Antiparasite and antimycobacterial activity of passifloricin analogues

Article abstract of DOI:10.1016/j.tet.2006.02.017

Several structural analogues of the polyketide passifloricin lactone were synthesized using asymmetric stereoselective allylations and ring-closing methateses as key reactions. These compounds were active in vitro against intracellular amastigotes of Leishmania panamensis (strain UA140), trophozoites of Plasmodium falciparum (strain NF54), and Mycobacterium tuberculosis (strain H₃₇Rv). However, in spite of the significative antiparasitic activity of some synthetic analogues a high cytotoxicity was also observed. Based on these results a lactam derivative was also synthesized. This compound maintained a good level of activity with less toxicity.

Full text of DOI:10.1016/j.tet.2006.02.017

Tetrahedron 62 (2006) 4086–4092
Antiparasite and antimycobacterial activity
of passifloricin analogues
a
Wilson Cardona, Winston Quinones, Sara Robledo, Ivan Darıo Velez, Juan Murga,
a
b
b
c
´
Jorge Garcıa-Fortanet, Miguel Carda, Diana Cardona and Fernando Echeverri
´
˜
c
c
a
a,
*
´
aGrupo de Quimica Organica de Productos Naturales-SIU, Universidad de Antioquia, PO BOX 1226, Medellin, Colombia
bPECET-SIU, Universidad de Antioquia, PO BOX 1226, Medellin, Colombia
cDepartamento de Quimica Inorganica y Organica, Universidad Jaume I, E-12071 Castellon, Spain
Received 7 November 2005; revised 2 February 2006; accepted 3 February 2006
Available online 6 March 2006
Abstract—Several structural analogues of the polyketide passifloricin lactone were synthesized using asymmetric stereoselective allylations
and ring-closing methateses as key reactions. These compounds were active in vitro against intracellular amastigotes of Leishmania
panamensis (strain UA140), trophozoites of Plasmodium falciparum (strain NF54), and Mycobacterium tuberculosis (strain H37Rv).
However, in spite of the significative antiparasitic activity of some synthetic analogues a high cytotoxicity was also observed. Based on these
results a lactam derivative was also synthesized. This compound maintained a good level of activity with less toxicity.
q 2006 Elsevier Ltd. All rights reserved.
1. Introduction
article, we describe the synthesis of other passifloricin
analogues, their activity against amastigotes of L. panamensis
Diseases caused by parasites such as malaria, leishmaniasis,
and American trypanosomiasis, and the ones caused by
mycobacteria (tuberculosis and leprae) represent approxi-
mately a 90% of morbility among the global population,
with a higher incidence in developing countries. These
ailments affect about 3 billion people, mainly inhabitants of
the third world, with very few effective drugs available and
with a growing incidence of drug resistant microorganisms.
Due to this fact, the World Health Organization through the
program ‘Tropical Disease Research’ (TDR) has classified
these diseases as a top priority for research. In this way, it
will be possible to find better diagnostic tools, control of
vectors, develop vaccines, and alternative treatments.1
Additionally, it is necessary to search for new molecules
using active natural compounds as templates and optimize
them through organic synthesis.
It has been reported that natural lactones such as (K)-
argentilactone2 and (C)-boronolide3 have significant bio-
logical activities4 against some species of Leishmania and
Plasmodium, respectively. Recently, several polyhydroxy-
lated pyrones, named passifloricins, were synthesized5 and
assayed against Leishmania panamensis amastigotes.6 In this
Keywords: Passifloricin;
Antituberculosis.
Allylation;
Lactone;
Antiparasite;
*
Corresponding author. Tel.: C57 4 2106595; fax: C57 4 2106565;
e-mail: echeveri@quimbaya.udea.edu.co
Scheme 1. Retrosynthetic analysis of passifloricin A.
0040–4020/$ - see front matter q 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.02.017

W. Cardona et al. / Tetrahedron 62 (2006) 4086–4092
4087
(strain UA140), trophozoites of Plasmodium falciparum
(strain NF54), and Mycobacterium tuberculosis (strain
H37Rv) as well as their cytotoxic activity.
followed by ring-closing metathesis, should finally yield
the desired unsaturated lactone. Among the existing
asymmetric allylation methodologies the Brown chiral
allylboranes are the most versatile for the synthesis of this
class of compounds due to the relative easy of preparing the
allyborane, the efficiency, and the enantiomeric excesses
reported.8 Thus, the synthesis of lactone 13 (Scheme 2)
started when n-hexadecanal9 was allowed to react with the
B-allyldiisopinocampheylborane (allylBIpc2) prepared
from allylmagnesium bromide and (C)-DIP-Cl (diisopino-
campheylboron chloride).10 This gave homoallyl alcohol 2
in a 92:8 enantiomeric ratio, as judged from NMR analysis
of the Mosher ester.11 Protection of the hydroxyl group as
the t-butyldimethylsilyl (TBS)12 derivative followed by
hydroboration13 yielded the primary alcohol 4. Swern
oxidation14 of the latter gave an intermediate g-silyloxy
aldehyde, which was subjected to Horner–Wadsworth–
Emmons (HWE)15 reaction. This provided, without further
chromatographic purification, a,b-unsaturated ester 5,
which was transformed into saturated ester 6 upon
hydrogenation.16 Reduction of 6 with DIBAL-H17 resulted
in alcohol 7, which was submitted to Swern oxidation to
give an intermediate silyloxy aldehyde, which, without
further chromatographic purification, was subjected to
2. Results and discussion
2.1. Synthetic plan
The synthesis of passifloricin analogues was carried out
following the methodology described7 in the literature
and according to a retrosynthetic analysis that relied mainly
upon asymmetric allylations to create new C–C bonds
(Scheme 1).
2.2. Synthesis of d-lactone of (2Z,5R,7S,12S)-trihydroxy-
heptacos-2-enoic acid (13)
The preparation of passifloricin analogues is exemplified by
the synthesis of lactone 13. Starting with n-pentadecanal, an
iterative three-step sequence (asymmetric allylation/
hydroxyl protection/C]C oxidative cleavage) was pro-
posed to create a new stereogenic carbon atom in each cycle.
Acylation of the hydroxyl group generated in the last cycle,
Scheme 2. Reagents and conditions: (a) allylBIpc2 [from (C)-DIP-Cl and allylmagnesium bromide], Et2O, K78 8C (80%, 92:8 enantiomeric mixture);
(b) TBSCl, DMF, imidazole, rt, 18 h, 80%; (c) 9-BBN, THF, rt, 20 h, then H2O2, NaOH, EtOH, 50 8C, 1 h, 80%; (d) Swern oxidation; (e) (EtO)2OPCH2CO2Et,
LiCl, DIPEA, CH3CN, 15 h, 70%; (f) Pd–C 10%, H2, AcOEt, 94%; (g) DIBAL-H, hexane, 0 8C, 95%; (h) Swern oxidation; (i) allylBIpc2 [from (C)-DIP-Cl
and allylmagnesium bromide], Et2O, K78 8C (65% overall for the two steps, 93:7 diastereomeric mixture); (j) TBSOTf, 2,6-lutidine, rt, 1 h, CH2Cl2, 88%;
(k) O3, CH2Cl2, K78 8C, then PPh3, 3 h, rt; (l) allylBIpc2 [from (C)-DIP-Cl and allylmagnesium bromide], Et2O, K78 8C (63% overall for the two steps, 91:9
diastereomeric mixture); (m) acryloyl chloride, EtNiPr2, CH2Cl2, K78 8C, 1 h, 81%; (n) 10 mol% PhCHZRuCl2(PCy3)2, CH2Cl2, 60 8C, 83%; (o) PPTS,
aqueous MeOH, 70 8C, 18 h, 94%.

4088
W. Cardona et al. / Tetrahedron 62 (2006) 4086–4092
Figure 1. Structures of synthesized lactones.
asymmetric allylation with the same reagent as above. This
gave homoallyl alcohol 8, as a 93:7 diastereomeric mixture,
which was then silylated18 to 9. Ozonolysis19 of the olefinic
bond in the latter compound was followed by asymmetric
allylation with the same reagent as above. This generated
the protected triol 10, which was then treated with acryloyl
chloride to produce in good yield the corresponding
acrylate.20 The latter was reactive enough as to undergo
RCM with the first generation Grubbs ruthenium catalyst
21
PhCHZRuCl2(PCy3)2 with formation of the unsaturated
lactone 12. Acid-catalyzed cleavage22 of all the silyl
protecting groups in 12 afforded lactone 13 in a 7.3%
overall yield from n-hexadecanal.
Following similar synthetic strategies a total of 16 lactones,
whose structures are shown in Figure 1, were
synthesized.23,24
Scheme 3. Reagents and conditions: (a) allylBIpc2 [from (K)-DIP-Cl and
allylmagnesium bromide], Et2O, K78 8C (78%, 90:10 enantiomeric
mixture); (b) TsCl, Py, 12 h, 80%; (c) NaN3, DMF, 25 8C, 16 h, 74%;
(d) PPh3, THF–H2O, 25 8C, 2 days, 80%; (e) crotonic acid, DCC, DMAP,
CH2Cl2, 25 8C, 6 h, 81%; (f) 10 mol% PhCHZRuCl2(PCy3)2, CH2Cl2,
60 8C, 82%.
2.3. Synthesis of d-lactam of (2Z,5S)-hydroxyicos-2-enoic
acid (34)
The a,b-unsaturated lactone group is a common feature in
many bioactive compounds and it is likely that the
electrophilicity of this functional group accounts for their
bioactive response. It should be possible to adjust this
reactivity through a functional analogue such as a lactam.
Therefore we decided to prepare lactam derivative 34. For
the lactam synthesis a similar synthetic strategy was carried
out (Scheme 3). Hexadecanal 1 was allowed to react with
(K)-B-allyldiisopinocampheylborane, prepared from allyl-
magnesium bromide and (K)-DIP-Cl, generating homoallyl
alcohol 29 as a 90:10 enantiomeric mixture. Tosylation25 of
alcohol 29 following reaction of the corresponding tosylate
30 with sodium azide26 yielded azide 31. Reduction of the
latter with triphenylphosphine in THF–H2O27 allowed us to
obtain the homoallylic amine 32, which was subjected
to amidation reaction with crotonic acid, DMAP and DCC28
to yield compound 33. The latter was reactive enough to
undergo RCM using the standard, first generation ruthenium
complex with formation of the unsaturated lactam 34.
2.4. Antiparasite activity studies
The antiprotozoal and antimycobacterial activities of
synthetic compounds, as well as passifloricin A are show
in the Figure 1. The other synthetic analogues reported
previously29 are shown in Figure 2.
Below are some conclusions concerning the structure and
activity:
† In general, all the compounds had a significant activity
against L. panamensis amastigotes, exhibiting an EC50
lower than 1.0 mg/mL (Fig. 3). Related to the selectivity

W. Cardona et al. / Tetrahedron 62 (2006) 4086–4092
4089
Figure 4. Antiplasmodial activity of passifloricins. Compounds 26, 27, 28,
34, and 38 were not evaluated.
Figure 2. Passifloricin A analogues reported elsewhere.
Table 1. Comparative activity of passifloricins against M. tuberculosis
H37Rv and Vero cell-line cytotoxicity
Activity against M. tuberculosis
Compound
Inhibition (%)
MIC (mg/mL,
mM)
LC50 (mg/mL,
mM)
GFP
MABA
Vero cells
Rifampin
13
14
15
18
19
20
21
22
23
24
25
26
27
28
34
35
99.6
97.4
63.7
98.9
97.4
95.8
97.3
79.1
84.3
98.3
94.7
48.1
66.3
76.8
53.6
74.7
81.7
82.9
0.72
17.31 (39.5)
O128
35.57 (101.0)
31.95 (84.0)
38.04 (89.6)
48.23 (113.7)
n.e.
117.4
1.80 (4.1)
n.e.
3.07 (8.7)
2.88 (7.6)
3.02 (7.2)
2.20 (5.2)
n.e.
n.e.
n.e.
61.47 (140.2)
24.08 (61.1)
O128
n.e.
n.e.
O128
O128
23.4 (53.0)
29.4 (67.0)
0.88 (2.0)
4.60 (12.0)
n.e.
n.e.
n.e.
n.e.
n.e.
8.34 (19.0)
5.61 (13.0)
Figure 3. Leishmanicidal activity of passifloricins. Numbering correspond-
ing to structures showed in Figures 1 and 2.
45
index (SIZLC50/EC50O10.0) compounds 14 (11.0), 16
(13.2), 17 (32,2), 20 (33.7) and 13 (31.4) are the most
promising leads, particularly the first one, because
simplest structure and lowest LC50 (12.0 mg/mL).
Passifloricin A, 45, displayed a SIZ6.4.
n.e.: no evaluated.
passifloricin A, 45, reached 82.9%. Additionally, the
minimal inhibitory concentration (MIC) of these
compounds was lower than 60 mg/mL, except for
compound 23. The other compounds (14, 21, 22, 25,
28 and 34) possesed an inhibition percentage less than
90%. However, the SI of all the compounds was
extremely low (0.05–0.36) because their high cyto-
toxicity levels.
Concerning the antiplasmodial activity, compounds with
an IC50†!50.0 mg/mL were considered promising.30
Accordingly, compounds 18 (19.8 mg/mL, 52.1 mM), passi-
floricin A, 45 (20.9 mg/mL, 47.5 mM), and 23 (26.7 mg/mL,
60.9 mM) exhibit the best activity. Products 20 (39.0 mg/mL,
91.9 mM), 17 (40.1 mg/mL, 97.7 mM), 22 (45.8 mg/mL,
111.6 mM) and 16 (50.1 mg/mL, 126.4 mM) showed mar-
ginal activity. The IC50 of chloroquine was 1.1 mg/mL
(34.5 mM) (Fig. 4).
There is not a clear relationship between the antiparasitic
activity and other structural facts such as the stereochem-
istry of the hydroxyl groups and their relative position to the
lactone. However, a comparison of the biological profiles
of these compounds indicated a tendency to increase the
activity against P. falciparum and M. tuberculosis according
to the number of hydroxy groups, but not against
L. panamensis.
† Regarding evaluation against M. tuberculosis (Table 1)
with the green fluorescent protein assay, compounds 13,
15, 18, 19, 20, 23 and 24 exhibited an inhibition
percentage higher than 90% at 128 mg/mL, while
The mechanism of action of these compounds could be
originated in the alkylating properties (Michael acceptor) of
† The IC50: concentration inhibitory dose of the parasite growth in relation
to control cultures without compounds.

4090
W. Cardona et al. / Tetrahedron 62 (2006) 4086–4092
Table 2. Comparative activity of lactam 34 against L. panamensis
Compound
Glucantime
Structure
Cytotoxicity
Leishmanicidal activity
LC 50 (mg/mL, mM)
EC 50 (mg/mL, mM)
SI
416.4
6.7
59.6
Passiflorici A, 45a
2.3 (5.2)
0.36 (0.8)
6.4
14
12.0 (39.0)
1.09 (3.5)
11.0
13.2
Lactam, 34
45.1 (146.8)
3.42 (11.1)
a Previous experimental results.
the a,b-unsaturated-d-lactone; this moiety is widely
distributed in nature and have been reported in number
bioactivities.4a,b,31,32
1H NMR: d 0.88 (t, 3H, CH3, JZ6.9 Hz), 1.20–1.36
(m, 26H), 1.40–1.52 (m, 2H, H-5), 2.06 (OH), 2.10–2.19
(m, 1H, H-30), 2.22–2.31 (m, 1H, H-3), 3.56–3.68 (m,
1H, H-4), 5.09 (d, 1H, H-1, JZ9.9 Hz), 5.09 (d, 1H, H-10,
JZ17.4 Hz), 5.72–5.92 (m, 1H, H-2); 13C NMR: d 14.1
(CH3), 22.7 (CH2), 25.7 (CH2), 29.4 (CH2), 29.7 (!9)
(CH2), 32.0 (CH2), 36.9 (CH2), 42.0 (CH2), 70.8 (CH),
117.7 (CH2), 135.0 (CH).
Lactam 34 exhibited high leishmanicidal activity
(3.42 mg/mL, 11.1 mM) versus 0.36 (0.8 mM) and 1.09
(3.5 mM) for passifloricin
A
and compound 14,
respectively, although it displayed less cytotoxicity
(45.1 mg/mL, 146.8 mM vs 2.3 mg/mL, 5.2 mM and
12.0 mg/mL, 39.0 mM) and the SI was almost doubled.
However, its profile against Mycobacterium was not
modified significantly (Table 2).
4.1.2. (R)-4-p-Toluensulphonate-nonadec-1-en (30). To a
solution of compound 29 (800 mg, 2.83 mmol) in pyridine
(2 mL) was added tosyl chloride (1.08 g, 5.67 mmol). The
mixture was stirred for 12 h and then CH2Cl2 (10 mL) was
added and washed with HCl 10% (3!15 mL) of saturated
aqueous NaHCO3 and water. Column chromatography on
silica gel (hexanes/EtOAc, 95:5) provided compound 30
(987 mg, 2.26 mmol, 80%) oil: [a]20 C5.4 (c 1.22, CHCl3);
1H NMR: d 0.87 (t, 3H, CH3, JZ6.9 Hz), 1.11–1.30 (m,
26H), 1.50–1.52 (m, 2H, H-5), 2.31–2.39 (m, 2H, H-3), 2.43
(s, 3H, Ph-CH3), 4.50–4.61 (m, 2H, H-4), 5.02 (d, 2H, H-1,
JZ12.3 Hz), 5.53–5.72 (m, 1H, H-2), 7.31 (d, 2H, Ar, JZ
8.2 Hz), 7.78 (d, 2H, Ar, JZ8.2 Hz); 13C NMR: d 14.5
(CH3), 22.0 (CH3), 23.1 (CH2), 25.1 (CH2), 29.6–30.1
(!10) (CH2), 32.4 (CH2), 34.1 (CH2), 39.2 (CH2), 83.5
(CH), 119.0 (CH2), 128.2 (!2) (CH), 130.0 (!2) (CH),
132.8 (CH).
3. Conclusion
A number of passifloricin analogues have been synthetized
and screened. Specific conclusions towards structure–
activity relationships point out that the presence of a,b-
electrophylic unsaturated lactone moiety is important for the
biological actions of these compounds to take place, but the
polyhydroxylated side chain seems to have minor influence
in their biological profile, as a more simple compound
without functionalization on the side chain (compound 14)
is as active as more complex analogues. In addition, this
compound displayed a considerable reduction of cytotox-
icity. As cytotoxic activity of some synthetic analogues is
quite high we intend to screen them as anticancer agents in
some cell cancer lines. Work along is in progress and will be
the subject of further investigation.
4.1.3. (S)-4-Azide-nonadec-1-en (31). Compound 30
(800 mg, 1.83 mmol) was dissolved in DMF (5 mL) and
NaN3 (954 mg, 14.67 mmol) was added. The mixture was
stirred for 16 h and then AcOEt (10 mL) was added and
washed with water. Column chromatography on silica gel
(hexanes/EtOAc, 95:5) afforded compound 31 (416 mg,
4. Experimental
4.1. General
1
1.35 mmol, 74%) oil: [a]20 K10.6 (c 0.80, CHCl3); H
NMR: d 0.82 (t, 3H, CH3, JZ6.9 Hz), 1.15–1.26 (m, 26H),
1.40–1.47 (m, 2H, H-5), 2.19–2.27 (m, 2H, H-3), 3.20–3.30
(m, 1H, H-4), 5.01–5.08 (m, 1H, H-1), 5.09–5.12 (m, 1H,
H-10), 5.65–5.83 (m, 1H, H-2); 13C NMR: d 14.5 (CH3),
23.1 (CH2), 26.5 (CH2), 29.8–30.1 (!10) (CH2), 32.4
(CH2), 34.4 (CH2), 39.2 (CH2), 62.8 (CH), 118.4 (CH2),
134.5 (CH).
4.1.1. (R)-Nonadec-1-en-4-ol (29). Hexadecanal (1.5 g,
6.25 mmol) was subjected to allyboration with (K)-DIP-Cl
as described.29 Workup as described29 and column
chromatography on silica gel (hexanes/EtOAc, 95:5)
provided compound 29 (90:10 mixture of diastereomers,
after chromatographic separation 1.37 g, 4.88 mmol, 78%).

W. Cardona et al. / Tetrahedron 62 (2006) 4086–4092
4091
4.1.4. (S)-Nonadec-1-en-4-amine (32). To a solution of
azide 31 (800 mg, 2.83 mmol) in THF (5 mL), PPh3
(445 mg, 1.71 mmol) and water (28 mL) were added.
The mixture was stirred for 12 h and then AcOEt (10 mL)
was added and washed with saturated NaHCO3 solution.
Column chromatography on silica gel (EtOAc) afforded
compound 32 (256 mg, 0.91 mmol, 80%) oil: [a]20 K8.6 (c
0.84, CHCl3); IR (KBr) nmax (cmK1): 3255 (N–H); 1H
NMR: d 0.88 (t, 3H, CH3, JZ6.9 Hz), 1.26–1.55 (m, 26H),
2.08–2.25 (m, 2H, H-5), 2.30–2.50 (m, 2H, H-3), 2.81 (s,
2H, N–H), 2.85–3.10 (m, 1H, H-4), 5.27 (d, 1H, H-10, JZ
9.9 Hz), 5.28 (d, 1H, H-1, JZ17.0 Hz), 5.93–6.01 (m, 1H,
H-2); 13C NMR: d 14.5 (CH3), 23.1 (CH2), 26.5 (CH2), 26.7
(CH2), 29.8–30.1 (!9) (CH2), 32.3 (CH2), 37.4 (CH2), 42.3
(CH2), 51.1 (CH), 117.9 (CH2), 135.9 (CH).
thank Dr. S. Blair (Malaria-Colombia) and Dr. Scott G.
Franzblau (Institute for Tuberculosis Research-University of
Illinois at Chicago), for biological assays, and Prof. A. Marco
(University of Valencia) for his support and advice.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tet.2005.09.
037. Complete antiparasite and antimycobacterial activity
data, NMR and Mass spectra, HPLC analysis and synthetic
procedures. This material is available free of charge via the
Internet at http://www.sciencedirect.com.
References and notes
4.1.5. (S)-N-(4-Nonadec-1-en)-crotonamide (33). Amine
32 (200 mg, 0.712 mmol) was dissolved in dry CH2Cl2
(20 mL), and treated sequentially with crotonic acid
(73.5 mg, 0.855 mmol), DMAP (261 mg, 2.14 mmol) and
DCC (193 mg, 0.935 mmol). The reaction mixture was
stirred for 6 h and filtered. Then CH2Cl2 (10 mL) was added
and washed with saturated aqueous NaHCO3. Column
chromatography on silica gel (hexanes/EtOAc, 6:4)
afforded compound 33 (210 mg, 0.577 mmol, 81%) oil:
mp: 87–89 8C; [a]20 K10.0 (c 0.95, CHCl3); IR (KBr) nmax
(cmK1): 3285 (N–H), 1630 (C]O), 1551 (C–N); 1H NMR:
d 0.82 (t, 3H, CH3, JZ6.9 Hz), 1.15–1.35 (m, 26H), 1.50–
1.60 (m, 2H, H-5), 1.78 (d, 3H, Hc, JZ6.9 Hz), 2.07–2.29
(m, 2H, H-3), 3.95–4.08 (m, 1H, H-4), 4.95–5.10 (m, 2H, H-
1/N–H), 5.63–5.80 (m, 2H, H-a/H-2), 6.68–6.82 (m, 1H,
Hb); 13C NMR: d 14.5 (CH3), 18.1 (CH3), 23.1 (CH2), 26.4
(CH2), 29.8–30.1 (!9) (CH2), 31.3 (CH2), 32.3 (CH2), 34.9
(CH2), 39.6 (CH2), 48.9 (CH), 118.1 (CH2), 125.8 (CH),
134.9 (CH), 140.0 (CH), 166.9 (C]O).
1. Remme, J.; Blas, E.; Chitsulo, L.; Desjeux, P. Parasitology
2002, 18, 421–426.
2. Saeed, M.; Thomas, H.; Schick, M.; Abbas, M.; Voelter, W.
Tetrahedron Lett. 2001, 42, 7401–7403.
3. Davies-Coleman, M.; Rivett, D. Phytochemistry 1987, 26,
3047–3050.
4. (a) Mollet, L. A.; Davies-Coleman, M. T.; Rivett, D. A.
Fortschr. Chem. Org. Naturst. 1998, 75, 181–209. (b)
Hoffmann, H. M. R.; Rabe, J. Angew. Chem., Int. Ed. Engl.
1985, 24, 94–110.
´
5. Murga, J.; Garcıa-Fortanet, J.; Carda, M.; Marco, J. A.
Tetrahedron Lett. 2003, 44, 7909–7912.
6. Cardona, W.; Quin˜ones, W.; Echeverri, F. Molecules 2004, 9,
666–672.
7. Garcia-Fortanet, J.; Murga, J.; Carda, M.; Marco, J. A. Org.
Lett. 2003, 5, 1447–1449.
8. (a) Veeraraghavan, R. P.; Ran Reddy, V. M.; Brown, H. C.
Tetrahedron Lett. 2000, 41, 583–586. (b) Ran Reddy, M. V.;
Brown, H. C.; Veeraraghavan, R. P. J. Organomet. Chem.
2001, 624, 239–243.
4.1.6. d-Lactam of (2Z,5S)-hydroxyicos-2-enoic acid (34).
Compound 33 (160 mg, 0.438 mmol) was dissolved under
N2 in dry, degassed CH2Cl2 (50 mL) and treated with
ruthenium catalyst PhCHZRuCl2(PCy3)2 (36 mg,
0.044 mmol). The mixture was heated at reflux until
consumption of the starting material (ca. 3 h, TLC
monitoring!). Solvent removal in vacuo and column
chromatography on silica gel (hexanes/EtOAc, 1:1) furn-
ished 34 (116 mg, 0.36 mmol, 82%): mp: 74–76 8C; [a]20
C37.7 (c 3.0, CHCl3); IR (KBr) nmax (cmK1): 3210 (N–H),
9. Prepared by PCC oxidation of n-hexadecanol.
10. Veeraraghavan, R. P.; Chen, G.; Brown, H. Tetrahedron Lett.
1997, 38, 2417–2420.
11. Latypov, S. K.; Seco, J. M.; Quin˜oa, E.; Riguera, R. J. Org.
Chem. 1996, 61, 8569–8577.
12. Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972, 94,
6190–6191.
13. Brown, H.; Rogic, M. J. Am. Chem. Soc. 1969, 91, 2146–2147.
14. Cossy, J.; Bauer, D.; Bellosta, V. Tetrahedron 2002, 58,
5909–5922.
1
1687 (C]O), 1550 (C–N); H NMR: d 0.88 (t, 3H, CH3,
15. Blanchette, M.; Choy, W.; Davis, J.; Essenfeld, A.;
Masamune, S.; Roush, W.; Sakai, T. Tetrahedron Lett. 1984,
25, 2183–2186.
JZ6.9 Hz), 1.20–1.45 (m, 26H), 1.50–1.60 (m, 2H, H-6),
2.01–2.21 (m, 1H, H-4), 2.30–2.46 (m, 1H, H-40), 3.50–3.66
(m, 1H, H-5), 5.84–5.98 (m, 2H, H-2/N–H), 6.54–6.64 (m,
1H, H-3); 13C NMR: d 14.5 (CH3), 23.1 (CH2), 25.7 (CH2),
29.8–30.4 (!11) (CH2), 32.3 (CH2), 35.9 (CH2), 51.5 (CH),
125.0 (CH), 141.0 (CH), 166.9 (C]O). HR EIMS, m/z (%
rel int.) 307.2805 [MC] (0.7), 240.2678 (2), 96.0417 (100).
Calcd for C20H37NO, 307.2875.
16. Angle, S.; Henry, R. J. Org. Chem. 1997, 62, 8549–8552.
17. Xu, D.; Sharpless, K. B. Tetrahedron Lett. 1994, 35,
4685–4688.
18. Corey, E. J.; Cho, H.; Rucker, C.; Hua, D. Tetrahedron Lett.
1981, 22, 3455–3458.
19. Sturmer, R.; Ritter, K. Angew. Chem., Int. Ed. Engl. 1993, 32,
101–103.
20. Cossy, J.; Bauer, D.; Bellosta, V. Tetrahedron 2002, 58,
5909–5922.
Acknowledgements
21. Trnka, T.; Grubbs, R. Acc. Chem. Res. 2001, 34, 18–29.
22. Prakash, C.; Saleh, S.; Blair, I. Tetrahedron Lett. 1989, 30,
19–22.
The authors thank COLCIENCIAS and the University of
Antioquia for financial support. Financial support, in part,
from the Spanish Ministry of Education and Science (project
BQU2002-00468) is also gratefully acknowleged. We want to
23. Compound 28 was obtained from lactone 14 by hydrogenation.
24. Compound 27 was obtained from decyl alcohol.

4092
W. Cardona et al. / Tetrahedron 62 (2006) 4086–4092
25. Iriarte, C.; Varela, O. Tetrahedron: Asymmetry 2000, 11,
4945–4954.
30. Cunico, W.; Cechinel, C.; Bonacorso, H.; Martins, M. A.;
Zanatta, N.; De Souza, M. V.; Freitas, I. O.; Soares, R.;
Krettli, U. A. Bioorg. Med. Chem. Lett. 2006, 16,
649–653.
26. Barrett, A.; Beall, J.; Braddock, D. C.; Flack, K.; Gibson,
V. C.; Salter, M. J. Org. Chem. 2000, 65, 6508–6514.
27. Taber, D.; You, K. J. Am. Chem. Soc. 1995, 117, 5757–5762.
28. Ireland, R.; Thompson, W.; Srouji, G.; Etter, R. J. Org. Chem.
1981, 46, 4863–4873.
31. Cateni, F.; Zilic, J.; Zacchigna, M.; Bonivento, P.; Frausin, F.;
Scarcia, V. Eur. J. Med. Chem. 2005, in press (consulted Jan
31-2006).
´
29. Murga, J.; Garcıa-Fortanet, J.; Carda, M.; Marco, J. A. J. Org.
Chem. 2004, 69, 7277–7283.
32. Ramana, C. V.; Srinivas, B.; Puranik, V. G.; Gurjar, M. K.
J. Org. Chem. 2005, 70, 8216–8219.