Stereoselective synthesis of the antiprotozoal lactone passifloricin A and seven isomers thereof

Article abstract of DOI:10.1021/jo049275d

The conjugated δ-lactone passifloricin A, a natural product with antiprotozoal activity, and seven isomers thereof have been synthesized in enantiopure form. It has been shown in this way that the proposed structure for the natural compound was erroneous. The correct structure is now evidenced. Key steps of the syntheses were asymmetric Brown-type aldehyde allylations and ring-closing metatheses.

Full text of DOI:10.1021/jo049275d

Ster eoselective Syn th esis of th e An tip r otozoa l La cton e
P a ssiflor icin A a n d Seven Isom er s Th er eof
J uan Murga,*,† J orge Garc´ıa-Fortanet,† Miguel Carda,† and J . Alberto Marco*,‡
Departamento de Quı´mica Inorga´nica y Orga´nica, Universidad J aume I, E-12080 Castello´n, Spain, and
Departamento de Quı´mica Orga´nica, Universidad de Valencia, E-46100 Burjassot, Valencia, Spain
alberto.marco@uv.es
Received April 29, 2004
The conjugated δ-lactone passifloricin A, a natural product with antiprotozoal activity, and seven
isomers thereof have been synthesized in enantiopure form. It has been shown in this way that
the proposed structure for the natural compound was erroneous. The correct structure is now
evidenced. Key steps of the syntheses were asymmetric Brown-type aldehyde allylations and ring-
closing metatheses.
In tr od u ction
Lactone rings are a structural feature of many natural
products.1 Many naturally occurring lactones, particu-
larly those that are Michael acceptors (R,â-unsaturated),1d
display a broad range of biological activities.2,3 Three
years ago, one such lactone, the polyketide-type R-pyrone
passifloricin A, was isolated together with two other
closely related lactones from the resin of Passiflora
foetida var. hispida, a species from the family Passiflo-
raceae that grows in tropical zones of America.4 The
compound has been found to display interesting antipro-
tozoal properties.5 On the basis of purely spectroscopic
findings, the structure of passifloricin A was originally
F IGURE 1. Structures initially proposed for passifloricin A.
proposed to be either 1 or 2 (Figure 1), although not all
of the stereogenic centers were assigned relative configu-
rations with the same amount of confidence. Indeed, the
configuration at C-5 relative to the other stereocenters
could not be established on the basis of the available data
and the absolute configuration was left undetermined.4
Within our general interest in the stereoselective
synthesis of bioactive natural lactones,6 we set out to
determine the structure of passifloricin A, including its
absolute configuration, by means of total synthesis. Thus,
we performed the stereoselective synthesis of structures
1 and 2. Our synthetic concept (Scheme 1) relied on
asymmetric allylations as the method to create the 1,3-
polyol system7 with its four stereocenters, whereas the
lactone moiety was to be made by means of ring-closing
metathesis (RCM).8
* Corresponding authors. (J . A. Marco) Phone: 34-96-3544337.
Fax: 34-96-3544328. (J . Murga) Phone No: 34-964-728174. Fax: 34-
964-728214.
† Universidad J aume I.
‡ Universidad de Valencia.
(1) (a) Negishi, E.; Kotora, M. Tetrahedron 1997, 53, 6707-6738.
(b) Collins, I. J . Chem. Soc., Perkin Trans. 1 1999, 1377-1395. (c)
Carter, N. B.; Nadany, A. E.; Sweeney, J . B. J . Chem. Soc., Perkin
Trans. 1 2002, 2324-2342. (d) Hoffmann, H. M. R.; Rabe, J . Angew.
Chem., Int. Ed. Engl. 1985, 24, 94-110.
(2) The following types of pharmacological activity, among other
examples, have been observed in lactones of various structures. (a)
Vasodilating and antiarrhythmic effects: Leite, L.; J ansone, D.;
Veveris, M.; Cirule, H.; Popelis, Y.; Melikyan, G.; Avetisyan, A.;
Lukevics, E. Eur. J . Med. Chem. 1999, 34, 859-865. (b) Inhibition of
the transcription factor NF-KB: Heinrich, M. Phytother. Res. 2000,
14, 479-488. Heinrich, M. Curr. Top. Med. Chem. 2003, 3, 141-154.
(c) Eczematous allergic reactions: Reider, N.; Komericki, P.; Hausen,
B. M.; Fritsch, P.; Aeerer, W.; Aberer, W. Contact Dermatitis 2001,
45, 269-272. Schempp, C. M.; Schopf, E.; Simon, J . C. Hautarzt 2002,
53, 93-97. (d) Inhibition of ribonucleotide reductase: Hakimelahi, G.
H.; Moosavi-Movahedi, A. A.; Sambaiah, T.; Zhu, J . L.; Ethiraj, K. S.;
Pasdar, M.; Hakimelahi, S. Eur. J . Med. Chem. 2002, 37, 207-217.
(e) Antiinflammatory effects: Siedle, B.; Cisielski, S.; Murillo, R.; Loser,
B.; Castro, V.; Klaas, C. A.; Hucke, O.; Labahn, A.; Melzig, M. F.;
Merfort, I. Bioorg. Med. Chem. 2002, 10, 2855-2861. (f) Cytotoxicity:
Lee, K. H.; Huang, B. R. Eur. J . Med. Chem. 2002, 37, 333-338. Hilmi,
F.; Gertsch, J .; Bremner, P.; Valovic, S.; Heinrich, M.; Sticher, O.;
Heilmann, J . Bioorg. Med. Chem. 2003, 11, 3659-3663. In many cases,
it has been specifically demonstrated that the presence of a conjugated
double bond is essential for the biological activity of the lactone because
of its role as a Michael acceptor. See, for example: Buck, S. B.;
Hardouin, C.; Ichikawa, S.; Soenen, D. R.; Gauss, C.-M.; Hwang, I.;
Swingle, M. R.; Bonness, K. M.; Honkanen, R. E.; Boger, D. L. J . Am.
Chem. Soc. 2003, 125, 15694-15695.
(3) For studies on the biological properties of lactones containing a
6-substituted 5,6-dihydropyran-2-one moiety, see, for example: (a)
Stampwala, S. S.; Bunge, R. H.; Hurley, T. R.; Willmer, N. E.;
Brankiewicz, A. J .; Steinman, C. E.; Smitka, T. A.; French, J . C. J .
Antibiot. 1983, 36, 1601-1605. (b) Davis, R. M.; Richard, J . L. Dev.
Food Sci. 1984, 8, 315-28. (c) Nagashima, H.; Nakamura, K.; Goto,
T. Biochem. Biophys. Res. Commun. 2001, 287, 829-832. (d) Raoelison,
G. E.; Terreaux, C.; Queiroz, E. F.; Zsila, F.; Simonyi, M.; Antus, S.;
Randriantsoa, A.; Hostettmann, K. Helv. Chim. Acta 2001, 84, 3470-
3476. (e) Kalesse, M.; Christmann, M. Synthesis 2002, 981-1003. (f)
Lewy, D. S.; Gauss, C.-M.; Soenen, D. R.; Boger, D. L. Curr. Med. Chem.
2002, 9, 2005-2032. (g) Larsen, A. K.; Escargueil, A. E.; Skladanowski,
A. Pharmacol. Ther. 2003, 99, 167-181. (h) Richetti, A.; Cavallaro,
A.; Ainis, T.; Fimiani, V. Immunopharmacol. Immunotoxicol. 2003, 25,
441-449.
(4) Echeverri, F.; Arango, V.; Quin˜ones, W.; Torres, F.; Escobar, G.;
Rosero, Y.; Archbold, R. Phytochemistry 2001, 56, 881-885.
(5) Passifloricin A has been found to be active against some
Plasmodium and Leishmania spp. (Echeverri, F. Personal communica-
tion).
10.1021/jo049275d CCC: $27.50 © 2004 American Chemical Society
Published on Web 09/22/2004
J . Org. Chem. 2004, 69, 7277-7283
7277

Murga et al.
reagent as above. This gave homoallyl alcohol 716 (93:7
diastereomeric ratio, dr) with the desired syn relative
configuration of the two oxygen functions.17 Silylation to
916 and oxidative cleavage of the olefinic bond was
followed by asymmetric allylation of the intermediate
â-silyloxy aldehyde. The allylating reagent was now
prepared from (-)-DIP-Cl and allylmagnesium bromide
in order to have the desired (S)-configuration at the new
stereogenic carbon. This afforded the protected triol 10,
which was silylated to 11 and subjected once more to the
same protocol to yield alcohol 12, where the hydroxyl
function was suitably placed to build up the unsaturated
lactone ring. To this end, 12 was treated with acryloyl
chloride to furnish the corresponding acrylate. However,
the yield was low. In view of this, we made use of another
recently proposed alternative. Alcohol 12 was treated
with cinnamoyl chloride18 to provide cinnamate 13 with
good yield. Ester 13 proved to be unresponsive to RCM
using the standard, first-generation ruthenium complex
PhCHdRuCl2(PCy3)2 but gave the desired lactone 14 in
the presence of the second-generation, carbene-modified
ruthenium catalyst C.8 Finally, acid-catalyzed cleavage19
of all silyl protecting groups in 14 gave lactone 1 in a
very satisfactory 75% yield. However, the NMR data of
synthetic 1 proved to be different from those published
for the natural product.4,20 The optical rotation was also
markedly different in value and opposite in sign. Stereo-
isomer 2 was then synthesized from intermediate 11
along the same methodology using the appropriate chiral
allyl borane (Scheme 2). Once again, however, the
spectral data and the optical rotation of synthetic 2
proved to be different from those of the natural prod-
uct.20,21
SCHEME 1. Retr osyn th etic P la n for Com p ou n d s 1
a n d 2
Resu lts a n d Discu ssion
The synthesis of 1 and 2 is shown in Scheme 2
(experimental details in Supporting Information).9 Asym-
metric allylations were performed with Brown’s chiral
allylboranes.10-13 Thus, n-hexadecanal14 was allowed to
react with the B-allyl diisopinocampheylborane (allyl-
BIpc2) prepared from allylmagnesium bromide and (+)-
DIP-Cl (diisopinocampheylboron chloride).10 This gave
homoallyl alcohol 5 with a 96:4 enantiomeric ratio (er,
Scheme 2), as judged from NMR analysis of the Mosher
ester. Protection of the hydroxyl group as the t-butyldi-
methylsilyl (TBS) derivative15 was followed by ozonolysis
of the olefinic bond to yield the intermediate â-silyloxy
aldehyde which, without chromatographic purification,
was subjected to asymmetric allylation with the same
(6) (a) Carda, M.; Rodr´ıguez, S.; Segovia, B.; Marco, J . A. J . Org.
Chem. 2002, 67, 6560-6563. (b) Carda, M.; Gonza´lez, F.; Castillo, E.;
Rodr´ıguez, S.; Marco, J . A. Eur. J . Org. Chem. 2002, 2649-2655. (c)
Murga, J .; Falomir, E.; Garc´ıa-Fortanet, J .; Carda, M.; Marco, J . A.
Org. Lett. 2002, 4, 3447-3449. (d) Falomir, E.; Murga, J .; Carda, M.;
Marco, J . A. Tetrahedron Lett. 2003, 44, 539-541. (e) Carda, M.;
Rodr´ıguez, S.; Castillo, E.; Bellido, A.; D´ıaz-Oltra, S.; Marco, J . A.
Tetrahedron 2003, 59, 857-864. (f) Murga, J .; Garc´ıa-Fortanet, J .;
Carda, M.; Marco, J . A. Tetrahedron Lett. 2003, 44, 1737-1739. (g)
Falomir, E.; Murga, J .; Ruiz, P.; Carda, M.; Marco, J . A.; Pereda-
Miranda, R.; Fragoso-Serrano, M.; Cerda-Garc´ıa-Rojas, C. M. J . Org.
Chem. 2003, 68, 5672-5676. (h) D´ıaz-Oltra, S.; Murga, J .; Falomir,
E.; Carda, M.; Marco, J . A. Tetrahedron 2004, 60, 2979-2985.
(7) For recent synthetic methodologies aimed at the stereoselective
creation of 1,3-polyol segments, see: (a) Oishi, T.; Nakata, T. Synthesis
1990, 635-645. (b) Palomo, C.; Aizpurua, J . M.; Urchegi, R.; Garc´ıa,
J . M. J . Org. Chem. 1993, 58, 1646-1648. (c) Rychnovsky, S. D.; Hoye,
R. C. J . Am. Chem. Soc. 1994, 116, 1753-1765. (d) Mori, Y.; Asai, M.;
Okumura, A.; Furukawa, H. Tetrahedron 1995, 51, 5299-5314. (e)
Schneider, C.; Rehfeuter, M. Chem. Eur. J . 1999, 5, 2850-2858. (f)
Trieselmann, T.; Hoffmann, R. W. Org. Lett. 2000, 2, 1209-1212. (g)
Sarraf, S. T.; Leighton, J . L. Org. Lett. 2000, 2, 3205-3208. (h) Hunter,
T. J .; O’Doherty, G. A. Org. Lett. 2001, 3, 2777-2780. (i) Cossy, J .;
BouzBouz, S.; Pradaux, F.; Willis, C.; Bellosta, V. Synlett 2002, 1595-
1606. (j) Evans, D. A.; Coˆte´, B.; Coleman, P. J .; Connell, B. T. J . Am.
Chem. Soc. 2003, 125, 10893-10898.
(8) Trnka, T.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18-29.
(9) Preliminary communication: Garc´ıa-Fortanet, J .; Murga, J .;
Carda, M.; Marco, J . A. Org. Lett. 2003, 5, 1447-1449.
(10) (a) Ramachandran, P. V.; Chen, G.-M.; Brown, H. C. Tetrahe-
dron Lett. 1997, 2417-2420. (b) For a recent review on asymmetric
allylborations, see: Ramachandran, P. V. Aldrichimica Acta 2002, 35,
23-35.
(11) Allylation under Keck and related conditions (ref 12) was
unsuccessful here (extremely slow reaction). The use of the Duthaler-
Hafner allylation reagent (ref 13) was discontinued because of its very
high price.
(12) (a) Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J . Am. Chem. Soc.
1993, 115, 8467-8468. (b) Doucert, H.; Santelli, M. Tetrahedron:
Asymmetry 2000, 11, 4163-4169.
These results led us to conjecture whether the assigned
configuration at C-7 was erroneous. We thus decided to
synthesize compounds 3 and 4 (Figure 2), epimeric of
each other at C-5 and opposite in their configuration at
C-7 to lactones 1 and 2, respectively. The same methodol-
ogy used for the latter compounds was applied again
here, with the appropriate chiral allyl borane being
selected in each case (details of these syntheses can be
found in the Supporting Information). However, we
experienced a new failure in that the data of synthetic
compounds 3 and 4 proved to be different from those of
the natural product.20,22
At this point, we started having serious doubts about
the validity of some of the data presented in the original
paper.4 We thus subjected them to a careful reexamina-
tion. The NMR data of this family of compounds first
(16) Chomatographic separation of diastereomers (7 + epimer)
proved to be difficult. After desilylation, separation was much easier
and the pure diol 8 was then resilylated to 9.
(17) This was shown by means of 13C NMR and NOE measurements
on the acetonide of diol 8. See: Rychnovsky, S. D.; Rogers, B. N.;
Richardson, T. I. Acc. Chem. Res. 1998, 31, 9-17.
(18) Ramachandran, P. V.; Chandra, J . S.; Reddy, M. V. R. J . Org.
Chem. 2002, 67, 7547-7550.
(19) The basic desilylation reagent TBAF gives rise to lactone
opening reactions in this type of compound: Nakata, T.; Hata, N.;
Oishi, T. Heterocycles 1990, 30, 333-334.
(20) Comparison with NMR spectra of the authentic sample showed
clear differences, most particularly in the 13C signals around 70 and
40 ppm (see Supporting Information of this paper and Supporting
Information to ref 9).
(21) After our preliminary communication (ref 9) had appeared, a
second report on the synthesis of the same two compounds by means
of the same retrosynthetic concept was published: BouzBouz, S.; Cossy,
J . Tetrahedron Lett. 2003, 44, 4471-4473.
(13) Duthaler, R. O.; Hafner, A. Chem. Rev. 1992, 92, 807-832.
(14) Freshly prepared by PCC oxidation of n-hexadecanol.
(15) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 3rd ed.; J ohn Wiley and Sons: New York, 1999; pp 127-
141.
7278 J . Org. Chem., Vol. 69, No. 21, 2004

Stereoselective Synthesis of Passifloricin A
SCHEME 2. Ster eoselective Syn th esis of Str u ctu r es 1 a n d 2a
a
Reagents and conditions: (a) allylBIpc2 from (+)-DIP-Cl and allylmagnesium bromide, Et2O, -100 °C. (b) TBSCl, DMF, imidazole,
rt. (c) O3, CH2Cl2, -78 °C, then PPh3, rt, then allylBIpc2 from (+)-DIP-Cl, Et2O, -100 °C. (d) TBAF, THF, rt, then chromatographic
separation of the two diastereomers. (e) TBSOTf, 2,6-lutidine, rt, CH2Cl2. (f) O3, CH2Cl2, -78 °C, then PPh3, rt, then allylBIpc2 from
(-)-DIP-Cl, Et2O, -100 °C, then chromatographic separation of the two diastereomers. (g) (E)-Cinnamoyl chloride, NEt3, cat. DMAP,
CH2Cl2, rt. (h) 10% catalyst C, CH2Cl2, ∆. (i) PPTS, aq MeOH, 70 °C. Abbreviations and acronyms: TBS ) tert-butyldimethylsilyl; DIP-
Cl ) diisopinocampheylboron chloride; TBAF ) tetra-n-butylammonium fluoride hydrate; er, enantiomeric ratio; dr, diastereomeric ratio.
SCHEME 3. Ion F r a gm en ta tion s in th e Ma ss
Sp ectr a of Str u ctu r es A a n d B
F IGURE 2. Two stereoisomers of the structures initially
proposed for passifloricin A.
1
caught our attention. As a matter of fact, the H and 13C
NMR spectra of the stereoisomeric lactones 1-4 were
very similar (see Supporting Information). Spin decou-
pling was not overly helpful in assigning proton signals
due to strong overlapping. As a consequence, many 13C
NMR signals could not be individually assigned, even
when using combined HMQC/HMBC measurements at
500 MHz. However, one feature of the 13C NMR data was
noteworthy, namely, that all four spectra showed three
signals in the range 40-45 ppm, whereas passifloricin
lactone had only two moieties of this class. Consequently,
A showed only two. According to our heteronuclear two-
one of the hydroxyl groups was misplaced.
dimensional measurements, these were the methylene
This finding alone, however, opened too many struc-
signals of the CH(OR)CH2CH(OR) fragments (C-6/C-8/
tural possibilities. We thus turned our attention to
C-10 in 1-4). This finding suggested that the natural
another spectral feature, namely, the prominent peak at
m/z 225 in the mass spectrum of passifloricin A. While
synthetic compounds 1-4, which can be represented by
the generic structure A (Scheme 3), displayed very
(22) Compound 3 is the enantiomer of a natural lactone isolated
from Eupatorium pilosum (Herz, W.; Ramakrishnan, G. Phytochemistry
1978, 17, 1327-1332). The absolute configuration of the natural
similar mass spectra, none of them showed a peak at m/z
225 (10% relative intensity at most). Conversely, the
intense peak appearing at m/z 193 (80-100%) in all four
spectra was absent in the mass spectrum of passifloricin
compound has been established by means of total synthesis (Nakata,
T.; Suenaga, T.; Nakashima, K.; Oishi, T. Tetrahedron Lett. 1989, 30,
6529-6532). The spectral properties of synthetic 3 were found to be
identical with those published for the natural product (see Supporting
Information).
J . Org. Chem, Vol. 69, No. 21, 2004 7279

Murga et al.
SCHEME 4. Ster eoselective Syn th esis of Com p ou n d 18b (P a ssiflor icin A)a
a
Reagents and conditions: (a) allylBIpc2 from (+)-DIP-Cl and allylmagnesium bromide, Et2O, -100 °C. (b) TBSCl, DMF, imidazole,
rt. (c) 9-BBN, THF, rt, then H2O2, NaOH, EtOH, 50 °C. (d) Swern oxidation. (e) TBSOTf, 2,6-lutidine, rt, CH2Cl2. (f) O3, CH2Cl2, -78 °C,
then PPh3, rt, then allylBIpc2 from (+)-DIP-Cl, Et2O, -100 °C, then chromatographic separation of the two diastereomers. (g) Acryloyl
chloride, EtNiPr2, CH2Cl2, -78 °C. (h) 10% PhCHdRuCl2(PCy3)2, CH2Cl2, ∆. (i) PPTS, aq MeOH, 70 °C. For abbreviations and acronyms,
see Scheme 2.
A. This latter peak was mechanistically explained, as
shown in Scheme 3, by invoking the known tendency of
alcohol parent peaks to undergo R-cleavage with charge
retention at the oxygen-bearing fragment (protonated
carbonyl ion).23 The resulting ion was then seen to lose
two successive water molecules to yield m/z 193 (the
intermediate peaks at m/z 229 and 211 were also visible
although weak). To explain the absence of the peak at
m/z 193 and the presence of a strong peak at m/z 225 in
the mass spectrum of passifloricin A on one hand and to
account for the aforementioned NMR features on the
F IGURE 3. Alternative stereoisomeric structures for passi-
floricin A or its enantiomer.
other, we reasoned that the hydroxyl at C-11 in generic
structure A should be shifted to C-12 as in B (Scheme
3). Assuming that this alternative structure was a
reasonable possibility for passifloricin A, we decided to
undertake its synthesis.
We started out with the assumption of the presence of
a syn-1,3-diol moiety in structure B. With this structural
fragment fixed, the other stereogenic centers were al-
lowed to vary. To reduce the amount of synthetic work,
we aimed to synthesize only one of the two possible
as previously, via RCM. Only the synthesis of stereoiso-
mer 18b, which finally proved to be identical to passi-
floricin A, is described hereafter (details of the synthesis
of the other three stereoisomers can be found in Sup-
porting Information).24
n-Pentadecanal25 was reacted with the B-allyl diiso-
pinocampheylborane prepared from allylmagnesium bro-
mide and (+)-DIP-Cl.10 This gave homoallyl alcohol 19
configurations for the 1,3-diol moiety; thus, we would end
as a 96:4 enantiomeric mixture (Scheme 4), as judged
up with either natural passifloricin A or its unnatural
from NMR analysis of the Mosher ester. Protection of the
enantiomer. On the basis of this reasoning, the four
hydroxyl group as the TBS derivative was followed by
hydroboration to yield primary alcohol 21. Swern oxida-
tion of the latter gave an intermediate γ-silyloxy aldehyde
stereoisomeric structures 18a -d were our synthetic
targets (Figure 3).
The synthetic concept for structures 18a -d (Scheme
which, without further chromatographic purification, was
4) deviates only slightly from that proposed for com-
subjected to asymmetric allylation with the same reagent
as above. This gave homoallyl alcohol 22, which was then
silylated to 23. Ozonolysis of the olefinic bond in the latter
compound was followed by asymmetric allylation with
pounds 1-4 and relies once again upon Brown’s asym-
metric allylations. The only difference is that, due to the
one-carbon shift of the first hydroxyl function made, the
initial asymmetric allylation was followed by hydro-
boration-oxidation of the olefinic bond, instead of oxida-
tive cleavage. The unsaturated lactone ring was formed,
(24) Preliminary communication: Murga, J .; Garcı´a-Fortanet, J .;
Carda, M.; Marco, J . A. Tetrahedron Lett. 2003, 44, 7909-7912. The
complete synthetic work and the results of the biological evaluations
(23) McLafferty, F. W.; Turecˇek, F. Interpretation of Mass Spectra,
4th ed.; University Science Books: Mill Valley, CA, 1993; Chapter 9.
will be a part of the projected Ph.D. Thesis of J .G.-F.
(25) Freshly prepared by PCC oxidation of n-pentadecanol.
7280 J . Org. Chem., Vol. 69, No. 21, 2004

Stereoselective Synthesis of Passifloricin A
(S)-4-(ter t-Bu tyld im eth ylsilyloxy)octa d ec-1-en e (20).
Alcohol 19 (1.21 g, 4.5 mmol) was dissolved under N2 in dry
DMF (30 mL) and treated sequentially with imidazole (460
mg, 6.75 mmol) and TBSCl (0.98 g, 6.45 mmol). The reaction
mixture was then stirred for 18 h at room temperature and
worked up (extraction with Et2O). Column chromatography
on silica gel (hexanes-EtOAc, 99:1) afforded 20 (1.55 g, 90%):
oil; [R]D -7.2 (c 2, CHCl3); 1H NMR (500 MHz) δ 5.82 (m, 1H),
5.05-5.00 (m, 2H), 3.70 (quint, 6 Hz, 1H), 2.20 (m, 2H), 1.50-
1.40 (m, 3H), 1.35-1.20 (br m, 23H), 0.90 (s, 9H), 0.88 (t, 6.5
Hz, 3H), 0.06 (s, 6H); 13C NMR (125 MHz) δ 18.2 (C), 135.6,
72.1 (CH), 116.5, 42.0, 36.9, 32.0, 29.8, 29.7 (several overlapped
peaks), 29.4, 25.4, 22.7 (CH2), 26.0 (x3), 14.1, -4.4, -4.5 (CH3);
HR FABMS m/z 383.3656 (M + H+). Calcd for C24H51OSi,
383.3709.
the same reagent as above. This afforded the protected
triol 24, which was silylated to 25 and subjected once
more to the same ozonolysis-allylation protocol to yield
alcohol 26. The latter was then treated with acryloyl
chloride to furnish in good yield the corresponding
acrylate 27. The latter was reactive enough as to undergo
RCM with the less expensive ruthenium catalyst PhCHd
RuCl2(PCy3)2 with formation of the unsaturated lactone
28. Acid-catalyzed cleavage of all the silyl protecting
groups in 28 afforded lactone 18b in a 92% yield. The
NMR data of 18b proved to be identical to those reported
for the natural product.4,26 Furthermore, treatment of 18b
with acetone and an acid catalyst gave only one ace-
tonide, the NMR features of which (see Supporting
Information) revealed its identity with those of the
acetonide prepared from the natural product.4
(S)-4-(ter t-Bu tyld im eth ylsilyloxy)octa d eca n ol (21). A
solution of olefin 20 (1.53 g, 4 mmol) in dry THF (40 mL) was
treated under N2 with 9-BBN (12 mL of a 0.5 M THF solution,
6 mmol). The reaction mixture was stirred for 18 h at room
temperature and then quenched by addition of MeOH (8 mL),
6 M aqueous NaOH (3 mL), and 30% H2O2 (5 mL). The
resulting mixture was then stirred at 50 °C for 1 h and worked
up (extraction with EtOAc). Column chromatography on silica
gel (hexanes-EtOAc, 19:1) afforded 21 (1.31 g, 82%): oil; [R]D
Con clu sion
We have performed a stereoselective, asymmetric
synthesis of the natural lactone passifloricin A and shown
it to be 18b. This has led not only to a correction of the
published structure and to the establishment of the
absolute configuration, but also to the preparation of
sizable amounts of the compound and of several isomers
thereof for the evaluation of its biological properties.5,24
The latter are now being determined and will be reported
in a future communication.
1
+3.0 (c 1.4, CHCl3); H NMR (500 MHz) δ 3.70 (quint, 6 Hz,
1H), 3.60 (m, 2H), 2.30 (br s, 1H, OH), 1.60 (m, 2H), 1.53 (m,
2H), 1.45 (m, 2H), 1.35-1.20 (br m, 25H), 0.89 (s, 9H), 0.88 (t,
overlapped, 3H), 0.05 (s, 6H); 13C NMR (125 MHz) δ 18.1 (C),
72.2 (CH), 63.2, 36.7, 33.4, 32.0, 29.8, 29.7 (several overlapped
peaks), 29.6, 29.4, 28.2, 25.4, 22.7 (CH2), 25.9 (x3), 14.1, -4.5
(x2) (CH3); IR νmax 3340 (br, OH) cm-1; HR FABMS m/z
401.3810 (M + H+). Calcd for C24H53O2Si, 401.3814.
(4S,7S)-7-(ter t-Bu t yld im et h ylsilyloxy)h en icos-1-en -4-
ol (22). DMSO (525 µL, 7.5 mmol) was dissolved under N2 in
dry CH2Cl2 (7 mL), cooled to -78 °C, and treated with oxalyl
chloride (328 µL, 3.75 mmol). After the mixture was stirred
at this temperature for 5 min, a solution of 21 (1.2 g, 3 mmol)
in dry CH2Cl2 (3 mL) was added dropwise, followed by
triethylamine (2.1 mL, 15 mmol). The reaction mixture was
stirred for 15 min at -78 °C and then for an additional 60
min at 0 °C. Workup (extraction with CH2Cl2) and evaporation
in vacuo provided a crude aldehyde that was subjected to
allyboration with (+)-DIP-Cl as described above (for weight
calculations, the yield of the oxidation was assumed to be
quantitative). Workup as above and column chromatography
on silica gel (hexanes-EtOAc, 19:1) furnished compound 22
(95:5 mixture of diastereomers, after chromatographic separa-
tion 727 mg, 55% overall): oil; [R]D +1.3 (c 1, CHCl3); 1H NMR
(500 MHz) δ 5.83 (m, 1H), 5.15-5.10 (m, 2H), 3.70 (quint, 6
Hz, 1H), 3.60 (m, 1H), 2.40 (br s, 1H, OH), 2.30-2.20 (m, 2H),
1.65-1.40 (m, 6H), 1.35-1.20 (br m, 24H), 0.90 (s, 9H), 0.88
(t, overlapped, 3H), 0.06 (s, 3H), 0.05 (s, 3H); 13C NMR (125
MHz) δ 18.1 (C), 135.1, 72.4, 71.2 (CH), 42.0, 36.7, 33.2, 32.4,
32.0, 29.8, 29.7 (several overlapped peaks), 29.6, 29.4, 25.4,
22.7 (CH2), 25.9 (x3), 14.1, -4.5 (x2) (CH3); IR νmax 3430 (br,
OH) cm-1; HR FABMS m/z 423.4027 (M + H+ - H2O). Calcd
for C27H57O2Si - H2O, 423.4022.
Exp er im en ta l Section
(S)-Octa d ec-1-en -4-ol (19). Allylmagnesium bromide (com-
mercial 1 M solution in Et2O, 7.5 mL, 7.5 mmol) was added
dropwise under N2 via syringe to a solution of (+)-DIP-Cl (2.89
g, 9 mmol) in dry Et2O (40 mL) cooled in a dry ice-acetone
bath. After replacing the latter by an ice bath, the mixture
was stirred for 1 h. The solution was then allowed to stand,
which caused precipitation of magnesium chloride. The su-
pernatant solution was then carefully transferred to another
flask via cannula. After the flask was cooled at -100 °C, a
solution of freshly prepared25 pentadecanal (1.36 g, 6 mmol)
in dry Et2O (15 mL) was added dropwise via syringe. The
resulting solution was further stirred at the same temperature
for 1 h. The reaction mixture was then quenched through
addition of phosphate pH 7 buffer solution (40 mL), MeOH
(40 mL), and 30% H2O2 (20 mL). After stirring for 30 min, the
mixture was poured onto saturated aqueous NaHCO3 and
worked up (extraction with Et2O). Column chromatography
on silica gel (hexanes-EtOAc, 9:1) afforded 19 (1.28 g, 80%,
96:4 mixture of enantiomers as estimated via the Mosher
ester): solid, mp 47-49 °C (from hexanes); [R]D -2.9 (c 1.9,
CHCl3); 1H NMR (500 MHz) δ 5.80 (m, 1H), 5.15-5.10 (m, 2H),
3.60 (m, 1H), 2.28 (m, 1H), 2.13 (m, 1H), 1.70 (br s, 1H, OH),
1.50-1.40 (m, 3H), 1.40-1.20 (br m, 23H), 0.87 (t, 6.5 Hz, 3H);
13C NMR (125 MHz) δ 134.9, 70.7 (CH), 117.8, 41.9, 36.8, 31.9,
29.7 (several overlapped peaks), 29.3, 25.6, 22.6 (CH2), 14.0
(CH3); IR νmax 3330 (br, OH) cm-1; HR EIMS m/z (% rel
intensity) 227.2338 (M+ - C3H5, 100), 125 (24), 111 (53), 97
(82), 83 (85). Calcd for C18H36O - C3H5, 227.2375.
(4S,7S)-4,7-Bis(ter t-b u t yld im et h ylsilyloxy)h en icos-1-
en e (23). Alcohol 22 (705 mg, 1.6 mmol) was dissolved under
N2 in dry CH2Cl2 (8 mL) and treated sequentially with 2,6-
lutidine (280 µL, 2.4 mmol) and TBSOTf (460 µL, 2 mmol).
The reaction mixture was then stirred for 1 h at room
temperature and worked up (extraction with CH2Cl2). Column
chromatography on silica gel (hexanes-EtOAc, 99:1) afforded
1
23 (755 mg, 85%): oil; [R]D -3 (c 2.1, CHCl3); H NMR (500
(26) The reported numerical value of the optical rotation of passi-
floricin A is very different from that found by us for 18b. This may be
due to the optical rotation having been measured in methanol (ref 4),
in which passifloricin A has a low solubility. Indeed, we have observed
that this gives rise to an inhomogeneous solution and thus to erratic
values. We then measured the optical rotation in CHCl3 solution, where
the natural product is more soluble. The synthetic and natural products
were then found to have almost identical optical rotations (see
Supporting Information).
MHz) δ 5.82 (m, 1H), 5.10-5.00 (m, 2H), 3.68 (m, 1H), 3.62
(m, 1H), 2.20 (t, 6.5 Hz, 2H), 1.60-1.50 (m, 2H), 1.50-1.20
(br m, 28H), 0.90 (s, 9H), 0.89 (s, 9H), 0.88 (t, overlapped, 3H),
0.05 (s, 6H), 0.04 (s, 6H); 13C NMR (125 MHz) δ 18.2 (x2) (C),
135.4, 72.7, 72.5 (CH), 116.7, 42.1, 37.2, 32.7, 32.5, 32.0, 29.9,
29.7 (several overlapped peaks), 29.5, 25.4, 22.7 (CH2), 26.0
(x3), 25.9 (x3), 14.1, -4.4 (x3), -4.5 (CH3); HR EIMS m/z (%
J . Org. Chem, Vol. 69, No. 21, 2004 7281

Murga et al.
rel intensity) 497.4187 (M+ - tBu, 28), 415 (14), 381 (80), 365
(48), 73 (100). Calcd for C33H70O2Si2 - tBu, 497.4204.
5 mmol). The reaction mixture was stirred for 2 h at -78 °C
and then worked up (extraction with CH2Cl2). Column chro-
matography on silica gel (hexanes-EtOAc, 19:1) afforded ester
27 (329 mg, 81%): amorphous solid; [R]D -13 (c 1.3, CHCl3);
1H NMR (500 MHz) δ 6.39 (dd, 17.3, 1.5 Hz, 1H), 6.09 (dd,
17.3, 10.5 Hz, 1H), 5.80-5.70 (m, 2H), 5.15 (m, 1H), 5.10-
5.05 (m, 2H), 3.80-3.75 (m, 2H), 3.60 (quint, 5.5 Hz, 1H), 2.40
(m, 1H), 2.33 (m, 1H), 1.82 (ddd, 14, 8, 4.8 Hz, 1H), 1.75 (ddd,
14, 6.6, 4.8 Hz, 1H), 1.65-1.40 (m, 5H), 1.35-1.20 (br m, 27H),
0.90 (s, 9H), 0.88 (s, 18H), 0.88 (t, overlapped, 3H), 0.07 (s,
3H), 0.05 (s, 9H), 0.04 (s, 3H), 0.03 (s, 3H); 13C NMR (125 MHz)
δ 165.4, 18.2, 18.1, 18.0 (C), 133.5, 128.9, 72.7, 70.7, 69.5, 67.0
(CH), 130.3, 117.9, 44.9, 41.5, 39.2, 37.2, 32.5, 32.0, 29.9, 29.7
(several overlapped peaks), 29.4, 25.3, 22.7 (CH2), 26.0 (x3),
25.9 (x6), 14.1, -4.3 (x3), -4.4 (x2), -4.5 (CH3); IR νmax 1729
(CdO) cm-1; FABMS m/z 811 (M + H+); HR EIMS m/z (% rel
intensity) 753.5723 (M+ - tBu, 2), 381 (100), 343 (56). Calcd
for C46H94O5Si3 - tBu, 753.5704.
(R)-5,6-Dih yd r o-6-[(2R,4S,7S)-2,4,7-t r is(ter t-b u t yld i-
m eth ylsilyloxy)h en icosyl]p yr a n -2-on e (28). Compound 27
(324 mg, 0.4 mmol) was dissolved under N2 in dry, degassed
CH2Cl2 (40 mL) and treated with ruthenium catalyst PhCHd
RuCl2(PCy3)2 (32 mg, 0.04 mmol). The mixture was heated at
reflux until consumption of the starting material (ca. 3 h, TLC
monitoring!). Solvent removal in vacuo and column chroma-
tography on silica gel (hexanes-EtOAc, 19:1) furnished lactone
28 (270 mg, 86%): amorphous solid; [R]D +23.4 (c 1.9, CHCl3);
1H NMR (500 MHz) δ 6.85 (m, 1H), 5.99 (dd, 9.7, 2 Hz, 1H),
4.60 (m, 1H), 4.00 (quint, 6 Hz, 1H), 3.76 (m, 1H), 3.62 (quint,
6 Hz, 1H), 2.39 (dt, 18, 5 Hz, 1H), 2.29 (ddt, 18, 11.5, 2.5 Hz,
1H), 2.00 (dt, 14, 6 Hz, 1H), 1.85 (dt, 14, 6 Hz, 1H), 1.70-1.40
(m, 6H), 1.35-1.20 (br m, 26H), 0.89 (s, 18H), 0.88 (s, 9H),
0.88 (t, overlapped, 3H), 0.07 (s, 3H), 0.05 (s, 6H), 0.04 (s, 3H),
0.03 (s, 6H); 13C NMR (125 MHz) δ 164.0, 18.0 (x 2), 17.9 (C),
144.6, 121.6, 75.1, 72.4, 69.5, 66.3 (CH), 44.4, 41.8, 37.0, 32.8,
32.2, 31.9, 29.9, 29.7 (several overlapped peaks), 29.3, 25.3,
22.7 (CH2), 25.9 (x6), 25.8 (x3), 14.1, -4.2, -4.4 (x2), -4.5 (x2),
-4.6 (CH3); IR νmax 1739 (CdO) cm-1; HR FABMS m/z
725.5376 (M+ - tBu). Calcd for C44H90O5Si3 - tBu, 753.5391.
(4R,6S,9S)-6,9-Bis(ter t-bu tyld im eth ylsilyloxy)tr icos-1-
en -4-ol (24). Compound 23 (721 mg, 1.3 mmol) was dissolved
in dry CH2Cl2 (12 mL) and cooled to -78 °C. A stream of ozone-
oxygen was bubbled through the solution until persistence of
the bluish color. Dry N2 was then bubbled through the solution
for 10 min at the same temperature. After addition of PPh3
(682 mg, 2.6 mmol), the solution was left to stir at room
temperature for 2 h and then worked up (extraction with CH2-
Cl2). Solvent removal gave a solid material, which was washed
three times with cold pentane (3 × 10 mL). The solid (Ph3PO)
was discarded, and the organic phase was evaporated in vacuo
to yield an oily product that was used as such in the
asymmetric allylation with (+)-DIP-Cl (for weight calcula-
tions, the yield of the ozonolysis step was assumed to be
quantitative). Workup as above and column chromatography
on silica gel (hexanes-EtOAc, 19:1) provided compound 24
(95:5 mixture of diastereomers, after chromatographic separa-
1
tion 499 mg, 64% overall): oil; [R]D +14.2 (c 1.2, CHCl3); H
NMR (500 MHz) δ 5.83 (m, 1H), 5.15-5.05 (m, 2H), 3.91 (m,
1H), 3.80 (m, 1H), 3.62 (quint, 6 Hz, 1H), 3.10 (br s, 1H, OH),
2.23 (t, 6.5 Hz, 2H), 1.65-1.40 (m, 6H), 1.35-1.20 (br m, 26H),
0.90 (s, 9H), 0.88 (s, 9H), 0.87 (t, overlapped, 3H), 0.11 (s, 3H),
0.10 (s, 3H), 0.04 (s, 6H); 13C NMR (125 MHz) δ 18.1, 18.0 (C),
134.9, 73.1, 72.3, 70.1 (CH), 117.4, 42.4, 42.2, 37.0, 33.2, 32.0,
31.7, 29.9, 29.7 (several overlapped peaks), 29.4, 25.3, 22.7
(CH2), 26.0 (x3), 25.9 (x3), 14.1, -4.0, -4.4, -4.5, -4.7 (CH3);
IR νmax 3480 (br, OH) cm-1; HR EIMS m/z (% rel intensity)
541.4410 (M+ - tBu, 1), 409 (100), 341 (48), 145 (64). Calcd
for C35H74O3Si2 - tBu, 541.4472.
(4R,6S,9S)-4,6,9-Tr is(ter t-bu tyld im eth ylsilyloxy)tr icos-
1-en e (25). Alcohol 24 (479 mg, 0.8 mmol) was subjected to
silylation as reported above for 23. Workup as above and
column chromatography on silica gel (hexanes-EtOAc, 19:1)
gave compound 25 (542 mg, 95%): oil; [R]D -4.3 (c 1.3, CHCl3);
1H NMR (500 MHz) δ 5.82 (m, 1H), 5.05-5.00 (m, 2H), 3.79
(m, 2H), 3.62 (quint, 6 Hz, 1H), 2.28 (m, 1H), 2.18 (m, 1H),
1.65-1.50 (m, 3H), 1.45-1.35 (m, 2H), 1.35-1.20 (br m, 27H),
0.90 (br s, 27H), 0.88 (t, overlapped, 3H), 0.07 (s, 3H), 0.06 (s,
6H), 0.05 (s, 6H), 0.03 (s, 3H); 13C NMR (125 MHz) δ 18.2,
18.1 (x2) (C), 135.1, 72.6, 69.8, 69.4 (CH), 117.0, 44.6, 42.1,
37.1, 32.6, 32.3, 32.0, 29.9, 29.7 (several overlapped peaks),
29.4, 25.4, 22.7 (CH2), 26.0 (x6), 25.9 (x3), 14.1, -4.3 (x3),
-4.4 (x2), -4.5 (CH3); HR EIMS m/z (% rel intensity) 655.5369
(M+ - tBu, 8), 523 (12), 455 (32), 381 (60), 185 (100), 73 (68).
Calcd for C41H88O3Si3 - tBu, 655.5337.
(4R,6R,8S,11S)-6,8,11-Tr is(ter t-bu tyld im eth ylsilyloxy)-
p en ta cos-1-en -4-ol (26). Olefin 25 (535 mg, 0.75 mmol) was
subjected to the same ozonolysis/allylation sequence as de-
scribed above for 24. Workup as above and column chroma-
tography on silica gel (hexanes-EtOAc, 19:1) afforded alcohol
26 (95:5 mixture of diastereomers, after chromatographic
separation 386 mg, 68% overall): oil; [R]D +20.9 (c 1.5, CHCl3);
1H NMR (500 MHz) δ 5.82 (m, 1H), 5.15-5.05 (m, 2H), 4.07
(m, 1H), 3.81 (m, 1H), 3.70 (m, 1H), 3.62 (quint, 6 Hz, 1H),
3.30 (br s, 1H, OH), 2.30-2.20 (m, 2H), 1.80-1.70 (m, 2H),
1.55-1.40 (m, 4H), 1.35-1.20 (br m, 28H), 0.90 (s, 9H), 0.88
(s, 18H), 0.88 (t, overlapped, 3H), 0.12 (s, 6H), 0.05 (s, 3H),
0.04 (s, 6H), 0.03 (s, 3H); 13C NMR (125 MHz) δ 18.1, 18.0,
17.9 (C), 135.0, 72.4, 70.8, 70.3, 69.6 (CH), 117.4, 45.6, 42.5,
42.3, 37.1, 33.2, 32.0, 31.9, 29.9, 29.7 (several overlapped
peaks), 29.4, 25.4, 22.7 (CH2), 26.0 (x3), 25.9 (x3), 25.8 (x3),
14.1, -3.9, -4.0, -4.4 (x2), -4.5 (x2) (CH3); IR νmax 3500 (br,
OH) cm-1; HR EIMS m/z (% rel intensity) 699.5545 (M+ - tBu,
1), 567 (17), 435 (55), 381 (53), 341 (36), 73 (100). Calcd for
(R)-5,6-Dih yd r o-6-[(2S,4S,6S)-2,4,6-tr ih yd r oxyh en ico-
syl]p yr a n -2-on e, P a ssiflor icin A (18b). Compound 28 (235
mg, 0.3 mmol) was dissolved in MeOH (15 mL) and treated
with PPTS (15 mg, 0.06 mmol) and water (0.15 mL). The
mixture was then heated at reflux for 18 h, cooled, and
neutralized by addition of solid NaHCO3. After being filtered,
the solution was evaporated in vacuo, and the oily residue was
subjected to column chromatography on silica gel (EtOAc-
MeOH, 19:1). This yielded lactone 18b (121 mg, 92%): colorless
solid, mp 103-106 °C (from EtOAc-MeOH), lit.4 for passiflo-
ricin A mp 97 °C; [R]D +28.9 (c 0.8, MeOH), lit.4 for passifloricin
A [R]D +123.45 (c 0.11, MeOH); [R]D +33.3 (c 0.8, CHCl3) for
18b; [R]D +34.1 (c 0.5, CHCl3) for
a sample of natural
passifloricin A; 1H NMR (500 MHz) δ 6.89 (ddd, 9.5, 5.5, 3 Hz,
1H), 6.00 (br d, 9.5 Hz, 1H), 4.66 (sext, 5.5 Hz, 1H), 4.30 (br s,
OH, 1H), 4.11 (m, 1H), 3.95 (m, 1H), 3.64 (m, 1H), 2.50-2.40
(m, 2H), 2.04 (dt, J ) 14, 7.5 Hz, 1H), 1.80 (dt, J ) 14, 5.5 Hz,
1H), 1.70-1.50 (br m, 4H), 1.50-1.40 (m, 2H), 1.35-1.20 (br
m, 28H), 0.87 (t, 7 Hz, 3H); 13C NMR (125 MHz) δ 164.4 (C),
145.5, 121.2, 76.2, 72.5, 71,9, 69.5 (CH), 42.8, 42.4, 37.5, 34.1,
32.7, 32.0, 29.7 (several overlapped peaks), 29.5, 29.4, 25.9,
22.7 (CH2), 14.1 (CH3); IR νmax 3260 (br, OH), 1715 (CdO) cm-1
;
HR EIMS m/z (rel intensity) 422.3411 (M+ - H2O, 2), 404
(M+ - 2H2O, 6), 267 (32), 225 (100), 141 (66). Calcd for
C
26H48O5 - H2O, 422.3396. The identity of natural and
synthetic product was confirmed by the measurement of the
NMR spectra of a mixture of both compounds.
C
43H92O4Si3 - tBu, 699.5599.
(4R,6R,8S,11S)-6,8,11-Tr is(ter t-bu tyld im eth ylsilyloxy)-
Aceton id e of P a ssiflor icin A. Compound 18b (13 mg, 0.03
mmol) was dissolved in acetone (800 µL) and treated with 2,2-
dimethoxypropane (200 µL) and camphorsulfonic acid (5 mg).
After adding a small amount of 4 Å molecular sieves, the
mixture was stirred at room temperature for 3 h. After being
filtered through a pad of Celite, the solution was evaporated
p en ta cos-1-en -4-yl Acr yla te (27). Alcohol 26 (379 g, 0.5
mmol) was dissolved under N2 in dry CH2Cl2 (20 mL), cooled
to -78 °C, and treated sequentially with ethyl diisopropyl-
amine (1.3 mL, 7.5 mmol) and acryloyl chloride (400 µL,
7282 J . Org. Chem., Vol. 69, No. 21, 2004

Stereoselective Synthesis of Passifloricin A
in vacuo and chromatographed on silica gel (hexanes-EtOAc,
1:1) to yield only an acetonide (9 mg, 65% yield): colorless oil;
1H NMR (500 MHz) δ 6.83 (ddd, 9.6, 5.8, 2.5 Hz, 1H), 5.97 (br
dd, 9.6, 2 Hz, 1H), 4.54 (sext, 5.5 Hz, 1H), 4.10 (m, 1H), 3.81
(m, 1H), 3.52 (m, 1H), 2.38 (ddt, J ) 18.5, 11.5, 2.6 Hz, 1H),
2.30 (br dt, J ) 18.5, 5 Hz, 1H), 2.00 (dt, J ) 14.5, 7 Hz, 1H),
1.70 (dt, J ) 14.5, 5.5 Hz, 1H), 1.60-1.35 (br m, 4H), 1.37 (3H,
s), 1.36 (m, 1H), 1.31 (s, 3H), 1.30-1.20 (br m, 28H), 0.84 (t, 7
Hz, 3H); 13C NMR (125 MHz) δ 164.4, 98.8 (C), 145.2, 121.5,
74.7, 71.5, 69.3, 65.1 (CH), 41.0, 37.5, 36.5, 33.2, 32.4, 31.9,
29.7 (several overlapped peaks), 29.4, 29.3, 25.9, 22.7 (CH2),
(Project PI-1B2002-06). J .M. and J .G.-F. thank the
Spanish Ministry of Education and Science for a Ramo´n
y Cajal fellowship and for a FPU predoctoral fellow-
ship, respectively. The authors further thank Prof. F.
Echeverri, from the University of Antioqu´ıa, Colombia,
for sending a sample of passifloricin A and copies of
NMR and mass spectra thereof.
Su p p or tin g In for m a tion Ava ila ble: General information
about spectral measurements and experimental procedures;
spectral data of compounds 1-6, 8-17, 18a -d , as well as of
the synthetic intermediates in the route toward lactones 1-4
and 18a -d . This material is available free of charge via the
Internet at http://pubs.acs.org.
30.2, 19.9, 14.1 (CH3); IR νmax 3300 (br, OH), 1715 (CdO) cm-1
.
Ack n ow led gm en t . Financial support has been
granted by the Spanish Ministry of Science and Tech-
nology (Project BQU2002-00468), the AVCyT (Project
Grupos03/180), and the BANCAJ A-UJ I Foundation
J O049275D
J . Org. Chem, Vol. 69, No. 21, 2004 7283