The synthesis of (-)-cis- and (-)-trans-crobarbatic acid

Article abstract of DOI:10.1016/S0957-4166(99)00097-X

The synthesis of both cis- and trans-crobarbatic acid is reported. The five-step sequence proceeds in high yield and with control of both relative and absolute stereochemistry. The key step in the synthesis is the Birch reductive alkylation of a chiral furoic acid which sets the absolute stereochemistry of the products. The stereochemistry of the compounds described was proven unambiguously by X-ray crystallography on one synthetic intermediate and on trans-crobarbatic acid.

Full text of DOI:10.1016/S0957-4166(99)00097-X

Pergamon
Tetrahedron: Asymmetry 10 (1999) 1315–1322
The synthesis of (−)-cis- and (−)-trans-crobarbatic acid
a,∗
a
a,†
a,†
Timothy J. Donohoe, Clare A. Stevenson, Madeleine Helliwell, Ranah Irshad and
Tamara Ladduwahetty b
a
Department of Chemistry, The University of Manchester, Oxford Road, Manchester, M13 9PL, UK
Merck Sharp and Dohme, Neuroscience Research Centre, Terlings Park, Harlow, Essex, CM20 2QR, UK
b
Received 2 March 1999; accepted 12 March 1999
Abstract
The synthesis of both cis- and trans-crobarbatic acid is reported. The five-step sequence proceeds in high yield
and with control of both relative and absolute stereochemistry. The key step in the synthesis is the Birch reductive
alkylation of a chiral furoic acid which sets the absolute stereochemistry of the products. The stereochemistry of
the compounds described was proven unambiguously by X-ray crystallography on one synthetic intermediate and
on trans-crobarbatic acid. © 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
The pyrrolizidine alkaloids are widespread in nature and can be found in many different plant
1
species; several of these alkaloids have interesting pharmacological properties such as hepatotoxicity
1
and carcinogenic activity. Pyrrolizidine alkaloids have been implicated in the poisoning of livestock and
2
are thought to be used by both plants and insects as protection against predators. In terms of structure,
pyrrolizidine alkaloids consist of two halves, joined through ester linkages. Cleavage of the esters under
standard conditions gives a pyrrolidizine diol (known as a necine base) and a diacid (necic acid). In view
of the interesting structure and manifold biological activity of these alkaloids, we aim to undertake the
synthesis of several of them using a flexible strategy. And, as the parent necine base (retronecine) is
3
common to many of these alkaloids and is available from natural sources, we wish to concentrate on the
necic acid moiety.
trans-Crobarbatic acid is the hydrolysis product of the alkaloid crobarbatine and represents the cyclised
4
form of the necic acid of this alkaloid. Although the relative stereochemistry of crobarbatic acid obtained
5
from natural sources is known, the absolute configuration and specific rotation are not; consequently, the
∗
†
Corresponding author. E-mail: t.j.donohoe@man.ac.uk
Authors to whom correspondence regarding the X-ray crystal structures should be addressed.
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00097-X

1316
T. J. Donohoe et al. / Tetrahedron: Asymmetry 10 (1999) 1315–1322
identity of crobarbatine is ambiguous with respect to the necic acid moiety (Scheme 1). The cis-isomer
of crobarbatic acid was originally isolated from the degradation of jaconecic acid with lead tetraacetate;
the absolute stereochemistry of the material thus produced was proven to be as shown.6
Scheme 1.
We decided to embark on a synthesis of crobarbatic acid using recently developed methodology
7
involving the Birch reduction of furans. Our route was designed to be short and also to be flexible
enough to produce any stereoisomer of the target at will.
2. Results and discussion
The synthesis began with commercially available 3-methyl-2-furoic acid 1 which was coupled to (S,S)-
bis(methoxymethyl)pyrrolidine under standard conditions (Scheme 2). The amide 2 was then subjected
to a Birch reductive alkylation reaction (quenching with methyl iodide) under our previously reported
conditions. This reaction proceeded in excellent yield and gave 3 with a 30:1 level of diastereoselectivity.
The diastereoselectivity of this step was assessed by GC in comparison with an authentic (1:1) mixture
of diastereoisomers; we were sure of the relative stereochemistry of the adduct from previous studies.
1
The H NMR spectrum of 3 clearly shows a multiplet attributable to one vinyl proton at δ 5.4 and does
not contain any resonances pertaining to a furan nucleus at δ 6–7. Allylic oxidation of 3 took place with
Jones’ reagent to give the lactone 4 in good yield (Scheme 2). The identity of 4 was most clear from
−1
IR spectroscopy (C_O at 1765 and 1627 cm ). The lactone was then hydrogenated with the aim of
investigating the stereoselectivity of the process (Table 1).
Reduction with either platinum or rhodium catalysts essentially gave a 1:1 mixture of the two
diastereoisomers (Table 1); an increase in pressure did little to alter the ratio. This lack of selectivity was,
as expected, based upon steric considerations. Fortunately, the two diastereoisomers were easily separable
on a silica column and a reasonable yield of trans-5 (50%) was thus obtained. Changing the metal catalyst
to palladium resulted in an immediate shift in the selectivity of the reaction, with cis-5 now being the
preferred product. An increase in pressure improved the ratio and enabled the isolation of cis-5 in good
8
(
83%) yield. The sense of the diastereoselectivity obtained with palladium is unusual; we presume that
the stereoselectivity originates from association between the polar amide group and the metal surface,
9
forming the cis-isomer preferentially. The literature contains some examples of polar groups directing
heterogeneous hydrogenation with palladium catalysis, although homogeneous catalysis with Crabtree’s
10
catalyst [Ir(cod)py(PCy )]PF is more commonly used in conjunction with amide directing groups.
3
6
The spectroscopic data obtained from cis- and trans-5 clearly showed that reduction of the alkene had
−1
1
occurred, IR of both isomers showed C_O at 1621 and 1785 cm , while H NMR revealed a (3H)
doublet for the C-4 methyl group at δ 1.28 (cis) and 1.05 (trans). The relative stereochemistry of these
two diastereoisomers was assigned by X-ray crystallography (Fig. 1).

T. J. Donohoe et al. / Tetrahedron: Asymmetry 10 (1999) 1315–1322
1317
Scheme 2.
Table 1
Ratio of cis:trans-5 was determined by GC on the crude reaction mixture
Figure 1. X-Ray crystal structures of cis-5 and trans-crobarbatic acid

1318
T. J. Donohoe et al. / Tetrahedron: Asymmetry 10 (1999) 1315–1322
All that remained to complete the synthesis was removal of the chiral auxiliary. This was accomplished
by heating cis-5 and trans-5 (separately) in aqueous acid in a high yielding protocol (Scheme 3). We know
that the Birch reduction proceeded with 30:1 stereoselectivity and, as racemisation under this sequence
7
is extremely unlikely, both isomers of crobarbatic acid are formed in ≥94% ee.
Scheme 3.
The structure of cis-5 and trans-crobarbatic acid was proven unambiguously by X-ray crystallography
(Fig. 1). As we know the absolute stereochemistry of the amine auxiliary used in this sequence, these
two structures prove the relative and absolute stereochemistry of all the compounds shown in Schemes 2
and 3.
Although we have prepared the antipode of cis-crobarbatic acid, compared to the material originally
isolated, the amine auxiliary is commercially available as either enantiomer and so (+)-cis-crobarbatic
acid could be produced with ease using this sequence.
The trans-crobarbatic acid displayed spectroscopic and physical data that was very similar to that
5
1
reported in the literature. We found that the H NMR spectra of the cis- and trans-acids did not
show much distinction between them; however, as the two 13C NMR spectra differed enough, a definite
correlation (all peaks within ꢀ0.5 ppm) could be made with our data for the trans-acid and that reported
5
by Meinwald.
There has been only one report in the literature that correlates the absolute stereochemistry of trans-
crobarbatic acid with the sign of its specific rotation: Honda and co-workers prepared the (4R,5S)
11
enantiomer and reported a specific rotation, [α]D +3.45 (c=0.4 in H O). However, we have also
2
prepared the (4R,5S) enantiomer and found that its rotation, [α]D −3.7 (c=1.4 in H O), was of an
2
opposite sign to that reported earlier. It is worth pointing out, however, that arguments based on such
small rotations are weak ones and that we did find some variation in rotation of trans-crobarbatic acid at
varying concentrations {although each rotation measured was always negative, e.g. [α] −8.0 (c=0.2 in
D
H O)}.
2
To conclude, we have prepared cis- and trans-crobarbatic acid in five steps with an overall yield of
66% for the cis-isomer and 40% for the trans-isomer. This chemistry fulfils our objective of being able
to prepare any stereoisomer of crobarbatic acid and allows the preparation of substantial quantities of
material for further synthetic studies.
3. Experimental
Proton nuclear magnetic resonance spectra (NMR) were recorded on a Bruker AC300/Varian XL300
13
at 300 MHz. C Nuclear magnetic resonance spectra were recorded on an AC300/Varian XL300 at 75
MHz. Spectra were recorded in deuterated chloroform unless otherwise indicated. Peak multiplicities are
abbreviated as follows: singlet (s); doublet (d); triplet (t); quartet (q); multiplet (m). Chemical shifts are
quoted in parts per million (ppm), downfield from Me Si. Coupling constants (J) are quoted in hertz.
4
Infrared spectra (IR) were recorded on an ATI Mattson Genesis FTIR as evaporated films: points of

T. J. Donohoe et al. / Tetrahedron: Asymmetry 10 (1999) 1315–1322
1319
maximum absorption (νmax) are recorded. Optical rotations were recorded on an Optical Activity Ltd
−
1
2
−1
AA-100 polarimeter and [α] values (all reported at 21°C) are given in units of 10 deg cm g ;
D
concentration c in units of g/100 ml. Mass spectra were recorded on a Kratos Concept or a Fisson VG
Trio 2000; chemical ionisation (CI) was performed using NH . Gas chromatography (GC) was carried
3
out using a CP-Chirasil DEXCB column (25 m×0.32 mm, 0.28 µ) controlled by a Shimadzu Cromatopac
R4AX unit.
All reactions were carried out under an atmosphere of dry nitrogen. All solvents and reagents
requiring purification were purified using standard laboratory techniques according to methods pu-
blished in Purification of Laboratory Chemicals by Perrin, Armarego and Perrin, Pergamon Press,
1
966. Tetrahydrofuran (THF) was dried and distilled from sodium metal using benzophenone as an
indicator. Dichloromethane (DCM) was distilled over calcium hydride. Petroleum ether (boiling range
0–60°C) was distilled prior to use. Ammonia was distilled from sodium metal and ferric chloride. (+)-
Bis(methoxymethyl)pyrrolidine was purchased from Oxford Asymmetry.
4
0
0
3
.1. (2 S,5 S)-2-(Bismethoxymethylpyrrolidinyl)carbonyl-3-methylfuran 2
Thionyl chloride (12 ml, xs) was added to 1 (2.39 g, 19.0 mmol) and the resulting dark mixture heated
at reflux for 3 h. Excess thionyl chloride was then removed under reduced pressure, azeotroping with
toluene. To the brown liquid was added dichloromethane (10 ml), and this solution was then added
dropwise to a stirred mixture of (S,S)-bis(methoxymethyl)pyrrolidine (3.32 g, 21.0 mmol), 2 M aq.
sodium hydroxide (40 ml, 80 mmol) and dichloromethane (40 ml) at 0°C. The mixture was allowed
to warm to room temperature and stirred overnight. The dichloromethane was then removed under
reduced pressure, and the residue extracted into ethyl acetate (4×75 ml). The combined organics were
then dried (MgSO ) and evaporated to dryness under reduced pressure to yield a brown oil. The crude
4
product was purified by column chromatography on silica, eluting with 25% ethyl acetate/petrol to
+
give the title compound as a pale yellow oil (4.6 g, 91%). [α] −123.8 (c=0.64 in EtOH); found: M
D
+
−1
2
67.1478, C H NO requires M , 267.1471; νmax/cm 1617 (C_O); δ (300 MHz) 7.25 (1H, d, J 1.5,
OCH_CH), 6.25 (1H, d, J 1.5, OCH_CH), 4.74–4.64 (1H, m, CONCH), 4.48–4.37 (1H, m, CONCH),
14
21
4
H
3
.48 (1H, dd, J 9.0 and 3.0, CH OCH ), 3.35–3.23 (1H, m, CH OCH ), 3.26 (3H, s, CH OCH ),
2A 3 2B 3 2 3
3
.12 (3H, s, CH OCH ), 3.04–2.88 (2H, m, CH OCH ), 2.25 (3H, s, C_CCH ) and 2.20–1.79 (4H, m,
2
3
2
3
3
CH CH ); δ (75 MHz, CDCl ) 159.5, 142.9, 141.5, 128.5, 114.8, 73.7, 71.8, 58.9, 58.8, 57.4, 57.0,
2
2
C
3
+
2
7.3, 23.9 and 11.5; m/z (CI) 268 (M+H , 100%).
0
0
3
.2. (2S,2 S,5 S)-2-(Bismethoxymethylpyrrolidinyl)carbonyl-2,3-dimethyl-2,5-dihydrofuran 3
A solution of 2 (1.0 g, 3.7 mmol) in THF (15 ml) was added to ammonia (200 ml) at −78°C under
N . Freshly cut sodium (258 mg, 11 mmol) was then added, and the mixture stirred at −78°C for 30
2
min, during which time the solution became blue. Isoprene was then added dropwise to disperse the blue
colour, followed immediately by methyl iodide (700 µl, 11 mmol), which resulted in the yellow solution
becoming colourless. After stirring for a further 40 min, the reaction was quenched by the addition of
solid ammonium chloride (0.5 g) and the stoppers removed from the reaction flask to allow evaporaton
of ammonia. The residual tetrahydrofuran was removed under reduced pressure and the crude product
was purified by column chromatography on silica, eluting with 25% ethyl acetate/petrol to afford the
+
title compound as a yellow oil (1.04 g, 98%). [α] −107.1 (c=2.0 in EtOH); found: M+H , 284.1853.
D
−1
+
C H NO requires M+H , 284.1862; νmax/cm 1621 (C_O); δH (300 MHz) 5.48–5.45 (1H, m,
CH_CCH ), 4.67 (1H, m, NCH), 4.57–4.53 (2H, m, OCH CH_C), 4.23 (1H, m, NCH), 3.45 (1H,
15
25
4
3
2

1320
T. J. Donohoe et al. / Tetrahedron: Asymmetry 10 (1999) 1315–1322
dd, J 9.0 and 3.0, CH OCH ), 3.30–3.09 (2H, m, CH OCH ), 3.27 (3H, s, OCH ), 3.21 (3H, s, OCH ),
2A
3
2
3
3
3
2
.97 (1H, t, J 9.0, CH OCH ), 2.12–1.74 (7H, m, C_CCH , CH CH ) and 1.44 (3H, s, OCCH ); δ
2B
3
3
2
2
3
C
(75 MHz) 172.1, 140.9, 120.3, 93.3, 74.0, 73.0, 71.3, 58.7, 58.6, 57.9, 57.6, 27.3, 25.9, 23.3 and 12.7;
+
m/z (CI) 284 (M+H , 100%).
0
0
3
.3. (5S,2 S,5 S)-5-(Bismethoxymethylpyrrolidinyl)carbonyl-4,5-dimethyl-5H-furan-2-one 4
To a solution of 3 (500 mg, 1.76 mmol) in acetone (10 ml) at room temperature, was added chromium
dioxide (2 M in 2 M aq. sulfuric acid, 2.7 ml, 5.3 mmol) and the brown solution was stirred at room
temperature overnight. Acetone was then removed under reduced pressure and the residue dissolved in
ethyl acetate (50 ml), and washed with 2 M aq. hydrochloric acid (5 ml) then 5% aq. sodium bicarbonate
(5 ml) then evaporated under reduced pressure. The crude bright orange material was purified by column
chromatography on silica, eluting with 30% ethyl acetate/petrol to give the title compound as a colourless
+
+
oil (470 mg, 90%). [α] −176.0 (c=1.89 in EtOH); found: M+H , 298.1663, C H NO requires M+H ,
D
15 23
5
−1
2
98.1654; νmax/cm 1765 (C_O) and 1627 (C_O); δ (300 MHz) 5.84 (1H, m, J 1.5, CH_CCH ),
.83 (1H, m, NCH), 4.38–4.28 (1H, m, NCH), 3.51 (1H, dd, J 9.0 and 2.5, CH OCH ), 3.37 (3H, s,
H
3
4
2A
3
CH OCH ), 3.23 (3H, s, CH OCH ), 3.44–3.12 (2H, m, CH OCH ), 3.00 (1H, m, CH OCH ), 2.29
2
3
2
3
2
3
2B
3
(
1
3H, d, J 1.5, CH_CCH ), 2.28–1.80 (4H, m, CH CH ) and 1.74 (3H, s, OCCH ); δ (75 MHz) 171.6,
3
2
2
3
C
+
71.3, 168.3, 116.1, 90.0, 73.9, 71.4, 58.9, 58.5, 58.4, 57.6, 27.2, 26.6, 24.0, 14.8; m/z (CI) 298 (M+H ,
100%).
0 0
.4. (4S,5S,2 S,5 S)-5-(Bismethoxymethylpyrrolidinyl)carbonyl-4,5-dimethyldihydrofuran-2-one cis-5
and (4R,5S,2 S,5 S)-5-(bismethoxymethylpyrrolidinyl)carbonyl-4,5-dimethyldihydrofuran-2-one trans-5
3
0
0
Compound 4 (490 mg, 1.6 mmol) and rhodium (5% on carbon, 50 mg) were stirred in ethanol (40
ml) and acetic acid (5 ml) under 1 atm of hydrogen overnight. The catalyst was removed by filtration
through Celite, and the solution evaporated to dryness under reduced pressure to give the crude product
as a yellow oil. Column purification on silica, eluting with 20% ethyl acetate/petrol afforded the two
diastereoisomers, (−)-cis-5: 223 mg (45%) and (−)-trans-5: 246 mg (50%), both as colourless oils.
Compound (−)-cis-5 crystallised on standing at −10°C: [α]D −38.4 (c=1.8 in EtOH); found: C,
+
6
0.30; H, 8.46; N, 4.54%, C H NO requires C, 60.18; H, 8.42; N, 4.68%. Found M+H , 300.1813,
1
5
25
5
+
−1
C H NO requires M+H , 300.1811; νmax/cm 1784 (C_O) and 1621 (C_O); δ (300 MHz) 4.73
1H, m, NCH), 4.30 (1H, m, NCH), 3.51 (1H, dd, J 9.0 and 2.5, CH OCH ), 3.43–3.24 (8H, m,
15
25
5
H
(
2A 3
CH OCH and 2×CH OCH ), 3.22–3.14 (1H, m, CH OCH ), 3.12–2.98 (1H, m, CH CHCH ), 2.62
2
3
2
3
2B
3
2
3
(
1H, dd, J 17.5, 9.0, COCH ), 2.20 (1H, dd, J 17.5 and 10.0, COCH ), 2.27–1.78 (4H, m, CH CH ),
2A B 2 2
1
.50 (3H, s, OC(CH )) and 1.28 (3H, d, J 7.0, CHCH ); δ (75 MHz) 174.8, 172.4, 88.4, 74.5, 71.3,
3
3
C
+
58.8, 58.7, 58.2, 57.4, 36.6, 35.6, 27.4, 24.2, 21.5 and 15.7; m/z (CI) 300 (M+H , 100%).
+
Compound (−)-trans-5: [α] −64.9 (c=0.8 in EtOH); found: M+H , 300.1811, C H NO requires
D
15 25
5
+
−1
M+H , 300.1811; νmax/cm 2976 (C–H), 1785 (C_O) and 1621 (C_O); δ (300 MHz) 4.51 (1H, m,
NCH), 4.24 (1H, m, NCH), 3.47 (1H, dd, J 9.0 and 2.5, CH OCH ), 3.38–3.14 (9H, m, CH OCH ,
H
2A
3
2B
3
CH OCH and 2×CH OCH ), 2.81 (1H, dd, J 17.5 and 8.0, COCH ), 2.69–2.57 (1H, m, CHCH ),
2
3
2
3
2B
3
2
7
2
.13 (1H, d, J 17.5, COCH ), 2.08–1.74 (4H, m, CH CH ), 1.54 (3H, s, OCCH ) and 1.05 (3H, d, J
2A 2 2 3
.0, CH(CH )); δ (75 MHz, CDCl ) 175.1, 169.5, 89.5, 74.9, 71.0, 58.7, 57.2, 38.4, 35.8, 27.3, 27.0,
3
C
3
+
4.0 and 17.3; m/z (CI) 300 (M+H , 100%).
Compound 4 (446 mg, 1.5 mmol) was dissolved in ethanol (10 ml) and acetic acid (1 ml) and 10%
palladium hydroxide (50 mg) was added. The mixture was shaken at 55 psi of hydrogen overnight, and

T. J. Donohoe et al. / Tetrahedron: Asymmetry 10 (1999) 1315–1322
1321
the catalyst was filtered off through Celite. The solvent was removed under reduced pressure to give
the crude product as an orange oil. Column purification on silica, eluting with 20% ethyl acetate/petrol
afforded (−)-cis-5 as a colourless oil (372 mg, 83%).
3.5. (4S,5S)-cis-Crobarbatic acid
Compound (−)-cis-5 (125 mg, 0.42 mmol) was heated at reflux for 4 h in 6 M aq. hydrochloric acid
(
2 ml). The reaction mixture was extracted into ethyl acetate (4×25 ml) and the combined organics
dried (MgSO ) and evaporated to dryness under reduced pressure to give the crude product as a white
4
solid. Recrystallisation from dichloromethane/petrol afforded colourless crystals (65 mg, 99%). M.p.
6
b
+
6
5–66.5°C [lit. 65–67°C (racemic)]; [α] −2.81 (c=1.78 in H O), found: M+NH 176.0920, C H O
D
2
4
7
10
4
+
−1
requires M+NH , 176.0922; νmax/cm 3497 (br, OH), 2979 (C–H), 1783, 1756 (C_O); δ (300 MHz)
4
H
9
.05 (1H, brs, CO H), 2.85–2.70 (2H, m, CH ), 2.24 (1H, m, CHCH ), 1.53 (3H, s, OCCH ), 1.15 (3H,
2 2 3 3
d, J 7.0, CCH ); δ (300 MHz, D O) 2.80–2.68 (2H, m, CH ), 2.33 (1H, m, CHCH ), 1.43 (3H, s,
3
H
2
2
3
CCH ), 1.05 (3H, d, J 6.5, CHCH ); δ (75 MHz, CDCl ) 176.5, 175.4, 85.9, 36.7, 36.0, 17.9, 14.9; δ
3
3
C
3
C
+
(
75 MHz, D O) 179.1, 175.6, 87.8, 36.5, 35.5, 17.2, 13.7; m/z (CI) 113 (M−CO H , 100%); m/z (EI) 176
2
2
+
(
M+NH , 100%).
4
3.6. (4R,5S)-trans-Crobarbatic acid
Compound (−)-trans-5 (350 mg, 1.17 mmol) was heated at reflux for 4 h in 6 M aq. hydrochloric
acid (4 ml). The reaction mixture was extracted into ethyl acetate (4×30 ml) and the combined organics
dried (MgSO ) and evaporated to dryness under reduced pressure to give the title compound as pale pink
4
6
b
crystals (185 mg, 100%). M.p. 170–180°C (lit. 181.5–183°C, (+)-enantiomorph); [α] −8.0 (c=0.2 in
D
11
+
H O, 22°C); [α] −3.7 (c=1.4 in H O) (lit. [α] +3.45 (c=0.4 in H O); found: M+NH 176.0923,
2
D
2
D
2
4
C H O requires M+NH 176.0923; ν /cm−1 3531 (br, OH), 2972, 2940 (C–H), 1783, 1765 (C_O)
+
7
10
4
4
max
δ (300 MHz) 7.80 (1H, brs, CO H), 2.66–2.35 (3H, m, COCH CH), 1.56 (3H, s, OCCH ), 1.07 (3H,
H
2
2
3
d, J 6.0, CHCH ); δ (300 MHz, D O) 2.71 (1H, dd, J 17.5 and 8.0, COCH CCH ), 2.62–2.47 (1H,
3
H
2
2A
3
m, CH CHCH ), 2.33 (1H, dd, J 17.5 and 10.0, COCH CCH ), 1.51 (3H, s, OCCH ) and 0.96 (3H,
2
3
2B
3
3
5
d, J 7.0, CHCH ); δ (75 MHz) 175.8, 172.9, 87.2, 40.6, 35.8, 21.8, 14.3; δ (75 MHz, D O) 179.9,
3
C
C
2
+
74.0, 89.1, 39.5, 35.5, 21.0 and 13.7; m/z (CI) 176 (M+NH , 100%).
4
1
Acknowledgements
We would like to thank Merck Sharp and Dohme for a CASE award (CAS), the EPSRC and Zeneca
Pharmaceuticals (Strategic Research Fund) for financial support.
References
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2
3
. See: (a) Liddell, J. R. Natural Products Reports 1997, 14, 653; (b) Liddell, J. R. Natural Products Reports 1996, 13, 187.
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5
. Puri, S. C.; Sawhney, R. S.; Atal, C. K. Experientia 1973, 29, 390.
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8
9
. (a) Bradbury, R. B.; Masamune, S. J. Am. Chem. Soc. 1959, 81, 5201; (b) Masamune, S. J. Am. Chem. Soc. 1960, 82, 5253.
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