). The mixture
was stirred at room temperature for 1 h after which piper-
idine (2.3 ml, 0.023 mmol) and glacial acetic acid (1.3 ml,
0.023 mmol) were added. After a further 2.5 h the solvent
was removed in vacuo and the residue dissolved in ether
(10 ml). The organic phase was washed with water (2 ml),
9
69m and 735m; d (300 MHz; CDCl ) 0.89 (3H, distorted
H
3
t, Jˆ7.5 Hz, 10-H ), 1.30–1.45 and 1.59–1.73 (4H and 2H
3
2
8
6
×m, 3-H , 4-H and 9-H ), 1.93–2.40 (4H, m, 5-H and
2
2
2
2
-H ), 2.43 (2H, td, Jˆ7.5 and 2 Hz, 2-H ), 5.40 (2H, mc,
2
2
-H and 7-H) and 9.77 (1H, t, Jˆ2 Hz, 1-H); d (50 MHz;
C
CDCl ) 13.44 (C10), 21.34, 22.51, 29.16, 32.11, 34.55,
saturated aqueous NaHCO (2 ml), water (2 ml), saturated
3
3
4
3.65 (C2, C3, C4, C5, C8 and C9), 129.76, 131.00 (C6
aqueous NaCl (2 ml) and dried (Na SO ). The solvent was
removed in vacuo and the crude material purified by flash
2
4
ϩ
ϩ
and C7) and 203.15 (C1); m/z (GCMS, CI ) 172 (MNH ,
4
8
1%), 110 (65), 81 (89), 67 (99) and 58 (100); m/z (accurate)
chromatography (SiO , 1:19 ether/hexanes) to yield methyl
(Z)-2-(methoxycarbonyl)dodeca-2,8-dienoate (9) (25 mg,
2
ϩ
found 153.1277 for [MϪH] , C H O requires 153.1279.
1
0
17
4
0%) as a colourless oil; R 0.2 in 1:9 ether/hexanes; n
f max
Ϫ1
9
(
Z)-6-Decenal (7). Following a standard procedure with
(film)/cm 3005m, 2955s, 2861m (C–H), 1728s (CyO)
purification as for (6), from (Z)-6-decen-1-ol (16)
1644m (CyC), 1436s, 1372m, 1259s, 1224s and 1062m;

R. M. Adlington et al. / Tetrahedron 56 (2000) 623–628
627
d (300 MHz; CDCl ) 0.90 (3H, distorted t, Jˆ7.5 Hz, 12-
crude material purified by flash chromatography (SiO2,
1:9 ether/hexanes) to yield a mixture of compounds
with Rf 0.2 (50 mg). Separation by preparative thin
layer chromatography (1:9 ether/hexanes, multiple elutions)
was partially successful and yielded an approximately
H
3
H ), 1.31–1.58 (6H, m, 5-H , 6-H and 11-H ), 1.96–2.08
3
2
2
2
(
4H, m, 7-H and 10-H ), 2.29 (2H, q, Jˆ7.5 Hz, 4-H ), 3.79
2
2
2
(3H, s, OCH ), 3.83 (3H, s, OCH ), 5.36 (2H, mc, 8-H and
3 3
9
1
-H) and 7.04 (1H, t, Jˆ8.0 Hz, 3-H); d (50 MHz; CDCl )
C
3
0 0 0
3.62 (C12), 22.68, 26.65, 27.67, 29.05, 29.60 (C4, C5, C6,
10:1 mixture of dimethyl (E)- and (Z)-1 ,2 -trans-2-(2 -
0
0
0
C7, C10 and C11 (two CH coincident)), 52.16, 52.24
buten-1 -ylcyclohex-1 -yl)propane-1,3-dioate (17 and 18)
(4 mg, 7%) as a colourless oil with spectral data as
above.
2
(
1
2×OCH ), 128.05 (C2), 129.36, 130.35 (C8 and C9),
3
50.65 (C3) and 164.63 (C1 and 2-CO CH coincident);
2 3
ϩ ϩ ϩ
m/z (APCI, CI ) 291 (MNa , 5%), 269 (MH , 21),
37 (13), 205 (100), 177 (12) and 137 (85); m/z (accu-
0
0
0
0
2
Dimethyl 1 ,2 -trans-2-(2 -butylcyclohex-1 -yl)propane-
1,3-dioate (19). To a solution of dimethyl (E)- and (Z)-
ϩ
rate) found 269.1748 for MH , C H O requires
1
5
25
4
0
0
0
00
0
2
69.1753.
1 ,2 -trans-2-(2 -but-1 -enylcyclohex-1 -yl)propane-1,3-
dioate (17 and 18) (22 mg, 0.082 mmol) in ethyl acetate
(2 ml) was added 10% Pd on activated carbon (15 mg).
The reaction mixture was stirred under an atmosphere of
hydrogen for 20 h then the catalyst removed by filtration.
The solvent was removed in vacuo to yield dimethyl 1 ,2 -
trans-2-(2 -butylcyclohex-1 -yl)propane-1,3-dioate (19) (22
0
0
0
00
Dimethyl (E)- and (Z)-1 ,2 -trans-2-(2 -but-1 -enylcyclo-
0
hex-1 -yl)propane-1,3-dioate (17 and 18). Method 1: To a
cooled (0ЊC) solution of methyl (E)-2-(methoxycarbonyl)-
0 0
dodeca-2,8-dienoate (8) (2.10 g, 7.83 mmol) in CH Cl2
2
0
0
(
100 ml) was added dropwise SnCl (10 ml of 1.0 M solu-
4
tion in CH Cl , 10 mmol). The reaction mixture was stirred
mg, 99%) as a colourless oil; R 0.2 in 1:9 ether/hexanes;
nmax (film)/cm 2930s, 2858s (C–H), 1738s (CyO), 1435s,
2
2
f
Ϫ1
at 25ЊC for 16 h then saturated aqueous NaHCO (50 ml)
3
was added followed by ether (500 ml). The layers were
separated and the organic layer was washed with 1 M
1217s, 1147s and 1020s; d (300 MHz; C D ) 0.87 (3H, t,
H
6
6
0
0
Jˆ7.0 Hz, 4 -H ), 1.11–1.26, 1.44–1.51, 1.61–1.72 (14H,
3
0
0
0
0
0
00
00
00
aqueous HCl, saturated aqueous NaHCO (100 ml), water
3×m, 2 -H, 3 -H , 4 -H , 5 -H , 6 -H , 1 -H , 2 -H and 3 -
0 0
2 eq
3
2
2
2
ax
2
2
(100 ml), saturated aqueous NaCl (100 ml) and dried
H ), 1.94 (1H, mc, 6 -H ), 2.10 (1H, mc, 1 -H), 3.33 (3H, s,
(
MgSO ). The solvent was removed in vacuo and the
OCH ), 3.35 (3H, s, OCH ) and 3.88 (1H, d, Jˆ5.5 Hz,
00
C 3
4
3
3
crude material purified by flash chromatography (SiO2,
:9 CH Cl /hexanes) to yield a 7:1 mixture of dimethyl
2-H); d (50 MHz; CDCl ) 13.91 (C4 ), 22.79, 25.10,
0 0 0 0
1
(
25.42, 27.61, 28.20, 30.66, 32.47 (C3 , C4 , C5 , C6 ,
2
2
0
0
0
00
0
00
00
00
0
0
E)- and (Z)-1 ,2 -trans-2-(2 -buten-1 -ylcyclohex-1 -yl)-
C1 , C2 and C3 ), 38.52 (C1 ), 41.90 (C2 ), 51.95, 52.28
propane-1,3-dioate (17 and 18) (1.00 g, 48%) as a colourless
(2×OCH ), 53.11 (C2), 169.55 and 170.54 (C1 and C3), m/z
3
Ϫ1
ϩ
ϩ
ϩ
oil; R 0.2 in 1:9 ether/hexanes; n
(film/cm 2930m,
max
(CI ) 293 (MNa , 35%), 271 (MH , 7), 239 (37), 237
f
2
855w (C–H), 1736s (CyO), 1435m, 1222m, 1153m,
(100), 205 (33), 139 (15) and 137 (64); m/z (accurate)
ϩ
1
019m and 973m; d (500 MHz; C D ) for 17: 0.98 (3H,
found 271.1907 for MH , C H O requires 271.1909.
H
6
6
15 27
4
0
0
0
0
0
t, Jˆ7.5 Hz, 4 -H ), 1.01–1.42 (4H, m, 3 -H , 4 -H , 5 -
3
ax
0
ax
0
0
0
H
and 6 -H ), 1.61–1.76 (4H, m, 3 -H , 4 -H , 5 -H
ax
ax
eq
eq
eq
0
00
0
and 6 -H ), 1.98 (2H, mc, 3 -H ), 2.06 (1H, m, 1 -H),
Acknowledgements
eq
2
0
.15 (1H, m, 2 -H), 3.39 (3H, s, OCH ), 3.42 (3H, s,
3
2
OCH ), 3.90 (1H, d, Jˆ4 Hz, 2-H), 5.22 (1H, ddt, Jˆ15.5,
The EPSRC is thanked for a studentship (G. L. C.).
3
00
9
2
and 1.5 Hz, 1 -H) and 5.56 (1H, dt, Jˆ15.5 and 6.5 Hz,
0
0
00
-H); for 18: 0.98 (3H, t, Jˆ7.5 Hz, 4 -H ), 1.01–1.42 (4H,
3
0
0
0
0
0
m, 3 -H , 4 -H , 5 -H and 6 -H ), 1.61–1.76 (4H, m, 3 -
References
ax
ax
ax
ax
0
0
0
00
H , 4 -H , 5 -H and 6 -H ), 1.98 (2H, mc, 3 -H ), 2.06
eq
eq
0
eq
eq
0
2
(
1H, m, 1 -H), 2.15 (1H, m, 2 -H), 3.51 (3H, s, OCH ), 3.53
1. Baker, B. J.; Scheuer, P. J.; Shoolery, J. N. J. Am. Chem. Soc.
1988, 110, 965–966.
2. Fahy, E.; Molinski, T. F.; Harper, M. K.; Sullivan, B. W.;
Faulkner, D. J.; Parkanyi, L.; Clardy, J. Tetrahedron Lett. 1988,
29, 3427–3428.
3. Tietze, L. F.; Beifuss, U.; Ruther, M. J. Org. Chem. 1989, 54,
3120–3129.
4. Kang, S.-K.; Kim, W.-S.; Moon, B.-H. Synthesis 1985, 1161–
1162.
3
(
3H, s, OCH ), 3.88 (1H, d, Jˆ4 Hz, 2-H), 5.12 (1H, tt,
3
00
Jˆ10.5 and 2 Hz, 1 -H) and 5.44 (1H, dt, Jˆ10.5 and
00
.5 Hz, 2 -H); d (50 MHz; CDCl ) for 17 (and 18):
C 3
5
1
0
0
0
0
5.58 (C4 ), 25.38, 25.53, 26.03, 28.14, 33.93 (C3 , C4 ,
0
0
00
0
0
C5 , C6 and C3 ), 42.32, 45.48 (C1 and C2 ), 51.84, 52.17
(
00
00
2×OCH ), 54.49 (C2), 132.61, 133.45 (C1 and C2 ),
3
ϩ
1
69.58 and 170.45 (C1 and C3); m/z (APCI, CI ) 270
ϩ
(2%), 269 (MH , 24), 237 (13), 209 (9), 205 (8), 167 (12)
ϩ
and 137 (100); m/z (accurate) found 269.1743 for MH ,
5. Bernady, K. F.; Floyd, M. B.; Poletto, J. F.; Weiss, M. J. J. Org.
Chem. 1979, 44, 1438–1447.
C H O requires 269.1753.
15
25
4
6
. Bengtsson, M.; Liljefors, T. Synthesis 1988, 250–252.
Method 2: To a cooled (0ЊC) solution of methyl (Z)-2-
methoxycarbonyl)dodeca-2,8-dienoate (9) (56 mg,
.21 mmol) in CH Cl (2 ml) was added dropwise SnCl
4
7. Warthen, J. D.; Jacobson, M. Synthesis 1973, 616–617.
8. Bongini, A.; Cardillo, G.; Orena, M.; Sandri, S. Synthesis 1979,
618–620.
(
0
2
2
(
0.25 ml of 1.0 M solution in CH Cl , 0.25 mmol). The
9. Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277–
7287.
2
2
reaction mixture was stirred at 25ЊC for 22 h then water
(
2 ml) was added followed by CH Cl (10 ml). The layers
10. Lindlar, H. Helv. Chim. Acta 1952, 35, 446–450.
11. Rylander, P. N. Catalytic Hydrogenation over Platinum
Metals; Academic Press: New York, 1967; pp 81–91.
12. Molecular mechanics calculations (Macromodel, MM2 force
2
2
were separated and the organic layer was washed with water
(
(
2 ml) and saturated aqueous NaCl (2 ml) and dried
Na SO ). The solvent was removed in vacuo and the
2
4

6
28
R. M. Adlington et al. / Tetrahedron 56 (2000) 623–628
field) are consistent with this explanation, indicating that the
transition state for the cyclisation of 9 contains significantly
more strain energy than that for the cyclisation of 8.
14. Adlington, R. M.; Baldwin, J. E.; Catterick, D.; Pritchard, G. J.
J. Chem. Soc., Perkin Trans. 1 1999, 855–866.
15. Ireland, R. E.; Liu, L. J. Org. Chem. 1993, 58, 2899.
16. Brown, H. C.; Basavaiah, D.; Singh, S. M.; Bhat, N. G. J. Org.
Chem. 1988, 53, 246–250.
1
3. Tietze, L. F.; Sch u¨ nke, C. Angew. Chem., Int. Ed. Engl. 1995,
3
4, 1731–1733.