A synthesis of (±)-sparteine

Article abstract of DOI:10.1039/b502213d

In a synthesis of racemic sparteine, Diels Alder reaction between dimethyl bromomesaconate 14 and dicyclopentenyl 4, followed by cyclopropane formation, set up the stereochemistry at C-1 and C-5 as S and R, respectively, in a meso intermediate 8. The ster

Full text of DOI:10.1039/b502213d

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A R T I C L E
A synthesis of (± )-sparteine
Thomas Buttler, Ian Fleming,* Sabine Gonsior, Bo-Hye Kim,† A.-Young Sung‡ and
Hee-Gweon Woo§
Department of Chemistry, Lensfield Road, Cambridge, CB2 1EW, UK.
E-mail: if10000@cam.ac.uk; Fax: +44 (0)1223 336362; Tel: +44 (0)1223 336372
Received 14th February 2005, Accepted 8th March 2005
First published as an Advance Article on the web 23rd March 2005
In a synthesis of racemic sparteine, Diels–Alder reaction between dimethyl bromomesaconate 14 and dicyclopentenyl
4, followed by cyclopropane formation, set up the stereochemistry at C-1 and C-5 as S and R, respectively, in a meso
intermediate 8. The stereochemistry at C-2 and C-4 was then secured by a moderately diastereoselective protonation
of the bis-enolate 17 derived from the diester 8 by reductive cleavage with lithium in liquid ammonia. The C=C in the
racemic diester 19 was ozonolysed and the diketone converted by Beckmann rearrangement into the bis-lactam 25.
Reduction of the bis-lactam with lithium aluminium hydride and intramolecular nucleophilic displacement gave
racemic sparteine 1. Some ideas for making this synthesis amenable to a synthesis of enantiomerically enriched
sparteine are presented.
Introduction
(
−)-Sparteine 1 has been used to induce absolute stereocontrol
1
in a number of lithiations, but is readily available only in one
enantiomeric series. Its importance has excited much interest in
its synthesis, first of the racemic alkaloid, but only relatively
2,3
4
recently of the unnatural (+)-enantiomer. Equally interesting
5
has been the successful quest to find simpler analogues. We
reported some of our work on a synthesis of the racemic alkaloid
6
in a preliminary communication, and we report it in full here.
In our retrosynthetic analysis, the disconnection 1 ⇒ 2 is
similar to that used in the earliest, but stereochemically random,
2
synthesis of (± )-sparteine by Leonard and Beyler. In particular,
we sought to find an intermediate in which the two stereocentres
numbered as C-1 and C-5 were firmly set up as R and S,
respectively, in a meso intermediate, and later to set up the two
stereocentres C-2 and C-4, either both R or both S, in such a
way as to make either enantiomer equally easy to prepare. In the
event we have synthesised racemic sparteine using this design,
showing that the approach is workable. We have not had time to
test its applicability to an enantiocontrolled synthesis, although
there are many intriguing ways in which this might be achieved.
Scheme 1
9
insert into a,b-unsaturated esters, but in practice it was too
basic for our compound 5. Instead of insertion it gave only the
aromatic compound 6 even with careful exclusion of air. Our
second attempt at methylene insertion, inspired by a Woodward
10
synthesis, was to use diazomethane. The cycloaddition to give
the adduct 7 took place, but very slowly, taking many days and
giving, even so, a low yield. Furthermore, all our attempts to
extrude the nitrogen were unavailing. Even when we had an
authentic sample of the cyclopropane 8, and of its stereoisomer
16, we were unable to detect either of them in the photolysis
mixtures.
Results and discussion
The key meso intermediate was the cyclopropane 8, and our first
7
route to it (Scheme 1) was to be the known Diels–Alder reaction
between dimethyl acetylenedicarboxylate 3 and the diene 4,
reliably setting up the stereochemical relationship between C-1
and C-5 in the adduct 5, which was to be subjected to a methylene
In our second route, we tried to introduce the methylene
1
1
group by treating another known Diels–Alder adduct 9 with
an excess of lithium diisopropylamide (LDA) and methylene
bromide, and obtained the bromomethyl compound 10 in low
yield (Scheme 2). On further treatment with LDA, this gave us
what we wanted for the first time, the cyclopropane 8, but the
overall yield was much too low.
In our third route, we turned to a Diels–Alder reaction
between a dienophile that would carry the extra carbon with
it, allowing a cyclopropane to be created in much the same
8
insertion. The dimethylsulfoxonium methylide is known to
†
Current address: Department of Oriental Medicine Materials and
Biotechnology Industralization Center, Dongshin University, Naju 520-
7
‡
14, Korea.
Current address: School of Health Sciences, Daebul University,
Chonnam 526-702, Korea.
§
Current address: Department of Chemistry and Nanotechnology
Research Center, Chonnam National University, Gwangju 500-757,
Korea.
12
way that Eschenmoser did in a synthesis of colchicine. As our
first dienophile with this feature, we tried bromomethylmaleic
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 , 1 5 5 7 – 1 5 6 7
1 5 5 7

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Except to characterise the major isomers, we did not separate the
bromides or the cyclopropanes before they were used in the next
step. Having a mixture of cyclopropanes was of no consequence,
beyond mild inconvenience, because the next step was to remove
the difference between them. Treatment with lithium in liquid
ammonia cleaved the bond between the carbonyl groups, and
gave the bis-enolate 17. This key intermediate is still essentially
a meso compound, if one ignores enolate geometry.
The interesting step, creating the stereochemistry at C-2 and
C-4, is the protonation of the bis-enolate. There are three
possible diastereoisomeric products, two of which, the R,S,R,S
and the R,R,S,S isomers 18 and 20, are meso, and the third of
which, the R*,R*,R*,S* isomer 19, the diastereoisomer required
for the synthesis of sparteine, is not. The isomers 18 and 20,
being meso, will each have a singlet for the methoxy protons in
Scheme 2 Reagents: i, 2 equiv. LDA; ii, CH
2
2 2
Br ; iii, 1 equiv. LDA; iv,
Et O, rt, 4 h; v, NaOMe, MeOH, reflux, 2.5 h; vi, 3 N HCl workup.
1
their H NMR spectra, whereas the racemic isomer 19 will have
two methoxy singlets, which we hoped would be resolved. In
practice we obtained only two, 18 and 19, of the three isomers in
the many conditions for protonation that we tried, with no trace
of the isomer 20 at any stage. The isomer 18 was distinguished
from the other meso isomer 20 by single crystal X-ray structural
analysis, and the racemic isomer 19 did have the two methoxy
singlets which identified it unambiguously.
anhydride 11, and obtained the adduct 12 in good yield
Scheme 2). This did not give a cyclopropane when treated
(
with lithium tetramethylpiperidide, and so we tried opening
the anhydride ring first. Using sodium methoxide, we obtained
only the lactone 13, presumably formed by an exceptionally
easy protonation of the double bond during the mild acidic
workup. Hoping to avoid this problem, we tried to carry out a
Diels–Alder reaction between the diene 4 and the corresponding
diester, dimethyl bromocitraconate, which we prepared from the
anhydride 11 by treating it with methanol and sulfuric acid. This
Diels–Alder reaction failed to take place, with or without Lewis
acid catalysis. A planar anhydride is a better dienophile than
a maleate ester, but our total failure to induce a Diels–Alder
reaction was disappointing. We simply recovered the starting
materials.
When isoprene was not used to quench the excess of solvated
electrons, yields were low and the proportions of the esters 18
and 19 varied as a consequence of the different rates at which
they were reduced, giving us at first a misleading impression
of selectivity in favour of the desired racemic isomer 19. Once
isoprene was added before the protonation, yields were reliably
high, and the only problem was to raise the proportion of
the racemic isomer 19. We tried several reduction conditions,
13
including sodium in the presence of trimethylsilyl chloride,
14
Finally, the Diels–Alder reaction of the corresponding Z-
diester, dimethyl bromomesaconate 14, took place smoothly
to give a mixture of adducts 10 and 15 in a ratio of 75 : 25
and lithium 2,6-di-tert-butylbiphenyl, but our best results were
with lithium in liquid ammonia, quenching with various proton
sources. In summary, quenching with ammonium chloride gave
the meso isomer as the major product (18 : 19 = 70 : 30),
and quenching with methanol gave the racemic isomer as the
major product (18 : 19 = 24 : 76). Crystallisation of the latter
mixture, followed by chromatography of the mother liquors,
gave a total yield of the diester 19 of 68% based on the mixture
of cyclopropanes 8 and 16.
(
Scheme 3). On treatment with sodium methoxide this mixture
gave a mixture of the cyclopropanes 8 and 16 in the same ratio.
Equilibration of the esters using sodium methoxide in
methanol unhelpfully gave the same two esters in a ratio even
more in favour of the meso isomer (18 : 19 = 84 : 16), with still no
sign of the other meso isomer 20. This result more or less agreed
with a calculated difference in energy between the isomers 18
and 19 of 5.55 kJ mol− in favour of the meso isomer, with the
1
−
1
other meso isomer 20 higher again in energy by 6.46 kJ mol .
With the relative stereochemistry set up, the remaining steps
looked, and eventually were, straightforward. The next step,
however, gave us some trouble, in spite of appearing to be
uncomplicated. Ozonolysis of the alkene 19 in dichloromethane
solution took place at low temperature as expected, but workup
with dimethyl sulfide or triphenylphosphine gave us mixtures
of isomeric diketones instead of a single diketone 23. We
deduced that one or more of the four stereocentres had to some
extent lost its configuration. Although all four are in principle
equilibratable, we did not at first see why any of them should have
been so easily disturbed in essentially neutral conditions at low
temperature. The explanation we offer is that the molozonide is
formed as usual, but an intermediate ketone oxide 21 (Scheme 4)
derived from it does not rapidly undergo the usual dipolar
cycloaddition to give the ozonide, because the ring size for
the intramolecular reaction is unfavourable—the smallest of the
rings which would be formed is 8-membered. The ketone oxide
group in the intermediate 21 is effectively an activated carbonyl
group, and its unusually long life allows epimerisation by the
equivalent of enolisation. We do not, of course, know on which
side of the molecule epimerisation occurs, and so the particular
ketone oxide drawn as 21 is an arbitrary choice.
Scheme 3
1
5 5 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 5 5 7 – 1 5 6 7

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Scheme 6
1
8 on treatment with trimethylsilyldiazomethane. Were we to
have used a chiral and enantiomerically enriched alcohol or
15
amine, there is some hope that we would have been able to make
an enantiotopically differentiated version of the monoester.
Unfortunately, the monoester 28 was not epimerised by sodium
methoxide in refluxing methanol over three days, and so more
work needs to be done to find a route to the enantiomerically
enriched natural or unnatural product following these more-or-
less conventional ideas.
There are several other ideas like this which might work, but
the most elegant solution to the problem would be to find an
enantiomerically enriched acid which was constitutionally either
R- or S-selective in the protonation of an enolate. It might be
better to delay the protonation until after the ozonolysis, in order
to avoid any steric bias imparted by the tricyclic framework
in the bis-enolate 17, but, at whatever stage the protonation
of the bis-enolate is carried out, an enantioselective proton
source would provide an extraordinarily simple way to set up
the stereochemistry at C-2 and C-4, in either sense. If only there
were such a reagent. . .
Scheme 4
The solution to the problem, which also supports our analysis,
was to carry out the ozonolysis in acetone, allowing the ketone
oxide to be trapped by the solvent. Under these conditions we
obtained the diketone 23 with 4% of epimerisation. Better still
was to add acetaldehyde to the acetone to trap the ketone oxide,
even more efficiently, as the ozonide 22. In this way we detected
among the products only the diketone 23, and isolated it in 98%
yield.
The remaining steps (Scheme 5) were relatively uneventful, but
were not optimised. The bis-oxime 24 was separable in 53% yield
from the geometrically isomeric oximes by chromatography and
crystallisation. The mixture of oxime byproducts—geometrical
isomers and mono-oximes—could almost certainly have been
recycled, but we did not test this. Beckmann rearrangement
took place when the bis-oxime methanesulfonate was warmed
in aqueous tetrahydrofuran. The bis-lactam 25 gave the bis-
piperidine diol 26 on reduction with lithium aluminium hydride,
and the diol gave (± )-sparteine 1 when treated with carbon
tetrachloride and triphenylphosphine.
Experimental
General
Infrared spectra were recorded on a Perkin–Elmer FT-IR 1620
infrared spectrometer and wave numbers measured relative to
−
1
polystyrene (1603 cm ), using sodium chloride solution cells
1
13
(
0.1 mm path length). H and C NMR spectra were recorded
on Bruker NMR spectrometers (Avance 700, Avance 500 Cryo
Ultrashield, DPX 400 and DPX 250). Chemical shifts were
measured relative to tetramethylsilane (d
H
0.00) or chloroform
(
d
H
7.27) as internal standards. The coupling constant J is
1
3
expressed in Hertz (Hz). In C attached proton test (APT) spec-
tra, + denotes a signal in the same direction as the solvent signal.
1
13
H and C NMR assignments were made in all but the most
simple compounds from COSY, HMQC, HMBC and NOESY
spectra. Mass spectra were recorded on Kratos Concept (EI)
and Micomas Q-TOF (ESI) spectrometers. X-Ray structures
were determined with a Nonius Kappa CCD. Mass spectra and
X-ray crystallography were carried out by technical staff. Flash
column chromatography was carried out using Merck Kieselgel
6
4
0 (230–400 mesh ASTM) and Merck LiChroprep RP-18 (25–
0 lm). Thin layer chromatography (TLC) was performed
on glass plates coated to a thickness of 1 mm with Merck
Kieselgel 60 PF254 and RP-18F254s. R values refer to TLC on
f
Kieselgel 60 PF254 plates. Melting points were determined using
Gallenkamp melting point apparatus and stand uncorrected.
Tetrahydrofuran (THF) and ether were freshly distilled from
lithium aluminium hydride under argon. Dichloromethane,
carbon tetrachloride, acetonitrile, methanol, light petroleum,
hexane and toluene were freshly distilled from calcium hydride
under argon. Light petroleum refers to the fraction boiling in
Scheme 5
Although we did not investigate the synthesis of an enan-
tiomerically enriched sparteine, we did prepare for one route
by which it might be achieved (Scheme 6). The meso diester 18
gave the corresponding dicarboxylic acid on hydrolysis, without
epimerisation, since acid gave back the diester 18 on treatment
with trimethylsilyldiazomethane. The dicarboxylic acid gave the
corresponding anhydride 27, and the anhydride could be opened
with methanol to give the monoester 28 in good overall yield,
again without epimerisation, since it also gave the meso diester
◦
the range 40–60 C. Ether refers to diethyl ether.
Dimethyl 1,2,3,3a,5a,6,7,8-octahydro-as-indacene-4,5-
7
dicarboxylate 5
16
Dicyclopentenyl (4.0 g, 0.03 mol), dimethyl acetylenedicar-
boxylate (4.26 g, 0.03 mol, freshly distilled), hydroquinone (0.1 g)
3
and dioxan (13 cm , freshly distilled from calcium hydride)
were refluxed under nitrogen for 15 h. Dioxan was removed
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 5 5 7 – 1 5 6 7
1 5 5 9

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3
under reduced pressure, pentane (20 cm ) was added to the light
CH
(CHCCO
A
H
B
CHCCO
2
MeCH
2
N
2
); d
C
(100 MHz; CDCl
MeN
), 134.0+
MeN
), 83.8+
), 52.6− (CHCCO Me-
), 47.6− (CHCCO MeN ),
), 30.0+, 29.8+, 29.75+, 28.5+
), 26.8+ (CH CH
C=C) and 26.5+
C=C); m/z (ESI) 341 (M + Na) (Found: M + Na ,
3
) 173.8+
yellow residue, the pentane-soluble portion decanted off and the
2
MeCH
2
N
2
), 170.0+ (CHCCO
2
2
◦
solution kept at −20 C overnight. The adduct (6.74 g, 82%) was
(C=C), 133.4+ (C=C), 106.7+ (CHCCO
2
2
◦
filtered off as large needles, mp 42–43 C (from hexane) (no mp in
(CH
CH
2
N
2
), 58.5+ (CHCCO
2
MeCH
MeN
2
N
2
2
◦
16
lit.; the mp of 127 C given for 5 is actually that of the aromatic
2
N
2
), 52.5− (CHCCO
MeCH
MeN
2
2
2
2
7
compound 6, as revealed by Courtot and Cl e´ ment ); R
f
(Et
)/cm 2952 (CH), 2870
(400 MHz,
) 3.78 (6 H, s, 2 × OMe), 3.15 (2 H, br s, 2 × = CCH),
and 2 × CH CH ), 1.87–1.80
2 H, m), 1.75–1.64 (2 H, m) and 1.32 (2 H, qd, J 11.8 and 7.5,
2
O–
45.9− (CHCCO
2
2
N
2
−
1
light petroleum, 1 : 1) 0.52; mmax(CDCl
3
(CH
(CH
2
2
CHCCO
CH
2
2
2
2
+
+
(
CH), 2841 (CH), 1716 (C=O) and 1258 (C–O–C); d
H
2
CDCl
3
341.1469. C17
H
22
N
2
O
4
requires M + Na, 341.1477). The aroma-
2
(
.23–2.13 (6 H, m, 2 × = CCH
2
A
B
tic compound 6 was also present in other chromatographic
fractions.
2
× CH
A
H
B
CH); d
C
(100 MHz, CDCl
3
) 168.7+, 137.1+, 130.7+,
51.9−, 43.8−, 31.9+, 27.3+ and 23.7+.
Dimethyl (3aRS,4SR,5SR,5aSR)-1,2,3,3a,4,5,5a,6,7,8-
11
decahydro-as-indacen-4,5-dicarboxylate 9
Dimethyl 1,2,3,6,7,8-hexahydro-as-indacene-4,5-
dicarboxylate 6
Diene 4 (2 g, 14.9 mmol) and dimethyl fumarate (2.22 g,
7,16
3
15.4 mmol) were refluxed in toluene (30 cm ) for 4 h. Toluene was
3
The diester 5 (2.5 g, 9 mmol) in dry DMSO (3 cm ) was
removed under reduced pressure to give a pale yellow oil, which
8
3
◦
added to the trimethylsulfoxonium methylide (9 mmol). A mild
was dissolved in n-pentane (20 cm ) and kept at −20 C overnight
◦
exothermic reaction took place and the mixture turned initially
slightly yellow (then orange, and finally dark brown with no
precipitate). The mixture was stirred at room temperature for
to give the diester (3.81 g, 92%) as plates, mp 75–75.5 C (from
1
1
◦
n-pentane) (lit., 72–74 C; R
0.27; mmax(CDCl
f
(Et
)/cm 2954 (CH), 2870 (CH) and 1731 (C=O);
(400 MHz; CDCl ) 3.69 (3 H, s, CO Me), 3.67 (3 H, s,
CO Me), 3.25 (1 H, dd, J 15.0 and 12.0, CHCO Me), 2.67
(1 H, m, CHCHCO Me), 2.31 (1 H, m, CHCHCO Me), 2.20–
2.12 (5 H, m, 2 × CH Me), 1.92 (1 H, quintet,
C=C and CHCO
J 6.0), 1.81–1.51 (5 H, m), 1.25 (1 H, quintetd, J 12.0 and
6.8, CH CH) and 1.05 (1 H, dtt, J 21.3, 10.3 and 2.2,
CH CH
C=C).
2
O–light petroleum, 1 : 1)
−
1
3
−
3
4
3
h, and poured into ice and hydrochloric acid (3 mol dm ,
d
H
3
2
3
3
0 cm ). The mixture was extracted with ether (3 × 50 cm ), dried
2
2
(
MgSO
4
), and filtered. The solvents were removed, and pentane
2
2
3
(
40 cm ) was added to the oil. The pentane-soluble portion was
2
2
◦
decanted and kept at −20 C overnight. The only recognisable
product, the aromatic diester (0.62 g, 25%), separated as yellow
A
H
B
◦
7
◦
needles, mp 135–136 C (from EtOH) (lit., 130 C); R
f
(Et
), 2878
), 1721 (C=O), 1583 (Ph) and 1287 (C–O–C);
(400 MHz; CDCl
) 3.86 (6 H, s, 2 × OMe), 3.05 (4 H, t,
J 7.5, 2 × CH CH CH ), 2.83 (4 H, t, J 7.5, 2 × CH CH CH
and 2.10 (4 H, quintet, J 7.5, 2 × CH CH CH ); d (100 MHz;
CDCl
) 168.8+, 143.6+, 142.9+, 126.0+, 52.1−, 32.5+, 31.4+,
5.0+.
2
O–
A
H
B
2
−
1
light petroleum, 1 : 1) 0.48; mmax(CDCl
CH ), 2840 (CH
3
)/cm 2952 (CH
3
18
(
3
2
2-Bromo-2-bromomethylsuccinic acid
d
H
3
3
3
Bromine (16 cm , 50 g, 313 mmol) in acetic acid (50 cm ) was
2
2
2
2
2
2
)
added dropwise over 2 h with stirring to itaconic acid (29 g,
2
2
2
C
3
3
00 mmol) in acetic acid (50 cm ) at room temperature, and
3
the mixture was refluxed for 1.5 h. Acetic acid and bromine
were removed under reduced pressure. Carbon tetrachloride
2
3
(
100 cm ) was added and evaporated. Additional carbon tetra-
Dimethyl (3aRS,3bRS,9aSR,9bSR)-3b,4,5,6,7,8,9,9a-
octahydro-3H-1,2-diazatrindene-3a,9b-dicarboxylate 7
3
chloride (50 cm ) was added to the residue and the solution
◦
stored at −20 C overnight to give the dibromide (60.7 g, 70%)
1
7
◦
18
Diazomethane (16.6 mmol, alcohol-free solution in ether)
as plates, mp 166–167 C (from CHCl –light petroleum) (lit.,
3
◦
−1
was added to a solution of Diels–Alder adduct 5 (0.765 g,
167–168 C); mmax(CD
3
OD)/cm 1732 (C=O); d
OD) 4.32 (1 H, d, J 10.0, CH Br), 4.30 (1 H, d, J 10.0,
Br), 3.36 (1 H, d, J 18.0, CH COOH) and 3.31 (1 H,
COOH).
H
(400 MHz;
3
2
.78 mmol) in dry ether (10 cm ). The solution was kept in the
dark, adding further aliquots of freshly prepared diazomethane
16.6 mmol, alcohol-free solution in ether) after 3, 5 and
days, successively. After 18 days, glacial acetic acid was
CD
CH
3
A
H
B
A
H
B
A
H
B
(
7
d, J 18.0, CH
A
H
B
18
added. The mixture was filtered, the filtrate washed with
3-Bromo-3-(bromomethyl)dihydrofuran-2,5-dione
aqueous sodium hydrogen carbonate and with brine, dried
3
Trifluoroacetic anhydride (42 cm , 61.6 g, 195 mmol) was
added to the dibromide (40 g, 138 mmol) under nitrogen at
room temperature, and the mixture refluxed for 30 min. The
solvent was removed under reduced pressure, and traces of
trifluoroacetic acid and trifluoroacetic anhydride were removed
under high vacuum to give the anhydride (37 g, 99%) as needles,
1
(
MgSO
4
) and evaporated under reduced pressure. The H NMR
spectrum showed 46% conversion of the starting material.
Diazomethane (16.6 mmol, alcohol-free solution in ether)
3
was added to a solution of the residue in dry ether (10 cm ).
The solution was again kept in the dark and diazomethane
(
16.6 mmol, alcohol-free solution in ether) added after 4
◦
◦
1
8
mp 59–60 C (from CHCl
3
–light petroleum) (lit., 58–60 C);
)/cm 2926 (CH), 2855 (CH), 1873 (C=O, antisym.)
and 1802 (C=O, sym.); d
(250 MHz; CDCl ) 4.23 (1 H, d,
J 10.6, CH Br), 3.93 (1 H, d, J 19.5, CH CO), 3.87
1 H, d, J 10.6, CH Br) and 3.44 (1 H, d, J 19.5, CH CO).
and 6 days, successively. After 14 days, glacial acetic acid
was added. The mixture was filtered, the filtrate washed with
aqueous sodium hydrogen carbonate and with brine, dried
−
1
mmax(CDCl
3
H
3
A
H
B
A
H
B
(
MgSO
4
) and evaporated under reduced pressure. The residue
(
A
H
B
A
H
B
was chromatographed (SiO
to give the pyrazoline (0.25 g, 29%) as needles, mp 85–86
2
, light petroleum–EtOAc, 4 : 1)
◦
C
10
3
-Bromomethylfuran-2,5-dione 11
(
m
1
(
from EtOAc–hexane); R
f
(Et
2954 (CH
747 (C=O) and 1255 (C–O–C); d
1 H, d, J 18.7, CH ), 4.23 (1 H, d, J 18.7, CH
Me), 3.64 (3 H, s, CO Me), 3.05 (1 H, m,
), 2.84 (1 H, m, CHCCO MeCH ), 2.45
1 H, dt, J 20.3, 7.2, CH CHCCO MeN ), 2.27–2.13 (3 H,
m, 2 × CH CHCCO Me)N ], 1.82 [1 H,
C=C and CH
dquintet, J 19.7 and 3.7, CH CH CHC(CO Me)CH ],
.71–1.61 [3 H, m, CH CH CHC(CO MeCH and
CH CH CHCCO MeN ) and 1.29 (1 H, m dq, J 17.0 and 8.4,
2
O–light petroleum, 1 : 1) 0.38;
), 2872 (CH ), 2834 (CH ),
(500 MHz; CDCl ) 5.05
),
−
1
3
max(CDCl
3
)/cm
3
3
2
Dry 2,6-lutidine (16.5 cm , 15.17 g, 141.6 mmol) was added
dropwise over 30 min to a vigorously stirred solution of the
anhydride (35 g, 128.7 mmol) in dry toluene (450 cm ) under
nitrogen at 0 C, and the mixture was kept at room temperature
for 1.5 h. The solvent was removed under reduced pressure.
Kugelrohr distillation gave the anhydride (15.67 g, 64%) as a
H
3
3
A
H
B
N
2
A
H
B
N
2
◦
3
.71 (3 H, s, CO
MeN
2
2
CHCCO
(
2
2
2
2
N
2
A
H
B
2
2
◦
10
◦
A
H
B
A
H
B
2
2
yellowish oil, bp 90 C at 0.3 mmHg (lit., 116–117 C at 1.2
1
−
H
B
2
2
2
N
2
mmHg); mmax(CDCl
antisym.) and 1802 (C=O, sym.); d
(1 H, t, J 1.5, CH=C) and 4.22 (2 H, d, J 1.5, CH
3
)/cm 2926 (CH), 2855 (CH), 1873 (C=O,
(250 MHz; CDCl ) 6.94
).
A
1
A
H
B
2
2
2
N
2
H
3
2
2
2
2
2
1
5 6 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 5 5 7 – 1 5 6 7

View Article Online
−
1
(
3
3aRS,3bSR,9aSR,9bRS)-3a-Bromomethyl-
a,3b,4,5,6,7,8,9,9a,9b-decahydro-2-oxatrindene-1,3-dione 12
l(Mo–Ka) = 2.717 mm , 8450 reflections measured at 180(2)
K using an Oxford Cryosystems Cryostream cooling apparatus,
2
640 unique (Rint = 0.044); R
1
= 0.047, wR = 0.116 [I>2r(I)].
2
Bromomethyl anhydride 11 (3.82 g, 20 mmol) and the
diene 4 (2.71 g, 20.2 mmol) were kept in ether (8 cm ) at room
temperature for 24 h. The solvent was evaporated under reduced
The structure was solved with SHELXS-97 and refined with
SHELXL-97.
CCDC reference number 263438. See http://www.rsc.org/
suppdata/ob/b5/b502213d/ for crystallographic data in CIF
or other electronic format.
3
19
pressure. The residue was chromatographed (SiO
2
, Et O–light
2
petroleum, 15 : 85) to give the anhydride (5.51 g, 85%) as needles,
◦
mp 66–67 C (from n-pentane); R
f
(Et O–light petroleum, 1 : 1)
2
−
1
0
.52; mmax(CDCl
sym.); d (500 MHz; CDCl
.53 (1 H, d, J 6.2, CHCO), 3.49 (1 H, d, J 10.6, CH
3
)/cm 1852 (C=O, antisym.) and 1776 (C=O,
20
Dimethyl 2-bromo-2-(bromomethyl)succinate
H
3
) 3.89 (1 H, d, J 10.6, CH
A
H
H
B
Br),
Br),
3
3
2
A
B
Bromine (56.6 g, 354 mmol) in dichloromethane (20 cm )
was added to a stirred solution of dimethyl itaconate (49.2 g,
311 mmol) in dichloromethane (200 cm ) at 0 C, and the
mixture was refluxed for 16 h. The solvent was evaporated under
reduced pressure and dichloromethane (100 cm ) was added to
the residue. The mixture was stirred with aqueous sodium sulfite
solution (100 cm ) for 30 min. The organic layer was washed
with distilled water (50 cm ), brine (50 cm ), dried (MgSO
and evaporated under reduced pressure to give the dibromide
(97.76 g, 99%); mmax(CDCl
CDCl ) 4.34 (1 H, d, J 10.7, CH
CH Br), 3.85 (3 H, s, CO Me), 3.73 (3 H, s, CO
3.42 (2 H, s, CH CO Me).
.57 (1 H, m, CHCHCO), 2.40–2.33 (2 H, m, CHCCOCH
CHCCOCH Br), 2.26–2.21 (2 H, m, CH
C=C),
.19–2.16 (2 H, m, CH
C=C), 2.07–1.99 (3 H, m, CH
CHCCOCH Br and CH CHCHCO), 1.89 (1 H, qt, J 12.0
and 7.0, CH CH CHCCOCH Br), 1.81 (1 H, qt, J 12.0
and 7.0, CH CH CHCHCO) and 1.69–1.60 (2 H, m,
CH CH CHCCOCH Br and CH CH CHCHCO); d
125 MHz; CDCl BrCO), 170.1+ (CHCO),
) 171.4+ C(CH
36.7+ (C=CCHCH(CO), 133.1+ (C=CCHCHCO), 56.7+
Br), 49.5− (CHCOO), 46.9− (CHCCOCH Br),
0.9− (CHCHCO), 35.0+ (CH Br), 29.3+ (CH
C=C),
C=C), 27.6+ (CH
CHCOCH Br), 27.5+
CHCHCO), 26.1+ (CH CH CHCOCH Br) and 25.9+
CH CHCHCO) (Found: C, 55.4; H, 5.25; Br, 24.7.
requires C, 55.4; H, 5.27; Br, 24.6%).
2
Br
3
◦
and CH
A
H
B
2
2
2
2
A
H
B
3
2
2
A
H
B
2
2
3
A
H
B
2
3
3
A
H
B
2
2
A
H
B
2
C
4
)
(
3
2
−
1
1
3
)/cm 1725 (C=O); d
Br), 4.25 (1 H, d, J 10.7,
Me) and
H
(250 MHz;
(
CCH
2
2
3
A
H
B
4
2
2
2
A
H
B
2
2
8.9+ (CH
2
2
2
2
2
(
(
CH
CH
2
2
2
2
2
20
2
Dimethyl (Z)-2-(bromomethyl)but-2-enedioate 14
C
15
H
17BrO
3
The dibromosuccinate (97.6 g, 307 mmol) and triethylamine
3
(
(
51 cm , 37.14 g, 367 mmol) were kept in dichloromethane
600 cm ) at room temperature for 4 h. The mixture was
Methyl (1RS,2RS,3SR,7RS,8RS,12SR)-1-bromomethyl-14-
3
3
,7 8,12
oxa-13-oxotetracyclo[5.5.2.0 .0 ]-tetradecane-2-carboxylate 13
filtered, and the filtrate was washed with dilute hydrochloric acid
3
3
(200 cm ), aqueous sodium hydrogencarbonate (100 cm ), brine
Freshly prepared sodium methoxide (150 mg) in methanol
3
3
(100 cm ), and dried (MgSO ). The volatiles were evaporated
under reduced pressure. Kugelrohr distillation gave the bromo-
mesaconate (53.72 g, 73%) as a greenish oil, oven temperature
(
3 cm ) and the anhydride 12 (1 g, 3.1 mmol) were refluxed
4
3
in methanol (25 cm ) for 2.5 h. The methanol was removed
under reduced pressure. Dilute hydrochloric acid (3 mol dm ;
0 cm ) was added to the residue and the mixture was
−
3
◦
20
◦
3
110 C at 3 mmHg (lit., 72 C at 0.1 mmHg); R (Et O–light
1
f
2
−
1
3
petroleum, 1 : 1) 0.49; mmax(CDCl )/cm 2955 (CH), 1727 (C=O)
extracted with ether (3 × 5 cm ). The extract was washed
3
3
and 1644 (C=C); d (400 MHz; CDCl ) 6.83 (1 H, s, HC=C),
with brine (10 cm ), dried (MgSO
4
) and evaporated under
H
3
4
.72 (2 H, s, CH
2
Br), 3.88 (3 H, s, CO Me) and 3.83 (3 H, s,
2
reduced pressure. The residue was chromatographed (SiO
2
,
CO Me).
2
Et O–light petroleum, 85 : 15) to give the lactone (953 mg,
2
◦
8
6%) as needles, mp 158–159 C (from EtOH); R
f
(Et
)/cm 2957 (CH), 2874
) 3.87 (1 H, d, J
Me), 3.66 (1 H, d, J 11.5,
Br), 3.41 (1 H, d, J 11.7, CHCO Me), 2.67 (1 H, q, J 9.6,
CHCCH BrCOO), 2.27 (1 H, td, J 12.5 and 7.0, CHC–O–CO),
.22 (1 H, q, J 10.5, CHCHCO Me), 2.07 (1 H, m, CH C–
O–CO), 1.97–1.88 (2 H, m, CH CHCCH BrCOOC and
BrCOOC), 1.84 (1 H, quintet, J 6.6
Me), 1.78–1.70 (4 H, m, CH C–O–CO,
CHCCH BrCOOC, CH CH CHCHCO Me
CHC–O–CO), 1.55–1.45 (2 H, m, CH
Me) and CH CH CHCHCO Me), 1.37–1.19
1 H, m, CH CHC–O–CO) and 1.12 [1 H, dddd, J 18.8,
.8, 6.3 and 3.5, CH CHCCH BrCOOC; d (125 MHz;
) 172.4+ (C–O–CO), 171.1+ (CO Me), 92.4+ (C–
O–CO), 51.6− (CO Me), 46.6+ (CCOOCCH Br), 46.1−
CHCO Me), 44.4− (CHC–O–
Me), 45.6− (CHCHCO
Br), 34.0+ (CH Br), 31.7+
C–O–CO), 28.5+ (CH CHCCOOCCH Br), 27.3+
CHCHCO CH C–O–CO), 25.4+
Me), 25.9+ (CH
CHC–O–CO) and 21.6+ (CH CH CHCHCOOCCH Br)
requires C,
3.8; H, 5.90; Br, 22.4%). Refluxing the anhydride 12 (572 mg,
2
O–light
−
1
Dimethyl (E)-2-(bromomethyl)but-2-enedioate
petroleum, 1 : 1) 0.30; mmax(CDCl
3
(
1
CH) and 1748 (C=O); d
1.5, CH
CH
H
(500 MHz; CDCl
Br), 3.70 (3 H, s, CO
3
The anhydride 11 (10.04 g, 52.6 mmol) and concentrated sulfuric
acid (0.5 cm ) were refluxed in methanol (10 cm ) for 3 h.
The mixture was diluted with distilled water (20 cm ) and
A
H
B
2
3
3
A
H
B
2
3
3
2
extracted with ether (4 × 10 cm ). The extract was washed with
2
2
A
H
B
3
brine (10 cm ), dried (MgSO
4
) and evaporated under reduced
A
H
B
2
pressure. The residue was chromatographed (SiO
petroleum, 5 : 95) to give the (bromomethyl)maleate (5.56 g,
, Et O–light
2
2
CH
CH
CH
and CH
CHCHCO
A
H
A
H
A
H
B
B
B
CH
CHCHCO
CH
2
CHCCH
2
2
A
H
B
4
5%) as a greenish oil; R
(Et O–light petroleum, 1 : 1) 0.40;
f
2
2
2
A
H
B
2
2
mmax(CDCl
)/cm 2953 (CH), 1735 (C=O) and 1635 (C=C);
−1
3
A
H
2
B
A
B
H -
d
(400 MHz; CDCl
Br), 3.85 (3 H, s, CO
) 6.24 (1 H, t, J 1.0, HC=C), 4.13 (2 H, d,
2 2
H
3
A
H
B
2
2
J 1.0, CH
Me) and 3.77 (3 H, s, CO
Me).
2
(
9
A
H
B
A
H
B
2
C
Dimethyl (3aRS,4SR,5RS,5aRS)-4-bromomethyl-
,2,3,3a,4,5,5a,6,7,8-decahydro-as-indacene-4,5-
dicarboxylate 10
CDCl
3
2
1
2
2
(
2
2
3
Method A. The diester 9 (0.557 g, 2.00 mmol) in THF (2 cm )
CO), 42.6− (CHCCOOCCH
2
2
−
3
was added dropwise to a stirred solution of LDA (0.84 mol dm
(
(
(
(
5
1
CH
CH
CH
2
2
2
2
2
3
◦
in THF–hexane, 5 cm , 4.20 mmol) at −78 C. After 1 h,
2
2
2
3
dibromomethane (3 cm , 7.43 g, 42.7 mmol) was added at
2
2
2
◦
◦
−
50 C. The mixture was kept at −50 C for another 3 h, and
Found: C, 53.7; H, 5.90; Br, 22.7. C16
H
21BrO
4
then at room temperature for 12 h. The mixture was quenched
3
3
with aqueous ammonium chloride (10 cm ) and extracted with
.76 mmol) and concentrated sulfuric acid (1 cm ) in methanol
20 cm ) for 12 h gave the same lactone in slightly better yield
570 mg, 91%).
3
3
3
ether (3 × 10 cm ). The extract was washed with brine (20 cm ),
dried (MgSO ) and evaporated under reduced pressure. The
residue was chromatographed (SiO , Et O–light petroleum, 15 :
85) to give the bromide (81 mg, 11%); R (Et O–light petroleum,
), 2872 (CH ) and 1731
Br),
(
(
4
2
2
Crystal data for 13.
C
16
H
21BrO
4
, M = 357.24, monoclinic,
f
2
−
1
˚
˚
space group P2
1
/n, a = 9.3004(5) A, b = 14.8301(9) A, c =
1 : 1) 0.59; mmax(CDCl
3
)/cm 2953 (CH
3
3
◦
3
˚
˚
=
1
1.6244(4) A, b = 108.53(1) , U = 1520.20(13) A , Z = 4,
(C O); d
H
(500 MHz; CDCl
3
) 3.88 (1 H, d, J 10.4, CH
A
H
B
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 5 5 7 – 1 5 6 7
1 5 6 1

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3
(
.82 (1 H, d, J 10.4, CH
3 H, s, CO Me), 3.01 (1 H, d, J 7.8, CHCO
H, m, CHCCO MeCH Br), 2.51 (1 H, m, CHCHCO
.26−2.05 (5 H, m, 2 × CH CHCHCO
C=C and CH
.86 (1 H, dt, J 13.0 and 8.2, CH CHCCO
.80 (1 H, dt, J 12.4 and 7.3, CH CH CHCHCO
.71 [1 H, m, CH CH CHCCO MeCH Br], 1.62–1.51 (3
CH CHCHCO Me), CH CHCCO MeCH Br
CH CHCCO Br) and 1.37 (1 H, qd, J
1.6 and 6.9, CH Me); d (125 MHz; CDCl
74.5+ (C=O), 172.7+ (C=O), 133.1+ (C=C), 131.7+ (C=C),
4.8+ (CCO MeCH Br), 51.7− (CO Me), 51.5− (CO Me),
0.7− (CHCO Me), 46.4− (CHCCO MeCH Br), 43.0−
Me), 36.8+ (CH Br), 33.4+ (CH CHCHCO Me),
CHCCO MeCH
A
H
B
Br), 3.69 (3 H, s, CO
2
Me), 3.65
Dimethyl (3aRS,4SR,5RS,5aRS)-4-chloromethyl-
1,2,3,3a,4,5,5a,6,7,8-decahydro-as-indacene-4,5-dicarboxylate
2
2
Me), 2.80 (1
2
2
2
2
Me),
Me),
3
Dimethyl ester 9 (0.566 g, 2.03 mmol) in THF (2 cm ) was
2
1
1
1
2
A
H
B
−
3
added to LDA (0.89 mol dm solution in THF–hexane,
A
H
B
2
Me)CH
2
Br),
3
◦
5
(
cm , 4.47 mmol) at −78 C. After 1 h, bromochloromethane
A
H
B
2
2
Me),
3
2.72 cm , 5.25 g, 40.6 mmol) was added. The mixture was kept
A
H
B
2
2
2
◦
at −78 C for another 3 h, and then at room temperature for 25 h.
H, m, CH
and CH
1
1
5
5
A
H
H
B
2
2
A
H
B
2
2
The mixture was worked up in the same way as for the corre-
A
B
2
2
MeCH
CHCHCO
2
sponding bromide 10 to give the chloride (53 mg, 8%); R
f
(Et
), 2928
), 1728 (C=O) and 1261 (C–O–
) 3.99 (1 H, d, J 11.4, CH Cl),
.95 (1 H, d, J 11.4, CH Cl), 3.70 (3 H, s, CO Me), 3.68
3 H, s, CO Me), 2.96 (1 H, d, J 8.5, CHCO Me), 2.74 (1 H, m,
CHCCO MeCH Cl), 2.55 (1 H, m, CHCHCO
5 H, m, 2 × CH CHCHCO
C=C and CH
2 H, m, CH CHCHCO MeCH
.75 (1 H, m, CH CH
CH CHCHCO MeCH
1 H, dq, J 11.4 and 7.0, CH
CDCl
2
O–
A
H
B
2
C
3
)
−
1
light petroleum, 1 : 1) 0.56; mmax(CDCl
CH2), 2870 (CH ), 2861 (CH
C); d (500 MHz; CDCl
3
)/cm 2955 (CH
3
(
3
2
2
2
2
2
H
3
A
H
B
2
2
2
3
A
H
B
2
(
CHCHCO
2
2
2
2
(
2
2
2
8.6+ (CH
2
2
2
Br), 28.3+ (CH
C=C), 28.2+
2 2
2
2
2
2
2
Me), 2.27–2.12
Me), 1.87–1.77
(
CH
2
C=C), 24.31+ (CH
2
CH
2
C=C) and 24.26+ (CH
CH
C=
(
2
A
H
B
+
79
C) (Found: M + Na , 393.0673. C17
H
23 BrO
4
requires M + Na,
[
1
A
H
B
2
2
Cl and CH
A
H
B
CH
2
C=C),
3
93.0677).
H
B
2
C=C), 1.63–1.50 (3 H, m,
A
Method B. Dimethyl aluminium chloride (1 mol dm−
3
=
A
H
B
2
2
Cl and CH
2
CH
2
C C) and 1.31
3
(
A
H
B
CHCHCO
2
Me); d
C
(125 MHz;
solution in hexanes, 20.3 cm , 20.3 mmol) was added dropwise
to a stirred solution of bromomethyl fumarate 14 (4.81 g,
) 174.6+ (C=O), 173.1+ (C=O), 133.5+ (C=C),
3
3
◦
=
1
5
4
(
(
31.9+ (C C), 54.4+ (CCO
1.7− (CO Me), 50.8− (CHCO
MeCH
Cl), 42.6− (CHCHCO
2
MeCH
Me), 47.9+ (CH
Me), 33.7+
2
Cl), 51.9− (CO
2
Me),
Cl),
2
2
0.3 mmol) in dichloromethane (60 cm ) at −78 C. After
3
0 min, diene 4 (3 g, 22.3 mmol) in dichloromethane (15 cm )
2
2
2
◦
5.8− (CHCCO
2
2
2
was added at −78 C. The mixture was allowed to warm slowly
to room temperature and stirred for 12 h. The mixture was
quenched dropwise with aqueous sodium hydrogencarbonate
CH
CH
2
2
CHCHCO
2
Me), 29.1+, 28.6+, 28.2+ (CH
C=C), 24.5+
2
CH
2
C=C) and 24.4+ (CH
2
CH
2
C=C); m/z (+ESI) 349
◦
3
+
+
3
(
3
100%, M + Na ) and 291 (15%, M − Cl) (Found: M + Na ,
(
15 cm ) at 0 C, and extracted with ether (3 × 25 cm ).
3
5
3
49.1190. C17
H
23 ClO
4
requires M + Na, 349.1183).
The extract was washed with brine (25 cm ), dried (MgSO
4
)
and evaporated under reduced pressure. Traces of solvent and
unreacted diene were removed under high vacuum to give a
mixture of the adducts 10 and 15 (7.46 g, 99%; 75 : 25 using
meso-Dimethyl (1aS,1bS,7aR,7bR)-1b,2,3,4,5,6,7,7a-
octahydrocyclopropa[e]-as-indacene-1a,7b-dicarboxylate 8
the signals d 3.65 of the major diastereoisomer and 3.60 of
the minor). The diastereoisomeric mixture was used in the next
step without further purification. On one occasion the mixture
H
Method A. The bromide 10 (0.802 g, 2.16 mmol) in
THF (5 cm ) was added dropwise to a stirred solution of
3
−3
3
LDA (0.84 mol dm in THF–hexane, 5 cm , 4.20 mmol) at
was chromatographed (SiO
2
, Et
2
O–light petroleum, 2 : 98 to 5 :
◦
◦
−
78 C. The mixture was kept for 1 h at −78 C, and then
9
5) to obtain a pure sample of the major diastereoisomer, as a
at room temperature for 3 h. The mixture was quenched with
colourless oil, identical with the earlier sample.
3
aqueous ammonium chloride (10 cm ) and extracted with ether
3
3
(
3 × 10 cm ). The extract was washed with brine (20 cm ), dried
Method C. Bromomethyl fumarate 14 (15.79 g, 66 mmol)
◦
(MgSO ) and evaporated under reduced pressure. The residue
4
and the diene 4 (8.80 g, 65.56 mmol) were kept at 45 C for 18 h.
was chromatographed (SiO
2
, Et O–light petroleum, 15 : 85) to
2
The mixture was chromatographed (SiO
1
8
2
, Et
5 : 85) to give the same mixture of bromides (20.74 g, 85%;
8 : 12).
2
O–light petroleum,
give the cyclopropane (321 mg, 72%) as plates, mp 77–
◦
78
C (from n-pentane); R
f
(Et
)/cm 2952 (CH
) 3.59 (6 H, s, 2 × CO
MeCH CCO Me), 2.29 (2 H,
C=C), 2.22 (2 H, m, 2 × CH C=C),
CHCCO Me), 1.98 (2 H, m,
Me), 1.92 (2 H, ddd, J 15.4, 7.4 and 3.8,
CH
C=C), 1.77 (2 H, quintet, J 9.0, 2 ×
CHCCO MeCH ), 1.57 (2 H, m, 2 × CH CH
C=C)
and 0.88 (1 H, d, J 5.2, CCO MeCH CCO Me); d (125 MHz;
CDCl
) 171.4+ (2 × C=O), 134.0+ (2 × C=C), 51.4− (2 ×
CO Me), 37.6+ (2 × CHCCO Me),
Me), 45.5− (2 × CHCCO
30.2+ (2 × CH CHCCO Me), 28.5+ (2 × CH
C=C), 28.3+
(CO MeCH CO Me) and 25.5+ (2 × CH CH
C=C) (Found:
C, 70.2; H, 7.65. C17 requires C, 70.3; H, 7.65%).
2
O–light petroleum, 1 : 1)
), 2870 (CH ) and 1728
Me),
−
1
0
(
2
.44; mmax(CDCl
3
3
3
C=O); d
(500 MHz; CDCl
.31 (1 H, d, J 5.2, CCO
H
3
2
Dimethyl (3aRS,3bRS,9aRS,9bRS)-1-oxo-
2
a
H
b
2
1
,3b,4,5,6,7,8,9,9a,9b-decahydro-2-oxatriindene-3a-carboxylate
m, 2 × CH
2.02 (2 H, m, 2 × CH
2 × CHCCO
2 × CH
CH
A
H
B
A
H
B
◦
When the Diels–Alder reaction was carried out at 250 C, the
A
H
B
2
lactone, formed by displacement of the bromide in the major
adduct by the cis ester group, was obtained as needles, mp
2
A
H
B
2
◦
9
1
8–99 C (from Et
2
O–n-pentane); R
f
(Et
)/cm 2955 (C-H), 2873 (C–H), 2848 (C–
(500 MHz;
O), 4.16 (1 H, d, J 9.1,
Me), 3.60 (1 H, m, CHC=O), 2.68
O), 2.49 (1 H, m, CH
C=C, CHCHC=OO) and C*H
C=C), 1.88–1.83 (2 H, m, CH
CH
CHCCO MeCH
CHCCO MeCH
CHCHCOO and CH CH
CH
(125 MHz; CDCl
38.6+ (C=CCHCCO
2.8+ (CH O), 53.6+ (CHCCO
2
O–light petroleum, 1 :
A
H
B
2
2
A
H
C
B
2
−
1
) 0.37; mmax(CDCl
3
2
a
H
b
2
H), 1760 (C=O, lactone) and 1731 (C=O, ester); d
CDCl ) 4.50 (1 H, d, J 9.1, CH
CH O), 3.77 (3 H, s, CO
1 H, m, CHCCO MeCH
H
3
3
A
H
B
2
2
2
A
H
B
2
2
2
2
(
2
2
A
H
B
C=C), 2.45–
2
2
2
2
2
2
2
1
.36 (3 H, m, CH
.18 (1 H, m, C*H
.78 (1 H, m, CH
A
H
B
A
H
B
C=C),
C=C),
H
22
O
4
A
H
A
B
2
2
Method B. The corresponding chloride (47 mg, 0.144 mmol)
H
B
2
2
O), 1.70 (1 H, qd,
3
in THF (2 cm ) under similar conditions gave the same
J 12.9 and 7.5, CH
m, CH
CH
A
H
B
2
2
O), 1.64–1.52 (2 H,
cyclopropane (13 mg, 32%).
C=C), 1.45 (1 H, m,
A
H
B
A
H
B
2
A
H
B
2
C=C) and 1.21 (1 H, m, CH
A
H
B
CHCHCOO);
Method C. The 75 : 25 diastereoisomeric mixture of bro-
momethyl dicarboxylates 10 and 15 (10.43 g, 28.1 mmol) in
d
C
3
) 174.22+ (C=O), 174.15+ (C=O),
Me), 126.0+ (C=CCHCHC=OO),
Me), 52.6− (CO Me), 42.3−
3
1
7
(
(
2
2
C
2
toluene (50 cm ) was added dropwise to a stirred solution
2
2
2
of freshly prepared sodium methoxide (6.68 g, 123.6 mmol)
3
CHCOO), 40.1− (CHCHCO)O), 37.5− (CHCOO), 33.3+
CH CHCCO Me),
CHCHCOO) and
Me) (Found: C, 69.6; H, 7.30.
requires C, 69.5; H, 7.30%).
in toluene (250 cm ) at room temperature, and refluxed for
C=C), 33.0+ (CH
6.8+ (CH CHCHCOO), 22.6+ (CH
1.5+ (CH CH CHCCO
C=C), 29.0+ (CH
12 h. The mixture was quenched with dilute hydrochloric acid
2
2
2
2
3
3
2
2
CH
2
(150 cm ) and extracted with ether (3 × 50 cm ). The extract was
washed with distilled water (100 cm ), brine (100 cm ), dried
(MgSO ) and evaporated under reduced pressure to give an
3
3
2
2
2
16
H
20
O
4
4
1
5 6 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 5 5 7 – 1 5 6 7

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3
◦
impure mixture of cyclopropanes 8 and 16 (75 : 25 measured using
(30 cm ) were kept at −78 C for 0.5 h. Freshly distilled isoprene
3
d
H
3.59 of the major diastereoisomer and d
H
3.67 of the minor).
O–light petroleum,
(26.22 cm , 262 mmol) was added dropwise until the colour
disappeared, and methanol (53 cm , 1.31 mol) was added rapidly
3
The residue was chromatographed (SiO , Et
2
2
1
0 : 90) to give the pure mixture (7.34 g, 90%). Recrystallisation
but cautiously through the top of the condenser immediately
from n-pentane gave the pure major cyclopropane.
afterwards. The ammonia was allowed to evaporate, water
3
(
1
150 cm ) was added and the mixture extracted with ether (1 ×
Method D. The 88 : 12 diastereoisomeric mixture of bro-
momethyl dicarboxylates 10 and 15 (5.06 g, 13.6 mmol) in
3
3
00 cm and 3 × 50 cm ) to give the mixture of diesters (7.322 g,
3
96%; 76 : 24 measured using the same signals as before). The
toluene (50 cm ) was added dropwise to a stirred solution of
residue was crystallised from n-pentane; the mother liquor was
evaporated under reduced pressure and chromatographed (SiO2,
freshly prepared potassium tert-butoxide (4.31 g, 38.4 mmol)
3
◦
◦
in toluene (100 cm ) at 75 C, and kept at 40 C for 3 h. The
mixture was worked up as in Method C to give the mixture of
cyclopropanes (3.43 g, 87%; 88 : 12).
Et O–light petroleum, 2 : 98 to 10 : 90). Recrystallisation of the
2
combined crops gave the pure diester 19 (5.17 g, 68%) as needles,
◦
mp 83–84 C (from n-pentane); R
f
(Et
)/cm 2952 (C-H), 2866 (C–H) and 1731
(500 MHz; CDCl ) 3.65 (3 H, s, CO Me), 3.64 (3 H, s,
Me), 2.85 [1 H, d, J 3.0, C(4)H], 2.65 [1 H, m, C(3a)H], 2.61
1 H, m, C(6a)], 2.34–2.27 [4 H, m, C(6)H, C(5)H , C(1)H , and
], 1.97 [1 H, m,
], 1.86 [1 H, m, C(7)H ], 1.77 [1
], 1.72–1.64 [2 H, m, C(3)H and C(8)H ], 1.50–
1.39 [2 H, m, C(2)H and C(8)H ] and 1.33 [1 H, m, C(7)H ];
(125 MHz; CDCl
) 175.9+ (C=O), 173.3+ (C=O), 136.6+
C=C), 134.4+ (C=C), 51.4− (CO
Me), 51.2− (CO Me), 45.9−
C(6)], 45.8− [C(6a)], 45.1− [C(3a)], 43.7− [C(4)], 35.9+ [C(5)],
2
O–light petroleum, 1 :
Method E. Bromomethyl dicarboxylate 10 (5.12 g,
3.8 mmol) in toluene (50 cm ) was added to a stirred solution
−
1
3
1) 0.48; mmax(CDCl
C=O); d
CO
3
1
(
H
3
2
of freshly prepared potassium amyloxide (4.5 g, 51.2 mmol) in
3
◦
◦
2
toluene (100 cm ) at 70 C, and kept at 40 C for 5.5 h. The
[
b
A
mixture was worked up as in Method C to give the cyclopropane
C(9)H
C(5)H
A
], 2.17–2.12 [2 H, m, C(1)H
], 1.92 [1 H, m, C(3)H
H, m, C(2)H
B
, and C(9)H
B
8
(1.29 g, 32%).
a
A
A
meso-Dimethyl (3aR,4S,6R,6aS)-2,3,3a,4,5,6,6a,7,8,9-
decahydro-1H-cyclopenta[e]azulene-4,6-dicarboxylate 18
A
B
A
B
B
B
d
C
3
The flask, condenser and glass-coated stirrer bar were dried
twice with a heat gun under high vacuum before distilling
(
2
2
[
3
3
ammonia (250 cm ) into the flask. Lithium (290 mg, 41.8 mmol)
3.65+, 33.61+, 33.2+, 32.8+, 25.3+ [C(2)] and 25.1+ [C(8)]
was dissolved in the ammonia, and the mixture cooled to
(
Found: C, 69.8; H, 8.30. C17
H
O
24 4
requires C, 69.8; H, 8.25%).
◦
−
78 C under argon. The 75 : 25 diastereoisomeric mixture
3
of cyclopropanes 8 and 16 (1.319 g, 4.54 mmol) in ether (10 cm )
Equilibration of diesters 18 and 19
was added with stirring to the dark blue solution, and the
mixture kept for 0.5 h. Freshly distilled isoprene (5 cm , 51 mmol)
was added dropwise until the colour disappeared. The mixture
was quenched with ammonium chloride (8.64 g, 159 mmol) over
3
3
The racemic diester 19 (216 mg, 0.74 mmol) in methanol (10 cm )
and freshly prepared sodium methoxide (1 g, 18.5 mmol) in
3
methanol (13.5 cm ) were refluxed for 3 days under nitrogen.
3
3
3
0 s. The ammonia was allowed to evaporate, water (100 cm )
The mixture was quenched with dilute hydrochloric acid (8 cm )
3
was added and the mixture extracted with ether (3 × 30 cm ).
and most of the methanol was evaporated off under reduced
pressure. The remaining aqueous layer was extracted with ether
3
The extract was washed with brine (20 cm ), dried (MgSO
4
)
3
3
and evaporated under reduced pressure to give the mixture of
diesters (1.197 g, 90%; 70 : 30 measured using the signals at d
(4 × 5 cm ). The extract was washed with brine (8 cm ), dried
H
(MgSO ) and evaporated under reduced pressure. Traces of
4
3
.65 from both methoxy groups of the major diastereoisomer
solvents were removed under high vacuum to give the mixture
1
8 and one of those of the minor isomer 19, and d 3.64 from
H
of diesters (216 mg; 18 : 19 = 84 : 16 measured using the
same signals as before). Similarly, the meso diester 18 (459 mg,
8.5 mmol) gave the mixture of diesters (450 mg; 18:19 = 84 : 16),
and a 30 : 70 mixture of the diesters (140 mg, 0.48 mmol) also
gave the mixture of diesters (140 mg; 18 : 19 = 84 : 16).
the other methoxy signal of the minor isomer 19). The mixture
was crystallised from n-pentane to give the pure meso diester
◦
18 (479 mg, 36%) as plates, mp 68–69 C (from n-pentane);
−
1
R
f
(Et
2
O–light petroleum, 1 : 1) 0.40; mmax(CDCl
(500 MHz; CDCl
Me), 2.60 [2 H, m, C(3a)H and C(6a)H], 2.29
and C(9)H ], 2.17–2.06 [5 H,
, C(4)H, C(6)H and C(5)H ], 1.99 [1 H, dt,
J 13.5 and 12.0, C(5)H ], 1.89 [2 H, dt, J 12.5 and 6.0, C(3)H
and C(7)H ], 1.71 [2 H, m, C(2)H and C(8)H ] and 1.31 [2 H, m,
C(3)H and C(7)H ]; d (125 MHz; CDCl
) 175.7+ (2 × C=O),
3
)/cm 2953
(
(
C–H), 2863 (C–H) and 1731 (C=O); d
H
3
) 3.65
6 H, s, 2 × CO
2
Formation and reprotonation of the enolate of diester 18
[
2 H, dd, J 16.0 and 7.0, C(1)H
A
A
3
Dimethyl dicarboxylate 18 (0.848 g, 2.9 mmol) in THF (5 cm )
m, C(1)H , C(9)H
B
B
b
−
3
was added dropwise to a stirred solution of LDA (0.45 mol dm
a
A
3
◦
solution in THF–hexane, 6.44 cm , 2.9 mmol) at −78 C. After
h, the mixture was allowed to warm slowly up to room
temperature. The reaction was quenched by adding equal
A
A
A
1
B
B
C
3
1
4
2
36.8+ (2 × C=C), 51.5− (2 × CO
Me), 49.0− [C(4) and C(6)],
2
3
3
volumes (3 cm ) of it to four different solutions [MeOH (15 cm ),
5.8− [C(3a) and C(6a)], 36.8+ [C(5)], 33.85+, 33.80+ and
3
3
−3
3
+
MeOH–AcOH (15 cm : 0.05 cm ), HCl (3 mol dm , 60 cm )
3
4.8+ [C(2) and C(8)] (Found: M + Na , 315.1592. C17
H
24
O
4
and aqueous NH Cl (25 cm )] at room temperature and the
4
requires M + Na, 315.1572).
four solutions were stirred for 1 h. The methanolic solutions
Crystal data for 18.
C
˚
17
H
24O, M = 292.36, triclinic, space
3
were diluted with distilled water (15 cm ) and acidified where
¯
˚
˚
group P1, a = 9.6393(2) A, b = 9.6637(2) A, c = 17.7208(4) A,
◦
◦
◦
necessary. All four aqueous solutions were extracted with ether
a = 78.73(1) , b = 79.019(1) , c = 76.781(1) , U = 1557.50(6)
3
3
(
3 × 10 cm ), washed with brine (10 cm ), dried (MgSO
4
) and
3
−1
˚
A , Z = 4, l(Mo–Ka) = 0.087 mm , 9537 reflections measured
evaporated under reduced pressure. Traces of solvents were
removed under high vacuum to give the mixtures of diesters
at 180(2) K using an Oxford Cryosystems Cryostream cooling
apparatus, 3046 unique (Rint = 0.031); R
1
= 0.038, wR
2
=
(
18 : 19 = 69 : 31 from MeOH, MeOH–AcOH and aqueous
0.088 [I>2r(I)]. The structure was solved with SHELXS-97 and
NH Cl, and 62 : 38 from HCl). Recombined, the four samples
4
19
refined with SHELXL-97.
gave recovered diester (806 mg, 95%).
CCDC reference number 263439. See http://www.rsc.org/
suppdata/ob/b5/b502213d/ for crystallographic data in CIF
or other electronic format.
Dimethyl (2RS,4RS)-2-[(SR)-2-oxocyclopentyl]-4-[(RS)-2-
oxocyclopentyl]pentanedioate 23
Dimethyl (3aRS,4RS,6RS,6aRS)-2,3,3a,4,5,6,6a,7,8,9-
decahydro-1H-cyclopenta[e]azulene-4,6-dicarboxylate 19
A stream of ozone was bubbled through a solution of the diester
3
1
9 (2.064 g, 7.06 mmol) in freshly distilled acetone (133 cm )
3
3
Similarly, lithium (1.3 g, 187 mmol), ammonia (300 cm ) and the
and freshly distilled acetaldehyde (13.35 g, 17 cm , 0.3 mol) at
◦
mixture of cyclopropanes 8 and 16 (7.599 g, 26.17 mmol) in ether
−78 C. After the appearance of a faint blue colour, a stream
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 5 5 7 – 1 5 6 7
1 5 6 3

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of oxygen was passed through the solution for 10 min, and
triphenylphosphine (4.64 g, 17.7 mmol) was added. The mixture
up to room temperature, washed with dilute hydrochloric acid
3
(2 × 10 cm ), dried (MgSO
4
) and evaporated under reduced
pressure. Traces of solvent were removed under high vacuum
◦
was kept at −78 C for 1 h and at room temperature for 12 h.
The solvent was evaporated off under reduced pressure. The
to give crude O-mesylate (1.313 g, 99%) as a viscous, yellowish
residue was chromatographed (SiO
2
, EtOAc–light petroleum,
(EtOAc–
)/cm 2956 (CH),
878 (CH) and 1732 (C=O, coincident ketone and ester);
(500 MHz; CDCl ) 3.75 (3 H, s, CO Me), 3.70 (3 H, s, CO Me),
.90 (1 H, dt, J 10.0 and 5.0, CHCO Me), 2.77 (1 H, ddd,
Me), 2.52 (1 H, dt, J 12.0 and 7.0,
CHC=O), 2.39–2.29 (2 H, m, 2 × CH C=O), 2.29–2.02 (7 H,
m, CHCO, 2 × CH CHCHCO Me, 2 × CH
C=O and
CH
oil; R
f
(CH
2
Cl
2
–Et O, 6 : 4) 0.55. The crude mesylate was used
2
4
0 : 60) to give the diketone (2.236 g, 98%) as an oil; R
f
directly in the next step without further purification because
it partly rearranged during attempted purification. The O-
mesylate (1.313 g, 2.57 mmol) was stirred in a mixture of THF
(60 cm ) and distilled water (30 cm ) at 60 C for 24 h. Most of the
THF was evaporated off under reduced pressure. The remaining
aqueous solution was saturated with sodium chloride and
−
1
light petroleum, 6 : 4) 0.29; mmax(CDCl
3
2
d
2
3
3
◦
H
3
2
2
2
J 10.5, 6.5 and 4.0, CHCO
2
3
A
H
B
extracted with chloroform (5 × 10 cm ). The extract was dried
A
H
B
2
A
H
B
(K
2
CO ) and concentrated under reduced pressure. The residue
3
2
× CH
A
H
MeCH
B
2
C=O), 1.99 (1 H, ddd, J 14.0, 10.0 and 4.5,
was chromatographed (SiO
to give the bis-lactam (471 mg, 52%) as plates, mp 158–159 C
2
, MeOH–CH
2
Cl
2
, 5 : 95 to 20 : 80)
◦
CHCO
CHCO
CHCHCO
CDCl
1
2
A
H
B
), 1.89 (1 H, ddd, J 14.0, 10.0 and 4.0,
) and 1.86–1.65 (4 H, m, 2 × CH
CH CO); d (125 MHz;
) 218.1+ (C=O), 217.9+ (C=O), 175.0+ (CO
Me),
73.6+ (CO Me), 51.9− (CO Me), 51.8− (CO Me), 51.2−
CHCHCO Me), 43.4− (CHCO Me),
Me), 50.7− (CHCHCO
2.5− (CHCO Me), 38.0+ (CH
C=O), 37.9+ (CH C=O),
MeCH CHCHCO
), 26.9+ (CH
CHCH(CO CH
−
1
2
MeCH
A
H
B
A
H
B
-
(from THF); R
2952 (CH), 2922 (CH), 2853 (CH), 1734 (C=O, ester), 1663
(C=O, lactam) and 1453 (NH); d
(500 MHz; CDCl ) 6.28 (1 H,
br s, NH), 6.17 (1 H, br s, NH), 3.72 (3 H, s, CO Me), 3.71
(3 H, s, CO Me), 3.66 [1 H, m, CHCH(CO Me)], 3.62 [1 H,
m, CHCH(CO Me) and
Me)], 2.48–2.33 [4 H, m, 2 × CH(CO
2 × CH C(O)N], 2.31–2.21 [2 H, m, 2 × CH C(O)N],
1.95–1.82 [5 H, m, CH(CO Me)CH CH(CO Me),
CH CH C(O)N and CH CHCH(CO Me)], 1.81–1.62 [3
H, m, CHA* B*CHCH(CO CH C(O)N]
Me) and 2 × CH
and 1.56–1.45 [2 H, m, CHA* B*CHCH(CO Me) and
CH CHCH(CO Me)]; (125 MHz; CDCl
173.6+
(CO
Me), 172.9+ (CO
[C(O)N], 54.3− [CHCH(CO
52.32− (CO Me), 52.28− (CO
7.7− [CH(CO Me)], 31.2+ [2 × CH
Me)CH CH(CO
Me)], 25.28+ [CH CHCH(CO
C(O)N] and 19.3+ [CH CH C(O)N] (Found: M +
requires M + Na, 377.1689).
f
(MeOH–CH
2
Cl
2
, 1 : 9) 0.35; mmax(CDCl
3
)/cm
2
Me and 2 × CH
A
H
B
2
C
3
2
H
3
2
2
2
2
(
2
2
2
2
2
4
3
2
2
2
2
2
0.3+ (CHCO
2
2
2
2
Me), 26.2+
A
H
B
A
H
B
(
(
(
CH
CH
95%, M − C
2
2
Me), 20.53+ (CH
2
2
C=O) and 20.49+
2
2
2
2
×
+
C=O); m/z (ESI) 347 (100%, M + Na) and 279
H
H
2
CH
2
A
B
2
A
B
2
+
2
H
5
O) (Found: M + Na , 347.1472. C17
H
24
O
6
H
2
A
H
B
2
requires M + Na, 347.1471).
H
2
A
H
B
2
d
C
3
)
Dimethyl (2RS,4RS)-2-{(SR)-2-[(E)-hydroxyimino]
cyclopentyl}-4-{(RS)-2-[(E)-hydroxyimino]cyclopentyl}
pentanedioate 24
2
2
Me), 172.4+ [C(O)N], 172.3+
2
Me)], 54.2− [CHCH(CO
2
2
Me)],
Me)],
2
2
Me), 48.8− [CH(CO
4
2
2
C(O)N, 2 coinci-
Me)], 25.31+
Me)], 19.7+
The diketone (2.044 g, 6.3 mmol), hydroxylamine hydrochloride
dent peaks], 26.1+ [CH(CO
2
2
2
3
(
2.19 g, 31.51 mmol) and pyridine (2.0 cm , 1.99 g, 25.2 mmol)
◦
◦
[
[
CH
2
2
CHCH(CO
CH
2
2
2
3
were kept in ethanol (80 cm ) at 0 C for 2 days at 0 C. Most
of the ethanol was evaporated off under reduced pressure. The
CH
2
2
2
+
Na , 377.1674. C17
H
26
N
2
O
6
3
remaining solid was dissolved in warm chloroform (50 cm ) and
3
washed with dilute hydrochloric acid (2 × 20 cm ). The aqueous
(2RS,4RS)-2-[(SR)-Piperidin-2-yl]-4-[(RS)-piperidin-2-yl]
pentane-1,5-diol 26
3
layer was extracted with warm chloroform (2 × 15 cm ). The
combined organic layers were dried (K
2
CO ) and evaporated
3
The bis-lactam (455 mg, 1.28 mmol) and lithium aluminium
hydride (585 mg, 15.4 mmol) were refluxed in THF (55 cm )
for 12 h. The mixture was quenched sequentially with aqueous
potassium sodium tartrate (1.9 cm ), aqueous potassium hydrox-
under reduced pressure. The residue was chromatographed
3
(
SiO
2
, EtOAc–CH
2
Cl
2
, 80 : 20) to give the dioxime (1.185 g, 53%)
◦
as needles, mp 147–148 C (from CHCl
CH
2
7
2
3
–hexane); R
)/cm 3291 (OH), 2958 (CH),
876 (CH), 1727 (C=O) and 1684 (C=N); d
(500 MHz; CDCl
Me),
Me), 2.72 (1 H, q, J 7.0,
f
(EtOAc–
3
−
1
2
Cl
2
, 4:6) 0.18; mmax(CDCl
3
3
ide [15% (w/v), 1.9 cm ] and aqueous potassium sodium tartrate
H
3
)
3
◦
(
5 cm ) at 0 C. After stirring the resulting suspension for 0.5 h
.55 (2 H, br s, 2 × C=NOH), 3.67 (6 H, s, 2 × CO
2
at room temperature, the supernatant was decanted off and the
remaining inorganic salts were washed with dichloromethane
.83 (1 H, q, J 8.0, CHCHCO
2
CHCHCO
2
Me), 2.64–2.53 (4 H, m, 2 × CHCO
2
Me and
C=N),
Me)CH ),
Me), 1.89 (1 H, ddd, J
), 1.88–1.77 (3 H, m,
3
(
5 × 5 cm ). The combined extracts were dried (K
2
CO )
3
2
2
1
1
× CH
A
H
B
C=N), 2.38–2.27 (2 H, m, 2 × CH
A
H
B
and evaporated under reduced pressure. Traces of solvents
.07 (1 H, ddd, J 13.5, 11.5 and 3.0, CHCO
.95 (1 H, m, CH CHCHCO
3.5, 11.0 and 3.0, CHCO MeCH
B*CHCHCO
Me and 2 × CH
.48 (4 H, m, 2 × CH CH
C=N, CHA*
and CH CHCHCO Me); d
CO Me), 174.5+ (CO
Me), 166.39+ (C=N), 166.38+ (C=N),
1.71− (CO Me), 51.66− (CO Me), 45.5− (CHCO Me),
5.25− (CHCHCO Me), 45.23− (CHCHCO Me), 44.5−
Me), 30.4+ (CHCO MeCH ), 29.2+ (CH CHCH-
Me), 29.1+ (CH CHCHCO Me), 27.1+ (CH
C=N), 27.0+
CH CH
C=N), 22.3+ (CH C=N) and 22.1+ (CH C=N)
Found: M + Na , 377.1683. C17 requires M + Na,
77.1689).
2
A
H
B
were removed under high vacuum to give the diol (311 mg,
A
H
B
2
9
8
0%) as a viscous, oil; R
0 : 2.5) 0.26; mmax(CDCl )/cm 3418 (OH and NH), 2940
(500 MHz; CDCl ) 3.90
OH), 3.69–3.60 (2 H, m,
B*OH), 3.49 (1 H, dd, J 11.0 and 4.0, CH OH),
.03 (2 H, m, CH NH and CHA* B*NH), 2.75 (1H, dt,
J 11.0 and 2.5, CHNH), 2.60 (1 H, dd, J 6.0 and 3.0,
CHNH), 2.56–2.45 (2 H, m, CH NH and CHA*
CH and CHA*
CHCH, CHA*
NH and CHCH OHCH ), 1.43–1.25
OH, CH
CHCH, 2 × CH
, CH CH CH and CHA*
and 1.21 (1 H, q, J 9.0, CHA* B*CHCH); d
CDCl OH), 64.2+ (CH OH), 61.80− (CHNH),
) 64.9+ (CH
1.77− (CHNH), 47.3+ (CH NH), 47.1+ (CH NH), 42.09−
(CHCH OH), 30.8+ (CH CHCH),
OH), 42.07− (CHCH
CH CH) and
f
(RP-18, MeOH–H
2
O–TFA, 20 :
2
A
H
B
−
1
3
CHA*
H
2
A
H
B
CH
H
2
C=N) and 1.65–
B*CHCHCO Me
) 175.1+
(
(
CH), 2860 (CH) and 1642 (NH); d
1 H, d, J 11.0 and 2.5, CH
H
3
1
A
H
2
B
2
2
A
H
B
A
H
B
C
(125 MHz; CDCl
3
CHA*
3
H
A
H
B
(
2
2
A
H
B
H
5
4
2
2
2
2
2
A
H
B
H
B*NH),
B*CH
HB*CHCH,
(
CHCO
2
2
2
2
1
1
2
.85–1.77 (2 H, m, CH
.68 (6 H, m, CHCH OH, CH
× CH CH
A
H
B
CH
2
H
2
CH),
CO
2
2
2
2
2
A
H
B
(
(
CH
2
2
2
2
2
A
H
B
2
2
A
H
B
+
H
26
N
2
O
6
(
7 H, m, CHCH
2
A
H
B
B
A
H
B
CH
2
NH,
CH)
3
CHCH OHCH
2
A
H
B
A
H
2
H
B*CH
2
H
C
(125 MHz;
Dimethyl (2RS,4RS)-2-[(SR)-6-oxopiperidin-2-yl]-4-[(RS)-6-
oxopiperidin-2-yl]pentanedioate 25
3
2
2
6
2
2
3
Methanesulfonyl chloride (0.9 cm , 1.34 g, 11.65 mmol) was
2
2
2
3
added over 10 min to a stirred solution of triethylamine (2.2 cm ,
26.6+, 26.5+, 26.25+, 26.23+, 24.57+ (CH
2
2
+
1
.57 g, 15.5 mmol) and the dioxime (917 mg, 2.59 mmol) in
24.55+ (CH
2
CH
2
CH)); m/z (ESI) 293 (82%, M + Na) and
3
◦
+
dichloromethane (50 cm ) at −20 C under nitrogen, and the
253 (84%, M − OH) (Found: M + Na , 293.2198. C15
requires M + Na, 293.2205).
H
30
N
2
O
2
mixture kept for 0.5 h. The mixture was allowed to warm
1
5 6 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 5 5 7 – 1 5 6 7

View Article Online
3
(
± )-Sparteine 1
Following Oinuma, Dan and Kakisawa, the diaminodiol
37 mg, 0.137 mmol), triphenylphosphine (144 mg, 0.547 mmol),
mixture kept for 30 min. Acetic acid (0.1 cm ) was added and the
3
mixture stirred for 30 min. Distilled water (2 cm ) was added and
21
3
the mixture was extracted with ether (3 × 1 cm ). The extract was
(
dried (MgSO ) and evaporated under reduced pressure. Traces
4
3
carbon tetrachloride (40 mm , 63 mg, 0.410 mmol) and triethy-
lamine (76 mm , 55 mg, 0.547 mmol) were stirred in acetonitrile
(
of solvents were removed under high vacuum to give the diester
8 (5.5 mg, 100%), identical ( H NMR) with the earlier sample.
3
1
1
3
2 cm ) at room temperature for 18 h. The solvent was evaporated
off under reduced pressure and the residue was dried under
high vacuum for 2 h. Trifluoroacetic acid (53 mm , 78 mg,
3
(3aR,4S,6R,6aS)-2,3,3a,4,5,6,6a,7,8,9-Decahydro-1H-
cyclopenta[e]azulene-4,6-dicarboxylic acid anhydride 27
0
.684 mmol) and LiChroprep RP-18 (300 mg) were added to a
3
solution of the residue in dichloromethane (5 cm ). The solvent
was evaporated under reduced pressure and the remaining,
solvent-free LiChroprep RP-18 was loaded onto a column. Col-
umn chromatography gave (± )-sparteine as its bis-trifluoroacetic
Method A. 1,3-Dicyclohexylcarbodiimide (505 mg,
.45 mmol) in anhydrous dichloromethane (1.7 cm ) was added
3
2
to a stirred suspension of the meso-dicarboxylic acid (588 mg,
3
2
.22 mmol) in anhydrous THF (8 cm ), and the mixture kept
3
acid salt (LiChroprep RP-18, MeOH–H
2
O–TFA, 20 : 80 :
for 22 h. Ether (10 cm ) was added, the mixture was cooled in
an ice-bath for 0.5 h to precipitate insoluble dicyclohexylurea,
and filtered through a sinter. The filter cake was washed with
2
.5); R
f
(RP-18, MeOH–H O–TFA, 20 : 80 : 2.5) 0.17.
2
All product-containing fractions were combined, basified
with potassium hydroxide (350 mg, pH 15), extracted with
3
cold ethyl acetate (3 × 10 cm ). The filtrate was evaporated
3
dichloromethane (5 × 5 cm ) and dried (K
2
CO ). The extract
3
under reduced pressure to give the crude anhydride (600 mg) as
a yellow oil, which was used directly in the next step without
further purification.
was concentrated under reduced pressure to give (± )-sparteine
1
(
17 mg, 53%) as a pale yellow oil, identical (IR, H NMR
1
3
and C NMR) with a sample of (–)-sparteine (Aldrich);
−
1
3
mmax(CDCl
3
)/cm 2927, 2854, 2757, 1464, 1442, 1350, 1288,
Method B. Trifluoroacetic anhydride (5 cm , 7.35 g,
1
266, 1180, 1145, 1125, 1113, 1073, 1015, 974, 881, 844, 785
35 mmol) was added to the meso-dicarboxylic acid (557 mg,
2.12 mmol) under nitrogen at room temperature, and the mixture
refluxed for 1 h. The solvent was removed under reduced pres-
sure. Traces of trifluoroacetic acid and trifluoroacetic anhydride
were removed under high vacuum to give the crude anhydride
(555 mg) as a yellow oil, which was used directly in the next
22
and 734; d
C(15)H ], 2.74–2.64 [2H, m, C(17)H
J 11.0 and 2.5, C(10)H ], 2.33 [1 H, dd, J 11.0 and 3.5, C(17)H
.08–1.89 [5 H, m, C(8)H , C(15)H , C(10)H , C(11)H and
], 1.83 [1 H, m, C(9)H], 1.74–1.65 [3 H, m, C(6)H, C(4)H
H
(500 MHz; CDCl
3
)
2.78 [1 H, d (not first order),
and C(2)H ], 2.52 [1 H, dt,
],
A
A
A
A
B
2
A
B
B
C(2)H
B
A
A
−
1
and C(13)H
and C(7)H], 1.42–1.14 [5 H, m, C(5)H
C(13)H ] and 1.05 [1 H, dt, J 12.0 and 2.5, C(8)H
A
], 1.61–1.43 [6 H, m, C(3)H
2
, C(14)H
2
, C(12)H
step without further purification; mmax(CDCl )/cm 2924 (CH),
3
, C(12)H
B
, C(4)H
B
and
2855 (CH), 1847 (C=O, antisym.) and 1760 (C=O, sym.).
2
B
B
]; d
C
(125 MHz;
22
CDCl )
3
66.5− [C(6)], 64.4− [C(11)], 62.0+ [C(10)], 56.2+
Methyl (3aRS,4SR,6RS,6aSR)-2,3,3a,4,5,6,6a,7,8,9-
decahydro-1H-cyclopenta[e]azulene-4,6-dicarboxylate 28
[
3
2
C(2)], 55.4+ [C(15)], 53.6+ [C(17)], 36.1− [C(7)], 34.7+ [C(12)],
3.0− [C(9)], 29.3+ [C(5)], 27.6+ [C(8)], 25.9+ [C(3) or C(14)],
Freshly prepared sodium methoxide (862 mg, 15.96 mmol)
5.8+ [C(3) or C(14)], 24.8+ [C(4) or C(13)] and 24.7+ [C(4) or
3
+
in methanol (10 cm ) was added to the crude anhydride 27
C(13)] (Found: M , 234.2088. C15
H
26
2
N requires M, 234.2096).
(600 mg) under nitrogen at room temperature, and the mixture
was stirred for 0.5 h. The mixture was acidified with dilute
(
3aR,4S,6R,6aS)-2,3,3a,4,5,6,6a,7,8,9-Decahydro-1H-
3
3
hydrochloric acid (5 cm ) and extracted with ether (5 × 10 cm ).
cyclopenta[e]azulene-4,6-dicarboxylic acid
3
The extract was washed with brine (10 cm ), dried (MgSO
4
)
The diester 18 (723 mg, 2.47 mmol) and sodium hydroxide
and evaporated under reduced pressure to give the monoester
(531 mg, 86% from the dicarboxylic acid) as needles, mp
3
3
(
920 mg, 23 mmol) in distilled water (17 cm ) and ethanol (8 cm )
◦
were refluxed for 1 h. Most of the ethanol was distilled off under
reduced pressure, the remaining aqueous solution was acidified
with concentrated hydrochloric acid and extracted with ethyl
126–127 C (from hexane–CHCl
3
); R
)/cm 3453 (OH), 2949 (CH), 2937
(CH), 2861 (CH), 1733 (C=O, ester) and 1698 (C=O, acid);
(700 MHz; CDCl ) 3.66, (3 H, s, CO
Me), 2.60 (2 H, m, 2 ×
CHCHCOO), 2.30 (2 H, ddd, J 16.0, 5.0 and 2.0, CH
C=C),
2.20–2.09 (5 H, m, 2 × CHCOO, 2 × CH
C=C and
CHCO MeCH ), 2.01 (2 H, m, CHCO MeCH and
CH CHCHCOO), 1.89 (1 H, m, CHA* B*CHCHCOO),
1.72 (2 H, m, 2 × CH
C=C), 1.48–1.35 (3 H, m,
CH CHCHCOO and 2 × CH CH
C=C) and 1.32 (1 H,
tdd, J 12.0, 10.0 and 6.0, CHA* (175 MHz;
CDCl ) 180.8+ (CO H), 175.6+ (CO
Me), 137.1+ (C=C),
136.7+ (C=C), 51.6− (CO
Me), 48.92− CHCOO), 48.88−
(CHCOO), 45.9− (CHCHCOO), 45.5− (CHCHCOO),
MeCH CHCO
f
(Et
2
O–light petroleum,
−
1
1 : 1) 0.28; mmax(CDCl
3
3
3
acetate (5 × 10 cm ). The extract was washed with brine (10 cm ),
d
H
3
2
dried (MgSO ) and evaporated under reduced pressure. Traces
4
A
H
B
of solvent were removed under high vacuum to give the crude
A
H
B
◦
dicarboxylic acid (637 mg, 98%) as needles, mp 117–120 C (dec.)
2
A
H
B
2
A
H
B
−
1
(
from hexane–EtOH); mmax(film)/cm 3408 (OH), 2923 (CH),
851 (CH) and 1689 (C=O); d
(700 MHz; CD OD) 2.57 (2 H,
m, 2 × CHCHCOOH), 2.34 (2 H, ddd, J 16.0, 5.0 and 2.0, 2 ×
CH
C=C), 2.16 (2 H, m, CH C=C), 2.12 (1 H, dt, J 13.5
and 2.0, CHCOOHCH CHCOOH), 2.05 (2 H, td, J 11.0 and
.0, 2 × CHCOOH), 1.98 (2 H, m, CH CHCHCCOOH),
.94 (1 H, dt, J 13.5 and 12.0, CHCOOHCH CHCOOH),
.74 (2 H, m, CH CH
C=C) and 1.49–1.45 (4 H, m,
CHCHCCOOH and CH CH (175 MHz;
C=C); d
OD) 179.2+ (2 × C=O), 138.0+ (2 × C=C), 50.7−
CHCOOH), 47.0− (2 CHCHCOOH), 38.7+
CHCOOHCH CHCHCOOH),
CHCOOH), 35.1+ (2 × CH
4.8+ (2 × CH CH
Found: M + Na , 287.1253. C15
87.1259).
A
H
B
H
2
H
3
A
H
B
CH
2
A
H
B
A
H
B
2
A
H
B
A
H
B
H
B*CHCHCOO); d
C
A
H
B
3
2
2
2
1
1
A
H
B
2
A
H
B
A
H
B
2
36.7+ (CHCO
2
2
2
H), 33.91+ (2 coincident
2 2
CH
CD
A
H
B
A
H
B
2
C
peaks), 33.90+, 33.85+, 24.89+ (CH
CH
C=C) and 24.88+
+
(CH
2
CH
2
C=C) (Found: M + Na , 301.1418. C16
H
O
22 4
requires
3
(
(
3
(
2
2
×
×
M + Na, 301.1416).
2
2
C=C) and 25.9+ (2 × CH
C=C)
2
+
2
2
Methylation of monoester 28
H
20
O
4
requires M + Na,
−
3
3
Trimethylsilyldiazomethane (2.0 mol dm in hexane, 0.1 cm ,
0
.2 mmol) was added dropwise at room temperature to the
3
monoester 28 (5 mg, 0.02 mmol) in methanol (1 cm ) and
the mixture kept for 30 min. Acetic acid (0.1 cm ) was added
and the mixture stirred for 30 min. Distilled water (2 cm )was
Methylation of meso-dicarboxylic acid
3
−
3
3
3
Trimethylsilyldiazomethane (2.0 mol dm in hexane, 0.1 cm ,
3
0
0
.2 mmol) was added dropwise to the dicarboxylic acid (5 mg,
.02 mmol) in methanol (1 cm ) at room temperature, and the
added and the mixture was extracted with ether (3 × 1 cm ), the
3
extracts dried (MgSO ) and evaporated under reduced pressure.
4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 5 5 7 – 1 5 6 7
1 5 6 5

View Article Online
Traces of solvents were removed under high vacuum to give the
diester 18 (5.3 mg, 100%), identical ( H NMR) with the earlier
sample.
74.1+ (CH
44.5− (CHCHCH
OTs), 35.1+ (CHCH
CHCHCH
OTs), 33.1+ (CH
OTs), 25.6+ (CH CH
C=C), 24.9+ (CH
Me) and 21.59− (Me) (Found: C, 63.9; H, 6.65. C29
requires C, 63.9; H, 6.65%).
2
OTs), 68.8+ (CH
OTs), 37.3− (CHCH
OTsCH
), 33.8+ (CH
C=C), 32.0+ (CH
CH
2
OTs), 45.1− (CHCHCH
OTs), 35.7− (CHCH
C=C), 33.4+ (CH
CHCHCH
2
OTs),
1
2
2
2
2
2
-
-
-
2
2
2
2
2
2
C=C), 21.63−
Compounds prepared for another route
2
2
2
2
(
H
36 6 2
O
S
The following compounds were prepared in anticipation of a
route in which reduction of the esters preceded the ozonolysis
and Beckmann rearrangement.
(
3aRS,4RS,6RS,6aSR)-4,6-Bis(benzoyloxymethyl)-
,3,3a,4,5,6,6a,7,8,9-decahydro-1H-cyclopenta[e]azulene
2
(
3aRS,4RS,6RS,6aSR)-6-Hydroxymethyl-2,3,3a,4,5,6,6a,7,8,9-
decahydro-1H-cyclopenta[e]azulen-4-ylmethanol
The diol (404 mg, 1.71 mmol), benzoyl chloride (1.2 g,
3
3
◦
8
1
.55 mmol, 1 cm ) and pyridine (5 cm ) were kept at 0 C for
3
Diester 19 (0.117 g, 0.4 mmol) in ether (5 cm ) was added
3
h. The mixture was diluted with distilled ice-water (15 cm )
dropwise to a stirred solution of lithium aluminium hydride
3
and extracted with ether (3 × 20 cm ). The extract was washed
3
(
91 mg, 2.4 mmol) in ether (5 cm ) maintaining a gentle reflux,
3
with dilute hydrochloric acid (2 × 10 cm ), aqueous sodium
and the mixture kept for 1 h at room temperature. The mixture
was quenched with ice-water, made homogeneous with dilute
3
3
3
hydrogencarbonate (5 cm ), water (5 cm ), brine (5 cm ), dried
(
MgSO
was chromatographed (SiO
95) to give the dibenzoate (721 mg, 95%) as an oil; R
4
) and evaporated under reduced pressure. The residue
, Et O–light petroleum, 2 : 98 to 5
(Et O–
)/cm 2865 (CH), 1725
O) and 1610 (Ph); d (500 MHz; CDCl ) 7.97 (2 H, d, J
3
hydrochloric acid and extracted with ether (6 × 5 cm ). The
3
2
2
extract was washed with brine (10 cm ), dried (MgSO
4
) and
:
f
2
evaporated under reduced pressure. The residue was chro-
−
1
light petroleum, 1 : 1) 0.65; mmax(CDCl
3
matographed (SiO
2
, MeOH–CH
2
Cl
2
, 10 : 90) to give the diol
(C
.0, o-H), 7.95 (2 H, d, J 8.0, o-H), 7.50 (2 H, q, J 7.0, 2 ×
=
H
3
◦
(87.2 mg, 92%) as needles, mp 117.5–118.5 C (from hexane–
8
−
1
EtOH); R
OH); d (500 MHz; CD
.46 (2 H, m, 2 × CH
.29–2.26 (4 H, m, CHCHCH
OHCH
f
(MeOH–CH
2
Cl
OD) 3.58 (2 H, m, 2 × CH
OH), 2.69 (1 H, m, CHCHCH
OH, 2 × CH
CH), 2.07–2.05 (3 H, m, 2 × CH
CHCHCH OH), 1.92–1.89 (2 H, m, CHCH
B*CHCHCH
2
, 1 : 9) 0.38; mmax(CDCl )/cm 3458
3
p-H), 7.36–7.29 (4 H, m, 2 × m-H), 4.40 (1 H, dd, J 11.0 and
(
3
2
H
3
A
H
B
OH),
OH),
4
4
7
.5, CH
.30 (1 H, t, J 11.0, CH
B*OBz), 2.81 (1 H, m, CHCHCH
OBz, CHCH
OBz, 2 × CH
OBz), 2.18–2.04 (3 H, m, 2 × CH
B*CHCHCH OBz), 1.99 (1 H, m, CHCH
) 1.82–1.64 (5 H, m, CHCH OBz, CHA*
OBz, CH CH B*CH
C=C, CHA* C=C and CHCH
CH ), 1.54–1.42 (2 H, m, CH CHCHCH OBz and
CH
C=C) and 1.37 (1 H, m, CH C=C);
(125 MHz; CDCl
A
H
B
OBz), 4.34 (1 H, dd, J 11.0 and 3.0, CHA*
OBz), 4.17 (1 H, dd, J 11.0 and
OBz), 2.48–2.26
HB*OBz),
A
H
B
2
A
H
B
H
B
C=C and
A B
2
A
.0, CHA*
H
2
CHCH
and CH
2
A
H
B
H
C=C
(
5 H, m, CHCHCH
2
2
A
H
B
C=C and
A
H
B
2
2
OH
CH CHCHCH
and CHA*
CH
A
H
B
2
H
A B
C=C
and CHA*
H
2
OH), 1.73 (2 H, m, 2 × CH
B*CHCHCH
, CHCH
CH
C=C); d
A
B
H -
H
2
2
OBz-
CH
2
C=C), 1.64 (1 H, m, CHA*
H
OHCH
2
OH) and 1.54–
OH, CH
(125 MHz;
OH),
OH), 46.5− (CHCH-
OH), 39.8− (CHCH OH), 35.0+
), 34.9+ (CH CHCHCH OH,
C=C and CH
coincident peaks], 34.0+ (CH CHCH-
C=C), 33.2+ (CH
CH OH), 26.9 (CH CH CH
C=C) and 26.3 (CH C=C)
Found: C, 76.2; H, 10.10. C15 requires C, 76.2; H, 10.25%).
A
H
B
2
H
B*CHCHCH
2
-
1
.30 (5 H, m, CHCH
2
A
H
B
2
A
B
H -
A
H
B
2
H
2
2
OBz-
CHCHCH
CD
1.5+ (CH
CH
OH), 42.0− (CHCH
CHCH OHCH
2
OH and 2 × CH
A
H
B
2
C
A
H
H
B
A
H
B
2
OD) 137.1+ (C=C), 136.3+ (C=C), 67.2+ (CH
3
2
CHA*
d
B*CH
2
A
H
B
2
6
2
OH), 47.4− (CHCHCH
2
) 166.8+ (C=O), 166.7+ (C=O), 136.3+
C
3
2
2
2
(
(
1
C=C), 135.3+ (C=C), 132.8− (p-C), 132.7− (p-C), 130.34+
(
2
2
2
2
2
ipso-C), 130.33+ (ipso-C), 129.5− (2 × o-C), 129.4− (2 × o-C),
2
2
28.4− (2 × m-C), 128.3− (2 × m-C), 69.1+ (CH
2
OBz), 64.0+
OBz),
CHCH-
OBz), 33.2+ (2 × CH
C=C,
OBzCH CH
), 25.8+ (CH
C=C) (Found: M + Na , 467.2203.
requires M + Na, 467.2198).
2
2
2
2
2
(
3
CH
CH
2
OBz), 45.9− (CHCHCH
7.5− (CHCH OBz), 36.1− (CHCH
OBz), 33.8+ (CH CHCHCH
coincident peaks), 32.2+ (CHCH
C=C) and 25.3+ (CH
CH
2
OBz), 45.7− (CHCHCH
OBz), 34.0+ (CH
2
2
(
H
24
O
2
2
2
2
2
2
2
(
2
3aRS,4RS,6RS,6aSR)-4,6-Bis(toluene-p-sulfonyloxymethyl)-
,3,3a,4,5,6,6a,7,8,9-decahydro-1H-cyclopenta[e]azulene
2
2
2
2
-
+
2
2
The diol (80 mg, 0.34 mmol), p-methylbenzenesulfonyl chloride
C
29
H
32
O
4
3
(
0.142 g, 0.74 mmol) and pyridine (95 mg, 1.2 mmol, 0.1 cm )
3
were kept in ethanol-free chloroform (5 cm ) for 1 h. The
mixture was diluted with ether (10 cm ) and washed with dilute
Acknowledgements
3
3
3
3
hydrochloric acid (5 cm ), water (5 cm ), brine (5 cm ), dried
MgSO ) and evaporated under reduced pressure. The residue
was chromatographed (SiO , Et O–light petroleum, 30 : 70)
We thank the SOKRATES programme of the European Union
(SG), the Korea Science and Engineering Foundation (Grant
No. R01-2001-000-00053-0) (HGW), the Studienstiftung des
Deutschen Volkes and the Bill and Melinda Gates Foundation
for Fellowships (TB), StylaCats Limited for a gift of dicyclopen-
tenyl, and Robert Richardson for the calculations, carried out
using MacroModel (version 8.0) and the MM2 forcefield.
(
4
2
2
to give the ditosylate (0.152 g, 82%) as needles, mp 100.5–
◦
1
m
01.5 C (from EtOH); R
f
(Et
)/cm 2869 (CH), 1598 (Ph), 1355 (SO
and 1179 (SO O, sym.); d (500 MHz; CDCl ) 7.78 (2 H, d, J
.0, 2 × o-Ts), 7.75 (2 H, d, J 8.0, 2 × o-Ts), 7.36 (2 H, d, J
.0, 2 × m-Ts), 7.33 (2 H, d, J 8.0, 2 × m-Ts), 4.04 (1 H, dd,
OTs), 3.93 (1 H, t, J 10.0, CH OTs),
.87 (1 H, dd, J 9.0 and 5.0, CH OTs), 3.77 (1 H, dd,
OTs), 2.60 (1 H, m, CHCHCH OTs),
2
O–light petroleum, 1 : 1) 0.32;
−
1
max(CDCl
3
2
O, antisym.)
2
H
3
8
8
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