Neat total synthesis of six monoterpenic alkaloids of the actinidine series

Article abstract of DOI:10.1016/j.tet.2007.02.090

A concise enantiopure synthesis of six monoterpenic alkaloids of the actinidine series possessing a cyclopenta[c]pyridine skeleton, (+)-deoxyrhexifoline (4), (+)-boschniakinic acid (5), (+)-boschniakine (6), (-)-plantagonine (7), (-)-indicaine (8) and (-)

Full text of DOI:10.1016/j.tet.2007.02.090

Tetrahedron 63 (2007) 3702–3706
Neat total synthesis of six monoterpenic alkaloids
of the actinidine series
*
Nicolas Robert, Christophe Hoarau and Francis Marsais
´ ´
Laboratoire de Chimie Organique Fine et Heterocyclique, UMR CNRS 6014, INSA and University of Rouen, ECOFH-IRCOF,
INSA de Rouen, BP 08, 76131 Mont-Saint-Aignan Cedex, France
Received 8 January 2007; revised 8 February 2007; accepted 21 February 2007
Available online 24 February 2007
Abstract—A concise enantiopure synthesis of six monoterpenic alkaloids of the actinidine series possessing a cyclopenta[c]pyridine skel-
eton, (+)-deoxyrhexifoline (4), (+)-boschniakinic acid (5), (+)-boschniakine (6), (ꢀ)-plantagonine (7), (ꢀ)-indicaine (8) and (ꢀ)-tecostidine
(9) is reported starting with the chiral precursor 3-bromo-5-((4R)-phenyloxazolin-2-yl)pyridine (10). It involves a C-4 regioselective connec-
tion of a butene appendice and an intramolecular 5-exo-trig Heck annulation sequence followed by hydrogenation of the exocyclic alkene.
Mixture of (3R)- and (3S)-7-((4R)-phenyloxazolin-2-yl)cyclopenta[c]pyridines was separated by HPLC before being transformed into enan-
tiopure natural products (4–9) by modification of the oxazoline group.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
studies have been devoted to the actinidine-type alkaloids
possessing the 3-methylcyclopenta[c]pyridine skeleton
(4–9) depicted in Figure 1. (+)-Deoxyrhexifoline (4) was ex-
tracted in very few quantities from the seed of Castilleja
rhexifolia aff. Miniata,4 a natural hybrid of Castilleja
rhexifolia from which (+)-rhexifoline was isolated. (+)-
Boschniakinic acid (5) and (+)-boshniakine (6) were both
isolated and characterized from a red-bracted species
Castilleja miniata (Indian paint brush)5 closely related to
C. rhexifolia. (+)-Boschniakine (6) was also isolated from
many other plants, Boschniakia rossica,6 Penstemon whip-
pleanus,8 Plantago sempervirens,7 and Tecoma stans,8
a bush common in Latin America used in Mexico for the
control of diabetes. However, Costantino and co-workers
recently showed that (+)-boschniakine (6) is not directly
A number of monoterpenic alkaloids containing the cyclo-
penta[c]pyridine system have been isolated from various
plants, most of them being used in traditional local medi-
cines. The great interest of the synthetic community for these
natural products stems mainly from their unique biological
activities. For instance, (ꢀ)-actinidine (1) shows a cat-
exciting action1a and a significant antifungal activity,1b
lousianines A–D (2) produced in the cultured broth of
Streptomyces sp. WK-40282a shows a high growth inhibition
of testosterone-responsive Shionogi carcinoma.2b (ꢀ)-Oxer-
ine (3) is isolated from the arial part of Oxera morieri,3a
a
species related to Oxera robsta, the bark extract of which is
known for its abortive activity.3b To date few synthetic
HO
OH
R
R
N
R
N
N
N
(-)-Actinidine (1)
(-)-Oxerine (3)
-
CO2Me
CO2H
CHO
(+)-Deoxyrhexifoline (4)
(+)-Boschniakinic acid (5)
(+)-Boschniakine (6)
-
O
(-)-Plantagonine (7)
(-)-Indicaine (8)
Louisianines A-D (2)
R'
R=OH, H
R' = allyl, isoallyl
CH2OH
(-)-Tecostidine (9)
N
R
Figure 1.
Keywords: Nucleophilic addition; Intramolecular Heck reaction; Oxazoline; Pyridine alkaloid; Pyridoterpene.
* Corresponding author. Tel.: +33 02 35 52 24 75; fax: +33 02 35 52 29 62; e-mail: francis.marsais@insa-rouen.fr
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.02.090

N. Robert et al. / Tetrahedron 63 (2007) 3702–3706
3703
responsible for the hypoglycaemic action.8 The correspond-
ing enantiomers of the (+)-boschniakinic acid and (+)-bosch-
niakine, (ꢀ)-plantagonine (7) and (ꢀ)-indicaine (8) are also
natural products isolated and characterized, respectively,
from Pedicularis olgae and Plantago indica,9 which are cu-
riously different from those previously described. (ꢀ)-Tecos-
tidine (9) was isolated from the leaves of Tecama stans
Juss.10
oxazoline should allow the tailored C-4 alkylation of 10 via
the regioselective addition of a Grignard reagent, avoiding
a preliminary N-activation step of the pyridine nucleus,
before oxidation of the resulting 1,4-dihydro intermediate
to 11. The construction of the 3-methylcyclopentane ring
should then be secured by a 5-exo-trig intramolecular Heck
reaction followed by a reduction step affording both key
diastereoisomers (3R)-12 and (3S)-13. This technique was
€
successfully used recently by Zhaı and co-workers for the
In 1967, Sakan and co-workers reported the first and unique
total synthesis of (+)-boschniakine (6) from (+)-pulegone
through a five-steps route in a moderate 5% overall yield.6
In 1990, Tillequin documented an efficient biomimetic syn-
thesis of (ꢀ)-tecostidine (9) from loganin in three-step syn-
thesis and a 36% overall yield.11 No literature precedent
gives sound of total synthesis of (ꢀ)-plantagonine (7) and
(ꢀ)-indicaine (8).
construction of the methylcyclopenta[c]pyridine skeleton.13
Thus, separation of diastereoisomers (3R)-12 and (3S)-13
and chemical modulation of the oxazoline function would
later lead to natural (3R)-4–6 and (3S)-7–9.
2. Results and discussion
The 3-bromo-5-((4R)-phenyloxazolin-2-yl)pyridine (10)
was prepared in a multi-grams scale in 89% yield from the
commercially available 3-cyano-5-bromo-pyridine (15) by
treatment with (R)-phenylglycinol in the presence of cata-
lytic amounts of zinc chloride. Regioselective introduction
of the butene chain at the C-4 position of 10 was achieved
by reaction with freshly prepared 4-but-1-enyl magnesium
bromide (Scheme 2). The quantitatively formed 1,4-dihy-
dropyridine intermediate was then subjected to oxidation
and different oxidants were checked. Chloranil allowed
clean oxidation of the dihydropyridine system but surpris-
ingly the (40-phenyl)oxazoline ring was also completely aro-
matized to the corresponding phenyloxazole.
Almost all synthetic routes to the cyclopenta[c]pyridine
skeleton reported during the last decade have been secured
by exploring diverse annulation techniques starting from
commercially available functionalized pyridines. The pyri-
dine radical-olefin condensation,12 the intramolecular Heck
ring closure,13 the fluorine-induced desilylation–cyclation
of aldehyde and recently a Dieckmann-type condensation14
have been successively envisaged for construction of the cy-
clopenta[c]pyridine framework. Thus, the development of
general versatile routes to cyclopenta[c]pyridine skeleton
mainly relies on the judicious choice of a parent pyridine,
which could be easily alkylated and equipped with suitable
functions for the cyclopentane ring formation by annulation.
In this context, we specifically selected the 3-bromo-5-((4R)-
phenyl-oxazolin-2-yl)pyridine (10) as avaluable precursor to
access to the six monoterpenic alkaloids 4–9. Our retrosyn-
thetic analysis is depicted in Scheme 1. The presence of the
We then turned our mind to oxygen and we found that bub-
bling O2 into a solution of the crude dihydropyridine in ethyl
acetate provided a clean access to the expected 4-but-1-enyl-
pyridine (11) in a 95% overall yield from 10.
Ph
Ph
Ph
N
N
N
Br
R
Br
O
3
O
O
7
N
N
N
N
(3R)-12 and (3S)-13
(3R)-4-6 and (3S)-7-9
10
11
R= CO2Me, COOH,
CHO, CH2OH
Scheme 1. Retrosynthetic analysis.
Ph
Ph
Ph
N
N
N
NC
Br
Br
Br
O
Br
(i)
(ii)
(iii)
O
O
(89%)
(95%)
N
15
N
11
N
10
N
16
H
Ph
Ph
Ph
N
O
N
N
(iv)
(v)
(96%)
O
and
O
(83%)
N
N
N
17
(45%)
(43%)
(3S)-13
(3R)-12
Scheme 2. Reagents and conditions: (i) (R)-phenylglycinol, ZnCl2 (10%), PhCl, reflux, 48 h; (ii) (a) freshly prepared solution of 4-but-1-enyl magnesium bro-
mide in Et2O (4 ml, c¼0.66 M), 10, THF, rt, 1 h; (iii) O2, ethyl acetate, 48 h; (iv) Pd(OAc)2 (0.1 mol %), dppp (25 mol %), Ag2CO3 (1 equiv), CH3CN, 80 ꢁC,
2 h; (v) H2 (1 bar), Pd/C (5 mol %), MeOH, rt, 3 h.

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N. Robert et al. / Tetrahedron 63 (2007) 3702–3706
The 5-exo-trig ring closure via an intermolecular Heck reac-
tion and subsequent reduction for elaboration of the 3-
methylcyclopenta[c]pyridine system were then investigated.
Among the possible 5-exo-trig intramolecular Heck ring
closure15 we first applied the Zhai’s procedure13 to the ortho-
bromobutenylpyridine (11) using Pd(OAc)2 (5 mol %),
PPh3 (10 mol %), NEt3 (2 equiv) in refluxing CH3CN for
4 h. The expected cyclopentene[c]pyridine 16 could be ob-
tained but in a modest 43% yield. Optimization of the ring
closure under the Boger’s conditions16a using Pd(OAc)2
(5 mol %), dppf (10 mol %), NEt3 (2 equiv) and Ag2CO3
(1 equiv) allowed the clean conversion of 11 to 17 in an ex-
cellent 83% yield with a reaction time of only 2 h (GC–MS
monitoring). The benefit of silver salts as additives for inter-
nal Heck coupling reaction has been often reported.16 In our
case, we found that the ring closure is much slower without
Ag2CO3 giving a full conversion of 11 in 18 h (GC–MS
monitoring) with a 79% yield of 16. Subsequent reduction
of 16 was then smoothly carried out with H2 and Pd/C as cat-
alyst at room temperature in MeOH for 48 h providing the
corresponding 3-methylcyclopenta[c]pyridines (3R)-12 and
(3S)-13 as a 1:1 diastereomeric mixture in 96% yield.
acid (5) using LiAlH4 in THF followed by Swern oxidation
afforded (+)-boschniakine (6) in 48% overall yield (Scheme
3). Similar reduction of (ꢀ)-plantagonine (7) led first to (ꢀ)-
tecostidine (9) in 80% yield before subsequent Swern oxida-
tion to (ꢀ)-indicaine (8) in 61% yield. Esterification of
(+)-boschniakinic acid (5) to (+)-deoxyrhexifoline (4) was
finally achieved by sequential treatment with oxalyl chloride
and MeOH in 65% overall yield.
3. Conclusion
In conclusion, an efficient enantiopure synthesis of six
monoterpenic alkaloids of the actinidine series have been
accomplished in five to seven steps from the chiral 3-bromo-
5-((4R)-phenyloxazolin-2-yl)pyridine precursor (10). The
construction of the 7-methylcyclopenta[c]pyridine skele-
ton involves sequential C-4 regioselective connection of a
butenyl appendice and 5-exo-trig intramolecular Heck anne-
lation. The subsequent reduction of the exocyclic methylene-
cyclopenta[c]pyridines produced a 1:1 diastereoisomeric
mixture of 3-methylcyclopenta[c]pyridines, which were
readily separated by HPLC on silica gel. The latter both
diastereopure isomers were used to prepare the enantiopure
target natural products by chemical transformation of the ox-
azoline group. (+)-Deoxyrhexifoline (4), (+)-boschniakinic
acid (5), (+)-boschniakine (6), (ꢀ)-plantagonine (7), (ꢀ)-
indicaine (8) and (ꢀ)-tecostidine (9) were thus selectively
prepared in 14%, 21%, 10%, 20%, 10% and 16% overall
yields, respectively.
However, preparative HPLC separation on silica gel (Li-
chrosorb 10 mm) of the latter diastereoisomers furnished di-
astereopure isomers (3R)-12 and (3S)-13, respectively, in
45% and 43% yields.
At this stage we focused our attention on the target natural
products by chemical transformations of the oxazoline group
into ester, aldehyde and hydroxymethyl functions. Hydroly-
sis of (3R)-12 and (3S)-13 to (+)-bocshniakinic acid (5) and
(ꢀ)-plantagonine (7) (Scheme 3) was achieved by treatment
with concentrated hydrochloric acid for 18 h under reflux
leading to the expected compounds, respectively, in 70%
and 72% yields.17 Complete reduction of (+)-boschniakinic
4. Experimental
4.1. General
Tetrahydrofuran (THF) and diethyl ether (Et2O) were
pre-dried with pellets of KOH and distilled over sodium
benzophenone ketyl under Ar before use. CH2Cl2, NEt3
and toluene were distilled from CaH2. Methanol and ethanol
were distilled from magnesium turning. Dimethylacetamide
O
MeO
(iv)
4
N
O
(65%)
(ii)
˚
was stored over 4 A molecular sieves before distillation.
HO
Flash chromatography separations were done on Merck sil-
ica gel (70–230 mesh). The melting points were measured
on a Kofler melting points apparatus and were not corrected.
The 1H NMR and 13C NMR spectra were recorded on
a Bruker Avance-300 spectrometer operating at 300 MHz.
Infrared spectra were recorded on a Perkin–Elmer FTIR
1650 spectrophotometer. Elemental analyses were carried
out on a Carlo Erba 1160. Optical rotations were measured
at 20 ꢁC on a Perkin–Elmer 341 polarimeter. Commercially
available starting materials were used without further purifi-
cation. The starting compound 15 is commercially available.
HO
(83%)
5
18
N
N
(iii)
(58%)
(i) (70%)
O
(3R)-12
H
6
N
O
(3S)-13
H
8
N
(i)
(72%)
4.2. Synthesis of the 3-bromo-5-((4R)-phenyloxazolin-
2-yl)pyridine (10)
(iii) (61%)
O
(ii)
In a 100 ml round bottom flask, commercial zinc chloride
(75 mg, 0.55 mmol) was melted three times under high vac-
uum and cooled under nitrogen. A solution of 5-bromonico-
tinonitrile 15 (1.0 g, 5.52 mmol) and (R)-phenylglycinol
(1.13 g, 8.2 mmol) in chlorobenzene (10 ml) was added
and the resulting mixture was refluxed under nitrogen for
HO
HO
(80%)
7
9
N
N
Scheme 3. Reagents and conditions: (i) HCl (4 M), reflux, 18 h; (ii) LiAlH4
(2 equiv), THF, rt, 24 h; (iii) Swern oxidation; (iv) (a) (COCl)2, cat. DMF,
reflux, 1 h, (b) MeOH, rt, 2 h.

N. Robert et al. / Tetrahedron 63 (2007) 3702–3706
3705
48 h and concentrated under vacuum. The residue was dis-
solved in CH2Cl2 (30 ml) and water was added (20 ml).
The separated aqueous solution was extracted with CH2Cl2
(3ꢂ10 ml) and the combined organic phases were dried
(MgSO4) and concentrated under vacuum. The crude prod-
uct was chromatographed on a silica gel using ethyl acetate
as an eluent to afford 10 (1.48 g, 89%, [a]2D0 +28.0 (c 1.20,
CH2Cl2)) as an oil. 1H NMR (CDCl3) d 4.26 (dd, 1H,
J¼8.7, 8.7 Hz, 1H), 4.77 (dd, 1H, J¼10.2, 8.7 Hz, 1H),
5.35 (dd, 1H, J¼10.2, 8.7 Hz, 1H), 7.20–7.26 (m, 5H),
8.41 (s, 1H), 8.73 (s, 1H), 9.06 (s, 1H); 13C NMR (CDCl3)
d 70.5, 75.5, 120.9, 125.5, 127.0, 129.3, 138.7, 141.9,
147.9, 153.6, 161.9; IR (KBr) n 3039, 1651, 1418, 1354;
Anal. Calcd for C14H11BrN2O (303.10): C, 55.47; H, 3.66;
N, 9.24. Found: C, 55.61; H, 3.72; N, 9.12%.
8.87 (s, 1H); 13C NMR (CDCl3) d 31.1, 32.1, 70.6, 74.7,
106.0, 121.3, 126.9, 128.0, 129.1, 138.1, 142.6, 145.1,
147.6, 149.2, 156.7, 163.1; IR (KBr) n 1545, 1644, 2894–
2969, 3076; Anal. Calcd for C18H16N2O (276.1): C, 78.24;
H, 5.84; N, 5.79. Found: C, 78.12; H, 5.69; N, 5.67%.
4.3.3. Synthesis of the (3R)- and (3S)-methyl-7-((4R)-phe-
nyloxazolin-2-yl)cyclopenta[c]pyridine ((3R)-12 and
(3S)-13). A suspension of palladium (124 mg, 10% on char-
coal, 0.12 mmol) in a solution of 17 (320 mg, 1.2 mmol) in
MeOH (13 ml) was vigorously stirred for 3 h at room tem-
perature under hydrogen. The mixture was then filtered
though a short pad of Celite washed with ethyl acetate
(20 ml) and the solvent was evaporated under vacuum. The
residue was chromatographed on silica gel using ethyl ace-
tate as an eluent to afford a mixture of diastereomers
(3R)-12 and (3S)-13 (310 mg, 96%) as a yellow oil, which
was then separately isolated by preparative high-perfor-
mance liquid chromatography (HPLC) on silica gel (LiChro-
sorb Alox T 10 mm) using heptane/isopropanol 97:3 (UV
254 nm) as an eluent to provide (3R)-12 (139.5 mg, 45%)
4.3. Synthesis of the cyclopenta[c]pyridines ((3R)-12 and
(3S)-13)
4.3.1. Synthesis of the 3-bromo-4-(but-3-enyl)-5-((4R)-
phenyloxazolin-2-yl)pyridine (11). The 4-bromobutene
(1 ml, 10 mmol) was added dropwise at a rate fast enough
to maintain reflux to a mixture of Mg turnings (239 mg,
10 mmol) in anhydrous Et2O (10 ml) containing an iodine
crystal. After complete addition, the mixture was refluxed
for 1 h. The concentration of the Grignard reagent was
then measured at 0 ꢁC using menthol and phenanthroline
as indicator (C¼0.66 M). To a solution of 10 (750 mg,
2.5 mmol) in anhydrous THF (20 ml) was added the above
prepared Grignard solution (3.93 ml, 2.6 mmol, c¼0.66 M)
at room temperature under nitrogen. After stirring 1 h, satd
aq NH4Cl (10 ml) was added and the product was extracted
with CH2Cl2 (3ꢂ20 ml). The combined organic phases were
dried (MgSO4) and concentrated under vacuum to give the
crude dihydropyridine 16, which was dissolved in ethyl ace-
tate (50 ml). The resulted solution was flushed by O2 for
48 h. The solvent was then evaporated under vacuum and
the residue was chromatographed on silica gel using ethyl
acetate as an eluent to afford 11 (846 mg, 95%) as a yellow
oil. 1H NMR (CDCl3) d 2.29 (m, 2H), 3.26 (m, 2H), 4.19 (dd,
J¼8.7, 8.7 Hz, 1H), 4.74 (dd, J¼10.2, 8.7 Hz, 1H), 4.88–
4.96 (m, 2H), 5.39 (dd, J¼10.2, 8.7 Hz, 1H), 5.75–5.84
(m, 1H), 7.24–7.28 (m, 5H), 8.68 (s, 1H), 8.85 (s, 1H);
13C NMR (CDCl3) d 33.1, 33.3, 70.9, 74.8, 115.8, 124.8,
125.4, 126.9, 128.2, 129.2, 137.5, 142.1, 150.0, 151.0,
154.1, 162.5; IR (KBr) n 953, 1089, 1352, 1643, 2361,
2896–2934; Anal. Calcd for C18H17BrN2O (357.2): C,
60.52; H, 4.80; N, 7.84. Found: C, 60.55; H, 4.94; N, 7.66%.
1
and (3S)-13 (133 mg, 43%). H NMR (CDCl3) d 1.29 (d,
J¼6.8 Hz, 3H), 1.56–1.63 (m, 1H), 2.28–2.31 (m, 1H),
3.03–3.14 (m, 1H), 3.22–3.35 (m, 2H), 4.17 (dd, J¼8.7,
8.7 Hz, 1H), 4.72 (dd, J¼10.2, 8.7 Hz, 1H), 5.36 (dd,
J¼10.2, 8.7 Hz, 1H), 8.45 (s, 1H), 8.92 (s, 1H); 13C NMR
(CDCl3) d 18.8, 31.7, 32.9, 36.5, 69.2, 73.3, 119.2, 125.6,
126.6, 127.7, 141.3, 143.9, 145.8, 146.8, 153.3, 162.1;
Anal. Calcd for C18H18N2O (278.3): C, 77.67; H, 6.52; N,
10.06. Found for (3R)-12: C, 77.56; H, 6.54; N, 9.98%.
Found for (3S)-13: C, 77.63; H, 6.57; N, 10.01%.
4.4. Synthesis of the pyridoterpenes alkaloids (4–9)
4.4.1. Synthesis of (D)-boschniakinic acid (5) and (L)-
plantagonine (7). The solution of (3R)-12 (respectively
(3S)-13) (120 mg, 0.43 mmol) in aq HCl (4 M, 4 ml) was re-
fluxed for 18 h. After cooling, the pH was adjusted to 4 by
adding K2CO3 and the product was extracted with ethyl ace-
tate. The combined organic phases were dried (MgSO4) and
evaporated under vacuum to give (+)-boschniakinic acid (5)
(53.5 mg, 70%, [a]D20 +28.0 (c 1.05, MeOH), [a]2D0 +31.417b
(c 0.35, MeOH)) and (ꢀ)-plantagonine (7) (53.5 mg, 72%,
[a]2D0 ꢀ27.0 (c 0.96, MeOH), [a]2D0 ꢀ30.817c (c 1.00,
1
MeOH)). Mp¼238–239 ꢁC. H NMR (DMSO) d 1.28 (d,
3H, J¼6.8 Hz), 1.56 (m, 1H), 2.29 (m, 1H), 3.04 (m, 1H),
3.25 (m, 2H), 8.60 (s, 1H), 8.82 (s, 1H); 13C NMR
(DMSO) d 19.9, 31.8, 33.4, 36.8, 123.2, 145.1, 147.9,
148.6, 154.8, 166.9; IR (KBr) n 3449, 2960, 2379, 1713,
1606, 1450; Anal. Calcd for C14H18N2O (177.2): C, 67.78;
H, 6.26; N, 7.90. Found for 5: C, 67.94; H, 6.39; N,
7.99%. Found for 7: C, 67.82; H, 6.29; N, 7.69%.
4.3.2. Synthesis of the 7-methylene-3-((4R)-phenyloxazo-
lin-2-yl)cyclopenta[c]pyridine (17). A degassed mixture of
11 (200 mg, 0.56 mmol), Pd(OAc)2 (15 mg, 0.067 mmol),
dppp (55 mg, 0.13 mmol), Et3N (160 ml, 1.1 mmol) and
Ag2CO3 (154 mg, 0.56 mmol) in CH3CN (10 ml) was
heated in a sealed tube at 80 ꢁC for 2 h. After filtration
through a short pad of Celite washed with AcOEt and con-
centrated under vacuum, the residue was chromatographed
on silica gel using ethyl acetate/petrol 40:60 as an eluent
to afford 17 (120 mg, 83%) as a beige oil. 1H NMR
(CDCl3) d 2.74–2.78 (m, 2H), 3.26–3.32 (m, 2H), 4.15
(dd, J¼8.7, 8.7 Hz, 1H), 4.70 (dd, J¼10.2, 8.7 Hz, 1H),
5.10 (d, J¼2.1 Hz, 1H), 5.35 (dd, J¼10.2, 8.7 Hz, 1H),
5.50 (d, J¼2.1 Hz, 1H), 7.30–7.34 (m, 5H), 8.73 (s, 1H),
4.4.2. Synthesis of (D)-tecostidine (18) and (L)-tecosti-
dine (9). Lithium aluminium hydride (22.0 mg, 0.56 mmol)
was added portionwise to a solution of boschniakinic acid
(5) (50 mg, 0.28 mmol) (respectively (ꢀ)-plantagonine
(7)) in THF (2 ml) under nitrogen. The resulting mixture
was then refluxed for 24 h. After cooling, water (1 ml),
NaOH (1 M, 1 ml) and water (1 ml) were successively added
in order to precipitate the aluminium salts. The aluminium
salts were removed by filtration and washed with ethyl
acetate. The separated organic phase was dried (MgSO4)

3706
N. Robert et al. / Tetrahedron 63 (2007) 3702–3706
and concentrated under vacuum to give non-natural (+)-
tecostidine (18) (37.9 mg, 83%, [a]2D0 +4.0 (c 1.10, CH2Cl2),
[a]2D0 +3.018 (c 1.10, CH2Cl2)) and (ꢀ)-tecostidine (9)
(36.5 mg, 80%, [a]2D0 ꢀ3.0 (c 0.95, CH2Cl2), [a]2D0 ꢀ4.019
References and notes
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Takayanagi, H.; Komiyama, K.; Woodruff, H. B.; Omura, S.
J. Antibiot. 1995, 48, 1090–1094; (b) Komiyama, K.;
Takamatsu, S.; Kim, Y.-P.; Matsumoto, A.; Takahashi, Y.;
Hayashi, M.; Woodruff, H. B.; Omura, S. J. Antibiot. 1995,
48, 1086–1089.
3. (a) Benkrief, R.; Skaltsounis, A.-L.; Tillequin, F.; Koch, M.;
Puset, J. Planta Med. 1991, 57, 79–80; (b) Skaltsounis,
A.-L.; Tillequin, F.; Koch, M.; Puset, J.; Chauviere, G.
Planta Med. 1989, 55, 191–192.
1
(c 1.22, CHCl3)) as yellow oils. H NMR (CDCl3) d 1.28
(d, J¼7.0 Hz, 3H), 1.59–1.63 (m, 1H), 2.31–2.37 (m, 1H),
2.80–2.84 (m, 1H), 2.91–2.97 (m, 1H), 3.21–3.27 (m, 1H),
4.67 (s, 2H), 8.26 (s, 1H), 8.29 (s, 1H); 13C NMR (CDCl3)
d 20.2, 29.5, 34.2, 37.8, 60.9, 132.7, 143.5, 144.7, 145.6,
152.6; IR (KBr) n 3361, 2958, 2867, 1740, 1596, 1455,
1024; Anal. Calcd for C10H13NO (163.2): C, 73.59; H,
8.03; N, 8.58. Found for 9: C, 73.59; H, 8.03; N, 8.58. Found
for 18: C, 73.10; H, 8.10; N, 8.63.
4.4.3. Synthesis of (D)-boschniakine (6) and (L)-indi-
caine (8). DMSO (21 ml, 0.30 mmol) was slowly added to
a solution of oxalyl chloride (11 ml, 0.13 mmol) in CH2Cl2
(2 ml) and the resulted solution was stirred at ꢀ78 ꢁC for
30 min. A second addition of DMSO (11 ml, 0.13 mmol)
was done and the resulting mixture was stirred at the same
temperature for 30 min. A solution of the non-natural (+)-
tecostidine (18) (20 mg, 0.12 mmol) (respectively (ꢀ)-
tecostidine (9)) in CH2Cl2 (2 ml) was then added and the
solution was stirred at ꢀ78 ꢁC for 30 min. Triethylamine
(87 ml, 0.60 mmol) was added and stirring was continued
for 30 min at the same temperature. Water (2 ml) and
CH2Cl2 (5 ml) were added and the separated organic layer
was washed with NaHCO3 (2ꢂ5 ml), dried (MgSO4) and
concentrated under vacuum. The residue was chromato-
graphed on silica gel using ethyl acetate as an eluent to
afford (+)-boschniakine (6) (11.5 mg, 58%, [a]2D0 +20.0
(c 0.90, CH2Cl2), [a]D20 +21.06 (c 0.99, CHCl3)) and (ꢀ)-
indicaine (8) (12.0 mg, 61%, [a]2D0 ꢀ22.0 (c 1.05,
4. Roby, M. R.; Stermitz, F. R. J. Nat. Prod. 1984, 47,
846–853.
5. McCoy, J. W.; Stermitz, F. R. J. Nat. Prod. 1983, 46, 902–907.
6. Sakan, T.; Murai, F.; Hayashi, Y.; Honda, Y.; Shono, T.;
Nakajima, M.; Kato, M. Tetrahedron 1967, 23, 4635–4652.
7. (a) Groos, D.; Berg, W.; Schutte, H. R. Z. Chem. 1973, 13, 296–
297; (b) Ripperger, H. Pharmazie 1979, 34, 577.
8. Costantino, L.; Raimondi, L.; Pirisino, R.; Brunetti, T.; Pesotto,
P.; Giannessi, F.; Lins, A. P.; Barlocco, D.; Antolini, L.;
El-Abady, S. A. Il Farmaco 2003, 58, 781–785.
9. Torssell, K. Acta Chem. Scand. 1968, 22, 2715–2741.
10. Hammouda, Y.; Le Men, J. Bull. Chem. Soc. Fr. 1963, 12,
2901–2902.
11. Ranarivelo, Y.; Hotellier, F.; Skaltsounis, A. L.; Tillequin, F.
Heterocycles 1990, 31, 1727–1731.
12. Jones, K.; Fiumana, A.; Escudero-Hernandez, M. L.
Tetrahedron 2000, 56, 397–406.
13. Zhai and co-workers reported first the construction of the
cyclopenta[c]pyridine framework via an intramolecular Heck
reaction: Zhao, J.; Yang, X.; Jia, X.; Luo, S.; Zhai, H.
Tetrahedron 2003, 59, 9379–9382.
1
CH2Cl2)) as oils. H NMR (CDCl3) d 1.35 (d, J¼6.8 Hz,
3H), 1.70 (m, 2H), 2.43 (m, 1H), 3.13 (m, 1H), 3.35 (m,
2H), 8.69 (s, 1H), 8.81 (s, 1H), 10.2 (s, 1H); 13C NMR
(CDCl3) d 19.6, 27.3, 30.5, 33.9, 36.9, 127.7, 145.7, 148.9,
150.9, 154.5, 191.4; IR (KBr) n 3435, 1637, 1456, 1124;
Anal. Calcd for C10H11NO (161.2): C, 74.51; H, 6.88; N,
8.69. Found for 6: C, 74.55; H, 6.91; N, 8.71. Found for 8:
C, 74.59; H, 6.74; N, 8.76.
14. Chang, C.-Y.; Liu, H.-M.; Chow, T. J. J. Org. Chem. 2006, 71,
6302–6304.
15. Reviews: (a) Dounay, A. B.; Overman, L. E. Chem. Rev. 2003,
103, 2945–2963; (b) Link, J. T. Org. React. 2002, 60, 157–534;
(c) Braese, S.; De Meijere, A. Handbook of Organopalladium
Chemistry for Organic Synthesis; Negishi, E., Ed.; Wiley and
Sons: Weinheim, Germany, 2002; pp 1223–1254.
4.4.4. Synthesis of (D)-deoxyrhexifoline (4). Oxalyl chlo-
ride (2 ml, 20 mmol) was added to a stirred solution of (+)-
boschniakinic acid 5 (15 mg, 0.08 mmol) in dry CH2Cl2
(2 ml) and DMF (0.1 ml) at 0 ꢁC. The resulting mixture
was stirred at room temperature for 1 h and the solvents
were removed under vacuum. MeOH (4 ml) was slowly
added to the crude acyl chloride at 0 ꢁC and the resulted so-
lution was stirred at room temperature for 2 h. After evapo-
ration of the excess of MeOH under vacuum, CH2Cl2 (5 ml)
was added and the organic phase was washed with aq K2CO3
(2 M), water (5 ml), brine (5 ml), dried (MgSO4) and con-
centrated under vacuum. The crude oil was chromato-
graphed on silica gel using ethyl acetate as an eluent to
afford (+)-deoxyrhexifoline (4) as an oil (10.5 mg, 65%,
[a]2D0 +21 (c 0.95, CH2Cl2).
16. (a) Boger, D. L.; Turnbull, P. J. Org. Chem. 1998, 63, 8004–
8011; (b) Abelman, M. M.; Oh, T.; Overman, L. E. J. Org.
Chem. 1987, 52, 4130–4133; (c) Karabelas, K.; Westerlund,
C.; Hallberg, A. J. Org. Chem. 1985, 50, 3896–3900.
17. (a) The identification of the enantiomers 12 and 13 was done by
measuring the specific optical rotations and compared to the
literature data: 5, [a]2D0 +28 (c 1.05, MeOH), [a]D20 +31.416b
(c 0.35, MeOH); 7, [a]2D0 ꢀ27 (c 0.96, MeOH), [a]D20
ꢀ30.816c (c 1.00, MeOH); (b) Hammouda, Y.; Plat, M.; Le
Men, J. Ann. Pharm. Fr. 1963, 21, 699–702; (c) Torsell, K.;
Wahlberg, K. Acta Chem. Scand. 1967, 21, 53–62.
18. Cavill, G. W. K.; Zeitlin, A. Aust. J. Chem. 1967, 20, 349–357.
19. Hammouda, Y.; Le Men, J. Bull. Chem. Soc. Chim. Fr. 1963,
2901–2902.